MK2 inhibitors and uses thereof

Abstract

The present invention provides MK2 inhibitor compounds having the formula: # imgabs0 #, compositions and methods of use thereof

Description

Related Applications

[0001] This application claims the priority and benefit of U.S. Provisional Patent Application 63 / 381,195, filed on October 27, 2022, the content of which is incorporated herein by reference in its entirety. Incorporation of Sequence Listing by Reference

[0002] This application submits the sequence listing in electronic format. The sequence listing is provided as a file named 055920-569001WO_ST26.xml, created on October 26, 2023, and with a size of 4 KB. The information of the sequence listing in this electronic format is incorporated herein by reference in its entirety. Technical Field

[0003] The present invention relates to compounds suitable as MK2 kinase inhibitors. The present invention also provides pharmaceutically acceptable compositions comprising the compounds of the present invention and methods of using these compositions to treat various diseases. Background Art

[0004] In recent years, by better understanding the structures of enzymes and other biomolecules related to diseases, it has provided great help in the search for new therapeutic agents. An important class of enzymes that has become a subject of extensive research is protein kinases.

[0005] Protein kinases constitute a large family of structurally related enzymes responsible for controlling various signal transduction processes within cells. Due to the conservation of the structure and catalytic function of protein kinases, they are thought to have evolved from a common ancestral gene. Almost all kinases contain a similar catalytic domain of 250-300 amino acids. Kinases can be classified into multiple families according to the substrates they phosphorylate (e.g., protein-tyrosine, protein-serine / threonine, lipids, etc.).

[0006] Mitogen-activiated protein kinase-activated protein kinase 2 (MAPKAP K2 or MK2) mediates a variety of p38 MAPK-dependent cellular responses. MK2 is an important intracellular regulator for the production of cytokines such as tumor necrosis factor α (TNF-α), interleukin 6 (IL-6) and interferon γ (IFNγ), and these cytokines are associated with many acute and chronic inflammatory diseases such as rheumatoid arthritis and inflammatory bowel disease. MK2 is located in the nucleus of unstimulated cells and upon stimulation, it translocates to the cytoplasm and phosphorylates and activates tuberin and HSP27. MK2 is also associated with heart failure, cerebral ischemic injury, stress resistance regulation and TNF-α production. (See Deak et al., EMBO. 17:4426-4441 (1998); Shi et al., Biol. Chem. 383:1519-1536 (2002); Staklatvala., Curr. Opin. Pharmacol. 4:372-377 (2004) and Shiroto et al., J. Mol. Cardiol. 38:93-97 (2005)).

[0007] Many diseases are associated with abnormal cellular responses caused by events mediated by the protein kinases described above. Such diseases include (but are not limited to) autoimmune diseases, inflammatory diseases, skeletal diseases, metabolic diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergy and asthma, Alzheimer's disease, and hormone-related diseases. Accordingly, there remains a need to find protein kinase inhibitors that can be used as therapeutic agents. SUMMARY OF THE INVENTION

[0008] It has now been found that the compounds of the present invention and their pharmaceutically acceptable compositions are effective as inhibitors of MK2. Such compounds have the general formula I: or a pharmaceutically acceptable salt thereof, wherein each of ring A, R 1 , R 1' , R 2 , R 3 and n is defined and described as in the embodiments herein.

[0009] The compounds of the present invention and their pharmaceutically acceptable compositions can be used to treat various diseases, disorders or conditions associated with abnormal cellular responses caused by events mediated by protein kinases. Such diseases, disorders or conditions include those diseases, disorders or conditions described herein.

[0010] The compounds provided by the present invention are also suitable for studying kinases in biological and pathological phenomena; studying intracellular signal transduction pathways mediated by such kinases; and comparative evaluation of new kinase inhibitors. Detailed Description of the Invention 1. General description of the compounds of the present invention:

[0011] In certain embodiments, the present invention provides irreversible inhibitors of MK2. In some embodiments, such compounds include compounds having the chemical formulas described herein, or pharmaceutically acceptable salts thereof, wherein each variable is defined and described as herein.

[0012] In some embodiments, the present invention provides compounds of Formula I: or pharmaceutically acceptable salts thereof, wherein: Ring A is a 5- to 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, provided that when Ring A is a 6-membered heteroaryl ring, the heteroatom is nitrogen; R 1 and R 1' each independently selected from hydrogen and C x aliphatic substituted with 0 to 3 R 1-4 , or: R 1 and R 1' may together with the intermediate atom to which they are attached form an optionally substituted 3- to 6-membered saturated, partially unsaturated heterocyclic or aryl ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R x is -CN, -NO2, halogen, -OR, -SR, -N(R)2, -C(O)N(R)2, -C(O)OR, -C(O)R, -N(R)C(O)R, -SO2N(R)2 or -N(R)SO2; R 2 is halogen, C2-C6 alkenyl or C2-C6 alkynyl, wherein the alkenyl or alkynyl is optionally substituted with m R y ; each R y independently selected from D, halogen, -CN, -CO2R, -N(R)2 and a 3- to 6-membered saturated or partially unsaturated heterocycle having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R 3 is optionally substituted C 1-6 aliphatic, -CN, halogen, -(CH2) q -OR 4 , -N(R)2, -C(O)OR, -(CH2)r -Cy or -O-(CH2) t -R 5 ; or: Two Rs on adjacent atoms 3 together with the intervening atom to which they are attached form an optionally substituted 5- to 6-membered saturated, partially unsaturated or aryl ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; Each R 4 is independently selected from hydrogen, optionally substituted C 1-6 aliphatic and -Cy; Each R 5 is independently selected from -OR and -Cy; Each Cy is independently an optionally substituted ring selected from: a 3- to 9-membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3- to 9-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; phenyl; a 5- to 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 7- to 12-membered saturated or partially unsaturated fused, spirofused or bridged bicyclic carbocyclic ring; or a 7- to 12-membered saturated or partially unsaturated fused, spirofused or bridged bicyclic heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; Each R is independently hydrogen or optionally substituted C 1-6 aliphatic, or: Two R groups on the same nitrogen are joined together with the nitrogen to form a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 3 heteroatoms selected from nitrogen, oxygen or sulfur; Each of m, n, q and r is independently 0 to 4; and t is 1 to 4. 2. Compounds and definitions:

[0013] The compounds of the present invention include those generally described above and are further illustrated by the classes, subclasses, and specific compounds disclosed herein. As used herein, unless otherwise indicated, the following definitions shall apply. For the purposes of the present invention, chemical elements are identified according to the CAS version of the Periodic Table of the Elements and the 75th edition of the Handbook of Chemistry and Physics. Additionally, general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999 and “March's Advanced Organic Chemistry”, 5th Edition, Editors: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are incorporated herein by reference.

[0014] As used herein, the term “aliphatic” or “aliphatic group” refers to a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or contains one or more unsaturated units, or a monocyclic or bicyclic hydrocarbon that is completely saturated or contains one or more unsaturated units but is not aromatic (also referred to herein as “carbocycle”, “carbocyclic”, “cycloaliphatic” or “cycloalkyl”), which has a single point of attachment to the remainder of the molecule. Unless otherwise specified, an aliphatic group contains 1 to 6 aliphatic carbon atoms. In some embodiments, the aliphatic group contains 1 to 5 aliphatic carbon atoms. In other embodiments, the aliphatic group contains 1 to 4 aliphatic carbon atoms. In other embodiments, the aliphatic group contains 1 to 3 aliphatic carbon atoms, and in yet other embodiments, the aliphatic group contains 1 to 2 aliphatic carbon atoms. In some embodiments, “carbocyclic” (or “cycloaliphatic” or “carbocycle” or “cycloalkyl”) refers to a monocyclic C3-C8 hydrocarbon that is completely saturated or contains one or more unsaturated units but is not aromatic, which has a single point of attachment to the remainder of the molecule. Suitable aliphatic groups include (but are not limited to) straight-chain or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl, and their hybrids, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl.

[0015] As used herein, the term "bridged bicyclic" refers to any bicyclic system having at least one bridge, i.e., a saturated or partially unsaturated carbocyclic or heterocyclic ring. As defined by IUPAC, a "bridge" is an unbranched chain or atom or valence bond connecting atoms of two bridgeheads, where a "bridgehead" is any skeletal atom of a ring system that is bonded to three or more skeletal atoms (other than hydrogen). In some embodiments, the bridged bicyclic group has 7 to 12 ring members and 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groups are well known in the art and include those groups set forth below, where each group is attached to the remainder of the molecule at any replaceable carbon or nitrogen atom. Unless otherwise specified, the bridged bicyclic group is optionally substituted with one or more substituents as described for aliphatic groups. Additionally or alternatively, any replaceable nitrogen of the bridged bicyclic group is optionally substituted. Exemplary bridged bicyclics include:

[0016] The term "heteroatom" refers to one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including any oxidized form of nitrogen, sulfur, phosphorus, or silicon; any quaternized form of any basic nitrogen; or a replaceable nitrogen of a heterocycle, such as N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR + (as in N-substituted pyrrolidinyl)).

[0017] As used herein, the term "unsaturated" means in part having one or more unsaturated units.

[0018] The term "alkylene" refers to a divalent alkyl group. An "alkylene chain" is a polymethylene, i.e., -(CH2) n -, where n is a positive integer, preferably 1 to 6, 1 to 4, 1 to 3, 1 to 2, or 2 to 3. A substituted alkylene chain is such a polymethylene where one or more methylene hydrogen atoms are replaced by substituents. Suitable substituents include those described below for substituted aliphatic groups.

[0019] The term "alkenylene" refers to a divalent alkenyl group. A substituted alkenylene chain is a polymethylene containing at least one double bond where one or more hydrogen atoms are replaced by substituents. Suitable substituents include those described below for substituted aliphatic groups.

[0020] As used herein, the term "cyclopropylidene" refers to a divalent cyclopropyl group having the following structure:

[0021] The term "halogen" refers to F, Cl, Br, or I.

[0022] The term "aryl", whether used alone or as part of a larger moiety, such as in "aralkyl", "aralkoxy", or "aryloxyalkyl", refers to a monocyclic or bicyclic system having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members. The term "aryl" may be used interchangeably with the term "aryl ring". In certain embodiments of the invention, "aryl" refers to an aromatic ring system and exemplary groups include phenyl, biphenyl, naphthyl, anthracenyl, etc., which may be substituted with one or more substituents. As used herein, also included within the scope of the term "aryl" are groups in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthalimido, phenanthridinyl, or tetrahydronaphthyl, etc.

[0023] The terms "heteroaryl" and "heteroar-", when used alone or as part of a larger moiety (e.g., "heteroalkyl" or "heteroalkoxy"), refer to a group having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 π electrons shared in a ring array; and having one to five heteroatoms other than carbon atoms. The term "heteroatom" refers to nitrogen, oxygen, or sulfur and includes any oxidized form of nitrogen or sulfur; and any quaternized form of basic nitrogen. Exemplary heteroaryls include thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. As used herein, the terms "heteroaryl" and "heteroar-" also include groups in which a heteroaryl ring is fused to one or more aryl, cycloaliphatic, or heterocyclic rings, wherein the linking group or point of attachment is on the heteroaryl ring. Exemplary groups include indolyl, isoindolyl, benzothienyl, benzofuryl, dibenzofuryl, indazolyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. Heteroaryl may be monocyclic or bicyclic. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring", "heteroaryl group", or "heteroaromatic", any of which includes an optionally substituted ring. The term "heteroalkyl" refers to an alkyl group substituted with a heteroaryl group, wherein the alkyl and heteroaryl moieties are independently optionally substituted.

[0024] As used herein, the terms "heterocycle", "heterocyclyl", "heterocyclic radical", and "heterocyclic ring" are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic moiety which is saturated or partially unsaturated and which has one or more, preferably one to four, heteroatoms as defined above in addition to carbon atoms. When used to refer to the ring atoms of a heterocycle, the term "nitrogen" includes substituted nitrogen. For example, in a saturated or partially unsaturated ring having from 0 to 3 heteroatoms selected from oxygen, sulfur, or nitrogen, nitrogen can be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or + NR (as in an N-substituted pyrrolidinyl).

[0025] The heterocycle can be attached to its pendant groups at any heteroatom or carbon atom, resulting in a stable structure, and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclyls include tetrahydrofuranyl, tetrahydrothienyl pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diaza yl, oxaza yl (oxazepinyl), thiaza yl (thiazepinyl), morpholinyl, and quinuclidinyl. The terms "heterocycle", "heterocyclyl", "heterocyclyl ring", "heterocyclic group", "heterocyclic moiety", and "heterocyclic radical" are used interchangeably herein and also include groups in which the heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl, where the linking group or point of attachment is on the heterocyclyl ring. The heterocyclyl can be monocyclic or bicyclic. The term "heterocyclylalkyl" refers to an alkyl group substituted with a heterocyclyl group, where the alkyl and heterocyclyl moieties are independently optionally substituted.

[0026] As used herein, the term "partially unsaturated" refers to a ring moiety that includes at least one double or triple bond. The term "partially unsaturated" is intended to cover rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties as defined herein.

[0027] As described herein, the compounds of the invention may contain "optionally substituted" moieties. In general, the term "substituted", whether preceded by the term "optionally" or not, means that one or more hydrogens of the designated moiety are replaced by a suitable substituent. "Substituted" applies to one or more hydrogens that are explicitly or implicitly defined by the structure (e.g., means at least and means at least ). Unless otherwise indicated, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from the designated group, the substituents at each position may be the same or different. Combinations of substituents contemplated by the invention are preferably those that result in the formation of stable or chemically viable compounds. As used herein, the term "stable" means that a compound does not undergo a substantial change when subjected to conditions that allow its production, detection, and (in certain embodiments) its recovery, purification, and use for one or more of the purposes disclosed herein.

[0028] Suitable monovalent substituents on the substitutable carbon atoms of an "optionally substituted" group are independently deuterium, halogen; -(CH2) 0-4 R°; -(CH2) 0-4 OR°; -O(CH2) 0-4 R°, -O-(CH2) 0-4 C(O)OR°; -(CH2) 0-4 CH(OR°)2; -(CH2) 0- 4SR°; -(CH2) that may be substituted with R° 0-4 Ph; -(CH2) that may be substituted with R° 0-4 O(CH2) 0-1 Ph; -CH=CHPh that may be substituted with R°; -(CH2) that may be substituted with R° 0-4 O(CH2) 0-1 -pyridyl; -NO2; -CN; -N3; -(CH2) 0-4 N(R°)2; -(CH2) 0-4 N(R°)C(O)R°; -N(R°)C(S)R°; -(CH2) 0-4 N(R°)C(O)NR°2; -N(R°)C(S)NR°2; -(CH2) 0-4 N(R°)C(O)OR°; -N(R°)N(R°)C(O)R°; -N(R°)N(R°)C(O)NR°2; -N(R°)N(R°)C(O)OR°; -(CH2) 0-4C(O)R°; -C(S)R°; -(CH2) 0-4 C(O)OR°; -(CH2) 0-4 C(O)SR°; -(CH2) 0-4 C(O)OSiR°3; -(CH2) 0-4 OC(O)R°; -OC(O)(CH2) 0-4 SR°; -(CH2) 0-4 SC(O)R°; -(CH2) 0-4 C(O)NR°2; -C(S)NR°2; -C(S)SR°; -SC(S)SR°, -(CH2) 0-4 OC(O)NR°2; -C(O)N(OR°)R°; -C(O)C(O)R°; -C(O)CH2C(O)R°; -C(NOR°)R°; -(CH2) 0- 4SSR°; -(CH2) 0-4 S(O)2R°; -(CH2) 0-4 S(O)2OR°; -(CH2) 0-4 OS(O)2R°; -S(O)2NR°2; -(CH2) 0-4 S(O)R°; -N(R°)S(O)2NR°2; -N(R°)S(O)2R°; -N(OR°)R°; -C(NH)NR°2; -P(O)2R°; -P(O)R°2; -OP(O)R°2; -OP(O)(OR°)2; SiR°3; -(C 1-4 linear or branched alkylene)O-N(R°)2; or -(C 1-4 linear or branched alkylene)C(O)O-N(R°)2, where each R° may be substituted as defined below and is independently hydrogen, C 1-6 aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, -CH2-(5 - to 6 - membered heteroaryl ring) or a 5 - to 6 - membered saturated, partially unsaturated or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or regardless of the above definition, two independently occurring R°s together with one or more of their intervening atoms combine to form a 3 - to 12 - membered saturated, partially unsaturated or aryl monocyclic or bicyclic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur, which may be substituted as defined below.

[0029] Suitable monovalent substituents on R° (or on the ring formed by the combination of two independently occurring R°s with their intervening atoms) are independently halogen, -(CH2) 0-2 R ● 、-(halo - R ● )、-(CH2) 0-2OH, -(CH2) 0-2 OR ● , -(CH2) 0-2 CH(OR ● )2; -O(haloalkyl R ● ), -CN, -N3, -(CH2) 0-2 C(O)R ● , -(CH2) 0-2 C(O)OH, -(CH2) 0-2 C(O)OR ● , -(CH2) 0-2 SR ● , -(CH2) 0-2 SH, -(CH2) 0-2 NH2, -(CH2) 0-2 NHR ● , -(CH2) 0-2 NR ● 2, -NO2, -SiR ● 3, -OSiR ● 3, -C(O)SR ● , -(C 1-4 linear or branched alkylene)C(O)OR ● or -SSR ● , wherein each R ● is unsubstituted or, in the case where "halo" is present in front, is substituted only by one or more halogens, and is independently selected from C 1-4 aliphatic, -CH2Ph, -O(CH2) 0-1 Ph or a 5- to 6-membered saturated, partially unsaturated or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur. Suitable divalent substituents for the saturated carbon atoms of R° include =O and =S.

[0030] Suitable divalent substituents on the saturated carbon atoms of the "optionally substituted" group include the following: =O ("oxo"), =S, =NNR * 2, =NNHC(O)R * , =NNHC(O)OR * , =NNHS(O)2R * , =NR * , =NOR * , -O(C(R * 2)) 2-3 O- or -S(C(R * 2)) 2-3 S-, wherein each independently occurring R * is selected from hydrogen, C substituted as defined below 1-6Aliphatic, or an unsubstituted 5- to 6-membered saturated, partially unsaturated or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur. Suitable divalent substituents bonded to the ortho-substitutable carbon of an "optionally substituted" group include: -O(CR * 2) 2-3 O-, where each independently occurring R * is selected from hydrogen, C 1-6 aliphatic which may be substituted as defined below, or an unsubstituted 5- to 6-membered saturated, partially unsaturated or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0031] R * Suitable substituents on the aliphatic groups of ● include halogen, -R ● , -(haloalkyl R ● ), -OH, -OR ● , -O(haloalkyl R ● ), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR ● 2 or -NO2, where each R ● is unsubstituted or, in the presence of "halo" prefix, is substituted only by one or more halogens and is independently C 1-4 aliphatic, -CH2Ph, -O(CH2) 0-1 Ph or a 5- to 6-membered saturated, partially unsaturated or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0032] Suitable substituents on the optionally substituted nitrogen of the "optionally substituted" group include or where each is independently hydrogen, C 1-6 aliphatic which may be substituted as defined below, unsubstituted -OPh or an unsubstituted 5- to 6-membered saturated, partially unsaturated or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur; or, regardless of the above definition, two independently occurring are joined together with the intervening atom to form an unsubstituted 3- to 12-membered saturated, partially unsaturated or aryl monocyclic or bicyclic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0033] Suitable substituents on the aliphatic groups of ● are independently halogen, -R ● , -(haloalkyl R ● ), -OH, -OR● )、 -CN, -C(O)OH, -C(O)OR ● 、 -NH2, -NHR ● 、 -NR ● 2 or -NO2, wherein each R ● is unsubstituted or, in the case of being preceded by "halo", is substituted only by one or more halogens, and is independently C 1-4 aliphatic, -CH2Ph, -O(CH2) 0-1 Ph or a 5- to 6-membered saturated, partially unsaturated or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0034] As used herein, the term "pharmaceutically acceptable salt" refers to those salts that are suitable for use in contact with the tissues of humans and lower animals within the scope of sound medical judgment, without undue toxicity, irritation, allergic response, etc., and commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S.M. Berge et al. described pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present invention include those pharmaceutically acceptable salts derived from suitable inorganic acids and organic acids, as well as inorganic bases and organic bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts formed by the reaction of an amino group with an inorganic acid (such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid) or with an organic acid (such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid), or salts formed by using other methods used in the art (such as ion exchange). Other pharmaceutically acceptable salts include adipates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonates, citrates, cyclopentanepropionates, digluconates, dodecyl sulfates, ethanesulfonates, formates, fumarates, glucoheptanoates, glycerophosphates, glucuronates, hemisulfates, heptanoates, hexanoates, hydroiodides, 2-hydroxyethanesulfonates, lactates, lactobionates, laurates, lauryl sulfates, malates, maleates, malonates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, oxalates, palmitates, pamoates, pectates, persulfates, 3-phenylpropionates, phosphates, pivalates, propionates, stearates, succinates, sulfates, tartrates, thiocyanates, p-toluenesulfonates, undecanoates, valerates, etc.

