HETEROBIFUNCTIONAL COMPOUNDS AND METHODS OF TREATING DISEASE CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit of and priority to United States Provisional Patent Application serial number 63/404,571, filed September 8, 2022, and United States Provisional Patent Application serial number 63/494,340, filed April 5, 2023; the contents of each of which are hereby incorporated by reference in their entirety. FIELD OF THE INVENTION [0002] The invention provides heterobifunctional compounds, pharmaceutical compositions, and their use treating disease, such as cancer. BACKGROUND [0003] Cancer continues to be a significant health problem despite the substantial research efforts and scientific advances reported in the literature for treating this disease. Solid tumors, including prostate cancer, breast cancer, and lung cancer remain highly prevalent among the world population. The incidence of prostate cancer increases with age, and with increasing longevity of human subjects, there continues to be a corresponding rise in the number of patients suffering from prostate cancer. Breast cancer is one of the most common cancers among women and is a leading cause of death for women between ages 50-55. Lung cancer is a leading cause of death among cancer patients, where over 85% of lung cancers are non-small cell lung cancer (NSCLC). Many lung cancers are attributed to tobacco smoking. Current treatment options for these cancers are not effective for all patients and/or can have substantial adverse side effects. [0004] New therapies are needed to address this unmet need in cancer therapy. In particular, new therapies are needed that achieve an anti-cancer effect through a different mechanism than commonly available therapies. Exemplary mechanisms for common anti-cancer therapies include (a) alkylation of DNA which limits ability of the cell to reproduce, (b) topoisomerase inhibition, in which the therapeutic agent inhibits the activity of a topoisomerases thereby limiting separation of strands of DNA, and (c) mitotic inhibition, where the therapeutic agent reduces ability of the cell to divide. New therapies that achieve an anti-cancer effect through a different mechanism present an opportunity to treat cancers more effectively and/or to treat cancers that have become resistant to currently available medicines. [0005] The present invention addresses the foregoing needs and provides other related advantages. SUMMARY [0006] The invention provides heterobifunctional compounds, pharmaceutical compositions, and their use in treating disease, such as cancer. In particular, one aspect of the invention provides a collection of heterobifunctional compounds, such as a compound represented by Formula I: or a pharmaceutically acceptable salt thereof, where the variables are as defined in the detailed description. Further description of additional collections of heterobifunctional compounds are described in the detailed description. The compounds may be part of a pharmaceutical composition comprising a pharmaceutically acceptable carrier. [0007] Another aspect of the invention provides a collection of heterobifunctional compounds, such as a compound represented by Formula II: or a pharmaceutically acceptable salt thereof, where the variables are as defined in the detailed description. Further description of additional collections of heterobifunctional compounds are described in the detailed description. The compounds may be part of a pharmaceutical composition comprising a pharmaceutically acceptable carrier. [0008] Another aspect of the invention provides a method of treating cancer. The method comprises administering to a patient in need thereof a therapeutically effective amount of a compound described herein, such as a compound of Formula I or II, to treat the cancer. [0009] Another aspect of the invention provides a method of causing death of a cancer cell. The method comprises contacting a cancer cell with an effective amount of a compound described herein, such as a compound of Formula I or II, to cause death of the cancer cell. DETAILED DESCRIPTION [0010] The invention provides heterobifunctional compounds, pharmaceutical compositions, and their use in treating disease, such as cancer. The practice of the present invention employs, unless otherwise indicated, conventional techniques of organic chemistry, pharmacology, molecular biology (including recombinant techniques), cell biology, biochemistry, and immunology. Such techniques are explained in the literature, such as in “Comprehensive Organic Synthesis” (B.M. Trost & I. Fleming, eds., 1991-1992); “Handbook of experimental immunology” (D.M. Weir & C.C. Blackwell, eds.); “Current protocols in molecular biology” (F.M. Ausubel et al., eds., 1987, and periodic updates); and “Current protocols in immunology” (J.E. Coligan et al., eds., 1991), each of which is herein incorporated by reference in its entirety. [0011] Various aspects of the invention are set forth below in sections; however, aspects of the invention described in one particular section are not to be limited to any particular section. Further, when a variable is not accompanied by a definition, the previous definition of the variable controls. Definitions [0012] Compounds of the present invention include those described generally herein, and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. These definitions apply regardless of whether a term is used by itself or in combination with other terms, unless otherwise indicated. Hence, the definition of “alkyl” applies to “alkyl” as well as the “alkyl” portions of “-O-alkyl” etc. For purposes of this invention, the chemical elements are identified in accordance with 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 hereby incorporated by reference. [0013] The term “aliphatic” or “aliphatic group”, as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as “cycloaliphatic”), that has a single point of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms. In some embodiments, “cycloaliphatic” refers to a monocyclic C ₃ -C ₆ hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl. [0014] As used herein, the term “bicyclic ring” or “bicyclic ring system” refers to any bicyclic ring system, i.e., carbocyclic or heterocyclic, saturated or having one or more units of unsaturation, having one or more atoms in common between the two rings of the ring system. Thus, the term includes any permissible ring fusion, such as ortho-fused or spirocyclic. As used herein, the term “heterobicyclic” is a subset of “bicyclic” that requires that one or more heteroatoms are present in one or both rings of the bicycle. Such heteroatoms may be present at ring junctions and are 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, a bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. As used herein, the term “bridged bicyclic” refers to any bicyclic ring system, i.e., carbocyclic or heterocyclic, saturated or partially unsaturated, having at least one bridge. As defined by IUPAC, a “bridge” is an unbranched chain of atoms or an atom or a valence bond connecting two bridgeheads, where a “bridgehead” is any skeletal atom of the ring system which is bonded to three or more skeletal atoms (excluding hydrogen). In some embodiments, a bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groups are well known in the art and include those groups set forth below where each group is attached to the rest of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise specified, a bridged bicyclic group is optionally substituted with one or more substituents as set forth for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted. Exemplary bicyclic rings include: [0015] Exemplary bridged bicyclics include: . [0016] The term “lower alkyl” refers to a C _1-4 straight or branched alkyl group. Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl. [0017] The term “lower haloalkyl” refers to a C _1-4 straight or branched alkyl group that is substituted with one or more halogen atoms. [0018] The term “heteroatom” means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR ⁺ (as in N-substituted pyrrolidinyl)). [0019] The term “unsaturated,” as used herein, means that a moiety has one or more units of unsaturation. [0020] As used herein, the term “bivalent C _1-8 (or C _1-6 ) saturated or unsaturated, straight or branched, hydrocarbon chain”, refers to bivalent alkylene, alkenylene, and alkynylene chains that are straight or branched as defined herein. [0021] The term “alkylene” refers to a bivalent alkyl group. An “alkylene chain” is a polymethylene group, i.e., –(CH ₂ ) _n –, wherein n is a positive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group. [0022] The term “-(C ₀ alkylene)-“ refers to a bond. Accordingly, the term “-(C _0-3 alkylene)-” encompasses a bond (i.e., C0) and a -(C _1-3 alkylene)- group. [0023] The term “alkenylene” refers to a bivalent alkenyl group. A substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group. [0024] The term “halogen” means F, Cl, Br, or I. [0025] The term “aryl” used alone or as part of a larger moiety as in “aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to monocyclic or bicyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 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 which includes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents. Also included within the scope of the term “aryl,” as it is used herein, is a group in which an aromatic ring is fused to one or more non–aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like. The term “haloaryl” refers to an aryl group that is substituted with at least one halogen. Exemplary haloaryl groups include chlorophenyl (e.g., 3-chlorophenyl, 4-chlorophenyl), fluorophenyl, and the like. The term “phenylene” refers to a bivalent phenyl group. [0026] The terms “heteroaryl” and “heteroar–,” used alone or as part of a larger moiety, e.g., “heteroaralkyl,” or “heteroaralkoxy,” refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 ^ electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms. The term “heteroatom” refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen. Heteroaryl groups include, without limitation, 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–”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where unless otherwise specified, the radical or point of attachment is on the heteroaromatic ring or on one of the rings to which the heteroaromatic ring is fused. Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H–quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, and tetrahydroisoquinolinyl. A heteroaryl group may be mono– or bicyclic. The term “heteroaryl” may be used interchangeably with the terms “heteroaryl ring,” “heteroaryl group,” or “heteroaromatic,” any of which terms include rings that are optionally substituted. The term “heteroaralkyl” refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted. The term “haloheteroaryl” refers to a heteroaryl group that is substituted with at least one halogen. Exemplary haloheteroaryl groups include chloropyridine, fluoropyridine, chloropyrazole, fluoropyrazole, and the like. The term “heteroarylene” refers to a bivalent heteroaryl group. Similarly, the terms “pyrazolylene”, “imidazolylene”, and “pyrrolylene”, respectively refer to bivalent pyrazolyl, imidazolyl, and pyrrolyl groups. Similarly, the terms “pyridinylene” and “pyrimidinylene”, respectively refer to bivalent pyridinyl and pyrimidinyl groups. Similarly, the terms “pyridazinylene,” “pyrimidinylene,” “pyrazinylene,” and “pyridinylene,” respectively refer to bivalent pyridazinyl, pyrimidinyl, pyrazinyl, and pyridinyl groups. [0027] As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclic radical,” and “heterocyclic ring” are used interchangeably and refer to a stable 5– to 7–membered monocyclic or 7–10–membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes a substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0–3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3,4–dihydro– 2H–pyrrolyl), NH (as in pyrrolidinyl), or ⁺ NR (as in N–substituted pyrrolidinyl). [0028] A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, 2-oxa-6- azaspiro[3.3]heptane, 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 cycloaliphatic rings, such as indolinyl, 3H–indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl. A heterocyclyl group may be mono– or bicyclic. The term “heterocyclylalkyl” refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted. The term “heterocyclylene” refers to a bivalent heterocyclyl group. [0029] The terms “piperidinylene,” “piperazinylene,” and “azetidinylene”, respectively refer to bivalent piperidinyl, piperazinyl, and azetidinyl groups. [0030] As used herein, the term “heterocycloalkyl” refers to a saturated heterocyclyl. The term “heterocycloalkylene” refers to a bivalent heterocycloalkyl group. [0031] As used herein, the term “partially unsaturated” refers to a ring moiety that includes 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 herein defined. [0032] As described herein, compounds of the invention may contain “optionally substituted” moieties. In general, the term “substituted,” whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds. The term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein. [0033] Each optional substituent on a substitutable carbon is a monovalent substituent independently selected from halogen; –(CH ₂ ) _0–4 R°; –(CH ₂ ) _0–4 OR°; -O(CH ₂ ) _0-4 R ^o , –O–(CH ₂ ) _{0– 4} C(O)OR°; –(CH ₂ ) _0–4 CH(OR°) ₂ ; –(CH ₂ ) _0–4 SR°; –(CH ₂ ) _0–4 Ph, which may be substituted with R°; – (CH ₂ ) _0–4 O(CH ₂ ) _0–1 Ph which may be substituted with R°; –CH=CHPh, which may be substituted with R°; –(CH ₂ )) _0–4 O(CH ₂ )0–1-pyridyl which may be substituted with R°; –NO2; –CN; – N3; -(CH ₂ )) _0–4 N(R°) ₂ ; –(CH ₂ )) _0– N ₄ (R°)C(O)R°; –N(R°)C(S)R°; –(CH ₂ )) _0– N ₄ (R°)C(O)NR° ₂ ; -N(R°)C(S)NR° ₂ ; –(CH ₂ )) _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°; –(CH ₂ )) _0–4 C(O)R°; –C(S)R°; –(CH ₂ )) _0–4 C(O)OR°; –(CH ₂ )) _0– C ₄ (O)SR°; -(CH ₂ )) _0–4 C(O)OSiR°3; –(CH ₂ )) _0–4 OC(O)R°; –OC(O)(CH ₂ )) _0–4 SR–, SC(S)SR°; –(CH ₂ )) _0–4 SC(O)R°; – (CH ₂ )) _0–4 C(O)NR° ₂ ; –C(S)NR° ₂ ; –C(S)SR°; –SC(S)SR°, -(CH ₂ )) _0–4 OC(O)NR° ₂ ; -C(O)N(OR°)R°; –C(O)C(O)R°; –C(O)CH ₂ C(O)R°; –C(NOR°)R°; -(CH ₂ )) _0–4 SSR°; –(CH ₂ )0– 4S(O) ₂ R°; –(CH ₂ )) _0–4 S(O) ₂ OR°; –(CH ₂ )) _0–4 OS(O) ₂ R°; –S(O) ₂ NR° ₂ ; –S(O)(NR°)R°; – S(O) ₂ N=C(NR° ₂ ) ₂ ; -(CH ₂ )) _0–4 S(O)R°; -N(R°)S(O) ₂ NR° ₂ ; –N(R°)S(O) ₂ R°; –N(OR°)R°; – C(NH)NR° ₂ ; –P(O) ₂ R°; -P(O)R° ₂ ; -OP(O)R° ₂ ; –OP(O)(OR°) ₂ ; SiR°3; –(C1–4 straight or branched alkylene)O–N(R°) ₂ ; or –(C _1–4 straight or branched alkylene)C(O)O–N(R°) ₂ . [0034] Each R° is independently hydrogen, C _1–6 aliphatic, –CH ₂ Ph, –O(CH ₂ ) _0–1 Ph, -CH ₂ -(5-6 membered heteroaryl ring), or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R°, taken together with their intervening atom(s), form a 3–12–membered saturated, partially unsaturated, or aryl mono– or bicyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted by a divalent substituent on a saturated carbon atom of R° selected from =O and =S; or each R° is optionally substituted with a monovalent substituent independently selected from halogen, – (CH ₂ ) _0–2 R ^● , –(haloR ^● ), –(CH ₂ ) _0–2 OH, –(CH ₂ ) _0–2 OR ^● , –(CH ₂ ) _0–2 CH(OR ^● ) ₂ ; -O(haloR ^● ), –CN, –N3, –(CH ₂ ) _0–2 C(O)R ^● , –(CH ₂ ) _0–2 C(O)OH, –(CH ₂ ) _0–2 C(O)OR ^● , –(CH ₂ ) _0–2 SR ^● , –(CH ₂ ) _0–2 SH, –(CH ₂ )0– ₂ NH ₂ , –(CH ₂ ) _0–2 NHR ^● , –(CH ₂ ) _0–2 NR ^● ₂ , –NO ₂ , –SiR ^● ₃ , –OSiR ^● ₃ , -C(O)SR ^● _, –(C _1–4 straight or branched alkylene)C(O)OR ^● , or –SSR ^● . [0035] Each R ^● is independently selected from C1–4 aliphatic, –CH ₂ Ph, –O(CH ₂ )0–1Ph, or a 5– 6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein each R ^● is unsubstituted or where preceded by halo is substituted only with one or more halogens; or wherein an optional substituent on a saturated carbon is a divalent substituent independently selected from =O, =S, =NNR ^* ₂ , =NNHC(O)R ^* , =NNHC(O)OR ^* , =NNHS(O) ₂ R ^* , =NR ^* , =NOR ^* , –O(C(R ^* ₂ )) _2–3 O–, or –S(C(R ^* ₂ )) _2– 3S–, or a divalent substituent bound to vicinal substitutable carbons of an “optionally substituted” group is –O(CR ^* 2) _2–3 O–, wherein each independent occurrence of R ^* is selected from hydrogen, C _1–6 aliphatic or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [0036] When 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 ^● , –NH ₂ , –NHR ^● , –NR ^● ₂ , or – NO ₂ , wherein each R ^● is independently selected from C _1–4 aliphatic, –CH ₂ Ph, –O(CH ₂ ) _0–1 Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein each R ^● is unsubstituted or where preceded by halo is substituted only with one or more halogens. [0037] An optional substituent on a substitutable nitrogen is independently –R ^† , –NR ^† 2, – C(O)R ^† , –C(O)OR ^† , –C(O)C(O)R ^† , –C(O)CH ₂ C(O)R ^† , -S(O) ₂ R ^† , -S(O) ₂ NR ^† ₂ , –C(S)NR ^† ₂ , – C(NH)NR ^† ₂ , or –N(R ^† )S(O) ₂ R ^† ; wherein each R ^† is independently hydrogen, C _1–6 aliphatic, unsubstituted –OPh, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, two independent occurrences of R ^† , taken together with their intervening atom(s) form an unsubstituted 3–12–membered saturated, partially unsaturated, or aryl mono– or bicyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; wherein when 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 ^● , –NH ₂ , –NHR ^● , –NR ^● ₂ , or –NO ₂ , wherein each R ^● is independently selected from C1–4 aliphatic, –CH ₂ Ph, –O(CH ₂ )0–1Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein each R ^● is unsubstituted or where preceded by halo is substituted only with one or more halogens. [0038] As used herein, the term "pharmaceutically acceptable salt" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1–19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by 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, lauryl sulfate, 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 salts, and the like. [0039] Further, acids which are generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, by P. Stahl et al., Camille G. (eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley-VCH; S. Berge et al., Journal of Pharmaceutical Sciences (1977) 66(1) 1- 19; P. Gould, International J. of Pharmaceutics (1986) 33201-217; Anderson et al., The Practice of Medicinal Chemistry (1996), Academic Press, New York; and in The Orange Book (Food & Drug Administration, Washington, D.C. on their website). These disclosures are incorporated herein by reference. [0040] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N ⁺ (C _1–4 alkyl) ₄ salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate. [0041] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. The invention includes compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a ¹³ C- or ¹⁴ C-enriched carbon are within the scope of this invention. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present invention. [0042] Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher’s acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. Alternatively, a particular enantiomer of a compound of the present invention may be prepared by asymmetric synthesis. Still further, where the molecule contains a basic functional group (such as amino) or an acidic functional group (such as carboxylic acid) diastereomeric salts are formed with an appropriate optically-active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means known in the art, and subsequent recovery of the pure enantiomers. [0043] Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers. Chiral center(s) in a compound of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations. Further, to the extent a compound described herein may exist as a atropisomer (e.g., substituted biaryls), all forms of such atropisomer are considered part of this invention. [0044] Chemical names, common names, and chemical structures may be used interchangeably to describe the same structure. If a chemical compound is referred to using both a chemical structure and a chemical name, and an ambiguity exists between the structure and the name, the structure predominates. It should also be noted that any carbon as well as heteroatom with unsatisfied valences in the text, schemes, examples and tables herein is assumed to have the sufficient number of hydrogen atom(s) to satisfy the valences. [0045] The terms “a” and “an” as used herein mean “one or more” and include the plural unless the context is inappropriate. [0046] The term “alkyl” refers to a saturated straight or branched hydrocarbon, such as a straight or branched group of 1-12, 1-10, or 1-6 carbon atoms, referred to herein as C1-C12 alkyl, C ₁ -C ₁₀ alkyl, and C ₁ -C ₆ alkyl, respectively. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3- methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4- methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, etc. [0047] The term “cycloalkyl” refers to a monovalent saturated cyclic, bicyclic, or bridged cyclic (e.g., adamantyl) hydrocarbon group of 3-12, 3-8, 4-8, or 4-6 carbons, referred to herein, e.g., as “C ₃ -C ₆ cycloalkyl,” derived from a cycloalkane. Exemplary cycloalkyl groups include cyclohexyl, cyclopentyl, cyclobutyl, and cyclopropyl. The term “cycloalkylene” refers to a bivalent cycloalkyl group. [0048] The term “haloalkyl” refers to an alkyl group that is substituted with at least one halogen. Exemplary haloalkyl groups include -CH ₂ F, -CHF2, -CF3, -CH ₂ CF3, -CF2CF3, and the like. The term “chloroalkyl” refers to an alkyl group that is substituted with at least one chloro. The term “bromoalkyl” refers to an alkyl group that is substituted with at least one bromo. The term “haloalkylene” refers to a bivalent haloalkyl group. [0049] The term “hydroxyalkyl” refers to an alkyl group that is substituted with at least one hydroxyl. Exemplary hydroxyalkyl groups include -CH ₂ CH ₂ OH, -C(H)(OH)CH ₃ , -CH ₂ C(H)(OH)CH ₂ CH ₂ OH, and the like. [0050] The term “heteroalkyl” refers to an alkyl group in which one or more carbon atoms has been replaced by a heteroatom (e.g., N, O, or S). Exemplary heteroalkyl groups include -OCH3, -CH ₂ OCH3, -CH ₂ CH ₂ N(CH3) ₂ , and -CH ₂ CH ₂ OH. The heteroalkyl group may contain, for example, from 2-4, 2-6, or 2-8 atoms selected from the group consisting of carbon and a heteroatom (e.g., N, O, or S). The phrase 3-8 membered heteroalkyl refers to a heteroalkyl group having from 3 to 8 atoms selected from the group consisting of carbon and a heteroatom. The term “heteroalkylene” refers to a bivalent heteroalkyl group. [0051] The terms “alkenyl” and “alkynyl” are art-recognized and refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively. The term “haloalkenyl” refers to an alkenyl group that is substituted with at least one halogen. The term “fluoroalkenyl” refers to an alkenyl group that is substituted with at least one fluoro. The term “nitroalkenyl” refers to an alkenyl group that is substituted with at least one nitro. [0052] The term “carbocyclylene” refers to a bivalent cycloaliphatic group. [0053] The terms “alkoxyl” or “alkoxy” are art-recognized and refer to an alkyl group, as defined above, having an oxygen radical attached thereto. Representative alkoxyl groups include methoxy, ethoxy, propyloxy, tert-butoxy and the like. The term “haloalkoxyl” refers to an alkoxyl group that is substituted with at least one halogen. Exemplary haloalkoxyl groups include - OCH ₂ F, -OCHF ₂ , -OCF ₃ , -OCH ₂ CF ₃ , -OCF ₂ CF ₃ , and the like. [0054] The term “oxo” is art-recognized and refers to a “=O” substituent. For example, a cyclopentane susbsituted with an oxo group is cyclopentanone. [0055] The term “amino” is art-recognized and refers to both unsubstituted and substituted amines, e.g., a moiety that may be represented by the general formulas: wherein R ⁵⁰ , R ⁵¹ , R ⁵² and R ⁵³ each independently represent a hydrogen, an alkyl, an alkenyl, -(CH ₂ ) _m -R ⁶¹ , or R ⁵⁰ and R ⁵¹ , taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure; R ⁶¹ represents an aryl, a 3-7 membered cycloalkyl, a 4-7 membered cycloalkenyl, 5-10 membered heteroaryl, or 3-10 membered heterocyclyl; and m is zero or an integer in the range of 1 to 8. [0056] The term “amido” is art-recognized and refers to both unsubstituted and substituted amides, e.g., a moiety that may be represented by the general formulas: wherein R ⁵⁰ and R ⁵¹ each independently represent a hydrogen, an alkyl, an alkenyl, -(CH ₂ )m-R ⁶¹ , or R ⁵⁰ and R ⁵¹ , taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure; R ⁶¹ represents an aryl, a 3-7 membered cycloalkyl, a 4-7 membered cycloalkenyl, 5-10 membered heteroaryl, or 3-10 membered heterocyclyl; and m is zero or an integer in the range of 1 to 8; and R ⁵² is an alkyl, an alkenyl, or -(CH ₂ )m-R ⁶¹ . [0057] The symbol “ ” indicates a point of attachment. [0058] When any substituent or variable occurs more than one time in any constituent or the compound of the invention, its definition on each occurrence is independent of its definition at every other occurrence, unless otherwise indicated. [0059] One or more compounds of the invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms. “Solvate” means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. “Solvate” encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like. “Hydrate” is a solvate wherein the solvent molecule is H ₂ O. [0060] As used herein, the terms “subject” and “patient” are used interchangeable and refer to organisms to be treated by the methods of the present invention. Such organisms preferably include, but are not limited to, mammals (e.g., murines, simians, equines, bovines, porcines, canines, felines, and the like), and most preferably includes humans. [0061] The term “IC50” is art-recognized and refers to the concentration of a compound that is required to achieve 50% inhibition of the target. [0062] As used herein, the term “effective amount” refers to the amount of a compound sufficient to effect beneficial or desired results (e.g., a therapeutic, ameliorative, inhibitory or preventative result). An effective amount can be administered in one or more administrations, applications or dosages and is not intended to be limited to a particular formulation or administration route. As used herein, the term “treating” includes any effect, e.g., lessening, reducing, modulating, ameliorating or eliminating, that results in the improvement of the condition, disease, disorder, and the like, or ameliorating a symptom thereof. [0063] As used herein, the term “pharmaceutical composition” refers to the combination of an active agent with a carrier, inert or active, making the composition especially suitable for diagnostic or therapeutic use in vivo or ex vivo. [0064] As used herein, the term “pharmaceutically acceptable carrier” refers to any of the standard pharmaceutical carriers, such as a phosphate buffered saline solution, water, emulsions (e.g., such as an oil/water or water/oil emulsions), and various types of wetting agents. The compositions also can include stabilizers and preservatives. For examples of carriers, stabilizers and adjuvants, see e.g., Martin, Remington’s Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, PA [1975]. [0065] For therapeutic use, salts of the compounds of the present invention are contemplated as being pharmaceutically acceptable. However, salts of acids and bases that are non- pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound. [0066] In addition, when a compound of the invention contains both a basic moiety (such as, but not limited to, a pyridine or imidazole) and an acidic moiety (such as, but not limited to, a carboxylic acid) zwitterions (“inner salts”) may be formed. Such acidic and basic salts used within the scope of the invention are pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts. Such salts of the compounds of the invention may be formed, for example, by reacting a compound of the invention with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization. [0067] Throughout the description, where compositions are described as having, including, or comprising specific components, or where processes and methods are described as having, including, or comprising specific steps, it is contemplated that, additionally, there are compositions of the present invention that consist essentially of, or consist of, the recited components, and that there are processes and methods according to the present invention that consist essentially of, or consist of, the recited processing steps. [0068] As a general matter, compositions specifying a percentage are by weight unless otherwise specified. I. Heterobifunctional Compounds [0069] One aspect of the invention provides heterobifunctional compounds. The compounds may be used in the pharmaceutical compositions and therapeutic methods described herein. Exemplary compounds are described in the following sections, along with exemplary procedures for making the compounds. Without being bound by theory, the compounds can facilitate therapeutic effects by binding to both an androgen receptor and PLK1 (polo like kinase 1). Part A: Compound of Formula I [0070] One aspect of the invention provides a compound represented by Formula I: or a pharmaceutically acceptable salt thereof; wherein: R ¹ is phenyl substituted by cyano, halogen, and m occurrences of R ⁴ ; R ² represents independently for each occurrence C _1-4 alkyl; R ³ is hydrogen or C _1-4 alkyl; R ⁴ is C _1-4 alkyl; R ⁵ represents independently for each occurrence C _1-4 alkyl or halogen; A ¹ is a pyridazinylene, pyrimidinylene, pyrazinylene, or pyridinylene, each of which is substituted with n occurrences of R ⁵ ; R ^1A represents independently for each occurrence C ₁ -C ₆ alkoxy, hydroxyl, or C ₁ -C ₆ alkyl; R ^2A , R ^3A , R ^4A , R ^5A , and R ^6A are independently hydrogen, C _1-4 alkyl, or C _3-4 cycloalkyl; R ^7A is C _3-7 cycloalkyl, C _1-6 alkyl, or -(C _1-6 alkylene)-(C _3-7 cycloalkyl); L is a linker; k is 1, 2, 3, or 4; and m, n, and p are independently 0, 1, or 2. [0071] The definitions of variables in Formula I above encompass multiple chemical groups. The application contemplates embodiments where, for example, i) the definition of a variable is a single chemical group selected from those chemical groups set forth above, ii) the definition of a variable is a collection of two or more of the chemical groups selected from those set forth above, and iii) the compound is defined by a combination of variables in which the variables are defined by (i) or (ii). [0072] In certain embodiments, the compound is a compound of Formula I. [0073] As defined generally above, R ¹ is phenyl substituted by cyano, halogen, and m occurrences of R ⁴ . In certain embodiments, R ¹ is phenyl substituted by cyano, halogen, and 0 occurrences of R ⁴ . In certain embodiments, R ¹ is phenyl substituted by cyano, chloro, and 0 occurrences of R ⁴ . In certain embodiments, R ¹ is . In certain embodiments, R ¹ is phenyl substituted by cyano, halogen, and 1 occurrence of R ⁴ . In certain embodiments, R ¹ is phenyl substituted by cyano, halogen, and 2 occurrences of R ⁴ . In certain embodiments, R ¹ is selected from the groups depicted in the compounds in Table 1 below. [0074] As defined generally above, R ² represents independently for each occurrence C _1-4 alkyl. In certain embodiments, R ² is C1-2 alkyl. In certain embodiments, R ² is methyl. In certain embodiments, R ² is selected from the groups depicted in the compounds in Table 1 below. [0075] As defined generally above, R ³ is hydrogen or C _1-4 alkyl. In certain embodiments, R ³ is hydrogen. In certain embodiments, R ³ is C _1-4 alkyl. In certain embodiments, R ³ is selected from the groups depicted in the compounds in Table 1 below. [0076] As defined generally above, R ⁴ is C _1-4 alkyl. In certain embodiments, R ⁴ is CH ₃ . In certain embodiments, R ⁴ is selected from the groups depicted in the compounds in Table 1 below. [0077] As defined generally above, R ⁵ represents independently for each occurrence C _1-4 alkyl or halogen. In certain embodiments, R ⁵ is C _1-4 alkyl. In certain embodiments, R ⁵ is halogen. In certain embodiments, R ⁵ is selected from the groups depicted in the compounds in Table 1 below. [0078] As defined generally above, A ¹ is a pyridazinylene, pyrimidinylene, pyrazinylene, or pyridinylene, each of which is substituted with n occurrences of R ⁵ . In certain embodments, A ¹ is pyridazinylene substituted with n occurrences of R ⁵ . In certain embodiments, A ¹ is . In certain embodiments, A ¹ is pyrimidinylene substituted with n occurrences of R ⁵ . In certain embodiments, A ¹ is , where ** is the point of attachment to L. In certain embodiments, A ¹ is , where ** is the point of attachment to L. In certain embodiments, A ¹ is pyrazinylene substituted with n occurrences of R ⁵ . In certain embodiments, A ¹ . In certain embodiments, A ¹ is pyridinylene substituted with n occurrences of R ⁵ . In certain embodiments, A ¹ is pyridinylene substituted with 0 occurrences of R ⁵ . In certain embodiments, A ¹ is , where ** is the point of attachment to L. In certain embodiments, A ¹ is selected from the groups depicted in the compounds in Table 1 below. [0079] As defined generally above, certain embodiments, certain embodiments, A ² is . In certain embodiments, certain embodiments, A ² is selected from the groups depicted in the compounds in Table 1 below. [0080] As defined generally above, R ^1A represents independently for each occurrence C ₁ -C ₆ alkoxy, hydroxyl, or C ₁ -C ₆ alkyl. In certain embodiments, R ^1A is C ₁ -C ₆ alkoxy. In certain embodiments, R ^1A is methoxy. In certain embodiments, R ^1A is hydroxyl. In certain embodiments, R ^1A is C ₁ -C ₆ alkyl. In certain embodiments, R ^1A is selected from the groups depicted in the compounds in Table 1 below. [0081] As defined generally above, R ^2A is hydrogen, C _1-4 alkyl, or C _3-4 cycloalkyl. In certain embodiments, R ^2A is hydrogen. In certain embodiments, R ^2A is C _1-4 alkyl. In certain embodiments, R ^2A is C _3-4 cycloalkyl. In certain embodiments, R ^2A is selected from the groups depicted in the compounds in Table 1 below. [0082] As defined generally above, R ^3A is hydrogen, C _1-4 alkyl, or C _3-4 cycloalkyl. In certain embodiments, R ^3A is hydrogen. In certain embodiments, R ^3A is C _1-4 alkyl. In certain embodiments, R ^3A is C _3-4 cycloalkyl. In certain embodiments, R ^3A is selected from the groups depicted in the compounds in Table 1 below. [0083] As defined generally above, R ^4A is hydrogen, C _1-4 alkyl, or C _3-4 cycloalkyl. In certain embodiments, R ^4A is hydrogen. In certain embodiments, R ^4A is C _1-4 alkyl. In certain embodiments, R ^4A is methyl. In certain embodiments, R ^4A is C _3-4 cycloalkyl. In certain embodiments, R ^4A is selected from the groups depicted in the compounds in Table 1 below. [0084] As defined generally above, R ^5A is hydrogen, C _1-4 alkyl, or C _3-4 cycloalkyl. In certain embodiments, R ^5A is hydrogen. In certain embodiments, R ^5A is C _1-4 alkyl. In certain embodiments, R ^5A is C _3-4 cycloalkyl. In certain embodiments, R ^5A is selected from the groups depicted in the compounds in Table 1 below. [0085] As defined generally above, R ^6A is hydrogen, C _1-4 alkyl, or C _3-4 cycloalkyl. In certain embodiments, R ^6A is hydrogen. In certain embodiments, R ^6A is C _1-4 alkyl. In certain embodiments, R ^6A is ethyl. In certain embodiments, R ^6A is C _3-4 cycloalkyl. In certain embodiments, R ^6A is selected from the groups depicted in the compounds in Table 1 below. [0086] As defined generally above, R ^7A is C _3-7 cycloalkyl, C _1-6 alkyl, or -(C _1-6 alkylene)-(C _3-7 cycloalkyl). In certain embodiments, R ^7A is C _3-7 cycloalkyl. In certain embodiments, R ^7A is cyclopentyl. In certain embodiments, R ^7A is C _1-6 alkyl. In certain embodiments, R ^7A is -(C _1-6 alkylene)-(C _3-7 cycloalkyl). In certain embodiments, R ^7A is selected from the groups depicted in the compounds in Table 1 below. [0087] As defined generally above, k is 1, 2, 3, or 4. In certain embodiments, k is 1. In certain embodiments, k is 2. In certain embodiments, k is 3. In certain embodiments, k is 4. In certain embodiments, k is selected from the corresponding value in the groups depicted in the compounds in Table 1 below. [0088] As defined generally above, m, n, and p are independently 0, 1, or 2. In certain embodiments, p is 2. In certain embodiments, p is 1. In certain embodiments, p is 0. In certain embodiments, m is 0. In certain embodiments, m is 1. In certain embodiments, m is 2. In certain embodiments, n is 0. In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, p is selected from the corresponding value in the groups depicted in the compounds in Table 1 below. In certain embodiments, m is selected from the corresponding value in the groups depicted in the compounds in Table 1 below. In certain embodiments, n is selected from the corresponding value in the groups depicted in the compounds in Table 1 below. [0089] In certain embodiments, the compound of Formula I is further defined by Formula Ia or a pharmaceutically acceptable salt thereof: In certain embodiments, the definition of variables R ² , R ³ , A ¹ , and A ² is one of the embodiments described above in connection with Formula I. [0090] In certain embodiments, the compound of Formula I is further defined by Formula Ib or a pharmaceutically acceptable salt thereof: (1b). In certain embodiments, the definition of variables R ² , R ³ , A ¹ , and A ² is one of the embodiments described above in connection with Formula I. [0091] In certain embodiments, the compound of Formula I is further defined by Formula Ic or a pharmaceutically acceptable salt thereof: (1c). In certain embodiments, the definition of variables variables A ¹ and A ² is one of the embodiments described above in connection with Formula I. [0092] In certain embodiments, the compound of Formula I is further defined by Formula 1d or a pharmaceutically acceptable salt thereof: (1d). In certain embodiments, the definition of variables A ¹ and A ² is one of the embodiments described above in connection with Formula I. [0093] The compounds may be further characterized according to, for example, the identity of L. Exemplary further embodiments for L are provided in Part C below. [0094] In certain embodiments, the compound is a compound of Formula Ie or a pharmaceutically acceptable salt thereof: L is one of the following ^ -N(C _1-3 alkyl)-[(C _2-4 alkylene)-O-]2-8-(C _2-6 alkylene)-N(H)C(O)-*** or -(3-7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(OCH ₂ CH ₂ ) _1-10 -***, wherein *** is the point of attachment to A ² ^ -(3-7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(C _1-10 alkylene where 1 or 2 methylene groups are optionally replaced by -O-, -N(H)-, or -N(C _1-4 alkyl)-)-(3-7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(C0-8 alkylene)- N(H)C(O)-***, -(3-7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-N(C _3-6 cycloalkyl)-(C _3-6 cycloalkylene)- N(H)C(O)-***, or -(3-7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(C _1-6 alkylene)-(C _3-6 cycloalkylene)- N(H)C(O)-***, wherein *** is the point of attachment to A ² ; or ^ -(6-10 membered, bicyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(C _0-4 alkylene)-N(H)C(O)-***, or -(6-10 membered, spirocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(C _0-4 alkylene)-N(H)C(O)-***, wherein *** is the point of attachment to A ² . [0095] In certain embodiments, A ² is In certain embodiments, A ² is [0096] In certain embodiments, L is -N(C _1-3 alkyl)-[(C _2-4 alkylene)-O-]2-8-(C _2-6 alkylene)- N(H)C(O)-*** or -(3-7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(OCH ₂ CH ₂ ) _1-10 -***, wherein *** is the point of attachment to A ² . In certain embodiments, L is -(3-7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(C _1-10 alkylene where 1 or 2 methylene groups are optionally replaced by -O-, -N(H)-, or -N(C _1-4 alkyl)-)-(3-7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(C _0-8 alkylene)- N(H)C(O)-***, -(3-7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-N(C _3-6 cycloalkyl)-(C _3-6 cycloalkylene)-N(H)C(O)-***, or - (3-7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(C _1-6 alkylene)-(C _3-6 cycloalkylene)-N(H)C(O)-***, wherein *** is the point of attachment to A ² . In certain embodiments, L is -(6-10 membered, bicyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(C _0-4 alkylene)-N(H)C(O)-***, or -(6- 10 membered, spirocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(C _0-4 alkylene)-N(H)C(O)-***, wherein *** is the point of attachment to A ² . [0097] In certain embodiments, the compound is a compound of Formula If or a pharmaceutically acceptable salt thereof: wherein A ² is and L is one of the following ^ -N(C _1-3 alkyl)-[(C _2-4 alkylene)-O-]2-8-(C _2-6 alkylene)-N(H)C(O)-*** or -(3-7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(OCH ₂ CH ₂ )1-10-***, wherein *** is the point of attachment to A ² ^ -(3-7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(C _1-10 alkylene where 1 or 2 methylene groups are optionally replaced by -O-, -N(H)-, or -N(C _1-4 alkyl)-)-(3-7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(C0-8 alkylene)- N(H)C(O)-***, -(3-7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-N(C _3-6 cycloalkyl)-(C _3-6 cycloalkylene)- N(H)C(O)-***, or -(3-7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(C _1-6 alkylene)-(C _3-6 cycloalkylene)- N(H)C(O)-***, wherein *** is the point of attachment to A ² ; or ^ -(6-10 membered, bicyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(C _0-4 alkylene)-N(H)C(O)-***, or -(6-10 membered, spirocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(C _0-4 alkylene)-N(H)C(O)-***, wherein *** is the point of attachment to A ² . [0098] In certain embodiments, A ² is In certain embodiments, A ² is [0099] In certain embodiments, L is -N(C _1-3 alkyl)-[(C _2-4 alkylene)-O-] _2-8 -(C _2-6 alkylene)- N(H)C(O)-*** or -(3-7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(OCH ₂ CH ₂ ) _1-10 -***, wherein *** is the point of attachment to A ² . In certain embodiments, L is -(3-7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(C _1-10 alkylene where 1 or 2 methylene groups are optionally replaced by -O-, -N(H)-, or -N(C _1-4 alkyl)-)-(3-7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(C _0-8 alkylene)- N(H)C(O)-***, -(3-7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-N(C _3-6 cycloalkyl)-(C _3-6 cycloalkylene)-N(H)C(O)-***, or - (3-7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(C _1-6 alkylene)-(C _3-6 cycloalkylene)-N(H)C(O)-***, wherein *** is the point of attachment to A ² . In certain embodiments, L is -(6-10 membered, bicyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(C _0-4 alkylene)-N(H)C(O)-***, or -(6- 10 membered, spirocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(C _0-4 alkylene)-N(H)C(O)-***, wherein *** is the point of attachment to A ² . Part B: Compound of Formula II [0100] Another aspect of the invention provides a compound represented by Formula II: or a pharmaceutically acceptable salt thereof; wherein: TPL is a group defined by Formula II-1 that is substituted by one occurrence of R ^II-1A , wherein Formula II-1 is represented by: (II-1) wherein: R ^II-1A is a bond to L; R ¹ is phenyl substituted by cyano, halogen, and m occurrences of R ⁴ ; R ² represents independently for each occurrence C _1-4 alkyl; R ³ is hydrogen or C _1-4 alkyl; R ⁴ is C _1-4 alkyl; R ⁵ represents independently for each occurrence C _1-4 alkyl or halogen; A ¹ is a pyridazinylene, pyrimidinylene, pyrazinylene, or pyridinylene, each of which is substituted with n occurrences of R ⁵ ; L is a linker; EPL is a moiety that binds to PLK1; k is 1, 2, 3, or 4; and m and n are independently 0, 1, or 2. [0101] The definitions of variables in Formula II above encompass multiple chemical groups. The application contemplates embodiments where, for example, i) the definition of a variable is a single chemical group selected from those chemical groups set forth above, ii) the definition of a variable is a collection of two or more of the chemical groups selected from those set forth above, and iii) the compound is defined by a combination of variables in which the variables are defined by (i) or (ii). [0102] In certain embodiments, the compound is a compound of Formula II. [0103] As defined generally above, R ¹ is phenyl substituted by cyano, halogen, and m occurrences of R ⁴ . In certain embodiments, R ¹ is phenyl substituted by cyano, halogen, and 0 occurrences of R ⁴ . In certain embodiments, R ¹ is . In certain embodiments, R ¹ is phenyl substituted by cyano, halogen, and 1 occurrences of R ⁴ . In certain embodiments, R ¹ is phenyl substituted by cyano, halogen, and 2 occurrences of R ⁴ . In certain embodiments, R ¹ is phenyl substituted by cyano, Cl, and 0 occurrences of R ⁴ . In certain embodiments, R ¹ is selected from the groups depicted in the compounds in Table 1 below. [0104] As defined generally above, R ² represents independently for each occurrence C _1-4 alkyl. In certain embodiments, R ² is C _1-2 alkyl. In certain embodiments, R ² is methyl. In certain embodiments, R ² is selected from the groups depicted in the compounds in Table 1 below. [0105] As defined generally above, R ³ is hydrogen or C _1-4 alkyl. In certain embodiments, R ³ is hydrogen. In certain embodiments, R ³ is C _1-4 alkyl. In certain embodiments, R ³ is selected from the groups depicted in the compounds in Table 1 below. [0106] As defined generally above, A ¹ is a pyridazinyl, pyrimidinyl, pyrazinyl, or pyridinyl, each of which is substituted with n occurrences of R ⁵ . In certain embodiments, A ¹ is pyridazinyl substituted with n occurrences of R ⁵ . In certain embodiments, A ¹ is pyrimidinyl substituted with n occurrences of R ⁵ . In certain embodiments, A ¹ is pyrazinyl substituted with n occurrences of R ⁵ . In certain embodiments, A ¹ is pyridinyl substituted with n occurrences of R ⁵ . In certain embodiments, A ¹ is selected from the groups depicted in the compounds in Table 1 below. [0107] As defined generally above, k is 1, 2, 3, or 4. In certain embodiments, k is 1. In certain embodiments, k is 2. In certain embodiments, k is 3. In certain embodiments, k is 4. In certain embodiments, k is selected from the corresponding value in the groups depicted in the compounds in Table 1 below. [0108] As defined generally above, m and n are independently 0, 1, or 2. In certain embodiments, m is 0. In certain embodiments, m is 1. In certain embodiments, m is 2. In certain embodiments, n is 0. In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, m is selected from the corresponding value in the groups depicted in the compounds in Table 1 below. In certain embodiments, n is selected from the corresponding value in the groups depicted in the compounds in Table 1 below. [0109] In certain embodiments, the that is substituted by one occurrence of R ^II-1A . [0110] In certain embodiments, the that is substituted by one occurrence of R ^II-1A . In certain embodiments, the TPL is In certain embodiments, the TPL is [0111] In certain embodiments, the EPL is defined by Formula II-2 that is substituted by one occurrence of R ^II-2A , wherein Formula II-2 is represented by: ; wherein R ^II-2A is a bond to L; R ^1A represents independently for each occurrence C ₁ -C ₆ alkoxy, hydroxyl, or C ₁ -C ₆ alkyl; R ^2A , R ^3A , R ^4A , R ^5A , and R ^6A are independently hydrogen, C _1-4 alkyl, or C _3-4 cycloalkyl; R ^7A is C _3-7 cycloalkyl, C _1-6 alkyl, or -(C _1-6 alkylene)-(C _3-7 cycloalkyl); and p is 0, 1, or 2. [0112] In certain embodiments, the substituted by one occurrence of R ^II-2A , wherein R ^II-2A is a bond to L. [0113] In certain embodiments, the R ^1A represents independently for each occurrence C ₁ -C ₆ alkoxy, hydroxyl, or C ₁ -C ₆ alkyl; R ^2A , R ^3A , R ^4A , R ^5A , and R ^6A are independently hydrogen, C _1-4 alkyl, or C _3-4 cycloalkyl; R ^7A is C _3-7 cycloalkyl, C _1-6 alkyl, or -(C _1-6 alkylene)-(C _3-7 cycloalkyl); and p is 0, 1, or 2 [0114] In certain embodiments, the certain embodiments, the certain embodiments, the EPL is . In certain embodiments, the . In certain embodiments, the certain embodiments, the [0115] In certain embodiments, R ^1A is C ₁ -C ₆ alkoxy. In certain embodiments, R ^1A is methoxy. In certain embodiments, R ^1A is hydroxyl. In certain embodiments, R ^1A is C ₁ -C ₆ alkyl. In certain embodiments, R ^1A is selected from the groups depicted in the compounds in Table 1 below. [0116] In certain embodiments, R ^2A is hydrogen. In certain embodiments, R ^2A is C _1-4 alkyl. In certain embodiments, R ^2A is C _3-4 cycloalkyl. In certain embodiments, R ^2A is selected from the groups depicted in the compounds in Table 1 below. [0117] In certain embodiments, R ^3A is hydrogen. In certain embodiments, R ^3A is C _1-4 alkyl. In certain embodiments, R ^3A is C _3-4 cycloalkyl. In certain embodiments, R ^3A is selected from the groups depicted in the compounds in Table 1 below. [0118] As In certain embodiments, R ^4A is hydrogen. In certain embodiments, R ^4A is C _1-4 alkyl. In certain embodiments, R ^4A is methyl. In certain embodiments, R ^4A is C _3-4 cycloalkyl. In certain embodiments, R ^4A is selected from the groups depicted in the compounds in Table 1 below. [0119] In certain embodiments, R ^5A is hydrogen. In certain embodiments, R ^5A is C _1-4 alkyl. In certain embodiments, R ^5A is C _3-4 cycloalkyl. In certain embodiments, R ^5A is selected from the groups depicted in the compounds in Table 1 below. [0120] In certain embodiments, R ^6A is hydrogen. In certain embodiments, R ^6A is C _1-4 alkyl. In certain embodiments, R ^6A is ethyl. In certain embodiments, R ^6A is C _3-4 cycloalkyl. In certain embodiments, R ^6A is selected from the groups depicted in the compounds in Table 1 below. [0121] In certain embodiments, R ^7A is C _3-7 cycloalkyl. In certain embodiments, R ^7A is cyclopentyl. In certain embodiments, R ^7A is C _1-6 alkyl. In certain embodiments, R ^7A is -(C _1-6 alkylene)-(C _3-7 cycloalkyl). In certain embodiments, R ^7A is selected from the groups depicted in the compounds in Table 1 below. [0122] In certain embodiments, p is 2. In certain embodiments, p is 1. In certain embodiments, p is 0. In certain embodiments, p is selected from the corresponding value in the groups depicted in the compounds in Table 1 below. [0123] In certain embodiments, the EPL is selected from the groups depicted in the compounds in Table 1 below. [0124] In certain embodiments, the EPL is defined by variable A ² set forth above in connection with Formula I. In certain embodiments, the EPL is defined by one or more of the embodiments for variable A ² set forth in connection with Formula I. [0125] The compounds may be further characterized according to, for example, the identity of L. Exemplary further embodiments for L are provided in Part C below. Part C: Exemplary Further Description of Linker (L) Component of Compounds of Formula I and II [0126] Compounds of Formula I and II may be further characterized according to, for example, the identity of the linker (L) component. A variety of linkers are known to one of skill in the art and may be used in the heterobifunctional compounds described herein. For example, in certain embodiments, L comprises one or more optionally substituted groups selected from amino acids, polyether chains, aliphatic groups, and any combinations thereof. In certain embodiments, L consists of one or more optionally substituted groups selected from amino acids, polyether chains, aliphatic groups, and any combinations thereof. In certain embodiments, L consists of one or more groups selected from amino acids, polyether chains, aliphatic groups, and any combinations thereof. [0127] In some embodiments, L is symmetrical. In some embodiments, L is asymmetric. In certain embodiments, L is a bond. [0128] In certain embodiments, L is a covalent bond or a bivalent C _1-30 saturated or unsaturated, straight or branched, hydrocarbon chain, wherein 1-15 methylene units of L are optionally and independently replaced by cyclopropylene, -N(H)-, -N(C _1-4 alkyl)-, -N(C _3-5 cycloalkyl)-, -O-, - C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, -S(O) ₂ -, -S(O) ₂ N(H)-, -S(O) ₂ N(C _1-4 alkyl)-, -S(O) ₂ N(C _3-5 cycloalkyl)-, -N(H)C(O)-, -N(C _1-4 alkyl)C(O)-, -N(C _3-5 cycloalkyl)C(O)-, -C(O)N(H)-, -C(O)N(C _1- 4 alkyl)-, -C(O)N(C _3-5 cycloalkyl)-, phenylene, an 8-10 membered bicyclic arylene, a 4-7 membered saturated or partially unsaturated carbocyclylene, an 8-10 membered bicyclic saturated or partially unsaturated carbocyclylene, a 3-7 membered saturated or partially unsaturated heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic saturated or partially unsaturated heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroarylene having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [0129] In certain embodiments, L is a bivalent, saturated or unsaturated, straight or branched C _1-6 0 hydrocarbon chain, wherein 0-20 methylene units of the hydrocarbon are independently replaced with -O-, -S-, -N(H)-, -N(C _1-6 alkyl)-, -OC(O)-, -C(O)O-, -S(O)-, -S(O) ₂ -, -N(H)S(O) ₂ -, - N(C _1-6 alkyl)S(O) ₂ -, -S(O) ₂ N(H)-, -S(O) ₂ N(C _1-6 alkyl)-, -N(H)C(O)-, -N(C _1-6 alkyl)C(O)-, - C(O)N(H)-, -C(O)N(C _1-6 alkyl)-, -OC(O)N(H)-, -OC(O)N(C _1-6 alkyl)-, -N(H)C(O)O-, -N(C _1-6 alkyl)C(O)O-, -N(C _3-7 cycloalkyl), -optionally substituted 3-10 membered carbocyclyl, or optionally substituted 3-10 membered heterocyclyl containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [0130] In certain embodiments, L is a bivalent, saturated or unsaturated, straight or branched C _1-6 0 hydrocarbon chain, wherein 0-20 methylene units of the hydrocarbon are independently replaced with -O-, -S-, -N(R**)-, -OC(O)-, -C(O)O-, -S(O)-, -S(O) ₂ -, -N(R**)S(O) ₂ -, - S(O) ₂ N(R**)-, -N(R**)C(O)-, -C(O)N(R**)-, -OC(O)N(R**)-, -N(R**)C(O)O-, optionally substituted 3-10 membered carbocyclyl, or optionally substituted 3-10 membered heterocyclyl containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R** represents independently for each occurrence hydrogen, C _1-6 alkyl, or C _3-6 cycloalkyl. [0131] In certain embodiments, L is a bivalent, saturated or unsaturated, straight or branched C _1-6 0 hydrocarbon chain, wherein 0-20 methylene units of the hydrocarbon are independently replaced with -O-, -S-, -N(H)-, -N(C _1-6 alkyl)-, -OC(O)-, -C(O)O-, -S(O)-, -S(O) ₂ -, -N(H)S(O) ₂ -, - N(C _1-6 alkyl)S(O) ₂ -, -S(O) ₂ N(H)-, -S(O) ₂ N(C _1-6 alkyl)-, -N(H)C(O)-, -N(C _1-6 alkyl)C(O)-, - C(O)N(H)-, -C(O)N(C _1-6 alkyl)-, -OC(O)N(H)-, -OC(O)N(C _1-6 alkyl)-, -N(H)C(O)O-, -N(C _1-6 alkyl)C(O)O-, optionally substituted 3-10 membered carbocyclyl, or optionally substituted 3-10 membered heterocyclyl containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [0132] In certain embodiments, L is a bivalent, saturated, straight or branched C _3-30 hydrocarbon chain, wherein 0-15 methylene units of the hydrocarbon are independently replaced with -O-, -N(H)-, -N(C _1-6 alkyl)-, -OC(O)-, -C(O)O-, -N(H)C(O)-, -N(C _1-6 alkyl)C(O)-, - C(O)N(H)-, -C(O)N(C _1-6 alkyl)-, 3-10 membered carbocyclyl, or 3-10 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [0133] In certain embodiments, L is a bivalent, saturated, straight or branched C _3-30 hydrocarbon chain, wherein 0-15 methylene units of the hydrocarbon are independently replaced with -O-, -N(H)-, -N(C _1-6 alkyl)-, -OC(O)-, -C(O)O-, -N(H)C(O)-, -N(C _1-6 alkyl)C(O)-, - C(O)N(H)-, or -C(O)N(C _1-6 alkyl)-. [0134] In yet other embodiments, L comprises a polyethylene glycol chain ranging in size from about 1 to about 12 ethylene glycol units, from about 1 to about 10 ethylene glycol units, from about 2 to about 6 ethylene glycol units, from about 2 to about 5 ethylene glycol units, or from about 2 to about 4 ethylene glycol units. In yet other embodiments, L is a diradical of a polyethylene glycol chain ranging in size from about 1 to about 12 ethylene glycol units, from about 1 to about 10 ethylene glycol units, from about 2 to about 6 ethylene glycol units, from about 2 to about 5 ethylene glycol units, or from about 2 to about 4 ethylene glycol units. [0135] In certain embodiments, L is a heteroalkylene having from 4 to 30 atoms selected from carbon, oxygen, nitrogen, and sulfur. In certain embodiments, L is a heteroalkylene having from 4 to 20 atoms selected from carbon, oxygen, nitrogen, and sulfur. In certain embodiments, L is a heteroalkylene having from 4 to 10 atoms selected from carbon, oxygen, nitrogen, and sulfur. In certain embodiments, L is a heteroalkylene having from 4 to 30 atoms selected from carbon, oxygen, and nitrogen. In certain embodiments, L is a heteroalkylene having from 4 to 20 atoms selected from carbon, oxygen, and nitrogen. In certain embodiments, L is a heteroalkylene having from 4 to 10 atoms selected from carbon, oxygen, and nitrogen. In certain embodiments, L is a heteroalkylene having from 4 to 30 atoms selected from carbon and oxygen. In certain embodiments, L is a heteroalkylene having from 4 to 20 atoms selected from carbon and oxygen. In certain embodiments, L is a heteroalkylene having from 4 to 10 atoms selected from carbon and oxygen. [0136] In additional embodiments, the L is an optionally substituted (poly)ethyleneglycol having between 1 and about 100 ethylene glycol units, between about 1 and about 50 ethylene glycol units, between 1 and about 25 ethylene glycol units, between about 1 and about 10 ethylene glycol units, between 1 and about 8 ethylene glycol units, between 1 and about 6 ethylene glycol units, between 2 and about 4 ethylene glycol units, or optionally substituted alkyl groups interdispersed with optionally substituted, O, N, S, P or Si atoms. In certain embodiments, L is substituted with an aryl, phenyl, benzyl, alkyl, alkylene, or heterocycle group. [0137] In certain embodiments, L is a bivalent, saturated or unsaturated, straight or branched C _1-45 hydrocarbon chain, wherein 0-10 methylene units of the hydrocarbon are independently replaced with -O-, -S-, -N(R**)-, -OC(O)-, -C(O)O-, -S(O)-, -S(O) ₂ -, -N(R**)S(O) ₂ -, - S(O) ₂ N(R**)-, -N(R**)C(O)-, -C(O)N(R**)-, -OC(O)N(R**)-, -N(R**)C(O)O-, optionally substituted carbocyclyl, or optionally substituted heterocyclyl, wherein R** represents independently for each occurrence hydrogen, C _1-6 alkyl, or C _3-6 cycloalkyl. [0138] In certain embodiments, L is a bivalent, saturated or unsaturated, straight or branched C _1-45 hydrocarbon chain, wherein 0-10 methylene units of the hydrocarbon are independently replaced with -O-, -S-, -N(R**)-, -OC(O)-, -C(O)O-, -S(O)-, -S(O) ₂ -, -N(R**)S(O) ₂ -, - S(O) ₂ N(R**)-, -N(R**)C(O)-, -C(O)N(R**)-, -OC(O)N(R**)-, -N(R**)C(O)O-, optionally substituted 3-10 membered carbocyclyl, or optionally substituted 3-10 membered heterocyclyl containing 1, 2, 3, or 4 heteroatoms selected from nitrogen, oxygen, and sulfur, wherein R** represents independently for each occurrence hydrogen, C _1-6 alkyl, or C _3-6 cycloalkyl. [0139] In certain embodiments, L has the formula -N(R)-(optionally substituted 3-20 membered heteroalkylene)p-CH ₂ -C(O)-, wherein R is hydrogen or optionally substituted C ₁ -C ₆ alkyl, and p is 0 or 1. [0140] In certain embodiments, L has the formula -N(R)-(3-20 membered heteroalkylene) _p - CH ₂ -C(O)-; wherein the 3-20 membered heteroalkylene is optionally substituted with 1, 2, 3, or 4 substituents independently selected from halogen, C ₁ -C ₆ haloalkyl, C ₃ -C ₆ cycloalkyl, hydroxyl, and cyano; R is hydrogen or optionally substituted C ₁ -C ₆ alkyl; and p is 0 or 1. [0141] In certain embodiments, L has the formula -N(R)-(3-20 membered heteroalkylene)p- CH ₂ -C(O)-; wherein the 3-20 membered heteroalkylene is optionally substituted with 1, 2, or 3 substituents independently selected from halogen and C ₁ -C ₆ haloalkyl; R is hydrogen or C ₁ -C ₆ alkyl; and p is 0 or 1. [0142] In certain embodiments, L is a bivalent, saturated or unsaturated, straight or branched C _1-60 hydrocarbon chain, wherein 0-20 methylene units of the hydrocarbon are independently replaced with -O-, -S-, -N(H)-, -N(C _1-6 alkyl)-, -OC(O)-, -C(O)O-, -S(O)-, -S(O) ₂ -, -N(H)S(O) ₂ -, - N(C _1-6 alkyl)S(O) ₂ -, -S(O) ₂ N(H)-, -S(O) ₂ N(C _1-6 alkyl)-, -N(H)C(O)-, -N(C _1-6 alkyl)C(O)-, - C(O)N(H)-, -C(O)N(C _1-6 alkyl)-, -OC(O)N(H)-, -OC(O)N(C _1-6 alkyl)-, -N(H)C(O)O-, -N(C _1-6 alkyl)C(O)O-, optionally substituted 3-10 membered carbocyclyl, or optionally substituted 3-10 membered heterocyclyl containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [0143] In certain embodiments, L is a bivalent, saturated, straight or branched C _3-30 hydrocarbon chain, wherein 0-15 methylene units of the hydrocarbon are independently replaced with -O-, -N(H)-, -N(C _1-6 alkyl)-, -OC(O)-, -C(O)O-, -N(H)C(O)-, -N(C _1-6 alkyl)C(O)-, - C(O)N(H)-, -C(O)N(C _1-6 alkyl)-, 3-10 membered carbocyclyl, or 3-10 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [0144] In certain embodiments, L is a bivalent, saturated, straight or branched C3-30 hydrocarbon chain, wherein 0-15 methylene units of the hydrocarbon are independently replaced with -O-, -N(H)-, -N(C _1-6 alkyl)-, -OC(O)-, -C(O)O-, -N(H)C(O)-, -N(C _1-6 alkyl)C(O)-, - C(O)N(H)-, or -C(O)N(C _1-6 alkyl)-. [0145] In certain embodiments, L is a bivalent, saturated or unsaturated, straight or branched C _5-40 hydrocarbon chain, wherein 1-20 methylene units of the hydrocarbon are independently replaced with -O-, -N(H)-, -N(C _1-6 alkyl)-, -N(H)C(O)-, -N(C _1-6 alkyl)C(O)-, -C(O)N(H)-, - C(O)N(C _1-6 alkyl)-, optionally substituted 3-10 membered carbocyclyl, or optionally substituted 3- 10 membered heterocyclyl containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [0146] In certain embodiments, L is -(3-7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(OCH ₂ CH ₂ ) _1-15 -N(H)C(O)-***, -(3-7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(OCH ₂ CH ₂ ) _1-15 -C(O)N(H)-***, -(3-7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(OCH ₂ CH ₂ ) _1-15 -N(C _1-6 alkyl)C(O)-***, or - (3-7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(OCH ₂ CH ₂ ) _1-15 -C(O)N(C _1-6 alkyl)-***, wherein *** is the point of attachment to A ² . [0147] In certain embodiments, L is -(3-7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(OCH ₂ CH ₂ ) _1-15 -(C _1-6 alkylene)-N(H)C(O)- ***, -(3-7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(OCH ₂ CH ₂ ) _1-15 -(C _1-6 alkylene)-C(O)N(H)-***, -(3-7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)- (OCH ₂ CH ₂ ) _1-15 -(C _1-6 alkylene)-N(C _1-6 alkyl)C(O)-***, or -(3-7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(OCH ₂ CH ₂ ) _1-15 -(C _1-6 alkylene)-C(O)N(C _1-6 alkyl)-***, wherein *** is the point of attachment to A ² . [0148] In certain embodiments, L is -(3-7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(OCH ₂ CH ₂ ) _1-10 -N(H)C(O)-***, -(3-7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(OCH ₂ CH ₂ ) _1-10 -C(O)N(H)-***, -(3-7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(OCH ₂ CH ₂ ) _1-10 -N(C _1-6 alkyl)C(O)-***, or - (3-7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(OCH ₂ CH ₂ ) _1-10 -C(O)N(C _1-6 alkyl)-***, wherein *** is the point of attachment to A ² . In certain embodiments, L is -(3-7 membered monocyclic saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(C _1-6 alkylene)-N(H)C(O)-***, wherein *** is the point of attachment to A ² . [0149] In certain embodiments, L is -(piperidinylene)-(OCH ₂ CH ₂ ) _1-10 -N(H)C(O)-***, - (piperidinylene)-(OCH ₂ CH ₂ ) _1-10 -C(O)N(H)-***, -(piperidinylene)-(OCH ₂ CH ₂ ) _1-10 -N(C _1-6 alkyl)C(O)-***, or -(piperidinylene)-(OCH ₂ CH ₂ ) _1-10 -C(O)N(C _1-6 alkyl)-***, wherein *** is the point of attachment to A ² . [0150] In certain embodiments, L is , wherein *** is the point of attachment to A ² . In certain embodiments, L is , wherein *** is the point of attachment to A ² . In certain embodiments, L is , wherein *** is the point of attachment to A ² . [0151] In certain embodiments, L is -(3-7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(OCH ₂ CH ₂ ) _1-15 -N(H)C(O)-C _1-10 alkylene- ***, -(3-7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(OCH ₂ CH ₂ ) _1-15 -N(C _1-4 alkyl)C(O)-C _1-10 alkylene-***, -(3-7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)- (OCH ₂ CH ₂ ) _1-15 -C(O)N(H)-C _1-10 alkylene-***, or -(3-7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(OCH ₂ CH ₂ ) _1-15 -C(O)N(C1- ₄ alkyl)-C _1-10 alkylene-***, wherein *** is the point of attachment to A ² . [0152] In certain embodiments, L is -piperidinylene-(OCH ₂ CH ₂ )1-5-N(H)C(O)-C1-5 alkylene- ***, -piperidinylene-(OCH ₂ CH ₂ )1-5-N(C _1-4 alkyl)C(O)-C1-5 alkylene-***, -piperidinylene- (OCH ₂ CH ₂ ) _1-5 -C(O)N(H)-C _1-5 alkylene-***, or -piperidinylene-(OCH ₂ CH ₂ ) _1-5 -C(O)N(C _1-4 alkyl)- C _1-5 alkylene-***, wherein *** is the point of attachment to A ² . [0153] In certain embodiments, L is -(3-7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(OCH ₂ CH ₂ )1-10-***, -(3-7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(C _0- 10 alkylene)-O-***, or -(3-7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-C _1-10 alkylene, wherein *** is the point of attachment to A ² . [0154] In certain embodiments, L is -piperidinylene-(OCH ₂ CH ₂ ) _1-5 -***, -piperidinylene-(C _0-5 alkylene)-O-***, or -piperidinylene-(C1-5 alkylene)-***, wherein *** is the point of attachment to A ² . [0155] In certain embodiments, L is -(3-7 membered monocyclic saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-X ¹ -N(H)C(O)-***, -(3-7 membered monocyclic saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-X ¹ - C(O)N(H)-***, -(3-7 membered monocyclic saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-X ¹ -N(C _1-4 alkyl)C(O)-***, or -(3-7 membered monocyclic saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-X ¹ -C(O)N(C _1-4 alkyl)-***, wherein *** is the point of attachment to A ² , and X ¹ is (a) a 3-7 membered monocyclic saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen, or (b) -(3-7 membered monocyclic saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(C _1-10 alkylene)-. [0156] In certain embodiments, L is -(3-7 membered monocyclic saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-X ¹ -***, wherein *** is the point of attachment to A ² , and X ¹ is (i) C _1-15 alkylene where 1, 2, 3, or 4 methylene groups are optionally replaced by -O-, -N(H)-, -N(C _1-4 alkyl)-, -N(H)C(O)-, -N(C _1-4 alkyl)C(O)-, -C(O)N(H)-, or - C(O)N(C _1-4 alkyl)-, (ii) a 3-7 membered monocyclic saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen, or (iii) -(3-7 membered monocyclic saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(C _1-10 alkylene)-. [0157] In certain embodiments, L is -(3-7 membered monocyclic saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-X ¹ -***, wherein *** is the point of attachment to A ² , and X ¹ is (i) C _1-10 alkylene where 1 or 2 methylene groups are optionally replaced by -O-, -N(H)-, -N(C _1-4 alkyl)-, -N(H)C(O)-, -N(C _1-4 alkyl)C(O)-, -C(O)N(H)-, or - C(O)N(C _1-4 alkyl)-, (ii) a 3-7 membered monocyclic saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen, or (iii) -(3-7 membered monocyclic saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(C _1-10 alkylene)-. [0158] In certain embodiments, L is -(piperidinylene)-X ¹ -***, wherein *** is the point of attachment to A ² , and X ¹ is (i) C _1-5 alkylene where 1 or 2 methylene groups are optionally replaced by -O-, -N(H)-, -N(C _1-4 alkyl)-, -N(H)C(O)-, -N(C _1-4 alkyl)C(O)-, -C(O)N(H)-, or -C(O)N(C _1-4 alkyl)-, (ii) a 3-4 membered monocyclic saturated heterocyclic ring containing 1 heteroatom selected from nitrogen, or (iii) -(3-4 membered monocyclic saturated heterocyclic ring containing 1 heteroatom selected from nitrogen)-(C1-5 alkylene)-. [0159] In certain embodiments, L is , wherein *** is the point of attachment to A ² , and X ¹ is (i) C _1-10 alkylene where 1 or 2 methylene groups are optionally replaced by -O-, - N(H)-, -N(C _1-4 alkyl)-, -N(H)C(O)-, -N(C _1-4 alkyl)C(O)-, -C(O)N(H)-, or -C(O)N(C _1-4 alkyl)-, (ii) a 3-7 membered monocyclic saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen, or (iii) -(3-7 membered monocyclic saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(C _1-10 alkylene)-. [0160] In certain embodiments, L is -(3-7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(C _1-10 alkylene where 1 or 2 methylene groups are optionally replaced by -O-, -N(H)-, or -N(C _1-4 alkyl)-)-(3-7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(C _0-8 alkylene)- N(H)C(O)-***, -(3-7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(C _1-10 alkylene where 1 or 2 methylene groups are optionally replaced by -O-, -N(H)-, -N(C _1-4 alkyl)-)-(3-7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(C _0-8 alkylene)-N(C _1-4 alkyl)C(O)-***, -(6- 10 membered, spirocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-C(O)-***, -(6-10 membered, spirocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(C _0-4 alkylene)-N(H)C(O)-***, -(6-10 membered, spirocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(C _0-4 alkylene)- C(O)-***, -(6-10 membered, spirocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(C _0-4 alkylene)-N(C _1-4 alkyl)C(O)-***, -(6-10 membered, bicyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-C(O)-***, -(6-10 membered, bicyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(C _0-4 alkylene)-N(H)C(O)-***, -(6-10 membered, bicycyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(C _0-4 alkylene)-C(O)-***, -(6-10 membered, bicycyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(C _0-4 alkylene)-N(C _1-4 alkyl)C(O)-***, or -(3-7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-N(C _3-6 cycloalkyl)-(C _3-6 cycloalkylene- N(H)C(O)-***, wherein *** is the point of attachment to A ² . [0161] In certain embodiments, L is -(3-7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(C _1-10 alkylene where 1 or 2 methylene groups are optionally replaced by -O-, -N(H)-, or -N(C _1-4 alkyl)-)-(3-7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(C0-8 alkylene)- N(H)C(O)-*** or -(3-7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(C _1-10 alkylene where 1 or 2 methylene groups are optionally replaced by -O-, -N(H)-, or -N(C _1-4 alkyl)-)-(3-7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(C _0-8 alkylene)-N(C _1-4 alkyl)C(O)-***, wherein *** is the point of attachment to A ² . [0162] In certain embodiments, L is L is -(C _3-6 cycloalkylene)-(C _1-10 alkylene where 1 or 2 methylene groups are optionally replaced by -O-, -N(H)-, or -N(C _1-4 alkyl)-)-N(H)C(O)-***, -(C _3-6 cycloalkylene)-(C _1-10 alkylene where 1 or 2 methylene groups are optionally replaced by -O-, - N(H)-, or -N(C _1-4 alkyl)-)-N(C _1-4 alkyl)C(O)-***, -(C _3-6 cycloalkylene)-(C _1-10 alkylene where 1 or 2 methylene groups are optionally replaced by -O-, -N(H)-, or -N(C _1-4 alkyl)-)-C(O)N(H)-***, -(C _3-6 cycloalkylene)-(C _1-10 alkylene where 1 or 2 methylene groups are optionally replaced by -O-, - N(H)-, or -N(C _1-4 alkyl)-)-C(O)N(C _1-4 alkyl)-***, wherein *** is the point of attachment to A ² . In certain embodiments, L is -(C _3-6 cycloalkylene)-(C _1-10 alkylene where 1 or 2 methylene groups are optionally replaced by -O-, -N(H)-, or -N(C _1-4 alkyl)-)-N(H)C(O)-*** or -(C _3-6 cycloalkylene)-(C _1- 10 alkylene where 1 or 2 methylene groups are optionally replaced by -O-, -N(H)-, or -N(C _1-4 alkyl)-)-N(C _1-4 alkyl)C(O)-***, wherein *** is the point of attachment to A ² . [0163] In certain embodiments, L is -N(C _1-3 alkyl)-(C _2-7 alkylene)-N(H)C(O)-***, -N(H)-(C _2-7 alkylene)-N(H)C(O)-***, -N(H)-(C2-7 alkylene)-N(C _1-3 alkyl)C(O)-***, -N(C _1-3 alkyl)-(C2-7 alkylene)-N(C _1-3 alkyl)C(O)-***, -N(C _1-3 alkyl)-(C _2-7 alkylene)-C(O)N(H)-***, -N(H)-(C _2-7 alkylene)-C(O)N(H)-***, -N(H)-(C _2-7 alkylene)-C(O)N(C _1-3 alkyl)-***, -N(C _1-3 alkyl)-(C _2-7 alkylene)-C(O)N(C _1-3 alkyl)-***, -N(C _1-3 alkyl)-[(C _2-4 alkylene)-O-]2-8-(C _2-6 alkylene)-N(H)C(O)- ***, -N(H)-[(C _2-4 alkylene)-O-]2-8-(C _2-6 alkylene)-N(H)C(O)-***, -N(H)-[(C _2-4 alkylene)-O-]2-8- (C _2-6 alkylene)-N(C _1-3 alkyl)C(O)-***, -N(C _1-3 alkyl)-[(C _2-4 alkylene)-O-] _2-8 -(C _2-6 alkylene)-N(C _1-3 alkyl)C(O)-***, -N(C _1-3 alkyl)-[(C _2-4 alkylene)-O-] _2-8 -(C _2-6 alkylene)-C(O)N(H)-***, -N(H)-[(C _2-4 alkylene)-O-]2-8-(C _2-6 alkylene)-C(O)N(H)-***, -N(H)-[(C _2-4 alkylene)-O-]2-8-(C _2-6 alkylene)- C(O)N(C _1-3 alkyl)-***, or -N(C _1-3 alkyl)-[(C _2-4 alkylene)-O-] _2-8 -(C _2-6 alkylene)-C(O)N(C _1-3 alkyl)- ***, where *** is a point of attachment to A ² . [0164] In certain embodiments, L is -N(C _1-3 alkyl)-(C2-7 alkylene)-N(H)C(O)-***, -N(H)-(C2-7 alkylene)-N(H)C(O)-***, -N(H)-(C _2-7 alkylene)-N(C _1-3 alkyl)C(O)-***, -N(C _1-3 alkyl)-(C _2-7 alkylene)-N(C _1-3 alkyl)C(O)-***, -N(C _1-3 alkyl)-(C _2-7 alkylene)-C(O)N(H)-***, -N(H)-(C _2-7 alkylene)-C(O)N(H)-***, -N(H)-(C2-7 alkylene)-C(O)N(C _1-3 alkyl)-***, -N(C _1-3 alkyl)-(C2-7 alkylene)-C(O)N(C _1-3 alkyl)-***, -N(C _1-3 alkyl)-[(C _2-4 alkylene)-O-]2-8-(C _2-6 alkylene)-N(H)C(O)- ***, -N(H)-[(C _2-4 alkylene)-O-] _2-8 -(C _2-6 alkylene)-N(H)C(O)-***, -N(H)-[(C _2-4 alkylene)-O-] _2-8 - (C _2-6 alkylene)-N(C _1-3 alkyl)C(O)-***, -N(C _1-3 alkyl)-[(C _2-4 alkylene)-O-] _2-8 -(C _2-6 alkylene)-N(C _1-3 alkyl)C(O)-***, -N(C _1-3 alkyl)-[(C _2-4 alkylene)-O-]2-8-(C _2-6 alkylene)-C(O)N(H)-***, -N(H)-[(C _2-4 alkylene)-O-] _2-8 -(C _2-6 alkylene)-C(O)N(H)-***, -N(H)-[(C _2-4 alkylene)-O-] _2-8 -(C _2-6 alkylene)- C(O)N(C _1-3 alkyl)-***, or -N(C _1-3 alkyl)-[(C _2-4 alkylene)-O-]2-8-(C _2-6 alkylene)-C(O)N(C _1-3 alkyl)- ***, where *** is a point of attachment to A ² . [0165] In certain embodiments, L is -N(CH ₃ )-(C _2-7 alkylene)-N(H)C(O)-***, -N(H)-(C _2-7 alkylene)-N(H)C(O)-***, -N(H)-(C2-7 alkylene)-N(CH3)C(O)-***, -N(CH3)-(C2-7 alkylene)- N(CH3)C(O)-***, -N(CH3)-(C2-7 alkylene)-C(O)N(H)-***, -N(H)-(C2-7 alkylene)-C(O)N(H)-***, - N(H)-(C _2-7 alkylene)-C(O)N(CH ₃ )-***, -N(CH ₃ )-(C _2-7 alkylene)-C(O)N(CH ₃ )-***, -N(CH ₃ )-[(C _2-4 alkylene)-O-]2-8-(C _2-6 alkylene)-N(H)C(O)-***, -N(H)-[(C _2-4 alkylene)-O-]2-8-(C _2-6 alkylene)- N(H)C(O)-***, -N(H)-[(C _2-4 alkylene)-O-]2-8-(C _2-6 alkylene)-N(CH3)C(O)-***, -N(CH3)-[(C _2-4 alkylene)-O-] _2-8 -(C _2-6 alkylene)-N(CH ₃ )C(O)-***, -N(CH ₃ )-[(C _2-4 alkylene)-O-] _2-8 -(C _2-6 alkylene)- C(O)N(H)-***, -N(H)-[(C _2-4 alkylene)-O-] _2-8 -(C _2-6 alkylene)-C(O)N(H)-***, -N(H)-[(C _2-4 alkylene)-O-]2-8-(C _2-6 alkylene)-C(O)N(CH3)-***, or -N(CH3)-[(C _2-4 alkylene)-O-]2-8-(C _2-6 alkylene)-C(O)N(CH ₃ )-***, where *** is a point of attachment to A ² . [0166] In certain embodiments, L is -N(C _1-3 alkyl)-(C _1-6 alkylene)-(5-6 membered saturated heterocyclylene containing 1 or 2 heteratoms independently selected from nitrogen and oxygen)- (C _1-6 alkylene)-N(H)C(O)-***, -N(C _1-3 alkyl)-(C _1-6 alkylene)-(5-6 membered saturated heterocyclylene containing 1 or 2 heteratoms independently selected from nitrogen and oxygen)- (C _1-6 alkylene)-N(C _1-3 alkyl)C(O)-***, -N(H)-(C _1-6 alkylene)-(5-6 membered saturated heterocyclylene containing 1 or 2 heteratoms independently selected from nitrogen and oxygen)- (C _1-6 alkylene)-N(C _1-3 alkyl)C(O)-***, -N(H)-(C _1-6 alkylene)-(5-6 membered saturated heterocyclylene containing 1 or 2 heteratoms independently selected from nitrogen and oxygen)- (C _1-6 alkylene)-N(H)C(O)-***, -N(C _1-3 alkyl)-(C _1-6 alkylene)-(5-6 membered saturated heterocyclylene containing 1 or 2 heteratoms independently selected from nitrogen and oxygen)- (C _1-6 alkylene)-C(O)N(H)-***, -N(C _1-3 alkyl)-(C _1-6 alkylene)-(5-6 membered saturated heterocyclylene containing 1 or 2 heteratoms independently selected from nitrogen and oxygen)- (C _1-6 alkylene)-C(O)N(C _1-3 alkyl)-***, -N(H)-(C _1-6 alkylene)-(5-6 membered saturated heterocyclylene containing 1 or 2 heteratoms independently selected from nitrogen and oxygen)- (C _1-6 alkylene)-C(O)N(C _1-3 alkyl)-***, or -N(H)-(C _1-6 alkylene)-(5-6 membered saturated heterocyclylene containing 1 or 2 heteratoms independently selected from nitrogen and oxygen)- (C _1-6 alkylene)-C(O)N(H)-***, where *** is a point of attachment to A ² . [0167] In certain embodiments, L is -N(CH ₃ )-(C _1-6 alkylene)-(5-6 membered saturated heterocyclylene containing 1 or 2 heteratoms independently selected from nitrogen and oxygen)- (C _1-6 alkylene)-N(H)C(O)-***, -N(CH ₃ )-(C _1-6 alkylene)-(5-6 membered saturated heterocyclylene containing 1 or 2 heteratoms independently selected from nitrogen and oxygen)-(C _1-6 alkylene)- N(CH ₃ )C(O)-***, -N(H)-(C _1-6 alkylene)-(5-6 membered saturated heterocyclylene containing 1 or 2 heteratoms independently selected from nitrogen and oxygen)-(C _1-6 alkylene)-N(CH ₃ )C(O)-***, -N(H)-(C _1-6 alkylene)-(5-6 membered saturated heterocyclylene containing 1 or 2 heteratoms independently selected from nitrogen and oxygen)-(C _1-6 alkylene)-N(H)C(O)-***, -N(CH3)-(C _1-6 alkylene)-(5-6 membered saturated heterocyclylene containing 1 or 2 heteratoms independently selected from nitrogen and oxygen)-(C _1-6 alkylene)-C(O)N(H)-***, -N(CH3)-(C _1-6 alkylene)-(5-6 membered saturated heterocyclylene containing 1 or 2 heteratoms independently selected from nitrogen and oxygen)-(C _1-6 alkylene)-C(O)N(CH ₃ )-***, -N(H)-(C _1-6 alkylene)-(5-6 membered saturated heterocyclylene containing 1 or 2 heteratoms independently selected from nitrogen and oxygen)-(C _1-6 alkylene)-C(O)N(CH3)-***, or -N(H)-(C _1-6 alkylene)-(5-6 membered saturated heterocyclylene containing 1 or 2 heteratoms independently selected from nitrogen and oxygen)- (C _1-6 alkylene)-C(O)N(H)-***, where *** is a point of attachment to A ² . [0168] In certain embodiments, L has the formula –(C0-12 alkylene)-(optionally substituted 3-40 membered heteroalkylene)-(C _0-12 alkylene)-. [0169] In certain embodimens, L is C _4-14 alkylene. [0170] In certain embodiments, L is one of the following:

