USP1 inhibitor and its use

Abstract

Inhibitors of ubiquitin-specific processing protease 1 (USP1), pharmaceutical compositions thereof, and methods of use for treating diseases or disorders such as cancer described herein are provided herein.

Description

Technical Field

[0001] (Cross - Reference to Related Applications) This application claims the benefit of U.S. Provisional Patent Application No. 63 / 367,268, filed on June 29, 2022, the entire content of which is incorporated herein by reference. (Field of the Invention) The present invention relates to compounds and methods useful for inhibiting ubiquitin - specific processing protease 1 (USP1). The present invention also provides pharmaceutically acceptable compositions comprising the compounds of the present invention, and methods of using such compositions in the treatment of various diseases, disorders, and conditions described herein.

Background Art

[0002] USP1 is a cysteine protease belonging to the DUB family. USP1 deubiquitinates various cellular targets involved in the DDR pathway, immune response, and cancer processes. USP1 interacts with UAF1 (USP1 - associated factor 1) to form a stable complex necessary for deubiquitinase activity. Well - characterized substrates of the USP1 / UAF1 complex, such as PCNA (proliferating cell nuclear antigen) and FANCD2 (Fanconi anemia group D2), are prominent players in the processes of DNA damage bypass synthesis (TLS) and interstrand cross - link (ICL) repair, respectively. These two pathways are essential for the repair of DNA damage contained in DNA - crosslinking agents such as cisplatin and mitomycin C. Thus, USP1 is an important regulator of genomic integrity through deubiquitination of Fanconi anemia proteins and PCNA, and is a potential synthetic lethal drug target for cancer cells that often have specific DDR pathway deficiencies.

Summary of the Invention

[0003] It has been found that the compounds of the present invention and their pharmaceutically acceptable compositions are effective as USP1 inhibitors. In one aspect, the present invention provides a compound of formula I:

Chemical Formula

[0004] The compounds of the present invention, as well as their pharmaceutically acceptable salts and compositions, are useful for treating various diseases, disorders, or conditions associated with USP1. Such diseases, disorders, or conditions include cell proliferative disorders (e.g., cancers as described herein). BRIEF DESCRIPTION OF THE DRAWINGS

[0005]

Figure 1

[0006]

Figure 2

[0007] 1. General description of certain embodiments of the present invention: The compounds of the present invention, as well as their pharmaceutical salts and compositions, are useful as inhibitors of USP1. Without wishing to be bound by any particular theory, it is believed that the compounds of the present invention and their pharmaceutical compositions inhibit the activity of USP1 and thereby treat diseases, disorders, or conditions associated with USP1 such as cancer.

[0008] In one aspect, the present invention provides a compound of formula I:

Chemical formula

Chemical formula

[0009] 2. Compounds and Definitions: The compounds of the present invention generally include those described herein and are further exemplified by the classes, subclasses, and species disclosed herein. As used herein, the following definitions apply unless otherwise indicated. For the purposes of the present invention, chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th Ed. Additionally, general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and “March’s Advanced Organic Chemistry”, 5 th Ed., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are incorporated herein by reference.

[0010] The term "aliphatic" or "aliphatic group", as used herein, refers to a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or contains one or more unsaturated units, or a monocyclic or bicyclic hydrocarbon that is completely saturated or contains one or more unsaturated units, but is not aromatic (also referred to herein as "carbocyclic", "alicyclic", or "cycloalkyl") and has a single point of attachment to the remainder of the molecule. Unless otherwise specified, an aliphatic group contains from 1 to 6 aliphatic carbon atoms. In some embodiments, the aliphatic group contains from 1 to 5 aliphatic carbon atoms. In other embodiments, the aliphatic group contains from 1 to 4 aliphatic carbon atoms. In still other embodiments, the aliphatic group contains from 1 to 3 aliphatic carbon atoms, and in still other embodiments, the aliphatic group contains from 1 to 2 aliphatic carbon atoms. In some embodiments, "alicyclic" (or "carbocyclic", or "cycloalkyl") refers to a monocyclic C3-C6 hydrocarbon that is completely saturated or contains one or more unsaturated units, but is not aromatic and has a single point of attachment to the remainder of the molecule. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups, and their hybrids such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl.

[0011] As used herein, the term "bicyclic ring" or "bicyclic ring system" refers to any bicyclic ring system, i.e., a carbocyclic or heterocyclic ring that is saturated or has one or more unsaturation units and has one or more common atoms between two rings of the ring system. Thus, this term includes any allowed ring fusion such as ortho-fusion or spirocyclic. As used herein, the term "heterobicyclic" is a subset of "bicyclic" that requires the presence of one or more heteroatoms in one or both rings of the bicycle. Such heteroatoms may be present at the ring junctions and may be optionally substituted and may be selected from nitrogen (including N-oxides), oxygen, sulfur (including oxidized forms such as sulfones and sulfonates), phosphorus (including oxidized forms such as phosphates), boron, etc. In some embodiments, the bicyclic group has 7 to 12 ring members and independently has 0 to 4 heteroatoms selected from nitrogen, oxygen, or sulfur. As used herein, the term "bridged bicyclic" refers to any saturated or partially unsaturated bicyclic ring system, i.e., a carbocyclic or heterocyclic ring, having at least one bridge. As defined by IUPAC, a "bridge" is a non-branched chain of multiple atoms or one atom or valence bond connecting two bridgeheads, and a "bridgehead" is any skeletal atom of a ring system that is bonded to three or more skeletal atoms (excluding hydrogen). In some embodiments, the bridged bicyclic group has 7 to 12 ring members and has 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groups are well known in the art and include the groups described below, where each group is bonded to the remainder of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise specified, the bridged bicyclic group is optionally substituted with one or more of the substituents described for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of the bridged bicyclic group is optionally substituted. Exemplary bicyclic rings include the following: [Chemical formula] Exemplary bridged bicyclics include the following: [Chemistry]

[0012] The term "lower alkyl" refers to a straight-chain or branched alkyl group of C 1~4 . Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0013] The term "lower haloalkyl" refers to a straight-chain or branched alkyl group of C 1~4 that is substituted with one or more halogen atoms.

[0014] The term "heteroatom" means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (any oxidized form of nitrogen, sulfur, phosphorus, or silicon; any quaternized form of any basic nitrogen, or; a replaceable nitrogen in a heterocyclic ring, such as in N(3,4-dihydro-2H-pyrrolyl), NH (such as in pyrrolidinyl), or NR + (such as in N-substituted pyrrolidinyl)).

[0015] The term "unsaturated", as used herein, means that a moiety has one or more unsaturation units.

[0016] As used herein, the term "divalent C 1~8 (or C 1~6 ) saturated or unsaturated straight-chain or branched hydrocarbon chain" refers to straight-chain or branched divalent alkylene, alkenylene, and alkynylene chains as defined herein.

[0017] The term "alkylene" refers to a divalent alkyl group. An "alkylene chain" is a polymethylene group, i.e., -(CH2) n- and in the formula, n is preferably a positive integer of 1 to 6, 1 to 4, 1 to 3, 1 to 2, or 2 to 3. The substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced by substituents. Suitable substituents include those described below for substituted aliphatic groups.

[0018] The term "alkenylene" refers to a divalent alkenyl group. The substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced by substituents. Suitable substituents include those described below for substituted aliphatic groups.

[0019] As used herein, the term "cyclopropylenyl" refers to a divalent cyclopropyl group having the following structure:

Chemical formula

[0020] The term "halogen" means F, Cl, Br, or I.

[0021] The term "aryl", used alone or as part of a larger moiety such as "aralkyl", "aralkoxy", or "aryloxyalkyl", refers to a monocyclic or bicyclic ring system having a total of 5 to 14 ring members, at least one ring of the system being aromatic and each ring of the system containing 3 to 7 ring members. The term "aryl" may be used interchangeably with the term "aryl ring". In certain embodiments of the present invention, "aryl" refers to an aromatic ring system including, but not limited to, phenyl, biphenyl, naphthyl, anthracyl, etc., and may have one or more substituents. Within the scope of the term "aryl" as used herein, groups in which the aromatic ring is fused to one or more non-aromatic rings such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl are also included.

[0022] The terms "heteroaryl" and "heteroar-" when used alone or as part of a larger moiety, such as "heteroalkyl" or "heteroalkoxy", refer to a group having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms, sharing 6, 10, or 14 π electrons in a cyclic array, and having 1 to 5 heteroatoms in addition to carbon atoms. The term "heteroatom" refers to nitrogen, oxygen, or sulfur and includes any oxidized form of nitrogen or sulfur and any quaternized form of basic nitrogen. Heteroaryl groups include, but are not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. The terms "heteroaryl" and "heteroar-" also include, as used herein, groups in which the heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings and the radical or point of attachment is on the heteroaromatic ring. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. The heteroaryl group may be monocyclic or bicyclic. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring", "heteroaryl group", or "heteroaromatic", and any of these terms includes optionally substituted rings. The term "heteroalkyl" refers to an alkyl group substituted by a heteroaryl group, and the alkyl portion and the heteroaryl portion are each independently optionally substituted.

[0023] As used herein, the terms "heterocycle", "heterocyclyl", "heterocyclic radical", and "heterocyclic ring" are used interchangeably and are either saturated or partially unsaturated and refer to a stable 5- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic moiety having, in addition to carbon atoms, one or more, preferably 1 to 4, heteroatoms as defined above. When used with respect to the ring atoms of a heterocycle, the term "nitrogen" includes substituted nitrogen. By way of example, in a saturated or partially unsaturated ring having 0 to 3 heteroatoms selected from oxygen, sulfur, or nitrogen, nitrogen can be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or + NR (as in N-substituted pyrrolidinyl).

[0024] The heterocycle can be attached by any heteroatom or carbon atom that results in a stable structure, and any of the ring atoms can optionally be substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The terms "heterocycle", "heterocyclyl", "heterocyclyl ring", "heterocyclic group", "heterocyclic moiety", and "heterocyclic radical" are used interchangeably herein and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or alicyclic rings, such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl. A heterocyclyl group can be monocyclic or bicyclic. The term "heterocyclylalkyl" refers to an alkyl group substituted by a heterocyclyl, and the alkyl portion and the heterocyclyl portion are each independently optionally substituted.

[0025] As used herein, the term "partially unsaturated" refers to a ring moiety containing at least one double or triple bond. The term "partially unsaturated" is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties as defined herein.

[0026] As described herein, the compounds of the invention may contain "optionally substituted" moieties. In general, the term "substituted", whether or not preceded by the term "optionally", means that one or more hydrogens on the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an "optionally substituted" group may have suitable substituents at each substitutable position of the group, and when two or more positions in any given structure may be substituted with two or more substituents selected from a particular group, the substituents may be the same or different at all positions. Combinations of substituents contemplated by the present invention preferably result in the formation of stable or chemically feasible compounds. The term "stable", as used herein, refers to compounds that do not substantially change when subjected to conditions that allow for their production, detection, and in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0027] Each optional substituent on a substitutable carbon is independently halogen; -(CH2) 0-4 R°; -(CH2) 0-4 OR°; -O(CH2) 0-4 R o , -O-(CH2) 0-4 C(O)OR°; -(CH2) 0-4 CH(OR°)2; -(CH2) 0-4 SR°; -(CH2) that may be substituted with R° 0-4 Ph; -(CH2) that may be substituted with R° 0-4 O(CH2) 0-1 Ph; -CH=CHPh that may be substituted with R°; -(CH2) that may be substituted with R° 0-4 O(CH2)0-1 -pyridyl; -NO2; -CN; -N3; -(CH2) 0-4 N(R°)2; -(CH2) 0-4 N(R°)C(O)R°; -N(R°)C(S)R°; -(CH2) 0-4 N(R°)C(O)NR°2; -N(R°)C(S)NR°2; -(CH2) 0-4 N(R°)C(O)OR°; -N(R°)N(R°)C(O)R°; -N(R°)N(R°)C(O)NR°2; -N(R°)N(R°)C(O)OR°; -(CH2) 0-4 C(O)R°; -C(S)R°; -(CH2) 0-4 C(O)OR°; -(CH2) 0-4 C(O)SR°; -(CH2) 0-4 C(O)OSiR°3; -(CH2) 0-4 OC(O)R°; -OC(O)(CH2) 0-4 SR-; SC(S)SR°; -(CH2) 0-4 SC(O)R°; -(CH2) 0-4 C(O)NR°2; -C(S)NR°2; -C(S)SR°; -SC(S)SR°; -(CH2) 0-4 OC(O)NR°2; -C(O)N(OR°)R°; -C(O)C(O)R°; -C(O)CH2C(O)R°; -C(NOR°)R°; -(CH2) 0-4 SSR°; -(CH2) 0-4 S(O)2R°; -(CH2) 0-4 S(O)2OR°; -(CH2) 0-4 OS(O)2R°; -S(O)2NR°2; -S(O)(NR°)R°; -S(O)2N=C(NR°2)2; -(CH2) 0-4 S(O)R°; -N(R°)S(O)2NR°2; -N(R°)S(O)2R°; -N(OR°)R°; -C(NH)NR°2; -P(O)2R°; -P(O)R°2; -OP(O)R°2; -OP(O)(OR°)2; SiR°3; -(C 1-4 linear or branched alkylene)O-N(R°)2; or -(C 1-4 linear or branched alkylene)C(O)O-N(R°)2 and is a monovalent substituent selected therefrom.

[0028] Each R° is independently hydrogen, C 1~6 aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, -CH2-(5- to 6-membered heteroaryl ring), or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, regardless of the above definition, the occurrence of two independent R°'s, together with the intervening atom(s) therebetween, forms a 3- to 12-membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and this ring may be substituted by a divalent substituent selected from =O and =S on a saturated carbon atom of R°, or each R° is halogen, -(CH2) 0-2 R ● , -(haloR ● ), -(CH2) 0-2 OH, -(CH2) 0-2 OR ● , -(CH2) 0-2 CH(OR ● ), -O(haloR ● ), -CN, -N3, -(CH2) 0-2 C(O)R ● , -(CH2) 0-2 C(O)OH, -(CH2) 0-2 C(O)OR ● , -(CH2) 0-2 SR ● , -(CH2) 0-2 SH, -(CH2) 0-2 NH2, -(CH2) 0-2 NHR ● , -(CH2) 0-2 NR ● 2, -NO2, -SiR ● 3, -OSiR ● 3, -C(O)SR ● 、 -(C 1~4 linear or branched alkylene)C(O)OR ● , or -SSR ● and is optionally substituted by a monovalent substituent independently selected from

[0029] Each R● is, independently, C 1~4 aliphatic, -CH2Ph, -O(CH2) 0-1 selected independently from Ph, or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms selected independently from nitrogen, oxygen, or sulfur, each R ● is unsubstituted or, when halo precedes, substituted with only one or more halogens, or an optional substituent on saturated carbon is =O, =S, =NNR * 2, =NNHC(O)R * =NNHC(O)OR * =NNHS(O)2R * =NR * =NOR * -O(C(R * 2)) 2-3 O-, or -S(C(R * 2)) 2-3 S- is a divalent substituent selected independently therefrom, or a divalent substituent bonded to an adjacent substitutable carbon of an "optionally substituted" group is -O(CR * 2) 2-3 O-, wherein each R * independent occurrence of is selected from hydrogen, C 1~6 aliphatic, or an unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms selected independently from nitrogen, oxygen, or sulfur.

[0030] R * is C 1~6 aliphatic, R * is optionally substituted with halogen, -R ● -(haloR ● ), -OH, -OR ● , -O(haloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR ● , -NR ● 2, or -NO2, and each R ● is independently C 1~4 aliphatic, -CH2Ph, -O(CH2) 0-1selected from a 5- to 6-membered saturated, partially unsaturated, or aryl ring having from 0 to 4 heteroatoms independently selected from Ph, or nitrogen, oxygen, or sulfur, each R ● is unsubstituted or, when halo precedes, substituted by only one or more halogens.

[0031] Optional substituents on replaceable nitrogen are independently -R † , -NR † 2, -C(O)R † , -C(O)OR † , -C(O)C(O)R † , -C(O)CH2C(O)R † , -S(O)2R † , -S(O)2NR † 2, -C(S)NR † 2, -C(NH)NR † 2, or -N(R † )S(O)2R † wherein each R † is independently hydrogen, C 1~6 aliphatic, unsubstituted -OPh, or an unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl ring having from 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or the occurrence of two independent R † together with the intervening atom(s) therebetween forms an unsubstituted 3- to 12-membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having from 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and when R † is C 1~6 aliphatic, R † is optionally substituted by halogen, -R ● , -(haloR ● ), -OH, -OR ● , -O(haloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR ● , -NR ● 2, or -NO2, and each R ● is independently C 1~4 aliphatic, -CH2Ph, -O(CH2)0-1 selected from a 5- to 6-membered saturated ring, partially unsaturated ring, or aryl ring having 0 to 4 heteroatoms independently selected from Ph, or nitrogen, oxygen, or sulfur, each R ● is unsubstituted or, when halo precedes, substituted only with one or more halogens.

[0032] As used herein, the term "pharmaceutically acceptable salt" refers to salts that, within the scope of sound medical judgment, are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., and that have a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S.M. Berge et al., J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference, describes pharmaceutically acceptable salts in detail. Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed using inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or using organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like.

[0033] Salts derived from suitable bases include alkali metals, alkaline earth metals, ammonium, and N+ (C 1~4 Examples of the (alkyl)4 salts include. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium and the like. Further, pharmaceutically acceptable salts, where appropriate, are non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0034] Unless otherwise indicated, the structures shown herein also include all isomeric forms (e.g., enantiomers, diastereomers, and geometric (or conformational) isomers) of that structure, e.g., the R and S configurations of each chiral center, the Z and E double bond isomers, and the Z and E conformational isomers. Thus, single stereochemical isomers of the compounds of the invention, as well as mixtures of enantiomers, diastereomers, and geometric (or conformational) isomers are within the scope of the invention. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention. Additionally, unless otherwise indicated, the structures shown herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, replacing hydrogen with deuterium or tritium, or carbon with 13 C or 14 C-enriched carbon, compounds having this structure are within the scope of the invention. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents according to the invention. In certain embodiments, the reactive warhead moiety of the provided compounds contains one or more deuterium atoms.

[0035] As used herein, the terms "inhibitor" or "USP1 inhibitor" or "USP1 antagonist" are defined as compounds that bind to USP1 with measurable affinity and / or inhibit USP1. In some embodiments, the inhibition in the presence of the inhibitor is observed in a dose-dependent manner. In some embodiments, the measured signal (e.g., signaling activity or biological activity) is at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% lower than the signal measured using a negative control under similar conditions. The potency of the inhibitor is typically defined by its IC 50 value (half maximal inhibitory concentration, i.e., the concentration required to inhibit 50% of the agonist response). The lower the IC 50 value, the higher the potency of the antagonist and the lower the concentration required to inhibit the maximal biological response. In certain embodiments, the inhibitor has an IC 50 and / or binding constant of less than about 100 μM, less than about 50 μM, less than about 1 μM, less than about 500 nM, less than about 100 nM, less than about 10 nM, or less than about 1 nM

[0036] The terms "measurable affinity" and "inhibit to a measurable extent" as used herein, when referring to a sample containing a compound or composition of the invention and USP1, and an equivalent sample containing USP1 without the compound or composition, mean a measurable change or inhibition of USP1 activity

[0037] 3. Description of Exemplary Embodiments: In one aspect, the present invention provides a compound of formula I:

Chemical formula

Chemical formula

[0038] Generally as defined above,

Chemical formula

[0039] In some embodiments,

Chemical formula

Chemical formula

[0040] In some embodiments,

Chemical formula

[0041] Generally as defined above, X 1 is O, N, N(R 11 ), C(O), CR 12 , or C(R 12 )2, wherein each variable is independently as defined herein and as described in the embodiments of this specification.

[0042] In some embodiments, X 1 is O. In some embodiments, X 1 is N. In some embodiments, X 1 is N(R 11 ), wherein R 11 is as defined herein and as described in the embodiments of this specification. In some embodiments, X 1 is C(O). In some embodiments, X 1 is CR 12 , wherein R 12 is as defined herein and as described in the embodiments of this specification. In some embodiments, X 1 is C(R 12 )2, wherein each R 12 is as defined herein and as described in the embodiments of this specification.

[0043] In some embodiments, X 1 is selected from those shown in Table 1 below.

[0044] Generally as defined above, X 2 is O, N, N(R 11 ), C(O), CR 12 , or C(R 12 )2, wherein each variable is independently as defined herein and as described in the embodiments of this specification.

[0045] In some embodiments, X 2 is O. In some embodiments, X 2 is N. In some embodiments, X 2 is N(R 11 ), where R 11 is as defined herein and as described in the embodiments of this specification. In some embodiments, X 2 is C(O). In some embodiments, X 2 is CR 12 , where R 12 is as defined herein and as described in the embodiments of this specification. In some embodiments, X 2 is C(R 12 )2, where each R 12 is as defined herein and as described in the embodiments of this specification.

[0046] In some embodiments, X 2 is selected from those shown in Table 1 below.

[0047] Generally as defined above, X 3 is N(R 11 ), C(O), or C(R 12 )2, where each variable is independently as defined herein and as described in the embodiments of this specification.

[0048] In some embodiments, X 3 is N(R 11 ), where R 11 is as defined herein and as described in the embodiments of this specification. In some embodiments, X 3 is C(O). In some embodiments, X 3 is C(R 12 )2, where each R 12 is as defined herein and as described in the embodiments of this specification.

[0049] In some embodiments, X 3 is selected from those shown in Table 1 below.

[0050] Generally as defined above, X 4 is N or CR 12 wherein R 12 is as defined herein and as described in the embodiments herein.

[0051] In some embodiments, X 4 is N. In some embodiments, X 3 is CR 12 wherein R 12 is as defined herein and as described in the embodiments herein.

[0052] In some embodiments, X 4 is selected from those shown in Table 1 below.

[0053] Generally as defined above, X 5 is N or CR 12 wherein R 12 is as defined herein and as described in the embodiments herein.

[0054] In some embodiments, X 5 is N. In some embodiments, X 5 is CR 12 wherein R 12 is as defined herein and as described in the embodiments herein.

[0055] In some embodiments, X 5 is selected from those shown in Table 1 below.

[0056] Generally as defined above, each R 11is, independently, hydrogen, deuterium, R, or -C(O)-R, wherein each R is independently as defined herein and as described in embodiments herein.

[0057] In some embodiments, R 11 is hydrogen. In some embodiments, R 11 is deuterium. In some embodiments, R 11 is R, where each R is independently as defined herein and as described in embodiments herein. In some embodiments, R 11 is -C(O)-R, wherein each R is independently as defined herein and as described in embodiments herein.

[0058] In some embodiments, R 11 is -CH3 or -CD3.

[0059] In some embodiments, R 11 is selected from those shown in Table 1 below.

[0060] Generally as defined above, each R 12 is independently hydrogen, deuterium, halogen, R, -OR, -NHR, -N(R)2, -C(O)-R, -COOR, -C(O)-NHR, or -C(O)-N(R)2, wherein each R is independently as defined herein and as described in embodiments herein.

[0061] In some embodiments, R 12 is hydrogen. In some embodiments, R 12 is deuterium. In some embodiments, R 12 is halogen. In some embodiments, R 12 is R, where R is as defined herein and as described in embodiments herein. In some embodiments, R 12is -OR, wherein R is as defined herein and as described in the embodiments herein. In some embodiments, R 12 is -NHR, wherein R is as defined herein and as described in the embodiments herein. In some embodiments, R 12 is -N(R)2, wherein each R is independently as defined herein and as described in the embodiments herein. In some embodiments, R 12 is -C(O)-R, wherein R is as defined herein and as described in the embodiments herein. In some embodiments, R 12 is -COOR, wherein R is as defined herein and as described in the embodiments herein. In some embodiments, R 12 is -C(O)-NHR, wherein R is as defined herein and as described in the embodiments herein. In some embodiments, R 12 is -C(O)-N(R)2, wherein each R is independently as defined herein and as described in the embodiments herein.

[0062] In some embodiments, R 12 is optionally substituted

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0063] In some embodiments, each R 12 is independently H, -F, -Br, -Cl, -CF3, -CHF2, -CH3, -CD3,

Chemical formula

[0064] In some embodiments, R 12 is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chem.

Chem.

Chem.

Chem.

[0065] In some embodiments, R 12 is selected from those shown in Table 1 below.

[0066] Generally as defined above, ring A is a 5- to 6-membered heteroaromatic ring having 1 to 4 heteroatoms selected from N, O, and S.

[0067] In some embodiments, ring A is a 5-membered heteroaromatic ring having 1, 2, 3, or 4 heteroatoms selected from N, O, and S. In some embodiments, ring A is a 6-membered heteroaromatic ring having 1, 2, 3, or 4 heteroatoms selected from N, O, and S.

[0068] In some embodiments, ring A is a 5- or 6-membered heteroaromatic ring having 1, 2, 3, or 4 heteroatoms N.

[0069] In some embodiments, ring A is

Chem.

[0070] In some embodiments, [Chemical formula] is [Chemical formula] as follows.

[0071] In some embodiments, ring A is selected from those shown in Table 1 below.

[0072] Generally as defined above, each R 1 is independently halogen, R, -OR, -NHR, -N(R)2, -C(O)-R, -C(O)-NHR, or -C(O)-N(R)2, where each R is independently as defined herein and as described in the embodiments herein.

[0073] In some embodiments, R 1 is halogen. In some embodiments, R 1 is R, where R is as defined herein and as described in the embodiments herein. In some embodiments, R 1 is -OR, where R is as defined herein and as described in the embodiments herein. In some embodiments, R 1 is -NHR, where R is as defined herein and as described in the embodiments herein. In some embodiments, R 1 is -N(R)2, where each R is independently as defined herein and as described in the embodiments herein. In some embodiments, R 1 is -C(O)-R, where R is as defined herein and as described in the embodiments herein. In some embodiments, R1 is -C(O)-NHR, where R is as defined herein and as described in the embodiments herein. In some embodiments, R 1 is -C(O)-N(R)2, where each R is independently as defined herein and as described in the embodiments herein.

[0074] In some embodiments, each R 1 is independently -Cl, -F, -OCH3, -OCD3,

Chemical formula

[0075] In some embodiments, R 1 is selected from those shown in Table 1 below.

[0076] Generally as defined above, ring B is selected from a phenyl ring, a 5- to 6-membered heteroaromatic ring having 1 to 4 heteroatoms selected from N, O, and S, or a 5- to 6-membered heterocyclyl ring having 1 to 4 heteroatoms selected from N, O, and S.

[0077] In some embodiments, ring B is a phenyl ring.

[0078] In some embodiments, ring B is a 5- to 6-membered heteroaromatic ring having 1, 2, 3, or 4 heteroatoms selected from N, O, and S. In some embodiments, ring B is a 5-membered heteroaromatic ring having 1, 2, 3, or 4 heteroatoms selected from N, O, and S. In some embodiments, ring B is a 6-membered heteroaromatic ring having 1, 2, 3, or 4 heteroatoms selected from N, O, and S. In some embodiments, ring A is a 5- or 6-membered heteroaromatic ring having 1, 2, 3, or 4 heteroatoms N.

[0079] In some embodiments, ring B is a 5- or 6-membered heterocyclyl ring having 1, 2, 3, or 4 heteroatoms selected from N, O, and S. In some embodiments, ring B is a 5- or 6-membered heterocyclyl ring having 1, 2, 3, or 4 heteroatoms N.

[0080] In some embodiments, ring B is

Chemical formula

[0081] In some embodiments, ring B is selected from those shown in Table 1 below.

[0082] Generally as defined above, each R 2 is independently halogen, R, -OR, -NHR, -N(R)2, or -C(O)-R, wherein each R is independently as defined herein and as described in the embodiments herein.

[0083] In some embodiments, R 2 is halogen. In some embodiments, R 2 is R, where R is as defined herein and as described in the embodiments herein. In some embodiments, R 2 is -OR, wherein R is as defined herein and as described in the embodiments herein. In some embodiments, R 2 is -NHR, wherein R is as defined herein and as described in the embodiments herein. In some embodiments, R 2 is -N(R)2, wherein each R is independently as defined herein and as described in the embodiments herein. In some embodiments, R 2 is -C(O)-R, wherein R is as defined herein and as described in the embodiments herein.

[0084] In some embodiments, each R 2 is, independently, -F, -OCH3, or -OCD3.

[0085] In some embodiments, R 2 is selected from those shown in Table 1 below.

[0086] In some embodiments,

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0087] In some embodiments,

Chemical formula

Chemical formula

[0088] In some embodiments,

Chemical formula

Chemical formula

[0089] Generally as defined above, R 3 is optionally substituted phenyl or optionally substituted 5- or 6-membered heteroaryl having 1 to 4 heteroatoms selected from N, O, and S.

[0090] In some embodiments, R 3 is optionally substituted phenyl.

[0091] In some embodiments, R 3 is optionally substituted 5- or 6-membered heteroaryl having 1, 2, 3, or 4 heteroatoms selected from N, O, and S. In some embodiments, R 3 is optionally substituted 5-membered heteroaryl having 1, 2, 3, or 4 heteroatoms selected from N, O, and S. In some embodiments, R 3 is optionally substituted 6-membered heteroaryl having 1, 2, 3, or 4 heteroatoms selected from N, O, and S. In some embodiments, R 3 is optionally substituted 5- or 6-membered heteroaryl having 1, 2, 3, or 4 heteroatoms N.

[0092] In some embodiments, R 3 is optionally substituted [Chemical formula] is.

[0093] In some embodiments, R3 is, [Chem.] wherein each R 13 is independently halogen, R, or -OR, and q is 0, 1, 2, or 3.

[0094] In some embodiments, R 13 is halogen. In some embodiments, R 13 is R, where R is as defined herein and as described in the embodiments of this specification. In some embodiments, R 13 is -OR, wherein R is as defined herein and as described in the embodiments of this specification.

[0095] In some embodiments, R 13 is -F, -CH3, -CD3, -CF3, -CHF2, -OCH3, -OCD3, [Chem.] is.

[0096] In some embodiments, q is 0. In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, q is 3.

[0097] In some embodiments, R 3 is [Chem.] is.

[0098] In some embodiments, R 3 is [Chem.] is, which is [Chem.] and in the formula, R 23 is an optionally substituted C 1~6 aliphatic, and R 24 is an optionally substituted C3-C7 carbocyclic ring. In some embodiments, R 23 is -CH3, -CD3, -CF3, -CHF2,

Chemical formula

Chemical formula

[0099] In some embodiments, R 3 is selected from those shown in Table 1 below.

[0100] Generally as defined above, each of R 4 and R 5 is independently hydrogen, deuterium, halogen, R, -OR, -NHR, or -N(R)2, or R 4 and R 5 together with the atom to which they are attached form an optionally substituted ring selected from a C3-C7 carbocyclic ring or a 3-7 membered heterocyclic ring having 1-4 heteroatoms selected from N, O, and S, and each R is independently as defined herein and as described in the embodiments herein.

[0101] In some embodiments, R 4 and R 5 are independently hydrogen, deuterium, halogen, R, -OR, -NHR, or -N(R)2, and in the formula, each R is independently as defined herein and as described in the embodiments herein.

[0102] In some embodiments, R 4 is hydrogen. In some embodiments, R 4is deuterium. In some embodiments, R 4 is a halogen. In some embodiments, R 4 is R, where R is as defined herein and as described in the embodiments herein. In some embodiments, R 4 is -OR, where R is as defined herein and as described in the embodiments herein. In some embodiments, R 4 is -NHR, where R is as defined herein and as described in the embodiments herein. In some embodiments, R 4 is -N(R)2, where each R is independently as defined herein and as described in the embodiments herein.

[0103] In some embodiments, R 5 is hydrogen. In some embodiments, R 5 is deuterium. In some embodiments, R 5 is a halogen. In some embodiments, R 5 is R, where R is as defined herein and as described in the embodiments herein. In some embodiments, R 5 is -OR, where R is as defined herein and as described in the embodiments herein. In some embodiments, R 5 is -NHR, where R is as defined herein and as described in the embodiments herein. In some embodiments, R 5 is -N(R)2, where each R is independently as defined herein and as described in the embodiments herein.