[0035] Salts derived from suitable bases include alkali metal salts, alkaline earth metal salts, ammonium salts and N + (C 1-4(alkyl)4 salts. Representative alkali metal or alkaline earth metal salts include sodium salts, lithium salts, potassium salts, calcium salts, magnesium salts, etc. Where appropriate, other pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide ions, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

[0036] Unless otherwise indicated, the structures depicted herein are also intended to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations of each asymmetric center, the Z and E double bond isomers, and the Z and E conformational isomers. Thus, the individual stereoisomers of the compounds of the present invention, as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures, are within the scope of the present invention. Unless otherwise indicated, all tautomeric forms of the compounds of the present invention are within the scope of the present invention. Additionally, unless otherwise indicated, the structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the structure of the present invention and including the replacement of hydrogen by deuterium or tritium or the replacement of carbon by 13 C or 14 C-enriched carbon are within the scope of the present invention. Such compounds are useful, for example, as analytical tools, probes in biological assays, or therapeutic agents according to the present invention. In certain embodiments, the warhead moiety of the provided compounds, ring A (R 2 )(R 3 ), contains one or more deuterium atoms.

[0037] The combinations of substituents and variables contemplated by the present invention are only those that result in the formation of stable compounds. As used herein, the term "stable" refers to compounds having sufficient stability to permit manufacture and maintaining the integrity of the compound for an adequate period of time suitable for the purposes detailed herein (e.g., therapeutic or prophylactic administration to a subject).

[0038] The recitation of a list of chemical groups in any definition of a variable herein includes the definition of the variable as any single group or combination of the listed groups. The recitation of an embodiment of a variable herein includes the embodiment as any single embodiment or in combination with any other embodiment or portion thereof.

[0039] As used herein, the term "biological sample" includes (but is not limited to) cell cultures or extracts thereof; biopsy materials obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof. Inhibition of the activity of a protein kinase (such as MK2) or a mutant thereof in a biological sample is applicable to various purposes known to those skilled in the art. Examples of such purposes include (but are not limited to) blood transfusion, organ transplantation, biological specimen storage, and biological assays.

[0040] As used herein, "a disease or disorder associated with MK2" or alternatively, "an MK2-mediated disease or disorder" refers to any disease or other adverse condition in which MK2 or a mutant thereof is known or suspected to play a role.

[0041] As used herein, the term "subject" refers to a mammal and includes human and animal subjects, such as domestic animals (e.g., horses, dogs, cats, etc.). The terms "subject" and "patient" may be used interchangeably. In some embodiments, a "patient" or "subject" refers to an animal, preferably a mammal and most preferably a human.

[0042] The term "pharmaceutically acceptable carrier, adjuvant, or vehicle" refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound formulated therewith. Pharmaceutically acceptable carriers, adjuvants, or vehicles that can be used in the compositions of the present invention include (but are not limited to) ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffering substances (such as phosphates), glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts), colloidal silicon dioxide, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polypropylene-block polymers, polyethylene glycol, and lanolin. The amount of the compound of the present invention that can be combined with the carrier material to produce a composition in a single dosage form will vary depending on the host being treated, the particular mode of administration, etc. The compositions provided are preferably formulated such that an inhibitor in a dose of 0.01 to about 100 mg, or about 0.1 mg to about 50 mg and preferably between about 1 mg and about 25 mg per kilogram of subject body weight per day can be administered to a patient receiving these compositions to obtain the desired therapeutic effect. The amount of the compound of the present invention in the composition also depends on the particular compound in the composition.

[0043] As used herein, the expression "unit dosage form" refers to a physically discrete unit of the provided compound and / or its composition that is suitable for the subject being treated. However, it should be understood that the total daily dosage of the active agent (i.e., the compounds and compositions of the present invention) will be determined by the attending physician within the scope of reasonable medical judgment. The specific effective dosage level for any particular subject (i.e., patient) or organism will depend on a variety of factors, including the disorder being treated and the severity of the disorder; the activity of the specific active agent being used; the specific composition being used; the age, weight, general health, gender and diet of the subject; the time of administration, the route of administration, and the rate of excretion of the specific active agent being used; the duration of the treatment; and similar factors well known in the medical arts.

[0044] As used herein, the term "parenteral" includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.

[0045] As used herein, a "therapeutically effective amount" refers to the amount of a substance (e.g., a therapeutic agent, composition and / or formulation) that elicits the desired biological response. In some embodiments, a therapeutically effective amount of a substance is an amount sufficient to treat, diagnose, prevent and / or delay the onset of a disease, disorder and / or condition when administered to a subject having or susceptible to the disease, disorder and / or condition as part of a dosing regimen. Those skilled in the art will understand that the effective amount of a substance depends on factors such as the desired biological endpoint, the substance being delivered, the target cell or tissue, etc. For example, the therapeutically effective amount of the provided compound in a formulation to treat a disease, disorder and / or condition is an amount that relieves, improves, alleviates, inhibits, prevents the disease, disorder and / or condition, delays its onset, reduces its severity and / or reduces the incidence of one or more of its symptoms or characteristics. In some embodiments, a "therapeutically effective amount" is at least the minimum amount of the provided compound or a composition containing the provided compound sufficient to treat one or more symptoms of an MK2-mediated disease or disorder.

[0046] As used herein, the terms "treatment", "treat" and "treating" refer to partially or fully alleviating, inhibiting, preventing, ameliorating and / or reducing a disorder or condition described herein, or one or more symptoms of the disorder or condition, or delaying its onset. In some embodiments, treatment may be administered after one or more symptoms have appeared. In some embodiments, the term "treatment" includes preventing or arresting the progression of a disease or disorder. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., based on a symptom history and / or based on genetic or other susceptibility factors). Treatment may also be continued after symptoms have subsided, e.g., to prevent or delay recurrence. Thus, in some embodiments, the term "treatment" includes preventing the recurrence or relapse of a disease or disorder.

[0047] As used herein, the term "inhibitor" is defined as a compound that binds to and / or inhibits the target protein kinase MK2 with measurable affinity. In certain embodiments, the IC 50 and / or binding constant of the inhibitor is less than about 50 μM, less than about 1 μM, less than about 500 nM, less than about 100 nM or less than about 10 nM.

[0048] As used herein, the terms "measurable affinity" and "inhibit in a measurable manner" refer to a measurable change in MK2 activity between a sample comprising a compound or composition of the invention and MK2 and an equivalent sample comprising MK2 but not the compound or composition.

[0049] As used herein, the term "irreversible" or "irreversible inhibitor" refers to an inhibitor (i.e., a compound) that is capable of covalently binding to a kinase in a substantially irreversible manner. That is, while a reversible inhibitor is capable of binding to a kinase (but generally not forming a covalent bond therewith) and can thus dissociate from the kinase, once a covalent bond is formed, the irreversible inhibitor will remain substantially bound to the kinase. Irreversible inhibitors generally exhibit time-dependence, whereby the degree of inhibition increases with the time of contact of the inhibitor with the enzyme. In certain embodiments, once a covalent bond is formed, the irreversible inhibitor will remain substantially bound to the kinase and will remain bound for a period of time longer than the lifetime of the protein.

[0050] Methods for identifying whether a compound acts as an irreversible inhibitor are known to those skilled in the art. Such methods include (but are not limited to) enzyme kinetic analysis of the inhibition profile of a compound using a kinase, mass spectrometry of a modified protein drug target in the presence of an inhibitor compound, discontinuous exposure (also known as "washout") experiments, and the use of labels (such as radiolabeled inhibitors) to show covalent modification of the enzyme, as well as other methods known to those skilled in the art.

[0051] As used herein, the term "resistance" refers to changes in the wild-type nucleic acid sequence encoding a target protein, and / or the amino acid sequence of the target protein, and / or the amino acid sequence of another protein, which reduce or eliminate the inhibitory effect of an inhibitor on the target protein. Without wishing to be bound by any particular theory, it is believed that certain compounds of the present invention, namely compounds that act as irreversible kinase inhibitors, may be effective inhibitors of resistant forms of protein kinases. 3. Description of Exemplary Embodiments:

[0052] As described herein, the present invention provides irreversible inhibitors of MK2 kinase. Without wishing to be bound by any particular theory, it is believed that the compounds of the present invention comprise a moiety capable of covalently binding to a key cysteine residue in the binding domain of MK2 kinase. Such a moiety is referred to herein as a "reactive moiety". Those skilled in the art will appreciate that MK2 kinase and its mutants have cysteine residues in the binding domain. Without wishing to be bound by any particular theory, it is believed that the proximity of the reactive moiety present on the provided MK2 inhibitor to the relevant cysteine facilitates covalent modification of the cysteine by the reactive moiety.

[0053] The relevant cysteine residue can also be described by an identifying portion of the amino acid sequence of MK2 kinase that includes the relevant cysteine. Thus, in certain embodiments, Cys140 of MK2 is characterized in that Cys140 is the cysteine embedded in the following amino acid sequence of MK2: SEQ ID NO.1: MLSNSQGQSPPVPFPAPAPPPQPPTPALPHPPAQPPPPPPQQFPQFHVKSGLQIKKNAII

[0054] For clarity, Cys140 is provided in the following simplified amino acid sequence form: SEQ ID NO.2:

[0055] In both SEQ ID NO.1 and 2, cysteine 140 is highlighted in bold and underlined.

[0056] In some embodiments, the compounds of the invention include a reactive moiety, characterized in that the provided compound covalently modifies Cys140 of MK2.

[0057] In certain embodiments, the compounds of the invention include a reactive moiety, characterized in that the compound covalently modifies the Cys140 target of MK2, thereby irreversibly inhibiting the kinase.

[0058] Thus, in some embodiments, the reactive moiety present on the provided MK2 inhibitor compounds is capable of covalently binding to a cysteine residue, thereby irreversibly inhibiting the enzyme. In some embodiments, the cysteine residue is Cys140 of MK2. Those skilled in the art will recognize that the various reactive moieties as defined herein are suitable for such covalent binding. Such reactive moieties include, but are not limited to, the reactive moieties described herein and depicted below.

[0059] According to one aspect, the invention provides a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein: Ring A is phenyl or a 5- to 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each of R 1 and R 1' is independently selected from hydrogen and C x aliphatic substituted with 0 to 3 R 1-4 , or: R 1 and R 1' may together with the intervening atom to which they are attached form an optionally substituted 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R x is -CN, -NO2, halogen, -OR, -SR, -N(R)2, -C(O)N(R)2, -C(O)OR, -C(O)R, -N(R)C(O)R, -SO2N(R)2, or -N(R)SO2; R 2 is halogen, -CN, or C y aliphatic substituted with m R 1-6 ; Each R y is independently selected from halogen, -CN, -CO2R, -N(R)2, and a 3- to 6-membered heterocycle having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R 3 is optionally substituted C1-6 aliphatic, -CN, halogen, -(CH2) q -OR 4 , -N(R)2, -C(O)OR, -(CH2) r -Cy or -O-(CH2) t -R 5 ; or: two Rs 3 together with the intervening atom to which they are attached form an optionally substituted 5- to 6-membered saturated, partially unsaturated or aryl ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; each R 4 is independently selected from hydrogen, optionally substituted C 1-6 aliphatic and -Cy; each R 5 is independently selected from -OR and -Cy; each Cy is independently an optionally substituted ring selected from: a 3- to 9-membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3- to 9-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; phenyl; a 5- to 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 7- to 12-membered saturated or partially unsaturated fused, spirofused or bridged bicyclic carbocyclic ring; or a 7- to 12-membered saturated or partially unsaturated fused, spirofused or bridged bicyclic heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; each R is independently hydrogen or optionally substituted C 1-6 aliphatic, or: two R groups on the same nitrogen are joined together with the nitrogen to form a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 3 heteroatoms selected from nitrogen, oxygen or sulfur; each of m, n, q and r is independently 0 to 4; and t is 1 to 4.

[0060] As generally defined above, each of R 1 and R 1' is independently selected from hydrogen and C x aliphatic substituted with 0 to 3 Rs 1-4 , or R 1 and R 1' may together with the intervening atom to which they are attached form an optionally substituted 3- to 6-membered saturated, partially unsaturated or aryl ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0061] In some embodiments, R 1' is hydrogen. Thus, in some embodiments, the present invention provides a compound of formula I-a: or a pharmaceutically acceptable salt thereof, wherein R 1 、R 2 、R 3 and each of n are as defined above and as described herein.

[0062] In some embodiments of Formula I or Formula I-a, R 1 is C x aliphatic substituted with from 0 to 3 R 1-4 s. In some embodiments, R 1 is C x aliphatic substituted with 1 R 1-4 . In some embodiments, R 1 is C x aliphatic substituted with 2 R 1-4 s. In some embodiments, R 1 is C x aliphatic substituted with 3 R 1-4 s. In some embodiments, R 1 is C x aliphatic substituted with 1 R 1-2 . In some embodiments, R 1 is C x aliphatic substituted with 2 R 1-2 s. In some embodiments, R 1 is C x aliphatic substituted with 3 R 1-2 s.

[0063] As generally defined above, R x is -CN, -NO2, halogen, -OR, -SR, -N(R)2, -C(O)N(R)2, -C(O)OR, -C(O)R, -N(R)C(O)R, -SO2N(R)2 or -N(R)SO2. In some embodiments, R x is halogen. In some embodiments, R x is -OR. In some embodiments, R x is -N(R)2.

[0064] In some embodiments of Formula I or Formula I-a, R 1 is -CH3. In some embodiments of Formula I or Formula I-a, R 1 is -CH2OH. In some embodiments of Formula I or Formula I-a, R 1 is -CH2F.

[0065] In some embodiments of Formula I, R 1 and R 1'Each is a C aliphatic optionally substituted with 0 to 3 Rs x substituted C 1-4 aliphatic. In some embodiments, R 1 and R 1' are each C 1-4 aliphatic. In some embodiments, R 1 and R 1' are each C 1-2 aliphatic. In some embodiments, R 1 and R 1' are each -CH3.

[0066] In some embodiments of Formula I, R 1 and R 1' together with the intermediate atom to which they are attached form an optionally substituted 3- to 6-membered saturated, partially unsaturated or aryl ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments of Formula I, R 1 and R 1' together with the intermediate atom to which they are attached form an optionally substituted 3-membered saturated ring having 0 to 1 heteroatom independently selected from nitrogen, oxygen and sulfur. In some embodiments of Formula I, R 1 and R 1' together with the intermediate atom to which they are attached form an optionally substituted 4-membered saturated ring having 0 to 1 heteroatom independently selected from nitrogen, oxygen and sulfur. In some embodiments of Formula I, R 1 and R 1' together with the intermediate atom to which they are attached form an optionally substituted 5-membered saturated ring having 0 to 1 heteroatom independently selected from nitrogen, oxygen and sulfur. In some embodiments of Formula I, R 1 and R 1' together with the intermediate atom to which they are attached form an optionally substituted 6-membered saturated ring having 0 to 1 heteroatom independently selected from nitrogen, oxygen and sulfur. In some embodiments of Formula I, R 1 and R 1' together with the intermediate atom to which they are attached form an optionally substituted

[0067] As generally defined above, Ring A is phenyl or a 5- to 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, Ring A is phenyl. In some embodiments, Ring A is phenyl and R 2 is in the meta position of the benzene ring.

[0068] In some embodiments, Ring A is a 5- to 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0069] In some embodiments, Ring A is a 5-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is a 5-membered heteroaryl ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is a 5-membered heteroaryl ring having 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0070] In some embodiments, Ring A is a 6-membered heteroaryl ring having 1 to 3 nitrogen atoms. In some embodiments, Ring A is a 6-membered heteroaryl ring having 1 to 2 nitrogen atoms. In some embodiments, Ring A is a 6-membered heteroaryl ring having 1 nitrogen atom. In some embodiments, Ring A is a 6-membered heteroaryl ring having 2 nitrogen atoms.

[0071] In some embodiments, selected from the group consisting of:

[0072] In some embodiments, selected from the group consisting of:

[0073] As generally defined above, R 2 is halogen, -CN, or C y aliphatic substituted with m R 1-6 . In some embodiments, R 2 is halogen. In some such embodiments, R 2 is fluorine, chlorine, or bromine. In some embodiments, R 2 is fluorine or chlorine. In some embodiments, R 2 is -CN.

[0074] In some embodiments, R 2 is C y aliphatic substituted with m R 1-6 . In some embodiments, R 2 is C y aliphatic substituted with m R 1-4 . In some embodiments, R 2 is C y aliphatic substituted with m R 1-2 .

[0075] In some embodiments, R 2 is C y aliphatic substituted with m R2-6 Aliphatic, wherein C 2-6 The aliphatic has at least one unsaturated unit. In some embodiments, R 2 is C substituted with m R y groups 2-4 Aliphatic, wherein C 2-4 The aliphatic has at least one unsaturated unit. In some embodiments, R 2 is C substituted with m R y groups 2-3 Aliphatic, wherein C 2-3 The aliphatic has one unsaturated unit.

[0076] In some embodiments, R 2 is selected from the group consisting of: -CH2-R y , -CH=CH2, -C≡CH, -C≡CCH3, -CH=CHCH3 (e.g., ), -CH=CH-R y (e.g., ), -CH=CHCH2-R y (e.g., ), -CH=CHCH(R y )2 (e.g., ), -CH=CHC(R y )3 (e.g., ),

[0077] As generally defined above, each R y is independently selected from halogen, -CN, -CO2R, -N(R)2, and 3- to 6-membered saturated or partially unsaturated heterocycles having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R y is halogen. In some embodiments, R y is fluorine. In some embodiments, R y is -CN. In some embodiments, R y is -CO2R. In some embodiments, R y is -N(R)2.

[0078] In some embodiments, R y is a 3- to 6-membered saturated or partially unsaturated heterocycle having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R y is a 5-membered saturated heterocycle having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R yis a 5-membered saturated heterocycle having 1 heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, R y is a 6-membered saturated heterocycle having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R y is a 6-membered saturated heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R y is pyrrolidinyl or morpholinyl.

[0079] In some embodiments, R y is selected from fluorine, -CN, -NH2, -N(CH3)2, -C(O)OCH3,

[0080] In some embodiments, m is from 0 to 4. In some embodiments, m is 0. In some embodiments, m is from 1 to 4. In some embodiments, m is from 1 to 3. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3.

[0081] In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is from 0 to 2. In some embodiments, n is from 0 to 3. In some embodiments, n is from 1 to 3.

