Heteroarylbiphenylamides for the treatment of PD-L1 disease

Abstract

Provided are compounds useful as immunomodulators. The compounds have formula (I), including stereoisomers and pharmaceutically acceptable salts thereof, wherein 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 preparing and using such compounds, as well as pharmaceutical compositions containing such compounds. #imgabs0#

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Application No. 62 / 915,779, filed on October 16, 2019, U.S. Provisional Application No. 63 / 042,796, filed on June 23, 2020, and U.S. Provisional Application No. 63 / 057,460, filed on July 28, 2020, the disclosures of which are incorporated herein by reference in their entirety.

[0003] Statement of Rights to Inventions Made Under Federally Sponsored Research and Development

[0004] not applicable

[0005] Reference to a "sequence listing", table or computer program listing annex submitted on CD-ROM

[0006] not applicable Background of the Invention

[0008] Programmed cell death protein-1 (PD-1), a member of the CD28 superfamily, transmits negative signals upon interaction with its two ligands, PD-L1 or PD-L2. PD-1 and its ligands are widely expressed in T cell activation and tolerance and exert a wide range of immunomodulatory effects. PD-1 and its ligands are involved in attenuating immunity to infection and tumors, promoting chronic infection and tumor progression.

[0009] Modulation of the PD-1 pathway has therapeutic potential in various human diseases (Hyun-Tak Jin et al., Curr Top Microbiol Immunol. (2011); 350: 17-37). Blocking the PD-1 pathway has become an attractive target for cancer therapy. Therapeutic antibodies that block the programmed cell death protein-1 (PD-1) immune checkpoint pathway prevent T cell downregulation and promote immune responses against cancer. Several PD-1 pathway inhibitors have shown strong activity in various stages of clinical trials (R.D. Harvey, Clinical Pharmacology & Therapeutics (2014); 96(2), 214-223).

[0010] Drugs that block the interaction of PD-L1 with PD-1 or CD80 are needed. Some antibodies have been developed and commercialized. Some patent applications disclosing non-peptide small molecules have been published (WO 2015 / 160641, WO 2015 / 034820, WO 2017 / 066227 and WO 2018 / 009505 from BMS; WO 2015 / 033299 and WO 2015 / 033301 from Aurigene; WO 2017 / 070089, US 2017 / 0145025, WO 2018 / 009505 from Incyte). 2017 / 106634, US2017 / 0174679, WO2017 / 192961, WO2017 / 222976, WO2017 / 205464, WO2017 / 112730, WO2017 / 041899 and WO2018 / 013789; WO2018 / 006795 from Maxinovel; and WO2018 / 005374 from us, ChemoCentryx). However, there remains a need for alternative compounds, such as small molecules, as inhibitors of PD-L1 that may have favorable properties with respect to oral administration, stability, bioavailability, therapeutic index, and toxicity. SUMMARY OF THE INVENTION

[0012] In one aspect, provided herein are compounds having Formula (I) or pharmaceutically acceptable salts, prodrugs, or bioisosteres thereof:

[0013]

[0014] Among them, A, Z, X 1 、R 2a 、R2 b 、R 3 、R 3a 、R 4 、R 6 、R 7 、R 8 and subscript n are as defined herein.

[0015] In addition to the compounds provided herein, the present disclosure also provides pharmaceutical compositions containing one or more of these compounds, as well as methods related to the preparation and use of these compounds. In some embodiments, the compounds are used in methods for treating diseases related to the PD-1 / PD-L1 pathway. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] not applicable. Detailed Description of the Invention

[0018] Abbreviations and definitions

[0019] As used herein, the terms "a," "an," or "the" include not only aspects having one member, but also aspects having multiple members. As used herein, the singular forms "a," "an," and "the" include the plural forms unless the context clearly dictates otherwise. Thus, for example, reference to "a cell" includes a plurality of such cells, reference to "an agent" includes reference to one or more agents known to those skilled in the art, and so forth.

[0020] The terms "about" and "approximately" generally refer to an acceptable degree of error in a measured quantity given the nature or precision of the measurement. Typical exemplary degrees of error are within 20 percent (%) of a given value or range of values, preferably within 10%, and more preferably within 5%. Alternatively, particularly in biological systems, the terms "about" and "approximately" can refer to values that are within an order of magnitude, preferably within 5 times, and more preferably within 2 times, of a given value. Unless otherwise indicated, numerical quantities given herein are approximate, meaning that the term "about" or "approximately" can be inferred where not expressly stated.

[0021] Unless otherwise indicated, the term "alkyl" by itself or as part of another substituent refers to a straight or branched chain hydrocarbon radical having the specified number of carbon atoms (i.e., C 1-8 = represents 1-8 carbons). 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, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, and 3-(1,4-pentadienyl). Examples of alkynyl groups include ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologs and isomers. The term "cycloalkyl" refers to a hydrocarbon ring (e.g., C 4-C ... 3-6 Cycloalkyl) and is fully saturated or has no more than one double bond between the ring vertices. "Cycloalkyl" also means bicyclic and polycyclic hydrocarbon rings, such as bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, etc. The bicyclic or polycyclic rings can be fused, bridged, spirocyclic, or a combination thereof. The term "heterocycloalkyl" or "heterocyclyl" 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. Heterocycloalkyl can be a monocyclic, bicyclic, or polycyclic ring system. The bicyclic or polycyclic rings can be fused, bridged, spirocyclic, or a combination thereof. It should be understood that C 4-12The description of heterocyclyl refers to a group having 4 to 12 ring members, at least one of which is a heteroatom. Non-limiting examples of heterocycloalkyl include pyrrolidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolinone, tetrazolone, hydantoin, dioxolane, phthalimide, piperidine, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S,S-oxide, piperazine, pyran, pyridone, 3-pyrroline, thiopyran, pyrone, tetrahydrofuran, tetrahydrothiophene, quinuclidine, etc. The heterocycloalkyl group can be attached to the rest of the molecule through a ring carbon or a heteroatom.

[0022] The term "alkylene" by itself or as part of another substituent refers to a divalent group derived from an alkane, for example -CH2CH2CH2CH2-. Alkylene can be straight or branched. Examples of the latter are -CH2C(CH3)2CH2-, -CH2C(CH3)2-, or -CH(CH3)CH2CH2-. Typically, an alkyl (or alkylene) group will have from 1 to 12 carbon atoms, with those having 8 or fewer carbon atoms being preferred in the present disclosure. Similarly, "alkenylene" and "alkynylene" refer to unsaturated forms of "alkylene" having double or triple bonds, respectively.

[0023] Unless otherwise indicated, the term "heteroalkyl" by itself or in combination with another term refers to a stable straight or branched chain or cyclic hydrocarbon radical, or combinations thereof, consisting of the recited number of carbon atoms and 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 interior position of the heteroalkyl radical. The heteroatom Si may be located at any position of the heteroalkyl radical, including the position at which the alkyl radical 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. Up to two heteroatoms may be consecutive, for example -CH2-NH-OCH3 and -CH2-O-Si(CH3)3. Similarly, unless otherwise indicated, the terms "heteroalkenyl" and "heteroalkynyl," by themselves or in combination with another term, refer to alkenyl or alkynyl groups, respectively, containing the recited 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 placed at any interior position of the heteroalkyl group.

[0024] The term "heteroalkylene" by itself or as part of another substituent refers to a saturated or unsaturated or polyunsaturated divalent radical derived from heteroalkyl, for example, -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, heteroatoms can also occupy one or both chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, etc.).

[0025] The terms "alkoxy," "alkylamino," and "alkylthio" (or thioalkoxy) are used in their conventional sense to refer to those alkyl groups that are attached to the remainder of the molecule through an oxygen atom, an amino group, or a sulfur atom. In addition, for dialkylamino groups, the alkyl moieties may be the same or different and may be combined with each nitrogen atom to form a 3-7 membered ring. Thus, the group represented by -NR a R b The group is meant to include piperidinyl, pyrrolidinyl, morpholinyl, azetidinyl and the like.

[0026] Unless otherwise indicated, the term "halo" or "halogen" by itself or as part of another substituent refers to a fluorine, chlorine, bromine, or iodine atom. In addition, terms such as "haloalkyl" are meant to include monohaloalkyl and polyhaloalkyl. For example, the term "C 1-4 "Haloalkyl" is meant to include trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

[0027] The term "hydroxyalkyl" or "alkyl-OH" refers to an alkyl group as defined above in which at least one (and up to three) hydrogen atoms are replaced by a hydroxy group. As with alkyl, the hydroxyalkyl group may have any suitable number of carbon atoms, such as C 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.

[0028] The term "C 1-3 "Alkyl-guanidino" refers to a C 1-3 An alkyl group in which at least one hydrogen atom is replaced by a guanidino group (-NHC(NH)NH2).

[0029] Unless otherwise indicated, the term "aryl" refers to a polyunsaturated, typically aromatic hydrocarbon radical which may be a single ring or multiple rings (up to three rings) fused together or linked covalently. The term "heteroaryl" refers to an aryl group (or ring) containing from 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. A heteroaryl group may be attached to the rest of the molecule through a heteroatom. It is understood that C 5-10 The recitation of heteroaryl refers to heteroaryl moieties having from 5 to 10 ring members, at least one of which is a heteroatom. Non-limiting examples of aryl groups include phenyl, naphthyl, and biphenyl, while non-limiting examples of heteroaryl groups include pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, quinolinyl, quinoxalinyl, quinazolinyl, cinnamyl, phthalazinyl, benzotriazinyl, purinyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl, benzisoxazolyl, isobenzofuranyl, isoindolyl, indolizinyl, benzotriazinyl, thienopyridinyl, thienopyrimidinyl, pyrazolopyrimidinyl, imidazopyridine, benzothiazolyl, benzofuranyl, benzothiophenyl, indolyl, quinolinyl, isoquinolinyl, isothiazolyl, pyrazolyl, indazolyl, pteridinyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiadiazolyl, pyrrolyl, thiazolyl, furanyl, thienyl, and the like. Substituents for each of the above noted aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below.

[0030] The term "carbocyclic ring" or "carbocyclyl" refers to a cyclic moiety having only carbon atoms as ring vertices. The carbocyclic moiety is saturated or unsaturated and can be aromatic. Typically, the carbocyclic moiety has 3 to 10 ring members. Carbocyclic moieties with polycyclic structures (e.g., bicyclic) can include cycloalkyl rings fused to aromatic rings (e.g., 1,2,3,4-tetrahydronaphthalene). Thus, carbocyclic rings include cyclopentyl, cyclohexenyl, naphthyl, and 1,2,3,4-tetrahydronaphthyl. The term "heterocycle" refers to "heterocycloalkyl" and "heteroaryl" moieties. Thus, heterocycles are saturated or unsaturated and can be aromatic. Typically, heterocycles have 4 to 10 ring members and include piperidinyl, tetrazinyl, pyrazolyl, and indolyl.

[0031] When any of the above terms (eg, "alkyl," "aryl," and "heteroaryl") are referred to as "substituted" without further specification of the substituents, substituted versions of the indicated groups are provided below.

[0032] Substituents for alkyl groups (including those groups commonly referred to as alkylene, alkenyl, alkynyl, and cycloalkyl) may be a variety of groups selected from the group consisting of: -halogen, -OR', -NR'R", -SR', -SiR'R"R"', -OC(O)R', -C(O)R', -C02R', -CONR'R", -OC(O)NR'R", -NR"C(O)R', -NR'-C(O)NR"R"', -NR"C R', -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, ranging in number from zero to (2m'+1), where m' is the total number of carbon atoms in such a group. R', R" and R'"' each independently refer to hydrogen, unsubstituted C 1-8 Alkyl, unsubstituted heteroalkyl, unsubstituted aryl, aryl substituted with 1-3 halogens, unsubstituted C 1-8 Alkyl, C 1-8 Alkoxy or C 1-8 Thioalkoxy group, or unsubstituted aryl-C 1-4 Alkyl. When R' and R" are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 3-, 4-, 5-, 6-, or 7-membered ring. For example, -NR'R" is meant to include 1-pyrrolidinyl and 4-morpholinyl. The term "acyl" used alone or as part of another group refers to an alkyl group in which both substituents on the carbon closest to the point of attachment of the group are replaced by the substituent =0 (e.g., -C(O)CH3, -C(O)CH2CH2OR', etc.).

[0033] Similarly, the substituents for aryl and heteroaryl groups are varied and are 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"', -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", -N3, perfluoro(C1-C4)alkoxy and perfluoro(C1-C4)alkyl, in a number ranging from zero to the total number of open valences on the aromatic ring system; wherein R', R" and R'"' are independently selected from hydrogen, C 1-8 Alkyl, C 3-6 Cycloalkyl, C 2-8 Alkenyl, C 2-8Alkynyl, unsubstituted aryl and heteroaryl, (unsubstituted aryl)-C 1-4 Alkyl and unsubstituted aryloxy-C 1-4 Other suitable substituents include each of the above-mentioned aryl substituents attached to a ring atom via an alkylene chain of 1 to 4 carbon atoms.

[0034] Two substituents on adjacent atoms of an aryl or heteroaryl ring may optionally be replaced by groups of the formula -TC(O)-(CH2) q -U-, wherein T and U are independently -NH-, -O-, -CH2- or a single bond, and q is an integer from 0 to 2. Alternatively, two substituents on adjacent atoms of the aryl or heteroaryl ring may be optionally replaced by a substituent of the formula -A-(CH2) r -B-, wherein A and B are independently -CH2-, -O-, -NH-, -S-, -S(O)-, -S(O)2-, -S(O)2NR'- or a single bond, and r is an integer from 1 to 3. One of the single bonds of the new ring thus formed may optionally be replaced by a double bond. Alternatively, two substituents on adjacent atoms of the aryl or heteroaryl ring may be optionally substituted by substituents of the formula -(CH2) s -X-(CH2) t -, wherein s and t are independently integers from 0 to 3, and X is -O-, -NR'-, -S-, -S(O)-, -S(O)2- or -S(O)2NR'-. The substituent R' in -NR'- and -S(O)2NR'- is selected from hydrogen or unsubstituted C 1-6 alkyl.

[0035] As used herein, the term "heteroatom" is meant to include oxygen (O), nitrogen (N), sulfur (S), and silicon (Si).

[0036] The disclosure herein further relates to prodrugs and bioisosteres thereof. For example, suitable bioisosteres will include carboxylate surrogates (phosphonic acid, phosphinic acid, sulfonic acid, sulfinic acid and acidic heterocyclic groups, such as tetrazole). Suitable prodrugs will include those conventional groups that are known to hydrolyze and / or oxidize under physiological conditions to provide compounds of Formula I.

[0037] The terms "patient" and "subject" include primates (particularly humans), domesticated companion animals (eg, dogs, cats, horses, etc.), and livestock (eg, cattle, pigs, sheep, etc.).

[0038] As used herein, the terms "treating" or "treatment" include disease-modifying treatment and symptomatic treatment, either of which can be prophylactic (i.e., prior to the onset of symptoms, to prevent, delay or lessen the severity of symptoms) or therapeutic (i.e., after symptoms have appeared, to lessen the severity and / or duration of symptoms).

[0039] The term "pharmaceutically acceptable salt" is intended to include salts of the active compounds prepared with relatively nontoxic acids or bases, depending on the specific substituents found on the compounds described herein. When the compounds of the present disclosure contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either pure or in a suitable inert solvent. Examples of salts derived from pharmaceutically acceptable inorganic bases include aluminum, ammonium, calcium, copper, iron, ferrous, lithium, magnesium, manganic, manganous, 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, naturally occurring amines, and the like, for example, arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, hepamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like. When compounds of the present disclosure contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid or phosphorous acid, and salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, and the like. 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 the present disclosure contain both basic and acidic functional groups, which allow the compounds to be converted into base or acid addition salts.

[0040] The neutral forms of the compounds can be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but for the purposes of this disclosure, the salts are equivalent to the parent form of the compound.

[0041] Certain compounds of the present disclosure may exist in unsolvated forms as well as solvated forms, including hydrated forms. Generally, solvated forms are equivalent to unsolvated forms and are intended to be included within the scope of the present disclosure. Certain compounds of the present disclosure may exist in a variety of crystalline or amorphous forms. Generally speaking, all physical forms are equivalent for the purposes contemplated by the present disclosure and are intended to fall within the scope of the present disclosure.

[0042] Certain compounds of the present invention have asymmetric carbon atoms (optical centers) or double bonds; racemates, diastereomers, geometric isomers, regioisomers, and individual isomers (e.g., individual enantiomers) are all intended to be encompassed within the scope of the present invention. When a stereochemical description is shown, it is intended to refer to a compound in which one isomer is present and substantially free of the other isomer. "Substantially free" of the other isomer means that the ratio of the two isomers is at least 80 / 20, more preferably 90 / 10, or 95 / 5 or higher. In some embodiments, one isomer will be present in an amount of at least 99%.

[0043] The compounds of the present disclosure may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, radioactive isotopes such as tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C) Radiolabeling the compound. All isotopic variants of the compounds of the present disclosure, whether radioactive or not, are intended to be encompassed within the scope of the present disclosure. For example, a compound can be prepared such that any number of hydrogen atoms are replaced by deuterium ( 2 H) isotope substitution. The compounds of the present disclosure may also contain unnatural proportions of atomic isotopes at one or more atoms that constitute such compounds. An unnatural proportion of an isotope can be defined as the amount from that found in nature to that consisting of 100% of the atoms in question. For example, a compound may contain a radioactive isotope, such as 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 may provide additional utility to those described elsewhere in this application. For example, isotopic variants of the compounds of the present disclosure may find additional uses, including but not limited to, as diagnostic and / or imaging agents, or as cytotoxic / radiotoxic therapeutic agents. In addition, isotopic variants of the compounds of the present disclosure may have altered pharmacokinetic and pharmacodynamic characteristics, which may help improve safety, tolerability, or efficacy during treatment. All isotopic variants of the compounds of the present disclosure, whether radioactive or not, are intended to be encompassed within the scope of this disclosure.

[0044] Compound

[0045] In one aspect, provided herein are compounds of formula (I) or pharmaceutically acceptable salts, prodrugs or

[0046] Bioisosteres:

[0047]

[0048] in:

[0049] A is a 5- to 10-membered heteroaryl group, which is unsubstituted or substituted with 1 to 5 members independently selected from the group consisting of halogen, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, OH, and CN;

[0050] X 1 C 1-3 Alkylene, which is unsubstituted or substituted by one or two members independently selected from the group consisting of: C 1-2 Alkyl and CO2H;

[0051] R 2a and R 2b Each independently selected from the following group: H, C 1-8 Alkyl, C 1-8 Haloalkyl, -Y, -X 2 -CO2R a 、-X 2 -OR a 、-X 2 -NR a R b 、-X 2 -C(O)NR 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 Alkylene is unsubstituted or substituted by one or two members independently selected from the group consisting of OH, SO2NH2, C(O)NH2, C(O)NHOH, PO3H2, CO2C 1-8Alkyl and CO2H, each Y is selected from the group consisting of: C 3-6 Cycloalkyl, C 4-8 Heterocyclyl and 5- to 6-membered heteroaryl, each of which is unsubstituted or substituted by one to four substituents independently selected from the group consisting of oxo, OH, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 1-4 Hydroxyalkoxy, SO2NH2, C(O)NH2, C(O)NHOH, PO3H2, CO2C 1-8 Alkyl, SO3H and CO2H;

[0052] or R 2a and R 2b Combined to form a 4- to 9-membered ring or spirocycle, with zero to two additional heteroatom ring vertices selected from O, N, or S;

[0053] By combining R 2a and R 2b The formed ring is unsubstituted or substituted by 1 to 4 substituents independently selected from the group consisting of oxo, C 1-8 Alkyl, C 1-8 Halogenated alkyl, C 1-8 Hydroxyalkyl, -X 3 -CO2R a 、-X 3 -OR a , -X 3 -NR a R b ,

[0054] -X 3 -C(O)NR a R b 、-X 3 -SO2R a 、-X 3 -SO2NR a R b 、-X 3 -N(R b )SO2R a and -X 3 -SO3R a ; where X 3 is key or C 1-6 alkylene;

[0055] R 3 and R 4 Each independently selected from the group consisting of H, F, Cl, CN, CH3, OCH3, CH2CH3 and CF3;

[0056] Subscript n is 0, 1, 2, or 3;

[0057] Each R 3a Independently selected from the group consisting of H, F, Cl, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Halogenated alkoxy, C 2-3 alkenyl and CN;

[0058] R 6 、R 7 and R 8 Each independently selected from the group consisting of H, F, Cl, CN, CH3, OCH3, CH2CH3 and CF3;

[0059] Z is selected from the following group:

[0060] i) a monocyclic, bicyclic or spirocyclic non-aromatic heterocycle, optionally substituted with one or two oxo groups and optionally substituted with up to four R a and / or R b Replacement; and

[0061] ii) a monocyclic 5-membered or 6-membered heteroaromatic ring, optionally surrounded by 1 to 3 R c replace;

[0062] Each R a Independently selected from the group consisting of H, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkylene -CO2H and C 1-6 Alkylene-SO3H;

[0063] Each R b Independently selected from the group consisting of H, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkylene -CO2H and C 1-6 Alkylene -SO3H, each of which is unsubstituted or substituted by one or two members independently selected from the group consisting of OH, SO2NH2, C(O)NH2, C(O)NHOH, PO3H2, CO2C l-8 Alkyl and CO2H;

[0064] And, R a and R bWhen attached to the same nitrogen atom, they are optionally combined to form a 4- to 8-membered ring or spirocyclic ring, which is unsubstituted or substituted with halogen, OH, SO2NH2, C(O)NH2, C(O)NHOH, PO3H2, CO2C 1-8 Alkyl or CO2H substitution;

[0065] Each R c Independently selected from the group consisting of H, halogen, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -Y 1 、-X 4 -CO2R a 、-OX 4 -CO2R a 、-X 4 -OR a 、-X 4 -NR a R b 、-X 4 -C(O)NR a R b 、-OX 4 -C(O)NR a R b 、-X 4 -SO2R a 、-X 4 -SO2NR a R b 、-X 4 -SO3R a and -N(R a )-X 4 -CO2R a , where each X 4 For key or C 1-6 Alkylene, each Y 1 Select from the following group: C 3-6 Cycloalkyl and C 4-8 heterocyclyl; and optionally, two R on adjacent ring vertices c Combine to form a fused 5- or 6-membered heterocyclic ring.

[0066] In one group of embodiments, the compounds of formula (I) are those wherein A is a 5- or 6-membered heteroaryl group which is unsubstituted or substituted with 1-3 members independently selected from the group consisting of halogen, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 In one group of embodiments, the compounds of formula (I) are those wherein A is a 5- or 6-membered heteroaryl group which is unsubstituted or substituted with 1-3 members independently selected from the group consisting of halogen, C 1-3 Alkyl, C 1-3Halogenated alkyl, C 1-3 Alkoxy and CN.

[0067] In one group of embodiments, the compounds of formula (I) are those wherein A is a 6-membered heteroaryl group which is unsubstituted or substituted with 1-3 members independently selected from the group consisting of halogen, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 In one group of embodiments, the compounds of formula (I) are those wherein A is a 6-membered heteroaryl group which is unsubstituted or substituted with 1-3 members independently selected from the group consisting of halogen, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy and CN.

[0068] In one group of embodiments, the compounds of formula (I) are those wherein A is a 6-membered heteroaryl selected from the group consisting of pyridine, pyrimidine, pyrazine, and 1,2,4-triazine, each of which is unsubstituted or substituted with one or two members independently selected from the group consisting of CF3, OH, Et, CN, OCH3, and F. In one group of embodiments, the compounds of formula (I) are those wherein A is a 6-membered heteroaryl selected from the group consisting of pyridine, pyrimidine, pyrazine, and 1,2,4-triazine, each of which is unsubstituted or substituted with one or two members independently selected from the group consisting of OCH3 and F.

[0069] In one group of embodiments, compounds of formula (I) are those wherein A is unsubstituted or substituted with one or two members independently selected from the group consisting of CF3, OH, Et, CN, OCH3, and F. In one group of embodiments, compounds of formula (I) are those wherein A is unsubstituted or substituted with one or two members independently selected from the group consisting of OCH3 and F.

[0070] In some embodiments, the present disclosure provides compounds of formula (I) represented by formula (Ia):

[0071]

[0072] The group R 2a 、R 2b 、R 3 、R 4 , A, X 1 and Z have the meanings provided in formula (I).

[0073] In some embodiments, the present disclosure provides compounds of formula (I) represented by formula (Ib):

[0074]

[0075] The group R2a 、R 2b 、R 3 、R 4 , A and Z have the meanings provided in formula (I).

[0076] In selected embodiments, including any of the embodiments described above with respect to compounds of formula (I), (Ia), or (Ib), further embodiments are those wherein Z is a 5- or 6-membered non-aromatic heterocycle, optionally substituted with one or two oxo groups and optionally substituted with R a and / or R b replace.

[0077] In some selected embodiments, compounds of Formula (I), (Ia) or (Ib) are those wherein Z is a non-aromatic heterocyclic ring having a formula selected from the group consisting of:

[0078]

[0079] In some selected embodiments, compounds of formula (I), (Ia) or (Ib) are those wherein Z is a non-aromatic heterocycle selected from piperidinyl, morpholinyl, tetrahydropyranyl and tetrahydrofuranyl, each of which is optionally replaced by up to four R a and / or R b replace.

[0080] In some selected embodiments, the compound of formula (I), (Ia) or (Ib) is wherein Z is a 5- or 6-membered heteroaryl ring, optionally substituted by 1 to 3 R c Those compounds substituted; the heteroaromatic ring is selected from the group consisting of pyridyl, pyrimidinyl, pyrazinyl, oxazolyl, thiazolyl and pyrazolyl.

[0081] In some selected embodiments, the compound of formula (I), (Ia) or (Ib) is wherein Z is a monocyclic 5 or 6 membered heteroaryl ring, optionally substituted by 1 to 3 R c Those compounds substituted; the heterocycle is selected from the group consisting of pyridyl, pyrimidinyl and pyrazinyl.

[0082] In selected embodiments, including any of the embodiments described above with respect to compounds of formula (I), (Ia), or (Ib), further embodiments are those wherein group A is a 5- or 6-membered heteroaryl and is unsubstituted or substituted with one or two members independently selected from OCH3 and F.

[0083] In selected embodiments, including any of the embodiments above with respect to compounds of formula (I), (Ia), or (Ib), further embodiments are wherein R 2a and R 2b Each is an embodiment of H.

[0084] In selected embodiments, including any of those described above with respect to compounds of formula (I), (Ia), or (Ib), further embodiments are wherein R 2a and R 2b an embodiment wherein the ring or spirocycle is combined to form a 4- to 9-membered ring or spirocycle, optionally with one or two additional ring vertices selected from O, N, or S; wherein the ring or spirocycle is substituted with 0 to 4 substituents independently selected from the group consisting of oxo, C 1-8 Alkyl, C 1-8 Halogenated alkyl, C 1-8 Hydroxyalkyl, -X 2 -CO2R a 、-X 2 -OR a 、-X 2 -NR a R b 、-X 2 -C(O)NR a R b 、-X 2 -SO2R a 、-X 2 -SO2NR a R b and –X 2 -SO3R a ; where X 2 is key or C 1-6 Alkylene.

[0085] In selected embodiments, including any of the embodiments above with respect to compounds of Formula (I), (Ia), or (Ib), further embodiments are wherein -(NR 2a )(R 2b ) is selected from the following embodiments:

[0086]

[0087] In selected embodiments, including any of the embodiments above with respect to compounds of Formula (I), (Ia), or (Ib), further embodiments are wherein -(NR 2a )(R 2b ) is selected from the following embodiments:

[0088]

[0089] In selected embodiments, including any of the embodiments above with respect to compounds of Formula (I), (Ia), or (Ib), further embodiments are wherein -(NR 2a )(R 2b ) is selected from the following embodiments:

[0090]

[0091] In selected embodiments, including any of the embodiments above with respect to compounds of formula (I), (Ia), or (Ib), further embodiments are wherein R 2a Is H or C 1-8 Those embodiments where R 2b Is –Y or –X 2 -Y.

[0092] In selected embodiments, including any of the embodiments above with respect to compounds of formula (I), (Ia), or (Ib), further embodiments are wherein R 2a Is H or C 1-8 Those embodiments where R 2b Is -Y or -X 2 -Y; Y is selected from the group consisting of: C 3-6 Cycloalkyl and C 4-8 heterocyclyl, each of which is further optionally substituted by one to four substituents independently selected from the group consisting of oxo, OH, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 1-4 Hydroxyalkoxy, SO2NH2, C(O)NH2, C(O)NHOH, PO3H2, CO2C 1-8 Alkyl and CO2H.