[0104] In some embodiments, R 4 and R 5Together with the atoms to which they are attached, form an optionally substituted ring selected from a C3-C7 carbocyclic ring or a 3-7 membered heterocyclic ring having 1-4 heteroatoms selected from N, O, and S. In some embodiments, R 4 and R 5 Together with the atoms to which they are attached, form an optionally substituted C3-C7 carbocyclic ring. In some embodiments, R 4 and R 5 Together with the atoms to which they are attached, form an optionally substituted 3, 4, 5, 6, or 7 membered heterocyclic ring having 1, 2, 3, or 4 heteroatoms selected from N, O, and S. In some embodiments, R 4 and R 5 Together with the atoms to which they are attached, form an optionally substituted 3, 4, 5, 6, or 7 membered heterocyclic ring having 1, 2, 3, or 4 heteroatoms selected from N and O. In some embodiments, R 4 and R 5 Together with the atoms to which they are attached, form an optionally substituted 4, 5, or 6 membered heterocyclic ring having 1, 2, or 3 heteroatoms selected from N, O, and S. In some embodiments, R 4 and R 5 Together with the atoms to which they are attached, form an optionally substituted 3, 4, 5, 6, or 7 membered heterocyclic ring having 1, 2, 3, or 4 heteroatoms N. In some embodiments, R 4 and R 5 Together with the atoms to which they are attached, form an optionally substituted 4, 5, or 6 membered heterocyclic ring having 1, 2, or 3 heteroatoms N.

[0105] In some embodiments, each of R 4 and R 5 is independently selected from those shown in Table 1 below.

[0106] Generally as defined above, each R is independently an optionally substituted C 1~6It is an optionally substituted ring selected from an aliphatic group, or a 5- to 6-membered heteroaromatic ring having 1 to 4 heteroatoms selected from a phenyl ring, N, O, and S, a C3-C7 carbocyclic ring, or a 3- to 7-membered heterocyclic ring having 1 to 4 heteroatoms selected from N, O, or S.

[0107] In some embodiments, R is optionally substituted C 1-6 is aliphatic. In some embodiments, R is unsubstituted C 1~6 is aliphatic. In some embodiments, R is C substituted 1, 2, 3, 4, 5, or 6 times by -halogen 1~6 is aliphatic. In some embodiments, R is C substituted 1, 2, 3, 4, 5, or 6 times by -F 1~6 is aliphatic. In some embodiments, R is -C substituted 1, 2, 3, 4, 5, or 6 times by -F 1~3 is aliphatic. In some embodiments, R is -CH3. In some embodiments, R is -CH2CH3. In some embodiments, R is -CF3. In some embodiments, R is -CHF2.

[0108] In some embodiments, R is an optionally substituted phenyl ring.

[0109] In some embodiments, R is an optionally substituted 5- or 6-membered heteroaromatic ring having 1, 2, 3, or 4 heteroatoms selected from N, O, and S. In some embodiments, R is an optionally substituted 5-membered heteroaromatic ring having 1, 2, 3, or 4 heteroatoms selected from N, O, and S. In some embodiments, R is an optionally substituted 6-membered heteroaromatic ring having 1, 2, 3, or 4 heteroatoms selected from N, O, and S. In some embodiments, R is an optionally substituted 5- or 6-membered heteroaromatic ring having 1, 2, 3, or 4 heteroatoms N.

[0110] In some embodiments, R is an optionally substituted C3-C7 carbocyclic ring.

[0111] In some embodiments, R is an optionally substituted 3-, 4-, 5-, 6-, or 7-membered heterocyclic ring having 1, 2, 3, or 4 heteroatoms selected from N, O, and S. In some embodiments, R is an optionally substituted 3-, 4-, 5-, 6-, or 7-membered heterocyclic ring having 1, 2, 3, or 4 heteroatoms selected from N and O. In some embodiments, R is an optionally substituted 4-, 5-, or 6-membered heterocyclic ring having 1, 2, or 3 heteroatoms selected from N, O, and S. In some embodiments, R is an optionally substituted 3-, 4-, 5-, 6-, or 7-membered heterocyclic ring having 1, 2, 3, or 4 heteroatoms N. In some embodiments, R is an optionally substituted 4-, 5-, or 6-membered heterocyclic ring having 1, 2, or 3 heteroatoms N.

[0112] In some embodiments, R is unsubstituted C 1~6 is aliphatic. In some embodiments, R is unsubstituted C 1~6 is alkyl. In some embodiments, R is C 1~6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by halogen or -OH. In some embodiments, R is C 1~6 alkyl substituted 1, 2, 3, 4, 5, or 6 times by halogen or -OH. In some embodiments, R is -CH3, -CD3,

Chemical formula

[0113] In some embodiments, R is optionally substituted

Chemical formula

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0114] In some embodiments, each R is independently -CH3, -CD3, -CF3, -CHF2,

Chemical formula

[0115] In some embodiments, R is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0116] In some embodiments, each R is independently selected from those shown in Table 1 below.

[0117] Generally as defined above, n is 0, 1, 2, or 3.

[0118] In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3.

[0119] In some embodiments, n is selected from those shown in Table 1 below.

[0120] Generally as defined above, m is 0, 1, 2, or 3.

[0121] In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3.

[0122] In some embodiments, m is selected from those shown in Table 1 below.

[0123] In some embodiments, the present invention provides a compound of formula II or II': [Chemical formula] or a pharmaceutically acceptable salt thereof, wherein each variable is, independently and in combination, as defined above and as described in the embodiments herein.

[0124] In some embodiments, the present invention provides a compound of formula II-1 or II'-1: [Chemical formula] or a pharmaceutically acceptable salt thereof, wherein each variable is, independently and in combination, as defined above and as described in the embodiments herein.

[0125] In some embodiments, the present invention provides a compound of formula II-2 or II'-2: [Chemical formula] or a pharmaceutically acceptable salt thereof, wherein each variable is, independently and in combination, as defined above and as described in the embodiments herein.

[0126] In some embodiments, the present invention provides a compound of formula II-3 or II'-3: [Chemical formula] or a pharmaceutically acceptable salt thereof, wherein each variable is, independently and in combination, as defined above and as described in the embodiments herein.

[0127] In some embodiments, the present invention provides a compound of formula II-4 or II'-4: [Chemical formula] or a pharmaceutically acceptable salt thereof, wherein each variable, alone and in combination, is as defined above and as described in the embodiments of the present specification.

[0128] In some embodiments, the present invention provides a compound of formula II-5:

Chemical formula

[0129] In some embodiments, the present invention provides a compound of formula II-6, II-7, II-8, or II-9:

Chemical formula

[0130] In some embodiments, the present invention provides a compound of formula II-6, II-7, II-8, or II-9:

Chemical formula

[0131] In some embodiments, the present invention provides a compound of formula III or III':

Chemical formula

[0132] In some embodiments, the present invention provides a compound of formula III-1 or III'-1:

Chemical formula

[0133] In some embodiments, the present invention provides a compound of formula III-2 or III'-2:

Chemical formula

[0134] In some embodiments, the present invention provides a compound of formula III-3 or III'-3:

Chemical formula

[0135] In some embodiments, the present invention provides a compound of Formula III-4 or III'-4:

Chemical formula

[0136] In some embodiments, the present invention provides a compound of Formula III-5:

Chemical formula

[0137] In some embodiments, the present invention provides a compound of Formula IV or IV':

Chemical formula

[0138] In some embodiments, the present invention provides a compound of formula V or V': [Chemical formula] or a pharmaceutically acceptable salt thereof, wherein each variable is, independently and in combination, as defined above and as described in the embodiments herein.

[0139] In some embodiments, the present invention provides a compound of formula VI or VI': [Chemical formula] or a pharmaceutically acceptable salt thereof, wherein each variable is, independently and in combination, as defined above and as described in the embodiments herein.

[0140] In some embodiments, the present invention provides a compound of formula VII or VII': [Chemical formula] or a pharmaceutically acceptable salt thereof, wherein each variable is, independently and in combination, as defined above and as described in the embodiments herein.

[0141] In some embodiments, the present invention provides a compound of formula VIII or VIII': [Chemical formula] or a pharmaceutically acceptable salt thereof, wherein each variable is, independently and in combination, as defined above and as described in the embodiments herein.

[0142] In some embodiments, the present invention provides a compound of formula IX or IX': [Chemical formula] or a pharmaceutically acceptable salt thereof, wherein each variable is, independently and in combination, as defined above and as described in the embodiments herein.

[0143] In some embodiments, the invention provides a compound of formula X or X':

Chemical formula

[0144] In some embodiments, the invention provides a compound of formula XI or XI':

Chemical formula

[0145] In some embodiments, the invention provides a compound of formula XI-1 to XI-4, or XI'-1 to XI'-4:

Chemical formula

[0146] In some embodiments, the invention provides a compound of formula XII or XII':

Chemical formula

[0147] In some embodiments, R 21 is unsubstituted C 1~6 is aliphatic. In some embodiments, R 21 is unsubstituted C 1~6 is alkyl. In some embodiments, R 21 is C 1~6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by halogen or -OH. In some embodiments, R 21 is C 1~6 alkyl substituted 1, 2, 3, 4, 5, or 6 times by halogen or -OH. In some embodiments, R 21 is -CH3, -CD3,

Chemical formula

[0148] In some embodiments, the present invention provides a compound of formula XII-1 to XII-5, or XII'-1 to XII'-5:

Chemical formula

[0149] In some embodiments, the present invention provides a compound of formula XII-6, XII-7, or XII-8, or XII-9:

Chemical formula

[0150] In some embodiments, the present invention provides a compound of formula XII-10, XII-11, XII-12, XII-13, XII-14, or XII-15: [Chemical formula] or a pharmaceutically acceptable salt thereof, wherein each variable is, independently and in combination, as defined above and as described in the embodiments of this specification.

[0151] In some embodiments, the present invention provides a compound of formula XIII or XIII': [Chemical formula] or a pharmaceutically acceptable salt thereof, wherein R 22 is an optionally substituted ring selected from a phenyl ring and a 5- to 6-membered heteroaromatic ring having 1 to 4 heteroatoms selected from N, O, and S, each of the remaining variables is, independently and in combination, as defined above and as described in the embodiments of this specification.

[0152] In some embodiments, the present invention provides a compound of formula XIII-1 to XIII-5, or XIII'-1 to XIII'-5: [Chemical formula] or a pharmaceutically acceptable salt thereof, wherein R 22is an optionally substituted ring selected from a phenyl ring and a 5- or 6-membered heteroaromatic ring having 1 to 4 heteroatoms selected from N, O, and S, Each of the remaining variables is, independently and in combination, as defined above and as described in the embodiments of this specification.

[0153] In some embodiments, R 22 is optionally substituted phenyl. In some embodiments, R 22 is phenyl optionally substituted one, two, or three times by halogen or C 1~6 alkyl. In some embodiments, R 22 is an optionally substituted 5- or 6-membered heteroaromatic ring having 1, 2, 3, or 4 heteroatoms selected from N, O, and S. In some embodiments, R 22 is a halogen or C 1~6 alkyl optionally substituted one, two, or three times, and is a 5- or 6-membered heteroaromatic ring having 1, 2, 3, or 4 heteroatoms selected from N, O, and S. In some embodiments, R 22 is optionally substituted

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0154] In some embodiments, R 22 is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0155] In some embodiments, the present invention provides a compound of formula XIV or XIV':

Chemical formula

[0156] In some embodiments, the present invention provides a compound of formula XIV-1 to XIV-5, or XIV'-1 to XIV'-5:

Chemical formula

Chemical formula

[0157] In some embodiments, the present invention provides a compound of formula XIV-6:

Chemical formula

[0158] Exemplary compounds of the present invention are shown in Table 1 below.

[0159] In some embodiments, the present invention provides a compound as shown in Table 1 below or a pharmaceutically acceptable salt thereof.

Table 1-1

Table 1-2

Table 1-3

Table 1-4

Table 1-5

Table 1-6

Table 1-7

Table 1-8

Table 1-9

Table 1-10

Table 1-11

[0160] The compounds of the present invention can generally be prepared or isolated by synthetic and / or semi-synthetic methods known to those skilled in the art for similar compounds, as well as by the methods described in detail in the examples herein. In some embodiments, the present invention provides the intermediate compounds described in the examples, or salts thereof.

[0161] 4. Use, Formulation, and Administration Pharmaceutically Acceptable Compositions According to another embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable derivative thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle. The amount of the compound in the composition of the present invention is an amount effective to inhibit USP1, or a variant or mutant thereof, to a measurable extent in a biological sample or patient. In certain embodiments, the amount of the compound in the composition of the present invention is an amount effective to inhibit USP1, or a variant or mutant thereof, to a measurable extent in a biological sample or patient. In certain embodiments, the composition of the present invention is formulated for administration to a patient in need thereof. In some embodiments, the composition of the present invention is formulated for oral administration to a patient.

[0162] The terms "patient" or "subject" as used herein mean an animal, preferably a mammal, most preferably a human.

[0163] The term "pharmaceutically acceptable carrier, adjuvant, or vehicle" refers to a non-toxic carrier, adjuvant, or vehicle that does not impair the pharmacological activity of the compound being formulated. Pharmaceutically acceptable carriers, adjuvants, or vehicles that can be used in the compositions of the present invention include ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffering substances such as phosphoric acid, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol, and lanolin, but are not limited thereto.

[0164] "Pharmaceutically acceptable derivative" means any non-toxic salt, ester, salt of an ester, or other derivative of a compound of the present invention that, when administered to a recipient, can provide directly or indirectly the compound of the present invention or its metabolite or residue having inhibitory activity.

[0165] As used herein, the term "its metabolite or residue having inhibitory activity" means that the metabolite or residue is also an inhibitor of USP1 or its variant or mutant.

[0166] The compositions of the present invention can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, intrabuccally, vaginally, or via an implantable reservoir. As used herein, the term "parenteral" includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intramedullary, intralesional, and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally, or intravenously. The sterile injectable preparations of the compositions of the present invention can be aqueous or oily suspensions. These suspensions can be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. Also, the sterile injectable preparations can be sterile injectable solutions or suspensions in a non-toxic parenterally acceptable diluent or solvent, for example, as a 1,3-butanediol solution. Acceptable vehicles and solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally used as a solvent or suspending medium.

[0167] For this purpose, any non-irritating fixed oil containing synthetic monoglycerides or diglycerides can be used. Fatty acids such as oleic acid and its glyceride derivatives, especially in their polyoxyethylated forms, are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils such as olive oil or castor oil. These oil solutions or suspensions can also contain long-chain alcohol diluents or dispersants, such as carboxymethylcellulose, or similar dispersants commonly used in the formulation of pharmaceutically acceptable dosage forms such as emulsions and suspensions. Other commonly used surfactants, such as Tween, Span, and other emulsifying agents or bioavailability enhancers commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms, can also be used for the purpose of formulation.

[0168] The pharmaceutically acceptable compositions of the present invention can be administered orally in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions, or aqueous solutions. In the case of oral tablets, commonly used carriers include lactose and corn starch. Lubricants such as magnesium stearate are also typically added. In the case of oral administration in capsule form, useful diluents include lactose and dried corn starch. When an aqueous suspension is required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring, or coloring agents can also be added.

[0169] Alternatively, the pharmaceutically acceptable compositions of the present invention can be administered in the form of suppositories for rectal administration. These can be prepared by mixing the drug with a suitable non-irritating additive that is solid at room temperature but liquid at rectal temperature and thus melts in the rectum to release the drug. Such materials include cocoa butter, beeswax, and polyethylene glycol.

[0170] Also, the pharmaceutically acceptable compositions of the present invention can be administered topically, particularly when the target of treatment includes areas or organs that are readily accessible by topical application, such as diseases of the eye, skin, or lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

[0171] Topical application to the lower intestinal tract can be effected using rectal suppository formulations (see above) or suitable enema formulations. Topical transdermal patches can also be used.

[0172] For topical application, the pharmaceutically acceptable compositions provided can be formulated into suitable ointments containing the active ingredient suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of the present invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax, and water. Alternatively, the pharmaceutically acceptable compositions provided can be formulated into suitable lotions or creams containing the active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.

[0173] For ophthalmic use, the pharmaceutically acceptable compositions provided can be formulated as a micronized suspension in isotonic, pH-adjusted sterile saline or, preferably, as a solution in isotonic, pH-adjusted sterile saline, with or without a preservative such as benzalkonium chloride. Alternatively, for ophthalmic use, the pharmaceutically acceptable compositions can be formulated into an ointment such as petrolatum.

[0174] Also, the pharmaceutically acceptable compositions of the present invention can be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the pharmaceutical arts and can be prepared as solutions in saline using benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0175] Most preferably, the pharmaceutically acceptable compositions of the present invention are formulated for oral administration. Such formulations can be administered with or without food. In some embodiments, the pharmaceutically acceptable compositions of the present invention are administered without food. In other embodiments, the pharmaceutically acceptable compositions of the present invention are administered with food.

[0176] The amount of the compounds of the present invention that can be combined with a carrier substance to produce a composition in a single dosage form varies depending on the host being treated and the particular method of administration. Preferably, the compositions provided should be formulated so that an inhibitor at a dosage of 0.01 to 100 mg / kg body weight / day can be administered to a patient receiving these compositions.

[0177] It should also be understood that the specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the particular compound being used, age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician, as well as the severity of the particular disease being treated. The amount of the compound of the present invention in the composition will also be determined by the particular compound in the composition.

[0178] Use of the Compounds and Pharmaceutically Acceptable Compositions According to another embodiment, the present invention provides a method for treating a disease or disorder associated with USP1 in a patient, the method comprising administering to the patient a compound of the present invention, or a pharmaceutically acceptable derivative thereof, or a pharmaceutical composition thereof. In some embodiments, the present invention provides the use of a compound of the present invention, or a pharmaceutically acceptable derivative thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for treating a disease or disorder associated with USP1. In some embodiments, the present invention provides the use of a compound of the present invention, or a pharmaceutically acceptable derivative thereof, or a pharmaceutical composition thereof, for treating a disease or disorder associated with USP1. In some embodiments, the disease or disorder associated with USP1 is a proliferative disease such as cancer described herein.

[0179] As used herein, the terms "treatment," "treat," and "treating" refer to reversing, alleviating, delaying the onset of, or inhibiting the progression of a disease or disorder, or one or more symptoms thereof, as described herein. In some embodiments, treatment can be administered after one or more symptoms have developed. In other embodiments, treatment can be administered in the absence of symptoms. For example, treatment can be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and / or in light of genetic or other susceptibility factors). Also, treatment can be continued after symptoms have resolved, for example, to prevent or delay recurrence.

[0180] As used herein, "proliferative disease" refers to a disease caused by abnormal growth or elongation due to cell proliferation (Walker, Cambridge Dictionary of Biology, Cambridge University Press: Cambridge, UK, 1990). Proliferative diseases can be associated with 1) the pathological proliferation of normal quiescent cells, 2) the pathological movement of cells from their normal location (e.g., metastasis of neoplastic cells), 3) the pathological expression of proteolytic enzymes such as matrix metalloproteinases (e.g., collagenase, gelatinase, and elastase), or 4) pathological angiogenesis as in proliferative retinopathy and tumor metastasis. Exemplary proliferative diseases include cancer (i.e., "malignant neoplasm"), benign neoplasm, angiogenesis, inflammatory disease, and autoimmune disease.

[0181] Cancer Cancers or proliferative disorders or tumors treated using the compounds, methods, and uses described herein include, but are not limited to, blood cancers, lymphomas, myelomas, leukemias, neurological cancers, skin cancers, breast cancers, prostate cancers, colorectal cancers, lung cancers, head and neck cancers, gastrointestinal cancers, liver cancers, pancreatic cancers, genitourinary cancers, bone cancers, kidney cancers, and vascular cancers.

[0182] In some embodiments of the methods and uses described herein, the cancer is lung cancer, thyroid cancer, ovarian cancer, colorectal cancer, prostate cancer, pancreatic cancer, esophageal cancer, liver cancer, breast cancer, skin cancer, or mesothelioma. In some embodiments, the cancer is lung cancer, thyroid cancer, ovarian cancer, colorectal cancer, prostate cancer, pancreatic cancer, esophageal cancer, liver cancer, breast cancer, skin cancer, mesothelioma, sarcoma, or epitheloid hemangioendothelioma (EHE). In some embodiments, the cancer is a mesothelioma such as malignant mesothelioma. In some embodiments, the cancer is EHE.

[0183] In some embodiments, the cancers include leukemia (e.g., acute leukemia, acute lymphocytic leukemia, acute myeloid leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroleukemia, chronic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia), polycythemia vera, lymphoma (e.g., Hodgkin's disease or non-Hodgkin's disease), Waldenström macroglobulinemia, multiple myeloma, heavy chain disease, and solid tumors such as sarcomas and carcinomas (e.g., fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteosarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, esophageal adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, medullary carcinoma, bronchiogenic carcinoma, renal cell carcinoma, hepatoma, cholangiocarcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, uterine cancer, testicular cancer, lung cancer, small cell lung cancer, bladder cancer, epithelial cancer, glioma, astrocytoma, glioblastoma multiforme (GBM, also known as glioblastoma), medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma, neurofibrosarcoma, meningioma, melanoma, neuroblastoma, and retinoblastoma), but are not limited thereto.

[0184] In some embodiments, the cancer is glioma, astrocytoma, glioblastoma multiforme (GBM, also known as glioblastoma), medulloblastoma, craniopharyngioma, ependymoma, pineal tumor, hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma, neurofibrosarcoma, meningioma, melanoma, neuroblastoma, or retinoblastoma.

[0185] In some embodiments, the cancer is acoustic neuroma, astrocytoma (e.g., grade I - pilocytic astrocytoma, grade II - low - grade astrocytoma, grade III - anaplastic astrocytoma, or grade IV - glioblastoma multiforme (GBM)), chordoma, CNS lymphoma, craniopharyngioma, brainstem glioma, ependymoma, mixed glioma, optic glioma, subependymoma, medulloblastoma, meningioma, metastatic brain tumor, oligodendroglioma, pituitary tumor, primitive neuroectodermal (PNET) tumor, or schwannoma. In some embodiments, the cancer is a type that is more commonly seen in pediatric patients than in adults, such as brainstem glioma, craniopharyngioma, ependymoma, juvenile pilocytic astrocytoma (JPA), medulloblastoma, optic glioma, pineal tumor, primitive neuroectodermal tumor (PNET), or rhabdoid tumor. In some embodiments, the patient is an adult human. In some embodiments, the patient is a child or pediatric patient.

[0186] In another embodiment, cancers include, but are not limited to, mesothelioma, hepatobiliary tract (hepatic ducts and bile ducts), bone cancer, pancreatic cancer, skin cancer, head and neck cancer, cutaneous or intraocular melanoma, ovarian cancer, colon cancer, rectal cancer, anal cancer, stomach cancer, gastrointestinal tract (stomach, colorectal, and duodenum), uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, testicular cancer, chronic or acute leukemia, chronic myelogenous leukemia, lymphocytic lymphoma, bladder cancer, kidney or ureteral cancer, renal cell cancer, renal pelvic cancer, non - Hodgkin's lymphoma, spinal cord axis tumor, brainstem glioma, pituitary adenoma, adrenocortical cancer, bladder cancer, multiple myeloma, bile duct cancer, fibrosarcoma, neuroblastoma, retinoblastoma, or a combination of one or more of the above - mentioned cancers.

[0187] In some embodiments, the cancer is selected from hepatocellular carcinoma, ovarian cancer, ovarian epithelial cancer, or fallopian tube cancer, papillary serous cystadenocarcinoma or uterine serous adenocarcinoma (UPSC), prostate cancer, testicular cancer, gallbladder cancer, cholangiocarcinoma, soft tissue and bone synovial sarcoma, rhabdomyosarcoma, osteosarcoma, chondrosarcoma, Ewing's sarcoma, anaplastic thyroid cancer, adrenocortical adenoma, pancreatic cancer, pancreatic ductal cancer or pancreatic adenocarcinoma, gastrointestinal / stomach (GIST) cancer, lymphoma, head and neck squamous cell carcinoma (SCCHN), salivary gland cancer, glioma, or brain cancer, neurofibromatosis type 1-related malignant peripheral nerve sheath tumor (MPNST), Waldenström macroglobulinemia, or medulloblastoma.

[0188] In some embodiments, the cancer is selected from hepatocellular carcinoma (HCC), hepatoblastoma, colon cancer, rectal cancer, ovarian cancer, ovarian epithelial cancer, fallopian tube cancer, papillary serous cystadenocarcinoma, uterine serous adenocarcinoma (UPSC), cholangiocarcinoma, soft tissue and bone synovial sarcoma, rhabdomyosarcoma, osteosarcoma, anaplastic thyroid cancer, adrenocortical adenoma, pancreatic cancer, pancreatic ductal cancer, pancreatic adenocarcinoma, glioma, neurofibromatosis type 1-related malignant peripheral nerve sheath tumor (MPNST), Waldenström macroglobulinemia, or medulloblastoma.

[0189] In some embodiments, the cancer is a solid tumor such as a sarcoma, carcinoma, or lymphoma. Solid tumors generally comprise abnormal tissue masses that typically do not contain cysts or liquid regions. In some embodiments, the cancer is selected from renal cell carcinoma or kidney cancer, hepatocellular carcinoma (HCC) or hepatoblastoma or liver cancer, melanoma, breast cancer, colorectal carcinoma or colorectal cancer, colon cancer, rectal cancer, anal cancer, lung cancer such as non-small cell lung cancer (NSCLC) or small cell lung cancer (SCLC), ovarian cancer, ovarian epithelial cancer, ovarian carcinoma, or fallopian tube cancer, papillary serous cystadenocarcinoma or uterine serous carcinoma (UPSC), prostate cancer, testicular cancer, gallbladder cancer, cholangiocarcinoma, soft tissue and bone synovial sarcoma, rhabdomyosarcoma, osteosarcoma, chondrosarcoma, Ewing sarcoma, anaplastic thyroid cancer, adrenocortical cancer, pancreatic cancer, pancreatic ductal cancer or pancreatic adenocarcinoma, gastrointestinal / stomach (GIST) cancer, lymphoma, head and neck squamous cell carcinoma (SCCHN), salivary gland cancer, glioma, or brain cancer, neurofibromatosis type 1-related malignant peripheral nerve sheath tumor (MPNST), Waldenström macroglobulinemia, or medulloblastoma.

[0190] In some embodiments, the cancer is selected from renal cell carcinoma, hepatocellular carcinoma (HCC), hepatoblastoma, colorectal carcinoma, colorectal cancer, colon cancer, rectal cancer, anal cancer, ovarian cancer, ovarian epithelial cancer, ovarian carcinoma, fallopian tube cancer, papillary serous cystadenocarcinoma, uterine serous carcinoma (UPSC), cholangiocarcinoma, soft tissue and bone synovial sarcoma, rhabdomyosarcoma, osteosarcoma, chondrosarcoma, anaplastic thyroid cancer, adrenocortical cancer, pancreatic cancer, pancreatic ductal cancer, pancreatic adenocarcinoma, glioma, brain cancer, neurofibromatosis type 1-related malignant peripheral nerve sheath tumor (MPNST), Waldenström macroglobulinemia, or medulloblastoma.

[0191] In some embodiments, the cancer is selected from hepatocellular carcinoma (HCC), hepatoblastoma, colon cancer, rectal cancer, ovarian cancer, ovarian epithelial cancer, ovarian carcinoma, fallopian tube cancer, papillary serous cystadenocarcinoma, uterine serous carcinoma (UPSC), cholangiocarcinoma, soft tissue and bone synovial sarcoma, rhabdomyosarcoma, osteosarcoma, anaplastic thyroid cancer, adrenocortical cancer, pancreatic cancer, pancreatic ductal cancer, pancreatic adenocarcinoma, glioma, neurofibromatosis type 1 - related malignant peripheral nerve sheath tumor (MPNST), Waldenström macroglobulinemia, or medulloblastoma.

[0192] In some embodiments, the cancer is hepatocellular carcinoma (HCC). In some embodiments, the cancer is hepatoblastoma. In some embodiments, the cancer is colon cancer. In some embodiments, the cancer is rectal cancer. In some embodiments, the cancer is ovarian cancer, or ovarian carcinoma. In some embodiments, the cancer is ovarian epithelial cancer. In some embodiments, the cancer is fallopian tube cancer. In some embodiments, the cancer is papillary serous cystadenocarcinoma. In some embodiments, the cancer is uterine serous carcinoma (UPSC). In some embodiments, the cancer is cholangiocarcinoma. In some embodiments, the cancer is soft tissue and bone synovial sarcoma. In some embodiments, the cancer is rhabdomyosarcoma. In some embodiments, the cancer is osteosarcoma. In some embodiments, the cancer is anaplastic thyroid cancer. In some embodiments, the cancer is adrenocortical cancer. In some embodiments, the cancer is pancreatic cancer, or pancreatic ductal cancer. In some embodiments, the cancer is pancreatic adenocarcinoma. In some embodiments, the cancer is glioma. In some embodiments, the cancer is malignant peripheral nerve sheath tumor (MPNST). In some embodiments, the cancer is neurofibromatosis type 1 - related MPNST. In some embodiments, the cancer is Waldenström macroglobulinemia. In some embodiments, the cancer is medulloblastoma.

[0193] In some embodiments, the cancer is a virus-related cancer, including human immunodeficiency virus (HIV)-associated solid tumors, human papillomavirus (HPV)-16 positive, treatment-refractory solid tumors, and adult T-cell leukemia, a highly aggressive form of CD4+ T-cell leukemia characterized by HTLV-I clone integration in leukemia cells caused by human T-cell leukemia virus type I (HTLV-I) (see https: / / clinicaltrials.gov / ct2 / show / study / NCT02631746), as well as virus-related tumors in gastric cancer, nasopharyngeal cancer, cervical cancer, vaginal cancer, vulvar cancer, head and neck squamous cell carcinoma, and Merkel cell carcinoma. (See also https: / / clinicaltrials.gov / ct2 / show / study / NCT02488759, https: / / clinicaltrials.gov / ct2 / show / study / NCT0240886, https: / / clinicaltrials.gov / ct2 / show / NCT02426892)

[0194] In some embodiments, the cancer is melanoma. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is small cell lung cancer (SCLC). In some embodiments, the cancer is non-small cell lung cancer (NSCLC).

[0195] In accordance with the methods of the present invention, compounds and compositions can be administered using any amount and any route of administration effective to treat or reduce the severity of cancer or tumors. The exact amount required will vary for each subject depending on the species, age, and general condition of the subject, the severity of the disease or condition, the particular agent, its method of administration, and the like. The compounds of the present invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage. As used herein, the expression "dosage unit form" refers to physically discrete units of drug appropriate to the patient to be treated. However, it will be understood that the total daily usage of the compounds and compositions of the present invention will be determined by the attending physician within the scope of sound medical judgment. The specific effective dosage level for any particular patient or organism depends on a variety of factors including the disorder being treated and the severity of the disorder, the activity of the particular compound used, the particular composition employed, the age, weight, general health status, sex, and diet of the patient, the time of administration, route of administration, and rate of excretion of the particular compound used, the duration of the treatment, drugs used in combination with or concurrently with the particular compound employed, and like factors well known in the medical arts. The terms "patient" or "subject" as used herein mean an animal, preferably a mammal, most preferably a human.

[0196] The pharmaceutically acceptable compositions of the present invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (by powders, ointments, or eyedrops), sublingually, as oral or nasal sprays, etc., depending on the severity of the disease or disorder being treated. In certain embodiments, the compounds of the present invention can be administered orally or parenterally at a dosage level of about 0.01 mg / kg to about 50 mg / kg, preferably about 1 mg / kg to about 25 mg / kg of the subject's body weight per day, one or more times a day to obtain the desired therapeutic effect.