[0082] As generally defined above, R 3 is optionally substituted C 1-6 aliphatic, -CN, halogen, -(CH2) q -OR 4 、-N(R)2、-C(O)OR、-(CH2) r -Cy or -O-(CH2) t -R 5 , or two R 3 groups together with the intervening atom to which they are attached form an optionally substituted 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 3 is optionally substituted C 1-6 aliphatic, -CN, halogen, -(CH2) q -OR 4 、-N(R)2、-C(O)OR、-(CH2) r -Cy or -O-(CH2) t -R 5 .

[0083] In some embodiments, R 3is an optionally substituted C 1-6 aliphatic. In some embodiments, R 3 is an optionally substituted C 1-4 aliphatic. In some embodiments, R 3 is an optionally substituted C 1-2 aliphatic. In some embodiments, R 3 is an optionally halogen-substituted C 1-6 aliphatic. In some embodiments, R 3 is an optionally -(CH2) 0-4 OR°-substituted C 1-6 aliphatic. In some such embodiments, R° is hydrogen. In some embodiments, R 3 is an optionally -OH-substituted C 1-6 aliphatic. In some embodiments, R 3 is an optionally halogen-substituted C 1-4 aliphatic. In some embodiments, R 3 is an optionally -(CH2) 0-4 OR°-substituted C 1-4 aliphatic. In some such embodiments, R° is hydrogen. In some embodiments, R 3 is an optionally -OH-substituted C 1-4 aliphatic. In some embodiments, R 3 is an optionally halogen-substituted C 1-2 aliphatic. In some embodiments, R 3 is an optionally -(CH2) 0-4 OR°-substituted C 1-2 aliphatic. In some such embodiments, R° is hydrogen. In some embodiments, R 3 is an optionally -OH-substituted C 1-2 aliphatic.

[0084] In some embodiments, R 3 is -CN. In some embodiments, R 3 is halogen. In some such embodiments, R 3 is fluorine or chlorine. In some embodiments, R 3 is -(CH2) q -OR 4 . In some embodiments, R 3 is -N(R)2. In some embodiments, R 3 is -C(O)OR. In some embodiments, R 3 is -(CH2) r -Cy. In some embodiments, R 3 is -O-(CH2)t -R 5 .

[0085] In some embodiments, two R on adjacent atoms 3 The group, together with the intermediate atom to which it is attached, forms an optionally substituted 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two R on adjacent atoms 3 The group, together with the intermediate atom to which it is attached, forms an optionally substituted 5-membered saturated ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two R on adjacent atoms 3 The group, together with the intermediate atom to which it is attached, forms an optionally substituted 6-membered saturated ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two R on adjacent atoms 3 The group, together with the central atom to which it is attached, forms an optionally substituted 6-membered aryl ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0086] In some embodiments, q is 0. Thus, in some embodiments, R 3 For-OR 4 In some embodiments, q is 1 to 4. In some embodiments, q is 1. Thus, in some embodiments, R 3 -CH2OR 4 In some embodiments, q is 2. In some embodiments, q is 3.

[0087] As generally defined above, each R 4 are independently selected from hydrogen, optionally substituted C 1-6 In some embodiments, R 4 In some embodiments, R 4 Selected from optionally substituted C 1-6 In some embodiments, R 4 is an optionally substituted C 1-6 In some embodiments, R 4 is an optionally substituted C 1-4 In some embodiments, R 4 is an optionally substituted C 1-2 Fatty.

[0088] In some embodiments, R 4 is C optionally substituted by halogen 1-6 In some embodiments, R 4 is C optionally substituted by halogen 1-4Aliphatic. In some embodiments, R 4 is optionally halogen-substituted C 1-2 aliphatic.

[0089] In some embodiments, R 4 is -Cy.

[0090] In some embodiments, r is 0. Thus, in some embodiments, R 3 is -Cy. In some embodiments, r is 1 to 4. In some embodiments, r is 1. Thus, in some embodiments, R 3 is -CH2Cy. In some embodiments, r is 2. Thus, in some embodiments, R 3 is -CH2CH2Cy. In some embodiments, r is 3.

[0091] As generally defined above, t is 1 to 4. In some embodiments, t is 1. Thus, in some embodiments, R 3 is -OCH2R 5 . In some embodiments, t is 2. Thus, in some embodiments, R 3 is -OCH2CH2R 5 . In some embodiments, t is 3. In some embodiments, t is 4.

[0092] As generally defined above, each R is independently hydrogen or optionally substituted C 1-6 aliphatic, or two R groups on the same nitrogen are joined together with the nitrogen to form a 3- to 7-membered saturated or partially unsaturated heterocycle having 1 to 3 heteroatoms selected from nitrogen, oxygen, or sulfur. In some embodiments, R is hydrogen. In some embodiments, R is optionally substituted C 1-6 aliphatic, or two R groups on the same nitrogen are joined together with the nitrogen to form a 3- to 7-membered saturated or partially unsaturated heterocycle having 1 to 3 heteroatoms selected from nitrogen, oxygen, or sulfur. In some embodiments, R is optionally substituted C 1-6 aliphatic. In some embodiments, R is optionally substituted C 1-4 aliphatic. In some embodiments, R is optionally substituted C 1-2 aliphatic. In some embodiments, R is optionally substituted by -(CH2) 0-4 OR° or halogen-substituted C 1-6 aliphatic. In some embodiments, R is optionally substituted by -(CH2) 0-4 OR° or halogen-substituted C 1-4 aliphatic. In some embodiments, R is optionally substituted by -(CH2) 0-4 OR° or halogen-substituted C 1-2Aliphatic. In some embodiments, R is hydrogen, -CH3, CH2CH3, or -CH2CH2CH3.

[0093] As generally defined above, each R 5 is independently selected from -OR and -Cy. In some embodiments, R 5 is -OR. In some embodiments, R 5 is -Cy.

[0094] As generally defined above, each Cy is independently an optionally substituted ring selected from: a 3- to 9-membered saturated or partially unsaturated monocyclic carbocycle; a 3- to 9-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; phenyl; a 5- to 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 7- to 12-membered saturated or partially unsaturated fused, spiro-fused, or bridged bicyclic carbocycle; or a 7- to 12-membered saturated or partially unsaturated fused, spiro-fused, or bridged bicyclic heterocycle having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0095] In some embodiments, Cy is an optionally substituted 3- to 9-membered saturated or partially unsaturated monocyclic carbocycle. In some embodiments, Cy is an optionally substituted 3-membered saturated carbocycle. In some embodiments, Cy is an optionally substituted 4-membered saturated carbocycle. In some embodiments, Cy is an optionally substituted 5-membered saturated carbocycle. In some embodiments, Cy is an optionally substituted 6-membered saturated monocyclic carbocycle.

[0096] In some embodiments, Cy is an optionally substituted 3- to 9-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy is an optionally substituted 3-membered saturated heterocycle having 1 heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy is an optionally substituted 4-membered saturated heterocycle having 1 heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy is an optionally substituted 5-membered saturated heterocycle having 1 heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy is an optionally substituted 6-membered saturated heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0097] In some embodiments, Cy is an optionally substituted phenyl.

[0098] In some embodiments, Cy is an optionally substituted 5- to 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy is an optionally substituted 5-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy is an optionally substituted 6-membered heteroaryl ring having 1 to 2 nitrogen atoms.

[0099] In some embodiments, Cy is an optionally substituted 7- to 12-membered saturated or partially unsaturated fused, spiro-fused, or bridged bicyclic carbocycle. In some embodiments, Cy is an optionally substituted 7- to 12-membered saturated or partially unsaturated fused bicyclic carbocycle. In some embodiments, Cy is an optionally substituted 7- to 12-membered saturated or partially unsaturated spiro-fused bicyclic carbocycle. In some embodiments, Cy is an optionally substituted 7- to 12-membered saturated or partially unsaturated bridged bicyclic carbocycle.

[0100] In some embodiments, Cy is an optionally substituted 7- to 12-membered saturated or partially unsaturated fused, spiro-fused, or bridged bicyclic heterocycle having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy is an optionally substituted 7- to 12-membered saturated or partially unsaturated fused bicyclic heterocycle having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy is an optionally substituted 7- to 12-membered saturated or partially unsaturated spiro-fused bicyclic heterocycle having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy is an optionally substituted 7-membered saturated spiro-fused bicyclic heterocycle having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy is an optionally substituted 8-membered saturated spiro-fused bicyclic heterocycle having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy is an optionally substituted 9-membered saturated spiro-fused bicyclic heterocycle having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy is an optionally substituted 10-membered saturated spiro-fused bicyclic heterocycle having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0101] In some embodiments, Cy is an optionally substituted 7- to 12-membered saturated or partially unsaturated bridged bicyclic heterocycle having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy is an optionally substituted 7-membered saturated bridged bicyclic heterocycle having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0102] In some embodiments, Cy is selected from

[0103] In some embodiments, Cy is selected from

[0104] In some embodiments, R 3 is selected from halogen, -CN, -N(R)2, -C(O)OR, -(CH2) q -OR 4 (e.g., -OR 4 or -CH2OR 4 ), -(CH2) r -Cy (e.g., -Cy, -CH2Cy or -CH2CH2Cy), -O-(CH2) t -R 5 (e.g., -OCH2R 5 or -OCH2CH2R 5 ) and optionally halogen- or -OR°-substituted C 1-6 aliphatic.

[0105] In some embodiments, R 3 is selected from: fluorine, chlorine, -CH3, -CD3, -CH2CH3, -CF3, -CF2H, -CN, -CH2OH, -CH2OCH3, -CH2OCH2CH3, -CH(OH)CD3, -C(OH)(CD3)2, -OCH3, -OCF3, -OCF2H, -OCH2CH2CH3, -OCH2CH2OCH2CH3, -NHCH3, -N(CH3)2, -C(O)OCH3, -C(O)OCH2CH3,

[0106] In some embodiments, is selected from

[0107] In some embodiments, the present invention provides a compound of any one of Formulas II, III, IV or V: or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 and each of n are as defined above and as described herein.

[0108] In some embodiments, the present invention provides a compound of any one of Formulas II-a, II-b, II-c, III-a, III-b, IV-a, IV-b, IV-c, V-a, V-b or V-c: or a pharmaceutically acceptable salt thereof, wherein R 1 , R 3 and each of n are as defined above and as described herein.

[0109] In some embodiments, the present invention provides a compound of any one of Formulas II-a-i, II-a-ii, II-b-i, II-b-ii, II-c-i, II-c-ii, III-a-i, III-b-i, IV-a-i, IV-a-ii, IV-b-i, IV-b-ii, IV-c-i, IV-c-ii, V-a-i, V-b-i or V-c-i: or a pharmaceutically acceptable salt thereof, wherein R 1 and R 3 each are as defined above and as described herein.

[0110] In some embodiments of any one of Formulas I, II, II-a, II-a-i, II-a-ii, II-b, II-b-i, II-b-ii, II-c, II-c-i, II-c-ii, III, III-a, III-a-i, III-b, III-b-i, IV, IV-a, IV-a-i, IV-a-ii, IV-b, IV-b-i, IV-b-ii, IV-c, IV-c-i, IV-c-ii, V, V-a, V-a-i, V-b, V-b-i, V-c and V-c-i, R 1 is -CH3.

[0111] In some embodiments of any one of Formulas I, II, III, IV and V, R 2 is selected from halogen, -CH2-R y, -C(CH3)=CH2, -C≡CCH3, -CH=CHCH3 (e.g., ), -CH=CH-R y (e.g., ), -CH=CHCH2-R y (e.g., ), -CH=CHCH(R y )2 (e.g., ), -CH=CHC(R y )3 (e.g., ), and

[0112] In some embodiments of any one of Formulas I, II, II-a, II-a-i, II-a-ii, II-b, II-b-i, II-b-ii, II-c, II-c-i, II-c-ii, III, III-a, III-a-i, III-b, III-b-i, IV, IV-a, IV-a-i, IV-a-ii, IV-b, IV-b-i, IV-b-ii, IV-c, IV-c-i, IV-c-ii, V, V-a, V-a-i, V-b, V-b-i, V-c and V-c-i, R 3 is selected from fluorine, chlorine, -CH3, -CD3, -CH2CH3, -CF3, -CF2H, -CN, -CH2OH, -CH2OCH3, -CH2OCH2CH3, -CH(OH)CD3, -C(OH)(CD3)2, -OCH3, -OCF3, -OCF2H, -OCH2CH2CH3, -OCH2CH2OCH2CH3, -NHCH3, -N(CH3)2, -C(O)OCH3, -C(O)OCH2CH3,

[0113] In some embodiments, the present invention provides compounds from the following groups or pharmaceutically acceptable salts thereof: 4. Use, Formulation and Administration Pharmaceutically acceptable compositions

[0114] According to another embodiment, the present invention provides a composition comprising a compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, adjuvant or vehicle. In certain embodiments, the amount of the compound in the composition of the present invention is such that it effectively inhibits MK2 or its mutants in a biological sample or a patient in a measurable manner. In certain embodiments, the composition of the present invention is formulated for administration to a patient in need of such a composition. In some embodiments, the composition of the present invention is formulated for oral administration to a patient.

[0115] Administer the compounds and compositions of the method according to the present invention in any amount and by any route of administration that can effectively treat or alleviate the severity of the conditions provided herein (i.e., MK2-mediated diseases or disorders). The exact amount required will vary for each subject, depending on the species, age and general condition of the subject, the severity of the infection, the particular agent, its mode of administration, etc. The compounds of the present invention are preferably formulated in unit dosage forms for ease of administration and uniformity of dosage.

[0116] The compositions of the present invention can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, intraperitoneally, intracisternally or by an implantable reservoir. In some embodiments, the composition is administered orally, intraperitoneally or intravenously.

[0117] The sterile injectable form of the compositions of the present invention may be aqueous or oleaginous suspensions. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a parenterally acceptable non-toxic diluent or solvent, such as in the form of a solution in 1,3 - butanediol. Among the acceptable vehicles and solvents, water, Ringer's solution, and isotonic sodium chloride solution can be used. Additionally, sterile, non-volatile oils are conventionally used as solvents or suspending media.

[0118] For this purpose, any mild non-volatile oil can be used, including synthetic monoglycerides or diglycerides. Fatty acids (such as oleic acid and its glyceride derivatives) are suitable for the preparation of injectables, as are natural pharmaceutically acceptable oils (such as olive oil or castor oil, especially their polyoxylated forms). These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersing agents, such as carboxymethyl cellulose or similar dispersing agents commonly used in formulating pharmaceutically acceptable dosage forms, including emulsions and suspensions. Other commonly used surfactants (such as Tween, Span, and other emulsifying agents) or bioavailability enhancers commonly used in manufacturing pharmaceutically acceptable solid, liquid, or other dosage forms can also be used for formulating purposes.

[0119] The injectable preparation can be sterilized, for example, by filtration through a bacteria-retaining filter or by the addition of a sterilizing agent in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile injectable media before use.

[0120] To prolong the effect of the compounds of the present invention, it is generally necessary to slow the absorption of the compounds from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of a crystalline or amorphous material with poor water solubility. The rate of absorption of the compound depends on its dissolution rate, which in turn can depend on crystal size and crystalline form. Alternatively, delayed absorption of the compound administered parenterally is achieved by dissolving or suspending the compound in an oily vehicle. Injectable depot forms are prepared by forming a microcapsule matrix of the compound in a biodegradable polymer, such as poly(lactide-co-glycolide). The rate of release of the compound can be controlled according to the ratio of the compound to the polymer and the nature of the specific polymer used. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Injectable depot preparations are also prepared by coating the compound in liposomes or microemulsions compatible with body tissues.

[0121] In some embodiments, the provided pharmaceutically acceptable compositions are formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, the pharmaceutically acceptable compositions of the invention are not administered with food. In other embodiments, the pharmaceutically acceptable compositions of the invention are administered with food. The pharmaceutically acceptable compositions of the invention may be orally administered in any acceptable oral dosage form, including (but not limited to) capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, common carriers include lactose and corn starch. Lubricants, such as magnesium stearate, are also generally added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When an aqueous suspension is required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.

[0122] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is admixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or calcium phosphate and / or a) fillers or extenders such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; c) humectants such as glycerol; d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) solution retarders such as paraffin; f) absorption accelerators such as quaternary ammonium compounds; g) wetting agents such as cetyl alcohol and glycerol monostearate; h) adsorbents such as kaolin and bentonite clay; and / or i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also contain buffering agents.

[0123] Excipients such as lactose or milk sugar and high molecular weight polyethylene glycols may also be used, and solid compositions of a similar type may be used as fillers in soft and hard gelatin capsules. Solid dosage forms of tablets, dragees, capsules, pills, and granules may be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulation art. They may optionally contain opacifying agents and may also have compositions that release the active ingredient only or preferentially in a delayed manner in a particular part of the intestine. Examples of embedding compositions that may be used include polymeric substances and waxes. Excipients such as lactose or milk sugar and high molecular weight polyethylene glycols may also be used, and solid compositions of a similar type may be used as fillers in soft and hard gelatin capsules.

[0124] The active compounds can also be present in microencapsulated form, alone or in combination with one or more excipients as indicated above. Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings, controlled-release coatings, and other coatings well known in the pharmaceutical formulation art. In such solid dosage forms, the active compound can be admixed with at least one inert diluent such as sucrose, lactose, or starch. As is common practice, these dosage forms may also contain other substances in addition to the inert diluent, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pills, the dosage forms can also contain buffering agents. It may optionally contain opacifying agents and may also have a composition that releases the active ingredient only, or preferentially, in a particular part of the intestine, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0125] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, the liquid dosage forms can contain inert diluents commonly used in the art, such as water or other solvents; solubilizing agents and emulsifying agents such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol, dimethylformamide, oils (especially cottonseed, peanut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols, and fatty acid esters of sorbitan; and mixtures thereof. In addition to the inert diluent, the oral compositions can also include adjuvants such as wetting agents, emulsifying agents, and suspending agents, sweetening agents, flavoring agents, and perfuming agents.

[0126] Alternatively, the pharmaceutically acceptable compositions of the present invention can be administered in the form of suppositories for rectal administration. These suppositories can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter, beeswax, and polyethylene glycols.

[0127] Compositions for rectal or vaginal administration are preferably suppositories, which can be prepared by mixing the compounds of the present invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol, or suppository waxes, which are solid at ambient temperature but liquid at body temperature and will therefore melt in the rectal or vaginal cavity and release the active compound.

[0128] The pharmaceutically acceptable compositions of the present invention can also be administered topically, especially when the treatment target includes diseases of regions or organs that are readily accessible by topical administration, including the eyes, skin, or lower intestine. Suitable topical formulations can be readily prepared for each of these regions or organs.

[0129] Local administration to the lower intestine can be achieved in the form of rectal suppository formulations (see above) or in the form of suitable enema formulations. Transdermal patches can also be used.

[0130] For topical administration, the provided pharmaceutically acceptable compositions can be formulated as suitable ointments containing the active ingredient suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of the present invention include (but are not limited to) mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax, and water. Alternatively, the provided pharmaceutically acceptable compositions can be formulated as suitable lotions or creams containing the active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include (but are not limited to) mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.

[0131] For ophthalmic use, the provided pharmaceutically acceptable compositions can be formulated as a micronized suspension in isotonic, pH-adjusted sterile saline with or without a preservative (such as benzylalkonium chloride), or preferably as a solution in isotonic, pH-adjusted sterile saline. Alternatively, for ophthalmic use, the pharmaceutically acceptable compositions can be formulated in the form of an ointment (such as petrolatum).

