Heteroaryl benzidines for the treatment of pd-l1 diseases

Abstract

Compounds useful as immunomodulators are provided. The compounds have the formula (I), including stereoisomers and pharmaceutically acceptable salts thereof, wherein R 2a ,R 2b ,R 3 ,R 3a ,R 4 ,R 6 ,R 7 ,R 8 ,A,Z,X 1 and n are as defined herein. Also disclosed are methods relating to the preparation and use of such compounds, as well as pharmaceutical compositions comprising such compounds.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Application No. 62 / 915,771, filed on October 16, 2019, the disclosure of which is incorporated herein by reference in its entirety.

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

[0004] not applicable

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

[0006] not applicable Background of the Invention

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

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

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

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

[0013]

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

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

[0017] not applicable. Detailed Description of the Invention

[0019] Abbreviations and definitions

[0020] As used herein, the terms "a," "an," or "the" include not only aspects having one member, but also aspects having multiple members. As used herein, the singular forms "a," "an," and "the" include the plural forms unless the context clearly dictates otherwise. Thus, for example, reference to "a cell" includes a plurality of such cells, reference to "an agent" includes reference to one or more agents known to those skilled in the art, and so forth.

[0021] The terms "about" and "approximately" generally refer to an acceptable degree of error in a measured quantity given the nature or precision of the measurement. Typical exemplary degrees of error are within 20 percent (%) of a given value or range of values, preferably within 10%, and more preferably within 5%. Alternatively, particularly in biological systems, the terms "about" and "approximately" can refer to values ​​that are within an order of magnitude, preferably within 5 times, and more preferably within 2 times, of a given value. Unless otherwise indicated, numerical quantities given herein are approximate, meaning that the term "about" or "approximately" can be inferred where not expressly stated.

[0022] Unless otherwise indicated, the term "alkyl" by itself or as part of another substituent refers to a straight or branched chain hydrocarbon radical having the specified number of carbon atoms (i.e., C 1-8 = represents 1-8 carbons). Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, etc. The term "alkenyl" refers to an unsaturated alkyl group having one or more double bonds. Similarly, the term "alkynyl" refers to an unsaturated alkyl group having one or more triple bonds. Examples of alkenyl groups include vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, and 3-(1,4-pentadienyl). Examples of alkynyl groups include ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologs and isomers. The term "cycloalkyl" refers to a hydrocarbon ring (e.g., C 4-C ... 3-6 Cycloalkyl) and is fully saturated or has no more than one double bond between the ring vertices. "Cycloalkyl" also means bicyclic and polycyclic hydrocarbon rings, such as bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, etc. The bicyclic or polycyclic rings can be fused, bridged, spirocyclic, or a combination thereof. The term "heterocycloalkyl" or "heterocyclyl" refers to a cycloalkyl group containing 1 to 5 heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen atom is optionally quaternized. Heterocycloalkyl can be a monocyclic, bicyclic, or polycyclic ring system. The bicyclic or polycyclic rings can be fused, bridged, spirocyclic, or a combination thereof. It should be understood that C 4-12The description of heterocyclyl refers to a group having 4 to 12 ring members, at least one of which is a heteroatom. Non-limiting examples of heterocycloalkyl include pyrrolidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolinone, tetrazolone, hydantoin, dioxolane, phthalimide, piperidine, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S,S-oxide, piperazine, pyran, pyridone, 3-pyrroline, thiopyran, pyrone, tetrahydrofuran, tetrahydrothiophene, quinuclidine, etc. The heterocycloalkyl group can be attached to the rest of the molecule through a ring carbon or a heteroatom.

[0023] The term "alkylene" by itself or as part of another substituent refers to a divalent group derived from an alkane, for example -CH2CH2CH2CH2-. Alkylene can be straight or branched. Examples of the latter are -CH2C(CH3)2CH2-, -CH2C(CH3)2-, or -CH(CH3)CH2CH2-. Typically, an alkyl (or alkylene) group will have from 1 to 12 carbon atoms, with those having 8 or fewer carbon atoms being preferred in the present disclosure. Similarly, "alkenylene" and "alkynylene" refer to unsaturated forms of "alkylene" having double or triple bonds, respectively.

[0024] Unless otherwise indicated, the term "heteroalkyl" by itself or in combination with another term refers to a stable straight or branched chain or cyclic hydrocarbon radical, or combinations thereof, consisting of the recited number of carbon atoms and one to three heteroatoms selected from O, N, Si, and S, wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. The heteroatoms O, N, and S may be located at any interior position of the heteroalkyl radical. The heteroatom Si may be located at any position of the heteroalkyl radical, including the position at which the alkyl radical is attached to the rest of the molecule. Examples include -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2, -S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, and -CH=CH-N(CH3)-CH3. Up to two heteroatoms may be consecutive, for example -CH2-NH-OCH3 and -CH2-O-Si(CH3)3. Similarly, unless otherwise indicated, the terms "heteroalkenyl" and "heteroalkynyl," by themselves or in combination with another term, refer to alkenyl or alkynyl groups, respectively, containing the recited number of carbon atoms and having one to three heteroatoms selected from O, N, Si, and S, wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. The heteroatoms O, N, and S may be placed at any interior position of the heteroalkyl group.

[0025] The term "heteroalkylene" by itself or as part of another substituent refers to a saturated or unsaturated or polyunsaturated divalent radical derived from heteroalkyl, for example, -CH2-CH2-S-CH2CH2- and -CH2-S-CH2-CH2-NH-CH2-, -O-CH2-CH=CH-, -CH2-CH=C(H)CH2-O-CH2-, and -S-CH2-C≡C-. For heteroalkylene, heteroatoms can also occupy one or both chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, etc.).

[0026] The terms "alkoxy," "alkylamino," and "alkylthio" (or thioalkoxy) are used in their conventional sense to refer to those alkyl groups that are attached to the remainder of the molecule through an oxygen atom, an amino group, or a sulfur atom. In addition, for dialkylamino groups, the alkyl moieties may be the same or different and may be combined with each nitrogen atom to form a 3-7 membered ring. Thus, the group represented by -NR a R b The group is meant to include piperidinyl, pyrrolidinyl, morpholinyl, azetidinyl and the like.

[0027] Unless otherwise indicated, the term "halo" or "halogen" by themselves or as part of another substituent refers to a fluorine, chlorine, bromine, or iodine atom. In addition, terms such as "haloalkyl" are meant to include monohaloalkyl and polyhaloalkyl. For example, the term "C 1-4 "Haloalkyl" is meant to include trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

[0028] The term "hydroxyalkyl" or "alkyl-OH" refers to an alkyl group as defined above in which at least one (and up to three) hydrogen atoms are replaced by a hydroxy group. As with alkyl, the hydroxyalkyl group may have any suitable number of carbon atoms, such as C 1-6 Exemplary hydroxyalkyl groups include, but are not limited to, hydroxymethyl, hydroxyethyl (wherein the hydroxyl group is at the 1 or 2 position), hydroxypropyl (wherein the hydroxyl group is at the 1, 2, or 3 position), and 2,3-dihydroxypropyl.

[0029] The term "C 1-3 "Alkyl-guanidino" refers to a C 1-3 An alkyl group in which at least one hydrogen atom is replaced by a guanidino group (-NHC(NH)NH2).

[0030] Unless otherwise indicated, the term "aryl" refers to a polyunsaturated, typically aromatic hydrocarbon radical which may be a single ring or multiple rings (up to three rings) fused together or linked covalently. The term "heteroaryl" refers to an aryl group (or ring) containing from one to five heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen atom is optionally quaternized. A heteroaryl group may be attached to the rest of the molecule through a heteroatom. It is understood that C 5-10 The recitation of heteroaryl refers to heteroaryl moieties having from 5 to 10 ring members, at least one of which is a heteroatom. Non-limiting examples of aryl groups include phenyl, naphthyl, and biphenyl, while non-limiting examples of heteroaryl groups include pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, quinolinyl, quinoxalinyl, quinazolinyl, cinnamyl, phthalazinyl, benzotriazinyl, purinyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl, benzisoxazolyl, isobenzofuranyl, isoindolyl, indolizinyl, benzotriazinyl, thienopyridinyl, thienopyrimidinyl, pyrazolopyrimidinyl, imidazopyridine, benzothiazolyl, benzofuranyl, benzothiophenyl, indolyl, quinolinyl, isoquinolinyl, isothiazolyl, pyrazolyl, indazolyl, pteridinyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiadiazolyl, pyrrolyl, thiazolyl, furanyl, thienyl, and the like. Substituents for each of the above noted aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below.

[0031] The term "carbocyclic ring" or "carbocyclyl" refers to a cyclic moiety having only carbon atoms as ring vertices. The carbocyclic moiety is saturated or unsaturated and can be aromatic. Typically, the carbocyclic moiety has 3 to 10 ring members. Carbocyclic moieties with polycyclic structures (e.g., bicyclic) can include cycloalkyl rings fused to aromatic rings (e.g., 1,2,3,4-tetrahydronaphthalene). Thus, carbocyclic rings include cyclopentyl, cyclohexenyl, naphthyl, and 1,2,3,4-tetrahydronaphthyl. The term "heterocycle" refers to "heterocycloalkyl" and "heteroaryl" moieties. Thus, heterocycles are saturated or unsaturated and can be aromatic. Typically, heterocycles have 4 to 10 ring members and include piperidinyl, tetrazinyl, pyrazolyl, and indolyl.

[0032] When any of the above terms (eg, "alkyl," "aryl," and "heteroaryl") are referred to as "substituted" without further specification of the substituents, substituted versions of the indicated groups are provided below.

[0033] Substituents for alkyl groups (including those groups commonly referred to as alkylene, alkenyl, alkynyl, and cycloalkyl) may be a variety of groups selected from the group consisting of: -halogen, -OR', -NR'R", -SR', -SiR'R"R"', -OC(O)R', -C(O)R', -C02R', -CONR'R", -OC(O)NR'R", -NR"C(O)R', -NR'-C(O)NR"R"', -NR"C R', -NH-C(NH2)=NH, -NR'C(NH2)=NH, -NH-C(NH2)=NR', -S(O)R', -S(O)2R', -S(O)2NR'R", -NR'S(O)2R", -CN and -NO2, ranging in number from zero to (2m'+1), where m' is the total number of carbon atoms in such a group. R', R" and R'"' each independently refer to hydrogen, unsubstituted C 1-8 Alkyl, unsubstituted heteroalkyl, unsubstituted aryl, aryl substituted with 1-3 halogens, unsubstituted C 1-8 Alkyl, C 1-8 Alkoxy or C 1-8 Thioalkoxy group, or unsubstituted aryl-C 1-4 Alkyl. When R' and R" are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 3-, 4-, 5-, 6-, or 7-membered ring. For example, -NR'R" is meant to include 1-pyrrolidinyl and 4-morpholinyl. The term "acyl" used alone or as part of another group refers to an alkyl group in which both substituents on the carbon closest to the point of attachment of the group are replaced by the substituent =0 (e.g., -C(O)CH3, -C(O)CH2CH2OR', etc.).

[0034] Similarly, the substituents for aryl and heteroaryl groups are varied and are generally selected from: -halogen, -OR', -OC(O)R', -NR'R", -SR', -R', -CN, -NO2, -CO2R', -CONR'R", -C(O)R', -OC(O)NR'R", -NR"C(O)R', -NR"C(O)2R', -NR'-C(O)NR"R"', -NH -C(NH2)=NH, -NR'C(NH2)=NH, -NH-C(NH2)=NR', -S(O)R', -S(O)2R', -S(O)2NR'R", -NR'S(O)2R", -N3, perfluoro(C1-C4)alkoxy and perfluoro(C1-C4)alkyl, in a number ranging from zero to the total number of open valences on the aromatic ring system; wherein R', R" and R'"' are independently selected from hydrogen, C 1-8 Alkyl, C 3-6 Cycloalkyl, C 2-8 Alkenyl, C 2-8Alkynyl, unsubstituted aryl and heteroaryl, (unsubstituted aryl)-C 1-4 Alkyl and unsubstituted aryloxy-C 1-4 Other suitable substituents include each of the above-mentioned aryl substituents attached to a ring atom via an alkylene chain of 1 to 4 carbon atoms.

[0035] Two substituents on adjacent atoms of an aryl or heteroaryl ring may optionally be replaced by groups of the formula -TC(O)-(CH2) q -U-, wherein T and U are independently -NH-, -O-, -CH2- or a single bond, and q is an integer from 0 to 2. Alternatively, two substituents on adjacent atoms of the aryl or heteroaryl ring may be optionally replaced by a substituent of the formula -A-(CH2) r -B-, wherein A and B are independently -CH2-, -O-, -NH-, -S-, -S(O)-, -S(O)2-, -S(O)2NR'- or a single bond, and r is an integer from 1 to 3. One of the single bonds of the new ring thus formed may optionally be replaced by a double bond. Alternatively, two substituents on adjacent atoms of the aryl or heteroaryl ring may be optionally substituted by substituents of the formula -(CH2) s -X-(CH2) t -, wherein s and t are independently integers from 0 to 3, and X is -O-, -NR'-, -S-, -S(O)-, -S(O)2- or -S(O)2NR'-. The substituent R' in -NR'- and -S(O)2NR'- is selected from hydrogen or unsubstituted C 1-6 alkyl.

[0036] As used herein, the term "heteroatom" is meant to include oxygen (O), nitrogen (N), sulfur (S), and silicon (Si).

[0037] The disclosure herein further relates to prodrugs and bioisosteres thereof. For example, suitable bioisosteres will include carboxylate surrogates (phosphonic acid, phosphinic acid, sulfonic acid, sulfinic acid and acidic heterocyclic groups, such as tetrazole). Suitable prodrugs will include those conventional groups that are known to hydrolyze and / or oxidize under physiological conditions to provide compounds of Formula I.

[0038] The terms "patient" and "subject" include primates (particularly humans), domesticated companion animals (eg, dogs, cats, horses, etc.), and livestock (eg, cattle, pigs, sheep, etc.).

[0039] As used herein, the terms "treating" or "treatment" include disease-modifying treatment and symptomatic treatment, either of which can be prophylactic (i.e., prior to the onset of symptoms, to prevent, delay or lessen the severity of symptoms) or therapeutic (i.e., after symptoms have appeared, to lessen the severity and / or duration of symptoms).

[0040] The term "pharmaceutically acceptable salt" is intended to include salts of the active compounds prepared with relatively nontoxic acids or bases, depending on the specific substituents found on the compounds described herein. When the compounds of the present disclosure contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either pure or in a suitable inert solvent. Examples of salts derived from pharmaceutically acceptable inorganic bases include aluminum, ammonium, calcium, copper, iron, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc, and the like. Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary, and tertiary amines, including substituted amines, cyclic amines, naturally occurring amines, and the like, for example, arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, hepamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like. When compounds of the present disclosure contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid or phosphorous acid, and salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, and the like. Also included are salts of amino acids such as arginine, and salts of organic acids such as glucuronic acid or galacturonic acid (see, for example, Berge, SM et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds of the present disclosure contain both basic and acidic functional groups, which allow the compounds to be converted into base or acid addition salts.

[0041] The neutral forms of the compounds can be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but for the purposes of this disclosure, the salts are equivalent to the parent form of the compound.

[0042] Certain compounds of the present disclosure may exist in unsolvated forms as well as solvated forms, including hydrated forms. Generally, solvated forms are equivalent to unsolvated forms and are intended to be included within the scope of the present disclosure. Certain compounds of the present disclosure may exist in a variety of crystalline or amorphous forms. Generally speaking, all physical forms are equivalent for the purposes contemplated by the present disclosure and are intended to fall within the scope of the present disclosure.

[0043] Certain compounds of the present invention have asymmetric carbon atoms (optical centers) or double bonds; racemates, diastereomers, geometric isomers, regioisomers, and individual isomers (e.g., individual enantiomers) are all intended to be encompassed within the scope of the present invention. When a stereochemical description is shown, it is intended to refer to a compound in which one isomer is present and substantially free of the other isomer. "Substantially free" of the other isomer means that the ratio of the two isomers is at least 80 / 20, more preferably 90 / 10, or 95 / 5 or higher. In some embodiments, one isomer will be present in an amount of at least 99%.

[0044] The compounds of the present disclosure may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, radioactive isotopes such as tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C) Radiolabeling the compound. All isotopic variants of the compounds of the present disclosure, whether radioactive or not, are intended to be encompassed within the scope of the present disclosure. For example, a compound can be prepared such that any number of hydrogen atoms are replaced by deuterium ( 2 H) isotope substitution. The compounds of the present disclosure may also contain unnatural proportions of atomic isotopes at one or more atoms that constitute such compounds. An unnatural proportion of an isotope can be defined as the amount from that found in nature to that consisting of 100% of the atoms in question. For example, a compound may contain a radioactive isotope, such as tritium ( 3 H), iodine 125 ( 125 I) or carbon 14 ( 14 C), or non-radioactive isotopes such as deuterium ( 2 H) or carbon 13 ( 13 C). Such isotopic variations may provide additional utility to those described elsewhere in this application. For example, isotopic variants of the compounds of the present disclosure may find additional uses, including but not limited to, as diagnostic and / or imaging agents, or as cytotoxic / radiotoxic therapeutic agents. In addition, isotopic variants of the compounds of the present disclosure may have altered pharmacokinetic and pharmacodynamic characteristics, which may help improve safety, tolerability, or efficacy during treatment. All isotopic variants of the compounds of the present disclosure, whether radioactive or not, are intended to be encompassed within the scope of this disclosure.

[0045] Compound

[0046] In one aspect, provided herein are compounds of Formula (I) or a pharmaceutically acceptable salt, prodrug, or solvate thereof:

[0047] Bioisostere:

[0048]

[0049] wherein:

[0050] A is 5- to 10-membered heteroaryl, which is unsubstituted or substituted with 1 to 5 members independently selected from the group consisting of halogen, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, OH, and CN;

[0051] X 1 is C 1-3 alkylene, which is unsubstituted or substituted with one or two members independently selected from the group consisting of C 1-2 alkyl and CO2H;

[0052] 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 -CO2R a , -X 2 -OR a , -X 2 -NR a R b , -X 2 -C(O)NR a R b , -X 2 -SO2R a , -X 2 -SO2NR a R b , -X 2 -SO3R a and -X 2 -Y, wherein each X 2 is C 1-6 alkylene and any C 1-8 alkyl or C 1-6 alkylene is unsubstituted or substituted with one or two members independently selected from the group consisting of OH, SO2NH2, C(O)NH2, C(O)NHOH, PO3H2, CO2C 1-8Alkyl and CO2H, each Y is selected from the group consisting of: C 3-6 Cycloalkyl, C 4-8 Heterocyclyl and 5- to 6-membered heteroaryl, each of which is unsubstituted or substituted by one to four substituents independently selected from the group consisting of oxo, OH, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 1-4 Hydroxyalkoxy, SO2NH2, C(O)NH2, C(O)NHOH, PO3H2, CO2C 1-8 Alkyl, SO3H and CO2H;

[0053] or R 2a and R 2b Combined to form a 4- to 9-membered ring or spirocycle, having zero to two additional heteroatom ring vertices selected from O, N, and S;

[0054] By combining R 2a and R 2b The formed ring is unsubstituted or substituted by 1 to 4 substituents independently selected from the group consisting of oxo, C 1-8 Alkyl, C 1-8 Halogenated alkyl, C 1-8 Hydroxyalkyl, -X 3 -CO2R a 、-X 3 -OR a , -X 3 -NR a R b ,

[0055] -X 3 -C(O)NR a R b 、-X 3 -SO2R a 、-X 3 -SO2NR a R b and -X 3 -SO3R a ; where X 3 is key or C 1-6 alkylene;

[0056] R 3 and R 4 Each independently selected from the group consisting of H, F, Cl, CN, CH3, OCH3, CH2CH3 and CF3;

[0057] Subscript n is 0, 1, 2, or 3;

[0058] Each R 3a Independently selected from the group consisting of H, F, Cl, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Halogenated alkoxy, C 2-3 alkenyl and CN;

[0059] R 6 、R 7 and R 8 Each independently selected from the group consisting of H, F, Cl, CN, CH3, OCH3, CH2CH3 and CF3;

[0060] Z is a fused bicyclic heteroaromatic ring, unsubstituted or substituted with 1-3 R c replace;

[0061] Each R a Independently selected from the group consisting of H, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkylene -CO2H and C 1-6 Alkylene-SO3H;

[0062] Each R b Independently selected from the group consisting of H, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkylene -CO2H and C 1-6 Alkylene -SO3H, each of which is unsubstituted or substituted by one or two members independently selected from the group consisting of OH, SO2NH2, C(O)NH2, C(O)NHOH, PO3H2, CO2C l-8 Alkyl and CO2H;

[0063] And, R a and R b When attached to the same nitrogen atom, they are optionally combined to form a 4- to 8-membered ring or spirocyclic ring, which is unsubstituted or substituted with halogen, OH, SO2NH2, C(O)NH2, C(O)NHOH, PO3H2, CO2C 1-8 Alkyl or CO2H substitution;

[0064] Each R c Independently selected from the group consisting of H, halogen, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -Y 1、-X 4 -CO2R a 、-OX 4 -CO2R a 、-X 4 -OR a 、-X 4 -NR a R b 、-X 4 -C(O)NR a R b 、-OX 4 -C(O)NR a R b 、-X 4 -SO2R a 、-X 4 -SO2NR a R b 、-X 4 -SO3R a and -N(R a )-X 4 -CO2R a , where each X 4 For key or C 1-6 Alkylene, each Y 1 Select from the following group: C 3-6 Cycloalkyl and C 4-8 heterocyclyl; and optionally, two R on adjacent ring vertices c Combine to form a fused 5- or 6-membered heterocyclic ring.

[0065] In some embodiments, the present disclosure provides compounds of formula (I) represented by formula (Ia):

[0066]

[0067] The group R 2a 、R 2b 、R 3 、R 4 , A, X 1 and Z have the meanings provided in formula (I).

[0068] In some embodiments, the present disclosure provides compounds of formula (I) represented by formula (Ib):

[0069]

[0070] The group R 2a 、R 2b 、R 3 、R 4 , A and Z have the meanings provided in formula (I).

[0071] In some selected embodiments, compounds of Formula (I), (Ia), or (Ib) are those wherein Z is a fused bicyclic heteroaromatic ring having a formula selected from the group consisting of:

[0072]

[0073] In some selected embodiments, the compound of formula (I), (Ia) or (Ib) is wherein Z is a monocyclic 5 or 6 membered heteroaryl ring, optionally substituted by 1 to 3 R c Those compounds substituted; the heterocycle is selected from the group consisting of pyridyl, pyrimidinyl, pyrazinyl, oxazolyl, thiazolyl and pyrazolyl.

[0074] In some embodiments, the A group is unsubstituted or substituted with one or two members independently selected from the group consisting of CF3, OH, Et, CN, OCH3, and F. In some embodiments, the A group is unsubstituted or substituted with one or two members independently selected from the group consisting of OCH3 and F.

[0075] In selected embodiments, including any of the above embodiments for compounds of formula (I), (Ia) or (Ib), further embodiments are those wherein group A is a 5- or 6-membered heteroaryl group and is unsubstituted or substituted with one or two substituted alkyl radicals independently selected from halogen, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 In selected embodiments, including any of the embodiments described above for compounds of formula (I), (Ia), or (Ib), further embodiments are those wherein group A is a 5- or 6-membered heteroaryl group and is unsubstituted or substituted with one or two members independently selected from the group consisting of halogen, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 In selected embodiments, including any of the embodiments described above for compounds of 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 substituted with one or two members independently selected from OCH3 and F.

[0076] In selected embodiments, including any of the above embodiments for compounds of formula (I), (Ia), or (Ib), further embodiments are those wherein group A is a 6-membered heteroaryl group, which is unsubstituted or substituted with 1-3 members independently selected from the group consisting of halogen, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3In selected embodiments, including any of the above embodiments for compounds of formula (I), (Ia) or (Ib), further embodiments are those wherein group A is a 6-membered heteroaryl group which is unsubstituted or substituted with 1-3 members independently selected from the group consisting of halogen, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy and CN.

[0077] In selected embodiments, including any of the embodiments above for compounds of formula (I), (Ia), or (Ib), further embodiments are those wherein group A is selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, oxazolyl, thiazolyl, and pyrazolyl, each of which is unsubstituted or substituted with one or two members independently selected from the group consisting of halogen, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 In selected embodiments, including any of the embodiments above for compounds of formula (I), (Ia) or (Ib), further embodiments are those wherein group A is selected from the group consisting of pyridyl, pyrimidinyl, pyrazinyl, oxazolyl, thiazolyl and pyrazolyl, each of which is unsubstituted or substituted with one or two members independently selected from the group consisting of halogen, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy and CN.

[0078] In selected embodiments, including any of the embodiments above for compounds of formula (I), (Ia) or (Ib), further embodiments are wherein group A is a 6-membered heteroaryl selected from the group consisting of pyridine, pyrimidine, pyrazine and 1,2,4-triazine, each of which is unsubstituted or substituted with one or two members independently selected from the group consisting of CF3, OH, Et, CN, OCH3 and F. In selected embodiments, including any of the embodiments above for compounds of formula (I), (Ia) or (Ib), further embodiments are wherein group A is a 6-membered heteroaryl selected from the group consisting of pyridine, pyrimidine, pyrazine and 1,2,4-triazine, each of which is unsubstituted or substituted with one or two members independently selected from the group consisting of OCH3 and F.

[0079] In selected embodiments, including any of the embodiments above for compounds of formula (I), (Ia), or (Ib), further embodiments are those wherein R 2a and R 2b Each is an embodiment of H.

[0080] In selected embodiments, including any of the embodiments above for compounds of formula (I), (Ia), or (Ib), further embodiments are those wherein R 2a and R 2b an embodiment wherein the ring or spirocycle is combined to form a 4- to 9-membered ring or spirocycle, optionally with one or two additional ring vertices selected from O, N, or S; wherein the ring or spirocycle is substituted with 0 to 4 substituents independently selected from the group consisting of oxo, C 1-8 Alkyl, C 1-8 Halogenated alkyl, C 1-8 Hydroxyalkyl, -X 2 -CO2R a 、-X 2 -OR a 、-X 2 -NR a R b 、-X 2 -CONR a R b 、-X 2 -SO2R a 、-X 2 -SO2NR a R b and –X 2 -SO3R a ; where X 2 is key or C 1-6 Alkylene.

