RU2848051C1 - Heteraryl biphenyl amides for the treatment of pd-l1 diseases - Google Patents

Abstract

FIELD: immunomodulators.

SUBSTANCE: compound of formula (I) or a pharmaceutically acceptable salt thereof is proposed, wherein R2a, R2b, R3, R3a, R4, R6, R7, R8, A, Z, X1 and n have the meanings given in the formula of the invention.

EFFECT: obtaining and using the specified compounds for modulating the immune response in a subject via the PD-1 signalling pathway, as well as pharmaceutical compositions containing the specified compounds, are disclosed.

36 cl, 1 tbl, 102 ex

Description

Prior art

Programmed cell death protein 1 (PD-1) is a member of the CD28 superfamily that mediates negative signals when interacting with its two ligands, PD-L1 or PD-L2. PD-1 and its ligands are widely expressed and perform a number of immunoregulatory functions in T-cell activation and tolerance. PD-1 and its ligands are involved in weakening immunity to infections and tumors, and contribute to the development of chronic infections and tumor progression.

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

There is a need for agents that block the interaction of PD-L1 with PD-1 or CD80. Several antibodies have been developed and launched. Several patent applications have been published disclosing non-peptide small molecules (WO 2015/160641, WO 2015/034820, and WO 2017/066227 and WO2018/009505 by BMS; WO 2015/033299 and WO 2015/033301 by Aurigene; WO 2017/070089, US 2017/0145025, WO 2017/106634, US2017/0174679, WO2017/192961, WO2017/222976, WO2017/205464, WO2017/112730, WO2017/041899 and WO2018/013789 by Incyte, WO2018/006795 by Maxinovel, and WO2018/005374 by the Applicant, ChemoCentryx). However, there is still a need for alternative compounds, such as small molecules, as PD-L1 inhibitors that have improved characteristics in terms of oral administration, stability, bioavailability, therapeutic index, and toxicity.

Brief description of the invention

In one aspect, the present invention provides compounds having formula (I):

or a pharmaceutically acceptable salt, prodrug or bioisostere thereof; wherein A, Z, ^X1 , ^R2a , ^R2b , ^R3 , ^R3a , ^R4 , ^R6 , ^R7 , ^R8 and the subscript n have the meanings specified herein.

In addition to the compounds described herein, the present invention also includes pharmaceutical compositions containing one or more of these compounds, as well as methods related to the preparation and use of these compounds. In some embodiments, the compounds described herein are used in therapeutic methods for the treatment of diseases associated with the PD-1/PD-L1 pathway.

Detailed description of the invention

Abbreviations and definitions

When used in this text, the singular encompasses not only aspects with a single representative but also aspects with multiple representatives. For example, singular forms may refer to multiple representatives unless the context clearly indicates otherwise. Thus, for example, the word "cell" includes instances with multiple cells, and "agent" may refer to one or more agents known in the art, etc.

The terms "about" and "approximately" generally mean an acceptable degree of error for a measured value, taking into account the nature and precision of the measurement performed. Typically, examples of the degree of error are in the range of 20 percent (%), preferably in the range of 10%, and more preferably in the range of 5%, of the stated value or range of values. Alternatively, and particularly in biological systems, the terms "about" and "approximately" may mean values within one order of magnitude, preferably within 5 times, and more preferably within 2 times, of the stated value. Numerical values given in this text are approximate unless otherwise stated, which means that the term "about" or "approximately" may be implied in cases where it is not explicitly used.

_The term "alkyl", by itself or as part of another substituent, means, unless otherwise specified, a straight or branched hydrocarbon group having the designated number of carbon atoms (e.g., C _1-8 means 1-8 carbon atoms). Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. The term "alkenyl" means an unsaturated alkyl group containing one or more double bonds. Similarly, the term "alkynyl" means an unsaturated alkyl group containing one or more triple bonds. Examples of alkenyl groups include vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl). Examples of alkynyl groups include ethynyl, 1- and 3-propynyl, 3-butynyl and their higher homologues and isomers. The term "cycloalkyl" refers to a hydrocarbon ring or rings containing the stated number of ring atoms (e.g., C _3-6 cycloalkyl) and being fully saturated or containing not more than one double bond between the ring vertices. The term "cycloalkyl" also refers to bicyclic and polycyclic hydrocarbon rings such as, for example, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, etc. Bicyclic or polycyclic rings may be fused, bridged, spiro, or a combination thereof. The term "heterocycloalkyl" or "heterocyclyl" refers to a cycloalkyl group containing 1-5 heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized. Heterocycloalkyl may be a monocyclic, bicyclic, or polycyclic ring system. Bicyclic or polycyclic rings may be fused, bridged, spiro, or a combination thereof. The term "C _4-12 heterocyclyl," for example, means a group containing from 4 to 12 ring members, wherein at least one of the ring members 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. The heterocycloalkyl group can be attached to the rest of the molecule through a carbon atom in the ring or a heteroatom in the ring.

The term "alkylene" alone or as part of another substituent means a divalent group derived from an alkane, such as _{-CH2CH2CH2CH2- .} An alkylene group may be linear or branched. Examples of the latter are _-CH2C ( _{CH3 ) 2CH2-} , _-CH2C (CH3) _2- , or -CH( _CH3 ) _{CH2CH2- .} Typically, an alkyl (or alkylene) group contains from 1 to ₁₂ carbon atoms, with those _containing 8 or fewer carbon atoms being preferred in the present invention. Similarly _, "alkenylene" and "alkynylene" mean unsaturated forms of "alkylene" containing double or triple bonds, respectively.

The term "heteroalkyl" by itself or in combination with another term, unless otherwise specified, means a stable linear, branched, or cyclic hydrocarbon group, or a combination thereof, containing the stated number of carbon atoms and one to three heteroatoms selected from the group consisting of O, N, Si, and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen atom may optionally be quaternized. The heteroatom(s) O, N, and S may be located at any internal position of the heteroalkyl group. The Si heteroatom may be located at any position of the heteroalkyl group, including the position through which the alkyl group is attached to the rest of the molecule. Examples include -CH2 _{- CH2-} O- _CH3 , -CH2 _{-CH2 -} NH- _CH3 , -CH2 _{-CH2 -} N( _CH3 ) _-CH3 , -CH2- _S -CH2- _CH3 , -CH2- _CH2 ,-S(O) _-CH3 , _{-CH2- CH2} -S(O) _{2- CH3 ,} -CH=CH-O _{-CH3, -Si(CH3)3 , -CH2 -} CH=N- _OCH3 , and -CH=CH-N( _CH3 )-CH3. Up _to two heteroatoms may be arranged sequentially, for example, _-CH2- NH- _OCH3 and _-CH2 -O-Si( _CH3 ) _{3 .} Similarly, the terms "heteroalkenyl" and "heteroalkynyl" by themselves or in combination with another term, unless otherwise specified, mean an alkenyl group or an alkynyl group, respectively, containing the indicated number of carbon atoms and from one to three heteroatoms selected from the group consisting of O, N, Si and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen atom may optionally be quaternized. The heteroatom(s) O, N and S may be in any internal position of the heteroalkyl group.

The term "heteroalkylene" alone or as part of another substituent means a divalent group, saturated or unsaturated or polyunsaturated, derived from heteroalkyl, and examples thereof are -CH ₂ -CH ₂ -S-CH ₂ CH ₂ -, -CH ₂ -S-CH ₂ -CH ₂ -NH-CH ₂ -, -O-CH ₂ -CH=CH-, -CH ₂ -CH=C(H)CH ₂ -O-CH ₂ - and -S-CH ₂ -C≡C-. In heteroalkylene groups, heteroatoms may also occupy one or both terminal positions in the chain (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, etc.).

The terms "alkoxy,""alkylamino," and "alkylthio" (or thioalkoxy) are used in their usual senses and refer to alkyl groups attached to the rest of the molecule through an oxygen atom, an amino group, or a sulfur atom, respectively. Additionally, for dialkylamino groups, the alkyl moieties may be the same or different and may combine to form a 3- to 7-membered ring with the nitrogen atom to which they are attached. Accordingly, the group depicted as -NR ^a R ^b includes piperidinyl, pyrrolidinyl, morpholinyl, azetidinyl, and the like.

The term "halogen" by itself or as part of another substituent means, unless otherwise specified, a fluorine, chlorine, bromine, or iodine atom. Furthermore, terms such as "haloalkyl" include monohaloalkyl and polyhaloalkyl. For example, the term "C _1-4 haloalkyl" includes trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

The term "hydroxyalkyl" or "alkyl-OH" means an alkyl group, as defined above, in which at least one (and up to three) hydrogen atoms are replaced by a hydroxy group. With respect to the alkyl group, hydroxyalkyl groups may contain any suitable number of carbon atoms, for example, C _1-6 . Examples of hydroxyalkyl groups include, but are not limited to, hydroxymethyl, hydroxyethyl (where the hydroxy group is at the 1- or 2-position), hydroxypropyl (where the hydroxy group is at the 1-, 2-, or 3-position), and 2,3-dihydroxypropyl.

The term "C _1-3 alkylguanidinyl" means a C _1-3 alkyl group in which at least one of the hydrogen atoms is replaced by a guanidinyl group (-NHC(NH)NH ₂ ).

The term "aryl" means, unless otherwise specified, a polyunsaturated, typically aromatic, hydrocarbon group which may be a single ring or multiple rings (up to three rings) conjugated or covalently linked. The term "heteroaryl" means aryl groups (or rings) that contain from 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. A heteroaryl group may be attached to the rest of the molecule through a heteroatom. By "C _5-10 heteroaryl" is meant a heteroaryl moiety containing 5-10 ring members, wherein at least one of the ring members is a heteroatom. Non-limiting examples of aryl groups include phenyl, naphthyl, and biphenyl, and non-limiting examples of heteroaryl groups include pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, quinolinyl, quinoxalinyl, quinazolinyl, cinnolyl, phthalazinyl, benzotriazinyl, purinyl, benzoimidazolyl, benzopyrazolyl, benzotriazolyl, benzisoxazalyl, isobenzofuryl, isoindolyl, indolizinyl, benzotriazinyl, thienopyridinyl, thienopyrimidinyl, pyrazolopyrimidinyl, imidazopyridines, benzothiaxolyl, benzofuranyl, benzothienyl, indolyl, quinolyl, isoquinolyl, isothiazolyl, pyrazolyl, indazolyl, pteridinyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiadiazolyl, pyrrolyl, thiazolyl, furyl, thienyl, etc. The substituents in each of the above aryl or heteroaryl ring systems are selected from the group of acceptable substituents described below.

The term "carbocyclic ring," "carbocyclic," or "carbocyclyl" refers to cyclic moieties containing only carbon atoms as ring members. Carbocyclic moieties may be saturated or unsaturated and may be aromatic. In general, carbocyclic moieties contain from 3 to 10 ring members. Carbocyclic moieties consisting of multiple rings (e.g., bicyclic) may include a cycloalkyl ring 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 may be saturated or unsaturated and may be aromatic. In general, heterocyclic moieties contain from 4 to 10 ring members and include piperidinyl, tetrazinyl, pyrazolyl, and indolyl.

When any of the above terms (e.g., "alkyl," "aryl," and "heteroaryl") is prefixed with the word "substituted" without further description of the substituents, the substituted forms of the indicated groups will be as described below.

Substituents for alkyl groups (including those often referred to as alkylene, alkenyl, alkynyl, and cycloalkyl) may be various groups selected from the following: -halogen, -OR', -NR'R", -SR', -SiR'R"R"', -OC(O)R', -C(O)R', -CO ₂ R', -CONR'R", -OC(O)NR'R", -NR"C(O)R', -NR'-C(O)NR"R"', -NR"C(O) ₂ R', -NH-C(NH ₂ )=NH, -NR'C(NH ₂ )=NH, -NH-C(NH ₂ )=NR', -S(O)R', -S(O) ₂ R', -S(O) ₂ NR'R", -NR'S(O) ₂ R", -CN, and -NO ₂ , in an amount from zero to (2m'+1), where m' is the total number of carbon atoms in such a group. R', R" and R"' each independently represent a hydrogen atom, unsubstituted _{C 1-8 alkyl} , unsubstituted heteroalkyl, unsubstituted aryl, aryl substituted with _{1-3 halogens, unsubstituted C 1-8 alkyl} , C _1-8 alkoxy or C _1-8 thioalkoxy groups, or _{unsubstituted aryl} -C _1-4 alkyl groups. When R' and R" are attached to the same nitrogen atom, they can combine with that nitrogen atom to form a 3-, 4-, 5-, 6-, or ₇ -membered ring. For example, -NR'R" includes 1-pyrrolidinyl and 4-morpholinyl. The term "acyl," when used alone or as part of another group, means an alkyl group in which two substituents on the carbon atom nearest the point of attachment of the group are replaced by an =O substituent (e.g., -C(O)CH ₃ , -C(O)CH ₂ CH ₂ OR', etc.).

Similarly, the substituents on the aryl and heteroaryl groups vary and are generally selected from the following: -halogen, -OR', -OC(O)R', -NR'R", -SR', -R', -CN, -NO ₂ , -CO ₂ R', -CONR'R", -C(O)R', -OC(O)NR'R", -NR"C(O)R', -NR"C(O) ₂ R', -NR'-C(O)NR"R"', -NH-C(NH ₂ )=NH, -NR'C(NH ₂ )=NH, -NH-C(NH ₂ )=NR', -S(O)R', -S(O) ₂ R', -S(O) ₂ NR'R", -NR'S(O) ₂ R", -N ₃ , perfluoro(C ₁ -C ₄ )alkoxy and perfluoro(C ₁ -C ₄ )alkyl, in an amount from zero to the total number of free valences in the aromatic system; and where R', R" and R"' are independently selected from a hydrogen atom, C _1-8 alkyl, C _3-6 cycloalkyl, C _2-8 alkenyl, C _2-8 alkynyl, unsubstituted aryl and heteroaryl, (unsubstituted aryl) _{-C 1-4 alkyl} and unsubstituted aryloxy- _{C 1-4 alkyl} . Other suitable substituents include all of the above-described aryl substituents attached to a ring atom through an alkylene bridge containing 1-4 carbon atoms.

Two substituents on adjacent atoms in the aryl or heteroaryl ring may be optionally replaced by a substituent of the formula -TC(O)-(CH ₂ ) _q -U-, where T and U independently represent -NH-, -O-, -CH ₂ -, or a single bond, and q is an integer from 0 to 2. Alternatively, two of the substituents on adjacent atoms in the aryl or heteroaryl ring may be optionally replaced by a substituent of the formula -A-(CH ₂ ) _r -B-, where A and B independently represent -CH ₂ -, -O-, -NH-, -S-, -S(O)-, -S(O) ₂ -, -S(O) ₂ NR'-, or a single bond, and r is an integer from 1 to 3. One of the single bonds in the new ring thus formed may optionally be replaced by a double bond. Alternatively, two of the substituents on adjacent atoms in the aryl or heteroaryl ring may be optionally replaced by a substituent of the formula -( _CH2 ) _s -X-( _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 selected from a hydrogen atom or _{unsubstituted C1-6} alkyl.

As used in this text, the term "heteroatom" includes oxygen (O), nitrogen (N), sulfur (S), and silicon (Si).

This description also concerns prodrugs and bioisosteres. Suitable bioisosteres, for example, include carboxylate substitutions (phosphonic acids, phosphinic acids, sulfonic acids, sulfinic acids, and acidic heterocyclic groups such as tetrazoles). Suitable prodrugs include common groups known to hydrolyze and/or oxidize under physiological conditions to yield a compound of Formula I.

The terms "patient" and "subject" include primates (especially humans), companion animals (such as dogs, cats, horses, etc.), and farm animals (such as cattle, pigs, sheep, etc.).