[0132] The pharmaceutically acceptable compositions of the present invention can also be administered by nasal aerosol or inhalation. Such compositions can be prepared according to techniques well known in the art of pharmaceutical formulation and can be prepared as solutions in saline using benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0133] Dosage forms for topical or transdermal administration of the compounds of the present invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. The active ingredient is mixed with a pharmaceutically acceptable carrier and any desired preservatives or buffering agents that may be required under sterile conditions. Ophthalmic preparations, otic drops, and eye drops are also within the scope of the present invention. Additionally, the present invention contemplates the use of transdermal patches, which have the additional advantage of providing a controlled release of the compound to the body. Such dosage forms can be prepared by dissolving or dispensing the compound in a suitable medium. Absorption enhancers can also be used to increase the amount of the compound permeating through the skin. The rate can be controlled by providing a rate-controlling membrane or by dispersing the compound in a polymeric matrix or gel. 5. Use of the Compounds and Pharmaceutically Acceptable Compositions

[0134] The compounds and compositions described herein are generally suitable for inhibiting the kinase activity of one or more enzymes. Examples of kinases inhibited by the compounds and compositions described herein and for which the methods described herein are useful include MK2 or mutants thereof.

[0135] The activity of compounds used as inhibitors of MK2 kinase or mutants thereof in the present invention can be assayed in vitro, in vivo, or in cell lines. In vitro assays include assays for inhibition of phosphorylation activity and / or subsequent functional outcomes, or for inhibition of the ATPase activity of activated MK2 kinase or mutants thereof. Alternative in vitro assays quantitatively test the ability of a test compound to bind to MK2. Inhibitor binding can be measured by radiolabeling the test compound prior to binding, separating the test compound / MK2 complex, and assaying the amount of radiolabeled binding. Alternatively, inhibitor binding can be assayed by running a competition experiment in which the test compound is incubated with MK2 kinase that is bound to a known radioligand. The detailed conditions for assaying compounds used as inhibitors of MK2 or mutants thereof in the present invention are set forth in the Examples below.

[0136] According to one embodiment, the present invention relates to a method of inhibiting protein kinase activity in a biological sample, comprising the step of contacting the biological sample with a compound of the present invention or a composition comprising the compound.

[0137] According to another embodiment, the present invention relates to a method of inhibiting the activity of MK2 kinase or mutants thereof in a biological sample, comprising the step of contacting the biological sample with a compound of the present invention or a composition comprising the compound. In certain embodiments, the present invention relates to a method of irreversibly inhibiting the activity of MK2 kinase or mutants thereof in a biological sample, comprising the step of contacting the biological sample with a compound of the present invention or a composition comprising the compound.

[0138] According to another embodiment, the present invention relates to a method of inhibiting the activity of MK2 kinase or mutants thereof in a patient, comprising the step of administering to the patient a compound of the present invention or a composition comprising the compound. According to certain embodiments, the present invention relates to a method of irreversibly inhibiting the activity of MK2 kinase or mutants thereof in a patient, comprising the step of administering to the patient a compound of the present invention or a composition comprising the compound. In other embodiments, the present invention provides a method for treating an MK2-mediated disease or disorder in a patient in need thereof, comprising the step of administering to the patient a compound of the present invention or a pharmaceutically acceptable composition thereof. Such disorders are described in detail herein. 6. MK2 Kinase

[0139] Mitogen-activated protein kinase-activated protein kinase 2 ("MK2") is an enzyme that in humans is encoded by the MAPKAPK2 gene. This gene encodes a member of the Ser / Thr protein kinase family. This kinase is regulated by direct phosphorylation by p38 MAP kinase. This kinase is known to be involved, together with p38 MAP kinase, in many cellular processes, including stress and inflammatory responses, nuclear export, regulation of gene expression, and cell proliferation. Heat shock protein HSP27 has been demonstrated to be one of the in vivo substrates of this kinase. Two transcript variants encoding two different isoforms have been found for this gene.

[0140] MK2 is a multi-domain protein consisting of an N-terminal proline-rich domain, a catalytic domain, an auto-inhibitory domain, and a C-terminal nuclear export signal (NES) and nuclear localization signal (NLS). Two isoforms of human MK2 have been characterized. One isoform consists of 400 amino acids while the other isoform consists of 370 residues and is thought to be a splice variant lacking the C-terminal NLS. MK2 is located in the cell nucleus and upon binding and phosphorylation by p38, the MK2 NES becomes functional and both kinases are co-transported out of the nucleus into the cytoplasm. Interestingly, the transport of the MK2 / p38 complex does not require catalytically active MK2 as the active site mutant Asp207Ala is still transported into the cytoplasm. Phosphorylation of human MK2 at residues T222, S272, and T334 by p38 is thought to activate the enzyme by inducing a conformational change in the auto-inhibitory domain, thereby exposing the active site for substrate binding. Mutations of two auto-inhibitory domain residues W332A and K326E in murine MK2 show increased basal activity and deletion of the C-terminus of the auto-inhibitory domain renders the enzyme constitutively active, providing additional evidence for the role of this domain in inhibiting MK2 activity.

[0141] Diseases or disorders related to MK2 that can be treated with the compounds of the present invention include autoimmune disorders, chronic inflammatory disorders, acute inflammatory disorders, autoinflammatory disorders, fibrotic disorders, metabolic disorders, neoplasms, or cardiovascular or cerebrovascular disorders. Accordingly, in some embodiments, the present invention provides a method for treating an MK2-mediated disease or disorder in a patient in need thereof, wherein the method comprises administering to the patient a therapeutically effective amount of the provided compound or a composition thereof. Such MK2-mediated diseases or disorders include (but are not limited to) the diseases or disorders described herein.

[0142] In some embodiments, the MK2-mediated disease or disorder is an autoimmune disorder, a chronic and / or acute inflammatory disorder, and / or an autoinflammatory disorder. Exemplary autoimmune and / or inflammatory and / or autoinflammatory disorders include: inflammatory bowel disease (e.g., ulcerative colitis or Crohn's disease), multiple sclerosis, psoriasis, arthritis, rheumatoid arthritis, osteoarthritis, juvenile arthritis, psoriatic arthritis, reactive arthritis, ankylosing spondylitis, cryopyrin associated periodic syndromes, Muckle-Wells syndrome, familial cold auto-inflammatory syndrome, neonatal-onset multisystem inflammatory disease, TNF receptor-associated periodic syndrome, acute and chronic pancreatitis, atherosclerosis, gout, ankylosing spondylitis, fibrotic disorders (e.g., liver fibrosis or idiopathic pulmonary fibrosis), kidney disease, sarcoidosis, scleroderma, anaphylactic shock, diabetes (e.g., type 1 diabetes or type 2 diabetes), diabetic retinopathy, Still's disease, vasculitis, sarcoidosis, pulmonary inflammation, acute respiratory distress syndrome, wet and dry age-related macular degeneration, autoimmune hemolytic syndrome, autoimmune and inflammatory hepatitis, autoimmune neuropathy, autoimmune ovarian failure, autoimmune orchitis, autoimmune thrombocytopenia, silicone implant-associated autoimmune disease, Sjogren's syndrome, familial Mediterranean fever, systemic lupus erythematosus, vasculitis syndromes (e.g., temporal arteritis, Takayasu's arteritis, and giant cell arteritis, Behcet's disease disease) or Wegener's granulomatosis), vitiligo, secondary hematological manifestations of autoimmune diseases (e.g., anemia), drug-induced autoimmunity, Hashimoto's thyroiditis, hypophysitis, idiopathic thrombocytopenic purpura, metal-induced autoimmunity, myasthenia gravis, pemphigus, autoimmune deafness (e.g., Meniere's disease), Goodpasture's syndrome, Graves' disease, HW-related autoimmune syndrome, Guillain-Barre disease, Addison's disease, antiphospholipid syndrome, asthma, atopic dermatitis, celiac disease, Cushing's syndrome, dermatomyositis, idiopathic adrenal atrophy, idiopathic thrombocytopenia, Kawasaki syndrome, Lambert-Eaton Syndrome, pernicious anemia, hay fever, polyarteritis nodosa, primary biliary cirrhosis, primary sclerosing cholangitis, Raynaud's Syndrome, Reiter's Syndrome, relapsing polychondritis, Schmidt's syndrome, thyrotoxicosis, sepsis, septic shock, endotoxin shock, exotoxin-induced toxic shock, gram negative sepsis, toxic shock syndrome, glomerulonephritis, peritonitis, interstitial cystitis, hyperoxia-induced inflammation, chronic obstructive pulmonary disease (COPD), vasculitis, graft-versus-host reaction (e.g., graft-versus-host disease), allograft rejection (e.g., acute allograft rejection or chronic allograft rejection), early transplant rejection (e.g., acute allograft rejection), reperfusion injury, pain (e.g., acute pain, chronic pain, neuralgia or myofibromyalgia), chronic infection, meningitis, encephalitis, myocarditis, gingivitis, postoperative trauma, tissue injury, traumatic brain injury, enterocolitis, sinusitis, uveitis, ocular inflammation, optic neuritis, gastric ulcer, esophagitis, peritonitis, periodontitis, dermatomyositis, gastritis, myositis, polymyalgia, pneumonia and bronchitis.

[0143] In some embodiments, the MK2-mediated disease or disorder is a fibrotic disorder. Exemplary fibrotic disorders include systemic sclerosis / scleroderma, lupus nephritis, connective tissue diseases, wound healing, surgical scars, spinal cord injury, CNS scars, acute lung injury, pulmonary fibrosis (e.g., idiopathic pulmonary fibrosis or cystic fibrosis), chronic obstructive pulmonary disease, adult respiratory distress syndrome, acute lung injury, drug-induced lung injury, glomerulonephritis, chronic kidney disease (e.g., diabetic nephropathy), hypertension-induced nephropathy, gastrointestinal or GI fibrosis, renal fibrosis, hepatic or biliary fibrosis, liver fibrosis (e.g., non-alcoholic steatohepatitis, hepatitis C or hepatocellular carcinoma), cirrhosis (e.g., primary biliary cirrhosis or cirrhosis caused by fatty liver disease (e.g., alcoholic and non-alcoholic steatohepatitis)), radiation-induced fibrosis (e.g., head and neck, gastrointestinal or lung), primary sclerosing cholangitis, restenosis, cardiac fibrosis (e.g., endomyocardial fibrosis or atrial fibrosis), ocular scars, fibrosclerosis, fibrotic cancers, fibroids, fibromas, fibroadenomas, fibrosarcomas, transplant arteriopathy, keloids, mediastinal fibrosis, myelofibrosis, retroperitoneal fibrosis, progressive massive fibrosis, and nephrogenic systemic fibrosis.

[0144] In some embodiments, the MK2-mediated disease or disorder is a metabolic disorder. Exemplary metabolic disorders include obesity, steroid resistance, glucose intolerance, and metabolic syndrome.

[0145] In some embodiments, the MK2-mediated disease or disorder is a neoplasm. Exemplary neoplasms include cancers. In some embodiments, exemplary neoplasms include angiogenic disorders, multiple myeloma, leukemia (e.g., acute lymphoblastic leukemia, acute and chronic myelogenous leukemia, chronic lymphocytic leukemia, acute lymphoblastic leukemia, or promyelocytic leukemia), lymphoma (e.g., B-cell lymphoma, T-cell lymphoma, mantle cell lymphoma, hairy cell lymphoma, Burkitt's lymphoma, mast cell tumor, Hodgkin's disease, or non-Hodgkin's disease), myelodysplastic syndrome, fibrosarcoma, rhabdomyosarcoma; astrocytoma, neuroblastoma, glioma, and schwannoma; melanoma, seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratoacanthoma, follicular cancer of the thyroid, Kaposi's sarcoma, melanoma, teratoma, rhabdomyosarcoma, metastatic and skeletal disorders, and bone cancer, oral / pharyngeal cancer, esophageal cancer, laryngeal cancer, gastric cancer, intestinal cancer, colon cancer, rectal cancer, lung cancer (e.g., non-small cell lung cancer or small cell lung cancer), liver cancer, pancreatic cancer, nerve cancer, brain cancer (e.g., glioma or glioblastoma multiforme), head and neck cancer, throat cancer, ovarian cancer, uterine cancer, prostate cancer, testicular cancer, bladder cancer, kidney cancer, breast cancer, gallbladder cancer, cervical cancer, thyroid cancer, prostate cancer, and skin cancer.

[0146] In some embodiments, the MK2-mediated disorder is a cardiovascular or cerebrovascular disorder. Exemplary cardiovascular disorders include atherosclerosis, restenosis of atherosclerotic coronary arteries, acute coronary syndrome, myocardial infarction, cardiac allograft vasculopathy, and stroke. Exemplary cerebrovascular diseases include central nervous system disorders with inflammatory or apoptotic components, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, spinal cord injury, neuronal ischemia, and peripheral neuropathy. Illustrative

[0147] As depicted in the Examples below, in certain exemplary embodiments, compounds are prepared according to the following general procedures. It should be understood that although the general methods depict the synthesis of certain compounds of the invention, the following general methods and other methods known to those of skill in the art can be applied to all of the compounds described herein and to each subclass and subgenus of these compounds.

[0148] The enantiomerically enriched compounds of the present invention are prepared in enantiomerically enriched form using chiral starting materials or by chiral chromatography after reaction with a racemic starting material. For compounds prepared in racemic or diastereomeric mixture form, the optically pure form of the single isomer can be prepared by using chiral starting materials or performing chiral chromatography.

[0149] In the following illustrative examples, unless otherwise stated, reactions are carried out at room temperature or ambient temperature in the range of 18 °C to 25 °C. Organic solutions are dried over anhydrous magnesium sulfate or sodium sulfate and the solvent is evaporated under reduced pressure using a rotary evaporator. Generally, TLC or LCMS is carried out after the reaction process and the reaction times are representative. The yields given are for illustrative purposes only and are not necessarily the yields that can be obtained through continuous process development.

[0150] Microwave reactions are carried out in a Biotage Explorer reaction microwave system. 1 1H NMR data are the δ values of the major diagnostic protons, given in parts per million (ppm) relative to tetramethylsilane (TMS) or the residual solvent. Measured at 400 MHz 1 1H NMR spectra. Solvent ratios are given as volume:volume (v / v). Mass spectrometry (MS) data are generated using an LCMS system, where the HPLC component typically comprises an Agilent or Shimadzu LCMS-2020 instrument and is eluted with an acidic eluent (e.g., using a gradient between 0 and 95% water / acetonitrile (containing 0.1% formic acid or trifluoroacetic acid)), operating on a Sepax BR-C18 (4.6×50 mm, 3 μm) column or the like. Chromatograms are electrospray (ESI) positive, negative, and / or UV. LCMS values of m / z are always provided and typically only the ions indicative of the parent mass are reported. Unless otherwise stated, the quoted values are (M+H) or (M+1) in cation mode. A decreasing polarity mixture is used as the eluent (e.g., a decreasing polarity mixture of water and acetonitrile containing 1% trifluoroacetic acid), on C 18 Preparative HPLC is carried out on reverse-phase silica.

[0151] Enantiomerically enriched intermediates and final compounds are synthesized using commercially available chiral materials and the stereochemistry recorded is absolute. Unless otherwise stated, starting materials are commercially available or synthesized according to known methods. List of Abbreviations Example 1: (R)-3-(6-Ethynylpyridin-2-yl)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino Synthesis of [5',6':4,5]thieno[3,2-f]quinolin-8-one

[0152] Step 1: (R)-10-Methyl-3-(6-((trimethylsilyl)ethynyl)pyridin-2-yl)-9,10,11,12-tetrahydro-8H-[1,4]diazepino Synthesis of [5',6':4,5]thieno[3,2-f]quinolin-8-one

[0153] To a solution of (R)-3-(6-chloropyridin-2-yl)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino and [5',6':4,5]thieno[3,2-f]quinolin-8-one (110 mg, 0.280 mmol, 1.00 equiv) in 1,4-dioxane (5.0 mL) was added trimethyl(2-tributylstannylethynyl)silane (323 mg, 0.840 mmol, 3.00 equiv) and Pd(PPh3)4 (32 mg, 0.030 mmol, 0.10 equiv). The resulting mixture was stirred overnight at 90 °C under a nitrogen atmosphere. LCMS showed completion of the reaction. The resulting solution was diluted with EA (20 mL). The solid was collected by filtration and washed with EA (50 mL). After drying, (R)-10-methyl-3-(6-((trimethylsilyl)ethynyl)pyridin-2-yl)-9,10,11,12-tetrahydro-8H-[1,4]diazepino and [5',6':4,5]thieno[3,2-f]quinolin-8-one (70 mg, 55%) was obtained as a green solid. LCMS (ESI, m / z): 457 [M+H] + 。

[0154] Step 2: (R)-3-(6-Ethynylpyridin-2-yl)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino Synthesis of [5',6':4,5]thieno[3,2-f]quinolin-8-one

[0155] To (R)-10-methyl-3-(6-((trimethylsilyl)ethynyl)pyridin-2-yl)-9,10,11,12-tetrahydro-8H-[1,4]diazepino To a solution of [5',6':4,5]thieno[3,2-f]quinolin-8-one (70 mg, 0.153 mmol, 1.00 equiv) in methanol (3.0 mL) was added K2CO3 (42 mg, 0.306 mmol, 2.00 equiv). The resulting mixture was stirred at room temperature for 1 h. LCMS showed the reaction was complete. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC using the following gradient conditions: column: Xselect CSH OBD column 30×150 mm, 5 μm, n; mobile phase A: water (0.05% TFA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 37% B to 42% B in 10 min, 42% B; wavelength: 254 / 220 nm; RT1 (min): 9.28. The purification yielded (R)-3-(6-ethynylpyridin-2-yl)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino [5',6':4,5]thieno[3,2-f]quinolin-8-one (36 mg, 38%). Analytical conditions: column: HALO C18 100A column 3.0×30 mm, 2.0 μm; mobile phase A: water / 0.05% TFA, mobile phase B: acetonitrile / 0.05% TFA; flow rate: 1.2000 mL / min; gradient: 5% B to 100% B in 1.95 min; 254 nm; Rt: 1.572 min.

[0156] 1 1H NMR (400 MHz, DMSO-d6) δ 9.33 (d, J = 9.2 Hz, 1H), 8.65 (d, J = 8.8 Hz, 1H), 8.57 (d, J = 8.8 Hz, 1H), 8.19 (d, J = 8.8 Hz, 1H), 8.11 - 8.05 (m, 3H), 7.71 (d, J = 8.4 Hz, 1H), 7.18 (s, 1H), 4.48 (s, 1H), 3.66 - 3.60 (m, 1H), 3.53 - 3.50 (m, 2H), 1.22 (d, J = 6.8 Hz, 3H). 19 19F NMR (376 MHz, DMSO-d6) δ -74.84. Example 2: Synthesis of racemic-(15R)-5-(2,6-dichloropyrimidin-4-yl)-15-methyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1,3,5,7,9,12(18)-hexaen-13-one

[0157] To a solution of 2,4,6-trichloropyrimidine (80 mg, 0.440 mmol, 1.00 equiv) and racemic-(15R)-15-methyl-5-tributylstannyl-11-thia-6,14,17-triazatricyclo[8.8.0.0^2,7.0^12,18]octadeca-1,3,5,7,9,12(18)-hexaen-13-one (251 mg, 0.440 mmol, 1.00 equiv) in THF (1.0 mL) was added Pd(PPh3)4 (51 mg, 0.05 mmol, 0.10 equiv). The resulting mixture was stirred overnight at 80 °C under a nitrogen atmosphere. LCMS showed completion of the reaction. The resulting solution was concentrated under reduced pressure. The residue was purified by preparative HPLC using the following gradient conditions: column: SunFire Prep C18 OBD column, 19×150 mm, 5 μm 10 nm; mobile phase A: water (0.05% TFA), mobile phase B: MeCN; flow rate: 20 mL / min; gradient: 25% B to 50% B, 50% B in 4.5 min; wavelength: 254 / 210 nm; RT1 (min): 4.35. Purification gave the desired racemic-(15R)-5-(2,6-dichloropyrimidin-4-yl)-15-methyl-11-thia-6,14,17-triazatricyclo[8.8.0.0^2,7.0^12,18]octadeca-1,3,5,7,9,12(18)-hexaen-13-one as a yellow solid (3.9 mg, 2%). LCMS (ESI, m / z): 430 and 432 (M+H) + . Analytical conditions: column: HALO C18 100A column, 3.0×30 mm, 2.7 μm; mobile phase A: water / 0.05% TFA, mobile phase B: acetonitrile / 0.05% TFA; flow rate: 1.2000 mL / min; gradient: 5% B to 100% B in 1.30 min; 254 nm; Rt: 1.223 min.

