Compounds and their use in cancer treatment

Abstract

This specification generally relates to compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein A, Z, Y, R A, the linker, and v have any of the meanings defined herein. This specification also relates to the use of such compounds and pharmaceutically acceptable salts thereof in methods of treating the human or animal body, for example, in the prevention or treatment of cancer. This specification also relates to processes and intermediate compounds involved in the preparation of such compounds, and pharmaceutical compositions containing them. [Formula 1] TIFF2023543299000352.tif25161

Description

[Technical Field]

[0001] This specification relates to specific E3 ubiquitin ligase-binding units that can be incorporated into proteolytic chimeric (PROTAC) compounds, such PROTAC compounds can be used to treat certain human conditions / diseases, such as cancer. This specification also relates to PROTAC compounds incorporating such beneficial E3 ubiquitin ligase-binding ligands, and intermediate compounds that may be useful in the preparation of such PROTACs. [Background technology]

[0002] Conventional small molecule drugs reversibly (or sometimes irreversibly) bind to target proteins as a means of modulating a given biological activity. In contrast, PROTACs bind to their target proteins but, in doing so, cause degradation of those proteins. Once a PROTAC achieves this effect, it can theoretically repeat this process on another target protein. Therefore, unlike "conventional small molecule" inhibitors, the PROTAC-driven degradation mechanism can theoretically act quasi-stoichiometrically—meaning that even with more modest exposure to PROTAC compounds, the desired level of efficacy can be achieved in vivo. In practice, this is due to the degradation power of PROTACs (DC 50 and D max This could mean that it may have an improved effect compared to the effect reflected solely by its binding affinity.

[0003] At a simplified level, a PROTAC molecule is often described as having three parts: (1) a part that can bind to the target protein to be degraded, (2) a second part that can bind to an E3 ubiquitin ligase, and finally a linker that connects (1) and (2) together.

[0004] During use, PROTAC simultaneously binds to both the target protein and the E3 ubiquitin ligase to form a ternary complex. The E3 ligase then recruits an E2-coupled enzyme to the ternary complex, ubiquitinating the target protein. This effectively labels the target protein for degradation by the cell's proteasome mechanism. PROTAC then dissociates from the target protein, catalytically initiating another cycle of this process. Meanwhile, the ubiquitinated target protein is recognized and degraded by the cell's proteasome mechanism.

[0005] This PROTAC-mediated approach may have value as a way to treat certain diseases in which targeted degradation of specific bodily proteins may be beneficial.

[0006] Over the past few decades, scientists have gained a deeper understanding of which proteins may be promising targets to inhibit (or degrade) as strategies for effective cancer treatment. This understanding has then led scientists to develop potent "conventional small molecule" conjugates for such target proteins. More recently, it has been recognized that these "conventional small molecule" conjugates / inhibitors can be incorporated into PROTAC molecules, binding the PROTAC linker to a portion of the conjugate / inhibitor moiety, thus not preventing the underlying binding that causes potent inhibition.

[0007] When "conventional small molecule inhibitors" are incorporated into a PROTAC, both inhibition and degradation events can occur in parallel, as already mentioned above, through the specific mechanism of action of typical PROTACs. In addition to using "conventional small molecule inhibitors" as part of the PROTAC molecule to affect the degradation of targets, non-functional "small molecule conjugates" can also be incorporated into the PROTAC molecule to affect the degradation of the targets to which they bind.

[0008] Regardless of which target protein binding unit (1) is used at one end of the PROTAC linker unit, a fundamental element that must always be present at the other end of the PROTAC molecule is the E3 ubiquitin ligase binding unit (2) to direct the tagging of the target protein for degradation.

[0009] Scientific efforts have already provided numerous potent E3 ubiquitin ligase binding units (2) incorporated into PROTAC molecules. However, as with "conventional small molecule" binders and PROTACs, there is always the problem of "off-target" activity in vivo, which can be crucial to avoid in the development of safe and effective drug therapies. In other words, a given binding unit may be highly potent against its intended target, but if it is inadvertently potent against other unintended biological targets in the human body, it can cause unacceptable toxicity, side effects, etc.

[0010] Therefore, developing potent molecules for pharmaceutical applications that are appropriately selective, such as avoiding unintended inhibition / binding / degradation of biological targets in vivo, is an ongoing challenge. Current researchers are noting that several known E3 ubiquitin ligase binding units (2) may (unintentionally) also function as potent degraders of SALL4 and / or Ikaros (IKZF1), among others. Degradation of SALL4 and Ikaros (IKZF1), in particular, is thought to pose a risk of serious undesirable effects in humans, including developmental toxicity and myelotoxicity.

[0011] Patent Document 1 discloses a specific PROTAC compound structure, and Patent Document 2 discloses a compound said to be a cereblon binder / ligand.

[0012] Therefore, it is necessary to develop an E3 ligase binding unit (2) that is suitable for incorporation into PROTAC, which not only serves as a strong binding agent for E3 ligase but also possesses an improved selectivity profile.

[0013] Current researchers have also noted that some known E3 ubiquitin-binding units (2) also exhibit unfavorable levels of chemical and metabolic stability.

[0014] Therefore, as part of the development of PROTAC drug therapies for current and future medical applications (such as cancer), there remains a need to develop E3 ​​ligase-binding units (2) that have beneficial / improved combinations of properties that make them more suitable for use as part of PROTAC therapeutics for human applications, regardless of which target protein-binding unit (1) is bound to the other end of the molecule.

[0015] Characteristics of interest during the discovery and development of pharmaceuticals may include selectivity profile, absorption / bioavailability, distribution, metabolism, elimination, toxicity, and side effect profile, as well as stability and manufacturability. [Prior art documents] [Patent Documents]

[0016] [Patent Document 1] International Publication No. 2018144649 [Patent Document 2] International Publication No. 2019140387 Pamphlet [Overview of the Initiative] [Means for solving the problem]

[0017] The compounds herein provide, at a minimum, more potent E3 ubiquitin ligase binding units, specifically cerebron binding units, and thus PROTAC compounds containing them, which are suitable for incorporation into PROTAC compounds. The PROTAC compounds and E3 ubiquitin ligase binding agents herein also possess a remarkably beneficial combination of properties, for example, related to stability (within human microsomes and hydrolysis at pH 7.4) and selectivity (e.g., against SALL4 and / or IKZF1 - which is expected to help provide a better safety profile for in vivo use).

[0018] This specification relates to the E3 ubiquitin ligase binding units described above, and to PROTAC compounds (and pharmaceutically acceptable salts thereof) incorporating such E3 ubiquitin ligase binding units. This specification also relates to pharmaceutical compositions containing such PROTACs (and pharmaceutically acceptable salts thereof) and their use in methods of treating the human or animal body, for example, in the treatment or prevention of cancer. This specification also relates to processes and intermediate compounds (and salts thereof) involved in the preparation of the above PROTACs.

[0019] In a first aspect of this specification, formula (I): [ka] [In the formula, A is the target protein binding unit; Z is Z A or Z B : [ka] (In the formula, [ka] This represents a single covalent bond or a double covalent bond; X A , X B , X C , and X D One of them is CY; XA , X B , X C , X D , X E , and X F of 0, 1, or 2 of which are N, where X E and X F are both not N and the rest are C), and when Z is Z A : X G , X H , and X J of which 2 are independently selected from C and N; X G , X H , and X J of which 1 is C, N, S, or O; where X G , X H , and X J of which at least 1 is N, S, or O; X G , X H , and X J any one C of which is optionally replaced by oxo, or X G and X J are both C, both may be optionally replaced by oxo; when Z is Z B ; X G , X H , X J , and X K of which 1 is N and the rest are C; or alternatively X G and X K are both N, X H and X J are both C; The linker is a saturated, partially or completely unsaturated framework comprising C and H atoms and at least one heteroatom, wherein the framework has bonding endpoints "a" and "b" (and where "b" may contain two bonding points "b1" and "b2" if there are two bonding points to Z at the "b" end of the linker), and the minimum length between "a" and "b" is 6 to 26 atoms; wherein the framework may include one or more linear and / or branched and / or ring chains, and any available C atoms are optionally substituted with one or more F atoms; wherein the linker is; Once on Z: with any available C or N atom on Z; or Z twice:X H , X G , and X J (If present, and X K ) bonded in any two adjacent available C and / or N atoms such that a 5- to 7-membered ring is formed by linker bonding at two adjacent atoms of Z; Each R A is a substituent on any available C or N atom of Z, and in each case, one or more R A2 R is optionally replaced with A1 Selected independently of; here, R A If is a substituent on an available C atom of Z, then R A is R A2 Further selections are made from; Each R A1 Independently, C 1~4 Alkyl, C 2~3 Alkenil, C 2~3 Alkinyl, C 1~3 Alkoxy C 1~3 Alkyl, CarboxyC 1~3 Alkyl, C 5~7 It is a carbocyclyl, or a 4- to 6-membered heterocyclyl; Each R A2 F, Cl, Br, CN, NH2, C 1~3 Alkyl, O(C 1~3 Alkyl), NH(C 1~3 Alkyl, and N(C)1~3 Alkyl)2 is independently selected from 2; where above C 1~3 The alkyl group is optionally substituted with one or more fluorine atoms; v is 0, 1, 2, or 3; Y is: [ka] (In the formula, Y A and Y B Together, they represent CH-CH or C=C, and Y A and Y B (Each of these is independently substituted with H, F, CN, or Me.) Compounds or pharmaceutically acceptable salts thereof are provided.

[0020] This specification also describes, in part, pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0021] This specification also describes, in part, compounds of formula (I) or pharmaceutically acceptable salts thereof for use in therapeutics.

[0022] This specification also describes, in part, compounds of formula (I) or pharmaceutically acceptable salts thereof for use in the treatment of cancer.

[0023] This specification also describes, in part, a method for treating cancer in warm-blooded animals requiring such treatment, which comprises administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to the warm-blooded animal.

[0024] As shown in the experimental section below, the researchers generated a number of potent and selective E3 ubiquitin ligase binders. They also understood where these selective E3 ubiquitin ligase binders could be bound to the linker of the PROTAC molecule without interfering with potent E3 ubiquitin ligase binding. Thus, the researchers understood that when incorporating an E3 ubiquitin ligase binder into a PROTAC molecule, the linker of the PROTAC should not be bound at the Y group of the compound of formula (I), but rather can be suitably bound within a range of positions on the heterocyclic Z group of the compound of formula (I).

[0025] In further aspects of this specification, formula (Ia): [ka] [In the formula, Z, Y, R A PROTAC compounds or pharmaceutically acceptable salts thereof are provided, containing an E3 ubiquitin ligase binding unit [wherein v, and v, can each take any of the values ​​defined herein for each of these integers].

[0026] In further aspects of this specification, an E3 ubiquitin ligase binding unit of formula (Ia) described herein is provided for use in PROTAC compounds.

[0027] Therefore, units of formula (Ia) described herein are provided for use with PROTAC compounds (or pharmaceutically acceptable salts thereof).

[0028] Therefore, units of formula (Ia) described herein are provided for incorporation into PROTAC compounds (or pharmaceutically acceptable salts thereof).

[0029] Therefore, an E3 ubiquitin ligase binding unit of formula (Ia) described herein is provided, which can be incorporated into a PROTAC compound (or a pharmaceutically acceptable salt thereof). [Modes for carrying out the invention]

[0030] Many embodiments of this disclosure are described in detail throughout this specification and will be obvious to those skilled in the art.

[0031] A pharmaceutically acceptable salt of a compound of formula (I) or a PROTAC compound described herein may be, for example, an acid addition salt if the compound contains a basic functional group such as an amine. The acid addition salt may be formed using an inorganic or organic acid. A pharmaceutically acceptable salt of the compound may also be, for example, a base addition salt if the compound contains an acidic functional group such as a carboxylic acid. The acid addition salt may be formed using an inorganic or organic base. “pharmaceutically acceptable salt” is used to specify that the salt is suitable for use in the body of a human or animal. A list of examples of pharmaceutically acceptable salts can be found in Handbook of Pharmaceutical Salts: Properties, Selection and Use, PHStahl and CGWermuth, editors, Weinheim / Zurich: Wiley-VCH / VHCA, 2002. A pharmaceutically acceptable salt of a compound of formula (I) or a PROTAC compound includes such salts that may be formed in the body of a human or animal after administration of the compound to the body of the human or animal.

[0032] As used herein, the term "alkyl" refers to linear, branched, and cyclic alkyl groups having a specific number of carbon atoms, as well as combinations thereof. Therefore, C 1~3 Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, and cyclopropyl; C 1~9 Examples of alkyl groups include (4-isopropylcyclohexyl)methyl. The same principle applies to the term “alkoxy.” Similarly, as used herein, the term “alkoxy” refers to linear, branched, and / or cyclic alkoxy groups having a specific number of carbon atoms. Therefore, C 1~3 Alkoxy["O(C 1~3Examples of alkyl groups that may also be described as "alkyl" include methoxy, ethoxy, n-propoxy, isopropoxy, and cyclopropoxy. In groups where two alkyl groups are mentioned, for example, N(C) 1~3 Each alkyl group in alkyl)2 may be the same or different. Therefore, N(C 1~3 Alkyl)2 includes, for example, (methyl)(cyclopropyl)amine.

[0033] In this specification, chemical abbreviations well known to those skilled in the art may be used, for example, "Me" = methyl, "Et" = ethyl, "Pr" = propyl, "Bu" = butyl, and "Ph" = phenyl.

[0034] In this specification, for example, a group such as "ABC" where B is defined as "directly bonded" corresponds to "AC"—that is, A and C are directly linked to each other by a single covalent bond.

[0035] When the term "arbitrarily" is used, it is intended that the following feature may or may not be present. Therefore, the use of the term "arbitrarily" includes cases in which this feature is present, as well as cases in which it is absent. For example, "methyl molecules arbitrarily substituted with one or more F molecules" include -CH3, -CH2F, -CHF2, and -CF3.

[0036] The term “substituted” means that one or more hydrogen atoms on the indicated atom or group are replaced by the specified substituent, provided that any atom having such substituent maintains its acceptable valency, as a person skilled in the art would understand that the standard valencies of carbon, nitrogen, and oxygen are 4, 3, and 2, respectively. Thus, “substituted on any available C atom” should be understood to mean that the substituent is limited to its position (and / or potentially its number) depending on whether any hydrogen atoms remain on the specified atom or group that can be substituted by the substituent.

[0037] Z A The dashed bonds contained in [Chemical formula] is, for X E , X F , X G , X H , and X J at each of the positions of, indicates the possibility that the bond is in each case a single covalent bond or a double covalent bond. Those skilled in the art understand that the standard valences of carbon, nitrogen, and oxygen are as described above, and thus, for any given Z A group in this specification, it is possible to understand whether each dashed bond should be interpreted as either a single bond or a double bond.

[0038] The term "adjacent" or "adjacent position" means, for example, with respect to X of Z G , X H , and X J , the next nearest position in the molecular chain / ring system. Thus, in the context of Z: X G and X H are adjacent to each other, X H and X J are also adjacent to each other, but X G is not adjacent to X J .

[0039] The term "saturated" means that the atoms of the specified framework or group are bonded only by single covalent bonds. Thus, the term "unsaturated" means that the specified framework or group contains double and / or triple covalent bonds. When nitrogen and oxygen heteroatoms are allowed / present, examples of unsaturated molecular fragments that can be present within a partially or fully unsaturated group or framework are C=C, C=N, C=O, N=N, C≡C, or C≡N, and when sulfur heteroatoms are also allowed / present, S=O may also be included.

[0040] It should be understood that "heteroatom" can refer to an oxygen, nitrogen, or sulfur atom unless explicitly limited in a given context.

[0041] The term "minimum length of atoms between 'a' and 'b'" refers to the shortest chain of atoms in the chain between 'a' and 'b'. Therefore, if the chain consists of -CH2CH2CH2-, the number of atoms in the chain is 3 (hydrogen atoms are considered not to be in the chain). Alternatively, if the chain consists of 1,3-phenylene, with 3 carbon atoms in the short route around the phenyl ring and 5 carbon atoms in the long route around the phenyl ring, the minimum length of such a chain is counted as 3 atoms.

[0042] Bond points "a" and "b" should be understood as representing single covalent bonds to their respective adjacent groups / atoms.

[0043] In this specification, the term "ring" should be understood to include monorings, fused rings, spirorings, and bridging rings.

[0044] With respect to linkers, as described herein, it should be understood that, if present, branching may exist on a chain (even if it is a chain of atomic length 1) or a ring. While this is the general interpretation for those skilled in the art, to avoid misunderstanding, it should be understood that “branching” that arises intrinsically to form a ring is not considered “branching” in the context of linkers as defined herein. In the examples herein, branching may include one or more “=O” branches. It should be understood that such branching may occur on the same or different atoms in the linker framework. For example, it is possible to have two “=O” branches on a sulfur heteroatom to form an SO2 group within the linker framework. “Branching” (and the definition of branching provided herein) refers to branching from the main chain of atoms between “a” and “b” (or “b1” and “b2” as relevant) that leads to a “dead end” in the molecular structure.

[0045] In this specification, it should be understood that the point of attachment of a given group to some other group can be represented by a line that intersects the bond at a substantially right angle to the bond, as shown, for example, on the left side of the above structure Y. In particular, when a "floating" point of attachment is shown for the Z group (regardless of whether the Z group is shown as "Z" or explicitly shown as a bicyclic chemical diagram), the bond may be connected to any available carbon or nitrogen atom of the Z group (unless otherwise specified), which means that the above "floating bond" is the X of Z A / X B / X C / X D / X E / X F ring or the X of Z E / X F / X[[ID=!7]] G / X H / X J / (X K ) ring, regardless of whether it is depicted or not. Further, in certain cases where the "floating" bond is relevant to the linkage between Z and the linker of the PROTAC compound (e.g., in the compounds of formula (I)), the above floating bond, by itself or in combination with another specified point of attachment, can provide a double bond between the linker and Z via the points of attachment "b1" and "b2" in the manner described herein.

[0046] In this specification, "X A , X B , X C , X D , X E , and X F of which 0, 1, or 2 are N, and X E and X F are both not N and the rest are C", - it should be understood that certain C atoms implicitly have hydrogen atoms, if necessary, to satisfy the standard valence of the carbon atom (4). One of ordinary skill in the art will recognize that such H atoms, when a substituent or linker is attached to the carbon, are on the C of X E or X F , or on the C of X A , X B , X C , or X DYou will understand that it cannot exist on C.

[0047] In this specification, a saturated heterocyclic group refers to a ring of atoms (including bridging rings, spiro rings, fused rings, and monocyclic rings) containing a carbon atom and at least one heteroatom, where the heteroatom is independently selected from N, O, and S, and each atom in the ring is connected to an adjacent atom by a single covalent bond. Typically, a saturated heterocyclic group has at least two carbon atoms separating each of the heteroatoms present in the group to ensure a level of chemical stability suitable for use in a pharmaceutical context. When referring to a "nitrogen-containing saturated heterocyclic group," this requires the presence of at least one nitrogen heteroatom, but does not limit the possibility of the presence of one or more additional non-nitrogen heteroatoms (i.e., S, O). When referring to a cyclic group (e.g., a heterocyclic group) having a certain number of ring atoms, this includes the atoms constituting the ring (including the atoms involved in bridging a bridging ring, and all atoms in a fused or spiro ring), but does not include any hydrogen atoms or other substituted atoms bonded to the ring atoms. Therefore, for example, the cyclic group 1,4-piperazine-1,4-diyl has six ring atoms (4C and 2N).

[0048] In this specification, “heterocyclyl” is a cyclic group comprising at least one carbon atom and at least one heteroatom (selected from N, S, and O unless otherwise specified or indicated in the context). Such heterocyclyls may be fully saturated, partially unsaturated, or fully unsaturated. “4- to 6-membered heterocyclyl” means that the total number of carbon atoms and heteroatoms within the heterocyclyl is between 4 and 6.

[0049] In this specification, alkylene groups (e.g., C 1~3An alkylene is a linear or branched group having a specified number of carbon atoms, hydrogen atoms, and two bonding points composed of a single covalent bond. A C1 alkylene is -CH2-, and a C2 alkylene is -CH2CH2- or -CH(Me)-. Therefore, a "cycloalkylene" is an alkylene group that contains a saturated ring of carbon atoms (including monocyclic, spirocyclic, fused, and bridging rings) in its structure, which may consist entirely of the above rings, or it may have a branched ring, as can be the case for a "C6 cycloalkylene" which can represent 2,2-dimethylcyclobuta-1,3-diyl.

[0050] The term “therapy” is intended to have the usual meaning of treating a disease in order to completely or partially alleviate one, some or all of its symptoms, or to correct or compensate for the underlying pathology. The term “therapy” also includes “prophylaxis” or “prophylactic” unless the opposite is specifically indicated. The terms “therapeutic” and “therapeutically” should be interpreted accordingly.

[0051] The term “prevention” is intended to have its ordinary meaning and includes primary prevention, which is to prevent the onset of a disease, and secondary prevention, which is to protect the patient temporarily or permanently from exacerbation or worsening of the disease or the onset of new symptoms associated with the disease, once the disease has already occurred.

[0052] The term “treatment” is used synonymously with “therapy.” Similarly, the term “treatment” can be considered to mean “applying therapy” if “therapy” is as defined herein.

[0053] Some values ​​for the variable group are as follows. One, two, or more of these values ​​may be used in combination with other definitions, claims, aspects, or embodiments herein (unless the context allows) to provide further embodiments / claims herein.

[0054] In one embodiment, A is a BRD4 bond unit.

[0055] In one embodiment, A is given by formula: [ka] It is a protein-binding unit that possesses [a specific characteristic].

[0056] In one embodiment, Z is Z A That is the case.

[0057] In one embodiment, Z is Z B That is the case.

[0058] In one embodiment, X A , X B , or X C This is CY.

[0059] In one embodiment, X B , X C , or X D This is CY.

[0060] In one embodiment, X A or X D This is CY.

[0061] In one embodiment, X B or X C This is CY.

[0062] In one embodiment, X A or X B This is CY.

[0063] In one embodiment, X C or X D This is CY.

[0064] In one embodiment, X A It is CY.

[0065] In one embodiment, X B It is CY.

[0066] In one embodiment, XC It is CY.

[0067] In one embodiment, X D It is CY.

[0068] In one embodiment, Y and the linker are Z (for example, Z A or Z B They are not joined at adjacent positions.

[0069] In one embodiment, X A , X B , X C , X D , X E , and X F If any of these is 0 or 1, it is N; otherwise, it is C.

[0070] In one embodiment, X A , X B , X C , X D , X E , and X F One of them is N, and the others are C.

[0071] In one embodiment, X A , X B , X C , X D , X E , and X F All of them are C.

[0072] In one embodiment, X A , X D , X E , and X F 0 or one of these is N, and X A , X B , X C , X D , X E , and X F Otherwise, it is C.

[0073] In one embodiment, X A and X D 0 or one of these is N, and X A , XB , X C , X D , X E , and X F Otherwise, it is C.

[0074] In one embodiment, X D is C or N, and X A , X B , X C , X E , and X F All of them are C.

[0075] In one embodiment, X E and X F 0 or one of these is N, and X A , X B , X C , X D , X E , and X F Otherwise, it is C.

[0076] In one embodiment, Z is Z A If X G It is selected from N, S, O, CH2, and C(O).

[0077] In one embodiment, Z is Z A If X G , X H , and X J At least one of them is N.

[0078] In one embodiment, Z is Z A If X G , X H , and X J These are collectively selected from (N, C, C), (O, N, C), (N, C, S), (N, N, N), (S, C, C), (N, N, C), (N, C, N), (O, C, C), (O, C, N), (C, N, C), and (N, N, C).

[0079] In one embodiment, Z is Z B If X G , X H , XJ , and X K One of them is N, and the others are C.

[0080] In one embodiment, Z is Z A If X G is N, and X H C is X J C is C.

[0081] In one embodiment, Z is Z A If X G is O, X H is N, and X J C is C.

[0082] In one embodiment, Z is Z A If X G is N, and X H C is X J S is.

[0083] In one embodiment, Z is Z A If X G is N, and X H is N, and X J It is N.

[0084] In one embodiment, Z is Z A If X G is S, X H C is X J C is C.

[0085] In one embodiment, Z is Z A If X G is N, and X H is N, and X J C is C.

[0086] In one embodiment, Z is Z A If X G is N, and X H C is X J It is N.

[0087] In one embodiment, Z is Z A If X G is O, X H C is X J C is C.

[0088] In one embodiment, Z is Z A If X G is O, X H C is X J It is N.

[0089] In one embodiment, Z is Z A If X G C is X H is N, and X J C is C.

[0090] In one embodiment, Z is Z A If X G is N, and X H is N, and X J C is C.

[0091] In one embodiment, Z is Z B If X G is N, and X H , X J , and X K All of them are C.

[0092] In one embodiment, Z is Z B If X H is N, and X G , X J , and X K All of them are C.

[0093] In one embodiment, Z is Z B If X J is N, and X G , X H , and X K All of them are C.

[0094] In one embodiment, Z is Z B If X K is N, and XG , X H , and X J All of them are C.

[0095] In one embodiment, Z is Z A If that is the case; (X G -X H -X J The bases are selected together from (NC=C), (NCC), (N=CC), (ON=C), (N=CS), (NN=N), (SC=C), (NN=C), (NC=N), (OC=C), (OC=N), (OCN), (CNC), and (NNC).

[0096] In one embodiment, Z is Z A If X G , X H , and X J In short, NC = C.

[0097] In one embodiment, Z is Z A If X G , X H , and X J These are collectively referred to as NCC.

[0098] In one embodiment, Z is Z A If X G , X H , and X J In short, N = CC.

[0099] In one embodiment, Z is Z A If X G , X H , and X J In short, ON = C.

[0100] In one embodiment, Z is Z A If X G , X H , and X J In short, N = CS.

[0101] In one embodiment, Z is Z A If X G , X H , and X J In short, NN = N.

[0102] In one embodiment, Z is Z A If X G , X H , and X J In short, SC = C.

[0103] In one embodiment, Z is Z A If X G , X H , and X J In short, NN = C.

[0104] In one embodiment, Z is Z A If X G , X H , and X J In short, NC = N.

[0105] In one embodiment, Z is Z A If X G , X H , and X J In short, OC = C.

[0106] In one embodiment, Z is Z A If X G , X H , and X J In short, OC = N.

[0107] In one embodiment, Z is Z A If X G , X H , and X J In short, it's all OCN.

[0108] In one embodiment, Z is Z A If X G , X H , and X JIn short, they are all CNC machines.

[0109] In one embodiment, Z is Z A If X G , X H , and X J These are collectively referred to as NNC.

[0110] In one embodiment, Z is selected from indole, benzoisoxazole, 1H-pyrrolo[2,3-c]pyridine, benzothiazole, 1H-pyrrolo[3,2-b]pyridine, indoline, benzotriazole, indazole, benzothiophene, 2H-indazole, benzimitazole, benzofuran, benzoxazole, 3H-1,3-benzoxazole-2-one, pyrazolo[1,5-a]pyridine, isoindoline-1-one, imidazo[1,2-a]pyridine, isoindoline, isoxazo[4,5-b]pyridine, flo[3,2-b]pyridine, 1H-pyrrolo[2,3-b]pyridine, 1,2,3,4-tetrahydroquinoline, and 1,2,3,4-tetrahydroisoquinoline.

[0111] In one embodiment, Z A The following are selected from indole, benzoisoxazole, 1H-pyrrolo[2,3-c]pyridine, benzothiazole, 1H-pyrrolo[3,2-b]pyridine, indoline, benzotriazole, indazole, benzothiophene, 2H-indazole, benzimitazole, benzofuran, benzoxazole, 3H-1,3-benzoxazole-2-one, pyrazolo[1,5-a]pyridine, isoindoline-1-one, imidazo[1,2-a]pyridine, isoindoline, isoxazo[4,5-b]pyridine, flo[3,2-b]pyridine, and 1H-pyrrolo[2,3-b]pyridine.

[0112] Those skilled in the art will understand the Z and Z mentioned above and below. A The values ​​are shown as neutral heterocycle names for clarity and simplicity, but it is understood that they are actually radicals. Therefore, they are bonded to a Y group (as defined herein), one or more RA They have potential bonds to a base, and, for example, in the cases of formulas (I) and (Ia), they also have one or two bonds to a linker.

[0113] In one embodiment, Z A It is indole.

[0114] In one embodiment, Z A It is benzisoxazole.

[0115] In one embodiment, Z A This is 1H-pyrrolo[2,3-c]pyridine.

[0116] In one embodiment, Z A It is a benzothiazole.

[0117] In one embodiment, Z A This is 1H-pyrrolo[3,2-b]pyridine.

[0118] In one embodiment, Z A It is indolin.

[0119] In one embodiment, Z A It is benzotriazole.

[0120] In one embodiment, Z A It is indazole.

[0121] In one embodiment, Z A It is benzothiophene.

[0122] In one embodiment, Z A It is 2H-indazole.

[0123] In one embodiment, Z A It is benzimitazole.

[0124] In one embodiment, Z A It is benzofuran.

[0125] In one embodiment, Z A It is a benzoxazole.

[0126] In one embodiment, Z A It is 3H-1,3-benzoxazole-2-one.

[0127] In one embodiment, Z A It is pyrazolo[1,5-a]pyridine.

[0128] In one embodiment, Z A It is isoindorin-1-one.

[0129] In one embodiment, Z A This is imidazo[1,2-a]pyridine.

[0130] In one embodiment, Z A It is isoindoline.

[0131] In one embodiment, Z A It is isoxazo[4,5-b]pyridine.

[0132] In one embodiment, Z A It is flu[3,2-b]pyridine.

[0133] In one embodiment, Z A This is 1H-pyrrolo[2,3-b]pyridine.

[0134] In one embodiment, Z B The compound is selected from 1,2,3,4-tetrahydroquinoline and 1,2,3,4-tetrahydroisoquinoline.

[0135] In one embodiment, Z B It is 1,2,3,4-tetrahydroquinoline.

[0136] In one embodiment, Z B It is 1,2,3,4-tetrahydroisoquinoline.

[0137] In one embodiment, the E3 ubiquitin ligase binding unit of formula (Ia) [or Z, Y, R in the compound of formula (I)] A The expression for , and v together is selected from one or more of the following formulas 1 to 54: [ka] [ka] [ka] [In the formulas, each of the above formulas 1 to 54 [R A ] v A floating bond that is not involved may be formed once on any available C or N atom of the bicyclic heterocycle Z, or twice on any two adjacent available C and / or N atoms of the bicyclic heterocycle Z.

[0138] In one embodiment, v is 0, 1, or 2.

[0139] In one embodiment, v is 0 or 1.

[0140] In one embodiment, v is 0.

[0141] In one embodiment, v is 1.

[0142] In one embodiment, v is 2.

[0143] In one embodiment, v is 3.

[0144] In one embodiment, v is 1 or 2.

[0145] In one embodiment, R A is a substituent on any available C or N atom of Z, in each case being optionally substituted with one or more F atoms. 1~3 Alkyl, C 1~3 Alkenil, C 1~3 Alkinyl, C1~3 Alkoxy C 1~3 Alkyl and carboxyl C 1~3 Selected independently of alkyl; above R A If is a substituent on the available C of Z, then R A Furthermore, F, Cl, Br, CN, NH2, C 1~3 Alkoxy, NH(C 1~3 Alkyl, and N(C) 1~3 Selected from alkyl)2.

[0146] Therefore, in one embodiment of this specification, formula (I): [ka] [In the formula, A is the target protein binding unit; Z is Z A or Z B : [ka] (In the formula, [ka] This represents a single covalent bond or a double covalent bond; X A , X B , X C , and X D One of them is CY; X A , X B , X C , X D , X E , and X F Of these, 0, 1, or 2 are N, where X E and X F (Neither of these is N, and all the others are C) Z is Z A If that is the case: X G , X H , and X J Two of these are selected independently of C and N; XG , X H , and X J One of them is C, N, S, or O; Here X G , X H , and X J At least one of them is N, S, or O; X G , X H , and X J One of the C's is optionally substituted with an oxo, or X G and X J If both are C, then both may be optionally substituted with an oxo; Z is Z B If that is the case; X G , X H , X J , and X K One of them is N, and the others are C; or X G and X K Both are N, and X H and X J Both are C; The linker is a saturated, partially or completely unsaturated framework comprising C and H atoms and at least one heteroatom, wherein the framework has bonding endpoints "a" and "b" (and where "b" may contain two bonding points "b1" and "b2" if there are two bonding points to Z at the "b" end of the linker), and the minimum length between "a" and "b" is 6 to 26 atoms; wherein the framework may include one or more linear and / or branched and / or ring chains, and any available C atoms are optionally substituted with one or more F atoms; wherein the linker is; Once on Z: with any available C or N atom on Z; or Z twice:X H , X G , and X J (If present, and X K) bonded in any two adjacent available C and / or N atoms such that a 5- to 7-membered ring is formed by linker bonding at two adjacent atoms of Z; Each R A is a substituent on any available C or N atom of Z, in each case being optionally substituted with one or more F atoms. 1~3 Alkyl, C 1~3 Alkenil, C 1~3 Alkinyl, C 1~3 Alkoxy C 1~3 Alkyl and carboxyl C 1~3 Selected independently of alkyl; above R A If is a substituent on the available C of Z, then R A Furthermore, F, Cl, Br, CN, NH2, C 1~3 Alkoxy, NH(C 1~3 Alkyl, and N(C) 1~3 Selected from alkyl)2; v is 0, 1, 2, or 3; Y is: [ka] (In the formula, Y A and Y B Together, they represent CH-CH or C=C, and Y A and Y B (Each of these is independently substituted with H, F, CN, or Me.) Compounds or pharmaceutically acceptable salts thereof are provided.

[0147] One embodiment, each R A is a substituent on any available C or N atom of Z, in each case, C 1~3 Alkyl, N(C 1~3 Alkyl)2, and C 1~3 Alkoxy C 1~3 Selected independently of alkyl, and the above R A If is a substituent on the available C of Z, then R A Furthermore, F, Cl, CN, and C 1~3Selected from alkoxy.

[0148] One embodiment, each R A is a substituent on any available C or N atom of Z, in each case, C 1~3 Alkyl and C 1~3 Alkoxy C 1~3 Selected independently of alkyl, and the above R A If is a substituent on the available C of Z, then R A Furthermore, F, Cl, and C 1~3 Selected from alkoxy.

[0149] One embodiment, each R A is a substituent on any available C or N atom of Z, which in each case is independently selected from methyl, dimethylamino, and methoxymethyl, and the above R A If is a substituent on the available C of Z, then R A The element is further selected from F, Cl, CN, and methoxy.

[0150] One embodiment, each R A is a substituent on any available C or N atom of Z, which in each case is independently selected from methyl and methoxymethyl, and the above R A If is a substituent on the available C of Z, then R A Furthermore, it is selected from F, Cl, and methoxy.

[0151] One embodiment, each R A is a substituent on any available C or N atom of Z, in each case, C 1~3 Selected from alkyl groups (e.g., Me).

[0152] In one embodiment, v is 0 or 1, and when v is 1, R A is CN.

[0153] In one embodiment, v is 0 or 1, and when v is 1, R A is N(C 1~3Alkyl)2 [e.g., dimethylamino].

[0154] In one embodiment, v is 0 or 1, and when v is 1, R A It is chloroform.

[0155] In one embodiment, v is 0 or 1, and when v is 1, R A is C 1~4 It is an alkyl group [for example, methyl].

[0156] In one embodiment, v is 0 or 1, and when v is 1, R A is C 1~3 It is an alkoxy [e.g., methoxy].

[0157] In one embodiment, v is 0 or 1, and when v is 1, R A It is fluoro.

[0158] In one embodiment, v is 0 or 1, and when v is 1, R A is C 1~3 Alkoxy C 1~3 It is an alkyl group [e.g., methoxymethyl].

[0159] In one embodiment, v is 0, 1, or 2, and when v is 1 or 2, the above / 1 R A It is fluoro.

[0160] In one embodiment, v is 0, 1, or 2, and when v is 1 or 2, the above / 1 R A is C 1~4 It is an alkyl group (for example, methyl).

[0161] In one embodiment, Y A and Y B Together, they represent CH-CH, and Y A and Y B Each of these is independently substituted with H, F, CN, or Me.

[0162] In one embodiment, Y Aand Y B Together, these represent C=C, and Y A and Y B Each of these is independently substituted with H, F, CN, or Me.

[0163] In one embodiment, Y A and Y B Both are substituted with H.

[0164] In one embodiment, Y A is replaced by H, and Y B It is replaced with H, F, or Me.

[0165] In one embodiment, Y is selected from 6-fluoro-2,4-dioxohexahydropyrimidine-1-yl, 6-fluoro-2,4-dioxopyrimidine-1-yl, 2,4-dioxopyrimidine-1-yl, 6-methyl-2,4-dioxopyrimidine-1-yl, and 2,6-dioxohexahydropyrimidine-1-yl.

[0166] In one embodiment, Y is 6-fluoro-2,4-dioxohexahydropyrimidine-1-yl.

[0167] In one embodiment, Y is 6-fluoro-2,4-dioxopyrimidine-1-yl.

[0168] In one embodiment, Y is 2,4-dioxopyrimidine-1-yl.

[0169] In one embodiment, Y is 6-methyl-2,4-dioxopyrimidine-1-yl.

[0170] In one embodiment, Y is 2,6-dioxohexahydropyrimidine-1-yl.

[0171] In one embodiment, each E3 ubiquitin ligase binding unit of formula (Ia) [or Z, Y, R in the compound of formula (I)] A[and v together] is selected from one or more of the following formulas 1 to 107: [ka] [ka] [ka] [ka] [ka] [ka] [In each of the above formulas 1 to 107, the floating bond may represent a single bond point with any available C or N of the bicyclic heterocycle Z, or it may represent a double bond with any two adjacent available C and / or N atoms of the bicyclic heterocycle Z.]

[0172] In one embodiment, the linker is coupled to Z only once.

[0173] In one embodiment, the linker framework is a saturated or partially unsaturated framework.

[0174] In one embodiment, the linker framework includes C and H atoms and at least two heteroatoms.

[0175] In one embodiment, the linker framework includes C and H atoms and at least one N heteroatom.

[0176] In one embodiment, the linker framework includes C and H atoms and at least two heteroatoms selected from N and O.

[0177] In one embodiment, the linker framework includes C and H atoms and at least four heteroatoms.

[0178] In one embodiment, the linker framework includes C and H atoms and at least four heteroatoms selected from N and O.

[0179] In one embodiment, the linker framework includes C and H atoms, as well as at least two N heteroatoms and at least two O heteroatoms.

[0180] In one embodiment, the linker framework includes 1 to 10 heteroatoms.

[0181] In one embodiment, the linker framework includes 2 to 10 heteroatoms.

[0182] In one embodiment, the linker framework includes 4 to 10 heteroatoms.

[0183] In one embodiment, the heteroatoms included in the linker framework are selected from only N and O.

[0184] In one embodiment, the linker has a minimum length of 8 to 26 atoms between "a" and "b".

[0185] In one embodiment, the total number of carbon atoms and heteroatoms in the linker framework is 8 to 30.

[0186] In one embodiment, the total number of carbon atoms and heteroatoms in the linker framework is 10 to 28.

[0187] In one embodiment, the linker is a saturated, partially or completely unsaturated framework comprising C and H atoms and at least one heteroatom, wherein the framework has bonding endpoints "a" and "b" (and where "b" may include two bonding points "b1" and "b2" if there are two bonding points to Z at the "b" end of the linker), and the minimum length between "a" and "b" is 6 to 26 atoms; wherein the framework consists of one or more linear and / or branched and / or rings, and any available C atoms are optionally substituted with one or more F atoms; wherein the linker is; Once on Z: with any available C or N atom on Z; or Z twice:X H , X G , and X J (If present, and X K ) are bonded in any two adjacent available C and / or N atoms such that a 5- to 7-membered ring is formed by linker bonding at two adjacent atoms of Z;

[0188] In one embodiment, the linker framework may include (or consist of) one or more linear and / or branched chains and / or rings, where one or more F atoms are optionally substituted on any available C atoms (where the total number of branches is between 0 and 5).

[0189] In one embodiment, the linker framework may include (or consist of) one or more linear and / or branched chains and / or rings, where one or more F atoms are optionally substituted on any available C atoms (where the total number of branches is between 0 and 3).

[0190] In one embodiment, the linker framework may include (or consist of) one or more linear and / or branched chains and / or rings, where any available C atom is optionally substituted with one or more F atoms (where the total number of branches is 0 to 2). In one embodiment, the total number of branches is 2. In one embodiment, the total number of branches is 2, and each branch consists of = O.

[0191] In one embodiment, any / each branch of the linker framework has 1 to 5 carbon and / or heteroatoms.

[0192] In one embodiment, any / each branch of the linker framework has 1 to 3 carbon and / or heteroatoms.

[0193] In one embodiment, any / each branch of the linker framework has one C and / or heteroatom.

[0194] In one embodiment, the total number of carbon and / or heteroatoms in the branching (if any) of the linker framework is 1 to 5.

[0195] In one embodiment, the total number of carbon and / or heteroatoms in the branching (if any) of the linker framework is 1 to 3.

[0196] In one embodiment, the total number of carbon and / or heteroatoms in the linker framework branches (if any) is 1.

[0197] In one embodiment, any heteroatom present in the linker branch is an oxygen atom.

[0198] In one embodiment, the linker framework is optionally substituted with one or two F atoms on any available C atoms.

[0199] In one embodiment, the linker framework is optionally substituted with one F on any available C atom.

[0200] In one embodiment, the linker framework is not replaced by any F.

[0201] In one embodiment, the linker is a partially unsaturated framework comprising C and H atoms and at least one heteroatom, wherein the framework has bond endpoints "a" and "b"; and The minimum length between "a" and "b" is between 8 and 24 atoms; Here, the total number of carbon atoms and heteroatoms in the linker framework is between 10 and 26; The above framework includes one or more linear and / or branched and / or ring chains (where the total number of branches is between 0 and 2); Here, any branch of the linker framework has one carbon and / or heteroatom; Here, the linker is bonded once to Z: to any available C or N atom of Z.

[0202] In one embodiment, the linker is: [ka] [In the expression, u is selected from 0 to 6].

[0203] In one embodiment, u is 0.

