Heteroaryl-biphenyl amides for the treatment of PD-L1 disease

Abstract

Compounds are provided that are effective as immunomodulatory agents, the compounds having formula (I) {wherein R 2a , R 2b , R 3 , R 3a , R 4 , R 6 , R 7 , R 8 , A, Z, X 1 and n is as defined herein}, and includes stereoisomers and pharmaceutically acceptable salts thereof. Methods relating to the preparation and use of such compounds, as well as pharmaceutical compositions containing such compounds, are also disclosed.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority under 35 U.S.C. §119(e) to U.S. Provisional Patent Application Nos. 62 / 915,779, filed October 16, 2019; 63 / 042,796, filed June 23, 2020; and 63 / 057,460, filed July 28, 2020, the disclosures of each of which are incorporated herein by reference in their entireties. STATEMENT REGARDING RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT

[0002] Not applicable Reference to a "Sequence Listing," Table, or Computer Program Listing Appendix Submitted on a Compact Disc

[0003] Not applicable [Background technology]

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

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

[0006] Agents that block the interaction of PD-L1 with either PD-1 or CD80 are desirable. Several antibodies have been developed and commercialized. Several patent applications disclosing non-peptide small molecules have been published (WO2015 / 160641, WO2015 / 034820, and WO2017 / 066227 and WO2018 / 009505 from BMS; WO2015 / 033299 and WO2015 / 033301 by Aurigene; WO2017 / 070089, US2017 / 0145025, (See WO2017 / 106634, US2017 / 0174679, WO2017 / 192961, WO2017 / 222976, WO2017 / 205464, WO2017 / 112730, WO2017 / 041899, and WO2018 / 013789; WO2018 / 006795 by Maxinovel, and WO2018 / 005374 by ChemoCentryx.) However, there remains a need for alternative compounds, such as small molecules, as inhibitors of PD-L1 that may have advantageous characteristics regarding oral administration, stability, bioavailability, therapeutic index, and toxicity. Summary of the Invention [Problem to be solved by the invention]

[0007] A brief summary of the disclosure In one embodiment, a compound of formula (I): [ka] {where A, Z, X 1 , R 2a , R 2b , R 3 , R 3a , R 4 , R 6 , R 7 , R 8 and the subscript n is as defined herein}, or a pharmaceutically acceptable salt, prodrug or bioequivalent thereof. [Means for solving the problem]

[0008] In addition to the compounds provided herein, the disclosure further provides pharmaceutical compositions containing one or more of these compounds, as well as methods related to the preparation and use of such compounds. In some embodiments, the compounds are used in therapeutic methods for treating diseases associated with the PD-1 / PD-L1 pathway.

[0009] BRIEF DESCRIPTION OF THE DRAWINGS Not applicable DETAILED DESCRIPTION OF THE INVENTION

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

[0011] The terms "about" and "approximately" generally refer to an acceptable degree of error for the measured quantity, given the nature or precision of the measurement. Typical and illustrative degrees of error are within 20 percent (%), preferably within 10%, and more preferably within 5% of a given value or range of values. Alternatively, particularly in biological systems, the terms "about" and "approximately" can refer to values ​​that are within an order of magnitude, preferably within 5-fold, and more preferably within 2-fold of a given value. Numerical values ​​given herein are approximate unless otherwise specified, and the term "about" or "approximately" means that values ​​can be inferred unless expressly stated.

[0012] The term “alkyl,” by itself or as part of another substituent, means, unless otherwise stated, a straight or branched chain hydrocarbon radical having the specified number of carbon atoms (i.e., C 1-8 means 1 to 8 carbons). Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. The term "alkenyl" refers to an unsaturated alkyl group having one or more double bonds. Similarly, the term "alkynyl" refers to an unsaturated alkyl group having one or more triple bonds. Examples of alkenyl groups include vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, and 3-(1,4-pentadienyl). Examples of alkynyl groups include ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologs and isomers. The term "cycloalkyl" refers to an alkyl group having the indicated number of ring atoms (e.g., C 3-6"Cycloalkyl" refers to a hydrocarbon ring that is fully saturated or has one or fewer double bonds between ring vertices. "Cycloalkyl" is also intended to refer to bicyclic and polycyclic hydrocarbon rings, such as, for example, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, and the like. The bicyclic or polycyclic ring may be fused, bridged, spiro, or combinations thereof. The term "heterocycloalkyl" or "heterocyclyl" refers to a cycloalkyl group containing 1 to 5 heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized. The heterocycloalkyl may be a monocyclic, bicyclic, or polycyclic ring system. The bicyclic or polycyclic ring may be fused, bridged, spiro, or combinations thereof. C 4-12 The term "heterocyclyl" is understood to refer to groups having 4 to 12 ring members, at least one of which is a heteroatom. Non-limiting examples of heterocycloalkyl groups include pyrrolidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, tetrazolone, hydantoin, dioxolane, phthalimide, piperidine, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S,S-oxide, piperazine, pyran, pyridone, 3-pyrroline, thiopyran, pyrone, tetrahydrofuran, tetrahydrothiophene, quinuclidine, and the like. Heterocycloalkyl groups can be attached to the remainder of the molecule through a ring carbon or a heteroatom.

[0013] The term "alkylene," by itself or as part of another substituent, means a divalent radical derived from an alkane, as exemplified by -CHCHCHCH-. Alkylene groups are straight-chained or branched. Examples of the latter are -CHC(CH)CH, -CHC(CH), or -CH(CH)CHCH. Typically, alkyl (or alkylene) groups have from 1 to 12 carbon atoms, with those groups having 8 or fewer carbon atoms being preferred in this disclosure. Similarly, "alkenylene" and "alkynylene" refer to unsaturated forms of "alkylene" having a double or triple bond, respectively.

[0014] The term "heteroalkyl," by itself or in combination with another term, means, unless otherwise stated, a stable linear or branched chain, or cyclic hydrocarbon radical, or combination thereof, consisting of the stated number of carbon atoms and one to three heteroatoms selected from the group consisting of O, N, Si, and S, wherein the nitrogen and sulfur atoms may be optionally oxidized and the nitrogen heteroatom may be optionally quaternized. The O, N, and S heteroatoms may be placed at any interior position of the heteroalkyl group. The Si heteroatom may be placed at any position of the heteroalkyl group, including the position at which the alkyl group is attached to the remainder of the molecule. Examples 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, the terms "heteroalkenyl" and "heteroalkynyl," by themselves or in combination with other terms, mean, respectively, an alkenyl or alkynyl group containing the stated number of carbon atoms and having from 1 to 3 heteroatoms selected from the group consisting of O, N, Si, and S, unless otherwise stated, wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen heteroatom is optionally quaternized. The O, N, and S heteroatoms can be placed at any interior position of the heteroalkyl group.

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

[0016] The terms "alkoxy," "alkylamino," and "alkylthio" (or thioalkoxy) are used in their conventional sense to refer to alkyl groups attached to the remainder of the molecule via an oxygen atom, an amino group, or a sulfur atom, respectively. Furthermore, in the case of dialkylamino groups, the alkyl portions may be the same or different and may combine to form a 3- to 7-membered ring with the nitrogen atom to which each is attached. Thus, -NR a R b A group represented as: is intended to include piperidinyl, pyrrolidinyl, morpholinyl, azetidinyl, and the like.

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

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

[0019] "C 1-3 The term "alkylguanidinyl" refers to a C alkyl group, as defined above. 1-3 It refers to an alkyl group in which at least one of the hydrogen atoms is replaced by a guanidinyl group (-NHC(NH)NH2).

[0020] The term "aryl," unless otherwise specified, refers to a polyunsaturated, typically aromatic hydrocarbon group that may be monocyclic or polycyclic (up to three rings) fused or covalently linked together. The term "heteroaryl" refers to an aryl group (or ring) containing 1 to 5 heteroatoms selected from N, O, and S, where the nitrogen and sulfur atoms are optionally oxidized and the nitrogen atom is optionally quaternized. A heteroaryl group can be bonded to the remainder of the molecule through a heteroatom. C 5-10References to heteroaryl refer to heteroaryl moieties having 5 to 10 ring members, where it is understood that at least one of the ring members is a heteroatom. Non-limiting examples of aryl groups include phenyl, naphthyl, and biphenyl, while non-limiting examples of heteroaryl groups include pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, quinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, benzotriazinyl, purinyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl, benzisoxazolyl, isobenzofuryl, isoindol ... Indolizinyl, benzotriazinyl, thienopyridinyl, thienopyrimidinyl, pyrazolopyrimidinyl, imidazopyridine, benzothiazolyl, benzofuranyl, benzothienyl, indolyl, quinolyl, isoquinolyl, isothiazolyl, pyrazolyl, indazolyl, pteridinyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiadiazolyl, pyrrolyl, thiazolyl, furyl, thienyl, etc. Substituents for each of the above noted aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below.

[0021] The terms "carbocyclic ring," "carbocyclic," or "carbocyclyl" refer to a ring moiety having only carbon atoms as ring vertices. Carbocyclic ring moieties can be saturated or unsaturated and aromatic. Typically, carbocyclic moieties have 3 to 10 ring members. Carbocyclic moieties with multiple ring structures (e.g., bicyclic) include cycloalkyl rings fused to an aromatic ring (e.g., 1,2,3,4-tetrahydronaphthalene). Thus, carbocyclic rings include cyclopentyl, cyclohexenyl, naphthyl, and 1,2,3,4-tetrahydronaphthyl. The term "heterocyclic ring" refers to both "heterocycloalkyl" and "heteroaryl" moieties. Thus, heterocyclic rings can be saturated or unsaturated and aromatic. Typically, heterocyclic rings have 4 to 10 ring members and include piperidinyl, tetrazinyl, pyrazolyl, and indolyl.

[0022] The above terms (e.g., "alkyl," "aryl," and "heteroaryl") are considered to be "substituted" without further indication of the substituent, and the substitution forms of the indicated group are as provided below.

[0023] Substituents for alkyl groups (including those groups often referred to as alkylene, alkenyl, alkynyl, and cycloalkyl) include -halogen, -OR', -NR'R", -SR', -SiR'R"R"', -OC(O)R', -C(O)R', -COR', -CONR'R", -OC( R', R" and R"' can each independently represent a variety of groups selected from hydrogen, unsubstituted C(O)NR'R", -NR"C(O)R', -NR'-C(O)NR"R"', -NR"C(O)R', -NH-C(NH)=NH, -NR'C(NH)=NH, -NH-C(NH)=NR', -S(O)R', -S(O)R', -S(O)NR'R", -NR'S(O)R", -CN and -NO. 1-8 Alkyl, unsubstituted heteroalkyl, unsubstituted aryl, aryl substituted with 1 to 3 halogens, unsubstituted C 1-8 Alkyl, C 1-8 Alkoxy or C 1-8 refers to a thioalkoxy group, or an unsubstituted aryl-Ci-4 alkyl group. When R' and R" are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 3-, 4-, 5-, 6-, or 7-membered ring. For example, -NR'R" is meant to include 1-pyrrolidinyl and 4-morpholinyl. The term "acyl," by itself or as part of another group, refers to an alkyl group in which two substituents on the carbon closest to the point of attachment of the group are replaced with the substituent =O (e.g., -C(O)CH3, -C(O)CH2CH2OR', etc.).

[0024] Similarly, substituents for the aryl and heteroaryl groups are varied and generally include -halogen, -OR', -OC(O)R', -NR'R", -SR', -R', -CN, -NO2, -C02R', -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)R", -N3, perfluoro(C1-C4)alkoxy, and perfluoro(C1-C4)alkyl; and wherein R', R" and R"' are independently selected from hydrogen, C 1-8 Selected from alkyl, C3-6 cycloalkyl, C2-8 alkenyl, C2-8 alkynyl, unsubstituted aryl and heteroaryl, (unsubstituted aryl)-C1-4 alkyl, and unsubstituted aryloxy-C1-4 alkyl. Other suitable substituents include each of the above aryl substituents attached to a ring atom by an alkylene ether of 1 to 4 carbon atoms.

[0025] Two substituents on adjacent atoms of an aryl or heteroaryl ring may be replaced with a substituent of the formula -TC(O)-(CH)U-, where T and U are independently -NH, -O-, -CH-, or a single bond, and q is an integer from 0 to 2. Alternatively, two substituents on adjacent atoms of an aryl or heteroaryl ring may be optionally replaced with a substituent of the formula -A-(CH)B-, where A and B are independently -CH-, -O-, -NH-, -S-, -S(O)-, -S(O)-, -S(O)NR'-, or a single bond, and r is an integer from 1 to 3. One single bond in the new ring thus formed may optionally be replaced with a double bond. Alternatively, two substituents on adjacent atoms of an aryl or heteroaryl ring may be optionally replaced by a substituent of the formula -(CH2)sX-(CH2)t-, where s and t are independently integers from 0 to 3, and X is -O-, -NR'-, -S-, -S(O)-, -S(O)2-, or -S(O)2NR'-. The substituent R' in -NR'- and -S(O)2NR'- is hydrogen or an unsubstituted C 1-6 alkyl.

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

[0027] The disclosure herein further relates to prodrugs and bioequivalents thereof. For example, suitable bioequivalents include carboxylate substitutions (phosphonic acid, phosphinic acid, sulfonic acid, sulfinic acid, and acidic heterocyclic groups such as tetrazole). Suitable prodrugs include conventional groups known to hydrolyze and / or oxidize under physiological conditions to provide compounds of Formula I.

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

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

[0030] The term "pharmaceutically acceptable salts" is intended to include salts of active compounds prepared with relatively non-toxic acids or bases, depending on the specific substituents found on the compounds described herein. When a compound of the present disclosure contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of salts derived from pharmaceutically acceptable inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganese, potassium, sodium, zinc, and the like salts. Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary, and tertiary amines, such as substituted amines, cyclic amines, naturally occurring amines, and the like, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucan, morpholine, piperazine, piperadine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like. When a compound of the present disclosure contains a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the desired acid, 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, monohydrogenphosphate, dihydrogenphosphate, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid, or phosphorous acid, and the like, 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-tolylsulfonic acid, citric acid, tartaric acid, methanesulfonic acid, and the like.Included are salts of amino acids, such as arginic acid and the like, and organic acids, such as glucuronic acid or galacturonic acid and the like (see, e.g., Berge, SM, et al, "Pharmaceutical Salts," Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain compounds of the present disclosure contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.

[0031] The neutral forms of the compounds can be regenerated by contacting the salt with a base or acid and isolating the parent compound by conventional means. The parent form of the compound may differ from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are similar to the parent form of the compound for purposes of this disclosure.

[0032] Certain compounds of the present disclosure can exist in unsolvated and solvated forms, such as hydrated forms. Generally, solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present disclosure. Certain compounds of the present disclosure can exist in multiple crystalline or amorphous forms. Generally, all physical forms are equivalent for the uses contemplated by the present disclosure and are intended to be within the scope of the present disclosure.

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

[0034] The compounds of the present disclosure may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may contain unnatural proportions of atomic isotopes, such as tritium ( 3 H), iodine-125( 125 I), or carbon-14 ( 14 C). All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are intended to be included within the scope of the present disclosure. The compounds of the present disclosure may also contain unnatural proportions of atomic isomers at one or more of the atoms that constitute such compounds. Unnatural proportions of isotopes may be defined as ranging from the amount found in nature to the amount consisting of 100% of the atom in question. For example, the compounds may be radiolabeled with radioactive isotopes, 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 can provide additional utilities beyond those described elsewhere in this application. For example, but not limited to, isotopic variants of the disclosed compounds can find additional utility as diagnostic and / or imaging reagents or as cytotoxic / radiotoxic therapeutic agents. Furthermore, isotopic variants of the disclosed compounds can possess pharmacokinetic and pharmacodynamic properties that can contribute to enhanced safety, tolerability, or efficacy during treatment. All isotopic variations of the disclosed compounds, whether radioactive or not, are intended to be encompassed within the scope of this disclosure. compound

[0035] In one aspect, the present disclosure provides a compound of formula (I): [ka] {In the formula, A is unsubstituted or halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3Alkoxy, C 1-3 a 5-10 membered heteroaryl group substituted with 1-5 members independently selected from the group consisting of haloalkoxy, OH, and CN; X 1 is C 1-3 alkylene, which is unsubstituted or 1-2 substituted with 1 or 2 members independently selected from the group consisting of alkyl and COH; R 2a and R 2b is 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, wherein each X 2 is C 1-6 alkylene and any C 1-8 Alkyl or C 1-6 Alkylene is unsubstituted or substituted with OH, SO2NH2, C(O)NH2, C(O)NHOH, PO3H2, CO2C 1-8 and each Y is substituted with 1 or 2 members independently selected from the group consisting of alkyl and COH; 3-6 Cycloalkyl, C 4-8 and 5- to 6-membered heteroaryl, each of which is unsubstituted or selected from the group consisting of oxo, OH, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, C1-4 Hydroxyalkoxy, SO2NH2, C(O)NH2, C(O)NHOH, PO3H2, CO2C 1-8 substituted with 1 to 4 substituents independently selected from the group consisting of alkyl, SO3H, and CO2H; or R 2a and R 2b are combined to form a 4-9 membered or spirocyclic ring having 0-2 additional heteroatom ring vertices selected from O, N, or S; where R 2a and R 2b The ring formed by combining 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Hydroxyalkyl, -X 3 -CO2R a , -X 3 -OR a , -X 3 -NR a R b , -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 substituted with 1 to 4 substituents independently selected from the group consisting of: where X 3 is a bond or C 1-6 is alkylene; R 3 and R 4 are each independently selected from the group consisting of H, F, Cl, CN, CH3, OCH3, CH2CH3, and CF3; The subscript n is 0, 1, 2 or 3; Each R 3a are H, F, Cl, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3Haloalkyl, C 1-3 Haloalkoxy, C 2-3 independently selected from the group consisting of alkenyl and CN; R 6 , R 7 and R 8 are each independently selected from the group consisting of H, F, Cl, CN, CH3, OCH3, CH2CH3, and CF3; Z is: i) optionally substituted with one or two oxo groups and up to four R a and / or R b a monocyclic, bicyclic, or spirocyclic non-aromatic heterocyclic ring optionally substituted with ii) 1 to 3 R c a monocyclic 5-6 membered heteroaryl ring optionally substituted with selected from the group consisting of: Each R a is H, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkylene-COH, and C 1-6 independently selected from the group consisting of alkylene-SO3H; Each R b is H, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkylene-COH, and C 1-6 alkylene-SO3H, each of which is unsubstituted or selected from the group consisting of OH, SO2NH2, C(O)NH2, C(O)NHOH, PO3H2, CO2C 1-8 substituted with 1 or 2 members independently selected from alkyl and COH; and R a and R bare optionally combined, when attached to the same nitrogen atom, to form a 4- to 8-membered ring or a spirocyclic ring, which may be unsubstituted or may contain halogen, OH, SO2NH2, C(O)NH2, C(O)NHOH, PO3H2, CO2C 1-8 substituted with alkyl or CO2H; Each R c 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 is a bond or C 1-6 alkylene, and each Y 1 But C 3-6 Cycloalkyl and C 4-8 heterocyclyl; and optionally two R on adjacent ring vertices c are combined to form a fused 5- or 6-membered heterocyclic ring}, or a pharmaceutically acceptable salt, prodrug or bioequivalent thereof.

[0036] In one group of embodiments, compounds of formula (I) are those in which A is unsubstituted or is selected from the group consisting of halogen, C 1-3Alkyl, C 1-3 Haloalkyl, C 1-3 In one group of embodiments, the compounds of formula (I) are those in which A is unsubstituted or is selected from the group consisting of halogen, C ... 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 and alkoxy, and CN.

[0037] In one group of embodiments, compounds of formula (I) are those in which A is unsubstituted or is selected from the group consisting of halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 In one group of embodiments, the compounds of formula (I) are those in which A is unsubstituted or is selected from the group consisting of halogen, C ... 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 and 6-membered heteroaryl groups substituted with 1 to 3 members independently selected from the group consisting of alkoxy, and CN.

