 tricyclic gyrase inhibitors
专利摘要:
TRICYCLICAL GYM INHIBITORS. Compounds with the structure of Formula I and pharmaceutically suitable salts, esters and prodrugs thereof, which are useful as tricyclic gyrase inhibitors effective as antibacterials are disclosed herein. Related pharmaceutical compositions and methods for making the compounds are also contemplated. 公开号:BR112013023266B1 申请号:R112013023266-8 申请日:2012-03-14 公开日:2020-12-29 发明作者:Daniel Bensen；John Finn；Suk Joong Lee；Zhiyong Chen；Thanh To Lam；Xiaoming Li；Michael Trzoss；Michael Jung；Toan B. Nguyen；Felice LIGHTSTONE；Leslie William Tari；Junhu Zhang；Paul Aristoff 申请人:Lawrence Livermore National Security, Llc；Merck Sharp & Dohme Corp； IPC主号:
专利说明:
CROSS REFERENCE TO RELATED ORDERS [001] This application claims priority under 35 U.S.C. § 119 (e) for US Provisional Application No. 61 / 453.011, filed on March 15, 2011, which is incorporated by reference into this document. APPROVAL FOR RESEARCH AND DEVELOPMENT PROMOTED BY THE FEDERAL GOVERNMENT [002] This claimed invention was made with government support under Contract No. HHSN272200800042C, granted by the National Institute of Allergy and Infectious Diseases. PARTIES TO THE JOINT RESEARCH AGREEMENT [003] The claimed invention was made under a joint research agreement between Trius Therapeutics, Inc. and Lawrence Livermore National Security, LLC, through its United States Department of Energy, Contract No. TC02128.0. FUNDAMENTALS [004] The present disclosure concerns the field of medical chemistry and, in particular, compounds and pharmaceutical compositions thereof, which are useful as antibiotics. In particular, tricyclic gyrase compounds inhibit DNA from Gyrase B (GyrB) and Topoisomerase IV enzymes (ParE). Related methods of treating bacterial infections and methods of making compounds using new intermediates are also contemplated. Description of the Related Art [005] Bacterial infections pose an ongoing medical problem due to the fact that antibacterial drugs eventually generate resistance in the bacteria against which they are used. Consequently, there is a need for new drugs effective against pathogenic bacteria for use in therapy and prophylaxis of bacterial infections. [006] A target for the development of antibacterial drugs has been the DNA of Girase B (GyrB) and Topoisomerase IV enzymes (ParE), necessary for DNA replication. Girase inhibitors have been published in RE40.245, a document that is incorporated here in its entirety by reference. [007] The GyrB enzyme receptor was characterized in detail in Wigley, DB. et al., Nature, 351 (6328), 624-629, 1991. See also Tsai FT, et al., The high-resolution crystal structure of a 24- kDa gyrase B fragment from E. coli complexed with one of the most potent coumarin inhibitors, clorobiocin, Proteins. 1997 May; 28 (1): 41-52. [008] The ParE enzyme receptor was characterized in detail in Bellon, S., et al. Crystal structures of Escherichia coli topoisomerase IV ParE subunit (24 and 43 kilodaltons): a single residue dictates differencesin novobiocin potency against topoisomerase IV and DNA gyrase, Antimicrob. Chemother Agents. 48: 1856-1864 (2004). These references are incorporated in their entirety into this document by reference. [009] Conversely, patent publications naming Hurley et at. as inventors, they target protein kinase inhibitors, which are useful for protein kinase-mediated diseases and conditions like cancer. See, for example, US 2008/0051414, US 2009/0143399 and US 2009/0099165. SUMMARY [0010] Formula I tricyclic gyrase compounds inhibit Girase B DNA (GyrB) and Topoisomerase IV enzymes (ParE). The compound of Formula I has the structure Formula I [0011] Pharmaceutically suitable salts, esters and prodrugs are also contemplated. The variables in Formula I are as follows. [0012] L can be O or S. [0013] R8 can be H or an interaction substituent with a length of about 1  to about 5  from the point of carbon attachment in ring A to the terminal atom at R8 and a width of about 3.3  or less . [0014] X, Y and Z can be independently selected from the group consisting of N, CRX, CRY and CRZ, respectively, as long as no more than X, Y and Z are N. RX can be H or an interaction substituent with a length of about 1 Å to about 2 Å from the carbon in CRX to the terminal atom in RX. RY can be H or an interaction substituent of about 1  to about 3  in length from the carbon in CRY to the terminal atom in RY. RZ can be H or an interaction substituent with a length of about 1 Å to about 2 Å from the carbon in CRZ to the terminal atom in RZ. [0015] R2 may be a 6-membered heteroaryl or aryl ring containing 0-3 O, S or N hetero atoms, optionally substituted by 0-3 non-interfering substituents, where 2 adjacent non-interfering substituents on R2 may form one or more rings fused with the 6-membered heteroaryl or aryl ring. In some respects, the 6-membered heteroaryl or aryl ring of R2 has a CH in the positions immediately adjacent to the position where R2 is attached to L. [0016] R4 can be: H; an optionally substituted OR; an optionally substituted secondary or tertiary amine attached to ring C via the secondary or tertiary amine N; or a 5-10 membered, optionally substituted, unsaturated cyclic or heterocyclic residue containing 0-3 N, O or S hetero atoms. [0017] The optional substituent can be 0-3 non-interfering substituents. Rapode may be 5-6 membered aryl or heteroaryl containing 0-3 O, S or N hetero atoms optionally substituted by 0-3 non-interfering substituents. In some respects, R4 does not protrude more than about 3  below the plane of rings A, B and C relative to the GyrB / ParE ligand receptor bottom in the linked conformation. Additionally, in some aspects, R4 does not interfere sterically with R2 or Z when the compound is in the linked conformation. [0018] Methods of using the compound to treat antibacterial infections and methods of making the compounds using new intermediates are also contemplated. [0019] These and other related aspects are set out in more detail below. BRIEF DESCRIPTION OF THE FIGURES [0020] Figure 1 illustrates a schematic representation of the receptor restrictions on the compound, particularly the ways of binding the tricyclic inhibitors to the GyrB / ParE active site receptor (from crystallography data). The measurements provided for the lengths are measured from the atom center of the ring member A to the atom center of the nearest non-hydrogen atom at the active site receptor. The figure indicates a length of about 6 Å to about 8 Å from atom C attached to R 8 to the atom at the active site receptor; about 4 Å to about 5 Å from ring atom A from X to the atom at the active site receptor; about 4 Å to about 6 Å from ring atom A of Y to the atom at the active site receptor; and about 4 Å to about 6 Å from ring atom A from Z to the atom at the active site receptor. The relative positions of the R8, R4 and R2 cyclic substituents are shown. The approximate shape of a cross section of a representative GyrB / ParE active site receptor on and on the plane of the tricyclic structure (i.e., rings A, B and C) is shown. The dashed area with continuous lines describes regions of the inhibitor, which are covered on both surfaces by the active site receptor. In addition, the approximate shape of a cross section of a representative GyrB / ParE active site receiver below the plane of the tricyclic structure is shown. The dashed area with dashed lines describes regions of the inhibitor that makes contact with the bottom surface of the active site receptor, while the plane above the tricyclic ring system is exposed to solvent. The approximate position of the Asp side chain that links conserved substrate and structural water molecule is shown in Figure 1, along with the constellation of potential hydrogen bonds (described with dotted lines), observed between the tricyclic structure, Asp and water. The faces of the exposed solvent and the solvent housed in the positive location receiver are highlighted. The solvent refers to the in vivo surroundings of the active GyrB / ParE site as part of a protein, which generally includes an environment in which the protein is located within a cell. Therefore, R4 moisture, in some respects, does not project atoms larger than about 3  below the plane of the tricyclic ring system relative to the GyrB / ParE binding receptor bottom in the bound state. [0021] Figure 2 illustrates a schematic representation of the intramolecular restrictions in the compound, where R2 is a 6-membered ring. Specifically, the molecular geometry and conformations of the R groups necessary to allow binding of tricyclic inhibitors to GyrB / ParE active site receptors restrict the size and composition of substituents at certain positions in the inhibitor structure. The figure illustrates regions of potential steric interference between the R4 substituent and the R2 or Rz substituent in the linked conformation. [0022] Figure 3 illustrates an example of relative positions of a primary amine that is enclosed within R4 when linked to GyrB / ParE. This illustration also applies to a secondary amine, which is not shown in Figure 3. The volume occupied by the R4 amine with respect to the tricyclic structure through the amines was determined using a four-point trilateration procedure based on the distances between the amine R4 and four different atoms in the tricyclic structure from 17 different crystal structures of E. faecalis GyrB complexes with tricyclic inhibitors containing a diverse set of R4 amines comprising a secondary or tertiary amine attached to ring C via the secondary or tertiary amine N and a primary or secondary amine that is not attached to ring C. The relative position of the primary (or secondary amine not shown) would be above the plane of the tricyclic structure, in order to avoid overloading the bottom of the active site. DETAILED DESCRIPTION [0023] Certain aspects of the compounds of Formula I are elaborated below. In Formula I above, L is a link that links R2 to ring C. L can be O or S. In some ways, L is O. In some ways, L is S. [0024] As used here, the term "aryl" refers to the optionally substituted fused and monocyclic hydrocarbon half. Any fused or monocyclic bicyclic ring system that has aromatic characteristics in terms of electron distribution throughout the ring system is included in this definition. Typically, ring systems contain atoms with 5-12 members in the ring. "Heteroaryl" refers to optionally substituted fused bicyclic and aromatic monocyclic heterocycles containing one or more heteroatoms selected from N, O and S. The inclusion of a heteroatom allows the inclusion of 5-membered rings as well as 6-membered rings. [0025] As used herein, the term "alkyl" includes straight chain, branched chain and cyclic monovalent substituents. Examples include methyl, ethyl, propyl, isopropyl and cyclopropyl. Where indicated, alkyl substituents may contain 1-10C (1 to 10 carbon atoms), such as 1-3C, 1-6C or 1-8C. [0026] As used in this document, “hydrocarbon residue” refers to a waste that contains only carbon and hydrogen. The hydrocarbyl residue can be saturated or unsaturated, aliphatic or aromatic, linear, branched or cyclic chair, including an individual ring, a fused ring system, a connecting ring system, or a spiro ring system, or a combination hydrocarbon groups. The hydrocarbyl residue, when so established, however, may contain heteroatoms above and on the carbon and hydrogen members of the substituting residue. Thus, when specifically noted to contain such heteroatoms, the hydrocarbon residue can also contain heteroatoms, such as O, S or N within the “backbone” of the hydrocarbil residue. A hydrocarbyl group can include a hydrocarbyl combination containing halves, such as a heterocyclic group, attached to a heteroalkyl containing a combination of a straight chain alkyl and a cycloalkyl group. [0027] As used in this document, "cyclic residue" refers to a cyclic hydrocarbil residue, which contains only carbon and hydrogen. The cyclic residue, when established in this way, however, may contain heteroatoms above and on the carbon and hydrogen members of the substituent residue. Therefore, when specifically noted to contain such heteroatoms, the heterocyclic residue can also contain heteroatoms, such as O, S or N within the "backbone" of the cyclic residue. In some respects, when so established, the cyclic residue is a cycloaliphatic or cycloheteroaliphatic residue. A saturated cycloaliphatic or saturated cycloheteroaliphatic residue refers to a ring containing saturated bonds between each ring member. [0028] As used herein, "unsaturated cyclic residue" refers to at least partially unsaturated residue or aromatic cyclic hydrocarbon residue, which contains only carbon and hydrogen. The unsaturated cyclic residue, when established in this way, however, may contain heteroatoms above and on the carbon and hydrogen members of the substituting residue. Therefore, when specifically noted to contain such heteroatoms, the unsaturated heterocyclic residue can also contain heteroatoms, such as O, S or N within the "backbone" of the unsaturated cyclic residue. [0029] The term "members" or "with members", in the context of heterocyclic and heteroaryl groups, refers to the total of atoms, carbon or N, O and / or S heteroatoms, which form the ring. Thus, an example of a 6-membered saturated cycloheteroaliphatic ring is piperidine and an example of a 6-membered heteroaryl ring is pyridine. [0030] The linked conformation refers to the conformation (that is, the spatial arrangement of atoms), which the compound tricyclic gyrase would assume if it were bound to the GyrB / ParE active site receptor inside the enzyme. In use, the compound can interact with the active site receptor and inhibit ATPase activity. When the compound is attached to the GyrB / ParE active site receptor, some substitutes interact with certain amino acids, and so the ability of the substituent to rotate freely over a link is restricted. Therefore, more useful measures can be taken to determine relevant distances to determine the dimensions of suitable substituents. When indicated, measurements are based on the relative positions of substituents on the compound, while the link is hypothetically linked to the GyrB / ParE active site receptor. References to the linked conformation, with respect to the compound, should not be construed as literally comprising the GyrB / ParE active site receptor in combination with the compound. The linked conformation is characterized via measurements derived from a three-dimensional structure derived from x-ray crystallography data in the inhibitor complexed with a protein construct that normally encompasses the ATP binding domain of 24 or 46 kDa from one or more ParE ortologists. Representative bacterial GyrB. Given the high degree of sequence identity between GyrB and ParE enzymes in various pathogenic organisms of interest, structural information derived from a protein orthologist from any pathogen of clinical relevance should be sufficient to describe the linked conformation. Briefly, crystallographic structures are generated using the following methods: proteins of interest (for example, E. faecalis GyrB, E. coli GyrB, F. tularensis ParE or E. coli ParE) are generated in a standard E expression system coli. The open reading frames are cloned into a plasmid expression (for example, pET28A) and expressed in an appropriate E. coli expression strain (for example, BL21 (DE3)). For crystallography, the 24 kDa and 46 kDa ATP binding domains are cloned with a C (His) 6 tag to assist in purification by metal affinity chromatography. This robust chromatography step usually yields more than 80% pure protein. Polishing steps including ion exchange and size exclusion chromatography are performed, as needed, until satisfactory purity (> 95%) is achieved. Once the purified protein is available, GyrB or ParE complexes and the inhibitor molecule of interest are generated by mixing a stoichiometric excess of the inhibitor of interest with the recombinant protein target in solution and crystallizing the complex using established crystallization methods (typically, vapor diffusion, as described in Drenth J. (1999). In Principles of protein x-ray crystallography, 2aEd. Springer, New York). Once crystallized, x-ray diffraction data is collected in single crystals of protein inhibitor complexes using monochromatic x-rays generated by a rotating anode or synchrotron radiation source. X-ray data processing, analysis and subsequent structure solution and refinement are performed using well-established computational methods (reviewed in Drenth J. (1999) In Principles of protein x-ray crystallography, 2nd Ed. Springer, New York ). [0031] Interaction substituents on the compound, which interact with the GyrB / ParE active site receptor, include those substituents that would be located inside the protein when the compound is in the linked conformation. Interactions of interaction substituents generally include hydrophobic interactions (which favor the apposition of lipophilic surfaces in the inhibitor and the active site receptor), and electrostatic interactions, such as Van der Waals, dipole-dipole, coulombic interactions or hydrogen bonding between atoms in the compound and atoms in the GyrB / ParE active site receptor. For example, R8, RX, RY and RZ interact with various portions of the interior of the protein. If R8, RX, RYou RZ is NH2 or NHR (where R is, for example, a small alkyl group), the H atom (s) in nitrogen can interact with electronegative atoms, such as nitrogen or oxygen, located nearby in the GyrB / ParE active site receptor to which the compound can bind. When R8, RX, RY and RZ are non-polar (for example, a methyl group), the interaction substituent can also electrostatically interact with an atom inside the protein via Van der Waals interactions, and remove the complementary solvent from lipophilic surfaces at the active site receptor to form favorable hydrophobic interactions. Additionally, in some respects, the shape and size of the active site may place restrictions on the dimensions of the substituents on the compounds that would be sterically compatible with the active site receptor. [0032] Where indicated, the dimensions of a substituent can be provided and are associated with the dimensions of the receptor in which the compound would be located, if it were in a linked conformation. For example, the length of a substituent can be given based on its distance from the atom in the tricyclic structure to the atom of the substituent that is positioned the furthest from the tricyclic structure, that is, the terminal atom. The distance is measured based on the center of a first atom, such as a C, in the tricyclic structure, in relation to the center of the terminal atom. The distance is measured from point to point in a straight line, in view of the fact that the bonds in the substituent are not linearly aligned, as in an ethyl or OH substituent. [0033] The width of the R8 substituent can be understood with respect to the size of the active site receptor in which the R8 (R8 receptor) resides, and with respect to the R8 substituent when it adopts a conformation in the R8 receptor, when the compound is in the linked conformation. The R8 substituent generally projects into the R8 receptor along an axis that projects through atom C in ring A, which is attached to R8, and atom C in the same ring at the meta position, which shares a common C atom with the B ring when the compound is in the bonded conformation. The width of the R8 substituent refers to the width at its largest point, measured from the center of the atom to the center of the atom that is farthest and approximately perpendicular about an axis, when the compound is in the linked conformation. Therefore, the R8 substituent may be able to adopt a conformation when the compound is in the bonded conformation, having a width that does not exceed around 3.3 Å. For example, the NHMe half on the R8 has a width of approximately 2.8 Â. This width is derived by adding the distance from the center of the atom of a methyl proton trans-oriented in relation to the N-H proton perpendicularly from the axis described above, with the distance from the center of the N-H proton perpendicularly from the same axis. In addition, the width of a cyclopropyl substituent would be approximately 3.1 Å, measured as the distance between the proton centers on adjacent carbon atoms on opposite faces of the cyclopropyl ring. [0034] R8 may be H or an interaction substituent with a length of about 1  to about 5  from the point of carbon attachment in ring A to the terminal atom at R8 and a width of about 3.3  or less. The length of R8 is appropriate to the length from the carbon of tricyclic structure for the active site receptor based on crystallography data, which is from about 6  to about 8 Â, as shown in Figure 1. In some respects , R8 is H, Cl, F, Br, NH2, OH, 1-3C alkyl, amino-1-3C alkyl, aminocyclopropyl, OCH3, OCH2CH3, cyclopropyl, CH2cyclopropyl, CH2C1, CH2F, CHF2, CF3, CH2CH2F, CH2CHF2, CH2CF3, NHNH2, NHOH, NHNHCH3, NHOCH3, NHCD3, SCH3, or NHCOH, where D is deuterium. In some respects, R8 is H, Cl, F, Br, NH2, 1-3C alkyl, amino-1-3C alkyl, aminocyclopropyl, OCH3, OCH2CH3, cyclopropyl, CH2cyclopropyl, CH2C1, CHCL2, CH2F, CHF2, CF3, CH2CH2F, CH2CHF2 , CH2CF3, NHNH2, NHOH, NHNHCH3, NHOCH3, NHCD3, SCH3, or NHCOH. For example, R8 may be H, CH3, CH2CH3, Cl, OCH3, NHCD3, NHCH3, NHCH2CH3, or NH2, such as NHCH3. [0035] X, Y and Z can be independently selected from the group consisting of N, CRX, CRY and CRZ, as long as no more than two of X, Y and Z are N. RX can be H or is an interaction substituent with a length of about 1  to about 2  ° from the carbon in CRX to the terminal atom in RX. RY can be H or an interaction substituent of about 1  to about 3  in length from the carbon in CRY to the terminal atom in RY. For example, RY would not be a methoxy substituent due to the fact that a methoxy substituent is longer than 3 Â. RZ can be H or an interaction substituent with a length of about 1 Å to about 2 Å from the carbon in CRZ to the terminal atom in RZ. These lengths of CRX, CRY and CRZ are appropriate compared to the lengths from the carbon of tricyclic structure in relation to the active site receptor, based on the crystallography data shown in Figure 1. In some respects, X, Y and Z are CRX, CRYe CRZ, respectively. RX can be H, CH3, Cl, Br, or F, such as H or F. RY can be H, CH3, CHF2, CF3, CN, CH2CH3, Cl, Br or F, such as H, F, Cl or CF3. Rz can be H, CH3, Cl, Br or F, such as H, CH3 or F. [0036] Without being bound by theory, R2 can be useful for conferring selectivity and potency against ATP-binding eukaryotic proteins, such as kinases and HSP90. Therefore, one of the benefits of the compound includes avoidance of toxicity due to off-target binding, such as a kinase, due in part to the selectivity of R2 as part of the compound. In general, in some respects, the compounds are not potent inhibitors for eukaryotic