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

The term "pharmaceutically acceptable salts" includes salts of substances prepared with relatively non-toxic acids or bases, depending on the particular substituents on the compounds described herein. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be prepared by reacting the neutral form of such compounds with a sufficient amount of the desired base, even without a solvent or in a suitable inert solvent. Examples of salts derived from pharmaceutically acceptable inorganic bases include aluminum, ammonium, calcium, copper, iron(II), iron(III), lithium, magnesium, manganese, potassium, sodium, zinc, etc. Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary and tertiary amines, including substituted amines, cyclic amines, natural amines, etc., such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be prepared by reacting the neutral form of such compounds with a sufficient amount of the desired acid, without a solvent or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include salts with inorganic acids such as hydrochloric, hydrobromic, nitric, carbonic, monohydrocarbonic, phosphoric, monohydrophosphoric, dihydrophosphoric, sulfuric, monohydrosulfuric, hydroiodic or phosphorous acid, and the like, as well as salts with relatively non-toxic organic acids such as acetic, propionic, isobutyric, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p-toluenesulfonic, citric, tartaric, methanesulfonic, and the like. Also encompassed are salts with amino acids such as arginates and the like, and salts of organic acids such as glucuronic or galacturonic acid and the like (see, for example, Berge, S.M., et al, "Pharmaceutical Salts," Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain particular compounds of the present invention contain both basic and acidic functional groups, allowing such compounds to form both base addition and acid addition salts.

Neutral forms of the compounds can be regenerated by reacting the salt with a base or acid and isolating the parent compound in the usual manner. The parent form of the compound differs from the various salt forms in certain physical characteristics, such as solubility in polar solvents, but in all other respects, the salts are equivalent to the parent compounds for the purposes of the present invention.

Certain compounds of the present invention may exist in unsolvated forms, as well as solvated forms, including hydrated forms. In general, solvated forms are equivalent to unsolvated forms, and all are encompassed by the present invention. Certain compounds of the present invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the applications covered by the present invention and are within the scope of the present invention.

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

The compounds of the present invention may also have unnatural isotopic ratios at one or more of the atoms that make up the compounds. For example, the compounds may be radioactively labeled with radioactive isotopes such as, for example, tritium ( ^3H ), iodine-125 ( ^125I ), or carbon-14 ( ^14C ). All isotopic variations of the compounds of the present invention, radioactive and non-radioactive, are within the scope of the present invention. For example, the compounds may be prepared such that a number of carbon atoms are replaced by the isotope deuterium ( ^2H ). The compounds of the present invention may also have unnatural isotopic ratios at one or more of the atoms that make up the compounds. The unnatural isotope content may range from the natural content to 100%. For example, the compounds may contain radioactive isotopes such as, for example, tritium ( ^3H ), iodine-125 ( ^125I ) or carbon-14 ( ^14C ), or non-radioactive isotopes such as deuterium ( ^2H ) or carbon-13 ( ^13C ). Such isotopic variations may provide additional uses in addition to those already described herein. For example, isotopic variations of the compounds of the present invention may find additional uses, including (but not limited to) use as diagnostic and/or imaging reagents, or as cytostatic/radiotoxic therapeutic agents. In addition, isotopic variations of the compounds of the present invention may have altered pharmacokinetic and pharmacodynamic characteristics that may contribute to improved safety, tolerability, or efficacy in treatment with them. All isotopic variations of the compounds of the present invention, both radioactive and non-radioactive, are within the scope of the present invention.

Connections

In one aspect, the present invention provides compounds having formula (I):

or a pharmaceutically acceptable salt, prodrug, or bioisostere thereof, wherein:

A is a 5- to 10-membered heteroaryl group which is unsubstituted or has one to five substituents independently selected from the group consisting of a halogen atom, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy, C _1-3 haloalkoxy, OH and CN;

X ¹ is C _1-3 alkylene which is unsubstituted or has one to two substituents independently selected from the group consisting of C _1-2 alkyl and CO ₂ H;

R ^2a and R ^2b are each independently selected from the group consisting of 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 has one to two substituents 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 H, and each Y is selected from the group consisting of C _3-6 cycloalkyl, C _4-8 heterocyclyl and 5-6-membered heteroaryl, each of which is unsubstituted or has from one to four substituents independently selected from the group consisting of oxo group, OH, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 hydroxyalkyl, C _1-4 alkoxy group, C _1-4 haloalkoxy group, C _1-4 hydroxyalkoxy group, 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 H;

or R ^2a and R ^2b are combined to form a 4-9 membered ring or a spirocyclic ring containing in the ring from 0 to 2 additional heteroatoms selected from O, N or S;

wherein the ring formed by combining R ^2a and R ^2b is unsubstituted or has from 1 to 4 substituents independently selected from the group consisting of oxo, C _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 , -X ³ -N(R ^b )SO ₂ R ^a and -X ³ -SO ₃ R ^a ; wherein X ³ is a bond or C _1-6 alkylene;

R ³ and R ⁴ are each independently selected from the group consisting of H, F, Cl, CN, CH ₃ , OCH ₃ , CH ₂ CH ₃ and CF ₃ ;

subscript n is 0, 1, 2, or 3;

each R ^3a is independently selected from the group consisting of H, F, Cl, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl, C _1-3 haloalkoxy, C _2-3 alkenyl and CN;

R ⁶ , R ⁷ and R ⁸ are each independently selected from the group consisting of H, F, Cl, CN, CH ₃ , OCH ₃ , CH ₂ CH ₃ and CF ₃ ;

Z is selected from the group consisting of:

i) a monocyclic, bicyclic or spirocyclic non-aromatic heterocyclic ring optionally substituted with one or two oxo groups and optionally substituted with up to four R ^a and/or R ^b ; and

ii) a monocyclic 5- or 6-membered heteroaryl ring optionally substituted with up to three R ^c ;

each R ^a is independently selected from the group consisting of H, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkylene-CO ₂ H and C _1-6 alkylene-SO ₃ H;

each R ^b is independently selected from the group consisting of 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 has one to two substituents independently selected from 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 R ^a and R ^b , when attached to the same nitrogen atom, optionally combine to form a 4-8 membered ring or spirocyclic ring that is unsubstituted or substituted with 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;

each R ^c is independently selected from the group consisting of H, a halogen atom, CN, C _1-6 alkyl, C _1-6 haloalkyl, -Y ¹ , -X ⁴ -CO ₂ R ^a , -OX ⁴ -CO ₂ R ^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 -SO ₂ R ^a , -X ⁴ -SO ₂ NR ^a R ^b , -X ⁴ -SO ₃ R ^a and -N(R ^a )-X ⁴ -CO ₂ R ^a , where each X ⁴ is a bond or C _1-6 alkylene, and each Y ¹ is selected from the group consisting of C _3-6 cycloalkyl and C _4-8 heterocyclyl; and optionally two R ^c at adjacent ring vertices are combined to form a fused 5- or 6-membered heterocyclic ring.

In one group of embodiments, the compounds having formula (I) are those wherein A is a 5- or 6-membered heteroaryl group that is unsubstituted or has one to three substituents independently selected from the group consisting of a halogen atom, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy group, OH and CN. In one group of embodiments, the compounds having formula (I) are those wherein A is a 5- or 6-membered heteroaryl group that is unsubstituted or has one to three substituents independently selected from the group consisting of a halogen atom, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy group and CN.

In one group of embodiments, the compounds having formula (I) are those wherein A is a 6-membered heteroaryl group that is unsubstituted or has one to three substituents independently selected from the group consisting of a halogen atom, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy group, OH and CN. In one group of embodiments, the compounds having formula (I) are those wherein A is a 6-membered heteroaryl group that is unsubstituted or has one to three substituents independently selected from the group consisting of a halogen atom, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy group and CN.

In one group of embodiments, compounds having formula (I) are those wherein A is a 6-membered heteroaryl selected from the group consisting of pyridine, pyrimidine, pyrazine, and 1,2,4-triazine, each of which is unsubstituted or has one to two substituents independently selected from the group consisting of _CF3 , OH, Et, CN, _OCH3 , and F. In one group of embodiments, compounds having formula (I) are those wherein A is a 6-membered heteroaryl selected from the group consisting of pyridine, pyrimidine, pyrazine, and 1,2,4-triazine, each of which is unsubstituted or has one to two substituents independently selected from the group consisting of _OCH3 and F.

In one group of embodiments, compounds having formula (I) are those wherein A is unsubstituted or has one to two substituents independently selected from the group consisting of _CF3 , OH, Et, CN, _OCH3 , and F. In one group of embodiments, compounds having formula (I) are those wherein A is unsubstituted or has one to two substituents independently selected from the group consisting of _OCH3 and F.

In some embodiments, the present invention provides compounds having formula (I), represented by formula (Ia):

where the groups R ^2a , R ^2b , R ³ , R ⁴ , A, X ¹ and Z have the meanings specified for formula (I).

In some embodiments, the present invention provides compounds having formula (I), represented by formula (Ib):

where the groups R ^2a , R ^2b , R ³ , R ⁴ , A and Z have the meanings specified for formula (I).

In particular embodiments, including any of those described above for compounds having formula (I), (Ia) or (Ib), further embodiments are those wherein Z is a 5- or 6-membered non-aromatic heterocyclic ring optionally substituted with one or two oxo groups and optionally containing a R ^a and/or R ^b substituent.

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

.

In some particular embodiments, compounds having formula (I), (Ia), or (Ib) are compounds wherein Z is a non-aromatic heterocyclic ring selected from the group consisting of piperidinyl, morpholinyl, tetrahydropyranyl, and tetrahydrofuranyl, each having up to four R ^a and/or R ^b substituents.

In some particular embodiments, compounds having formula (I), (Ia), or (Ib) are compounds wherein Z is a 5- or 6-membered heteroaryl ring optionally having one to three R ^c substituents; and said heteroaryl ring is selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, oxazolyl, thiazolyl, and pyrazolyl.

In some particular embodiments, compounds having formula (I), (Ia), or (Ib) are compounds wherein Z is a monocyclic 5- or 6-membered heteroaryl ring optionally having from one to three R ^c substituents; and said heterocyclic ring is selected from the group consisting of pyridinyl, pyrimidinyl, and pyrazinyl.

In particular embodiments, including any of those described above for compounds having formula (I), (Ia), or (Ib), further embodiments are those wherein the group A is a 5- or 6-membered heteroaryl group and is unsubstituted or has one or two substituents independently selected from OCH ₃ and F.

In particular embodiments, including any of those described above for compounds having formula (I), (Ia), or (Ib), further embodiments are those wherein R ^2a and R ^2b are each H.

In particular embodiments, including any of those described above for compounds having formula (I), (Ia), or (Ib), further embodiments are those wherein R ^2a and R ^2b are combined to form a 4-9 membered ring or spirocyclic ring optionally having one or two ring members selected from O, N, or S; wherein said ring or spirocyclic ring has 0-4 substituents independently selected from the group consisting of oxo, C _1-8 alkyl, C _1-8 haloalkyl, C _1-8 hydroxyalkyl, -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 , and -X ² -SO ₃ R ^a ; where X ² is a bond or C _1-6 alkylene.

In particular embodiments, including any of those described above for compounds having formula (I), (Ia), or (Ib), further embodiments are those wherein -N(R ^2a )(R ^2b ) is selected from the group consisting of:

.

In particular embodiments, including any of those described above for compounds having formula (I), (Ia), or (Ib), further embodiments are those wherein -N(R ^2a )(R ^2b ) is selected from the group consisting of:

.

In particular embodiments, including any of those described above for compounds having formula (I), (Ia), or (Ib), further embodiments are those wherein -N(R ^2a )(R ^2b ) is selected from the group consisting of:

.

In particular embodiments, including any of those described above for compounds having formula (I), (Ia), or (Ib), further embodiments are those wherein R ^2a is H or C _1-8 alkyl; and R ^2b is -Y or -X ² -Y.

In particular embodiments, including any of those described above for compounds having formula (I), (Ia), or (Ib), further embodiments are those wherein R ^2a is H or C _1-8 alkyl; R ^2b is -Y or -X ² -Y; and Y is selected from the group consisting of _C3-6 cycloalkyl and _C4-8 heterocyclyl, each of which optionally further has from 1 to 4 substituents independently selected from the group consisting of oxo group, OH, _C1-4 alkyl, _C1-4 haloalkyl, _C1-4 hydroxyalkyl, _C1-4 alkoxy group, _C1-4 haloalkoxy group, _C1-4 hydroxyalkoxy group, _SO2NH2 , C ₍ O) _NH2 , C(O ₎ NHOH, _PO3H2 , _{CO2C1-8 alkyl} and _CO2H .

In particular embodiments, including any of those described above for compounds having formula (I), (Ia) or (Ib), further embodiments are those wherein R ³ and R ⁴ are each independently selected from the group consisting of F, Cl, CN, CH ₃ , OCH ₃ , CH ₂ CH ₃ and CF ₃ . In particular embodiments, including any of those described above for compounds having formula (I), (Ia) or (Ib), further embodiments are those wherein R ³ and R ⁴ are each independently selected from the group consisting of H, F, Cl, CN, CH ₃ and CF ₃ .

In particular embodiments, including any of those described above for compounds having formula (I), (Ia), or (Ib), further embodiments are those wherein the compound is selected from the compounds presented in Table 1.

In particular embodiments, including any of those described above for compounds having formula (I), (Ia) or (Ib), further embodiments are those wherein the compound is selected from the compounds presented in Table 1 having an activity of ++ or +++.

In particular embodiments, including any of those described above for compounds having formula (I), (Ia) or (Ib), further embodiments are those wherein the compound is selected from the compounds presented in Table 1 having an activity of +++.

In addition to the compounds described above, the present invention also encompasses pharmaceutically acceptable salts of these compounds. In some embodiments, the pharmaceutically acceptable salts are selected from ammonium, calcium, magnesium, potassium, sodium, zinc, arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, salts with hydrochloric acid, carbonic acid, from monohydrogen carbonates, salts with phosphoric acid, monohydrogen phosphates, dihydrogen phosphates, salts with acetic acid, propionic, isobutyric, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, arginates, salts with glucuronic acid and galacturonic acid. In some embodiments, pharmaceutically acceptable salts are selected from ammonium, calcium, magnesium, potassium, sodium salts, salts with hydrochloric acid, carbonic acid, monohydrogen carbonates, salts with phosphoric acid, monohydrogen phosphates, dihydrogen phosphates, salts with acetic, propionic, isobutyric, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, arginates, salts with glucuronic acid and galacturonic acid. In some embodiments, pharmaceutically acceptable salts are sodium salts or hydrochlorides.

In addition to salt forms, the present invention also describes compounds in prodrug form. Prodrugs of the compounds described herein are compounds that readily undergo chemical changes under physiological conditions to yield the compounds of the present invention. Furthermore, prodrugs can be converted into the compounds of the present invention by chemical or biological methods ex vivo. For example, prodrugs can be slowly converted into the compounds of the present invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.

An ester can be used as a prodrug for the corresponding carboxylic acid. A C _1-10 alkyl ester or a C _1-10 haloalkyl ester can be used as a prodrug for the corresponding carboxylic acid. The following esters can be used: tert-butyl ester, methyl ester, ethyl ester, and isopropyl ester.

Methods of obtaining

In addition to the methods described below in the examples, general methods for preparing compounds having formula (I) are shown in Schemes 1 and 2.

Scheme 1

Scheme 1 illustrates a general method for preparing compounds of formula (I), where A is a 6-membered nitrogen-containing heteroaryl ring (e.g., pyridyl, pyrimidinyl), and X ¹ is CH ₂ . In the above scheme, R ^s represents one or more substituents on the heteroaryl ring.

