Compounds and methods for the targeted degradation of androgen receptor

Abstract

This invention relates to compounds, their formulations, and the use of such compounds in the treatment of prostate cancer, including metastatic and / or castration-resistant prostate cancer, in individuals in need.

Description

Technical Field

[0001] Cross-reference of related applications This application claims priority and benefits to U.S. Application No. 63 / 089,497, filed October 8, 2020; U.S. Application No. 63 / 032,473, filed May 29, 2020; and U.S. Application No. 62 / 950,815, filed December 19, 2019, the entire contents of which are incorporated herein by reference. [The sequence list is incorporated by reference] [ ]

[0002] The contents of the text file named "ARVN-007_001WO_SeqList_ST25", which was created on December 16, 2020 and is 9 KB in size, are hereby incorporated in full.

[0003] This invention provides compounds based on aceimine, including bifunctional compounds comprising the same, and related methods of use. The bifunctional compounds are suitable as regulators of targeted ubiquitination, particularly with respect to various polypeptides and other proteins that are degraded and / or additionally inhibited by the bifunctional compounds according to this invention. Prior Technology

[0004] Most small molecule drugs bind to enzymes or receptors in tightly bound and well-defined pouches. On the other hand, protein-protein interactions are very difficult to target with small molecules due to their large contact surfaces and the shallow grooves or flat interfaces involved. E3 ubiquitin ligases (hundreds of which are known in the human body) endow receptors with specificity for ubiquitination and are therefore attractive therapeutic targets. The development of ligands for E3 ligases has proven challenging, partly because they inevitably disrupt protein-protein interactions. However, current research has provided specific ligands that bind to these ligases.

[0005] Celeblon is an E3 ubiquitin ligase with therapeutic potential. Celeblon is a protein encoded by the CRBN gene in the human body. Thalidomide and its analogues (such as pomalidomide and lenalidomide) are known to bind to cereblon. These drugs bind to cereblon, thereby altering the specificity of the complex to induce ubiquitination and degradation of transcription factors essential for the growth of multiple myeloma. In fact, higher efficacy of cereblon is associated with increased efficacy of imipenem drugs in the treatment of multiple myeloma.

[0006] The androgen receptor (AR) belongs to the nuclear hormone receptor family activated by androgens such as testosterone and dihydrotestosterone (Pharmacol. Rev. 2006, 58(4), 782-97; Vitam. Horn. 1999, 55:309-52.). In the absence of androgens, the AR is bound by heat shock protein 90 (Hsp90) in the cytosol. When an androgen binds to the AR, its conformation changes from Hsp90, releasing the AR and exposing the nuclear localization signal (NLS). The latter causes the AR to translocate to the nucleus, where it acts as a transcription factor that promotes the expression of genes responsible for male sexual characteristics (Endocr. Rev. 1987, 8(1):1-28; Mol. Endocrinol. 2002, 16(10), 2181-7). AR deficiency causes androgen desensitization syndrome, previously known as testicular feminization.

[0007] Although the androgen-associated antigen (AR) is responsible for male sexual characteristics, it is also a recognized oncogene for certain forms of cancer, including prostate cancer (Endocr. Rev. 2004, 25(2), 276-308). The commonly measured target gene for AR activity is the secreted prostate-specific antigen (PSA) protein. Current treatment options for prostate cancer involve two approaches to inhibit the androgen-AR axis. The first approach relies on reducing androgens, while the second strategy aims to inhibit AR function (Nat. Rev. Drug Discovery, 2013, 12, 823-824). Despite the development of effective targeted therapies, most patients develop resistance and disease progression. Alternative approaches to treating prostate cancer involve eliminating AR proteins.

[0008] Since adenocarcinoma (AR) is a key driver of tumor formation in many forms of prostate cancer, its elimination should elicit a therapeutically beneficial response. There remains a need for effective treatments for diseases, particularly cancer, prostate cancer, and Kennedy's disease, within this technology.

[0009] However, non-specificity and the inability to target and regulate certain classes of proteins (such as transcription factors) remain obstacles to the development of effective anticancer agents. Therefore, small molecule therapeutics that fully utilize or enhance the receptor specificity of silebron while being "tunable" so as to specifically target and regulate a wide range of protein classes will be extremely suitable as therapeutic agents. Summary of the Invention

[0010] This invention describes bifunctional compounds for recruiting endogenous proteins to E3 ubiquitin ligases for degradation, and methods of using them. Specifically, this invention provides bifunctional or protein degradation-targeting chimeric compounds, practically acting as regulators of targeted ubiquitination of various peptides and other proteins, which are subsequently degraded and / or further inhibited by the bifunctional compounds described herein. The advantage of the compounds provided herein lies in the possibility of a broad range of pharmaceutical activities, consistent with the degradation / inhibition of targeted peptides from virtually any protein class or family. Furthermore, embodiments provide methods for treating or alleviating disease symptoms, such as cancer (e.g., multiple myeloma or prostate cancer), using effective amounts of the compounds described herein. [ ] [ ]

[0011] In one state, this application provides a bifunctional compound having the following structure: ABM-L-CLM, Or its pharmaceutically acceptable salts, solvates, enantiomers, stereoisomers, or isotopic derivatives, in: (a) The ABM is an androgen receptor (AR) binding site with the following structure: in: Q1, Q2, Q3, Q4, and Q5 are each independently CR1 or N; It is a 4-6 membered cycloalkyl, C6-C10 aryl, 4-6 membered heterocycloalkyl, or 4-6 membered heteroaryl, wherein the heterocycloalkyl or heteroaryl contains 0-4 heteroatoms; Q6, Q7, Q8, Q9, and Q10 are each independently CR3 or N; Each R1 group is independently selected from the group consisting of: H, substituted linear or branched C1-C6 alkyl, cyano, halogen, and substituted linear or branched C1-C6 alkoxy, wherein the alkyl or alkoxy is substituted with one or more halogen groups as appropriate; Each R2 group is independently selected from the group consisting of:, where appropriate, substituted straight-chain or branched C1-C6 alkyl, cyano, halogen, and, where appropriate, substituted straight-chain or branched C1-C6 alkoxy groups, wherein the alkyl or alkoxy group is substituted with one or more halogen groups; Each R3 group is independently selected from the group consisting of: H, straight-chain or branched C1-C6 alkyl, cyano, halogen, and, where appropriate, substituted straight-chain or branched C1-C6 alkoxy groups, wherein the alkyl or alkoxy group is, where appropriate, substituted with one or more halogen groups; and n is 0, 1, 2, 3, or 4; (b) L is a chemical linker with the following structure: in: ABM is connected to W and CLM is connected to Z, or ABM is connected to Z and CLM is connected to W; W does not exist or is It is a 4-7 membered cycloalkyl, a 4-7 membered heterocyclic or spiro-bicyclic heterocyclic alkyl, wherein each ring in the spiro-bicyclic is 4-7 members; X is -CH2-, or does not exist; Y is -NR6-, -O-, or does not exist; It is a 4-7 membered cycloalkyl or a 4-7 membered heterocyclic ring; Z is -C(R7)2-, -NR7-, -O-, or does not exist; R6 is H, a straight-chain or branched C1-6 alkyl, a straight-chain or branched C1-6 alkoxy-C1-6 alkyl, or... ,in The indicator is connected to the Y key, and Instructions connected to One key; Each R7 group is independently selected from the following groups: H, straight-chain or branched C1-6 alkyl groups, and straight-chain or branched C1-6 alkoxy groups; p is 1, 2, 3, or 4; and q is 1, 2, 3, 4, or 5; (c) CLM is a cereblon E3 ubiquitin ligase-binding moiety with the following structure: in: It is a C6-C10 aryl, 4-7 member heteroaryl, or a bridged bicyclic cycloalkyl group; The connection portion L is connected to the ring S by one or two covalent bonds; Each R4 group is independently selected from the group consisting of:, where appropriate, substituted straight-chain or branched C1-C6 alkyl, cyano, halogen, and, where appropriate, substituted straight-chain or branched C1-C6 alkoxy groups, wherein the alkyl or alkoxy group is substituted with one or more halogen groups; R5 is H, or a substituted straight-chain or branched C1-C6 alkyl group, or a substituted straight-chain or branched C1-C6 alkoxy group, wherein the alkyl or alkoxy group is substituted with one or more halogen groups, and m can be 0, 1, 2, 3, or 4.

[0012] In some embodiments, when When it is pyridyl, When R1 is tetramethylcyclobutyl, Q2 is CR1 and Q4 is CR1; R1 is not chlorine.

[0013] In some embodiments, other limiting conditions are that the compound is not N-(4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-((4-(4-(((2,6-dioxypiperidin-3-yl)aminomethyl)phenyl)piperidin -1-yl)methyl)piperidin-1-yl)tad -3-methamide.

[0014] In another embodiment, this application provides a bifunctional compound of technical solution 1, wherein the compound is a compound of formula (I): Or a pharmaceutically acceptable salt, solvate, enantiomer, stereoisomer, or isotopic derivative thereof.

[0015] In some embodiments, L is in: It is a 4-7 membered cycloalkyl or a 4-7 membered heterocyclic ring; Y is -NR6-, -O-, or does not exist; R6 is H, a straight-chain or branched C1-6 alkyl group, or a straight-chain or branched C1-6 alkoxy group; and It is a 4-7 member cycloalkyl or a 4-7 member heterocyclic ring.

[0016] In some embodiments, L is in: It is a 4-7 membered cycloalkyl or a 4-7 membered heterocyclic ring; Y is either -NR6- or -O-; R6 is H, a straight-chain or branched C1-6 alkyl group, or a straight-chain or branched C1-6 alkoxy group; and It is a 4-7 member cycloalkyl or a 4-7 member heterocyclic ring.

[0017] In some embodiments, L is in: Piperidinyl or phyllyl; Y is either -NR6- or -O-; R6 is ; It is cyclobutyl; and Z is -O-.

[0018] In some embodiments, L is in: Piperidinyl or phyll group; and For Piper base.

[0019] In some embodiments, It is piperidinyl.

[0020] In some embodiments, the compound is a compound of formula (Ib): Or a pharmaceutically acceptable salt, solvate, enantiomer, stereoisomer, or isotopic derivative thereof.

[0021] In some embodiments, the compound is a compound of formula (Ic): Or a pharmaceutically acceptable salt, solvate, enantiomer, stereoisomer, or isotopic derivative thereof.

[0022] In some embodiments, Q1-Q5 are each CR1.

[0023] In some embodiments, exactly one of Q1-Q5 is N.

[0024] In some embodiments, exactly two of Q1-Q5 are N.

[0025] In some embodiments, exactly three of Q1-Q5 are N.

[0026] In some embodiments, Q6-Q10 are each CR3.

[0027] In some embodiments, exactly one of Q6-Q10 is N.

[0028] In some embodiments, exactly two of Q6-Q10 are N.

[0029] In some embodiments, exactly three of Q6-Q10 are N.

[0030] In some embodiments, Q1 is CH, Q2 is C(CH3), Q3 is C(CN), Q4 is C(CH3), and Q5 is CH.

[0031] In some embodiments, Q1 is CH, Q2 is C(OCH3), Q3 is C(CN), Q4 is CH, and Q5 is CH.

[0032] In some embodiments, Q1 is CH, Q2 is C(Cl), Q3 is C(CN), Q4 is CH, and Q5 is CH.

[0033] In some embodiments, It is a 4-6 member cycloalkyl group.

[0034] In some embodiments, It is cyclobutyl or cyclohexyl.

[0035] In some embodiments, It is cyclobutyl.

[0036] In some embodiments, n is 4.

[0037] In some embodiments, each R2 is a methyl group.

[0038] In some embodiments, Q is cyclohexyl.

[0039] In some embodiments, n is 0.

[0040] In some embodiments, R2 is a straight-chain or branched-chain C1-C6 alkyl group.

[0041] In some embodiments, It is phenyl, pyridyl, or tert-phenyl. pyrimidinyl or pyridine base.

[0042] In some embodiments, It is a phenyl group.

[0043] In some embodiments, It is pyridyl.

[0044] In some embodiments, For Ta base.

[0045] In some embodiments, It is a pyrimidinyl group.

[0046] In some embodiments, For pyr base.

[0047] In some embodiments, each R4 system is independently selected from the group consisting of: F, methoxy, ethoxy, methyl, and ethyl.

[0048] In some embodiments, each R4 group is independently selected from the group consisting of F, methoxy, and methyl.

[0049] In some embodiments, m is 0, 1, or 2.

[0050] In some embodiments, m is 0.

[0051] In some embodiments, m is 1.

[0052] In some embodiments, m is 2.

[0053] In one state sample, this application provides a bifunctional compound, wherein the compound is: , Or a medically acceptable salt, enantiomer, stereoisomer, or isotope derivative of any of the foregoing.

[0054] In one state sample, this application provides a bifunctional compound, wherein the compound is: , Or a medically acceptable salt, enantiomer, stereoisomer, or isotope derivative of any of the foregoing.

[0055] In one embodiment, this application provides a pharmaceutical composition comprising a bifunctional compound described herein and one or more pharmaceutically acceptable excipients.

[0056] In one embodiment, the composition is formulated as an tablet and comprises one or more of the following: an emulsifier; a surfactant; an adhesive; a disintegrant; a lubricant; and a slurry.

[0057] In one embodiment, the composition further comprises an effective amount of at least one additional anticancer agent.

[0058] In one embodiment, the anticancer agent is estramustine, docetaxel, ketoconazole, goserelin, histrelin, triptorelin, buserelin, cyproterone, flutamide, bicalutamide, nilutamide, pamidronate, or zolendronate.

[0059] In one embodiment, this application provides a method of treating an individual with prostate cancer, comprising administering to the individual in need a therapeutically effective amount of the bifunctional compound described herein or a therapeutically effective amount of the pharmaceutical composition described herein.

[0060] In one embodiment, an individual is orally administered a therapeutically effective amount of a bifunctional compound.

[0061] In one embodiment, a therapeutically effective amount of the bifunctional compound is administered to an individual once, twice, three times, or four times a day.

[0062] In one embodiment, an individual is given a therapeutically effective amount of a bifunctional compound once a day.

[0063] In one embodiment, a therapeutically effective amount of the bifunctional compound is administered to the individual in a single, whole dose or in two, three, or four doses.

[0064] In one embodiment, the therapeutically effective amount of the bifunctional compound is about 1 mg to about 1000 mg.

[0065] In one embodiment, the therapeutically effective amount of the bifunctional compound is about 5 mg to about 750 mg.

[0066] In one embodiment, the therapeutically effective amount of the bifunctional compound is about 10 mg to about 500 mg.

[0067] In one embodiment, the therapeutically effective amount of the bifunctional compound is about 20 mg to about 250 mg.

[0068] In one embodiment, the individual was eating when the medication was administered.

[0069] In one embodiment, the individual is fasting when the medication is administered.

[0070] In one embodiment, the method further includes administering an effective amount of at least one additional anticancer agent to the individual in need.

[0071] In one embodiment, the anticancer agent is abiraterone, estradiol mustard, docetaxel, ketoconazole, goserelin, histamine relin, triptorelin, buterrelin, cyproterone acetate, flutamide, bicalutamide, niludamide, pamidronate, or levodopa.

[0072] In one embodiment, an individual with prostate cancer contains at least one somatic AR tumor mutation.

[0073] In one embodiment, the prostate cancer is castration-resistant prostate cancer.

[0074] In one embodiment, the prostate cancer is metastatic prostate cancer.

[0075] In one embodiment, this application provides a method for treating prostate cancer in a subgroup of individuals with prostate cancer, comprising: Individuals with prostate cancer were selected for treatment based on their somatic AR tumor biomarker status; and Administer a therapeutically effective amount of a bifunctional compound of formula (I) or a pharmaceutical composition containing a therapeutically effective amount of a bifunctional compound of formula (I).

[0076] In one embodiment, the somatic AR tumor biomarker status of an individual includes at least one somatic AR tumor mutation.

[0077] In one embodiment, the AR biomarker status of an individual is determined by ctDNA analysis, fluorescence in situ hybridization, immunohistochemistry, PCR analysis, or sequencing.

[0078] In one embodiment, the individual's AR biomarker status is determined in a blood sample derived from the individual.

[0079] In one embodiment, the individual's AR biomarker status is determined in a solid tissue section derived from a tumor.

[0080] In one embodiment, the prostate cancer is castration-resistant prostate cancer.

[0081] In one embodiment, the prostate cancer is metastatic prostate cancer.

[0082] In one embodiment, at least one somatic AR tumor mutation line is selected from the group consisting of: L702H, M895V, M896V, T878A, F877L, and H875Y. Simple Explanation of the Diagram

[0083] The accompanying drawings, which are incorporated in and form part of this specification, illustrate several embodiments of the invention and, together with the embodiments, serve to explain the principles of the invention. The drawings are for illustrative purposes only and should not be construed as limiting the invention. Other objects, features, and advantages of the invention will become apparent from the following detailed description in conjunction with the accompanying drawings, which illustrate illustrative embodiments of the invention, wherein: [ ] [ ]

[0084] [Figures 1A and 1B] illustrate the general principle of the functionality of protein degradation-targeting chimeric compounds. Figure 1A shows an exemplary protein degradation-targeting chimeric compound comprising a protein-targeting moiety (PTM; dark shaded rectangle), a thiebulone ubiquitin ligase-binding moiety (CLM; unshaded triangle), and a linker moiety (black line) that couples or links the PTM to the CLM. Figure 1B illustrates the functional applications of the protein degradation-targeting chimeric compound as described herein. In short, the CLM recognizes and binds to thiebulone (E3 ubiquitin ligase), and the PTM binds to and recruits the intracellular target protein, thereby bringing the intracellular target protein very close to the thiebulone E3 ubiquitin ligase. Typically, the thiebulone E3 ubiquitin ligase complexes with an E2 ubiquitin-binding protein, and the ubiquitin (black circle) is linked to the target protein via a heteropeptide bond, either alone or via the E2 protein. The target polyubiquitin-binding protein (far right) is then targeted for degradation by the cell's proteasome apparatus. [ ] [ ]

[0085] [Figure 2] shows the process of synthesizing compound No. 4. [ ] [ ]

[0086] [Figure 3] shows the process of synthesizing compound No. 9. [ ] [ ]

[0087] [Figure 4] shows the process of synthesizing compound No. 17. Implementation

[0088] definition All references concerning amino acid mutations in the androgen receptor are numbered relative to SEQ ID NO: 1 provided herein.

[0089] The term "ubiprotein ligase" refers to a family of proteins that facilitate the transfer of ubiproteins to specific recipient proteins, thereby targeting the recipient proteins for degradation. For example, selebromen is an E3 ubiprotein ligase protein, alone or in combination with E2 ubiprotein conjugating enzymes, that causes ubiprotein to be linked to a lysine residue on a target protein; and subsequently targets a specific protein recipient for degradation by the proteasome. Therefore, E3 ubiprotein ligases, alone or in combination with E2 ubiprotein conjugating enzymes, are responsible for transferring ubiproteins to the targeted protein. Generally, ubiprotein ligases participate in polyubiquitination, causing a second ubiprotein to link to a first ubiprotein; a third ubiprotein to link to a second ubiprotein, and so on. Polyubiquitination labels the protein for degradation by the proteasome. However, there are some ubiquitination events limited to monoubiquitination, where only a single ubiprotein is added to the recipient molecule by a ubiprotein ligase. Monoubiquitinated proteins do not target the proteasome for degradation, but can actually alter their cellular location or function, for example, by binding to other proteins with a domain capable of binding ubiproteins. More complexly, E3 can target different lysines on ubiquitin to generate chains. The most common lysine is Lys48 on the ubiquitin chain. This is the lysine used to generate polyubiquitin, which is recognized by the proteasome. [ ] [ ]

[0090] As used herein, "compound", "bifunctional compound" or "compound of the present invention" refers to the compound whose structure is disclosed in the table and examples below. [ ] [ ]

[0091] The term "substituted" or "substituted as appropriate" shall mean one or more substituents (independently up to five substituents, preferably up to three substituents, typically one or two substituents on a portion of the compound according to the invention and including substituents that are themselves susceptible to further substitution) at any carbon (or nitrogen) position on the molecule in an independent context (i.e., in the case of more than one substitution, each substituent is independent of the other substituents), and includes the following as substituents: hydroxyl, thiol, carboxyl, cyano (C≡N), nitro (N O2), halogens (preferably 1, 2, or 3 halogens, especially on an alkyl group, particularly methyl, such as trifluoromethyl), alkyl groups (preferably C1-C10, more preferably C1-C6), aryl groups (especially phenyl and substituted phenyl groups, such as benzyl or benzoyl), alkoxy groups (preferably C1-C6 alkyl or aryl, including phenyl and substituted phenyl groups), thioethers (C1-C6 alkyl or aryl), acetyl groups (preferably C1-C6 acetyl), esters or thioesters including alkyl esters (preferably C1-C6 alkyl or aryl). (so that the linkage is on the alkyl group rather than at the ester functional group, which is preferably substituted with a C1-C6 alkyl or aryl group), preferably, a C1-C6 alkyl or aryl group, a halogen (preferably F or Cl), an amine (including five- or six-membered cyclic alkylamines, further including C1-C6 alkylamines or C1-C6 dialkylamines, the alkyl group of which may be substituted with one or two hydroxyl groups) or, where appropriate, a substituted -N(C0-C6 alkyl)C( O)(O-C1-C6 alkyl) groups (which may be substituted with a polyethylene glycol chain, which is further bonded to an alkyl group containing a single halogen, preferably a chlorinated substituent), hydrazine, preferably acetamipridyl groups substituted with one or two C1-C6 alkyl groups (including methylamine substituted with one or two C1-C6 alkyl groups, depending on the case), alkanols (preferably C1-C6 alkyl or aryl), or alkyl acids (preferably C1-C6 alkyl or aryl). Substituents according to the invention may include, for example, -SiR1R2R3 groups, wherein each of R1 and R2 is as otherwise described herein and R3 is H or C1-C6 alkyl, preferably, in this context, R1, R2, and R3 are C1-C3 alkyl groups (including isopropyl or tertiary butyl). Each of the above groups can be directly attached to the substituted portion, or alternatively, the substituent can be attached to the substituted portion (preferably in the case of the aryl or heteroaryl portion) via a substituted -(CH2)m- or alternatively, a substituted -(OCH2)m-, -(OCH2CH2)m-, or -(CH2CH2O)m- group (which may be substituted by any one or more of the above substituents). As identified above, the alkyl-(CH2)m- or -(CH2)n- group or other chains (such as ethylene glycol chains) can be substituted at any position on the chain.Preferred substituents on the alkyl group include halogens or C1-C6 (preferably, C1-C3) alkyl groups, which may be substituted with one or two hydroxyl groups, one or two diethyl ether groups (O-C1-C6 groups), up to three halogen groups (preferably, F) or amino acid side chains as otherwise described herein, and optionally substituted amides (preferably, substituted methylamides as described above) or carbamate groups (typically having one or two C0-C6 alkyl substituents, which may be further substituted). In some embodiments, the alkyl group (typically a single methylene group) is substituted with one or two optionally substituted C1-C6 alkyl groups, preferably C1-C4 alkyl groups, most typically methyl or O-methyl or amino acid side chains as otherwise described herein. In this invention, a portion of the molecule may be substituted with up to five substituents, preferably up to three substituents. Most typically, in this invention, the substituted portion is substituted with one or two substituents. [ ] [ ]

[0092] The term "substituted" (each substituent being independent of any other substituent) should also mean, in its context, the use of C1-C6 alkyl, C1-C6 alkoxy, halogen, amide, methylamide, benzoyl, including sulfonamide, ketone, carboxyl, C1-C6 ester (oxy-ester or carbonyl-ester), C1-C6 ketone, carbamate -OC(O)-NR1R2 or -N(R1)-C(O)-O-R1, nitro, cyano, and amines (especially including C1-C6 alkyl-NR1R2, amines substituted with mono- or di-C1-C6 alkyl, which may be substituted with one or two hydroxyl groups, as appropriate). Unless otherwise indicated, in the context, each of these groups contains a carbon atom between 1 and 6 carbon atoms. In some embodiments, depending on the context in which the substituents are used, preferred substituents will include, for example, -NH-, -NHC(O)-, -O-, =O, -(CH2)m- (here, in the context, m and n are 1, 2, 3, 4, 5, or 6), -S-, -S(O)-, SO2-, or -NH-C(O)-NH-. -(CH2)nOH, -(CH2)nSH, -(CH2)nCOOH, C1-C6 alkyl groups -(CH2)nO-(C1-C6 alkyl), -(CH2)nC(O)-(C1-C6 alkyl), -(CH2)nOC(O)-(C1-C6 alkyl), -(CH2)nC(O)O-(C1-C6 alkyl), -(CH2)nNHC(O)-R1, -(CH2)nC(O)-NR1R2, -(OCH2)nOH, -(CH2O)nCOOH, C1-C6 alkyl, -(OCH2)nO-(C1-C6 alkyl), -(CH2O)nC(O)-(C1-C6 alkyl), -(OCH2)nNHC(O)-R1, -(CH2O)nC(O)-NR1R2, -S(O)2-RS, -S(O)-RS (RS is a C1-C6 alkyl group or a -(CH2)m-NR1R2 group), NO2, CN, or a halogen (F, Cl, Br, I, preferably F or Cl). In the context, R1 and R2 are each H or C1-C6 alkyl (which may be substituted with one or two hydroxyl groups or up to three halogen groups, preferably fluorine). In the chemical context of the defined compounds and the substituents used, the term "substituted" should also mean, where appropriate, a substituted aryl or heteroaryl group, or, as otherwise described herein, a substituted heterocyclic group. Alkyl groups may also be substituted as otherwise disclosed herein, preferably by C1-C6 alkyl groups (preferably methyl, ethyl, or hydroxymethyl or hydroxyethyl, thus providing a symmetric center), side chains of amino acid groups as otherwise described herein, amide groups as described above, or urethane OC(O)-NR1R2 groups (where R1 and R2 are as otherwise described herein), but numerous other groups may also be used as substituents. Various substituted portions may be substituted by three or more substituents, preferably no more than three substituents and preferably one or two substituents. It should be noted that in compounds where substitution is required at specific positions (primarily due to valence), but where substitution is not indicated, the substituents are interpreted or understood as H unless substitution is otherwise suggested. [ ] [ ]

[0093] In this context, the term "aryl" or "aromatic" refers to a substituted (as otherwise described herein) or unsubstituted monovalent aromatic group having a single ring (e.g., benzene, phenyl, benzyl) or a fused ring (e.g., naphthyl, anthracene, phenanthrene, etc.) and being incorporated in a compound according to the invention at any available stable position on the ring or as otherwise indicated in the presented chemical structure. Other examples of aryl in this context may include heterocyclic aromatic ring systems; "heteroaryl" groups having one or more nitrogen, oxygen, or sulfur atoms in a ring (monocyclic ring), such as imidazole, furyl, pyrrole, furanyl, thiophene, thiazole, pyridine, pyrimidine, pyridine, etc. Triazole azoles; or, as described above, substituted fused-ring systems, such as indole, quinoline, and indole. , azain Benzofurans, etc., and others. Among the heteroaryl groups that can be mentioned are nitrogen-containing heteroaryl groups, such as pyrrole, pyridine, pyridone, and terpineol. pyrimidine, pyrimidine pyrazole, imidazole, triazole, triazole Tetraazole, Indole, Isoindole, Indole , azain Purine, indazole, quinoline, dihydroquinoline, tetrahydroquinoline, isoquinoline, dihydroisoquinoline, tetrahydroisoquinoline, quinoline , phthal , Phenylacetylene, Quinolones, Quinazoline Pterin, imidazopyridine, imidazopyridine pyr despair Acridine, caffeine, carbazole, carbazolin, pyrimidine, caffeine, benzo[a]phenacene Diazoles, benzimidazoles, pyrrolopyridines, pyrrolopyrimidines, and pyridopyrimidines; sulfur-containing aromatic heterocycles, such as thiophene and benzothiophene; oxygen-containing aromatic heterocycles, such as furan, piperan, cyclopentadienylpiperan, benzofuran, and isobenzofuran; and aromatic heterocycles containing two or more heteroatoms selected from nitrogen, sulfur, and oxygen, such as thiazoles, thiadiazoles, isothiazoles, and benzo[[...]] azole, benzothiazole, benzothiadiazole, phenazine 、different Azoxystrobin, furazolidone, phenazine pyrazole azole, imidazothiazole, thienofuran, furanopyrrole, pyridoxine Furanopyridine, furanopyrimidine, thiophenopyrimidine and Azole, and others, can all be substituted as appropriate. [ ] [ ]

[0094] The term "substituted aryl" refers to an aromatic carbocyclic group comprising at least one aromatic ring or multiple fused rings (at least one of which is aromatic), wherein the ring is substituted with one or more substituents. For example, an aryl group may comprise substituents selected from: -(CH2)nOH, -(CH2)nO-(C1-C6)alkyl, -(CH2)nO-(CH2)n-(C1-C6)alkyl, -(CH2)nC(O)(C0-C6)alkyl, -(CH2)nC(O)O(C0-C6)alkyl, -(CH2)n-OC(O)(C0-C6)alkyl, amine, mono- or di-(C1-C6 alkyl)amine (wherein the alkyl group on the amine is substituted with one or two hydroxyl groups or up to three halogen groups (preferably F, Cl)), OH, COOH, C1-C6 alkyl, etc. Preferably, a CH3, CF3, OMe, OCF3, NO2, or CN group (each of which may be substituted at the ortho, meta, and / or para position, preferably para, on the phenyl ring), a substituted phenyl group (preferably substituted by a linker group attached to an ABM group (including a ULM group), and / or at least one of the F, Cl, OH, COOH, CH3, CF3, OMe, OCF3, NO2, or CN group (at the ortho, meta, and / or para position, preferably para, on the phenyl ring), a naphthyl group (which may be substituted), a substituted heteroaryl group, preferably a substituted isoaryl group, may be substituted. azoles (including isoazoles with methyl substitution) (azole), or alternatives as appropriate azoles (including those substituted with methyl groups) substituted thiazoles, substituted isothiazoles, substituted pyrroles, substituted imidazoles (including methyl-substituted thiazoles), substituted benzimidazoles or methoxybenzyl imidazoles, substituted oximidazoles or methyl oxime imidazoles, substituted diazolyl groups (including methyl diazolyl groups), substituted triazolyl groups (including methyl-substituted triazolyl groups), substituted pyridyl groups (including halogenated (preferably F) or methyl-substituted pyridyl or oxapyridyl groups) (wherein the pyridyl group is linked to a phenyl group via oxygen), substituted furans, substituted benzofurans, substituted dihydrobenzofurans, substituted indoles, and indoles. or azinoin (2,3 or 4-azain) ), substituted quinolines as appropriate, and combinations thereof

[0095] The term "heteroaryl / hetaryl" may mean, but is by no means limited to, substituted quinolines (which may be attached to a pharmacophore or substituted on any carbon atom within the quinoline ring), substituted indoles (including dihydroindoles), and substituted indoles. Substituted azain (2,3 or 4-azain) ), depending on the substituted benzimidazole, benzodiazole, benzofuran, depending on the substituted imidazole, depending on the substituted iso... azole, or alternatives as needed Zyrazole (preferably substituted with methyl), diazole (substituted as desired), triazole (substituted as desired), tetraazole (substituted as desired), benzofuran (substituted as desired), thiophene (substituted as desired), thiazole (preferably substituted with methyl and / or thiol), isothiazole (substituted as desired), triazole (preferably substituted with methyl, triisopropylsilyl, -(CH2)mO-C1-C6 alkyl, or -(CH2)mC(O)-O-C1-C6 alkyl, 1,2,3-triazole), pyridine (2-, 3-, or 4-pyridine) or groups according to the following chemical structures: [ ] [ ]in Sc can be CHRSS, NRURE, or O; [ ] [ ]RHET is H, CN, NO2, a halogen (preferably Cl or F), a substituted C1-C6 alkyl group (preferably substituted with one or two hydroxyl groups or up to three halogen groups (e.g., CF3)), a substituted O (C1-C6 alkyl group) (preferably substituted with one or two hydroxyl groups or up to three halogen groups), or a substituted alkyne group -C≡C-Ra, wherein Ra is H or a C1-C6 alkyl group (preferably C1-C3 alkyl group); [ ] [ ]RSS is H, CN, NO2, a halogen (preferably F or Cl), a substituted C1-C6 alkyl group (preferably substituted with one or two hydroxyl groups or up to three halogen groups), a substituted O-(C1-C6 alkyl group) (preferably substituted with one or two hydroxyl groups or up to three halogen groups), or a substituted -C(O)(C1-C6 alkyl group) (preferably substituted with one or two hydroxyl groups or up to three halogen groups); [ ] [ ]RURE is H, C1-C6 alkyl (preferably H or C1-C3 alkyl) or -C(O) (C1-C6 alkyl) (each of which may be substituted with one or two hydroxyl groups or up to three halogens, preferably fluorine), or, as appropriate, a substituted heterocycle, such as piperidine, Phosphorione, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperidine Each of these was replaced as appropriate, and [ ] [ ]

[0096] YC is N or C-RYC, wherein RYC is H, OH, CN, NO2, a halogen (preferably Cl or F), a substituted C1-C6 alkyl group (preferably substituted with one or two hydroxyl groups or up to three halogen groups (e.g., CF3)), a substituted O (C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogen groups), or a substituted alkyne group -C≡C-Ra, wherein Ra is H or C1-C6 alkyl (preferably C1-C3 alkyl). [ ] [ ]

[0097] The term "heterocyclic" refers to a cyclic group containing at least one heteroatom (e.g., N, O, or S) and can be aromatic (heteroaryl) or non-aromatic. Therefore, depending on the intended use of the heteroaryl portion, it is classified as a heterocyclic group. The above describes illustrative heteroaryl groups.

[0098] Exemplary heterocycles include: acrylyl, benzimidazolyl, 1,4-benzodiyl... 1,3-benzodi ergol, benzo[a] Azolyl, benzothiazolyl, benzothiaphenyl, dihydroimidazolyl, dihydropiperanyl, dihydrofuranyl, di alkyl, dioxacyclopentane, ethyl urea, 1,3-dioxacyclopentane, 1,3-dioxacyclopentane 1,4-II Furanyl, Hooperidinyl, Imidazolyl, Imidazolinyl, Imidazolyl, Indololinyl, Indolyl, Isoquinolinyl, Isothiazolyl, Isothiazolyl, Isothiazolyl azole, iso azole group, phyllyl, pyridyl, azoleidine group, Azolyl, pyridone, 2-pyrrolidone, pyridine, piperidine methyl, N-methylpiperazine Piperidinyl, phthalimide, butadieneimide, pyridine , pyrazolinyl, pyridinyl, pyrimidinyl, pyrrolidyl, pyrrololinyl, pyrroleyl, quinolinyl, tetrahydrofuranyl, tetrahydropiperanyl, tetrahydroquinoline, thiazolinyl, thiazolyl, thiophene, tetrahydrothiophene, , oxo-2-yl, oxothio-2-pyrocyclopentane, thia , and others.

[0099] Heterocyclic groups may be substituted, as appropriate, with one member selected from the following group: alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acetyl, aceamino, acetoxy, amino, substituted amino, aminoacetyl, aminoacetoxy, oxyaminoacetyl, azide, cyano, halogen, hydroxyl, ketone, thionyl, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclic, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclic, hydroxylamine, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-substituted alkyl, -SO2-aryl, sideoxy (=O) and -SO2-heteroaryl. Such heterocyclic groups can have a single ring or multiple fused rings. Examples of nitrogen heterocycles and heteroaryl groups include (but are not limited to) pyrrole, imidazole, pyrazole, pyridine, and pyridine. pyrimidine, tadalafil Indene Isoindole, indole, indazole, purine, quinone Isoquinoline, Quinoline, Phthaloline Naphthylpyridine, quinoline, quinazoline Pterin, carbazole, carboline, phenazine, acridine, phenazine, isothiazine, phenazine ,different Azole, phenazine , phlegm Imidazolidine, imidazoline, piperidine, piperidine Indoline, N- Linoyl, piperidinyl, tetrahydrofuranyl and similar, as well as heterocycles containing N-alkoxy-nitrogen. The term "heterocycle" also includes bicyclic groups (e.g., indole, quinolinyl, isoquinolinyl, tetrahydroquinolinyl and similar) in which any of the heterocycles is fused to a benzene ring or a cyclohexane ring or another heterocycle. [ ] [ ]

[0100] The term "cycloalkyl" may mean, but is not limited to, a monovalent group derived from a monocyclic or polycyclic alkyl or cycloalkanes, as defined herein, such as a saturated monocyclic hydrocarbon group having three to twenty carbon atoms in the ring, including (but not limited to) cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like. The term "substituted cycloalkyl" may mean, but is not limited to, a monocyclic or polycyclic alkyl group substituted with one or more substituents, such as amino, halogen, alkyl, substituted alkyl, carboxyl, carboxyl mercapto, aryl, nitro, mercapto, or sulfonic acid groups; however, such substituents generally have the same meaning as the corresponding groups defined in this illustration. [ ] [ ]

[0101] "Heterocyclic alkyl" refers to a monocyclic or polycyclic alkyl group in which at least one ring carbon atom of its cyclic structure is replaced by a heteroatom selected from the group consisting of N, O, S, and P. "Substituted heterocyclic alkyl" refers to a monocyclic or polycyclic alkyl group in which at least one ring carbon atom of its cyclic structure is replaced by a heteroatom selected from the group consisting of N, O, S, and P, and the group contains one or more substituents selected from the group consisting of: halogen, alkyl, substituted alkyl, carboxylic acid, carboxyl mercapto, and sulfonic acid groups; however, these general substituents have the same meaning as the corresponding groups defined in this illustration.

[0102] The term "spirocyclic" or "spiro-fused cycloalkyl" refers to a polycyclic alkyl group containing at least two rings, wherein the two rings share exactly one ring atom. The term "spiro-heterocyclic" or "spiro-fused heterocyclic alkyl" refers to a spiro-fused cycloalkyl group in which at least one ring carbon atom of its cyclic structure is replaced by a heteroatom selected from the group consisting of N, O, S, and P. Spiro-fused cycloalkyl and spiro-fused heterocyclic alkyl can be further defined by the number of rings, such as bicyclic, tricyclic, tetracyclic, etc.

[0103] The term "bridged cycloalkyl" may refer to a polycyclic alkyl group containing at least two rings, wherein the two rings share at least three ring atoms. The term "bridged heterocyclic" refers to a bridged cycloalkyl group in which at least one ring carbon atom of its cyclic structure is replaced by a heteroatom selected from the group consisting of N, O, S, and P. Bridged cycloalkyl and spiro-fused heterocyclic alkyl groups may be further defined by the number of rings, such as bicyclic, tricyclic, tetracyclic, etc.

[0104] "Halogen" or "halogen group" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I). [ ] [ ]

[0105] "C1-C6 alkyl" refers to a straight-chain or branched saturated hydrocarbon containing 1 to 6 carbon atoms. Examples of (C1-C6) alkyl include (but are not limited to) methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, dibutyl, tributyl, isopentyl, neopentyl, and isohexyl. [ ] [ ]

[0106] As used herein with respect to the compounds of the present invention, "medically acceptable salt" means the salt form of the compounds of the present invention and the hydrate of such salt form with one or more water molecules present. Such salts and hydrated forms retain the biological activity of the compounds of the present invention and are not biologically or otherwise undesirable, i.e., exhibit minimal (if present) toxicological activity. Representative "medically acceptable salts" include, for example, water-soluble and water-insoluble salts, such as acetates and amsonates. (4,4-Diaminostilbene-2,2-disulfonate), benzenesulfonate, benzoate, bicarbonate, bisulfate, tartrate, borate, bromide, butyrate, calcium salt, calcium ethylenediaminetetraacetate, camphorsulfonate, carbonate, chloride, citrate, clavulariate, dihydrochloride, ethylenediaminetetraacetate, ethylenedisulfonate, estolate, ethanesulfonate, transbutenedioic acid, glucono-2-heptyl ether, gluconate, glutamate, acetylamine benzoarsyl ether, hexafluorophosphate, hexylresorcinate, hydrabamine salt, hydrobromide, hydrochloride, hydroxynaphthyl carboxylate, iodide, isothionate, lactate, Lactobionate, laurate, magnesium salt, malate, maleate, amygdalinate, methanesulfonate, methyl bromide, methyl nitrate, methyl sulfate, galactobionate, naphthalenesulfonate, nitrate, N-methylglucosamine ammonium salt, 3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, bis(hydroxynaphthoate) (1,1-methylene-bis-2-hydroxy-3-naphthoate, einbonate), pantothenate, phosphate / bisphosphonate, picrate, polygalacturonic acid, propionate, p-toluenesulfonate, salicylate, stearate, hypoacetate, succinate, sulfate, sulfosalicylate, suramate, tannate, tartrate, theochloroate, toluenesulfonate, triethyliodide, and valerate.

[0107] The term "isomer" refers to salts and / or compounds having the same composition and molecular weight but different physical and / or chemical properties. Structural differences may lie in their configuration (geometric isomers) or ability to rotate the polarizing plane (stereoisomers). Regarding stereoisomers, the salts of the compounds of this invention may have one or more asymmetric carbon atoms and may exist as racemic mixtures, racemic mixtures, and as individual enantiomers or diastereomers.

[0108] The compounds of the present invention can exist in unsolvated and solvated forms, such as (for example) hydrates.

[0109] "Solvate" means a solvation form containing a stoichiometric or non-stoichiometric amount of solvent. Non-limiting examples of suitable solvates include ethanolides, methanolides, and the like. Some compounds have a tendency to retain solvent molecules in a crystalline solid state at a fixed molar ratio, thereby forming solvates. If the solvent is water, the resulting solvate is a hydrate; if the solvent is an alcohol, the resulting solvate is an alcohol. Hydrates are formed by combining one or more water molecules with one of the substances in which water is held in the molecular state of water (H₂O). Such combinations can form one or more hydrates. In hydrates, water molecules are connected by intermolecular forces, specifically hydrogen bridges, via secondary valence. Solid hydrates contain water in a stoichiometric ratio, such as so-called crystalline water, where the binding states of water molecules need not be equal. Examples of hydrates are sesquihydrates, monohydrates, dihydrates, or trihydrates. Hydrates of salts of the compounds of this invention are also suitable.

[0110] As mentioned herein, "isotope derivatives" refers to the compounds of the present invention enriched or labeled with one or more stable isotopes (regarding one or more atoms of the compound). Therefore, in this application, the compounds of the present invention include, for example, compounds enriched or labeled with one or more atomic isotopes such as deuterium.