[0197] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing and emulsifying agents, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3 - butylene glycol, dimethylformamide, oils (in particular, cottonseed oil, groundnut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof. In addition to the inert diluent, oral compositions may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0198] Injectable preparations, for example sterile aqueous or oleaginous suspensions, may be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. In addition, sterile injectable preparations may be sterile injectable solutions, suspensions or emulsions in a non - toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3 - butanediol. Acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil containing synthetic mono - or diglycerides may be used. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0199] Injectable formulations can be sterilized, for example, by filtration through a bacteria - retaining filter or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0200] In order to sustain the effects of the compounds of the present invention, it is often desirable to retard the absorption of the compounds from subcutaneous or intramuscular injection. This can be achieved by using a crystalline or amorphous liquid suspension that is poorly water-soluble. The absorption rate of the compound then depends on its dissolution rate, which in turn can depend on the crystal size and crystal form. Alternatively, delayed absorption of the parenterally administered compound form is achieved by dissolving or suspending the compound in an oily vehicle. Injectable depot forms are prepared by forming a microcapsule matrix of the compound in a biodegradable polymer such as polylactide-polyglycolide. Depending on the ratio of the compound to the polymer and the nature of the specific polymer used, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injection formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

[0201] Compositions for rectal or vaginal administration can preferably be prepared by mixing the compounds of the present invention with a suitable non-irritating additive or carrier that is solid at ambient temperature but liquid at body temperature, such as cocoa butter, polyethylene glycol, or suppository wax, and thus melt in the rectal or vaginal cavity and release the active compound.

[0202] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is combined with at least one inert pharmaceutically acceptable additive or carrier such as sodium citrate or dicalcium phosphate, and / or a) excipients or diluents such as starch, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and acacia, c) wetting agents such as glycerol, d) disintegrants such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retardants such as paraffin, f) absorption promoters such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also include buffering agents.

[0203] Solid compositions of the same type can also be used as excipients for soft and hard gelatin capsules using additives such as lactose or milk sugar, and high molecular weight polyethylene glycol. Solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared using coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical art. These may optionally contain opacifying agents and may be compositions that release only the active ingredient(s) or, preferably, in a particular part of the gastrointestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of the same type can also be used as excipients for soft and hard gelatin capsules using additives such as lactose or milk sugar, and high molecular weight polyethylene glycol.

[0204] The active compound can also be in microencapsulated form containing one or more of the above additives. Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shells such as enteric coatings, release control coatings, and other coatings well known in the pharmaceutical art. In such solid dosage forms, the active compound can be mixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms can also, as a normal practice, contain additional substances other than inert diluents, for example, tableting lubricants and other tableting aids such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pills, the dosage form can also contain buffering agents. They may optionally contain an opacifying agent and may optionally be compositions that release only or preferentially the active ingredient(s) in a particular part of the gastrointestinal tract in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0205] Dosage forms for topical or transdermal administration of the compounds of the present invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. The active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservatives or buffering agents as required. Ophthalmic formulations, ear drops, and eye drops are also contemplated to be within the scope of the present invention. Additionally, the present invention contemplates the use of transdermal patches which have the additional advantage of providing controlled delivery of the compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in a suitable medium. Absorption promoters can also be used to increase the flux of the compound across the skin. The rate can be controlled either by providing a rate controlling membrane or by dispersing the compound in a polymeric matrix or gel.

[0206] Combined administration with one or more other therapeutic agents Depending on the specific condition or disease to be treated, additional therapeutic agents that are normally administered to treat that condition may also be present in the compositions of the present invention. As used herein, additional therapeutic agents that are normally administered to treat a particular disease or condition are known as "appropriate for the disease or condition being treated."

[0207] In some embodiments, the present invention provides a method of treating a disclosed disease or condition, the method comprising administering to a patient in need thereof an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof, and co-administering simultaneously or sequentially an effective amount of one or more additional therapeutic agents such as those described herein. In some embodiments, the method comprises co-administering one additional therapeutic agent. In some embodiments, the method comprises co-administering two additional therapeutic agents. In some embodiments, the combination of the disclosed compound and the additional therapeutic agent(s) act synergistically.

[0208] The compounds of the present invention can also be used in combination with known treatment processes, such as administration of hormones or radiation. In certain embodiments, the compounds provided are used as radiosensitizers for the treatment of tumors that exhibit particularly low sensitivity to radiotherapy.

[0209] The compounds of the present invention can be administered alone or in combination with one or more other therapeutic compounds, and possible combination therapies can take the form of a formulation, or the compound of the present invention and one or more other therapeutic compounds can be administered at staggered times or independently of each other, or a formulation and one or more other therapeutic compounds can be administered in combination. The compounds of the present invention can further, or in addition, be administered in combination with chemotherapy, radiotherapy, immunotherapy, phototherapy, surgical intervention, or combinations thereof, particularly for the treatment of tumors. As noted above, long-term treatment is also possible, such as adjuvant therapy in the case of other treatment strategies. Other possible treatments are therapies for maintaining the patient's condition after tumor regression, or chemoprevention, for example, in at-risk patients.

[0210] One or more other therapeutic agents can be administered separately from the compound or composition of the present invention as part of a multiple dosing regimen. Alternatively, one or more other therapeutic agents can be part of a single dosage form and can be mixed in a single composition with the compound of the present invention. When administered as a multiple dosing regimen, the one or more other therapeutic agents and the compound or composition of the present invention can be administered simultaneously, sequentially, or within a period of time relative to each other, for example, within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 18, 20, 21, 22, 23, or 24 hours of each other. In some embodiments, the one or more other therapeutic agents and the compound or composition of the present invention are administered as a multiple dosing regimen with intervals greater than 24 hours.

[0211] As used herein, "in combination", "administered in combination", and related terms indicate the simultaneous or sequential administration of a therapeutic agent according to the present invention. For example, the compound of the present invention can be administered simultaneously or sequentially in a separate unit dosage form from one or more other therapeutic agents, or can be administered together in a single unit dosage form. Accordingly, the present invention provides a single unit dosage form comprising the compound of the present invention, one or more other therapeutic agents, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0212] The amounts of the compound of the present invention and one or more other therapeutic agents (in a composition comprising the additional therapeutic agents described above) that can be combined with a carrier substance to produce a single dosage form vary depending on the host being treated and the particular method of administration. Preferably, the composition of the present invention should be formulated such that the compound of the present invention can be administered at a dosage of 0.01 to 100 mg / kg body weight / day.

[0213] In these compositions containing one or more other therapeutic agents, the one or more other therapeutic agents and the compounds of the present invention may act synergistically. Thus, the amount of one or more other therapeutic agents in such compositions may be less than the amount required in a monotherapy using only that therapeutic agent. In such compositions, one or more other therapeutic agents can be administered at a dosage of 0.01 to 1,000 μg / kg body weight / day.

[0214] The amount of one or more other therapeutic agents present in the compositions of the present invention may be less than or equal to the amount normally administered in a composition containing that therapeutic agent as the sole active agent. Preferably, the amount of one or more other therapeutic agents in the compositions of the present disclosure is in the range of about 50% to 100% of the amount normally present in a composition containing that agent as the sole therapeutic active agent. In some embodiments, the one or more other therapeutic agents are administered at a dosage of about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95% of the amount normally administered for that agent. As used herein, the expression "normally administered" means the amount at which an FDA-approved therapeutic agent is approved for administration according to the FDA label insert.

[0215] The compounds of the present invention, or pharmaceutical compositions thereof, may also be incorporated into compositions for coating implantable medical devices such as prostheses, artificial valves, artificial blood vessels, stents, and catheters. For example, vascular stents are used to overcome restenosis (the re-narrowing of the blood vessel wall after injury). However, patients using stents or other implantable devices are at risk of thrombosis or platelet activation. These undesirable effects can be prevented or mitigated by pre-coating the device with a pharmaceutically acceptable composition containing a kinase inhibitor. An implantable device coated with a compound of the present invention is another embodiment of the present invention.

[0216] Exemplary other therapeutic agents In some embodiments, one or more other therapeutic agents are poly (ADP - ribose) polymerase (PARP) inhibitors. In some embodiments, the PARP inhibitor is selected from olaparib (Lynparza®, AstraZeneca), rucaparib (Rubraca®, Clovis Oncology), niraparib (Zejula®, Tesaro), talazoparib (MDV3800 / BMN673 / LT00673, Medivation / Pfizer / Biomarin), veliparib (ABT - 888, AbbVie), and BGB - 290 (BeiGene, Inc.).

[0217] In some embodiments, one or more other therapeutic agents are histone deacetylase (HDAC) inhibitors. In some embodiments, the HDAC inhibitor is selected from vorinostat (Zolinza®, Merck), romidepsin (Istodax®, Celgene), panobinostat (Farydak®, Novartis), belinostat (Beleodaq®, Spectrum Pharmaceuticals), entinostat (SNDX - 275, Syndax Pharmaceuticals) (NCT00866333), and chidamide (Epidaza®, HBI - 8000, Chipscreen Biosciences, China).

[0218] In some embodiments, one or more other therapeutic agents are CDK inhibitors such as CDK4 / CDK6 inhibitors. In some embodiments, the CDK4 / 6 inhibitor is selected from palbociclib (Ibrance®, Pfizer), ribociclib (Kisqali®, Novartis), abemaciclib (Ly2835219, Eli Lilly), and trilaciclib (G1T28, G1 Therapeutics).

[0219] In some embodiments, one or more other therapeutic agents are phosphatidylinositol 3-kinase (PI3K) inhibitors. In some embodiments, the PI3K inhibitor is selected from idelalisib (Zydelig®, Gilead), alpelisib (BYL719, Novartis), taselisib (GDC-0032, Genentech / Roche), pictilisib (GDC-0941, Genentech / Roche), copanlisib (BAY806946, Bayer), duvelisib (previously IPI-145, Infinity Pharmaceuticals), PQR309 (Piqur Therapeutics, Switzerland), and TGR1202 (previously RP5230, TG Therapeutics).

[0220] In some embodiments, one or more other therapeutic agents are platinum-based therapeutic agents, also referred to as platinums. Platinum causes DNA cross-linking to inhibit DNA repair and / or DNA synthesis, mainly in rapidly replicating cells such as cancer cells.

[0221] In some embodiments, the platinum-based therapeutic agent is selected from cisplatin (Platinol®, Bristol-Myers Squibb), carboplatin (Paraplatin®, Bristol-Myers Squibb; also, Teva; Pfizer), oxaliplatin (Eloxitin®, Sanofi-Aventis), nedaplatin (Aqupla®, Shionogi), picoplatin (Poniard Pharmaceuticals), and satraplatin (JM-216, Agennix).

[0222] In some embodiments, one or more other therapeutic agents are taxane compounds that cause disruption of microtubules essential for cell division. In some embodiments, the taxane compound is selected from paclitaxel (Taxol®, Bristol-Myers Squibb), docetaxel (Taxotere®, Sanofi-Aventis; Docefrez®, Sun Pharmaceutical), albumin-bound paclitaxel (Abraxane®; Abraxis / Celgene), cabazitaxel (Jevtana®, Sanofi-Aventis), and SID530 (SK Chemicals, Co.) (NCT00931008).

[0223] In some embodiments, one or more other therapeutic agents are nucleoside inhibitors, or therapeutic agents that prevent normal DNA synthesis, protein synthesis, cell replication, or otherwise inhibit rapidly proliferating cells.

[0224] In some embodiments, the nucleoside inhibitor is trabectedin (a guanidine alkylating agent, Yondelis®, Janssen Oncology), mechlorethamine (an alkylating agent, Valchlor®, Aktelion Pharmaceuticals), vincristine (Oncovin®, Eli Lilly; Vincasar®, Teva Pharmaceuticals; Marqibo®, Talon Therapeutics), temozolomide (a prodrug of 5-(3-methyltriazen-1-yl)-imidazole-4-carboxamide (MTIC), an alkylating agent, Temodar®, Merck), cytarabine for injection (ara-C, a metabolic antagonist cytidine analogue, Pfizer), lomustine (an alkylating agent, CeeNU®, Bristol-Myers Squibb; Gleostine®, NextSource Biotechnology), azacitidine (a pyrimidine nucleoside analogue of cytidine, Vidaza®, Celgene), omacetaxine mepesuccinate (cephalotaxine ester) (a protein synthesis inhibitor, Synribo®, Teva Pharmaceuticals), asparaginase Erwinia chrysanthemi (an enzyme for depleting asparagine, Elspar®, Lundbeck;Selected from Erwinaze (registered trademark, EUSA Pharma), eribulin mesylate (a microtubule inhibitor, a tubulin-based anti-mitotic agent, Halaven (registered trademark, Eisai)), cabazitaxel (a microtubule inhibitor, a tubulin-based anti-mitotic agent, Jevtana (registered trademark, Sanofi-Aventis)), capecitabine (a thymidylate synthase inhibitor, Xeloda (registered trademark, Genentech)), bendamustine (a bifunctional mechlorethamine derivative, thought to form interstrand DNA crosslinks, Treanda (registered trademark, Cephalon / Teva)), ixabepilone (a semi-synthetic analogue of epothilone B, a microtubule inhibitor, a tubulin-based anti-mitotic agent, Ixempra (registered trademark, Bristol-Myers Squibb)), nelarabine (a prodrug of a deoxyguanosine analogue, a nucleoside metabolism inhibitor, Arranon (registered trademark, Novartis)), cladribine (a prodrug of a ribonucleotide reductase inhibitor, a competitive inhibitor of deoxycytidine, Clolar (registered trademark, Sanofi-Aventis)), and trifluridine and tipiracil (a thymidine-based nucleoside analogue and a thymidine phosphorylase inhibitor, Lonsurf (registered trademark, Taiho Oncology)).;

[0225] In some embodiments, one or more other therapeutic agents are kinase inhibitors or VEGF-R antagonists. In some embodiments, one or more other therapeutic agents are MEK inhibitors. As used herein, “MEK inhibitor” refers to any inhibitor or blocker or antagonist that binds to and / or inhibits the mitogen-activated protein kinase enzymes MEK1 and / or MEK2. In some embodiments, the MEK inhibitor is selected from those described in Cheng et al., “Current Development Status of MEK Inhibitors,” Molecules 2017, 22, 1551, the entire content of which is incorporated herein by reference. In certain embodiments, the MEK inhibitor is binimetinib (MEK162, ARRY-438162, ARRAY BIOPHARMA INC.), cobimetinib (COTELLIC®, Exelexis / Genentech / Roche), refametinib (BAY 86-9766, RDEA119; Bayer AG), selumetinib (AZD6244, ARRY-142886; ASTRAZENECA), trametinib (MEKINIST®, Novartis), mirdametinib (PD-0325901, Spring Works Therapeutics), pimasertib (AS703026, MSC1936369B, Merck KGaA), or any pharmaceutically acceptable salt and / or solvate of any of the foregoing. In certain embodiments, the second anti-cancer agent is binimetinib, cobimetinib, selumetinib, trametinib, mirdametinib, pimasertib, or any pharmaceutically acceptable salt and / or solvate of any of the foregoing.Other examples of MEK inhibitors for use as other therapeutic agents in the methods and uses described herein include, but are not limited to, E6201 (Eisai Co Ltd. / Strategia Theraputics), GDC-0623 (RG 7421, Genentech, Inc.), CH5126766 (RO5126766, Chugai 232 Pharmaceutical Co., Roche), HL-085 (Shanghai Kechow Pharma, Inc.), SHR7390 (HENGRUI MEDICINE), TQ-B3234 (CHIATAI TIANQING), CS-3006 (CSTONE Pharmaceuticals), FCN-159 (Fosun Pharmaceuticals), VS-6766 (Verastem Oncology), and IMM-1-104 (Immuneering Corp.). Other examples of MEK inhibitors for use as a second anti-cancer agent in the methods and uses described herein include, but are not limited to, those described in WO2005 / 121142, WO2014 / 169843, WO2016 / 035008, WO2016 / 168704, WO2020 / 125747, WO2021 / 142144, WO2021 / 142345, WO2021 / 149776, the contents of each of which are hereby incorporated by reference in their entirety.

[0226] In some embodiments, one or more other therapeutic agents are EGFR inhibitors. As used herein, "EGFR inhibitor" refers to any inhibitor or blocker or antagonist that binds to and / or inhibits the epidermal growth factor receptor (EGFR). In some embodiments, the EGFR inhibitor is selected from those described in Ayati et al., "A review on progression of epidermal growth factor receptor (EGFR) inhibitors as an efficient approach in cancer targeted therapy," Bioorganic Chemistry 2020, 99:103811, the entire content of which is incorporated herein by reference. In some embodiments, the EGFR inhibitor is selected from cetuximab, necitumumab, panitumumab, zalutumumab, nimotuzumab, and matuzumab. In some embodiments, the EGFR inhibitor is cetuximab. In some embodiments, the EGFR inhibitor is necitumumab. In some embodiments, the EGFR inhibitor is panitumumab. In some embodiments, the EGFR inhibitor is zalutumumab. In some embodiments, the EGFR inhibitor is nimotuzumab. In some embodiments, the EGFR inhibitor is matuzumab.

[0227] In some embodiments, the EGFR inhibitor is selected from osimertinib, gefitinib, erlotinib, lapatinib, neratinib, vandetanib, afatinib, brigatinib, dacomitinib, and icotinib. In some embodiments, the EGFR inhibitor is osimertinib. In some embodiments, the EGFR inhibitor is gefitinib. In some embodiments, the EGFR inhibitor is erlotinib. In some embodiments, the EGFR inhibitor is lapatinib. In some embodiments, the EGFR inhibitor is neratinib. In some embodiments, the EGFR inhibitor is vandetanib. In some embodiments, the EGFR inhibitor is afatinib. In some embodiments, the EGFR inhibitor is brigatinib. In some embodiments, the EGFR inhibitor is dacomitinib. In some embodiments, the EGFR inhibitor is icotinib.

[0228] In some embodiments, the EGFR inhibitor is a "first-generation EGFR tyrosine kinase inhibitor" (first-generation TKI). First-generation TKIs refer to reversible EGFR inhibitors such as gefitinib and erlotinib, which are effective for the first-line treatment of NSCLC with EGFR-activating mutations such as exon 19 deletions and the L858R mutation in exon 21.

[0229] In some embodiments, the EGFR inhibitor is a "second-generation EGFR tyrosine kinase inhibitor" (second-generation TKI). Second-generation TKIs refer to covalent irreversible EGFR inhibitors such as afatinib and dacomitinib, which are effective for the first-line treatment of NSCLC with EGFR-activating mutations such as exon 19 deletions and the L858R mutation in exon 21.

[0230] In some embodiments, the EGFR inhibitor is a "third-generation EGFR tyrosine kinase inhibitor" (third-generation TKI). Third-generation TKIs refer to covalent irreversible EGFR inhibitors such as osimertinib and lazertinib, which are selective for EGFR activation mutations alone, such as exon 19 deletions and L858R in exon 21, or in combination with the T790M mutation, and have low inhibitory activity against wild-type EGFR.

[0231] In some embodiments, one or more other therapeutic agents useful in the present invention selected from approved VEGF inhibitors and kinase inhibitors include bevacizumab (Avastin®, Genentech / Roche), an anti-VEGF monoclonal antibody; ramucirumab (Cyramza®, Eli Lilly), an anti-VEGFR-2 antibody; and ziv-aflibercept (Zaltrap®; Regeneron / Sanofi), also known as VEGF Trap. VEGFR inhibitors such as regorafenib (Stivarga®, Bayer), vandetanib (Caprelsa®, AstraZeneca), axitinib (Inlyta®, Pfizer), and lenvatinib (Lenvima®, Eisai); Raf inhibitors such as sorafenib (Nexavar®, Bayer AG and Onyx), dabrafenib (Tafinlar®, Novartis), and vemurafenib (Zelboraf®, Genentech / Roche); MEK inhibitors such as cobimetinib (Cotellic®, Exelexis / Genentech / Roche), trametinib (Mekinist®, Novartis); Bcr-Abl tyrosine kinase inhibitors such as imatinib (Gleevec®, Novartis), nilotinib (Tasigna®, Novartis), dasatinib (Sprycel®, BristolMyersSquibb), bosutinib (Bosulif®, Pfizer), and ponatinib (Inclusig®, Ariad Pharmaceuticals); Her2 and EGFR inhibitors such as gefitinib (Iressa®, AstraZeneca), erlotinib (Tarceeva®, Genentech / Roche / Astellas), lapatinib (Tykerb®, Novartis), afatinib (Gilotrif®, BoehringerIngelheim), osimertinib (targeting activated EGFR, Tagrisso®, AstraZeneca), and brigatinib (Alunbrig®, Ariad Pharmaceuticals), c-Met and VEGFR2 inhibitors, such as cabozantinib (Cometriq®, Exelexis), and multi-kinase inhibitors, such as sunitinib (Sutent®, Pfizer), pazopanib (Votrient®, Novartis), ALK inhibitors, such as crizotinib (Xalkori®, Pfizer), ceritinib (Zykadia®, Novartis), and alectinib (Alecenza®, Genentech / Roche), Bruton's tyrosine kinase inhibitors, such as ibrutinib (Imbruvica®, Pharmacyclics / Janssen), and Flt3 receptor inhibitors, such as midostaurin (Rydapt®, Novartis).

[0232] Other kinase inhibitors and VEGF-R antagonists that are under development and can be used in the present invention include tivozanib (Aveo Pharmaceuticals), batatinib (Bayer / Novartis), lucitanib (Clovis Oncology), dovitinib (TKI258, Novartis), chiauanib (Chipscreen Biosciences), CEP-11981 (Cephalon), lenvatinib (Abbott Laboratories), neratinib (HKI-272, Puma Biotechnology), radotinib (Supect®, IY5511, Il-Yang Pharmaceuticals, S.Korea), ruxolitinib (Jakafi®, Incyte Corporation), PTC299 (PTC Therapeutics), CP-547,632 (Pfizer), foretinib (Exelexis, GlaxoSmithKline), xidaniinib (Daiichi Sankyo), and motesanib (Amgen / Takeda).

[0233] In some embodiments, one or more other therapeutic agents are mTOR inhibitors that inhibit cell proliferation, angiogenesis, and glucose uptake. In some embodiments, the mTOR inhibitors are everolimus (Afinitor®, Novartis), temsirolimus (Torisel®, Pfizer), and sirolimus (Rapamune®, Pfizer).

[0234] In some embodiments, one or more other therapeutic agents are proteasome inhibitors. Approved proteasome inhibitors useful in the present invention include bortezomib (Velcade®, Takeda), carfilzomib (Kyprolis®, Amgen), and ixazomib (Ninlaro®, Takeda).

[0235] In some embodiments, one or more other therapeutic agents are growth factor antagonists, such as platelet-derived growth factor (PDGF), or antagonists of epidermal growth factor (EGF) or its receptor (EGFR). Approved PDGF antagonists that can be used in the present invention include olaratumab (Lartruvo®; Eli Lilly). Approved EGFR antagonists that can be used in the present invention include cetuximab (Erbitux®, Eli Lilly), necitumumab (Portrazza®, Eli Lilly), panitumumab (Vectibix®, Amgen), and osimertinib (targeting activated EGFR, Tagrisso®, AstraZeneca).

[0236] In some embodiments, one or more other therapeutic agents are aromatase inhibitors. In some embodiments, the aromatase inhibitor is selected from exemestane (Aromasin®, Pfizer), anastrozole (Arimidex®, AstraZeneca), and letrozole (Femara®, Novartis).

[0237] In some embodiments, one or more other therapeutic agents are antagonists of the hedgehog pathway. Approved hedgehog pathway inhibitors that can be used in the present invention include sonidegib (Odomzo®, Sun Pharmaceuticals) and vismodegib (Erivedge®, Genentech), both of which are for the treatment of basal cell carcinoma.

[0238] In some embodiments, one or more other therapeutic agents are folic acid inhibitors. An approved folic acid inhibitor useful in the present invention includes pemetrexed (Alimta®, Eli Lilly).

[0239] In some embodiments, one or more other therapeutic agents are CC chemokine receptor 4 (CCR4) inhibitors. A CCR4 inhibitor under investigation that may be useful in the present invention includes mogamulizumab (Poteligeo®, Kyowa Hakko Kirin, Japan).

[0240] In some embodiments, one or more other therapeutic agents are isocitrate dehydrogenase (IDH) inhibitors. IDH inhibitors under investigation that can be used in the present invention include AG120 (Celgene; NCT02677922), AG221 (Celgene, NCT02677922; NCT02577406), BAY1436032 (Bayer, NCT02746081), and IDH305 (Novartis, NCT02987010).

[0241] In some embodiments, one or more other therapeutic agents are arginase inhibitors. Arginase inhibitors under investigation that can be used in the present invention include AEB1102 (pegylated recombinant arginase, Aeglea Biotherapeutics), which is being studied in Phase 1 clinical trials for acute myeloid leukemia and myelodysplastic syndromes (NCT02732184) and solid tumors (NCT02561234), and CB-1158 (Calithera Biosciences).

[0242] In some embodiments, one or more other therapeutic agents are glutaminase inhibitors. A glutaminase inhibitor under investigation that can be used in the present invention is CB-839 (Calithera Biosciences).

[0243] In some embodiments, one or more other therapeutic agents are antibodies that bind to tumor antigens, i.e., proteins expressed on the cell surface of tumor cells. Approved antibodies that bind to tumor antigens that can be used in the present invention include rituximab (Rituxan®, Genentech / BiogenIdec), ofatumumab (anti-CD20, Arzerra®, GlaxoSmithKline), obinutuzumab (anti-CD20, Gazyva®, Genentech), ibritumomab (anti-CD20 and yttrium-90, Zevalin®, Spectrum Pharmaceuticals), daratumumab (anti-CD38, Darzalex®, Janssen Biotech), dinutuximab (anti-glycolipid GD2, Unituxin®, United Therapeutics), trastuzumab (anti-HER2, Herceptin®, Genentech), ado-trastuzumab emtansine (anti-HER2, fused to emtansine, Kadcyla®, Genentech), and pertuzumab (anti-HER2, Perjeta®, Genentech), and brentuximab vedotin (anti-CD30 drug conjugate, Adcetris®, Seattle Genetics).

[0244] In some embodiments, one or more other therapeutic agents are topoisomerase inhibitors. Approved topoisomerase inhibitors useful in the present invention include irinotecan (Onivyde®, Merrimack Pharmaceuticals), topotecan (Hycamtin®, GlaxoSmithKline). Investigational topoisomerase inhibitors that can be used in the present invention include pixantrone (Pixuvri®, CTI Biopharma).

[0245] In some embodiments, one or more other therapeutic agents are inhibitors of anti-apoptotic proteins such as BCL-2. Approved anti-apoptotic agents that can be used in the present invention include venetoclax (Venclexta®, AbbVie / Genentech), and blinatumomab (Blincyto®, Amgen). Other therapeutic agents that have been clinically tested and can be used in the present invention to target apoptotic proteins include navitoclax (ABT-263, Abbott), a BCL-2 inhibitor (NCT02079740).

[0246] In some embodiments, one or more other therapeutic agents are androgen receptor inhibitors. Approved androgen receptor inhibitors useful in the present invention include enzalutamide (Xtandi®, Astellas / Medivation), approved androgen synthesis inhibitor includes abiraterone (Zytiga®, Centocor / Ortho), and approved gonadotropin-releasing hormone (GnRH) receptor antagonists (degarelix, Firmagon®, Ferring Pharmaceuticals).

[0247] In some embodiments, one or more other therapeutic agents are selective estrogen receptor modulators (SERMs) that interfere with estrogen synthesis or activity. An approved SERM useful in the present invention is raloxifene (Evista®, Eli Lilly).

[0248] In some embodiments, one or more other therapeutic agents are inhibitors of bone resorption. An approved therapeutic agent that inhibits bone resorption is denosumab (Xgeva®, Amgen), an antibody that binds to RANKL and prevents binding to its receptor RANK found on the surface of osteoclasts, their precursors, and osteoclast-like giant cells, which mediate bone lesions in solid tumors with bone metastases. Other approved therapeutic agents that inhibit bone resorption include bisphosphonates such as zoledronic acid (Zometa®, Novartis).

[0249] In some embodiments, one or more other therapeutic agents are inhibitors of the interaction between the two major p53 inhibitory proteins MDMX and MDM2. An inhibitor of p53 inhibitory proteins under investigation that can be used in the present invention is ALRN-6924 (Aileron), a stapled peptide that binds with equal potency to the interaction between MDMX and MDM2 and p53 and interferes. ALRN-6924 is currently being evaluated in clinical trials for the treatment of AML, advanced myelodysplastic syndrome (MDS), and peripheral T cell lymphoma (PTCL) (NCT02909972; NCT02264613).

[0250] In some embodiments, one or more other therapeutic agents are inhibitors of transforming growth factor beta (TGF-beta or TGF-β). Inhibitors of TGF-beta proteins under investigation for use in the present invention include NIS793 (Novartis), an anti-TGF-beta antibody, which is in clinical trials for the treatment of various cancers including breast cancer, lung cancer, hepatocellular cancer, colorectal cancer, pancreatic cancer, prostate cancer, and kidney cancer (NCT02947165). In some embodiments, the inhibitor of TGF-beta protein is fresolimumab (GC1008; Sanofi-Genzyme), which has been studied for melanoma (NCT00923169), renal cell carcinoma (NCT00356460), and non-small cell lung cancer (NCT02581787). Additionally, in some embodiments, the additional therapeutic agent is a TGF-beta trap as described in Connolly et al. (2012) Int’l J. Biological Sciences 8:964-978. Currently, one therapeutic compound in clinical trials for the treatment of solid tumors is M7824 (Merck KgaA - formerly MSB0011459X), which is a bispecific anti-PD-L1 / TGF-β trap compound (NCT02699515) and (NCT02517398). M7824 consists of a fully human IgG1 antibody against PD-L1 fused to the extracellular domain of human TGF-beta receptor II that functions as a TGF-β "trap".

[0251] In some embodiments, one or more other therapeutic agents are selected from glembatumumab vedotin - monomethyl auristatin E (MMAE) (Celldex), an anti-glycoprotein NMB (gpNMB) antibody (CR011) conjugated to the cytotoxic MMAE. gpNMB is a protein overexpressed by multiple tumor types associated with the metastatic ability of cancer cells.

[0252] In some embodiments, one or more other therapeutic agents are anti-proliferative compounds. Such anti-proliferative compounds include aromatase inhibitors, anti-estrogen agents, topoisomerase I inhibitors, topoisomerase II inhibitors, microtubule-active compounds, alkylating compounds, histone deacetylase inhibitors, compounds that induce cell differentiation processes, cyclooxygenase inhibitors, MMP inhibitors, mTOR inhibitors, anti-neoplastic metabolic antagonists, platinum compounds, compounds that target / reduce protein or lipid kinase activity, and additional anti-angiogenic compounds, compounds that target, reduce, or inhibit the activity of protein or lipid phosphatases, gonadorelin agonists, anti-androgen agents, methionine aminopeptidase inhibitors, matrix metalloproteinase inhibitors, bisphosphonates, biologic response modifiers, anti-proliferative antibodies, heparanase inhibitors, inhibitors of Ras oncogenic isoforms, telomerase inhibitors, proteasome inhibitors, compounds used in the treatment of hematologic malignancies, compounds that target, reduce, or inhibit the activity of Flt-3, Hsp90 inhibitors such as 17-AAG (17-allylaminogeldanamycin, NSC330507), 17-DMAG (17-dimethylaminoethylamino-17-demethoxy-geldanamycin, NSC707545), IPI-504, CNF1010, CNF2024, CNF1010 (from Conforma Therapeutics), temozolomide (Temodal®), kinesin spindle protein inhibitors such as SB715992 or SB743921 from GlaxoSmithKline, or pentamidine / chlorpromazine from CombinatoRx, MEK inhibitors such as ARRY142886 from Array BioPharma, AZd6244 from AstraZeneca, PD181461 from Pfizer, and leucovorin, but are not limited to these.

[0253] As used herein, the term "aromatase inhibitor" relates to a compound that inhibits estrogen production, for example, the conversion of the substrates androstenedione and testosterone to estrone and estradiol, respectively. This term includes, but is not limited to, steroids, particularly aminoglutethimide, logretimide, pyridoglutethimide, trilostane, testolactone, ketoconazole, vorozole, fadrozole, anastrozole, and letrozole. Exemestane is sold under the trade name Aromasin™. Formestane is sold under the trade name Lentaron™. Fadrozole is sold under the trade name Afema™. Anastrozole is sold under the trade name Arimidex™. Letrozole is sold under the trade name Femara™ or Femar™. Aminoglutethimide is sold under the trade name Orimeten™. The combination of the present invention comprising a chemotherapeutic agent that is an aromatase inhibitor is particularly useful for the treatment of hormone receptor-positive tumors such as breast tumors.