wherein *** is the point of attachment to A ² . [0171] In certain embodiments, L is one of the following:

wherein *** is the point of attachment to A ² . of attachment to A ² . Additional Exemplary Embodiments for L [0173] In certain embodiments, L is -N(H)-(C _2-9 alkylene)-O-(C _1-6 alkylene)-C(O)-***, -N(H)- (C _10-20 alkylene)-O-(C _1-6 alkylene)-C(O)-***, -N(H)-[(C _2-4 alkylene)-O-]2-6-(C _1-6 alkylene)-C(O)- ***, -N(H)-[(C _2-4 alkylene)-O-]7-15-(C _1-6 alkylene)-C(O)-***, -N(H)-(C _1-6 alkylene)-C(O)-***, - N(H)-(C _7-15 alkylene)-C(O)-***, -N(H)-[(C _2-4 alkylene)-O-] _2-6 -(C _1-6 alkylene)-***, -N(H)-[(C _2-4 alkylene)-O-]7-15-(C _1-6 alkylene)-***, -N(H)-(C2-9 alkylene)-O-(C _1-6 alkylene)-C(O)N(C _1-6 alkyl)- (C _1-6 alkylene)-***, -N(H)-(C2-9 alkylene)-O-(C _1-6 alkylene)-C(O)N(H)-(C _1-6 alkylene)-***, -N(H)- [(C _2-4 alkylene)-O-] _2-6 -(C _1-6 alkylene)-N(H)-(C _1-6 alkylene)-***, -N(H)-[(C _2-4 alkylene)-O-] _7-15 -(C _1-6 alkylene)-N(H)-(C _1-6 alkylene)-***, -N(H)-[(C _2-4 alkylene)-O-]2-6-(C _1-6 alkylene)-N(C _1-6 alkyl)-(C1- 6 alkylene)-***, or -N(H)-[(C _2-4 alkylene)-O-]7-15-(C _1-6 alkylene)-N(C _1-6 alkyl)-(C _1-6 alkylene)-***, where *** is a point of attachment to A ² . [0174] In certain embodiments, L is -N(H)-(C _2-9 alkylene)-O-(C _1-6 alkylene)-C(O)-***, -N(H)- (C _10-20 alkylene)-O-(C _1-6 alkylene)-C(O)-***, -N(H)-[CH ₂ CH ₂ -O-]2-6-(C _1-6 alkylene)-C(O)-***, - N(H)-[CH ₂ CH ₂ -O-] _7-15 -(C _1-6 alkylene)-C(O)-***, -N(H)-(C _1-6 alkylene)-C(O)-***, -N(H)-(C _7-15 alkylene)-C(O)-***, -N(H)-[CH ₂ CH ₂ -O-] _2-6 -(C _1-6 alkylene)-***, -N(H)-[CH ₂ CH ₂ -O-] _7-15 -(C _1-6 alkylene)-***, -N(H)-(C2-9 alkylene)-O-(C _1-6 alkylene)-C(O)N(C _1-6 alkyl)-(C _1-6 alkylene)-***, - N(H)-(C2-9 alkylene)-O-(C _1-6 alkylene)-C(O)N(H)-(C _1-6 alkylene)-***, -N(H)-[CH ₂ CH ₂ -O-]2-6-(C _1-6 alkylene)-N(H)-(C _1-6 alkylene)-***, -N(H)-[CH ₂ CH ₂ -O-] _7-15 -(C _1-6 alkylene)-N(H)-(C _1-6 alkylene)- ***, -N(H)-[CH ₂ CH ₂ -O-]2-6-(C _1-6 alkylene)-N(C _1-6 alkyl)-(C _1-6 alkylene)-***, or -N(H)-[CH ₂ CH ₂ - O-]7-15-(C _1-6 alkylene)-N(C _1-6 alkyl)-(C _1-6 alkylene)-***, where *** is a point of attachment to A ² . [0175] In certain embodiments, L is -N(H)-[(C _2-4 alkylene)-O-] _2-6 -(C _1-6 alkylene)-C(O)-***, - N(H)-[(C _2-4 alkylene)-O-] _7-15 -(C _1-6 alkylene)-C(O)-***, -N(H)-(C _1-6 alkylene)-N(C _1-6 alkyl)C(O)- (C _1-6 alkylene)***, -N(H)-(C _1-6 alkylene)-N(H)C(O)-(C _1-6 alkylene)***, -N(H)-(C _2-6 alkylene)-***, -N(H)-(C _7-15 alkylene)-***, -N(C _1-6 alkyl)-(C _2-6 alkylene)-***, -N(C _1-6 alkyl)-(C _7-15 alkylene)-***, - N(H)-[(C _2-4 alkylene)-O-] _2-6 -(C _1-6 alkylene)-***, -N(H)-[(C _2-4 alkylene)-O-] _7-15 -(C _1-6 alkylene)-***, -N(H)-(C _1-6 alkylene)-(3-6 membered heterocycloalkylene)-(C _1-6 alkylene)-N(C _1-6 alkyl)-(C _1-6 alkylene)-***, -N(H)-(C _1-6 alkylene)-(3-6 membered heterocycloalkylene)-(C _1-6 alkylene)-N(H)- (C _1-6 alkylene)-***, -N(H)-(C _2-6 alkylene)-N(H)-(C _1-6 alkylene)-***, or -N(H)-(C _2-6 alkylene)- N(C _1-6 alkyl)-(C _1-6 alkylene)-***, where *** is a point of attachment to A ² . [0176] In certain embodiments, L is -N(H)-[CH ₂ CH ₂ -O-]2-6-(C _1-6 alkylene)-C(O)-***, -N(H)- [CH ₂ CH ₂ -O-] _7-15 -(C _1-6 alkylene)-C(O)-***, -N(H)-(C _1-6 alkylene)-N(C _1-6 alkyl)C(O)-(C _1-6 alkylene)***, -N(H)-(C _1-6 alkylene)-N(H)C(O)-(C _1-6 alkylene)***, -N(H)-(C _2-6 alkylene)-***, - N(H)-(C7-15 alkylene)-***, -N(C _1-6 alkyl)-(C _2-6 alkylene)-***, -N(C _1-6 alkyl)-(C7-15 alkylene)-***, - N(H)-[CH ₂ CH ₂ -O-] _2-6 -(C _1-6 alkylene)-***, -N(H)-[CH ₂ CH ₂ -O-] _7-15 -(C _1-6 alkylene)-***, -N(H)-(C _{1- 6} alkylene)-(3-6 membered heterocycloalkylene)-(C _1-6 alkylene)-N(C _1-6 alkyl)-(C _1-6 alkylene)-***, - N(H)-(C _1-6 alkylene)-(3-6 membered heterocycloalkylene)-(C _1-6 alkylene)-N(H)-(C _1-6 alkylene)- ***, -N(H)-(C _2-6 alkylene)-N(H)-(C _1-6 alkylene)-***, or -N(H)-(C _2-6 alkylene)-N(C _1-6 alkyl)-(C _1-6 alkylene)-***, where *** is a point of attachment to A ² . [0177] In certain embodiments, L is -[(C _2-4 alkylene)-O-]2-6-(C _1-6 alkylene)-***, -[(C _2-4 alkylene)-O-]7-15-(C _1-6 alkylene)-***, -[(C _2-4 alkylene)-O-]2-6-(C _1-6 alkylene)-N(C _1-6 alkyl)(C _1-6 alkylene)-***, -[(C _2-4 alkylene)-O-] _7-15 -(C _1-6 alkylene)-N(C _1-6 alkyl)(C _1-6 alkylene)-***, -[(C _2-4 alkylene)-O-] _2-6 -(C _1-6 alkylene)-N(H)(C _1-6 alkylene)-***, -[(C _2-4 alkylene)-O-] _7-15 -(C _1-6 alkylene)- N(H)(C _1-6 alkylene)-***, -(C1-9 alkylene)-C(O)N(H)-(C _1-6 alkylene)-***, -(C1-9 alkylene)- N(H)C(O)-(C _1-6 alkylene)-***, -(C _1-9 alkylene)-C(O)N(H)-[(C _2-4 alkylene)-O-] _2-6 -(C _1-6 alkylene)- ***, -(C1-9 alkylene)-N(H)C(O)-[(C _2-4 alkylene)-O-]2-6-(C _1-6 alkylene)-***, -(C1-9 alkylene)- C(O)N(H)-[(C _2-4 alkylene)-O-] _7-15 -(C _1-6 alkylene)-***, -(C _1-9 alkylene)-N(H)C(O)-[(C _2-4 alkylene)- O-] _7-15 -(C _1-6 alkylene)-***, -(C _1-9 alkylene)-C(O)N(H)-[(C _2-4 alkylene)-O-] _2-6 -(C _1-6 alkylene)-N(C _1-6 alkyl)-(C _1-6 alkylene)-***, -(C1-9 alkylene)-N(H)C(O)-[(C _2-4 alkylene)-O-]2-6-(C _1-6 alkylene)-N(C _1-6 alkyl)-(C _1-6 alkylene)-***, -(C1-9 alkylene)-C(O)N(H)-[(C _2-4 alkylene)-O-]7-15-(C _1-6 alkylene)-N(C1- ₆ alkyl)-(C _1-6 alkylene)-***, or -(C _1-9 alkylene)-N(H)C(O)-[(C _2-4 alkylene)-O-] _7-15 -(C _1-6 alkylene)- N(C _1-6 alkyl)-(C _1-6 alkylene)-***, where *** is a point of attachment to A ² . [0178] In certain embodiments, L is -[CH ₂ CH ₂ -O-]2-6-(C _1-6 alkylene)-***, -[CH ₂ CH ₂ -O-]7-15- (C _1-6 alkylene)-***, -[CH ₂ CH ₂ -O-] _2-6 -(C _1-6 alkylene)-N(C _1-6 alkyl)(C _1-6 alkylene)-***, -[CH ₂ CH ₂ - O-] _7-15 -(C _1-6 alkylene)-N(C _1-6 alkyl)(C _1-6 alkylene)-***, -[CH ₂ CH ₂ -O-] _2-6 -(C _1-6 alkylene)-N(H)(C _1-6 alkylene)-***, -[CH ₂ CH ₂ -O-]7-15-(C _1-6 alkylene)-N(H)(C _1-6 alkylene)-***, -(C1-9 alkylene)- C(O)N(H)-(C _1-6 alkylene)-***, -(C _1-9 alkylene)-N(H)C(O)-(C _1-6 alkylene)-***, -(C _1-9 alkylene)- C(O)N(H)-[CH ₂ CH ₂ -O-] _2-6 -(C _1-6 alkylene)-***, -(C _1-9 alkylene)-N(H)C(O)-[CH ₂ CH ₂ -O-] _2-6 -(C _1-6 alkylene)-***, -(C1-9 alkylene)-C(O)N(H)-[CH ₂ CH ₂ -O-]7-15-(C _1-6 alkylene)-***, -(C1-9 alkylene)- N(H)C(O)-[CH ₂ CH ₂ -O-] _7-15 -(C _1-6 alkylene)-***, -(C _1-9 alkylene)-C(O)N(H)-[CH ₂ CH ₂ -O-] _2-6 -(C _1-6 alkylene)-N(C _1-6 alkyl)-(C _1-6 alkylene)-***, -(C _1-9 alkylene)-N(H)C(O)-[CH ₂ CH ₂ -O-] _2-6 -(C _1-6 alkylene)-N(C _1-6 alkyl)-(C _1-6 alkylene)-***, -(C1-9 alkylene)-C(O)N(H)-[CH ₂ CH ₂ -O-]7-15-(C _1-6 alkylene)-N(C _1-6 alkyl)-(C _1-6 alkylene)-***, or -(C1-9 alkylene)-N(H)C(O)-[(CH ₂ CH ₂ -O-]7-15-(C _1-6 alkylene)-N(C _1-6 alkyl)-(C _1-6 alkylene)-***, where *** is a point of attachment to A ² . [0179] In certain embodiments, L is -N(H)-[(C _2-4 alkylene)-O-] _2-6 -(C _1-6 alkylene)-N(H)-***, - N(H)-[(C _2-4 alkylene)-O-]7-15-(C _1-6 alkylene)-N(H)-***, -N(C _1-6 alkyl)-[(C _2-4 alkylene)-O-]2-6-(C _1-6 alkylene)-N(H)-***, -N(C _1-6 alkyl)-[(C _2-4 alkylene)-O-] _7-15 -(C _1-6 alkylene)-N(H)-***, -N(C _1-6 alkyl)-[(C _2-4 alkylene)-O-] _2-6 -(C _1-6 alkylene)-N(C _1-6 alkyl)-***, or -N(C _1-6 alkyl)-[(C _2-4 alkylene)-O- ]7-15-(C _1-6 alkylene)-N(C _1-6 alkyl)-***, where *** is a point of attachment to A ² . [0180] In certain embodiments, L is -N(H)-[CH ₂ CH ₂ -O-] _2-6 -(C _1-6 alkylene)-N(H)-***, -N(H)- [CH ₂ CH ₂ -O-] _7-15 -(C _1-6 alkylene)-N(H)-***, -N(C _1-6 alkyl)-[CH ₂ CH ₂ -O-] _2-6 -(C _1-6 alkylene)-N(H)- ***, -N(C _1-6 alkyl)-[CH ₂ CH ₂ -O-]7-15-(C _1-6 alkylene)-N(H)-***, -N(C _1-6 alkyl)-[CH ₂ CH ₂ -O-]2-6-(C _1-6 alkylene)-N(C _1-6 alkyl)-***, or -N(C _1-6 alkyl)-[CH ₂ CH ₂ -O-]7-15-(C _1-6 alkylene)-N(C _1-6 alkyl)-***, where *** is a point of attachment to A ² . [0181] In some embodiments, L is one of the following:

; wherein a dashed bond indicates a point of attachment. [0182] In certain embodiments, L is -C(H)(R ¹⁰⁰ )-, -C(R ¹⁰⁰ ) ₂ -, O, -N(R ¹⁰¹ )-, -S(O) ₂ -, an optionally substituted C _3-7 cycloalkylene, an optionally substituted C _4-7 cycloalkenylene, or an optionally substituted 3-7 membered heterocyclylene containing 1, 2 or 3 heteroatoms selected from oxygen, nitrogen, and sulfur; wherein R ¹⁰⁰ represents independently for each occurrence hydrogen, halogen, C _1-6 alkyl, or C _3-6 cycloalkyl, and R ^{101 is} hydrogen, C _1-6 alkyl, or C _3-6 cycloalkyl. In certain embodiments, R ¹⁰⁰ represents independently for each occurrence hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl. In certain embodiments, R ¹⁰¹ is hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl. [0183] In certain embodiments, L is -CH ₂ -Y ²⁰ -, -C(H)(R ¹⁰⁰ )-Y ²⁰ -, -C(R ¹⁰⁰ ) ₂ -Y ²⁰ -, -O-Y ²⁰ -, - N(R ¹⁰¹ )-Y ²⁰ -, -S(O) ₂ -Y ²⁰ -, -C(O)-Y ²⁰ -, -(optionally substituted C _3-7 cycloalkylene)-Y ²⁰ -, - (optionally substituted C4-7 cycloalkenylene)-Y ²⁰ -, -(optionally substituted 3-7 membered heterocyclylene containing 1, 2 or 3 heteroatoms selected from oxygen, nitrogen, and sulfur)-Y ²⁰ -, -Y ²⁰ -CH ₂ -, -Y ²⁰ -C(H)(R ¹⁰⁰ )-, -Y ²⁰ -C(R ¹⁰⁰ ) ₂ -, -Y ²⁰ -O-, -Y ²⁰ -N(R ¹⁰¹ )-, -Y ²⁰ -S(O) ₂ -, -Y ²⁰ -C(O)-, - Y ²⁰ -(optionally substituted C _3-7 cycloalkylene)-, -Y ²⁰ -(optionally substituted C4-7 cycloalkenylene)- , or -Y ²⁰ -(optionally substituted 3-7 membered heterocyclylene containing 1, 2 or 3 heteroatoms selected from oxygen, nitrogen, and sulfur)-; wherein R ¹⁰⁰ represents independently for each occurrence hydrogen, halogen, C _1-6 alkyl, or C _3-6 cycloalkyl, and R ¹⁰¹ is hydrogen, C _1-6 alkyl, or C _{3- 6} cycloalkyl. In certain embodiments, R ¹⁰⁰ represents independently for each occurrence hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl. In certain embodiments, R ¹⁰¹ is hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl. [0184] In certain embodiments, L is one of the following: [0185] wherein X ²⁰ , Y ²⁰ , and Z ²⁰ are independently -CH ₂ -, -C(H)(R ¹⁰⁰ )-, -C(R ¹⁰⁰ ) ₂ -, O, - N(R ¹⁰¹ )-, -S(O) ₂ -, -C(O)-, an optionally substituted C _3-7 cycloalkylene, or an optionally substituted C _4-7 cycloalkenylene; wherein R ¹⁰⁰ represents independently for each occurrence hydrogen, halogen, C _1-6 alkyl, or C _3-6 cycloalkyl, and R ^{101 is} hydrogen, C _1-6 alkyl, or C _3-6 cycloalkyl. In certain embodiments, R ¹⁰⁰ represents independently for each occurrence hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl. In certain embodiments, R ¹⁰¹ is hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl. [0186] In certain embodiments, L is one of the following: [0187] wherein X ²⁰ , Y ²⁰ , and Z ²⁰ are independently -C(R ¹⁰⁰ )- or -N-; wherein R ¹⁰⁰ represents independently for each occurrence hydrogen, halogen, C _1-6 alkyl, or C _3-6 cycloalkyl. In certain embodiments, R ¹⁰⁰ represents independently for each occurrence hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl. [0188] In certain embodiments, L is -X ²⁰ -Y ²⁰ -Z ²⁰ -, wherein X ²⁰ , Y ²⁰ , and Z ²⁰ are independently -CH ₂ -, -C(H)(R ¹⁰⁰ )-, -C(R ¹⁰⁰ ) ₂ -, O, -N(R ¹⁰¹ )-, -S(O) ₂ -, -C(O)-, an optionally substituted C _3-7 cycloalkylene, an optionally substituted C4-7 cycloalkenylene, or optionally substituted 3-7 membered heterocyclylene containing 1, 2 or 3 heteroatoms selected from oxygen, nitrogen, and sulfur; wherein R ¹⁰⁰ represents independently for each occurrence hydrogen, halogen, C _1-6 alkyl, or C _3-6 cycloalkyl, and R ¹⁰¹ is hydrogen, C _1-6 alkyl, or C _3-6 cycloalkyl. In certain embodiments, R ¹⁰⁰ represents independently for each occurrence hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl. In certain embodiments, R ¹⁰¹ is hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl. [0189] In certain embodiments, L is -X ²⁰ =Y ²⁰ -Z ²¹ -, wherein X ²⁰ and Y ²⁰ are independently - C(R ¹⁰⁰ )- or -N-, and Z ²¹ is -CH ₂ -, -C(H)(R ¹⁰⁰ )-, -C(R ¹⁰⁰ ) ₂ -, O, -N(R ¹⁰¹ )-, -S(O) ₂ -, -C(O)-, an optionally substituted C _3-7 cycloalkylene, or an optionally substituted C _4-7 cycloalkenylene; wherein R ¹⁰⁰ represents independently for each occurrence hydrogen, halogen, C _1-6 alkyl, or C _3-6 cycloalkyl, and R ¹⁰¹ is hydrogen, C _1-6 alkyl, or C _3-6 cycloalkyl. In certain embodiments, R ¹⁰⁰ represents independently for each occurrence hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl. In certain embodiments, R ¹⁰¹ is hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl. [0190] In certain embodiments, L is -C≡C-Z ²⁰ -, wherein Z ²⁰ is -CH ₂ -, -C(H)(R ¹⁰⁰ )-, -C(R ¹⁰⁰ ) ₂ -, O, -N(R ¹⁰¹ )-, -S(O) ₂ -, -C(O)-, an optionally substituted C _3-7 cycloalkylene, or an optionally substituted C4-7 cycloalkenylene; wherein R ¹⁰⁰ represents independently for each occurrence hydrogen, halogen, C _1-6 alkyl, or C _3-6 cycloalkyl, and R ¹⁰¹ is hydrogen, C _1-6 alkyl, or C _3-6 cycloalkyl. In certain embodiments, R ¹⁰⁰ represents independently for each occurrence hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl. In certain embodiments, R ¹⁰¹ is hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl. [0191] In certain embodiments, L is one of the following: [0192] wherein X ²⁰ , Y ²⁰ , and Z ²⁰ are independently -CH ₂ -, -C(H)(R ¹⁰⁰ )-, -C(R ¹⁰⁰ ) ₂ -, O, - N(R ¹⁰¹ )-, -S(O) ₂ -, -C(O)-, an optionally substituted C _3-7 cycloalkylene, an optionally substituted C _4- 7 cycloalkenylene, or optionally substituted 3-7 membered heterocyclylene containing 1, 2 or 3 heteroatoms selected from oxygen, nitrogen, and sulfur; wherein R ¹⁰⁰ represents independently for each occurrence hydrogen, halogen, C _1-6 alkyl, or C _3-6 cycloalkyl, and R ¹⁰¹ is hydrogen, C _1-6 alkyl, or C _3-6 cycloalkyl. In certain embodiments, R ¹⁰⁰ represents independently for each occurrence hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl. In certain embodiments, R ¹⁰¹ is hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl. [0193] In certain embodiments, L is one of the following:

[0194] wherein V ²⁰ , W ²⁰ , X ²⁰ , Y ²⁰ , and Z ²⁰ are independently -CH ₂ -, -C(H)(R ¹⁰⁰ )-, -C(R ¹⁰⁰ ) ₂ -, O, -N(R ¹⁰¹ )-, -S(O) ₂ -, -C(O)-, an optionally substituted C _3-7 cycloalkylene, an optionally substituted C _4-7 cycloalkenylene, or optionally substituted 3-7 membered heterocyclylene containing 1, 2 or 3 heteroatoms selected from oxygen, nitrogen, and sulfur; wherein R ¹⁰⁰ represents independently for each occurrence hydrogen, halogen, C _1-6 alkyl, or C _3-6 cycloalkyl, and R ¹⁰¹ is hydrogen, C _1-6 alkyl, or C _3-6 cycloalkyl. In certain embodiments, R ¹⁰⁰ represents independently for each occurrence hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl. In certain embodiments, R ¹⁰¹ is hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl. [0195] In certain embodiments, L is one of the following: [0196] wherein W ²⁰ , X ²⁰ , Y ²⁰ , and Z ²⁰ are independently -C(R ¹⁰⁰ )- or -N-; wherein R ¹⁰⁰ represents independently for each occurrence hydrogen, halogen, C _1-6 alkyl, or C _3-6 cycloalkyl. In certain embodiments, R ¹⁰⁰ represents independently for each occurrence hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl. [0197] In certain embodiments, L is one of the following: [0198] wherein W ²⁰ , X ²⁰ , Y ²⁰ , and Z ²⁰ are independently -C(R ¹⁰⁰ )- or -N-; wherein R ¹⁰⁰ represents independently for each occurrence hydrogen, halogen, C _1-6 alkyl, or C _3-6 cycloalkyl. In certain embodiments, R ¹⁰⁰ represents independently for each occurrence hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl. [0199] In certain embodiments, L is one of the following:

[0200] wherein U, V, W, X, Y, and Z are independently -CH ₂ -, -C(H)(R ¹⁰⁰ )-, -C(R ¹⁰⁰ ) ₂ -, O, - N(R ¹⁰¹ )-, -S(O) ₂ -, -C(O)-, an optionally substituted C _3-7 cycloalkylene, an optionally substituted C4- 7 cycloalkenylene, or optionally substituted 3-7 membered heterocyclylene containing 1, 2 or 3 heteroatoms selected from oxygen, nitrogen, and sulfur; wherein R ¹⁰⁰ represents independently for each occurrence hydrogen, halogen, C _1-6 alkyl, or C _3-6 cycloalkyl; R ¹⁰¹ is hydrogen, C _1-6 alkyl, or C _3-6 cycloalkyl; and a dashed bond indicates a point of attachment. In certain embodiments, R ¹⁰⁰ represents independently for each occurrence hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl. In certain embodiments, R ¹⁰¹ is hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl. [0201] In certain embodiments, L is one of the following: [0202] wherein X, Y, and Z are independently -C(R ¹⁰⁰ )- or -N-; V and W are independently - CH ₂ -, -C(H)(R ¹⁰⁰ )-, -C(R ¹⁰⁰ ) ₂ -, O, -N(R ¹⁰¹ )-, -S(O) ₂ -, -C(O)-, an optionally substituted C _3-7 cycloalkylene, an optionally substituted C _4-7 cycloalkenylene, or optionally substituted 3-7 membered heterocyclylene containing 1, 2 or 3 heteroatoms selected from oxygen, nitrogen, and sulfur; wherein R ¹⁰⁰ represents independently for each occurrence hydrogen, halogen, C _1-6 alkyl, or C _3-6 cycloalkyl; R ¹⁰¹ is hydrogen, C _1-6 alkyl, or C _3-6 cycloalkyl; and a dashed bond indicates a point of attachment. In certain embodiments, R ¹⁰⁰ represents independently for each occurrence hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl. In certain embodiments, R ¹⁰¹ is hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl. [0203] In certain embodiments, L is one of the following: [0204] wherein W, X, Y, and Z are independently -C(R ¹⁰⁰ )- or -N-; V is -CH ₂ -, -C(H)(R ¹⁰⁰ )-, - C(R ¹⁰⁰ ) ₂ -, O, -N(R ¹⁰¹ )-, -S(O) ₂ -, -C(O)-, an optionally substituted C _3-7 cycloalkylene, an optionally substituted C4-7 cycloalkenylene, or optionally substituted 3-7 membered heterocyclylene containing 1, 2 or 3 heteroatoms selected from oxygen, nitrogen, and sulfur; wherein R ¹⁰⁰ represents independently for each occurrence hydrogen, halogen, C _1-6 alkyl, or C _3-6 cycloalkyl; R ¹⁰¹ is hydrogen, C _1-6 alkyl, or C _3-6 cycloalkyl; and a dashed bond indicates a point of attachment. In certain embodiments, R ¹⁰⁰ represents independently for each occurrence hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl. In certain embodiments, R ¹⁰¹ is hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl. [0205] In certain embodiments, L is one of the following:

[0206] wherein T, U, V, W, X, Y, and Z are independently -CH ₂ -, -C(H)(R ¹⁰⁰ )-, -C(R ¹⁰⁰ ) ₂ -, O, - N(R ¹⁰¹ )-, -S(O) ₂ -, -C(O)-, an optionally substituted C _3-7 cycloalkylene, an optionally substituted C _4- 7 cycloalkenylene, or optionally substituted 3-7 membered heterocyclylene containing 1, 2 or 3 heteroatoms selected from oxygen, nitrogen, and sulfur; wherein R ¹⁰⁰ represents independently for each occurrence hydrogen, halogen, C _1-6 alkyl, or C _3-6 cycloalkyl; R ¹⁰¹ is hydrogen, C _1-6 alkyl, or C _3-6 cycloalkyl; and a dashed bond indicates a point of attachment. In certain embodiments, R ¹⁰⁰ represents independently for each occurrence hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl. In certain embodiments, R ¹⁰¹ is hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl. [0207] In certain embodiments, L is one of the following: [0208] wherein W, X, Y, and Z are independently -C(R ¹⁰⁰ )- or -N-; U and V are independently -CH ₂ -, -C(H)(R ¹⁰⁰ )-, -C(R ¹⁰⁰ ) ₂ -, O, -N(R ¹⁰¹ )-, -S(O) ₂ -, -C(O)-, an optionally substituted C _3-7 cycloalkylene, an optionally substituted C _4-7 cycloalkenylene, or optionally substituted 3-7 membered heterocyclylene containing 1, 2 or 3 heteroatoms selected from oxygen, nitrogen, and sulfur; R ¹⁰⁰ represents independently for each occurrence hydrogen, halogen, C _1-6 alkyl, or C _3-6 cycloalkyl; R ¹⁰¹ is hydrogen, C _1-6 alkyl, or C _3-6 cycloalkyl; and a dashed bond indicates a point of attachment. In certain embodiments, R ¹⁰⁰ represents independently for each occurrence hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl. In certain embodiments, R ¹⁰¹ is hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl. [0209] In certain embodiments, L is one of the following: [0210] wherein X, Y, and Z are independently -C(R ¹⁰⁰ )- or -N-; U, V, and W are independently -CH ₂ -, -C(H)(R ¹⁰⁰ )-, -C(R ¹⁰⁰ ) ₂ -, O, -N(R ¹⁰¹ )-, -S(O) ₂ -, -C(O)-, an optionally substituted C _3-7 cycloalkylene, an optionally substituted C _4-7 cycloalkenylene, or optionally substituted 3-7 membered heterocyclylene containing 1, 2 or 3 heteroatoms selected from oxygen, nitrogen, and sulfur; wherein R ¹⁰⁰ represents independently for each occurrence hydrogen, halogen, C _1-6 alkyl, or C _3-6 cycloalkyl; R ¹⁰¹ is hydrogen, C _1-6 alkyl, or C _3-6 cycloalkyl; and a dashed bond indicates a point of attachment. In certain embodiments, R ¹⁰⁰ represents independently for each occurrence hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl. In certain embodiments, R ¹⁰¹ is hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl. [0211] In certain embodiments, L is one of the following:

[0212] variables m, n, o, p, and q are independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

[0213] In certain embodiments, L is one of the following:

wherein any m or n are independently 0, 1, 2, 3, 4, 5, or 6; and any X is H or F. [0214] In certain embodiments, L is one of the following:

wherein any m or n are independently 0, 1, 2, 3, 4, 5, or 6. [0215] In certain embodiments, L is one of the following:

[0216] wherein any m or n are independently 0, 1, 2, 3, 4, 5, or 6. [0217] In certain embodiments, L is one of the following:

[0218] In certain embodiments, L is one of the following:

[0219] In certain embodiments, L has the formula –(C0-12 alkylene)-(optionally substituted 3-40 membered heteroalkylene)-(C0-12 alkylene)-. In certain embodiments, L is C4-14 alkylene. In certain embodiments, L is -(CH ₂ ) _6-10 -. [0220] In certain embodiments, L is -CH ₂ CH ₂ (OCH ₂ CH ₂ )-***, -CH ₂ CH ₂ (OCH ₂ CH ₂ ) ₂ -***, - CH ₂ CH ₂ (OCH ₂ CH ₂ )3-***, -CH ₂ CH ₂ (OCH ₂ CH ₂ )4-***, -CH ₂ CH ₂ (OCH ₂ CH ₂ )5-***, - CH ₂ CH ₂ (OCH ₂ CH ₂ ) ₆ -***, -CH ₂ CH ₂ (OCH ₂ CH ₂ ) ₇ -***, -CH ₂ CH ₂ (OCH ₂ CH ₂ ) ₈ -***, - CH ₂ CH ₂ (OCH ₂ CH ₂ ) ₉ -***, -CH ₂ CH ₂ (OCH ₂ CH ₂ ) ₁₀ -***, -CH ₂ CH ₂ (OCH ₂ CH ₂ ) ₁₁ -***, - CH ₂ CH ₂ (OCH ₂ CH ₂ )12-***, -CH ₂ CH ₂ (OCH ₂ CH ₂ )13-***, -CH ₂ CH ₂ (OCH ₂ CH ₂ )14-***, - point of attachment to [0221] In certain embodiments, L is -(C2-20 alkylene)-(OCH ₂ CH ₂ ) ₂ -4-(C _0-4 alkylene)-***, -(C2-20 alkylene)-(OCH ₂ CH ₂ )5-7-(C _0-4 alkylene)-***, -(C2-20 alkylene)-(OCH ₂ CH ₂ )8-10-(C _0-4 alkylene)-***, -(C _2-20 alkylene)-(OCH ₂ CH ₂ ) _11-13 -(C _0-4 alkylene)-***, -(C _2-20 alkylene)-(OCH ₂ CH ₂ ) _14-16 -(C _0-4 alkylene)-***, -(C _2-20 alkylene)-(OCH ₂ CH ₂ ) _17-20 -(C _0-4 alkylene)-***, -(C _1-20 alkylene)- (OCH ₂ CH ₂ )1-10-(C _0-4 alkylene)-C(O)-***, or -(C1-20 alkylene)-(OCH ₂ CH ₂ )11-20-(C _0-4 alkylene)- C(O)-***, where *** is a point of attachment to A ² . [0222] In certain embodiments, L is -O(CH ₂ CH ₂ O) _2-4 -(C _0-4 alkylene)-***, -O(CH ₂ CH ₂ O) _5-7 - (C _0-4 alkylene)-***, -O(CH ₂ CH ₂ O)8-10-(C _0-4 alkylene)-***, -O(CH ₂ CH ₂ O)11-13-(C _0-4 alkylene)-***, -O(CH ₂ CH ₂ O) _14-16 -(C _0-4 alkylene)-***, -O(CH ₂ CH ₂ O) _16-20 -(C _0-4 alkylene)-***, -O(CH ₂ CH ₂ O) _2-10 - (C _0-4 alkylene)C(O)-***, or -O(CH ₂ CH ₂ O) _11-20 -(C _0-4 alkylene)C(O)-***, where *** is a point of attachment to A ² . [0223] In certain embodiments, L is -(C0-20 alkylene)-(OCH ₂ CH ₂ )1-10-(N(C _1-4 alkyl))-***, -(C0-20 alkylene)-(OCH ₂ CH ₂ ) _11-20 -(N(C _1-4 alkyl))-***, -(C _0-20 alkylene)-(CH ₂ CH ₂ O) _1-10 -(C _2-10 alkylene)- (N(C _1-4 alkyl))-(C0-10 alkylene)-***, or -(C0-20 alkylene)-(CH ₂ CH ₂ O)11-20-(C2-10 alkylene)-(N(C _1-4 alkyl))-(C0-10 alkylene)-***, where *** is a point of attachment to A ² . [0224] In certain embodiments, L is selected from those depicted in the compounds in Table 1, below. Exemplary Specific Compounds [0225] In certain embodiments, the compound is a compound in Table 1, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound in Table 1. In certain embodiments, the compound is any one of compounds I-1 to I-54 in Table 1, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is any one of compounds I-1 to I-54 in Table 1. In certain embodiments, the compound is any one of compounds I-1 to I-67 in Table 1, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is any one of compounds I-1 to I-67 in Table 1.

TABLE 1.

Synthetic Methods [0226] Methods for preparing compounds described herein are illustrated in the following synthetic Schemes. The Schemes are given for the purpose of illustrating the invention, and are not intended to limit the scope or spirit of the invention. Starting materials shown in the Schemes can be obtained from commercial sources or can be prepared based on procedures described in the literature. [0227] In the Schemes, it is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule should be compatible with the reagents and reactions proposed. Substituents not compatible with the reaction conditions will be apparent to one skilled in the art, and alternate methods are therefore indicated (for example, use of protecting groups or alternative reactions). Protecting group chemistry and strategy is well known in the art, for example, as described in detail in “Protecting Groups in Organic Synthesis”, T. W. Greene and P. G. M. Wuts, 3 ^rd edition, John Wiley & Sons, 1999, the entire contents of which are hereby incorporated by reference. [0228] The synthetic route illustrated in Scheme 1 is a general method for preparing compounds of Formula F. Reaction of carboxylic acid A and amine B under amide coupling conditions provides amide C. Removal of the protection group (Pg) from compound C provides compound D. The Pg may be, for example, a Boc protecting group that can be removed by treating the compound with trifluoroacetic acid. Coupling of compound D with compound E (such as a nucleophilic aromatic substitution reaction when X is an amino group and the leaving group in compound E is chloro) provides the final compound of Formula F.

SCHEME 1. [0229] The modular synthetic route illustrated in Scheme 1 can be readily modified to provide additional compounds by conducting functional group transformations on the intermediate and/or final compounds. Such functional group transformations are well known in the art, as described in, for example, Comprehensive Organic Synthesis (B.M. Trost & I. Fleming, eds., 1991-1992); Organic Synthesis, 3 ^rd Ed. (Michael B. Smith, Wavefunction, Inc., Irvine: 2010); Modern Methods of Organic Synthesis, 4 ^th Ed. (William Carruthers and Iain Coldham, Cambridge University Press, Cambridge: 2004); March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 8 ^th Ed., (Michael B. Smith, John Wiley & Sons, New York: 2020); and Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 3rd Ed. (Richard C. Larock, ed., John Wiley & Sons, New York: 2018). Protecting group strategies may be deployed as appropriate to accommodate differing functional groups in the molecules used in the synthetic route. Protecting group chemistry and strategy is described in, for example, Protecting Groups in Organic Synthesis, 3 ^rd Edition, T. W. Greene and P. G. M. Wuts, John Wiley & Sons, 1999 and Greene's Protective Groups in Organic Synthesis, 5th Ed., (Peter G. M. Wuts, John Wiley & Sons: 2014). II. Therapeutic Applications [0230] The heterobifunctional compounds described herein, such as a compound of Formula I, II, or other compounds in Section I, provide therapeutic benefits to patients suffering from cancer. Accordingly, one aspect of the invention provides a method of treating cancer. The method comprises administering to a patient in need thereof a therapeutically effective amount of a compound described herein, such as a compound of Formula I, II, or other compound in Section I, to treat the cancer. In certain embodiments, the compound is a compound of Formula I. In certain embodiments, the particular compound of Formula I is a compound defined by one of the embodiments described above. Cancer [0231] In certain embodiments, the cancer is ovarian cancer, uterine cancer, endometrial cancer, cervical cancer, prostate cancer, testicular cancer, breast cancer, brain cancer, lung cancer, oral cancer, esophageal cancer, head and neck cancer, stomach cancer, colon cancer, rectal cancer, skin cancer, sebaceous gland carcinoma, bile duct and gallbladder cancers, liver cancer, pancreatic cancer, bladder cancer, urinary tract cancer, kidney cancer, eye cancer, thyroid cancer, lymphoma, or leukemia. In certain embodiments, the cancer is prostate cancer. [0232] In certain embodiments, the cancer is squamous cell cancer, lung cancer including small cell lung cancer, non-small cell lung cancer, vulval cancer, thyroid cancer, adenocarcinoma of the lung and squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastric or stomach cancer including gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney or renal cancer, prostate cancer, hepatic carcinoma, anal carcinoma, penile carcinoma, and head and neck cancer. In certain embodiments, the cancer is at least one selected from the group consisting of ALL, T-lineage Acute lymphoblastic Leukemia (T-ALL), T-lineage lymphoblastic Lymphoma (T-LL), Peripheral T-cell lymphoma, Adult T-cell Leukemia, Pre-B ALL, Pre-B Lymphomas, Large B-cell Lymphoma, Burkitts Lymphoma, B-cell ALL, Philadelphia chromosome positive ALL, Philadelphia chromosome positive CML, lymphoma, leukemia, multiple myeloma myeloproliferative diseases, large B cell lymphoma, or B cell Lymphoma. [0233] In certain embodiments, the cancer is a solid tumor or leukemia. In certain other embodiments, the cancer is colon cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, lung cancer, leukemia, bladder cancer, stomach cancer, cervical cancer, testicular cancer, skin cancer, rectal cancer, thyroid cancer, kidney cancer, uterus cancer, espophagus cancer, liver cancer, an acoustic neuroma, oligodendroglioma, meningioma, neuroblastoma, or retinoblastoma. In certain other embodiments, the cancer is small cell lung cancer, non-small cell lung cancer, melanoma, cancer of the central nervous system tissue, brain cancer, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, cutaneous T-Cell lymphoma, cutaneous B-Cell lymphoma, or diffuse large B-Cell lymphoma. In certain other embodiments, the cancer is breast cancer, colon cancer, small-cell lung cancer, non-small cell lung cancer, prostate cancer, renal cancer, ovarian cancer, leukemia, melanoma, or cancer of the central nervous system tissue. In certain other embodiments, the cancer is colon cancer, small-cell lung cancer, non-small cell lung cancer, renal cancer, ovarian cancer, renal cancer, or melanoma. [0234] In certain embodiments, the cancer is a fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, Ewing’s tumor, leiomyosarcoma, rhabdomyosarcoma, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms’ tumor, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, or hemangioblastoma. [0235] In certain embodiments, the cancer is a neuroblastoma, meningioma, hemangiopericytoma, multiple brain metastase, glioblastoma multiforms, glioblastoma, brain stem glioma, poor prognosis malignant brain tumor, malignant glioma, anaplastic astrocytoma, anaplastic oligodendroglioma, neuroendocrine tumor, rectal adeno carcinoma, Dukes C & D colorectal cancer, unresectable colorectal carcinoma, metastatic hepatocellular carcinoma, Kaposi’s sarcoma, karotype acute myeloblastic leukemia, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, cutaneous T-Cell lymphoma, cutaneous B-Cell lymphoma, diffuse large B-Cell lymphoma, low grade follicular lymphoma, metastatic melanoma, localized melanoma, malignant mesothelioma, malignant pleural effusion mesothelioma syndrome, peritoneal carcinoma, papillary serous carcinoma, gynecologic sarcoma, soft tissue sarcoma, scelroderma, cutaneous vasculitis, Langerhans cell histiocytosis, leiomyosarcoma, fibrodysplasia ossificans progressive, hormone refractory prostate cancer, resected high-risk soft tissue sarcoma, unrescectable hepatocellular carcinoma, Waidenstrom’s macroglobulinemia, smoldering myeloma, indolent myeloma, fallopian tube cancer, androgen independent prostate cancer, androgen dependent stage IV non-metastatic prostate cancer, hormone-insensitive prostate cancer, chemotherapy-insensitive prostate cancer, castrate resistant prostate cancer, castrate resistant metastatic prostate cancer, papillary thyroid carcinoma, follicular thyroid carcinoma, medullary thyroid carcinoma, or leiomyoma. [0236] In certain embodiments, the cancer is bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, ovarian cancer, colon cancer, rectal cancer, cancer of the anal region, stomach cancer, gastrointestinal (gastric, colorectal, and duodenal), uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, testicular cancer, chronic or acute leukemia, chronic myeloid leukemia, lymphocytic lymphomas, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis, non-Hodgkins's lymphoma, spinal axis tumors, brain stem glioma, pituitary adenoma, adrenocortical cancer, gall bladder cancer, multiple myeloma, cholangiocarcinoma, fibrosarcoma, neuroblastoma, retinoblastoma, or a combination of one or more of the foregoing cancers. [0237] In certain embodiments, the cancer is hepatocellular carcinoma, ovarian cancer, ovarian epithelial cancer, or fallopian tube cancer; papillary serous cystadenocarcinoma or uterine papillary serous carcinoma (UPSC); prostate cancer; testicular cancer; gallbladder cancer; hepatocholangiocarcinoma; soft tissue and bone synovial sarcoma; rhabdomyosarcoma; osteosarcoma; chondrosarcoma; Ewing sarcoma; anaplastic thyroid cancer; adrenocortical adenoma; pancreatic cancer; pancreatic ductal carcinoma or pancreatic adenocarcinoma; gastrointestinal/stomach (GIST) cancer; lymphoma; squamous cell carcinoma of the head and neck (SCCHN); salivary gland cancer; glioma, or brain cancer; neurofibromatosis-1 associated malignant peripheral nerve sheath tumors (MPNST); Waldenstrom's macroglobulinemia; or medulloblastoma. [0238] In certain embodiments, the cancer is hepatocellular carcinoma (HCC), hepatoblastoma, colon cancer, rectal cancer, ovarian cancer, ovarian epithelial cancer, fallopian tube cancer, papillary serous cystadenocarcinoma, uterine papillary serous carcinoma (UPSC), hepatocholangiocarcinoma, soft tissue and bone synovial sarcoma, rhabdomyosarcoma, osteosarcoma, anaplastic thyroid cancer, adrenocortical adenoma, pancreatic cancer, pancreatic ductal carcinoma, pancreatic adenocarcinoma, glioma, neurofibromatosis-1 associated malignant peripheral nerve sheath tumors (MPNST), Waldenstrom's macroglobulinemia, or medulloblastoma. [0239] In certain embodiments, the cancer is a solid tumor, such as a sarcoma, carcinoma, or lymphoma. In certain embodiments, the cancer is 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 papillary serous carcinoma (UPSC); prostate cancer; testicular cancer; gallbladder cancer; hepatocholangiocarcinoma; soft tissue and bone synovial sarcoma; rhabdomyosarcoma; osteosarcoma; chondrosarcoma; Ewing sarcoma; anaplastic thyroid cancer; adrenocortical carcinoma; pancreatic cancer; pancreatic ductal carcinoma or pancreatic adenocarcinoma; gastrointestinal/stomach (GIST) cancer; lymphoma; squamous cell carcinoma of the head and neck (SCCHN); salivary gland cancer; glioma, or brain cancer; neurofibromatosis-1 associated malignant peripheral nerve sheath tumors (MPNST); Waldenstrom's macroglobulinemia; or medulloblastoma. [0240] In certain embodiments, the cancer is 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 papillary serous carcinoma (UPSC), hepatocholangiocarcinoma, soft tissue and bone synovial sarcoma, rhabdomyosarcoma, osteosarcoma, chondrosarcoma, anaplastic thyroid cancer, adrenocortical carcinoma, pancreatic cancer, pancreatic ductal carcinoma, pancreatic adenocarcinoma, glioma, brain cancer, neurofibromatosis-1 associated malignant peripheral nerve sheath tumors (MPNST), Waldenstrom's macroglobulinemia, or medulloblastoma. [0241] In certain embodiments, the cancer is hepatocellular carcinoma (HCC), hepatoblastoma, colon cancer, rectal cancer, ovarian cancer, ovarian epithelial cancer, ovarian carcinoma, fallopian tube cancer, papillary serous cystadenocarcinoma, uterine papillary serous carcinoma (UPSC), hepatocholangiocarcinoma, soft tissue and bone synovial sarcoma, rhabdomyosarcoma, osteosarcoma, anaplastic thyroid cancer, adrenocortical carcinoma, pancreatic cancer, pancreatic ductal carcinoma, pancreatic adenocarcinoma, glioma, neurofibromatosis-1 associated malignant peripheral nerve sheath tumors (MPNST), Waldenstrom's macroglobulinemia, or medulloblastoma. [0242] In certain 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 papillary serous carcinoma (UPSC). In some embodiments, the cancer is hepatocholangiocarcinoma. 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 carcinoma. In some embodiments, the cancer is pancreatic cancer, or pancreatic ductal carcinoma. 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 tumors (MPNST). In some embodiments, the cancer is neurofibromatosis-1 associated MPNST. In some embodiments, the cancer is Waldenstrom's macroglobulinemia. In some embodiments, the cancer is medulloblastoma. Causing Death of Cancer Cell [0243] Another aspect of the invention provides a method of causing death of a cancer cell. The method comprises contacting a cancer cell with an effective amount of a compound described herein, such as a compound of Formula I or II, or other compounds in Section I, to cause death of the cancer cell. In certain embodiments, the particular compound of Formula I or II is a compound defined by one of the embodiments described above. [0244] In certain embodiments, the cancer cell is selected from ovarian cancer, uterine cancer, endometrial cancer, cervical cancer, prostate cancer, testicular cancer, breast cancer, brain cancer, lung cancer, oral cancer, esophageal cancer, head and neck cancer, stomach cancer, colon cancer, rectal cancer, skin cancer, sebaceous gland carcinoma, bile duct and gallbladder cancers, liver cancer, pancreatic cancer, bladder cancer, urinary tract cancer, kidney cancer, eye cancer, thyroid cancer, lymphoma, or leukemia. In certain embodiments, the cancer cell is one or more of the cancers recited in the section above entitled “Cancer.” In certain embodiments, the cancer cell is a prostate cancer cell. Combination Therapies [0245] The compounds useful within the methods of the invention may be used in combination with one or more additional therapeutic agents useful for treating any disease contemplated herein. These additional therapeutic agents may comprise compounds that are commercially available or synthetically accessible to those skilled in the art. These additional therapeutic agents are known to treat, prevent, or reduce the symptoms, of a disease or disorder contemplated herein. [0246] Accordingly, in certain embodiments, the method further comprises administering to the subject an additional therapeutic agent that treats the disease contemplated herein. [0247] In certain embodiments, administering the compound of the invention to the subject allows for administering a lower dose of the additional therapeutic agent as compared to the dose of the additional therapeutic agent alone that is required to achieve similar results in treating the disease contemplated herein. For example, in certain embodiments, the compound of the invention enhances the therapeutic activity of the additional therapeutic compound, thereby allowing for a lower dose of the additional therapeutic compound to provide the same effect. [0248] A synergistic effect may be calculated, for example, using suitable methods such as, for example, the Sigmoid-Emax equation (Holford & Scheiner, 1981, Clin. Pharmacokinet.6:429-453), the equation of Loewe additivity (Loewe & Muischnek, 1926, Arch. Exp. Pathol Pharmacol. 114:313-326) and the median-effect equation (Chou & Talalay, 1984, Adv. Enzyme Regul.22:27- 55). Each equation referred to above may be applied to experimental data to generate a corresponding graph to aid in assessing the effects of the drug combination. The corresponding graphs associated with the equations referred to above are the concentration-effect curve, isobologram curve and combination index curve, respectively. [0249] In certain embodiments, the compound of the invention and the therapeutic agent are co- administered to the subject. In other embodiments, the compound of the invention and the therapeutic agent are coformulated and co-administered to the subject. [0250] In certain embodiments, the compound is administered in combination with a second therapeutic agent having activity against cancer. In certain embodiments, the second therapeutic agent is mitomycin, tretinoin, ribomustin, gemcitabine, vincristine, etoposide, cladribine, mitobronitol, methotrexate, doxorubicin, carboquone, pentostatin, nitracrine, zinostatin, cetrorelix, letrozole, raltitrexed, daunorubicin, fadrozole, fotemustine, thymalfasin, sobuzoxane, nedaplatin, cytarabine, bicalutamide, vinorelbine, vesnarinone, aminoglutethimide, amsacrine, proglumide, elliptinium acetate, ketanserin, doxifluridine, etretinate, isotretinoin, streptozocin, nimustine, vindesine, flutamide, drogenil, butocin, carmofur, razoxane, sizofilan, carboplatin, mitolactol, tegafur, ifosfamide, prednimustine, picibanil, levamisole, teniposide, improsulfan, enocitabine, lisuride, oxymetholone, tamoxifen, progesterone, mepitiostane, epitiostanol, formestane, interferon-alpha, interferon-2 alpha, interferon-beta, interferon-gamma, colony stimulating factor- 1, colony stimulating factor-2, denileukin diftitox, interleukin-2, and leutinizing hormone releasing factor. [0251] In certain embodiments, the second therapeutic agent is an mTOR inhibitor, which inhibits cell proliferation, angiogenesis and glucose uptake. Approved mTOR inhibitors useful in the present invention include everolimus (Afinitor®, Novartis); temsirolimus (Torisel®, Pfizer); and sirolimus (Rapamune®, Pfizer). [0252] In certain embodiments, the second therapeutic agent is a Poly ADP ribose polymerase (PARP) inhibitor. Approved PARP inhibitors useful in the present invention include olaparib (Lynparza®, AstraZeneca); rucaparib (Rubraca®, Clovis Oncology); and niraparib (Zejula®, Tesaro). Other PARP inhibitors being studied which may be used in the present invention include talazoparib (MDV3800/BMN 673/LT00673, Medivation/Pfizer/Biomarin); veliparib (ABT-888, AbbVie); and BGB-290 (BeiGene, Inc.). [0253] In certain embodiments, the second therapeutic agent is a phosphatidylinositol 3 kinase (PI3K) inhibitor. Approved PI3K inhibitors useful in the present invention include idelalisib (Zydelig®, Gilead). Other PI3K inhibitors being studied which may be used in the present invention include alpelisib (BYL719, Novartis); taselisib (GDC-0032, Genentech/Roche); pictilisib (GDC-0941, Genentech/Roche); copanlisib (BAY806946, Bayer); duvelisib (formerly IPI-145, Infinity Pharmaceuticals); PQR309 (Piqur Therapeutics, Switzerland); and TGR1202 (formerly RP5230, TG Therapeutics). [0254] In certain embodiments, the second therapeutic agent is a proteasome inhibitor. Approved proteasome inhibitors useful in the present invention include bortezomib (Velcade®, Takeda); carfilzomib (Kyprolis®, Amgen); and ixazomib (Ninlaro®, Takeda). [0255] In certain embodiments, the second therapeutic agent is a histone deacetylase (HDAC) inhibitor. Approved HDAC inhibitors useful in the present invention include vorinostat (Zolinza®, Merck); romidepsin (Istodax®, Celgene); panobinostat (Farydak®, Novartis); and belinostat (Beleodaq®, Spectrum Pharmaceuticals). Other HDAC inhibitors being studied which may be used in the present invention include entinostat (SNDX-275, Syndax Pharmaceuticals) (NCT00866333); and chidamide (Epidaza®, HBI-8000, Chipscreen Biosciences, China). [0256] In certain embodiments, the second therapeutic agent is a CDK inhibitor, such as a CDK 4/6 inhibitor. Approved CDK 4/6 inhibitors useful in the present invention include palbociclib (Ibrance®, Pfizer); and ribociclib (Kisqali®, Novartis). Other CDK 4/6 inhibitors being studied which may be used in the present invention include abemaciclib (Ly2835219, Eli Lilly); and trilaciclib (G1T28, G1 Therapeutics). [0257] In certain embodiments, the second therapeutic agent is an indoleamine (2,3)- dioxygenase (IDO) inhibitor. IDO inhibitors being studied which may be used in the present invention include epacadostat (INCB024360, Incyte); indoximod (NLG-8189, NewLink Genetics Corporation); capmanitib (INC280, Novartis); GDC-0919 (Genentech/Roche); PF-06840003 (Pfizer); BMS:F001287 (Bristol-Myers Squibb); Phy906/KD108 (Phytoceutica); and an enzyme that breaks down kynurenine (Kynase, Kyn Therapeutics). [0258] In certain embodiments, the second therapeutic agent is a growth factor antagonist, such as an antagonist of platelet-derived growth factor (PDGF), or epidermal growth factor (EGF) or its receptor (EGFR). Approved PDGF antagonists which may be used in the present invention include olaratumab (Lartruvo®; Eli Lilly). Approved EGFR antagonists which may 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). [0259] In certain embodiments, the second therapeutic agent is an aromatase inhibitor. Approved aromatase inhibitors which may be used in the present invention include exemestane (Aromasin®, Pfizer); anastazole (Arimidex®, AstraZeneca) and letrozole (Femara®, Novartis). [0260] In certain embodiments, the second therapeutic agent is an antagonist of the hedgehog pathway. Approved hedgehog pathway inhibitors which may be used in the present invention include sonidegib (Odomzo®, Sun Pharmaceuticals); and vismodegib (Erivedge®, Genentech), both for treatment of basal cell carcinoma. [0261] In certain embodiments, the second therapeutic agent is a folic acid inhibitor. Approved folic acid inhibitors useful in the present invention include pemetrexed (Alimta®, Eli Lilly). [0262] In certain embodiments, the second therapeutic agent is a CC chemokine receptor 4 (CCR4) inhibitor. CCR4 inhibitors being studied that may be useful in the present invention include mogamulizumab (Poteligeo®, Kyowa Hakko Kirin, Japan). [0263] In certain embodiments, the second therapeutic agent is an isocitrate dehydrogenase (IDH) inhibitor. IDH inhibitors being studied which may be used in the present invention include AG120 (Celgene; NCT02677922); AG221 (Celgene, NCT02677922; NCT02577406); BAY1436032 (Bayer, NCT02746081); IDH305 (Novartis, NCT02987010). [0264] In certain embodiments, the second therapeutic agent is an arginase inhibitor. Arginase inhibitors being studied which may 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 syndrome (NCT02732184) and solid tumors (NCT02561234); and CB-1158 (Calithera Biosciences). [0265] In certain embodiments, the second therapeutic agent is a glutaminase inhibitor. Glutaminase inhibitors being studied which may be used in the present invention include CB-839 (Calithera Biosciences). [0266] In certain embodiments, the second therapeutic agent is an antibody that binds to tumor antigens, that is, proteins expressed on the cell surface of tumor cells. Approved antibodies that bind to tumor antigens which may 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). [0267] In certain embodiments, the second therapeutic agent is a topoisomerase inhibitor. Approved topoisomerase inhibitors useful in the present invention include irinotecan (Onivyde®, Merrimack Pharmaceuticals); topotecan (Hycamtin®, GlaxoSmithKline). Topoisomerase inhibitors being studied which may be used in the present invention include pixantrone (Pixuvri®, CTI Biopharma). [0268] In certain embodiments, the second therapeutic agent is a nucleoside inhibitor, or other therapeutic that interfere with normal DNA synthesis, protein synthesis, cell replication, or will otherwise inhibit rapidly proliferating cells. Such nucleoside inhibitors or other therapeutics include trabectedin (guanidine alkylating agent, Yondelis®, Janssen Oncology), mechlorethamine (alkylating agent, Valchlor®, Aktelion Pharmaceuticals); vincristine (Oncovin®, Eli Lilly; Vincasar®, Teva Pharmaceuticals; Marqibo®, Talon Therapeutics); temozolomide (prodrug to alkylating agent 5-(3-methyltriazen-1-yl)-imidazole-4-carboxamide (MTIC) Temodar®, Merck); cytarabine injection (ara-C, antimetabolic cytidine analog, Pfizer); lomustine (alkylating agent, CeeNU®, Bristol-Myers Squibb; Gleostine®, NextSource Biotechnology); azacitidine (pyrimidine nucleoside analog of cytidine, Vidaza®, Celgene); omacetaxine mepesuccinate (cephalotaxine ester) (protein synthesis inhibitor, Synribo®; Teva Pharmaceuticals); asparaginase Erwinia chrysanthemi (enzyme for depletion of asparagine, Elspar®, Lundbeck; Erwinaze®, EUSA Pharma); eribulin mesylate (microtubule inhibitor, tubulin-based antimitotic, Halaven®, Eisai); cabazitaxel (microtubule inhibitor, tubulin-based antimitotic, Jevtana®, Sanofi-Aventis); capacetrine (thymidylate synthase inhibitor, Xeloda®, Genentech); bendamustine (bifunctional mechlorethamine derivative, believed to form interstrand DNA cross-links, Treanda®, Cephalon/Teva); ixabepilone (semi-synthetic analog of epothilone B, microtubule inhibitor, tubulin-based antimitotic, Ixempra®, Bristol-Myers Squibb); nelarabine (prodrug of deoxyguanosine analog, nucleoside metabolic inhibitor, Arranon®, Novartis); clorafabine (prodrug of ribonucleotide reductase inhibitor, competitive inhibitor of deoxycytidine, Clolar®, Sanofi- Aventis); and trifluridine and tipiracil (thymidine-based nucleoside analog and thymidine phosphorylase inhibitor, Lonsurf®, Taiho Oncology). [0269] In certain embodiments, the second therapeutic agent is a platinum-based therapeutic, also referred to as platins. Platins cause cross-linking of DNA, such that they inhibit DNA repair and/or DNA synthesis, mostly in rapidly reproducing cells, such as cancer cells. Approved platinum-based therapeutics which may be used in the present invention include cisplatin (Platinol®, Bristol-Myers Squibb); carboplatin (Paraplatin®, Bristol-Myers Squibb; also, Teva; Pfizer); oxaliplatin (Eloxitin® Sanofi-Aventis); and nedaplatin (Aqupla®, Shionogi). Other platinum-based therapeutics which have undergone clinical testing and may be used in the present invention include picoplatin (Poniard Pharmaceuticals); and satraplatin (JM-216, Agennix). [0270] In certain embodiments, the second therapeutic agent is a taxane compound, which causes disruption of microtubules, which are essential for cell division. Approved taxane compounds which may be used in the present invention include paclitaxel (Taxol®, Bristol-Myers Squibb), docetaxel (Taxotere®, Sanofi-Aventis; Docefrez®, Sun Pharmaceutical), albumin-bound paclitaxel (Abraxane®; Abraxis/Celgene), and cabazitaxel (Jevtana®, Sanofi-Aventis). Other taxane compounds which have undergone clinical testing and may be used in the present invention include SID530 (SK Chemicals, Co.) (NCT00931008). [0271] In certain embodiments, the second therapeutic agent is an inhibitor of anti-apoptotic proteins, such as BCL-2. Approved anti-apoptotics which may be used in the present invention include venetoclax (Venclexta®, AbbVie/Genentech); and blinatumomab (Blincyto®, Amgen). Other therapeutic agents targeting apoptotic proteins which have undergone clinical testing and may be used in the present invention include navitoclax (ABT-263, Abbott), a BCL-2 inhibitor (NCT02079740). [0272] In certain embodiments, the second therapeutic agent is a selective estrogen receptor modulator (SERM), which interferes with the synthesis or activity of estrogens. Approved SERMs useful in the present invention include raloxifene (Evista®, Eli Lilly). [0273] In certain embodiments, the second therapeutic agent is an inhibitor of interaction between the two primary p53 suppressor proteins, MDMX and MDM2. Inhibitors of p53 suppression proteins being studied which may be used in the present invention include ALRN- 6924 (Aileron), a stapled peptide that equipotently binds to and disrupts the interaction of MDMX and MDM2 with p53. 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). [0274] In certain embodiments, the second therapeutic agent is an inhibitor of transforming growth factor-beta (TGF-beta or TGFβ). Inhibitors of TGF-beta proteins being studied which may be used in the present invention include NIS793 (Novartis), an anti-TGF-beta antibody being tested in the clinic for treatment of various cancers, including breast, lung, hepatocellular, colorectal, pancreatic, prostate and renal cancer (NCT 02947165). In some embodiments, the inhibitor of TGF-beta proteins is fresolimumab (GC1008; Sanofi-Genzyme), which is being 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, such as described in Connolly et al. (2012) Int'l J. Biological Sciences 8:964- 978. One therapeutic compound currently in clinical trials for treatment of solid tumors is M7824 (Merck KgaA—formerly MSB0011459X), which is a bispecific, anti-PD-L1/TGFβ trap compound (NCT02699515); and (NCT02517398). M7824 is comprised of a fully human IgG1 antibody against PD-L1 fused to the extracellular domain of human TGF-beta receptor II, which functions as a TGFβ “trap.” [0275] In certain embodiments, the second therapeutic agent is a cancer vaccine. In some embodiments, the cancer vaccine is selected from sipuleucel-T (Provenge®, Dendreon/Valeant Pharmaceuticals), which has been approved for treatment of asymptomatic, or minimally symptomatic metastatic castrate-resistant (hormone-refractory) prostate cancer; and talimogene laherparepvec (Imlygic®, BioVex/Amgen, previously known as T-VEC), a genetically modified oncolytic viral therapy approved for treatment of unresectable cutaneous, subcutaneous and nodal lesions in melanoma. In some embodiments, the additional therapeutic agent is selected from an oncolytic viral therapy such as 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); pelareorep (Reolysin®, Oncolytics Biotech), a variant of respiratory enteric orphan virus (reovirus) which does not replicate in cells that are not RAS-activated, in numerous cancers, including colorectal cancer (NCT01622543); prostate cancer (NCT01619813); head and neck squamous cell cancer (NCT01166542); pancreatic adenocarcinoma (NCT00998322); and non-small cell lung cancer (NSCLC) (NCT 00861627); enadenotucirev (NG-348, PsiOxus, formerly known as ColoAd1), an adenovirus engineered to express a full length CD80 and an antibody fragment specific for the T-cell receptor CD3 protein, in ovarian cancer (NCT02028117); metastatic or advanced epithelial tumors such as in colorectal cancer, bladder cancer, head and neck squamous cell carcinoma and salivary gland cancer (NCT02636036); ONCOS-102 (Targovax/formerly Oncos), an adenovirus engineered to express GM-CSF, in melanoma (NCT03003676); and peritoneal disease, colorectal cancer or ovarian cancer (NCT02963831); GL-ONC1 (GLV- 1h68/GLV-1h153, Genelux GmbH), vaccinia viruses engineered to express beta-galactosidase (beta-gal)/beta-glucoronidase or beta-gal/human sodium iodide symporter (hNIS), respectively, were studied in peritoneal carcinomatosis (NCT01443260); fallopian tube cancer, ovarian cancer (NCT 02759588); or CG0070 (Cold Genesys), an adenovirus engineered to express GM-CSF, in bladder cancer (NCT02365818). [0276] In certain embodiments, the second therapeutic agent is an immune checkpoint inhibitor selected from a PD-1 antagonist, a PD-L1 antagonist, or a CTLA-4 antagonist. In some embodiments, a compound disclosed herein or a pharmaceutically acceptable salt thereof is administered in combination with 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); or atezolizumab (anti-PD-L1 antibody, Tecentriq®, Genentech). Other immune checkpoint inhibitors suitable for use in the present invention include REGN2810 (Regeneron), an anti-PD-1 antibody tested in patients with basal cell carcinoma (NCT03132636); NSCLC (NCT03088540); cutaneous squamous cell carcinoma (NCT02760498); lymphoma (NCT02651662); and melanoma (NCT03002376); pidilizumab (CureTech), also known as CT- 011, an antibody that binds to PD-1, in clinical trials for diffuse large B-cell lymphoma and multiple myeloma; avelumab (Bavencio®, Pfizer/Merck KGaA), also known as MSB0010718C), a fully human IgG1 anti-PD-L1 antibody, in clinical trials for non-small cell lung cancer, Merkel cell carcinoma, mesothelioma, solid tumors, renal cancer, ovarian cancer, bladder cancer, head and neck cancer, and gastric cancer; and 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 that has been in studied in clinical trials for a number of 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, squamous cell cancer of the head and neck, hepatocellular carcinoma, prostate cancer, endometrial cancer, metastatic cancer in the liver, 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 that is being studied in Phase 1 clinical trials for advanced solid tumors (NCT02694822). [0277] Another aspect of the invention provides for the use of a compound described herein (such as a compound of Formula I, Formula II, or other compounds in Section I) in the manufacture of a medicament. In certain embodiments, the medicament is for treating a disease described herein, such as cancer. [0278] Another aspect of the invention provides for the use of a compound described herein (such as a compound of Formula I, Formula II, or other compounds in Section I) for treating a medical disease, such a disease described herein (e.g., cancer). Evaluation of Cellular Growth Inhibition of HEK293 cells and HeLa cells [0279] Compounds can be evaluated for ability to inhibit the proliferation of HEK293 cells or HeLa cells according to the following procedure. HEK293 and HeLa cells are cultured in DMEM medium supplemented with 10% fetal bovine serum and 1% Penn/Strep. Cells are seeded in white 384-well plates at 500 cells/well in 25 ^L complete medium. Following seeding, plates are spun at 300 × g^for three minutes and cultured at 37 °C with 5% CO2^in a humidified tissue culture incubator. After 24 hours, compounds are titrated in 100% DMSO and diluted in complete cell culture medium. A 25 ^L aliquot of compound/media mixture is added to cells to bring total volume in well to 50 ^L. DMSO alone is used as a negative control. Plates are then spun at 300×g^for three minutes and stored at 37 °C with 5% CO ₂ for three days. On Day 0 and Day 3 of compound treatment, cell viability is quantified with CellTiter-Glo 2.0 reagent (Promega). After equilibrating microplates at room temperature for 30 minutes, 25 µL CellTiter-Glo 2.0 reagent is dispensed into each well to bring total volume to 75 ^L. Plates are mixed on shaker for 2 minutes at 500rpm, followed by a 10-minute incubation at room temperature. Following a quick spin, luminescence readings are measured with an EnVision Plate Reader. Data is normalized to DMSO treated Day 0 and Day 3 readings. A four-parameter non-linear regression curve fit is applied to dose-response data in GraphPad Prism data analysis software to determine the half maximal growth inhibitory concentration (GI ₅₀ ) for each compound. III. Pharmaceutical Compositions and Dosing Considerations [0280] As indicated above, the invention provides pharmaceutical compositions, which comprise a therapeutically-effective amount of one or more of the compounds described above, formulated together with one or more pharmaceutically acceptable carriers (additives) and/or diluents. The pharmaceutical compositions may be specially formulated for administration in solid or liquid form, including those adapted for the following: (1) oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; (2) parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; (3) topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin; (4) intravaginally or intrarectally, for example, as a pessary, cream or foam; (5) sublingually; (6) ocularly; (7) transdermally; or (8) nasally. In certain embodiments, the invention provides a pharmaceutical composition comprising a compound described herein (e.g., a compound of Formula I) and a pharmaceutically acceptable carrier. [0281] The phrase “therapeutically effective amount” as used herein means that amount of a compound, material, or composition comprising a compound of the present invention which is effective for producing some desired therapeutic effect in at least a sub-population of cells in an animal at a reasonable benefit/risk ratio applicable to any medical treatment. [0282] The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. [0283] Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions. [0284] Examples of pharmaceutically-acceptable antioxidants include: (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha- tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like. [0285] Formulations of the present invention include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal and/or parenteral administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 0.1 percent to about ninety-nine percent of active ingredient, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent to about 30 percent. [0286] In certain embodiments, a formulation of the present invention comprises an excipient selected from the group consisting of cyclodextrins, celluloses, liposomes, micelle forming agents, e.g., bile acids, and polymeric carriers, e.g., polyesters and polyanhydrides; and a compound of the present invention. In certain embodiments, an aforementioned formulation renders orally bioavailable a compound of the present invention. [0287] Methods of preparing these formulations or compositions include the step of bringing into association a compound of the present invention with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product. [0288] Formulations of the invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient. A compound of the present invention may also be administered as a bolus, electuary or paste. [0289] In solid dosage forms of the invention for oral administration (capsules, tablets, pills, dragees, powders, granules, trouches and the like), the active ingredient is mixed with one or more pharmaceutically-acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds and surfactants, such as poloxamer and sodium lauryl sulfate; (7) wetting agents, such as, for example, cetyl alcohol, glycerol monostearate, and non-ionic surfactants; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, zinc stearate, sodium stearate, stearic acid, and mixtures thereof; (10) coloring agents; and (11) controlled release agents such as crospovidone or ethyl cellulose. In the case of capsules, tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-shelled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like. [0290] A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. [0291] The tablets, and other solid dosage forms of the pharmaceutical compositions of the present invention, such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres. They may be formulated for rapid release, e.g., freeze-dried. They may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes. The active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients. [0292] Liquid dosage forms for oral administration of the compounds of the invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. [0293] Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents. [0294] Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof. [0295] Formulations of the pharmaceutical compositions of the invention for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing one or more compounds of the invention with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound. [0296] Formulations of the present invention which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate. [0297] Dosage forms for the topical or transdermal administration of a compound of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically- acceptable carrier, and with any preservatives, buffers, or propellants which may be required. [0298] The ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof. [0299] Powders and sprays can contain, in addition to a compound of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane. [0300] Transdermal patches have the added advantage of providing controlled delivery of a compound of the present invention to the body. Such dosage forms can be made by dissolving or dispersing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel. [0301] Ophthalmic formulations, eye ointments, powders, solutions and the like, are also contemplated as being within the scope of this invention. [0302] Pharmaceutical compositions of this invention suitable for parenteral administration comprise one or more compounds of the invention in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain sugars, alcohols, antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents. [0303] Examples of suitable aqueous and nonaqueous carriers which may be employed in the pharmaceutical compositions of the invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. [0304] These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms upon the subject compounds may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin. [0305] In some cases, in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally- administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle. [0306] Injectable depot forms are made by forming microencapsule matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissue. [0307] When the compounds of the present invention are administered as pharmaceuticals, to humans and animals, they can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99% (more preferably, 10 to 30%) of active ingredient in combination with a pharmaceutically acceptable carrier. [0308] The preparations of the present invention may be given orally, parenterally, topically, or rectally. They are of course given in forms suitable for each administration route. For example, they are administered in tablets or capsule form, by injection, inhalation, eye lotion, ointment, suppository, etc. administration by injection, infusion or inhalation; topical by lotion or ointment; and rectal by suppositories. Oral administrations are preferred. [0309] The phrases “parenteral administration” and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion. [0310] The phrases “systemic administration,” “administered systemically,” “peripheral administration” and “administered peripherally” as used herein mean the administration of a compound, drug or other material other than directly into the central nervous system, such that it enters the patient’s system and, thus, is subject to metabolism and other like processes, for example, subcutaneous administration. [0311] These compounds may be administered to humans and other animals for therapy by any suitable route of administration, including orally, nasally, as by, for example, a spray, rectally, intravaginally, parenterally, intracisternally and topically, as by powders, ointments or drops, including buccally and sublingually. [0312] Regardless of the route of administration selected, the compounds of the present invention, which may be used in a suitable hydrated form, and/or the pharmaceutical compositions of the present invention, are formulated into pharmaceutically-acceptable dosage forms by conventional methods known to those of skill in the art. [0313] Actual dosage levels of the active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient. [0314] The selected dosage level will depend upon a variety of factors including the activity of the particular compound of the present invention employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion or metabolism of the particular compound being employed, the rate and extent of absorption, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts. [0315] A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the compounds of the invention employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. [0316] In general, a suitable daily dose of a compound of the invention will be that amount of the compound which is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above. Preferably, the compounds are administered at about 0.01 mg/kg to about 200 mg/kg, more preferably at about 0.1 mg/kg to about 100 mg/kg, even more preferably at about 0.5 mg/kg to about 50 mg/kg. When the compounds described herein are co-administered with another agent (e.g., as sensitizing agents), the effective amount may be less than when the agent is used alone. [0317] If desired, the effective daily dose of the active compound may be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms. Preferred dosing is one administration per day. [0318] The invention further provides a unit dosage form (such as a tablet or capsule) comprising a heterobifunctional substituted phenylpyrimidinone or related compound described herein in a therapeutically effective amount for the treatment of a medical disorder described herein. IV. MEDICAL KITS [0319] Another aspect of this invention is a kit comprising (i) a compound described herein, such as a compound of Formula I, and (ii) instructions for use, such as treating cancer. EXAMPLES [0320] The invention now being generally described, will be more readily understood by reference to the following examples, which are included merely for purposes of illustration of certain aspects and embodiments of the present invention, and is not intended to limit the invention. General Methods [0321] All reactions were carried out under an atmosphere of dry nitrogen or argon. Glassware was oven-dried prior to use. Unless otherwise indicated, common reagents or materials were obtained from commercial sources and used without further purification. N,N- Diisopropylethylamine (DIPEA) was obtained anhydrous by distillation over potassium hydroxide. Tetrahydrofuran (THF), Dichloromethane (CH ₂ Cl ₂ ), and dimethylformamide (DMF) was dried by a PureSolv ^TM solvent drying system. PTLC refers to preparatory thin layer chromatographic separation. Abbreviations: HFIP (hexafluoroisopropanol), HEPES (4-(2-hydroxyethyl)-1- piperazineethanesulfonic acid. Flash column chromatography was performed using silica gel 60 (230-400 mesh). Analytical thin layer chromatography (TLC) was carried out on Merck silica gel plates with QF-254 indicator and visualized by UV or KMnO ₄ . [0322] ¹ H and ¹³ C NMR spectra were recorded on an Agilent DD2500 (500 MHz ¹ H; 125 MHz ¹³ C) or Agilent DD ₂ 600 (600 MHz ¹ H; 150 MHz ¹³ C) or Agilent DD ₂ 400 (400 MHz ¹ H; 100 MHz ¹³ C) spectrometer at room temperature. Chemical shifts were reported in ppm relative to the residual CDCl3 (δ 7.26 ppm ¹ H; δ 77.0 ppm ¹³ C), CD3OD (δ 3.31 ppm ¹ H; δ 49.00 ppm ¹³ C), or d6- DMSO (δ 2.50 ppm ¹ H; δ 39.52 ppm ¹³ C). NMR chemical shifts were expressed in ppm relative to internal solvent peaks, and coupling constants were measured in Hz. (bs = broad signal). In most cases, only peaks of the major rotamer are reported. [0323] Mass spectra were obtained using Agilent 1100 series LC/MSD spectrometers. Analytical HPLC analyses were carried out on 250 x 4.6 mm C-18 column using gradient conditions (10-100% B, flow rate = 1.0 mL/min, 20 min), or as as described in the LC-MS Method tables. [0324] Unless indicated otherwise, preparative HPLC was carried out on 250 x 21.2 mm C-18 column using gradient conditions (10-100% B, flow rate = 10.0 mL/min, 20 min). The eluents used were: solvent A (H2O with 0.1% TFA) and solvent B (CH3CN with 0.1% TFA). Final products were typically purified via reversed-phase HPLC, PTLC, or flash column chromatography.