[0081] In selected embodiments, including any of the embodiments above for compounds of Formula (I), (Ia), or (Ib), further embodiments are those wherein -N(R 2a )(R 2b ) is selected from the following embodiments:

[0082]

[0083] In selected embodiments, including any of the embodiments above for compounds of Formula (I), (Ia), or (Ib), further embodiments are those wherein -N(R 2a )(R 2b ) is selected from the following embodiments:

[0084]

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

[0086]

[0087] In selected embodiments, including any of the embodiments above for compounds of 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 -Those embodiments of Y.

[0088] In selected embodiments, including any of the embodiments above for compounds of 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; Y is selected from the group consisting of: C 3-6 Cycloalkyl and C 4-8 heterocyclyl, each of which is further optionally substituted by one to four substituents independently selected from the group consisting of oxo, OH, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 1-4 Hydroxyalkoxy, SO2NH2, C(O)NH2, C(O)NHOH, PO3H2, C(O)2C 1-8 Those embodiments of alkyl and CO2H.

[0089] In selected embodiments, including any of the embodiments above for compounds of formula (I), (Ia), or (Ib), further embodiments are those wherein R 3 and R 4 Each is independently selected from the group consisting of F, Cl, CN, CH3, OCH3, CH2CH3, and CF3. In selected embodiments, including any of the above embodiments of compounds of formula (I), (Ia), or (Ib), further embodiments are those wherein R 3 and R 4 Each is independently selected from the group consisting of Cl, CN, CH3, and CF3.

[0090] In selected embodiments, including any of the embodiments above for compounds of formula (I), (Ia), or (Ib), further embodiments are those wherein Z is a 5- or 6-membered non-aromatic heterocycle, optionally substituted with one or two oxo groups and optionally substituted with R a and / or R b replace.

[0091] In selected embodiments, including any of the above embodiments for compounds of formula (I), (Ia), or (Ib), further embodiments are those wherein Z is a monocyclic 5- or 6-membered heteroaryl ring, optionally substituted by 1-3 R c replace.

[0092] In selected embodiments, including any of the embodiments above for compounds of formula (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 substituted with R a and / or R b replace.

[0093] In selected embodiments, including any of the embodiments above for compounds of formula (Ia) or (Ib), further embodiments are those wherein Z is a monocyclic 5- or 6-membered heteroaryl ring, optionally substituted by 1-3 R c replace.

[0094] In selected embodiments, including any of the embodiments above for compounds of 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 substituted with R a and / or R b Substituted; the non-aromatic heterocycle is selected from the group consisting of piperidinyl, morpholinyl, tetrahydropyranyl and tetrahydrofuranyl.

[0095] In selected embodiments, including any of the above embodiments for compounds of formula (I), (Ia) or (Ib), further embodiments are those wherein Z is a monocyclic 5- or 6-membered heteroaromatic ring optionally substituted with 1-3 R c Substituted; the heterocycle is selected from the group consisting of pyridyl, pyrimidinyl, pyrazinyl, oxazolyl, thiazolyl and pyrazolyl.

[0096] In selected embodiments, including any of the embodiments described above with respect to compounds of Formula (I), (Ia), or (Ib), further embodiments are those wherein the compound is selected from Table 1.

[0097] In selected embodiments, including any of the embodiments above for compounds of formula (I), (Ia), or (Ib), further embodiments are compounds selected from Table 1 having ++ or +++ activity.

[0098] In selected embodiments, including any of the embodiments above for compounds of formula (I), (Ia), or (Ib), further embodiments are compounds selected from Table 1 having +++ activity.

[0099] In addition to the compounds provided above, pharmaceutically acceptable salts of these compounds are also provided. Selected from ammonium, calcium, magnesium, potassium, sodium, zinc, arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, hepamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperazine, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, hydrochloric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, acetic acid, propionic acid, isobutyric acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, In some embodiments, the pharmaceutically acceptable salt is selected from ammonium salt, calcium salt, magnesium salt, potassium salt, sodium salt, hydrochloride, carbonate, bicarbonate, phosphate, hydrogen phosphate, dihydrogen phosphate, acetate, propionate, isobutyrate, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, arginine, glucuronic acid and galacturonic acid. In some embodiments, the pharmaceutically acceptable salt is sodium salt or hydrochloride.

[0100] In addition to the salt form The invention also provides a prodrug form of the compound Prodrugs of the compounds described herein are compounds that readily undergo chemical changes under physiological conditions to provide compounds of the present disclosure. Additionally, prodrugs can be converted to compounds of the present disclosure by chemical or biochemical methods in an ex vivo environment. For example, when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent, a prodrug can be slowly converted to a compound of the present disclosure.

[0101] Esters can be used as prodrugs of the corresponding carboxylic acids. 1-10 Alkyl ester or C 1-10 Haloalkyl esters can be used as prodrugs of the corresponding carboxylic acids. The following esters can be used: tert-butyl ester, methyl ester, ethyl ester, isopropyl ester.

[0102] Preparation method

[0103] In addition to the methods described in the Examples below, general methods for preparing compounds of formula (I) are provided in Schemes 1 and 2.

[0104] Solution 1

[0105]

[0106] Scheme 1 illustrates a general method for preparing compounds of formula (I). In the above reaction scheme, A is a six-membered nitrogen-containing heteroaromatic ring (such as pyridyl, pyrimidinyl), X 1 CH2, R s represents one or more substituents on the heteroaryl ring.

[0107] In the presence of a catalyst, Suzuki coupling of (a) with (b) provides the biphenyl compound (c). The Z group from reagent (d) is added to the exocyclic amine of compound (c) in a substitution reaction to form compound (e). Compound (e) can then be converted to the boronate compound (f) and then subjected to a second Suzuki coupling (with the halo-heteroaryl compound (g)) to provide the triarylaldehyde compound (h). The HNR 2a R 2b Reductive amination of the aldehyde can provide compounds of formula (Ia).

[0108] Alternatively, a second Suzuki-type coupling of compound (c) in the presence of compound (g') and a catalyst provides triarylaldehyde compound (h), which can be used for reductive amination as described above to provide compound (Ia) below.

[0109] Option 2

[0110]

[0111] In another method based on Suzuki-type coupling, the exocyclic amine of compound (a) is first displaced with reagent (d) to give compound (j). In the presence of a catalyst, Suzuki-type coupling of (j) with (k) can provide compound (h). Triarylaldehyde compound (h) can be used for reductive amination as described in Scheme 1 to provide compounds of formula (Ia).

[0112] Pharmaceutical composition

[0113] In addition to the compound provided herein, compositions of these compounds generally contain a pharmaceutical carrier or diluent.

[0114] As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. By "pharmaceutically acceptable" is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient.

[0115] In another embodiment, a pharmaceutical composition is provided, comprising a compound of the present disclosure, including a compound of Formula (I), (Ia), or (Ib), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0116] In some embodiments, the pharmaceutical composition further comprises one or more additional therapeutic agents. In certain embodiments, the one or more additional therapeutic agents are selected from antimicrobial agents, antiviral agents, cytotoxic agents, gene expression regulators, chemotherapeutic agents, anticancer agents, antiangiogenic agents, immunotherapeutic agents, antihormonal agents, antifibrotic agents, radiotherapy, radiotherapeutic agents, antitumor agents and antiproliferative agents. In certain embodiments, the one or more additional therapeutic agents are antagonists of chemokines and / or chemotactic receptors, including but not limited to CCR1, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10, CCR11, CCR12, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, CXCR6, CXCR7, C3aR and / or C5aR. Chemokine and / or chemokine receptor antagonists are known in the art and are described, for example, in WO 2007 / 002667, WO 2007 / 002293, WO / 2003 / 105853, WO / 2007 / 022257, WO / 2007 / 059108, WO / 2007 / 044804, WO 2007 / 115232, WO 2007 / 115231, WO 2008 / 147815,WO2010 / 030815,WO2010 / 075257,WO2011 / 163640,WO2010 / 054006,WO2010 / 051561 ,WO2011 / 035332,WO2013 / 082490,WO2013 / 082429,WO2014 / 085490,WO2014 / 100735,WO201 4 / 089495,WO2015 / 084842,WO2016 / 187393,WO2017 / 127409,WO2017 / 087607,WO2017 / 087 610,WO2017 / 176620,WO2018 / 222598,WO2018 / 222601,WO2013 / 130811,WO2006 / 076644,WO 2008 / 008431,WO2009 / 038847,WO2008 / 008375,WO2008 / 008374,WO2008 / 010934,WO2009 / 0 09740,WO2005 / 112925,WO2005 / 112916,WO2005 / 113513,WO2004 / 085384,WO2004 / 046092.Chemokine and / or chemokine receptor antagonists also include CCX354, CCX9588, CCX140, CCX872, CCX598, CCX6239, CCX9664, CCX2553, CCX3587, CCX3624, CCX 2991, CCX282, CCX025, CCX507, CCX430, CCX765, CCX224, CCX662, CCX650, CCX832, CCX168, CCX168-M1, CCX3022, and / or CCX3384.

[0117] Pharmaceutical compositions for administration of the compounds of the present disclosure can conveniently be presented in unit dosage form and can be prepared by any methods known in the art of pharmacy and pharmaceutical delivery. All methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general, the pharmaceutical compositions are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired formulation. In the pharmaceutical compositions, the active object compound is included in an amount sufficient to produce the desired effect in as small a total dose as possible.

[0118] Pharmaceutical compositions containing the active ingredient can be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, and self-emulsifying solutions, hard or soft capsules, syrups, elixirs, solutions, oral gels, chewing gum, chewable tablets, effervescent powders and effervescent tablets, as described in U.S. Patent Application 2002-0012680. Compositions intended for oral use can be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and such compositions can contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents, antioxidants and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients can be, for example, inert diluents, such as cellulose, silicon dioxide, aluminum oxide, calcium carbonate, sodium carbonate, dextrose, mannitol, sorbitol, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, such as corn starch or alginic acid; binding agents, such as PVP, cellulose, PEG, starch, gelatin or acacia, and lubricating agents, such as magnesium stearate, stearic acid or talc. The tablets can be uncoated or they can be coated, enterically or otherwise, by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over an extended period of time. For example, a time delay material such as a glyceryl monostearate or a glyceryl distearate can be employed. They can also be coated by the techniques described in U.S. Pat. Nos. 4,256,108; 4,166,452; and 4,265,874 to form osmotic therapeutic tablets for controlled release.

[0119] Formulations for oral administration can also be provided as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate or kaolin, polyethylene glycols (PEG) of various average sizes (e.g., PEG 400, PEG 4000) and certain surfactants such as Cremophor or solutol, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil. In addition, emulsions can be prepared with water-immiscible ingredients such as oils and stabilized with surfactants such as mono- or diglycerides, PEG esters, and the like.

[0120] Aqueous suspensions contain the active substance mixed with excipients suitable for the manufacture of aqueous suspensions. Such excipients include suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, and gum arabic. Dispersants or wetting agents may be naturally occurring phospholipids such as lecithin, or condensation products of alkylene oxides with fatty acids such as polyoxyethylene stearate, or condensation products of ethylene oxide with long-chain fatty alcohols such as heptadecaethyleneoxyhexadecyl alcohol, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitols such as polyoxyethylene sorbitan monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitols such as polysorbitan monooleate. Aqueous suspensions may also contain one or more preservatives such as ethyl or n-propyl p-hydroxybenzoate, one or more colorants, one or more flavoring agents, and one or more sweeteners such as sucrose or saccharin.

[0121] Oily suspensions can be prepared by suspending the active ingredient in a vegetable oil such as peanut oil, olive oil, sesame oil, or coconut oil, or a mineral oil such as liquid paraffin. Oily suspensions may contain thickeners such as beeswax, hard paraffin, or cetyl alcohol. Sweeteners and flavorings such as those mentioned above may be added to provide a palatable oral formulation. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.

[0122] Dispersible powders and granules suitable for preparing aqueous suspensions are provided by adding water to the active ingredient in admixture with a dispersant or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersants or wetting agents and suspending agents are, for example, those mentioned above. Other excipients, such as sweeteners, flavorings, and coloring agents, may also be present.

[0123] Pharmaceutical compositions of the present disclosure can also be in the form of oil-in-water emulsions. The oil phase can be a vegetable oil, such as olive oil or peanut oil, or a mineral oil, such as liquid paraffin or a mixture thereof. Suitable emulsifiers can be naturally occurring gums, such as gum arabic or tragacanth, naturally occurring phospholipids, such as soybeans, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of the partial esters and ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion can also contain sweeteners and flavorings.

[0124] Syrups and elixirs can be formulated with sweeteners such as glycerol, propylene glycol, sorbitol, or sucrose. Such formulations may also contain a demulcent, a preservative, and flavoring and coloring agents. Oral solutions can be prepared in combination with, for example, cyclodextrins, PEG, and a surfactant.

[0125] The pharmaceutical composition can be in the form of a sterile injectable aqueous or oily suspension. The suspension can be prepared according to known techniques using those suitable dispersants or wetting agents and suspending agents mentioned above. Sterile injectable preparations can also be sterile injectable solutions or suspensions in nontoxic parenteral acceptable diluents or solvents, for example as solutions in 1,3-butanediol. Acceptable carriers and solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils are commonly used as solvents or suspending media. For this purpose, any mild fixed oil can be used, including synthetic monoglycerides or diglycerides. In addition, fatty acids such as oleic acid can be used to prepare injections.

[0126] The compounds of the present invention can also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient, which is solid at room temperature but liquid at rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter and polyethylene glycol. In addition, the compound can be administered by eye administration in the form of a solution or ointment. Furthermore, transdermal delivery of the subject compound can be achieved by iontophoresis patches, etc. For topical use, creams, ointments, gels, solutions or suspensions containing the compounds of the present invention are used. As used herein, topical application also means including the use of mouthwashes and gargles.

[0127] Compound of the present disclosure can also be coupled with a carrier as a suitable polymer for targetable drug carriers. Such polymers can include polyvinyl pyrrolidone, pyran copolymer, polyhydroxy-propyl-methacrylamide-phenol, polyhydroxyethyl-asparagine-phenol or polyethylene oxide-polylysine substituted with palmitoyl residues. In addition, compound of the present disclosure can be coupled with a carrier, which is a class of biodegradable polymers that can be used to realize controlled release of drugs, such as crosslinked or amphiphilic block copolymers of polylactic acid, polyglycolic acid, polylactic acid and polyglycolic acid, poly-ε caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and hydrogels. Polymer and semipermeable polymer matrix can form shaped articles, such as valves, stents, tubing, prostheses, etc. In one embodiment of the invention, compound of the present invention is coupled with a polymer or semipermeable polymer matrix formed as stent or stent graft device.

[0128] Methods of treating diseases and disorders

[0129] The compounds of the present disclosure can be used as immunomodulators. The compounds of the present disclosure can be used as agonists, antagonists, partial agonists, inverse agonists, inhibitors of PD-1 and / or PD-L1 in various situations in vitro and in vivo. In some embodiments, the compounds of the present disclosure can be used as inhibitors of PD-1 / PD-L1 protein interactions. In some embodiments, the compounds of the present disclosure can be used as inhibitors of PD-L1. In some embodiments, the compounds of the present disclosure can be used as inhibitors of CD80 / PD-L1 protein interactions. In some embodiments, the compounds of the present disclosure can be used to inhibit the interaction between PD-1 and PD-L1 and / or PD-1 and CD80 and / or PD-1 and PD-L2 in vitro or in vivo. In some embodiments, the compounds of the present disclosure can be used to inhibit VISTA and / or TIM-3. In some embodiments, the compounds of the present disclosure can be inhibitors of PD-1 / PD-L1 protein interactions and inhibitors of VISTA and / or TIM-3. In some embodiments, in addition to being inhibitors of PD-1 / PD-L1 protein interactions, the compounds of the present disclosure may be inhibitors of CTLA-4 and / or BTLA and / or LAG-3 and / or KLRG-1 and / or 2B4 and / or CD160 and / or HVEM and / or CD48 and / or E-cadherin and / or MHC-II and / or Galectin-9 and / or CD86 and / or PD-L2 and / or VISTA and / or TIM-3 and / or CD80.

[0130] The compounds of the present disclosure can be contacted with the receptors with which they interact in aqueous solution and under conditions otherwise suitable for ligand-receptor binding. The receptors can be present in suspension (e.g., in isolated membranes or cell preparations), in cultured or isolated cells, or in tissues or organs.

[0131] Preferably, the amount of the disclosed compound contacted with the receptor should be sufficient to inhibit PD-1 / PD-L1 binding in vitro, as measured, for example, using an ELISA. The receptor may be present in solution or suspension, in a cultured or isolated cell preparation, or in a patient.

[0132] In some embodiments, the compounds of the present disclosure can be used to restore and enhance T cell activation. In some embodiments, the compounds of the present disclosure can be used to enhance the immune response of patients. In some embodiments, the compounds of the present disclosure can be used to treat, prevent or slow the progression of diseases or conditions in various therapeutic areas, such as cancer and infectious diseases.

[0133] In some embodiments, the compounds of the present disclosure may be used to treat patients suffering from disorders responsive to modulation of the PD-1 / PD-L1 protein interaction.

[0134] In some embodiments, methods are provided for modulating an immune response mediated by the PD-1 signaling pathway in a subject, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure, including a compound of Formula (I), (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, or a composition comprising a compound of Formula (I), (Ia) or (Ib) or a pharmaceutically acceptable salt thereof.

[0135] In some embodiments, methods are provided for enhancing, stimulating, regulating and / or increasing an immune response in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure, including a compound of Formula (I), (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, or a composition of a compound of the present disclosure, including a compound of Formula (I), (Ia) or (Ib), or a pharmaceutically acceptable salt thereof.

[0136] In some embodiments, a method of inhibiting cancer cell growth, proliferation, or metastasis in a subject in need thereof is provided, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure, including a compound of Formula (I), (Ia), or (Ib), or a pharmaceutically acceptable salt thereof, or a composition of a compound of the present disclosure comprising a compound of Formula (I), (Ia), or (Ib), or a pharmaceutically acceptable salt thereof.

[0137] In some embodiments, methods of treating a subject in need thereof are provided, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure, including a compound of Formula (I), (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, or a composition of a compound of the present disclosure comprising a compound of Formula (I), (Ia) or (Ib) or a pharmaceutically acceptable salt thereof.

[0138] In some embodiments, the subject suffers from a disease or condition selected from the group consisting of an infectious disease, a bacterial infectious disease, a viral infectious disease, a fungal infectious disease, a solid tumor, a malignant blood disease, an immune disorder, an inflammatory disease, and a cancer. In some embodiments, the disease or condition is selected from the group consisting of melanoma, glioblastoma, esophageal tumor, nasopharyngeal carcinoma, uveal melanoma, lymphoma, lymphocytic lymphoma, primary CNS lymphoma, T-cell lymphoma, diffuse large B-cell lymphoma, primary mediastinal large B-cell lymphoma, prostate cancer, castration-resistant prostate cancer, chronic myeloid leukemia, Kaposi's sarcoma, fibrosarcoma, liposarcoma, chondrosarcoma, osteosarcoma, angiosarcoma, lymphangiosarcoma, synovial tumor, meningioma, leiomyosarcoma, rhabdomyosarcoma, soft tissue sarcoma , sarcoma, sepsis, biliary tract tumors, basal cell carcinoma, thymus tumors, thyroid cancer, parathyroid cancer, uterine cancer, adrenal cancer, liver infection, Merkel cell carcinoma, neural tumors, follicle center lymphoma, colon cancer, Hodgkin's disease, non-Hodgkin's lymphoma, leukemia, chronic or acute leukemia, including acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, multiple myeloma, ovarian tumors, myelodysplastic syndrome, malignant melanoma of the skin or eye, renal cell carcinoma, small cell lung cancer, lung cancer, Mesothelioma, breast cancer, squamous non-small cell lung cancer (SCLC), non-squamous non-small cell lung cancer, colorectal cancer, ovarian cancer, gastric cancer, hepatocellular carcinoma, pancreatic cancer, pancreatic ductal adenocarcinoma, head and neck squamous cell carcinoma, head and neck cancer, gastrointestinal cancer, stomach cancer, HIV, hepatitis A, hepatitis B, hepatitis C, hepatitis D, herpes simplex virus, papillomavirus, influenza, bone cancer, skin cancer, rectal cancer, anal cancer, testicular cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, esophageal cancer, small intestine cancer, endocrine system cancer, urinary tract cancer carcinoma, penile cancer, bladder cancer, kidney cancer, ureteral cancer, renal pelvic cancer, central nervous system (CNS) tumors, tumor angiogenesis, spinal cord tumors, brainstem gliomas, pituitary adenomas, epidermoid carcinomas, incontinence, carcinomas, adenocarcinomas, papillary carcinomas, cystadenocarcinomas, bronchogenic carcinomas, renal cell carcinomas, transitional cell carcinomas, choriocarcinomas, seminoma, embryonal carcinomas, Wilm's tumor, pleomorphic adenoma, hepatocellular papilloma, renal tubular adenoma, cystadenoma, papilloma, adenoma, leiomyoma, rhabdomyomas, hemangiomas, lymphangiomas, osteomas, chondromas, lipomas, and fibromas.

[0139] In certain embodiments, one or more other therapeutic agents of a therapeutically effective amount are further administered to the subject. In certain embodiments, one or more other therapeutic agents are selected from antimicrobial agents, antiviral agents, cytotoxic agents, gene expression regulators, chemotherapeutics, anticancer agents, antiangiogenic agents, immunotherapeutics, antihormones, antifibrotics, radiotherapy, radiotherapeutics, antitumor agents and antiproliferative agents. In certain embodiments, one or more other therapeutic agents are antagonists of chemokines and / or chemoattractant receptors, including but not limited to CCR1, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10, CCR11, CCR12, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, CXCR6, CXCR7, C3aR and / or C5aR. Chemokine and / or chemokine receptor antagonists are known in the art and are described, for example, in WO 2007 / 002667, WO 2007 / 002293, WO / 2003 / 105853, WO / 2007 / 022257, WO / 2007 / 059108, WO / 2007 / 044804, WO 2007 / 115232, WO 2007 / 115231, WO 2008 / 147815,WO2010 / 030815,WO2010 / 075257,WO2011 / 163640,WO2010 / 054006,WO2010 / 051561 ,WO2011 / 035332,WO2013 / 082490,WO2013 / 082429,WO2014 / 085490,WO2014 / 100735,WO201 4 / 089495,WO2015 / 084842,WO2016 / 187393,WO2017 / 127409,WO2017 / 087607,WO2017 / 087 610,WO2017 / 176620,WO2018 / 222598,WO2018 / 222601,WO2013 / 130811,WO2006 / 076644,WO 2008 / 008431,WO2009 / 038847,WO2008 / 008375,WO2008 / 008374,WO2008 / 010934,WO2009 / 0 09740,WO2005 / 112925,WO2005 / 112916,WO2005 / 113513,WO2004 / 085384,WO2004 / 046092.Chemokine and / or chemokine receptor antagonists also include CCX354, CCX9588, CCX140, CCX872, CCX598, CCX6239, CCX9664, CCX2553, CCX3587, CCX3624, CCX 2991, CCX282, CCX025, CCX507, CCX430, CCX765, CCX224, CCX662, CCX650, CCX832, CCX168, CCX168-M1, CCX3022, and / or CCX3384.

[0140] In some embodiments, the compounds of the present disclosure can be used to inhibit infectious diseases. Infectious diseases include, but are not limited to, HIV, influenza, herpes, giardia, malaria, leishmania, pathogenic infection by hepatitis virus (types A, B, and C), herpes virus (e.g., VZV, HSV-I, HAV-6, HSV-II, and CMV, Epstein-Barr virus), adenovirus, influenza virus, flavivirus, echovirus, rhinovirus, coxsackie virus, coronavirus, respiratory syncytial virus, mumps virus, rotavirus, measles virus, rubella virus, parvovirus, vaccinia virus, HTLV virus, dengue virus, papillomavirus, molluscum virus, poliovirus, rabies virus, JC virus, and arboviral encephalitis virus, pathogenic infection by chlamydia, rickettsia, mycobacteria, staphylococcus, streptococcus, pneumococcus, meningococcus, and coccobacillus, klebsiella, proteus, serratia, pseudomonas, escherichia coli, legionella, diphtheria, salmonella, bacillus, cholera, tetanus, botulism, anthrax, plague, leptospirosis, and Lyme disease bacteria, pathogenic infection by fungal candida (albicans, krusei, glabrata, tropicalis, etc.), cryptococcus neoformans, aspergillus (fumigatus, niger, etc.), mucorales (mucor, absidia, rhizopus), sporothrix schenckii, blastomyces dermatitidis, paracoccidioides brasiliensis, coccidioides immitis, and histoplasma capsulatum, and pathogenic infection by parasitic entamoeba histolytica, balantidium coli, naegleria fourleri, acanthamoeba, giardia lamblia, cryptosporidium, pneumocystis carinii, plasmodium vivax, babesia microti, trypanosoma brucei, trypanosoma cruzi, leishmania donovani, toxoplasma gondii, and brugia malayi.

[0141] In some embodiments, the compounds of the present disclosure can be used to inhibit HIV infection, delay progression of AIDS, deplete HIV viral reservoirs, or reduce the severity of symptoms or HIV infection and AIDS.

[0142] The compounds of the present disclosure can be used to treat cancer and precancerous conditions in a subject.

[0143] The treatment methods provided herein generally comprise administering to a patient an effective amount of one or more compounds provided herein. Suitable patients include those suffering from or susceptible to (i.e., prophylactic treatment of) the conditions or diseases identified herein. Typical patients for the treatment described herein include mammals, particularly primates, and especially humans. Other suitable patients include domesticated companion animals such as dogs, cats, horses, etc., or livestock such as cattle, pigs, sheep, etc.