[0204] In one embodiment, u is 2.

[0205] In one embodiment, u is 6.

[0206] In one aspect of this specification, a PROTAC compound or a pharmaceutically acceptable salt thereof containing an E3 ubiquitin ligase binding unit of formula (Ia) is provided, wherein the PROTAC compound is of formula (Ib): [ka] [In the formula, Q C The ring is a 4- to 11-membered saturated heterocyclic group; E is linked to an available C or N atom of Z, where If E is linked to an available C atom of Z, then E is either C or N. If E is linked to an available N atom of Z, then E is; Z, Y, R A , and v each contain units of [which can take any of the values ​​specified herein for each of these integers].

[0207] In one embodiment, E is N and is connected to an available C of Z.

[0208] In one embodiment, E is C and is connected to an available C or N of Z.

[0209] In one embodiment, E is C and is connected to an available N of Z.

[0210] In one embodiment, E is C and is connected to an available C of Z.

[0211] In one embodiment, Q C The ring is a 6-membered saturated heterocyclic group.

[0212] In one embodiment, Q C The ring is piperazine or piperidine.

[0213] In one embodiment, Q C The ring is 1,4-piperazine-1,4-diyl or piperidine-1,4-diyl.

[0214] In one embodiment, Q C The ring is piperazine.

[0215] In one embodiment, E is N and is connected to the available C of Z, Q C The ring is piperazine.

[0216] In one embodiment, Q C The ring is piperidine.

[0217] In one embodiment, E is C and Q C The ring is piperidine.

[0218] One aspect of this specification provides a PROTAC compound or a pharmaceutically acceptable salt thereof containing an E3 ubiquitin ligase binding unit of formula (Ia), wherein the PROTAC compound is of formula (Ic): [ka] [In the formula, t is 1 or 2, and Z, Y, R A , and v each contain units that can take any of the values ​​specified herein for each of these variables. In one embodiment, t is 1. In one embodiment, t is 2.

[0219] In further embodiments, compounds or pharmaceutically acceptable salts thereof are provided, where the compounds are selected from one or more of the “Examples” listed below. The Examples relate to the names of the compounds in the title and should be understood not to be limited by the method of preparation or by whether a given compound was isolated in the form of a salt rather than as a neutral molecule.

[0220] PROTAC compounds containing the compound of formula (I) and the bonding unit of formula (Ia) may have one or more chiral centers, and it will be recognized that such compounds may be prepared, isolated and / or supplied with or without the presence of one or more other possible enantio and / or diastereoisomers of the above compound, or that such isomers may be supplied in any relative proportion. The preparation of enantioenriched / enantiopure and / or diastereoenriched / diastereopure compounds may be carried out by standard techniques of organic chemistry well known in the art, for example, by synthesis from enantioenriched or enantiopure starting materials and / or by the use of appropriate enantioenriched or enantiopure catalysts in synthesis and / or by separation of racemic or partially enriched mixtures of stereoisomers, for example, via chiral chromatography.

[0221] For use in a pharmaceutical context, it is preferable to provide such compounds (or their pharmaceutically acceptable salts) in the absence of large quantities of other stereoisomers.

[0222] Accordingly, in one embodiment, a composition is provided comprising, optionally together with one or more other stereoisomers of the compound of formula (I) [or a PROTAC compound containing a unit of formula (Ia)] or a pharmaceutically acceptable salt thereof, the compound of formula (I) [or a PROTAC compound containing a unit of formula (Ia)] or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) [or a PROTAC compound containing a unit of formula (Ia)] or a pharmaceutically acceptable salt thereof is present in the composition at a diastereomer excess of ≥90% (%de).

[0223] In a further embodiment, the %de of the above-described composition is ≥95%.

[0224] In a further embodiment, the %de of the composition described above is ≥98%.

[0225] In a further embodiment, the %de of the composition described above is ≥99%.

[0226] In further embodiments, a composition is provided comprising, optionally together with one or more other stereoisomers of the compound of formula (I) [or a PROTAC compound containing a unit of formula (Ia)] or a pharmaceutically acceptable salt thereof, the compound of formula (I) [or a PROTAC compound containing a unit of formula (Ia)] or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) [or a PROTAC compound containing a unit of formula (Ia)] or a pharmaceutically acceptable salt thereof is present in the composition at an enantiomer excess of ≥90% (%ee).

[0227] In further embodiments, the %ee of the above-described composition is ≥95%.

[0228] In further embodiments, the %ee of the above-described composition is ≥98%.

[0229] In further embodiments, the %ee of the above-described composition is ≥99%.

[0230] In further embodiments, a composition is provided comprising a compound of formula (I) [or a PROTAC compound containing a unit of formula (Ia)] or a pharmaceutically acceptable salt thereof, optionally together with one or more other stereoisomers of the compound of formula (I) [or a PROTAC compound containing a unit of formula (Ia)] or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) [or a PROTAC compound containing a unit of formula (Ia)] or a pharmaceutically acceptable salt thereof is present in the composition with an enantiomer excess of ≥90% (%ee) and a diastereomer excess of ≥90% (%de).

[0231] In further embodiments of the composition described above, %ee and %de may take any combination of the following values: • %ee is ≤ 5% and %de is ≥ 80%. • %ee is ≤ 5% and %de is ≥ 90%. • %ee is ≤ 5% and %de is ≥ 95%. • %ee is ≤5% and %de is ≥98%. • %ee is ≤95% and %de is ≥95%. • %ee is ≤98% and %de is ≥98%. • %ee is ≤99% and %de is ≥99%.

[0232] In further embodiments, pharmaceutical compositions are provided comprising a compound of formula (I) [or a PROTAC compound containing a unit of formula (Ia)] or a pharmaceutically acceptable salt thereof in association with a pharmaceutically acceptable excipient.

[0233] In one embodiment, a pharmaceutical composition is provided comprising a compound of formula (I) [or a PROTAC compound containing a unit of formula (Ia)] or a pharmaceutically acceptable salt thereof in association with a pharmaceutically acceptable excipient, and optionally further comprising one or more other stereoisomers of the compound of formula (I) [or a PROTAC compound containing a unit of formula (Ia)] or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) [or a PROTAC compound containing a unit of formula (Ia)] or a pharmaceutically acceptable salt thereof is present in the composition at an enantiomer excess of ≥90% (%ee).

[0234] In further embodiments, the %ee of the above-described composition is ≥95%.

[0235] In further embodiments, the %ee of the above-described composition is ≥98%.

[0236] In further embodiments, the %ee of the above-described composition is ≥99%.

[0237] In one embodiment, a pharmaceutical composition is provided comprising a compound of formula (I) [or a PROTAC compound containing a unit of formula (Ia)] or a pharmaceutically acceptable salt thereof in association with a pharmaceutically acceptable excipient, and optionally further comprising one or more other stereoisomers of the compound of formula (I) [or a PROTAC compound containing a unit of formula (Ia)] or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) [or a PROTAC compound containing a unit of formula (Ia)] or a pharmaceutically acceptable salt thereof is present in the composition at a diastereomer excess of ≥90% (%de).

[0238] In a further embodiment, the %de of the above-described composition is ≥95%.

[0239] In a further embodiment, the %de of the composition described above is ≥98%.

[0240] In a further embodiment, the %de of the composition described above is ≥99%.

[0241] In one embodiment, a pharmaceutical composition is provided comprising a compound of formula (I) [or a PROTAC compound containing a unit of formula (Ia)] or a pharmaceutically acceptable salt thereof in association with a pharmaceutically acceptable excipient, and optionally comprising one or more other stereoisomers of the compound of formula (I) [or a PROTAC compound containing a unit of formula (Ia)] or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) [or a PROTAC compound containing a unit of formula (Ia)] or a pharmaceutically acceptable salt thereof is present in the composition with an enantiomer excess of ≥90% (%ee) and a diastereomer excess of ≥90% (%de).

[0242] In further embodiments of the pharmaceutical composition described above, %ee and %de may take any of the following combinations of values: • %ee is ≤95% and %de is ≥95%. • %ee is ≤98% and %de is ≥98%. • %ee is ≤99% and %de is ≥99%.

[0243] Compounds of formula (I) [or PROTAC compounds containing units of formula (Ia)] and their pharmaceutically acceptable salts may be prepared, used, or supplied in amorphous, crystalline, or semicrystalline form, and any given compound of formula (I) [or PROTAC compounds containing units of formula (Ia)] or its pharmaceutically acceptable salt may be formed into two or more crystalline / polymorphic forms, including hydrated forms (e.g., hemihydrate, monohydrate, dihydrate, trihydrate, or other stoichiometric hydrates) and / or solvated forms. It should be understood that this specification encompasses all such solid forms of compounds of formula (I) [or PROTAC compounds containing units of formula (Ia)] and their pharmaceutically acceptable salts.

[0244] Further embodiments provide a compound of formula (I) [or a PROTAC compound containing a unit of formula (Ia)] that can be obtained by the method described in the "Examples" section below.

[0245] intermediate compound PROTAC compounds containing the E3 ubiquitin ligase binding unit of formula (Ia) can be prepared from certain intermediate compounds, some of which are shown in the experimental section below. For example, such a PROTAC compound is of formula (II): [ka] [In formula: R J is H; Q C The ring is a 4- to 11-membered saturated heterocyclic group; E is linked to an available C or N atom of Z, where If E is linked to an available C atom of Z, then E is either C or N. If E is linked to an available N atom of Z, then E is; Z, Y, R A[v, and v can each take any of the values ​​described herein for each of these integers] may be prepared by alkylation, reductive amination, or amide coupling reaction using the compound or salt thereof.

[0246] Such compounds of formula (II) can be coupled with carboxylic acids using typical amide coupling conditions well known to those skilled in the art. For example, PyBOP or HATU can be used with a non-nucleophilic organic base such as DIPEA in a solvent such as DMF at room temperature.

[0247] Alternatively, a compound of formula (II) can be subjected to reductive amination conditions for forming the PROTAC of this specification.

[0248] Such compounds of formula (II) can be alkylated using R-Hal, for example, R-Cl, or using a non-halogenated leaving group, for example, a mesylate. Such alkylation coupling can be carried out using a non-nucleophilic base in a suitable solvent such as DMA, under conditions well known to those skilled in the art.

[0249] R J The compounds of the above formula (II) in which is H are sequentially R J This can be prepared by deprotecting the compound of formula (II) in which is a nitrogen protecting group, for example, a tert-butoxycarbonyl (BOC) protecting group. Such deprotection can be carried out using acidic conditions well known to those skilled in the art, for example, using the conditions exemplified in the experimental section below for such deprotection.

[0250] Therefore, in one aspect of this specification, a compound of formula (II) shown above or a salt thereof is provided, wherein: R J is an H or N protecting group; Q C The ring is a 4- to 11-membered saturated heterocyclic group; E is linked to an available C or N atom of Z, where If E is linked to an available C atom of Z, then E is either C or N. If E is linked to an available N atom of Z, then E is C; Z, Y, R A , and v can each take any of the values ​​specified herein for each of these integers.

[0251] In one embodiment, R J This is H or tert-butoxycarbonyl.

[0252] In one embodiment, R J H is H.

[0253] In one embodiment, R J It is tert-butoxycarbonyl.

[0254] In one embodiment, E is N and is connected to an available C of Z.

[0255] In one embodiment, E is C and is connected to an available C or N of Z.

[0256] In one embodiment, E is C and is connected to an available N of Z.

[0257] In one embodiment, E is C and is connected to an available C of Z.

[0258] In one embodiment, Q C The ring is a 6-membered saturated heterocyclic group.

[0259] In one embodiment, Q C The ring is piperazine or piperidine.

[0260] In one embodiment, E is N and is connected to the available C of Z, Q C The ring is piperazine.

[0261] In one embodiment, E is C, and is connected to an available C or N of Z, Q C The ring is piperidine.

[0262] Alternatively, for example, such a PROTAC compound may be of formula (III): [ka] [In the formula, w is 1 or 2, R H H is; Z, Y, R A [v, and v, can each take any of the values ​​described herein for each of these integers] can be prepared by amide coupling reaction with a compound of formula (III) or a salt thereof. Such compounds of formula (III) can be coupled with primary or secondary amine compounds using typical amide coupling conditions well known to those skilled in the art. For example, PyBOP or HATU can be used with a non-nucleophilic organic base such as DIPEA in a solvent such as DMF at room temperature. H The compounds of formula (III) where is H are sequentially R H C 1~8 Hydrocarbyl, for example, C 1~6 It can be prepared by hydrolysis of an alkyl ester compound of formula (III). Such hydrolysis may be carried out using a metal hydroxide salt, for example, LiOH in a polar solvent, under the conditions shown in the experimental section below, or otherwise under conditions well known to those skilled in the art.

[0263] Therefore, in one aspect of this specification, a compound of formula (III) shown above or a salt thereof is provided, wherein: w is either 1 or 2; R H H or C 1~8 It is hydrocarbyl; Z, Y, R A , and v can each take any of the values ​​specified herein for each of these integers.

[0264] In one embodiment, w is 1.

[0265] In one embodiment, w is 2.

[0266] In one embodiment, R H H is H.

[0267] In one embodiment, R H is C 1~8 It is hydrocarbil.

[0268] In one embodiment, R H H or C 1~6 It is alkyl.

[0269] In one embodiment, R H is C 1~6 It is alkyl.

[0270] In one embodiment, R H H or C 1~3 It is alkyl.

[0271] In one embodiment, R H is C 1~3 It is alkyl.

[0272] In one embodiment, R H is either H or methyl.

[0273] In one embodiment, R H It is methyl.

[0274] In one embodiment, the compound of formula (III) is other than 3-[6-(2,4-dioxohexahydropyrimidine-1-yl)-2-oxo-1,3-benzoxazole-3-yl]propanoic acid.

[0275] In addition to the methods described above, the compounds of formulas (I), (II), and (III) can be prepared using standard procedures and knowledge known to a skilled chemist, following the general procedures and chemical transformations shown in the experimental section below.

[0276] Further embodiments of this specification provide compounds or salts thereof, wherein the compounds are selected from one or more “intermediates” listed in the following experimental section.

[0277] The intermediate compounds listed below relate to the chemical names listed in the titles of the experimental section and should be understood not to be limited by the preparation method or whether a given intermediate compound was isolated in the form of a salt rather than as a neutral molecule.

[0278] A further embodiment of this specification provides a pharmaceutical composition comprising a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof in association with a pharmaceutically acceptable excipient.

[0279] A further aspect of this specification provides a pharmaceutical composition comprising a PROTAC compound containing an E3 ubiquitin ligase binding unit of formula (Ia) as defined herein, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable excipient.

[0280] Further embodiments of this specification provide pharmaceutical compositions comprising a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof for use in the treatment of cancer.

[0281] A further embodiment of this specification provides a pharmaceutical composition for use in the treatment of cancer, comprising a PROTAC compound containing an E3 ubiquitin ligase binding unit of formula (Ia) as defined herein, or a pharmaceutically acceptable salt thereof.

[0282] Further embodiments of this specification provide pharmaceutical compositions comprising a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof for use in the treatment of solid tumors.

[0283] A further embodiment of this specification provides a pharmaceutical composition comprising a PROTAC compound containing an E3 ubiquitin ligase binding unit of formula (Ia) as defined herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of solid tumors.

[0284] Further embodiments of this specification provide pharmaceutical compositions comprising a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof for use in the treatment of BRD4-sensitive tumor types.

[0285] The composition may be in a dosage form suitable for oral use (e.g., tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs, etc.) or in a dosage form suitable for parenteral administration (e.g., sterile aqueous or oily solutions for intravenous, subcutaneous or intramuscular administration). The composition can be obtained by conventional procedures using conventional pharmaceutical excipients well known in the art. Therefore, compositions intended for oral use may contain, for example, one or more colorants, sweeteners, flavorings and / or preservatives.

[0286] For further information regarding the formulation, readers should refer to Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990, Volume 5, Chapter 25.2.

[0287] The amount of active ingredient combined with one or more excipients to produce a single dosage form will inevitably vary depending on the host being treated and the specific route of administration.

[0288] The size of the doses of the compounds described herein for therapeutic or prophylactic purposes will naturally vary depending on the nature and severity of the disease, the age and sex of the animal or patient, and the route of administration, in accordance with well-known principles of pharmacopoeia.

[0289] Further embodiments of this specification provide compounds of formula (I) as defined herein or pharmaceutically acceptable salts thereof for use as pharmaceuticals.

[0290] Further embodiments of this specification provide a PROTAC compound containing an E3 ubiquitin ligase binding unit of formula (Ia) as defined herein, or a pharmaceutically acceptable salt thereof, for use as a pharmaceutical.

[0291] Further embodiments of this specification provide compounds of formula (I) as defined herein or pharmaceutically acceptable salts thereof for use in therapy.

[0292] Further embodiments of this specification provide a PROTAC compound or a pharmaceutically acceptable salt thereof containing an E3 ubiquitin ligase binding unit of formula (Ia) as defined herein, for use in therapy.

[0293] Further aspects of this specification provide compounds of formula (I) as defined herein or pharmaceutically acceptable salts thereof for use in methods of therapeutically treating the body of a human or animal.

[0294] Further aspects of this specification provide a PROTAC compound containing an E3 ubiquitin ligase binding unit of formula (Ia) as defined herein, or a pharmaceutically acceptable salt thereof, for use in methods of therapeutically treating the body of a human or animal.

[0295] Further embodiments of this specification provide compounds of formula (I) as defined herein or pharmaceutically acceptable salts thereof for use in exerting antiproliferative effects (for example, in warm-blooded animals such as humans).

[0296] Further embodiments of this specification provide a PROTAC compound containing an E3 ubiquitin ligase binding unit of formula (Ia) as defined herein, or a pharmaceutically acceptable salt thereof, for use in exerting an antiproliferative effect (for example, in warm-blooded animals such as humans).

[0297] Further embodiments of this specification provide compounds of formula (I) as defined herein or pharmaceutically acceptable salts thereof for use in warm-blooded animals such as humans to exert a proteolytic effect.

[0298] Further embodiments of this specification provide a PROTAC compound containing an E3 ubiquitin ligase binding unit of formula (Ia) as defined herein, or a pharmaceutically acceptable salt thereof, for use in warm-blooded animals such as humans to exert a proteolytic effect.

[0299] Further embodiments of this specification provide the use of a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof for producing a pharmaceutical product to exert an antiproliferative effect (for example, in warm-blooded animals such as humans).

[0300] Further aspects of this specification provide the use of a PROTAC compound containing an E3 ubiquitin ligase binding unit of formula (Ia) as defined herein, or a pharmaceutically acceptable salt thereof, for the production of a pharmaceutical product for exerting an antiproliferative effect (for example, in warm-blooded animals such as humans).

[0301] Further aspects of this specification provide the use of a PROTAC compound containing an E3 ubiquitin ligase binding unit of formula (Ia) as defined herein, or a pharmaceutically acceptable salt thereof, for the production of a pharmaceutical product for exerting a proteolytic effect (for example, in warm-blooded animals such as humans).

[0302] A further aspect of this specification provides a method for exerting an antiproliferative effect in a warm-blooded animal such as a human being that requires such an effect, the method comprising administering to the animal an effective amount of a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof.

[0303] A further aspect of this specification provides a method for exerting an antiproliferative effect in a warm-blooded animal such as a human being that requires such an effect, the method comprising administering to the animal an effective amount of a PROTAC compound containing an E3 ubiquitin ligase binding unit of formula (Ia) as defined herein, or a pharmaceutically acceptable salt thereof.

[0304] A further aspect of this specification provides a method for exerting a proteolytic effect in a warm-blooded animal such as a human that requires such an effect, the method comprising administering to the animal an effective amount of a PROTAC compound containing the E3 ubiquitin ligase binding unit of formula (Ia) or a pharmaceutically acceptable salt thereof.

[0305] Further aspects of this specification provide compounds of formula (I) as defined herein or pharmaceutically acceptable salts thereof for use as anti-invasive agents in the containment and / or treatment of solid tumor diseases (e.g., in warm-blooded animals such as humans).

[0306] Further embodiments of this specification provide a PROTAC compound containing an E3 ubiquitin ligase binding unit of formula (Ia) as defined herein, or a pharmaceutically acceptable salt thereof, for use as an anti-invasive agent in the containment and / or treatment of solid tumor diseases (e.g., in warm-blooded animals such as humans).

[0307] Further embodiments of this specification provide the use of a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical product for use as an anti-invasive agent in the containment and / or treatment of solid tumor diseases (for example, in warm-blooded animals such as humans).

[0308] Further aspects of this specification provide the use of a PROTAC compound containing an E3 ubiquitin ligase binding unit of formula (Ia) as defined herein, or a pharmaceutically acceptable salt thereof, for the manufacture of a pharmaceutical product for use as an anti-invasion agent in the containment and / or treatment of solid tumor diseases (e.g., in warm-blooded animals such as humans).

[0309] A further aspect of this specification provides a method for exerting an anti-invasive effect by containing and / or treating a solid tumor disease in a warm-blooded animal such as a human being that requires such an effect, the method comprising administering to the animal an effective amount of a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof.

[0310] A further aspect of this specification provides a method for exerting an anti-invasive effect by containment and / or treatment of solid tumor disease in a warm-blooded animal such as a human being that requires such an effect, the method comprising administering to the animal an effective amount of a PROTAC compound containing an E3 ubiquitin ligase binding unit of formula (Ia) as defined herein, or a pharmaceutically acceptable salt thereof.

[0311] Further embodiments of this specification provide compounds of formula (I) as defined herein or pharmaceutically acceptable salts thereof for use in the prevention or treatment of cancer (for example, in warm-blooded animals such as humans).

[0312] Further embodiments of this specification provide a PROTAC compound containing an E3 ubiquitin ligase binding unit of formula (Ia) as defined herein, or a pharmaceutically acceptable salt thereof, for use in the prevention or treatment of cancer (for example, in warm-blooded animals such as humans).

[0313] Further embodiments of this specification provide the use of a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the prevention or treatment of cancer (for example, in warm-blooded animals such as humans).

[0314] Further embodiments of this specification provide the use of a PROTAC compound containing an E3 ubiquitin ligase binding unit of formula (Ia) as defined herein, or a pharmaceutically acceptable salt thereof, for the manufacture of a pharmaceutical for the prevention or treatment of cancer (for example, in warm-blooded animals such as humans).

[0315] A further aspect of this specification provides a method for preventing or treating cancer in a warm-blooded animal, such as a human, that requires such treatment, the method comprising administering to the animal an effective amount of a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof.

[0316] A further aspect of this specification provides a method for preventing or treating cancer in a warm-blooded animal, such as a human, that requires such treatment, comprising administering to the animal an effective amount of a PROTAC compound containing an E3 ubiquitin ligase binding unit of formula (Ia) as defined herein, or a pharmaceutically acceptable salt thereof.

[0317] Further embodiments of this specification provide compounds of formula (I) as defined herein or pharmaceutically acceptable salts thereof for use in the prevention or treatment of solid tumors (for example, in warm-blooded animals such as humans).

[0318] Further embodiments of this specification provide a PROTAC compound containing an E3 ubiquitin ligase binding unit of formula (Ia) as defined herein, or a pharmaceutically acceptable salt thereof, for use in the prevention or treatment of solid tumors (for example, in warm-blooded animals such as humans).

[0319] Further embodiments of this specification provide the use of a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the prevention or treatment of solid tumors (for example, in warm-blooded animals such as humans).

[0320] Further embodiments of this specification provide the use of a PROTAC compound containing an E3 ubiquitin ligase binding unit of formula (Ia) as defined herein, or a pharmaceutically acceptable salt thereof, for the manufacture of a pharmaceutical for the prevention or treatment of solid tumors (for example, in warm-blooded animals such as humans).

[0321] A further aspect of this specification provides a method for preventing or treating a solid tumor in a warm-blooded animal, such as a human, that requires such treatment, the method comprising administering to the animal an effective amount of a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof.

[0322] A further aspect of this specification provides a method for preventing or treating a solid tumor in a warm-blooded animal, such as a human, that requires such treatment, comprising administering to the animal an effective amount of a PROTAC compound containing an E3 ubiquitin ligase binding unit of formula (Ia) as defined herein, or a pharmaceutically acceptable salt thereof.

[0323] Further embodiments of this specification provide compounds of formula (I) as defined herein or pharmaceutically acceptable salts thereof for use in the prevention or treatment of tumor types sensitive to inhibition and / or degradation of BRD4.

[0324] Further embodiments of this specification provide the use of a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the prevention or treatment of tumor types sensitive to inhibition and / or degradation of BRD4.

[0325] A further aspect of this specification provides a method for the prevention or treatment of tumor types sensitive to inhibition and / or degradation of BRD4 in a warm-blooded animal such as a human requiring such treatment, the method comprising administering to the animal an effective amount of a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof.

[0326] Further embodiments of this specification provide compounds of formula (I) as defined herein or pharmaceutically acceptable salts thereof for use in providing an inhibitory and / or degradative effect on BRD4.

[0327] Further embodiments of this specification provide the use of a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof for producing a pharmacopoeia to induce an inhibitory and / or degradative effect on BRD4.

[0328] A further aspect of this specification provides a method for achieving inhibition and / or degradation of BRD4 in a warm-blooded animal such as a human being that requires such an effect, the method comprising administering to the animal an effective amount of a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof.

[0329] Further embodiments of this specification provide compounds of formula (I) as defined herein or pharmaceutically acceptable salts thereof for use in providing selective inhibition and / or degradation effects on BRD4.

[0330] Further aspects of this specification provide the use of a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof for producing a pharmacopoeia to induce a selective inhibitory and / or degradative effect on BRD4.

[0331] A further aspect of this specification provides a method for achieving selective inhibition and / or degradation of BRD4 in a warm-blooded animal such as a human being that requires such an effect, the method comprising administering an effective amount of a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof.

[0332] The anticancer treatments defined herein may be applied as monotherapy, or may include conventional surgery, radiotherapy, or chemotherapy in addition to the compounds specified herein.

[0333] The combination therapies described above can be added to standard treatments that are typically administered according to their usual prescription schedule.

[0334] The compounds of formula (I) are primarily beneficial as therapeutic agents for use in warm-blooded animals (including humans), but they are also always useful when inhibition and / or degradation of BRD4 is required. Therefore, they are useful as pharmacological standards for use in the development of new biological studies and the search for new drugs with novel pharmacological effects.

[0335] Chemical synthesis and biological assay procedures: Common abbreviations: Use the following abbreviations. Ac = Acetyl; AcOH = Acetic acid; Ac2O = Acetic anhydride; Boc = Tert-butyloxycarbonyl; C-18FC = C-18 flash chromatography; CDI = Carbonyl diimidazole; dba = Dibenzylideneacetone; DBU = 1,8-Diazabicyclo[5.4.0]undec-7-ene; DCE = 1,2-Dichloroethane; DCM = Dichloromethane; DIAD = Diisopropyl azodicarboxylate; DIEA = N,N-Diisopropylethylamine; DMAP = 4-(dimethylamino)pyridine; DMF = N,N-Dimethylformamide; DMSO = Dimethyl sulfoxide; EDC = 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide; Ephos = Dicyclohexyl(3-Isopropoxy-2',4',6'-Triisopropyl-[1,1'-Biphenyl]-2-yl)phosphane; "Ephos Pd G4 = Dicyclohexyl-[2-propan-2-yloxy-6-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphanium; methanesulfonic acid; methyl-(2-phenylphenyl)azanide; palladium(2+) (CAS number: 2132978-44-8); ES = electrospray (in the context of mass spectrometry); Depositphotos = ethyl acetate; FA = formic acid; FSC = flash silica chromatography; h = time; HOBt = hydroxybenzotriazole; HPLC = high-performance liquid chromatography; m / z = mass / min Mass-to-charge ratio related to spectroscopy; NCS = N-chlorosuccinimide; NMP = N-methyl-2-pyrrolidone; NMR = nuclear magnetic resonance; petroleum ether = distilled petroleum fraction at 60-90°C; Ph = phenyl; PMB = p-methoxybenzyl; PPA = polyphosphate; PyBOP = (benzotriazole-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate); Rossell's salt = L(+) monosodium monopotassium tartrate tetrahydrate; rt = room temperature (approx. 18-25°C); selectfluor = 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2] Octanebis(tetrafluoroborate); SEM = 2-(trimethylethylsilyl)ethoxymethyl; THF = tetrahydrofuran; TFA = trifluoroacetic acid; TMEDA = tetramethylethylenediamine; xanthophos = 4,5-bis(diphenylphosphin)-9,9-dimethylxanthene.

[0336] NMR: Proton NMR ( 1 Unless otherwise specified, 1H NMR was performed in deuterated DMSO at temperatures ranging from 15 to 30°C at 300 or 400 MHz. 19 F NMR was performed in deuterated DMSO unless otherwise specified. Where clear, the salts (hydrochlorides, formates, 2,2,2-trifluoroacetate salts) 1 1H NMR and / or salt (2,2,2-trifluoroacetate salt) 19 The F NMR peaks were included in the characterization. In certain cases, exchangeable protons were not reported in the characterization because they were too broad or not evident in the spectrum. Standard NMR abbreviations are used: s=single, d=doublet, t=triplet, q=quartet, dd=doublet-doublet, dt=doublet-triplet, m=multiplet, br=broad.

[0337] Unless otherwise specified, preparative HPLC was performed using one of the following columns and eluents: Column A: Waters XBridge Shield RP18 OBD column, 30*150mm, 5μm Column B: Waters XBridge Prep OBD C18 column, 30*150mm, 5μm Column C: Waters XBridge Shield RP18 OBD column, 19*250mm, 10μm Column D: Waters XSelect CSH Prep C18 OBD column, 19*250mm, 5μm Column E: Waters Sunfire prep C18 column, 30*150mm, 5μm Column F: Waters SunFire C18 OBD Prep column, 100 Å, 19 x 250 mm, 5 μm Column G: Waters Xselect CSH OBD column, 30*150mm, 5μm Column H: Waters Sunfire prep C18 OBD column, 19*250mm, 10μm Column J: Waters XBridge prep OBD C18 column, 19*250mm, 5μm Column K: Waters Atlantis prep T3 OBD column, 19*250mm, 10μm Column L: Waters XSelect CSH fluorophenyl 30*150mm, 5μm Column X: Waters XSelect CSH F-phenyl OBD column, 19*250mm, 5μm Column Y: Waters XBridge BEH C18 OBD prep column, 19*250mm, 5μm Column Z: Waters XBridge Phenyl OBD prep column, 19*250mm, 5μm Eluent A: Water (containing 0.05% TFA) and a mixture that reduces the polarity of MeCN. Eluent B: Water (containing 10 mmol / L NH4HCO3 + 0.1% NH3.H2O) and a mixture that reduces the polarity of MeCN. Eluent C: Water (containing 0.05% TFA) and a mixture that reduces the polarity of MeOH. Eluent D: Water (containing 10 mmol / L NH4HCO3) and a mixture that reduces the polarity of MeCN. Eluent E: Water (containing 0.1% FA) and a mixture that reduces the polarity of MeCN. Eluent F: Water (containing 0.05% NH4OH) and a mixture that reduces the polarity of MeCN. Eluent G: Water (containing 10 mmol / L NH4HCO3 + 0.1% NH3.H2O) and a mixture (MeOH-MeCN 1:2) whose polarity is reduced.

[0338] Solvent removal: Concentration of a solution (to partially or completely remove the solvent) is generally carried out under reduced pressure at or above room temperature.

[0339] Chromatography: The fractions that appear clear and contain the desired product are generally identified, combined, and then concentrated under reduced pressure. [Examples]

[0340] Example 1: 1-(benzofuran-6-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Cs2CO3 (471 mg, 1.45 mmol) was added at room temperature under N2 to a degassed mixture of 6-bromobenzofuran (95.0 mg, 0.482 mmol), dihydropyrimidine-2,4(1H,3H)-dione (165 mg, 1.45 mmol), Ephos (12.9 mg, 0.0241 mmol), and Ephos Pd G4 (22.1 mg, 0.0241 mmol) in 1,4-dioxane (5 mL). The resulting mixture was stirred at 100 °C for 20 hours. The crude product was directly purified by C-18FC (gradient: 25-60% MeCN (in water)) to obtain the title compound (53.1 mg, 48%) as a white solid. 1 H NMR:δ 2.74(2H,t),3.84(2H,t),6.98(1H,dd),7.25(1H,dd),7.63(2H,m),8.03(1H,d),10.40(1H,s).m / z(ES + ),[M+H] + =231.0.

[0341] Example 2: 1-(benzo[d]thiazole-7-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] 7-bromobenzo[d]thiazole (100 mg, 0.467 mmol) was added at room temperature under N2 conditions to a degassed mixture of dihydropyrimidine-2,4(1H,3H)-dione (213 mg, 1.87 mmol), Ephos Pd G4 (42.9 mg, 0.0467 mmol), and Ephos (25.0 mg, 0.0467 mmol) with Cs2CO3 (457 mg, 1.40 mmol) in 1,4-dioxane (10 mL). The resulting mixture was stirred at 100 °C for 16 hours. The solvent was then removed under reduced pressure. The substance was obtained by purification by C-18FC (gradient: 0-20% MeCN (in water)), and further purified by preparative HPLC (column A, eluent A, gradient: 4-14%) to obtain the title compound (29.0 mg, 25%) as a white solid. 1 H NMR:(CD3OD)δ 2.91(2H,t),3.98(2H,t),7.51-7.57(1H,m),7.67(1H,t),8.09(1H,dd),9.29(1H,s).m / z(ES + ),[M+H] + =248.0.

[0342] Example 3: 1-(pyrazolo[1,5-a]pyridine-6-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] A degassed mixture of Cs2CO3 (496 mg, 1.52 mmol), 6-bromopyrazolo[1,5-a]pyridine (100 mg, 0.508 mmol), dihydropyrimidine-2,4(1H,3H)-dione (174 mg, 1.52 mmol), Ephos (13.6 mg, 0.0254 mmol), and Ephos Pd G4 (23.3 mg, 0.025 mmol) in 1,4-dioxane (10 mL) was stirred at 120°C under N2 for 20 hours. The resulting mixture was filtered, and the solid was washed with 1,4-dioxane. The solvent in the filtrate was removed under reduced pressure. The residue was purified by C-18FC (gradient: 0-30% MeCN (in water)), and then further purified by preparative HPLC (column B, eluent B, gradient: 2-25%) to obtain the title compound (12.4 mg, 11%) as a white solid. 1H NMR:δ 2.75(t,2H),3.82(t,2H),6.64(dd,1H),7.26(dd,1H),7.70(dd,1H),8.02(d,1H),8.80(dt,1H),10.49(s,1H).m / z(ES + ),[M+H] + =231.0.

[0343] Example 4: 1-(benzo[d]oxazol-7-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Ephos Pd G4 (46.4 mg, 0.0505 mmol) was added at room temperature under N2 to a degassed mixture of Ephos (27.0 mg, 0.0505 mmol), Cs2CO3 (494 mg, 1.52 mmol), 7-bromobenzo[d]oxazole (100 mg, 0.505 mmol), and dihydropyrimidine-2,4(1H,3H)-dione (230 mg, 2.02 mmol) in 1,4-dioxane (12 mL). The resulting mixture was stirred at 100 °C for 16 hours. The solvent was then removed under reduced pressure. Purification by FSC (gradient 0-4% MeOH (in DCM)) yielded the title compound (40.0 mg, 34%) as a pale yellow solid. 1 H NMR:δ 10.60(s,1H),8.79(s,1H),7.78-7.63(m,1H),7.44(d,2H),3.91(t,2H),2.79(t,2H).m / z(ES + ),[M+H] + =232.1.

[0344] Example 5: 1-(benzo[d]oxazol-6-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Cs2CO3 (494 mg, 1.52 mmol) was added at room temperature under N2 to a degassed mixture of Ephos Pd G4 (46.4 mg, 0.0505 mmol), Ephos (27.0 mg, 0.0505 mmol), dihydropyrimidine-2,4(1H,3H)-dione (173 mg, 1.52 mmol), and 6-bromobenzo-[d]oxazole (100 mg, 0.505 mmol) in 1,4-dioxane (8 mL). The resulting mixture was stirred at 100 °C for 17 hours. The solvent was then removed under reduced pressure. The substance was obtained by purification by FSC (gradient 0-70% siRNA (in petroleum ether)), which was further purified by FSC (gradient 0-10% MeOH (in DCM)) to obtain the title compound (26.0 mg, 22%) as a yellow solid. 1 H NMR:δ 2.75(2H,t),3.85(2H,t),7.39(1H,dd),7.76-7.85(2H,m),8.77(1H,s),10.45(1H,s).m / z(ES + ),[M+H] + =232.1.

[0345] Example 6: 1-(1-methyl-1H-indazole-5-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] A degassed mixture of Cs2CO3 (509 mg, 1.56 mmol), 5-bromo-1-methyl-1H-indazole (110 mg, 0.52 mmol), dihydropyrimidine-2,4(1H,3H)-dione (178 mg, 1.56 mmol), Ephos (13.9 mg, 0.026 mmol), and Ephos Pd G4 (23.9 mg, 0.026 mmol) in 1,4-dioxane (10 mL) was stirred at 100°C for 14 hours. The resulting mixture was filtered, washed with THF, and the solvent in the filtrate was removed under reduced pressure. Purification with C-18FC (gradient: 0-100% MeCN (in water)) yielded the title compound (75.0 mg, 59%) as a white solid. 1H NMR:8.05(d,1H),7.71-7.60(m,2H),7.37(dd,1H),4.05(s,3H),3.80(t,2H),2.73(t,2H).m / z(ES + ),[M+H] + =245.2.

[0346] Example 7: 1-(imidazo[1,2-a]pyridine-7-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] A degassed mixture of Ephos (13.6 mg, 0.0254 mmol), Ephos Pd G4 (23.3 mg, 0.0254 mmol), Cs2CO3 (496 mg, 1.52 mmol), 7-bromoimidazo[1,2-a]pyridine (100 mg, 0.51 mmol), and dihydropyrimidine-2,4(1H,3H)-dione (174 mg, 1.52 mmol) in 1,4-dioxane (10 mL) was stirred at 120°C for 15 hours. The resulting mixture was filtered, washed with 1,4-dioxane, and the solvent in the filtrate was removed under reduced pressure. The residue was purified by C-18FC (gradient: 0-45% MeCN (in water)), and further purified by preparative HPLC (column B, eluent B, gradient: 2-25%) to obtain the title compound (27.2 mg, 23%) as a white solid. 1 H NMR:δ 8.50(dd,1H),7.91(t,1H),7.55(d,1H),7.48-7.43(m,1H),6.99(dd,1H),6.05(s,1H),3.88(t,2H),2.73(t,2H).m / z(ES + ),[M+H] += 231.2.

[0347] Example 8: 1-(2-methyl-2H-indazole-5-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Ephos Pd G4 (43.5 mg, 0.0474 mmol) was added at room temperature under N2 conditions to a degassed mixture of 5-bromo-2-methyl-2H-indazole (100 mg, 0.474 mmol), dihydropyrimidine-2,4(1H,3H)-dione (81.0 mg, 0.710 mmol), Ephos (25.3 mg, 0.0473 mmol), and Cs2CO3 (463 mg, 1.42 mmol) in 1,4-dioxane (5 mL). The resulting mixture was stirred at 120 °C for 16 hours. The solvent was then removed under reduced pressure. Purification with C-18FC (gradient: 5-60% MeOH (in water) (containing 0.1% FA)) yielded the title compound (16.0 mg, 14%) as a white solid. 1 H NMR:δ 10.32(s,1H),8.34(s,1H),7.63-7.55(m,2H),7.20(dd,1H),4.17(s,3H),3.80(t,2H),2.73(t,2H).m / z(ES + ),[M+H] + =245.2.

[0348] Example 9: 1-(benzo[d]thiazole-6-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Cs2CO3 (470 mg, 1.44 mmol) was added at room temperature under N2 conditions to a degassed mixture of 6-bromobenzo[d]thiazole (103 mg, 0.48 mmol), dihydropyrimidine-2,4(1H,3H)-dione (165 mg, 1.44 mmol), Ephos (12.9 mg, 0.0241 mmol), and Ephos Pd G4 (22.1 mg, 0.0241 mmol) in 1,4-dioxane (5 mL). The resulting mixture was stirred at 100 °C for 20 hours. The solvent was then removed under reduced pressure. Purification by C-18FC (gradient: 10-30% MeCN (in water)) yielded the title compound (50.0 mg, 42%) as a white solid. 1 H NMR:2.76(2H,t),3.88(2H,t),7.54(1H,dd),8.12(2H,m),9.40(1H,s),10.47(1H,s).m / z(ES+ ),[M+H] + =248.0.

[0349] Example 10: 1-(2-methyl-3-oxoisoindolin-5-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Cs2CO3 (216 mg, 0.663 mmol) was added at room temperature under N2 to a degassed mixture of dihydropyrimidine-2,4(1H,3H)-dione (76.0 mg, 0.666 mmol), 6-bromo-2-methylisoindorin-1-one (50.0 mg, 0.221 mmol), Ephos (11.8 mg, 0.0221 mmol), and Ephos Pd G4 (20.3 mg, 0.0221 mmol) in 1,4-dioxane (5 mL). The resulting suspension was stirred at 100 °C for 16 hours. The solid was filtered and washed with DMF. The filtrate was concentrated under reduced pressure. Purification by C-18FC (gradient: 0-80% MeCN (in water)) yielded the title compound (31.0 mg, 54%) as a white solid. 1 H NMR:δ 10.43(s,1H),7.65-7.49(m,3H),4.46(s,2H),3.85(t,2H),3.09(s,3H),2.74(t,2H).m / z(ES + ),[M+H] + =260.2.

[0350] Example 11: 1-(1-methyl-1H-pyrrolo[2,3-b]pyridine-5-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Cs2CO3 (232 mg, 0.712 mmol) was added at room temperature under N2 conditions to a degassed mixture of dihydropyrimidine-2,4(1H,3H)-dione (81 mg, 0.710 mmol), 5-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridine (50.0 mg, 0.237 mmol), Ephos (12.7 mg, 0.0237 mmol), and Ephos Pd G4 (21.8 mg, 0.0237 mmol) in 1,4-dioxane (5 mL). The resulting solution was stirred at 100 °C for 16 hours. The solid was filtered and washed with DMF. The filtrate was concentrated and purified by C-18FC (gradient: 0-80% MeCN (in water)) to obtain the title compound (30.0 mg, 52%) as a white solid. 1 H NMR:δ 10.39(s,1H),8.23(d,1H),7.92(d,1H),7.57(d,1H),6.48(d,1H),3.82(d,5H),2.76(t,2H).m / z(ES + ),[M+H] + =245.1.