kinases. In some respects, R2 is a 6-membered heteroaryl or aryl ring containing 0-3 O, S or N hetero atoms, optionally substituted by 0-3 non-interfering substituents, where 2 adjacent non-interfering substituents on R2 may form one or more rings fused with the 6-membered heteroaryl or aryl ring. For example, R2 may be a 6-membered heteroaryl or aryl ring containing 0-3 O, S or N heteroatoms, optionally substituted, such as pyrimidinyl, phenyl or pyridyl. In some respects, R2 is a heteroaryl ring, such as a 6-membered heteroaryl. In some respects, R2 can be attached to L via a carbon atom in the 6-membered heteroaryl or aryl ring. Without being bound by theory, solvent-protected faces of GryB / ParE active site receptors can restrict the size of the substituents in the compound near those solvent-protected faces. Thus, with respect to R2, the 6-membered heteroaryl or aryl ring may contain a CH in the ring positions immediately adjacent to the position where R2 is attached to L. In some respects, there is no N in the 6-membered heteroaryl or aryl ring in R2nas ring positions immediately adjacent to the ring position where R2 is attached to L. [0037] Figure 2 illustrates R2 as an optionally substituted 6-membered heteroaryl ring, although the positioning of the substituents also applies to a 6-membered aryl ring. In this illustration, A and E are C. Rbe Facing the solvent in the limit conformation and thus the substituents in this position can be varied and can include prodrugs. Cycling between Rbe Rc may be allowed. Rd is partially exposed solvent, and cyclization between Rce Rd (for example, with an H-bond acceptor in the Rd position) may be allowed. Large substituents, such as large groups branched in Rd, can collide with the outer edge of the receptor. [0038] In some respects, the optionally substituted aryl or heteroaryl ring of R2 in the 6-membered combination with one or more fused rings formed between the optional substituents can be selected from the group consisting of optionally substituted indolyl, azaindolyl, pyrimidopyridyl, quinazolinyl, quinoxalinyl , naphthyridinyl, purinyl, imidizopiridinil, furopyridinyl, isoindolilinil, benzodioxinyl, dihidrobenzodioxinil, benzothiazolyl, pirrolopiridinil, dihidropirrolopiridinil, benzimidazolyl, imidazopyridinyl, dihidroimidazopiridinil, tetrahidroisoindolil, chromenyl, benzthiophene, benztriazolil, benzfuranil, benzoxadiazolyl, indazolyl, quinolinyl, isoquinolinyl, indoline, azaindolinil or [0039] Faces exposed to the solvent of GyrB / ParE active site receptors allow portions of the compound to be exposed to a solvent environment when in use, as illustrated in Figure 1. In some respects, without interference, substituents may be soluble in water to provide compatibility with an aqueous solvent medium. Proportions of substituents in the direction of the potential of a solvent environment are not critical, but one skilled in the art would understand that steric clearance substituents are useful. Thus, the proportions of the substituents exposed to the solvent can be varied. [0040] In contrast to an "interfering substituent", certain positions of the molecule can be described as allowing "non-interfering substituents". This terminology is used because the substituents at these positions, in general, are less relevant to the activity of the molecule as a whole. A wide variety of substituents can be employed in these positions, and it is well within current knowledge to determine whether any particular substituent is arbitrary or not "non-interfering". [0041] As used herein, a "non-interfering substituent" is a substituent that leaves the Formula I compound's ability to inhibit bacterial growth of at least one type of bacteria qualitatively intact. For example, the non-interfering substituent would leave the compound's ability to provide antibacterial efficacy based on a minimum inhibitory concentration (MIC) less than 32 μg / ml, or based on inhibition of DNA Girase B (GyrB) ATPase activity or topoisomerase IV (ParE) of less than 10 nm. Thus, the substituent can change the degree of inhibition based on MIC or ATPase activity. However, while the Formula I compound retains the ability to inhibit bacterial / ATPase activity, the substituent will be classified as "non-interfering". A number of assays for determining MIC or the ability of a compound to inhibit DNA Girase B (GyrB) or topoisomerase IV (ParE) ATPase activity are available in the art, and some are exemplified in the Examples below. For example, a coupled spectrophotometric assay, in which the release of inorganic phosphate-dependent enzyme from ATP hydrolysis is measured, determines the inhibitory activity of a compound chosen arbitrarily during incubation with GyrB or stops after adding ATP. The characteristics related to the activity of the molecule are well defined. The positions that are occupied by "non-interfering substituents" can be replaced by conventional radicals, as is understood in the art. It is irrelevant to test the outer limits of such substitutions. The relevant characteristics of the compounds are those established with particularity here. [0042] R2 may have 0-3 substituents without interference from the 6-membered aryl or heteroaryl ring. For example, R2 may have a substituent selected from the group consisting of OH, CO2H, CN, NH2, Br, Cl, F, SO3H, SO2NH2, SO2CH3, SOCH3, NHOH, NHOCH3, and NO2. R2 may also have a substituent which is an optionally substituted C1-15 alkyl hydrocarbyl residue containing 0-5 0, S or N hetero atoms, optionally substituted with OH, CN = 0, NH2, NHOH = NOH, = NNH2 = NOCH3, Br , F, Cl, SO3H or NO2. Substitutions can be on a carbon atom or a hetero atom, thus allowing groups, such as S = O. In cases where the heteroaryl contains a pyridine ring, the nitrogen atom can be oxidized to an N-oxide of pyridine, thus, an OH substituent can be in the form of an oxide, thus, for example, allowing a pyridyl group having an N-oxide, where N is a ring hetero atom. The C1-15 alkyl hydrocarbyl residue containing 0-5 0, S or N heteroatoms can include a combination of hydrocarbyl groups, such as a combination of aliphatic or chain rings and aromatic rings bonded together. [0044] In some respects, two adjacent substituents in the non-interfering form R2um or more fused rings. For example, the combination of one or more fused rings with the 6-membered aryl or heteroaryl ring of R2 contains 5-15 members, and 0-5 0, S or N, optionally substituted by hetero atoms, such as with OH, = 0 , CN, NH2, Br, F, or Cl. [0045] Optional substituents can occupy all positions of the R2 ring structure that are not adjacent to a linker, such as position, positions 1-2 or positions 1-3. In some ways, a position is optionally replaced. These substituents can optionally be substituted with substituents similar to those listed. Of course, some substituents, such as halogen, are not yet substituted, as is known to one skilled in the art. [0046] In some respects, the R2 symbol may be pyrimidinyl or pyridinyl optionally substituted by CH (OH) CH3, C (OH) (CH3) 2, OCH3, CN, CH3, CH2CH3, 0-cyclopropyl, SCH3, Br, Cl, F, or NH2. [0047] Non-interfering substituents on the 6-membered aryl or heteroaryl ring of R2 that can be exposed to the solvent in the linked conformation may include large substituents, such as prodrugs. [0048] In some respects, the R2 symbol can be selected from among the substituents in the following Table 1. Graph 1 [0049] In some respects, R2 can be selected from the substituents in Graph 2 below. Graph 2 [0050] Figures 1 and 2 show that the compound is exposed to the solvent in the bonded conformation along the axis of the R4e connection in a scan of 0-90 ° to the left of the connection axis in R4. Choices for prodrugs and substituents on R4, therefore, can be varied. When selecting the R4 substituent, in some respects, the R4 groups do not interfere sterically with R2 or Z groups in the limit conformation, which is illustrated in Figure 2. An expert in the art would understand that, to avoid steric interference, atoms in R4 should not approach atoms in R2 or Rz (in the linked conformation) such that the inter-atomic distances of the nearby atoms are less than the sum of their van der Waals rays. [0051] Additionally, in some respects, the R4 substituent does not protrude more than about 3  below the plane of rings A, B and C in relation to the GyrB / ParE binding receptor in the linked conformation. "In relation to the GyrB / ParE bottom connection receiver" refers to the non-projection greater than about 3  below the plane within about 5-6 connections from the point of attachment of the R4 to the structure. Thus, portions of R4 that extend greater than about 5-6 bonds distant from the point of attachment of R4 to ring C can be projected larger than about 3  below the plane of rings A, B and C, since these portions are not constrained by the bottom of the GyrB / ParE binding receiver. [0052] The distance is defined as the particular distance from the plane aligned with the atom centers of the tricyclic structure to the center of the most distal atom (from the plane) in the substituent R4 in the linked co-formation. [0053] In some ways, R4 can be H. [0054] In some respects, R4 can also be an optionally substituted ORa; where Ra is a 5-6 membered heteroaryl or aryl containing 0-3 O, S or N hetero atoms optionally substituted with 0-3 non-interfering substituents. In some respects, the ring positions adjacent to the position where O is attached to Rapodem may be substituted for small substituents, such as those having 2 atoms in the backbone, such as OCH3, CH3, CH2CH3, OH, NH2, F, Cl, Br, I or NO. In the remaining positions, substituents can be wider and diverge, since substituents in these positions are solvents exposed in the bonded conformation. In some respects, Ra is an optionally substituted pyrimidinyl or pyridinyl, such as an unsubstituted pyrimidinyl or pyrimidinyl substituted by CH3 or NH2. In some respects, ORa is one of the following substituents in Graph 3. Graph 3 [0055] In some respects, R4 may be an optionally substituted secondary or tertiary amine attached to ring C through secondary or tertiary amine N. “Secondary amine” refers to a substituent containing N that contains an H attached to secondary amine N, when the substituent is attached to the rest of the molecule. "Tertiary amine" refers to a substituent containing N that does not contain H attached to tertiary amine N, when the substituent is attached to the rest of the molecule. [0056] When R4 is the optionally substituted secondary or tertiary amine attached to ring C via the secondary or tertiary amine N, R4 may additionally comprise a primary or secondary amine, wherein the primary or secondary amine is not directly attached to ring C "Primary amine" refers to an amine group that contains two H atoms attached to primary N amine, when attached to the rest of the substituent. With respect to the "secondary amine" that is not directly attached to ring C, in this case, the secondary amine refers to an amine group that contains an H atom attached to the secondary amine N, when attached to the rest of the substituent. The primary or secondary amine that is not directly attached to the C ring can be positioned on the compound in the bonded conformation, where: a) the distance between the C or N atom of Y and the primary or secondary amine N is about 7  at about 10.5 Å; b) the distance between atom C to which R8 is attached and the primary or secondary amine N is about 6  to about 9 Â; c) the distance between atom C to which R4 is attached and the primary or secondary amine N is about 3.5 Å to about 6 Å; and d) the distance between atom C to which R2 is attached and the primary or secondary amine N is from about 5 Å to about 7.5 Å. [0057] "Not directly attached to ring C", with respect to the primary or secondary amine, refers to the lack of a bond joining the primary or secondary amine to ring C. [0058] In some respects, R4 may be an optionally substituted tertiary amine which is a 4-14 membered, optionally substituted, saturated cycloheteroaliphatic tertiary amine ring containing 1-3 N atoms, 0-3 O atoms and 0-1 atoms S; and wherein the 4-14 membered saturated cycloheteroaliphatic ring system is an individual ring, a fused ring system, a bridged ring system or a spiro ring system. [0059] In some respects, R4 may be the optionally substituted tertiary amine attached to ring C via tertiary amine N, where the optionally substituted tertiary amine contains at least one additional N separated from tertiary amine N by 2-3 atoms. The atoms separating the N's need not be located on the same ring. For example, an atom separating the N's can be in a ring and the second atom can be found in a substituent, or both atoms separating the N's can be in the backbone, or a substituent on or in the same or different rings. [0060] In some respects, the optionally substituted secondary or tertiary amine of R4 is one of the following substituents in Graph 4. Graph 4 [0061] In some respects, R4 may be a non-cyclic secondary or tertiary amine substituted by 1-2 non-interfering substituents. [0062] In some respects, R4 may be selected from the group consisting of optionally substituted pyrazolyl, phenyl, piperazinyl, pyridinyl and tetrahydropyridinyl. [0063] In some respects, R4 may be a cyclic or heterocyclic unsaturated residue with 5-10, optionally substituted, containing 0-3 N, O or S heteroatoms. Optional substituents can include 0-2 optional substituents selected from the group consisting of CH3, NH2, F, Cl and CH2NH2. In some respects, a 5-10 membered, optionally substituted unsaturated cyclic or heterocyclic residue containing 0-3 N, O or S heteroatoms of R4 is one of the following substituents in Graph 5. Graph 5 [0064] The optional substituent on R4 may include 0-3 non-interfering substituents. A non-interfering substituent on R4 may be a substituent selected from the group consisting of OH, NO, CO2H, CN, NH2, Br, Cl, F, SO3H and NO2 or is a C1-15 hydrocarbon residue containing 0-5 O, S or N heteroatoms, optionally substituted by OH, CN, = O, NH2, = NOH, = NNH2, = NOCH3, Br, F, Cl, SO3H or NO2. Substitutions can be in a C or in a hetero atom, thus allowing groups like S = O. In addition, an OH substituent can be in the form of an oxide, thus allowing, for example, that a pyridyl has an N oxide, where N is a ring heteroatom. The C1-15 hydrocarbyl residue containing 0-5 O, S or N heteroatoms can include a combination of hydrocarbyl groups, such as a combination of aliphatic rings or aromatic chains and rings bonded together. [0065] In some respects, R4 can be selected from substituents in Graph 6 below. Graph 6 [0066] The compound can be one among the compounds exemplified in the Examples. [0067] In some ways, the compound can be a compound in Graph 7. Graph 7 [0068] When compounds of Formula I contain one or more chiral centers, optically pure forms, as well as mixtures of stereoisomers or enantiomers, are also contemplated. [0069] Various processes of making the compounds are also contemplated. The substituents, unless noted, are the same substituents as those of Formula I. In some respects where R4 is an optionally substituted secondary or tertiary amine attached to ring C via the secondary or tertiary amine N, the process comprises treating with HR4 to make the compound of Formula I; and optionally further comprising, before the treatment step, protecting R8 with a protecting group, or protecting an amine in R4 which is not the secondary or tertiary amine N, if present, with a protecting group; and optionally remove the protection groups after the treatment step. [0070] Protective groups are useful for chemoselectivity and are known in the art. Typical protective groups included tert-butyloxycarbonyl (BOC) and carbobenzyloxy (Cbz). When the protecting group is BOC, an acid can be used for deprotection, the protecting group is Cbz, catalytic hydrogenation can be used for deprotection. [0071] Before the treatment step immediately above, the process can also comprise the compound of Formula II with R2LH under basic conditions, where G1 and G2 are abandonment groups selected independently from the group consisting of Cl, Br, F, I, SR, SOR, SO2R, OSO2R and O-benzotriazole (OBt); wherein R may be C1-8 alkyl, aryl or heteroaryl containing 0-5 O, S or N atoms, optionally substituted with C1-4 alkyl, C1-4 alkyloxy, Cl, Br, F, I or NO2, such as methyl , benzyl and p-methoxybenzyl, to make the compound having the structure [0072] In some respects, compounds in which R4 is an optionally substituted secondary or tertiary amine attached to ring C via the secondary or tertiary amine N, can also be made using a process comprising treating with R2LH under basic conditions, such as with the phenol anion, thiophenol, or heteroarylhydroxy heteroarylthiol, where the symbol G2 represents a separable group selected from the group consisting of Cl, Br, F and I, and optionally comprising additionally, before the treatment step immediately above, protecting R8 with a protecting group, protecting an amine or where R4 is not the secondary or tertiary amine N, if present, with a protecting group, and R8 and R4protection after the treatment step. [0073] Before the treatment step immediately above, the process may further comprise the reaction of the compound of Formula II where G1 is an abandonment group selected from the group consisting of Cl, Br, F and I. [0074] In some respects, when L is S, a process for making the compound in which R4 is optionally substituted secondary or tertiary amine, attached to ring C via the secondary or tertiary amine N, may comprise treating where G1 is a leaving group derived from SO2halide, bis (2-oxo-3-oxazolidinyl) phosphine (BOP) or benzotriazol-1-yl-oxitripyrrolidinophosphonium hexafluorophosphate (PyBOP), with HR4 to make the compounds here. This process may also optionally further comprise, before the treatment step immediately above, protecting R8 with a protecting group, protecting an amine or in which R4 is not the secondary or tertiary amine N, if present, with a protecting group, and R8e unprotecting R4 after the treatment step. [0075] Before the treatment step immediately above, the process may also comprise, react where G1X1 is SO2halide, bis (2-oxo-oxazolidinyl) phosphine (BOP) or benzotriazol-1-yl-oxitripyrrolidinophosphonium hexafluorophosphate (pyBOP). [0076] Before the treatment step immediately above, the process may additionally comprise coupling [0077] In another aspect, an intermediate compound has the structure of Formula II: or a protected amine intermediate thereof; where: G1 and G2 are leaving groups independently selected from the group consisting of SH, OH, Cl, Br, F, I, SR, SOR, SO2R, OSO2R, OAr, and OBt, R is C1-8 alkyl, aryl or heteroaryl; Ar is aryl or heteroaryl containing 0-5 0, S, or N atoms, optionally substituted with C1-C4 alkyl, C1-4 alkoxy, halogen or NO2; Bt is benzotriazole; R8 is an interaction substituent having a length of about 1 µ to about 5  from the point of attachment of the carbon in ring a to the terminal atom at R8 and a width of about 3.3  or less, and X, Y and Z are independently selected from the group consisting of N, CRX CRY and CRZ respectively, provided that no more than two of X, Y and Z are N, where Rx is H or an interaction substituent with a length of about 1  to about 2  from the carbon in CRX to the terminal atom Rx, where Ry is H or an interaction substituent with a length of about 1  to about 3  from the carbon in CRY to the atom terminal RY, where Rzé H or an interaction substituent having a length of about 1  to about 2  ° from the carbon in CRZ to the terminal atom of Rz, with a condition that R8 does not represent a CH3 group, and with a condition of when the symbol R8 represents OCH3, then Rx and Ryn are not OH. [0078] When the intermediate compound is an amine protected intermediate, one or more nitrogen atoms in the compound can be protected with carbobenzyloxy (Cbz), or BOC. G1 and G2 can be abandonment groups selected independently from the group consisting of tosylate, mesylate, triphylate, O-pyrimidine, S-phenyl and O-pyridine. [0079] The following schemes describe the aspects of reaction steps for making the starting materials, intermediates and compounds described herein, which are described in the Examples. The starting materials for the R2 and R4 substituents are commercially available or can be made by a person skilled in the art, using methods described in the literature. 