[0144] In general, the methods of treatment provided herein include administering to the patient an effective amount of a compound, one or more compounds provided herein. In a preferred embodiment, the compounds of the present disclosure are preferably administered to a patient (e.g., a human) intravenously, orally, or topically. An effective amount may be an amount sufficient to modulate the PD-1 / PD-L1 interaction and / or an amount sufficient to reduce or alleviate the symptoms presented by the patient. Preferably, the amount administered is sufficient to produce a plasma concentration of the compound (or its active metabolite, if the compound is a prodrug) sufficient to fully modulate the PD-1 / PD-L1 interaction. The treatment regimen may vary depending on the compound used and the specific condition to be treated; for the treatment of most diseases, a dosing frequency of 4 times a day or less is preferred. In general, a dosing regimen of 2 times a day is more preferred, with once a day dosing being particularly preferred. However, it should be understood that the specific dosage level and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the specific compound used, age, weight, general health status, sex, diet, treatment duration, route of administration, excretion rate, drug combination (i.e., other drugs given to the patient), and the severity of the specific disease being treated, as well as the judgment of the prescribing physician. Typically, it is preferred to use the minimum dose sufficient to provide effective treatment. Patients can generally be monitored for effectiveness of treatment using medical or veterinary criteria appropriate to the condition being treated or prevented.

[0145] combination

[0146] Concomitant drugs comprising a compound of the present invention and other drugs can be administered as a combination formulation in which the two components are contained in a single formulation, or as separate formulations. Administration by separate formulations includes simultaneous administration and administration at certain time intervals. In the case of administration at certain time intervals, a compound of the present invention can be administered first, followed by another drug, or another drug can be administered first, followed by a compound of the present invention. The administration methods of each drug can be the same or different.

[0147] The dosage of other drugs can be appropriately selected according to the dosage used clinically. According to the age and weight of the subject to be administered, the method of administration, the time of administration, the condition to be treated, the symptoms and combinations thereof, the compound ratio of the compound of the present disclosure and other drugs can be appropriately selected. For example, based on 1 part by mass of the compound of the present disclosure, 0.01 to 100 parts by mass of other drugs can be used. Other drugs can be two or more arbitrary drugs combined in an appropriate ratio.

[0148] The compounds described herein can be used or combined with one or more therapeutic agents, such as antimicrobial agents, antiviral agents, cytotoxic agents, gene expression regulators, chemotherapeutic agents, anticancer agents, anti-angiogenic agents, immunotherapeutic agents, antihormonal agents, antifibrotic agents, radiotherapy, radiotherapeutic agents, antitumor agents and antiproliferative agents. These therapeutic agents can be in the form of compounds, antibodies, polypeptides or polynucleotides.

[0149] The compounds described herein can be combined with one or more therapeutic antibodies, bispecific antibodies, and "antibody-like" therapeutic proteins (e.g., Fab derivatives), antibody-drug conjugates (ADCs), viruses, oncolytic viruses, gene modifiers or editors, such as CRISPR (including CRISPRCas9), zinc finger nucleases or synthetic nucleases (TALENs), CAR (chimeric antigen receptor) T cell immunotherapeutics, or any combination thereof used together or in combination.

[0150] Examples of chemotherapeutic agents include alkylating agents, nitrosoureas, antimetabolites, anticancer antibiotics, plant-derived alkaloids, topoisomerase inhibitors, hormone drugs, hormone antagonists, aromatase inhibitors, P-glycoprotein inhibitors, platinum complex derivatives, other immunotherapeutic drugs, and other anticancer drugs.

[0151] The compounds described herein can be used or combined simultaneously or in the form of a mixture with cancer treatment adjuvants such as leukopenia (neutropenia) treatment drugs, thrombocytopenia treatment drugs, antiemetic drugs, and cancer pain intervention drugs.

[0152] The compounds described herein may be used or combined with kinase inhibitors.

[0153] In one embodiment, the compounds of the present disclosure can be used simultaneously with other immunomodulators and / or enhancers or used in a mixture. Examples of immunomodulators include various cytokines, vaccines, and adjuvants. Examples of these cytokines, vaccines, and adjuvants that stimulate immune responses include, but are not limited to, GM-CSF, M-CSF, G-CSF, interferon-α, β, or γ, IL-1, IL-2, IL-3, IL-12, poly (I: C), and CPG. Enhancers include cyclophosphamide and cyclophosphamide analogs, anti-TGF and imatinib (Gleevec), mitotic inhibitors, such as paclitaxel, sunitinib (Sutent), or other anti-angiogenic agents, aromatase inhibitors, such as letrozole, A2a adenosine receptor (A2AR) antagonists, angiogenesis inhibitors, anthracyclines, oxaliplatin, doxorubicin, TLR4 antagonists, and IL-18 antagonists.

[0154] In some embodiments, the compounds described herein can be used in or in combination with one or more modulators of CCR1, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10, CCR11, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, CXCR6, CXCR7, ChemR23, C5aR, C5a, and C5. In some embodiments, the modulator is an antagonist.

[0155] In some embodiments, the compounds described herein may be combined with one or more of the compounds described in, for example, WO2007 / 002667, WO2007 / 002293, WO / 2003 / 105853, WO / 2007 / 022257, WO / 2007 / 059108, WO / 2007 / 044804, WO2007 / 115232, WO2007 / 115231, WO2008 / 147815, WO2 010 / 030815, WO2010 / 075257, WO2011 / 163640, WO2010 / 054006, WO2010 / 051561, WO2011 / 035332 , WO2011 / 035332, WO2013 / 082490, WO2013 / 082429, WO2013 / 085490, WO2014 / 100735, WO2014 / 089 495, WO2015 / 084842, WO2016 / 187393, WO2017 / 127409, WO2017 / 087607, WO2017 / 087610, WO2017 / 176620, WO2018 / 222598, WO2018 / 222601, WO2013 / 130811, WO2006 / 076644, WO2008 / 008431, WO2 009 / 038847, WO2008 / 008375, WO2008 / 008374, WO2008 / 010934, WO2009 / 009740, WO2005 / 112925, WO2005 / 112916, WO2005 / 113513, WO2004 / 085384, WO2004 / 046092. Chemokine and / or chemokine receptor antagonists useful in the present disclosure also include CCX354, CCX9588, CCX140, CCX872, CCX598, CCX6239, CCX9664, CCX2553, CCX3587, CCX3624, CCX 2991, CCX282, CCX025, CCX507, CCX430, CCX765, CCX224, CCX662, CCX650, CCX832, CCX168, CCX168-M1, CCX3022, and / or CCX3384.

[0156] dose

[0157] Dosage levels of the order of about 0.1 mg to about 140 mg per kilogram of body weight per day can be used to treat or prevent disorders involving PD-1 / PD-L1 interactions (about 0.5 mg to about 7 g per patient per day). The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary depending on the host being treated and the specific mode of administration. A unit dosage form typically contains about 1 mg to about 500 mg of active ingredient. For compounds administered orally, transdermally, intravenously, or subcutaneously, it is preferred that a sufficient amount of the compound be administered to achieve a serum concentration of 5 ng (nanograms) / mL-10 μg (micrograms) / mL serum, more preferably sufficient compound to achieve a serum concentration of 20 ng-1 μg / ml serum, sufficient compound should be administered to achieve a serum concentration of 50 ng / ml-200 ng / ml serum. For direct injection into the synovium (for the treatment of arthritis), sufficient compound should be administered to achieve a local concentration of about 1 micromolar.

[0158] The frequency of administration may also vary depending on the compound used and the specific disease being treated. However, for the treatment of most diseases, a dosage regimen of 4 times a day, 3 times a day or less is preferred, with a dosage regimen of once a day or twice a day being particularly preferred. However, it should be understood that the specific dosage level for any particular patient will depend on a variety of factors, including the activity of the specific compound used, age, body weight, general health, sex, diet, duration of treatment, route of administration, excretion rate, drug combination (i.e., other drugs given to the patient), and the severity of the specific disease being treated, as well as other factors including the judgment of the prescribing physician.

[0159] In another aspect of the present disclosure, the compounds of the present disclosure can be used for a variety of non-drug in vitro and in vivo applications. The compounds of the present disclosure can also be used as positive controls in PD-1 / PD-L1 interaction activity assays, i.e., as standards for determining the ability of candidate agents to bind to PD-1 and / or PD-L1, or as radioactive tracers for positron emission tomography (PET) imaging or single photon emission computed tomography (SPECT).

[0160] Kits comprising a compound of the present disclosure or a pharmaceutically acceptable salt thereof and instructions for use are also within the scope of the present disclosure. The kit may further comprise at least one additional reagent. Kits typically include a label indicating the intended use of the kit contents. The term label includes any written or recorded material on or provided with the kit, or otherwise accompanying the kit. Example

[0161] The following examples illustrate various methods of preparing compounds of the present disclosure, including compounds of Formula (I), (Ia), or (Ib).The following examples are provided to illustrate, but not to limit, the claimed disclosure.

[0162] The reagents and solvents used below can be obtained from commercial sources, such as Aldrich Chemical Company (Milwaukee, WI, USA). Spectra were recorded on a Varian Mercury 400 MHz NMR spectrometer. 1 H-NMR spectra. Significant peaks relative to TMS are provided and listed in the following order: multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet) and number of protons. Mass spectrometric results are reported as mass-to-charge ratios. In the examples, a single m / z value is reported for the M+H (or MH as previously described) ion containing the most common atomic isotope. The isotope pattern corresponds to the expected formula in all cases. Electrospray ionization (ESI) mass spectrometry analysis was performed on a Hewlett-Packard MSD electrospray mass spectrometer using an HP1100 HPLC for sample delivery. The analyte was typically dissolved in methanol or CH3CN at 0.1 mg / mL and 1 μL was injected into the mass spectrometer along with the delivery solvent over a scan range of 100 to 1000 Daltons. All compounds could be analyzed in either positive or negative ESI mode using acetonitrile / water and 1% formic acid as the delivery solvent.

[0163] The following abbreviations are used in the examples and throughout the description of the present disclosure: TLC stands for thin layer chromatography.

[0164] Compounds within the scope of the present disclosure can be synthesized using a variety of reactions known to those skilled in the art as described below. Those skilled in the art will also recognize that alternative methods can be employed to synthesize the target compounds of the present disclosure, and that the methods described in the body of this document are not exhaustive, but do provide broadly applicable and practical pathways to compounds of interest.

[0165] Certain molecules claimed in this patent may exist in different enantiomeric and diastereomeric forms, and all such variations of these compounds are claimed unless a specific enantiomer is specified.

[0166] In this paper, a detailed description of the experimental procedures used to synthesize key compounds resulted in molecules that are described by the physical data that identify them and by the structural descriptions associated with them.

[0167] Those skilled in the art will also recognize that acids and bases are frequently employed in standard workup procedures in organic chemistry. Salts are sometimes produced during the experimental procedures described herein if the parent compound possesses the necessary inherent acidity or basicity.

[0168] Example 1: (S)-5-(((5-(2,2'-dichloro-3'-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1'-biphenyl]-3-yl)-3-methoxypyrazin-2-yl)methyl)amino)methyl)pyrrolidin-2-one

[0169]

[0170] Step a: A mixture of 2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (10 g, 39.44 mmol), 1,3-dibromo-2-chlorobenzene (32 g, 118.3 mmol), K2CO3 (18.53 g, 134 mmol) and Pd(dppf)Cl2 complexed with DCM (3.22 g, 3.94 mmol) in dioxane (200 mL) and water (30 mL) was stirred at 90°C under N2 for 3 hours. The contents were cooled to room temperature and purified by silica gel flash chromatography to provide 3'-bromo-2,2'-dichloro-[1,1'-biphenyl]-3-amine. MS: (ES) m / z C 12 H9BrCl2N[M+H] + The calculated value is 315.9 and the measured value is 315.9.

[0171] Step b: A mixture of 5-chloropyrido[3,4-b]pyrazine (7.20 g, 22.7 mmol), 3'-bromo-2,2'-dichloro-[1,1'-biphenyl]-3-amine (3.76 g, 22.7 mmol) and Cs2CO3 (11.09 g, 34 mmol) in DMSO (80 mL) was stirred at 75°C overnight. The contents were cooled to room temperature, diluted with EtOAc and washed with water. The filtrate was collected, washed with water and purified by silica gel flash chromatography to give N-(3'-bromo-2,2'-dichloro-[1,1'-biphenyl]-3-yl)pyrido[3,4-b]pyrazin-5-amine. MS: (ES) m / z C 19 H 12 BrCl2N4[M+H] + The calculated value is 445.0, and the measured value is 445.0.

[0172] Step c: A mixture of N-(3'-bromo-2,2'-dichloro-[l,l'-biphenyl]-3-yl)pyrido[3,4- b]pyrazin-5-amine (4.88 g, 10.94 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'- bis(l,3,2-dioxaborolane) (3.05 g, 12 mmol), KOAc (2.68 g, 27.35 mmol), and Pd(dppf)Cl2with DCM (893 mg, 1.09 mmol) complex in dioxane (100 mL) was stirred under N2at 100 °C for 10 h. The contents were cooled to room temperature and purified by silica gel flash chromatography to give N-(2,2'-dichloro-3'-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- [l,l'-biphenyl]-3-yl)pyrido[3,4-b]pyrazin-5-amine. MS: (ES) m / z C 25 H 24 BC12N4O2[M+H] + Calcd 493.1, Found 492.9.

[0173] Step d: A mixture of N-(2,2'-dichloro-3'-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- [l,l'-biphenyl]-3-yl)pyrido[3,4-b]pyrazin-5-amine (340 mg, 0.69 mmol), 5-bromo-3- methoxypyrazine-2-carbaldehyde (180 mg, 0.83 mmol), K2CO3(238 mg, 1.73 mmol), and Pd(dppf)Cl2with DCM (81 mg, 0.10 mmol) complex in dioxane (5 mL) and water (0.75 mL) was stirred under N2at 90 °C for 3 h. The contents were cooled to room temperature and purified by silica gel flash chromatography to give 5-(2,2'-dichloro-3'-(pyrido[3,4-b]pyrazin-5- ylamino)-[l,l'-biphenyl]-3-yl)-3-methoxypyrazine-2-carbaldehyde. MS: (ES) m / z C 25 H 17 Cl2N6O2[M+H] + Calcd 503.1, Found 503.0.

[0174] Step e: A mixture of 5-(2,2'-dichloro-3'-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1'-biphenyl]-3-yl)-3-methoxypyrazine-2-carbaldehyde (40 mg, 0.080 mmol), (S)-5-(aminomethyl)pyrrolidin-2-one hydrochloride (15 mg, 0.10 mmol), Et3N (15 mg, 0.15 mmol), and AcOH (90 mg, 1.5 mmol) in EtOH (1 mL) and DCM (1 mL) was heated at 65°C for 0.5 h. The contents were cooled to room temperature and NaBH(OAc)3 (45 mg, 0.71 mmol) was added. After stirring for 30 min, the reaction was quenched with saturated NaHCO3 and extracted with DCM. The organic layer was collected and concentrated in vacuo. The obtained residue was purified by silica gel flash chromatography and preparative HPLC to give (S)-5-(((5-(2,2'-dichloro-3'-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1'-biphenyl]-3-yl)-3-methoxypyrazin-2-yl)methyl)amino)methyl)pyrrolidin-2-one. 1 H NMR (400MHz, CD3OD) δ9.25 (s, 1H), 9.06 (s, 1H), 8.54 (s, 1H), 8.03 (d, J = 7.6Hz, 1H),7.93(d,J=6.4Hz,1H),7.40(d,J=7.6Hz,1H),7.68(dd,J=7.6,7.6Hz,1H),7 .61(dd,J=7.6,7.6Hz,1H),7.53(m,2H),7.47(d,J=6.8Hz,1H),4.53(s,2H),4.1 2(s,2H),4.11(s,3H),3.41–3.21(m,1H),2.50–2.32(m,3H),2.04–1.92(m,1H). MS:(ES)m / zC 30 H 27 Cl2N8O2[M+H] + The calculated value is 601.2 and the measured value is 600.9.

[0175] Example 2: (R)-1-((6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)pyrrolidin-3-ol

[0176]

[0177] This compound was prepared using a method similar to that in Example 1, starting with 6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxynicotinaldehyde and (R)-pyrrolidin-3-ol hydrochloride. The crude product was purified by silica gel column chromatography to yield (R)-1-((6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4)-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)pyrrolidin-3-ol.

[0178] The crude product was purified by silica gel column chromatography to give (R)-1-((6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4))-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)pyrrolidin-3-ol. 1 HNMR(400MHz,CD3OD)δ8.81(dd,J=4.2,1.5Hz,1H),8.09–8.01(m,2H),7.84–7.74(m,2H),7.61(d d,J=7.6,1.7Hz,1H),7.47(dd,J=7.6,7.6Hz,1H),7.41–7.31(m,2H),7.26(d,J=7.5Hz,1H),7.14 –7.07(m,1H),4.38(m,1H),4.00(s,3H),3.89–3.75(m,2H),2.94(ddd,J=16.8,9.4,6.7Hz,2H),2 .71(ddd,J=23.4,10.2,4.7Hz,2H),2.57(s,3H),2.15(s,4H),1.78(d,J=8.7Hz,1H).MS:(ES)m / z C 32 H 32 ClN6O2[M+H] + The calculated value is 567.2 and the measured value is 567.5.

[0179] Example 3: (S)-5-(((6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)methyl)pyrrolidin-2-one

[0180]

[0181] Step a: To a stirred solution of N-(2'-chloro-2-methyl-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-yl)-2-methylpyrido[3,2-d]pyrimidin-4-amine (370 mg, 0.76 mmol), 6-chloro-2-methoxynicotinaldehyde (160 mg, 0.91 mmol), and KPO (570 mg, 2.7 mmol) in 1,4-dioxane / HO (8 mL) 1:1 was added Pd(PPh) (110 mg, 0.091 mmol) under N2. After stirring at 90°C for 16 hours, the mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel column chromatography to give 6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxynicotinaldehyde. MS: (ES) m / z C 28 H 23 ClN5O2[M+H] + The calculated value is 496.2 and the measured value is 496.2.

[0182] Step b: To a stirred solution of 6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxynicotinaldehyde (53 mg, 0.106 mmol), (S)-5-(aminomethyl)pyrrolidin-2-one hydrochloride (64 mg, 0.42 mmol), and triethylamine (60 μL, 0.42 mmol) in a 4:1 solution of DCM / MeOH (2 mL) was added NaBH(OAc)3 (230 mg, 1.1 mmol). After stirring for 30 minutes, the mixture was filtered through celite and the volatiles were removed in vacuo. The crude residue was purified by silica gel column chromatography to give the desired product, (S)-5-(((6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)methyl)pyrrolidin-2-one. 1H NMR (400MHz, CDCl3) δ9.23(s,1H),8.72(dd,J=4.3,1.5Hz,1H),8.58(dd,J=8.2,1.3Hz,1H),8.09(dd,J=8.4,1.5Hz,1H),7.67(dd ,J=8.5,4.2Hz,1H),7.63(dd,J=7.7,1.8Hz,1H),7.58(d,J=7.4Hz,1H),7.42(d,J=7.6Hz,1H),7.38(d,J=8.1Hz,1H),7.29(dd,J=7 .5,1.8Hz,1H),7.26(d,J=1.3Hz,1H),7.09–7.03(m,1H),6.42(s,1H),4.02(s,3H),3.80(s,2H),3.78–3.71(m,1H),2.78(dd,J=1 2.0, 4.2Hz, 1H), 2.72 (s, 3H), 2.57 (dd, J = 12.0, 8.5Hz, 1H), 2.39–2.32 (m, 3H), 2.26 (s, 3H), 2.25–2.16 (m, 1H), 1.83–1.67 (m, 1H). MS:(ES)m / zC 33 H 33 ClN7O2[M+H] + The calculated value is 594.2 and the measured value is 594.2.

[0183] Example 4: N-(3'-(5-((((1H-imidazol-2-yl)methyl)amino)methyl)-6-methoxypyridin-2-yl)-2'-chloro-2-methyl-[1,1'-biphenyl]-3-yl)-2-methylpyrido[3,2-d]pyrimidin-4-amine

[0184]

[0185] This compound was prepared using a method similar to that in Example 1, step e, starting with 6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxynicotinaldehyde and (1H-imidazol-2-yl)methanamine hydrochloride. The product was purified by preparative HPLC to yield the desired product, N-(3'-(5-((((1H-imidazol-2-yl)methyl)amino)methyl)-6-methoxypyridin-2-yl)-2'-chloro-2-methyl-[1,1'-biphenyl]-3-yl)-2-methylpyrido[3,2-d]pyrimidin-4-amine. 1H NMR(400MHz, CDCl3) δ9.84(s,1H),8.93(dd,J=4.3,1.4Hz,1H),8.73(dd,J=8.6,1.4Hz ,1H),8.15(d,J=8.1Hz,1H),7.92(dd,J=8.6,4.3Hz,1H),7.84(d,J=7.6Hz,1H),7.65(d d,J=7.7,1.7Hz,1H),7.48(d,J=7.6Hz,1H),7.44(d,J=7.6Hz,1H),7.34(dd,J=7.6,1.7 Hz,2H),7.31(s,2H),4.66(s,2H),4.32(s,2H),4.06(s,3H),2.89(s,3H),2.24(s,3H). MS:(ES)m / z C 32 H 30 ClN8O[M+H] + The calculated value is 577.2 and the measured value is 577.2.

[0186] Example 5: N-(3'-(5-(((2-(1H-imidazol-1-yl)ethyl)amino)methyl)-6-methoxypyridin-2-yl)-2'-chloro-2-methyl-[1,1'-biphenyl]-3-yl)-2-methylpyrido[3,2-d]pyrimidin-4-amine

[0187]

[0188] This compound was prepared using a method similar to that in Example 1, step e, starting with 6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxynicotinaldehyde and 2-(1H-imidazol-1-yl)ethan-1-amine dihydrochloride. The product was purified by preparative HPLC to yield the desired product, N-(3'-(5-(((2-(1H-imidazol-1-yl)ethyl)amino)methyl)-6-methoxypyridin-2-yl)-2'-chloro-2-methyl-[1,1'-biphenyl]-3-yl)-2-methylpyrido[3,2-d]pyrimidin-4-amine. 1H NMR (400MHz, CDCl3) δ9.90 (s, 1H), 9.23 (s, 1H), 8.97–8.88 (m, 1H), 8.70 (d, J = 8.5Hz, 1H), 8. 10–8.03(m,1H),7.90(dd,J=8.6,4.4Hz,1H),7.73(d,J=7.6Hz,1H),7.58(dd,J=7.6,1.1Hz, 1H),7.49–7.39(m,3H),7.32(dd,J=7.6,1.1Hz,1H),7.23(dd,J=7.5,2.3Hz,2H),7.18(s,1H ),4.81–4.72(m,2H),4.23(s,2H),3.98(s,3H),3.75–3.64(m,2H),2.86(s,3H),2.19(s,3H). MS:(ES)m / z C 33 H 32 ClN8O[M+H] + The calculated value is 591.2 and the measured value is 591.2.

[0189] Example 6: (S)-5-(((6-(2,2'-dichloro-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)methyl)pyrrolidin-2-one

[0190]

[0191] This compound was prepared using a method similar to that in Step e of Example 1, starting with 6-(2,2'-dichloro-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxynicotinaldehyde and (S)-5-(aminomethyl)pyrrolidin-2-one hydrochloride. The product was purified by silica gel column chromatography to yield the desired product, (S)-5-((((6-(2,2'-dichloro-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)methyl)pyrrolidin-2-one. 1H NMR(400MHz, DMSO-d6)δ9.99(s,1H),8.92(d,J=4.1Hz,1H),8.88–8.80(m,1H),8.24–8.16(m,1H), 7.96–7.90(m,1H),7.87–7.80(m,1H),7.69(s,1H),7.60–7.53(m,2H),7.45(d,J=7.2Hz,1H),7.30 (d,J=7.4Hz,1H),7.23(dd,J=7.7,5.9Hz,1H),7.17(d,J=7.7Hz,1H),3.93(s,3H),3.75(s,2H),3. 66(s,1H),2.64(s,3H),2.59(s,1H),2.30(s,2H),2.19–2.04(m,3H),1.70(dt,J=14.2,7.7Hz,1H). MS:(ES)m / z C 32 H 30 Cl2N7O2[M+H] + The calculated value is 614.2 and the measured value is 614.2.

[0192] Example 7: 1-((6-(2,2'-dichloro-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl))-2-methoxypyridin-3-yl)methyl)-3-methylazetidine-3-carboxylic acid

[0193]

[0194] This compound was prepared using a method similar to that in Example 1, step e, starting with 6-(2,2'-dichloro-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxynicotinaldehyde and 3-methylazetidine-3-carboxylic acid. The product was purified by silica gel column chromatography to obtain the desired product, 1-((6-(2,2'-dichloro-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)-3-methylazetidine-3-carboxylic acid. 1H NMR (400MHz, CDCl3) δ9.99 (s, 1H), 9.12 (d, J = 8.4Hz, 1H), 8.78 (d, J = 4.2Hz, 1 H),8.11(d,J=8.5Hz,1H),7.87(s,1H),7.68(dd,J=17.8,7.8Hz,2H),7.50(m ,2H),7.37–7.28(m,2H),7.08(d,J=7.3Hz,1H),4.36(s,2H),4.08–4.00(m,5 H), 3.39 (d, J = 12.8Hz, 2H), 2.79 (s, 3H), 1.46 (s, 3H), 1.31 (d, J = 6.4Hz, 2H). MS:(ES)m / z C 32 H 29 Cl2N6O2[M+H] + The calculated value is 615.2 and the measured value is 615.2.

[0195] Example 8: (1S,2S)-2-(((6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)cyclobutan-1-ol

[0196]

[0197] This compound was prepared using a method similar to that in Example 1, step e, starting with 6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxynicotinaldehyde and (1S,2S)-2-aminocyclobutan-1-ol. The product was purified by preparative HPLC to yield the desired product, (1S,2S)-2-(((6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)cyclobutan-1-ol. 1H NMR (400 MHz, DMSO-d6) δ 9.01 (d, J = 4.4 Hz, 1H), 8.89 (s, 1H), 8.22 (d, J = 8.5 Hz, 1H), 8.05 (dd, J = 8.5, 4.4 Hz, 1H), 7.93 (d, J = 7.6 Hz, 1H), 7.68 - 7.61 (m, 2H), 7.58 (dd, J = 7.6, 7.6 Hz, 1H), 7.48 - 7.36 (m, 3H), 7.23 (d, J = 7.6 Hz, 1H), 4.50 - 4.40 (m, 1H), 4.17 - 4.03 (m, 2H), 4.01 - 3.92 (m, 3H), 3.80 - 3.67 (m, 1H), 2.55 (s, 3H), 2.20 - 2.07 (m, 2H), 2.04 (s, 3H), 1.99 - 1.82 (m, 2H). MS: (ES) m / z C 32 H 32 ClN6O2[M+H] + Calculated 567.2, found 567.5.