[0093] In selected embodiments, including any of the embodiments above with respect to compounds of formula (I), (Ia), or (Ib), further embodiments are wherein R 3 and R 4 Each is independently selected from the group consisting of F, Cl, CN, CH 3 , OCH 3 , CH 2 CH 3 and CF 3 . In selected embodiments, including any of the embodiments above regarding compounds of formula (I), (Ia) or (Ib), further embodiments are wherein R 3 and R 4 Each is independently selected from the group consisting of H, F, Cl, CN, CH3 and CF3.

[0094] In selected embodiments, including any of the embodiments described above with respect to compounds of Formula (I), (Ia), or (Ib), further embodiments are those wherein the compound is selected from Table 1.

[0095] In selected embodiments, including any of the embodiments above for compounds of formula (I), (Ia), or (Ib), further embodiments are compounds selected from Table 1 having ++ or +++ activity.

[0096] In selected embodiments, including any of the embodiments above for compounds of formula (I), (Ia), or (Ib), further embodiments are compounds selected from Table 1 having +++ activity.

[0097] 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 ammonium, calcium, magnesium, potassium, sodium, zinc, arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, hepamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperazine, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, hydrochloric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, acetic acid, propionic acid, isobutyric acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, arginine, glucuronic acid, and galacturonic acid. In some embodiments, the pharmaceutically acceptable salt is selected from ammonium salt, calcium salt, magnesium salt, potassium salt, sodium salt, hydrochloride, carbonate, bicarbonate, phosphate, hydrogen phosphate, dihydrogen phosphate, acetate, propionate, isobutyrate, malonic acid, benzoic acid, succinic acid, suberic 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 salt or hydrochloride.

[0098] In addition to salt forms, the present invention also provides compounds in the form of prodrugs. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide compounds of the present disclosure. In addition, prodrugs can be converted into compounds of the present disclosure by chemical or biochemical methods in an ex vivo environment. For example, when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent, the prodrug can slowly be converted into a compound of the present disclosure.

[0099] Esters can be used as prodrugs of the corresponding carboxylic acids. 1-10 Alkyl ester or C 1-10 Haloalkyl esters can be used as prodrugs of the corresponding carboxylic acids. The following esters can be used: tert-butyl ester, methyl ester, ethyl ester, isopropyl ester.

[0100] Preparation method

[0101] In addition to the methods described in the Examples below, general methods for preparing compounds of formula (I) are provided in Schemes 1 and 2.

[0102] Solution 1

[0103]

[0104] Scheme 1 illustrates a general method for preparing compounds of formula (I) wherein A is a six-membered nitrogen-containing heteroaromatic ring (e.g., pyridinyl, pyrimidinyl), X 1 is CH2. In the above scheme, R s represents one or more substituents on the heteroaryl ring.

[0105] In the presence of a coupling reagent, the amide formation process between the carboxylic acid (a) and the boronic acid-aniline compound (b) smoothly produces (c). In the presence of a catalyst, the Suzuki coupling of (c) with (d) can give the biphenyl compound (e). Compound (e) can then be converted to the borate salt (f) and then subjected to a second Suzuki coupling (with the halo-heteroaryl compound (g)) to give the triaryl aldehyde (h). Then, HNR 2a R 2b Reductive amination of the aldehyde can provide compounds of formula (Ia).

[0106] Option 2

[0107]

[0108] In another Suzuki-type coupling-based approach, the boronate ester compound (a1) can be combined with the aldehyde (b1) to form an aryl-heteroaryl adduct (c1), which, when subjected to a second Suzuki-type coupling with (d1), can provide the triaryl aldehyde (e1). As shown in Scheme 1, the aldehyde is reacted with HNR 2a R 2b Reductive amination can then provide compounds of formula (Ia).

[0109] Pharmaceutical composition

[0110] In addition to the compound provided herein, compositions of these compounds generally contain a pharmaceutical carrier or diluent.

[0111] As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. By "pharmaceutically acceptable" is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient.

[0112] In another embodiment, a pharmaceutical composition is provided, comprising a compound of the present disclosure, including a compound of Formula (I), (Ia), or (Ib), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0113] In some embodiments, the pharmaceutical composition further comprises one or more additional therapeutic agents. In certain embodiments, the one or more additional therapeutic agents are selected from antimicrobial agents, antiviral agents, cytotoxic agents, gene expression regulators, chemotherapeutic agents, anticancer agents, antiangiogenic agents, immunotherapeutic agents, antihormonal agents, antifibrotic agents, radiotherapy, radiotherapeutic agents, antitumor agents and antiproliferative agents. In certain embodiments, the one or more additional therapeutic agents are antagonists of chemokines and / or chemotactic receptors, including but not limited to CCR1, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10, CCR11, CCR12, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, CXCR6, CXCR7, C3aR and / or C5aR. Chemokine and / or chemokine receptor antagonists are known in the art and are described, for example, in WO 2007 / 002667, WO 2007 / 002293, WO / 2003 / 105853, WO / 2007 / 022257, WO / 2007 / 059108, WO / 2007 / 044804, WO 2007 / 115232, WO 2007 / 115231, WO 2008 / 147815,WO2010 / 030815,WO2010 / 075257,WO2011 / 163640,WO2010 / 054006,WO2010 / 051561 ,WO2011 / 035332,WO2013 / 082490,WO2013 / 082429,WO2014 / 085490,WO2014 / 100735,WO201 4 / 089495,WO2015 / 084842,WO2016 / 187393,WO2017 / 127409,WO2017 / 087607,WO2017 / 087 610,WO2017 / 176620,WO2018 / 222598,WO2018 / 222601,WO2013 / 130811,WO2006 / 076644,WO 2008 / 008431,WO2009 / 038847,WO2008 / 008375,WO2008 / 008374,WO2008 / 010934,WO2009 / 0 09740,WO2005 / 112925,WO2005 / 112916,WO2005 / 113513,WO2004 / 085384,WO2004 / 046092.Chemokine and / or chemokine receptor antagonists also include CCX354, CCX9588, CCX140, CCX872, CCX598, CCX6239, CCX9664, CCX2553, CCX3587, CCX3624, CCX 2991, CCX282, CCX025, CCX507, CCX430, CCX765, CCX224, CCX662, CCX650, CCX832, CCX168, CCX168-M1, CCX3022, and / or CCX3384.

[0114] The pharmaceutical composition for administering the compound of the present disclosure can be conveniently present in unit dosage form and can be prepared by any method well-known in the field of pharmacy and drug delivery. All methods include the step of combining the active ingredient with a carrier constituting one or more auxiliary ingredients. Typically, the pharmaceutical composition is prepared by uniformly and closely combining the active ingredient with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, molding the product into the desired formulation. In the pharmaceutical composition, the content of the active target compound is sufficient to produce the desired effect on the process or condition of the disease.

[0115] Pharmaceutical compositions containing active ingredients can be in forms suitable for oral administration, for example, 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 gums, chewable tablets, effervescent powders and effervescent tablets as described in U.S. Patent Application 2002-0012680. Compositions intended for oral administration can be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions can include one or more agents selected from sweeteners, flavorings, coloring agents, antioxidants and preservatives to provide pharmaceutically elegant and palatable preparations. Tablets contain a mixture of active ingredients and non-toxic pharmaceutically acceptable excipients suitable for making tablets. These excipients may 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 alginic acid; binders such as PVP, cellulose, PEG, starch, gelatin or gum arabic, and lubricants such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or coated, enteric or otherwise, by known techniques to delay disintegration and gastrointestinal absorption, thereby providing a longer duration of action. For example, time-delay materials such as glyceryl monostearate or glyceryl distearate may be used. They may also be coated by the techniques described in U.S. Patent Nos. 4,256,108; 4,166,452; and 4,265,874 to form osmotic therapeutic tablets for controlled release.

[0116] Formulations for oral administration can also be provided as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate or kaolin, polyethylene glycols (PEG) of various average sizes (e.g., PEG 400, PEG 4000) and certain surfactants such as Cremophor or solutol, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil. In addition, emulsions can be prepared with water-immiscible ingredients such as oils and stabilized with surfactants such as mono- or diglycerides, PEG esters, and the like.

[0117] Aqueous suspensions contain the active substance mixed with excipients suitable for the manufacture of aqueous suspensions. Such excipients include suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, and gum arabic. Dispersants or wetting agents may be naturally occurring phospholipids such as lecithin, or condensation products of alkylene oxides with fatty acids such as polyoxyethylene stearate, or condensation products of ethylene oxide with long-chain fatty alcohols such as heptadecaethyleneoxyhexadecyl alcohol, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitols such as polyoxyethylene sorbitan monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitols such as polysorbitan monooleate. Aqueous suspensions may also contain one or more preservatives such as ethyl or n-propyl p-hydroxybenzoate, one or more colorants, one or more flavoring agents, and one or more sweeteners such as sucrose or saccharin.

[0118] Oily suspensions can be prepared by suspending the active ingredient in a vegetable oil such as peanut oil, olive oil, sesame oil, or coconut oil, or a mineral oil such as liquid paraffin. Oily suspensions may contain thickeners such as beeswax, hard paraffin, or cetyl alcohol. Sweeteners and flavorings such as those mentioned above may be added to provide a palatable oral formulation. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.

[0119] Dispersible powders and granules suitable for preparing aqueous suspensions are provided by adding water to the active ingredient in admixture with a dispersant or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersants or wetting agents and suspending agents are, for example, those mentioned above. Other excipients, such as sweeteners, flavorings, and coloring agents, may also be present.

[0120] Pharmaceutical compositions of the present disclosure can also be in the form of oil-in-water emulsions. The oil phase can 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 can be naturally occurring gums, such as gum arabic or tragacanth, naturally occurring phospholipids, such as soybeans, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of the partial esters and ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion can also contain sweeteners and flavorings.

[0121] Syrups and elixirs can be formulated with sweeteners such as glycerol, propylene glycol, sorbitol, or sucrose. Such formulations may also contain a demulcent, a preservative, and flavoring and coloring agents. Oral solutions can be prepared in combination with, for example, cyclodextrins, PEG, and a surfactant.

[0122] The pharmaceutical composition can be in the form of a sterile injectable aqueous or oily suspension. The suspension can be prepared according to known techniques using those suitable dispersants or wetting agents and suspending agents mentioned above. Sterile injectable preparations can also be sterile injectable solutions or suspensions in nontoxic parenteral acceptable diluents or solvents, for example as solutions in 1,3-butanediol. Acceptable carriers and solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils are commonly used as solvents or suspending media. For this purpose, any mild fixed oil can be used, including synthetic monoglycerides or diglycerides. In addition, fatty acids such as oleic acid can be used to prepare injections.

[0123] The compounds of the present invention can also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient, which is solid at room temperature but liquid at rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter and polyethylene glycol. In addition, the compound can be administered by eye administration in the form of a solution or ointment. Furthermore, transdermal delivery of the subject compound can be achieved by 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 mouthwashes and gargles.

[0124] Compound of the present disclosure can also be coupled with a carrier as a suitable polymer for targetable drug carriers. Such polymers can include polyvinyl pyrrolidone, pyran copolymer, polyhydroxy-propyl-methacrylamide-phenol, polyhydroxyethyl-asparagine-phenol or polyethylene oxide-polylysine substituted with palmitoyl residues. In addition, compound of the present disclosure can be coupled with a carrier, which is a class of biodegradable polymers that can be used to realize controlled release of drugs, such as crosslinked or amphiphilic block copolymers of polylactic acid, polyglycolic acid, polylactic acid and polyglycolic acid, poly-ε caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and hydrogels. Polymer and semipermeable polymer matrix can form shaped articles, such as valves, stents, tubing, prostheses, etc. In one embodiment of the invention, compound of the present invention is coupled with a polymer or semipermeable polymer matrix formed as stent or stent graft device.

[0125] Methods of treating diseases and disorders

[0126] The compounds of the present disclosure can be used as immunomodulators. The compounds of the present disclosure can be used as agonists, antagonists, partial agonists, inverse agonists, inhibitors of PD-1 and / or PD-L1 in various situations in vitro and in vivo. In some embodiments, the compounds of the present disclosure can be used as inhibitors of PD-1 / PD-L1 protein interactions. In some embodiments, the compounds of the present disclosure can be used as inhibitors of PD-L1. In some embodiments, the compounds of the present disclosure can be used as inhibitors of CD80 / PD-L1 protein interactions. In some embodiments, the compounds of the present disclosure can be used to inhibit the interaction between PD-1 and PD-L1 and / or PD-1 and CD80 and / or PD-1 and PD-L2 in vitro or in vivo. In some embodiments, the compounds of the present disclosure can be used to inhibit VISTA and / or TIM-3. In some embodiments, the compounds of the present disclosure can be inhibitors of PD-1 / PD-L1 protein interactions and inhibitors of VISTA and / or TIM-3. In some embodiments, in addition to being inhibitors of PD-1 / PD-L1 protein interactions, the compounds of the present disclosure may be inhibitors of CTLA-4 and / or BTLA and / or LAG-3 and / or KLRG-1 and / or 2B4 and / or CD160 and / or HVEM and / or CD48 and / or E-cadherin and / or MHC-II and / or Galectin-9 and / or CD86 and / or PD-L2 and / or VISTA and / or TIM-3 and / or CD80.

[0127] The compounds of the present disclosure can be contacted with the receptors with which they interact in aqueous solution and under conditions otherwise suitable for ligand-receptor binding. The receptors can be present in suspension (e.g., in isolated membranes or cell preparations), in cultured or isolated cells, or in tissues or organs.

[0128] Preferably, the amount of the disclosed compound contacted with the receptor should be sufficient to inhibit PD-1 / PD-L1 binding in vitro, as measured, for example, using an ELISA. The receptor may be present in solution or suspension, in a cultured or isolated cell preparation, or in a patient.

[0129] In some embodiments, the compounds of the present disclosure can be used to restore and enhance T cell activation. In some embodiments, the compounds of the present disclosure can be used to enhance the immune response of patients. In some embodiments, the compounds of the present disclosure can be used to treat, prevent or slow the progression of diseases or conditions in various therapeutic areas, such as cancer and infectious diseases.

[0130] In some embodiments, the compounds of the present disclosure may be used to treat patients suffering from disorders responsive to modulation of the PD-1 / PD-L1 protein interaction.

[0131] In some embodiments, methods are provided for modulating an immune response mediated by the PD-1 signaling pathway in a subject, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure, including a compound of Formula (I), (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, or a composition comprising a compound of Formula (I), (Ia) or (Ib) or a pharmaceutically acceptable salt thereof.

[0132] In some embodiments, methods are provided for enhancing, stimulating, regulating and / or increasing an immune response in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure, including a compound of Formula (I), (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, or a composition of a compound of the present disclosure, including a compound of Formula (I), (Ia) or (Ib), or a pharmaceutically acceptable salt thereof.

[0133] In some embodiments, a method of inhibiting cancer cell growth, proliferation, or metastasis in a subject in need thereof is provided, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure, including a compound of Formula (I), (Ia), or (Ib), or a pharmaceutically acceptable salt thereof, or a composition of a compound of the present disclosure comprising a compound of Formula (I), (Ia), or (Ib), or a pharmaceutically acceptable salt thereof.

[0134] In some embodiments, methods of treating a subject in need thereof are provided, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure, including a compound of Formula (I), (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, or a composition of a compound of the present disclosure comprising a compound of Formula (I), (Ia) or (Ib) or a pharmaceutically acceptable salt thereof.

[0135] In some embodiments, the subject suffers from a disease or condition selected from the group consisting of an infectious disease, a bacterial infectious disease, a viral infectious disease, a fungal infectious disease, a solid tumor, a malignant blood disease, an immune disorder, an inflammatory disease, and a cancer. In some embodiments, the disease or condition is selected from the group consisting of melanoma, glioblastoma, esophageal tumor, nasopharyngeal carcinoma, uveal melanoma, lymphoma, lymphocytic lymphoma, primary CNS lymphoma, T-cell lymphoma, diffuse large B-cell lymphoma, primary mediastinal large B-cell lymphoma, prostate cancer, castration-resistant prostate cancer, chronic myeloid leukemia, Kaposi's sarcoma, fibrosarcoma, liposarcoma, chondrosarcoma, osteosarcoma, angiosarcoma, lymphangiosarcoma, synovial tumor, meningioma, leiomyosarcoma, rhabdomyosarcoma, soft tissue sarcoma , sarcoma, sepsis, biliary tract tumors, basal cell carcinoma, thymus tumors, thyroid cancer, parathyroid cancer, uterine cancer, adrenal cancer, liver infection, Merkel cell carcinoma, neural tumors, follicle center lymphoma, colon cancer, Hodgkin's disease, non-Hodgkin's lymphoma, leukemia, chronic or acute leukemia, including acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic 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, head and neck squamous cell carcinoma, head and neck cancer, gastrointestinal cancer, stomach cancer, HIV, hepatitis A, hepatitis B, hepatitis C, hepatitis D, herpes simplex virus, papillomavirus, influenza, bone cancer, skin cancer, rectal cancer, anal cancer, testicular cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, esophageal cancer, small intestine cancer, endocrine system cancer, urinary tract cancer carcinoma, penile cancer, bladder cancer, kidney cancer, ureteral cancer, renal pelvic cancer, central nervous system (CNS) tumors, tumor angiogenesis, spinal cord tumors, brainstem gliomas, pituitary adenomas, epidermoid carcinomas, incontinence, carcinomas, adenocarcinomas, papillary carcinomas, cystadenocarcinomas, bronchogenic carcinomas, renal cell carcinomas, transitional cell carcinomas, choriocarcinomas, seminoma, embryonal carcinomas, Wilm's tumor, pleomorphic adenoma, hepatocellular papilloma, renal tubular adenoma, cystadenoma, papilloma, adenoma, leiomyoma, rhabdomyomas, hemangiomas, lymphangiomas, osteomas, chondromas, lipomas, and fibromas.

[0136] In certain embodiments, one or more other therapeutic agents of a therapeutically effective amount are further administered to the subject. In certain embodiments, one or more other therapeutic agents are selected from antimicrobial agents, antiviral agents, cytotoxic agents, gene expression regulators, chemotherapeutics, anticancer agents, antiangiogenic agents, immunotherapeutics, antihormones, antifibrotics, radiotherapy, radiotherapeutics, antitumor agents and antiproliferative agents. In certain embodiments, one or more other therapeutic agents are antagonists of chemokines and / or chemoattractant receptors, including but not limited to CCR1, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10, CCR11, CCR12, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, CXCR6, CXCR7, C3aR and / or C5aR. Chemokine and / or chemokine receptor antagonists are known in the art and are described, for example, in WO 2007 / 002667, WO 2007 / 002293, WO / 2003 / 105853, WO / 2007 / 022257, WO / 2007 / 059108, WO / 2007 / 044804, WO 2007 / 115232, WO 2007 / 115231, WO 2008 / 147815,WO2010 / 030815,WO2010 / 075257,WO2011 / 163640,WO2010 / 054006,WO2010 / 051561 ,WO2011 / 035332,WO2013 / 082490,WO2013 / 082429,WO2014 / 085490,WO2014 / 100735,WO201 4 / 089495,WO2015 / 084842,WO2016 / 187393,WO2017 / 127409,WO2017 / 087607,WO2017 / 087 610,WO2017 / 176620,WO2018 / 222598,WO2018 / 222601,WO2013 / 130811,WO2006 / 076644,WO 2008 / 008431,WO2009 / 038847,WO2008 / 008375,WO2008 / 008374,WO2008 / 010934,WO2009 / 0 09740,WO2005 / 112925,WO2005 / 112916,WO2005 / 113513,WO2004 / 085384,WO2004 / 046092.Chemokine and / or chemokine receptor antagonists also include CCX354, CCX9588, CCX140, CCX872, CCX598, CCX6239, CCX9664, CCX2553, CCX3587, CCX3624, CCX 2991, CCX282, CCX025, CCX507, CCX430, CCX765, CCX224, CCX662, CCX650, CCX832, CCX168, CCX168-M1, CCX3022, and / or CCX3384.

[0137] In some embodiments, the compounds of the present disclosure can be used to inhibit infectious diseases. Infectious diseases include but are not limited to HIV, influenza, herpes, Giardia, malaria, Leishmania, pathogenic infections caused by hepatitis viruses (type A, B and C), herpes viruses (e.g., VZV, HSV-I, HAV-6, HSV-II and CMV, Epstein-Barr virus), adenovirus, influenza virus, flavivirus, echovirus, rhinovirus, coxsackievirus, coronavirus, respiratory syncytial virus, mumps virus, rotavirus, measles virus, rubella virus, parvovirus, vaccinia virus, HTLV virus, dengue virus, papillomavirus, molluscum virus, poliovirus, rabies virus, JC virus and arboviral encephalitis virus, pathogenic infections caused by Chlamydia, Rickettsia, Mycobacterium, Staphylococcus, Streptococcus, Pneumococcus, Meningococcus and coccus, Klebsiella, Proteus, Pathogenic infections caused by bacteria such as Serratia, Pseudomonas, Escherichia coli, Legionella, diphtheria, Salmonella, Bacillus, cholera, tetanus, botulism, anthrax, plague, leptospirosis and Lyme disease, infections caused by fungi such as Candida albicans, Klebsiella, Glechoma, Tropical fungus, Cryptococcus neoformans, Aspergillus (Aspergillus fumigatus, Niger, etc.), Mucor (Mucor, Absidia, Rhizopus), Sporothrix schenkii, dermatitis Pathogenic infections caused by Blastomyces, Paracoccidioides brasiliensis, Coccidioides and Histoplasma capsulatum, as well as pathogenic infections caused by the parasites Entamoeba histolytica, Balantidium coli, Naegleria fowleri, Acanthamoeba, Giardia lamblia, Cryptosporidium, Pneumocystis carinii, Plasmodium vivax, Babesia gonorrhoeae, Trypanosoma brucei, Trypanosoma cruzi, Leishmania donovani, Toxoplasma gondii and Nipponstrongylus brasiliensis.

[0138] In some embodiments, the compounds of the present disclosure can be used to inhibit HIV infection, slow AIDS progression, deplete HIV viral reservoirs, or reduce the symptoms or severity of HIV infection and AIDS.

[0139] The compounds of the present disclosure are useful for treating cancer and precancerous conditions in a subject.

[0140] The treatment methods provided herein generally comprise administering to a patient an effective amount of one or more compounds provided herein. Suitable patients include those suffering from or susceptible to (i.e., prophylactic treatment of) the conditions or diseases identified herein. Typical patients for the treatment described herein include mammals, particularly primates, and especially humans. Other suitable patients include domesticated companion animals such as dogs, cats, horses, etc., or livestock such as cattle, pigs, sheep, etc.

[0141] In general, the methods of treatment provided herein include administering to the patient an effective amount of a compound, one or more compounds provided herein. In a preferred embodiment, the compounds of the present disclosure are preferably administered to a patient (e.g., a human) intravenously, orally, or topically. An effective amount may be an amount sufficient to modulate the PD-1 / PD-L1 interaction and / or an amount sufficient to reduce or alleviate the symptoms presented by the patient. Preferably, the amount administered is sufficient to produce a plasma concentration of the compound (or its active metabolite, if the compound is a prodrug) sufficient to fully modulate the PD-1 / PD-L1 interaction. The treatment regimen may vary depending on the compound used and the specific condition to be treated; for the treatment of most diseases, a dosing frequency of 4 times a day or less is preferred. In general, a dosing regimen of 2 times a day is more preferred, with once a day dosing being particularly preferred. However, it should be understood that the specific dosage 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 status, sex, diet, treatment duration, route of administration, excretion rate, drug combination (i.e., other drugs given to the patient), and the severity of the specific disease being treated, as well as the judgment of the prescribing physician. Typically, it is preferred to use the minimum dose sufficient to provide effective treatment. Patients can generally be monitored for effectiveness of treatment using medical or veterinary criteria appropriate to the condition being treated or prevented.

[0142] combination

[0143] Concomitant drugs comprising a compound of the present invention and other drugs can be administered as a combination formulation in which the two components are contained in a single formulation, or as separate formulations. Administration by separate formulations includes simultaneous administration and administration at certain time intervals. In the case of administration at certain time intervals, a compound of the present invention can be administered first, followed by another drug, or another drug can be administered first, followed by a compound of the present invention. The administration methods of each drug can be the same or different.

[0144] The dosage of other drugs can be appropriately selected according to the dosage used clinically. According to the age and weight of the subject to be administered, the method of administration, the time of administration, the condition to be treated, the symptoms and combinations thereof, the compound ratio of the compound of the present disclosure and other drugs can be appropriately selected. For example, based on 1 part by mass of the compound of the present disclosure, 0.01 to 100 parts by mass of other drugs can be used. Other drugs can be two or more arbitrary drugs combined in an appropriate ratio.

[0145] The compounds described herein can be used or combined with one or more therapeutic agents, such as antimicrobial agents, antiviral agents, cytotoxic agents, gene expression regulators, chemotherapeutic agents, anticancer agents, anti-angiogenic agents, immunotherapeutic agents, antihormonal agents, antifibrotic agents, radiotherapy, radiotherapeutic agents, antitumor agents and antiproliferative agents. These therapeutic agents can be in the form of compounds, antibodies, polypeptides or polynucleotides.

[0146] The compounds described herein can be combined 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 modifiers or editors, such as CRISPR (including CRISPRCas9), zinc finger nucleases or synthetic nucleases (TALENs), CAR (chimeric antigen receptor) T cell immunotherapeutics, or any combination thereof used together or in combination.

[0147] Examples of chemotherapeutic agents include alkylating agents, nitrosoureas, antimetabolites, anticancer antibiotics, plant-derived alkaloids, topoisomerase inhibitors, hormone drugs, hormone antagonists, aromatase inhibitors, P-glycoprotein inhibitors, platinum complex derivatives, other immunotherapeutic drugs, and other anticancer drugs.

[0148] The compounds described herein can be used or combined simultaneously or in the form of a mixture with cancer treatment adjuvants such as leukopenia (neutropenia) treatment drugs, thrombocytopenia treatment drugs, antiemetic drugs, and cancer pain intervention drugs.

[0149] The compounds described herein may be used or combined with kinase inhibitors.

[0150] In one embodiment, the compounds of the present disclosure can be used simultaneously with other immunomodulators and / or enhancers or used in a mixture. Examples of immunomodulators include various cytokines, vaccines, and adjuvants. Examples of these 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 (Gleevec), 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.

[0151] In some embodiments, the compounds described herein can be used in or in combination with one or more modulators of CCR1, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10, CCR11, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, CXCR6, CXCR7, ChemR23, C5aR, C5a, and C5. In some embodiments, the modulator is an antagonist.

[0152] In some embodiments, the compounds described herein may be combined with one or more of the compounds described in, for example, WO2007 / 002667, WO2007 / 002293, WO / 2003 / 105853, WO / 2007 / 022257, WO / 2007 / 059108, WO / 2007 / 044804, WO2007 / 115232, WO2007 / 115231, WO2008 / 147815, WO2 010 / 030815, WO2010 / 075257, WO2011 / 163640, WO2010 / 054006, WO2010 / 051561, WO2011 / 035332 , WO2011 / 035332, WO2013 / 082490, WO2013 / 082429, WO2013 / 085490, WO2014 / 100735, WO2014 / 089 495, WO2015 / 084842, WO2016 / 187393, WO2017 / 127409, WO2017 / 087607, WO2017 / 087610, WO2017 / 176620, WO2018 / 222598, WO2018 / 222601, WO2013 / 130811, WO2006 / 076644, WO2008 / 008431, WO2 009 / 038847, WO2008 / 008375, WO2008 / 008374, WO2008 / 010934, WO2009 / 009740, WO2005 / 112925, WO2005 / 112916, WO2005 / 113513, WO2004 / 085384, WO2004 / 046092. Chemokine and / or chemokine receptor antagonists useful in the present disclosure also include CCX354, CCX9588, CCX140, CCX872, CCX598, CCX6239, CCX9664, CCX2553, CCX3587, CCX3624, CCX 2991, CCX282, CCX025, CCX507, CCX430, CCX765, CCX224, CCX662, CCX650, CCX832, CCX168, CCX168-M1, CCX3022, and / or CCX3384.

[0153] dose

[0154] Dosage levels of the order of about 0.1 mg to about 140 mg per kilogram of body weight per day can be used to treat or prevent disorders involving PD-1 / PD-L1 interactions (about 0.5 mg to about 7 g per patient per day). The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary depending on the host being treated and the specific mode of administration. A unit dosage form typically contains about 1 mg to about 500 mg of active ingredient. For compounds administered orally, transdermally, intravenously, or subcutaneously, it is preferred to administer a sufficient amount of the compound to achieve a serum concentration of 5 ng (nanograms) / mL-10 μg (micrograms) / mL serum, more preferably sufficient compound to achieve a serum concentration of 20 ng-1 μg / ml serum, sufficient compound should be administered to achieve a serum concentration of 50 ng / ml-200 ng / ml serum. For direct injection into the synovium (for the treatment of arthritis), sufficient compound should be administered to achieve a local concentration of about 1 micromolar.