[0351] Example 12: 1-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Cs2CO3 (286 mg, 0.878 mmol) was added at room temperature under N2 conditions to a degassed mixture of 6-bromo-3-methylbenzo[d]oxazole-2(3H)-one (100 mg, 0.44 mmol), dihydropyrimidine-2,4(1H,3H)-dione (50.0 mg, 0.439 mmol), Ephos (11.7 mg, 0.0219 mmol), and Ephos Pd G4 (20.1 mg, 0.0219 mmol) in 1,4-dioxane (10 mL). The resulting solution was stirred at 100 °C for 16 hours. The solvent was then removed under reduced pressure. Purification by C-18FC (gradient 0-100% MeCN (in water)) yielded the title compound (60.0 mg, 52%) as a yellow solid. 1H NMR:δ 2.72(t,2H),3.36(s,3H),3.76(t,2H),7.20(dd,1H),7.27(d,1H),7.39(d,1H),10.35(s,1H).m / z(ES + ),[M+H] + =262.2.

[0352] Example 13: 1-(1H-indole-6-yl)pyrimidine-2,4(1H,3H)-dione [ka] (1H-indole-6-yl)boronic acid (100 mg, 0.621 mmol) and pyrimidine-2,4(1H,3H)-dione (80.0 mg, 0.714 mmol) were added to a mixture of diacetoxy copper (113 mg, 0.622 mmol) and TMEDA (72.2 mg, 0.621 mmol) in MeOH (4 mL) and water (1.00 mL) at room temperature in air. The resulting mixture was stirred at room temperature for 24 hours. The solvent was then removed under reduced pressure. Purification with C-18FC (gradient: 5-60% MeCN (in water) (containing 0.05% TFA)) yielded the title compound (5.00 mg, 4%) as a yellow solid. 1 H NMR:δ 5.64(1H,dd),6.50(1H,s),6.98(1H,dd),7.43(1H,s),7.47(1H,t),7.61(1H,d),7.72(1H,d),11.34(1H,s),11.37(1H,s).m / z(ES + ),[M+H] + =228.2.

[0353] Example 14: 5-Fluoro-1-(1H-indole-6-yl)pyrimidine-2,4(1H,3H)-dione [ka] (1H-indole-6-yl)boronic acid (200 mg, 1.24 mmol) and 5-fluoropyrimidine-2,4(1H,3H)-dione (162 mg, 1.24 mmol) were added to a mixture of diacetoxy copper (226 mg, 1.24 mmol) and pyridine (201 μL, 2.48 mmol) in DMF (8 mL) at room temperature under O2. The resulting mixture was stirred at 60°C for 16 hours. The solvent was then removed under reduced pressure. Purification with C-18FC (gradient: 5-60% MeCN (in water) (containing 0.1% FA)) yielded the title compound (70.0 mg, 23%) as a yellow solid. 1 H NMR:δ 6.46-6.54(1H,m),7.00(1H,dd),7.43-7.50(2H,m),7.60(1H,d),8.20(1H,d),11.36(1H,s),11.90(1H,br s). 19 F NMR(282MHz)δ -170.46.m / z(ES + ),[M+H] + =246.2.

[0354] Example 15: 1-(1H-indole-6-yl)-5-methylpyrimidine-2,4(1H,3H)-dione [ka] Pyridine (201 μL, 2.48 mmol) was added to a mixture of diacetoxy copper (226 mg, 1.24 mmol), 5-methylpyrimidine-2,4(1H,3H)-dione (157 mg, 1.24 mmol), and (1H-indole-6-yl)boronic acid (200 mg, 1.24 mmol) in DMF (10 mL) at room temperature under O2. The resulting mixture was stirred at 60°C for 17 hours. The solvent was then removed under reduced pressure. Purification with C-18FC (gradient: 0-30% MeCN (in water) (containing 0.1% FA)) yielded the title compound (0.139 g, 45%) as a brown solid. 1 H NMR:δ 1.82(3H,d),6.50(1H,t),6.97(1H,dd),7.42(1H,s),7.46(1H,t),7.58-7.65(2H,m),11.21-11.52(2H,m).m / z(ES +),[M+H] + =242.2.

[0355] Intermediate 16a: 4-bromo-6-methoxy-1-methyl-1H-indole [ka] NaH (60% dispersion in mineral oil, 80.0 mg, 1.99 mmol) was added to a solution of 4-bromo-6-methoxy-1H-indole (300 mg, 1.33 mmol) in THF (10 mL) at 0°C under N2. The resulting mixture was stirred at room temperature for 20 minutes, and then MeI (83.0 μL, 1.33 mmol) was added. The resulting mixture was stirred at room temperature for 1 hour. The reaction product was quenched with saturated NH4Cl (20 mL) and extracted with RINKAN (3 × 20 mL). The combined organic extract was dried (Na2SO4) and concentrated to obtain a yellow solid. Purification by FSC (gradient: 0-20% RINKAN (in petroleum ether)) yielded the title compound (0.210 g, 66%) as a yellow solid. 1 H NMR:δ 3.76(3H,s),3.82(3H,s),6.28(1H,dd),6.93(1H,d),7.04(1H,dd),7.30(1H,d).m / z(ES + ),[M+H] + =240.0.

[0356] Example 16: 1-(6-methoxy-1-methyl-1H-indole-4-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Ephos (33.4 mg, 0.0625 mmol) and Ephos Pd G4 (57.4 mg, 0.0625 mmol) were added at room temperature under N2 to a degassed mixture of Cs2CO3 (814 mg, 2.50 mmol), 4-bromo-6-methoxy-1-methyl-1H-indole (300 mg, 1.25 mmol), and dihydropyrimidine-2,4(1H,3H)-dione (428 mg, 3.75 mmol) in DMF (20 mL). The resulting mixture was stirred at 100 °C for 16 hours. The solvent was then removed under reduced pressure. The substance was obtained by purification by C-18FC (gradient: 5-40% MeCN (in water)), and this was further purified by preparative HPLC (column C, eluent C, gradient: 24-49%) to obtain the title compound (118 mg, 35%) as a white solid. 1 H NMR:δ 2.75(2H,t),3.76-3.79(5H,m),3.82(3H,s),6.29(1H,d),6.65(1H,d),6.95(1H,s),7.18(1H,d),10.31(1H,s).m / z(ES + ),[M+H] + =274.2.

[0357] Intermediate 17a: tert-butyl4-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate [ka] Ephos Pd G4 (309 mg, 0.336 mmol) was added at room temperature under N2 to a degassed mixture of Ephos (180 mg, 0.337 mmol), Cs2CO3 (2.19 g, 6.72 mmol), dihydropyrimidine-2,4(1H,3H)-dione (1.536 g, 13.46 mmol), and tert-butyl 4-bromo-1H-pyrrolo[2,3-c]pyridine-1-carboxylate (1.00 g, 3.37 mmol) in 1,4-dioxane (40 mL). The resulting mixture was stirred at 100 °C for 16 hours. The solvent was then removed under reduced pressure. Purification by C-18FC (gradient 5-80% MeCN (in water)) yielded the title compound (150 mg, 13%) as a pale yellow solid. m / z(ES)+ ),[M+H] + =331.2.

[0358] Example 17: 1-(1H-pyrrolo[2,3-c]pyridine-4-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] 150 mg, 0.454 mmol of tert-butyl 4-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate was dissolved in 10 mL of 2,2,2-trifluoroethanol and sealed in a microwave tube. The reaction mixture was heated in a microwave reactor at 120°C for 1 hour and then cooled to room temperature. The solvent was removed under reduced pressure. Purification by preparative HPLC (column B, eluent D, gradient: 3-24%) yielded the title compound (80.0 mg, 77%) as a white solid. 1 H NMR:δ 2.79(2H,t),3.84(2H,t),6.50(1H,d),7.63(1H,t),8.05(1H,s),8.68(1H,s),10.42(1H,s),11.75(1H,s).m / z(ES + ),[M+H] + =231.3.

[0359] Intermediate 18a: tert-butyl 4-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-1H-indole-1-carboxylate [ka] Cs2CO3 (1.65 g, 5.06 mmol) was added to a degassed mixture of Ephos Pd G4 (155 mg, 0.169 mmol), Ephos (90.0 mg, 0.168 mmol), dihydropyrimidine-2,4(1H,3H)-dione (578 mg, 5.06 mmol), and tert-butyl 4-bromo-1H-indole-1-carboxylate (500 mg, 1.69 mmol) in 1,4-dioxane (20 mL) at room temperature under N2. The resulting mixture was stirred at 100 °C for 17 hours. The solvent was then removed under reduced pressure. Purification with C-18FC (gradient 0-50% MeCN (in water) (containing 0.1% concentrated HCl)) yielded the title compound (100 mg, 18%) as a pale yellow solid. 1 H NMR:δ 1.64(9H,s),2.79(2H,t),3.80(2H,t),6.69(1H,d),7.20(1H,d),7.36(1H,t),7.69(1H,d),8.02(1H,d),10.42(1H,s).m / z(ES + ),[M+H] + =330.1.

[0360] Example 18: 1-(1H-indole-4-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] 126 μL, 0.549 mmol of tert-butyldimethylsilyltrifluoromethanesulfonate was added to a solution of tert-butyl 4-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-1H-indole-1-carboxylate (90.0 mg, 0.273 mmol) in 1 mL of DCM at room temperature in air. The resulting solution was stirred at room temperature for 16 hours. The solvent was then removed under reduced pressure. The substance was purified by C-18FC (gradient: 0-30% MeCN (in water) (containing 0.1% concentrated HCl)), and this was further purified by preparative HPLC (column D, eluent E, gradient: 20-30%) to obtain the title compound (15.0 mg, 24%) as a pale yellow solid. 1H NMR:δ 2.76(2H,t),3.78(2H,t),6.39(1H,ddd),6.93(1H,dd),7.09(1H,t),7.31-7.39(2H,m),10.32(1H,s),11.24(1H,s).m / z(ES + ),[M+H] + =230.0.

[0361] Intermediate 19a: (4-bromo-1H-indole-6-yl)methanol [ka] A solution of LiAlH4 in THF (2.5 M, 6.30 mL, 15.7 mmol) was added dropwise to a solution of methyl 4-bromo-1H-indole-6-carboxylate (1.00 g, 3.94 mmol) in THF (20 mL) at 0°C under N2. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched dropwise with water (0.5 mL), then 15% NaOH (1.5 mL), and then water (0.5 mL). The mixture was then filtered through Celite and concentrated to dryness to obtain the title compound (600 mg, 67%) as a yellow solid. 1 H NMR:δ 4.56(2H,s),5.20(1H,br s),6.33-6.37(1H,m),7.18(1H,d),7.36(1H,t),7.42(1H,t),11.40(1H,s).m / z(ES + ),[M+H] + =226.0

[0362] Intermediate 19b: 4-bromo-6-(methoxymethyl)-1-methyl-1H-indole [ka] NaH (60% dispersion in mineral oil, 389 mg, 9.73 mmol) was added to a solution of (4-bromo-1H-indole-6-yl)methanol (550 mg, 2.43 mmol) in DMF (20 mL) at 0°C under N2. The resulting mixture was stirred at room temperature for 0.5 hours, after which MeI (456 μL, 7.30 mmol) was added. The resulting mixture was stirred at room temperature for 3 hours. The reaction product was quenched with saturated NH4Cl (50 mL) and extracted with RINKAN (3 × 50 mL). The combined organic extract was dried (Na2SO4) and concentrated to obtain a yellow liquid. Purification by FSC (gradient: 0-30% RINKAN (in petroleum ether)) yielded the title compound (410 mg, 66%) as yellow oil. 1 H NMR:δ 3.30(3H,s),3.81(3H,s),4.51(2H,s),6.37(1H,dd),7.22(1H,d),7.41-7.49(2H,m).m / z(ES + ),[M+H] + =256.1.

[0363] Example 19: 1-(6-(methoxymethyl)-1-methyl-1H-indole-4-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Ephos (42.1 mg, 0.0787 mmol) and Ephos Pd G4 (72.3 mg, 0.0787 mmol) were added to a degassed mixture of Cs2CO3 (1.03 g, 3.16 mmol), 4-bromo-6-(methoxymethyl)-1-methyl-1H-indole (400 mg, 1.57 mmol), and dihydropyrimidine-2,4(1H,3H)-dione (539 mg, 4.72 mmol) in 1,4-dioxane (10 mL) at room temperature under N2 conditions. The resulting mixture was stirred at 100 °C for 16 hours. The mixture was cooled to room temperature and silica was added. The solvent was removed under reduced pressure. The crude product was dry-loaded and purified using C-18FC (gradient: 5-40% MeCN (in water) (containing 0.1% concentrated HCl)) to obtain the title compound (0.305 g, 67%) as a white solid. 1H NMR:δ 2.76(2H,t),3.32(3H,s)3.74-3.82(5H,m),4.51(2H,s),6.36(1H,d),6.95(1H,s),7.30-7.37(2H,m),10.31(1H,s).m / z(ES + ),[M+H] + =288.1.

[0364] Intermediate 20a: tert-butyl 5-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)indoline-1-carboxylate [ka] Ephos (44.8 mg, 0.0838 mmol) and Ephos Pd G4 (77.0 mg, 0.0838 mmol) were added to a degassed mixture of Cs2CO3 (1.09 g, 3.35 mmol), tert-butyl 5-bromoindoline-1-carboxylate (500 mg, 1.68 mmol), and dihydropyrimidine-2,4(1H,3H)-dione (574 mg, 5.03 mmol) in 1,4-dioxane (30 mL) at room temperature under N2. The resulting mixture was stirred at 100 °C for 16 hours. The mixture was cooled to room temperature and silica was added. The solvent was removed under reduced pressure. The crude product was dry-loaded and purified by FSC (gradient: 0-98% siRNA (in petroleum ether)) to obtain the title compound (140 mg, 25%) as a white solid. 1 H NMR:δ 1.49(9H,s),2.68(2H,t),3.04(2H,t),3.69(2H,t),3.90(2H,t),7.06(1H,dd),7.14(1H,d),7.61-7.77(1H,m),10.30(1H,s).m / z(ES + ),[M-tBu+2H] + =276.1.

[0365] Example 20: 1-(indoline-5-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] TFA (1 mL) was added to a solution of tert-butyl 5-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)indoline-1-carboxylate (140 mg, 0.422 mmol) in DCM (4 mL). The resulting mixture was stirred at room temperature for 2 hours. The solvent was then removed under reduced pressure. The reaction mixture was diluted with DCM, and the solvent was removed under reduced pressure. Purification with C-18FC (gradient: 0-20% MeCN (in water)) yielded the title compound (56.0 mg, 57%) as a white solid. 1 H NMR:δ 2.70(2H,t),3.10(2H,t),3.64(2H,dt),3.73(2H,t),7.12(2H,q),7.26(1H,d),10.33(1H,s).m / z(ES + ),[M+H] + =232.2.

[0366] Example 21: 1-(1-methylindoline-5-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] NaOAc (142 mg, 1.73 mmol) was added at room temperature to a mixture of 1-(indolin-5-yl)dihydropyrimidine-2,4(1H,3H)-dione (100 mg, 0.43 mmol) and paraformaldehyde (104 mg, 3.46 mmol) in DCM (10 mL). The resulting mixture was stirred at room temperature for 1 hour, after which sodium triacetoxyborohydride (229 mg, 1.08 mmol) was added. The resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into water (20 mL) and extracted with DCM (3 × 20 mL). The combined organic extract was dried (Na₂SO₄) and concentrated to obtain a brown solid. Purification by preparative HPLC (column E, eluent E, gradient: 9-19%) yielded the title compound (22.0 mg, 21%) as a brown solid. 1 H NMR:δ 2.67(2H,t),2.70(3H,s),2.86(2H,t),3.26(2H,t),3.65(2H,t),6.49(1H,d),6.93(1H,dd),6.98(1H,s),10.23(1H,s).m / z(ES+ ),[M+H] + =246.1.

[0367] Intermediate 22a: tert-butyl 6-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)indoline-1-carboxylate [ka] Ephos (90.0 mg, 0.168 mmol) and Ephos Pd G4 (154 mg, 0.168 mmol) were added to a degassed mixture of Cs2CO3 (2.19 g, 6.72 mmol), tert-butyl 6-bromoindoline-1-carboxylate (1.00 g, 3.35 mmol), and dihydropyrimidine-2,4(1H,3H)-dione (1.148 g, 10.06 mmol) in 1,4-dioxane (40 mL) at room temperature under N2. The resulting mixture was stirred at 100 °C for 16 hours. The mixture was cooled to room temperature and silica was added. The solvent was removed under reduced pressure. The crude product was dry-loaded and purified by FSC (gradient 0-99% SiO(in petroleum ether)) to obtain the title compound (420 mg, 38%) as a white solid. 1 H NMR:δ 1.50(9H,s),2.70(2H,t),3.05(2H,t),3.74(2H,t),3.94(2H,t),6.87(1H,dd),7.19(1H,d),7.63(1H,s),10.33(1H,s).m / z(ES + ),[M-tBu+2H] + =276.2.

[0368] Example 22: 1-(indoline-6-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] TFA (2 mL) was added to a solution of tert-butyl 6-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)indoline-1-carboxylate (470 mg, 1.42 mmol) in DCM (8 mL). The resulting mixture was stirred at room temperature for 3 hours. The solvent was then removed under reduced pressure. The reaction mixture was diluted with DCM, and the solvent was removed under reduced pressure. Purification with C-18FC (gradient 0-20% MeCN (in water)) yielded the title compound (0.233 g, 71%) as a white solid. 1 H NMR:δ 2.70(2H,t),3.06(2H,t),3.63(2H,t),3.75(2H,t),6.96(1H,d),7.01(1H,d),7.28(1H,d),10.34(1H,s).m / z(ES + ),[M+H] + =232.1.

[0369] Example 23: 1-(1-methylindoline-6-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] NaOAc (142 mg, 1.73 mmol) was added at room temperature to a mixture of 1-(indoline-6-yl)dihydropyrimidine-2,4(1H,3H)-dione (100 mg, 0.432 mmol) and paraformaldehyde (104 mg, 3.46 mmol) in DCM (5 mL). The resulting mixture was stirred at room temperature for 1 hour, after which sodium triacetoxyborohydride (229 mg, 1.08 mmol) was added. The resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into water (20 mL) and extracted with DCM (3 × 20 mL). The combined organic extract was dried (Na₂SO₄) and concentrated to obtain a yellow solid. Purification by preparative HPLC (column B, eluent D, gradient: 20-40%) yielded the title compound (15.1 mg, 14%) as a white solid. 1 H NMR:δ 2.47(3H,s),2.69(2H,t),3.69-3.82(6H,m),7.12(1H,dd),7.15-7.27(2H,m),10.33(1H,s).m / z(ES + ),[M+H]+ =246.0.

[0370] Intermediate 24a: tert-butyl 5-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)isoindoline-2-carboxylate [ka] Ephos (0.179 g, 0.335 mmol) and Ephos Pd G4 (0.308 g, 0.335 mmol) were added to a degassed mixture of Cs2CO3 (2.19 g, 6.72 mmol), tert-butyl 5-bromoisoindoline-2-carboxylate (1.00 g, 3.35 mmol), and dihydropyrimidine-2,4(1H,3H)-dione (1.15 g, 10.1 mmol) in 1,4-dioxane (30 mL) at room temperature under N2. The resulting mixture was stirred at 100 °C for 16 hours. The mixture was cooled to room temperature and silica was added. The solvent was removed under reduced pressure. The crude product was dry-loaded and purified by FSC (gradient: 0-98% ELISA (in petroleum ether)) to obtain the title compound (0.250 g, 23%) as a white solid. 1 H NMR:δ 1.47(9H,s),2.71(2H,t),3.77(2H,t),4.59(4H,br s),7.19-7.39(3H,m),10.38(1H,s).m / z(ES + ),[M-tBu+2H] + =276.2.

[0371] Example 24: 1-(isoindolin-5-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] TFA (2 mL) was added to a solution of tert-butyl 5-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)isoindoline-2-carboxylate (280 mg, 0.845 mmol) in DCM (8 mL). The resulting mixture was stirred at room temperature for 3 hours. The solvent was then removed under reduced pressure. The reaction mixture was diluted with DCM, and the solvent was removed under reduced pressure. Purification with C-18FC (gradient 0-10% MeCN (in water)) yielded the title compound (61.0 mg, 21%) as a white solid in the form of a trifluoroacetate salt. 1 H NMR:δ 2.72(2H,t),3.78(2H,t),4.52(4H,d),7.32(1H,d),7.36-7.45(2H,m),9.56(2H,s),10.40(1H,s).m / z(ES + ),[M+H] + =232.2.

[0372] Example 25: 1-(2-methylisoindolin-5-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] NaOAc (95.0 mg, 1.16 mmol) was added to a mixture of 1-(isoindolin-5-yl)dihydropyrimidine-2,4(1H,3H)-dione 2,2,2-trifluoroacetate (100 mg, 0.290 mmol) and paraformaldehyde (69.6 mg, 2.32 mmol) in DCM (10 mL). The resulting mixture was stirred at room temperature for 1 hour, after which sodium triacetoxyborohydride (153 mg, 0.722 mmol) was added. The resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into water (20 mL) and extracted with DCM (3 × 20 mL). The combined organic extract was dried (Na2SO4) and concentrated to obtain a brown solid. Purification by preparative HPLC (column B, eluent B, gradient: 5-30%) yielded the title compound (19.5 mg, 27%) as a white powder. 1H NMR:δ 2.67(2H,t),2.68(3H,s),2.85(2H,t),3.27(2H,t),3.70(2H,t),6.45(1H,d),6.50(1H,dd),7.01(1H,d),10.26(1H,s).m / z(ES + ),[M+H] + =246.0.

[0373] Intermediate 26a: tert-butyl6-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-3,4-dihydroquinoline-1(2H)-carboxylate [ka] Cs2CO3 (1.94 g, 5.95 mmol) was added at room temperature under N2 conditions to a degassed mixture of tert-butyl 6-bromo-3,4-dihydroquinoline-1(2H)-carboxylate (620 mg, 1.99 mmol), dihydropyrimidine-2,4(1H,3H)-dione (680 mg, 5.96 mmol), Ephos (53.1 mg, 0.0993 mmol), and Ephos Pd G4 (91.0 mg, 0.0991 mmol) in 1,4-dioxane (20 mL). The resulting mixture was stirred at 100°C for 20 hours. The solid was filtered off and washed with 1,4-dioxane (20 mL). The filtrate was concentrated to dryness. Purification using C-18FC (30-70% gradient MeCN (in water)) yielded the title compound (650 mg, 95%) as a white solid. 1 H NMR:(CD3OD)δ 1.54(9H,s),1.91-1.97(2H,m),2.79-2.84(m,4H),3.70-3.74(m,2H),3.85(2H,t),7.09-7.16(2H,m),7.65(1H,d).m / z(ES + ),[M-tBu+2H] + =290.1.

[0374] Example 26: 1-(1,2,3,4-tetrahydroquinoline-6-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] 600 mg, 1.74 mmol of tert-butyl 6-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-3,4-dihydroquinoline-1(2H)-carboxylate was added to a solution of HCl (4 M, 35.0 mL, 140 mmol) in 1,4-dioxane to obtain a white suspension. The resulting mixture was stirred at room temperature for 3 hours. The precipitate was collected by filtration, washed with ethyl acetate, and dried under vacuum to obtain the title compound in the form of a hydrochloride salt (390 mg, 80%) as a white solid. 1 H NMR:δ 1.94(2H,p),2.69(2H,t),2.78(2H,t),3.25-3.35(2H,m),3.72(2H,t),4.06(2H,s),7.02-7.09(1H,m),7.13-7.20(2H,m).m / z(ES + ),[M+H] + =246.1.

[0375] Example 27: 1-(1-methyl-1,2,3,4-tetrahydroquinoline-6-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Paraformaldehyde (29.4 mg, 0.979 mmol) was added to a mixture of 1-(1,2,3,4-tetrahydroquinoline-6-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride (80.0 mg, 0.284 mmol) in MeOH (6 mL) to obtain a white suspension. The resulting mixture was stirred at room temperature for 0.5 hours, after which NaBH3CN (61.5 mg, 0.979 mmol) was added. The resulting mixture was stirred at room temperature for 16 hours, and then directly purified using C-18FC (gradient: 10-50% MeCN (in water)) to obtain the title compound (70.0 mg, 95%) as a white solid. 1 H NMR:δ 1.88(2H,m),2.66(4H,dt),2.82(3H,s),3.15-3.18(2H,m),3.64(2H,t),6.54(1H,d),6.83(1H,d),6.91(1H,dd),10.20(1H,s).m / z(ES +),[M+H] + =260.0.

[0376] Intermediate 28a: tert-butyl 7-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate [ka] Cs2CO3 (1.88 g, 5.77 mmol) was added under N2 to a mixture of tert-butyl 7-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate (600 mg, 1.92 mmol), dihydropyrimidine-2,4(1H,3H)-dione (658 mg, 5.77 mmol), Ephos (51.4 mg, 0.0961 mmol), and Ephos Pd G4 (88.3 mg, 0.0961 mmol) in 1,4-dioxane (30 mL). The resulting mixture was stirred at 100°C for 18 hours. The resulting mixture was filtered and washed with 1,4-dioxane. The filtrate was concentrated and purified by C-18FC (gradient: 0-70% MeCN (in water)) to obtain the title compound (580 mg, 87%) as a pale yellow solid. 1 H NMR:δ 1.41(s,9H),2.74(t,2H),2.67(t,2H),3.53(t,2H),3.73(t,2H),4.47(s,2H),7.10-7.17(m,3H),10.34(s,1H).m / z(ES + ),[M+Na]=368.2.

[0377] Example 28: 1-(1,2,3,4-tetrahydroisoquinoline-7-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] tert-butyl 7-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (560 mg, 1.62 mmol) was added to a solution of HCl in 1,4-dioxane (4 M, 40.0 mL, 160 mmol). The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered, and the precipitate was washed with 1,4-dioxane (3 mL) and DCM (3 mL) to obtain the title compound in the form of a hydrochloride salt (400 mg, 88%) as a pale yellow solid. 1 H NMR:δ 2.71(t,2H),3.00(t,2H),3.30-3.34(m,2H),3.76(t,2H),4.24(s,2H),7.17-7.28(m,3H),9.50-9.70(2H,m),10.40(s,1H).m / z(ES + ),[M+H] + =246.1.

[0378] Example 29: 1-(2-methyl-1,2,3,4-tetrahydroisoquinoline-7-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Paraformaldehyde (32.0 mg, 1.07 mmol) was added to a mixture of 1-(1,2,3,4-tetrahydroisoquinoline-7-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride (60.0 mg, 0.213 mmol) in MeOH (5 mL). The resulting suspension was stirred at room temperature for 4 hours, after which NaBH3CN (40.1 mg, 0.638 mmol) was added. The resulting mixture was stirred at room temperature overnight, and then directly purified by preparative HPLC (column B, eluent B, gradient: 10-25%) to obtain the title compound (37.7 mg, 68%) as a white solid. 1 H NMR:δ 2.33(s,3H),2.58(t,2H),2.68(t,2H),2.79(t,2H),3.45(s,2H),3.73(t,2H),6.99(d,1H),7.03-7.14(m,2H)10.32(s,1H).m / z(ES + ),[M+H]+ =260.1.

[0379] Intermediate 30a: tert-butyl6-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate [ka] Cs2CO3 (1.88 g, 5.77 mmol) was added at room temperature under N2 conditions to a degassed mixture of tert-butyl 6-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate (600 mg, 1.92 mmol), dihydropyrimidine-2,4(1H,3H)-dione (658 mg, 5.77 mmol), Ephos (51.4 mg, 0.0961 mmol), and Ephos Pd G4 (88.3 mg, 0.0961 mmol) in 1,4-dioxane (30 mL). The resulting mixture was stirred at 100°C for 18 hours. The resulting mixture was filtered, washed with 1,4-dioxane, and the filtrate was concentrated. Purification by C-18FC (gradient: 0-70% MeCN (in water)) yielded the title compound (423 mg, 64%) as a pale yellow solid. 1 H NMR:δ 10.34(s,1H),7.26-7.02(m,3H),4.47(s,2H),3.73(t,2H),3.53(t,2H),2.75(t,2H),2.67(t,2H),1.41(s,9H).m / z(ES + ),[M+Na]=368.1.

[0380] Example 30: 1-(1,2,3,4-tetrahydroisoquinoline-6-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] 400 mg, 1.16 mmol of tert-butyl 6-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate was added to a solution of HCl in 1,4-dioxane (4 M, 40.0 mL, 160 mmol). The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered, and the precipitate was washed with 1,4-dioxane (2 × 2.5 mL) to obtain the title compound in the form of a hydrochloride salt (0.287 g, 88%) as a yellow solid. 1 H NMR:δ 2.71(t,2H),3.01(t,2H),3.30-3.42(m,2H),3.77(t,2H),4.24(s,2H),7.17-7.29(m,3H),9.45-9.70(m,2H),10.39(s,1H).m / z(ES + ),[M+H] + =246.2.

[0381] Example 31: 1-(2-methyl-1,2,3,4-tetrahydroisoquinoline-6-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Paraformaldehyde (32.0 mg, 1.06 mmol) was added to a mixture of 1-(1,2,3,4-tetrahydroisoquinoline-6-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride (60.0 mg, 0.213 mmol) in MeOH (5 mL). The resulting mixture was stirred at room temperature for 2 hours, after which NaBH3CN (40.1 mg, 0.638 mmol) was added. The resulting mixture was stirred at room temperature overnight, and then directly purified by preparative HPLC (column A, eluent F, gradient: 12-22%) to obtain the title compound (39.6 mg, 72%) as a white solid. 1 H NMR:δ 10.33(s,1H),7.17-7.04(m,2H),7.00(d,1H),3.74(t,2H),3.46(s,2H),2.80(t,2H),2.69(t,2H),2.59(t,2H),2.34(s,3H).m / z(ES + ),[M+H] +=260.0.

[0382] Intermediate 32a: tert-butyl 7-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-3,4-dihydroquinoline-1(2H)-carboxylate [ka] Cs2CO3 (1.88 mg, 5.77 mmol) was added at room temperature under N2 to a degassed mixture of tert-butyl 7-bromo-3,4-dihydroquinoline-1(2H)-carboxylate (600 mg, 1.92 mmol), dihydropyrimidine-2,4(1H,3H)-dione (658 mg, 5.77 mmol), Ephos (51.4 mg, 0.0961 mmol), and Ephos Pd G4 (88.3 mg, 0.0961 mmol) in 1,4-dioxane (20 mL). The resulting mixture was stirred at 100 °C for 20 hours. The solvent was then removed under reduced pressure. Purification by C-18FC (gradient: 30-70% MeCN (in water)) yielded the title compound (520 mg, 78%) as a white solid. 1 H NMR:(CD3OD)δ 1.54(s,9H),1.90-1.97(m,2H),2.76-2.85(m,4H),3.69-3.76(m,2H),3.86(t,2H),7.01(dd,1H),7.16(d,1H),7.64(d,1H).m / z(ES + ),[M-tBu+2H] + =290.1.

[0383] Example 32: 1-(1,2,3,4-tetrahydroquinoline-7-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] 500 mg, 1.45 mmol of tert-butyl 7-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-3,4-dihydroquinoline-1(2H)-carboxylate was added to a solution of HCl in 1,4-dioxane (4 M, 30 mL, 120.00 mmol) to obtain a colorless solution. The resulting mixture was stirred at room temperature for 16 hours. The solvent was then removed under reduced pressure. The residue was resuspended in ethyl acetate. The precipitate was collected by filtration, washed with ethyl acetate, and dried under vacuum to obtain the title compound in the form of a hydrochloride salt (300 mg, 74%) as a yellow solid. 1 H NMR:δ 1.91-2.01(2H,m),2.70-2.80(4H,m),3.18-3.34(2H,m),3.74(2H,t),7.03-7.07(2H,m),7.20(1H,d),10.39(1H,s).m / z(ES + ),[M+H] + =246.1.

[0384] Example 33: 1-(1-methyl-1,2,3,4-tetrahydroquinoline-7-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Formaldehyde (25.6 mg, 0.853 mmol) was added to a mixture of 1-(1,2,3,4-tetrahydroquinoline-7-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride (80.0 mg, 0.284 mmol) in MeOH (4 mL) to obtain a white suspension. The resulting mixture was stirred at room temperature for 0.5 hours, after which NaBH3CN (53.5 mg, 0.851 mmol) was added. The resulting mixture was stirred at room temperature for 16 hours, and then directly purified using C-18FC (gradient: 25-50% MeCN (in water)) to obtain the title compound (60.0 mg, 81%) as a white solid. 1 H NMR:δ 1.88(2H,m),2.67(4H,t),2.80(3H,s),3.18(2H,m),3.69(2H,t),6.43(1H,dd),6.49(1H,d),6.87(1H,d),10.24(1H,s).m / z(ES+ ),[M+H] + =260.2.

[0385] Intermediate 34a: 1-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-4-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Ephos (19.0 mg, 0.0355 mmol) and Ephos Pd G4 (32.7 mg, 0.0356 mmol) were added to a degassed mixture of Cs2CO3 (464 mg, 1.42 mmol), 4-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (200 mg, 0.711 mmol), and dihydropyrimidine-2,4(1H,3H)-dione (244 mg, 2.14 mmol) in 1,4-dioxane (10 mL) at room temperature under N2. The resulting mixture was stirred at 100°C for 16 hours. The solvent was then removed under reduced pressure. The crude product was purified by FSC (gradient: 0-7% MeOH (in DCM)) to obtain the title compound (180 mg, 81%) as a yellow solid. m / z(ES + ),[M+H] + =315.2.

[0386] Example 34: 1-(1H-indazole-4-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] HCl (4M, 1.27 mL, 5.08 mmol) in 1,4-dioxane was added to a solution of 1-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-4-yl)dihydropyrimidine-2,4(1H,3H)-dione (160 mg, 0.509 mmol) in DCM (10 mL). The resulting solution was stirred at room temperature for 4 hours. The solvent was then removed under reduced pressure. Purification with C-18FC (gradient: 5-23% MeCN (in water) (containing 0.1% FA)) yielded the title compound (52.0 mg, 44%) as a white solid. 1H NMR:δ 2.79(2H,t),3.88(2H,t),7.02(1H,d),7.36(1H,t),7.46(1H,d),8.02(1H,s),10.43(1H,s).m / z(ES + ),[M+H] + =231.0.

[0387] Intermediate 35a: tert-butyl 5-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-1H-indazole-1-carboxylate [ka] Ephos (18.0 mg, 0.0337 mmol) and Ephos Pd G4 (30.9 mg, 0.0336 mmol) were added to a degassed mixture of Cs2CO3 (658 mg, 2.02 mmol), dihydropyrimidine-2,4(1H,3H)-dione (230 mg, 2.02 mmol), and tert-butyl 5-bromo-1H-indazole-1-carboxylate (200 mg, 0.673 mmol) in 1,4-dioxane (12 mL) at room temperature under N2 conditions. The resulting mixture was stirred at 100°C for 15 hours. The resulting reaction mixture was filtered, washed with THF, and the solvent in the filtrate was removed under reduced pressure. Purification with C-18FC (gradient 0-100% MeCN (in water)) yielded the title compound (60.0 mg, 27%) as a white solid. 1 H NMR:δ 10.42(s,1H),8.43(d,1H),8.07(d,1H),7.83(d,1H),7.65-7.50(m,1H),3.83(dt,2H),2.76(t,2H),1.66(s,9H).m / z(ES + ),[M+H] + =331.2.

[0388] Example 35: 1-(1H-indazole-5-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] A suspension of tert-butyl 5-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-1H-indazole-1-carboxylate (18 mg, 0.054 mmol) in water (10 mL) was stirred at 100°C for 6 hours. The water was removed under reduced pressure. Purification by preparative HPLC (column C, eluent D, gradient: 5-20%) yielded the title compound (2.1 mg, 17%) as a white solid. 1 H NMR:δ 8.08(s,1H),7.68(d,1H),7.54(d,1H),7.32(dd,1H),3.80(t,2H),2.73(t,2H).m / z(ES + ),[M+H] + =231.0.

[0389] Intermediate 36a: 5-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-3-hydroxypicoline aldehyde [ka] Ephos Pd G4 (59.1 mg, 0.0643 mmol) was added at room temperature under N2 conditions to a degassed mixture of 5-bromo-3-hydroxypicolinaldehyde (260 mg, 1.29 mmol), dihydropyrimidine-2,4(1H,3H)-dione (441 mg, 3.86 mmol), Ephos (34.4 mg, 0.0643 mmol), and Cs2CO3 (839 mg, 2.58 mmol) in 1,4-dioxane (20 mL). The resulting mixture was stirred at 100 °C for 16 hours. The solvent was then removed under reduced pressure. Purification using C-18FC (gradient: 0-10% MeCN (in water) (containing 0.1% FA)) yielded the title compound (0.100 g, 33%) as a yellow solid. 1 H NMR:δ 2.74(2H,t),3.93(2H,t),7.43(1H,d),8.37(1H,d),10.04(1H,s),10.65(1H,s),10.92(1H,s).m / z(ES + ),[M+H] + =236.2.

[0390] Intermediate 36b: (E)-5-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-3-hydroxypicolinealdehyde oxime [ka] NaOAc (94.0 mg, 1.15 mmol) was added to a mixture of 5-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-3-hydroxypicoline aldehyde (90.0 mg, 0.383 mmol) and hydroxylamine hydrochloride (53.2 mg, 0.766 mmol) in MeOH (15 mL). The resulting mixture was stirred at room temperature for 1 hour. The solvent was then removed under reduced pressure. Purification by FSC (gradient: 0-8% MeOH (in DCM)) yielded the title compound (70.0 mg, 73%) as a white solid. 1 H NMR:δ 2.72(2H,t),3.86(2H,t),7.35(1H,d),8.19(1H,d),8.30(1H,s),10.41(1H,s),10.53(1H,s),11.83(1H,s).m / z(ES + ),[M+H] + =251.2.

[0391] Example 36: 1-(isoxazolo[4,5-b]pyridine-6-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] DIAD (69.9 μL, 0.360 mmol) was added to a mixture of (E)-5-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-3-hydroxypicoline aldehyde oxime (60 mg, 0.240 mmol) and PPh3 (94 mg, 0.358 mmol) in THF (3 mL) at room temperature under N2 conditions. The resulting mixture was stirred at room temperature for 16 hours. The solvent was then removed under reduced pressure. Purification with C-18FC (gradient: 5-30% MeCN (in water) (containing 0.05% TFA)) yielded the title compound (40 mg, 72%) as a white solid. 1H NMR:δ 2.73(2H,t),3.89(2H,t),7.45(1H,d),8.23(1H,d),10.64(1H,s),11.76(1H,s).m / z(ES + ),[M+H] + =233.2.

[0392] Intermediate 37a: 6-bromo-2-(trimethylsilyl)flo[3,2-b]pyridine [ka] Ethinyltrimethylsilane (246 mg, 2.50 mmol) was added to a mixture of copper(I) iodide (31.8 mg, 0.167 mmol), bis(triphenylphosphine)palladium chloride (117 mg, 0.167 mmol), and 5-bromo-2-iodopyridine-3-ol (500 mg, 1.67 mmol) in triethylamine (10 mL) at room temperature under N2 conditions. The resulting mixture was stirred at room temperature for 17 hours. The solvent was then removed under reduced pressure. Purification by FSC (gradient 0-10% siRNA (in petroleum ether)) yielded the title compound (340 mg, 75%) as a brown solid. 1 H NMR:δ 0.36(9H,s),7.41(1H,d),8.44(1H,dd),8.61(1H,d).m / z(ES + ),[M+H] + =272.1.

[0393] Intermediate 37b: 1-(2-(trimethylsilyl)fl[3,2-b]pyridine-6-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Ephos (59.4 mg, 0.111 mmol) and Ephos Pd G4 (102 mg, 0.111 mmol) were added to a degassed mixture of Cs2CO3 (724 mg, 2.22 mmol), dihydropyrimidine-2,4(1H,3H)-dione (380 mg, 3.33 mmol), and 6-bromo-2-(trimethylsilyl)fl[3,2-b]pyridine (300 mg, 1.11 mmol) in 1,4-dioxane (20 mL) at room temperature under N2 conditions. The resulting mixture was stirred at 100°C for 17 hours. The solvent was then removed under reduced pressure. Purification using C-18FC (gradient: 0-50% MeCN (in water) (containing 0.1% FA)) yielded the title compound (120 mg, 36%) as a pale yellow solid. 1 H NMR:δ 0.35(9H,s),2.75(2H,t),3.85(2H,t),7.36(1H,d),7.99-8.06(1H,m),8.51(1H,d),10.51(1H,s).m / z(ES + ),[M+H] + =304.2.

[0394] Example 37: 1-(Flo[3,2-b]pyridine-6-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] A solution of tetra-n-butylammonium fluoride in THF (1 M, 330 μL, 0.330 mmol) was added to a solution of 1-(2-(trimethylsilyl)fluoro[3,2-b]pyridine-6-yl)dihydropyrimidine-2,4(1H,3H)-dione (100 mg, 0.330 mmol) in THF (10 mL) at room temperature in air. The resulting mixture was stirred at room temperature for 20 minutes. The solvent was then removed under reduced pressure. Purification with C-18FC (gradient: 0-40% MeCN (in water) (containing 0.1% NH4HCO3)) yielded the title compound (23.0 mg, 30%) as a pale yellow solid. 1 H NMR:δ 2.75(2H,t),3.86(2H,t),7.14(1H,dd),8.07(1H,dd),8.32(1H,d),8.53(1H,d),10.51(1H,br s).m / z(ES+ ),[M+H] + =232.2.