The formation of an amide between a carboxylic acid (a) and a boronate compound (b) proceeds readily in the presence of a coupling reagent, yielding (c) Suzuki coupling of (c) with (d) in the presence of a catalyst then yields the biphenyl compound (e). Compound (e) is converted to the boronate (f), followed by a second Suzuki coupling (with the halogenated heteroaryl compound (g)) to yield the triaryl aldehyde (h). Reductive amination of the aldehyde with HNR ^2a R ^2b then yields compounds of formula (Ia).

Scheme 2

In another approach using Suzuki coupling, the boronate compound (a1) is combined with the aldehyde (b1) to form an arylheteroaryl adduct (c1), which after a second Suzuki coupling with (d1) yields a triaryl aldehyde (e1). As in Scheme 1, reductive amination of the aldehyde with HNR ^2a R ^2b then yields compounds of formula (Ia).

Pharmaceutical compositions

In addition to the compounds of the present invention, compositions of these compounds typically contain a pharmaceutically acceptable carrier or diluent.

The term "composition," as used herein, encompasses a product containing the stated ingredients in the stated amounts, as well as any product formed, directly or indirectly, from the combination of the stated ingredients in the stated amounts. The term "pharmaceutically acceptable" means that the carrier, diluent, or excipient must be compatible with the other ingredients of the preparation and not harmful to the patient.

In another embodiment, a pharmaceutical composition is described comprising a compound of the present invention, including a compound of formula (I), (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

In some embodiments, the pharmaceutical composition further comprises one or more additional therapeutic agents. In some embodiments, said one or more additional therapeutic agents are selected from the group consisting of an antimicrobial agent, an antiviral agent, a cytotoxic agent, a gene expression modulating agent, a chemotherapeutic agent, an anticancer agent, an antiangiogenic agent, an immunotherapeutic agent, an antihormonal agent, an antifibrotic agent, a radiation therapy agent, a radiation therapy agent, an antitumor agent, and an antiproliferative agent. In some embodiments, one or more additional therapeutic agents is a chemokine and/or chemotactic receptor antagonist, which includes, but is not limited to, CCR1, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10, CCR11, CCR12, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, CXCR6, CXCR7, C3aR and/or C5aR. Chemokine and/or chemotactic receptor antagonists are known in the art and are described, for example, in WO 2007/002667, WO 2007/002293, WO 2003/105853, WO 2007/022257, WO 2007/059108, WO 2007/044804, WO 2007/115232, WO 2007/115231, WO 2008/147815, WO 2010/030815, WO 2010/075257, WO 2011/163640, WO 2010/054006, WO 2010/051561, WO 2011/035332, WO 2013/082490, WO 2013/082429, WO 2014/085490, WO 2014/100735, WO 2014/089495, WO 2015/084842, WO 2016/187393, WO 2017/127409, WO 2017/087607, WO 2017/087610, WO 2017/176620, WO 2018/222598, WO 2018/222601, WO 2013/130811, WO 2006/076644, WO 2008/008431, WO 2009/038847, WO 2008/008375, WO 2008/008374, WO 2008/010934, WO 2009/009740, WO 2005/112925, WO 2005/112916, WO 2005/113513, WO 2004/085384, WO 2004/046092. Chemokine and/or chemotactic receptor antagonists also include CCX354, CCX9588, CCX140, CCX872, CCX598, CCX6239, CCX9664, CCX2553, CCX3587, CCX3624, CCX 2991, CCX282, CCX025, CCX507, CCX430, CCX765, CCX224, CCX662, CCX650, CCX832, CCX168, CCX168-M1, CCX3022 and/or CCX3384.

Pharmaceutical compositions for administering the compounds of the present invention can be formulated as unit dosage forms and can be prepared by any of the methods known in pharmacology and drug administration. All methods include the step of combining the active ingredient with a carrier containing one or more auxiliary ingredients. In general, pharmaceutical compositions are prepared by uniformly and intimately mixing the active ingredient with a liquid carrier or a finely divided solid carrier, or both, and then, if necessary, shaping the product into the desired formulation. In a pharmaceutical composition, the active ingredient is present in an amount sufficient to exert the desired effect on the disease or pathological condition.

Pharmaceutical compositions containing the active substance may be in a form suitable for oral administration, such as tablets, sachets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions and self-emulsifying preparations as described in U.S. Patent Application 2002-0012680, hard or soft capsules, syrups, elixirs, solutions, buccal patches, oral gels, chewing gum, chewable tablets, effervescent powders, and effervescent tablets. Compositions intended for oral administration may be prepared by any methods known in the art of pharmaceutical composition manufacturing. Such compositions may contain one or more agents selected from the group consisting of sweeteners, flavoring agents, coloring agents, antioxidants, and preservatives to create pharmaceutically attractive and palatable preparations. The tablets contain the active substance mixed with non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets. Such excipients may include, for example, inert diluents such as cellulose, carbon dioxide, aluminum oxide, calcium carbonate, sodium carbonate, glucose, mannitol, sorbitol, lactose, calcium phosphate, or sodium phosphate; granulating agents and agents that accelerate tablet disintegration, such as corn starch or alginic acid; binding agents such as polyvinylpyrrolidone, cellulose, starch, gelatin, or acacia gum; and lubricants such as magnesium stearate, stearic acid, or talc. Tablets may be uncoated, enteric-coated, or coated by some other known method to delay disintegration and absorption in the gastrointestinal tract, thereby providing prolonged action over a longer period of time. For example, disintegration-delaying materials such as glyceryl monostearate or glyceryl distearate can be used. Tablets can also be coated by the methods described in U.S. Patents 4,256,108; 4,166,452; and 4,265,874 to form osmotic, sustained-release tablets.

Oral formulations may also be presented as hard gelatin capsules, where the active substance is mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate, or kaolin, or polyethyleneglycol (PEG) of varying average molecular sizes (e.g., PEG400, PEG4000), or as soft gelatin capsules, where the active substance is mixed with an aqueous or oily medium, such as peanut oil, liquid paraffin, or olive oil. Emulsions may also be prepared with water-insoluble ingredients, such as oils, and stabilized with surfactants, such as mono- or diglycerides, PEG esters, etc.

Aqueous suspensions contain the active ingredients in a mixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, and acacia gum; Dispersing or wetting agents may be natural phosphatides, such as lecithin, or condensation products of alkylene oxide with fatty acids, such as polyoxyethylene stearate, or condensation products of ethylene oxide with long-chain aliphatic alcohols, such as heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol, such as polyoxyethylene sorbitan monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, such as polyethylene sorbitan monooleate. Aqueous suspensions may also contain one or more preservatives, such as ethyl or n-propyl parahydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.

Oily suspensions can be prepared by suspending the active ingredient in a vegetable oil, such as peanut oil, olive oil, sesame oil, or coconut oil, or in a mineral oil such as liquid paraffin. Oily suspensions may contain thickening agents, such as beeswax, solid paraffin, or cetyl alcohols. Sweeteners, such as those listed above, and coloring agents may be added to produce a palatable oral composition. Such compositions can be stabilized by the addition of an antioxidant, such as ascorbic acid.

Dispersible powders and granules suitable for the preparation of an aqueous suspension by adding water contain the active substance mixed with a dispersing or wetting agent, a suspending agent, and one or more preservatives. Examples of dispersing, wetting agents, and suspending agents are listed above. Additional excipients, such as sweeteners, flavorings, and colorings, may also be present.

The pharmaceutical compositions of the present invention may also take the form of oil-in-water emulsions. The oil phase may be a vegetable oil, such as olive oil or peanut oil, or a mineral oil, such as liquid paraffin, or a mixture thereof. Suitable emulsifiers may include natural gums, such as acacia or tragacanth, natural phosphatides, such as soybean oil, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweeteners and flavoring agents.

Syrups and elixirs may contain sweeteners such as glycerin, propylene glycol, sorbitol, or sucrose. These preparations may also contain demulcents, preservatives, flavorings, and colorings. Oral solutions can be prepared in combination with, for example, cyclodextrin, PEG, and surfactants.

Pharmaceutical compositions may take the form of sterile injectable aqueous or oleaginous suspensions. Such suspensions can be prepared according to art-known techniques using suitable dispersing or wetting agents and suspending agents, as previously mentioned. Sterile injectable preparations may also be sterile injectable solutions or suspensions in a nontoxic parenterally acceptable diluent or solvent, for example, a solution in 1,3-butanediol. Suitable carriers and solvents that can be employed include water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile oils are often employed as a solvent or suspending medium. Any flavorless, fixed oil, including synthetic mono- and diglycerides, can be used for this purpose. In addition, fatty acids, such as oleic acid, are used in the preparation of injectable preparations.

The compounds described herein can also be administered in the form of suppositories for rectal administration of the drug. Such compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at room temperature but liquefies at body temperature and therefore melts in the rectum to release the drug. Such materials include cocoa butter and polyethylene glycols. In addition, the compounds can be administered as ophthalmic drops or ointments. Furthermore, transdermal administration of the compounds in question can be accomplished via iontophoretic patches and the like. For topical application, creams, ointments, gels, solutions, or suspensions containing the compounds of the present invention are used. In the context of the present invention, topical application also includes the use of mouth rinses and solutions.

The compounds of the present invention can also be combined with a carrier comprising suitable polymers as targeted drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidephenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues. In addition, the compounds of the present invention can be combined with a carrier belonging to the class of biodegradable polymers that can be used to achieve controlled drug release, such as: polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and cross-linked or amphipathic hydrogel block copolymers. Polymers and semipermeable polymer matrices can be formed into articles such as valves, stents, tubes, prostheses, etc. In one embodiment of the present invention, the compound of the present invention is combined with a polymer or semipermeable polymer matrix formed into a stent or stent graft.

Treatment methods for diseases and disorders

The compounds of the present invention can be used as immunomodulators. The compounds of the present invention can be used as agonists, antagonists, partial agonists, inverse agonists, and inhibitors of PD-1 and/or PD-L1 in a variety of contexts, both in vitro and in vivo. In some embodiments, the compounds of the present invention can be used as inhibitors of PD-1/PD-L1 protein-protein interaction. In some embodiments, the compounds of the present invention can be used as inhibitors of PD-L1. In some embodiments, the compounds of the present invention can be used as inhibitors of CD80/PD-L1 protein-protein interaction. In some embodiments, the compounds of the present invention can be used to inhibit the interaction between PD-1 and PD-L1 and/or PD-1 and CD80 and/or PD-L1 and PD-L2 in vitro or in vivo. In some embodiments, the compounds of the present invention can be used to inhibit VISTA and/or TIM-3. In some embodiments, the compounds of the present invention can be inhibitors of PD-1/PD-L1 protein-protein interaction and inhibitors of VISTA and/or TIM-3. In some embodiments, in addition to functioning as inhibitors of PD-1/PD-L1 protein-protein interaction, the compounds of the present invention 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.

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

Preferably, the amount of compounds of the present invention that contact the receptor should be sufficient to inhibit PD-1/PD-L1 binding in vitro, as measured, for example, by ELISA. The receptor may be in solution or suspension, in a preparation of cultured or isolated cells, or in the patient's body.

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

In some embodiments, the compounds of the present invention can be used to treat patients suffering from pathological conditions responsive to modulation of PD-1/PD-L1 protein-protein interaction.

In some embodiments, a method for modulating an immune response in a subject mediated through the PD-1 signaling pathway is described, comprising administering to the subject a therapeutically effective amount of a compound of the present invention, 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.

In some embodiments, a method is described for enhancing, stimulating, modulating and/or increasing an immune response in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present invention, 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.

In some embodiments, a method for suppressing the growth, proliferation, or metastasis of cancer cells in a subject in need thereof is described, comprising administering to the subject a therapeutically effective amount of a compound of the present invention, including a compound of formula (I), (Ia), or (Ib), or a pharmaceutically acceptable salt thereof, or a composition of a compound of the present invention, including a compound of formula (I), (Ia), or (Ib), or a pharmaceutically acceptable salt thereof.

In some embodiments, a method of treating a subject in need thereof is described, comprising administering to the subject a therapeutically effective amount of a compound of the present invention, including a compound of Formula (I), (Ia) or (Ib) or a pharmaceutically acceptable salt thereof, or a composition of a compound of the present invention, including a compound of Formula (I), (Ia) or (Ib) or a pharmaceutically acceptable salt thereof.

In some embodiments, the subject suffers from a disease or disorder selected from the group consisting of an infectious disease, a bacterial infectious disease, a viral infectious disease, a fungal infectious disease, a solid tumor, a hematological malignancy, an immune disorder, an inflammatory disease, and cancer. In some embodiments, the disease or disorder is selected from the group consisting of: melanoma, glioblastoma, esophageal cancer, nasopharyngeal cancer, 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 myelocytic leukemia, Kaposi's sarcoma, fibrosarcoma, liposarcoma, chondrosarcoma, osteosarcoma, angiosarcoma, lymphangiosarcoma, synovioma, meningioma, leiomyosarcoma, rhabdomyosarcoma, soft tissue sarcoma, sarcoma, sepsis, gallbladder cancer, basal cell carcinoma, thymus cancer, thyroid cancer, parathyroid cancer, uterine cancer, adrenal cancer, liver infection, Merkel cell carcinoma, nervous system cancer, follicular center cell lymphoma, colon cancer, Hodgkin's lymphoma, non-Hodgkin's lymphoma, leukemia, chronic or acute leukemia including acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphoblastic leukemia, multiple myeloma, ovarian cancer, myelodysplastic syndrome, cutaneous or intraocular malignant melanoma, renal cell carcinoma, small cell lung cancer, lung cancer, mesothelioma, breast cancer, squamous cell non-small cell lung cancer, non-squamous cell non-small cell lung cancer, colorectal cancer, ovarian cancer, gastric cancer, hepatocellular cancer, pancreatic carcinoma, pancreatic cancer, pancreatic ductal adenocarcinoma, squamous cell carcinoma of the head and neck, head and neck cancer, gastrointestinal cancer, stomach cancer, HIV, hepatitis A, hepatitis B, hepatitis C, hepatitis D, herpes virus, human papillomavirus, influenza, bone cancer, skin cancer, rectal cancer, anal cancer, testicular cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, esophageal cancer, small bowel cancer, endocrine cancer, urethral cancer, penile cancer, bladder cancer, kidney cancer, urethral cancer, renal pelvis cancer, central nervous system (CNS) neoplasms, tumor angiogenesis, spinal axis cancer, brainstem glioma, pituitary adenoma, epidermoid carcinoma, asbestosis, carcinoma, Adenocarcinoma, papillary carcinoma, cystadenocarcinoma, bronchogenic carcinoma, renal cell carcinoma, transitional cell carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, pleomorphic adenoma, liver cell papilloma, renal tubular adenoma, cystadenoma, papilloma, adenoma, leiomyoma, rhabdomyoma, hemangioma, lymphangioma, osteoma, chondroma, lipoma, and fibroma.