[0155] The frequency of administration may also vary depending on the compound used and the specific disease being treated. However, for the treatment of most diseases, a dosage regimen of 4 times a day, 3 times a day or less is preferred, with a dosage regimen of once a day or twice a day being particularly preferred. However, it should be understood that the specific dosage level for any particular patient will depend on a variety of factors, including the activity of the specific compound used, age, body weight, general health, sex, diet, duration of treatment, route of administration, excretion rate, drug combination (i.e., other drugs given to the patient), and the severity of the specific disease being treated, as well as other factors including the judgment of the prescribing physician.

[0156] In another aspect of the present disclosure, the compounds of the present disclosure can be used for a variety of non-drug in vitro and in vivo applications. The compounds of the present disclosure can also be used as positive controls in PD-1 / PD-L1 interaction activity assays, i.e., as standards for determining the ability of candidate agents to bind to PD-1 and / or PD-L1, or as radioactive tracers for positron emission tomography (PET) imaging or single photon emission computed tomography (SPECT).

[0157] Kits comprising a compound of the present disclosure or a pharmaceutically acceptable salt thereof and instructions for use are also within the scope of the present disclosure. The kit may further comprise at least one additional reagent. Kits typically include a label indicating the intended use of the kit contents. The term label includes any written or recorded material on or provided with the kit, or otherwise accompanying the kit. Example

[0158] The following examples illustrate various methods of preparing compounds of the present disclosure, including compounds of Formula (I), (Ia), or (Ib).The following examples are provided to illustrate, but not to limit, the claimed disclosure.

[0159] The reagents and solvents used below can be obtained from commercial sources, such as Aldrich Chemical Company (Milwaukee, WI, USA). Spectra were recorded on a Varian Mercury 400 MHz NMR spectrometer. 1 H-NMR spectra. Significant peaks relative to TMS are provided and listed in the following order: multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet) and number of protons. Mass spectrometric results are reported as mass-to-charge ratios. In the examples, a single m / z value is reported for the M+H (or MH as previously described) ion containing the most common atomic isotope. The isotope pattern corresponds to the expected formula in all cases. Electrospray ionization (ESI) mass spectrometry analysis was performed on a Hewlett-Packard MSD electrospray mass spectrometer using an HP1100 HPLC for sample delivery. The analyte was typically dissolved in methanol or CH3CN at 0.1 mg / mL and 1 μL was injected into the mass spectrometer along with the delivery solvent over a scan range of 100 to 1000 Daltons. All compounds could be analyzed in positive or negative ESI mode using acetonitrile / water and 1% formic acid as the delivery solvent.

[0160] The following abbreviations are used in the examples and throughout the description of the present disclosure: TLC stands for thin layer chromatography.

[0161] Compounds within the scope of the present disclosure can be synthesized using a variety of reactions known to those skilled in the art as described below. Those skilled in the art will also recognize that alternative methods can be employed to synthesize the target compounds of the present disclosure, and that the methods described in the body of this document are not exhaustive, but do provide broadly applicable and practical pathways to compounds of interest.

[0162] Certain molecules claimed in this patent may exist in different enantiomeric and diastereomeric forms, and all such variations of these compounds are claimed unless a specific enantiomer is specified.

[0163] In this paper, a detailed description of the experimental procedures used to synthesize key compounds resulted in molecules that are described by the physical data that identify them and by the structural descriptions associated with them.

[0164] Those skilled in the art will also recognize that acids and bases are frequently employed in standard workup procedures in organic chemistry. Salts are sometimes produced during the experimental procedures described herein if the parent compound possesses the necessary inherent acidity or basicity.

[0165] Example 1: N-(2'-chloro-3'-(5-((((3R,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)methyl)-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0166]

[0167] Step a: To a mixture of 1,3-dimethyl-N-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (3.6 g, 9.0 mmol), 1,3-dibromo-2-chlorobenzene (6.9 g, 25.5 mmol) and KCO (3.8 g, 27.5 mmol) in p-dioxane (40 mL) and DI H0 (6 mL) was added Pd(dppf)Cl complex with dichloromethane (912 mg, 1.12 mmol). The reaction mixture was degassed and stirred at 90° C. under N for 2 h. The contents were diluted with EtOAc, filtered through celite, washed with brine and dried over MgSO. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel to give N-(3'-bromo-2'-chloro-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. MS: (ES) m / z C 20 H 18 BrClN3O3[M+H] + The calculated value is 462.0 and the measured value is 462.0.

[0168] Step b: To a mixture of N-(3'-bromo-2'-chloro-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (1.4 g, 3.03 mmol), pinacol diborane (1.0 g, 3.94 mmol), and KOAc (1.2 g, 10.2 mmol) in p-dioxane (18 mL) was added Pd(dppf)Cl2 complex with dichloromethane (350 mg, 0.43 mmol). The reaction mixture was degassed (N2) and stirred at 90°C under N2 for 3 hours. The contents were diluted with EtOAc, filtered through celite, washed with brine, and dried over MgSO4. The solvent was removed under reduced pressure, and the residue was purified by silica gel flash chromatography to give N-(2'-chloro-2-methyl-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. MS: (ES) m / zC 26 H 30 BClN3O5[M+H] + The calculated value is 510.2 and the measured value is 510.1.

[0169] Step c: To a mixture of N-(2'-chloro-2-methyl-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (400 mg, 0.78 mmol), 6-chloro-2-methoxynicotinaldehyde (200 mg, 1.17 mmol) and KCO (350 mg, 2.53 mmol) in p-dioxane (10 mL) and DI H2O (2 mL) was added Pd(dppf)Cl2 complex with dichloromethane (70 mg, 0.086 mmol). The reaction mixture was degassed and stirred at 95°C under N2 for 2 hours. The contents were diluted with EtOAc, filtered through celite, washed with brine and dried over MgSO4. The solvent was removed under reduced pressure, and the residue was purified by flash chromatography on silica gel to give N-(2'-chloro-3'-(5-formyl-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. MS: (ES) m / z C 27 H 24 ClN4O5[M+H] + The calculated value is 519.1 and the measured value is 519.1.

[0170] Step d: To a stirred solution of N-(2'-chloro-3'-(5-formyl-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (40 mg, 0.077 mmol) and (3R,4R)-4-aminotetrahydro-2H-pyran-3-ol hydrochloride (24 mg, 0.154 mmol) in dichloroethane (2 mL) and ethanol (1 mL) was added triethylamine (2 drops) followed by acetic acid (2 drops). The reaction mixture was stirred at 70°C for 1 hour, then cooled to 0°C and NaBH3CN (10 mg, 0.154 mmol) was slowly added. The contents were stirred at 0 °C for 10 minutes, filtered, and then purified by preparative HPLC to give N-(2'-chloro-3'-(5-((((3R,4R)-3-hydroxytetrahydro-2H-pyran))-4-yl)amino)methyl)-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 1 H NMR(400MHz,CD3OD)δ11.18(s,1H),8.63(s,1H),8.13–8.06(m,1H),7.88(d, J=7.6Hz,1H),7.61(dd,J=7.6,1.7Hz,1H),7.49(t,J=7.6Hz,1H),7.39–7.25( m,3H),7.00(d,J=7.7Hz,1H),4.35(d,J=13.3Hz,1H),4.24(d,J=13.2Hz,1H) ,4.11–3.93(m,6H),3.61–3.36(m,10H),2.13(s,4H),1.87(d,J=12.4Hz,1H). MS:(ES)m / zC 32 H 34 ClN5O6[M+H] + The calculated value is 620.2 and the measured value is 620.2.

[0171] Example 2: (S)-N-(2'-chloro-3'-(6-methoxy-5-(((5-oxopyrrolidin-3-yl)amino)methyl)pyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0172]

[0173] The title compound was prepared using a procedure similar to step d in Example 1 starting from N-(2'-chloro-3'-(5-formyl-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide and (4S)-4-aminopyrrolidin-2-one hydrochloride. The product was purified by preparative HPLC to give the desired product, (S)-N-(2'-chloro-3'-(6-methoxy-5-(((5-oxopyrrolidin-3-yl)amino)methyl)pyridin)-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 1 H NMR (400MHz, CD3OD) δ11.17(s,1H),8.63(s,1H),8.11(t,J=7.5Hz,1H),7.89(d,J=7.6Hz,1H),7.61(dd,J =7.7,1.6Hz,1H),7.49(t,J=7.6Hz,1H),7.40–7.25(m,3H),7.04–6.97(m,1H),4.32(s,2H),4.24(tt,J=8 .3,4.2Hz,1H),4.10(d,J=0.8Hz,3H),3.87(dd,J=11.7,7.6Hz,1H),3.63–3.53(m,4H),3.39(s,3H),3.31 (p,J=1.6Hz,11H),2.90(dd,J=17.8,8.8Hz,1H),2.57(dd,J=17.8,4.7Hz,1H),2.13(s,3H).MS:(ES)m / zC 31 H 31 ClN6O5[M+H] + The calculated value is 603.2 and the measured value is 603.2.

[0174] Example 3: (S)-N-(2'-chloro-3'-(6-methoxy-5-((((5-oxopyrrolidin-2-yl)methyl)amino)methyl)pyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0175]

[0176] The title compound was prepared using a procedure similar to step d in Example 1 from N-(2'-chloro-3'-(5-formyl-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide and (S)-5-aminomethylpyrrolidin-2-one hydrochloride. The product was purified by preparative HPLC to give the desired product, (S)-N-(2'-chloro-3'-(6-methoxy-5-(((5-oxopyrrolidin-2-yl)methyl)amino)methyl)pyridin)-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 1 H NMR (400MHz, CD3OD) δ8.63(d,J=1.1Hz,1H),8.12(dd,J=7.9,1.3Hz,1H),7.88(d,J=7.6 Hz,1H),7.61(d,J=7.7Hz,1H),7.50(dd,J=7.6,7.6Hz,1H),7.41–7.25(m,3H),7.00(d, J=7.5Hz,1H),4.34(d,J=2.0Hz,2H),4.13–4.00(m,4H),3.55(d,J=1.0Hz,3H),3.39(d, J=1.0Hz,3H),3.34–3.22(m,2H),2.49–2.32(m,3H),2.13(s,3H),1.92(q,J=7.5Hz,1H). MS:(ES)m / z C 32 H 33 ClN6O5[M+H] + The calculated value is 617.2, and the measured value is 617.2.

[0177] Example 4: N-(2,2'-dichloro-3'-(5-((((3R,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)methyl)-6-methoxypyrazin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0178]

[0179] A compound was prepared using a procedure similar to step d in Example 1, starting from N-(2'-chloro-3'-(5-formyl-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide and (3R,4R)-4-aminotetrahydro-2H-pyran-3-ol hydrochloride. The product was purified by preparative HPLC to give the desired product, N-(2,2'-dichloro-3'-(5-((((3R,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino))methyl)-6-methoxypyrazin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 1 H NMR (400MHz, CD3OD) δ11.70(s,1H),8.67(s,1H),8.56(d,J=6.9Hz,2H),7.77–7.67(m,1H),7.57(t,J=7.9Hz,1H),7.43(d,J=20.5Hz,2H),7.12(d,J =8.8Hz,1H),4.49(s,2H),4.13(s,3H),4.10–3.95(m,3H),3.64–3.53(m,5 H),3.52–3.42(m,1H),3.39(s,3H),2.23–2.09(m,1H),1.97–1.88(m,1H). MS:(ES)m / z C 30 H 30 Cl2N6O6[M+H] + The calculated value is 641.2 and the measured value is 641.1.

[0180] Example 5: N-(2,2'-dichloro-3'-(5-((((3S,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)methyl)-6-methoxypyrazin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0181]

[0182] The title compound was prepared using a procedure similar to step d in Example 1 starting with N-(2'-chloro-3'-(5-formyl-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide and (3S,4S)-4-aminotetrahydro-2H-pyran-3-ol hydrochloride. The product was purified by preparative HPLC to give the desired product, N-(2,2'-dichloro-3'-(5-((((3S,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)amino))methyl)-6-methoxypyrazin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 1 H NMR (400MHz, CD3OD) δ11.71(s,1H),8.67(s,1H),8.56(d,J=6.9Hz,2H),7.73–7.71(m,1H),7.57(t,J=7.9Hz,1H),7.46–7.41(m,2H),7.12(d,J=8 .8Hz,1H),4.49(s,2H),4.13(s,3H),4.10–3.96(m,3H),3.62–3.56(m,5H ),3.50–3.47(m,1H),3.39(s,3H),2.20–2.14(m,1H),1.97–1.91(m,1H). MS:(ES)m / z C 30 H 30 Cl2N6O6[M+H] + The calculated value is 641.2 and the measured value is 641.0.

[0183] Example 6: (S)-N-(2,2'-dichloro-3'-(6-methoxy-5-((((5-oxopyrrolidin-2-yl)methyl)amino)methyl)pyrazin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0184]

[0185] The title compound was prepared using a procedure similar to step d in Example 1 starting from N-(2,2'-dichloro-3'-(5-formyl-6-methoxypyrazin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide and (S)-5-aminomethylpyrrolidin-2-one hydrochloride. The product was purified by preparative HPLC to give the desired product, (S)-N-(2,2'-dichloro-3'-(6-methoxy-5-(((((5-oxopyrrolidin-2-yl)methyl)amino)methyl)pyrazin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 1 H NMR (400MHz, CD3OD) δ8.67(s,1H),8.59–8.52(m,2H),7.71(dd,J=7.6,1.5Hz,1H),7.57(dd,J=7.7,7.7Hz,1H),7.48–7.37(m,2H),7.11(d,J= 7.5Hz, 1H), 4.53 (d, J = 3.8Hz, 2H), 4.13 (d, J = 1.1Hz, 4H), 3.56 (d, J = 1.1Hz, 3H), 3.41–3.29 (m, 6H), 2.50–2.34 (m, 3H), 1.97 (q, J = 10.0Hz, 1H). MS:(ES)m / z C 30 H 29 Cl2N7O5[M+H] + The calculated value is 638.1 and the measured value is 638.0.

[0186] Example 7: (S)-N-(2,2'-dichloro-3'-(6-methoxy-5-(((5-oxopyrrolidin-3-yl)amino)methyl)pyrazin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0187]

[0188] The title compound was prepared using a procedure similar to step d in Example 1 from N-(2,2'-dichloro-3'-(5-formyl-6-methoxypyrazin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide and (S)-4-aminopyrrolidin-2-one hydrochloride. The product was purified by preparative HPLC to give the desired product, (S)-N-(2,2'-dichloro-3'-(6-methoxy-5-(((5-oxopyrrolidin-3-yl)amino)methyl))pyrazin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 1 HNMR(400MHz,CD3OD)δ11.70(s,1H),8.67(s,1H),8.55(d,J=9.1Hz,2H),7.72(d ,J=8.2Hz,1H),7.57(d,J=14.8Hz,1H),7.46–7.41(m,2H),7.11(d,J=7.8Hz,1H) ,4.53(s,2H),4.37–4.28(m,1H),4.14(s,3H),3.94–3.86(m,1H),3.69–3.60(m, 1H), 3.56 (s, 3H), 3.39 (s, 3H), 2.96–2.86 (m, 1H), 2.65 (dd, J = 18.5, 6.6Hz, 1H). MS:(ES)m / zC 29 H 27 Cl2N7O5[M+H] + The calculated value is 624.2 and the measured value is 624.0.

[0189] Example 8: (R)-N-(2,2'-dichloro-3'-(6-methoxy-5-(((6-oxopiperidin-3-yl)amino)methyl)pyrazin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0190]

[0191] The title compound was prepared using a procedure similar to step d in Example 1 starting from N-(2,2'-dichloro-3'-(5-formyl-6-methoxypyrazin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide and (R)-5-aminopiperidin-2-one hydrochloride. The product was purified by preparative HPLC to give the desired product, (R)-N-(2,2'-dichloro-3'-(6-methoxy-5-(((6-oxopiperidin-3-yl)amino)methyl))pyrazin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 1 H NMR (400MHz, CD3OD) δ11.70 (s, 1H), 8.67 (s, 1H), 8.56 (d, J = 3.3Hz, 2H), 7.72 ( d,J=7.7Hz,1H),7.57(t,J=7.9Hz,1H),7.46–7.40(m,2H),7.11(d,J=8.6Hz,1H ),4.65–4.49(m,2H),4.14(s,3H),3.88–3.73(m,2H),3.56(s,3H),3.55–3.48 (m,1H),3.39(s,3H),2.55–2.49(m,2H),2.45–2.38(m,1H),2.18–2.08(m,1H). MS:(ES)m / z C 29 H 27 Cl2N7O5[M+H] + The calculated value is 638.2 and the measured value is 638.0.

[0192] Example 9: (S)-N-(2'-chloro-3'-(6-ethoxy-5-((((5-oxopyrrolidin-2-yl)methyl)amino)methyl)pyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0193]

[0194] The compound was prepared using a procedure similar to step d in Example 1 starting from N-(2'-chloro-3'-(6-ethoxy-5-formylpyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide and (S)-(5-oxopyrrolidin-2-yl)methanamine hydrochloride. The crude product was purified by preparative HPLC to give the desired product, (S)-N-(2'-chloro-3'-(6-ethoxy-5-((((5-oxopyrrolidin-2-yl)methyl)amino)methyl)pyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 1 H NMR (400MHz, CDCl3) δ10.93(d,J=5.0Hz,1H),8.55(d,J=7.4Hz,1H),8.18(dd,J=8.1,4.2Hz,1H),8.02 (s,1H),7.80–7.70(m,1H),7.61–7.52(m,1H),7.40(dd,J=7.6,7.6Hz,1H),7.29(td,J=6.8,5.6,2.8H z,3H),7.02(d,J=7.6Hz,1H),4.51(d,J=7.9Hz,2H),4.21(d,J=33.5Hz,3H),3.58(d,J=2.1Hz,3H),3. 44(s,3H),3.20–3.00(m,2H),2.34(s,4H),2.16(d,J=1.4Hz,3H),1.73(s,1H),1.40(t,J=7.0Hz,3H). MS:(ES)m / zC 33 H 36 ClN6O5[M+H] + The calculated value is 631.2 and the measured value is 631.2.

[0195] Example 10: N-(2,2'-dichloro-3'-(6-methoxy-5-((6-oxo-2,5-diazaspiro[3.4]octan-2-yl)methyl)pyrazin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0196]

[0197] The compound was prepared using a procedure similar to step d in Example 1 starting from N-(2,2'-dichloro-3'-(5-formyl-6-methoxypyrazin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide and 2,5-diazaspiro[3.4]octan-6-one hydrochloride. The crude product was purified by preparative HPLC to give the desired product, N-(2,2'-dichloro-3'-(6-methoxy-5-((6-oxo-2,5-diazaspiro[3.4]octan-2-yl)methyl)pyrazin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 1 H NMR(400MHz,CD3OD)δ11.70(s,1H),8.67(d,J=1.2Hz,1H),8.58–8.48(m,2H),7.70(d ,J=7.9Hz,1H),7.56(dd,J=7.6,7.6Hz,1H),7.47–7.37(m,2H),7.14–7.07(m,1H),4. 75(s,2H),4.63(s,1H),4.34(s,1H),4.12(d,J=1.1Hz,3H),3.56(d,J=1.3Hz,3H),3. 39(d,J=1.1Hz,3H),3.35–3.29(m,3H),2.57(t,J=7.8Hz,2H),2.43(d,J=7.9Hz,2H). MS:(ES)m / z C 31 H 30 Cl2N7O5[M+H] + The calculated value is 650.2 and the measured value is 650.0.

[0198] Example 11: N-(2,2'-dichloro-3'-(5-((3-hydroxyazetidin-1-yl)methyl)-6-methoxypyrazin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0199]

[0200] The compound was prepared using a procedure similar to step d in Example 1 starting from N-(2,2'-dichloro-3'-(5-formyl-6-methoxypyrazin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide and azetidin-3-ol. The crude product was purified by preparative HPLC to give N-(2,2'-dichloro-3'-(5-((3-hydroxyazetidin-1-yl)methyl)-6-methoxypyrazin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 1 H NMR (400MHz, CD3OD) δ11.71(s,1H),8.67(s,1H),8.56–8.50(m,2H),7.70(d,J=7.5Hz,1H),7.56(dd,J=7.7,7.7Hz,1H),7.47–7.40( m,2H),7.11(dd,J=7.6,1.4Hz,1H),4.81–4.63(m,3H),4.42–4.27(m,2H),4.12(m,5H),4.06–4.03(m,1H),3.56(s,3H),3.35(m,3H). MS:(ES)m / z C 28 H 27 Cl2N6O5[M+H] + The calculated value is 597.1 and the measured value is 597.0.

[0201] Example 12: N-(2,2'-dichloro-3'-(5-((3-hydroxyazetidin-1-yl)methyl)-6-methoxypyridin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0202]

[0203] The compound was prepared using a procedure similar to step d in Example 1 starting from N-(2,2'-dichloro-3'-(5-formyl-6-methoxypyridin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide and azetidin-3-ol. The crude product was purified by preparative HPLC to give N-(2,2'-dichloro-3'-(5-((3-hydroxyazetidin-1-yl)methyl)-6-methoxypyridin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide.1 H NMR (400MHz, CD3OD) δ11.67(s,1H),8.65(s,1H),8.53(d,J=7.9Hz,1H),7.93–7.86(m,1H),7.66–7.60(m,1H),7.47(d,J=7.4H z,1H),7.42–7.36(m,3H),7.09(d,J=7.1Hz,1H),4.76(s,1H),4.62–4.41(m,4H),4.09–4.02(m,5H),3.54(s,3H),3.37(s,3H). MS:(ES)m / z C 29 H 28 Cl2N5O5[M+H] + The calculated value is 596.1 and the measured value is 596.2.

[0204] Example 13: N-(2,2'-dichloro-3'-(5-((((3R,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)methyl)-4-methoxypyrimidin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0205]

[0206] Step a: To a mixture of N-(2,2'-dichloro-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (1.0 g, 1.9 mmol), 2-chloro-4-methoxypyrimidine-5-carbaldehyde (400 mg, 2.3 mmol), and 2M K2CO3 (3 mL, 6 mmol) in p-dioxane (20 mL) was added Pd(PPh3)4 (260 mg, 0.22 mmol). The reaction mixture was degassed for 5 minutes and stirred at 80°C for 2 hours. Dioxane was removed from the reaction mixture under reduced pressure and the residue was taken up in a mixture of chloroform and water. The contents were filtered, and the filtrate was evaporated and dried to give N-(2,2'-dichloro-3'-(5-formyl-4-methoxypyrimidin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. MS: (ES) m / z C 25 H 20 Cl2N2O5[M+H] + The calculated value is 540.0 and the measured value is 540.1.

[0207] Step b: To a stirred suspension of N-(2,2'-dichloro-3'-(5-formyl-4-methylpyrimidin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (39 mg, 0.07 mmol) and (3R,4R)-aminooxa-3-ol hydrochloride (47 mg, 0.3 mmol) in 20% (v / v) methanol in DCM was added Et3N (43 μL, 0.31 mmol). After stirring for 5 minutes, Na(OAc)3BH (78 mg, 0.37 mmol) was added to the reaction mixture. An additional portion of Na(OAc)3BH (82 mg, 0.39 mmol) was added and the contents were stirred for an additional 15 hours. The solvent was removed in vacuo and the residue was dissolved in a mixture of p-dioxane, DMSO, TFA, and water and then filtered. The crude residue was purified by preparative HPLC to give N-(2,2'-dichloro-3'-(5-((((3R,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)methyl))-4-methoxypyrimidin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 1 H NMR (400MHz, CD3OD) δ11.69(s,1H),8.70(s,1H),8.66(s,1H),8.54(d,J=8.4Hz,1H ),7.78(d,J=8.0Hz,1H),7.55(dd,J=7.6,7.6Hz,1H),7.48–7.38(m,2H),7.10(d,J =7.6Hz,1H),4.41–3.23(m,2H),4.17(s,3H),4.08–3.96(m,3H),3.62–3.52(m,5H) ,3.52–3.43(m,1H),3.38(s,3H),2.18–2.05(m,1H),1.87(d,J=7.6Hz,12.4Hz,1H). MS:(ES)m / zC 30 H 31 Cl2N6O6[M+H] + The calculated value is 641.2 and the measured value is 641.0.

[0208] Example 14: (S)-N-(2,2'-dichloro-3'-(6-methoxy-5-((((5-oxopyrrolidin-2-yl)methyl)amino)methyl)pyridin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0209]

[0210] The compound was prepared using a procedure similar to step d in Example 1 starting from N-(2,2'-dichloro-3'-(5-formyl-6-methoxypyridin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide and (S)-5-(aminomethyl)pyrrolidin-2-one hydrochloride. The crude product was purified by preparative HPLC to give (S)-N-(2,2'-dichloro-3'-(6-methoxy-5-((((5-oxopyrrolidin-2-yl)methyl)amino)methyl)pyridin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 1 HNMR(400MHz,CD3OD)δ11.69(s,1H),8.66(s,1H),8.54(d,J=8.3Hz,1H),7.93–7.85(m,1H) ,7.65(dd,J=7.8,1.8Hz,1H),7.51(dd,J=7.7,7.7Hz,1H),7.45–7.35(m,3H),7.10(d,J=7. 6Hz,1H),4.34(s,2H),4.14–4.01(m,4H),3.56(d,J=1.6Hz,3H),3.39(d,J=1.8Hz,3H),3.3 0–3.20(m,3H),2.40(dd,J=11.8,11.1Hz,2H),2.03(d,J=1.7Hz,1H),1.92(d,J=6.9Hz,1H). MS:(ES)m / z C 31 H 31 Cl2N6O5[M+H] + The calculated value is 637.2 and the measured value is 637.2.

[0211] Example 15: N-(2,2'-dichloro-3'-(5-((((3R,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)methyl)-6-methoxypyridin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0212]

[0213] This compound was prepared starting from N-(2,2'-dichloro-3'-(5-formyl-6-methoxypyridin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide and (3R,4R)-4-aminotetrahydro-2H-pyran-3-ol hydrochloride using a procedure similar to step d in Example 1. The crude product was purified by preparative HPLC to give N-(2,2'-dichloro-3'-(5-((((3R,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)methyl)-6-methoxypyridin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 1 H NMR (400MHz, CD3OD) δ11.69(s,1H),8.67(s,1H),8.53(d,J=8.3Hz,1H),7.88(d,J=7.7 Hz,1H),7.69–7.62(m,1H),7.51(dd,J=7.7,7.7Hz,1H),7.45–7.33(m,3H),7.13–7.06 (m,1H),4.35(d,J=13.2Hz,1H),4.24(d,J=13.2Hz,1H),4.12–3.93(m,6H),3.62–3.42 (m,6H),3.39(s,3H),2.18–2.07(m,1H),2.03(d,J=1.6Hz,2H),1.87(d,J=12.7Hz,1H). MS:(ES)m / z C 31 H 32 Cl2N5O6[M+H] + The calculated value is 640.2 and the measured value is 640.5.

[0214] Example 16: (S)-N-(2,2'-dichloro-3'-(6-methoxy-5-((((5-oxopyrrolidin-2-yl)methyl)amino)methyl)pyridin-2-yl)-[1,1'-biphenyl]-3-yl)-2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide

[0215]

[0216] Step a: To a mixture of 2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid (200 mg, 1.1 mmol), 2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (350 mg, 1.4 mmol) and N,N-diisopropylethylamine (0.35 mL, 2.0 mmol) in DMF (3 mL) was added (1-[bis(dimethylamino)methylene]-1H -1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (600 mg, 1.6 mmol). The mixture was heated at 60°C for 1.5 hours, cooled to room temperature, and then added to water. The resulting precipitate was collected by filtration and dried under vacuum to obtain N-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide. 1 H NMR (400MHz, DMSO-d6) δ11.34(s,1H),8.47(d,J=8.0Hz,1H),7.44–7.38(m,2H),3.68(s,3H),3.25(s,3H),1.32(s,12H).

[0217] Step b: To a mixture of N-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide (100 mg, 0.24 mmol), 6-(3-bromo-2-chlorophenyl)-2-methoxynicotinaldehyde (70 mg, 0.21 mmol), and 2M KCO (1 mL, 2 mmol) in dioxane (4 mL) was added Pd(dppf)Cl complex with DCM (39 mg, 0.05 mmol). The reaction mixture was degassed and stirred at 90° C. under N for 1 hour. The contents were diluted with EtOAc and water, the organic phase was collected, and the solvent was removed under reduced pressure. The resulting residue was purified by flash chromatography on silica gel to give N-(2,2'-dichloro-3'-(5-formyl-6-methoxypyridin-2-yl)-[1,1'-biphenyl]-3-yl)-2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide. MS: (ES) m / zC 25 H 20 Cl2N5O5[M+H] + The calculated value is 640.1 and the measured value is 639.7.