1. General procedures for preparing the blindole core [4-5] tricyclic pimirido [0080] A wide variety of amines and substituted amines can be introduced into ring A of the pyrimidoindole system as shown in Scheme 1. Ortho-fluorine-Nitrobenzenes S1 can be readily displaced by amines to obtain the orthoamino S2 analogs. A protecting group can be introduced by incorporation into the starting material (as in S 3b) or introduced after the fluoroaryl displacement reaction (as in S 3c). With an alkyl or alkoxy group R8, nitration can be used to introduce the nitro ortho group in relation to the R8S3d group. When the nitration reaction provides mixtures of regioisomers, chromatography can be used to isolate the desired isomer. Scheme 1: general procedure for preparing starting materials for substituted phenyl Scheme 1: [0081] R1 = H, Me, Et, Cyclopropyl [0082] Scheme 2 describes the general methods for preparing a wide variety of pyridine and pyrimidine starting materials. The nitration of 4,6-dihydroxypyrimidine followed by conversion of the hydroxyl groups to a chlorine group, with POCl3 provides intermediate S4c. Chlorine is readily displaced by amines and alcohols to provide the desired intermediate S3e. Similarly, commercially available pyridine S4d is readily substituted with amines and alcohols to form intermediate S3f. Scheme 2: general procedure for preparing substituted pyrimidine and starting materials for pyridine [0083] The orthofluoro-nitroaromatics S3 are converted (scheme 2) to indoles, and substituted nitrogen Indoles S6a and S6b (pyrrolopyrimidines and pyrrolopyridines) by treatment with ethyl acetate or cyanomalonate followed by reduction with zinc in acetic acid, alternatively, the nitro group can be reduced with many alternative reducing agents, such as sodium bisulfite. Scheme 3: Formation of indole intermediates [0084] The indole intermediates are converted to tricyclic intermediates as shown in Scheme 4. The reaction of an amino acid ester with an S6a acylisothiocinate indole followed by base treatment provides the S8a tricycle with an SH in position 2 and an OH in the position 4. Alternatively, treatment with an acylisocinate, followed by base, provides S8b with an OH substituent in both positions 2 and 4 of the tricycle. These are versatile intermediates that can be converted as S8a to a bisulfone by first alkylation at position 2 of sulfur, followed by activation of position 4, with a reagent, such as BOP or mesyl chloride, followed by displacement with a sulfide, then , by oxidizing bisulfone S8f with a reagent, such as sulfone. [0085] Scheme 4: preparation of key tricyclic intermediates [0086] Alternatively, the nucleus of S8b can be converted to S8g dichloro-tricycle. Amino nitrile indole S6b intermediates can be converted to bisulfone by treatment with carbon disulfide and an alcohol to provide the anion of the 2,4-dithiol trichloride. This intermediate can be alkylated in situ and then oxidized to provide bisulfone S8f. Scheme 4. Preparation of key tricyclic intermediates (cont.) 2. General procedures for converting tricyclic nuclei to Formula I compounds [0087] There are several methods for converting key tricyclic intermediaries to Compounds of Formula I. [0088] In Scheme 5, any intermediate S8f or S8g can be converted to the bis-aryloxy compound 9. The Aryloxy group at position 4 can be displaced by amines or alcohols to provide the desired compound of Formula I, where R4 is both a amine as an alkoxide. In some cases, it is desirable to use protection groups over intermediates S8 and / or the group R4. In such cases, an additional step may be necessary to remove the protective group. Scheme 5: [0089] As an alternative method, the tricyclic intermediate dichloro S8g can be treated first with the group R4, then by displacement in position 2 with an R2OH alkoxide (Scheme 6). Typically, this method requires protection groups, especially when a diamine such as the R4 group is used. In these cases, removal of the protecting groups provides compounds of Formula I. This method is particularly useful when an R2OH group is used or the R2 group is electron rich Scheme 6: [0090] In cases where L is S, the compounds of Formula I can be prepared directly from S8A by the method of Scheme 7. In this method, the sulfide is coupled to an aryl halide (preferably an iodine or aromatic bromine atom ). Activation of the hydroxyl group at position 4 by reagents, such as a sulfonylhalide or with a coupling reagent such as BOP followed by displacement with an amine provides the desired Formula I compound. Layout 7 [0091] Compounds of Formula I, where R4 is an aryl or heteroaryl, can be made as shown in Scheme 8. In this case, the dichloro intermediate S8g is coupled to a boronic acid using Suzuki coupling conditions. The resulting product is then treated with an alkoxide to provide the compound of Formula I. Scheme 8: [0092] Prodrugs can also be prepared from compounds of Formula I or II. The term "pro-drug", as used here, represents compounds that can be transformed in vivo to the active parent compounds defined herein. [0093] Examples of pro-drugs, for example, in R4 include NHNHCH3, [0094] A pharmaceutically acceptable salt, ester or prodrug of the compounds is also contemplated here. Those skilled in the art will appreciate that a wide variety of prodrugs, salts, hydrates, solvates, and polymorphs can be produced from the compounds described here, and that several isotopically substituted variants (by, for example, substituting hydrogen for deuterium, 13C for carbon, 15N for nitrogen, or phosphorus for 32P), known as "isotopomers" can also be readily produced. All of these derivatives are included within the scope of this description. [0095] Many of the compounds described herein are in the form of hydrochloride, or other salts, but those skilled in medicinal chemistry will appreciate that the choice of salt is not critical, and other pharmaceutically acceptable salts can be prepared by well-known methods. Handbook of Pharmaceutical Salts: Properties, Selction and Use. (P. Heinrich Stahl and Camille G. Wermuth, eds.) International Union of Pure and Applied Chemistry, Wiley-VCH 2002 and LD Bighley, SM Berge, DC Monkhouse, in "Encyclopedia of Pharmaceutical, Technology ', Eds, J. Swarbrick and JC Boylan, vol. 13, Marcel Dekker, Inc., New York, Basel, Hong Kong, 1995, pp 453-499 discuss such salts in detail. [0096] The compounds here include those structures that are fixed throughout the examples and their pharmaceutically acceptable salts, esters and their prodrugs. In some embodiments, the compound is in a pharmaceutical composition or dosage form, wherein the pharmaceutical composition or dosage form provides an effective amount of antibiotic in the compound to treat or prevent infection. [0097] In another aspect, the present disclosure relates to a pharmaceutical composition comprising one or more physiologically acceptable surface active agents, additional carriers, diluents, excipients, smoothing agents, suspending agents, film-forming substances, and auxiliaries coating, or a combination thereof, and a composition described herein. Additional carriers or acceptable diluents for therapeutic use are well known in the pharmaceutical art, and are described, for example, in Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing Co., Easton, PA (1990), which is incorporated herein by reference in its entirety. Preservatives, stabilizers, dyes, sweeteners, flavors, flavoring agents, and the like can be provided in the pharmaceutical composition. For example, sodium benzoate, ascorbic acid and esters of p-hydroxybenzoic acid can be added as preservatives. In addition, antioxidants and suspending agents can be used. In various modalities, alcohols, esters, sulfated aliphatic alcohols, and the like can be used as surface active agents, sucrose, glucose, lactose, starch, microcrystalline cellulose, crystallized cellulose, mannitol, light anhydrous silicate, magnesium aluminate, magnesium metasilicate aluminate , synthetic aluminum silicate, calcium carbonate, acid sodium carbonate, calcium hydrogen phosphate, carboxymethyl cellulose, and the like can be used as excipients, magnesium stearate, talc, hardened oil and the like can be used as leveling, coconut oil, olive oil, sesame oil, peanut oil, soy can be used as suspending agents or lubricants; cellulose acetate phthalate as a carbohydrate derivative such as cellulose or sugar, or methylacetate-methacrylate copolymer as a polyvinyl derivative can be used as suspending agents, and plasticizers, such as esters phthalates and the like can be used as suspending agents. [0098] The term "pharmaceutical composition" refers to a mixture of a compound described herein with other chemical components, such as additional diluents or carriers. The pharmaceutical composition facilitates the administration of the compound to an organism. Various techniques for administering a pharmaceutical composition exist in the art, including, but not limited to, oral, injection, aerosol, parenteral and topical. In some embodiments, pharmaceutically acceptable salts of the compounds described herein are provided. [0099] The term "carrier" refers to a chemical compound that facilitates the incorporation of a compound into cells or tissues. [00100] The term "diluent" refers to chemical compounds diluted in water that will dissolve the composition of interest, as well as stabilize the biologically active form of the compound. The salts dissolved in the buffered solutions are used as diluents in the art. A buffer solution generally used is phosphate buffered saline, because it mimics the saline conditions of human blood. Since buffer salts can control the pH of a solution at low concentrations, a buffered diluent rarely modifies a compound's biological activity. As used herein, an "excipient" refers to an inert substance that is added to a composition to provide, without limitation, in bulk, consistency, stability, bonding, lubricating, disintegrating capacity, etc. , for the composition. A "thinner" is a type of excipient. [00101] The term "physiologically acceptable" refers to a vehicle or diluent that does not negate the biological activity and properties of the compound. [00102] The pharmaceutical compounds described herein can be administered to a human patient per se, or in pharmaceutical compositions where they are mixed with the other active ingredient (s), as well as in combination therapy, or suitable carriers or excipient (s). In some embodiments, a dosage form includes the forms in which the compound is admitted per se. In addition, a dosage form can contain a pharmaceutical composition. In any event, the dosage form may comprise a sufficient amount of the compound to treat a bacterial infection dimer, as part of a particular administration protocol, as would be understood by those skilled in the art. Techniques for formulating and administering instantaneous compounds can be found in "Remington's Pharmaceutical Sciences," Mack Publishing Co., Easton, PA, 18th edition, 1990. [00103] Suitable routes of administration may, for example, include oral, rectal, transmucosal, topical or intestinal administration, parenteral administration, including intramuscular, subcutaneous, intravenous injections, as well as intrathecal, direct intraventricular, intraperitoneal, intranasal injections , or intraocular injections. The compound can also be administered in sustained or controlled release dosage forms, including injection deposits, osmotic pumps, pills, transdermals (including electrotransport), patches and the like, for prolonged, timed and / or pulsed administration at a predetermined rate. [00104] Pharmaceutical compositions can be manufactured in a manner that is known per se, for example, by means of conventional mixing, dissolving, granulating, drag making, levigation, emulsion, encapsulation, trapping or compression processes. [00105] The pharmaceutical compositions can be formulated in any conventional way using one or more physiologically acceptable carriers comprising excipients and auxiliaries that facilitate the processing of the active compounds in preparations that can be used pharmaceutically. Proper formulation is dependent on the chosen route of administration. Any of the well-known techniques, diluents, carriers, and excipients can be used as appropriate and as understood in the art, for example, in Remington's Pharmaceutical Sciences, supra. [00106] Injectables can be prepared in conventional forms, either as liquids, solutions or suspensions, solid forms suitable for solution or suspension in liquid before injection, or as emulsions. Suitable excipients are, for example, water, saline, dextrose, mannitol, lactose, lecithin, albumin, sodium glutamate, cysteine hydrochloride, and the like. In addition, if desired, injectable pharmaceutical compositions may contain minor amounts of non-toxic auxiliary substances, such as wetting agents, pH buffering agents, and the like. Physiologically compatible buffers include, but are not limited to, Hanks' solution, Ringer's solution, or physiological saline buffer. If desired, increasing absorption preparations can be used. [00107] For transmucosal administration, penetrants appropriate to the barrier to be permeated can be used in the formulation. [00108] Pharmaceutical formulations for parenteral administration, for example, by bolus injection or continuous infusion include aqueous solutions of the active compounds in water-soluble form. In addition, suspensions of the active compounds can be prepared as appropriate oily injection suspensions. Aqueous suspensions for injection may contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol or dextran. Optionally, the suspension can also contain suitable stabilizers or agents that increase the solubility of the compounds to allow the preparation of highly concentrated solutions. Injection formulations can be presented in unit dosage form, for example, in ampoules or in multi-dose containers, with an added preservative. The compositions can take forms such as suspensions, solutions or emulsions in oily or aqueous vehicles, and can contain formulation agents, such as suspensions, stabilizers and / or dispersants. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, for example, sterile pyrogen-free water, before use. [00109] For oral administration, the composition can be easily formulated by combining the compositions of interest with pharmaceutically acceptable carriers well known in the art. Such vehicles that can be used in addition to the cationic polymeric carrier allow the compositions to be formulated as tablets, pills, dragons, capsules, liquids, gels, syrups, pastes, suspensions and the like, for oral ingestion by a patient to be treated. Pharmaceutical preparations for oral use can be obtained by combining the active compound with solid excipients, optionally crushing a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol, cellulose preparations such as, for example, corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone (PVP), for example, Povidone. If desired, disintegrating agents can be added, such as cross-linked polyvinylpyrrolidone (for example, Crospovidone), agar, or alginic acid or a salt thereof, such as sodium alginate. Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyes or pigments can be added to tablets or dragee coatings for identification or to characterize different combinations of active compound doses. [00110] Pharmaceutical preparations that can be used orally include capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Plug-in capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches and / or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds can be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers can be added. All formulations for oral administration must be in appropriate dosages for such administration. [00111] For oral administration, the compositions may take the form of tablets or lozenges formulated in a conventional manner. Administration to the buccal and sublingual mucosa are contemplated. [00112] For administration by inhalation, the composition can be conveniently delivered in the form of an aerosol spray presentation from pressurized packages or a nebulizer, using a suitable propellant, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to deliver a metered amount. Capsules and cartridges of, for example, gelatin for use in an inhaler or insufflator can be formulated containing a powder mixture of the compound and a suitable powder base such as lactose or starch. [00113] In addition, several pharmaceutical compositions known in the pharmaceutical art are well described herein for uses including intraocular, intranasal, and intraauricular delivery. Penetrating agents suitable for such uses are generally known in the art. Such suitable pharmaceutical formulations are most often and preferably formulated to be sterile, isotonic and buffered for stability and comfort. Pharmaceutical compositions for intranasal administration can also include drops and sprays often prepared to simulate nasal secretions in many aspects to ensure the maintenance of normal ciliary action. As disclosed in Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing Co., Easton, PA (1990), which is incorporated herein by reference in its entirety, and well known to those of skill in the art, suitable formulations are most often and preferably isotonic, slightly buffered to maintain a pH of 5.5 to 6.5, and more often and preferably includes appropriate antimicrobial preservatives and drug stabilizers. Pharmaceutical formulations for intra-auricular delivery include suspensions and ointments for topical application to the ear. Common solvents for such formulations include glycerin and water phonetics. [00114] The compositions can also be formulated in rectal compositions, such as suppositories or retention enemas, for example, containing conventional suppository bases, such as cocoa butter or other glycerides. [00115] In addition to the formulations described previously, the compositions can also be formulated as a depot preparation. Such long-acting formulations can be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds can be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a poorly soluble salt. [00116] For hydrophobic compounds, a suitable pharmaceutical carrier can be a co-solvent system comprising benzyl alcohol, a non-polar surfactant, a water-miscible organic polymer, and an aqueous phase. A common co-solvent system used is the VPD co-solvent system, which is a solution of 3% by weight of benzyl alcohol, 8% by weight of the non-polar surfactant Polysorbate 80TM, and 65% by weight of polyethylene glycol 300, made the volume in absolute ethanol. Naturally, the proportions of a co-solvent system can be varied considerably without destroying its characteristics of solubility and toxicity. In addition, the identity of the co-solvent components can be varied: for example, other non-polar surfactants of low toxicity can be used instead of polysorbate 80TM, the size of the polyethylene glycol fraction can be varied; other biocompatible polymers can replace polyethylene glycol, for example, polyvinylpyrrolidone, and other sugars or polysaccharides can replace dextrose. [00117] Methods for treating bacterial infections may include administering a therapeutically effective amount of the therapeutic compounds, as described herein. Treatment of a bacterial infection may also include the prophylactic administration of the therapeutic compounds to prevent infection or the spread of an infection in an individual at imminent risk of infection, such as a recipient or about to undergo surgery, an immunosuppressed subject, or a otherwise subjects at risk of an infection if the compound was not administered. The compounds show inhibitory activity against a broad spectrum of bacteria, including H. influenzae, E. coli, S. aureus, E. faecalis, E. facium, K pneumonia, Acinetobacter baumannii, S. pneumoniae and P. aeruginosa. The compounds show activity against most resistant strains, for example, methicillin resistant Staphylococcus aureus (MRSA). In addition, the compounds show broad-spectrum activity against all A, B, and C biodefensive bacterial pathogens including B. anthracis, B. pseudomallei, B. mallei, F. tularensis and Y. psetis category. See the examples. The compounds have excellent antibiotic activity in relation to a relatively low concentration. In addition, the compounds can exert a potent antibacterial activity against various human and animal pathogens, including Gram-positive and Gram-negative bacteria. In one embodiment, the bacterial infection that can be treated or alleviated is MRSA. [00118] The pharmaceutical compositions or compositions described herein can be administered to the subject by any suitable means. Non-limiting examples of methods of administration include, but are not limited to (a) although the routes of oral administration, which include administration in capsules, tablets, granules, spray, syrup, or other such forms, (b) via routes of administration non-oral administration such as rectal, vaginal, intra-urethral, intraocular, intranasal or intra-auricular, which includes administration as an aqueous suspension, an oily preparation or the like, or as a drip, spray, suppository, ointment, ointment or similar, (c) administration by injection, by subcutaneous, intraperitoneal, intravenous, intramuscular, intradermal, intraorbital, intracapsular, intraspinal or similar, including delivery of an infusion pump, as well as (d) topical administration, as deemed appropriate by those skilled in the art to bring the active compound into contact with living tissue. [00119] Pharmaceutical compositions suitable for administration include compositions in which the active ingredients are contained in an amount effective to achieve their intended purpose. In some embodiments, a therapeutically effective amount of a compound is an amount effective to treat a bacterial infection, for example, in a mammalian individual (for example, a human). The therapeutically effective amount of the compounds described herein as a required dose will depend on the route of administration, the type of animal, including human, to be treated, and the physical characteristics of the specific animal under consideration. The dose can be adjusted to achieve a desired effect, but it will depend on factors such as weight, diet, competing medication and other factors that experts in the medical arts will recognize. More specifically, a therapeutically effective amount means an amount of compound effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject to be treated. The determination of a therapeutically effective amount is well within the capabilities of those skilled in the art, especially in light of the detailed disclosure provided herein. [00120] As will be readily apparent to one skilled in the art, the in vivo utility of the dosage to be administered and the particular mode of administration will vary depending on the age, weight and species of the treated mammal, the particular compounds employed, and the specific use for that these compounds are employed. Determination of effective dosage levels, i.e., the levels necessary to achieve the desired dosage result, can be accomplished by one skilled in the art using routine pharmacological methods. Typically, human clinical applications of products that are started at lower dosage levels, with the dosage level being increased until the desired effect is achieved. Alternatively, acceptable in vitro studies can be used to establish the useful doses and routes of administration for the compositions identified by the present methods using established pharmacological methods. [00121] In studies with non-human animals, applications of potential products are initiated at higher dosage levels, with the dosage being decreased until the desired effect has no longer reached adverse side effects disappear. The dosage can vary widely, depending on the desired effects and the therapeutic indication. Typically, dosages can be from about 10 micrograms / kg to about 100 mg / kg of body weight, preferably about 100 micrograms / kg to about 10 mg / kg of body weight. Alternatively, dosages can be based and calculated on the patient's surface area, as understood by those skilled in the art. [00122] The exact formulation, route of administration and dosage for pharmaceutical compositions can be chosen by the doctor individually in view of the patient's condition. (See, for example, Fingi et al. 1975, in "The Pharmacological Basis of Therapeutics", which is incorporated herein by reference in its entirety, with particular reference to chapter 1, p. 1). In some embodiments, the dose range of the composition administered to the patient can be from about 0.5 to about 1000 mg / kg of the patient's body weight. The dosage can be a single or a series of two or more given over the course of one or more days, as is necessary for the patient. In cases where human dosages for the compounds have been established for at least some conditions, the same dosages or dosages which are about 0.1% to about 500%, more preferably about can be used up to about 25% at 250% of the established human dosage. Where no established human dosage, as will be the case for newly discovered pharmaceutical compositions, an appropriate human dosage can be inferred from ED50 or ID50 values, or other suitable values