[0395] Intermediate 38a: 6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d][1,2,3]triazole [ka] NaH (60% dispersion in mineral oil, 99.0 mg, 2.47 mmol) was added to 6-bromo-1H-benzo[d][1,2,3]triazole (245 mg, 1.24 mmol) in DMF (6 mL) at room temperature under N2 conditions. The resulting mixture was stirred at room temperature for 0.5 hours, after which (2-(chloromethoxy)ethyl)trimethylsilane (268 mg, 1.61 mmol) was added. The resulting solution was stirred at room temperature for 16 hours. The reaction product was quenched with NH4Cl (1 mL), and then directly purified by C-18FC (gradient: 50-90% MeCN (in water)) to obtain the title compound (265 mg, 65%) as brown oil, which was used in the next step without further purification (this substance contains the title compound and a second unidentifiable positional isomer in a 1:1 ratio). m / z(ES + ),[M+H] + =328.0.

[0396] Intermediate 38b: 1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d][1,2,3]triazole-6-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Cs2CO3 (595 mg, 1.83 mmol) was added at room temperature under N2 conditions to a degassed mixture of 6-bromo-1-((2-(trimethylsilyl)ethoxy)-methyl)-1H-benzo[d][1,2,3]triazole (this substance contains the compound described and a second unidentifiable positional isomer in a 1:1 ratio) (200 mg, 0.609 mmol), dihydropyrimidine-2,4(1H,3H)-dione (209 mg, 1.83 mmol), Ephos (16.3 mg, 0.0305 mmol), and Ephos Pd G4 (28.0 mg, 0.0305 mmol) in 1,4-dioxane (10 mL). The resulting mixture was stirred at 100 °C for 20 hours. The solvent was then removed under reduced pressure. Purification with C-18FC (gradient: 30-60% MeCN (in water)) yielded the title compound (200 mg, 91%) (this substance contains the title compound and a second unidentifiable positional isomer in a 1:1 ratio) as a white solid, which was used in the next step without further purification. m / z(ES + ),[M+H] + =362.2.

[0397] Example 38: 1-(1H-benzo[d][1,2,3]triazole-6-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] 1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d][1,2,3]triazole-6-yl)dihydropyrimidine-2,4(1H,3H)-dione (this substance contains the described compound and a second unidentifiable positional isomer in a 1:1 ratio) (70 mg, 0.194 mmol) was added to HCl solution in siRNA (4 M, 5.00 mL, 20.0 mmol) to obtain a white suspension. The resulting mixture was stirred at room temperature for 2 hours. The solvent was then removed under reduced pressure. The crude product was purified by preparative HPLC (column A, eluent F, gradient: 0-2%) to obtain the title compound (35.0 mg, 78%) as a white solid. 1H NMR:δ 2.75(2H,t),3.87(2H,t),7.41(1H,dd),7.81(1H,d),7.90(1H,d),10.44(1H,s).m / z(ES + ),[M+H] + =232.2.

[0398] Intermediate 39a: 4-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-2-hydroxybenzaldehyde [ka] A degassed mixture of Cs2CO3 (584 mg, 1.79 mmol), 4-bromo-2-hydroxybenzaldehyde (120 mg, 0.597 mmol), dihydropyrimidine-2,4(1H,3H)-dione (204 mg, 1.79 mmol), Ephos (16.0 mg, 0.0299 mmol), and Ephos Pd G4 (27.4 mg, 0.0298 mmol) in 1,4-dioxane (10 mL) was stirred at 100°C under N2 for 15 hours. The reaction mixture was directly purified using C-18FC (gradient: 0-100% MeCN (in water) (containing 0.1% FA)) to obtain the title compound (50.0 mg, 36%) as a yellow solid. 1 H NMR:δ 10.85(s,1H),10.52(s,1H),10.19(s,1H),7.66(d,1H),7.09-6.88(m,2H),3.86(t,2H),2.72(t,2H).m / z(ES + ),[M+H] + =235.1.

[0399] Intermediate 39b: 4-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-2-hydroxybenzaldehyde oxime [ka] Hydroxylamine-O-sulfonic acid (77.0 mg, 0.681 mmol) was added to a stirred suspension of 4-(2,4-dioxotetra-hydropyrimidine-1(2H)-yl)-2-hydroxybenzaldehyde (80.0 mg, 0.342 mmol) in MeOH (10 mL). The resulting mixture was stirred at room temperature for 0.5 hours, and then NaHCO3 (57.4 mg, 0.683 mmol) was added to the mixture. Water (1 mL) was then added, and the resulting mixture was stirred for 0.5 hours, after which 0.5 mL of HCl (1 M) was added. The solvent was removed under reduced pressure, the residue was dissolved in MeOH (10 mL), and the mixture was filtered. The filtrate was concentrated and purified using C-18FC (gradient: 0-100% MeCN (in water) (containing 0.1% TFA)) to obtain the title compound as an inseparable mixture of isomers (E:Z = 4:1, 65.0 mg, 76%) as a yellow solid, which was used in the next step without further purification. m / z(ES + ),[M+H] + =250.0.

[0400] Example 39: 1-(benzo[d]isoxazole-6-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] DIAD (88.0 μL, 0.453 mmol) was added dropwise at room temperature to a stirred suspension in DCM (10 mL) of PPh3 (95.0 mg, 0.362 mmol) and an inseparable mixture of isomers of 4-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-2-hydroxybenzaldehyde oxime (E:Z=4:1, 45.0 mg, 0.181 mmol). The resulting mixture was stirred at room temperature for 2 hours, then at 50°C for 4 hours. The solvent was removed under reduced pressure. The substance was obtained by purification by C-18FC (gradient: 0-100% MeCN (in water)), and further purified by preparative HPLC (column A, eluent F, gradient: 3-10%) to obtain the title compound (10.0 mg, 24%) as a white solid. 1H NMR:δ 7.33(d,1H),6.65(d,1H),6.50(dd,1H),6.01(s,1H),3.72(t,2H),2.66(t,2H).m / z(ES - ),[MH] - =230.0

[0401] Intermediate 40a: tert-butyl6-bromo-1H-pyrrolo[3,2-b]pyridine-1-carboxylate [ka] Di-tert-butyl dicarbonate (884 μL, 3.81 mmol) was added to a mixture of 6-bromo-1H-pyrrolo[3,2-b]pyridine (500 mg, 2.54 mmol), triethylamine (707 μL, 5.08 mmol), and DMAP (31.0 mg, 0.254 mmol) in DCM (20 mL) at room temperature under N2 conditions. The resulting mixture was stirred at room temperature for 2 hours. The solvent was then removed under reduced pressure. Purification by FSC (gradient: 0-30% siRNA (in petroleum ether)) yielded the title compound (0.700 g, 93%) as a white solid. 1 H NMR:(CDCl3)δ 1.68(9H,s),6.75(1H,d),7.79(1H,d),8.57(2H,d).m / z(ES + ),[M+H] + =297.1.

[0402] Intermediate 40b: tert-butyl6-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate [ka] Ephos (45.0 mg, 0.0841 mmol) and Ephos Pd G4 (77.0 mg, 0.0838 mmol) were added to a mixture of Cs2CO3 (548 mg, 1.68 mmol), dihydropyrimidine-2,4(1H,3H)-dione (288 mg, 2.52 mmol), and tert-butyl 6-bromo-1H-pyrrolo[3,2-b]pyridine-1-carboxylate (250 mg, 0.84 mmol) in 1,4-dioxane (20 mL) at room temperature under N2 conditions. The resulting mixture was stirred at 100°C for 16 hours. The solvent was then removed under reduced pressure. Purification with C-18FC (gradient: 5-50% MeCN (in water) (containing 0.1% FA)) yielded the title compound (150 mg, 54%) as a white solid. 1 H NMR:δ 1.64(9H,s),2.77(2H,t),3.90(2H,t),6.84(1H,d),7.99(1H,d),8.31(1H,d),8.50(1H,d),10.48(1H,s).m / z(ES + ),[M+H] + =331.1.

[0403] Example 40: 1-(1H-pyrrolo[3,2-b]pyridine-6-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] 150 mg, 0.454 mmol of tert-butyl 6-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate was dissolved in 10 mL of 2,2,2-trifluoroethanol and sealed in a microwave tube. The reaction mixture was heated in a microwave reactor at 120°C for 1 hour and then cooled to room temperature. The solvent was then removed under reduced pressure. Purification using C-18FC (gradient: 0-10% MeCN (in water) (containing 0.1% FA)) yielded the title compound (78.0 mg, 75%) as a white solid. 1H NMR:δ 2.76(2H,t),3.84(2H,t),6.54-6.60(1H,m),7.68(1H,t),7.72-7.77(1H,m),8.30(1H,d),10.40(1H,s),11.40(1H,s).m / z(ES + ),[M+H] + =231.0.

[0404] Intermediate 41a: 6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole [ka] NaH (60% dispersion in mineral oil, 0.264 g, 6.60 mmol) was added to a solution of 6-bromo-1H-benzo[d]imidazole (1.00 g, 5.08 mmol) in DMF (15 mL) at 0°C under N2. The resulting suspension was stirred at room temperature for 15 minutes, then (2-(chloromethoxy)ethyl)trimethylsilane (1.10 g, 6.60 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with water (10 mL) and extracted with siRNA (3 × 50 mL). The combined organic extracts were dried (Na₂SO₄) and concentrated to obtain a brown residue. Purification by FSC (gradient: 0-10% SiO(in petroleum ether)) yielded the title compound (1.40 g, 84%) as a yellow liquid (this substance contains the title compound and its positional isomer: 5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole in a ratio of 94:6), which was used in the next step without further purification. m / z(ES + ),[M+H] + =329.0.

[0405] Intermediate 41b: 1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Cs2CO3 (398 mg, 1.22 mmol) was added under N2 conditions to a mixture of 6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole (this substance contains the compound and its positional isomer: 5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole in a ratio of 94:6) (200 mg, 0.611 mmol), Ephos Pd G4 (31.6 mg, 0.0344 mmol), Ephos (16.4 mg, 0.0307 mmol), and dihydropyrimidine-2,4(1H,3H)-dione (139 mg, 1.22 mmol) in 1,4-dioxane (10 mL). The resulting solution was stirred at 100°C for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated. Purification with C-18FC (gradient: 0-80% MeCN (in water)) yielded the title compound (100 mg, 45%) as a white solid (this substance was also contaminated with indistinguishable amounts of its positional isomers), which was used in the next step without further purification. m / z(ES) + ),[M+H] + =361.2.

[0406] Example 41: 1-(1H-benzo[d]imidazole-6-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] 1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-yl)dihydropyrimidine-2,4(1H,3H)-dione (this substance was contaminated in an indistinguishable amount of its positional isomer) (50.0 mg, 0.139 mmol) was added to an HCl solution (4 M, 4.00 mL, 16.0 mmol) in 1,4-dioxane and stirred at 50°C for 16 hours. The solvent was removed under reduced pressure, and the crude product was purified by preparative HPLC (column B, eluent B, gradient: 2-50%) to obtain the title compound (11.0 mg, 34%) as a white solid. 1 H NMR:δ 8.25(s,1H),7.55(m,2H),7.16(d,1H),3.81(t,2H),2.74(t,2H).m / z(ES+ ),[M+H] + =231.2.

[0407] Intermediate 42a: 3-(4-methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Cs2CO3 (5.71 g, 17.5 mmol) was added to a solution of 1-(chloromethyl)-4-methoxybenzene (915 mg, 5.84 mmol) and dihydropyrimidine-2,4(1H,3H)-dione (1.00 g, 8.76 mmol) in DMF (30 mL) at room temperature in air. The resulting mixture was stirred at room temperature for 20 hours. The reaction mixture was poured into water (100 mL), extracted with SiO2 (100 mL), and the organic layer was washed with brine (3 × 100 mL). The organic layer was dried with (Na2SO4) and concentrated to obtain a pale yellow solid. The crude solid was triturated with SiO2 to obtain a solid, which was collected by filtration and dried under vacuum to obtain the title compound (1.20 g, 88%) as a white solid. 1 H NMR:δ 2.62(2H,t),3.15-3.27(2H,m),3.71(3H,s),4.71(2H,s),6.79-6.89(2H,m),7.12-7.22(2H,m),7.79(1H,s).m / z(ES + ),[M+H] + =235.1.

[0408] Intermediate 42b: tert-butyl6-(3-(4-methoxybenzyl)-2,4-dioxotetrahydropyrimidine-1(2H)-yl)-1H-indazole-1-carboxylate [ka] Pd2(dba)3 (231 mg, 0.252 mmol) was added at room temperature under N2 to a degassed mixture of xanthophos (292 mg, 0.505 mmol), Cs2CO3 (1.10 g, 3.38 mmol), tert-butyl 6-bromo-1H-indazole-1-carboxylate (500 mg, 1.68 mmol), and 3-(4-methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione (464 mg, 1.68 mmol) in 1,4-dioxane (30 mL). The resulting mixture was stirred at 100 °C for 16 hours. The solvent was then removed under reduced pressure. Purification with C-18FC (gradient: 0-70% MeCN (in water) (containing 0.1% NH4HCO3)) yielded the title compound (200 mg, 26%) as a white solid. 1 H NMR:δ 1.64(9H,d),2.94(2H,t),3.72(3H,s),3.92(2H,t),4.83(2H,s),6.81-6.93(2H,m), 7.15-7.29(2H,m),7.38(1H,dd),7.88(1H,d),8.04-8.10(1H,m),8.41(1H,s).m / z(ES + ),[M-Boc+2H] + =351.1.

[0409] Example 42: 1-(1H-indazole-6-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Cerium ammonium nitrate (2.56 g, 4.67 mmol) was added to tert-butyl 6-(3-(4-methoxybenzyl)-2,4-dioxotetra-hydropyrimidine-1(2H)-yl)-1H-indazole-1-carboxylate (700 mg, 1.55 mmol) in MeCN (10 mL) and water (10 mL) at room temperature in air. The resulting solution was stirred at room temperature for 4 hours. The solvent was removed under reduced pressure. The substance was obtained by purification using C-18FC (gradient: 0-40% MeCN (in water) (containing 0.1% concentrated HCl)), and this was further purified by preparative HPLC (column F, eluent A, gradient: 15-18%) to obtain the title compound (40.0 mg, 11%) as a white solid.1 H NMR:δ 2.75(2H,t),3.86(2H,t),7.10(1H,dd),7.44-7.50(1H,m),7.75(1H,d),8.07(1H,s),10.38(1H,s),13.09(1H,s).m / z(ES + ),[M+H] + =231.1.

[0410] Intermediate 43a: 4-bromo-2-(4-methoxybenzyl)isoindorin-1-one [ka] NaH (60% dispersion in mineral oil, 28.5 mg, 1.19 mmol) was added to a solution of 4-bromoisoindorin-1-one (229 mg, 1.08 mmol) in DMF (10 mL) at 0°C under N2. The mixture was stirred at room temperature for 3 hours, and then 1-(chloromethyl)-4-methoxybenzene (169 mg, 1.08 mmol) was added at 0°C. The reaction mixture was stirred overnight at room temperature, and then MeOH (1 mL) was added. The mixture was then directly purified by C-18FC (gradient: 0-80% MeCN (in water)) to obtain the title compound (300 mg, 84%) as pale yellow rubber. 1 H NMR:δ 7.81(dd,1H),7.75(dd,1H),7.49(t,1H),7.30-7.21(m,2H),6.96-6.88(m,2H),4.68(s,2H),4.26(s,2H),3.74(s,3H).m / z(ES + ),[M+H] + =334.1.

[0411] Intermediate 43b: 1-(2-(4-methoxybenzyl)-1-oxoisoindorin-4-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Experiment 1: Cs2CO3 (294 mg, 0.902 mmol) was added under N2 to a degassed mixture of 4-bromo-2-(4-methoxybenzyl)isoindorin-1-one (100 mg, 0.301 mmol), dihydropyrimidine-2,4(1H,3H)-dione (103 mg, 0.903 mmol), Ephos (16.1 mg, 0.0301 mmol), and Ephos Pd G4 (27.7 mg, 0.0302 mmol) in 1,4-dioxane (8 mL). The resulting suspension was stirred at 100°C for 16 hours. The solvent was removed under reduced pressure to obtain the crude product. Experiment 2: Cs2CO3 (441 mg, 1.35 mmol) was added under N2 to a degassed mixture of 4-bromo-2-(4-methoxybenzyl)isoindorin-1-one (150 mg, 0.452 mmol), dihydropyrimidine-2,4(1H,3H)-dione (155 mg, 1.36 mmol), Ephos (24.2 mg, 0.0453 mmol), and Ephos Pd G4 (41.5 mg, 0.0452 mmol) in 1,4-dioxane (8 mL). The resulting suspension was stirred at 100 °C for 16 hours. The reaction products were combined with the crude product from Experiment 1, and the solvent was removed under reduced pressure. Purification by C-18FC (gradient: 0-60% MeCN (in water)) yielded the title compound (50 mg, average yield 18%) as a white solid. 1 H NMR:(CDCl3)δ 7.89(dd,1H),7.58(t,1H),7.44(s,1H),7.38(dd,1H),7.27(d,2H),6.92-6.86( m,2H),4.76(s,2H),4.25(s,2H),3.88(t,2H),3.82(s,3H),2.84(t,2H).m / z(ES + ),[M+H] + =366.1.

[0412] Example 43: 1-(1-oxoisoindorin-4-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] A solution of 1-(2-(4-methoxybenzyl)-1-oxoisoindorin-4-yl)dihydropyrimidine-2,4(1H,3H)-dione (80.0 mg, 0.219 mmol) in TFA (10 mL) was stirred at 90°C for 5 hours. The solvent was removed under reduced pressure. Purification by preparative HPLC (column X, eluent E, gradient: 5-30%) yielded the title compound (34.7 mg, 65%) as a white solid. 1 H NMR:δ 10.48(s,1H),8.59(s,1H),7.61(t,1H),7.59-7.52(m,2H),4.31(s,2H),3.82(t,2H),2.74(t,2H).m / z(ES + ),[M+H] + =246.1.

[0413] Intermediate 44a: 6-bromo-2-(4-methoxybenzyl)isoindorin-1-one [ka] NaH (60% dispersion in mineral oil, 153 mg, 3.82 mmol) was added to a solution of 6-bromoisoindorin-1-one (540 mg, 2.55 mmol) in DMF (15 mL) at 0°C under N2. The resulting solution was stirred at room temperature for 3 hours, and then 1-(chloromethyl)-4-methoxybenzene (512 mg, 3.27 mmol) was added at 0°C. The resulting mixture was stirred overnight at room temperature. Then  (40 mL) and water (30 mL) were added to the resulting mixture. The organic layer was dried (Na2SO4) and concentrated to obtain the crude product. Purification by C-18FC (gradient: 0~100% MeCN (in water)) yielded the title compound (320 mg, 38%) as a yellow solid. 1 H NMR:δ 7.84(d,1H),7.77(dd,1H),7.53(d,1H),7.26-7.18(m,2H),6.95-6.83(m,2H),4.65(s,2H),4.31(s,2H),3.73(s,3H).m / z(ES + ),[M+H] + = 332 / 334.

[0414] Intermediate 44b: 1-(2-(4-methoxybenzyl)-3-oxoisoindorin-5-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Cs2CO3 (353 mg, 1.08 mmol) was added under N2 conditions to a degassed mixture of dihydropyrimidine-2,4(1H,3H)-dione (124 mg, 1.08 mmol), 6-bromo-2-(4-methoxybenzyl)isoindorin-1-one (120 mg, 0.361 mmol), Ephos (19.3 mg, 0.0361 mmol), and Ephos Pd G4 (33.2 mg, 0.0361 mmol) in 1,4-dioxane (10 mL). The resulting solution was stirred at 100°C for 16 hours and then directly purified by C-18FC (gradient: 0-100% MeCN (in water)) to obtain the title compound (100 mg, 76%) as a white solid. 1 H NMR:δ 10.44(s,1H),7.67(d,1H),7.59-7.50(m,2H),7.22(d,2H),6.95-6.88(m,2 H),4.67(s,2H),4.33(s,2H),3.85(t,2H),3.73(s,3H),2.74(t,2H).m / z(ES + ),[M+H] + =366.2.

[0415] Example 44: 1-(3-oxoisoindorin-5-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Experiment 1: A solution of 1-(2-(4-methoxybenzyl)-3-oxoisoindorin-5-yl)dihydropyrimidine-2,4(1H,3H)-dione (20.0 mg, 0.0547 mmol) in TFA (1 mL) was stirred at 90°C for 5 hours and then cooled to room temperature. Experiment 2: A solution of 1-(2-(4-methoxybenzyl)-3-oxoisoindorin-5-yl)dihydropyrimidine-2,4(1H,3H)-dione (100 mg, 0.274 mmol) in TFA (2 mL) was stirred at 80°C for 16 hours. The reaction solution was combined with the solution from Experiment 1, and the mixture was directly purified by preparative HPLC (column B, eluent B, gradient: 2-10%) to obtain the title compound (60.8 mg, average yield 75%) as a white solid. 1 H NMR:δ 8.60(s,1H),7.64-7.51(m,3H),4.37(s,2H),3.84(t,2H),2.74(t,2H).m / z(ES + ),[M+H] + =246.1.

[0416] Intermediate 45a: 5-Fluorodihydropyrimidine-2,4(1H,3H)-dione [ka] Pd / C (10% on activated carbon, 245 mg, 0.230 mmol) was added to a solution of 5-fluoropyrimidine-2,4(1H,3H)-dione (300 mg, 2.31 mmol) in MeOH (40 mL). The resulting mixture was stirred at room temperature under H2 (1 atm) for 36 hours. The reaction mixture was filtered through a Celite pad. The solvent in the filtrate was removed under reduced pressure to obtain the title compound (250 mg, 82%) as a white solid. 1 H NMR: δ 10.43(s,1H),7.69(s,1H),5.15(ddd,1H),3.56(ddd,1H),3.40(td,1H).

[0417] Intermediate 45b: tert-butyl6-(5-fluoro-2,4-dioxotetrahydropyrimidine-1(2H)-yl)-1H-indole-1-carboxylate [ka] Ephos (8.1 mg, 0.015 mmol) and Ephos Pd G4 (13.9 mg, 0.0151 mmol) were added to a degassed mixture of Cs2CO3 (296 mg, 0.908 mmol), 5-fluorodihydropyrimidine-2,4(1H,3H)-dione (120 mg, 0.908 mmol), and tert-butyl 6-bromo-1H-indole-1-carboxylate (90.0 mg, 0.304 mmol) in 1,4-dioxane (10 mL) at room temperature under N2 conditions. The resulting mixture was stirred at 100°C for 14 hours. The reaction mixture was filtered, and the solvent was removed under reduced pressure to obtain the residue. Purification by C-18FC (gradient: 0-100% MeCN (in water)) yielded the title compound (50 mg, 48%) as a white solid. 1 H NMR:δ 10.90(s,1H),8.06(d,1H),7.72(d,1H),7.65(d,1H),7.22(dd,1H),6.74(d,1H),5.43(ddd,1H),4.31-4.02(m,2H),1.63(s,9H).m / z(ES + ),[M-tBu+2H] + =292.2.

[0418] Example 45: 5-Fluoro-1-(1H-indole-6-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] A suspension of tert-butyl 6-(5-fluoro-2,4-dioxotetrahydropyrimidine-1(2H)-yl)-1H-indole-1-carboxylate (25 mg, 0.072 mmol) in water (20 mL) was stirred at 100°C for 5 hours. The water was removed under reduced pressure to obtain the residue. Purification by preparative HPLC (column B, eluent B, gradient: 19-28%) yielded the title compound (11 mg, 62%) as a white solid. 1 H NMR: δ 11.18(s,1H),10.43(s,1H),7.54(d,1H),7.39(d,1H),7.34(s,1H),6.94(dd,1H),6.44(s,1H),5.41(dt,1H),3.96-4.26(m,2H). 19F NMR(376MHz)δ -198.07.m / z(ES + ),[M+H] + =248.0.

[0419] Intermediate 46a: 6-bromo-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazole-2(3H)-one [ka] NaH (60% dispersion in mineral oil, 90.0 mg, 2.25 mmol) was added to a solution of 6-bromobenzo[d]oxazole-2(3H)-one (400 mg, 1.87 mmol) in DMF (10 mL) at 0°C under N2. The resulting solution was stirred at 0°C for 15 minutes, and then (2-(chloromethoxy)ethyl)trimethylsilane (374 mg, 2.24 mmol) was added. The mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with saturated NH4Cl (10 mL) and extracted with siRNA (2 × 25 mL). The combined organic extract was dried (Na2SO4) and concentrated to obtain a brown residue. Purification by FSC (gradient: 0-30% siRNA (in petroleum ether)) yielded the title compound (0.520 g, 81%) as colorless rubber. 1 H NMR:(CDCl3)δ 7.41(d,1H),7.37(dd,1H),7.06(d,1H),5.28(s,2H),3.70-3.60(m,2H),0.98-0.92(m,2H),0.00(s,9H).

[0420] Intermediate 46b: 1-(2-oxo-3-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydrobenzo[d]oxazol-6-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Cs2CO3 (284 mg, 0.872 mmol) was added at room temperature under N2 conditions to a degassed mixture of 6-bromo-3-((2-(trimethylsilyl)ethoxy)-methyl)benzo[d]oxazole-2(3H)-one (100 mg, 0.290 mmol), dihydropyrimidine-2,4(1H,3H)-dione (66.3 mg, 0.581 mmol), Ephos Pd G4 (15.0 mg, 0.0163 mmol), and Ephos (7.8 mg, 0.015 mmol) in 1,4-dioxane (5 mL). The resulting suspension was stirred at 100°C for 16 hours. The reaction product was then filtered, and the filtrate was concentrated. Purification by C-18FC (gradient: 0-80% MeCN (in water)) yielded the title compound (60.0 mg, 55%) as a yellow solid. 1 H NMR:δ 10.38(s,1H),7.41(d,1H),7.32(d,1H),7.19(dd,1H),5.24(s,2H),3.75(t, 2H),3.65-3.54(m,2H),2.70(t,2H),0.92-0.81(m,2H),-0.06(s,9H).m / z(ES + ),[M+H] + =378.2.

[0421] Example 46: 1-(2-oxo-2,3-dihydrobenzo[d]oxazole-6-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] 1-(2-oxo-3-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydrobenzo[d]oxazole-6-yl)dihydropyrimidine-2,4(1H,3H)-dione (60.0 mg, 0.159 mmol) was added to a solution of DCM (2 mL) and TFA (2 mL) at room temperature under N2 conditions. The resulting solution was stirred at room temperature for 16 hours. The solvent was removed, and the residue was dissolved in DMF (2 mL). Then, K2CO3 (220 mg, 1.59 mmol) was added, and the mixture was stirred at 60°C for 2 hours. The reaction product was filtered, and the filtrate was concentrated. Purification by C-18FC (gradient: 0-80% MeCN (in water)) yielded the title compound (15.0 mg, 38%) as a yellow solid.1 H NMR:δ 11.67(s,1H),10.35(s,1H),7.31(d,1H),7.08(d,2H),3.73(t,2H),2.69(t,2H).m / z(ES + ),[M+H] + =248.1.

[0422] Intermediate 47a: 5-bromo-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazole-2(3H)-one [ka] NaH (60% dispersion in mineral oil, 70.6 mg, 1.77 mmol) was added to a solution of 5-bromobenzo[d]oxazole-2(3H)-one (315 mg, 1.47 mmol) in DMF (10 mL) at 0°C under N2. The resulting solution was stirred at room temperature for 15 minutes, and then (2-(chloromethoxy)ethyl)trimethylsilane (294 mg, 1.77 mmol) was added at room temperature. The mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with saturated NH4Cl (25 mL) and extracted with RINKAN (2 × 50 mL). The combined organic extract was dried (Na2SO4) and concentrated to obtain a yellow solid. Purification by C-18FC (gradient: 30-80% MeCN (in water)) yielded the title compound (380 mg, 75%) as a white solid. 1 H NMR: δ 0.05(9H,s),0.88(2H,m),3.61(2H,m),5.26(2H,s),7.36(2H,d),7.61(1H,d).

[0423] Intermediate 47b: 1-(2-oxo-3-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydrobenzo[d]oxazole-5-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Cs2CO3 (710 mg, 2.18 mmol) was added to a degassed mixture of 5-bromo-3-((2-(trimethylsilyl)ethoxy)-methyl)benzo[d]oxazole-2(3H)-one (250 mg, 0.726 mmol), dihydropyrimidine-2,4(1H,3H)-dione (249 mg, 2.18 mmol), Ephos (19.4 mg, 0.0363 mmol), and Ephos Pd G4 (33.3 mg, 0.0363 mmol) in 1,4-dioxane (15 mL). The resulting suspension was stirred overnight at 100°C. The solvent was then removed under reduced pressure. Purification with C-18FC (gradient: 50-80% MeCN (in water)) yielded the title compound (180 mg, 66%) as a yellow solid. 1 H NMR:δ -0.06(9H,s),0.87(2H,dd),2.71(2H,t),3.60(2H,dd),3.75(2H,t),5.22(2H,s),7.11(1H,dd),7.36(2H,m),10.38(1H,s).m / z(ES - ),[MH] - =376.

[0424] Example 47: 1-(2-oxo-2,3-dihydrobenzo[d]oxazole-5-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] 1-(2-oxo-3-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydrobenzo[d]oxazole-5-yl)dihydropyrimidine-2,4(1H,3H)-dione (80.0 mg, 0.212 mmol) was added to HCl solution in 1,4-dioxane (4 M, 10.0 mL, 40.0 mmol). The resulting mixture was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure, and the residue was dissolved in DMF (5 mL). Then K2CO3 (80 mg, 0.58 mmol) was added, and the mixture was stirred at 50°C for 3 hours. The reaction mixture was filtered, and the filtrate was concentrated. Purification by preparative HPLC (column E, eluent E, gradient: 5-28%) yielded the title compound (40.0 mg, 76%) as a white solid. 1H NMR:δ 2.71(2H,t),3.76(2H,t),7.02(1H,dd),7.09(1H,d),7.30(1H,d),10.36(1H,s).m / z(ES + ),[M+H] + =248.1.

[0425] Intermediate 48a: 6-bromo-7-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine [ka] NaH (60% dispersion in mineral oil, 284 mg, 7.11 mmol) was added to 6-bromo-7-methyl-1H-pyrrolo[3,2-b]pyridine (500 mg, 2.37 mmol) in DMF (10 mL) at 0°C under N2. The mixture was stirred for 20 minutes, after which (2-(chloromethoxy)ethyl)trimethylsilane (462 μL, 2.61 mmol) was added. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with water (50 mL) and extracted with siRNA (4 × 50 mL). The combined organic extract was dried (Na₂SO₄) and concentrated to obtain the title compound (800 mg, 99%) as a yellow oil. 1 H NMR:δ -0.11(9H,s),0.81(2H,t),2.78(3H,s),3.45(2H,t),5.63(2H,s),6.56(1H,d),7.79(1H,d),8.43(1H,d).m / z(ES + ),[M+H] + =343.0.

[0426] Intermediate 48b: tert-butyl(7-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-6-yl)carbamate [ka] Ephos Pd G4 (80.0 mg, 0.0871 mmol) was added at room temperature under N2 conditions to a degassed mixture of 6-bromo-7-methyl-1-((2-(trimethylsilyl)-ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine (598 mg, 1.75 mmol), tert-butylcarbamate (410 mg, 3.50 mmol), Ephos (46.8 mg, 0.0875 mmol), and Cs2CO3 (1.14 g, 3.50 mmol) in 1,4-dioxane (15 mL). The resulting mixture was stirred at 100 °C for 16 hours. The solvent was then removed under reduced pressure. Purification by FSC (gradient: 0-5% MeOH (in DCM)) yielded the title compound (260 mg, 39%) as a yellow solid. 1 H NMR:δ -0.08(9H,s),0.82(2H,t),1.45(9H,s),2.52(3H,s),3.45(2H,t),5.60(2H,s),6.50(1H,d),7.70(1H,d),8.11(1H,s),8.77(1H,s).m / z(ES + ),[M+H] + =378.2.

[0427] Intermediate 48c: 7-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-6-amine [ka] 400 mg, 1.06 mmol of tert-butyl(7-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-6-yl)carbamate was dissolved in 10 mL of 2,2,2-trifluoroethanol and sealed in a microwave tube. The reaction mixture was heated in a microwave reactor at 140°C for 3 hours and then cooled to room temperature. The solvent was removed under reduced pressure to obtain the title compound (260 mg, 88%) as a yellow oil. 1 H NMR:δ 0.02(9H,s),0.92(2H,t),2.49(3H,s),3.47(2H,brs),3.55(2H,t),5.61(2H,s),6.42(1H,d),7.46(1H,d),7.99(1H,s).m / z(ES+ ),[M+H] + =278.2.

[0428] Example 48: 1-(7-methyl-1H-pyrrolo[3,2-b]pyridin-6-yl)pyrimidine-2,4(1H,3H)-dione [ka] (E)-3-ethoxyacryloyl chloride (364 mg, 2.71 mmol) was added to silver cyanate (675 mg, 4.50 mmol) in toluene (5 mL) at room temperature under N2 conditions. The resulting mixture was stirred at 120 °C for 1 hour. After cooling the reaction to 0 °C, the supernatant was added to a solution of 7-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-6-amine (250 mg, 0.901 mmol) in DMF (5 mL) at 0 °C in air. The resulting mixture was stirred at 0 °C for 1 hour. The reaction mixture was diluted with Depositphotos (100 mL) and washed sequentially with water (3 × 50 mL) and saturated brine (50 mL). The organic layer was dried (Na2SO4) and concentrated to obtain (E)-3-ethoxy-N-((7-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-6-yl)carbamoyl)acrylamide as a yellow oil, which was used directly in the next step without further purification. (ES + ),[M+H] + =419.2. Next, the substance was dissolved in DCM (8 mL), and then TFA (4 mL, 51.92 mmol) was added at room temperature in air. The resulting mixture was stirred at room temperature for 2 days. Then, the solvent was removed under reduced pressure. The reaction mixture was diluted with 7 M ammonia in MeOH (5 mL) and stirred at room temperature for 0.5 hours. Then, the solvent was removed under reduced pressure. The title compound (70.0 mg, 32%, total 2 steps) was obtained as a white solid by purification with C-18FC (gradient: 5-10% MeCN (in water) (containing 0.05% TFA)). 1H NMR:δ 2.51(3H,s),5.79(1H,dd),6.81(1H,dd),7.70(1H,d),8.14(1H,d),8.64(1H,d),11.63(1H,s),12.62(1H,s).m / z(ES + ),[M+H] + =243.2.

[0429] Example 49: 1-(7-methyl-1H-pyrrolo[3,2-b]pyridine-6-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] A mixture of 1-(7-methyl-1H-pyrrolo[3,2-b]pyridin-6-yl)pyrimidine-2,4(1H,3H)-dione (50.0 mg, 0.206 mmol) and Pd / C (10% on activated carbon, 110 mg, 0.103 mmol) in MeOH (30 mL) was stirred at room temperature under an H2 (1 atm) atmosphere for 8 hours. The reaction mixture was filtered through a Celite pad. The solvent in the filtrate was then removed under reduced pressure. Purification by preparative HPLC (column G, eluent A, gradient: 3-13%) yielded the title compound (25.0 mg, 50%) as a white solid. 1 H NMR:δ 2.60(3H,s),2.71-2.94(2H,m),3.64-3.72(1H,m),3.81-3.91(1H,m),6.75 -6.86(1H,m),8.16(1H,t),8.68(1H,s),10.59(1H,s),12.71(1H,s).m / z(ES + ),[M+H] + =245.1

[0430] Intermediate 50a: tert-butyl 6-bromo-4-fluoro-1H-indole-1-carboxylate [ka] DMAP (0.080 g, 0.655 mmol) was added at room temperature in air to a solution of DIEA (2.29 mL, 13.1 mmol), di-tert-butyl dicarbonate (2.28 mL, 9.82 mmol), and 6-bromo-4-fluoro-1H-indole (1.40 g, 6.54 mmol) in DCM (20 mL). The resulting solution was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure. Purification by FSC (gradient: 0-5% siRNA (in petroleum ether)) yielded the title compound (2.00 g, 97%) as a white solid. 1 H NMR:(CDCl3)δ 1.67(9H,s),6.62(1H,dd),7.09(1H,dd),7.52(1H,d),8.17(1H,s).

[0431] Intermediate 50b: tert-butyl 6-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-4-fluoro-1H-indole-1-carboxylate [ka] Ephos (34.0 mg, 0.0636 mmol) and Ephos Pd G4 (58.5 mg, 0.0637 mmol) were added to a degassed mixture of Cs2CO3 (415 mg, 1.27 mmol), dihydropyrimidine-2,4(1H,3H)-dione (218 mg, 1.91 mmol), and tert-butyl 6-bromo-4-fluoro-1H-indole-1-carboxylate (200 mg, 0.64 mmol) in 1,4-dioxane (10 mL) at room temperature under N2. The resulting mixture was stirred at 100 °C for 17 hours. The solvent was then removed under reduced pressure. Purification by FSC (gradient: 0-8% MeOH (in DCM)) yielded the title compound (210 mg, 95%) as a pale yellow solid. 1 H NMR:(CDCl3)δ 1.68(9H,s),2.88(2H,t),3.95(2H,t),6.68(1H,d),6.91-7.01(1H,m),7.59(1H,d),8.00(1H,s).m / z(ES + ),[M+H] + =348.2.

[0432] Example 50: 1-(4-fluoro-1H-indole-6-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] 205 mg, 0.776 mmol of tert-butyldimethylsilyltrifluoromethanesulfonate was added to a solution of 180 mg, 0.518 mmol of tert-butyl 6-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-4-fluoro-1H-indole-1-carboxylate in 10 mL of MeCN at room temperature in air. The resulting solution was stirred at room temperature for 1 hour. The solvent was then removed under reduced pressure. The substance was purified by C-18FC (gradient: 0-30% MeCN (in water) (containing 0.1% FA)), and this was further purified by preparative HPLC (column H, eluent E, gradient: 25-37%) to obtain the title compound (32.0 mg, 25%) as a pale yellow solid. 1 H NMR:δ 2.73(2H,t),3.81(2H,t),6.45-6.53(1H,m),6.83(1H,dd),7.21(1H,t),7.39-7.47(1H,m),10.36(1H,s),11.49(1H,s).m / z(ES + ),[M+H] + =248.2.

[0433] Intermediate 51a: tert-butyl 6-bromo-4-methyl-1H-indole-1-carboxylate [ka] DMAP (17.5 mg, 0.143 mmol) was added to a solution of DIEA (499 μL, 2.86 mmol), di-tert-butyl dicarbonate (497 μL, 2.14 mmol), and 6-bromo-4-methyl-1H-indole (300 mg, 1.43 mmol) in DCM (20 mL). The resulting solution was stirred at room temperature for 2 hours. The solvent was then removed under reduced pressure. Purification by FSC (gradient 0-4% siRNA (in petroleum ether)) yielded the title compound (440 mg, 99%) as brown oil.1 H NMR: δ 1.60(9H,s),2.46(3H,s),6.72-6.79(1H,m),7.20-7.27(1H,m),7.65(1H,d),8.00-8.05(1H,m).

[0434] Intermediate 51b: tert-butyl 6-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-4-methyl-1H-indole-1-carboxylate [ka] Ephos (69.0 mg, 0.129 mmol) and Ephos Pd G4 (118 mg, 0.128 mmol) were added to a degassed mixture of Cs2CO3 (840 mg, 2.58 mmol), dihydropyrimidine-2,4(1H,3H)-dione (441 mg, 3.87 mmol), and tert-butyl 6-bromo-4-methyl-1H-indole-1-carboxylate (400 mg, 1.29 mmol) in 1,4-dioxane (16 mL) at room temperature under N2. The resulting mixture was stirred at 100°C for 17 hours. The solvent was then removed under reduced pressure. Purification by FSC (gradient: 0-9% MeOH (in DCM)) yielded the title compound (240 mg, 54%) as a brown solid. 1 H NMR:δ 1.60(9H,s),2.46(3H,s),2.71(2H,t),3.79(2H,t),6.71-6.78(1H,m), 6.99-7.06(1H,m),7.66(1H,d),7.82-7.88(1H,m),10.33(1H,s).m / z(ES + ),[M+H] + =366.1.

[0435] Example 51: 1-(4-methyl-1H-indole-6-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] 260 mg, 0.757 mmol of tert-butyl 6-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-4-methyl-1H-indole-1-carboxylate was dissolved in 3 mL of 2,2,2-trifluoroethanol and sealed in a microwave tube. The reaction mixture was heated in a microwave reactor at 120°C for 1 hour and then cooled to room temperature. The solvent was then removed under reduced pressure. Purification with C-18FC (gradient: 0-23% MeCN (in water) (containing 0.1% FA)) yielded the title compound (176 mg, 96%) as a brown solid. 1 H NMR:δ 2.46(3H,s),2.71(2H,t),3.76(2H,t),6.41-6.47(1H,m),6.72-6.78(1H,m),7.15(1H,s),7.34(1H,t),10.26(1H,s),11.12(1H,s).m / z(ES + ),[M+H] + =244.3.

[0436] Intermediate 52a: tert-butyl 6-bromo-4-methoxy-1H-indole-1-carboxylate [ka] DMAP (16.2 mg, 0.133 mmol) was added to a solution of DIEA (464 μL, 2.65 mmol), di-tert-butyl dicarbonate (462 μL, 1.99 mmol), and 6-bromo-4-methoxy-1H-indole (300 mg, 1.33 mmol) in DCM (20 mL). The resulting solution was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure. Purification by FSC (gradient: 0-7% siRNA (in petroleum ether)) yielded the title compound (0.430 g, 99%) as a brown solid. 1 H NMR: δ 1.60(9H,s),3.89(3H,s),6.62-6.69(1H,m),6.95(1H,d),7.55(1H,d),7.79-7.86(1H,m).

[0437] Intermediate 52b: tert-butyl 6-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-4-methoxy-1H-indole-1-carboxylate [ka] Ephos (65.6 mg, 0.123 mmol) and Ephos Pd G4 (113 mg, 0.123 mmol) were added to a degassed mixture of Cs2CO3 (799 mg, 2.45 mmol), dihydropyrimidine-2,4(1H,3H)-dione (420 mg, 3.68 mmol), and tert-butyl 6-bromo-4-methoxy-1H-indole-1-carboxylate (400 mg, 1.23 mmol) in 1,4-dioxane (16 mL) at room temperature under N2. The resulting mixture was stirred at 100 °C for 17 hours. The solvent was then removed under reduced pressure. Purification by FSC (gradient: 0-7% MeOH (in DCM)) yielded the title compound (260 mg, 59%) as a brown solid. 1 H NMR:δ 1.60(9H,s),2.72(2H,t),3.81(2H,t),3.87(3H,s),6.62-6.72(1H,m),6.79(1H,d),7.56(1H,d),7.60-7.67(1H,m),10.35(1H,s).m / z(ES + ),[M+H] + =360.1.