[0218] Step c: To a mixture of N-(2,2'-dichloro-3'-(5-formyl-6-methoxypyridin-2-yl)-[1,1'-biphenyl]-3-yl)-2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide (94 mg, 0.17 mmol) and (S)-5-aminomethylpyrrolidin-2-one hydrochloride (51 mg, 0.34 mmol) in 20% (v / v) methanol in DCM was added Et3N (47 μL, 0.34 mmol). The mixture was stirred at room temperature for 10 minutes, and Na(OAc)3BH (116 mg, 0.55 mmol) was added. After stirring for 25 minutes, the solvent was removed in vacuo, and the residue was dissolved in dioxane, MeCN, water, and TFA, then filtered. The crude material was purified by preparative HPLC to give (S)-N-(2,2'-dichloro-3'-(6-methoxy-5-((((5-oxopyrrolidin-2-yl)methyl)amino))methyl)pyridin-2-yl)-[1,1'-biphenyl]-3-yl)-2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide. 1 H NMR (400MHz, CD3OD) δ11.68(s,1H),8.58(d,J=8.4Hz,1H),7.89(d,J=7.6Hz,1H),7 .66(d,J=7.6Hz,1H),7.52(dd,J=8.0,8.0Hz,1H),7.46(dd,J=8.0,8.0Hz,1H),7.42 –7.36(m,2H),7.17(d,J=8.0Hz,1H),4.34(s,2H),4.11(s,3H),4.09–4.02(m,1H), 3.79(s,3H),3.39(s,3H),3.28–3.22(m,2H),2.48–2.34(m,3H),1.97–1.87(m,1H). MS:(ES)m / z C 30 H 30 Cl2N7O5[M+H] + The calculated value is 638.2 and the measured value is 638.5.

[0219] Example 17: (S)-N-(2-chloro-2'-fluoro-3'-(6-methoxy-5-((((5-oxopyrrolidin-2-yl)methyl)amino)methyl)pyridin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0220]

[0221] This compound was prepared starting from N-(2-chloro-2'-fluoro-3'-(5-formyl-6-methoxypyridin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide and (S)-5-aminomethylpyrrolidin-2-one hydrochloride using a procedure similar to step d in Example 1. The crude product was purified by preparative HPLC to give (S)-N-(2-chloro-2'-fluoro-3'-(6-methoxy-5-((((5-oxopyrrolidin-2-yl)methyl)amino)methyl)pyridin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 1 H NMR (400MHz, CD3OD) δ11.71 (s, 1H), 8.67 (s, 1H), 8.56 (d, J = 8.4Hz, 1H), 8.22 –8.14(m,1H),7.87(d,J=7.6Hz,1H),7.57(d,J=7.6Hz,1H),7.46–7.39(m,3H ),7.18(d,J=7.6Hz,1H),4.34(s,2H),4.17(s,3H),4.09–4.00(m,1H),3.56( s,3H),3.39(s,3H),3.28–3.20(m,2H),2.52–2.28(m,3H),1.99–1.90(m,1H). MS:(ES)m / z C 31 H 31 ClFN6O5[M+H] + The calculated value is 621.2 and the measured value is 621.5.

[0222] Example 18: (S)-N-(2,2'-dichloro-3'-(6-methoxy-5-((((5-oxopyrrolidin-2-yl)methyl)amino)methyl)pyridin-2-yl)-[1,1'-biphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide

[0223]

[0224] This compound was prepared starting from N-(2,2'-dichloro-3'-(5-formyl-6-methoxypyridin-2-yl)-[1,1'-biphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide and (S)-5-(aminomethyl)pyrrolidin-2-one hydrochloride using a procedure similar to step d in Example 1. The crude product was purified by preparative HPLC to give (S)-N-(2,2'-dichloro-3'-(6-methoxy-5-((((5-oxopyrrolidin-2-yl)methyl)amino)methyl)pyridin-2-yl)-[1,1'-biphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide. 1 H NMR (400MHz, CD3OD) δ11.94–11.89(m,1H),8.94(d,J=1.1Hz,1H),8.67(s, 1H),8.62–8.55(m,1H),7.92–7.85(m,1H),7.66(dd,J=7.8,1.9Hz,1H),7.5 6–7.35(m,4H),7.13(d,J=7.6Hz,1H),4.34(s,2H),4.13–3.99(m,4H),3.6 5(d,J=1.3Hz,3H),3.29(d,J=19.8Hz,3H),2.49–2.32(m,3H),1.92(m,1H). MS:(ES)m / z C 30 H 29 Cl2N6O4[M+H] + The calculated value is 607.2 and the measured value is 607.1.

[0225] Example 19: N-(2'-chloro-3'-(5-(((2-hydroxyethyl)amino)methyl)-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0226]

[0227] A mixture of N-(2,2'-dichloro-3'-(5-formyl-6-methoxypyridin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (50 mg, 0.096 mmol), 2-aminoethane-1-ol (40 mg, 0.65 mmol) and AcOH (50 mg, 0.83 mmol) in DCM (2 mL) was stirred at room temperature for 1 hour. NaBH(OAc)3 (61 mg, 0.29 mmol) was added to the mixture. After 2 hours, the reaction was quenched with saturated NaHCO3 aqueous solution and extracted with DCM. The organic layer was separated, concentrated in vacuo and purified by preparative HPLC to give N-(2'-chloro-3'-(5-(((2-hydroxy-2-methylpropyl)amino)methyl)-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 1 H NMR (400MHz, CD3OD) δ11.16(s,1H),8.62(s,1H),8.10(dd,J=6.8,6.8Hz,1H),7.87( d,J=7.6Hz,1H),7.61(dd,J=7.6,1.6Hz,1H),7.49(dd,J=7.6,7.6Hz,1H),7.36–7.3 3(m,2H),7.29(dd,J=7.8,7.8Hz,1H),6.99(d,J=7.2Hz,1H),4.31(s,2H),4.09(s,3 H), 3.86 (m, 2H), 3.54 (s, 3H), 3.37 (s, 3H), 3.20 (d, J = 4.8, 4.8Hz, 2H), 2.13 (s, 3H). MS:(ES)m / z C 29 H 31 ClN5O5[M+H] + The calculated value is 564.2 and the measured value is 564.5.

[0228] Example 20: N-(2'-chloro-3'-(5-(((2-hydroxy-2-methylpropyl)amino)methyl)-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0229]

[0230] A mixture of N-(2,2'-dichloro-3'-(5-formyl-6-methoxypyridin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (50 mg, 0.096 mmol), 1-amino-2-methylpropan-2-ol (50 mg, 0.56 mmol) and AcOH (50 mg, 0.83 mmol) in DCM (2 mL) was stirred at room temperature for 1 hour. NaBH(OAc)3 (70 mg, 0.33 mmol) was added to the mixture. After 1 hour, the reaction was quenched with saturated aqueous NaHCO3 and extracted with DCM. The organic layer was separated, concentrated in vacuo and purified by preparative HPLC to give N-(2'-chloro-3'-(5-(((2-hydroxy-2-methylpropyl)amino)methyl)-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 1 H NMR (400MHz, CD3OD) δ11.16 (s, 1H), 8.61 (s, 1H), 8.12 (dd, J = 6.8, 6.8Hz, 1H), 7. 87(d,J=7.6Hz,1H),7.62(dd,J=8.0,1.6Hz,1H),7.49(dd,J=7.6,7.6Hz,1H),7. 37–7.33(m,2H),7.30(dd,J=7.8,7.8Hz,2H),6.99(d,J=7.6Hz,1H),4.33(s,2H) ,4.09(s,3H),3.53(s,3H),3.36(s,3H),3.02(s,2H),2.13(s,3H),1.30(s,6H). MS:(ES)m / z C 31 H 35 ClN5O5[M+H] + The calculated value is 592.2 and the measured value is 592.5.

[0231] Example 21: 1-((6-(2-chloro-3'-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide)-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)-3-methylazetidine-3-carboxylic acid

[0232]

[0233] A mixture of N-(2'-chloro-3'-(5-formyl-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (50 mg, 0.096 mmol), 3-methylazetidine-3-carboxylic acid (30 mg, 0.26 mmol) and AcOH (30 mg, 0.50 mmol) in DMF (2 mL) was stirred at room temperature for 1.5 hours. NaBH(OAc)3 (70 mg, 0.33 mmol) was added to the mixture. After stirring at 0°C for 30 minutes, the reaction was quenched with 2 drops of water. The crude material was purified by preparative HPLC to give 1-((6-(2-chloro-3'-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamido)-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)-3-methylazetidine-3-carboxylic acid. 1 H NMR (400MHz, CD3OD) δ11.16(s,1H),8.60(s,1H),8.12(dd,J=7.0,7.0Hz,1H),7.87(d,J =7.6Hz,1H),7.61(dd,J=8.0,1.6Hz,1H),7.48(dd,J=7.6,7.6Hz,1H),7.37–7.32(m,2H ),7.30(dd,J=7.8,7.8Hz,1H),6.99(d,J=7.6Hz,1H),4.56–4.50(m,2H),4.50(s,2H),4 .13(d,J=10.4Hz,2H),4.07(s,3H),3.53(s,3H),3.36(s,3H),3.12(s,3H),1.61(s,3H). MS:(ES)m / z C 32 H 33 ClN5O6[M+H] + The calculated value is 618.2 and the measured value is 618.6.

[0234] Example 22: N-(2'-chloro-3'-(5-(((2-hydroxyethyl)(methyl)amino)methyl)-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0235]

[0236] A mixture of N-(2'-chloro-3'-(5-formyl-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (50 mg, 0.096 mmol), 2-(methylamino)ethan-1-ol (40 mg, 0.53 mmol) and AcOH (30 mg, 0.50 mmol) in DCM (2 mL) and EtOH (1 mL) was heated at 60 ° C for 0.5 h. The mixture was cooled to 0 ° C and NaBH3CN (25 mg, 0.40 mmol) was added. After stirring at 0 ° C for 30 minutes, the reaction was quenched with 1 drop of water. The crude material was purified by preparative HPLC to give N-(2'-chloro-3'-(5-(((2-hydroxyethyl)(methyl)amino)methyl)-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 1 H NMR (400MHz, CD3OD) δ11.14(s,1H),8.58(s,1H),8.13(dd,J=7.0,7.0Hz,1H),7.92(d,J=7.6Hz,1H),7. 63(dd,J=7.6,2.0Hz,1H),7.49(dd,J=7.6,7.6Hz,1H),7.38(d,J=7.6Hz,1H),7.34(dd,J=7.2,1.6Hz,1 H),7.27(dd,J=7.8,7.8Hz,1H),6.98(d,J=6.8Hz,1H),4.60(d,J=13.2Hz,1H),4.31(d,J=13.2Hz,1H), 4.08(s,3H),3.97–3.90(m,2H),3.51(s,3H),3.42–3.34(m,2H),3.33(s,3H),2.91(s,3H),2.12(s,3H). MS:(ES)m / z C 30 H 33 ClN5O5[M+H] + The calculated value is 578.2 and the measured value is 578.5.

[0237] Example 23: N-(2'-chloro-3'-(5-(((3-hydroxy-2,2-dimethylpropyl)amino)methyl)-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0238]

[0239] The compound was prepared using a procedure similar to that of Example 1 starting from N-(2'-chloro-3'-(5-formyl-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide and 3-amino-2,2-dimethylpropan-1-ol. The crude product was purified by preparative HPLC to give N-(2'-chloro-3'-(5-(((3-hydroxy-2,2-dimethylpropyl)amino)methyl)-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 1 H NMR (400MHz, CDCl3) δ10.89(s,1H),8.53(s,1H),8.22(d,J=7.4Hz,1H),7.63(dd,J=7.6,1.8Hz,1H),7.56(d,J=7.4Hz,1H),7.40(dd,J=7.6,7.6Hz,1H), 7.35–7.22(m,3H),7.03(dd,J=7.6,1.2Hz,1H),4.02(s,3H),3.80(s,2H),3. 58(s,3H),3.52(s,2H),3.44(s,3H),2.65(s,2H),2.19(s,3H),0.94(s,6H). MS:(ES)m / z C 32 H 37 ClN5O5[M+H] + The calculated value is 606.2 and the measured value is 606.6.

[0240] Example 24: (R)-N-(2'-chloro-3'-(5-((3-hydroxy-3-methylpyrrolidin-1-yl)methyl)-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0241]

[0242] The compound was prepared using a procedure similar to step d in Example 1, starting from N-(2'-chloro-3'-(5-formyl-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide and (3R)-3-methylpyrrolidin-3-ol hydrochloride. The crude product was purified by silica gel flash chromatography to give (R)-N-(2'-chloro-3'-(5-((3-hydroxy-3-methylpyrrolidin-1-yl)methyl)-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 1 HNMR(400MHz,CD3OD)δ8.62(s,1H),8.12(d,J=8.0Hz,1H),7.79(d,J=7.2Hz,1H) ,7.66(dd,J=8.0,2.0Hz,1H),7.46(dd,J=7.6,7.6Hz,1H),7.33–7.24(m,3H),7.0 0(d,J=8.0Hz,1H),4.01(s,3H),3.89–3.80(m,2H),3.54(s,3H),3.38(s,3H),3. 09–3.00(m,1H),2.88–2.69(m,3H),2.14(s,3H),1.96–1.89(m,2H),1.37(s,3H). MS:(ES)m / z C 32 H 35 ClN5O5[M+H] + The calculated value is 604.2 and the measured value is 604.5.

[0243] Example 25: N-(2'-chloro-3'-(5-((4-hydroxypiperidin-1-yl)methyl)-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0244]

[0245] The compound was prepared using a procedure similar to step d in Example 1 starting from N-(2'-chloro-3'-(5-formyl-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide and piperidin-4-ol hydrochloride. The crude product was purified by preparative HPLC to give N-(2'-chloro-3'-(5-((4-hydroxypiperidin-1-yl)methyl)-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 1 H NMR(400MHz,DMSO-d6)δ11.08(s,1H),8.77(s,1H),8.27–8.25(m,1H),7.74(d,J =7.5Hz,1H),7.65(dd,J=7.6,1.7Hz,1H),7.52(dd,J=7.6,7.6Hz,1H),7.37–7.28 (m,3H),7.00–6.98(m,1H),4.57(s,1H),3.90(s,3H),3.50–3.45(m,6H),3.27(s, 3H),2.73–2.69(m,2H),2.14–2.09(m,5H),1.74–1.70(m,2H),1.47–1.37(m,2H). MS:(ES)m / z C 32 H 35 ClN5O5[M+H] + The calculated value is 604.2 and the measured value is 604.5.

[0246] Example 26: (R)-N-(2'-chloro-3'-(5-(((2,3-dihydroxypropyl)amino)methyl)-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0247]

[0248] The compound was prepared using a procedure similar to step d in Example 1 starting from N-(2'-chloro-3'-(5-formyl-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide and (R)-3-amino-1,2-propanediol. The crude product was purified by silica gel flash chromatography to afford (R)-N-(2'-chloro-3'-(5-(((2,3-dihydroxypropyl)amino)methyl)-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 1 H NMR (400MHz, CD3OD) δ8.62(s,1H),8.11(d,J=8.0Hz,1H),7.73(d,J=7.2Hz,1H),7 .60(dd,J=7.2,1.6Hz,1H),7.46(dd,J=8.0,8.0Hz,1H),7.33–7.22(m,3H),7.00(d ,J=8.0Hz,1H),4.03(s,3H),3.96–3.83(m,2H),3.83–3.76(m,1H),3.55(s,3H),3 .54–3.50(m,2H),3.38(s,3H),2.86–2.79(m,1H),2.72–2.65(m,1H),2.14(s,3H). MS:(ES)m / z C 30 H 33 ClN5O6[M+H] + The calculated value is 594.2 and the measured value is 594.3.

[0249] Example 27: N-(2'-chloro-3'-(5-((((3S,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)methyl)-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0250]

[0251] The compound was prepared using a procedure similar to step d in Example 1 starting from N-(2'-chloro-3'-(5-formyl-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide and (3S,4S)-4-aminotetrahydro-2H-pyran-3-ol hydrochloride. The crude product was purified by preparative HPLC to give N-(2'-chloro-3'-(5-((((3S,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)methyl)-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 1 H NMR (400MHz, CD3OD) δ11.07(s,1H),8.77(s,1H),8.27–8.25(m,1H),7.85(d,J=7.5Hz,1H ),7.63(dd,J=7.7,1.8Hz,1H),7.52(dd,J=7.6,7.6Hz,1H),7.37–7.27(m,3H),6.99(dd, J=7.7,1.4Hz,1H),4.66(s,1H),3.92(s,3H),3.79–3.61(m,5H),3.55(s,3H),3.49(s,3H) ), 3.25 (s, 3H), 2.73 (d, J = 9.0Hz, 1H), 2.09 (s, 3H), 1.73–1.65 (m, 1H), 1.58–1.50 (m, 1H). MS:(ES)m / zC 32 H 34 ClN5O6[M+H] + The calculated value is 620.2 and the measured value is 620.2.

[0252] Example 28: N-(3'-(5-(((3-amino-2,2-dimethyl-3-oxopropyl)amino)methyl)-6-methoxypyridin-2-yl)-2'-chloro-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0253]

[0254] The compound was prepared using a procedure similar to step d in Example 1 starting from N-(2'-chloro-3'-(5-formyl-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide and 3-amino-2,2-dimethylpropionamide. The crude product was purified by preparative HPLC to give N-(3'-(5-(((3-amino-2,2-dimethyl-3-oxopropyl)amino)methyl)-6-methoxypyridin-2-yl)-2'-chloro-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 1 HNMR(400MHz,CD3OD)δ8.63(s,1H),8.13–8.10(m,1H),7.86(d,J=7.5Hz,1H),7.63(dd,J=7.7,1.7Hz,1H),7.50(dd,J=7.6,7.6Hz,1H ),7.36–7.28(m,3H),7.02–7.00(m,1H),4.28(s,2H),4.12(s,3H),3.55(s,3H),3.39(s,3H),3.14(s,2H),2.14(s,3H),1.35(s,6H). MS:(ES)m / z C 32 H 36 ClN6O5[M+H] + The calculated value is 619.2 and the measured value is 619.5.

[0255] Example 29: N-(2,2'-dichloro-3'-(5-(((2-hydroxyethyl)amino)methyl)-6-methoxypyridin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0256]

[0257] A mixture of N-(2,2'-dichloro-3'-(5-formyl-6-methoxypyridin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (42 mg, 0.078 mmol), 2-aminoethane-1-ol (15 mg, 0.25 mmol) and AcOH (32 mg, 0.53 mmol) in DCM (1.5 mL) and EtOH (0.75 mL) was heated at 60 ° C for 0.5 h. The mixture was cooled to 0 ° C and NaBH3CN (25 mg, 0.40 mmol) was added. After stirring at 0 ° C for 15 minutes, the reaction was quenched with 1 drop of water. The crude material was purified by preparative HPLC to give N-(2,2'-dichloro-3'-(5-(((2-hydroxyethyl)amino)methyl)-6-methoxypyridin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 1 H NMR (400MHz, CD3OD) δ11.66(s,1H),8.63(s,1H),8.60–8.50(m,1H),7.87(d,J=8.0Hz,1H),7.65(dd,J=7.6,1.6Hz,1H),7.50(dd,J=7.6,7.6Hz,1H) ,7.42–7.33(m,3H),7.09(dd,J=7.6,1.6Hz,1H),4.31(s,2H),4.09(s,3H ), 3.85 (t, J = 5.2Hz, 2H), 3.53 (s, 3H), 3.36 (s, 3H), 3.20 (t, J = 5.2Hz, 2H). MS:(ES)m / z C 28 H 28 Cl2N5O5[M+H] + The calculated value is 584.1 and the measured value is 584.4.

[0258] Example 30: N-(2'-chloro-3'-(5-((3-hydroxy-3-methylazetidin-1-yl)methyl)-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0259]

[0260] The compound was prepared using a procedure similar to step d in Example 1 starting from N-(2'-chloro-3'-(5-formyl-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide and 3-methylazetidin-3-ol hydrochloride. The crude product was purified by preparative HPLC to give N-(2'-chloro-3'-(5-((3-hydroxy-3-methylazetidin-1-yl)methyl)-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 1 H NMR (400MHz, CDCl3) δ10.89(s,1H),8.53(s,1H),8.25–8.18(m,1H),7.62(dd,J=7.7,1.9Hz,2H),7.43–7.21(m,4H),7.0 3(d,J=7.7Hz,1H),4.00(s,3H),3.70(s,2H),3.58(s,3H),3.44(m,5H),3.19(d,J=7.8Hz,2H),2.18(s,3H),1.54(s,3H). MS:(ES)m / z C 31 H 33 ClN5O5[M+H] + The calculated value is 590.2 and the measured value is 590.5.

[0261] Example 31: N-(2'-chloro-3'-(5-((isopropylamino)methyl)-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0262]

[0263] The compound was prepared using a procedure similar to step d in Example 1 starting from N-(2'-chloro-3'-(5-formyl-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide and isopropylamine hydrochloride. The crude product was purified by preparative HPLC to give N-(2'-chloro-3'-(5-((isopropylamino)methyl)-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 1H NMR (400MHz, CD3OD) δ8.64(s,1H),8.13–8.11(m,1H),7.85(d,J=7.5Hz,1H),7.61(dd,J=7.7,1.7Hz,1H),7.49(dd,J=7.6,7.6Hz,1H),7.36–7.28 (m,3H),7.01(dd,J=7.6,1.2Hz,1H),4.16(s,2H),4.08(s,3H),3.56(s, 3H), 3.39 (s, 3H), 3.38–3.33 (m, 1H), 2.14 (s, 3H), 1.37 (d, J = 6.5Hz, 6H). MS:(ES)m / zC 30 H 33 ClN5O4[M+H] + The calculated value is 562.2 and the measured value is 562.5.

[0264] Example 32: N-(2,2'-dichloro-3'-(5-(((3-hydroxypropyl)amino)methyl)-6-methoxypyridin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0265]

[0266] A mixture of N-(2,2'-dichloro-3'-(5-formyl-6-methoxypyridin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (42 mg, 0.078 mmol), 1-(aminomethyl)cyclopropan-1-ol (40 mg, 0.46 mmol), and AcOH (32 mg, 0.53 mmol) in DCM (1.5 mL) and EtOH (0.5 mL) was heated at 60 ° C for 0.5 h. The contents were cooled to 0 ° C and NaBH3CN (25 mg, 0.40 mmol) was added. After stirring at 0 ° C for 5 minutes, the reaction was quenched with 1 drop of water. The crude material was purified by preparative HPLC to give N-(2,2'-dichloro-3'-(5-(((3-hydroxypropyl)amino)methyl)-6-methoxypyridin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 1H NMR(400MHz,CD3OD)δ11.66(s,1H),8.63(s,1H),8.55–8.50(m,1H),7.86(d, J=7.6Hz,1H),7.65(dd,J=7.6,2.0Hz,1H),7.50(dd,J=7.6,7.6Hz,1H),7.42 –7.33(m,3H),7.08(dd,J=8.0,1.6Hz,1H),4.27(s,2H),4.08(s,3H),3.74(t ,J=5.8Hz,2H),3.52(s,3H),3.35(s,3H),3.26(t,J=6.8Hz,2H),1.95(m,2H). MS:(ES)m / zC 29 H 30 Cl2N5O5[M+H] + The calculated value is 598.2 and the measured value is 598.2.

[0267] Example 33: N-(2,2'-dichloro-3'-(5-((((1-hydroxycyclopropyl)methyl)amino)methyl)-6-methoxypyridin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0268]

[0269] A mixture of N-(2,2'-dichloro-3'-(5-formyl-6-methoxypyridin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (42 mg, 0.078 mmol), 1-(aminomethyl)cyclopropan-1-ol (40 mg, 0.46 mmol), and AcOH (32 mg, 0.53 mmol) in DCM (1.5 mL) and EtOH (0.5 mL) was heated at 60 ° C for 0.5 h. The contents were cooled to 0 ° C and NaBH3CN (25 mg, 0.40 mmol) was added. After stirring at 0 ° C for 5 minutes, the reaction was quenched with 1 drop of water. The crude material was purified by preparative HPLC to give N-(2,2'-dichloro-3'-(5-((((1-hydroxycyclopropyl)methyl)amino)methyl)-6-methoxypyridin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 1H NMR(400MHz,CD3OD)δ11.67(s,1H),8.65(s,1H),8.56–8.51(m,1H),7.87(d, J=7.6Hz,1H),7.65(dd,J=7.6,2.0Hz,1H),7.51(dd,J=7.6,7.6Hz,1H),7.43 –7.35(m,3H),7.10(dd,J=7.6,1.6Hz,1H),4.37(s,2H),4.10(s,3H),3.55(s ,3H),3.38(s,3H),3.19(s,2H),0.91(t,J=6.4Hz,2H),0.73(d,J=6.2Hz,2H). MS:(ES)m / z C 30 H 30 Cl2N5O5[M+H] + The calculated value is 610.2 and the measured value is 610.1.

[0270] Example 34: (S)-N-(2,2'-dichloro-3'-(5-(((2-hydroxypropyl)amino)methyl)-6-methoxypyridin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0271]

[0272] A mixture of N-(2,2'-dichloro-3'-(5-formyl-6-methoxypyridin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (45 mg, 0.083 mmol), (S)-1-aminopropan-2-ol (30 mg, 0.40 mmol), and AcOH (27 mg, 0.45 mmol) in DCM (1.5 mL) and EtOH (0.5 mL) was heated at 60°C for 0.5 h. The contents were cooled to 0°C and NaBH3CN (20 mg, 0.32 mmol) was added. After stirring at 0°C for 5 minutes, the reaction was quenched with 1 drop of water. The crude material was purified by preparative HPLC to give (S)-N-(2,2'-dichloro-3'-(5-(((2-hydroxypropyl)amino)methyl)-6-methoxypyridin-2-yl))-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 1H NMR (400MHz, CD3OD) δ11.68(s,1H),8.65(s,1H),8.53(dd,J=8.8,1.8Hz,1H),7.87(d,J =7.6Hz,1H),7.65(dd,J=7.6,1.6Hz,1H),7.51(dd,J=7.6,7.6Hz,1H),7.43–7.34(m,3H ),7.10(dd,J=7.2,1.6Hz,1H),4.30(s,2H),4.09(s,3H),4.12–4.04(m,1H),3.55(s,3H) ),3.38(s,3H),3.13(dd,J=12.8,2.8Hz,1H),2.94–2.87(m,1H),1.24(d,J=6.4Hz,3H). MS:(ES)m / z C 29 H 30 Cl2N5O5[M+H] + The calculated value is 598.2 and the measured value is 598.5.

[0273] Example 35: (R)-N-(2,2'-dichloro-3'-(5-(((2-hydroxypropyl)amino)methyl)-6-methoxypyridin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0274]

[0275] A mixture of N-(2,2'-dichloro-3'-(5-formyl-6-methoxypyridin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (42 mg, 0.078 mmol), (R)-1-aminopropan-2-ol (20 mg, 0.27 mmol), and AcOH (27 mg, 0.45 mmol) in DCM (1.5 mL) and EtOH (0.5 mL) was heated at 60°C for 0.5 h. The contents were cooled to 0°C and NaBH3CN (20 mg, 0.32 mmol) was added. After stirring at 0°C for 5 minutes, the reaction was quenched with 1 drop of water. The crude material was purified by preparative HPLC to give (R)-N-(2,2'-dichloro-3'-(5-(((2-hydroxypropyl)amino)methyl)-6-methoxypyridin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 1H NMR (400MHz, CD3OD) δ11.67(s,1H),8.63(s,1H),8.52(dd,J=8.4,1.6Hz,1H),7.86(d,J =7.6Hz,1H),7.65(dd,J=7.6,2.0Hz,1H),7.50(dd,J=7.6,7.6Hz,1H),7.42–7.34(m,3H ),7.09(dd,J=8.0,1.6Hz,1H),4.30(s,2H),4.09(s,3H),4.12–4.04(m,1H),3.53(s,3H) ), 3.36 (s, 3H), 3.11 (dd, J = 12.4, 3.2Hz, 1H), 2.95–2.87 (m, 1H), 1.24 (d, J = 6.4Hz, 3H). MS:(ES)m / z C 29 H 30 Cl2N5O5[M+H] + The calculated value is 598.2 and the measured value is 598.5.

[0276] Example 36: N-(2'-chloro-3'-(6-methoxy-5-((methylamino)methyl)pyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0277]

[0278] The compound was prepared using a procedure similar to step d in Example 1 starting from N-(2'-chloro-3'-(5-formyl-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide and methylamine hydrochloride. The crude product was purified by preparative HPLC to give N-(2'-chloro-3'-(6-methoxy-5-((methylamino)methyl)pyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 1H NMR (400MHz, DMSO-d6) δ11.08(s,1H),8.77(s,1H),8.27–8.25(m,1H),7.79(d,J=7.5Hz,1H),7.64(dd,J=7.7,1.7Hz,1H),7.52(dd,J=7.6,7.6Hz ,1H),7.37–7.28(m,3H),6.99(dd,J=7.6,1.2Hz,1H),3.92(s,3H),3.71( s,2H),3.50(s,3H),3.27(s,3H),3.20(s,1H),2.36(s,3H),2.09(s,3H). MS:(ES)m / zC 28 H 29 ClN5O4[M+H] + The calculated value is 534.2 and the measured value is 534.1.