[0038] In one group of embodiments, compounds of formula (I) are those where 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 1 or 2 members independently selected from the group consisting of CF, OH, Et, CN, OCH, and F. In one group of embodiments, compounds of formula (I) are those where 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 1 or 2 members independently selected from the group consisting of OCH and F.

[0039] 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 CF, OH, Et, CN, OCH, 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 OCH and F.

[0040] In some embodiments, the present disclosure provides a compound of formula (Ia): [ka] {wherein the group R 2a , R 2b , R 3 , R 4 , A, X 1 and Z has the meaning given for formula (I).

[0041] In some embodiments, the present disclosure provides a compound of formula (Ib): [ka] {wherein the group R 2a , R 2b , R 3 , R 4 , A and Z have the meanings given in relation to formula (I).

[0042] In selected embodiments, including any of those previously described with respect to compounds of Formula (I), (Ia) or (Ib), further embodiments include those in which Z is optionally substituted with one or two oxo groups, and optionally R a and / or R b is a 5- or 6-membered non-aromatic heterocyclic ring substituted with

[0043] In some selected embodiments, compounds of Formula (I), (Ia), or (Ib) include those wherein Z is one of the following: [ka] and n is a non-aromatic heterocyclic ring having a formula selected from the group consisting of:

[0044] In some selected embodiments, compounds of Formula (I), (Ia), or (Ib) include compounds wherein Z is a non-aromatic heterocyclic ring selected from the group consisting of piperidinyl, morpholinyl, tetrahydropyranyl, and tetrahydrofuranyl, each of which optionally contains up to four R a and / or R b and those compounds in which the compound is substituted with

[0045] In some selected embodiments, compounds of Formula (I), (Ia), or (Ib) are those in which Z is optionally 1 to 3 R c and wherein said heteroaryl ring is selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, oxazolyl, thiazolyl, and pyrazolyl.

[0046] In some selected embodiments, compounds of Formula (I), (Ia), or (Ib) are those in which Z is optionally 1 to 3 R c and wherein said heterocyclic ring is selected from the group consisting of pyridinyl, pyrimidinyl, and pyrazinyl.

[0047] In selected embodiments, including any of those previously described with respect to compounds of Formula (I), (Ia) or (Ib), a further embodiment is one in which the group A is a 5- or 6-membered heteroaryl group and is unsubstituted or substituted with 1 or 2 members independently selected from OCH and F.

[0048] In selected embodiments, including any of those previously described with respect to compounds of formula (I), (Ia) or (Ib), further embodiments include R 2a and R 2b are H, respectively.

[0049] In selected embodiments, including any of those previously described with respect to compounds of formula (I), (Ia) or (Ib), further embodiments include R 2a and R 2b are combined to form a 4-9 membered ring or spirocyclic ring, optionally having one or two additional ring vertices selected from O, N, or S; 1-8 Alkyl, C 1-8 Haloalkyl, 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 substituted with 0 to 4 substituents independently selected from the group consisting of: 2 is a bond or C 1-6 It is an alkylene.

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

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

[0052] In selected embodiments, including any of those previously described with respect to compounds of formula (I), (Ia) or (Ib), further embodiments include -N(R 2a )(R 2b ) but the following: [ka] is selected from the group consisting of:

[0053] In selected embodiments, including any of those previously described with respect to compounds of formula (I), (Ia) or (Ib), further embodiments include R 2a is H or C 1-8 alkyl; and R 2b is -Y or -X 2 -Y is something.

[0054] In selected embodiments, including any of those previously described with respect to compounds of formula (I), (Ia) or (Ib), further embodiments include R 2a is H or C 1-8 alkyl; R 2b is -Y or -X 2 -Y; and Y is C 3-6 Cycloalkyl and C 4-8 heterocyclyl, each of which is optionally oxo, OH, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 1-4 Hydroxyalkoxy, SO2NH2, C(O)NH2, C(O)NHOH, PO3H2, CO2C 1-8 and CO2H.

[0055] In selected embodiments, including any of those previously described with respect to compounds of formula (I), (Ia) or (Ib), further embodiments include R 3 and R 4 are each independently selected from the group consisting of F, Cl, CN, CH3, OCH3, CH2CH3, and CF3. In selected embodiments, including any of those previously described with respect to compounds of formula (I), (Ia), or (Ib), further embodiments include those in which R 3 and R 4 are each independently selected from the group consisting of H, F, Cl, CN, CH3, and CF3.

[0056] In selected embodiments, including any of those described above with respect to compounds of Formula (I), (Ia) or (Ib), a further embodiment is one in which the compound is selected from Table 1.

[0057] In selected embodiments, including any of those described above with respect to compounds of Formula (I), (Ia) or (Ib), a further embodiment is one in which the compound is selected from Table 1 and has an activity of ++ or +++.

[0058] In selected embodiments, including any of those described above with respect to compounds of Formula (I), (Ia) or (Ib), a further embodiment is one in which the compound is selected from Table 1 and has an activity of +++.

[0059] In addition to the compounds provided above, pharmaceutically acceptable salts of these compounds are also provided. In some embodiments, the pharmaceutically acceptable salts include ammonium salts, calcium salts, magnesium salts, potassium salts, sodium salts, zinc salts, arginine salts, betaine salts, caffeine salts, choline salts, N,N'-dibenzylethylenediamine salts, diethylamine salts, 2-diethylaminoethanol salts, 2-dimethylaminoethanol salts, ethanolamine salts, ethylenediamine salts, N-ethylmorpholine salts, N-ethylpiperidine salts, glucamine salts, glucosamine salts, histidine salts, hydrabamine salts, isopropylamine salts, lysine salts, methylglucamine salts, and morpholine salts. , piperazine salt, piperazine salt, piperadine salt, procaine salt, purine salt, theobromine salt, triethylamine salt, trimethylamine salt, tripropylamine salt, tromethamine salt, hydrochloride, carbonate, monohydrogen carbonate, phosphate, monohydrogen phosphate, dihydrogen phosphate, acetate, propionate, isobutyrate, malonate, benzoate, succinate, suberate, fumarate, mandelate, phthalate, benzenesulfonate, p-tolylsulfonate, citrate, tartrate, methanesulfonate, alginate, glucuronate, and galacturonate. In some embodiments, the pharmaceutically acceptable salt is selected from ammonium, calcium, magnesium, potassium, sodium, hydrochloride, carbonate, monohydrogen carbonate, phosphate, monohydrogen phosphate, dihydrogen phosphate, acetate, propionate, isobutyrate, malonate, benzoate, succinate, suberate, fumarate, mandelate, phthalate, benzenesulfonate, p-tolylsulfonate, citrate, tartrate, methanesulfonate, alginate, glucuronate, and galacturonate. In some embodiments, the pharmaceutically acceptable salt is sodium or hydrochloride.

[0060] The present disclosure provides compounds in the form of prodrugs in addition to salts. Prodrugs of the compounds described herein are compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present disclosure. In addition, prodrugs can be converted to the compounds of the present disclosure by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present disclosure by placing them in a transdermal patch reservoir containing a suitable enzyme or chemical reagent.

[0061] The esters can be used as prodrugs for the corresponding carboxylic acids. 1-10 Alkyl ester or C 1-10 Haloalkyl esters can be used as prodrugs for the corresponding carboxylic acids. T-butyl esters, methyl esters, ethyl esters, isopropyl esters can be used. Preparation method

[0062] In addition to the methods described in the Examples below, general methods for the preparation of compounds of formula (I) are provided in Schemes 1 and 2. [ka]

[0063] Scheme 1 illustrates a general method for the preparation of compounds having formula (I), where A is a 6-membered nitrogen-containing heteroaryl ring (e.g., pyridyl, pyrimidinyl), and X 1 is CH2. In the above scheme, R s represents one or more substituents on the heteroaryl ring.

[0064] Amide formation between carboxylic acid (a) and boronate-aniline compound (b) proceeds smoothly in the presence of a coupling reagent to provide (c). Suzuki-type coupling of (d) with (c) in the presence of a catalyst then provides biphenyl compound (e). Compound (e) is then converted to boronate (f), followed by a second Suzuki-type coupling (with haloheteroaryl compound (g)) to provide triarylaldehyde (h). Next, HNR 2a R 2b Reductive amination of the aldehyde with can provide compounds of formula (Ia). [ka]

[0065] In another Suzuki coupling-based approach, boronate compound (a1) is combined with aldehyde (b1) to form arylheteroaryl adduct (c1), which, when subjected to Suzuki-type coupling with (d1), provides triarylaldehyde (e1). Then, as shown in Scheme 1, HNR 2a R 2b Reductive amination of the aldehyde with can provide compounds of formula (Ia). Pharmaceutical Composition

[0066] Compositions of these compounds will typically contain a pharmaceutical carrier or diluent in addition to the compounds presented herein.

[0067] As used herein, the term "composition" is intended to encompass any product containing the specified ingredients in the specified amounts, as well as any product resulting directly or indirectly from combining the specified ingredients in the specified amounts. "Pharmaceutically acceptable" means that the carrier, diluent, or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient of the formulation.

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

[0069] In some embodiments, the pharmaceutical composition further comprises one or more additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are selected from the group consisting of antimicrobial agents, antiviral agents, cytotoxic agents, gene expression modulators, chemotherapeutic agents, anticancer agents, antiangiogenic agents, immunotherapeutic agents, antihormonal agents, antifibrotic agents, radiation therapy, radiotherapeutic agents, anti-neoplastic agents, and anti-proliferative agents. In some embodiments, the one or more additional therapeutic agents are antagonists of chemokine and / or chemoattractant receptors, including, but not limited to, CCR1, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10, CCR11, CCR12, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, CXCR6, CXCR7, C3aR, and / or C5aR.Antagonists of chemokine and / or chemoattractant receptors are known in the art and are described, for example, in WO2007 / 002667, WO2007 / 002293, WO / 2003 / 105853, WO / 2007 / 022257, WO / 2007 / 059108, WO / 2007 / 044804, WO2007 / 115232, WO2007 / 115231, WO2008 / 14781 5, WO2010 / 030815, WO2010 / 075257, WO2011 / 163640, WO2010 / 054006, WO2010 / 051561, WO2011 / 035332 , WO2013 / 082490, WO2013 / 082429, WO2014 / 085490, WO2014 / 100735, WO2014 / 089495, WO2015 / 084842; WO2016 / 187393, WO2017 / 127409, WO2017 / 087607, WO2017 / 087610, WO2017 / 176620, WO 2018 / 222598, WO2018 / 222601, WO2013 / 130811, WO2006 / 076644, WO2008 / 008431, WO20 09 / 038847, WO2008 / 008375, WO2008 / 008374, WO2008 / 010934, WO2009 / 009740, WO2005 / 112925, WO2005 / 112916, WO2005 / 113513, WO2004 / 085384, WO2004 / 046092. Chemokine and / or chemoattractant receptor antagonists also include CCX354, CCX9588, CCX140, CCX872, CCX598, CCX6239, CCX9664, CCX2553, CCX3587, CCX3624, CCX2991, CCX282, CCX025, CCX507, CCX430, CCX765, CCX224, CCX662, CCX650, CCX832, CCX168, CCX168-M1, CCX3022, and / or CCX3384.

[0070] Pharmaceutical compositions for administering the compounds of the present disclosure may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy and drug delivery. All methods include the step of bringing the active ingredient into association with a carrier which constitutes one or more accessory ingredients. In general, pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier and / or a finely divided solid carrier, and then, if necessary, shaping the product into the desired formulation. The pharmaceutical composition contains an amount of the active compound sufficient to produce the desired effect on the process or condition of a disease.

[0071] Pharmaceutical compositions containing the active compound can be in a form suitable for oral use, such as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions and self-emulsifying formulations described in U.S. Patent Application No. 2002-0012680, hard or soft capsules, syrups, elixirs, solutions, oral patches, oral gels, chewing gum, chewable tablets, effervescent powders, and effervescent tablets. Compositions intended for oral use can be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents selected from the group consisting of sweeteners, flavoring agents, coloring agents, antioxidants, and preservatives to provide a pharmaceutically acceptable and palatable preparation. Tablets contain the active ingredient in admixture with pharmaceutically acceptable, non-toxic excipients suitable for the manufacture of tablets. These excipients may be, for example, inert diluents (e.g., cellulose, silicon dioxide, aluminum oxide, calcium carbonate, sodium carbonate, glucose, mannitol, sorbitol, lactose, calcium phosphate, sodium phosphate); granulating or disintegrating agents (e.g., corn starch, alginic acid); binders (e.g., PVP, cellulose, PEG, starch, gelatin, gum arabic); and lubricants (e.g., magnesium stearate, stearic acid, talc). The tablets may be uncoated or may be enteric-coated or otherwise coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, time-delay materials (e.g., glyceryl monostearate or glyceryl distearate) can be used. Tablets may also be coated by techniques described in U.S. Pat. Nos. 4,256,108; 4,166,452; and 4,265,874 to form osmotic therapeutic tablets for control release.

[0072] Oral formulations may be provided as hard gelatin capsules containing the active ingredient mixed with an inert solid diluent (e.g., calcium carbonate, calcium phosphate, kaolin, polyethylene glycols (PEG) of various average sizes (e.g., PEG400, PEG4000)) and some surfactants (e.g., Cremophor or Solutol), or as soft gelatin capsules containing the active ingredient mixed with water or an oil medium (e.g., peanut oil, liquid paraffin, olive oil). Additionally, emulsions may be prepared with water-immiscible ingredients (e.g., oils) and stabilized with surfactants (e.g., monodiglycerides, PEG esters, etc.).

[0073] Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents (e.g., sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, gum arabic), and dispersing or wetting agents can be natural phosphatides (e.g., lecithin), or condensation products of alkylene oxides with fatty acids (e.g., polyoxyethylene stearate), or condensation products of ethylene oxide with long-chain aliphatic alcohols (e.g., heptadecaethyleneoxycetanol), or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitols (e.g., polyoxyethylene sorbitol monooleate), or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides (e.g., polyethylene sorbitan monooleate). The aqueous suspensions may also contain one or more preservatives (for example, ethyl p-hydroxybenzoate, n-propyl p-hydroxybenzoate), one or more coloring agents, one or more flavoring agents, and one or more sweetening agents (for example, sucrose or saccharin).

[0074] Oily suspensions can be prepared by suspending the active ingredient in a vegetable oil (e.g., peanut oil, olive oil, sesame oil, coconut oil) or a mineral oil (e.g., liquid paraffin). Oily suspensions can contain thickening agents (e.g., beeswax, hard paraffin, cetyl alcohol). Sweeteners and flavoring agents, as described above, can be added to make oral preparations palatable. These compositions can be preserved by adding an antioxidant (e.g., ascorbic acid).

[0075] Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent, and one or more preservatives. Examples of suitable dispersing or wetting agents and suspending agents have already been exemplified above. Additional excipients (for example sweetening, flavoring, coloring agents) can also be present.

[0076] The pharmaceutical compositions of the present disclosure can also be in the form of an oil-in-water emulsion. The oil phase can be a vegetable oil (e.g., olive oil, peanut oil), a mineral oil (e.g., liquid paraffin), or a mixture thereof. Suitable emulsifiers include natural gums (e.g., gum arabic, gum tragacanth), natural phosphatides (e.g., soybean lecithin), esters or partial esters derived from fatty acids and hexitol anhydrides (e.g., sorbitan monooleate), and condensation products of the partial esters with ethylene oxide (e.g., polyoxyethylenesorbitan monooleate). The emulsions can also contain sweeteners and flavoring agents.

[0077] Syrups and elixirs can be formulated with sweetening agents (e.g., glycerol, propylene glycol, sorbitol, sucrose). Such formulations can also contain demulcents, preservatives, flavorings, and coloring agents. Oral solutions can be prepared in combination with, for example, cyclodextrin, PEG, or surfactants.

[0078] The pharmaceutical compositions can be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension can be formulated using suitable dispersing or wetting agents and suspending agents, as described above, according to known techniques. A sterile injectable preparation can also be prepared as a sterile injectable solution or suspension in a pharmaceutically acceptable non-toxic diluent or solvent, for example, a solution in 1,3-butane. Acceptable vehicles and solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile, fixed oils are commonly used as solvents or suspending media. For this purpose, any bland, fixed oil can be used, including synthetic monoglycerides or diglycerides. Additionally, fatty acids, such as oleic acid, are used to prepare injectable solutions.

[0079] The compounds of the present disclosure can also be administered in the form of suppositories for rectal administration. This composition can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature, thereby dissolving in the rectum and releasing the drug. Such materials include cocoa butter and polyethylene glycol. Additionally, the compounds can be delivered to the eye via solutions or ointments. Furthermore, transdermal delivery of the compounds of the present disclosure can be achieved via iontophoretic patches, etc. For topical use, creams, ointments, jellies, solutions, suspensions, etc., containing the compounds of the present disclosure are utilized. As used herein, topical application also includes the use of mouthwashes and gargles.

[0080] The compounds of the present disclosure can also be combined with polymeric substrates suitable as drug carriers for targeted delivery. Examples of such polymers include polyvinylpyrrolidone, pyran copolymers, polyhydroxypropylmethacrylamidephenol, polyhydroxyethylaspartamidephenol, and palmitoyl-substituted polyethyleneoxide-polylysine. Furthermore, the compounds of the present disclosure can be combined with substrates (e.g., polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsiloncaprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, crosslinked block polymers or amphiphilic block polymers of hydrogels) that are useful for achieving controlled drug release. The polymer and semipermeable polymer matrix can be formed into a shaped article (e.g., a valve, a stent, a tube, a prosthesis, etc.). In one embodiment of the present disclosure, the compounds of the present disclosure are combined with a polymer or semipermeable polymer matrix and formed into a stent or stent-graft device. Methods of Treating Diseases and Disorders

[0081] Compounds of the present disclosure can be used as immunomodulatory agents. Compounds of the present disclosure can be used as agonists, antagonists, partial agonists, inverse agonists, or inhibitors of PD-1 and / or PD-L1 in a variety of contexts in vitro and in vivo. In some embodiments, compounds of the present disclosure can be used as inhibitors of the PD-1 / PD-L1 protein-protein interaction. In some embodiments, compounds of the present disclosure can be used as inhibitors of PD-L1. In some embodiments, compounds of the present disclosure can be used as inhibitors of the CD80 / PD-L1 protein-protein interaction. In some embodiments, compounds of the present disclosure can be used to inhibit the interaction between PD-1 and PD-L1, and / or the interaction between PD-1 and CD80, and / or the interaction between PD-1 and PD-L2, in vitro or in vivo. In some embodiments, compounds of the present disclosure can be used to inhibit VISTA and / or TIM-3. In some embodiments, compounds of the disclosure can be inhibitors of PD-1 / PD-L1 protein-protein interaction and inhibitors of VISTA and / or TIM-3. In some embodiments, compounds of the disclosure can 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 in addition to being inhibitors of PD-1 / PD-L1 protein-protein interaction.

[0082] A compound of the present disclosure can be contacted with a receptor with which it interacts in aqueous solution under conditions not suitable for the ligand to bind to the receptor. The receptor can be in suspension (e.g., isolated membrane or cell preparation), in cultured or isolated cells, or in tissues or organs.

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

[0084] In some embodiments, compounds of the present disclosure are useful for restoring and increasing T cell activation. In some embodiments, compounds of the present disclosure are useful for enhancing immune responses in patients. In some embodiments, compounds of the present disclosure are useful for treating, preventing, or delaying the progression of diseases or disorders (e.g., cancer, infectious diseases) in various therapeutic areas.

[0085] In some embodiments, compounds of the present disclosure can be used to treat patients suffering from diseases that respond to modulation of PD-1 / PD-L1 protein-protein interactions.

[0086] In some embodiments, provided are methods of 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.

[0087] In some embodiments, provided are methods of promoting, stimulating, modulating, and / or increasing an immune response in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure, including a compound of Formula (I), (Ia), 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.

[0088] In some embodiments, provided are methods of inhibiting the growth, proliferation, or metastasis of cancer cells in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure, including a compound of Formula (I), (Ia), 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.

[0089] In some embodiments, provided are methods of treating a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure, including a compound of Formula (I), (Ia), 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.