[0111] Metastatic prostate cancer, or cancer metastasis, refers to prostate cancer that has spread beyond the prostate to other parts of the body, such as bones, lymph nodes, liver, lungs, and brain.

[0112] Castration-resistant prostate cancer is a type of prostate cancer that continues to grow even when testosterone levels in the body are reduced to very low levels.

[0113] Metastatic castration-resistant prostate cancer is a type of prostate cancer that metastasizes and continues to grow even when testosterone levels in the body are reduced to very low levels.

[0114] As used in this article, “treatment” describes the management and care of an individual for the purpose of combating a disease, symptom, or condition, and includes reducing or alleviating symptoms or complications, or eliminating the disease, symptom, or condition.

[0115] As used in this article, the term "prevention" describes stopping the onset of symptoms or complications of a disease, condition, or illness.

[0116] "Drug administration" refers to the introduction of a drug, such as the compound of this invention, into an individual. The related terms "administration" and "...administration of drug" (and their grammatical equivalents) refer to direct drug administration, which can be administered to an individual by a medical professional or by the individual themselves, and / or indirect drug administration, which can be the act of prescribing medication. For example, a physician who instructs a patient to administer medication themselves and / or who prescribes medication to a patient administers medication to the patient.

[0117] The terms "co-administration," "co-dosing," or "combination therapy" refer to simultaneous administration (administration of two or more therapeutic agents simultaneously) and administration at different times (administration of one or more therapeutic agents at a time different from administration of additional therapeutic agents or drugs), as long as the therapeutic agents are present in the patient simultaneously to a certain extent, preferably in an effective amount. In some preferred embodiments, one or more of the compounds of the present invention described herein are co-administered in combination with at least one additional bioactive agent (particularly including anticancer agents). In particularly preferred embodiments, the co-administration of the compounds produces synergistic activity and / or therapy, including anticancer activity.

[0118] As used herein, "therapeutic effective amount" means an amount of free base of the compound of the present invention sufficient to treat, alleviate, or prevent a specified disease (e.g., prostate cancer), disease symptoms, condition, or symptom, or to exhibit detectable therapeutic or inhibitory effects. The effect can be detected by any analytical method known in this art. The effective amount for a particular individual may depend on the individual's weight, size, and health; the nature and severity of the symptom; and whether additional therapeutic agents will be administered to the individual. Therapeutic effective amounts for a given situation can be determined by routine laboratory tests within the skill and judgment of a clinician.

[0119] As used in this article, "Cmax" refers to the maximum (peak) plasma concentration of the specified compound observed in an individual after a certain dose of the compound has been administered to the individual.

[0120] As used herein, "AUC" refers to the total area under the plasma concentration-time curve, which is the integer value of the concentration-time curve after a single dose or at steady state for exposure to the compound of interest. AUC is expressed in units of ng*H / mL (ng × H / mL), where "H" refers to hours.

[0121] As used in this article, "AUCtau" refers to the AUC from 0 hours to the end of the dosing interval.

[0122] "AUC0 - 24" means the AUC from 0 to 24 hours after self-administration or a single dose.

[0123] As used herein with respect to oral dosage forms, "controlled release" or "CR" refers to the release of the compound of the present invention from the dosage form according to a predetermined profile, which may include the time and place of release after oral administration and / or a specified release rate within a specified time period.

[0124] As used herein with respect to the oral dosage forms of this invention, "controlled release agent" refers to one or more substances or materials that regulate the release of the compounds of this invention from the dosage form. Controlled release agents can be organic or inorganic, naturally occurring or synthetic materials, such as polymers, triglycerides, triglyceride derivatives, fatty acids and salts of fatty acids, talc, etc. Boric acid, colloidal silica and their combinations.

[0125] As used herein in relation to the dosage form of the present invention, "enteric coating" refers to a pH-dependent material that surrounds the core of the compound comprising the present invention, remains substantially intact in the acidic environment of the stomach, but dissolves in the pH environment of the intestine.

[0126] The terms "gastric tolerance" or "GR" for the oral CR formulations described herein mean that the release of the compound of the present invention in an individual's stomach should not exceed 5%, 2.5%, 1%, or 0.5% of the total amount of the compound of the present invention in the formulation.

[0127] As used herein, "oral dosage form" refers to a pharmaceutical product containing a specified amount (dosage) of the compound of the present invention as an active ingredient or a pharmaceutically acceptable salt and / or solvate thereof and an inactive component (excipient), formulated into a specific configuration suitable for oral administration, such as an oral tablet, liquid, or capsule. In one embodiment, the composition is in the form of a scoreable tablet.

[0128] As used in this invention, the term "carrier" includes pharmaceutically acceptable excipients and diluents and means a material, composition, or medium, such as liquid or solid fillers, diluents, excipients, solvents, or encapsulating materials, that participates in carrying or transporting a pharmaceutical agent from one organ or part of a body to another organ or part of a body.

[0129] The term "about" (such as "about X"), as part of a quantitative expression, includes any value that is 10% higher or lower than X, and also includes any value between X-10% and X+10%. Therefore, for example, a weight of about 40 g includes a weight between 36 and 44 g.

[0130] The term "comprising / comprises" as used in relation to a particular dosage form, composition, use, method, or process described or claimed herein means that the dosage form, composition, use, method, or process includes all elements listed in the specific description or claims, but does not exclude other elements. "Consists essentially of / consisting essentially of" means that the described or claimed composition, dosage form, method, use, or process does not exclude other materials or steps that do not materially affect the listed physical, pharmaceutical, pharmacokinetic, or therapeutic properties of the composition, dosage form, method, use, or process. "Consists of / consisting of" means excluding other components beyond trace elements and substantial method or process steps.

[0131] The terms "fasting status" and "fasting condition" used to describe an individual mean that the individual has not eaten for at least 4 hours prior to the time of interest (such as the time of administration of the compound of the present invention). In one embodiment, the individual in a fasting condition has not eaten for at least any one of 6, 8, 10, or 12 hours prior to administration of the compound of the present invention.

[0132] The terms "feeding status" and "feeding condition" used to describe an individual mean that the individual has eaten within 4 hours prior to the time of interest (such as the time of administration of the compound of the present invention). In one embodiment, an individual in a feeding condition has eaten within at least any one of 3, 2, 1, or 0.5 hours prior to administration of the compound of the present invention.

[0133] As used herein, the term "anticancer agent" is used to describe the co-administration of an anticancer agent (e.g., palonosetron) with other anticancer agents or therapeutic agents, which may be co-administered and / or co-formulated with the compounds of the present invention to treat cancer and cancer treatment-related side effects. These medications include, for example, everolimus, trabectedin, abraxane, TLK 286, AV-299, DN-101, pazopanib, GSK690693, RTA 744, ON 0910.Na, AZD 6244 (ARRY-142886), AMN-107, TKI-258, GSK461364, AZD 1152, enzastaurin, vandetanib, ARQ-197, MK-0457, MLN8054, PHA-739358, R-763, AT-9263, FLT-3 inhibitors, VEGFR inhibitors, and EGFR inhibitors. TK inhibitors, aurora kinase inhibitors, PIK-1 modulators, Bcl-2 inhibitors, HDAC inhibitors, c-MET inhibitors, PARP inhibitors, CdK inhibitors, EGFR TK inhibitors, IGFR-TK inhibitors, anti-HGF antibodies, PI3 kinase inhibitors, AKT inhibitors, mTORC1 / 2 inhibitors, JAK / STAT inhibitors, checkpoint-1 or 2 inhibitors, focal adhesion kinase inhibitors, Map kinase (mek) inhibitors, VEGF capture antibodies, pemetrexed, erlotinib, dasatanib, nilotinib, decatanib, panitumumab, amrubicin, orevovaginab govomab), Lep-etu, nolatrexed, azd2171, batabulin, ofatumumab, zanolimumab, edotecarin, tetrandrine, rubitecan, tesmilifene, oblimersen, ticilimumab, ipilimumab, gossypol, Bio 111, 131-I-TM-601, ALT-110, BIO 140, CC8490, cilengitide, gimatecan, IL13-PE38QQR, INO 1001, IPdR1 KRX-0402, lucanthone, LY317615, neuradiab, vitespan, Rta 744, Sdx 102, talampanel, atrasentan, Xr 311, Romidesin, ADS-100380, Sunitinib, 5-Fluorouracil, Vorinostat, Etoposide, Gemcitabine, Doxorubicin, Lipid-rich Cranberry, 5'-Deoxy-5-Fluorouracil, Vincristine, Temozolomide, ZK-304709, Selixib liciclib);PD0325901, AZD-6244, capecitabine, L-glutamic acid, N-[4-[2-(2-amino-4,7-dihydro-4-sideoxy-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-, disodium salt, heptahydrate, camptothecin, PEG-labeled irinotecan, tamoxifen, toremifene citrate citrate), anastrozole, exemestane, letrozole, DES (diethylstilbestrol), estradiol, estrogen, conjugated estrogen, bevacizumab, IMC-1C11, CHIR-258); 3-[5-(methylsulfonylopiridinemethyl)-indolyl-quinolinone, vatalanib, AG-013736, AVE-0005, goserelin acetate, leuprolide acetate, triptorelin pamoate, medroxyprogesterone acetate, hydroxyprogesterone caproate, megestrol acetateAcetate), raloxifene, bicalutamide, flutamide, nilutamide, medroxyprogesterone acetate, CP-724714; TAK-165, HKI-272, erlotinib, lapatinib, canertinib, ABX-EGF antibody, erbitux, EKB-569, PKI-166, GW-572016, Ionafarnib, BMS-214662, tipifarnib; amifostine, NVP-LAQ824, octanoic acid, valproic acid, trichostocin A, FK-228, SU11248, sorafenib, KRN951, aminoglutethimide, arnsacrine, anagrelide, L-aspartate aminotransferase, Bacillus subtilisCalmette-Guerin (BCG) vaccine, adriamycin, bleomycin, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, clodronate, cyproterone acetate, cytarabine, dacarbazine, actinomycin (dactinomycin), daunorubicin, diethylstilbestrol, epirubicin, fludarabine, fludrocortisone, fluoxymesterone, flutamide, gleevec, gemcitabine, hydroxyurea, idarubicin, ifosfamide, imatinib, leuprol ide), levamisole, lomustine, mechlorethamine, melphalan, 6-mercaptopurine, mesna, methotrexate, mitomycin, mitotane, mitoxantrone, niluamide, octreotide, oxaliplatin, pamidronate, pentostatin, and more. plicamycin, porfimer, procarbazine, raltitrexed, rituximab, streptozocin, teniposide, testosterone, tharidosulfonamide, thioguanine, thiotepa, tretinoin, vindesine, 13-cis-retinoic acid, phenylalanine mustard, uracilMustard, estradiol, altretamine, fluxuridine, 5-deoxyuridine, cytosine, arabinoside, 6-mercaptopurine, deoxycoformycin, calcitriol, valrubicin, mithramycin, vinblastine, vinorelbine, topotecan, razoxin, marimastat, COL-3, neovastatin Vasat), BMS-275291, Squalamine, Endostatin, SU5416, SU6668, EMD121974, Interleukin-12, IM862, Angiostatin, Vitaxin, Droloxifen, Idoxyfen, Spironolactone, Finasteride, Cimitidine, Trastuzumab, Denileukin Diftitox, Gefitinib, Bortezomib, Paclitaxel, Cremophor-free Paclitaxel, Docetaxel, Epihilone B, BMS-247550, BMS-310705, Traloxifen, 4-Hydroxytamoxifen, Pipendoxifene, ERA-923, Arzoxifene, Fulvestrant, Acolbifene, Lasofoxifene, Idoxifene, TSE-424, HMR-3339, ZK186619, Topotecan, PTK787 / ZK 222584, VX-745, PD184352, Rapamycin, 40-O-(2-hydroxyethyl)-Rapamycin, Temsirolimus, AP-23573, RAD001, ABT-578, BC-210, LY294002, LY292223, LY292696, LY293684, LY293646, Wortmannin, ZM336372, L-779,450, PEG-Figrastim, Darbepoetin, Erythropoietin, Granulocyte Colony-Stimulating Factor, Levophosphonate Prednisone, Cetuximab, Granulocyte-Macrophage Community-Stimulating Factor, Histamine Relin, Pegylated Interferon Alpha-2a, Interferon Alpha-2a, Pegylated Interferon Alpha-2b, Interferon Alpha-2b, Azacitidine, PEG-L-Aspartate, Lenalidomide, Gemtuzumab, Hydrocortisone, Interleukin-11, Dexrazoxane, Alemtuzumab, All-Trans Retinoic Acid (The following are listed as unrelated to the previous sentence and are likely separate entries): acid, ketoconazole, interleukin-2, megestrol, immunoglobulin, nitrogen mustard, methylprednisolone, ibritgumomab tiuxetan, androgens, decitabine, hexamethylmelamine, bexarotene, tositumomab, arsenic trioxide, cortisone, editronate, mitotan, cyclosporine, liposomal daunorubicin, Edwina-asparaginase, strontium.89. Caspopitant, netupitant, NK-1 receptor antagonists, palonosetron, aprepitant, diphenhydramine, hydroxyzine, metoclopramide, lorazepam, alprazolam, haloperidol, droperidol, dronabinol, dexamethasone, methylprednisolone, prochlorperazine, granisetron, ondansetron, dolasetron, tropisetron, pegfilgrastim, erythropoietin, epoetin alfa, darbepoetin alfa, and mixtures thereof. In one embodiment, the anticancer agent is selected from the group consisting of: abiraterone, estradiol mustard, docetaxel, ketoconazole, goserelin, histamine relin, triptorelin, buterelin, cyproterone acetate, flutamide, bicalutamide, nilutamide, pamidronate, and levodopa. In another embodiment, the anticancer agent is selected from the group consisting of: FLT-3 inhibitors, androgen receptor inhibitors, VEGFR inhibitors, EGFR TK inhibitors, olora kinase inhibitors, PIK-1 modulators, Bcl-2 inhibitors, HDAC inhibitors, c-Met inhibitors, PARP inhibitors, CDK 4 / 6 inhibitors, anti-HGF antibodies, IGFR TK inhibitors, PI3 kinase inhibitors, AKT inhibitors, JAK / STAT inhibitors, checkpoint 1 inhibitors, checkpoint 2 inhibitors, focal adhesion kinase inhibitors, Map kinase inhibitors, VEGF-capturing antibodies, and chemical castration agents.

[0134] In one embodiment, the anticancer agent is selected from the group consisting of: temozolomide, capecitabine, irinotecan, tamoxifen, anastrozole, exemestane, letrozole, DES, estradiol, estrogen, bevacizumab, goserelin acetate, leuprolide acetate, triptorelin dinaphthylnaphthyl acetate, medroxyprogesterone acetate, rhinoxifene, megestrol acetate, carboplatin, cisplatin, dacarbazine, methotrexate, vincristine, vinorelbine, topotecan, finasteride, azoxifen. Fulvestrant, Presson, Abiraterone, Enzalutamide, Apalutamide, Darolutamide, Sipuleucel-T, Pembrolizumab, Nivolumab, Cemiplimab, Atezolizumab (Tecentriq), Avelumab (Bavencio), Durvalumab (Imfinzi), Taxotere, Cabazitaxel (Jevtana), Novantrone, Emcyt, Docetaxel, Ketoconazole, Histamine Relin, Triptorelin, Buterelin, Cyproterone Acetate, Flutamide, Bicalutamide, Niludamide, Pamidronate, and Levodrone.

[0135] Abiraterone acetate is a commercially available drug developed by Janssen and marketed under the brand name Zytiga® for the treatment of metastatic castration-resistant prostate cancer.

[0136] In this invention, the articles "a" and "an" are used to refer to a grammatical object with one or more articles (i.e., at least one). By way of example, "element" means one or more elements.

[0137] Unless otherwise stated, the term "and / or" is used in this invention to mean "and" or "or".

[0138] The terms “patient” and “individual” are used interchangeably in this document and refer to mammals such as humans, mice, rats, guinea pigs, dogs, cats, horses, cows, pigs, or non-human primates such as monkeys, chimpanzees, baboons, or rhesus monkeys.

[0139] In one embodiment, the individual is a human being.

[0140] In one embodiment, the individual is a human who has been diagnosed with prostate cancer.

[0141] In one embodiment, the individual is a human who has been diagnosed with metastatic prostate cancer.

[0142] In one embodiment, the individual is a person who has been diagnosed with castration-resistant prostate cancer.

[0143] In one embodiment, the individual is a human who has been diagnosed with metastatic castration-resistant prostate cancer. Compounds of the present invention

[0144] In one embodiment, this application relates to a bifunctional or multifunctional compound suitable for modulating protein activity by inducing the degradation of a target protein. In some embodiments, the bifunctional compound comprises an E3 ubiquitin ligase-binding moiety and a protein-targeting moiety preferably linked via a linker portion as further described herein, wherein the E3 ubiquitin ligase-binding moiety is coupled to the protein-targeting moiety, and wherein the E3 ubiquitin ligase-binding moiety recognizes ubiquitin pathway proteins (e.g., ubiquitin ligases, preferably E3 ubiquitin ligases) and the protein-targeting moiety recognizes a target protein, such that when the target protein is placed in proximity to the ubiquitin ligase, degradation of the target protein occurs, thereby degrading / inhibiting the action of the target protein and controlling protein content. In some embodiments, the bifunctional compound comprises a CLM coupled (e.g., covalently, directly, or indirectly linked) to a chemical linker L, and a PTM, which can be described as follows: PTM-L-CLM

[0145] CLM recognizes and binds to selebloon (E3 ubiquitin ligase). PTM is a small protein-binding moiety that binds to and recruits intracellular target proteins or peptides, bringing them very close to the CLM to achieve target protein degradation, thereby inducing target protein ubiquitination. In some embodiments, PTM is the AR-binding moiety (ABM).

[0146] In any of the compounds described herein, PTM comprises the following chemical structures: .

[0147] In any of the compounds described herein, L comprises the following chemical structure: .

[0148] In any of the compounds described herein, CLM comprises the following chemical structures: .

[0149] In another embodiment, this application relates to a bifunctional compound having the following structure: ABM-L-CLM, Or its pharmaceutically acceptable salts, solvates, enantiomers, stereoisomers, or isotopic derivatives, in: (a) The ABM is an androgen receptor (AR) binding site with the following structure: in: Q1, Q2, Q3, Q4, and Q5 are each independently CR1 or N; It is a 4-6 membered cycloalkyl, C6-C10 aryl, 4-6 membered heterocycloalkyl, or 4-6 membered heteroaryl, wherein the heterocycloalkyl or heteroaryl contains 0-4 heteroatoms; Q6, Q7, Q8, Q9, and Q10 are each independently CR3 or N; Each R1 group is independently selected from the group consisting of: H, substituted linear or branched C1-C6 alkyl, cyano, halogen, and substituted linear or branched C1-C6 alkoxy, wherein the alkyl or alkoxy is substituted with one or more halogen groups as appropriate; Each R2 group is independently selected from the group consisting of:, where appropriate, substituted straight-chain or branched C1-C6 alkyl, cyano, halogen, and, where appropriate, substituted straight-chain or branched C1-C6 alkoxy groups, wherein the alkyl or alkoxy group is substituted with one or more halogen groups; Each R3 group is independently selected from the group consisting of: H, straight-chain or branched C1-C6 alkyl, cyano, halogen, and, where appropriate, substituted straight-chain or branched C1-C6 alkoxy groups, wherein the alkyl or alkoxy group is, where appropriate, substituted with one or more halogen groups; and n is 0, 1, 2, 3, or 4; (b) L is a chemical linker with the following structure: in: ABM is connected to W and CLM is connected to Z, or ABM is connected to Z and CLM is connected to W; W does not exist or is It is a 4-7 membered cycloalkyl, a 4-7 membered heterocyclic or spiro-bicyclic heterocyclic alkyl, wherein each ring in the spiro-bicyclic is 4-7 members; X is -CH2-, or does not exist; Y is -NR6-, -O-, or does not exist; It is a 4-7 membered cycloalkyl or a 4-7 membered heterocyclic ring; Z is -C(R7)2-, -NR7-, -O-, or does not exist; R6 is H, a straight-chain or branched C1-6 alkyl, a straight-chain or branched C1-6 alkoxy-C1-6 alkyl, or... ,in The indicator is connected to the Y key, and Instructions connected to One key; Each R7 group is independently selected from the following groups: H, straight-chain or branched C1-6 alkyl groups, and straight-chain or branched C1-6 alkoxy groups; p is 1, 2, 3, or 4; and q is 1, 2, 3, 4, or 5; (c) CLM is the selebloon E3 ubiquitin ligase-binding moiety with the following structure: in: It is a C6-C10 aryl, 4-7 member heteroaryl, or a bridged bicyclic cycloalkyl group; The connection portion L is connected to the ring S by one or two covalent bonds; Each R4 group is independently selected from the group consisting of:, where appropriate, substituted straight-chain or branched C1-C6 alkyl, cyano, halogen, and, where appropriate, substituted straight-chain or branched C1-C6 alkoxy groups, wherein the alkyl or alkoxy group is substituted with one or more halogen groups; R5 is H, or a substituted straight-chain or branched C1-C6 alkyl group, or a substituted straight-chain or branched C1-C6 alkoxy group, wherein the alkyl or alkoxy group is substituted with one or more halogen groups, and m can be 0, 1, 2, 3, or 4.

[0150] In another embodiment, this application relates to compound of formula (I):

[0151] Or its pharmaceutically acceptable salts, solvates, enantiomers, stereoisomers, or isotopic derivatives, All variables are defined as described in this paper.

[0152] In some embodiments, when When it is pyridyl, If R1 is tetramethylcyclobutyl, Q2 is CR1, and Q4 is CR1, then R1 is not chlorine.

[0153] In some embodiments, the compound of formula (I) is not N-(4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-((4-(4-((2,6-dioxypiperidin-3-yl)aminomethyl)phenyl)piperidin -1-yl)methyl)piperidin-1-yl)tad -3-methamide.

[0154] In some embodiments, the compound of formula (I) is not .

[0155] In some embodiments, L is in: It is a 4-7 membered cycloalkyl or a 4-7 membered heterocyclic ring; Y is -NR6-, -O-, or does not exist; R6 is H, a straight-chain or branched C1-6 alkyl group, or a straight-chain or branched C1-6 alkoxy group; and It is a 4-7 member cycloalkyl or a 4-7 member heterocyclic ring.

[0156] In some embodiments, L is in: It is a 4-7 membered cycloalkyl or a 4-7 membered heterocyclic ring; Y is either -NR6- or -O-; R6 is H, a straight-chain or branched C1-6 alkyl group, or a straight-chain or branched C1-6 alkoxy group; and It is a 4-7 member cycloalkyl or a 4-7 member heterocyclic ring.

[0157] In some embodiments, L is in: Piperidinyl or phyllyl; Y is either -NR6- or -O-; R6 is ; It is cyclobutyl; and Z is -O-.

[0158] In some embodiments, L is in: Piperidinyl or phyll group; and For Piper base.

[0159] In some embodiments, It is piperidinyl.

[0160] In some embodiments, the compound is a compound of formula (Ib): , All variables are defined as described in this paper.

[0161] In some embodiments, the compound is a compound of formula (Ic): , All variables are defined as described in this paper.

[0162] In some embodiments, Q1-Q5 are each CR1. In some embodiments, 1 to 3 of Q1-Q5 are N. In some embodiments, exactly 1 of Q1-Q5 is N. In some embodiments, exactly 2 of Q1-Q5 are N. In some embodiments, exactly 3 of Q1-Q5 are N.

[0163] In some embodiments, Q6-Q10 are each CR1. In some embodiments, 1 to 3 of Q6-Q10 are N. In some embodiments, exactly 1 of Q6-Q10 is N. In some embodiments, exactly 2 of Q6-Q10 are N. In some embodiments, exactly 3 of Q6-Q10 are N.

[0164] In some embodiments, Q1 is CH, Q2 is C(CH3), Q3 is C(CN), Q4 is C(CH3), and Q5 is CH.

[0165] In some embodiments, Q1 is CH, Q2 is C(OCH3), Q3 is C(CN), Q4 is CH, and Q5 is CH.

[0166] In some embodiments, Q1 is CH, Q2 is C(Cl), Q3 is C(CN), Q4 is CH, and Q5 is CH.

[0167] In some embodiments, R1 is selected from the group consisting of CN and CH3. In some embodiments, R1 is selected from the group consisting of CN and OCH3. In some embodiments, R1 is selected from the group consisting of CN and Cl. In some embodiments, at least one R1 is CF3.

[0168] In some embodiments, It is a 4-6 membered cycloalkyl group. In some embodiments, It is cyclobutyl or cyclohexyl. In some embodiments, It is cyclobutyl. In some embodiments, It is cyclopentyl. In some embodiments, It is a cyclohexyl group.

[0169] In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

[0170] In some embodiments, R2 is a straight-chain or branched C1-C6 alkyl group. In some embodiments, R2 is methyl. In some embodiments, R2 is ethyl. In some embodiments, R2 is propyl. In some embodiments, R2 is n-propyl. In some embodiments, R2 is isopropyl. In some embodiments, R2 is butyl. In some embodiments, R2 is n-butyl. In some embodiments, R2 is isobutyl. In some embodiments, R2 is a second butyl. In some embodiments, R2 is a third butyl. In some embodiments, R2 is pentyl. In some embodiments, R2 is hexyl.

[0171] In some embodiments, It is phenyl, pyridyl, or tert-phenyl. pyrimidinyl or pyridine Base. In some embodiments, It is phenyl. In some embodiments, It is pyridinyl. In some embodiments, For Ta Base. In some embodiments, It is a pyrimidinyl group. In some embodiments, For pyr base.

[0172] In some embodiments, each R4 system is independently selected from the group consisting of: F, methoxy, ethoxy, methyl, and ethyl.

[0173] In some embodiments, m is 0, 1, or 2. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2.

[0174] In one state sample, this application relates to a compound of formula (Id): , All variables are defined as described in this paper.

[0175] In one state, this application relates to a compound of formula (Ie): , All variables are defined as described in this paper.

[0176] In one state, this application relates to a compound of formula (If): , All variables are defined as described in this paper.

[0177] In one state sample, this application relates to a compound of formula (Ig): , All variables are defined as described in this paper.

[0178] In one state, this application relates to a compound of formula (Ih): , All variables are defined as described in this paper.

[0179] In one state, this application relates to a compound of formula (Ii): , All variables are defined as described in this paper.

[0180] In one state, this application relates to a compound of formula (Ij): , All variables are defined as described in this paper.

[0181] In one state, this application relates to a compound of formula (Ik): , All variables are defined as described in this paper.

[0182] In one embodiment, this application relates to a compound of formula (Il): , All variables are defined as described in this paper.

[0183] In one state, this application relates to a compound of formula (Im): , All variables are defined as described in this paper.

[0184] In one state, this application relates to a compound of formula (Io): , All variables are defined as described in this paper.

[0185] In one state, this application relates to a compound of formula (Ip): , All variables are defined as described in this paper.

[0186] In one state, this application relates to a compound of formula (Iq): , All variables are defined as described in this paper.

[0187] In one state, this application relates to a compound of formula (Ir): , All variables are defined as described in this paper.

[0188] In one state, this application relates to a compound of formula (Is): , All variables are defined as described in this paper.

[0189] In another embodiment, this application relates to a compound, wherein the compound is: Or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, or isotopic derivative thereof.

[0190] The compounds of this invention can be synthesized using standard synthetic methods and procedures for the preparation of organic molecules and the transformation and manipulation of functional groups (including the use of protecting groups), as available from relevant scientific literature or from standard reference textbooks in the field of this invention. While not limited to any one or more sources, recognized reference textbooks for organic synthesis include Smith, MB; March, J. March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th edition; John Wiley & Sons: New York, 2001; and Greene, TW; Wuts, PGM Protective Groups in Organic Synthesis, 3rd edition; John Wiley & Sons: New York, 1999. The synthetic methods described in U.S. Patent Application Publication No. 2018 / 0099940 and International Publication No. 2018 / 144649 are incorporated herein by reference in their entirety.

[0191] In one embodiment, the compounds of the present invention can be prepared according to the procedures and methods disclosed herein, including, for example, the procedures and methods indicated in Table 1. Other bifunctional compounds of the present invention can be prepared from common intermediates or derivatives thereof using similar methods.

[0192] Table 1. Synthetic routes for preparing various compounds of the present invention Compound numbering Synthetic pathway 1 Example 3 3 Example 4 4 Figure 2 5 Example 5 9 Figure 3 14 Example 6 15 Example 7 16 Figure 4 twenty one Example 8 twenty three Example 9 twenty four Example 10 27 Example 11 28 Example 12 33 Example 13 34 Example 14 35 Example 15 37 Example 16 38 Example 17 39 Example 18 40 Example 19 41 Example 20 43 and 44 Example 21 48 and 49 Example 22 64 Example 23 70 Example 24 Methods for ubiquitination / degradation of target proteins in cells

[0193] This invention provides a method for ubiquitinizing / degrading a target protein in cells. The method comprises administering a bifunctional composition comprising an E3 ubiquitin ligase-binding moiety and a protein-targeting moiety preferably linked via a linker portion as further described herein, wherein the E3 ubiquitin ligase-binding moiety is coupled to the protein-targeting moiety, and wherein the E3 ubiquitin ligase-binding moiety recognizes ubiquitin pathway proteins (e.g., ubiquitin ligases, preferably E3 ubiquitin ligases) and the protein-targeting moiety recognizes a target protein, such that when the target protein is placed in proximity to the ubiquitin ligase, degradation of the target protein occurs, thereby degrading / inhibiting the action of the target protein and controlling protein levels. The protein levels obtained by controlling the protein levels obtained by this invention provide a treatment for disease conditions or symptoms, which are modulated by reducing the protein levels in the patient's cells via the target protein.

[0194] In one embodiment, this application provides a compound of formula (I) or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotope derivative, or precursor thereof that degrades androgen receptor (AR) proteins. In one embodiment, the AR degraded by the compound of formula (I) is wild-type AR. In another embodiment, the AR degraded by the compound of formula (I) is a mutant form of AR.

[0195] In one embodiment, the mutant form of AR degraded by the compound of formula (I) includes at least one AR somatic tumor mutation. In one embodiment, the at least one somatic AR tumor mutation is selected from: L702H, M895V, M896V, T878A, F877L, and H875Y.

[0196] In one embodiment, the mutant form of AR degraded by the compound of formula (I) comprises at least two AR somatic tumor mutations. In one embodiment, the at least two somatic AR tumor mutations are selected from: L702H, M895V, M896V, T878A, F877L, and H875Y.

[0197] In one embodiment, the present invention relates to a method for treating a disease condition or symptom in a patient in need, the disease condition or symptom being mediated by a protein, wherein the degradation of that protein will produce a therapeutic effect in the patient, the method comprising administering to the patient in need an effective amount of a compound of formula (I), and, if appropriate, in combination with another anticancer agent. The disease condition or symptom may be a disease caused by a microbial agent or other exogenous agent such as a virus, bacteria, fungus, protozoa, or other microorganism, or may be a disease condition caused by the overexpression of a protein (which causes the disease condition and / or symptom). Treatment

[0198] In one embodiment, this application relates to a method of treating and / or preventing cancer, comprising administering to an individual in need a therapeutically effective amount of the compound of the present invention or a medically acceptable salt, enantiomer, stereoisomer, solvate, or isotope derivative thereof.

[0199] In one embodiment, this application relates to a method of treating and / or preventing cancer, comprising administering to an individual in need a therapeutically effective amount of a compound of formula (I) or a medically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotope derivative or precursor thereof, and one or more additional anticancer agents.

[0200] The cancer treatment methods described in this article can reduce tumor size. Alternatively or additionally, the cancer is metastatic and this treatment method includes inhibiting the invasion of metastatic cancer cells.

[0201] In one embodiment, the cancer is prostate cancer.

[0202] In one embodiment, the cancer is metastatic prostate cancer.

[0203] In one embodiment, the cancer is castration-resistant prostate cancer.

[0204] In one embodiment, the cancer is metastatic castration-resistant prostate cancer (mCRPC).

[0205] In one embodiment, depending on an individual’s AR biomarker status (i.e., whether the individual has one or more somatic tumor mutations of AR), an individual with prostate cancer (e.g., mCRPC) will respond differently to treatment with the compounds of the present invention or their pharmaceutically acceptable salts, enantiomers, stereoisomers, solvates, polymorphs, isotope derivatives or precursors.

[0206] In one embodiment, an individual with prostate cancer contains at least one somatic AR tumor mutation.

[0207] In one embodiment, an individual with prostate cancer contains at least the L702 somatic AR tumor mutation.

[0208] In one embodiment, an individual with prostate cancer contains at least the L702H somatic AR tumor mutation.

[0209] In one embodiment, an individual with prostate cancer contains at least the M895 somatic AR tumor mutation.

[0210] In one embodiment, an individual with prostate cancer contains at least the M895V somatic AR tumor mutation.

[0211] In one embodiment, an individual with prostate cancer contains at least the M896 somatic AR tumor mutation.

[0212] In one embodiment, an individual with prostate cancer contains at least the M896V somatic AR tumor mutation.

[0213] In one embodiment, an individual with prostate cancer contains at least the T878 somatic AR tumor mutation.

[0214] In one embodiment, an individual with prostate cancer contains at least the T878A somatic AR tumor mutation.

[0215] In one embodiment, an individual with prostate cancer contains at least the F877 somatic AR tumor mutation.

[0216] In one embodiment, an individual with prostate cancer contains at least the F877L somatic AR tumor mutation.

[0217] In one embodiment, an individual with prostate cancer contains at least the H875 somatic AR tumor mutation.

[0218] In one embodiment, an individual with prostate cancer contains at least an H875Y somatic AR tumor mutation.

[0219] In one embodiment, an individual with prostate cancer contains at least two somatic AR tumor mutations.

[0220] In one embodiment, this application relates to a method for treating prostate cancer using the compound of the present invention, wherein the compound of the present invention is: Or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, or isotopic derivative thereof.

[0221] In one embodiment, this application relates to the treatment of prostate cancer with the compounds of the present invention and another anticancer agent. In one embodiment, the prostate cancer treated with the combination of the compounds of the present invention and another anticancer agent is metastatic prostate cancer. In one embodiment, the prostate cancer treated with the combination of the compounds of the present invention and another anticancer agent is castration-resistant prostate cancer. In one embodiment, the prostate cancer treated with the combination of the compounds of the present invention and another anticancer agent is metastatic castration-resistant prostate cancer. In one embodiment, the other anticancer agent is abiraterone, estradiol mustard, docetaxel, ketoconazole, goserelin, histamine relin, triptorelin, buterrelin, cyproterone acetate, flutamide, bicalutamide, niludamide, pamidronate, levodopa, or a pharmaceutically acceptable salt thereof. In one embodiment, the other anticancer agent is abiraterone or a pharmaceutically acceptable salt thereof. In one embodiment, the other anticancer agent is abiraterone acetate.

[0222] In one scenario, cancer treatment results in a reduction in tumor size. This reduction in tumor size is also referred to as "tumor regression." Preferably, after treatment, the tumor size decreases by 5% or more relative to its pre-treatment size; more preferably, by 10% or more; more preferably, by 20% or more; more preferably, by 30% or more; more preferably, by 40% or more; even more preferably, by 50% or more; and best of all, by more than 75% or more. Tumor size can be measured using any reproducible measurement method. In a preferred scenario, tumor size can be measured as tumor diameter.

[0223] In another scenario, cancer treatment results in a reduction in tumor volume. Preferably, after treatment, the tumor volume decreases by 5% or more relative to its pre-treatment volume; more preferably, by 10% or more; more preferably, by 20% or more; more preferably, by 30% or more; more preferably, by 40% or more; even more preferably, by 50% or more; and most preferably, by more than 75% or more. Tumor size can be measured using any reproducible measurement method.

[0224] In another embodiment, cancer treatment results in a reduction in the number of tumors. Preferably, after treatment, the number of tumors is reduced by 5% or more compared to the number before treatment; more preferably, the number of tumors is reduced by 10% or more; more preferably, by 20% or more; more preferably, by 30% or more; more preferably, by 40% or more; even more preferably, by 50% or more; and most preferably, by more than 75%. The number of tumors can be measured by any reproducible measurement method. In a preferred embodiment, the number of tumors can be measured by counting tumors visible to the naked eye or at a specified magnification. In a preferred embodiment, the specified magnification is 2×, 3×, 4×, 5×, 10×, or 50×.

[0225] In another aspect, cancer treatment results in a reduction in the number of metastatic lesions in tissues or organs distant from the primary tumor site. Preferably, after treatment, the number of metastatic lesions is reduced by 5% or more compared to the number before treatment; more preferably, the number of metastatic lesions is reduced by 10% or more; more preferably, by 20% or more; more preferably, by 30% or more; more preferably, by 40% or more; even more preferably, by 50% or more; and most preferably, by more than 75%. The number of metastatic lesions can be measured by any reproducible measurement method. In a preferred aspect, the number of metastatic lesions can be measured by counting the metastatic lesions visible to the naked eye or at a specified magnification. In a preferred aspect, the specified magnification is 2×, 3×, 4×, 5×, 10×, or 50×.

[0226] In another embodiment, cancer treatment results in an increase in the mean survival time of the treated individual population compared to the population receiving a single carrier. Preferably, the increase in mean survival time exceeds 30 days; more preferably, exceeds 60 days; even better, exceeds 90 days; and most preferably, exceeds 120 days. The increase in mean survival time can be measured by any reproducible means. In a preferred embodiment, for example, the increase in mean survival time can be measured by calculating the mean survival time of the population after initiation of treatment with the active agent or the compound of the present invention. In another preferred embodiment, the increase in mean survival time can also be measured, for example, by calculating the mean survival time of the population after completion of the first round of treatment with the active agent or the compound of the present invention.

[0227] In another sample, cancer treatment resulted in an increase in the mean survival time of the treated individual group compared to the untreated group. Preferably, the increase in mean survival time exceeded 30 days; more preferably, exceeded 60 days; even better, exceeded 90 days; and most preferably, exceeded 120 days. The increase in mean survival time of the group can be measured by any reproducible means. In a preferred sample, the increase in mean survival time of the group can be measured by calculating the mean survival time of the group after initiation of treatment with the active agent or the compound of the present invention. In another preferred sample, the increase in mean survival time of the group can be measured by calculating the mean survival time of the group after completion of the first round of treatment with the compound of the present invention.

[0228] In another scenario, cancer treatment leads to a reduction in tumor growth rate. Preferably, after treatment, the tumor growth rate is reduced by at least 5% relative to the pre-treatment growth rate; more preferably, by at least 10%; more preferably, by at least 20%; more preferably, by at least 30%; more preferably, by at least 40%; more preferably, by at least 50%; even more preferably, by at least 50%; and most preferably, by at least 75%. The tumor growth rate can be measured by any reproducible measurement method. In a preferred scenario, the tumor growth rate is measured based on the change in tumor diameter per unit time.

[0229] In another scenario, cancer treatment reduces tumor regeneration. Preferably, after treatment, tumor regeneration is less than 5%; more preferably, less than 10%; more preferably, less than 20%; more preferably, less than 30%; more preferably, less than 40%; more preferably, less than 50%; even more preferably, less than 50%; and best, less than 75%. Tumor regeneration can be measured by any reproducible measurement method. In a preferred scenario, tumor regeneration is measured by measuring the increase in tumor diameter after initial tumor shrinkage following treatment. In another preferred scenario, tumor recurrence failure after treatment cessation indicates reduced tumor regeneration.

[0230] The dosage of the compound of the invention used in any of the methods and uses described herein varies depending on the pharmaceutical agent, the age, weight and clinical condition of the recipient, the experience and judgment of the clinician or practicing physician administering the therapy, and other factors that affect the selected dosage.

[0231] The therapeutically effective dose of the compound of this invention can be administered once or multiple times a day for up to 30 days or more, followed by one or more days without administration of the compound. This type of treatment schedule (i.e., administering the compound of this invention for several consecutive days, followed by several consecutive days without administration of the compound) can be referred to as a treatment cycle. The treatment cycle can be repeated multiple times as needed to achieve the desired effect.

[0232] In one embodiment, the therapeutically effective dose of the compound of the present invention is once, twice, three times, four times or more daily for one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, twenty, twenty-five, or thirty consecutive days, or once, twice, three times, four times or more daily, in a single or divided dose, for two, three, four, five, six months or longer, administering 0.01, 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7. 7.5, 8, 8.5, 9, 9.5, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 4 6, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 2 10, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, 300, 305, 310, 315, 320, 325, 330, 335, 340, 345, 350, 355, 360, 36 5, 370, 375, 380, 385, 390, 395, 400, 405, 410, 415, 420, 425, 430, 435, 440, 445, 450, 455, 460, 465, 470, 475, 480, 485, 490, 495, 500, 505, 510, 515, 520 525, 530, 535, 540, 545, 550, 555, 560, 565, 570, 575, 580, 585, 590, 595, 600, 605, 610, 615, 620, 625, 630, 635, 640, 645, 650, 655, 660, 665, 670, 675680, 685, 690, 695, 700, 705, 710, 715, 720, 725, 730, 735, 740, 745, 750, 755, 760, 765, 770, 775, 780, 785, 790, 795, 800, 805, 810, 815, 820, 825, 830, 835, 84 0, 845, 850, 855, 860, 865, 870, 875, 880, 885, 890, 895, 900, 905, 910, 915, 920, 925, 930, 935, 940, 945, 950, 955, 960, 965, 970, 975, 980, 985, 990, 995, or 1,000 mg.