[0279] Example 37: (R)-N-(2,2'-dichloro-3'-(5-(((2,3-dihydroxypropyl)amino)methyl)-6-methoxypyridin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0280]

[0281] The compound was prepared using a procedure similar to step d in Example 1 starting from N-(2'-chloro-3'-(5-formyl-6-methoxypyridin-2-yl)-2-chloro-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide and (R)-3-amino-1,2-propanediol. The crude product was purified by preparative HPLC to give (R)-N-(2,2'-dichloro-3'-(5-(((2,3-dihydroxypropyl)amino)methyl)-6-methoxypyridin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 1H NMR (400MHz, CD3OD) δ11.69(s,1H),8.66(s,1H),8.53(dd,J=8.4,1.6Hz,1H),7.87( d,J=7.6Hz,1H),7.66(dd,J=7.6,1.6Hz,1H),7.51(dd,J=8.0,8.0Hz,1H),7.43–7.3 4(m,3H),7.10(dd,J=7.6,1.6Hz,1H),4.32(s,2H),4.09(s,3H),3.99–3.92(m,1H), 3.67–3.56(m,2H),3.55(s,3H),3.38(s,3H),3.29–3.22(m,1H),3.15–3.07(m,1H). MS:(ES)m / z C 29 H 30 Cl2N5O6[M+H] + The calculated value is 614.2 and the measured value is 614.5.

[0282] Example 38: (S)-N-(2'-chloro-3'-(5-(((2-hydroxypropyl)amino)methyl)-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0283]

[0284] A mixture of N-(2'-chloro-3'-(5-formyl-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (45 mg, 0.086 mmol), (S)-1-aminopropan-2-ol (20 mg, 0.27 mmol), and HOAc (27 mg, 0.45 mmol) in DCM (1.5 mL) and EtOH (0.5 mL) was heated at 60°C for 0.5 h. The contents were cooled to 0°C and NaBHCN (20 mg, 0.32 mmol) was added. After stirring at 0°C for 10 minutes, the reaction was quenched with 1 drop of water. The crude material was purified by preparative HPLC to give (S)-N-(2'-chloro-3'-(5-(((2-hydroxypropyl)amino)methyl)-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 1H NMR (400MHz, CD3OD) δ11.16(s,1H),8.61(s,1H),8.11(dd,J=6.8,6.8Hz,1H),7.86(d,J=7.6Hz,1 H),7.61(dd,J=7.6,2.0Hz,1H),7.49(dd,J=7.6,7.6Hz,1H),7.34(dd,J=7.2,1.6Hz,2H),7.28(t ,J=8.0Hz,1H),7.00(d,J=7.2Hz,1H),4.30(s,2H),4.08(s,3H),4.12–4.04(m,1H),3.54(s,3H), 3.37(s,3H),3.13(dd,J=13.2,3.2Hz,1H),2.94–2.87(m,1H),2.13(s,3H),1.24(d,J=6.4Hz,3H). MS:(ES)m / zC 30 H 33 ClN5O5[M+H] + The calculated value is 578.2 and the measured value is 578.5.

[0285] Example 39: (R)-N-(2'-chloro-3'-(5-(((2-hydroxypropyl)amino)methyl)-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0286]

[0287] A mixture of N-(2'-chloro-3'-(5-formyl-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (45 mg, 0.086 mmol), (R)-1-aminopropan-2-ol (20 mg, 0.27 mmol), and AcOH (27 mg, 0.45 mmol) in DCM (1.5 mL) and EtOH (0.5 mL) was heated at 60°C for 0.5 h. The contents were cooled to 0°C and NaBH3CN (20 mg, 0.32 mmol) was added. After stirring at 0°C for 10 minutes, the reaction was quenched with 1 drop of water. The crude material was purified by preparative HPLC to give (R)-N-(2'-chloro-3'-(5-(((2-hydroxypropyl)amino)methyl)-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 1H NMR (400MHz, CD3OD) δ11.16(s,1H),8.61(s,1H),8.11(dd,J=6.8,6.8Hz,1H),7.86(d,J=7.6Hz,1H ),7.61(dd,J=8.0,2.0Hz,1H),7.49(dd,J=7.6,7.6Hz,1H),7.34(dd,J=7.2,1.6Hz,2H),7.29(dd,J =7.8,7.8Hz,1H),7.00(d,J=7.2Hz,1H),4.30(s,2H),4.08(s,3H),4.12–4.04(m,1H),3.53(s,3H) ,3.37(s,3H),3.13(dd,J=12.4,3.2Hz,1H),2.94–2.87(m,1H),2.15(s,3H),1.24(d,J=6.4Hz,3H). MS:(ES)m / z C 30 H 33 ClN5O5[M+H] + The calculated value is 578.2 and the measured value is 578.5.

[0288] Example 40: (R)-N-(2,2'-dichloro-3'-(5-((3-hydroxy-3-methylpyrrolidin-1-yl)methyl)-6-methoxypyridin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0289]

[0290] The compound was prepared using a procedure similar to step d in Example 1, starting from N-(2'-chloro-3'-(5-formyl-6-methoxypyridin-2-yl)-2-chloro-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide and (3R)-3-methylpyrrolidin-3-ol hydrochloride. The crude product was purified by silica gel flash chromatography to give (R)-N-(2,2'-dichloro-3'-(5-((3-hydroxy-3-methylpyrrolidin-1-yl)methyl)-6)-methoxypyridin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 1H NMR (400MHz, CD3OD) δ8.66(s,1H),8.54(dd,J=8.4,1.5Hz,1H),7.89(d,J=7.6Hz,1 H),7.66(dd,J=7.6,1.6Hz,1H),7.51(dd,J=7.6,7.6Hz,1H),7.44–7.35(m,3H),7.1 0(dd,J=7.6,1.3Hz,1H),4.36(s,2H),4.08(s,3H),3.66–3.53(m,1H),3.55(s,3H), 3.47–3.36(s,1H),3.38(s,3H),3.27–3.11(m,2H),2.14–2.03(m,2H),1.43(s,3H). MS:(ES)m / zC 31 H 32 Cl2N5O5[M+H] + The calculated value is 624.2 and the measured value is 624.5.

[0291] Example 41: N-(2'-chloro-3'-(5-(((3-hydroxy-3-methylbutyl)amino)methyl)-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0292]

[0293] A mixture of N-(2'-chloro-3'-(5-formyl-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (50 mg, 0.096 mmol), 4-amino-2-methylbutan-2-ol (20 mg, 0.19 mmol), and AcOH (22 mg, 0.37 mmol) in DCM (1.5 mL) and EtOH (0.5 mL) was heated at 60°C for 0.5 h. The contents were cooled to 0°C and NaBH3CN (25 mg, 0.40 mmol) was added. After stirring at 0°C for 10 minutes, the reaction was quenched with 1 drop of water. The crude material was purified by preparative HPLC to give N-(2'-chloro-3'-(5-(((3-hydroxy-3-methylbutyl)amino)methyl)-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 1H NMR (400MHz, CD3OD) δ11.18(s,1H),8.63(s,1H),8.11(dd,J=7.4,7.4Hz,1H),7.85(d,J =7.2Hz,1H),7.60(dd,J=7.6,1.6Hz,1H),7.49(dd,J=7.6,7.6Hz,1H),7.36–7.33(m,2H) ,7.29(dd,J=8.2,8.2Hz,1H),7.00(d,J=8.0Hz,1H),4.26(s,2H),4.08(s,3H),3.55(s,3 H), 3.38 (s, 3H), 3.26 (t, J = 6.8Hz, 2H), 2.13 (s, 3H), 1.85 (t, J = 6.8Hz, 2H), 1.27 (s, 6H). MS:(ES)m / z C 32 H 37 ClN5O5[M+H] + The calculated value is 606.2 and the measured value is 606.6.

[0294] Example 42: N-(2'-chloro-3'-(5-((((1-hydroxycyclopropyl)methyl)amino)methyl)-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0295]

[0296] A mixture of N-(2'-chloro-3'-(5-formyl-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (45 mg, 0.086 mmol), 1-(aminomethyl)cyclopropan-1-ol (25 mg, 0.29 mmol), and AcOH (22 mg, 0.37 mmol) in DCM (1.5 mL) and EtOH (0.5 mL) was heated at 60°C for 0.5 h. The contents were cooled to 0°C and NaBHCN (25 mg, 0.40 mmol) was added. After stirring at 0°C for 10 minutes, the reaction was quenched with 1 drop of water. The crude material was purified by preparative HPLC to give N-(2'-chloro-3'-(5-((((1-hydroxycyclopropyl)methyl)amino)methyl)-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 1H NMR (400MHz, CD3OD) δ11.17(s,1H),8.61(s,1H),8.11(dd,J=6.8,6.8Hz,1H),7.87(d,J=8. 0Hz,1H),7.61(dd,J=8.0,1.2Hz,1H),7.49(dd,J=7.6,7.6Hz,1H),7.36–7.33(m,2H),7.29 (dd,J=8.0,8.0Hz,1H),6.99(d,J=7.6Hz,1H),4.37(s,2H),4.09(s,3H),3.54(s,3H),3.38 (s,3H),3.20(s,2H),2.13(s,3H),0.91(dd,J=6.4,6.4Hz,2H),0.73(dd,J=6.2,6.2Hz,2H). MS:(ES)m / z C 31 H 33 ClN5O5[M+H] + The calculated value is 590.2 and the measured value is 590.5.

[0297] Example 43: (S)-N-(2'-chloro-3'-(5-(((1-hydroxypropyl-2-yl)amino)methyl)-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0298]

[0299] A mixture of N-(2'-chloro-3'-(5-formyl-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (45 mg, 0.086 mmol), L-alaninol (30 mg, 0.40 mmol) and AcOH (27 mg, 0.45 mmol) in DCM (1.5 mL) and EtOH (0.5 mL) was heated at 60 ° C for 0.5 h. The contents were cooled to 0 ° C and NaBH3CN (30 mg, 0.48 mmol) was added. After stirring at 0 ° C for 15 minutes, the reaction was quenched with 1 drop of water. The crude material was purified by preparative method to give (S)-N-(2'-chloro-3'-(5-(((1-hydroxypropan-2-yl)amino)methyl)-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 1H NMR (400MHz, CD3OD) δ11.14(s,1H),8.58(s,1H),8.13(dd,J=7.4,7.4Hz,1H),7.88(d,J=7.6Hz,1 H),7.60(dd,J=7.6,1.6Hz,1H),7.48(dd,J=7.6,7.6Hz,1H),7.33(d,J=8.0Hz,2H),7.27(dd,J=7 .8,7.8Hz,1H),6.98(d,J=7.2Hz,1H),4.31(s,2H),4.08(s,3H),3.86(dd,J=12.0,4.0Hz,1H),3. 66–3.60(m,1H),3.51(s,3H),3.44–3.36(m,1H),3.33(s,3H),2.11(s,3H),1.38(d,J=6.8Hz,3H). MS:(ES)m / zC 30 H 33 ClN5O5[M+H] + The calculated value is 578.2 and the measured value is 578.5.

[0300] Example 44: (R)-N-(2'-chloro-3'-(5-(((1-hydroxypropyl-2-yl)amino)methyl)-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0301]

[0302] A mixture of N-(2'-chloro-3'-(5-formyl-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (45 mg, 0.086 mmol), D-alaninol (30 mg, 0.40 mmol), and AcOH (27 mg, 0.45 mmol) in DCM (1.5 mL) and EtOH (0.5 mL) was heated at 60° C. for 0.5 h. The contents were cooled to 0° C. and NaBH3CN (30 mg, 0.48 mmol) was added. After stirring at 0° C. for 15 minutes, the reaction was quenched with 1 drop of water. The crude material was purified by preparative HPLC to give (R)-N-(2'-chloro-3'-(5-(((1-hydroxypropan-2-yl)amino)methyl)-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 1H NMR (400MHz, CD3OD) δ11.13(s,1H),8.56(s,1H),8.12(d,J=6.8Hz,1H),7.87(d,J=7.6Hz,1H), 7.60(dd,J=7.6,1.6Hz,1H),7.47(dd,J=7.6,7.6Hz,1H),7.34–7.31(m,2H),7.26(dd,J=8.0,8 .0Hz,1H),6.97(d,J=6.8Hz,1H),4.30(s,2H),4.08(s,3H),3.86(dd,J=12.0,4.0Hz,1H),3.66 –3.60(m,1H),3.50(s,3H),3.43–3.36(m,1H),3.31(s,3H),2.11(s,3H),1.38(d,J=7.2Hz,3H). MS:(ES)m / zC 30 H 33 ClN5O5[M+H] + The calculated value is 578.2 and the measured value is 578.5.

[0303] Example 45: N-(2-chloro-2'-fluoro-3'-(5-((((3R,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)methyl)-6-methoxypyridin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0304]

[0305] The compound was prepared using a procedure similar to step d in Example 1 starting from N-(2-chloro-2'-fluoro-3'-(5-formyl-6-methoxypyridin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide and (3R,4R)-4-aminooxa-3-ol hydrochloride. The crude product was purified by preparative HPLC to give N-(2-chloro-2'-fluoro-3'-(5-((((3R,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)methyl)-6-methoxypyridin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 1H NMR (400MHz, CD3OD) δ11.70 (s, 1H), 8.66 (s, 1H), 8.55 (dd, J = 8.4, 1.5Hz, 1H), 8.20 –8.14(m,1H),7.86(d,J=7.6Hz,1H),7.55(dd,J=7.6,1.8Hz,1H),7.45–7.38(m,3H ),7.18(dd,J=7.6,1.7Hz,1H),4.37–4.21(m,2H),4.15(s,3H),4.07–3.94(m,3H), 3.59–3.42(m,3H),3.55(s,3H),3.37(s,3H),2.19–2.05(m,1H),1.91–1.83(m,1H). MS:(ES)m / zC 31 H 32 ClFN5O6[M+H] + The calculated value is 624.2 and the measured value is 624.5.

[0306] Example 46: N-(2'-chloro-3'-(5-((((1R,2S)-2-hydroxycyclohexyl)amino)methyl)-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0307]

[0308] The compound was prepared using a procedure similar to step d in Example 1 starting from N-(2'-chloro-3'-(5-formyl-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide and (1S,2R)-2-aminocyclohexan-1-ol hydrochloride. The crude product was purified by preparative HPLC to give N-(2'-chloro-3'-(5-(((((1R,2S)-2-hydroxycyclohexyl)amino)methyl)-6-methoxypyridin-2-yl))-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 1H NMR (400MHz, DMSO-d6) δ11.07(s,1H),8.77(s,1H),8.26(dd,J=8.0,1.2Hz,1H),7.84(d,J=7.5Hz ,1H),7.64(dd,J=7.7,1.7Hz,1H),7.52(dd,J=7.6,7.6Hz,1H),7.37–7.27(m,3H),6.99(dd,J=7. 7,1.3Hz,1H),4.40(s,1H),3.91(s,3H),3.81–3.75(m,3H),3.50(s,3H),3.27(s,3H),2.58–2.53 (m,1H),2.09(s,3H),1.75–1.67(m,1H),1.63–1.43(m,4H),1.39–1.33(m,1H),1.28–1.16(m,2H). MS:(ES)m / z C 33 H 37 ClN5O5[M+H] + The calculated value is 618.2 and the measured value is 618.2.

[0309] Example 47: 1-((5-(2,2'-dichloro-3'-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamido)-[1,1'-biphenyl]-3-yl)-3-methoxypyrazin-2-yl)methyl)azetidine-3-carboxylic acid

[0310]

[0311] The compound was prepared using a procedure similar to step d in Example 1 starting with N-(2,2'-dichloro-3'-(5-formyl-6-methoxypyrazin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide and azetidine-3-carboxylic acid hydrochloride. The crude material was purified by preparative HPLC to give the desired product, 1-((5-(2,2'-dichloro-3'-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamido)-[1,1'-biphenyl]-3-yl)-3-methoxypyrazin-2-yl)methyl)azetidine-3-carboxylic acid. 1H NMR (400MHz, CD3OD) δ11.70(s,1H),8.67(s,1H),8.56(d,J=8.1Hz,1H),8.52(s,1H),7.69(d,J=7.8Hz,1H),7.56(dd,J=8.0,8.0Hz,1H),7.46– 7.38(m,2H),7.11(d,J=7.3Hz,1H),4.74(s,2H),4.70–4.55(bs,2H),4. 50–4.35(bs,2H),4.12(s,3H),3.78(bs,1H),3.56(s,3H),3.39(s,3H). MS:(ES)m / zC 29 H 27 Cl2N6O6[M+H] + The calculated value is 625.1 and the measured value is 625.0.

[0312] Example 48: N-(2,2'-dichloro-3'-(6-methoxy-5-((5-oxo-2,6-diazaspiro[3.4]octan-2-yl)methyl)pyrazin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0313]

[0314] The compound was prepared starting from N-(2,2'-dichloro-3'-(5-formyl-6-methoxypyrazin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide and 2,6-diazaspiro[3.4]octan-5-one tosylate using a procedure similar to step d in Example 1. The crude material was purified by preparative HPLC to give the desired product, N-(2,2'-dichloro-3'-(6-methoxy-5-((5-oxo-2,6-diazaspiro[3.4]octan-2-yl)methyl)pyrazin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 1H NMR (400MHz, CD3OD) δ11.70 (s, 1H), 8.67 (s, 1H), 8.56 (d, J = 8.1Hz, 1H), 8.53 (s, 1H),7.70(d,J=7.8Hz,1H),7.56(dd,J=8.0,8.0Hz,1H),7.46–7.38(m,2H),7.11 (d,J=7.3Hz,1H),4.71(bs,1H),4.47(bs,1H),4.33(s,2H),4.12(s,3H),3.56(s ,3H),3.47(m,1H),3.36(s,3H),3.41–3.29(bs,2H),3.12(m,1H),2.58(bs,2H). MS:(ES)m / zC 31 H 30 Cl2N7O5[M+H] + The calculated value is 650.2 and the measured value is 650.0.

[0315] Example 49: (S)-N-(2'-chloro-3'-(5-(((((4,4-dimethyl-5-oxopyrrolidin-2-yl)methyl)amino)methyl)-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0316]

[0317] The compound was prepared using a procedure similar to step d in Example 1 starting from N-(2'-chloro-3'-(5-formyl-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide and (S)-5-(aminomethyl)-3,3-dimethylpyrrolidin-2-one. The crude product was purified by preparative HPLC to give (S)-N-(2'-chloro-3'-(5-((((4,4-dimethyl-5-oxopyrrolidin-2-yl)methyl)amino)methyl)-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 1H NMR(400MHz, CDCl3)δ10.89(s,1H),8.53(s,1H),8.21(d,J=7.6Hz,1H),7.66–7.53(m,2H),7 .40(dd,J=7.6,7.6Hz,1H),7.35–7.22(m,3H),7.06–6.99(m,1H),5.94(s,1H),4.02(s,3H), 3.80(s,2H),3.75–3.63(m,1H),3.58(s,3H),3.44(s,3H),2.81(dd,J=12.0,4.0Hz,1H),2.5 1(dd,J=12.0,8.9Hz,1H),2.19(s,3H),2.05(dd,J=12.8,6.9Hz,1H),1.18(d,J=5.3Hz,6H). MS:(ES)m / z C 34 H 38 ClN6O5[M+H] + The calculated value is 645.2 and the measured value is 645.6.

[0318] Example 50: N-(2'-chloro-3'-(6-methoxy-5-((((2-methyl-5-oxopyrrolidin-2-yl)methyl)amino)methyl)pyridin-2-yl)-2-methyl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0319]

[0320] The compound was prepared using a procedure similar to step d in Example 1 starting from N-(2'-chloro-3'-(5-formyl-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide and 5-(aminomethyl)-5-methylpyrrolidin-2-one hydrochloride. The crude product was purified by preparative HPLC to give N-(2'-chloro-3'-(6-methoxy-5-((((2-methyl-5-oxopyrrolidin-2-yl)methyl)amino)methyl)pyridin-2-yl)-2-methyl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 1H NMR (400MHz, CDCl3) δ10.89(s,1H),8.53(s,1H),8.25–8.18(m,1H),7.67–7.54(m,2H),7.40(dd,J =7.6,7.6Hz,1H),7.35–7.22(m,3H),7.03(d,J=7.5Hz,1H),5.72(s,1H),4.02(s,3H),3.88–3.75(m ,2H),3.57(s,3H),3.44(s,3H),2.67(d,J=12.1Hz,1H),2.54(d,J=12.1Hz,1H),2.48–2.38(m,2H) ,2.19(s,3H),2.08(ddd,J=12.7,8.9,7.6Hz,1H),1.85(ddd,J=12.9,8.3,8.3Hz,1H),1.27(s,3H). MS:(ES)m / zC 33 H 36 ClN6O5[M+H] + The calculated value is 631.2 and the measured value is 631.2.

[0321] Example 51: N-(2'-chloro-3'-(5-((((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)methyl)-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0322]

[0323] The compound was prepared using a procedure similar to step d in Example 1 starting from N-(2'-chloro-3'-(5-formyl-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide and (3S,4R)-4-aminotetrahydro-2H-pyran-3-ol hydrochloride. The crude product was purified by preparative HPLC to give N-(2'-chloro-3'-(5-((((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)methyl)-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 1H NMR (400MHz, CDCl3) δ10.89 (s, 1H), 8.52 (s, 1H), 8.22 (d, J = 8.0Hz, 1H), 7.67–7 .58(m,2H),7.40(t,J=7.6Hz,1H),7.35–7.22(m,3H),7.02(d,J=7.3Hz,1H),4. 10–3.92(m,6H),3.75(d,J=13.7Hz,1H),3.57(s,3H),3.51–3.36(m,6H),3.17( dd,J=10.9,9.8Hz,1H),2.63–2.52(m,1H),2.19(s,3H),2.06(d,J=13.6Hz,1H). MS:(ES)m / zC 32 H 35 ClN5O6[M+H] + The calculated value is 620.2 and the measured value is 620.2.

[0324] Example 52: N-(2'-chloro-3'-(5-((((3R,4R)-4-hydroxytetrahydrofuran-3-yl)amino)methyl)-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0325]

[0326] The compound was prepared using a procedure similar to step d in Example 1 starting from N-(2'-chloro-3'-(5-formyl-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide and (3R,4R)-4-aminotetrahydrofuran-3-ol hydrochloride. The crude product was purified by preparative HPLC to give N-(2'-chloro-3'-(5-((((3R,4R)-4-hydroxytetrahydrofuran-3-yl)amino)methyl)-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 1H NMR (400MHz, CD3OD) δ11.19(s,1H),8.64(s,1H),8.11(d,J=8.0Hz,1H),7.89(d, J=7.6Hz,1H),7.62(dd,J=7.7,1.7Hz,1H),7.50(dd,J=7.6,7.6Hz,1H),7.37–7.2 8(m,3H),7.01(d,J=7.5Hz,1H),4.60–4.58(m,1H),4.41–4.26(m,2H),4.09(s,3 H),4.07–4.01(m,1H),3.97–3.83(m,4H),3.55(s,3H),3.39(s,3H),2.14(s,3H). MS:(ES)m / zC 31 H 33 ClN5O6[M+H] + The calculated value is 606.2 and the measured value is 606.5.

[0327] Example 53: ((6-(2-chloro-3'-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamido)-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)glycine

[0328]

[0329] A mixture of N-(2'-chloro-3'-(5-formyl-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (50 mg, 0.096 mmol), glycine (30 mg, 0.04 mmol), and AcOH (75 mg, 1.3 mmol) in DMF (1 mL) was stirred at room temperature for 1.5 hours. NaBH(OAc) (70 mg, 0.33 mmol) was added to the mixture. After stirring at room temperature for 1 hour, the crude material was purified by preparative HPLC to give ((6-(2-chloro-3'-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamido)-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)glycine. 1H NMR (400MHz, CD3OD) δ11.18(s,1H),8.63(s,1H),8.11(dd,J=72,7.2Hz,1H),7. 86(d,J=7.2Hz,1H),7.62(dd,J=8.0,1.6Hz,1H),7.49(dd,J=7.6,7.6Hz,1H),7 .35(dd,J=7.6,2.0Hz,2H),7.29(dd,J=8.0,8.0Hz,1H),7.00(d,J=7.2Hz,1H), 4.34(s,2H),4.09(s,3H),3.96(s,2H),3.55(s,3H),3.39(s,3H),2.13(s,3H). MS:(ES)m / z C 29 H 29 ClN5O6[M+H] + The calculated value is 578.2 and the measured value is 578.5.

[0330] Example 54: (R)-N-(2,2'-dichloro-3'-(6-methoxy-5-((((5-oxopyrrolidin-2-yl)methyl)amino)methyl)pyridin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0331]

[0332] The compound was prepared using a procedure similar to step d in Example 1, starting from N-(2,2'-dichloro-3'-(5-formyl-6-methoxypyridin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide and (R)-5-aminomethylpyrrolidin-2-one hydrochloride. The crude product was purified by silica gel flash chromatography. The material was treated with 1N HCl in Et2O (1 mL) and triturated with MeCN (5 mL) to give (R)-N-(2,2'-dichloro-3'-(6-methoxy-5-((((5-oxopyrrolidin-2-yl)methyl)amino)methyl)pyridin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 1H NMR (400MHz, CD3OD) δ11.69(s,1H),8.66(d,J=1.9Hz,1H),8.54(d,J=8.4Hz,1H),7.9 2(d,J=7.6Hz,1H),7.66(d,J=7.8Hz,1H),7.51(dd,J=7.7,7.7Hz,1H),7.45–7.34(m,3 H),7.14–7.07(m,1H),4.35(d,J=2.2Hz,2H),4.14–4.03(m,4H),3.56(d,J=1.9Hz,3H ),3.39(d,J=1.9Hz,3H),3.26(d,J=6.1Hz,2H),2.49–2.32(m,3H),1.98–1.88(m,1H). MS:(ES)m / z C 31 H 31 Cl2N6O5[M+H] + The calculated value is 637.2 and the measured value is 637.5.

[0333] Example 55: (S)-N-(2,2'-dichloro-3'-(6-ethyl-5-((((5-oxopyrrolidin-2-yl)methyl)amino)methyl)pyrazin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0334]

[0335] The compound was prepared using a procedure similar to step d in Example 1 starting from N-(2,2'-dichloro-3'-(6-ethyl-5-formylpyrazin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide and (S)-5-aminomethylpyrrolidin-2-one hydrochloride. The crude product was purified by silica gel flash chromatography followed by preparative HPLC to afford (S)-N-(2,2'-dichloro-3'-(6-ethyl-5-((((5-oxopyrrolidin-2-yl)methyl)amino)methyl)pyrazin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 1H NMR (400MHz, CD3OD) δ11.70(s,1H),8.84(s,1H),8.67(d,J=1.8Hz,1H),8.55(d,J=8.4 Hz,1H),7.73–7.66(m,1H),7.58(dd,J=7.7,7.7Hz,1H),7.48–7.38(m,2H),7.12(d,J=7 .8Hz,1H),4.73–4.58(m,2H),4.16–4.09(m,1H),3.56(d,J=1.6Hz,3H),3.42–3.27(m,5 H), 2.95 (q, J = 7.5Hz, 2H), 2.50–2.35 (m, 3H), 2.02–1.94 (m, 1H), 1.40 (t, J = 7.5Hz, 3H). MS:(ES)m / z C 31 H 32 Cl2N7O4[M+H] + The calculated value is 636.2 and the measured value is 636.2.

[0336] Example 56: (S)-N-(2'-chloro-3'-(6-methoxy-5-((((5-oxopyrrolidin-2-yl)methyl)amino)methyl)pyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0337]

[0338] The compound was prepared using a procedure similar to step d in Example 1 starting from N-(2'-chloro-3'-(5-formyl-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide and (S)-5-aminomethylpyrrolidin-2-one hydrochloride. The crude product was purified by silica gel flash chromatography followed by preparative HPLC to give (S)-N-(2'-chloro-3'-(6-methoxy-5-((((5-oxopyrrolidin-2-yl)methyl)amino)methyl)pyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 1H NMR (400MHz, CD3OD) δ11.17(s,1H),8.42(s,1H),8.10(d,J=8.2Hz,1H),7.88(d,J=7.5Hz,1H),7.61(d,J=7.4Hz,1H),7.50(dd,J=8.4,6.9Hz,1H),7. 41–7.25(m,3H),7.01(d,J=7.5Hz,1H),4.38–4.31(m,2H),4.13–4.00(m,4 H),3.39–3.22(m,5H),2.49–2.32(m,3H),2.13(s,3H),1.96–1.88(m,1H). MS:(ES)m / z C 31 H 32 ClN6O5[M+H] + The calculated value is 603.2 and the measured value is 603.6.