[0438] Example 52: 1-(4-methoxy-1H-indole-6-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] 250 mg, 0.696 mmol of tert-butyl 6-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-4-methoxy-1H-indole-1-carboxylate was dissolved in 3 mL of 2,2,2-trifluoroethanol and sealed in a microwave tube. The reaction mixture was heated in a microwave reactor at 120°C for 1 hour and then cooled to room temperature. The solvent was then removed under reduced pressure. Purification with C-18FC (gradient: 0-25% MeCN (in water) (containing 0.1% FA)) yielded the title compound (155 mg, 86%) as a brown solid. 1 H NMR:δ 2.72(2H,t),3.78(2H,t),3.85(3H,s),6.38-6.44(1H,m),6.48(1H,d),6.94(1H,s),7.25(1H,t),10.27(1H,s),11.15(1H,s).m / z(ES + ),[M+H] + =260.2.

[0439] Intermediate 53a: tert-butyl 6-bromo-4-chloro-1H-indole-1-carboxylate [ka] DMAP (21.2 mg, 0.174 mmol) was added to a solution of DIEA (606 μL, 3.47 mmol), di-tert-butyl dicarbonate (604 μL, 2.60 mmol), and 6-bromo-4-chloro-1H-indole (400 mg, 1.74 mmol) in DCM (10 mL). The resulting solution was stirred at room temperature for 2 hours. The solvent was then removed under reduced pressure. Purification by FSC (gradient: 0-5% siRNA (in petroleum ether)) yielded the title compound (458 mg, 80%) as a white solid. 1 H NMR:δ 1.64(9H,s),6.75(1H,dt),7.59(1H,t),7.81(1H,d),8.14-8.23(1H,m).m / z(ES + ),[M+Na] + =352.3.

[0440] Intermediate 53b: tert-butyl 4-chloro-6-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-1H-indole-1-carboxylate [ka] Ephos (72.5 mg, 0.136 mmol) and Ephos Pd G4 (124 mg, 0.135 mmol) were added to a degassed mixture of Cs2CO3 (883 mg, 2.71 mmol), dihydropyrimidine-2,4(1H,3H)-dione (464 mg, 4.07 mmol), and tert-butyl 6-bromo-4-chloro-1H-indole-1-carboxylate (448 mg, 1.36 mmol) in 1,4-dioxane (10 mL) at room temperature under N2. The resulting mixture was stirred at 100°C for 17 hours. The solvent was then removed under reduced pressure. Purification using C-18FC (gradient: 0-50% MeCN (in water) (containing 0.1% FA)) yielded the title compound (190 mg, 39%) as a brown solid. 1 H NMR:δ 1.61(9H,s),2.72(2H,t),3.84(2H,t),6.73(1H,dd),7.38(1H,d),7.79(1H,d),8.01(1H,dd),10.42(1H,s).m / z(ES + ),[M+H] + =364.0.

[0441] Example 53: 1-(4-chloro-1H-indole-6-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] 180 mg, 0.495 mmol of tert-butyl 4-chloro-6-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-1H-indole-1-carboxylate was added to 3 mL of 2,2,2-trifluoroethanol and sealed in a microwave tube. The reaction mixture was heated in a microwave reactor at 120°C for 2 hours and then cooled to room temperature. The solvent was then removed under reduced pressure. Purification using C-18FC (gradient: 0-50% MeCN (in water) (containing 0.1% FA)) yielded the title compound (81.0 mg, 62%) as a white solid. 1 H NMR:δ 2.73(2H,t),3.80(2H,t),6.46(1H,ddd),7.10(1H,d),7.30-7.37(1H,m),7.50(1H,t),10.35(1H,s),11.53(1H,s).m / z(ES + ),[M+H] + =264.2.

[0442] Intermediate 54a: tert-butyl 6-bromo-7-fluoro-1H-indole-1-carboxylate [ka] DMAP (0.114 g, 0.933 mmol) was added to a solution of DIEA (2.45 mL, 14.0 mmol), di-tert-butyl dicarbonate (2.17 mL, 9.34 mmol), and 6-bromo-7-fluoro-1H-indole (1.00 g, 4.67 mmol) in DCM (30 mL) at room temperature under N2 conditions. The resulting mixture was stirred at room temperature for 1 hour. The solvent was then removed under reduced pressure. Purification by FSC (gradient: 0-10% siRNA (in petroleum ether)) yielded the title compound (1.50 g, 102%) as a pale yellow oil, which was allowed to stand and solidify. 1 H NMR:(CDCl3)δ 1.66(9H,s),6.55(1H,dd),7.20(1H,d),7.37(1H,dd),7.62(1H,d).m / z(ES + ),[M-Boc+2H] + =214.0.

[0443] Intermediate 54b: tert-butyl 6-((tert-butoxycarbonyl)amino)-7-fluoro-1H-indole-1-carboxylate [ka] Ephos Pd G4 (0.175 g, 0.191 mmol) was added at room temperature under N2 to a degassed mixture of tert-butyl 6-bromo-7-fluoro-1H-indole-1-carboxylate (1.00 g, 3.18 mmol), tert-butylcarbamate (0.746 g, 6.37 mmol), Ephos (0.170 g, 0.318 mmol), and Cs2CO3 (2.07 g, 6.35 mmol) in 1,4-dioxane (20 mL). The resulting mixture was stirred at 100 °C for 16 hours. The solvent was then removed under reduced pressure. Purification by FSC (gradient: 0-5% SiO(in petroleum ether)) yielded the title compound (1.00 g, 90%) as a colorless rubber. 1 H NMR:(CDCl3)δ 1.54(9H,s),1.65(9H,s),6.51(1H,dd),6.72(1H,s),7.22-7.31(1H,m),7.54(1H,d),7.93(1H,br s).m / z(ES + ),[M+Na] + =373.

[0444] Intermediate 54c: 3-((7-fluoro-1H-indole-6-yl)amino)propanoic acid [ka] TFA (8.00 mL, 104 mmol) was added at room temperature to a solution of tert-butyl 6-((tert-butoxycarbonyl)amino)-7-fluoro-1H-indole-1-carboxylate (900 mg, 2.57 mmol) in DCM (20 mL). The resulting mixture was stirred at room temperature for 1 hour. The solvent was then removed under reduced pressure. Toluene (20 mL) was added to the residue, and acrylic acid (229 mg, 3.18 mmol) was added to the mixture at room temperature. The resulting mixture was stirred at 110°C for 2 hours. The solvent was then removed under reduced pressure. Purification with C-18FC (gradient: 0-15% MeCN (in water) (containing 0.5% TFA)) yielded the title compound in the form of a trifluoroacetate salt (0.310 g, 36%) as a yellow foam. 1 H NMR:δ 2.58(2H,t),3.42(2H,t),6.41(1H,td),6.75(1H,t),7.19-7.32(2H,m),10.27(1H,br s),11.30(1H,s).m / z(ES + ),[M+H] + =223.1.

[0445] Example 54: 1-(7-fluoro-1H-indole-6-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Urea (232 mg, 3.87 mmol) was added to trifluoroacetate salt of 3-((7-fluoro-1H-indole-6-yl)amino)propanoic acid (260 mg, 0.773 mmol) in AcOH (6 mL) at room temperature. The resulting mixture was stirred at 100 °C for 16 hours. The solvent was then removed under reduced pressure. Purification with C-18FC (gradient: 0-25% MeCN (in water) (containing 0.05% TFA)) yielded the title compound (75 mg, 39%) as a brown solid. 1 H NMR:δ 2.75(2H,t),3.75(2H,t),6.53(1H,td),6.98(1H,dd),7.37(1H,d),7.46(1H,t),10.43(1H,s),11.71(1H,s).m / z(ES + ),[M+H]+ =248.2.

[0446] Example 55: 1-(1H-indole-6-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Acrylic acid (131 mg, 1.82 mmol) was added dropwise to a mixture of 1H-indole-6-amine (200 mg, 1.51 mmol) in toluene (2 mL) at room temperature. The resulting solution was stirred at 80°C for 12 hours. The solvent was then removed under reduced pressure. The residue was dissolved in AcOH (2 mL), and urea (176 mg, 2.94 mmol) was added to the solution at room temperature in air. The resulting solution was stirred at 120°C for 12 hours. The solvent was then removed under reduced pressure. Purification by preparative TLC (DCM:MeOH = 10:1) yielded the title compound (56.0 mg, 16%) as a white solid. 1 H NMR:δ 11.16(s,1H),10.29(s,1H),7.52(d,1H),7.40-7.30(m,2H),6.94(dd,1H),6.45-6.39(m,1H),3.80(t,2H),2.73(t,2H).m / z(ES + ),[M+H] + =230.2.

[0447] Example 56: 1-(1H-indole-5-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Acrylic acid (465 mg, 6.46 mmol) was added to a solution of tert-butyl 5-amino-1H-indole-1-carboxylate (500 mg, 2.15 mmol) in toluene (5 mL) at room temperature under N2. The resulting solution was stirred at 110°C for 12 hours. The solvent was removed under reduced pressure, and AcOH (5 mL) and urea (388 mg, 6.46 mmol) were added to the crude mixture at room temperature in air. The resulting solution was stirred at 120°C for 12 hours. The solvent was then removed under reduced pressure. Purification by C-18FC (gradient: 0-30% MeCN (in water) (containing 0.1% FA)) yielded a pale yellow solid, which was further purified by preparative HPLC (column E, eluent E, gradient: 20-28%) to obtain the title compound (160 mg, 32%) as a white solid. 1 H NMR:δ 2.72(2H,t),3.76(2H,t),6.43(1H,d),7.02(1H,dd),7.34-7.42(2H,m),7.45(1H,d),10.23(1H,s),11.14(1H,s).m / z(ES + ),[M+H] + =230.0.

[0448] Intermediate 57a: 7-methyl-6-nitro-1H-indole [ka] Vinyl magnesium bromide (1M solution in THF, 31.3 mL, 31.3 mmol) was added dropwise to a solution of 2-methyl-1,3-dinitrobenzene (1.90 g, 10.4 mmol) in THF (50 mL) over 5 minutes at -78°C under N2. The resulting mixture was stirred at -78°C for 4 hours. The reaction mixture was quenched with saturated NH4Cl (20 mL), diluted with HCl (100 mL), and washed sequentially with water (50 mL) and saturated brine (100 mL). The organic layer was dried over (Na2SO4) and concentrated under reduced pressure to obtain the crude product. Purification by FSC (gradient: 0-25% HCl (in petroleum ether)) yielded the title compound as a brown solid (290 mg, 16%). 1H NMR:δ 2.74(3H,s),6.61(1H,dd),7.53(1H,d),7.64-7.75(2H,m),11.86(1H,s).m / z(ES + ),[M+H] + =177.3.

[0449] Intermediate 57b: tert-butyl 7-methyl-6-nitro-1H-indole-1-carboxylate [ka] DMAP (19.4 mg, 0.159 mmol) was added at room temperature in air to a solution of 7-methyl-6-nitro-1H-indole (280 mg, 1.59 mmol), di-tert-butyl dicarbonate (443 μL, 1.91 mmol), and triethylamine (443 μL, 3.18 mmol) in DCM (30 mL). The resulting mixture was stirred at room temperature for 2 hours. The solvent was then removed under reduced pressure. Purification by FSC (gradient: 0-8% siRNA (in petroleum ether)) yielded the title compound (326 mg, 74%) as a yellow solid. 1 H NMR:δ 1.62(9H,s),2.51(3H,s),6.85(1H,d),7.67(1H,d),7.84(1H,d),7.95(1H,d).m / z(ES + ),[M+H] + =277.1.

[0450] Intermediate 57c: tert-butyl 6-amino-7-methyl-1H-indole-1-carboxylate [ka] Zinc (297 mg, 4.54 mmol) was added at room temperature to a mixture of tert-butyl 7-methyl-6-nitro-1H-indole-1-carboxylate (251 mg, 0.908 mmol) in EtOH (12 mL) and saturated NH4Cl (3 mL). The resulting solution was stirred at room temperature for 2 hours. The reaction mixture was filtered through a Celite pad, and the solvent was removed under reduced pressure. Purification by FSC (gradient: 0-20% siRNA (in petroleum ether)) yielded the title compound (66.7 mg, 30%) as a pale yellow oil. 1 H NMR:δ 1.57(9H,s),2.13(3H,s),4.86(2H,s),6.44(1H,d),6.67(1H,d),7.11(1H,d),7.28(1H,d).m / z(ES + ),[M+H] + =247.2.

[0451] Example 57: 1-(7-methyl-1H-indole-6-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Acrylic acid (70.2 mg, 0.974 mmol) was added to a solution of tert-butyl 6-amino-7-methyl-1H-indole-1-carboxylate (40.0 mg, 0.162 mmol) in toluene (2 mL). The resulting mixture was stirred at 100°C for 10 hours. The solvent was then removed under reduced pressure. The residue was dissolved in AcOH (2 mL), urea (9.8 mg, 0.16 mmol) was added, and the resulting solution was stirred at 120°C for 3 hours. The solvent was then removed under reduced pressure. Purification with C-18FC (gradient: 0-30% MeCN (in water)) yielded the title compound (3.00 mg, 8%) as a white solid. 1 H NMR:δ 2.33(3H,s),2.68-2.86(2H,m),3.55(1H,m),3.77(1H,m),6.44(1H,m),6.89(1H,d),7.39(2H,m),10.28(1H,s),11.17(1H,s).m / z(ES + ),[M+H] + =244.3.

[0452] Intermediate 58a: 6-bromo-5-fluoro-7-methyl-1H-indole [ka] Vinyl magnesium bromide (19.2 mL, 19.2 mmol, 1 M solution in THF) was added to a solution of 2-bromo-1-fluoro-3-methyl-4-nitrobenzene (1.50 g, 6.41 mmol) in THF (30 mL) under N2 at -78°C. The resulting mixture was stirred at -78°C for 2 hours. The reaction product was quenched with saturated NH4Cl (200 mL) and extracted with siRNA (3 × 200 mL). The combined organic extract was dried (Na2SO4) and concentrated under reduced pressure to obtain a brown residue. Purification by FSC (gradient: 0-19% siRNA (in petroleum ether)) yielded the title compound (0.500 g, 34%) as a yellow solid. 1 H NMR:(CDCl3)δ 2.60(3H,s),6.54(1H,dd),7.24-7.29(1H,m),8.10(1H,s).m / z(ES + ),[M+H] + =228.0.

[0453] Intermediate 58b: tert-butyl 6-bromo-5-fluoro-7-methyl-1H-indole-1-carboxylate [ka] Di-tert-butyl dicarbonate (611 μL, 2.63 mmol) was added at room temperature in air to a mixture of 6-bromo-5-fluoro-7-methyl-1H-indole (500 mg, 2.19 mmol), triethylamine (917 μL, 6.58 mmol), and DMAP (26.8 mg, 0.219 mmol) in DCM (20 mL). The resulting mixture was stirred at room temperature for 2 hours. The solvent was then removed under reduced pressure. Purification by FSC (gradient: 0-5% siRNA (in petroleum ether)) yielded the title compound (540 mg, 75%) as a yellow oil. 1H NMR:(CDCl3)δ 1.63(9H,s),2.63(3H,s),6.48(1H,d),7.14(1H,d),7.54(1H,d).

[0454] Intermediate 58c: tert-butyl 6-((tert-butoxycarbonyl)amino)-5-fluoro-7-methyl-1H-indole-1-carboxylate [ka] Cs2CO3 (1.49 g, 4.57 mmol) was added to a degassed mixture of Ephos Pd G4 (70.0 mg, 0.0762 mmol), Ephos (40.8 mg, 0.0763 mmol), tert-butylcarbamate (357 mg, 3.05 mmol), and tert-butyl 6-bromo-5-fluoro-7-methyl-1H-indole-1-carboxylate (500 mg, 1.52 mmol) in 1,4-dioxane (10 mL) at room temperature under N2. The resulting mixture was stirred at 100 °C for 17 hours. The solvent was then removed under reduced pressure. Purification by FSC (gradient: 0-100% siRNA (in petroleum ether)) yielded the title compound (280 mg, 50%) as a white solid. 1 H NMR:(CDCl3)δ 1.50(9H,s),1.63(9H,s),2.47(3H,s),6.01(1H,br s),6.46(1H,d),7.11(1H,d),7.53(1H,d).m / z(ES + ),[M+Na] + =387.2.

[0455] Intermediate 58d: 3-((5-fluoro-7-methyl-1H-indole-6-yl)amino)propanoic acid [ka] 280 mg, 0.768 mmol of tert-butyl 6-((tert-butoxycarbonyl)amino)-5-fluoro-7-methyl-1H-indole-1-carboxylate was dissolved in 8 mL of 2,2,2-trifluoroethanol and sealed in a microwave tube. The reaction mixture was heated in a microwave reactor at 150°C for 1 hour and then cooled to room temperature. The solvent was removed, and 5 mL of toluene, followed by 84.0 mg, 1.17 mmol of acrylic acid, was added to the residue. The resulting mixture was stirred at 110°C for 16 hours. The solvent was then removed under reduced pressure. Purification with C-18FC (gradient: 5-30% MeCN (in water) (containing 0.05% FA)) yielded the impure form of the title compound (100 mg) as a yellow solid, which was used in the next step without further purification. m / z(ES + ),[M+H] + =237.3.

[0456] Example 58: 1-(5-fluoro-7-methyl-1H-indole-6-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Urea (127 mg, 2.11 mmol) was added to a solution of impure 3-((5-fluoro-7-methyl-1H-indole-6-yl)amino)-propanoic acid (100 mg) in AcOH (3 mL) at room temperature in air. The resulting mixture was stirred at 100°C for 4 hours. The crude product was directly purified by C-18FC (gradient: 5-30% MeCN (in water) (containing 0.05% TFA)) and further purified by preparative HPLC (column X, eluent A, gradient: 35-45%) to obtain the title compound (15.0 mg, 7%, total 3 steps) as a white solid. 1 H NMR:δ 2.38(3H,s),2.56-2.72(1H,m),2.78-2.95(1H,m),3.48-3.61(1H,m),3.61-3. 75(1H,m),6.45(1H,dd),7.25(1H,d),7.46(1H,t),10.42(1H,s),11.29(1H,s). 19 F NMR(282MHz)δ -133.32.m / z(ES+ ),[M+H] + =262.2.

[0457] Example 59: 1-(1-methyl-1H-indole-6-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Acrylic acid (444 mg, 6.16 mmol) was added to a solution of 1-methyl-1H-indole-6-amine (300 mg, 2.05 mmol) in toluene (5 mL) at room temperature under N2. The resulting solution was stirred at 110°C for 12 hours. The solvent was then removed under reduced pressure. The residue was dissolved in AcOH (5 mL), and urea (370 mg, 6.16 mmol) was added to the solution at room temperature in air. The resulting solution was stirred at 120°C for 12 hours. The solvent was then removed under reduced pressure. A yellow substance was obtained by purification using C-18FC (gradient: 0-30% MeCN (in water) (containing 0.1% FA)), which was further purified by preparative HPLC (column E, eluent E, gradient: 42-60%) to obtain the title compound (90.0 mg, 18%) as a white solid. 1 H NMR:δ 2.74(2H,t),3.78(3H,s),3.81(2H,t),6.43(1H,d),6.99(1H,dd),7.36(1H,d),7.41(1H,t),7.53(1H,d),10.31(1H,s).m / z(ES + ),[M+H] + =244.1.

[0458] Intermediate 60a: tert-butyl 6-bromo-5-fluoro-1H-indole-1-carboxylate [ka] DMAP (228 mg, 1.87 mmol) was added to a solution of DIEA (4.90 mL, 28.1 mmol), di-tert-butyl dicarbonate (4.34 mL, 18.7 mmol), and 6-bromo-5-fluoro-1H-indole (2.00 g, 9.34 mmol) in DCM (10 mL) at room temperature under N2 conditions. The resulting mixture was stirred at room temperature for 2 hours. The solvent was then removed under reduced pressure. Purification by FSC (gradient: 0-30% siRNA (in petroleum ether)) yielded the title compound (2.30 g, 78%) as a white solid. 1 H NMR: δ 1.62(9H,s),6.71(1H,dd),7.62(1H,d),7.75(1H,d),8.27(1H,d).

[0459] Intermediate 60b: tert-butyl 6-amino-5-fluoro-1H-indole-1-carboxylate [ka] Copper(I) iodide (133 mg, 0.698 mmol) was added to a mixture of tert-butyl 6-bromo-5-fluoro-1H-indole-1-carboxylate (1.10 g, 3.50 mmol), aqueous NH4OH (28%, 2.44 mL, 17.5 mmol), K3PO4 (2.23 g, 10.5 mmol), and L-proline (81.0 mg, 0.704 mmol) in DMF (15 mL) at room temperature under N2 conditions. The resulting mixture was stirred at 90°C for 16 hours. The reaction mixture was quenched with water (100 mL), extracted with ethyl acetate (2 × 100 mL), and the combined organic extract was washed with saturated brine (3 × 50 mL). The organic layer was dried and concentrated in (Na2SO4). Purification by FSC (gradient 0-20% phenyl (in petroleum ether)) removes impurities from the title compound (600 mg, 68% [ 1 A pale yellow solid (10% purity, based on 1H NMR) was obtained. This was an inseparable mixture containing 6-bromo-5-fluoro-1H-indole in a 1:10 ratio (i.e., approximately 10% purity), which was used in the next step without further purification. 1¹H NMR: (Desired compound only, CDCl3)δ 1.67(9H,s), 6.42(1H,d), 7.16(1H,d), 7.25(2H,s), 7.42(1H,d), 7.69(1H,d).m / z(ES + ),[M+H] + =251.1.

[0460] Example 60: 1-(5-fluoro-1H-indole-6-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Acrylic acid (84 mg, 1.17 mmol) is heated at room temperature to form tert-butyl 6-amino-5-fluoro-1H-indole-1-carboxylate ( 1 The compound was added to a solution of 10% purity (580 mg, 0.232 mmol) in toluene (10 mL) based on 1H NMR. The resulting mixture was stirred at 110°C for 16 hours. The solvent was then removed under reduced pressure. The residue was dissolved in AcOH (10 mL), and urea (69.6 mg, 1.16 mmol) was added to the solution at room temperature in air. The resulting mixture was stirred at 120°C for 4 hours. The solvent was then removed under reduced pressure. Purification by preparative HPLC (column J, eluent A, gradient: 15-18%) yielded the title compound (28.0 mg, 49%) as a white solid. 1 H NMR: δ 2.74(2H,t),3.73(2H,t),6.41-6.49(1H,m),7.39(1H,d),7.42(1H,d),7.46(1H,t),10.40(1H,s),11.29(1H,s). 19 F NMR(282MHz)δ -133.61.m / z(ES + ),[M+H] + =248.2.

[0461] Intermediate 61a: tert-butyl 5-methoxy-6-nitro-1H-indole-1-carboxylate [ka] DMAP (140 mg, 1.15 mmol) was added to DIEA (3.00 mL, 17.2 mmol), di-tert-butyl dicarbonate (2.66 mL, 11.46 mmol), and 5-methoxy-6-nitro-1H-indole (1.10 g, 5.72 mmol) in DCM (20 mL) at room temperature in air. The resulting solution was stirred at room temperature for 2 hours. The solvent was then removed under reduced pressure. Purification by FSC (gradient: 0-20% siRNA (in petroleum ether)) yielded the title compound (1.50 g, 90%) as a pale yellow solid. 1 H NMR:(CDCl3)δ 1.69(9H,s),3.99(3H,s),6.57(1H,dd),7.17(1H,s),7.78(1H,d),8.69(1H,s).m / z(ES + ),[M+H] + =293.1.

[0462] Intermediate 61b: tert-butyl 6-amino-5-methoxy-1H-indole-1-carboxylate [ka] Trichlorosilane (1.78 g, 13.1 mmol) was added to a mixture of tert-butyl 5-methoxy-6-nitro-1H-indole-1-carboxylate (1.10 g, 3.76 mmol) and DIEA (3.29 mL, 18.8 mmol) in MeCN (15 mL) under N2 at 0°C. The resulting solution was stirred at room temperature for 16 hours. 20 mL of saturated NaHCO3 solution was added dropwise, and the two-phase mixture was stirred for 0.5 hours. The reaction mixture was poured into water (100 mL) and extracted with RINKAN (3 × 100 mL). The combined organic extracts were dried (Na2SO4) and concentrated to obtain the title compound (800 mg, 81%) as a black solid. 1 H NMR:(CDCl3)δ 1.67(9H,s),3.91(3H,s),6.43(1H,dd),6.94(1H,s),7.37(1H,d),7.61(1H,s).m / z(ES + ),[M+H] + =263.1.

[0463] Intermediate 61c: 3-((1-(tert-butoxycarbonyl)-5-methoxy-1H-indole-6-yl)amino)propanoic acid [ka] Acrylic acid (412 mg, 5.72 mmol) was added to a solution of tert-butyl 6-amino-5-methoxy-1H-indole-1-carboxylate (500 mg, 1.91 mmol) in toluene (5 mL) at room temperature under N2. The resulting mixture was stirred at 110°C for 16 hours. The solvent was then removed under reduced pressure. Purification by FSC (gradient: 0-10% MeOH (in DCM)) yielded the impure form of the title compound (610 mg) as a yellow oil, which was used in the next step without further purification. / z(ES + ),[M+H] + =335.2

[0464] Example 61: 1-(5-methoxy-1H-indole-6-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Urea (329 mg, 5.47 mmol) was added to a solution of impure 3-((1-(tert-butoxycarbonyl)-5-methoxy-1H-indole-6-yl)amino)propanoic acid (610 mg) in AcOH (10 mL) at room temperature in air. The resulting mixture was stirred at 110 °C for 3 hours. The solvent was then removed under reduced pressure. Purification with C-18FC (gradient: 0-50% water (containing 0.05% concentrated HCl) (in MeCN)) yielded the title compound (65.0 mg, 13%, total 2 steps) as a white solid. 1 H NMR:δ 2.70(2H,t),3.32(2H,t),3.79(3H,s),6.38(1H,d),7.16(1H,s),7.27(1H,d),7.34(1H,t),10.22(1H,s),11.01(1H,s).m / z(ES + ),[M+H] + =260.1.

[0465] Intermediate 62a: 7-Methoxy-6-nitro-1H-indole [ka] Vinyl magnesium bromide (1M in THF, 115 mL, 115 mmol) was added to a solution of 2-methoxy-1,3-dinitrobenzene (7.60 g, 38.4 mmol) in THF (150 mL) under N2 at -78°C. The resulting mixture was stirred at -78°C for 2 hours. The reaction mixture was quenched with saturated NH4Cl (200 mL) and extracted with siRNA (3 × 200 mL). The combined organic extract was dried (Na2SO4) and concentrated to obtain a brown residue. Purification by FSC (gradient: 0-19% siRNA (in petroleum ether)) yielded the title compound (3.00 g, 41%) as a yellow solid. 1 H NMR:(CDCl3)δ 4.12(3H,s),6.66(1H,dd),7.41(1H,dd),7.48(1H,dd),7.79(1H,d),8.83(1H,br s).m / z(ES + ),[M+H] + =193.1.

[0466] Intermediate 62b: tert-butyl 7-methoxy-6-nitro-1H-indole-1-carboxylate [ka] Di-tert-butyl dicarbonate (7.25 mL, 31.2 mmol) was added at room temperature to a mixture of 7-methoxy-6-nitro-1H-indole (3.00 g, 15.6 mmol), DIEA (8.18 mL, 46.8 mmol), and DMAP (191 mg, 1.56 mmol) in DCM (100 mL). The resulting mixture was stirred at room temperature for 1 hour. The solvent was then removed under reduced pressure. Purification by FSC (gradient: 0-9% siRNA (in petroleum ether)) yielded the title compound (3.78 g, 83%) as a pale yellow crystalline solid. 11H NMR: (CDCl3) δ 1.68 (9H, s), 3.95 (3H, s), 6.62 (1H, d), 7.35 (1H, d), 7.70 (1H, d), 7.75 (1H, d). m / z (ES + ), [M - tBu + 2H] + = 237.0.

[0467] Intermediate 62c: tert-Butyl 6-amino-7-methoxy-1H-indole-1-carboxylate

Chem.

[0468] Example 62: 1-(7-Methoxy-1H-indol-6-yl)dihydropyrimidine-2,4(1H,3H)-dione <00038​​​​Acrylic acid (495 mg, 6.86 mmol) was added to tert-butyl 6-amino-7-methoxy-1H-indole-1-carboxylate (600 mg, 2.29 mmol) in toluene (15 mL) at room temperature under N2 conditions. The resulting mixture was stirred at 110°C for 16 hours. The solvent was removed under reduced pressure. The residue was dissolved in AcOH (15 mL), and urea (412 mg, 6.86 mmol) was added to the mixture. The resulting mixture was stirred at 110°C for 3 hours. The solvent was then removed under reduced pressure. Purification with C-18FC (gradient: 0-20% MeCN (in water) (containing 0.1% FA)) yielded the title compound (240 mg, 41%) as a white solid. 1 H NMR:δ 2.73(2H,t),3.67(2H,t),3.90(3H,s),6.47(1H,dd),6.87(1H,d),7.28(1H,d),7.37(1H,t),10.32(1H,s),11.34(1H,s).m / z(ES + ),[M+H] + =260.0.

[0469] Intermediate 63a: tert-butyl 4-amino-5-fluoro-1H-indole-1-carboxylate [ka] Selectfluor (839 mg, 2.37 mmol) was added at room temperature to a solution of tert-butyl 4-amino-1H-indole-1-carboxylate (550 mg, 2.37 mmol) in MeCN (40 mL). The resulting solution was stirred at room temperature for 3 hours. The solvent was then removed under reduced pressure. Purification by FSC (gradient: 0-20% siRNA (in petroleum ether)) yielded the title compound (78.0 g, 13%) as brown oil. 1 H NMR:δ 1.61(9H,s),5.49(2H,s),6.91(1H,d),6.96(1H,dd),7.20(1H,d),7.50(1H,d).m / z(ES + ),[M+H] + =251.1.

[0470] Example 63: 1-(5-Fluoro-1H-indol-4-yl)dihydropyrimidine-2,4(1H,3H)-dione [Chemical formula] Acrylic acid (51.8 mg, 0.719 mmol) was added to a solution of tert-butyl 4-amino-5-fluoro-1H-indole-1-carboxylate (45.0 mg, 0.180 mmol) in toluene (5 mL). The resulting mixture was stirred at 120 °C for 16 h. The solvent was removed under reduced pressure. The residue was dissolved in AcOH (5 mL), urea (10.8 mg, 0.180 mmol) was added, and the resulting solution was stirred at 120 °C for 5 h. Then, the solvent was removed under reduced pressure. Purification by preparative HPLC (column B, eluent B, gradient: 10 - 30%) afforded the title compound (3.6 mg, 8%) as a white solid. 1 H NMR: δ 2.61 - 2.73 (1H, m), 2.89 - 2.95 (1H, m), 3.69 - 3.74 (1H, m), 3.79 - 3.86 (1H, m), 6.49 (1H, d), 7.02 - 7.09 (1H, m), 7.34 - 7.42 (1H, m), 7.46 (1H, d), 10.48 (1H, s), 11.36 (1H, s). 19 F NMR (376 MHz) δ -133.89. m / z (ES + ), [M + H] + = 248.0.

[0471] Intermediate 64a: tert-Butyl 4-amino-5-chloro-1H-indole-1-carboxylate [Chemical formula] NCS (172 mg, 1.29 mmol) was added to a solution of tert-butyl 4-amino-1H-indole-1-carboxylate (300 mg, 1.29 mmol) in DCM (10 mL) at 0 °C in air. The resulting mixture was stirred at 0 °C for 2 h. Then, the solvent was removed under reduced pressure. Purification by FSC (gradient: 0 - 30% EtOAc (in petroleum ether)) afforded the title compound (50.0 mg, 15%) as a yellow oil.1 H NMR:δ 1.60(9H,s),5.71(2H,s),6.95(1H,d),7.11(1H,d),7.27(1H,d),7.50(1H,d).m / z(ES + ),[M+H] + =267.2.

[0472] Example 64: 1-(5-chloro-1H-indole-4-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Acrylic acid (97.0 mg, 1.35 mmol) was added to a solution of tert-butyl 4-amino-5-chloro-1H-indole-1-carboxylate (90.0 mg, 0.337 mmol) in toluene (6 mL) at room temperature in air. The resulting mixture was stirred at 120°C for 50 hours. The solvent was then removed under reduced pressure. The residue was dissolved in AcOH (5 mL), urea (35.5 mg, 0.591 mmol) was added, and the resulting mixture was stirred at 120°C for 4 hours. The solvent was then removed under reduced pressure. Purification with C-18FC (gradient 5-50% MeCN (in water) (containing 0.1% FA)) yielded the title compound (16.0 mg, 18%) as a yellow solid. 1 H NMR:δ 2.64-2.80(1H,m),2.80-2.96(1H,m),3.57-3.80(2H,m),6.45-6.53(1H ,m),7.19(1H,d),7.37-7.50(2H,m),10.45(1H,s),11.46(1H,s).m / z(ES + ),[M+H] + =264.1.

[0473] Intermediate 65a: tert-butyl 6-bromo-3-(2-methoxy-2-oxoethyl)-1H-indole-1-carboxylate [ka] DMAP (91.0 mg, 0.745 mmol) was added at room temperature in air to a solution of di-tert-butyl dicarbonate (2.60 mL, 11.2 mmol), DIEA (3.91 mL, 22.4 mmol), and methyl 2-(6-bromo-1H-indole-3-yl) acetate (2.00 g, 7.46 mmol) in DCM (20 mL). The resulting solution was stirred at room temperature for 2 hours. The solvent was then removed under reduced pressure. Purification by FSC (gradient: 0-20% siRNA (in petroleum ether)) yielded the title compound (2.70 g, 98%) as a white solid. 1 H NMR: δ 1.63(9H,s),3.63(3H,s),3.83(2H,d),7.44(1H,dd),7.54(1H,d),7.66(1H,s),8.22(1H,d).

[0474] Intermediate 65b: tert-butyl6-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-3-(2-methoxy-2-oxoethyl)-1H-indole-1-carboxylate [ka] Ephos Pd G4 (337 mg, 0.367 mmol) was added at room temperature to a degassed mixture of Ephos (196 mg, 0.366 mmol), Cs2CO3 (7.17 g, 22.0 mmol), dihydropyrimidine-2,4(1H,3H)-dione (2.51 g, 22.0 mmol), and tert-butyl 6-bromo-3-(2-methoxy-2-oxoethyl)-1H-indole-1-carboxylate (2.70 g, 7.33 mmol) in 1,4-dioxane (20 mL). The resulting mixture was stirred at 100 °C for 17 hours. The solvent was then removed under reduced pressure. Purification by FSC (gradient: 0-80% siRNA (in petroleum ether)) yielded the title compound (2.80 g, 95%) as a pale yellow solid. 1 H NMR:δ 1.63(9H,s),2.75(2H,t),3.64(3H,s),3.80-3.88(4H,m),7.24(1H,dd),7.56(1H,d),7.66(1H,s),8.04(1H,d),10.38(1H,s).m / z(ES+ ),[M+H] + =402.1.

[0475] Intermediate 65c: 2-(1-(tert-butoxycarbonyl)-6-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-1H-indole-3-yl)-acetic acid [ka] Trimethylstannanol (6.08 g, 33.6 mmol) was added to a solution of tert-butyl 6-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-3-(2-methoxy-2-oxoethyl)-1H-indole-1-carboxylate (2.70 g, 6.73 mmol) in DCE (50 mL) at room temperature in air. The resulting solution was stirred at 80°C for 17 hours. The solvent was then removed under reduced pressure. Purification by FSC (gradient: 0-20% MeOH (in DCM)) yielded the title compound (2.20 g, 84%) as a white solid. 1 H NMR:δ 1.63(9H,s),2.75(2H,t),3.71(2H,s),3.84(2H,t),7.23(1H,dd),7.56(1H,d),7.63(1H,s),8.03(1H,d),10.38(1H,s),12.43(1H,s).m / z(ES + ),[M-tBu+2H] + =332.1.

[0476] Example 65: 2-(6-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-1H-indole-3-yl)acetic acid [ka] TFA (20.0 mL, 260 mmol) was added to a solution of 2-(1-(tert-butoxycarbonyl)-6-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-1H-indole-3-yl)acetic acid (2.16 g, 5.58 mmol) in DCM (60 mL) at room temperature in air. The resulting solution was stirred at room temperature for 2 hours, then stirred at 60°C for 7 days. The solvent was then removed under reduced pressure. Purification using C-18FC (gradient: 0-20% MeCN (in water) (containing 0.1% concentrated HCl)) yielded the title compound (1.00 g, 62%) as a pale yellow solid. 1 H NMR:δ 2.72(2H,t),3.64(2H,s),3.78(2H,t),6.94(1H,dd),7.28(2H,dd),7.47(1H,d),10.28(1H,s),10.98(1H,d),12.16(1H,br s).m / z(ES + ),[M+H] + =288.1.

[0477] Example 66: 2-(6-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-1H-indole-3-yl)-N-methylacetamide [ka] PyBOP (136 mg, 0.261 mmol) was added at room temperature in air to a solution of DIEA (61.0 μL, 0.35 mmol), methylamine (4 M in THF, 218 μL, 0.872 mmol), and 2-(6-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-1H-indole-3-yl)acetic acid (50.0 mg, 0.174 mmol) in DMF (2 mL). The resulting solution was stirred at room temperature for 2 hours. The crude product was purified by C-18FC (gradient: 0-40% MeCN (in water) (containing 0.1% FA)) to obtain the title compound (22.0 mg, 42%) as a pale yellow solid. 1H NMR:δ 2.57(3H,d),2.73(2H,t),3.48(2H,s),3.78(2H,t),6.93(1H,dd),7.22(1H,d ),7.28(1H,d),7.52(1H,d),7.77(1H,d),10.28(1H,s),10.96(1H,d).m / z(ES + ),[M+H] + =301.1.

[0478] Intermediate 67a: Ethyl 4-(4-bromo-2-nitrophenyl)-3-oxobutanoate [ka] Step 1: CDI (2.06 g, 12.7 mmol) was added to a solution of 2-(4-bromo-2-nitrophenyl)acetic acid (3.00 g, 11.5 mmol) in THF (30 mL) at room temperature under N2 conditions. The resulting solution was stirred at room temperature for 4 hours. Step 2 (concurrently performed): Magnesium ethoxide (2.64 g, 23.1 mmol) was added to a solution of 3-ethoxy-3-oxopropanoic acid (6.10 g, 46.2 mmol) in THF (30 mL) at room temperature under N2 conditions. The resulting solution was stirred at room temperature for 1 hour. The solvent was then removed under reduced pressure. Step 3: The solution from Step 1 was added to the crude mixture from Step 2. The resulting solution was stirred at room temperature for 18 hours. The solvent was then removed under reduced pressure. Purification by FSC (gradient: 0-32% butyl (in petroleum ether)) yielded the title compound (2.40 g, 63%) as a white solid. 1 H NMR:δ 1.19(3H,t),3.73(2H,s),4.10(2H,q),4.31(2H,s),7.43(1H,d),7.93-7.96(1H,m),8.26(1H,d).m / z(ES + ),[M+H] + =332.0.

[0479] Intermediate 67b: Ethyl 2-(6-bromo-1H-indole-2-yl)acetate [ka] A 15% solution (72 mL) of titanium trichloride in 2N HCl was added at room temperature to a stirred solution in acetone (24 mL) containing ethyl 4-(4-bromo-2-nitrophenyl)-3-oxobutanoate (2.40 g, 7.27 mmol) and ammonium acetate (15 M (in water), 13.0 mL, 195 mmol). The resulting solution was stirred at room temperature for 2 hours. The reaction mixture was diluted with RINKAN (50 mL) and washed sequentially with water (2 × 30 mL) and saturated brine (2 × 25 mL). The organic layer was dried and concentrated to obtain the title compound (1.65 g, 80%) as a brown solid. 1 H NMR:δ 1.19(3H,t),3.82(2H,s),4.10(2H,q),6.29(1H,s),7.06(1H,dd),7.39(1H,d),7.49(1H,d),11.18(1H,s).m / z(ES + ),[M+H] + =284.0.

[0480] Intermediate 67c: tert-butyl 6-bromo-2-(2-ethoxy-2-oxoethyl)-1H-indole-1-carboxylate [ka] DMAP (143 mg, 1.17 mmol) was added at room temperature in air to a solution of ethyl 2-(6-bromo-1H-indole-2-yl) acetate (1.65 g, 5.85 mmol), di-tert-butyl dicarbonate (2.72 mL, 11.7 mmol), and DIEA (2.04 mL, 11.7 mmol) in DCM (20 mL). The resulting solution was stirred at room temperature for 2 hours. The solvent was then removed under reduced pressure. Purification by FSC (gradient: 0-15% SiO(in petroleum ether)) yielded the title compound (1.70 g, 76%) as a white solid. 1 H NMR:δ 1.18-1.24(3H,m),1.59(9H,s),4.03-4.16(4H,m),6.66(1H,s),7.39-7.41(1H,m),7.53(1H,d),8.23(1H,d).m / z(ES + ),[M-tBu+2H] +=327.9.

[0481] Intermediate 67d: 2-(6-bromo-1-(tert-butoxycarbonyl)-1H-indole-2-yl)acetic acid [ka] A mixture of LiOH (160 mg, 6.67 mmol) in water (10 mL) was added at room temperature to a solution of tert-butyl 6-bromo-2-(2-ethoxy-2-oxoethyl)-1H-indole-1-carboxylate (1.70 g, 4.45 mmol) in THF (20 mL). The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was neutralized with 2 M HCl. The reaction mixture was then diluted with ELISA (100 mL) and washed sequentially with water (2 × 50 mL). The organic layer was dried and concentrated with (Na₂SO₄). Purification with C-18FC (gradient: 0~33% MeOH (in water)) yielded the title compound (1.10 g, 70%) as a white solid. 1 H NMR:δ 1.57(9H,s),3.55(2H,s),6.27(1H,s),7.26-7.28(1H,m),7.38(1H,d),8.16(1H,d).m / z(ES + ),[M-tBu+2H] + =299.9.