[0233] In one embodiment, the therapeutically effective amount of the compound of the present invention is administered once, twice, three times, four times or more daily in a single or divided dose of about 10 to about 40 mg, about 20 to about 50 mg, about 30 to about 60 mg, about 40 to about 70 mg, about 50 to about 80 mg, about 60 to about 90 mg, about 70 to about 100 mg, about 80 to about 110 mg, about 90 to about 120 mg, about 100 to about 130 mg, about 110 to about 140 mg, about 120 to about 150 mg, about 130 to about 160 mg, about 140 to about 170 mg, about 150 to about 180 mg, about 160 to about 190 mg, about 170 to about 200 mg, about 180 to about 210 mg, about 190 to about 220 mg, about 200 to about 230 mg, about 210 to about 240 mg, about 220 to about 250 mg, about 230 to about 260 mg, or about 230 to about 260 mg. mg, about 240 to about 270 mg, about 250 to about 280 mg, about 260 to about 290 mg, about 270 to about 300 mg, about 280 to about 310 mg, about 290 to about 320 mg, about 300 to about 330 mg, about 310 to about 340 mg, about 320 to about 350 mg, about 330 to about 360 mg, about 340 to about 370 mg, about 350 to about 380 mg, about 360 to about 390 mg, about 370 to about 400 mg, about 380 to about 410 mg, about 390 to about 420 mg, about 400 to about 430 mg, about 410 to about 440 mg, about 420 to about 450 mg, about 430 to about 460 mg, about 440 to about 470 mg, about 450 to about 480 mg, about 460 to about 490 mg, about 470 to about 500 mg mg, about 480 to about 510 mg, about 490 to about 520 mg, about 500 to about 530 mg, about 510 to about 540 mg, about 520 to about 550 mg, about 530 to about 560 mg, about 540 to about 570 mg, about 550 to about 580 mg, about 560 to about 590 mg, about 570 to about 600 mg, about 580 to about 610 mg, about 590 to about 620 mg, about 600 to about 630 mg, about 610 to about 640 mg, about 620 to about 650 mg, about 630 to about 660 mg, about 640 to about 670 mg, about 650 to about 680 mg, about 660 to about 690 mg, about 670 to about 700 mg, about 680 to about 710 mg, about 690 to about 720 mg, about 700 to about 730 mg, about 710 to about 740 mg mg, approximately 720 to approximately 750 mg, approximately 730 to approximately 760 mg, approximately 740 to approximately 770 mgmg, about 750 to about 780 mg, about 760 to about 790 mg, about 770 to about 800 mg, about 780 to about 810 mg, about 790 to about 820 mg, about 800 to about 830 mg, about 810 to about 840 mg, about 820 to about 850 mg, about 830 to about 860 mg, about 840 to about 870 mg, about 850 to about 880 mg, about 860 to about 890 mg, about 870 to about 900 mg, about 880 to about 910 mg, about 890 to about 920 mg, about 900 to about 930 mg, about 910 to about 940 mg, about 920 to about 950 mg, about 930 to about 960 mg, about 940 to about 970 mg, about 950 to about 980 mg, about 960 to about 990 mg, or about 970 to about 1,000 mg (This dosage can be adjusted based on the patient's weight (in kg), body surface area (in m2), and / or age (in years).

[0234] In one embodiment, the therapeutically effective dose of the compound of the present invention is about 70 mg to about 1000 mg once, twice, three times, four times or more daily in a single or divided dose (this dose may be adjusted according to the patient’s weight (in kg), body surface area (in m2) and / or age (in years).

[0235] In one embodiment, the therapeutically effective dose of the compound of the present invention is administered once, twice, three times, four times or more daily in a single or divided dose of about 70 mg, 105 mg, 140 mg, 175 mg, 210 mg, 245 mg, 280 mg, 315 mg, 350 mg, 385 mg, 420 mg, 455 mg, 490 mg, 525 mg, 560 mg, 595 mg, 630 mg, 665 mg or 700 mg (this dose may be adjusted according to the patient's weight (in kg), body surface area (in m2) and / or age (in years).

[0236] The therapeutically effective amount of the compound of the present invention may range from about 0.01 mg / kg / day to about 100 mg / kg / day. In one embodiment, the therapeutically effective amount of the compound of the present invention may range from about 0.05 mg / kg / day to about 10 mg / kg / day. In one embodiment, the therapeutically effective amount of the compound of the present invention may range from about 0.075 mg / kg / day to about 5 mg / kg / day. In one embodiment, the therapeutically effective amount of the compound of the present invention may range from about 0.10 mg / kg / day to about 1 mg / kg / day. In one embodiment, the therapeutically effective amount of the compound of the present invention may range from about 0.20 mg / kg / day to about 0.70 mg / kg / day.

[0237] In one embodiment, the therapeutically effective amount of the compound of the present invention is about 0.10 mg / kg / day, about 0.15 mg / kg / day, about 0.20 mg / kg / day, about 0.25 mg / kg / day, about 0.30 mg / kg / day, about 0.35 mg / kg / day, about 0.40 mg / kg / day, about 0.45 mg / kg / day, about 0.50 mg / kg / day, about 0.55 mg / kg / day, about 0.60 mg / kg / day, about 0.65 mg / kg / day, about 0.70 mg / kg / day, about 0.75 mg / kg / day, about 0.80 mg / kg / day, about 0.85 mg / kg / day, about 0.90 mg / kg / day, about 0.95 mg / kg / day, or about 1.00 mg / kg / day.

[0238] In one embodiment, the therapeutically effective amount of the compound of the present invention is about 1.05 mg / kg / day, about 1.10 mg / kg / day, about 1.15 mg / kg / day, about 1.20 mg / kg / day, about 1.25 mg / kg / day, about 1.30 mg / kg / day, about 1.35 mg / kg / day, about 1.40 mg / kg / day, about 1.45 mg / kg / day, about 1.50 mg / kg / day, about 1.55 mg / kg / day, about 1.60 mg / kg / day, about 1.65 mg / kg / day, about 1.70 mg / kg / day, about 1.75 mg / kg / day, about 1.80 mg / kg / day, about 1.85 mg / kg / day, about 1.90 mg / kg / day, about 1.95 mg / kg / day, or about 2.00 mg / kg / day.

[0239] In one embodiment, the therapeutically effective amount of the compound of the present invention is about 2 mg / kg / day, about 2.5 mg / kg / day, about 3 mg / kg / day, about 3.5 mg / kg / day, about 4 mg / kg / day, about 4.5 mg / kg / day, about 5 mg / kg / day, about 5.5 mg / kg / day, about 6 mg / kg / day, about 6.5 mg / kg / day, about 7 mg / kg / day, about 7.5 mg / kg / day, about 8.0 mg / kg / day, about 8.5 mg / kg / day, about 9.0 mg / kg / day, about 9.5 mg / kg / day, or about 10 mg / kg / day.

[0240] In one embodiment, a therapeutically effective dose of the compound of the present invention is administered to an individual once daily. In one embodiment, the entire daily dose of the compound of the present invention may be administered to an individual in a single dose. In one embodiment, the daily dose of the compound of the present invention may be administered to an individual in two portions (i.e., fractionated doses). In one embodiment, the daily dose of the compound of the present invention may be administered to an individual in three fractionated doses. In one embodiment, the daily dose of the compound of the present invention may be administered to an individual in four fractionated doses. In one embodiment, the daily dose of the compound of the present invention may be administered to an individual in five or more fractionated doses. In one embodiment, such portions or fractionated doses are administered to an individual at regular intervals throughout the day, for example, every 12 hours, every 8 hours, every 6 hours, every 5 hours, every 4 hours, etc.

[0241] The therapeutically effective amount of the compounds of the present invention can initially be estimated in cell culture analysis or in animal models, typically rats, mice, rabbits, dogs, or pigs. Animal models can also be used to determine appropriate concentration ranges and routes of administration. This information can then be used to determine the appropriate dosage and route of administration for human use. Therapeutic / prophylactic efficacy and toxicity can be determined in cell cultures or laboratory animals using standard pharmaceutical procedures, such as ED50 (the dose that is therapeutically effective in 50% of the population) and LD50 (the dose that causes death in 50% of the population). The dose ratio between toxicity and therapeutic effect is the therapeutic index, which can be expressed as the ratio LD50 / ED50. Pharmaceutical compositions exhibiting a larger therapeutic index are preferred. Dosage can vary within this range depending on the dosage form used, patient sensitivity, and route of administration.

[0242] The dosage and administration are adjusted to provide an adequate amount of the compound of the present invention or to maintain the desired effect. Factors to consider include the severity of the disease condition, the individual's general health status, the individual's age, weight and sex, diet, timing and frequency of administration, drug combination, sensitivity to response, and tolerance / response to the therapy. Long-acting pharmaceutical compositions may be administered every 3 to 4 days, weekly, bi-weekly, or monthly, depending on the half-life and clearance rate of the specific formulation.

[0243] In one embodiment, for a method of treating prostate cancer using a combination of the compound of the present invention and another anticancer agent, the therapeutically effective amount of the compound of the present invention is described herein, and the therapeutically effective amount of the anticancer agent is once, twice, three times, four times or more daily for one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen or thirty consecutive days, or once, twice, three times, four times or more daily, in a single or divided dose, for two months, three months, four months, five months, six months or longer, administering 0.01, 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, 300, 305, 310, 315, 3 20, 325, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 395, 400, 405, 410, 415, 420, 425, 430, 435, 440, 445, 450, 455, 460, 465, 470, 47 5, 480, 485, 490, 495, 500, 505, 510, 515, 520, 525, 530, 535, 540, 545, 550, 555, 560, 565, 570, 575, 580, 585, 590, 595, 600, 605, 610, 615, 620, 625, 630635, 640, 645, 650, 655, 660, 665, 670, 675, 680, 685, 690, 695, 700, 705, 710, 715, 720, 725, 730, 735, 740, 745, 750, 755, 760, 765, 770, 775, 780, 785, 790, 795, 800, 805, 810, 815 820, 825, 830, 835, 840, 845, 850, 855, 860, 865, 870, 875, 880, 885, 890, 895, 900, 905, 910, 915, 920, 925, 930, 935, 940, 945, 950, 955, 960, 965, 970, 975, 980, 985, 990, 995 or 1,000 mg.

[0244] In one embodiment, for a method of treating prostate cancer with a combination of the compound of the present invention and abiraterone or a pharmaceutically acceptable salt thereof, the therapeutically effective amount of the compound of the present invention is described herein, and the therapeutically effective amount of abiraterone or a pharmaceutically acceptable salt thereof is once, twice, three times, four times or more daily for one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, or thirty consecutive days, or once, twice, three times, four times or more daily, in a single or divided dose, for two months, three months, four months, five months, six months or longer, at doses of 0.01, 0.05, 0.1, 0.2, 0.3, 0. 4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 2 6, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 105, 110, 115, 120, 125, 130, 1 35, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 29 0, 295, 300, 305, 310, 315, 320, 325, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 395, 400, 405, 410, 415, 420, 425, 430, 435, 440, 445 450, 455, 460, 465, 470, 475, 480, 485, 490, 495, 500, 505, 510, 515, 520, 525, 530, 535, 540, 545, 550, 555, 560, 565, 570, 575, 580, 585, 590, 595, 600605, 610, 615, 620, 625, 630, 635, 640, 645, 650, 655, 660, 665, 670, 675, 680, 685, 690, 695, 700, 705, 710, 715, 720, 725, 730, 735, 740, 745, 750, 755, 760, 765, 770, 775, 780, 785, 790, 795, 800 805, 810, 815, 820, 825, 830, 835, 840, 845, 850, 855, 860, 865, 870, 875, 880, 885, 890, 895, 900, 905, 910, 915, 920, 925, 930, 935, 940, 945, 950, 955, 960, 965, 970, 975, 980, 985, 990, 995, or 1,000 mg. In one embodiment, abiraterone is abiraterone acetate.

[0245] In one embodiment, for the method of treating prostate cancer with a combination of the compound of the present invention and abiraterone acetate, the therapeutically effective amount of the compound of the present invention is described herein, and the therapeutically effective amount of abiraterone acetate is 1,000 mg orally once daily for one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, twenty, twenty-five, thirty or more consecutive days, administered orally in a single or divided dose. In one embodiment, abiraterone acetate is administered in combination with 5 mg of prisson orally twice daily. In one embodiment, the combination of the compound of the present invention and abiraterone acetate is administered to a fasting individual in need. In one embodiment, the individual has not eaten for at least two hours before and at least one hour after the administration of the combination of the compound of the present invention and abiraterone acetate.

[0246] In one embodiment, the compound of the present invention and abiraterone acetate are simultaneously administered to an individual. In another embodiment, the compound of the present invention and abiraterone acetate are administered to an individual sequentially.

[0247] In one embodiment, the compounds and anticancer agents of the present invention are administered to an individual in a temporal proximity manner.

[0248] In some embodiments, "time proximity" means that the administration of the compound of the present invention occurs within a period of time before or after the administration of the anticancer agent, such that the therapeutic effects of the compound of the present invention overlap with the therapeutic effects of the anticancer agent. In some embodiments, the therapeutic effects of the compound of the present invention completely overlap with the therapeutic effects of the anticancer agent. In some embodiments, "time proximity" means that the administration of the compound of the present invention occurs within a period of time before or after the administration of the anticancer agent, such that there is a synergistic effect between the compound of the present invention and the anticancer agent. In one embodiment, the anticancer agent is abiraterone acetate.

[0249] "Time proximity" can vary depending on various factors, including but not limited to the individual's age, sex, weight, genetic background, medical condition, medical history, and treatment history; the disease or condition to be treated or alleviated; the treatment outcome to be achieved; the dosage, frequency, and duration of administration of the therapeutic agent; the pharmacokinetics and pharmacodynamics of the therapeutic agent; and the route of administration of the therapeutic agent. In some embodiments, "time proximity" means within 15 minutes, 30 minutes, one hour, two hours, four hours, six hours, eight hours, 12 hours, 18 hours, 24 hours, 36 hours, two days, three days, four days, five days, six days, one week, two weeks, three weeks, four weeks, six weeks, or eight weeks. In some embodiments, multiple administrations of one therapeutic agent may be time-proximity to a single administration of another therapeutic agent. In some embodiments, time proximity may vary during treatment or within the administration regimen. Pharmaceutical Composition

[0250] In one embodiment, the compounds of the present invention are formulated for oral administration. For example, in one embodiment, the compounds of the present invention are formulated as tablets comprising zero, one, two or more of the following: emulsifiers, surfactants, binders, disintegrants, lubricants, and slurries.

[0251] In one embodiment, the emulsifier is hydroxypropyl methylcellulose.

[0252] In one embodiment, the surfactant is vitamin E polyethylene glycol succinate.

[0253] In one embodiment, the adhesive (also referred to herein as a filler) is selected from the group consisting of microcrystalline cellulose, lactose monohydrate, sucrose, glucose, and sorbitol.

[0254] In one embodiment, the disintegrant is croscarmellose sodium.

[0255] In one embodiment, a lubricant refers to a substance used to promote powder flow by reducing the cohesive forces between particles. In one embodiment, in the dosage form of the present invention, the lubricant is selected from the group consisting of: silica, anhydrous silica gel, starch, and talc.

[0256] In one embodiment, a lubricant refers to a substance that prevents components from sticking together and / or agglomerating in a machine used to prepare the dosage form of the present invention. In one embodiment, in the dosage form of the present invention, the lubricant is selected from the group consisting of: magnesium stearate, sodium stearate fumarate, stearic acid, and vegetable stearic acid.

[0257] Pharmaceutical compositions containing the compounds of the present invention can be manufactured in generally known ways, such as by means of conventional mixing, dissolving, granulation, forming sugar-coated pills, water milling, emulsification, encapsulation, coating, or lyophilization processes. The pharmaceutical compositions can be formulated in conventional ways using one or more pharmaceutically acceptable carriers (including excipients and adjuvants that facilitate the formulation of the compounds of the present invention into pharmaceutically usable preparations). Of course, suitable formulations depend on the chosen route of administration.

[0258] Suitable injectable pharmaceutical compositions include sterile aqueous solutions (in the water-soluble case) or dispersions and sterile powders for the ad hoc preparation of sterile injectable solutions or dispersions. For intravenous administration, suitable carriers include physiological saline, antibacterial water, Cremophor EL™ (BASF, Parsippany, NJ), or phosphate-buffered saline (PBS). In all cases, the composition must be sterile and fluid to the extent necessary for injectability. It must be stable under manufacturing and storage conditions and must be protected against contamination by microorganisms such as bacteria and fungi. Carriers may be solvents or dispersion media containing, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol and the like), and suitable mixtures thereof. Appropriate flowability can be maintained, for example, by using coatings such as lecithin, by maintaining the desired particle size in the case of dispersions, and by using surfactants. Microbial activity can be prevented by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenols, ascorbic acid, thimerosal, and their analogues. In many cases, isotonic agents, such as sugars, polyols (e.g., mannitol, sorbitol), and sodium chloride, are preferred in the composition. Prolonged absorption of injectable compositions can be achieved by including agents that delay absorption (e.g., aluminum monostearate and gelatin) in the composition.

[0259] A sterile injectable solution can be prepared by incorporating the compounds of the present invention in the desired amount with one or a combination of the ingredients listed above into a suitable solvent, followed by filtration and sterilization as needed. Generally, dispersants are prepared by incorporating an active agent or compound into a sterile medium containing a basic dispersion medium and other desired components from the aforementioned ingredients. In the case of sterile powders used to prepare sterile injectable solutions, the preparation method is vacuum drying and freeze-drying, which produces a powder containing the active ingredient plus any additional desired components from a previously sterile filtered solution.

[0260] Oral compositions generally include an inert diluent or an edible, pharmaceutically acceptable carrier. They may be encapsulated in gelatin capsules or compressed into tablets. For oral therapeutic administration, the compounds of the present invention may be incorporated with excipients and used in tablet, sugar-coated tablet, or capsule form. Oral compositions may also be prepared using fluid carriers suitable for use as mouthwashes, wherein the pharmaceutical agent or compound in the fluid carrier is applied orally and rinsed and spat out or swallowed. Pharmaceutically compatible binders and / or adjuvant materials may be included as part of the composition. Tablets, pills, capsules, sugar-coated tablets and the like may contain any of the following ingredients or compounds with similar properties: binders, such as microcrystalline cellulose, tragacanth gum or gelatin; excipients, such as starch or lactose; disintegrants, such as alginic acid, sodium hydroxyacetate (Primogel) or corn starch; lubricants, such as magnesium stearate; slurries, such as colloidal silicon dioxide; sweeteners, such as sucrose or saccharin; or flavorings, such as peppermint, methyl salicylate or orange flavoring.

[0261] For drug administration via inhalation, the agent or compound is delivered in the form of an aerosol spray from a pressurized container or dispenser containing a suitable propellant (such as a gas like carbon dioxide) or a sprayer.

[0262] Systemic drug administration can also be performed via mucosal or transdermal routes. For mucosal or transdermal drug administration, a penetrant suitable for the barrier to be penetrated is used in the formulation. Such penetrants are generally known in this art, and for mucosal drug administration, they include, for example, detergents, bile salts, and clostridial acid derivatives. Mucosal drug administration can be achieved by using nasal sprays or suppositories. For transdermal drug administration, as is generally known in this art, the active agent or compound is formulated into an ointment, cream, gel, or lotion.

[0263] In one embodiment, the compounds of the present invention are prepared using pharmaceutically acceptable carriers that protect the agent or compound from rapid elimination by the body, such carriers being controlled-release formulations, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers such as ethylene vinyl acetate, polyanhydride, polyglycolic acid, collagen, polyorthoesters, and polylactic acid can be used. Methods for preparing such formulations are readily apparent to those skilled in the art. Materials are also commercially available from Alza Corporation and Nova Pharmaceuticals, Inc. Liposome suspensions (including liposomes targeting infected cells with monoclonal antibodies against viral antigens) can also be used as pharmaceutically acceptable carriers. These carriers can be prepared according to methods known to those skilled in the art, for example as described in U.S. Patent No. 4,522,811.

[0264] For ease of administration and dosage uniformity, unit dosage forms are particularly advantageous for preparing oral or non-enteral compositions. As used herein, a unit dosage form refers to a physically discrete unit suitable for a unit dose to be treated individual; each unit contains a predetermined amount of active agent or compound calculated to produce the desired therapeutic effect associated with the desired pharmaceutical carrier. The specifications of the unit dosage forms used in this application are determined directly by and specified by the unique characteristics of the compounds of this invention and the specific therapeutic effect to be achieved.

[0265] Pharmaceutical compositions may be included in containers, packages or dispensers along with instructions for use.

[0266] The illustrative administration modes of the compounds of this invention include systemic or local administration, such as oral, nasal, non-enteric, transdermal, subcutaneous, vaginal, buccal, rectal, or local administration. In one embodiment, the compounds of this invention are administered orally. In one embodiment, the compounds of this invention are administered in the form of lozenges, capsules, tablets, solutions, suspensions, syrups, granules, beads, powders, or pellets.

[0267] The illustrative pharmaceutical compositions are tablets and gelatin capsules comprising salts of the compounds of the present invention and pharmaceutically acceptable carriers, such as a) diluents, such as purified water, triglyceride oils (such as hydrogenated or partially hydrogenated vegetable oils or mixtures thereof), corn oil, olive oil, sunflower oil, safflower oil, fish oil (such as EPA or DHA) or esters or triglycerides or mixtures thereof, omega-3 fatty acids or derivatives thereof, lactose, dextran, sucrose, mannitol, sorbitol, cellulose, sodium, saccharin, glucose and / or glycine; b) lubricants, such as silica, talc, stearic acid, its magnesium or calcium salts, sodium oleate, sodium stearate, stearic acid, etc. Magnesium silicate, sodium benzoate, sodium acetate, sodium chloride and / or polyethylene glycol; the same applies to tablets; c) binders, such as magnesium aluminum silicate, starch paste, gelatin, tragali, methylcellulose, sodium carboxymethylcellulose, magnesium carbonate, natural sugars (such as glucose or β-lactose), corn sweeteners, natural and synthetic gums (such as gum arabic, tragali or sodium alginate), waxes and / or polyvinylpyrrolidone (as needed); d) disintegrants, such as starch, agar, methylcellulose, bentonite, succinate, alginic acid or its sodium salt or foaming mixtures; e) absorbents, colorants, flavorings and sweeteners; f) emulsifiers or dispersants, such as Tween 80. Labrasol, HPMC, DOSS, hexyl 909, labrafac, labrafil, peceol, transcutol, capmul MCM, capmul PG-12, captex 355, glyceryl laurate, vitamin E, TGPS or other acceptable emulsifiers; and / or g) agents that enhance salt absorption, such as cyclodextrin, hydroxypropyl-cyclodextrin, PEG400 and / or PEG200.

[0268] For pharmaceutical compositions prepared from the compounds of the present invention or their salts or hydrates, inert, pharmaceutically acceptable carriers may be solid or liquid. Solid formulations include powders, tablets, dispersible granules, capsules, pouches, and suppositories. Powders and tablets may contain about 5% to about 95% of the active ingredient. Suitable solid carriers are known in the art, such as magnesium carbonate, magnesium stearate, talc, sugar, or lactose. Tablets, powders, pouches, and capsules can be used as solid dosage forms suitable for oral administration. Examples of pharmaceutically acceptable carriers and methods for preparing various compositions can be found in A. Gennaro (ed.), Remington's Pharmaceutical Sciences, 18th edition, (1990), Mack Publishing Co., Easton, Pa.

[0269] Liquid formulations include solutions, suspensions, and emulsions. Examples include water or water-propylene glycol solutions for non-enteral injection, or oral solutions, suspensions, and emulsions for which sweeteners and emulsifiers are added. Liquid formulations may also include solutions for intranasal administration.

[0270] Liquids, especially injectable compositions, can be prepared, for example, by dissolution, dispersion, etc. For instance, the disclosed salt can be dissolved in or mixed with a pharmaceutically acceptable solvent, such as (e.g.) water, physiological saline, aqueous dextran, glycerol, ethanol, and the like, to form an injectable isotonic solution or suspension. Proteins (such as albumin, chylomicron particles, or serum proteins) can be used to dissolve the disclosed compound.

[0271] Non-enteral injectable drugs are generally used for subcutaneous, intramuscular, or intravenous injection and infusion. Injectable preparations can be made in conventional forms, as liquid solutions or suspensions, or in solid forms suitable for dissolving in a liquid prior to injection.

[0272] Suitable inhalation formulations may include solutions and solids in powder form, which may be combined with medically acceptable carriers such as inert compressed gases (e.g., nitrogen).

[0273] This also includes solid formulations intended to be converted into a liquid form for oral or non-enteral administration immediately before use. Such liquid forms include solutions, suspensions, and emulsions.

[0274] Depending on the intended mode of administration, the disclosed composition may be in solid, semi-solid, or liquid dosage forms, such as injections, tablets, suppositories, pills, time-release capsules, elixirs, tinctures, emulsions, syrups, powders, liquids, suspensions, or similar forms, sometimes in a unit dosage form and in accordance with conventional pharmaceutical practice. Similarly, it may be administered intravenously (both bolus and infusion), intraperitoneally, intrathecally, subcutaneously, or intramuscularly, and all forms of administration are well known to those skilled in pharmaceutical technology.

[0275] The pharmaceutical composition may be prepared according to conventional mixing, granulation or coating methods, and may contain, by weight or volume, about 0.1% to about 99%, about 5% to about 90% or about 1% to about 20% of the disclosed free base or salt.

[0276] Pharmaceutical compositions containing compounds of the present invention may further comprise one or more additional anticancer agents, including any of the anticancer agents disclosed herein.

[0277] Unless otherwise indicated, all amounts of any component of an oral dosage form (e.g., tablets) described herein based on % w / w indicate the total weight of the oral dosage form. Example [ ] [ ]

[0278] The invention is further illustrated by the following examples, which should not be construed as limiting the scope or spirit of the invention to the specific procedures described herein. It should be understood that the examples provided are for illustrating certain embodiments and are not intended to limit the scope of the invention. It should be further understood that various other embodiments, modifications, and equivalents may be employed, and those skilled in the art will conceive of such other embodiments, modifications, and equivalents without departing from the spirit of the invention and / or the scope of the appended claims.

[0279] abbreviation: ACN: Acetonitrile ADDP: 1,1'-(azadicarbonyl)dipiperidine BAST: N,N-bis(2-methoxyethyl)aminothiotrifluoride Binap: 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl Boc: Tertiary butoxycarbonyl BPO: Benzoyl peroxide Cbz: Carbonylbezyloxy DAST: Diethylaminosulfuric trifluoride DBE: 1,2-Dibromoethane DCE: 1,2-Dichloroethane DCM: Dichloromethane DEAD: Diethyl azodicarbonate DIAD: Diisopropyl azodicarbonate DIBAL: Diisobutylaluminum Hydrogenation DIEA or DIPEA: Diisopropylethylamine DMA: N,N-dimethylacetamide DMF: N,N-dimethylformamide DMP: Dess-Martin periodinane DMSO: Dimethyl sulfoxide EA: Ethyl acetate EDCI: 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridine 3-oxyhexafluorophosphate HBTU:N,N,N'N'-Tetramethyl-O-(1H-benzotriazol-1-yl) hexafluorophosphate HMDS: Bis(trimethylsilyl)amine HOBt: Hydroxybenzotriazole HPLC: High Performance Liquid Chromatography HMPA: Hexamethylphosphatidylcholine LDA: Lithium diisopropylamine LCMS: Liquid Chromatography-Mass Spectrometry MCPBA: m-chloroperoxybenzoic acid MsCl: Methylsulfonic acid chloride MW: Microwave NBS: N-bromosuccinimide NMM: N-methyl phyto NMP: N-methylpyrrolidone PCC: Pyridine Chlorochromate Pd-118 or Pd(dtpf)Cl2:1,1'-bis(di-tert-butylphosphine)ferrocene dichloropalladium Pd(dppf)Cl2:1,1'-bis(diphenylphosphino)ferrocene dichloropalladium Pd(dba)2:bis(diphenylmethyleneacetone)palladium Pd2(dba)3: (diphenylmethyleneacetone)dipalladium PPTS: Pyridine p-toluenesulfonate PTSA: p-Toluenesulfonic acid RuPhos-Pd-G3:XPhos-Pd-G3:[(2-Dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium methanesulfonate(II) RuPhos-Pd-G2: Chlorine[(2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) SEM-Cl: 2-(trimethylsilyl)ethoxymethyl chloride SFC: Supercritical Fluid Chromatography STAB: Sodium Triethoxyborohydride t-BuXPhos-Pd-G3:[(2-di-tert-butylphosphine-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium methanesulfonate(II) TEA: Triethylamine THF: Tetrahydrofuran TFA: Trifluoroacetic acid TLC: Thin-layer chromatography TMP: 2,2,6,6-Tetramethylpiperidine TEMPO: 2,2,6,6-Tetramethylpiperidine-N-oxide TosCl or TsCl: p-Toluenesulfonate chloride TsOH: p-Toluenesulfonic acid Xantphos: 4,5-bis(diphenylphosphino)-9,9-dimethyl XPhos:2-Dicyclohexylphosphino-2'4'6'-triisopropylbiphenyl XPhos-Pd-G3:[(2-Dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium methanesulfonate(II) 12354-85-7: Bis(pentamethylcyclopentadienyl rhodium dichloride)

[0280] Example 1 - Compound of the present invention

[0281] Example 2 - Synthesis intermediate 4-((1R,3R)-3-amino-2,2,4,4-tetramethylcyclobutoxy)-2-methoxybenzonitrile

[0282] Step 1: Preparation of ((1R,3R)-3-(4-cyano-3-methoxyphenoxy)-2,2,4,4-tetramethylcyclobutyl)aminocarbamate tributyl ester [ ]

[0283] Sodium hydride (3.29 g, 82.19 mmol, 60% purity, 2.00 eq) was added dropwise to a solution of N-(3-hydroxy-2,2,4,4-tetramethyl-cyclobutyl)aminocarbamate (10.00 g, 41.09 mmol, 1.00 eq) in dimethylformamide (100 mL) at 0 °C for 0.5 h. Then, a solution of 4-fluoro-2-methoxybenzonitrile (6.83 g, 45.20 mmol, 1.10 eq) in dimethylformamide (10 mL) was added dropwise to the mixture at 0 °C. The mixture was heated to 20 °C and stirred at 20 °C for 3.5 h. The reaction mixture was quenched with saturated ammonium chloride solvent (600 mL) and extracted with ethyl acetate (300 mL). The organic layer was washed with brine (300 mL × 2), dried over sodium sulfate, and concentrated under reduced pressure to obtain the residue. The residue was purified by silicone column chromatography (petroleum ether:ethyl acetate = 20:1 to 8:1) to give N-[3-(4-cyano-3-methoxy-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]aminocarbamate tributyl ester (10.00 g, 26.70 mmol, 64% yield) as a white solid. 1H-NMR (400MHz, DMSO-d6) δ 7.62 (d, J=8.4 Hz, 1H) 6.76 - 6. 59 (m, 2H) 6.50 (d, J=8.4 Hz, 1H) 4.12 (s, 1H) 3.89 (s, 3H) 3.64 - 3.44 (m, 1H) 1.41 (s, 9H) 1.13 (s, 6H) 1.06 (s, 6H).

[0284] Step 2: Preparation of 4-((1R,3R)-3-amino-2,2,4,4-tetramethylcyclobutoxy)-2-methoxybenzonitrile

[0285] Add hydrochloric acid / dichloromethane to a solution of N-[3-(4-cyano-3-methoxy-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]carbamate tributyl ester (10.00 g, 26.70 mmol, 1.00 eq) in dichloromethane (50 mL). Alkane (4 M, 48.00 mL, 7.19 eq). The mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give 4-(3-amino-2,2,4,4-tetramethyl-cyclobutoxy)-2-methoxy-benzonitrile (8.20 g, 26.38 mmol, 98% yield, hydrochloride) as a white solid. 1H-NMR (400MHz, DMSO-d6 ) δ 8.49 (s, 3H) 7.64 (d, J=8.8 Hz, 1H) 6.63 (d, J=2.0 Hz, 1H) 6.53 (d, J=8.8, 2.0 Hz, 1H) 4.31 (s, 1H) 3.90 (s, 3H) 3.06 (d, J=5.2 Hz, 1H) 1.33 (s, 6H) 1.11 (s, 6H).

[0286] Example 3 - Synthesis of 4-(4-((1-(4-(((1R,3R)-3-(4-cyano-3-methoxyphenoxy)-2,2,4,4-tetramethylcyclobutyl)aminomethyl)phenyl)piperidin-4-yl)methyl)piperidin -1-yl)-N-2,6-di-oxypiperidin-3-yl)-2-fluorobenzamide (Compound 1)

[0287] Step 1: Preparation of 4-((1-(tert-butoxycarbonyl)piperidin-4-yl)methyl)piperidin 1-Benzyl carboxylate

[0288] Add piperonyl ester (10.00 g, 46.89 mmol, 1.00 eq) to a solution of 4-methoxypiperidine-1-carboxylic acid tributyl ester in methanol (20 mL) at 25 °C. Benzyl 1-carboxylate (10.33 g, 46.89 mmol, 9.06 mL, 1.00 eq) was added and stirred for 10 h. Sodium cyanoborohydride (4.42 g, 70.33 mmol, 1.50 eq) was then added to the mixture. The mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (20 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with brine (100 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 3 / 1) to give 4-[(1-tert-butoxycarbonyl-4-piperidinyl)methyl]piperidinyl ester as a colorless oil. 1-Benzyl 1-carboxylate (15.00 g, 35.92 mmol, 76% yield). ¹H-NMR (400 MHz, CD₃OD) δ 7.22–7.43 (m, 5H), 5.09–5.14 (m, 2H), 4.03–4.13 (m, 2H), 3.49 (s, 4H), 2.75 (s, 2H), 2.39 (s, 4H), 2.20 (d, J = 6.4 Hz, 2H), 1.63–1.82 (m, 3H), 1.44 (s, 9H), 0.97–1.13 (m, 2H).

[0289] Step 2: Preparation of 4-(piperazine) 1-(1-ylmethyl)piperidine-1-carboxylic acid tert-butyl ester

[0290] To 4-[(1-tert-butoxycarbonyl-4-piperidinyl)methyl]piperidin 4-(piperazine) benzoate (8.00 g, 19.16 mmol, 1.00 eq) was added to a mixture of 4-(piperazine) benzoate in ethanol (50 mL) with palladium hydroxide / activated carbon catalyst (2.69 g, 10% purity). The mixture was degassed and purged three times with hydrogen. The mixture was then stirred at 50 °C for 12 h under a hydrogen atmosphere (50 psi). The reaction mixture was filtered and concentrated under reduced pressure to give 4-(piperazine) benzoate as a black oil. (-1-ylmethyl)piperidin-1-carboxylic acid tributyl ester (4.50 g, 15.88 mmol, 82% yield). ¹H-NMR (400 MHz, CD3OD) δ 4.00 - 4.10 (m, 1H), 3.96 - 4.12 (m, 1H), 3.29 - 3.43 (m, 1H), 2.81 - 2.95 (m, 4H), 2.75 (s, 2H), 2.42 (d, J=2.8 Hz, 3H), 2.19 (d, J=6.8 Hz, 2H), 1.71 - 1.80 (m, 3H), 1.45 (s, 9H), 1.01 - 1.12 (m, 2H).

[0291] Step 3: Preparation of 4-[[4-(3-fluoro-4-methoxycarbonyl-phenyl)piperazine] -1-yl]methyl]piperidine-1-carboxylic acid tert-butyl ester

[0292] Methyl 4-bromo-2-fluorobenzoate (500.00 mg, 2.15 mmol, 1.00 eq) was reacted at 110 °C with dimethyl 4-bromo-2-fluorobenzoate. Palladium(II) acetate (24.09 mg, 107.28 μmol, 0.05 eq), bis(diphenylphosphino)-1,1'-bidinaphthalene (133.60 mg, 214.56 μmol, 0.10 eq), cesium carbonate (1.54 g, 4.72 mmol, 2.20 eq), and 4-(piperazine) were added to a solution of alkylene (6 mL). 4-[[4-(3-fluoro-4-methoxycarbonyl-phenyl)piperidine-1-carboxylic acid tert-butyl ester (669.00 mg, 2.36 mmol, 1.10 eq). The mixture was stirred at 110 °C for 16 h. The mixture was filtered and the filtrate was concentrated under vacuum to obtain the residue. The residue was purified by silicone column chromatography (petroleum ether / ethyl acetate = 8 / 1 to 1:1) to give 4-[[4-(3-fluoro-4-methoxycarbonyl-phenyl)piperidine-1-carboxylic acid tert-butyl ester) as a dark brown solid. -1-yl]methyl]piperidin-1-carboxylic acid tert-butyl ester (750.00 mg, 1.72 mmol, 80% yield). LC / MS (ESI) m / z: 436.3 [M+1] +; 1H-NMR (400MHz, CDCl3) δ 7.82 (t, J=8.8 Hz, 1H), 6.62 (dd, J=8.8, 2.0, 1H), 6.50 (dd, J=14.8, 2.4, 1H), 4.03 - 4.09 (m, 1H), 3.88 (s, 3H), 3.23 - 3.36 (m, 4H), 2.71 (t, J=12.4 Hz, 2H), 2.47 - 2.57 (m, 4H), 2.22 (d, J=7.2 Hz, 2H), 1.75 (d, J=13.2 Hz, 2H), 1.59 - 1.71 (m, 2H), 1.46 (s, 9H), 1.02 - 1.18 (m, 2H).

[0293] Step 4: Preparation of 2-fluoro-4-(4-(piperidin-4-ylmethyl)piperidin Methyl 1-yl)benzoate [ ] [ ] [ ]

[0294] To 4-[[4-(3-fluoro-4-methoxycarbonyl-phenyl)piperazine 1-[4-(4-piperidinylmethyl)piperidin-1-carboxylic acid tert-butyl ester (1.00 g, 2.30 mmol, 1.00 eq) was added to a solution of ethyl acetate (10 mL) with hydrochloride / ethyl acetate (4 M, 574.01 μL, 1.00 eq). The mixture was stirred at 25 °C for 1 h. The mixture was concentrated under reduced pressure to give 2-fluoro-4-[4-(4-piperidinylmethyl)piperidinyl]piperidin-1-carboxylic acid tert-butyl ester (1.00 g, 2.30 mmol, 1.00 eq) as a white solid. Methyl benzoate (850.00 mg, 2.29 mmol, 99% yield, hydrochloride). LC / MS (ESI) m / z: 336.1 [M+1] +; 1H-NMR (400MHz, DMSO-d6 ) δ 8.90 (s, 1H), 8.74 (s, 1H), 7.76 (t, J=8.8 Hz, 1H), 6.91 (d, J=3.2 Hz, 1H), 3.96 - 4.11 (m, 2H), 3.78 (s, 3H), 3.32 - 3.39 (m, 2H), 3.27 (d, J=12.8 Hz, 3H), 3.07 (d, J=6.8 Hz, 4H), 2.80 - 2.93 (m, 2H), 2.17 (s, 1H), 2.01 (d, J=13.6 Hz, 2H), 1.91 (s, 1H), 1.44 (q, J=11.2 Hz, 2H). [ ] [ ]

[0295] Step 5: Preparation of 4-(4-((1-(4-(tert-butoxycarbonyl)phenyl)piperidin-4-yl)methyl)piperidin Methyl 1-(1-yl)-2-fluorobenzoate [ ] [ ] [ ]

[0296] To 2-fluoro-4-[4-(4-piperidinylmethyl)piperidin Methyl benzoate (850.00 mg, 2.29 mmol, 1.00 eq, hydrochloric acid) was dissolved in diethyl benzoate. Diethoxypalladium (51.32 mg, 228.57 μmol, 0.10 eq), 2,2'-bis(diphenylphosphino)-1,1'-bidinaphthalene (213.49 mg, 342.86 μmol, 0.15 eq), cesium carbonate (1.86 g, 5.71 mmol, 2.50 eq), and tributyl 4-bromobenzoate (705.25 mg, 2.74 mmol, 1.20 eq) were added to a solution of alkylene (20 mL). The mixture was stirred at 110 °C for 12 h under a nitrogen atmosphere. The mixture was filtered. The filtrate was concentrated under reduced pressure to obtain the residue. The residue was purified by gel silica column chromatography (petroleum ether / ethyl acetate = 20 / 1 to 3 / 1) to obtain 4-[4-[[1-(4-tert-butoxycarbonylphenyl)-4-piperidinyl]methyl]piperidinyl as a white solid. Methyl 1-[1-yl]-2-fluorobenzoate (588.00 mg, 1.15 mmol, 50% yield). LC / MS (ESI) m / z: 512.2 [M+1]+. [ ] [ ]

[0297] Step 6: Preparation of 4-(4-((1-(4-(tert-butoxycarbonyl)phenyl)piperidin-4-yl)methyl)piperidin -1-yl)-2-fluorobenzoic acid [ ] [ ] [ ]

[0298] To 4-[4-[[1-(4-tert-butoxycarbonylphenyl)-4-piperidinyl]methyl]piperidinyl]piperidinyl Methyl 4-[4-[[1-(4-tert-butoxycarbonylphenyl)-4-piperidinyl]methyl]piperidinyl]-2-fluorobenzoate (588.00 mg, 1.15 mmol, 1.00 eq) was added to a solution of methanol (8.00 mL) and water (2.00 mL) with LiOH·H₂O (144.68 mg, 3.45 mmol, 3.00 eq). The mixture was stirred at 40 °C for 10 h. The reaction mixture was concentrated under reduced pressure. The residue was adjusted to pH 5-6 with hydrochloric acid (1 M) and extracted with ethyl acetate (30 mL × 2). The combined organic layers were washed with brine (20 mL × 1), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 4-[4-[[1-(4-tert-butoxycarbonylphenyl)-4-piperidinyl]methyl]piperidinyl ... 1-[1-yl]-2-fluorobenzoic acid (563.00 mg, 1.13 mmol, 98% yield). LC / MS (ESI) m / z: 498.2 [M+1]+. [ ] [ ]

[0299] Step 7: Preparation of 4-(4-((4-(((2,6-di-dioxypiperidin-3-yl)aminomethoxy)-3-fluorophenyl)piperidin -1-yl)methyl)piperidin-1-yl)tert-butyl benzoate [ ] [ ] [ ]

[0300] To 4-[4-[[1-(4-tert-butoxycarbonylphenyl)-4-piperidinyl]methyl]piperidinyl]piperidinyl [-1-yl]-2-fluorobenzoic acid (563.00 mg, 1.13 mmol, 1.00 eq) was added to a solution of dimethylformamide (6 mL) along with 1-hydroxybenzotriazole (229.32 mg, 1.70 mmol, 1.50 eq), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (325.35 mg, 1.70 mmol, 1.5 eq), diisopropylethylamine (731.15 mg, 5.66 mmol, 985.37 μL, 5.00 eq), and 3-aminopiperidin-2,6-dione (223.47 mg, 1.36 mmol, 1.20 eq, hydrochloride). The mixture was stirred at 25 °C for 10 h. The reaction mixture was quenched by adding water (50 mL), and a purple solid was separated. The mixture was filtered to obtain a purple solid, 4-[4-[[4-[4-[(2,6-dioxy-3-piperidinyl)aminomethyl]-3-fluoro-phenyl]piperidinyl -1-yl]methyl]-1-piperidinyl]benzoate tributyl ester (600.00 mg, 987.31 μmol, 87% yield). LC / MS (ESI) m / z: 608.0 [M+1] +; 1H-NMR (400MHz, DMSO-d6 ) δ 10.83 (s, 1H), 8.03 (t, J=7.2 Hz, 1H), 7.94 (s, 1H), 7.69 (d, J=8.8 Hz, 2H), 7.63 (t, J=9.2 Hz, 1H), 6.92 (d, J=9.2 Hz, 2H), 6.72 - 6.84 (m, 2H), 4.72 (td, J=12.8, 6.4 Hz, 1H), 3.87 (d, J=12.8 Hz, 2H), 3.28 (s, 4H), 2.88 (s, 3H), 2.81 (br t, J=12.0 Hz, 2H), 2.72 (s, 3H), 2.53 (d, J=4.0 Hz, 2H), 2.11 (dd, J=12.8, 4.0 Hz, 1H), 1.79 (d, J=11.2 Hz, 3H), 1.50 (s, 9H), 1.13 - 1.24 (m, 2H).