[0339] Example 57: (S)-N-(2'-chloro-3'-(6-ethyl-5-((((5-oxopyrrolidin-2-yl)methyl)amino)methyl)pyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0340]

[0341] The compound was prepared using a procedure similar to step d in Example 1 starting from N-(2'-chloro-3'-(6-ethyl-5-formylpyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide and (S)-5-aminomethylpyrrolidin-2-one hydrochloride. The crude product was purified by silica gel flash chromatography followed by preparative HPLC to give (S)-N-(2'-chloro-3'-(6-ethyl-5-((((5-oxopyrrolidin-2-yl)methyl)amino)methyl)pyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 1H NMR (400MHz, CD3OD) δ11.18(s,1H),8.63(s,1H),8.10(d,J=8.0Hz,1H),8.00(d,J=8.2Hz,1H),7 .65(d,J=8.0Hz,1H),7.59–7.48(m,2H),7.39(dd,J=7.1,2.2Hz,1H),7.29(dd,J=7.9,7.9Hz,1H ),7.00(d,J=7.7Hz,1H),4.50–4.42(m,2H),4.09–4.02(s,1H),3.55(s,3H),3.42–3.31(m,5H), 3.01(t,J=7.5Hz,2H),2.48–2.35(m,3H),2.14(s,3H),1.96–1.88(m,1H),1.35(t,J=7.5Hz,3H). MS:(ES)m / z C 33 H 36 ClN6O4[M+H] + The calculated value is 615.2 and the measured value is 615.6.

[0342] Example 58: N-(2'-chloro-3'-(6-((((3R,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)methyl)-5-methoxypyridin-3-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0343]

[0344] A mixture of N-(2'-chloro-3'-(6-formyl-5-methoxypyridin-3-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (32 mg, 0.061 mmol), (3R,4R)-4-aminotetrahydro-2H-pyran-3-ol hydrochloride (20 mg, 0.13 mmol), Et3N (75 mg, 0.74 mmol), and AcOH (150 mg, 2.5 mmol) in EtOH (1.5 mL) and DCM (1.5 mL) was heated at 70°C for 0.5 h. The contents were cooled to 0°C and NaBH3CN (30 mg, 0.44 mmol) was added. After stirring at 0°C for 5 minutes, the mixture was concentrated in vacuo. The obtained residue was purified by preparative HPLC to give N-(2'-chloro-3'-(6-((((3R,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)methyl)-5-methoxypyridin-3-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 1 H NMR (400MHz, CD3OD) δ8.62(s,1H),8.33(d,J=1.6Hz,1H),8.12(d,J=8.4Hz,1H),7.65(d,J =1.6Hz,1H),7.56–7.47(m,2H),7.37(dd,J=7.6,1.6Hz,1H),7.29(d,J=8.2,8.2Hz,1H),6. 99(d,J=7.6Hz,1H),4.47(s,2H),4.08–3.94(m,3H),3.99(s,3H),3.62–3.54(m,2H),3.55( s,3H),3.50–3.42(m,1H),3.38(s,3H),2.20–2.10(m,1H),2.14(s,3H),1.96–1.88(m,1H). MS:(ES)m / z C 32 H 35 ClN5O6[M+H] + The calculated value is 620.2 and the measured value is 620.2.

[0345] Example 59: N-(2'-chloro-3'-(6-methoxy-5-((6-oxo-2,5,7-triazaspiro[3.4]octan-2-yl)methyl)pyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0346]

[0347] The compound was prepared using a procedure similar to step d in Example 1 starting from N-(2'-chloro-3'-(5-formyl-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide and 2,5,7-triazaspiro[3.4]octan-6-one hydrochloride. The crude product was purified by preparative HPLC to give N-(2'-chloro-3'-(6-methoxy-5-((6-oxo-2,5,7-triazaspiro[3.4]octan-2-yl)methyl)pyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 1 H NMR(400MHz,DMSO-d6)δ11.07(s,1H),8.77(s,1H),8.27–8.25(m,1H),7.71–7.62(m,2H),7.54–7.50(m,1H),7.37–7.2 6(m,3H),6.99–6.92(m,2H),6.29(s,1H),3.91(s,3H),3.56–3.43(m,9H),3.27(s,3H),3.14–3.12(m,2H),2.09(s,3H). MS:(ES)m / zC 32 H 32 ClN7O5[M+H] + The calculated value is 630.2 and the measured value is 630.2.

[0348] Example 60: (S)-N-(2,2'-dichloro-3'-(6-hydroxy-5-((((5-oxopyrrolidin-2-yl)methyl)amino)methyl)pyridin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0349]

[0350] To a solution of (S)-N-(2,2'-dichloro-3'-(6-methoxy-5-((((5-oxopyrrolidin-2-yl)methyl)amino)methyl)pyridin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (50 mg, 0.078 mmol) in 2 mL of MeOH was slowly added hydrochloric acid solution (0.5 mL, 37% in water) at 0° C. The mixture was heated to 100° C. for 16 hours. The crude product was purified by preparative HPLC to give (S)-N-(2,2'-dichloro-3'-(6-hydroxy-5-((((5-oxopyrrolidin-2-yl)methyl)amino)methyl)pyridin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 1 H NMR (400MHz, CD3OD) δ11.69(s,1H),8.66(s,1H),8.55(ddd,J=8.4,2.4,1.5Hz,1H ),7.66(d,J=7.1Hz,1H),7.59–7.36(m,4H),7.12–7.04(m,1H),6.46(d,J=7.1Hz,1 H),4.53–4.38(m,2H),3.89–3.85(m,1H),3.79–3.68(m,1H),3.64–3.56(m,1H),3 .55(s,3H),3.39(s,3H),2.57–2.54(m,2H),2.28–2.20(m,1H),2.04–1.93(m,1H). MS:(ES)m / zC 30 H 29 Cl2N6O5[M+H] + The calculated value is 623.2 and the measured value is 623.5.

[0351] Example 61: (S)-N-(2'-chloro-3'-(6-methoxy-5-((((1-methyl-5-oxopyrrolidin-2-yl)methyl)amino)methyl)pyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0352]

[0353] The compound was prepared using a procedure similar to step d in Example 1 starting from N-(2'-chloro-3'-(5-formyl-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide and (S)-5-(aminomethyl)-1-methylpyrrolidin-2-one hydrochloride. The crude product was purified by preparative HPLC to give (S)-N-(2'-chloro-3'-(6-methoxy-5-((((1-methyl-5-oxopyrrolidin-2-yl)methyl)amino)methyl)pyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 1 H NMR (400MHz, DMSO-d6) δ11.07(s,1H),8.77(s,1H),8.27–8.25(m,1H),7.80(d,J=7.5Hz, 1H),7.64(dd,J=7.7,1.7Hz,1H),7.52(dd,J=7.6,7.6Hz,1H),7.37–7.28(m,3H),6.99(dd ,J=7.7,1.2Hz,1H),3.92(s,3H),3.73(s,2H),3.61–3.55(m,1H),3.50(s,3H),3.27(s,3H ),2.68(s,5H),2.28(ddd,J=16.1,9.9,6.6Hz,1H),2.20–1.98(m,5H),1.91–1.79(m,1H). MS:(ES)m / z C 33 H 36 ClN6O5[M+H] + The calculated value is 631.2 and the measured value is 631.2.

[0354] Example 62: N-(3'-(5-(((3-amino-2,2-dimethyl-3-oxopropyl)amino)methyl)-6-methoxypyridin-2-yl)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0355]

[0356] The compound was prepared using a procedure similar to step d in Example 1 starting from N-(2,2'-dichloro-3'-(5-formyl-6-methoxypyridin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide and 3-amino-2,2-dimethylpropionamide. The crude product was purified by preparative HPLC to give N-(3'-(5-(((3-amino-2,2-dimethyl-3-oxopropyl)amino)methyl)-6-methoxypyridin-2-yl)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 1 H NMR (400MHz, CD3OD) δ11.68(s,1H),8.65(s,1H),8.53(d,J=7.9Hz,1H),7.86(s,1H),7.65(d,J=7.2Hz,1H),7.50(dd,J=7.2,7.2 Hz,1H),7.42–7.36(m,3H),7.09(d,J=7.2Hz,1H),4.27(s,2H),4.12(s,3H),3.55(s,3H),3.38(s,3H),3.13(s,2H),1.34(s,6H). MS:(ES)m / zC 31 H 33 Cl2N6O5[M+H] + The calculated value is 639.2 and the measured value is 639.2.

[0357] Example 63: (S)-N-(2,2'-dichloro-3'-(6-methoxy-5-((methyl((5-oxopyrrolidin-2-yl)methyl)amino)methyl)pyridin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0358]

[0359] The compound was prepared using a procedure similar to step d in Example 1 starting from N-(2,2'-dichloro-3'-(5-formyl-6-methoxypyridin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide and (S)-5-((methylamino)methyl)pyrrolidin-2-one. The crude product was purified by preparative HPLC to give (S)-N-(2,2'-dichloro-3'-(6-methoxy-5-((methyl((5-oxopyrrolidin-2-yl)methyl)amino)methyl)pyridin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 1 H NMR (400MHz, CD3OD) δ11.70(s,1H),8.67(s,1H),8.54(d,J=8.2Hz,1H),7.96(d,J=7 .6Hz,1H),7.69–7.66(m,1H),7.55–7.44(m,1H),7.44–7.39(m,3H),7.10(d,J=7.5H z,1H),4.68(s,1H),4.16(s,3H),4.01–3.97(m,1H),3.56(s,3H),3.38(s,3H),3.31 (s,3H),3.20–3.10(m,3H),2.95–2.86(m,1H),2.68–2.50(m,2H),2.20–2.10(m,1H). MS:(ES)m / zC 32 H 33 Cl2N6O5[M+H] + The calculated value is 651.2 and the measured value is 651.1.

[0360] Example 64: (S)-N-(2,2'-dichloro-3'-(6-methoxy-5-((((5-oxopyrrolidin-2-yl)methyl)amino)methyl)pyridin-2-yl)-[1,1'-biphenyl]-3-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

[0361]

[0362] This compound was prepared using a procedure similar to step d in Example 1 starting from N-(2,2'-dichloro-3'-(5-formyl-6-methoxypyridin-2-yl)-[1,1'-biphenyl]-3-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide and (S)-5-(aminomethyl)pyrrolidin-2-one hydrochloride. The crude product was purified by preparative HPLC to give (S)-N-(2,2'-dichloro-3'-(6-methoxy-5-((((5-oxopyrrolidin-2-yl)methyl)amino)methyl)pyridin-2-yl)-[1,1'-biphenyl]-3-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide. 1 H NMR(400MHz,CD3OD)δ12.66(s,1H),8.62–8.61(m,2H),8.03(d,J=6.5Hz,1H),7.91 (d,J=7.7Hz,1H),7.68–7.66(m,1H),7.53(dd,J=7.7,7.7Hz,1H),7.42–7.38(m,3H ),7.12(d,J=7.6Hz,1H),6.63(dd,J=7.0,7.0Hz,1H),4.35(s,2H),4.07–4.02(m,4 H), 3.71 (d, J = 1.9Hz, 3H), 3.29–3.25 (m, 2H), 2.48–2.35 (m, 3H), 1.98–1.89 (s, 1H). MS:(ES)m / zC 31 H 29 Cl2N5O4[M+H] + The calculated value is 606.2 and the measured value is 606.2.

[0363] Example 65: 1-((6-(2,2'-dichloro-3'-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamido)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)azetidine-3-carboxylic acid

[0364]

[0365] The compound was prepared using a procedure similar to step d in Example 1 starting from N-(2,2'-dichloro-3'-(5-formyl-6-methoxypyridin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide and azetidine-3-carboxylic acid. The crude product was purified by preparative HPLC to give 1-((6-(2,2'-dichloro-3'-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamido)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)azetidine-3-carboxylic acid. 1 H NMR(400MHz,CD3OD)δ11.69(s,1H),8.66(d,J=1.9Hz,1H),8.57–8.49(m,1H) ,7.89(d,J=7.7Hz,1H),7.66(dd,J=7.8,1.8Hz,1H),7.53–7.50(m,1H),7.45– 7.34(m,3H),7.10(dd,J=7.6,1.8Hz,1H),4.51(s,2H),4.42(d,J=8.9Hz,4H), 4.09(d,J=1.8Hz,3H),3.79–3.65(m,1H),3.56(d,J=2.1Hz,3H),3.39(s,3H). MS:(ES)m / z C 30 H 28 Cl2N5O6[M+H] + The calculated value is 624.1 and the measured value is 624.1.

[0366] Example 66: 1-((6-(2,2'-dichloro-3'-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamido)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)-3-methylazetidine-3-carboxylic acid

[0367]

[0368] The compound was prepared using a procedure similar to step d in Example 1 starting from N-(2,2'-dichloro-3'-(5-formyl-6-methoxypyridin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide and 3-methylazetidine-3-carboxylic acid. The crude product was purified by preparative HPLC to give 1-((6-(2,2'-dichloro-3'-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamido)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)-3-methylazetidine-3-carboxylic acid. 1 H NMR (400MHz, CD3OD) δ11.68(s,1H),8.65(d,J=1.7Hz,1H),8.54(dd,J=8.7,1.8Hz,1H),7.89(d,J=7.6Hz,1H),7.66(dd,J=7.9,1.9Hz,1H),7. 53–7.49(m,1H),7.42–7.36(m,3H),7.10(dd,J=7.7,1.8Hz,1H),4.55– 4.51(m,4H),4.16–4.09(m,5H),3.55(s,3H),3.37(s,3H),1.62(s,3H). MS:(ES)m / z C 31 H 30 Cl2N5O6[M+H] + The calculated value is 638.2 and the measured value is 638.1.

[0369] Example 67: (S)-1-((5-(2,2'-dichloro-3'-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamido)-[1,1'-biphenyl]-3-yl)-3-methoxypyrazin-2-yl)methyl)piperidine-2-carboxylic acid

[0370]

[0371] The compound was prepared using a procedure similar to step d in Example 1 starting from N-(2,2'-dichloro-3'-(5-formyl-6-methoxypyrazin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide and (S)-piperidine-2-carboxylic acid. The crude product was purified by preparative HPLC to give (S)-1-((5-(2,2'-dichloro-3'-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamido)-[1,1'-biphenyl]-3-yl)-3-methoxypyrazin-2-yl)methyl)piperidine-2-carboxylic acid. 1 H NMR (400MHz, CD3OD) δ11.70(s,1H),8.66(s,1H),8.60–8.54(m,2H),7.74(dd,J=7.7,1.8Hz,1H),7.60–7.56(m,1H),7.47–7.41(m,2H),7.12(dd,J=7 .6,1.8Hz,1H),4.69(s,2H),4.27–4.21(m,1H),4.11(s,3H),3.79(d,J=12 .6Hz,1H),3.56(s,3H),3.39(s,3H),2.38–2.32(m,1H),2.09–1.65(m,6H). MS:(ES)m / z C 31 H 31 Cl2N6O6[M+H] + The calculated value is 653.2 and the measured value is 653.1.

[0372] Example 68: (R)-1-((5-(2,2'-dichloro-3'-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamido)-[1,1'-biphenyl]-3-yl)-3-methoxypyrazin-2-yl)methyl)piperidine-2-carboxylic acid

[0373]

[0374] The compound was prepared using a procedure similar to step d in Example 1 starting from N-(2,2'-dichloro-3'-(5-formyl-6-methoxypyrazin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide and (R)-piperidine-2-carboxylic acid. The crude product was purified by preparative HPLC to afford (R)-1-((5-(2,2'-dichloro-3'-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamido)-[1,1'-biphenyl]-3-yl)-3-methoxypyrazin-2-yl)methyl)piperidine-2-carboxylic acid. 1 H NMR (400MHz, CD3OD) δ11.70(s,1H),8.67(s,1H),8.59–8.54(m,2H),7.74(dd,J=7.7,1.8Hz,1H),7.59–7.56(m,1H),7.46–7.40(m,2H),7.12(dd,J=7 .6,1.8Hz,1H),4.69(s,2H),4.27–4.20(m,1H),4.11(s,3H),3.79(d,J=12 .6Hz,1H),3.56(s,3H),3.39(s,3H),2.38–2.33(m,1H),2.09–1.65(m,6H). MS:(ES)m / z C 31 H 31 Cl2N6O6[M+H] + The calculated value is 653.2 and the measured value is 653.2.

[0375] Example 69: N-(2'-chloro-3'-(5-((3-hydroxyazetidin-1-yl)methyl)-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0376]

[0377] Step a: To a flask containing 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (15 g, 65 mmol) and 1,3-dibromo-2-chlorobenzene (52.5 g, 194 mmol) in 375 mL of dioxane was added 2M KCO (110 mL) and a complex of Pd(dppf)Cl in DCM (5.25 g, 6.4 mmol). The mixture was degassed with N for 10 minutes and then heated at 90°C for 2 hours. The reaction was quenched with saturated NaHCO, and the aqueous layer was extracted with EtOAc. The organic layers were combined, dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography to give 3'-bromo-2'-chloro-2-methyl-[1,1'-biphenyl]-3-amine.

[0378] Step b: To a solution of 3'-bromo-2'-chloro-2-methyl-[1,1'-biphenyl]-3-amine (7 g, 23.7 mmol) in 40 mL of dioxane was added bis(pinacolato)diboron (6.3 g, 24.9 mmol), followed by KOAc (5.8 g, 59.1 mmol) and a complex of Pd(dppf)Cl2 in DCM (1.93 g, 2.4 mmol). The mixture was degassed with N2 for 10 minutes and then heated at 90°C overnight. The contents were filtered through celite and washed with EtOAc. The filtrate was concentrated and the resulting residue was purified by silica gel column chromatography to give 2'-chloro-2-methyl-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-amine. MS: (ES) m / z C 19 H 24 BClNO2[M+H] + The calculated value is 344.2 and the measured value is 344.1.

[0379] Step c: To a solution of 2'-chloro-2-methyl-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-amine (6.4 g, 18.6 mmol) in 124 mL of DMF was added 1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (3.4 g, 18.6 mmol), DIPEA (4.9 mL, 27.9 mmol) and HATU (8.5 g, 22.3 mmol). The mixture was stirred at room temperature for 2 hours and additional amounts of 1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (0.34 g, 0.99 mmol), DIPEA (0.49 mL, 2.8 mmol) and HATU (0.85 g, 2.23 mmol) were added. After stirring overnight, the reaction was quenched with water. The aqueous layer was extracted with EtOAc, the organic layers were combined, dried over sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel column chromatography to provide N-(2'-chloro-2-methyl-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. MS:(ES)m / z C 26 H 29 BClN3O5[M+H] + The calculated value is 510.2 and the measured value is 510.1.

[0380] Step d: To a solution of N-(2'-chloro-2-methyl-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (4.2 g, 8.3 mmol) in 82.5 mL of dioxane was added 6-chloro-2-methoxynicotinaldehyde (1.4 g, 8.3 mmol), 2M K2CO3 (14 mL), and Pd(PPh3)4 (0.95 g, 0.82 mmol). The mixture was degassed with N2 for 10 minutes and then heated at 100°C for 2 hours. The contents were filtered through celite and the organic and aqueous layers were separated. The aqueous layer was washed with EtOAc, and the combined organic layers were dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography to provide N-(2'-chloro-3'-(5-formyl-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. MS: (ES) m / zC 27 H 24 ClN4O5[M+H] +The calculated value is 519.1 and the measured value is 519.0.

[0381] Step e: To a solution of N-(2'-chloro-3'-(5-formyl-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (100 mg, 0.19 mmol) in 3.2 ml of DCM and 1.5 ml of ethanol was added azetidin-3-ol (17 mg, 0.23 mmol), Et3N (0.07 mL, 0.5 mmol) and AcOH (0.04 mL, 0.70 mmol). The reaction mixture was heated at 70 ° C for 1 hour, then cooled to 0 ° C and NaBH3CN (18 mg, 0.29 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour and then quenched with water. The aqueous layer was extracted with EtOAc, and the organic layers were combined, dried over sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel column chromatography and preparative HPLC to give N-(2'-chloro-3'-(5-((3-hydroxyazetidin-1-yl)methyl)-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 1 HNMR(400MHz,DMSO-d6)δ11.05(s,1H),8.74(s,1H),8.24(d,J=9.5Hz,1H),7.7 1(d,J=7.5Hz,1H),7.61(dd,J=7.9,1.7Hz,1H),7.50(dd,J=7.6,7.6Hz,1H),7. 40–7.16(m,3H),6.96(dd,J=7.5,1.6Hz,1H),4.45–4.13(m,1H),3.90(s,3H),3 .70(bs,4H),3.49(s,3H),3.32(s,1H),3.27(s,3H),3.01(bs,2H),2.07(s,3H). MS:(ES)m / z C 30 H 31 ClN5O5[M+H] + The calculated value is 576.2 and the measured value is 576.0.

[0382] Example 70: N-(2'-chloro-3'-(6-methoxy-5-((5-oxo-2,6-diazaspiro[3.4]octan-2-yl)methyl)pyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0383]

[0384] The compound was prepared using a procedure similar to step d in Example 1 starting from N-(2'-chloro-3'-(5-formyl-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide and 2,6-diazaspiro[3.4]octan-5-one. The crude product was purified by preparative HPLC to give N-(2'-chloro-3'-(6-methoxy-5-((5-oxo-2,6diazaspiro[3.4]octan-2-yl)methyl)pyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 1 HNMR(400MHz,DMSO-d6)δ11.05(s,1H),8.75(s,1H),8.24(d,J=9.7Hz,1H),7.79–7.56(m,3H),7.50(dd,J=7.6,7.6Hz,1H),7.42–7.13(m,3H),6.97 (d,J=7.6Hz,1H),3.89(s,3H),3.55(s,2H),3.49(s,3H),3.34–3.29(m,3H ),3.28–3.17(m,3H),3.25(s,3H),3.12(s,1H),2.32(s,1H),2.07(s,3H). MS:(ES)m / z C 33 H 34 ClN6O5[M+H] + The calculated value is 629.2 and the measured value is 629.0.

[0385] Example 71: 1-((6-(2-chloro-3'-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide)-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)azetidine-3-carboxylic acid

[0386]

[0387] The compound was prepared using a procedure similar to step d in Example 1 starting from N-(2'-chloro-3'-(5-formyl-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide and azetidine-3-carboxylic acid. The crude product was purified by preparative HPLC to give 1-((6-(2-chloro-3'-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamido)-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)azetidine-3-carboxylic acid. 1 H NMR (400MHz, CD3OD) δ8.63(s,1H),8.11(d,J=8.1Hz,1H),7.86(d,J=7.7Hz,1H),7.61(d,J=7.6Hz,1H),7.49(dd,J=7.6,7.6Hz,1H),7.35–7.23( m,3H),7.01(d,J=7.7Hz,1H),4.37(bs,2H),4.19(dd,J=9.2,2.3Hz,4H) ,4.07(s,3H),3.55(s,3H),3.48–3.42(m,1H),3.39(s,3H),2.13(s,3H). MS:(ES)m / z C 31 H 31 ClN6O6[M+H] + The calculated value is 604.2 and the measured value is 603.9.

[0388] Example 72: (S)-N-(2'-chloro-3'-(6-methoxy-5-((((5-oxopyrrolidin-2-yl)methyl)amino)methyl)pyrazin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0389]

[0390] Step a: To a solution of N-(2'-chloro-2-methyl-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (1.0 g, 2.0 mmol) in 20 mL of dioxane was added 5-chloro-3-methoxypyrazine-2-carbaldehyde (0.42 g, 2.0 mmol), 2M KCO (6.7 mL), and Pd(PPh) (0.23 g, 0.20 mmol). The mixture was degassed with N for 10 minutes and then heated at 100°C for 1 hour. The reaction was quenched with water and the aqueous layer was washed with EtOAc. The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography to provide N-(2'-chloro-3'-(5-formyl-6-methoxypyrazin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. MS: (ES) m / zC 26 H 23 ClN5O5[M+H] + The calculated value is 520.1 and the measured value is 519.9.

[0391] Step b: To a solution of N-(2'-chloro-3'-(5-formyl-6-methoxypyrazin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (100 mg, 0.19 mmol) in 3.2 mL of DCM and 1.5 mL of ethanol was added (S)-5-(aminomethyl)pyrrolidin-2-one (35 mg, 0.23 mmol), Et3N (0.07 mL, 0.5 mmol), and AcOH (0.04 mL, 0.70 mmol). The contents were heated at 70°C for 1 hour, then cooled to 0°C and NaBH3CN (18 mg, 0.29 mmol) was added. After stirring at room temperature for 1 hour, the reaction was quenched with water. The aqueous layer was extracted with EtOAc, and the combined organic layers were dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography and preparative HPLC to give (S)-N-(2'-chloro-3'-(6-methoxy-5-((((5-oxopyrrolidin-2-yl)methyl)amino)methyl)pyrazin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 1H NMR (400MHz, CD3OD) δ: 8.63 (s, 1H), 8.42 (s, 1H), 8.12 (d, J = 8.2Hz, 1H), 7.65 (d, J = 7. 2Hz,1H),7.52(dd,J=7.6,7.6Hz,1H),7.38(d,J=7.6Hz,1H),7.30(dd,J=8.1,8.1Hz, 1H),7.01(d,J=7.6Hz,1H),4.06(s,3H),4.04(s,2H),3.90–3.84(m,1H),3.55(s,3H) ,3.39(s,3H),2.91–2.72(m,2H),2.38–2.23(m,3H),2.14(s,3H),1.90–1.76(m,1H). MS:(ES)m / zC 31 H 33 ClN7O5[M+H] + The calculated value is 618.2 and the measured value is 618.2.

[0392] Example 73: N-(2'-chloro-3'-(5-((((3R,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)methyl)-6-methoxypyrazin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0393]

[0394] This compound was prepared starting from N-(2'-chloro-3'-(5-formyl-6-methoxypyrazin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide and (3R,4R)-4-aminotetrahydro-2H-pyran-3-ol using a procedure similar to step d in Example 1. The crude product was purified by preparative HPLC to give N-(2'-chloro-3'-(5-((((3R,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)methyl)-6-methoxypyrazin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 1H NMR (400MHz, DMSO-d6) δ11.06(s,1H),8.75(s,1H),8.44(s,1H),8.25(d,J=8.2Hz,1H),7.68(d,J=7.6Hz,1H) ,7.56(dd,J=7.7,7.7Hz,1H),7.41(d,J=7.5Hz,1H),7.30(dd,J=7.9,7.9Hz,1H),6.98(d,J=7.6Hz,1H),4.76 (s,1H),4.06–3.93(m,1H),3.87(d,J=15.6Hz,1H),3.96(s,3H),3.76–3.69(m,1H),3.68–3.60(m,2H),3.49( s,3H),3.38–3.28(m,3H),3.26(s,3H),2.85–2.79(m,1H),2.08(s,3H),1.75–1.62(m,1H),1.58–1.50(m,1H). MS:(ES)m / z C 31 H 34 ClN6O6[M+H] + The calculated value is 621.2 and the measured value is 621.2.

[0395] Example 74: (S)-N-(2'-chloro-3'-(6-methoxy-5-((((5-oxopyrrolidin-2-yl)methyl)amino)methyl)pyridin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0396]

[0397] Step a: To a solution of 1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (3.0 g, 16.3 mmol) in 110 mL of DMF was added 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (3.59 g, 16.3 mmol), DIPEA (4.33 mL, 24.8 mmol), and HATU (7.53 g, 19.8 mmol). The mixture was stirred at room temperature for 2 hours and then quenched with water. The solid was filtered and washed with water and then with heptane to give 1,3-dimethyl-2,4-dioxo-N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide. MS: (ES) m / z C 19 H 25 BN3O5[M+H] +The calculated value is 386.2 and the measured value is 386.4.

[0398] Step b: To a solution of 1,3-dimethyl-2,4-dioxo-N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide (100 mg, 0.26 mmol) in 2 mL THF and 2 mL H2O was added 6-(3-bromo-2-chlorophenyl)-2-methoxynicotinaldehyde (85 mg, 0.26 mmol), K3PO4 (137 mg, 0.65 mmol) and XPhosPdG2 (20 mg, 0.03 mmol). The mixture was degassed with N2 for 10 minutes and stirred at room temperature overnight. The solid content was filtered and washed with EtOAc to give N-(2'-chloro-3'-(5-formyl-6-methoxypyridin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. MS: (ES) m / z C 26 H 22 ClN4O5[M+H] + The calculated value is 505.1 and the measured value is 505.4.