LC-MS METHOD 40

EXAMPLE 1 – Synthesis of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]-2-[2-[[4-[(8-cyclopentyl-7-ethyl-5-methyl-6-oxo- 7H-pteridin-2-yl)amino]-3- methoxy-benzoyl]amino]ethyl-methyl-amino]pyrimidine-5-carbox amide (I-1). [0325] The title compound was prepared according to the following procedures. 1.1 Preparation of compound 2 [0326] To a solution of 4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2- yl]amino]-3- methoxy-benzoic acid (100 mg, 235 μmol, 1.0 eq) in DMF (2 mL) was added tert- butyl N-(2-aminoethyl)-N-methyl-carbamate (53 mg, 305 μmol, 54 ^L, 1.3 eq), HATU (107 mg, 282 μmol, 1.2 eq) and DIEA (91 mg, 705 μmol, 122 ^L, 3.0 eq) and stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge 150 x 25 mm, 10 μm;mobile phase: [water(NH4HCO3)-ACN]; B%: 40%-70%, 8min) to give the tert-butyl N-[2-[[4-[(8- cyclopentyl-7- ethyl-5-methyl-6-oxo-7H-pteridin-2-yl)amino]-3-methoxy-benzo yl]amino] ethyl]-N-methyl- carbamate (113 mg, 194 μmol, 82% yield) as a yellow gum. ¹ H NMR: (400 MHz, CDCl ₃ ) δ = 8.53 - 8.51 (m, 1H), 7.69 (s, 1H), 7.47 - 7.39 (m, 1H), 7.38 - 7.37 (m, 1H), 7.35 - 7.34 (m, 2H), 4.57 - 4.51 (m, 1H), 4.20 (m, 1H), 3.98 (s, 3H), 3.63 - 3.53 (m, 4H), 3.33 (s, 3H), 2.93 (s, 3H), 2.15-2.01 (m, 2H), 2.01-2.04 (m, 4H), 1.85-1.83 (m, 4H), 1.44 (s, 9H), 0.88 (t, J = 4.8 Hz, 3H). 2.2 Preparation of compound 3 [0327] To a solution of tert-butyl N-[2-[[4-[(8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H- pteridin- 2-yl)amino]-3-methoxy-benzoyl]amino]ethyl]-N-methyl-carbamat e (100 mg, 171 μmol, 1.0 eq) in DCM (3 mL) was added TFA (1 mL). The mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give 4-[(8-cyclopentyl-7- ethyl-5- methyl-6-oxo-7H-pteridin-2-yl)amino]-3-methoxy-N-[2-(methyla mino)ethyl] benzamide (82 mg, crude) as a yellow liquid. 2.3 Preparation of compound I-1

[0328] To a solution of 4-[(8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl)am ino]-3- methoxy-N-[2-(methylamino)ethyl]benzamide (80 mg, 166 μmol, 1.0 eq) in NMP (2 mL) was added 2-chloro-N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl -cyclobutyl]pyrimidine-5- carboxamide(69 mg, 166 μmol, 1.0 eq) and K ₂ CO ₃ (68 mg, 498 μmol, 3.0 eq), then mixture was stirred at 60 °C for 6 h. The reaction mixture was concentrated under reduced pressure to give a residue and was purified by prep-HPLC (column: Waters Xbridge 150 x 25 mm 10 μm; mobile phase: [water(NH ₄ HCO ₃ )-ACN];B%: 54%-84%,11min) to give the N-[3-(3-chloro-4-cyano- phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]-2-[2-[[4-[(8- cyclopentyl-7-ethyl-5-methyl-6-oxo-7H- pteridin-2-yl)amino]-3-methoxy-benzoyl]amino]ethyl-methyl-am ino]pyrimidine-5-carboxamide (30 mg, 136 μmol, 21% yield, 98% purity) as a yellow liquid. ¹ H NMR: (400 MHz, MeOD) δ = 8.68 (s, 2H), 8.45 (d, J = 8.4 Hz, 1H), 7.76 (s, 1H), 7.70 (d, J = 8.8 Hz, 1H), 7.38 - 7.22 (m, 2H), 7.08 (d, J = 2.4 Hz, 1H), 6.97 - 6.90 (m, 1H), 4.51 - 4.41 (m, 1H), 4.30 - 4.23 (m, 1H), 4.20 (s, 1H), 4.08 (s, 1H), 4.06 - 3.97 (m, 2H), 3.95 (s, 3H), 3.76 - 3.62 (m, 2H), 3.31 (s, 3H), 3.28 (s, 3H), 2.26 - 2.10 (m, 1H), 2.03 - 1.95 (m, 1H), 1.94 (m, 5H), 1.77 - 1.62 (m, 3H), 1.19 (d, J = 5.6 Hz, 6H), 1.14 (d, J = 3.6 Hz, 6H), 0.92 - 0.77 (m, 3 H). LC-MS: MS (ES ⁺ ): RT = 3.29 min, m/z = 864.3 (M+H ⁺ ). LC-MS Method 05. EXAMPLE 2 – Synthesis of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]-2-[2-[2-[2-[[4-[[(7S)-8-cyclopentyl-7-ethyl-5-me thyl-6-oxo-7H-pteridin-2-yl] amino]-3-methoxy-benzoyl]amino]ethoxy]ethoxy]ethyl-methyl-am ino]pyrimidine-5- carboxamide (I-2). [0329] The title compound was prepared according to the following procedures. 1.1 Preparation of compound 2 [0330] A mixture of 2-[2-[2-[methyl(2-trimethylsilylethoxycarbonyl)amino]ethoxy] ethoxy] ethyl 4-methylbenzenesulfonate (2.4 g, 5.2 mmol, 1.0 eq), NaN ₃ (1.1 g, 16 mmol, 3.1 eq) in DMF (15 mL) was degassed and purged with N ₂ for 3 times, and then the mixture was stirred at 70 °C for 12 h under N2 atmosphere. The mixture was poured into H2O (40 mL) and was adjusted to pH > 9 by (1N, NaOH), then the mixture was extracted with EA (80 mL x 3), the combined organic layers were washed with brine (60 mL), dried over Na ₂ SO ₄ , filtered and concentrated to give the residue. The residue was used for next step without further purification. Compound 2- trimethylsilylethyl N-[2-[2-(2-azidoethoxy)ethoxy]ethyl]- N-methyl-carbamate (1.6 g, 4.8 mmol, 92% yield) was obtained as a colorless oil. ¹ H NMR: (400 MHz, CDCl ₃ ) δ = 4.20 - 4.12 (m, 2H), 3.72 - 3.56 (m, 2H), 3.44 (s, 2H), 3.41 - 3.35 (m, 2H), 2.95 (s, 3H), 1.13 - 0.93 (m, 2H), 0.04 (s, 9H) 1.2 Preparation of compound 3 [0331] A mixture of 2-trimethylsilylethyl N-[2-[2-(2-azidoethoxy)ethoxy]ethyl]-N-methyl- carbamate (1.5 g, 4.5 mmol, 1.0 eq), Pd/C (200 mg, 10% purity), in MeOH (10 mL) was degassed and purged with H ₂ for 3 times and then the mixture was stirred at 25 °C for 12 h. The mixture was filtered and the filtrate was concentrated to give 2-trimethylsilylethyl N-[2-[2-(2- aminoethoxy)ethoxy]ethyl]-N-methyl-carbamate (1.2 g, 3.9 mmol, 86% yield) as a colorless oil. ¹ H NMR: (400 MHz, CDCl3) δ = 4.19 - 4.07 (m, 2H), 3.63 - 3.52 (m, 7H), 3.51 - 3.45 (m, 1H), 3.40 (s, 2H), 2.92 (s, 3H), 2.86 - 2.73 (m, 2H), 1.61 (s, 2H), 1.11 - 0.87 (m, 2H), 0.00 (s, 9H) 1.3 Preparation of compound 4 [0332] To a solution of 4-[(8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl) amino]-3- methoxy-benzoic acid (100 mg, 235 μmol, 1.0 eq) in DMF (3 mL) was added 2-trimethylsilylethyl N-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N-methyl-carbamate (79 mg, 258 μmol, 1.1 eq), DIEA (91. mg, 705 μmol, 122 ^L, 3.0 eq) and HATU (107 mg, 282 μmol, 1.2 eq) at 25 °C and the mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18, (250 x 70mm, 10 μm);mobile phase: [water(NH4HCO3)-ACN]; B%: 60%-90%, 20 min) to give the 2- trimethylsilylethyl N-[2-[2-[2-[[4-[[(7S)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7 H-pteridin-2- yl]amino]-3-methoxy-benzoyl]amino]ethoxy]ethoxy]ethyl]-N-met hyl-carbamate (79 mg, 110 μmol, 47% yield) as a light yellow gum. 2.4 Preparation of compound 5 [0333] A solution of 2-trimethylsilylethyl N-[2-[2-[2-[[4-[[(7S)-8-cyclopentyl-7-ethyl-5- methyl-6- oxo-7H-pteridin-2-yl]amino]-3-methoxy-benzoyl]amino]ethoxy]e thoxy]ethyl]-N- methyl-carbamate (80 mg, 1112 μmol, 1 eq) in TFA (3 mL), DCM (3 mL) was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give 4-[[(7S)-8-cyclopentyl- 7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-3-methoxy-N-[ 2-[2-[2- (methylamino)ethoxy]ethoxy]ethyl]benzamide (60 mg, 105 μmol, 93% yield) as a yellow liquid. 2.5 Preparation of compound I-2 [0334] To a solution of 4-[[(7S)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2- yl]amino]- 3-methoxy-N-[2-[2-[2-(methylamino)ethoxy]ethoxy]ethyl]benzam ide (20 mg, 35 μmol, 1.0 eq) in NMP (2 mL) was added 2-chloro-N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4- tetramethyl-cyclobutyl]pyrimidine-5-carboxamide (14 mg, 35 μmol, 1.0 eq) and K2CO3 (14 mg, 105 μmol, 3.0 eq) and mixture was stirred at 60 °C for 12 h under N2 protection. The reaction mixture was concentrated under reduced pressure to give a residue and was purified by prep-HPLC (column: Waters Xbridge 150 x 25 mm, 10 μm; mobile phase: [water (NH4HCO3)-ACN];B%: %- %,11min) to give N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4- tetramethyl-cyclobutyl]-2-[2-[2-[2- [[4-[[(7S)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin- 2-yl]amino]-3-methoxy- benzoyl]amino]ethoxy]ethoxy]ethyl-methyl-amino]pyrimidine-5- carboxamide (20 mg, 83 μmol, 79% yield) as a yellow oil. ¹ H NMR: (400 MHz, MeOD) δ = 8.73 (s, 2H), 8.51 (d, J = 8.4 Hz, 1H), 7.80 (s, 1H), 7.71 (d, J = 8.8 Hz, 1H), 7.55 - 7.47 (m, 2H), 7.11 (d, J = 2.4 Hz, 1H), 6.97 - 6.91 (m, 1H), 4.63 - 4.48 (m, 2H), 4.33 - 4.27 (m, 1H), 4.25 (s, 1H), 4.12 (s, 1H), 4.02 (s, 3H), 3.94 - 3.87 (m, 2H), 3.79 - 3.72 (m, 2H), 3.67 - 3.64 (m, 5H), 3.59 - 3.49 (m, 3H), 3.35 (s, 2H), 3.25 (s, 3H), 2.23 - 2.12 (m, 1H), 2.04 - 1.98 (m, 1H), 1.96 - 1.83 (m, 5H), 1.80 - 1.67 (m, 3H), 1.27 (s, 6H), 1.21 (s, 6H), 0.93 - 0.83 (m, 3H). LC-MS: MS (ES ⁺ ): RT = 3.32 min, m/z = 476.9 (M+2H ⁺ )/2. LC-MS Method 05. EXAMPLE 3 – Synthesis of 4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin- 2- yl]amino]-3-methoxy-N-[2-[2-[2-[2-[2-(methylamino)ethoxy]eth oxy]ethoxy]ethoxy] ethyl]benzamide (I-3). [0335] The title compound was prepared according to the following procedures. 1.1 Preparation of compound 2 [0336] To a mixture of 2-[2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethoxy]ethyl 4- methylbenzenesulfonate (11.0 g, 28.0 mmol, 1.0 eq) and K2CO3 (7.75 g, 56.1 mmol, 2.0 eq) in MeCN (50 mL) was added N-methyl-1-phenyl-methanamine (6.79 g, 56.1 mmol, 7.23 mL, 2.0 eq) at 22 °C. Then the resulting mixture was stirred at 85 °C under N ₂ for 12 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC(water(NH4HCO3)-ACN];B%: 10%-40%,24min) to give compound 2-[2-[2-[2-[2-[benzyl(methyl)amino]ethoxy]ethoxy]ethoxy]etho xy]ethanol (8.70 g, 24.8 mmol, 88% yield) was obtained as yellow oil. ¹ H NMR: (400 MHz, CDCl3) 7.33 - 7.27 (m, 4H), 7.26 - 7.20 (m, 1H), 3.73 - 3.69 (m, 2H), 3.68 - 3.62 (m, 11H), 3.62 - 3.57 (m, 6H), 3.55 - 3.54 (m, 2H), 2.63 (t, J = 12 Hz, 2H), 2.25 (s, 3H) 2.2 Preparation of compound 3 [0337] To a solution of 2-trimethylsilylethyl N-[2-[2-[2-[2-(2-azidoethoxy)ethoxy] ethoxy]ethoxy]ethyl]-N-methyl-carbamate (2.00 g, 5.80 mmol, 1.0 eq) in MeOH (7 mL) was added Pd/C (1.20 g, 10% purity) under nitrogen. The suspension was degassed and purged with H ₂ for 3 times. The mixture was stirred under H2 (15 psi) at 25 °C for 16 h. The reaction mixture was filtered and concentrated under reduced pressure to give a compound 2-[2-[2-[2-[2- (methylamino)ethoxy]ethoxy]ethoxy]ethoxy]ethanol (1.20 g, crude) as a colorless oil. ¹ H NMR: (400 MHz, CDCl ₃ ) 3.71 - 3.66 (m, 2H), 3.65 - 3.53 (m, 18H), 3.05 - 2.79 (m, 2H), 2.40 (s, 3H) 2.3 Preparation of compound 4 [0338] To a solution of 2-[2-[2-[2-[2-(methylamino)ethoxy]ethoxy]ethoxy]ethoxy]ethan ol (1.00 g, 3.98 mmol, 1.0 eq), K ₂ CO ₃ (1.65 g, 11.9 mmol, 3.0 eq) in THF (30 mL) and H ₂ O (10 mL) was added (2,5-dioxopyrrolidin-1-yl) 2-trimethylsilylethyl carbonate (1.03 g, 3.98 mmol, 1.0 eq) at 20 °C. Then the mixture was stirred at 20 °C under N2 for 12 h. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with water (40 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (40 mL × 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give the compound 2-trimethylsilylethyl N-[2-[2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethoxy] ethyl]-N- methyl-carbamate (1.30 g, crude) as a colorless oil. ¹ H NMR: (400 MHz, CDCl3) δ 4.18- 4.14 (m, 2H), 3.72 (t, J = 12 Hz, 2H), 3.70 - 3.58 (m, 17H), 3.47 - 3.39 (m, 2H), 2.94 (s, 3H), 1.03 - 0.97 (m, 2H), 0.04 (s, 9H) 2.4 Preparation of compound 5 [0339] To a solution of 2-trimethylsilylethyl N-[2-[2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy] ethoxy]ethyl]-N-methyl-carbamate (1.30 g, 3.29 mmol, 1.0 eq) in CH ₂ Cl ₂ (30 mL) was added TEA (997 mg, 9.86 mmol, 1.37 mL, 3 eq) at 0 °C. Then the resulting mixture was drop in 4- methylbenzenesulfonyl chloride (627 mg, 3.29 mmol, 1.0 eq) in CH ₂ Cl ₂ (5 mL) at 0 °C under N2. The mixture was stirred at 20 °C for 12 h. The reaction mixture was diluted with water (30 mL) and extracted with CH ₂ Cl ₂ (20 mL × 3). The combined organic layers were washed with brine (40 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 50-100% Ethyl acetate/Petroleum ether gradient at 80 mL/min) to give compound 2-[2-[2-[2-[2-[methyl(2-trimethylsilyl-ethoxycarbonyl)amino] - ethoxy]ethoxy]ethoxy]ethoxy]ethyl 4-methylbenzenesulfonate (0.97 g, 1.72 mmol, 52% yield) as a colorless oil. ¹ H NMR: (400 MHz, CDCl ₃ ) δ 7.79 (d, J = 8.0 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 4.18 - 4.13 (m, 4H), 3.70 - 3.66 (m, 2H), 3.64 - 3.56 (m, 16H), 3.44 - 3.37 (m, 2H), 2.94 (s, 3H), 2.45 (s, 3H), 0.04 (s, 9H) 2.5 Preparation of compound 6 [0340] To a solution 2-[2-[2-[2-[2-[methyl(2-trimethylsilylethoxycarbonyl)amino]e thoxy] ethoxy]ethoxy]ethoxy]ethyl 4-methylbenzenesulfonate (870 mg, 1.58 mmol, 1.0 eq) in DMF (5 mL) was added NaN3 (310 mg, 4.77 mmol, 3.0 eq) slowly at 0 °C. The mixture was stirred at 70 °C for 12 h. The reaction mixture was diluted with H2O (10 mL), basified by NH3.H2O to pH>9, and extracted with EtOAc (20 ml × 2). The combined organic layers were washed with (brine 50 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a Compound 2- trimethylsilylethyl N-[2-[2-[2-[2-(2-azidoethoxy)ethoxy]ethoxy]ethoxy]ethyl]-N-m ethyl- carbamate (700 mg, crude) as a light-yellow oil. ¹ H NMR: (400 MHz, CDCl ₃ ) δ 4.21 - 4.14 (m, 2H), 3.71 - 3.59 (m, 15H), 3.52 - 3.36 (m, 4H), 2.95 (s, 3H), 1.77 - 1.68 (m, 1H), 1.07 - 0.96 (m, 2H), 0.04 (s, 9H). 2.6 Preparation of compound 7 [0341] To a solution of 2-trimethylsilylethyl N-[2-[2-[2-[2-(2-azidoethoxy)ethoxy]ethoxy]- ethoxy]ethyl]-N-methyl-carbamate (700 mg, 1.66 mmol, 1.0 eq) in MeOH (7 mL) was added Pd/C (1.04 g, 10% purity) under nitrogen. The suspension was degassed and purged with H2 for 3 times. The mixture was stirred under H ₂ (15psi) at 25 °C for 16 h. The reaction mixture was filtered and the filter was concentrated to give compound 2-trimethylsilylethyl N-[2-[2-[2-[2-(2- aminoethoxy)ethoxy]ethoxy]ethoxy]ethyl]-N-methyl-carbamate (330 mg, crude) as a colorless oil. ¹ H NMR: (400 MHz, CDCl ₃ ) δ 4.19 - 4.12 (m, 2H), 3.74 - 3.38 (m, 20H), 2.94 (s, 3H), 2.89 - 2.80 (m, 2H), 0.98 (t, J = 12.0 Hz, 2H), 0.03(s, 9H) 2.7 Preparation of compound 9 [0342] To a mixture of 2-trimethylsilylethyl N-[2-[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy] ethoxy]ethyl]-N-methyl-carbamate (96.0 mg, 244 μmol, 1.3 eq), 4-[[(7R)-8-cyclopentyl-7-ethyl-5- methyl-6-oxo-7H-pteridin-2-yl]amino]-3-methoxy-benzoic acid (80.0 mg, 188 μmol, 1.0 eq) and DIEA (29.0 mg, 226 μmol, 39.3 ^L, 1.2 eq) in DMF (1 mL) was added HATU (214 mg, 564 μmol, 3.0 eq). Then the resulting mixture was stirred at 22 °C for 12 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge 150 x 25 mm, 10 μm; mobile phase: [water (NH4HCO3)- ACN];B%: 48%-78%,8min) to give compound 2-trimethylsilylethyl N-[2-[2-[2-[2-[2-[[4-[(8- cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl)amino]-3 -methoxy-benzoyl]amino] ethoxy]ethoxy]ethoxy]ethoxy]ethyl]-N-methyl-carbamate (70.0 mg, 85.3 μmol, 45% yield) as a colorless oil. ¹ H NMR: (400 MHz, CD3OD) δ 8.51 (d, J = 8.0 Hz, 1H), 7.79 (s, 1H), 7.53 - 7.46 (m, 2H), 4.58 - 4.48 (m, 2H), 4.29 (dd, J = 12.0 Hz, 1H), 4.20 - 4.11 (m, 2H), 4.01 (m, 3H), 3.69 - 3.65 (m, 7H), 3.65 - 3.61 (m, 3H), 3.61 - 3.52 (m, 11H), 3.42 - 3.36 (m, 3H), 2.91 (s, 3H), 2.24 - 2.12 (m, 1H), 2.05 - 1.82 (m, 7H), 1.76 - 1.71 (m, 2H), 1.04 - 0.95 (m, 2H), 0.87 (t, J = 12.0 Hz, 3H), 0.04 (m, 9H). 2.8 Preparation of compound 10 [0343] To a solution of 2-trimethylsilylethyl N-[2-[2-[2-[2-[2-[[4-[[(7R)-8-cyclopentyl-7-ethyl- 5- methyl-6-oxo-7H-pteridin-2-yl]amino]-3-methoxy-benzoyl]amino ]ethoxy]ethoxy] ethoxy]ethoxy]ethyl]-N-methyl-carbamate (70 mg, 87 μmol, 1.0 eq) in DCM (1 mL) was added TFA (4.62 g, 40.5 mmol, 3.00 mL, 464 eq) at 20 °C. Then the resulting mixture was stirred at 20 °C for 0.5 hr. The reaction mixture was concentrated under reduced pressure to give a compound 4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2- yl]amino]-3-methoxy-N-[2-[2-[2-[2- [2-(methylamino)ethoxy]ethoxy]ethoxy]ethoxy]ethyl]benzamide (57 mg, crude) as a yellow oil.

2.9 Preparation of I-3 [0344] To a solution of 4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2- yl]amino]- 3-methoxy-N-[2-[2-[2-[2-[2-(methylamino)ethoxy]ethoxy]ethoxy ]ethoxy]ethyl] benzamide (58.0 mg, 88.7 μmol, 8.89e-1 eq) in NMP (2 mL) was added K2CO3 (41.0 mg, 299 μmol, 3.0 eq) and 2-chloro-N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl -cyclobutyl]- pyrimidine-5-carboxamide (54 mg, 130 μmol, 1.3 eq). Then the resulting mixture was stirred at 50 °C under N2 for 12 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge 150 x 25 mm, 10 μm;mobile phase: [water(NH ₄ HCO ₃ )-ACN];B%: 53%-83%,8min) to give N-[3-(3-chloro-4-cyano- phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]-2-[2-[2-[2-[2-[2-[[ 4-[[(7R)-8-cyclopentyl-7-ethyl-5- methyl-6-oxo-7H-pteridin-2-yl]amino]-3-methoxy-benzoyl]amino ]ethoxy] ethoxy]ethoxy]ethoxy]ethyl-methyl-amino]pyrimidine-5-carboxa mide (22.36 mg, 21 μmol, 21% yield) as a white solid. ¹ H NMR: (400 MHz, CD3OD) δ 8.71 (s, 2H), 8.51 - 8.49 (d, J = 8.0 Hz, 1H), 7.78 (s, 1H), 7.71 - 7.69 (d, J = 8.0 Hz, 1H), 7.53 - 7.45 (m, 2H), 7.11 - 7.10 (d, J = 4.0 Hz, 1H), 6.96 - 6.93 (dd, J = 12.0 Hz, 1H), 4.57 - 4.48 (m, 2H), 4.29 - 4.26 (m, 1H), 4.24 (s, 1H), 4.12 (s, 1H), 3.85 - 3.82 (t, J = 12.0 Hz, 1H), 3.87 - 3.79 (m, 2H), 3.71 - 3.62 (m, 9H), 3.62 - 3.53 (m, 11H), 3.33 (s, 3H), 3.22 (s, 3H), 2.21 - 2.11 (m, 1H), 2.05 - 1.97 (m, 1H), 1.95 - 1.83 (m, 5H), 1.79 - 1.70 (m, 3H), 1.79 - 1.67 (m, 3H), 1.28 - 1.26 (m, 6H), 1.27 (s, 6H), 1.20 (s, 6H), 0.87 - 0.84 (t, J = 12.0 Hz, 1H). LC-MS: MS (ES ⁺ ): RT = 2.91 min, m/z = 520.9 (M+2H ⁺ )/2. LC-MS Method 05. EXAMPLE 4 – Synthesis of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]-2-[2-[2-[2-[2-[2-[2-[2-[[4-[[(7R)-8-cyclopentyl- 7-ethyl-5-methyl-6-oxo-7H- pteridin-2-yl]amino]-3-methoxy-benzoyl]amino]ethoxy]ethoxy]e thoxy] ethoxy]ethoxy]ethoxy]ethyl-methyl-amino]pyrimidine-5-carboxa mide (I-4). [0345] The title compound was prepared according to the following procedures. 1.1 Preparation of compound 2 [0346] A mixture of 2-[2-[2-[2-[2-[2-[2-[methyl(2-trimethylsilylethoxycarbonyl)- amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl 4-methylbenzenesulfonate (1.5 g, 2.4 mmol, 1.0 eq), NaN3 (0.54 g, 8.3 mmol, 3.5 eq) in DMF (10 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 70 ^o C for 12 h under N2 atmosphere. The mixture was poured into H ₂ O (40 mL) and was adjusted to pH > 9 by NaOH (1 N), then the mixture was extracted with EA (80 mL x 3). The combined organic layers were washed with brine (60 mL), dried over Na2SO4, filtered and concentrated to give 2-trimethylsilylethyl N-[2-[2-[2-[2-[2-[2-(2- azidoethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]-N-meth yl-carbamate (1.0 g, 1.9 mmol, 83% yield) as a colorless oil. ¹ H NMR: (400 MHz, CDCl ₃ ) δ = 4.31 - 4.02 (m, 2H), 3.70 - 3.50 (m, 24H), 3.38 - 3.32 (m, 2H), 2.92 (s, 3H), 1.05 - 0.91 (m, 2H), 0.00 (s, 9H) 2.2 Preparation of compound 3

3 [0347] A mixture of 2-trimethylsilylethyl N-[2-[2-[2-[2-[2-[2-(2-azidoethoxy)ethoxy] ethoxy]ethoxy]ethoxy]ethoxy]ethyl]-N-methyl-carbamate (1.0 g, 1.9 mmol, 1.0 eq), PPh ₃ (1.0 g, 3.9 mmol, 2.0 eq) in THF (2 mL), H2O (1 mL) was degassed and purged with N2 for 3 times and then the mixture was stirred at 25 °C for 12 h under N2 atmosphere. The mixture was filtered and the filtrate was concentrated to give the residue and was purified by column chromatography (SiO ₂ , DCM: MeOH = 10:1) to give the 2-trimethylsilylethyl N-[2-[2-[2-[2-[2-[2-(2-aminoethoxy) ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]-N-methyl-carbamate (470 mg, 1.95 mmol, 49% yield) as a colorless oil. 2.3 Preparation of compound 4 [0348] A mixture of 4-[(8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl)am ino]-3- methoxy-benzoic acid (80 mg, 188 μmol, 1.0 eq), 2-trimethylsilylethyl N-[2-[2-[2-[2-[2-[2-(2- aminoethoxy)- ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]-N-methyl-carbamate (109 mg, 225 μmol, 1.2 eq), HATU (71 mg, 188 μmol, 1.0 eq), DIPEA (73 mg, 564 μmol, 98 ^L, 3.0 eq) in DMF (2 mL) was degassed and purged with N ₂ for 3 times, and then the mixture was stirred at 25 °C for 2 h under N2 atmosphere. The mixture was concentrated to give a residue and was purified by prep-HPLC (column: Waters Xbridge 150 x 25 mm, 10um; mobile phase: [water(NH ₄ HCO ₃ )- ACN];B%: 48%-78%,8min) to give 2-trimethylsilylethyl N-[2-[2-[2-[2-[2-[2-[2-[[4-[(8- cyclopentyl-7-ethyl-5-methyl- 6-oxo-7H-pteridin-2-yl)amino]-3-methoxy- benzoyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethy l]-N-methyl-carbamate (80 mg, 90 μmol, 47% yield) as a colorless oil ¹ H NMR: (400 MHz, CDCl ₃ ) δ = 8.55 (d, J = 8.4 Hz, 1H), 7.72 - 7.66 (m, 1H), 7.47 (d, J = 1.6 Hz, 1H), 7.36 (d, J = 8.4 Hz, 1H), 4.57 - 4.48 (m, 1H), 4.27 - 4.20 (m, 1H), 4.19 - 4.13 (m, 2H), 3.98 (s, 3H), 3.71 - 3.57 (m, 31H), 2.95 (s, 3H), 2.19 - 1.98 (m, 2H), 1.92 - 1.78 (m, 5H), 1.76 - 1.68 (m, 5H), 1.04 - 0.97 (m, 2H), 0.90 - 0.86 (m, 3H), 0.04 (s, 9H) 2.4 Preparation of compound 5 [0349] A mixture of 2-trimethylsilylethyl N-[2-[2-[2-[2-[2-[2-[2-[[4-[[(7R)-8-cyclopentyl-7- ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-3-methoxy-benzo yl]amino]ethoxy]ethoxy] ethoxy] ethoxy]ethoxy]ethoxy]ethyl]-N-methyl-carbamate (80 mg, 89 μmol, 1.0 eq) in TFA (1 mL), DCM (3 mL) was degassed and purged with N ₂ for 3 times, and then the mixture was stirred at 25 °C for 2 h under N ₂ atmosphere. The mixture was concentrated to give 4-[[(7R)-8-cyclopentyl-7-ethyl-5- methyl-6-oxo- 7H-pteridin-2-yl]amino]-3-methoxy-N-[2-[2-[2-[2-[2-[2-[2- (methylamino)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy] ethoxy]ethyl]benzamide (66 mg, 88 μmol, 98% yield) was obtained as a yellow oil. 2.5 Preparation of compound I-4 [0350] A mixture of 4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2- yl]amino]- 3-methoxy-N-[2-[2-[2-[2-[2-[2-[2-(methylamino)ethoxy]ethoxy] ethoxy]ethoxy] ethoxy]ethoxy]ethyl]benzamide (65 mg, 87 μmol, 1.0 eq), 2-chloro-N-[3-(3-chloro-4-cyano- phenoxy)- 2,2,4,4-tetramethyl-cyclobutyl]pyrimidine-5-carboxamide (44 mg, 104 μmol, 1.2 eq), K ₂ CO ₃ (24 mg, 174 μmol, 2.0 eq) in NMP (2 mL) was degassed and purged with N ₂ for 3 times, and then the mixture was stirred at 50 °C for 6 h under N2 atmosphere. The mixture was filtered and the filtrate was concentrated to give the residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18, 100 x 30 mm, 5 μm; mobile phase: [water(FA)-ACN];B%: 35%- 65%,8min) to give N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]-2-[2-[2-[2- [2-[2-[2-[2-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo- 7H-pteridin-2-yl]amino]-3-methoxy- benzoyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethy l-methyl-amino]pyrimidine-5- carboxamide (30 mg, 25 μmol, 29% yield, 96% purity) as a white solid. ¹ H NMR: (400 MHz, MeOD) δ = 8.73 (s, 2 H), 8.50 (d, J = 8.4 Hz, 1H), 8.48 - 8.44 (m, 1H), 7.78 (s, 1H), 7.70 (d, J = 8.8 Hz, 1H), 7.54 - 7.46 (m, 2H), 7.11 (d, J = 2.4 Hz, 1H), 6.99 - 6.91 (m, 1H), 4.54 - 4.47 (m, 1H), 4.31 - 4.26 (m, 1H), 4.25 (s, 1H), 4.12 (s, 1H), 4.00 (s, 3H), 3.90 - 3.81 (m, 2H), 3.72 - 3.53 (m, 26H), 3.33 (s, 3H), 3.25 (s, 3H), 2.23 - 2.09 (m, 1H), 2.07 - 1.97 (m, 1H), 1.96 - 1.80 (m, 5H), 1.80 - 1.67 (m, 3H), 1.27 (s, 6H), 1.20 (s, 6H), 0.93 - 0.77 (m, 3H). LC-MS: MS (ES ⁺ ): RT = 2.90 min, m/z = 565.0 (M+2H ⁺ )/2. LC-MS Method 05. EXAMPLE 5 – Synthesis of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]-2-[3-[4-[3-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-me thyl-6-oxo-7H-pteridin-2- yl]amino]-3-methoxy-benzoyl]amino]propyl]piperazin-1-yl]prop yl-methyl- amino]pyrimidine-5-carboxamide (I-5). [0351] The title compound was prepared according to the following procedures. [0352] To a solution of tert-butyl N-[3-[4-(3-aminopropyl)piperazin-1-yl]propyl]-N-methyl- carbamate (80.0 mg, 254 μmol, 1.0 eq) and 4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo- 7H- pteridin-2-yl]amino]-3-methoxy-benzoic acid (108 mg, 254 μmol, 1.0 eq) in DMF (2 mL) was added HATU (193 mg, 509 μmol, 2.0 eq) and DIEA (132 mg, 1.02 mmol, 4.0 eq). The mixture was stirred at 25 °C for 6 h. The mixture was filtered under reduced pressure and solvent was removed from the filtrate under reduced pressure to afford a residue. The residue was purified by prep-HPLC (column: 3_Phenomenex Luna C18, 75 x 30 mm, 3 μm; mobile phase: [water (TFA)- ACN]; B%: 18%-48%, 7 min). Compound tert-butyl N-[3-[4-[3-[[4-[[(7R)-8-cyclopentyl-7-ethyl- 5-methyl-6-oxo-7H-pteridin-2-yl]amino]-3-methoxy-benzoyl]ami no]propyl]piperazin-1- yl]propyl]-N-methyl-carbamate (200 mg, 239 μmol, 94% yield, TFA salt) was obtained as a yellow gum. 1.2 Preparation of compound 3 [0353] To a solution of tert-butyl N-[3-[4-[3-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl- 6-oxo- 7H-pteridin-2-yl]amino]-3-methoxy-benzoyl]amino]propyl]piper azin-1-yl]propyl]-N-methyl- carbamate (200 mg, 239 μmol, 1.0 eq, TFA salt) in DCM (4 mL) was added TFA (1.54 g, 13.5 mmol, 1 mL). The mixture was stirred at 25 °C for 3 h. The mixture was concentrated under reduced pressure. Compound 4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2- yl]amino]-3-methoxy-N-[3-[4-[3-(methylamino)propyl]piperazin -1-yl]propyl]benzamide (175 mg, 238 μmol, 99% yield, TFA salt) was obtained as a yellow gum and used into the next step without purification. 1.3 Preparation of I-5 [0354] To a solution of 4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin- 2- yl]amino]-3-methoxy-N-[3-[4-[3-(methylamino)propyl]piperazin -1-yl]propyl]benzamide (77 mg, 0.11 mmol, 1.0 eq, TFA salt) in NMP (1.5 mL) was added K2CO3 (72 mg, 0.52 mmol, 5.0 eq) and 2-chloro-N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl - cyclobutyl]pyrimidine-5- carboxamide (44 mg, 0.10 mmol, 1.0 eq). The mixture was stirred at 50 °C for 2 h. The mixture was filtered and solvent from the filtrate was removed under reduced pressure to afford a residue. The residue was purified by prep-HPLC (column: Waters Xbridge 150 x 25 mm, 5 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 60%-90%, 10min). Compound N-[3-(3-chloro-4-cyano- phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]-2-[3- [4-[3-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl- 6-oxo-7H-pteridin-2- yl]amino]-3-methoxy-benzoyl]amino]propyl]piperazin-1-yl]prop yl-methyl- amino]pyrimidine-5-carboxamide (49 mg, 47 μmol, 45% yield) was obtained as an off-white solid. ¹ H NMR (400 MHz, MeOD): δ 8.80 (s, 2H), 7.92 (d, J = 8.4 Hz, 1H), 7.84 (d, J = 9.2 Hz, 1H), 7.74 (d, J = 8.8 Hz, 1H), 7.65 (d, J = 2.0 Hz, 1H), 7.64 (s, 1H), 7.59 (m, 1H), 7.15 (d, J = 2.4 Hz, 1H), 7.00 (m, 1H), 4.52 (m, 1H), 4.39-4.31 (m, 1H), 4.30 (s, 1H), 4.16 (d, J = 8.8 Hz, 1H), 4.01 (s, 3H), 3.84 (t, J = 6.8 Hz, 2H), 3.54 (br t, J = 6.8 Hz, 2H), 3.33 (m, 15H), 3.03 (m, 3H), 2.14-2.00 (m, 7H), 1.99-1.88 (m, 3H), 1.75-1.56 (m, 4H), 1.30 (s, 6H), 1.23 (s, 6H), 0.88 (t, J = 7.6 Hz, 3H). LC-MS: MS (ES ⁺ ): RT = 1.97 min; m/z = 502.9 (M+2H ⁺ )/2 and 1004.5 (M+H ⁺ ). LC-MS Method 25. EXAMPLE 6 – Synthesis of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]-2-[4-[2-[[4-[(8-cyclopentyl-7-ethyl-5-methyl-6-o xo-7Hpteridin-2-yl)amino]-3- methoxy-benzoyl]amino]ethoxy]-1-piperidyl]pyrimidine-5-carbo xamide (I-6). [0355] The title compound was prepared according to the following procedures. [0356] To a solution of 2-chloro-N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl - cyclobutyl]pyrimidine-5-carboxamide (38 mg, 90 μmol, 1.0 eq) in NMP (1 mL) was added DIEA (58 mg, 451 μmol, 5.0 eq), 4-[(8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2- yl)amino]-3- methoxy-N-[2-(4-piperidyloxy)ethyl]benzamide (60 mg, 90 μmol, 1.0 eq, TFA salt) and K ₂ CO ₃ (25 mg, 180 μmol, 2.0 eq). The mixture was stirred at 50 °C for 2 h. The mixture was concentrated and purified by prep-HPLC (column: Phenomenex luna C18, 250*50 mm*15 μm; mobile phase: [water (FA)-ACN]; B%: 48%-78%, 10 min) to give N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4- tetramethyl-cyclobutyl]-2-[4-[2-[[4-[(8-cyclopentyl-7-ethyl- 5-methyl-6-oxo-7Hpteridin-2- yl)amino]-3-methoxy-benzoyl]amino]ethoxy]-1-piperidyl]pyrimi dine-5-carboxamide (39 mg, 44% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ 8.74 (s, 2H), 8.46-8.38 (m, 2H), 7.89 (d, J = 8.8 Hz, 1H), 7.84 (s, 1H), 7.72 (d, J = 9.2 Hz, 1H), 7.61 (s, 1H), 7.53-7.46 (m, 2H), 7.21 (d, J = 2.4 Hz, 1H), 7.00 (m, J = 2.4, 8.8 Hz, 1H), 4.43-4.16 (m, 6H), 4.03 (d, J = 9.2 Hz, 1H), 3.93 (s, 3H), 3.66-3.56 (m, 4H), 3.50 (s, 2H), 3.24 (s, 3H), 2.01 (d, J = 7.2 Hz, 1H), 1.89 (d, J = 6.8 Hz, 4H), 1.77 (s, 4H), 1.68-1.56 (m, 3H), 1.44 (d, J = 8.8 Hz, 2H), 1.20 (s, 6H), 1.10 (s, 6H), 0.76 (t, J = 7.6 Hz, 3H). LC-MS: MS (ES ⁺ ): RT = 3.02 min, m/z = 514.0 (M+2H ⁺ )/2. LC-MS Method 05. EXAMPLE 7 - Synthesis of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]-2-[4-[2-[2-[2-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5 -methyl-6-oxo-7H-pteridin-2- yl]amino]-3-methoxy-benzoyl]amino]ethoxy]ethoxy]ethoxy]-1-pi peridyl]pyrimidine-5- carboxamide (I-7). [0357] The title compound was prepared according to the following procedures. 1.4 Preparation of Compound 3 [0358] To a solution of tert-butyl 4-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]piperidine-1- carboxylate (70 mg, 210 μmol, 1.0 eq) and 4-[(8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin- 2- yl)amino]-3-methoxy-benzoic acid (99 mg, 232 μmol, 1.1 eq) in DMF (1.5 mL) was added DIEA (89 mg, 689 μmol, 3.3 eq) and HATU (120 mg, 316 μmol, 1.5 eq). The solution was stirred at 20 °C for 0.5 h and concentrated. The residue was purified by prep-TLC(SiO ₂ , Ethyl acetate : Methanol=10:1) to give tert-butyl 4-[2-[2-[2-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7 H- pteridin-2-yl]amino]-3-methoxy-benzoyl]amino]ethoxy]ethoxy]e thoxy] piperidine-1-carboxylate (100 mg, 64% yield) as brown oil. 1.5 Preparation of Compound 4 [0359] A solution of tert-butyl 4-[2-[2-[2-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo- 7H-pteridin-2-yl]amino]-3-methoxy-benzoyl]amino]ethoxy]ethox y]ethoxy]piperidine-1- carboxylate (50 mg, 68 μmol, 1.0 eq) in DCM (5 mL) and TFA (1 mL) was stirred at 20 °C for 0.5 h. The solution was concentrated to give 4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H- pteridin-2-yl]amino]-3-methoxy-N-[2-[2-[2-(4-piperidyloxy)et hoxy]ethoxy]ethyl]benzamide (51 mg, crude, TFA salt) as brown oil. 1.6 Preparation of I-7 [0360] A solution of 4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2- yl]amino] - 3-methoxy-N-[2-[2-[2-(4-piperidyloxy)ethoxy]ethoxy]ethyl]ben zamide (51 mg, 68 μmol, 1 eq, TFA salt) and 2-chloro-N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl -cyclobutyl] pyrimidine-5-carboxamide (31 mg, 74 μmol, 1.1 eq) and K ₂ CO ₃ (28 mg, 203 μmol, 3.0 eq) in NMP (2 mL) was stirred at 50 °C for 2 h. The mixture was filtered and solvent from the filtrate was removed under reduced pressure to afford a residue which was purified by prep-HPLC (column: Waters Xbridge 150 x 25 mm, 5 μm; mobile phase: [water(NH4HCO3)-ACN];B%: 62%- 92%,8min) to give N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl-cyclobut yl]-2-[4-[2-[2- [2-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pterid in-2-yl]amino]-3-methoxy- benzoyl]amino]ethoxy]ethoxy]ethoxy]-1-piperidyl]pyrimidine-5 -carboxamide (23 mg, 34% yield) as a white solid. ¹ H NMR (400 MHz, MeOD): δ 8.69 (s, 2H), 8.53 (d, J = 8.0 Hz, 1H), 7.87-7.70 (m, 2H), 7.60-7.46 (m, 2H), 7.20-7.09 (m, 1H), 7.06-6.95 (m, 1H), 4.60-4.46 (m, 1H), 4.36-4.20 (m, 4H), 4.14 (s, 1H), 4.08-3.93 (m, 3H), 3.80-3.52 (m, 14H), 3.49-3.39 (m, 3H), 2.24- 2.13 (m, 1H), 2.08-1.67 (m, 12H), 1.55-1.42 (m, 2H), 1.30 (s, 6H), 1.23 (s, 6H), 0.92-0.81 (m, 3H). LC-MS: MS (ES ⁺ ): RT = 2.94 min, m/z = 528.0 (M+2H ⁺ )/2. LC-MS Method 05. EXAMPLE 8 – Synthesis of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]-2-[4-[2-[2-[2-[2-[2-[[4-[[(7R)-8-cyclopentyl-7-e thyl-5-methyl-6-oxo-7H-pteridin-2- yl]amino]-3-methoxy-benzoyl]amino]ethoxy]ethoxy]ethoxy]ethox y]ethoxy]-1- piperidyl]pyrimidine-5-carboxamide (I-8). [0361] The title compound was prepared according to the following procedures. 1.1 Preparation of compound 3 [0362] To a solution of tert-butyl 4-[2-[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethoxy] ethoxy]piperidine-1-carboxylate (60 mg, 142 μmol, 1.0 eq) and 4-[[(7R)-8-cyclopentyl-7-ethyl-5- methyl-6-oxo-7H-pteridin-2-yl]amino]-3-methoxy-benzoic acid (60 mg, 142 μmol, 1.0 eq) in DMF (3 mL) was added HATU (65 mg, 171 μmol, 1.2 eq) and DIEA (55 mg, 428 μmol, 3.0 eq). The mixture was stirred at 20 °C for 0.5 h. The solution was purified by prep-HPLC (column: Phenomenex luna C18, 250*50mm*15um;mobile phase: [water(FA)-ACN];B%: 32%-62%,10min) to give tert-butyl 4-[2-[2-[2-[2-[2-[[4-[[(7R)-8-cyclopentyl-7-ethyl- 5-methyl-6-oxo-7H-pteridin-2- yl]amino]-3-methoxybenzoyl]amino]ethoxy]ethoxy]ethoxy]ethoxy ] ethoxy]piperidine-1- carboxylate (50 mg, 42% yield). 1.2 Preparation of compound 4 [0363] To a solution of tert-butyl 4-[2-[2-[2-[2-[2-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6 - oxo-7H-pteridin-2-yl]amino]-3-methoxy-benzoyl]amino]ethoxy]e thoxy]ethoxy]ethoxy] ethoxy]piperidine-1-carboxylate (50 mg, 61 μmol, 1.0 eq) in DCM (5 mL) was added TFA (500 ^ L). The mixture was stirred at 20 °C for 0.3 h and concentrated to give 4-[[(7R)-8- cyclopentyl-7- ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-3-methoxy-N-[2- [2-[2-[2-[2-(4- piperidyloxy)ethoxy]ethoxy]ethoxy]ethoxy]ethyl]benzamide (40 mg, 91% yield) as a yellow gum. 1.3 Preparation of compound I-8 [0364] To a solution of 2-chloro-N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl - cyclobutyl]pyrimidine-5-carboxamide (23 mg, 55 μmol, 1.0 eq) in NMP (3 mL) was added K2CO3 (15 mg, 110 μmol, 2.0 eq) and4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo- 7H-pteridin-2- yl]amino]-3-methoxy-N-[2-[2-[2-[2-[2-(4- piperidyloxy)ethoxy]ethoxy]ethoxy] ethoxy]ethyl]benzamide (40 mg, 55 μmol, 1.0 eq). The mixture was stirred at 50 °C for 2 h. The solution was purified by prep-HPLC (column: Phenomenex C18, 75*30mm*3um;mobile phase: [water(FA)-ACN];B%:40%-70%,7min) to give N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4- tetramethyl-cyclobutyl]-2-[4-[2-[2-[2-[2-[2-[[4-[[(7R)-8-cyc lopentyl-7-ethyl-5-methyl-6-oxo-7H- pteridin-2-yl]amino]-3-methoxy-benzoyl]amino]ethoxy]ethoxy]e thoxy]ethoxy]ethoxy]-1- piperidyl]pyrimidine-5-carboxamide (15 mg, 24% yield) as a light yellow solid. ¹ H NMR (400 MHz, MeOD): δ 8.73 (s, 2H), 8.53 (d, J = 8.4 Hz, 1H), 7.80 (s, 1H), 7.73 (d, J = 8.8 Hz, 1H), 7.55- 7.49 (m, 2H), 7.13 (d, J = 2.4 Hz, 1H), 6.98 (dd, J = 8.8, 2.4 Hz, 1H), 4.54 (d, J = 7.6 Hz, 1H), 4.31-4.25 (m, 4H), 4.14 (s, 1H), 4.03 (s, 3H), 3.76-3.41 (m, 28H), 2.21-2.18 (m, 1H), 2.04-2.01 (m, 1H), 1.90-1.88 (m, 6H), 1.80-1.74 (m, 2H), 1.58-1.50 (m, 2H), 1.29 (s, 6H), 1.23 (s, 6H), 0.87 (t, J = 7.6 Hz, 3H). LC-MS: MS (ES ⁺ ): RT = 2.94 min, m/z = 528.0 (M+2H ⁺ )/2. LC-MS Method 05. EXAMPLE 9 - Synthesis of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]-2-[4-[2-[2-[2-[2-[2-[2-[2-[[4-[[(7R)-8-cyclopent yl-7-ethyl-5-methyl-6-oxo-7H- pteridin-2-y]amino]-3-methoxy-enzoyl]amino]ethoxy]ethoxy]eth oxy]ethoxy]ethoxy]ethoxy] ethoxy]-1-piperidyl]pyrimidine-5-carboxamide (I-9). [0365] The title compound was prepared according to the following procedures. 1.1 Preparation of compound 2 [0366] To a solution of tert-butyl 4-[2-[2-[2-[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethoxy]- ethoxy]ethoxy]ethoxy]piperidine-1-carboxylate (100 mg, 197 μmol, 1 eq) in DMF (1 mL) was added HATU (90 mg, 236 μmol, 1.2 eq) 4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo- 7H- pteridin-2-yl]amino]-3-methoxy- benzoic acid (84 mg, 197 μmol, 1 eq) and DIEA (127 mg, 983 μmol, 5 eq). The mixture was stirred at 25 °C for 0.5 h and concentrated. The residue was purified by prep-TLC (SiO2, DCM: MeOH from 10 to 1) to give tert-butyl 4-[2-[2-[2-[2-[2-[2-[2-[[4- [[(7R)-8-cyclopentyl- 7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]- amino]-3-methoxy- benzoyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]etho xy]piperidine-1-carboxylate (180 mg, 99% yield) as yellow oil. 1.2 Preparation of compound 3 [0367] To a solution of tert-butyl 4-[2-[2-[2-[2-[2-[2-[2-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5- methyl-6-oxo-7H-pteridin-2-yl]amino]-3-methoxy-benzoyl]amino ]ethoxy]ethoxy]ethoxy] ethoxy]ethoxy]ethoxy]ethoxy]piperidine-1-carboxylate (180 mg, 196 μmol, 1 eq) in DCM (2 mL) was added TFA (1 mL). The mixture was stirred at 25 °C for 0.5 h and concentrated under reduced pressure to give 4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2- yl]amino]-3- methoxy-N-[2-[2-[2-[2-[2-[2-[2-(4-piperidyloxy)ethoxy]ethoxy ]ethoxy]ethoxy] ethoxy]ethoxy]ethyl]benzamide (180 mg, 99% yield, TFA salt) as a yellow oil. 1.3 Preparation of compound I-9

[0368] To a solution of 4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2- yl]amino]- 3-methoxy-N-[2-[2-[2-[2-[2-[2-[2-(4-piperidyloxy)ethoxy]etho xy]ethoxy] ethoxy]ethoxy]ethoxy]ethyl]benzamide (90 mg, 97 μmol, 1 eq, TFA) in NMP (3 mL) was added K ₂ CO ₃ (40 mg, 290 μmol, 3 eq) and2-chloro-N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4- tetramethyl- cyclobutyl]pyrimidine-5-carboxamide (45 mg, 106 μmol, 1.1 eq). The mixture was stirred at 50 °C for 2 h and concentrated. The residue was purified by prep-HPLC (column: Boston Prime C18, 150 x 25 mm x 5 μm; mobile phase: [water(NH ₄ HCO ₃ )-ACN];B%: 55%-85%,10 min) to give N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl-cyclobut yl]- 2-[4-[2-[2-[2-[2-[2-[2- [2-[[4-[[(7R) -8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]- amino]-3-methoxy- benzoyl]amino]ethoxy]ethoxy]ethoxy] ethoxy]ethoxy]ethoxy]ethoxy]-1-piperidyl]pyrimidine-5- carboxamide (16 mg, 11% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.62 (s, 2H), 8.47 (d, J = 8.4 Hz, 1H), 7.61 (s, 1H), 7.53 - 7.47 (m, 2H), 7.40 (d, J = 1.6 Hz, 1H), 7.29 (dd, J = 1.8, 8.6 Hz, 1H), 6.90 - 6.82 (m, 2H), 6.72 (dd, J = 2.4, 8.8 Hz, 1H), 5.96 (d, J = 8.0 Hz, 1H), 4.44 (m, J = 8.0 Hz, 1H), 4.23 - 4.12 (m, 3H), 4.06 (d, J = 8.4 Hz, 1H), 3.97 (s, 1H), 3.90 (s, 3H), 3.61 - 3.59 (m, 8H), 3.58 - 3.54 (m, 21H), 3.52 - 3.46 (m, 1H), 3.52 - 3.44 (m, 2H), 3.26 (s, 3H), 2.12 - 2.04 (m, 1H), 1.98 - 1.91 (m, 1H), 1.88 - 1.79 (m, 3H), 1.79 - 1.74 (m, 3H), 1.56 (m, 2H), 1.16 (d, J = 14.8 Hz, 15H), 0.81 (t, J = 7.6 Hz, 3H). LC-MS: MS (ES ⁺ ): RT = 2.56 min, m/z = 511.8 (M+2H ⁺ )/2 and 1022.3 (M+H ⁺ ). LC-MS Method 25. EXAMPLE 10 - Synthesis of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]-2-[4-[3-[4-[3-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5 -methyl-6-oxo-7H-pteridin-2- yl]amino]-3-methoxy-benzoyl]amino]propyl]piperazin-1-yl]prop oxy]-1-piperidyl]pyrimidine- 5-carboxamide (I-10). [0369] The title compound was prepared according to the following procedures. 1.1 Preparation of compound 3 [0370] To a solution of benzyl N-(3-bromopropyl)carbamate (1.00 g, 3.67 mmol, 1.0 eq) and tert-butyl piperazine-1-carboxylate (1.37 g, 7.35 mmol, 2.0 eq) in THF (15 mL) was added DIEA (1.42 g, 11.0 mmol, 1.92 mL, 3.0 eq). The mixture was stirred at 50 °C for 12 h. To the reaction mixture was added water (50 mL) and the mixture was extracted with EtOAc (50 mL). The combined organic phase was washed with brine (3 x 50 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by prep-HPLC (column: Waters Xbridge C18, 150 x 50mm, 10 μm; mobile phase: [water(NH4HCO3)-ACN]; B%: 37%- 67%,11min) to afford tert-butyl 4-[3-(benzyloxycarbonylamino)propyl]piperazine-1-carboxylate (1.2 g, 3.2 mmol, 87% yield) as a yellow oil. 1.2 Preparation of compound 4 [0371] To a solution of tert-butyl 4-[3-(benzyloxycarbonylamino)propyl]piperazine-1- carboxylate (508 mg, 1.35 mmol, 1.0 eq) in dioxane (1 mL) was added HCl/dioxane (2 mL). The mixture was stirred at 20 °C for 0.5 h. It was concentrated in vacuum to afford benzyl N-(3- piperazin-1-ylpropyl)carbamate (422 mg, 1.34 mmol, crude, HCl salt) as a yellow oil and it was used by next step directly. 1.3 Preparation of compound 7 [0372] To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (20.0 g, 99.0 mmol, 1.0 eq) in THF (200 mL) was added NaH (5.96 g, 149 mmol, 60% purity, 1.5 eq) at 0 °C. The mixture was stirred at 20 °C for 1 h. Then 3-bromoprop-1-ene (12.0 g, 99.4 mmol, 4.4 mL, 1.0 eq) was added. The mixture was stirred at 20 °C for 11 h. This reaction was quenched by aq. NH4Cl (5 mL) and concentrated to afford crude product. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 1:0 to 10:1) to give tert-butyl 4- allyloxypiperidine-1-carboxylate (21.5 g, 89.1 mmol, 90% yield) as a colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.00-5.84 (m, 1H), 5.33-5.24 (m, 1H), 5.20-510 (m, 1H), 4.05-3.99 (m, 2H), 3.85- 3.70 (m, 2H), 3.55-3.45 (m, 1H), 3.15-3.00 (m, 2H), 1.88-1.78 (m, 2H), 1.58-1.48 (m, 2H), 1.46 (s, 9H) 1.4 Preparation of compound 8 [0373] 9-BBN (0.5 M, 24.86 mL, 3.0 eq) in THF (6 mL) was added to tert-butyl 4- allyloxypiperidine-1-carboxylate (1.0 g, 4.1 mmol, 1.0 eq) under the atmosphere of N ₂ at 0 °C and the mixture was stirred at 25 °C for 4 h. Then NaBO ₃ (2.55 g, 16.6 mmol, 3.19 mL, 4.0 eq) and H2O (4 mL) was added and the mixture was stirred at 25 °C for 12 h. To the reaction mixture was added water (50 mL) and the mixture was extracted with EtOAc (50 mL). The combined organic phase was washed with brine (3 x 50 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuum. The crude product was purified by column chromatography on silica gel (petroleum ether/ethyl acetate = 10:1 to 0:1 and DCM/MeOH = 5:1) to give tert-butyl 4-(3- hydroxypropoxy)piperidine-1-carboxylate (1.2 g, crude) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 3.86 - 3.71 (m, 4H), 3.70-3.64 (m, 2H), 3.53-3.43 (m, 1H), 3.16-3.05 (m, 2H), 1.91-1.83 (m, 5H), 1.69-1.58 (m, 2H), 1.46 (s, 9H) 1.5 Preparation of compound 9 [0374] To a solution of tert-butyl 4-(3-hydroxypropoxy)piperidine-1-carboxylate (1.2 g, 4.6 mmol, 1.0 eq) in DCM (4 mL) was added Et ₃ N (1.6 g, 16 mmol, 2.3 mL, 3.5 eq) and TosCl (2.2 g, 12 mmol, 2.5 eq). The mixture was stirred at 25 °C for 12 h. To the reaction mixture was added water (50 mL) and the mixture was extracted with EtOAc (50 mL). The combined organic phase was washed with brine (3 x 50 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuum. The residue was purified by prep-HPLC (column: Waters Xbridge C18, 150 x 50mm*10um; mobile phase: [water(NH4HCO3)-ACN]; B%: 46%-76%,11min) to afford tert-butyl 4-[3-(p-tolylsulfonyloxy)propoxy]piperidine-1-carboxylate (660 mg, 1.60 mmol, 34% yield) as a yellow oil. 1.6 Preparation of compound 10 [0375] To a solution of benzyl N-(3-piperazin-1-ylpropyl)carbamate (422 mg, 1.34 mmol, 1.0 eq, HCl salt) in DMF (5 mL) was added NaHCO3 (565 mg, 6.72 mmol, 261 ^L, 5.0 eq) and tert- butyl 4-[3-(p-tolylsulfonyloxy)propoxy]piperidine-1-carboxylate (556 mg, 1.34 mmol, 1.0 eq). The mixture was stirred at 50 °C for 12 h. After filtration, the filtrate was purified by prep-HPLC (column: Waters Xbridge C18, 150 x 50mm*10um; mobile phase: [water(NH4HCO3)-ACN]; B%: 35%-65%,11min) to afford tert-butyl 4-[3-[4-[3-(benzyloxycarbonylamino)propyl] piperazin-1- yl]propoxy]piperidine-1-carboxylate (140 mg, 267 μmol, 20% yield) as a yellow oil. 1.7 Preparation of compound 11 [0376] To a solution of tert-butyl 4-[3-[4-[3-(benzyloxycarbonylamino)propyl]piperazin-1- yl]propoxy]piperidine-1-carboxylate (140 mg, 270 μmol, 1.0 eq) in THF (5 mL) was added Pd/C (14 mg, 10% purity) under N ₂ atmosphere. The suspension was degassed and purged with H ₂ for 3 times. The mixture was stirred under H ₂ (15 Psi) at 25 °C for 2 h. After filtration, the filtrate was concentrated to afford tert-butyl 4-[3-[4-(3-aminopropyl)piperazin-1-yl]propoxy]piperidine-1- carboxylate (90.0 mg, 234 μmol, 87% yield) as a yellow oil and it was used directly for next step. 1.8 Preparation of compound 13 [0377] To a solution of tert-butyl 4-[3-[4-(3-aminopropyl)piperazin-1-yl]propoxy]piperidine-1- carboxylate (80 mg, 0.21mmol, 1.0 eq) and 4-[(8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin- 2-yl)amino]-3-methoxy-benzoic acid (97 mg, 0.23mmol, 1.1 eq) DMF (2 mL) was added DIEA (134 mg, 1.04 mmol, 181 ^L, 5.0 eq) and HATU (119 mg, 312 μmol, 1.5 eq). The mixture was stirred at 25 °C for 12 h. H2O (0.1mL) was added to quench this reaction. The residue was purified by prep-HPLC (column: Waters Xbridge 150 x 25 mm*5um; mobile phase: [water(NH ₄ HCO ₃ )- ACN]; B%: 55%-85%,10min) (column: Phenomenex Synergi Polar-RP 100*25 mm*4um; mobile phase: [water(TFA)-ACN]; B%: 26%-46%,7min) to afford tert-butyl 4-[3-[4-[3-[[4-[[(7R)-8- cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-3 -methoxy- benzoyl]amino]propyl]piperazin-1-yl]propoxy]piperidine-1-car boxylate (80 mg, 0.1 mmol, 49% yield) as a yellow oil. 1.9 Preparation of compound 14 [0378] To a solution of tert-butyl 4-[3-[4-[3-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo- 7H-pteridin-2-yl]amino]-3-methoxy-benzoyl]amino]propyl]piper azin-1-yl]propoxy]piperidine-1- carboxylate (72 mg, 91 μmol, 1.0 eq) in DCM (2 mL) was added TFA (1 mL).The mixture was stirred at 25 °C for 1 h. It was concentrated in vacuum. It was concentrated in vacuum to give 4- [[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl ]amino]-3-methoxy-N-[3-[4-[3-(4- piperidyloxy)propyl]piperazin-1-yl]propyl]benzamide (73 mg, 91 μmol, TFA salt) as a yellow oil and it was used directly for next step. 1.10 Preparation of I-10