[0301] Step 8: Preparation of 4-(4-((4-(((2,6-di-side-oxypiperidin-3-yl)aminomethoxy)-3-fluorophenyl)piperidin -1-yl)methyl)piperidin-1-yl)benzoic acid [ ] [ ] [ ]

[0302] To 4-[4-[[4-[4-[(2,6-dioxy-3-piperidinyl)aminomethoxy]-3-fluoro-phenyl]piperidinyl [-1-yl]methyl]-1-piperidinyl]benzoate tributyl ester (600.00 mg, 987.31 μmol, 1.00 eq) was added to a solution of ethyl acetate (8 mL) with hydrochloric acid / ethyl acetate (4 M, 246.83 μL, 1.00 eq). The mixture was stirred at 25 °C for 1 h. The mixture was concentrated under reduced pressure to give a white solid of 4-[4-[[4-[4-[(2,6-dioxy-3-piperidinyl)aminomethyl]-3-fluoro-phenyl]piperidinyl]benzoate. [-1-yl]methyl]-1-piperidinyl]benzoic acid (510.00 mg, 924.57 μmol, 93% yield). LC / MS (ESI) m / z: 552.2 [M+1]+. [ ] [ ]

[0303] Step 9: Preparation of 4-(4-((1-(4-(((1R,3R)-3-(4-cyano-3-methoxyphenoxy)-2,2,4,4-tetramethylcyclobutyl)aminomethyl)phenyl)piperidin-4-yl)methyl)piperidin -1-yl)-N-(2,6-dioxypiperidin-3-yl)-2-fluorobenzoamide

[0304] To 4-[4-[[4-[4-[(2,6-dioxy-3-piperidinyl)aminomethoxy]-3-fluoro-phenyl]piperidinyl [-1-yl]methyl]-1-piperidinyl]benzoic acid (170.00 mg, 308.19 μmol, 1.00 eq) was added to a solution of dimethylformamide (2 mL) with 1-hydroxybenzotriazole (54.14 mg, 400.65 μmol, 1.30 eq), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (76.80 mg, 400.65 μmol, 1.30 eq), diisopropylethylamine (199.16 mg, 1.54 mmol, 268.41 μL, 5.00 eq), and 4-(3-amino-2,2,4,4-tetramethyl-cyclobutoxy)-2-methoxy-benzonitrile (114.95 mg, 369.83 μmol, 1.20 eq, hydrochloric acid). The mixture was stirred at 25 °C for 24 h. The mixture was filtered to obtain a filtrate. The filtrate was purified by prep-HPLC to obtain a white solid, 4-[4-[[1-[4-[[3-(4-cyano-3-methoxy-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]aminomethyl]phenyl]-4-piperidinyl]methyl]piperidinyl ... [-1-yl]-N-(2,6-di-sideoxy-3-piperidinyl)-2-fluoro-benzoamide (55.10 mg, 64.42 μmol, 20% yield, 99% purity, formic acid). LC / MS (ESI) m / z: 808.3 [M+1] +; 1H-NMR (400MHz, DMSO-d6 ) δ 10.84 (s, 1H), 8.17 (s, 1H), 8.04 (t, J=7.2 Hz, 1H), 7.74 (d, J=8.8 Hz, 2H), 7.60 - 7.68 (m, 2H), 7.49 (d, J=9.2 Hz, 1H), 6.96 (d, J=9.2 Hz, 2H), 6.74 - 6.86 (m, 2H), 6.64 (d, J=2.0 Hz, 1H), 6.55 (dd, J=8.4, 2.0 Hz, 1H), 4.69 - 4.78 (m, 1H), 4.28 (s, 1H), 4.06 (d, J=9.2 Hz, 1H), 3.91 (s, 3H), 3.86 (d, J=13.2 Hz, 2H), 3.31 (s, 4H), 2.73 - 2.85 (m, 3H), 2.54 (d, J=4.0 Hz, 1H), 2.49 (s, 4H), 2.21 (d, J=6.8 Hz, 2H), 2.06 - 2.16 (m, 1H), 1.98 - 2.05 (m, 1H), 1.76 - 1.85 (m, 3H), 1.23 (s, 6H), 1.22 - 1.17 (m, 2H), 1.15 (s, 6H).

[0305] Example 4 - Synthesis of N-[3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]-6-[4-[(4-[4-[(2,6-dioxypiperidin-3-yl)aminomethyl]phenyl]piperidin] -1-yl)methyl]piperidin-1-yl]tadalafil -3-Methylamine (Compound 3)

[0306] Process 1. Overview of the synthesis of compound 3.

[0307] Step 1. Synthesis of N-[(1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]carbamate tributyl ester (I)

[0308] A solution of N-[(1r,3r)-3-hydroxy-2,2,4,4-tetramethylcyclobutyl]carbamate tributyl ester (312.9 mg, 1.29 mmol, 1 equivalent) in DMF (10 mL) was placed in a 25 mL round-bottom flask. NaH (154.4 mg, 3.86 mmol, 3 equivalent, 60%) was added to this solution at 0 °C. The mixture was stirred for 15 min, and then 2-chloro-4-fluorobenzonitrile (200 mg, 1.29 mmol, 1 equivalent) was added at 0 °C. The reaction mixture was stirred at 0 °C for 2 h. The reaction mixture was then quenched by adding water (45 mL). The resulting mixture was extracted with ethyl acetate (3 × 50 mL) and the organic layers were combined, washed with brine (50 mL × 3), dried over sodium sulfate and concentrated under vacuum to give 400 mg (crude matter) of N-[(1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]carbamate tributyl ester as a yellow oil.

[0309] LC-MS (ES+): m / z 379.17 [MH+], tR = 1.1.46 min, (running for 2.00 minutes).

[0310] Step 2. Synthesis of 2-chloro-4-[(1r,3r)-3-amino-2,2,4,4-tetramethylcyclobutoxy]benzonitrile(II)

[0311] Place 400 mg (1.06 mmol, 1 equivalent) of N-[(1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]carbamate in a 25-mL round-bottom flask and then in a solution of hydrogen chloride and 1,4-di(2,4-di)carbamate. The solution was prepared in alkyl (4 M, 20 mL). The resulting solution was stirred at room temperature for 2 hours. The mixture was concentrated under vacuum to obtain 250 mg (crude substance) of 2-chloro-4-[(1r,3r)-3-amino-2,2,4,4-tetramethylcyclobutoxy]benzonitrile as a yellow oil.

[0312] Step 3. Synthesis of 6-chloro-N-[(1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]tadalafil -3-Methylamine(III)

[0313] Place 250 mg (0.90 mmol, 1 equivalent) of 2-chloro-4-[(1r,3r)-3-amino-2,2,4,4-tetramethylcyclobutoxy]benzonitrile and 6-chlorobenzonitrile into a 25 mL round-bottom flask. 3-Carboxylic acid (142.17 mg, 0.90 mmol, 1 equivalent), DIEA (347.70 mg, 2.69 mmol, 3 equivalent), and T3P (856.00 mg, 2.69 mmol, 3 equivalent) in DMF (10 mL). The resulting solution was stirred at room temperature for 2 hours. The reaction mixture was then quenched by adding water (20 mL). The resulting mixture was extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine (3 × 50 mL) and concentrated under vacuum. The residue was applied to a silicone column and dissociated with ethyl acetate / petroleum ether (0:100 to 6:1) to give 250 mg (66.49%) of 6-chloro-N-[(1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]pyrene as a yellow solid. -3-methamide.

[0314] LC-MS (ES+): m / z 419.10 [MH+], tR = 1.38 min, (running for 2.00 minutes).

[0315] Step 4. Synthesis of N-(2,6-dioxypiperidin-3-yl)-4-[4-[(piperidin-4-yl)methyl]piperidin -1-yl]benzoylamine(IV)

[0316] Procedure 2. Synthesis of N-(2,6-dioxypiperidin-3-yl)-4-[4-[(piperidin-4-yl)methyl]piperidin Overview of 1-yl]benzoylamine (IV).

[0317] Step 4a. Synthesis of 4-[4-[(2,6-dioxypiperidin-3-yl)aminomethoxy]phenyl]piperidin -1-Tetrabutyl formate (IVa)

[0318] Place a container containing 4-[4-[(tert-butoxy)carbonyl]piperidine in a 100-mL round-bottom flask purged and maintained under an inert nitrogen atmosphere. [-1-yl]benzoic acid (1.30 g, 4.24 mmol, 1.00 equivalent), 3-aminopiperidin-2,6-dione (543.70 mg, 4.24 mmol, 1.00 equivalent), DIEA (1.64 g, 12.73 mmol, 3.00 equivalent), and T3P (4.05 g, 12.73 mmol, 3.00 equivalent) in DMF (20 mL). The resulting solution was stirred at room temperature for 2 hours. The reaction mixture was then quenched by adding water (100 mL). The resulting mixture was extracted with ethyl acetate (3 × 150 mL), and the organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. This yielded 900 mg (crude matter) of a yellow oil of 4-[4-[(2,6-dioxypiperidin-3-yl)aminomethoxy]phenyl]piperidin -1-Tetrabutyl carboxylate.

[0319] Step 4b. Synthesis of N-(2,6-dioxypiperidin-3-yl)-4-(piperidin-3-yl) -1-yl)benzamide (IVb)

[0320] Place 4-[4-[(2,6-dioxypiperidin-3-yl)aminomethoxy]phenyl]piperidin into a 50-mL round-bottom flask DCM (20 mL) of tert-1-formate (900 mg, 2.16 mmol, 1 equivalent) was added, followed by the addition of TFA (5 mL). The resulting solution was stirred at room temperature for 1.5 hours. The mixture was then concentrated under vacuum. This yielded 600 mg (crude matter) of N-(2,6-dioxypiperidin-3-yl)-4-(piperidin) as a yellow oil. -1-yl)benzamide.

[0321] Step 4c. Synthesis of 4-((4-(4-((2,6-dioxypiperidin-3-yl)aminomethoxy)phenyl)piperidin -1-yl)methyl)piperidin-1-carboxylic acid tertiary butyl ester (IVc)

[0322] Place N-(2,6-dioxypiperidin-3-yl)-4-(piperidin) into a 100-mL round-bottom flask purged and maintained under an inert nitrogen atmosphere. 25 mL of DCM containing 1.00 g (3.16 mmol, 1.00 equivalent) of 4-(4-(4-((2,6-dioxypiperidin-3-yl)aminomethyl)phenyl)piperidin (1.00 g, 3.16 mmol, 1.00 equivalent), 4-methoxypiperidin-1-carboxylic acid tributyl ester (0.70 g, 3.28 mmol, 1.00 equivalent) and STAB (2.00 g, 0.01 mmol, 3 equivalent) was stirred at room temperature for 3 hours. The reaction mixture was then quenched by adding water (100 mL). The resulting mixture was extracted with ethyl acetate (3 × 150 mL), and the organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. This yielded 900 mg (crude matter) of a yellow oil containing 4-((4-(4-((2,6-dioxypiperidin-3-yl)aminomethyl)phenyl)piperidin -1-yl)methyl)piperidine-1-carboxylic acid tert-butyl ester

[0323] Step 4d. Synthesis of N-(2,6-dioxypiperidin-3-yl)-4-[4-[(piperidin-4-yl)methyl]piperidin -1-yl]benzoylamine(IV)

[0324] Place 4-[(4-[4-[(2,6-dioxypiperidin-3-yl)aminomethoxy]phenyl]piperidin into a 50-mL round-bottom flask DCM (10 ml) of tert-butyl piperidin-1-carboxylate (500 mg, 0.97 mmol, 1.00 equivalent) was added to the solution, followed by the addition of TFA (3 ml). The solution was stirred at room temperature for 1.5 hours. The mixture was then concentrated under vacuum. This yielded 350 mg (crude matter) of N-(2,6-dioxypiperidin-3-yl)-4-[4-[(piperidin-4-yl)methyl]piperidin-1-carboxylate as a yellow oil. -1-yl]benzamide.

[0325] LC-MS (ES+): m / z 414.30 [MH+], tR = 0.703 min, (run for 2.00 minutes).

[0326] Step 5. Synthesis of N-[3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]-6-[4-[(4-[4-[(2,6-dioxypiperidin-3-yl)aminomethyl]phenyl]piperidin] -1-yl)methyl]piperidin-1-yl]tadalafil -3-Methylamine (3)

[0327] Place a container containing 6-chloro-N-[(1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl] into a 25-mL round-bottom flask. 3-Methylamine (200 mg, 0.48 mmol, 1 equivalent), N-(2,6-dioxypiperidin-3-yl)-4-[4-[(piperidin-4-yl)methyl]piperidin -1-yl]benzoylamine (197.20 mg, 0.48 mmol, 1 equivalent) and K2CO3 (197.80 mg, 1.43 mmol, 3 equivalent) in DMF (11 mL). The mixture was stirred at room temperature for 12 hours. The solid was filtered off and the filtrate was concentrated. The residue was purified by Prep-HPLC under the following conditions: column, XBridge Prep C18 OBD column, 5 μm, 19*150 mm; mobile phase A: water (with 10 mmol / L NH4HCO3), mobile phase B: CH3CN; gradient: 60% to 70% of phase B within 8 min; detector, UV. After lyophilization, 27.8 mg (7.32%) was a white solid of N-[3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]-6-[4-[(4-[4-[(2,6-dioxypiperidin-3-yl)aminomethyl]phenyl]piperidin -1-yl)methyl]piperidin-1-yl]tadalafil -3-methamide.

[0328] 1H NMR (300 MHz, DMSO) δ10.81 (s, 1H), 8.46-8.43 (m, 1H), 8.25-8.22 (m, 1H), 7.91-7.89 (m, 1H), 7.83 -7.81 (m, 1H), 7.77-7.45 (m, 2H), 7.38-7.35 (m, 1H), 7.25 (s, 1H), 7.05-6.97(m, 3H), 4.76-4.74 (m,1H), 4.52-4.46 (m, 3H), 4.02-4.00 (m, 1H), 3.20 (m, 4H), 3.08-3.02 (m, 2H), 2.83-2.76 (m, 1H), 2.60 (m, 4H), 2.23-2.13 (m, 2H), 2.10-2.00 (m, 1H), 1.97-1.84 (m, 4H), 1.28-1.03 (m, 15H); LC-MS (ES+): m / z 796.35 [MH+], tR = 1.95 min, (run for 3.00 minutes).

[0329] Chemical formula: C42H50ClN9O5 [796.37]

[0330] Example 5 - Synthesis of Compound 5

[0331] Process 3. Overview of the synthesis of compound 5.

[0332] Step 1. Synthesis of 4-[5-(methoxycarbonyl)pyridin-3-yl]piperazine -1-Tetrabutylformate (I)

[0333] 5-Bromopyridine-3-carboxylate (2 g, 9.258 mmol, 1 equivalent) and piperazine were added to a 250 mL round-bottom flask at room temperature. 1-Butyl 1-carboxylate (1.90 g, 0.010 mmol, 1.1 equivalents), toluene (40 mL, 375.956 mmol, 40.61 equivalents), and Cs₂CO₃ (6.03 g, 18.516 mmol, 2.0 equivalents) were added fractionally to the mixture at room temperature over 2 min. The mixture was stirred overnight at 90 °C. The mixture was then cooled to room temperature. The resulting mixture was diluted with ethyl acetate (400 mL). The combined organic layers were washed with brine (1 × 300 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silicone column chromatography and dissolved in hexane / EtOAc (100% to 35%) to obtain 4-[5-(methoxycarbonyl)pyridin-3-yl]piperazine, a grayish-white solid. -1-Tetrabutyl carboxylate (1.4 g, 47.05%). LC-MS (ES, m / z): 322.00 [MH+], tR = 0.911 min, (run for 2.00 min).

[0334] Step 2. Synthesis of 5-(4-(tert-butoxycarbonyl)piperazine) -1-yl)nicotinic acid(II)

[0335] Add 4-[5-(methoxycarbonyl)pyridin-3-yl]piperazine to a 50 mL round-bottom flask at room temperature 1-Butyl 1-carboxylate (1.4 g, 4.356 mmol, 1 equivalent), MeOH (1.3 mL, 32.109 mmol, 7.37 equivalent), and H₂O (12 mL, 666.100 mmol, 152.91 equivalent) were added fractionally to the stirred solution at room temperature. The mixture was stirred overnight at room temperature. The resulting mixture was diluted with ethyl acetate (30 mL). The mixture was filtered, and the filter cake was washed with MeOH (3 × 50 mL). The filtrate was concentrated under reduced pressure. The crude product was used directly in the next step without further purification. LC-MS (ES, m / z): 308.05 [MH+], tR = 0.627 min (run for 2.00 min). [ ] [ ]

[0336] Step 3. Synthesis of 4-[5-[(2,6-dioxypiperidin-3-yl)aminomethoxy]pyridin-3-yl]piperidin -1-Tetrabutylformate(III)

[0337] Add 5-[4-[(tert-butoxy)carbonyl]piperazine to a 25 mL round-bottom flask at room temperature. [-1-yl]pyridine-3-carboxylic acid (500 mg, 1.627 mmol, 1 equivalent), 3-aminopiperidine-2,6-dione hydrochloride (267.76 mg, 1.627 mmol, 1.00 equivalent), DMF (0.00 mL, 0.052 mmol, 0.03 equivalent), DIEA (1051.27 mg, 8.134 mmol, 5.0 equivalent), and HATU (1237.12 mg, 3.254 mmol, 2.00 equivalent). The mixture was stirred at room temperature under a nitrogen atmosphere for 3 h. The reaction mixture was quenched at room temperature by adding water (30 mL). The mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (3 × 30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silicone column chromatography and dissolved in PE / EtOAc (1:1) to obtain a grayish-white solid, 4-[5-[(2,6-dioxypiperidin-3-yl)aminomethoxy]pyridin-3-yl]piperidin. -1-Tetrabutyl carbamate (290 mg, 42.70%). LC-MS (ES, m / z): 418.05 [MH+], tR = 0.796 min, (run 2.00 min).

[0338] Step 4. Synthesis of N-(2,6-dioxypiperidin-3-yl)-5-(piperidin-3-yl) -1-yl)nicotinamide hydrochloride (IV)

[0339] Add 4-[5-[(2,6-dioxypiperidin-3-yl)aminomethoxy]pyridin-3-yl]piperidin to a 10 mL round-bottom flask at room temperature -1-Tetrabutyl formate (290 mg), MeOH (2 mL), and 1,4-di(2-ethylhexyl) containing HCl (gas) Alkane (3 mL). The mixture was stirred at 30 °C in air for 2 h. The mixture was concentrated under vacuum to give N-(2,6-dioxypiperidin-3-yl)-5-(piperidine) as a grayish-white solid. (-1-yl)pyridine-3-methamide hydrochloride (300 mg). The crude product can be used directly in the next step without further purification.

[0340] Step 5. Synthesis of N-(2,6-dioxypiperidin-3-yl)-5-(4-[[1-(4-[[(1r,3r)-3-(4-cyano-3,5-dimethylphenoxy)-2,2,4,4-tetramethylcyclobutyl]aminomethyl]piperidin-4-yl]methyl]piperidin -1-yl)pyridine-3-methylamine (VI)

[0341] Stirring at room temperature under a nitrogen atmosphere (V), 4-(4-methoxypiperidin-1-yl)-N-[(1r,3r)-3-(4-cyano-3,5-dimethylphenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide (100 mg, 0.205 mmol, 1 equivalent) and N-(2,6-dioxypiperidin-3-yl)-5-(piperidin) A solution / mixture of 1-yl)pyridine-3-methylamine hydrochloride (87.07 mg, 0.246 mmol, 1.2 equivalents) in dichloromethane was prepared for 30 min. STAB (130.39 mg, 0.615 mmol, 3.0 equivalents) was added fractionally to the mixture over 5 min at 0 °C. The mixture was stirred overnight at room temperature. The mixture was cooled to 0 °C. The reaction mixture was quenched with water / ice at 0 °C. The mixture was extracted with EtOAc (3 × 15 mL). The combined organic layers were washed with brine (1 × 30 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC under the following conditions (2#SHIMADZU (HPLC-01)): column, Xselect CSH OBD column 30*150mm 5um, n; mobile phase, water (10 mmol / L NH4HCO3) and ACN (maintained at 57% phase B for 8 min); detector, UV 254nm. This produced a white solid N-(2,6-dioxypiperidin-3-yl)-5-(4-[[1-(4-[[(1r,3r)-3-(4-cyano-3,5-dimethylphenoxy)-2,2,4,4-tetramethylcyclobutyl]aminomethyl]phenyl)piperidin-4-yl]methyl]piperidin -1-yl)pyridine-3-methamide (22.6 mg, 13.97%).

[0342] LC-MS (ES, m / z): 789.35[MH+], tR = 2.168min, (running for 3.00 minutes).

[0343] 1H-NMR: (CD3OD, 300MHz): δ 8.42 (m, 2H),7.79 (s, 1H), 7.73 (d, 2H), 7.0(d, 2H), 6.71 (s, 2H), 4.92-4.89(m, 1H), 4.23 (s, 1H), 4.11 (m, 1H), 3.91 (d, 2H), 3.38-3.35 (m, 5H), 2.89-2.79 (m, 3H), 2.76-2.74 (m, 1H), 2.69-2.64 (m, 4H), 2.47 (s, 6H), 2.33 (d, 2H), 2.25-2.16 (m, 3H), 1.39-1.31(m, 3H), 1.28(s, 6H), 1.21(s, 6H).

[0344] Chemical formula: C45H56N8O5 [788.99].

[0345] Example 6 - Synthesis of 4-(4-((1-(4-(((1R,3R)-3-(4-cyano-3-methoxyphenoxy)-2,2,4,4-tetramethylcyclobutyl)aminomethyl)phenyl)piperidin-4-yl)methyl)piperidin -1-yl)-N-((R)-2,6-di-dioxypiperidin-3-yl)-2-fluorobenzamide (Compound 14)

[0346] Compound 14 was separated from compound 1 (prepared as described in Example 3) using supercritical fluid chromatography. 118 mg of compound 14 was separated from compound 1 using the process outlined in Table 2 below.

[0347] Table 2. SFC conditions used for separating compound 14 instrument Waters 80Q tubular Chiralpak AD 250×30mm ID, 10um Moving phase Phase A for supercritical CO2 Phase B used in IPA:ACN=3:1 (0.1%NH3H2O) isocratic dissolution 80% Phase B (20% Phase A) Flow rate 80 g / min Cycle time 8.2 min back pressure 100 bar to maintain CO2 in supercritical flow UV 220nm injection 4.0ml

[0348] 1H NMR (400 MHz, DMSO-d6) δ: 10.84 (s, 1H), 8.05 (t, J=7.2 Hz, 1H), 7.75 (d, J=8.8 Hz, 2H), 7.69 - 7.60 (m, 2H), 7.51 (d, J=9.2 Hz, 1H), 6.96 (d, J=8.8 Hz, 2H), 6.87 - 6.74 (m, 2H), 6.65 (d, J=2.0 Hz, 1H), 6.55 (d, J=8.8, 2.0 Hz, 1H), 4.83 - 4. 65 (m, 1H), 4.29 (s, 1H), 4.06 (d, J=9.2 Hz, 1H), 3.95 - 3.79 (m, 5H), 3.32 - 3.24 (m, 4H), 2.87 - 2.72 (m, 3H), 2.56 - 2.53 (m, 2H), 2.49 - 2.46 (m, 3H), 2.25 - 2.17 (m, 2H), 2.17 - 2.08 (m, 1H), 2.06 - 2.00 (m, 1H), 1.81 (d, J=12.0 Hz, 3H), 1.27 - 1.10 (m, 14H).

[0349] Example 7 - Synthesis of Compound 15

[0350] Process 4. Overview of the synthesis of compound 15.

[0351] Step 1. Synthesis of N-[(1r,3r)-3-(4-cyano-3,5-dimethylphenoxy)-2,2,4,4-tetramethylcyclobutyl]carbamate tributyl ester (I)

[0352] Sodium hydride (60% in oil, 390 mg) was added to a solution of N-[(1r,3r)-3-hydroxy-2,2,4,4-tetramethylcyclobutyl]aminocarbamate (1.5 g, 6.164 mmol, 1 equivalent) in DMF at 0 °C. The mixture was stirred for 15 min. 4-fluoro-2,6-dimethylbenzonitrile (1.10 g, 7.397 mmol, 1.20 equivalent) was added, and the mixture was heated to RT and stirred for 2 h. The resulting mixture was diluted with ethyl acetate (50 mL). The reaction mixture was quenched at 0 °C by adding water / ice (20 mL). The aqueous layer was extracted with EtOAc (2 × 30 mL). The resulting mixture was washed with 3 × 50 mL of water. The residue was purified by Prep-TLC (CH2Cl2 / MeOH 10:1) to obtain N-[(1r,3r)-3-(4-cyano-3,5-dimethylphenoxy)-2,2,4,4-tetramethylcyclobutyl]carbamate tributyl ester (1.8 g, 78.39%) as a pale yellow solid.

[0353] LC-MS (ES+): m / z 317.00 [MH+-56], tR = 1.469 min, (running for 2.00 minutes).

[0354] Step 2. Synthesis of 2,6-dimethyl-4-[(1r,3r)-3-amino-2,2,4,4-tetramethylcyclobutoxy]benzonitrile hydrochloride (II)

[0355] At room temperature, N-[(1r,3r)-3-(4-cyano-3,5-dimethylphenoxy)-2,2,4,4-tetramethylcyclobutyl]carbamate tributyl ester (1.8 g, 4.832 mmol, 1 equivalent) was reacted with 1,4-dimethylcyclobutyl]carbamate. Add dropwise a solution containing 4M HCl to the stirred solution of alkane. Alkane. The mixture was stirred at 30°C for 1 h. The mixture was concentrated under reduced pressure. This produced 1.4 g, 93.81%, of 2,6-dimethyl-4-[(1r,3r)-3-amino-2,2,4,4-tetramethylcyclobutoxy]benzonitrile hydrochloride as a pale yellow solid.

[0356] LC-MS (ES+): m / z 273.25 [MH+], tR = 0.949 min, (running for 2.00 minutes).

[0357] Step 3. Synthesis of 5-chloro-N-[(1r,3r)-3-(4-cyano-3,5-dimethylphenoxy)-2,2,4,4-tetramethylcyclobutyl]pyridine -2-Methylamine(III)

[0358] At room temperature, 2,6-dimethyl-4-[(1r,3r)-3-amino-2,2,4,4-tetramethylcyclobutoxy]benzonitrile hydrochloride (500 mg, 1.619 mmol, 1 equivalent) and 5-chloropyridine were reacted. 2-Carboxylic acid (282.33 mg, 1.781 mmol, 1.1 equivalents) was added fractionally to a stirred solution in DMF containing DIEA (1.05 g, 8.095 mmol, 5 equivalents) and HATU (1.85 g, 4.857 mmol, 3 equivalents). The mixture was stirred at room temperature for 1 h. The mixture was diluted with ethyl acetate (50 mL). The mixture was washed with 3 × 40 mL of water. The residue was purified by Prep-TLC (PE / EtOAc 1:1) to give a pale yellow solid, 5-chloro-N-[(1r,3r)-3-(4-cyano-3,5-dimethylphenoxy)-2,2,4,4-tetramethylcyclobutyl]pyridine. -2-methoxymethylamine (500 mg, 74.80%).

[0359] LC-MS (ES+): m / z 413.25 [MH+], tR = 1.430 min, (running for 2.00 minutes).

[0360] Step 4. Synthesis of 2,2,2-trifluoroacetaldehyde; N-(2,6-di-side-oxypiperidin-3-yl)-3-[(1r,3r)-3-[[(piperidin-4-yl)methyl](propyl-2-yl)amino]cyclobutoxy]benzamide (IV)

[0361] At room temperature, 100 mg of 1 ethyl 4-[[(propyl-2-yl)[(1r,3r)-3-[3-[(2,6-dioxypiperidin-3-yl)aminomethyl]phenoxy]cyclobutyl]amino]methyl]piperidin-1-carboxylic acid tert-butyl ester (piperidin-1-carboxylic acid) was reacted with 1,4-diethyl-2- ... 1,4-di(HCl) (gaseous) is added dropwise to a stirred solution of alkane. Alkane (5 mL). The mixture was stirred at 30 °C for 2 h. The mixture was then concentrated under reduced pressure. The crude product was used directly in the next step without further purification.

[0362] LC-MS (ES+): m / z 457.27 [MH+], tR = 0.806 min, (running for 2.00 minutes).

[0363] Step 5. Synthesis of 5-(4-[[(propyl-2-yl)[(1r,3r)-3-[3-[(2,6-dioxypiperidin-3-yl)aminomethyl]phenoxy]cyclobutyl]amino]methyl]piperidin-1-yl)-N-[(1r,3r)-3-(4-cyano-3,5-dimethylphenoxy)-2,2,4,4-tetramethylcyclobutyl]pyr -2-Methylamine (Compound 3)

[0364] At room temperature, 2,2,2-trifluoroacetaldehyde; N-(2,6-di-side-oxypiperidin-3-yl)-3-[(1r,3r)-3-[[(piperidin-4-yl)methyl](propyl-2-yl)amino]cyclobutoxy]benzamide (100 mg, 0.180 mmol, 1 equivalent) and 5-chloro-N-[(1r,3r)-3-(4-cyano-3,5-dimethylphenoxy)-2,2,4,4-tetramethylcyclobutyl]pyridine 2-Methylamine (81.90 mg, 0.198 mmol, 1.1 equivalents) was added to a stirred solution in DMF with K2CO3 (74.76 mg, 0.541 mmol, 3 equivalents). The mixture was stirred overnight at 60°C. This produced a white solid 5-(4-[[(propyl-2-yl)[(1r,3r)-3-[3-[(2,6-dioxypiperidin-3-yl)aminomethyl]phenoxy]cyclobutyl]amino]methyl]piperidin-1-yl)-N-[(1r,3r)-3-(4-cyano-3,5-dimethylphenoxy)-2,2,4,4-tetramethylcyclobutyl]pyridine -2-methamide (25.8 mg, 17.18%).

[0365] 1H-NMR (400 MHz, methanol-d4) δ 8.67 (d, J = 1.4 Hz, 1H), 8.24 (d, J = 1.3 Hz, 1H), 7.45 (d, J = 7.6 Hz, 1H), 7.39 (t, J = 7.9 Hz, 1H), 7.32 (s, 1H), 7.04 (d, J = 8.3 Hz, 1H), 6.74 (s, 2H), 4.77 (s, 1H), 4.60 (d, J = 13.3 Hz, 2H), 4.27 (s, 1H), 4.06 (s, 1H), 3.77 (s, 1H), 3.03 (t, J = 12.5 Hz, 3H), 2.84 (dd, J = 17.3, 7.4 Hz, 1H), 2.78 - 2.69 (m, 1H), 2.49 (s, 6H), 2.36 (s, 2H), 2.23 (tt, J = 11.6, 7.0 Hz, 4H), 2.00 (d, J = 13.1 Hz, 2H), 1.79 (s, 1H), 1.29 (s, 6H), 1.22 (s, 6H), 1.18 (s, 2H), 1.03 (d, J = 6.5 Hz, 6H), 0.92 (s, 0H), 0.12 (s, 1H).

[0366] LC-MS (ES+): m / z 833.55 [MH+], tR = 1.646 min, (running for 3.00 minutes).

[0367] Example 8 - Synthesis of 4-(4-((1-(4-(((1R,3R)-3-(4-cyano-3-methoxyphenoxy)-2,2,4,4-tetramethylcyclobutyl)aminomethyl)phenyl)piperidin-4-yl)methyl)piperidin -1-yl)-N-((S)-2,6-di-dioxypiperidin-3-yl)-2-fluorobenzamide (Compound 21)

[0368] Compound 21 was separated from compound 1 (prepared as described in Example 3) using supercritical fluid chromatography. 71 mg of compound 21 was separated from compound 1 using the process outlined in Table 2 above.

[0369] 1H NMR (400 MHz, DMSO-d6) δ: 10.84 (s, 1H), 8.05 (t, J=7.2 Hz, 1H), 7.75 (d, J=8.8 Hz, 2H), 7.69 - 7.60 (m, 2H), 7.51 (d, J=9.2 Hz, 1H), 6.96 (d, J=8.8 Hz, 2H), 6.87 - 6.74 (m, 2H), 6.65 (d, J=2.0 Hz, 1H), 6.55 (d, J=8.8, 2.0 Hz, 1H), 4.83 - 4. 65 (m, 1H), 4.29 (s, 1H), 4.06 (d, J=9.2 Hz, 1H), 3.95 - 3.79 (m, 5H), 3.32 - 3.24 (m, 4H), 2.87 - 2.72 (m, 3H), 2.56 - 2.53 (m, 2H), 2.49 - 2.46 (m, 3H), 2.25 - 2.17 (m, 2H), 2.17 - 2.08 (m, 1H), 2.06 - 2.00 (m, 1H), 1.81 (d, J=12.0 Hz, 3H), 1.27 - 1.10 (m, 14H).

[0370] Example 9 - Synthesis of Compound 23

[0371] Process 5. - Overview of the synthesis of compound 23.

[0372] Step 1. Preparation of (I), 4-[4-[(2,6-dioxy-3-piperidinyl)aminomethoxy]phenyl]piperidinyl ... -1-Tetrabutyl carboxylate

[0373] To 4-(4-tert-butoxycarbonylpiperyl) A solution of o-(7-azabenzotriazol-1-yl)-n,n,n',n'-tetramethylbenzyl benzoic acid (500 mg, 1.63 mmol, 1 eq) and 3-aminopiperidin-2,6-dione (209 mg, 1.27 mmol, 1 eq, hydrochloride) in N,N-dimethylformamide (3 mL) was added. Hexafluorophosphate (930 mg, 2.45 mmol, 1.5 eq) and triethylamine (495 mg, 4.90 mmol, 3 eq). The mixture was stirred at 15 °C for 1 hour. LC-MS showed that the reaction was complete and detectable. Water (100 mL) was added to the mixture and stirred for 1 minute. The aqueous phase was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by prep-TLC (dichloromethane:methanol = 20:1). A compound 4-[4-[(2,6-dioxy-3-piperidinyl)aminomethyl]phenyl]piperidine was given as a grayish-white solid. -1-Tetrabutyl carboxylate (370 mg, 0.88 mmol, 54% yield).

[0374] Chemical formula: C21H28O5N4, Molecular weight: 416.47

[0375] Step 2. Preparation of (II), N-(2,6-di-side-oxy-3-piperidinyl)-4-piperidinyl -1-yl-benzoylamine

[0376] To 4-[4-[(2,6-dioxy-3-piperidinyl)aminomethoxy]phenyl]piperidinyl A solution of tert-1-formate (370 mg, 0.88 mmol, 1 eq) in dichloromethane (2 mL) was prepared by adding hydrochloric acid / dichloromethane. Alkane (4 M, 10 mL, 45.02 eq). The mixture was stirred at 15 °C for 1 hour. The desired MS was detected by LC-MS. The reaction mixture was filtered and concentrated under reduced pressure to give the residue. Crude product N-(2,6-dioxy-3-piperidinyl)-4-piperidine -1-yl-benzylamine was used in the next step without further purification. The compound N-(2,6-dioxy-3-piperidinyl)-4-piperidine, a grayish-white solid, was obtained. -1-yl-benzoylamine (300 mg, 0.85 mmol, 95% yield, hydrochloride).

[0377] [LCMS:] MS (ESI) m / z: 317.1 [M+1] +

[0378] Chemical formula: C16H20O3N4, Molecular weight: 316.1

[0379] Step 3. Preparation of III Preparation of IIIa:

[0380] To 6-chlorota Methyl 3-carboxylate (100 g, 579.48 mmol, 1 eq) was added fractionally to a solution of tetrahydrofuran (1 L) and water (1 L) with lithium hydrate (48.63 g, 1.16 mol, 2 eq). The reaction mixture was stirred at 25 °C for 1 hour. Thin-layer chromatography (petroleum ether: ethyl acetate = 1:1) showed 6-chloro-3-carboxylate. methyl 3-carboxylate was completely consumed. The reaction mixture was poured into hydrochloric acid (2.0 M, 600 mL) and extracted with dichloromethane (800 mL * 2). The combined organic layers were washed with brine (2 L * 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was wet-milled with ethyl acetate (500 mL). 6-chloro-3-carboxylate was given as a white solid. 3-Carboxylic acid (70 g, 436.22 mmol, 75% yield, 98% purity).

[0381] 1H NMR: (400MHz, DMSO-d6),

[0382] δ: 14.08 (s, 1H), 8.24 (d, J=9.2 Hz, 1H), 8.09 (d, J=9.2 Hz, 1H).

[0383] Chemical formula: C5H3ClN2O2, molecular weight: 158.54.

[0384] Total H count from HNMR data: 3

[0385] To 4-(4-aminocyclohexyloxy)-2-chlorobenzonitrile (40 g, 139.28 mmol, 1 eq, HCl salt), 6-chlorobenzonitrile 3-Carboxylic acid (28.71 g, 181.07 mmol, 1.3 eq) and triethylamine (56.38 g, 557.13 mmol, 4 eq) in dichloromethane (400 mL) were slowly added to a solution of 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphacyclohexane-2,4,6-trioxide (106.36 g, 167.14 mmol, 50% in ethyl acetate, 1.2 eq). The reaction mixture was stirred at 30 °C for 2.5 h. Thin-layer chromatography (petroleum ether:ethyl acetate = 1:1) indicated complete depletion of 4-(4-aminocyclohexyloxy)-2-chlorobenzonitrile. The reaction mixture was poured into a saturated sodium bicarbonate solution (3 L) and extracted with dichloromethane (2 L * 3). The combined organic layers were washed with brine (4 L * 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was wet-milled with ethyl acetate (500 mL). A white solid, 6-chloro-N-[4-(3-chloro-4-cyano-phenoxy)cyclohexyl]pyrrolidone, was obtained. -3-methamide (50 g, 125.24 mmol, 90% yield, 98% purity).

[0386] 1H NMR: (400MHz, DMSO-d6),

[0387] δ: 9.12 (d, J=8.0 Hz, 1H), 8.22 (d, J=8.8 Hz, 1H), 8.09 (d, J=8.8 Hz, 1H), 7.84 (d, J=8.8 Hz, 1H), 7.38 (d, J=2.4 Hz, 1H), 7.13 (dd, J=2.4, 8.8 Hz, 1H), 4.55- 4.49 (m, 1H), 3.92 - 3.88 (m, 1H), 2.13 - 2.10 (m, 2H), 1.92 - 1.89 (m, 2H), 1.72 - 1.66 (m, 2H), 1.55 - 1.53 (m, 2H).

[0388] Chemical formula: C18H16Cl2N4O2, molecular weight: 391.25.

[0389] Total H count from HNMR data: 18

[0390] Preparation (IIIc): 6-chloro-N-[4-(3-chloro-4-cyano-phenoxy)cyclohexyl]pyroxyl was stirred at 80 °C. A solution of 3-methoxymethyl)piperidine (5 g, 12.78 mmol, 1 eq), 4-(dimethoxymethyl)piperidine (2.03 g, 12.78 mmol, 1 eq), and diisopropylethylamine (4.95 g, 38.34 mmol, 3 eq) in dimethyl sulfoxide (50 mL) was continuously dissolved for 12 hours. The desired compound was detected by LC-MS. The reaction mixture was poured into 500 mL of water and stirred at 25 °C for 1 hour. The precipitate was collected by filtration and dried under high vacuum. The residue was wet-milled with ethyl acetate and petroleum ether (30 mL, 1:3) to give N-[4-(3-chloro-4-cyano-phenoxy)cyclohexyl]-6-[4-(dimethoxymethyl)-1-piperidinyl]pyridine as a yellow solid. -3-methamide (3.2 g, 6.23 mmol, 48% yield).

[0391] LCMS: MS (ESI) m / z: 514.1 [M+1] +.

[0392] Chemical formula: C26H32ClN5O4, Molecular weight: 514.02

[0393] Preparation (III)

[0394] To N-[4-(3-chloro-4-cyano-phenoxy)cyclohexyl]-6-[4-(dimethoxymethyl)-1-piperidinyl] 3-Methylamine (3 g, 5.84 mmol, 1 eq) was dissolved in tetrahydrofuran (80 mL) and sulfuric acid (2 M in water, 87 mL, 30 eq) was added. The reaction mixture was stirred at 70 °C for 3 hours. Thin-layer chromatography (petroleum ether: ethyl acetate = 1:1) indicated complete exhaustion of reactant 1. The pH was adjusted to 8 with sodium hydroxide (2 M in water), followed by extraction with ethyl acetate (50 mL × 3). The combined organic layers were washed with brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give N-[4-(3-chloro-4-cyano-phenoxy)cyclohexyl]-6-(4-methyl-1-piperidinyl)pyridine as a yellow solid. -3-methamide (2.6 g, 5.56 mmol, 95% yield).

[0395] 1H NMR: (400MHz, DMSO-d6)

[0396] δ = 9.75 - 9.55 (m, 1H), 8.62 (d, J=8.4 Hz, 1H), 7.84 (dd, J=9.2, 15.2 Hz, 2H), 7.43 - 7.33 (m, 2H), 7.14 (dd, J=2.4, 8.8 Hz, 1H), 4.58 - 4.50 (m, 1H), 4.32 (m, 2H), 3.92 - 3.78 (m, 1H), 3.33 - 3.21 (m, 2H), 2.76 - 2.64 (m, 1H), 2.11 (d, J=10.0 Hz, 2H), 1.98 - 1.85 (m, 4H), 1.69 - 1.48 (m, 6H)

[0397] Chemical formula: C24H26ClN5O3, Molecular weight: 467.95

[0398] Total H count from HNMR data: 26.