derived from in vitro or in vivo studies, as qualified by toxicity studies and efficacy studies in animals. [00123] It should be noted that the attending physician would know how and when to end, interrupt or adjust the administration due to toxicity or organ dysfunction. Conversely, the attending physician also knows how to adjust treatment to higher levels if the clinical response was not adequate (precludent toxicity). The magnitude of a dose administered to manage the disorder of interest will vary with the severity of the condition being treated and the route of administration. The severity of the condition can, for example, be assessed, in part, by standard methods of assessing prognosis. In addition, the frequency of dose and dose may also vary according to the age, body weight, and response of the individual patient. A program comparable to the one discussed above can be used in veterinary medicine. [00124] Although the exact dosage will be determined on a drug-by-drug basis, in most cases, some generalizations regarding the dose can be made. The daily dosage regimen for an adult human patient can be, for example, an oral dose of about 0.1 mg to 2000 mg of the active ingredient, preferably about 1 mg to about 500 mg, for example, 5 to 200 mg. In other embodiments, an intravenous, subcutaneous or intramuscular dose of the active ingredient from about 0.01 mg to about 100 mg, preferably about 0.1 mg to about 60 mg, for example, about 1 to about 40 mg is used. In cases of administration of a pharmaceutically acceptable salt, the dosage can be calculated as the free acid. In some embodiments, the composition is administered 1 to 4 times a day. Alternatively, the compositions can be administered by continuous intravenous infusion, preferably at a dose of up to about 1000 mg per day. As will be understood by those skilled in the art, in certain situations, it may be necessary to administer the compounds disclosed herein, in amounts that exceed, or even greatly exceed, the aforementioned, the preferred dosage range to effectively and aggressively treat particularly aggressive diseases or infections . In some embodiments, the compounds will be administered over a period of continuous therapy, for example, for a week or more, or for months or years. [00125] Dosage amount and interval can be adjusted individually to provide plasma levels of the active portion that are sufficient to maintain the effects of antibiotics, or the minimum effective concentration (MEC). The MEC will vary for each compound but can be estimated from in vitro data. The dosages required to achieve ECM will depend on individual characteristics and the route of administration. However, HPLC assays or bioassays can be used to determine plasma concentrations. Dosage ranges can also be determined using the MEC value. [00126] Compositions should be administered using a regimen that maintains plasma levels above the MEC for 10-90% of the time, preferably between 30-90% and most preferably between 50-90% [00127] In cases of local administration or selective absorption, the local effective, drug concentration cannot be related to plasma concentration. [00128] The amount of composition administered may be dependent on the subject being treated, the subject's weight, the severity of the infection, the mode of administration and the judgment of the prescribing physician. [00129] The compositions disclosed herein can be evaluated for efficacy and toxicity using known methods. For example, the toxicology of the compound can be established by determining in vitro toxicity for a cell line, such as a mammalian, and preferably human, cell line. The results of these studies are often predictive of toxicity in animals, such as mammals, or, more specifically, humans. Alternatively, the toxicity of particular compounds in an animal model, such as mice, rats, rabbits or monkeys, can be determined using known methods. The effectiveness of a particular compound can be established using several recognized methods, such as in vitro methods, animal models, or human clinical trials. Recognized in in vitro models, they exist for almost all condition classes. Similarly, acceptable animal models can be used to establish the effectiveness of chemicals for treating such conditions. When selecting a model to determine effectiveness, the person skilled in the art can be guided by the state of the art to choose an appropriate model, dose and route of administration, and the regimen. Of course, clinical trials in humans can also be used to determine the effectiveness of a compound in humans. [00130] The compositions may, if desired, be presented in a packaging or device dispenser which may contain one or more unit dosage forms containing the active ingredient. The package may for example comprise metal or plastic foil, such as a blister package. The packaging or dispensing device may be accompanied by instructions for administration. The package or distributor may also be accompanied with a notice associated with the container in the form prescribed by a government agency that regulates the manufacture, use or sale of pharmaceutical products, which notice is a reflection of the organ's form approval for the human being or veterinary administration. Such a warning, for example, could be the labeling approved by the US Food and Drug Administration for prescription drugs, or the label on the approved product. Compositions comprising a compound formulated in a compatible pharmaceutical carrier can also be prepared, placed in an appropriate container and labeled for treating an indicated condition. [00131] In some embodiments, in the pharmaceutical industry, it is normal practice to supply substantially pure material when formulating pharmaceutical compositions. Therefore, in some embodiments, "substantially pure" refers to the amount of purity required for the formulation of pharmaceutical products, which may include, for example, a small amount of other material that does not affect suitability for pharmaceutical use. In some embodiments, the substantially pure compound contains at least about 96% of the compound by weight, such as at least about 97%, 98%, 99% or 100% of the compound. [00132] The terms "approximately", "about" and "substantially", as used herein, represent a value close to the indicated value that still performs the intended function, or achieves the desired result. For example, the terms "approximately", about "and" substantially "may refer to an amount that is less than 10%, less than 5%, less than 1%, less than 0.1% and less than 0.01% of the indicated quantity. EXPERIMENTAL SECTION SECTION A Synthesis of unique R2 parts [00133] All of the substituted pyrimidinols 2 not commercially available were prepared according to the procedures described in US 5,162,529 or with the documents published in Tetrahedron, 65 (4), 757-764; 2009. Examples: General Scheme: R = Cyclopropyl, Isobutyl, CH2OH, CHOHCH3, C (CH3) 2OH, CH2F, CHF2, CHF3 Experimental: Scheme 1: [00134] Preparation of compound A2: Phosphorus oxychloride (96 g, 0.62 mol) was added to anhydrous DMF (46 g, 0.62 mol) at 0 ° C and the mixture was stirred at room temperature for 1 h. Then, CHCL3 (500 mL) was added and benzyloxyacetaldehyde ethyl acetate (40 g, 0.18 mol) was added dropwise. Once completed, the reaction mixture was heated to reflux for 2.5 h and then allowed to cool to room temperature. The orange solution was slowly poured into ice water (500 ml) at 0 ° C, and the biphasic mixture was stirred for 15 min. The organic phase was washed with water (500 ml). The combined aqueous phases were added dropwise to a solution of dimethylamine hydrochloride (59 g, 0.72 mol) in water (200 ml). The pH was adjusted to 8.5 by adding an aqueous 5N sodium hydroxide solution, maintaining the temperature at about 15 ° C. The solution was stirred for 1 h, and sodium hexafluorophosphate (40 g, 0.23 mol) in water (100 ml) was added. The resulting precipitate was collected by filtration, washed with water, and dried under high vacuum to give compound 2 (22 g, yield: 30%) as a pale beige solid, which was used in the next step without any additional purification. [00135] 1H NMR (400 MHz, DMSO-d6): δ: 7.42-7.39 (m, 5H), 4.74 (s, 2H), 3.32 (s, 3H), 3.21 (s, 3H). [00136] Preparation of compound A3: To a stirred suspension of compound A2 (14 g, 39 mmol) and cyclopropanecarboximidamide hydrochloride (5.65 g, 47 mmol) in CH3CN (100 mL) was added potassium carbonate (16.2 g, 117mmol). The reaction mixture was heated to 90 ° C for 12h, then cooled to room temperature, poured into ice water, extracted with ethyl acetate (2 x 50 ml). The organic layer was dried over Na2SO4, filtered and concentrated to give compound A3 (2.5 g, yield: 26%) as a yellow solid. [00137] 1H NMR (400 MHz, CDC13): δ: 8.44 (s, 2H), 7.46-7.28 (m, 5H), 5.24 (s, 2H), 2.18-2 , 12 (m, 1H), 0.99-0.90 (m, 2H), 0.89-0.86 (m, 2H). [00138] Preparation of compound A4: A solution of compound A3 (3.50 g, 15.8 mmol) in MeOH (30 mL) was added 10% palladium on carbon (350 mg) and the mixture was stirred under a hydrogen for 4h. The solid was filtered and the filtrate was concentrated to obtain compound A4 (2.0 g, yield: 98%). [00139] 1H NMR (300 MHz, DMSO-d6): δ: 10.05 (s, 1H), 8.17 (s, 2H), 2.12-2.05 (m, 1H), 0.93 -0.91 (m, 2H), 0.86-0.83 (m, 2H). LCMS [Mobile phase: 2-60% acetonitrile-0.05% TFA in 6 min, finally under these conditions for 0.5 min] purity is> 95%, Tr = 2.564 min, MS Cale: 136.1; Determined MS :. 137.1 ([M +1] +). Scheme 2: [00140] Preparation of Compound A5: To a stirred suspension of compound A2 (14 g, 39 mmol) and 2-hydroxypropanimidamide hydrochloride (5.65 g, 47 mmol) in CH3CN (100 mL) was added potassium carbonate (16.2 g, 117 mmol). The reaction mixture was heated to 90 ° C for 12h, then it was cooled to room temperature, poured into ice water, extracted with ethyl acetate (2 x 50 mL). The organic layer was dried with Na2SO4, filtered and concentrated to give the compound A5 (2.5 g, yield: 26%) as a yellow solid. [00141] 1H NMR (300 MHz, CDC13): δ: 8.84 (s, 2H), 7.48 (m, 3H), 7.37 (m, 2H), 5.20 (s, 2H), 4.68 (m, 1H), 3.25 (m, 1H), 1.48 (d, 3H). [00142] Preparation of compound A6: A solution of compound A5 (3.50 g, 15.8 mmol) in. McOH (30 mL) was added palladium on charcoal 10% (350 mg) and the mixture was stirred under hydrogen atmosphere for 4h. The solid was filtered off and the filtrate was concentrated to get compound A6 (2.0 g, yield: 98%). [00143] 1H NMR (400 MHz, CDCl3): δ: 8.84 (s, 2H), 5.40 (brd, 1H), 4.66 (m, 1H), 3.25 (m, 1H), 1.46 (d, 3H). LCMS Found: 141.1 ([M + 1] +) Scheme 3: [00144] Preparation of compound A8: To a solution of compound A7 (50 g, 0.26 mol) in DCM (300 ml) was added Nal (80 g, 0.52 mol) at room temperature, then HI ( 75 g, 0.52 mol) was added. After stirring at 50 ° C for 5 h, the mixture was poured into ice water and carefully neutralized by adding solid sodium bicarbonate until the mixture became colorless. Then, the mixture was extracted with DCM (2 x 200 ml). The organic layer was dried over Na2SO4, filtered and concentrated to give compound A8 (60 g, yield: 81%) as a white solid. [00145] 1H NMR (400 MHz, CDCl3): 6: 8.54 (s, 2H). [00146] Preparation of compound A9: To a solution of compound A8 (50 g; 0.18 mol) in THF (300 ml) was added Pd (PPh3) 4 (11.5 g, 0.01 mol), followed by addition of a solution of the zinc reagent 3 (prepared from 2,2-iodomethyl dimethylpropanoate) in THF (500 ml, 0.36 mol) and stirred at room temperature for 12h. Then, ice water was added and the mixture was extracted with ethyl acetate (2 x 200 ml). The organic layer was dried over Na2SO4, filtered and concentrated to give crude product. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 10: 1) to obtain compound A9 (41 g, yield: 85%) as a yellow solid. [00147] 1H NMR (400 MHz, CDCl3): δ: 8.75 (s, 2H), 5.26 (s, 2H), 5.06 (s, 1H), 1.28 (s, 9H). [00148] Preparation of compound A10: To a stirred solution of compound A9 (15.0 g, 54.9 mmol) in dioxane (100 mL) was added bis (pinacolate) diboro (17.0 g, 65.4 mmol) under nitrogen, followed by Pd (dppf) C12 (2.20 g, 2.72 mmol) and KOAc (16 g; 163 mmol). The reaction mixture was heated to 85 ° C for 3 h. The black suspension was cooled to room temperature, filtered, concentrated to obtain the crude product. The residue was purified by chromatography on silica gel (petroleum ether / ethyl acetate = 15: 1) to obtain the compound Al (15.4 g) as a white solid, contaminated with pinacol derivatives. [00149] 1H NMR (400 MHz, CDCl3): δ: 8.97 (s, 2H), 5.30 (s, 2H), 1.35 (s, 9H), 1.28 (s, 9H). [00150] Preparation of compound A11: To a solution of compound A10 (15.6 g; 48.7 mmol) in McOH (100 mL) was added H2O (16.0 g, 140 mmol). The mixture was stirred at room temperature for 12 h. 2N sodium thiosulfate (200 ml) was added and the mixture was extracted with ethyl acetate (200 ml) The aqueous phase was adjusted to pH 4-5 with 2N HCL, then the mixture was extracted with ethyl acetate (2 x 200 ml). The organic layer was dried over Na2SO4, filtered and concentrated to obtain the compound All (9.4 g, yield: 82% in two steps). [00151] 1H NMR (400 MHz, DMSO-d6): 6: 10.48 (s, 1H), 8.31 (s, 2H), 5.11 (s, 2H), 1.21 (s, 9H). [00152] Preparation of compound A12: To a solution of the compound (10 g; 30 mmol) in McOH (200 ml) was added McONa (50 ml, 1M in McOH). After stirring at room temperature for 12 h, the mixture was poured into water and extracted with ethyl acetate (2 x 200 ml). The organic layer was dried over Na2SO4, filtered and concentrated to give the Alt compound (7.3 g, yield: 98%) as a white solid. [00153] 1H NMR (300 MHz, CDC13): 6: 8.43 (s, 2H), 7.35 (d, J = 8.8 Hz, 2H), 6.93 (d, J = 8.8 Hz, 2H), 5.09 (s, 2H ), 4.78 (s, 2H). Scheme 4: [00154] Preparation of compound A13: to a solution of compounds A11 (12.3 g, 58.5 mmol) in CH3CN (100 mL) was added K2CO3 (10.5g, 76 mmol) and PMBCl (12 g, 76 mmol) and the mixture was stirred at room temperature for 12 h and heated to 50 ° C for 3 hours. Then the mixture was poured into water and extracted with ethyl acetate (2 x 200 ml). The organic layer was dried with Na2SO4, filtered and concentrated, the residue was purified by chromatography on silica gel (petroleum ether / ethyl acetate = 10: 1) to yield compound A13 (10.0 g, yield: 52%) as a solid White. [00155] 1H NMR (300 MHz, CDC13): 6: 8.41 (s, 2H), 7.34 (d, J = 8.8 Hz, 2H), 6.93 (d, J = 8.8 Hz, 2H), 5.24 (s, 2H ), 5.07 (s, 2H), 3.82 (s, 3H), 1.26 (s, 9H). [00156] Preparation of compound A14: To a solution of compound Al3 (10 g; 30 mmol) in McOH (200 ml) was added MeONa (50 ml, 1M in McOH). After stirring at room temperature for 12 h, the mixture was poured into water and extracted with ethyl acetate (2 x 200 ml). The organic layer was dried over Na2SO4, filtered and concentrated to obtain compound A14 (7.3 g, yield: 98%) as a white solid. [00157] 111 NMR (300 MHz, CDC13): δ: 8.43 (s, 2H), 7.35 (d, J = 8.8 Hz, 2H), 6.93 (d, J = 8.8 Hz, 2H), 4.78 (s, 2H ). [00158] Preparation of compound A16: To a solution of compound A14 (15 g; 61 mmol) in DCM (200 ml) was added thionyl chloride (10.8 g, 91 mmol). After stirring at room temperature for 2 h, then the mixture was poured into water and extracted with ethyl acetate (2 x 200 ml). The organic layer was dried over Na2SO4, filtered and concentrated to obtain compound A15 (16 g) as a white solid. To a solution of compound al5 (15 g) in McOH (200 ml) was added a McONa solution (50 ml, 50% in McOH). The mixture was stirred at 50 ° C for 5h, then cooled to room temperature, concentrated to obtain the crude product. The residue was purified by chromatography on silica gel (petroleum ether / ethyl acetate = 5: 1) to obtain compound A16 (12.5 g, yield: 80%) as a yellow solid. [00159] 1H NMR (400 MHz, CDC13): S: 8.45 (s, 2H), 7.34 (d, J = 8.8 Hz, 2H), 6.92 (d, J = 8.8 Hz, 2H), 5.08 (s, 2H ), 4.64 (s, 2H), 3.82 (s, 3H), 3.52 (s, 3H). [00160] Preparation of compound A17: A solution of compound A16 (3.0 g) in McOH (30 ml) was added 10% palladium on carbon (350 mg) and the mixture was stirred under a hydrogen atmosphere for 4 h. The solid was filtered and the filtrate was concentrated, the residue was purified by chromatography on silica gel (petroleum ether / ethyl acetate = 1: 1) to give compound A17 (1.2 g, yield: 74%) as a white solid. [00161] 1H NMR (400 MHz, DMSO-d6): δ: 10.45 (s, 1H), 8.33 (s, 2H), 4.44 (s, 2H), 3.31 (s, 3H ). LCMS [. Mobile phase: 95-5% acetonitrile-0.02% NH4Ac in 6 min, finally under these conditions for 0.5 min] purity is> 95%, Tr = 3.3 min, MS Calcd.140.1.1; MS found: 141.1 ([M +1] +). Scheme 5: Examples: Scheme 6: [00162] Synthesis of 2- (methylamino) pyrimidin-5-ol: A (benzyloxy) -2-chloropyrimidine A18 (0.500 g, 2.27 mmol), methylamine (1.25 mL, 2.50 mmol, solution 2, 0 M in MeOH) and DIPEA (0.594 ml, 3.41 mmol) in n-BuOH (5.0 ml) was stirred for 48 hours at 100 ° C. After being stirred for 48 hours, the reaction was checked by LC / MS. The resulting mixture was cooled to 23 ° C and concentrated under reduced pressure. The crude material was purified by column chromatography (Si02, EtOAc: n-Hex 1: 1 (v / v)) to provide 5 - (benzyloxy) -N-methyl-pyrimidin-2-amine A19 (0.355 g, 1, 65 mmol, 73%) as a colorless crystal. LC / MS (M + H +) = 216. The mixture of palladium on carbon (0.176 g, 0.165 mmol, 10.0 mol%) and 5 - (benzyloxy) -N-methyl-pyrimidin-2-amine A19 ( 0.355 g, 1.65 mmol) in ethanol (7.0 mL) was stirred for 20 h under a hydrogen atmosphere at 23 ° C. The resulting mixture was filtered through Celite and the pad was washed with methanol (25 ml). The filtrate was concentrated under reduced pressure to provide the title compound 2 - (methylamino) A20 pyrimidin-5-ol (0.196 g, 1.57 mmol, 95%) as a light yellow solid. LC / MS (M + H +) = 126. Scheme 7: [00163] Preparation of compound A22: To a solution of A21 (50.0 g, 0.303 mol) in DCM (200 ml) was added m-CPBA (80.0 g, 0.455 mol) at 0 ° C. After stirring at 0 ° C for 1 hour, at room temperature overnight, the mixture was poured into ice water. 2N NaOH was added to adjust the pH to 8-9 and the resulting mixture was extracted with DCM (3 x 200 ml). The organic layer was dried over Na2SO4, filtered and concentrated to obtain compound A22 (50.0 g, yield: 91%) as a yellow solid. [00164] Preparation of compound A23: The solution of A22 (50.0 g, 0.276 mmol) in acetic anhydride (300 ml) was heated at 90 ° C for 1.5 hours. Then, the mixture was concentrated and the residue was poured into ice water; 2N NaOH was added to adjust the pH to 8-9 and the resulting mixture was extracted with ethyl acetate (3 x 100 ml). The organic layer was dried over Na2SO4 and concentrated to give the cured which was purified by chromatography on silica gel (petroleum ether / ethyl acetate = 5: 1) to obtain compound A23 (10.0 g, yield: 16 %) as a yellow oil. [00165] 1H NMR (400 MHz, CDC13): 6: 8.43 (d, J = 2.4 Hz, 1H), 7.99 (d, J = 1.6 Hz, 1H), 4.41 4.35 (q, J = 3.2 Hz, 3H); 2.83 (s, 3H), 2.34 (s, 3H), 1.42-4.39 (t, J = 3.2 Hz, 3H). [00166] Preparation of compound A24: To a solution of A23 (10.0 g, 44.8 mmol) in McOH (300 mL) was added potassium carbonate (12.4 g, 89.8 mmol). After stirring at room temperature for 12 hours, the mixture was poured into ice water. 2N HCL was added to adjust the pH to 8-9 and the mixture was extracted with ethyl acetate (2 x 100 ml). The organic layer was dried over Na2SO4, filtered and concentrated to obtain compound A24 (8.00 g, 99% yield) as a yellow solid. [00167] 1H NMR (400 MHz, DMSO -d6) δ: 10.0 (s, 1H), 8.18 (d, J = 2.4 Hz, 1H), 7.54 (d, J = 2, 8 Hz, 1H), 4.32-4.26 (q, J = 3.2 Hz, 3H), 2.57 (s, 3H), 1.33-1.29 (t, J = 3.2 Hz, 3H). [00168] Preparation of compound A25: To a solution of compound A24 (2.50 g; 13.8 mmol) in DCM (50 mL) was added imidazole (3.00 g, 44.1 mmol) and tert - chloride butyldimethylsilyl (2.50 g, 16.7 mmol) and the mixture was stirred at room temperature for 3 hours. Then, the solvent was evaporated, the residue was purified by chromatography (petroleum ether / ethyl acetate = 5: 1) to yield compound A25 (2.80 g, 69% yield) as yellow oil. [00169] 1H NMR (400 MHz, CDC13): S: 8.12 (d, J = 2.8 Hz, 1H), 7.54 (d, J = 2.8 Hz, 1H), 4.30-4.26 (q, J = 3.2 Hz, 3H ), 2.64 (s, 3H), 1.32-1.28 (t, J = 3.2 Hz, 3H), 0.92 (s, 9H), 0.12 (s, 6H). [00170] Preparation of compound A26: To a solution of compound A25 (2.80 g; 9.48 mmol) in CC14 (100 mL) was added azodiisobutyronitrile (280 mg) and NBS (1.80 g, 10.1 mmol ), the mixture was stirred at 70 ° C for 15 hours, then the solvent was evaporated, the residue was purified by chromatography (petroleum ether / ethyl acetate = 5: 1) to give compound A26 (1.60 g, 45% yield) as a yellow oil. [00171] 1H NMR (400 MHz, CDC13): δ: 8.28 (d, J = 3.2 Hz, 1H), 7.68 (d, J = 3.2 Hz, 1H), 4.98 ( s, 3H), 4.45-4.40 (q, J = 3.2 Hz, 3H), 1.45-1.42 (t, J = 2.8 Hz, 3H), 1.00 (s , 9H), 0.26 (s, 6H). [00172] Preparation of compound A27: To a solution of compound A26 (1.60 g; 4.27 mmol) in EtOH (100 mL) was added the solution of methylamine in EtOH (1.24 g, 12.0 mmol, 30% w / w) and the mixture was stirred at room temperature for 3 hours. Then, the solvent was evaporated and the residue was purified by chromatography (petroleum ether / ethyl acetate = 5: 1) to give compound A27a (300 mg, yield: 25%) as a yellow solid. [00173] 1H NMR (400 MHz, DMSO-d6): 6: 8.34 (d, J = 2.8 Hz, 1H), 7.43 (d, J = 2.8 Hz, 1H), 4, 42 (s, 2H), 3.06 (s, 3H), 0.95 (s, 9H), 0.20 (s, 6H). [00174] To a solution of compound A27a (300 mg, 1.14 mmol) in THF (5 ml) was added 6N HCL (0.5 ml). After stirring at room temperature for 1 hour, the mixture was concentrated to obtain compound A27 (150 mg, 80% yield) as a yellow solid. [00175] 1H NMR (400 MHz, DMSO-d6): δ: 10.27 (s, 1H), 8.27 (d, J = 2.4 Hz, 1H), 7.32 (d, J = 2 , 8 Hz, 1H), 4.37 (s, 2H), 3.0 (s, 3H). LCMS mobile phase :. From 40% water (0.05% TFA) and 60% CH3CN to 10% water (0.05% TFA) and 90% CH3CN in 6 min, finally under these conditions for 0.5 min] Purity is> 95%, Rt = 3.7 min, MS Cale: 164.1; Determined MS :. 