[0254] As used herein, the term "antiestrogen agent" relates to a compound that antagonizes the effects of estrogen at the estrogen receptor level. This term includes, but is not limited to, tamoxifen, fulvestrant, raloxifene and raloxifene hydrochloride. Tamoxifen is sold under the trade name Nolvadex™. Raloxifene hydrochloride is sold under the trade name Evista™. Fulvestrant can be administered under the trade name Faslodex™. The combination of the present invention comprising a chemotherapeutic agent that is an antiestrogen agent is particularly useful for the treatment of estrogen receptor-positive tumors such as breast tumors.

[0255] As used herein, the term "antiandrogen agent" relates to any substance capable of inhibiting the biological effects of androgen hormones, including but not limited to bicalutamide (Casodex (trademark)). As used herein, the term "gonadorelin agonist" includes but is not limited to abarelix, goserelin, and goserelin acetate. Goserelin may be administered under the trade name Zoladex (trademark).

[0256] As used herein, the term "topoisomerase I inhibitor" includes but is not limited to topotecan, gemitecan, irinotecan, camptothecin and its analogs, 9-nitrocamptothecin, and the macromolecular camptothecin conjugate PNU-166148. Irinotecan may be administered, for example, in the form commercially available under the trade name Camptosar (trademark). Topotecan is sold under the trade name Hycamptin (trademark).

[0257] As used herein, the term "topoisomerase II inhibitor" includes but is not limited to anthracyclines such as doxorubicin (including liposomal formulations such as Caelyx (trademark)), daunorubicin, epirubicin, idarubicin, and nemorubicin, anthraquinones mitoxantrone and losoxantrone, and podophyllotoxins etoposide and teniposide. Etoposide is sold under the trade name Etopophos (trademark). Teniposide is sold under the trade name VM26-Bristol. Doxorubicin is sold under the trade name Acriblastin (trademark) or Adriamycin (trademark). Epirubicin is sold under the trade name Farmorubicin (trademark). Idarubicin is sold under the trade name Zavedos (trademark). Mitoxantrone is sold under the trade name Novantron (trademark).

[0258] The term "microtubule agent" relates to microtubule stabilizers, microtubule destabilizing compounds, and microtubule polymerization inhibitors, including but not limited to taxanes such as paclitaxel and docetaxel, vinca alkaloids such as vinblastine or vinblastine sulfate, vincristine or vincristine sulfate, and vinorelbine, discodermolide, cochicine and epothilone, and their derivatives. Paclitaxel is sold under the trade name Taxol(®). Docetaxel is sold under the trade name Taxotere(®). Vinblastine sulfate is sold under the trade name Vinblastin R.P(®). Vincristine sulfate is sold under the trade name Farmistin(®).

[0259] The term "alkylating agent" as used herein includes but is not limited to cyclophosphamide, ifosfamide, melphalan, or nitrosourea (BCNU or Gliadel). Cyclophosphamide is sold under the trade name Cyclostin(®). Ifosfamide is sold under the trade name Holoxan(®).

[0260] The term "histone deacetylase inhibitor" or "HDAC inhibitor" relates to compounds that inhibit histone deacetylases and have antiproliferative activity. This term includes but is not limited to suberoylanilide hydroxamic acid (SAHA).

[0261] The term "antineoplastic antimetabolite" includes but is not limited to DNA demethylating compounds such as 5-fluorouracil or 5-FU, capecitabine, gemcitabine, 5-azacitidine and decitabine, folic acid antagonists such as methotrexate and edatrexate, and pemetrexed. Capecitabine is sold under the trade name Xeloda(®). Gemcitabine is sold under the trade name Gemzar(®).

[0262] As used herein, the term "platinum compound" includes, but is not limited to, carboplatin, cisplatin, cisplatinum, and oxaliplatin. Carboplatin can be administered, for example, in the form commercially available under the trade name Carboplat(™). Oxaliplatin can be administered, for example, in the form commercially available under the trade name Eloxatin(™).

[0263] The term "compound that targets / reduces protein or lipid kinase activity; or protein or lipid phosphatase activity; or further anti-angiogenic compound" as used herein includes, but is not limited to, protein tyrosine kinases and / or serine and / or threonine kinase inhibitors or lipid kinase inhibitors, for example, a) compounds that target, reduce, or inhibit the activity of platelet-derived growth factor receptor (PDGFR), for example, compounds that target, reduce, or inhibit the activity of PDGFR, particularly compounds that inhibit the PDGF receptor, for example, N-phenyl-2-pyrimidine-amine derivatives, such as imatinib, SU101, SU6668, and GFB-111; b) compounds that target, reduce, or inhibit the activity of fibroblast growth factor receptor (FGFR); c) compounds that target, reduce, or inhibit the activity of insulin-like growth factor receptor I (IGF-IR), for example, compounds that target, reduce, or inhibit the activity of IGF-IR, particularly compounds that inhibit the kinase activity of the IGF-I receptor, or antibodies that target the extracellular domain of the IGF-I receptor or its growth factor; d) compounds that target, reduce, or inhibit the activity of the Trk receptor tyrosine kinase family, or ephrin B4 inhibitors; e) compounds that target, reduce, or inhibit the activity of the AxI receptor tyrosine kinase family; f) compounds that target, reduce, or inhibit the activity of the Ret receptor tyrosine kinase; g) compounds that target, reduce, or inhibit the activity of the Kit / SCFR receptor tyrosine kinase, such as imatinib; h) compounds that target, reduce, or inhibit the activity of the C-kit receptor tyrosine kinase, which is part of the PDGFR family, for example, compounds that target, reduce, or inhibit the activity of the c-Kit receptor tyrosine kinase family, particularly compounds that inhibit the c-Kit receptor, such as imatinib;i) Compounds that target, reduce, or inhibit the activity of members of the c-Abl family, their gene fusion products (e.g., BCR-Abl kinase), and variants, e.g., compounds that target, reduce, or inhibit the activity of c-Abl family members and their gene fusion products, e.g., N-phenyl-2-pyrimidine-amine derivatives, e.g., imatinib or nilotinib (AMN107); PD180970; AG957; NSC680410; PD173955 from ParkeDavis; or dasatinib (BMS-354825); j) Compounds that target, reduce, or inhibit the activity of members of the protein kinase C (PKC) and Raf family of serine / threonine kinases, MEK, SRC, JAK / pan-JAK, FAK, PDK1, PKB / Akt, Ras / MAPK, PI3K, SYK, TYK2, BTK and TEC families, and / or members of the cyclin-dependent kinase family (CDK) including staurosporine derivatives such as midostaurin; Further examples of compounds include UCN-01, safingol, BAY43-9006, bryostatin 1, perifosine; llmofosine; RO318220 and RO320432; GO6976; lsis3521; LY333531 / LY379196; isoquinoline compounds; FTIs; PD184352 or QAN697 (PI3K inhibitor) or AT7519 (CDK inhibitor); k) Compounds that target, reduce, or inhibit the activity of protein-tyrosine kinase inhibitors, e.g., as compounds that target, reduce, or inhibit the activity of protein-tyrosine kinase inhibitors, imatinib mesylate (Gleevec (trademark)) or tyrphostin, e.g., tyrphostin A23 / RG-50810; AG99; tyrphostin AG213; tyrphostin AG1748; tyrphostin AG490; tyrphostin B44; tyrphostin B44(+) enantiomer; tyrphostin AG555; AG494; tyrphostin AG556, AG957 and adafostin (4-{[(2,5-dihydroxyphenyl)methyl]amino}-benzoic acid adamantyl ester; NSC680410, adafostin);l) Compounds that target, reduce, or inhibit the activity of receptor tyrosine kinases of the epidermal growth factor family (EGFR1, ErbB2, ErbB3, ErbB4 as homo- or hetero-dimers) and their variants, for example, compounds that target, reduce, or inhibit the activity of the epidermal growth factor receptor family, in particular, compounds that inhibit members of the EGF receptor tyrosine kinase family such as the EGF receptor, ErbB2, ErbB3, and ErbB4, or compounds, proteins, or antibodies that bind to EGF or EGF-related ligands, CP358774, ZD1839, ZM105180; trastuzumab (Herceptin (trademark)), cetuximab (Erbitux (trademark)), Iressa, Tarceva, OSI-774, Cl-1033, EKB-569, GW-2016, E1.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3, or E7.6.3, and 7H-pyrrolo-[2,3-d]pyrimidine derivatives; m) Compounds that target, reduce, or inhibit the activity of the c-Met receptor, for example, compounds that target, reduce, or inhibit the activity of c-Met, in particular, compounds that inhibit the kinase activity of the c-Met receptor, or antibodies that target the extracellular domain of c-Met or bind to HGF; n) Compounds that target, reduce, or inhibit the kinase activity of one or more JAK family members (JAK1 / JAK2 / JAK3 / TYK2 and / or pan-JAK), for example, including but not limited to PRT-062070, SB-1578, baricitinib, pacritinib, momelotinib, VX-509, AZD-1480, TG-101348, tofacitinib, and ruxolitinib; o) Compounds that target, reduce, or inhibit the kinase activity of PI3 kinase (PI3K), for example, ATU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, buparlisib, pictilisib, PF-4691502, BYL-719, dactolisib, XL-147, XL-765, and idelalisib; and;and compounds that target, reduce, or inhibit the signaling effects of the Hedgehog protein (Hh) or smoothened receptor (SMO) pathway, such as, but not limited to, cyclopamine, vismodegib, itraconazole, erismodegib, and IPI-926 (saridegib).;

[0264] As used herein, the term "PI3K inhibitor" includes compounds having inhibitory activity against one or more enzymes within the phosphatidylinositol-3-kinase family, including but not limited to PI3Kα, PI3Kγ, PI3Kδ, PI3Kβ, PI3K-C2α, PI3K-C2β, PI3K-C2γ, Vps34, p110-α, p110-β, p110-γ, p110-δ, p85-α, p85-β, p55-γ, p150, p101, and p87. Examples of PI3K inhibitors useful in the present invention include, but are not limited to, ATU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, buparlisib, pictilisib, PF-4691502, BYL-719, dactolisib, XL-147, XL-765, and idelalisib.

[0265] As used herein, the term "Bcl-2 inhibitor" includes, but is not limited to, compounds having inhibitory activity against B-cell lymphoma 2 protein (Bcl-2), including ABT-199, ABT-731, ABT-737, apogossypol, Ascenta's pan-Bcl-2 inhibitor, curcumin (and its analogs), Bcl-2 / Bcl-xL dual inhibitors (Infinity Pharmaceuticals / Novartis Pharmaceuticals), Genasense (G3139), HA14-1 (and its analogs, see WO2008118802), navitoclax (and its analogs, see US7390799), NH-1 (Shenayng Pharmaceutical University), obatoclax (and its analogs, see WO2004106328), S-001 (Gloria Pharmaceuticals), TW series compounds (Univ. of Michigan), and venetoclax. In some embodiments, the Bcl-2 inhibitor is a small molecule therapeutic agent. In some embodiments, the Bcl-2 inhibitor is a peptidomimetic.

[0266] As used herein, the term "BTK inhibitor" includes, but is not limited to, compounds having inhibitory activity against Bruton's tyrosine kinase (BTK), including AVL-292 and ibrutinib.

[0267] As used herein, the term "SYK inhibitor" includes, but is not limited to, compounds having inhibitory activity against spleen tyrosine kinase (SYK), including PRT-062070, R-343, R-333, Excellair, PRT-062607, and fostamatinib.

[0268] Further examples of BTK inhibitory compounds, and conditions treatable by such compounds in combination with the compounds of the present invention, can be found in WO2008039218 and WO2011090760, which are hereby incorporated by reference in their entirety.

[0269] Further examples of SYK inhibitory compounds and conditions treatable by such compounds in combination with the compounds of the present invention can be found in WO2003063794, WO2005007623, and WO2006078846, which are hereby incorporated by reference in their entirety.

[0270] Further examples of PI3K inhibitory compounds and conditions treatable by such compounds in combination with the compounds of the present invention can be found in WO2004019973, WO2004089925, WO2007016176, US8138347, WO2002088112, WO2007084786, WO2007129161, WO2006122806, WO2005113554, and WO2007044729, which are hereby incorporated by reference in their entirety.

[0271] Further examples of JAK inhibitory compounds and conditions treatable by such compounds in combination with the compounds of the present invention can be found in WO2009114512, WO2008109943, WO2007053452, WO2000142246, and WO2007070514, which are hereby incorporated by reference in their entirety.

[0272] Examples of further anti-angiogenic compounds include, for example, compounds having a different mechanism of action for activity, such as thalidomide (Thalomid™) and TNP-470, which are unrelated to protein or lipid kinase inhibition.

[0273] Examples of proteasome inhibitors useful for use in combination with the compounds of the present invention include, but are not limited to, bortezomib, disulfiram, epigallocatechin-3-gallate (EGCG), salinosporamide A, carfilzomib, ONX-0912, CEP-18770, and MLN9708.

[0274] Compounds that target, reduce, or inhibit the activity of a protein or lipid phosphatase are inhibitors of phosphatase 1, phosphatase 2A, or CDC25, such as okadaic acid or its derivatives.

[0275] Examples of compounds that induce the cell differentiation process include, but are not limited to, retinoic acid, α-, γ-, or δ-tocopherol, or α-, γ-, or δ-tocotrienol.

[0276] As used herein, the term cyclooxygenase inhibitor includes, but is not limited to, Cox-2 inhibitors, 5-alkyl-substituted 2-arylaminophenylacetic acids, and derivatives such as celecoxib (Celebrex™), rofecoxib (Vioxx™), etoricoxib, valdecoxib, or 5-alkyl-2-arylaminophenylacetic acids such as 5-methyl-2-(2'-chloro-6'-fluoroanilino)phenylacetic acid, lumiracoxib.

[0277] As used herein, the term "bisphosphonate" includes, but is not limited to, etidronic acid, clodronic acid, tiludronic acid, pamidronic acid, alendronic acid, ibandronic acid, risedronic acid, and zoledronic acid. Etidronic acid is sold under the trade name Didronel™. Clodronic acid is sold under the trade name Bonefos™. Tiludronic acid is sold under the trade name Skelid™. Pamidronic acid is sold under the trade name Aredia™. Alendronic acid is sold under the trade name Fosamax™. Ibandronic acid is sold under the trade name Bondranat™. Risedronic acid is sold under the trade name Actonel™. Zoledronic acid is sold under the trade name Zometa™. The term "mTOR inhibitor" relates to compounds that inhibit the mammalian target of rapamycin (mTOR) and have antiproliferative activity, such as sirolimus (Rapamune®), everolimus (Certican™), CCI-779, and ABT578.

[0278] As used herein, the term "heparanase inhibitor" refers to compounds that target, reduce, or inhibit heparan sulfate degradation. This term includes, but is not limited to, PI-88. As used herein, the term "biological response modifier" refers to lymphokines or interferons.

[0279] As used herein, the term "inhibitor of Ras oncogene isoforms" such as H-Ras, K-Ras, or N-Ras refers to compounds that target, reduce, or inhibit the oncogenic activity of Ras, such as "farnesyltransferase inhibitors" such as L-744832, DK8G557, or R115777 (Zarnestra™). As used herein, the term "telomerase inhibitor" refers to compounds that target, reduce, or inhibit the activity of telomerase. Compounds that target, reduce, or inhibit the activity of telomerase are, in particular, compounds that inhibit the telomerase receptor, such as telomestatin.

[0280] As used herein, the term "methionine aminopeptidase inhibitor" refers to a compound that targets, reduces, or inhibits the activity of methionine aminopeptidase. Compounds that target, reduce, or inhibit the activity of methionine aminopeptidase include, but are not limited to, benagmid or its derivatives.

[0281] As used herein, the term "proteasome inhibitor" refers to a compound that targets, reduces, or inhibits the activity of the proteasome. Examples of compounds that target, reduce, or inhibit the activity of the proteasome include, but are not limited to, bortezomib (Velcade (trademark)) and MLN341.

[0282] As used herein, the term "matrix metalloproteinase inhibitor" or ("MMP" inhibitor) includes, but is not limited to, collagen peptide mimetics and non-peptide mimetic inhibitors, tetracycline derivatives, such as the hydroxamate peptide mimetic inhibitor batimastat and its orally bioavailable analog marimastat (BB-2516), prinomastat (AG3340), metastat (NSC683551), BMS-279251, BAY12-9566, TAA211, MMI270B, or AAJ996.

[0283] As used herein, the term "compound used in the treatment of hematological malignancies" includes, but is not limited to, FMS-like tyrosine kinase inhibitors, interferons, 1-β-D-arabinofuranosylcytosine (ara-c), and busulfan, which are compounds that target, reduce, or inhibit the activity of the FMS-like tyrosine kinase receptor (Flt-3R), and ALK inhibitors, which are compounds that target, reduce, or inhibit the activity of anaplastic lymphoma kinase.

[0284] Compounds that target, reduce, or inhibit the activity of the FMS-like tyrosine kinase receptor (Flt-3R) are, in particular, compounds, proteins, or antibodies that inhibit members of the Flt-3R receptor kinase family, such as PKC412, midostaurin, staurosporine derivatives, SU11248, and MLN518.

[0285] As used herein, the term "HSP90 inhibitor" includes, but is not limited to, compounds that target, reduce, or inhibit the intrinsic ATPase activity of HSP90, and compounds that target, reduce, or inhibit the degradation of HSP90 client proteins via the ubiquitin proteasome pathway. Compounds that target, reduce, or inhibit the intrinsic ATPase activity of HSP90 are, in particular, compounds, proteins, or antibodies that inhibit the ATPase activity of HSP90, such as 17-allylamino,17-demethoxygeldanamycin (17AAG), geldanamycin derivatives, other geldanamycin-related compounds, radicicol, and HDAC inhibitors.

[0286] As used herein, the term "anti-proliferative antibody" includes, but is not limited to, trastuzumab (Herceptin™), trastuzumab-DM1, erbitux, bevacizumab (Avastin™), rituximab (Rituxan®), PRO64553 (anti-CD40), and the 2C4 antibody. The term "antibody" means intact monoclonal antibodies, polyclonal antibodies, multispecific antibodies formed from at least two intact antibodies, and antibody fragments, so long as they exhibit the desired biological activity.

[0287] For the treatment of acute myeloid leukemia (AML), the compounds of the present invention can be used in combination with standard leukemia treatment methods, particularly in combination with treatment methods used specifically for the treatment of AML. In particular, the compounds of the present invention can be administered in combination with, for example, farnesyl transferase inhibitors and / or other drugs useful for the treatment of AML, such as daunorubicin, doxorubicin, Ara-C, VP-16, teniposide, mitoxantrone, idarubicin, carboplatin, and PKC412.

[0288] As other anti-leukemia compounds, for example, 2 of deoxycytidine ’Examples include Ara-C, a pyrimidine analogue that is an -α-hydroxyribose (arabinoside) derivative. Also included are 6-mercaptopurine (6-MP), a purine analogue of hypoxanthine, and fludarabine phosphate. Compounds that target, reduce, or inhibit the activity of histone deacetylase (HDAC) inhibitors, such as sodium butyrate and suberoylanilide hydroxamic acid (SAHA), inhibit the activity of an enzyme known as histone deacetylase. Specific HDAC inhibitors include MS275, SAHA, FK228 (formerly FR901228), trichostatin A, and the compounds disclosed in US 6,552,065, such as N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide, or a pharmaceutically acceptable salt thereof, and N-hydroxy-3-[4-[(2-hydroxyethyl){2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide, or a pharmaceutically acceptable salt thereof, particularly the lactate salt, but are not limited thereto. As used herein, somatostatin receptor antagonists refer to compounds that target, reduce, or inhibit somatostatin receptors, such as octreotide and SOM230. The tumor cell damage approach refers to approaches such as ionizing radiation. The term "ionizing radiation" as referred to above and below means ionizing radiation that occurs as either electromagnetic waves (such as X-rays and gamma rays) or particles (such as α and β particles). Ionizing radiation is provided by, but not limited to, radiation therapy and is known in the art. See Hellman, Principles of Radiation Therapy, Cancer, in Principles and Practice of Oncology, Devita et al., Eds., 4 th Edition, Vol. 1, pp. 248-275 (1993).

[0289] Also included are an EDG binder and a ribonucleotide reductase inhibitor. As used herein, the term "EDG binder" refers to a class of immunosuppressive agents, such as FTY720, that regulate lymphocyte recirculation. The term "ribonucleotide reductase inhibitor" refers to pyrimidine or purine nucleoside analogs, including, but not limited to, fludarabine and / or cytosine arabinoside (ara-C), 6-thioguanine, 5-fluorouracil, cladribine, 6-mercaptopurine (especially in combination with ara-C for ALL), and / or pentostatin. Ribonucleotide reductase inhibitors are particularly hydroxyurea or 2-hydroxy-1H-isoindole-1,3-dione derivatives.

[0290] Also particularly included are VEGF compounds, proteins or monoclonal antibodies, such as 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or a pharmaceutically acceptable salt thereof, 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine succinate, Angiostatin™, Endostatin™, anthranilic acid amide, ZD4190, Zd6474, SU5416, SU6668, bevacizumab, or an anti-VEGF antibody or anti-VEGF receptor antibody, such as rhuMAb and RHUFab, VEGF aptamers such as Macugon, FLT-4 inhibitors, FLT-3 inhibitors, VEGFR-2 IgGI antibodies, angiostatin (RPI4610) and bevacizumab (Avastin™).

[0291] As used herein, photodynamic therapy refers to a treatment method that uses specific chemical substances known as photosensitizing compounds to treat or prevent cancer. Examples of photodynamic therapy include treatment with compounds such as Visudyne™ and porfimer sodium.

[0292] As used herein, an angiogenesis-inhibiting steroid refers to a compound that blocks or inhibits angiogenesis, such as, for example, anecortave, triamcinolone, hydrocortisone, 11-α-epihydrocortisol, cortisone, 17α-hydroxyprogesterone, corticosterone, desoxycorticosterone, testosterone, estrone, and dexamethasone.

[0293] Implants containing corticosteroids refer to compounds such as fluocinolone and dexamethasone.

[0294] Other chemotherapeutic compounds include, but are not limited to, plant alkaloids, hormone compounds and antagonists, biologic response modifiers, preferably lymphokines or interferons, antisense oligonucleotides or oligonucleotide derivatives, shRNA or siRNA, or other compounds, or compounds having other or unknown mechanisms of action.

[0295] The structure of an active compound identified by a code number, common name, or trade name can be obtained from the latest edition of the standard compendium “The Merck Index” or from a database, such as, for example, Patents International (e.g., IMS World Publications).

[0296] Exemplary Immuno-Oncology agents In some embodiments, one or more other therapeutic agents are immuno-oncology agents. As used herein, the term “immuno-oncology agent” refers to an agent effective to enhance, stimulate, and / or upregulate an immune response in a subject. In some embodiments, administering an immuno-oncology agent together with a compound of the invention has a synergistic effect in the treatment of cancer.

[0297] A tumor immunotherapeutic agent can be, for example, a small molecule drug, an antibody, or a biological molecule or small molecule. Examples of biological tumor immunotherapeutic agents include, but are not limited to, cancer vaccines, antibodies, and cytokines. In some embodiments, the antibody is a monoclonal antibody. In some embodiments, the monoclonal antibody is humanized or human.

[0298] In some embodiments, the tumor immunotherapeutic agent is (i) an agonist of a stimulatory (including co-stimulatory) receptor, or (ii) an antagonist of an inhibitory (including co-inhibitory) signal on T cells, both of which result in amplification of the antigen-specific T cell response.

[0299] Certain stimulatory and inhibitory molecules are members of the immunoglobulin superfamily (IgSF). One important family of membrane-bound ligands that bind to co-stimulatory or co-inhibitory receptors is the B7 family, including B7-1, B7-2, B7-H1 (PD-L1), B7-DC (PD-L2), B7-H2 (ICOS-L), B7-H3, B7-H4, B7-H5 (VISTA), and B7-H6. Another family of membrane-bound ligands that bind to co-stimulatory or co-inhibitory receptors is the TNF molecule family that binds to the corresponding TNF receptor family members, including CD40 and CD40L, OX-40, OX-40L, CD70, CD27L, CD30, CD30L, 4-1BBL, CD137 (4-1BB), TRAIL / Apo2-L, TRAILR1 / DR4, TRAILR2 / DR5, TRAILR3, TRAILR4, OPG, RANK, RANKL, TWEAKR / Fn14, TWEAK, BAFFR, EDAR, XEDAR, TACI, APRIL, BCMA, LTβR, LIGHT, DcR3, HVEM, VEGI / TL1A, TRAMP / DR3, EDAR, EDA1, XEDAR, EDA2, TNFR1, lymphotoxin α / TNFβ, TNFR2, TNFα, LTβR, lymphotoxin α1β2, FAS, FASL, RELT, DR6, TROY, NGFR.

[0300] In some embodiments, the tumor immunotherapeutic agent is a cytokine that inhibits T cell activation (e.g., IL-6, IL-10, TGF-β, VEGF, and other immunosuppressive cytokines) or a cytokine that stimulates T cell activation for stimulating an immune response.

[0301] In some embodiments, the combination of a compound of the invention and a tumor immunotherapeutic agent can stimulate a T cell response. In some embodiments, the tumor immunotherapeutic agent is (i) an antagonist of a protein that inhibits T cell activation (e.g., an immune checkpoint inhibitor) such as CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, TIM-3, galectin 9, CEACAM-1, BTLA, CD69, galectin-1, TIGIT, CD113, GPR56, VISTA, 2B4, CD48, GARP, PD1H, LAIR1, TIM-1, and TIM-4, or (ii) an agonist of a protein that stimulates T cell activation such as B7-1, B7-2, CD28, 4-1BB (CD137), 4-1BBL, ICOS, ICOS-L, OX40, OX40L, GITR, GITRL, CD70, CD27, CD40, DR3, and CD28H.

[0302] In some embodiments, the tumor immunotherapeutic agent is an antagonist of an inhibitory receptor on NK cells or an agonist of an activating receptor on NK cells. In some embodiments, the tumor immunotherapeutic agent is an antagonist of KIR such as lirilumab.

[0303] In some embodiments, the tumor immunotherapeutic agent is an agent that inhibits or depletes macrophages or monocytes, including but not limited to CSF-1R antagonist antibodies such as RG7155 (WO11 / 70024, WO11 / 107553, WO11 / 131407, WO13 / 87699, WO13 / 119716, WO13 / 132044) or FPA-008 (WO11 / 140249; WO13169264; WO14 / 036357).

[0304] In some embodiments, the tumor immunotherapeutic agent is an agonist agent that binds to a positive co-stimulatory receptor, a blocker that attenuates signaling via an inhibitory receptor, an antagonist, and one or more agents that systemically increase the frequency of anti-tumor T cells, an agent that overcomes unique immunosuppressive pathways within the tumor microenvironment (e.g., blocking the involvement of inhibitory receptors (e.g., PD-L1 / PD-1 interaction), depleting or inhibiting Tregs (e.g., using an anti-CD25 monoclonal antibody (e.g., daclizumab) or by ex vivo anti-CD25 bead depletion), inhibiting metabolic enzymes such as IDO, or restoring / preventing T cell energy or exhaustion), and an agent that activates innate immunity and / or induces inflammation at the tumor site.

[0305] In some embodiments, the tumor immunotherapeutic agent is a CTLA-4 antagonist. In some embodiments, the CTLA-4 antagonist is a CTLA-4 antagonist antibody. In some embodiments, the CTLA-4 antagonist antibody is YERVOY (ipilimumab) or tremelimumab.

[0306] In some embodiments, the tumor immunotherapeutic agent is a PD-1 antagonist. In some embodiments, the PD-1 antagonist is administered by injection. In some embodiments, the tumor immunotherapeutic agent is an antibody or antigen-binding portion thereof that specifically binds to the programmed death-1 (PD-1) receptor and inhibits PD-1 activity. In some embodiments, the PD-1 antagonist is a PD-1 antagonist antibody. In some embodiments, the PD-1 antagonist antibody is OPDIVO (nivolumab), KEYTRUDA (pembrolizumab), or MEDI-0680 (AMP-514; WO2012 / 145493). In some embodiments, the tumor immunotherapeutic agent can be pidilizumab (CT-011). In some embodiments, the tumor immunotherapeutic agent is a recombinant protein composed of the extracellular domain of PD-L2 (B7-DC) fused to the Fc portion of IgG1, called AMP-224.

[0307] In some embodiments, the tumor immunotherapy agent is a PD-L1 antagonist. In some embodiments, the PD-L1 antagonist is a PD-L1 antagonist antibody. In some embodiments, the PD-L1 antibody is MPDL3280A (RG7446; WO2010 / 077634), durvalumab (MEDI4736), BMS-936559 (WO2007 / 005874), and MSB0010718C (WO2013 / 79174).

[0308] In some embodiments, the tumor immunotherapy agent is a LAG-3 antagonist. In some embodiments, the LAG-3 antagonist is a LAG-3 antagonist antibody. In some embodiments, the LAG3 antibody is BMS-986016 (WO10 / 19570, WO14 / 08218), or IMP-731 or IMP-321 (WO08 / 132601, WO009 / 44273).

[0309] In some embodiments, the tumor immunotherapy agent is a CD137 (4-1BB) agonist. In some embodiments, the CD137 (4-1BB) agonist is a CD137 agonist antibody. In some embodiments, the CD137 antibody is urelumab or PF-05082566 (WO12 / 32433).

[0310] In some embodiments, the tumor immunotherapy agent is a GITR agonist. In some embodiments, the GITR agonist is a GITR agonist antibody. In some embodiments, the GITR antibody is BMS-986153, BMS-986156, TRX-518 (WO006 / 105021, WO009 / 009116), or MK-4166 (WO11 / 028683).

[0311] In some embodiments, the tumor immunotherapy agent is an indoleamine (2,3)-dioxygenase (IDO) antagonist. In some embodiments, the IDO antagonist is selected from epacadostat (INCB024360, Incyte), indoximod (NLG-8189, NewLink Genetics Corporation), capmatinib (INC280, Novartis), GDC-0919 (Genentech / Roche), PF-06840003 (Pfizer), BMS:F001287 (Bristol-Myers Squibb), Phy906 / KD108 (Phytoceutica), the enzyme that degrades kynurenine (Kynase, Ikena Oncology, formerly known as Kyn Therapeutics), and NLG-919 (WO09 / 73620, WO009 / 1156652, WO11 / 56652, WO12 / 142237).

[0312] In some embodiments, the tumor immunotherapy agent is an OX40 agonist. In some embodiments, the OX40 agonist is an OX40 agonist antibody. In some embodiments, the OX40 antibody is MEDI-6383 or MEDI-6469.

[0313] In some embodiments, the tumor immunotherapy agent is an OX40L antagonist. In some embodiments, the OX40L antagonist is an OX40 antagonist antibody. In some embodiments, the OX40L antagonist is RG-7888 (WO06 / 029879).

[0314] In some embodiments, the tumor immunotherapy agent is a CD40 agonist. In some embodiments, the CD40 agonist is a CD40 agonist antibody. In some embodiments, the tumor immunotherapy agent is a CD40 antagonist. In some embodiments, the CD40 antagonist is a CD40 antagonist antibody. In some embodiments, the CD40 antibody is lucatumumab or dacetuzumab.

[0315] In some embodiments, the tumor immunotherapeutic agent is a CD27 agonist. In some embodiments, the CD27 agonist is a CD27 agonist antibody. In some embodiments, the CD27 antibody is balstilimab.

[0316] In some embodiments, the tumor immunotherapeutic agent is MGA271 (WO11 / 109400) (against B7H3).

[0317] In some embodiments, the tumor immunotherapeutic agent is abagovomab, adecatumumab, afutuzumab, alemtuzumab, anatumomab mafenatox, apolizumab, atezolizumab, avelumab, blinatumomab, BMS-936559, catumaxomab, durvalumab, epacadostat, epratuzumab, indoximod, inotuzumab ozogamicin, intelumumab, ipilimumab, isatuximab, ramucirumab, MED14736, MPDL3280A, nivolumab, obinutuzumab, ocaratuzumab, ofatumumab, olatatumab, pembrolizumab, pidilizumab, rituximab, tislelizumab, samalizumab, or tremelimumab.