[0198] Example 9: (S)-5-((((6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4- yl)amino)-[l,l'-biphenyl]-3-yl)-2-ethoxypyridin-3-yl)methyl)amino)methyl)pyrrolidin- 2-one

[0199]

[0200] This compound was prepared using a procedure analogous to Example 1, step e, starting from 6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[l,l'- biphenyl]-3-yl)-2-ethoxynicotinaldehyde and (S)-5-(aminomethyl)pyrrolidin-2-one hydrochloride. The product was purified by preparative HPLC to give the desired product (S)-5-((((6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[l,l'- biphenyl]-3-yl)-2-ethoxypyridin-3-yl)methyl)amino)methyl)pyrrolidin-2-one. 1H NMR (400MHz, CDCl3) δ9.86 (s, 1H), 8.96–8.89 (m, 1H), 8.68 (d, J = 8.5Hz, 1H), 8.11 (d, J = 8.1Hz, 1H) ,8.05(s,1H),7.92(dd,J=8.6,4.4Hz,1H),7.80(d,J=7.6Hz,1H),7.62(dd,J=7.7,1.7Hz,1H),7.5 0–7.40(m,2H),7.35–7.29(m,2H),4.51(q,J=7.0Hz,2H),4.35–4.24(m,2H),4.22–4.07(m,1H),3. 24–3.03(m,2H),2.86(s,3H),2.42–2.26(m,2H),2.22(s,3H),1.41(t,J=7.0Hz,3H),1.25(s,2H). MS:(ES)m / z C 34 H 35 ClN7O2[M+H] + The calculated value is 608.3 and the measured value is 608.3.

[0201] Example 10: (S)-5-((((6-(2,2'-dichloro-3'-(pyrido[3,2-d]pyrimidin-4-ylamino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)methyl)pyrrolidin-2-one

[0202]

[0203] Step a: To a stirred solution of 4-chloropyrido[3,2-d]pyrimidine (600 mg, 3.6 mmol) and 2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (920 mg, 3.6 mmol) in 7 mL of MeCN was added AcOH (0.68 mL, 12 mmol). The reaction was stirred for 30 minutes, and then the volatiles were removed in vacuo. The crude residue was purified by silica gel column chromatography to afford N-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrido[3,2-d]pyrimidin-4-amine. MS: (ES) m / z C 19 H 21 BClN4O2[M+H] + The calculated value is 383.1 and the measured value is 383.2.

[0204] Step b: To a stirred solution of N-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrido[3,2-d]pyrimidin-4-amine (550 mg, 1.4 mmol), 6-(3-bromo-2-chlorophenyl)-2-methoxynicotinaldehyde (470 mg, 1.4 mmol), and KCO (710 mg, 4.9 mmol) in a 1:1 solution of dioxane / HO (14 mL) was added a complex of Pd(dppf)Cl in DCM (140 mg, 0.17 mmol) under N. The mixture was stirred at 90°C under N for 4 hours and then diluted with H. The aqueous mixture was extracted with CHCl, and the combined organic layers were dried over MgSO, filtered, and concentrated in vacuo. The crude residue was purified by silica gel column chromatography to give 6-(2-chloro-2'-methyl-3'-(pyrido[3,2-d]pyrimidin-4-ylamino)-[1,1'-biphenyl]-3-yl)-2-methoxynicotinaldehyde. MS: (ES) m / z C 26 H 18 Cl2N5O2[M+H] + The calculated value is 502.1 and the measured value is 502.1.

[0205] Step c: To a stirred solution of 6-(2,2'-dichloro-3'-(pyrido[3,2-d]pyrimidin-4-ylamino)-[1,1'-biphenyl]-3-yl)-2-methoxynicotinaldehyde (58 mg, 0.12 mmol), (S)-5-(aminomethyl)pyrrolidin-2-one hydrochloride (72 mg, 0.48 mmol), and trimethylamine (64 μL, 0.46 mmol) in a 4:1 solution of DCM / MeOH (2.5 mL) was added NaBH(OAc) (240 mg, 1.2 mmol). After 30 minutes, the mixture was filtered through celite and the filtrate was concentrated. The product was purified by preparative HPLC to give the desired product (S)-5-(((6-(2,2'-dichloro-3'-(pyrido[3,2-d]pyrimidin-4-ylamino))-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)methyl)pyrrolidin-2-one. 1H NMR (400 MHz, CDC13) δ 10.01 (s, 1H), 9.07 - 8.98 (m, 1H), 8.86 (d, J = 2.3 Hz, 2H), 8.22 (d, J = 8.4 Hz, 1H), 7.81 - 7.71 (m, 2H), 7.68 (d, J = 7.6 Hz, 1H), 7.50 - 7.27 (m, 2H), 7.37 - 7.27 (m, 2H), 7.10 (d, J = 7.4 Hz, 1H), 7.00 (s, 1H), 4.05 (d, J = 1.9 Hz, 3H), 3.98 (s, 3H), 3.02 - 2.65 (m, 3H), 2.40 - 2.20 (m, 3H), 1.76 (d, J = 8.6 Hz, 1H). MS: (ES) m / z C 31 H 28 Cl2N7O2[M+H] + Calcd 600.2, Found 600.2.

[0206] Example 11: (S)-5-((((6-(2-chloro-2'-methyl-3'-((7-methylpyrido[3,4-b]pyrazin-5- yl)amino)-[l,l'-biphenyl]-3-yl)-2-hydroxypyridin-3-yl)methyl)amino)methyl)pyrrolidin- 2-one

[0207]

[0208] Step a: To a stirred suspension of 2,4-dichloro-6-methyl-3-nitropyridine (2.5 g, 12 mmol) in 24 mL of THF was added a solution of 7 N NH3in MeOH (14 mL, 98 mmol). After stirring for 3 h, the volatiles were removed in vacuo. The crude residue was purified by column chromatography on silica gel to give 2-chloro-6-methyl-3-nitropyridin-4-amine. MS: (ES) m / z C6H7ClN3O2[M+H] + 188.0, Found 188.0.

[0209] Step b: To a stirred mixture of 2-chloro-6-methyl-3-nitropyridin-4-amine (760 mg, 4.1 mmol) and Fe (1.1 g, 20 mmol) in 5: 1 EtOH / H2O (24 mL) was added 4.4 mL of concentrated HCl. The contents were refluxed for 30 min, then cooled to room temperature and quenched with 100 mL of saturated NaHCO3(aq). The mixture was extracted with EtOAc, the combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to give 2-chloro-6-methylpyridine-3,4-diamine. MS: (ES) m / z C6H9ClN3[M+H] + Calcd 158.0, Found 158.0.

[0210] Step c: To a stirred solution of 2-chloro-6-methylpyridine-3,4-diamine (0.49 g, 3.1 mmol) in 3 mL of EtOH was added 40% w / w aqueous glyoxal (2.0 mL, 12 mmol). After refluxing for 16 h, the mixture was diluted with H2O and extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel column chromatography to afford 5-chloro-7-methylpyrido[3,4-b]pyrazine. MS: (ES) m / z C8H7ClN3 [M+H] + The calculated value is 180.0 and the measured value is 180.1.

[0211] Step d: To a stirred solution of 5-chloro-7-methylpyrido[3,4-b]pyrazine (200 mg, 1.0 mmol) and 2'-chloro-2-methyl-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-amine (350 mg, 1.0 mmol) in 2 mL of MeCN was added AcOH (0.18 mL, 3.1 mmol). After 30 minutes, the volatiles were concentrated in vacuo. The crude residue was purified by silica gel column chromatography to afford N-(2'-chloro-2-methyl-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-yl)-7-methylpyrido[3,4-b]pyrazin-5-amine. MS: (ES) m / z C 27 H 29 BClN4O2[M+H] + The calculated value is 487.2 and the measured value is 487.2.

[0212] Step e: To a stirred solution of N-(2'-chloro-2-methyl-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-yl)-7-methylpyrido[3,4-b]pyrazin-5-amine (390 mg, 0.66 mmol), 6-chloro-2-methoxynicotinaldehyde (240 mg, 1.4 mmol), and K3PO4 (490 mg, 2.3 mmol) in 1,4-dioxane / HO (3.3 mL) 1:1 was added Pd(PPh3)4 (76 mg, 0.066 mmol) under N2. The mixture was stirred at 90°C under N2(g) for 3 hours. The mixture was diluted with HO and then extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated. The crude residue was purified by silica gel column chromatography to give 6-(2-chloro-2'-methyl-3'-((7-methylpyrido[3,4-b]pyrazin-5-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxynicotinaldehyde. MS: (ES) m / z C 28 H 23 ClN5O2[M+H] + The calculated value is 496.2 and the measured value is 496.2.

[0213] Step f: To a stirred mixture of 6-(2-chloro-2'-methyl-3'-((7-methylpyrido[3,4-b]pyrazin-5-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxynicotinaldehyde (120 mg, 0.25 mmol), (S)-5-(aminomethyl)pyrrolidin-2-one hydrochloride (150 mg, 0.99 mmol), and trimethylamine (0.14 mL, 0.99 mmol) in a 4:1 solution of DCM / MeOH (5 mL) was added NaBH(OAc) (530 mg, 2.5 mmol). After stirring for 30 minutes, the mixture was filtered through celite and the filtrate was concentrated in vacuo. The product was purified by preparative HPLC to give the product (S)-5-(((6-(2-chloro-2'-methyl-3'-((7-methylpyrido[3,4-b]pyrazin-5-yl)amino)-[1,1'-biphenyl]-3-yl)-2-hydroxypyridin-3-yl)methyl)amino)methyl)pyrrolidin-2-one. 1H NMR (400 MHz, DMSO-d6) δ 12.59 (s, 1H), 9.32 (s, 1H), 9.07 (d, J = 2.0 Hz, 1H), 8.86 (d, J = 2.0 Hz, 1H), 8.23 (d, J = 8.7 Hz, 1H), 7.76 (d, J = 7.0 Hz, 1H), 7.62 (s, 1H), 7.55 (d, J = 7.5 Hz, 1H), 7.50 - 7.43 (m, 1H), 7.35 (dd, J = 7.9, 7.9 Hz, 1H), 7.12 (s, 1H), 6.96 (d, J = 7.5 Hz, 1H), 6.55 (s, 2H), 6.43 (d, J = 7.1 Hz, 1H), 4.07 (s, 3H), 3.95 - 3.84 (m, 1H), 2.48 (s, 4H), 2.26 - 2.15 (m, 3H), 2.11 (s, 3H), 1.86 - 1.70 (m, 1H). MS: (ES) m / z C 32 H 31 ClN7O2[M+H] + Calc. 580.2, found 580.1.

[0214] Example 12: (S)-5-((((6-(2-chloro-2'-methyl-3'-((2- (trifluoromethyl)pyrido[3,2-d]pyrimidin-4-yl)amino)-[l,l'-biphenyl]-3-yl)-2- methoxypyridin-3-yl)methyl)amino)methyl)pyrrolidin-2-one

[0215]

[0216] Step a: To a stirred solution of 3-aminopyridinecarboxamide (5.0 g, 36 mmol) and pyridine (4.4 mL, 55 mmol) in 70 mL of DCM was added trifluoroacetic anhydride (7.7 mL, 55 mmol) dropwise at -78 °C under N2. The reaction was stirred at room temperature for 18 h. The volatiles were removed to give 3-(2,2,2-trifluoroacetamido)picolinamide. MS: (ES) m / z C8H7F3N3O2 [M+H] + Calc. 234.0, found 234.1.

[0217] A solution of 3-(2,2,2-trifluoroacetamido)picolinamide and pyridine (7.7 mL, 55 mmol) in 35 mL of 1,2-dichloroethane was stirred at 115°C for 72 hours. The mixture was cooled to room temperature and quenched with a NaCl solution (aqueous). The layers were separated and the aqueous layer was extracted with a 10% MeOH solution in DCM. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel column chromatography to give 2-(trifluoromethyl)pyrido[3,2-d]pyrimidin-4(1H)-one. MS: (ES) m / z C8H5F3N3O[M+H] + The calculated value is 216.0 and the measured value is 216.0.

[0218] Step b: To a stirred solution of 2-(trifluoromethyl)pyrido[3,2-d]pyrimidin-4(1H)-one (2.5 g, 11 mmol) in 50 mL of DCM was added 0.2 mL of DMF, followed by dropwise addition of oxalyl chloride (1.4 mL, 17 mmol) under N2. After stirring for 18 hours, the volatiles were removed in vacuo. The crude residue was purified by silica gel column chromatography to afford 4-chloro-2-(trifluoromethyl)pyrido[3,2-d]pyrimidine. MS: (ES) m / z C8H4ClF3N3[M+H] + The calculated value is 234.0 and the measured value is 234.0.

[0219] Step c: To a stirred solution of 4-chloro-2-(trifluoromethyl)pyrido[3,2-d]pyrimidine (1.9 g, 8.0 mmol) and 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.9 mg, 8.0 mmol) in 16 mL of MeCN was added AcOH (1.4 mL, 24 mmol). After 30 minutes, the volatiles were concentrated in vacuo. The crude residue was purified by silica gel column chromatography to afford N-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-(trifluoromethyl)pyrido[3,2-d]pyrimidin-4-amine. MS: (ES) m / z C 21 H 23 BF3N4O2[M+H] + The calculated value is 431.2, and the measured value is 431.2.

[0220] Step d: To a stirred solution of N-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-(trifluoromethyl)pyrido[3,2-d]pyrimidin-4-amine (730 mg, 1.7 mmol), 6-(3-bromo-2-chlorophenyl)-2-methoxynicotinaldehyde (590 mg, 1.9 mmol), and KCO (690 mg, 5.0 mmol) in a 1:1 solution of 1,4-dioxane / HO (14 mL) was added a complex of Pd(dppf)Cl in DCM (160 mg, 0.20 mmol) under N. The mixture was stirred at 90°C under N for 4 hours and then diluted with 100 mL of HO. The contents were extracted with EtOAc, and the combined organic layers were dried over MgSO, filtered, and concentrated in vacuo. The crude residue was purified by silica gel column chromatography to give 6-(2-chloro-2'-methyl-3'-((2-(trifluoromethyl)pyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxynicotinaldehyde. MS: (ES) m / z C 28 H 20 ClF3N5O2[M+H] + The calculated value is 550.1 and the measured value is 550.1.

[0221] Step e: To a stirred solution of 6-(2-chloro-2'-methyl-3'-((2-(trifluoromethyl)pyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxynicotinaldehyde (200 mg, 0.36 mmol), (S)-5-(aminomethyl)pyrrolidin-2-one hydrochloride (220 mg, 1.5 mmol), and trimethylamine (0.21 mL, 1.5 mmol) in a 4:1 solution of DCM / MeOH (7 mL) was added NaBH(OAc)3 (760 mg, 3.6 mmol). After stirring for 30 minutes, the mixture was filtered through celite and the filtrate was concentrated in vacuo. The product was purified by preparative HPLC to give the desired product (S)-5-(((6-(2-chloro-2'-methyl-3'-((2-(trifluoromethyl)pyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)methyl)pyrrolidin-2-one. 1H NMR(400MHz, CDCl3)δ9.50(s,1H),8.91(dd,J=4.3,1.5Hz,1H),8.59–8.53(m,1H),8.33(dd,J=8.5,1.5Hz,1H),7.83(dd ,J=8.5,4.3Hz,1H),7.66(dd,J=7.7,1.8Hz,1H),7.59(d,J=7.4Hz,1H),7.44(t,J=7.7Hz,2H),7.31(dd,J=7.5,1.8Hz,1 H),7.29(m,1H),7.12(dd,J=7.6,1.2Hz,1H),5.99(s,1H),4.04(s,3H),3.81(s,2H),3.76(d,J=13.4Hz,1H),2.81(dd,J =12.0,4.2Hz,1H),2.57(dd,J=12.0,8.7Hz,1H),2.41–2.33(m,2H),2.29(s,3H),2.28–2.19(m,1H),1.84–1.71(m,1H). MS:(ES)m / zC 33 H 30 ClF3N7O2[M+H] + The calculated value is 648.2 and the measured value is 648.2.

[0222] Example 13: 1-((6-(2-chloro-2'-methyl-3'-((2-(trifluoromethyl)pyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)-3-methylazetidine-3-carboxylic acid

[0223]

[0224] This compound was prepared using a method similar to that in Example 1, step e, starting with 6-(2-chloro-2'-methyl-3'-((2-(trifluoromethyl)pyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxynicotinaldehyde and 3-methylazetidine-3-carboxylic acid. The product was purified by silica gel column chromatography to yield the desired product, 1-((6-(2-chloro-2'-methyl-3'-((2-(trifluoromethyl)pyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)-3-methylazetidine-3-carboxylic acid. 1H NMR (400 MHz, CDC13) δ 9.48 (s, 1H), 8.89 (d, J = 4.4 Hz, 1H), 8.55 (d, J = 8.1 Hz, 1H), 8.31 (d, J = 8.5 Hz, 1H), 7.89 (s, 1H), 7.81 (dd, J = 8.4, 4.4 Hz, 1H), 7.62 (d, J = 7.5 Hz, 1H), 7.41 (dd, J = 7.8, 7.8 Hz, 2H), 7.30 (d, J = 7.4 Hz, 2H), 7.09 (d, J = 7.7 Hz, 1H), 4.42 (s, 1H), 4.09 (s, 1H), 4.02 (s, 3H), 3.43 (s, 2H), 2.28 - 2.23 (m, 8H). MS: (ES) m / z C 33 H 29 ClF3N6O3[M+H] + Calculated 649.2, found 649.5.

[0225] Example 14: (S)-5-((((6-(2-chloro-3'-((2-isopropylpyrido[3,2-d]pyrimidin-4-yl)amino)-2'- methyl-[1,1))'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)methyl)pyrrolidin-2-one

[0226]

[0227] Step a: To a stirred solution of 3-aminopicolinamide (2.5 g, 18 mmol) and triethylamine (5.8 mL, 42 mmol) in 3:1 DCM / THF (80 mL) was added isobutyryl chloride (2.9 mL, 27 mmol) dropwise under N2. The reaction mixture was stirred at room temperature for 3.5 hours, then adjusted to pH = 7 with 1 N HC1 (aq). The contents were extracted with DCM and concentrated. The crude residue was diluted with EtOH and stirred with NaOH (3.8 g, 54 mmol). After 6 hours, the mixture was neutralized with AcOH in H2O, then extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography to give 2-isopropylpyrido[3,2-d]pyrimidin-4(lH)-one. MS: (ES) m / z C 10 H 12 N3O[M+H] + Calculated 190.1, found 190.2.

[0228] Step b: To a solution of 2-isopropylpyrido[3,2-d]pyrimidin-4(1H)-one (2.0 g, 11 mmol) in DCM (70 mL) was added oxalyl chloride (1.1 mL, 13 mmol) followed by DMF (4 drops) under N2. After stirring at room temperature for 4 hours, the volatiles were removed in vacuo. The residue was purified by silica gel column chromatography to afford 4-chloro-2-isopropylpyrido[3,2-d]pyrimidine. MS: (ES) m / z C 10 H 11 ClN3[M+H] + The calculated value is 208.1 and the measured value is 208.1.

[0229] Step c: To a stirred mixture of 4-chloro-2-isopropylpyrido[3,2-d]pyrimidine (180 mg, 0.85 mmol) and 2'-chloro-2-methyl-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-amine (300 mg, 0.87 mmol) in 1.7 mL of MeCN was added AcOH (0.15 mL, 2.6 mmol). The mixture was stirred for 1.5 hours, and then the volatiles were concentrated in vacuo. The 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)-2-isopropylpyrido[3,2-d]pyrimidin-4-amine. MS:(ES)m / z C 29 H 33 BClN4O2[M+H] + The calculated value is 515.2 and the measured value is 515.2.

[0230] Step d: To a stirred mixture of N-(2'-chloro-2-methyl-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-yl)-2-isopropylpyrido[3,2-d]pyrimidin-4-amine (200 mg, 0.39 mmol), 6-chloro-2-methoxynicotinaldehyde (130 mg, 0.77 mmol), and KPO (280 mg, 1.3 mmol) in a 1:1 solution of dioxane / HO (2 mL) was added Pd(PPh) (45 mg, 0.039 mmol) under N. The reaction was stirred at 90°C under N for 2 hours, cooled to room temperature, and diluted with 5 mL of HO. The contents were extracted with EtOAc, and the combined organic layers were dried over MgSO, filtered, and concentrated. The residue was purified by silica gel column chromatography to give 6-(2-chloro-3'-((2-isopropylpyrido[3,2-d]pyrimidin-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxynicotinaldehyde. MS: (ES) m / z C 30 H 27 ClN5O2[M+H] + The calculated value is 524.2 and the measured value is 524.2.

[0231] Step e: To a stirred solution of 6-(2-chloro-3'-((2-isopropylpyrido[3,2-d]pyrimidin-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxynicotinaldehyde (100 mg, 0.19 mmol), (S)-5-(aminomethyl)pyrrolidin-2-one hydrochloride (120 mg, 0.77 mmol), and trimethylamine (0.11 mL, 0.76 mmol) in a 4:1 solution of DCM / methanol (4 ml) was added NaBH(OAc)3 (410 mg, 1.9 mmol). After stirring for 30 minutes, the mixture was filtered through celite and then concentrated in vacuo. The product was purified by preparative HPLC to give the desired product (S)-5-(((6-(2-chloro-3'-((2-isopropylpyrido[3,2-d]pyrimidin-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)methyl)pyrrolidin-2-one. 1H NMR (400 MHz, DMSO-d6) δ 9.06 - 8.90 (m, 1H), 8.73 (s, 1H), 8.26 (dd, J = 8.6, 1.5 Hz, 1H), 8.04 (dd, J = 8.5, 4.3 Hz, 1H), 7.96 (d, J = 7.6 Hz, 1H), 7.68 (d, J = 8.5 Hz, 1H), 7.66 (dd, J = 7.7, 1.8 Hz, 1H), 7.61 (s, 1H), 7.58 (t, J = 7.6 Hz, 1H), 7.45 - 7.38 (m, 3H), 7.23 - 7.18 (m, 1H), 4.30 - 4.17 (m, 2H), 3.98 (s, 3H), 3.90 (ddd, J = 6.7, 6.7, 6.7 Hz, 1H), 3.23 - 3.12 (m, 1H), 3.12 - 3.02 (m, 2H), 2.27 - 2.12 (m, 3H), 2.03 (s, 3H), 1.87 - 1.68 (m, 1H), 1.23 (d J = 6.8 Hz, 3H), 1.21 (d, J = 6.8 Hz, 3H). MS: (ES) m / z C 35 H 37 ClN7O2[M+H] + Calc. 622.3, found 622.3.

[0232] Example 15: N-(2'-chloro-3'-(6-methoxy-5-((methylamino)methyl)pyridin-2-yl)-2- methyl-[1,1'-biphenyl]-3-yl)-2-methylpyrido[3,2-d]pyrimidin-4-amine

[0233]

[0234] A mixture of 6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4- yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxybenzaldehyde (50 mg, 0.10 mmol), methylamine hydrochloride (35 mg, 0.052 mmol), and AcOH (0.10 mL, 0.71 mmol) in DCM (2 mL) was stirred at room temperature for 1.5 h. To the mixture was added NaBH(OAc)3(40 mg, 0.18 mmol). After stirring for another 1.5 h, the reaction was quenched with saturated NaHCO3and extracted with DCM. The organic layer was separated, dried over Na2SO4, concentrated in vacuo and purified by silica gel chromatography to give N-(2'-chloro-3'-(6-methoxy-5-((methylamino)methyl)pyridin-2-yl)-2-methyl-[1,1'- biphenyl]-3-yl)-2-methylpyrido[3,2-d]pyrimidin-4-amine. 1HNMR(400MHz, CDCl3) δ9.23(s,1H),8.73(dd,J=4.0,1.6Hz,1H),8.59(d,J=7.6 Hz,1H),8.09(dd,J=8.8,1.6Hz,1H),7.66–7.58(m,1H),7.60(d,J=7.2Hz,1H),7 .40(dd,J=7.6,2.0Hz,1H),7.44–7.37(m,2H),7.31–7.24(m,3H),7.06(dd,J=7. 6,1.2Hz,1H),4.03(s,3H),3.76(s,2H),2.73(s,3H),2.48(s,3H),2.27(s,3H). MS:(ES)m / z C 29 H 28 ClN6O[M+H] + The calculated value is 511.2 and the measured value is 511.5.

[0235] Example 16: 2-(((6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)acetamide

[0236]

[0237] A mixture of 6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxynicotinaldehyde (50 mg, 0.10 mmol), 2-aminoacetamide hydrochloride (30 mg, 0.27 mmol), Et3N (0.070 mL, 0.50 mmol), and AcOH (0.080 mL, 1.37 mmol) in DCM (2 mL) was stirred at room temperature for 1.5 hours. To the mixture was added NaBH(OAc)3 (80 mg, 0.36 mmol). After stirring for an additional 1.5 hours, the reaction was quenched with saturated NaHCO3 and extracted with DCM. The organic layer was separated, dried over Na2SO4, concentrated in vacuo and purified by silica gel chromatography to give 2-(((6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)acetamide. 1H NMR(400MHz, CDCl3) δ9.23(s,1H),8.72(dd,J=4.0,1.2Hz,1H),8.58(d,J=8.4Hz,1H),8.0 9(dd,J=8.4,1.6Hz,1H),7.70–7.65(m,1H),7.63(dd,J=8.0,1.6Hz,1H),7.55(d,J=7.6Hz ,1H),7.44–7.37(m,2H),7.30(dd,J=5.6,2.0Hz,1H),7.32–7.24(m,2H),7.06(d,J=7.2Hz ,1H),4.03(s,3H),3.79(s,2H),3.31(s,2H),2.36(s,br,2H),2.26(s,3H),2.04(s,3H). MS:(ES)m / z C 30 H 29 ClN7O2[M+H] + The calculated value is 554.2 and the measured value is 554.1.