[0090] In some embodiments, the subject is suffering from a disease or disorder, the disease or disorder being selected from an infectious disease, a bacterial infection, a viral infection, a fungal infection, a solid tumor, a hematological malignancy, an immune disorder, an inflammatory disease, or cancer. In some embodiments, the disease or disorder is melanoma, glioblastoma, esophageal tumor, nasopharyngeal carcinoma, uveal melanoma, lymphoma, lymphocytic lymphoma, primary CNS lymphoma, T-cell lymphoma, diffuse large B-cell lymphoma, primary mediastinal large B-cell lymphoma, prostate cancer, castration-resistant prostate cancer, chronic myeloid leukemia, Kaposi's sarcoma, fibrosarcoma, liposarcoma, chondrosarcoma, osteosarcoma, angiosarcoma, lymphangiosarcoma, synovium, meningioma, leiomyosarcoma, rhabdomyosarcoma, sarcoma of soft tissue, sarcoma, or sepsis. , bile duct tumor, basal cell carcinoma, thymus tumor, thyroid cancer, parathyroid cancer, uterine cancer, adrenal gland cancer, liver infection, Merkel cell carcinoma, nerve tumor, follicle center lymphoma, colon cancer, Hodgkin's disease, non-Hodgkin's lymphoma, leukemia, chronic or acute leukemia (including acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, and chronic lymphocytic leukemia), multiple myeloma, ovarian tumor, myelodysplastic syndrome, cutaneous or intraocular malignant melanoma, renal cell carcinoma, small cell lung cancer, lung cancer, mesothelioma, breast cancer, squamous non-small cell lung cancer (SCLC), Non-Squamous NSCLC, Colon Cancer, Ovarian Cancer, Gastric Cancer, Hepatocellular Carcinoma, Pancreatic Carcinoma, Pancreatic Cancer, Pancreatic Ductal Adenocarcinoma, Squamous Cell Carcinoma of the Head and Neck, Cancer of the Head or Neck, Cancer of the Gastrointestinal Tract, Stomach Cancer, HIV, Hepatitis A, Hepatitis B, Hepatitis C, Hepatitis D, Herpes Virus, Papillomavirus, Influenza, Bone Cancer, Skin Cancer, Rectal Cancer, Cancer of the Anal Region, Testicular Cancer, Carcinoma of the Fallopian Tubes, Carcinoma of the Endometrium, Carcinoma of the Cervix, Carcinoma of the Vagina, Carcinoma of the Vulva, Cancer of the Esophagus, Cancer of the Small Intestine, Cancer of the Endocrine System, Cancer of the Urethra, Cancer of the Penis cancer, cancer of the bladder, cancer of the kidney, cancer of the ureter, carcinoma of the renal pelvis, neoplasms of the central nervous system (CNS), tumor angiogenesis, spinal cord tumor, brain stem glioma, pituitary adenoma, squamous cell carcinoma, asbestosis, carcinoma, adenocarcinoma, papillary carcinoma, cystadenocarcinoma, bronchial carcinoma, renal cell carcinoma, transitional cell carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, pleomorphic adenoma, hepatocellular papilloma, tubular adenoma, cystadenoma, papilloma, adenoma, leiomyoma, rhabdomyoma, hemangioma, lymphangioma, osteoma, chondroma, lipoma, fibroma.

[0091] In some embodiments, the subject is further administered a therapeutically effective amount of one or more additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are selected from the group consisting of antimicrobial agents, antiviral agents, cytotoxic agents, gene expression modulators, chemotherapeutic agents, anticancer agents, antiangiogenic agents, immunotherapeutic agents, antihormonal agents, antifibrotic agents, radiation therapy, radiotherapeutic agents, anti-neoplastic agents, and anti-proliferative agents. In some embodiments, the one or more additional therapeutic agents are antagonists of chemokine and / or chemoattractant receptors, including, but not limited to, CCR1, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10, CCR11, CCR12, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, CXCR6, CXCR7, C3aR, and / or C5aR.Antagonists of chemokine and / or chemoattractant receptors are known in the art and are described, for example, in WO2007 / 002667, WO2007 / 002293, WO / 2003 / 105853, WO / 2007 / 022257, WO / 2007 / 059108, WO / 2007 / 044804, WO2007 / 115232, WO2007 / 115231, WO2008 / 14781 5, WO2010 / 030815, WO2010 / 075257, WO2011 / 163640, WO2010 / 054006, WO2010 / 051561, WO2011 / 035332 , WO2013 / 082490, WO2013 / 082429, WO2014 / 085490, WO2014 / 100735, WO2014 / 089495, WO2015 / 084842; WO2016 / 187393, WO2017 / 127409, WO2017 / 087607, WO2017 / 087610, WO2017 / 176620, WO 2018 / 222598, WO2018 / 222601, WO2013 / 130811, WO2006 / 076644, WO2008 / 008431, WO20 09 / 038847, WO2008 / 008375, WO2008 / 008374, WO2008 / 010934, WO2009 / 009740, WO2005 / 112925, WO2005 / 112916, WO2005 / 113513, WO2004 / 085384, WO2004 / 046092. Chemokine and / or chemoattractant receptor antagonists also include CCX354, CCX9588, CCX140, CCX872, CCX598, CCX6239, CCX9664, CCX2553, CCX3587, CCX3624, CCX2991, CCX282, CCX025, CCX507, CCX430, CCX765, CCX224, CCX662, CCX650, CCX832, CCX168, CCX168-M1, CCX3022, and / or CCX3384.

[0092] In some embodiments, the compounds of the present disclosure can be used to inhibit infectious diseases.Non-limiting examples of infectious diseases include HIV infection, influenza infection, herpes infection, giardiasis, malaria infection, leishmaniasis; viruses such as hepatitis virus (A, B, C), herpes virus (e.g., VZV, HSV-I, HAV-6, HSV-II, 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 contagiosum virus, poliovirus, rabies virus, JC virus, Pathogenic infections caused by arboviral encephalitis viruses; bacterial infections caused by bacteria such as Chlamydia, Rickettsia, Mycobacteria, Staphylococcus, Streptococcus, Pneumococcus, Meningococcus, Gonococcus, Klebsiella, Proteus, Serratia, Pseudomonas, Escherichia coli, Legionella, Diphtheria, Salmonella, Bacillus, Cholera, Tetanus, Botulinum, Anthrax, Yersinia pestis, Leptospira, and Lyme disease; fungal infections caused by fungi such as Candida (albicans, krusei, glabrata, tropicalis, etc.), Cryptococcus neoformans, Aspergillus (fumigatus, niger, etc.), Mucosae (Mucorrhoea, Pseudomonas, Rhizopus), Sporo Pathogenic infections caused by Trichoderma schenckii, Blastomyces dermatotichidis, Paracoccidioides brasiliensis, Coccidioides immitis, and Histoplasma capsulatum; and pathogenic infections caused by the parasites Entamoeba histolytica, Balantidium coli, Naegleria fowleri, Acanthamoeba species, Giardia lamblia, Cryptosporidium species, Pneumocystis carinii, Plasmodium vivax, Babesia microti, Trypanosoma brucei, Trypanosoma cruzi, Leishmania donovani, Toxoplasma gondii, and Nippostrongylus brasiliensis.

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

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

[0095] The treatment methods provided herein generally involve administering to a patient an effective amount of one or more compounds provided herein. Suitable patients include those suffering from or susceptible to the disorders or diseases described herein (i.e., suitable for preventative treatment). Typical patients for treatment as described herein include mammals, particularly primates, and especially humans. Other suitable patients include domesticated pets (e.g., dogs, cats, horses, etc.) and livestock (e.g., cows, pigs, sheep, etc.).

[0096] In general, the methods of treatment provided herein involve administering to a patient an effective amount of one or more compounds provided herein. In a preferred embodiment, the compounds of the present disclosure are administered intravenously to a patient, orally to a patient, or topically to a patient. An effective amount can be an amount sufficient to modulate PD-1 / PD-L1 interaction and / or reduce or alleviate symptoms exhibited by the patient. The amount administered is preferably an amount sufficient to increase the plasma concentration of the compound (or, if the compound is a prodrug, its active metabolite) sufficiently to alter the PD-1 / PD-L1 interaction. Treatment regimens may vary depending on the compound used and the particular condition being treated, but for the treatment of most disorders, a dosing frequency of four times per day or less is preferred. Generally, a twice-daily dosing regimen is more preferred, with once-daily administration being particularly preferred. It will be understood, however, that specific dosage levels and treatment regimens for any individual patient will depend on a variety of factors, including the activity of the specific compound used, the patient's age, body weight, general health, sex, diet, time of administration, route of administration, excretion rate, drug combinations (i.e., other drugs being administered to the patient), and the severity of the specific condition being treated, as well as the judgment of the prescribing medical practitioner. In general, it is preferable to use the lowest dose sufficient to provide effective treatment. In general, the effectiveness of treatment can be monitored in patients using medical or veterinary standards appropriate to the condition being treated or prevented. combination

[0097] A combination drug containing a compound of the present disclosure and another drug can be administered as a combined preparation in which both components are contained in a single formulation, or as separate formulations. Administration in separate formulations includes simultaneous administration and administration with some time interval between them. In the case of administration with some time interval between them, the compound of the present disclosure can be administered first, followed by the other drug, or the other drug can be administered first, followed by the compound of the present disclosure. The administration methods for each drug may be the same or different.

[0098] The dosage of the other drug can be appropriately selected based on dosages previously used in clinical practice. The ratio of the compound of the present disclosure to the other drug can be appropriately selected depending on the age and weight of the subject to be administered, the administration method, the administration time, the disorder and symptoms to be treated, or a combination thereof. For example, the other drug can be used in an amount of 0.01 to 100 parts by mass based on 1 part by mass of the compound of the present disclosure. The other drug can be a combination of two or more drugs in an appropriate ratio.

[0099] The compounds described herein may be used in combination with one or more therapeutic agents, such as antimicrobial agents, antiviral agents, cytotoxic agents, gene expression modulating agents, chemotherapeutic agents, anticancer agents, antiangiogenic agents, immunotherapeutic agents, antihormonal agents, antifibrotic agents, radiation therapy, radiotherapeutic agents, anti-neoplastic agents, anti-proliferative agents, etc. These therapeutic agents may be in the form of chemical compounds, antibodies, polypeptides, polynucleotides, etc.

[0100] The compounds described herein can be used or combined with one or more of therapeutic antibodies, bispecific antibodies and "antibody-like" therapeutic proteins (e.g., DART®, Duobodies®, Bites®, XmAb®, TandAb®, Fab derivatives), antibody-drug conjugates (ADCs), viruses, oncolytic viruses, gene-modifying or gene-editing agents (e.g., CRISPR (including CRISPR Cas9), zinc finger nucleases or synthetic nucleases (TALENs), CAR (chimeric antigen receptor) T-cell immunotherapeutics, or combinations thereof.

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

[0102] The compounds described herein can be used in combination with adjunctive cancer treatment drugs (e.g., drugs for treating leukopenia (neutropenia), drugs for treating thrombocytopenia, antiemetic drugs, cancer pain intervention drugs) or in the form of mixtures.

[0103] The compounds described herein can be used in conjunction with or combined with kinase inhibitors.

[0104] In one embodiment, the compounds of the present disclosure can be used in combination with or in the form of a mixture with other immunomodulators and / or enhancers. Examples of immunomodulators include various cytokines, vaccines, and adjuvants. Non-limiting examples of cytokines, vaccines, and adjuvants that stimulate the immune response include GM-CSF, M-CSF, G-CSF, interferon alpha, interferon beta, interferon gamma, IL-1, IL-2, IL-3, IL-12, poly(I:C), and CPG. Potentiating agents include cyclophosphamide, cyclophosphamide analogs, anti-TGF, imatinib (Gleevec), antimitotic agents (e.g., paclitaxel, sunitinib (stent), other antiangiogenic agents), aromatase inhibitors (e.g., letrozole), A2a adenosine receptor (A2AR) antagonists, angiogenesis inhibitors, anthracyclines, oxaliplatin, doxorubicin, TLR4 antagonists, and IL-18 antagonists.

[0105] In some embodiments, the compounds described herein can be used or combined with a modulator of one or more of CCR1, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10, CCR11, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, CXCR6, CXCR7, ChemR23, C5aR, C5a, or C5. In some embodiments, the modulator is an antagonist.

[0106] In some embodiments, the compounds described herein may be used in combination with other compounds, such as those described in WO2007 / 002667, WO2007 / 002293, WO / 2003 / 105853, WO / 2007 / 022257, WO / 2007 / 059108, WO / 2007 / 044804, WO2007 / 115232, WO2007 / 115231, WO2008 / 147815, WO 2010 / 030815, WO2010 / 075257, WO2011 / 163640, WO2010 / 054006, WO2010 / 051561, WO2011 / 035332, W O2013 / 082490, WO2013 / 082429, WO2014 / 085490, WO2014 / 100735, WO2014 / 089495, WO2015 / 084842; WO2016 / 187393, WO2017 / 127409, WO2017 / 087607, WO2017 / 087610, WO2017 / 176620, WO2018 / 222598, WO2018 / 222601, WO2013 / 130811, WO2006 / 076644, WO2008 / 008431, WO2009 / 038847, WO2008 / 008375, W The compounds may be used in combination with one or more chemokine and / or chemoattractant receptor antagonists described in WO2008 / 008374, WO2008 / 010934, WO2009 / 009740, WO2005 / 112925, WO2005 / 112916, WO2005 / 113513, WO2004 / 085384, and WO2004 / 046092. Chemokine and / or chemoattractant receptor antagonists useful in the present disclosure also include CCX354, CCX9588, CCX140, CCX872, CCX598, CCX6239, CCX9664, CCX2553, CCX3587, CCX3624, CCX2991, CCX282, CCX025, CCX507, CCX430, CCX765, CCX224, CCX662, CCX650, CCX832, CCX168, CCX168-M1, CCX3022, and / or CCX3384. dose

[0107] Dosage levels on the order of about 0.1 mg to about 140 mg per kg of body weight per day are useful in treating or preventing diseases involving PD-1 / PD-L1 interactions (about 0.5 mg to about 7 g per human 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 treated and the particular mode of administration. Unit dosage forms will generally contain about 1 mg to about 500 mg of active ingredient. For compounds administered orally, transdermally, intravenously, or subcutaneously, it is preferred to administer an amount sufficient to achieve a serum concentration of 5 ng (nanogram) / ml to 10 μg (microgram) / ml, more preferably an amount sufficient to achieve a serum concentration of 20 ng to 1 μg / ml, and most preferably an amount sufficient to achieve a serum concentration of 50 ng / ml to 200 ng / ml. For direct injection into the synovium (to treat joints), sufficient compound should be administered to achieve a local concentration of about 1 micromolar.

[0108] The frequency of administration may also vary depending on the compound used and the particular disease being treated. However, for the treatment of most disorders, a dosing regimen of four times per day, three times per day, or fewer times per day is preferred, with a once-daily or twice-daily regimen being particularly preferred. It will be understood, however, that the specific dose level and frequency of administration for a particular patient may vary and will depend upon a variety of factors, including the activity of the specific compound used, metabolic stability, duration of action of the compound, age, body weight, genetics, general health, sex, diet, mode and time of administration, excretion rate, drug combinations (i.e., other drugs administered to the patient), the severity of the particular disease being treated, and other factors, such as the judgment of the prescribing medical practitioner.

[0109] In another aspect of the present disclosure, the compounds of the present disclosure can be used in a variety of non-pharmaceutical applications in vitro and in vivo: The compounds of the present disclosure can be used as positive controls in assays of PD-1 / PD-L1 interaction activity, i.e., as standards to characterize the ability of drug candidates to bind to PD-1 and / or PD-L1, or as radiotracers for positron emission tomography (PET) or single photon emission computed tomography (SPECT).

[0110] The scope of the present disclosure also includes a kit comprising a compound of the present disclosure or a pharmaceutically acceptable salt thereof and instructions for use. The kit may further comprise at least one additional agent. The kit typically includes a label indicating the intended use of the contents of the kit. The term label includes any writing or recorded material provided on, with, or otherwise accompanying the kit. [Example]

[0111] 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 for illustrative purposes and are not intended to limit the disclosure as claimed.

[0112] The reagents and solvents used below are available from commercial sources (e.g., Aldrich Chemical Co. (Milwaukee, Wisconsin, USA)). 1H-NMR spectra were recorded on a Varian Mercury 400 MHz NMR spectrometer. Prominent peaks relative to TMS are listed in the table in order of multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet) and number of protons. Mass spectrometry results are reported as mass / charge ratios. In the examples, the single m / z value listed is for the M+H (or MH, as indicated) ion, which contains the most common atomic isotopes. The isotopic pattern corresponds to the expected formula in all cases. Electrospray ionization (ESI) mass spectrometry was performed on a Hewlett-Packard MSD electrospray mass analyzer using an HP1100 HPLC for sample delivery. Typically, the analyte was dissolved in methanol or CH3CN at a concentration of 0.1 mg / ml, and 1 microliter was flowed into the mass analyzer along with the delivery solvent. The mass analyzer then scanned from 100 to 1000 daltons. All compounds could be analyzed in either positive or negative ESI mode using acetonitrile / water with 1% formic acid as the delivery solvent.

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

[0114] Compounds within the scope of the present disclosure can be synthesized as described below using a variety of reactions known to those skilled in the art. Those skilled in the art will also recognize that alternative methods are available for synthesizing the target compounds of the present disclosure and that the approaches described herein are not exhaustive but provide broadly applicable and practical routes to compounds of interest.

[0115] Some molecules disclosed in this application can exist in different enantiomeric and diastereomeric forms, and unless a particular enantiomer is specified, all such variants of these compounds are claimed.

[0116] Detailed descriptions of the experimental procedures used to synthesize key compounds herein lead to molecules described by identifying physical data and accompanying structural diagrams.

[0117] Those skilled in the art will also recognize that acids and bases are frequently used during standard work-up procedures in organic chemistry. Where the parent compound possesses the necessary inherent acidity or basicity, salts of the parent compound are sometimes formed during the experimental procedures described in this patent application. 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 [ka]

[0118] 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 H2O (6 mL) was added Pd(dppf)Cl2 complex along with dichloromethane (912 mg, 1.12 mmol). The reaction mixture was degassed and stirred at 90 °C under N2 for 2 h. 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-(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 C20 H 18 BrClN3O3[M + H] + Calculated value: 462.0, measured value: 462.0.

[0119] 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), pinacoldiborane (1.0 g, 3.94 mmol), and KOAc (1.2 g, 10.2 mmol) in p-dioxane (18 mL) was added Pd(dppf)Cl complex along with dichloromethane (350 mg, 0.43 mmol). The reaction mixture was degassed (N) and stirred at 90 °C under N for 3 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 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 / z C 26 H 30 BClN3O5[M + H] + Calculated value: 510.2, measured value: 510.1.

[0120] 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 along with dichloromethane (70 mg, 0.086 mmol). The reaction mixture was degassed and stirred at 95 °C under N2 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 silica gel flash chromatography 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] + Calculated value: 519.1, measured value: 519.1.