[0399] Step c: To a solution of N-(2'-chloro-3'-(5-formyl-6-methoxypyridin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (72 mg, 0.14 mmol) in 3.2 mL of DCM and 1 mL of ethanol was added (S)-5-(aminomethyl)pyrrolidin-2-one (25 mg, 0.17 mmol), Et3N (0.06 mL, 0.43 mmol), and AcOH (0.04 mL, 0.70 mmol). The contents were heated at 70°C for 1 hour, then cooled to room temperature and Na(OAc)3BH (90 mg, 0.42 mmol) was added. After stirring at room temperature for 20 minutes, the reaction was quenched with water. The aqueous layer was extracted with EtOAc, and the combined organic layers were dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography and preparative HPLC to give (S)-N-(2'-chloro-3'-(6-methoxy-5-((((5-oxopyrrolidin-2-yl)methyl)amino)methyl)pyridin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 1H NMR(400MHz,DMSO-d6)δ11.12(s,1H),8.69(s,1H),7.82–7.78(m,2H),7.74–7.60 (m,2H),7.60–7.52(m,1H),7.52–7.39(m,3H),7.23(d,J=7.4Hz,1H),7.20–7.12(m ,1H),3.89(s,3H),3.71–3.67(bs,2H),3.66–3.58(m,1H),3.47(s,3H),3.30–3.28 (m,1H),3.26(s,3H),2.53(d,J=6.1Hz,2H),2.22–1.97(m,3H),1.81–1.58(m,1H). MS:(ES)m / z C 31 H 32 ClN6O5[M+H] + The calculated value is 603.2 and the measured value is 603.5.

[0400] Example 75: (S)-N-(2'-chloro-2-fluoro-3'-(6-methoxy-5-((((5-oxopyrrolidin-2-yl)methyl)amino)methyl)pyridin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0401]

[0402] Step a: To a solution of 1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (1.62 g, 8.8 mmol) in 59 mL of DMF was added 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (2.09 g, 8.8 mmol), DIPEA (2.3 mL, 13.2 mmol), and HATU (8.04 g, 21.2 mmol). The mixture was stirred at room temperature for 2 hours and then quenched with water. The solid was filtered and washed with water and then with heptane to give N-(2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. MS: (ES) m / z C 19 H 24 BFN3O5[M+H] + The calculated value is 404.2 and the measured value is 404.4.

[0403] Step b: To a solution of N-(2-fluoro-3(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (100 mg, 0.26 mmol) in 1 mL THF and 1 mL H2O was added 6-(3-bromo-2-chlorophenyl)-2-methoxynicotinaldehyde (81 mg, 0.25 mmol), K3PO4 (132 mg, 0.62 mmol) and XPhosPdG2 (20 mg, 0.03 mmol). The mixture was degassed with N2 for 10 minutes and stirred at room temperature for 5 hours. The solid content was filtered and washed with EtOAc to give N-(2'-chloro-2-fluoro-3'-(5-formyl-6-methoxypyridin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. MS: (ES) m / zC 26 H 21 ClFN4O5[M+H] + The calculated value is 523.1 and the measured value is 523.3.

[0404] Step c: To a solution of N-(2'-chloro-2-fluoro-3'-(5-formyl-6-methoxypyridin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (83 mg, 0.16 mmol) in 1 mL of DCM and 1 mL of EtOH was added (S)-5-(aminomethyl)pyrrolidin-2-one (28 mg, 0.19 mmol), Et3N (0.07 mL, 0.5 mmol), and AcOH (0.04 mL, 0.70 mmol). The contents were heated at 70 °C for 1 hour, then cooled to room temperature and Na(OAc)3BH (100 mg, 0.47 mmol) was added. After stirring at room temperature for 1 hour, the reaction was quenched with water. The aqueous layer was extracted with EtOAc, and the organic layers were combined, dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography and preparative HPLC to give (S)—N-(2′-chloro-2-fluoro-3′-(6-methoxy-5-((((5-oxopyrrolidin-2-yl)methyl)amino)methyl)pyridin-2-yl)-[1,1′-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 1HNMR(400MHz,DMSO-d6)δ11.46(s,1H),8.76(s,1H),8.47(dd,J=7.8,7.8Hz,1H),7.81(d,J=7.5Hz,1H),7 .69(s,1H),7.64(d,J=7.6Hz,1H),7.53(dd,J=7.3,7.3Hz,1H),7.46(d,J=7.5Hz,1H),7.30(dd,J=8.0,8.0 Hz,1H),7.25(d,J=7.2Hz,1H),7.12(dd,J=7.2,7.2Hz,1H),3.89(s,3H),3.69(bs,2H),3.66–3.57(s,1H), 3.48(s,3H),3.30–3.28(m,1H),3.15(s,3H),2.53(d,J=6.0Hz,2H),2.18–2.00(m,3H),1.71–1.62(m,1H). MS:(ES)m / zC 31 H 31 ClFN6O5[M+H] + The calculated value is 621.2 and the measured value is 621.5.

[0405] Example 76: (S)-N-(2'-chloro-2-methyl-3'-(5-((((5-oxopyrrolidin-2-yl)methyl)amino)methyl)-6-(trifluoromethyl)pyridin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0406]

[0407] Step a: To a solution of (3-bromo-2-chlorophenyl)boronic acid (860 mg, 3.6 mmol) and 6-chloro-2-(trifluoromethyl)nicotinaldehyde (650 mg, 3.1 mmol) in 25.5 mL of dioxane was added 2M KCO (4.7 mL, 10.9 mmol) and Pd(PPh) (420 mg, 0.36 mmol). The mixture was degassed with N for 10 minutes and stirred at 100°C for 2 hours. The reaction was quenched with water and the aqueous layer was extracted with EtOAc. The combined organic layers were combined, dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography to give 6-(3-bromo-2-chlorophenyl)-2-(trifluoromethyl)nicotinaldehyde. MS: (ES) m / z C 13 H7BrClF3NO[M+H] + The calculated value is 363.9 and the measured value is 364.2.

[0408] Step b: To a solution of 1,3-dimethyl-N-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (270 mg g, 0.68 mmol) in 10 mL of dioxane was added 6-(3-bromo-2-chlorophenyl)-2-(trifluoromethyl)nicotinaldehyde (250 mg, 0.69 mmol), 2M KCO (1.2 mL, 2.4 mmol), and a complex of Pd(dppf)Cl in DCM (170 mg, 0.21 mmol). The mixture was degassed with N for 10 minutes and then heated at 100° C. for 1 hour. The contents were filtered through celite and the filtrate was concentrated and purified by silica gel column chromatography to provide N-(2'-chloro-3'-(5-formyl-6-(trifluoromethyl)pyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. MS: (ES) m / z C 27 H 21 ClF3 N4O4[M+H] + The calculated value is 557.1 and the measured value is 557.4.

[0409] Step c: To a solution of N-(2'-chloro-3'-(5-formyl-6-(trifluoromethyl)pyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (100 mg, 0.18 mmol) in 1 mL of DCM and 1 mL of EtOH was added (S)-5-(aminomethyl)pyrrolidin-2-one (40 mg, 0.27 mmol), Et3N (0.09 mL, 0.65 mmol), and AcOH (0.06 mL, 1.0 mmol). The contents were heated at 70°C for 1 hour, then cooled to room temperature and Na(OAc)3BH (114 mg, 0.54 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour and an additional amount of Na(OAc)3BH (114 mg, 0.54 mmol) was added. After stirring at room temperature overnight, the contents were concentrated and the resulting residue was purified by silica gel column chromatography to give (S)-N-(2'-chloro-2-methyl-3'-(5-((((5-oxopyrrolidin-2-yl)methyl)amino)methyl)-6-(trifluoromethyl)pyridin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 1H NMR (400MHz, CD3OD) δ8.62(s,1H),8.29(d,J=8.2Hz,1H),8.12(dd,J=8.4,1.6Hz,1H),7.93(d,J=8.2Hz,1H),7. 60(dd,J=7.7,1.8Hz,1H),7.52(dd,J=7.6,7.6Hz,1H),7.38(dd,J=7.5,1.8Hz,1H),7.29(dd,J=7.9,7.9Hz,1H) ,7.02(dd,J=7.4,1.2Hz,1H),4.06(bs,2H),3.84(dddd,J=6.5,6.5,6.5,6.5Hz,1H),3.55(s,3H),3.39(s,3H), 2.76(dd,J=12.0,4.8Hz,1H),2.69(dd,J=12.0,7.2Hz,1H),2.42–2.19(m,3H),2.15(s,3H),1.97–1.75(m,1H). MS:(ES)m / z C 32 H 31 ClF3N6O4[M+H] + The calculated value is 655.2 and the measured value is 655.2.

[0410] Example 77: N-(2'-chloro-3'-(5-((((1R,2S)-2-hydroxycyclopentyl)amino)methyl)-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0411]

[0412] Step a: To a solution of N-(2'-chloro-3'-(5-formyl-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (52 mg, 0.1 mmol) and (1S,2R)-2-aminocyclopentan-1-ol hydrochloride (28 mg, 0.2 mmol) in dichloroethane (2 mL) and EtOH (1 mL) was added Et3N (2 drops) and AcOH (2 drops). The contents were stirred at 70°C for 1 hour, then cooled to 0°C and NaBH3CN (13 mg, 0.2 mmol) was slowly added. After stirring at 0 °C for 10 minutes, the crude mixture was filtered and then purified by preparative HPLC to give N-(2'-chloro-3'-(5-((((1R,2S)-2-hydroxycyclopentyl)amino)methyl)-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 1 H NMR (400MHz, CDCl3) δ10.89(s,1H),8.52(s,1H),8.25–8.18(m,1H),7.66–7. 55(m,2H),7.40(dd,J=7.6,7.6Hz,1H),7.35–7.22(m,3H),7.03(dd,J=7.5,1. 2Hz,1H),4.08(t,J=4.8Hz,1H),4.03(s,3H),3.87–3.73(m,2H),3.57(s,3H), 3.44(s,3H),3.00(m,1H),2.19(s,3H),1.90–1.70(m,4H),1.60–1.40(m,2H). MS:(ES)m / z C 32 H 35 ClN5O5[M+H] + The calculated value is 604.2 and the measured value is 604.5.

[0413] Example 78: N-(2'-chloro-3'-(5-((((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)methyl)-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0414]

[0415] This compound was prepared starting from N-(2'-chloro-3'-(5-formyl-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide and (3R,4S)-4-aminotetrahydro-2H-pyran-3-ol hydrochloride using a procedure similar to step d in Example 1. The crude product was purified by preparative HPLC to give N-(2'-chloro-3'-(5-((((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)methyl)-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 1 H NMR(400MHz, CDCl3)δ10.89(s,1H),8.53(s,1H),8.22(d,J=8.2Hz,1H),7.67–7.59(m,2H),7 .40(dd,J=7.6,7.6Hz,1H),7.35–7.23(m,3H),7.06–6.99(m,1H),4.10–3.95(m,2H),4.03(s ,3H),3.77(d,J=13.8Hz,1H),3.58(s,3H),3.53–3.35(m,2H),3.44(s,3H),3.22–3.12(m,1H ),2.63–2.55(m,1H),2.19(s,3H),2.09–2.01(m,1H),1.90–1.70(bs,1H),1.54–1.43(m,1H). MS:(ES)m / z C 32 H 35 ClN5O6[M+H] + The calculated value is 620.2 and the measured value is 620.2.

[0416] Example 79: N-(2'-cyano-3'-(5-((((3R,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)methyl)-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0417]

[0418] This compound was prepared starting from N-(2'-cyano-3'-(5-formyl-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide and (3R,4R)-4-aminotetrahydro-2H-pyran-3-ol hydrochloride using a procedure similar to step d in Example 1. The crude product was purified by preparative HPLC to give N-(2'-cyano-3'-(5-((((3R,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)methyl)-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 1 H NMR (400MHz, CDCl3) δ10.93(s,1H),8.53(s,1H),8.30(d,J=7.9Hz,1H),7.80(dd,J=7.8 ,1.1Hz,1H),7.73–7.63(m,2H),7.42–7.30(m,3H),7.10(d,J=7.8Hz,1H),4.10(s,3H), 4.04(dd,J=11.6,4.1Hz,1H),3.97–3.76(m,4H),3.58(s,3H),3.50–3.35(m,2H),3.44( s,3H),2.81(dt,J=11.1,4.1Hz,1H),2.25(s,3H),1.89–1.76(m,1H),1.65–1.50(m,1H). MS:(ES)m / z C 33 H 35 N6O6[M+H] + The calculated value is 611.3 and the measured value is 611.2.

[0419] Example 80: N-(2'-chloro-3'-(5-((3-(2-hydroxypropan-2-yl)azetidin-1-yl)methyl)-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0420]

[0421] This compound was prepared starting from N-(2'-chloro-3'-(5-formyl-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide and 2-(azetidin-3-yl)propan-2-ol hydrochloride using a procedure similar to step d in Example 1. The crude product was purified by preparative HPLC to give N-(2'-chloro-3'-(5-((3-(2-hydroxypropan-2-yl)azetidin-1-yl)methyl)-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 1 H NMR (400MHz, CDCl3) δ10.89(s,1H),8.53(s,1H),8.21(dd,J=7.8,1.1Hz,1H),7.65–7.57(m,2H),7.38(dd,J=7.8Hz,1H),7.30(dd,J=7.8Hz,1H),7.26–7 .21(m,2H),7.03(dd,J=7.8,1.1Hz,1H),4.00(s,3H),3.66(s,2H),3.58(s, 3H),3.44(s,3H),3.44–3.30(m,4H),2.49(s,1H),2.18(s,3H),1.18(s,6H). MS:(ES)m / z C 33 H 37 ClN5O5[M+H] + The calculated value is 618.2 and the measured value is 618.6.

[0422] Example 81: N-(2'-chloro-3'-(5-(((4-hydroxy-2-methylbutan-2-yl)amino)methyl)-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0423]

[0424] The compound was prepared starting from N-(2'-chloro-3'-(5-formyl-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide and 3-amino-3-methylbutan-1-ol using a procedure similar to step d in Example 1. The crude product was purified by preparative HPLC to give N-(2'-chloro-3'-(5-(((4-hydroxy-2-methylbutan-2-yl)amino)methyl)-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 1 H NMR (400MHz, CDCl3) δ10.89 (s, 1H), 8.52 (s, 1H), 8.22 (dd, J = 7.6, 1.2Hz, 1H), 7. 64–7.56(m,2H),7.39(dd,J=7.6,7.6Hz,1H),7.30(dd,J=7.6Hz,1H),7.30–7.19 (m,2H),7.02(dd,J=7.6,1.3Hz,1H),4.02(s,3H),3.88(t,J=5.6Hz,2H),3.82(s ,2H),3.57(s,3H),3.44(s,3H),2.18(s,3H),1.73(t,J=5.4Hz,2H),1.32(s,6H). MS:(ES)m / z C 32 H 37 ClN5O5[M+H] + The calculated value is 606.2 and the measured value is 606.6.

[0425] Example 82: (S)-N-(3'-(6-methoxy-5-((((5-oxopyrrolidin-2-yl)methyl)amino)methyl)pyridin-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0426]

[0427] This compound was prepared starting from N-(3'-(5-formyl-6-methoxypyridin-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide and (S)-5-(aminomethyl)pyrrolidin-2-one hydrochloride using a procedure similar to step d in Example 1. The crude product was purified by preparative HPLC to give (S)-N-(3'-(6-methoxy-5-((((5-oxopyrrolidin-2-yl)methyl)amino)methyl)pyridin-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 1 H NMR (400MHz, CD3OD) δ11.16(s,1H),8.63(d,J=1.3Hz,1H),8.06(d,J=7.9Hz,1H),7.87(d,J=7.5Hz,1 H),7.41(d,J=7.8Hz,1H),7.35(dd,J=7.8Hz,1H),7.28(dd,J=7.5,7.5Hz,1H),7.28(d,J=7.5Hz,1H) ,7.18(d,J=7.8Hz,1H),6.98(d,J=7.5Hz,1H),4.33(s,2H),4.10–4.01(m,1H),4.07(s,3H),3.55(s, 3H),3.39(s,3H),3.34–3.18(m,2H),2.49–2.32(m,3H),2.10(s,3H),2.10(s,3H),1.97–1.85(m,1H). MS:(ES)m / z C 33 H 37 N6O5[M+H] + The calculated value is 597.3 and the measured value is 597.3.

[0428] Example 83: 1-((6-(2,2'-dichloro-3'-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamido)-[1,1'-biphenyl]-3-yl)-2-ethylpyridin-3-yl)methyl)azetidine-3-carboxylic acid

[0429]

[0430] This compound was prepared using a procedure similar to step d in Example 1 starting from N-(2,2'-dichloro-3'-(6-ethyl-5-formylpyridin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide and azetidine-3-carboxylic acid. The crude product was purified by preparative HPLC to give 1-((6-(2,2'-dichloro-3'-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamido)-[1,1'-biphenyl]-3-yl)-2-ethylpyridin-3-yl)methyl)azetidine-3-carboxylic acid. 1 H NMR (400MHz, CD3OD) δ11.69(s,1H),8.66(s,1H),8.53(d,J=8.0Hz,1H),7.92(d,J=7.8Hz, 1H),7.64(d,J=7.8Hz,1H),7.60(d,J=7.8Hz,1H),7.54(dd,J=8.0Hz,1H),7.41(dd,J=8.0 Hz,2H),7.10(dd,J=7.3,1.7Hz,1H),4.65(s,2H),4.49–4.42(m,4H),3.82–3.68(m,1H),3 .55(d,J=1.5Hz,3H), 3.39(d,J=1.8Hz,3H), 3.05(q,J=7.6Hz,2H), 1.35(t,J=9.6Hz,3H). MS:(ES)m / zC 31 H 30 Cl2N5O5[M+H] + The calculated value is 622.2 and the measured value is 622.1.

[0431] Example 84: N-(2,2'-dichloro-3'-(6-ethyl-5-((3-hydroxyazetidin-1-yl)methyl)pyridin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0432]

[0433] This compound was prepared starting from N-(2,2'-dichloro-3'-(6-ethyl-5-formylpyridin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide and azetidin-3-ol using a procedure similar to step d in Example 1. The crude product was purified by preparative HPLC to give N-(2,2'-dichloro-3'-(6-ethyl-5-((3-hydroxyazetidin-1-yl)methyl)pyridin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 1 H NMR (400MHz, CD3OD) δ11.69(s,1H),8.66(d,J=1.9Hz,1H),8.54(d,J=8.6Hz,1H),7.95(d ,J=8.1Hz,1H),7.64(d,J=7.8Hz,1H),7.60(d,J=7.8Hz,1H),7.54(dd,J=8.0,8.0Hz,1H), 7.41(dd,J=8.0,8.0Hz,2H),7.13(dd,J=7.3,1.8Hz,1H),4.63(s,2H),4.45(t,J=8.9Hz, 2H), 4.09 (s, 2H), 3.56 (s, 3H), 3.39 (s, 3H), 3.00 (q, J = 7.6Hz, 2H), 1.36 (t, J = 7.6Hz, 3H). MS:(ES)m / z C 30 H 30 Cl2N5O4[M+H] + The calculated value is 594.2 and the measured value is 594.1.

[0434] Example 85: N-(2,2'-dichloro-3'-(6-ethyl-5-((((3R,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)methyl)pyridin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0435]

[0436] This compound was prepared starting from N-(2,2'-dichloro-3'-(6-ethyl-5-formylpyridin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide and (3R,4R)-4-aminotetrahydro-2H-pyran-3-ol hydrochloride using a procedure analogous to step d in Example 1. The crude product was purified by preparative HPLC to afford N-(2,2'-dichloro-3'-(6-ethyl-5-((((3R,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)methyl)pyridin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 1 H NMR (400MHz, CD3OD) δ11.69(s,1H),8.66(s,1H),8.54(dd,J=8.5,1.8Hz,1H),8.00(d,J=8.0Hz,1H),7.64(d,J=7.8 Hz,1H),7.60(d,J=7.8Hz,1H),7.54(dd,J=8.0Hz,1H),7.41(dd,J=8.0Hz,2H),7.10(d,J=7.3Hz,1H),4.49(d,J=13 .5Hz,1H),4.30(d,J=12.6Hz,1H),4.13(s,1H),4.02(d,J=12.6Hz,2H),3.62(t,J=12.4Hz,2H),3.58(s,3H),3.48( t,J=12.4Hz,2H),3.39(s,3H),3.15–2.29(m,2H),2.21–2.07(m,1H),1.86(d,J=13.1Hz,1H),1.36(t,J=7.2Hz,3H). MS:(ES)m / z C 32 H 34 Cl2N5O5[M+H] + The calculated value is 638.2 and the measured value is 638.2.

[0437] Example 86: (S)-N-(2,2'-dichloro-3'-(6-ethyl-5-((((5-oxopyrrolidin-2-yl)methyl)amino)methyl)pyridin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0438]

[0439] This compound was prepared starting from N-(2,2'-dichloro-3'-(6-ethyl-5-formylpyridin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide and (S)-5-(aminomethyl)pyrrolidin-2-one hydrochloride using a procedure similar to step d in Example 1. The crude product was purified by preparative HPLC to give (S)-N-(2,2'-dichloro-3'-(6-ethyl-5-((((5-oxopyrrolidin-2-yl)methyl)amino)methyl)pyridin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 1 HNMR (400MHz, CD3OD) δ11.69(s,1H),8.66(s,1H),8.54(d,J=8.1Hz,1H),8.01(d,J=8.1Hz, 1H),7.64(d,J=7.8Hz,1H),7.61(d,J=7.8Hz,1H),7.54(dd,J=8.0Hz,1H),7.42(dd,J=8.0Hz ,2H),7.10(dd,J=7.3,1.8Hz,1H),4.46(s,2H),4.06(m,1H),3.56(s,3H),3.37(s,3H),3.35 (m,2H),3.02(q,J=7.6Hz,2H),2.47–2.33(m,3H),2.00–1.91(m,1H),1.36(t,J=7.5Hz,3H). MS:(ES)m / z C 32 H 33 Cl2N6O4[M+H] + The calculated value is 635.2 and the measured value is 635.2.

[0440] Example 87: 1-((5-(2,2'-dichloro-3'-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamido)-[1,1'-biphenyl]-3-yl)-3-methoxypyrazin-2-yl)methyl)-3-methylazetidine-3-carboxylic acid

[0441]

[0442] This compound was prepared using a procedure similar to step d in Example 1 starting from N-(2,2'-dichloro-3'-(5-formyl-6-methoxypyrazin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide and 3-methylazetidine-3-carboxylic acid hydrochloride. The crude product was purified by preparative HPLC to give 1-((5-(2,2'-dichloro-3'-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamido)-[1,1'-biphenyl]-3-yl)-3-methoxypyrazin-2-yl)methyl)-3-methylazetidine-3-carboxylic acid. 1 H NMR (400MHz, CD3OD) δ11.70(s,1H),8.67(s,1H),8.55(d,J=8.1Hz,1H),8.49(s,1H),7.70(d,J=7.8Hz,1H),7.56(dd,J=8.0,8.0Hz,1H),7.47– 7.37(m,2H),7.10(dd,J=7.3,1.8Hz,1H),4.74(s,2H),4.54(bs,1H),4 .29–4.13(bs,3H),4.11(s,3H),3.56(s,3H),3.39(s,3H),1.65(s,3H). MS:(ES)m / z C 30 H 29 Cl2N6O6[M+H] + The calculated value is 639.1 and the measured value is 639.0.

[0443] Example 88: N-(3'-(6-(((2-hydroxyethyl)amino)methyl)-5-methoxypyridin-3-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0444]

[0445] A mixture of N-(3'-(6-formyl-5-methoxypyridin-3-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (40 mg, 0.080 mmol), 2-aminoethane-1-ol (60 mg, 1.0 mmol) and AcOH (90 mg, 1.5 mmol) in EtOH (2.0 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 minutes, the mixture was concentrated in vacuo. The resulting residue was purified by preparative HPLC to give N-(3'-(6-(((2-hydroxyethyl)amino)methyl)-5-methoxypyridin-3-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 1 H NMR (400MHz, CD3OD) δ11.15(s,1H),8.61(s,1H),8.20(d,J=1.6Hz,1H),8.07(ddd,J=8. 4,8.4,1.2Hz,1H),7.49(d,J=1.6Hz,1H),7.36(dd,J=7.6,7.6Hz,1H),7.30–7.25(m,2H) ,7.18(dd,J=7.2,1.2Hz,1H),6.97(dd,J=7.6,0.8Hz,1H),4.45(s,2H),3.97(s,3H),3. 93–3.87(m,2H),3.54(s,3H),3.36(s,3H),3.38–3.28(m,2H),2.10(s,3H),1.94(s,3H). MS:(ES)m / zC 30 H 34 N5O5[M+H] + The calculated value is 544.3 and the measured value is 544.3.

[0446] Example 89: (S)-N-(2'-chloro-3'-(5-((3-hydroxy-3-methylpyrrolidin-1-yl)methyl)-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0447]

[0448] Step a: 1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (50.0 g, 271 mmol) and dichloromethane (800 mL) were placed in a 3-L flask. To this suspension was added oxalyl chloride (32 mL, 370 mmol), followed by DMF (0.5 mL, 6 mmol). After stirring for 90 minutes, the resulting yellow solution was concentrated under reduced pressure. The solid was transferred to a 3-L 3-necked flask and dissolved in anhydrous dichloromethane (800 mL). The solution was cooled to 0°C and 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (64.0 g, 275 mmol) was added, followed by the dropwise addition of Et3N (116 mL, 832 mmol). The reaction mixture was stirred for an additional 13 hours. The volatiles were removed under reduced pressure and the residue was transferred to a 1-L flask and triturated with 600 mL of water. The slurry was stirred for 1 day, then filtered, washed with water, and dried to yield 1,3-dimethyl-N-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-)dioxaborolan-2-yl)phenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 1 H NMR (400MHz, CDCl3) δ10.81(s,1H),8.50(s,1H),8.19(d,J=8.8Hz,1H),7.58(d,J=7.6Hz ,1H),7.23(dd,J=7.6,7.6Hz,1H),3.57(s,3H),3.45(s,3H),2.59(s,3H),1.36(s,12H). MS:(ES)m / z C 20 H 27 BN3O5[M+H] + The calculated value is 400.2 and the measured value is 400.2.

[0449] Step b: To a mixed solution of (3-bromo-2-chlorophenyl)boronic acid (30.0 g, 127.5 mmol), 6-chloro-2-methoxynicotinaldehyde (23.0 g, 134.0 mmol), and K2CO3 (48.0 g, 347.8 mmol) in p-dioxane (450 mL) and DI H2O (80 mL) was added Pd(PPh3)4 (7.4 g, 6.4 mmol). The contents were degassed and stirred at 92°C under N2 for 2 hours. The reaction mixture was cooled to room temperature, diluted with DCM (1 L), washed with brine, dried over MgSO4 and filtered. The solvent was removed under reduced pressure and the residue was triturated with Et2O (500 mL). The solid was collected by filtration to give 6-(3-bromo-2-chlorophenyl)-2-methoxynicotinaldehyde. MS: (ES) m / z C 13 H 10 BrClNO2[M+H]+ The calculated value is 326.0 and the measured value is 325.9.

[0450] Step c: To a mixture of 1,3-dimethyl-N-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (27.4 g, 68.6 mmol), 6-(3-bromo-2-chlorophenyl)-2-methoxynicotinaldehyde (22.4 g, 68.6 mmol), and KCO (28.4 g, 205.8 mmol) in p-dioxane (500 mL) and DIHO (80 mL) was added Pd(dppf)Cl complex with DCM (5.6 g, 6.9 mmol). The contents were degassed and stirred at 92° C. under N for 3 hours. The reaction mixture was cooled to room temperature, filtered through celite, washed with EtOAc (300 mL x 3), and the solvent was removed under reduced pressure. The residue was diluted with DCM, washed with brine and dried over MgSO4. The solvent was removed under reduced pressure, and the solid was triturated with MeCN, filtered and washed with MeCN to give N-(2'-chloro-3'-(5-formyl-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. MS: (ES) m / z C 27 H 24 ClN4O5[M+H] + The calculated value is 519.1 and the measured value is 519.1.

[0451] Step d: To a mixture of N-(2'-chloro-3'-(5-formyl-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (58 mg, 0.11 mmol) and (S)-3-methylpyrrolidin-3-ol (43 mg, 0.31 mmol) in 20% v / v MeOH in DCM (2 mL) was added trimethylamine (0.043 mL, 0.31 mmol). After stirring at room temperature for 20 min, sodium triacetoxyborohydride (91 mg, 0.43 mmol) was added and stirring was continued for 1 day. The reaction was quenched with water (2 mL) and 2:1 CHCl3 / 2-propanol. The organic layer was evaporated to dryness and the crude material was purified by preparative HPLC to give the desired product (S)-N-(2'-chloro-3'-(5-((3-hydroxy-3-methylpyrrolidin-1-yl)methyl)-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide.1 H NMR (400MHz, CD3OD) δ11.18(s,1H),8.63(s,1H),8.10(d,J=8.4Hz,1H),7.91(d,J=8.4Hz,1H),7.65–7.61(m,1H ),7.50(dd,J=7.6,7.6Hz,1H),7.38(d,J=7.6Hz,1H),7.35(dd,J=7.6,1.6Hz,1H),7.29(dd,J=8.0,8.0Hz,1H), 7.00(d,J=7.6Hz,1H),4.55(s,1H),4.51–4.39(m,1H),4.12–4.06(m,3H),3.88–3.57(m,1H),3.55(s,3H),3.53 –3.35(m,1H),3.39(s,3H),3.24–3.10(m,1H),2.32–2.14(m,1H),2.13(s,3H),2.10–1.93(m,1H),1.45(s,3H). MS:(ES)m / z C 32 H 35 ClN5O5[M+H] + The calculated value is 604.2 and the measured value is 604.5.