[0399] Step 4. Preparation of (IV), N-[4-(3-chloro-4-cyano-phenoxy)cyclohexyl]-6-[4-[[4-[4-[(2,6-dioxy-3-piperidinyl)aminomethyl]phenyl]piperidinyl ... -1-yl]methyl]-1-piperidinyl]tadala -3-methionine

[0400] To N-(2,6-dioxy-3-piperidinyl)-4-piperidinyl Sodium acetate (52 mg, 0.64 mmol, 2 eq) was added to a solution of 1-yl-benzoylamine (113 mg, 0.32 mmol, 1 eq, HCl) in methanol (2 mL). The mixture was stirred at 15 °C for 0.5 h. Then, a solution containing N-[4-(3-chloro-4-cyano-phenoxy)cyclohexyl]-6-(4-methoxy-1-piperidinyl)-di(N-methyl-1-piperidinyl)-di(methyl-1-methyl-1-phenyl-2 ... 3-Methylamine (150 mg, 0.32 mmol, 1 eq) was added to the mixture in dichloromethane (2 mL), followed by acetic acid (0.5 mL) and sodium cyanoborohydride (40 mg, 0.64 mmol, 2 eq). The mixture was stirred at 15 °C for 1 h. LC-MS showed that the reaction was complete and the desired MS signal was detectable. Water (20 mL) was added to the mixture and stirred for 1 min. The aqueous phase was extracted with dichloromethane (10 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by prep-HPLC (column: Phenomenex Synergi C18 150*25*10 μm; mobile phase: [water (0.225% FA)-ACN]; B%: 12%-42%, 10 min). The compound N-[4-(3-chloro-4-cyano-phenoxy)cyclohexyl]-6-[4-[[4-[4-[(2,6-dioxy-3-piperidinyl)aminomethyl]phenyl]piperidinyl was obtained as a white solid. -1-yl]methyl]-1-piperidinyl]tadala -3-methamide (51.1 mg, 0.06 mmol, 19% yield, 99% purity, formate).

[0401] LCMS: MS (ESI) m / z: 770.3 [M+23] +

[0402] 1H NMR: (400MHz, DMSO-d6)

[0403] δ : 10.83 (s, 1H), 8.59 (d, J=7.6 Hz, 1H), 8.47 (d, J=7.6 Hz, 1H), 8.20 (s, 1H), 7.85 (d, J=8.8 Hz, 1H), 7.77 (dd, J=8.8, 18.4 Hz, 3H), 7.39 (s, 1H), 7.33 (d, J=9.6 Hz, 1H), 7.13 (d, J=8.4 Hz, 1H), 6.97 (d, J=8.4 Hz, 2H), 4.74 (s, 1H), 4.59 - 4.43 (m, 4H), 3.85 (s, 1H), 3.28 - 3.24 (m, 2H), 3.02 (t, J=12.0 Hz, 2H), 2.85 - 2.73 (m, 3H), 2.20 (d, J=7.6 Hz, 3H), 2.10 (d, J=9.2 Hz, 4H), 2.02 - 1.77 (m, 6H), 1.71 - 1.58 (m, 3H), 1.51 (d, J=12.8 Hz, 3H), 1.12 (d, J=11.6 Hz, 2H)

[0404] Chemical formula: C40H46ClO5N9, Molecular weight: 767.33

[0405] Example 10 - Synthesis of Compound 24

[0406] Process 6. Overview of the synthesis of compound 24.

[0407] Step 1. Preparation of (I), methyl 5-[3-(tert-butoxycarbonylamino)cyclobutoxy]pyridine-2-carboxylate

[0408] Diisopropyl azodicarbonate (990 mg, 4.90 mmol, 1.5 eq) was added to a solution of methyl 5-hydroxypyridine-2-carboxylate (500 mg, 3.27 mmol, 1 eq), N-(3-hydroxycyclobutyl)aminocarboxylate (611 mg, 3.27 mmol, 1 eq), and triphenylphosphine (1.28 g, 4.90 mmol, 1.5 eq) in tetrahydrofuran (5 mL). The reaction mixture was stirred at 15 °C for 12 hours. The desired compound was detected by LCMS. The reaction mixture was quenched by adding water (30 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with brine (80 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silicone column chromatography (petroleum ether / ethyl acetate = 100 / 1 to 3 / 1). Methyl 5-[3-(tert-butoxycarbonylamino)cyclobutoxy]pyridine-2-carboxylate (3 g, crude material) was obtained as a colorless oil.

[0409] LCMS: MS (ESI) m / z: 323.1 [M+1] +

[0410] Chemical formula: C16H22N2O5, Molecular weight: 322.36

[0411] Step 2. Preparation of (II), methyl 5-(3-aminocyclobutoxy)pyridine-2-carboxylate

[0412] Add hydrochloric acid (4 M) to a solution of methyl 5-[3-(tert-butoxycarbonylamino)cyclobutoxy]pyridine-2-carboxylate (3 g, 9.31 mmol, 1 eq) in dichloromethane (5 mL). In alkyl, 3 mL). The reaction mixture was stirred at 15 °C for 1 hour. TLC (petroleum ether:ethyl acetate = 3:1) indicated complete depletion of methyl 5-[3-(tert-butoxycarbonylamino)cyclobutoxy]pyridine-2-carboxylate. The reaction mixture was concentrated under reduced pressure. The residue was wet-milled with ethyl acetate (15 mL). Methyl 5-(3-aminocyclobutoxy)pyridine-2-carboxylate (760 mg, 2.94 mmol, 31% yield in two steps, hydrochloride) was given as a white solid.

[0413] 1H NMR: (400 MHz, DMSO-d6)

[0414] δ: 8.63 (s, 3H), 8.32 - 8.28 (m, 1H), 8.06 - 7.99 (m, 1H), 7.36 (dd, J=2.8, 8.8 Hz, 1H), 5.30 - 5.12 (m, 1H), 3.84 (s, 4H), 2.76 - 2.64 (m, 2H), 2.48 - 2.40 (m, 2H), 2.01 - 1.88 (m, 1H)

[0415] Chemical formula: C11H14N2O3, molecular weight: 222.24

[0416] Total H count from HNMR data: 16.

[0417] Step 3. Preparation of (III), 5-[3-[(1-tert-butoxycarbonyl-4-piperidinyl)methylamino]cyclobutoxy]pyridine-2-carboxylic acid methyl ester

[0418] A solution of methyl 5-(3-aminocyclobutoxy)pyridine-2-carboxylate (700 mg, 2.71 mmol, 1 eq, hydrochloride) and triethylamine (821 mg, 8.12 mmol, 3 eq) in methanol (10 mL) and dichloromethane (10 mL) was stirred at 15 °C for 0.5 h. Tertiary 4-methylpiperidin-1-carboxylate (577 mg, 2.71 mmol, 1 eq) was added. Sodium borohydride (1.72 g, 8.12 mmol, 3 eq) was then added. The reaction mixture was stirred at 15 °C for 0.5 h. The desired compound was detected by LCMS. The reaction mixture was quenched with water (50 mL) and extracted with dichloromethane (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was wet-milled with ethyl acetate (10 mL). Methyl 5-[3-[(1-tert-butoxycarbonyl-4-piperidinyl)methylamino]cyclobutoxy]pyridine-2-carboxylate was obtained as a white solid (460 mg, 1.10 mmol, 40% yield).

[0419] LCMS: MS (ESI) m / z: 418.2 [M+1] +

[0420] 1H NMR: (400MHz, DMSO-d6)

[0421] δ: 9.28 (s, 2H), 8.32 (d, J=2.8 Hz, 1H), 8.05 (d, J=8.8 Hz, 1H), 7.37 (dd, J=2.8, 8.8 Hz, 1H), 5.29 - 5.03 (m, 1H), 4.04 - 3.89 (m, 2H), 3.85 (s, 4H), 2.87 - 2.78 (m, 2H), 2.76 - 2.66 (m, 3H), 2.48 - 2.38 (m, 2H), 1.89 (d, J=19.2 Hz, 1H), 1.76 (d, J=12.0 Hz, 2H), 1.40 (s, 9H), 1.07 (dq, J=4.0, 12.0 Hz, 2H)

[0422] Chemical formula: C20H27N5O5, Molecular weight: 417.46

[0423] Total H count from HNMR data: 27.

[0424] Step 4. Preparation of (IV), methyl 5-[3-[(1-tert-butoxycarbonyl-4-piperidinyl)methyl-isopropyl-amino]cyclobutoxy]pyridine-2-carboxylate

[0425] 2-Iodopropane (1.66 g, 9.77 mmol, 1 eq) was added to a solution of methyl 5-[3-[(1-tert-butoxycarbonyl-4-piperidinyl)methylamino]cyclobutoxy]pyridine-2-carboxylate (410 mg, 0.97 mmol, 1 eq) and triethylamine (494 mg, 4.89 mmol, 5 eq) in acetonitrile (5 mL). The reaction mixture was stirred at 70 °C for 48 h. Thin-layer chromatography (dichloromethane:methanol = 10:1) indicated complete depletion of methyl 5-[3-[(1-tert-butoxycarbonyl-4-piperidinyl)methylamino]cyclobutoxy]pyridine-2-carboxylate. The reaction mixture was diluted with ethyl acetate (80 mL), washed with brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silicone column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 1 / 1). Methyl 5-[3-[(1-tert-butoxycarbonyl-4-piperidinyl)methyl-isopropyl-amino]cyclobutoxy]pyridine-2-carboxylate (300 mg, 0.64 mmol, 66% yield) was given as a yellow solid.

[0426] 1H NMR: (400MHz, DMSO-d6)

[0427] δ: 8.30 (s, 1H), 8.01 (d, J=7.8 Hz, 1H), 7.34 (d, J=7.2 Hz, 1H), 4.82 (s, 1H), 4.08 - 3.89 (m, 3H), 3.84 (s, 3H), 3.64 (s, 1H), 3.32 (s, 3H), 2.87 (s, 1H), 2.66 (s, 1H), 2.37 (s, 3H), 2.18 (d, J=13.6 Hz, 4H), 1.99 (s, 1H), 1.70 (d, J=10.4 Hz, 2H), 1.39 (s, 11H), 1.17 (s, 2H), 0.90 (d, J=4.0 Hz, 8H)

[0428] Chemical formula: C25H39N3O5, Molecular weight: 461.59

[0429] Total H count from HNMR data: 39.

[0430] Step 5. Preparation of (V), 5-[3-[(1-tert-butoxycarbonyl-4-piperidinyl)methyl-isopropyl-amino]cyclobutoxy]pyridine-2-carboxylic acid

[0431] Lithium hydroxide (109 mg, 2.60 mmol, 4 eq) was added to a solution of methyl 5-[3-[(1-tert-butoxycarbonyl-4-piperidinyl)methyl-isopropyl-amino]cyclobutoxy]pyridine-2-carboxylate (300 mg, 0.64 mmol, 1 eq) in methanol (2 mL), tetrahydrofuran (2 mL), and water (2 mL). The reaction mixture was stirred at 15 °C for 12 h. The desired compound was detected by LCMS. The reaction mixture was concentrated under reduced pressure. The pH was adjusted to 6 with 1 M hydrochloric acid, and the mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex Synergi C18 150*25*10 μm; mobile phase: [water (0.1% TFA)-ACN]; B%: 23%-53%, 9 min). 5-[3-[(1-tert-butoxycarbonyl-4-piperidinyl)methyl-isopropyl-amino]cyclobutoxy]pyridine-2-carboxylic acid (230 mg, 0.40 mmol, 63% yield, trifluoroacetic acid) was obtained as a white solid.

[0432] LCMS: MS (ESI) m / z: 448.4 [M+1] +

[0433] 1H NMR: (400MHz, DMSO-d6)

[0434] δ: 9.00 (s, 1H), 8.33 (d, J=2.8 Hz, 1H), 8.04 (d, J=8.8 Hz, 1H), 7.42 (dd, J=2.8, 8.8 Hz, 1H), 4.99 (t, J=6.4 Hz, 1H), 4.31 - 4.09 (m, 1H), 3.96 (d, J=10.0 Hz, 2H), 3.63 - 3.49 (m, 1H), 3.13 - 3.01 (m, 1H), 2.98 - 2.84 (m, 2H), 2.82 - 2.63 (m, 3H), 2.61 - 2.53 (m, 1H), 1.90 - 1.68 (m, 3H), 1.40 (s, 9H), 1.27 (d, J=6.4 Hz, 3H), 1.19 (d, J=6.4 Hz, 3H), 1.12 - 1.01 (m, 2H)

[0435] Chemical formula: C24H37N3O5, Molecular weight: 447.57

[0436] Total H count from HNMR data: 37.

[0437] Step 6. Preparation of (VI), 4-[[[3-[[6-[(2,6-di-oxy-3-piperidinyl)aminomethyl]-3-pyridinyl]oxy]cyclobutyl]-isopropyl-amino]methyl]piperidin-1-carboxylic acid tributyl ester

[0438] 5-[3-[(1-tert-butoxycarbonyl-4-piperidinyl)methyl-isopropyl-amino]cyclobutoxy]pyridine-2-carboxylic acid (180 mg, 0.32 mmol, 1 eq, trifluoroacetic acid), triethylamine (64 mg, 0.64 mmol, 2 eq), and o-(7-azabenzotriazol-1-yl)-n,n,n',n'-tetramethyl were stirred at 15 °C. A solution of hexafluorophosphate (182 mg, 0.48 mmol, 1.5 eq) in dimethylformamide (3 mL) was added for 0.5 h. Then, a solution of triethylamine (64 mg, 0.64 mmol, 2 eq) and 3-aminopiperidine-2,6-dione (79 mg, 0.48 mmol, 1.5 eq, hydrochloric acid) in dimethylformamide (2 mL) was added. The reaction mixture was stirred at 15 °C for 0.5 h. LC-MS detected the desired compound. The reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silicone column chromatography (dichloromethane / methanol = 100 / 1 to 20 / 1). The yellow oily product 4-[[[3-[[6-[(2,6-di-side-oxy-3-piperidinyl)aminomethoxy]-3-pyridinyl]oxy]cyclobutyl]-isopropyl-amino]methyl]piperidin-1-carboxylic acid tert-butyl ester (160 mg, 0.28 mmol, 89% yield) was obtained.

[0439] LCMS: MS (ESI) m / z: 558.0 [M+1] +

[0440] 1H NMR: (400MHz, chloroform-d)

[0441] δ: 8.50 (d, J=6.4 Hz, 1H), 8.21 - 8.09 (m, 2H), 8.00 (s, 1H), 7.20 - 7.10 (m, 1H), 4.89 - 4.64 (m, 2H), 4.30 - 3.97 (m, 6H), 3.83 - 3.59 (m, 1H), 2.99 - 2.82 (m, 3H), 2.75 - 2.56 (m, 3H), 2.45 - 2.20 (m, 6H), 2.08 - 2.03 (m, 6H), 1.78 (d, J=12.4 Hz, 2H), 1.55 - 1.41 (m, 1H), 1.55 - 1.41 (m, 10H), 1.30 - 1.24 (m, 6H), 0.97 (d, J=6.4 Hz, 7H)

[0442] Chemical formula: C29H43N5O6, Molecular weight: 557.68

[0443] Total H count from HNMR data: 43.

[0444] Step 7 Preparation of (VII), N-(2,6-di-side-oxy-3-piperidinyl)-5-[3-[isopropyl(4-piperidinylmethyl)amino]cyclobutoxy]pyridine-2-methylamine

[0445] Add hydrochloric acid (4 M) to a solution of 4-[[[3-[[6-[(2,6-dioxy-3-piperidinyl)aminomethyl]-3-pyridinyl]oxy]cyclobutyl]-isopropyl-amino]methyl]piperidin-1-carboxylic acid tert-butyl ester (160 mg, 0.28 mmol, 1 eq) in dichloromethane (5 mL). In alkane, 3 mL). The reaction mixture was stirred at 15 °C for 1 hour. The desired compound was detected by LCMS. The reaction mixture was concentrated under reduced pressure. N-(2,6-dioxy-3-piperidinyl)-5-[3-[isopropyl(4-piperidinylmethyl)amino]cyclobutoxy]pyridine-2-methylamine (140 mg, crude, hydrochloride) was obtained as a gray solid.

[0446] LCMS: MS (ESI) m / z: 458.1 [M+1] +

[0447] Chemical formula: C24H35N5O4, Molecular weight: 457.57

[0448] Step 8. Preparation of compound No. 24, N-[4-(3-chloro-4-cyano-phenoxy)cyclohexyl]-5-[4-[[[3-[[6-[(2,6-dioxy-3-piperidinyl)aminomethyl]-3-pyridinyl]oxy]cyclobutyl]-isopropyl-amino]methyl]-1-piperidinyl]pyridinyl]pyridinyl] -2-methionine

[0449] N-(2,6-dioxy-3-piperidinyl)-5-[3-[isopropyl(4-piperidinylmethyl)amino]cyclobutoxy]pyridine-2-methamide (140 mg, 0.28 mmol, 1 eq, hydrochloride) and 5-chloro-N-[4-(3-chloro-4-cyano-phenoxy)cyclohexyl]pyridine-2-methamide were stirred at 120 °C. A solution of 2-methylamine (110 mg, 0.28 mmol, 1 eq) and diisopropylethylamine (109 mg, 0.85 mmol, 3 eq) in dimethyl sulfoxide (5 mL) was continuously incubated for 4 hours. LC-MS detected the desired compound. The reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex Synergi C18 150*25*10 μm; mobile phase: [water (0.225% FA)-ACN]; B%: 21%-48%, 10 min). The following substance, N-[4-(3-chloro-4-cyano-phenoxy)cyclohexyl]-5-[4-[[[3-[[6-[(2,6-dioxy-3-piperidinyl)aminomethyl]-3-pyridinyl]oxy]cyclobutyl]-isopropyl-amino]methyl]-1-piperidinyl]pyridinyl, was obtained as a grayish-white solid. -2-methamide (108 mg, 0.12 mmol, 43% yield, 99% purity, formate).

[0450] LCMS: MS (ESI) m / z: 812.2 [M+1] +

[0451] 1H NMR: (400MHz, DMSO-d6)

[0452] δ: 10.84 (s, 1H), 8.84 (d, J=8.4 Hz, 1H), 8.58 (s, 1H), 8.29 - 8.21 (m, 2H), 8.17 (s, 1H), 8.07 - 7.95 (m, 2H), 7.85 (d, J=8.8 Hz, 1H), 7.41 - 7.32 (m, 2H), 7.11 (dd, J=2.4, 8.8 Hz, 1H), 4.90 - 4.68 (m, 2H), 4.59 - 4.37 (m, 3H), 3.90 - 3.58 (m, 2H), 3.02 - 2.85 (m, 3H), 2.84 - 2.71 (m, 1H), 2.53 (d, J=2.8 Hz, 2H), 2.44 - 2.31 (m, 3H), 2.30 - 1.95 (m, 9H), 1.92 - 1.79 (m, 4H), 1.73 - 1.42 (m, 5H), 1.05 (q, J=10.8 Hz, 2H), 0.92 (d, J=6.4 Hz, 6H)

[0453] Chemical formula: C42H50ClN9O6, Molecular weight: 812.36

[0454] Total H count from HNMR data: 51.

[0455] Example 11 - Synthesis of Compound 27

[0456] Process 7. Overview of the synthesis of compound 27.

[0457] Step 1. Preparation of (I), methyl 4-[3-(tert-butoxycarbonylamino)cyclobutoxy]benzoate

[0458] Triphenylphosphine (4.14 g, 15.77 mmol, 1 eq) and diisopropyl azodicarbonate (3.19 g, 15.77 mmol, 3.07 mL, 1.2 eq) were added to a solution of methyl 4-hydroxybenzoate (2 g, 13.15 mmol, 1 eq) in tetrahydrofuran (150 mL) at 0 °C. The mixture was stirred at 15 °C for 12 hours. The desired MS was detected by LCMS. Water (100 mL) was added to the mixture and stirred for 1 minute. The aqueous phase was extracted with ethyl acetate (100 mL × 3). The combined organic phases were washed with brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude product was used in the next step without further purification. Methyl 4-[3-(tert-butoxycarbonylamino)cyclobutoxy]benzoate (6 g, crude substance) was obtained as a yellow oil.

[0459] LCMS: MS (ESI) m / z: 266.0 [M-56+1] +

[0460] Chemical formula: C17H23O5N, Molecular weight: 321.37

[0461] Step 2. Preparation of (II), 4-(3-aminocyclobutoxy)benzoate methyl ester

[0462] Add hydrochloric acid / dichloromethane to a solution of methyl 4-[3-(tert-butoxycarbonylamino)cyclobutoxy]benzoate (6 g, 18.67 mmol, 1 eq) in dichloromethane (20 mL). Alkane (4 M, 93 mL, 20 eq). The mixture was stirred at 20 °C for 12 hours. Thin-layer chromatography (dichloromethane:methanol = 20:1) indicated complete depletion of the starting material and the formation of a new spot. The reaction mixture was filtered and concentrated under reduced pressure. The crude product was used in the next step without further purification. Methyl 4-(3-aminocyclobutoxy)benzoate (2.5 g, 9.70 mmol, 51% yield, hydrochloride) was given as a yellow solid.

[0463] Step 3. Preparation of (III), 4-[[[3-(4-methoxycarbonylphenoxy)cyclobutyl]amino]methyl]piperidine-1-carboxylic acid tributyl ester

[0464] Triethylamine (1.96 g, 19.40 mmol, 1 eq) was added to a solution of methyl 4-(3-aminocyclobutoxy)benzoate (2.5 g, 9.70 mmol, 1 eq) in 1,2-dichloroethane (30 mL), and the mixture was stirred at 15 °C for 0.5 h. Then, sodium triethoxyborohydride (6.17 g, 29.10 mmol, 3 eq) was added to the mixture. The mixture was stirred at 15 °C for 0.5 h. The desired MS was detected by LC-MS. Water (100 mL) was added to the mixture and stirred for 1 min. The aqueous phase was extracted with dichloromethane (100 mL × 3). The combined organic phases were washed with brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate = 30:1 to 10:1, dichloromethane:methanol = 50:1). A white solid, 4-[[[3-(4-methoxycarbonylphenoxy)cyclobutyl]amino]methyl]piperidine-1-carboxylic acid tert-butyl ester (1.6 g, 3.82 mmol, 39% yield) was obtained.

[0465] LCMS: MS (ESI) m / z: 419.2 [M+1] +

[0466] Chemical formula: C23H34O5N2, Molecular weight: 418.53

[0467] Step 4. Preparation of (IV), 4-[[isopropyl-[3-(4-methoxycarbonylphenoxy)cyclobutyl]amino]methyl]piperidine-1-carboxylic acid tert-butyl ester

[0468] Triethylamine (483 mg, 4.78 mmol, 5 eq) and 2-iodopropane (1.62 g, 9.56 mmol, 10 eq) were added to a solution of 4-[[[3-(4-methoxycarbonylphenoxy)cyclobutyl]amino]methyl]piperidin-1-carboxylic acid tributyl ester (400 mg, 0.95 mmol, 1 eq) in acetonitrile (5 mL). The mixture was stirred at 70 °C for 72 h. Thin-layer chromatography (petroleum ether:ethyl acetate = 1:1) showed complete exhaustion of the reactants and a new major spot was detected (Rf = 0.65). Water (100 mL) was added to the mixture and stirred for 1 min. The aqueous phase was extracted with ethyl acetate (100 mL × 3). The combined organic phases were washed with brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate = 50:1 to 0:1). The compound 4-[[isopropyl-[3-(4-methoxycarbonylphenoxy)cyclobutyl]amino]methyl]piperidine-1-carboxylic acid tert-butyl ester (325 mg, 0.70 mmol, 36% yield) was given as a brown solid.

[0469] Step 5. Preparation of (V), 4-[3-[(1-tert-butoxycarbonyl-4-piperidinyl)methyl-isopropyl-amino]cyclobutoxy]benzoic acid

[0470] Lithium hydroxide monohydrate (236 mg, 5.64 mmol, 4 eq) was added to a solution of 4-[[isopropyl-[3-(4-methoxycarbonylphenoxy)cyclobutyl]amino]methyl]piperidin-1-carboxylic acid tributyl ester (650 mg, 1.41 mmol, 1 eq) in methanol (5 mL), tetrahydrofuran (5 mL), and water (3 mL). The mixture was stirred at 40 °C for 1 hour. LCMS showed that the reactants were not completely exhausted. The mixture was stirred at 40 °C for 10 hours. LCMS showed that the reaction was complete and the desired MS was detectable. The reaction mixture was concentrated under reduced pressure. The pH of the reaction mixture was adjusted to 5 with hydrochloric acid (1 M). Water (50 mL) was added to the mixture and stirred for 1 minute. The aqueous phase was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with brine (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The compound 4-[3-[(1-tert-butoxycarbonyl-4-piperidinyl)methylisopropyl-amino]cyclobutoxy]benzoic acid (500 mg, 1.12 mmol, 79% yield) was obtained as a brown solid.

[0471] LCMS: MS (ESI) m / z: 447.2 [M+1] +

[0472] Chemical formula: C25H38O5N2, Molecular weight: 446.58

[0473] Step 6. Preparation of (VI), 4-[[[3-[4-[(2,6-di-oxy-3-piperidinyl)aminomethyl]phenoxy]cyclobutyl]-isopropyl-amino]methyl]piperidin-1-carboxylic acid tributyl ester

[0474] Add o-(7-azabenzotriazol-1-yl)-n,n,n',n'-tetramethyl to a solution of 4-[3-[(1-tert-butoxycarbonyl-4-piperidinyl)methyl-isopropyl-amino]cyclobutoxy]benzoic acid (500 mg, 1.12 mmol, 1 eq) in N,N-dimethylformamide (5 mL) Hexafluorophosphate (638 mg, 1.68 mmol, 1.5 eq) and triethylamine (339 mg, 3.36 mmol, 3 eq) were then added to the mixture. 3-Aminopiperidin-2,6-dione (184 mg, 1.12 mmol, 1 eq, hydrochloride) was then added. The desired MS was detected by LC-MS. Water (100 mL) was added to the mixture and stirred for 1 min. The aqueous phase was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by prep-TLC (dichloromethane:methanol = 10:1). The compound 4-[[[3-[4-[(2,6-di-side-oxy-3-piperidinyl)aminomethyl]phenoxy]cyclobutyl]-isopropyl-amino]methyl]piperidin-1-carboxylic acid tert-butyl ester (100 mg, 0.17 mmol, 16% yield) was obtained as a yellow oil.

[0475] LCMS: MS (ESI) m / z: 557.3 [M+1] +

[0476] Chemical formula: C30H44N4O6, Molecular weight: 556.69

[0477] Step 7. Preparation of (VII), N-(2,6-di-side-oxy-3-piperidinyl)-4-[3-[isopropyl(4-piperidinylmethyl)amino]cyclobutoxy]benzamide

[0478] Add hydrochloric acid / dimethylpyridine to a solution of 4-[[[3-[4-[(2,6-dioxy-3-piperidinyl)aminomethyl]phenoxy]cyclobutyl]-isopropyl-amino]methyl]piperidin-1-carboxylic acid tert-butyl ester (100 mg, 0.17 mmol, 1 eq) in dichloromethane (2 mL). Alkane (4 M, 4 mL, 89.07 eq). The mixture was stirred at 15 °C for 1 hour. The desired MS was detected by LCMS. The reaction mixture was concentrated under reduced pressure. The crude product was used in the next step without further purification. The compound N-(2,6-dioxy-3-piperidinyl)-4-[3-[isopropyl(4-piperidinylmethyl)amino]cyclobutoxy]benzamide (70 mg, 0.14 mmol, 79% yield, hydrochloride) was obtained as a brown solid.

[0479] LCMS: MS (ESI) m / z: 457.4 [M+1] +

[0480] Chemical formula: C25H36N4O4, Molecular weight: 456.27

[0481] Step 8. Preparation of compound 27,N-[4-(3-chloro-4-cyano-phenoxy)cyclohexyl]-6-[4-[[4-[6-[(2,6-dioxy-3-piperidinyl)aminomethoxy]-3-pyridinyl]piperidinyl]piperidinyl -1-yl]methyl]-1-piperidinyl]tadala -3-methionine

[0482] To N-(2,6-dioxy-3-piperidinyl)-4-[3-[isopropyl(4-piperidinylmethyl)amino]cyclobutoxy]benzamide (70 mg, 0.14 mmol, 1 eq, hydrochloride) and (VIII), 5-chloro-N-[4-(3-chloro-4-cyano-phenoxy)cyclohexyl]pyridine Diisopropylethylamine (110 mg, 0.85 mmol, 6 eq) was added to a solution of 2-methylmethylamine (55 mg, 0.14 mmol, 1 eq) in dimethyl sulfoxide (2 mL). The mixture was stirred at 120 °C for 2 hours. The desired MS was detected by LC-MS. Water (50 mL) was added to the mixture and stirred for 1 minute. The aqueous phase was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by prep-HPLC (column: Phenomenex Synergi C18 150*25*10 μm; mobile phase: [water (0.225% FA)-ACN]; B%: 14%-44%, 10 min). The compound N-[4-(3-chloro-4-cyano-phenoxy)cyclohexyl]-5-[4-[[[3-[4-[(2,6-dioxy-3-piperidinyl)aminomethyl]phenoxy]cyclobutyl]-isopropyl-amino]methyl]-1-piperidinyl]pyridine was obtained as a yellow solid. -2-methamide (34.4 mg, 0.03 mmol, 27% yield, 98% purity, formate).

[0483] LCMS: MS (ESI) m / z: 811.3 [M+1] +

[0484] 1H NMR: (400MHz, DMSO-d6)

[0485] δ : 10.82 (s, 1H), 8.62 - 8.54 (m, 2H), 8.23 ​​(d, J=8.8 Hz, 2H), 8.04 (d, J=8.0 Hz, 1H), 7.89 - 7.75 (m, 3H), 7.36 (d, J=2.4 Hz, 1H), 7.12 (dd, J=2.4, 8.8 Hz, 1H), 6.88 (d, J=8.8 Hz, 2H), 4.79 - 4.68 (m, 2H), 4.49 (d, J=12.4 Hz, 3H), 3.88 - 3.77 (m, 1H), 3.69 - 3.67 (m, 1H), 3.01 - 2.86 (m, 3H), 2.84 - 2.72 (m, 1H), 2.57 - 2.52 (m, 1H), 2.38 (d, J=13.8 Hz, 1H), 2.25 (d, J=6.8 Hz, 2H), 2.21 - 2.03 (m, 6H), 1.96 (dd, J=4.0, 8.8 Hz, 1H), 1.92 - 1.82 (m, 4H), 1.76 - 1.41 (m, 5H), 1.13 - 0.98 (m, 2H), 0.92 (d, J=6.4 Hz, 6H)

[0486] Chemical formula: C43H51ClO6N8, Molecular weight: 810.36

[0487] Example 12 - Synthesis of Compound 28

[0488] Process 8. Overview of the synthesis of compound 28.

[0489] Step 1. Preparation of (II), 6-[4-[(1-tert-butoxycarbonyl-4-piperidinyl)methyl]piperidinyl]piperidinyl -1-base]ta Methyl 3-carboxylate

[0490] To (I), 6-chlorotadala A solution of methyl 3-carboxylate (500.00 mg, 2.90 mmol, 1.00 eq) in N,N-dimethylformamide (6 mL) was prepared by adding potassium carbonate (1.00 g, 7.24 mmol, 2.50 eq) and 4-(piperazine) 1-(1-ylmethyl)piperidin-1-carboxylic acid tert-butyl ester (A, 903.26 mg, 3.19 mmol, 1.10 eq). The mixture was stirred at 80 °C for 15 h. LC-MS showed the desired MS and 6-chloro-2-ethylhexylene. methyl 3-carboxylate was completely exhausted. The mixture was diluted with water (40 mL) and extracted with ethyl acetate (2 × 30 mL). The combined organic phases were washed with saturated sodium chloride solution (20 mL), dried over sodium sulfate, and concentrated under reduced pressure to give a yellow solid. The solid was dissolved in a petroleum ether:ethyl acetate solution (5:1, 12 mL) and stirred for 0.5 h. The suspension was then filtered and the filter cake was dried under vacuum to give 6-[4-[(1-tert-butoxycarbonyl-4-piperidinyl)methyl]piperidinyl]piperidinyl, a pale yellow solid. -1-base]ta Methyl 3-carboxylate (880.00 mg, 2.10 mmol, 72% yield) was used directly in the next step. [ ] [ ]

[0491] LCMS: MS (ESI) m / z: 420.2 [M+1] +.

[0492] 1H NMR: (400 MHz, CDCl3)

[0493] δ: 7.88 (d, J=9.6 Hz, 1H), 6.85 (d, J=9.6 Hz, 1H), 4.04 - 4.20 (m, 2H), 4.00 (s, 3H), 3.75 - 3.84 (m, 4H), 2.71 (t, J=11.6 Hz, 2H), 2.53 (t, J=4.8 Hz, 4H), 2.23 (d, J=7.2 Hz, 2H), 1.76 (d, J=13.2 Hz, 2H), 1.65 - 1.71 (m, 1H), 1.46 (s, 9H), 1.04 - 1.16 (m, 2H).

[0494] Chemical formula: C21H33N5O4, Molecular weight: 419.52

[0495] Step 2. Preparation of (III), 6-[4-[(1-tert-butoxycarbonyl-4-piperidinyl)methyl]piperidinyl]piperidinyl -1-base]ta 3-Formic acid

[0496] At 15°C, 6-[4-[(1-tert-butoxycarbonyl-4-piperidinyl)methyl]piperidin... -1-base]ta Methyl 3-carboxylate (880.00 mg, 2.10 mmol, 1.00 eq) was added to a solution of methyl 3-carboxylate in methanol (10 mL) and water (3 mL) with lithium hydroxide (264.07 mg, 6.29 mmol, 3.00 eq). The mixture was stirred at 15 °C for 2.5 h. LCMS (EW10815-22-P1A) showed the desired MS and 6-[4-[(1-tert-butoxycarbonyl-4-piperidinyl)methyl]piperidinyl]piperidinyl -1-base]ta methyl 3-carboxylate was completely consumed. The mixture was concentrated under vacuum to obtain a yellow solid. The solid was dissolved in water (10 mL) and the pH was adjusted to 3 by hydrochloric acid solution (1 M). The suspension was then filtered. The filter cake was dried under vacuum to obtain a pale yellow solid of 6-[4-[(1-tert-butoxycarbonyl-4-piperidinyl)methyl]piperidinyl]piperidinyl -1-base]ta 3-Carboxylic acid (760.00 mg, 1.87 mmol, 89% yield) was used directly in the next step.

[0497] LCMS: MS (ESI) m / z: 406.1 [M+1] +.

[0498] 1H NMR: (400 MHz, DMSO-d6)

[0499] δ: 11.30 (br s, 1H), 7.92 (d, J=9.6 Hz, 1H), 7.44 (d, J=9.2 Hz, 1H), 4.57 (d, J=13.2 Hz, 2H), 3.91 (d, J=11.6 Hz, 2H), 3.75 (t, 1.87 (d, J=12.0 Hz, 2H), 1.39 (s, 9H), 1.00 - 1.15 (m, 2H).

[0500] Chemical formula: C20H31N5O4, Molecular weight: 405.49

[0501] Step 3. Preparation of (IV), 4-[[4-[6-[(2,6-dioxy-3-piperidinyl)aminomethoxy]pyr -3-base]piper -1-yl]methyl]piperidine-1-carboxylic acid tert-butyl ester

[0502]

[0503] At 15°C, 6-[4-[(1-tert-butoxycarbonyl-4-piperidinyl)methyl]piperidin... -1-base]ta 3-Carboxylic acid (200.00 mg, 493.23 μol, 1.00 eq) was added to a solution of N,N-dimethylformamide (3 mL) with hydroxybenzotriazole (86.64 mg, 641.20 μol, 1.30 eq), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (122.92 mg, 641.20 μol, 1.30 eq), diisopropylethylamine (254.99 mg, 1.97 mmol, 343.65 μL, 4.00 eq), and 3-aminopiperidin-2,6-dione hydrochloride (97.42 mg, 591.88 μol, 1.20 eq). The mixture was stirred at 15 °C for 16 h. LCMS (EW10815-25-P1C2) showed that the reaction was complete. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (2 × 5 mL). The combined organic phases were washed with brine (10 mL), dried over sodium sulfate, and concentrated under vacuum to obtain the residue. The residue was purified by preparative thin-layer chromatography (dichloromethane:methanol = 10:1) to give a pale yellow oil of 4-[[4-[6-[(2,6-dioxy-3-piperidinyl)aminomethyl]pyrrolidone] -3-base]piper -1-yl]methyl]piperidin-1-carboxylic acid tert-butyl ester (200.00 mg, 387.89 umol, 79% yield).

[0504] LCMS: MS (ESI) m / z: 516.3 [M+1] +.

[0505] Step 4. Preparation of (V), N-(2,6-di-side-oxy-3-piperidinyl)-6-[4-(4-piperidinylmethyl)piperidinyl] -1-base]ta -3-methionine

[0506] At 15°C, 4-[[4-[6-[(2,6-dioxy-3-piperidinyl)aminomethyl] tadalafiloyl] -3-base]piper -1-yl]methyl]piperidin-1-carboxylic acid tert-butyl ester (200.00 mg, 387.89 μmol, 1.00 eq) was added to a solution of dichloromethane (2 mL) with hydrochloride / dimethyl]methyl]methyl]methyl]methyl]methyl]methyl]methyl]methyl]methyl]methyl]methyl]methyl]methyl]methyl]methyl]methyl]methyl]methyl]methyl]methyl]methyl]methyl]methyl]methyl]methyl]methyl]methyl]methyl]methyl]methyl] 2 ... Alkane (4 M, 2 mL, 20.62 eq). The mixture was stirred at 15 °C for 2 h. Thin-layer chromatography (dichloromethane:methanol = 10:1) showed 4-[[4-[6-[(2,6-dioxy-3-piperidinyl)aminomethyl]pyridine] -3-base]piper -1-yl]methyl]piperidin-1-carboxylic acid tert-butyl ester was completely exhausted and a major spot was observed. The mixture was concentrated under vacuum to give N-(2,6-dioxy-3-piperidinyl)-6-[4-(4-piperidinylmethyl)piperidinyl]-1-carboxylic acid tert-butyl ester as a pale yellow solid. -1-base]ta -3-methamide (160.00 mg, 354.02 μmol, 91% yield, hydrochloride), as confirmed by LCMS (EW10815-27-P1C2) and NMR.

[0507] LCMS: MS (ESI) m / z: 434.3 [M+19] +.

[0508] 1H NMR: (400 MHz, DMSO-d6)

[0509] δ: 11.40 (br s, 1H), 10.86 (s, 1H), 9.16 (br d, J=8.4 Hz, 1H), 8.86 - 9.08 (m, 1H), 7.97 (d, J=9.6 Hz, 1H), 7.55 (d, J=9.6 Hz, 1H), 4.81 - 4.87 (m, 2H), 4.58 (d, J=13.6 Hz, 2H), 3.75 (t, J=12.4 Hz, 2H), 3.64 (d, J=11.6 Hz, 2H), 3.25 (d, J=12.4 Hz, 2H), 3.02 - 3.18 (m, 4H), 2.76 - 2.87 (m, 3H), 2.14 - 2.29 (m, 2H), 1.94 - 2.09 (m, 3H), 1.40 - 1.55 (m, 2H).

[0510] Chemical formula: C20H29N7O3, molecular weight: 415.19

[0511] Total H count from HNMR data: 30.

[0512] Step 5. Preparation of compound 28,N-[4-(3-chloro-4-cyano-phenoxy)cyclohexyl]-6-[4-[[4-[6-[(2,6-dioxy-3-piperidinyl)aminomethyl]ta] -3-base]piper -1-yl]methyl]-1-piperidinyl]tadala -3-methionine

[0513] At 100°C, N-(2,6-dioxy-3-piperidinyl)-6-[4-(4-piperidinylmethyl)piperidinyl] -1-base]ta A solution of 3-methamide (100.00 mg, 221.26 μol, 1.00 eq, hydrochloride) in dimethyl methoxide (2 mL) was supplemented with diisopropylethylamine (114.39 mg, 885.06 μol, 154.16 μL, 4.00 eq) and 6-chloro-N-[4-(3-chloro-4-cyano-phenoxy)cyclohexyl]pyridine. -3-Methylamine (B, 100.00 mg, 255.59 μmol, 1.16 eq). The mixture was stirred at 100 °C for 16 h. The reaction was complete as shown by LCMS. The mixture was filtered. The filtrate was purified by prep-HPLC (column: Phenomenex Synergi C18 150*25*10 μm; mobile phase: [water (0.225% FA)-ACN]; B%: 18%-48%, 10 min) to give N-[4-(3-chloro-4-cyano-phenoxy)cyclohexyl]-6-[4-[[4-[6-[(2,6-dioxy-3-piperidinyl)aminomethylamine]pyr -3-base]piper -1-yl]methyl]-1-piperidinyl]tadala -3-methamide (25.70 mg, 31.17 μmol, 14% yield, 99% purity, formate), confirmed by 1H NMR and QC-LCMS.

[0514] QC-LCMS: MS (ESI) m / z: 770.2 [M+1] +.

[0515] 1H NMR: (400 MHz, DMSO-d6)

[0516] δ: 10.83 (br s, 1H), 9.08 (d, J=8.4 Hz, 1H), 8.56 (d, J=8.4 Hz, 1H), 8.30 (s, 1H), 7.86 (dd, J=9.6, 4.0 Hz, 2H), 7.80 (d, J=9.6 Hz, 1H), 7.31 - 7.39 (m, 3H), 7.13 (dd, J=8.8, 2.4 Hz, 1H), 4.71 - 4.89 (m, 1H), 4.45 - 4.59 (m,3 H), 3.80 - 3.92 (m, 1H), 3.69 - 3.76 (m, 4H), 3.44 - 3.58 (m, 4H), 2.97 - 3.10 (m, 2H), 2.73 - 2.86 (m, 1H), 2.53 - 2.58 (m, 1H), 2.18 - 2.25(m, 3H), 2.11 (d, J=9.6 Hz, 2H), 1.97 - 2.04 (m, 1H), 1.83 - 1.96 (m, 5H), 1.58 - 1.69 (m, 2H), 1.46 - 1.58 (m, 2H), 1.07 - 1.21 (m, 2H).