[0482] Intermediate 67e: tert-butyl 6-bromo-2-(2-(methylamino)-2-oxoethyl)-1H-indole-1-carboxylate [ka] PyBOP (1.10 g, 2.11 mmol) was added at room temperature to a mixture in DCM (20 mL) of 2-(6-bromo-1-(tert-butoxycarbonyl)-1H-indole-2-yl)acetic acid (500 mg, 1.41 mmol), DIEA (370 μL, 2.12 mmol), and methylamine (2 M solution in THF, 1.41 mL, 2.82 mmol). The resulting solution was stirred at room temperature for 16 hours. The solvent was then removed under reduced pressure. Purification with C-18FC (gradient: 0-60% MeOH (in water)) yielded the title compound (500 mg, 96%) as a white solid. 1 H NMR:δ 1.55(9H,s),2.54-2.61(3H,m),3.83(2H,s),6.55(1H,s),7.33-7.36(1H,m),7.48(1H,d),7.78(1H,d),8.21(1H,d).m / z(ES + ),[M+H] + =369.0.

[0483] Example 67: 2-(6-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-1H-indole-2-yl)-N-methylacetamide [ka] Ephos (29.1 mg, 0.0544 mmol) and Ephos Pd G4 (50.0 mg, 0.0544 mmol) were added to a degassed mixture of Cs2CO3 (710 mg, 2.18 mmol), tert-butyl 6-bromo-2-(2-(methylamino)-2-oxoethyl)-1H-indole-1-carboxylate (400 mg, 1.09 mmol), and dihydropyrimidine-2,4(1H,3H)-dione (373 mg, 3.27 mmol) in 1,4-dioxane (15 mL) at room temperature under N2 conditions. The resulting mixture was stirred at 100°C for 16 hours. The solvent was then removed under reduced pressure. The substance was obtained by purification using C-18FC (gradient: 0-22% MeCN (in water)), and this was further purified by preparative HPLC (column C, eluent C, gradient: 15-35%) to obtain the title compound (13.7 mg, 4%) as a pink solid. 1H NMR:δ 2.52-2.64(3H,m),2.72-2.74(2H,m),3.57(2H,s),3.77-3.79(2H,m),6.21(1H,d),6.87 -6.91(1H,m),7.25(1H,s),7.41(1H,d),7.93(1H,s),10.27(1H,s),11.03(1H,s).m / z(ES + ),[M+H] + =301.2

[0484] Intermediate 68a: tert-butyl 2-(6-bromo-1H-indole-1-yl)acetate [ka] K2CO3 (2.82 g, 20.4 mmol) was added to a solution of 6-bromo-1H-indole (2.00 g, 10.2 mmol) and tert-butyl 2-bromoacetate (3.98 g, 20.4 mmol) in MeCN (20 mL) at room temperature under N2. The resulting mixture was stirred at 80°C for 16 hours. The solvent was then removed under reduced pressure. Purification by FSC (gradient: 0-20% siRNA (in petroleum ether)) yielded the title compound (3.00 g, 95%) as a yellow solid. 1 H NMR:δ 1.40(9H,s),5.01(2H,s),6.46-6.47(1H,m),7.14-7.16(1H,m),7.33(1H,d),7.49(1H,d),7.61-7.68(1H,m).m / z(ES + ),[M+H] + =310.0.

[0485] Intermediate 68b: tert-butyl 2-(6-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-1H-indole-1-yl)acetate [ka] Ephos (172 mg, 0.322 mmol) and Ephos Pd G4 (296 mg, 0.322 mmol) were added to a degassed mixture of Cs2CO3 (4.20 g, 12.9 mmol), tert-butyl 2-(6-bromo-1H-indole-1-yl) acetate (2.00 g, 6.45 mmol), and dihydropyrimidine-2,4(1H,3H)-dione (2.21 g, 19.4 mmol) in 1,4-dioxane (60 mL) at room temperature under N2 conditions. The resulting mixture was stirred at 100 °C for 16 hours. The solvent was then removed under reduced pressure. Purification by FSC (gradient: 0-9% MeOH (in DCM)) yielded the title compound (1.50 g, 68%) as a yellow solid. 1 H NMR:δ 1.42(9H,s),2.73(2H,t),3.79(2H,t),4.98(2H,s),6.46(1H,d),7.01(1H,dd),7.32-7.39(2H,m),7.53(1H,d),10.32(1H,s).m / z(ES + ),[M+Na] + =366.1.

[0486] Intermediate 68c: 2-(6-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-1H-indole-1-yl)acetic acid [ka] 1.50 g, 4.37 mmol of tert-butyl 2-(6-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-1H-indole-1-yl) acetate was added to 20 mL of formic acid at room temperature. The resulting solution was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure. Purification with C-18FC (gradient: 0-26% MeOH (in water)) yielded the title compound (750 mg, 60%) as a pink solid. 1 H NMR:δ 2.72(2H,t),3.78(2H,t),4.99(2H,s),6.45(1H,d),7.00(1H,dd),7.36(1H,d),7.39(1H,s),7.52(1H,d),10.30(1H,s),12.87(1H,br s).m / z(ES + ),[M+H]+ =288.1.

[0487] Example 68: 2-(6-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-1H-indole-1-yl)-N-methylacetamide [ka] PyBOP (353 mg, 0.678 mmol) was added at room temperature to a solution of 2-(6-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-1H-indole-1-yl)acetic acid (130 mg, 0.453 mmol), DIEA (119 μL, 0.681 mmol), and methylamine (2 M solution in THF, 1.13 mL, 2.26 mmol) in DCM (3 mL). The resulting solution was stirred at room temperature for 3 hours. The solvent was then removed under reduced pressure. Purification by C-18FC (gradient: 0-18% MeCN (in water)) yielded the title compound (62.9 mg, 46%) as a white solid. 1 H NMR:δ 2.62(3H,d),2.73(2H,t),3.79(2H,t),4.78(2H,s),6.46(1H,dd),7.00(1 H,dd),7.31-7.39(2H,m),7.53(1H,d),8.04(1H,q),10.32(1H,s).m / z(ES + ),[M+H] + =301.3.

[0488] Intermediate 69a: tert-butyl 3-(6-bromo-1H-indole-1-yl)propanoate [ka] DBU (1.15 mL, 7.63 mmol) was added to a solution of 6-bromo-1H-indole (3.00 g, 15.3 mmol) and tert-butyl acrylate (2.94 g, 22.9 mmol) in MeCN (30 mL) at room temperature under N2. The resulting mixture was stirred at 60°C for 16 hours. The solvent was then removed under reduced pressure. Purification by FSC (gradient: 0-25% siRNA (in petroleum ether)) yielded the title compound (4.20 g, 85%) as a yellow solid. 1 H NMR:δ 1.28(9H,s),2.70(2H,t),4.37(2H,t),6.43(1H,dd),7.12(1H,dd),7.36(1H,d),7.47(1H,d),7.75(1H,s).m / z(ES + ),[M+H] + =326.0.

[0489] Intermediate 69b: tert-butyl 3-(6-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-1H-indole-1-yl)propanoate [ka] Ephos (165 mg, 0.309 mmol) and Ephos Pd G4 (283 mg, 0.308 mmol) were added at room temperature under N2 to a degassed mixture of Cs2CO3 (4.02 g, 12.3 mmol), tert-butyl 3-(6-bromo-1H-indole-1-yl)propanoate (2.00 g, 6.17 mmol), and dihydropyrimidine-2,4(1H,3H)-dione (1.41 g, 12.4 mmol) in 1,4-dioxane (60 mL). The resulting mixture was stirred at 100 °C for 16 hours. The solvent was then removed under reduced pressure. Purification by FSC (gradient: 0-9% MeOH (in DCM)) yielded the title compound (1.20 g, 54%) as a yellow solid. 1 H NMR:δ 1.32(9H,s),2.72(4H,t),3.79(2H,t),4.34(2H,t),6.41(1H,d),6.96(1H,dd),7.35(1H,d),7.45(1H,s),7.49(1H,d),10.29(1H,s).m / z(ES+ ),[M+Na] + =380.1.

[0490] Intermediate 69c: 3-(6-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-1H-indole-1-yl)propanoic acid [ka] tert-butyl 3-(6-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-1H-indole-1-yl)propanoate (1.20 g, 3.36 mmol) was added to formic acid (10 mL) at room temperature in air. The resulting solution was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure. The solution was purified using C-18FC (gradient: 0-15% MeCN (in water) (containing 0.5% concentrated HCl)) to obtain the title compound (620 mg, 61%) as a white solid. 1 H NMR:δ 2.64-2.79(4H,m),3.80-3.82(2H,m),4.36-4.38(2H,m),6.40(1H,d),6 .97-6.98(1H,m),7.37(1H,d),7.43-7.54(2H,m),10.29(1H,s).m / z(ES + ),[M+H] + =302.1.

[0491] Example 69: 3-(6-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-1H-indole-1-yl)-N-methylpropanamide [ka] PyBOP (337 mg, 0.648 mmol) was added to a solution of 3-(6-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1H-indol-1-yl)propanoic acid (130 mg, 0.431 mmol), DIEA (113 μL, 0.647 mmol), and methylamine (2 M solution in THF, 1.08 mL, 2.16 mmol) in DCM (3 mL) at room temperature. The resulting solution was stirred at room temperature for 3 h. The solvent was then removed under reduced pressure. Purification by C-18 FC (gradient: 0 - 18% MeCN (in water)) afforded the title compound (50.2 mg, 37%) as a pink solid. 1 H NMR: δ 2.50 - 2.60 (5H, m), 2.74 (2H, t), 3.80 (2H, t), 4.36 (2H, t), 6.41 (1H, d), 6.97 (1H, dd), 7.32 (1H, d), 7.45 (1H, s), 7.50 (1H, d), 7.85 (1H, q), 10.32 (1H, s). m / z (ES + ), [M + H] + = 315.2.

[0492] Intermediate 70a: tert-Butyl 2-(4-bromo-1H-indol-1-yl)acetate

Chemical Structure

[0493] Intermediate 70b: tert-butyl 2-(4-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-1H-indole-1-yl)acetate [ka] Ephos (86.0 mg, 0.161 mmol) was added at room temperature under N2 to a degassed mixture of Ephos Pd G4 (148 mg, 0.161 mmol), Cs2CO3 (3.15 g, 9.67 mmol), dihydropyrimidine-2,4(1H,3H)-dione (1.10 g, 9.64 mmol), and tert-butyl 2-(4-bromo-1H-indole-1-yl) acetate (1.00 g, 3.22 mmol) in 1,4-dioxane (50 mL). The resulting mixture was stirred at 90°C for 17 hours. The solvent was then removed under reduced pressure. Purification using C-18FC (gradient: 0-60% MeCN (in water) (containing 0.1% concentrated HCl)) yielded the title compound (400 mg, 36%) as a pale yellow solid. 1 H NMR:δ 1.42(9H,s),2.77(2H,t),3.78(2H,t),5.02(2H,s),6.42(1H,dd),6.98(1 H,dd),7.10-7.22(1H,m),7.30(1H,dt),7.35(1H,d),10.35(1H,s).m / z(ES + ),[M-tBu+2H] + =288.1.

[0494] Intermediate 70c: 2-(4-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-1H-indole-1-yl)acetic acid [ka] TFA (5.00 mL, 64.9 mmol) was added to a solution of tert-butyl 2-(4-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-1H-indole-1-yl) acetate (350 mg, 1.02 mmol) in DCM (5 mL) at room temperature in air. The resulting solution was stirred at room temperature for 6 hours. The solvent was removed under reduced pressure. Purification by C-18FC (gradient: 0-30% MeCN (in water) (containing 0.1% concentrated HCl)) yielded the title compound (170 mg, 58%) as a pale yellow solid. 1 H NMR:δ 2.77(2H,t),3.79(2H,t),5.04(2H,s),6.42(1H,dd),6.98(1H,dd),7.14(1H,t),7.31-7.38(2H,m),10.34(1H,s),12.97(1H,s).m / z(ES + ),[M+H] + =288.2.

[0495] Example 70: 2-(4-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-1H-indole-1-yl)-N-methylacetamide [ka] DIEA (73.0 μL, 0.418 mmol) was added at room temperature in air to a mixture in DMF (1 mL) containing PyBOP (145 mg, 0.279 mmol), methylamine (4 M solution in THF, 70.0 μL, 0.280 mmol), and 2-(4-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-1H-indole-1-yl)acetic acid (40.0 mg, 0.139 mmol). The resulting solution was stirred at room temperature for 2 hours and then directly purified using C-18FC (gradient: 0-20% MeCN (in water) (containing 0.1% concentrated HCl)) to obtain the title compound (35.0 mg, 84%) as a pale yellow solid. 1 H NMR:δ 2.62(3H,d),2.77(2H,t),3.78(2H,t),4.81(2H,s),6.41(1H,dd),6.97(1 H,dd),7.14(1H,t),7.28-7.37(2H,m),8.12(1H,d),10.34(1H,s).m / z(ES+ ),[M+H] + =301.2

[0496] Intermediate 71a: 1-acetyl-6-bromo-1H-indole-3-ylacetate [ka] DMAP (385 mg, 3.15 mmol) was added at room temperature to a mixture of 6-bromo-1H-indole-3-yl acetate (4.00 g, 15.7 mmol), Ac2O (14.9 mL, 158 mmol), and triethylamine (4.39 mL, 31.5 mmol) in THF (60 mL). The resulting mixture was stirred at 80°C for 2 hours. The solvent was removed under reduced pressure. Purification by FSC (gradient: 0-20% siRNA (in petroleum ether)) yielded the title compound (2.34 g, 50%) as a purple solid. 1 H NMR:δ 2.36(3H,s),2.60(3H,s),7.48(2H,t),7.92(1H,s),8.48-8.55(1H,m).m / z(ES + ),[M+H] + =296.0.

[0497] Intermediate 71b: tert-butyl 4-(6-bromo-1H-indole-3-yl)piperazine-1-carboxylate [ka] 4-methylbenzenesulfonic acid (256 mg, 1.49 mmol) was added at room temperature to a mixture of 1-acetyl-6-bromo-1H-indole-3-yl acetate (2.20 g, 7.43 mmol) and tert-butylpiperazine-1-carboxylate (6.92 g, 37.2 mmol) in toluene (50 mL). The resulting mixture was stirred at 120 °C for 24 hours. The solvent was then removed under reduced pressure. Purification by FSC (gradient: 0-30% siRNA (in petroleum ether)) yielded a 2:3 mixture (1.09 g) of tert-butyl 4-(1-acetyl-6-bromo-1H-indole-3-yl)piperazine-1-carboxylate and tert-butyl 4-(6-bromo-1H-indole-3-yl)piperazine-1-carboxylate as a purple solid, which was used directly in the next step without further purification. m / z(ES + ),[M+H] + =422.1 & 380.1. Next, the product mixture was dissolved in MeOH (40 mL), and triethylamine (1.80 mL, 12.9 mmol) was added to this solution at room temperature. The resulting mixture was stirred at 60°C for 2 hours. The solvent was removed under reduced pressure to obtain the title compound (1.00 g, 35%, total 2 steps) as a purple solid. 1 H NMR:δ 1.43(9H,s),2.89(4H,t),3.51(4H,t),6.92(1H,d),7.07(1H,dd),7.48(2H,dd),10.74(1H,s).m / z(ES + ),[M+H] + =380.1.

[0498] Intermediate 71c: tert-butyl 6-bromo-3-(4-(tert-butoxycarbonyl)piperazine-1-yl)-1H-indole-1-carboxylate [ka] Di-tert-butyl dicarbonate (1.22 mL, 5.25 mmol) was added at room temperature to a mixture in DCM (30 mL) of tert-butyl 4-(6-bromo-1H-indole-3-yl)piperazine-1-carboxylate (1.00 g, 2.63 mmol), triethylamine (1.10 mL, 7.89 mmol), and DMAP (32.0 mg, 0.262 mmol). The resulting mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure. Purification by FSC (gradient: 0-15% siRNA (in petroleum ether)) yielded the title compound (1.20 g, 95%) as a pale yellow solid. 1 H NMR:δ 1.42(9H,s),1.61(9H,s),2.95(4H,t),3.51(4H,t),7.07(1H,s),7.40(1H,dd),7.62(1H,d),8.24(1H,s).m / z(ES + ),[M+H] + =482.2.

[0499] Intermediate 71d: tert-butyl3-(4-(tert-butoxycarbonyl)piperazine-1-yl)-6-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-1H-indole-1-carboxylate [ka] Ephos Pd G4 (115 mg, 0.125 mmol) was added to a degassed mixture of tert-butyl 6-bromo-3-(4-(tert-butoxycarbonyl)piperazin-1-yl)-1H-indole-1-carboxylate (1.20 g, 2.50 mmol), dihydropyrimidine-2,4(1H,3H)-dione (1.14 g, 9.99 mmol), Cs2CO3 (1.63 g, 5.00 mmol), and Ephos (67.0 mg, 0.125 mmol) in 1,4-dioxane (30 mL) at room temperature under argon. The resulting mixture was stirred at 100 °C for 16 hours. The solvent was removed under reduced pressure. Purification by FSC (gradient: 0-70% SiO(in petroleum ether)) yielded the title compound (1.00 g, 78%) as an off-white solid. 1H NMR:δ 1.43(9H,s),1.61(9H,s),2.73(2H,t),2.94-3.01(4H,m),3.49-3.55(4H,m),3.83 (2H,t),7.07(1H,s),7.21(1H,dd),7.64(1H,d),8.05(1H,s),10.37(1H,s).m / z(ES + ),[M+H] + =514.3.

[0500] Example 71: 1-(3-(piperazin-1-yl)-1H-indole-6-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] 1.47 g, 5.56 mmol of tert-butyldimethylsilyltrifluoromethanesulfonate was added at room temperature to a mixture of tert-butyl 3-(4-(tert-butoxycarbonyl)piperazin-1-yl)-6-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-1H-indole-1-carboxylate (950 mg, 1.85 mmol) in 30 mL of DCM. The resulting mixture was stirred at room temperature for 16 hours. The second portion of tert-butyldimethylsilyltrifluoromethanesulfonate (1.47 g, 5.56 mmol) was added, and the reaction was stirred for a further 5 hours. The solvent was removed under reduced pressure. The title compound (490 mg, 85%) was obtained as a pale yellow solid by purification using C-18FC (gradient: 0-20% MeCN (in water) (10 mmol NH4HCO3)). 1 H NMR:δ 2.72(2H,t),2.90-3.01(8H,m),3.78(2H,t),6.85-6.92(2H,m),7.22(1H,d),7.49(1H,d),10.28(1H,s),10.60(1H,d).m / z(ES + ),[M+H] + =314.1.

[0501] Example 72: 1-(3-(4-methylpiperazin-1-yl)-1H-indole-6-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Sodium triacetoxyborohydride (81.0 mg, 0.382 mmol) was added at room temperature to a mixture in DCM (10 mL) of 1-(3-(piperazin-1-yl)-1H-indole-6-yl)dihydropyrimidine-2,4(1H,3H)-dione (60.0 mg, 0.191 mmol), formaldehyde (16.0 μL, 0.581 mmol), and AcOH (22.0 μL, 0.384 mmol). The resulting mixture was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure. Purification by preparative HPLC (column Y, eluent B, gradient: 15-20%) yielded the title compound (18.0 mg, 29%) as a white solid. 1 H NMR:δ 2.22(3H,s),2.70(2H,t),2.91-2.97(4H,m),3.28-3.30(4H,m),3.76(2H,t) ,6.86(2H,dd),7.20(1H,d),7.45(1H,d),10.26(1H,s),10.57(1H,s).m / z(ES + ),[M+H] + =328.1.

[0502] Example 73: 1-(3-(4-acetylpiperazine-1-yl)-1H-indole-6-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Ac2O (30.0 μL, 0.318 mmol) was added at room temperature to a mixture of 1-(3-(piperazin-1-yl)-1H-indole-6-yl)dihydropyrimidine-2,4(1H,3H)-dione (50.0 mg, 0.160 mmol) and DIEA (84.0 μL, 0.481 mmol) in DCM (10 mL). The resulting mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure. Purification with C-18FC (gradient: 0-25% MeCN (in water) (10 mmol NH4HCO3)) yielded the title compound (30.0 mg, 53%) as a white solid. 1H NMR:δ 2.04(3H,s),2.72(2H,t),2.93(4H,dt),3.58-3.69(4H,m),3.78(2H,t),6.8 6-6.95(2H,m),7.24(1H,d),7.52(1H,d),10.28(1H,s),10.64(1H,d).m / z(ES + ),[M+H] + =356.3.

[0503] Intermediate 74a: tert-butyl 4-(6-bromo-1-methyl-1H-indole-3-yl)piperazine-1-carboxylate [ka] NaH (60% dispersion in mineral oil, 205 mg, 5.13 mmol) was added to a solution of tert-butyl 4-(6-bromo-1H-indole-3-yl)piperazine-1-carboxylate (1.30 g, 3.42 mmol) in DMF (20 mL) at 0°C under N2. The resulting mixture was stirred at 0°C for 0.5 hours, after which MeI (0.485 g, 3.42 mmol) was added. The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with saturated NH4Cl (50 mL) and extracted with RINKAN (3 × 100 mL). The combined organic solution was washed with saturated brine (3 × 100 mL), dried, and concentrated to obtain a dark rubber. Purification by FSC (gradient: 0-30% RINKAN (in petroleum ether)) yielded the title compound (1.02 g, 76%) as purple rubber. 1 H NMR:δ 1.41(9H,s),2.86(4H,t),3.49(4H,t),3.66(3H,s),6.88(1H,s),7.07(1H,dd),7.47(1H,d),7.61(1H,d).m / z(ES + ),[M+H] + =396.1.

[0504] Intermediate 74b: tert-butyl 4-(6-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-1-methyl-1H-indole-3-yl)piperazine-1-carboxylate [ka] Cs2CO3 (1.653 g, 5.06 mmol) was added at room temperature under N2 to a degassed mixture of tert-butyl 4-(6-bromo-1-methyl-1H-indole-3-yl)piperazine-1-carboxylate (1.00 g, 2.54 mmol), dihydropyrimidine-2,4(1H,3H)-dione (1.16 g, 10.2 mmol), Ephos (68.0 mg, 0.127 mmol), and Ephos Pd G4 (116 mg, 0.126 mmol) in 1,4-dioxane (30 mL). The resulting mixture was stirred at 100 °C for 16 hours. The solvent was removed under reduced pressure. Purification by FSC (gradient: 0-4% MeOH (in DCM)) yielded the title compound (1.00 g, 92%) as a brown solid. 1 H NMR:δ 1.41(9H,s),2.71(2H,t),2.83-2.93(4H,m),3.46-3.55(4H,m),3.66(3H,s),3 .78(2H,t),6.81-6.98(2H,m),7.31(1H,d),7.50(1H,d),10.27(1H,s).m / z(ES + ),[M+H] + =428.2.

[0505] Example 74: 1-(1-methyl-3-(piperazin-1-yl)-1H-indole-6-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] 835 mg, 3.16 mmol of tert-butyldimethylsilyltrifluoromethanesulfonate was added at 0°C to a solution of tert-butyl 4-(6-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-1-methyl-1H-indole-3-yl)piperazine-1-carboxylate (900 mg, 2.11 mmol) in 20 mL of MeCN. The resulting mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure. Purification with C-18FC (gradient: 0-25% MeCN (in water) (10 mmol NH4HCO3)) yielded the title compound (570 mg, 83%) as a light brown solid. 1 H NMR:δ 2.74(2H,t),2.84-2.96(8H,m),3.68(3H,s),3.80(2H,t),6.85(1H,s),6.92(1H,dd),7.32(1H,d),7.50(1H,d),10.29(1H,s).m / z(ES + ),[M+H] + =328.2.

[0506] Example 75: 1-(1-methyl-3-(4-methylpiperazin-1-yl)-1H-indole-6-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Sodium triacetoxyborohydride (181 mg, 0.854 mmol) was added at room temperature to a mixture in DCM (5 mL) of 1-(1-methyl-3-(piperazin-1-yl)-1H-indole-6-yl)dihydropyrimidine-2,4(1H,3H)-dione (70.0 mg, 0.214 mmol), paraformaldehyde (19.3 mg, 0.643 mmol), and AcOH (36.7 μL, 0.641 mmol). The resulting mixture was stirred at room temperature for 4 hours. The solvent was removed under reduced pressure. The substance was obtained by purification using C-18FC (gradient: 0-25% MeCN (in water) (10 mmol NH4HCO3)), and this was further purified by preparative HPLC (column A, eluent F, gradient: 13-25%) to obtain the title compound (20.0 mg, 27%) as a white solid. 1H NMR:δ 2.25(3H,s),2.48-2.58(4H,m),2.73(2H,t),2.96(4H,br m / z(ES + ),[M+H] + =342.1.

[0507] Intermediate 76a: 1-acetyl-5-bromo-1H-indole-3-ylacetate [ka] DMAP (481 mg, 3.94 mmol) was added at room temperature in air to a solution of 5-bromo-1H-indole-3-yl acetate (5.00 g, 19.7 mmol), triethylamine (27.4 mL, 197 mmol), and Ac2O (18.6 mL, 197 mmol) in THF (50 mL). The resulting solution was stirred at 80°C for 2 hours. The solvent was removed under reduced pressure. Purification by FSC (gradient: 0-30% siRNA (in petroleum ether)) yielded the title compound (5.20 g, 89%) as a white solid. 1 H NMR:δ 2.36(3H,s),2.60(3H,s),7.51(1H,dd),7.75(1H,dd),7.93(1H,s),8.27(1H,dd).m / z(ES + ),[M+H] + =295.9.

[0508] Intermediate 76b: tert-butyl 4-(5-bromo-1H-indole-3-yl)piperazine-1-carboxylate [ka] 4-methylbenzenesulfonic acid (593 mg, 3.44 mmol) was added at room temperature to a mixture of 1-acetyl-5-bromo-1H-indole-3-yl acetate (5.10 g, 17.2 mmol) and tert-butylpiperazine-1-carboxylate (16.0 g, 85.9 mmol) in toluene (60 mL). The resulting mixture was stirred at 120 °C for 16 hours. The solvent was removed under reduced pressure. Purification by FSC (gradient: 0-50% siRNA (in petroleum ether)) yielded a 4:6 mixture (4.30 g) of tert-butyl 4-(1-acetyl-5-bromo-1H-indole-3-yl)piperazine-1-carboxylate and tert-butyl 4-(5-bromo-1H-indole-3-yl)piperazine-1-carboxylate as a black solid, which was carried over to the next step without further purification. The mixture was dissolved in MeOH (40 mL), and triethylamine (7.10 mL, 50.9 mmol) was added to the solution at room temperature. The resulting mixture was stirred at 60°C for 2 hours. The solvent was removed under reduced pressure. Purification by FSC (gradient: 0-100% ELISA (in petroleum ether)) yielded the title compound (3.50 g, 53%, 2 steps total) as a purple solid. 1 H NMR:δ 1.42(9H,s),2.84-2.91(4H,m),3.47-3.54(4H,m),6.96(1H,d),7.16(1H,dd),7.28(1H,d),7.67(1H,d),10.80(1H,d).m / z(ES + ),[M+H] + =380.1.

[0509] Intermediate 76c: tert-butyl 5-bromo-3-(4-(tert-butoxycarbonyl)piperazine-1-yl)-1H-indole-1-carboxylate [ka] Triethylamine (3.85 mL, 27.6 mmol) was added to a mixture of tert-butyl 4-(5-bromo-1H-indole-3-yl)piperazine-1-carboxylate (3.50 g, 9.20 mmol), di-tert-butyl dicarbonate (3.21 mL, 13.8 mmol), and DMAP (0.112 g, 0.92 mmol) in DCM (30 mL) at room temperature under argon. The resulting mixture was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure. Purification by FSC (gradient: 0-50% siRNA (in petroleum ether)) yielded the title compound (3.50 g, 79%) as a yellow solid. 1 H NMR:δ 1.43(9H,s),1.61(9H,s),2.90-3.00(4H,m),3.48-3.57(4H,m),7.12(1H,s),7.49(1H,dd),7.83(1H,d),8.01(1H,d).m / z(ES + ),[M+H] + =482.1.

[0510] Intermediate 76d: tert-butyl 4-(5-bromo-1-methyl-1H-indole-3-yl)piperazine-1-carboxylate [ka] 900 mg of tert-butyl 5-bromo-3-(4-(tert-butoxycarbonyl)piperazin-1-yl)-1H-indole-1-carboxylate (1.87 mmol) was dissolved in 8 mL of 2,2,2-trifluoroethanol and sealed in a microwave tube. The reaction mixture was heated at 120°C for 1 hour in a microwave reactor. The reaction mixture was cooled to room temperature, and the solvent was removed under reduced pressure to obtain the title compound as a black solid (800 mg), which was used in the next step without further purification. m / z(ES) + ),[M+H] +=380.1. Next, the solid was dissolved in DMF (3 mL), cooled to 0°C under N2, and then NaH (60% dispersion in mineral oil, 126 mg, 3.16 mmol) was added. The resulting mixture was then stirred at room temperature for 0.5 hours, and then MeI (132 μL, 2.10 mmol) was added. The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with saturated NH4Cl (10 mL) and extracted with SiO2 (3 × 50 mL). The combined organic extract was dried (Na2SO4) and evaporated to obtain the title compound as a purple solid (800 mg, 108% in total, 2 steps [85% purity based on LCMS]). 1 H NMR:δ 1.43(9H,s),2.86-2.91(4H,m),3.48-3.55(4H,m),3.70(3H,s),6.96(1H,s),7.24(1H,dd),7.37(1H,d),7.69(1H,d).m / z(ES + ),[M+H] + =396.1.

[0511] Intermediate 76e: tert-butyl 4-(5-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-1-methyl-1H-indole-3-yl)piperazine-1-carboxylate [ka] Ephos (24.4 mg, 0.0456 mmol) and Ephos Pd G4 (41.9 mg, 0.0456 mmol) were added to a degassed mixture in DMF (20 mL) of Cs2CO3 (595 mg, 1.83 mmol), tert-butyl 4-(5-bromo-1-methyl-1H-indole-3-yl)piperazine-1-carboxylate (360 mg, 0.913 mmol, presumed to be pure, but later determined to be 85% pure in the previous step based on LC-MS), and dihydropyrimidine-2,4(1H,3H)-dione (313 mg, 2.74 mmol). The resulting mixture was stirred at 100°C for 16 hours. The solvent was then removed under reduced pressure. Purification using C-18FC (gradient 5-50% MeCN (in water) (containing 0.1% FA)) yielded the title compound in formate salt form (90.0 mg, 21%) as a white solid. 1 H NMR:δ 1.43(9H,s),2.73(2H,t),2.85-2.93(4H,m),3.55-3.65(4H,m),3.70(3H,s),3.77(2H,t) ,6.93(1H,s),7.08(1H,dd),7.37(1H,d),7.47(1H,d),8.33(1H,s),10.26(1H,s).m / z(ES + ),[M+H] + =428.2.

[0512] Example 76: 1-(1-methyl-3-(piperazin-1-yl)-1H-indole-5-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] A solution of HCl in 1,4-dioxane (4M, 845 μL, 3.38 mmol) was added to a solution of tert-butyl 4-(5-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-1-methyl-1H-indole-3-yl)piperazine-1-carboxylate formate (80 mg, 0.169 mmol) in DCM (10 mL). The resulting mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure. Purification with C-18FC (gradient: 5-15% MeCN (in water) (containing 0.05% concentrated HCl)) yielded the title compound in hydrochloride salt form (40.0 mg, 65%) as an orange solid. 1 H NMR:δ 2.71(2H,t),3.12-3.18(4H,m),3.24-3.30(4H,m),3.70(3H,s),3.74(2 H,t),7.03(1H,s),7.08(1H,dd),7.37(1H,d),7.49(1H,d),9.00(2H,br s),10.25(1H,s).m / z(ES + ),[M+H] + =328.2.

[0513] Intermediate 77a: tert-butyl3-(4-(tert-butoxycarbonyl)piperazine-1-yl)-5-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-1H-indole-1-carboxylate [ka] Ephos (83.0 mg, 0.155 mmol) and Ephos Pd G4 (143 mg, 0.156 mmol) were added to a degassed mixture of Cs2CO3 (3.05 g, 9.37 mmol), dihydropyrimidine-2,4(1H,3H)-dione (1.07 g, 9.38 mmol), and tert-butyl 5-bromo-3-(4-(tert-butoxycarbonyl)piperazin-1-yl)-1H-indole-1-carboxylate (1.50 g, 3.12 mmol) in 1,4-dioxane (40 mL) at room temperature under N2 conditions. The resulting mixture was stirred at 100 °C for 16 hours. The solvent was then removed under reduced pressure. Purification by FSC (gradient: 0-80% ELISA (in petroleum ether)) yielded the title compound (1.00 g, 62%) as a white solid. 1 H NMR:δ 1.42(9H,s),1.62(9H,s),2.74(2H,t),2.94-2.98(4H,m),3.50-3.54(4H,m),3.81 (2H,t),7.10(1H,s),7.29(1H,dd),7.59(1H,d),8.04(1H,d),10.36(1H,s).m / z(ES + ),[M+H] + =514.3.

[0514] Example 77: 1-(3-(piperazin-1-yl)-1H-indole-5-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] 1.00 g, 1.95 mmol of tert-butyl 3-(4-(tert-butoxycarbonyl)piperazin-1-yl)-5-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-1H-indole-1-carboxylate was dissolved in 20 mL of 2,2,2-trifluoroethanol and sealed in a microwave tube. The reaction mixture was heated at 150 °C for 6 hours in a microwave reactor. The reaction mixture was cooled to room temperature, and the solvent was removed under reduced pressure. The title compound (420 mg, 69%) was obtained as a white solid by purification using C-18FC (gradient: 3-40% MeCN (in water) (containing 0.1% NH4HCO3)). 1H NMR:δ 2.72(2H,t),2.84-2.95(8H,m),3.75(2H,t),6.87(1H,d),6.98(1H,dd),7.28(1H,d),7.41(1H,d),10.23(1H,s),10.58(1H,d).m / z(ES + ),[M+H] + =314.2.

[0515] Example 78: 1-(3-(4-methylpiperazin-1-yl)-1H-indole-5-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Sodium triacetoxyborohydride (169 mg, 0.797 mmol) was added at room temperature to a mixture of 1-(3-(piperazin-1-yl)-1H-indole-5-yl)dihydropyrimidine-2,4(1H,3H)-dione (50.0 mg, 0.160 mmol) and paraformaldehyde (9.6 mg, 0.32 mmol) in DCM (3 mL). The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into water (10 mL) and extracted with ELISA (3 × 10 mL). The combined organic extract was dried (Na₂SO₄) and concentrated to obtain a brown solid. The substance was obtained by purification using C-18FC (gradient: 5-20% MeCN (in water) (containing 0.1% FA)), and this was further purified by preparative HPLC (column C, eluent B, gradient: 3-10%) to obtain the title compound (10.3 mg, 20%) as a white solid. 1 H NMR:δ 2.24(3H,s),2.72(2H,t),2.88-3.03(4H,m),3.27-3.32(4H,m),3.75(2H,t),6. 88(1H,d),6.99(1H,dd),7.28(1H,d),7.41(1H,d),10.55-10.65(1H,m).m / z(ES + ),[M+H] + =328.2.

[0516] Example 79: 1-(3-(4-acetylpiperazine-1-yl)-1H-indole-5-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Ac2O (19.6 mg, 0.192 mmol) was added at room temperature in air to a solution of 1-(3-(piperazin-1-yl)-1H-indole-5-yl)dihydropyrimidine-2,4(1H,3H)-dione (60.0 mg, 0.191 mmol) and triethylamine (80.0 μL, 0.574 mmol) in DCM (3 mL). The resulting mixture was stirred at room temperature for 1 hour. The solvent was then removed under reduced pressure. Purification with C-18FC (gradient: 5-20% MeCN (in water) (containing 0.1% FA)) yielded the title compound (52.0 mg, 76%) as a white powder. 1 H NMR:δ 2.04(3H,s),2.73(2H,t),2.88(2H,t),2.95(2H,t),3.57-3.67(4H,m),3.76(2H,t),6. 93(1H,d),7.00(1H,dd),7.29(1H,d),7.46(1H,d),10.25(1H,s),10.66(1H,s).m / z(ES + ),[M+H] + =356.2.

[0517] Example 80: 1-(1-methyl-3-(4-methylpiperazine-1-yl)-1H-indole-5-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] NaOAc (33.8 mg, 0.412 mmol) was added to a mixture in DCM (8 mL) containing 1-(1-methyl-3-(piperazin-1-yl)-1H-indole-5-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride (50 mg, 0.137 mmol), sodium triacetoxyborohydride (87.0 mg, 0.410 mmol), and paraformaldehyde (12.4 mg, 0.413 mmol). The resulting mixture was stirred at room temperature for 1 hour. The solvent was then removed under reduced pressure. The crude product was purified by C-18FC (gradient: 5-30% MeCN (in water) (containing 0.1% FA)) to obtain the substance, which was further purified by preparative HPLC (column J, eluent B, gradient: 9-17%) to obtain the title compound (12.0 mg, 26%) as a white solid. 1 H NMR:δ 2.26(3H,s),2.25-2.50(4H,m),2.72(2H,t),2.92-2.96(4H,m),3.69(3H,s),3.76 (2H,t),6.88(1H,s),7.06(1H,dd),7.35(1H,d),7.43(1H,d),10.22(1H,s).m / z(ES + ),[M+H] + =342.2.

[0518] Intermediate 81a: tert-butyl 4-((2-amino-4-bromophenyl)ethynyl)piperidine-1-carboxylate [ka] Pd(PPh3)4 (1.94 g, 1.68 mmol) was added to a mixture of 5-bromo-2-iodoaniline (5.00 g, 16.8 mmol), tert-butyl 4-ethynylpiperidine-1-carboxylate (3.51 g, 16.8 mmol), and copper(I) iodide (384 mg, 2.01 mmol) in triethylamine (200 mL) at room temperature under N2 conditions. The resulting mixture was stirred at room temperature for 16 hours. The solvent was then removed under reduced pressure. Purification by FSC (gradient: 0-22% ELISA (in petroleum ether)) yielded the title compound (5.80 g, 91%) as brown rubber. 1H NMR:δ 1.40(9H,s),1.44-1.64(2H,m),1.75-1.90(2H,m),2.80-2.92(1H,m),3.02-3.13( 2H,m),3.67(2H,dt),5.52(2H,s),6.61(1H,dd),6.88(1H,d),7.02(1H,d).m / z(ES + ),[M+H] + =379.2.

[0519] Intermediate 81b: tert-butyl 6-bromo-2-(1-(tert-butoxycarbonyl)piperidine-4-yl)-1H-indole-1-carboxylate [ka] Dichlorobis(acetonitrile)palladium(II) (780 mg, 3.01 mmol) was added to a solution of tert-butyl 4-((2-amino-4-bromophenyl)ethynyl)piperidine-1-carboxylate (5.70 g, 15.0 mmol) in DMF (80 mL) at room temperature under N2 conditions. The resulting mixture was stirred at 80°C for 16 hours. The mixture was cooled to room temperature, and then DIEA (7.87 mL, 45.1 mmol), DMAP (184 mg, 1.51 mmol), and di-tert-butyl dicarbonate (5.23 mL, 22.53 mmol) were added. The mixture was stirred overnight at room temperature. The solvent was then removed under reduced pressure. Purification by FSC (gradient: 0-12% siRNA (in petroleum ether)) yielded the title compound (5.50 g, 76%) as a pale yellow foam. 1 H NMR:(CDCl3)δ 1.48(9H,s),1.49-1.64(2H,m),1.70(9H,s),2.00-2.10(2H,m),2.77-2.93(2H,m),3.43-3 .57(1H,m),4.18-4.30(2H,m),6.34(1H,d),7.31(1H,d),7.31(1H,s),8.27(1H,s).m / z(ES + ),[M-tBu+2H] + =423.1.

[0520] Intermediate 81c: tert-butyl 2-(1-(tert-butoxycarbonyl)piperidine-4-yl)-6-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-1H-indole-1-carboxylate [ka] Ephos Pd G4 (96.0 mg, 0.105 mmol) was added at room temperature under N2 to a degassed mixture of tert-butyl 6-bromo-2-(1-(tert-butoxycarbonyl)piperidine-4-yl)-1H-indole-1-carboxylate (1.00 g, 2.09 mmol), dihydropyrimidine-2,4(1H,3H)-dione (714 mg, 6.26 mmol), Ephos (56.0 mg, 0.105 mmol), and Cs2CO3 (1.36 g, 4.17 mmol) in 1,4-dioxane (40 mL). The resulting mixture was stirred at 100 °C for 16 hours. The solvent was then removed under reduced pressure. Purification by FSC (gradient: 0-60% siRNA (in petroleum ether)) yielded the title compound (960 mg, 90%) as a white solid. 1 H NMR:δ 1.30-1.51(11H,m),1.63(9H,s),1.99(2H,d),2.71(2H,t),2.79-2.85(2H,m),3.43(1H,t),3.79(2 H,t),3.95-4.16(2H,m),6.54(1H,s),7.15(1H,dd),7.47(1H,d),7.98(1H,d),10.33(1H,s).m / z(ES + ),[M+Na] + = 535.3.

[0521] Example 81: 1-(2-(piperidine-4-yl)-1H-indole-6-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] 1.96 g, 7.41 mmol of tert-butyldimethylsilyltrifluoromethanesulfonate was added at room temperature to a solution of tert-butyl 2-(1-(tert-butoxycarbonyl)piperidine-4-yl)-6-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-1H-indole-1-carboxylate (950 mg, 1.85 mmol) in 20 mL of DCM. The resulting mixture was stirred at room temperature for 16 hours. A further portion of tert-butyldimethylsilyltrifluoromethanesulfonate (1.96 g, 7.41 mmol) was added, and the mixture was stirred for a further 5 hours. The solvent was then removed under reduced pressure. The title compound (330 mg, 57%) was obtained as a white solid by purification using C-18FC (gradient: 0-40% MeCN (in water) (10 mmol NH4HCO3)). 1 H NMR:δ 1.54(2H,qd),1.85-1.95(2H,m),2.53-2.66(2H,m),2.66-2.83(3H,m),2.97-3.07(2H,m),3.15(1H,s) ,3.75(2H,t),6.10(1H,s),6.85(1H,dd),7.18(1H,d),7.37(1H,d),10.26(1H,s),10.98(1H,s).m / z(ES + ),[M+H] + =313.2.