[0452] Example 90: N-(2'-Fluoro-3'-(5-((((3R,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)methyl)-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0453]

[0454] This compound was prepared starting from N-(2'-fluoro-3'-(5-formyl-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide and (3R,4R)-4-aminooxa-3-ol hydrochloride using a procedure analogous to step d in Example 89. The crude product was purified by preparative HPLC to afford the desired product, N-(2'-fluoro-3'-(5-((((3R,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)methyl)-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 1H NMR (400MHz, CD3OD) δ11.19(s,1H),8.63(s,1H),8.16–8.08(m,2H),7.86(d,J=7. 6Hz,1H),7.55(dd,J=7.6,1.6Hz,1H),7.43–7.28(m,3H),7.10(d,J=7.6Hz,1H),4. 38–4.20(m,2H),4.14(s,3H),4.06–3.93(m,3H),3.60–3.53(m,1H),3.55(s,3H),3 .52–3.41(m,2H),3.39(s,3H),2.20(s,3H),2.17–2.05(m,1H),1.90–1.82(m,1H). MS:(ES)m / z C 32 H 35 FN5O6[M+H] + The calculated value is 604.3 and the measured value is 604.5.

[0455] Example 91: (S)-N-(2-chloro-3'-(6-methoxy-5-((((5-oxopyrrolidin-2-yl)methyl)amino)methyl)pyridin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0456]

[0457] This compound was prepared starting from N-(2-chloro-3'-(5-formyl-6-methoxypyridin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide and (S)-5-aminomethylpyrrolidin-2-one using a procedure analogous to step d in Example 89. The crude product was purified by preparative HPLC to afford (S)-N-(2-chloro-3'-(6-methoxy-5-((((5-oxopyrrolidin-2-yl)methyl)amino)methyl)pyridin)-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 1H NMR (400MHz, CD3OD) δ11.71(s,1H),8.66(s,1H),8.50(d,J=8.8Hz,1H),8.19(s,1H),8.16(d,J=8 .0Hz,1H),7.87(d,J=7.6Hz,1H),7.64(d,J=7.6Hz,1H),7.58(dd,J=7.6,7.6Hz,1H),7.49(d,J=7. 6Hz,1H),7.41(dd,J=7.6,7.6Hz,1H),7.19(d,J=7.6Hz,1H),4.37–4.27(m,2H),4.15(s,3H),4.10 –4.00(m,1H),3.55(s,3H),3.38(s,3H),3.27–3.19(m,2H),2.48–2.31(m,3H),1.97–1.86(m,1H). MS:(ES)m / z C 31 H 32 ClN6O5[M+H] + The calculated value is 603.2 and the measured value is 602.8.

[0458] Example 92: (S)-N-(2-chloro-3'-(6-methoxy-5-((((5-oxopyrrolidin-2-yl)methyl)amino)methyl)pyridin-2-yl)-2'-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0459]

[0460] This compound was prepared starting from N-(2-chloro-3'-(5-formyl-6-methoxypyridin-2-yl)-2'-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide and (S)-5-aminomethylpyrrolidin-2-one using a procedure analogous to step d in Example 89. The crude product was purified by preparative HPLC to afford (S)-N-(2-chloro-3'-(6-methoxy-5-((((5-oxopyrrolidin-2-yl)methyl)amino)methyl)pyridin)-2-yl)-2'-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 1H NMR (400MHz, CD3OD) δ11.69(s,1H),8.67(s,1H),8.51(d,J=8.4Hz,1H),7.88(d,J =7.6Hz,1H),7.45(d,J=7.2Hz,1H),7.43–7.34(m,2H),7.25–7.19(m,2H),7.07(d ,J=7.2Hz,1H),4.38–4.29(m,2H),4.11–4.02(m,1H),4.08(s,3H),3.56(s,3H),3 .38(s,3H),3.29–3.20(m,2H),2.50–2.33(m,3H),2.11(s,3H),1.99–1.86(m,1H). MS:(ES)m / zC 32 H 34 ClN6O5[M+H] + The calculated value is 617.2 and the measured value is 617.5.

[0461] Example 93: (S)-2-(((6-(2,2'-dichloro-3'-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamido)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)-3-hydroxy-2-methylpropanoic acid

[0462]

[0463] This compound was prepared starting from N-(2,2'-dichloro-3'-(5-formyl-6-methoxypyridin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide and (S)-2-amino-3-hydroxy-2-methylpropanoic acid using a procedure analogous to step d in Example 89. The crude product was purified by preparative HPLC to afford (S)-2-(((6-(2,2'-dichloro-3'-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamido)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)-3-hydroxy-2-methylpropanoic acid. 1H NMR (400MHz, CD3OD) δ11.69(s,1H),8.66(s,1H),8.53d,J=8.4Hz,1H),7.91(d,J=7.6Hz,1H),7.65(d,J=7.6Hz,1H),7.51(t,J=7.6Hz,1H),7.44–7 .33(m,3H),7.10(d,J=7.6Hz,1H),4.41–4.29(m,2H),4.09(s,3H),4.11– 4.05(m,1H),3.88(d,J=12Hz,1H),3.56(s,3H),3.39(s,3H),1.63(s,3H). MS:(ES)m / z C 30 H 30 Cl2N5O7[M+H] + The calculated value is 642.2 and the measured value is 642.5.

[0464] Example 94: N-(2,2'-dichloro-3'-(6-methoxy-5-((3-(methylsulfonamido)azetidin-1-yl)methyl)pyridin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0465]

[0466] This compound was prepared starting from N-(2,2'-dichloro-3'-(5-formyl-6-methoxypyridin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide and N-(azetidinyl)methanesulfonamide hydrochloride using a procedure analogous to step d in Example 89. The crude product was purified by preparative HPLC to afford N-(2,2'-dichloro-3'-(6-methoxy-5-((3-(methylsulfonamido)azetidin-1-yl)methyl)pyridin-2-yl))-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 1H NMR (400MHz, CD3OD) δ11.69(s,1H),8.66(s,1H),8.53(d,J=8.0Hz,1H),7.87(d,J=7.2Hz,1H),7.65(d,J=7.6Hz,1H),7.51(dd,J=7.6,7.6H z,1H),7.44–7.36(m,3H),7.10(d,J=7.6Hz,1H),4.61–4.34(m,5H),4.32–4.13(m,2H),4.10(s,3H),3.56(s,3H),3.39(s,3H),2.99(s,3H). MS:(ES)m / z C 30 H 31 Cl2N6O6S[M+H] + The calculated value is 673.1 and the measured value is 672.7.

[0467] Example 95: (R)-1-((6-(2,2'-dichloro-3'-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamido)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)pyrrolidine-3-carboxylic acid

[0468]

[0469] This compound was prepared starting from N-(2,2'-dichloro-3'-(5-formyl-6-methoxypyridin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide and (R)-pyrrolidine-3-carboxylic acid using a procedure analogous to step d in Example 89. The crude product was purified by preparative HPLC to afford (R)-1-((6-(2,2'-dichloro-3'-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamido)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)pyrrolidine-3-carboxylic acid. 1H NMR (400MHz, CD3OD) δ11.69(s,1H),8.66(s,1H),8.54(d,J=6.8Hz,1H),7.92(d,J=7.2Hz,1H),7.67(d,J=8.4Hz,1H),7.52(dd,J=8.0,8.0H z,1H),7.44–7.36(m,3H),7.10(d,J=7.6Hz,1H),4.49(s,2H),4.11(s,3H),3.95–3.34(m,5H),3.55(s,3H),3.38(s,3H),2.66–2.18(m,2H). MS:(ES)m / zC 31 H 30 Cl2N5O6[M+H] + The calculated value is 638.2 and the measured value is 637.8.

[0470] Example 96: N-(2,2'-dichloro-3'-(5-((3-hydroxyazetidin-1-yl)methyl)-4-methoxypyridin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0471]

[0472] The compound was prepared starting from N-(2,2'-dichloro-3'-(5-formyl-4-methoxypyridin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide and azetidin-3-ol hydrochloride using a procedure similar to step d in Example 89. The crude product was purified by preparative HPLC to give N-(2,2'-dichloro-3'-(5-((3-hydroxyazetidin-1-yl)methyl)-4-methoxypyridin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 1HNMR(400MHz,CD3OD)δ11.69(s,1H),8.66(s,1H),8.59(s,1H),8.55(d,J= 8.4Hz,1H),7.64–7.54(m,2H),7.53(s,1H),7.48(d,J=6.4Hz,1H),7.42(d d,J=8.0,8.0Hz,1H),7.10(d,J=7.2Hz,1H),4.65(bs,1H),4.55(s,2H),4. 11–4.38(m,2H),4.13–4.02(m,2H),4.10(s,3H),3.55(s,3H),3.38(s,3H). MS:(ES)m / z C 29 H 28 Cl2N5O5[M+H] + The calculated value is 596.1 and the measured value is 595.8.

[0473] Example 97: (S)-N-(2,2'-dichloro-3'-(4-methoxy-5-((((5-oxopyrrolidin-2-yl)methyl)amino)methyl)pyrimidin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0474]

[0475] This compound was prepared starting from N-(2,2'-dichloro-3'-(5-formyl-4-methoxypyrimidin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide and (S)-5-aminomethylpyrrolidin-2-one hydrochloride using a procedure analogous to step d in Example 89. The crude product was purified by preparative HPLC to afford (S)-N-(2,2'-dichloro-3'-(4-methoxy-5-((((5-oxopyrrolidin-2-yl)methyl)amino)methyl)pyrimidin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 1HNMR (400MHz, CD3OD) δ11.70(s,1H),8.71(s,1H),8.66(s,1H),8.55(d,J=8. 0Hz,1H),7.78(d,J=8.0Hz,1H),7.75(dd,J=8.0,8.0Hz,1H),7.48–7.38(m,2H ),7.10(d,J=7.6Hz,1H),4.37(s,2H),4.19(s,3H),4.09–4.01(m,1H),3.55( s,3H),3.38(s,3H),3.30–3.27(m,2H),2.49–2.32(m,3H),2.00–1.88(m,1H). MS:(ES)m / z C 30 H 30 Cl2N7O5[M+H] + The calculated value is 638.2 and the measured value is 638.2.

[0476] Example 98: 1-((6-(2,2'-dichloro-3'-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamido)-[1,1'-biphenyl]-3-yl)-4-methoxypyridin-3-yl)methyl)-3-methylazetidine-3-carboxylic acid

[0477]

[0478] This compound was prepared starting from N-(2,2'-dichloro-3'-(5-formyl-4-methoxypyridin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide and 3-methyl-3-azetidinecarboxylic acid using a procedure analogous to step d in Example 89. The crude product was purified by preparative HPLC to afford 1-((6-(2,2'-dichloro-3'-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamido)-[1,1'-biphenyl]-3-yl)-4-methoxypyridin-3-yl)methyl)-3-methylazetidine-3-carboxylic acid. 1H NMR (400MHz, CD3OD) δ11.70(s,1H),8.67(s,1H),8.57(s,1H),8.55(d,J=8.8Hz,1H),7.62–7.54(m,2H),7.50(s,1H),7.47(d,J=7.2Hz,1H),7.4 1(dd,J=7.2,7.2Hz,1H),7.10(d,J=7.2Hz,1H),4.62–4.51(m,4H),4.15 (d,J=10.8Hz,2H),4.09(s,3H),3.55(s,3H),3.39(s,3H),1.62(s,3H). MS:(ES)m / z C 31 H 30 Cl2N5O6[M+H] + The calculated value is 638.2 and the measured value is 638.0.

[0479] Example 99: 1-((6-(2,2'-dichloro-3'-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamido)-[1,1'-biphenyl]-3-yl)-4-methoxypyridin-3-yl)methyl)azetidine-3-carboxylic acid

[0480]

[0481] This compound was prepared starting from N-(2,2'-dichloro-3'-(5-formyl-4-methoxypyridin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide and 3-azetidinecarboxylic acid using a procedure analogous to step d in Example 89. The crude product was purified by preparative HPLC to afford 1-((6-(2,2'-dichloro-3'-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamido)-[1,1'-biphenyl]-3-yl)-4-methoxypyridin-3-yl)methyl)azetidine-3-carboxylic acid. 1H NMR (400MHz, CD3OD) δ11.70(s,1H),8.66(s,1H),8.59(s,1H),8.55(d,J=8.0Hz,1H),7.64–7.54(m,2H),7.52(s,1H),7.48(d,J=7.6Hz,1H),7 .42(dd,J=8.0,8.0Hz,1H),7.10(d,J=7.2Hz,1H),4.57(s,2H),4.49–4.38(m,4H),4.10(s,3H),3.78–3.66(m,1H),3.55(s,3H),3.39(s,3H). MS:(ES)m / zC 30 H 28 Cl2N5O6[M+H] + The calculated value is 624.1 and the measured value is 623.9.

[0482] Example 100: (S)-N-(2,2'-dichloro-3'-(4-methoxy-5-((((5-oxopyrrolidin-2-yl)methyl)amino)methyl)pyridin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0483]

[0484] This compound was prepared starting from N-(2,2'-dichloro-3'-(5-formyl-4-methoxypyridin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide and (S)-5-aminomethylpyrrolidin-2-one hydrochloride using a procedure analogous to step d in Example 89. The crude product was purified by preparative HPLC to afford (S)-N-(2,2'-dichloro-3'-(4-methoxy-5-((((5-oxopyrrolidin-2-yl)methyl)amino)methyl)pyridin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 1HNMR(400MHz,CD3OD)δ11.70(s,1H),8.67(s,1H),8.59(s,1H),8.55(d,J=8.4Hz ,1H),7.63–7.55(m,2H),7.53(s,1H),7.47(d,J=6.8Hz,1H),7.42(dd,J=8.0,8. 0Hz,1H),7.10(d,J=8.0Hz,1H),4.41(s,2H),4.11(s,3H),4.09–4.02(m,1H),3. 56(s,3H),3.39(s,3H),3.30–3.27(m,2H),2.48–2.33(m,3H),1.99–1.86(m,1H). MS:(ES)m / z C 31 H 31 Cl2N6O5[M+H] + The calculated value is 637.2 and the measured value is 636.9.

[0485] Example 101: N-(2,2'-dichloro-3'-(5-((((3R,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)methyl)-4-methoxypyridin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0486]

[0487] This compound was prepared starting from N-(2,2'-dichloro-3'-(5-formyl-4-methoxypyridin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide and (3R,4R)-4-aminotetrahydro-2H-pyran-3-ol hydrochloride using a procedure analogous to step d in Example 89. The crude product was purified by preparative HPLC to afford N-(2,2'-dichloro-3'-(5-((((3R,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)methyl)-4-methoxypyridin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 1H NMR (400MHz, CD3OD) δ11.70(s,1H),8.67(s,1H),8.58(s,1H),8.55(d,J=8.4Hz,1 H),7.63–7.54(m,2H),7.50(s,1H),7.47(d,J=7.6Hz,1H),7.42(dd,J=7.6,7.6Hz ,1H),7.10(d,J=7.6Hz,1H),4.46–4.26(m,2H),4.10(s,3H),4.08–3.95(m,3H),3 .61–3.42(m,3H),3.56(s,3H),3.39(s,3H),2.18–2.04(m,1H),1.90–1.83(m,1H). MS:(ES)m / z C 31 H 32 Cl2N5O6[M+H] + The calculated value is 640.2 and the measured value is 639.9.

[0488] Example 102: N-(2'-chloro-3'-(6-methoxy-5-((6-oxo-2,5-diazaspiro[3.4]octan-2-yl)methyl)pyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide

[0489]

[0490] This compound was prepared starting from N-(2'-chloro-3'-(5-formyl-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide and 2,5-diazaspiro[3.4]octan-6-one using a procedure analogous to step d in Example 89. The product was purified by preparative HPLC to afford N-(2'-chloro-3'-(6-methoxy-5-((6-oxo-2,5-diazaspiro[3.4]octan-2-yl)methyl)pyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 1H NMR (400MHz, DMSO-d6) δ: 11.05 (s, 1H), 8.75 (s, 1H), 8.24 (d, J = 8.0Hz, 1H), 8.1 8(bs,1H),7.62(d,J=7.6Hz,1H),7.52(dd,J=7.6,7.6Hz,1H),7.36(d,J=7.4Hz, 1H),7.30(dd,J=7.8,7.8Hz,1H),6.97(d,J=7.5Hz,1H),3.93(s,3H),3.49(s,3H ),3.32(s,6H),3.25(s,3H),2.34–2.24(m,2H),2.20–2.12(m,2H),2.07(s,3H). MS:(ES)m / z C 33 H 34 ClN6O5[M+H] + The calculated value is 629.2 and the measured value is 629.0.

[0491] Biological example: Enzyme-linked immunosorbent assay (ELISA)

[0492] 96-well plates were coated with 1 μg / mL human PD-L1 (obtained from R&D) in PBS at 4°C overnight. The wells were then blocked with 2% BSA in 0.05% TWEEN-20 in PBS (W / V) at 37°C for 1 hour. The plates were washed three times with PBS / 0.05% TWEEN-20, and the compounds were serially diluted (1:5) in dilution medium and added to the ELISA plates. Human PD-1 and biotin 0.3 μg / mL (ACRO Biosystems) were added, incubated at 37°C for 1 hour, and then washed three times with PBS / 0.05% TWEEN-20. A second blocking was performed with 2% BSA in PBS (W / V) / 0.05% TWEEN-20 at 37°C for 10 minutes, and the plates were then washed three times with PBS / 0.05% TWEEN-20. Streptavidin-HRP was added at 37°C for 1 hour, and the plate was then washed three times with PBS / 0.05% TWEEN-20. TMB substrate was added and reacted at 37°C for 20 minutes. Stop solution (2N H2SO4 aqueous solution) was added. The absorbance was read at 450 nm using a microplate spectrophotometer. The results are shown in Table 1: IC 50 Values are provided as follows: from 1000 to 10,000 nM (+); from 10 to 1000 nM (++); less than 10 nM (+++).

[0493] Table 1:

[0494]

[0495]

[0496]

[0497]

[0498]

[0499]

[0500]

[0501]

[0502]

[0503]

[0504]

[0505]

[0506]

[0507]

[0508]

[0509]

[0510] Specific embodiments of the present invention are described herein, including the best mode known to the inventors for carrying out the invention. After reading the above description, variations of the disclosed embodiments will be apparent to those skilled in the art, and it is expected that those skilled in the art will appropriately adopt such variations. Therefore, it is intended to implement the present invention in a manner other than that specifically described herein, and the present invention includes all modifications and equivalents of the subject matter recited in the appended claims as permitted by applicable law. Unless otherwise indicated herein or clearly contradicted by the context, the present invention encompasses its scope.

[0511] All publications, patent applications, accession numbers, and other references cited in this specification are herein incorporated by reference as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.

Claims

1. A compound represented by formula (I), or a pharmaceutically acceptable salt thereof, a racemate thereof, a diastereomer thereof, a geometric isomer thereof, or an enantiomer thereof, in: A is selected from the group consisting of pyridine, pyrimidine and pyrazine, which is unsubstituted or substituted with 1 member selected from the group consisting of C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy and OH; X 1 C 1-3 alkylene; R 2a and R 2b Each independently selected from the following group: H, C 1-8 Alkyl, -Y, -X 2 -CO2R a 、-X 2 -OR a 、-X 2 -C(O)NR a R b and -X 2 -Y, where each X 2 It is C 1-6 Alkylene, any C 1-8 Alkyl is unsubstituted or substituted with one or two members independently selected from the group consisting of OH, C(O)NH2 and CO2H, each Y selected from the group consisting of C 3-6 Cycloalkyl and C 4-8 heterocyclic groups, each of which is unsubstituted or substituted by one to four substituents independently selected from the group consisting of oxo, OH and C 1-4 alkyl; or R 2a and R 2b combine to form 4- to 9-membered rings with zero additional heteroatom ring vertices; By combining R 2a and R 2b The formed ring is unsubstituted or substituted by 1 to 4 substituents independently selected from the group consisting of oxo, C 1-8 Alkyl, C 1-8 Hydroxyalkyl, -X 3 -CO2R a 、-X 3 -N(R b )SO2R a and -X 3 -OR a ; where X 3 It is a key; R 3 and R 4 Each independently selected from the group consisting of F, Cl, CN and CH3; Subscript n is 0; R 6 、R 7 and R 8 is H; Z is selected from the following group: Each R a Independently selected from the group consisting of H, C 1-6 alkyl; Each R b Independently selected from the group consisting of H, C 1-6 alkyl.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, having formula (Ia):

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, having formula (Ib):

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein A is unsubstituted or substituted with one OCH3.

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

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

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

8. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is an optically pure or enriched isomer.

9. The compound of claim 1, wherein the compound is selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

10. The compound according to claim 1, having the formula or a pharmaceutically acceptable salt thereof.

11. The compound according to claim 1, having the formula or a pharmaceutically acceptable salt thereof.

12. The compound according to claim 1, having the formula or a pharmaceutically acceptable salt thereof.

13. The compound according to claim 1, having the formula or a pharmaceutically acceptable salt thereof.

14. The compound according to claim 1, having the formula or a pharmaceutically acceptable salt thereof.

15. The compound according to claim 1, having the formula or a pharmaceutically acceptable salt thereof.

16. The compound according to claim 1, having the formula or a pharmaceutically acceptable salt thereof.

17. The compound according to claim 1, having the formula or a pharmaceutically acceptable salt thereof.

18. The compound according to claim 1, having the formula or a pharmaceutically acceptable salt thereof.

19. A compound selected from the group consisting of or a pharmaceutically acceptable salt thereof.

20. A pharmaceutical composition comprising the compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

21. The pharmaceutical composition of claim 20, further comprising one or more additional therapeutic agents.

22. The pharmaceutical composition of claim 21, wherein the one or more additional therapeutic agents are selected from the group consisting of antimicrobial agents, cytotoxic agents, gene expression regulators, antihormonal agents, antifibrotic agents, antitumor agents, and antiproliferative agents.

23. The pharmaceutical composition of claim 22, wherein the antimicrobial agent is an antiviral agent; and the antitumor agent is an anticancer agent.

24. The pharmaceutical composition of claim 22, wherein the anti-tumor agent is an anti-angiogenic agent, an immunotherapeutic agent, or a radiotherapeutic agent.

25. Use of a compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof, or a composition according to any one of claims 20 to 24, for preparing a medicament for modulating an immune response mediated by the PD-1 signaling pathway in a subject.

26. Use of a compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof, or a composition according to any one of claims 20 to 24, for the preparation of a medicament for modulating an immune response in a subject in need thereof.

27. Use of a compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof, or a composition according to any one of claims 20 to 24, for the preparation of a medicament for inhibiting the growth, proliferation or metastasis of cancer cells in a subject in need thereof.

28. Use of a compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof, or a composition according to any one of claims 20 to 24, for the preparation of a medicament for treating a subject suffering from or susceptible to a disease or condition mediated by the PD-1 signaling pathway.

29. The use of any one of claims 25-28, wherein the subject suffers from a disease or condition selected from the group consisting of an infectious disease, an immune disease, and cancer.

30. The use of any one of claims 25-28, wherein the subject suffers from an inflammatory disease.

31. The use according to claim 29, wherein the infectious disease is a bacterial infectious disease, a viral infectious disease or a fungal infectious disease.

32. The use of claim 29, wherein the cancer is a solid tumor or a hematological malignancy.

33. The method of claim 29, wherein the disease or condition is selected from the group consisting of esophageal cancer, lymphoma, prostate cancer, synovioma, sarcoma, sepsis, bile duct cancer, thymus cancer, uterine cancer, liver infection, neurological tumors, colon cancer, leukemia, multiple myeloma, ovarian cancer, myelodysplastic syndrome, lung cancer, mesothelioma, breast cancer, stomach cancer, pancreatic cancer, head and neck cancer, HIV, herpes virus, papillomavirus, influenza, skin cancer, rectal cancer, anal cancer, testicular cancer, small intestine cancer, endocrine system cancer, urethra cancer, penile cancer, bladder cancer, kidney cancer, ureteral cancer, seminoma, adenoma, leiomyoma, rhabdomyomas, hemangiomas, lymphangiomas, osteomas, lipomas, and fibromas.

34. The use according to claim 33, wherein the leukemia is selected from the group consisting of chronic or acute leukemia including acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia; The sarcoma is selected from the group consisting of Kaposi's sarcoma, fibrosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, angiosarcoma, lymphangiosarcoma, leiomyosarcoma, rhabdomyosarcoma, and soft tissue sarcoma; The bone tumor is selected from the group consisting of bone cancer and chondroma; The lung cancer is selected from the group consisting of small cell lung cancer, squamous non-small cell lung cancer, and non-squamous non-small cell lung cancer; The renal cancer is Wilms tumor; The skin cancer is epidermoid carcinoma or melanoma; The esophageal tumor is esophageal cancer; The lymphoma is Hodgkin's disease; The liver infection is selected from the group consisting of hepatitis A, hepatitis B, hepatitis C, and hepatitis D; The neural tumor is a central nervous system tumor; The prostate cancer is castration-resistant prostate cancer; The adenoma is selected from the group consisting of cystadenoma, pituitary adenoma, pleomorphic adenoma, renal tubular adenoma, and papilloma; The endocrine system cancer is selected from the group consisting of thyroid cancer, parathyroid cancer, and adrenal cancer.

35. The use according to claim 34, wherein The central nervous system tumor is selected from the group consisting of glioblastoma, meningioma, spinal axis tumor, and brainstem glioma; The papilloma is hepatocellular papilloma.

36. The use of any one of claims 26-35, further comprising administering to the subject a therapeutically effective amount of one or more additional therapeutic agents.

37. The use of claim 36, wherein the one or more additional therapeutic agents are selected from the group consisting of antimicrobial agents, cytotoxic agents, gene expression regulators, antihormonal agents, antifibrotic agents, antitumor agents, and antiproliferative agents.

38. The use of claim 37, wherein the antimicrobial agent is an antiviral agent; and the antitumor agent is an anticancer agent.

39. The use according to claim 37, wherein the anti-tumor agent is an anti-angiogenic agent, an immunotherapeutic agent or a radiotherapeutic agent.

40. A method for preparing a compound of formula (II), The method includes: (a) contacting a compound having formula (2c) with a compound having formula (2d) and a first catalyst under Suzuki-type conditions to produce a compound having formula (2e); (b) converting a compound of formula (2e) into a compound of formula (2f) using a borate reagent and a second catalyst; (c) contacting a compound having formula (2f) with a compound having formula (2g) and a third catalyst under Suzuki-type conditions to produce a compound having formula (2h); (d) Using HN(R 2a )(R 2b ) and a hydride reagent to reductively aminize a compound of formula (2h) to provide a compound of formula (II), In the above formulas (2c), (2d), (2e), (2f), (2h) and (II), Z, R 2a 、R 2b 、R 3 、R 3a , subscript n, R 4 、R 5 、R 6 、R 7 、R 8 Each of has the meaning provided in claim 1; R and R' are each independently selected from the group consisting of H and C1-C6 alkyl; X is selected from the group consisting of Br and Cl; X' is selected from the group consisting of I, Br and Cl; With R s The ring is a six-membered nitrogen heteroaryl ring selected from the group consisting of pyridine, pyrimidine and pyrazine, Rs is 0, 1, 2 or 3 substituents independently selected from the group consisting of: C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, OH.

41. A method for preparing a compound of formula (II), The method includes: (a) contacting a compound having formula (2a1) with a compound having formula (2b1) and a first catalyst under Suzuki-type conditions to produce a compound having formula (2c1); (b) contacting a compound having formula (2c1) with a compound having formula (2d1) and a second catalyst under Suzuki-type conditions to produce a compound having formula (2e1); (c) Using HN(R 2a )(R 2b ) and a hydride reagent to reductively aminize a compound of formula (2e1) to provide a compound of formula (II), In the above formulas (2a1), (2b1), (2c1), (2d1), (2e1) and (II), Z, R 2a 、R 2b 、R 3 、R 3a , subscript n, R 4 、R 5 、R 6 、R 7 、R 8 Each of has the meaning provided in claim 1; R and R' are each independently selected from the group consisting of H and C1-C6 alkyl; X' is selected from the group consisting of I, Br and Cl; With R s The ring is a six-membered nitrogen heteroaryl ring selected from the group consisting of pyridine, pyrimidine and pyrazine, R s is 0, 1, 2 or 3 substituents independently selected from the group consisting of: C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, OH.

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