[0517] Chemical formula: C38H44ClN11O5, Molecular weight: 770.28

[0518] Example 13 - Synthesis of 5-[4-[[1-[4-[[3-(4-cyano-3,5-dimethyl-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]aminomethyl]phenyl]-4-piperidinyl]methyl]piperidinyl ... -1-yl]-N-[(3S)-2,6-dioxy-3-piperidinyl]pyridine -2-Methylamine (Compound 33)

[0519] Process 8. Overview of the synthesis of compound 33

[0520] Step 1: Preparation of 5-(4-((1-(4-(((1r,3r)-3-(4-cyano-3-methoxyphenoxy)-2,2,4,4-tetramethylcyclobutyl)aminomethyl)phenyl)piperidin-4-yl)methyl)piperidin -1-yl)pyrene Methyl 2-carboxylate

[0521] To 5-piperazine -1-pyr A solution of methyl 2-carboxylate (159 mg, 0.61 mmol, 1.00 eq, hydrochloric acid) in dichloromethane (2 mL) and dimethylformamide (1 mL) was prepared by adding triethylamine (62 mg, 0.61 mmol, 1.00 eq), acetic acid (36 mg, 0.615 mmol, 1.00 eq), and N-[3-(4-cyano-3,5-dimethyl-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]-4-(4-methoxy-1-piperidinyl)benzamide (300 mg, 0.61 mmol, 1.00 eq). The mixture was stirred at 30 °C for 12 h. Then, sodium borohydride (260 mg, 1.23 mmol, 2.00 eq) was added to the mixture. The mixture was stirred at 30 °C for 1 h. LC-MS showed that the reaction was complete. Water (50 mL) was added to the reactants and the mixture was extracted with dichloromethane (30 mL × 3). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: Waters Xbridge C18 150*50mm*10um; mobile phase: [water (0.05% ammonium hydroxide v / v)-ACN]; B%: 58%-88%, 11.5 min) to obtain a yellow solid, 5-[4-[[1-[4-[[3-(4-cyano-3,5-dimethyl-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]aminomethyl]phenyl]-4-piperidinyl]methyl]piperidinyl]phenyl ... -1-yl]pyrene Methyl 2-carboxylate (300 mg, 0.43 mmol, 70% yield).

[0522] MS (ESI) m / z: 694.4 [M+1] +.

[0523] Chemical formula: C40H51N7O4, Molecular weight: 693.88

[0524] Step 2: Preparation of 5-(4-((1-(4-(((1r,3r)-3-(4-cyano-3,5-dimethylphenoxy)-2,2,4,4-tetramethylcyclobutyl)aminomethyl)phenyl)piperidin-4-yl)methyl)piperidin -1-yl)pyrene 2-Formic acid

[0525] To 5-[4-[[1-[4-[[3-(4-cyano-3,5-dimethyl-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]aminomethyl]phenyl]-4-piperidinyl]methyl]piperidinyl ... -1-yl]pyrene Methyl 2-carboxylate (300 mg, 0.43 mmol, 1.00 eq) was dissolved in tetrahydrofuran (5 mL), methanol (5 mL), and water (5 mL) with sodium hydroxide (138 mg, 3.46 mmol, 8.00 eq). The mixture was stirred at 50 °C for 12 h. LC-MS showed that the reaction was complete. The mixture was adjusted to pH 5 with diluted hydrochloric acid (4 M) and filtered to give a white solid. The white solid was further purified by preparative HPLC (column: Waters Xbridge C18 150*50mm*10um; mobile phase: [water (10mM NH4HCO3)-ACN]; B%: 33%-63%, 11.5min) to obtain 5-[4-[[1-[4-[[3-(4-cyano-3,5-dimethyl-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]aminomethyl]phenyl]-4-piperidinyl]methyl]piperidinyl ... -1-yl]pyrene 2-Carboxylic acid (200 mg, 0.27 mmol, 64% yield, hydrochloric acid).

[0526] MS (ESI) m / z: 678.4 [M-1] +.

[0527] Chemical formula: C39H49N7O4, Molecular weight: 679.85

[0528] Step 3: Preparation of 5-(4-((1-(4-(((1r,3r)-3-(4-cyano-3,5-dimethylphenoxy)-2,2,4,4-tetramethylcyclobutyl)aminomethyl)phenyl)piperidin-4-yl)methyl)piperidin -1-yl)-N-((S)-2,6-dioxypiperidin-3-yl)pyridine -2-Methylamine, compound 33

[0529] To 5-[4-[[1-[4-[[3-(4-cyano-3,5-dimethyl-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]aminomethyl]phenyl]-4-piperidinyl]methyl]piperidinyl ... -1-yl]pyrene 2-Carboxylic acid (100 mg, 0.14 mmol, 1.00 eq, hydrochloric acid) was added to a solution of dimethylformamide (2 mL) with 4-methyl Phosphorus (74 mg, 0.73 mmol, 5.00 eq), hydroxybenzotriazole (23 mg, 0.17 mmol, 1.20 eq), 3-(ethyliminomethyleneamino)-N,N-dimethyl-prop-1-amine; hydrochloride (33 mg, 0.17 mmol, 1.20 eq), and (3S)-3-aminopiperidin-2,6-dione (36 mg, 0.22 mmol, 1.50 eq, hydrochloric acid). The mixture was stirred at 20 °C for 12 h. The reaction was complete as indicated by LCMS. Dichloromethane (20 mL) and water (20 mL) were added to the mixture. The mixture was extracted with dichloromethane (20 mL × 3). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: Shim-pack C18 150*25*10um; mobile phase: [water (0.225% FA)-ACN]; B%: 25%-55%, 10 min) to obtain a white solid 5-[4-[[1-[4-[[3-(4-cyano-3,5-dimethyl-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]aminomethyl]phenyl]-4-piperidinyl]methyl]piperidinyl ... -1-yl]-N-[(3S)-2,6-dioxy-3-piperidinyl]pyridine -2-methamide (52.7 mg, 62.41 μmol, 42.43% yield, 99% purity, formate).

[0530] MS (ESI) m / z: 790.5 [M+1] +.

[0531] 1H NMR: (400 MHz, DMSO-d6)

[0532] δ:10.86 (s, 1H), 8.70 - 8.59 (m, 2H), 8.32 (s, 1H), 7.75 (d, J = 8.8 Hz, 2H), 7.49 (d, J = 9.2 Hz, 1H), 6.97 (d, J = 9.2 Hz, 2H), 6.74 (s, 2H), 4.81 - 4.68 (m, 1H), 4.23 (s, 1H), 4.04 (d, J = 9.2 Hz, 1H), 3.87 (br d, J = 13.2 Hz, 2H), 3.73 (br s, 5H), 2.87 - 2.73 (m, 3H), 2.56 - 2.53 (m, 4H), 2.44 (s, 6H), 2.25 - 2.17 (m, 3H), 1.99 (br d, J = 12.4 Hz, 1H), 1.83 (br d, J = 11.6 Hz, 3H), 1.23 (s, 8H), 1.13 (s, 6H).

[0533] Chemical formula: C44H55N9O5, Molecular weight: 789.96

[0534] Total H count from HNMR data: 55.

[0535] Example 14 - Synthesis of 4-[3-[9-[4-[[3-(4-cyano-3-methoxy-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]aminomethyl]phenyl]-1-oxa-4,9-diazaspiro[5.5]undecane-4-yl]cyclobutoxy]-N-[(3S)-2,6-disideloxy-3-piperidinyl]-2-methoxy-benzylamine (Compound 34)

[0536] Process 9. Overview of the synthesis of compound 34

[0537] Step 1: Preparation of methyl 4-[3-[9-[4-[[3-(4-cyano-3-methoxy-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]aminomethoxy]phenyl]-1-oxa-4,9-diazaspiro[5.5]undecane-4-yl]cyclobutoxy]-2-methoxy-benzoate

[0538] Add 3-(ethyliminomethyleneamino)-N,N-dimethyl-propane-1-amine; hydrochloride (113 mg, 0.59 mmol, 1.20 eq), hydroxybenzotriazole (79 mg, 0.59 mmol, 1.20 eq) and 4-(3-amino-2,2,4,4-tetramethyl-cyclobutoxy)-2-methoxy-benzonitrile (134 mg, 0.49 mmol, 1.00 eq) to a mixture of 4-[4-[3-(3-methoxy-4-methoxycarbonyl-phenoxy)cyclobutyl]-1-oxa-4,9-diazaspiro[5.5]undecane-9-yl]benzoic acid (250 mg, 0.49 mmol, 1.00 eq) and triethylamine (248 mg, 2.45 mmol, 0.34 mL, 5.00 eq) in N,N-dimethylformamide (4 mL ...); hydroxybenzotriazole (79 mg, 0.59 mmol, 1.20 eq) and triethylamine (248 mg, 2.45 mmol, 0.34 mL, 5.00 eq) in N,N-dimethylformamide (4 mL); hydroxybenzotriazole (79 mg, 0.59 mmol, 1.20 eq) in N,N-dimethylformamide (4 mL); hydroxybenzotriazole mmol, 1.00 eq, hydrochloric acid). The mixture was stirred at 25 °C for 12 h. LCMS showed that the reaction was complete. The reaction mixture was filtered and the filtrate was directly purified by preparative HPLC (column: Phenomenex luna C18 150*40mm*15um, conditions: water (0.225% FA)-ACN) to give methyl 4-[3-[9-[4-[[3-(4-cyano-3-methoxy-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]aminomethyl]phenyl]-1-oxa-4,9-diazaspiro[5.5]undecane-4-yl]cyclobutoxy]-2-methoxy-benzoate (180 mg, 0.23 mmol, 48% yield) as a pale yellow solid.

[0539] MS (ESI) m / z: 767.6 [M+1] +.

[0540] Chemical formula: C44H54N4O8, Molecular weight: 766.92

[0541] Step 2: Preparation of 4-[3-[9-[4-[[3-(4-cyano-3-methoxy-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]aminomethoxy]phenyl]-1-oxa-4,9-diazaspiro[5.5]undecane-4-yl]cyclobutoxy]-2-methoxy-benzoic acid

[0542] Sodium hydroxide (47 mg, 1.17 mmol, 5.00 eq) was added to a mixture of methyl 4-[3-[9-[4-[[3-(4-cyano-3-methoxy-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]aminomethoxy]phenyl]-1-oxa-4,9-diazaspiro[5.5]undecane-4-yl]cyclobutoxy]-2-methoxy-benzoate (180 mg, 0.23 mmol, 1.00 eq) in methanol (2 mL), water (2 mL), and tetrahydrofuran (2 mL). The mixture was stirred at 50 °C for 12 h. The reaction was shown to be complete by LCMS. The reaction mixture was then concentrated under reduced pressure to obtain a residue. The residue was adjusted to pH 6 with hydrochloric acid (1 M). The mixture was then filtered. The filter cake was dried under reduced pressure to obtain 4-[3-[9-[4-[[3-(4-cyano-3-methoxy-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]aminomethoxy]phenyl]-1-oxa-4,9-diazaspiro[5.5]undecane-4-yl]cyclobutoxy]-2-methoxy-benzoic acid (160 mg, 0.21 mmol, 91% yield) as a white solid.

[0543] MS (ESI) m / z: 753.2 [M+1] +.

[0544] Chemical formula: C43H52N4O8, molecular weight: 752.89

[0545] Step 3: Preparation of 4-[3-[9-[4-[[3-(4-cyano-3-methoxy-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]aminomethoxy]phenyl]-1-oxa-4,9-diazaspiro[5.5]undecane-4-yl]cyclobutoxy]-N-[(3S)-2,6-disideloxy-3-piperidinyl]-2-methoxy-benzylamine, compound 34

[0546]

[0547] Add 4-methyl to a solution of 4-[3-[9-[4-[[3-(4-cyano-3-methoxy-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]aminomethyl]phenyl]-1-oxa-4,9-diazaspiro[5.5]undecane-4-yl]cyclobutoxy]-2-methoxy-benzoic acid (160 mg, 0.21 mmol, 1.00 eq) in N,N-dimethylformamide (4 mL). Phosphorus (107 mg, 1.06 mmol, 0.12 mL, 5.00 eq), hydroxybenzotriazole (34 mg, 0.26 mmol, 1.20 eq), 3-(ethyliminomethyleneamino)-N,N-dimethyl-propane-1-amine; hydrochloride (49 mg, 0.26 mmol, 1.20 eq), and (3S)-3-aminopiperidin-2,6-dione (70 mg, 0.43 mmol, 2 eq, hydrochloric acid). The mixture was stirred at 25 °C for 9 h. The reaction was complete as indicated by LCMS. The reaction mixture was filtered. The filtrate was directly purified by preparative HPLC (column: Phenomenex luna C18 150*40mm*15um, conditions: water (0.225%FA)-ACN) to obtain 4-[3-[9-[4-[[3-(4-cyano-3-methoxy-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]aminomethyl]phenyl]-1-oxa-4,9-diazaspiro[5.5]undecane-4-yl]cyclobutoxy]-N-[(3S)-2,6-disideloxy-3-piperidinyl]-2-methoxy-benzylamine (130.0 mg, 0.15 mmol, 70% yield, 99% purity).

[0548] MS (ESI) m / z: 863.3 [M+1] +.

[0549] 1H NMR: (400 MHz, DMSO-d6)

[0550] δ: 10.88 (s, 1H), 8.48 (d, J=6.8 Hz, 1H), 7.86 (d, J=8.8 Hz, 1H), 7.75 (d, J=9.2 Hz, 2H), 7.65 (d, J=8.8 Hz, 1H), 7.50 (d, J=9.2 Hz, 1H), 6.98 (d, J=9.2 Hz, 2H), 6.64 (d, J=2.0 Hz, 1H), 6.57-6.49 (m, 3H), 4.92-4.80 (m, 1H), 4.76-4.67 (m, 1H), 4.31-4.27 (m, 1H), 4.09-4.02 (m, 1H), 3.91 (s, 6H), 3.72-3.66 (m, 2H), 3.55-3.47 (m, 2H), 3.22-3.10 (m, 3H), 2.95-2.70 (m, 3H), 2.43-2.37 (m, 2H), 2.30-2.25 (m, 1H), 2.21-2.07 (m, 6H), 1.97-1.88 (m, 2H), 1.69-1.59 (m, 2H), 1.23 (s, 6H), 1.15 (s, 6H).

[0551] Chemical formula: C48H58N6O9, Molecular weight: 863.01

[0552] Example 15 - Synthesis of 4-[3-[9-[4-[[3-(4-cyano-3,5-dimethyl-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]aminomethyl]phenyl]-1-oxa-4,9-diazaspiro[5.5]undecane-4-yl]cyclobutoxy]-N-[(3S)-2,6-dioxy-3-piperidinyl]-2-methoxy-benzylamine (Compound 35)

[0553] Process 10. Overview of the synthesis of compound 35

[0554] Step 1: Preparation of methyl 4-benzooxy-2-hydroxybenzoate

[0555] Benzyl bromide (1.02 g, 5.95 mmol, 1.00 eq) was added to a solution of methyl 2,4-dihydroxybenzoate (1.00 g, 5.95 mmol, 1.00 eq) and potassium carbonate (1.64 g, 11.89 mmol, 2.00 eq) in acetonitrile (20 mL). The mixture was stirred at 80 °C for 12 h under a nitrogen atmosphere. The reaction was complete by LC-MS. The mixture was filtered. The filtrate was concentrated under reduced pressure to obtain a residue. The crude product was wet-milled at 25 °C with petroleum ether:ethyl acetate = 25:1, 20 mL for 0.5 h. The mixture was filtered. The filter cake was collected and dried under reduced pressure to give methyl 4-benzoxy-2-hydroxybenzoate (1.00 g, 3.87 mmol, 65% yield) as a white solid, which was used directly in the next step.

[0556] MS (ESI) m / z: 259.1 [M+1] +.

[0557] HNMR: (400MHz, CDCl3)δ = 10.98 (brs, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.50-7.34 (m, 5H), 6.59-6.52 (m, 2H), 5.11 (s, 2H), 3.94 (s, 3H).

[0558] Chemical formula: C15H14O4, molecular weight: 258.27

[0559] Step 2: Preparation of methyl 4-benzoxy-2-methoxy-benzoate

[0560] Iodoform (1.28 g, 9.02 mmol, 0.56 mL, 2.33 eq) was added to a mixture of methyl 4-benzoxy-2-hydroxybenzoate (1.00 g, 3.87 mmol, 1.00 eq) and potassium carbonate (1.61 g, 11.62 mmol, 3.00 eq) in N,N-dimethylformamide (10 mL) at 25 °C. The mixture was stirred at 25 °C for 3 h. LC-MS showed that the reaction was complete. The mixture was diluted with ethyl acetate (50 mL × 3) and washed with water (50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was wet-milled at 25 °C with petroleum ether:ethyl acetate = 10:1, 20 mL for 0.5 h. The mixture was filtered. The filter cake was collected and dried under reduced pressure to give methyl 4-benzoxy-2-methoxy-benzoate (0.80 g, 2.94 mmol, 76% yield) as a white solid.

[0561] MS (ESI) m / z: 273.1 [M+1] +.

[0562] HNMR: (400MHz, CDCl3)δ = 7.88 (d, J = 4.0 Hz, 1H), 7.50-7.33 (m, 5H), 6.61-6.50 (m, 2H), 5.13 (s, 2H), 3.87-3.82 (m, 6H).

[0563] Chemical formula: C16H16O4, molecular weight: 272.30

[0564] Step 3: Preparation of methyl 4-hydroxy-2-methoxy-benzoate

[0565] Under a nitrogen atmosphere, palladium on carbon (10%, 0.30 g) was added to a solution of methyl 4-phenylmethoxy-2-methoxybenzoate (0.80 g, 2.94 mmol, 1.00 eq) in methanol (10 mL). The suspension was degassed and purged three times with hydrogen. The mixture was stirred for 12 h at 25 °C under a hydrogen atmosphere (15 Psi). Thin-layer chromatography (petroleum ether:ethyl acetate = 3:1) showed that the reaction was complete. The mixture was filtered. The filtrate was concentrated under reduced pressure to give methyl 4-hydroxy-2-methoxybenzoate (0.51 g, 2.82 mmol, 96% yield) as a white solid, which was used directly in the next step.

[0566] Chemical formula: C9H10O4, molecular weight: 182.17

[0567] HNMR: (400MHz, CDCl3)δ = 7.81 (d, J = 8.4 Hz, 1H), 6.52-6.48 (m, 2H), 3.88 (s, 3H), 3.84 (s, 3H).

[0568] Step 4: Preparation of terbutyl 1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylic acid

[0569] Under a nitrogen atmosphere, palladium on carbon (0.40 g, 10% purity) was added to a mixture of 4-benzyl-9-tert-butyl-1-oxa-4,9-diazaspiro[5.5]undecane-4,9-dicarboxylate (2.00 g, 5.12 mmol, 1.00 eq) in methanol (100 mL). The suspension was degassed and purged three times with hydrogen. The mixture was stirred at 50 °C under a hydrogen atmosphere (50 Psi) for 12 h. Thin-layer chromatography (petroleum ether: ethyl acetate = 3:1) showed that the reaction was complete. The reaction mixture was then filtered. The filtrate was concentrated under reduced pressure to give 1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate tributyl ester (1.10 g, 4.29 mmol, 84% yield) as a pale yellow oil, which was used directly in the next step.

[0570] Chemical formula: C13H24N2O3, molecular weight: 256.34

[0571] HNMR: (400MHz, DMSO-d6)δ = 3.62-3.40 (m, 6H), 3.08-2.93 (m, 2H), 2.72-2.58 (m, 2H), 1.88-1.72 (m, 2H),1.39 (s, 9H), 1.35-1.22 (m, 2H).

[0572] Step 5: Preparation of methyl 4-(3-benzoxycyclobutoxy)-2-methoxybenzoate

[0573] Diisopropyl azodicarbonate (1.86 g, 9.22 mmol, 1.79 mL, 1.20 eq) was added to a solution of methyl 4-hydroxy-2-methoxybenzoate (1.40 g, 7.69 mmol, 1.00 eq), 3-benzoxycyclobutanol (1.51 g, 8.45 mmol, 1.10 eq), and triphenylphosphine (3.02 g, 11.53 mmol, 1.50 eq) in tetrahydrofuran (15 mL). The mixture was stirred at 25 °C for 12 h under a nitrogen atmosphere. LC-MS showed that the reaction was complete. The reaction mixture was concentrated under reduced pressure. The residue was purified by silicone column chromatography (petroleum ether / ethyl acetate = 20 / 1 to 5 / 1) to give methyl 4-(3-benzyloxycyclobutoxy)-2-methoxybenzoate (2.00 g, 5.84 mmol, 76% yield) as a yellow oil.

[0574] Chemical formula: C20H22O5, molecular weight: 342.39

[0575] LCMS: MS (ESI) m / z: 343.2 [M+1] +.

[0576] Step 6: Preparation of methyl 4-(3-hydroxycyclobutoxy)-2-methoxybenzoate

[0577] Under a nitrogen atmosphere, palladium on carbon (0.50 g, 10% purity) was added to a mixture of methyl 4-(3-benzyloxycyclobutoxy)-2-methoxybenzoate (5.00 g, 14.60 mmol, 1.00 eq) in methanol (50 mL). The suspension was degassed and purged three times with hydrogen. The mixture was stirred at 50 °C under a hydrogen atmosphere (50 Psi) for 12 h. Thin-layer chromatography (petroleum ether:ethyl acetate = 3:1) showed that the reaction was complete. The reaction mixture was then filtered. The filtrate was concentrated under reduced pressure to give methyl 4-(3-hydroxycyclobutoxy)-2-methoxybenzoate (2.70 g, 10.70 mmol, 73% yield) as a white solid.

[0578] HNMR: (400MHz, CDCl3)δ = 7.82 (d, J = 8.8 Hz, 1H), 6.43 (d, J = 2.4 Hz, 1H), 6.37 (dd, J = 8.8, 2.4 Hz, 1H), 4.33-4.10 (m, 2H), 3.88 (s, 3H), 3.86 (s, 3H), 2.99-2.95 (m, 2H), 2.17-2.05 (m, 2H), 1.61 (brs, 1H).

[0579] Chemical formula: C13H16O5, molecular weight: 252.26

[0580] Step 7: Preparation of methyl 2-methoxy-4-[3-(trifluoromethylsulfonyloxy)cyclobutoxy]benzoate

[0581] Under nitrogen atmosphere and at 0 °C, trifluoromethane anhydride (3.36 g, 11.89 mmol, 1.96 mL, 1.2 eq) was added to a mixture of methyl 4-(3-hydroxycyclobutoxy)-2-methoxybenzoate (2.50 g, 9.91 mmol, 1.00 eq) and pyridine (1.57 g, 19.82 mmol, 1.60 mL, 2.00 eq) in dichloromethane (50 mL). The mixture was stirred at 25 °C for 1 h. Thin-layer chromatography (petroleum ether:ethyl acetate = 3:1) showed that the reaction was complete. Water (200 mL) was added to the mixture, and the mixture was extracted with dichloromethane (50 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by silicone column chromatography (petroleum ether: ethyl acetate = 3:1) to give methyl 2-methoxy-4-[3-(trifluoromethylsulfonyluoxy)cyclobutoxy]benzoate (3.00 g, 7.81 mmol, 79% yield) as a yellow solid.

[0582] HNMR: (400MHz, DMSO-d6)δ = 7.70 (d, J = 8.8 Hz, 1H), 6.54 (d, J = 2.0 Hz, 1H), 6.49 (dd, J = 8.8, 2.4 Hz, 1H), 5.24-5.21 (m, 1H), 5.05-5.02 (m, 1H), 3.81 (s, 3H), 3.74 (s, 3H), 2.81-2.76 (m, 2H), 2.65-2.55 (m, 2H).

[0583] Chemical formula: C14H15F3O7S, Molecular weight: 384.32

[0584] Step 8: Preparation of tert-butyl 4-[3-(3-methoxy-4-methoxycarbonyl-phenoxy)cyclobutyl]-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylic acid

[0585] To a solution of terbutyl 1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (1.00 g, 3.90 mmol, 1.00 eq) in acetonitrile (30 mL), methyl 2-methoxy-4-[3-(trifluoromethylsulfonyluoxy)cyclobutoxy]benzoate (1.50 g, 3.90 mmol, 1.00 eq) and diisopropylethylamine (2.52 g, 19.51 mmol, 3.40 mL, 5.00 eq) were added. The reaction mixture was stirred at 70 °C for 12 h. LC-MS showed that the reaction was complete. The reaction mixture was then concentrated under reduced pressure to obtain the residue. The residue was purified by silicone column chromatography (petroleum ether: ethyl acetate = 3:1) to give 4-[3-(3-methoxy-4-methoxycarbonyl-phenoxy)cyclobutyl]-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylic acid tert-butyl ester (1.50 g, 3.06 mmol, 78% yield) as a yellow oil.

[0586] LCMS: MS (ESI) m / z: 491.4 [M+1] +.

[0587] HNMR: (400MHz, DMSO-d6)δ = 7.68 (d, J = 8.8 Hz, 1H), 6.52 (d, J = 2.0 Hz, 1H), 6.44 (dd, J = 8.4, 2.4 Hz, 1H), 4.88-4.78 (m, 1H), 3.80 (s, 3H), 3.74 (s, 3H), 3.68-3.54 (m, 4H), 3.12-2.96 (m, 2H), 2.89-2.79 (m, 1H), 2.71-2.63 (m, 1H), 2.46-2.34 (m, 2H), 2.32-2.22 (m, 2H), 2.20-2.09 (m, 3H), 1.85-1.77 (m, 2H), 1.49-1.41 (m, 2H), 1.40 (s, 9H).

[0588] Chemical formula: C26H38N2O7, Molecular weight: 490.59

[0589] Step 9: Preparation of methyl 2-methoxy-4-[3-(1-oxa-4,9-diazaspiro[5.5]undecane-4-yl)cyclobutoxy]benzoate

[0590] Add hydrogen chloride / di(2-ethylhexyl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylic acid tert-butyl ester (1.50 g, 3.06 mmol, 1.00 eq) to a mixture of 4-[3-(3-methoxy-4-methoxycarbonyl-phenoxy)cyclobutyl]-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylic acid tert-butyl ester (1.50 g, 3.06 mmol, 1.00 eq). Alkane (4 M, 25 mL, 32.71 eq). The mixture was stirred at 25 °C for 12 h. LCMS showed that the reaction was complete. The reaction mixture was then concentrated under reduced pressure to give methyl 2-methoxy-4-[3-(1-oxa-4,9-diazaspiro[5.5]undecyl-4-yl)cyclobutoxy]benzoate (1.30 g, 3.04 mmol, 99% yield, hydrogen chloride) as a pale yellow solid.

[0591] LCMS: MS (ESI) m / z: 391.3 [M+1] +.

[0592] Chemical formula: C21H30N2O5, molecular weight: 390.47

[0593] Step 10: Preparation of methyl 4-[3-[9-(4-tert-butoxycarbonylphenyl)-1-oxa-4,9-diazaspiro[5.5]undecane-4-yl]cyclobutoxy]-2-methoxybenzoate

[0594] Potassium carbonate (2.10 g, 15.22 mmol, 5.00 eq) and tributyl 4-fluorobenzoate (0.90 g, 4.57 mmol, 1.50 eq) were added to a mixture of methyl 2-methoxy-4-[3-(1-oxa-4,9-diazaspiro[5.5]undecyl-4-yl)cyclobutoxy]benzoate (1.30 g, 3.04 mmol, 1.00 eq, hydrogen chloride) in dimethyl sulfoxide (40 mL). The mixture was stirred at 120 °C for 12 h. The reaction was complete as indicated by LC-MS. Water (200 mL) was added to the solution and the mixture was extracted with ethyl acetate (50 mL × 2). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 250*80mm*10 μm; mobile phase: [water (0.225% FA)-ACN]; B%: 26%-56%, 19 min) to obtain methyl 4-[3-[9-(4-tert-butoxycarbonylphenyl)-1-oxa-4,9-diazaspiro[5.5]undecane-4-yl]cyclobutoxy]-2-methoxybenzoate (0.55 g, 970.56 μmol, 32% yield) as a yellow oil.

[0595] LCMS: MS (ESI) m / z: 567.5 [M+1] +.

[0596] HNMR: (400MHz, DMSO-d6)δ = 7.88 (d, J = 9.2 Hz, 2H), 7.84 (d, J = 8.8 Hz, 1H), 6.89 (d, J = 9.2 Hz, 2H), 6.43 (d, J = 1.6 Hz, 1H), 6.33 (dd, J = 8.4, 2.4 Hz, 1H), 4.85-4.77 (m, 1H), 3.90 (s, 3H), 3.87 (s, 3H), 3.82-3.73 (m, 2H), 3.58-3.50 (m, 2H), 3.34-3.22 (m, 2H), 3.01-2.92 (m, 1H), 2.40-2.26 (m, 6H), 2.22-2.14 (m, 2H), 2.12-2.07 (m, 2H), 1.70-1.63 (m, 2H), 1.59 (s, 9H).

[0597] Chemical formula: C32H42N2O7, Molecular weight: 566.69

[0598] Step 11: Preparation of methyl 4-[3-[9-(4-tert-butoxycarbonylphenyl)-1-oxa-4,9-diazaspiro[5.5]undecane-4-yl]cyclobutoxy]-2-methoxybenzoate

[0599] Adding hydrogen chloride / dichlorophenyl chloride to compound 4-[3-[9-(4-tert-butoxycarbonylphenyl)-1-oxa-4,9-diazaspiro[5.5]undecane-4-yl]cyclobutoxy]-2-methoxybenzoate (550 mg, 0.97 mmol, 1.00 eq) Alkane (4 M, 20 mL, 82.43 eq). The mixture was stirred at 25 °C for 12 h. LCMS showed that the reaction was complete. The reaction mixture was concentrated under reduced pressure to give 4-[4-[3-(3-methoxy-4-methoxycarbonyl-phenoxy)cyclobutyl]-1-oxa-4,9-diazaspiro[5.5]undecane-9-yl]benzoic acid (500 mg, 0.91 mmol, 94% yield, hydrogen chloride) as a white solid, which was used directly in the next step.

[0600] LCMS: MS (ESI) m / z: 511.3 [M+1] +.

[0601] Chemical formula: C28H34N2O7, Molecular weight: 510.58

[0602] Step 12: 4-[3-[9-[4-[[3-(4-cyano-3,5-dimethylphenoxy)-2,2,4,4-tetramethyl-cyclobutyl]aminomethyl]phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-4-yl]cyclobutoxy]-2-methoxy-benzoate methyl ester

[0603] Add 3-(ethyliminomethyleneamino)-N,N-dimethyl-propane-1-amine; hydrochloride (113 mg, 0.59 mmol, 1.20 eq), hydroxybenzotriazole (79 mg, 0.59 mmol, 1.20 eq) and 4-(3-amino-2,2,4,4-tetramethyl-cyclobutoxy)-2,6-dimethylbenzonitrile (151 mg, 0.49 mmol, 1.00 eq) to a mixture of 4-[4-[3-(3-methoxy-4-methoxycarbonyl-phenoxy)cyclobutyl]-1-oxa-4,9-diazaspiro[5.5]undecane-9-yl]benzoic acid (250 mg, 0.49 mmol, 1.00 eq) and triethylamine (248 mg, 2.45 mmol, 0.34 mL, 5.00 eq) in N,N-dimethylformamide (4 mL ...); hydroxybenzotriazole (79 mg, 0.59 mmol, 1.20 eq) and 4-(3-amino-2,2,4,4-tetramethyl-cyclobutoxy)-2,6-dimethylbenzonitrile (151 mg, 0.49 mmol, 1.20 eq) in N,N-dimethylformamide (4 mL) in N,N-dimethylformamide (4 mL) in N,N- mmol, 1.00 eq, hydrochloric acid). The mixture was stirred at 25 °C for 3 h. LCMS showed that the reaction was complete. The reaction mixture was purified by preparative HPLC (column: Phenomenex luna C18 150*40mm* 15um, conditions: water (0.225% FA)-ACN) to give methyl 4-[3-[9-[4-[[3-(4-cyano-3,5-dimethyl-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]aminomethyl]phenyl]-1-oxa-4,9-diazaspiro[5.5]undecane-4-yl]cyclobutoxy]-2-methoxybenzoate (200 mg, 0.26 mmol, 53% yield) as a pale yellow solid.

[0604] LCMS: MS (ESI) m / z: 765.6 [M+1] +.

[0605] 1HNMR: (400MHz, CDCl3)δ: 7.82 (d, J=8.4 Hz, 1H), 7.70-7.67 (m, 2H), 6.96-6.90 (m, 2H), 6.59 (s, 2H), 6.45-6.41 (m, 1H), 6.39-6.29 (m, 1H), 6.16-6.09 (m, 1H), 4.87-4.74 (m, 1H), 4.55-4.43 (m, 1H), 4.15-4.11 (m, 1H), 4.05-4.01 (m, 1H), 3.89 (s, 3H), 3.86 (s, 3H), 3.80-3.74 (m, 2H), 3.56-3.47 (m, 2H), 3.31-3.22 (m, 2H), 2.99-2.91 (m, 1H), 2.77-2.67 (m, 1H), 2.49 (s, 6H), 2.40-2.31 (m, 4H), 2.21-2.16 (m, 2H), 2.12-1.99(m, 4H), 1.26 (s, 6H), 1.22 (s, 6H).

[0606] Chemical formula: C45H56N4O7, Molecular weight: 764.95

[0607] Step 13: Preparation of 4-[3-[9-[4-[[3-(4-cyano-3,5-dimethyl-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]aminomethyl]phenyl]-1-oxa-4,9-diazaspiro[5,5]undecane-4-yl]cyclobutoxy]-2-methoxy-benzoic acid

[0608] Sodium hydroxide (52 mg, 1.31 mmol, 5.00 eq) was added to a mixture of methyl 4-[3-[9-[4-[[3-(4-cyano-3,5-dimethyl-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]aminomethyl]phenyl]-1-oxa-4,9-diazaspiro[5.5]undecane-4-yl]cyclobutoxy]-2-methoxybenzoate (200 mg, 0.26 mmol, 1.00 eq) in methanol (2 mL), water (2 mL), and tetrahydrofuran (2 mL). The mixture was stirred at 50 °C for 12 h. The reaction was shown to be complete by LCMS. The reaction mixture was then concentrated under reduced pressure to obtain a residue. The residue was adjusted to pH 6 with hydrochloric acid (1 M). The mixture was then filtered. The filter cake was dried under reduced pressure to obtain 4-[3-[9-[4-[[3-(4-cyano-3,5-dimethyl-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]aminomethyl]phenyl]-1-oxa-4,9-diazaspiro[5.5]undecane-4-yl]cyclobutoxy]-2-methoxybenzoic acid (200 mg, crude material) as a white solid.

[0609] LCMS: MS (ESI) m / z: 751.2 [M+1] +.

[0610] Chemical formula: C44H54N4O7, Molecular weight: 750.92

[0611] Step 14: Preparation of 4-[3-[9-[4-[[3-(4-cyano-3,5-dimethyl-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]aminomethyl]phenyl]-1-oxa-4,9-diazaspiro[5.5]undecane-4-yl]cyclobutoxy]-N-[(3S)-2,6-disideloxy-3-piperidinyl]-2-methoxy-benzylamine, compound 35

[0612] Add 4-methyl[9-[4-[[3-(4-cyano-3,5-dimethyl-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]aminomethyl]phenyl]-1-oxa-4,9-diazaspiro[5.5]undecane-4-yl]cyclobutoxy]-2-methoxybenzoic acid (190.0 mg, 0.25 mmol, 1.00 eq) to a solution of 4-[3-[9-[4-[[3-(4-cyano-3,5-dimethyl-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]aminomethyl]phenyl]-1-oxa-4,9-diazaspiro[5.5]undecane-4-yl]cyclobutoxy]-2-methoxy-benzoic acid (190.0 mg, 0.25 mmol, 1.00 eq) in N,N-dimethylformamide (4 mL) Phosphorus (128.0 mg, 1.27 mmol, 0.14 mL, 5.00 eq), hydroxybenzotriazole (41 mg, 0.30 mmol, 1.20 eq), and 3-(ethyliminomethyleneamino)-N,N-dimethyl-prop-1-amine; hydrochloride (58 mg, 0.30 mmol, 1.20 eq) and (3S)-3-aminopiperidin-2,6-dione (83 mg, 0.51 mmol, 2.00 eq, hydrochloric acid). The mixture was stirred at 25 °C for 9 h. The reaction was complete as indicated by LCMS. The reaction mixture was filtered. The filtrate was directly purified by preparative HPLC (column: Phenomenex luna C18 150*40mm* 15um, conditions: water (0.225% FA)-ACN) to obtain 4-[3-[9-[4-[[3-(4-cyano-3,5-dimethyl-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]aminomethyl]phenyl]-1-oxa-4,9-diazaspiro[5.5]undecane-4-yl]cyclobutoxy]-N-[(3S)-2,6-disideloxy-3-piperidinyl]-2-methoxy-benzylamine (104.6 mg, 0.12 mmol, 47% yield, 97% purity).

[0613] LCMS: MS (ESI) m / z: 861.5 [M+1] +.

[0614] HNMR: (400MHz, DMSO-d6)δ: 10.88 (s, 1H), 8.48 (d, J=6.8 Hz, 1H), 7.86 (d, J=8.8 Hz, 1H), 7.75 (d, J=8.8 Hz, 2H), 7.49 (d, J=8.8 Hz, 1H), 6.98 (d, J=9.2 Hz, 2H), 6.74 (s, 2H), 6.57 (d, J=2.4 Hz, 1H), 6.51 (dd, J=8.4, 2.4 Hz, 1H), 4.87-4.82 (m, 1H), 4.75-4.70 (m, 1H), 4.25-4.23 (m, 1H), 4.07-4.03 (m, 1H), 3.92 (s, 3H), 3.72-3.65 (m, 3H), 3.55-3.47 (m, 4H), 3.22-3.10 (m, 2H), 2.92-2.75 (m, 3H), 2.45-2.39 (m, 7H), 2.32-2.26 (m, 1H), 2.20-2.10 (m, 5H), 2.00-1.81 (m, 2H), 1.71-1.57 (m, 2H), 1.23 (s, 6H), 1.13 (s, 6H).

[0615] Chemical formula: C49H60N6O8, Molecular weight: 861.04

[0616] Example 16 - Synthesis of 5-[4-[[1-[4-[[3-(4-cyano-3-methoxy-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]aminomethyl]phenyl]-4-piperidinyl]methyl]piperidinyl ... -1-yl]-N-[(3S)-2,6-dioxy-3-piperidinyl]pyridine -2-Methylamine (Compound 37)

[0617] Process 11. Overview of the synthesis of compound 37

[0618] Step 1: Preparation of 5-(4-(tert-butoxycarbonyl)piperazine) -1-yl)pyrene Methyl 2-carboxylate

[0619] To 5-chloropyr Methyl 2-carboxylate (2.00 g, 11.59 mmol, 1.00 eq) was added to a solution of dimethyl methacrylate (20 mL) in dimethyl methacrylate (20 mL) along with diisopropylethylamine (3.00 g, 23.18 mmol, 4.04 mL, 2.00 eq) and piperazine. 1-Teratobutyl 1-carboxylate (2.16 g, 11.59 mmol, 1.00 eq). The mixture was stirred at 100 °C for 12 h. LCMS showed that the reaction was complete. The mixture was poured into ice water (30 mL) and ethyl acetate (30 mL). The mixture was filtered and the filter cake was concentrated under reduced pressure to give 5-(4-teratobutylcarboxylate) as a yellow solid. -1-yl)pyrene Methyl 2-carboxylate (3.50 g, 10.86 mmol, 93% yield) was used directly in the next step.

[0620] LCMS: MS (ESI) m / z: 323.8 [M+1] +.

[0621] 1H NMR: (400 MHz, DMSO-d6)δ:8.81 (d, J = 1.2 Hz, 1H), 8.14 (d, J = 1.2 Hz, 1H), 3.96 (s, 3H), 3.80 - 3.68 (m, 4H), 3.63 - 3.51 (m, 4H), 1.49 (s, 9H).

[0622] Chemical formula: C15H22N4O4, Molecular weight: 322.36

[0623] Step 2: Preparation of 5-(piperazine) -1-yl)pyrene Methyl 2-carboxylate

[0624] To 5-(4-tert-butoxycarbonylpiperyl) -1-yl)pyrene A solution of methyl 2-carboxylate (1.50 g, 4.65 mmol, 1.00 eq) in dichloromethane (30 mL) was prepared by adding hydrochloric acid / dichloromethane. Alkane (4 M, 5 mL, 4.28 eq). The mixture was stirred at 25 °C for 12 h. LC-MS showed that the reaction was complete. The mixture was filtered and the filter cake was concentrated under reduced pressure to give 5-piperane as a yellow solid. -1-pyr Methyl 2-carboxylate (1.00 g, 3.87 mmol, 83% yield, hydrochloride).

[0625] LCMS: MS (ESI) m / z: 223.2 [M+1] +.

[0626] Chemical formula: C10H14N4O2, Molecular weight: 222.24

[0627] Step 3: Preparation of 5-(4-((1-(4-(((1r,3r)-3-(4-cyano-3-methoxyphenoxy)-2,2,4,4-tetramethylcyclobutyl)aminomethyl)phenyl)piperidin-4-yl)methyl)piperidin -1-yl)pyrene Methyl 2-carboxylate

[0628] To 5-piperazine -1-pyr Methyl 2-carboxylate (158 mg, 0.61 mmol, 1.00 eq, hydrochloride) was added to a solution of dichloromethane (2 mL) and dimethylformamide (1 mL), along with triethylamine (62 mg, 0.61 mmol, 1.00 eq), acetic acid (36 mg, 0.61 mmol, 1.00 eq), and N-[3-(4-cyano-3-methoxy-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]-4-(4-methoxy-1-piperidinyl)benzamide (300 mg, 0.61 mmol, 1.00 eq). The mixture was stirred at 30 °C for 12 h. Then, sodium borohydride (259 mg, 1.23 mmol, 2.00 eq) was added to the mixture, and the mixture was stirred at 30 °C for 1 h. LC-MS showed that the reaction was complete. Water (20 mL) was added to the reactants and the mixture was extracted with dichloromethane (30 mL × 3). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative high-performance liquid chromatography (Phonemenex Luna C18 150*40mm*15um column; mobile phase: [water (0.1% TFA)-ACN]; B%: 30%-50%, 10 min) to obtain a yellow solid, 5-[4-[[1-[4-[[3-(4-cyano-3-methoxy-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]aminomethyl]phenyl]-4-piperidinyl]methyl]piperidinyl]phenyl ... -1-yl]pyrene Methyl 2-carboxylate (260 mg, 0.37 mmol, 60% yield).