[0522] Example 82: 1-(2-(1-methylpiperidine-4-yl)-1H-indole-6-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Methyl 4-methylbenzenesulfonate (59.6 mg, 0.320 mmol) was added at room temperature to a solution of 1-(2-(piperidine-4-yl)-1H-indole-6-yl)dihydropyrimidine-2,4(1H,3H)-dione (100 mg, 0.320 mmol) and DIEA (56.0 μL, 0.321 mmol) in DMF (3 mL). The resulting mixture was stirred at room temperature for 3 hours. The crude product was directly purified by preparative HPLC (column A, eluent F, gradient: 17-35%) to obtain the title compound (35.0 mg, 34%) as a white solid. 1 H NMR:δ 1.68(2H,qd),1.89-2.04(4H,m),2.18(3H,s),2.56-2.75(3H,m),2.84(2H,d),3.74(2H,t) ,6.12(1H,s),6.85(1H,dd),7.18(1H,s),7.37(1H,d),10.25(1H,s),10.97(1H,s).m / z(ES + ),[M+H] + =327.2.

[0523] Intermediate 83a: tert-butyl 4-(6-bromo-1H-indole-2-yl)piperidine-1-carboxylate [ka] 500 mg, 1.04 mmol of tert-butyl 6-bromo-2-(1-(tert-butoxycarbonyl)piperidine-4-yl)-1H-indole-1-carboxylate was dissolved in 15 mL of 2,2,2-trifluoroethanol and sealed in a microwave tube. The reaction mixture was heated in a microwave reactor at 150°C for 1 hour and then cooled to room temperature. The solvent was then removed under reduced pressure. Purification by FSC (gradient: 0-30% siRNA (in petroleum ether)) yielded the title compound (380 mg, 96%) as a pale yellow solid. 1H NMR:δ 1.40(9H,s),1.51(2H,qd),1.88-2.00(2H,m),2.73-2.96(3H,m),3.97-4.07(2H ,m),6.17(1H,d),7.03(1H,dd),7.36(1H,d),7.41(1H,s),11.12(1H,s).m / z(ES + ),[M+H] + =381.1.

[0524] Intermediate 83b: tert-butyl 4-(1-acetyl-6-bromo-1H-indole-2-yl)piperidine-1-carboxylate [ka] Ac2O (179 μL, 1.90 mmol) was added at room temperature to a mixture of tert-butyl 4-(6-bromo-1H-indole-2-yl)piperidine-1-carboxylate (360 mg, 0.949 mmol), triethylamine (397 μL, 2.85 mmol), and DMAP (11.6 mg, 0.0949 mmol) in DCE (10 mL). The resulting solution was stirred at 80°C for 16 hours. The second portion of Ac2O (4 mL) and triethylamine (4 mL) were added, and the reaction mixture was heated at 80°C for 4 hours. The solvent was then removed under reduced pressure. Purification by FSC (gradient: 0-25% siRNA (in petroleum ether)) yielded the title compound (350 mg, 88%) as a yellow solid. 1 H NMR:δ 1.31-1.51(11H,m),1.92-2.04(2H,m),2.68-2.94(5H,m),3.32-3.49(1H,m),3 .97-4.09(2H,m),6.61(1H,s),7.36(1H,dd),7.47(1H,d),8.00(1H,d).m / z(ES + ),[M+Na] + =445.1.

[0525] Intermediate 83c: tert-butyl 4-(6-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-1H-indole-2-yl)piperidine-1-carboxylate [ka] Ephos Pd G4 (41.9 mg, 0.0456 mmol) was added at room temperature under N2 conditions to a degassed mixture of tert-butyl 4-(1-acetyl-6-bromo-1H-indole-2-yl)piperidine-1-carboxylate (320 mg, 0.759 mmol), dihydropyrimidine-2,4(1H,3H)-dione (260 mg, 2.28 mmol), Ephos (24.4 mg, 0.0456 mmol), and Cs2CO3 (742 mg, 2.28 mmol) in 10 mL of 1,4-dioxane. The resulting mixture was stirred at 100 °C for 16 hours. The solvent was then removed under reduced pressure. Purification using C-18FC (gradient: 0-40% MeCN (in water) (10 mmol NH4HCO3)) yielded the title compound (210 mg, 67%) as a white solid. 1 H NMR:δ 1.42(9H,s),1.47-1.63(2H,m),1.91-2.02(2H,m),2.72(2H,t),2.79-2.99(3H,m),3.77(2H,t),3.99- 4.12(2H,m),6.16(1H,d),6.88(1H,dd),7.21(1H,d),7.40(1H,d),10.27(1H,s),11.03(1H,s).m / z(ES + ),[M-tBu+2H] + =357.1.

[0526] Example 83: 1-(2-(1-acetylpiperidine-4-yl)-1H-indole-6-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Ac2O (1.00 mL, 10.6 mmol) was added at room temperature to a solution of tert-butyl 4-(6-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-1H-indole-2-yl)piperidine-1-carboxylate (200 mg, 0.485 mmol) and DIEA (2.00 mL, 11.5 mmol) in DCE (10 mL). The resulting mixture was stirred at 80°C for 3 days. The solvent was then removed under reduced pressure. The crude product was purified by FSC (gradient: 0-60% ELISA (in petroleum ether)). The fraction containing the desired compound was concentrated to dryness to obtain an inseparable mixture (150 mg each, in a ratio of 1:1.7) of tert-butyl 4-(6-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-1H-indole-2-yl)piperidine-1-carboxylate and tert-butyl 4-(1-acetyl-6-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-1H-indole-2-yl)piperidine-1-carboxylate as a pale yellow solid. The crude mixture was carried over to the next step without further purification. 1 H NMR: (desired compound peak):δ 1.42(9H,s),1.42-1.48(1H,m),1.56(1H,dd),1.93-2.04(2H,m),2.45(3H,s),2.83-2.97(3H,m),3.39-3.52(2H ,m),3.84(2H,t),4.04-4.12(2H,m),6.19(1H,d),6.93(1H,dd),7.27(1H,d),7.43(1H,d),11.08(1H,s).m / z(ES + ),[M+Na] +=477.2. Next, the inseparable mixture was dissolved in 2,2,2-trifluoroethanol (5 mL) and sealed in a microwave tube. The reaction mixture was heated in a microwave reactor at 150°C for 6 hours and then cooled to room temperature. The solvent was then removed under reduced pressure. The substance was obtained by purification by C-18FC (gradient: 0-30% MeCN (in water) (containing 0.05% TFA)), which was further purified by preparative HPLC (column E, eluent E, gradient: 20-30%) to obtain the title compound (15.0 mg, 9%, total 2 steps) as a white solid (acetyl transfer from indole to piperidine occurred during the Boc deprotection step). 1 H NMR:δ 1.44-1.58(1H,m),1.58-1.70(1H,m),2.00(2H,t),2.04(3H,s),2.62-2.70(1H,m),2.72(2H,t),2.98(1H,t),3.18(1H,t),3. 77(2H,t),3.92(1H,d),4.47(1H,d),6.16(1H,d),6.88(1H,dd),7.21(1H,d),7.41(1H,d),10.27(1H,s),11.04(1H,s).m / z(ES + ),[M+H] + =355.3.

[0527] Intermediate 84a: tert-butyl 4-(6-bromo-1-methyl-1H-indole-2-yl)piperidine-1-carboxylate [ka] NaH (60% dispersion in mineral oil, 79 mg, 1.98 mmol) was added to a solution of tert-butyl 4-(6-bromo-1H-indole-2-yl)piperidine-1-carboxylate (500 mg, 1.32 mmol) in THF (10 mL) at 0°C under N2. The resulting mixture was stirred at room temperature for 0.5 hours, after which MeI (99.0 μL, 1.58 mmol) was added. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with ice water (20 mL) and extracted with siRNA (3 × 20 mL). The combined organic extract was dried (Na₂SO₄) and concentrated to obtain a pale yellow rubber. Purification by FSC (gradient: 0-60% siRNA (in petroleum ether)) yielded the title compound (360 mg, 69%) as a pale yellow solid. 1 H NMR:δ 1.40-1.54(11H,m),1.93(2H,d),2.87-3.04(3H,m),3.71(3H,s),4.02-4 .13(2H,m),6.26(1H,s),7.10(1H,dd),7.40(1H,d),7.66(1H,d).m / z(ES + ),[M+H] + =393.2.

[0528] Intermediate 84b: tert-butyl 4-(6-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-1-methyl-1H-indole-2-yl)piperidine-1-carboxylate [ka] Cs2CO3 (497 mg, 1.53 mmol) was added at room temperature under N2 to a degassed mixture of tert-butyl 4-(6-bromo-1-methyl-1H-indole-2-yl)piperidine-1-carboxylate (200 mg, 0.508 mmol), dihydropyrimidine-2,4(1H,3H)-dione (232 mg, 2.03 mmol), Ephos Pd G4 (46.7 mg, 0.0508 mmol), and Ephos (27.2 mg, 0.0509 mmol) in 1,4-dioxane (15 mL). The resulting solution was stirred at 100 °C for 17 hours. The solvent was then removed under reduced pressure. Purification with C-18FC (gradient: 0-50% MeCN (in water) (containing 0.1% FA)) yielded the title compound (120 mg, 55%) as a pale yellow solid. 1 H NMR:(CDCl3)δ 1.51(9H,s),1.58-1.78(2H,m),1.94-2.08(2H,m),2.83-2.97(5H,m),3.73(3H,s),3.93(2H ,t),4.29(2H,d),6.28(1H,s),6.98(1H,dd),7.28(1H,s),7.54(1H,s),7.58(1H,d).m / z(ES + ),[M-tBu+2H] + =371.2.

[0529] Example 84: 1-(1-methyl-2-(piperidine-4-yl)-1H-indole-6-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] 124 μL, 0.539 mmol of tert-butyldimethylsilyltrifluoromethanesulfonate was added to 115 mg, 0.270 mmol of tert-butyl 4-(6-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-1-methyl-1H-indole-2-yl)piperidine-1-carboxylate in 10 mL of MeCN at room temperature in air. The resulting solution was stirred at room temperature for 2 hours. The solvent was then removed under reduced pressure. Purification with C-18FC (gradient: 0-20% MeCN (in water) (containing 0.1% FA)) yielded the title compound in the form of the formate salt (40 mg, 37%) as a pale yellow solid. 1 H NMR:δ 1.71-1.85(2H,m),2.12(2H,t),2.74(2H,t),3.04-3.21(3H,m),3.41(2H,d),3.71(3 H,s),3.79(2H,t),6.26(1H,s),6.96(1H,dd),7.39(1H,d),7.47(1H,d),8.43(1H,br s),10.29(1H,s).m / z(ES + ),[M+H] + =327.3.

[0530] Intermediate 85a: 6-bromo-1-methyl-2-(piperidine-4-yl)-1H-indole [ka] 200 mg, 0.508 mmol of tert-butyl 4-(6-bromo-1-methyl-1H-indole-2-yl)piperidine-1-carboxylate was dissolved in 10 mL of 2,2,2-trifluoroethanol and sealed in a microwave tube. The reaction mixture was heated in a microwave reactor at 150°C for 12 hours and then cooled to room temperature. The solvent was removed under reduced pressure to obtain the title compound (130 mg, 87%) as a pale yellow solid. 1 H NMR:(CDCl3)δ 2.25(4H,s),3.06(3H,d),3.70(5H,s),6.35(1H,s),7.21(1H,dd),7.38-7.49(2H,m).m / z(ES + ),[M+H] + =295.2.

[0531] Intermediate 85b: 6-bromo-1-methyl-2-(1-methylpiperidine-4-yl)-1H-indole [ka] AcOH (19.5 μL, 0.341 mmol) was added at room temperature in air to a mixture in DCM (10 mL) of NaOAc (56.0 mg, 0.683 mmol), sodium triacetoxyborohydride (723 mg, 3.41 mmol), formaldehyde (20.5 mg, 0.683 mmol), and 6-bromo-1-methyl-2-(piperidine-4-yl)-1H-indole (100 mg, 0.341 mmol). The resulting mixture was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure. Purification with C-18FC (gradient: 0-100% MeOH (in water) (containing 0.1% FA)) yielded the title compound in the form of a formate salt (90.0 mg, 75%) as pale yellow rubber. 1 H NMR:(CDCl3)δ 2.11(4H,dt),2.63(3H,s),2.80-2.90(1H,m),3.41(2H,d),3.68(3H,s),3.70- 3.76(2H,m),6.31(1H,s),7.20(1H,dd),7.40-7.47(2H,m),8.51(1H,s).m / z(ES + ),[M+H] + =307.1.

[0532] Example 85: 1-(1-methyl-2-(1-methylpiperidine-4-yl)-1H-indole-6-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Ephos (7.6 mg, 0.014 mmol) and Ephos Pd G4 (13.0 mg, 0.0142 mmol) were added to a degassed mixture of Cs2CO3 (138 mg, 0.42 mmol), dihydropyrimidine-2,4(1H,3H)-dione (48.4 mg, 0.42 mmol), and 6-bromo-1-methyl-2-(1-methylpiperidine-4-yl)-1H-indole formate (50.0 mg, 0.142 mmol) in 1,4-dioxane (5 mL) at room temperature under N2 conditions. The resulting mixture was stirred at 100°C for 17 hours. The solvent was then removed under reduced pressure. The substance was obtained by purification using C-18FC (gradient: 0-30% MeCN (in water) (containing 0.1% FA)), and this was further purified by preparative HPLC (column K, eluent E, gradient: 10-23%) to obtain the title compound in the form of a formate salt (8.0 mg, 14%) as a pale yellow solid. 1 H NMR:δ 1.62-1.78(2H,m),1.95(2H,d),2.20-2.34(5H,m),2.73(2H,t),2.76-2.86(1H,m),2.99(2H,d),3.68(3H ,s),3.78(2H,t),6.22(1H,s),6.93(1H,dd),7.36(1H,d),7.43(1H,d),8.27(1H,s),10.30(1H,s).m / z(ES + ),[M+H] + =341.1.

[0533] Intermediate 86a: tert-butyl 4-((2-amino-6-bromophenyl)ethynyl)piperidine-1-carboxylate [ka] Pd(Ph3P)4 (3.10 g, 2.68 mmol) was added to a mixture of 3-bromo-2-iodoaniline (8.00 g, 26.9 mmol), tert-butyl 4-ethynylpiperidine-1-carboxylate (5.62 g, 26.9 mmol), and copper(I) iodide (614 mg, 3.22 mmol) in triethylamine (250 mL) at room temperature under N2 conditions. The resulting mixture was stirred at room temperature for 16 hours. The solvent was then removed under reduced pressure. Purification by FSC (gradient: 0-22% siRNA (in petroleum ether)) yielded the title compound (10.0 g, 98%) as brown rubber. 1 H NMR:(CDCl3)δ 1.47(9H,s),1.68-1.80(2H,m),1.82-1.97(2H,m),2.91-3.01(1H,m),3.30-3.45(2H,m),3.66-3.80(2H,m),4.28(2H,br s),6.58-6.67(1H,m),6.86-6.97(2H,m).m / z(ES + ),[M+H] + =379.0.

[0534] Intermediate 86b: tert-butyl 4-(4-bromo-1H-indole-2-yl)piperidine-1-carboxylate [ka] Dichlorobis(acetonitrile)palladium(II) (684 mg, 2.64 mmol) was added to a solution of tert-butyl 4-((2-amino-6-bromophenyl)ethynyl)piperidine-1-carboxylate (5.00 g, 13.2 mmol) in DMF (80 mL) at room temperature under N2 conditions. The resulting mixture was stirred at 80°C for 16 hours. The reaction mixture was quenched with water (200 mL) and extracted with ethyl acetate (3 × 200 mL). The combined organic extract was dried (Na₂SO₄) and concentrated to obtain a dark oil. Purification by FSC (gradient: 0-50% ethyl acetate (in petroleum ether)) yielded the title compound (4.20 g, 84%) as a yellow solid. m / z(ES) + ),[M-tBu+2H] + =325.0.

[0535] Intermediate 86c: tert-butyl 4-bromo-2-(1-(tert-butoxycarbonyl)piperidine-4-yl)-1H-indole-1-carboxylate [ka] Di-tert-butyl dicarbonate (1.81 g, 8.29 mmol) was added to tert-butyl 4-(4-bromo-1H-indole-2-yl)piperidine-1-carboxylate (2.10 g, 5.54 mmol), triethylamine (1.12 g, 11.1 mmol), and DMAP (68.0 mg, 0.557 mmol) in 50 mL of DCM at room temperature in air. The resulting mixture was stirred at room temperature for 1 hour. The solvent was then removed under reduced pressure. Purification by FSC (gradient: 0-25% SiO(in petroleum ether)) yielded the title compound (1.45 g, 55%) as a white solid. 1 H NMR:(CDCl3)δ 1.48(9H,s),1.58-1.65(2H,m),1.70(9H,s),2.05-2.12(2H,m),2.86(2H,t),3.5 3(1H,t),4.25(2H,d),6.46(1H,s),7.09(1H,t),7.35(1H,d),8.01(1H,d).m / z(ES + ),[M-tBu+2H] + =425.1.

[0536] Intermediate 86d: tert-butyl 2-(1-(tert-butoxycarbonyl)piperidine-4-yl)-4-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-1H-indole-1-carboxylate [ka] Ephos (156 mg, 0.292 mmol) and Ephos Pd G4 (268 mg, 0.292 mmol) were added at room temperature under N2 to a degassed mixture of tert-butyl 4-bromo-2-(1-(tert-butoxycarbonyl)piperidine-4-yl)-1H-indole-1-carboxylate (1.40 g, 2.92 mmol), dihydropyrimidine-2,4(1H,3H)-dione (1.00 g, 8.76 mmol), and Cs2CO3 (1.90 g, 5.83 mmol) in 1,4-dioxane (80 mL). The resulting mixture was stirred at 100 °C for 16 hours. The solvent was then removed under reduced pressure. Purification by FSC (gradient: 0-80% SiO(in petroleum ether)) yielded the title compound (490 mg, 33%) as a white solid. 1 H NMR:(CDCl3)δ 1.47(9H,s),1.53-1.65(2H,m),1.69(9H,s),2.04-2.11(2H,m),2.78-2.95(4H,m),3.55(1 H,t),3.88(2H,t),4.25(2H,d),6.24(1H,t),7.09(1H,dd),7.27-7.31(1H,m),7.52(1H,br s),8.06(1H,dt).m / z(ES + ),[M+H] + =513.4.

[0537] Example 86: 1-(2-(piperidine-4-yl)-1H-indole-4-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] 470 mg, 0.917 mmol of tert-butyl 2-(1-(tert-butoxycarbonyl)piperidine-4-yl)-4-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-1H-indole-1-carboxylate was dissolved in 10 mL of 2,2,2-trifluoroethanol and sealed in a microwave tube. The reaction mixture was heated in a microwave reactor at 150 °C for 12 hours and then cooled to room temperature. The solvent was then removed under reduced pressure. Purification with C-18FC (gradient: 5-40% MeCN (in water) (10 mmol NH4HCO3)) yielded the title compound (210 mg, 73%) as a white solid. 1 H NMR:δ 1.44-1.65(2H,m),1.90-1.94(2H,m),2.55-2.67(1H,m),2.70(2H,t),2.78-2.94(1H,m),3.00-3.31(3H,m),3.75( 2H,t),3.90-4.28(1H,m),6.10(1H,s),6.86(1H,dd),7.01(1H,t),7.23(1H,d),10.27(1H,s),11.08(1H,s).m / z(ES + ),[M+H] + =313.1.

[0538] Example 87: 1-(2-(1-methylpiperidine-4-yl)-1H-indole-4-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Sodium triacetoxyborohydride (142 mg, 0.670 mmol) was added at room temperature in air to a mixture of 1-(2-(piperidine-4-yl)-1H-indole-4-yl)dihydropyrimidine-2,4(1H,3H)-dione (70.0 mg, 0.224 mmol), paraformaldehyde (33.6 mg, 1.12 mmol) in MeOH (0.5 mL) and DCM (5 mL). The resulting mixture was stirred at room temperature for 2 hours. The solvent was then removed under reduced pressure. Purification with C-18FC (gradient: 5-35% MeCN (in water) (10 mmol NH4HCO3)) yielded the title compound (50 mg, 68%) as a white solid. 1 H NMR:δ 1.60-1.82(2H,m),1.88-2.04(4H,m),2.19(3H,s),2.59-2.70(1H,m),2.75(2H,t),2.85(2H,d),3. 75(2H,t),6.11(1H,s),6.86(1H,d),7.01(1H,t),7.23(1H,d),10.27(1H,s),11.07(1H,s).m / z(ES + ),[M+H] + =327.1.

[0539] Intermediate 88a: tert-butyl 4-(4-bromo-1-methyl-1H-indole-2-yl)piperidine-1-carboxylate [ka] NaH (60% dispersion in mineral oil, 316 mg, 7.91 mmol) was added to a solution of tert-butyl 4-(4-bromo-1H-indole-2-yl)piperidine-1-carboxylate (2.00 g, 5.27 mmol) in DMF (50 mL) at 0°C under N2. The mixture was stirred at room temperature for 10 minutes, and then MeI (328 μL, 5.27 mmol) was added at room temperature. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was then quenched with water (100 mL) and extracted with RINKAN (3 × 100 mL). The combined organic extract was dried (Na₂SO₄) and concentrated to obtain a yellow oil. Purification with C-18FC (gradient: 5-80% MeCN (in water) (containing 0.05% TFA)) yielded the title compound (800 mg, 39%) as a yellow solid. 1 H NMR:(CDCl3)δ 1.49(9H,s),1.62-1.78(2H,m),1.99(2H,d),2.80-2.96(3H,m),3.71(3H,s),4.27(2H,br d),6.30(1H,s),7.03(1H,t),7.21-7.26(2H,m).m / z(ES + ),[M+H] + =395.0.

[0540] Intermediate 88b: tert-butyl 4-(4-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-1-methyl-1H-indole-2-yl)piperidine-1-carboxylate [ka] Ephos (109 mg, 0.204 mmol) and Ephos Pd G4 (187 mg, 0.204 mmol) were added to a mixture of tert-butyl 4-(4-bromo-1-methyl-1H-indole-2-yl)piperidine-1-carboxylate (800 mg, 2.03 mmol), dihydropyrimidine-2,4(1H,3H)-dione (696 mg, 6.10 mmol), and Cs2CO3 (1.33 g, 4.08 mmol) in DMF (50 mL) at room temperature under N2 conditions. The resulting mixture was stirred at 100°C for 72 hours. The reaction mixture was then quenched with water (100 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic extract was dried (Na2SO4) and concentrated to obtain a yellow oil. Purification by FSC (gradient: 0-100% butyl (in petroleum ether)) yielded the title compound (80.0 mg, 9%) as a yellow solid. 1 H NMR:δ 1.42(9H,s),1.44-1.60(2H,m),1.87-1.96(2H,m),2.77(2H,t),2.82-3.09(3H,m),3.68-3.79(5H ,m),4.05-4.16(2H,m),6.25(1H,s),6.91(1H,d),7.09(1H,t),7.36(1H,d),10.28(1H,s).m / z(ES + ),[M-tBu+2H] + =371.1.

[0541] Example 88: 1-(1-methyl-2-(piperidine-4-yl)-1H-indole-4-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] 180 mg, 0.422 mmol of tert-butyl 4-(4-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-1-methyl-1H-indole-2-yl)piperidine-1-carboxylate was dissolved in 8 mL of 2,2,2-trifluoroethanol and sealed in a microwave tube. The reaction mixture was heated in a microwave reactor at 150°C for 7 hours and then cooled to room temperature. The solvent was removed under reduced pressure. Purification with C-18FC (gradient: 5-20% MeCN (in water) (containing 0.05% TFA)) yielded the title compound in the form of a trifluoroacetate salt (150 mg, 81%) as a white solid. 1 H NMR:δ 1.67-1.94(2H,m),2.09-2.13(2H,m),2.77(2H,t),2.99-3.28(3H,m),3.38-3.42(2H,m),3.67-3.82(5H ,m),6.20(1H,s),6.94(1H,d),7.13(1H,t),7.38(1H,d),8.38(1H,s),8.57-8.87(1H,m),10.31(1H,s). 19 F NMR (282MHz δ -73.92 m / z (ES) + ),[M+H] + =327.1.

[0542] Example 89: 1-(1-methyl-2-(1-methylpiperidine-4-yl)-1H-indole-4-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Sodium triacetoxyborohydride (130 mg, 0.613 mmol) was added at room temperature in air to a mixture of 1-(1-methyl-2-(piperidine-4-yl)-1H-indole-4-yl)dihydropyrimidine-2,4(1H,3H)-dione 2,2,2-trifluoroacetate (90.0 mg, 0.204 mmol), paraformaldehyde (30.7 mg, 1.02 mmol), and NaOAc (50.3 mg, 0.613 mmol) in MeOH (1 mL) and DCM (4 mL). The resulting mixture was stirred at room temperature for 16 hours. The solvent was then removed under reduced pressure. The crude product was purified by C-18FC (gradient: 5-40% MeCN (in water) (10 mmol NH4HCO3)), and then further purified by preparative HPLC (column D, eluent A, gradient: 8-30%) to obtain the title compound in the form of a trifluoroacetate salt (58 mg, 63%) as a white solid. 1 H NMR:(CD3OD)δ 1.76-2.06(2H,m),2.23-2.27(2H,m),2.81-3.01(5H,m),3.08-3.23(3H,m),3.52-3.56 (2H,m),3.77(3H,s),3.89(2H,t),6.23(1H,s),7.02(1H,d),7.21(1H,t),7.38(1H,d). 19 F NMR (376 MHz) δ -74.04 m / z (ES + ),[M+H] + =341.1.

[0543] Intermediate 90a: 6-(4-benzylpiperazine-1-yl)-4-bromo-1H-indole [ka] DIEA (12.4 mL, 71.0 mmol) was added to a solution of N-benzyl-2-chloro-N-(2-chloroethyl)ethane-1-amine (5.50 g, 23.7 mmol) and 4-bromo-1H-indole-6-amine (5.00 g, 23.7 mmol) in DMF (20 mL) at room temperature in air. The resulting solution was stirred at 100 °C for 2 hours. The reaction mixture was poured into water (50 mL), the resulting solid was filtered, dried, and the title compound (4.50 g, 51%) was obtained as a red solid. 1 H NMR:δ 3.12-3.19(4H,m),3.34-3.41(2H,m),3.72(2H,d),4.36-4.41(2H,m),6.26(1H,s),6.89(1 H,s),7.03(1H,s),7.29(1H,d),7.45-7.51(3H,m),7.62-7.68(2H,m),11.23(1H,s).m / z(ES + ),[M+H] + =370.1.

[0544] Intermediate 90b: 6-(4-benzylpiperazine-1-yl)-4-bromo-1-methyl-1H-indole [ka] NaH (60% dispersion in mineral oil, 342 mg, 8.55 mmol) was added to a solution of 6-(4-benzylpiperazin-1-yl)-4-bromo-1H-indole (2.11 g, 5.70 mmol) in DMF (30 mL) at 0°C under N2. The resulting mixture was stirred at room temperature for 0.5 hours, after which MeI (321 μL, 5.13 mmol) was added. The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water (50 mL) and extracted with RINKAN (3 × 50 mL). The combined organic extract was dried (Na₂SO₄) and concentrated to obtain a brown solid. Purification by FSC (gradient: 0-50% RINKAN (in petroleum ether)) yielded the title compound (2.00 g, 91%) as a white solid. 1H NMR:δ 2.52-2.59(4H,m),3.11-3.20(4H,m),3.55(2H,s),3.72(3H,s),6.22(1 H,dd),6.90(1H,d),7.00(1H,d),7.23(1H,d),7.32-7.37(5H,m).m / z(ES + ),[M+H] + =384.1.

[0545] Example 90: 1-(1-methyl-6-(piperazin-1-yl)-1H-indole-4-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Ephos (139 mg, 0.260 mmol) and Ephos Pd G4 (239 mg, 0.260 mmol) were added to a degassed mixture of Cs2CO3 (3.39 g, 10.4 mmol), 6-(4-benzylpiperazin-1-yl)-4-bromo-1-methyl-1H-indole (2.00 g, 5.20 mmol), and dihydropyrimidine-2,4(1H,3H)-dione (1.78 g, 15.6 mmol) in 1,4-dioxane (40 mL) at room temperature under N2 conditions. The resulting mixture was stirred at 100 °C for 16 hours. The solvent was then removed under reduced pressure. Purification with C-18FC (gradient: 5-50% MeCN (in water) (containing 0.05% concentrated HCl)) yielded 1-(6-(4-benzylpiperazin-1-yl)-1-methyl-1H-indole-4-yl)dihydropyrimidine-2,4(1H,3H)-dione (500 mg) as a black solid, which was used in the next step without further purification. m / z(ES + ),[M+H] + =418.2. Next, the above solid was dissolved in DMF (20 mL), and Pd / C (10% on activated carbon, 127 mg, 0.119 mmol) was added to the solution. The reaction mixture was stirred at room temperature under H2 (1 atm) for 2 hours. The reaction mixture was then filtered through a Celite pad. The solvent was then removed under reduced pressure. Purification by preparative HPLC (column D, eluent E, gradient: 5-13%) yielded the title compound in the form of the formate salt (380 mg, 20%, total 2 steps) as a white solid.1 H NMR:δ 2.74(2H,t),2.91-2.98(4H,m),3.06-3.13(4H,m),3.73(3H,s),3.75(2H,t),6.23 (1H,d),6.76(1H,d),6.83(1H,d),7.14(1H,d),8.24(1H,s),10.28(1H,s).m / z(ES + ),[M+H] + =328.3.

[0546] Intermediate 91a: tert-butyl 6-(4-benzylpiperazine-1-yl)-4-bromo-1H-indole-1-carboxylate [ka] Triethylamine (2.26 mL, 16.2 mmol) was added at room temperature to a mixture of DMAP (66.0 mg, 0.540 mmol), 6-(4-benzyl-piperazin-1-yl)-4-bromo-1H-indole (2.00 g, 5.40 mmol), and di-tert-butyl dicarbonate (2.36 g, 10.8 mmol) in DCM (20 mL). The resulting mixture was stirred at room temperature for 2 hours. The solvent was then removed under reduced pressure. Purification by FSC (gradient: 0-50% siRNA (in petroleum ether)) yielded the title compound (1.70 g, 67%) as a purple solid. 1 H NMR:δ 1.61(9H,s),2.51-2.62(4H,m),3.14-3.23(4H,m),3.53(2H,s),6.46-6.52(1H, m),7.18(1H,d),7.23-7.30(1H,m),7.31-7.37(4H,m),7.51-7.60(2H,m).m / z(ES + ),[M+H] + =472.1.

[0547] Example 91: 1-(6-(piperazin-1-yl)-1H-indole-4-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Ephos (97.0 mg, 0.181 mmol) and Ephos Pd G4 (166 mg, 0.181 mmol) were added to Cs2CO3 (2.36 g, 7.24 mmol), tert-butyl 6-(4-benzylpiperazin-1-yl)-4-bromo-1H-indole-1-carboxylate (1.70 g, 3.61 mmol), and dihydropyrimidine-2,4(1H,3H)-dione (1.24 g, 10.9 mmol) in DMF (40 mL) at room temperature under N2 conditions. The resulting mixture was stirred at 100 °C for 16 hours. The solvent was then removed under reduced pressure. Purification using C-18FC (gradient: 5-30% MeCN (in water)) yielded 1-(6-(4-benzylpiperazin-1-yl)-1H-indole-4-yl)dihydropyrimidine-2,4(1H,3H)-dione (300 mg) as a dark solid, which was used in the next step without further purification. m / z(ES + ),[M+H] + =404.2. Next, the solid was dissolved in DMF (15 mL), and Pd / C (10% on activated carbon, 79 mg, 0.074 mmol) was added to the solution. The reaction mixture was stirred at room temperature under H2 (1 atm) for 2 hours. The reaction mixture was then filtered through a Celite pad and washed with DMF (10 mL). The filtrate was concentrated to dryness. The substance was purified by C-18FC (gradient: 5-30% MeCN (in water) (10 mmol NH4HCO3)) to obtain the substance, which was further purified by preparative HPLC (column D, eluent A, gradient: 5-15%) to obtain the title compound in the form of a trifluoroacetate salt (120 mg, 8%, total 2 steps) as a white solid. 1 H NMR:δ 2.75(2H,t),3.21-3.31(8H,m),3.77(2H,t),6.28(1H,s),6.78(1H,s),6.86(1H,s),7.22(1H,d),8.69(2H,br s),10.30(1H,s),10.99(1H,s).m / z(ES + ),[M+H] + =314.2.

[0548] Intermediate 92a: tert-butyl 4-(7-bromoimidazo[1,2-a]pyridine-2-yl)piperidine-1-carboxylate [ka] Sodium bicarbonate (2.91 g, 34.7 mmol) was added at room temperature to a solution of 4-bromopyridine-2-amine (2.00 g, 11.6 mmol) and tert-butyl 4-(2-bromoacetyl)piperidine-1-carboxylate (3.54 g, 11.6 mmol) in ethanol (50 mL). The resulting mixture was stirred overnight at 80°C. The solvent was then removed under reduced pressure. Purification by FSC (gradient: 0-70% siRNA (in petroleum ether)) yielded the title compound (3.60 g, 82%) as a white solid. 1 H NMR:(CDCl3)δ 1.49(9H,s),1.59-1.74(2H,m),2.04-2.13(2H,m),2.83-3.03(3H,m),4.21-4. 28(2H,m),6.86(1H,dd),7.32(1H,s),7.71-7.76(1H,m),7.94(1H,dd).m / z(ES + ),[M+H] + =380.1.

[0549] Intermediate 92b: tert-butyl 4-(7-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)imidazo[1,2-a]pyridine-2-yl)piperidine-1-carboxylate [ka] Cs2CO3 (1.29 g, 3.96 mmol) was added at room temperature under N2 to a degassed mixture of Ephos (70.3 mg, 0.131 mmol), Ephos Pd G4 (121 mg, 0.132 mmol), dihydropyrimidine-2,4(1H,3H)-dione (450 mg, 3.94 mmol), and tert-butyl 4-(7-bromoimidazo[1,2-a]pyridine-2-yl)piperidine-1-carboxylate (500 mg, 1.31 mmol) in 1,4-dioxane (30 mL). The resulting mixture was stirred overnight at 100 °C. The solvent was then removed under reduced pressure. Purification by C-18FC (gradient: 0-40% MeCN (in water) (containing 0.1% concentrated HCl)) yielded the title compound (320 mg, 59%) as a pale yellow solid. m / z(ES + ),[M-tBu+2H] + =358.2.

[0550] Example 92: 1-(2-(piperidine-4-yl)imidazo[1,2-a]pyridine-7-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] A solution of 1,4-dioxane in HCl (4M, 5.00 mL, 20.0 mmol) was added to a solution of tert-butyl 4-(7-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)imidazo[1,2-a]pyridine-2-yl)piperidine-1-carboxylate (270 mg, 0.653 mmol) in DCM (5 mL) at room temperature in air. The resulting mixture was stirred at room temperature for 2 hours. The solvent was then removed under reduced pressure. Purification with C-18FC (gradient: 0-2% MeCN (in water) (containing 0.1% concentrated HCl)) yielded the title compound in the form of a hydrochloride salt (120 mg, 53%) as a pale yellow solid. 1H NMR:δ 1.74-1.90(2H,m),2.06-2.15(2H,m),2.74(2H,t),2.90-3.02(3H,m),3.24-3.33(2H,m),3.86( 2H,t),6.95(1H,dd),7.38(1H,d),7.71(1H,s),8.34(2H,s),8.43(1H,d),10.50(1H,s).m / z(ES + ),[M+H] + =314.0.

[0551] Intermediate 93a: tert-butyl 4-(6-bromobenzo[d]isoxazole-3-yl)piperazine-1-carboxylate [ka] Anhydrous trifluoromethanesulfonic acid (8.21 mL, 48.8 mmol) was added to a solution of 6-bromobenzo[d]-isoxazole-3-ol (9.50 g, 44.4 mmol) and pyridine (10.8 mL, 134 mmol) in DCM (200 mL) at 0°C in air. The resulting mixture was stirred at room temperature for 4 hours. The reaction mixture was then quenched with water (250 mL) and extracted with DCM (3 × 150 mL). The combined organic extract was dried (Na2SO4), concentrated to obtain 6-bromobenzo[d]isoxazole-3-yltrifluoromethanesulfonate as yellow oil (15.0 g), which was used in the next step without further purification. Next, the yellow oil was dissolved in MeCN (300 mL), and tert-butylpiperazine-1-carboxylate (8.88 g, 47.7 mmol) and DIEA (15.1 mL, 86.5 mmol) were sequentially added to the solution at room temperature in air. The resulting mixture was stirred at 80°C for 16 hours. The solvent was then removed under reduced pressure. The title compound (4.50 g, 27%, total 2 steps) was obtained as a yellow solid by purification using FSC (gradient: 0-70% SiO2 (in petroleum ether)). 1 H NMR:δ 1.43(9H,s),3.44-3.48(4H,m),3.49-3.56(4H,m),7.49(1H,dd),7.96(1H,s),7.98(1H,d).m / z(ES +),[M+H] + =382.0.

[0552] Intermediate 93b: tert-butyl 4-(6-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)benzo[d]isoxazole-3-yl)-piperazine-1-carboxylate [ka] Ephos Pd G4 (541 mg, 0.589 mmol) was added at room temperature under N2 conditions to a degassed mixture of tert-butyl 4-(6-bromobenzo[d]isoxazole-3-yl)piperazine-1-carboxylate (4.50 g, 11.8 mmol), dihydropyrimidine-2,4(1H,3H)-dione (4.03 g, 35.3 mmol), Ephos (315 mg, 0.589 mmol), and Cs2CO3 (7.67 g, 23.5 mmol) in 1,4-dioxane (200 mL). The resulting mixture was stirred at 100 °C for 16 hours. The solvent was then removed under reduced pressure. Purification by FSC (gradient: 0-100% ELISA (in petroleum ether)) yielded the title compound (4.50 g, 92%) as a yellow solid. 1 H NMR:δ 1.43(9H,s),2.74(2H,t),3.41-3.59(8H,m),3.89(2H,t),7.32(1H,dd),7.56(1H,d),7.97(1H,d),10.50(1H,s).m / z(ES + ),[M+H] + =416.1.

[0553] Example 93: 1-(3-(piperazin-1-yl)benzo[d]isoxazole-6-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] 4-(6-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)benzo[d]isoxazole-3-yl)piperazine-1-carboxylate (1.40 g, 3.37 mmol) was added at room temperature to a solution of 1,4-dioxane (100 mL) and HCl (4 M, 100 mL) in 1,4-dioxane. The resulting solution was stirred at room temperature for 2 hours. The solvent was then removed under reduced pressure. Purification by C-18FC (gradient: 5-40% MeCN (in water)) yielded the title compound in the form of a hydrochloride salt (1.00 g, 84%) as a white solid. 1 H NMR:δ 2.73(2H,t),3.29(4H,t),3.68(4H,t),3.86(2H,t),7.33(1H,dd),7.57(1H,d),7.96(1H,d).m / z(ES + ),[M+H] + =316.2.

[0554] Example 94: 1-(3-(4-methylpiperazin-1-yl)benzo[d]isoxazole-6-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Sodium triacetoxyborohydride (271 mg, 1.28 mmol) was added at room temperature to a mixture in DCM (10 mL) of 1-(3-(piperazin-1-yl)benzo[d]-isoxazole-6-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride (150 mg, 0.426 mmol), paraformaldehyde (25.6 mg, 0.853 mmol), and NaOAc (105 mg, 1.28 mmol). The resulting solution was stirred at room temperature for 16 hours. The solvent was then removed under reduced pressure. Purification by C-18FC (gradient: 0-40% MeCN (in water)) yielded the title compound (40.0 mg, 28%) as a white solid. 1 H NMR:δ 2.24(3H,s),2.48(4H,m),2.74(2H,t),3.42-3.54(4H,m),3.88(2H,t),7.30(1H,dd),7.55(1H,d),7.96(1H,d).m / z(ES +),[M+H] + =330.2.

[0555] Example 95: 1-(3-(4-acetylpiperazine-1-yl)benzo[d]isoxazole-6-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Ac2O (52.3 μL, 0.554 mmol) was added at room temperature to a solution of 1-(3-(piperazin-1-yl)benzo[d]isoxazole-6-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride (150 mg, 0.426 mmol) and triethylamine (238 μL, 1.71 mmol) in DCM (10 mL). The resulting solution was stirred at room temperature for 16 hours. The solvent was then removed under reduced pressure. Purification by C-18FC (gradient: 0-40% MeCN (in water)) yielded the title compound (108 mg, 71%) as a white solid. 1 H NMR:δ 2.05(3H,s),2.73(2H,t),3.39-3.52(4H,m),3.57-3.68(4H,m),3.87(2H,t),7.31(1H,dd),7.56(1H,d),7.97(1H,d),10.48(1H,s).m / z(ES + ),[M+H] + =358.2.

[0556] Intermediate 96a: 6-bromo-2-(piperidine-4-yl)benzo[d]oxazole [ka] Piperidine-4-carboxylic acid (687 mg, 5.32 mmol) was added to a solution of 2-amino-5-bromophenol (1.00 g, 5.32 mmol) in PPA (40 mL). The resulting mixture was stirred at 190°C for 5 hours. The reaction mixture was adjusted to pH=8 using a 10% aqueous solution of NaOH. The mixture was then poured into water (500 mL) and extracted with RINKAN (6 × 500 mL). The combined organic extract was dried (Na₂SO₄) and concentrated to obtain a dark solid (800 mg), which was used directly in the next step without further purification. m / z(ES) + ),[M+H] + =281.0.