[0379] To a solution of 4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2- yl]amino]-3-methoxy-N-[3-[4-[3-(4-piperidyloxy)propyl]pipera zin-1-yl]propyl]benzamide (73 mg, 91 μmol, 1.0 eq, TFA salt) and 2-chloro-N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl - cyclobutyl]pyrimidine-5-carboxamide (38 mg, 91 μmol, 1.0 eq) in NMP (5 mL) was added K2CO3 (38 mg, 0.27 mmol, 3.0 eq). The mixture was stirred at 50 °C for 1 h. It was filtered. It was purified by prep-HPLC (column: Waters Xbridge 150 x 25 mm* 5um; mobile phase: [water(NH ₄ HCO ₃ )-ACN]; B%: 60%-90%,9min) and (column: Phenomenex C18, 75*30mm*3um; mobile phase: [water(FA)-ACN]; B%: 25%-55%,7min) to afford N-[3-(3-chloro-4-cyano- phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]-2-[4-[3-[4-[3-[[4-[ [(7R)-8-cyclopentyl-7-ethyl-5-methyl- 6-oxo-7H-pteridin-2-yl]amino]-3-methoxy-benzoyl]amino] propyl]piperazin-1-yl]propoxy]-1- piperidyl]pyrimidine-5-carboxamide (18 mg, 16 μmol, 18% yield) as a white solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.73 (s, 2H), 8.55-8.45 (m, 1H), 7.82-7.69 (m, 2H), 7.52-7.43 (m, 2H), 7.12 (d, J = 1.6 Hz, 1H), 7.01-6.93 (m, 1H), 4.54-4.45 (m, 1H), 4.36-4.21 (m, 4H), 4.13 (s, 1H), 4.00 (s, 3H), 3.67-3.51 (m, 5H), 3.49-3.41 (m, 2H), 3.33 (s, 3H), 2.87-2.43 (m, 11H), 2.35-1.61 (m, 17H), 1.60- 1.46 (m, 2H), 1.28 (s, 6H), 1.21 (s, 6H), 0.89-0.82 (m, 3H). LC-MS: MS (ES ⁺ ): RT = 2.53 min, m/z = 934.4 (M+H ⁺ ) and 467.8 (M+2H ⁺ )/2. LC-MS Method 25. EXAMPLE 11 - Synthesis of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]-2-[4-[2-[2-[4-[[4-[(8-cyclopentyl-7-ethyl-5-meth yl-6-oxo-7H-pteridin-2-yl)- amino]-3-methoxy-benzoyl]amino]-1-piperidyl]ethoxy]ethyl]-1- piperidyl]pyrimidine- 5- carboxamide (I-11). [0380] The title compound was prepared according to the following procedures. 1.1 Preparation of compound 2 [0381] To a solution of tert-butyl 4-(2-hydroxyethyl)piperidine-1-carboxylate (1 g, 4.36 mmol, 1.0 eq) in THF (10 mL) was added NaH (262 mg, 6.54 mmol, 60% purity, 1.5 eq) at 0 °C. The mixture was stirred at 25 °C for 1 h and 2-bromoethoxymethylbenzene (1.03 g, 4.8 mmol, 1.1 eq) was added. The mixture was stirred at 25 °C for 11 h and concentrated. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate=20/1 to 5/1) to give tert-butyl 4- [2-(2-benzyloxyethoxy)ethyl]piperidine-1-carboxylate (480 mg, 30% yield) as a yellow oil. ¹ H NMR (400 MHz, CDCl3): δ 7.24-7.39 (m, 5 H), 4.58 (s, 1 H), 3.97-4.15 (m, 2 H), 3.58-3.67 (m, 4 H), 3.52 (t, J = 6.4 Hz, 2 H), 2.68 (t, J = 12.2 Hz, 2 H), 1.50-1.72 (m, 6 H), 1.46 (s, 9 H), 1.03-1.17 (m, 2 H) 1.2 Preparation of compound 3 [0382] To a solution of tert-butyl 4-[2-(2-benzyloxyethoxy)ethyl]piperidine-1-carboxylate (480 mg, 1 mmol, 1.0 eq) in THF (5 mL) was added Pd/C (48 mg, 10% purity) under N ₂ atmosphere. The mixture was stirred under H2 (15 Psi) at 25 °C for 2 h. The mixture was filtered and the filtrate was concentrated to give tert-butyl 4-[2-(2-hydroxyethoxy)ethyl]piperidine-1-carboxylate (359 mg, crude). 1.3 Preparation of compound 4 [0383] To a solution of tert-butyl 4-[2-(2-hydroxyethoxy)ethyl]piperidine-1-carboxylate (359 mg, 1 mmol, 1.0 eq) in DCM (4 mL) was added TEA (797 mg, 7.88 mmol, 6.0 eq) and 4- methylbenzenesulfonyl chloride (751 mg, 4 mmol, 3.0 eq). The mixture was stirred at 25 °C for 18 h and concentrated. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate=20/1 to 5/1) to give tert-butyl 4-[2-[2-(p-tolylsulfonyloxy)ethoxy]ethyl] piperidine-1-carboxylate (440 mg, 78% yield). ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.81 (d, J = 8.4 Hz, 2 H), 7.35 (d, J = 8.0 Hz, 2 H), 3.96-4.21 (m, 4 H), 3.54-3.68 (m, 2 H), 3.45 (t, J = 6.4 Hz, 2 H), 2.67 (t, J = 12.0 Hz, 2 H), 2.46 (s, 3 H), 1.59-1.65 (m, 2 H), 1.57 (s, 1 H), 1.47-1.55 (m, 2 H), 1.46 (s, 9 H), 1.00-1.15 (m, 2 H) 1.4 Preparation of compound 5 [0384] To a solution of tert-butyl 4-[2-[2-(p-tolylsulfonyloxy)ethoxy]ethyl]piperidine-1- carboxylate (440 mg, 1 mmol, 1.0 eq) in CH ₃ CN (5 mL) was added K ₂ CO ₃ (427 mg, 3.1 mmol, 3.0 eq) and benzyl N-(4-piperidyl)carbamate (279 mg, 1.0 mmol, 1.0 eq, HCl salt). The mixture was stirred at 80 °C for 12 h and concentrated. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate=1/1 to 0/1) to give tert-butyl 4-[2-[2-[4- (benzyloxycarbonylamino)-1-piperidyl]ethoxy]ethyl]piperidine -1-carboxylate (394 mg, 78% yield) as a yellow oil. ¹ H NMR (400 MHz, CDCl3): δ 7.30-7.39 (m, 5 H), 4.69 (d, J = 7.0 Hz, 1 H), 4.04-4.10 (m, 1 H), 3.54 (t, J = 5.8 Hz, 2 H), 3.47 (t, J = 6.2 Hz, 2 H), 2.90 (d, J = 10.6 Hz, 2 H), 2.57-2.72 (m, 4 H), 2.15-2.24 (m, 2 H), 1.93-2.03 (m, 6 H), 1.60-1.69 (m, 2 H), 1.47-1.58 (m, 6 H), 1.46 (s, 9 H) 1.5 Preparation of compound 6 [0385] To a solution of tert-butyl 4-[2-[2-[4-(benzyloxycarbonylamino)-1-piperidyl]ethoxy] ethyl]piperidine-1-carboxylate (390 mg, 796 μmol, 1.0 eq) in THF (4 mL) was added Pd/C (40 mg, 10% purity) under N2 atmosphere. The mixture was stirred under H2 (15 Psi) at 25 °C for 1 h. The mixture was filtered and the filtrate was concentrated to give tert-butyl 4-[2-[2-(4-amino-1- piperidyl)ethoxy]ethyl]piperidine-1-carboxylate (210 mg, crude) as a brown oil. ¹ H NMR (400 MHz, CDCl ₃ ): δ 3.99-4.16 (m, 2 H), 3.75 (m, 1 H), 3.55 (t, J = 6.0 Hz, 2 H), 3.47 (t, J = 6.4 Hz, 2 H), 2.91 (d, J = 12.0 Hz, 2 H), 2.64-2.70 (m, 2 H), 2.58 (t, J = 6.0 Hz, 2 H), 2.10 (m, 2 H), 1.76- 1.90 (m, 8 H), 1.66 (d, J = 12.8 Hz, 2 H), 1.52 (t, J = 6.0 Hz, 2 H), 1.45 (s, 9 H), 1.40 (d, J = 2.4 Hz, 1 H) 1.6 Preparation of compound 7 [0386] To a solution of tert-butyl 4-[2-[2-(4-amino-1-piperidyl)ethoxy]ethyl]piperidine-1- carboxylate (100 mg, 281 μmol, 1.0 eq) in DMF (1 mL) was added 4-[[(7R)-8-cyclopentyl-7- ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-3-methoxy-benzo ic acid (132 mg, 309 μmol, 1.1 eq), DIEA (182 mg, 1.41 mmol, 5.0 eq) and HATU (139 mg, 366 μmol, 1.3 eq). The mixture was stirred at 25 °C for 1 h and concentrated. The residue was purified by prep-TLC (SiO ₂ , DCM: MeOH = 10:1) to give tert-butyl 4-[2-[2-[4-[[4-[(8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H- pteridin-2-yl)amino]-3-methoxy-benzoyl]amino]-1-piperidyl]et hoxy]ethyl]piperidine-1- carboxylate (120 mg, 56% yield) as a colorless oil. ¹ H NMR (400 MHz, CDCl3): δ 8.55 (d, J = 8.4 Hz, 1 H), 7.69 (s, 1 H), 7.60 (s, 1 H), 7.43 (d, J = 1.8 Hz, 1 H), 7.25 (m, 1 H), 5.96 (d, J = 8.4 Hz, 1 H), 4.47-4.58 (m, 1 H), 4.23 (m, 1 H), 4.03 (m, 1 H), 3.99 (s, 3 H), 3.58 (t, J = 5.8 Hz, 2 H), 3.48- 3.52 (m, 4 H), 3.34 (s, 3 H), 2.95-3.02 (m, 2 H), 2.62-2.72 (m, 4 H), 2.26-2.33 (m, 2 H), 2.08 (s, 1 H), 1.78-1.91 (m, 6 H), 1.68 (m, 10 H), 1.52-1.57 (m, 4 H), 1.46 (s, 9 H), 0.87-0.90 (m, 3 H) 1.7 Preparation of compound 8

[0387] To a solution of tert-butyl 4-[2-[2-[4-[[4-[(8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H- pteridin-2-yl) amino]-3-methoxy-benzoyl]amino]-1-piperidyl]ethoxy]ethyl]pip eridine-1- carboxylate (120 mg, 157 μmol, 1.0 eq) in DCM (3 mL) was added TFA (1 mL). The mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give a crude product. 1.8 Preparation of I-11 [0388] To a solution of 4-[(8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl)am ino]-3- methoxy-N-[1-[2-[2-(4-piperidyl)ethoxy]ethyl]-4-piperidyl]be nzamide (122 mg, 157 μmol, 1.0 eq, TFA) in NMP (1.5 mL) was added K ₂ CO ₃ (65.11 mg, 471.12 μmol, 3.0 eq) and 2-chloro-N-[3-(3- chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]pyrim idine-5-carboxamide (72.43 mg, 172.74 μmol, 1.1 eq). The mixture was stirred at 50 °C for 2 h and concentrated. The residue was purified by prep-HPLC (column: Waters Xbridge 150 x 25 mm, 5 μm; mobile phase: [water(NH ₄ HCO ₃ )-ACN]; B%: 75%-100%, 10min) to give N-[3-(3-chloro-4-cyano-phenoxy)- 2,2,4,4-tetramethyl-cyclobutyl]-2-[4-[2-[2-[4-[[4-[(8-cyclop entyl-7-ethyl-5-methyl-6-oxo-7H- pteridin-2-yl)amino]-3-methoxy-benzoyl]amino]-1-piperidyl]et hoxy]ethyl]-1-piperidyl] pyrimidine-5-carboxamide (44 mg, 27% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.74 (s, 2 H), 8.41 (d, J = 8.8 Hz, 1 H), 8.08 (d, J = 7.6 Hz, 1 H), 7.89 (d, J = 8.8 Hz, 1 H), 7.84 (s, 1 H), 7.71 (d, J = 9.0 Hz, 1 H), 7.60 (s, 1 H), 7.45-7.50 (m, 2 H), 7.21 (d, J = 2.0 Hz, 1 H), 7.00 (m, 1 H), 4.73 (d, J = 12.6 Hz, 2 H), 4.35 (t, J = 8.0 Hz, 1 H), 4.28 (s, 1 H), 4.23 (m, 1 H), 4.03 (d, J = 9.2 Hz, 1 H), 3.93 (s, 3 H), 3.70-3.77 (m, 1 H), 3.41-3.50 (m, 6 H), 3.24 (s, 3 H), 2.88-2.97 (m, 4 H), 1.95-2.14 (m, 4 H), 1.83-1.90 (m, 2 H), 1.76 (d, J = 12.8 Hz, 9 H), 1.52-1.67 (m, 6 H), 1.42- 1.48 (m, 2 H), 1.20 (s, 6 H), 1.10 (s, 6 H), 0.76 (t, J = 7.4 Hz, 3 H). LC-MS: MS (ES ⁺ ): RT = 2.27 min, m/z = 1045.4 (M+H ⁺ ) and 523.2 (M+2H ⁺ )/2. LC-MS Method 25. EXAMPLE 12 - Synthesis of N-((1R, 3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4- tetramethylcyclobutyl)-2-(4-(2-(2-(2-(4-(((R)-8-cyclopentyl- 7-ethyl-5-methyl-6-oxo-5,6,7,8- tetrahydropteridin-2-yl)(methyl)amino)-3-methoxybenzamido)et hoxy)ethoxy)ethoxy) piperidin-1-yl)pyrimidine-5-carboxamide (I-12). [0389] The title compound was prepared according to the following procedures. 1.1 Preparation of compound 2 [0390] To a solution of (R)-4-((8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8- tetrahydropteridin-2-yl)amino)-3-methoxybenzoic acid (0.500 g, 1.18 mmol, 1.0 eq) in DMF (10 mL) was added NaH (94.0 mg, 2.35 mmol, 60% purity, 2.0 eq) at 0 °C. The reaction mixture was stirred at 0 °C for 0.5 hr. Then MeI (334 mg, 2.35 mmol, 146 ^L, 2.0 eq) was added. The mixture was stirred at 25 °C for 4 hr to give a colorless solution. The reaction mixture was quenched by addition saturated NH4Cl (50 mL) at 0 °C, diluted with water (50 mL x 2), extracted with DCM (75 mL x 2). The combined organic layers were washed with water (50 mL x 2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. Compound (R)-methyl 4-((8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydrop teridin-2-yl)(methyl)amino)-3- methoxybenzoate (0.500 g, 1.10 mmol, 94% yield) was obtained as a yellow oil. ¹ H NMR: (400 MHz, CDCl ₃ ) δ 7.95 - 7.94 (s, 1H), 7.62 - 7.57 (m, 1H), 7.55 - 7.53 (m, 1H), 7.25 - 7.18 (m, 1H), 3.86 - 3.85 (m, 2H), 3.77 - 3.75 (m, 2H), 3.31 - 3.30 (m, 2H), 3.20 - 3.19 (m, 2H), 2.90 - 2.87 (m, 4H), 2.82 - 2.80 (m, 4H), 1.78 - 1.74 (m, 1H), 1.67 - 1.61 (m, 2H), 1.30 (m, 2H), 1.20 - 1.17 (m, 2H), 0.84 - 0.80 (m, 1H), 0.78 - 0.72 (m, 3H) 1.2 Preparation of compound 3 [0391] To a solution of (R)-methyl 4-((8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8- tetrahydropteridin-2-yl)(methyl)amino)-3-methoxybenzoate (0.500 g, 1.10 mmol, 1.0 eq) in THF (1 mL) and H2O (0.3 mL) was added LiOH (52.8 mg, 2.20 mmol, 2.0 eq). The mixture was stirred at 50 °C for 18 h to give a yellow solution. The reaction mixture was concentrated under reduced pressure to give a residue. It was used into the next step without further purification. Compound (R)-4-((8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahy dropteridin-2-yl)(methyl)amino)-3- methoxybenzoic acid (0.470 g, 1.07 mmol, 97% yield) was obtained as a brown oil. 1.3 Preparation of compound 5 [0392] To a solution of (R)-4-((8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8- tetrahydropteridin-2-yl)(methyl)amino)-3-methoxybenzoic acid (200 mg, 455 μmol, 1.0 eq) in DMF (2 mL) was added HATU (173 mg, 455 μmol, 1.0 eq), DIEA (176 mg, 1.37 mmol, 238 ^L, 3.0 eq) and tert-butyl 4-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]piperidine-1-carboxylat e (151 mg, 455 μmol, 1.0 eq). The mixture was stirred at 25 °C for 8 hr. The reaction mixture was diluted with water (50 mL) and extracted with EA (50 mL x 3). The combined organic layers were washed with water (100 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , DCM/MeOH = 20/1 to 10/1). Compound (R)-tert-butyl 4-(2-(2-(2-(4-((8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8 - tetrahydropteridin-2-yl)(methyl)amino)-3-methoxybenzamido)et hoxy) ethoxy)ethoxy)piperidine- 1-carboxylate (180 mg, 238 μmol, 52% yield) was obtained as a yellow oil. ¹ H NMR (400 MHz, CDCl3) δ 7.95 (s, 2H), 7.53 - 7.52 (m, 1H), 7.46 - 7.45 (m, 1H), 7.24 - 7.23 (m, 1H), 7.21 - 7.20 (m, 1H), 3.77 - 3.76 (m, 4H), 3.61 - 3.61 (m, 3H), 3.60 - 3.60 (m, 4H), 3.31 - 3.30 (m, 3H), 3.19 (s, 3H), 2.89 - 2.89 (m, 5H), 2.82 - 2.81 (m, 5H), 1.77 - 1.72 (m, 8H), 1.66 - 1.63 (m, 6H), 1.37 (s, 9H), 0.78 - 0.75 (m, 3H) 1.4 Preparation of compound 6 [0393] A solution of (R)-tert-butyl 4-(2-(2-(2-(4-((8-cyclopentyl-7-ethyl-5-methyl-6-oxo- 5,6,7,8-tetrahydropteridin-2-yl)(methyl)amino)-3-methoxybenz amido)ethoxy)ethoxy) ethoxy)piperidine-1-carboxylate (180 mg, 239 μmol, 1.0 eq) in TFA (0.5 mL) and DCM (1.5 mL) was stirred at 25 °C for 2 hr. The reaction mixture was concentrated under reduced pressure to give a residue and without purification to used next steps directly. Compound (R)-4-((8-cyclopentyl-7- ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)(methyl )amino)-3-methoxy-N-(2-(2-(2- (piperidin-4-yloxy)ethoxy)ethoxy)ethyl)benzamide (150 mg, 229 μmol, TFA) was obtained as a brown oil. 1.5 Preparation of I-12 [0394] To a solution of (R)-4-((8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8- tetrahydropteridin-2-yl)(methyl)amino)-3-methoxy-N-(2-(2-(2- (piperidin-4-yloxy)ethoxy) ethoxy)ethyl)benzamide (150 mg, 229 μmol, 1.0 eq) in NMP (2 mL) was added K2CO3 (95.1 mg, 688 μmol, 3.0 eq) and 2-chloro-N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4- tetramethylcyclobutyl)pyrimidine-5-carboxamide (96.2 mg, 229 μmol, 1.0 eq). The mixture was stirred at 50 °C for 18 h to give a yellow solution. The reaction mixture was filtered to give a solution. The solution was diluted with water (30 mL) and extracted with EA (30 mL x 3). The combined organic layers were washed with water (25 mL x 2), dried over Na ₂ SO ₄ filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reversed- phase HPLC column: Phenomenex C18, 150 x 25 mm*10um;mobile phase: [water(NH ₄ HCO ₃ )- ACN];B%: 54%-84%,5min. Compound N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4- tetramethylcyclobutyl)-2-(4-(2-(2-(2-(4-(((R)-8-cyclopentyl- 7-ethyl-5-methyl-6-oxo-5,6,7,8- tetrahydropteridin-2-yl)(methyl)amino)-3-methoxybenzamido)et hoxy) ethoxy)ethoxy)piperidin-1- yl)pyrimidine-5-carboxamide (24.0 mg, 23.2 μmol, 10% yield) was obtained as a white solid. ¹ H NMR: (400 MHz, CD3OD) δ 8.77 - 8.69 (s, 2H), 7.77 - 7.69 (d, J = 8.8 Hz, 1H), 7.62 - 7.56 (d, J = 2.4 Hz, 2H), 7.54 - 7.49 (m, 1H), 7.33 - 7.27 (d, J = 8.4 Hz, 1H), 7.17 - 7.12 (m, 1H), 7.03 - 6.96 (m, 1H), 4.61 - 4.56 (m, 1H), 4.35 - 4.28 (m, 3H), 4.19 - 4.13 (m, 2H), 3.86 - 3.81 (m, 3H), 3.72 - 3.68 (m, 10H), 3.64 - 3.60 (m, 2H), 3.59 - 3.52 (m, 2H), 3.36 - 3.34 (m, 6H), 3.31 - 3.28 (m, 3H), 1.95 - 1.90 (m, 2H), 1.80 (s, 2H), 1.68 (m, 2H), 1.60 (m, 2H), 1.38 - 1.32 (m, 4H), 1.32 - 1.29 (m, 6H), 1.23 (m, 5H), 1.26 - 1.20 (m, 1H), 0.86 - 0.77 (m, 3H). LC-MS: MS (ES ⁺ ): RT = 2.01 min, m/z = 1074.5 (M+H ⁺ ) and 537.8 (M+2H ⁺ )/2. LC-MS Method 25. EXAMPLE 13 - Synthesis of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]-2-[4-[[3-[4-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-m ethyl-6-oxo-7H-pteridin-2- yl]amino]-3-methoxy-benzoyl]amino]-1-piperidyl]propyl-methyl -amino]methyl]-1- piperidyl]pyrimidine-5-carboxamide (I-13). [0395] The title compound was prepared according to the following procedures. 1.1 Preparation of compound 2 [0396] To a solution of tert-butyl N-methylcarbamate (1 g, 8 mmol, 1.0 eq) in THF (10 mL) was added NaH (396 mg, 9.9 mmol, 60% purity, 1.3 eq) at 0 °C. The mixture was stirred at 25 °C for 1 h and 3-dibromopropane (7.7 g, 38.1 mmol, 5.0 eq) was added. The mixture was stirred at 25 °C for 11 h and concentrated. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate=1/0 to 15/1) to give tert-butyl N-(3-bromopropyl)-N-methyl- carbamate (190 mg, 10% yield) as a yellow oil. ¹ H NMR (400 MHz, CDCl3): δ 3.31-3.45 (m, 4 H), 2.88 (s, 3 H), 2.02-2.15 (m, 2 H), 1.47 (s, 9 H) 1.2 Preparation of compound 3 [0397] To a solution of tert-butyl N-(3-bromopropyl)-N-methyl-carbamate (190 mg, 753 μmol, 1.0 eq) in CH ₃ CN (2 mL) was added K ₂ CO ₃ (312 mg, 2.26 mmol, 3.0 eq) and benzyl N-(4- piperidyl)carbamate (204 mg, 753 μmol, 1.0 eq, HCl salt). The mixture was stirred at 80 °C for 12 h and concentrated. The residue was purified by prep-TLC (SiO2, DCM: MeOH = 10:1) to give tert-butyl N-[3-[4-(benzyloxycarbonylamino)-1-piperidyl]propyl]-N-methy l-carbamate (110 mg, 36% yield). ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.30-7.39 (m, 5 H), 5.09 (s, 2 H), 4.60-4.72 (m, 1 H), 3.49-3.59 (m, 1 H), 3.23 (t, J = 6.2 Hz, 2 H), 2.84 (s, 3 H), 2.33 (s, 2 H), 1.91-2.14 (m, 5 H), 1.71 (s, 2 H), 1.48 (s, 2 H), 1.45 (s, 9 H) 1.3 Preparation of compound 4 [0398] To a solution of tert-butyl N-[3-[4-(benzyloxycarbonylamino)-1-piperidyl]propyl]-N- methyl-carbamate (110 mg, 271 μmol, 1.0 eq) in DCM (1 mL) was added TFA (0.2 mL). The mixture was stirred at 25 °C for 1 h and concentrated under reduced pressure to give crude product. 1.4 Preparation of compound 5 [0399] To a solution of benzyl N-[1-[3-(methylamino)propyl]-4-piperidyl]carbamate (82 mg, 196 μmol, 1.0 eq, TFA) in DCE (1 mL) was added NaOAc (80 mg, 977 μmol, 5.0 eq) and tert- butyl 4-formylpiperidine-1-carboxylate (42 mg, 195 μmol, 1.0 eq), then NaBH(OAc) ₃ (124 mg, 586 μmol, 3.0 eq) was added. The mixture was stirred at 25 °C for 1 h and concentrated. The residue was purified by prep-TLC (SiO ₂ , DCM: MeOH = 20:1) to give tert-butyl 4-[[3-[4- (benzyloxycarbonylamino)-1-piperidyl]propyl-methyl-amino]met hyl]piperidine-1-carboxylate (67 mg, 68% yield). ¹ H NMR (400 MHz, CDCl3): δ 7.30-7.40 (m, 5 H), 5.10 (s, 2 H), 4.81-4.91 (m, 1 H), 4.05-4.18 (m, 2 H), 3.66-3.76 (m, 1 H), 3.29-3.37 (m, 2 H), 2.83-2.88 (m, 2 H), 2.70 (s, 4 H), 2.55-2.63 (m, 2 H), 2.42 (s, 3 H), 2.05-2.15 (m, 4 H), 1.68-2.01 (m, 8 H), 1.46 (s, 9 H) 1.5 Preparation of compound 6 [0400] To a solution of tert-butyl 4-[[3-[4-(benzyloxycarbonylamino)-1-piperidyl]propyl- methyl-amino]methyl]piperidine-1-carboxylate (67 mg, 133 μmol, 1.0 eq) in THF (1 mL) was added Pd/C (7 mg, 10% purity) under N2 atmosphere. The mixture was stirred under H2 (15 Psi) at 25 °C for 1 h. The mixture was filtered and the filtrate was concentrated to give tert-butyl 4-[[3- (4-amino-1-piperidyl)propyl-methyl-amino]methyl]piperidine-1 -carboxylate (49 mg, crude). 1.6 Preparation of compound 7 [0401] To a solution of tert-butyl 4-[[3-(4-amino-1-piperidyl)propyl-methyl-amino]methyl] piperidine-1-carboxylate (49 mg, 133 μmol, 1.0 eq) in DMF (1 mL) was added 4-[[(7R)-8- cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-3 -methoxy-benzoic acid (62 mg, 146 μmol, 1.1 eq), DIEA (86 mg, 665 μmol, 5.0 eq) and HATU (66 mg, 173 μmol, 1.3 eq). The mixture was stirred at 25 °C for 1 h and concentrated. The residue was purified by prep-TLC (SiO ₂ , DCM: MeOH = 10:1) to give tert-butyl 4-[[3-[4-[[4-[(8-cyclopentyl-7-ethyl-5-methyl-6- oxo-7H-pteridin-2-yl)amino]-3-methoxy-benzoyl]amino]-1-piper idyl]propyl-methyl- amino]methyl]piperidine-1-carboxylate (19 mg, 18% yield) as a colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.56 (d, J = 8.5 Hz, 1 H), 7.68 (s, 1 H), 7.62 (s, 1 H), 7.42 (s, 2 H), 5.31 (s, 1 H), 4.49-4.59 (m, 1 H), 4.22 (m, 1 H), 4.00 (s, 3 H), 3.33 (s, 3 H), 3.04-3.08 (m, 1 H), 2.55-2.81 (m, 8 H), 2.26-2.41 (m, 3 H), 2.14-2.18 (m, 1 H), 2.09 (s, 2 H), 1.95-2.04 (m, 10 H), 1.79-1.85 (m, 6 H), 1.72 (s, 3 H), 1.46 (s, 12 H), 1.13-1.23 (m, 2 H), 0.88 (t, J = 7.4 Hz, 3 H) 1.7 Preparation of compound 8 [0402] To a solution of tert-butyl 4-[[3-[4-[[4-[(8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H- pteridin-2-yl)amino]-3-methoxy-benzoyl]amino]-1-piperidyl]pr opyl-methyl-amino]methyl] piperidine-1-carboxylate (19 mg, 24 μmol, 1.0 eq) in DCM (0.5 mL) was added TFA (0.1 mL). The mixture was stirred at 25 °C for 1 h and concentrated under reduced pressure to give a crude product. 1.8 Preparation of I-13 [0403] To a solution of 4-[(8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl)am ino]-3- methoxy-N-[1-[3-[methyl(4-piperidylmethyl)amino]propyl]-4-pi peridyl]benzamide (19 mg, 24 μmol, 1.0 eq, TFA salt) in NMP (0.5 mL) was added K2CO3 (9.97 mg, 72 μmol, 3.0 eq) and 2- chloro-N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl-c yclobutyl]pyrimidine-5- carboxamide (10 mg, 24 μmol, 1.0 eq). The mixture was stirred at 50 °C for 2 h and concentrated. The residue was purified by prep-HPLC (column: Phenomenex C18, 75 x 30 mm, 3 μm; mobile phase: [water(FA)-ACN]; B%: 15%-45%, 7min) to give N-[3-(3-chloro-4-cyano-phenoxy)- 2,2,4,4-tetramethyl-cyclobutyl]-2-[4-[[3-[4-[[4-[[(7R)-8-cyc lopentyl-7-ethyl-5-methyl-6-oxo-7H- pteridin-2-yl]amino]-3-methoxy-benzoyl]amino]-1-piperidyl]pr opyl-methyl-amino]methyl]-1- piperidyl]pyrimidine-5-carboxamide (10.3 mg, 40% yield) as a white solid. ¹ H NMR (400 MHz, MeOD): δ 8.75 (s, 2 H), 8.48 (d, J = 9.0 Hz, 1 H), 7.78 (s, 1 H), 7.72 (d, J = 8.8 Hz, 1 H), 7.48- 7.54 (m, 2 H), 7.12 (d, J = 2.4 Hz, 1 H), 6.97 (m, 1 H), 4.51 (t, J = 7.6 Hz, 1 H), 4.29 (m, 1 H), 4.26 (s, 1 H), 4.13 (s, 1 H), 4.01 (s, 3 H), 3.46-3.56 (m, 2 H), 3.33 (s, 3 H), 3.31 (m, 6 H), 3.01- 3.13 (m, 6 H), 2.93 (m, 4 H), 2.81 (s, 3 H), 2.11-2.23 (m, 6 H), 1.83-1.95 (m, 8 H), 1.63-1.80 (m, 4 H), 1.27 (s, 6 H), 1.21 (s, 6 H), 0.86 (t, J = 7.6 Hz, 3 H). LC-MS: MS (ES ⁺ ): RT = 1.90 min, m/z = 1058.5 (M+H ⁺ ) and 530.0 (M+2H ⁺ )/2. LC-MS Method 25. EXAMPLE 14 - Synthesis of N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4- tetramethylcyclobutyl)-2-((1-(4-(((R)-8-cyclopentyl-7-ethyl- 5-methyl-6-oxo-5,6,7,8- tetrahydropteridin-2-yl)(methyl)amino)-3-methoxyphenyl)-1-ox o-5,8,11,14-tetraoxa-2- azahexadecan-16-yl)(methyl)amino)pyrimidine-5-carboxamide (I-14). [0404] The title compound was prepared according to the following procedures. 1.1 Preparation of compound 1 [0405] To a solution of 2-[2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethoxy]ethyl 4- methylbenzenesulfonate (10.0 g, 25.5 mmol, 1.0 eq) and tert-butyl N-tert- butoxycarbonylcarbamate (6.09 g, 28.0 mmol, 1.1 eq) in MeCN (100 mL) was added K2CO3 (5.28 g, 38.2 mmol, 1.5 eq) at 25 °C. The mixture was stirred at 80 °C for 16 h. The mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate = 3/1 to 1/2) to give tert-butyl N-tert-butoxycarbonyl-N-[2-[2-[2-[2- (2-hydroxyethoxy)ethoxy]ethoxy]ethoxy]ethyl]carbamate (9.60 g, 21.8 mmol, 85% yield) as a colorless oil. ¹ H NMR: (400 MHz, CDCl ₃ ) δ 3.82 (br s, 2H), 3.75 - 3.69 (m, 2H), 3.69 - 3.59 (m, 16H), 1.50 (s, 18H). LC-MS: MS (ES ⁺ ): RT = 2.99 min, m/z = 1035.5 (M+H ⁺ ). LC-MS Method 05. 1.2 Preparation of compound 2 [0406] To a solution of tert-butyl N-tert-butoxycarbonyl-N-[2-[2-[2-[2-(2- hydroxyethoxy)ethoxy] ethoxy]ethoxy]ethyl]carbamate (2.00 g, 4.57 mmol, 1.0 eq) in DCM (10 mL) was added TsCl (484 mg, 6.86 mmol, 1.5 eq) and TEA (1.39 g, 13.7 mmol, 1.91 mL, 3.0 eq). The mixture was stirred at 25 °C for 18 hr. The residue was diluted with water (100 mL) and extracted with DCM (100 mL x 3). The combined organic layers were washed with water (150 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , PE/EA = 3:1-1:1).2-[2-[2-[2-[2-[bis(tert- butoxycarbonyl)amino]ethoxy]ethoxy]ethoxy]ethoxy]ethyl 4-methylbenzenesulfonate (1.00 g, 1.69 mmol) was obtained as a light-yellow oil. To a solution of 2-[2-[2-[2-[2-[bis(tert- butoxycarbonyl)amino]ethoxy]ethoxy]ethoxy] ethoxy]ethyl 4-methylbenzenesulfonate (1.0g, 1.69 mmol, 1.0 eq) in ACN (10 mL) was added K ₂ CO ₃ (561 mg, 4.06 mmol, 3.0 eq) and N-methyl-1- phenyl-methanamine (180 mg, 1.49 mmol, 192 ^L, 1.1 eq). The mixture was stirred at 50 °C for 8 hr to give a light white solution. The reaction mixture was poured into water 100 mL and extracted with DCM (150 mL x 3). The combined organic phase was concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO ₂ , DCM: MeOH = 20:1-10:1). Tert-butyl N-[2-[2-[2-[2-[2-[benzyl(methyl)amino]ethoxy]ethoxy]ethoxy] ethoxy]ethyl]-N-tert- butoxycarbonyl-carbamate (0.400 g, 740 μmol, 16% yield for two steps ) was obtained as a yellow oil. ¹ H NMR: (400 MHz, CDCl3) δ 7.28 - 7.12 (m, 5H), 3.74 - 3.68 (t, J = 6.0 Hz, 2H), 3.57 - 3.51 (m, 15H), 3.50 - 3.47 (m, 2H), 3.43 - 3.37 (s, 1H), 2.59 - 2.52 (t, J = 5.6 Hz, 2H), 2.21 - 2.16 (s, 3H), 1.43 (s, 18H) 1.3 Preparation of compound 3 [0407] Tert-butyl N-[2-[2-[2-[2-[2-[benzyl(methyl)amino]ethoxy]ethoxy]ethoxy]e thoxy] ethyl]-N-tert-butoxycarbonyl-carbamate (0.40 g, 74 μmol, 1.0 eq) in MeOH (5 mL) was added to a solution of Pd/C (0.30 g, 10% purity) in MeOH (1 mL) under N2. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2 (15 psi) at 25 °C for 12 hours to give a dark solution. The reaction mixture was filtered and the filtrate was concentrated to give a light-yellow oil. Compound tert-butyl N-tert-butoxycarbonyl-N-[2-[2-[2-[2- [2-(methylamino)ethoxy]ethoxy]ethoxy]ethoxy]ethyl]carbamate (0.200 g, 444 μmol, 60% yield) was obtained as a yellow oil. 1.4 Preparation of compound 5

[0408] To a solution of tert-butyl N-tert-butoxycarbonyl-N-[2-[2-[2-[2-[2-(methylamino) ethoxy]ethoxy]ethoxy]ethoxy]ethyl]carbamate (190 mg, 422 μmol, 1.0 eq) in NMP (1 mL) was added K2CO3 (175 mg, 1.27 mmol, 3.0 eq) and 2-chloro-N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)- 2,2,4,4-tetramethylcyclobutyl)pyrimidine-5-carboxamide (177 mg, 422 μmol, 1.0 eq). The mixture was stirred at 50 °C for 18 h to give a yellow solution. The reaction mixture was diluted with water (30 mL) and extracted with EA (30 mL x 3). The combined organic layers were washed with water (25 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , DCM: MeOH = 20:1-10:1). Compound tert-butyl N-tert-butoxycarbonyl-N-[2-[2-[2-[2-[2-[[5-[[3-(3-chloro-4-c yano-phenoxy)- 2,2,4,4-tetramethyl-cyclobutyl]carbamoyl] pyrimidin-2-yl]-methyl- amino]ethoxy]ethoxy]ethoxy]ethoxy] ethyl]carbamate (100 mg, 120 μmol, 28% yield) was obtained as a yellow oil. ¹ H NMR: (400 MHz, CDCl3) δ 9.08 (s, 1H), 8.77 - 8.67 (s, 1H), 7.64 - 7.51 (m, 1H), 7.02 - 6.95 (m, 1H), 6.86 - 6.78 (dd, J = 6.0 , 2.8Hz, 1H), 4.21 - 4.06 (m, 2H), 3.94 - 3.88 (m, 1H), 3.84 - 3.77 (m, 1H), 3.76 - 3.70 (m, 1H), 3.65 - 3.64 (m, 3H), 3.63 - 3.61 (m, 3H), 3.44 - 3.37 (m, 3H), 3.33 - 3.30 (m, 1H), 2.88 - 2.84 (m, 4H), 2.44 - 2.35 (m, 3H), 2.09 - 2.01 (m, 3H), 1.64 - 1.61 (s, 6H), 1.52 (s, 9H), 1.32 - 1.31 (m, 3H), 1.29 - 1.25 (m, 9H), 1.24 - 1.22 (m, 3H) 1.5 Preparation of compound 6 [0409] A solution of tert-butyl N-tert-butoxycarbonyl-N-[2-[2-[2-[2-[2-[[5-[[3-(3-chloro-4- cyano-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]carbamoyl]pyri midin-2-yl]-methyl- amino]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]carbamate (90.0 mg, 108 μmol, 1.0 eq) in TFA (0.5 mL) and DCM (1.5 mL) was stirred at 25 °C for 2 h to give a yellow solution. The reaction mixture was concentrated under reduced pressure to give a residue. Compound 2-((14-amino- 3,6,9,12-tetraoxatetradecyl)(methyl)amino)-N-((1r,3r)-3-(3-c hloro-4-cyanophenoxy)-2,2,4,4- tetramethylcyclobutyl)pyrimidine-5-carboxamide (68.0 mg, 107 μmol, 99% yield) was obtained as a yellow oil. It was used into the next step without further purification. 1.6 Preparation of compound I-14 [0410] To a solution of 2-((14-amino-3,6,9,12-tetraoxatetradecyl)(methyl)amino)-N-(( 1r,3r)-3- (3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)pyri midine-5-carboxamide (35.0 mg, 55.3 μmol, 1.0 eq) in DMF (1 mL) was added HATU (31.5 mg, 82.9 μmol, 1.5 eq), DIEA (21.4 mg, 166 μmol, 28.9 ^L, 3.0 eq) and (R)-4-((8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8- tetrahydropteridin-2-yl)(methyl)amino)-3-methoxybenzoic acid (24.3 mg, 55.3 μmol, 1.0 eq). The mixture was stirred at 25 °C for 8 h. The mixture was directly purified by reversed-phase HPLC purification solution. column: Phenomenex C18, 150 x 25 mm*10um;mobile phase: [water(FA)- ACN];B%: 33%-63%,5min. Compound N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4- tetramethylcyclobutyl)-2-((1-(4-(((R)-8-cyclopentyl-7-ethyl- 5-methyl-6-oxo-5,6,7,8- tetrahydropteridin-2-yl)(methyl)amino)-3-methoxyphenyl)-1-ox o-5,8,11,14-tetraoxa-2- azahexadecan-16-yl)(methyl)amino)pyrimidine-5-carboxamide (8.00 mg, 7.59 μmol, 14% yield) was obtained as a white solid. ¹ H NMR: (400 MHz, CD3OD) δ 8.75 (s, 2H), 8.55 - 8.46 (s, 1H), 7.77 - 7.71 (d, J = 8.4 Hz, 1H), 7.61 - 7.57 (m, 2H), 7.54 - 7.49 (m, 1H), 7.33 - 7.28 (d, J = 8.4 Hz, 1H), 7.15 - 7.12 (m, 1H), 7.02 - 6.97 (m, 1H), 4.63 (s, 1H), 4.31 - 4.24 (m, 1H), 4.20 - 4.13 (m, 2H), 3.92 - 3.88 (m, 2H), 3.85 - 3.81 (m, 3H), 3.74 - 3.68 (m, 5H), 3.66 (s, 4H), 3.64 - 3.60 (m, 10H), 3.34 (s, 3H), 3.31 - 3.29 (m, 3H), 3.29 - 3.27 (m, 3H), 1.95 - 1.81 (m, 3H), 1.78 - 1.69 (m, 2H), 1.69 - 1.64 (m, 1H), 1.36 - 1.33 (m, 2H), 1.31 - 1.29 (s, 6H), 1.24 - 1.20 (s, 6H), 0.83 - 0.78 (t, J = 7.6 Hz, 3H). EXAMPLE 15 - Synthesis of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]-2-[4-[3-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methy l-6-oxo-7H-pteridin-2-yl]amino]- 3-methoxy-benzoyl]amino]propoxy]-1-piperidyl]pyrimidine-5-ca rboxamide (I-15). [0411] The title compound was prepared according to the following procedures. 1.1 Preparation of compound 3 [0412] To a solution of tert-butyl 4-[3-(p-tolylsulfonyloxy)propoxy]piperidine-1-carboxylate (290 mg, 701 μmol, 1.0 eq) in CH3CN (2 mL) was added K2CO3 (291 mg, 2.10 mmol, 3.0 eq) and N-benzyl-1-phenyl-methanamine (166 mg, 842 μmol, 161 ^L, 1.2 eq). The mixture was stirred at 80 °C for 12 h. The reaction mixture was concentrated to afford crude product. The residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 20:1 to 15:1) to afford tert-butyl 4-[3-(dibenzylamino)propoxy]piperidine-1-carboxylate (250 mg, 570 μmol, 81% yield) as a yellow oil. 1.2 Preparation of compound 4 [0413] To a solution of tert-butyl 4-[3-(dibenzylamino)propoxy]piperidine-1-carboxylate (250 mg, 570 μmol, 1.0 eq) in TFE (50 mL) was added Pd(OH) ₂ (250 mg, 50% purity). The suspension was degassed under vacuum and purged with H ₂ for several times. The mixture was stirred under H2 (15 psi) at 20 °C for 1 h. After filtration, the filtrate was concentrated to afford tert-butyl 4-(3- aminopropoxy)piperidine-1-carboxylate (190 mg, crude) as a yellow oil and it was used by next step directly. ¹ H NMR (400 MHz, CDCl ₃ ) 3.99-3.90 (m, 2H), 3.82-3.65 (m, 2H), 3.58-3.50 (m, 2H), 3.47-3.39 (m, 1H), 3.15-3.00 (m, 2H), 2.87-2.75 (m, 2H), 1.87-1.69 (m, 4H), 1.57-1.48 (m, 2H), 1.48-1.43 (m, 9H) 1.3 Preparation of compound 6 [0414] To a solution of tert-butyl 4-(3-aminopropoxy)piperidine-1-carboxylate (75 mg, 0.29 mmol, 1.0 eq) and 4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2- yl]amino]-3- methoxy-benzoic acid (136 mg, 319 μmol, 1.1 eq) in DMF (1 mL) was added DIEA (188 mg, 1.45 mmol, 253 ^L, 5.0 eq) and HATU (166 mg, 435 μmol, 1.5 eq). The mixture was stirred at 20 °C for 2 h. The residue was purified by prep-HPLC (column: Waters Xbridge 150 x 25 mm*5um; mobile phase: [water(NH4HCO3)-ACN]; B%: 53%-83%,9min) to afford tert-butyl 4-[3-[[4-[[(7R)- 8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino] -3-methoxy- benzoyl]amino]propoxy]piperidine-1-carboxylate (65 mg, 98 μmol, 34% yield) as a yellow oil. 1.4 Preparation of compound 7 [0415] To a solution of tert-butyl 4-[3-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H- pteridin-2-yl]amino]-3-methoxy-benzoyl]amino]propoxy]piperid ine-1-carboxylate (65 mg, 98 μmol, 1.0 eq) in DCM (2 mL) was added TFA (1 mL). The mixture was stirred at 20 °C for 0.5 h. It was concentrated in vacuum to give 4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin- 2-yl]amino]-3-methoxy-N-[3-(4-piperidyloxy)propyl]benzamide (100 mg, TFA salt) as a yellow oil and it was used by next step directly. 1.5 Preparation of I-15

[0416] To a solution of 4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2- yl]amino]-3-methoxy-N-[3-(4-piperidyloxy)propyl]benzamide (100 mg, 147 μmol, 1.0 eq, TFA salt) in NMP (2 mL) was added K2CO3 (60 mg, 0.44 mmol, 3.0 eq) and 2-chloro-N-[3-(3-chloro-4- cyano-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]pyrimidine-5-c arboxamide (62 mg, 0.15 mmol, 1.0 eq). The mixture was stirred at 50 °C for 1 h. After filtration, the filtrate was purified by prep- HPLC (column: Phenomenex C18, 75*30mm*3um; mobile phase: [water(FA)-ACN]; B%: 42%- 72%,7min) to afford N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl-cyclobut yl]-2-[4-[3- [[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin- 2-yl]amino]-3-methoxy- benzoyl]amino]propoxy]-1-piperidyl]pyrimidine-5-carboxamide (34 mg, 36 μmol, 25% yield) as an off-white solid. ¹ H NMR (400 MHz, CD ₃ OH-d ₄ ) δ 8.71 (s, 2H), 8.42-8.28 (m, 1H), 7.80-7.67 (m, 3H), 7.52-7.43 (m, 2H), 7.12 (d, J = 2.4 Hz, 1H), 6.97 (m, 1H), 4.51-4.40 (m, 1H), 4.36-4.22 (m, 4H), 4.16-4.09 (m, 1H), 3.99 (s, 3H), 3.69-3.46 (m, 7H), 3.33 (s, 2H), 2.19-2.10 (m, 1H), 2.05- 1.64 (m, 13H), 1.62-1.50 (m, 2H), 1.31-1.24 (m, 6H), 1.23-1.17 (m, 6H), 0.86 (t, J = 7.6 Hz, 3H). LC-MS: MS (ES ⁺ ): RT = 2.56 min, m/z = 948.3 (M+H ⁺ ) and 474.7 (M+2H ⁺ )/2. LC-MS Method 25. EXAMPLE 16 - Synthesis of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]-2-[4-[4-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methy l-6-oxo-7H-pteridin-2-yl]amino]- 3-methoxy-benzoyl]amino]butoxy]-1-piperidyl]pyrimidine-5-car boxamide (I-16). [0417] The title compound was prepared according to the following procedures. 1.1 Preparation of compound 2 [0418] To a solution of 4-benzyloxybutan-1-ol (25.00 g, 138.7 mmol, 24.3 mL, 1.0 eq) in DCM (250 mL) was added TosCl (39.66 g, 208.1 mmol, 1.5 eq) and TEA (28.07 g, 277.4 mmol, 38.7 mL, 2.0 eq). The mixture was stirred at 25 °C for 12 h. Then it was concentrated to afford crude product and the residue was purified by silica chromatography (PE:EA=5:1-3:1) to afford 4- benzyloxybutyl 4-methylbenzenesulfonate (34.60 g, 103.5 mmol, 75% yield) as a colorless oil. ¹ H NMR (400 MHz, CDCl3) 7.73 - 7.69 (m, 2H), 7.27 (s, 1H), 7.30 - 7.18 (m, 2H), 4.41 - 4.35 (m, 2H), 4.02 - 3.96 (m, 2H), 3.39 - 3.31 (m, 2H), 2.38 - 2.35 (m, 3H), 1.75 - 1.63 (m, 2H), 1.61 - 1.52 (m, 2H) 1.2 Preparation of compound 4 [0419] To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (13.84 g, 68.77 mmol, 1.0 eq) in THF (80 mL) was added NaH (4.13 g, 103 mmol, 60% purity, 1.5 eq) at 0 °C, and then it was stirred for 0.5 h at 25 °C.4-benzyloxybutyl 4-methylbenzenesulfonate (23.00 g, 68.77 mmol, 1.0 eq) in THF (20 mL) was added at 0 °C, and the mixture was stirred at 25 °C for 12.5 h. The reaction mixture was quenched by 20mL sat.NH ₄ Cl at 0 °C, and then 500 mL water was added. After extracted with EtOAc (3 x 200 mL), the organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to afford crude product, the residue was purified by silica chromatography (PE:EA=10:1-5:1) to afford tert-butyl 4-(4-benzyloxybutoxy)piperidine-1- carboxylate (15.50 g, 42.64 mmol, 62% yield) as a colorless oil. ¹ H NMR: (400 MHz, CDCl ₃ ) 7.38 - 7.25 (m, 5H), 4.51 (s, 2H), 3.79 - 3.70 (m, 2H), 3.54 - 3.38 (m, 5H), 3.09 (m, 2H), 1.86 - 1.76 (m, 2H), 1.74 - 1.62 (m, 4H), 1.54 - 1.45 (m, 11H) 1.3 Preparation of compound 5 [0420] To a solution of tert-butyl 4-(4-benzyloxybutoxy)piperidine-1-carboxylate (15.50 g, 42.64 mmol, 1.0 eq) in TFE (100 mL) was added Pd/C (4.00 g, 10% purity) under N ₂ atmosphere. The suspension was degassed and purged with H2 for three times. The mixture was stirred under H2 (15 psi ) at 25 °C for 12 h. The residue was filtered to remove Pd/C and concentrated to afford (tert-butyl 4-(4-hydroxybutoxy) piperidine-1-carboxylate (11.30 g, crude) was a colorless oil. ¹ H NMR: (400 MHz, CDCl3)= 3.80 - 3.70 (m, 2H), 3.65 (t, J = 5.9 Hz, 2H), 3.55 - 3.42 (m, 3H), 3.08 (m, 2H), 1.83 - 1.78 (m, 2H), 1.75 - 1.62 (m, 4H), 1.57 - 1.40 (m, 11H) 1.4 Preparation of compound 6 [0421] To a solution of tert-butyl 4-(4-hydroxybutoxy) piperidine-1-carboxylate (3.00 g, 11.0 mmol, 1.0 eq) in DCM (15 mL) was added TosCl (3.14 g, 16.5 mmol, 1.5 eq) and TEA (2.22 g, 22.0 mmol, 3.1 mL, 2.0 eq).The mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated to afford crude product. The residue was purified by silica chromatography (PE:EA=10:1-3:1) to afford tert-butyl 4-[4-(p-tolylsulfonyloxy)butoxy]piperidine-1-carboxylate (2.86 g, 6.69 mmol, 61% yield) as a yellow oil. ¹ H NMR: (400 MHz, CDCl3) 7.82 - 7.76 (m, 2H), 7.35 (d, J = 8.2 Hz, 2H), 4.06 (t, J = 6.5 Hz, 2H), 3.75 - 3.64 (m, 2H), 3.44 - 3.33 (m, 3H), 3.13 - 3.01 (m, 2H), 2.49 - 2.41 (s, 3H), 1.81 - 1.71 (m, 4H), 1.63 - 1.55 (m, 2H), 1.46 (s, 11H) 1.5 Preparation of compound 8 [0422] To a solution of tert-butyl 4-[4-(p-tolylsulfonyloxy)butoxy]piperidine-1-carboxylate (1.90 g, 4.44 mmol, 1.0 eq) in CH3CN (10 mL) was added K2CO3 (1.84 g, 13.3 mmol, 3.0 eq) and N-benzyl-1-phenyl-methanamine (1.05 g, 5.33 mmol, 1.0 mL, 1.2 eq) .The mixture was stirred at 80 °C or 12 h .The residue was filtered to remove K ₂ CO ₃ and concentrated to afford crude product . The residue was purified by silica chromatography (PE:EA = 30:1-10:1) to afford tert-butyl 4-[4- (dibenzylamino)butoxy]piperidine-1-carboxylate (1.48 g, 3.27 mmol, 74% yield) as a yellow oil. ¹ H NMR: (400 MHz, CDCl ₃ ) 7.36 - 7.31 (m, 4H), 7.27 (s, 4H), 7.23 - 7.17 (m, 2H), 3.77 - 3.61 (m, 2H), 3.51 (m, 4H), 3.35 - 3.23 (m, 3H), 3.05 - 2.93 (m, 2H), 2.47 - 2.32 (m, 2H), 1.74 - 1.65 (m, 2H), 1.53 (m, 4H), 1.42 (s, 9H), 1.41 - 1.34 (m, 2H) 1.6 Preparation of compound 9 [0423] To a solution of tert-butyl 4-[4-(dibenzylamino)butoxy]piperidine-1-carboxylate (1.48 g, 3.27 mmol, 1.0 eq) in TFE (15 mL) was added H2 (6.60 mg, 3.27 mmol, 1.0 eq) and Pd(OH) ₂ (459.2 mg, 3.27 mmol, 1.0 eq).The mixture was stirred at 25 °C for 1 h . Then the residue was filtered to remove Pd(OH) ₂ ,and concentrated to afford crude product ., the crude product was used into the next step without further purification ,the product(tert-butyl 4-(4-aminobutoxy) piperidine- 1-carboxylate (800 mg, 2.94 mmol, crude) was a white oil. ¹ H NMR: (400 MHz, CDCl3) 3.81 - 3.64 (m, 3H), 3.50 - 3.36 (m, 3H), 3.14 - 3.00 (m, 2H), 2.75 - 2.42 (m, 5H), 1.87 - 1.74 (m, 2H), 1.64 - 1.52 (m, 4H), 1.48 - 1.43 (m, 9H) 1.7 Preparation of compound 11 [0424] To a solution of tert-butyl 4-(4-aminobutoxy)piperidine-1-carboxylate (75 mg, 0.28 mmol, 1.0 eq) and 4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2- yl]amino]-3- methoxy-benzoic acid (117 mg, 275 μmol, 1.0 eq) in DMF (2 mL) was added DIEA (108 mg, 826 μmol, 478 ^L, 1.0 eq) and HATU (157 mg, 413 μmol, 1.5 eq). The mixture was stirred at 25 °C for 0.5 h. The residue was purified by prep-HPLC column: Phenomenex Synergi Polar-RP 100*25 mm*4um; mobile phase: [water(TFA)-ACN]; B%: 42%-72%,7min） to afford tert-butyl 4-[4-[[4- [[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl ]amino]-3-methoxy- benzoyl]amino]butoxy]piperidine-1-carboxylate (85 mg, 0.13 mmol, 45% yield) as a yellow oil. 1.8 Preparation of compound 12 [0425] To a solution of tert-butyl 4-[4-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H- pteridin-2-yl]amino]-3-methoxy-benzoyl]amino]butoxy]piperidi ne-1-carboxylate (85 mg, 0.13 mmol, 1.0 eq) in DCM (2 mL) was added TFA (1 mL). The mixture was stirred at 25 °C for 0.5 h. The reaction mixture was concentrated to afford (4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo- 7H-pteridin-2-yl]amino]-3-methoxy-N-[4-(4-piperidyloxy)butyl ]benzamide (87 mg, 0.13 mmol, TFA salt ) as a yellow oil. 1.9 Preparation of I-16 [0426] To a solution of 4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2- yl]amino]-3-methoxy-N-[4-(4-piperidyloxy)butyl]benzamide (87 mg, 0.13 mmol, 1.0 eq) and 2- chloro-N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl-c yclobutyl]pyrimidine-5- carboxamide (63 mg, 0.13 mmol, 1.0 eq) in NMP (2 mL) was added K ₂ CO ₃ (62 mg, 0.39 mmol, 3.0 eq). The mixture was stirred at 50 C for 1 h. After filtration, the filtrate was purified by prep- HPLC (column: Phenomenex Luna C18, 150 x 25 mm*10um; mobile phase: [water(FA)-ACN]; B%: 45%-75%,10min) to afford N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]-2-[4-[4-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methy l-6-oxo-7H-pteridin-2-yl]amino]-3- methoxy-benzoyl]amino]butoxy]-1-piperidyl]pyrimidine-5-carbo xamide (29 mg, 0.3 mmol, 20% yield) as an off-white solid. ¹ H NMR: (400 MHz, CD ₃ OD) 8.75 - 8.69 (m, 2H), 8.49 - 8.43 (m, 1H), 7.79 - 7.74 (m, 1H), 7.73 - 7.69 (m, 1H), 7.50 - 7.44 (m, 2H), 7.12 (d, J = 2.3 Hz, 1H), 6.99 - 6.94 (m, 1H), 4.54 - 4.44 (m, 1H), 4.34 - 4.31 (m, 1H), 4.30 - 4.24 (m, 3H), 4.15 - 4.09 (m, 1H), 4.04 - 3.96 (m, 3H), 3.64 (td, J = 4.2, 7.8 Hz, 1H), 3.61 - 3.51 (m, 4H), 3.47 - 3.39 (m, 1H), 2.21 - 2.09 (m, 1H), 1.98 - 1.80 (m, 8H), 1.79 - 1.73 (m, 3H), 1.72 - 1.64 (m, 4H), 1.60 - 1.49 (m, 2H), 1.43 - 1.06 (m, 15H), 0.89 - 0.82 (m, 3H). LC-MS: MS (ES ⁺ ): RT = 2.64 min, m/z = 962.3 (M+H ⁺ ) and 481.7 (M+2H ⁺ )/2. LC-MS Method 25. EXAMPLE 17 - Synthesis of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]-2-[4-[5-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methy l-6-oxo-7H-pteridin-2-yl]amino]- 3-methoxy-benzoyl]amino]pentoxy]-1-piperidyl]pyrimidine-5-ca rboxamide (I-17). [0427] The title compound was prepared according to the following procedures. 1.1 Preparation of compound 3 [0428] To a solution of tert-butyl 4-[5-(p-tolylsulfonyloxy)pentoxy]piperidine-1-carboxylate (2.00 g, 4.53 mmol, 1.0 eq) in ACN (20 mL) was added K ₂ CO ₃ (1.88 g, 13.59 mmol, 3.0 eq) and N-benzyl-1-phenyl-methanamine (893 mg, 4.53 mmol, 1.0 eq). The mixture was stirred at 80 °C for 12 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate=30/1 to 10/1). The desired compound tert-butyl 4-[5-(dibenzylamino)pentoxy]piperidine-1- carboxylate (1.30 g, 2.79 mmol, 62% yield) was obtained as colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ):δ = 7.40 - 7.34 (m, 4H), 7.31 (t, J = 7.4 Hz, 4H), 7.26 - 7.20 (m, 2H), 3.75 (br d, J = 11.4 Hz, 2H), 3.55 (s, 4H), 3.42 - 3.35 (m, 3H), 3.08 (m, 2H), 2.45 - 2.38 (m, 2H), 1.84 - 1.74 (m, 2H), 1.56 - 1.48 (m, 5H), 1.46 (s, 9H), 1.38 - 1.28 (m, 2H) 1.2 Preparation of compound 4 [0429] To a solution of tert-butyl 4-[5-(dibenzylamino)pentoxy]piperidine-1-carboxylate (300 mg, 643 μmol, 1.0 eq) in TFE (3 mL) was added Pd/C (300 mg, 10% purity) under N2 atmosphere. The mixture was stirred under H2 (15 psi) at 25 °C for 12 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The reaction mixture was used into the next step without further purification. The desired compound tert-butyl 4-(5-aminopentoxy)piperidine- 1-carboxylate (130 mg) was obtained as colorless oil. 1.3 Preparation of compound 6 [0430] To a solution of tert-butyl 4-(5-aminopentoxy)piperidine-1-carboxylate (10 mg, 35 μmol, 1.0 eq) in DMF (1 mL) was added DIEA (23.0 mg, 175 μmol, 5.0. eq) and then was added 4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2- yl]amino]-3-methoxy-benzoic acid (15 mg, 35 μmol, 1.0 eq) and HATU (66.0 mg, 175 μmol, 5.0 eq). The reaction mixture was stirred at 25 °C for 12 h. The reaction mixture was filtered to give a residue. The crude product was purified by reversed-phase HPLC (0.1% FA, column: Unisil 3-100 C18, Ultra 150 x 50mm*3 μm; mobile phase: [water(FA)-ACN];B%: 31%-61%,10min). The desired compound tert-butyl 4-[5- [[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin- 2-yl]amino]-3-methoxy- benzoyl]amino]pentoxy]piperidine-1-carboxylate (13 mg, 19 μmol, 54% yield) was obtained as white solid. 1.4 Preparation of compound 7 [0431] To a solution of tert-butyl 4-[5-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H- pteridin-2-yl]amino]-3-methoxy-benzoyl]amino]pentoxy]piperid ine-1-carboxylate (100 mg, 144 μmol, 1.0 eq) in DCM (2 mL) was TFA (115 mg, 1.01 mmol, 7.0 eq). The mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue. The reaction mixture was used into the next step without further purification. The desired compound 4- [[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl ]amino]-3-methoxy-N-[5-(4- piperidyloxy)pentyl]benzamide (85 mg) was obtained. 1.5 Preparation of compound I-17 [0432] To a solution of 4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2- yl]amino]-3-methoxy-N-[5-(4-piperidyloxy)pentyl]benzamide (85.0 mg, 143 μmol, 1.0 eq) and 2- chloro-N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl-c yclobutyl]pyrimidine-5- carboxamide (60.0 mg, 143 μmol, 1.0 eq) in NMP (2 mL) was added K2CO3 (198 mg, 1.43 mmol, 10.0 eq). The reaction mixture was stirred at 50 °C for 12 h. The reaction mixture was filtered. The crude product was purified by reversed-phase HPLC(0.1% FA, column: Unisil 3-100 C18, Ultra 150 x 50mm*3 μm; mobile phase: [water(FA)-ACN];B%: 44%-74%,7min). The desired compound N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl-cyclobut yl]-2-[4-[5-[[4-[[(7R)-8- cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-3 -methoxy-benzoyl]amino] pentoxy]-1-piperidyl]pyrimidine-5-carboxamide (46 mg, 45 μmol, 31% yield) was obtained as off- white solid. ¹ H NMR (400 MHz, MeOD): δ = 8.69 (s, 2H), 8.50 - 8.44 (m, 1H), 7.77 (s, 1H), 7.72 (d, J = 8.8 Hz, 1H), 7.51 - 7.44 (m, 2H), 7.14 - 7.10 (m, 1H), 7.00 - 6.94 (m, 1H), 4.64 - 4.54 (m, 1H), 4.54 - 4.47 (m, 1H), 4.31 - 4.18 (m, 4H), 4.14 - 4.10 (m, 1H), 3.99 (s, 3H), 3.65 - 3.50 (m, 5H), 3.41 (t, J = 6.9 Hz, 2H), 3.33 (s, 3H), 2.22 - 2.11 (m, 1H), 2.07 - 1.81 (m, 8H), 1.79 - 1.61 (m, 7H), 1.58 - 1.46 (m, 4H), 1.27 (s, 6H), 1.22 - 1.19 (m, 6H), 0.86 (t, J = 7.5 Hz, 3H). LC-MS: MS (ES ⁺ ): RT = 2.85 min, m/z = 1004.3 (M+H ⁺ ) and 502.7 (M+2H ⁺ )/2. LC-MS Method 25. EXAMPLE 18 - Synthesis of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]-2-[4-[6-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methy l-6-oxo-7H-pteridin-2-yl]- amino]-3-methoxy-benzoyl]amino]hexoxy]-1-piperidyl]pyrimidin e-5-carboxamide (I-18). [0433] The title compound was prepared according to the following procedures. 1.1 Preparation of compound 3 [0434] To a solution of tert-butyl 4-(6-aminohexoxy)piperidine-1-carboxylate (71.0 mg, 235 μmol, 1.0 eq) in DMF (1 mL) was added DIEA (152 mg, 1.18 mmol, 5.0 eq) and 4-[[(7R)-8- cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-3 -methoxy-benzoic acid (100 mg, 235 μmol, 1.0 eq), and then was added HATU (447 mg, 1.18 mmol, 5.0 eq). The reaction mixture was stirred at 25 °C for 12 h. The reaction mixture was quenched by addition water 5 mL, and then diluted with water 10 mL and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (50 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (0.1% FA, column: Unisil 3-100 C18, Ultra 150 x 50mm*3 μm; mobile phase: [water(FA)-ACN];B%: 38%- 68%,7min).The desired compound tert-butyl 4-[6-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6- oxo-7H-pteridin-2-yl]amino]-3-methoxy-benzoyl]amino] hexoxy]piperidine-1-carboxylate (75.0 mg, 106 μmol, 45% yield) was obtained as yellow solid. 1.2 Preparation of compound 4 [0435] To a solution of tert-butyl 4-[6-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H- pteridin-2-yl]amino]-3-methoxy-benzoyl]amino]hexoxy]piperidi ne-1-carboxylate (85.0 mg, 120 μmol, 1.0 eq) in DCM (2 mL) was TFA (96.0 mg, 841 μmol, 7.0 eq). The mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue. The reaction mixture was used into the next step without further purification. The desired compound 4- [[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl ]amino]-3-methoxy-N-[6-(4- piperidyloxy)hexyl]benzamide (72 mg) was obtained as brown oil. 1.3 Preparation of compound I-18 [0436] To a solution of 2-chloro-N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl - cyclobutyl]pyrimidine-5-carboxamide (50.0 mg, 118 μmol, 1.0 eq) and 4-[[(7R)-8-cyclopentyl-7- ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-3-methoxy-N-[6- (4-piperidyloxy)hexyl] benzamide (72.0 mg, 118 μmol, 1.0 eq) in NMP (2 mL) was added K ₂ CO ₃ (164 mg, 1.18 mmol, 10.0 eq). The reaction mixture was stirred at 50 °C for 12 h. The reaction mixture was filtered. The crude product was purified by reversed-phase HPLC (0.1% FA, column: Unisil 3-100 C18, Ultra 150 x 50mm*3 μm; mobile phase: [water(FA)-ACN];B%: 45%-75%,7min). The desired compound N- [3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl ]-2-[4-[6-[[4-[[(7R)-8-cyclopentyl- 7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-3-methoxy-ben zoyl]amino] hexoxy]-1- piperidyl]pyrimidine-5-carboxamide (42 mg, 41 μmol, 35% yield) was obtained as off-white solid. ¹ H NMR (400 MHz, MeOD): δ = 8.73 - 8.68 (m, 2H), 8.49 (d, J = 8.3 Hz, 1H), 7.77 (s, 1H), 7.72 (d, J = 8.7 Hz, 1H), 7.51 - 7.46 (m, 2H), 7.14 - 7.11 (m, 1H), 7.00 - 6.95 (m, 1H), 4.64 - 4.59 (m, 1H), 4.55 - 4.47 (m, 1H), 4.31 - 4.25 (m, 4H), 4.12 (s, 1H), 4.00 (s, 3H), 3.62 - 3.56 (m, 1H), 3.55 - 3.47 (m, 4H), 3.40 (t, J = 7.0 Hz, 2H), 3.33 (s, 3H), 2.22 - 2.12 (m, 1H), 2.07 - 1.98 (m, 1H), 1.94 - 1.82 (m, 7H), 1.79 - 1.70 (m, 3H), 1.68 - 1.59 (m, 4H), 1.56 - 1.49 (m, 2H), 1.48 - 1.42 (m, 4H), 1.27 (s, 6H), 1.21 (s, 6H), 0.86 (t, J = 7.5 Hz, 3H). LC-MS: MS (ES ⁺ ): RT = 2.89 min, m/z = 1018.5 (M+H ⁺ ) and 509.7 (M+2H ⁺ )/2. LC-MS Method 25. EXAMPLE 19 - Synthesis of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]-2-[4-[7-[[4-[[(7R)-8- cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]- 3-methoxy-benzoyl]amino]-heptoxy]-1-piperidyl]pyrimidine-5-c arboxamide (I-19). [0437] The title compound was prepared according to the following procedures. 1.1 Preparation of compound 3 [0438] To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (10 g, 50 mmol, 1.0 eq) in THF (100 mL) was added NaH (2.2 g, 54.6 mmol, 60% purity, 1.1 eq) at 0 °C, the mixture was stirred at 0 °C for 0.5 h., then 1, 7-dibromoheptane (15.4 g, 60 mmol, 1.2 eq) was added and the mixture was stirred at 25 °C for 16 h. The mixture was diluted with water (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate=100/1 to 10/1) to give the desired product tert-butyl 4-(7- bromoheptoxy)piperidine-1-carboxylate (5.3 g, 28% yield) as a colorless oil. ¹ H NMR (400 MHz, CDCl3): δ 3.95 - 3.61 (m, 2H), 3.52 - 3.30 (m, 5H), 3.15 - 3.00 (m, 2H), 1.93 - 1.73 (m, 4H), 1.62 - 1.40 (m, 15H), 1.39 - 1.26 (m, 4H) 1.2 Preparation of compound 5 [0439] A solution of tert-butyl 4-(7-bromoheptoxy)piperidine-1-carboxylate (2.0 g, 5.3 mmol, 1.0 eq) and (1,3-dioxoisoindolin-2-yl)potassium (979 mg, 5.3 mmol, 1.0 eq) in DMF (15 mL) was stirred at 50 °C for 16 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=20/1 to 3/1) to give the desired product tert-butyl 4-[7-(1,3- dioxoisoindolin-2-yl)heptoxy]piperidine-1-carboxylate (2.28 g, 97% yield) as a colorless oil. ¹ H NMR (400 MHz, CDCl3): δ 7.88 - 7.81 (m, 2H), 7.75 - 7.69 (m, 2H), 3.73 - 3.73 (m, 1H), 3.81 - 3.72 (m, 1H), 3.71 - 3.64 (m, 2H), 3.46 - 3.35 (m, 3H), 3.12 - 3.01 (m, 2H), 1.87 - 1.74 (m, 2H), 1.74 - 1.63 (m, 2H), 1.60 - 1.42 (m, 13H), 1.35 (s, 6H) 1.3 Preparation of 6 [0440] To a solution of tert-butyl 4-[7-(1,3-dioxoisoindolin-2-yl)heptoxy]piperidine-1- carboxylate (2.28 g, 5.1 mmol, 1.0 eq) in EtOH (40 mL) was added N O (4.98 g, 99 mmol, 19.4 eq), the mixture was stirred at 70 °C for 16 h. The mixture was concentrated and purified by prep-HPLC (column: Waters Xbridge 150 x 25 mm* 5um;mobile phase: [water(NH4HCO3)-ACN];B%: 30%-60%,10min) to give tert-butyl 4-(7-aminoheptoxy) piperidine- 1-carboxylate (1.2 g, 74% yield) as a light-yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ): δ 3.87 - 3.69 (m, 2H), 3.50 - 3.34 (m, 3H), 3.13 - 2.98 (m, 2H), 2.75 - 2.62 (m, 2H), 1.87 - 1.76 (m, 2H), 1.60 - 1.40 (m, 16H), 1.37 - 1.29 (m, 6H) 1.4 Preparation of 8 [0441] To a solution of tert-butyl 4-(7-aminoheptoxy)piperidine-1-carboxylate (100 mg, 318 μmol, 1.0 eq) and 4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2- yl]amino]-3- methoxy-benzoic acid (135 mg, 318 μmol, 1.0 eq) in DMF (2 mL) was added DIEA (164 mg, 1.27 mmol, 4.0 eq) and HATU (145 mg, 381 μmol, 1.2 eq), the mixture was stirred at 25 °C for 1 h. The mixture was concentrated and purified by prep-HPLC (column: Waters Xbridge 150 x 25 mm* 5um;mobile phase: [water(NH4HCO3)-ACN];B%: 65%-95%,8min) to give tert-butyl 4-[7- [[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin- 2-yl]amino]-3-methoxy- benzoyl]amino]heptoxy]piperidine-1-carboxylate (150 mg, 65% yield) as a white solid. ¹ H NMR (400 MHz, MeOD): δ 8.53 - 8.44 (m, 1H), 7.82 - 7.75 (m, 1H), 7.53 - 7.42 (m, 2H), 4.57 - 4.43 (m, 1H), 4.32 - 4.23 (m, 1H), 4.00 (s, 3H), 3.76 - 3.66 (m, 2H), 3.53 - 3.43 (m, 3H), 3.41 - 3.36 (m, 2H), 3.33 (s, 3H), 3.16 - 3.03 (m, 2H), 2.22 - 2.11 (m, 1H), 2.07 - 1.69 (m, 12H), 1.66 - 1.54 (m, 4H), 1.49 - 1.36 (m, 18H), 0.86 (t, J = 7.6 Hz, 3H) 1.5 Preparation of 9 [0442] To a solution of tert-butyl 4-[7-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H- pteridin-2-yl]amino]-3-methoxy-benzoyl]amino]heptoxy]piperid ine-1-carboxylate (70 mg, 97 μmol, 1.0 eq) in DCM (1.5 mL) was added TFA (898 mg, 7.9 mmol, 81 eq), the mixture was stirred at 25 °C for 0.5 h. The mixture was concentrated to give 4-[[(7R)-8-cyclopentyl-7-ethyl-5- methyl-6-oxo-7H-pteridin-2-yl]amino]-3-methoxy-N-[7-(4-piper idyloxy)heptyl]benzamide (71 mg, crude, TFA salt) as a yellow gum. 1.6 Preparation of I-19 [0443] To a solution of 4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2- yl]amino]-3-methoxy-N-[7-(4-piperidyloxy)heptyl]benzamide (71 mg, 97 μmol, 1.0 eq, TFA salt) and 2-chloro-N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl -cyclobutyl]pyrimidine-5- carboxamide (45 mg, 106 μmol, 1.1 eq) in NMP (1.5 mL) was added K ₂ CO ₃ (67 mg, 482 μmol, 5.0 eq). The mixture was stirred at 50 °C for 16 h. The mixture was concentrated and purified by prep-HPLC (column: Unisil 3-100 C18, Ultra 150 x 50mm*3 μm; mobile phase: [water(FA)- ACN];B%: 60%-90%,10min) to give N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]-2-[4-[7-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methy l-6-oxo-7H-pteridin-2-yl]amino]-3- methoxy-benzoyl]amino]heptoxy]-1-piperidyl]pyrimidine-5-carb oxamide (39.3 mg, 38% yield) as a white solid. ¹ H NMR (400 MHz, MeOD): δ 8.71 (s, 2H), 8.51 - 8.45 (m, 1H), 8.40 - 8.33 (m, 1H), 7.77 (s, 1H), 7.71 (d, J = 8.8 Hz, 1H), 7.51 - 7.41 (m, 2H), 7.15 - 7.07 (m, 1H), 7.00 - 6.94 (m, 1H), 4.55 - 4.42 (m, 1H), 4.35 - 4.22 (m, 4H), 4.15 - 4.09 (m, 1H), 4.04 - 3.95 (m, 3H), 3.60 - 3.47 (m, 5H), 3.43 - 3.36 (m, 2H), 3.32 (s, 3H), 2.21 - 2.10 (m, 1H), 2.06 - 1.96 (m, 1H), 1.95 - 1.81 (m, 7H), 1.78 - 1.68 (m, 3H), 1.68 - 1.56 (m, 4H), 1.55 - 1.47 (m, 2H), 1.41 (s, 6H), 1.27 (s, 6H), 1.21 (s, 6H), 0.85 (t, J = 7.6 Hz, 3H). LC-MS: MS (ES ⁺ ): RT = 2.57 min, m/z = 992.3 (M+H ⁺ ) and 496.7 (M+2H ⁺ )/2. LC-MS Method 25. EXAMPLE 20 - Synthesis of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]-2-[4-[8-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methy l-6-oxo-7H-pteridin-2-yl]amino]- 3-methoxy-benzoyl]amino]octoxy]-1-piperidyl]pyrimidine-5- carboxamide (I-20). [0444] The title compound was prepared according to the following procedures. 1.1 Preparation of compound 2 [0445] To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (5.0 g, 24.9 mmol, 1 eq) in THF (100 mL) was added NaH (1.1 g, 27.5 mmol, 60% purity, 1.1 eq) under 0 °C. The mixture was stirred at 25 °C for 0.5 h and then 8-bromooctoxymethylbenzene (8.2 g, 27.4 mmol, 1.1 eq) was added. The mixture was stirred at 25 °C for 10 h. The residue was purified by silica column chromatography on silica gel (Petroleum ether: Ethyl acetate from 10/1 to 5/1) to give tert- butyl 4-(8-benzyloxyoctoxy) piperidine-1-carboxylate (5.5 g, 53% yield) as a yellow oil. 1.2 Preparation of compound 3 [0446] To a solution of tert-butyl 4-(8-benzyloxyoctoxy)piperidine-1-carboxylate (5.2 g, 12.4 mmol, 1 eq) in MeOH (50 mL) was added Pd(OH) ₂ (2 g, 1.4 mmol, 10% purity, 1.15e ^-1 eq) under N2 atmosphere. The mixture was stirred under H2 (50 Psi.) at 25 °C for 12 h. The mixture was filtered and the filtrate was concentrated to give tert-butyl 4-(8-hydroxyoctoxy) piperidine-1- carboxylate (3.8 g, crude) as a yellow oil. ¹ H NMR (400 MHz, DMSO-d6) δ 3.81 - 3.67 (m, 2H), 3.58 - 3.39 (m, 5H), 3.18 - 3.06 (m, 2H), 1.86 - 1.79 (m, 2H), 1.61 - 1.49 (m, 4H), 1.45 (s, 12H), 1.35 (s, 7H) 1.3 Preparation of compound 4 [0447] To a solution of tert-butyl 4-(8-hydroxyoctoxy) piperidine-1-carboxylate (3.3 g, 10 mmol, 1 eq) and TosCl (2.8 g, 15.0 mmol, 1.5 eq) in DCM (30 mL) was added TEA (3.0 g, 30 mmol, 3 eq). The mixture was stirred at 25 °C for 3 h. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate=10/1 to 5/1) to give tert-butyl 4-[8-(p- tolylsulfonyloxy) octoxy] piperidine-1-carboxylate (4.5 g, 92% yield) was obtained as a yellow oil. 1.4 Preparation of compound 5 [0448] To a solution of tert-butyl 4-[8-(p-tolylsulfonyloxy) octoxy] piperidine-1-carboxylate (2 g, 4.14 mmol, 1 eq) and (1, 3-dioxoisoindolin-2-yl) potassium (766 mg, 4.1 mmol, 1 eq) in DMF (15 mL). The mixture was stirred at 50 °C for 12 h. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate=10/1 to 3/1) to give tert-butyl 4-[8-(1, 3- dioxoisoindolin-2-yl) octoxy] piperidine-1-carboxylate (1.7 g, 92% yield) was obtained as a yellow oil. ¹ H NMR (400 MHz, MeOD) δ 7.95 - 7.72 (m, 3H), 3.76 - 3.63 (m, 4H), 3.50 - 3.43 (m, 3H), 3.13-3.11 (m, 2H), 1.86 - 1.77 (m, 2H), 1.71 - 1.61 (m, 2H), 1.59 - 1.50 (m, 2H), 1.46 - 1.41 (m, 11H), 1.34 (br s, 8H) 1.5 Preparation of compound 6 [0449] To a solution of tert-butyl 4-[8-(1, 3-dioxoisoindolin-2-yl) octoxy] piperidine-1- carboxylate (1.75 g, 3.82 mmol, 1 eq) in EtOH (30 mL) was added NH2NH2‧H2O (5.77 g, 115 mmol, 30 eq) and the mixture was stirred at 70 °C for 12 h. The mixture was by prep-HPLC (column: Waters Xbridge 150 x 25 mm* 5um; mobile phase: [water (NH4HCO3)-ACN]; B%: 25%-55%, 10min) to give tert-butyl 4-(8-aminooctoxy) piperidine-1-carboxylate (500 mg, 40% yield) as a yellow oil. 1.6 Preparation of compound 8 [0450] To a solution of tert-butyl 4-(8-aminooctoxy)piperidine-1-carboxylate (100 mg, 304 μmol, 1 eq) and 4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2- yl]amino]-3- methoxy-benzoic acid (129 mg, 304 μmol, 1.0 eq) in DMF (0.5 mL) was added HATU (116mg, 304 μmol, 1.0 eq) and DIEA (118 mg, 913 μmol, 3.0 eq). The mixture was stirred at 25 °C for 1 h. The residue was purified by prep-HPLC (column: column: Waters Xbridge 150 x 25 mm* 5um;mobile phase: [water(NH ₄ HCO ₃ )-ACN];B%: 70%-100%,8min) to give tert-butyl 4-[8- [[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin- 2-yl]amino]-3-methoxy- benzoyl]amino]octoxy]piperidine-1-carboxylate (150 mg, 66% yield) as a white solid. 1.7 Preparation of compound 9 [0451] To a solution of tert-butyl 4-[8-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H- pteridin-2-yl]amino]-3-methoxy-benzoyl]amino]octoxy]piperidi ne-1-carboxylate (44 mg, 60 μmol, 1.0 eq) in DCM (2 mL) was added TFA (500 μL). The mixture was stirred at 25 °C for 0.5 h. The mixture was concentrated to give 4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2- yl]amino]-3-methoxy-N-[8-(4-piperidyloxy)octyl]benzamide (44.8 mg, crude, TFA) as a yellow oil. 1.8 Preparation of I-20 [0452] To a solution of 2-chloro-N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl - cyclobutyl]pyrimidine-5-carboxamide (25 mg, 59 μmol, 1.0 eq) and 4-[[(7R)-8-cyclopentyl-7- ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-3-methoxy-N-[8- (4-piperidyloxy)octyl] benzamide (44 mg, 59 μmol, 1 eq, TFA) in NMP (1 mL) was added K2CO3 (40 mg, 293 μmol, 5.0 eq). The mixture was stirred at 50 °C for 2 h. The residue was purified by prep-HPLC (column: Unisil 3- 100 C18, Ultra 150 x 50 mm*3 μm; mobile phase: [water (0.225%FA)-ACN]; B%: 15%-45%, 10 min) and prep-HPLC (column: Unisil 3-100 C18, Ultra 150 x 50mm*3 μm; mobile phase: [water(FA)-ACN];B%: 50%-80%,10min) to give N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4- tetramethyl-cyclobutyl]-2-[4-[8-[[4-[[(7R)-8-cyclopentyl-7-e thyl-5-methyl-6-oxo-7H-pteridin-2- yl]amino]-3-methoxy-benzoyl]amino]octoxy]-1-piperidyl]pyrimi dine-5-carboxamide (20.8 mg, 34% yield) as a light yellow solid. ¹ H NMR (400 MHz, MeOD): δ 8.71 (s, 1H), 8.49 - 8.47(m, 1H), 7.80 - 7.68 (m, 2H), 7.53 - 7.43 (m, 2H), 7.17 - 7.08 (m, 1H), 7.02 - 6.94 (m, 1H), 4.62 - 4.43 (m, 2H), 4.32-4.26 (m, 4H), 4.15 (s, 1H), 4.06 - 3.96 (m, 3H), 3.60 - 3.45 (m, 5H), 3.40 - 3.33 (m, 5H), 2.18 - 1.99 (m, 2H), 1.95 - 1.69 (m, 10H), 1.67 - 1.48 (m, 6H), 1.42 - 1.37 (m, 7H), 1.29 - 1.25 (m, 6H), 1.21 (s, 6H), 0.89 - 0.83 (m, 3H). LC-MS: MS (ES ⁺ ): RT = 2.64 min, m/z = 1006.4 (M+H ⁺ ) and 503.8 (M+2H ⁺ )/2. LC-MS Method 25. EXAMPLE 21 - Synthesis of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]-2-[4-[2-[3-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-me thyl-6-oxo-7H-pteridin-2-yl]- amino]-3-methoxy-benzoyl]amino]propoxy]ethoxy]-1-piperidyl]p yrimidine-5- carboxamide (I-21). [0453] The title compound was prepared according to the following procedures. 1.1 Preparation of compound 2 [0454] To a solution of tert-butyl 4-[2-[3-(p-tolylsulfonyloxy) propoxy]ethoxy]piperidine-1- carboxylate (900 mg, 1.97 mmol, 1.0 eq) and (1,3-dioxoisoindolin-2-yl)potassium (364 mg, 1.97 mmol, 1.0 eq) in DMF (8 mL). The mixture was stirred at 50 °C for 12 h. The mixture was partitioned between H ₂ O (40 mL) and ethyl acetate (100 mL). The organic phase was separated, washed with ethyl acetate 50 mL (2 X 50 mL), dried over Na2SO4, filtered and concentrated to give tert-butyl 4-[2-[3-(1, 3-dioxoisoindolin-2-yl) propoxy] ethoxy] piperidine-1-carboxylate (750 mg, 88% yield) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ): δ 1.47 (s, 10 H), 1.76 - 1.85 (m, 2 H), 1.95 - 2.01 (m, 2 H), 3.01 - 3.08 (m, 2 H), 3.38 - 3.49 (m, 1 H), 3.50 - 3.63 (m, 6 H), 3.69 - 3.89 (m, 4 H), 7.72 - 7.74 (m, 2 H), 7.85 - 7.87 (m, 2 H) 1.2 Preparation of compound 3 [0455] To a solution of tert-butyl 4-[2-[3-(1, 3-dioxoisoindolin-2-yl) propoxy] ethoxy] piperidine-1-carboxylate (750 mg, 1.73 mmol, 1.0 eq) in EtOH (10 mL) was added NH ₂ NH ₂ .H ₂ O (2.0 g, 40.6 mmol, 23 eq). The mixture was stirred at 70 °C for 12 h. The residue was purified by prep-HPLC (column: Waters Xbridge 150 x 25 mm* 5um; mobile phase: [water (NH4HCO3)- ACN]; B%: 12%-42%, 10min) to give tert-butyl 4-[2-(3-aminopropoxy) ethoxy]piperidine-1- carboxylate (378 mg, 72% yield) as a yellow oil. ¹ H NMR (400 MHz, CDCl3): δ 1.47 (s, 9 H), 1.50 - 1.58 (m, 4 H), 1.68 - 1.93 (m, 4 H), 2.83 (t, J=6.66 Hz, 2 H), 3.07 (t, J=13.20, 9.54, 3.42 Hz, 2 H), 3.50 (t, J=8.15, 3.84 Hz, 1 H), 3.56 - 3.70 (m, 6 H), 3.78-3.80 (m, 2 H) 1.3 Preparation of compound 5 [0456] To a solution of tert-butyl 4-[2-(3-aminopropoxy)ethoxy]piperidine-1-carboxylate (80 mg, 264 μmol, 1.0 eq) and 4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2- yl]amino]-3-methoxy-benzoic acid (112 mg, 264 μmol, 1.0 eq) in DMF (2 mL) was added HATU (110 mg, 291 μmol, 1.1 eq) and DIEA (102 mg, 793 μmol, 3.0 eq). The mixture was stirred at 25 °C for 1 h. The residue was purified by prep-HPLC (column: Phenomenex Synergi C18, 150 x 25 mm* 10um; mobile phase: [water (FA)-ACN]; B%: 28%-58%, 10min) to give tert-butyl 4-[2-[3- [[4-[(8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl) amino]-3-methoxy-benzoyl] amino] propoxy]ethoxy]piperidine-1-carboxylate (130 mg, 69% yield). 1.4 Preparation of compound 6 [0457] To a solution of tert-butyl 4-[2-[3-[[4-[(8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H- pteridin-2-yl)amino]-3-methoxy-benzoyl]amino]propoxy]ethoxy] piperidine-1-carboxylate (60 mg, 85 μmol, 1.0 eq) in DCM (3 mL) was added TFA (1 mL). The mixture was stirred at 25 °C for 0.5 h and concentrated. The residue was used for next step directly. 1.5 Preparation of I-21