[0238] Example 17: N-(2'-chloro-3'-(6-methoxy-5-(morpholinomethyl)pyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-2-methylpyrido[3,2-d]pyrimidin-4-amine

[0239]

[0240] A mixture of 6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxynicotinaldehyde (50 mg, 0.10 mmol), morpholine (30 mg, 0.57 mmol), and AcOH (80 mg, 1.37 mmol) in DCM (2 mL) was stirred at room temperature for 1 hour. NaBH(OAc) (75 mg, 0.35 mmol) was added to the mixture. After stirring for an additional 40 minutes, the reaction was quenched with saturated NaHCO and extracted with DCM. The organic layer was separated, dried over Na2SO4, concentrated in vacuo and purified by silica gel chromatography to give N-(2'-chloro-3'-(6-methoxy-5-(morpholinomethyl)pyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-2-methylpyrido[3,2-d]pyrimidin-4-amine. 1H NMR (400MHz, CDCl3) δ9.23 (s, 1H), 8.73 (dd, J = 4.4, 1.6Hz, 1H), 8.59 (d, J = 8.0Hz, 1H),8.09(dd,J=8.8,1.6Hz,1H),7.73(d,J=7.2Hz,1H),7.70–7.63(m,2H),7.44–7 .37(m,2H),7.31–7.25(m,2H),7.06(d,J=6.8Hz,1H),4.01(s,3H),3.75(dd,J=4. 8, 4.8Hz, 4H), 3.56 (s, 2H), 2.73 (s, 3H), 2.55 (dd, J = 4.4, 4.4Hz, 4H), 2.27 (s, 3H). MS:(ES)m / z C 32 H 32 ClN6O2[M+H] + The calculated value is 567.2 and the measured value is 567.5.

[0241] Example 18: N-(2'-chloro-3'-(6-methoxy-5-(((tetrahydro-2H-pyran-4-yl)amino)methyl)pyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-2-methylpyrido[3,2-d]pyrimidin-4-amine

[0242]

[0243] A mixture of 6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxynicotinaldehyde (60 mg, 0.12 mmol), tetrahydro-2H-pyran-4-amine (25 mg, 0.24 mmol), and AcOH (28 mg, 0.48 mmol) in DCM (1.5 mL) was stirred at room temperature for 1 hour. NaBH(OAc) (88 mg, 0.41 mmol) was added to the mixture. After stirring for an additional 40 minutes, the reaction was quenched with saturated NaHCO and extracted with DCM. The organic layer was separated, dried over Na2SO4, concentrated in vacuo and purified by silica gel chromatography to give N-(2'-chloro-3'-(6-methoxy-5-(((tetrahydro-2H-pyran-4-)yl)amino)methyl)pyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-2-methylpyrido[3,2-d]pyrimidin-4-amine. 1H NMR (400MHz, CDCl3) δ9.23 (s, 1H), 8.73 (dd, J = 4.0, 1.2Hz, 1H), 8.58 (d, J = 7.6Hz, 1H) ,8.09(dd,J=8.8,1.6Hz,1H),7.70–7.61(m,3H),7.44–7.37(m,2H),7.31–7.25(m,2H) ,7.06(d,J=7.2Hz,1H),4.03(s,3H),4.04–3.96(m,2H),3.84(s,2H),3.41(ddd,J=11 .6,11.6,2.0Hz,2H),2.73(s,3H),2.80–2.70(m,1H),2.27(s,3H),1.80–1.94(m,4H). MS:(ES)m / z C 33 H 34 ClN6O2[M+H] + The calculated value is 581.2 and the measured value is 581.5.

[0244] Example 19: (S)-5-(((5-(2,2'-dichloro-3'-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1'-biphenyl]-3-yl)-3-ethylpyrazin-2-yl)methyl)amino)methyl)pyrrolidin-2-one

[0245]

[0246] Step a: A mixture of 2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (15 g, 59.2 mmol), 1,3-dibromo-2-chlorobenzene (48 g, 177.5 mmol), K2CO3 (27.8 g, 201 mmol), and Pd(dppf)Cl2 in dioxane (300 mL) and water (45 mL) with DCM (4.83 g, 5.9 mmol) was stirred at 90° C. under N2 for 3 hours. The contents were cooled to room temperature, filtered through a pad of celite / Na2SO4, concentrated in vacuo, and purified by silica gel chromatography to give 3'-bromo-2,2'-dichloro-[1,1'-biphenyl]-3-amine.

[0247] Step b: A mixture of 3'-bromo-2,2'-dichloro-[1,1'-biphenyl]-3-amine (6.0 g, 14.6 mmol), 5-chloropyrido[3,4-b]pyrazine (2.42 g, 14.6 mmol) and Cs2CO3 (7.14 g, 21.9 mmol) in DMSO (100 mL) was stirred at 75°C overnight. The contents were cooled to room temperature, diluted with water and EtOAc, and then filtered through celite. The organic layer of the filtrate was separated, dried over Na2SO4, concentrated in vacuo and purified by silica gel chromatography to give N-(3'-bromo-2,2'-dichloro-[1,1'-biphenyl]-3-yl)pyrido[3,4-b]pyrazin-5-amine. MS: (ES) m / z C 19 H 12 BrCl2N4[M+H] + The calculated value is 445.0 and the measured value is 444.7.

[0248] Step c: A mixture of N-(3'-bromo-2,2'-dichloro-[1,1'-biphenyl]-3-yl)pyrido[3,4-b]pyrazin-5-amine (2.80 g, 6.3 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborolane) (1.76 g, 6.94 mmol), KOAc (1.55 g, 15.75 mmol) and a complex of Pd(dppf)Cl2 with DCM (1.30 g, 1.6 mmol) in dioxane (100 mL) was stirred overnight at 98° C. under N2. The contents were cooled to room temperature and filtered through celite. The filtrate was collected, concentrated in vacuo and purified by flash chromatography on silica gel to give N-(2,2'-dichloro-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-yl)pyrido[3,4-b]pyrazin-5-amine. MS: (ES) m / z C 25 H 24 BCl2N4O2[M+H] + The calculated value is 493.1 and the measured value is 493.1.

[0249] Step d: A mixture of N-(2,2'-dichloro-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-yl)pyrido[3,4-b]pyrazin-5-amine (125 mg, 0.25 mmol), 5-bromo-3-ethylpyrazine-2-carbaldehyde (54 mg, 0.25 mmol), K3PO4 (161 mg, 0.76 mmol) and X-PhosPdGen2 (40 mg, 0.050 mmol) in THF (2.5 mL) and water (2.5 mL) was stirred at room temperature for 3 h. The contents were filtered through a pad of celite and Na2SO4. The filtrate was collected, concentrated in vacuo and purified by flash chromatography on silica gel to give 5-(2,2'-dichloro-3'-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1'-biphenyl]-3-yl)-3-ethylpyrazine-2-carbaldehyde. MS: (ES) m / z C 26 H 19 Cl2N6O[M+H] + The calculated value is 501.1 and the measured value is 501.1.

[0250] Step e: A mixture of 5-(2,2'-dichloro-3'-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1'-biphenyl]-3-yl)-3-ethylpyrazine-2-carbaldehyde (40 mg, 0.080 mmol), (S)-5-(aminomethyl)pyrrolidin-2-one hydrochloride (15 mg, 0.10 mmol), Et3N (60 mg, 0.60 mmol) and AcOH (90 mg, 1.5 mmol) in EtOH (1 mL) and DCM (1 mL) was heated at 65° C. for 20 minutes. The contents were cooled to room temperature and NaBH(OAc)3 (40 mg, 0.19 mmol) was added, followed by stirring for an additional 15 minutes. The volatiles were removed in vacuo and the resulting residue was purified by HPLC to afford (S)-5-(((5-(2,2'-dichloro-3'-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1'-biphenyl]-3-yl)-3-ethylpyrazin-2-yl)methyl)amino)methyl)pyrrolidin-2-one. 1H NMR(400MHz,CD3OD)δ9.14(s,1H),8.97(s,1H),8.83(s,1H),8.57(d,J=8.4Hz,1H), 8.16(d,J=6.8Hz,1H),7.71(d,J=8.0Hz,1H),7.64–7.50(m,3H),7.40(d,J=6.8Hz,1 H),7.29(d,J=7.6Hz,1H),4.72–4.60(m,2H),4.20–4.10(m,1H),3.41–3.40(m,2H), 2.94(q,J=7.6Hz,2H),2.50–2.32(m,3H),2.04–1.90(m,1H),1.40(t,J=7.4Hz,3H). MS:(ES)m / z C 31 H 29 Cl2N8O[M+H] + The calculated value is 599.2 and the measured value is 599.5.

[0251] Example 20: 1-((6-(2,2'-dichloro-3'-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)-3-methylazetidine-3-carboxylic acid

[0252]

[0253] Step a: A mixture of N-(2,2'-dichloro-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-yl)pyrido[3,4-b]pyrazin-5-amine (250 mg, 0.50 mmol), 6-chloro-2-methoxynicotinaldehyde (94 mg, 0.55 mmol), K3PO4 (265 mg, 2.5 mmol) and X-PhosPdGen2 (70 mg, 0.090 mmol) in THF (4 mL) and water (4 mL) was stirred at room temperature for 5 hours. The contents were filtered through a pad of celite and Na2SO4. The filtrate was collected, concentrated in vacuo and purified by flash chromatography on silica gel to give 6-(2,2'-dichloro-3'-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1'-biphenyl]-3-yl)-2-methoxynicotinaldehyde. MS: (ES) m / z C 26 H 18 Cl2N5O2[M+H] + The calculated value is 502.1 and the measured value is 502.1.

[0254] Step b: A mixture of 6-(2,2'-dichloro-3'-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1'-biphenyl]-3-yl)-2-methoxynicotinaldehyde (40 mg, 0.080 mmol), 3-methylazetidine-3-carboxylic acid (30 mg, 0.26 mmol), and AcOH (75 mg, 1.25 mmol) in DMF (1 mL) was stirred at room temperature. After 1 hour, NaBH(OAc)3 (70 mg, 0.33 mmol) was added and the contents were stirred for an additional 1 hour. The volatiles were removed in vacuo and the resulting residue was purified by HPLC to afford 1-((6-(2,2'-dichloro-3'-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)-3-methylazetidine-3-carboxylic acid. 1 H NMR (400MHz, CD3OD) δ9.15(d,J=1.6Hz,1H),8.97(s,1H),8.48(d,J=7.6Hz,1H),8.12(d,J=6.4Hz,1H),7.88(d,J=8.0Hz,1H),7.67(d,J=8.0Hz,1H), 7.60–7.51(m,2H),7.46–7.35(m,3H),7.30(d,J=6.8Hz,1H),4.53(d,J=14 .4Hz,1H),4.51(s,3H),4.14(d,J=10.8Hz,2H),4.08(s,3H),1.61(s,3H). MS:(ES)m / z C 31 H 27 Cl2N6O3[M+H] + The calculated value is 601.1 and the measured value is 600.9.

[0255] Example 21: (S)-5-(((6-(2,2'-dichloro-3'-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)methyl)pyrrolidin-2-one

[0256]

[0257] A mixture of 6-(2,2'-dichloro-3'-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1'-biphenyl]-3-yl)-2- methoxypyridine-3-carbaldehyde (30 mg, 0.060 mmol), (S)-5-(aminomethyl)pyrrolidin-2-one hydrochloride (15 mg, 0.10 mmol), Et3N (60 mg, 0.60 mmol), and AcOH (90 mg, 1.5 mmol) in EtOH (1 mL) and DCM (1 mL) was heated at 65 °C for 30 min. The contents were cooled to room temperature and NaBH(OAc)3(40 mg, 0.19 mmol) was added. After stirring for another 30 min, the volatiles were removed in vacuo. The resulting residue was purified by HPLC to give (S)-5-((((6-(2,2'-dichloro-3'-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1'-biphenyl]-3-yl)-2- methoxypyridin-3-yl)methyl)amino)methyl)pyrrolidin-2-one. 1 H NMR (400 MHz, CD3OD) δ 9.11 (s, 1H), 8.93 (s, 1H), 8.80 (d, J = 7.6 Hz, 1H), 8.27 (d, J = 6.0 Hz, 1H), 7.90 (d, J = 7.2 Hz, 1H), 7.67 (d, J = 7.6 Hz, 1H), 7.56 - 7.49 (m, 2H), 7.46 - 7.37 (m, 3H), 7.17 (d, J = 6.8 Hz, 1H), 4.34 (s, 2H), 4.11 (s, 3H), 4.10 - 4.02 (m, 1H), 3.30 - 3.20 (m, 2H), 2.48 - 2.30 (m, 3H), 1.96 - 1.84 (m, 1H). MS: (ES) m / z C 31 H 28 Cl2N7O2[M+H] + Calc. 600.2, found 599.8.

[0258] Example 22: (3R,4R)-4-(((5-(2,2'-dichloro-3'-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1'- biphenyl]-3-yl)-3-methoxypyrazin-2-yl)methyl)amino)tetrahydro-2H-pyran-3-ol

[0259]

[0260] A mixture of 5-(2,2'-dichloro-3'-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1'- biphenyl]-3-yl)-3-methoxypyrazine-2-carbaldehyde (50 mg, 0.10 mmol), (3R,4R)-4- aminotetrahydro-2H-pyran-3-ol hydrochloride (20 mg, 0.13 mmol), Et3N (75 mg, 0.75 mmol), and AcOH (120 mg, 2.0 mmol) in EtOH (2 mL) and DCM (2 mL) was heated at 65 °C for 40 min. The contents were cooled to room temperature and NaBH(OAc)3 (65 mg, 0.30 mmol) was added. After stirring for another 10 min, the volatiles were removed in vacuo. The resulting residue was purified by HPLC to give (3R,4R)-4-(((5-(2,2'-dichloro-3'-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1'- biphenyl]-3-yl)-3-methoxypyrazin-2-yl)methyl)amino)tetrahydro-2H-pyran-3-ol. 1 H NMR (400 MHz, CD3OD) δ 9.14 (d, J = 1.2 Hz, 1H), 8.96 (d, J = 1.6 Hz, 1H), 8.58 - 8.56 (m, 1H), 8.54 (s, 1H), 8.15 (d, J = 6.4 Hz, 1H), 7.73 (d, J = 7.2 Hz, 1H), 7.62 - 7.54 (m, 2H), 7.51 (d, J = 6.8 Hz, 1H), 7.40 (d, J = 6.8 Hz, 1H), 7.29 (d, J = 7.6 Hz, 1H), 4.84 (s, 2H), 4.12 (s, 3H), 4.08 - 3.94 (m, 3H), 3.64 - 3.53 (m, 2H), 3.46 (dd, J = 11.2, 11.2 Hz, 1H), 2.24 - 2.10 (m, 1H), 1.93 (dd, J = 12.0, 3.6 Hz, 1H). MS: (ES) m / z C 30 H 28 Cl2N7O3[M+H] + Calc. 604.2, found 603.9.

[0261] Example 23: 1-((5-(2,2'-dichloro-3'-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1'- biphenyl]-3-yl)-3-methoxypyrazin-2-yl)methyl)azetidine-3-carboxylic acid

[0262]

[0263] A mixture of 5-(2,2'-dichloro-3'-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1'-biphenyl]-3-yl)-3-methoxypyrazine-2-carbaldehyde (35 mg, 0.10 mmol), azetidine-3-carboxylic acid (25 mg, 0.25 mmol), and AcOH (60 mg, 1.0 mmol) in DMF (0.5 mL) was stirred at room temperature. After 40 minutes, NaBH(OAc)3 (65 mg, 0.30 mmol) was added and the contents were stirred for an additional hour. The volatiles were removed in vacuo, and the resulting residue was purified by HPLC to afford 1-((5-(2,2'-dichloro-3'-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1'-biphenyl]-3-yl)-3-methoxypyrazine-2-yl)methyl)azetidine-3-carboxylic acid. 1 H NMR (400MHz, CD3OD) δ9.15(d,J=1.6Hz,1H),8.97(s,1H),8.48(s,1H),8.46(d,J=8.4Hz,1H),8.11(d,J=6.8Hz,1H),7.71(d,J=7.2Hz,1H),7.60– 7.55(m,2H),7.50(d,J=7.2Hz,1H),7.40(d,J=6.4Hz,1H),7.31(d,J=7.2 Hz,1H),4.74(s,2H),4.74–4.30(m,4H),4.11(s,3H),3.84–3.72(m,1H). MS:(ES)m / zC 29 H 24 Cl2N7O3[M+H] + The calculated value is 588.1 and the measured value is 588.0.

[0264] Example 24: 1-((5-(2,2'-dichloro-3'-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1'-biphenyl]-3-yl)-3-methoxypyrazin-2-yl)methyl)-3-methylazetidine-3-carboxylic acid

[0265]

[0266] A mixture of 5-(2,2'-dichloro-3'-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1'-biphenyl]-3-yl)-3-methoxypyrazine-2-carbaldehyde (37 mg, 0.10 mmol), 3-methylazetidine-3-carboxylic acid (25 mg, 0.25 mmol), and AcOH (60 mg, 1.0 mmol) in DMF (1 mL) was stirred at room temperature. After 1 hour, NaBH(OAc)3 (50 mg, 0.23 mmol) was added and the contents were stirred for an additional 15 minutes. The volatiles were removed in vacuo and the resulting residue was purified by HPLC to afford 1-((5-(2,2'-dichloro-3'-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1'-biphenyl]-3-yl)-3-methoxypyrazin-2-yl)methyl)-3-methylazetidine-3-carboxylic acid. 1 H NMR (400MHz, CD3OD) δ9.14(d,J=1.6Hz,1H),8.96(d,J=1.6Hz,1H),8.54(d,J=8.0Hz,1H),8.49(s,1H),8.15(d,J=6.0Hz,1H),7.71(d,J=6.8Hz,1H) ,7.61–7.54(m,2H),7.50(d,J=7.6Hz,1H),7.40(d,J=6.4Hz,1H),7.28(d ,J=7.2Hz,1H),4.75(s,2H),4.70–4.10(m,4H),4.11(s,3H),1.65(s,3H). MS:(ES)m / z C 30 H 26 Cl2N7O3[M+H] + The calculated value is 602.1 and the measured value is 602.0.

[0267] Example 25: 1-((((6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl])-3-yl)-2-methoxypyridin-3-yl)methyl)amino)methyl)cyclopropan-1-ol

[0268]

[0269] This compound was prepared using a method analogous to Example 1, Step e, starting from 6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[l,l'-biphenyl]-3-yl)-2-methoxybenzaldehyde and 1-(aminomethyl)-cyclopropan-l-ol. The crude material was purified by preparative HPLC to give the desired product 1-((((6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-)yl)amino)-[l,l'-biphenyl]-3-yl)-2-methoxy-pyridin-3-yl)methyl)amino)methyl)cyclopropan-l-ol. 1 H NMR (400 MHz, CD3OD) δ 9.03 (d, J = 3.9 Hz, 1H), 8.17 - 8.13 (m, 1H), 8.06 - 8.01 (m, 1H), 7.88 (d, J = 7.6 Hz, 1H), 7.66 - 7.62 (m, 2H), 7.53 (dd, J = 8.0, 8.0 Hz, 1H) 7.46 - 7.38 (m, 2H), 7.36 (d, J = 7.6 Hz, 1H), 7.27 (d, J = 7.6 Hz, 1H), 4.37 (s, 2H), 4.09 (s, 3H), 3.20 (s, 2H), 2.65 (s, 3H), 2.12 (s, 3H), 0.94 - 0.90 (m, 2H), 0.76 - 0.72 (m, 2H). MS: (ES) m / z C 32 H 32 ClN6O2[M+H] + Calcd 567.2, Found 567.5.

[0270] Example 26: 3-(((6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[l,l'-biphenyl]-3-yl)-2-methoxy-pyridin-3-yl)methyl)amino)propan-l-ol

[0271]

[0272] This compound was prepared using a method analogous to Example 1, Step e, starting from 6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[l,l'-biphenyl]-3-yl)-2-methoxybenzaldehyde and 3-aminopropan-l-ol. The crude material was purified by preparative HPLC to give the desired product 3-(((6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl))amino)-[l,l'-biphenyl]-3-yl)-2-methoxy-pyridin-3-yl)methyl)amino)propan-l-ol. 1H NMR (400MHz, CD3OD) δ9.05(dd,J=4.3,1.4Hz,1H),8.17(dd,J=8.6,1.4Hz,1H),8.05(dd,J=8.6,4.3Hz,1H),7.87(d,J=7.5Hz,1H),7.68–7.48( m,3H),7.48–7.24(m,4H),4.28(s,2H),4.08(s,3H),3.75(t,J=5.7Hz,2 H),3.25(t,J=6.9Hz,2H),2.65(s,3H),2.12(s,3H),2.00–1.89(m,2H). MS:(ES)m / zC 31 H 32 ClN6O2[M+H] + The calculated value is 555.2 and the measured value is 555.5.

[0273] Example 27: 1-((6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)-3-methylazetidin-3-ol

[0274]

[0275] This compound was prepared using a procedure similar to that in Example 1, step e, starting with 6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxynicotinaldehyde and 3-methylazetidin-3-ol hydrochloride. The crude material was purified by preparative HPLC to yield the desired product, 1-((6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)-3-methylazetidin-3-ol. 1H NMR (400MHz, CD3OD) δ9.05 (dd, J=4.3, 1.4Hz, 1H), 8.17 (dd, J=8.6, 1.4Hz, 1H), 8.05(dd,J=8.6,4.3Hz,1H),7.88(d,J=7.5Hz,1H),7.68–7.48(m,3H),7.40(ddd ,J=18.2,16.1,7.6Hz,3H),7.28(dd,J=7.7,1.3Hz,1H),4.52(s,1H),4.46(s,1 H), 4.22 (d, J = 10.9Hz, 2H), 4.07 (s, 5H), 2.66 (s, 3H), 2.11 (s, 3H), 1.53 (s, 3H). MS:(ES)m / z C 32 H 32 ClN6O2[M+H] + The calculated value is 567.2 and the measured value is 567.6.

[0276] Example 28: (3R,4R)-4-(((6-(2'-chloro-2-fluoro-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)tetrahydro-2H-pyran-3-ol

[0277]

[0278] This compound was prepared using a procedure similar to that in Example 1, step e, starting with 6-(2'-chloro-2-fluoro-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxynicotinaldehyde and (3R,4R)-4-aminotetrahydro-2H-pyran-3-ol hydrochloride. The crude material was purified by preparative HPLC to afford the desired product, (3R,4R)-4-(((6-(2'-chloro-2-fluoro-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)tetrahydro-2H-pyran-3-ol. 1H NMR(400MHz,CD3OD)δ9.03(dd,J=4.4,1.4Hz,1H),8.33(dd,J=8.3,1.5Hz,1H),8.24– 8.15(m,2H),8.04(dd,J=8.6,4.4Hz,1H),7.87(d,J=7.7Hz,1H),7.64–7.52(m,2H),7. 50–7.39(m,3H),4.34(d,J=13.2Hz,1H),4.24(d,J=13.3Hz,1H),4.15(s,3H),4.06–3. 93(m,3H),3.61–3.40(m,3H),2.75(s,3H),2.16–2.03(m,1H),1.86(d,J=12.8Hz,1H). MS:(ES)m / z C 32 H 31 ClFN6O3[M+H] + The calculated value is 601.2 and the measured value is 601.5.

[0279] Example 29: (S)-5-(((6-(2'-chloro-2-fluoro-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1)'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)methyl)pyrrolidin-2-one

[0280]

[0281] This compound was prepared using a procedure similar to that in Example 1, step e, starting with 6-(2'-chloro-2-fluoro-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxynicotinaldehyde and (S)-5-aminomethylpyrrolidin-2-one hydrochloride. The crude material was purified by preparative HPLC to afford the desired product, (S)-5-((((6-(2'-chloro-2-fluoro-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)methyl)pyrrolidin-2-one. 1H NMR (400MHz, CD3OD) δ9.04 (dd, J=4.3, 1.4Hz, 1H), 8.32 (d, J=8.2Hz, 1H), 8.24 –8.15(m,2H),8.05(dd,J=8.6,4.3Hz,1H),7.88(d,J=7.7Hz,1H),7.64–7.54( m,2H),7.51–7.40(m,3H),4.34(d,J=2.9Hz,2H),4.16(s,3H),4.09–4.01(m,1 H), 3.30–3.21 (m, 2H), 2.75 (s, 3H), 2.46–2.32 (m, 3H), 1.91 (d, J = 6.4Hz, 1H). MS:(ES)m / z C 32 H 30 ClFN7O2[M+H] + The calculated value is 598.2 and the measured value is 598.5.

[0282] Example 30: (3R,4R)-4-(((6-(2-fluoro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)tetrahydro-2H-pyran-3-ol

[0283]

[0284] This compound was prepared using a procedure similar to that in Example 1, step e, starting from 6-(2-fluoro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxynicotinaldehyde and (3R,4R)-4-aminotetrahydro-2H-pyran-3-ol hydrochloride. The crude material was purified by preparative HPLC to afford the desired product, (3R,4R)-4-(((6-(2-fluoro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)tetrahydro-2H-pyran-3-ol. 1H NMR (400 MHz, CD3OD) δ 9.08 - 9.02 (m, 1H), 8.21 - 8.11 (m, 2H), 8.05 (dd, J = 8.6, 4.4 Hz, 1H), 7.87 (d, J = 7.7 Hz, 1H), 7.65 - 7.51 (m, 2H), 7.50 - 7.34 (m, 4H), 4.34 (d, J = 13.3 Hz, 1H), 4.24 (d, J = 13.3 Hz, 1H), 4.14 (s, 3H), 4.06 - 3.93 (m, 3H), 3.61 - 3.40 (m, 3H), 2.67 (s, 3H), 2.19 (s, 3H), 2.18 - 2.05 (m, 1H), 1.91 - 1.82 (m, 1H). MS: (ES) m / z C 33 H 34 FN6O3[M+H] + Calc. 581.3, found 581.5.