165.1 ([M +1] +). [00176] Preparation of compound A29: A mixture of compound A28 (25.0 g, 180 mmol) and H2SO4 (10 mL) in CH3OH (100 mL) was heated and heated to reflux overnight. The mixture was concentrated, the residue was washed with aqueous NaHCO3 solution (50 ml) and extracted with ethyl acetate (2 x 100 ml). The organic layer was dried over Na2SO4, filtered and concentrated to obtain compound A29 (18.7 g, yield: 68%). [00177] 1RMN (300 MHz, DMSO-d6) δ: 10.42 (s, 1H), 8.60 (d, J = 1.6 Hz, 1H), 8.36 (d, J = 2.8 Hz, 1H), 7.60-7.61 (m, 1H), 3.87 (s, 3H). [00178] Preparation of compound A30: BnOH (3.90 g, 36.1 mmol, 1.1 eq) and PPh3 (17.1 g, 65.4 mmol, 2.0eq) was added to a solution of compound A29 ( 5.00 g, 32.7 mmol) in THE (100 ml), then DEAD (6.80 g, 39.2 mmol, 1.2 eq) was added at 0 ° C. The mixture was stirred at room temperature overnight. The solvent was evaporated, the residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 10: 1) to obtain compound A30 (5.70 g, yield: 71%) as a white solid. [00179] 1H NMR (300 MHz, CDC13): δ: 8.83 (d, J = 1.6 Hz, 1H), 8.54 (d, J = 2.8 Hz, 1H), 7.85- 7.86 (m, 1H), 7.27-7.46 (m, 5H), 5.15 (s, 2H), 3.95 (s, 3H). [00180] Preparation of compound A31: A solution of compound A30 (12.8 g; 52.9 mmol) in methylamine solution in sealed alcohol tube was stirred at 70 ° C overnight. Then, the mixture was cooled to room temperature and the solvent was evaporated to obtain compound A31 (12.0 g, yield: 100%). [00181] 1H NMR (300 MHz, CDC13): 6: 8.50 (d, J = 1.6 Hz, 1H), 8.48 (d, J = 2.8 Hz, 1H), 7.73- 7.74 (m, 1H), 7.73-7.74 (m, 5H), 6.16 (s, 1H), 3.15 (s, 2H), 3.04 (d, J = 4, 4 Hz, 3H). [00182] Preparation of compound A32: The solution of compound A31 (11.0 g; 45.5 mmol) in SOC12 (100 ml) was heated to reflux for 4h. Then, SOCl2 was removed in vacuo and the residue was dissolved in MeCN (200 ml). TMSN3 (12.5 g, 90.0 mmol, 2.0eq) was added slowly and the mixture was stirred at 90 ° C for 3 h. Then, the solvent was evaporated and the residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 2: 3) to obtain compound A32 (9.50 g, yield: 78%). [00183] 1H NMR (300 MHz, CDC13): S: 8.59 (d, J = 2.8 Hz, 1H), 8.56 (d, J = 1.6 Hz, 1H), 7.68- 7.69 (m, 1H), 7.3-7.46 (m, 5H), 5.21 (s, 2H), 4.17 (s, 3H). [00184] Preparation of compound A33: To a solution of compound A32 (5.00 g; [00185] 18.7 mmol) in CH3OH (100 mL) Pd (OH) 2 (0.50 g) was added. The mixture was stirred at room temperature under H2 for 3 h. The solid was filtered and the filtrate was concentrated to obtain compound A33 (1.60 g, yield: 48%). [00186] 1H NMR (300 MHz, DMSO-d6): δ: 10.56 (s, 1H), 8.49 (d, J = 1.6 Hz, 1H), 8.36 (d, J = 2 , 8 Hz, 1H), 7.61-7.62 (m, 1H), 4.19 (s, 3H). [00187] Preparation of compound A34: Thionyl chloride (15.0 g, 107 mmol) was added to DMF (200 mL) at 0 ° C, and the mixture was stirred at 0 ° C for 30 min, then A31 (12.2 g, 53.5 mmol) was added to the mixture, and stirred at 0 ° C for 1 h. Then the reaction mixture was poured into ice water and extracted with ethyl acetate (2 x 100 ml). The organic layer was dried over Na2SO4, filtered and concentrated to obtain compound A34 (11.5 g, yield: 100%). [00188] 1HNMR (300 MHz, CDC13): δ: 8.57 (d, J = 2.8 Hz, 1H), 8.48 (d, J = 1.6 Hz, 1H), 7.45-7 , 39 (m, 6H), 5.15 (s, 2H). [00189] Preparation of compound A35: To a solution of A34 (12.0 g, 57.1 mmol) in DMF (200 mL) was added NH4C1 (5.20 g, 97.1 mmol) and NaN3 (6.31 g, 97.1 mmol). The resulting mixture was heated to 100 ° C for 14 h, cooled to room temperature, poured into ice water, 2N HCL was added to adjust the pH to 3-4, and extracted with ethyl acetate (2 x 100 ml ). The organic layer was dried over Na2SO4, filtered and concentrated to obtain compound A35 (13.0 g, yield: 90%). [00190] 1H NMR (300 MHz, DMSO-d6): δ: 8.82 (d, J = 1.6 Hz, 1H), 8.57 (d, J = 2.8 Hz, 1H), 8, 04-8.02 (m, 1H), 7.52-7.35 (m, 5H), 5.30 (s, 2H). [00191] Preparation of compound A36: Compound A35 (7.00 g, 27.7 mmol) was dissolved in acetone (150 mL), potassium carbonate (5.70 g, 41.2 mmol) was added to the mixture, and stirred at room temperature for 20 min, then iodomethane (5.89 g, 41.2 mmol) was added to the mixture, and heated to 45 ° C for 1h, cooled to room temperature, poured into water chilled, extracted with ethyl acetate (2 x 100 ml). The organic layer was dried over Na2SO4, filtered and concentrated to give crude product, the residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 3: 1) to obtain compound A36 (4.5 g, yield: 61%) as a white solid. [00192] 1H NMR (300 MHz, CDC13): δ: 8.97 (d, J = 1.6 Hz, 1H), 8.48 (d, J = 2.4 Hz, 1H), 8.00- 7.99 (m, 1H), 7.47-7.26 (m, 5H), 5.19 (s, 2H), 4.43 (s, 3H). [00193] Preparation of compound A37: To a solution of compound A36 (7.5 g; 28.0 mmol) in CH3OH (100 mL) was added Pd (OH) 2 (500 mg), The mixture was stirred at room temperature under H2 atmosphere for 3 hours. The solid was filtered and the filtrate was concentrated to obtain compound A37 (4.3 g, yield: 87%). LC-MS: M +1: 178.16. [00194] 1H NMR (300 MHz, DMSO-d6): δ: 10.42 (s, 1H), 8.68 (d, J = 1.6, 1H), 8.28 (d, J = 2, 8, 1H), 7.74-7.73 (m, 1H), 4.45 (s, 3H). SECTION B: Synthesis of single pieces of R4 Asymmetric synthesis of (1R, 4R, 5R) tert-butyl15-amino-2-azabicyclo [2.2.1] heptane-2-carboxylate General Scheme: (1R, 4S) -tert-Butyl 2-azabicyclo [2.2.1] hept-5-ene-2-carboxylate (B2) [00195] (1R) - (-) - 2-azabicyclo [2.2.1] hept-5-en-3-one (5.00 g, 45.8 mmol, ee = 99%) dissolved in anhydrous THF (15 , 0 mL) was slowly added to a solution of lithium aluminum hydride (57.3 mL, 57.3 mmol, 1M solution in THF), in anhydrous THF (35.0 mL) under a nitrogen atmosphere at 0 ° C . After the addition was successfully completed, the mixture was stirred for 3 h at 23 ° C and then heated at 60 ° C for 12 h. The resulting heterogeneous mixture was cooled to 0 ° C and H2O (5.00 ml) was carefully added to the mixture using a syringe. The white suspension was filtered through a Celite filter aid and the pad was washed with anhydrous ethyl ether (50.0 ml). The filtrate was then treated with (Boc) 20 (15.0 g, 68.7 mmol) and stirred for 24h at 23 ° C. The mixture was concentrated in vacuo and the crude material was purified by column chromatography (SiO2, EtOAc: n-Hex 1: 7 (v / v)) to provide the title compound B2 as a colorless crystal. (After the solvent was evaporated by rotary evaporator, the resulting colorless oil rapidly crystallized at 23 ° C) (1R, 4R, 5S) -tert-Butyl 5-hydroxy-2-azabicyclo [2.2.1] heptane-2-carboxylate (B3) [00196] The mixture of (1R, 45) -tert-butyl-2-azabicyclo [2.2.1] hept-5-ene-2-carboxylate (1.50 g, 7.68 mmol) and sodium borohydride (0.24 g, 6.30 mmol) in THF (9.5 mL) was stirred for 0.5 h under a nitrogen atmosphere at 23 ° C. After being stirred for 0.5 h, the mixture was heated to 35 ° C and then dimethyl sulfate (0.57 ml, 6.30 mmol) dissolved in THF (2.0 ml) was added dropwise through of a syringe. The resulting mixture was stirred for 4 h at 35 ° C, then cooled to 0 ° C and quenched by dropwise addition of H2O (5.0 ml). A sodium hydroxide solution (15.0 mL, 15.0 mmol, 1 M NaOH solution) was added at 0 ° C, followed by the addition of hydrogen peroxide (0.96 mL, 30% by weight of H2O) . The mixture was heated to 23 ° C and stirred for an additional 1 h. The resulting colorless solution was diluted with diethyl ether (75.0 ml) and the organic layer was separated, washed with brine (50.0 ml) and dried over magnesium sulfate. The mixture was concentrated by rotary evaporator and the resulting colorless oil as a crude product was purified by column chromatography (SiO2, EtOAc: n-Hex 1: 1 (v / v)) to provide the title compound B3 (1.00 g, 4.69 mmol, 61%) as a colorless oil. (1R, 4R) -tert-Butyl 5-oxo-2-azabicyclo [2.2.1] heptane-2-carboxylate (B4) [00197] 2-Iodobenzoic acid (3.43 g, 5.52 mmol, 45% by weight (SIBX)) was added to a solution of (1R, 4R, 5S) -tert-butyl-5-hydroxy-2- azabicyclo [2.2.1] heptane-2-carboxylate (0.87 g, 4.09 mmol) dissolved in dimethylsulfoxide (5.0 ml) and toluene (10.0 ml) under a nitrogen atmosphere, at 23 ° C. The mixture was stirred for 3 h at 60 ° C and cooled to 23 ° C. The resulting mixture was treated with saturated sodium carbonate (aq.) (50.0 ml) and filtered under reduced pressure to remove a white solid. The filtrate was extracted with ethyl acetate (75.0 ml x 3) and the organic extracts were washed with brine, dried over magnesium sulfate and concentrated in vacuo. The crude material as a colorless oil was purified by column chromatography (SiO2, EtOAc: n-Hex 1: 2 (v / v)) to provide the title compound B4 (0.62 g, 2.91 mmol, 71 %) as a white solid. (1R, 4R, 5R) -tert-Butyl 5- (benzylamino) -2-azabicyclo [2.2.1] heptane-2-carboxylate (B5) [00198] Sodium triacetoxyborohydride (23.4 g, 105 mmol) and glacial acetic acid (4.66 g, 77.6 mmol) were added to a solution of (1R, 4R) -tert-butyl-5- oxo-2-azabicyclo [2.2.1] ethyl heptane-2-carboxylate (16.4 g, 77.6 mmol) and benzylamine (8.32 g, 77.6 mmol) in 1,2-dichloroethane (250 mL ) under a nitrogen atmosphere at 23 ° C. The resulting mixture was stirred for 5 h at 23 ° C and then quenched with saturated sodium bicarbonate (aq.) (300 ml). The mixture was extracted with ethyl acetate (350 ml x 3) and the organic extracts were washed with brine, dried over magnesium sulfate and concentrated in vacuo. The crude material was purified by column chromatography (SiO2, EtOAc: from 9: 1 (v / v) n-Hex) to provide the title compound B5 (20.0 g, 66.1 mmol, 85%) like a colorless oil. [00199] 1H NMR (300 MHz, CDC13): δ 7.35-7.27 (m, 5H), 4.21 (s, 0.5 H), 4.08 (s, 0.5 H), 3.80-3.68 (m, 2H), 3.58 (d, J = 10.0 Hz, 1H), 3.28-3.22 (m, 1H), 3.20-3.11 ( m, 1H), 2.62 (m, 1H), 2.05-1.97 (m, 1H), 1.76-1.69 (m, 1H), 1.55 -1.51 (m, 1H) , 1.48 (s, 9H), 1.30-1.14 (m, 1H). (1R, 4R, 5R) -tert-Butyl 5-amino-2-azabicyclo [2.2.1] heptane-2-carboxylate (B6) [00200] The palladium hydroxide mixture (4.30 g, 6.12 mmol, 10.0 mol%, 20% by weight on carbon, 50% moisture) and (1R, 4R, 5R) -tert-butyl Ethyl (benzylamino) -2-azabicyclo [2.2.1] heptane-2-carboxylate (18.5 g, 61.2 mmol) in ethanol (100 mL) was stirred for 36 h under an atmosphere of hydrogen at 23 ° C. The resulting mixture was filtered through Celite and the pad was washed with ethyl acetate (500 ml). The filtrate was concentrated under reduced pressure to provide the title compound B6 (12.8 g, 60.3 mmol, 99%) as a colorless crystal. [00201] 1H NMR (300 MHz, McOD): δ 4.11 (s, 1H), 3.56-3.51 (m, 1H), 3.43-3.39 (m, 1H), 3, 18-3.15 (m, 1H), 2.49 (bs, 1H), 2.14-2.05 (m, 1H), 1.74-1.68 (m, 1H), 1.61 ( d, J = 10.0 Hz, 1H), 1.48 (s, 9H), 1.18-1.10 (m, 1H). [00202] Preparation of (1R, 4R, 5R) -2-azabicyclo [2.2.1] heptan-5-amine (B7): Boc-protected Amine (200 mg, 0.94 mmol) in CH2C12 (10 mL) TFA (5 ml) was added dropwise and the mixture was stirred at room temperature for 10 minutes. The solvent was removed in vacuo and the amine (100 mg, 99%) was used for the reactions without further purification. Synthesis of octahydrocyclopenta [c] pyrrole-4-amine: [00203] (3aR, 6aS) -2-benzylhexahydrocyclopenta [c] pyrrole-4- (51 /) - one (B9): to a solution of N-methoxymethyl) - N- (trimethylsilylmethyl) benzylamine (50 g, 0, 21 mol) in acetonitrile (134 ml) 2-cyclopenten-1-one was added. The mixture was stirred under argon at 45 ° C overnight. After the solvent was removed by rotary evaporation, the residue was purified by C18 column chromatography to produce the title compound as a clear oil (30 g, 66.4%). Chirality was resolved by chiral HPLC to obtain the desired enantiomer (B9), with an ee> 99%. [00204] (3aR, 4R, 6aS) -2-benzyl-N- (4-methoxybenzyl) octahydrocyclopenta [c] pyrrole-B10 4-amine (a) and B10 (b): the solution of compound (B9) (2.9 g, 13.43 mmol) in acetic acid (25 ml) 4 Molecular sieves (5.7 g) and 4-methoxybenzylamine (2.76 g, 20.15 mmol) were added. Then the mixture was stirred at 75 ° C for one hour, added with sodium triacetoxyborohydride per portion of the total of 1.2 equivalents (285 mg, 1.35 mmol every 20 minutes). The reaction was continued at 75 ° C to room temperature overnight. The molecular sieve was removed by filtration and washed with MeOH. The solution was concentrated by rotary evaporation, and the resulting residue was purified by C18 column chromatography. The combined collected eluent pH was adjusted to slightly basic sodium carbonate and extracted with DCM (150 mL x 3). The combined organic layers were dried over sodium sulfate and concentrated by rotary evaporation, to provide the title product B10 (a) as a yellow oil (2.56 g, 56.7%). [00205] (3aR, 4R, 6aS) octahydrocyclopenta - [c] pyrrole-4-amine, HCl salt (B11): the solution of compound B10 (a) (2.56 g, 7.61 mmol) in McOH (100 ml) was added Pd (OH) 2 in 20% carbon - 50% water (2 g), followed by the slow addition of 37% concentrated HCL (3G). Hydrogen from a double layer flask was bubbled through the reaction mixture for 16 hours. The palladium on charcoal was filtered and washed with McOH (10 ml). The filtrate was concentrated by rotary evaporation and the excess HCL was removed by McOH-toluene azeotrope to obtain the title compound (B11) as a light yellow HCL salt (1.51 g, 100% yield) . Asymmetric synthesis of tert-butyl (1R, 4R, 5R) -2-azabicyclo [2.2.1] heptan - 5-ylcarbamate Asymmetric synthesis of tert-butyl (1R, 4R, 5R) -2-azabicyclo [2.2.1] heptan-5-ylcarbamate (1R, 4S) -benzyl 2-azabicyclo [2.2.1] hept-5-ene-2-carboxylate (B12) [00206] (1R) - (-) - 2-azabicyclo [2.2.1] hept-5-en-3-one (5.00 g, 45.8 mmol, ee = 99%) dissolved in anhydrous THF (45 , 0 mL) was slowly added to a solution of lithium aluminum hydride (28.7 mL, 57.3 mmol, 2M solution in THF), in anhydrous THF (50.0 mL) under a 0 ° nitrogen atmosphere. Ç. After the addition was successfully completed, the mixture was stirred for 3 h at 23 ° C and then heated for 24 h at 60 ° C. The resulting heterogeneous mixture was cooled to 0 ° C and H2O (5.00 ml) was carefully added to the mixture using a syringe. The white suspension was filtered through a Celite filter aid and the pad was washed with anhydrous THF (250.0 ml). The filtrate as a clear solution was cooled to 0 ° C and then treated with triethylamine (12.8 ml, 91.6 mmol) and CbzCl (10.3 ml, 68.7 mmol) in that order. The resulting heterogeneous mixture, including a white precipitate, was slowly heated to 23 ° C and left to stir for 48 h. The white precipitates were separated by filtration under reduced pressure and the resulting clear solution was concentrated in vacuo. The crude material as a light yellow oil was purified by column chromatography (Si02, EtOAc: n-Hex 01:04 (v / v)) to provide the title compound B12 (8.68 g, 37.9 mmol, 83%) as a colorless oil. (1R, 4R, 5S) -Benzyl 5-hydroxy-2-azabicyclo-2-azabicyclo [2.2.1] heptane-2-carboxylate (B13) [00207] The mixture of methyl (1R, 4S) -benzyl-2-azabicyclo [2.2.1] hept-5-eno-2-carboxylate (8.679 g, 37.86 mmol) and sodium borohydride (1 , 17 g, 31.0 mmol) in THF (60.0 mL) was stirred for 0.5 h under nitrogen at 23 ° C. After being stirred for 0.5 h, the mixture was heated to 35 ° C and then dimethyl sulfate (2.93 ml, 31.0 mmol) dissolved in THF (2.0 ml) was added dropwise through from a syringe (Note: dimethyl sulfate was added slowly, due to the release of gas). the resulting heterogeneous mixture was stirred for 4 h at 35 ° C, then cooled to 0 ° C and quenched by the dropwise addition of H2O (5.0 ml). A sodium hydroxide solution (80.0 mL, 80.0 mmol, 1 M NaOH solution) was added at 0 ° C, followed by the addition of hydrogen peroxide (5.0 mL, 30% by weight of H2O ). The mixture was heated to 23 ° C and stirred for an additional 1 h. The resulting colorless solution was diluted with ethyl acetate (250 ml) and the organic layer was separated, washed with brine (150 ml) and dried over magnesium sulfate. The mixture was concentrated by rotary evaporator and the resulting colorless oil as a crude product was purified by column chromatography (Si02, EtOAc: n-Hex 1: 1 (v / v)) to provide the title compound B13 (4.02 g, 16.3 mmol, 43%) as a colorless oil. (1R, 4R) -Benzyl 5-oxo-2-azabicyclo [2.2.1] heptane-2-carboxylate (B14) [00208] 2-Iodobenzoic acid (13.7 g, 22.0 mmol, 45 wt.% (SIBX)) was added to a solution of (1R, 4R, 5S) -5-hydroxy-benzyl-2-azabicyclo [ 2.2.1] ethyl heptane-2-carboxylate (4.02 g, 16.3 mmol) dissolved in dimethylsulfoxide (20.0 mL) and toluene (40.0 mL) under a nitrogen atmosphere at 23 ° C. The mixture was stirred for 3 h 30 min at 60 ° C and then cooled to 23 ° C. The resulting heterogeneous mixture was treated with saturated sodium carbonate (aq.) (250 ml) and filtered under reduced pressure to remove a white solid. The filtrate was extracted with ethyl acetate (250 ml x 3) and the organic extracts were washed with brine, dried over magnesium sulfate and concentrated in vacuo. The crude material as a colorless oil was purified by column chromatography (SiO2, EtOAc: n-Hex 1: 2 (v / v)) to provide the title compound B14 (2.99 g, 12.2 mmol, 75 %) as a colorless oil. (1R, 4R, 5R) -Benzyl 5- (4-methoxyphenylamine) -2-azabicyclo [2.2.1] heptane-2-carboxylate (B15) [00209] Sodium triacetoxyborohydride (0.904 g, 4.05 mmol) and glacial acetic acid (0.180 g, 3.00 mmol) were added to a solution of (1R, 4R) -benzyl-5-oxo-2- azabicyclo [2.2.1] methyl heptane-2-carboxylate (0.736 g, 3.00 mmol) and p-anisidine (0.370 g, 3.00 mmol) in 1,2-dichloroethane (10.0 mL) under an atmosphere of nitrogen, at 23 ° C. The resulting mixture was stirred for 3 h at 23 ° C. The heterogeneous mixture was cooled to 0 ° C and quenched with saturated sodium bicarbonate (aq.) (150 ml). The mixture was extracted with ethyl acetate (200 ml x 3) and the organic extracts were washed with brine, dried over magnesium sulfate and concentrated in vacuo. The crude material as a light yellow oil was purified by column chromatography (Si02, EtOAc: From n-Hex 1: 2 (v / v)) to provide the title compound B15 (0.964 g, 2.73 mmol, 91%) as a white solid. (1R, 4R, 5R) -Benzyl 5- (tert-butoxycarbonyl (4-methoxyphenyl) amino) -2-azabicyclo [2.2.1] heptane-2-carboxylate (B16) [00210] The mixture of methyl (1R, 4R, 5R) -benzyl 5 - (4-methoxyphenylamino) -2-azabicyclo [2.2.1] heptane-2-carboxylate (0.352 g, 1.00 mmol) and KHMDS ( 1.30 mL, 1.30 mmol, 1.0 M THF solution), in anhydrous THF (15.0 mL) was stirred for 15 min under nitrogen at 23 ° C. The resulting greenish mixture was treated with (Boc) 20 (0.470 g, 2.15 mmol) and then stirred for 16 h at 23 ° C. The mixture was concentrated under reduced pressure to provide yellow oil. The crude material was purified by column chromatography (Si02, EtOAc: De n-Hex 1: 2 (v / v)) to give the title compound B16 (0.408 g, 0.901 mmol, 90%) as a colorless oil. (1R, 4R, 5R) -Benzyl 5- (tert-butoxycarbonylamino) -2-azabicyclo [2.2.1] heptane-2-carboxylate (B17) [00211] Ceric ammonium nitrate (1.73 g, 3.15 mmol) dissolved in H2O (5.0 mL) was added to a solution of (1R, 4R, 5R) -benzyl 5 - (tert-butoxycarbonyl (4 -methoxyphenyl) amino) -2-azabicyclo [2.2.1] heptane-2-methyl carboxylate (0.408 g, 0.901 mmol) in acetonitrile (25 mL) under a nitrogen atmosphere at 0 ° C. The resulting mixture was stirred for 1 hour at 0 ° C and then diluted with H2O (100 ml), extracted with ethyl acetate (150 ml x 3). The combined organic phase was washed with 1 N Ns2SO3 (75 ml), dried over MgSO4 and concentrated in vacuo. The crude material was purified by column chromatography (Si02, EtOAc: De n-Hex 1: 2 (v / v)) to give the title compound B17 (0.229 g, 0.661 mmol, 73%) as a colorless oil. tert-Butyl (1R, 4R, 5R) -2-azabicyclo [2.2.1] heptane-5-carboxylate (B18) [00212] The palladium hydroxide mixture (0.015 g, 0.022 mmol, 10.0 mol%, 20% by weight on carbon, 50% moisture) and (1R, 4R, 5R) - benzyl 5 - (tert-butoxycarbonylamino ) Methyl -2-azabicyclo [2.2.1] heptane-2-carboxylate (0.077 g, 0.222 mmol) in ethanol (5.0 mL) was stirred for 3 h 30 min under a hydrogen atmosphere at 23 ° C. The resulting mixture was filtered through Celite and the pad was washed with ethyl acetate (100 ml). The filtrate was concentrated under reduced pressure to provide the title compound B18 (0.045 g, 0.212 mmol, 95%) as a colorless oil. [00213] 1H NMR (300 MHz, McOD): 8 3.89 (d, J = 11.2 Hz, 1H), 3.42 (s, 1H), 3.01 (d, J = 10.4 Hz , 1H), 2.74-2.69 (m, 1H), 2.58 (bs, 1H), 2.12-2.02 (m, 1H), 1.64 (s, 2H), 1, 46 (s, 9H), 1.19 - 1.13 (m, 1H). SECTION C: Section for compounds where L = S General Scheme 1: 3,5-difluoro-N-methyl-2-nitroaniline (C2): 1,3,5-Trifluoro-2-nitrobenzene (35.16 g, 0.2 mol) was dissolved in 100 ml of THF and cooled in an ice-water bath. To this solution, the 40% aqueous solution of methylamine (23.25g, 0.3 mol) was added dropwise over 20 minutes via an additional funnel. The reaction mixture was stirred for 1 hour. It was then diluted with hexane (50 ml), and the solvents were divided into two layers. The aqueous solution was removed, and the organic layer was washed with water (20 ml). The solution was concentrated by gentle rotary evaporation at room temperature and then dried under high vacuum to obtain the crude product (C2) as an orange solid (36g, 96%). [00214] 1H NMR (CDCl3, 300 MHz): 6 = 6.97-6.88 (m, 2H), 3.27 (s, 3H). [00215] Terc-butyl 3,5-difluoro-2-nitrophenyl (methyl) carbamate (C3): [00216] To a solution of crude 3,5-N-methyl-2-nitroaniline (C2) (36g, 0.191 mol) in 100 ml of THE was added di-tert-butyl-dicarbonate (54.3 g, 0.249 mol), followed by 4-dimethylaminopyridine (4.68 g, 0.038 mol). The reaction mixture was stirred at room temperature for 7 hours. Water (50 ml) was then added and the resulting solution was stirred for 1.5 hours. Then it was diluted with hexane (100 ml), the solution was divided into two layers, and the aqueous phase was removed by means of an extraction funnel and extracted back with ethyl acetate (50 ml). The combined organic layer was then washed first with a 5% NH4Cl solution (100 ml) and then with a 5% K2CO3 solution (100 ml). After the combined organic solvent was concentrated by rotary evaporation at room temperature, the resulting residue was redissolved in McOH (-50 ml) and then added dropwise in 600 ml of -0.01% K2CO3 solution . The solid orange product (C3) was filtered, washed with water, and dried under high vacuum (46.78 g, 85%). [00217] 1H NMR (CDCl3, 300 MHz): 6 = 6.93-6.85 (m, 2H), 3.20 (s, 3H), 1.32 (s, 9H). [00218] The synthesis of compound C4: To a solution of C3 (40 g, 0.14 mol) in DMF (200 mL) was added potassium carbonate (19 g, 0.14 mol), followed by a portion of cyan ethyl acetate (15 g, 0.14 mol). The mixture was stirred at room temperature for 2 hours. Then, an additional portion of potassium carbonate (19 g, 0.14 mol) and a portion of ethyl cyan acetate (15 g, 0.14 mol) were added. Then the mixture was stirred at room temperature for 4 h, potassium carbonate (19 g, 0.14 mol) was added and the mixture was stirred at room temperature for an additional 12 h. Then the mixture was poured into ice water and extracted with ethyl acetate (2 x 200 ml). The organic layer was dried over Na2SO4, filtered, concentrated and purified by silica gel chromatography (petroleum ether / ethyl acetate = 5: 1) to obtain the C4 compound (33 g, yield: 63%) as a yellow solid. [00219] 1H NMR (CDC13, 300 MHz): δ = 6.93-6.85 (m, 2H), 4.88 (m, 1H), 4.33 (m, 2H), 3.20 (s, 3H), 1.32 (s, 9H) , 1.28 (t, 3H). [00220] Synthesis of compound C5 To a solution of C4 (20 g, 52 mmol) in toluene (100 ml) and acetic acid (100 ml) was added zinc powder (30 g, 0.46 mol) and the mixture was stirred at 75 ° C for 2h. Then, another Zn powder (10 g, 0.15 mol) was added. After stirring at 75 ° C for an additional 0.5 h, the mixture was cooled to room temperature, filtered and poured into ice water. 