[0458] To a solution of 4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2- yl]amino]-3-methoxy-N-[3-[2-(4-piperidyloxy)ethoxy]propyl]be nzamide (61 mg, 84 μmol, 1.0 eq, TFA salt) and 2-chloro-N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl - cyclobutyl]pyrimidine-5-carboxamide (35 mg, 84 μmol, 1.0 eq) in NMP (1 mL) was added K2CO3 (58 mg, 421 μmol, 5.0 eq). The mixture was stirred at 25 °C for 12 h. The residue was purified by prep-HPLC (column: Unisil 3-100 C18, Ultra 150 x 50mm*3 μm; mobile phase: [water (FA)- ACN]; B%: 40%-70%, 7min) to give N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]-2-[4-[2-[3-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-me thyl-6-oxo-7H-pteridin-2-yl]amino]- 3-methoxy-benzoyl]amino]propoxy]ethoxy]-1-piperidyl]pyrimidi ne-5-carboxamide (21 mg, 24% yield). ¹ H NMR (400 MHz, DMSO-d6): δ 0.76 (t, J=7.46 Hz, 3 H), 1.11 (s, 6 H), 1.21 (s, 6 H), 1.34 - 1.48 (m, 2 H), 1.54 - 1.70 (m, 3 H), 1.70 - 1.96 (m, 10 H), 1.97 - 2.09 (m, 1 H), 3.25 (s, 3 H), 3.38 - 3.56 (m, 7 H), 3.57 - 3.69 (m, 3 H), 3.94 (s, 3 H), 4.04 (d, J=9.2 Hz, 1 H), 4.18 - 4.40 (m, 5 H), 6.99 - 7.02 (m, 1 H), 7.22 (d, J=2.40 Hz, 1 H), 7.41 - 7.52 (m, 2 H), 7.60 (s, 1 H), 7.69 - 7.72 (m, 1 H), 7.84 (s, 1 H), 7.90 (d, J=8.80 Hz, 1 H), 8.31 (t, J=5.44 Hz, 1 H), 8.42 (d, J=8.40 Hz, 1 H), 8.75 (s, 2 H). LC-MS: MS (ES ⁺ ): RT = 2.66 min, m/z = 1020.4 (M+H ⁺ ) and 510.7 (M+2H ⁺ )/2. LC-MS Method 25. EXAMPLE 22 - Synthesis of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]- 2-[4-[3-[2-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7 H-pteridin-2- yl]amino]-3- methoxy-benzoyl]amino]ethoxy]propoxy]-1-piperidyl]pyrimidine -5- carboxamide (I-22). [0459] The title compound was prepared according to the following procedures. 1.1 Preparation of compound 3 [0460] To a solution of 4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2- yl]amino]-3-methoxy-benzoic acid (116 mg, 273 μmol, 1.1 eq) and tert-butyl 4-[3-(2- aminoethoxy)propoxy]piperidine-1-carboxylate (75 mg, 0.25 mmol, 1.0 eq) in DMF (1 mL) was added DIEA (160 mg, 1.24 mmol, 216 ^L, 5.0 eq) and HATU (141 mg, 372 μmol, 1.5 eq). The mixture was stirred at 20 °C for 2 h. The residue was purified by prep-HPLC (column: Phenomenex Synergi Polar-RP 100*25 mm*4um; mobile phase: [water(TFA)-ACN]; B%: 42%- 62%,7min) to afford tert-butyl 4-[3-[2-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H- pteridin-2-yl]amino]-3-methoxy-benzoyl]amino]ethoxy]propoxy] piperidine-1-carboxylate (150 mg, 211 μmol, 85% yield) as an off-white solid. 1.2 Preparation of compound 4 [0461] To a solution of tert-butyl 4-[3-[2-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H- pteridin-2-yl]amino]-3-methoxy-benzoyl]amino]ethoxy]propoxy] piperidine-1-carboxylate (73 mg, 0.10 mmol, 1.0 eq) in DCM (1 mL) was added TFA (0.5 mL). The mixture was stirred at 20 °C for 0.5 h. The reaction mixture was concentrated to afford 4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6- oxo-7H-pteridin-2-yl]amino]-3-methoxy-N-[2-[3-(4-piperidylox y)propoxy]ethyl] benzamide (73 mg, 0.10 mmol, TFA salt) as a yellow oil and it was used directly for the next step. 1.3 Preparation of I-22 [0462] To a solution of 4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2- yl]amino]-3-methoxy-N-[2-[3-(4-piperidyloxy)propoxy]ethyl]be nzamide (73 mg, 0.10 mmol, 1.0 eq, TFA salt) in NMP (1 mL) was added K ₂ CO ₃ (50 mg, 0.30 mmol, 3.0 eq) and 2-chloro-N-[3-(3- chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]pyrim idine-5-carboxamide (60 mg, 0.12 mmol, 1.2 eq). The mixture was stirred at 50 °C for 1 h. After filtration, the filtrate was purified by prep-HPLC (column: Phenomenex C18, 75*30mm*3um; mobile phase: [water(FA)-ACN]; B%: 42%-72%,7min) and (column: Waters Xbridge 150 x 25 mm*5um; mobile phase: [water(NH4HCO3)-ACN]; B%: 61%-91%,8 min) to afford N-[3-(3-chloro-4-cyano-phenoxy)- 2,2,4,4-tetramethyl-cyclobutyl]-2-[4-[3-[2-[[4-[[(7R)-8-cycl opentyl-7-ethyl-5-methyl-6-oxo-7H- pteridin-2-yl]amino]-3-methoxy-benzoyl]amino]ethoxy]propoxy] -1-piperidyl]pyrimidine-5- carboxamide (27 mg, 27 μmol, 23% yield) as a white solid. ¹ H NMR (400 MHz, CD3OD) 8.67 (s, 2H), 8.52 (d, J = 8.4 Hz, 1H), 7.79-7.69 (m, 2H), 7.57-7.48 (m, 2H), 7.13 (d, J = 2.4 Hz, 1H), 6.98 (m, 1H), 4.55-4.45 (m, 1H), 4.31-4.18 (m, 4H), 4.12 (s, 1H), 4.01 (s, 3H), 3.67-3.54 (m, 8H), 3.51- 3.32 (m, 5H), 2.25-2.10 (m, 1H), 2.07 - 1.65 (m, 14H), 1.48-1.36 (m, 2H), 1.28 (s, 6H), 1.21 (s, 6H). LC-MS: MS (ES ⁺ ): RT = 2.09 min, m/z = 1016.4 (M+H ⁺ ) and 508.8 (M+2H ⁺ )/2. LC-MS Method 25. EXAMPLE 23 - Synthesis of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]-2-[4-[2-[4-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-me thyl-6-oxo-7H-pteridin-2- yl]amino]-3-methoxy-benzoyl]amino]-butoxy]ethoxy]-1-piperidy l]pyrimidine-5-carboxamide ( [0463] The title compound was prepared according to the following procedures. 1.1 Preparation of compound 2 [0464] To a solution of To a solution of tert-butyl 4-[2-(4-aminobutoxy)ethoxy]piperidine- 1- carboxylate (80 mg, 252 μmol, 1 eq) and 4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo- 7H- pteridin-2-yl]amino]-3-methoxy-benzoic acid (107mg, 252 μmol, 1 eq) in DMF (2 mL) was added HATU (105 mg, 278 μmol, 1.1 eq) and DIEA (98 mg, 758 μmol, 3 eq). The mixture was stirred at 25 °C for 2 h. The residue was purified by prep-HPLC (column: Unisil 3-100 C18, Ultra 150 x 50mm*3 μm; mobile phase: [water(FA)-ACN];B%: 30%-60%,7min) to give tert-butyl 4-[2-[4- [[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin- 2-yl]- amino]-3-methoxy- benzoyl]amino]butoxy]ethoxy]piperidine-1-carboxylate (120 mg, 65% yield). 1.2 Preparation of compound 3 [0465] To a solution of 4-[2-[4-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-p teridin-2- yl]amino]-3-methoxy-benzoyl]amino]butoxy]ethoxy]piperidine-1 -carboxylate (60 mg, 82 μmol, 1 eq) in DCM (2 mL) was added TFA (0.5 mL). The mixture was stirred at 30 °C for 2 h and concentrated to give 4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2- yl]amino]-3- methoxy-N-[4-[2-(4-piperidyloxy)ethoxy]butyl]benzamide (61 mg, TFA salt) which was used directly for next step. 1.3 Preparation of compound I-23

[0466] To a solution of 4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2- yl]amino]-3-methoxy-N-[4-[2-(4-piperidyloxy)ethoxy]butyl]ben zamid (60 mg, 81 μmol, 1.0 eq) and 2-chloro-N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl -cyclobutyl]pyrimidine-5- carboxamide (34mg, 81 μmol, 1.0 eq ) in NMP (2 mL) was added K ₂ CO ₃ (33 mg, 243 μmol, 3.0 eq). The mixture was stirred at 25 °C for 2 h. The residue was purified by prep-HPLC (column: Unisil 3-100 C18, Ultra 150 x 50mm*3 μm; mobile phase: [water(FA)-ACN];B%: 42%- 72%,7min) to give N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl-cyclobut yl]-2-[4-[2-[4- [[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin- 2-yl]amino]-3-methoxy- benzoyl]amino]butoxy]ethoxy]-1-piperidyl]pyrimidine-5-carbox amide (57 mg, 67% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.60 (s, 2 H), 8.46 (d, J=8.4 Hz, 1 H) 7.59 - 7.63 (1 H, m), 7.48 - 7.56 (m, 2 H) 7.38 (d, J=1.6 Hz, 1 H), 6.89 (d, J=2.4 Hz, 1 H), 6.73 (dd, J=8.8, 2.4 Hz, 1 H), 6.42 (t, J=5.6 Hz, 1 H), 5.90 - 5.99 (m, 1 H), 4.38 - 4.50 (m, 1 H), 4.12 - 4.26 (m, 3 H), 4.12 - 4.26 (m, 3 H), 4.03 - 4.10 (m, 1 H), 3.97 (s, 1 H), 3.90 (s, 3 H), 3.57 - 3.61 (m, 2 H), 3.52 - 3.57 (m, 3 H), 3.49 (s, 2 H), 3.39 - 3.45 (m, 4 H), 3.26 (s, 3 H), 2.03 - 2.12 (m, 1 H) 1.89 - 1.98 (m, 1 H), 1.72 - 1.87 (m, 8 H), 1.59 - 1.66 (m, 6 H), 1.52 (d, J=8.8 Hz, 2 H), 1.18 (s, 6 H), 1.14 (s , 6 H), 0.81 (t, J=7.2 Hz, 3 H). LC-MS: MS (ES ⁺ ): RT = 2.05 min, m/z = 1030.3 (M+H ⁺ ) and 515.8 (M+2H ⁺ )/2. LC-MS Method 25.

EXAMPLE 24 - Synthesis of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]-2-[4-[3-[3-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-me thyl-6-oxo-7H-pteridin-2- yl]amino]-3-methoxy-benzoyl]amino]prop oxy]propoxy]-1-piperidyl]pyrimidine-5- carboxamide (I-24). [0467] The title compound was prepared according to the following procedures. 1.1 Preparation of compound 3 [0468] To a solution of tert-butyl 4-[3-[3-(p-tolylsulfonyloxy)propoxy]propoxy]piperidine-1- carboxylate (385 mg, 816 μmol, 1.0 eq) in CH ₃ CN (2 mL) was added K ₂ CO ₃ (338 mg, 2.45 mmol, 3.0 eq) and N-benzyl-1-phenyl-methanamine (322 mg, 1.63 mmol, 313 ^L, 2.0 eq) .The mixture was stirred at 80 °C for 12 h. The reaction mixture was filtered and the filtrate was concentrated to afford crude product. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate=30/1 to 10/1) to afford tert-butyl 4-[3-[3-(dibenzylamino) propoxy]propoxy]piperidine-1-carboxylate (270 mg, 533 μmol, 65% yield) was obtained as a colorless oil. ¹ H NMR: (CDCl ₃ , 400 MHz) 7.23 (s, 10H), 3.80 - 3.69 (m, 2H), 3.63 - 3.50 (m, 4H), 3.49 - 3.38 (m, 6H), 3.13 - 3.02 (m, 2H), 2.56 - 2.45 (m, 2H), 1.89 - 1.69 (m, 6H), 1.67 - 1.57 (m, 2H), 1.54 - 1.49 (m, 1H), 1.48 - 1.44 (m, 9H) 1.2 Preparation of compound 4 [0469] To a solution of tert-butyl 4-[3-[3-(dibenzylamino)propoxy]propoxy]piperidine-1- carboxylate (0.27 g, 0.54 mmol, 1.0 eq) in TFE (5 mL) was added Pd(OH) ₂ (270 mg, 50% purity) under N ₂ atmosphere. The suspension was degassed and purged with H ₂ for 3 times. The mixture was stirred under H ₂ (15 psi) at 25 °C for 2 h. The reaction mixture was filtered and the filtrate was concentrated to afford tert-butyl 4-[3-(3-aminopropoxy)propoxy]piperidine-1-carboxylate (172 mg, crude) as a yellow oil and it was used directly for the next step. 1.3 Preparation of compound 6 [0470] To a solution of tert-butyl 4-[3-(3-aminopropoxy)propoxy]piperidine-1-carboxylate (86 mg, 0.27 mmol, 1.0 eq) in DMF (2 mL) was added 4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6- oxo-7H-pteridin-2-yl]amino]-3-methoxy-benzoic acid (116 mg, 272 μmol, 1.0 eq), DIEA (105 mg, 815 μmol, 142 ^L, 3.0 eq) and HATU (155 mg, 408 μmol, 1.5 eq). The mixture was stirred at 25 °C for 0.5 h. The residue was purified by prep-HPLC (column: Waters Xbridge 150 x 25 mm*5um; mobile phase: [water(NH4HCO3)-ACN]; B%: 54%-84%,8min) to afford tert-butyl 4-[3- [3-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pterid in-2-yl]amino]-3-methoxy- benzoyl]amino]propoxy]propoxy]piperidine-1-carboxylate (136 mg, 182 μmol, 67% yield) as a yellow oil. 1.4 Preparation of compound 7 [0471] To a solution of tert-butyl 4-[3-[3-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H- pteridin-2-yl]amino]-3-methoxy-benzoyl]amino]propoxy]propoxy ]piperidine-1-carboxylate (136 mg, 188 μmol, 1.0 eq) in DCM (8 mL) was added TFA (4 mL). The mixture was stirred at 25 °C for 0.5 h. The reaction mixture was concentrated to afford 4-[[(7R)-8-cyclopentyl-7-ethyl-5- methyl-6-oxo-7H-pteridin-2-yl]amino]-3-methoxy-N-[3-[3-(4-pi peridyloxy)propoxy] propyl]benzamide (139 mg, crude, TFA salt) as a yellow oil and it was used directly for the next s [0472] To a solution of 4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2- yl]amino]-3-methoxy-N-[3-[3-(4-piperidyloxy)propoxy]propyl]b enzamide (139 mg, 188 μmol, 1.0 eq, TFA salt) and 2-chloro-N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl - cyclobutyl]pyrimidine-5-carboxamide (79 mg, 0.19 mmol, 1.0 eq) in NMP (3 mL) was added K ₂ CO ₃ (78 mg, 0.56 mmol, 3.0 eq). The mixture was stirred at 50 °C for 1 h. The reaction mixture was filtered and the filtrate was purified by prep-HPLC (column: Phenomenex C18, 75*30mm*3um; mobile phase: [water(FA)-ACN]; B%: 45%-75%,7min) to afford N-[3-(3-chloro- 4-cyano-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]-2-[4-[3-[3- [[4-[[(7R)-8-cyclopentyl-7-ethyl-5- methyl-6-oxo-7H-pteridin-2-yl]amino]-3-methoxy-benzoyl]amino ]prop oxy]propoxy]-1- piperidyl]pyrimidine-5-carboxamide (107 mg, 101 μmol, 54% yield) was obtained as a white solid. ¹ H NMR: (CD3OD, 400 MHz) 8.68 (s, 2H), 8.47 - 8.39 (m, 1H), 7.74 - 7.69 (m, 2H), 7.53 - 7.41 (m, 2H), 7.17 - 7.04 (m, 1H), 7.01 - 6.90 (m, 1H), 4.52 - 4.41 (m, 1H), 4.32 - 4.17 (m, 4H), 4.16 - 4.07 (m, 1H), 4.02 - 3.96 (m, 3H), 3.61 - 3.40 (m, 12H), 2.19 - 2.10 (m, 1H), 1.98 - 1.71 (m, 14H), 1.53 - 1.40 (m, 2H), 1.35 (s, 15H), 0.97 - 0.67 (m, 3H). LC-MS: MS (ES ⁺ ): RT = 2.66 min, m/z = 976.4 (M+H ⁺ ) and 488.7 (M+2H ⁺ )/2. LC-MS Method 25. EXAMPLE 25 - Synthesis of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]-2-[4-[4-[2-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-me thyl-6-oxo-7H-pteridin-2- yl]amino]-3-methoxy-benzoyl]amino]ethoxy]butoxy]-1-piperidyl ]pyrimidine-5-carboxamide (I-25) [0473] The title compound was prepared according to the following procedures.

1.1 Preparation of compound 2 [0474] To a solution of tert-butyl 4-[4-(2-aminoethoxy)butoxy]piperidine-1-carboxylate (50 mg, 0.16 mmol, 1.0 eq), 4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2- yl]amino]- 3-methoxy-benzoic acid (67 mg, 0.16 mmol, 1.0 eq) in DMF (1 mL) was added DIEA (20 mg, 0.16 mmol, 28 ^L, 1.0 eq) and HATU (60 mg, 0.16 mmol, 1.0 eq). The mixture was stirred at 25 °C for 12 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (FA condition; column: Unisil 3-100 C18, Ultra 150 x 50mm*3 μm; mobile phase: [water(FA)-ACN];B%: 28%-58%,7min). Compound tert-butyl 4-[4-[2-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-p teridin-2-yl]amino]-3-methoxy- benzoyl]amino]ethoxy]butoxy]piperidine-1-carboxylate (70 mg, 97 μmol, 61% yield) was obtained as a white solid.

1.2 Preparation of compound 3 [0475] To a solution of tert-butyl 4-[4-[2-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H- pteridin-2-yl]amino]-3-methoxy-benzoyl]amino]ethoxy]butoxy]p iperidine-1-carboxylate (70 mg, 97 μmol, 1 eq) in DCM (1 mL) was added TFA (770 mg, 6.75 mmol, 0.5 mL, 69.8 eq). The mixture was stirred at 25 °C for 0.5 h. The reaction mixture was concentrated in vacuo to give the crude product. The crude product 4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2- yl]amino]-3-methoxy-N-[2-[4-(4-piperidyloxy)butoxy]ethyl]ben zamide (71 mg, 96 μmol, 99% yield, TFA) as a white solid was used into the next step without further purification. 1.3 Preparation of I-25 [0476] To a solution of 4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2- yl]amino]-3-methoxy-N-[2-[4-(4-piperidyloxy)butoxy]ethyl]ben zamide (60 mg, 81 μmol, 1.0 eq, TFA) in NMP (1 mL) was added K2CO3 (34 mg, 0.23 mmol, 3.0 eq), and added 2-chloro-N-[3-(3- chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]pyrim idine-5-carboxamide (34 mg, 81 μmol, 1.0 eq). The mixture was stirred at 50 °C for 12 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (FA condition; column: Unisil 3-100 C18, Ultra 150 x 50mm*3 μm; mobile phase: [water(FA)- ACN];B%: 43%-73%,7min). Compound N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]-2-[4-[4-[2-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-me thyl-6-oxo-7H-pteridin-2-yl]amino]- 3-methoxy-benzoyl]amino]ethoxy]butoxy]-1-piperidyl]pyrimidin e-5-carboxamide (40 mg, 40 μmol, 49% yield) was obtained as a white solid. ¹ H NMR (400 MHz, MeOD):δ 8.68 (s, 2H), 8.51 (d, J = 8.4 Hz, 1H), 7.78 - 7.69 (m, 2H), 7.53 - 7.46 (m, 2H), 7.13 (d, J = 2.4 Hz, 1H), 6.98 (m, 1H), 4.60 - 4.45 (m, 2H), 4.30 - 4.18 (m, 4H), 4.13 (s, 1H), 4.01 (s, 3H), 3.68 - 3.40 (m, 12H), 2.23 - 2.11 (m, 1H), 2.07 - 1.96 (m, 1H), 1.94 - 1.79 (m, 7H), 1.78 - 1.70 (m, 3H), 1.69 - 1.60 (m, 5H), 1.51 - 1.40 (m, 2H), 1.28 (s, 6H), 1.21 (s, 6H), 0.85 (t, J = 7.4 Hz, 3H). LC-MS: MS (ES ⁺ ): RT = 2.73 min, m/z = 990.3 (M+H ⁺ ) and 495.8 (M+2H ⁺ )/2. LC-MS Method 25. EXAMPLE 26 - Synthesis of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]-2-[4-[2-[5-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-me thyl-6-oxo-7H-pteridin-2- yl]amino]-3-methoxy-benzoyl]amino]pentoxy]ethoxy]-1-piperidy l]pyrimidine-5carboxamide ( [0477] The title compound was prepared according to the following procedures. 1.1 Preparation of compound 2 [0478] To a solution of tert-butyl 4-[2-[5-(p-tolylsulfonyloxy)pentoxy] ethoxy]piperidine-1- carboxylate (1.0 g, 2.1 mmol, 1.0 eq) in DMF(10 mL) was added (1,3-dioxoisoindolin-2- yl)potassium (381 mg, 2.1 mmol, 1.0 eq). The mixture was stirred at 50 °C for 12 h. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica column chromatography on silica gel (Petroleum ether: Ethyl acetate from 50/1 to 3/1) to give tert-butyl 4-[2-[5-(1,3-dioxoisoindolin-2- yl)pentoxy]ethoxy]piperidine-1-carboxylate (830 mg, 88% yield) as a colorless oil. 1.2 Preparation of compound 3 [0479] To a solution of tert-butyl 4-[2-[5-(1, 3-dioxoisoindolin-2-yl)pentoxy]ethoxy] piperidine-1-carboxylate (830 mg, 1.8 mmol, 1.0 eq) in EtOH (20 mL) was added NH2NH2.H2O (2.22 g, 44.4 mmol, 24.6 eq). The mixture was stirred at 70 °C for 12 h. The mixture was concentrated and purified by prep-HPLC (column: Waters Xbridge 150 x 25 mm* 5 μm; mobile phase: [water (NH ₄ HCO ₃ )-ACN]; B%: 20%-50%, 10 min) to give tert-butyl 4-[2-(5- aminopentoxy) ethoxy] piperidine-1-carboxylate (350 mg, 59% yield). ¹ H NMR (400 MHz, DMSO-d6) δ 3.61 (m, J = 4.8, 13.6 Hz, 2H), 3.53-3.49 (m, 2H), 3.48-3.44 (m, 3H), 3.37 (t, J = 6.4 Hz, 4H), 2.99 (t, J = 10.0 Hz, 2H), 1.83-1.71 (m, 2H), 1.47 (q, J = 6.6 Hz, 2H), 1.38 (s, 9H), 1.36- 1.21 (m, 6H). 1.3 Preparation of compound 5 [0480] To a solution of 4-[(8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl)am ino]-3- methoxy-benzoic acid (100 mg, 235 μmol, 1.0 eq) in DMF (1 mL) was added HATU (107 mg, 282 μmol, 1.2 eq), tert-butyl 4-[2-(5-aminopentoxy)ethoxy]piperidine-1-carboxylate (78 mg, 235 μmol, 1.0 eq) and DIEA (91 mg, 705 μmol, 3.0 eq). The mixture was stirred at 25 °C for 1 h, concentrated and purified by prep-HPLC (column: Unisil 3-100 C18, Ultra 150 x 50 mm, 3 μm; mobile phase: [water (FA)-ACN]; B%: 35%-65%, 10 min) to give tert-butyl 4-[2-[5-[[4-[[(7R)-8- cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-3 -methoxybenzoyl]amino] pentoxy]ethoxy] piperidine-1-carboxylate (120 mg, 69% yield) as a white solid. 1.4 Preparation of compound 6 [0481] To a solution of tert-butyl 4-[2-[5-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H- pteridin-2-yl]amino]-3-methoxybenzoyl]amino]pentoxy]ethoxy]p iperidine-1-carboxylate (60 mg, 81 μmol, 1.0 eq) in DCM (0.5 mL) was added TFA (0.2 mL). The mixture was stirred at 30 °C for 1 h and concentrated to give 4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2- yl]amino]-3-methoxy-N-[5-[2-(4-piperidyloxy)ethoxy]pentyl]be nzamide (60 mg, TFA salt) as a yellow oil. 1.5 Preparation of I-26

[0482] To a solution of 2-chloro-N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl - cyclobutyl]pyrimidine-5-carboxamide (33 mg, 80 μmol, 1.0 eq) in NMP (1 mL) was added K2CO3 (33 mg, 239 μmol, 3.0 eq) and 4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2- yl]amino]-3-methoxy-N-[5-[2-(4-piperidyloxy)ethoxy]pentyl]be nzamide (60 mg, 80 μmol, 1.0 eq, TFA salt). The mixture was stirred at 50 °C for 2 h. The mixture was concentrated and purified by prep-HPLC (column: Unisil 3-100 C18, Ultra 150 x 50 mm, 3 μm; mobile phase: [water (FA)- ACN]; B%: 43%-73%, 7 min) to give N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]-2-[4-[2-[5-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-me thyl-6-oxo-7H-pteridin-2-yl]amino]- 3-methoxy-benzoyl]amino]pentoxy]ethoxy]-1-piperidyl]pyrimidi ne-5carboxamide (44 mg, 52% yield) as a light yellow solid. ¹ H NMR (400 MHz, DMSO-d6): δ 8.75 (s, 2H), 8.42 (d, J = 8.8 Hz, 1H), 8.32 (t, J = 5.6 Hz, 1H), 7.91 (d, J = 8.8 Hz, 1H), 7.85 (s, 1H), 7.72 (d, J = 9.2 Hz, 1H), 7.60 (s, 1H), 7.51-7.46 (m, 2H), 7.22 (d, J = 2.4 Hz, 1H), 7.01 (m, J = 2.4, 8.8 Hz, 1H), 4.39-4.31 (m, 1H), 4.29 (s, 1H), 4.24 (m, J = 3.6, 7.6 Hz, 3H), 4.04 (d, J = 9.2 Hz, 1H), 3.94 (s, 3H), 3.64-3.56 (m, 3H), 3.51-3.48 (m, 2H), 3.45-3.39 (m, 4H), 3.28-3.25 (m, 4H), 2.05-1.98 (m, 1H), 1.92-1.84 (m, 4H), 1.82-1.71 (m, 4H), 1.65-1.60 (m, 2H), 1.58-1.51 (m, 4H), 1.45-1.34 (m, 4H), 1.25-1.18 (m, 7H), 1.12 (s, 7H), 0.77 (t, J = 7.6 Hz, 3H). LC-MS: MS (ES ⁺ ): RT = 2.58 min, m/z = 992.3 (M+H ⁺ ) and 496.8 (M+2H ⁺ )/2. LC-MS Method 25.

EXAMPLE 27 - Synthesis of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4- tetramethyl- cyclobutyl]-2-[4-[3-[4-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-me thyl-6-oxo-7H-pteridin-2- yl]amino]-3-methoxy-benzoyl]amino]butoxy]propoxy]-1-piperidy l]pyrimidine-5- carboxamide (I-27). [0483] The title compound was prepared according to the following procedures. 1.1 Preparation of compound 3 [0484] To a solution of tert-butyl 4-[3-(4-aminobutoxy)propoxy]piperidine-1-carboxylate (70 mg, 0.21 mmol, 1.0 eq) and 4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2- yl]amino]-3-methoxy-benzoic acid (90mg, 0.21 mmol, 1.0 eq) in DMF (1 mL) was added DIEA (82 mg, 0.63 mmol, 110 ^L, 3.0 eq)and HATU (121 mg, 318 μmol, 1.5 eq). The mixture was stirred at 25 °C for 1 h. The residue was purified by prep-HPLC (column: Waters Xbridge 150 x 25 mm, 5um; mobile phase:[water(NH ₄ HCO ₃ )-ACN];B%: 59%-79%,8min). Compound tert-butyl 4-[3-[4-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-p teridin-2-yl]amino]-3-methoxy- benzoyl]amino]butoxy]propoxy]piperidine-1-carboxylate (30 mg, 41 μmol, 19.19% yield) was obtained as a white solid. 1.2 Preparation of compound 4 [0485] To a solution of tert-butyl 4-[3-[4-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H- pteridin-2-yl]amino]-3-methoxy-benzoyl]amino]butoxy]propoxy] piperidine-1-carboxylate (30 mg, 41 μmol, 1.0 eq) in DCM (1 mL) was added TFA (0.5 mL) .The mixture was stirred at 25 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure to afford 4-[[(7R)-8- cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-3 -methoxy-N-[4-[3-(4- piperidyloxy)propoxy]butyl]benzamide (30 mg, 39.90 μmol, 98.15% yield, TFA salt) as a yellow oil. 1.3 Preparation of compound I-27 [0486] To a solution of 4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2- yl]amino]-3-methoxy-N-[4-[3-(4-piperidyloxy)propoxy]butyl]be nzamide (20 mg, 27 μmol, 1.0 eq, TFA salt) and2-chloro-N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramet hyl- cyclobutyl]pyrimidine-5-carboxamide (11 mg, 27 μmol, 1.0 eq) in NMP (1.5 mL) was added K2CO3 (11 mg, 80 μmol, 3.0 eq). The mixture was stirred at 50 °C for 1 h. The residue was purified by prep-HPLC (column: Phenomenex C18, 75 x 30mm, 3um; mobile phase: [water(FA)- ACN]; B%: 45%-75%,7min) and (column: Waters Xbridge 150 x 25 mm, 5um; mobile phase: [water(NH ₄ HCO ₃ )-ACN]; B%: 65%-95%,8min) to provide compound N-[3-(3-chloro-4-cyano- phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]-2-[4-[3-[4-[[4-[[(7 R)-8-cyclopentyl-7-ethyl-5-methyl-6- oxo-7H-pteridin-2-yl]amino]-3-methoxy-benzoyl]amino]butoxy]p ropoxy]-1-piperidyl]pyrimidine- 5-carboxamide (20 mg, 18 μmol, 66% yield) as a white solid. ¹ HNMR: (400 MHz, CD ₃ OD) 8.70 (s, 2H), 8.49 (d, J = 8.4 Hz, 1H), 7.78 (s, 1H), 7.72 (d, J = 8.8 Hz, 1H), 7.50 - 7.46 (m, 2H), 7.12 (d, J = 2.4 Hz, 1H), 6.99 - 6.95 (m, 1H), 4.51 (m, J = 7.3 Hz, 1H), 4.30 - 4.23 (m, 4H), 4.12 (s, 1H), 4.00 (s, 3H), 3.61 - 3.47 (m, 10H), 3.41 (t, J = 6.7 Hz, 2H), 3.33 - 3.33 (m, 3H), 2.17 (m, 1H), 2.00 (m, 1H), 1.93 - 1.66 (m, 17H), 1.57 - 1.46 (m, 2H), 1.27 (s, 7H), 1.21 (s, 6H), 0.86 (t, J = 7.5 Hz, 3H). LC-MS: MS (ES ⁺ ): RT = 2.60 min, m/z = 1006.4 (M+H ⁺ ) and 503.8 (M+2H ⁺ )/2. LC- MS Method 25. EXAMPLE 28 - Synthesis of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]-2-[4-[4-[3-[[4-[(8-cyclo-pentyl-7-ethyl-5-methyl -6-oxo-7H-pteridin- 2-yl)amino]-3- methoxy-benzoyl]amino]- propoxy]butoxy]-1-piperidyl]pyrimidine-5- carboxamide (I-28). [0487] The title compound was prepared according to the following procedures. 1.1 Preparation of compound 2 [0488] To a solution of tert-butyl 4-[4-(p-tolylsulfonyloxy)butoxy]piperidine-1-carboxylate (1.0 g, 2.3 mmol, 1.0 eq) in DMF (7 mL) was added dropwise NaH (140 mg, 3.51 mmol, 60% purity, 1.5 eq) at 0 °C. After addition, the mixture was stirred at 25 °C for 0.5h, and then 3- benzyloxypropan-1-ol (389 mg, 2.34 mmol, 370 ^L, 1.0 eq) in DMF (7 mL) was added dropwise at 0 °C. The resulting mixture was stirred at 25 °C for 12h. To the reaction mixture was added water (100 mL) and the mixture was extracted with ethyl acetate (200mL x 3). The combined organic phase was washed with brine (200 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 10:1 to 5:1) to give. Compound tert-butyl 4-[4-(3- benzyloxypropoxy)butoxy]piperidine-1-carboxylate (690 mg, 1.47 mmol, 63% yield, 90% purity) was obtained as a colorless Oil. 1.2 Preparation of compound 3 [0489] To a solution of tert-butyl 4-[4-(3-benzyloxypropoxy)butoxy]piperidine-1-carboxylate (690 mg, 1.64 mmol, 1.0 eq) in TFE (10 mL) was added Pd/C (690 mg, 2.09 mmol, 10% purity, 1.3 eq) under N2. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2 (15 psi) at 25 °C for 12 h. The reaction mixture was filtered and concentrated in vacuo to give the crude product. The crude product tert-butyl 4-[4-(3- hydroxypropoxy)butoxy]piperidine-1-carboxylate (500 mg, crude) as a colorless Oil was used into the next step without further purification. 1.3 Preparation of compound 4 [0490] To a solution of tert-butyl 4-[4-(3-hydroxypropoxy)butoxy]piperidine-1-carboxylate (560 mg, 1.69 mmol, 1.0 eq) in DCM (10 mL) was added TEA (684 mg, 6.76 mmol, 941 ^L, 4.0 eq) and TosCl (644 mg, 3.38 mmol, 2.0 eq). The mixture was stirred at 25 °C for 12 h. To the reaction mixture was added water (100 mL) and the mixture was extracted with ethyl acetate (200 mL x 3). The combined organic phase was washed with brine (200 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 10:1 to 3:1) to give. Compound tert- butyl 4-[4-[3-(p-tolylsulfonyloxy)propoxy]butoxy]piperidine-1-carb oxylate (360 mg, 704 μmol, 42% yield, 95% purity) was obtained as a colorless oil. 1.4 Preparation of compound 5 [0491] To a solution of tert-butyl 4-[4-[3-(p-tolylsulfonyloxy)propoxy]butoxy]piperidine-1- carboxylate (260 mg, 535 μmol, 1.0 eq) in ACN (5 mL) was added K ₂ CO ₃ (222 mg, 1.61 mmol, 3.0 eq) and N-benzyl-1-phenyl-methanamine (127 mg, 642 μmol, 123 ^L, 1.2 eq). The mixture was stirred at 80 °C for 24 h. To the reaction mixture was added water (100 mL) and the mixture was extracted with ethyl acetate (200 mL x 3). The combined organic phase was washed with brine (200 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 10:1 to 3:1) to give. Compound tert-butyl 4-[4-[3-(dibenzylamino)propoxy]butoxy]piperidine-1-carboxyla te (156 mg, 290 μmol, 54% yield, 95% purity) was obtained as a colorless Oil. 1.5 Preparation of compound 6 [0492] To a solution of tert-butyl 4-[4-[3-(dibenzylamino)propoxy]butoxy]piperidine-1- carboxylate (156 mg, 305 μmol, 1.0 eq) in TFE (2 mL) was added Pd/C (156 mg, 473 μmol, 10% purity, 1.6 eq) under N2. The suspension was degassed under vacuum and purged with H23 times. The mixture was stirred under H2 (15 psi) at 25 °C for 12 h. The reaction mixture was filtered and concentrated in vacuo to give the crude product. The crude product tert-butyl 4-[4-(3- aminopropoxy)butoxy]piperidine-1-carboxylate (100 mg, crude) as a colorless Oil was used into the next step without further purification. 1.6 Preparation of compound 7 [0493] To a solution of tert-butyl 4-[4-(3-aminopropoxy)butoxy]piperidine-1-carboxylate (50 mg, 0.15 mmol, 1.0 eq) in DMF (4 mL) was added DIEA (98 mg, 0.76 mmol, 132 ^L, 5.0 eq) and 4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2- yl]amino]-3-methoxy-benzoic acid (64 mg, 151 mmol, 1.0 eq) and HATU (115 mg, 303 μmol, 2.0 eq). The mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated in vacuo to give the crude product. The residue was purified by prep-HPLC (column: Unisil 3-100 C18, Ultra 150 x 50 mm, 3 μm; mobile phase: [water(FA)-ACN];B%: 32%-62%,7min). Compound tert-butyl 4-[4-[3-[[4-[[(7R)-8-cyclopentyl- 7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-3-methoxy-ben zoyl]amino] propoxy]butoxy]piperidine-1-carboxylate (50 mg, 64 μmol, 43% yield, 95% purity) was obtained as a colorless Oil.

1.7 Preparation of compound 8 [0494] To a solution of tert-butyl 4-[4-[3-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H- pteridin-2-yl]amino]-3-methoxy-benzoyl]amino]propoxy]butoxy] piperidine-1-carboxylate (50 mg, 68 μmol, 1.0 eq) in DCM (2 mL) was added TFA (3.08 g, 27.0 mmol, 2.0 mL, 399 eq). The mixture was stirred at 25 °C for 0.5 h. The reaction mixture was concentrated in vacuo to give the crude product. The crude product 4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2- yl]amino]-3-methoxy-N-[3-[4-(4-piperidyloxy)butoxy]propyl]be nzamide (40 mg, crude) was White Solid used into the next step without further purification. 1.8 Preparation of I-28 [0495] To a solution of 4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2- yl]amino]-3-methoxy-N-[3-[4-(4-piperidyloxy)butoxy]propyl]be nzamide (40 mg, 63 μmol, 1.0 eq) in NMP (2 mL) was added K ₂ CO ₃ (26 mg, 0.19 mmol, 3 eq) and 2-chloro-N-[3-(3-chloro-4-cyano- phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]pyrimidine-5-carboxa mide (26 mg, 63 μmol, 1.0 eq). The mixture was stirred at 50 °C for 12 h. The reaction mixture was concentrated in vacuo to give the crude product. The residue was purified by prep-HPLC (column: Unisil 3-100 C18, Ultra 150 x 50 mm, 3 μm; mobile phase: [water(FA)-ACN];B%: 46%-76%,7min). Compound N-[3-(3-chloro-4- cyano-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]-2-[4-[4-[3-[[ 4-[(8-cyclopentyl-7-ethyl-5-methyl- 6-oxo-7H-pteridin-2-yl)amino]-3-methoxy-benzoyl]amino] propoxy]butoxy]-1- piperidyl]pyrimidine-5-carboxamide (23 mg, 22 μmol, 35% yield, 95% purity) was obtained as a white solid. ¹ H NMR (CD3OD, 400 MHz) :δ 8.70 (s, 2H), 8.50 (d, J = 8.6 Hz, 1H), 7.78 (s, 1H), 7.72 (d, J = 8.8 Hz, 1H), 7.49 (d, J = 1.7 Hz, 1H), 7.45 (m, 1H), 7.12 (d, J = 2.4 Hz, 1H), 6.98 (m, 1H), 4.58 (s, 3H), 4.54 - 4.47 (m, 1H), 4.29 - 4.21 (m, 4H), 4.13 (s, 1H), 4.01 (s, 3H), 3.60 - 3.54 (m, 3H), 3.53 - 3.45 (m, 9H), 2.20 - 2.13 (m, 1H), 2.05 - 1.98 (m, 1H), 1.95 - 1.83 (m, 9H), 1.77 - 1.72 (m, 2H), 1.63 (br s, 4H), 1.53 - 1.45 (m, 2H), 1.28 (s, 6H), 1.21 (s, 6H), 0.85 (t, J = 7.5 Hz, 3H). LC-MS: MS (ES ⁺ ): RT = 2.66 min, m/z = 1120.3 (M+H ⁺ ) and 510.8 (M+2H ⁺ )/2. LC-MS Method 25. EXAMPLE 29 - Synthesis of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]-2-[4-[5-[2-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-me thyl-6-oxo-7H-pteridin- 2- yl]amino]-3-methoxy-benzoyl]amino]ethoxy]pentoxy]-1-piperidy l]pyrimidine-5- carboxamide (I-29). [0496] The title compound was prepared according to the following procedures. 1.1 Preparation of compound 3 [0497] To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (2.89 g, 14.4 mmol, 1.0 eq) in THF (50 mL) was added NaH (861 mg, 21.5 mmol, 60% purity, 1.5 eq) and 5- benzyloxypentyl 4-methylbenzenesulfonate (5.0 g, 14 mmol, 1.0 eq) at 0 °C. The mixture was stirred at 25 °C for 12 h. To the reaction mixture was added water (100 mL) and the mixture was extracted with ethyl acetate (100 mL x 3). The combined organic phase was washed with brine (100 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether/ethyl acetate=20/1 to 3/1). Compound tert-butyl 4-(5-benzyloxypentoxy)piperidine-1-carboxylate (3.3 g, 8.7 mmol, 61% yield) was obtained as a white solid. 1.2 Preparation of compound 4 [0498] To a solution of tert-butyl 4-(5-benzyloxypentoxy)piperidine-1-carboxylate (3.3 g, 8.7 mmol, 1.0 eq) in TFE (30 mL) was added Pd/C (2.0 g, 10% purity) under N ₂ . The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2 (15 psi) at 25 °C for 2 h. The reaction was filtered and the filtrate was concentrated in vacuo to give the crude product. Compound tert-butyl 4-(5-hydroxypentoxy)piperidine-1-carboxylate (2.4 g, crude) was obtained as a white solid. 1.3 Preparation of compound 6 [0499] To a solution of tert-butyl 4-(5-hydroxypentoxy)piperidine-1-carboxylate (2.4 g, 8.4 mmol, 1.0 eq) in DCM (30 mL) was added TosCl (3.18 g, 16.7 mmol, 2.0 eq) and TEA (3.38 g, 33.4 mmol, 4.65 mL, 4.0 eq). The mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated in vacuo to give the crude product. The residue was purified by column chromatography (SiO2, petroleum ether/ethyl acetate=20/1 to 3/1). Compound tert-butyl 4-[5-(p- tolylsulfonyloxy)pentoxy]piperidine-1-carboxylate (3.3 g, 7.5 mmol, 89% yield) was obtained as a white solid. 1.4 Preparation of compound 7 [0500] To a solution of tert-butyl 4-[5-(p-tolylsulfonyloxy)pentoxy]piperidine-1-carboxylate (1.0 g, 2.3 mmol, 1.0 eq) in DMF (7 mL) was added dropwise NaH (136 mg, 3.39 mmol, 60% purity, 1.5 eq) at 0 °C. After addition, the mixture was stirred at 25 °C for 0.5h, and then 2- benzyloxyethanol (344 mg, 2.26 mmol, 321 ^L, 1.0 eq) in DMF (7 mL) was added dropwise at 0 °C. The resulting mixture was stirred at 25 °C for 12 h. To the reaction mixture was added water (100 mL) and the mixture was extracted with ethyl acetate (200mL x 3). The combined organic phase was washed with brine (200 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 10:1 to 5:1) to give. Compound tert-butyl 4-[5-(2-benzyloxyethoxy) pentoxy]piperidine-1-carboxylate (741 mg, 1.67 mmol, 74% yield, 95% purity) was obtained as a colorless Oil. 1.5 Preparation of compound 8 [0501] To a solution of tert-butyl 4-[5-(2-benzyloxyethoxy)pentoxy]piperidine-1-carboxylate (740 mg, 1.76 mmol, 1.0 eq) in TFE (10 mL) was added Pd/C (740 mg, 2.24 mmol, 10% purity, 1.3 eq) under N ₂ . The suspension was degassed under vacuum and purged with H ₂ several times. The mixture was stirred under H2 (15 psi) at 25 °C for 12 h. The reaction mixture was filtered and concentrated in vacuo to give the crude product. The crude product tert-butyl 4-[5-(2- hydroxyethoxy)pentoxy]piperidine-1-carboxylate (500 mg, crude) as a colorless Oil was used into the next step without further purification. 1.6 Preparation of compound 9 [0502] To a solution of tert-butyl 4-[5-(2-hydroxyethoxy)pentoxy]piperidine-1-carboxylate (500 mg, 1.51 mmol, 1.0 eq) in DCM (10 mL) was added TEA (611 mg, 6.03 mmol, 840 ^L, 4.0 eq) and TosCl (575 mg, 3.02 mmol, 2.0 eq). The mixture was stirred at 25 °C for 12 h. To the reaction mixture was added water (100 mL) and the mixture was extracted with ethyl acetate (200 mL x 3). The combined organic phase was washed with brine (200 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 10:1 to 3:1) to give. Compound tert- butyl 4-[5-[2-(p-tolylsulfonyloxy)ethoxy]pentoxy]piperidine-1-carb oxylate (640 mg, 1.25 mmol, 83% yield, 95% purity) was obtained as a colorless Oil. 1.7 Preparation of compound 11 [0503] To a solution of tert-butyl 4-[5-[2-(p-tolylsulfonyloxy)ethoxy]pentoxy]piperidine-1- carboxylate (640 mg, 1.32 mmol, 1.0 eq) in ACN (10 mL) was added K ₂ CO ₃ (546 mg, 3.95 mmol, 3.0 eq) and N-benzyl-1-phenyl-methanamine (260 mg, 1.32 mmol, 252 ^L, 1.0 eq). The mixture was stirred at 80 °C for 24 h. To the reaction mixture was added water (100 mL) and the mixture was extracted with ethyl acetate (200 mL x 3). The combined organic phase was washed with brine (200 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 10:1 to 2:1) to give. Compound tert-butyl 4-[5-[2-(dibenzylamino)ethoxy]pentoxy] piperidine-1-carboxylate (319 mg, 593 μmol, 45% yield, 95% purity) was obtained as a colorless Oil. 1.8 Preparation of compound 12 [0504] To a solution of tert-butyl 4-[5-[2-(dibenzylamino)ethoxy]pentoxy]piperidine-1- carboxylate (319 mg, 625 μmol, 1.0 eq) in TFE (5 mL) was added Pd/C (80 mg, 0.24 mmol, 10% purity) under N2. The suspension was degassed under vacuum and purged with H23 times. The mixture was stirred under H ₂ (15 psi) at 25 °C for 12 h. The reaction mixture was filtered and concentrated in vacuo to give the crude product. The crude product tert-butyl 4-[5-(2- aminoethoxy)pentoxy]piperidine-1-carboxylate (152 mg, crude) as a colorless oil was used into the next step without further purification. 1.9 Preparation of compound 14 [0505] To a solution of 4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2- yl]amino]-3-methoxy-benzoic acid (85 mg, 0.20 mmol, 1.0 eq) in DMF (2 mL) was added DIEA (129 mg, 999 μmol, 174 ^L, 5.0 eq) and tert-butyl 4-[5-(2-aminoethoxy)pentoxy]piperidine-1- carboxylate (66 mg, 0.20 mmol, 1.0 eq) and HATU (152 mg, 399 μmol, 2.0 eq). The mixture was stirred at 25 °C for 12 h. The reaction mixture was filtered and concentrated in vacuo to give the crude product. The residue was purified by prep-HPLC (column: Waters Xbridge 150 x 25 mm, 5 μm; mobile phase: [water(NH4HCO3)-ACN];B%: 57%-87%,8min). Compound tert-butyl 4-[5-[2- [[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin- 2-yl]amino]-3-methoxy- benzoyl]amino]ethoxy]pentoxy]piperidine-1-carboxylate (140 mg, 180 μmol, 90% yield, 95% purity) was obtained as a white solid. 1.10 Preparation of compound 15 15 [0506] To a solution of tert-butyl 4-[5-[2-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H- pteridin-2-yl]amino]-3-methoxy-benzoyl]amino]ethoxy]pentoxy] piperidine-1-carboxylate (140 mg, 190 μmol, 1.0 eq) in DCM (2 mL) was added TFA (2.61 g, 22.9 mmol, 1.70 mL, 121 eq). The mixture was stirred at 25 °C for 0.5 h. The reaction mixture was concentrated in vacuo to give the crude product. The crude product 4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2- yl]amino]-3-methoxy-N-[2-[5-(4-piperidyloxy)pentoxy]ethyl]be nzamide (110 mg, crude) was Yellow Oil used into the next step without further purification. 1.11 Preparation of I-29 [0507] To a solution of 4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2- yl]amino]-3-methoxy-N-[2-[5-(4-piperidyloxy)pentoxy]ethyl]be nzamide (100 mg, 157 μmol, 1.0 eq) in NMP (2 mL) was added K ₂ CO ₃ (65 mg, 0.47 mmol, 3.0 eq) and 2-chloro-N-[3-(3-chloro-4- cyano-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]pyrimidine-5-c arboxamide (66 mg, 0.16 mmol, 1.0 eq). The mixture was stirred at 50 °C for 12 h. The reaction mixture was filtered and concentrated in vacuo to give the crude product. The residue was purified by prep-HPLC (column: Unisil 3-100 C18, Ultra 150 x 50 mm, 3 μm; mobile phase: [water(FA)-ACN];B%: 45%-75%,7min). Compound N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl-cyclobut yl]-2-[4-[5-[2-[[4- [[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl ]amino]-3-methoxy- benzoyl]amino]ethoxy]pentoxy]-1-piperidyl]pyrimidine-5-carbo xamide (46 mg, 42 μmol, 27% yield, 95% purity) was obtained as a white solid. ¹ H NMR (CD3OD, 400 MHz)： δ 8.69 (s, 2H), 8.53 (d, J = 8.3 Hz, 1H), 7.77 (s, 1H), 7.72 (d, J = 8.7 Hz, 1H), 7.53 - 7.48 (m, 2H), 7.13 (d, J = 2.4 Hz, 1H), 6.98 (m, 1H), 4.51 (br d, J = 8.3 Hz, 1H), 4.29 - 4.26 (m, 2H), 4.26 - 4.20 (m, 2H), 4.13 (s, 1H), 4.01 (s, 3H), 3.64 - 3.61 (m, 2H), 3.59 - 3.55 (m, 2H), 3.52 (t, J = 6.1 Hz, 2H), 3.49 - 3.42 (m, 2H), 3.42 - 3.34 (m, 4H), 2.23 - 2.14 (m, 1H), 2.13 - 1.92 (m, 2H), 1.92 - 1.75 (m, 8H), 1.74 - 1.64 (m, 2H), 1.62 - 1.57 (m, 2H), 1.56 - 1.50 (m, 2H), 1.46 - 1.38 (m, 4H), 1.28 (s, 6H), 1.21 (s, 6H), 1.19 - 1.16 (m, 1H), 0.85 (t, J = 7.5 Hz, 3H). LC-MS: MS (ES ⁺ ): RT = 2.71 min, m/z = 1020.4 (M+H ⁺ ) and 510.7 (M+2H ⁺ )/2. LC-MS Method 25.

EXAMPLE 30 - Synthesis of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]-2-[4-[[4-[2-[[4-[(8-cyclopentyl-7-ethyl-5-methyl -6-oxo-7H-pteridin-2-yl)amino]-3- methoxy-benzoyl]amino]ethyl]piperazin-1-yl]methyl]-1- piperidyl]pyrimidine-5-carboxamide (I-30). [0508] The title compound was prepared according to the following procedures. 1.1 Preparation of compound 2 [0509] To a solution of tert-butyl 4-[[4-(2-aminoethyl)piperazin-1-yl]methyl]piperidine-1- carboxylate (30 mg, 91 μmol, 1.0 eq), 4-[(8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2- yl)amino]-3-methoxy-benzoic acid (39 mg, 91 μmol, 1.0 eq) in DMF (1 mL) was added DIEA (35 mg, 275 μmol, 3.0 eq) and HATU (41 mg, 110 μmol, 1.2 eq). The mixture was stirred at 20 °C for 0.5 h and concentrated. The residue was purified by prep-HPLC (column: Waters Xbridge 150 x 25 mm, 5um; mobile phase: [water (NH4HCO3)-ACN]; B%: 53%-83%,8min) to give tert- butyl 4- [[4-[2-[[4-[(8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridi n-2-yl)amino]-3-methoxy- benzoyl]amino]ethyl]piperazin-1-yl]methyl]piperidine-1-carbo xylate (130 mg, 72%).

1.2 Preparation of compound 4 [0510] To a solution of tert-butyl 4-[[4-[2-[[4-[(8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H- pteridin-2-yl)amino]-3-methoxy-benzoyl]amino]ethyl]piperazin -1-yl]methyl]piperidine-1- carboxylate (65 mg, 88 μmol, 1.0 eq) in DCM (1 mL) was added TFA (0.3 mL). The mixture was stirred at 20 °C for 0.5 h and concentrated to give 4-[(8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H- pteridin-2-yl)amino ]-3-methoxy-N-[2-[4-(4-piperidylmethyl)piperazin-1-yl]ethyl] benzamide (65 mg, 98% yield, TFA salt). 1.3 Preparation of I-30 [0511] To a solution of 4-[(8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl)am ino]-3- methoxy-N-[2-[4-(4-piperidylmethyl)piperazin-1-yl]ethyl]benz amide (65 mg, 86 μmol, 1.0 eq, TFA salt) in NMP (1.00 mL) was added K2CO3 (120 mg, 869 μmol, 10 eq) and 2-chloro-N-[3-(3- chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]pyrim idine-5-carboxamide (36 mg, 86 μmol, 1.0 eq). The mixture was stirred at 70 °C for 3h and concentrated. The residue was purified by prep-HPLC (column: Unisil 3-100 C18, Ultra 150 x 50 mm, 3 μm; mobile phase: [water(FA)- ACN];B%: 20%-50%,10min) to give N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]-2-[4-[[4-[2-[[4-[(8-cyclopentyl-7-ethyl-5-methyl -6-oxo-7H-pteridin-2-yl)amino]-3- methoxy-benzoyl]amino]ethyl]piperazin-1-yl]methyl]-1-piperid yl]pyrimidine-5-carboxamide (38 mg, 43% yield,). ¹ H NMR (400 MHz, MeOD) δ 8.75-8.69 (m, 2H), 8.52-8.49 (m, 1H), 7.79 (s, 1H), 7.72 (d, J = 8.8 Hz, 1H), 7.53-7.44 (m, 2H), 7.12 (d, J = 2.4 Hz, 1H), 6.98 (s, 1H), 4.61-4.55 (m, 1H), 4.51 (s, 1H), 4.32-4.25 (m, 2H), 4.13 (s, 1H), 4.01 (s, 3H), 3.63-3.54 (m, 2H), 3.34 (s, 3H), 3.04-2.94 (m, 2H), 2.72 (s, 6H), 2.69-2.52 (m, 4H), 2.34 (s, 2H), 2.20-2.13 (m, 1H), 2.06-1.82 (m, 10H), 1.79-1.68 (m, 3H), 1.28 (s, 6H), 1.21 (s, 6H), 1.19-1.10 (m, 2H), 0.86 (s, 3H). LC-MS: MS (ES ⁺ ): RT = 2.01 min, m/z = 1044.4 (M+H ⁺ ) and 522.7 (M+2H ⁺ )/2. LC-MS Method 25. EXAMPLE 31 - Synthesis of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]-2-[4-[[4-[3-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-m ethyl-6-oxo-7H-pteridin-2- yl]amino]-3-methoxy-benzoyl]amino]propyl]piperazin-1-yl]meth yl]-1-piperidyl]pyrimidine- 5-carboxamide (I-31). [0512] The title compound was prepared according to the following procedures. 1.1 Preparation of compound 3 [0513] To a solution of tert-butyl 4-[[4-(3-aminopropyl)piperazin-1-yl]methyl]piperidine-1- carboxylate (86 mg, 252 μmol, 1eq) in DMF (1 mL) was added 4-[(8-cyclopentyl-7-ethyl-5- methyl-6-oxo-7H-pteridin-2-yl) amino]-3-methoxy-benzoic acid (118 mg, 277 μmol, 1.1 eq), HATU (124 mg, 328 μmol, 1.3 eq) and DIEA (163 mg, 1.26 mmol, 5 eq). The mixture was stirred at 20 °C for 1 h and concentrated. The residue was purified by prep-TLC(SiO2, DCM:MeOH=10:1) to give tert-butyl 4-[[4-[3-[[4-[[(7R)-8-cyclopentyl- 7-ethyl-5-methyl-6-oxo- 7H-pteridin-2-yl]amino]-3-methoxy-benzoyl]amino]propyl]piper azin-1-yl]methyl]piperidine-1- carboxylate (127 mg, 67% yield) as a white solid. 1.2 Preparation of compound 4 [0514] To a solution of tert-butyl 4-[[4-[3-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo- 7H-pteridin-2-yl] amino]-3-methoxy-benzoyl]amino]propyl]piperazin-1-yl]methyl] piperidine-1- carboxylate (127 mg, 169 μmol, 1 eq) in DCM (3 mL) was added TFA (1 mL). The mixture was stirred at 25 °C for 1 h. The mixture was used for next step directly without further purification. 1.3 Preparation of compound I-31 [0515] To a solution of 4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2- yl] amino]-3-methoxy-N-[3-[4-(4-piperidylmethyl)piperazin-1-yl]p ropyl]benzamide (127 mg, 166 μmol, 1 eq, TFA salt) in NMP(1.5 mL) was added K ₂ CO ₃ (69 mg, 500 μmol, 3 eq) and2-chloro-N- [3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl ]pyrimidine-5-carboxamide (76 mg, 183 μmol, 1.1 eq). The mixture was stirred at 50 °C for 6 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge 150 x 25 mm, 5 μm; mobilephase: [water(NH4HCO3)-ACN];B%:65%- 95%,8min) to give: N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl-cyclobut yl]- 2-[4-[[4-[3- [[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin- 2-yl]amino]-3-methoxy- benzoyl]amino]propyl]piperazin-1-yl]methyl]-1-piperidyl]pyri midine-5-carboxamide (75 mg, 43% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d6): δ 8.74 (s, 2H), 8.41 (d, J = 8.2 Hz, 1H), 8.44-8.39 (m, 1H), 8.36 (m, 1H), 8.39-8.33 (m, 1H), 7.90 (d, J = 8.8 Hz, 1H), 7.84 (s, 1H), 7.69 (d, J = 9.2 Hz, 1H), 7.60 (s, 1H), 7.47 (s, 1H), 7.46 (d, J = 9.2 Hz, 2H), 7.21 (d, J = 2.4 Hz, 1H), 7.00 (m, 1H), 4.72 (m,2H), 4.35 (m, 1H), 4.28 (s, 1H), 4.24 (m, 1H), 4.03 (d, J = 9.2 Hz, 1H), 3.93 (s, 3H), 3.26-3.23 (m, 3H), 2.95 (m, 2H), 2.67 (s, 1H), 2.58-2.52 (m, 3H), 2.43-2.25 (m, 9H), 2.12 (m, 2H), 2.02 (m, 1H), 1.93 - 1.86 (m, 2H), 1.84-1.73 (m, 7H), 1.71-1.56 (m, 5H), 1.21 (s, 6H), 1.11 (s, 6H), 1.05 - 0.94 (m, 2H), 0.76 (t, J = 7.6 Hz, 3H). LC-MS: MS (ES ⁺ ): RT = 2.67 min, m/z = 1006.4 (M+H ⁺ ) and 503.8 (M+2H ⁺ )/2. LC-MS Method 25. EXAMPLE 32 - Synthesis of N-[3-(3-chloro-4-cyano- phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]-2-[4-[[4-[4-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-m ethyl-6-oxo-7H-pteridin-2- yl]amino]-3-methoxy-benzoyl]amino]butyl]piperazin-1-yl]methy l]-1-piperidyl]pyrimidine-5- carboxamide (I-32). [0516] The title compound was prepared according to the following procedures. 1.1 Preparation of compound 2 [0517] To a solution of tert-butyl 4-[[4-(4-aminobutyl)piperazin-1-yl]methyl]piperidine-1- carboxylate (75 mg, 211 μmol, 1.0 eq) in DMF (2 mL) was added DIEA (136 mg, 1.06 mmol, 5.0 eq) and HATU (104 mg, 275 μmol, 1.3 eq) and 4-[(8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H- pteridin-2-yl)amino]-3- methoxy-benzoic acid (90 mg, 211 μmol, 1.0 eq). The mixture was stirred at 25 °C for 0.5 h. The mixture was diluted with water (2 mL) and extracted with Ethyl acetate (3 x 5 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by prep-TLC (SiO2, DCM: MeOH = 1:1) to give tert-butyl 4-[[4-[4-[[4-[(8- cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl)amino]-3 -methoxy- benzoyl]amino]butyl]piperazin-1-yl]methyl]piperidine-1-carbo xylate (80 mg, 49% yield) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.60-8.55 (m, 1H), 7.69 (s, 1H), 7.62 (s, 1H), 7.43- 7.39 (m, 1H), 7.37-7.31 (m, 1H), 4.18-4.03 (m, 2H), 4.00 (s, 3H), 3.50 (s, 6H), 3.34 (s, 3H), 2.99- 2.76 (m, 4H), 2.75-2.52 (m, 6H), 2.28-2.21 (m, 2H), 2.20-2.11 (m, 1H), 2.07-1.97 (m, 1H), 1.90- 1.81 (m, 4H), 1.80-1.66 (m, 12H), 1.46 (s, 9H), 1.11-1.02 (m, 2H), 0.89 (t, J = 7.6 Hz, 3H) 1.2 Preparation of compound 3 [0518] To a solution of tert-butyl 4-[[4-[4-[[4-[(8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H- pteridin-2-yl)amino]-3-methoxy-benzoyl]amino]butyl]piperazin -1-yl]methyl]piperidine-1- carboxylate (80 mg, 105 μmol, 1.0 eq) in DCM (1.5 mL) and TFA (0.5 mL). The mixture was stirred at 20 °C for 0.5 h. The solution was concentrated under reduced pressure to give 4-[(8- cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl)amino]-3 -methoxy-N-[4-[4- (4- piperidylmethyl)piperazin-1-yl]butyl]benzamide (80 mg, crude, TFA salt) as a yellow oil 1.3 Preparation of I-32