[0629] LCMS: MS (ESI) m / z: 696.4 [M+1] +.

[0630] Chemical formula: C39H49N7O5, Molecular weight: 695.85

[0631] Step 4: Preparation of 5-(4-((1-(4-(((1r,3r)-3-(4-cyano-3-methoxyphenoxy)-2,2,4,4-tetramethylcyclobutyl)aminomethyl)phenyl)piperidin-4-yl)methyl)piperidin -1-yl)pyrene 2-Formic acid

[0632] To 5-[4-[[1-[4-[[3-(4-cyano-3-methoxy-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]aminomethyl]phenyl]-4-piperidinyl]methyl]piperidinyl ... -1-yl]pyrene Methyl 2-carboxylate (260 mg, 0.37 mmol, 1.00 eq) was added to a solution of tetrahydrofuran (5 mL), methanol (5 mL), and water (5 mL) with sodium hydroxide (119 mg, 2.99 mmol, 8.00 eq). The mixture was stirred at 50 °C for 12 h. LC-MS showed that the reaction was complete. The mixture was adjusted to pH 5 with hydrochloric acid (4 M). The mixture was filtered and the filter cake was concentrated under reduced pressure to give a yellow solid of 5-[4-[[1-[4-[[3-(4-cyano-3-methoxy-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]aminomethyl]phenyl]-4-piperidinyl]methyl]piperidinyl]piperidinyl]phenyl ... -1-yl]pyrene 2-Carboxylic acid (240 mg, 0.33 mmol, 89% yield, hydrochloride).

[0633] LCMS: MS (ESI) m / z: 682.1 [M+1] +.

[0634] Chemical formula: C38H47N7O5, Molecular weight: 681.82

[0635] Step 5: Preparation of 5-(4-((1-(4-(((1r,3r)-3-(4-cyano-3-methoxyphenoxy)-2,2,4,4-tetramethylcyclobutyl)aminomethyl)phenyl)piperidin-4-yl)methyl)piperidin -1-yl)-N-((S)-2,6-dioxypiperidin-3-yl)pyridine -2-Methylamine, compound 37

[0636] To 5-[4-[[1-[4-[[3-(4-cyano-3-methoxy-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]aminomethyl]phenyl]-4-piperidinyl]methyl]piperidinyl ... -1-yl]pyrene 2-Carboxylic acid (200 mg, 0.27 mmol, 1.00 eq, hydrochloride) was added to a solution of dimethylformamide (2 mL) with 4-methyl Phosphorus (140 mg, 1.39 mmol, 5.00 eq), hydroxybenzotriazole (45 mg, 0.33 mmol, 1.20 eq), 3-(ethyliminomethyleneamino)-N,N-dimethyl-prop-1-amine; hydrochloride (64 mg, 0.33 mmol, 1.20 eq), and (3S)-3-aminopiperidin-2,6-dione (68 mg, 0.41 mmol, 1.50 eq, hydrochloride). The mixture was stirred at 20 °C for 12 h. The reaction was complete as indicated by LCMS. Dichloromethane (20 mL) and water (20 mL) were added to the mixture. The mixture was then filtered. The filtrate was extracted with dichloromethane (20 mL × 3). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative high-performance liquid chromatography (pHPLC) (column: Shim-pack C18 150*25*10um; mobile phase: [water (0.225% FA)-ACN]; B%: 22%-52%, 10 min) to obtain a white solid 5-[4-[[1-[4-[[3-(4-cyano-3-methoxy-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]aminomethyl]phenyl]-4-piperidinyl]methyl]piperidinyl ... -1-yl]-N-[(3S)-2,6-dioxy-3-piperidinyl]pyridine -2-methamide (158 mg, 0.19 mmol, 70% yield, 99% purity).

[0637] QC-LCMS: (ESI) m / z: 792.5 [M+1] +.

[0638] 1H NMR: (400 MHz, DMSO-d6)δ:10.85 (s, 1H), 8.62 (d, J = 2.4 Hz, 1H), 8.54 (d, J = 8.4 Hz, 1H), 7.97 (dd, J = 2.4, 9.2 Hz, 1H), 7.74 (d, J = 8.4 Hz, 2H), 7.65 (d, J = 8.4 Hz, 1H), 7.50 (d, J = 9.2 Hz, 1H), 7.01 - 6.92 (m, 1H), 6.96 (br d, J = 8.8 Hz, 2H), 6.88 (d, J = 9.2 Hz, 1H), 6.64 (d, J = 2.0 Hz, 1H), 6.54 (dd, J = 2.0, 8.8 Hz, 1H), 4.81 - 4.69 (m, 1H), 4.28 (s, 1H), 4.06 (d, J = 9.2 Hz, 1H), 3.91 (s, 3H), 3.86 (br d, J = 12.0 Hz, 2H), 3.62 (br s, 4H), 2.79 (br t, J = 12.0 Hz, 3H), 2.56 (br d, J = 3.6 Hz, 1H), 2.45 (br s, 4H), 2.25 - 2.05 (m, 3H), 2.02 - 1.93 (m, 1H), 1.82 (br d, J = 12.0 Hz, 3H), 1.23 (s, 8H), 1.15 (s, 6H).

[0639] Chemical formula: C43H53N9O6, Molecular weight: 791.94

[0640] Total H count from HNMR data: 53.

[0641] Example 17 - Synthesis of 6-[4-[[1-[4-[[3-(4-cyano-3,5-dimethyl-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]aminomethyl]phenyl]-4-piperidinyl]methyl]piperidinyl ... -1-yl]-N-[(3S)-2,6-dioxy-3-piperidinyl]pyridine-3-methamide (compound 38)

[0642] Process 12. Overview of the synthesis of compound 38

[0643] Step 1: Preparation of 4-[4-(hydroxymethyl)-1-piperidinyl]benzoic acid

[0644]

[0645] Tertiary butyl 4-[4-(hydroxymethyl)-1-piperidinyl]benzoate (5.00 g, 17.16 mmol, 1.00 eq) was reacted at 25 °C. Add hydrochloric acid to the solution of [ethyl acetate] (50 mL) [Ethyl acetate] (4 M, 10 mL, 2.33 eq). The mixture was stirred at 25 °C for 35 h. LC-MS showed the reaction was complete. The mixture was concentrated under reduced pressure to give a solid. The solid was then... Washed with ethyl acetate (40 mL) and concentrated under reduced pressure to give 4-[4-(hydroxymethyl)-1-piperidinyl]benzoic acid (4.30 g, 16.45 mmol, 96% yield, 90% purity) as a white solid, which was used directly in the next step.

[0646] LCMS: MS (ESI) m / z: 236.1[M+1]+.

[0647] 1H NMR: (400 MHz, DMSO-d6)δ: 7.77 (d, J=8.8 Hz, 2H), 7.04 (s, 2H), 3.87 (d, J=12.8 Hz, 2H), 3.28 (d, J=6.0 Hz, 2H), 2.87 (t, J=11.6 Hz, 2H), 1.74 (d, J=12.8 Hz, 2H), 1.55 - 1.68 (m, 1H), 1.17 - 1.33 (m, 2H).

[0648] Chemical formula: C13H17NO3, molecular weight: 235.28.

[0649] Step 2: Preparation of N-[3-(4-cyano-3,5-dimethyl-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]-4-[4-(hydroxymethyl)-1-piperidinyl]benzamide

[0650] Hydroxybenzotriazole (525.00 mg, 3.89 mmol, 1.50 eq), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (744.84 mg, 3.89 mmol, 1.50 eq), diisopropylethylamine (1.67 g, 12.95 mmol, 2.26 mL, 5.00 eq), and 4-(3-amino-2,2,4,4-tetramethyl-cyclobutoxy)-2,6-dimethylbenzonitrile (800.00 mg, 2.59 mmol, 1.00 eq, hydrochloric acid) were added to a solution of 4-[4-(hydroxymethyl)-1-piperidinyl]benzoic acid (798.37 mg, 3.39 mmol, 1.31 eq) in N,N-dimethylformamide (10 mL). The mixture was stirred at 20 °C for 12 h. LC-MS showed complete exhaustion of 4-(3-amino-2,2,4,4-tetramethyl-cyclobutoxy)-2,6-dimethylbenzonitrile and the desired MS was found. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (20 mL). The organic layer was washed with brine (2 × 20 mL), dried over sodium sulfate, and concentrated under reduced pressure to give the residue. The residue was purified by silicone column chromatography (petroleum ether:ethyl acetate = 8:1 to 1:1) to give N-[3-(4-cyano-3,5-dimethyl-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]-4-[4-(hydroxymethyl)-1-piperidinyl]benzoamide (510.00 mg, 1.04 mmol, 40% yield) as a white solid.

[0651] LCMS: MS (ESI) m / z: 490.4[M+1]+.

[0652] 1H NMR: (400 MHz, DMSO-d6)δ: 7.73 (d, J=8.8 Hz, 2H), 7.48 (d, J=9.2 Hz, 1H), 6.95 (d, J=8.8 Hz, 2H), 6.73 (s, 2H), 4.49 (t, J=5.2 Hz, 1H), 4.22 (s, 1H), 4.03 (d, J=9.2 Hz, 1H), 3.87 (d, J=13.2 Hz, 2H), 3.27 (t, J=5.6 Hz, 2H), 2.75 (s, 2H), 2.43 (s, 6H), 1.73 (d, J=12.0 Hz, 2H), 1.51 - 1.64 (m, 1H), 1.21 (s, 6H), 1.14 - 1.20 (m, 2H), 1.11 (s, 6H).

[0653] Chemical formula: C30H39N3O3, Molecular weight: 489.65

[0654] Step 3: Preparation of N-[3-(4-cyano-3,5-dimethyl-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]-4-(4-methoxy-1-piperidinyl)benzamide

[0655] Add Dess-Martin reagent (662.66 mg, 1.56 mmol, 483.69 μL, 1.50 eq) to a solution of N-[3-(4-cyano-3,5-dimethyl-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]-4-[4-(hydroxymethyl)-1-piperidinyl]benzamide (510.00 mg, 1.04 mmol, 1.00 eq) in 10 mL of dichloromethane. Stir the mixture at 20 °C for 3 h. LC-MS showed the reaction was complete. Quench the mixture with saturated sodium sulfate and saturated sodium bicarbonate (10 mL, 1:1) and then extract with 15 mL of dichloromethane. Wash the organic layer with 15 mL of brine, dry over sodium sulfate, and concentrate under reduced pressure to obtain the residue. By using silicone column chromatography ( Petroleum ether [:] [ethyl acetate]= [8] [:] [1] to 1: [1]) The residue was purified to give N-[3-(4-cyano-3,5-dimethyl-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]-4-(4-methoxy-1-piperidinyl)benzamide (350.00 mg, 717.75 μol, 69% yield), which was a pale yellow oil.

[0656] LCMS: MS (ESI) m / z: 488.2[M+1]+.

[0657] 1H NMR: (400 MHz, DMSO-d6)

[0658] δ: 9.64 (s, 1H), 7.75 (d, J=8.8 Hz, 2H), 7.50 (d, J=9.2 Hz, 1H), 6.98 (d, J=8.8 Hz, 2H), 6.74 (s, 2H), 4.23 (s, 1H), 4.04 (d, J=9.2 Hz, 1H), 3.72 - 3.83 (m, 2H), 2.89 - 3.04 (m, 2H), 2.54 - 2.63 (m, 1H), 2.43 (s, 6H), 1.88 - 1.97 (m, 2H), 1.49 - 1.63 (m, 2H), 1.22 (s, 6H), 1.12 (s, 6H).

[0659] Chemical formula: C30H37N3O3, Molecular weight: 487.63

[0660] Step 4: Preparation of 5-(4-((1-(4-(((1r,3r)-3-(4-cyano-3,5-dimethylphenoxy)-2,2,4,4-tetramethylcyclobutyl)aminomethyl)phenyl)piperidin-4-yl)methyl)piperidin Methyl 1-(1-yl)pyrimidin-2-carboxylate

[0661] To 5-piperazine Methyl 1-pyrimidin-2-carboxylate (106 mg, 0.41 mmol, 1.00 eq, hydrochloride) was added to a solution of dichloromethane (2 mL) and dimethylformamide (1 mL). Triethylamine (41 mg, 0.41 mmol, 1.00 eq), acetic acid (24 mg, 0.41 mmol, 1.00 eq), and N-[3-(4-cyano-3,5-dimethyl-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]-4-(4-methoxy-1-piperidinyl)benzamide (200 mg, 0.41 mmol, 1.00 eq) were then stirred at 30 °C for 12 h. Sodium borohydride (173 mg, 0.82 mmol, 2.00 eq) was then added to the mixture, and the mixture was stirred at 30 °C for 1 h. LC-MS showed that the reaction was complete. Water (20 mL) was added to the reactants and the mixture was extracted with dichloromethane (30 mL × 3). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative high-performance liquid chromatography (Phonemenex Luna C18 150*40mm*15um column; mobile phase: [water (0.1% TFA)-ACN]; B%: 27%-57%, 10 min) to obtain a yellow solid, 5-[4-[[1-[4-[[3-(4-cyano-3,5-dimethyl-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]aminomethyl]phenyl]-4-piperidinyl]methyl]piperidinyl]piperidinyl]phenyl ... Methyl 1-[1-yl]pyrimidine-2-carboxylate (200 mg, 0.28 mmol, 70% yield).

[0662] LCMS: MS (ESI) m / z: 693.1 [M+1] +.

[0663] Chemical formula: C41H52N6O4, Molecular weight: 692.89

[0664] Step 5: Preparation of 5-(4-((1-(4-(((1r,3r)-3-(4-cyano-3,5-dimethylphenoxy)-2,2,4,4-tetramethylcyclobutyl)aminomethyl)phenyl)piperidin-4-yl)methyl)piperidin -1-yl)pyrimidin-2-carboxylic acid

[0665] To 5-[4-[[1-[4-[[3-(4-cyano-3,5-dimethyl-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]aminomethyl]phenyl]-4-piperidinyl]methyl]piperidinyl ... methyl 5-[4-[[1-[4-[[3-(4-cyano-3,5-dimethyl-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]aminomethyl]phenyl]-4-piperidinyl]methyl]piperidinyl]pyrimidine-2-carboxylate (200 mg, 0.28 mmol, 1.00 eq) in tetrahydrofuran (5 mL), methanol (5 mL), and water (5 mL) were mixed with sodium hydroxide (92 mg, 2.31 mmol, 8.00 eq). The mixture was stirred at 50 °C for 12 h. The reaction was completed by LCMS. The mixture was adjusted to pH 5 with hydrochloric acid (6 M). The mixture was filtered and the filter cake was concentrated under reduced pressure to give a yellow solid of 5-[4-[[1-[4-[[3-(4-cyano-3,5-dimethyl-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]aminomethyl]phenyl]-4-piperidinyl]methyl]piperidinyl]phenyl ... 1-yl]pyrimidine-2-carboxylic acid (200 mg, 0.027 mmol, 96% yield, hydrochloride).

[0666] LCMS: MS (ESI) m / z: 679.1 [M+1] +.

[0667] Chemical formula: C40H50N6O4, Molecular weight: 678.86

[0668] Step 6: Preparation of 6-(4-((1-(4-(((1r,3r)-3-(4-cyano-3,5-dimethylphenoxy)-2,2,4,4-tetramethylcyclobutyl)aminomethyl)phenyl)piperidin-4-yl)methyl)piperidin -1-yl)-N-((S)-2,6-di-dioxypiperidin-3-yl)nicotinamide, compound 38

[0669] To 6-[4-[[1-[4-[[3-(4-cyano-3,5-dimethyl-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]aminomethyl]phenyl]-4-piperidinyl]methyl]piperidinyl ... 4-methyl-1-yl]pyridine-3-carboxylic acid (150 mg, 0.22 mmol, 1.00 eq, hydrochloride) was added to a solution of dimethylformamide (2 mL). Phosphorus (111 mg, 1.10 mmol, 5.00 eq), hydroxybenzotriazole (35 mg, 0.26 mmol, 1.20 eq), 3-(ethyliminomethyleneamino)-N,N-dimethyl-prop-1-amine; hydrochloride (50 mg, 0.26 mmol, 1.20 eq), and (3S)-3-aminopiperidin-2,6-dione (54 mg, 0.33 mmol, 1.50 eq, hydrochloride). The mixture was stirred at 20 °C for 1 h. The reaction was complete as indicated by LCMS. Dichloromethane (20 mL) and water (20 mL) were added to the mixture. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative high-performance liquid chromatography (Phenomenex Synergi C18 150*25*10um column; mobile phase: [water (0.225% FA)-ACN]; B%: 30%-60%, 9 min) to obtain a white solid 6-[4-[[1-[4-[[3-(4-cyano-3,5-dimethyl-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]aminomethyl]phenyl]-4-piperidinyl]methyl]piperidinyl ... -1-yl]-N-[(3S)-2,6-di-sideoxy-3-piperidinyl]pyridine-3-methamide (69.3 mg, 0.08 mmol, 38% yield, 96% purity).

[0670] QC-LCMS: MS (ESI) m / z: 789.3 [M+1] +.

[0671] 1H NMR: (400 MHz, DMSO-d6)δ:10.84 (s, 1H), 8.61 (d, J = 2.4 Hz, 1H), 8.54 (d, J = 8.4 Hz, 1H), 8.17 (s, 1H), 7.96 (dd, J = 2.4, 9.2 Hz, 1H), 7.73 (d, J = 8.8 Hz, 2H), 7.47 (d, J = 9.2 Hz, 1H), 6.96 (d, J = 8.8 Hz, 2H), 6.87 (d, J = 8.8 Hz, 1H), 6.73 (s, 2H), 4.85 - 4.68 (m, 1H), 4.22 (s, 1H), 4.03 (d, J = 9.2 Hz, 1H), 3.86 (br d, J = 12.4 Hz, 2H), 3.61 (br s, 4H), 2.79 (br t, J = 12.4 Hz, 3H), 2.60 - 2.52 (m, 1H), 2.43 (s, 10H), 2.20 (br d, J = 6.4 Hz, 2H), 2.15 - 2.04 (m, 1H), 1.96 (br d, J = 5.6 Hz, 1H), 1.81 (br d, J = 11.0 Hz, 3H), 1.21 (s, 8H), 1.12 (s, 6H).

[0672] Chemical formula: C45H56N8O5, Molecular weight: 788.98

[0673] Example 18 - Synthesis of [4-[[1-[4-[[3-(4-cyano-3-methoxy-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]aminomethyl]phenyl]-4-piperidinyl]methyl]piperidinyl ... -1-yl]-N-[(3S)-2,6-dioxy-3-piperidinyl]pyrimidine-2-methamide (compound 39)

[0674] Process 13. Overview of the synthesis of compound 39

[0675] Step 1: Preparation of 5-(4-(tert-butoxycarbonyl)piperazine) Methyl 1-(1-yl)pyrimidin-2-carboxylate

[0676] Methyl 5-bromopyrimidine-2-carboxylate (2.00 g, 9.22 mmol, 1.00 eq) was subjected to dihydropyrimidine-2-carboxylate reaction. Cesium carbonate (6.01 g, 18.43 mmol, 2.00 eq) and piperazine were added to a solution in alkyl (20 mL). -1-Butyl 1-carboxylate (1.72 g, 9.22 mmol, 1.00 eq), palladium acetate (310 mg, 1.38 mmol, 0.15 eq), and (R)-(+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (860 mg, 1.38 mmol, 0.15 eq) were added. The mixture was stirred at 100 °C for 12 h. The reaction was complete as indicated by LCMS. The mixture was poured into water (100 mL) and extracted with ethyl acetate (50 mL × 3). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the residue. The residue was purified by silicone column chromatography (petroleum ether:ethyl acetate = 10:1 to 1:2) to give 5-(4-tert-butoxycarbonylpiperazine) as a yellow solid. Methyl 1-(1-yl)pyrimidine-2-carboxylate (1.50 g, 4.65 mmol, 50% yield).

[0677] LCMS: EW6807-1109-P1A1, MS (ESI) m / z: 323.1 [M+1] +.

[0678] Chemical formula: C15H22N4O4, Molecular weight: 322.36

[0679] Step 2: Preparation of 5-(piperazine) Methyl 1-(1-yl)pyrimidin-2-carboxylate

[0680] To 5-(4-tert-butoxycarbonylpiperyl) A solution of methyl 1-(1-yl)pyrimidine-2-carboxylate (1.50 g, 4.65 mmol, 1.00 eq) in dichloromethane (30 mL) was prepared by adding hydrochloric acid / dichloromethane. Alkane (4 M, 5 mL, 4.28 eq). The mixture was stirred at 25 °C for 12 h. Thin-layer chromatography (petroleum ether: ethyl acetate = 3:1) showed that the reaction was complete. The mixture was filtered and the filter cake was concentrated under reduced pressure to give 5-piperane as a yellow solid. Methyl 1-pyrimidin-2-carboxylate (1.00 g, 3.87 mmol, 83% yield, hydrochloride) is used directly in the next step.

[0681] Step 3: Preparation of 5-(4-((1-(4-(((1r,3r)-3-(4-cyano-3-methoxyphenoxy)-2,2,4,4-tetramethylcyclobutyl)aminomethyl)phenyl)piperidin-4-yl)methyl)piperidin Methyl 1-(1-yl)pyrimidin-2-carboxylate

[0682] To 5-piperazine A solution of methyl 1-pyrimidin-2-carboxylate (159 mg, 0.61 mmol, 1.00 eq, hydrochloride) in dichloromethane (2 mL) and dimethylformamide (1 mL) was prepared by adding triethylamine (62 mg, 0.61 mmol, 1.00 eq), acetic acid (73 mg, 1.23 mmol, 2.00 eq), and N-[3-(4-cyano-3-methoxy-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]-4-(4-methoxy-1-piperidinyl)benzamide (301 mg, 0.61 mmol, 1.00 eq). The mixture was stirred at 30 °C for 12 h. Then, sodium borohydride (260 mg, 1.23 mmol, 2.00 eq) was added to the mixture. The mixture was stirred at 30 °C for 1 h. LC-MS showed that the reaction was complete. Water (20 mL) was added to the reactants and the mixture was extracted with dichloromethane (30 mL × 3). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative high-performance liquid chromatography (Phonemenex Luna C18 150*40mm*15um column; mobile phase: [water (0.1% TFA)-ACN]; B%: 27%-47%, 10 min) to obtain a yellow solid, 5-[4-[[1-[4-[[3-(4-cyano-3-methoxy-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]aminomethyl]phenyl]-4-piperidinyl]methyl]piperidinyl]phenyl ... Methyl 1-[1-yl]pyrimidine-2-carboxylate (200 mg, 0.28 mmol, 46% yield).

[0683] LCMS: MS (ESI) m / z: 696.0 [M+1] +.

[0684] Chemical formula: C39H49N7O5, Molecular weight: 695.85

[0685] Step 4: Preparation of 5-(4-((1-(4-(((1r,3r)-3-(4-cyano-3-methoxyphenoxy)-2,2,4,4-tetramethylcyclobutyl)aminomethyl)phenyl)piperidin-4-yl)methyl)piperidin -1-yl)pyrimidin-2-carboxylic acid

[0686] To 5-[4-[[1-[4-[[3-(4-cyano-3-methoxy-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]aminomethyl]phenyl]-4-piperidinyl]methyl]piperidinyl ... methyl 5-[4-[[1-[4-[[3-(4-cyano-3-methoxy-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]aminomethyl]phenyl]-4-piperidinyl]methyl]piperidinyl]pyrimidine-2-carboxylate (200 mg, 0.28 mmol, 1.00 eq) in tetrahydrofuran (5 mL), methanol (5 mL), and water (5 mL) were mixed with sodium hydroxide (91 mg, 2.30 mmol, 8.00 eq). The mixture was stirred at 50 °C for 12 h. The reaction was completed by LCMS. The mixture was adjusted to pH 5 with hydrochloric acid (4 M). The mixture was filtered and the filter cake was concentrated under reduced pressure to give a yellow solid of 5-[4-[[1-[4-[[3-(4-cyano-3-methoxy-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]aminomethyl]phenyl]-4-piperidinyl]methyl]piperidinyl]phenyl ... 1-yl]pyrimidine-2-carboxylic acid (200 mg, 0.27 mmol, 96% yield, hydrochloride).

[0687] LCMS: MS (ESI) m / z: 682.0 [M+1] +.

[0688] Chemical formula: C38H47N7O5, Molecular weight: 681.82

[0689] Step 5: Preparation of 5-(4-((1-(4-(((1r,3r)-3-(4-cyano-3-methoxyphenoxy)-2,2,4,4-tetramethylcyclobutyl)aminomethyl)phenyl)piperidin-4-yl)methyl)piperidin -1-yl)-N-((S)-2,6-di-dioxypiperidin-3-yl)pyrimidin-2-methylamine, compound 39

[0690]

[0691] To 5-[4-[[1-[4-[[3-(4-cyano-3-methoxy-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]aminomethyl]phenyl]-4-piperidinyl]methyl]piperidinyl ... 4-methyl-1-yl]pyrimidine-2-carboxylic acid (200 mg, 0.29 mmol, 1.00 eq, hydrochloride) was added to a solution of dimethylformamide (2 mL). Phosphorus (148 mg, 1.47 mmol, 5.00 eq), hydroxybenzotriazole (47 mg, 0.35 mmol, 1.20 eq), 3-(ethyliminomethyleneamino)-N,N-dimethyl-prop-1-amine; hydrochloride (67 mg, 0.35 mmol, 1.20 eq), and (3S)-3-aminopiperidin-2,6-dione (72 mg, 0.44 mmol, 1.50 eq, hydrochloride). The mixture was stirred at 20 °C for 12 h. The reaction was complete as indicated by LCMS. Dichloromethane (20 mL) and water (20 mL) were added to the mixture. The mixture was then filtered. The filtrate was extracted with dichloromethane (20 mL × 3). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative high-performance liquid chromatography (Phenomenex Synergi C18 150*25*10um column; mobile phase: [water (0.225% FA)-ACN]; B%: 25%-55%, 10min) to obtain a white solid 5-(4-((1-(4-(((1r,3r)-3-(4-cyano-3-methoxyphenoxy)-2,2,4,4-tetramethylcyclobutyl)aminomethyl)phenyl)piperidin-4-yl)methyl)piperidin -1-yl)-N-((S)-2,6-di-sideoxypiperidin-3-yl)pyrimidin-2-methamide (200.5 mg, 0.22 mmol, 78% yield, 95% purity, formate).

[0692] QC-LCMS: (ESI) m / z: 792.5 [M+1] +.

[0693] 1H NMR: (400 MHz, DMSO-d6)δ:10.86 (s, 1H), 8.86 (d, J = 8.4 Hz, 1H), 8.57 (s, 2H), 8.16 (s, 1H), 7.75 (d, J = 8.4 Hz, 2H), 7.49 (d, J = 9.2 Hz, 1H), 6.97 (d, J = 9.2 Hz, 2H), 6.65 (d, J = 2.4 Hz, 1H), 6.55 (dd, J = 2.4, 8.4 Hz, 1H), 4.83 - 4.72 (m, 1H), 4.28 (s, 1H), 4.06 (d, J = 9.2 Hz, 1H), 3.92 (s, 3H), 3.88 -3.85 (m, 2H), 2.27 - 2.17 (m, 3H), 2.03 - 2.01 (m, 1H), 1.84 -1.81 (m, 3H), 1.23 (s, 8H), 1.16 (s, 6H).

[0694] Chemical formula: C43H53N9O6, Molecular weight: 791.94

[0695] Example 19 - Synthesis of 5-[4-[[1-[4-[[3-(4-cyano-3-methoxy-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]aminomethyl]phenyl]-4-piperidinyl]methyl]piperidinyl ... -1-yl]-N-[(3S)-2,6-dioxy-3-piperidinyl]pyridine-2-methamide (compound 40)

[0696] Process 14. Overview of the synthesis of compound 40

[0697]

[0698] Step 1: Prepare 5-(4-((1-(4-(((1r,3r)-3-(4-cyano-3-methoxyphenoxy)-2,2,4,4-tetramethylcyclobutyl)aminomethyl)phenyl)piperidin-4-yl)methyl)piperidin Methyl 1-yl)pyridinecarboxylate

[0699] To 5-piperazine Methyl 1-pyridine-2-carboxylate (189 mg, 0.73 mmol, 1.20 eq, hydrochloric acid) was added to a solution of dimethylformamide (6 mL) and dichloromethane (2 mL), along with triethylamine (145.40 mg, 1.44 mmol, 0.2 mL, 2.35 eq), acetic acid (210 mg, 3.50 mmol, 0.2 mL, 5.71 eq), and N-[3-(4-cyano-3-methoxy-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]-4-(4-methoxy-1-piperidinyl)benzamide (300 mg, 0.61 mmol, 1.00 eq). The mixture was stirred at 25 °C for 10 h. Next, sodium triacetylated borohydride (259 mg, 1.23 mmol, 2.00 eq) was added to the mixture and stirred at 25 °C for 1 h. LC-MS showed that the reaction was complete. The mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by preparative high-performance liquid chromatography (column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water (0.1% TFA)-ACN]; B%: 26%-56%, 10 min) to obtain a white solid 5-[4-[[1-[4-[[3-(4-cyano-3-methoxy-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]aminomethyl]phenyl]-4-piperidinyl]methyl]piperidinyl]piperidinyl]phenyl ... Methyl 1-[1-yl]pyridine-2-carboxylate (280 mg, 402.96 μmol, 66% yield).

[0700] LCMS: MS (ESI) m / z: 695.3 [M+1] +

[0701] Chemical formula: C40H50N6O5, Molecular weight: 694.86

[0702] Step 2: Preparation of 5-(4-((1-(4-(((1r,3r)-3-(4-cyano-3-methoxyphenoxy)-2,2,4,4-tetramethylcyclobutyl)aminomethyl)phenyl)piperidin-4-yl)methyl)piperidin -1-yl)pyridinecarboxylic acid

[0703] To 5-[4-[[1-[4-[[3-(4-cyano-3-methoxy-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]aminomethyl]phenyl]-4-piperidinyl]methyl]piperidinyl ... Methyl pyridine-2-carboxylate (280 mg, 0.40 mmol, 1.00 eq) was added to a solution of methanol (6 mL) and water (2 mL) with sodium hydroxide (48.35 mg, 1.21 mmol, 3.00 eq). The mixture was stirred at 50 °C for 10 h. LC-MS showed that the reaction was complete. The mixture was concentrated under reduced pressure to obtain a residue. The residue was adjusted to pH 3-4 with hydrochloric acid (1 M). The mixture was then extracted with ethyl acetate (10 mL × 2). The organic layer was concentrated under reduced pressure to give a white solid of 5-[4-[[1-[4-[[3-(4-cyano-3-methoxy-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]aminomethyl]phenyl]-4-piperidinyl]methyl]piperidinyl]phenyl ... [-1-yl]pyridine-2-carboxylic acid (170.00 mg, 249.69 μmol, 62% yield) was used in the next step without further purification.

[0704] LCMS: MS (ESI) m / z: 681.3 [M+1] +

[0705] Chemical formula: C39H48N6O5, Molecular weight: 680.84

[0706] Step 3: Preparation of 5-(4-((1-(4-(((1r,3r)-3-(4-cyano-3-methoxyphenoxy)-2,2,4,4-tetramethylcyclobutyl)aminomethyl)phenyl)piperidin-4-yl)methyl)piperidin -1-yl)-N-((S)-2,6-di-dioxypiperidin-3-yl)pyridinecarboxamide, compound 40

[0707] To 5-[4-[[1-[4-[[3-(4-cyano-3-methoxy-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]aminomethyl]phenyl]-4-piperidinyl]methyl]piperidinyl ... 1-methylpyridine-2-carboxylic acid (170 mg, 249.69 μmol, 1.00 eq) was added to a solution of dimethylformamide (3 mL). (101 mg, 998.78 μol, 109.81 μL, 4.00 eq), 1-hydroxybenzotriazole (51 mg, 374.54 μol, 1.50 eq), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (72 mg, 374.54 μol, 1.50 eq), and (3S)-3-aminopiperidine-2,6-dione (82.19 mg, 499.39 μol, 2.00 eq, hydrochloric acid). The mixture was stirred at 25 °C for 10 h. LCMS showed that the reaction was complete. The mixture was filtered to obtain the residue. The residue was purified by preparative high-performance liquid chromatography (Phenomenex Synergi C18 150*25*10um column; mobile phase: [water (0.225% FA)-ACN]; B%: 20%-50%, 10 min) to obtain a white solid 5-[4-[[1-[4-[[3-(4-cyano-3-methoxy-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]aminomethyl]phenyl]-4-piperidinyl]methyl]piperidinyl ... -1-yl]-N-[(3S)-2,6-di-sideoxy-3-piperidinyl]pyridine-2-methamide (70.60 mg, 87.39 μmol, 35% yield).

[0708] QC-LCMS: MS (ESI) m / z: 791.4 [M+1] +.

[0709] 1H NMR: (400 MHz, DMSO-d6)δ:10.85 (s, 1H), 8.73 (d, J = 8.4 Hz, 1H), 8.33 (d, J = 2.8 Hz, 1H), 7.87 (d, J = 8.8 Hz, 1H), 7.74 (d, J = 8.8 Hz, 2H), 7.65 (d, J = 8.8 Hz, 1H), 7.50 (d, J = 9.2 Hz, 1H), 7.43 (dd, J = 2.8, 8.4 Hz, 1H), 6.96 (d, J = 9.2 Hz, 2H), 6.64 (d, J = 2.0 Hz, 1H), 6.54 (dd, J = 2.0, 8.8 Hz, 1H), 4.75 (ddd, J = 5.2, 7.6, 12.8 Hz, 1H), 4.27 (s, 1H), 4.05 (d, J = 9.2 Hz, 1H), 3.91 (s, 3H), 3.87 (br dd, J = 2.0, 11.6 Hz, 2H), 3.35 (br s, 4H), 3.30 (br s, 1H), 2.87 - 2.72 (m, 3H), 2.55 (br s, 2H), 2.53 (br d, J = 2.0 Hz, 2H), 2.27 - 2.14 (m, 3H), 2.05 - 1.98 (m, 1H), 1.86 - 1.75 (m, 3H), 1.27 - 1.18 (m, 8H), 1.15 (s, 6H).

[0710] Chemical formula: C44H54N8O6, Molecular weight: 790.95

[0711] Example 20 - Synthesis of 5-[4-[[1-[4-[[3-(4-cyano-3,5-dimethyl-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]aminomethyl]phenyl]-4-piperidinyl]methyl]piperidinyl ... -1-yl]-N-[(3S)-2,6-dioxy-3-piperidinyl]pyridine-2-methamide (compound 41)

[0712] Process 15. Overview of the synthesis of compound 41

[0713] Step 1: Preparation of 4-(6-(methoxycarbonyl)pyridin-3-yl)piperazine -1-Tetrabutyl carboxylate

[0714] Diisopropylethylamine (1.50 g, 11.60 mmol, 2.02 mL, 2.00 eq) and piperazine were added to a solution of methyl 5-fluoropyridine-2-carboxylate (900 mg, 5.80 mmol, 1.00 eq) in dimethyl methoxide (10 mL). 1-Tere-1-carboxylic acid tert-butyl ester (1.08 g, 5.80 mmol, 1.00 eq). The mixture was stirred at 100 °C for 2 h. LC-MS showed that the reaction was complete. The mixture was added to ice water (20 mL) and ethyl acetate (20 mL), and the filter cake was concentrated under reduced pressure to give 4-(6-methoxycarbonyl-3-pyridyl)piperazine as a white solid. -1-Tetrabutyl carboxylate (1.20 g, 3.73 mmol, 64% yield) was used directly in the next step.

[0715] LCMS: MS (ESI) m / z: 322.7 [M+1] +.

[0716] Chemical formula: C16H23N3O4, Molecular weight: 321.37

[0717] Step 2: Preparation of 5-(piperazine) Methyl 1-yl)pyridinecarboxylate

[0718] To 4-(6-methoxycarbonyl-3-pyridyl)piperazine A solution of 1,1-tributyl carboxylate (1.20 g, 3.73 mmol, 1.00 eq) in dichloromethane (30 mL) was prepared by adding hydrochloric acid / dibutyl carboxylate. Alkane (4 M, 4 mL, 4.28 eq). The mixture was stirred at 20 °C for 12 h. LC-MS showed that the reaction was complete. The mixture was filtered and the filter cake was concentrated under reduced pressure to give 5-piperane as a yellow solid. Methyl 1-ylpyridin-2-carboxylate (0.90 g, 3.49 mmol, 93% yield, hydrochloride). This solid is used directly in the next step.

[0719] LCMS: MS (ESI) m / z: 222.2 [M+1] +.

[0720] Chemical formula: C11H15N3O2, Molecular weight: 221.26

[0721] Step 3: Preparation of 5-(4-((1-(4-(((1r,3r)-3-(4-cyano-3,5-dimethylphenoxy)-2,2,4,4-tetramethylcyclobutyl)aminomethyl)phenyl)piperidin-4-yl)methyl)piperidin Methyl 1-yl)pyridinecarboxylate

[0722] To 5-piperazine A solution of methyl 1-pyridine-2-carboxylate (159 mg, 0.61 mmol, 1.00 eq, hydrochloride) in dichloromethane (3 mL) and dimethylformamide (2 mL) was prepared by adding triethylamine (62 mg, 0.61 mmol, 1.00 eq), acetic acid (37 mg, 0.61 mmol, 1.00 eq), and N-[3-(4-cyano-3,5-dimethyl-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]-4-(4-methoxy-1-piperidinyl)benzamide (300 mg, 0.61 mmol, 1.00 eq). The mixture was stirred at 30 °C for 12 h. Then, sodium borohydride (261 mg, 1.23 mmol, 2.00 eq) was added to the mixture. The mixture was then stirred at 30 °C for 1 h. LCMS showed the reaction was complete. Water (20 mL) was added to the reactants and the mixture was extracted with dichloromethane (30 mL × 3). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative high-performance liquid chromatography (column: Phenomenex luna C18 150*40mm*15um; mobile phase: [water (0.1% TFA)-ACN]; B%: 32%-52%, 10 min) to obtain a yellow solid 5-[4-[[1-[4-[[3-(4-cyano-3,5-dimethyl-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]aminomethyl]phenyl]-4-piperidinyl]methyl]piperidinyl]piperidinyl]phenyl ... Methyl 1-[1-yl]pyridine-2-carboxylate (260 mg, 0.37 mmol, 60% yield).

[0723] LCMS: MS (ESI) m / z: 693.4 [M+1] +.

[0724] Chemical formula: C41H52N6O4, Molecular weight: 692.89

[0725] Step 4: Preparation of 5-(4-((1-(4-(((1r,3r)-3-(4-cyano-3,5-dimethylphenoxy)-2,2,4,4-tetramethylcyclobutyl)aminomethyl)phenyl)piperidin-4-yl)methyl)piperidin -1-yl)pyridinecarboxylic acid

[0726] To 5-[4-[[1-[4-[[3-(4-cyano-3,5-dimethyl-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]aminomethyl]phenyl]-4-piperidinyl]methyl]piperidinyl ... methyl 5-[4-[[1-[4-[[3-(4-cyano-3,5-dimethyl-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]aminomethyl]phenyl]-4-piperidinyl]methyl]piperidinyl]pyridine-2-carboxylate (260 mg, 0.37 mmol, 1.00 eq) was added to a solution of tetrahydrofuran (5 mL), methanol (5 mL), and water (5 mL). Sodium hydroxide (120 mg, 3.00 mmol, 8.00 eq) was added. The mixture was stirred at 50 °C for 12 h. LC-MS showed that the reaction was complete. The mixture was adjusted to pH 5 with diluted hydrochloric acid (6 M). The mixture was then filtered and the filter cake was concentrated under reduced pressure to give a yellow solid, 5-[4-[[1-[4-[[3-(4-cyano-3,5-dimethyl-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]aminomethyl]phenyl]-4-piperidinyl]methyl]piperidinyl]phenyl]pyridine-2-carboxylate. [-1-yl]pyridine-2-carboxylic acid (200 mg, 0.27 mmol, 74% yield, hydrochloride).

[0727] LCMS: MS (ESI) m / z: 679.2 [M+1] +.

[0728] Chemical formula: C40H50N6O4, Molecular weight: 678.86

[0729] Step 5: Preparation of 5-(4-((1-(4-(((1r,3r)-3-(4-cyano-3,5-dimethylphenoxy)-2,2,4,4-tetramethylcyclobutyl)aminomethyl)phenyl)piperidin-4-yl)methyl)piperidin -1-yl)-N-((S)-2,6-di-dioxypiperidin-3-yl)pyridinecarboxamide, compound 41

[0730] To 5-[4-[[1-[4-[[3-(4-cyano-3,5-dimethyl-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]aminomethyl]phenyl]-4-piperidinyl]methyl]piperidinyl ... 4-methyl-1-yl]pyridine-2-carboxylic acid (200 mg, 0.27 mmol, 1.00 eq, hydrochloride) was added to a solution of dimethylformamide (2 mL). Phosphorus (141 mg, 1.40 mmol, 5.00 eq), hydroxybenzotriazole (45 mg, 0.33 mmol, 1.20 eq), and 3-(ethyliminomethyleneamino)-N,N-dimethyl-prop-1-amine; hydrochloride (64 mg, 0.33 mmol, 1.20 eq), and (3S)-3-aminopiperidin-2,6-dione (69 mg, 0.41 mmol, 1.50 eq, hydrochloride). The mixture was stirred at 20 °C for 12 h. The reaction was complete as indicated by LCMS. Dichloromethane (20 mL) and water (20 mL) were added to the mixture. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative high-performance liquid chromatography (pHPLC) (column: Shim-pack C18 150*25*10um; mobile phase: [water (0.225% FA)-ACN]; B%: 26%-56%, 10 min) to obtain a white solid 5-[4-[[1-[4-[[3-(4-cyano-3,5-dimethyl-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]aminomethyl]phenyl]-4-piperidinyl]methyl]piperidinyl ... -1-yl]-N-[(3S)-2,6-di-sideoxy-3-piperidinyl]pyridine-2-methamide (60.10 mg, 0.07 mmol, 26% yield, 99% purity).

[0731] QC-LCMS: MS (ESI) m / z: 791.4 [M+1] +.