2N NaOH was added to adjust the pH to 8-9 and the resulting mixture was extracted with ethyl acetate (2 x 200 ml). The organic layer was dried over Na2SO4, filtered, concentrated and purified by silica gel chromatography (petroleum ether / ethyl acetate = 5: 1) to give compound C5 as a brown solid (8.3 g, yield: 45 %). [00221] Synthesis of compound C7: To a stirred suspension of compound C5 (7.4 g, 20 mmol) in acetone (140 mL) was added dropwise a solution of acetyl thioisocynate (12 mL, 140 mmol) in acetone (50 mL) at room temperature. The reaction mixture was heated to reflux for 16 h. LCMS showed that the reaction was completed. The reaction mixture was concentrated to the next step without purification. LC-MS: M +1: 453.21. [00222] Above residue was dissolved in 50 ml of methanol and 50 ml of H2O, then 10 ml of 10% KOH solution was added, the mixture solution was heated to reflux for 30 minutes. When LCMS showed that the reaction was completed, the reaction was cooled to room temperature, acidified to pH 5 with 1 M aq. HCL, and the precipitate was collected by filtration to give compound C7 as a solid (5 g, 65.4% in two steps). LC-MS: M +1: 365.13. [00223] Synthesis of compound C10: Cul's solution (67 mg, 0.35 mmol), N, N'-dimethyl-cyclohexane-1,2-diamine (100 mg, 0.70 mmol) in 9 mL of NMP was added to a stirred suspension of tert-butyl (4-hydroxy-2-mercapto-9H-pyrimido [4,5-b] indol-8-yl) (methyl) carbamate (5, 350 mg, 1 , 0 mmol), an appropriate I-air (1.17 mmol), K2CO3 (324 mg, 2.35 mmol) and PPh3 (400 mg, 1.53 mmol) in NMP (9 mL). The mixture was heated at 130 ° C for 2 to 12 hours monitored by LC-MS to complete the reaction. When the reaction was complete, the mixture was cooled to 0 ° C, BOP (621 mg, 1.40 mmol) and Et 3 N (0.41 mL, 2.93 mmol), stirred for 30 minutes at 0 ° C, then warmed to room temperature, protected with Boc-diamine (2.34 mmol) was added. The reaction mixture was heated to 50 ° C for 30 minutes. LC-MS indicated that the reaction has completed. After the reaction was completed, the mixture was partitioned with ethyl acetate and water, the aqueous layer was extracted with ethyl acetate twice, the combined organic layer was dried and purified by flash chromatography to give the compound C10 products as a solid ( 420mg, 63% in two stages). LC-MS: M +1: 673.25. [00224] Synthesis of compound C11: The above compound (420 mg, 0.63 mmol) was dissolved in 10 ml of TFA and stirred for 30 minutes at room temperature. After removing the solvents, the residue was redissolved in methanol and 10 ml of 10m1 H2O, then 1N NaOH was added to neutralize the solution at pH 14, the base solution, then diluted by another H2O 100M1, and the solution was stirred vigorously for an additional 1 hour, the precipitate collected and dried to give final compounds, such as a white solid (200 mg, 70%). LC-MS: M +1: 473.13. [00225] 1H NMR (300 MHz, DMSO) δ (ppm): 11.75 (s, 1H), 8.09 (d, 1H), 8.95 (s, 1H), 8.52 (m, 1H ), 8.35 (s, 1H), 7.75 (m, 1H), 7.01 (d, J = 11.2, 1H), 5.96 (d, 1H), 4.10 (s, 1H), 2.98 (s, 3H), 2.85 (m, 2H), 2.67 (m, 2H), 1.38 (m, 1H), 0.75 (br m, 2H). [00226] 7- (4- (6-amino-3-azabicyclo [3.1.0] hexan-3-yl) -8 - (deuteratedmethylamino) -9H-pyrimido [4,5-b] indole-2-yl) -1,5-naphthyridine-1-C13 oxide (analog CD3 of 1.13): For the mixture of Cul (76 mg, 0.4 mmol) and K2CO3 (112 mg, 0.8 mmol) in NMP (1 ml) was added trans-N, N '-dimethylcyclohexane-1,2-diamine (113.6 mg (0.8 mmol). The mixture was stirred at 120 ° C for 10 minutes. It was then added with the compound ( 1) (70 mg, 0.2 mmol) and 7-iodo-1,5-naphthyridine-1-oxide (59.8 mg, 0.22 mmol). The reaction was maintained at 120 ° C for 20 minutes. cooled to -4 ° C and then Et 3 N (0.3 mL) was added followed by [benzotriazole-1-yl-oxy-tris- (dimethylamino) phosphonium hexafluorophosphate] (BOP reagent) (97.3 mg , 0.22 mmol). After stirring at -4 ° C to room temperature for 30 minutes, the reaction mixture was added with the amine (3) (79.3 mg, 0.4 mmol) and then then heated to 60 ° C for one hour. It was then purified by HPLC. Boc-adduct was removed by extraction with DCM (20 mL x 2). The combined organic layers were concentrated by rotary evaporation. The residue was redissolved in DCM (2 ml) and trifluoroacetic acid (-0.2 ml). It was stirred at 40 ° C for 30 minutes to remove the BOC-protection. The reaction mixture was purified by flash HPLC to produce the title compound (C13) as a white solid (52. 1 mg, 55%). [00227] 1H NMR (300 MHz, DMSO) δ (ppm): 11.75 (s, 1H), 8.09 (d, 1H), 8.95 (s, 1H), 8.52 (m, 1H ), 8.35 (s, 1H), 7.75 (m, 1H), 7.01 (d, J = 11.2, 1H), 5.96 (d, 1H), 4.10 (s, 1H), 2.85 (m, 2H), 2.67 (m, 2H), 1.38 (m, 1H), 0.75 (br m, 2H). Table of compounds of Formula I, where L = S SECTION D: SYNTHESIS OF THE COMPOUNDS OF FORMULA 1, WHERE L = O Synthesis of tricyclic nuclei L = O, where R8 is not NH alkyl [00228] Synthesis of compound D2: To a solution of D1 (40 g, 0.28 mol) in H2SO4 (200 ml) was added HNO3 (26 g, 0.42 mol) at 0 ° C. After stirring at 0 ° C for 1 h, the mixture was poured into ice water and extracted with ethyl acetate (2 x 200 ml). The organic layer was dried over Na2SO4, filtered, concentrated and purified by silica gel chromatography (petroleum ether / ethyl acetate = 15: 1) to give compound D2 (37 g, yield: 70%) as a yellow oil . [00229] 1H NMR (400 MHz, CDC13): δ: 6.93 (s, 1H), 6.91 (s, 1H), 4.33-4.27 (m, 2H), 2.73-2 , 68 (m, 2H), 1.29-1.25 (t, J = 7.6 Hz, 2H). [00230] Synthesis of compound D3: To a solution of 2 (37 g, 0.20 mol) in DMF (200 mL) was added potassium carbonate (54.8 g, 0.40 mol), followed by a portion of cyano ethyl acetate (22.3 g, 0.20 mol). The mixture was stirred at room temperature for 2 hours. Then, an additional portion of potassium carbonate (54.8 g, 0.40 mol) and a portion of ethyl cyan acetate (22.3 g, 0.20 mol) were added. Then the mixture was stirred at room temperature for 4 h, potassium carbonate (27.4 g, 0.2 mol) was added and the mixture was stirred at room temperature for an additional 12 h. Then the mixture was poured into ice water and extracted with ethyl acetate (2 x 200 ml). The organic layer was dried over Na2SO4, filtered, concentrated and purified by silica gel chromatography (petroleum ether / ethyl acetate = 5: 1) to give compound D3 (25 g, yield: 67%) as a yellow solid. . [00231] 1H NMR (400 MHz, CDC13): δ: 7.33-7.04 (dd, J = 4.4, 2.4 Hz, 1H), 7.16-7.13 (dd, J = 4.4, 2.4 Hz, 1H), 5.06 (s, 1H), 4.32-4.27 (m, 2H), 2.74-2.68 (m, 2H), 1.35 -1.26 (m, 6H). [00232] Synthesis of compound D4 and D4 ': To a solution of D3 (22 g, 79 mmol) in toluene (100 mL) and acetic acid (100 mL) was added zinc powder (30 g, 0.46 mol) and the mixture was stirred at 75 ° C for 2h. Then, another Zn powder (10 g, 0.15 mol) was added. After stirring at 75 ° C for an additional 0.5 h, the mixture was cooled to room temperature, filtered and poured into ice water. 2N NaOH was added to adjust the pH to 8-9 and the resulting mixture was extracted with ethyl acetate (2 x 200 ml). The organic layer was dried over Na2SO4, filtered, concentrated and purified by silica gel chromatography (petroleum ether / ethyl acetate = 5: 1) to obtain a brown solid, which was recrystallized from petroleum ether / EtOAc (10 : 1) to give a mixture of compound D4 and D4 '(7.2 g, yield: 35%) as a brown solid. [00233] Synthesis of compound D5: A mixture solution of compound D4 and D4 '(5.8 g) in EtOH (100 ml) / AcOH (5 ml) was hydrogenated with 10% Pd / C catalyst (580 mg) overnight under 50 psi pressure. The catalyst was filtered and the filtrate was concentrated to obtain compound D5 (5.3 g, yield: 93%). [00234] 1H NMR (400 MHz, DMSO-d6): δ: 10.75 (s, 1H), 7.08 (dd, J = 9.6, 2.4 Hz, 1H), 6.55 (dd , J = 10.8, 2.4 Hz, 1H), 6.44 (s, 2H), 4.21 (q, J = 7.2 Hz, 2H), 2.71 (q, J = 7, 6 Hz, 2H), 1.31 (t, J = 6.8 Hz, 3H), 1.20 (t, J = 7.6 Hz, 3H). LCMS [.Mobile phase: 30% -95% acetonitrile-NH4Ac 0.02% in 6 min, finally under these conditions for 0.5 min] purity is> 95%, Tr = 2.953 min, MS Cale: 250, MS observed: 251 ([M +1] +). [00235] To a stirred suspension of compound D5 (7.4 g, 20 mmol) in acetone (140 mL) was added dropwise a solution of acetyl thioisocynate (12 mL, 140 mmol) in acetone (50 mL) at temperature environment. The reaction mixture was heated to reflux for 16 h. LCMS showed that the reaction was completed. The reaction mixture was concentrated to the next step without purification. LC-MS: M +1: 453.21. [00236] To a stirred suspension of D6 (9.13 g, 20.0 mmol) in water / EtOH (75 mL / 25 mL) was added a solution of KOH in 20 mL of water at room temperature. The resulting mixture was refluxed for 4 h. TLC showed that the reaction was complete, then the reaction was cooled to room temperature, acidified with 1M aq. until pH = 5, the precipitate was collected by filter, washed with water (200 ml X 1) and then ethyl acetate (200 ml x 1) to give the product D7 as a pale yellow solid (5.90 g, 87.1% yield). TLC: Rf = 0.05 (silica gel, methanol: DCM = 1: 10, v / v). LC-MS: M-1: 248.10 [00237] 1H NMR (400 MHz, DMSO-d6): δ: 11.44 (s, 1H), 10.75 (s, 1H), 7.22 (s, 1H), 7.08 (dd, J = 9.6, 2.4 Hz, 1H), 6.55 (dd, J = 10.8, 2.4 Hz, 1H, 2.70 (q, J = 7.6 Hz, 2H), 1, 22 (t, J = 7.6 Hz, 3H). [00238] Compound D7 (2 g, 8.06 mmol) was placed with a solution of POC13 (50 ml) in a pressure tube and a few drops of N-ethyldiisopropyl amine. The reaction mixture was heated to 185 ° C, under sealed condition over 10 h. The mixture was cooled and poured into ice water and the yellow solid was collected by filtration, dried under reduced pressure to give D8 (2.1 g, 95% yield) as a yellow solid. LC-MS: M +1: 285.01 [00239] To a stirred solution of compound D8 (250 mg, 0.88 mmol) in 2 ml of NMP at 110 ° C, (R) -tert-butyl-5-aza-spiro [2.4] heptan was added -7-ylcarbamate (98 mg, 0.88 mmol) and K2CO3 (7 mg, 0.05 mmol). After the completion of the reaction, in 10 minutes, the reaction mixture was added 2-methylpimiridin-5-ol (28 mg, 0.25 mmol) in a microwave tube. The reaction mixture was sealed and placed in the microwave at 180 ° C for 10 minutes. The desired product was obtained by purification by HPLC, to give D9 (115 mg, 30%) as a white solid. LC-MS: M +1: 434.25. [00240] 1H NMR (300 MHz, DMSO-d6) δ: 11.44 (s, 1H), 10.75 (s, 1H), 7.22 (s, 1H), 7.08 (dd, J = 9.6, 2.4 Hz, 1H), 6.55 (dd, J = 10.8, 2.4 Hz, 1H), 2.70 (q, J = 7.6 Hz, 2H), 2, 64 (m, 2H), 2.62 (m, 2H), 2.01-2.41 (m, 4H), 1.22 (t, J = 7.6 Hz, 3H). [00241] Synthesis of compound D11 (2.06): The title compound was synthesized using the same method described for compound 1629 from 2,4-dichloro-6-fluoro-8-methyl-9H-pyrimido [4,5 -b] indole and (R) -tert-butyl-5-aza-spiro [2.4] heptan-7-ylcarbamate. LC-MS: M +1: 434.25. [00242] 1H NMR (300 MHz, DMSO) δ (ppm): 11.75 (s, 1H), 8.72 (s, 2H), 8.09 (br s, 3H), 7.01 (d, J = 11.2, 1H), 6.31 (d, J = 9.7, 1H), 4.40 (d, J = 9.9, 1H), 4.32 (dd, J = 7.6.4.5 , 1H), 4.03 (d, J = 12.3, 1H), 3.50 (d, J = 9.8, 2H), 2.67 (s, 3H), 2.05 (s, 3H ), 1.09 (m, 1H), 0.81 (m wide, 3H). [00243] Table of Compounds of Formula I, where L is O and R8 is not NHCH3 Synthesis of Compounds of Formula I, where L = O and R8 is NH alkyl General scheme for the bis-sulfone route Terc-butyl-2-amino-3-cyano-5-fluoro-1H-indol-7-yl (methyl) carbamate [00244] (D13): Crude tent-butyl-3,5-difluoro-2-nitro-phenyl (methyl) carbamate of (C3) (46.12 g, 0.162 mol) was dissolved in DMF (80 ml) and cooled in an ice-water bath. To this was added malononitrile (11.8 g, 179 mmol), followed by the addition of the NaOH solution (12.98 g, 325 mmol) in water (20 ml). After the exothermic reaction mixture was stirred for an hour, the ice-water bath was removed and the reaction was stirred for an additional hour. It was then diluted with DMF (80 ml) and water (80 ml) and the atmosphere was displaced with argon. Sodium bicarbonate (109 g, 1.3 mol), followed by sodium hydrosulfite (123 g, 649 mmol) was added. The mixture was stirred well, under argon, at 40 ° C for 12 hours (additional sodium hydrosulfite can be added, if the reaction was slower to complete). Then the reaction was cooled to room temperature, diluted with EtOAc (100 ml) and then filtered through an equipped glass funnel. The solids were washed with EtOAc / hexane (1: 1, 400 ml). The aqueous layer was separated, and the organic layer was extracted with 10% buffer 7 solution (3x 100 ml). The combined aqueous layers were extracted again with EtOAc / hexane (1: 1, 200m1). The combined organic phases were washed with 5% K2CO3 solution (300 ml). The extracts were then dried over sodium sulfate and concentrated by rotary evaporation, to provide the crude compound (D13) as a brown solid (32.6 g, 66%). LC -MS: M +1: 305.16. [00245] 1H NMR (DMSO, 300 MHz): 8 = 10.77 (s, 1H), 6.84-6.80 (m, 1H), 6.69 (s, 2H), 6.69-6 , 66 (m, 1H), 3.14 (s, 3H), 1.33 (s, 9H). [00246] Terc-butyl-2,4-bis (benzylthio) - 6-fluor-9H-pyrimido [4,5-b] indol -8-yl (methyl) carbamate (D15): Crude tert-butyl- 2 - amino -3- cyano -5-fluoro- 1H - indol-7-yl (methyl) carbamate (D13) (4 g, 13.14 mmol), sodium hydroxide (756 mg, 18.9 mmol), and EtOH (40 ml) was added to a 350m1 sealing tube. The mixture was stirred at 50 ° C for 15 min to dissolve all NaOH and then cooled to room temperature. After the atmosphere was displaced with argon, the solution with carbon disulfide (10 ml) and dimethyl sulfoxide (1 ml) was added. The reaction was stirred at room temperature for 1h then refluxed at 80 ° C for 42 hours. It was then cooled to room temperature and placed in an ice-water bath. Water (20 ml) was added, followed by the addition of benzyl chloride (3.33 g, 26.27 mmol). The ice-water bath was removed, and the reaction was stirred at room temperature for 5 hours. An additional benzyl chloride (1.66 g, 13.13 mmol) was added, and the resulting solution was stirred at room temperature overnight. It was diluted with EtOAc (60 ml) and water (100 ml). The resulting solution was divided into two layers, and the aqueous phase was removed by means of an extraction funnel and extracted again with 50 ml of ethyl acetate. The combined organic layers were concentrated by rotary evaporation, and the residue was purified by silica gel column chromatography (15% EtOAc in hexane) to give the title compound (D15) as a yellow foam (2.65 g, 36%). LC-MS: M +1: 561.05. [00247] 1H NMR (CDC13, 300 MHz): δ = 8.72 (s, 1H), 7.66-7.62 (dd, J = 8.37, 2.28 Hz, 1H), 7.48 -7.27 (m, 10H), 7.05-7.01 (dd, J = 10.14, 2.28 Hz, 1H), 4.69 (s, 2H), 4.55 (s, 2H ), 3.37 (s, 3H), 1.48 (s, 9H). [00248] Terc-butyl 2,4-bis- (benzylsulfonyl) -6-fluor-9H-pyrimido [4,5- b] indol-8-yl (methyl) carbamate (D16): The tert-butyl solution 2,4-bis (benzylthio) -6-fluor-9H-pyrimido [4,5-b] indol-8-yl (methyl) carbamate from (D15) (2.28 g, 4.07 mmol) in DCM ( 50 ml) was cooled in an ice-water bath and 77% 3-chloroperoxybenzoic acid (2.01 g, 8.95 mmol) was added. After the reaction was stirred for 1 hour, the ice-water bath was removed and an additional mCPBA (2.01 g) was added. The resulting solution was stirred at room temperature for 7 hours. It was then extracted with 5% K2CO3 solution (100 ml), and the aqueous layer was extracted with DCM (100Ml). The combined organic layers were washed first with 5% K2CO3 (100 ml) and then with a 5% NaCl solution (50 ml). It was dried over sodium sulfate and concentrated by rotary evaporation to obtain the crude title compound (D16) as a bright yellow solid (2.54 g, quantitative yield). LC-MS: M +1: 625.05. [00249] 1H NMR (CDC13, 300 MHz): 8 = 10.07 (s, 1H), 8.49-8.46 (dd, J = 8.64, 2.22 Hz, 1H), 7.54 -7.51 (m, 1H), 7.38-7.27 (m, 10H), 4.95 (s, 2H), 4.84 (s, 2H), 3.40 (s, 3H), 1.52 (s, 9H). Scheme: [00250] Preparation of D17: Bisulfone 2 (11.80 g, 17.23 mmol) was dissolved in NMP (60 mL), followed by the addition of 2-methylpyrimidin-5-ol 1 (7.59 g, 68.93 mmol). The homogeneous solution was obtained. K2CO3 (9.53 g, 68.93 mmol) was added and the resulting suspension was heated to 100 ° C for 1 hour, then Boc-protected amine (7.32 g, 34.46 mmol) was added and the mixture The resulting mixture was heated to 100 ° C for an additional hour, cooled to room temperature and water (450 ml) was poured into the mixture, with stirring. The mixture was cooled to 0 ° C, filtered and the precipitates were washed with water (2X25 ml), dried to give about 12 g of the white solid crude product. The crude solid was dissolved in dichloromethane and silica gel was added. The solvents were removed. Flash chromatography of the residue on silica gel (EtOAc / hexane: 20% to 50% to 90%) to give pure D17 as a white solid (7.76 g, 75%). LC-MS: M +1: 635.30. [00251] Preparation of D18 (4.069): Compound D17 was dissolved in 50 ml of TFA and stirred for 1 minute at room temperature. After removing the solvent, water (50 ml) and EtOH (25 ml) was added. The homogeneous solution was neutralized with 1 N NaOH (about 150 mL, pH> 10). The gummy solid was formed and separated. The gummy solid was suspended in water (50 ml) and the gummy solid was broken into small pieces with a spatula. The precipitates were filtered, washed twice with water and dried in air to give 4.40 pure gram D18 (4.069) as a light white solid (85%, total 63% from D16). LC-MS: M +1: 435.24. [00252] 1H NMR (300 MHz, DMSO) δ (ppm): 11.75 (s, 1H), 8.72 (s, 2H), 8.09 (br s, 3H), 7.01 (d, J = 11.2, 1H), 6.31 (d, J = 9.7, 1H), 4.40 (d, J = 9.9, 1H), 4.32 (dd, J = 7.6.4.5 , 1H), 4.03 (d, J = 12.3, 1H), 3.50 (d, J = 9.8, 2H), 2.85 (s, 3H), 2.67 (s, 3H ), 1.09 (m, 1H), 0.81 (m wide, 3H). [00253] Preparation of D20 (4,131): The title compound was synthesized using the method described above starting with tert-butyl (1R, 4R, 5R) -2-azabicyclo [2.2.1] heptan-5-ylcarbamate. [00254] LC-MS: M + 1: 435.24. [00255] 1H NMR (500 MHz, DMSO) δ (ppm): 11.75 (brm, 1H), 8.92 (brm, 1H), 8.66 (brs, 1H), 7.44 [00256] (d, J = 9.7, 1H), 7.04 (d, J = 5.2), 6.31 (d, J = 12.2, 1H), 5.56 (s, 1H), 4.38 (m, 1H), 4.04 (s , 1H), 3.37 (m, 1H), 3.01 (m, 1H), 2.87 (m, 1H), 2.85 (m, 3H), 2.66 (s, 3H), 2.16 (m, 1H), 1.86 (m, 1H), 1.79 (m, 1H), 1.75 (m, 1H). [00257] Preparation of D22 (4,408): The subtitle compound was synthesized using the method described above, starting with 2- (1-hydroxyethyl) pyrimidin-5-ol. [00258] LC-MS: M + 1: 465.22. [00259] 1H NMR (300 MHz, DMSO) S (ppm): 11.75 (s, 1H), 8.72 (s, 2H), 7.01 (d, J = 11.2, 1H), 6.31 (d, J = 9.7, 1H ), 4.82 (brm, 1H), 4.02 (m, 1H), 3.81 (m, 1H), 3.49 (m, 1H), 2.85 (s, 3H), 2.63 (brs, 1H), 2.14 (m, 1H) , 1.65-182 (m, 2H), 1.47 (d, 3H), 1.38 (m, 1H). [00260] Preparation of D24 (4,412): The title compound was synthesized using the method described above starting with 2 - (2-hydroxypropane-2-yl) pyrimidin-5-ol and (6R) -3-azabicycles [3.2 .0] heptan-6-amine. [00261] LC-MS: M + 1: 479.25. [00262] 111 NMR (500 MHz, DMSO) δ (ppm): 11.35 (brm, 1H), 8.82 (s, 2H), 7.07 (d, J = 9.7, 1H), 6.31 (d, J = 12.2, 1H ), 5.63 (m, 2H), 5.11 (brs, 11-1), 4.67 (m, 1H), 3.96 (m, 1H), 3.33-3.53 (m, 6H), 3.01 (m, 1H), 2.85 ( s, 3H), 2.70 (m, 1H), 2.51 (m, 1H), 1.55 (s, 6H). [00263] Preparation of D26 (4.103): The title compound was synthesized using the method described above starting with (3aR, 6aR) - octahydropyrrolo [3,4-b] pyrrole. [00264] LC-MS: M + 1: 435.21. [00265] 1H NMR (300 MHz, DMSO) δ (ppm): 8.71 (s, 2H), 6.96 (d, J = 11.2, 1H), 6.28 (d, J = 11.9, 1H), 5.56 (m, 1H ), 3.85 (m, 1H), 3.73 (m, 1H), 3.68 (d, J = 11.2, 1H), 3.60 (d, J = 11.3, 1H), 2.92 (m, 1H), 2.83 (m, 4H ), 2.77 (m, 1H), 2.67 (s, 3H), 1.85 (m, 1H), 1.62 (m, 1H). [00266] Preparation of D28 (4,160): The title compound was synthesized using the method described above starting with (1R, 5S, 6R) -6-amino-3-azabicyclo [3.1.0] hexane-6-carboxamide. LC-MS: M +1: 435.24. [00267] 1H NMR (300 MHz, DMSO) δ (ppm): 11.05 (s, 1H), 8.72 (s, 2H), 7.21 (s, 2H), 7.01 (d, J = 11.2, 1H), 6.11 ( d, J = 9.7, 1H), 5.01 (s, 211), 4.03 (d, J = 12.3, 1H), 2.95 (s, 3H), 2.81 (m, 2H), 2.75 (m, 2H), 2.67 ( s, 311), 0.85 (br m, 2H). [00268] The subtitle compound D30 was synthesized using the same method as described for the compound above, starting with bisulfone and (R) -2-azaspiro [3.3] heptan-5-amine (the diamine was prepared from column separation of commercially available newsletters). LC-MS: M + 1 435.21. [00269] The subtitle compound D32 was synthesized using the same method described above for the starting compound with bis-sulfone and (1S, 5R, 6R) -3-azabicyclo [3.2.0] heptan-6-amine (the diamine was prepared according to PCT patent procedure Int. Appl. (1994), WO 9415933 A1 19940721 and separation from the chiro column). LC-MS: M +1: 435.21. [00270] The subtitle compound D34 was synthesized using the same method described above for the starting compound with bis-sulfone and (1S, 5R, 6R) -1-methyl-3-azabicyclo [3.2.0] heptan-6- amine (the diamine was prepared according to patent procedure WO 2001053273 Al and the separation from the chiro column). LC-MS: M +1: 449.25. [00271] The subtitle compound D36 was synthesized using the same method, described above for the starting compound with bis-sulfone and (3aR, 6aR) -3a-methyloctahydropyrrolo [3,4-b] pyrrole (diamine was prepared from according to patent procedure US5202337 (A) and the separation of the chiro column). LC-MS: M +1: 449.23. Dichloro Route General Scheme: [00272] Example of compounds made by adding R4 before R2 [00273] To a stirred suspension of BnNHMe (34.2g, 0.282 mol) and K2CO3 (50.6 g, 0.367moL) in 400 ml of THF was added dropwise a solution of compound 1 (50.Og, 0.282 mol) in 100 mL of THF, below 10 ° C. After the addition, the reaction was slowly warmed to room temperature and stirred overnight. TCL showed that the reaction was completed, the reaction mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate (300 ml) and water (500 ml), the organic layer was washed with brine (300 ml x 3), dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography (pet. Ether / EtOAc, 100/1 to 50/1, v / v) to give the product in D37 as a pale yellow solid. (69.0 g, 87.9% yield). LC-MS: M +1: 279 [00274] 1H-NMR (400 MHz, CDCl3) δ (ppm): = 7.37 (5H, m), 6.43 (2H, m), 4.40 (2H, s), 2.84 (3H ,s). [00275] To a stirred suspension of K2CO3 (57.6 g, 0.417 mol) and cyanoacetate acetate (35.4g, 0.313moL) in 200 ml of DMF was added a solution of compound D37 (58.0g, 0.208 mol) in 100 ml DMF under N2 protection. After the addition, the reaction was stirred at room temperature for two days.TLC showed the SM was consumed, the reaction mixture was diluted with ethyl acetate (400mL) and water (1500 mL), the organic layer was separated, the layer aqueous solution is extracted with ethyl acetate (200 ml). The combined organic layer was washed with brine (300 ml x 3), dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by chromatography (pet. Ether / EtOAc, 100/1 to 20/1, v / v) to give the product in D38 as a pale yellow solid. (61.0 g, 79.2% yield). LC-MS: M +1: 371 [00276] 1H-NMR (400 MHz, CDC13) δ (ppm): 7.33 (5H, m), 6.92 (1H, d, J = 8 Hz), 6.84 (1H, d, J = 8 Hz), 5.13 (1H, s), 4.37 (2H, $). 