[0121] 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 NaBHCN (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 (400 MHz, CD3OD) δ 11.18 (s, 1H), 8.63 (s, 1H), 8.13-8.06 (m, 1H), 7.88 (d, J = 7.6 Hz, 1H), 7.61 (dd, J = 7.6, 1.7 Hz, 1H), 7.49 (t, J = 7.6 Hz, 1H), 7.39-7.25 (m, 3H), 7.00 (d, J = 7.7 Hz, 1H), 4.35 (d, J = 13.3 Hz, 1H), 4.24 (d, J = 13.2 Hz, 1H), 4.11-3.93 (m, 6H), 3.61-3.36 (m, 10H), 2.13 (s, 4H), 1.87 (d, J = 12.4 Hz, 1H). MS: (ES) m / z C 32 H 34 ClNO[M + H] + Calculated value: 620.2, measured value: 620.2. 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 [ka]

[0122] The title compound was prepared 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 using a procedure similar to step d of Example 1. 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. 1H NMR (400 MHz, CD3OD) δ 11.17 (s, 1H), 8.63 (s, 1H), 8.11 (t, J = 7.5 Hz, 1H), 7.89 (d, J = 7.6 Hz, 1H), 7.61 (dd, J = 7.7, 1.6 Hz, 1H), 7.49 (t, J = 7.6 Hz, 1H), 7.40-7.25 (m, 3H), 7.04-6.97 (m, 1H), 4.32 (s, 2H), 4.24 (tt, J = 8.3, 4.2 Hz, 1H), 4.10 (d, J = 0.8 Hz, 3H), 3.87 (dd, J = 11.7, 7.6 Hz, 1H), 3.63-3.53 (m, 4H), 3.39 (s, 3H), 3.31 (p, J = 1.6 Hz, 11H), 2.90 (dd, J = 17.8, 8.8 Hz, 1H), 2.57 (dd, J = 17.8, 4.7 Hz, 1H), 2.13 (s, 3H). MS: (ES) m / z C 31 H 31 ClN6O5[M + H] + Calculated value: 603.2, measured value: 603.2. 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 [ka]

[0123] The title compound was prepared 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 using a procedure similar to step d of Example 1. 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 (400 MHz, CD3OD) δ 8.63 (d, J = 1.1 Hz, 1H), 8.12 (dd, J = 7.9, 1.3 Hz, 1H), 7.88 (d, J = 7.6 Hz, 1H), 7.61 (d, J = 7.7 Hz, 1H), 7.50 (dd, J = 7.6, 7.6 Hz, 1H), 7.41-7.25 (m, 3H), 7.00 (d, J = 7.5 Hz, 1H), 4.34 (d, J = 2.0 Hz, 2H), 4.13-4.00 (m, 4H), 3.55 (d, J = 1.0 Hz, 3H), 3.39 (d, J = 1.0 Hz, 3H), 3.34-3.22 (m, 2H), 2.49-2.32 (m, 3H), 2.13 (s, 3H), 1.92 (q, J = 7.5 Hz, 1H). MS: (ES) m / z C 32 H 33 ClN6O5[M + H] + Calculated value: 617.2, measured value: 617.2. 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 [ka]

[0124] The compound was prepared 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 using a procedure similar to step d of Example 1. 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 (400 MHz, CD3OD) δ 11.70 (s, 1H), 8.67 (s, 1H), 8.56 (d, J = 6.9 Hz, 2H), 7.77-7.67 (m, 1H), 7.57 (t, J = 7.9 Hz, 1H), 7.43 (d, J = 20.5 Hz, 2H), 7.12 (d, J = 8.8 Hz, 1H), 4.49 (s, 2H), 4.13 (s, 3H), 4.10-3.95 (m, 3H), 3.64-3.53 (m, 5H), 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 30Cl2N6O6[M + H] + Calculated value: 641.2, measured value: 641.1. 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 [ka]

[0125] The title compound was prepared 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 using a procedure similar to step d of Example 1. 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. 1H NMR (400 MHz, CD3OD) δ 11.71 (s, 1H), 8.67 (s, 1H), 8.56 (d, J = 6.9 Hz, 2H), 7.73-7.71 (m, 1H), 7.57 (t, J = 7.9 Hz, 1H), 7.46-7.41 (m, 2H), 7.12 (d, J = 8.8 Hz, 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 was 641.2 and the measured value was 641.0. 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 [ka]

[0126] The title compound was prepared 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 using a procedure similar to step d of Example 1. 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 (400 MHz, CD3OD) δ 8.67 (s, 1H), 8.59-8.52 (m, 2H), 7.71 (dd, J = 7.6, 1.5 Hz, 1H), 7.57 (dd, J = 7.7, 7.7 Hz, 1H), 7.48-7.37 (m, 2H), 7.11 (d, J = 7.5 Hz, 1H), 4.53 (d, J = 3.8 Hz, 2H), 4.13 (d, J = 1.1 Hz, 4H), 3.56 (d, J = 1.1 Hz, 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] + Calculated value: 638.1, measured value: 638.0. 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 [ka]

[0127] The title compound was prepared 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 using a procedure similar to step d of Example 1. 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 H NMR (400 MHz, CD3OD) δ 11.70 (s, 1H), 8.67 (s, 1H), 8.55 (d, J = 9.1 Hz, 2H), 7.72 (d, J = 8.2 Hz, 1H), 7.57 (d, J = 14.8 Hz, 1H), 7.46-7.41 (m, 2H), 7.11 (d, J = 7.8 Hz, 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, 6.6 Hz, 1H). MS: (ES) m / z C 29 H 27 Cl2N7O5[M + H] + The calculated value was 624.2, and the measured value was 624.0. 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 [ka]

[0128] The title compound was prepared 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 using a procedure similar to step d of Example 1. 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 (400 MHz, CD3OD) δ 11.70 (s, 1H), 8.67 (s, 1H), 8.56 (d, J = 3.3 Hz, 2H), 7.72 (d, J = 7.7 Hz, 1H), 7.57 (t, J = 7.9 Hz, 1H), 7.46-7.40 (m, 2H), 7.11 (d, J = 8.6 Hz, 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. 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 [ka]

[0129] The compound was prepared 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 using a procedure similar to step d of Example 1. 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 (400 MHz, CDCl3) δ 10.93 (d, J = 5.0 Hz, 1H), 8.55 (d, J = 7.4 Hz, 1H), 8.18 (dd, J = 8.1, 4.2 Hz, 1H), 8.02 (s, 1H), 7.80-7.70 (m, 1H), 7.61-7.52 (m, 1H), 7.40 (dd, J = 7.6, 7.6 Hz, 1H), 7.29 (td, J = 6.8, 5.6, 2.8 Hz, 3H), 7.02 (d, J = 7.6 Hz, 1H), 4.51 (d, J = 7.9 Hz, 2H), 4.21 (d, J = 33.5 Hz, 3H), 3.58 (d, J = 2.1 Hz, 3H), 3.44 (s, 3H), 3.20-3.00 (m, 2H), 2.34 (s, 4H), 2.16 (d, J = 1.4 Hz, 3H), 1.73 (s, 1H), 1.40 (t, J = 7.0 Hz, 3H). MS: (ES) m / z C 33 H 36 ClN6O5[M + H] + Calculated value: 631.2, measured value: 631.2. 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 [ka]

[0130] The compound was prepared 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 using a procedure similar to step d of Example 1. 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. 1H NMR (400 MHz, CD3OD) δ 11.70 (s, 1H), 8.67 (d, J = 1.2 Hz, 1H), 8.58-8.48 (m, 2H), 7.70 (d, J = 7.9 Hz, 1H), 7.56 (dd, J = 7.6, 7.6 Hz, 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 = 1.1 Hz, 3H), 3.56 (d, J = 1.3 Hz, 3H), 3.39 (d, J = 1.1 Hz, 3H), 3.35-3.29 (m, 3H), 2.57 (t, J = 7.8 Hz, 2H), 2.43 (d, J = 7.9 Hz, 2H). MS: (ES) m / z C 31 H 30 Cl2N7O5[M + H] + The calculated value was 650.2 and the measured value was 650.0. 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 [ka]

[0131] The compound was prepared 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 using a procedure similar to step d of Example 1. 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 (400 MHz, CD3OD) δ 11.71 (s, 1H), 8.67 (s, 1H), 8.56-8.50 (m, 2H), 7.70 (d, J = 7.5 Hz, 1H), 7.56 (dd, J = 7.7, 7.7 Hz, 1H), 7.47-7.40 (m, 2H), 7.11 (dd, J = 7.6, 1.4 Hz, 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] + Calculated value: 597.1, measured value: 597.0. 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 [ka]

[0132] The compound was prepared 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 using a procedure similar to step d of Example 1. 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 (400 MHz, CD3OD) δ 11.67 (s, 1H), 8.65 (s, 1H), 8.53 (d, J = 7.9 Hz, 1H), 7.93-7.86 (m, 1H), 7.66-7.60 (m, 1H), 7.47 (d, J = 7.4 Hz, 1H), 7.42-7.36 (m, 3H), 7.09 (d, J = 7.1 Hz, 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] + Calculated value: 596.1, measured value: 596.2. 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 [ka]

[0133] 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 2 M KCO (3 mL, 6 mmol) in p-dioxane (20 mL) was added Pd(PPh) (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 dissolved 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.

[0134] Step b: To a stirred suspension of 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 (39 mg, 0.07 mmol) and (3R,4R)-aminooxan-3-ol hydrochloride (47 mg, 0.3 mmol) in 20% (v / v) MeOH in DCM, EtN (43 μL, 0.31 mmol) was added. After stirring for 5 min, Na(OAc)BH (78 mg, 0.37 mmol) was added to the reaction mixture. An additional portion of Na(OAc)BH (82 mg, 0.39 mmol) was added, and the contents were stirred for an additional 15 h. The solvent was removed in vacuo, and the residue was dissolved in a mixture of p-dioxane, DMSO, TFA, and water, 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 (400 MHz, CD3OD) δ 11.69 (s, 1H), 8.70 (s, 1H), 8.66 (s, 1H), 8.54 (d, J = 8.4 Hz, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.55 (dd, J = 7.6, 7.6 Hz, 1H), 7.48-7.38 (m, 2H), 7.10 (d, J = 7.6 Hz, 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 = 7.6 Hz, 12.4 Hz, 1H). MS: (ES) m / z C 30 H 31 Cl2N6O6[M + H] +The calculated value was 641.2 and the measured value was 641.0. 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 [ka]

[0135] The compound was prepared 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 using a procedure similar to step d of 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)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 1H NMR (400 MHz, CD3OD) δ 11.69 (s, 1H), 8.66 (s, 1H), 8.54 (d, J = 8.3 Hz, 1H), 7.93-7.85 (m, 1H), 7.65 (dd, J = 7.8, 1.8 Hz, 1H), 7.51 (dd, J = 7.7, 7.7 Hz, 1H), 7.45-7.35 (m, 3H), 7.10 (d, J = 7.6 Hz, 1H), 4.34 (s, 2H), 4.14-4.01 (m, 4H), 3.56 (d, J = 1.6 Hz, 3H), 3.39 (d, J = 1.8 Hz, 3H), 3.30-3.20 (m, 3H), 2.40 (dd, J = 11.8, 11.1 Hz, 2H), 2.03 (d, J = 1.7 Hz, 1H), 1.92 (d, J = 6.9 Hz, 1H). MS: (ES) m / z C 31 H 31 Cl2N6O5[M + H] + Calculated value: 637.2, measured value: 637.2. 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 [ka]

[0136] The compound was prepared 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 of 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 (400 MHz, CD3OD) δ 11.69 (s, 1H), 8.67 (s, 1H), 8.53 (d, J = 8.3 Hz, 1H), 7.88 (d, J = 7.7 Hz, 1H), 7.69-7.62 (m, 1H), 7.51 (dd, J = 7.7, 7.7 Hz, 1H), 7.45-7.33 (m, 3H), 7.13-7.06 (m, 1H), 4.35 (d, J = 13.2 Hz, 1H), 4.24 (d, J = 13.2 Hz, 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 = 1.6 Hz, 2H), 1.87 (d, J = 12.7 Hz, 1H). MS: (ES) m / z C 31 H 32 Cl2N5O6[M + H] + The calculated value was 640.2 and the measured value was 640.5. 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 [ka]

[0137] 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-triazole[4,5- b] Pyridinium 3-oxide hexafluorophosphate (600 mg, 1.6 mmol) was added. The mixture was heated at 60° C. for 1.5 hours, cooled to room temperature, and added to water. The resulting precipitate was collected by filtration and dried under vacuum to give 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 (400 MHz, DMSO-d6) δ 11.34 (s, 1H), 8.47 (d, J = 8.0 Hz, 1H), 7.44-7.38 (m, 2H), 3.68 (s, 3H), 3.25 (s, 3H), 1.32 (s, 12H).

[0138] 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 2 M KCO (1 mL, 2 mmol) in dioxane (4 mL) was added Pd(dppf)Cl complex along with DCM (39 mg, 0.05 mmol). The reaction mixture was degassed and stirred at 90 °C under N for 1 h. 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 silica gel flash chromatography 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 / z C 25 H 20 Cl2N5O5[M + H] + The calculated value was 640.1 and the measured value was 639.7.

[0139] 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) MeOH in DCM was added EtN (47 μL, 0.34 mmol). The mixture was stirred at room temperature for 10 min, and Na(OAc)BH (116 mg, 0.55 mmol) was added. After stirring for 25 min, 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 (400 MHz, CD3OD) δ 11.68 (s, 1H), 8.58 (d, J = 8.4 Hz, 1H), 7.89 (d, J = 7.6 Hz, 1H), 7.66 (d, J = 7.6 Hz, 1H), 7.52 (dd, J = 8.0, 8.0 Hz, 1H), 7.46 (dd, J = 8.0, 8.0 Hz, 1H), 7.42-7.36 (m, 2H), 7.17 (d, J = 8.0 Hz, 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] + Calculated value: 638.2, measured value: 638.5. 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 [ka]

[0140] The compound was prepared 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 of 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 (400 MHz, CD3OD) δ 11.71 (s, 1H), 8.67 (s, 1H), 8.56 (d, J = 8.4 Hz, 1H), 8.22-8.14 (m, 1H), 7.87 (d, J = 7.6 Hz, 1H), 7.57 (d, J = 7.6 Hz, 1H), 7.46-7.39 (m, 3H), 7.18 (d, J = 7.6 Hz, 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. 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 [ka]

[0141] The compound was prepared 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 of 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 (400 MHz, CD3OD) δ 11.94-11.89 (m, 1H), 8.94 (d, J = 1.1 Hz, 1H), 8.67 (s, 1H), 8.62-8.55 (m, 1H), 7.92-7.85 (m, 1H), 7.66 (dd, J = 7.8, 1.9 Hz, 1H), 7.56-7.35 (m, 4H), 7.13 (d, J = 7.6 Hz, 1H), 4.34 (s, 2H), 4.13-3.99 (m, 4H), 3.65 (d, J = 1.3 Hz, 3H), 3.29 (d, J = 19.8 Hz, 3H), 2.49-2.32 (m, 3H), 1.92 (m, 1H). MS: (ES) m / z C 30 H 29 Cl2N6O4[M + H]+ Calculated value: 607.2, measured value: 607.1. 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 [ka]

[0142] 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-aminoethan-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 h. To the mixture was added NaBH(OAc) (61 mg, 0.29 mmol). After 2 h, the reaction was quenched with saturated aqueous NaHCO 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. 1H NMR (400 MHz, CD3OD) δ 11.16 (s, 1H), 8.62 (s, 1H), 8.10 (dd, J = 6.8, 6.8 Hz, 1H), 7.87 (d, J = 7.6 Hz, 1H), 7.61 (dd, J = 7.6, 1.6 Hz, 1H), 7.49 (dd, J = 7.6, 7.6 Hz, 1H), 7.36-7.33 (m, 2H), 7.29 (dd, J = 7.8, 7.8 Hz, 1H), 6.99 (d, J = 7.2 Hz, 1H), 4.31 (s, 2H), 4.09 (s, 3H), 3.86 (m, 2H), 3.54 (s, 3H), 3.37 (s, 3H), 3.20 (d, J = 4.8, 4.8 Hz, 2H), 2.13 (s, 3H). MS: (ES) m / z C 29 H 31 ClNO5[M + H] + The calculated value was 564.2 and the measured value was 564.5. 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 [ka]

[0143] 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 h. To the mixture was added NaBH(OAc) (70 mg, 0.33 mmol). After 1 h, the reaction was quenched with saturated aqueous NaHCO 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 (400 MHz, CD3OD) δ 11.16 (s, 1H), 8.61 (s, 1H), 8.12 (dd, J = 6.8, 6.8 Hz, 1H), 7.87 (d, J = 7.6 Hz, 1H), 7.62 (dd, J = 8.0, 1.6 Hz, 1H), 7.49 (dd, J = 7.6, 7.6 Hz, 1H), 7.37-7.33 (m, 2H), 7.30 (dd, J = 7.8, 7.8 Hz, 2H), 6.99 (d, J = 7.6 Hz, 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 ClNO5[M + H] + Calculated value: 592.2, measured value: 592.5. Example 21: 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 [ka]

[0144] 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 (1 mL) was stirred at room temperature for 1.5 hours. To the mixture was added NaBH(OAc) (70 mg, 0.33 mmol). 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. 1H NMR (400 MHz, CD3OD) δ 11.16 (s, 1H), 8.60 (s, 1H), 8.12 (dd, J = 7.0, 7.0 Hz, 1H), 7.87 (d, J = 7.6 Hz, 1H), 7.61 (dd, J = 8.0, 1.6 Hz, 1H), 7.48 (dd, J = 7.6, 7.6 Hz, 1H), 7.37-7.32 (m, 2H), 7.30 (dd, J = 7.8, 7.8 Hz, 1H), 6.99 (d, J = 7.6 Hz, 1H), 4.56-4.50 (m, 2H), 4.50 (s, 2H), 4.13 (d, J = 10.4 Hz, 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 ClNO[M + H] + Calculated value: 618.2, measured value: 618.6. 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 [ka]

[0145] 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 NaBHCN (25 mg, 0.40 mmol) was added. After stirring at 0°C for 30 min, the reaction was quenched with a 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 (400 MHz, CD3OD) δ 11.14 (s, 1H), 8.58 (s, 1H), 8.13 (dd, J = 7.0, 7.0 Hz, 1H), 7.92 (d, J = 7.6 Hz, 1H), 7.63 (dd, J = 7.6, 2.0 Hz, 1H), 7.49 (dd, J = 7.6, 7.6 Hz, 1H), 7.38 (d, J = 7.6 Hz, 1H), 7.34 (dd, J = 7.2, 1.6 Hz, 1H), 7.27 (dd, J = 7.8, 7.8 Hz, 1H), 6.98 (d, J = 6.8 Hz, 1H), 4.60 (d, J = 13.2 Hz, 1H), 4.31 (d, J = 13.2 Hz, 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 ClNO5[M + H] +Calculated value: 578.2, measured value: 578.5. 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 [ka]

[0146] The compound was prepared 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 using a procedure similar to Example 1. 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 (400 MHz, CDCl3) δ 10.89 (s, 1H), 8.53 (s, 1H), 8.22 (d, J = 7.4 Hz, 1H), 7.63 (dd, J = 7.6, 1.8 Hz, 1H), 7.56 (d, J = 7.4 Hz, 1H), 7.40 (dd, J = 7.6, 7.6 Hz, 1H), 7.35-7.22 (m, 3H), 7.03 (dd, J = 7.6, 1.2 Hz, 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 H37 ClNO5[M + H] + Calculated value: 606.2, measured value: 606.6. 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 [ka]

[0147] The compound was prepared 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 using a procedure similar to step d of Example 1. 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. 1H NMR (400 MHz, CD3OD) δ 8.62 (s, 1H), 8.12 (d, J = 8.0 Hz, 1H), 7.79 (d, J = 7.2 Hz, 1H), 7.66 (dd, J = 8.0, 2.0 Hz, 1H), 7.46 (dd, J = 7.6, 7.6 Hz, 1H), 7.33-7.24 (m, 3H), 7.00 (d, J = 8.0 Hz, 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 ClNO5[M + H] + Calculated value: 604.2, measured value: 604.5. 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 [ka]

[0148] The compound was prepared 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 using a procedure similar to step d of Example 1. 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 (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 8.77 (s, 1H), 8.27-8.25 (m, 1H), 7.74 (d, J = 7.5 Hz, 1H), 7.65 (dd, J = 7.6, 1.7 Hz, 1H), 7.52 (dd, J = 7.6, 7.6 Hz, 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 ClNO5[M + H] + Calculated value: 604.2, measured value: 604.5. 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 [ka]

[0149] The compound was prepared 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 using a procedure similar to step d of Example 1. The crude product was purified by silica gel flash chromatography to give (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 (400 MHz, CD3OD) δ 8.62 (s, 1H), 8.11 (d, J = 8.0 Hz, 1H), 7.73 (d, J = 7.2 Hz, 1H), 7.60 (dd, J = 7.2, 1.6 Hz, 1H), 7.46 (dd, J = 8.0, 8.0 Hz, 1H), 7.33-7.22 (m, 3H), 7.00 (d, J = 8.0 Hz, 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 ClNO[M + H] + Calculated value: 594.2, measured value: 594.3. 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 [ka]