[0158] 1 1H NMR (400 MHz, DMSO-d6) δ 9.38 (d, J = 8.8 Hz, 1H), 8.63 (s, 1H), 8.52 (d, J = 8.8 Hz, 1H), 8.27 (d, J = 8.8 Hz, 1H), 8.17 (d, J = 3.6 Hz, 1H), 8.11 (d, J = 8.8 Hz, 1H), 7.22 (s, 1H), 3.67 - 3.60 (m, 1H), 3.50 - 3.40 (m, 1H), 1.21 (d, J = 6.8 Hz, 3H). Example 3: Synthesis of (15R)-5-[6-ethynyl-2-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-15-methyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one

[0159] Step 1: Synthesis of di-tert-butyl (15R)-5-[6-chloro-2-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-15-methyl-13-oxo-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaene-14,17-dicarboxylate

[0160] To a solution of (15R)-5-[6-chloro-2-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-15-methyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one (50 mg, 0.100 mmol, 1.00 equiv), (Boc)2O (109 mg, 0.500 mmol, 5.0 equiv) and DMAP (2 mg, 0.010 mmol, 0.10 equiv) in 1,4-dioxane (3.0 mL). The resulting solution was stirred overnight at 80 °C under a nitrogen atmosphere. LCMS showed the reaction was complete. The reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with brine (2 × 20 mL), dried over sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate (3:1) to give di-tert-butyl (15R)-5-[6-chloro-2-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-15-methyl-13-oxo-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaene-14,17-dicarboxylate as a white solid (60 mg, 85%). LCMS (ESI, m / z): 694 (M+H) + 。

[0161] Step 2: Synthesis of Di-tert-butyl (15R)-15-methyl-5-[2-(4-methylpiperazin-1-yl)-6-(2-trimethylsilylethynyl)pyrimidin-4-yl]-13-oxo-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaene-14,17-dicarboxylate

[0162] To a solution of Di-tert-butyl (15R)-5-[6-chloro-2-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-15-methyl-13-oxo-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaene-14,17-dicarboxylate (50 mg, 0.070 mmol, 1.00 equiv) and trimethyl(2-tributylstannylethynyl)silane (41 mg, 0.110 mmol, 1.50 equiv) in 1,4-dioxane (3.0 mL) was added Pd(PPh3)4 (12 mg, 0.010 mmol, 0.20 equiv). The resulting solution was stirred overnight at 80 °C under a nitrogen atmosphere. LCMS showed completion of the reaction. The reaction mixture was then quenched with water (20 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with brine (2 × 20 mL), dried over sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate (1:4) to give Di-tert-butyl (15R)-15-methyl-5-[2-(4-methylpiperazin-1-yl)-6-(2-trimethylsilylethynyl)pyrimidin-4-yl]-13-oxo-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaene-14,17-dicarboxylate as a yellow solid (50 mg, 92%). LCMS (ESI, m / z): 756 (M+H) + 。

[0163] Step 3: Synthesis of (15R)-15-methyl-5-[2-(4-methylpiperazin-1-yl)-6-(2-trimethylsilylethynyl)pyrimidin-4-yl]-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one

[0164] To a solution of di-tert-butyl (15R)-15-methyl-5-[2-(4-methylpiperazin-1-yl)-6-(2-trimethylsilylethynyl)pyrimidin-4-yl]-13-oxo-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaene-14,17-dicarboxylate (50 mg, 0.070 mmol, 1.00 eq) in DCM (4.0 mL) was added dropwise TFA (1.0 mL). The resulting solution was stirred at room temperature for 1 h. LCMS showed completion of the reaction. The resulting solution was concentrated under reduced pressure to give the crude product (15R)-15-methyl-5-[2-(4-methylpiperazin-1-yl)-6-(2-trimethylsilylethynyl)pyrimidin-4-yl]-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one (30 mg, 83%) as a yellow solid. LCMS (ESI, m / z): 556 (M+H) + .

[0165] Step 4: Synthesis of (15R)-5-[6-Ethynyl-2-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-15-methyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one

[0166] To a solution of (15R)-15-methyl-5-[2-(4-methylpiperazin-1-yl)-6-(2-trimethylsilylethynyl)pyrimidin-4-yl]-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one (30 mg, 0.050 mmol, 1.00 equiv) and K2CO3 (11 mg, 0.080 mmol, 1.50 equiv) in methanol (2.0 mL). The resulting solution was stirred at room temperature for 1 h. LCMS showed completion of the reaction. The resulting solution was diluted with DMSO (5 mL). The solid was filtered off. The filtrate was purified by preparative HPLC using the following conditions: column: SunFire Prep C18 OBD column, 19×150 mm, 5 μm; mobile phase A: water (0.05% TFA), mobile phase B: MeCN; flow rate: 20 mL / min; gradient: 30% B to 50% B in 4.5 min, 50% B; wavelength: 254 / 210 nm; RT1. Purification gave the desired (15R)-5-[6-ethynyl-2-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-15-methyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one as a brown solid (15.5 mg, 58% yield). LCMS (ESI, m / z): 484 (M+H) + . Analytical conditions: column: HALO C18 100A column 3.0×30 mm, 2.7 μm; mobile phase A: water / 0.05% TFA, mobile phase B: acetonitrile / 0.05% TFA; flow rate: 1.5000 mL / min; gradient: 5% B to 65% B in 1.7 min; 254 nm; Rt: 1.396 min.

[0167] 1 H NMR (400 MHz, DMSO-d6) δ 9.34 (d, J = 8.8 Hz, 1H), 8.65 (d, J = 8.8 Hz, 1H), 8.23 (d, J = 9.2 Hz, 1H), 8.15 (d, J = 4.0 Hz, 1H), 8.09 (d, J = 8.8 Hz, 1H), 7.93 (s, 1H), 4.98 - 4.88 (m, 2H), 4.73 (s, 1H), 3.70 - 3.55 (m, 3H), 3.50 - 3.30 (m, 4H), 3.25 - 3.10 (m, 2H), 2.88 (s, 3H), 1.21 (d, J = 6.8 Hz, 3H). Example 4: Synthesis of (15R)-5-[2-Ethynyl-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-15-methyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one

[0168] Step 1: Synthesis of (15R)-15-methyl-5-[6-(4-methylpiperazin-1-yl)-2-(2-trimethylsilylethynyl)pyrimidin-4-yl]-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one

[0169] To a solution of (15R)-5-[2-chloro-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-15-methyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one (100 mg, 0.200 mmol, 1.00 equiv) and trimethyl(2-tributylstannylethynyl)silane (156 mg, 0.400 mmol, 2.00 equiv) in 1,4-dioxane (2.0 mL) was added Pd(PPh3)4 (46 mg, 0.040 mmol, 0.10 equiv). The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 6 h. LCMS showed completion of the reaction. The resulting solution was diluted with water (50 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using ethyl acetate / petroleum ether (2:1) to give (15R)-15-methyl-5-[6-(4-methylpiperazin-1-yl)-2-(2-trimethylsilylethynyl)pyrimidin-4-yl]-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one as a white solid (40 mg, 35%). LCMS (ESI, m / z): 556 (M+H) + 。

[0170] Step 2: Synthesis of (15R)-5-[2-Ethynyl-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-15-methyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one

[0171] To a solution of (15R)-15-methyl-5-[6-(4-methylpiperazin-1-yl)-2-(2-trimethylsilylethynyl)pyrimidin-4-yl]-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one (40 mg, 0.070 mmol, 1.00 equiv) in methanol (2.0 mL) was added K2CO3 (20 mg, 0.140 mmol, 2.00 equiv). The resulting mixture was stirred at room temperature for 1 h. LCMS showed completion of the reaction. The resulting solution was diluted with DMSO (2.0 mL). The solid was filtered off. The filtrate was purified by preparative HPLC using the following gradient conditions: column: SunFire Prep C18 OBD column, 19×150 mm, 5 μm; mobile phase A: water (0.05% TFA), mobile phase B: MeCN; flow rate: 20 mL / min; gradient: 10% B to 40% B in 5 min, 40% B; wavelength: 254 / 210 nm; RT1 (min): 4.35. Purification gave the desired (15R)-5-[2-ethynyl-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-15-methyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one as a red solid (4.9 mg, 13%). LCMS (ESI, m / z): 484 (M+H) + . Analytical conditions: column: HALOC18 100A column 3.0×50 mm, 3.0 μm; mobile phase A: water / 0.05% TFA, mobile phase B: acetonitrile / 0.05% TFA; flow rate: 1.2000 mL / min; gradient: 10% B to 55% B in 1.90 min; 254 nm; Rt: 1.852 min.

[0172] 11H NMR (300 MHz, DMSO-d6) δ 9.32 (d, J = 8.8 Hz, 1H), 8.59 (d, J = 8.8 Hz, 1H), 8.26 - 8.13 (m, 2H), 7.25 (s, 1H), 4.79 (s, 1H), 4.54 (s, 1H), 4.34 - 4.02 (m, 1H), 3.73 - 3.30 (m, 7H), 3.28 - 3.01 (m, 2H), 2.86 (s, 3H), 1.20 (d, J = 6.6 Hz, 3H). 19 19F NMR (282 MHz, DMSO-d6) δ -74.09. Example 5: Synthesis of (15R)-5-[4-Ethynyl-6-(4-methylpiperazin-1-yl)pyrimidin-2-yl]-15-methyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one

[0173] Step 1: Synthesis of (15R)-15-Methyl-5-[4-(4-methylpiperazin-1-yl)-6-(2-trimethylsilylethynyl)pyrimidin-2-yl]-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one

[0174] To a solution of (15R)-5-[4-chloro-6-(4-methylpiperazin-1-yl)pyrimidin-2-yl]-15-methyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one (100 mg, 0.200 mmol, 1.00 equiv) and trimethyl(2-tributylstannylethynyl)silane (156 mg, 0.400 mmol, 2.00 equiv) in 1,4-dioxane (2.0 mL) was added Pd(PPh3)4 (23 mg, 0.020 mmol, 0.10 equiv). The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 5 h. LCMS showed completion of the substance. The resulting solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography with ethyl acetate to give (15R)-15-methyl-5-[4-(4-methylpiperazin-1-yl)-6-(2-trimethylsilylethynyl)pyrimidin-2-yl]-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one (40 mg, 35%) as a brown solid. LCMS (ESI, m / z): 556 (M+H) + 。

[0175] Step 2: Synthesis of (15R)-5-[4-ethynyl-6-(4-methylpiperazin-1-yl)pyrimidin-2-yl]-15-methyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one

[0176] To a solution of (15R)-15-methyl-5-[4-(4-methylpiperazin-1-yl)-6-(2-trimethylsilylethynyl)pyrimidin-2-yl]-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one (40 mg, 0.070 mmol, 1.00 equiv) in methanol (2.0 mL) was added K2CO3 (19 mg, 0.140 mmol, 2.00 equiv). The resulting mixture was stirred at room temperature for 2 h. LCMS showed completion of the reaction. The resulting solution was diluted with DMSO (3 mL). The solid was filtered off. The filtrate was purified by preparative HPLC using the following gradient conditions: column: SunFirePrep C18 OBD column, 19 × 150 mm, 5 μm; mobile phase A: water (0.05% TFA), mobile phase B: MeCN; flow rate: 20 mL / min; gradient: 10% B to 40% B in 5 min, 40% B; wavelength: 210 / 245 nm; RT1 (min): 4.8. Purification gave the desired (15R)-5-[4-ethynyl-6-(4-methylpiperazin-1-yl)pyrimidin-2-yl]-15-methyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one as a brown solid (8.3 mg, 22%). LCMS (ESI, m / z): 484 (M+H) + . Analytical conditions: column: HALO C18 100A column 3.0 × 30 mm, 2.7 μm; mobile phase A: water / 0.05% TFA, mobile phase B: acetonitrile / 0.05% TFA; flow rate: 1.5000 mL / min; gradient: 5% B to 100% B in 1.30 min; 254 nm; Rt: 0.755 min.

[0177] 11H NMR (400 MHz, DMSO-d6) δ 9.85 (s, 1H), 9.34 (d, J = 8.8 Hz, 1H), 8.51 (d, J = 8.8 Hz, 1H), 8.23 (d, J = 9.2 Hz, 1H), 8.14 (d, J = 4.4 Hz, 1H), 8.08 (d, J = 8.8 Hz, 1H), 8.00 (s, 1H), 7.19 (s, 1H), 4.71 (d, J = 13.2 Hz, 2H), 4.33 (s, 1H), 3.69 - 3.59 (m, 3H), 3.55 - 3.49 (m, 2H), 3.42 - 3.31 (m, 2H), 3.20 - 3.15 (m, 2H), 2.88 (s, 3H), 1.22 (d, J = 6.8 Hz, 3H). 19 19F NMR (376 MHz, DMSO-d6) δ -74.21. Example 6: Synthesis of (15R)-15-methyl-5-[4-(4-methylpiperazin-1-yl)-6-ethenyl-pyrimidin-2-yl]-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one

[0178] (15R)-5-[4-chloro-6-(4-methylpiperazin-1-yl)pyrimidin-2-yl]-15-methyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one (100 mg, 0.200 mmol, 1.00 equiv), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (62 mg, 0.40 mmol, 2.00 equiv), and K2CO3 (83 mg, 0.600 mmol, 3.0 equiv) were added to a stirred solution of Pd(PPh3)4 (46 mg, 0.040 mmol, 0.20 equiv) in 1,4-dioxane (2.0 mL) and water (0.2 mL). The resulting mixture was stirred at 90 °C under a nitrogen atmosphere for 2 h. LCMS showed completion of the reaction. The resulting solution was diluted with water (20 mL). The solid was collected by filtration. The solid was purified by reverse-phase flash chromatography using water (0.05% TFA) / MeCN (1:1) to give 50 mg of the crude product. The crude product was purified by preparative HPLC using the following gradient conditions: column: SunFire Prep C18 OBD column, 19 × 150 mm, 5 μm 10 nm; mobile phase A: water (0.05% TFA), mobile phase B: MeCN; flow rate: 20 mL / min; gradient: 10% B to 40% B in 5 min, 40% B; wavelength: 210 / 245 nm; RT1 (min): 4.8. Purification gave the desired (15R)-15-methyl-5-[4-(4-methylpiperazin-1-yl)-6-vinyl-pyrimidin-2-yl]-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one (26.5 mg, 25%) as an orange solid. LCMS (ESI, m / z): 486 (M+H) + Analytical conditions: column: Shim-pack ScepterC18 100A column 3.0 × 33 mm, 3.0 μm; mobile phase A: water / 5 mM NH4HCO3, mobile phase B: acetonitrile; flow rate: 1.5000 mL / min; gradient: 10% B to 95% B in 1.20 min; 254 nm; Rt: 1.046 min.

[0179] 11H NMR (400 MHz, DMSO-d6) δ 10.03 (s, 1H), 9.35 (d, J = 8.8 Hz, 1H), 8.63 (d, J = 8.8 Hz, 1H), 8.23 (d, J = 8.8 Hz, 1H), 8.14 (d, J = 4.4 Hz, 1H), 8.09 (d, J = 9.2 Hz, 1H), 7.90 (s, 1H), 7.19 (s, 1H), 6.85 (dd, J = 17.2, 10.4 Hz, 1H), 6.68 (d, J = 17.2 Hz, 1H), 5.81 (t, J = 12.0 Hz, 1H), 4.79 (d, J = 11.2 Hz, 2H), 3.67 - 3.57 (m, 3H), 3.55 - 3.49 (m, 2H), 3.42 - 3.30 (m, 2H), 3.18 - 3.10 (m, 2H), 2.90 (s, 3H), 1.22 (d, J = 6.4 Hz, 3H). 19 19F NMR (376 MHz, DMSO-d6) δ -74.53. Example 7: Synthesis of (15R)-5-[6-(3-Amino-3-methyl-but-1-ynyl)-2-chloro-pyrimidin-4-yl]-15-methyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one

[0180] To a solution of (15R)-5-(2,6-dichloropyrimidin-4-yl)-15-methyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one (60 mg, 0.140 mmol, 1.00 equiv), 2-methylbut-3-yn-2-amine (11 mg, 0.140 mmol, 1.00 equiv) and TEA (0.12 mL, 0.700 mmol, 5.00 equiv) in DMF (1.0 mL) was added CuI (11 mg, 0.056 mmol, 0.04 equiv) and Pd(PPh3)4 (16 mg, 0.04 mmol, 0.10 equiv). The resulting mixture was stirred overnight at 60 °C under a nitrogen atmosphere. LCMS showed completion of the reaction. The resulting solution was diluted with DMSO (2.0 mL). The solid was filtered off. The filtrate was purified by preparative HPLC using the following gradient conditions: column: SunFire Prep C18 OBD column, 19×150 mm, 5 μm; mobile phase A: water (0.05% TFA), mobile phase B: MeCN; flow rate: 20 mL / min; gradient: 25% B to 50% B in 4.5 min, then 50% B; wavelength: 254 / 210 nm; RT1 (min): 4.3. Purification gave the desired (15R)-5-[6-(3-amino-3-methyl-but-1-ynyl)-2-chloro-pyrimidin-4-yl]-15-methyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one as a brown solid (9.0 mg, 12%). LCMS (ESI, m / z): 477 (M+H) + . Analytical conditions: column: Xselect HSS T3 column 4.6×100 mm, 3.5 μm; mobile phase A: water / 0.1% H3PO4, mobile phase B: acetonitrile; flow rate: 1.2000 mL / min; gradient: 10% B to 95% B in 6.0 min; 254 nm; Rt: 3.071 min.

[0181] 1H NMR (300MHz, DMSO-d6) δ9.40(d,J=9.3Hz,1H),8.78(s,3H),8.61(s,1H),8.55(d,J=9.0Hz,1H),8.28(d,J=9.0Hz,1H),8.18(d ,J=3.9Hz,1H),8.08(d,J=8.7Hz,1H),7.23(s,1H),3.70-3.60(m,1H),3.55-3.45(m,1H),1.73(s,6H),1.22(d,J=6.6Hz,3H). 19 FNMR(282MHz,DMSO-d6)δ-73.89. Example 8: (R)-3-(2-(3-amino-3-methylbut-1-yn-1-yl)-6-chloropyrimidin-4-yl)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepine Synthesis of 5',6':4,5'-thieno[3,2-f]quinolin-8-one

[0182] Step 1: Synthesis of 4-(4,6-dichloropyrimidin-2-yl)-2-methyl-but-3-yn-2-amine

[0183] To a solution of 4,6-dichloro-2-iodo-pyrimidine (1.0 g, 3.640 mmol, 1.00 equiv), 2-methylbut-3-yn-2-amine (604 mg, 7.280 mmol, 2.00 equiv) and TEA (940 mg, 7.280 mmol, 2.00 equiv) in THF (30.0 mL) was added CuI (69 mg, 0.360 mmol, 0.10 equiv), Pd(dba)2 (209 mg, 0.360 mmol, 0.10 equiv) and P(o-furyl)3 (84 mg, 0.360 mmol, 0.10 equiv). The resulting solution was stirred at room temperature under a nitrogen atmosphere for 2 hours. LCMS showed that the reaction was complete. The resulting solution was diluted with water (50 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine (2×100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using ethyl acetate / petroleum ether (1:1) to give 4-(4,6-dichloropyrimidin-2-yl)-2-methyl-but-3-yn-2-amine (400 mg, 47%) as a yellow solid. LCMS (ESI, m / z): 229 [M+H] + .