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 an antimicrobial agent, an antiviral agent, a cytotoxic agent, a gene expression modulating agent, a chemotherapeutic agent, an anticancer agent, an antiangiogenic agent, an immunotherapeutic agent, an antihormonal agent, an antifibrotic agent, a radiation therapy agent, a radiation therapy agent, an antitumor agent, and an antiproliferative agent. In some embodiments, one or more additional therapeutic agents is a chemokine and/or chemotactic receptor antagonist, which includes, but is not limited to, CCR1, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10, CCR11, CCR12, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, CXCR6, CXCR7, C3aR and/or C5aR. Chemokine and/or chemotactic receptor antagonists are known in the art and are described, for example, in WO 2007/002667, WO 2007/002293, WO 2003/105853, WO 2007/022257, WO 2007/059108, WO 2007/044804, WO 2007/115232, WO 2007/115231, WO 2008/147815, WO 2010/030815, WO 2010/075257, WO 2011/163640, WO 2010/054006, WO 2010/051561, WO 2011/035332, WO 2013/082490, WO 2013/082429, WO 2014/085490, WO 2014/100735, WO 2014/089495, WO 2015/084842, WO 2016/187393, WO 2017/127409, WO 2017/087607, WO 2017/087610, WO 2017/176620, WO 2018/222598, WO 2018/222601, WO 2013/130811, WO 2006/076644, WO 2008/008431, WO 2009/038847, WO 2008/008375, WO 2008/008374, WO 2008/010934, WO 2009/009740, WO 2005/112925, WO 2005/112916, WO 2005/113513, WO 2004/085384, WO 2004/046092. Chemokine and/or chemotactic receptor antagonists also include CCX354, CCX9588, CCX140, CCX872, CCX598, CCX6239, CCX9664, CCX2553, CCX3587, CCX3624, CCX 2991, CCX282, CCX025, CCX507, CCX430, CCX765, CCX224, CCX662, CCX650, CCX832, CCX168, CCX168-M1, CCX3022 and/or CCX3384.

In some embodiments, the compounds of the present invention may be used to suppress an infectious disease. Infectious disease includes, but is not limited to, HIV, influenza, giardiasis, malaria, leishmaniasis, pathogenic infections caused by hepatitis virus (A, B, and C), herpes virus (e.g., VZV, HSV-I, HAV-6, HSV-II, and CMV, Epstein-Barr virus), adenovirus, influenza virus, flaviviruses, echovirus, rhinovirus, coxsackievirus, coronavirus, respiratory syncytial virus, mumps virus, rotavirus, measles virus, rubella virus, carvovirus, vaccinia virus, human T-lymphotropic virus, dengue virus, papillomavirus, molluscum virus, polio virus, rabies virus, John Cunningham virus, and arbovirus encephalitis virus, pathogenic Bacterial infections caused by chlamydia, rickettsial bacteria, mycobacteria, staphylococci, streptococci, pneumococci, meningococci and gonococci, Klebsiella, Proteus, Serratia, Pseudomonas aeruginosa, Escherichia coli, Legionella, diphtheria bacteria, salmonella, rod-shaped bacteria (bacilli), bacteria that cause cholera, tetanus, botulism, anthrax, plague, leptospirosis and Lyme disease, pathogenic infections caused by fungi of the genus Candida (albicans, krusei, glabrata, tropicalis, etc.), yeast fungi, fungi of the genus Aspergillus (fumigatus, niger, etc.), mold fungi (mucor, absidia, rhizophus), Sporothrix schenkii, Blastomyces dermatitidis, Paracoccidioides brasiliensis, Coccidioides immitis and Histoplasma capsulatum, and pathogenic infections caused by the parasites Entamoeba histolytica, Balantidium coli, Naegleriafowleri, Acanthamoeba sp., Giardia lambia, Cryptosporidium sp., Pneumocystis carinii, Plasmodium vivax, Babesia microti, Trypanosoma brucei, Trypanosoma cruzi, Leishmania donovani, Toxoplasma gondi, Nippostrongylus brasiliensis.

In some embodiments, the compounds of the present invention may be used to suppress HIV infection, slow the progression of AIDS, eradicate the HIV viral reservoir, or reduce the severity of symptoms of either HIV infection or AIDS.

The compounds of the present invention can be used to treat cancerous and precancerous conditions in a subject.

The treatment methods described in the present invention comprise administering to a patient an effective amount of one or more compounds described herein. Suitable patients include those suffering from, or susceptible to (i.e., prophylactic treatment of), a disease or disorder described herein. Typical patients for the treatment described in the present invention include mammals, particularly primates, and especially humans. Other suitable patients include companion animals such as dogs, cats, horses, and the like, or farm animals such as cattle, pigs, sheep, and the like.

In general, the methods of treatment described herein comprise administering to a patient an effective amount of one or more compounds described herein. In a preferred embodiment, the compound(s) of the present invention are preferably administered to a patient (e.g., a human) intravenously, orally, or topically. An effective amount can be an amount sufficient to modulate PD-1/PD-L1 interaction and/or an amount sufficient to reduce or alleviate symptoms in the patient. Preferably, the amount administered is sufficient to create a plasma concentration of the compound (or its active metabolite, if the compound is a prodrug) high enough to significantly modulate PD-1/PD-L1 interaction. Treatment regimens can vary depending on the compound used and the particular condition being treated; for the treatment of most disorders, the preferred frequency of administration is 4 times daily or less. In general, twice daily administration is more preferred, and once daily administration is particularly preferred. It should be understood, however, that the specific dosage level and administration regimen for each individual patient depends on a number of factors, including the potency of the specific compound, age, body weight, general health, gender, diet, time of administration, route of administration, rate of elimination, drug combinations (e.g., other medications administered to the patient), and the severity of the specific condition being treated, as well as the judgment of the treating physician. In general, the lowest dosage sufficient to ensure effective therapy is preferred. Therapeutic efficacy in patients can be monitored using medical or veterinary criteria appropriate to the specific condition being treated.

Combinations

A combination preparation containing the compounds of the present invention and another medicinal agent can be administered as a combination preparation in which both components are contained in a single formulation, or as separate preparations. Administration of separate preparations includes simultaneous administration and administration at intervals. In the case of administration at intervals, the compound of the present invention can be administered first, followed by the other medicinal agent, or the other medicinal agent can be administered first, followed by the compound of the present invention. The route of administration of the respective medicinal agents may be the same or different.

The dosage of the other drug can be appropriately selected based on clinically applicable dosages. The ratio of the amount of the compound of the present invention to the other drug can be appropriately selected based on the age and body weight of the subject to be administered, the route of administration, the time of administration, the disease being treated, its symptoms, and their combination. For example, the other drug can be administered in an amount of 0.01 to 100 parts by weight relative to 1 part by weight of the compound of the present invention. The other drug may be a combination of two or more types of independent drugs in the desired ratio.

The compounds of the present invention can be used or combined with one or more therapeutic agents, such as an antimicrobial agent, an antiviral agent, a cytotoxic agent, a gene expression modulating agent, a chemotherapeutic agent, an anticancer agent, an antiangiogenic agent, an immunotherapeutic agent, an antihormonal agent, an antifibrotic agent, a radiation therapy agent, an antitumor agent, and an antiproliferative agent. These therapeutic agents can be in the form of compounds, antibodies, polypeptides, or polynucleotides.

The compounds of the present invention can be used or combined with one or more of the following: therapeutic antibodies, bispecific antibodies and “antibody-like” therapeutic proteins (such as DARTs®, Duobodies®, Bites®, XmAbs®, TandAbs®, Fab derivatives), antibody-drug conjugates, a virus, an oncolytic virus, gene modifiers or editors such as CRISPR (including CRISPR Cas9), zinc finger nucleases or synthetic nucleases (TALENs), immunotherapy agents using chimeric antigen receptor T cells, or any combination thereof.

Examples of chemotherapeutic agents include alkylating agent, nitrosourea agent, antimetabolite, anticancer antibiotics, plant alkaloid, topoisomerase inhibitor, hormonal drug, hormone antagonist, aromatase inhibitor, P-glycoprotein inhibitor, platinum complex derivatives, other immunotherapeutic agents, and other anticancer drugs.

The compounds of the present invention can be used or combined with an adjuvant anticancer therapy agent such as a drug for treating leukopenia (neutropenia), a drug for treating thrombocytopenia, an antiemetic drug, and a drug for treating cancer pain, in the form of concomitant or combination therapy.

The compounds of the present invention may be used or combined with a kinase inhibitor.

In one embodiment, the compounds of the present invention can be used with another immunomodulator and/or stimulant in the form of concomitant or combination therapy. Examples of an immunomodulator include various cytokines, vaccines, and adjuvants. Examples of such cytokines, vaccines, and adjuvants that stimulate an immune response include, but are not limited to, GM-CSF, M-CSF, G-CSF, interferon-alpha, beta, or gamma, IL-1, IL-2, IL-3, IL-12, Poly (I:C), and CPG. Stimulating agents include cyclophosphamide and cyclophosphamide analogs, anti-TGF and imatinib (Gleevac), a mitotic inhibitor such as paclitaxel, sunitinib (Sutent) or other antiangiogenic agents, an aromatase inhibitor such as letrozole, an A2a adenosine receptor (A2AR) antagonist, an angiogenesis inhibitor, anthracyclines, oxaliplatin, doxorubicin, TLR4 antagonists, and IL-18 antagonists.

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

In some embodiments, the compounds of the present invention may be used or combined with one or more chemokine and/or chemotactic receptor antagonists described, for example, in WO 2007/002667, WO 2007/002293, WO 2003/105853, WO 2007/022257, WO 2007/059108, WO 2007/044804, WO 2007/115232, WO 2007/115231, WO 2008/147815, WO 2010/030815, WO 2010/075257, WO 2011/163640, WO 2010/054006, WO 2010/051561, WO 2011/035332, WO 2013/082490, WO 2013/082429, WO 2014/085490, WO 2014/100735, WO 2014/089495, WO 2015/084842, WO 2016/187393, WO 2017/127409, WO 2017/087607, WO 2017/087610, WO 2017/176620, WO 2018/222598, WO 2018/222601, WO 2013/130811, WO 2006/076644, WO 2008/008431, WO 2009/038847, WO 2008/008375, WO 2008/008374, WO 2008/010934, WO 2009/009740, WO 2005/112925, WO 2005/112916, WO 2005/113513, WO 2004/085384, WO 2004/046092. Chemokine and/or chemotactic receptor antagonists that can be used according to the present invention also include CCX354, CCX9588, CCX140, CCX872, CCX598, CCX6239, CCX9664, CCX2553, CCX3587, CCX3624, CCX 2991, CCX282, CCX025, CCX507, CCX430, CCX765, CCX224, CCX662, CCX650, CCX832, CCX168, CCX168-M1, CCX3022 and/or CCX3384.

Dosage

Dosages ranging from approximately 0.1 mg to approximately 140 mg per kilogram of body weight per day can be used to treat or prevent conditions involving the PD-1/PD-L1 interaction (from approximately 0.5 mg to approximately 7 g per person per day). The amount of active ingredient that can be combined with carriers to produce a single dosage form varies depending on the specific patient being treated and the route of administration used. Dosage formulations typically contain from approximately 1 mg to approximately 500 mg of active ingredient. For compounds administered orally, transdermally, intravenously, or subcutaneously, it is preferred that a sufficient amount of the compound be administered to achieve a plasma concentration of 5 ng (nanogram)/mL to 10 μg (microgram)/mL of blood plasma, more preferably a sufficient amount of the compound to achieve a plasma concentration of 20 ng/mL to 1 μg/mL of blood plasma, and most preferably a sufficient amount of the compound to achieve a plasma concentration of 50 ng/mL to 200 ng/mL of blood plasma. For direct administration into the synovial membrane (for the treatment of arthritis), a sufficient amount of the compound should be administered to locally achieve a concentration of approximately 1 micromolar.

The frequency of administration may also vary depending on the compound being used and the specific condition being treated. However, for the treatment of most conditions, a regimen of four times daily, three times daily, or less is preferred, with once-daily or twice-daily administration being particularly preferred. It should be understood, however, that the specific dosage level for each individual patient depends on a number of factors, including the potency of the specific compound, age, body weight, general health, gender, diet, time of administration, route of administration, rate of elimination, drug combinations (e.g., other drugs being administered to the patient), the severity of the specific condition being treated, and other factors, including the judgment of the treating physician.

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

Also included within the scope of the present invention are kits containing a compound of the present invention or a pharmaceutically acceptable salt thereof and instructions for use. The kit may also contain at least one additional reagent. Kits typically include a label indicating the intended use of the kit's contents. The term "label" includes any written or recorded materials located on or within the kit's packaging or otherwise accompanying the kit.

Examples

The following examples illustrate various methods for preparing compounds of the present invention, including compounds of formula (I), (Ia), or (Ib). The following examples are provided for illustration and not to limit the scope of the present invention.

The reagents and solvents described below can be obtained from commercial sources such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA). ¹ H NMR spectra were recorded on a Varian Mercury 400 MHz NMR spectrometer. Chemical shifts are reported relative to tetramethylsilane (TMS) and are described in the order of multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet) and proton number. Mass spectrometry results are reported as mass per charge. In the examples, one m/e value is given for each M+H (or MH, when indicated) ion containing the most abundant isotopes of the atoms. In all cases, the isotopic distribution corresponds to the expected formula. Electrospray ionization (ESI) mass spectrometry was performed on a Hewlett-Packard MSD electrospray ionization mass spectrometer equipped with an HP1100 HPLC for sample injection. Typically, the analyte was dissolved in methanol or _CH3CN at a concentration of 0.1 mg/mL, and 1 microliter of the resulting solution was injected into the mass spectrometer, scanning ions in the 100 to 1000 Dalton range. All compounds were analyzed in ESI mode with positive or negative ion detection, using an acetonitrile/water mixture with 1% formic acid as the solvent.

The following abbreviations are used in the examples and throughout the rest of the application: TLC means Thin Layer Chromatography.

The compounds of the present invention 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 appreciate that alternative methods for synthesizing the target compounds can be used, and that the approaches used herein are not exhaustive but provide workable and practical methods for preparing the compounds of the present invention.

Certain molecules claimed in this patent may exist in different enantiomeric and diastereomeric forms, and all such variants of the compounds are within the scope of the present invention unless a specific enantiomer is indicated.

The detailed descriptions of the experimental procedures used to synthesize the key compounds in this text lead to molecules that are described by identifying physical data and by depicting their chemical structures.

Those skilled in the art will also appreciate that acids and bases are frequently used during standard organic chemistry workup procedures. Salts of the parent compounds are sometimes formed during the experimental procedures described herein, provided they possess the necessary intrinsic acidity or basicity.

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

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 K ₂ CO ₃ (3.8 g, 27.5 mmol) in p-dioxane (40 mL) and deionized water (6 mL) was added Pd(dppf)Cl ₂ dichloromethane complex (912 mg, 1.12 mmol). The reaction mixture was degassed and stirred under nitrogen at 90°C for 2 h. The mixture was diluted with ethyl acetate, filtered through celite, washed with saturated aqueous sodium chloride solution and dried over MgSO ₄ . The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel to give N-(3'-bromo-2'-chloro-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. MS: (ES) m/z calculated for C ₂₀ H ₁₈ BrClN ₃ O ₃ [M + H] ⁺ 462.0, found: 462.0 .

Step b. To a mixture of N-(3'-bromo-2'-chloro-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (1.4 g, 3.03 mmol), pinacol diborane (1.0 g, 3.94 mmol), and KOAc (1.2 g, 10.2 mmol) in p-dioxane (18 mL) was added Pd(dppf)Cl ₂ dichloromethane complex (350 mg, 0.43 mmol). The reaction mixture was degassed (N ₂ ) and stirred under nitrogen at 90°C for 3 h. The mixture was diluted with ethyl acetate, filtered through celite, washed with saturated aqueous sodium chloride solution and dried over MgSO ₄ . The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel 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 calculated for C ₂₆ H ₃₀ BClN ₃ O ₅ [M + H] ⁺ 510.2, found: 510.1.

Step c. In 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 K₂CO₃(350 mg, 2.53 mmol) in p-dioxane (10 ml) and deionized water (2 ml) was added the complex Pd(dppf)Cl₂with dichloromethane (70 mg, 0.086 mmol). The reaction mixture was degassed and stirred under nitrogen at 95°C for 2 hours. The mixture was diluted with ethyl acetate, filtered through Celite, washed with saturated aqueous sodium chloride solution, and dried over MgSO₄The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel to give N-(2'-chloro-3'-(5-formyl-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. MS: (ES) m/z calculated for C₂₇H₂₄ClN₄O₅[M + H]⁺ 519.1, found: 519.1.