[0150] The compound was prepared 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 using a procedure similar to step d of Example 1. 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 (400 MHz, CD3OD) δ 11.07 (s, 1H), 8.77 (s, 1H), 8.27-8.25 (m, 1H), 7.85 (d, J = 7.5 Hz, 1H), 7.63 (dd, J = 7.7, 1.8 Hz, 1H), 7.52 (dd, J = 7.6, 7.6 Hz, 1H), 7.37-7.27 (m, 3H), 6.99 (dd, J = 7.7, 1.4 Hz, 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 = 9.0 Hz, 1H), 2.09 (s, 3H), 1.73-1.65 (m, 1H), 1.58-1.50 (m, 1H). MS: (ES) m / z C 32 H 34 ClNO[M + H] + Calculated value: 620.2, measured value: 620.2. 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 [ka]

[0151] The compound was prepared 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-dimethylpropanamide using a procedure similar to step d of Example 1. 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 H NMR (400 MHz, CD3OD) δ 8.63 (s, 1H), 8.13-8.10 (m, 1H), 7.86 (d, J = 7.5 Hz, 1H), 7.63 (dd, J = 7.7, 1.7 Hz, 1H), 7.50 (dd, J = 7.6, 7.6 Hz, 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] + Calculated value: 619.2, measured value: 619.5. 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 [ka]

[0152] 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-aminoethan-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 NaBHCN (25 mg, 0.40 mmol) was added. After stirring at 0°C for 15 min, the reaction was quenched with a 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. 1H NMR (400 MHz, CD3OD) δ 11.66 (s, 1H), 8.63 (s, 1H), 8.60-8.50 (m, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.65 (dd, J = 7.6, 1.6 Hz, 1H), 7.50 (dd, J = 7.6, 7.6 Hz, 1H), 7.42-7.33 (m, 3H), 7.09 (dd, J = 7.6, 1.6 Hz, 1H), 4.31 (s, 2H), 4.09 (s, 3H), 3.85 (t, J = 5.2 Hz, 2H), 3.53 (s, 3H), 3.36 (s, 3H), 3.20 (t, J = 5.2 Hz, 2H). MS: (ES) m / z C 28 H 28 Cl2N5O5[M + H] + Calculated value: 584.1, measured value: 584.4. 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 [ka]

[0153] The compound was prepared 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 using a procedure similar to step d of Example 1. 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 (400 MHz, CDCl3) δ 10.89 (s, 1H), 8.53 (s, 1H), 8.25-8.18 (m, 1H), 7.62 (dd, J = 7.7, 1.9 Hz, 2H), 7.43-7.21 (m, 4H), 7.03 (d, J = 7.7 Hz, 1H), 4.00 (s, 3H), 3.70 (s, 2H), 3.58 (s, 3H), 3.44 (m, 5H), 3.19 (d, J = 7.8 Hz, 2H), 2.18 (s, 3H), 1.54 (s, 3H). MS: (ES) m / z C 31 H 33 ClNO5[M + H] + Calculated value: 590.2, measured value: 590.5. 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 [ka]

[0154] The compound was prepared 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 using a procedure similar to step d of Example 1. 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. 1 H NMR (400 MHz, CD3OD) δ 8.64 (s, 1H), 8.13-8.11 (m, 1H), 7.85 (d, J = 7.5 Hz, 1H), 7.61 (dd, J = 7.7, 1.7 Hz, 1H), 7.49 (dd, J = 7.6, 7.6 Hz, 1H), 7.36-7.28 (m, 3H), 7.01 (dd, J = 7.6, 1.2 Hz, 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 = 6.5 Hz, 6H). MS: (ES) m / z C 30 H 33 ClNO4[M + H] + Calculated value: 562.2, measured value: 562.5. 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 [ka]

[0155] 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 NaBHCN (25 mg, 0.40 mmol) was added. After stirring at 0°C for 5 min, the reaction was quenched with a 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. 1 H NMR (400 MHz, CD3OD) δ 11.66 (s, 1H), 8.63 (s, 1H), 8.55-8.50 (m, 1H), 7.86 (d, J = 7.6 Hz, 1H), 7.65 (dd, J = 7.6, 2.0 Hz, 1H), 7.50 (dd, J = 7.6, 7.6 Hz, 1H), 7.42-7.33 (m, 3H), 7.08 (dd, J = 8.0, 1.6 Hz, 1H), 4.27 (s, 2H), 4.08 (s, 3H), 3.74 (t, J = 5.8 Hz, 2H), 3.52 (s, 3H), 3.35 (s, 3H), 3.26 (t, J = 6.8 Hz, 2H), 1.95 (m, 2H). MS: (ES) m / z C 29 H 30 Cl2N5O5[M + H] + Calculated value: 598.2, measured value: 598.2. 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 [ka]

[0156] 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 NaBHCN (25 mg, 0.40 mmol) was added. After stirring at 0°C for 5 min, the reaction was quenched with a 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 (400 MHz, CD3OD) δ 11.67 (s, 1H), 8.65 (s, 1H), 8.56-8.51 (m, 1H), 7.87 (d, J = 7.6 Hz, 1H), 7.65 (dd, J = 7.6, 2.0 Hz, 1H), 7.51 (dd, J = 7.6, 7.6 Hz, 1H), 7.43-7.35 (m, 3H), 7.10 (dd, J = 7.6, 1.6 Hz, 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 = 6.4 Hz, 2H), 0.73 (d, J = 6.2 Hz, 2H). MS: (ES) m / z C 30 H 30 Cl2N5O5[M + H] + Calculated value: 610.2, measured value: 610.1. 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 [ka]

[0157] 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 NaBHCN (20 mg, 0.32 mmol) was added. After stirring at 0°C for 5 min, the reaction was quenched with a 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. 1 H NMR (400 MHz, CD3OD) δ 11.68 (s, 1H), 8.65 (s, 1H), 8.53 (dd, J = 8.8, 1.8 Hz, 1H), 7.87 (d, J = 7.6 Hz, 1H), 7.65 (dd, J = 7.6, 1.6 Hz, 1H), 7.51 (dd, J = 7.6, 7.6 Hz, 1H), 7.43-7.34 (m, 3H), 7.10 (dd, J = 7.2, 1.6 Hz, 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, 2.8 Hz, 1H), 2.94-2.87 (m, 1H), 1.24 (d, J = 6.4 Hz, 3H). MS: (ES) m / z C 29 H 30 Cl2N5O5[M + H] + Calculated value: 598.2, measured value: 598.5. 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 [ka]

[0158] 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 NaBHCN (20 mg, 0.32 mmol) was added. After stirring at 0°C for 5 min, the reaction was quenched with a 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 (400 MHz, CD3OD) δ 11.67 (s, 1H), 8.63 (s, 1H), 8.52 (dd, J = 8.4, 1.6 Hz, 1H), 7.86 (d, J = 7.6 Hz, 1H), 7.65 (dd, J = 7.6, 2.0 Hz, 1H), 7.50 (dd, J = 7.6, 7.6 Hz, 1H), 7.42-7.34 (m, 3H), 7.09 (dd, J = 8.0, 1.6 Hz, 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, 3.2 Hz, 1H), 2.95-2.87 (m, 1H), 1.24 (d, J = 6.4 Hz, 3H). MS: (ES) m / z C 29 H 30 Cl2N5O5[M + H] + Calculated value: 598.2, measured value: 598.5. 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 [ka]

[0159] The compound was prepared 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 using a procedure similar to step d of Example 1. 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. 1 H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 8.77 (s, 1H), 8.27-8.25 (m, 1H), 7.79 (d, J = 7.5 Hz, 1H), 7.64 (dd, J = 7.7, 1.7 Hz, 1H), 7.52 (dd, J = 7.6, 7.6 Hz, 1H), 7.37-7.28 (m, 3H), 6.99 (dd, J = 7.6, 1.2 Hz, 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 / z C 28 H 29 ClNO4[M + H] + Calculated value: 534.2, measured value: 534.1. 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 [ka]

[0160] The compound was prepared 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 using a procedure similar to step d of Example 1. 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. 1 H NMR (400 MHz, CD3OD) δ 11.69 (s, 1H), 8.66 (s, 1H), 8.53 (dd, J = 8.4, 1.6 Hz, 1H), 7.87 (d, J = 7.6 Hz, 1H), 7.66 (dd, J = 7.6, 1.6 Hz, 1H), 7.51 (dd, J = 8.0, 8.0 Hz, 1H), 7.43-7.34 (m, 3H), 7.10 (dd, J = 7.6, 1.6 Hz, 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] + Calculated value: 614.2, measured value: 614.5. 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 [ka]

[0161] 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 min, the reaction was quenched with a 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. 1 H NMR (400 MHz, CD3OD) δ 11.16 (s, 1H), 8.61 (s, 1H), 8.11 (dd, J = 6.8, 6.8 Hz, 1H), 7.86 (d, J = 7.6 Hz, 1H), 7.61 (dd, J = 7.6, 2.0 Hz, 1H), 7.49 (dd, J = 7.6, 7.6 Hz, 1H), 7.34 (dd, J = 7.2, 1.6 Hz, 2H), 7.28 (t, J = 8.0 Hz, 1H), 7.00 (d, J = 7.2 Hz, 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, 3.2 Hz, 1H), 2.94-2.87 (m, 1H), 2.13 (s, 3H), 1.24 (d, J = 6.4 Hz, 3H). MS: (ES) m / z C 30 H 33ClNO5[M + H] + Calculated value: 578.2, measured value: 578.5. 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 [ka]

[0162] 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 NaBHCN (20 mg, 0.32 mmol) was added. After stirring at 0°C for 10 min, the reaction was quenched with a 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 (400 MHz, CD3OD) δ 11.16 (s, 1H), 8.61 (s, 1H), 8.11 (dd, J = 6.8, 6.8 Hz, 1H), 7.86 (d, J = 7.6 Hz, 1H), 7.61 (dd, J = 8.0, 2.0 Hz, 1H), 7.49 (dd, J = 7.6, 7.6 Hz, 1H), 7.34 (dd, J = 7.2, 1.6 Hz, 2H), 7.29 (dd, J = 7.8, 7.8 Hz, 1H), 7.00 (d, J = 7.2 Hz, 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, 3.2 Hz, 1H), 2.94-2.87 (m, 1H), 2.15 (s, 3H), 1.24 (d, J = 6.4 Hz, 3H). MS: (ES) m / z C 30 H 33 ClNO5[M + H] + Calculated value: 578.2, measured value: 578.5. 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 [ka]

[0163] The compound was prepared 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 using a procedure similar to step d of Example 1. 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. 1 H NMR (400 MHz, CD3OD) δ 8.66 (s, 1H), 8.54 (dd, J = 8.4, 1.5 Hz, 1H), 7.89 (d, J = 7.6 Hz, 1H), 7.66 (dd, J = 7.6, 1.6 Hz, 1H), 7.51 (dd, J = 7.6, 7.6 Hz, 1H), 7.44-7.35 (m, 3H), 7.10 (dd, J = 7.6, 1.3 Hz, 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 / z C 31 H 32 Cl2N5O5[M + H] + Calculated value: 624.2, measured value: 624.5. 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 [ka]

[0164] 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 NaBHCN (25 mg, 0.40 mmol) was added. After stirring at 0°C for 10 min, the reaction was quenched with a 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. 1 H NMR (400 MHz, CD3OD) δ 11.18 (s, 1H), 8.63 (s, 1H), 8.11 (dd, J = 7.4, 7.4 Hz, 1H), 7.85 (d, J = 7.2 Hz, 1H), 7.60 (dd, J = 7.6, 1.6 Hz, 1H), 7.49 (dd, J = 7.6, 7.6 Hz, 1H), 7.36-7.33 (m, 2H), 7.29 (dd, J = 8.2, 8.2 Hz, 1H), 7.00 (d, J = 8.0 Hz, 1H), 4.26 (s, 2H), 4.08 (s, 3H), 3.55 (s, 3H), 3.38 (s, 3H), 3.26 (t, J = 6.8 Hz, 2H), 2.13 (s, 3H), 1.85 (t, J = 6.8 Hz, 2H), 1.27 (s, 6H). MS: (ES) m / z C 32 H 37 ClNO5[M + H]+ Calculated value: 606.2, measured value: 606.6. 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 [ka]

[0165] 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 min, the reaction was quenched with a 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 (400 MHz, CD3OD) δ 11.17 (s, 1H), 8.61 (s, 1H), 8.11 (dd, J = 6.8, 6.8 Hz, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.61 (dd, J = 8.0, 1.2 Hz, 1H), 7.49 (dd, J = 7.6, 7.6 Hz, 1H), 7.36-7.33 (m, 2H), 7.29 (dd, J = 8.0, 8.0 Hz, 1H), 6.99 (d, J = 7.6 Hz, 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, 6.4 Hz, 2H), 0.73 (dd, J = 6.2, 6.2 Hz, 2H). MS: (ES) m / z C 31 H 33 ClNO5[M + H] + Calculated value: 590.2, measured value: 590.5. Example 43: (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 [ka]

[0166] 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 NaBHCN (30 mg, 0.48 mmol) was added. After stirring at 0°C for 15 min, the reaction was quenched with a drop of water. The crude material was purified by preparative chromatography 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. 1 H NMR (400 MHz, CD3OD) δ 11.14 (s, 1H), 8.58 (s, 1H), 8.13 (dd, J = 7.4, 7.4 Hz, 1H), 7.88 (d, J = 7.6 Hz, 1H), 7.60 (dd, J = 7.6, 1.6 Hz, 1H), 7.48 (dd, J = 7.6, 7.6 Hz, 1H), 7.33 (d, J = 8.0 Hz, 2H), 7.27 (dd, J = 7.8, 7.8 Hz, 1H), 6.98 (d, J = 7.2 Hz, 1H), 4.31 (s, 2H), 4.08 (s, 3H), 3.86 (dd, J = 12.0, 4.0 Hz, 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 = 6.8 Hz, 3H). MS: (ES) m / z C 30 H 33 ClNO5[M + H] + Calculated value: 578.2, measured value: 578.5. Example 44: (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 [ka]

[0167] 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 NaBHCN (30 mg, 0.48 mmol) was added. After stirring at 0°C for 15 min, the reaction was quenched with a 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 (400 MHz, CD3OD) δ 11.13 (s, 1H), 8.56 (s, 1H), 8.12 (d, J = 6.8 Hz, 1H), 7.87 (d, J = 7.6 Hz, 1H), 7.60 (dd, J = 7.6, 1.6 Hz, 1H), 7.47 (dd, J = 7.6, 7.6 Hz, 1H), 7.34-7.31 (m, 2H), 7.26 (dd, J = 8.0, 8.0 Hz, 1H), 6.97 (d, J = 6.8 Hz, 1H), 4.30 (s, 2H), 4.08 (s, 3H), 3.86 (dd, J = 12.0, 4.0 Hz, 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 = 7.2 Hz, 3H). MS: (ES) m / z C 30 H 33 ClNO5[M + H] + Calculated value: 578.2, measured value: 578.5. 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 [ka]

[0168] The compound was prepared 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-aminooxan-3-ol hydrochloride using a procedure similar to step d of Example 1. 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. 1 H NMR (400 MHz, CD3OD) δ 11.70 (s, 1H), 8.66 (s, 1H), 8.55 (dd, J = 8.4, 1.5 Hz, 1H), 8.20-8.14 (m, 1H), 7.86 (d, J = 7.6 Hz, 1H), 7.55 (dd, J = 7.6, 1.8 Hz, 1H), 7.45-7.38 (m, 3H), 7.18 (dd, J = 7.6, 1.7 Hz, 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 / z C 31 H 32 ClFN5O6[M + H] + Calculated value: 624.2, measured value: 624.5. 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 [ka]

[0169] The compound was prepared 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 using a procedure similar to step d of Example 1. 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. 1 H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 8.77 (s, 1H), 8.26 (dd, J = 8.0, 1.2 Hz, 1H), 7.84 (d, J = 7.5 Hz, 1H), 7.64 (dd, J = 7.7, 1.7 Hz, 1H), 7.52 (dd, J = 7.6, 7.6 Hz, 1H), 7.37-7.27 (m, 3H), 6.99 (dd, J = 7.7, 1.3 Hz, 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 ClNO5[M + H] + Calculated value: 618.2, measured value: 618.2. 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 [ka]

[0170] The compound was prepared 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 azetidine-3-carboxylic acid hydrochloride using a procedure similar to step d of Example 1. 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-carboxamide)-[1,1'-biphenyl]-3-yl)-3-methoxypyrazin-2-yl)methyl)azetidine-3-carboxylic acid. 1 H NMR (400 MHz, CD3OD) δ 11.70 (s, 1H), 8.67 (s, 1H), 8.56 (d, J = 8.1 Hz, 1H), 8.52 (s, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.56 (dd, J = 8.0, 8.0 Hz, 1H), 7.46-7.38 (m, 2H), 7.11 (d, J = 7.3 Hz, 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 / z C 29 H 27 Cl2N6O6[M + H] + Calculated value: 625.1, measured value: 625.0. 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 [ka]

[0171] The compound was prepared 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 of 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. 1 H NMR (400 MHz, CD3OD) δ 11.70 (s, 1H), 8.67 (s, 1H), 8.56 (d, J = 8.1 Hz, 1H), 8.53 (s, 1H), 7.70 (d, J = 7.8 Hz, 1H), 7.56 (dd, J = 8.0, 8.0 Hz, 1H), 7.46-7.38 (m, 2H), 7.11 (d, J = 7.3 Hz, 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 / z C 31 H 30Cl2N7O5[M + H] + The calculated value was 650.2 and the measured value was 650.0. 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 [ka]

[0172] The compound was prepared 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 using a procedure similar to step d of Example 1. 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 (400 MHz, CDCl3) δ 10.89 (s, 1H), 8.53 (s, 1H), 8.21 (d, J = 7.6 Hz, 1H), 7.66-7.53 (m, 2H), 7.40 (dd, J = 7.6, 7.6 Hz, 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, 4.0 Hz, 1H), 2.51 (dd, J = 12.0, 8.9 Hz, 1H), 2.19 (s, 3H), 2.05 (dd, J = 12.8, 6.9 Hz, 1H), 1.18 (d, J = 5.3 Hz, 6H). MS: (ES) m / z C 34 H 38 ClN6O5[M + H] + Calculated value: 645.2, measured value: 645.6. 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 [ka]

[0173] The compound was prepared 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 using a procedure similar to step d of Example 1. 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. 1 H NMR (400 MHz, CDCl3) δ 10.89 (s, 1H), 8.53 (s, 1H), 8.25-8.18 (m, 1H), 7.67-7.54 (m, 2H), 7.40 (dd, J = 7.6, 7.6 Hz, 1H), 7.35-7.22 (m, 3H), 7.03 (d, J = 7.5 Hz, 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 = 12.1 Hz, 1H), 2.54 (d, J = 12.1 Hz, 1H), 2.48-2.38 (m, 2H), 2.19 (s, 3H), 2.08 (ddd, J = 12.7, 8.9, 7.6 Hz, 1H), 1.85 (ddd, J = 12.9, 8.3, 8.3 Hz, 1H), 1.27 (s, 3H). MS: (ES) m / z C 33 H 36 ClN6O5[M + H] + Calculated value: 631.2, measured value: 631.2. 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 [ka]

[0174] The compound was prepared 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 using a procedure similar to step d of Example 1. 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. 1 H NMR (400 MHz, CDCl3) δ 10.89 (s, 1H), 8.52 (s, 1H), 8.22 (d, J = 8.0 Hz, 1H), 7.67-7.58 (m, 2H), 7.40 (t, J = 7.6 Hz, 1H), 7.35-7.22 (m, 3H), 7.02 (d, J = 7.3 Hz, 1H), 4.10-3.92 (m, 6H), 3.75 (d, J = 13.7 Hz, 1H), 3.57 (s, 3H), 3.51-3.36 (m, 6H), 3.17 (dd, J = 10.9, 9.8 Hz, 1H), 2.63-2.52 (m, 1H), 2.19 (s, 3H), 2.06 (d, J = 13.6 Hz, 1H). MS: (ES) m / z C32 H 35 ClNO[M + H] + Calculated value: 620.2, measured value: 620.2. 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 [ka]