[0285] Example 31: (S)-5-((((6-(2-fluoro-2'-methyl-3'-((2-methylpyrido[3,2- d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)methyl)pyrrolidin-2-one

[0286]

[0287] This compound was prepared using procedures analogous to Example 1, step e, starting from 6-(2-fluoro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxybenzaldehyde and (S)-5-(aminomethyl)pyrrolidin-2-one hydrochloride. The crude product was purified by preparative HPLC to give the desired product (S)-5-((((6-(2-fluoro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)methyl)pyrrolidin-2-one. 1H NMR (400MHz, CD3OD) δ8.83(d,J=4.3Hz,1H),8.15–7.99(m,3H),7.82(dd,J=8.6,4.3Hz,1H),7.70(d,J=7.5Hz,1H),7.48–7.33(m,4H) ,7.21(d,J=7.5Hz,1H),4.07(s,3H),3.88–3.79(m,3H),2.73–2.63(m,2H),2.59(s,3H),2.38–2.23(m,3H),2.23(s,3H),1.81(s,1H). MS:(ES)m / z C 33 H 33 FN7O2[M+H] + The calculated value is 578.3 and the measured value is 578.5.

[0288] Example 32: N-(3'-(5-((azetidin-3-ylamino)methyl)-6-methoxypyridin-2-yl)-2'-chloro-2-methyl-[1,1'-biphenyl]-3-yl)-2-methylpyrido[3,2-d]pyrimidin-4-amine

[0289]

[0290] This compound was prepared using a method similar to that of Example 1, step e, starting from 6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxynicotinaldehyde and tert-butyl 3-aminoazetidine-1-carboxylate. The crude material was purified by silica gel chromatography to afford tert-butyl 3-(((6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)azetidine-1-carboxylate. 10% TFA in DCM was added to the Boc-protected intermediate. The contents were lyophilized to obtain the product N-(3'-(5-((azetidin-3-ylamino)methyl)-6-methoxypyridin-2-yl)-2'-chloro-2-methyl-[1,1'-biphenyl]-3-yl)-2-methylpyrido[3,2-d]pyrimidin-4-amine. 1H NMR (400MHz, CD3OD) δ9.05(dd,J=4.3,1.4Hz,1H),8.21–8.09(m,1H),8.05(dd,J=8.6,4.3Hz,1H),7.88(d,J=7.6Hz ,1H),7.69–7.48(m,3H),7.48–7.25(m,4H),4.45–4.34(m,5H),4.24(s,2H),4.08(s,3H),2.66(s,3H),2.12(s,3H). MS:(ES)m / z C 31 H 31 ClN7O[M+H] + The calculated value is 552.2 and the measured value is 552.5.

[0291] Example 33: N-(2'-chloro-3'-(6-methoxy-5-((piperidin-4-ylamino)methyl)pyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-2-methylpyrido[3,2-d]pyrimidin-4-amine

[0292]

[0293] This compound was prepared using a procedure similar to that in Example 1, step e, starting with 6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxynicotinaldehyde and tert-butyl 4-aminopiperidine-1-carboxylate. The crude material was purified by silica gel chromatography to afford tert-butyl 4-(((6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)piperidine-1-carboxylate. The Boc-protected intermediate was treated with 10% TFA in DCM, and the solution was lyophilized to afford the pure product, N-(2'-chloro-3'-(6-methoxy-5-((piperidin-4-ylamino))methyl)pyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-2-methylpyrido[3,2-d]pyrimidin-4-amine. 1H NMR (400MHz, CD3OD) δ9.05 (dd, J=4.4, 1.4Hz, 1H), 8.16 (dd, J=8.6, 1.4Hz, 1H), 8.06 (dd ,J=8.6,4.3Hz,1H),7.90(d,J=7.6Hz,1H),7.67–7.48(m,3H),7.48–7.32(m,3H),7.28(d d,J=7.6,1.3Hz,1H),4.35(s,2H),4.09(s,3H),3.59(dd,J=9.9,6.4Hz,3H),3.19–3.08 (m,2H),2.66(s,3H),2.47(d,J=13.6Hz,2H),2.12(s,3H),1.97(q,J=14.2,12.4Hz,2H). MS:(ES)m / z C 33 H 35 ClN7O[M+H] + The calculated value is 580.3 and the measured value is 580.5.

[0294] Example 34: 2-(((6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)(methyl)amino)ethan-1-ol

[0295]

[0296] This compound was prepared using a method similar to that in Example 1, step e, starting with 6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxynicotinaldehyde and 2-(methylamino)ethane-1-ol. The crude product was purified by silica gel chromatography to yield 2-(((6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)(methyl)amino)ethane-1-ol. 1H NMR (400MHz, CD3OD) δ8.83 (dd, J=4.3, 1.5Hz, 1H), 8.05 (ddd, J=10.4, 8.5, 1.4Hz, 2H ),7.86–7.75(m,2H),7.62(dd,J=7.7,1.8Hz,1H),7.48(dd,J=7.6,7.6Hz,1H),7.42 –7.32(m,2H),7.25(d,J=7.5Hz,1H),7.16–7.09(m,1H),3.99(s,3H),3.72(t,J=6.0 Hz, 2H), 3.66 (s, 2H), 2.65 (t, J = 6.1Hz, 2H), 2.58 (s, 3H), 2.33 (s, 3H), 2.16 (s, 3H). MS:(ES)m / z C 31 H 32 ClN6O2[M+H] + The calculated value is 555.2 and the measured value is 555.5.

[0297] Example 35: (S)-3-(((6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)propane-1,2-diol

[0298]

[0299] This compound was prepared using a method similar to that in Example 1, step e, starting with 6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxynicotinaldehyde and (S)-3-aminopropane-1,2-diol. The crude product was purified by silica gel chromatography to yield (S)-3-(((6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)propane-1,2-diol. 1H NMR(400MHz,CD3OD)δ8.83(dd,J=4.2,1.5Hz,1H),8.10–8.00(m,2H),7.82(dd,J=8.5,4.2Hz,1 H),7.71(d,J=7.4Hz,1H),7.61(dd,J=7.7,1.7Hz,1H),7.48(t,J=7.6Hz,1H),7.42–7.32(m,2H) ,7.24(d,J=7.4Hz,1H),7.12(dd,J=7.6,1.2Hz,1H),4.02(s,3H),3.92–3.75(m,3H),3.56–3.4 6(m,2H),2.77(dd,J=12.1,3.8Hz,1H),2.63(dd,J=12.1,8.3Hz,1H),2.58(s,3H),2.16(s,3H). MS:(ES)m / z C 31 H 32 ClN6O3[M+H] + The calculated value is 571.2 and the measured value is 571.5.

[0300] Example 36: (R)-3-(((6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)propane-1,2-diol

[0301]

[0302] This compound was prepared using a method similar to that in Example 1, step e, starting with 6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxynicotinaldehyde and (R)-3-aminopropane-1,2-diol. The crude product was purified by silica gel chromatography to yield (R)-3-(((6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin))-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)propane-1,2-diol. 1H NMR (400MHz, CD3OD) δ8.82 (dd, J=4.2, 1.5Hz, 1H), 8.05 (ddd, J=8.5, 7.4, 1.4Hz, 2H), 7.81 (dd, J=8.5,4.2Hz,1H),7.71(d,J=7.5Hz,1H),7.60(dd,J=7.6,1.7Hz,1H),7.47(dd,J=7.6,7.6Hz,1 H),7.41–7.32(m,2H),7.24(d,J=7.4Hz,1H),7.15–7.08(m,1H),4.02(s,3H),3.93–3.74(m,3H) ,3.58–3.46(m,2H),2.79(dd,J=12.1,3.7Hz,1H),2.69–2.55(m,1H),2.58(s,3H),2.15(s,3H). MS:(ES)m / z C 31 H 32 ClN6O3[M+H] + The calculated value is 571.2 and the measured value is 571.5.

[0303] Example 37: (R)-1-((6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)-3-methylpyrrolidine-3-carboxylic acid

[0304]

[0305] This compound was prepared using a procedure similar to that in Example 1, step e, starting with 6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxynicotinaldehyde and (R)-3-methylpyrrolidine-3-carboxylic acid. The crude material was purified by silica gel chromatography to afford (R)-1-((6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)-3-methylpyrrolidine-3-carboxylic acid. 1H NMR (400MHz, CD3OD) δ8.82 (dd, J=4.3, 1.5Hz, 1H), 8.05 (ddd, J=9.7, 8.3, 1.4Hz, 2H), 7.92 –7.78(m,2H),7.63(dd,J=7.7,1.7Hz,1H),7.50(dd,J=7.6,7.6Hz,1H),7.43–7.32(m,3H), 7.16–7.08(m,1H),4.49–4.36(m,2H),4.10(s,3H),3.71(s,1H),3.50(s,1H),3.38(s,1H) ,2.98(d,J=10.7Hz,1H),2.58(s,3H),2.39(s,1H),2.15(s,3H),1.96(s,1H),1.34(s,3H). MS:(ES)m / z C 34 H 34 ClN6O3[M+H] + The calculated value is 609.2 and the measured value is 609.5.

[0306] Example 38: (R)-1-((6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)-3-methylpyrrolidin-3-ol

[0307]

[0308] This compound was prepared using a procedure similar to that in Example 1, step e, starting with 6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxynicotinaldehyde and (R)-3-methylpyrrolidin-3-ol hydrochloride. The crude material was purified by silica gel chromatography to yield (R)-1-((6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)-3-methylpyrrolidin-3-ol. 1H NMR (400 MHz, CD3OD) δ 8.82 (dd, J = 4.3, 1.5 Hz, 1H), 8.05 (ddd, J = 9.4, 8.4, 1.4 Hz, 2H), 7.86 - 7.75 (m, 2H), 7.61 (dd, J = 7.7, 1.8 Hz, 1H), 7.48 (t, J = 7.6 Hz, 1H), 7.42 - 7.32 (m, 2H), 7.25 (d, J = 7.5 Hz, 1H), 7.15 - 7.08 (m, 1H), 4.00 (s, 3H), 3.83 - 3.70 (m, 2H), 2.96 (q, J = 7.9 Hz, 1H), 2.79 - 2.61 (m, 3H), 2.58 (s, 3H), 2.16 (s, 3H), 1.90 (t, J = 7.0 Hz, 2H), 1.36 (s, 3H). MS: (ES) m / z C 33 H 34 ClN6O2[M+H] + Calc. 581.2, found 581.5.

[0309] Example 39: (3R,4R)-4-(((6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2- d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)(methyl)amino)tetrahydro-2H-pyran-3-ol

[0310]

[0311] (3R,4R)-4-(((6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2- d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)(methyl)amino)tetrahydro-2H-pyran-3-ol (43 mg, 0.072 mmol) and formalin (37% in water, 0.15 mL, 2.0 mmol) in MeOH (1 mL) and DCE (1 mL) was stirred at room temperature for 30 min. To the reaction was added NaBH(OAc)3 (80 mg, 0.38 mmol). After an additional 30 min, the mixture was quenched with water and extracted with 2:1 v / v CHCl3:IPA. The organic phase was purified by silica gel chromatography to give the product (3R,4R)-4-(((6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2- d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)(methyl)amino)tetrahydro-2H-pyran-3-ol. 1H NMR(400MHz,CD3OD)δ8.82(dd,J=4.2,1.5Hz,1H),8.05(ddd,J=8.1,6.0,1.4Hz,2H),7.85–7.73(m ,2H),7.62(dd,J=7.7,1.8Hz,1H),7.48(dd,J=7.6,7.6Hz,1H),7.42–7.32(m,2H),7.25(d,J=7.4Hz ,1H),7.15–7.08(m,1H),4.06–3.87(m,4H),3.99(s,3H),3.62(d,J=13.9Hz,1H),3.54–3.37(m,2H ),2.66–2.56(m,1H),2.58(s,3H),2.32(s,3H),2.16(s,3H),2.08–1.95(m,1H),1.79–1.70(m,1H). MS:(ES)m / z C 34 H 36 ClN6O3[M+H] + The calculated value is 611.3 and the measured value is 611.5.

[0312] Example 40: (R)-1-((6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)pyrrolidine-3-carboxylic acid

[0313]

[0314] This compound was prepared using a procedure similar to that in Example 1, step e, starting with 6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxynicotinaldehyde and (R)-pyrrolidine-3-carboxylic acid. The crude material was purified by silica gel chromatography to afford (R)-1-((6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)pyrrolidine-3-carboxylic acid. 1H NMR (400 MHz, CD3OD) δ 8.82 (dd, J = 4.3, 1.5 Hz, 1H), 8.05 (ddd, J = 8.2, 5.4, 1.4 Hz, 2H), 7.90 (d, J = 7.6 Hz, 1H), 7.81 (dd, J = 8.5, 4.2 Hz, 1H), 7.63 (dd, J = 7.7, 1.7 Hz, 1H), 7.50 (dd, J = 7.6, 7.6 Hz, 1H), 7.42 - 7.32 (m, 3H), 7.15 - 7.07 (m, 1H), 4.40 (s, 2H), 4.08 (s, 3H), 3.57 (dd, J = 11.3, 5.6 Hz, 1H), 3.40 (m, 3H), 3.16 - 3.04 (m, 1H), 2.57 (s, 3H), 2.31 (m, 2H), 2.15 (s, 3H). MS: (ES) m / z C 33 H 32 ClN6O3[M+H] + Calc. 595.2, found 595.5.

[0315] Example 41: 2-(((6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)propane-1,3-diol

[0316]

[0317] This compound was prepared using a method analogous to Example 1, step e, using 6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxybenzaldehyde and 2-aminopropane-1,3-diol as starting materials. The crude product was purified by silica gel chromatography to give the product 2-(((6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)propane-1,3-diol. 1H NMR (400MHz, CD3OD) δ9.07–9.01(m,1H),8.16(dd,J=8.6,1.4Hz,1H),8.05(dd,J=8. 6,4.3Hz,1H),7.94–7.87(m,1H),7.68–7.58(m,2H),7.53(dd,J=7.6,7.6Hz,1H),7.4 8–7.32(m,3H),7.28(d,J=7.6Hz,1H),4.41(s,2H),4.09(s,3H),3.90(dd,J=12.0,4. 4Hz, 2H), 3.80 (dd, J = 11.9, 6.3Hz, 2H), 3.38–3.32 (m, 1H), 2.65 (s, 3H), 2.12 (s, 3H). MS:(ES)m / z C 31 H 32 ClN6O3[M+H] + The calculated value is 571.2 and the measured value is 571.5.

[0318] Example 42: 2-(((6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)ethan-1-ol

[0319]

[0320] This compound was prepared using a procedure similar to that in Example 1, step e, starting with 6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxynicotinaldehyde and 2-aminoethan-1-ol. The crude material was purified by flash chromatography to afford the product, 2-(((6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)ethan-1-ol. 1 H NMR (400MHz, CD3OD) δ9.06(dd,J=4.3,1.4Hz,1H),8.16(dd,J=8.6,1.5Hz,1H),8.06(dd,J=8.6,4.4Hz,1H),7.93–7.85(m,1H),7 .68–7.49(m,3H),7.48–7.25(m,4H),4.32(s,2H),4.09(s,3H),3.89–3.81(m,2H),3.24–3.16(m,2H),2.66(s,3H),2.12(s,3H). MS:(ES)m / z C30 H 30 ClN6O2[M+H] + The calculated value is 541.2 and the measured value is 541.5.

[0321] Example 43: 2-(((6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)-2-(hydroxymethyl)propane-1,3-diol

[0322]

[0323] This compound was prepared using a method similar to that in Example 1, step e, starting with 6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxynicotinaldehyde and 2-amino-2-(hydroxymethyl)propane-1,3-diol. The crude product was purified by silica gel chromatography to yield 2-(((6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)-2-(hydroxymethyl)propane-1,3-diol. 1 H NMR(400MHz, CD3OD) δ9.06(dd,J=4.4,1.4Hz,1H),8.17(dd,J=8.6,1.4Hz,1H),8.06(dd,J=8.6,4.4Hz,1H),7.93–7 .86(m,1H),7.67–7.48(m,3H),7.48–7.25(m,4H),4.43(s,2H),4.08(s,3H),3.83(s,6H),2.66(s,3H),2.12(s,3H). MS:(ES)m / z C 32 H 34 ClN6O4[M+H] + The calculated value is 601.2 and the measured value is 601.5.

[0324] Example 44: 1-((6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)-4-methylpiperidin-4-ol

[0325]

[0326] This compound was prepared using a method similar to that in Example 1, step e, starting with 6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxynicotinaldehyde and 4-methylpiperidin-4-ol. The crude product was purified by silica gel chromatography to yield 1-((6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)-4-methylpiperidin-4-ol. 1 HNMR(400MHz,CD3OD)δ9.06(dd,J=4.3,1.5Hz,1H),8.17(dd,J=8.6,1.5Hz,1H), 8.06(dd,J=8.6,4.3Hz,1H),7.99–7.88(m,1H),7.66(dd,J=7.8,1.7Hz,1H),7.6 2–7.49(m,2H),7.48–7.36(m,3H),7.29(d,J=7.5Hz,1H),4.39(s,2H),4.09(s,3 H),3.44–3.66(m,4H),2.66(s,3H),2.12(s,3H),1.90–1.77(m,4H),1.29(s,3H). MS:(ES)m / z C 34 H 36 ClN6O2[M+H] + The calculated value is 595.3 and the measured value is 595.5.

[0327] Example 45: (3R,4R)-4-(((6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)tetrahydro-2H-pyran-3-ol

[0328]

[0329] This compound was prepared using a method analogous to Example 1, step e, starting from 6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxybenzaldehyde and (3R,4R)-4-aminotetrahydro-2H-pyran-3-ol hydrochloride. The crude was purified by silica gel chromatography to give the product (3R,4R)-4-(((6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)tetrahydro-2H-pyran-3-ol. 1 H NMR (400 MHz, CD3OD) δ 8.82 (dd, J = 4.2, 1.5 Hz, 1H), 8.10 - 8.00 (m, 2H), 7.86 - 7.72 (m, 2H), 7.61 (dd, J = 7.7, 1.7 Hz, 1H), 7.48 (dd, J = 7.6 Hz, 1H), 7.42 - 7.32 (m, 2H), 7.25 (d, J = 7.4 Hz, 1H), 7.15 - 7.08 (m, 1H), 4.02 (s, 3H), 3.96 - 3.82 (m, 5H), 3.54 - 3.38 (m, 2H), 2.88 (d, J = 10.9 Hz, 1H), 2.58 (s, 3H), 2.16 (s, 3H), 1.92 - 1.78 (m, 1H), 1.71 (d, J = 13.2 Hz, 1H). MS: (ES) m / z C 33 H 34 ClN6O3[M+H] + Calcd 597.2, Found 597.6.

[0330] Example 46: 2-((6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)-2,5,7-triazaspiro[3.4]octan-6-one

[0331]

[0332] This compound was prepared using a method similar to that in Example 1, step e, starting with 6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxynicotinaldehyde and 2,5,7-triazaspiro[3.4]octan-6-one hydrochloride. The product was purified by preparative HPLC to yield the desired product, 2-((6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)-2,5,7-triazaspiro[3.4]octan-6-one. 1 H NMR(400MHz, DMSO-d6)δ9.91(s,1H),8.88(dd,J=4.3,1.5Hz,1H),8.14(dd,J=8.5,1.5Hz,1H),7.93–7.87(m,2H),7.65(dd,J=7.7,1.8Hz,1H),7. 56(dd,J=7.6,7.6Hz,1H),7.42–7.33(m,3H),7.13(dd,J=7.6,1.3Hz,1H) ,7.00(s,1H),3.95(s,3H),3.62–3.50(m,8H),2.50(s,3H),2.08(s,3H). MS:(ES)m / zC 33 H 32 ClN8O2[M+H] + The calculated value is 607.2 and the measured value is 607.2.

[0333] Example 47: 1-((6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)-3-methylazetidine-3-carboxylic acid

[0334]

[0335] This compound was prepared using a method similar to that in Example 1, starting from 6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxynicotinaldehyde and 3-methylazetidine-3-carboxylic acid. The crude product was purified by preparative HPLC to afford 1-((6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)-3-methylazetidine-3-carboxylic acid. 1H NMR (400MHz, CD3OD) δ9.06 (dd, J=4.4, 1.4Hz, 1H), 8.26 (dd, J=8.6, 1.4Hz, 1H), 8.07 (dd, J=8.6, 4. 4Hz,1H),8.03–7.93(m,2H),7.64(dd,J=7.7,1.7Hz,1H),7.62–7.57(m,1H),7.53(dd,J=7.6,7.6Hz ,1H),7.49–7.42(m,1H),7.42–7.37(m,1H),7.35(d,J=7.5Hz,1H),7.27(dd,J=7.8,1.3Hz,1H),4.6 3–4.43(m,4H),4.18(dd,J=16.9,11.5Hz,2H),4.07(s,3H),2.68(s,3H),2.10(s,3H),1.63(s,3H). MS:(ES)m / zC 33 H 32 ClN6O3[M+H] + The calculated value is 595.2 and the measured value is 595.5.

[0336] Example 48: 3-(((6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)-2,2-dimethylpropanamide

[0337]

[0338] This compound was prepared using a method similar to that in Example 1, step e, starting with 6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxynicotinaldehyde and 3-amino-2,2-dimethylpropanamide. The product was purified by preparative HPLC to yield the desired product, 3-(((6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)-2,2-dimethylpropanamide. 1H NMR (400MHz, CD3OD) δ9.06(dd,J=4.3,1.4Hz,1H),8.17(dd,J=8.6,1.4Hz,1H),8.06(dd,J=8.6,4.4Hz,1H),7.87(d,J=7.6H z,1H),7.68–7.51(m,3H),7.48–7.29(m,4H),4.29(s,2H),4.12(s,3H),3.14(s,2H),2.66(s,3H),2.12(s,3H),1.35(s,6H). MS:(ES)m / zC 33 H 34 ClN7O2[M+H] + The calculated value is 596.3 and the measured value is 596.5.

[0339] Example 49: (S)-5-(((6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)piperidin-2-one

[0340]

[0341] This compound was prepared using a method similar to that in Example 1, step e, starting with 6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxynicotinaldehyde and (S)-5-aminopiperidin-2-one hydrochloride. The product was purified by preparative HPLC to yield the desired product, (S)-5-(((6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)piperidin-2-one. 1H NMR (400 MHz, CD3OD) δ 8.82 (dd, J = 4.3, 1.5 Hz, 1H), 8.05 (ddd, J = 8.1, 5.3, 1.4 Hz, 2H), 7.83 - 7.74 (m, 2H), 7.61 (dd, J = 7.7, 1.7 Hz, 1H), 7.50 - 7.34 (m, 3H), 7.24 (d, J = 7.5 Hz, 1H), 7.12 (dd, J = 7.6, 1.3 Hz, 1H), 4.02 (s, 3H), 3.90 - 3.81 (m, 2H), 3.49 (ddd, J = 12.1, 4.6, 1.5 Hz, 1H), 3.13 (dd, J = 12.2, 7.6 Hz, 1H), 3.04 - 2.98 (m, 1H), 2.58 (s, 3H), 2.50 - 2.29 (m, 2H), 2.16 (s, 3H), 2.16 - 2.04 (m, 1H), 1.83 - 1.73 (m, 1H). MS: (ES) m / z C 33 H 33 ClN7O2[M+H] + Calc. 594.2, found 594.6.

[0342] Example 50: (R)-4-(((6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4- yl)amino)-[l,l'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)pyrrolidin-2-one

[0343]

[0344] This compound was prepared using a method analogous to Example 1, step e, starting from 6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[l,l'- biphenyl]-3-yl)-2-methoxynicotinaldehyde and (R)-4-aminopyrrolidin-2-one hydrochloride. The product was purified by preparative HPLC to give the desired product (R)-4-(((6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[l,l'- biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)pyrrolidin-2-one. 1H NMR (400MHz, CD3OD) δ8.82 (dd, J=4.2, 1.5Hz, 1H), 8.06 (ddd, J=8.2, 6.0, 1.4Hz, 2H), 7.83 –7.73(m,2H),7.61(dd,J=7.6,1.7Hz,1H),7.48(dd,J=7.6,7.6Hz,1H),7.39–7.35(m,2H), 7.25(d,J=7.4Hz,1H),7.13–7.11(m,1H),4.02(s,3H),3.82(d,J=2.3Hz,2H),3.69–3.60( m,2H),3.27–3.24(m,1H),2.64–2.60(m,1H),2.58(s,3H),2.30–2.24(m,1H),2.16(s,3H). MS:(ES)m / z C 32 H 31 ClN7O2[M+H] + The calculated value is 580.2 and the measured value is 580.5.

[0345] Example 51: (R)-5-(((6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)methyl)pyrrolidin-2-one

[0346]

[0347] This compound was prepared using a method similar to that in Example 1, step e, starting with 6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxynicotinaldehyde and (R)-5-(aminomethyl)pyrrolidin-2-one hydrochloride. The product was purified by preparative HPLC to yield the desired product, (R)-5-((((6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin))-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)methyl)pyrrolidin-2-one. 1H NMR (400MHz, CD3OD) δ8.85 (dd, J=4.3, 1.5Hz, 1H), 8.06 (ddd, J=11.5, 8.3, 1.4Hz, 2H), 7.8 3(dd,J=8.5,4.3Hz,1H),7.74(d,J=7.5Hz,1H),7.61(dd,J=7.6,1.8Hz,1H),7.49(dd,J=7. 6,7.6Hz,1H),7.40–7.32(m,2H),7.25(d,J=7.4Hz,1H),7.13(dd,J=7.6,1.2Hz,1H),4.03( s,3H),3.86(s,3H),2.78–2.68(m,2H),2.59(s,3H),2.37–2.13(m,6H),1.85–1.75(m,1H). MS:(ES)m / z C 33 H 33 ClN7O2[M+H] + The calculated value is 594.2 and the measured value is 594.5.