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 h, then cooled to 0°C and _NaBH3CN (10 mg, 0.154 mmol) was slowly added. The reaction mixture was stirred at 0°C for 10 min, 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. ^1H NMR (400 MHz, CD ₃ OD) 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 calculated for C ₃₂ H ₃₄ ClN ₅ O ₆ [M + H] ⁺ 620.2, found: 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

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 in 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, CD ₃ OD) 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 calculated for C ₃₁ H ₃₁ ClN ₆ O ₅ [M + H] ⁺ 603.2, found: 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

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 in 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, CD ₃ OD) 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 calculated for C ₃₂ H ₃₃ ClN ₆ O ₅ [M + H] ⁺ 617.2, found: 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

This 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 in 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. ^1H NMR (400 MHz, CD ₃ OD) 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 calculated for C ₃₀ H ₃₀ Cl ₂ N ₆ O ₆ [M + H] ⁺ 641.2, found: 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

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 in 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, CD ₃ OD) 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 calculated for C ₃₀ H ₃₀ Cl ₂ N ₆ O ₆ [M + H] ⁺ 641.2, found: 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

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 in 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. ^1H NMR (400 MHz, CD ₃ OD) 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 = 10.0 Hz, 1H). MS: (ES) m/z calcd for C ₃₀ H ₂₉ Cl ₂ N ₇ O ₅ [M + H] ⁺ 638.1, found: 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

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 in 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. ^1H NMR (400 MHz, CD ₃ OD) 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 calculated for C ₂₉ H ₂₇ Cl ₂ N ₇ O ₅ [M + H] ⁺ 624.2, found: 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

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 in 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. ^1H NMR (400 MHz, CD ₃ OD) 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 calculated for C ₂₉ H ₂₇ Cl ₂ N ₇ O ₅ [M + H] ⁺ 638.2, found: 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

This 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 in 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, CDCl ₃ ) 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 calculated for C ₃₃ H ₃₆ ClN ₆ O ₅ [M + H] ⁺ 631.2, found: 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

This 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 in 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, CD ₃ OD) 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 calculated for C ₃₁ H ₃₀ Cl ₂ N ₇ O ₅ [M + H] ⁺ 650.2, found: 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

This 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 in 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. ^1H NMR (400 MHz, CD ₃ OD) 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 calculated for C ₂₈ H ₂₇ Cl ₂ N ₆ O ₅ [M + H] ⁺ 597.1, found: 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

This 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 in 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. ^1H NMR (400 MHz, CD ₃ OD) 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 calculated for C ₂₉ H ₂₈ Cl ₂ N ₅ O ₅ [M + H] ⁺ 596.1, found: 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

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), 2M _K2CO3 (3 mL, 6 mmol) in p-dioxane (20 mL) was added Pd( _PPh3 ) ₄ (260 mg, 0.22 mmol). The reaction mixture was degassed for 5 _min and stirred at 80°C for 2 h. Dioxane was removed from the reaction mixture under reduced pressure and the residue was dissolved in a mixture of chloroform and water. The mixture was 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 calculated for C ₂₅ H ₂₀ Cl ₂ N ₂ O ₅ [M + H] ⁺ 540.0, found: 540.1.

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 was added Et ₃ N (43 μL, 0.31 mmol). After stirring for 5 min, Na(OAc) ₃ BH (78 mg, 0.37 mmol) was added to the reaction mixture. An additional portion of Na(OAc) ₃ BH (82 mg, 0.39 mmol) was added and the mixture was stirred for another 15 h. The solvent was removed in vacuo and the residue was dissolved in a mixture of p-dioxane, DMSO, TFA and water and filtered. The resulting 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. ^1H NMR (400 MHz, CD ₃ OD) 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 calculated for C ₃₀ H ₃₁ Cl ₂ N ₆ O ₆ [M + H] ⁺ 641.2, found: 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

This 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 in Example 1. The crude product was purified by preparative HPLC to give (S)-N-(2,2'-dichloro-3'-(6-methoxy-5-((((5-oxopyrrolidin-2-yl)methyl)amino)methyl)pyridin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. ^1H NMR (400 MHz, CD ₃ OD) 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 calculated for C ₃₁ H ₃₁ Cl ₂ N ₆ O ₅ [M + H] ⁺ 637.2, found: 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

This 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 in Example 1. The crude product was purified by preparative HPLC to give N-(2,2'-dichloro-3'-(5-((((3R,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)methyl)-6-methoxypyridin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. ^1H NMR (400 MHz, CD ₃ OD) 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 calculated for C ₃₁ H ₃₂ Cl ₂ N ₅ O ₆ [M + H] ⁺ 640.2, found: 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

Stage a. To a mixture of 2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid (200 mg, 1.1 mmol), 2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (350 mg, 1.4 mmol) and N,N-diisopropylethylamine (0.35 mL, 2.0 mmol) in DMF (3 mL) was added (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (600 mg, 1.6 mmol). The mixture was heated at 60°C for 1.5 h, cooled to room temperature and poured into water. The precipitated The precipitate was filtered off and dried in vacuo 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-d ₆ ) 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).

Step b. To a mixture of N-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide (100 mg, 0.24 mmol), 6-(3-bromo-2-chlorophenyl)-2-methoxynicotinaldehyde (70 mg, 0.21 _mmol ), and 2M _K2CO3 (1 mL, 2 mmol) in dioxane (4 mL) was added Pd(dppf) _Cl2 DCM complex (39 mg, 0.05 mmol). The reaction mixture was degassed and stirred under nitrogen at 90°C for 1 h. The mixture was diluted with ethyl acetate and water, the organic phase was separated and the solvent was removed under reduced pressure. The resulting residue was purified by flash chromatography on silica gel to give N-(2,2'-dichloro-3'-(5-formyl-6-methoxypyridin-2-yl)-[1,1'-biphenyl]-3-yl)-2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide. MS: (ES) m/z calculated for C ₂₅ H ₂₀ Cl ₂ N ₅ O ₅ [M + H] ⁺ 640.1, found: 639.7.

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 Et ₃ N (47 μL, 0.34 mmol). The mixture was stirred at room temperature for 10 min and Na(OAc) ₃ 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 a mixture of dioxane, MeCN, water, and TFA and filtered. 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)-2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide. ^1H NMR (400 MHz, CD ₃ OD) 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 calculated for C ₃₀ H ₃₀ Cl ₂ N ₇ O ₅ [M + H] ⁺ 638.2, found: 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

This 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 in Example 1. The crude product was purified by preparative HPLC to give (S)-N-(2-chloro-2'-fluoro-3'-(6-methoxy-5-((((5-oxopyrrolidin-2-yl)methyl)amino) methyl)pyridin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. ^1H NMR (400 MHz, CD ₃ OD) 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 calculated for C ₃₁ H ₃₁ ClFN ₆ O ₅ [M + H] ⁺ 621.2, found: 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

This 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 in Example 1. The crude product was purified by preparative HPLC to give (S)-N-(2,2'-dichloro-3'-(6-methoxy-5-((((5-oxopyrrolidin-2-yl)methyl)amino)methyl)pyridin-2-yl)-[1,1'-biphenyl]-3-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide. ^1H NMR (400 MHz, CD ₃ OD) 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 calculated for C ₃₀ H ₂₉ Cl ₂ N ₆ O ₄ [M + H] ⁺ 607.2, found: 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

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. NaBH(OAc) ₃ (61 mg, 0.29 mmol) was added to the mixture. After 2 h, the reaction was quenched with saturated aqueous NaHCO ₃ and extracted with dichloromethane. The organic layer was separated, evaporated 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, CD ₃ OD) 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 calculated for C ₂₉ H ₃₁ ClN ₅ O ₅ [M + H] ⁺ 564.2, found: 564.5.

Example 20

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. NaBH(OAc) ₃ (70 mg, 0.33 mmol) was added to the mixture. After 1 h, the reaction was quenched with saturated aqueous NaHCO ₃ and extracted with dichloromethane. The organic layer was separated, evaporated 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, CD ₃ OD) 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 calcd for C ₃₁ H ₃₅ ClN ₅ O ₅ [M + H] ⁺ 592.2, found: 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

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 h. NaBH(OAc) ₃ (70 mg, 0.33 mmol) was added to the mixture. After stirring for 30 min at 0°C, the reaction was quenched by adding 2 drops of water. The crude product was purified by preparative HPLC to give 1-((6-(2-chloro-3'-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamido)-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)-3-methylazetidine-3-carboxylic acid. ^1H NMR (400 MHz, CD ₃ OD) 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 calculated for C ₃₂ H ₃₃ ClN ₅ O ₆ [M + H] ⁺ 618.2, found: 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

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 NaBH ₃ CN (25 mg, 0.40 mmol) was added. After stirring for 30 min at 0°C, the reaction was quenched by adding 1 drop of water. The crude product 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, CD ₃ OD) 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 calculated for C ₃₀ H ₃₃ ClN ₅ O ₅ [M + H] ⁺ 578.2, found: 578.5.

Example 23

This 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 that described in Example 1. The crude product was purified by preparative HPLC to yield 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. ^1H NMR (400 MHz, CDCl ₃ ) 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 calculated for C ₃₂ H ₃₇ ClN ₅ O ₅ [M + H] ⁺ 606.2, found: 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

This 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 in Example 1. The crude product was purified by flash chromatography on silica gel 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, CD ₃ OD) 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 calculated for C ₃₂ H ₃₅ ClN ₅ O ₅ [M + H] ⁺ 604.2, found: 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

This 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 in 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. ^1H 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 calculated for C ₃₂ H ₃₅ ClN ₅ O ₅ [M + H] ⁺ 604.2, found: 604.5.

Example 26. (R)-N-(2'-chloro-3'-(5-(((2,3-di-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

This 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 in Example 1. The crude product was purified by flash chromatography on silica gel to give (R)-N-(2'-chloro-3'-(5-(((2,3-di-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, CD ₃ OD) 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 calculated for C ₃₀ H ₃₃ ClN ₅ O ₆ [M + H] ⁺ 594.2, found: 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

This 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 in 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. ^1H NMR (400 MHz, CD ₃ OD) 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 calculated for C ₃₂ H ₃₄ ClN ₅ O ₆ [M + H] ⁺ 620.2, found: 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

This 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 in 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. ^1H NMR (400 MHz, CD ₃ OD) 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 calcd for C ₃₂ H ₃₆ ClN ₆ O ₅ [M + H] ⁺ 619.2, found: 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

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 NaBH ₃ CN (25 mg, 0.40 mmol) was added. After stirring for 15 min at 0°C, the reaction was quenched by adding 1 drop of water. The crude product 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, CD ₃ OD) 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 calculated for C ₂₈ H ₂₈ Cl ₂ N ₅ O ₅ [M + H] ⁺ 584.1, found: 584.4.

Example 30

This 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 in 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. ^1H NMR (400 MHz, CDCl ₃ ) 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 calcd for C ₃₁ H ₃₃ ClN ₅ O ₅ [M + H] ⁺ 590.2, found: 590.5.

Example 31

This 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 in 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. ^1H NMR (400 MHz, CD ₃ OD) 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 calculated for C ₃₀ H ₃₃ ClN ₅ O ₄ [M + H] ⁺ 562.2, found: 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

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 mixture was cooled to 0°C and NaBH ₃ CN (25 mg, 0.40 mmol) was added. After stirring for 5 min at 0°C, the reaction was quenched by adding 1 drop of water. The crude product was purified by preparative HPLC to give N-(2,2'-dichloro-3'-(5-(((3-hydroxypropyl)amino)methyl)-6-methoxypyridin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. ^1H NMR (400 MHz, CD ₃ OD) 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 calculated for C ₂₉ H ₃₀ Cl ₂ N ₅ O ₅ [M + H] ⁺ 598.2, found: 598.2.

Example 33

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 mixture was cooled to 0°C and NaBH ₃ CN (25 mg, 0.40 mmol) was added. After stirring for 5 min at 0°C, the reaction was quenched by adding 1 drop of water. The crude product 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, CD ₃ OD) 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 calculated for C ₃₀ H ₃₀ Cl ₂ N ₅ O ₅ [M + H] ⁺ 610.2, found: 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

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 mixture was cooled to 0°C and NaBH ₃ CN (20 mg, 0.32 mmol) was added. After stirring for 5 min at 0°C, the reaction was quenched by adding 1 drop of water. The crude product was purified by preparative HPLC to give (S)-N-(2,2'-dichloro-3'-(5-(((2-hydroxypropyl)amino)methyl)-6-methoxypyridin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. ^1H NMR (400 MHz, CD ₃ OD) 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 calculated for C ₂₉ H ₃₀ Cl ₂ N ₅ O ₅ [M + H] ⁺ 598.2, found: 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

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 mixture was cooled to 0°C and NaBH ₃ CN (20 mg, 0.32 mmol) was added. After stirring for 5 min at 0°C, the reaction was quenched by adding 1 drop of water. The crude product 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, CD ₃ OD) 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 calculated for C ₂₉ H ₃₀ Cl ₂ N ₅ O ₅ [M + H] ⁺ 598.2, found: 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

This 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 in 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. ^1H 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 calculated for C ₂₈ H ₂₉ ClN ₅ O ₄ [M + H] ⁺ 534.2, found: 534.1.

Example 37. (R)-N-(2,2'-dichloro-3'-(5-(((2,3-di-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

This 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 in Example 1. The crude product was purified by preparative HPLC to give (R)-N-(2,2'-dichloro-3'-(5-(((2,3-di-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, CD ₃ OD) 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 calculated for C ₂₉ H ₃₀ Cl ₂ N ₅ O ₆ [M + H] ⁺ 614.2, found: 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

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 mixture was cooled to 0°C and NaBH ₃ CN (20 mg, 0.32 mmol) was added. After stirring for 10 min at 0°C, the reaction was quenched by adding 1 drop of water. The crude product was purified by preparative HPLC to give (S)-N-(2'-chloro-3'-(5-(((2-hydroxypropyl)amino)methyl)-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. ^1H NMR (400 MHz, CD ₃ OD) 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 calculated for C ₃₀ H ₃₃ ClN ₅ O ₅ [M + H] ⁺ 578.2, found: 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

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 mixture was cooled to 0°C and NaBH ₃ CN (20 mg, 0.32 mmol) was added. After stirring for 10 min at 0°C, the reaction was quenched by adding 1 drop of water. The crude product 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, CD ₃ OD) 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 calculated for C ₃₀ H ₃₃ ClN ₅ O ₅ [M + H] ⁺ 578.2, found: 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

This 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 in Example 1. The crude product was purified by flash chromatography on silica gel to give (R)-N-(2,2'-dichloro-3'-(5-((3-hydroxy-3-methylpyrrolidin-1-yl) (methyl)-6-methoxypyridin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. ^1H NMR (400 MHz, CD ₃ OD) 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 calculated for C ₃₁ H ₃₂ Cl ₂ N ₅ O ₅ [M + H] ⁺ 624.2, found: 624.5.

Example 41

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 mixture was cooled to 0°C and NaBH ₃ CN (25 mg, 0.40 mmol) was added. After stirring for 10 min at 0°C, the reaction was quenched by adding 1 drop of water. The crude product was purified by preparative HPLC to give N-(2'-chloro-3'-(5-(((3-hydroxy-3-methylbutyl)amino)methyl)-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. ^1H NMR (400 MHz, CD ₃ OD) 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 calculated for C ₃₂ H ₃₇ ClN ₅ O ₅ [M + H] ⁺ 606.2, found: 606.6.