[0519] To a solution of 4-[(8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl)am ino]-3- methoxy-N-[4-[4- (4-piperidylmethyl)piperazin-1-yl]butyl]benzamide (80 mg, 103 μmol, 1.0 eq, TFA) in NMP (1 mL) was added K2CO3 (43 mg, 309 μmol, 3.0 eq) and 2-chloro-N-[3-(3-chloro-4- cyano-phenoxy)-2,2,4,4- tetramethyl-cyclobutyl]pyrimidine-5-carboxamide (43 mg, 103 μmol, 1.0 eq). The mixture was stirred at 50 °C for 4 h and concentrated. The residue was purified by prep- HPLC (column: Unisil 3-100 C18, Ultra 150 x 50 mm, 3 μm; mobile phase: [water(FA)- ACN];B%: 21%-51%,7min) to give N-[3-(3-chloro-4-cyano- phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]-2-[4-[[4-[4-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-m ethyl-6-oxo-7H-pteridin-2-yl]amino]- 3-methoxy-benzoyl]amino]butyl]piperazin-1-yl]methyl]-1-piper idyl]pyrimidine-5-carboxamide (55 mg, 47% yield) as a white solid. ¹ H NMR (400 MHz, MeOD): δ 8.76-8.71 (m, 2H), 8.44-8.37 (m, 1H), 8.31 (s, 1H), 7.93-7.86 (m, 1H), 7.84 (s, 1H), 7.73-7.66 (m, 1H), 7.60 (s, 1H), 7.51-7.43 (m, 2H), 7.21 (s, 1H), 7.04-6.97 (m, 1H), 4.77-4.65 (m, 2H), 4.38-4.31 (m, 1H), 4.28 (s, 1H), 4.26- 4.21 (m, 1H), 4.06-4.00 (m, 1H), 3.93 (s, 3H), 2.99-2.87 (m, 3H), 2.31-2.18 (m, 6H), 2.15-2.06 (m, 3H), 2.06-1.95 (m, 2H), 1.93-1.70 (m, 11H), 1.69-1.34 (m, 10H), 1.20 (s, 6H), 1.10 (s, 6H), 1.06- 0.93 (m, 3H), 0.79-0.72 (m, 3H). LC-MS: MS (ES ⁺ ): RT = 2.70 min, m/z = 1020.5 (M+H ⁺ ) and 510.7 (M+2H ⁺ )/2. LC-MS Method 25. EXAMPLE 33 - Synthesis of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]-2- [4-[[4-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pt eridin- 2- yl]amino]-3-methoxy-benzoyl]amino]-1-piperidyl]methyl]-1-pip eridyl]pyrimidine-5- carboxamide (I-33). [0520] The title compound was prepared according to the following procedures. 1.1 Preparation of compound 3 [0521] To a solution of benzyl N-(4-piperidyl)carbamate (500 mg, 1.85 mmol, 1.0 eq, HCl salt) and tert-butyl 4-formylpiperidine-1-carboxylate (433 mg, 2.03 mmol, 1.1 eq) in DCE (10 mL) was added AcOH (222 mg, 3.69 mmol, 211 ^L, 2.0 eq) and TEA (561 mg, 5.54 mmol, 771 ^L, 3.0 eq), then it was stirred for 1 h. NaBH(OAc) ₃ (1.17 g, 5.54 mmol, 3.0 eq) was added and it was stirred at 20 °C for 17 h. To the reaction mixture was added water (50 mL) and the mixture was extracted with EtOAc (50 mL). The combined organic phase was washed with brine (3 x 50 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuum. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 2:1 to 0:1) to give tert-butyl 4-[[4-(benzyloxycarbonylamino)-1-piperidyl]methyl]piperidine -1-carboxylate (700 mg, 1.62 mmol, 88% yield) as a yellow oil. 1.2 Preparation of compound 4 [0522] To a solution of tert-butyl 4-[[4-(benzyloxycarbonylamino)-1- piperidyl]methyl]piperidine-1-carboxylate (150 mg, 348 μmol, 1.0 eq) in TFE (5 mL) was added Pd/C (30 mg, 10% purity) under N ₂ atmosphere. The suspension was degassed and purged with H ₂ for 3 times. The mixture was stirred under H2 (15 psi) at 20 °C for 12 h. After filtration, the filtrate was concentrated to afford tert-butyl 4-[(4-amino-1-piperidyl)methyl]piperidine-1-carboxylate (100 mg, 336 μmol) as a colorless oil and it was used directly for the next step. 1.3 Preparation of compound 6 [0523] To a solution of tert-butyl 4-[(4-amino-1-piperidyl)methyl]piperidine-1-carboxylate (90 mg, 0.30 mmol, 1.0 eq) and 4-[(8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl)am ino]-3- methoxy-benzoic acid (135 mg, 318 μmol, 1.05 eq) in DMF (2 mL) was added DIEA (196 mg, 1.51 mmol, 264 ^L, 5.0 eq) and HATU (230 mg, 605 μmol, 2.0 eq). The mixture was stirred at 20 °C for 1 h. The residue was purified by prep-HPLC (column: Phenomenex luna C18, 150 x 25 mm, 10 μm; mobile phase: [water(TFA)-ACN]; B%: 19%-49%,11min) to afford tert-butyl 4-[[4- [[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin- 2-yl]amino]-3-methoxy- benzoyl]amino]-1-piperidyl]methyl]piperidine-1-carboxylate (150 mg, 213 μmol, 70% yield) as an off-white solid. 1.4 Preparation of compound 7 [0524] To a solution of tert-butyl 4-[[4-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H- pteridin-2-yl]amino]-3-methoxy-benzoyl]amino]-1-piperidyl]me thyl]piperidine-1-carboxylate (60 mg, 85 μmol, 1.0 eq) in DCM (1 mL) was added TFA (0.5 mL). The mixture was stirred at 20 °C for 1 h. The reaction mixture was concentrated in vacuum to afford 4-[[(7R)-8-cyclopentyl-7- ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-3-methoxy-N-[1- (4-piperidylmethyl)-4- piperidyl]benzamide (61 mg, 85 μmol, TFA salt) as a yellow oil and it was used directly for the next step. 1.5 Preparation of compound I-33 [0525] To a solution of 4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2- yl]amino]-3-methoxy-N-[1-(4-piperidylmethyl)-4-piperidyl]ben zamide (60 mg, 83 μmol, 1.0 eq, TFA salt) in NMP (1 mL) was added K ₂ CO ₃ (35 mg, 0.25 mmol, 3.0 eq) and 2-chloro-N-[3-(3- chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]pyrim idine-5-carboxamide (35 mg, 83 μmol, 1.0 eq). The mixture was stirred at 50 °C for 1 h. After filtration, the filtrate was purified by prep-HPLC (column: Phenomenex C18, 75 x 30 mm, 3 μm; mobile phase: [water(FA)-ACN]; B%: 22%-52%,7min) to afford N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl-cyclobut yl]-2-[4- [[4-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteri din-2-yl]amino]-3-methoxy- benzoyl]amino]-1-piperidyl]methyl]-1-piperidyl]pyrimidine-5- carboxamide (19 mg, 19 μmol, 23% yield) as a yellow solid. ¹ H NMR (400 MHz, CD ₃ OD) 8.74 (s, 2H), 8.50 (d, J = 9.2 Hz, 1H), 7.79 (s, 1H), 7.72 (d, J = 8.4 Hz, 1H), 7.53-7.46 (m, 2H), 7.13 (d, J = 2.4 Hz, 1H), 6.98 (m, 1H), 4.95- 4.89 (m, 2H), 4.63-4.45 (m, 2H), 4.33-4.21 (m, 2H), 4.13 (s, 1H), 4.05-3.92 (m, 4H), 3.33 (s, 3H), 3.24-3.13 (m, 2H), 3.08-2.96 (m, 2H), 2.65-2.30 (m, 4H), 2.25-1.64 (m, 18H), 1.28 (s, 6H), 1.21 (s, 6H), 0.86 (t, J = 7.6 Hz, 3H). LC-MS: MS (ES ⁺ ): RT = 2.16 min, m/z = 987.4 (M+H ⁺ ) and 494.3 (M+2H ⁺ )/2. LC-MS Method 25. EXAMPLE 34 - Synthesis of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]-2-[4-[3-[4-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-me thyl-6-oxo-7H-pteridin-2- yl]amino]-3-methoxy-benzoyl]amino]-1-piperidyl]propyl]-1-pip eridyl]pyrimidine-5- carboxamide (I-34). [0526] The title compound was prepared according to the following procedures. 1.1 Preparation of compound 3 [0527] To a solution of benzyl N-(4-piperidyl)carbamate (477 mg, 2.04 mmol, 1.0 eq, HCl salt) in ACN (20 mL) was added K ₂ CO ₃ (844 mg, 6.11 mmol, 3.0 eq) and tert-butyl 4-[3-(p- tolylsulfonyloxy)propyl]piperidine-1-carboxylate (890 mg, 2.24 mmol, 1.1 eq). The mixture was stirred at 80 °C for 12 h. The reaction mixture was concentrated to afford crude product. The residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 2:1 to 0:1) to afford tert-butyl 4-[3-[4-(benzyloxycarbonylamino)-1-piperidyl]propyl]piperidi ne-1- carboxylate (770 mg, 1.68 mmol, 82% yield) as a yellow oil. 1.2 Preparation of compound 4 [0528] To a solution of tert-butyl 4-[3-[4-(benzyloxycarbonylamino)-1-piperidyl]propyl] piperidine-1-carboxylate (150 mg, 326 μmol, 1.0 eq) in TFE (5 mL) was added Pd/C (30 mg, 10% purity) under N2 atmosphere. The suspension was degassed and purged with H2 for 3 times. The mixture was stirred under H2 (15 psi) at 20 °C for 12 h. After filtration, the filtrate was concentrated to afford tert-butyl 4-[3-(4-amino-1-piperidyl)propyl]piperidine-1-carboxylate (106 mg, 326 μmol) as a colorless oil and it was used directly for the next step. 1.3 Preparation of compound 6 [0529] To a solution of tert-butyl 4-[3-(4-amino-1-piperidyl)propyl]piperidine-1-carboxylate (90 mg, 0.28 mmol, 1.0 eq) and 4-[(8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2- yl)amino]-3-methoxy-benzoic acid (124 mg, 290 μmol, 1.05 eq) in DMF (1 mL) was added DIEA (179 mg, 1.38 mmol, 241 ^L, 5.0 eq) and HATU (210 mg, 553 μmol, 2.0 eq). The mixture was stirred at 20 °C for 1 h. The residue was purified by prep-HPLC (column: Phenomenex luna C18, 150 x 25 mm, 10 μm; mobile phase: [water(TFA)-ACN]; B%: 23-53%, 11min) to afford tert-butyl 4-[3-[4-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-p teridin-2-yl]amino]-3-methoxy- benzoyl]amino]-1-piperidyl]propyl]piperidine-1-carboxylate (150 mg, 205 μmol, 74% yield) as an off-white solid. 1.4 Preparation of compound 7 [0530] To a solution of tert-butyl 4-[3-[4-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H- pteridin-2-yl]amino]-3-methoxy-benzoyl]amino]-1-piperidyl]pr opyl]piperidine-1-carboxylate (70 mg, 96 μmol, 1.0 eq) in DCM (1 mL) was added TFA (0.5 mL). The mixture was stirred at 20 °C for 0.5 h. The reaction mixture was concentrated to afford 4-[[(7R)-8-cyclopentyl-7-ethyl-5- methyl-6-oxo-7H-pteridin-2-yl]amino]-3-methoxy-N-[1-[3-(4-pi peridyl) propyl]-4- piperidyl]benzamide (70 mg, 94 μmol, TFA salt) as a yellow oil and it was used directly for the next step. 1.5 Preparation of compound I-34 [0531] To a solution of 4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2- yl]amino]-3-methoxy-N-[1-[3-(4-piperidyl)propyl]-4-piperidyl ]benzamide (70 mg, 94 μmol, 1.0 eq, TFA salt) in NMP (1 mL) was added K ₂ CO ₃ (39 mg, 0.28 mmol, 3.0 eq) and 2-chloro-N-[3-(3- chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]pyrim idine-5-carboxamide (39 mg, 94 μmol, 1.0 eq). The mixture was stirred at 50 °C for 1 h. After filtration, the filtrate was purified by prep-HPLC (column: Phenomenex C18, 75 x 30 mm, 3 μm; mobile phase: [water(FA)-ACN]; B%: 25%-55%,7min) to afford N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl-cyclobut yl]- 2-[4-[3-[4-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7 H-pteridin-2-yl]amino]-3-methoxy- benzoyl]amino]-1-piperidyl]propyl]-1-piperidyl]pyrimidine-5- carboxamide (19 mg, 19 μmol, 20% yield) as an off-white solid. ¹ H NMR (400 MHz, CD ₃ OD) 8.72 (s, 2H), 8.50 (d, J = 8.8 Hz, 1H), 7.79 (s, 1H), 7.72 (d, J = 8.8 Hz, 1H), 7.53-7.45 (m, 2H), 7.12 (d, J = 2.4 Hz, 1H), 7.01-6.94 (m, 1H), 4.90-4.88 (m, 2H), 4.63-4.47 (m, 1H), 4.32-4.25 (m, 2H), 4.13 (s, 1H), 4.05-3.97 (m, 4H), 3.33 (s, 3H), 3.29-3.25 (m, 1H), 3.02-2.91 (m, 2H), 2.75-2.63 (m, 2H), 2.61-2.49 (m, 2H), 2.19- 1.65 (m, 20H), 1.38-1.25 (m, 9H), 1.24-1.14 (m, 8H), 0.86 (t, J = 7.6 Hz, 3H). LC-MS: MS (ES ⁺ ): RT = 2.25 min, m/z = 1015.4 (M+H ⁺ ) and 508.3 (M+2H ⁺ )/2. LC-MS Method 25. EXAMPLE 35 - Synthesis of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]-2-[4-[2-[4-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-me thyl-6-oxo-7H-pteridin-2- yl]amino]-3-methoxy-benzoyl]amino]-1-piperidyl]ethoxy]-1-pip eridyl]pyrimidine-5- carboxamide (I-35). [0532] The title compound was prepared according to the following procedures. 1.1 Preparation of compound 3 [0533] To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (5.0 g, 24 mmol, 1.0 eq) in THF (16 mL) was added NaH (1.49 g, 37.3 mmol, 60% purity, 1.5 eq) at 0 °C. After addition, the mixture was stirred at this temperature for 0.5 h.2-bromoethoxymethylbenzene (5.3 g, 25 mmol, 3.9 mL, 1.0 eq) in THF (4 mL) was added dropwise at 0 °C. The resulting mixture was stirred at 25 °C for 12 h. The reaction mixture was quenched by 20 mL sat.NH4Cl at 0 °C, and then 500 mL water was added. After extracted with EtOAc (3 x 200 mL), the organic layers were dried over anhydrous Na2SO4, filtered and concentrated to afford crude product. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=10/1 to 3/1) to afford tert-butyl 4-(2-benzyloxyethoxy)piperidine-1-carboxylate (2.1 g, 6.2 mmol, 25% yield) was obtained as a yellow oil. ¹ H NMR: (CDCl ₃ , 400 MHz) δ 7.35 (d, J = 4.4 Hz, 4H), 7.32 (br d, J = 2.1 Hz, 1H), 4.59 (s, 2H), 3.86 - 3.73 (m, 2H), 3.69 - 3.62 (m, 4H), 3.54 - 3.45 (m, 1H), 3.12 - 3.01 (m, 2H), 1.90 - 1.80 (m, 2H), 1.58 - 1.54 (m, 2H), 1.47 - 1.46 (m, 9H) 1.2 Preparation of compound 4 [0534] To a solution of tert-butyl 4-(2-benzyloxyethoxy)piperidine-1-carboxylate (2.1 g, 6.3 mmol, 1.0 eq) in TFE (20 mL) was added Pd/C (700 mg, 10% purity) under N2 atmosphere. The suspension was degassed and purged with H ₂ (12 mg, 6.3 mmol, 1.0 eq) for 3 times. The mixture was stirred under H ₂ (15 Psi.) at 25 °C for 12 h. The reaction mixture was filtered and the filtrate was concentrated to afford crude product tert-butyl 4-(2-hydroxyethoxy)piperidine-1-carboxylate (1.5 g, crude) as a yellow oil was used for the next step without further purification. ¹ H NMR: (CDCl ₃ , 400 MHz) δ 3.95 (d, J = 8.6 Hz, 1H), 3.87 - 3.68 (m, 4H), 3.61 - 3.56 (m, 2H), 3.55 - 3.47 (m, 1H), 3.15 - 3.03 (m, 2H), 2.10 - 1.99 (m, 1H), 1.92 - 1.78 (m, 2H), 1.71 - 1.60 (m, 1H), 1.49 - 1.42 (m, 9H) 1.3 Preparation of compound 5 [0535] To a solution of tert-butyl 4-(2-hydroxyethoxy)piperidine-1-carboxylate (1.5 g, 6.1 mmol, 1.0 eq) in DCM (15 mL) was added TosCl (1.75 g, 9.17 mmol, 1.5 eq) and TEA (1.24 g, 12.2 mmol, 1.7 mL, 2.0 eq). The mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated to afford crude product. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=1/0 to 4/1) to afford tert-butyl 4-[2-(p- tolylsulfonyloxy)ethoxy]piperidine-1-carboxylate (1.39 g, 3.44 mmol, 56% yield) was obtained as a yellow oil. 1.3 Preparation of compound 7 [0536] To a solution of tert-butyl 4-[2-(p-tolylsulfonyloxy)ethoxy]piperidine-1-carboxylate (1.0 g, 2.5 mmol, 1.0 eq) in CH3CN (10 mL) was added K2CO3 (692 mg, 5.01 mmol, 2.0 eq) and benzyl N-(4-piperidyl)carbamate (678 mg, 2.50 mmol, 1.0 eq, HCl salt). The mixture was stirred at 80 °C for 12 h. The reaction mixture was filtered and the filtrate was concentrated to afford crude product. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=2/1 to MeOH/Ethyl acetate= 1/3) to afford tert-butyl 4-[2-[4-(benzyloxycarbonylamino)-1- piperidyl]ethoxy]piperidine-1-carboxylate (1.0 g, 2.1 mmol, 84% yield) was obtained as a yellow oil. ¹ H NMR: (CDCl3, 400 MHz) δ 7.39 - 7.31 (m, 5H), 5.14 - 5.04 (m, 2H), 4.83 - 4.72 (m, 1H), 3.83 - 3.35 (m, 7H), 3.14 - 3.01 (m, 3H), 2.84 - 2.70 (m, 2H), 2.49 - 2.29 (m, 3H), 1.86 - 1.77 (m, 2H), 1.70 - 1.58 (m, 2H), 1.54 - 1.47 (m, 2H), 1.47 - 1.44 (m, 9H) 1.4 Preparation of compound 8 [0537] To a solution of tert-butyl 4-[2-[4-(benzyloxycarbonylamino)-1-piperidyl]ethoxy] piperidine-1-carboxylate (150 mg, 324 μmol, 1.0 eq) in TFE (4 mL) was added Pd/C (50 mg, 324 μmol, 10% purity, 1.0 eq) under N2 atmosphere. The suspension was degassed and purged with H2 for 3 times. The mixture was stirred under H2 (15 psi) at 25 °C for 12 h. After filtration, the filtrate was concentrated to afford tert-butyl 4-[2-(4-amino-1-piperidyl)ethoxy]piperidine-1-carboxylate (106 mg, crude) as a yellow oil and it was used directly for the next step. 1.5 Preparation of compound 10 [0538] To a solution of tert-butyl 4-[2-(4-amino-1-piperidyl)ethoxy]piperidine-1-carboxylate (106 mg, 324 μmol, 1.0 eq) and 4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2- yl]amino]-3-methoxy-benzoic acid (138 mg, 324 μmol, 1.0 eq) in DMF (1.5 mL) was added DIEA (126 mg, 971 μmol, 169 ^L, 3.0 eq) and HATU (185 mg, 486 μmol, 1.5 eq). The mixture was stirred at 25 °C for 0.5 h. The residue was purified by prep-HPLC (column: Waters Xbridge 150 x 25 mm, 5 μm; mobile phase: [water(NH4HCO3)-ACN]; B%: 50%-80%,8min). Compound tert- butyl 4-[2-[4-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-p teridin-2-yl]amino]-3- methoxy-benzoyl]amino]-1-piperidyl]ethoxy]piperidine-1-carbo xylate (100 mg, 127 μmol, 39% yield) was obtained as a white solid. 1.6 Preparation of compound 11 [0539] To a solution of tert-butyl 4-[2-[4-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H- pteridin-2-yl]amino]-3-methoxy-benzoyl]amino]-1-piperidyl]et hoxy]piperidine-1-carboxylate (100 mg, 136 μmol, 1.0 eq) in DCM (4 mL) was added TFA (2 mL). The mixture was stirred at 25 °C for 0.5 h. The reaction mixture was concentrated to afford 4-[[(7R)-8-cyclopentyl-7-ethyl-5- methyl-6-oxo-7H-pteridin-2-yl]amino]-3-methoxy-N-[1-[2-(4-pi peridyloxy)ethyl]-4- piperidyl]benzamide (102 mg, crude, TFA salt) as a yellow oil and it was used directly for the next step. 1.7 Preparation of compound I-35 [0540] To a solution of 4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2- yl]amino]-3-methoxy-N-[1-[2-(4-piperidyloxy)ethyl]-4-piperid yl]benzamide (102 mg, 136 μmol, 1.0 eq, TFA) in NMP (1.5 mL) was added K ₂ CO ₃ (56 mg, 408 μmol, 3.0 eq) and 2-chloro-N-[3-(3- chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]pyrim idine-5-carboxamide (57 mg, 0.14 mmol, 1.0 eq). The mixture was stirred at 50 °C for 1 h. The reaction mixture was filtered and the filtrate was concentrated to afford crude product. The residue was purified by prep-HPLC (column: Phenomenex C18, 75 x 30 mm, 3 μm; mobile phase: [water(FA)-ACN]; B%: 25%-55%,7min). Compound N-[3-(3-chloro-4-cyano-phenoxy)- 2,2,4,4-tetramethyl-cyclobutyl]-2-[4-[2-[4-[[4- [[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl ]amino]-3-methoxy- benzoyl]amino]-1-piperidyl]ethoxy]-1-piperidyl]pyrimidine-5- carboxamide (100 mg, 97.5 μmol, 72% yield) was obtained as an off-white solid. ¹ H NMR: (CD3OD, 400 MHz) δ 8.74 (s, 2H), 8.50 (d, J = 9.0 Hz, 1H), 7.82 - 7.74 (m, 1H), 7.74 - 7.67 (m, 1H), 7.52 - 7.44 (m, 2H), 7.15 - 7.09 (m, 1H), 7.00 - 6.87 (m, 1H), 4.57 - 4.47 (m, 1H), 4.44 - 4.33 (m, 2H), 4.32 - 4.23 (m, 2H), 4.20 - 4.07 (m, 2H), 4.05 - 3.97 (m, 3H), 3.92 - 3.80 (m, 2H), 3.78 - 3.67 (m, 1H), 3.61 - 3.50 (m, 4H), 3.33 (s, 3H), 3.28 - 3.23 (m, 2H), 3.11 - 2.99 (m, 2H), 2.21 - 2.16 (m, 2H), 2.07 - 1.67 (m, 14H), 1.65 - 1.54 (m, 2H), 1.30 - 1.26 (m, 6H), 1.24 - 1.18 (m, 6H), 0.90 - 0.79 (m, 3H). LC-MS: MS (ES ⁺ ): RT = 2.14 min, m/z = 1017.4 (M+H ⁺ ) and 509.3 (M+2H ⁺ )/2. LC-MS Method 25. EXAMPLE 36 - Synthesis of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]-2-[4-[4-[4-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-me thyl-6-oxo-7H-pteridin-2- yl]amino]-3-methoxy-benzoyl]amino]-1-piperidyl]butoxy]-1-pip eridyl] pyrimidine-5- carboxamide (I-36). [0541] The title compound was prepared according to the following procedures. 1.1 Preparation of compound 2 [0542] To a solution of tert-butyl 4-(4-hydroxybutoxy)piperidine-1-carboxylate (1.50 g, 5.49 mmol, 1.0 eq) in DCM (10 mL) was added TosCl (2.09 g, 10.9 mmol, 2.0 eq) and TEA (1.11 g, 10.9 mmol, 1.53 mL, 2.0 eq). The mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated to afford crude product .The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate=1/0 to 3/1) to afford tert-butyl 4-[4-(p-tolylsulfonyloxy) butoxy]piperidine-1-carboxylate (1.38 g, 3.23 mmol, 59% yield) as a yellow oil. ¹ H NMR: (CDCl ₃ , 400 MHz) 7.79 (d, J = 8.3 Hz, 2H), 7.38 - 7.31 (m, 2H), 4.09 - 4.03 (m, 2H), 3.75 - 3.64 (m, 2H), 3.44 - 3.36 (m, 3H), 3.13 - 3.02 (m, 2H), 2.47 - 2.45 (m, 3H), 1.79 - 1.71 (m, 4H), 1.64 - 1.57 (m, 3H), 1.51 - 1.47 (m, 1H), 1.46 - 1.45 (m, 9H) 1.2 Preparation of compound 4 [0543] To a solution of tert-butyl 4-[4-(p-tolylsulfonyloxy)butoxy]piperidine-1-carboxylate (1.00 g, 2.34 mmol, 1.0 eq) in CH ₃ CN (10 mL) was added K ₂ CO ₃ (646 mg, 4.68 mmol, 2.0 eq) and benzyl N-(4-piperidyl)carbamate (633 mg, 2.34 mmol, 1.0 eq, HCl). The mixture was stirred at 80 °C for 12 h . The reaction mixture was filtered and the filtrate was concentrated to afford crude product. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate=1/1 to MeOH/Ethyl acetate= 1/4) to afford tert-butyl 4-[4-[4-(benzyloxycarbonylamino)-1- piperidyl]butoxy]piperidine-1-carboxylate (1.12 g, 2.20 mmol, 94% yield) as a yellow oil . 1.3 Preparation of compound 5 [0544] To a solution of tert-butyl 4-[4-[4-(benzyloxycarbonylamino)-1- piperidyl]butoxy]piperidine-1-carboxylate (150 mg, 306 μmol, 1.0 eq) in TFE (2 mL) was added Pd/C (50 mg, 10% purity) under N2 atmosphere. The suspension was degassed and purged with H2 for 3 times. The mixture was stirred under H2 (15 psi) at 25 °C for 12 h. The reaction mixture was filtered and the filtrate was concentrated to afford tert-butyl 4-[4-(4-amino-1-piperidyl) butoxy]piperidine-1-carboxylate (108 mg, 99% yield) as a yellow oil was used directly for the next step. 1.4 Preparation of compound 7 [0545] To a solution of tert-butyl 4-[4-(4-amino-1-piperidyl)butoxy]piperidine-1-carboxylate (108 mg, 303 μmol, 1.0 eq) in DMF (1.5 mL) was added 4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl- 6-oxo-7H-pteridin-2-yl]amino]-3-methoxy-benzoic acid (129 mg, 303 μmol, 1.0 eq), DIEA (117 mg, 911 μmol, 158 ^L, 3.0 eq) and HATU (173 mg, 455 μmol, 1.5 eq). The mixture was stirred at 25 °C for 0.5 h. The residue was purified by prep-HPLC (column: Phenomenex luna C18, 150 x 25 mm, 10 μm; mobile phase: [water(TFA)-ACN]; B%: 22%-52%,11min) and prep-TLC (SiO ₂ , DCM: MeOH = 10:1) to afford tert-butyl 4-[4-[4-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6- oxo-7H-pteridin-2-yl]amino]-3-methoxy-benzoyl]amino]-1-piper idyl]butoxy] piperidine-1- carboxylate (45 mg, 58 μmol, 19% yield) as a yellow oil. 1.5 Preparation of compound 8 [0546] To a solution of tert-butyl 4-[4-[4-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H- pteridin-2-yl]amino]-3-methoxy-benzoyl]amino]-1-piperidyl]bu toxy]piperidine-1-carboxylate (45 mg, 58 μmol, 1.0 eq) in DCM (3.0 mL) was added TFA (1.5 mL). The mixture was stirred at 25 °C for 0.5 h. The reaction mixture was concentrated to afford 4-[[(7R)-8-cyclopentyl-7-ethyl-5- methyl-6-oxo-7H-pteridin-2-yl]amino]-3-methoxy-N-[1-[4-(4-pi peridyloxy)butyl]-4- piperidyl]benzamide (45 mg, TFA salt) as a yellow oil and it was used directly for the next step. 1.6 Preparation of compound I-36 [0547] To a solution of 4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2- yl]amino]-3-methoxy-N-[1-[4-(4-piperidyloxy)butyl]-4-piperid yl]benzamide (45 mg, 58 μmol, 1.0 eq, TFA) in NMP (1.5 mL) was added K2CO3 (24 mg, 176 μmol, 3.0 eq) and 2-chloro-N-[3-(3- chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]pyrim idine-5-carboxamide (24 mg, 59 μmol, 1.0 eq) .The mixture was stirred at 50 °C for 1 h . After filtration, the filtrate was purified by prep-HPLC (column: Phenomenex C18, 75 x 30 mm, 3 μm; mobile phase: [water(FA)-ACN]; B%: 25%-55%,7min) to afford N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl-cyclobut yl]-2-[4- [4-[4-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pte ridin-2-yl]amino]-3-methoxy- benzoyl]amino]-1-piperidyl]butoxy]-1-piperidyl] pyrimidine-5-carboxamide (26 mg, 23 μmol, 40% yield) was obtained as a white solid. ¹ H NMR: (CD ₃ OD, 400 MHz) 8.73 (s, 2H), 8.52 - 8.45 (m, 1H), 7.81 - 7.75 (m, 1H), 7.73 - 7.67 (m, 1H), 7.52 - 7.46 (m, 2H), 7.14 - 7.08 (m, 1H), 7.02 - 6.93 (m, 1H), 4.66 - 4.47 (m, 2H), 4.37 - 4.26 (m, 4H), 4.14 - 4.11 (m, 1H), 4.05 - 3.94 (m, 4H), 3.68 - 3.63 (m, 1H), 3.60 (m, 4H), 3.33 (s, 3H), 3.29 - 3.23 (m, 2H), 2.75 - 2.67 (m, 2H), 2.63 - 2.47 (m, 2H), 2.20 - 1.94 (m, 7H), 1.92 - 1.72 (m, 12H), 1.64 - 1.57 (m, 2H), 1.28 - 1.24 (m, 6H), 1.21 (s, 6H), 0.90 - 0.83 (m, 3H). LC-MS: MS (ES ⁺ ): RT = 2.21 min, m/z = 1045.4 (M+H ⁺ ) and 523.2 (M+2H ⁺ )/2. LC-MS Method 25. EXAMPLE 37 – Synthesis of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]-2-[4-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6 -oxo-7H-pteridin-2-yl]amino]-3- methoxy-benzoyl]amino]-1-piperidyl]pyrimidine-5-carboxamide (I-55) [0548] Step 1: Preparation of tert-butyl4-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo- 7H-pteridin-2-yl]amino]-3-methoxy-benzoyl]amino]piperidine-1 -carboxylate. To a solution of4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin- 2-yl]amino]-3-methoxy-benzoic acid (100 mg, 235 umol, 1.0 equiv) ,tert-butyl 4-aminopiperidine-1-carboxylate (47 mg, 235 umol, 1.0 equiv) in DMF (1 mL) was added DIEA (91 mg, 705 umol, 3.0 equiv) and HATU (116 mg, 305 umol, 1.3 eq). The mixture was stirred at 25 °C for 12 h and concentrated. The residue was purified by prep-HPLC (column: Waters Xbridge 150*25mm* 5um;mobile phase: [water( NH4HCO3)-ACN];B%: 51%-81%,8min) to give tert-butyl4-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5- methyl-6-oxo-7H-pteridin-2-yl]amino]-3-methoxy-benzoyl]amino ]piperidine-1-carboxylate (130 mg, 91% yield). [0549] Step 2: Preparation of of 4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H- pteridin-2-yl]amino]-3-methoxy-N-(4-piperidyl)benzamide. A mixture of tert-butyl 4-[[4- [[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl ]amino]-3-methoxy- benzoyl]amino]piperidine-1-carboxylate (120 mg, 198 umol, 1.0 equiv) in DCM (5 mL) and TFA(2 mL) was stirred at 25 °C for 1 h. The mixture was concentrated. The product was used directly for next step. [0550] Step 3: Preparation of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]-2-[4-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6 -oxo-7H-pteridin-2-yl]amino]-3- methoxy-benzoyl]amino]-1-piperidyl]pyrimidine-5-carboxamide (I-55). To a solution of 4- [[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl ]amino]-3-methoxy-N-(4- piperidyl)benzamide (120 mg, 193 umol, 1.0 equiv, TFA salt) in NMP (1 mL) was added K2CO3 (27 mg, 193 umol, 1.0 equiv) and 2-chloro-N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl - cyclobutyl]pyrimidine-5-carboxamide (81 mg, 193 umol, 1.0 equiv). The mixture was stirred at 50 °C for 1h. The mixture was filtered and concentrated. The residue was purified by prep-HPLC (column: Waters Xbridge 150*25mm* 5um; mobile phase: [water( NH ₄ HCO ₃ )-ACN];B%: 65%- 95%,8min) to give N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl-cyclobut yl]-2-[4-[[4- [[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl ]amino]-3-methoxy- benzoyl]amino]-1-piperidyl]pyrimidine-5-carboxamide (137 mg, 79 % yield). ¹ H NMR (400 MHz, MeOD) δ 8.76 (s, 2H), 8.53 - 8.47 (m, 1H), 7.79 (s, 1H), 7.73 (d, J = 8.8 Hz, 1H), 7.52 - 7.47 (m, 2H), 7.13 (d, J = 2.4 Hz, 1H), 6.98 (s, 1H), 4.59 (s, 4H), 4.32 - 4.24 (m, 3H), 4.14 (s, 1H), 4.01 (s, 3H), 3.35 (s, 1H), 3.19 - 3.11 (m, 2H), 2.21 - 2.14 (m, 1H), 2.12 (s, 2H), 1.94 - 1.83 (m, 5H), 1.80 - 1.70 (m, 3H), 1.68 - 1.55 (m, 2H), 1.29 (s, 6H), 1.22 (s, 6H), 0.86 (s, 3H). LC-MS: MS (ES ⁺ ): RT = 1.582 min, m/z = 890.6 [M + H ⁺ ]; LCMS Method: 40. EXAMPLE 38 – Synthesis of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]-2-[4-[[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl- 6-oxo-7H-pteridin-2-yl]amino]-3- methoxy-benzoyl]amino]methyl]-1-piperidyl]pyrimidine-5-carbo xamide (I-56)

[0551] Step 1: Preparation of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]-2-[4-[[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl- 6-oxo-7H-pteridin-2-yl]amino]-3- methoxy-benzoyl]amino]methyl]-1-piperidyl]pyrimidine-5-carbo xamide. To a solution of 4- [[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl ]amino]-3-methoxy-benzoic acid (100 mg, 235 umol, 1.0 equiv) and tert-butyl 4-(aminomethyl)piperidine-1-carboxylate (50 mg, 235 umol, 1.0 equiv) in DMF (2 mL) was added HATU (107 mg, 282 umol, 1.2 equiv) and DIEA (91 mg, 705 umol, 3.0 equiv). The mixture was stirred at 25 °C for 12 h. The reaction mixture was filtered and purified by prep-HPLC (column: Unisil 3-100 C18 Ultra 150*50mm*3 um;mobile phase: [water(FA)-ACN];B%: 29%-59%,7min) to give N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4- tetramethyl-cyclobutyl]-2-[4-[[[4-[[(7R)-8-cyclopentyl-7-eth yl-5-methyl-6-oxo-7H-pteridin-2- yl]amino]-3-methoxy-benzoyl]amino]methyl]-1-piperidyl]pyrimi dine-5-carboxamide (85 mg, 57 % yield). [0552] Step 2: Preparation of 4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin- 2-yl]amino]-3-methoxy-N-(4-piperidylmethyl)benzamide. To a solution of tert-butyl 4-[[[4- [[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl ]amino]-3-methoxy- benzoyl]amino]methyl]piperidine-1-carboxylate (100 mg, 160 umol, 1.0 equiv) in DCM (1.5 mL) was added TFA (500 uL). The mixture was stirred at 25 °C for 1 h and concentrated to give 4- [[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl ]amino]-3-methoxy-N-(4- piperidylmethyl)benzamide (83 mg, 98 % yield). [0553] Step 3: Preparation of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]-2-[4-[[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl- 6-oxo-7H-pteridin-2-yl]amino]-3- methoxy-benzoyl]amino]methyl]-1-piperidyl]pyrimidine-5-carbo xamide (I-56). To a solution of 4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2- yl]amino]-3-methoxy-N-(4- piperidylmethyl)benzamide (83 mg, 159 umol, 1.0 equiv) and 2-chloro-N-[3-(3-chloro-4-cyano- phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]pyrimidine-5-carboxa mide (73 mg, 175 umol, 1.1 equiv) in NMP (1.5 mL) was added K ₂ CO ₃ (109 mg, 795 umol, 5.0 equiv). The mixture was stirred at 50 °C for 1 h and purified by prep-HPLC (column: Waters Xbridge 150*25mm* 5um; mobile phase: [water (NH4HCO3)-ACN]; B%: 63%-93%, 8min) to give N-[3-(3-chloro-4-cyano-phenoxy)- 2,2,4,4-tetramethyl-cyclobutyl]-2-[4-[[[4-[[(7R)-8-cyclopent yl-7-ethyl-5-methyl-6-oxo-7H- pteridin-2-yl]amino]-3-methoxy-benzoyl]amino]methyl]-1-piper idyl]pyrimidine-5-carboxamide (85 mg, 57 % yield). ¹ H NMR (400 MHz, DMSO-d6) δ: 8.75 (s, 2H), 8.46 - 8.37 (m, 2H), 7.91 - 7.88 (m, 1H), 7.86 - 7.83 (m, 1H), 7.73 - 7.67 (m, 1H), 7.60 (s, 1H), 7.53 - 7.46 (m, 2H), 7.24 - 7.17 (m, 1H), 7.01 (d, J = 2.4 Hz, 1H), 7.00 - 6.98 (m, 1H), 4.80 - 4.70 (m, 2H), 4.40 - 4.32 (m, 1H), 4.28 (s, 1H), 4.24 (d, J = 3.6, 7.3 Hz, 1H), 4.03 (d, J = 9.2 Hz, 1H), 3.97 - 3.89 (m, 3H), 3.25 (s, 3H), 3.19 (d, J = 5.6 Hz, 2H), 2.97 (s, 2H), 2.05 - 1.87 (m, 4H), 1.78 (s, 6H), 1.63 (d, J = 6.4, 14.0 Hz, 3H), 1.21 (s, 6H), 1.14 (s, 1H), 0.76 (d, J = 7.2 Hz, 3H) LC-MS: MS (ES ⁺ ): RT = 2.085 min, m/z = 906.4 [M + 1]; LCMS method: 25. EXAMPLE 39 – Synthesis of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]-2-[4-[[3-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-meth yl-6-oxo-7H-pteridin-2-yl]amino]- 3-methoxy-benzoyl]amino]azetidin-1-yl]methyl]-1-piperidyl]py rimidine-5-carboxamide (I- 57)

[0554] Step 1: Preparation of tert-butyl 4-[[3-(benzyloxycarbonylamino)azetidin-1- yl]methyl]piperidine-1-carboxylate. To a solution of tert-butyl 4-formylpiperidine-1-carboxylate (450 mg, 2.11 mmol, 1 equiv) and benzyl N-(azetidin-3-yl)carbamate (512 mg, 2.11 mmol, 1 equiv, HCl) in DCM (10 mL) was added NaOAc (346 mg, 4.22 mmol, 2 equiv) and NaBH(OAc) ₃ (1.34 g, 6.33 mmol, 3 equiv). The mixture was stirred at 20 °C for 12 h. The mixture was filtered and concentrated. The residue was purified by prep-HPLC (column: Waters Xbridge C18 150*50mm* 10um; mobile phase: [water (NH ₄ HCO ₃ )-ACN]; B%: 39%-69%, 10min) to give tert- butyl 4-[[3-(benzyloxycarbonylamino)azetidin-1-yl]methyl]piperidin e-1-carboxylate (700 mg, 82 % yield). [0555] Step 2: Preparation of tert-butyl 4-[(3-aminoazetidin-1-yl)methyl]piperidine-1- carboxylate. To a solution of tert-butyl 4-[[3-(benzyloxycarbonylamino)azetidin-1- yl]methyl]piperidine-1-carboxylate (670 mg, 1.66 mmol, 1.0 equiv) in THF (20 mL) was added Pd/C (200 mg, 10 % purity) under N2. The mixture was stirred under H2 (15psi) at 20 °C for 1 h. The mixture was filtered and concentrated to give the compound tert-butyl 4-[(3- aminoazetidin-1-yl)methyl]piperidine-1-carboxylate (400 mg, crude). [0556] Step 3: Preparation of tert-butyl 4-[[3-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6- oxo-7H-pteridin-2-yl]amino]-3-methoxy-benzoyl]amino]azetidin -1-yl]methyl]piperidine-1- carboxylate. To a solution of 4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2- yl]amino]-3-methoxy-benzoic acid (157 mg, 371 umol, 1.0 equiv) and tert-butyl 4-[(3- aminoazetidin-1-yl)methyl]piperidine-1-carboxylate (100 mg, 371 umol, 1.0 equiv) in DMF (1.5 mL) was added DIEA (143 mg, 1.11 mmol, 3.0 equiv) and HATU (169 mg, 445 umol, 1.2 equiv). The mixture was stirred at 20 °C for 1 h. The mixture was diluted with H2O 20 mL and extracted with EA 60 mL. The combined organic layers were washed with brine, filtered and concentrated. The residue was purified by prep-TLC (SiO2, EA: MeOH = 10: 1) to afford tert-butyl 4-[[3-[[4- [[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl ]amino]-3-methoxy- benzoyl]amino]azetidin-1-yl]methyl]piperidine-1-carboxylate (83 mg, 33 % yield). [0557] Step 4: Preparation of 4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin- 2-yl]amino]-3-methoxy-N-[1-(4-piperidylmethyl)azetidin-3-yl] benzamide. To a solution of tert-butyl 4-[[3-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pte ridin-2-yl]amino]-3- methoxy-benzoyl]amino]azetidin-1-yl]methyl]piperidine-1-carb oxylate (83 mg, 122 umol, 1.0 equiv) in DCM (2 mL) was added TFA (1 mL). The mixture was stirred at 20 °C for 0.5 h. After filtration, the filtrate was concentrated to afford crude product. [0558] Step 5: Preparation of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]-2-[4-[[3-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-meth yl-6-oxo-7H-pteridin-2-yl]amino]- 3-methoxy-benzoyl]amino]azetidin-1-yl]methyl]-1-piperidyl]py rimidine-5-carboxamide (I- 57). To a solution of 4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2- yl]amino]-3- methoxy-N-[1-(4-piperidylmethyl)azetidin-3-yl]benzamide (84 mg, 145 umol, 1.0 equiv) and 2- chloro-N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl-c yclobutyl]pyrimidine-5- carboxamide (61 mg, 145 umol, 1.0 equiv) in NMP (1.5 mL) was added K ₂ CO ₃ (201 mg, 1.46 mmol, 10.0 equiv). The mixture was stirred at 50 °C for 1 h. After filtration, The residue was purified by prep-HPLC (column: Waters Xbridge 150*25mm* 5um;mobile phase: [water( NH ₄ HCO ₃ )-ACN]; B %: 70 %-100 %,8 min) to afford Compound N-[3-(3-chloro-4-cyano- phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]-2-[4-[[3-[[4-[[(7R) -8-cyclopentyl-7-ethyl-5-methyl-6- oxo-7H-pteridin-2-yl]amino]-3-methoxy-benzoyl]amino]azetidin -1-yl]methyl]-1- piperidyl]pyrimidine-5-carboxamide (16 mg, 11 % yield) as a white solid. ¹ H NMR (400 MHz, METHANOL-d4) δ 8.74 (s, 2 H), 8.53 (d, J=8.8 Hz, 1 H), 7.81 (s, 1 H), 7.74 (d, J=8.80 Hz, 1 H), 7.54-7.51 (m, 2 H), 7.15 (d, J=2.45 Hz, 1 H), 7.00-6.98 (m, 1 H), 4.74 - 4.49 (m, 3 H), 4.34 - 4.26 (m, 2 H), 4.15 (s, 1 H), 4.03 (s, 3 H), 3.85 - 3.76 (m, 2 H), 3.36 (s, 3 H), 3.20 ( t, J=7.2 Hz, 2 H), 3.04 – 2.95 (m, 2 H), 2.57 - 2.44 (m, 2 H), 2.24 - 2.14 (m, 1 H), 2.05 – 1.74 (m, 12 H), 1.34 - 1.19 (m, 15 H), 0.88 (t, J=7.2 Hz, 3 H). LC-MS: MS (ES+): RT = 1.701 min, m/z =959.6 [M]; LCMS method: 25. EXAMPLE 40 – Synthesis of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]-2-[2-[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6- oxo-7H-pteridin-2-yl]amino]-3- methoxy-benzoyl]-2,6-diazaspiro[3.3]heptan-6-yl]pyrimidine-5 -carboxamide (I-58) [0559] Step 1: Preparation of tert-butyl 6-[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo- 7H-pteridin-2-yl]amino]-3-methoxy-benzoyl]-2,6-diazaspiro[3. 3]heptane-2-carboxylate. To a solution of 4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2- yl]amino]-3-methoxy- benzoic acid (100 mg, 235.03 umol, 1.0 equiv) in DMF (1 mL) was added DIEA (91 mg, 705 umol, 3.0 equiv) and HATU (134 mg, 353 umol, 1.5 equiv), tert-butyl 2,6-diazaspiro[3.3]heptane- 2-carboxylate (56 mg, 282 umol, 1.2 equiv). The mixture was stirred at 25 °C for 1 h and concentrated. The residue was purified by prep-HPLC (column: Waters Xbridge C18150*50mm* 10um; mobile phase: [water (NH ₄ HCO ₃ )-ACN];B%: 50%-80%,10min) to give tert-butyl 6-[4- [[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl ]amino]-3-methoxy-benzoyl]-2,6- diazaspiro[3.3]heptane-2-carboxylate (130 mg, 91% yield). [0560] Step 2: Preparation of (7R)-8-cyclopentyl-2-[4-(2,6-diazaspiro[3.3]heptane-2- carbonyl)-2-methoxy-anilino]-7-ethyl-5-methyl-7H-pteridin-6- one. To a solution of tert-butyl 6-[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin -2-yl]amino]-3-methoxy-benzoyl]- 2,6-diazaspiro[3.3]heptane-2-carboxylate (130 mg, 215 umol, 1.0 equiv) in DCM (1 mL) was added TFA (0.5 mL). The mixture was stirred at 25 °C for 0.5 h and concentrated to give (7R)-8- cyclopentyl-2-[4-(2,6-diazaspiro[3.3]heptane-2-carbonyl)-2-m ethoxy-anilino]-7-ethyl-5-methyl- 7H-pteridin-6-one (106 mg, 98% yield). [0561] Step 3: Preparation of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]-2-[2-[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6- oxo-7H-pteridin-2-yl]amino]-3- methoxy-benzoyl]-2,6-diazaspiro[3.3]heptan-6-yl]pyrimidine-5 -carboxamide (I-58). To a solution of (7R)-8-cyclopentyl-2-[4-(2,6-diazaspiro[3.3]heptane-2-carbon yl)-2-methoxy-anilino]- 7-ethyl-5-methyl-7H-pteridin-6-one (105 mg, 208 umol, 1.0 equiv) in NMP (1 mL) was added K2CO3 (143 mg, 1.04 mmol, 5.0 equiv) and 2-chloro-N-[3-(3-chloro-4-cyano-phenoxy)- 2,2,4,4-tetramethyl-cyclobutyl]pyrimidine-5-carboxamide (87 mg, 208 umol, 1.0 equiv). The mixture was stirred at 50 °C for 1 h and concentrated. The residue was purified by prep-HPLC (column: Unisil 3-100 C18 Ultra 150*50mm*3 um;mobile phase: [water(FA)-ACN];B%: 40%- 70%,7min) to give N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl-cyclobut yl]-2-[2-[4- [[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl ]amino]-3-methoxy-benzoyl]-2,6- diazaspiro[3.3]heptan-6-yl]pyrimidine-5-carboxamide (103 mg, 55% yield). ¹ H NMR (400 MHz, DMSO-d6) δ 8.75 (s, 2H), 8.48-8.38 (m, 1H), 7.90 (d, J = 8.8 Hz, 1H), 7.84 (s, 1H), 7.76 (d, J = 9.2 Hz, 1H), 7.62 (s, 1H), 7.28-7.19 (m, 3H), 7.01 (d, J = 2.4Hz, 1H), 4.60 (s, 2H), 4.37-4.22 (m, 9H), 4.04 (s, 1H), 3.93 (s, 3H), 3.25 (s, 3H), 2.01 (s, 1H), 1.94-1.83 (m, 2H), 1.82-1.72 (m, 4H), 1.69-1.56 (m, 3H), 1.21 (s, 6H), 1.11 (s, 6H), 0.76 (s, 3H). LC-MS: MS (ES ⁺ ): RT = 1.922 min, m/z = 888.6 [M + H ⁺ ]; LCMS method: 25.

EXAMPLE 41 – Synthesis of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]-2-[5-[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6- oxo-7H-pteridin-2-yl]amino]-3- methoxy-benzoyl]-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol -2-yl]pyrimidine-5- carboxamide (I-59) [0562] Step 1: Preparation of tert-butyl 2-[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo- 7H-pteridin-2-yl]amino]-3-methoxy-benzoyl]-1,3,3a,4,6,6a-hex ahydropyrrolo[3,4-c]pyrrole- 5-carboxylate. To a solution of 4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2- yl]amino]-3-methoxy-benzoic acid (100 mg, 235 umol, 1.0 equiv) and tert-butyl 2,3,3a,4,6,6a- hexahydro-1H-pyrrolo[3,4-c]pyrrole-5-carboxylate (49 mg, 235 umol, 1.0 equiv) in DMF (2 mL)was added HATU (107 mg, 282 umol, 1.2 equiv) and DIEA (91 mg, 705 umol, 3.0 equiv). The mixture was stirred at 25 °C for 12 h and purified by prep-HPLC (column: Unisil 3-100 C18 Ultra 150*50mm*3 um;mobile phase: [water(FA)-ACN];B%: 29%-59%,7min) to give tert-butyl 2-[4- [[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl ]amino]-3-methoxy-benzoyl]- 1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole-5-carboxylate (101 mg, 69 % yield). [0563] Step 2: Preparation of (7R)-2-[4-(2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4- c]pyrrole-5-carbonyl)-2-methoxy-anilino]-8-cyclopentyl-7-eth yl-5-methyl-7H-pteridin-6-one. To a solution of tert-butyl 2-[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin -2- yl]amino]-3-methoxy-benzoyl]-1,3,3a,4,6,6a-hexahydropyrrolo[ 3,4-c]pyrrole-5-carboxylate (100 mg, 161 umol, 1 equiv) in DCM (1.5 mL) was added TFA (0.5 mL). The mixture was stirred at 25 °C for 1 h and concentrated to give a crude (7R)-2-[4-(2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4- c]pyrrole-5-carbonyl)-2-methoxy-anilino]-8-cyclopentyl-7-eth yl-5-methyl-7H-pteridin-6-one (83 mg). [0564] Step 3: Preparation of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]-2-[5-[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6- oxo-7H-pteridin-2-yl]amino]-3- methoxy-benzoyl]-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol -2-yl]pyrimidine-5- carboxamide (I-59). To a solution of (7R)-2-[4-(2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4- c]pyrrole-5-carbonyl)-2-methoxy-anilino]-8-cyclopentyl-7-eth yl-5-methyl-7H-pteridin-6-one (83 mg, 159 umol, 1.0 equiv) and 2-chloro-N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl - cyclobutyl]pyrimidine-5-carboxamide (73 mg, 175 umol, 1.1 equiv) in NMP (1.5 mL) was added K ₂ CO ₃ (110 mg, 798 umol, 5.0 equiv). The mixture was stirred at 50 °C for 1 h. The mixture was filtered and purified by prep-HPLC (column: Waters Xbridge 150*25mm* 5um; mobile phase: [water (NH ₄ HCO ₃₎ -ACN]; B%: 63%-93%, 8min) to give N-[3-(3-chloro-4-cyano- phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]-2-[5-[4-[[(7R)-8-cy clopentyl-7-ethyl-5-methyl-6-oxo- 7H-pteridin-2-yl]amino]-3-methoxy-benzoyl]-1,3,3a,4,6,6a-hex ahydropyrrolo[3,4-c]pyrrol-2- yl]pyrimidine-5-carboxamide (95 mg, 64 % yield). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ: 8.84 - 8.74 (m, 2H), 8.41 - 8.31 (m, 1H), 7.91 (d, J = 8.8 Hz, 1H), 7.84 - 7.81 (m, 1H), 7.76 - 7.67 (m, 1H), 7.63 - 7.51 (m, 1H), 7.25 - 7.20 (m, 1H), 7.18 - 7.11 (m, 2H), 7.04 - 6.98 (m, 1H), 4.38 - 4.27 (m, 2H), 4.26 - 4.21 (m, 1H), 4.08 - 4.02 (m, 1H), 3.90 (s, 3H), 3.87 (s, 4H), 3.67 - 3.41 (m, 4H), 3.25 (s, 3H), 3.12 - 2.96 (m, 2H), 2.04 - 1.95 (m, 1H), 1.93 - 1.84 (m, 2H), 1.82 - 1.70 (m, 4H), 1.69 - 1.54 (m, 3H), 1.22 (s, 6H), 1.15 - 1.09 (m, 6H), 0.83 - 0.71 (m, 3H). LC-MS: MS (ES ⁺ ): RT = 2.411min, m/z = 902.3 [M + 1]; LCMS method: 25. EXAMPLE 42 – Synthesis of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]-2-[4-[[3-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-meth yl-6-oxo-7H-pteridin-2-yl]amino]- 3-methoxy-benzoyl]amino]cyclobutyl]amino]-1-piperidyl]pyrimi dine-5-carboxamide (I-60) [0565] Step 1: Preparation of tert-butyl 4-[[3-(benzyloxycarbonylamino) cyclobutyl] amino] piperidine-1-carboxylate. To a mixture of benzyl N-(3-oxocyclobutyl)carbamate (300 mg, 1.37 mmol, 1.0 equiv) and tert-butyl 4-aminopiperidine-1-carboxylate (274 mg, 1.37 mmol, 1.0 equiv) in DCM (10 mL) was added TEA (415 mg, 4.11 mmol, 3 equiv) and NaBH(OAc)3 (435 mg, 2.05 mmol, 1.5 equiv), the mixture was stirred at 25 °C for 12 h. The mixture was diluted with water (30 mL), extracted with DCM (30 mL * 3). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated. The residue was purified by prep-HPLC (column: Waters Xbridge C18150*50mm* 10um; mobile phase: [water (NH ₄ HCO ₃ ) -ACN]; B%: 35%-65%, 10min) to give tert-butyl 4-[[3-(benzyloxycarbonylamino) cyclobutyl] amino] piperidine-1-carboxylate (320 mg, 57 % yield). [0566] Step 2: Preparation of tert-butyl 4-[(3-aminocyclobutyl) amino] piperidine-1- carboxylate. To a solution of tert-butyl 4-[[3-(benzyloxycarbonylamino) cyclobutyl] amino] piperidine-1-carboxylate (320 mg, 793 umol, 1.0 equiv) in THF (4 mL) was added Pd/C (50 mg, 10 % purity) under N2. The mixture was stirred under H2 (15 psi) at 25 °C for 2 h. The mixture was filtered and concentrated to give tert-butyl 4-[(3-aminocyclobutyl) amino] piperidine-1-carboxylate (120 mg, crude). [0567] Step 3: Preparation of tert-butyl 4-[[3-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6- oxo-7H-pteridin-2-yl] amino] -3-methoxy-benzoyl]amino]cyclobutyl]amino]piperidine-1- carboxylate. To a solution of tert-butyl 4-[(3-aminocyclobutyl)amino]piperidine-1-carboxylate (120 mg, 445 umol, 1.0 equiv) and 4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2- yl]amino]-3-methoxy-benzoic acid (189 mg, 445 umol, 1.0 equiv) in DMF (2 mL) was added DIEA (172 mg, 1.34 mmol, 3.0 equiv) and HATU (203 mg, 534 umol, 1.2 equiv). The mixture was stirred at 25 °C for 1 h. The mixture was filtered and concentrated. The residue was purified by prep-HPLC (column: Waters Xbridge C18150*50mm* 10um;mobile phase: [water( NH4HCO3)-ACN];B%: 48%-78%,10min) to give tert-butyl 4-[[3-[[4-[[(7R)-8-cyclopentyl-7- ethyl-5-methyl-6-oxo-7H-pteridin-2-yl] amino] -3-methoxy-benzoyl]amino]cyclobutyl] amino]piperidine-1-carboxylate (180 mg, 59 % yield). [0568] Step 4: Preparation of 4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin- 2-yl]amino]-3-methoxy-N-[3-(4-piperidylamino)cyclobutyl]benz amide. To a solution of tert- butyl 4-[[3-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pte ridin-2-yl]amino]-3-methoxy- benzoyl]amino]cyclobutyl]amino]piperidine-1-carboxylate (120 mg, 177 umol, 1.0 equiv) in DCM (3 mL) was added TFA (1 mL). The mixture was stirred at 25 °C for 1 h and concentrated to give 4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2- yl]amino]-3-methoxy-N-[3-(4- piperidylamino)cyclobutyl]benzamide (120 mg, TFA salt). [0569] Step 5: Preparation of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]-2-[4-[[3-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-meth yl-6-oxo-7H-pteridin-2-yl]amino]- 3-methoxy-benzoyl]amino]cyclobutyl]amino]-1-piperidyl]pyrimi dine-5-carboxamide (I-60). To a solution of 4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2- yl]amino]-3- methoxy-N-[3-(4-piperidylamino)cyclobutyl]benzamide (120 mg, 173 umol, 1.0 equiv, TFA salt) and 2-chloro-N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl -cyclobutyl]pyrimidine-5- carboxamide (72 mg, 173 umol, 1.0 equiv) in NMP (1.5 mL) was added K2CO3 (120 mg, 868 umol, 5.0 equiv). The mixture was stirred at 50 °C for 1 h. The mixture was filtered and concentrated. The residue was purified by prep-HPLC (column: Waters Xbridge C18150*50mm* 10um; mobile phase: [water (NH4HCO3)-ACN]; B%: 60%-90%, 10 min) to give N-[3-(3-chloro-4- cyano-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]-2-[4-[[3-[[4- [[(7R)-8-cyclopentyl-7-ethyl-5- methyl-6-oxo-7H-pteridin-2-yl]amino]-3-methoxy-benzoyl]amino ]cyclobutyl]amino]-1- piperidyl]pyrimidine-5-carboxamide (102 mg, 56 % yield) as a white solid. NMR (400 MHz, DMSO-d6): δ 8.75 (s, 2H), 8.48 - 8.34 (m, 2H), 7.92 - 7.87 (m, 1H), 7.85 (s, 1H), 7.75 - 7.67 (m, 1H), 7.60 (s, 1H), 7.55 - 7.45 (m, 2H), 7.24 - 7.19 (m, 1H), 7.04 - 6.97 (m, 1H), 4.61 - 4.50 (m, 2H), 4.49 - 4.31 (m, 2H), 4.29 (s, 1H), 4.26 - 4.19 (m, 1H), 4.06 - 4.01 (m, 1H), 3.98 - 3.92 (m, 3H), 3.58 - 3.46 (m, 1H), 3.25 (s, 3H), 3.21 - 3.08 (m, 2H), 2.78 - 2.68 (m, 1H), 2.30 - 2.13 (m, 2H), 2.13 - 1.97 (m, 3H), 1.94 - 1.71 (m, 9H), 1.69 - 1.55 (m, 3H), 1.24 - 1.15 (m, 8H), 1.11 (s, 6H), 0.81 - 0.70 (m, 3H). LC-MS: MS (ES ⁺ ): RT = 1.650 min, m/z = 960.6 [M + 1]; LCMS method: 25 EXAMPLE 43 – Synthesis of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]-2-[4-[1-[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl -6-oxo-7H-pteridin-2-yl]amino]- 3-methoxy-benzoyl]azetidin-3-yl]-1-piperidyl]pyrimidine-5-ca rboxamide (I-61) [0570] Step 1: Preparation of tert-butyl 4-[1-[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6- oxo-7H-pteridin-2-yl]amino]-3-methoxy-benzoyl]azetidin-3-yl] piperidine-1-carboxylate. To a solution of 4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2- yl]amino]-3-methoxy- benzoic acid (177 mg, 416 umol, 1.0 equiv) and tert-butyl 4-(azetidin-3-yl)piperidine-1- carboxylate (100 mg, 416 umol, 1.0 equiv) in DMF (1.5 mL) was added DIEA (161 mg, 1 mmol, 3.0 equiv) and HATU (189 mg, 499 umol, 1.2 equiv). The mixture was stirred at 20 °C for 1 h. The mixture was diluted with H2O 20 mL and extracted with EA 60 mL. The combined organic layers were washed with brine, filtered and concentrated. The residue was purified by prep-TLC (SiO2, EA: PE = 10: 1) to afford Compound tert-butyl 4-[1-[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6- oxo-7H-pteridin-2-yl]amino]-3-methoxy-benzoyl]azetidin-3-yl] piperidine-1-carboxylate (171 mg, 63 % yield) as a white solid. [0571] Step 2: Preparation of (7R)-8-cyclopentyl-7-ethyl-2-[2-methoxy-4-[3-(4- piperidyl)azetidine-1-carbonyl]anilino]-5-methyl-7H-pteridin -6-one. To a solution of tert- butyl 4-[1-[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteri din-2-yl]amino]-3-methoxy- benzoyl]azetidin-3-yl]piperidine-1-carboxylate (85 mg, 131 umol, 1.0 equiv) in DCM (2 mL) was added TFA (1 mL). The mixture was stirred at 20 °C for 0.5 h and concentrated to afford crude product. [0572] Step 3: Preparation of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]-2-[4-[1-[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl -6-oxo-7H-pteridin-2-yl]amino]- 3-methoxy-benzoyl]azetidin-3-yl]-1-piperidyl]pyrimidine-5-ca rboxamide (I-61). To a solution of (7R)-8-cyclopentyl-7-ethyl-2-[2-methoxy-4-[3-(4-piperidyl)az etidine-1-carbonyl]anilino]-5- methyl-7H-pteridin-6-one (86 mg, 129 umol, 1.0 equiv, TFA salt) and 2-chloro-N-[3-(3-chloro-4- cyano-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]pyrimidine-5-c arboxamide (54 mg, 129 umol, 1.0 eq) in NMP (1.5 mL) was added K2CO3 (179 mg, 1 mmol, 10.0 eq). The mixture was stirred at 50 °C for 1 h. After filtration, The residue was purified by prep-HPLC (column: Waters Xbridge 150*25mm* 5um;mobile phase: [water( NH ₄ HCO ₃ )-ACN];B %: 68 %-98 %,8 min) to give N-[3- (3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]-2 -[4-[1-[4-[[(7R)-8-cyclopentyl-7- ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-3-methoxy-benzo yl]azetidin-3-yl]-1- piperidyl]pyrimidine-5-carboxamide (50 mg, 39 % yield). ¹ H NMR (400 MHz, METHANOL-d4) δ 8.75 (s, 2 H), 8.49 (d, J=8.4 Hz, 1 H), 7.81 (s, 1 H), 7.74 (d, J=8.8 Hz, 1 H), 7.34 - 7.26 (m, 2 H), 7.15 (d, J=2.4 Hz, 1 H), 7.01 - 6.98 (m, 1 H), 4.64 - 4.48 (m, 3 H), 4.36 - 4.21 (m, 4 H), 4.15 (s, 1 H), 4.05 -3.94 (m, 4 H), 3.35 (s, 3 H), 3.08 – 2.95 (m, 2 H), 2.58 - 2.44 (m, 1 H), 2.23 - 2.11 (m, 1 H), 2.06 – 1.72 (m, 12 H), 1.32 - 1.10 (m, 13 H), 0.88 (t, J=7.6 Hz, 3 H). LC-MS: MS (ES ⁺ ): RT = 2.18 min, m/z = 931.6 [M - H ⁺ ]; LCMS method: 25. EXAMPLE 44 – Synthesis of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]-2-[2-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6 -oxo-7H-pteridin-2-yl]amino]-3- methoxy-benzoyl]amino]-7-azaspiro[3.5]nonan-7-yl]pyrimidine- 5-carboxamide (I-62) [0573] Step 1: Preparation of tert-butyl 2-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo- 7H-pteridin-2-yl]amino]-3-methoxy-benzoyl]amino]-7-azaspiro[ 3.5]nonane-7-carboxylate. To a solution of tert-butyl 2-amino-7-azaspiro[3.5]nonane-7-carboxylate (100 mg, 416 umol, 1.0 equiv) and 4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2- yl]amino]-3-methoxy- benzoic acid (177 mg, 416 umol, 1.0 equiv) in DMF (1.5 mL) was added DIEA (161 mg, 1.25 mmol, 3.0 equiv) and HATU (189 mg, 499 umol, 1.2 equiv). The mixture was stirred at 20 °C for 1 h. The mixture was diluted with H ₂ O (20 mL) and extracted with EA (3 x 20 mL). The combined organic layers were washed with brine, filtered and concentrated. The residue was purified by prep-TLC (SiO2, EA: PE = 10: 1) to afford tert-butyl 2-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl- 6-oxo-7H-pteridin-2-yl]amino]-3-methoxy-benzoyl]amino]-7-aza spiro[3.5]nonane-7-carboxylate (200 mg, 74 % yield) as a white solid. [0574] Step 2: Preparation of N-(7-azaspiro[3.5]nonan-2-yl)-4-[[(7R)-8-cyclopentyl-7- ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-3-methoxy-benza mide. To a solution of tert- butyl 2-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridi n-2-yl]amino]-3-methoxy- benzoyl]amino]-7-azaspiro[3.5]nonane-7-carboxylate (100 mg, 154 umol, 1.0 equiv) in DCM (2 mL) was added TFA (1 mL). The mixture was stirred at 20 °C for 0.5 h and concentrated to afford crude product. [0575] Step 3: Preparation of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]-2-[2-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6 -oxo-7H-pteridin-2-yl]amino]-3- methoxy-benzoyl]amino]-7-azaspiro[3.5]nonan-7-yl]pyrimidine- 5-carboxamide (I-62). To a solution of N-(7-azaspiro[3.5]nonan-2-yl)-4-[[(7R)-8-cyclopentyl-7-ethyl -5-methyl-6-oxo-7H- pteridin-2-yl]amino]-3-methoxy-benzamide (100 mg, 151 umol, 1.0 equiv, TFA salt) and 2-chloro- N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl-cyclobut yl]pyrimidine-5-carboxamide (63 mg, 151 umol, 1.0 eq) in NMP (1.5 mL) was added K ₂ CO ₃ (208 mg, 1 mmol, 10. eq). The mixture was stirred at 50 °C for 1 h. After filtration, The residue was purified by prep-HPLC (column: Waters Xbridge 150*25mm* 5um;mobile phase: [water( NH ₄ HCO ₃ )-ACN]; B %: 70 %- 100 %, 8 min) to afford N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl-cyclobut yl]-2-[2- [[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin- 2-yl]amino]-3-methoxy- benzoyl]amino]-7-azaspiro[3.5]nonan-7-yl]pyrimidine-5-carbox amide (36 mg, 25 % yield). ¹ H NMR (400 MHz, METHANOL-d4) δ 8.73 (s, 2 H), 8.56 - 8.37 (m, 1 H), 7.87 - 7.62 (m, 2 H), 7.60 - 7.31 (m, 2 H), 7.21 - 6.48 (m, 2 H), 4.68 - 4.44 (m, 3 H), 4.32 - 4.22 (m, 2 H), 4.13 (s, 1 H), 4.07 - 3.81 (m, 7 H), 2.51 - 2.34 (m, 2 H), 2.08 - 1.62 (m, 16 H), 1.36 - 1.12 (m, 14 H), 0.93 - 0.77 (m, 3 H). LC-MS: MS (ES ⁺ ): RT = 2.228 min, m/z = 930.6 [M + H ⁺ ]; LCMS method: 25. EXAMPLE 45 – Synthesis of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]-2-[2-[2-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methy l-6-oxo-7H-pteridin-2-yl]amino]- 3-methoxy-benzoyl]amino]ethyl]-1,3,3a,4,6,6a-hexahydropyrrol o[3,4-c]pyrrol-5- yl]pyrimidine-5-carboxamide (I-63) [0576] Step 1: Preparation of tert-butyl 2-(cyanomethyl)-1,3,3a,4,6,6a-hexahydro- pyrrolo[3,4-c]pyrrole-5-carboxylate. To a solution of tert-butyl 2,3,3a,4,6,6a-hexahydro-1H- pyrrolo[3,4-c]pyrrole-5-carboxylate (800 mg, 3.7 mmol, 1.0 equiv) in ACN (8 mL) was added 2- bromoacetonitrile (452 mg, 3.7 mmol, 1.0 equiv) and DIEA (1.4 g, 11.3 mmol, 3.0 equiv). The mixture was stirred at 25 °C for 12 h. The mixture was diluted with H ₂ O(25 mL) and extracted with EtOAc (15 mL *3). The combined organic layers were washed with brine dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=10/1 to 5/1) to give tert-butyl 2-(cyanomethyl)-1,3,3a,4,6,6a- hexahydropyrrolo[3,4-c]pyrrole-5-carboxylate (900 mg, 95 % yield) as a white solid. [0577] Step 2: Preparation of tert-butyl 2-(2-aminoethyl)-1,3,3a,4,6,6a-hexahydro- pyrrolo[3,4-c]pyrrole-5-carboxylate. To a solution of tert-butyl 2-(cyanomethyl)-1,3,3a,4,6,6a- hexahydropyrrolo[3,4-c]pyrrole-5-carboxylate (900 mg, 3.5 mmol, 1.0 equiv) in EtOH (30 mL) was added Raney-Ni (100 mg, 1.1 mmol, 2.3 mL) and NH ₃ ^. H ₂ O (15 mL) under N ₂ atmosphere. The mixture was stirred under H2 (15 Psi ) at 25 °C for 12 h. The mixture was filtered and concentrated. The residue was purification by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate=10/1 to 5/1) to give tert-butyl 2-(2-aminoethyl)-1,3,3a,4,6,6a- hexahydropyrrolo[3,4-c]pyrrole-5-carboxylate (700 mg, 76 % yield). [0578] Step 3: Preparation of tert-butyl 2-[2-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6- oxo-7H-pteridin-2-yl]amino]-3-methoxy-benzoyl]amino]ethyl]-1 ,3,3a,4,6,6a-hexahydro- pyrrolo[3,4-c]pyrrole-5-carboxylate. To a solution of tert-butyl 2-(2-aminoethyl)-1,3,3a,4,6,6a- hexahydropyrrolo[3,4-c]pyrrole-5-carboxylate (200 mg, 783 umol, 1.0 equiv) and 4-[[(7R)-8- cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-3 -methoxy-benzoic acid (366 mg, 861 umol, 1.1 equiv) in DMF (2 mL) was added HATU (446 mg, 1.1 mmol, 1.5 equiv) and DIEA (303 mg, 2.3 mmol, 3.0 equiv) . The mixture was stirred at 25 °C for 0.5 h. The mixture was filtered and concentrated. The residue was purified by prep-HPLC (column: Waters Xbridge 150*25mm* 5um;mobile phase: [water( NH4HCO3)-ACN];B%: 55 %-85 %,10 min) to give tert- butyl 2-[2-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pter idin-2-yl]amino]-3-methoxy- benzoyl]amino]ethyl]-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]py rrole-5-carboxylate (320 mg, 61 % yield). [0579] Step 4: Preparation of N-[2-(2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrol-5- yl)ethyl]-4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-p teridin-2-yl]amino]-3-methoxy- benzamide. To a solution of tert-butyl 2-[2-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H- pteridin-2-yl]amino]-3-methoxy-benzoyl]amino]ethyl]-1,3,3a,4 ,6,6a-hexahydropyrrolo[3,4- c]pyrrole-5-carboxylate (100 mg, 150 umol, 1.0 equiv) in DCM (3 mL) was added TFA (1 mL). The mixture was stirred at 25 °C for 1 h. The mixture was filtered and concentrated under reduced pressure to give a residue. The residue was used into the next step without further purification. [0580] Step 5: Preparation of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]-2-[2-[2-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methy l-6-oxo-7H-pteridin-2-yl] amino]- 3-methoxy-benzoyl]amino]ethyl]-1,3,3a,4,6,6a-hexahydropyrrol o[3,4-c]pyrrol-5- yl]pyrimidine-5-carboxamide (I-63). To a solution of N-[2-(2,3,3a,4,6,6a-hexahydro-1H- pyrrolo[3,4-c]pyrrol-5-yl)ethyl]-4-[[(7R)-8-cyclopentyl-7-et hyl-5-methyl-6-oxo-7H-pteridin-2- yl]amino]-3-methoxy-benzamide (100 mg, 147 umol, 1.0 equiv, TFA salt) in NMP (1 mL) was added K ₂ CO ₃ (61 mg, 443 umol, 3.0 equiv) and 2-chloro-N-[3-(3-chloro-4-cyano-phenoxy)- 2,2,4,4-tetramethyl-cyclobutyl]pyrimidine-5-carboxamide (61 mg, 147 umol, 1.0 equiv). The mixture was stirred at 50 °C for 2 h. The mixture was filtered and concentrated. The residue was purified by prep-HPLC (column: Waters Xbridge 150*25mm* 5um;mobile phase: [water( NH4HCO3)-ACN];B%: 58%-88%,8min) to give N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4- tetramethyl-cyclobutyl]-2-[2-[2-[[4-[[(7R)-8-cyclopentyl-7-e thyl-5-methyl-6-oxo-7H-pteridin-2- yl]amino]-3-methoxy-benzoyl]amino]ethyl]-1,3,3a,4,6,6a-hexah ydropyrrolo[3,4-c]pyrrol-5- yl]pyrimidine-5-carboxamide (97 mg, 67 % yield). ¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.74 (s, 2H), 8.52 (d, J = 8.3 Hz, 1H), 7.73 (s, 1H), 7.60-7.54 (m, 2H), 7.43 (d, J = 1.6 Hz, 1H), 7.26-7.21 (m, 1H), 6.96 (d, J = 2.4 Hz, 1H), 6.85-6.76 (m, 1H), 6.73-6.58 (m, 1H), 6.01-5.85 (m, 1H), 4.60-4.41 (m, 1H), 4.25-4.16 (m, 1H), 4.10 (d, J = 8.3 Hz, 1H), 4.03 (s, 1H), 3.95 (s, 3H), 3.92-3.87 (m, 2H), 3.70-3.61 (m, 2H), 3.60-3.52 (m, 2H), 3.35 (s, 3H), 3.10-2.97 (m, 2H), 2.87- 2.77 (m, 2H), 2.76-2.71 (m, 2H), 2.70-2.64 (m, 2H), 2.20-2.07 (m, 1H), 2.03-1.92 (m, 1H), 1.89- 1.77 (m, 4H), 1.75-1.66 (m, 4H), 1.23-1.16 (m, 12H), 0.88 (t, J = 7.4 Hz, 3H). LC-MS: MS (ES ⁺ ): RT = 1.664 min, m/z = 946.4 [M + H] ⁺ ：LCMS Method: 25.