[0184] Step 2: (R)-3-(2-(3-Amino-3-methylbut-1-yn-1-yl)-6-chloropyrimidin-4-yl)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino Synthesis of [5',6':4,5]thieno[3,2-f]quinolin-8-one

[0185] To a solution of (R)-10-methyl-3-(tributylstannyl)-9,10,11,12-tetrahydro-8H-[1,4]diazepino and [5',6':4,5]thieno[3,2-f]quinolin-8-one (80 mg, 0.140 mmol, 1.00 equiv) and 4-(4,6-dichloro-2-pyridyl)-2-methylbut-3-yn-2-amine (38 mg, 0.170 mmol, 1.20 equiv) in 1,4-dioxane (5.0 mL) was added Pd(PPh3)4 (11 mg, 0.010 mmol, 0.10 equiv). The resulting solution was stirred at 90 °C under a nitrogen atmosphere. LCMS showed completion of the reaction. The resulting solution was concentrated under reduced pressure. The residue was purified by preparative HPLC using the following gradient conditions: column: SunFire Prep C18 OBD column, 19 × 150 mm, 5 μm; mobile phase A: water (0.05% TFA), mobile phase B: MeCN; flow rate: 20 mL / min; gradient: 20% B to 50% B in 4.5 min, 50% B; wavelength: 254 / 210 nm; RT1 (min): 4.35. Purification gave the desired (R)-3-(2-(3-Amino-3-methylbut-1-yn-1-yl)-6-chloropyrimidin-4-yl)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino and [5',6':4,5]thieno[3,2-f]quinolin-8-one (16.9 mg, 24%). Analytical conditions: column: HALO C18 100A column 3.0 × 30 mm, 2.0 μm; mobile phase A: water / 0.05% TFA, mobile phase B: acetonitrile / 0.05% TFA; flow rate: 1.2000 mL / min; gradient: 5% B to 100% B in 2.40 min; 254 nm; Rt: 1.613 min.

[0186] 11H NMR (400 MHz, DMSO-d6 + D2O) δ 9.36 (d, J = 8.8 Hz, 1H), 8.62 (d, J = 2.8 Hz, 1H), 8.49 (d, J = 8.8 Hz, 1H), 8.24 (d, J = 8.8 Hz, 1H), 8.10 (d, J = 8.8 Hz, 1H), 3.70 - 3.60 (m, 1H), 3.55 - 3.45 (m, 2H), 1.73 (s, 6H), 1.21 (d, J = 6.8 Hz, 3H). 19 19F NMR (376 MHz, DMSO-d6) δ 73.70. Example 9: Synthesis of (15R)-5-[6-(3-amino-3-methyl-but-1-ynyl)-2-ethynyl-pyrimidin-4-yl]-15-methyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one

[0187]

[0188] ​To a solution of (15R)-5-[6-(3-amino-3-methyl-but-1-ynyl)-2-chloro-pyrimidin-4-yl]-15-methyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one (170 mg, 0.356 mmol, 1.00 equiv) and trimethyl((tributylstannyl)ethynyl)silane (275 mg, 0.713 mmol, 2.00 equiv) in 1,4-dioxane (3.0 mL) was added Pd(PPh3)4 (41 mg, 0.036 mmol, 0.10 equiv). The resulting mixture was stirred overnight at 60 °C under a nitrogen atmosphere. LCMS showed completion of the reaction. The resulting solution was diluted with ethyl acetate (20 mL). The solid was filtered off. The filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using water (0.05% TFA) / MeCN (1:1) to give (15R)-5-[6-(3-amino-3-methyl-but-1-ynyl)-2-chloro-pyrimidin-4-yl]-15-methyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one as a yellow solid (45 mg, 23%). LCMS (ESI, m / z): 539 (M+H) + 。

[0189] Step 2: Synthesis of (15R)-5-[6-(3-amino-3-methyl-but-1-ynyl)-2-ethynyl-pyrimidin-4-yl]-15-methyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one

[0190] To a solution of (15R)-5-[6-(3-amino-3-methyl-but-1-ynyl)-2-(2-trimethylsilylethynyl)pyrimidin-4-yl]-15-methyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one (35 mg, 0.065 mmol, 1.00 equiv) in THF (2.0 mL) was added dropwise TEA·3HF (0.1 mL). The resulting mixture was stirred at room temperature for 2 h. LCMS showed the reaction was complete. The resulting solution was concentrated under reduced pressure. The residue was purified by preparative HPLC using the following gradient conditions: column: SunFire Prep C18 OBD column, 19×150 mm, 5 μm; mobile phase A: water (0.05% TFA), mobile phase B: MeCN; flow rate: 20 mL / min; gradient: 22% B to 35% B in 5 min, then 35% B; wavelength: 254 nm; RT1 (min): 4.95. Purification gave the desired (15R)-5-[6-(3-amino-3-methyl-but-1-ynyl)-2-ethynyl-pyrimidin-4-yl]-15-methyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one as a yellow solid (3.4 mg, 11%). LCMS (ESI, m / z): 467 (M+H) + Analytical conditions: column: HALO C18 100A column 3.0×30 mm, 2.7 μm; mobile phase A: water / 0.05% TFA, mobile phase B: acetonitrile / 0.05% TFA; flow rate: 1.2000 mL / min; gradient: 5% B to 60% B in 1.80 min; 254 nm; Rt: 1.312 min.

[0191] 1 1H NMR (300 MHz, DMSO-d6) δ 9.39 (d, J = 9.0 Hz, 1H), 8.79 (s, 3H), 8.59 (s, 1H), 8.58 (d, J = 9.0 Hz, 1H), 8.26 (8.55 (d, J = 9.0 Hz, 1H), 8.15 (d, J = 3.9 Hz, 1H), 8.08 (d, J = 9.0 Hz, 1H), 7.23 (s, 1H), 4.64 (s, 1H), 3.70 - 3.40 (m, 3H), 1.73 (s, 6H), 1.21 (d, J = 6.6 Hz, 3H). 19 19F NMR (282 MHz, DMSO-d6) δ -73.69. Example 10: (R)-3-(2-(3-amino-3-methylbut-1-yn-1-yl)-6-vinylpyrimidin-4-yl)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepine Synthesis of 5',6':4,5'-thieno[3,2-f]quinolin-8-one

[0192] To (R)-3-(2-(3-amino-3-methylbut-1-yn-1-yl)-6-chloropyrimidin-4-yl)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepine To a solution of 5',6':4,5'-thieno[3,2-f]quinolin-8-one (50 mg, 0.100 mmol, 1.00 equiv) and tributyl(vinyl)stannane (99 mg, 0.310 mmol, 3.00 equiv) in 1,4-dioxane (2.0 mL) was added Pd(PPh3)4 (8 mg, 0.010 mmol, 0.10 equiv). The resulting solution was stirred at 90°C under a nitrogen atmosphere overnight. LCMS indicated the reaction was complete. The resulting solution was concentrated under reduced pressure. The residue was purified by preparative HPLC using the following gradient conditions: Column: SunFire Prep C18 OBD column, 19×150 mm, 5 μm; Mobile phase A: water (0.05% TFA), Mobile phase B: MeCN; Flow rate: 20 mL / min; Gradient: 20% B to 50% B, 50% B in 4.5 min; Wavelength: 254 / 210 nm; RT1 (min): 4.350. Purification yielded the desired (R)-3-(2-(3-amino-3-methylbut-1-yn-1-yl)-6-vinylpyrimidin-4-yl)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepine as a red solid. 1,3-Dimethoxy-1-thiazolin-1-one (3.8 mg, 7%). LCMS (ESI, m / z): 469 [M+H] + Analytical conditions: Column: HALO C18 100A column 3.0×30 mm, 2.0 μm; Mobile phase A: water / 0.05% TFA, Mobile phase B: acetonitrile / 0.05% TFA; Flow rate: 1.2000 mL / min; Gradient: 5% B to 100% B in 2.40 min; 254 nm; Rt: 1.546 min.

[0193] 1H NMR (400MHz, DMSO-d6+D2O) δ9.36(d,J=8.8Hz,1H),8.61(s,1H),8.53(d,J=8.8Hz,1H),8.24(d,J=9.2Hz,1H),8.12(d,J=9.2Hz,1H),7.02(d d,J=17.2,10.4Hz,1H),6.64(d,J=17.2Hz,1H),5.89(d,J=11.6Hz,1H),3.62-3.59(m,1H),3.49(s,2H),1.73(s,6H),1.21(d,J=6.8Hz,3H). 19 F NMR (376MHz, DMSO-d6) δ74.57. Example 11: (R)-3-(2-(3-amino-3-methylbut-1-yn-1-yl)-6-ethynylpyrimidin-4-yl)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepine Synthesis of 5',6':4,5'-thieno[3,2-f]quinolin-8-one

[0194] Step 1: (R)-3-(2-(3-amino-3-methylbut-1-yn-1-yl)-6-((trimethylsilyl)ethynyl)pyrimidin-4-yl)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepine Synthesis of 5',6':4,5'-thieno[3,2-f]quinolin-8-one

[0195] To (R)-3-(2-(3-amino-3-methylbut-1-yn-1-yl)-6-chloropyrimidin-4-yl)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepine A solution of benzo[5',6':4,5]thieno[3,2-f]quinolin-8-one (100 mg, 0.210 mmol, 1.00 equiv) and trimethyl(2-tributylstannylethynyl)silane (243 mg, 0.630 mmol, 3.00 equiv) in 1,4-dioxane (5.0 mL) was added with Pd(PPh3)4 (17 mg, 0.020 mmol, 0.10 equiv). The resulting solution was stirred overnight at 90 °C under a nitrogen atmosphere. LCMS showed the reaction was complete. The resulting solution was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using water (0.05% TFA) / MeCN (1:1) to give (R)-3-(2-(3-amino-3-methylbut-1-yn-1-yl)-6-((trimethylsilyl)ethynyl)pyrimidin-4-yl)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino benzo[5',6':4,5]thieno[3,2-f]quinolin-8-one (40 mg, 35%). LCMS (ESI, m / z): 539 [M+H] + .

[0196] Step 2: Synthesis of (R)-3-(2-(3-amino-3-methylbut-1-yn-1-yl)-6-ethynylpyrimidin-4-yl)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino benzo[5',6':4,5]thieno[3,2-f]quinolin-8-one

[0197] To (R)-3-(2-(3-amino-3-methylbut-1-yn-1-yl)-6-((trimethylsilyl)ethynyl)pyrimidin-4-yl)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino A solution of [5',6':4,5]thieno[3,2-f]quinolin-8-one (40 mg, 0.070 mmol, 1.00 equiv) in methanol (2.0 mL) was added with K2CO3 (20 mg, 0.150 mmol, 2.00 equiv). The resulting solution was stirred at room temperature for 1 h. LCMS showed the reaction was complete. The resulting solution was concentrated under reduced pressure. The residue was purified by preparative HPLC using the following gradient conditions: column: SunFire Prep C18 OBD column, 19×150 mm, 5 μm; mobile phase A: water (0.05% TFA), mobile phase B: MeCN; flow rate: 20 mL / min; gradient: 20% B to 50% B in 5 min, 50% B; wavelength: 254 nm; RT1 (min): 4.85. The purification yielded the desired (R)-3-(2-(3-amino-3-methylbut-1-yn-1-yl)-6-vinylpyrimidin-4-yl)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino [5',6':4,5]thieno[3,2-f]quinolin-8-one (3.8 mg, 10%). LCMS (ESI, m / z): 467 [M+H] + . Analytical conditions: column: HALO C18 100A column 3.0×30 mm, 2.7 μm; mobile phase A: water / 0.05% TFA, mobile phase B: acetonitrile / 0.05% TFA; flow rate: 1.2000 mL / min; gradient: 5% B to 100% B in 1.2 min; 254 nm; Rt: 0.932 min.

[0198] 1 1H NMR (400 MHz, DMSO-d6+D2O) δ 9.39 (d, J = 8.8 Hz, 1H), 8.74 (s, 2H), 8.63 (s, 1H), 8.51 (d, J = 8.4 Hz, 1H), 8.27 (d, J = 8.8 Hz, 1H), 8.16 - 8.11 (m, 2H), 7.20 (s, 1H), 5.01 (s, 1H), 3.64 (s, 1H), 3.50 (s, 2H), 1.73 (s, 6H), 1.22 (d, J = 5.6 Hz, 3H). 19 19F NMR (376 MHz, DMSO-d6) δ 73.45. Example 12: Synthesis of (15R)-5-(2-chloro-5-fluoro-4-pyridyl)-15-methyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one

[0199] To a solution of (15R)-15-methyl-5-tributylstannyl-11-thia-6,14,17-triazatricyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one (40 mg, 0.070 mmol, 1.00 equiv) and 2-chloro-5-fluoro-4-iodopyridine (21 mg, 0.080 mmol, 1.10 equiv) in DMF (1.0 mL) was added Pd2(dba)3 (15 mg, 0.010 mmol, 0.20 equiv) and P(o-Tol)3 (8 mg, 0.030 mmol, 0.40 equiv). The resulting solution was stirred overnight at 80 °C under a nitrogen atmosphere. LCMS showed completion of the reaction. The resulting solution was diluted with water (20 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine (2 × 40 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash silica chromatography using ethyl acetate / petroleum ether (5:1) to give 20 mg of the crude product. The crude product was purified by preparative HPLC using the following gradient conditions: column: Xselect CSH OBD column 30 × 150 mm 5 μm; mobile phase A: water (0.05% TFA), mobile phase B: MeCN; flow rate: 60 mL / min; gradient: 38% B to 62% B in 7 min, 62% B; wavelength: 254 / 220 nm; RT1 (min): 6.5. Purification gave the desired (15R)-5-(2-chloro-5-fluoropyridin-4-yl)-15-methyl-11-thia-6,14,17-triazatricyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one as a yellow solid (3.7 mg, 12%). LCMS (ESI, m / z): 414 [M+H] + . Analytical conditions: column: HALO C18 column 3.0 × 30 mm, 2.7 μm; mobile phase A: water / 0.05% TFA, mobile phase B: acetonitrile / 0.05% TFA; flow rate: 1.200 mL / min; gradient: 20% B to 80% B in 2.1 min; 254 / 210 nm; RT: 1.518 min.

[0200] 11H NMR (400 MHz, DMSO-d6) δ 9.34 (d, J = 8.8 Hz, 1H), 8.68 (d, J = 2.4 Hz, 1H), 8.28 - 8.04 (m, 5H), 7.20 (s, 1H), 3.62 (s, 1H), 3.48 (s, 2H), 1.20 (d, J = 6.8 Hz, 3H). 19 19F NMR (376 MHz, DMSO-d6) δ -74.71, -134.09. Example 13: Synthesis of (15R)-5-(2-Ethynyl-5-fluoro-4-pyridyl)-15-methyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one

[0201] Step 1: Synthesis of (15R)-5-[5-Fluoro-2-(2-trimethylsilylethynyl)-4-pyridyl]-15-methyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one

[0202] To a solution of (15R)-5-(2-chloro-5-fluoro-4-pyridyl)-15-methyl-11-thia-6,14,17-triazatricyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one (40 mg, 0.100 mmol, 1.00 equiv) and trimethyl(2-tributylstannylethynyl)silane (56 mg, 0.150 mmol, 1.50 equiv) in 1,4-dioxane (2.0 mL) was added Pd(PPh3)4 (11 mg, 0.010 mmol, 0.10 equiv). The resulting solution was stirred overnight at 100 °C under a nitrogen atmosphere. LCMS showed completion of the reaction. The reaction solution was diluted with ethyl acetate / petroleum ether (1:1) (10 mL). The solid was collected by filtration and washed with ethyl acetate / petroleum ether (1:1) (2 × 10 mL). The solid was dried to give (15R)-5-[5-fluoro-2-(2-trimethylsilylethynyl)-4-pyridyl]-15-methyl-11-thia-6,14,17-triazatricyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one as a grayish green solid (20 mg, 43%). LCMS (ESI, m / z): 475 [M+H] + .

[0203] Step 2: Synthesis of (15R)-5-(2-ethynyl-5-fluoro-4-pyridyl)-15-methyl-11-thia-6,14,17-triazatricyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one

[0204] To a solution of (15R)-5-[5-fluoro-2-(2-trimethylsilylethynyl)-4-pyridinyl]-15-methyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one (20 mg, 0.040 mmol, 1.00 equiv) in methanol (1.0 mL) was added K2CO3 (12 mg, 0.090 mmol, 2.00 equiv). The solution was stirred at room temperature under a nitrogen atmosphere for 2 h. LCMS showed completion of the reaction. The resulting solution was diluted with DMSO (3.0 mL). The solid was filtered off and the filtrate was purified by preparative HPLC using the following gradient conditions: column: Xselect CSH C18 OBD column 30×150 mm 5 μm; mobile phase A: water (0.05% TFA), mobile phase B: MeCN; flow rate: 60 mL / min; gradient: 33% B to 57% B in 7 min, 57% B; wavelength: 254 / 220 nm; RT1 (min): 6.1. Purification gave the desired (15R)-5-(2-ethynyl-5-fluoro-4-pyridinyl)-15-methyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one as a yellow solid (2.1 mg, 11%). LCMS (ESI, m / z): 403 [M+H] + . Analytical conditions: column: HALO C18 column 3.0×30 mm, 2.7 μm; mobile phase A: water / 0.05% TFA, mobile phase B: acetonitrile / 0.05% TFA; flow rate: 1.200 mL / min; gradient: 5% B to 70% B in 1.7 min; 254 / 210 nm; RT: 1.538 min.