Example 42

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 mixture was cooled to 0°C and NaBH ₃ CN (25 mg, 0.40 mmol) was added. After stirring for 10 min at 0°C, the reaction was quenched by adding 1 drop of water. The crude product 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, CD ₃ OD) 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 calcd for C ₃₁ H ₃₃ ClN ₅ O ₅ [M + H] ⁺ 590.2, found: 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

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 mixture was cooled to 0°C, and NaBH ₃ CN (30 mg, 0.48 mmol) was added. After stirring for 15 min at 0°C, the reaction was quenched by adding 1 drop of water. The crude product was purified by preparative HPLC to give (S)-N-(2'-chloro-3'-(5-(((1-hydroxypropan-2-yl)amino)methyl)-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. ^1H NMR (400 MHz, CD ₃ OD) 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 calculated for C ₃₀ H ₃₃ ClN ₅ O ₅ [M + H] ⁺ 578.2, found: 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

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 mixture was cooled to 0°C, and NaBH ₃ CN (30 mg, 0.48 mmol) was added. After stirring for 15 min at 0°C, the reaction was quenched by adding 1 drop of water. The crude product 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, CD ₃ OD) 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 calculated for C ₃₀ H ₃₃ ClN ₅ O ₅ [M + H] ⁺ 578.2, found: 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

This 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 in 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. ^1H NMR (400 MHz, CD ₃ OD) 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 calculated for C ₃₁ H ₃₂ ClFN ₅ O ₆ [M + H] ⁺ 624.2, found: 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

This 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 in 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. ^1H 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 calculated for C ₃₃ H ₃₇ ClN ₅ O ₅ [M + H] ⁺ 618.2, found: 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

This 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 in Example 1. The crude product was purified by preparative HPLC to give the desired product 1-((5-(2,2'-dichloro-3'-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamido)-[1,1'-biphenyl]-3-yl)-3-methoxypyrazin-2-yl)methyl)azetidine-3-carboxylic acid. ^1H NMR (400 MHz, CD ₃ OD) 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 (brs, 2H), 4.12 (s, 3H), 3.78 (b.s, 1H), 3.56 (s, 3H), 3.39 (s, 3H). MS: (ES) m/z calculated for C ₂₉ H ₂₇ Cl ₂ N ₆ O ₆ [M + H] ⁺ 625.1, found: 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

This 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 in Example 1. The crude product was purified by preparative HPLC to give the desired product N-(2,2'-dichloro-3'-(6-methoxy-5-((5-oxo-2,6-diazaspiro[3,4]octan-2-yl)methyl) pyrazin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. ^1H NMR (400 MHz, CD ₃ OD) 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 (brs, 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 (brs, 2H), 3.12 (m, 1H), 2.58 (brs, 2H). MS: (ES) m/z calculated for C ₃₁ H ₃₀ Cl ₂ N ₇ O ₅ [M + H] ⁺ 650.2, found: 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

This 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 in 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, CDCl ₃ ) 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 calculated for C ₃₄ H ₃₈ ClN ₆ O ₅ [M + H] ⁺ 645.2, found: 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

This 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 in 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. ^1H NMR (400 MHz, CDCl ₃ ) 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 calculated for C ₃₃ H ₃₆ ClN ₆ O ₅ [M + H] ⁺ 631.2, found: 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

This 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 in 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. ^1H NMR (400 MHz, CDCl ₃ ) 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 calculated for C ₃₂ H ₃₅ ClN ₅ O ₆ [M + H] ⁺ 620.2, found: 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

This 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 in 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, CD ₃ OD) 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 calculated for C ₃₁ H ₃₃ ClN ₅ O ₆ [M + H] ⁺ 606.2, found: 606.5.

Example 53

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. NaBH(OAc) ₃ (70 mg, 0.33 mmol) was added to the mixture. After stirring for 1 h at room temperature, the crude product was purified by preparative HPLC to give ((6-(2-chloro-3'-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamido)-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)glycine. ^1H NMR (400 MHz, CD ₃ OD) 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 calcd for C ₂₉ H ₂₉ ClN ₅ O ₆ [M + H] ⁺ 578.2, found: 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

This 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 in Example 1. The crude product was purified by flash chromatography on silica gel. To the resulting material was added 1N HCl solution in Et ₂ O (1 mL) and triturated with MeCN (5 mL) to give (R)-N-(2,2'-dichloro-3'-(6-methoxy-5-((((5-oxopyrrolidin-2-yl)methyl)amino)methyl)pyridin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. ^1H NMR (400 MHz, CD ₃ OD) 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 calculated for C ₃₁ H ₃₁ Cl ₂ N ₆ O ₅ [M + H] ⁺ 637.2, found: 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

This 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 in Example 1. The crude product was purified by flash chromatography on silica gel 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, CD ₃ OD) 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 calculated for C ₃₁ H ₃₂ Cl ₂ N ₇ O ₄ [M + H] ⁺ 636.2, found: 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

This 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 in Example 1. The crude product was purified by flash chromatography on silica gel followed by preparative HPLC to give (S)-N-(2'-chloro-3'-(6-methoxy-5-((((5-oxopyrrolidin-2-yl)methyl)amino)methyl)pyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. ^1H NMR (400 MHz, CD ₃ OD) 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 calculated for C ₃₁ H ₃₂ ClN ₆ O ₅ [M + H] ⁺ 603.2, found: 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

This 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 in Example 1. The crude product was purified by flash chromatography on silica gel followed by preparative HPLC to give (S)-N-(2'-chloro-3'-(6-ethyl-5-((((5-oxopyrrolidin-2-yl)methyl)amino)methyl)pyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. ^1H NMR (400 MHz, CD ₃ OD) 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 calculated for C ₃₃ H ₃₆ ClN ₆ O ₄ [M + H] ⁺ 615.2, found: 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

A mixture of N-(2'-chloro-3'-(6-formyl-5-methoxypyridin-3-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (32 mg, 0.061 mmol), (3R,4R)-4-aminotetrahydro-2H-pyran-3-ol hydrochloride (20 mg, 0.13 mmol), _Et3N (75 mg, 0.74 mmol), and AcOH (150 mg, 2.5 mmol) in EtOH (1.5 mL) and DCM (1.5 mL) was heated at 70°C for 0.5 h. The mixture was cooled to 0°C and _NaBH3CN (30 mg, 0.44 mmol) was added. After stirring for 5 min at 0°C, the mixture was evaporated 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, CD ₃ OD) 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 calculated for C ₃₂ H ₃₅ ClN ₅ O ₆ [M + H] ⁺ 620.2, found: 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

This 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 in 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. ^1H 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 calcd for C ₃₂ H ₃₂ ClN ₇ O ₅ [M + H] ⁺ 630.2, found: 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

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 MeOH at 0°C was slowly added hydrochloric acid solution (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.¹H 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 calculated for C₃₀H₂₉Cl₂N₆O₅[M + H]⁺623.2, found: 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

This 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 in 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 calculated for C₃₃H₃₆ClN₆O₅[M + H]⁺631.2, found: 631.2.

Example 62

This 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 in 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. ^1H NMR (400 MHz, CD ₃ OD) 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 calculated for C ₃₁ H ₃₃ Cl ₂ N ₆ O ₅ [M + H] ⁺ 639.2, found: 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

This 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 in 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. ^1H NMR (400 MHz, CD ₃ OD) 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 calculated for C ₃₂ H ₃₃ Cl ₂ N ₆ O ₅ [M + H] ⁺ 651.2, found: 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

This 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 in Example 1. The crude product was purified by preparative HPLC to give (S)-N-(2,2'-dichloro-3'-(6-methoxy-5-((((5-oxopyrrolidin-2-yl)methyl)amino)methyl)pyridin-2-yl)-[1,1'-biphenyl]-3-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide.¹H 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 calculated for C₃₁H₂₉Cl₂N₅O₄[M + H]⁺606.2, found: 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

This 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 in 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-carboxamido)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)azetidine-3-carboxylic acid. ^1H NMR (400 MHz, CD ₃ OD) 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 calculated for C ₃₀ H ₂₈ Cl ₂ N ₅ O ₆ [M + H] ⁺ 624.1, found: 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

This 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 in 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-carboxamido)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)-3-methylazetidine-3-carboxylic acid. ^1H NMR (400 MHz, CD ₃ OD) 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 calcd for C ₃₁ H ₃₀ Cl ₂ N ₅ O ₆ [M + H] ⁺ 638.2, found: 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

This 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 in 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-carboxamido)-[1,1'-biphenyl]-3-yl)-3-methoxypyrazin-2-yl)methyl)piperidine-2-carboxylic acid. ^1H NMR (400 MHz, CD ₃ OD) 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 calculated for C ₃₁ H ₃₁ Cl ₂ N ₆ O ₆ [M + H] ⁺ 653.2, found: 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

This 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 in 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-carboxamido)-[1,1'-biphenyl]-3-yl)-3-methoxypyrazin-2-yl)methyl)piperidine-2-carboxylic acid. ^1H NMR (400 MHz, CD ₃ OD) 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 calculated for C ₃₁ H ₃₁ Cl ₂ N ₆ O ₆ [M + H] ⁺ 653.2, found: 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

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 were added 2 M K ₂ CO ₃ (110 mL) and Pd(dppf)Cl ₂ DCM complex (5.25 g, 6.4 mmol). The mixture was degassed with nitrogen for 10 min, then heated at 90 °C for 2 h. The reaction was quenched with saturated NaHCO ₃ solution, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate, filtered, and evaporated. The resulting residue was purified by silica gel column chromatography to give 3'-bromo-2'-chloro-2-methyl-[1,1'-biphenyl]-3-amine.

Step b. To a solution of 3'-bromo-2'-chloro-2-methyl-[1,1'-biphenyl]-3-amine (7 g, 23.7 mmol) in 40 mL of dioxane was added bispinacolatodiborone (6.3 g, 24.9 mmol), followed by KOAc (5.8 g, 59.1 mmol) and Pd(dppf) _Cl2 DCM complex (1.93 g, 2.4 mmol). The mixture was degassed with nitrogen for 10 min, then heated at 90°C overnight. The mixture was filtered through Celite and washed with ethyl acetate. The filtrate was evaporated and the resulting residue was purified by column chromatography on silica gel 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 calculated for C ₁₉ H ₂₄ BClNO ₂ [M + H] ⁺ 344.2, found: 344.1.

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 were 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 h, and additional 1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (0.34 g, 0.99 mmol), DIPEA (0.49 mL, 2.8 mmol), and HATU (0.85 g, 2.23 mmol) were added. After stirring overnight, the reaction was quenched with water. The aqueous layer was extracted with ethyl acetate, and the organic layers were combined, dried over sodium sulfate, filtered, and evaporated. 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 calculated for C ₂₆ H ₂₉ BClN ₃ O ₅ [M + H] ⁺ 510.2, found: 510.1.

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 were added 6-chloro-2-methoxynicotinaldehyde (1.4 g, 8.3 mmol), 2M K ₂ CO ₃ (14 mL), and Pd(PPh ₃ ) ₄ (0.95 g, 0.82 mmol). The mixture was degassed with nitrogen for 10 min, then heated at 100°C for 2 h. The mixture was filtered through celite and the organic and aqueous layers were separated. The aqueous layer was washed with ethyl acetate and the combined organic layers were dried over sodium sulfate, filtered and evaporated. The resulting residue was purified by column chromatography on silica gel to give N-(2'-chloro-3'-(5-formyl-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. MS: (ES) m/z calculated for C ₂₇ H ₂₄ ClN ₄ O ₅ [M + H] ⁺ 519.1, found: 519.0.

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 DCM and 1.5 mL EtOH were added azetidin-3-ol (17 mg, 0.23 mmol), Et ₃ N (0.07 mL, 0.5 mmol), and AcOH (0.04 mL, 0.70 mmol). The reaction mixture was heated at 70 °C for 1 h, then cooled to 0 °C and NaBH ₃ CN (18 mg, 0.29 mmol) was added. The reaction mixture was stirred at room temperature for 1 h, then quenched with water. The aqueous layer was extracted with ethyl acetate, the organic layers were combined, dried over sodium sulfate, filtered and evaporated. The resulting residue was purified by silica gel column chromatography and then 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. ^1H 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 (br.s, 4H), 3.49 (s, 3H), 3.32 (s, 1H), 3.27 (s, 3 H), 3.01 (br s, 2H), 2.07 (s, 3H). MS: (ES) m/z calculated for C ₃₀ H ₃₁ ClN ₅ O ₅ [M + H] ⁺ 576.2, found: 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

This 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 in 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. ^1H 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 calculated for C ₃₃ H ₃₄ ClN ₆ O ₅ [M + H] ⁺ 629.2, found: 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

This 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 in 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-carboxamido)-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)azetidine-3-carboxylic acid. ^1H NMR (400 MHz, CD ₃ OD) 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 calculated for C ₃₁ H ₃₁ ClN ₆ O ₆ [M + H] ⁺ 604.2, found: 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

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 were added 5-chloro-3-methoxypyrazine-2-carbaldehyde (0.42 g, 2.0 mmol), 2 M K ₂ CO ₃ (6.7 mL), and Pd(PPh ₃ ) ₄ (0.23 g, 0.20 mmol). The mixture was degassed with nitrogen for 10 min, then heated at 100°C for 1 h. The reaction was quenched with water, and the aqueous layer was washed with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and evaporated. The resulting residue was purified by column chromatography on silica gel 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 calculated for C ₂₆ H ₂₃ ClN ₅ O ₅ [M + H] ⁺ 520.1, 519.9.

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 DCM and 1.5 mL EtOH were added (S)-5-(aminomethyl)pyrrolidin-2-one (35 mg, 0.23 mmol), Et ₃ N (0.07 mL, 0.5 mmol), and AcOH (0.04 mL, 0.70 mmol). The mixture was heated at 70°C for 1 h, then cooled to 0°C and _NaBH3CN (18 mg, 0.29 mmol) was added. After stirring at room temperature for 1 h, the reaction was quenched with water. The aqueous layer was extracted with ethyl acetate, the organic layers were combined, dried over sodium sulfate, filtered and evaporated. The resulting residue was purified by silica gel column chromatography and then 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. ^1H NMR (400 MHz, CD ₃ OD) 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 calculated for C ₃₁ H ₃₃ ClN ₇ O ₅ [M + H] ⁺ 618.2, found: 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

This 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 in Example 1. The crude product was purified by preparative HPLC to give N-(2'-chloro-3'-(5-((((3R,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)methyl)-6-methoxypyrazin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. ¹ H NMR (400 MHz, DMSO-d ₆ ) 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 calculated for C ₃₁ H ₃₄ ClN ₆ O ₆ [M + H] ⁺ 621.2, found: 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

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, then quenched with water. The solid precipitate was filtered off, washed with water 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 calculated for C ₁₉ H ₂₅ BN ₃ O ₅ [M + H] ⁺ 386.2, found: 386.4.

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 H ₂ O were added 6-(3-bromo-2-chlorophenyl)-2-methoxynicotinaldehyde (85 mg, 0.26 mmol), K ₃ PO ₄ (137 mg, 0.65 mmol), and XPhosPdG2 (20 mg, 0.03 mmol). The mixture was degassed with nitrogen for 10 min and stirred at room temperature overnight. The solid precipitate was filtered and washed with ethyl acetate 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 calculated for C ₂₆ H ₂₂ ClN ₄ O ₅ [M + H] ⁺ 505.1, found: 505.4.