[0175] The compound was prepared 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 using a procedure similar to step d of Example 1. 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 (400 MHz, CD3OD) δ 11.19 (s, 1H), 8.64 (s, 1H), 8.11 (d, J = 8.0 Hz, 1H), 7.89 (d, J = 7.6 Hz, 1H), 7.62 (dd, J = 7.7, 1.7 Hz, 1H), 7.50 (dd, J = 7.6, 7.6 Hz, 1H), 7.37-7.28 (m, 3H), 7.01 (d, J = 7.5 Hz, 1H), 4.60-4.58 (m, 1H), 4.41-4.26 (m, 2H), 4.09 (s, 3H), 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 / z C 31 H 33 ClNO[M + H] + Calculated value: 606.2, measured value: 606.5. 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 [ka]

[0176] 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 h. To the mixture was added NaBH(OAc) (70 mg, 0.33 mmol). 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. 1 H NMR (400 MHz, CD3OD) δ 11.18 (s, 1H), 8.63 (s, 1H), 8.11 (dd, J = 72, 7.2 Hz, 1H), 7.86 (d, J = 7.2 Hz, 1H), 7.62 (dd, J = 8.0, 1.6 Hz, 1H), 7.49 (dd, J = 7.6, 7.6 Hz, 1H), 7.35 (dd, J = 7.6, 2.0 Hz, 2H), 7.29 (dd, J = 8.0, 8.0 Hz, 1H), 7.00 (d, J = 7.2 Hz, 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 ClNO[M + H] + Calculated value: 578.2, measured value: 578.5. 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 [ka]

[0177] The compound was prepared 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 using a procedure similar to step d of Example 1. The crude product was purified by silica gel flash chromatography. This material was treated with 1 N HCl in EtO (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. 1 H NMR (400 MHz, CD3OD) δ 11.69 (s, 1H), 8.66 (d, J = 1.9 Hz, 1H), 8.54 (d, J = 8.4 Hz, 1H), 7.92 (d, J = 7.6 Hz, 1H), 7.66 (d, J = 7.8 Hz, 1H), 7.51 (dd, J = 7.7, 7.7 Hz, 1H), 7.45-7.34 (m, 3H), 7.14-7.07 (m, 1H), 4.35 (d, J = 2.2 Hz, 2H), 4.14-4.03 (m, 4H), 3.56 (d, J = 1.9 Hz, 3H), 3.39 (d, J = 1.9 Hz, 3H), 3.26 (d, J = 6.1 Hz, 2H), 2.49-2.32 (m, 3H), 1.98-1.88 (m, 1H). MS: (ES) m / z C 31 H 31 Cl2N6O5[M + H] + Calculated value: 637.2, measured value: 637.5. 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 [ka]

[0178] The compound was prepared 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 using a procedure similar to step d of Example 1. The crude product was purified by silica gel flash chromatography followed by preparative HPLC to give (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 (400 MHz, CD3OD) δ 11.70 (s, 1H), 8.84 (s, 1H), 8.67 (d, J = 1.8 Hz, 1H), 8.55 (d, J = 8.4 Hz, 1H), 7.73-7.66 (m, 1H), 7.58 (dd, J = 7.7, 7.7 Hz, 1H), 7.48-7.38 (m, 2H), 7.12 (d, J = 7.8 Hz, 1H), 4.73-4.58 (m, 2H), 4.16-4.09 (m, 1H), 3.56 (d, J = 1.6 Hz, 3H), 3.42-3.27 (m, 5H), 2.95 (q, J = 7.5 Hz, 2H), 2.50-2.35 (m, 3H), 2.02-1.94 (m, 1H), 1.40 (t, J = 7.5 Hz, 3H). MS: (ES) m / z C 31 H 32 Cl2N7O4[M + H] + Calculated value: 636.2, measured value: 636.2. 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 [ka]

[0179] The compound was prepared 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 using a procedure similar to step d of Example 1. 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. 1 H NMR (400 MHz, CD3OD) δ 11.17 (s, 1H), 8.42 (s, 1H), 8.10 (d, J = 8.2 Hz, 1H), 7.88 (d, J = 7.5 Hz, 1H), 7.61 (d, J = 7.4 Hz, 1H), 7.50 (dd, J = 8.4, 6.9 Hz, 1H), 7.41-7.25 (m, 3H), 7.01 (d, J = 7.5 Hz, 1H), 4.38-4.31 (m, 2H), 4.13-4.00 (m, 4H), 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] + Calculated value: 603.2, measured value: 603.6. 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 [ka]

[0180] The compound was prepared 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 using a procedure similar to step d of Example 1. 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. 1 H NMR (400 MHz, CD3OD) δ 11.18 (s, 1H), 8.63 (s, 1H), 8.10 (d, J = 8.0 Hz, 1H), 8.00 (d, J = 8.2 Hz, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.59-7.48 (m, 2H), 7.39 (dd, J = 7.1, 2.2 Hz, 1H), 7.29 (dd, J = 7.9, 7.9 Hz, 1H), 7.00 (d, J = 7.7 Hz, 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 = 7.5 Hz, 2H), 2.48-2.35 (m, 3H), 2.14 (s, 3H), 1.96-1.88 (m, 1H), 1.35 (t, J = 7.5 Hz, 3H). MS: (ES) m / z C 33 H 36 ClN6O4[M + H] + Calculated value: 615.2, measured value: 615.6. 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 [ka]

[0181] 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), EtN (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 NaBHCN (30 mg, 0.44 mmol) was added. After stirring at 0 °C for 5 min, the mixture was concentrated in vacuo. The resulting 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. 1H NMR (400 MHz, CD3OD) δ 8.62 (s, 1H), 8.33 (d, J = 1.6 Hz, 1H), 8.12 (d, J = 8.4 Hz, 1H), 7.65 (d, J = 1.6 Hz, 1H), 7.56-7.47 (m, 2H), 7.37 (dd, J = 7.6, 1.6 Hz, 1H), 7.29 (d, J = 8.2, 8.2 Hz, 1H), 6.99 (d, J = 7.6 Hz, 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 ClNO[M + H] + Calculated value: 620.2, measured value: 620.2. 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 [ka]

[0182] The compound was prepared 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 using a procedure similar to step d of Example 1. 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 (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 8.77 (s, 1H), 8.27-8.25 (m, 1H), 7.71-7.62 (m, 2H), 7.54-7.50 (m, 1H), 7.37-7.26 (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 / z C 32 H 32 ClNO5[M + H] + Calculated value: 630.2, measured value: 630.2. 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 [ka]

[0183] 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 at 0° C. was slowly added hydrochloric acid (0.5 mL, 37% in water). The mixture was heated to 100° C. for 16 h. 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 (400 MHz, CD3OD) δ 11.69 (s, 1H), 8.66 (s, 1H), 8.55 (ddd, J = 8.4, 2.4, 1.5 Hz, 1H), 7.66 (d, J = 7.1 Hz, 1H), 7.59-7.36 (m, 4H), 7.12-7.04 (m, 1H), 6.46 (d, J = 7.1 Hz, 1H), 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 / z C 30 H 29 Cl2N6O5[M + H] + Calculated value: 623.2, measured value: 623.5. 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 [ka]

[0184] The compound was prepared 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 using a procedure similar to step d of Example 1. 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. 1H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 8.77 (s, 1H), 8.27-8.25 (m, 1H), 7.80 (d, J = 7.5 Hz, 1H), 7.64 (dd, J = 7.7, 1.7 Hz, 1H), 7.52 (dd, J = 7.6, 7.6 Hz, 1H), 7.37-7.28 (m, 3H), 6.99 (dd, J = 7.7, 1.2 Hz, 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, 6.6 Hz, 1H), 2.20-1.98 (m, 5H), 1.91-1.79 (m, 1H). MS: (ES) m / z C 33 H 36 ClN6O5[M + H] + Calculated value: 631.2, measured value: 631.2. 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 [ka]

[0185] The compound was prepared 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-dimethylpropanamide using a procedure similar to step d of Example 1. 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 (400 MHz, CD3OD) δ 11.68 (s, 1H), 8.65 (s, 1H), 8.53 (d, J = 7.9 Hz, 1H), 7.86 (s, 1H), 7.65 (d, J = 7.2 Hz, 1H), 7.50 (dd, J = 7.2, 7.2 Hz, 1H), 7.42-7.36 (m, 3H), 7.09 (d, J = 7.2 Hz, 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 / z C 31 H 33 Cl2N6O5[M + H] + Calculated value: 639.2, measured value: 639.2. 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 [ka]

[0186] The compound was prepared 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 using a procedure similar to step d of Example 1. 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 (400 MHz, CD3OD) δ 11.70 (s, 1H), 8.67 (s, 1H), 8.54 (d, J = 8.2 Hz, 1H), 7.96 (d, J = 7.6 Hz, 1H), 7.69-7.66 (m, 1H), 7.55-7.44 (m, 1H), 7.44-7.39 (m, 3H), 7.10 (d, J = 7.5 Hz, 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 / z C 32 H 33 Cl2N6O5[M + H] + Calculated value: 651.2, measured value: 651.1. 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 [ka]

[0187] The compound was prepared 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 using a procedure similar to step d of 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-2-oxo-1,2-dihydropyridine-3-carboxamide. 1 H NMR (400 MHz, CD3OD) δ 12.66 (s, 1H), 8.62-8.61 (m, 2H), 8.03 (d, J = 6.5 Hz, 1H), 7.91 (d, J = 7.7 Hz, 1H), 7.68-7.66 (m, 1H), 7.53 (dd, J = 7.7, 7.7 Hz, 1H), 7.42-7.38 (m, 3H), 7.12 (d, J = 7.6 Hz, 1H), 6.63 (dd, J = 7.0, 7.0 Hz, 1H), 4.35 (s, 2H), 4.07-4.02 (m, 4H), 3.71 (d, J = 1.9 Hz, 3H), 3.29-3.25 (m, 2H), 2.48-2.35 (m, 3H), 1.98-1.89 (s, 1H). MS: (ES) m / z C 31 H 29 Cl2N5O4[M + H] + Calculated value: 606.2, measured value: 606.2. 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 [ka]

[0188] The compound was prepared 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 using a procedure similar to step d of Example 1. 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-carboxamide)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)azetidine-3-carboxylic acid. 1 H NMR (400 MHz, CD3OD) δ 11.69 (s, 1H), 8.66 (d, J = 1.9 Hz, 1H), 8.57-8.49 (m, 1H), 7.89 (d, J = 7.7 Hz, 1H), 7.66 (dd, J = 7.8, 1.8 Hz, 1H), 7.53-7.50 (m, 1H), 7.45-7.34 (m, 3H), 7.10 (dd, J = 7.6, 1.8 Hz, 1H), 4.51 (s, 2H), 4.42 (d, J = 8.9 Hz, 4H), 4.09 (d, J = 1.8 Hz, 3H), 3.79-3.65 (m, 1H), 3.56 (d, J = 2.1 Hz, 3H), 3.39 (s, 3H). MS: (ES) m / z C 30 H 28 Cl2N5O6[M + H] + Calculated value: 624.1, measured value: 624.1. 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 [ka]

[0189] The compound was prepared 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 using a procedure similar to step d of Example 1. 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-carboxamide)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)-3-methylazetidine-3-carboxylic acid. 1 H NMR (400 MHz, CD3OD) δ 11.68 (s, 1H), 8.65 (d, J = 1.7 Hz, 1H), 8.54 (dd, J = 8.7, 1.8 Hz, 1H), 7.89 (d, J = 7.6 Hz, 1H), 7.66 (dd, J = 7.9, 1.9 Hz, 1H), 7.53-7.49 (m, 1H), 7.42-7.36 (m, 3H), 7.10 (dd, J = 7.7, 1.8 Hz, 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] + Calculated value: 638.2, measured value: 638.1. 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 [ka]

[0190] The compound was prepared 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 using a procedure similar to step d of Example 1. 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-carboxamide)-[1,1'-biphenyl]-3-yl)-3-methoxypyrazin-2-yl)methyl)piperidine-2-carboxylic acid. 1 H NMR (400 MHz, CD3OD) δ 11.70 (s, 1H), 8.66 (s, 1H), 8.60-8.54 (m, 2H), 7.74 (dd, J = 7.7, 1.8 Hz, 1H), 7.60-7.56 (m, 1H), 7.47-7.41 (m, 2H), 7.12 (dd, J = 7.6, 1.8 Hz, 1H), 4.69 (s, 2H), 4.27-4.21 (m, 1H), 4.11 (s, 3H), 3.79 (d, J = 12.6 Hz, 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] + Calculated value: 653.2, measured value: 653.1. 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 [ka]

[0191] The compound was prepared 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 using a procedure similar to step d of Example 1. The crude product was purified by preparative HPLC to give (R)-1-((5-(2,2'-dichloro-3'-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide)-[1,1'-biphenyl]-3-yl)-3-methoxypyrazin-2-yl)methyl)piperidine-2-carboxylic acid. 1 H NMR (400 MHz, CD3OD) δ 11.70 (s, 1H), 8.67 (s, 1H), 8.59-8.54 (m, 2H), 7.74 (dd, J = 7.7, 1.8 Hz, 1H), 7.59-7.56 (m, 1H), 7.46-7.40 (m, 2H), 7.12 (dd, J = 7.6, 1.8 Hz, 1H), 4.69 (s, 2H), 4.27-4.20 (m, 1H), 4.11 (s, 3H), 3.79 (d, J = 12.6 Hz, 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] + Calculated value: 653.2, measured value: 653.2. 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 [ka]

[0192] 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 2 M K2CO3 (110 mL) and Pd(dppf)Cl2 complex along with DCM (5.25 g, 6.4 mmol). The mixture was degassed with N2 for 10 minutes and then heated at 90 °C for 2 hours. The reaction was quenched with saturated NaHCO3, 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.

[0193] 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, bispinacolato diboron (6.3 g, 24.9 mmol) was added, followed by KOAc (5.8 g, 59.1 mmol) and Pd(dppf)Cl complex with DCM (1.93 g, 2.4 mmol). The mixture was degassed with N for 10 min 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] + Calculated value: 344.2, measured value: 344.1.

[0194] 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 an additional amount 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) was added. After stirring overnight, the reaction was quenched with HO. 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 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 / z C 26 H 29 BClN3O5[M + H] + Calculated value: 510.2, measured value: 510.1.

[0195] 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), 2 M 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 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] + Calculated value: 519.1, measured value: 519.0.

[0196] 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 EtOH was added azetidin-3-ol (17 mg, 0.23 mmol), EtN (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 NaBHCN (18 mg, 0.29 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour and then quenched with HO. 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 followed by 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 H NMR (400 MHz, DMSO-d6) δ 11.05 (s, 1H), 8.74 (s, 1H), 8.24 (d, J = 9.5 Hz, 1 H), 7.71 (d, J = 7.5 Hz, 1H), 7.61 (dd, J = 7.9, 1.7 Hz, 1H), 7.50 (dd, J = 7.6, 7.6 Hz, 1H), 7.40-7.16 (m, 3H), 6.96 (dd, J = 7.5, 1.6 Hz, 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 ClNO5[M + H] +The calculated value was 576.2, and the measured value was 576.0. 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 [ka]

[0197] The compound was prepared 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 using a procedure similar to step d of Example 1. The crude product was purified by preparative HPLC to give 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. 1 H NMR (400 MHz, DMSO-d6) δ 11.05 (s, 1H), 8.75 (s, 1H), 8.24 (d, J = 9.7 Hz, 1H), 7.79-7.56 (m, 3H), 7.50 (dd, J = 7.6, 7.6 Hz, 1H), 7.42-7.13 (m, 3H), 6.97 (d, J = 7.6 Hz, 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 34ClN6O5[M + H] + Calculated value: 629.2, measured value: 629.0. Example 71: 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 [ka]

[0198] The compound was prepared 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 using a procedure similar to step d of Example 1. 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-carboxamide)-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)azetidine-3-carboxylic acid. 1 H NMR (400 MHz, CD3OD) δ 8.63 (s, 1H), 8.11 (d, J = 8.1 Hz, 1H), 7.86 (d, J = 7.7 Hz, 1H), 7.61 (d, J = 7.6 Hz, 1H), 7.49 (dd, J = 7.6, 7.6 Hz, 1H), 7.35-7.23 (m, 3H), 7.01 (d, J = 7.7 Hz, 1H), 4.37 (bs, 2H), 4.19 (dd, J = 9.2, 2.3 Hz, 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]+ Calculated value: 604.2, measured value: 603.9. 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 [ka]

[0199] 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), 2 M K2CO3 (6.7 mL), and Pd(PPh3)4 (0.23 g, 0.20 mmol). The mixture was degassed with N2 for 10 minutes and then heated at 100 °C for 1 hour. The reaction was quenched with HO, 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 give 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 / z C 26 H 23 ClNO5[M + H] + Calculated values ​​are 520.1 and 519.9.

[0200] 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 EtOH was added (S)-5-(aminomethyl)pyrrolidin-2-one (35 mg, 0.23 mmol), EtN (0.07 mL, 0.5 mmol), and AcOH (0.04 mL, 0.70 mmol). The contents were heated at 70 °C for 1 h, then cooled to 0 °C, and NaBHCN (18 mg, 0.29 mmol) was added. After stirring at room temperature for 1 hour, the reaction was quenched with HO. 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 followed by 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. 1 H NMR (400 MHz, CD3OD) δ: 8.63 (s, 1H), 8.42 (s, 1H), 8.12 (d, J = 8.2 Hz, 1H), 7.65 (d, J = 7.2 Hz, 1H), 7.52 (dd, J = 7.6, 7.6 Hz, 1H), 7.38 (d, J = 7.6 Hz, 1H), 7.30 (dd, J = 8.1, 8.1 Hz, 1H), 7.01 (d, J = 7.6 Hz, 1H), 4.06 (s, 3 H), 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 / z C 31 H33 ClNO5[M + H] + Calculated value: 618.2, measured value: 618.2. 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 [ka]

[0201] The compound was prepared 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 of 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 (400 MHz, DMSO-d6) δ 11.06 (s, 1H), 8.75 (s, 1H), 8.44 (s, 1H), 8.25 (d, J = 8.2 Hz, 1H), 7.68 (d, J = 7.6 Hz, 1H), 7.56 (dd, J = 7.7, 7.7 Hz, 1H), 7.41 (d, J = 7.5 Hz, 1H), 7.30 (dd, J = 7.9, 7.9 Hz, 1H), 6.98 (d, J = 7.6 Hz, 1H), 4.76 (s, 1H), 4.06-3.93 (m, 1H), 3.87 (d, J = 15.6 Hz, 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] + Calculated value: 621.2, measured value: 621.2. 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 [ka]

[0202] 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 h and then quenched with HO. The solid was filtered and washed with HO and then 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 was 386.2 and the measured value was 386.4.

[0203] 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 of THF and 2 mL of HO was added 6-(3-bromo-2-chlorophenyl)-2-methoxynicotinaldehyde (85 mg, 0.26 mmol), KPO (137 mg, 0.65 mmol), and XPhosPdG (20 mg, 0.03 mmol). The mixture was degassed with N for 10 min and stirred at room temperature overnight. The solid contents were 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] + Calculated value: 505.1, measured value: 505.4.

[0204] 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 EtOH was added (S)-5-(aminomethyl)pyrrolidin-2-one (25 mg, 0.17 mmol), EtN (0.06 mL, 0.43 mmol), and AcOH (0.04 mL, 0.70 mmol). The contents were heated at 70 °C for 1 h, then cooled to room temperature, and Na(OAc)BH (90 mg, 0.42 mmol) was added. After stirring at room temperature for 20 min, the reaction was quenched with HO. 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 followed by 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. 1 H NMR (400 MHz, DMSO-d6) δ 11.12 (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 = 7.4 Hz, 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 = 6.1 Hz, 2H), 2.22-1.97 (m, 3H), 1.81-1.58 (m, 1H). MS: (ES) m / z C 31 H 32 ClN6O5[M + H]+ Calculated value: 603.2, measured value: 603.5. 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 [ka]

[0205] 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 h and then quenched with HO. The solid was filtered and washed with HO and then 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] + Calculated value: 404.2, measured value: 404.4.