[0205] 1 H NMR (400 MHz, DMSO-d6) δ 9.34 (d, J = 8.8 Hz, 1H), 8.79 (d, J = 2.4 Hz, 1H), 8.32 (d, J = 10.0 Hz, 1H), 8.23 (d, J = 9.2 Hz, 1H), 8.18 - 8.08 (m, 3H), 7.22 (s, 1H), 4.46 (s, 1H), 3.70 - 3.60 (m, 1H), 3.54 - 3.44 (m, 1H), 1.20 (d, J = 6.8 Hz, 3H). 19 F NMR (376 MHz, DMSO-d6) δ -74.67, -129.68. Example 14: Synthesis of (15R)-5-(2-chloro-6-vinyl-4-pyridyl)-15-methyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one

[0206] Step 1: Synthesis of Di-tert-butyl (15R)-5-(2,6-dichloro-4-pyridyl)-15-methyl-13-oxo-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaene-14,17-dicarboxylate

[0207] To a solution of (15R)-5-(2,6-dichloro-4-pyridyl)-15-methyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one (200 mg, 0.467 mmol, 1.00 equiv) and Boc2O (251 mg, 1.168 mmol, 2.50 equiv) in 1,4-dioxane (5.0 mL) was added DMAP (6 mg, 0.047 mmol, 0.10 equiv). The resulting mixture was stirred overnight at 60 °C under a nitrogen atmosphere. LCMS showed completion of the reaction. The resulting solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using ethyl acetate / petroleum ether (1:3) to give di-tert-butyl (15R)-5-(2,6-dichloro-4-pyridyl)-15-methyl-13-oxo-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaene-14,17-dicarboxylate (190 mg, 64%) as a yellow solid. LCMS (ESI, m / z): 629 (M+H) + 。

[0208] Step 2: Synthesis of Di-tert-butyl (15R)-5-(2-chloro-6-vinyl-4-pyridyl)-15-methyl-13-oxo-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaene-14,17-dicarboxylate

[0209] To a solution of di-tert-butyl (15R)-5-(2,6-dichloro-4-pyridyl)-15-methyl-13-oxo-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaene-14,17-dicarboxylate (70 mg, 0.111 mmol, 1.00 equiv) and tributyl(vinyl)stannane (40 mg, 0.122 mmol, 1.10 equiv) in 1,4-dioxane (5.0 mL) was added Pd(PPh3)4 (9 mg, 0.011 mmol, 0.10 equiv). The resulting mixture was stirred overnight at 60 °C under a nitrogen atmosphere. LCMS showed completion of the reaction. The resulting solution was diluted with water (10 mL) and extracted with ethyl acetate (3 × 10 mL). The combined organic layers were washed with brine (2 × 10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using water (10 mmol / L NH4HCO3) / MeCN (1:1) to give di-tert-butyl (15R)-5-(2-chloro-6-vinyl-4-pyridyl)-15-methyl-13-oxo-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaene-14,17-dicarboxylate (25 mg, 36%) as a yellow oil. LCMS (ESI, m / z): 621 (M+H) + 。

[0210] Step 3: Synthesis of (15R)-5-(2-chloro-6-vinyl-4-pyridyl)-15-methyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one

[0211] To a solution of di-tert-butyl (15R)-5-(2-chloro-6-ethenyl-4-pyridyl)-15-methyl-13-oxo-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaene-14,17-dicarboxylate (25 mg, 0.040 mmol, 1.00 equiv) in DCM (5.0 mL) was added dropwise TFA (1.0 mL). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 3 h. LCMS showed completion of the reaction. The resulting solution was concentrated under reduced pressure. The residue was purified by preparative HPLC using the following gradient conditions: column: XBridge Prep OBD C18 column, 30×150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: MeCN; flow rate: 25 mL / min; gradient: 45% B to 80% B in 5.2 min, 80% B; wavelength: 254 nm; RT1 (min): 4.76. Purification gave the desired (15R)-5-(2-chloro-6-ethenyl-4-pyridyl)-15-methyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one as a yellow solid (2 mg, 12%). LCMS (ESI, m / z): 421 (M+H) + . Analytical conditions: column: HALO C18 column 3.0×30 mm, 2.7 μm; mobile phase A: water + 0.05% TFA, mobile phase B: acetonitrile + 0.05% TFA; flow rate: 1.5000 mL / min; gradient: 30% B to 70% B in 1.75 min; 254 nm; Rt: 1.585 min.

[0212] 1 H NMR (300 MHz, DMSO-d6) δ 9.34 (d, J = 9.3 Hz, 1H), 8.47 (d, J = 9.3 Hz, 1H), 8.40 (s, 1H), 8.29 (s, 1H), 8.23 (d, J = 11.7 Hz, 1H), 8.16 - 8.07 (m, 2H), 7.23 (t, J = 4.4 Hz, 1H), 6.99 (dd, J = 17.1 Hz, 11.4 Hz, 1H), 6.42 (d, J = 17.1 Hz, 1H), 5.67 (d, J = 11.4 Hz, 1H), 3.70 - 3.60 (m, 1H), 3.52 - 3.40 (m, 2H), 1.22 (d, J = 6.6 Hz, 3H)

[0213] Example 15: Synthesis of (15R)-5-(2-chloro-6-ethynyl-4-pyridinyl)-15-methyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one

[0214] Step 1: Synthesis of Di-tert-butyl (15R)-5-[2-chloro-6-(2-trimethylsilylethynyl)-4-pyridinyl]-15-methyl-13-oxo-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaene-14,17-dicarboxylate

[0215] To a solution of di-tert-butyl (15R)-5-(2,6-dichloro-4-pyridinyl)-15-methyl-13-oxo-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaene-14,17-dicarboxylate (70 mg, 0.111 mmol, 1.00 equiv) and trimethyl(2-tributylstannylethynyl)stannane (56 mg, 0.133 mmol, 1.20 equiv) in 1,4-dioxane (5.0 mL) was added Pd(PPh3)4 (12 mg, 0.011 mmol, 0.10 equiv). The resulting mixture was stirred overnight at 60 °C under a nitrogen atmosphere. LCMS showed completion of the reaction. The resulting solution was diluted with water (10 mL) and extracted with ethyl acetate (3 × 10 mL). The combined organic layers were washed with brine (2 × 10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using water (0.05% TFA) / MeCN (1:1) to give di-tert-butyl (15R)-5-[2-chloro-6-(2-trimethylsilylethynyl)-4-pyridinyl]-15-methyl-13-oxo-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaene-14,17-dicarboxylate (40 mg, 51%) as a yellow oil. LCMS (ESI, m / z): 635 (M + H - tBu) + 。

[0216] Step 2: Synthesis of (15R)-5-[2-chloro-6-(2-trimethylsilylethynyl)-4-pyridyl]-15-methyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one

[0217] To a solution of (15R)-5-[2-chloro-6-(2-trimethylsilylethynyl)-4-pyridyl]-15-methyl-13-oxo-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaene-14,17-dicarboxylic acid di-tert-butyl ester (40 mg, 0.060 mmol, 1.00 equiv) in DCM (5.0 mL) was added dropwise TFA (1.0 mL). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 3 h. LCMS showed completion of the reaction. The resulting solution was concentrated under reduced pressure to give the crude product. The crude product was used directly in the next step without further purification. LCMS (ESI, m / z): 491 (M+H) + 。

[0218] Step 3: Synthesis of (15R)-5-(2-chloro-6-ethynyl-4-pyridyl)-15-methyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one

[0219] To a solution of (15R)-5-[2-chloro-6-(2-trimethylsilylethynyl)-4-pyridyl]-15-methyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one (30 mg, 0.061 mmol, 1.00 equiv) in methanol (3.0 mL) was added K2CO3 (12 mg, 0.092 mmol, 1.50 equiv). The reaction mixture was stirred at room temperature for 15 minutes. LCMS showed completion of the reaction. The resulting solution was diluted with DMSO (3 mL). The solid was filtered off. The filtrate was purified by preparative HPLC using the following gradient conditions: column: XBridge Prep OBD C18 column, 30×150 mm, 5 μm; mobile phase A: water (0.05% TFA), mobile phase B: MeCN; flow rate: 25 mL / min; gradient: 30% B to 75% B, 80% B in 5.2 min; wavelength: 254 nm; RT1 (min): 4.62. Purification gave the desired (15R)-5-(2-chloro-6-ethynyl-4-pyridyl)-15-methyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one as a yellow solid (2.7 mg, 10%). LCMS (ESI, m / z): 419 (M+H) + . Analytical conditions: column: Shim-pack Scepter C18 column 3.0×33 mm, 3.0 μm; mobile phase A: water / 5 mM NH4HCO3, mobile phase B: acetonitrile; flow rate: 1.5000 mL / min; gradient: 10% B to 95% B in 1.20 min; 254 nm; Rt: 1.106 min.

[0220] 1 H NMR (300 MHz, DMSO-d6) δ 9.33 (d, J = 8.7 Hz, 1H), 8.52 - 8.46 (m, 3H), 8.23 (d, J = 9.0 Hz, 1H), 8.13 (d, J = 5.1 Hz, 1H), 8.11 (d, J = 9.0 Hz, 1H), 7.23 (t, J = 5.4 Hz, 1H), 4.65 (s, 1H), 3.64 - 3.60 (m, 1H), 3.50 - 3.40 (m, 2H), 1.22 (d, J = 6.9 Hz, 3H) Example 16: Synthesis of (15R)-5-[6-chloro-2-(hydroxymethyl)pyrimidin-4-yl]-15-methyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2,4,6,8,12(18)-hexaen-13-one

[0221] Step 1: Synthesis of (15R)-5-[6-chloro-2-(hydroxymethyl)pyrimidin-4-yl]-15-methyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2,4,6,8,12(18)-hexaen-13-one

[0222] To a solution of (4,6-dichloropyrimidin-2-yl)methanol (200 mg, 1.117 mmol, 1.00 equiv) and (15R)-15-methyl-5-tributylstannyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2,4,6,8,12(18)-hexaen-13-one (640 mg, 1.117 mmol, 1.00 equiv) in 1,4-dioxane (10.0 mL) was added Pd(PPh3)4 (95 mg, 0.110 mmol, 0.10 equiv). The resulting solution was stirred overnight at 100 °C under a nitrogen atmosphere. LCMS showed completion of the reaction. The resulting solution was diluted with dichloromethane (10 mL). The solid was collected by filtration and washed with dichloromethane (2 × 10 mL). The solid was purified by preparative HPLC using the following gradient conditions: column: SunFire Prep C18 OBD column, 19 × 150 mm, 5 μm; mobile phase A: water (0.05% TFA), mobile phase B: ACN; flow rate: 20 mL / min; gradient: 20% B to 50% B in 4.5 min, 50% B; wavelength: 254 / 210 nm; RT1 (min): 4.35; number of rounds: 0. Purification yielded the desired (15R)-5-[6-chloro-2-(hydroxymethyl)pyrimidin-4-yl]-15-methyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2,4,6,8,12(18)-hexaen-13-one as a yellow solid (26.5 mg, 5.4%). LCMS (ESI, m / z): 426 (M+H) +Analysis conditions: Column: HALO C18 100A column, 3.0×30 mm, 2.7 μm; Mobile phase A: water + 0.05% TFA, Mobile phase B: acetonitrile + 0.05% TFA; Flow rate: 1.5000 mL / min; Gradient: 5% B to 70% B in 1.70 min; 254 nm; Rt: 1.531 min.

[0223] 1 H NMR (400 MHz, DMSO-d6 + D2O) δ 9.36 (d, J = 9.2 Hz, 1H), 8.67 (d, J = 8.8 Hz, 1H), 8.47 (s, 1H), 8.23 (d, J = 8.4 Hz, 1H), 8.14 - 8.08 (m, 2H), 7.19 (s, 1H), 5.63 (d, J = 5.6 Hz, 1H), 4.76 (d, J = 4.8 Hz, 2H), 3.65 - 3.59 (m, 1H), 3.49 (s, 2H), 1.21 (d, J = 6.8 Hz, 3H). 19 F NMR (376 MHz, DMSO-d6) δ 73.44. Example 17: Synthesis of (15R)-5-[2-(hydroxymethyl)-6-ethenyl-pyrimidin-4-yl]-15-methyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2,4,6,8,12(18)-hexaen-13-one

[0224] Step 1: Synthesis of (15R)-5-[6-chloro-2-(hydroxymethyl)pyrimidin-4-yl]-15-methyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2,4,6,8,12(18)-hexaen-13-one

[0225] To a solution of (4,6-dichloropyrimidin-2-yl)methanol (200 mg, 1.117 mmol, 1.00 equiv) and (15R)-15-methyl-5-tributylstannyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one (640 mg, 1.117 mmol, 1.00 equiv) in 1,4-dioxane (8.0 mL) was added Pd(PPh3)4 (95 mg, 0.112 mmol, 0.10 equiv). The resulting mixture was stirred overnight at 100 °C under a nitrogen atmosphere. The reaction was monitored by LCMS. The solid was collected by filtration and washed with DCM. Drying gave (15R)-5-[6-chloro-2-(hydroxymethyl)pyrimidin-4-yl]-15-methyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2,4,6,8,12(18)-hexaen-13-one (230 mg, 48%) as a yellow solid. LCMS (ESI, m / z): 426 (M+H) + .

[0226] Step 2: Synthesis of (15R)-5-[2-(hydroxymethyl)-6-vinyl-pyrimidin-4-yl]-15-methyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2,4,6,8,12(18)-hexaen-13-one

[0227] To a solution of (15R)-5-[6-chloro-2-(hydroxymethyl)pyrimidin-4-yl]-15-methyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2,4,6,8,12(18)-hexaen-13-one (80 mg, 0.188 mmol, 1.00 equiv) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (35 mg, 0.225 mmol, 1.20 equiv) in 1,4-dioxane (3.0 mL) and water (0.3 mL) was added Pd(PPh3)4 (16 mg, 0.019 mmol, 0.10 equiv). The resulting mixture was stirred overnight at 100 °C under a nitrogen atmosphere. LCMS showed completion of the reaction. The resulting solution was diluted with DCM. The solid was collected by filtration and washed with DCM. The solid was purified by preparative HPLC using the following gradient conditions: column: SunFire Prep C18 OBD column, 19 × 150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 20 mL / min; gradient: 25% B to 50% B in 4.5 min, 50% B in 0.3 min; wavelength: 254 / 210 nm; RT1 (min): 4.35. Purification yielded the desired (15R)-5-[2-(hydroxymethyl)-6-vinyl-pyrimidin-4-yl]-15-methyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2,4,6,8,12(18)-hexaen-13-one as a yellow solid (24.5 mg, 29%). LCMS (ESI, m / z): 418 (M+H) + . Analytical conditions: column: HALO C18 100A column 3.0 × 30 mm, 2.7 μm; mobile phase A: water / 0.05% TFA, mobile phase B: acetonitrile / 0.05% TFA; flow rate: 1.5000 mL / min; gradient: 5% B to 60% B in 2.10 min; 254 nm; Rt: 1.533 min.

[0228] 1H NMR(400MHz, DMSO-d6+D2O)δ9.36(d,J=8.8Hz,1H),8.72(d,J=8.8Hz,1H),8. 47(s,1H),8.23(d,J=8.8Hz,1H),8.15-8.03(m,2H),7.21(s,1H),7.04(dd,J= 17.2,10.4Hz,1H),6.69(d,J=18.0Hz,1H),5.83(d,J=11.6Hz,1H),5.40(s,1 H), 4.77 (s, 2H), 3.68-3.59 (m, 1H), 3.50-3.40 (m, 2H), 1.21 (d, J = 6.8Hz, 3H). Example 18: (R)-10-methyl-3-(3-(2-(pyrrolidin-1-yl)ethoxy)-6-vinylpyridazin-4-yl)-9,10,11,12-tetrahydro-8H-[1,4]diazepine Synthesis of 5',6':4,5'-thieno[3,2-f]quinolin-8-one

[0229] Step 1: Synthesis of 4-bromo-6-chloro-3-(2-pyrrolidin-1-ylethoxy)pyridazine

[0230] To a solution of 5-bromo-3-chloro-1H-pyridazin-6-one (1.5 g, 7.200 mmol, 1.00 equiv) and 2-pyrrolidin-1-ylethanol (0.8 g, 7.200 mmol, 1.00 equiv) and PPh3 (3.8 g, 14.300 mmol, 2.00 equiv) in THF (40.0 mL) was added DIAD (2.8 mL, 14.300 mmol, 2.00 equiv) dropwise. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. LCMS showed that the reaction was complete. The resulting material was diluted with water (100 ml) and extracted with ethyl acetate (3 × 50 mL). The organic layer was washed with brine (2 × 50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC using the following gradient conditions: Column: SunFire Prep C18 OBD column, 19×150 mm, 5 μm; Mobile phase A: water (0.05% TFA), Mobile phase B: MeCN; Flow rate: 25 mL / min; Gradient: 20% B to 40% B, 40% B over 6 min; Wavelength: 210 / 254 nm; RT1 (min): 5.51. Purification yielded the desired 4-bromo-6-chloro-3-(2-pyrrolidin-1-ylethoxy)pyridazine (160 mg, 7.3%) as a yellow oil. LCMS (ESI, m / z): 306 [M+H] + .

[0231] Step 2: (R)-3-(6-chloro-3-(2-(pyrrolidin-1-yl)ethoxy)pyridazin-4-yl)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepine Synthesis of 5',6':4,5'-thieno[3,2-f]quinolin-8-one

[0232] To the reaction mixture were added 4-bromo-6-chloro-3-(2-pyrrolidin-1-ylethoxy)pyridazine (10 mg, 0.030 mmol, 1.00 equiv) and (R)-10-methyl-3-(tributylstannyl)-9,10,11,12-tetrahydro-8H-[1,4]diazepine. A solution of [5',6':4,5]thieno[3,2-f]quinolin-8-one (22 mg, 0.040 mmol, 1.30 equiv) in 1,4-dioxane (1.0 mL) was added to Pd2(dba)3 (7 mg, 0.010 mmol, 0.20 equiv) and P(o-Tol.)3 (2 mg, 0.010 mmol, 0.20 equiv). The resulting mixture was stirred at 90 °C under a nitrogen atmosphere for 2 h. LCMS showed the reaction was complete. The resulting solution was diluted with water (10 mL) and extracted with ethyl acetate (2 × 10 mL). The combined organic layers were washed with brine (2 × 20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC using the following gradient conditions: column: SunFire Prep C18 OBD column, 19 × 150 mm, 5 μm; mobile phase A: water (0.05% TFA), mobile phase B: MeCN; flow rate: 25 mL / min; gradient: 20% B to 40% B in 6 min, hold at 40% B; wavelength: 210 / 254 nm; RT1 (min): 5.51. Purification gave the desired (R)-3-(6-chloro-3-(2-(pyrrolidin-1-yl)ethoxy)pyridazin-4-yl)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino [5',6':4,5]thieno[3,2-f]quinolin-8-one (1.8 mg, 10.3%). LCMS (ESI, m / z): 509 [M+H] + . Analytical conditions: column: HALO C18 column 3.0 × 30 mm, 1.9 μm; mobile phase A: water + 0.05% TFA, mobile phase B: acetonitrile + 0.05% TFA; flow rate: 1.5000 mL / min; gradient: 5% B to 65% B in 2.10 min. 254 nm; Rt: 1.429 min.

[0233] 1H NMR (400MHz, DMSO-d6) δ9.69(s,1H),9.32(d,J=9.2Hz,1H),8.37(s,1H),8.31(d,J=9.2 Hz,1H),8.24(d,J=8.8Hz,1H),8.15(d,J=4.4Hz,1H),8.06(d,J=8.8Hz,1H),7.18(t,J= 5.2Hz,1H),4.93(t,J=4.8Hz,2H),3.72(d,J=4.0Hz,2H),3.70-3.60(m,3H),3.50-3.40 (m,2H),3.12-3.06(m,2H),2.01-1.96(m,2H),1.83-1.80(m,2H),1.21(d,J=6.4Hz,3H). 19 F NMR (376 MHz, DMSO-d6) δ -73.50

[0234] Step 3: (R)-10-methyl-3-(3-(2-(pyrrolidin-1-yl)ethoxy)-6-vinylpyridazin-4-yl)-9,10,11,12-tetrahydro-8H-[1,4]diazepine Synthesis of 5',6':4,5'-thieno[3,2-f]quinolin-8-one

[0235] To (R)-3-(6-chloro-3-(2-(pyrrolidin-1-yl)ethoxy)pyridazin-4-yl)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepine A solution of [5',6':4,5]thieno[3,2-f]quinolin-8-one (20 mg, 0.040 mmol, 1.00 equiv) and tributyl(vinyl)stannane (19 mg, 0.060 mmol, 1.50 equiv) in 1,4-dioxane (1.0 mL) was added Pd(PPh3)4 (7 mg, 0.010 mmol, 0.20 equiv). The resulting mixture was stirred at 90 °C under a nitrogen atmosphere for 2 h. LCMS showed completion of the reaction. The resulting solution was diluted with water (5 mL) and extracted with ethyl acetate (3 × 5 mL). The organic layer was washed with brine (2 × 5 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions: column: SunFire Prep C18 OBD column, 19 × 150 mm, 5 μm; mobile phase A: water (0.05% TFA), mobile phase B: MeCN; flow rate: 25 mL / min; gradient: 20% B to 40% B in 6 min, 40% B; wavelength: 254 nm; RT1 (min): array. Purification gave the desired (R)-10-methyl-3-(3-(2-(pyrrolidin-1-yl)ethoxy)-6-vinylpyridazin-4-yl)-9,10,11,12-tetrahydro-8H-[1,4]diazepino [5',6':4,5]thieno[3,2-f]quinolin-8-one (6.8 mg, 33%). LCMS (ESI, m / z): 501 (M + H) + . Analytical conditions: column: HALO C18 column 3 × 30 mm, 1.9 □m; mobile phase A: water + 0.05% TFA, mobile phase B: acetonitrile + 0.05% TFA; flow rate: 1.5000 mL / min; gradient: 5% B to 60% B in 2.10 min; 254 nm; Rt: 1.432 min.