[0318] In some embodiments, the tumor immunotherapeutic agent is an immunostimulant. For example, antibodies that block the PD-1 and PD-L1 inhibitory axes can release activated tumor-reactive T cells and have been shown in clinical trials to induce a sustained anti-tumor response in an increasing number of tumor histotypes, including some tumor types that were previously thought to be insensitive to immunotherapy. See, for example, Okazaki, T. et al. (2013) Nat. Immunol. 14, 1212-1218; Zou et al. (2016) Sci. Transl. Med. 8. The anti-PD-1 antibody nivolumab (also known as Opdivo®, Bristol-Myers Squibb, ONO-4538, MDX1106, and BMS-936558) has shown the potential to improve the overall survival of patients with RCC who experienced disease progression during or after previous anti-angiogenic therapy.

[0319] In some embodiments, the immunomodulatory therapeutic agent specifically induces apoptosis of tumor cells. Approved immunomodulatory therapeutic agents that can be used in the present invention include pomalidomide (Pomalyst®, Celgene), lenalidomide (Revlimid®, Celgene), ingenol mebutate (Picato®, LEO Pharma).

[0320] In some embodiments, the tumor immunotherapy agent is a cancer vaccine. In some embodiments, the cancer vaccine is selected from Sipuleucel-T (Provenge®, Dendreon / Valeant Pharmaceuticals), which is approved for the treatment of asymptomatic or minimally symptomatic metastatic castration-resistant (hormone-refractory) prostate cancer, and talimogene laherparepvec (Imlygic®, BioVex / Amgen, previously known as T-VEC), a genetically modified oncolytic virus therapy approved for the treatment of unresectable cutaneous, subcutaneous, and nodal lesions in melanoma. In some embodiments, the tumor immunotherapy agent is pexastimogene devacirepvec (PexaVec / JX-594, SillaJen / formerly Jennerex Biotherapeutics), a thymidine kinase-(TK-)deficient vaccinia virus engineered to express GM-CSF, for hepatocellular carcinoma (NCT02562755) and melanoma (NCT00429312); Reolysin® (Oncolytics Biotech), a variant of respiratory enteric orphan virus (reovirus) that does not replicate in RAS-inactivated cells, in a number of cancers such as colorectal cancer (NCT01622543), prostate cancer (NCT01619813), head and neck squamous cell carcinoma (NCT01166542), pancreatic adenocarcinoma (NCT00998322), and non-small cell lung cancer (NSCLC) (NCT00861627); enadenotucirev (NG-348, PsiOxus, previously known as ColoAd1), an adenovirus engineered to express antibody fragments specific for full-length CD80 and the T cell receptor CD3 protein, in metastatic or advanced epithelial tumors such as ovarian cancer (NCT02028117), colorectal cancer, bladder cancer, head and neck squamous cell carcinoma, and salivary gland cancer (NCT02636036);Selected from oncolytic virus therapeutics such as ONCOS-102 (Targovax / formerly Oncos), an adenovirus engineered to express GM-CSF, in melanoma (NCT03003676), peritoneal diseases, colorectal cancer or ovarian cancer (NCT02963831); GL-ONC1 (GLV-1h68 / GLV-1h153, Genelux GmbH), a vaccinia virus engineered to express β-galactosidase (β-gal) / β-glucuronidase or β-gal / human sodium iodide symporter (hNIS) respectively, tested in peritoneal carcinomatosis (NCT01443260), fallopian tube cancer, ovarian cancer (NCT02759588); or CG0070 (Cold Genesys), an adenovirus engineered to express GM-CSF, in bladder cancer (NCT02365818).;

[0321] In some embodiments, the tumor immunotherapeutic agent is JX-929 (SillaJen / formerly Jennerex Biotherapeutics), a TK engineered to express cytosine deaminase, which can convert the prodrug 5-fluorocytosine to the cytotoxic drug 5-fluorouracil, and a vaccinia growth factor-deficient vaccinia virus; TG01 and TG02 (Targovax / formerly Oncos), peptide-based immunotherapeutic agents targeting treatment-resistant RAS mutations; and TILT-123 (TILT Biotherapeutics), an engineered adenovirus named Ad5 / 3-E2F-delta24-hTNFα-IRES-hIL20; and vesicular stomatitis virus (VSV) engineered to express the glycoprotein (GP) of lymphocytic choriomeningitis virus (LCMV), which can be further engineered to express an antigen designed to boost antigen-specific CD8 + T cell responses, selected from VSV-GP (ViraTherapeutics).

[0322] In some embodiments, the tumor immunotherapy agent is a T cell engineered to express a chimeric antigen receptor, or CAR. T cells engineered to express such chimeric antigen receptors are referred to as CAR-T cells.

[0323] The CAR consists of and is constructed from a binding domain that can be derived from a native ligand, a single-chain variable fragment (scFv) derived from a monoclonal antibody specific for a cell surface antigen, and an endodomain that is the functional terminus of a T cell receptor (TCR), for example, the CD3-zeta signaling domain of a TCR that can generate an activation signal in T lymphocytes. When bound to an antigen, such a CAR couples to the endogenous signaling pathway within the effector cell and generates an activation signal similar to that initiated by the TCR complex.

[0324] For example, in some embodiments, the CAR-T cell is one described in U.S. Patent No. 8,906,682 (June et al; incorporated herein by reference in its entirety), which discloses CAR-T cells engineered to include an extracellular domain having an antigen-binding domain (such as a domain that binds to CD19) fused to the intracellular signaling domain of the T cell antigen receptor complex zeta chain (such as CD3 zeta). When expressed in a T cell, the CAR can be newly induced to recognize an antigen based on its antigen-binding specificity. In the case of CD19, the antigen is expressed on malignant B cells. Over 200 clinical trials using CAR-T are currently underway in a wide range of indications. [https: / / clinicaltrials.gov / ct2 / results?term=chimeric+antigen+receptors&pg=1].

[0325] In some embodiments, the immunostimulant is an activator of retinoic acid receptor-related orphan receptor γ (RORγt). RORγt is a transcription factor that plays an important role in the differentiation and maintenance of the type 17 effector subsets of CD4+ (Th17) and CD8+ (Tc17) T cells, as well as in the differentiation of IL-17-expressing innate immune cell subpopulations such as NK cells. In some embodiments, the activator of RORγt is LYC-55716 (Lycera), which is currently being evaluated in clinical trials for the treatment of solid tumors (NCT02929862).

[0326] In some embodiments, the immunostimulant is an agonist or activator of a toll-like receptor (TLR). Suitable activators of TLRs include agonists or activators of TLR9, such as SD-101 (Dynavax). SD-101 is an immunostimulatory CpG that is being studied for B cells, follicular and other lymphomas (NCT02254772). Agonists or activators of TLR8 that can be used in the present invention include motolimod (VTX-2337, VentiRx Pharmaceuticals), which is being studied for head and neck squamous cell carcinoma (NCT02124850) and ovarian cancer (NCT02431559).

[0327] Other tumor immunotherapy agents that can be used in the present invention include urelumab (BMS-663513, Bristol-Myers Squibb), an anti-CD137 monoclonal antibody; balstilimab (CDX-1127, Celldex Therapeutics), an anti-CD27 monoclonal antibody; BMS-986178 (Bristol-Myers Squibb), an anti-OX40 monoclonal antibody; lirilumab (IPH2102 / BMS-986015, Innate Pharma, Bristol-Myers Squibb), an anti-KIR monoclonal antibody; monalizumab (IPH2201, Innate Pharma, AstraZeneca), an anti-NKG2A monoclonal antibody; andecaliximab (GS-5745, Gilead Sciences), an anti-MMP9 antibody; and MK-4166 (Merck & Co.), an anti-GITR monoclonal antibody.

[0328] In some embodiments, the immunostimulant is selected from elotuzumab, mifamurtide, an agonist or activator of a toll-like receptor, and an activator of RORγt.

[0329] In some embodiments, the immunostimulatory therapeutic agent is recombinant human interleukin 15 (rhIL-15). rhIL-15 has been clinically tested as a treatment for melanoma and renal cell carcinoma (NCT01021059 and NCT01369888) and leukemia (NCT02689453). In some embodiments, the immunostimulant is recombinant human interleukin 12 (rhIL-12). In some embodiments, the IL-15-based immunotherapeutic agent is heterodimeric IL-15 (hetIL-15, Novartis / Admune), which is a fusion complex consisting of a synthetic form of endogenous IL-15 complexed with the soluble IL-15 binding protein IL-15 receptor alpha chain (IL15:sIL-15RA) and has been tested in a Phase 1 clinical trial for melanoma, renal cell carcinoma, non-small cell lung cancer, and head and neck squamous cell carcinoma (NCT02452268). In some embodiments, the recombinant human interleukin 12 (rhIL-12) is NM-IL-12 (Neumedicines, Inc.), NCT02544724, or NCT02542124.

[0330] In some embodiments, the tumor immunotherapeutic agent is selected from those described in Jerry L. Adams et al., “Big opportunities for small molecules in immuno-oncology,” Cancer Therapy 2015, Vol. 14, pages 603-622, the entire contents of which are incorporated herein by reference. In some embodiments, the tumor immunotherapeutic agent is selected from the examples described in Table 1 of the literature by Jerry L. Adams et al. In some embodiments, the tumor immunotherapeutic agent is a small molecule that targets a tumor immunotarget selected from those listed in Table 2 of the literature by Jerry L. Adams et al. In some embodiments, the tumor immunotherapeutic agent is a small molecule agent selected from those listed in Table 2 of the literature by Jerry L. Adams et al.

[0331] In some embodiments, the tumor immunotherapy agent is selected from the small molecule tumor immunotherapy agents described in Peter L. Toogood, “Small molecule immuno-oncology therapeutic agents,” Bioorganic & Medicinal Chemistry Letters 2018, Vol. 28, pages 319 - 329, the entire content of which is incorporated herein by reference. In some embodiments, the tumor immunotherapy agent is an agent that targets a pathway as described in Peter L. Toogood's literature.

[0332] In some embodiments, the tumor immunotherapeutic agent is selected from those described in Sandra L. Ross et al., “Bispecific T cell engager (BiTE®) antibody constructs can mediate bystander tumor cell killing”, PLoS ONE 12(8): e0183390, the entire content of which is incorporated herein by reference. In some embodiments, the tumor immunotherapeutic agent is a bispecific T cell engager (BiTE®) antibody construct. In some embodiments, the bispecific T cell engager (BiTE®) antibody construct is a CD19 / CD3 bispecific antibody construct. In some embodiments, the bispecific T cell engager (BiTE®) antibody construct is an EGFR / CD3 bispecific antibody construct. In some embodiments, the bispecific T cell engager (BiTE®) antibody construct activates T cells. In some embodiments, the bispecific T cell engager (BiTE®) antibody construct activates T cells, whereby cytokines are released that induce upregulation on bystander cells of intercellular adhesion molecule 1 (ICAM-1) and FAS. In some embodiments, the bispecific T cell engager (BiTE®) antibody construct activates T cells, whereby lysis of bystander cells is induced. In some embodiments, the bystander cells are present in solid tumors. In some embodiments, the bystander cells to be lysed are in proximity to BiTE®-activated T cells. In some embodiments, the bystander cells include tumor-associated antigen (TAA)-negative cancer cells. In some embodiments, the bystander cells include EGFR-negative cancer cells. In some embodiments, the tumor immunotherapeutic agent is an antibody that blocks the PD-L1 / PD1 axis and / or CTLA4. In some embodiments, the tumor immunotherapeutic agent is tumor-infiltrating T cells expanded ex vivo. In some embodiments, the tumor immunotherapeutic agent is a bispecific antibody construct or a chimeric antigen receptor (CAR) that directly connects T cells to tumor-associated surface antigen (TAA).

[0333] Exemplary immune checkpoint inhibitors In some embodiments, the tumor immunotherapy agent is an immune checkpoint inhibitor described herein.

[0334] As used herein, the term “checkpoint inhibitor” relates to agents useful for preventing cancer cells from evading a patient's immune system. One of the major mechanisms of anti-tumor immune destruction is known as “T cell exhaustion,” which results from chronic exposure to antigen, leading to upregulation of inhibitory receptors. These inhibitory receptors function as immune checkpoints to prevent uncontrolled immune responses.

[0335] PD-1 and co-inhibitory receptors such as cytotoxic T lymphocyte antigen 4 (CTLA-4), B and T lymphocyte attenuator (BTLA; CD272), T cell immunoglobulin and mucin domain-3 (Tim-3), lymphocyte activation gene 3 (Lag-3; CD223), etc. are often referred to as checkpoint regulators. These function as molecular “gatekeepers” that allow extracellular information to determine whether cell cycle progression and other intracellular signaling processes should proceed.

[0336] In some embodiments, the immune checkpoint inhibitor is an antibody against PD-1. PD-1 binds to the programmed cell death 1 receptor (PD-1) and prevents this receptor from binding to the inhibitory ligand PDL-1, thereby exceeding the tumor's ability to suppress the host anti-tumor immune response.

[0337] In one aspect, the checkpoint inhibitor is a biological therapeutic agent or a small molecule. In another aspect, the checkpoint inhibitor is a monoclonal antibody, a humanized antibody, a fully human antibody, a fusion protein, or a combination thereof. In a further aspect, the checkpoint inhibitor inhibits a checkpoint protein selected from CTLA-4, PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK1, CHK2, A2aR, B-7 family ligands, or a combination thereof. In a further aspect, the checkpoint inhibitor interacts with a ligand of a checkpoint protein selected from CTLA-4, PDL1, PDL2, PDl, B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK1, CHK2, A2aR, B-7 family ligands, or a combination thereof. In one aspect, the checkpoint inhibitor is an immune stimulant, a T cell growth factor, an interleukin, an antibody, a vaccine, or a combination thereof. In a further aspect, the interleukin is IL-7 or IL-15. In a particular aspect, the interleukin is glycosylated IL-7. In a further aspect, the vaccine is a dendritic cell (DC) vaccine.

[0338] Checkpoint inhibitors include any agent that blocks or inhibits an inhibitory pathway of the immune system in a statistically significant manner. Such inhibitors can include small molecule inhibitors or antibodies that bind to and block or inhibit an immune checkpoint receptor, or antigen-binding fragments thereof, or antibodies that bind to and block or inhibit an immune checkpoint receptor ligand. Exemplary checkpoint molecules that can be targeted for blocking or inhibition include CTLA-4, PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, GAL9, LAG3, TIM3, VISTA, KIR, 2B4 (belongs to the CD2 molecule family and includes any NK, γδ, and CD8 +(expressed in (αβ) T cells), CD160 (also known as BY55), CGEN-15049, CHK1 and CHK2 kinases, A2aR, and various B-7 family ligands, including but not limited to these. B7 family ligands include, but are not limited to, B7-1, B7-2, B7-DC, B7-H1, B7-H2, B7-H3, B7-H4, B7-H5, B7-H6, and B7-H7. Checkpoint inhibitors include antibodies, or antigen-binding fragments thereof, other binding proteins, biological therapeutics, or small molecules that bind to one or more of CTLA-4, PDL1, PDL2, PD1, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, and CGEN-15049 and block or inhibit their activity. Exemplary immune checkpoint inhibitors include tremelimumab (CTLA-4 blocking antibody), anti-OX40, PD-L1 monoclonal antibody (anti-B7-Hl; MEDI4736), MK-3475 (PD-1 blocker), nivolumab (anti-PD1 antibody), CT-011 (anti-PD1 antibody), BY55 monoclonal antibody, AMP224 (anti-PDL1 antibody), BMS-936559 (anti-PDL1 antibody), MPLDL3280A (anti-PDL1 antibody), MSB0010718C (anti-PDL1 antibody), and ipilimumab (anti-CTLA-4 checkpoint inhibitor), including but not limited to these. Checkpoint protein ligands include, but are not limited to, PD-L1, PD-L2, B7-H3, B7-H4, CD28, CD86, and TIM-3.

[0339] In certain embodiments, the immune checkpoint inhibitor is selected from a PD-1 antagonist, a PD-L1 antagonist, and a CTLA-4 antagonist. In some embodiments, the checkpoint inhibitor is selected from the group consisting of nivolumab (Opdivo®), ipilimumab (Yervoy®), and pembrolizumab (Keytruda®). In some embodiments, the checkpoint inhibitor is selected from nivolumab (anti-PD-1 antibody, Opdivo®, Bristol-Myers Squibb), pembrolizumab (anti-PD-1 antibody, Keytruda®, Merck), ipilimumab (anti-CTLA-4 antibody, Yervoy®, Bristol-Myers Squibb), durvalumab (anti-PD-L1 antibody, Imfinzi®, AstraZeneca), and atezolizumab (anti-PD-L1 antibody, Tecentriq®, Genentech).

[0340] In some embodiments, the checkpoint inhibitor is selected from the group consisting of pembrolizumab (MK-3475), nivolumab (BMS-936558), pidilizumab (CT-011), AMP-224, MDX-1105, MEDI4736, MPDL3280A, BMS-936559, ipilimumab, lirilumab, IPH2101, pembrolizumab (Keytruda®), and tremelimumab.

[0341] In some embodiments, the immune checkpoint inhibitor is REGN2810 (Regeneron), an anti-PD-1 antibody that has been tested in patients with basal cell carcinoma (NCT03132636), NSCLC (NCT03088540), cutaneous squamous cell carcinoma (NCT02760498), lymphoma (NCT02651662), and melanoma (NCT03002376); pidilizumab (CureTech), an antibody that binds to PD-1 and is also known as CT-011, in clinical trials for diffuse large B-cell lymphoma and multiple myeloma; avelumab (Bavencio®, Pfizer / Merck KGaA), also known as MSB0010718C, an anti-PD-L1 fully human IgG1 antibody, in clinical trials for non-small cell lung cancer, Merkel cell carcinoma, mesothelioma, solid tumors, kidney cancer, ovarian cancer, bladder cancer, head and neck cancer, and gastric cancer; or PDR001 (Novartis), an inhibitory antibody that binds to PD-1, in clinical trials for non-small cell lung cancer, melanoma, triple-negative breast cancer, and advanced or metastatic solid tumors. Tremelimumab (CP-675,206; Astrazeneca) is a fully human monoclonal antibody against CTLA-4 and has been studied in clinical trials for many indications including mesothelioma, colorectal cancer, kidney cancer, breast cancer, lung cancer and non-small cell lung cancer, pancreatic ductal adenocarcinoma, pancreatic cancer, germ cell cancer, head and neck squamous cell carcinoma, hepatocellular carcinoma, prostate cancer, endometrial cancer, liver metastases, liver cancer, large B-cell lymphoma, ovarian cancer, cervical cancer, metastatic anaplastic thyroid cancer, urothelial cancer, fallopian tube cancer, multiple myeloma, bladder cancer, soft tissue sarcoma, and melanoma. AGEN-1884 (Agenus) is an anti-CTLA4 antibody being studied in a Phase 1 clinical trial for advanced solid tumors (NCT02694822).

[0342] In some embodiments, the checkpoint inhibitor is an inhibitor of T cell immunoglobulin and mucin domain-containing protein-3 (TIM-3). Examples of TIM-3 inhibitors that can be used in the present invention include TSR-022, LY3321367, and MBG453. TSR-022 (Tesaro) is an anti-TIM-3 antibody being studied in solid tumors (NCT02817633). LY3321367 (Eli Lilly) is an anti-TIM-3 antibody being studied in solid tumors (NCT03099109). MBG453 (Novartis) is an anti-TIM-3 antibody being studied in advanced malignancies (NCT02608268).

[0343] In some embodiments, the checkpoint inhibitor is an immune receptor on specific T cells and NK cells and is an inhibitor of the T cell immune receptor with Ig and ITIM domains, namely TIGIT. Examples of TIGIT inhibitors that can be used in the present invention include BMS-986207 (Bristol-Myers Squibb), an anti-TIGIT monoclonal antibody (NCT02913313), OMP-313M32 (Oncomed), and an anti-TIGIT monoclonal antibody (NCT03119428).

[0344] In some embodiments, the checkpoint inhibitor is an inhibitor of lymphocyte activation gene-3 (LAG-3). Examples of LAG-3 inhibitors that can be used in the present invention include BMS-986016, REGN3767, and IMP321. BMS-986016 (Bristol-Myers Squibb), an anti-LAG-3 antibody, is being studied in glioblastoma and gliosarcoma (NCT02658981). REGN3767 (Regeneron) is also an anti-LAG-3 antibody and is being studied in malignancies (NCT03005782). IMP321 (Immutep S.A.) is a LAG-3-Ig fusion protein and is being studied in melanoma (NCT02676869), adenocarcinoma (NCT02614833), and metastatic breast cancer (NCT00349934).

[0345] Checkpoint inhibitors that can be used in the present invention include OX40 agonists. OX40 agonists being studied in clinical trials include PF-04518600 / PF-8600 (Pfizer), an anti-OX40 agonist antibody, in metastatic renal cancer (NCT03092856) and advanced cancer and neoplasms (NCT02554812; NCT05082566); GSK3174998 (Merck), an anti-OX40 agonist antibody, in a Phase 1 cancer trial (NCT02528357); MEDI0562 (Medimmune / AstraZeneca), an anti-OX40 agonist antibody, in advanced solid tumors (NCT02318394 and NCT02705482); MEDI6469 (Medimmune / AstraZeneca), an anti-OX40 agonist antibody, in patients with colorectal cancer (NCT02559024), breast cancer (NCT01862900), head and neck cancer (NCT02274155), and metastatic prostate cancer (NCT01303705); and BMS-986178 (Bristol-Myers Squibb), an anti-OX40 agonist antibody, in advanced cancer (NCT02737475).

[0346] Checkpoint inhibitors that can be used in the present invention include CD137 (also called 4-1BB) agonists. CD137 agonists being studied in clinical trials include utomilumab (PF-05082566, Pfizer), an anti-CD137 agonist antibody, in diffuse large B-cell lymphoma (NCT02951156) and advanced cancer and neoplasms (NCT02554812 and NCT05082566); urelumab (BMS-663513, Bristol-Myers Squibb), an anti-CD137 agonist antibody, in melanoma and skin cancer (NCT02652455) and glioblastoma and gliosarcoma (NCT02658981); and CTX-471 (Compass Therapeutics), an anti-CD137 agonist antibody, in metastatic or locally advanced malignancies (NCT03881488).

[0347] Checkpoint inhibitors that can be used in the present invention include CD27 agonists. CD27 agonists being studied in clinical trials include balstilimab (CDX-1127, Celldex Therapeutics), an anti-CD27 agonist antibody, in squamous cell head and neck cancer, ovarian cancer, colorectal cancer, renal cell cancer, and glioblastoma (NCT02335918), lymphoma (NCT01460134), and glioblastoma and astrocytoma (NCT02924038).

[0348] Checkpoint inhibitors that can be used in the present invention include glucocorticoid-induced tumor necrosis factor receptor (GITR) agonists. GITR agonists being studied in clinical trials include TRX518 (Leap Therapeutics), an anti-GITR agonist antibody, in melanoma and other solid malignancies (NCT01239134 and NCT02628574); GWN323 (Novartis), an anti-GITR agonist antibody, in solid tumors and lymphoma (NCT02740270); INCAGN01876 (Incyte / Agenus), an anti-GITR agonist antibody, in advanced cancer (NCT02697591 and NCT03126110); MK-4166 (Merck), an anti-GITR agonist antibody, in solid tumors (NCT02132754); and MEDI1873 (Medimmune / AstraZeneca), an agonist hexameric GITR ligand molecule having a human IgG1 Fc domain, in advanced solid tumors (NCT02583165).

[0349] Checkpoint inhibitors that can be used in the present invention include inducible T cell costimulatory agent (ICOS, also known as CD278) agonists. ICOS agonists being studied in clinical trials include MEDI-570 (Medimmune), an anti-ICOS agonist antibody, in lymphoma (NCT02520791); GSK3359609 (Merck), an anti-ICOS agonist antibody, in Phase 1 (NCT02723955); and JTX-2011 (Jounce Therapeutics), an anti-ICOS agonist antibody, in Phase 1 (NCT02904226).

[0350] Checkpoint inhibitors that can be used in the present invention include killer IgG-like receptor (KIR) inhibitors. KIR inhibitors being studied in clinical trials include lirilumab (IPH2102 / BMS-986015, Innate Pharma / Bristol-Myers Squibb), an anti-KIR antibody, in leukemia (NCT01687387, NCT02399917, NCT02481297, NCT02599649), multiple myeloma (NCT02252263), and lymphoma (NCT01592370); IPH2101 (1-7F9, Innate Pharma) in myeloma (NCT01222286 and NCT01217203); and IPH4102 (Innate Pharma), an anti-KIR antibody that binds to three domains of the long cytoplasmic tail (KIR3DL2), in lymphoma (NCT02593045).

[0351] Checkpoint inhibitors that can be used in the present invention include CD47 inhibitors that interfere with the interaction between CD47 and signal regulatory protein α (SIRPa). CD47 / SIRPa inhibitors being studied in clinical trials include ALX-148 (Alexo Therapeutics), an antagonist variant of (SIRPa) that binds to CD47 and interferes with CD47 / SIRPa-mediated signal transduction in Phase 1 (NCT03013218); TTI-621 (SIRPa-Fc, Trillium Therapeutics), a soluble recombinant fusion protein produced by linking the N-terminal CD47-binding domain of SIRPa and the Fc domain of human IgG1, which acts by binding to human CD47 and interfering with CD47's "don't eat me" signal from being transmitted by CD47 to macrophages, and is in Phase 1 clinical trials (NCT02890368 and NCT02663518); CC-90002 (Celgene), an anti-CD47 antibody in leukemia (NCT02641002); and Hu5F9-G4 (Forty Seven, Inc.) in colorectal neoplasms and solid tumors (NCT02953782), acute myeloid leukemia (NCT02678338), and lymphoma (NCT02953509).

[0352] Checkpoint inhibitors that can be used in the present invention include CD73 inhibitors. CD73 inhibitors being studied in clinical trials include MEDI9447 (Medimmune), an anti-CD73 antibody in solid tumors (NCT02503774), and BMS-986179 (Bristol-Myers Squibb), an anti-CD73 antibody in solid tumors (NCT02754141).

[0353] Checkpoint inhibitors that can be used in the present invention include agonists of stimulator of interferon genes protein (STING, also known as transmembrane protein 173, or TMEM173). Agonists of STING being studied in clinical trials include MK-1454 (Merck), an agonist synthetic cyclic dinucleotide, in lymphoma (NCT03010176), and ADU-S100 (MIW815, Aduro Biotech / Novartis), an agonist synthetic cyclic dinucleotide, in phase I (NCT02675439 and NCT03172936).

[0354] Checkpoint inhibitors that can be used in the present invention include CSF1R inhibitors. CSF1R inhibitors being studied in clinical trials include pexidartinib (PLX3397, Plexxikon), a CSF1R small molecule inhibitor, in colorectal cancer, pancreatic cancer, metastatic and advanced cancer (NCT02777710), and melanoma, non-small cell lung cancer, squamous cell head and neck cancer, gastrointestinal stromal tumor (GIST), and ovarian cancer (NCT02452424); IMC-CS4 (LY3022855, Lilly), an anti-CSF-1R antibody, in pancreatic cancer (NCT03153410), melanoma (NCT03101254), and solid tumors (NCT02718911); and BLZ945 (4-[2((1R,2R)-2-hydroxycyclohexylamino)-benzothiazol-6-yloxyl]-pyridine-2-carboxylic acid methylamide, Novartis), an orally available inhibitor of CSF1R, in advanced solid tumors (NCT02829723).

[0355] Checkpoint inhibitors that can be used in the present invention include NKG2A receptor inhibitors. NKG2A receptor inhibitors being studied in clinical trials include monalizumab (IPH2201, Innate Pharma), an anti-NKG2A antibody, in head and neck neoplasms (NCT02643550) and chronic lymphocytic leukemia (NCT02557516).

[0356] In some embodiments, the immune checkpoint inhibitor is selected from nivolumab, pembrolizumab, ipilimumab, avelumab, durvalumab, atezolizumab, or pidilizumab.

Example

[0357] The following examples are intended to illustrate the present invention and should not be construed as limiting it. Unless otherwise stated, one or more tautomeric forms of the compounds of the examples described below may be prepared and / or isolated in situ. All tautomeric forms of the compounds of the examples described below should be considered to be disclosed. Temperatures are indicated in degrees Celsius. Unless otherwise stated, all evaporations are carried out under reduced pressure, preferably at about 15 mmHg to 100 mmHg (= 20 to 133 mbar). The structures of the final products, intermediates, and starting materials are confirmed by standard analytical methods, such as microanalysis and spectroscopic properties, such as MS, IR, NMR. The abbreviations used are conventional in the art.

[0358] All starting materials, components, reagents, acids, bases, dehydrating agents, solvents, and catalysts utilized for synthesizing the compounds of the present invention are either commercially available or can be prepared by organic synthesis methods known to those skilled in the art. Further, the compounds of the present invention can be prepared by organic synthesis methods known to those skilled in the art, as shown in the following examples.