EXAMPLE 46 – Synthesis of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]-2-[4-[[3-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-meth yl-6-oxo-7H-pteridin-2-yl]amino]- 3-methoxy-benzoyl]amino]cyclobutyl]-cyclopropyl-amino]-1-pip eridyl]pyrimidine-5- carboxamide (I-64) [0581] Step 1: Preparation of tert-butyl 4-[[3-(benzyloxycarbonylamino)cyclobutyl]- cyclopropyl-amino]piperidine-1-carboxylate. To a solution of benzyl N-(3-oxocyclobutyl) carbamate (251 mg, 1.14 mmol, 1.1 equiv) in DCM (15 mL) and DMF (3 mL) was added TEA (316 mg, 3.12 mmol, 3.0 equiv) , tert-butyl 4-(cyclopropylamino)piperidine-1-carboxylate (250 mg, 1.04 mmol, 1.0 equiv) and NaBH(OAc) ₃ (331 mg, 1.56 mmol, 1.5 equiv). The mixture was stirred at 25 °C for 12 h. The mixture was diluted with water (10 mL) and extracted with DCM (20 mL*3). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by prep-HPLC (column: Waters Xbridge 150*25 mm* 5 um; mobile phase: [water (NH4HCO3)-ACN]; B%: 45%-75%, 10 min) to give tert- butyl 4-[[3-(benzyloxycarbonylamino)cyclobutyl]-cyclopropyl-amino] piperidine-1-carboxylate (40 mg, 9% yield) as a brown oil. [0582] Step 2: Preparation of tert-butyl 4-[(3-aminocyclobutyl)-cyclopropyl- amino]piperidine-1-carboxylate. To a solution of tert-butyl 4-[[3-(benzyloxycarbonylamino) cyclobutyl]-cyclopropyl-amino]piperidine-1-carboxylate (40 mg, 90 umol, 1.0 equiv) in THF (1 mL) was added Pd/C (20 mg, 10% purity) under N2. The mixture was stirred under H2 (15 psi) at 25 °C for 1 h. The mixture was filtered and concentrated to give tert-butyl 4-[(3-amino- cyclobutyl)-cyclopropyl-amino]piperidine-1-carboxylate (25 mg, 90% yield) as a yellow oil. [0583] Step 3: Preparation of tert-butyl 4-[[3-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6- oxo-7H-pteridin-2-yl]amino]-3-methoxybenzoyl]amino]cyclobuty l]-cyclopropyl- amino]piperidine-1-carboxylate. To a solution of tert-butyl 4-[(3-aminocyclobutyl)-cyclopropyl- amino]piperidine-1-carboxylate (25 mg, 81 umol, 1.0 equiv) in DMF (1 mL) was added HATU (37 mg, 97 umol, 1.2 equiv), 4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7Hpteridin-2-y l]amino]- 3-methoxy-benzoic acid (34 mg, 81 umol, 1.0 equiv) and DIEA (31 mg, 24 umol, 3.0 equiv). The mixture was stirred at 25 °C for 1 h and concentrated. The residue was purified by prep-HPLC (column: Waters Xbridge C ₁₈ 150*50 mm* 10 um; mobile phase: [water (NH ₄ HCO ₃ )-ACN]; B%: 52%-82%, 10 min) to give tert-butyl 4-[[3-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H- pteridin-2-yl]amino]-3-methoxybenzoyl]amino]cyclobutyl]-cycl opropyl-amino]piperidine-1- carboxylate (20 mg, 35% yield) as a white solid. [0584] Step 4: Preparation of 4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin- 2-yl]amino]-N-[3-[cyclopropyl(4-piperidyl)amino]cyclobutyl]- 3-methoxy-benzamide. To a solution of tert-butyl 4-[[3-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pte ridin-2- yl]amino]-3-methoxybenzoyl]amino]cyclobutyl]-cyclopropyl-ami no]piperidine-1-carboxylate (20 mg, 28 umol, 1.0 equiv) in DCM (1 mL) was added TFA (0.2 mL). The mixture was stirred at 25 °C for 1 h. The mixture was concentrated to give 4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo- 7H-pteridin-2-yl]amino]-N-[3-[cyclopropyl(4-piperidyl)amino] cyclobutyl] -3-methoxy-benzamide (20 mg, 98% yield, TFA salt) as a yellow oil. [0585] Step 5: Preparation of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]-2-[4-[[3-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-meth yl-6-oxo-7H-pteridin-2-yl]amino]- 3-methoxy-benzoyl]amino]cyclobutyl]-cyclopropyl-amino]-1-pip eridyl] pyrimidine-5- carboxamide (I-64). To a solution of 2-chloro-N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4- tetramethyl-cyclobutyl]pyrimidine-5-carboxamide (11 mg, 27 umol, 1.0 equiv) in NMP (1 mL) was added K2CO3 (19 mg, 137 umol, 5.0 equiv) and 4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6- oxo-7H-pteridin-2-yl]amino]-N-[3-[cyclopropyl(4-piperidyl)am ino] cyclobutyl]-3-methoxy- benzamide (20 mg, 27 umol, 1.0 equiv, TFA salt). The mixture was stirred at 50 °C for 2 h and concentrated. The residue was purified by prep-HPLC (column: Unisil 3-100 C18 Ultra 150*50mm*3 um; mobile phase: [water (FA)-ACN]; B%: 25%-55%, 7 min) to give N-[3-(3- chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]-2-[4 -[[3-[[4-[[(7R)-8-cyclopentyl-7- ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-3-methoxy-benzo yl] amino]cyclobutyl]- cyclopropyl-amino]-1-piperidyl]pyrimidine-5-carboxamide(16 mg, 58% yield, 98% purity) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.86-8.70 (m, 2H), 8.60-8.31 (m, 2H), 7.93-7.81 (m, 2H), 7.77-7.69 (m, 1H), 7.63 (d, J = 4.0 Hz, 1H), 7.54-7.43 (m, 2H), 7.21 (d, J = 2.0 Hz, 1H), 7.01 (m, J = 2.0, 8.8 Hz, 1H), 4.99-4.80 (m, 2H), 4.38-4.22 (m, 3H), 4.04 (d, J = 9.2 Hz, 2H), 3.94 (s, 3H), 3.25 (s, 4H), 2.96-2.86 (m, 2H), 2.80-2.61 (m, 4H), 2.16-1.97 (m, 4H), 1.95-1.85 (m, 3H), 1.78 (d, J = 2.0 Hz, 6H), 1.68-1.53 (m, 5H), 1.22 (s, 6H), 1.11 (s, 6H), 0.76 (t, J = 7.2 Hz, 3H), 0.46-0.31 (m, 2H). LC-MS: MS (ES ⁺ ): RT = 1.719 min, m/z = 1001.7 [M + H ⁺ ]; LCMS method: 25. EXAMPLE 47 – Synthesis of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]-2-[4-[3-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methy l-6-oxo-7H-pteridin-2-yl]amino]- 3-methoxy-benzoyl]amino]cyclobutoxy]-1-piperidyl]pyrimidine- 5-carboxamide (I-65)

[0586] Step 1: Preparation of 2-trimethylsilylethyl 4-[3-(tert-butoxycarbonylamino) cyclobutoxy] piperidine-1-carboxylate. To a solution of tert-butyl N-[3-(4-piperidyloxy) cyclobutyl] carbamate (2.5 g, 9.2 mmol, 1.0 equiv) in THF (25 mL) was added Et ₃ N (2.8 g, 27.7 mmol, 3.9 mL, 3.0 equiv) and (2, 5-dioxopyrrolidin-1-yl) 2-trimethylsilylethyl carbonate (4.8 g, 18.5 mmol, 2.0 equiv). The mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated to afford crude product. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate=3/1 to 1/1) to give compound 2-trimethylsilylethyl 4-[3-(tert- butoxycarbonylamino) cyclobutoxy] piperidine-1-carboxylate (3 g, 78 % yield) as a colorless oil.

[0587] Step 2: Preparation of 2-trimethylsilylethyl 4-(3-aminocyclobutoxy) piperidine-1- carboxylate. To a solution of 2-trimethylsilylethyl 4-[3-(tert-butoxycarbonylamino)cyclo- butoxy]piperidine-1-carboxylate (1.5 g, 3.6 mmol, 1.0 equiv) in MeOH (10 mL) was added TsOH.H ₂ O (1.4 g, 7.2 mmol, 2.0 equiv) at 0 °C. The mixture was stirred at 50 °C for 2 h. The residue was purified by prep-HPLC (column: Waters Xbridge 150*25mm*5um; mobile phase: [water (NH4HCO3)-ACN]; B%: 25%-55%, 10 min) to give compound 2-trimethylsilylethyl 4-(3- aminocyclobutoxy) piperidine-1-carboxylate (0.7 g, 62 % yield) as a colorless oil. [0588] Step 3: Preparation of 2-trimethylsilylethyl 4-[3-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5- methyl-6-oxo-7H-pteridin-2-yl]amino]-3-methoxy benzoyl]amino] cyclobutoxy] piperidine-1- carboxylate. To a solution of 4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2- yl]amino]-3-methoxy-benzoic acid (150 mg, 353 umol, 1.0 equiv), 2-trimethylsilyl-ethyl 4-(3- aminocyclobutoxy)piperidine-1-carboxylate (166 mg, 529 umol, 1.5 equiv) in DMF (1 mL) was added DIEA (136 mg, 1.0 mmol, 3.0 equiv) and HATU (201 mg, 528 umol, 1.5 equiv). The mixture was stirred at 25 °C for 12 h. The residue was purified by prep-HPLC (column: Waters Xbridge C18150*50mm*10um; mobile phase: [water (NH ₄ HCO ₃ )-ACN]; B%: 60%-90%, 10 min) to give compound 2-trimethylsilylethyl 4-[3-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6- oxo-7H-pteridin-2-yl]amino]-3-methoxy benzoyl]amino] cyclobutoxy]piperidine-1-carboxylate (150 mg, 59 % yield) as a white solid. [0589] Step 4: Preparation of 4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin- 2-yl]amino]-3-methoxy-N-[3-(4-piperidyloxy)cyclobutyl]benzam ide. To a solution of 2- trimethylsilylethyl 4-[3-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pter idin-2-yl]amino]- 3-methoxy-benzoyl]amino]cyclobutoxy]piperidine-1-carboxylate (150 mg, 208 umol, 1.0 equiv) in DCM (1 mL) was added TFA (0.5 mL). The mixture was stirred at 25 °C for 3 h. The reaction mixture was concentrated under reduced pressure to remove solvent. Compound 4-[[(7R)-8- cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-3 -methoxy-N-[3-(4- piperidyloxy)cyclobutyl]benzamide (140 mg, 97 % yield, TFA salt) was obtained as a yellow oil. [0590] Step 5: Preparation of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]-2-[4-[3-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methy l-6-oxo-7H-pteridin-2-yl]amino]- 3-methoxy-benzoyl]amino]cyclobutoxy]-1-piperidyl]pyrimidine- 5-carboxamide (I-65). To a solution of 4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2- yl]amino]-3-methoxy-N- [3-(4-piperidyloxy)cyclobutyl]benzamide (143 mg, 207 umol, 1.0 equiv, TFA salt), 2-chloro-N-[3- (3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl] pyrimidine-5-carboxamide (87 mg, 0.21 mmol, 1.0 equiv) in NMP (2 mL) was added K ₂ CO ₃ (86 mg,0.62 mmol, 3.0 equiv). The mixture was stirred at 50 °C for 12 h. The residue was purified by prep-HPLC (column: Waters Xbridge C18150*50mm*10um; mobile phase: [water (NH ₄ HCO ₃ )-ACN]; B%: 64%-94%, 8min) to give compound N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl-cyclobut yl]-2-[4-[3-[[4- [[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl ]amino]-3-methoxy- benzoyl]amino]cyclobutoxy]-1-piperidyl]pyrimidine-5-carboxam ide (114 mg, 57 % yield, 100% purity) as an off-white solid. ¹ H NMR (400 MHz, CD ₃ OD): δ 8.73 (s, 2 H), 8.44 - 8.53 (m, 1 H) 7.76 - 7.79 (m, 1 H) 7.69 - 7.75 (m, 1 H), 7.43 - 7.55 (m, 2 H), 7.12 (d, J = 2.38 Hz, 1 H), 6.90 - 7.03 (m, 1 H), 4.48 - 4.63 (m, 2 H), 4.36 - 4.45 (m, 2 H), 4.22 - 4.31 (m, 2 H), 4.07 - 4.17 (m, 1 H), 3.92 - 4.04 (m, 3 H), 3.60 - 3.78 (m, 1 H) 3.43 - 3.57 (m, 2 H), 3.33 (s, 3 H), 2.72 - 2.82 (m, 1 H), 2.36 - 2.53 (m, 3 H), 1.85 - 2.22 (m, 9 H), 1.68 - 1.80 (m, 3 H), 1.45 - 1.58 (m, 2 H), 1.40 (s, 1 H), 1.28 (s, 6 H), 1.21 (s, 6 H), 0.81 - 0.93 (m, 3 H). LC-MS: MS (ES ⁺ ): RT = 2.646 min, m/z =960.3 [M + H ⁺ ]; LCMS method: 25. EXAMPLE 48 – Synthesis of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]-2-[4-[2-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methy l-6,7-dihydropteridin-2- yl]amino]-3-methoxy-benzoyl]amino]ethoxy]-1-piperidyl]pyrimi dine-5-carboxamide (I-66)

[0591] Step 1: Preparation of methyl 4-[(8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H- pteridin-2-yl)amino]-3-methoxy-benzoate. To a solution of 4-[(8-cyclopentyl-7-ethyl-5-methyl- 6-oxo-7H-pteridin-2-yl)amino]-3-methoxy-benzoic acid (2.0 g, 4.7 mmol, 1.0 equiv), H2SO4 (461 mg, 4.7 mmol, 250 uL, 1.0 equiv) in MeOH (20 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80 °C for 24 h under N ₂ atmosphere. The reaction mixture was filtered and concentrated under reduced pressure. The residue was diluted with H ₂ O (10 mL) and extracted with EA (10 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate = 50/1 to 10/1) to give methyl 4-[(8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl)am ino]-3-methoxy- benzoate (2.0 g, 4.5 mmol, 96% yield) as a yellow solid.

[0592] Step 2: Preparation of methyl 4-[(8-cyclopentyl-7-ethyl-5-methyl-6,7- dihydropteridin-2-yl)amino]-3-methoxy-benzoate. To a solution of methyl 4-[(8-cyclopentyl-7- ethyl-5-methyl-6-oxo-7H-pteridin-2-yl)amino]-3-methoxy-benzo ate (1.0 g, 2.2 mmol, 1.0 equiv), BH ₃ ·THF (1 M, 22.7 mL, 10.0 equiv) in THF (10 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 25 °C for 12 h under N2 atmosphere. The reaction was quenched with methanol (20 mL) and concentrated. The residue was diluted with H2O (10 mL) and extracted with EA (10 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, DCM/ MeOH = 50/1 to 20/1) to give methyl 4-[(8- cyclopentyl-7-ethyl-5-methyl-6,7-dihydropteridin-2-yl)amino] -3-methoxy-benzoate (475 mg, 1.1 mmol, 49% yield) as a yellow oil. [0593] Step 3: Preparation of 4-[(8-cyclopentyl-7-ethyl-5-methyl-6,7-dihydropteridin-2- yl)amino]-3-methoxy-benzoic acid. A solution of methyl 4-[(8-cyclopentyl-7-ethyl-5-methyl- 6,7-dihydropteridin-2-yl)amino]-3-methoxy-benzoate (475 mg, 1.1 mmol, 1.0 equiv), LiOH·H2O (234 mg, 5.5 mmol, 5.0 equiv) in THF (6.0 mL), H ₂ O (3.0 mL), MeOH (6.0 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 25 °C for 12 h under N2 atmosphere. The reaction mixture was adjusted pH to 5 with HCl (1N). Then the reaction mixture was concentrated under reduced pressure to remove organic solvent. Then the mixture was filtered and the filter cake was dried to give 4-[(8-cyclopentyl-7-ethyl-5-methyl-6,7-dihydropteridin-2- yl)amino]-3-methoxy-benzoic acid (266 mg, 646 umol, 57% yield) as a white solid. [0594] Step 4: Preparation of tert-butyl 4-[4-[4-[(8-cyclopentyl-7-ethyl-5-methyl-6,7- dihydropteridin-2-yl)amino]-3-methoxy-phenyl]-4-oxo-butoxy]p iperidine-1-carboxylate. To a solution of 4-[(8-cyclopentyl-7-ethyl-5-methyl-6,7-dihydropteridin-2-yl) amino]-3-methoxy- benzoic acid (150 mg, 364 umol, 1.0 equiv), tert-butyl 4-(2-aminoethoxy)piperidine-1-carboxylate (106 mg, 437 umol, 1.2 equiv), HATU (207 mg, 546 umol, 1.5 equiv), DIEA (141 mg, 1.0 mmol, 190 uL, 3.0 equiv) in DMF (2 mL) was degassed and purged with N ₂ for 3 times, and then the mixture was stirred at 25 °C for 12 h under N2 atmosphere. The residue was diluted with H2O (10 mL) and extracted with EA (10 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO ₂ , DCM/MeOH = 10/1) to give tert-butyl 4-[4-[4-[(8- cyclopentyl-7-ethyl-5-methyl-6,7-dihydropteridin-2-yl)amino] -3-methoxy-phenyl]-4-oxo- butoxy]piperidine-1-carboxylate (215 mg, 337 umol, 92% yield) as a yellow oil. [0595] Step 5: Preparation of 4-[(8-cyclopentyl-7-ethyl-5-methyl-6,7-dihydropteridin-2- yl)amino]-3-methoxy-N-[2-(4-piperidyloxy)ethyl]benzamide. A solution of tert-butyl 4-[4-[4- [(8-cyclopentyl-7-ethyl-5-methyl-6,7-dihydropteridin-2-yl)am ino]-3-methoxy-phenyl]-4-oxo- butoxy]piperidine-1-carboxylate (215 mg, 337 umol, 1.0 equiv) in DCM (3.0 mL), TFA (1.0 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 25 °C for 1 h under N2 atmosphere. The reaction mixture was concentrated to afford crude product. The residue 4-[(8-cyclopentyl-7-ethyl-5-methyl-6,7-dihydropteridin-2-yl) amino]-3-methoxy-N-[2-(4- piperidyloxy)ethyl]benzamide (181 mg, 336 umol) as a yellow oil was used for next step without further purification. [0596] Step 6: Preparation of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]-2-[4-[2-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methy l-6,7-dihydropteridin-2- yl]amino]-3-methoxy-benzoyl]amino]ethoxy]-1-piperidyl]pyrimi dine-5-carboxamide (I-66). To a solution of 4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6,7-dihydropteridin- 2-yl]amino]-3- methoxy-N-[2-(4-piperidyloxy)ethyl]benzamide (160 mg, 297 umol, 1.0 equiv), 2-chloro-N-[3-(3- chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]pyrim idine-5-carboxamide (149 mg, 357 umol, 1.2 equiv), K ₂ CO ₃ (82 mg, 595 umol, 2.0 equiv) in NMP (3 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 60 °C for 12 h under N2 atmosphere. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex luna C18150*25mm* 10um;mobile phase: [water(FA)- ACN];B%: 38%-68%,8min) to give N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]-2-[4-[2-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methy l-6,7-dihydropteridin-2-yl]amino]-3- methoxy-benzoyl]amino]ethoxy]-1-piperidyl]pyrimidine-5-carbo xamide (45 mg, 48 umol, 16% yield, 98% purity) as a yellow solid. ¹ H NMR:(400 MHz, MeOD) δ = 8.72 (s, 2H), 8.36 (d, J = 8.4 Hz, 1H), 7.72 (d, J = 8.8 Hz, 1H), 7.52 - 7.41 (m, 2H), 7.23 - 7.07 (m, 2H), 7.00 - 6.93 (m, 1H), 4.59 (s, 1H), 4.33 - 4.21 (m, 3H), 4.12 (s, 1H), 3.98 (s, 3H), 3.75 - 3.67 (m, 3H), 3.66 - 3.52 (m, 5H), 3.25 - 3.17 (m, 1H), 2.81 (s, 3H), 2.78 - 2.73 (m, 1H), 2.13 - 2.04 (m, 1H), 1.99 - 1.89 (m, 3H), 1.84 - 1.53 (m, 10H), 1.27 (s, 6H), 1.21 (s, 6H), 1.02 - 0.92 (m, 3H). LC-MS: MS (ES ⁺ ): RT = 2.886 min, m/z = 920.7 [M + H ⁺ ]. EXAMPLE 49 – Synthesis of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]-2-[4-[2-[[4-[(8-cyclopentyl-7-ethyl-5-methyl-6-o xo-7H-pteridin-2-yl)-methyl- amino]-3-methoxy-benzoyl]amino]ethoxy]-1-piperidyl]pyrimidin e-5-carboxamide (I-67) [0597] Step 1: Preparation of methyl 4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H- pteridin-2-yl]-methyl-amino]-3-methoxy-benzoate. To a solution of 4-[[(7R)-8-cyclopentyl-7- ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-3-methoxy-benzo ic acid (1.0 g, 2.4 mmol, 1.0 equiv) in DMF (20 mL) stirred was added NaH (207 mg, 5.2 mmol, 60% purity, 2.2 equiv) and then stirred at 0 °C for 0.5 h. Then CH3I (734 mg, 5.2 mmol, 322 uL, 2.2 equiv) was added to the mixture. The mixture was stirred at 25 °C for 12 h to give a colorless solution. The reaction mixture was quenched by saturated NH ₄ Cl (50 mL) at 0 °C, and then diluted with H ₂ O (50 mL x 2), extracted with DCM (75 mL x 2). The combined organic layers were washed with H2O (50 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The oil was used for next step directly without further purification. The methyl 4-[[(7R)-8-cyclopentyl-7- ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]-methyl-amino]-3-metho xy-benzoate (1.0 g, 2.2 mmol, 94% yield) was obtained as a yellow oil. [0598] Step 2: Preparation of 4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin- 2-yl]-methyl-amino]-3-methoxy-benzoic acid. To a solution of methyl 4-[[(7R)-8-cyclopentyl-7- ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]-methyl-amino]-3-metho xy-benzoate (1.0 g, 2.2 mmol, 1.0 equiv) in THF (10 mL) and H ₂ O (10 mL) was added LiOH.H ₂ O (278 mg, 6.6 mmol, 3.0 equiv) at 0 °C. The mixture was stirred at 25 °C for 12 h. The reaction mixture was added HCl to adjust pH to 3-4. The solution was extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with saturated brine (20 mL), dried over Na ₂ SO _4, filtered and concentrated under reduced pressure to give a residue. The crude product was triturated with petroleum ether and ethyl acetate (petroleum ether : ethyl acetate = 5:1) at 25 °C for 30 min to give the 4-[[(7R)-8-cyclopentyl-7- ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]-methyl-amino]-3-metho xy-benzoic acid (400 mg, 910 umol, 41% yield) as a yellow solid. [0599] Step 3: Preparation of tert-butyl 4-[2-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6- oxo-7H-pteridin-2-yl]-methyl-amino]-3-methoxy-benzoyl]amino] ethoxy]piperidine-1- carboxylate. To a solution of 4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2- yl]- methyl-amino]-3-methoxy-benzoic acid (120 mg, 273 umol, 1.0 equiv), tert-butyl 4-(2- aminoethoxy)piperidine-1-carboxylate (80 mg, 328 umol, 1.2 equiv) in DMF (3 mL) was added HATU (155 mg, 409 umol, 1.5 equiv) and DIEA (106mg, 819 umol, 143uL, 3.0 equiv). The mixture was stirred at 25 °C for 12 h. The residue was filtered and concentrated to give the residue. The residue was purified by prep-TLC (SiO ₂ , DCM: MeOH = 20:1) to give the tert-butyl 4-[2-[[4- [[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl ]-methyl-amino]-3-methoxy- benzoyl]amino]ethoxy]piperidine-1-carboxylate (90 mg, 135umol, 50% yield) as a yellow oil. [0600] Step 4: Preparation of 4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin- 2-yl]-methyl-amino]-3-methoxy-N-[2-(4-piperidyloxy)ethyl]ben zamide. A mixture of tert-butyl 4-[2-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pter idin-2-yl]-methyl-amino]-3- methoxy-benzoyl]amino]ethoxy]piperidine-1-carboxylate (80 mg, 120 umol, 1.0 equiv), TFA (0.5 mL) in DCM (3 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 25 °C for 0.5 h under N ₂ atmosphere. The mixture was filtered and concentrated to give the residue. The oil was used into the next step directly without further purification. The 4-[[(7R)- 8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]-methy l-amino]-3-methoxy-N-[2-(4- piperidyloxy)ethyl]benzamide (65 mg, 115 umol, 96% yield) was obtained as a yellow oil. [0601] Step 5: Preparation of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]-2-[4-[2-[[4-[(8-cyclopentyl-7-ethyl-5-methyl-6-o xo-7H-pteridin-2-yl)-methyl- amino]-3-methoxy-benzoyl]amino]ethoxy]-1-piperidyl]pyrimidin e-5-carboxamide (I-67). A mixture of 4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2- yl]-methyl-amino]-3- methoxy-N-[2-(4-piperidyloxy)ethyl]benzamide (45 mg, 79 umol, 1.0 equiv), 2-chloro-N-[3-(3- chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]pyrim idine-5-carboxamide (40 mg, 95 umol, 1.2 equiv), K2CO3 (33 mg, 239 umol, 3.0 equiv) in NMP (2 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 60 °C for 2 h under N2 atmosphere. The residue was filtered and concentrated to give the residue. The crude product was purified by reversed-phase HPLC (column: Phenomenex luna C18150*25mm* 10um;mobile phase: [water (FA)-ACN];B%: 35%-65%,8min) to get the N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4- tetramethyl-cyclobutyl]-2-[4-[2-[[4-[(8-cyclopentyl-7-ethyl- 5-methyl-6-oxo-7H-pteridin-2-yl)- methyl-amino]-3-methoxy-benzoyl]amino]ethoxy]-1-piperidyl]py rimidine-5-carboxamide (56 mg, 56 umol, 71% yield, 96% purity) was obtained as an off-white solid. ¹ H NMR: (400 MHz, MeOD) δ = 8.72 (s, 2H), 7.72 (d, J = 8.8 Hz, 1H), 7.58 - 7.55 (m, 2H), 7.51 - 7.46 (m, 1H), 7.31 - 7.27 (m, 1H), 7.14 - 7.10 (m, 1H), 7.00 - 6.95 (m, 1H), 4.61 - 4.56 (m, 1H), 4.32 - 4.23 (m, 3H), 4.18 - 4.11 (m, 2H), 3.81 (s, 3H), 3.76 - 3.58 (m, 8H), 3.50 - 3.40 (m, 1H), 2.84 - 2.81 (m, 1H), 2.42 - 2.00 (m, 1H), 1.98 - 1.49 (m, 11H), 1.38 - 1.12 (m, 18H), 0.82 - 0.76 (m, 3H). LC-MS: MS (ES ⁺ ): RT = 2.681 min, m/z = 948.7 [M +H ⁺ ]. EXAMPLE 50 – Synthesis of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]-2-[2-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6 -oxo-7H-pteridin-2-yl]amino]-3- methoxy-benzoyl]-methyl-amino]-7-azaspiro[3.5]nonan-7-yl]pyr imidine-5-carboxamide (I- 68) [0602] Step 1: Preparation of tert-butyl 2-(methylamino)-7-azaspiro[3.5]nonane-7- carboxylate. To a solution of tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (500 mg, 2.09 mmol, 1 equiv) and methanamine (2 M, 5.22 mL, 5 equiv) in CH ₂ Cl ₂ (6 mL) was added AcOH (12.6 mg, 0.21 mmol, 0.1 equiv) at 20 °C. The mixture was stirred at 20 °C for 1 h. Then to the mixture was added NaBH(OAc)3 (1.33 g, 6.27 mmol, 3 equiv) at 20 °C. The resulting mixture was stirred at 20 °C for 12 h. The reaction mixture was quenched by addition saturated NH4Cl solution (15 mL), and then extracted with CH ₂ Cl ₂ (8 mL*3). The combined water layers were concentrated in vacuo. The crude product was purified by prep-HPLC (column: Phenomenex luna C18 150*40mm* 15um;mobile phase: [water(FA)-ACN];gradient:5%-35% B over 15 min) to afford tert-butyl 2-(methylamino)-7-azaspiro[3.5]nonane-7-carboxylate (260 mg, 1.02 mmol, 49% yield) as a colorless solid. [0603] Step 2: Preparation of tert-butyl 2-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo- 7H-pteridin-2-yl]amino]-3-methoxy-benzoyl]-methyl-amino]-7-a zaspiro[3.5]nonane-7- carboxylate. To a solution of tert-butyl 2-(methylamino)-7-azaspiro[3.5]nonane-7-carboxylate (60.0 mg, 0.24 mmol, 1 equiv) in DMF (2 mL) was added HOBt (47.8 mg, 0.35 mmol, 1.5 equiv), EDCl (67.8 mg, 0.35 mmol, 1.5 equiv), DIEA (91.5 mg, 0.71 mmol, 3 equiv) and 4-[[(7R)-8- cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-3 -methoxy-benzoic acid (100 mg, 0.24 mmol, 1 equiv) at 20 °C. The mixture was stirred at 20 °C for 1 h. The reaction mixture was diluted with H ₂ O (10 mL) and extracted with ethyl acetate (5 mL*3). The combined organic phase was washed with brine (5 mL*5), dried with anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by prep-TLC on silica gel (Dichloromethane/Methanol = 10/1) to afford tert-butyl 2-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridi n-2-yl]amino]-3- methoxy-benzoyl]-methyl-amino]-7-azaspiro[3.5]nonane-7-carbo xylate (104 mg, 0.16 mmol, 67% yield) as a colorless oil. [0604] Step 3: Preparation of N-(7-azaspiro[3.5]nonan-2-yl)-4-[[(7R)-8-cyclopentyl-7- ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-3-methoxy-N-met hyl-benzamide. To a solution of tert-butyl 2-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridi n-2-yl]amino]-3- methoxy-benzoyl]-methyl-amino]-7-azaspiro[3.5]nonane-7-carbo xylate (90.0 mg, 0.14 mmol, 1 equiv) in CH ₂ Cl ₂ (2 mL) was added TFA (1 mL) at 20 °C. The mixture was stirred at 20 °C for 1 h. The mixture was concentrated in vacuo to afford N-(7-azaspiro[3.5]nonan-2-yl)-4-[[(7R)-8- cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-3 -methoxy-N-methyl-benzamide (91.8 mg, crude, TFA salt) as a yellow solid. [0605] Step 4: Preparation of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]-2-[2-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6 -oxo-7H-pteridin-2-yl]amino]-3- methoxy-benzoyl]-methyl-amino]-7-azaspiro[3.5]nonan-7-yl]pyr imidine-5-carboxamide (I- 68). To a solution of N-(7-azaspiro[3.5]nonan-2-yl)-4-[[(7R)-8-cyclopentyl-7-ethyl -5-methyl-6- oxo-7H-pteridin-2-yl]amino]-3-methoxy-N-methyl-benzamide (81.0 mg, 0.12 mmol, 1 equiv, TFA salt) in DMF (1 mL) was added DIEA (55.9 mg, 0.43 mmol, 3.61 equiv) and 2-chloro-N-[3-(3- chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]pyrim idine-5-carboxamide (60.5 mg, 0.14 mmol, 1.20 equiv). The mixture was stirred at 50 °C for 1 h. The reaction mixture was diluted with H2O (10 mL) and extracted with ethyl acetate (5 mL*3). The combined organic layers were washed with brine (5 mL*5), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was purified by prep-HPLC (column: Phenomenex luna C18 150*25mm* 10um;mobile phase: [water(FA)-ACN];gradient:59%-80% B over 7 min) to afford N- [3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl ]-2-[2-[[4-[[(7R)-8-cyclopentyl-7- ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-3-methoxy-benzo yl]-methyl-amino]-7- azaspiro[3.5]nonan-7-yl]pyrimidine-5-carboxamide (25.7 mg, 0.03 mmol, 20% yield for 2 steps, 99% purity) as a white solid. ¹ H NMR (400 MHz, MeOH-d ₄ ): δ 8.71 (s, 1H), 8.26 (d, 1H, J = 8.2 Hz), 7.77-7.68 (m, 3H), 7.15-7.06 (m, 2H), 7.05-6.94 (m, 2H), 4.83-4.76 (m, 1H), 4.48-4.40 (m, 1H), 4.35 (dd, 1H, J = 8.0, 4.0 Hz), 4.26 (s, 1H), 4.15-4.11 (m, 1H), 3.97 (s, 3H), 3.91-3.79 (m, 4H), 3.33 (s, 3H), 3.09 (s, 3H), 2.26-2.08 (m, 5H), 2.04 – 1.88 (m, 4H), 1.88-1.74 (m, 4H), 1.74- 1.62 (m, 5H), 1.27 (s, 6H), 1.21 (s, 6H), 0.87 (t, 3H, J = 8.0 Hz). LC-MS: MS (ES ⁺ ): RT = 2.247 min, m/z = 944.6 [M + H ⁺ ]; LCMS Method: 25. EXAMPLE 51 – Synthesis of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]-2-[3-[[3-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-meth yl-6-oxo-7H-pteridin-2-yl]amino]- 3-methoxy-benzoyl]-methyl-amino]cyclobutyl]methyl]azetidin-1 -yl]pyrimidine-5- carboxamide (I-69)

[0606] Step 1: Preparation of tert-butyl 3-[(2,2-dichloro-3-oxo-cyclobutyl)methyl] azetidine-1-carboxylate. To a mixture of tert-butyl 3-allylazetidine-1-carboxylate (2.00 g, 10.1 mmol, 1 equiv) and Zn (8.62 g, 132 mmol, 13 equiv) in dioxane (28 mL) was added a solution of 2,2,2-trichloroacetyl chloride (5.53 g, 30.4 mmol, 3.39 mL, 3 equiv) and 1,2-dimethoxyethane (2.74 g, 30.4 mmol, 3.16 mL, 3 equiv) in dioxane (10 mL) in dropwise at 0°C for 0.5 h under N2. The resulting mixture was stirred at 25 °C for 23.5 h. The reaction mixture was quenched by addition saturated aqueous NaHCO3 solution (30 mL). The mixture was filtered and the mixture was extracted with ethyl acetate (15 mL*3). The combined organic phase was washed with brine (15 mL*4), dried with anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (Petroleum ether/Ethyl acetate = 5/1 to 3/1) to afford tert-butyl 3-[(2,2-dichloro-3-oxo-cyclobutyl)methyl]azetidine-1-carboxy late (2.86 g, 9.28 mmol, 92% yield) as a yellow oil. [0607] Step 2: Preparation of tert-butyl 3-[(3-oxocyclobutyl)methyl]azetidine-1- carboxylate. A mixture of tert-butyl 3-[(2,2-dichloro-3-oxo-cyclobutyl)methyl]azetidine-1- carboxylate (2.86 g, 9.28 mmol, 1 equiv), Zn (4.85 g, 74.2 mmol, 8 equiv) and NH ₄ Cl (3.97 g, 74.2 mmol, 8 equiv) in MeOH (30 mL) was stirred at 30 °C for 12 h under N ₂ atmosphere. The reaction mixture was filtered and the filtrated was concentrated in vacuo. The residue was purified by column chromatography on silica gel (Petroleum ether/Ethyl acetate = 4/1 to 3/1) to afford tert- butyl 3-[(3-oxocyclobutyl)methyl]azetidine-1-carboxylate (0.73 g, 3.05 mmol, 33% yield) as a white solid. [0608] Step 3: Preparation of tert-butyl 3-[[3-(methylamino)cyclobutyl]methyl] azetidine- 1-carboxylate. To a solution of tert-butyl 3-[(3-oxocyclobutyl)methyl]azetidine-1-carboxylate (200 mg, 0.84 mmol, 1 equiv) and methanamine (2 M, 2.09 mL, 5 equiv) in CH ₂ Cl ₂ (3 mL) was added AcOH (5.02 mg, 0.08 mmol, 0.01 mL, 0.1 equiv) at 20 °C. After addition, the mixture was stirred at 20 °C for 1 h. Then to the reaction mixture was added NaBH(OAc)3 (531 mg, 2.51 mmol, 3 equiv) at 20 °C. The resulting mixture was stirred at 20 °C for 12 h. The reaction mixture was quenched by addition saturated NH ₄ Cl solution (10 mL), and the mixture was extracted with CH ₂ Cl ₂ (8 mL*3). The water phase was concentrated in vacuo. The crude product was purified by prep-HPLC (column: Phenomenex Luna C18150*25mm*10um;mobile phase: [water(FA)- ACN];gradient:0%-30% B over 9 min) to afford tert-butyl 3-[[3- (methylamino)cyclobutyl]methyl]azetidine-1-carboxylate (126 mg, 0.50 mmol, 59% yield) as a colorless oil. [0609] Step 4: Preparation of tert-butyl 3-[[3-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6- oxo-7H-pteridin-2-yl]amino]-3-methoxy-benzoyl]-methyl-amino] cyclobutyl]methyl] azetidine-1-carboxylate. To a solution of tert-butyl 3-[[3-(methylamino)cyclobutyl]methyl] azetidine-1-carboxylate (74.7 mg, 0.29 mmol, 1 equiv) in DMF (2 mL) was added EDCI (84.5 mg, 0.44 mmol, 1.5 equiv), HOBt (59.6 mg, 0.44 mmol, 1.5 equiv), DIEA (114 mg, 0.88 mmol, 0.15 mL, 3 equiv) and 4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2- yl]amino]-3- methoxy-benzoic acid (150 mg, 0.35 mmol, 1.2 equiv) at 20 °C. The mixture was stirred at 30 °C for 12 h. The reaction mixture was diluted with H ₂ O (10 mL) and extracted with ethyl acetate (5 mL*3). The combined organic phase was washed with brine (5 mL*5), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by prep-TLC on silica gel (Dichloromethane/Methanol = 10/1) to afford tert-butyl 3-[[3-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5- methyl-6-oxo-7H-pteridin-2-yl]amino]-3-methoxy-benzoyl]-meth yl-amino]cyclobutyl]methyl] azetidine-1-carboxylate (111 mg, 0.17 mmol, 57% yield) as a colorless oil. [0610] Step 5: Preparation of N-[3-(azetidin-3-ylmethyl)cyclobutyl]-4-[[(7R)-8- cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-3 -methoxy-N-methyl- benzamide. To a solution of tert-butyl 3-[[3-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H- pteridin-2-yl]amino]-3-methoxy-benzoyl]-methyl-amino]cyclobu tyl]methyl]azetidine-1- carboxylate (110 mg, 0.17 mmol, 1 equiv) in CH ₂ Cl ₂ (2 mL) and TFA (1 mL) at 20 °C. The mixture was stirred at 20 °C for 1h. The mixture was concentrated in vacuo to afford N-[3- (azetidin-3-ylmethyl)cyclobutyl]-4-[[(7R)-8-cyclopentyl-7-et hyl-5-methyl-6-oxo-7H-pteridin-2- yl]amino]-3-methoxy-N-methyl-benzamide (112 mg, crude, TFA salt) as a yellow oil. [0611] Step 6: Preparation of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]-2-[3-[[3-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-meth yl-6-oxo-7H-pteridin-2-yl]amino]- 3-methoxy-benzoyl]-methyl-amino]cyclobutyl]methyl]azetidin-1 -yl]pyrimidine-5- carboxamide (I-69). To a solution of N-[3-(azetidin-3-ylmethyl)cyclobutyl]-4-[[(7R)-8- cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-3 -methoxy-N-methyl-benzamide (100 mg, 0.15 mmol, 1 equiv, TFA salt) and 2-chloro-N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4- tetramethyl-cyclobutyl]pyrimidine-5-carboxamide (62.1 mg, 0.15 mmol, 1 equiv) in DMF (2 mL) was added DIEA (57.4 mg, 0.44 mmol, 0.08 mL, 3 equiv) at 20 °C. The mixture was stirred at 50 °C for 1 h. The residue was poured into water (10 mL). The aqueous phase was extracted with ethyl acetate (5 mL*3). The combined organic phase was washed with brine (5 mL*3), dried with anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by prep- HPLC (column: Phenomenex luna C18150*25mm* 10um;mobile phase: [water(FA)- ACN];gradient:43%-73% B over 10 min) to afford N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4- tetramethyl-cyclobutyl]-2-[3-[[3-[[4-[[(7R)-8-cyclopentyl-7- ethyl-5-methyl-6-oxo-7H-pteridin-2- yl]amino]-3-methoxy-benzoyl]-methyl-amino]cyclobutyl]methyl] azetidin-1-yl]pyrimidine-5- carboxamide (55.9 mg, 0.06 mmol, 36% yield for 2 steps) as a white solid. ¹ H NMR (400 MHz, MeOH-d ₄ ) δ 8.72-8.69 (m, 2H), 8.43 (t, 1H, J = 8.4 Hz), 7.77 (s, 1H), 7.72 (d, 1H, J = 8.8 Hz), 7.12 (d, 1H, J = 2.4 Hz), 7.04 (s, 1H), 6.97 (dd, 2H, J = 8.4, 2.4 Hz), 4.51-4.43 (m, 1H), 4.31-4.24 (m, 4H), 4.15-4.11 (m, 1H), 3.97 (s, 3H), 3.86-3.76 (m, 2H), 3.33 (s, 3H), 3.10 (s, 1H), 3.05 (s, 1H), 2.81-2.67 (m, 1H), 2.64-2.47 (m, 1H), 2.43-1.53 (m, 18H), 1.27 (s, 6H), 1.20 (s, 6H), 0.86 (t, 3H, J = 8.0 Hz). LC-MS: MS (ES ⁺ ): RT = 2.155 min, m/z = 944.6 [M + H ⁺ ]; LCMS Method: 25. EXAMPLE 52 – Synthesis of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]-2-[4-[[3-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-meth yl-6-oxo-7H-pteridin-2-yl]amino]- 3-methoxy-benzoyl]amino]cyclobutyl]methyl]-1-piperidyl]pyrim idine-5-carboxamide (I-70)

[0612] Step 1: Preparation of tert-butyl 4-[(2,2-dichloro-3-oxo-cyclobutyl)methyl] piperidine-1-carboxylate. To a solution of tert-butyl 4-allylpiperidine-1-carboxylate (6.60 g, 29.0 mmol, 1 equiv) and Zn (19.0 g, 291 mmol, 10 equiv) in dioxane (50 mL) was slowly dropwise added a solution of 1,2-dimethoxyethane (8.00 g, 88.0 mmol, 3 equiv) and 2,2,2-trichloroacetyl chloride (16.0 g, 88.0 mmol, 3 equiv) in dioxane (50 mL) over a period of 0.5 h under N ₂ at 0 °C. The mixture was stirred at 25 °C for 12 h. To the reaction mixture was added EtOAc (200 mL) and stirred at 25 °C for 10 min. The mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (Petroleum ether/Ethyl acetate = 20/1 to 5/1) to afford tert-butyl 4-[(2,2-dichloro-3-oxo-cyclobutyl)methyl]piperidine-1-carbox ylate (8.40 g, 25 mmol, 85 % yield) as a yellow oil [0613] Step 2: Preparation of tert-butyl 4-[(3-oxocyclobutyl)methyl]piperidine-1- carboxylate. To a solution of tert-butyl 4-[(2,2-dichloro-3-oxo-cyclobutyl)methyl]piperidine-1- carboxylate (8.40 g, 25 mmol, 1 equiv) in MeOH (100 mL) were added Zn (16.5 g, 252 mmol, 10 equiv) and NH ₄ Cl (13.4 g, 250 mmol, 10 equiv) at 20 °C. The mixture was stirred at 30 °C for 12 h. The reaction mixture was filtered and concentrated in vacuo. The residue was purified by column chromatography (Petroleum ether/Ethyl acetate = 10/1 to 3/1) to afford tert-butyl 4-[(3- oxocyclobutyl)methyl]piperidine-1-carboxylate (2.70 g, 10.1 mmol, 40 % yield) as a yellow oil. [0614] Step 3: Preparation of tert-butyl 4-[(3-hydroxyiminocyclobutyl)methyl] piperidine- 1-carboxylate. To a solution of tert-butyl 4-[(3-oxocyclobutyl)methyl]piperidine-1-carboxylate (500 mg, 1.9 mmol, 1 equiv) in EtOH (20 mL) was added NH2OH·HCl (650 mg, 9.4 mmol, 5 equiv) and KOAc (918 mg, 9.4 mmol, 5 equiv) at 20 °C. The mixture was stirred at 80 °C for 12 h. The reaction mixture was diluted with water (20 mL) and the mixture was extracted with EtOAc (30 mL x 2). The combined organic phase was washed with brine (50 mL), dried withe Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate = 5/1 to 3/1) to afford tert-butyl 4-[(3- hydroxyiminocyclobutyl)methyl]piperidine-1-carboxylate (390 mg, 1.38 mmol, 74% yield) was obtained as a yellow solid. [0615] Step 4: Preparation of tert-butyl 4-[(3-aminocyclobutyl)methyl]piperidine-1- carboxylate. To a solution of tert-butyl 4-[(3-hydroxyiminocyclobutyl)methyl]piperidine-1- carboxylate (390 mg, 1.4 mmol, 1 equiv) in MeOH (40 mL) and NH ₃ ·H ₂ O (5 mL) was added Raney-Ni at 20 °C under N ₂ atmosphere. The mixture was stirred at 50 °C for 12 h under H ₂ (50 Psi). The mixture was filtered and the filtrate was purified by prep-HPLC (Column: Waters x bridge 150*25mm 10um; Mobile phase: water(NH ₄ HCO ₃ )-ACN; Gradient: 10%-40% B over 10 min) to afford tert-butyl 4-[(3-aminocyclobutyl)methyl]piperidine-1-carboxylate (200 mg, 0.75 mmol, 54% yield) was obtained as a colorless oil. [0616] Step 5: Preparation of tert-butyl 4-[[3-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6- oxo-7H-pteridin-2-yl]amino]-3-methoxybenzoyl]amino]cyclobuty l]methyl]piperidine-1- carboxylate. To a solution of tert-butyl 4-[(3-aminocyclobutyl)methyl]piperidine-1-carboxylate (200 mg, 0.8 mmol, 1 equiv) in DMF (3 mL) was added 4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl- 6-oxo-7H-pteridin-2-yl]amino]-3-methoxy-benzoic acid (317 mg, 0.8 mmol, 1 equiv), HOBt (151 mg, 1.1 mmol, 1.5 equiv), DIEA (289 mg, 2.2 mmol, 3 equiv) and EDCI (214 mg, 1.1 mmol, 1.5 equiv) at 20 °C. The mixture was stirred at 20 °C for 1 h. The reaction mixture was filtered and the filtrate was purified by prep-HPLC (Column: Phenomenex luna C18150*25mm* 10um; Mobile phase: water(FA)-ACN; Gradient: 41%-71% B over 10 min) to afford tert-butyl 4-[[3-[[4- [[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl ]amino]-3- methoxybenzoyl]amino]cyclobutyl]methyl]piperidine-1-carboxyl ate (250 mg, 0.37 mmol, 49% yield) as a yellow solid. [0617] Step 6: Preparation of 4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin- 2-yl]amino]-3-methoxy-N-[3-(4-piperidylmethyl)cyclobutyl]ben zamide. To a solution of tert- butyl 4-[[3-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H -pteridin-2-yl]amino]-3-methoxy- benzoyl]amino]cyclobutyl]methyl]piperidine-1-carboxylate (50.0 mg, 74 μmol, 1 equiv) in CH ₂ Cl ₂ (1.5 mL) was added TFA (0.5 mL) at 20 °C. The mixture was stirred at 20 °C for 1 h. The mixture was concentrated in vacuo to afford 4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H- pteridin-2-yl]amino]-3-methoxy-N-[3-(4-piperidylmethyl)cyclo butyl]benzamide (57.0 mg, crude, TFA) was obtained as a yellow oil. [0618] Step 7: Preparation of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]-2-[4-[[3-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-meth yl-6-oxo-7H-pteridin-2-yl]amino]- 3-methoxy-benzoyl]amino]cyclobutyl]methyl]-1-piperidyl]pyrim idine-5-carboxamide (I-70). To a solution of 4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2- yl]amino]-3- methoxy-N-[3-(4-piperidylmethyl)cyclobutyl]benzamide (57.0 mg, 83.0 μmol, 1 equiv, TFA) in NMP (1 mL) was added 2-chloro-N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl - cyclobutyl]pyrimidine-5-carboxamide (29.0 mg, 70.0 μmol, 0.8 equiv), DIEA (33 mg, 240 μmol, 3 equiv). The mixture was stirred at 20 °C for 1 h. The reaction mixture was filtered. The residue was purified prep-TLC (SiO2, CH ₂ Cl ₂ /MeOH = 10/1) to afford N-[3-(3-chloro-4-cyano-phenoxy)- 2,2,4,4-tetramethyl-cyclobutyl]-2-[4-[[3-[[4-[[(7R)-8-cyclop entyl-7-ethyl-5-methyl-6-oxo-7H- pteridin-2-yl]amino]-3-methoxy-benzoyl]amino] cyclobutyl]methyl]-1-piperidyl]pyrimidine-5- carboxamide (15.8 mg, 16.0 μmol, 20% yield for 2 steps, 100% purity) was obtained as a yellow solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.72 (2H, s), 8.51-8.44 (1H, m), 7.77 (1H, s), 7.72 (1H, d, J = 8.8 Hz), 7.54-7.43 (2H, m), 7.12 (1H, d, J = 2.0 Hz), 6.97 (1H, dd, J = 2.0, 8.4 Hz), 4.84 (2H, br d, J = 12.8 Hz), 4.66-4.32 (2H, m), 4.31-4.24 (2H, m), 4.16-4.10 (1H, m), 4.00 (3H, s), 3.33 (3H, s), 3.01-2.88 (2H, m), 2.58-2.07 (5H, m), 2.01-1.60 (13H, m), 1.55-1.42 (2H, m), 1.28 (6H, s), 1.21 (6H, s), 1.17-1.08 (2H, m), 0.86 (3H, t, J = 7.6 Hz). LC-MS: MS (ES ⁺ ): RT = 1.943 min, m/z = 985.6 [M + H ⁺ ]; LCMS Method: 40. EXAMPLE 53 – Synthesis of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]-2-[3-[[3-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-meth yl-6-oxo-7H-pteridin-2-yl]amino]- 3-methoxy-benzoyl]amino]cyclobutyl]methyl]azetidin-1-yl]pyri midine-5-carboxamide (I-71) [0619] Step 1: Preparation of tert-butyl 3-[(2,2-dichloro-3-oxo-cyclobutyl)methyl] azetidine-1-carboxylate. To a mixture of tert-butyl 3-allylazetidine-1-carboxylate (2.00 g, 10.1 mmol, 1 equiv) and Zn (8.62 g, 132 mmol, 13 equiv) in dioxane (28 mL) was added a solution of 2,2,2-trichloroacetyl chloride (5.53 g, 30.4 mmol, 3.39 mL, 3 equiv) and 1,2-dimethoxyethane (2.74 g, 30.4 mmol, 3.16 mL, 3 equiv) in dioxane (10 mL) in dropwise at 0°C for 0.5 h under N ₂ . The resulting mixture was stirred at 25 °C for 23.5 h. The reaction mixture was quenched by addition saturated aqueous NaHCO3 solution (30 mL). The mixture was filtered and the mixture was extracted with ethyl acetate (15 mL*3). The combined organic phase was washed with brine (15 mL*4), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (Petroleum ether/Ethyl acetate = 5/1 to 3/1) to afford tert-butyl 3-[(2,2-dichloro-3-oxo-cyclobutyl)methyl]azetidine-1-carboxy late (2.86 g, 9.28 mmol, 92% yield) as a yellow oil. [0620] Step 2: Preparation of tert-butyl 3-[(3-oxocyclobutyl)methyl]azetidine-1- carboxylate. A mixture of tert-butyl 3-[(2,2-dichloro-3-oxo-cyclobutyl)methyl]azetidine-1- carboxylate (2.86 g, 9.28 mmol, 1 equiv), Zn (4.85 g, 74.2 mmol, 8 equiv) and NH4Cl (3.97 g, 74.2 mmol, 8 equiv) in MeOH (30 mL) was stirred at 30 °C for 12 h under N2 atmosphere. The reaction mixture was filtered and the filtrated was concentrated in vacuo. The residue was purified by column chromatography on silica gel (Petroleum ether/Ethyl acetate = 4/1 to 3/1) to afford tert- butyl 3-[(3-oxocyclobutyl)methyl]azetidine-1-carboxylate (0.73 g, 3.05 mmol, 33% yield) as a white solid. [0621] Step 3: Preparation of tert-butyl 3-[(3-hydroxyiminocyclobutyl)methyl]azetidine-1- carboxylate. To a solution of tert-butyl 3-[(3-oxocyclobutyl)methyl]azetidine-1-carboxylate (300 mg, 1.0 mmol, 1 equiv) in EtOH (3 mL) was added NH ₂ OH·HCl (435 mg, 6.0 mmol, 5 equiv) and KOAc (615 mg, 6.0 mmol, 5 equiv)·at 20 ^o C. The mixture was stirred at 80 ^o C for 12 h. The reaction mixture was diluted with water (20 mL) and the mixture was extracted with EtOAc (10 mL x 2). The combined organic phase was washed with brine (20 mL), dried with Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate = 10/1 to 3/1) to afford tert-butyl 3-[(3- hydroxyiminocyclobutyl)methyl]azetidine-1-carboxylate (280 mg, 1.1 mmol, 88% yield) was obtained as a yellow solid. [0622] Step 4: Preparation of tert-butyl 3-[(3-aminocyclobutyl)methyl]azetidine-1- carboxylate. To a solution of tert-butyl 3-[(3-hydroxyiminocyclobutyl)methyl]azetidine-1- carboxylate (230 mg, 904 μmol, 1 equiv) in MeOH (5 mL) and NH ₃ ·H ₂ O (0.5 mL) was added Raney-Ni (77 mg, 904 μmol, 1 equiv) under N ₂ atmosphere. The suspension was stirred at 50 °C for 12 h under H ₂ (50 Psi ). The mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Waters xbridge 150*25mm 10um; mobile phase: [water( NH4HCO3)- ACN];gradient:16%-46% B over 10 min) to afford tert-butyl 3-[(3-aminocyclobutyl) methyl]azetidine-1-carboxylate (130 mg, 541 μmol, 60% yield) was obtained as a yellow oil. [0623] Step 5: Preparation of tert-butyl 3-[[3-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6- oxo-7H-pteridin-2-yl]amino]-3-methoxy-benzoyl]amino]cyclobut yl]methyl]azetidine-1- carboxylate. To a solution of tert-butyl 3-[(3-aminocyclobutyl)methyl]azetidine-1-carboxylate (80.0 mg, 333 μmol, 1 equiv) in DMF (1 mL) was added HOBt (67.0 mg, 500 μmol, 1.5 equiv) and DIEA (129 mg, 998 μmol, 3 equiv), 4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin- 2-yl]amino]-3-methoxy-benzoic acid (142 mg, 333 μmol, 1 equiv) and EDCI (96 mg, 500 μmol, 1.5 equiv) at 20 °C. The mixture was stirred at 20 °C for 1 h. The reaction mixture was filtered and the filtrate was purified by prep-HPLC (FA condition: column: Phenomenex Luna C18 150*25mm*10um;mobile phase: [water(FA)-ACN];gradient:34%-64% B 10 min) to afford tert- butyl 3-[[3-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pte ridin-2-yl]amino]-3-methoxy- benzoyl]amino]cyclobutyl]methyl]azetidine-1-carboxylate (90 mg, 139 μmol, 42% yield) was obtained as a yellow oil. [0624] Step 6: Preparation of N-[3-(azetidin-3-ylmethyl)cyclobutyl]-4-[[(7R)-8- cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-3 -methoxy-benzamide. To a solution of tert-butyl 3-[[3-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pte ridin-2- yl]amino]-3-methoxy-benzoyl]amino]cyclobutyl]methyl]azetidin e-1-carboxylate (90 mg, 139 μmol, 1 equiv) in CH ₂ Cl ₂ (2 mL) was added TFA (0.5 mL) at 20 °C. The mixture was stirred at 20 °C for 1 h. The mixture was concentrated in vacuo to afford N-[3-(azetidin-3- ylmethyl)cyclobutyl]-4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl -6-oxo-7H-pteridin-2-yl]amino]-3- methoxy-benzamide (150 mg, crude, TFA) was obtained as a yellow oil. [0625] Step 7: Preparation of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]-2-[3-[[3-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-meth yl-6-oxo-7H-pteridin-2-yl]amino]- 3-methoxy-benzoyl]amino]cyclobutyl]methyl]azetidin-1-yl]pyri midine-5-carboxamide (I-71). To a solution of N-[3-(azetidin-3-ylmethyl)cyclobutyl]-4-[[(7R)-8-cyclopentyl -7-ethyl-5-methyl-6- oxo-7H-pteridin-2-yl]amino]-3-methoxy-benzamide (75 mg, 113 μmol, 1 equiv, TFA) in NMP (1 mL) was added DIEA (44 mg, 340 μmol, 3 equiv) and 2-chloro-N-[3-(3-chloro-4-cyano-phenoxy)- 2,2,4,4-tetramethyl-cyclobutyl]pyrimidine-5-carboxamide (38 mg, 90 μmol, 0.8 equiv) at 20 °C. The mixture was stirred at 50 °C for 1 h. The reaction mixture was filtered and the filtrate was purified by prep-HPLC (FA condition:column: Phenomenex Luna C18150*25mm*10um;mobile phase: [water(FA)-ACN];gradient:41%-71% B 10 min) to afford N-[3-(3-chloro-4-cyano- phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]-2-[3-[[3-[[4-[[(7R) -8-cyclopentyl-7-ethyl-5-methyl-6- oxo-7H-pteridin-2-yl]amino]-3-methoxy-benzoyl]amino]cyclobut yl]methyl] azetidin-1- yl]pyrimidine-5-carboxamide (25 mg, 26 μmol, 23% yield for 2 steps, 98% purity)was obtained as a yellow solid. ¹ H NMR (400 MHz, MeOH) δ 8.72 (2H, s), 8.47 (1H, dd, J = 1.6, 8.8 Hz), 7.77 (1H, s), 7.71 (1H, d, J = 8.4 Hz), 7.53-7.45 (2H, m), 7.12 (1H, d, J = 2.4 Hz), 6.97 (1H, dd, J = 2.4, 8.8 Hz), 4.68-4.42 (2H, m), 4.41-4.21 (5H, m), 4.15-4.10 (1H, m), 4.00 (3H, s), 3.86-3.78 (2H, m), 3.33 (3H, s), 2.84-2.70 (1H, m), 2.57-2.49 (1H, m), 2.38-1.69 (17H, m), 1.28 (6H, s), 1.21 (6H, s), 0.86 (3H, t, J = 7.4 Hz). LC-MS: MS (ES ⁺ ): RT = 2.147 min, m/z = 930.6 [M + H ⁺ ]; LCMS Method: 25. EXAMPLE 54 – Synthesis of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]-2-[4-[2-[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl -6-oxo-7H-pteridin-2- yl]amino]phenoxy]ethoxy]-1-piperidyl]pyrimidine-5-carboxamid e (I-72) [0626] Step 1: Preparation of tert-butyl 4-[2-(p-tolylsulfonyloxy)ethoxy]piperidine-1- carboxylate. To a solution of tert-butyl 4-(2-hydroxyethoxy) piperidine-1-carboxylate (3.0 g, 12.2 mmol, 1.0 equiv) in DCM (30 mL) was added TEA (3.7 g, 36.7 mmol, 5.1 mL, 3.0 equiv) and then the TosCl (4.7 g, 24.5 mmol, 2.0 equiv) was added at 0 °C. The mixture was stirred at 25 ℃ for 12 h. The reaction mixture was partitioned between DCM 200 mL and H2O 100 mL. The organic phase was separated, washed with brine 200 mL (100 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=8/1 to 4/1) to give the tert-butyl 4-[2-(p- tolylsulfonyloxy)ethoxy]piperidine-1-carboxylate (3.7 g, 9.3 mmol, 75% yield) obtained as a yellow oil. [0627] Step 2: Preparation of tert-butyl 4-[2-(4-nitrophenoxy)ethoxy]piperidine-1- carboxylate. A mixture of tert-butyl 4-[2-(p-tolylsulfonyloxy)ethoxy]piperidine-1-carboxylate (1.1 g, 2.8 mmol, 1.0 equiv), 4-nitrophenol (766 mg, 5.5 mmol, 2.0 equiv), K2CO3 (761 mg, 5.5 mmol, 2.0 equiv) in DMF (10 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80 °C for 12 h under N ₂ atmosphere. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with EtOAc 150 mL and extracted with H2O (100 mL). The combined organic layers were washed with brine 200 mL (100 mL x 2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate=5/1 to 3/1) to give the tert-butyl 4-[2-(4-nitrophenoxy)ethoxy]piperidine-1-carboxylate (1.0 g, 2.7 mmol, 99% yield) obtained as a yellow solid. [0628] Step 3: Preparation of tert-butyl 4-[2-(4-aminophenoxy) ethoxy] piperidine-1- carboxylate. To a solution of tert-butyl 4-[2-(4-nitrophenoxy)ethoxy]piperidine-1-carboxylate (500 mg, 1.4 mmol, 1.0 equiv) in MeOH (10 mL) and H ₂ O (10 mL) was added NH ₄ Cl (365 mg, 6.8 mmol, 5.0 equiv) and Fe (381 mg, 6.8 mmol, 5.0 equiv). The mixture was stirred at 90 °C for 12 h. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with EtOAc 200 mL and extracted with H ₂ O 200 mL. The combined organic layers were washed with brine 300 mL (150 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate=4/1 to 2/1) to give the tert-butyl 4-[2-(4-aminophenoxy) ethoxy] piperidine-1-carboxylate (300 mg, 891 μmol, 65% yield) obtained as a yellow oil. [0629] Step 4: Preparation of (7R)-8-cyclopentyl-7-ethyl-5-methyl-2-[4-[2-(4- piperidyloxy)ethoxy]anilino]-7H-pteridin-6-one. To a solution of tert-butyl 4-[2-(4- aminophenoxy)ethoxy]piperidine-1-carboxylate (228 mg, 678 μmol, 2.0 equiv) and (7R)-2-chloro- 8-cyclopentyl-7-ethyl-5-methyl-7H-pteridin-6-one (100 mg, 339 μmol, 1.0 equiv) in EtOH (0.5 mL), H2O (2 mL). After addition, the mixture was warmed at 100 °C, and then HCl (12 M, 28 μL, 1.0 equiv) was added dropwise at 100 °C. The resulting mixture was stirred at 100 °C for 2 h. The residue was purified by prep-HPLC (column: Phenomenex luna C18150 x 25mm x 10um; mobile phase: [water(FA)-ACN];gradient:5%-35% B over 10 min) to give the (7R)-8-cyclopentyl-7-ethyl- 5-methyl-2-[4-[2-(4-piperidyloxy)ethoxy]anilino]-7H-pteridin -6-one (160 mg, 323 μmol, 95% yield) obtained as a brown solid. [0630] Step 5: Preparation of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]-2-[4-[2-[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl -6-oxo-7H-pteridin-2- yl]amino]phenoxy]ethoxy]-1-piperidyl]pyrimidine-5-carboxamid e (I-72). A mixture of (7R)- 8-cyclopentyl-7-ethyl-5-methyl-2-[4-[2-(4-piperidyloxy)ethox y]anilino]-7H-pteridin-6-one (160 mg, 323 μmol, 1.0 equiv), 2-chloro-N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl - cyclobutyl]pyrimidine-5-carboxamide (136 mg, 323 μmol, 1.0 equiv), DIEA (42 mg, 323 μmol, 56 μL, 1.0 equiv), K2CO3 (134 mg, 970 μmol, 3.0 equiv) in NMP (2 mL) was degassed and purged with N ₂ for 3 times, and then the mixture was stirred at 25 °C for 12 h under N ₂ atmosphere. The residue was purified by prep-HPLC (column: Waters X bridge C18150 x 50mm x 10um; mobile phase: [water( NH4HCO3)-ACN]; gradient: 62%-92% B over 10 min) to give the N-[3-(3-chloro-4- cyano-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]-2-[4-[2-[4-[[ (7R)-8-cyclopentyl-7-ethyl-5- methyl-6-oxo-7H-pteridin-2-yl]amino]phenoxy]ethoxy]-1-piperi dyl] pyrimidine-5-carboxamide (176 mg, 198 μmol, 61% yield) obtained as a white solid. ¹ H NMR: (400 MHz, MeOD-d4) δ = 8.73 (s, 2H), 7.79 - 7.57 (m, 2H), 7.42 (d, J = 8.8 Hz, 2H), 7.12 (s, 1H), 7.05 - 6.81 (m, 3H), 4.58 (s, 3H), 4.45 - 4.24 (m, 4H), 4.21 (d, J = 3.2, 7.6 Hz, 1H), 4.13 (s, 3H), 3.88 (s, 2H), 3.81 - 3.71 (m, 1H), 3.60 (d, J = 9.6 Hz, 2H), 2.14 - 1.68 (m, 10H), 1.67 - 1.53 (m, 4H), 1.39 - 1.10 (m, 11H), 0.84 (d, J = 7.2 Hz, 3H). LC-MS: MS (ES ⁺ ): RT = 2.222 min, m/z = 877.4 [M +H ⁺ ]. EXAMPLE 55 – Synthesis of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]-2-[4-[2-[2-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl -6-oxo-7H-pteridin-2- yl]amino]phenoxy]ethoxy]-1-piperidyl]pyrimidine-5-carboxamid e (I-73)