[0732] 1H NMR: (400 MHz, DMSO-d6)δ: 10.85 (s, 1H), 8.73 (d, J = 8.0 Hz, 1H), 8.33 (d, J = 2.8 Hz, 1H), 8.14 (s, 1H), 7.87 (d, J = 8.8 Hz, 1H), 7.74 (d, J = 8.8 Hz, 2H), 7.51 - 7.39 (m, 2H), 6.97 (d, J = 9.2 Hz, 2H), 6.74 (s, 2H), 4.81 - 4.66 (m, 1H), 4.23 (s, 1H), 4.04 (d, J = 9.2 Hz, 1H), 3.87 (br d, J = 12.0 Hz, 2H), 2.53 (br d, J = 2.0 Hz, 6H), 2.44 (s, 6H), 2.05 - 1.96 (m, 1H), 1.82 (br d, J = 11.6 Hz, 3H), 1.22 (s, 8H), 1.13 (s, 6H).

[0733] Chemical formula: C45H56N8O5, Molecular weight: 788.98

[0734] Example 21 - Synthesis of 4-[(2R)-2-([isopropyl[(1R,3R)-3-(4-[[(3S)-2,6-di-sideoxypiperidin-3-yl]aminomethyl]-3-fluorophenoxy)cyclobutyl]amino]methyl) [Lin-4-yl]-N-[(1R,3R)-3-(4-cyano-3-methoxyphenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide ((compound 43) and 4-[(2S)-2-([isopropyl[(1R,3R)-3-(4-[[(3S)-2,6-di-side-oxypiperidin-3-yl]aminomethyl]-3-fluorophenoxy)cyclobutyl]amino]methyl) [Lin-4-yl]-N-[(1R,3R)-3-(4-cyano-3-methoxyphenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide (compound 44):

[0735] Procedure 16. Overview of the synthesis of compounds 43 and 44

[0736] Step 1: Synthesis of 4-[(2R)-2-(hydroxymethyl)] Tertiary butyl benzoate of 4-yl]lin-4-yl]benzoate

[0737] Place (2R)- into a 250 mL round-bottom flask 25 mL of DMSO was prepared with lin-2-ylmethanol (10.0 g, 85.4 mmol, 1.0 equivalent), tributyl 4-fluorobenzoate (16.7 g, 85.4 mmol, 1.0 equivalent), and DIEA (33.1 g, 25.1 mmol, 3.0 equivalent). The solution was stirred in an oil bath at 120 °C for 16 hours. The reactants were then quenched by adding 10 mL of water. The resulting solution was extracted with ethyl acetate (50 mL × 2), dried over anhydrous sodium sulfate, and concentrated. The residue was fed onto a silicone column with ethyl acetate / petroleum ether (1:1). This produced 4.5 g (18%) of a yellow oil containing 4-[(2R)-2-(hydroxymethyl)]. [Pin-4-yl ester] Tertiary butyl benzoate.

[0738] LC-MS (ES+): m / z 294.40[MH+], tR = 1.58min (running for 2.9 minutes).

[0739] Step 2: Synthesize 4-[(2R)-2-methoxy] Tertiary butyl benzoate of 4-yl]lin-4-yl]benzoate

[0740] Place 20 mL of DCM into a 250 mL three-necked round-bottom flask purged and maintained under an inert nitrogen atmosphere. Then add 1.5 mL of (COCl)₂ at -78 °C. Next, add a solution of 3 mL of DMSO to the DCM mixture at -78 °C. Finally, add 4-[(2R)-2-(hydroxymethyl)]₂ to the mixture at -78 °C. A solution of 4-[(2R)-2-methylbenzoate]tert-butyl benzoate (2.0 g) in DCM (10 mL) was prepared. A solution of TEA (6 mL) in DCM (15 mL) was added to the mixture at -78 °C. The solution was stirred at -78 °C for 1.5 hours. The reactants were then quenched by adding 100 mL of water. The solution was extracted with dichloromethane (100 mL × 3) and the organic layers were combined. The mixture was washed with brine. The mixture was dried over anhydrous sodium sulfate. The solid was filtered off. The mixture was concentrated under vacuum. This produced 1.37 g of a yellow oily substance of 4-[(2R)-2-methylbenzoate]. [Pin-4-yl ester] Tertiary butyl benzoate.

[0741] Step 3: 4-[2-([isopropyl[(1r, 3r)-3-[3-fluoro-4-(methoxycarbonyl)phenoxy]cyclobutyl]amino]methyl) Tertiary butyl benzoate of 4-yl]lin-4-yl]benzoate

[0742] Place 4-[(2R)-2-methoxyl] into a 100 mL round-bottom flask The reaction mixture consisted of DCE (3 mL) of methyl 2-fluoro-4-[(1r, 3r)-3-(isopropylamino)cyclobutoxy]benzoate (1.1 g, 3.9 mmol, 1.0 equivalent) and STAB (2.5 g, 0.1 mmol, 3.0 equivalent). The resulting solution was stirred at room temperature for 2 hours. The reactants were then quenched by adding 1 mL of water. The resulting solution was extracted with dichloromethane (20 mL × 2), dried over anhydrous sodium sulfate, and concentrated. The residue was then applied to a silicone column with ethyl acetate / petroleum ether (1:1). This produces 650.0 mg (31%) of a yellow solid containing 4-[2-([isopropyl[(1r, 3r)-3-[3-fluoro-4-(methoxycarbonyl)phenoxy]cyclobutyl]amino]methyl) Tertiary butyl benzoate of 4-yl]lin-4-yl]benzoate

[0743] LC-MS (ES+): m / z 557.35 [MH+], tR = 2.41 min (running for 2.9 minutes)

[0744] Step 4: Synthesis of 4-[2-([isopropyl[(1r, 3r)-3-[3-fluoro-4-(methoxycarbonyl)phenoxy]cyclobutyl]amino]methyl) [Lin-4-yl]benzoic acid: Place 4-[2-([isopropyl[(1r, 3r)-3-[3-fluoro-4-(methoxycarbonyl)phenoxy]cyclobutyl]amino]methyl) into a 50 mL round-bottom flask. [P-4-yl ester]tert-butyl benzoate (650.0 mg, 1.2 mmol, 1.0 equivalent) in DCM (10 mL) and trifluoroacetaldehyde (5 mL). The resulting solution was stirred at room temperature for 1 hour. The resulting mixture was concentrated. This produced 495.0 mg (84%) of a yellow oil of 4-[2-([isopropyl[(1r,3r)-3-[3-fluoro-4-(methoxycarbonyl)phenoxy]cyclobutyl]amino]methyl) [Lin-4-yl]benzoic acid

[0745] LC-MS (ES+): m / z 501.2 [MH+], tR = 1.32 min (running for 4.9 minutes)

[0746] Step 5: Synthesize 2-fluoro-4-[(1r, 3r)-3-[isopropyl([[4-(4-[[(1r, 3r)-3-(4-cyano-3-methoxyphenoxy)-2,2,4,4-tetramethylcyclobutyl]aminomethyl]phenyl) Methyl benzoate containing 4-[2-([isopropyl[(1r,3r)-3-[3-fluoro-4-(methoxycarbonyl)phenoxy]cyclobutyl]amino]methyl] The following were prepared in DMF (5 mL) of lino-4-yl]benzoic acid (495.0 mg, 0.9 mmol, 1.0 equivalent), 2-methoxy-4-[(1r,3r)-3-amino-2,2,4,4-tetramethylcyclobutoxy]benzonitrile (271.3 mg, 0.9 mmol, 1.0 equivalent), DIEA (383.4 mg, 2.9 mmol, 3.0 equivalent), and BOP (524.8 mg, 1.2 mmol, 1.2 equivalent). The resulting solution was stirred at room temperature for 1 hour. The reactants were then quenched by adding 2 mL of water. The resulting solution was extracted with ethyl acetate (20 mL × 2), dried over anhydrous sodium sulfate, and concentrated. The residue was fed onto a silicone column with ethyl acetate / petroleum ether (2:1). This produces 435.0 mg (58%) of 2-fluoro-4-[(1r, 3r)-3-[isopropyl([[4-(4-[[(1r, 3r)-3-(4-cyano-3-methoxyphenoxy)-2,2,4,4-tetramethylcyclobutyl]aminomethyl]phenyl) as a yellow solid. Methyl benzoate of 2-yl]methyl]amino]cyclobutoxy]benzoate.

[0747] LC-MS (ES+): m / z 757.2 [MH+], tR = 3.49 min (running for 4.9 minutes)

[0748] Step 6: Synthesis of 2-fluoro-4-[(1r,3r)-3-[isopropyl([[4-(4-[[(1r,3r)-3-(4-cyano-3-methoxyphenoxy)-2,2,4,4-tetramethylcyclobutyl]aminomethyl]phenyl) [Lin-2-yl]methyl]amino]cyclobutoxy]benzoic acid: Place 2-fluoro-4-[(1r, 3r)-3-[isopropyl([[4-(4-[[(1r,3r)-3-(4-cyano-3-methoxyphenoxy)-2,2,4,4-tetramethylcyclobutyl]aminomethyl]phenyl) into a 100 mL round-bottom flask. Methyl benzoate (435.0 mg, 0.6 mmol, 1.0 equivalent) in MeOH (5 mL) and H₂O (91.9 mg, 2.3 mmol, 4.0 equivalent) in H₂O (2.00 mL). The solution was stirred at room temperature for 2 hours. The solution was extracted with ethyl acetate (20 mL × 2), dried over anhydrous sodium sulfate, and concentrated. This yielded 380.0 mg (89%) of 2-fluoro-4-[(1r, 3r)-3-[isopropyl([[4-(4-[[(1r, 3r)-3-(4-cyano-3-methoxyphenoxy)-2,2,4,4-tetramethylcyclobutyl]aminomethyl]phenyl) as a yellow solid. [Lin-2-yl]methyl]amino]cyclobutoxy]benzoic acid.

[0749] LC-MS (ES+): m / z 743.35 [MH+], tR = 1.26 min (running for 2.9 minutes)

[0750] Step 7a. Synthesis of 4-[(2R)-2-([isopropyl[(1r, 3r)-3-(4-[[(3S)-2,6-di-side-oxypiperidin-3-yl]aminomethyl]-3-fluorophenoxy)cyclobutyl]amino]methyl) [Lin-4-yl]-N-[(1r, 3r)-3-(4-cyano-3-methoxyphenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide, Compound 43: Place 2-fluoro-4-[(1r, 3r)-3-[isopropyl([[4-(4-[[(1r, 3r)-3-(4-cyano-3-methoxyphenoxy)-2,2,4,4-tetramethylcyclobutyl]aminomethyl]phenyl) into a 50 mL round-bottom flask. [Lin-2-yl]methyl]amino]cyclobutoxy]benzoic acid (280.0 mg, 0.4 mmol, 1.0 equivalent), (3S)-3-aminopiperidin-2,6-dione (72.4 mg, 0.5 mmol, 1.5 equivalent) in DMF (3 mL), NMM (114.4 mg, 1.1 mmol, 3.0 equivalent), HOBT (61.1 mg, 0.4 mmol, 1.2 equivalent), and EDCI (86.7 mg, 0.4 mmol, 1.2 equivalent). The resulting solution was stirred at room temperature for 4 hours. The reactants were then quenched by adding 1 mL of water. The resulting solution was extracted with ethyl acetate (20 mL × 2), dried over anhydrous sodium sulfate, and concentrated. The residue was fed onto a silicone column with dichloromethane / methanol (10:1). The crude product was purified by preparative HPLC under the following conditions: MTBE (0.1% DEA): EtOH = 50:50, column: ChiralWHELK-014, size: 6*50mm, 3.5 μm; this yielded 74.9 mg (23%) of a grayish-white solid, 4-[(2R)-2-([isopropyl[(1r,3r)-3-(4-[[(3S)-2,6-dioxypiperidin-3-yl]aminomethyl]-3-fluorophenoxy)cyclobutyl]amino]methyl) [Lin-4-yl]-N-[(1r,3r)-3-(4-cyano-3-methoxyphenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide.

[0751] 1H NMR (400 MHz, DMSO-d6) δ 10.90 (s, 1H),8.45-8.20 (m, 1H), 7.90-7.73 (m, 2H),7.72-7.60 (m, 2H), 7.59-7.42 (m, 1H), 7.06-6.87 (m, 2H), 6.86-6.70 (m, 2H), 6.69-6.60 (m, 1H), 6.59-6.45 (m, 1H), 4.90-4.69 (m, 2H), 4.33-4.21 (m, 1H), 4.15-4.00 (m, 1H), 3.99-3.83 (m, 4H), 3.82-3.45 (m, 7H), 3.05-2.90 (m, 1H), 2.85-2.70 (m, 2H), 2.46-2.35 (m, 3H), 2.22-1.83 (m, 4H), 1.25-1.20 (m, 7H),1.18-1.10 (m, 6H), 1.05-0.88 (m, 6H).

[0752] LC-MS (ES+): m / z 853.45 [MH+], tR = 3.61 min (running for 4.9 minutes).

[0753] Chemical formula: C47H57FN6O8 [852.42]

[0754] Step 7b. Synthesis of 4-[(2S)-2-([isopropyl[(1r, 3r)-3-(4-[[(3S)-2,6-dioxypiperidin-3-yl]aminomethyl]-3-fluorophenoxy)cyclobutyl]amino]methyl) [Lin-4-yl]-N-[(1r, 3r)-3-(4-cyano-3-methoxyphenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide, Compound 44: Place 2-fluoro-4-[(1r, 3r)-3-[isopropyl([[4-(4-[[(1r, 3r)-3-(4-cyano-3-methoxyphenoxy)-2,2,4,4-tetramethylcyclobutyl]aminomethyl]phenyl) into a 50 mL round-bottom flask. [Lin-2-yl]methyl]amino]cyclobutoxy]benzoic acid (280.0 mg, 0.4 mmol, 1.0 equivalent), (3S)-3-aminopiperidin-2,6-dione (72.4 mg, 0.5 mmol, 1.5 equivalent) in DMF (3 mL), NMM (114.4 mg, 1.1 mmol, 3.0 equivalent), HOBT (61.1 mg, 0.4 mmol, 1.2 equivalent), and EDCI (86.7 mg, 0.4 mmol, 1.2 equivalent). The resulting solution was stirred at room temperature for 4 hours. The reactants were then quenched by adding 1 mL of water. The resulting solution was extracted with ethyl acetate (20 mL × 2), dried over anhydrous sodium sulfate, and concentrated. The residue was fed onto a silicone column with dichloromethane / methanol (10:1). The crude product was purified by preparative HPLC under the following conditions: MTBE (0.1% DEA): EtOH = 50:50, column: ChiralWHELK-014, size: 6*50mm, 3.5 μm; this yielded 58.1 mg (18%) of a grayish-white solid of 4-[(2S)-2-([isopropyl[(1r,3r)-3-(4-[[(3S)-2,6-di-side-oxypiperidin-3-yl]aminomethyl]-3-fluorophenoxy)cyclobutyl]amino]methyl) [Lin-4-yl]-N-[(1r,3r)-3-(4-cyano-3-methoxyphenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide.

[0755] 1H NMR (400 MHz, DMSO-d6) δ 10.85 (s, 1H), 8.52-8.15 (m, 1H), 7.88-7.72 (m, 2H),7.71-7.57 (m, 2H), 7.56-7.35 (m, 1H),7.15-6.87 (m, 2H), 6.86-6.70 (m, 2H), 6.69-6.59 (m, 1H), 6.58-6.40 (m, 1H), 4.95-4.63 (m, 2H), 4.40-4.23 (m, 1H), 4.10-4.00 (m, 1H), 3.99-3.95 (m, 1H), 3.94-3.88 (m, 3H), 3.86-3.75 (m, 1H), 3.70-3.60 (m, 3H), 3.59-3.48 (m, 1H), 3.47-3.40 (m, 1H), 3.05-2.92 (m, 1H), 2.85-2.70 (m, 2H), 2.55-2.50 (m, 2H), 2.48-2.32 (m, 3H), 2.30-2.05 (m, 3H), 2.04-1.90 (m, 1H), 1.30-1.21 (m, 6H), 1.20-1.03 (m, 6H), 1.01-0.80 (m, 6H).

[0756] LC-MS (ES+): m / z 853.45 [MH+], tR = 2.03 min (running for 2.9 min). Chemical formula: C47H57FN6O8 [852.42]

[0757] Example 22 - Synthesis of N-[(3R)-2,6-dioxypiperidin-3-yl]-2-fluoro-4-(4-[[(2R)-4-(4-[[(1R,3R)-3-(4-cyano-3,5-dimethylphenoxy)-2,2,4,4-tetramethylcyclobutyl]aminomethyl]phenyl) [Prin-2-yl]methyl]piperazine -1-yl)benzoylamine (compound 48) and N-[(3S)-2,6-dioxypiperidin-3-yl]-2-fluoro-4-(4-[[(2R)-4-(4-[[(1R,3R)-3-(4-cyano-3,5-dimethylphenoxy)-2,2,4,4-tetramethylcyclobutyl]aminomethyl]phenyl) [Prin-2-yl]methyl]piperazine -1-yl)benzamide; bis(formic acid) (compound 49)

[0758] Process 17. Overview of the synthesis of compounds 48 and 49.

[0759] Step 1: Synthesis of 4-[(2S)-2-(hydroxymethyl)] Tertiary butyl benzoate of 4-yl]lin-4-yl]benzoate

[0760] Place [(2S)-] into a 50-mL round-bottom flask 8.00 mL of DMSO was prepared with 200.00 mg (1.30 mmol, 1.00 equivalent) of lin-2-yl]methanol hydrochloride, to which DIEA (841.37 mg, 6.51 mmol, 5.00 equivalent) and tributyl 4-fluorobenzoate (383.22 mg, 1.95 mmol, 1.50 equivalent) were added. The solution was stirred in an oil bath at 120 °C for 30 hours. The reaction mixture was cooled to room temperature. The solution was diluted with 50 mL of DCM. The mixture was washed with 50 mL of H2O and (3 × 50 mL) of brine. The mixture was dried over anhydrous sodium sulfate. The solid was filtered off. The mixture was concentrated under vacuum. This produced 180 mg (crude matter) of 4-[(2S)-2-(hydroxymethyl)] as a pale yellow oil. Tertiary butyl benzoate of 4-yl]lin-benzoate.

[0761] LC-MS (ES+): m / z 294.10 [M+H+], tR = 0.93 min (running for 1.9 minutes).

[0762] Step 2: Synthesis of 4-[(2S)-2-methoxy] Tertiary butyl benzoate of 4-yl]lin-4-yl]benzoate

[0763] A 100-mL three-necked round-bottom flask containing 0.40 mL (COCl)₂ (4.70 mmol, 9.18 equivalents) of DCM was placed in the flask. After purging and maintaining an inert nitrogen atmosphere, a 6.00 mL (0.80 mL, 11.26 mmol, 22.03 equivalents) DCM of DMSO was added. After the addition was complete, the mixture was stirred at -78°C for 5 min, followed by the addition of 4-[(2S)-2-(hydroxymethyl)] at -78°C for 20 min. A solution of tert-butyl 4-[(2S)-2-methylbenzoate](150.00 mg, 0.51 mmol, 1.00 equivalent) was prepared in DCM (6.00 mL) and stirred for 20 min. Then, Et3N (3.50 mL, 25.18 mmol, 49.25 equivalent) was added dropwise over 10 min. The resulting solution was heated to 0°C and stirred at 0°C for 1 hour, followed by 30 min. The reactants were then quenched by adding 50 mL of water. The resulting solution was diluted with 50 mL of DCM. The mixture was washed with 50 mL of H2O and (3 × 50 mL) of brine. The mixture was dried over anhydrous sodium sulfate. The solid was filtered off. The mixture was concentrated under vacuum. This produced 120 mg (crude matter) of 4-[(2S)-2-methylbenzoate](crude matter) as a yellow solid. Tertiary butyl benzoate of 4-yl]lin-benzoate.

[0764] Step 3: Synthesis of 4-(4-[(2R)-4-[4-(tert-butoxycarbonyl)phenyl] [Prin-2-yl]methyl]piperazine Methyl 1-(1-yl)-2-fluorobenzoate

[0765] Place 4-[(2S)-2-methoxy] into a 100-mL round-bottom flask [Lin-4-yl]tert-butyl benzoate (950 mg, 3.26 mmol, 1.00 equivalent), DCE (25 mL), MeOH (10 mL), 2-fluoro-4-(piperazine) Methyl benzoate (780 mg, 3.26 mmol, 1.00 equivalent) and STAB (690 mg, 3.26 mmol, 1.00 equivalent) were stirred at room temperature for 15 min. The resulting mixture was washed with 1 × 60 mL of water. The resulting solution was extracted with 3 × 60 mL of dichloromethane, and the organic layers were combined and dried over anhydrous sodium sulfate. The solid was filtered off. The resulting mixture was concentrated. The residue was applied to a silicone column with ethyl acetate / petroleum ether (0%:100% to 30%:70%). This produced 515 mg (31%) of 4-(4-[[(2R)-4-[4-(tert-butoxycarbonyl)phenyl] as a grayish-white solid. [Prin-2-yl]methyl]piperazine Methyl 1-(1-yl)-2-fluorobenzoate. LC-MS (ES+): m / z 514.25 [MH+], tR = 0.64 min (run for 1.2 minutes).

[0766] Step 4: Synthesis of 4-(4-[(2R)-4-[4-(tert-butoxycarbonyl)phenyl] [Prin-2-yl]methyl]piperazine -1-yl)-2-fluorobenzoic acid Place 4-(4-[(2R)-4-[4-(tert-butoxycarbonyl)phenyl] into a 250 mL round-bottom flask. [Prin-2-yl]methyl]piperazine Methyl 1-(4-(2R)-2-fluorobenzoate (540 mg, 1.05 mmol, 1.00 equivalent), MeOH (40 mL), H₂O (12 mL), LiOH·H₂O (880 mg, 21.04 mmol, 20.00 equivalent). The resulting solution was stirred at 40 °C for 3 hours. The mixture was concentrated under vacuum. The pH of the solution was adjusted to 7 with HCl / H₂O (1 mol / L). The solid was collected by filtration. This yielded 0.39 g (74%) of 4-(4-[[(2R)-4-[4-(tert-butoxycarbonyl)phenyl] as a pale yellow solid. [Prin-2-yl]methyl]piperazine -1-yl)-2-fluorobenzoic acid.

[0767] LC-MS (ES+): m / z 500.30 [MH+], tR = 0.79 min (run for 1.5 minutes).

[0768] Step 5: Synthesis of 4-[(2R)-2-[[4-(4-[[(3S)-2,6-di-sideoxypiperidin-3-yl]aminomethoxy]-3-fluorophenyl)piperidin -1-yl]methyl] Tertiary butyl benzoate of 4-yl]lin-4-yl]benzoate Place 4-(4-[(2R)-4-[4-(tert-butoxycarbonyl)phenyl)] into a 100-mL round-bottom flask. [Prin-2-yl]methyl]piperazine (-1-yl)-2-fluorobenzoic acid (330 mg, 0.66 mmol, 1.00 equivalent), DMF (20 mL), HATU (380 mg, 0.99 mmol, 1.50 equivalent), DIEA (850 mg, 6.62 mmol, 10.00 equivalent) in DMF (15 mL), and (3S)-3-aminopiperidine-2,6-dione (130 mg, 1.02 mmol, 1.50 equivalent). The resulting solution was stirred at room temperature for 1 hour. The reactants were then quenched by adding 50 mL of water. The resulting solution was extracted with 3 × 50 mL of ethyl acetate, and the organic layers were combined. The resulting mixture was washed with 1 × 100 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied to a silicone column with dichloromethane / methanol (15:1). This produces 302 mg (74%) of 4-[(2R)-2-[[4-(4-[[(3S)-2,6-dioxypiperidin-3-yl]aminomethyl]-3-fluorophenyl)piperidin-3-yl]aminomethyl ... -1-yl]methyl] Tertiary butyl benzoate of 4-yl]lin-benzoate.

[0769] LC-MS (ES+): m / z 610.30 [MH+], tR = 0.57 min (run for 1.2 minutes).

[0770] Step 6: Synthesis of 4-[(2R)-2-[[4-(4-[[(3S)-2,6-di-sideoxypiperidin-3-yl]aminomethoxy]-3-fluorophenyl)piperidin -1-yl]methyl] [Lin-4-yl]benzoic acid Place 4-[(2R)-2-[[4-(4-[[(3S)-2,6-di-sideoxypiperidin-3-yl]aminomethoxy]-3-fluorophenyl)piperidin into a 100-mL round-bottom flask -1-yl]methyl] Tertiary butyl benzoate (400 mg, 0.66 mmol, 1.50 equivalent), dichloromethane (20 mL), and TFA (5 mL) were added. The resulting solution was stirred at room temperature for 30 min. The mixture was concentrated under vacuum. The residue was applied to a silicone column with dichloromethane / methanol (5:1). This produced 113 mg (30%) of 4-[(2R)-2-[[4-(4-[[(3S)-2,6-di-side-oxypiperidin-3-yl]aminomethyl]-3-fluorophenyl)piperidin as a grayish-white solid. -1-yl]methyl] [Lin-4-yl]benzoic acid.

[0771] LC-MS (ES+): m / z 554.20 [MH+], tR = 0.45 min (run for 1.2 minutes).

[0772] Step 7a: Synthesis of N-[(3R)-2,6-di-side-oxypiperidin-3-yl]-2-fluoro-4-(4-[[(2R)-4-(4-[[(1r,3r)-3-(4-cyano-3,5-dimethylphenoxy)-2,2,4,4-tetramethylcyclobutyl]aminomethyl]phenyl) [Prin-2-yl]methyl]piperazine -1-yl)benzylamine, compound 48:

[0773] Place 4-[(2R)-2-[[4-(4-[[(3S)-2,6-di-sideoxypiperidin-3-yl]aminomethoxy]-3-fluorophenyl)piperidin into a 100-mL round-bottom flask -1-yl]methyl] [Lin-4-yl]benzoic acid (90.00 mg, 0.16 mmol, 1.00 equivalent), DMF (12 mL), HATU (92.80 mg, 0.24 mmol, 1.50 equivalent), DIEA (209.90 mg, 1.62 mmol, 10.00 equivalent) in DMF (2 mL), and 2,6-dimethyl-4-[(1r,3r)-3-amino-2,2,4,4-tetramethylcyclo-butoxy]benzonitrile (61.00 mg, 0.20 mmol, 1.20 equivalent). The resulting solution was stirred at room temperature for 10 min. The mixture was washed with 1 × 30 mL of water. The resulting solution was extracted with 3 × 30 mL of ethyl acetate and the organic layers were combined. The mixture was washed with 1 × 50 mL of brine. The mixture was dried over anhydrous sodium sulfate. The solid was filtered off. The mixture was concentrated under vacuum. The residue was applied to a silica gel column along with dichloromethane / methanol (15:1). The crude product was purified by Flash-Prep-HPLC under the following conditions: column, C18 silica gel; mobile phase, H2O / methanol = 100% / 0% gradually increased to H2O / methanol = 14% / 86% over 45 min; detector. The product was purified by palmar separation under the following conditions: column: Chiralpak IC, 2*25cm, 5µm; mobile phase A: DCM, mobile phase B: EtOH (8mmol / L NH3·MeOH); flow rate: 20 mL / min; gradient: 50% B / 50% B over 11 min; 220 / 254 nm; this produced 21.5 mg of N-[(3R)-2,6-dioxypiperidin-3-yl]-2-fluoro-4-(4-[[(2R)-4-(4-[[(1r,3r)-3-(4-cyano-3,5-dimethylphenoxy)-2,2,4,4-tetramethylcyclobutyl]aminomethyl]phenyl) as a white solid. [Prin-2-yl]methyl]piperazine -1-yl)benzamide (exploratory designation of absolute stereochemistry).

[0774] 1HNMR (400 MHz, DMSO-d6) δ 10.85 (s, 1H), 8.06 (m, 1H), 7.78 (m, 2H), 7.64 (m, 1H), 7.53 (m, 1H),7.00 (m, 2H), 6.87 - 6.72 (m, 4H), 4.73 (s, 1H), 4.23 (s, 1H), 4.04 (m, 3H), 3.77 (m, 5H), 2.77 (m, 3H), 2.60 (m, 6H), 2.43 (s, 5H), 2.18-1.92 (m, 4H), 1.22 -1.12 (m, 14H); LC-MS (ES+): m / z 808.25 [M+H+], tR = 1.21 min (running for 3.00 minutes).

[0775] Chemical formula: C45H54FN7O6 [807.41]

[0776] Step 7b: Synthesis of N-[(3R)-2,6-di-side-oxypiperidin-3-yl]-2-fluoro-4-(4-[[(2R)-4-(4-[[(1r,3r)-3-(4-cyano-3,5-dimethylphenoxy)-2,2,4,4-tetramethylcyclobutyl]aminomethyl]phenyl) [Prin-2-yl]methyl]piperazine -1-yl)benzylamine, compound 49: Place 4-[(2R)-2-[[4-(4-[[(3S)-2,6-di-sideoxypiperidin-3-yl]aminomethoxy]-3-fluorophenyl)piperidin into a 100-mL round-bottom flask -1-yl]methyl] [Lin-4-yl]benzoic acid (90.00 mg, 0.16 mmol, 1.00 equivalent), DMF (12 mL), HATU (92.80 mg, 0.24 mmol, 1.50 equivalent), DIEA (209.90 mg, 1.62 mmol, 10.00 equivalent) in DMF (2 mL), and 2,6-dimethyl-4-[(1r,3r)-3-amino-2,2,4,4-tetramethylcyclo-butoxy]benzonitrile (61.00 mg, 0.20 mmol, 1.20 equivalent). The resulting solution was stirred at room temperature for 10 min. The mixture was washed with 1 × 30 mL of water. The resulting solution was extracted with 3 × 30 mL of ethyl acetate and the organic layers were combined. The mixture was washed with 1 × 50 mL of brine. The mixture was dried over anhydrous sodium sulfate. The solid was filtered off. The mixture was concentrated under vacuum. The residue was applied to a silicone column along with dichloromethane / methanol (15:1). The crude product (90.00 mg) was purified by Flash-Prep-HPLC (IntelFlash-1) under the following conditions: column, C18 silicone; mobile phase, H2O / MeOH = 100% / 0% gradually increased to H2O / MeOH = 14% / 86% over 45 min; detector. The product (60.00 mg) was purified by tactile separation under the following conditions: column: Chiralpak IC, 2*25cm, 5µm; mobile phase A: DCM, mobile phase B: EtOH (8mmol / L NH3·MeOH); flow rate: 20 mL / min; gradient: 50 B / 50 B over 11 min; 220 / 254 nm; RT1: 5.86; RT2: 9.36; product obtained. This produces 11.2 mg of N-[(3S)-2,6-di-sideoxypiperidin-3-yl]-2-fluoro-4-(4-[[(2R)-4-(4-[[(1r,3r)-3-(4-cyano-3,5-dimethylphenoxy)-2,2,4,4-tetramethylcyclobutyl]aminomethyl]phenyl) as a white solid. [Prin-2-yl]methyl]piperazine -1-yl)benzamide; bis(formic acid) (tentatively specified stereochemistry).

[0777] 1H NMR (400 MHz, DMSO-d6) δ 10.85 (s, 1H), 8.06 (m, 1H), 7.78 (m, 2H), 7.64 (m, 1H), 7.53 (m, 1H), 7.00 (m, 2H), 6.87 (m, 1H), 6.72 (m, 3H), 4.73 (s, 1H), 4.23 (s, 1H), 4.04 (m, 2H), 3.43-3.82 (m, 6H), 2.77 (m, 3H), 2.60 (m, 6H), 2.43 (m, 5H), 2.28-1.92 (m, 4H), 1.22 (s, 7H), 1.12 (s, 7H); LC-MS (ES+): m / z 808.20 [M+H+], tR = 1.17 min (running for 3.00 minutes).

[0778] Chemical formula: C45H54FN7O6 [807.41]

[0779] Example 23 - Synthesis of (31R,33R)-4-((1-(4-(((1R,3R)-3-(4-cyano-3,5-dimethylphenoxy)-2,2,4,4-tetramethylcyclobutyl)aminomethyl)phenyl)piperidin-4-yl)methyl)-N-(2,6-dioxypiperidin-3-yl)-2,7,12-trioxa-4-aza-1(1,2)-benzene-3(1,3)cyclobutanecyclododecane-14-methylamine (Compound 64)

[0780] Procedure 18: Overview of the synthesis of compound 64

[0781] Step 1: Methyl 4-benzoxy-3-hydroxybenzoate

[0782] Benzyl bromide (10.17 g, 59.47 mmol, 1.00 eq) was added to a solution of methyl 3,4-dihydroxybenzoate (10.00 g, 59.47 mmol, 1.00 eq) and potassium carbonate (8.22 g, 59.47 mmol, 1.00 eq) in acetonitrile (120 mL). The mixture was stirred at 80 °C for 12 h under a hydrogen atmosphere. The reaction was complete by LC-MS. The mixture was filtered. The filtrate was concentrated under reduced pressure to obtain a residue. The residue was diluted with water (100 mL) and extracted with dichloromethane (200 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by silicone column chromatography (petroleum ether: ethyl acetate = 20:1 to 10:1) to give methyl 4-benzoxy-3-hydroxybenzoate as a white solid (12.00 g, 46.46 mmol, 78% yield).

[0783] LCMS: MS (ESI) m / z: 259.1[M+1]+.

[0784] 1H NMR: (400 MHz, CDCl3)δ:7.69 - 7.57 (m, 2 H), 7.50 - 7.35 (m, 5 H), 6.97 (d, J=8.4 Hz, 1 H), 5.82 - 5.70 (m, 1 H), 5.19 (s, 2 H), 3.94 - 3.84 (m, 3 H).

[0785] Chemical formula: C15H14O4, molecular weight: 258.27

[0786] Step 2: Preparation of methyl 4-benzoxy-3-(2-trimethylsilylethoxymethoxy)benzoate

[0787] Potassium carbonate (2.46 g, 17.81 mmol, 2.00 eq) and 2-(trimethylsilyl)ethoxymethyl chloride (4.45 g, 26.72 mmol, 4.73 mL, 3.00 eq) were added to a solution of methyl 4-benzoxy-3-hydroxybenzoate (2.30 g, 8.91 mmol, 1.00 eq) in dimethylformamide (20 mL). The mixture was stirred at 60 °C for 12 h. LC-MS showed that the reaction was complete. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was diluted with water (100 mL) and extracted with ethyl acetate (200 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by silicone column chromatography (petroleum ether: ethyl acetate = 20:1 to 10:1) to give methyl 4-benzoxy-3-(2-trimethylsilylethoxymethoxy)benzoate (2.30 g, 5.92 mmol, 66% yield) as a colorless oil.

[0788] LCMS: MS (ESI) m / z: 411.1[M+23]+.

[0789] 1H NMR: (400 MHz, CDCl3)δ: 7.83 - 7.79 (m, 1 H), 7.69 - 7.64 (m, 1 H), 7.45 - 7.34 (m, 5 H), 6.95 - 6.90 (m, 1 H), 5.32 (s, 2 H), 5.22 (s, 2 H), 3.87 (s, 3 H), 3.86 - 3.80 (m, 2 H), 0.98 - 0.94 (m, 2 H), 0.00 (s, 9 H).

[0790] Chemical formula: C21H28O5Si, molecular weight: 388.53

[0791] Step 3: Prepare methyl 4-hydroxy-3-(2-trimethylsilylethoxymethoxy)benzoate.

[0792] Under a nitrogen atmosphere, palladium / activated carbon catalyst (10%, 1.20 g) was added to a solution of methyl 4-phenylmethoxy-3-(2-trimethylsilylethoxymethoxy)benzoate (6.25 g, 16.09 mmol, 1.00 eq) in methanol (80 mL). The suspension was degassed and purged three times with hydrogen. The mixture was stirred at 40 °C under a hydrogen atmosphere (15 Psi) for 12 h. Thin-layer chromatography (petroleum ether:ethyl acetate = 3:1) showed that the reaction was complete. The mixture was filtered. The filtrate was concentrated under reduced pressure to give methyl 4-hydroxy-3-(2-trimethylsilylethoxymethoxy)benzoate (3.70 g, 12.40 mmol, 77% yield) as a colorless oil.

[0793] 1H NMR: (400 MHz, CDCl3)δ: 7.75 (d, J=2.0 Hz, 1 H), 7.70 - 7.65 (m, 1 H), 6.95 (d, J=8.4 Hz, 1 H), 5.30 - 5.24 (m, 2 H), 3.87 - 3.85 (m, 3 H), 3.81 - 3.76 (m, 2 H), 1.02 - 0.96 (m, 2 H), 0.01 - 0.01 (m, 9 H).

[0794] Chemical formula: C14H22O5Si, molecular weight: 298.41

[0795] Step 4: Preparation of methyl 4-[3-(tert-butoxycarbonylamino)cyclobutoxy]-3-(2-trimethylsilylethoxymethoxy)benzoate

[0796] Diisopropyl azodicarbonate (3.01 g, 14.88 mmol, 2.89 mL, 1.20 eq) was added to a solution of methyl 4-hydroxy-3-(2-trimethylsilylethoxymethoxy)benzoate (3.70 g, 12.40 mmol, 1.00 eq), triphenylphosphine (4.88 g, 18.60 mmol, 1.50 eq) in tetrahydrofuran (40 mL) at 0 °C. The mixture was stirred at 25 °C for 12 h under a nitrogen atmosphere. LC-MS showed complete depletion of the starting material. The reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by silicone column chromatography (petroleum ether: ethyl acetate = 10:1 to 5:1) to give methyl 4-[3-(tert-butoxycarbonylamino)cyclobutoxy]-3-(2-trimethylsilylethoxymethoxy)benzoate (5.20 g, 11.12 mmol, 89% yield) as a colorless oil.

[0797] LCMS: MS (ESI) m / z: 490.3[M+23]+.

[0798] 1H NMR: (400 MHz, CDCl3)δ: 7.79 (d, J=2.0 Hz, 1 H), 7.70 - 7.63 (m, 1 H), 6.64 (d, J=8.4 Hz, 1 H), 5.27 (s, 2 H), 4.92 - 4.85 (m, 1 H), 4.84 - 4.70 (m, 1 H), 4.34 - 4.23 (m, 1 H), 3.87 - 3.86 (m, 3 H), 3.81 (dd, J=8.8, 7.6 Hz, 2 H), 2.70 - 2.53 (m, 2 H), 2.44 (br d, J=6.0 Hz, 2 H), 1.26 (d, J=6.0 Hz, 9 H), 0.98 - 0.93 (m, 2 H), 0.00 (s, 9 H).

[0799] Chemical formula: C23H37NO7Si, Molecular weight: 467.63

[0800] Step 5: Preparation of methyl 4-(3-aminocyclobutoxy)-3-hydroxybenzoate

[0801] Add hydrochloric acid / dichloromethane to a solution of methyl 4-[3-(tert-butoxycarbonylamino)cyclobutoxy]-3-(2-trimethylsilylethoxymethoxy)benzoate (5.20 g, 11.12 mmol, 1.00 eq) in dichloromethane (30 mL). Alkane (4 M, 24 mL, 8.63 eq). The mixture was stirred at 35 °C for 1 h. Thin-layer chromatography (petroleum ether: ethyl acetate = 3:1) showed that the reaction was complete. The reaction mixture was concentrated under reduced pressure to give methyl 4-(3-aminocyclobutoxy)-3-hydroxybenzoate (1.90 g, 6.94 mmol, 62% yield, hydrochloride) as a white solid, which was used directly in the next step.

[0802] LCMS: MS (ESI) m / z: 238.1[M+1] +

[0803] 1H NMR: (400 MHz, DMSO-d6)δ: 9.53 (br s, 1 H), 8.34 (br s, 3 H), 7.47 - 7.34 (m, 2 H), 6.76 (d, J=8.8 Hz, 1 H), 5.05 (br d, J=4.4 Hz, 1 H), 3.85 (br d, J=5.2 Hz, 1 H), 3.79 (s, 3 H), 2.71 - 2.55 (m, 2 H), 2.49 - 2.41 (m, 2 H).

[0804] Chemical formula: C12H15NO4, molecular weight: 237.25 ...

Claims

1. A compound of formula (Ic), or a pharmaceutically acceptable salt thereof, wherein: Q1, Q2, Q3, Q4, and Q5 are each independently CR1; cyclobutyl or cyclohexyl; Q6, Q7, Q8, Q9, and Q10 are each CR3; each R1 is independently selected from the group consisting of: H, substituted linear or branched C1-C6 alkyl, cyano, halogen, and substituted linear or branched C1-C6 alkoxy, wherein the alkyl or alkoxy is substituted with one or more halogen groups as appropriate; each R2 is independently selected from the group consisting of: substituted linear or branched C1-C6 alkyl, cyano, halogen, and substituted linear or branched C1-C6 alkoxy, wherein the alkyl or alkoxy is substituted with one or more halogen groups as appropriate; Each R3 group is independently selected from the group consisting of: H, a linear or branched C1-C6 alkyl, cyano, halogen, and a linear or branched C1-C6 alkoxy group, wherein the alkyl or alkoxy group is substituted with one or more halogen groups as appropriate; and n is 0, 1, 2, 3, or 4; L is wherein: is piperidinyl or □□yl; and is piperidinyl; and is phenyl; Each R4 group is independently selected from the group consisting of: a linear or branched C1-C6 alkyl, cyano, halogen, and a linear or branched C1-C6 alkoxy group, wherein the alkyl or alkoxy group is substituted with one or more halogen groups as appropriate; R5 is H, a linear or branched C1-C6 alkyl group that is substituted as appropriate, or a linear or branched C1-C6 alkoxy group that is substituted as appropriate, wherein the alkyl or alkoxy group is substituted with one or more halogen groups as appropriate; and m is 0, 1, 2, 3 or 4.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is piperidinyl.

3. The compound of claim 1 or its pharmaceutically acceptable salt, wherein Q1 is CH, Q2 is C(OCH3), Q3 is C(CN), Q4 is CH, and Q5 is CH.

4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is cyclobutyl.

5. The compound of claim 1 or its pharmaceutically acceptable salt, wherein n is 4.

6. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein each R2 is a straight-chain or branched C1-C6 alkyl group.

7. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein each R4 is independently selected from the group consisting of: F, methoxy, ethoxy, methyl and ethyl.

8. The compound of claim 1 or its pharmaceutically acceptable salt, wherein m is 1.

9. A compound or a pharmaceutically acceptable salt thereof, as described in any of claims 1 to 8, wherein the compound is: .

10. A compound or a pharmaceutically acceptable salt thereof, as claimed in any of claims 1 to 8, wherein the compound is a pharmaceutically acceptable salt: .

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