[0359] Example 1: Synthesis of an exemplary compound I-1

Chemical formula

[0360] Step 2: 2-(Methylsulfanyl)-8H-pyrido[2,3-d]pyrimidin-7-one To a stirred solution of ethyl (2E)-3-[4-amino-2-(methylsulfanyl)pyrimidin-5-yl]prop-2-enoate (10 g, 41.79 mmol, 1 equiv) in DIEA (100 mL) was added DBU (9.54 g, 62.68 mmol, 1.5 equiv) at room temperature. The resulting mixture was stirred at 130 °C for 3 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (C18 silica gel column, eluting with 0% - 100% MeCN / H2O (0.1% FA) for 15 min using a UV detector (254 nm)) to afford 2-(methylsulfanyl)-8H-pyrido[2,3-d]pyrimidin-7-one (5.5 g, 68.11%) as a pale yellow solid. LC-MS (ESI) m / z 194.2 [M+H]

[0361] Step 3: 2-Chloro-8H-pyrido[2,3-d]pyrimidin-7-one A solution of 2-(methylsulfanyl)-8H-pyrido[2,3-d]pyrimidin-7-one (6 g, 31.053 mmol, 1 equiv) in SO2Cl2 (60 mL) was stirred at 50 °C for 3 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (C18 silica gel column, eluted with 0% - 100% MeCN / H2O (0.1% FA) for 10 min using a UV detector (254 nm)) to give 2-chloro-8H-pyrido[2,3-d]pyrimidin-7-one (3 g, 53.21%) as an off-white solid. LC-MS (ESI) m / z 182.5 [M+H]

[0362] Step 4: 2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-8H-pyrido[2,3-d]pyrimidin-7-one To a stirred solution of 2-chloro-8H-pyrido[2,3-d]pyrimidin-7-one (3 g, 16.522 mmol, 1 equiv) and 4-cyclopropyl-6-methoxypyrimidin-5-ylboronic acid (4.81 g, 24.7 mmol, 1.5 equiv) in 1,4-dioxane (60 mL) and H2O (12 mL), Pd(dppf)Cl2 (2.42 g, 3.3 mmol, 0.2 equiv) and K3PO4 (8.77 g, 41.305 mmol, 2.5 equiv) were added at room temperature. The resulting mixture was stirred at 90 °C for 2 h under a nitrogen atmosphere. The resulting mixture was filtered and the filter cake was washed with 1,4-dioxane (3 * 50 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (C18 silica gel column, mobile phase, eluted with 0% - 100% MeCN / H2O (0.1% FA) for 10 min using a UV detector (254 nm)) to give 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8H-pyrido[2,3-d]pyrimidin-7-one (2.3 g, 47.14%) as an off-white solid. LC-MS (ESI) m / z 296.3 [M+H]

[0363] Step 5: 2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-8-({4-[1-methyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)pyrido[2,3-d]pyrimidin-7-one To a stirred solution of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8H-pyrido[2,3-d]pyrimidin-7-one (1.9 g, 6.4 mmol, 1.1 eq) and 2-[4-(chloromethyl)phenyl]-1-methyl-4-(trifluoromethyl)imidazole (1.61 g, 5.8 mmol, 1 eq) in DMF (20 mL) was added 1,1,3,3-tetramethylguanidine (1.01 g, 8.774 mmol, 1.5 eq) at room temperature. The resulting mixture was stirred at room temperature for 3 h under a nitrogen atmosphere. The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with water (3 × 100 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (C18 silica gel column, eluting with 0% - 100% MeCN / water (0.1% FA) for 20 min using a UV detector (254 nm)) to give 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-({4-[1-methyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)pyrido[2,3-d]pyrimidin-7-one (2.16 g, 69.22%) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6) δ 9.29 (s, 1H), 8.69 (s, 1H), 8.16 (d, J = 9.6 Hz, 1H), 7.91 (d, J = 1.4 Hz, 1H), 7.68 - 7.58 (m, 2H), 7.40 (d, J = 8.2 Hz, 2H), 6.90 (d, J = 9.5 Hz, 1H), 5.57 (s, 2H), 3.78 (d, J = 36.0 Hz, 6H), 1.72 (m, 1H), 1.01 (m, 2H), 0.77 (m, 2H). LC-MS (ESI) m / z 534.0 [M+H]

[0364] I-2

Chemical Structure

[0365] Step 2: 2-Chloro-5-(2-chloroethoxy)pyrimidin-4-amine To a stirred solution of 4-amino-2-chloropyrimidin-5-ol (732 mg, 5.029 mmol, 1 equiv) and K2CO3 (4170.36 mg, 30.174 mmol, 6 equiv) in DMF (10 ml, 129.215 mmol, 25.69 equiv), 1-bromo-2-chloroethane (2163.71 mg, 15.087 mmol, 3 equiv) was added dropwise at room temperature under a nitrogen atmosphere. The final reaction mixture was stirred overnight at room temperature. The obtained mixture was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (3 × 10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 2-chloro-5-(2-chloroethoxy)pyrimidin-4-amine (450 mg, 43.01%) as an off-white solid. The crude product mixture was used directly in the next step without further purification. LC-MS (ESI) m / z 208 [M+H]

[0366] Step 3: 2-Chloro-6H,7H,8H-pyrimido[5,4-b][1,4]oxazine To a stirred solution of 2-chloro-5-(2-chloroethoxy)pyrimidin-4-amine (450 mg, 2.163 mmol, 1 equiv) in DMF (5 mL, 64.608 mmol, 24.63 equiv), K2CO3 (1195.77 mg, 8.652 mmol, 4 equiv) was added portionwise at room temperature under a nitrogen atmosphere. The final reaction mixture was stirred at 100 °C overnight. The resulting mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (3 × 10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with PE / EA (5:1)) to afford 2-chloro-6H,7H,8H-pyrimido[5,4-b][1,4]oxazine (300 mg, 80.83%) as an off-white solid. LC-MS (ESI) m / z 172 [M+H]

[0367] Step 4: 2-[4-({2-Chloro-6H,7H-pyrimido[5,4-b][1,4]oxazin-8-yl}methyl)phenyl]-1-methyl-4-(trifluoromethyl)imidazole A stirred solution of 2-chloro-6H,7H,8H-pyrimido[5,4-b][1,4]oxazine (280 mg, 1.632 mmol, 2.5 equiv) and 2-[4-(chloromethyl)phenyl]-1-methyl-4-(trifluoromethyl)imidazole (179.29 mg, 0.653 mmol, 1 equiv) in DMF (5 mL, 64.608 mmol, 39.59 equiv) was added K2CO3 (270.64 mg, 1.958 mmol, 3 equiv) portionwise at room temperature under a nitrogen atmosphere. The final reaction mixture was stirred at 45 °C for 3 h. The reaction was quenched with water at 0 °C. The resulting mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (1 × 10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (C18 silica gel column, eluting with 10% - 100% MeCN / water (10 mmol / L NH4HCO3) for 10 min using a UV detector (254 nm)) to afford 2-[4-({2-chloro-6H,7H-pyrimido[5,4-b][1,4]oxazin-8-yl}methyl)phenyl]-1-methyl-4-(trifluoromethyl)imidazole (226.1 mg, 84.52%) as an orange solid. LC-MS (ESI) m / z 410 [M+H]

[0368] Step 5: 4-Cyclopropyl-6-methoxy-5-[8-({4-[1-methyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)-6H,7H-pyrimido[5,4-b][1,4]oxazin-2-yl]pyrimidine A stirred solution of 2-[4-({2-chloro-6H,7H-pyrimido[5,4-b][1,4]oxazin-8-yl}methyl)phenyl]-1-methyl-4-(trifluoromethyl)imidazole (160 mg, 0.390 mmol, 1 equiv) and 4-cyclopropyl-6-methoxypyrimidin-5-ylboronic acid (113.62 mg, 0.585 mmol, 1.5 equiv) in 1,4-dioxane (3 mL, 12.000 mmol, 30.74 equiv) was added with K3PO4 (207.19 mg, 0.975 mmol, 2.5 equiv) and H2O (0.3 mL, 16.653 mmol, 42.65 equiv) at room temperature under a nitrogen atmosphere. To the above mixture, Pd(dppf)Cl2 (57.14 mg, 0.078 mmol, 0.2 equiv) was added at room temperature. The resulting mixture was stirred at 90 °C for an additional 2 h. The reaction was quenched with water at 0 °C. The resulting mixture was extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (1 × 10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (C18 silica gel column, eluting with 0% - 100% MeCN / water (0.1% FA) for 10 min using a UV detector (254 nm)) to afford 4-cyclopropyl-6-methoxy-5-[8-({4-[1-methyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)-6H,7H-pyrimido[5,4-b][1,4]oxazin-2-yl]pyrimidine (76.3 mg, 37.33%) as an off-white solid.

[0369] 1 H NMR (400 MHz, DMSO-d6) δ 8.66 (s, 1H), 8.15 (s, 1H), 7.94 (d, J = 1.4 Hz, 1H), 7.72 - 7.65 (m, 2H), 7.46 (d, J = 8.1 Hz, 2H), 4.96 (s, 2H), 4.35 (s, 3H), 3.88 (s, 3H), 3.77 (s, 3H), 3.69 (s, 2H), 1.86 (s, 1H), 1.05 - 0.98 (m, 2H), 0.89 - 0.81 (m, 2H). LC-MS (ESI) m / z 524.20 [M + H]

[0370] I-3 [Chemical formula] I-3 was synthesized in the same manner as I-2.

[0371] 1 H NMR (400 MHz, chloroform-d) δ 8.72 (s, 1H), 8.19 (s, 1H), 7.57 (s, 2H), 7.47 (s, 1H), 7.41 (s, 2H), 5.11 (s, 2H), 4.53 (s, 1H), 4.36 (s, 2H), 4.07 (s, 3H), 3.72 (s, 2H), 1.93 (s, 1H), 1.49 (d, J = 5.5 Hz, 6H), 1.34 (s, 2H), 0.95 (s, 2H). LC-MS (ESI) m / z 552.40 [M + H]

[0372] I-4 [Chemical formula] Step 1: 8 - ({4 - [1 - Isopropyl - 4 - (trifluoromethyl)imidazol - 2 - yl]phenyl}methyl) - 2 - (methylsulfanyl)pyrido[2,3 - d]pyrimidin - 7 - one To a stirred solution of 2 - (methylsulfanyl) - 8H - pyrido[2,3 - d]pyrimidin - 7 - one (200 mg, 1.035 mmol, 1 equivalent) and 2 - [4 - (chloromethyl)phenyl] - 1 - isopropyl - 4 - (trifluoromethyl)imidazole (313.35 mg, 1.035 mmol, 1 equivalent) in DMF (2 mL), 1,1,3,3 - tetramethylguanidine (178.83 mg, 1.552 mmol, 1.5 equivalents) was added dropwise at room temperature. The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The reaction was quenched with water (10 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (3 × 10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was used directly in the next step without further purification. LC-MS (ESI) m / z: 460.1 [M + H]

[0373] Step 2: 2-Chloro-8-({4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)pyrido[2,3-d]pyrimidin-7-one To a stirred solution of 8-({4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)-2-(methylsulfanyl)pyrido[2,3-d]pyrimidin-7-one (150 mg, 0.326 mmol, 1 equiv) in CHCl3 (1 mL) and EtOH (0.1 mL), SO2Cl2 (132.17 mg, 0.978 mmol, 3 equiv) was added dropwise at room temperature. The resulting mixture was stirred at room temperature for 2 h and concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography (C18 silica gel column, eluted with 10% - 100% MeCN / H2O (0.1% NH3●H2O) for 10 min using a UV detector (254 nm)) to give 2-chloro-8-({4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)pyrido[2,3-d]pyrimidin-7-one (100 mg, 68.40%) as a light brown solid. LC-MS (ESI) m / z: 448.1 [M+H]

[0374] Step 3: 2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-8-({4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)pyrido[2,3-d]pyrimidin-7-one A stirred solution of 2-chloro-8-({4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)pyrido[2,3-d]pyrimidin-7-one (100 mg, 0.223 mmol, 1 equiv) and 4-cyclopropyl-6-methoxypyrimidin-5-ylboronic acid (64.98 mg, 0.335 mmol, 1.5 equiv) in 1,4-dioxane (0.8 mL) and water (0.2 mL) was added with Pd(dppf)Cl2 (32.68 mg, 0.045 mmol, 0.2 equiv) and K3PO4 (118.49 mg, 0.557 mmol, 2.5 equiv) at room temperature. The resulting mixture was stirred at 90 °C for 2 h under a nitrogen atmosphere. The resulting mixture was filtered and the filter cake was washed with 1,4-dioxane (3 × 15 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC under the following conditions (column: YMC-Actus Triart C18 ExRS, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 55% B to 65% B in 7 min, 65% B; wavelength: 220 nm; RT1 (min): 5.03) to give 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-({4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)pyrido[2,3-d]pyrimidin-7-one (26.1 mg, 20.42%) as a yellowish brown liquid. 1 H NMR (400 MHz, chloroform-d) δ 9.02 (s, 1H), 8.69 (s, 1H), 7.77 (d, J = 9.5 Hz, 1H), 7.61 (d, J = 8.0 Hz, 2H), 7.47 - 7.36 (m, 3H), 6.87 (d, J = 9.5 Hz, 1H), 5.71 (s, 2H), 4.51 (p, J = 6.7 Hz, 1H), 3.93 (s, 3H), 1.70 (m, 1H), 1.42 (d, J = 6.7 Hz, 6H), 1.30 - 1.15 (m, 2H), 0.86 (m, 2H). LC-MS (ESI) m / z 562.3 [M+H].

[0375] I-5

Chemical Structure

[0376] Step 2: 2-Chloro-6H,8H-pyrimido[5,4-b][1,4]oxazin-7-one To a stirred solution of ethyl 2-[(4-amino-2-chloropyrimidin-5-yl)oxy]acetate (465 mg, 2.007 mmol, 1 equiv) in DMF (8 mL, 103.372 mmol, 51.49 equiv), K2CO3 (138.72 mg, 1.004 mmol, 0.5 equiv) was added portionwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 60 °C for an additional overnight. The resulting mixture was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (3 × 10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting mixture was concentrated under vacuum to give 2-chloro-6H,8H-pyrimido[5,4-b][1,4]oxazin-7-one (214.9 mg, 57.69%) as a yellow solid. The crude product mixture was used directly in the next step without further purification. LC-MS (ESI) m / z 186 [M+H]

[0377] Step 3: 2-Chloro-8-({4-[1-methyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)-6H-pyrimido[5,4-b][1,4]oxazin-7-one To a stirred solution of 2-chloro-6H,8H-pyrimido[5,4-b][1,4]oxazin-7-one (215 mg, 1.159 mmol, 1 eq) and K2CO3 (160 mg, 1.158 mmol, 1.00 eq) in DMF (4 mL, 51.686 mmol, 44.61 eq), 2-[4-(chloromethyl)phenyl]-1-methyl-4-(trifluoromethyl)imidazole (106 mg, 0.386 mmol, 0.33 eq) was added dropwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 50 °C for 3 h. The resulting mixture was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (3 × 10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with PE / EA (1:1)) to give 2-chloro-8-({4-[1-methyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)-6H-pyrimido[5,4-b][1,4]oxazin-7-one (125 mg, 25.46%) as an off-white solid. LC-MS (ESI) m / z 424 [M+H]

[0378] Step 4: Synthesis of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-({4-[1-methyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)-6H-pyrimido[5,4-b][1,4]oxazin-7-one A stirred solution of 2-chloro-8-({4-[1-methyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)-6H-pyrimido[5,4-b][1,4]oxazin-7-one (130 mg, 0.307 mmol, 1 equiv) and 4-cyclopropyl-6-methoxypyrimidin-5-ylboronic acid (89.27 mg, 0.461 mmol, 1.5 equiv) in 1,4-dioxane (2 mL, 8.000 mmol, 26.08 equiv) was added with K3PO4 (162.79 mg, 0.767 mmol, 2.5 equiv) and H2O (0.18 mL, 9.992 mmol, 32.57 equiv) at room temperature under a nitrogen atmosphere. To the above mixture, Pd(dppf)Cl2 (44.89 mg, 0.061 mmol, 0.2 equiv) was added at room temperature. The resulting mixture was stirred at 90 °C for 3 h. The resulting mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (3 × 10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (C18 silica gel column, eluting with 0% - 100% MeCN / water (0.1% FA) for 10 min using a UV detector (254 nm)) to give 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-({4-[1-methyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)-6H-pyrimido[5,4-b][1,4]oxazin-7-one (80 mg, 48.52%) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.64 (s, 1H), 8.53 (s, 1H), 7.92 (d, J = 1.4 Hz, 1H), 7.68 - 7.61 (m, 2H), 7.46 (d, J = 8.2 Hz, 2H), 5.24 (s, 2H), 5.05 (s, 2H), 3.81 (s, 3H), 3.75 (s, 3H), 1.68 (tt, J = 8.2, 4.6 Hz, 1H), 1.03 - 0.95 (m, 2H), 0.77 (dq, J = 7.0, 3.4 Hz, 2H). LC-MS (ESI) m / z 538 [M + H]

[0379] I-6

Chemical Structure

[0380] 1 H NMR (400 MHz, DMSO-d6) δ 8.70 - 8.64 (m, 1H), 8.17 (d, J = 8.0 Hz, 1H), 7.53 (q, J = 8.4 Hz, 4H), 6.76 (s, 1H), 4.98 (d, J = 3.6 Hz, 2H), 4.36 (s, 2H), 3.91 - 3.86 (m, 3H), 3.72 (s, 2H), 2.35 - 2.30 (m, 3H), 1.87 (s, 1H), 1.02 (s, 2H), 0.85 (dd, J = 8.0, 3.4 Hz, 2H). LC-MS (ESI) m / z 566 [M + H].

[0381] I-7

Chem.

[0382] 1 H NMR (400 MHz, DMSO-d6) δ 8.70 - 8.64 (m, 1H), 8.17 (d, J = 8.0 Hz, 1H), 7.53 (q, J = 8.4 Hz, 4H), 6.76 (s, 1H), 4.98 (d, J = 3.6 Hz, 2H), 4.36 (s, 2H), 3.91 - 3.86 (m, 3H), 3.72 (s, 2H), 2.35 - 2.30 (m, 3H), 1.87 (s, 1H), 1.02 (s, 2H), 0.85 (dd, J = 8.0, 3.4 Hz, 2H). LC-MS (ESI) m / z 524 [M + H]

[0383] I-8

Chem.

[0384] Step 2: 2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-8-({4-[5-methyl-3-(trifluoromethyl)pyrazol-1-yl]phenyl}methyl)pyrido[2,3-d]pyrimidin-7-one A stirred solution of 2-chloro-8-({4-[5-methyl-3-(trifluoromethyl)pyrazol-1-yl]phenyl}methyl)pyrido[2,3-d]pyrimidin-7-one (50 mg, 0.119 mmol, 1 equiv) and 4-cyclopropyl-6-methoxypyrimidin-5-ylboronic acid (34.66 mg, 0.178 mmol, 1.5 equiv) in 1,4-dioxane (1 mL) and H2O (0.2 mL) was added with K3PO4 (63.21 mg, 0.297 mmol, 2.5 equiv) and Pd(dppf)Cl2 (17.43 mg, 0.024 mmol, 0.2 equiv) at room temperature. The resulting mixture was stirred at 90 °C for 2 h under a nitrogen atmosphere. The resulting mixture was filtered and the filter cake was washed with 1,4-dioxane (3 × 5 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC under the following conditions (column: Xselect CSH C18 OBD column 30*150 mm 5 μm, n; mobile phase A: water (0.05% TFA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 55% B to 95% B in 7 min, 95% B; wavelength: 254 / 220 nm; RT1 (min): 6.02) to give 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-({4-[5-methyl-3-(trifluoromethyl)pyrazol-1-yl]phenyl}methyl)pyrido[2,3-d]pyrimidin-7-one (15.0 mg, 22.68%) as an off-white solid. 1 H NMR (300 MHz, DMSO-d6) δ 9.30 (s, 1H), 8.70 (s, 1H), 8.17 (d, J = 9.5 Hz, 1H), 7.68 - 7.27 (m, 4H), 6.92 (d, J = 9.5 Hz, 1H), 6.74 (s, 1H), 5.59 (s, 2H), 3.83 (s, 3H), 2.31 (d, J = 0.7 Hz, 3H), 1.81 - 1.65 (m, 1H), 1.02 (d, J = 4.2 Hz, 2H), 0.78 (dd, J = 7.9, 3.3 Hz, 2H). LC-MS (ESI) m / z 534.1 [M+H].

[0385] I-9

Chemical Structure

[0386] Step 2: Ethyl 2-[(6-chloro-1-oxo-1λ5-pyridin-3-yl)oxy]acetate A solution of ethyl 2-[(6-chloropyridin-3-yl)oxy]acetate (5 g, 23.188 mmol, 1 equiv) in DCE (100.00 mL, 1263.282 mmol, 54.48 equiv) was treated with m-CPBA (8.00 g, 46.376 mmol, 2.0 equiv) at 50 °C for 4 h under a nitrogen atmosphere and then stirred at room temperature overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (C18 silica gel column, eluting with 0% - 100% ACN / water (0.1% FA) for 10 min using a UV detector (254 nm)). The resulting mixture was concentrated under reduced pressure and lyophilized to give ethyl 2-[(6-chloro-1-oxo-1λ5-pyridin-3-yl)oxy]acetate (4 g, 74.47%) as a yellow solid. LC-MS (ESI) m / z 232.15 [M+H]

[0387] Step 3 Methyl 2-[(6-chloro-4-nitro-1-oxo-1λ5-pyridin-3-yl)oxy]acetate A solution of ethyl 2-[(6-chloro-1-oxido-1λ⁵-pyridin-3-yl)oxy]acetate (1000 mg, 4.317 mmol, 1 equiv) in H2SO4 (4 mL, 75.048 mmol, 17.38 equiv) was treated dropwise with HNO3 (2 mL, 44.595 mmol, 10.33 equiv) at 0 °C for several minutes under a nitrogen atmosphere. The reaction mixture was heated to 40 °C in an oil bath. The temperature was gradually raised to 75 °C over 1 hour and then maintained at that temperature for 2 hours. The mixture was then cooled on ice, 50% NaOH was added to adjust the pH to 9, dehydrated in vacuo, washed with 3 × 2 mL of MeOH, and concentrated under reduced pressure. The residue was dissolved in MeOH (50 ml) and treated with H2SO4 (1 mL) at 70 °C for 2 hours under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure, diluted with water (20 ml), basified to pH 9 with NaOH, and extracted with EtOAc (3 × 15 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (C18 silica gel column, eluted with 0% - 100% ACN / water (0.1% FA) for 10 minutes using a UV detector (254 nm)), concentrated under reduced pressure, and lyophilized to obtain methyl 2-[(6-chloro-4-nitro-1-oxido-1λ⁵-pyridin-3-yl)oxy]acetate (200 mg, 17.64%) as a white solid. LC-MS (ESI) m / z 263.15[M+H]

[0388] Step 4: 7-Chloro-1H,3H-pyrido[3,4-b][1,4]oxazin-2-one A solution of methyl 2-[(6-chloro-4-nitro-1-oxido-1λ⁵-pyridin-3-yl)oxy]acetate (210 mg, 0.800 mmol, 1 equiv) in MeOH (6 mL) was treated with Fe (312.61 mg, 5.600 mmol, 7 equiv) and AcOH (0.25 mg, 0.004 mmol, 0.01 equiv) at 70 °C for 4 h under a nitrogen atmosphere. The hot solution was filtered through a pad of Celite and concentrated. The residue was purified by reverse-phase flash chromatography (C18 silica gel column, eluting with 0% - 100% ACN / H2O (0.1% NH3-H2O) for 10 min using a UV detector (254 nm)) to give 7-chloro-1H,3H-pyrido[3,4-b][1,4]oxazin-2-one (140 mg, 94.85%) as a reddish-brown solid. LC-MS (ESI) m / z 185.00 [M+H]

[0389] Step 5 7-Chloro-1-({4-[1-methyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)-3H-pyrido[3,4-b][1,4]oxazin-2-one A solution of 7-chloro-1H,3H-pyrido[3,4-b][1,4]oxazin-2-one (200 mg, 1.084 mmol, 1 equiv) in DMF (10.00 mL) was treated with K2CO3 (449.25 mg, 3.252 mmol, 3 equiv) and 2-[4-(bromomethyl)phenyl]-1-methyl-4-(trifluoromethyl)imidazole (449.52 mg, 1.409 mmol, 1.3 equiv) at 50 °C for 3 h under a nitrogen atmosphere. The residue was purified by reverse-phase flash chromatography (C18 silica gel column, eluting with 0% - 100% ACN / H2O (0.1% NH3-H2O) for 10 min using a UV detector (254 nm)) to give 7-chloro-1-({4-[1-methyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)-3H-pyrido[3,4-b][1,4]oxazin-2-one (250 mg, 54.57%) as an off-white solid. LC-MS (ESI) m / z 423.2 [M+H]

[0390] Step 6.2 - [4-({7-Chloro-2H,3H-pyrido[3,4-b][1,4]oxazin-1-yl}methyl)phenyl]-1-methyl-4-(trifluoromethyl)imidazole A mixture of 7-chloro-1-({4-[1-methyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)-3H-pyrido[3,4-b][1,4]oxazin-2-one (100 mg, 0.237 mmol, 1 equiv) and BH3-THF (0.59 mL, 0.593 mmol, 2.5 equiv, 1 M in THF) in THF (1.5 mL) was stirred at 75 °C for 1 h under a nitrogen atmosphere. The reaction was quenched with MeOH at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (C18 silica gel column, eluting with 0% - 100% ACN / H2O (0.1% FA) for 10 min using a UV detector (254 nm)) and lyophilized to give 2-[4-({7-chloro-2H,3H-pyrido[3,4-b][1,4]oxazin-1-yl}methyl)phenyl]-1-methyl-4-(trifluoromethyl)imidazole (60 mg, 62.05%) as an off-white solid. LC-MS (ESI) m / z 409.1 [M+H]

[0391] Step 7.4 - Cyclopropyl-6-methoxy-5-[1-({4-[1-methyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)-2H,3H-pyrido[3,4-b][1,4]oxazin-7-yl]pyrimidine A solution of 2-[4-({7-chloro-2H,3H-pyrido[3,4-b][1,4]oxazin-1-yl}methyl)phenyl]-1-methyl-4-(trifluoromethyl)imidazole (60 mg, 0.147 mmol, 1 equiv) and 4-cyclopropyl-6-methoxypyrimidin-5-ylboronic acid (42.71 mg, 0.220 mmol, 1.5 equiv) in 1,4-dioxane (1.8 mL) and H2O (0.2 mL) was treated with K3PO4 (77.88 mg, 0.367 mmol, 2.5 equiv) and Pd(dppf)Cl2 (32.22 mg, 0.044 mmol, 0.3 equiv) at 90 °C for 2 h under a nitrogen atmosphere. The residue was purified by reverse-phase flash chromatography (C18 silica gel column, eluted with 0% - 100% ACN / H2O (0.1% NH3-H2O) for 10 min using a UV detector (254 nm)). The crude product was purified by preparative HPLC under the following conditions (column: Sunfire prep C18 column, 30*150 mm, 5 μm, mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: from 15% B to 45% B in 7 min, 45% B; wavelength: 254 / 220 nm; RT1 (min): 4.45) to give 4-cyclopropyl-6-methoxy-5-[1-({4-[1-methyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)-2H,3H-pyrido[3,4-b][1,4]oxazin-7-yl]pyrimidine (10.9 mg, 14.21%) as an off-white solid. 1 1H-NMR (400 MHz, DMSO-d6): δ 8.54 (s, 1H), 7.92 (d, J = 4.5 Hz, 2H), 7.70 (d, J = 7.9 Hz, 2H), 7.42 (d, J = 7.9 Hz, 2H), 6.80 (s, 1H), 4.68 (s, 2H), 4.31 (t, J = 4.3 Hz, 2H), 3.75 (d, J = 11.0 Hz, 6H), 3.57 (t, J = 4.4 Hz, 2H), 1.78 (dd, J = 8.2, 3.9 Hz, 1H), 0.93 (p, J = 3.7 Hz, 2H), 0.77 (dq, J = 7.1, 3.4 Hz, 2H). LC-MS (ESI) m / z 523.25 [M + H]

[0392] I-10

Chem.

[0393] I-11

Chem.

[0394] Step 2: {6-Chloro-4-[({4-[1-Methyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)amino]pyridin-3-yl}methanol 1-{6-Chloro-4-[({4-[1-methyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)amino]pyridin-3-yl}-2-methoxyethanone (78 mg, 0.178 mmol, 1 equiv) in stirred tetrahydrofuran (1.5 mL, 20 equiv) was treated portionwise with LiAlH4 (20.24 mg, 0.534 mmol, 3 equiv) at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at 0 °C for 1 h under a nitrogen atmosphere. The reaction was quenched at 0 °C with 10H2O.Na2SO4 (100 mg). The resulting mixture was filtered and the filter cake was washed with THF (3 x 5 mL). The filtrate was concentrated under reduced pressure. The residue was dissolved in THF (2 mL). The residue was purified by reverse-phase flash chromatography (C18 silica gel column, eluting with 10% - 50% MeCN / water (0.1% FA) for 10 min using a UV detector (254 nm)) to afford {6-chloro-4-[({4-[1-methyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)amino]pyridin-3-yl}methanol (23.5 mg, 33.32%) as a white solid. LC-MS (ESI) m / z 397.1 [M+H]

[0395] Step 3. 6-Chloro-4-[({4-[1-methyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)amino]pyridine-3-carbaldehyde To a stirred solution of {6-chloro-4-[({4-[1-methyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)amino]pyridin-3-yl}methanol (85 mg, 0.214 mmol, 1 equiv) in methylene chloride (4 mL, 20 equiv) was added manganese dioxide (55.87 mg, 0.642 mmol, 3.0 equiv) at room temperature under a nitrogen atmosphere. The reaction mixture was held at room temperature overnight. The resulting mixture was filtered and the filter cake was washed with CH2Cl2 (3 × 5 mL). The filtrate was concentrated under reduced pressure. The residue was dissolved in MeOH (2 mL). The residue was purified by reverse-phase flash chromatography (C18 silica gel column, eluting with 0% to 100% MeCN / water (0.1% FA) for 10 min using a UV detector (254 nm)) to afford 6-chloro-4-[({4-[1-methyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)amino]pyridine-3-carbaldehyde (60 mg, 70.95%) as a pale yellow solid. LC-MS (ESI) m / z 395.0 [M+H].

[0396] Step 4. 6-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-4-[({4-[1-methyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)amino]pyridine-3-carbaldehyde A stirred mixture of 6-chloro-4-[({4-[1-methyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)amino]pyridine-3-carbaldehyde (20 mg, 0.051 mmol, 1 equiv), 4-cyclopropyl-6-methoxypyrimidin-5-ylboronic acid (14.74 mg, 0.076 mmol, 1.5 equiv) in 1,4-dioxane (0.9 mL, 1.020 mmol, 20 equiv) and water (0.1 mL, 1.020 mmol, 20 equiv) was added with K3PO4 (32.26 mg, 0.153 mmol, 3 equiv) and Pd(dppf)Cl2 (7.41 mg, 0.010 mmol, 0.2 equiv) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100 °C for 2 h under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in THF (1 mL). The residue was purified by reverse-phase flash chromatography (C18 silica gel column, eluted with 0% - 100% MeCN / water (0.1% FA) for 10 min using a UV detector (254 nm)) to give 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-[({4-[1-methyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)amino]pyridine-3-carbaldehyde (15 mg, 58.23%) as a yellow solid. LC-MS (ESI) m / z 509.1 [M+H]

[0397] Step 5: 7-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-1-({4-[1-methyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)-1,6-naphthyridin-2-one A stirred solution of ethyl acetate (34.65 mg, 0.392 mmol, 4.0 equiv) in THF (2 mL, 20 equiv) was added dropwise with LiHMDS (0.392 mL, 0.392 mmol, 4.0 equiv, 1 M in THF) at -78 °C under a nitrogen atmosphere. The resulting mixture was stirred at -78 °C for 10 min under a nitrogen atmosphere. To the above mixture, 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-[({4-[1-methyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)amino]pyridine-3-carbaldehyde (50 mg, 0.098 mmol, 1 equiv) was added dropwise at -78 °C. The resulting mixture was stirred at room temperature for an additional 3 h. The reaction was quenched with water at 0 °C. The resulting mixture was extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (2 × 2 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (XBridge Shield RP18 OBD column, 30*150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 40% B to 75% B in 7 min, 75% B; wavelength: 254 / 220 nm; RT1 (min): 3.45;) to give 7-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-({4-[1-methyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)-1,6-naphthyridin-2-one (21.1 mg, 40.26%) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 9.03 (s, 1H), 8.64 (s, 1H), 8.17 (d, J = 9.6 Hz, 1H), 7.92 (d, J = 1.4 Hz, 1H), 7.73 - 7.61 (m, 3H), 7.37 (d, J = 8.1 Hz, 2H), 6.88 (d, J = 9.5 Hz, 1H), 5.58 (s, 2H), 3.75 (s, 3H), 3.69 (s, 3H), 1.74 - 1.64 (m, 1H), 0.97 (d, J = 4.4 Hz, 2H), 0.75 (dd, J = 8.1, 3.3 Hz, 2H). LC-MS (ESI) m / z 533.10 [M+H]

[0398] I-89

Chem.

[0399] Step 2: 6-Chloro-N4-({4-[1-methyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)pyridine-3,4-diamine A solution of 2-chloro-N-({4-[1-methyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)-5-nitropyridin-4-amine (260 mg, 0.631 mmol, 1 equiv), iron (280 mg, 5.014 mmol, 7.94 equiv), NH4Cl (180 mg, 3.365 mmol, 5.33 equiv), and H2O (2 mL, 111.019 mmol, 175.82 equiv) in EtOH (8 mL) was stirred at 40 °C for 2 h under a nitrogen atmosphere. The resulting mixture was filtered, and the filter cake was washed with EtOH (2 × 100 mL). The filtrate was concentrated under reduced pressure to give 6-chloro-N4-({4-[1-methyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)pyridine-3,4-diamine (350 mg, 145.19%) as a brown solid. LC-MS (ESI) m / z 382 [M+H].

[0400] Step 3: N-(5-Amino-2-chloropyridin-4-yl)-2-chloro-N-({4-[1-methyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)acetamide To a solution of 6-chloro-N4-({4-[1-methyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)pyridine-3,4-diamine (450 mg, 1.179 mmol, 1 equiv) in DCM (10 mL) was added TEA (430 mg, 4.249 mmol, 3.61 equiv) at room temperature under a nitrogen atmosphere, followed by dropwise addition of chloroacetyl chloride (170 mg, 1.505 mmol, 1.28 equiv) at 0 °C. The resulting mixture was stirred at room temperature for 2 h under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (C18 silica gel column, eluted with 0% - 100% MeCN / water (0.1% FA) for 10 min using a UV detector (254 nm)) to give N-(5-amino-2-chloropyridin-4-yl)-2-chloro-N-({4-[1-methyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)acetamide (150 mg, 27.77%) as a colorless oil. LC-MS (ESI) m / z 458 [M+H].