4.30 (2H, dd, J = 14.4 Hz), 2.78 (3H, s), 1.35 (3H, t, J = 7.2 Hz). [00277] To a stirred solution of compound D38 (61.0 g, 0.164 mol) in 400 ml AcOH was cooled in an ice bath, powdered zinc was added in portions. After the addition, the reaction was heated to 60 ° C and stirred at this temperature for 5 h. TLC showed that the reaction was complete. The reaction mixture was cooled to room temperature, filtered, the filtrate was concentrated in vacuo, the residue was dissolved in ethyl acetate (400 ml), basified with a saturated aqueous solution of NaHCO3 (400 ml), then organic layer was separated, washed with brine (200 ml x 3), dried over Na2SO4, filtered and concentrated in vacuo to give a dark oil which was purified by chromatography (pet. ether / DCM, 5/1 to DCM, v / v ) to give the product as a pale yellow solid D39. (26.0 g, 46.4% yield). LC-MS: M +1: 342 [00278] 1H-NMR (400 MHz, CDCl3) S (ppm): 8.02 (1H, s), 7.33 (5H, m), 6.52 (1H, d, J = 2.4 Hz) , 6.49 1H, d, J = 2.4 Hz), 5.73 (2H, s), 4.35 (2H, dd, J = 15.2 Hz). 4.19 (2H, s), 2.73 (3H, s), 1.44 (3H, t, J = 7.2 Hz). [00279] To a stirred suspension of D39 (16.0 g, 46.9mmoL) in 200 ml of DCM was added dropwise isocyanate acetate (resolved in 50 ml of DCM) with ice bath cooling. After the addition, the resulting mixture was stirred at room temperature the SM was gradually dissolved then precipitate was generated from the reaction. 4 hours later, TLC showed that the reaction was complete. The reaction mixture was filtered. The filtration was concentrated in vacuo. The residue was suspended in 50 ml of DCM, stirred, then filtered. The two filter cakes in batches were combined, dried in vacuo to give the product in D40 as a pale yellow solid. (14.4 g, 67.3% yield). LC-MS: M +1: 457 [00280] 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 12.01 (1H, S), 11.12 (1H, S), 11.06 (1H, S), 10.41 ( 1H, S), 7.33 (5H, m), 6.63 (1H, d, J = 2.0 Hz), 6.60 (1H, d, J = 2.4 Hz), 4.34 ( 2H, dd, J = 7.2 Hz), 4.28 (2H, s), 4.24 (2H, dd, J = 7.2 Hz), 4.14 (2H, dd, J = 7.2 Hz), 2.75 (3H, s), 1.37 (3H, t, J = 7.2 Hz) 1.27 (3H, t, J = 7.2 Hz), 1.22 (3H, t , J = 6.8 Hz). [00281] To a stirred suspension of D40 (9.13 g, 20.0 mmol) in water / EtOH (75 mL / 25 mL) was added a solution of KOH in 20 mL of water at room temperature. The resulting mixture was refluxed for 4 h. TLC showed that the reaction was complete, then the reaction was cooled to room temperature, acidified with 1M aq. until pH = 5, the precipitate was collected by filter, washed with water (200 ml X 1) and then ethyl acetate (200 ml X 1) to give D41, the product as a pale yellow solid (5.90 g, 87 , 1% yield) CL-EM: .. M-1: 337. [00282] 1H-NMR (400 MHz, DMSO-d6) 8 (ppm): 7.25 (5H, m), 7.01 (1H, dd, J = 8.8 Hz), 6.35 (1H, d, J = 12.0 Hz), 4.45 (2H, $), 2.76 (3H, s). [00283] Compound D41 (2 g, 5.75 mmol) was placed with a solution of POCl3 (100 ml) in a pressure tube and a few drops of N-ethyldiisopropyl amine. The reaction mixture was heated to 185 ° C, under sealed condition over 10 h. The mixture was cooled and poured into ice water and the yellow solid was collected by filtration, dried under reduced pressure to give D42 (1.6 g, 98% yield) as a yellow solid. LC-MS: M +1: 286.02 [00284] To a stirred solution of compound D42 (250 mg, 0.87 mmol) in 5 ml of NMP at 110 ° C, (R) -tert-butyl-5-aza-spiro [2.4] heptan was added -7-ylcarbamate (175 mg, 0.88 mmol) and K2CO3 (7 mg, 0.05 mmol). Upon completion of the reaction, within 10 minutes, the reaction mixture was added to a solution of 2-methylpymiridin-5-ol (90 mg, 0.90 mmol) in a microwave tube. The reaction mixture was sealed and placed in the microwave at 220 ° C for 10 minutes. The desired product was obtained by purification by HPLC, to give D43 (90 mg, 25%) as a white solid. LC-MS: M +1: 421.18. [00285] The subtitle compound D44 was synthesized using the method described above starting with (1R, 4R, 5R) -2-azabicyclo [2.2.1] heptan-5-amine and 3-hydroxy-6-methyl-6,7 -dihydro-5H-pyrrolo [3,4-b] pyridin -5-one. LC-MS: M +1: 489.22. [00286] The subtitle compound D45 was synthesized using the method described above starting with tert-butyl-3-azabicyclo [3.1.0] hexan-6-ylcarbamate and 5 - (1-methyl-1H-tetrazol-5-yl ) pyridin-3-ol. LC-MS: M +1: 488.20. [00287] The subtitle compound D46 was synthesized using the method described above starting with (6R) -3-azabicyclo [3.2.0] heptan-6-amine and 2-aminopyrimidin-5-ol. LC-MS: M +1: 436.20. [00288] The subtitle compound D43 was synthesized using the same method as described above for the starting compound with bis-sulfone and tert-butyl-3-azabicyclo [3.1.0] hexane-6-ylcarbamate. LC-MS: M +1: 421.18. [00289] The subtitle compound D49 was synthesized using the same method as described above for the starting compound with bis-sulfone and (1R) -5-aza-spiro [2.4] heptan-1-amine. LC-MS: M +1: 435.23. [00290] The subtitle compound D51 was synthesized using the same method as described above for the starting compound with bis-sulfone and (1S, 4R) -6-azaspiro [3.4] CTAN-1-amine. LC-MS: M +1: 449.25. [00291] The subtitle compound D53 was synthesized using the same method as described above for the bis-sulfone starting compound, octahydrocyclopenta [c] pyrrole-4-amine. LC-MS: M +1: 449.21. [00292] The subtitle compound D55 was synthesized using the same method described above for the starting compound with bis-sulfone and (4aR, 7aR) -tert-butyl-octahydro-1H-pyrrole [3,4-b] ethyl pyridine-1-carboxylate. LC-MS: M +1: 449.23. [00293] The subtitle compound D57 was synthesized using the same method as described above for the starting compound with bis-sulfone, quinazolin-7-ol and (1S, 5R, 6R) -3-azabicyclo [3.2.0] heptan- 6-amine. LC-MS: M +1: 471.26. [00294] The subtitle compound D59 was synthesized using the same method as described above for the starting compound with bis-sulfone, 1,5-naphthyridin-3-ol and (1S, 5R, 6R) -3-azabicycles [3.2. 0] heptan-6-amine. LC-MS: M +1: 471.20. [00295] The subtitle compound D61 was synthesized using the same method as described above for the starting compound with bis-sulfone, 1,5-naphthyridin-3-ol and tert-butyl-3-azabicyclo [3.1.0] hexan -6-ilcarbamate. LC-MS: M +1: 457.20. [00296] The subtitle compound D63 was synthesized using the same method described above for the starting compound with bis-sulfone, 1,5-naphthyridin-3-ol and (S) -2-azaspiro [3.3] heptan-5- the mine. LC-MS: M +1: 471.22. [00297] The subtitle compound D65 was synthesized using the same method described above for the compound starting with bis-sulfone, 5-hydroxypicolinonitrile and (1R, 4R, 5R) -2-azabicyclo [2.2.1] heptan-5-amine . LC-MS: M + 1: 445.18. Synthesis of analogues, where R4 is not attached by a nitrogen [00298] 22-chloro-6-fluoro-4- (1H-imidazol-4-yl) -N-methyl-9H-pyrimido [4,5-b] indole-8-amine: The mixture of the compound (1) (150 mg, 0.52 mmol), 4 - (4,4,5,5-tetramethyl-1,2,2-dioxaborolan-2-yl) -1H-imidazole (2) (100 mg, 0.52 mmol ), K2CO3 (100 mg, 0.5 mmol), and a catalytic amount of Pd [(PPh3)] C12 was dissolved in DMF (3 ml) and water (0.3 ml). It was heated to 150 ° C in a microwave for 10 minutes. The mixture was then purified by means of HPLC to produce the title compound as a yellow solid (91 mg, 55% yield). LC-MS: M +1: 317.08. [00299] 1H NMR (300 MHz, DMSO) δ (ppm): 14.01 (S, 1H), 11.71 (s, 1H), 7.98 (s, 2H), 7.51 (d, J = 11.2, 1H), 6.30 (d, J = 9.7, 1H), 4.12 (s, 1H), 3.15 (s, 3H). [00300] 6-fluoro-4- (1H-imidazol-4-yl) -N-methyl-2- (2-methylpyrimidin-5-yloxy) -9H-pyrimido [4,5-b] indole-8-amine D66: For the solution of compound (3) (80 mg, 2.52 mmol) in NMP (5 mL), 2-methyl-pyrimidine-5-ol (33 mg, 3.0 mmol) and potassium carbonate ( 43.6 mg, 0.31 mmol). It was then heated to 160 ° C, under microwave condition for 15 minutes. The mixture was then purified by means of HPLC to produce the title compound as a yellow solid (59 mg, 60%). LC-MS: M +1: 391.15. [00301] 1H NMR (300 MHz, DMSO) δ (ppm): 14.01 (S, 1H), 11.71 (s, 1H), 7.98 (s, 2H), 7.69 (s, 2H ), 7.51 (d, J = 11.2, 1H), 5.98 (d, J = 9.7, 1H), 4.02 (s, 1H), 3.10 (s, 3H), 2.65 (s, 3H). [00302] The subtitle compound D67 was synthesized using the method described above starting from 3-fluoro-5- (4,4,5,5-tetramethyl-1,2,2-dioxaborolan-2-yl) pyridine. LC-MS: M +1: 420.16. [00303] 1H NMR (300 MHz, DMSO) δ (ppm): 11.71 (s, 1H), 9.10 (s, 1H), 8.52 (d, 1H), 7.63-7.80 (m, 3H), 7.31 (brs, 1H), 5.98 (d, J = 9.7, 1H), 4.10 (s, 1H), 2.98 (s, 3H), 2, 66 (s, 3H). [00304] 6-Fluoro-4- (4-methoxybenzylthio) -N-methyl-2- (2-methylpyrimidin-5-yloxy) -9H-pyrimido [4,5-b] indole-8-amine (D69): To the solution of compound (1) (2.923 g, 5 mmol) in NMP (12 mL), potassium carbonate (2.073 g, 15 mmol) was added followed by 4-methoxyphenyl) methanethiol (0.771 g, 5 mmol). The reaction mixture was stirred at room temperature for one hour. 2-methyl-pyrimidine-5-ol (1.101 g, 10 mmol) was then added. The resulting mixture was heated at 100 ° C for 3 hours. This was purified by C18 column chromatography to give the title compound as a light yellow solid (2.4 g, 83%). [00305] 6-Fluoro-8- (methylamino) -2- (2-methylpyrimidin-5-yloxy) -9H-pyrimido [4,5-b] indole-4-ol (D70): For the solution of the compound ( 3) (2.48 g, 4.3 mmol) in dioxane (12 ml) 3-chloroperoxy benzoic acid (1.484 g, 8.6 mmol) was added per portion over 10 minutes. Then the reaction was stirred at room temperature for 30 minutes, lithium hydroxide (1.8 g, 75 mmol) and water (5 ml) were added. The resulting solution was stirred at room temperature to 100 ° C for one hour. It was then purified by means of C18 column chromatography to produce the title compound as a white solid (1.39 g, 95%). [00306] 4-Chloro-6-fluoro-N-methyl-2- (2-methylpyrimidin-5-yloxy) -9H-pyrimido [4,5-b] indole-8-amine (D71): Compound (D70) (1.06 g, 2.407 mmol) was dissolved in POCl3 (20 ml) and N-ethyl-isopropylpropan-2-amine (0.43 g; 3.33 mmol). The mixture was heated to 50 ° C for 4 hours. After the reaction was cooled to room temperature, it was poured into a 1L flask containing ice (-500 g) and NaOH (20 g) and the resultant was seated for one hour. It was then extracted with ethyl acetate (100 ml x 3). The combined organic layers were dried over Na2SO4 and concentrated by rotary evaporation to obtain the title compound as a white solid (492 mg, 57%). [00307] 4- (2-amino-4-chlorophenyl) -6-fluoro-N-methyl-2- (2-methylpyrimidin-5-yloxy) -9H-pyrimido [4,5-b] indole-8-amine - (D72): The mixture of compound (D71) (36 mg, 0.1 mmol), pinacol boronic acid ester (6) (38 mg, 0.15 mmol), potassium phosphate (64 mg, 0 , 3 mmol) and catalytic amount of Pd (PPh3) 4 was dissolved in DMF (1 ml) and water (0.3 ml). The reaction mixture was refluxed at 100 ° C for one hour. It was then purified by means of HPLC to produce the title compound as a yellow product (17 mg, 37.8%). [00308] The subtitle compound D73 was synthesized using the method described above, starting with 3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2-amine. Synthesis of Prodrugs at R4 (S) -2-amino-N - ((R) -5- (6-fluoro-8- (methylamino) -2- (2-methylpyrimidin-5-yloxy) -9H-pyrimido [4.5-b] indol-4-yl) -5-azaspiro [2.4] heptan-7yl) propanamide D76 (4,424) [00309] The mixture of D16 (0.342 g, 0.500 mmol), 2-methylpyrimidin-5-ol (0.165 g, 1.50 mmol) and K2CO3 (0.276 g, 2.00 mmol) in NMP (5.0 mL) it was stirred for 1 h 30 min at 100 ° C. After being stirred for 1 h 30 min, the reaction was checked by LC / MS. (R) -5-aza-spiro [2.4] hepten-7-amine (0.168 g, 1.50 mmol) was added in one go, the mixture was allowed to stir for 1 h 30 min at 100 ° C . The resulting heterogeneous mixture was cooled to 23 ° C and purified by HPLC to give D74 (0.100 g, 0.187 mmol) as a light yellow solid. LC / MS (ESI, M + H +) = 535. To a solution of D74 (0.100 g, 0.187 mmol) and K2CO3 (0.052 g, 0.374 mmol) in CH2C12 (8.0 mL) was added (S) -2 - propanoyl chloride (1,3-dioxoisoindoline-2-yl) (0.089 g, 0.374 mmol) dissolved in CH2Cl2 (2.0 mL) at 23 ° C. The mixture was allowed to stir for 1 h 30 min at 60 ° C and then cooled to 23 ° C. The reaction mixture was concentrated by Rotavap and the crude material was purified by HPLC to give D75 as a yellow solid. LC / MS (ESI, M + H +) = 736. To a solution of D75 in ethanol (7.0 mL) was added hydrazine (1.5 mL, 30 wt.% Solution in water) via a syringe 23 ° C. The mixture was stirred for 1 hour at 23 ° C. The reaction mixture was concentrated by Rotavap and the crude material was purified by HPLC to provide D76 as a light yellow solid. LC / MS (ESI, M + H +) = 606. The mixture of D76 in trifluoroacetic acid (1.00 ml) was stirred for 1 hour at 23 ° C. The crude material was purified by HPLC to provide a title compound D76 (0.026 g, 0.051 mmol) as a white solid. LC / MS (ESI, M + H +) = 506. Synthesis of R8 (S) -2-Amino-N- (4 - ((R) -7-amino-5-azaspiro [2.4] heptan prodrugs) -5-yl) -6-fluoro-2- (2-methylpyrimidin-5-yloxy) -9H-pyrimido [4.5-b] indol-8-yl) -N- methylpropanamide [00310] The mixture of D16 (1.00 g, 1.46 mmol) in trifluoroacetic acid (3.0 mL). Stir for 30 min at 23 ° C. Trifluoroacetic acid was evaporated under reduced pressure to provide D77 (quantitative yield) as a deep orange solid. This crude material was used for the next reaction without further purification. LC / MS (ESI, M + H +) = 585. The mixture of D77 (0.292 g, 0.50 mmol), 2-methylpyrimidin-5-ol (0.165 g, 1.50 mmol) and K2CO3 (0.276 g, 2.00 mmol) in NMP (5.0 mL) was stirred for 2 hours at 100 ° C. After being stirred for 2 hours, the reaction was checked by LC / MS. (R) -tert-butyl-5-aza-spiro [2.4] hepten-7-ylcarbamate (0.318 g, 1.50 mmol) was added in one go, the mixture was allowed to stir for 1 h 30 min at 100 ° C. The resulting heterogeneous mixture was cooled to 23 ° C and purified by HPLC to provide D78 (0.182 g, 0.34 mmol) as a yellow solid. LC / MS (ESI, M + H +) = 535. To a solution of D78 (0.182 g, 0.34 mmol) and K2CO3 (0.094 g, 0.68 mmol) in CH2C12 (10.0 ml) was added ( 5) -2 - (1,3-dioxoisoindoline-2-yl) propanoyl chloride (0.161 g, 0.68 mmol) dissolved in CH2 Cl2 (2.0 mL) at 23 ° C. The mixture was left to stir for 2 hours at 60 ° C and then cooled to 23 ° C. The reaction mixture was concentrated by Rotavap and the crude material was purified by HPLC to give D79 as a yellow solid. LC / MS (ESI, M + H) = 736. To a solution of D79 in ethanol (7.0 mL), hydrazine (1.5 mL, 30 wt.% Solution in water) was added via a syringe at 23 ° C. The mixture was stirred for 1 hour at 23 ° C. The reaction mixture was concentrated by Rotavap and the crude material was purified by HPLC to provide 5 as a light yellow solid. LC / MS (ESI, M + H +) = 606. The mixture of 5 in trifluoroacetic acid (1.50 ml) was stirred for 30 min at 23 ° C. The crude material was purified by HPLC to provide a title compound D80 (0.031 g, 0.061 mmol) as a white solid. LC / MS (ESI, M + H +) = 506. R4 and R8 prodrug: (R) -2-Amino-N- (4- (7- (2-aminoacetamide) -5-azaspiro [2.4] heptan-5-yl) -6-fluoro-2- (2-methylpyrimidin-5-yloxy) -9H-pyrimido [4.5-b] ondol-8-yl) -N-methylacetamide [00311] To a solution of D16 (0.075 g, 0.173 mmol) and K2CO3 (0.084 g, 0.606 mmol) in CH2C12 (8.0 mL) was added 2 - (1,3-dioxoisoindoline-2-yl) acetyl chloride (0.136 g, 0.606 mmol) dissolved in CH2Cl2 (2.0 mL) at 23 ° C. The mixture was left to stir for 3 h 30 min at 60 ° C and then cooled to 23 ° C. The reaction mixture was concentrated by Rotavap and the crude material was purified by HPLC to give D81 as a light yellow solid. LC / MS (ESI, M + H +) = 809. To a solution of D81 in ethanol (5.0 ml) was added hydrazine (1.0 ml, 30 wt solution.% In water) via a syringe at 23 ° C. The mixture was stirred for 1 hour at 23 ° C. The reaction mixture was concentrated by Rotavap and the crude material was purified by HPLC to provide a title compound D82 (0.084 g, 0.153 mmol) as a white solid. LC / MS (ESI, M + H +) = 549. Table of compounds of Formula I, where L = O, Rx, Ry, Rz = H, R8 = NHCH3 Table of Compounds of Formula I, where L is O, Rx, Rz is CH, Ry is F and R8 is NHCH3 Difluorophenyl Experimental Analogs: [00312] Preparation of compound D84: Tri-flow aniline (250g) was added only in portions in 500 ml of acetic anhydride under the ice-water bath, after the addition, the reaction was stirred vigorously for 4 hours, then poured into beaten ice, the precipitate (white granular solid) was collected and dried for the next step (quantitative yield). [00313] Preparation of compound D85: The above converted acetyl aniline (126g, 666mmol) was added only in portions of sodium hydride (40g, 1mmol, 60% in oil) in dry THF solution (1L) under the water bath then the solution was stirred for another hour, then honey (64m1, 1mol) in 100M1 THF by dripping into the solution, the mixture was stirred overnight (12 hours), and quenched with water icy. The aqueous solution was extracted with ethyl acetate 3X 500m1, the combined solution was dried and concentrated to the next steps without further purification. [00314] Preparation of compound D86: The crude compounds above were dissolved in 1500 ml of acetic anhydride under the ice-water bath, followed by KNO3 (168g, 1.66mol) was added to the solution only in a portion of TFAA, kept at temperature below 35 ° C, controlling the KNO3 rate, after the addition, the reaction was stirred for another 36 hours, then the reaction was quenched with ice water, the red solution was extracted with ethyl acetate 3X 500ml, the combined solution was dried and concentrated for further steps without further purification. [00315] Preparation of compound D87: The above solid was dissolved in 1D (2M HCL), the reaction solution was refluxed for 4 hours, the CCF monitored the reaction, cooled to room temperature when the starting material disappeared, the dark red solution was extracted with 3X DCM 500ml, the combined solution was dried and concentrated. the residue was purified by flash chromatography, nice dark granular solids (105 g) was obtained in 75% yield. [00316] Preparation of compound D88: The above N-methylaniline (21 g, 100 mmol) was added in portions of sodium hydride (40 g, lmmol, 60% in oil) in dry THF solution (1L) under the ice-water bath, then the solution was stirred for another hour, then Boc anhydride (24 g, 110 mol) in 100Ml THF by dripping into the solution, the mixture was stirred overnight (12 hours) , and was extinguished with 10% HOAc / water and ice. the aqueous solution was extracted with ethyl acetate 3X 500m1, the combined solution was dried and concentrated to remove the solvent, then the residue was purified by flash chromatography to give 26g of desired product, 82% yield. [00317] Preparation of compound D89: To a stirred suspension of K2CO3 (13.8 g, 0.1 mol) and ethyl cyanoacetate (11.2 g, 0.1 mol) in 200 ml of DMF was added a solution of the compound D88 (20.0 g, 066 mmol) in 100 mL of DMF under N2 protection. After the addition, the reaction was stirred at room temperature for two days.TLC showed the SM was consumed, the reaction mixture was diluted with ethyl acetate (400 ml) and water (1500 ml), the organic layer was separated, the aqueous layer extracted with ethyl acetate (200 ml). The combined organic layer was washed with brine (300 ml x 3), dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by chromatography (pet. Ether / EtOAc, 100/1 to 20/1, v / v) to give compound D89 as a pale yellow solid (12.0 g, 45% yield). [00318] Preparation of the compound: To a solution of the compounds D89 (12g, 30mmol) in acetic acid (200ml) was added zinc powder portionly (13g, 200mmol). After the addition, the reaction mixture was heated to 50 degrees, LCMS monitored the reaction process. The reaction was concentrated after the reaction was completed (about 4 hours), and the residue was partitioned with H2O (200m1) and ethyl acetate (200ml), the aqueous layer was extracted twice with ethyl acetate, the solvent combined was dried and concentrated, the residue was purified by flash chromatography to produce D90 products (9 g, 81% yield). %). LC-MS: M +1: 370. [00319] Preparation of compound D91: To a stirred suspension of compound D90 (7.4 g, 20 mmol) in acetone (140 mL) was added dropwise a solution of acetyl thioisocynate (12 mL, 140 mmol) in acetone (50 mL) at room temperature. The reaction mixture was heated to reflux for 16 h. LCMS showed that the reaction was completed. The reaction mixture was concentrated to the next step without purification. [00320] Preparation of compound D92: above residue was dissolved in 50 ml of methanol and 50 ml of H2O, then 10 ml of 10% KOH solution was added, the mixture solution was heated to reflux for 30 minutes. When LCMS showed that the reaction was completed, the reaction was cooled to room temperature, acidified to pH 5 with 1 M aq. HCl, and the precipitate was collected by filtration to give compound D92 as a solid (5 g, 65.4% in two steps). LC-MS: M +1: 383. [00321] Preparation of compound D93: To a stirred suspension of compound D92 (3.8 g, 10 mol) and K2CO3 (2.8 g, 20 mol) in 50 ml of NMP was added dropwise a solution of 1 - (chloromethyl) -4-methoxybenzene (1.5 g, 9.6 mol) in 5 ml of NMP at room temperature. LCMS showed that the reaction was completed in 40 minutes. The reaction mixture was cooled to 0 ° C, BOP (4.86 g, 11 mmol) and Et3N (1.5 g, 15 mmol) were added. After 30 minutes, (4-methoxyphenyl) methanethiol (2 g, 12 mmol) was added to the reaction mixture and was warmed to room temperature and then heated to 40 ° C for 1 h. The reaction mixture was diluted with ethyl acetate (200 ml) and water (500 ml), the organic layer was separated, the aqueous layer was extracted with ethyl acetate (200 ml). The combined organic layer was washed with brine (100 ml x 3), dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by chromatography (pet. Ether / EtOAc, 100/1 to 20/1, v / v) to give compound D93 as a pale yellow solid (5.4 g, 84% yield). LC-MS: M +1: 639. [00322] Preparation of compound D94: To a stirred suspension of compound D93 (2 g, 3.1 mmol) in 200 ml of CH2Cl2 at 0 ° C was added MCPBA (2.8 g, 21 mmol) in portions. The reaction mixture was stirred at room temperature for 16 h, 30 ml of saturated Na2S2O3 was added. The reaction mixture was diluted with ethyl acetate (200 ml) and water (500 ml), the organic layer was separated, the aqueous layer was extracted with ethyl acetate (100 ml). The combined organic layer was washed with 100 ml of saturated Na2CO3 and brine (100 ml x 3), dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by chromatography to give compound D94 as a yellow solid (1.4 g, 64%). LC-MS: M +1: 703. [00323] Preparation of compound D95: The mixture of tert-butyl (1R, 4R, 5R) -2-azabicyclo [2.2.1] heptan-5-ylcarbamate (430 mg, 2 mmol), 7 (1.40 g, 2 mmol), and K2CO3 (280 mg, 2 mmol) in NMP (5 mL) was stirred overnight at room temperature, then 2-methylpyrimidin -5-ol (330 mg, 3 mmol) was added and the mixture The resulting mixture was heated to 50 ° C overnight. The crude product was purified by HPLC to give compound D95 (a protected BOC D96) as a white solid (700 g, 54%). LC-MS: M +1: 653. [00324] Preparation of compound D96: The above compound (700 mg, 1.1 mmol) was dissolved in 10 ml of TFA and stirred for 1 minute at room temperature. After removing the solvents, the residue was redisolved 10m1 in methanol and 10 ml of H2O, then 1N NaOH was added to neutralize the solution at pH 14, the base solution, then diluted by another 100M1 H2O, and the solution was stirred vigorously for another 1 hour, the precipitate collected and dried for final compounds D96 gave as a white solid (400 mg, 80%). LC-MS: M +1: 453.20. [00325] 1H NMR (300 MHz, DMSO) S (ppm): 11.75 (s, 1H), 8.72 (s, 2H), 6.45 (dd, J = 2.7, J = 5, 2. 