[0206] 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 of THF and 1 mL of HO was added 6-(3-bromo-2-chlorophenyl)-2-methoxynicotinaldehyde (81 mg, 0.25 mmol), KPO (132 mg, 0.62 mmol), and XPhosPdG (20 mg, 0.03 mmol). The mixture was degassed with N for 10 min and stirred at room temperature for 5 h. The solid contents were 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 / z C 26 H 21 ClFN4O5[M + H] + Calculated value: 523.1, measured value: 523.3.

[0207] 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), EtN (0.07 mL, 0.5 mmol), and AcOH (0.04 mL, 0.70 mmol). The contents were heated at 70 °C for 1 h, then cooled to room temperature, and Na(OAc)BH (100 mg, 0.47 mmol) was added. After stirring at room temperature for 1 hour, the reaction was quenched with HO. 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 followed 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. 1H NMR (400 MHz, DMSO-d6) δ 11.46 (s, 1H), 8.76 (s, 1H), 8.47 (dd, J = 7.8, 7.8 Hz, 1H), 7.81 (d, J = 7.5 Hz, 1H), 7.69 (s, 1 H), 7.64 (d, J = 7.6 Hz, 1H), 7.53 (dd, J = 7.3, 7.3 Hz, 1H), 7.46 (d, J = 7.5 Hz, 1H), 7.30 (dd, J = 8.0, 8.0 Hz, 1H), 7.25 (d, J = 7.2 Hz, 1H), 7.12 (dd, J = 7.2, 7.2 Hz, 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 = 6.0 Hz, 2H), 2.18-2.00 (m, 3H), 1.71-1.62 (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. 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 [ka]

[0208] 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, 2 M K2CO3 (4.7 mL, 10.9 mmol) and Pd(PPh3)4 (420 mg, 0.36 mmol) were added. The mixture was degassed with N2 for 10 minutes and stirred at 100 °C for 2 hours. The reaction was quenched with H2O, and the aqueous layer was extracted 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 give 6-(3-bromo-2-chlorophenyl)-2-(trifluoromethyl)nicotinaldehyde. MS: (ES) m / z C 13 H7BrClF3NO [M + H] + The calculated value was 363.9 and the measured value was 364.2.

[0209] 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), 2 M KCO (1.2 mL, 2.4 mmol), and Pd(dppf)Cl complex along with DCM (170 mg, 0.21 mmol). The mixture was degassed with N for 10 min and then heated at 100 °C for 1 h. The contents were filtered through Celite, and the filtrate was concentrated and purified by silica gel column chromatography to give 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 21ClF3N4O4[M + H] + Calculated value: 557.1, measured value: 557.4.

[0210] 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), EtN (0.09 mL, 0.65 mmol), and AcOH (0.06 mL, 1.0 mmol). The contents were heated at 70 °C for 1 h, then cooled to room temperature, and Na(OAc)BH (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)BH (114 mg, 0.54 mmol) was added. After stirring overnight at room temperature, 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 (400 MHz, CD3OD) δ 8.62 (s, 1H), 8.29 (d, J = 8.2 Hz, 1H), 8.12 (dd, J = 8.4, 1.6 Hz, 1H), 7.93 (d, J = 8.2 Hz, 1H), 7.60 (dd, J = 7.7, 1.8 Hz, 1H), 7.52 (dd, J = 7.6, 7.6 Hz, 1H), 7.38 (dd, J = 7.5, 1.8 Hz, 1H), 7.29 (dd, J = 7.9, 7.9 Hz, 1H), 7.02 (dd, J = 7.4, 1.2 Hz, 1H), 4.06 (bs, 2H), 3.84 (dddd, J = 6.5, 6.5, 6.5, 6.5 Hz, 1H), 3.55 (s, 3H), 3.39 (s, 3H), 2.76 (dd, J = 12.0, 4.8 Hz, 1H), 2.69 (dd, J = 12.0, 7.2 Hz, 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] + Calculated value: 655.2, measured value: 655.2. 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 [ka]

[0211] Step a: 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 (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 EtN (2 drops) and AcOH (2 drops). The contents were stirred at 70 °C for 1 h, then cooled to 0 °C, and NaBHCN (13 mg, 0.2 mmol) was slowly added. After stirring at 0° C. for 10 min, 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 (400 MHz, CDCl3) δ 10.89 (s, 1H), 8.52 (s, 1H), 8.25-8.18 (m, 1H), 7.66-7.55 (m, 2H), 7.40 (dd, J = 7.6, 7.6 Hz, 1H), 7.35-7.22 (m, 3H), 7.03 (dd, J = 7.5, 1.2 Hz, 1H), 4.08 (t, J = 4.8 Hz, 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 ClNO5[M + H] + Calculated value: 604.2, measured value: 604.5. 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 [ka]

[0212] The compound was prepared 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 of 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. 1H NMR (400 MHz, CDCl3) δ 10.89 (s, 1H), 8.53 (s, 1H), 8.22 (d, J = 8.2 Hz, 1H), 7.67-7.59 (m, 2H), 7.40 (dd, J = 7.6, 7.6 Hz, 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 = 13.8 Hz, 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 ClNO[M + H] + Calculated value: 620.2, measured value: 620.2. 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 [ka]

[0213] The compound was prepared 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 of 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 (400 MHz, CDCl3) δ 10.93 (s, 1H), 8.53 (s, 1H), 8.30 (d, J = 7.9 Hz, 1H), 7.80 (dd, J = 7.8, 1.1 Hz, 1H), 7.73-7.63 (m, 2H), 7.42-7.30 (m, 3H), 7.10 (d, J = 7.8 Hz, 1H), 4.10 (s, 3H), 4.04 (dd, J = 11.6, 4.1 Hz, 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, 4.1 Hz, 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] + Calculated value: 611.3, measured value: 611.2. 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 [ka]

[0214] The compound was prepared 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 of 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 (400 MHz, CDCl3) δ 10.89 (s, 1H), 8.53 (s, 1H), 8.21 (dd, J = 7.8, 1.1 Hz, 1H), 7.65-7.57 (m, 2H), 7.38 (dd, J = 7.8 Hz, 1H), 7.30 (dd, J = 7.8 Hz, 1 H), 7.26-7.21 (m, 2H), 7.03 (dd, J = 7.8, 1.1 Hz, 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 ClNO5[M + H] + Calculated value: 618.2, measured value: 618.6. 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 [ka]

[0215] The compound was prepared 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 of Example 1. The crude product was purified by preparative-phase 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 (400 MHz, CDCl3) δ 10.89 (s, 1H), 8.52 (s, 1H), 8.22 (dd, J = 7.6, 1.2 Hz, 1H), 7.64-7.56 (m, 2H), 7.39 (dd, J = 7.6, 7.6 Hz, 1H), 7.30 (dd, J = 7.6 Hz, 1H), 7.30-7.19 (m, 2H), 7.02 (dd, J = 7.6, 1.3 Hz, 1H), 4.02 (s, 3H), 3.88 (t, J = 5.6 Hz, 2H), 3.82 (s, 2H), 3.57 (s, 3H), 3.44 (s, 3H), 2.18 (s, 3H), 1.73 (t, J = 5.4 Hz, 2H), 1.32 (s, 6H). MS: (ES) m / z C 32 H 37ClNO5[M + H] + Calculated value: 606.2, measured value: 606.6. 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 [ka]

[0216] The compound was prepared 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 of 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. 1H NMR (400 MHz, CD3OD) δ 11.16 (s, 1H), 8.63 (d, J = 1.3 Hz, 1H), 8.06 (d, J = 7.9 Hz, 1H), 7.87 (d, J = 7.5 Hz, 1H), 7.41 (d, J = 7.8 Hz, 1H), 7.35 (dd, J = 7.8 Hz, 1H), 7.28 (dd, J = 7.5, 7.5 Hz, 1H), 7.28 (d, J = 7.5 Hz, 1H), 7.18 (d, J = 7.8 Hz, 1H), 6.98 (d, J = 7.5 Hz, 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] + Calculated value: 597.3, measured value: 597.3. 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 [ka]

[0217] The compound was prepared 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 using a procedure similar to step d of Example 1. 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-carboxamide)-[1,1'-biphenyl]-3-yl)-2-ethylpyridin-3-yl)methyl)azetidine-3-carboxylic acid. 1 H NMR (400 MHz,CD3OD) δ 11.69 (s, 1H), 8.66 (s, 1H), 8.53 (d, J = 8.0 Hz, 1H), 7.92 (d, J = 7.8 Hz, 1H), 7.64 (d, J = 7.8 Hz, 1H), 7.60 (d, J = 7.8 Hz, 1H), 7.54 (dd, J = 8.0 Hz, 1H), 7.41 (dd, J = 8.0 Hz, 2H), 7.10 (dd, J = 7.3, 1.7 Hz, 1H), 4.65 (s, 2H), 4.49-4.42 (m, 4H), 3.82-3.68 (m, 1H), 3.55 (d, J = 1.5 Hz, 3H), 3.39 (d, J = 1.8 Hz, 3H), 3.05 (q, J =7.6 Hz, 2H), 1.35 (t, J = 9.6 Hz, 3H). MS: (ES) m / z C 31 H 30 Cl2N5O5[M + H] + Calculated value: 622.2, measured value: 622.1. 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 [ka]

[0218] The compound was prepared 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 of 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 (400 MHz, CD3OD) δ 11.69 (s, 1H), 8.66 (d, J = 1.9 Hz, 1H), 8.54 (d, J = 8.6 Hz, 1H), 7.95 (d, J = 8.1 Hz, 1H), 7.64 (d, J = 7.8 Hz, 1H), 7.60 (d, J = 7.8 Hz, 1H), 7.54 (dd, J = 8.0, 8.0 Hz, 1H), 7.41 (dd, J = 8.0, 8.0 Hz, 2H), 7.13 (dd, J = 7.3, 1.8 Hz, 1H), 4.63 (s, 2H), 4.45 (t, J = 8.9 Hz, 2H), 4.09 (s, 2H), 3.56 (s, 3H), 3.39 (s, 3H), 3.00 (q, J = 7.6 Hz, 2H), 1.36 (t, J = 7.6 Hz, 3H). MS: (ES) m / z C 30 H 30 Cl2N5O4[M + H] + Calculated value: 594.2, measured value: 594.1. 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 [ka]

[0219] The compound was prepared 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 similar to step d of Example 1. The crude product was purified by preparative phase HPLC to give 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. 1H NMR (400 MHz,CD3OD) δ 11.69 (s, 1H), 8.66 (s, 1H), 8.54 (dd, J = 8.5, 1.8 Hz, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.64 (d, J = 7.8 Hz, 1 H), 7.60 (d, J = 7.8 Hz, 1H), 7.54 (dd, J = 8.0 Hz, 1H), 7.41 (dd, J = 8.0 Hz, 2H), 7.10 (d, J = 7.3 Hz, 1H), 4.49 (d, J = 13.5 Hz, 1H), 4.30 (d, J = 12.6 Hz, 1H), 4.13 (s, 1H), 4.02 (d, J = 12.6 Hz, 2H), 3.62 (t, J = 12.4 Hz, 2H),3.58 (s, 3H), 3.48 (t, J = 12.4 Hz, 2H), 3.39 (s, 3H), 3.15-2.29 (m, 2H), 2.21-2.07 (m, 1H), 1.86 (d, J = 13.1 Hz, 1H), 1.36 (t, J = 7.2 Hz, 3H). MS: (ES) m / z C 32 H 34 Cl2N5O5[M + H] + Calculated value: 638.2, measured value: 638.2. 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 [ka]

[0220] The compound was prepared 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 of 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 H NMR (400 MHz, CD3OD) δ 11.69 (s, 1H), 8.66 (s, 1H), 8.54 (d, J = 8.1 Hz, 1H), 8.01 (d, J = 8.1 Hz, 1H), 7.64 (d, J = 7.8 Hz, 1H), 7.61 (d, J = 7.8 Hz, 1H), 7.54 (dd, J = 8.0 Hz, 1H), 7.42 (dd, J = 8.0 Hz, 2H), 7.10 (dd, J = 7.3, 1.8 Hz, 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 = 7.6 Hz, 2H), 2.47-2.33 (m, 3H), 2.00-1.91 (m, 1H), 1.36 (t, J = 7.5 Hz, 3H). MS: (ES) m / z C 32 H 33 Cl2N6O4[M + H] + Calculated value: 635.2, measured value: 635.2. 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 [ka]

[0221] The compound was prepared 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 using a procedure similar to step d of Example 1. 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-carboxamide)-[1,1'-biphenyl]-3-yl)-3-methoxypyrazin-2-yl)methyl)-3-methylazetidine-3-carboxylic acid. 1 H NMR (400 MHz, CD3OD) δ 11.70 (s, 1H), 8.67 (s, 1H), 8.55 (d, J = 8.1 Hz, 1H), 8.49 (s, 1H), 7.70 (d, J = 7.8 Hz, 1H), 7.56 (dd, J = 8.0, 8.0 Hz, 1H), 7.47-7.37 (m, 2H), 7.10 (dd, J = 7.3, 1.8 Hz, 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] + Calculated value: 639.1, measured value: 639.0. 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 [ka]

[0222] 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-aminoethan-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 NaBHCN (40 mg, 0.63 mmol) was added. After stirring at 0°C for 5 min, 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 (400 MHz, CD3OD) δ 11.15 (s, 1H), 8.61 (s, 1H), 8.20 (d, J = 1.6 Hz, 1H), 8.07 (ddd, J = 8.4, 8.4, 1.2 Hz, 1H), 7.49 (d, J = 1.6 Hz, 1H), 7.36 (dd, J = 7.6, 7.6 Hz, 1H), 7.30-7.25 (m, 2H), 7.18 (dd, J = 7.2, 1.2 Hz, 1H), 6.97 (dd, J = 7.6, 0.8 Hz, 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 / z C 30 H 34 N5O5[M + H] + Calculated value: 544.3, measured value: 544.3. 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 [ka]

[0223] Step a: A 3 L flask was charged with 1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (50.0 g, 271 mmol) and dichloromethane (800 mL). 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 three-neck 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 EtN (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 give 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. 1H NMR (400 MHz, CDCl3) δ 10.81 (s, 1H), 8.50 (s, 1H), 8.19 (d, J = 8.8 Hz, 1H), 7.58 (d, J = 7.6 Hz, 1H), 7.23 (dd, J = 7.6, 7.6 Hz, 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] + Calculated value: 400.2, measured value: 400.2.

[0224] Step b: To a mixture of (3-bromo-2-chlorophenyl)boronic acid (30.0 g, 127.5 mmol), 6-chloro-2-methoxynicotinaldehyde (23.0 g, 134.0 mmol), and KCO (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 h. 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 was 326.0 and the measured value was 325.9.

[0225] 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 DI H2O (80 mL) was added Pd(dppf)Cl2 complex along with DCM (5.6 g, 6.9 mmol). The contents were degassed and stirred at 92 °C under N2 for 3 h. 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 MgSO. 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] + Calculated value: 519.1, measured value: 519.1.

[0226] 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 minutes, 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 resulting 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. 1H NMR (400 MHz, CD3OD) δ 11.18 (s, 1H), 8.63 (s, 1H), 8.10 (d, J = 8.4 Hz, 1H), 7.91 (d, J = 8.4 Hz, 1H), 7.65-7.61 (m, 1H), 7.50 (dd, J = 7.6, 7.6 Hz, 1H), 7.38 (d, J = 7.6 Hz, 1H), 7.35 (dd, J = 7.6, 1.6 Hz, 1H), 7.29 (dd, J = 8.0, 8.0 Hz, 1H), 7.00 (d, J = 7.6 Hz, 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 ClNO5[M + H] + Calculated value: 604.2, measured value: 604.5. 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 [ka]

[0227] This compound was prepared 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-aminooxan-3-ol hydrochloride using a procedure similar to step d of Example 89. The crude product was purified by preparative HPLC to give 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. 1 H NMR (400 MHz, CD3OD) δ 11.19 (s, 1H), 8.63 (s, 1H), 8.16-8.08 (m, 2H), 7.86 (d, J = 7.6 Hz, 1H), 7.55 (dd, J = 7.6, 1.6 Hz, 1H), 7.43-7.28 (m, 3H), 7.10 (d, J = 7.6 Hz, 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] + Calculated value: 604.3, measured value: 604.5. 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 [ka]

[0228] This compound was prepared 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 similar to step d of Example 89. The crude product was purified by 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. 1 H NMR (400 MHz, CD3OD) δ 11.71 (s, 1H), 8.66 (s, 1H), 8.50 (d, J = 8.8 Hz, 1H), 8.19 (s, 1H), 8.16 (d, J = 8.0 Hz, 1H), 7.87 (d, J = 7.6 Hz, 1H), 7.64 (d, J = 7.6 Hz, 1H), 7.58 (dd, J = 7.6, 7.6 Hz, 1H), 7.49 (d, J = 7.6 Hz, 1H), 7.41 (dd, J = 7.6, 7.6 Hz, 1H), 7.19 (d, J = 7.6 Hz, 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. 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 [ka]

[0229] The compound was prepared 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 similar to step d of Example 89. The crude product was purified 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)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 1 H NMR (400 MHz, CD3OD) δ 11.69 (s, 1H), 8.67 (s, 1H), 8.51 (d, J = 8.4 Hz, 1H), 7.88 (d, J = 7.6 Hz, 1H), 7.45 (d, J = 7.2 Hz, 1H), 7.43-7.34 (m, 2H), 7.25-7.19 (m, 2H), 7.07 (d, J = 7.2 Hz, 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 / z C 32 H 34ClN6O5[M + H] + Calculated value: 617.2, measured value: 617.5. 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 [ka]

[0230] The compound was prepared 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 similar to step d of Example 89. The crude product was purified by preparative HPLC to give (S)-2-(((6-(2,2'-dichloro-3'-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)-3-hydroxy-2-methylpropanoic acid. 1 H NMR (400 MHz, CD3OD) δ 11.69 (s, 1H), 8.66 (s, 1H), 8.53 d, J = 8.4 Hz, 1H), 7.91 (d, J = 7.6 Hz, 1H), 7.65 (d, J = 7.6 Hz, 1H), 7.51 (t, J = 7.6 Hz, 1H), 7.44-7.33 (m, 3H), 7.10 (d, J = 7.6 Hz, 1H), 4.41-4.29 (m, 2H), 4.09 (s, 3H), 4.11-4.05 (m, 1H), 3.88 (d, J = 12 Hz, 1H), 3.56 (s, 3H), 3.39 (s, 3H), 1.63 (s, 3H). MS: (ES) m / z C30 H 30 Cl2N5O7[M + H] + Calculated value: 642.2, measured value: 642.5. 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 [ka]

[0231] The compound was prepared 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 similar to step d of Example 89. The crude product was purified by preparative HPLC to give 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. 1 H NMR (400 MHz, CD3OD) δ 11.69 (s, 1H), 8.66 (s, 1H), 8.53 (d, J = 8.0 Hz, 1H), 7.87 (d, J = 7.2 Hz, 1H), 7.65 (d, J = 7.6 Hz, 1H), 7.51 (dd, J = 7.6, 7.6 Hz, 1H), 7.44-7.36 (m, 3H), 7.10 (d, J = 7.6 Hz, 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 C30 H 31 Cl2N6O6S [M + H] + The calculated value is 673.1 and the measured value is 672.7. 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 [ka]