[0401] Step 4: 7-Chloro-1-({4-[1-methyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)-2H,4H-pyrido[3,4-b]pyrazin-3-one A solution of 2-chloro-N-{6-chloro-4-[({4-[1-methyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)amino]pyridin-3-yl}acetamide (100 mg, 0.218 mmol, 1 equiv) and K2CO3 (60 mg, 0.434 mmol, 1.99 equiv) in DMF (5 mL) was stirred at 80 °C for 2 h under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (C18 silica gel column, eluted with 0% - 100% MeCN / water (0.1% FA) for 10 min using a UV detector (254 nm)) to give 7-chloro-1-({4-[1-methyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)-2H,4H-pyrido[3,4-b]pyrazin-3-one (30 mg, 32.59%) as an off-white solid. LC-MS (ESI) m / z 422 [M+H].

[0402] Step 5. Synthesis of 4-cyclopropyl-5-[1-({4-[1-ethyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)pyrazolo[4,3-c]pyridin-6-yl]-6-methoxypyrimidine A solution of 2-[4-({6-chloropyrazolo[4,3-c]pyridin-1-yl}methyl)phenyl]-1-ethyl-4-(trifluoromethyl)imidazole (70 mg, 0.172 mmol, 1 equiv), 4-cyclopropyl-6-methoxypyrimidin-5-ylboronic acid (38 mg, 0.196 mmol, 1.14 equiv), and Pd(dppf)Cl2 (20 mg, 0.027 mmol, 0.16 equiv) in H2O (1 mL) and dioxane (4 mL) was stirred at 90 °C for 2 h under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (C18 silica gel column, eluted with 0% - 100% MeCN / H2O (0.1% FA) for 10 min using a UV detector (254 nm)) to obtain 4-cyclopropyl-5-[1-({4-[1-ethyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)pyrazolo[4,3-c]pyridin-6-yl]-6-methoxypyrimidine (8 mg, 8.63%) as an off-white solid. 1 1H NMR: 1H NMR(400 MHz, DMSO-d6) δ 10.75(s, 1H), 8.55(s, 1H), 7.94(d, J = 8.8 Hz, 2H), 7.70(d, J = 8.0 Hz, 2H), 7.45(d, J = 7.9 Hz, 2H), 6.82(s, 1H), 4.63(s, 2H), 4.05(s, 2H), 3.76(d, J = 10.6 Hz, 6H), 1.80(s, 1H), 1.24(s, 1H), 0.94(s, 2H), 0.79(d, J = 7.7 Hz, 2H). LC-MS(ESI) m / z 536.15[M + H].

[0403] I-13

Chemical Structure

[0404] Step 2: 6-Chloro-N4-({4-[1-methyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)pyridine-3,4-diamine To a stirred solution of 2-chloro-N-({4-[1-methyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)-5-nitropyridin-4-amine (150 mg, 0.364 mmol, 1 equiv) and NH4Cl (97.43 mg, 1.820 mmol, 5 equiv) in ethanol (2.5 mL) and water (0.6 mL), Fe (122.06 mg, 2.184 mmol, 6 equiv) was added at room temperature. The resulting mixture was stirred at 40 °C for 2 h. The resulting mixture was filtered and the filter cake was washed with ethanol (3 × 10 mL). The filtrate was concentrated under reduced pressure. The crude product was used directly in the next step without further purification. LC-MS (ESI) m / z 382.7 [M+H].

[0405] Step 3: 7-Chloro-1-({4-[1-methyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)pyrido[3,4-b]pyrazin-2-one A stirred solution of 6-chloro-N4-({4-[1-methyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)pyridine-3,4-diamine (130 mg, 0.341 mmol, 1 equiv) and ethyl glyoxylate (104.28 mg, 1.023 mmol, 3 equiv) in MeOH (2 mL) was added dropwise with AcOH (0.1 mL) at room temperature. The resulting mixture was stirred at 100 °C for 2 h and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (C18 silica gel column, eluting with 10%–100% MeCN / H2O (0.1% FA) for 10 min using a UV detector (254 nm)) to afford 7-chloro-1-({4-[1-methyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)pyrido[3,4-b]pyrazin-2-one (60 mg, 41.9%) as a yellowish brown solid. LC-MS (ESI) m / z 420.7 [M+H].

[0406] Step 4: 7-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-1-({4-[1-methyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)pyrido[3,4-b]pyrazin-2-one A stirred solution of 7-chloro-1-({4-[1-methyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)pyrido[3,4-b]pyrazin-2-one (60 mg, 0.143 mmol, 1 equiv) and 4-cyclopropyl-6-methoxypyrimidin-5-ylboronic acid (41.59 mg, 0.214 mmol, 1.5 equiv) in 1,4-dioxane (2 mL) and H2O (0.4 mL) was added with Pd(dppf)Cl2 (20.92 mg, 0.029 mmol, 0.2 equiv) and K3PO4 (75.85 mg, 0.357 mmol, 2.50 equiv) at room temperature. The resulting mixture was stirred at 90 °C for 2 h. The resulting mixture was filtered and the filter cake was washed with 1,4-dioxane (2 × 10 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by reverse-phase flash chromatography (C18 silica gel column, eluting with 0% to 100% MeCN / H2O (0.1% FA) for 10 min using a UV detector (254 nm)) to give 7-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-({4-[1-methyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)pyrido[3,4-b]pyrazin-2-one (7.7 mg, 9.88%) as a yellowish brown solid. 1 1H NMR (300 MHz, DMSO-d6) δ 9.12 (s, 1H), 8.65 (s, 1H), 8.46 (s, 1H), 7.93 (s, 1H), 7.75 (s, 1H), 7.69 (d, J = 8.1 Hz, 2H), 7.47 (d, J = 8.1 Hz, 2H), 5.52 (s, 2H), 3.73 (d, J = 12.9 Hz, 6H), 1.81 - 1.62 (m, 1H), 0.99 (d, J = 4.1 Hz, 2H), 0.78 (dd, J = 8.1, 3.3 Hz, 2H). LC-MS (ESI) m / z 534.2 [M + H].

[0407] I-14

Chemical Structure

[0408] I-15

Chem.

[0409] I-16

Chem.

[0410] Step 2: 2-Bromo-1-methyl-4-(trifluoromethyl)imidazole A solution of 1-methyl-4-(trifluoromethyl)imidazole (100 mg, 0.666 mmol, 1 equiv) in THF (10 mL) was treated with n-BuLi (76.82 mg, 1.199 mmol, 1.8 equiv) at -78 °C for 30 min under a nitrogen atmosphere, followed by the dropwise addition of CBr4 (441.86 mg, 1.332 mmol, 2 equiv) at -78 °C. The resulting mixture was stirred at room temperature for 2 h under a nitrogen atmosphere. The mixture was acidified to pH 5 with 1M HCl (5 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (C18 silica gel column, eluted with 0% - 100% MeCN / water (0.1% FA) for 10 min using a UV detector (254 nm)) to obtain 2-bromo-1-methyl-4-(trifluoromethyl)imidazole (50 mg, 32.77%) as a colorless oil. LC-MS (ESI) m / z 229 [M+H].

[0411] Step 3: {1-[1-Methyl-4-(trifluoromethyl)imidazol-2-yl]piperidin-4-yl}methanol To a stirred solution of 2-bromo-1-methyl-4-(trifluoromethyl)imidazole (50 mg, 0.233 mmol, 1 equiv) and piperidin-4-ylmethanol (80.37 mg, 0.699 mmol, 3 equiv) in n-BuOH (2 mL, 21.880 mmol, 94.07 equiv) was added DIEA (90.18 mg, 0.699 mmol, 3 equiv) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 160 °C overnight under a nitrogen atmosphere. The residue was purified by reverse-phase flash chromatography (C18 silica gel column, eluting with 0% - 100% MeCN / water (0.1% FA) for 10 min using a UV detector (254 nm)) to give {1-[1-Methyl-4-(trifluoromethyl)imidazol-2-yl]piperidin-4-yl}methanol (50 mg, 81.66%) as a yellow oil. LC-MS (ESI) m / z 263 [M+H].

[0412] Step 4: 4-(Chloromethyl)-1-[1-methyl-4-(trifluoromethyl)imidazol-2-yl]piperidine To a stirred solution of {1-[1-Methyl-4-(trifluoromethyl)imidazol-2-yl]piperidin-4-yl}methanol (180 mg, 0.684 mmol, 1 equiv) and pyridine (0.1 mL, 0.001 mmol, 0.01 equiv) in DCM (3 mL) was added thionyl chloride (0.5 mL, 0.004 mmol, 0.01 equiv) at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at 40 °C overnight under a nitrogen atmosphere. The reaction was quenched with water (20 mL) at room temperature. The residue was purified by reverse-phase flash chromatography (C18 silica gel column, eluting with 0% - 100% MeCN / water (0.1% FA) for 10 min using a UV detector (254 nm)) to give 4-(chloromethyl)-1-[1-methyl-4-(trifluoromethyl)imidazol-2-yl]piperidine (85 mg, 44.13%) as a yellow solid. LC-MS (ESI) m / z 282 [M+H].

[0413] Step 5: 2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-8-({1-[1-methyl-4-(trifluoromethyl)imidazol-2-yl]piperidin-4-yl}methyl)pyrido[2,3-d]pyrimidin-7-one A solution of 4-(chloromethyl)-1-[1-methyl-4-(trifluoromethyl)imidazol-2-yl]piperidine (70 mg, 0.248 mmol, 1 equiv), 1,1,3,3-tetramethylguanidine (42.93 mg, 0.372 mmol, 1.5 equiv), and 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8H-pyrido[2,3-d]pyrimidin-7-one (73.38 mg, 0.248 mmol, 1 equiv) in DMF (27.24 mg, 0.372 mmol, 1.5 equiv) was stirred at 100 °C overnight under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (C18 silica gel column, eluted with 0% - 100% MeCN / H2O (0.1% FA) for 10 min using a UV detector (254 nm)) to give 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-({1-[1-methyl-4-(trifluoromethyl)imidazol-2-yl]piperidin-4-yl}methyl)pyrido[2,3-d]pyrimidin-7-one (12.3 mg, 9.08%) as an off-white solid. 1 H-NMR: 1 H NMR (400 MHz, DMSO-d6) δ 9.24 (s, 1H), 8.71 (s, 1H), 8.10 (d, J = 9.5 Hz, 1H), 7.51 (s, 1H), 6.85 (d, J = 9.5 Hz, 1H), 4.29 (d, J = 7.2 Hz, 2H), 3.87 (s, 3H), 3.46 (s, 3H), 3.22 (d, J = 12.2 Hz, 3H), 2.62 (t, J = 11.8 Hz, 2H), 2.06 (d, J = 16.2 Hz, 1H), 1.80 (td, J = 8.3, 4.4 Hz, 1H), 1.59 (d, J = 12.7 Hz, 2H), 1.53 - 1.36 (m, 2H), 1.13 - 1.07 (m, 2H), 0.91 (dq, J = 7.0, 3.4 Hz, 2H). LC-MS (ESI) m / z 541.10 [M+H].

[0414] I-17

Chem.

[0415] Step 2: 2-Chloro-N4-({4-[1-methyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)pyrimidine-4,5-diamine A stirred solution of 2-chloro-N-({4-[1-methyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)-5-nitropyrimidin-4-amine (50 mg, 0.121 mmol, 1 equiv) and NH4Cl (32.40 mg, 0.605 mmol, 5 equiv) in ethanol (0.8 mL) and water (0.2 mL) was added Fe (54.12 mg, 0.968 mmol, 8 equiv) at room temperature. The resulting mixture was stirred at 40 °C for 2 h. The resulting mixture was filtered and the filter cake was washed with ethanol (3 × 10 mL). The filtrate was concentrated under reduced pressure. The crude product was used directly in the next step without further purification. LC-MS (ESI) m / z 383.7 [M+H].

[0416] Step 3: 7-chloro-1-({4-[1-methyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)pyrido[3,4-b]pyrazin-2-one To a stirred solution of 2-chloro-N4-({4-[1-methyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)pyrimidine-4,5-diamine (150 mg, 0.392 mmol, 1 equiv) and ethyl glyoxylate (120.02 mg, 1.176 mmol, 3 equiv) in MeOH (2 mL) was added AcOH (20.45 mg, 0.341 mmol, 1 equiv) dropwise at room temperature. The resulting mixture was stirred at 100 °C for 2 h and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (C18 silica gel column, eluting with 0% - 100% MeCN / water (0.1% FA) for 10 min using a UV detector (254 nm)) to afford 7-chloro-1-({4-[1-methyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)pyrido[3,4-b]pyrazin-2-one (40 mg, 24.3%) as a yellow oil. LC-MS (ESI) m / z 420.7 [M+H].

[0417] Step 4: 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-({4-[1-methyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)pteridin-7-one To a stirred solution of 2-chloro-8-({4-[1-methyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)pteridin-7-one (50 mg, 0.119 mmol, 1 equiv) and 4-cyclopropyl-6-hydroxypyrimidin-5-ylboronic acid (32.08 mg, 0.178 mmol, 1.5 equiv) in 1,4-dioxane (0.4 mL) and H2O (0.1 mL), K3PO4 (63.06 mg, 0.297 mmol, 2.5 equiv) and Pd(dppf)Cl2 (17.39 mg, 0.024 mmol, 0.2 equiv) were added at room temperature. The resulting mixture was stirred at 90 °C for 2 h under a nitrogen atmosphere. The resulting mixture was filtered and the filter cake was washed with 1,4-dioxane (3 × 5 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (C18 silica gel column, eluting with 0% - 100% MeCN / H2O (0.1% FA) for 10 min using a UV detector (254 nm)) to give 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-({4-[1-methyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)pteridin-7-one (16.1 mg, 23.35%) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 9.37 (d, J = 1.5 Hz, 1H), 8.70 (s, 1H), 8.48 (s, 1H), 7.92 (s, 1H), 7.69 - 7.57 (m, 2H), 7.48 (d, J = 8.0 Hz, 2H), 5.49 (s, 2H), 3.79 (dd, J = 40.2, 1.4 Hz, 6H), 1.76 (m, 1H), 1.03 (m, 2H), 0.78 (m, 2H). LC-MS (ESI) m / z 535.1 [M+H].

[0418] I-18

Chemical Structure

[0419] Step 2: 2-chloro-N4-({4-[1-methyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)pyrimidine-4,5-diamine A solution of 2-chloro-N-({4-[1-methyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)-5-nitropyrimidin-4-amine (375 mg, 0.909 mmol, 1 equiv), iron (400 mg, 7.163 mmol, 7.88 equiv), NH4Cl (240 mg, 4.487 mmol, 4.94 equiv), and H2O (1 mL, 55.509 mmol, 61.10 equiv) in EtOH (4 mL) was stirred at 40 °C for 2 h under a nitrogen atmosphere. The resulting mixture was filtered and the filter cake was washed with MeOH (2×10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with PE / EA (1:1)) to give 2-chloro-N4-({4-[1-methyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)pyrimidine-4,5-diamine (175 mg, 50.32%) as a yellow solid. LC-MS (ESI) m / z 383 [M+H].

[0420] Step 3: 2-Chloro-N-{2-chloro-4-[({4-[1-methyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)amino]pyrimidin-5-yl}acetamide A solution of 2-chloro-N4-({4-[1-methyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)pyrimidine-4,5-diamine (200 mg, 0.522 mmol, 1 equiv) in DCM (2 mL, 31.461 mmol, 60.21 equiv) was treated with TEA (1.4 mL, 10.072 mmol, 19.28 equiv) at 0 °C for 5 min under a nitrogen atmosphere, followed by the dropwise addition of chloroacetyl chloride (150 mg, 1.328 mmol, 2.54 equiv) at 0 °C. The resulting mixture was stirred at room temperature for 2 h under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (C18 silica gel column, eluted with 0% to 100% MeCN / H2O (0.1% FA) for 10 min using a UV detector (254 nm)) to give 2-chloro-N-{2-chloro-4-[({4-[1-methyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)amino]pyrimidin-5-yl}acetamide (100 mg, 41.67%) as a colorless oil. LC-MS (ESI) m / z 459 [M+H].

[0421] Step 4: 2-Chloro-8-({4-[1-methyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)-5,7-dihydropteridin-6-one A solution of 2-chloro-N-{2-chloro-4-[({4-[1-methyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)amino]pyrimidin-5-yl}acetamide (130 mg, 0.283 mmol, 1 eq) and K2CO3 (78.24 mg, 0.566 mmol, 2 eq) in DMF (10 mL, 129.215 mmol, 456.48 eq) was stirred at 80 °C for 2 h under a nitrogen atmosphere. The mixture was cooled to room temperature. The residue was purified by reverse-phase flash chromatography (C18 silica gel column, eluted with 0% - 100% MeCN / H2O (0.1% FA) for 10 min using a UV detector (254 nm)) to give 2-chloro-8-({4-[1-methyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)-5,7-dihydropteridin-6-one (23 mg, 19.22%) as an off-white solid. LC-MS (ESI) m / z 423 [M+H].

[0422] Step 5: 2-chloro-8-({4-[1-methyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)-6,7-dihydro-5H-pteridine A solution of 2-chloro-8-({4-[1-methyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)-5,7-dihydropteridin-6-one (20 mg, 0.047 mmol, 1 eq) and BH3-THF (1.4 mL, 14.629 mmol, 309.25 eq) in THF (2 mL, 24.686 mmol, 521.85 eq) was stirred at 65 °C for 2 h under a nitrogen atmosphere. The reaction was quenched by adding MeOH (4 mL) at 0 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (C18 silica gel column, eluted with 0% - 100% MeCN / H2O (0.1% FA) for 10 min using a UV detector (254 nm)) to give 2-chloro-8-({4-[1-methyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)-6,7-dihydro-5H-pteridine (10 mg, 51.71%) as a colorless solid. LC-MS (ESI) m / z 409 [M+H].

[0423] Step 6: 2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-8-({4-[1-methyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)-6,7-dihydro-5H-pteridine A solution of 2-chloro-8-({4-[1-methyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)-6,7-dihydro-5H-pteridine (50 mg, 0.122 mmol, 1 equiv), 4-cyclopropyl-6-methoxypyrimidin-5-ylboronic acid (28.47 mg, 0.146 mmol, 1.2 equiv), Pd(dppf)Cl2 (17.90 mg, 0.024 mmol, 0.2 equiv), H2O (1 mL, 55.509 mmol, 453.86 equiv), and K3PO4 (38.94 mg, 0.183 mmol, 1.5 equiv) in dioxane (4 mL) was stirred at 90 °C for 2 h under a nitrogen atmosphere. The mixture was cooled to room temperature. The residue was purified by reverse-phase flash chromatography (C18 silica gel column, eluting with 0% - 100% MeCN / water (0.1% FA) for 10 min using a UV detector (254 nm)) to give 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-({4-[1-methyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)-6,7-dihydro-5H-pteridine (1.7 mg, 2.47%) as an off-white solid. LC-MS (ESI) m / z 523 [M+H]

[0424] I-19

Chemical Structure

[0425] I-20 I-20 was synthesized in the same manner as I-1

Chemical Structure

[0426] 1 1H NMR: (300 MHz, DMSO-d6) δ 9.31 (s, 1H), 8.70 (s, 1H), 8.48 (s, 1H), 8.22 - 8.12 (m, 1H), 7.45 (q, J = 8.3 Hz, 4H), 6.91 (d, J = 9.5 Hz, 1H), 5.58 (s, 2H), 5.05 (t, J = 7.3 Hz, 1H), 4.03 (d, J = 8.5 Hz, 2H), 3.94 (s, 1H), 3.84 (s, 3H), 2.63 (s, 3H), 1.73 (td, J = 7.9, 4.1 Hz, 1H), 1.02 (q, J = 3.3 Hz, 2H), 0.83 - 0.72 (m, 2H). LC-MS (ESI) m / z 589.05 [M + H].

[0427] I-21

Chemical Structure

[0428] Step 2: {4-[1-Cyclopropyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methanol A stirred solution of methyl 4-[1-cyclopropyl-4-(trifluoromethyl)imidazol-2-yl]benzoate (160 mg, 0.516 mmol, 1 equiv) in THF (5 mL) was added dropwise with diisobutylaluminum hydride (2.58 mL, 2.580 mmol, 5 equiv, 1 M in hexane) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred for 1 h at room temperature under a nitrogen atmosphere. The reaction was quenched with saturated NH4Cl (aqueous solution) at room temperature. The resulting mixture was filtered and the filter cake was washed with water (3 × 10 mL). The aqueous layer was extracted with EtOAc (3 × 10 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (C18 silica gel column, eluted with 10% - 50% MeCN / water (10 mmol / L NH4HCO3) for 10 min using a UV detector (254 nm)) to give {4-[1-cyclopropyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methanol (120 mg, 82.44%) as a brown oil. LC-MS (ESI) m / z 283.10 [M+H].

[0429] Step 3: 2-[4-(Chloromethyl)phenyl]-1-cyclopropyl-4-(trifluoromethyl)imidazole A stirred solution of {4-[1-cyclopropyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methanol (120 mg, 0.425 mmol, 1 equiv) in DCE (5 mL) was added dropwise with thionyl chloride (252.87 mg, 2.125 mmol, 5 equiv) at room temperature. The resulting mixture was stirred at 50 °C for 20 min under a nitrogen atmosphere. The resulting mixture was diluted with DCM (10 mL). The resulting mixture was washed with water (3 × 10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 2-[4-(chloromethyl)phenyl]-1-cyclopropyl-4-(trifluoromethyl)imidazole (110 mg, 86.04%) as a brown oil. LC-MS (ESI) m / z 301.06 [M+H].

[0430] Step 4: Synthesis of 8-({4-[1-Cyclopropyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)-2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)pyrido[2,3-d]pyrimidin-7-one A mixture of 2-[4-(Chloromethyl)phenyl]-1-cyclopropyl-4-(trifluoromethyl)imidazole (28 mg, 0.093 mmol, 1 equiv), 2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-8H-pyrido[2,3-d]pyrimidin-7-one (27.50 mg, 0.093 mmol, 1 equiv), and 1,1,3,3-Tetramethylguanidine (16.09 mg, 0.140 mmol, 1.5 equiv) in DMF (2 mL) was stirred at room temperature overnight under a nitrogen atmosphere. The crude product was purified by reverse-phase flash chromatography (C18 silica gel column, eluted with 10% - 50% MeCN / H2O (10 mmol / L NH4HCO3) for 10 minutes using a UV detector (254 nm)) to give 8-({4-[1-Cyclopropyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)-2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)pyrido[2,3-d]pyrimidin-7-one (10 mg, 18.48%) as an off-white solid. 1 H NMR: (400 MHz, DMSO-d6) δ 9.29 (d, J = 2.6 Hz, 1H), 8.69 (s, 1H), 8.16 (dd, J = 9.5, 2.6 Hz, 1H), 7.91 (d, J = 1.4 Hz, 1H), 7.84 - 7.78 (m, 2H), 7.39 (d, J = 8.0 Hz, 2H), 6.91 (dd, J = 9.5, 3.5 Hz, 1H), 5.57 (s, 2H), 3.85 - 3.79 (m, 3H), 3.70 (d, J = 4.5 Hz, 1H), 1.73 (dd, J = 8.2, 4.0 Hz, 1H), 1.07 - 0.83 (m, 6H), 0.76 (dt, J = 7.1, 3.5 Hz, 2H). LC-MS (ESI) m / z 560.10 [M + H].

[0431] I-22

Chemical Structure

[0432] Step 2: 2-(4-Bromo-2-fluoro-6-methoxyphenyl)-1-isopropyl-4-(trifluoromethyl)imidazole To 2-(4-bromo-2-fluoro-6-methoxyphenyl)-4-(trifluoromethyl)-1H-imidazole (90 mg, 0.265 mmol, 1 equiv) in stirred dimethylformamide (1 mL, 20 equiv), caesio methaneperoxoate caesium (173.49 mg, 0.530 mmol, 2 equiv) and 2-iodopropane (135.36 mg, 0.795 mmol, 3 equiv) were added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 65 °C for 3 h under a nitrogen atmosphere. The resulting mixture was filtered and the filter cake was washed with THF (3 × 5 mL). The filtrate was concentrated under reduced pressure. The residue was dissolved in THF (2 mL). The residue was purified by reverse-phase flash chromatography (C18 silica gel column, eluting with 0% - 100% MeCN / H2O (0.1% FA) for 10 min using a UV detector (254 nm)) to afford 2-(4-bromo-2-fluoro-6-methoxyphenyl)-1-isopropyl-4-(trifluoromethyl)imidazole (70 mg, 69.19%) as a yellow solid. LC-MS (ESI) m / z 383.1 [M+H]

[0433] Step 3: Methyl 3-fluoro-4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]-5-methoxybenzoate To 2-(4-bromo-2-fluoro-6-methoxyphenyl)-1-isopropyl-4-(trifluoromethyl)imidazole (100 mg, 0.262 mmol, 1 equiv) in stirred MeOH (8 mL, 197.591 mmol), Pd(dppf)Cl2 (35 mg, 0.048 mmol, 0.18 equiv) and TEA (1 mL, 7.194 mmol, 27.42 equiv) were added under a carbon monoxide atmosphere at room temperature. The resulting mixture was stirred at 90 °C overnight under a carbon monoxide atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in THF (2 mL). The residue was purified by reverse-phase flash chromatography (C18 silica gel column, eluting with 0% to 100% MeCN / water (0.1% FA) for 10 min using a UV detector (254 nm)) to give methyl 3-fluoro-4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]-5-methoxybenzoate (70 mg, 74.05%) as a yellow solid. LC-MS (ESI) m / z 361.1 [M+H]

[0434] Step 4: {3-Fluoro-4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]-5-methoxyphenyl}methanol A stirred mixture of methyl 3-fluoro-4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-5-methoxybenzoate (70 mg, 0.202 mmol, 1 equiv) in THF (3 mL, 37.028 mmol, 190.59 equiv) was treated portionwise with LiAlH4 (22.12 mg, 0.582 mmol, 3.0 equiv) at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at 0 °C for 1 h under a nitrogen atmosphere. The reaction was quenched with 10 H2O.Na2SO4 at 0 °C. The resulting mixture was filtered and the filter cake was washed with THF (2 × 2 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (C18 silica gel column, eluting with 0% to 100% MeCN / H2O (0.1% FA) for 10 min using a UV detector (254 nm)) to afford {3-fluoro-4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]-5-methoxyphenyl}methanol (50 mg, 77.45%) as a brown solid. LC-MS (ESI) m / z 333.1 [M+H]

[0435] Step 5: 2-[4-(Chloromethyl)-2-fluoro-6-methoxyphenyl]-1-methyl-4-(trifluoromethyl)imidazole {3-Fluoro-4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]-5-methoxyphenyl}methanol (100 mg, 0.301 mmol, 1 equiv) in stirred DCM (2 mL, 0.024 mmol) was added SOCl2 (107.5 mg, 0.904 mmol, 3.00 equiv) at 50 °C under a nitrogen atmosphere. The resulting mixture was stirred at 50 °C for 30 min under a nitrogen atmosphere. The reaction was quenched with water / ice at 0 °C. The resulting mixture was extracted with CH2Cl2 (3 × 5 mL). The combined organic layers were washed with brine (3 × 5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 2-[4-(chloromethyl)-2-fluoro-6-methoxyphenyl]-1-methyl-4-(trifluoromethyl)imidazole (110 mg, 113.28%) as a brown solid. The crude product was used directly in the next step without further purification. LC-MS (ESI) m / z 351.1 [M+H]

[0436] Step 6: 2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-8-({3-fluoro-4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]-5-methoxyphenyl}methyl)pyrido[2,3-d]pyrimidin-7-one A solution of 2-[4-(chloromethyl)-2-fluoro-6-methoxyphenyl]-1-isopropyl-4-(trifluoromethyl)imidazole (21.3 mg, 0.061 mmol, 1 equiv), 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8H-pyrido[2,3-d]pyrimidin-7-one (17.93 mg, 0.061 mmol, 1 equiv), and 1,1,3,3-tetramethylguanidine (10.49 mg, 0.091 mmol, 1.5 equiv) in DMF (2 mL, 25.843 mmol, 425.55 equiv) was stirred at room temperature overnight under a nitrogen atmosphere. The crude product was purified by preparative HPLC under the following conditions (column: Xselect CSH F-Phenyl OBD column, 19*250 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: MeOH--HPLC; flow rate: 25 mL / min; gradient: 60% B to 80% B in 8 min, 80% B; wavelength: 220 nm; RT1 (min): 7.56;) to give 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-({3-fluoro-4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]-5-methoxyphenyl}methyl)pyrido[2,3-d]pyrimidin-7-one (9 mg, 23.41%) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6) δ 9.30 (s, 1H), 8.69 (s, 1H), 8.18 (t, J = 4.8 Hz, 2H), 7.04 (s, 1H), 6.92 (d, J = 9.5 Hz, 1H), 6.72 (d, J = 9.6 Hz, 1H), 5.56 (s, 2H), 3.91 (p, J = 6.9 Hz, 1H), 3.82 (s, 3H), 3.69 (s, 3H), 1.75 (dq, J = 8.7, 5.2, 4.4 Hz, 1H), 1.35 (d, J = 6.7 Hz, 3H), 1.23 (d, J = 6.7 Hz, 3H), 1.02 (d, J = 4.6 Hz, 2H), 0.77 (d, J = 7.5 Hz, 2H). LC-MS (ESI) m / z 610.05 [M+H].