1H), 5.37 (brm, 1H), 4.46 (s, 1H), 3.78 (m, 1H), 3.67 (m, 1H), 3.33 (brs, 1H), 2.83 (brs, 3H), 2.67 (s, 3H), 2.37 (brs, 1H), 2.01 (brt, 1H), 1.20 (brt, 1H). [00326] Preparation of compound D97: The title compound was synthesized, using the same method as described for the previous compound starting with (R) -2-azaspiro [3.3] heptan-5-amine. LC-MS: M +1: 453.18. [00327] 1H NMR (300 MHz, DMSO) δ (ppm): 11.75 (s, 1H), 8.72 (s, 2H), 6.37 (dd, J = 2.7, J = 5, 2. 1H), 5.45 (brs, 1H), 4.63 (d, J = 3, 1H), 4.12 (s, 3H), 3.20 (t, 1H), 2.83 (d , J = 2, 3H), 2.67 (s, 3H), 1.75-2.01 (m, 7H), 1.39 (m, 1H). [00328] The subtitle compound D98 was synthesized using the same method described above for the starting compound with bis-sulfone, 2-aminopyrimidin-5-ol and (1R, 4R, 5R) -2-azabicycles [2.2.1] heptan-5-amine (the diamine was prepared according to the procedure of Eur. Pat. Appl. (1990), EP 357047 A1 19900307). LC-MS: M +1: 454.18. [00329] The subtitle compound D99 was synthesized using the same method as described above for the starting compound with bis-sulfone, 2-aminopyrimidin-5-ol and tert-butyl (1R, 5S, 6R) -3-azabicycles [3.1 .0] hexan-6-ylcarbamate. LC-MS: M +1: 440.15. [00330] The subtitle compound D101 was synthesized using the same method written above for the starting compound with bis-sulfone and (R) -tert-butyl-5-aza-spiro [2.4] heptan-7-ylcarbamate. LC-MS: M +1: 449.24 [00331] The compound subtitle D102 was synthesized using the same method as described for the previous compound starting with bis-sulfone and tert-butyl (1R, 4R, 5R) -2-azabicyclo [2.2.1] heptan-5-ylcarbamate. LC-MS: M +1: 449.21. Table of Compounds of Formula I, where L is O, Rxé CH, Rye Rzsão F and R8é NHCH3 Table of Compounds of Formula I, where L is O, R8 is NHCH3, Alternative Rx, Ry, Rz Combinations Synthesis of Analogs, where both X, Y, and Z are N Pyrimidines [00332] Preparation of compound D104: Compound D103 (280 g, 2.50 mol) was added to a solution of nitric acid (90%, 1120 ml) at -10 ° C for 1 h, and stirred at -10 ° C for an additional 1.5 h, followed by heating to room temperature and stirred for 2 h. The mixture was poured into ice water and the yellow solid was collected by filtration, dried under reduced pressure to give D104 (200 g, 51% yield) as a yellow solid. LC-MS: M +1: 158 Preparation of compound D105: Compound D104 (200 g, 1.27 mol) was added to the mixture of POC13 (1,300 ml) and DMA (255 ml) at room temperature, and the whole was heated at reflux for 2-3 h, and the reaction is monitored by TLC. The reaction mixture was poured into ice water, extracted with EtOAc (1 L * 3), washed with aq. brine, dried (Na2SO4) and concentrated in vacuo to give compound D105 crude product (170 g) as a black solid. It was used directly in the next step without further purification. LC-MS: M +1: 194 [00333] Preparation of compound D106: To a mixture of compound D105 (170 g, 1.27 mol) obtained above and triethylamine (107 g, 1.06 mol) in THE (500 ml) was added the N-methyl solution (phenyl) amino methane (38.4 g, 316 mmol) in THF at - 40 ° C, dropwise, and stirred at that temperature. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with H2O and extracted with EtOAc, washed with aq. NaCl, dried (Na2SO4) and concentrated in vacuo to give the crude product. It was purified by column chromatography to give the product of compound D106 (101 g, 41.4% as an oil. LC-MS: M +1: 279. [00334] Preparation of compound D107: To a mixture of compound D106 (5.0 g, 17.94 mmol) and K2CO3 (5.25 g, 35.89 mmol) in DMF (30 ml) was added 2-cyanoacetate ( 4.06 g, 35.89 mmol) at room temperature of ethyl, which was heated to 50 ° C for 3 h and monitored by TLC. The reaction mixture was diluted with H2O and extracted with EtOAc. The organic layer was washed with aq. brine, dried (Na2SO4) and concentrated in vacuo to give the crude product. It was purified by column chromatography to give the product compound D107 (2.67 g, 42% yield) as a yellow solid. LC-MS: M +1: 356 [00335] Preparation of compound D108: To a mixture of compound D107 (39 g, 110 mmol) in acetic acid (300 mL) was added Zn (56 g, 858 mmol) at 80 ° C over 0.5 h, and the whole was heated to 90 ° C for an additional 3 hours and the reaction was monitored by TLC. After the reaction was complete the mixture was cooled to room temperature and filtered to remove the inorganic salts. The filtrate was concentrated in vacuo, and the residue was diluted with H2O and basified with NaHCO3 to pH 7-8. Then, it was extracted with EtOAc. The organic layer was washed with aq. brine, dried (Na2SO4) and concentrated in vacuo to give the product compound D108 (35 g, 98.0% yield) as a white solid. It was used in the next step directly. LC-MS: M +1: 326. Preparation of compound D109: The mixture of compound D108 (10.00 g, 30.73 mmol) and urea (50.0 g) was heated to 180 ° C overnight, at TLC and LCMS showed that the reaction was completed. Diluted with DMSO and heated to 180 ° C for 10 min. Then the insoluble material was cooled down, filtered and the filtrate was poured into H2O. The solid precipitated post was collected by filtration. The solid was treated with H2O, and the suspension was heated to reflux. It filtered while hot. The collected solid was washed with hot water an additional 4 times. Then, it was washed with hot water McOH and EtOAc, dried in vacuo to give the compound in sufficiently pure product D109 (6.20 g, 62% yield) as a sold white solid. LC-MS: M +1: 323. [00336] 1H-NMR (300 MHz, DMSO-d6) 8 (ppm): 8.23 (1H, $), 7.25- 7.36 (5H, m), 3.37 (2H, s), 2.51 (3H, s). [00337] Preparation of compound D110: Compound D109 (1.5 g, 4.64 mmol) was placed with a solution of POC13 (50 mL) in a pressure tube and a few drops of N-ethyldiisopropyl amine. The reaction mixture was heated to 185 ° C, under sealed condition over 10 h. The mixture was cooled and poured into ice water and the yellow solid was collected by filtration, dried under reduced pressure to give D110 (1.2 g, 98% yield) as a yellow solid. LC-MS: M +1: 270. [00338] Preparation of compound D111: Compound D110 (100 mg, 0.37 mmol) was added to a solution of 2-methylpymiridin-5-ol (120 mg, 1.1 mmol) and K2CO3 (15 mg, 1.0 mmol) in NMP (4 mL) in a microwave tube. The reaction mixture was sealed and placed in a microwave at 150 ° C for 10 minutes. The desired product was obtained by purification by HPLC, to give D111 (100 mg, 75%) as a white solid. LC-MS: M +1: 417. [00339] Preparation of compound D112: To a stirred solution of compound D111 (50 mg, 0.12 mmol) in 2 ml of NMP at 110 ° C was added tert-butyl-3-azabicycles [3.1.0] hexan-6 -ylcarbamate (27 mg, 0.1 mmol) and K2CO3 (2 mg, 0.05 mmol). Upon completion of the reaction, within 10 minutes, the reaction mixture was purified by HPLC to give the product Dl 12 (38 mg, 63%) as a white solid. LC-MS: M +1: 505. [00340] Preparation of compound D113: To a stirred solution of compound D112 (38 mg, 0.07 mmol) in 5 ml of acetonitrile at room temperature, 2 ml of TFA was added. After completion of the reaction in 20 minutes. The reaction mixture was concentrated and purified by HPLC to give the product D113 (28 mg, 95%) as a white solid. LC-MS: M +1: 405. [00341] 1H-NMR (300 MHz, DMSO-d6) 8 (ppm): 8.23 (1H, $), 7.26 (2H, s), 2.51 (3H, s), 2.55 ( 3H, s), 2.88 (2H, m), 2.63 (2H, m), 1.22 (1H, m), 0.66 (2H, m). Pyridines [00342] 4-chloro-3-nitropyridin-2-amine (1.73 g, 10mmol) in 10 ml of THF was added to sodium hydride (2 g, 50 mmol, 60% in oil) in dry THF solution (200m1) with the cold water bath, then the solution was stirred for another hour, then Boc2O (2.4g, 1mol) in 10m1 THF was added dropwisely to the solution, the solution was stirred for 4 hours at room temperature, then Mel (2.8 g, 20 mol) in THF was added 10m1 dropwisely to the solution, the mixture was stirred overnight (12 hours), and quenched with ice water. The aqueous solution was extracted with 3X 100M1 ethyl acetate, the combined organic solution was dried and concentrated. The residue was purified by flash chromatography to give the desired products 2.1g D115 in 73% yield. [00343] For the mixture of NaH (0.8 g, 20 mmol, 60% in oil) and 2-cyanoacetate acetate (2.2 g, 20 mmol) in dry DMF (100M1), at room temperature, was added tert-butyl- (4-chloro-3-nitropyridin-2-y1) (methyl) carbamate (2 g, 7 mmol), the mixture was stirred overnight at 100 ° C for 12 hours, then the mixture of The reaction was carefully quenched with water, then the solution was partitioned between water and ethyl acetate (100 100M1 M1), the organic layer was then dried and concentrated. The residue was purified by flash chromatography to give the desired products 2.4g D116 in 66% yield. LC-MS: M +1: 365.15. [00344] To a stirred suspension of the compound 2-amino-7 - ((tert-butoxycarbonyl) (methyl) amino) -1H-pyrrolo [2,3-c] pyridine-3-carboxylate (500 mg, 1, 5 mmol) in acetone (20 ml) a solution of acetyl isothiocyanate (0.24 ml, 3 mmol) in acetone (5 ml) was added dropwise at room temperature. The reaction mixture was heated to reflux for 16 h. LCMS showed that the reaction was completed. The reaction mixture was concentrated to the next step without purification. [00345] Above residue was dissolved in 20 ml of methanol and 20 ml of H2O, and then 5 ml of 10% KOH solution was added, the mixture solution was heated to reflux for 30 minutes. When LCMS showed that the reaction was completed, the reaction was cooled to room temperature, acidified to pH 5 with 1 M aq. HCl, and the precipitate was collected by filtration to give the desired compound tert-butyl (4-hydroxy-2-mercapto-9H-pyrido [4 ', 3': 4,5] pyrrolo [2,3-d] pyrimidin- 8-yl) (methyl) carbamate of D119, as a solid (340 mg, 65.4% in two steps). LC-MS: M +1: 348. [00346] The solution of Cul (67 mg, 0.35 mmol), N, N '- dimethylcyclohexane-1,2-diamine (100 mg, 0.70 mmol) in 9 mL of NMP was added to a stirred suspension of tert-butyl (4-hydroxy-2-mercapto-9H-pyrido [4 ', 3': 4.5] pyrrolo [2,3 -d] pyrimidin-8-y1) (methyl) carbamate (350 mg, 1, 0 mmol), an appropriate I-ar (1.17 mmol), K2CO3 (324 mg, 2.35 mmol) and PPh3 (400 mg, 1.53 mmol) in NMP (9 ml). The mixture was heated at 130 ° C for 2 to 12 hours monitored by LC-MS to complete the reaction. When the reaction was complete, the mixture was cooled to 0 ° C, BOP (621 mg, 1.40 mmol) and Et 3 N (0.41 mL, 2.93 mmol), stirred for 30 minutes at 0 ° C, then warmed to room temperature, a suitable protected with Boc-diamine (2.34 mmol) was added. The reaction mixture was heated to 50 ° C for 30 minutes. LC-MS indicated that the reaction has completed. After the reaction was completed, the mixture was partitioned with ethyl acetate and water, the aqueous layer was extracted with ethyl acetate twice, the combined organic layer was dried and purified by flash chromatography to give compound D120 products as a solid ( 420mg, 65% in two stages). LC-MS: M +1: 644. [00347] The above compound (420 mg, 0.64 mmol) was dissolved in 10 ml of TFA and stirred for 30 minutes at room temperature. After removing the solvents, the residue was redissolved in methanol and 10 ml of 10m1 H2O, then 1N NaOH was added to neutralize the solution at pH 14, the base solution, then diluted by another 100 ml H2O, and the solution was stirred vigorously for an additional hour, the precipitate was collected and dried to the final compound D121 giving as a white solid (200 mg, 70%). LC-MS: M +1: 444. Table of Compounds of Formula I, where L is O, where one or more Rx, Ry, Rz and R8 are NHCH3 Aryloxy bis [00348] N-methyl-2,4-bis (2-methylpyrimidin-5-yloxy) -9H-pyrimido [4,5-b] indole-8-amine: To a solution of compound (D122) (100 mg, 0.37 mmol) in NMP (5 ml) 2-methyl-pyrimidine-5-ol (100 mg, 0.9 mmol) and potassium carbonate (43.6 mg, 0.31 mmol) were added. It was then heated to 180 ° C, under microwave condition for 15 minutes. The mixture was then purified by HPLC to give the title compound D123 as a yellow solid (80 mg, 52%). LC-MS: M +1: 415.15. [00349] 1H NMR (300 MHz, DMSO) δ (ppm): 14.01 (S, 1H), 11.71 (s, 1H), 8.98 (s, 2H), 8.78 (s, 2H ), 7.84 (d, J = 7.5, 1H), 7.47 (m, 1H), 6.90 (d, J = 9.7, 1H), 4.18 (s, 1H), 3.10 (s, 3H), 2.65 (s, 3H), 2.64 (s, 3H). Table of Compounds of Formula I, where R4 is OR [00350] The subtitle compound D125 was synthesized using the same method described for the compound above with bis-sulfone, 2- (1-hydroxyethyl) pyrimidin-5-ol and 1-methyl-3-azabicyclo [3.2.0] heptane -6-amine (the diamine was prepared according to the procedure described in PCT Int. Appl. (1194), WO 9415933 A1 19940721). LC-MS: M + 1: 479.25. Determination of antibacterial efficacy [00351] Colonies of H. influenzae, E. coli, S. aureus, A. baumannii, S. pneumoniae, P. aeruginosa and B. thailandensis were removed from the discs over night and resuspended in 3 mL of DPBS solution. Absorbance was read at 600 nM and suspensions were diluted to an OD of 0.1. [00352] Inoculae were added to the appropriate growth medium, and 98 μL of the mixture was placed in 1-11 columns of a 96-well, flat-bottomed cell culture plate. Column 12 was placed only with the medium. [00353] 2 μL of compound dilution series in 100% DMSO was added to columns 1-10. Discs were shaken on a disc shaker for 1 minute. [00354] 1000x cell and media mixtures were diluted in DPBS and 100 μl were seeded in appropriate media and incubated overnight to count UFC. [00355] The plates were incubated overnight at 35 ° C. H. influenza and S. pneumoniae plates were incubated with 5% CO2. [00356] 10 μL of Alamar Blue (Invitrogen) was added to plates, and the plates were shaken for 1 min on a plate shaker. The plates were incubated at 35 ° C for 1 h. The plates were read visually, with any change in color from blue read to live. Table 9. MIC data for compounds in Tables 1-8 (Concentration in μg / mL) Table 10. MC data for selecting Corrupt Formula 1 versus a Broad Bacteria Panel ' Sa = S '. aureus, Spn = 5, pneumoniae, Ec = £. coii, Ab -A. baumannii, Kpn = K, pneumoniae, Pa = aeruginosa, Bt = R. thailandensls, Et = F Yp = E pestis
权利要求:
Claims (34) [0001] 1. Composed with the structure of Formula I [0002] 2. Compound, according to claim 1, CHARACTERIZED by the fact that L is O. [0003] 3. Composed, according to claim 1, CHARACTERIZED by the fact that L is S. [0004] A compound according to any one of claims 1 to 3, CHARACTERIZED by the fact that R8 is H, CH3, CH2CH3, Cl, OCH3, NHCD3, NHCH3, NHCH2CH3 or NH2. [0005] A compound according to any one of claims 1 to 4, CHARACTERIZED by the fact that R8 is NHCH3. [0006] 6. Compound according to claim 1, CHARACTERIZED by the fact that R2 is a heteroaryl ring. [0007] 7. Compound according to claim 1, CHARACTERIZED by the fact that R2 is selected from the group consisting of a pyrimidinyl, phenyl and pyridyl. [0008] 8. Compound according to claim 1, CHARACTERIZED by the fact that R2 is pyrimidinyl or pyridinyl in which pyrimidinyl or pyridinyl is replaced by CH (OH) CH3, C (OH) (CH3) 2, OCH3, CN, CH3, CH2CH3, 0-cyclopropyl, SCH3, Br, Cl, F or NH2. [0009] 9. Compound according to claim 1, CHARACTERIZED by the fact that R2 is selected from the group of substituents consisting of [0010] 10. Compound according to claim 1, CHARACTERIZED by the fact that R4 is the 4-14 membered saturated cycloheteroaliphatic tertiary amine attached to ring C via tertiary amine N, wherein the tertiary amine contains at least one additional N from the tertiary amine N for 2-3 atoms. [0011] 11. Compound according to claim 1, CHARACTERIZED by the fact that R4 is selected from the group consisting of piperazinyl and tetrahydropyridinyl. [0012] 12. Compound according to claim 1, CHARACTERIZED by the fact that R4 is substituted with 0-3 non-interfering substituents selected from the group consisting of OH, NO, CO2H, CN, NH2, Br, Cl, F, SO3H and NO2 is either a C1-15 hydrocarbon residue containing 0-5 O, S or N hetero atoms. [0013] 13. A compound according to any one of claims 1 to 12, CHARACTERIZED by the fact that R4 is a substituent selected from the group of substituents consisting of [0014] 14. Composed, according to claim 1, CHARACTERIZED by the fact that L is O; R8 is NHCH3; X, Y and Z are CRX, CRY or CRZ, respectively, and where RX is H or F; RY is H, F, Cl or CF3; and RZ is H, CH3 or F; R2 is selected from the substituents consisting of [0015] 15. Composed, according to claim 1, CHARACTERIZED by the fact that it is selected from the group consisting of [0016] 16. Composed, according to claim 1, CHARACTERIZED by the fact that it is selected from the group consisting of [0017] 17. Process for making the compound as defined in claim 1, CHARACTERIZED by the fact that R4 is a secondary or tertiary amine attached to ring C via the secondary or tertiary amine N, comprising: treating [0018] 18. Process, according to claim 17, CHARACTERIZED by the fact that before the treatment stage, the process additionally comprises: reacting [0019] 19. Process for making the compound as defined in claim 1, CHARACTERIZED by the fact that R4 is a secondary or tertiary amine attached to ring C via the secondary or tertiary amine N, comprising: treating [0020] 20. Process, according to claim 19, CHARACTERIZED by the fact that, before the treatment stage, the process additionally comprises: reacting [0021] 21. Process for making the compound as defined in claim 1, CHARACTERIZED by the fact that R4 is a secondary or tertiary amine attached to ring C via the secondary or tertiary amine N, comprising: treating [0022] 22. Process, according to claim 21, CHARACTERIZED by the fact that before the treatment step, the process additionally comprises: coupling, before said reaction step, [0023] 23. Intermediate compound with structure [0024] 24. Intermediate compound according to claim 23, CHARACTERIZED by the fact that G1 and G2 are abandonment groups independently selected from the group consisting of tosylate, mesylate, triphylate, O-pyrimidine, O-phenyl and O-pyridine. [0025] 25. Compound according to claim 1, CHARACTERIZED by the fact that the C1-15 hydrocarbon residue of the non-interfering substituent for R2 is replaced by OH, CN, = O, NH2, NHOH, = NOH, = NNH2, = NOCH3, Br, F, Cl, SO3H, or NO2. [0026] 26. Compound according to claim 12, CHARACTERIZED by the fact that R4 is a 4-14 membered saturated cycloheteroaliphatic tertiary amine ring optionally containing 1-3 atom of N atoms of 0-3 atom of O and 0- 1 atoms of S. [0027] 27. Process according to claim 17, CHARACTERIZED by the fact that it also comprises, before the treatment stage, the protection of R8 with a protecting group or the protection of an amine in R4 that is not the saturated N tertiary cycloheteroaliphatic amine of 4 -14 members, if present, with a protective group; and removal of the protective group after the treatment stage. [0028] 28. Process, according to claim 19, CHARACTERIZED by the fact that it also includes, before the treatment stage, the protection of R8 with a protecting group or the protection of an amine in R4 that is not the tertiary N-cycloheteroaliphatic saturated amine of 4-14 members, if present, with a protective group; and unprotect R8 and R4 after the treatment step. [0029] 29. Process according to claim 21, CHARACTERIZED by the fact that it also comprises, before the treatment stage, the protection of R8 with a protecting group or the protection of an amine in R4 that is not the saturated N tertiary cycloheteroaliphatic amine of 4 -14 N members, if present, with a protective group; and unprotect R8 and R4 after the treatment step. [0030] 30. Compound according to claim 1, CHARACTERIZED by the fact that the compound is [0031] 31. Compound according to claim 1, CHARACTERIZED by the fact that the compound is [0032] 32. Compound according to claim 1, CHARACTERIZED by the fact that the compound is [0033] 33. Compound according to claim 1, CHARACTERIZED by the fact that the compound is [0034] 34. Compound according to claim 1, CHARACTERIZED by the fact that the compound is or a pharmaceutically suitable salt.
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同族专利:
公开号 | 公开日 MX345780B|2017-02-15| IL228220D0|2013-11-25| JP6140083B2|2017-05-31| US20170369498A1|2017-12-28| EP2686320B1|2016-05-18| TW201245200A|2012-11-16| AU2012229997B2|2016-04-14| CN103562208B|2016-08-31| RU2626979C2|2017-08-02| KR20140059164A|2014-05-15| RU2013140798A|2015-04-20| JP2014508173A|2014-04-03| WO2012125746A9|2013-10-24| WO2012125746A1|2012-09-20| TWI527818B|2016-04-01| EP2686320A1|2014-01-22| AR085806A1|2013-10-30| US20120238751A1|2012-09-20| ZA201307583B|2014-08-27| AU2012229997A1|2013-09-19| KR102132574B1|2020-07-09| MX2013010511A|2014-03-27| US10858360B2|2020-12-08| IL228220A|2017-04-30| KR20190104632A|2019-09-10| CA2829939C|2020-10-13| CN103562208A|2014-02-05| CA2829939A1|2012-09-20| BR112013023266B8|2021-04-06| NZ614983A|2016-07-29| US9732083B2|2017-08-15|
引用文献:
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法律状态:
2018-03-27| B25C| Requirement related to requested transfer of rights|Owner name: TRIUS THERAPEUTICS INC (US) , LAWRENCE LIVERMORE N | 2018-04-03| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]| 2018-06-05| B25L| Entry of change of name and/or headquarter and transfer of application, patent and certificate of addition of invention: publication cancelled|Owner name: LAWRENCE LIVERMORE NATIONAL SECURITY, LLC (US) ; M | 2018-06-12| B25A| Requested transfer of rights approved|Owner name: LAWRENCE LIVERMORE NATIONAL SECURITY, LLC (US) ; M | 2018-06-19| B25L| Entry of change of name and/or headquarter and transfer of application, patent and certificate of addition of invention: publication cancelled|Owner name: LAWRENCE LIVERMORE NATIONAL SECURITY, LLC (US) ; M | 2018-12-11| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|Free format text: DE ACORDO COM O ARTIGO 229-C DA LEI NO 10196/2001, QUE MODIFICOU A LEI NO 9279/96, A CONCESSAO DA PATENTE ESTA CONDICIONADA A ANUENCIA PREVIA DA ANVISA. CONSIDERANDO A APROVACAO DOS TERMOS DO PARECER NO 337/PGF/EA/2010, BEM COMO A PORTARIA INTERMINISTERIAL NO 1065 DE 24/05/2012, ENCAMINHA-SE O PRESENTE PEDIDO PARA AS PROVIDENCIAS CABIVEIS. | 2020-01-21| B07E| Notice of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]| 2020-02-18| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]| 2020-06-23| B06A| Notification to applicant to reply to the report for non-patentability or inadequacy of the application [chapter 6.1 patent gazette]| 2020-10-20| B09A| Decision: intention to grant [chapter 9.1 patent gazette]| 2020-12-29| B16A| Patent or certificate of addition of invention granted|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 14/03/2012, OBSERVADAS AS CONDICOES LEGAIS. | 2021-04-06| B16C| Correction of notification of the grant|Free format text: REF. RPI 2608 DE 29/12/2020 QUANTO AO INVENTOR. |
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申请号 | 申请日 | 专利标题 US201161453011P| true| 2011-03-15|2011-03-15| US61/453,011|2011-03-15| PCT/US2012/029104|WO2012125746A1|2011-03-15|2012-03-14|Tricyclic gyrase inhibitors| 相关专利
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