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 DCM and 1 mL EtOH was added (S)-5-(aminomethyl)pyrrolidin-2-one (25 mg, 0.17 mmol), Et ₃ N (0.06 mL, 0.43 mmol), and AcOH (0.04 mL, 0.70 mmol). The mixture was heated at 70 °C for 1 h, then cooled to room temperature, and Na(OAc) ₃ BH (90 mg, 0.42 mmol) was added. After stirring at room temperature for 20 min, the reaction was quenched with water. The aqueous layer was extracted with ethyl acetate, and the organic layers were combined, dried over sodium sulfate, filtered, and evaporated. The resulting residue was purified by silica gel column chromatography and then 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. ^1H 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 (brs, 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 calculated for C ₃₁ H ₃₂ ClN ₆ O ₅ [M + H] ⁺ 603.2, found: 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

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, then quenched with water. The solid precipitate was filtered off, washed with water 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 calculated for C ₁₉ H ₂₄ BFN ₃ O ₅ [M + H] ⁺ 404.2, found: 404.4.

Step b. To a solution of N-(2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (100 mg, 0.26 mmol) in 1 mL THF and 1 mL H ₂ O were added 6-(3-bromo-2-chlorophenyl)-2-methoxynicotinaldehyde (81 mg, 0.25 mmol), K ₃ PO ₄ (132 mg, 0.62 mmol), and XPhosPdG2 (20 mg, 0.03 mmol). The mixture was degassed with nitrogen for 10 min and stirred at room temperature for 5 h. The solid precipitate was filtered and washed with ethyl acetate 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 calculated for C ₂₆ H ₂₁ ClFN ₄ O ₅ [M + H] ⁺ 523.1, found: 523.3.

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 DCM and 1 mL EtOH were added (S)-5-(aminomethyl)pyrrolidin-2-one (28 mg, 0.19 mmol), Et ₃ N (0.07 mL, 0.5 mmol), and AcOH (0.04 mL, 0.70 mmol). The mixture was heated at 70 °C for 1 h, then cooled to room temperature, and Na(OAc) ₃ BH (100 mg, 0.47 mmol) was added. After stirring at room temperature for 1 h, the reaction was quenched with water. The aqueous layer was extracted with ethyl acetate, and the organic layers were combined, dried over sodium sulfate, filtered, and evaporated. The resulting residue was purified by silica gel column chromatography and then 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, DMSO-d ₆ ) 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 (br s, 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 calculated for C ₃₁ H ₃₁ ClFN ₆ O ₅ [M + H] ⁺ 621.2, found: 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

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 were added 2 M K ₂ CO ₃ (4.7 mL, 10.9 mmol) and Pd(PPh ₃ ) ₄ (420 mg, 0.36 mmol). The mixture was degassed with nitrogen for 10 min and stirred at 100°C for 2 h. The reaction was quenched with water, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were combined, dried over sodium sulfate, filtered, and evaporated. The resulting residue was purified by column chromatography on silica gel to give 6-(3-bromo-2-chlorophenyl)-2-(trifluoromethyl)nicotinaldehyde. MS: (ES) m/z calcd for C ₁₃ H ₇ BrClF ₃ NO [M + H] ⁺ 363.9, found: 364.2.

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, 0.68 mmol) in 10 mL of dioxane were added 6-(3-bromo-2-chlorophenyl)-2-(trifluoromethyl)nicotinaldehyde (250 mg, 0.69 mmol), 2M K ₂ CO ₃ (1.2 mL, 2.4 mmol), and Pd(dppf)Cl ₂ DCM complex (170 mg, 0.21 mmol). The mixture was degassed with nitrogen for 10 min, then heated at 100°C for 1 h. The mixture was filtered through celite, the filtrate was evaporated and purified by column chromatography on silica gel 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 calculated for C ₂₇ H ₂₁ ClF ₃ N ₄ O ₄ [M + H] ⁺ 557.1, found: 557.4.

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), 1 mL DCM, and 1 mL EtOH were added (S)-5-(aminomethyl)pyrrolidin-2-one (40 mg, 0.27 mmol), Et ₃ N (0.09 mL, 0.65 mmol), and AcOH (0.06 mL, 1.0 mmol). The mixture was heated at 70°C for 1 h, then cooled to room temperature and Na(OAc) _3BH (114 mg, 0.54 mmol) was added. The reaction mixture was stirred at room temperature for 1 h and additional Na(OAc) _3BH (114 mg, 0.54 mmol) was added. After stirring at room temperature overnight, the mixture was evaporated, 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. ¹ H NMR (400 MHz, CD ₃ OD) 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 (br s, 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 calcd for C ₃₂ H ₃₁ ClF ₃ N ₆ O ₄ [M + H] ⁺ 655.2, found: 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

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) were added Et ₃ N (2 drops) and AcOH (2 drops). The mixture was stirred at 70°C for 1 h, then cooled to 0°C and NaBH ₃ CN (13 mg, 0.2 mmol) was slowly added. After stirring at 0°C for 10 minutes, the reaction 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. ^1H NMR (400 MHz, CDCl ₃ ) 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 calculated for C ₃₂ H ₃₅ ClN ₅ O ₅ [M + H] ⁺ 604.2, found: 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

This 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 in Example 1. The crude product was purified by preparative HPLC to give N-(2'-chloro-3'-(5-((((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)methyl)-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. ^1H NMR (400 MHz, CDCl ₃ ) 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 (br s, 1H), 1.54 - 1.43 (m, 1H). MS: (ES) m/z calculated for C ₃₂ H ₃₅ ClN ₅ O ₆ [M + H] ⁺ 620.2, found: 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

This 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 in Example 1. The crude product was purified by preparative HPLC to give N-(2'-cyano-3'-(5-((((3R,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)methyl)-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. ^1H NMR (400 MHz, CDCl ₃ ) 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 calculated for C ₃₃ H ₃₅ N ₆ O ₆ [M + H] ⁺ 611.3, found: 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

This 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 in Example 1. The crude product was purified by preparative HPLC to give N-(2'-chloro-3'-(5-((3-(2-hydroxypropan-2-yl)azetidin-1-yl)methyl)-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. ^1H NMR (400 MHz, CDCl ₃ ) 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, 1H), 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 calculated for C ₃₃ H ₃₇ ClN ₅ O ₅ [M + H] ⁺ 618.2, found: 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

This 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 in Example 1. The crude product was purified by preparative HPLC to give N-(2'-chloro-3'-(5-(((4-hydroxy-2-methylbutan-2-yl)amino)methyl)-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. ^1H NMR (400 MHz, CDCl ₃ ) 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 calculated for C ₃₂ H ₃₇ ClN ₅ O ₅ [M + H] ⁺ 606.2, found: 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

This 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 in Example 1. The crude product was purified by preparative HPLC to give (S)-N-(3'-(6-methoxy-5-((((5-oxopyrrolidin-2-yl)methyl)amino)methyl)pyridin-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. ¹ H NMR (400 MHz, CD ₃ OD) 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 calculated for C ₃₃ H ₃₇ N ₆ O ₅ [M + H] ⁺ 597.3, found: 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

This 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 in 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-carboxamido)-[1,1'-biphenyl]-3-yl)-2-ethylpyridin-3-yl)methyl)azetidine-3-carboxylic acid. ^1H NMR (400 MHz, CD ₃ OD) 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 calculated for C ₃₁ H ₃₀ Cl ₂ N ₅ O ₅ [M + H] ⁺ 622.2, found: 622.1.

Example 84

This 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 in Example 1. The crude product was purified by preparative HPLC to give N-(2,2'-dichloro-3'-(6-ethyl-5-((3-hydroxyazetidin-1-yl)methyl)pyridin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. ^1H NMR (400 MHz, CD ₃ OD) 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 calcd for C ₃₀ H ₃₀ Cl ₂ N ₅ O ₄ [M + H] ⁺ 594.2, found: 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

This 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 in Example 1. The crude product was purified by preparative 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. ¹ H NMR (400 MHz, CD ₃ OD) 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 calculated for C ₃₂ H ₃₄ Cl ₂ N ₅ O ₅ [M + H] ⁺ 638.2, found: 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

This 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 in Example 1. The crude product was purified by preparative HPLC to give (S)-N-(2,2'-dichloro-3'-(6-ethyl-5-((((5-oxopyrrolidin-2-yl)methyl)amino)methyl)pyridin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. ^1H NMR (400 MHz, CD ₃ OD) 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 (kv, 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 calculated for C ₃₂ H ₃₃ Cl ₂ N ₆ O ₄ [M + H] ⁺ 635.2, found: 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

This 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 in 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-carboxamido)-[1,1'-biphenyl]-3-yl)-3-methoxypyrazin-2-yl)methyl)-3-methylazetidine-3-carboxylic acid acid. ^1H NMR (400 MHz, CD ₃ OD) 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 (brs, 1H), 4.29 - 4.13 (brs, 3H), 4.11 (s, 3H), 3.56 (s, 3H), 3.39 (s, 3H), 1.65 (s, 3H). MS: (ES) m/z calculated for C ₃₀ H ₂₉ Cl ₂ N ₆ O ₆ [M + H] ⁺ 639.1, found: 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

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 NaBH ₃ CN (40 mg, 0.63 mmol) was added. After stirring for 5 min at 0°C, the reaction mixture was evaporated 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. ^1H NMR (400 MHz, CD ₃ OD) 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 calculated for C ₃₀ H ₃₄ N ₅ O ₅ [M + H] ⁺ 544.3, found: 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

Step a. 1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (50.0 g, 271 mmol) and dichloromethane (800 mL) were placed in a 3-L flask. Oxalyl chloride (32 mL, 370 mmol) was added to the resulting suspension, followed by DMF (0.5 mL, 6 mmol). After stirring for 90 min, the resulting yellow solution was evaporated under reduced pressure. The residue was transferred to a 3-L 3-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 dropwise addition of _Et3N (116 mL, 832 mmol). The reaction mixture was stirred for another 13 h. The volatiles were evaporated under reduced pressure and the residue was transferred to a 1 L flask and triturated with 600 mL of water. The resulting suspension was stirred for 1 day, then filtered, washed with water and dried to yield 1,3-dimethyl-N-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. ^1H NMR (400 MHz, CDCl ₃ ) 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 calculated for C ₂₀ H ₂₇ BN ₃ O ₅ [M + H] ⁺ 400.2, found: 400.2.

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 _{K2CO3 (} 48.0 g, 347.8 mmol) in p-dioxane (450 mL) and deionized water (80 mL) was added Pd( _PPh3 ) ₄ (7.4 g, 6.4 mmol). The mixture was degassed and stirred under nitrogen at 92°C for 2 h. The reaction mixture was cooled to room temperature, diluted with dichloromethane (1 L), washed with saturated aqueous sodium chloride solution, dried over _MgSO4 , and filtered. The solvent was removed under reduced pressure, and the residue was triturated with diethyl ether (500 mL). The solid precipitate was isolated by filtration to give 6-(3-bromo-2-chlorophenyl)-2-methoxynicotinaldehyde. MS: (ES) m/z calcd for C ₁₃ H ₁₀ BrClNO ₂ [M + H] ⁺ 326.0, found: 325.9.

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 _K2CO3 (28.4 g, 205.8 mmol) in p-dioxane (500 mL) and deionized water (80 mL) was added Pd(dppf) _Cl2 DCM complex (5.6 g, 6.9 mmol). The mixture was degassed and stirred under nitrogen at 92°C for 3 h. The reaction mixture was cooled to room temperature, filtered through Celite, washed with ethyl acetate (300 mL × 3), and the solvent was removed under reduced pressure. The residue was diluted with dichloromethane, washed with saturated aqueous sodium chloride solution, and dried over MgSO ₄ . The solvent was removed under reduced pressure, the solid residue was triturated with acetonitrile, filtered, and washed with acetonitrile to yield 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 calcd for C ₂₇ H ₂₄ ClN ₄ O ₅ [M + H] ⁺ 519.1, found: 519.1.

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 for 20 min at room temperature, 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 a 2:1 mixture of _CHCl3 and 2-propanol. The organic layer was evaporated to dryness, and the resulting crude product was purified by preparative HPLC to give the desired product (S)-N-(2'-chloro-3'-(5-((3-hydroxy-3-methylpyrrolidin-1-yl)methyl)-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. ¹ H NMR (400 MHz, CD ₃ OD) 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 calculated for C ₃₂ H ₃₅ ClN ₅ O ₅ [M + H] ⁺ 604.2, found: 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

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 in 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. ^1H NMR (400 MHz, CD ₃ OD) 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 calculated for C ₃₂ H ₃₅ FN ₅ O ₆ [M + H] ⁺ 604.3, found: 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

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 in 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, CD ₃ OD) 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 calculated for C ₃₁ H ₃₂ ClN ₆ O ₅ [M + H] ⁺ 603.2, found: 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

This 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 in 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. ^1H NMR (400 MHz, CD ₃ OD) 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 calculated for C ₃₂ H ₃₄ ClN ₆ O ₅ [M + H] ⁺ 617.2, found: 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

This 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 in 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-carboxamido)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)-3-hydroxy-2-methylpropanoic acid. ^1H NMR (400 MHz, CD ₃ OD) 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 calculated for C ₃₀ H ₃₀ Cl ₂ N ₅ O ₇ [M + H] ⁺ 642.2, found: 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

This 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 in 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. ^1H NMR (400 MHz, CD ₃ OD) 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 calculated for C ₃₀ H ₃₁ Cl ₂ N ₆ O ₆ S [M + H] ⁺ 673.1, found: 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

This 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 in 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-carboxamido)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)pyrrolidine-3-carboxylic acid. ^1H NMR (400 MHz, CD ₃ OD) 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 calculated for C ₃₁ H ₃₀ Cl ₂ N ₅ O ₆ [M + H] ⁺ 638.2, found: 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

This 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 in Example 89. The crude product was purified by preparative HPLC to give N-(2,2'-dichloro-3'-(5-((3-hydroxyazetidin-1-yl)methyl)-4-methoxypyridin-2-yl)-[1,1'-biphenyl]-3-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. ^1H NMR (400 MHz, CD ₃ OD) 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 calcd for C ₂₉ H ₂₈ Cl ₂ N ₅ O ₅ [M + H] ⁺ 596.1, found: 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

This 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 in 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, CD ₃ OD) 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 calculated for C ₃₀ H ₃₀ Cl ₂ N ₇ O ₅ [M + H] ⁺ 638.2, found: 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

This 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 in 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-carboxamido)-[1,1'-biphenyl]-3-yl)-4-methoxypyridin-3-yl)methyl)-3-methylazetidine-3-carboxylic acid. ^1H NMR (400 MHz, CD ₃ OD) 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 calculated for C ₃₁ H ₃₀ Cl ₂ N ₅ O ₆ [M + H] ⁺ 638.2, found: 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

This 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 in 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-carboxamido)-[1,1'-biphenyl]-3-yl)-4-methoxypyridin-3-yl)methyl)azetidine-3-carboxylic acid. ^1H NMR (400 MHz, CD ₃ OD) 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 calculated for C ₃₀ H ₂₈ Cl ₂ N ₅ O ₆ [M + H] ⁺ 624.1, found: 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

This 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 in 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. ^1H NMR (400 MHz, CD ₃ OD) 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 calculated for C ₃₁ H ₃₁ Cl ₂ N ₆ O ₅ [M + H] ⁺ 637.2, found: 636.9.

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

This 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 in 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. ^1H NMR (400 MHz, CD ₃ OD) 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 calculated for C ₃₁ H ₃₂ Cl ₂ N ₅ O ₆ [M + H] ⁺ 640.2, found: 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

This 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 in 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. ^1H NMR (400 MHz, DMSO- _d6 ) δ: 11.05 (s, 1H), 8.75 (s, 1H), 8.24 (d, J = 8.0 Hz, 1H), 8.18 (br s, 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 calculated for C ₃₃ H ₃₄ ClN ₆ O ₅ [M + H] ⁺ 629.2, found: 629.0.