[0437] I-23

Chemical Structure

[0438] Step 2: 2-(4-Bromo-2-fluoro-3-methoxycyclohexyl)-1-isopropyl-4-(trifluoromethyl)imidazolidine To a stirred mixture of 2-(4-bromo-2-fluoro-3-methoxycyclohexyl)-4-(trifluoromethyl)imidazolidine (880 mg, 2.520 mmol, 1 equiv) and Cs2CO3 (1642.31 mg, 5.040 mmol, 2 equiv) in DMF (4 mL), 2-iodopropane (1285.29 mg, 7.560 mmol, 3 equiv) was added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 65 °C for 2 h. The resulting mixture was filtered and the filter cake was washed with MeCN (1 × 1 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (C18 silica gel column, eluting with 10% - 50% MeCN / water (10 mmol / L NH4HCO3) for 10 min using a UV detector (254 nm)) to give 2-(4-bromo-2-fluoro-3-methoxycyclohexyl)-1-isopropyl-4-(trifluoromethyl)imidazolidine (880 mg, 89.24%) as a yellow solid. LC-MS (ESI) m / z 381 [M+H]

[0439] Step 3: Methyl 3-fluoro-4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]-2-methoxybenzoate A stirred mixture of 2-(4-chloro-2-fluoro-3-methoxyphenyl)-1-isopropyl-4-(trifluoromethyl)imidazole (860 mg, 2.554 mmol, 1 equiv) and TEA (1550.76 mg, 15.324 mmol, 6 equiv) in MeOH (16.00 mL, 395.181 mmol, 154.72 equiv) was added with Pd(dppf)Cl2 (186.89 mg, 0.255 mmol, 0.1 equiv) at room temperature under a carbon monoxide atmosphere. The resulting mixture was stirred at 90 °C for 12 h. The resulting mixture was filtered and the filter cake was washed with MeOH (3 × 4 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (C18 silica gel column, eluting with 10% - 50% MeCN / water (10 mmol / L NH4HCO3) for 10 min using a UV detector (254 nm)) to give methyl 3-fluoro-4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]-2-methoxybenzoate (600 mg, 65.20%) as a yellow oil. LC-MS (ESI) m / z 361 [M+H]

[0440] Step 4: {3-Fluoro-4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]-2-methoxyphenyl}methanol To a stirred mixture of methyl 3-fluoro-4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]-2-methoxybenzoate (600 mg, 1.665 mmol, 1 equiv) in THF (8.82 mL, 108.891 mmol, 65.40 equiv) was added LiAlH4 (189.59 mg, 4.995 mmol, 3 equiv) portionwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 h. The reaction was quenched with 10 H2O.Na2SO4 at 0 °C. The resulting mixture was filtered and the filter cake was washed with THF (2 × 2 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with PE / EA (1:1)) to give {3-fluoro-4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]-2-methoxyphenyl}methanol (320 mg, 57.83%) as a white oil. LC-MS (ESI) m / z 333 [M+H]

[0441] Step 5: 2-[4-(Chloromethyl)-2-fluoro-3-methoxyphenyl]-1-isopropyl-4-(trifluoromethyl)imidazole To a stirred mixture of {3-fluoro-4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]-2-methoxyphenyl}methanol (30 mg, 0.090 mmol, 1 equiv) in DCM (1 mL, 15.731 mmol, 174.24 equiv) was added SOCl2 (0.02 mL, 0.270 mmol, 3 equiv) at room temperature under a nitrogen atmosphere. The reaction was quenched with saturated NaHCO3 (aqueous solution) and extracted with CH2Cl2 (3 × mL). The combined organic layers were washed with water (2 × 2 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was used directly in the next step without further purification. LC-MS (ESI) m / z 351 [M+H]

[0442] Step 6: 2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-8-({3-fluoro-4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]-2-methoxyphenyl}methyl)pyrido[2,3-d]pyrimidin-7-one To a stirred mixture of 2-[4-(chloromethyl)-2-fluoro-3-methoxyphenyl]-1-isopropyl-4-(trifluoromethyl)imidazole (40 mg, 0.114 mmol, 0.9 eq) and 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8H-pyrido[2,3-d]pyrimidin-7-one (37.42 mg, 0.127 mmol, 1 eq) in DMF (4.44 mL, 57.407 mmol, 453.21 eq), 1,1,3,3-tetramethylguanidine (21.89 mg, 0.190 mmol, 1.5 eq) was added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (C18 silica gel column, eluting with 0% - 100% MeCN / H2O (0.1% FA) for 10 min using a UV detector (254 nm)) to give 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-({3-fluoro-4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]-2-methoxyphenyl}methyl)pyrido[2,3-d]pyrimidin-7-one (20 mg, 25.89%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 9.31 (s, 1H), 8.66 (s, 1H), 8.25 - 8.16 (m, 2H), 7.08 (t, J = 7.3 Hz, 1H), 6.93 (d, J = 9.6 Hz, 1H), 6.70 (d, J = 8.1 Hz, 1H), 5.59 (s, 2H), 4.17 - 4.09 (m, 1H), 3.89 (s, 3H), 3.78 (s, 3H), 1.74 - 1.67 (m, 1H), 1.35 (d, J = 6.6 Hz, 6H), 1.01 - 0.95 (m, 2H), 0.70 (dd, J = 7.9, 3.4 Hz, 2H). LC-MS (ESI) m / z 610.25 [M + H]

[0443] I-24 [Chemistry] Step 1: 2-Chloro-4-[({4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)amino]pyrimidine-5-carbonitrile To a stirred solution of 2,4-dichloropyrimidine-5-carbonitrile (1.7 g, 9.771 mmol, 1 equiv) and 1-{4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methanamine (2.77 g, 9.771 mmol, 1 equiv) in THF (20 mL) was added dropwise TEA (1.98 g, 19.542 mmol, 2 equiv) at room temperature. The resulting mixture was stirred at room temperature for 2 h under a nitrogen atmosphere. The residue was purified by reverse-phase flash chromatography (C18 silica gel column, eluting with 0% - 100% MeCN / water (0.1% FA) for 10 min using a UV detector (254 nm)) to give 2-chloro-4-[({4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)amino]pyrimidine-5-carbonitrile (900 mg, 21.89%) as an off-white solid. LC-MS (ESI) m / z 421.8 [M+H]

[0444] Step 2: 4’-Cyclopropyl-4-[({4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)amino]-6’-methoxy-[2,5’-bipyrimidine]-5-carbonitrile A stirred solution of 2-chloro-4-[({4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)amino]pyrimidine-5-carbonitrile (438 mg, 1.041 mmol, 1 equiv), 4-cyclopropyl-6-methoxypyrimidin-5-ylboronic acid (302.88 mg, 1.561 mmol, 1.5 equiv) in H2O (0.5 mL) and dioxane (5 mL) was added with K3PO4 (552.33 mg, 2.603 mmol, 2.5 equiv) and Pd(dppf)Cl2 (152.32 mg, 0.208 mmol, 0.2 equiv) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 90 °C for 2 h under a nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with THF (3 × 5 mL), and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (C18 silica gel column, eluting with 0% - 100% MeCN / H2O (0.1% FA) for 10 min using a UV detector (254 nm)) to give 4’-cyclopropyl-4-[({4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)amino]-6’-methoxy-[2,5’-bipyrimidine]-5-carbonitrile (422.4 mg, 75.92%) as a pale yellow solid. LC-MS (ESI) m / z 535.5 [M+H]

[0445] Step 3 5-(Aminomethyl)-4’-cyclopropyl-N-({4-[4-(difluoromethyl)-1-isopropylimidazol-2-yl]phenyl}methyl)-6’-methoxy-[2,5’-bipyrimidine]-4-amine To a stirred solution of 4'-cyclopropyl-4-[({4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)amino]-6'-methoxy-[2,5'-bipyrimidine]-5-carbonitrile (422.4 mg, 0.790 mmol, 1 equiv) in THF (5 mL) was added LiAlH4 (89.96 mg, 2.370 mmol, 3 equiv) at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at 0 °C for 1 h under a nitrogen atmosphere. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EA (3 × 10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (C18 silica gel column, eluting with 10% - 50% MeCN / water (0.1% FA) for 10 min using a UV detector (254 nm)) to give 5-(aminomethyl)-4'-cyclopropyl-N-({4-[4-(difluoromethyl)-1-isopropylimidazol-2-yl]phenyl}methyl)-6'-methoxy-[2,5'-bipyrimidine]-4-amine (161.5 mg, 39.26%) as a colorless oil. LC-MS (ESI) m / z 539.5 [M+H]

[0446] Step 4: 7-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-1-({4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)-3H,4H-pyrimido[4,5-d][1,3]diazin-2-one To a stirred solution of 5-(aminomethyl)-4'-cyclopropyl-N-({4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)-6'-methoxy-[2,5'-bipyrimidin]-4-amine (187 mg, 0.347 mmol, 1 equiv) in DMF (2 mL), NaH (16.66 mg, 0.694 mmol, 2 equiv) was added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred for 5 minutes at room temperature under a nitrogen atmosphere. To the above mixture, CDI (112.60 mg, 0.694 mmol, 2 equiv) was added at room temperature. The resulting mixture was stirred further overnight at room temperature. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EA (3 × 10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (C18 silica gel column, eluting with 0% - 100% MeCN / water (0.1% FA) for 10 minutes using a UV detector (254 nm)) to give 7-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-({4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)-3H,4H-pyrimido[4,5-d][1,3]diazin-2-one (11.7 mg, 5.89%) as an off-white solid. 1 H NMR: (400 MHz, DMSO-d6) δ 8.70 (s, 1H), 8.62 (s, 1H), 8.23 (s, 1H), 7.78 (s, 1H), 7.54 (d, J = 7.9 Hz, 2H), 7.46 (d, J = 7.9 Hz, 2H), 5.24 (s, 2H), 4.60 (s, 2H), 4.56 - 4.45 (m, 1H), 3.87 (s, 3H), 1.71 (s, 1H), 1.46 (d, J = 6.6 Hz, 6H), 1.02 (d, J = 4.5 Hz, 2H), 0.79 (dd, J = 8.0, 3.8 Hz, 2H). LC-MS (ESI) m / z 565.10 [M+H]

[0447] I-25

Chemical Structure

[0448] I-25

Chemical Structure

[0449] Step 2: 4-[1-Isopropyl-4-(trifluoromethyl)imidazol-2-yl]benzonitrile To a stirred solution of 4-[4-(trifluoromethyl)-1H-imidazol-2-yl]benzonitrile (5 g, 21.081 mmol, 1 equiv) in DMF (80 mL), Cs2CO3 (13.74 g, 42.162 mmol, 2 equiv) was added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred for 2 minutes at room temperature under a nitrogen atmosphere. To the above mixture, 2-iodopropane (10.75 g, 63.243 mmol, 3 equiv) was added dropwise at room temperature. The resulting mixture was stirred at 60 °C for an additional overnight. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EA (3 × 60 mL). The combined organic layers were washed with brine (3 × 60 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with PE / EA (5:1)), and 4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]benzonitrile (3.3 g, 56.05%) was obtained as a yellow solid. LC-MS (ESI) m / z 280.2 [M+H]

[0450] Step: 3 1-{4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methanamine To a stirred solution of 4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]benzonitrile (3.5 g, 12.533 mmol, 1 equiv) in EA (40 mL) and NH3H2O (20 mL), Raney Ni (3.96 g, 46.264 mmol, 3.4 equiv) was added at room temperature under an air atmosphere. The resulting mixture was stirred for 5 hours at room temperature under a hydrogen atmosphere. The resulting mixture was filtered, and the filter cake was washed with EA (3 × 20 mL) and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (using a C18 silica gel column and eluting with 0% - 100% MeCN / water (0.1% FA) for 10 minutes using a UV detector (254 nm)), and 1-{4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methanamine (3.3 g, 85.61%) was obtained as an off-white solid. 11H NMR (400 MHz, DMSO-d6) δ 8.44 (s, 1H), 8.19 (d, J = 1.4 Hz, 1H), 7.59 (s, 5H), 4.47 (p, J = 6.6 Hz, 1H), 4.02 (s, 2H), 1.41 (d, J = 6.7 Hz, 6H). LC-MS (ESI) m / z 284.2 [M+H]

[0451] Step 4: 2-Chloro-4-[({4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)amino]pyrimidine-5-carboxamide To a stirred solution of 2,4-dichloropyrimidine-5-carboxamide (638 mg, 3.323 mmol, 1 equiv) and 1-{4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methanamine (941.38 mg, 3.323 mmol, 1 equiv) in THF (5 mL), TEA (672.51 mg, 6.646 mmol, 2 equiv) was added dropwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 h under a nitrogen atmosphere. The residue was purified by reverse-phase flash chromatography (C18 silica gel column, eluting with 0% - 100% MeCN / water (0.1% FA) for 10 min using a UV detector (254 nm)) to give 2-chloro-4-[({4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)amino]pyrimidine-5-carboxamide (780 mg, 53.49%) as an off-white solid. LC-MS (ESI) m / z 439.8 [M+H]

[0452] Step 5: 4’-Cyclopropyl-4-[({4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)amino]-6’-methoxy-[2,5’-bipyrimidine]-5-carboxamide A stirred solution of 2-chloro-4-[({4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)amino]pyrimidine-5-carboxamide (400 mg, 0.911 mmol, 1 equiv) and 4-cyclopropyl-6-methoxypyrimidin-5-ylboronic acid (265.24 mg, 1.367 mmol, 1.5 equiv) in dioxane (4 mL) and H2O (0.5 mL) was added with K3PO4 (483.70 mg, 2.277 mmol, 2.5 equiv) and Pd(dppf)Cl2 (133.39 mg, 0.182 mmol, 0.2 equiv) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 90 °C for 2 h under a nitrogen atmosphere. The residue was purified by reverse-phase flash chromatography (C18 silica gel column, eluting with 10% - 50% MeCN / H2O (0.1% FA) for 10 min using a UV detector (254 nm)) to give 4'-cyclopropyl-4-[({4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)amino]-6'-methoxy-[2,5'-bipyrimidine]-5-carboxamide (485 mg, 96.30%) as a pale yellow solid. LC-MS (ESI) m / z 553.5 [M+H]

[0453] Step 6: 7-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-1-({4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)-3H-pyrimido[4,5-d][1,3]diazine-2,4-dione To a stirred solution of 4'-cyclopropyl-4-[({4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)amino]-6'-methoxy-[2,5'-bipyrimidine]-5-carboxamide (435 mg, 0.787 mmol, 1 equiv) in DMF (5 mL) was added NaH (37.78 mg, 1.574 mmol, 2 equiv) at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred for 5 min at room temperature under a nitrogen atmosphere. To the above mixture was added CDI (255.31 mg, 1.574 mmol, 2 equiv) at room temperature. The resulting mixture was stirred for an additional 2 h at room temperature. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EA (3 × 15 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (C18 silica gel column, eluting with 10% - 50% MeCN / water (0.1% FA) for 10 min using a UV detector (254 nm)) to afford 7-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-({4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)-3H-pyrimido[4,5-d][1,3]diazine-2,4-dione (370 mg, 81.24%) as an off-white solid. LC-MS (ESI) m / z 579.5 [M+H]

[0454] Step 7: 7-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-1-({4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)-3-methylpyrimido[4,5-d][1,3]diazine-2,4-dione A stirred solution of 7-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-({4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)-3H-pyrimido[4,5-d][1,3]diazine-2,4-dione (30 mg, 0.052 mmol, 1 equiv) in DMF (1 mL) was added with K2CO3 (14.33 mg, 0.104 mmol, 2 equiv) and MeI (14.72 mg, 0.104 mmol, 2 equiv) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The residue was purified by reverse-phase flash chromatography (C18 silica gel column, eluting with 10% - 50% MeCN / water (0.1% FA) for 10 min using a UV detector (254 nm)) to obtain 7-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-({4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)-3-methylpyrimido[4,5-d][1,3]diazine-2,4-dione (19.7 mg, 63.73%) as an off-white solid. 1 H NMR: (400 MHz, DMSO-d6) δ 9.37 (s, 1H), 8.69 (s, 1H), 8.17 (s, 1H), 7.50 (t, J = 6.4 Hz, 4H), 5.44 (s, 2H), 4.42 (p, J = 6.7 Hz, 1H), 3.83 (s, 3H), 3.34 (s, 3H), 1.72 (tt, J = 8.5, 4.7 Hz, 1H), 1.39 (d, J = 6.6 Hz, 6H), 1.01 (p, J = 3.5 Hz, 2H), 0.75 (dq, J = 7.3, 3.6 Hz, 2H). LC-MS (ESI) m / z 593.10 [M + H].

[0455] I-27

Chemical Structure

[0456] Step 2: {6-Chloro-5-fluoro-4-[({4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)amino]pyridin-3-yl}methanol To a stirred solution of ethyl 6-chloro-5-fluoro-4-[({4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)amino]pyridine-3-carboxylate (400 mg, 0.825 mmol, 1 equiv) in THF (5 mL), LiAlH4 (40.70 mg, 1.073 mmol, 1.3 equiv) was added portionwise at 0 °C. The resulting mixture was stirred at 0 °C for 2 h under a nitrogen atmosphere. The resulting mixture was filtered and the filter cake was washed with THF (3 × 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (C18 silica gel column, eluting with 10% - 50% MeCN / H2O (0.1% FA) for 10 min using a UV detector (254 nm)) to afford {6-chloro-5-fluoro-4-[({4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)amino]pyridin-3-yl}methanol (200 mg, 54.7%) as a brown solid. LC-MS (ESI) m / z 443.8 [M+H].

[0457] Step 3: 6-Chloro-5-fluoro-4-[({4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)amino]pyridine-3-carbaldehyde To a stirred solution of {6-chloro-5-fluoro-4-[({4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)amino]pyridin-3-yl}methanol (200 mg, 0.452 mmol, 1 equiv) in DCM (2 mL), DMP (383.11 mg, 0.904 mmol, 2 equiv) was added at room temperature. The resulting mixture was stirred at room temperature for 2 h and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (C18 silica gel column, eluting with 10% - 100% MeCN / H2O (0.1% FA) for 10 min using a UV detector (254 nm)) to give 6-chloro-5-fluoro-4-[({4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)amino]pyridine-3-carbaldehyde (150 mg, 75.34%) as a pale yellow solid. LC-MS (ESI) m / z: 441.1 [M+H]

[0458] Step 4: 6-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-5-fluoro-4-[({4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)amino]pyridine-3-carbaldehyde A stirred solution of 6-chloro-5-fluoro-4-[({4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)amino]pyridine-3-carbaldehyde (50 mg, 0.113 mmol, 1 equiv) and 4-cyclopropyl-6-methoxypyrimidin-5-ylboronic acid (33.01 mg, 0.170 mmol, 1.5 equiv) in 1,4-dioxane (1 mL) and H2O (0.2 mL) was added with Pd(dppf)Cl2 (16.60 mg, 0.023 mmol, 0.2 equiv) and K3PO4 (60.19 mg, 0.283 mmol, 2.5 equiv) at room temperature. The resulting mixture was stirred at 90 °C for 2 h under a nitrogen atmosphere. The resulting mixture was filtered and the filter cake was washed with 1,4-dioxane (3 × 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (C18 silica gel column, eluting with 10% - 50% MeCN / H2O (0.1% TFA) for 10 min using a UV detector (254 nm)) to give 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-5-fluoro-4-[({4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)amino]pyridine-3-carbaldehyde (35 mg, 55.6%) as an off-white solid. LC-MS (ESI) m / z 555.5 [M+H].

[0459] Step 5: 7-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-8-fluoro-1-({4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)-1,6-naphthyridin-2-one To a stirred solution of ethyl acetate (79.44 mg, 0.900 mmol, 10 equiv) in THF (2 mL), LiHMDS (0.90 mL, 0.900 mmol, 10 equiv, 1 M in THF) was added dropwise at -78 °C under a nitrogen atmosphere. The resulting mixture was stirred at -78 °C for 10 min under a nitrogen atmosphere. Next, a solution of 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-5-fluoro-4-[({4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)amino]pyridine-3-carbaldehyde (50 mg, 0.090 mmol, 1 equiv) in THF (1 mL) was added to the reaction mixture at -78 °C. The resulting mixture was stirred at room temperature overnight under a nitrogen atmosphere and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (C18 silica gel column, eluting with 10% - 100% MeCN / H2O (0.1% FA) for 15 min using a UV detector (254 nm)) to give 7-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-fluoro-1-({4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)-1,6-naphthyridin-2-one (16.6 mg, 31.6%) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.92 (s, 1H), 8.66 (s, 1H), 8.26 - 8.19 (m, 1H), 8.15 (s, 1H), 7.51 (d, J = 8.0 Hz, 2H), 7.27 (d, J = 8.0 Hz, 2H), 6.96 (d, J = 9.5 Hz, 1H), 5.69 - 5.64 (m, 2H), 4.43 (p, J = 6.6 Hz, 1H), 3.73 (s, 3H), 1.60 (s, 1H), 1.38 (d, J = 6.6 Hz, 6H), 1.11 - 1.03 (m, 1H), 0.92 - 0.81 (m, 2H), 0.70 (s, 1H). LC-MS (ESI) m / z 579.1 [M+H]

[0460] I-28

Chemical Structure

[0461] I-29

Chem.

[0462] I-30

Chem.

[0463] Step 2: 6-Bromo-2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-({4-[1-ethyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)pyrido[2,3-d]pyrimidin-7-one A stirred solution of 6-bromo-2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8H-pyrido[2,3-d]pyrimidin-7-one (150 mg, 0.401 mmol, 1 equiv) and 2-[4-(chloromethyl)phenyl]-1-ethyl-4-(trifluoromethyl)imidazole (104.15 mg, 0.361 mmol, 0.9 equiv) in DMF (2 mL) was added dropwise with 1,1,3,3-tetramethylguanidine (69.25 mg, 0.602 mmol, 1.5 equiv) at room temperature. The resulting mixture was stirred at room temperature overnight under a nitrogen atmosphere. The residue was purified by reverse-phase flash chromatography (C18 silica gel column, eluting with 0% - 100% MeCN / H2O (0.1% FA) for 10 min using a UV detector (254 nm)) to give 6-bromo-2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-({4-[1-ethyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)pyrido[2,3-d]pyrimidin-7-one (150 mg, 59.7%) as a yellow solid. LC-MS (ESI) m / z 626.4 [M+H].

[0464] Step 3: 2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-8-({4-[1-ethyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)-6-(4-methylpiperazine-1-carbonyl)pyrido[2,3-d]pyrimidin-7-one A stirred solution of 6-bromo-2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-({4-[1-ethyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)pyrido[2,3-d]pyrimidin-7-one (50 mg, 0.080 mmol, 1 equiv) and piperazine, 1-methyl- (31.98 mg, 0.320 mmol, 4 equiv) in THF (4 mL) was added with TEA (40.38 mg, 0.400 mmol, 5 equiv) and Pd(dppf)Cl2 (11.68 mg, 0.016 mmol, 0.2 equiv) at room temperature. The resulting mixture was stirred at 65 °C for 6 h under a carbon monoxide atmosphere. The resulting mixture was filtered and the filter cake was washed with 1,4-dioxane (3 × 20 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC under the following conditions (column: YMC-Actus Triart C18, 30*150 mm, 5 μm, mobile phase A: water (0.05% TFA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 25% B to 45% B in 7 min, 45% B; wavelength: 254 / 220 nm, RT1 (min): 6.18) to give 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-({4-[1-ethyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)-6-(4-methylpiperazine-1-carbonyl)pyrido[2,3-d]pyrimidin-7-one (22.3 mg, 40.1%) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6) δ 9.36 (s, 1H), 8.71 (s, 1H), 8.30 (s, 1H), 8.02 (d, J = 1.4 Hz, 1H), 7.55 (d, J = 8.2 Hz, 2H), 7.44 (d, J = 8.1 Hz, 2H), 5.60 (s, 2H), 4.56 (s, 1H), 4.05 (q, J = 7.2 Hz, 2H), 3.84 (s, 4H), 3.54 (s, 1H), 3.37 (s, 2H), 3.10 (d, J = 42.9 Hz, 3H), 2.86 (s, 3H), 1.72 (m, 1H), 1.29 (t, J = 7.3 Hz, 3H), 1.03 (t, J = 4.0 Hz, 2H), 0.77 (m, 2H). LC-MS (ESI) m / z: 674.3 [M+H]

[0465] I-31

Chem.

[0466] Step 2: {4-[1-(2H3)methyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methanol A stirred mixture of methyl 4-[1-(2H3)methyl-4-(trifluoromethyl)imidazol-2-yl]benzoate (2.3 g, 8.007 mmol, 1 equiv) in THF (45 mL, 555.425 mmol, 69.37 equiv) was added dropwise with AlH(Bu-i)2 (24.02 mL, 24.021 mmol, 3 equiv) at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 h under a nitrogen atmosphere. The reaction was quenched with saturated NH4Cl (aqueous solution) at 0 °C. The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (3 × 10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (C18 silica gel column, eluting with 0% - 100% MeCN / water (0.1% FA) for 10 min using a UV detector (254 nm)) to afford {4-[1-(2H3)methyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methanol (1.6 g, 77.08%) as an off-white solid. LC-MS (ESI) m / z 260.1 [M+H]

[0467] Step 3: 2-[4-(Chloromethyl)phenyl]-1-(2H3)methyl-4-(trifluoromethyl)imidazole A stirred mixture of {4-[1-(2H3)methyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methanol (1.5 g, 5.786 mmol, 1 equiv) in DCE (30 mL, 378.979 mmol, 65.50 equiv) was added dropwise with thionyl chloride (2.06 g, 17.358 mmol, 3 equiv) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 50 °C for 30 min under a nitrogen atmosphere. The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (3 × 10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford 2-[4-(chloromethyl)phenyl]-1-(2H3)methyl-4-(trifluoromethyl)imidazole (1.6 g, 99.58%) as an off-white solid. LC-MS (ESI) m / z 254.06 [M+H]

[0468] Step 4: 2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-8-({4-[1-(2H3)methyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)pyrido[2,3-d]pyrimidin-7-one A mixture of 2-[4-(chloromethyl)phenyl]-1-(2H3)methyl-4-(trifluoromethyl)imidazole (36.39 mg, 0.131 mmol, 0.9 eq), 1,1,3,3-tetramethylguanidine (25.16 mg, 0.219 mmol, 1.5 eq), and 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8H-pyrido[2,3-d]pyrimidin-7-one (43 mg, 0.146 mmol, 1.00 eq) in DMF (1 mL, 12.922 mmol, 88.74 eq) was stirred overnight at room temperature under a nitrogen atmosphere. The residue was purified by reverse-phase flash chromatography (C18 silica gel column, eluting with 0% - 100% MeCN / H2O (0.1% FA) for 10 min using a UV detector (254 nm)) to give 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-({4-[1-(2H3)methyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)pyrido[2,3-d]pyrimidin-7-one (36.3 mg, 45.91%) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6) δ 9.29 (s, 1H), 8.69 (s, 1H), 8.16 (d, J = 9.6 Hz, 1H), 7.91 (d, J = 1.4 Hz, 1H), 7.66 - 7.58 (m, 2H), 7.40 (d, J = 8.1 Hz, 2H), 6.90 (d, J = 9.5 Hz, 1H), 5.57 (s, 2H), 3.83 (s, 3H), 1.73 (dq, J = 8.1, 4.1, 3.6 Hz, 1H), 1.01 (p, J = 3.8 Hz, 2H), 0.76 (dq, J = 6.9, 3.5 Hz, 2H). LC-MS (ESI) m / z 537.2 [M+H]

[0469] I-32

Chemical Structure

[0470] Step 2: Methyl 4’-cyclopropyl-4-[({4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)amino]-6’-methoxy-[2,5’-bipyrimidine]-5-carboxylate A stirred mixture of methyl 2-chloro-4-[({4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]phenyl}methyl)amino]pyrimidine-5-carboxylate (130 mg, 0.286 mmol, 1 equiv), 4-cyclopropyl-6-methoxypyrimidin-5-ylboronic acid (83.35 mg, 0.429 mmol, 1.5 equiv) in 1,4-dioxane (2.7 mL, 20 equiv) and H2O (0.3 mL, 20 equiv) was added with pd(dppf)Cl2 (20.96 mg, 0.029 mmol, 0.1 equiv) and K3PO4 (182.40 mg, 0.858 mmol, 3.0 equiv) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 90 °C for 2 h under a nitrogen atm...

Claims

1. A compound of formula I: 【Chemical 1】 (I) or a pharmaceutically acceptable salt thereof, wherein 【Chemical 2】 is a single bond or a double bond, X １ is O, N, N(R １１ ), C(O), CR １２ or C(R １２ ), ２ and X ２ is O, N, N(R １１ ), C(O), CR １２ or C(R １２ ), ２ and X ３ is N(R １１ ), C(O), or C(R １２ ), ２ and X ４ is N or CR １２ and X ５ is N or CR １２ and Each R １１ is, independently, hydrogen, deuterium, R, or -C(O)-R, Each R １２ is, independently, hydrogen, deuterium, halogen, R, -OR, -NHR, -N(R) ２ , -C(O)-R, -COOR, -C(O)-NHR, or -C(O)-N(R) ２ and Ring A is a 5- to 6-membered heteroaromatic ring having 1 to 4 heteroatoms selected from N, O, and S, Each R １ is independently halogen, R, -OR, -NHR, -N(R) ２ , -C(O)-R, -C(O)-NHR, or -C(O)-N(R) ２ and Ring B is selected from a phenyl ring, a 5- to 6-membered heteroaromatic ring having 1 to 4 heteroatoms selected from N, O, and S, or a 5- to 6-membered heterocyclyl ring having 1 to 4 heteroatoms selected from N, O, and S, Each R ２ is independently halogen, R, -OR, -NHR, -N(R) ２ , or -C(O)-R, and R ３ is optionally substituted phenyl or optionally substituted 5- to 6-membered heteroaryl having 1 to 4 heteroatoms selected from N, O, and S, R ４ and R ５ each independently is hydrogen, deuterium, halogen, R, -OR, -NHR, or -N(R) ２ or R ４ and R ５ together with the atoms to which they are attached form an optionally substituted ring selected from a C ３ -C ７ carbocyclic ring or a 3- to 7-membered heterocyclic ring having 1 to 4 heteroatoms selected from N, O, and S Each R is, independently, an optionally substituted C １～６ aliphatic group, or an optionally substituted ring selected from a phenyl ring, a 5- to 6-membered heteroaromatic ring having 1 to 4 heteroatoms selected from N, O, and S, a C ３ -C ７ carbocyclic ring, or a 3- to 7-membered heterocyclic ring having 1 to 4 heteroatoms selected from N, O, or S n is 0, 1, 2, or 3, or m is 0, 1, 2, or 3, a compound of formula I or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, wherein the compound is a compound of formula II or II'. 【Chemical Formula 3】

3. The compound according to claim 1, wherein the compound is a compound of formula III or III'. 【Chemical Formula 4】

4. The compound according to claim 1, wherein the compound is a compound of formula IV or IV'. 【Chemical Formula 5】

5. The compound according to claim 1, wherein the compound is a compound of formula V or V'. 【Chemical Formula 6】

6. The compound according to claim 1, wherein the compound is a compound of formula VI or VI'. 【Chemical Formula 7】

7. The compound according to claim 1, wherein the compound is a compound of formula VII or VII'. 【Chemical 8】

8. The compound according to claim 1, wherein the compound is a compound of formula VIII or VIII'. 【Chemical Formula 9】

9. The compound according to claim 1, wherein the compound is a compound of formula IX or IX'. 【Chemical Formula 10】

10. The compound according to claim 1, wherein the compound is a compound of formula X or X'. 【Chemical 11】

11. The compound according to claim 1, wherein the compound is a compound of formula XI or XI'. 【Chemical Formula 12】

12. The compound according to claim 1, wherein the compound is a compound of formula XII or XII', 【Chemical Formula 13】 In the formula, R ２１ is an optionally substituted C １～６ The compound according to claim 1, which is aliphatic.

13. The compound according to claim 1, wherein the compound is a compound of formula XIII or XIII', 【Chemical 14】 In the formula, R ２２ is an optionally substituted ring selected from a phenyl ring and a 5- to 6-membered heteroaromatic ring having 1 to 4 heteroatoms selected from N, O, and S, the compound according to claim 1.

14. The compound according to claim 1, wherein the compound is a compound of formula XIV or XIV', 【Chemical Formula 15】 In the formula, R ２１ is an optionally substituted C １～６ aliphatic, the compound according to claim 1.

15. Each R １１ is independently hydrogen or optionally substituted C １～６ aliphatic, a compound according to any one of claims 1 to 14.

16. Each R １２ is independently hydrogen, halogen, optionally substituted C １～６ aliphatic, -C(O)-R, -COOR, or -C(O)-N(R) ２ and is a compound according to any one of claims 1 to 15

17. The compound according to any one of claims 1 to 16, wherein Ring A is a 5- to 6-membered heteroaromatic ring having 1 to 4 heteroatoms N.

18. Ring A is 【Chemical 16】 the compound according to claim 17.

19. Each R １ The compound according to any one of claims 1 to 18, wherein each R is independently halogen, R, or -OR.

20. Each R １ is independently, -Cl, -F, -OCH ３ , -OCD ３ , 【Chemical 17】 -O-CHF ２ , -O-CF ３ or 【Chemical Formula 18】 is the compound according to claim 19.

21. The compound according to any one of claims 1 to 20, wherein Ring B is a phenyl ring, a 6-membered heteroaromatic ring having 1 to 4 heteroatoms N, or a 6-membered heterocyclyl ring having 1 to 4 heteroatoms N.

22. Ring B is 【Chemical 19】 the compound according to claim 21, wherein

23. Each R ２ The compound according to any one of claims 1 to 22, wherein each R is independently halogen, R, -OR, or -C(O)-R.

24. Each R ２ is independently, -F, -CH ３ , -CD ３ , -OCH ３ , or -OCD ３ and is the compound according to claim 23.

25. R ３ is optionally substituted with 【Chemical 20】 the compound according to any one of claims 1 to 24, wherein

26. R ３ is 【Chemical 21】 and in the formula, each R １３ is independently halogen, R, or -OR, and q is 0, 1, 2, or 3. The compound according to claim 25.

27. R １３ is -F, -CH ３ , -CD ３ , -CHF ２ , -CF ３ , -OCH ３ , -OCD ３ , 【Chemical 22】 the compound according to claim 26, wherein

28. R ３ is 【Chemical 23】 the compound according to claim 26, wherein

29. R ４ and R ５ each independently is hydrogen, deuterium, or optionally substituted C １～６ is aliphatic, the compound according to any one of claims 1 to 28.

30. a compound selected from those listed in Table 1, or a pharmaceutically acceptable salt thereof.

31. A pharmaceutical composition comprising a compound according to any one of claims 1 to 30 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

32. A method for treating a disease or disorder associated with ubiquitin-specific processing protease 1 (USP1) in a patient, the method comprising administering to the patient a compound according to any one of claims 1 to 30 or a pharmaceutically acceptable salt thereof.

33. The method according to claim 32, wherein the disease or disorder is cancer.

Images