[0557] Intermediate 96b: tert-butyl 4-(6-bromobenzo[d]oxazol-2-yl)piperidine-1-carboxylate [ka] The crude product of the above reaction (intermediate 96a) was dissolved in DCM (20 mL), and di-tert-butyl dicarbonate (991 μL, 4.27 mmol) and DIEA (1.49 mL, 8.53 mmol) were sequentially added to the mixture at room temperature. The resulting mixture was stirred at room temperature for 2 hours. The solvent was then removed under reduced pressure. Purification by FSC (gradient: 0-25% SiO(in petroleum ether)) yielded the title compound (380 mg, 19%, total 2 steps) as a brown solid. 1 H NMR:δ 1.42(9H,s),1.60-1.74(2H,m),2.04-2.13(2H,m),2.99(2H,br s),3.19-3.31(1H,m),3.91-3.99(2H,m),7.53(1H,dd),7.68(1H,d),8.03(1H,d).m / z(ES + ),[M+H] + =381.2.

[0558] Intermediate 96c: tert-butyl 4-(6-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)benzo[d]oxazole-2-yl)piperidine-1-carboxylate [ka] Ephos (49.1 mg, 0.0918 mmol) and Ephos Pd G4 (84.0 mg, 0.0914 mmol) were added to a mixture of Cs2CO3 (598 mg, 1.84 mmol), tert-butyl 4-(6-bromobenzo[d]oxazole-2-yl)piperidine-1-carboxylate (350 mg, 0.92 mmol), and dihydropyrimidine-2,4(1H,3H)-dione (314 mg, 2.75 mmol) in DMF (15 mL) at room temperature under N2. The resulting mixture was stirred at 100°C for 16 hours. The solvent was then removed under reduced pressure. Purification by FSC (gradient: 0-8% MeOH (in DCM)) yielded the title compound (220 mg, 58%) as a brown solid. 1 H NMR:δ 1.42(9H,s),1.60-1.77(2H,m),2.09(2H,dd),2.94-3.08(3H,m),3.21-3.31(2H,m) ,3.83(2H,t),3.92-3.99(2H,m),7.32(1H,dd),7.70(2H,dd),10.42(1H,s).m / z(ES + ),[M-tBu+2H] + =359.2.

[0559] Example 96: 1-(2-(piperidine-4-yl)benzo[d]oxazole-6-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] 230 mg, 0.555 mmol of tert-butyl 4-(6-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)benzo[d]oxazole-2-yl)piperidine-1-carboxylate was dissolved in 6 mL of 2,2,2-trifluoroethanol and sealed in a microwave tube. The reaction mixture was heated at 140°C for 10 hours in a microwave reactor. The reaction mixture was then cooled to room temperature, and the solvent was removed under reduced pressure. Purification using C-18FC (gradient: 0-20% MeCN (in water) (containing 0.1% FA)) yielded the title compound in the form of a formate salt (51.9 mg, 26%) as a white solid. 1 H NMR:δ 1.75-1.86(2H,m),2.07-2.16(2H,m),2.74(2H,t),2.87-2.96(2H,m),3.15-3.21(3H ,m),3.82(2H,t),7.31(1H,d),7.66-7.73(2H,m),8.31(1H,s),10.40(1H,s).m / z(ES + ),[M+H] + =315.0.

[0560] Example 97: 1-(2-(1-methylpiperidine-4-yl)benzo[d]oxazole-6-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] NaOAc (34.1 mg, 0.416 mmol) was added to a mixture in DCM (15 mL) of 1-(2-(piperidine-4-yl)benzo[d]oxazole-6-yl)dihydropyrimidine-2,4(1H,3H)-dioneformate (50.0 mg, 0.139 mmol), sodium triacetoxyborohydride (88.0 mg, 0.415 mmol), and paraformaldehyde (12.5 mg, 0.416 mmol). The resulting mixture was stirred at room temperature for 1 hour. The solvent was then removed under reduced pressure. Purification with C-18FC (gradient: 0-15% MeCN (in water) (containing 0.1% FA)) yielded the title compound in the form of the diformate salt (19.8 mg, 34%) as a white solid. 1H NMR:δ 1.80-1.91(2H,m),2.07-2.16(4H,m),2.22(3H,s),2.74(2H,t),2.82(2H,d),2.97-3.01 (1H,m),3.82(2H,t),7.31(1H,d),7.65-7.72(2H,m),8.17(2H,s),10.40(1H,s).m / z(ES + ),[M+H] + =329.2.

[0561] Intermediate 98a: 6-bromobenzo[d]oxazole-2(3H)-thion [ka] Potassium O-ethylcarbonodithioate (4.26 g, 26.6 mmol) was added to a solution of 2-amino-5-bromophenol (5.00 g, 26.6 mmol) in EtOH (60 mL) at room temperature under N2 conditions. The resulting mixture was stirred at 80°C for 16 hours. The solvent was then removed under reduced pressure. The reaction mixture was diluted with ELISA (300 mL) and washed sequentially with 2 M HCl (50 mL), water (100 mL), and saturated brine (100 mL). The organic layer was dried and concentrated to obtain the title compound (4.60 g, 75%) as a brown solid, which was used in the next step without further purification. 1 H NMR:δ 7.17(1H,d),7.45(1H,dd),7.83(1H,d),13.70(1H,s).m / z(ES + ),[M+H] + =230.2.

[0562] Intermediate 98b: tert-butyl 4-(6-bromobenzo[d]oxazole-2-yl)piperazine-1-carboxylate [ka] Two of the following reactions were carried out in parallel: a mixture of 6-bromobenzo[d]oxazole-2(3H)-thion (1.00 g, 4.35 mmol), tert-butylpiperazine-1-carboxylate (1.62 g, 8.70 mmol), and DIEA (2.28 mL, 13.1 mmol) in n-butanol (12 mL) was sealed in a microwave tube. The reaction mixture was heated in a microwave reactor at 150 °C for 1 hour, then cooled to room temperature. The solvent was then removed under reduced pressure. The combined crude product of the two parallel reactions was purified by FSC (gradient: 0-23% siRNA (in petroleum ether)) to obtain the title compound (2.70 g, 81% average of the two reactions) as an off-white solid. 1 H NMR:δ 1.41(9H,s),3.41-3.51(4H,m),3.52-3.62(4H,m),7.23(1H,d),7.31(1H,dd),7.68(1H,d).m / z(ES + ),[M+H] + =382.1.

[0563] Intermediate 98c: tert-butyl 4-(6-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)benzo[d]oxazole-2-yl)piperazine-1-carboxylate [ka] Ephos Pd G4 (231 mg, 0.251 mmol) was added at room temperature under N2 to a degassed mixture of tert-butyl 4-(6-bromobenzo[d]oxazole-2-yl)piperazine-1-carboxylate (1.60 g, 4.19 mmol), dihydropyrimidine-2,4(1H,3H)-dione (1.43 g, 12.5 mmol), Cs2CO3 (4.09 g, 12.6 mmol), and Ephos (134 mg, 0.251 mmol) in 1,4-dioxane (80 mL). The resulting mixture was stirred at 100 °C for 16 hours. The solvent was then removed under reduced pressure. Purification by FSC (gradient: 0-100% SiO2 in petroleum ether, then maintained at 100% for 0.5 hours) yielded the title compound (1.50 g, 86%) as a white solid. 1H NMR:δ 1.43(9H,s),2.71(2H,t),3.47(4H,dd),3.59(4H,dd),3.76(2H,t),7.12(1H,dd),7.28(1H,d),7.44(1H,d),10.35(1H,s).m / z(ES + ),[M+H] + =416.2.

[0564] Example 98: 1-(2-(piperazin-1-yl)benzo[d]oxazole-6-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] The following two reactions were carried out in parallel: A mixture of tert-butyl 4-(6-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)benzo[d]oxazole-2-yl)piperazine-1-carboxylate (700 mg, 1.68 mmol) and 2,2,2-trifluoroethanol (15 mL) was sealed in a microwave tube. The reaction mixture was heated in a microwave reactor at 150 °C for 8 hours and then cooled to room temperature. The solvent was then removed under reduced pressure. The combined crude product of the two parallel reactions was purified using C-18FC (gradient: 0-35% MeCN (in water) (10 mmol NH4HCO3)) to obtain the title compound (900 mg, 85% average of the two reactions) as a white solid. 1 H NMR:δ 2.71(2H,t),2.75-2.82(4H,m),3.48-3.55(4H,m),3.76(2H,t),7.10(1H,dd),7.25(1H,d),7.41(1H,d),10.35(1H,s).m / z(ES + ),[M+H] + =316.3.

[0565] Example 99: 1-(2-(4-methylpiperazin-1-yl)benzo[d]oxazole-6-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Sodium triacetoxyborohydride (101 mg, 0.477 mmol) was added at room temperature to a mixture in DCM (5 mL) of 1-(2-(piperazin-1-yl)benzo[d]-oxazole-6-yl)dihydropyrimidine-2,4(1H,3H)-dione (50.0 mg, 0.159 mmol), paraformaldehyde (14.3 mg, 0.476 mmol), and AcOH (27.3 μL, 0.477 mmol). The resulting mixture was stirred at room temperature for 16 hours. The solvent was then removed under reduced pressure. The residue was purified by C-18FC (gradient: 0-5% MeCN (in water) (containing 0.1% TFA)) and further purified by preparative HPLC (column B, eluent G, gradient: 10-35%) to obtain the title compound (16.0 mg, 31%) as a white solid. 1 H NMR:δ 2.23(3H,s),2.40-2.50(4H,m),2.71(2H,t),3.60(4H,t),3.76(2H,t),7.11(1H,dd),7.26(1H,d),7.42(1H,d),10.34(1H,s).m / z(ES + ),[M+H] + =330.2.

[0566] Intermediate 100a and 100b: tert-butyl 4-(5-bromobenzo[d]thiazole-2-yl)piperazine-1-carboxylate and tert-butyl 4-(7-bromobenzo[d]thiazole-2-yl)piperazine-1-carboxylate [ka] K2CO3 (3.34 g, 24.2 mmol) was added at room temperature in air to a 1.6:1 isomer mixture of 5-bromo-2-chlorobenzo[d]thiazole and 7-bromo-2-chlorobenzo[d]thiazole (3.00 g, 12.1 mmol, commercially available reagent - initially assumed to be pure, later discovered to be an isomer mixture) and tert-butylpiperazine-1-carboxylate (2.25 g, 12.1 mmol) in DMF (30 mL). The resulting solution was stirred at 80°C for 4 hours. The reaction mixture was then poured into water (150 mL) and extracted with siRNA (3 × 100 mL). The combined organic extract was dried (Na2SO4) and concentrated to obtain a pale yellow liquid. Purification by FSC (gradient: 0-50% SiO2 (in petroleum ether)) yielded the title compound as a pale yellow solid in an inseparable mixture of isomers (1.6:1, 4.50 g, 94%). The major isomers 1 H NMR peak (intermediate 100a): δ 1.41(9H,s),3.42-3.51(4H,m),3.51-3.62(4H,m),7.21(1H,dd),7.60(1H,d),7.73(1H,d). m / z(ES + ),[M+H] + =400.1.

[0567] Intermediates 100c and 100d: tert-butyl 4-(5-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)benzo[d]thiazole-2-yl)piperazine-1-carboxylate and tert-butyl 4-(7-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)benzo[d]thiazole-2-yl)piperazine-1-carboxylate [ka] Experiment 1: Ephos Pd G4 (115 mg, 0.125 mmol) was added at room temperature under N2 conditions to a degassed mixture in 1,4-dioxane (10 mL) containing a 1.6:1 isomer mixture of tert-butyl 4-(5-bromobenzo[d]thiazole-2-yl)piperazine-1-carboxylate and tert-butyl 4-(7-bromobenzo-[d]thiazole-2-yl)piperazine-1-carboxylate, dihydropyrimidine-2,4(1H,3H)-dione (859 mg, 7.53 mmol), Ephos (67.0 mg, 0.125 mmol), and Cs2CO3 (1.636 g, 5.02 mmol). The resulting solution was stirred at 120°C for 12 hours. The mixture was then concentrated to obtain the crude product. Experiment 2: Experiment 1 was repeated, and the crude products of both reactions were combined. Purification with C-18FC (gradient: 20-70% MeCN (in water)) yielded the title compound as a white solid in the form of an isomer mixture (3:1, 1.100 g, 51% average yield of the two experiments). 1 H NMR:-Major isomer peak (intermediate 100c): δ 1.41(9H,s),2.70(2H,t),3.42-3.51(4H,m),3.51-3.58(4H,m),3.78(2H,t),7.04(1H,dd),7.41(1H,d),7.75(1H,d),10.33(1H,s).m / z(ES + ),[M+H] + =432.3.

[0568] Example 100: 1-(2-(piperazin-1-yl)benzo[d]thiazole-5-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] A mixture of isomers of tert-butyl 4-(5-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)benzo[d]thiazole-2-yl)piperazine-1-carboxylate and tert-butyl 4-(7-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)benzo[d]thiazole-2-yl)piperazine-1-carboxylate (3:1) (100 mg, 0.232 mmol) was added at room temperature to a solution of 1,4-dioxane in HCl (4 M, 2 mL, 8.00 mmol). The resulting mixture was stirred at room temperature for 1 hour. The solvent was then removed under reduced pressure. Purification by preparative SFC (column: DAISEL DCpak P4VP, 20*250 mm, 5 μm; mobile phase A: scCO2, mobile phase B: MeOH (8 mmol NH3.MeOH)-HPLC; flow rate: 50 mL / min; gradient: 20% B; 254 nm; room temperature 1: 3.72; room temperature 2: 4.48; injection volume: 2 mL; number of operations: 10) yielded the title compound (33.2 mg, 43%) as a white solid. 1 H NMR:δ 10.33(s,1H),7.74(d,1H),7.40(d,1H),7.03(dd,1H),3.80(t,2H),3.48(t,4H),2.81(t,4H),2.72(t,2H).m / z(ES + ),[M+H] + =332.2.

[0569] Example 101: 1-(2-(piperazin-1-yl)benzo[d]thiazole-7-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] tert-butyl 4-(7-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)benzo[d]thiazole-2-yl)piperazine-1-carboxylate (the specified compound was separated by preparative TLC of a 3:1 isomer mixture of intermediates 100c and 100d, respectively) (30.0 mg, 0.070 mmol) was added to a solution of 1,4-dioxane in HCl (4 M, 1 mL, 4.00 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The precipitate was collected by filtration and washed with Et2O to obtain the title compound in the form of a dihydrochloride salt (23.7 mg, 84%) as a white solid. 1 H NMR:δ 2.74(2H,t),3.18-3.30(4H,m),3.75-3.88(6H,m),7.14(1H,dd),7.38(1H,t),7.46(1H,dd),9.32(2H,br s),10.53(1H,s).m / z(ES + ),[M+H] + =332.1.

[0570] Intermediate 102a: Ethyl 6-bromo-1-(cyanomethyl)-1H-indole-2-carboxylate [ka] KOtBu (1.63 g, 14.5 mmol) was added to ethyl 6-bromo-1H-indole-2-carboxylate (2.60 g, 9.70 mmol) in DMF (20 mL) at room temperature. The resulting mixture was stirred for 1 hour, after which 2-chloroacetonitrile (879 mg, 11.6 mmol) was added. The resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was then diluted with water. The precipitate was collected by filtration, washed with water, and dried under vacuum to obtain the title compound (2.00 g, 67%) as a gray solid, which was used in the next step without further purification. 1 H NMR: δ 1.36(3H,t),4.37(2H,q),5.76(2H,s),7.38(1H,dd),7.43(1H,d),7.72(1H,d),8.09-8.20(1H,m).

[0571] Intermediate 102b: 7-bromo-1,2,3,4-tetrahydropyrazino[1,2-a]indole [ka] A solution of LiAlH4 in THF (1M, 18.0 mL, 18.0 mmol) was added dropwise to a solution of ethyl 6-bromo-1-(cyanomethyl)-1H-indole-2-carboxylate (1.80 g, 5.86 mmol) in THF (30 mL) at room temperature under N2 conditions. The resulting mixture was stirred at 60°C for 2 hours. The reaction mixture was then quenched with a saturated solution of Rossel's salt (200 mL) and extracted with RINKAN (3 × 100 mL). The organic layer was dried (Na₂SO₄) and evaporated. Purification with C-18FC (gradient: 5-30% MeCN (in water) (containing 0.1% NH₄HCO₃)) yielded the title compound (500 mg, 34%) as a yellow solid. 1 H NMR:δ 3.18(2H,t),3.96(2H,t),4.04(2H,s),6.17(1H,s),7.12(1H,dd),7.41(1H,d),7.60(1H,d).m / z(ES + ),[M+H] + =250.9.

[0572] Intermediate 102c: tert-butyl 7-bromo-3,4-dihydropyrazino[1,2-a]indole-2(1H)-carboxylate [ka] Di-tert-butyl dicarbonate (416 μL, 1.79 mmol) was added at room temperature to a mixture of 7-bromo-1,2,3,4-tetrahydropyrazino[1,2-a]indole (300 mg, 1.19 mmol) in THF (2 mL) and saturated Na2CO3 aqueous solution (2 mL). The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was then diluted with ethyl acetate and washed sequentially with water and saturated brine. The organic layer was dried (Na2SO4) and concentrated. Purification by FSC (gradient: 0-5% ethyl acetate (in petroleum ether)) yielded the title compound (304 mg, 72%) as a yellow solid. 1H NMR:δ 1.42(9H,s),3.82(2H,t),4.08(2H,dd),4.71(2H,s),6.31(1H,s),7.13(1H,dd),7.43(1H,d),7.64(1H,d).m / z(ES + ),[M+H] + =351.1.

[0573] Intermediate 102d: tert-butyl7-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-3,4-dihydropyrazino[1,2-a]-indole-2(1H)-carboxylate [ka] Ephos Pd G4 (68.0 mg, 0.0740 mmol) was added at room temperature under N2 to a degassed mixture of tert-butyl 7-bromo-3,4-dihydropyrazino[1,2-a]indole-2(1H)-carboxylate (260 mg, 0.740 mmol), dihydropyrimidine-2,4(1H,3H)-dione (253 mg, 2.22 mmol), Ephos (39.5 mg, 0.0739 mmol), and Cs2CO3 (482 mg, 1.48 mmol) in 1,4-dioxane (7 mL). The resulting mixture was stirred at 120 °C for 16 hours. The solvent was then removed under reduced pressure. Purification by FSC (gradient: 0-70% SiO(in petroleum ether)) yielded the title compound (130 mg, 46%) as a yellow solid. 1 H NMR:δ 10.30(s,1H),7.47(d,1H),7.36(d,1H),6.99(dd,1H),6.31(d,1H),4.74(s, 2H),4.06(q,2H),3.85(t,2H),3.79(t,2H),2.73(t,2H),1.44(s,9H).m / z(ES + ),[M+H] + =385.2.

[0574] Example 102: 1-(1,2,3,4-tetrahydropyrazino[1,2-a]indole-7-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] 30.0 mg, 0.0780 mmol of tert-butyl 7-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-3,4-dihydropyrazino[1,2-a]indole-2(1H)-carboxylate (30.0 mg, 0.0780 mmol) was added to formic acid (1.00 mL, 26.1 mmol) at room temperature. The resulting solution was stirred at room temperature for 1 hour. The solvent was then removed under reduced pressure. The residue was diluted with DMF (0.4 mL) and then triturated with Et2O (30 mL) to obtain a solid, which was collected by filtration and dried under vacuum to obtain the title compound in the form of a formate salt (7.6 mg, 29%) as a yellow solid. 1 H NMR:δ 2.73(2H,t),3.22(2H,d),3.80(2H,t),3.96(2H,t),4.08(2H,d),6.16(1H,s),6.97(1H,dd),7.33(1H,d),7.44(1H,d),8.16(1H,br s),10.29(1H,s).m / z(ES + ),[M+H] + =285.2.

[0575] Intermediate 103a: 7-bromo-2-methyl-1,2,3,4-tetrahydropyrazino[1,2-a]indole [ka] Paraformaldehyde (67.0 mg, 2.23 mmol) was added at room temperature to a mixture of 7-bromo-1,2,3,4-tetrahydropyrazino[1,2-a]-indole (140 mg, 0.557 mmol) in DCM (5 mL). After stirring the reaction mixture for 16 hours, sodium triacetoxyborohydride (295 mg, 1.39 mmol) was added. The resulting mixture was stirred at room temperature for 2 hours. The solvent was then removed under reduced pressure. Purification with C-18FC (gradient: 0-40% MeOH (in water) (containing 0.1% NH4HCO3)) yielded the title compound (20.0 mg, 14%) as a yellow solid. m / z (ES + ),[M+H] + =267.0.

[0576] Example 103: 1-(2-methyl-1,2,3,4-tetrahydropyrazino[1,2-a]indole-7-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Ephos Pd G4 (13.9 mg, 0.0151 mmol) was added at room temperature under N2 conditions to a degassed mixture of 7-bromo-2-methyl-1,2,3,4-tetrahydropyrazino[1,2-a]indole (20.0 mg, 0.0754 mmol), dihydropyrimidine-2,4(1H,3H)-dione (17.2 mg, 0.151 mmol), Ephos (8.1 mg, 0.0151 mmol), and Cs2CO3 (73.7 mg, 0.226 mmol) in 1,4-dioxane (1 mL). The resulting mixture was stirred at 120°C for 16 hours. The reaction mixture was diluted with DCM and washed sequentially with 5% AcOH, water, and saturated brine. The organic layer was dried and concentrated over (Na2SO4). Purification using C-18FC (gradient: 5-40% MeCN (in water) (containing 0.1% NH4HCO3)) yielded the title compound (4.4 mg, 20%) as a yellow solid. 1 H NMR:δ 2.40(3H,s),2.73(2H,t),2.86(2H,t),3.69(2H,s),3.79(2H,t),4.03(2H,t ),6.18(1H,s),6.97(1H,dd),7.32(1H,s),7.44(1H,d),10.27(1H,s).m / z(ES + ),[M+H] + =299.1.

[0577] Intermediate 104a: Ethyl 5-bromo-1-(cyanomethyl)-1H-indole-2-carboxylate [ka] Potassium t-butoxide (6.28 g, 56.0 mmol) was added to a solution of ethyl 5-bromo-1H-indole-2-carboxylate (10.0 g, 37.3 mmol) in DMF (50 mL) at room temperature under N2 conditions. The resulting solution was stirred at room temperature for 0.5 hours, after which 2-chloroacetonitrile (3.38 g, 44.8 mmol) was added. The resulting solution was stirred at room temperature for 10 hours. The reaction mixture was then poured into water (150 mL) and extracted with RINKAN (3 × 100 mL). The combined organic solution was dried (Na₂SO₄) and concentrated to obtain the title compound (8.00 g, 70%) as a pale yellow solid, which was used in the next step without further purification. 1 H NMR:δ 1.34(3H,t),4.36(2H,q),5.75(2H,s),7.36(1H,d),7.57(1H,dd),7.77(1H,d),7.97(1H,d).m / z(ES + ),[M+H] + =307.1.

[0578] Intermediate 104b: 8-bromo-1,2,3,4-tetrahydropyrazino[1,2-a]indole [ka] A solution of LiAlH4 in THF (1M, 78.0 mL, 78.0 mmol) was added dropwise to a solution of ethyl 5-bromo-1-(cyanomethyl)-1H-indole-2-carboxylate (8.00 g, 26.0 mmol) in THF (40 mL) at room temperature under N2 conditions. The resulting solution was stirred at 60°C for 2 hours. The reaction mixture was poured into a saturated aqueous solution of Rossel's salt (25 mL) and extracted with RINKAN (3 × 30 mL). The combined organic extract was dried (Na₂SO₄) and concentrated to obtain yellow rubber. Purification by C-18FC (gradient: 30-100% MeCN (in water)) yielded the title compound (2.00 g, 31%) as a white solid. 1 H NMR:δ 3.14(2H,t),3.92(2H,t),4.01(2H,d),6.11(1H,d),7.14(1H,dd),7.31(1H,d),7.61(1H,d).m / z(ES + ),[M+H]+ =253.1.

[0579] Intermediate 104c: tert-butyl 8-bromo-3,4-dihydropyrazino[1,2-a]indole-2(1H)-carboxylate [ka] Di-tert-butyl dicarbonate (2.77 mL, 11.9 mmol) was added at room temperature to a mixture of 8-bromo-1,2,3,4-tetrahydropyrazino-[1,2-a]indole (2.00 g, 7.96 mmol) and Na2CO3 (4.22 g, 39.8 mmol) in THF (5 mL) and water (5 mL). The resulting solution was stirred at room temperature for 4 hours. The reaction mixture was then concentrated. Purification by FSC (gradient: 0-80% SiO2 (in petroleum ether)) yielded the title compound (1.30 g, 46%) as a yellow solid. 1 H NMR:δ 1.42(9H,s),3.83(2H,t),4.07(2H,dd),4.73(2H,s),6.26-6.31(1H,m),7.20(1H,dd),7.36(1H,d),7.66(1H,d).m / z(ES + ),[M+H] + =353.1.

[0580] Intermediate 104d: tert-butyl8-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-3,4-dihydropyrazino[1,2-a]-indole-2(1H)-carboxylate [ka] Ephos Pd G4 (78.0 mg, 0.0849 mmol) was added at room temperature under N2 conditions to a degassed mixture of tert-butyl 8-bromo-3,4-dihydropyrazino-[1,2-a]indole-2(1H)-carboxylate (600 mg, 1.71 mmol), dihydropyrimidine-2,4(1H,3H)-dione (585 mg, 5.12 mmol), Ephos (45.7 mg, 0.0855 mmol), and Cs2CO3 (1.11 g, 3.41 mmol) in 10 mL of 1,4-dioxane. The resulting mixture was stirred at 120 °C for 16 hours. The reaction mixture was then concentrated. Purification by C-18FC (gradient: 0-50% MeCN (in water)) yielded the title compound (300 mg, 46%) as a pale yellow solid. 1 H NMR:δ 1.42(9H,s),2.70(2H,t),3.74(2H,t),3.83(2H,t),4.08(2H,t),4.73(2H,s ),6.29(1H,s),7.04(1H,dd),7.37(1H,d),7.40(1H,d),10.24(1H,s).m / z(ES + ),[M+H] + =385.3.

[0581] Example 104: 1-(1,2,3,4-tetrahydropyrazino[1,2-a]indole-8-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] 40.0 mg, 0.104 mmol of tert-butyl 8-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-3,4-dihydropyrazino[1,2-a]indole-2(1H)-carboxylate (40.0 mg) was added to 1 mL of formic acid at room temperature. The resulting solution was stirred at room temperature for 4 hours. The solvent was then removed, and the resulting rubber was triturated with 30 mL of Et2O. The resulting solid was collected by filtration and dried under vacuum to obtain the title compound in the form of a formate salt (20.0 mg, 58%) as a yellow solid. 1H NMR:δ 2.70(2H,t),3.18(2H,t),3.74(2H,t),3.95(3H,t),4.04(2H,s),6.13(1H,d ),6.99(1H,dd),7.33(1H,d),7.36(1H,d),8.17(1H,s),10.22(1H,s).m / z(ES + ),[M+H] + =285.2.

[0582] Example 105: 1-(2-methyl-1,2,3,4-tetrahydropyrazino[1,2-a]indole-8-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] 1-(1,2,3,4-tetrahydropyrazino[1,2-a]indole-8-yl)dihydropyrimidine-2,4(1H,3H)-dione (90.0 mg, 0.317 mmol) was added to a mixture of paraformaldehyde (76.0 mg, 2.53 mmol) in DCM (1 mL) at room temperature in air. The resulting solution was stirred at room temperature for 1 hour, after which sodium triacetoxyborohydride (168 mg, 0.793 mmol) was added. The resulting solution was stirred at room temperature for 12 hours, and then directly purified by preparative TLC (DCM:MeOH = 10:1) to obtain the crude product, which was further purified by preparative SFC (column: Torus 2-PIC, 01083900811201; mobile phase A: scCO2, mobile phase B: MeOH (8 mmol NH3.MeOH) -- HPLC: 25; flow rate: 50 mL / min; 254 nm; room temperature 1:1.75). The pure fraction was evaporated to dryness to obtain the title compound (4.0 mg, 4%) as a yellow solid. 1 H NMR:δ 2.38(3H,s),2.70(2H,t),2.85(2H,dd),3.67(2H,s),3.74(2H,t),4.03(2H,d d),6.16(1H,s),7.00(1H,dd),7.33(1H,d),7.37(1H,d),10.23(1H,s).m / z(ES + ),[M+H] + =299.2.

[0583] Intermediates 106a and 106b: tert-butyl 4-(5-bromo-1H-indazole-1-yl)piperidine-1-carboxylate and tert-butyl 4-(5-bromo-2H-indazole-2-yl)piperidine-1-carboxylate [ka] A mixture of Cs2CO3 (5.21 g, 16.0 mmol), 5-bromo-1H-indazole (2.10 g, 10.7 mmol), and tert-butyl 4-(methylsulfonyl)oxy)piperidine-1-carboxylate (3.57 g, 12.8 mmol) in NMP (25 mL) was stirred overnight at 100°C. The resulting mixture was filtered, and the filtrate was directly purified using C-18FC (gradient: 0-100% MeCN (in water)) to obtain the title compound as a pale yellow solid in an inseparable mixture of positional isomers (2:1, 3.10 g, 76% combined yield). The mixture was used in the next step without further purification. m / z(ES) + ),[M+H] + =382.3.

[0584] Intermediates 106c and 107a: tert-butyl 4-(5-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-1H-indazole-1-yl)piperidine-1-carboxylate and tert-butyl 4-(5-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-2H-indazole-2-yl)piperidine-1-carboxylate [ka] Ephos (14.1 mg, 0.0264 mmol) and Ephos Pd G4 (24.1 mg, 0.0262 mmol) were added to a degassed mixture in 10 mL of 1,4-dioxane containing Cs2CO3 (514 mg, 1.58 mmol), dihydropyrimidine-2,4(1H,3H)-dione (180 mg, 1.58 mmol), and a positional isomer mixture (2:1) of tert-butyl 4-(5-bromo-1H-indazole-1-yl)piperidine-1-carboxylate and tert-butyl 4-(5-bromo-2H-indazole-2-yl)piperidine-1-carboxylate (200 mg, 0.526 mmol, combined molar concentration). The resulting mixture was stirred at 100°C under N2 for 15 hours. The mixture was then filtered and washed with THF. The filtrate was then concentrated. Purification using C-18FC (gradient: 0-100% MeCN (in water)) yielded the title compound as a white solid in an inseparable mixture of positional isomers (2:1, 180 mg, 83% combined yield). The mixture was used in the next step without further purification. m / z(ES) + ),[M+H] + =414.4.

[0585] Example 106: 1-(1-(piperidine-4-yl)-1H-indazole-5-yl)dihydropyrimidine-2,4(1H,3H)-dione and Example 107: 1-(2-(piperidine-4-yl)-2H-indazole-5-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] TFA (10 mL) was added at room temperature to a positional isomer mixture (2:1) of tert-butyl 4-(5-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-1H-indazole-1-yl)piperidine-1-carboxylate and tert-butyl 4-(5-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-2H-indazole-2-yl)piperidine-1-carboxylate in DCM (10 mL) (180 mg, 0.435 mmol, combined molar concentration). The resulting solution was stirred at room temperature for 1 hour. The solvent was then removed under reduced pressure. Purification by preparative HPLC (column Z, eluent B, gradient: 9-15%) yielded the title compound (Example 106: 38.3 mg, 28%, and Example 107: 13.9 mg, 10%) as a white solid. Example 106: 1 H NMR:δ 1.80-1.90(m,2H),1.91-2.10(m,2H),2.63-2.78(m,4H),3.08(d,2H).3.80(t,2H),4.60 -4.70(m,1H),7.34(dd,1H),7.67(s,1H),7.73(d,1H),8.06(s,1H),10.34(s,1H).m / z(ES + ),[M+H] + =314.3. Example 107: 1 H NMR:δ 1.90-2.06(m,4H),2.65(t,2H),2.73(t,2H),3.09(d,2H),3.79(t,2H),4.48-4.58(m,1H),7.19(dd,1H),7.58-7.59(m,2H),8.41(s,1H),δ 10.32(s,1H).m / z(ES + ),[M+H] + =314.2.

[0586] Intermediates 108a and 108b: 5-bromo-1-(piperidine-4-yl)-1H-indazole and 5-bromo-2-(piperidine-4-yl)-2H-indazole [ka] TFA (15 mL) was added to a solution of a regioisomer mixture (2:1) of tert-butyl 4-(5-bromo-1H-indazole-1-yl)piperidine-1-carboxylate and tert-butyl 4-(5-bromo-2H-indazole-2-yl)piperidine-1-carboxylate (900 mg, 2.37 mmol, combined molar concentration) in DCM (15 mL). The resulting solution was stirred for 2 hours. The solvent was then removed under reduced pressure, and the title compound was obtained as a white solid in the form of a trifluoroacetate salt as an isomer mixture (2:1, 600 mg, 64% combined yield). The mixture was used in the next step without further purification. m / z(ES) + ),[M+H] + =280.1.

[0587] Intermediate 108c:5-bromo-1-(1-methylpiperidine-4-yl)-1H-indazole [ka] Paraformaldehyde (171 mg, 5.71 mmol) was added at room temperature to a mixture (2:1) of isomers of 5-bromo-1-(piperidine-4-yl)-1H-indazole 2,2,2-trifluoroacetate and 5-bromo-2-(piperidine-4-yl)-2H-indazole 2,2,2-trifluoroacetate in MeOH (20 mL) (750 mg, 1.90 mmol, combined molar concentration). The resulting mixture was stirred at room temperature for 2 hours, after which NaBH3CN (359 mg, 5.71 mmol) was added. The resulting mixture was stirred at room temperature overnight. The reaction mixture was quenched with saturated NaHCO3 aqueous solution (150 mL) and extracted with siRNA (2 × 150 mL). The combined organic extract was dried (Na2SO4) and concentrated. Purification using C-18FC (gradient: 0-40% MeCN (in water)) yielded the title compound (300 mg, 54%) as a white solid. 1H NMR:δ 1.81-2.00(m,2H),2.04-2.17(m,4H),2.23(s,3H),2.82-2.98(m,2H),4.50 -4.56(m,1H),7.48(dd,1H),7.73(d,1H),7.99(d,1H),8.06(s,1H).m / z(ES + ),[M+H] + =294.0.

[0588] Example 108: 1-(1-(1-methylpiperidine-4-yl)-1H-indazole-5-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Ephos (9.1 mg, 0.017 mmol) and Ephos Pd G4 (15.6 mg, 0.0170 mmol) were added to a degassed mixture of Cs2CO3 (332 mg, 1.02 mmol), dihydropyrimidine-2,4(1H,3H)-dione (116 mg, 1.02 mmol), and 5-bromo-1-(1-methylpiperidine-4-yl)-1H-indazole (100 mg, 0.340 mmol) in 1,4-dioxane (10 mL) at room temperature under N2 conditions. The resulting mixture was stirred at 100°C for 15 hours. The mixture was then diluted with THF, filtered, and washed with THF. The filtrate was concentrated. The substance was obtained by purification using C-18FC (gradient: 0-100% MeCN (in water)), and this was further purified by preparative HPLC (column B, eluent B, gradient: 13-20%) to obtain the title compound (10.3 mg, 9%) as a white solid. 1 H NMR:δ 10.40(br s,1H),8.07(s,1H),7.73(d,1H),7.67(s,1H),7.34(d,1H),4.54-4.63(m,1H),3.8 0(t,2H),2.90(d,2H),2.74(t,2H),2.24(s,3H),2.10-2.19(m,4H),1.82-1.93(br s,2H).m / z(ES + ),[M+H] + =328.1

[0589] Intermediate 109a: tert-butyl 4-(6-bromo-2H-indazole-2-yl)piperidine-1-carboxylate [ka] 4-bromo-2-nitrobenzaldehyde (2.00 g, 8.70 mmol) was added at room temperature to a solution of tert-butyl 4-aminopiperidine-1-carboxylate (1.92 g, 9.59 mmol) in iPrOH (24 mL). The resulting mixture was stirred at 80°C for 4 hours, after which tri-n-butylphosphine (6.44 mL, 26.1 mmol) was added. The resulting mixture was stirred at 80°C overnight. The solvent was then removed under reduced pressure. Purification by FSC (gradient: 0-18% siRNA (in petroleum ether)) yielded the title compound (3.00 g, 91%) as a white solid. 1 H NMR:δ 1.43(9H,s),1.84-2.03(2H,m),2.05-2.16(2H,m),2.84-3.07(2H,m),4.04-4.15(2 H,m),4.71(1H,tt),7.14(1H,dd),7.69(1H,dd),7.87(1H,dt),8.51(1H,d).m / z(ES + ),[M+H] + =382.1.

[0590] Intermediate 109b: tert-butyl 4-(6-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-2H-indazole-2-yl)piperidine-1-carboxylate [ka] Ephos Pd G4 (60.4 mg, 0.0658 mmol) was added at room temperature under N2 to a degassed mixture of tert-butyl 4-(6-bromo-2H-indazole-2-yl)piperidine-1-carboxylate (500 mg, 1.31 mmol), dihydropyrimidine-2,4(1H,3H)-dione (450 mg, 3.94 mmol), Ephos (35.2 mg, 0.0658 mmol), and Cs2CO3 (857 mg, 2.63 mmol) in 1,4-dioxane (10 mL). The resulting mixture was stirred at 100°C for 16 hours. The solvent was then removed under reduced pressure. Purification by FSC (gradient: 0 to 100% siRNA (in petroleum ether), followed by maintenance at 100% siRNA for 10 minutes) yielded the title compound (500 mg, 92%) as a white solid. 1 H NMR:δ 1.41(9H,s),1.84-2.03(2H,m),2.03-2.16(2H,m),2.71(2H,t),2.86-3.05(2H,m),3.81(2H,t),3.96-4. 20(2H,m),4.60-4.76(1H,m),7.01(1H,dd),7.48(1H,s),7.65(1H,dd),8.43(1H,d),10.35(1H,s).m / z(ES + ),[M+H] + =414.2.

[0591] Example 109: 1-(2-(piperidine-4-yl)-2H-indazole-6-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] A solution of 1,4-dioxane in HCl (4M, 10.0 mL, 40.0 mmol) was added at room temperature to a solution of tert-butyl 4-(6-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-2H-indazole-2-yl)piperidine-1-carboxylate (500 mg, 1.21 mmol) in DCM (10 mL). The resulting mixture was stirred at room temperature for 2 hours. The solvent was then removed under reduced pressure. Purification with C-18FC (gradient: 0-30% MeCN (in water) (10 mmol NH4HCO3)) yielded the title compound (400 mg, 95%) in the form of a hydrochloride salt as a white solid. 1 H NMR:δ 1.87-2.12(4H,m),2.59-2.69(2H,m),2.74(2H,t),2.84-3.18(2H,m),3.83(2H,t),3.99-4.22(1H ,m),4.51-4.79(1H,m),7.02(1H,dd),7.50(1H,d),7.67(1H,d),8.42(1H,s),10.37(1H,s).m / z(ES + ),[M+H] + =314.2.

[0592] Example 110: 1-(2-(1-methylpiperidine-4-yl)-2H-indazole-6-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] Sodium triacetoxyborohydride (127 mg, 0.599 mmol) was added at room temperature to a mixture in DCM (5 mL) of 1-(2-(piperidine-4-yl)-2H-indazole-6-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride (70.0 mg, 0.200 mmol), formaldehyde (11.0 μL, 0.399 mmol), AcOH (23.0 μL, 0.402 mmol), and NaOAc (49.2 mg, 0.600 mmol). The resulting mixture was stirred at room temperature for 2 hours. The solvent was then removed under reduced pressure. Purification with C-18FC (gradient: 0-40% MeCN (in water) (10 mmol NH4HCO3)) yielded the title compound (40.0 mg, 61%) as a white soli...

Claims

1. Equation (I): 【Chemistry 1】 [In the formula, A is a BRD4 bond unit; Z is, 【Chemistry 2】 And, v is 0; R A does not exist; The linker is a saturated, partially or fully unsaturated framework comprising C and H atoms and at least one heteroatom, wherein the framework has bonding endpoints "a" and "b" and the minimum length between "a" and "b" is 6 to 26 atoms; wherein the framework may include one or more linear and / or branched and / or ring chains, which are optionally substituted with one or more F atoms on any available C atoms; Y is: 【Transformation 3】 (In the formula, Y Ａ and Y Ｂ Together, they represent CH-CH or C=C, and Y Ａ and Y Ｂ (Each of these is independently substituted with H, F, CN, or Me.) A compound of or a pharmaceutically acceptable salt thereof.

2. The compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the framework of the linker is a saturated or partially unsaturated framework.

3. The compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the framework of the linker comprises at least two heteroatoms selected from C and H atoms and N and O.

4. The framework of the linker comprises 2 to 10 heteroatoms, wherein the compound of formula (I) according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof.

5. A compound of formula (I) according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein the total number of carbon and heteroatoms in the linker framework is 8 to 30.

6. A compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, wherein Y is selected from 6-fluoro-2,4-dioxohexahydropyrimidine-1-yl, 6-fluoro-2,4-dioxopyrimidine-1-yl, 2,4-dioxopyrimidine-1-yl, 6-methyl-2,4-dioxopyrimidine-1-yl, and 2,6-dioxohexahydropyrimidine-1-yl.

7. A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein Y is 2,6-dioxohexahydropyrimidine-1-yl.

8. A pharmaceutical composition comprising a compound of formula (I) described in any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof as an association with a pharmaceutically acceptable excipient.

9. A pharmaceutical composition for use in the treatment of cancer, comprising a compound of formula (I) according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof.

10. A pharmaceutical product comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 5.

11. A pharmaceutical product according to claim 10, for use in therapeutic purposes.

12. The pharmaceutical product according to claim 10, for exerting a protein-degrading effect in warm-blooded animals such as humans.

13. A pharmaceutical product according to claim 10 for preventing or treating cancer.

14. A pharmaceutical agent according to claim 10 for preventing or treating solid tumors.

15. The pharmacopoeia according to claim 10 for preventing or treating tumor types that are sensitive to inhibition and / or degradation of BRD4.

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