[0348] Example 52: N-(2'-chloro-3'-(5-((isopropylamino)methyl)-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-2-methylpyrido[3,2-d]pyrimidin-4-amine

[0349]

[0350] This compound was prepared using a method similar to that in Example 1, step e, starting with 6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxynicotinaldehyde and propan-2-amine. The product was purified by preparative HPLC to yield the desired product, N-(2'-chloro-3'-(5-((isopropylamino)methyl)-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-2-methylpyrido[3,2-d]pyrimidin-4-amine. 1H NMR (400MHz, CD3OD) δ8.82(dd,J=4.3,1.5Hz,1H),8.06(ddd,J=8.2,3.1,1.4Hz,2H),7.81( dd,J=8.5,4.2Hz,1H),7.73(d,J=7.5Hz,1H),7.61(dd,J=7.7,1.8Hz,1H),7.47(dd,J=7.6, 7.6Hz,1H),7.41–7.32(m,2H),7.25(d,J=7.4Hz,1H),7.11(dd,J=7.6,1.2Hz,1H),4.03(s, 3H), 3.84 (s, 2H), 2.91 (sep, J = 6.3Hz, 1H), 2.58 (s, 3H), 2.16 (s, 3H), 1.16 (d, J = 6.3Hz, 6H). MS:(ES)m / z C 31 H 32 ClN6O[M+H] + The calculated value is 539.2, and the measured value is 539.2.

[0351] Example 53: 2-(((6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)-2-methylpropanoic acid

[0352]

[0353] This compound was prepared using a method similar to that in Example 1, step e, starting with 6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxynicotinaldehyde and 2-amino-2-methylpropionic acid. The product was purified by preparative HPLC to yield the desired product, 2-(((6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)-2-methylpropionic acid. 1H NMR (400MHz, CD3OD) δ9.05(dd,J=4.4,1.5Hz,1H),8.17(dd,J=8.6,1.4Hz,1H),8.06(dd,J=8.6,4.3Hz,1H),7.91(d,J =7.6Hz,1H),7.65–7.48(m,3H),7.46–7.28(m,4H),4.29(s,2H),4.09(s,3H),2.66(s,3H),2.13(s,3H),1.70(s,6H). MS:(ES)m / zC 32 H 32 ClN6O3[M+H] + The calculated value is 583.2 and the measured value is 583.2.

[0354] Example 54: ((6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl))-2-methoxypyridin-3-yl)methyl)glycine

[0355]

[0356] This compound was prepared using a method similar to that in Example 1, step e, starting with 6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxynicotinaldehyde and glycine. The product was purified by preparative HPLC to yield the desired product ((6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)glycine. 1 H NMR (400MHz, CD3OD) δ9.06(dd,J=4.4,1.4Hz,1H),8.18(dd,J=8.6,1.4Hz,1H),8.06(dd,J=8.6,4.3Hz,1H),7.88(d,J =7.6Hz,1H),7.67–7.48(m,3H),7.46–7.28(m,4H),4.35(s,2H),4.09(s,3H),3.96(s,2H),2.66(s,3H),2.12(s,3H). MS:(ES)m / z C 30 H 28 ClN6O3[M+H] + The calculated value is 555.2 and the measured value is 555.2.

[0357] Example 55: N-(2'-chloro-3'-(5-((dimethylamino)methyl)-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-2-methylpyrido[3,2-d]pyrimidin-4-amine

[0358]

[0359] This compound was prepared using a method similar to that in Example 1, step e, starting with 6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxynicotinaldehyde and dimethylamine. The product was purified by preparative HPLC to yield the desired product, N-(2'-chloro-3'-(5-((dimethylamino)methyl)-6-methoxypyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-2-methylpyrido[3,2-d]pyrimidin-4-amine. 1 H NMR (400MHz, CD3OD) δ8.83 (dd, J=4.3, 1.5Hz, 1H), 8.06 (ddd, J=8.3, 8.3, 1.4Hz, 2H ),7.82(dd,J=8.5,4.2Hz,1H),7.72(d,J=7.5Hz,1H),7.63(dd,J=7.7,1.8Hz,1H), 7.49(dd,J=7.6,7.6Hz,1H),7.43–7.33(m,2H),7.26(d,J=7.5Hz,1H),7.12(dd,J= 7.5,1.3Hz,1H),4.00(s,3H),3.61(s,2H),2.59(s,3H),2.34(s,6H),2.16(s,3H). MS:(ES)m / z C 30 H 30 ClN6O[M+H] + The calculated value is 525.2, and the measured value is 525.2.

[0360] Example 56: 1-((6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)piperidin-4-ol

[0361]

[0362] This compound was prepared using a method similar to that in Example 1, step e, starting with 6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxynicotinaldehyde and piperidin-4-ol. The product was purified by preparative HPLC to yield the desired product, 1-((6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)piperidin-4-ol. 1 HNMR(400MHz,CD3OD)δ8.83(dd,J=4.3,1.5Hz,1H),8.06(ddd,J=9.5,8.2,1.4Hz,2H),7.8 6–7.72(m,2H),7.62(dd,J=7.6,1.7Hz,1H),7.48(dd,J=7.6,7.6Hz,1H),7.42–7.31(m,2H) ,7.27(d,J=7.5Hz,1H),7.13(dd,J=7.6,1.2Hz,1H),4.00(s,3H),3.67(s,3H),2.95–2.91( m,2H),2.59(s,3H),2.42–2.34(m,2H),2.16(s,3H),1.92–1.87(m,2H),1.67–1.58(m,2H). MS:(ES)m / z C 33 H 34 ClN6O2[M+H] + The calculated value is 581.2 and the measured value is 581.2.

[0363] Example 57: (3S,4S)-4-(((6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)tetrahydro-2H-pyran-3-ol

[0364]

[0365] This compound was prepared using a method similar to that in Example 1, step e, starting with 6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxynicotinaldehyde and (3S,4S)-4-aminotetrahydro-2H-pyran-3-ol. The product was purified by preparative HPLC to afford the desired product, (3S,4S)-4-(((6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)tetrahydro-2H-pyran-3-ol. 1 H NMR(400MHz,CD3OD)δ8.83(dd,J=4.3,1.5Hz,1H),8.06(ddd,J=12.0,8.3,1.4Hz,2H),7.86–7.76 (m,2H),7.62(dd,J=7.7,1.8Hz,1H),7.49(dd,J=7.6,7.6Hz,1H),7.42–7.33(m,2H),7.29(d,J=7 .4Hz,1H),7.13(dd,J=7.7,1.2Hz,1H),4.09–3.87(m,8H),3.56–3.39(m,1H),3.08(d,J=11.2Hz, 1H), 2.59 (s, 3H), 2.16 (s, 3H), 1.98–1.88 (m, 1H), 1.77 (d, J = 12.2Hz, 1H), 1.29 (t, J = 7.3Hz, 1H). MS:(ES)m / z C 33 H 34 ClN6O3[M+H] + The calculated value is 597.2 and the measured value is 597.6.

[0366] Example 58: (S)-5-(((6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methylpyridin-3-yl)methyl)amino)methyl)pyrrolidin-2-one

[0367]

[0368] This compound was prepared using a method similar to that in Example 1, step e, starting with 6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methylnicotinaldehyde and (S)-5-(aminomethyl)pyrrolidin-2-one. The product was purified by preparative HPLC to yield the desired product, (S)-5-((((6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methylpyridin-3-yl)methyl)amino)methyl)pyrrolidin-2-one. 1 H NMR (400MHz, CD3OD) δ8.84(dd,J=4.3,1.5Hz,1H),8.07(ddd,J=16.4,8.3,1.4Hz,2H),7.92–7.78(m,2H),7.56–7.33(m,5H),7.12(dd,J=7.5,1. 2Hz,1H),4.02–3.82(m,2H),3.24–3.19(m,1H),2.89–2.78(m,2H),2.64 (s,3H),2.58(s,3H),2.40–2.22(m,3H),2.17(s,3H),1.93–1.84(m,1H). MS:(ES)m / z C 33 H 33 ClN7O[M+H] + The calculated value is 578.2 and the measured value is 578.5.

[0369] Example 59: 1-((6-(2,2'-dichloro-3'-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)azetidin-3-ol

[0370]

[0371] This compound was prepared using a method similar to that in Example 1, step e, starting with 6-(2,2'-dichloro-3'-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1'-biphenyl]-3-yl)-2-methoxynicotinaldehyde and azetidin-3-ol. The product was purified by preparative HPLC to yield the desired product, 1-((6-(2,2'-dichloro-3'-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)azetidin-3-ol. 1H NMR (400MHz, CD3OD) δ9.14(d,J=1.8Hz,1H),8.96(d,J=1.9Hz,1H),8.69–8.62(m,1H),8.21(d,J=6.4Hz,1H),7.89(d,J=7.7Hz,1H),7.68( dd,J=7.8,1.9Hz,1H),7.57–7.52(m,2H),7.48–7.34(m,3H),7.28–7.20(m,1H),4.78–4.60(m,1H),4.49–4.39(m,4H),4.11–3.98(m,5H). MS:(ES)m / z C 29 H 25 Cl2N6O2[M+H] + The calculated value is 559.1 and the measured value is 559.1.

[0372] Example 60: (S)-4-(((6-(2,2'-dichloro-3'-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)pyrrolidin-2-one

[0373]

[0374] This compound was prepared using a method similar to that in Example 1, step e, starting with 6-(2,2'-dichloro-3'-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1'-biphenyl]-3-yl)-2-methoxynicotinaldehyde and (S)-4-aminopyrrolidin-2-one. The product was purified by preparative HPLC to yield the desired product, (S)-4-(((6-(2,2'-dichloro-3'-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)pyrrolidin-2-one. 1 HNMR (400MHz, CD3OD) δ9.10 (s, 1H), 8.93 (s, 1H), 8.86 (d, J = 8.3Hz, 1H), 8. 30(d,J=6.4Hz,1H),7.91(d,J=7.6Hz,1H),7.70–7.63(m,1H),7.58–7.35(m ,5H),7.16(d,J=7.6Hz,1H),4.33(s,2H),4.28–4.21(m,1H),4.12(s,3H),3 .91–3.83(m,1H),3.61–3.57(m,1H),2.95–2.87(m,1H),2.66–2.55(m,1H). MS:(ES)m / zC 30 H26 Cl2N7O2[M+H] + The calculated value is 586.2 and the measured value is 586.1.

[0375] Example 61: 1-((6-(2,2'-dichloro-3'-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)azetidine-3-carboxylic acid

[0376]

[0377] This compound was prepared using a method similar to that in Example 1, step e, starting with 6-(2,2'-dichloro-3'-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1'-biphenyl]-3-yl)-2-methoxynicotinaldehyde and azetidine-3-carboxylic acid. The product was purified by preparative HPLC to yield the desired product, 1-((6-(2,2'-dichloro-3'-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)azetidine-3-carboxylic acid. 1 H NMR (400MHz, CD3OD) δ9.13(s,1H),8.95(s,1H),8.70–8.63(m,1H),8.21(d,J=6.3Hz,1H),7.89(d,J=7.5Hz,1H),7.68(dd,J=7.7,1.8Hz ,1H),7.56–7.52(m,2H),7.47–7.34(m,3H),7.23(dd,J=7.7,1.7Hz,1H),4.5(s,2H),4.43–4.41(m,4H),4.09(s,3H),3.78–3.69(m,1H). MS:(ES)m / z C 30 H 25 Cl2N6O3[M+H] + The calculated value is 587.1 and the measured value is 587.1.

[0378] Example 62: 3-(5-((((3R,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)methyl)-6-methoxypyridin-2-yl)-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-2-carbonitrile

[0379]

[0380] This compound was prepared using a procedure similar to that in Example 1, step e, starting from 3-(5-formyl-6-methoxypyridin-2-yl)-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-2-carbonitrile and (3R,4R)-4-aminotetrahydropyran-3-ol hydrochloride. The product was purified by preparative HPLC to afford the desired product, 3-(5-((((3R,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)methyl)-6-methoxypyridin-2-yl)-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-2-carbonitrile. 1 H NMR (400MHz, CDCl3) δ9.24 (s, 1H), 8.74 (dd, J=4.3, 1.5Hz, 1H), 8.63 (dd, J=8.4, 1.5Hz, 1H), 8.10 (dd, J= 8.4,1.5Hz,1H),7.82(dd,J=7.9,1.2Hz,1H),7.76–7.64(m,3H),7.49–7.40(m,2H),7.37(d,J=7.9Hz,1H ),7.14(d,J=7.9Hz,1H),4.11(s,3H),4.05(dd,J=12.8,2.8Hz,1H),3.98–3.77(m,3H),3.43(ddd,J=23. 8,12.0,2.0Hz,2H),2.84–2.78(m,1H),2.74(s,3H),2.34(s,3H),1.89–1.75(m,1H),1.70–1.50(m,2H). MS:(ES)m / z C 34 H 34 N7O3[M+H] + The calculated value is 588.3 and the measured value is 588.2.

[0381] Example 63: (S)-5-((((6-(2-chloro-2'-methyl-3'-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)methyl)pyrrolidin-2-one

[0382]

[0383] This compound was prepared using a method similar to that in Example 1, step e, starting with 6-(2-chloro-2'-methyl-3'-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1'-biphenyl]-3-yl)-2-methoxynicotinaldehyde and (S)-5-(aminomethyl)pyrrolidin-2-one. The crude product was purified by preparative HPLC to afford (S)-5-((((6-(2-chloro-2'-methyl-3'-(pyrido[3,4-b]pyrazin-5-ylamino))-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)methyl)pyrrolidin-2-one. 1 H NMR (400MHz, CD3OD) δ9.01(s,1H),8.85(s,1H),8.14(d,J=6.2Hz,1H),8.04(d,J=8 .4Hz,1H),7.72(d,J=7.5Hz,1H),7.59(d,J=8.0Hz,1H),7.46(dd,J=7.7,7.7Hz,1H ),7.39–7.32(m,2H),7.25–7.19(m,2H),7.07(d,J=7.4Hz,1H),4.01(s,3H),3.87– 3.77(m,3H),2.77–2.61(m,2H),2.36–2.20(m,3H),2.15(s,3H),1.85–1.75(s,1H). MS:(ES)m / zC 32 H 31 ClN7O2[M+H] + The calculated value is 580.2 and the measured value is 580.5.

[0384] Example 64: (3R,4R)-4-(((6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-ethylpyridin-3-yl)methyl)amino)tetrahydro-2H-pyran-3-ol

[0385]

[0386] This compound was prepared using a method similar to that in Example 1, step e, starting with 6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-ethylnicotinaldehyde and (3R,4R)-4-aminotetrahydro-2H-pyran-3-ol hydrochloride. The product was purified by preparative HPLC to yield the desired product, (3R,4R)-4-(((6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-ethylpyridin-3-yl)methyl)amino)tetrahydro-2H-pyran-3-ol. 1 H NMR (400MHz, CDCl3) δ9.35(s,1H),8.77(dd,J=4.2,1.5Hz,1H),8.50(d,J=7.9Hz,1H),8.18(dd,J=8.5,1.5Hz,1H) ,7.80(d,J=7.9Hz,1H),7.72(dd,J=8.5,4.0Hz,1H),7.61(dd,J=7.7,1.8Hz,1H),7.53(d,J=8.0Hz,1H),7.46–7.3 6(m,2H),7.31(dd,J=7.6,1.8Hz,1H),7.09(d,J=7.6Hz,1H),4.17–3.89(m,4H),3.55–3.39(m,2H),3.12–3.00(m, 2H), 2.96 (q, J = 7.2Hz, 2H), 2.75 (s, 3H), 2.25 (s, 3H), 1.95–1.85 (m, 1H), 1.80–1.73 (m, 1H), 1.36 (t, J = 7.3Hz, 3H). MS:(ES)m / z C 34 H 36 ClN6O2[M+H] + The calculated value is 595.3 and the measured value is 595.2.

[0387] Example 65: (S)-5-(((6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-ethylpyridin-3-yl)methyl)amino)methyl)pyrrolidin-2-one

[0388]

[0389] This compound was prepared using a method similar to that in Example 1, step e, starting with 6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-ethylnicotinaldehyde and (S)-5-(aminomethyl)pyrrolidin-2-one hydrochloride. The product was purified by preparative HPLC to yield the desired product, (S)-5-((((6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-ethylpyridin-3-yl)methyl)amino)methyl)pyrrolidin-2-one. 1 H NMR (400MHz, CDCl3) δ9.26(s,1H),8.74(dd,J=4.3,1.5Hz,1H),8.57(d,J=8.2Hz,1H),8.11(dd,J=8.5,1.5H z,1H),7.76–7.65(m,2H),7.61(dd,J=7.7,1.8Hz,1H),7.50(d,J=8.2Hz,1H),7.45–7.36(m,2H),7.30(dd,J= 7.5,1.8Hz,1H),7.06(d,J=8.2Hz,1H),6.35(s,1H),3.95(m,2H),3.83(bs,1H),3.09(q,J=7.3Hz,2H),2.99 –2.88(m,2H),2.73(s,3H),2.42–2.30(m,2H),2.25(s,3H),2.04(d,1H),1.83(m,1H),1.36(t,J=7.3Hz,3H). MS:(ES)m / z C 34 H 35 ClN7O[M+H] + The calculated value is 592.3 and the measured value is 592.2.

[0390] Example 66: 3-(((6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)-3-methylbutan-1-ol

[0391]

[0392] This compound was prepared using a method similar to that in Example 1, step e, starting with 6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxynicotinaldehyde and 3-amino-3-methylbutan-1-ol. The product was purified by preparative HPLC to yield the desired product, 3-(((6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)-3-methylbutan-1-ol. 1 H NMR (400MHz, CD3OD) δ9.06(dd,J=4.4,1.5Hz,1H),8.17(dd,J=8.7,1.5Hz,1H),8.06(dd,J=8.6,4.3Hz,1H),7.89(d,J=7.5Hz,1H),7.66–7.48(m,3H),7 .48–7.25(m,4H),4.26(s,2H),4.07(s,3H),3.92(t,J=5.8Hz,2H),2.66(s, 3H), 2.12 (s, 3H), 1.96 (t, J = 5.8Hz, 2H), 1.53 (s, 6H), 1.38 (d, J = 4.2Hz, 1H). MS:(ES)m / z C 33 H 36 ClN6O2[M+H] + The calculated value is 583.3 and the measured value is 583.5.

[0393] Example 67: 3-(((6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)-2,2-dimethylpropan-1-ol

[0394]

[0395] This compound was prepared using a method similar to that in Example 1, step e, starting with 6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxynicotinaldehyde and 3-amino-2,2-dimethylpropan-1-ol. The product was purified by preparative HPLC to yield the desired product, 3-(((6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)-2,2-dimethylpropan-1-ol. 1H NMR (400 MHz, CD3OD) δ 9.06 (dd, J = 4.4, 1.4 Hz, 1H), 8.18 (dd, J = 8.6, 1.5 Hz, 1H), 8.06 (dd, J = 8.6, 4.4 Hz, 1H), 7.86 (d, J = 7.5 Hz, 1H), 7.68 - 7.49 (m, 3H), 7.48 - 7.25 (m, 4H), 4.26 (s, 2H), 4.08 (s, 3H), 3.48 (s, 2H), 3.09 (s, 2H), 2.66 (s, 3H), 2.12 (s, 3H), 1.02 (s, 6H). MS: (ES) m / z C 33 H 36 ClN6O2[M+H] + Calc. 583.3, found 583.5.

[0396] Example 68: 1-((6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)azetidin-3-ol

[0397]

[0398] This compound was prepared using a method analogous to Example 1, step e, starting from 6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxybenzaldehyde and azetidin-3-ol. The product was purified by preparative HPLC to give the desired product 1-((6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)azetidin-3-ol. 1 H NMR (400 MHz, CD3OD) δ 9.04 (dd, J = 4.3, 1.4 Hz, 1H), 8.16 (dd, J = 8.6, 1.4 Hz, 1H), 8.04 (dd, J = 8.6, 4.3 Hz, 1H), 7.90 (d, J = 7.5 Hz, 1H), 7.68 - 7.58 (m, 2H), 7.53 (dd, J = 7.6 Hz, 1H), 7.46 - 7.39 (m, 2H), 7.36 (d, J = 7.5 Hz, 1H), 7.27 (d, J = 7.5 Hz, 1H), 4.63 (b, 1H), 4.49 (s, 2H), 4.41 (bs, 2H), 4.08 (s, 3H), 4.03 (b, 2H), 2.65 (s, 3H), 2.12 (s, 3H). MS: (ES) m / z C31 H 30 ClN6O2[M+H] + Calculated 553.2, found 553.5.

[0399] Example 69: (S)-N-(2'-chloro-3'-(6-methoxy-5-(((tetrahydrofuran-3-yl)amino)methyl)pyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-2-methylpyrido[3,2-d]pyrimidin-4-amine

[0400]

[0401] This compound was prepared using a method analogous to Example 1, step e, starting from 6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxynicotinaldehyde and (S)-tetrahydrofuran-3-amine. The product was purified by preparative HPLC to give the desired product (S)-N-(2'-chloro-3'-(6-methoxy-5-(((tetrahydrofuran-3-yl)amino)methyl)pyridin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-2-methylpyrido[3,2-d]pyrimidin-4-amine. 1 H NMR (400 MHz, CDC13) δ 9.24 (s, 1H), 8.73 (dd, J = 4.3, 1.5 Hz, 1H), 8.58 (dd, J = 8.2, 1.3 Hz, 1H), 8.11 (dd, J = 8.5, 1.5 Hz, 1H), 7.73 - 7.59 (m, 3H), 7.41 (dd, J = 7.8 Hz, 2H), 7.33 - 7.24 (m, 2H), 7.06 (dd, J = 7.8, 1.3 Hz, 1H), 4.04 (s, 3H), 3.98 (m, 1H), 3.90 - 3.78 (m, 4H), 3.71 (dd, J = 9.6, 3.6 Hz 1H), 3.55 - 3.45 (m, 1H), 2.73 (s, 3H), 2.27 (s, 3H), 2.22 - 2.09 (m, 1H), 1.90 - 1.80 (m, 1H). MS: (ES) m / z C 32 H 32 ClN6O2[M+H] + Calculated 567.2, found 567.5.

[0402] Example 70: 3-(((6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)-2,2-dimethylpropanoic acid

[0403]

[0404] This compound was prepared using a method similar to that in Example 1, step e, starting with 6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxynicotinaldehyde and 3-amino-2,2-dimethylpropanoic acid. The product was purified by preparative HPLC to yield the desired product, 3-(((6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)-2,2-dimethylpropanoic acid. 1 H NMR(400MHz, CDCl3)δ9.23(s,1H),8.73(dd,J=4.1,1.5Hz,1H),8.58(d,J=8.3Hz,1H),8.10(dd,J=8.4,1.5Hz,1H),7.73–7.60(m,3H),7.46–7.3 6(m,2H),7.32–7.28(m,2H),7.06(d,J=7.6Hz,1H),4.10(s,3H),4.00(s ,2H),2.75(s,2H),2.73(s,3H),2.26(s,3H),2.06(s,1H),1.23(s,6H). MS:(ES)m / z C 33 H 34 ClN6O3[M+H] + The calculated value is 597.2 and the measured value is 597.5.

[0405] Example 71: 1-(((6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)-2-methylpropan-2-ol

[0406]

[0407] This compound was prepared using a method similar to that in Example 1, step e, starting with 6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxynicotinaldehyde and 1-amino-2-methylpropan-2-ol. The product was purified by preparative HPLC to yield the desired product, 1-(((6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)-2-methylpropan-2-ol. 1 H NMR (400MHz, CD3OD) δ9.05 (dd, J=4.3, 1.4Hz, 1H), 8.17 (dd, J=8.6, 1.4Hz, 1H), 8.06 (dd, J=8.6,4.4Hz,1H),7.90(d,J=7.6Hz,1H),7.66(dd,J=7.6,1.4Hz,1H),7.60(d,J=8.6Hz, 1H),7.53(dd,J=7.6Hz,1H),7.46–7.38(m,2H),7.37(d,J=7.6Hz,1H),7.28(dd,J=7.6,1 .4Hz,1H),4.34(s,2H),4.09(s,3H),3.03(s,2H),2.66(s,3H),2.12(s,3H),1.31(s,6H). MS:(ES)m / z C 32 H 34 ClN6O2[M+H] + The calculated value is 569.2 and the measured value is 569.5.

[0408] Example 72: (R)-4-(((6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)-3-hydroxybutanoic acid

[0409]

[0410] This compound was prepared using a method similar to that in Example 1, step e, starting with 6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxynicotinaldehyde and (R)-4-amino-3-hydroxybutyric acid. The crude product was purified by preparative HPLC to yield (R)-4-(((6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-)yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)-3-hydroxybutyric acid. 1 H NMR (400MHz, CD3OD) δ9.03 (dd, J=4.4, 1.4Hz, 1H), 8.15 (dd, J=8.6, 1.4Hz, 1H), 8.03 (dd, J=8.6, 4 .3Hz,1H),7.88(d,J=7.5Hz,1H),7.64(ddd,J=7.7,1.9,1.9Hz,2H),7.53(dd,J=7.6,7.6Hz,1H), 7.48–7.38(m,2H),7.35(d,J=7.5Hz,1H),7.25(d,J=7.6Hz,1H),4.37–4.31(m,3H),4.09(s,3H), 3.30–3.26(m,1H),3.07(dd,J=12.7,9.8Hz,1H),2.65(s,3H),2.57(d,J=6.3Hz,2H),2.12(s,3H). MS:(ES)m / z C 32 H 32 ClN6O4[M+H] + The calculated value is 599.2 and the measured value is 599.4.

[0411] Example 73: (S)-5-(((6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-(trifluoromethyl)pyridin-3-yl)methyl)amino)methyl)pyrrolidin-2-one

[0412]

[0413] This compound was prepared using a method similar to that in Example 1, step e, starting with 6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-(trifluoromethyl)nicotinaldehyde and (S)-5-(aminomethyl)pyrrolidin-2-one. The crude product was purified by preparative HPLC to afford (S)-5-((((6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4)-yl)amino)-[1,1'-biphenyl]-3-yl)-2-(trifluoromethyl)pyridin-3-yl)methyl)amino)methyl)pyrrolidin-2-one. 1 H NMR (400MHz, CD3OD) δ8.83(dd,J=4.3,1.5Hz,1H),8.30(d,J=8.2Hz,1H),8.06(ddd,J=9.5,8.3,1.4Hz,2 H),7.94(d,J=8.2Hz,1H),7.82(dd,J=8.5,4.3Hz,1H),7.61(dd,J=7.7,1.8Hz,1H),7.53(dd,J=7.6,7.6H z,1H),7.44(dd,J=7.5,1.8Hz,1H),7.39(dd,J=7.9,7.9Hz,1H),7.14(dd,J=7.7,1.3Hz,1H),4.06(s,2H ),3.88–3.79(m,1H),2.83–2.62(m,2H),2.58(s,3H),2.42–2.21(m,3H),2.17(s,3H),1.91–1.80(m,1H). MS:(ES)m / z C 33 H 30 ClF3N7O[M+H] + The calculated value is 632.2 and the measured value is 632.5.