[0232] The compound was prepared 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 similar to step d of Example 89. The crude product was purified by preparative HPLC to give (R)-1-((6-(2,2'-dichloro-3'-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)pyrrolidine-3-carboxylic acid. 1 H NMR (400 MHz, CD3OD) δ 11.69 (s, 1H), 8.66 (s, 1H), 8.54 (d, J = 6.8 Hz, 1H), 7.92 (d, J = 7.2 Hz, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.52 (dd, J = 8.0, 8.0 Hz, 1H), 7.44-7.36 (m, 3H), 7.10 (d, J = 7.6 Hz, 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 / z C 31 H 30Cl2N5O6[M + H] + The calculated value was 638.2 and the measured value was 637.8. 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 [ka]

[0233] The compound was prepared 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 of 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. 1 H NMR (400 MHz, CD3OD) δ 11.69 (s, 1H), 8.66 (s, 1H), 8.59 (s, 1H), 8.55 (d, J = 8.4 Hz, 1H), 7.64-7.54 (m, 2H), 7.53 (s, 1H), 7.48 (d, J = 6.4 Hz, 1H), 7.42 (dd, J = 8.0, 8.0 Hz, 1H), 7.10 (d, J = 7.2 Hz, 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 28Cl2N5O5[M + H] + The calculated value was 596.1 and the measured value was 595.8. 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 [ka]

[0234] The compound was prepared 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 similar to step d of Example 89. The crude product was purified by preparative HPLC to give (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. 1H NMR (400 MHz, CD3OD) δ 11.70 (s, 1H), 8.71 (s, 1H), 8.66 (s, 1H), 8.55 (d, J = 8.0 Hz, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.75 (dd, J = 8.0, 8.0 Hz, 1H), 7.48-7.38 (m, 2H), 7.10 (d, J = 7.6 Hz, 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] + Calculated value: 638.2, measured value: 638.2. 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 [ka]

[0235] The compound was prepared 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 similar to step d of Example 89. 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-carboxamide)-[1,1'-biphenyl]-3-yl)-4-methoxypyridin-3-yl)methyl)-3-methylazetidine-3-carboxylic acid.1 H NMR (400 MHz, CD3OD) δ 11.70 (s, 1H), 8.67 (s, 1H), 8.57 (s, 1H), 8.55 (d, J = 8.8 Hz, 1H), 7.62-7.54 (m, 2H), 7.50 (s, 1H), 7.47 (d, J = 7.2 Hz, 1H), 7.41 (dd, J = 7.2, 7.2 Hz, 1H), 7.10 (d, J = 7.2 Hz, 1H), 4.62-4.51 (m, 4H), 4.15 (d, J = 10.8 Hz, 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. 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 [ka]

[0236] The compound was prepared 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 similar to step d of Example 89. 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-carboxamide)-[1,1'-biphenyl]-3-yl)-4-methoxypyridin-3-yl)methyl)azetidine-3-carboxylic acid. 1H NMR (400 MHz, CD3OD) δ 11.70 (s, 1H), 8.66 (s, 1H), 8.59 (s, 1H), 8.55 (d, J = 8.0 Hz, 1H), 7.64-7.54 (m, 2H), 7.52 (s, 1H), 7.48 (d, J = 7.6 Hz, 1H), 7.42 (dd, J = 8.0, 8.0 Hz, 1H), 7.10 (d, J = 7.2 Hz, 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 / z C 30 H 28 Cl2N5O6[M + H] + Calculated value: 624.1, measured value: 623.9. 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 [ka]

[0237] The compound was prepared 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 similar to step d of Example 89. The crude product was purified by preparative HPLC to give (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. 1 H NMR (400 MHz, CD3OD) δ 11.70 (s, 1H), 8.67 (s, 1H), 8.59 (s, 1H), 8.55 (d, J = 8.4 Hz, 1H), 7.63-7.55 (m, 2H), 7.53 (s, 1H), 7.47 (d, J = 6.8 Hz, 1H), 7.42 (dd, J = 8.0, 8.0 Hz, 1H), 7.10 (d, J = 8.0 Hz, 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] + Calculated value: 637.2, measured value: 636.9. 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 [ka]

[0238] The compound was prepared 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 similar to step d of Example 89. 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)-4-methoxypyridin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. 1 H NMR (400 MHz, CD3OD) δ 11.70 (s, 1H), 8.67 (s, 1H), 8.58 (s, 1H), 8.55 (d, J = 8.4 Hz, 1H), 7.63-7.54 (m, 2H), 7.50 (s, 1H), 7.47 (d, J = 7.6 Hz, 1H), 7.42 (dd, J = 7.6, 7.6 Hz, 1H), 7.10 (d, J = 7.6 Hz, 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 was 640.2 and the measured value was 639.9. 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 [ka]

[0239] The compound was prepared 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 similar to step d of Example 89. The product was purified by preparative HPLC to give 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. 1 H NMR (400 MHz, DMSO-d6) δ: 11.05 (s, 1H), 8.75 (s, 1H), 8.24 (d, J = 8.0 Hz, 1H), 8.18 (bs, 1H), 7.62 (d, J = 7.6 Hz, 1H), 7.52 (dd, J = 7.6, 7.6 Hz, 1H), 7.36 (d, J = 7.4 Hz, 1H), 7.30 (dd, J = 7.8, 7.8 Hz, 1H), 6.97 (d, J = 7.5 Hz, 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 34ClN6O5[M + H] + Calculated value: 629.2, measured value: 629.0. Biological Example: Enzyme-Linked Immunosorbent Assay - ELISA

[0240] A 96-well plate was coated with 1 μg / ml human PD-L1 (obtained from R&D) in PBS overnight at 4°C. The wells were then blocked with 2% BSA in PBS (w / v) / 0.05% TWEEN®-20 for 1 hour at 37°C. The plate was washed three times with PBS / 0.05% TWEEN®-20, and compounds were serially diluted (1:5) in dilution medium and added to the ELISA plate. Human PD-1 and biotin at 0.3 μg / ml (ACRO Biosystems) were added and incubated for 1 hour at 37°C, followed by washing three times with PBS / 0.05% TWEEN®-20. A second blocking step was performed with 2% BSA in PBS (w / v) / 0.05% TWEEN®-20 for 10 minutes at 37°C, and the plate was washed three times with PBS / 0.05% TWEEN®-20. Streptavidin-HRP was added for 1 hour at 37°C, and then the plate was washed three times with PBS / 0.05% TWEEN®-20. TBM substrate was added and allowed to react for 20 minutes at 37°C. Stop solution (2N H2SO4 in water) was added. Absorbance was read at 450 nm using a microplate spectrophotometer. The results are shown in Table 1: IC 50 Values ​​were defined as follows: 1000-10,000 nM (+); 10-1000 nM (++); and less than 10 nM (+++). Table 1 [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4]

Table 1-5

Table 1-6

Table 1-7

Table 1-8

Table 1-9

Table 1-10

Table 1-11

Table 1-12

Table 1-13

Table 1-14

Table 1-15

[0241] Certain embodiments of the present invention are described herein, including the best mode known to the inventors for carrying out the invention. It is expected that variations of the disclosed embodiments may become apparent to those skilled in the art upon reading the foregoing specification, and that such variations will be employable by those skilled in the art. Accordingly, the invention may be practiced otherwise than as specifically described herein, and the invention is intended to include all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is included in the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

[0242] All publications, patent applications, accession numbers, and other references cited herein are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.

Claims

1. Formula (I): 【Chemical 1】 {During the ceremony, A is a 6-membered heteroaryl group selected from the group consisting of pyridine, pyrimidine, and pyrazine, which is unsubstituted or in which 1 to 3 members are halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 substituted with substituents independently selected from the group consisting of haloalkoxy and CN; X 1 is C 1-3 alkylene, which is unsubstituted or one or two members of which are C 1-2 Alkyl and CO 2 substituted with substituents independently selected from the group consisting of H; R 2a and R 2b is H, C 1-8 Alkyl, C 1-8 Haloalkyl, -Y, -X 2 -CO 2 R a , -X 2 -OR a , -X 2 -NR a R b , -X 2 -C(O)NR a R b , -X 2 -SO 2 R a , -X 2 -SO 2 NR a R b , -X 2 -SO 3 R a and -X 2 -Y, wherein each X 2 is C 1-6 alkylene and any C 1-8 Alkyl or C 1-6 Alkylene is unsubstituted or one or two of its members are OH, SO 2 NH 2 , C(O)NH 2 , C(O)NHOH, PO 3 H 2 , CO 2 C 1-8 Alkyl and CO 2 H; and each Y is substituted with a substituent independently selected from the group consisting of C 3-6 Cycloalkyl, C 4-8 and 5- to 6-membered heteroaryl, each of which is unsubstituted or selected from the group consisting of oxo, OH, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 1-4 Hydroxyalkoxy, SO 2 NH 2 , C(O)NH 2 , C(O)NHOH, PO 3 H 2 , CO 2 C 1-8 Alkyl, SO 3 H and CO 2 substituted with 1 to 4 substituents independently selected from the group consisting of H; or R 2a and R 2b are combined to form a 4-9 membered or spirocyclic ring having 0-2 additional heteroatom ring vertices selected from O, N and S; where R 2a and R 2b The 4- to 9-membered ring or spirocyclic ring formed by combining 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Hydroxyalkyl, -X 3 -CO 2 R a , -X 3 -OR a , -X 3 -NR a R b , -X 3 -C(O)NR a R b , -X 3 -SO 2 R a , -X 3 -SO 2 NR a R b , and -X 3 -SO 3 R a substituted with 1 to 4 substituents independently selected from the group consisting of: where X 3 is a bond or C 1-6 alkylene; R 3 and R 4 are F, Cl, CN, CH 3 , OCH 3 , C.H. 2 CH 3 and CF 3 are each independently selected from the group consisting of: The subscript n is 0, 1, 2 or 3; Each R 3a are H, F, Cl, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Haloalkoxy, C 2-3 independently selected from the group consisting of alkenyl and CN; R 6 , R 7 and R 8 are H, F, Cl, CN, CH 3 , OCH 3 , C.H. 2 CH 3 and CF 3 are each independently selected from the group consisting of: Z is: 【Chemistry 2】 a non-aromatic heterocycle having a structure selected from the group consisting of: Each R a is H, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkylene-CO 2 H and C 1-6 Alkylene-SO 3 H; and Each R b is H, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkylene-CO 2 H and C 1-6 Alkylene-SO 3 H, each of which is unsubstituted or one or two of which members are independently selected from the group consisting of OH, SO 2 NH 2 , C(O)NH 2 , C(O)NHOH, PO 3 H 2 , CO 2 C 1-8 Alkyl and CO 2 substituted with substituents independently selected from H; and R a and R b when attached to the same nitrogen atom, are optionally combined to form a 4- to 8-membered ring or a spirocyclic ring, which may be unsubstituted or may contain halogen, OH, SO 2 NH 2 , C(O)NH 2 , C(O)NHOH, PO 3 H 2 , CO 2 C 1-8 Alkyl or CO 2 H}, or a pharmaceutically acceptable salt thereof.

2. Formula (Ia): 【Chemistry 2】 2. The compound of claim 1, having the formula:

3. The A is unsubstituted or 1 to 3 members thereof are C 1-3 Alkyl, C 1-3 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, substituted with substituents independently selected from the group consisting of alkoxy, and CN.

4. Formula (Ib): 【Chemistry 4】 2. The compound of claim 1 having the formula: or a pharmaceutically acceptable salt thereof.

5. A is unsubstituted or one or two of its members are OCH 3 and F, or a pharmaceutically acceptable salt thereof.

6. -N(R 2a )(R 2b ) but the following: 【Chemistry 5】 10. The compound of claim 1, selected from the group consisting of:

7. -N(R 2a )(R 2b ) but the following: 【Chemistry 6】 10. The compound of claim 1, selected from the group consisting of:

8. -N(R 2a )(R 2b ) but the following: 【Chemistry 7】 10. The compound of claim 1, selected from the group consisting of:

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

10. The Y is C 3-6 Cycloalkyl and C 4-8 heterocyclyl, each of which is unsubstituted or selected from the group consisting of oxo, OH, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 1-4 Hydroxyalkoxy, SO 2 NH 2 , C(O)NH 2 , C(O)NHOH, PO 3 H 2 , CO 2 C 1-8 Alkyl, SO 3 H and CO 2 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, substituted with 1 to 4 substituents independently selected from the group consisting of H.

11. The compound is selected from the group consisting of: 【Chemistry 8-1】 【Chemistry 8-2】 【Chemistry 8-3】 【Chemistry 8-4】 【Chemistry 8-5】 【Chemistry 8-6】 【Chemistry 8-7】 【Hua 8-8】 【Chemistry 8-9】 【Chemistry 8-10】 【Chemistry 8-11】 【Chemistry 8-12】 【Chemistry 8-13】 【Chemistry 8-14】 【Chemistry 8-15】 10. The compound of claim 1, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

12. The compound is 【Chemistry 9】 10. The compound of claim 1, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

13. The compound is 【Chemistry 10】 13. The compound of claim 12, wherein:

14. The compound is 【Chemistry 11】 13. The compound of claim 12, wherein:

15. The compound is 【Chemistry 12】 13. The compound of claim 12, wherein:

16. The compound is 【Chemistry 13】 13. The compound of claim 12, wherein:

17. The compound is 【Chemistry 14】 13. The compound of claim 12, wherein:

18. The compound is 【Chemistry 15】 13. The compound of claim 12, wherein:

19. The compound is 【Chemistry 16】 13. The compound of claim 12, wherein:

20. The compound is 【Chemistry 17】 13. The compound of claim 12, wherein:

21. The compound is 【Chemistry 18】 13. The compound of claim 12, wherein:

22. A pharmaceutical composition comprising a compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

23. 23. The pharmaceutical composition of claim 22, further comprising one or more additional therapeutic agents.

24. 24. The pharmaceutical composition of claim 23, wherein the one or more additional therapeutic agents are selected from the group consisting of antimicrobial agents, antiviral agents, cytotoxic agents, gene expression modulators, chemotherapeutic agents, anticancer agents, antiangiogenic agents, immunotherapeutic agents, antihormonal agents, antifibrotic agents, radiation therapy, radiotherapeutic agents, anti-neoplastic agents, and anti-proliferative agents.

25. 22. A pharmaceutical composition comprising the compound of any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, for use in a method for modulating an immune response mediated by the PD-1 signaling pathway in a subject.

26. 22. A pharmaceutical composition comprising a compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, for use in a method of promoting, stimulating, modulating and / or augmenting an immune response in a subject in need thereof.

27. 22. A pharmaceutical composition comprising a compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, for use in a method of inhibiting the growth, proliferation, or metastasis of cancer cells in a subject in need thereof.

28. 22. A pharmaceutical composition comprising a compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, for use in a method of treating a subject suffering from or susceptible to a disease or disorder mediated by the PD-1 signaling pathway.

29. 26. The pharmaceutical composition of claim 25, wherein the subject is suffering from a disease or disorder selected from an infectious disease, a bacterial infectious disease, a viral infectious disease, a fungal infectious disease, a solid tumor, a hematological malignancy, an immune disorder, an inflammatory disease, and cancer.

30. The disease or disorder is selected from the group consisting of melanoma, glioblastoma, esophageal tumor, nasopharyngeal carcinoma, uveal melanoma, lymphoma, lymphocytic lymphoma, primary CNS lymphoma, T-cell lymphoma, diffuse large B-cell lymphoma, primary mediastinal large B-cell lymphoma, prostate cancer, castration-resistant prostate cancer, chronic myeloid leukemia, Kaposi's sarcoma, fibrosarcoma, liposarcoma, chondrosarcoma, osteosarcoma, angiosarcoma, lymphangiosarcoma, synovium, meningioma, leiomyosarcoma, rhabdomyosarcoma, sarcoma of soft tissue, sarcoma, sepsis, bile duct tumor, basal cell carcinoma, Thymus tumor, thyroid cancer, parathyroid cancer, uterine cancer, adrenal gland cancer, liver infection, Merkel cell carcinoma, nerve tumor, follicle center lymphoma, colon cancer, Hodgkin's disease, non-Hodgkin's lymphoma, leukemia, chronic or acute leukemia, acute myeloid leukemia, chronic myelogenous leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, multiple myeloma, ovarian tumor, myelodysplastic syndrome, cutaneous or intraocular malignant melanoma, renal cell carcinoma, small cell lung cancer, lung cancer, mesothelioma, breast cancer, squamous non-small cell lung cancer (SCLC), non-squamous NSCLC, Colon cancer, ovarian cancer, stomach cancer, hepatocellular carcinoma, pancreatic carcinoma, pancreatic cancer, pancreatic ductal adenocarcinoma, squamous cell carcinoma of the head and neck, cancer of the head or neck, cancer of the gastrointestinal tract, stomach cancer, HIV, hepatitis A, hepatitis B, hepatitis C, hepatitis D, herpes virus, papillomavirus, influenza, bone cancer, skin cancer, rectal cancer, cancer of the anal region, testicular cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the urethra, cancer of the penis, cancer of the bladder, cancer of the kidneys, cancer of the ureters The pharmaceutical composition of claim 28, wherein the therapeutic agent is selected from the group consisting of cancer, carcinoma of the renal pelvis, neoplasms of the central nervous system (CNS), tumor angiogenesis, spinal cord tumor, brainstem glioma, pituitary adenoma, squamous cell carcinoma, asbestosis, carcinoma, adenocarcinoma, papillary carcinoma, cystadenocarcinoma, bronchial carcinoma, renal cell carcinoma, transitional cell carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, pleomorphic adenoma, hepatocellular papilloma, tubular adenoma, cystadenoma, papilloma, adenoma, leiomyoma, rhabdomyoma, hemangioma, lymphangioma, osteoma, chondroma, lipoma, and fibroma.

31. 30. The pharmaceutical composition of claim 28, wherein the method further comprises administering to the subject a therapeutically effective amount of one or more additional therapeutic agents.

32. 32. The pharmaceutical composition of claim 31, wherein the one or more additional therapeutic agents are selected from the group consisting of antimicrobial agents, antiviral agents, cytotoxic agents, gene expression modulators, chemotherapeutic agents, anticancer agents, antiangiogenic agents, immunotherapeutic agents, antihormonal agents, antifibrotic agents, radiation therapy, radiotherapeutic agents, anti-neoplastic agents, and antiproliferative agents.

33. Formula (II): 【Chemistry 19】 1. A process for preparing a compound of formula (I), comprising: (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); 【Chemistry 20】 (b) converting a compound having formula (2e) to a compound having formula (2f) using a borate reagent and a second catalyst; 【Chemical 21】 (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); 【Chemical 22】 (d) HN(R 2a )(R 2b reductively amminating a compound having formula (2h) with a hydride reagent to provide a compound having formula (II); 【Chemical 23】 {During the ceremony, 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 6 , R 7 , and R 8 each of which has the meaning provided in claim 1; R and R' are H and C 1 -C 6 are each independently selected from the group consisting of alkyl; X is selected from the group consisting of Br and Cl; X' is selected from the group consisting of I, Br, and Cl; and R s is a 6-membered nitrogen heteroaryl ring selected from the group consisting of pyridine, pyrimidine, and pyrazine, and R s is a halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 are 0, 1, 2 or 3 substituents independently selected from the group consisting of haloalkoxy, OH, and CN.

34. Formula (II): 【Chemistry 24】 1. A process for preparing a compound of formula (I), comprising: (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); 【Chemistry 25】 (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); 【Chemical 26】 (c) HN(R 2a )(R 2b reductively amminating a compound having formula (2e1) with a hydride reagent to provide a compound having formula (II); 【Chemical 27】 {During the ceremony, In the above formulae (2a1), (2b1), (2c1), (2d1), (2e1), and (II), Z, R 2a , R 2b , R 3 , R 3a , subscript n, R 4 , R 6 , R 7 , and R 8 each of which has the meaning provided in claim 1; R and R' are H and C 1 -C 6 are each independently selected from the group consisting of alkyl; X' is selected from the group consisting of I, Br, and Cl; and R s is a 6-membered nitrogen heteroaryl ring selected from the group consisting of pyridine, pyrimidine, and pyrazine, and R s is a halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 are 0, 1, 2 or 3 substituents independently selected from the group consisting of haloalkoxy, OH, and CN.

35. The compound is selected from the group consisting of: 【Chemical 28】 2. The compound of claim 1, wherein:

Images