[0631] Step 1: Preparation of tert-butyl 4-(2-benzyloxyethoxy)piperidine-1-carboxylate. To a mixture of NaH (1.9 g, 48.9 mmol, 60 % purity, 3.0 equiv) in THF (50 mL) was added tert- butyl 4-hydroxypiperidine-1-carboxylate (9.8 g, 48.9 mmol, 3.0 equiv) at 0 °C. The mixture was stirred at 0 °C for 0.5 h. Then 2-benzyloxyethyl 4-methylbenzenesulfonate (5 g, 16.3 mmol, 1.0 equiv) was added at 0 °C. The mixture was stirred at 25 °C for 12 h under N2. The mixture was poured into ice saturated NH ₄ Cl solution (50 mL). The solution was extracted with EA (3 x 50 mL). The combined organic layers were washed with saturated brine (50 mL), dried, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate = 5/1 to 3/1) to give the tert-butyl 4-(2-benzyloxyethoxy) piperidine- 1-carboxylate (4.2 g, 12.5 mmol, 76 % yield) as a yellow oil. [0632] Step 2: Preparation of tert-butyl 4-(2-hydroxyethoxy)piperidine-1-carboxylate. To a solution of tert-butyl 4-(2-benzyloxyethoxy)piperidine-1-carboxylate (4.2 g, 12.5 mmol, 1.0 equiv) in MeOH (40 mL) was added Pd/C (1 g, 10 % purity). The mixture was stirred at 25 °C for 12 h under H ₂ . The mixture was cooled to 25 °C and filtered. The filtrate was concentrated to get the tert-butyl 4-(2-hydroxyethoxy)piperidine-1-carboxylate (2.8 g, 11.6 mmol, 93 % yield) as a yellow oil. [0633] Step 3: Preparation of tert-butyl 4-[2-(p-tolylsulfonyloxy)ethoxy]piperidine-1- carboxylate. To a solution of tert-butyl 4-(2-hydroxyethoxy) piperidine-1-carboxylate (1.5 g, 6.1 mmol, 1.0 equiv) in DCM (15 mL) was added TEA (1.8 g, 18.3 mmol, 2.5 mL, 3.0 equiv) and TosCl (1.7 g, 9.1 mmol, 1.5 equiv). The mixture was stirred at 25 °C for 12 h. The mixture was added 30 mL water, the aqueous phase was extracted with DCM (30 mL × 3).The combined organic phase was washed with brine (30 mL × 3), dried with anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate = 5/1 to 3/1) to give the tert-butyl 4-[2-(p- tolylsulfonyloxy)ethoxy]piperidine-1-carboxylate (2 g, 5.0 mmol, 81 % yield) as a yellow oil. [0634] Step 4: Preparation of tert-butyl 4-[2-(2-nitrophenoxy)ethoxy]piperidine-1- carboxylate. To a solution of tert-butyl 4-[2-(p-tolylsulfonyloxy)ethoxy]piperidine-1-carboxylate (1.2 g, 3.0 mmol, 1.0 equiv) in DMF (15 mL) was added 2-nitrophenol (835 mg, 6.0 mmol, 2.0 equiv) and K2CO3 (830 mg, 6.0 mmol, 2.0 equiv). The mixture was stirred at 70 °C for 12 h. The reaction mixture was partitioned between Ethyl acetate 100 mL and H ₂ O 100 mL. The organic phase was separated, washed with brine 100 mL, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate = 10/1 to 3/1) to give the tert-butyl 4-[2-(2- nitrophenoxy)ethoxy]piperidine-1-carboxylate (870 mg, 2.3 mmol, 79% yield) as a yellow oil. [0635] Step 5: Preparation of tert-butyl 4-[2-(2-aminophenoxy)ethoxy]piperidine-1- carboxylate. A mixture of tert-butyl 4-[2-(2-nitrophenoxy)ethoxy]piperidine-1-carboxylate (770 mg, 2.10 mmol, 1.0 equiv), NH4Cl (562 mg, 10.5 mmol, 5.0 equiv) and Fe (586 mg, 10.5 mmol, 5.0 equiv) in H ₂ O (5.0 mL) and MeOH (5.0 mL) was degassed and purged with N ₂ for 3 times, and then the mixture was stirred at 90 °C for 12 h under N ₂ atmosphere. The reaction mixture was partitioned between Ethyl acetate 100 mL and H2O 200 mL (100 mL x 2). The organic phase was separated, washed with brine 100 mL, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate = 1/0 to 3/1) to give the tert-butyl 4-[2-(2-aminophenoxy)ethoxy]piperidine-1- carboxylate (570 mg, 1.7 mmol, 80% yield) as a yellow oil. [0636] Step 6: Preparation of (7R)-8-cyclopentyl-7-ethyl-5-methyl-2-[2-[2-(4- piperidyloxy)ethoxy]anilino]-7H-pteridin-6-one. To a solution of tert-butyl 4-[2-(2- aminophenoxy)ethoxy]piperidine-1-carboxylate (228 mg, 678 μmol, 2.0 equiv) and (7R)-2-chloro- 8-cyclopentyl-7-ethyl-5-methyl-7H-pteridin-6-one (100 mg, 339 μmol, 1.0 equiv) in EtOH (0.5 mL) and H2O (2.0 mL). After addition, the mixture was warmed at 100 °C, and then HCl (12 M, 28 μL, 1.0 equiv) was added dropwise at 100 °C. The resulting mixture was stirred at 100 °C for 2 h. The reaction mixture was quenched by addition NaHCO ₃ 10 mL at 0 °C, and then diluted with Ethyl acetate 50 mL. The reaction mixture was partitioned between Ethyl acetate 80 mL and H2O 20 mL. The organic phase was separated washed with H2O 20 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The mixture was purified by prep-HPLC (column: Phenomenex luna C18150*25mm* 10um;mobile phase: [water(FA)- ACN];gradient:10%-40% B over 10 min) to give the (7R)-8-cyclopentyl-7-ethyl-5-methyl-2-[2-[2- (4-piperidyloxy)ethoxy]anilino]-7H-pteridin-6-one (80 mg, 161 μmol, 47% yield) as a yellow solid. [0637] Step 7: Preparation of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]-2-[4-[2-[2-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl -6-oxo-7H-pteridin-2- yl]amino]phenoxy]ethoxy]-1-piperidyl]pyrimidine-5-carboxamid e (I-73). To a solution of (7R)-8-cyclopentyl-7-ethyl-5-methyl-2-[2-[2-(4-piperidyloxy) ethoxy]anilino]-7H-pteridin-6-one (80 mg, 161 μmol, 1.0 equiv) in NMP (1 mL) was added 2-chloro-N-[3-(3-chloro-4-cyano- phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]pyrimidine-5-carboxa mide (67 mg, 161 μmol, 1.0 equiv), DIEA (21 mg, 161 μmol, 28 μL, 1.0 equiv) and K ₂ CO ₃ (156 mg, 1.1 mmol, 7 equiv). The mixture was stirred at 20 °C for 12 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150*25mm* 10um;mobile phase: [water(FA)-ACN];gradient:44%-74% B over 10 min) to give the N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl-cyclobut yl]-2-[4-[2-[2-[[(7R)-8- cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]ph enoxy]ethoxy]-1- piperidyl]pyrimidine-5-carboxamide (41 mg, 46 μmol, 28% yield, 99% purity) as a white solid. ¹ H NMR: (400 MHz, DMSO-d6) δ = 8.75 (s, 2H), 8.37 - 8.29 (m, 1H), 7.91 (d, J = 8.8 Hz, 1H), 7.78 - 7.67 (m, 2H), 7.53 (s, 1H), 7.22 (d, J = 2.4 Hz, 1H), 7.10 - 6.98 (m, 2H), 6.96 - 6.87 (m, 2H), 4.31 - 4.18 (m, 7H), 4.04 (d, J = 8.8 Hz, 1H), 3.83 (d, J = 3.6 Hz, 2H), 3.76 - 3.68 (m, 1H), 3.57 - 3.45 (m, 2H), 3.22 (s, 3H), 1.98 - 1.83 (m, 5H), 1.81 - 1.69 (m, 4H), 1.58 - 1.47 (m, 4H), 1.26 - 1.19 (m, 7H), 1.11 (s, 6H), 0.79 - 0.69 (m, 3H). LC-MS: MS (ES ⁺ ): RT = 2.236 min, m/z = 877.4 [M] . EXAMPLE 56 – Synthesis of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]-2-[4-[2-[2-[4-[[(7R)-8-cyclopentyl-7-ethyl-5-met hyl-6-oxo-7H-pteridin-2- yl]amino]phenoxy]ethoxy]ethoxy]-1-piperidyl]pyrimidine-5-car boxamide (I-74) [0638] Step 1: Preparation of 2-(2-benzyloxyethoxy)ethyl 4-methylbenzenesulfonate. To a solution of 2-(2-benzyloxyethoxy)ethanol (10.00 g, 50.96 mmol, 1.0 equiv) in DCM (100 mL) was added TosCl (14.57 g, 76.44 mmol, 1.5 equiv) and TEA (15.47 g, 152.9 mmol, 21.28 mL, 3.0 equiv). The mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated in vacuo to give the crude product. The residue was purified by column chromatography (SiO2, petroleum ether/ethyl acetate = 20/1 to 3/1). Compound 2-(2-benzyloxyethoxy)ethyl 4- methylbenzenesulfonate (17.00 g, 48.51 mmol, 95 % yield) was obtained as a white solid. [0639] Step 2: Preparation of tert-butyl 4-[2-(2-benzyloxyethoxy)ethoxy]piperidine-1- carboxylate. To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (10.00 g, 49.69 mmol, 1.0 equiv) in DMF (200 mL) was added a solution of NaH (3.97 g, 99.4 mmol, 60% purity, 2.0 equiv) dropwise at 0 °C under N ₂ and stirred at 0 °C for 1 h. Then 2-(2-benzyloxyethoxy)ethyl 4- methylbenzenesulfonate (16.54 g, 47.20 mmol, 1.0 equiv) at 0 °C was added dropwise. The reaction mixture was warmed to 25 °C and stirred at 25 °C for 12 h. The reaction mixture was quenched with saturated aqueous NH4Cl (100 mL) solution at 0 °C dropwise. And the resulting mixture was extracted with ethyl acetate (200 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO2, petroleum ether/ethyl acetate = 20/1 to 3/1). Compound tert-butyl 4-[2-(2- benzyloxyethoxy)ethoxy]piperidine-1-carboxylate (16.00 g, 42.16 mmol, 85 % yield) was obtained as a white solid. [0640] Step 3: Preparation of tert-butyl 4-[2-(2-hydroxyethoxy)ethoxy]piperidine-1- carboxylate. To a solution of tert-butyl 4-[2-(2-benzyloxyethoxy)ethoxy]piperidine-1-carboxylate (15.00 g, 39.53 mmol, 1.0 equiv) in MeOH (200 mL) was added Pd/C (8.00 g, 7.52 mmol, 10% purity, 0.2 equiv) under N ₂ . The suspension was degassed under vacuum and purged with H ₂ several times. The mixture was stirred under H ₂ (50 psi) at 50 °C for 12 h. The reaction was filtered and the filtrate was concentrated in vacuo to give the crude product. Compound tert-butyl 4-[2-(2-hydroxyethoxy)ethoxy]piperidine-1-carboxylate (11.0 g, crude) was obtained as a white solid. [0641] Step 4: Preparation of tert-butyl 4-[2-[2-(4-nitrophenoxy)ethoxy]ethoxy] piperidine-1-carboxylate. To a solution of tert-butyl 4-[2-(2-hydroxyethoxy)ethoxy]piperidine-1- carboxylate (1.00 g, 3.46 mmol, 1.0 equiv) in DMSO (15 mL) was added K ₂ CO ₃ (2.39 g, 17.3 mmol, 5.0 equiv) and 1-fluoro-4-nitro-benzene (1.46 g, 10.4 mmol, 1.10 mL, 3.0 equiv). The mixture was stirred at 100 °C for 12 h. The reaction was filtered and the filtrate was concentrated in vacuo to give the crude product. The residue was purified by column chromatography (SiO2, petroleum ether/ethyl acetate = 20/1 to 3/1). Compound tert-butyl 4-[2-[2-(4- nitrophenoxy)ethoxy]ethoxy]piperidine-1-carboxylate (1.40 g, 3.41 mmol, 99% yield) was obtained as a white solid. [0642] Step 5: Preparation of tert-butyl 4-[2-[2-(4-aminophenoxy)ethoxy]ethoxy] piperidine-1-carboxylate. To a solution of tert-butyl 4-[2-[2-(4-nitrophenoxy)ethoxy]ethoxy] piperidine-1-carboxylate (1.30 g, 3.17 mmol, 1.0 equiv) in EtOH (20 mL) and H ₂ O (10 mL) was added Fe (1.06 g, 19.0 mmol, 6.0 equiv) and NH4Cl (1.69 g, 31.7 mmol, 10.0 equiv). The mixture was stirred at 50 °C for 12 h. The reaction was filtered and the filtrate was concentrated in vacuo to give the crude product. Compound tert-butyl 4-[2-[2-(4-aminophenoxy)ethoxy] ethoxy]piperidine- 1-carboxylate (1.2 g, crude) was obtained as a white solid. [0643] Step 6: Preparation of (7R)-8-cyclopentyl-7-ethyl-5-methyl-2-[4-[2-[2-(4- piperidyloxy)ethoxy]ethoxy]anilino]-7H-pteridin-6-one. To a mixture of (7R)-2-chloro-8- cyclopentyl-7-ethyl-5-methyl-7H-pteridin-6-one (100 mg, 339 μmol, 1.0 equiv) and tert-butyl 4-[2- [2-(4-aminophenoxy)ethoxy]ethoxy]piperidine-1-carboxylate (258 mg, 678 μmol, 2.0 equiv) in EtOH (1.25 mL) and H ₂ O (5 mL) was added HCl (1 M, 1.02 mL, 3.0 equiv). The reaction mixture was heated to 100 °C and stirred at 100 °C for 12 h under N2 atmosphere. The reaction mixture was filtered and the filter was concentrated. The residue was purified by prep-HPLC (column: Phenomenex luna C18150 x 40mm x 15um;mobile phase: [water(HCl)-ACN];B%:10%, isocratic elution mode ). Compound (7R)-8-cyclopentyl-7-ethyl-5-methyl-2-[4-[2-[2-(4- piperidyloxy)ethoxy]ethoxy]anilino]-7H-pteridin-6-one (191 mg, 332 μmol, 98% yield, HCl) was obtained as a yellow oil. [0644] Step 7: Preparation of Compound N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4- tetramethyl-cyclobutyl]-2-[4-[2-[2-[4-[[(7R)-8-cyclopentyl-7 -ethyl-5-methyl-6-oxo-7H- pteridin-2-yl]amino]phenoxy]ethoxy]ethoxy]-1-piperidyl]pyrim idine-5-carboxamide (I-74). To a solution of (7R)-8-cyclopentyl-7-ethyl-5-methyl-2-[4-[2-[2-(4-piperidylo xy)ethoxy]ethoxy] anilino]-7H-pteridin-6-one (190 mg, 330 μmol, 1.0 equiv, HCl) in NMP (3 mL) was added DIEA (213 mg, 1.65 mmol, 288 μL, 5.0 equiv) and 2-chloro-N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4- tetramethyl-cyclobutyl]pyrimidine-5-carboxamide (139 mg, 330. μmol, 1.0 equiv). The mixture was stirred at 50 °C for 2 h. The reaction mixture was filtered and the filter was concentrated. The residue was purified by prep-HPLC (column: Phenomenex luna C18150 x 40mm x 15um; mobile phase: [column: Phenomenex Luna C18150 x 25mm x 10um;mobile phase: [water(FA)- ACN];gradient:39%-69% B over 10 min ). Compound N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4- tetramethyl-cyclobutyl]-2-[4-[2-[2-[4-[[(7R)-8-cyclopentyl-7 -ethyl-5-methyl-6-oxo-7H-pteridin-2- yl]amino]phenoxy]ethoxy]ethoxy]-1-piperidyl]pyrimidine-5-car boxamide (116.86 mg, 126.81 μmol, 38.39% yield) was obtained as a white solid. ¹ H NMR (400 MHz, METHANOL-d4) δ = 8.72 (s, 2H), 7.72 (d, J = 8.8 Hz, 1H), 7.64 - 7.61 (m, 1H), 7.65 - 7.61 (m, 1H), 7.43 - 7.38 (m, 2H), 7.14 - 7.11 (m, 1H), 6.98 (dd, J = 2.4, 8.8 Hz, 1H), 6.93 - 6.87 (m, 2H), 4.58 (br s, 3H), 4.37 - 4.25 (m, 4H), 4.24 - 4.20 (m, 1H), 4.15 - 4.11 (m, 3H), 3.89 - 3.83 (m, 2H), 3.75 - 3.64 (m, 5H), 3.61 - 3.50 (m, 2H), 2.08 - 1.98 (m, 1H), 1.97 - 1.88 (m, 4H), 1.86 - 1.81 (m, 1H), 1.78 - 1.71 (m, 3H), 1.63 - 1.52 (m, 4H), 1.27 (s, 6H), 1.21 (s, 6H), 0.84 (t, J = 7.6 Hz, 3H). LC-MS: MS (ES ⁺ ): RT = 2.197 min, m/z = 921.6 [M + H ⁺ ]; LCMS Method: 25. EXAMPLE 57 – Synthesis of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]-2-[4-[2-[2-[3-[[(7R)-8-cyclopentyl-7-ethyl-5-met hyl-6-oxo-7H-pteridin-2- yl]amino]phenoxy]ethoxy]ethoxy]-1-piperidyl]-pyrimidine-5-ca rboxamide (I-75)

[0645] Step 1: Preparation of 2-(2-benzyloxyethoxy)ethyl 4-methylbenzenesulfonate. To a solution of 2-(2-benzyloxyethoxy)ethanol (10.00 g, 50.96 mmol, 1.0 equiv) in DCM (100 mL) was added TosCl (14.57 g, 76.44 mmol, 1.5 equiv) and TEA (15.47 g, 152.9 mmol, 21.28 mL, 3.0 equiv). The mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated in vacuo to give the crude product. The residue was purified by column chromatography (SiO2, petroleum ether/ethyl acetate = 20/1 to 3/1). Compound 2-(2-benzyloxyethoxy)ethyl 4- methylbenzenesulfonate (17.00 g, 48.51 mmol, 95 % yield) was obtained as a white solid. [0646] Step 2: Preparation of tert-butyl 4-[2-(2-benzyloxyethoxy)ethoxy]piperidine-1- carboxylate. To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (10.00 g, 49.69 mmol, 1.0 equiv) in DMF (200 mL) was added a solution of NaH (3.97 g, 99.4 mmol, 60% purity, 2.0 equiv) dropwise at 0 °C under N2 and stirred at 0 °C for 1 h. Then 2-(2-benzyloxyethoxy)ethyl 4- methylbenzenesulfonate (16.54 g, 47.20 mmol, 1.0 equiv) at 0 °C was added dropwise. The reaction mixture was warmed to 25 °C and stirred at 25 °C for 11 h. The reaction mixture was quenched with saturated aqueous NH4Cl (100 mL) solution at 0 °C dropwise. And the resulting mixture was extracted with ethyl acetate (200 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 20/1 to 3/1). Compound tert-butyl 4-[2-(2- benzyloxyethoxy)ethoxy]piperidine-1-carboxylate (16.00 g, 42.16 mmol, 85 % yield) was obtained as a white solid. [0647] Step 3: Preparation of tert-butyl 4-[2-(2-hydroxyethoxy)ethoxy]piperidine-1- carboxylate. To a solution of tert-butyl 4-[2-(2-benzyloxyethoxy)ethoxy]piperidine-1-carboxylate (15.00 g, 39.53 mmol, 1.0 equiv) in MeOH (200 mL) was added Pd/C (8.00 g, 7.52 mmol, 10% purity, 0.2 equiv) under N ₂ . The suspension was degassed under vacuum and purged with H ₂ several times. The mixture was stirred under H2 (50 psi) at 50 °C for 12 h. The reaction was filtered and the filtrate was concentrated in vacuo to give the crude product. Compound tert-butyl 4-[2-(2-hydroxyethoxy)ethoxy]piperidine-1-carboxylate (11.0 g, crude) was obtained as a white solid. [0648] Step 4: Preparation of tert-butyl 4-[2-[2-(3-nitrophenoxy)ethoxy]ethoxy] piperidine-1-carboxylate. To a mixture of PPh3 (2.9 g, 11.1 mmol, 3.2 equiv) in THF (10 mL) was addded DIAD (2.1 g, 10.4 mmol, 2.0 mL, 3.0 equiv) at 0 °C. The mixture was stirred at 0 °C for 0.5 h. Then the mixture was added to the solution of tert-butyl 4-[2-(2-hydroxyethoxy) ethoxy]piperidine-1-carboxylate (1.0 g, 3.5 mmol, 1.0 equiv) and 3-nitrophenol (961 mg, 6.9 mmol, 1.4 mL, 2.0 equiv) in THF (10 mL) at 0 °C. The mixture was stirred at 50 °C for 1 h. H2O (5 mL) was added to the mixture and it was concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ , Petroleum ether Ethyl acetate = 2/1) to afford tert-butyl 4-[2-[2-(3-nitrophenoxy)ethoxy]ethoxy]piperidine-1-carboxyla te (1.1 g, 2.7 mmol, 77% yield) as a yellow oil. [0649] Step 5: Preparation of tert-butyl 4-[2-[2-(3-aminophenoxy)ethoxy]ethoxy] piperidine-1-carboxylate. To a solution of tert-butyl 4-[2-[2-(3-nitrophenoxy)ethoxy]ethoxy] piperidine-1-carboxylate (1.3 g, 3.2 mmol, 1.0 equiv) in EtOH (20 mL) was added Fe (1.1 g, 19.0 mmol, 6.0 equiv) and NH4Cl (1.7 g, 31.7 mmol, 10.0 equiv) in H2O (10 mL). The mixture was stirred at 50 °C for 12 h. The reaction was filtered and the filtrate was concentrated in vacuo to give the residue. EA (50 mL) was added to the mixture, and the mixture was extracted with EA (50 mL x 2), the combined organic layer was dried over Na2SO4, filtrated and concentrated to give tert-butyl 4-[2-[2-(3-aminophenoxy)ethoxy]ethoxy]piperidine-1-carboxyla te (1.0 g, 2.3 mmol, 72% yield) as a yellow solid. [0650] Step 6: Preparation of (7R)-8-cyclopentyl-7-ethyl-5-methyl-2-[3-[2-[2-(4- piperidyloxy)ethoxy]ethoxy]anilino]-7H-pteridin-6-one. To a mixture of (7R)-2-chloro-8- cyclopentyl-7-ethyl-5-methyl-7H-pteridin-6-one (100 mg, 339 μmol, 1.0 equiv) and tert-butyl 4- [2-[2-(3-aminophenoxy)ethoxy]ethoxy]piperidine-1-carboxylate (194 mg, 509 μmol, 1.5 equiv) in EtOH (1.5 mL) was added HCl (1 M, 1 mL, 3.0 equiv) and H2O (6 mL) at 25 °C. The reaction mixture was heated to 100 °C and stirred at 100 °C for 12 hours under N2 atmosphere. The reaction mixture was concentrated and purified by prep-HPLC (column: Phenomenex luna C18150 * 40mm * 15 um; mobile phase: [water (HCl) - ACN]; gradient: 10% - 40% B over 10 min) to afford (7R)-8-cyclopentyl-7-ethyl-5-methyl-2-[3-[2-[2-(4-piperidylo xy)ethoxy] ethoxy]anilino]-7H- pteridin-6-one (195 mg, 339 μmol, 99% yield) as a yellow solid. [0651] Step 7: Preparation of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]-2-[4-[2-[2-[3-[[(7R)-8-cyclopentyl-7-ethyl-5-met hyl-6-oxo-7H-pteridin-2- yl]amino]phenoxy]ethoxy]ethoxy]-1-piperidyl]-pyrimidine-5-ca rboxamide (I-75). A mixture of (7R)-8-cyclopentyl-7-ethyl-5-methyl-2-[3-[2-[2-(4-piperidylo xy)ethoxy] ethoxy]anilino]-7H- pteridin-6-one (231 mg, 402 μmol, 1.0 equiv), 2-chloro-N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4- tetrameth-yl-cyclobutyl]pyrimidine-5-carboxamide (174 mg, 415 μmol, 1.0 equiv), DIEA (260 mg, 2.0 mmol, 350 μL, 5.0 equiv) in NMP (3 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 60 °C for 2 h under N ₂ atmosphere. The mixture was filtrated and purified by prep-HPLC (column: Phenomenex luna C18150 * 25 mm * 10 um; mobile phase: [water (FA) - ACN]; gradient: 49% - 79% B over 10 min) to afford N-[3-(3-chloro-4-cyano- phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]-2-[4-[2-[2-[3-[[(7R )-8-cyclopentyl-7-ethyl-5-methyl-6- oxo-7H-pteridin-2-yl]amino]phenoxy]ethoxy]ethoxy]-1-piperidy l]-pyrimidine-5-carboxamide (76 mg, 80 μmol, 20% yield) as a yellow solid. ¹ H NMR (400 MHz, METHANOL-d4) δ= 8.70 (s, 2H), 8.35 (s, 1H), 7.74 - 7.68 (m, 2H), 7.43 (t, J = 2.0 Hz, 1H), 7.18 - 7.10 (m, 2H), 7.06 - 7.01 (m, 1H), 6.98 (dd, J = 2.4, 8.8 Hz, 1H), 6.61 - 6.53 (m, 1H), 4.55 - 4.43 (m, 1H), 4.32 - 4.21 (m, 4H), 4.18 - 4.07 (m, 3H), 3.86 (dd, J = 4.0, 5.2 Hz, 2H), 3.75 - 3.64 (m, 5H), 3.59 - 3.47 (m, 2H), 2.17 - 2.07 (m, 1H), 2.03 - 1.62 (m, 12H), 1.60 - 1.49 (m, 2H), 1.28 (s, 6H), 1.22 - 1.19 (m, 6H), 0.85 (t, J = 7.6 Hz, 3H). LC-MS: MS (ES ⁺ ): RT = 2.229 min, m/z = 921.6 [M + H] ⁺ . EXAMPLE 58 – Synthesis of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]-2-[4-[2-[2-[2-[[(7R)-8-cyclopentyl-7-ethyl-5-met hyl-6-oxo-7H-pteridin-2- yl]amino]phenoxy]ethoxy]ethoxy]-1-piperidyl]pyrimidine-5-car boxamide (I-76) [0652] Step 1: Preparation of 2-(2-benzyloxyethoxy)ethyl 4-methylbenzenesulfonate. To a solution of 2-(2-benzyloxyethoxy)ethanol (10.00 g, 50.96 mmol, 1.0 equiv) in DCM (100 mL) was added TosCl (14.57 g, 76.44 mmol, 1.5 equiv) and TEA (15.47 g, 152.9 mmol, 21.28 mL, 3.0 equiv). The mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated in vacuo to give the crude product. The residue was purified by column chromatography (SiO2, petroleum ether/ethyl acetate = 20/1 to 3/1). Compound 2-(2-benzyloxyethoxy)ethyl 4- methylbenzenesulfonate (17.00 g, 48.51 mmol, 95 % yield) was obtained as a white solid. [0653] Step 2: Preparation of tert-butyl 4-[2-(2-benzyloxyethoxy)ethoxy]piperidine-1- carboxylate. To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (10.00 g, 49.69 mmol, 1.0 equiv) in DMF (200 mL) was added a solution of NaH (3.97 g, 99.4 mmol, 60% purity, 2.0 equiv) dropwise at 0 °C under N2 and stirred at 0 °C for 1 h. Then 2-(2-benzyloxy ethoxy)ethyl 4- methylbenzenesulfonate (16.54 g, 47.20 mmol, 1.0 equiv) at 0 °C was added dropwise. The reaction mixture was warmed to 25 °C and stirred at 25 °C for 11 h. The reaction mixture was quenched with saturated aqueous NH4Cl (100 mL) solution at 0 °C dropwise. And the resulting mixture was extracted with ethyl acetate (200 mL x 3). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO2, petroleum ether/ethyl acetate = 20/1 to 3/1). Compound tert-butyl 4-[2-(2- benzyloxyethoxy)ethoxy]piperidine-1-carboxylate (16.00 g, 42.16 mmol, 85 % yield) was obtained as a white solid. [0654] Step 3: Preparation of tert-butyl 4-[2-(2-hydroxyethoxy)ethoxy]piperidine-1- carboxylate. To a solution of tert-butyl 4-[2-(2-benzyloxyethoxy)ethoxy]piperidine-1-carboxylate (15.00 g, 39.53 mmol, 1.0 equiv) in MeOH (200 mL) was added Pd/C (8.00 g, 7.52 mmol, 10% purity, 0.2 equiv) under N ₂ . The suspension was degassed under vacuum and purged with H ₂ several times. The mixture was stirred under H ₂ (50 psi) at 50 °C for 12 h. The reaction was filtered and the filtrate was concentrated in vacuo to give the crude product. Compound tert-butyl 4-[2-(2-hydroxyethoxy)ethoxy]piperidine-1-carboxylate (11.0 g, crude) was obtained as a white solid. [0655] Step 4: Preparation of tert-butyl 4-[2-[2-(2-nitrophenoxy)ethoxy]ethoxy] piperidine-1-carboxylate. To a solution of tert-butyl 4-[2-(2-hydroxyethoxy)ethoxy]piperidine-1- carboxylate (1.00 g, 3.46 mmol, 1.0 equiv), K2CO3 (2.39 g, 17.2 mmol, 5.0 equiv) in DMSO (15 mL) was added 1-fluoro-2-nitro-benzene (1.46 g, 10.3 mmol, 1.10 mL, 3.0 equiv). The mixture was stirred at 100 °C for 2 h. The reaction was filtered and the filtrate was poured into ice water (50 mL) and the mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 20/1 to 3/1). Compound tert-butyl 4-[2-[2-(2-nitrophenoxy)ethoxy]ethoxy]piperidine-1- carboxylate (1.6 g, crude) was obtained as a white solid. [0656] Step 5: Preparation of tert-butyl 4-[2-[2-(2-aminophenoxy)ethoxy] ethoxy]piperidine-1-carboxylate. A mixture of tert-butyl 4-[2-[2-(2-nitrophenoxy)ethoxy] ethoxy]piperidine-1-carboxylate (1.50 g, 3.65 mmol, 1.0eq), NH ₄ Cl (1.95 g, 36.5 mmol, 10 equiv), Fe (1.22 g, 21.9 mmol, 6.0 equiv) in EtOH (15 mL) and H ₂ O (7.5 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 50 °C for 2 h under N2 atmosphere. To the reaction mixture was added NaHCO3 (50 mL) and the mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. Compound tert-butyl 4-[2-[2-(2- aminophenoxy)ethoxy]ethoxy]piperidine-1-carboxylate (1.3 g, crude) was obtained as a black brown oil. [0657] Step 6: Preparation of (7R)-8-cyclopentyl-7-ethyl-5-methyl-2-[2-[2-[2-(4- piperidyloxy)ethoxy]ethoxy]anilino]-7H-pteridin-6-one. A mixture of (7R)-2-chloro-8- cyclopentyl-7-ethyl-5-methyl-7H-pteridin-6-one (110 mg, 373 μmol, 1.0 equiv), tert-butyl 4-[2-[2- (2-aminophenoxy)ethoxy]ethoxy]piperidine-1-carboxylate (283 mg, 746 μmol, 2.0 equiv), HCl (12 M, 62 μL, 2.0 equiv) in EtOH (1.25 mL) and H ₂ O (5 mL) was degassed and purged with N ₂ for 3 times, and then the mixture was stirred at 100 °C for 12 h under N ₂ atmosphere. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (column: Phenomenex luna C18150 x 40mm x 15um;mobile phase: [water(HCl)- ACN];gradient:15%-45% B over 10 min). Compound (7R)-8-cyclopentyl-7-ethyl-5-methyl-2-[2- [2-[2-(4-piperidyloxy)ethoxy]ethoxy]anilino]-7H-pteridin-6-o ne (115 mg, 213 μmol, 57 % yield) was obtained as a yellow oil. [0658] Step 7: Preparation of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]-2-[4-[2-[2-[2-[[(7R)-8-cyclopentyl-7-ethyl-5-met hyl-6-oxo-7H-pteridin-2- yl]amino]phenoxy]ethoxy]ethoxy]-1-piperidyl]pyrimidine-5-car boxamide (I-76). A mixture of (7R)-8-cyclopentyl-7-ethyl-5-methyl-2-[2-[2-[2-(4-piperidylo xy)ethoxy]ethoxy]anilino]-7H- pteridin-6-one (115 mg, 199 μmol, 1.0 equiv, HCl), 2-chloro-N-[3-(3-chloro-4-cyano-phenoxy)- 2,2,4,4-tetramethyl-cyclobutyl]pyrimidine-5-carboxamide (83 mg, 0.19 μmol, 1.0 equiv), DIEA (129 mg, 999 μmol, 174 μL, 5.0 equiv) in NMP (1.2 mL) was degassed and purged with N ₂ for 3 times, and then the mixture was stirred at 50 °C for 2 h under N2 atmosphere. The reaction mixture was concentrated in vacuo to give the crude product. The residue was purified by prep-HPLC (column: Phenomenex Luna C18150 x 25mm x 10um;mobile phase: [water(FA)- ACN];gradient:56%-86% B over 10 min). Compound N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4- tetramethyl-cyclobutyl]-2-[4-[2-[2-[2-[[(7R)-8-cyclopentyl-7 -ethyl-5-methyl-6-oxo-7H-pteridin-2- yl]amino]phenoxy]ethoxy]ethoxy]-1-piperidyl]pyrimidine-5-car boxamide (170 mg, 175 μmol, 87 % yield, 95 % purity) was obtained as a white solid. ¹ H NMR: (400 MHz, METHANOL-d4) δ = 8.68 (s, 2H), 8.21 (s, 1H), 8.19 - 8.15 (m, 1H), 7.72 (d, J = 8.8 Hz, 1H), 7.68 (s, 1H), 7.13 (d, J = 2.4 Hz, 1H), 7.05 - 7.02 (m, 1H), 7.00 - 6.90 (m, 3H), 4.42 - 4.33 (m, 1H), 4.29 - 4.15 (m, 6H), 4.14 - 4.11 (m, 1H), 3.92 - 3.88 (m, 2H), 3.74 - 3.71 (m, 2H), 3.70 - 3.67 (m, 2H), 3.66 - 3.62 (m, 1H), 3.51 - 3.43 (m, 2H), 3.35 (br s, 2H), 2.14 - 2.06 (m, 1H), 1.99 - 1.91 (m, 2H), 1.89 - 1.72 (m, 7H), 1.70 - 1.60 (m, 2H), 1.55 - 1.43 (m, 2H), 1.29 (s, 6H), 1.22 (s, 6H), 0.84 (t, J = 7.6 Hz, 3H). LC-MS: MS (ES ⁺ ): RT = 2.278 min, m/z = 921.4 [M + H ⁺ ]; LCMS Method: 25. EXAMPLE 59 – Synthesis of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]-2-[4-[2-[2-[2-[4-[[(7R)-8-cyclopentyl-7-ethyl-5- methyl-6-oxo-7H-pteridin-2- yl]amino]phenoxy]ethoxy]ethoxy]ethoxy]-1-piperidyl]pyrimidin e-5-carboxamide (I-77) 75% yield

[0659] Step 1: Preparation of tert-butyl 4-[2-[2-[2-(4-nitrophenoxy)ethoxy]ethoxy] ethoxy]piperidine-1-carboxylate. To a solution of tert-butyl 4-[2-[2-[2-(p-tolylsulfonyloxy) ethoxy]ethoxy]ethoxy]piperidine-1-carboxylate (600 mg, 1.2 mmol, 1.0 equiv) in DMF (6.0 mL) was added K2CO3 (340 mg, 2.4 mmol, 2.0 equiv) and 4-nitrophenol (342 mg, 2.4 mmol, 2.0 equiv). The mixture was stirred under N ₂ atmosphere at 80 °C for 12 h. The residue was diluted with EtOAc (50 mL) and extracted with brine (50 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO ₂ , Petroleum ether/Ethyl acetate = 2:1). Compound tert-butyl 4-[2-[2-[2- (4-nitrophenoxy)ethoxy]ethoxy]ethoxy]piperidine-1-carboxylat e (450 mg, 983 μmol, 80% yield, 99.3% purity) was obtained as a white solid. [0660] Step 2: Preparation of tert-butyl 4-[2-[2-[2-(4-aminophenoxy)ethoxy]ethoxy] ethoxy]piperidine-1-carboxylate. To a solution of tert-butyl 4-[2-[2-[2-(4-nitrophenoxy) ethoxy]ethoxy]ethoxy]piperidine-1-carboxylate (450 mg, 990 μmol, 1.0 equiv) in MeOH (9.00 mL) and H2O (9.0 mL) was added Fe (276 mg, 4.95 mmol, 5.0 equiv) and NH4Cl (265 mg, 4.95 mmol, 5.0 equiv). The mixture was stirred under N2 atmosphere at 90 °C for 12 h. The reaction mixture was filtered and concentrated under reduced pressure to remove solvent. The residue was diluted with EtOAc (50mL x 3). Compound tert-butyl 4-[2-[2-[2-(4-aminophenoxy)ethoxy] ethoxy]ethoxy]piperidine-1-carboxylate (320 mg, 740 μmol, 75% yield, 98.2% purity) was obtained as a yellow oil. [0661] Step 3: Preparation of (7R)-8-cyclopentyl-7-ethyl-5-methyl-2-[4-[2-[2-[2-(4- piperidyloxy)ethoxy]ethoxy]ethoxy]anilino]-7H-pteridin-6-one . To a solution of tert-butyl 4-[2- [2-[2-(4-aminophenoxy)ethoxy]ethoxy]ethoxy]piperidine-1-carb oxylate (233 mg, 549 μmol, 1.6 equiv) in EtOH (0.5 mL) and H ₂ O (2.0 mL) was added (7R)-2-chloro-8-cyclopentyl-7-ethyl-5- methyl-7H-pteridin-6-one (100 mg, 339 μmol, 1.0 equiv). After addition, the mixture was warmed at 100 °C, and then HCl (12.0 M, 28.3 μL, 1.0 equiv) was added dropwise at 100 °C. The resulting mixture was stirred at 100 °C for 12 h. The residue mixture was filtered. The residue was purified by prep-HPLC (column: Phenomenex luna C18150*40mm* 15um;mobile phase: [water(TFA)- ACN];gradient:15%-45% B over 10 min). Compound (7R)-8-cyclopentyl-7-ethyl-5-methyl-2-[4- [2-[2-[2-(4-piperidyloxy)ethoxy]ethoxy]ethoxy]anilino]-7H-pt eridin-6-one (140 mg, 240 μmol, 70% yield, 99.0% purity) was obtained as a yellow oil. [0662] Step 4: Preparation of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]-2-[4-[2-[2-[2-[4-[[(7R)-8-cyclopentyl-7-ethyl-5- methyl-6-oxo-7H-pteridin-2- yl]amino]phenoxy]ethoxy]ethoxy]ethoxy]-1-piperidyl]pyrimidin e-5-carboxamide (I-77). To a solution of (7R)-8-cyclopentyl-7-ethyl-5-methyl-2-[4-[2-[2-[2-(4-piperid yloxy)ethoxy]ethoxy] ethoxy]anilino]-7H-pteridin-6-one (80 mg, 137 μmol, 1.0 equiv) in NMP (1.00 mL) was added K2CO3 (57 mg, 412 μmol, 3.0 equiv) and DIEA (35 mg, 275 μmol, 47.8 μL, 2.0 equiv) at 25 °C for 5 min. And then was added 2-chloro-N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl - cyclobutyl]pyrimidine-5-carboxamide (69 mg, 165 μmol, 1.2 equiv) at 25 °C. The mixture was stirred at 25 °C for 4 h under N2 atmosphere. The reaction mixture was diluted with 50 mL ethyl acetate and washed by water (20 mL * 3), then the organic phase was dried over anhydrous Na ₂ SO ₄ , evaporated in vacuum. The residue was purified by prep-HPLC (column: Phenomenex luna C18150*25mm* 10um;mobile phase: [water(FA)-ACN]; gradient:36%-66% B over 10 min). Compound N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl-cyclobut yl]-2-[4-[2-[2-[2-[4- [[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl ]amino]phenoxy]ethoxy] ethoxy]ethoxy]-1-piperidyl]pyrimidine-5-carboxamide (35.1 mg, 36.9 μmol, 27% yield, 99% purity) was obtained as a white solid. ¹ H NMR (400 MHz, MeOD) δ = 8.71 (s, 2H), 7.73 - 7.71 (m, 2H), 7.51(s, 1H), 7.36 - 7.34 (m, 2H), 7.13 - 7.21 (d, J = 4.0 Hz 1H), 7.00 - 6.93 (m, 3H), 4.34 - 4.21 (m, 5H), 4.16 - 4.11 (m, 3H), 3.88 - 3.83 (m, 2H), 3.74 - 3.64 (m, 9H), 3.60 - 3.50 (m, 2H), 3.30 (s, 3H), 2.04 - 1.76 (m, 8H), 1.75 - 1.65 (m, 2H), 1.62 - 1.50 (m, 4H), 1.27 (s, 6H), 1.21 (s, 6H), 0.86 - 0.82 (m, 3H). LC-MS: MS (ES ⁺ ): RT = 0.535 min, m/z = 871.3 [M+H] ⁺ ; LCMS Method: 25. EXAMPLE 60 – Synthesis of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]-2-[4-[2-[2-[2-[3-[[(7R)-8-cyclopentyl-7-ethyl-5- methyl-6-oxo-7H-pteridin-2- yl]amino]phenoxy]ethoxy]ethoxy]ethoxy]-1-piperidyl]pyrimidin e-5-carboxamide (I-78) [0663] Step 1: Preparation of tert-butyl 4-[2-[2-[2-(3-nitrophenoxy)ethoxy]ethoxy] ethoxy]piperidine-1-carboxylate. To a solution of tert-butyl 4-[2-[2-[2-(p-tolylsulfonyloxy) ethoxy]ethoxy]ethoxy]piperidine-1-carboxylate (600 mg, 1.23 mmol, 1.0 equiv) in MeCN (6 mL) was added K2CO3 (340 mg, 2.46 mmol, 2.0 equiv) and 3-nitrophenol (342 mg, 2.46 mmol, 489 μL, 2.0 equiv). The mixture was stirred at 80 °C for 8 h. The reaction mixture was filtered and the filtrate was concentrated to afford crude product. The residue was purified by column chomatography (SiO2, Petroleum ether/Ethyl acetate=50/1 to 10/1) to give tert-butyl 4-[2-[2-[2-(3- nitrophenoxy)ethoxy]ethoxy]ethoxy]piperidine-1-carboxylate (530 mg, 1.17 mmol, 95% yield) as a colorless oil. [0664] Step 2: Preparation of tert-butyl 4-[2-[2-[2-(3-aminophenoxy)ethoxy]ethoxy] ethoxy]piperidine-1-carboxylate. To a solution of tert-butyl 4-[2-[2-[2-(3-nitrophenoxy) ethoxy]ethoxy]ethoxy]piperidine-1-carboxylate (260 mg, 572 μmol, 1.0 equiv) in H2O (5 mL) and MeOH (5 mL) was added Fe (160 mg, 2.86 mmol, 5.0 equiv) and NH4Cl (153 mg, 2.86 mmol, 5.0 equiv). The mixture was stirred at 90 °C for 8 h. The reaction mixture was filtered and concentrated to afford crude product. The residue was purified by prep-HPLC(column: Phenomenex luna C18150*25mm* 10um;mobile phase: [water(FA)-ACN];gradient:26%-56% B over 10 min) to afford tert-butyl 4-[2-[2-[2-(3-aminophenoxy)ethoxy]ethoxy]ethoxy] piperidine-1- carboxylate (150 mg, 353 μmol, 62% yield) as a colorless oil. [0665] Step 3: Preparation of (7R)-8-cyclopentyl-7-ethyl-5-methyl-2-[3-[2-[2-[2-(4- piperidyloxy)ethoxy]ethoxy]ethoxy]anilino]-7H-pteridin-6-one . To a solution of tert-butyl 4-[2- [2-[2-(3-aminophenoxy)ethoxy]ethoxy]ethoxy]piperidine-1-carb oxylate (72 mg, 170 μmol, 2.0 equiv) in EtOH (0.3 mL) and H ₂ O (1 mL) was added HCl (12 M, 7.1μL, 1.0 equiv) and (7R)-2- chloro-8-cyclopentyl-7-ethyl-5-methyl-7H-pteridin-6-one (25 mg, 85 μmol, 1.0 equiv). The mixture was stirred at 100 °C for 8 h. The reaction mixture was filtered and the filter was concentrated. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150*25mm* 10um;mobile phase: [water(FA)-ACN];gradient:12%-32% B over 9 min) to give (7R)-8-cyclopentyl-7-ethyl-5-methyl-2-[3-[2-[2-[2-(4-piperid yloxy)ethoxy]ethoxy] ethoxy]anilino]-7H-pteridin-6-one (100 mg, crude) as a colorless oil. [0666] Step 4: Preparation of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]-2-[4-[2-[2-[2-[3-[[(7R)-8-cyclopentyl-7-ethyl-5- methyl-6-oxo-7H-pteridin-2- yl]amino]phenoxy]ethoxy]ethoxy]ethoxy]-1-piperidyl]pyrimidin e-5-carboxamide (I-78). To a solution of (7R)-8-cyclopentyl-7-ethyl-5-methyl-2-[3-[2-[2-[2-(4-piperid yloxy)ethoxy] ethoxy]ethoxy]anilino]-7H-pteridin-6-one (100 mg, 172 μmol, 1.0 equiv) in NMP (1 mL) was added K ₂ CO ₃ (71 mg, 515 μmol, 3.0 equiv) and 2-chloro-N-[3-(3-chloro-4-cyano-phenoxy)- 2,2,4,4-tetramethyl-cyclobutyl]pyrimidine-5-carboxamide (86 mg, 206 μmol, 1.2 equiv). The mixture was stirred at 25 °C for 4 h. The reaction mixture was filtered and the filtrate was collected. The residue was purified by prep-HPLC (column: Phenomenex luna C18150*25mm* 10um;mobile phase: [water(FA)-ACN];gradient:42%-72% B over 10 min) to afford compound N- [3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl ]-2-[4-[2-[2-[2-[3-[[(7R)-8- cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]ph enoxy]ethoxy]ethoxy]ethoxy]-1- piperidyl]pyrimidine-5-carboxamide (61 mg, 63 μmol, 37% yield, 99% purity) as a white solid. ¹ H NMR (400 MHz, CD3OD) 8.72 (s, 2H), 7.79 - 7.70 (m, 2H), 7.45 - 7.41 (m, 1H), 7.20 - 7.13 (m, 2H), 7.10 - 7.05 (m, 1H), 7.03 - 6.96 (m, 1H), 6.61 - 6.55 (m, 1H), 5.04 - 4.95 (m, 2H), 4.61 (s, 2H), 4.34 - 4.23 (m, 4H), 4.15 (t, J = 4.6 Hz, 3H), 3.91 - 3.84 (m, 2H), 3.76 - 3.72 (m, 2H), 3.72 - 3.69 (m, 2H), 3.68 (s, 4H), 3.57 - 3.48 (m, 3H), 2.14 (d, J = 7.0 Hz, 1H), 2.07 - 1.97 (m, 1H), 1.96 - 1.66 (m, 11H), 1.60 - 1.49 (m, 2H), 1.30 (s, 6H), 1.23 (s, 6H). LC-MS: MS (ES ⁺ ): RT = 2.226 min, m/z = 966.6 [M + H ⁺ ]; LCMS Method: 25. EXAMPLE 61 – Synthesis of N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4- tetramethylcyclobutyl)-6-(4-(2-(2-(2-(2-(((R)-8-cyclopentyl- 7-ethyl-5-methyl-6-oxo-5,6,7,8- tetrahydropteridin-2-yl)amino)phenoxy)ethoxy)ethoxy)ethoxy)p iperidin-1-yl)nicotinamide (I-79)

[0667] Step 1: Preparation of tert-butyl 4-[2-[2-[2-(2-nitrophenoxy)ethoxy]ethoxy] ethoxy]piperidine-1-carboxylate. To a solution of tert-butyl 4-[2-[2-[2-(p-tolylsulfonyloxy) ethoxy]ethoxy]ethoxy]piperidine-1-carboxylate (600 mg, 1.2 mmol, 1.0 equiv) and 2-nitrophenol (342 mg, 2.4 mmol, 2.0 equiv) in DMF (6.0 mL) was added K2CO3 (340 mg, 2.4 mmol, 2.0 equiv) at 25 °C. The mixture was stirred at 80 °C for 8 h under N2, and then the reaction mixture was diluted with EtOAc (30 mL) and extracted with H ₂ O (30 mL x 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, Petroleum ether/Ethyl acetate=1/1) to afford tert-butyl 4- [2-[2-[2-(2-nitrophenoxy)ethoxy]ethoxy]ethoxy]piperidine-1-c arboxylate (497 mg, 1.08 mmol, 88 % yield, 99.0 % purity) was obtained as a yellow oil. [0668] Step 2: Preparation of tert-butyl 4-[2-[2-[2-(2-aminophenoxy)ethoxy]ethoxy] ethoxy]piperidine-1-carboxylate. To a solution of tert-butyl 4-[2-[2-[2-(2- nitrophenoxy)ethoxy]ethoxy]ethoxy]piperidine-1-carboxylate (497 mg, 1.1 mmol, 1.0 equiv) in MeOH (10.0 mL) and H2O (10.0 mL) was added Fe (305mg, 5.5 mmol, 5.0 equiv) and NH4Cl (292 mg, 5.5 mmol, 5.0 equiv) at 25 °C. The mixture was stirred at 90 °C for 12 h under N ₂ , and then the reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate=20/1 to 2/1) to afford tert-butyl 4-[2-[2-[2-(2-aminophenoxy)ethoxy]ethoxy] ethoxy]piperidine-1-carboxylate (350 mg, 808 μmol, 74 % yield, 98.0 % purity) was obtained as a yellow oil. [0669] Step 3: Preparation of (7R)-8-cyclopentyl-7-ethyl-5-methyl-2-[2-[2-[2-[2-(4- piperidyloxy)ethoxy]ethoxy]ethoxy]anilino]-7H-pteridin-6-one . To a solution of tert-butyl 4-[2- [2-[2-(2-aminophenoxy)ethoxy]ethoxy]ethoxy]piperidine-1-carb oxylate (288 mg, 678 μmol, 2.0 equiv) and (7R)-2-chloro-8-cyclopentyl-7-ethyl-5-methyl-7H-pteridin-6-o ne (100 mg, 339 μmol, 1.0 equiv) in EtOH (0.5 mL) and H2O (2.0 mL) was added HCl (12.0 M, 28 μL, 1.0 equiv) at 25 °C .The mixture was stirred at 100 °C for 12 h under N ₂ , and then the reaction mixture was filtered. The residue was purified by prep-HPLC (column: Phenomenex luna C18150*40mm* 15um;mobile phase: [water(TFA)-ACN];gradient:15%-45% B over 10 min) to afford (7R)-8- cyclopentyl-7-ethyl-5-methyl-2-[2-[2-[2-[2-(4-piperidyloxy)e thoxy] ethoxy]ethoxy]anilino]-7H- pteridin-6-one (200 mg, 326 μmol, 96 % yield, 95.0 % purity) was obtained as a yellow oil. [0670] Step 4: Preparation of N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4- tetramethylcyclobutyl)-6-(4-(2-(2-(2-(2-(((R)-8-cyclopentyl- 7-ethyl-5-methyl-6-oxo-5,6,7,8- tetrahydropteridin-2-yl)amino)phenoxy)ethoxy)ethoxy)ethoxy)p iperidin-1-yl)nicotinamide (I-79). To a solution of (7R)-8-cyclopentyl-7-ethyl-5-methyl-2-[2-[2-[2-[2-(4-piperid yloxy) ethoxy]ethoxy]ethoxy]anilino]-7H-pteridin-6-one (80.0 mg, 137 μmol, 1.0 equiv) in NMP (1.00 mL)was added K ₂ CO ₃ (56.9 mg, 412 μmol, 3.0 equiv) and DIEA (36 mg, 275 μmol, 48 μL, 2.0 equiv) at 25 °C for 5 min. And then was added 2-chloro-N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4- tetramethyl-cyclobutyl]pyrimidine-5-carboxamide (69 mg, 165 μmol, 1.2 equiv) at 25 °C .The mixture was stirred at 25 °C for 4 h under N2.Then the reaction mixture was diluted with EtOAc (20 mL) and extracted with H ₂ O (20 mL x 2). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150*25mm* 10um;mobile phase: [water(FA)-ACN];gradient:42%-72% B over 10 min) to give the N-((1r,3r)-3-(3-chloro-4- cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(2-(2-(2-( 2-(((R)-8-cyclopentyl-7-ethyl-5- methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)phenoxy)e thoxy)ethoxy)ethoxy)piperidin-1- yl)nicotinamide (36 mg, 37 μmol, 27 % yield, 98 % purity) as an off-white solid. ¹ H NMR: (400 MHz, MeOD) δ = 8.75 - 8.66 (m, 2H), 8.16 - 8.08 (m, 1H), 7.75 - 7.66 (m, 3H), 7.16 - 7.10 (m, 1H), 6.90 (s, 4H), 4.44 - 4.32 (m, 1H), 4.31 - 4.18 (m, 6H), 4.16 - 4.08 (m, 1H), 3.93 - 3.84 (m, 2H), 3.76 - 3.56 (m, 9H), 3.55 - 3.41 (m, 2H), 3.35 - 3.31 (m, 11H), 2.15 - 2.03 (m, 1H), 2.00 - 1.72 (m, 9H), 1.70 - 1.57 (m, 2H), 1.55 - 1.39 (m, 2H), 1.33 - 1.25 (m, 6H), 1.24 - 1.18 (m, 6H), 0.89 - 0.80 (m, 3H). LC-MS: MS (ES ⁺ ): RT =2.296 min, m/z = 965.6 [M + H] ⁺ ; LCMS Method: 25. EXAMPLE 62 – Synthesis of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]-2-[4-[[3-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-meth yl-6-oxo-7H-pteridin-2-yl]amino]- 3-methoxy-benzoyl]-methyl-amino]cyclobutyl]methyl]-1-piperid yl]pyrimidine-5- carboxamide (I-80) [0671] Step 1: Preparation of tert-butyl 4-[(2,2-dichloro-3-oxo-cyclobutyl)methyl] piperidine-1-carboxylate. To a solution of tert-butyl 4-allylpiperidine-1-carboxylate (6.60 g, 29.0 mmol, 1 equiv) and Zn (19.0 g, 291 mmol, 10 equiv) in dioxane (50 mL) was slowly dropwise added a solution of 1,2-dimethoxyethane (8.00 g, 88.0 mmol, 3 equiv) and 2,2,2-trichloroacetyl chloride (16.0 g, 88.0 mmol, 3 equiv) in dioxane (50 mL) over a period of 0.5 h under N ₂ at 0 °C. The mixture was stirred at 25 °C for 12 h. To the reaction mixture was added EtOAc (200 mL) and stirred at 25 °C for 10 min. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (Petroleum ether/ Ethyl acetate = 20/1 to 5/1) to afford tert-butyl 4-[(2,2-dichloro-3-oxo-cyclobutyl)methyl] piperidine-1- carboxylate (8.40 g, 25 mmol, 85 % yield) as a yellow oil [0672] Step 2: Preparation of tert-butyl 4-[(3-oxocyclobutyl)methyl]piperidine-1- carboxylate. To a solution of tert-butyl 4-[(2,2-dichloro-3-oxo-cyclobutyl)methyl]piperidine-1- carboxylate (8.40 g, 25 mmol, 1 equiv) in MeOH (100 mL) were added Zn (16.5 g, 252 mmol, 10 equiv) and NH ₄ Cl (13.4 g, 250 mmol, 10 equiv) at 20 °C. The mixture was stirred at 30 °C for 12 h. The reaction mixture was filtered and concentrated in vacuo. The residue was purified by column chromatography (Petroleum ether/Ethyl acetate = 10/1 to 3/1) to afford tert-butyl 4-[(3- oxocyclobutyl)methyl]piperidine-1-carboxylate (2.70 g, 10.1 mmol, 40 % yield) as a yellow oil. [0673] Step 3: Preparation of tert-butyl 4-[[3-(methylamino)cyclobutyl]methyl] piperidine-1-carboxylate. To a solution of tert-butyl 4-[(3-oxocyclobutyl)methyl]piperidine-1- carboxylate (300 mg, 1.12 mmol, 1 equiv) in CH ₂ Cl ₂ (5 mL) were added methanamine (2 M, 42.3 mL, 75 equiv) and AcOH (6.80 mg, 0.1 mmol, 0.1 equiv) at 20 °C. The mixture was stirred at 20 °C for 1 h. And then the mixture was added NaBH(OAc) ₃ (720 mg, 3.40 mmol, 3 equiv) at 20 °C and the mixture was stirred for 11 h. The reaction mixture was quenched by addition saturated NH4Cl solution 15 mL, and then extracted with CH ₂ Cl ₂ (5 mL x 3). The combined water layers were concentrated in reduced pressure. The residue was purified by prep-HPLC (FA condition: Column: Phenomenex luna C18150*25mm* 10um; Mobile phase: water(FA)-ACN; Gradient: 4%-34% B, 10 min) to afford tert-butyl 4-[[3-(methylamino)cyclobutyl]methyl] piperidine-1- carboxylate (150 mg, 0.50 mmol, 47 % yield) as a white solid. [0674] Step 4: Preparation of tert-butyl 4-[[3-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6- oxo-7H-pteridin-2-yl]amino]-3-methoxybenzoyl]-methyl-amino]c yclobutyl]methyl] piperidine-1-carboxylate. To a solution of tert-butyl 4-[[3-(methylamino)cyclobutyl] methyl]piperidine-1-carboxylate (140 mg, 0.50 mmol, 1 equiv) in DMF (3 mL) was added 4- [[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl ]amino]-3-methoxybenzoic acid (169 mg, 0.40 mmol, 0.2 equiv), DIEA (192 mg, 1.49 mmol, 3 equiv), HOBt (100 mg, 0.70 mmol, 1.5 equiv) and EDCI (143 mg, 0.70 mmol, 1.5 equiv) at 20 °C. The mixture was stirred at 20 °C for 1 h. The reaction mixture was diluted with water (20 mL). The mixture was extracted with EtOAc (10 mL x 2). The combined organic phase was washed with brine (100 mL), dried with Na ₂ SO ₄ , filtered and concentrated under vacuum to give a residue. The residue was purified by prep-HPLC (Column: Phenomenex luna C18150*25mm* 10um; Mobile phase: water(FA)-ACN; Gradient: 38%-68% B, 10min) to afford tert-butyl 4-[[3-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5- methyl-6-oxo-7H-pteridin-2-yl]amino]-3-methoxybenzoyl]-methy l- amino]cyclobutyl]methyl]piperidine-1-carboxylate (65.0 mg, 0.09 mmol, 19% yield) as a colorless solid. [0675] Step 5: Preparation of 4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin- 2-yl]amino]-3-methoxy-N-methyl-N-[3-(4-piperidylmethyl)cyclo butyl]benzamide. To a solution of tert-butyl 4-[[3-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pte ridin-2- yl]amino]-3-methoxy-benzoyl]-methyl-amino]cyclobutyl]methyl] piperidine-1-carboxylate (30.0 mg, 0.04 mmol, 1 equiv) in CH ₂ Cl ₂ (0.75 mL) was added TFA (0.25 mL). The mixture was stirred at 20 °C for 1 h. The mixture was concentrated in vacuo to afford 4-[[(7R)-8-cyclopentyl-7-ethyl- 5-methyl-6-oxo-7H-pteridin-2-yl]amino]-3-methoxy-N-methyl-N- [3-(4- piperidylmethyl)cyclobutyl]benzamide (40 mg, crude, TFA) as a yellow oil. [0676] Step 6: Preparation of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]-2-[4-[[3-[[4-[[(7R)-8-cyclopentyl-7-ethyl-5-meth yl-6-oxo-7H-pteridin-2-yl]amino]- 3-methoxy-benzoyl]-methyl-amino]cyclobutyl]methyl]-1-piperid yl]pyrimidine-5- carboxamide (I-80). To a solution of 4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H- pteridin-2-yl]amino]-3-methoxy-N-methyl-N-[3-(4-piperidylmet hyl)cyclobutyl]benzamide (40.0 mg, 0.06 mmol, 1 equiv, TFA) in NMP (1 mL) was added 2-chloro-N-[3-(3-chloro-4-cyano- phenoxy)-2,2,4,4-tetramethyl-cyclobutyl] pyrimidine-5-carboxamide (20 mg, 0.05 mmol, 0.2 equiv) and DIEA (7.5 mg, 0.06 mmol, 1 equiv) at 20 °C. The mixture was stirred at 20 °C for 1 h. The reaction mixture was filtered. The residue was purified by prep-HPLC (Column: Phenomenex luna C18150*25mm* 10um; Mobile phase: water(FA)-ACN; Gradient: 53%-83% B, 10 min) to afford N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl-cyclobut yl]-2-[4-[[3-[[4-[[(7R)-8- cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-3 -methoxy-benzoyl]-methyl- amino]cyclobutyl]methyl]-1-piperidyl]pyrimidine-5-carboxamid e (28.0 mg, 0.03 mmol, 47 % yield, 100% purity) as a yellow solid. ¹ H NMR (400 MHz, CH ₃ OD) δ 8.71 (2H, s), 8.33-8.22 (1H, m), 7.74-7.70 (2H, m), 7.12 (1H, d, J = 2.0 Hz), 7.07 (1H, br s), 7.03-6.91 (2H, m), 4.81 (1H, br s), 4.41 (1H, br t, J = 8.4 Hz), 4.35-4.31 (1H, m), 4.26 (1H, s), 4.17-4.09 (1H, m), 3.96 (3H, s), 3.32 (3H, br s), 3.12-3.01 (3H, m), 2.92 (2H, br t, J = 12.0 Hz), 2.59-2.25 (2H, m), 2.21-1.30 (20H, m), 1.27 (6H, s), 1.21 (6H, s), 1.16-1.03 (2H, m), 0.86 (3H, t, J = 7.6 Hz). LC-MS: MS (ES ⁺ ): RT = 1.940 min, m/z = 972.6 [M + H ⁺ ]; LCMS Method: 40. EXAMPLE 63 – Assay for Binding Affinity to Androgen Receptor [0677] Exemplary compounds were tested for ability to bind to the androgen receptor. Experimental procedures and results are provided below. Part I – Experimental Procedure [0678] Fractions of cell cytosol (106 cell/point) were incubated for 24 hr at 4 °C with 1 nM [ ³ H]methyltrienolone in the absence or presence of the test compound in a buffer containing 25 mM Hepes-Tris (pH 7.4), 1 mM EDTA, 10 mM Na2MoO4, 2 mM DTT, 5 μM triamcinolone acetonide, and 10% glycerol. Nonspecific binding was determined in the presence of 1 μM testosterone. Following incubation, the samples were filtered rapidly under vacuum through glass fiber filters (GF/B, Packard) presoaked with 0.3% PEI and rinsed several times with ice-cold 50 mM Tris-HCl using a 96-sample cell harvester (Unifilter, Packard). The filters were dried then counted for radioactivity in a scintillation counter (Topcount, Packard) using a scintillation cocktail (Microscint 0, Packard). The results are expressed as a percent inhibition of the control radioligand specific binding. The standard reference compound is testosterone, which is tested in each experiment at several concentrations to obtain a competition curve from which its IC ₅₀ is calculated. Part II – Results [0679] Results showing ability of exemplary compounds to bind to the androgen receptor are provided in Table 2 below. The symbol “++++” indicates a Kd less than 0.05 ^M. The symbol “+++” indicates an Kd in the range of 0.05 ^M to 0.5 ^M. The symbol “++” indicates a Kd in the range of greater than 0.5 ^M to 2.5 ^M. The symbol “+” indicates a Kd greater than 2.5 ^M. TABLE 2.

EXAMPLE 64 – Assay for Binding Affinity to PLK1 [0680] Exemplary compounds were tested for ability to bind to PLK1. Experimental procedures and results are provided below. Part I – Experimental Procedure [0681] Compounds were tested using a KdELECT assay. Kinase-tagged T7 phage strains were prepared in an E. coli host derived from the BL21 strain. E. coli were grown to log-phase and infected with T7 phage and incubated with shaking at 32 °C until lysis. The lysates were centrifuged and filtered to remove cell debris. The remaining kinases were produced in HEK-293 cells and subsequently tagged with DNA for qPCR detection. Streptavidin-coated magnetic beads were treated with biotinylated small molecule ligands for 30 minutes at room temperature to generate affinity resins for kinase assays. The liganded beads were blocked with excess biotin and washed with blocking buffer (SeaBlock (Pierce), 1% BSA, 0.05% Tween 20, 1 mM DTT) to remove unbound ligand and to reduce non-specific binding. Binding reactions were assembled by combining kinases, liganded affinity beads, and test compounds in 1x binding buffer (20% SeaBlock, 0.17x PBS, 0.05% Tween 20, 6 mM DTT). Test compounds were prepared as 111X stocks in 100% DMSO. Kd values were determined using an 11-point 3-fold compound dilution series with three DMSO control points. All compounds for Kd measurements are distributed by acoustic transfer (non-contact dispensing) in 100% DMSO. The compounds were then diluted directly into the assays such that the final concentration of DMSO was 0.9%. All reactions performed in polypropylene 384-well plate. Each was a final volume of 0.02 mL. The assay plates were incubated at room temperature with shaking for 1 hour and the affinity beads were washed with wash buffer (1x PBS, 0.05% Tween 20). The beads were then re-suspended in elution buffer (1x PBS, 0.05% Tween 20, 0.5 μM nonbiotinylated affinity ligand) and incubated at room temperature with shaking for 30 minutes. The kinase concentration in the eluates was measured by qPCR. Part II – Results [0682] Results showing ability of exemplary compounds to bind to PLK1 are provided in Table 3 below. The symbol “++++” indicates a Kd less than 0.05 ^M. The symbol “+++” indicates a Kd in the range of 0.05 ^M to 0.5 ^M. The symbol “++” indicates a Kd in the range of greater than 0.5 ^M to 2.5 ^M. The symbol “+” indicates a Kd greater than 2.5 ^M. TABLE 3. EXAMPLE 65 – Cellular Growth Inhibition Assay Using T-Rex 293 Cells [0683] Exemplary compounds were tested for ability to inhibit the proliferation of the following types of cells: (i) a T-Rex 293 cell line having increased expression of androgen receptor protein due to exposure to doxycycline and (ii) a T-Rex 293 cell line lacking increased expression of androgen receptor protein. Experimental procedures and results are provided below. Part I – Experimental Procedure [0684] The following types of cells were prepared for this experiment: (i) a T-Rex 293 cell line having increased expression of androgen receptor protein due to exposure to doxycycline and (ii) a T-Rex 293 cell line lacking increased expression of androgen receptor protein. Ability of the test compounds to inhibit proliferation of the foregoing cell types was evaluated according to the procedures set forth below. [0685] The doxycycline-inducible androgen receptor protein expressing cell line was established using the following protocol: T-Rex 293 cells were purchased from Invitrogen (Cat#R71007) and transfected using Lipofectamine 2000 with the wild-type androgen receptor protein sequence cloned into the pcDNA4/TO vector. Transfected cells were selected using 400 µg/mL Zeocin (Invitrogen Cat#R25001). Following selection, single clones were raised and maintained in Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10% w/w Tetracycline-free fetal bovine serum (FBS) and 250 µg/mL Zeocin. Clones were analyzed for expression of androgen receptor protein in the presence and absence of 10 ng/mL doxycycline (Sigma Cat#D9891), and a single doxycycline-inducible clone (hereinafter “SC3”) was selected for use in downstream assays. [0686] The SC3 cells were seeded on poly-D-lysine coated, black clear-bottom 384-well plates at 2500/well, in 25 ^L Phenol Red Free Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10% w/w charcoal-dextran treated fetal bovine serum (FBS) and 1% w/w pen- strep, with or without 10 ng/mL doxycycline. Pen-Strep is a commercially available mixture of penicillin G and streptomycin, which is used in mammalian cell culture media to prevent bacterial contamination. Phenol Red Free Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10% w/w charcoal-dextran treated fetal bovine serum (FBS) and 1% w/w pen-strep, with or without 10 ng/mL doxycycline is herein referred to as Treatment Medium. Following seeding of cells in the plates, the plates were spun at 300 × g^for 30 seconds, then equilibrated to room temperature for 30 minutes, and then deposited^in a humidified tissue culture incubator maintained at 37 °C with 5% CO2. [0687] At 24 hours after seeding of the cells, dilutions of test compound were prepared in DMSO and dissolved in Treatment Medium, to achieve a final DMSO concentration of 0.5% w/w, thereby providing the Test Compound Solution. A 25 ^L aliquot of the Test Compound Solution was added to cells in the well plates. An equal volume of a solution containing DMSO and Treatment Medium was used as a negative control. Following treatment of cells with Test Compound Solution or said equal volume of a solution containing DMSO and Treatment Medium, the plates were spun at 300 × g for 30 seconds, and then left in an incubator for 72 hours. [0688] At the end of the treatment duration, cell viability was quantified with CellTiter-Glo 2.0 reagent (Promega Cat#G9243). For this purpose, plates were equilibrated to room temperature for 30 minutes, and then 25 µL of CellTiter-Glo 2.0 reagent was added to cells in the plate wells. Plates were then agitated on a shaker for two minutes at 500 rpm and subsequently incubated at room temperature for 10 minutes. Following incubation, the plates were spun at 3000 x g for 30 seconds, then sealed with an optical adhesive cover, and luminescence readings were measured with an EnVision Plate Reader. [0689] Data was normalized using zero luminescence for baseline. A four-parameter non-linear regression curve fit was applied to dose-response data in GraphPad Prism data analysis software to determine the half-maximal growth inhibitory concentration (GI50) for each test compound. Part II – Results [0690] The half-maximal growth inhibitory concentration (GI ₅₀ ) results are provided in Tables 4 and 5 below for exemplary compounds. Table 4 provides results from the experiment analyzing ability of test compounds to inhibit proliferation of the T-Rex 293 cell line SC3 cells having increased expression of androgen receptor protein due to exposure to doxycycline. The symbol “++++” indicates a GI50 less than 0.5 ^M. The symbol “+++” indicates an GI50 in the range of 0.5 ^M to 1.5 ^M. The symbol “++” indicates a GI50 in the range of greater than 1.5 ^M to 3 ^M. The symbol “+” indicates a GI50 greater than 3 ^M. TABLE 4.

[0691] Table 5 provides results from the experiment analyzing ability of test compounds to inhibit proliferation of the T-Rex 293 cell line SC3 cells lacking increased expression of androgen receptor protein since such cells were not exposed to doxycycline. The symbol “++++” indicates a GI50 less than 0.5 ^M. The symbol “+++” indicates an GI50 in the range of 0.5 ^M to 1.5 ^M. The symbol “++” indicates a GI50 in the range of greater than 1.5 ^M to 3 ^M. The symbol “+” indicates a GI ₅₀ greater than 3 ^M. TABLE 5.

EXAMPLE 66 – Cellular Growth Inhibition Assay for VCaP Cells [0692] Exemplary compounds were tested for ability to inhibit the proliferation of VCaP cells. VCap cells are a commercially available human prostate cancer cell line. Experimental procedures and results are provided below. Part I – Experimental Procedure [0693] VCaP cells were purchased from American Type Cell Culture (ATCC Cat#CRL2876) and then seeded on poly-D-lysine coated, black clear-bottom 384-well plates at 5000/well in 25 ^L Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10% w/w Fetal bovine serum (FBS) and 1% w/w Pen-Strep. Pen-Strep is a commercially available mixture of penicillin G and streptomycin, which is used in mammalian cell culture media to prevent bacterial contamination. Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10% w/w fetal bovine serum (FBS) and 1% w/w Pen-Strep is herein referred to as Treatment Medium. Following seeding of cells in the plates, the plates were spun at 300 × g^for 30 seconds, then equilibrated to room temperature for 30 minutes, and then deposited^in a humidified tissue culture incubator maintained at 37 °C with 5% CO ₂ . [0694] At 24 hours after seeding of the cells, dilutions of test compound were prepared in DMSO and dissolved in Treatment Medium, to achieve a final DMSO concentration of 0.5% w/w, thereby providing the Test Compound Solution. A 25 ^L aliquot of the Test Compound Solution was added to cells in the well plates. An equal volume of a solution containing DMSO and Treatment Medium was used as a negative control. Following treatment of cells with Test Compound Solution or said equal volume of a solution containing DMSO and Treatment Medium, the plates were spun at 300 × g for 30 seconds, and then left in an incubator for 72 hours. [0695] At the end of the treatment duration, cell viability was quantified with CellTiter-Glo 2.0 reagent (Promega Cat#G9243). For this purpose, plates were equilibrated to room temperature for 30 minutes, and then 25 µL of CellTiter-Glo 2.0 reagent was added to cells in the plate wells. Plates were then agitated on a shaker for two minutes at 500 rpm and subsequently incubated at room temperature for 10 minutes. Following incubation, the plates were spun at 3000 x g for 30 seconds, then sealed with an optical adhesive cover, and luminescence readings were measured with an EnVision Plate Reader. [0696] Data was normalized using zero luminescence for baseline. A four-parameter non-linear regression curve fit was applied to dose-response data in GraphPad Prism data analysis software to determine the half-maximal growth inhibitory concentration (GI ₅₀ ) for each test compound. Part II – Results [0697] The half-maximal growth inhibitory concentration (GI50) results are provided in Table 6 below for exemplary compounds. The symbol “++++” indicates a GI ₅₀ less than 0.5 ^M. The symbol “+++” indicates an GI ₅₀ in the range of 0.5 ^M to 1.5 ^M. The symbol “++” indicates a GI50 in the range of greater than 1.5 ^M to 3 ^M. The symbol “+” indicates a GI50 greater than 3 ^M. TABLE 6.

EXAMPLE 67– Cellular Growth Inhibition Assay Using T-Rex 293 Cells [0698] Exemplary compounds were tested for ability to inhibit the proliferation of the following types of cells: (i) a T-Rex 293 cell line having increased expression of progesterone receptor isoform B protein due to exposure of doxycycline and (ii) a T-Rex 293 cell line lacking increased expression of progesterone receptor isoform B protein. Experimental procedures and results are provided below. Part I – Experimental Procedure [0699] The following types of cells were prepared for this experiment: (i) a T-Rex 293 cell line having increased expression of progesterone receptor isoform B protein due to exposure to doxycycline and (ii) a T-Rex 293 cell line lacking increased expression of progesterone receptor isoform B protein. Ability of the test compounds to inhibit proliferation of the foregoing cell types was evaluated according to the procedures set forth below. [0700] The doxycycline-inducible progesterone receptor isoform B protein expressing cell line was established using the following protocol: T-Rex 293 cells were purchased from Invitrogen (Cat#R71007) and transfected using Lipofectamine 2000 with the wild-type progesterone receptor B protein sequence cloned into the pcDNA4/TO vector. Transfected cells were selected using 400 µg/mL Zeocin (Invitrogen Cat#R25001). Following selection, single clones were raised and maintained in Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10% w/w Tetracycline-free fetal bovine serum (FBS) and 250 µg/mL Zeocin. Clones were analyzed for expression of progesterone receptor isoform B protein in the presence and absence of 10 ng/mL doxycycline (Sigma Cat#D9891), and a single doxycycline-inducible clone (hereinafter “SC”) was selected for use in downstream assays. [0701] The SC cells were seeded on poly-D-lysine coated, black clear-bottom 384-well plates at 2500/well, in 25 ^L Phenol Red Free Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10% w/w charcoal-dextran treated fetal bovine serum (FBS) and 1% w/w pen- strep, with or without 10 ng/mL doxycycline. Pen-Strep is a commercially available mixture of penicillin G and streptomycin, which is used in mammalian cell culture media to prevent bacterial contamination. Phenol Red Free Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10% w/w charcoal-dextran treated fetal bovine serum (FBS) and 1% w/w pen-strep, with or without 10 ng/mL doxycycline is herein referred to as Treatment Medium. Following seeding of cells in the plates, the plates were spun at 300 × g^for 30 seconds, then equilibrated to room temperature for 30 minutes, and then deposited^in a humidified tissue culture incubator maintained at 37 °C with 5% CO ₂ . [0702] At 24 hours after seeding of the cells, dilutions of test compound were prepared in DMSO and dissolved in Treatment Medium, to achieve a final DMSO concentration of 0.5% w/w, thereby providing the Test Compound Solution. A 25 ^L aliquot of the Test Compound Solution was added to cells in the well plates. An equal volume of a solution containing DMSO and Treatment Medium was used as a negative control. Following treatment of cells with Test Compound Solution or said equal volume of a solution containing DMSO and Treatment Medium, the plates were spun at 300 × g for 30 seconds, and then left in an incubator for 72 hours. [0703] At the end of the treatment duration, cell viability was quantified with CellTiter-Glo 2.0 reagent (Promega Cat#G9243). For this purpose, plates were equilibrated to room temperature for 30 minutes, and then 25 µL of CellTiter-Glo 2.0 reagent was added to cells in the plate wells. Plates were then agitated on a shaker for two minutes at 500 rpm and subsequently incubated at room temperature for 10 minutes. Following incubation, the plates were spun at 3000 x g for 30 seconds, then sealed with an optical adhesive cover, and luminescence readings were measured with an EnVision Plate Reader (Perkin Elmer). [0704] Data was normalized using zero luminescence for baseline. A four-parameter non-linear regression curve fit was applied to dose-response data in GraphPad Prism data analysis software to determine the half-maximal growth inhibitory concentration (GI ₅₀ ) for each test compound. Part II – Results [0705] The half-maximal growth inhibitory concentration (GI50) results are provided in Tables 7 and 8 below for exemplary compounds. Table 7 provides results from the experiment analyzing ability of test compounds to inhibit proliferation of the T-Rex 293 cell line SC cells having increased expression of progesterone receptor isoform B protein due to exposure to doxycycline. The symbol “+++” indicates an GI50 in the range of 0.5 ^M to 1.5 ^M. The symbol “++” indicates a GI50 in the range of greater than 1.5 ^M to 3 ^M. The symbol “+” indicates a GI50 greater than 3 ^M. TABLE 7. [0706] Table 8 provides results from the experiment analyzing ability of test compounds to inhibit proliferation of the T-Rex 293 cell line SC cells lacking increased expression of progesterone receptor isoform B protein since such cells were not exposed to doxycycline. The symbol “++++” indicates a GI50 less than 0.5 ^M. The symbol “+++” indicates an GI50 in the range of 0.5 ^M to 1.5 ^M. The symbol “++” indicates a GI ₅₀ in the range of greater than 1.5 ^M to 3 ^M. The symbol “+” indicates a GI ₅₀ greater than 3 ^M. TABLE 8. EXAMPLE 68 – Cellular Growth Inhibition Assay for T47D Cells [0707] Exemplary compounds were tested for ability to inhibit the proliferation of T47D cells. T47D cells are a commercially available human breast cancer cell line. Experimental procedures and results are provided below. Part I – Experimental Procedure [0708] T47D cells were purchased from American Type Cell Culture (ATCC Cat# HTB-133) and then seeded on poly-D-lysine coated, black clear-bottom 384-well plates at 3000/well in 25 ^L Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10% w/w Fetal bovine serum (FBS), 0.2 units/mL recombinant human insulin (Gibco Cat# 12585014), and 1% w/w Pen-Strep. Pen-Strep is a commercially available mixture of penicillin G and streptomycin, which is used in mammalian cell culture media to prevent bacterial contamination. Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10% w/w fetal bovine serum (FBS), 0.2 units/mL recombinant human insulin, and 1% w/w Pen-Strep is herein referred to as Treatment Medium. Following seeding of cells in the plates, the plates were spun at 300 × g^for 30 seconds, then equilibrated to room temperature for 30 minutes, and then deposited^in a humidified tissue culture incubator maintained at 37 °C with 5% CO2. [0709] At 24 hours after seeding of the cells, dilutions of test compound were prepared in DMSO and dissolved in Treatment Medium, to achieve a final DMSO concentration of 0.5% w/w, thereby providing the Test Compound Solution. A 25 ^L aliquot of the Test Compound Solution was added to cells in the well plates. An equal volume of a solution containing DMSO and Treatment Medium was used as a negative control. Following treatment of cells with Test Compound Solution or said equal volume of a solution containing DMSO and Treatment Medium, the plates were spun at 300 × g for 30 seconds, and then left in an incubator for 72 hours. [0710] At the end of the treatment duration, cell viability was quantified with CellTiter-Glo 2.0 reagent (Promega Cat#G9243). For this purpose, plates were equilibrated to room temperature for 30 minutes, and then 25 µL of CellTiter-Glo 2.0 reagent was added to cells in the plate wells. Plates were then agitated on a shaker for two minutes at 500 rpm and subsequently incubated at room temperature for 10 minutes. Following incubation, the plates were spun at 3000 x g for 30 seconds, then sealed with an optical adhesive cover, and luminescence readings were measured with an EnVision Plate Reader (Perkin Elmer). [0711] Data was normalized using zero luminescence for baseline. A four-parameter non-linear regression curve fit was applied to dose-response data in GraphPad Prism data analysis software to determine the half-maximal growth inhibitory concentration (GI50) for each test compound. Part II – Results [0712] The half-maximal growth inhibitory concentration (GI ₅₀ ) results are provided in Table 9 below for exemplary compounds. The symbol “++++” indicates a GI50 less than 0.5 ^M. The symbol “+++” indicates an GI50 in the range of 0.5 ^M to 1.5 ^M. The symbol “ ” indicates a GI50 in the range of greater than 1.5 ^M to 3 ^M. The symbol “+” indicates a GI50 greater than 3 ^M. TABLE 9. INCORPORATION BY REFERENCE [0713] The entire disclosure of each of the patent documents and scientific articles referred to herein is incorporated by reference for all purposes. EQUIVALENTS [0714] The invention may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The foregoing embodiments are therefore to be considered in all respects illustrative rather than limiting the invention described herein. Scope of the invention is thus indicated by the appended claims rather than by the foregoing description, and all changes that come within the meaning and range of equivalency of the claims are intended to be embraced therein.