[0414] Example 74: (R)-1-((6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)piperidine-3-carboxylic acid

[0415]

[0416] This compound was prepared using a method similar to that in Example 1, step e, starting from 6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxynicotinaldehyde and (R)-piperidine-3-carboxylic acid. The crude product was purified by preparative HPLC to yield (R)-1-((6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)piperidine-3-carboxylic acid. 1 H NMR (400MHz, CD3OD) δ8.83(dd,J=4.2,1.5Hz,1H),8.07(dd,J=8.5,1.5Hz,1H),8.04(d,J=8.0Hz,1H),7 .87(d,J=7.5Hz,1H),7.82(dd,J=8.5,4.3Hz,1H),7.66(dd,J=7.6,1.6Hz),7.51(dd,J=7.6,7.6Hz,1H) ,7.43–7.33(m,3H),7.12(dd,J=7.5,1.3Hz,1H),4.25(t,J=13.7Hz,2H),4.10(s,3H),3.30–3.24(m,1H ),3.17–3.04(m,3H),2.70(bs,1H),2.58(s,3H),2.16(s,3H),2.08–1.74(m,3H),1.28(t,J=7.3Hz,1H). MS:(ES)m / z C 34 H 34 ClN6O3[M+H] + The calculated value is 609.2 and the measured value is 609.6.

[0417] Example 75: (S)-4-(((6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)-3-hydroxybutanoic acid

[0418]

[0419] This compound was prepared using a method similar to that in Example 1, step e, starting with 6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxynicotinaldehyde and (S)-4-amino-3-hydroxybutyric acid. The crude product was purified by preparative HPLC to yield (S)-4-(((6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)-3-hydroxybutyric acid. 1 H NMR(400MHz,CD3OD)δ8.74(dd,J=16.8,4.4Hz,1H),8.11–7.94(m,2H),7.82–7.66(m,2H ),7.54(dt,J=7.7,2.3Hz,1H),7.38(ddd,J=7.6,7.6,1.6Hz,1H),7.35–7.24(m,2H),7. 12(dd,J=7.6,1.5Hz,1H),7.03(dd,J=7.6,3.0Hz,1H),4.62(bs,2H),4.30(bs,1H),3.9 6(s,3H),4.08–3.72(m,2H),3.34(s,3H),2.82(m,1H),2.53(s,3H),2.52–2.28(m,1H). MS:(ES)m / z C 32 H 32 ClN6O4[M+H] + The calculated value is 599.2 and the measured value is 599.5.

[0420] Example 76: (S)-1-((6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)piperidine-2-carboxylic acid

[0421]

[0422] This compound was prepared using a method similar to that in Example 1, step e, starting with 6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxynicotinaldehyde and (S)-piperidine-2-carboxylic acid. The crude product was purified by preparative HPLC to yield (S)-1-((6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)piperidine-2-carboxylic acid. 1 H NMR (400MHz, CD3OD) δ8.82 (dd, J=4.3, 1.5Hz, 1H), 8.06 (dd, J=8.8, 1.6Hz, 1H), 8.04 (d, J=8.0Hz, 1H) ,7.97(d,J=7.6Hz,1H),7.81(dd,J=8.5,4.2Hz,1H),7.63(dd,J=7.7,1.7Hz,1H),7.49(dd,J=7.6,7. 6Hz,1H),7.43–7.33(m,3H),7.11(d,J=7.6Hz,1H),4.51–4.15(m,2H),4.04(s,3H),3.48–3.33(m,2H ),2.88(bs,1H),2.58(s,3H),2.25–2.16(m,1H),2.15(s,3H),1.93–1.63(m,4H),1.58–1.45(m,1H). MS:(ES)m / zC 34 H 34 ClN6O3[M+H] + The calculated value is 609.2 and the measured value is 609.6.

[0423] Example 77: 2-((6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)-2,6-diazaspiro[3.4]octan-5-one

[0424]

[0425] This compound was prepared using a procedure analogous to that of Example 1, step e, starting from 6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxynicotinaldehyde and (2,6-diazaspiro[3.4]octan-5-one. The crude product was purified by preparative HPLC to give 2-((6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)-2,6-diazaspiro[3.4]octan-5-one. 1 H NMR (400MHz, CD3OD) δ8.82 (dd, J=4.3, 1.5Hz, 1H), 8.05 (ddd, J=7.9, 6.5, 1.4Hz, 2H), 7.81 (dd, J=8. 4,4.3Hz,1H),7.68(d,J=7.5Hz,1H),7.59(dd,J=7.7,1.7Hz,1H),7.47(dd,J=7.6,7.6Hz,1H),7.43 –7.31(m,2H),7.22(d,J=7.5Hz,1H),7.11(dd,J=7.6,1.3Hz,1H),3.99(s,3H),3.73(s,2H),3.53(d ,J=8.8Hz,2H),3.40(d,J=8.4Hz,2H),3.34(s,2H),2.58(s,3H),2.49(t,J=6.8Hz,2H),2.15(s,3H). MS:(ES)m / zC 34 H 33 ClN7O2[M+H] + The calculated value is 606.2 and the measured value is 606.5.

[0426] Example 78: 2-((6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)-2,5-diazaspiro[3.4]octan-6-one

[0427]

[0428] This compound was prepared using a method similar to that in Example 1, step e, starting with 6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxynicotinaldehyde and 2,5-diazaspiro[3.4]octan-6-one. The crude product was purified by preparative HPLC to yield 2-((6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)-2,5-diazaspiro[3.4]octan-6-one. 1 H NMR (400MHz, CD3OD) δ9.06 (dd, J=4.3, 1.4Hz, 1H), 8.17 (dd, J=8.6, 1.5Hz, 1H), 8.06 (dd, J=8.6, 4.4H z,1H),7.92(dd,J=7.3,7.3Hz,1H),7.64(dd,J=7.7,1.9Hz,1H),7.58(d,J=7.7Hz,1H),7.53(dd,J=6 .8Hz,1H),7.48–7.37(m,2H),7.37(dd,J=7.6,2.0Hz,1H),7.28(d,J=7.7Hz,1H),4.66–4.44(m,3H), 4.39–4.23(m,3H),4.09(s,3H),3.37–3.32(m,2H),2.66(s,3H),2.54(t,J=6.8Hz,2H),2.11(s,3H). MS:(ES)m / zC 34 H 33 ClN7O2[M+H] + The calculated value is 606.2 and the measured value is 606.5.

[0429] Example 79: (R)-5-(((6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)piperidin-2-one

[0430]

[0431] This compound was prepared using a method similar to that in Example 1, step e, starting with 6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxynicotinaldehyde and (R)-5-aminopiperidin-2-one. The crude product was purified by preparative HPLC to yield (R)-5-(((6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)piperidin-2-one. 1 H NMR (400MHz, CD3OD) δ9.05 (dd, J=4.4, 1.4Hz, 1H), 8.17 (dd, J=8.6, 1.5Hz, 1H), 8.05 (dd, J=8.6, 4.3Hz, 1H), 7.95 (d, J=7. 6Hz,1H),7.64(dd,J=7.7,1.8Hz,1H),7.61(d,J=7.9Hz,1H),7.53(dd,J=7.7,7.7Hz,1H),7.47–7.39(m,2H),7.37(d,J=7. 5Hz,1H),7.28(d,J=8.8Hz,1H),4.40(d,J=12.8Hz,1H),4.35(d,J=13.2Hz,1H),4.10(s,3H),3.81–3.73(m,2H),3.53–3. 46(m,1H),2.66(s,3H),2.52(d,J=6.4,Hz,1H),2.50(d,J=6.0Hz,1H),2.43–2.35(bs,1H),2.16–2.06(m,1H)2.12(s,3H). MS:(ES)m / z C 33 H 33 ClN7O2[M+H] + The calculated value is 594.2 and the measured value is 594.5.

[0432] Example 80: (S)-4-(((6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)pyrrolidin-2-one

[0433]

[0434] This compound was prepared using a method similar to that in Example 1, step e, starting with 6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxynicotinaldehyde and (S)-4-aminopyrrolidin-2-one. The crude product was purified by preparative HPLC to yield (S)-4-(((6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)pyrrolidin-2-one. 1 H NMR (400MHz, CD3OD) δ9.06 (dd, J=4.3, 1.4Hz, 1H), 8.18 (dd, J=8.6, 1.5Hz, 1H), 8.06 (dd, J=8.6, 4.4Hz, 1H), 7.94 (d, J=7.6 Hz,1H),7.64(dd,J=7.7,1.7Hz,1H),7.58(dd,J=8.0,1.2Hz,1H),7.53(dd,J=7.6,7.6Hz,1H),7.48–7.39(m,2H),7.37(d, J=7.5Hz,1H),7.28(dd,J=7.7,1.3Hz,1H),4.33(s,2H),4.24(dq,J=8.4,4.2Hz,1H),4.10(s,3H),3.88(dd,J=11.6,7.6Hz ,1H),3.61(dd,J=11.6,4.0Hz,1H),2.91(dd,J=17.7,8.8Hz,1H),2.66(s,3H),2.59(dd,J=17.7,4.7Hz,1H),2.12(s,3H). MS:(ES)m / zC 32 H 31 ClN7O2[M+H] + The calculated value is 580.2 and the measured value is 580.5.

[0435] Example 81: 1-((6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)azetidine-3-carboxylic acid

[0436]

[0437] This compound was prepared using a method similar to that in Example 1, step e, starting from 6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxynicotinaldehyde and azetidine-3-carboxylic acid. The crude product was purified by preparative HPLC to afford 1-((6-(2-chloro-2'-methyl-3'-((2-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)azetidine-3-carboxylic acid. 1 H NMR (400MHz, CD3OD) δ9.05 (dd, J=4.4, 1.4Hz, 1H), 8.19 (dd, J=8.6, 1.4Hz, 1H), 8.05 (dd, J=8.6, 4.4Hz, 1 H),7.89(d,J=7.5Hz,1H),7.64(dd,J=7.8,1.7Hz,1H),7.59(dd,J=8.0,1.3Hz,1H),7.53(ddd,J=7.6,7.6 ,3.4Hz,1H),7.44(d,J=8.1Hz,1H),7.40(ddd,J=7.6,2.9,1.6Hz,1H),7.36(d,J=7.6Hz,1H),7.28(d,J=7 .7Hz,1H),4.60–4.30(m,4H),4.08(s,3H),3.74(p,J=8.6Hz,1H),2.92(s,2H),2.66(s,3H),2.11(s,3H). MS:(ES)m / zC 32 H 29 ClN6O3[M+H] + The calculated value is 581.2 and the measured value is 581.5.

[0438] Example 82: (3R,4R)-4-(((6-(2-chloro-2'-methyl-3'-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)tetrahydro-2H-pyran-3-ol

[0439]

[0440] This compound was prepared using a method similar to that in step e of Example 1, starting with 6-(2-chloro-2'-methyl-3'-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1'-biphenyl]-3-yl)-2-methoxynicotinaldehyde and (3R,4R)-4-aminotetrahydro-2H-pyran-3-ol. The crude product was purified by preparative HPLC to yield (3R,4R)-4-(((6-(2-chloro-2'-methyl-3'-(pyrido[3,4-b]pyrazin-5-ylamino))-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)amino)tetrahydro-2H-pyran-3-ol. 1 H NMR (400MHz, DMSO-d6) δ9.36(s,1H),9.11(s,1H),8.93(s,1H),8.22(d,J=5.9Hz,1H),8.14(d,J =8.1Hz,1H),7.82(d,J=7.5Hz,1H),7.61(d,J=7.1Hz,1H),7.51(dd,J=7.7,7.7Hz,1H),7.40–7. 29(m,2H),7.29–7.19(m,2H),7.01(d,J=7.6Hz,1H),4.63(bs,1H),3.90(s,3H),3.79–3.58(m,4 H), 3.36–3.25 (m, 4H), 2.67 (s, 1H), 2.09 (s, 3H), 1.65 (t, J = 10.2Hz, 1H), 1.51 (d, J = 13.2Hz, 1H). MS:(ES)m / z C 32 H 32 ClN6O3[M+H] + The calculated value is 583.2 and the measured value is 583.5.

[0441] Example 83: 1-((6-(2-chloro-2'-methyl-3'-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)azetidine-3-carboxylic acid

[0442]

[0443] This compound was prepared using a method similar to that in Example 1, step e, starting with 6-(2-chloro-2'-methyl-3'-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1'-biphenyl]-3-yl)-2-methoxynicotinaldehyde and azetidine-3-carboxylic acid. The crude product was purified by preparative HPLC to afford 1-((6-(2-chloro-2'-methyl-3'-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)azetidine-3-carboxylic acid. 1 H NMR(400MHz,DMSO-d6)δ9.36(s,1H),9.12(s,1H),8.93(s,1H),8.22(d,J=6 .1Hz,1H),8.13(d,J=8.0Hz,1H),7.74–7.63(m,1H),7.61(d,J=7.4Hz,1H),7 .51(dd,J=7.7,7.7Hz,1H),7.40–7.29(m,2H),7.24(dd,J=8.3,6.6Hz,2H),7 .08–6.96(m,1H),3.89(s,3H),3.54(s,2H),3.49–3.15(m,6H),2.08(s,3H). MS:(ES)m / z C 31 H 28 ClN6O3[M+H] + The calculated value is 567.2 and the measured value is 567.5.

[0444] Example 84: 1-((6-(2-chloro-2'-methyl-3'-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)azetidin-3-ol

[0445]

[0446] This compound was prepared using a method similar to that in Example 1, step e, starting with 6-(2-chloro-2'-methyl-3'-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1'-biphenyl]-3-yl)-2-methoxynicotinaldehyde and azetidin-3-ol. The crude product was purified by preparative HPLC to afford 1-((6-(2-chloro-2'-methyl-3'-(pyrido[3,4-b]pyrazin-5-ylamino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl)methyl)azetidin-3-ol. 1H NMR (400MHz, DMSO-d6) δ9.36 (s, 1H), 9.11 (d, J = 1.8Hz, 1H), 8.93 (d, J = 1.9Hz, 1H), 8.22 (d, J = 6. 0Hz,1H),8.17–8.14(d,J=8.0Hz,1H),7.66(d,J=7.6Hz,1H),7.61(dd,J=7.8,1.7Hz,1H),7.50(d d,J=7.7,7.7Hz,1H),7.40–7.30(m,2H),7.26–7.21(m,2H),7.02(d,J=7.2Hz,1H),5.31(d,J=6. 5Hz, 1H), 4.20 (q, J = 6.2Hz, 1H), 3.89 (s, 3H), 3.64–3.49 (m, 4H), 2.91–2.75 (m, 2H), 2.08 (s, 3H). MS:(ES)m / z C 30 H 28 ClN6O2[M+H] + The calculated value is 539.2 and the measured value is 539.4.

[0447] Biological example: Enzyme-linked immunosorbent assay (ELISA)

[0448] 96-well plates were coated with 1 μg / mL human PD-L1 (obtained from R&D) in PBS at 4°C overnight. The wells were then blocked with 2% BSA in 0.05% TWEEN-20 in PBS (W / V) at 37°C for 1 hour. The plates were washed three times with PBS / 0.05% TWEEN-20, and the compounds were serially diluted (1:5) in dilution medium and added to the ELISA plates. Human PD-1 and biotin 0.3 μg / mL (ACRO Biosystems) were added, incubated at 37°C for 1 hour, and then washed three times with PBS / 0.05% TWEEN-20. A second blocking was performed with 2% BSA in PBS (W / V) / 0.05% TWEEN-20 at 37°C for 10 minutes, and the plates were then washed three times with PBS / 0.05% TWEEN-20. Streptavidin-HRP was added at 37°C for 1 hour, and the plate was then washed three times with PBS / 0.05% TWEEN-20. TMB substrate was added and reacted at 37°C for 20 minutes. Stop solution (2N H2SO4 aqueous solution) was added. The absorbance was read at 450 nm using a microplate spectrophotometer. The results are shown in Table 1: IC 50 Values ​​are provided as follows: from 1000 to 10,000 nM (+); from 10 to 1000 nM (++); less than 10 nM (+++).

[0449] Table 1:

[0450]

[0451]

[0452]

[0453]

[0454]

[0455]

[0456]

[0457]

[0458]

[0459]

[0460]

[0461]

[0462]

[0463]

[0464]

[0465] Specific embodiments of the present invention are described herein, including the best mode known to the inventors for carrying out the invention. After reading the above description, variations of the disclosed embodiments will be apparent to those skilled in the art, and it is expected that those skilled in the art will appropriately adopt such variations. Therefore, it is intended to implement the present invention in a manner other than that specifically described herein, and the present invention includes all modifications and equivalents of the subject matter recited in the appended claims as permitted by applicable law. Unless otherwise indicated herein or clearly contradicted by the context, the present invention encompasses its scope.

[0466] All publications, patent applications, accession numbers, and other references cited in this specification are herein incorporated by reference as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.

Claims

1. A compound represented by formula (I) or a pharmaceutically acceptable salt thereof: in A is a 6-membered heteroaryl group selected from the group consisting of pyridine, pyrazine, which is unsubstituted or substituted with 1 to 3 members independently selected from the group consisting of C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy and OH; X 1 C 1-3 alkylene; R 2a and R 2b Each independently selected from the following group: H, C 1-8 Alkyl, -Y, -X 2 -OR a 、-X 2 -C(O)NR a R b and -X 2 -Y, where each X 2 It is C 1-6 Alkylene, C 1-8 Alkyl or C 1-6 Alkylene is unsubstituted or substituted by one or two members independently selected from the group consisting of OH, C(O)NH2 and CO2H, each Y selected from the group consisting of C 3-6 Cycloalkyl and C 4-8 heterocyclyl, each of which is unsubstituted or substituted with one to four substituents independently selected from the group consisting of oxo and OH; or R 2a and R 2b Combined to form a 4- to 9-membered ring with zero to two additional heteroatoms selected from O or N at the ring vertices; wherein by combining R 2a and R 2b The 4- to 9-membered ring formed is unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of: C 1-8 Alkyl, -X 3 -CO2R a ; where X 3 It is a key; R 3 and R 4 Each independently selected from the group consisting of F, Cl and CH3; Subscript n is 0; R 6 、R 7 and R 8 Each independently is H; Z is a fused bicyclic heteroaromatic ring, unsubstituted or substituted with 1 R c Substituted, wherein Z is selected from the group consisting of: Each R a Independently selected from the group consisting of H, C 1-6 alkyl; Each R b Independently selected from the group consisting of H, C 1-6 alkyl; Each R c Independently selected from the group consisting of: C 1-6 Alkyl, C 1-6 Halogenated alkyl.

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

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

4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein A is a 6-membered heteroaryl group selected from the group consisting of pyridine and pyrazine, each of which is unsubstituted or substituted with one or two members independently selected from the group consisting of CF3, OH, Et and OCH3.

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

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

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

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

9. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the following compounds:

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

11. A pharmaceutical composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

12. The pharmaceutical composition of claim 11, further comprising one or more additional therapeutic agents.

13. The pharmaceutical composition of claim 12, wherein the one or more additional therapeutic agents are selected from the group consisting of antimicrobial agents, cytotoxic agents, gene expression regulators, antitumor agents, antihormonal agents, antifibrotic agents, and antiproliferative agents.

14. The pharmaceutical composition of claim 13, wherein the antimicrobial agent is an antiviral agent; and the antitumor agent is an anticancer agent.

15. The pharmaceutical composition of claim 13, wherein the anti-tumor agent is an anti-angiogenic agent, an immunotherapeutic agent, or a radiotherapeutic agent.

16. Use of the compound according to claim 1 or a pharmaceutically acceptable salt thereof for manufacturing a medicament for regulating an immune response mediated by the PD-1 signaling pathway in a subject.

17. Use of the compound of claim 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for modulating an immune response in a subject in need thereof.

18. Use of the compound according to claim 1 or a pharmaceutically acceptable salt thereof for manufacturing a medicament for inhibiting the growth, proliferation or metastasis of cancer cells in a subject in need thereof.

19. Use of the compound of claim 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating a subject suffering from or susceptible to a disease or condition mediated by the PD-1 signaling pathway.

20. The use of claim 19, wherein the subject suffers from a disease or condition selected from the group consisting of an infectious disease, an immune disorder, and cancer.

21. The use of claim 19, wherein the subject suffers from an inflammatory disease.

22. The method of claim 19, wherein the disease or condition is selected from the group consisting of esophageal cancer, lymphoma, prostate cancer, synovioma, sarcoma, sepsis, bile duct cancer, thymus cancer, uterine cancer, liver infection, neurological tumors, colon cancer, leukemia, multiple myeloma, ovarian cancer, myelodysplastic syndrome, lung cancer, mesothelioma, breast cancer, stomach cancer, pancreatic cancer, head and neck cancer, HIV, herpes virus, papillomavirus, influenza, skin cancer, rectal cancer, anal cancer, testicular cancer, small intestine cancer, endocrine system cancer, urethra cancer, penile cancer, bladder cancer, kidney cancer, ureteral cancer, seminoma, adenoma, leiomyoma, rhabdomyomas, hemangiomas, lymphangiomas, osteomas, lipomas, and fibromas.

23. The use according to claim 22, wherein the sarcoma is selected from the group consisting of Kaposi's sarcoma, fibrosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, angiosarcoma, lymphangiosarcoma, leiomyosarcoma, rhabdomyosarcoma, and soft tissue sarcoma; The bone tumor is selected from the group consisting of bone cancer and chondroma; The lung cancer is selected from the group consisting of small cell lung cancer, squamous non-small cell lung cancer, and non-squamous non-small cell lung cancer; The renal cancer is Wilms tumor; The skin cancer is epidermoid carcinoma or melanoma; The esophageal tumor is esophageal cancer; The lymphoma is Hodgkin's disease; The liver infection is selected from the group consisting of hepatitis A, hepatitis B, hepatitis C, and hepatitis D; The neural tumor is a central nervous system tumor; The prostate cancer is castration-resistant prostate cancer; The adenoma is selected from the group consisting of pituitary adenoma and papilloma; The endocrine system cancer is selected from the group consisting of thyroid cancer, parathyroid cancer, and adrenal cancer.

24. The use according to claim 23, characterized in that The central nervous system tumor is selected from the following group: Glioblastoma, meningioma, spinal axis tumors, brainstem glioma; The papilloma is hepatocellular papilloma.

25. The use according to any one of claims 17 to 24, wherein The medicament is suitable for use in combination with a therapeutically effective amount of one or more additional therapeutic agents.

26. The use of claim 25, wherein the one or more additional therapeutic agents are selected from the group consisting of antimicrobial agents, cytotoxic agents, gene expression regulators, antihormonal agents, antifibrotic agents, radiation therapy, antitumor agents, and antiproliferative agents.

27. The use according to claim 26, wherein the antimicrobial agent is an antiviral agent; and the antitumor agent is an anticancer agent.

28. The use according to claim 26, wherein the anti-tumor agent is an anti-angiogenic agent, an immunotherapeutic agent or a radiotherapeutic agent.

29. A method for preparing a compound of formula (II), The method includes: (a) converting a compound having formula (2e1) into a compound having formula (2f1) using a borate reagent and a first catalyst; (b) contacting a compound having formula (2f1) with a compound having formula (2g1) and a second catalyst under Suzuki-type conditions to produce a compound having formula (2h1); (c) Using HN(R 2a )(R 2b ) and a hydride reagent to reductively aminize a compound of formula (2h1) to provide a compound of formula (II), In the above formulas (2e1), (2f1), (2g1), (2h1) and (II), Z, R 2a ,R 2b ,R 3 ,R 3a , subscript n, R 4 ,R 6 ,R 7 , and R 8 Each of has the meaning provided in claim 1; Each R' is independently selected from the group consisting of H and C1-C6 alkyl; X is selected from the group consisting of Br and Cl; X' is selected from the group consisting of I, Br and Cl; With R s The ring is a six-membered nitrogen heteroaryl ring selected from the group consisting of pyridine and pyrazine, R s is 0, 1, 2 or 3 substituents independently selected from the group consisting of: C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy and OH.

30. A method for preparing a compound of formula (II), The method includes: (a) contacting a compound having formula (2e1) with a compound having formula (2g'1) and a first catalyst under Suzuki-type conditions to produce a compound having formula (2h1); (b) Using HN(R 2a )(R 2b ) and a hydride reagent to reductively aminize a compound of formula (2h1) to provide a compound of formula (II), In the above formulas (2e1), (2g'1), (2h1) and (II), Z, R 2a 、R 2b 、R 3 、R 3a ,, subscript n, R 4 、R 6 、R 7 , and R 8 respectively have the meanings provided in claim 1; Each R' is independently selected from the group consisting of H and C1-C6 alkyl; X is selected from the group consisting of Br and Cl; With R s The ring is a six-membered nitrogen heteroaryl ring selected from the group consisting of pyridine and pyrazine, R s is 0, 1, 2 or 3 substituents independently selected from the group consisting of: C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy and OH.

31. A method for preparing a compound of formula (II), The method includes: (a) contacting a compound of formula (2j1) with a compound of formula (2k1) and a first catalyst under Suzuki-type conditions to produce a compound of formula (2h1); (b) Using HN(R 2a )(R 2b ) and a hydride reagent to reductively aminize a compound of formula (2h1) to provide a compound of formula (II), In the above formulas (2j1), (2k1), (2h1) and (II), Z, R 2a 、R 2b 、R 3 、R 3a , subscript n, R 4 、R 6 、R 7 , and R 8 respectively have the meanings provided in claim 1; Each R is independently selected from the group consisting of H and C1-C6 alkyl; X is selected from the group consisting of I, Br and Cl; With R s The ring is a six-membered nitrogen heteroaryl ring selected from the group consisting of pyridine and pyrazine, R s is 0, 1, 2 or 3 substituents independently selected from the group consisting of: C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy and OH.

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