Biological example. Enzyme-linked immunosorbent assay (ELISA)

96-well plates were coated with 1 μg/ml human PD-L1 (obtained from R&D) in phosphate-buffered saline (PBS) overnight at 4°C. The wells were then blocked with 2% BSA in PBS (w/v) containing 0.05% TWEEN-20 for 1 h at 37°C. The plates were then washed three times with PBS/0.05% TWEEN-20, and test compounds were serially diluted (1:5) in medium and added to the ELISA plates. Human PD-1 and 0.3 μg/ml biotin (ACRO Biosystems) were added and the plates were incubated for 1 h at 37°C, then washed three times with PBS/0.05% TWEEN-20. A second block was performed with 2% BSA in PBS (w/v)/0.05% TWEEN-20 for 10 min at 37°C, and the plates were washed three times with PBS/0.05% TWEEN-20. Streptavidin-HRP was added for 1 h at 37°C, then the plates were washed three times with PBS/0.05% TWEEN-20. TMB substrate was added and the reaction was carried out for 20 min at 37°C. Stop solution (2 N aqueous _H2SO4 ) _was added. Absorbance was read at 450 nm using a microplate reader. The results are shown in Table 1. _IC50 values are given as follows: 1000 to 10000 nM (+); 10 to 1000 nM (++); less than 10 nM (+++).

Table 1

Compound Structure ELISA IC ₅₀ 1.001 +++ 1.002 +++ 1.003 +++ 1.004 +++ 1.005 +++ 1.006 +++ 1.007 +++ 1.008 +++ 1.009 +++ 1.010 +++ 1.011 +++ 1.012 +++ 1.013 +++ 1.014 +++ 1.015 +++ 1.016 +++ 1.017 +++ 1.018 +++ 1.019 +++ 1.020 +++ 1.021 +++ 1.022 + 1.023 +++ 1.024 +++ 1.025 +++ 1.026 +++ 1.027 +++ 1.028 +++ 1.029 +++ 1.030 +++ 1.031 +++ 1.032 +++ 1.033 ++ 1.034 +++ 1.035 +++ 1.036 +++ 1.037 +++ 1.038 +++ 1.039 +++ 1.040 +++ 1.041 +++ 1.042 +++ 1.043 +++ 1.044 +++ 1.045 +++ 1.046 +++ 1.047 +++ 1.048 +++ 1.049 +++ 1.050 +++ 1.051 +++ 1.052 +++ 1.053 +++ 1.054 +++ 1.055 +++ 1.056 +++ 1.057 +++ 1.058 ++ 1.059 +++ 1.060 +++ 1.061 +++ 1.062 +++ 1.063 +++ 1.064 +++ 1.065 +++ 1.066 +++ 1.067 +++ 1.068 +++ 1.069 +++ 1.070 +++ 1.071 +++ 1.072 ++ 1.073 +++ 1.074 +++ 1.075 +++ 1.076 +++ 1.077 +++ 1.078 +++ 1.079 +++ 1.080 ++ 1.081 +++ 1.082 +++ 1.083 +++ 1.084 +++ 1.085 +++ 1.086 +++ 1.087 +++ 1.088 +++ 1.089 +++ 1.090 +++ 1.091 +++ 1.092 +++ 1.093 +++ 1.094 +++ 1.095 +++ 1.096 +++ 1.097 +++ 1.098 +++ 1.099 +++ 1.100 +++ 1.101 +++ 1.102 +++

This text describes specific embodiments of the invention, including the best mode for carrying out the invention known to the inventors. Upon reading the above description, variations of the described embodiments may be apparent to those skilled in the art, and a skilled person would be expected to be able to properly apply such variations. Accordingly, the present invention may be practiced in a manner different from the specific embodiments described herein, and the present invention includes all modifications and equivalents of the subject matter of the invention characterized in the appended claims, within the scope of applicable law. Furthermore, any combination of the above-described elements in all their possible variations is included in the present invention, unless otherwise specifically indicated or clearly contradicted by the context.

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

Claims (210)

1. A compound having the formula (I): or a pharmaceutically acceptable salt thereof, where: A is a 6-membered heteroaryl group containing 1 or 2 N heteroatoms, which is unsubstituted or has from one to five substituents independently selected from the group consisting of C _1-3 alkyl, C _1-3 haloalkyl and C _1-3 alkoxy; X ¹ is C _1-3 alkylene; R ^2a and R ^2b are each independently selected from the group consisting of H, C _1-8 alkyl, -Y, -X ² -CO ₂ R ^a , -X ² -OR ^a , -X ² -C(O)NR ^a R ^b and -X ² -Y, where each X ² is C _1-6 alkylene, and any C _1-8 alkyl or C _1-6 alkylene is unsubstituted or has one to two substituents independently selected from the group consisting of OH and CO ₂ H, and each Y is selected from the group consisting of C _3-6 cycloalkyl, C _4-8 heterocyclyl containing heteroatoms selected from N and O , each of which is unsubstituted or has one to four substituents independently selected from the group consisting of oxo, OH, and C _1-4 alkyl; or R ^2a and R ^2b are combined to form a 4-9 membered ring or a spirocyclic ring containing in the ring from 0 to 2 additional heteroatoms selected from N; wherein the 4-9 membered ring or spirocyclic ring formed by combining R ^2a and R ^2b is unsubstituted or has from 1 to 4 substituents independently selected from the group consisting of oxo, C _1-8 alkyl, C _1-8 hydroxyalkyl, -X ³ -CO ₂ R ^a , and -X ³ -OR ^a , where X ³ is a bond; R ³ and R ⁴ are each independently selected from the group consisting of F, Cl, and CH ₃ ; subscript n is 0, 1, 2, or 3; each R ^3a represents independently H; R ⁶ , R ⁷ , and R ⁸ each independently represent H; Z is selected from the group consisting of: each R ^a is independently selected from the group consisting of H and C _1-6 alkyl; and each R ^b is independently selected from the group consisting of H and C _1-6 alkyl. 2. The compound according to claim 1, having formula (Ia): or a pharmaceutically acceptable salt thereof. 3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein A is a 6-membered heteroaryl group that is unsubstituted or has one to three substituents independently selected from the group consisting of C _1-3 alkyl, C _1-3 haloalkyl, and C _1-3 alkoxy. 4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein A is a 6-membered heteroaryl group that is unsubstituted or has one to three substituents independently selected from the group consisting of C _1-3 alkyl and C _1-3 alkoxy. 5. The compound according to claim 1, having the formula (Ib): or a pharmaceutically acceptable salt thereof. 6. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein A is unsubstituted or has one to two substituents independently selected from the group consisting of OCH ₃ and -CH ₂ CH ₃ . 7. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein A is a 6-membered heteroaryl selected from the group consisting of pyridine, pyrimidine, pyrazine, each of which is unsubstituted or has one to two substituents independently selected from the group consisting of OCH ₃ and -CH ₂ CH ₃ . 8. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein -N(R ^2a )(R ^2b ) is selected from the group consisting of: 9. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein -N(R ^2a )(R ^2b ) is selected from the group consisting of: . 10. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein -N(R ^2a )(R ^2b ) is selected from the group consisting of: . 11. The compound of claim 1, wherein the compound is an optically pure or enriched isomer, or a pharmaceutically acceptable salt thereof. 12. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Y is selected from the group consisting of C _3-6 cycloalkyl and C _4-8 heterocyclyl, each of which is unsubstituted or has from one to four substituents independently selected from the group consisting of oxo group and OH. 13. A compound selected from the group consisting of , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , And , or a pharmaceutically acceptable salt thereof. 14. The compound of claim 13, selected from the group consisting of And or a pharmaceutically acceptable salt thereof. 15. The compound of claim 13, wherein the compound is or a pharmaceutically acceptable salt thereof. 16. The compound of claim 13, wherein the compound is or a pharmaceutically acceptable salt thereof. 17. The compound of claim 13, wherein the compound is or a pharmaceutically acceptable salt thereof. 18. The compound of claim 13, wherein the compound is or a pharmaceutically acceptable salt thereof. 19. The compound of claim 13, wherein the compound is or a pharmaceutically acceptable salt thereof. 20. The compound of claim 13, wherein the compound is or a pharmaceutically acceptable salt thereof. 21. The compound of claim 13, wherein the compound is or a pharmaceutically acceptable salt thereof. 22. The compound of claim 13, wherein the compound is or a pharmaceutically acceptable salt thereof. 23. The compound of claim 13, wherein the compound is or a pharmaceutically acceptable salt thereof. 24. A pharmaceutical composition for inhibiting PD-L1, comprising an effective amount of a compound according to any one of claims 1-23 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. 25. The pharmaceutical composition of claim 24, further comprising one or more additional therapeutic agents. 26. The pharmaceutical composition of claim 25, wherein said one or more therapeutic agents are selected from the group consisting of an antimicrobial agent, an antiviral agent, a cytotoxic agent, a gene expression modulating agent, a chemotherapeutic agent, an anticancer agent, an antiangiogenic agent, an immunotherapeutic agent, an antihormonal agent, an antifibrotic agent, a radiation therapy agent, an agent for radiation therapy, an antitumor agent, and an antiproliferative agent. 27. A method for modulating an immune response in a subject mediated through the PD-1 signaling pathway, comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1-23 or a pharmaceutically acceptable salt thereof, or a composition according to any one of claims 24-26. 28. A method for enhancing, stimulating, modulating and/or increasing an immune response in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1-23 or a pharmaceutically acceptable salt thereof, or a composition according to any one of claims 24-26. 29. A method for suppressing 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 according to any one of claims 1-23 or a pharmaceutically acceptable salt thereof, or a composition according to any one of claims 24-26. 30. A method of treating a subject suffering from or susceptible to a disease or disorder involving the PD-1 signaling pathway, comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1-23 or a pharmaceutically acceptable salt thereof, or a composition according to any one of claims 24-26. 31. The method of claim 27, wherein the subject suffers from a disease or disorder selected from the group consisting of an infectious disease, a bacterial infectious disease, a viral infectious disease, a fungal infectious disease, a solid tumor, a hematological malignancy, an immune disorder, an inflammatory disease, and cancer. 32. The method of claim 30, wherein the disease or disorder is selected from the group consisting of the following: melanoma, glioblastoma, esophageal cancer, nasopharyngeal cancer, 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 myelocytic leukemia, Kaposi's sarcoma, fibrosarcoma, liposarcoma, chondrosarcoma, osteosarcoma, angiosarcoma, lymphangiosarcoma, synovioma, meningioma, leiomyosarcoma, rhabdomyosarcoma, soft tissue sarcoma, sarcoma, sepsis, gallbladder cancer bladder, basal cell carcinoma, thymus cancer, thyroid cancer, parathyroid cancer, uterine cancer, adrenal cancer, liver infection, Merkel cell carcinoma, nervous system cancer, follicular center cell lymphoma, colon cancer, Hodgkin's lymphoma, non-Hodgkin's lymphoma, leukemia, chronic or acute leukemia, acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphoblastic leukemia, multiple myeloma, ovarian cancer, myelodysplastic syndrome, cutaneous or intraocular malignant melanoma, renal cell carcinoma, small cell lung cancer, lung cancer, mesothelioma, breast cancer, squamous cell non-small cell lung cancer, non-squamous cell non-small cell lung cancer, colorectal cancer, ovarian cancer, stomach cancer, Hepatocellular carcinoma, pancreatic carcinoma, pancreatic cancer, pancreatic ductal adenocarcinoma, squamous cell carcinoma of the head and neck, head and neck cancer, gastrointestinal cancer, stomach cancer, HIV, hepatitis A, hepatitis B, hepatitis C, hepatitis D, herpes virus, human papillomavirus, influenza, bone cancer, skin cancer, rectal cancer, anal cancer, testicular cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, esophageal cancer, small bowel cancer, endocrine cancer, urethral cancer, penile cancer, bladder cancer, kidney cancer, urethral cancer, renal pelvis cancer, central nervous system (CNS) neoplasms, tumor angiogenesis, spinal axis cancer, brain stem glioma, pituitary adenoma, epidermoid carcinoma, asbestosis, Carcinoma, adenocarcinoma, papillary carcinoma, cystadenocarcinoma, bronchogenic carcinoma, renal cell carcinoma, transitional cell carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, pleomorphic adenoma, liver cell papilloma, renal tubular adenoma, cystadenoma, papilloma, adenoma, leiomyoma, rhabdomyoma, hemangioma, lymphangioma, osteoma, chondroma, lipoma, and fibroma. 33. The method of claim 30, further comprising administering to the subject a therapeutically effective amount of one or more additional therapeutic agents. 34. The method of claim 33, wherein one or more additional therapeutic agents are selected from the group consisting of an antimicrobial agent, an antiviral agent, a cytotoxic agent, a gene expression modulating agent, a chemotherapeutic agent, an anticancer agent, an antiangiogenic agent, an immunotherapeutic agent, an antihormonal agent, an antifibrotic agent, a radiation therapy agent, a radiotherapy agent, an antitumor agent, and an antiproliferative agent. 35. A method for producing a compound having formula (II), which includes: (a) contacting a compound having formula (2c) with a compound having formula (2d) and a first catalyst under Suzuki coupling conditions to produce a compound having formula (2e); (b) converting a compound having formula (2e) into a compound having formula (2f) by reaction with a borate reagent and a second catalyst; (c) contacting a compound of formula (2f) with a compound of formula (2g) and a third catalyst under Suzuki coupling conditions to produce a compound of formula (2h); (d) reductive amination of a compound having formula (2h) with a reagent HN(R ^2a )(R ^2b ) and a hydride reagent to obtain a compound having formula (II), where in formulas (2c), (2d), (2e), (2f), (2h) and (II) each of Z, R ^2a , R ^2b , R ³ , R ^3a , subscript n, R ⁴ , R ⁶ , R ⁷ , and R ⁸ have the meanings specified in paragraph 1; R and R' are each independently selected from the group consisting of H and C ₁ -C ₆ alkyl; X is a substituent selected from the group consisting of Br and Cl; X' is a substituent selected from the group consisting of I, Br, and Cl; and the ring containing R ^s is a 6-membered nitrogen-containing heteroaryl ring selected from the group consisting of pyridine, pyrimidine, and pyrazine, and R ^s is 0, 1, 2, or 3 substituents independently selected from the group consisting of C _1-3 alkyl, C _1-3 haloalkyl, and C _1-3 alkoxy. 36. A method for producing a compound having formula (II), including: (a) contacting a compound having formula (2a1) with a compound having formula (2b1) and a first catalyst under Suzuki coupling reaction conditions to obtain a compound having formula (2c1); (b) contacting a compound having formula (2c1) with a compound having formula (2d1) and a second catalyst under Suzuki coupling conditions to obtain a compound having formula (2e1); (c) reductive amination of a compound having formula (2e1) with a reagent HN(R ^2a )(R ^2b ) and a hydride reagent to obtain a compound having formula (II), where in formulas (2a1), (2b1), (2c1), (2d1), (2e1) and (II), each of Z, R ^2a , R ^2b , R ³ , R ^3a , subscript n, R ⁴ , R ⁶ , R ⁷ , and R ⁸ have the meanings specified in paragraph 1; R and R' are each independently selected from the group consisting of H and C ₁ -C ₆ alkyl; X' is a substituent selected from the group consisting of I, Br and Cl; and the ring containing R ^s is a 6-membered nitrogen-containing heteroaryl ring selected from the group consisting of pyridine, pyrimidine, and pyrazine, and R ^s is 0, 1, 2, or 3 substituents independently selected from the group consisting of C _1-3 alkyl, C _1-3 haloalkyl, and C _1-3 alkoxy.