[0236] 11H NMR (400 MHz, DMSO-d6) δ 9.65 (s, 1H), 9.30 (d, J = 9.2 Hz, 1H), 8.42 (s, 1H), 8.26 (d, J = 8.8 Hz, 1H), 8.23 (d, J = 9.2 Hz, 1H), 8.15 (d, J = 4.4 Hz, 1H), 8.06 (d, J = 8.8 Hz, 1H), 7.21 (t, J = 5.2 Hz, 1H), 7.09 (dd, J = 17.6, 11.4 Hz, 1H), 6.39 (d, J = 17.6 Hz, 1H), 5.70 (d, J = 11.6 Hz, 1H), 4.94 (t, J = 4.4 Hz, 2H), 3.72 (d, J = 4.0 Hz, 2H), 3.70 - 3.60 (m, 3H), 3.50 - 3.42 (m, 2H), 3.12 - 3.02 (m, 2H), 2.00 - 1.90 (m, 2H), 1.86 - 1.78 (m, 2H), 1.21 (d, J = 6.8 Hz, 3H). 19 19F NMR (376 MHz, DMSO-d6) δ -73.65

[0237] Example 19: Synthesis of (R)-3-(6-Ethynyl-3-(2-(pyrrolidin-1-yl)ethoxy)pyridazin-4-yl)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino <5',6':4,5>thieno[3,2-f]quinolin-8-one

[0238] Step 1: Synthesis of (R)-10-Methyl-3-(3-(2-(pyrrolidin-1-yl)ethoxy)-6-((trimethylsilyl)ethynyl)pyridazin-4-yl)-9,10,11,12-tetrahydro-8H-[1,4]diazepino <5',6':4,5>thieno[3,2-f]quinolin-8-one

[0239] To (R)-3-(6-Chloro-3-(2-(pyrrolidin-1-yl)ethoxy)pyridazin-4-yl)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino And [5',6':4,5]thieno[3,2-f]quinolin-8-one (35 mg, 0.070 mmol, 1.00 equiv) and trimethyl(2-tributylstannylethynyl)silane (133 mg, 0.340 mmol, 5.00 equiv) were added to a solution of Pd(PPh3)4 (11.6 mg, 0.01 mmol, 0.10 equiv) in 1,4-dioxane (1.0 mL). The resulting mixture was stirred at 90 °C under a nitrogen atmosphere for 2 h. LCMS showed completion of the reaction. The reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (3 × 15 mL). The organic layer was washed with brine (2 × 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using water (0.05% TFA) / MeCN (2:1) to give (R)-10-methyl-3-(3-(2-(pyrrolidin-1-yl)ethoxy)-6-((trimethylsilyl)ethynyl)pyridazin-4-yl)-9,10,11,12-tetrahydro-8H-[1,4]diazepino And [5',6':4,5]thieno[3,2-f]quinolin-8-one (30 mg, 76%). LCMS (ESI, m / z): 571 [M+H] + .

[0240] Step 2: Synthesis of (R)-3-(6-ethynyl-3-(2-(pyrrolidin-1-yl)ethoxy)pyridazin-4-yl)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino And [5',6':4,5]thieno[3,2-f]quinolin-8-one

[0241] To (R)-10-methyl-3-(3-(2-(pyrrolidin-1-yl)ethoxy)-6-((trimethylsilyl)ethynyl)pyridazin-4-yl)-9,10,11,12-tetrahydro-8H-[1,4]diazepino To a solution of [5',6':4,5]thieno[3,2-f]quinolin-8-one (20 mg, 0.040 mmol, 1.00 equiv) in methanol (1.0 mL) was added K2CO3 (10 mg, 0.08 mmol, 2.00 equiv). The resulting mixture was stirred at room temperature for 1 h. LCMS showed completion of the reaction. The resulting solution was diluted with DMSO (2 mL). The solid was filtered off. The filtrate was purified by preparative HPLC using the following conditions: column: SunFire Prep C18 OBD column, 19×150 mm, 5 μm; mobile phase A: water (0.05% TFA), mobile phase B: MeCN; flow rate: 25 mL / min; gradient: 20% B to 40% B in 6 min, 40% B; wavelength: 254 nm; RT1 (min): 5.35. The purification yielded the desired (R)-3-(6-ethynyl-3-(2-(pyrrolidin-1-yl)ethoxy)pyridazin-4-yl)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino [5',6':4,5]thieno[3,2-f]quinolin-8-one (3.4 mg, 18.9%). LCMS (ESI, m / z): 499 [M+H] + . Analytical conditions: column: HALO C18 column 3×30 mm, 1.9 □m; mobile phase A: water + 0.05% TFA, mobile phase B: acetonitrile + 0.05% TFA; flow rate: 1.5000 mL / min; gradient: 5% B to 60% B in 2.10 min; 254 nm; Rt: 1.426 min.

[0242] 1 1H NMR (400 MHz, DMSO-d6) δ 9.65 (s, 1H), 9.31 (d, J = 9.2 Hz, 1H), 8.35 (s, 1H), 8.31 (d, J = 8.8 Hz, 1H), 8.23 (d, J = 9.2 Hz, 1H), 8.15 (d, J = 4.4 Hz, 1H), 8.06 (d, J = 9.2 Hz, 1H), 7.19 (t, J = 4.8 Hz, 1H), 4.93 (t, J = 4.8 Hz, 2H), 4.72 (s, 1H), 3.80 - 3.70 (m, 2H), 3.68 - 3.56 (m, 2H), 3.50 - 3.40 (m, 3H), 3.17 - 3.08 (m, 2H), 1.95 - 1.91 (m, 2H), 1.89 - 1.81 (m, 2H), 1.22 (d, J = 6.8 Hz, 3H). 19 19F NMR (376 MHz, DMSO-d6) δ -73.44. Example 20: Synthesis of (R)-3-(6-chloro-3-methoxypyridazin-4-yl)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazino and[5',6':4,5]thieno[3,2-f]quinolin-8-one

[0243] Step 1: Synthesis of (R)-3-(6-chloro-3-methoxypyridazin-4-yl)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazino and[5',6':4,5]thieno[3,2-f]quinolin-8-one

[0244] To a solution of (R)-10-methyl-3-(tributylstannyl)-9,10,11,12-tetrahydro-8H-[1,4]diazino and[5',6':4,5]thieno[3,2-f]quinolin-8-one (422 mg, 0.740 mmol, 1.10 eq) and 4-bromo-6-chloro-3-methoxy-pyridazine (150 mg, 0.670 mmol, 1.00 eq) in 1,4-dioxane (5.0 mL) was added Pd(PPh3)4 (51 mg, 0.060 mmol, 0.10 eq). The resulting solution was stirred overnight at 90 °C under a nitrogen atmosphere. LCMS showed completion of the reaction. The resulting solution was diluted with ethyl acetate / petroleum ether (1:1) (30 mL). The solid was collected by filtration and washed with ethyl acetate / petroleum ether (1:1) (100 mL), dichloromethane (50 mL), and hexane (50 mL). The solid was dried to give the desired (R)-3-(6-chloro-3-methoxypyridazin-4-yl)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazino and[5',6':4,5]thieno[3,2-f]quinolin-8-one (160.4 mg, 53%) as a red solid. LCMS (ESI, m / z): 426 [M+H] + . Analytical conditions: Column: Shim-pack GIST C18-AQ column 4.6×100 mm, 3.0 μm; Mobile phase A: 0.1% H3PO4 + H2O, Mobile phase B: acetonitrile; Flow rate: 1.5000 mL / min; Gradient: 10% B to 95% B in 6.00 min; 254 nm; Rt: 4.869 min.

[0245] 1H NMR (400MHz, DMSO-d6) δ9.25(d,J=9.2Hz,1H),8.78(d,J=9.2Hz,1H),8.36(s,1H),8.18(d,J=8.8Hz,1H),8.10(d,J=4.0Hz, 1H), 8.04 (d, J = 8.8Hz, 1H), 7.18 (t, J = 4.8Hz, 1H), 3.78 (s, 3H), 3.66-3.58 (m, 1H), 3.54-3.42 (m, 2H), 1.20 (d, J = 7.2Hz, 3H).

[0246] Step 2: (R)-3-(3-methoxy-6-vinylpyridazin-4-yl)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepine Synthesis of 5',6':4,5'-thieno[3,2-f]quinolin-8-one

[0247] To (R)-3-(6-chloro-3-methoxypyridazin-4-yl)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepine To a solution of 5',6':4,5'-thieno[3,2-f]quinolin-8-one (50 mg, 0.120 mmol, 1.00 equiv) and tributyl(vinyl)stannane (111 mg, 0.350 mmol, 3.00 equiv) in 1,4-dioxane (2.0 mL) was added Pd(PPh3)4 (13 mg, 0.011 mmol, 0.10 equiv). The resulting solution was stirred at 100°C overnight under a nitrogen atmosphere. LCMS indicated the reaction was complete. The resulting solution was concentrated under reduced pressure. The crude product was purified by preparative HPLC using the following gradient conditions: Column: SunFire Prep C18 OBD column, 19×150 mm, 5 μm; Mobile phase A: water (0.05% TFA), Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 30% B to 65% B, 65% B in 6 min; Wavelength: 210 / 254 nm; RT1 (min): 5.60. Purification yielded the desired (R)-3-(3-methoxy-6-vinylpyridazin-4-yl)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepine as a red solid. 1,3-Dimethoxy-1-thiazolin-1-one (6.2 mg, 12%). LCMS (ESI, m / z): 418 [M+H] +Analysis conditions: Column: HALOWA C18 column 3.0×30 mm, 1.9 μm; Mobile phase A: water / 0.05% TFA, Mobile phase B: acetonitrile / 0.05% TFA; Flow rate: 1.2000 mL / min; Gradient: 5% B to 100% B in 2.40 min; 254 nm; Rt: 1.658 min.

[0248] 1 1H NMR (400 MHz, DMSO-d6) δ 9.25 (d, J = 9.2 Hz, 1H), 8.73 (d, J = 8.8 Hz, 1H), 8.63 (s, 1H), 8.18 (d, J = 9.2 Hz, 1H), 8.12 - 8.04 (m, 3H), 7.19 (s, 1H), 6.75 (dd, J = 17.6 Hz, 10.8 Hz, 1H), 6.14 (d, J = 17.6 Hz, 1H), 5.62 (d, 11.2 Hz, 1H), 3.83 (s, 3H), 3.60 - 3.40 (m, 3H), 1.20 (d, J = 7.2 Hz, 3H). 19 19F NMR (376 MHz, DMSO-d6) δ -74.54. Example 21: Synthesis of (15R)-15-methyl-5-[3-(methylamino)-6-ethenyl-pyridazin-4-yl]-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2,4,6,8,12(18)-hexaen-13-one

[0249] Step 1: Synthesis of N-(4-bromo-6-chloro-pyridazin-3-yl)-N-tert-butoxycarbonyl-carbamic acid tert-butyl ester

[0250] To a solution of 4-bromo-6-chloro-pyridazin-3-amine (2.0 g, 9.615 mmol, 1.00 equiv), Boc2O (4.2 g, 19.231 mmol, 2.00 equiv) and TEA (1.9 g, 2.880 mmol, 2.00 equiv) in DCM (100.0 mL) was added DMAP (117 mg, 0.962 mmol, 0.10 equiv). The resulting solution was stirred for 2 h at room temperature under a nitrogen atmosphere. LCMS showed the reaction was complete. The resulting solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using ethyl acetate / petroleum ether (1:1) to give N-(4-bromo-6-chloro-pyridazin-3-yl)-N-tert-butoxycarbonyl-carbamic acid tert-butyl ester (2.5 g, 64%) as a white solid. LCMS (ESI, m / z): 408 and 410 (M+H) + 。

[0251] Step 2: Synthesis of tert-butyl N-(4-bromo-6-chloro-pyridazin-3-yl)carbamate

[0252] To a solution of N-(4-bromo-6-chloro-pyridazin-3-yl)-N-tert-butoxycarbonyl-carbamic acid tert-butyl ester (2.5 g, 6.112 mmol, 1.00 equiv) in THF (20.0 mL) was added NH3.H2O (20.0 mL). The resulting solution was stirred at room temperature for 1 h. LCMS showed the reaction was complete. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (3 × 200 mL). The combined organic layers were washed with brine (2 × 100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product tert-butyl N-(4-bromo-6-chloro-pyridazin-3-yl)carbamate (2.0 g) was used directly in the next step without purification. LCMS (ESI, m / z): 308 and 309 (M+H) + 。

[0253] Step 3: Synthesis of tert-butyl N-(4-bromo-6-chloro-pyridazin-3-yl)-N-methylcarbamate

[0254] To a solution of tert-butyl N-(4-bromo-6-chloropyridazin-3-yl)carbamate (1.0 g, 3.236 mmol, 1.00 equiv) in THF (20.0 mL) at 0 °C was added NaH (116 mg, 0.730 mmol, 1.50 equiv) over 0.5 h. Subsequently, CH3I (544 mg, 0.620 mmol, 1.20 equiv) was added. The resulting solution was stirred at room temperature for 1 h. LCMS showed completion of the reaction. The reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (3 × 100 mL). The organic layer was washed with brine (2 × 50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using ethyl acetate / petroleum ether (1:4) to give tert-butyl N-(4-bromo-6-chloropyridazin-3-yl)-N-methylcarbamate (850 mg, 81%) as a white solid. LCMS (ESI, m / z): 322 and 324 (M+H) + 。

[0255] Step 4: Synthesis of tert-butyl N-[6-chloro-4-[(15R)-15-methyl-13-oxo-11-thia-6,14,17-triazatricyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-5-yl]pyridazin-3-yl]-N-methylcarbamate

[0256] To a solution of (15R)-15-methyl-5-tributylstannyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one (150 mg, 0.261 mmol, 1.00 equiv) and tert-butyl N-(4-bromo-6-chloropyridazin-3-yl)-N-methylcarbamate (101 mg, 0.314 mmol, 1.20 equiv) in 1,4-dioxane (1.0 mL) was added Pd(PPh3)4 (30 mg, 0.026 mmol, 0.10 equiv). The resulting solution was stirred at 100 °C under a nitrogen atmosphere for 6 h. LCMS showed completion of the reaction. The resulting solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using ethyl acetate / petroleum ether (1:2) to give tert-butyl N-[6-chloro-4-[(15R)-15-methyl-13-oxo-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-5-yl]pyridazin-3-yl]-N-methylcarbamate (50 mg, 36%) as a yellow solid. LCMS (ESI, m / z): 525 (M+H) + 。

[0257] Step 5: Synthesis of tert-butyl N-methyl-N-[4-[(15R)-15-methyl-13-oxo-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-5-yl]-6-vinylpyridazin-3-yl]carbamate

[0258] To a solution of tert-butyl N-[6-chloro-4-[(15R)-15-methyl-13-oxo-11-thia-6,14,17-triazatricyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-5-yl]pyridazin-3-yl]-N-methyl-carbamate (30 mg, 0.060 mmol, 1.00 equiv) and tributyl(vinyl)stannane (54 mg, 0.170 mmol, 3.00 equiv) in 1,4-dioxane (2.0 mL) was added Pd(PPh3)4 (4 mg, 0.010 mmol, 0.10 equiv). The resulting solution was stirred at 100 °C under a nitrogen atmosphere for 6 h. LCMS showed completion of the reaction. The resulting solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using dichloromethane / methanol (15:1) to give tert-butyl N-methyl-N-[4-[(15R)-15-methyl-13-oxo-11-thia-6,14,17-triazatricyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-5-yl]-6-vinyl-pyridazin-3-yl]carbamate (20 mg, 67%). LCMS (ESI, m / z): 517 [M+H] + 。

[0259] Step 6: Synthesis of (15R)-15-methyl-5-[3-(methylamino)-6-vinyl-pyridazin-4-yl]-11-thia-6,14,17-triazatricyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2,4,6,8,12(18)-hexaen-13-one

[0260] To a solution of tert-butyl N-methyl-N-[4-[(15R)-15-methyl-13-oxo-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2,4,6,8,12(18)-hexaen-5-yl]-6-vinyl-pyridazin-3-yl]carbamate (20 mg, 0.0400 mmol, 1.00 equiv) in DCM (3.0 mL) was added dropwise TFA (0.5 mL). The resulting solution was stirred at room temperature for 1 h. LCMS showed completion of the reaction. The solution was concentrated under reduced pressure and the residue was purified by preparative HPLC using the following conditions: column: SunFire Prep C18 OBD column, 19×150 mm, 5 μm; mobile phase A: water (0.05% TFA), mobile phase B: MeCN; flow rate: 20 mL / min; gradient: 25% B to 43% B in 5 min, 43% B; wavelength: 210 / 254 nm; RT1 (min): 4.95. Purification gave the desired (15R)-15-methyl-5-[3-(methylamino)-6-vinyl-pyridazin-4-yl]-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2,4,6,8,12(18)-hexaen-13-one (8.7 mg, 52%) as an orange solid. LCMS (ESI, m / z): 417 [M+H] + . Analytical conditions: column: HALO C18 100A column 3.0×30 mm, 1.9 μm; mobile phase A: water / 0.05% TFA, mobile phase B: acetonitrile / 0.05% TFA; flow rate: 1.2000 mL / min; gradient: 5% B to 100% B in 2.40 min; 254 nm; Rt: 1.429 min.

[0261] 1 1H NMR (400 MHz, DMSO-d6) δ 10.75 (s, 1H), 9.40 (d, J = 8.8 Hz, 1H), 8.70 (t, J = 6.0 Hz, 2H), 8.37 (d, J = 8.8 Hz, 1H), 8.30 (d, J = 8.8 Hz, 1H), 8.17 (d, J = 4.4 Hz, 1H), 7.23 (d, J = 8.4 Hz, 1H), 6.95 (dd, J = 17.6 Hz, 11.2 Hz, 1H), 6.49 (d, J = 17.6 Hz, 1H), 5.77 (d, J = 11.2 Hz, 1H), 3.51 (d, J = 8.0 Hz, 2H), 3.27 (s, 3H), 1.21 (d, J = 7.2 Hz, 3H). 1919F NMR (376 MHz, DMSO-d6) δ -74.60. Example 22: Synthesis of (R)-3-(3-(dimethylamino)-6-vinylpyridazin-4-yl)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazino [5',6':4,5]thieno[3,2-f]quinolin-8-one

[0262] Step 1: Synthesis of 4-bromo-6-chloro-N,N'-dimethyl-pyridazin-3-amine

[0263] To a solution of 4-bromo-6-chloro-pyridazin-3-amine (300 mg, 1.440 mmol, 1.00 equiv) in THF (5.0 mL) in an ice bath was added NaH (41 mg, 1.730 mmol, 1.20 equiv) and the mixture was stirred at 0 °C for 30 min. Subsequently, CH3I (617 mg, 4.320 mmol, 3.00 equiv) was added to the resulting solution and the mixture was stirred overnight at room temperature. LCMS showed completion of the reaction. The resulting solution was quenched with water (30 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine (2 × 50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by thin layer chromatography, developed with ethyl acetate / petroleum ether (1:4), to give 4-bromo-6-chloro-N,N'-dimethyl-pyridazin-3-amine as a yellow oil (250 mg, 73%). LCMS (ESI, m / z): 236 [M+H] + .

[0264] Step 2: Synthesis of (R)-3-(6-chloro-3-(dimethylamino)pyridazin-4-yl)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazino [5',6':4,5]thieno[3,2-f]quinolin-8-one

[0265] To (R)-10-methyl-3-(tributylstannyl)-9,10,11,12-tetrahydro-8H-[1,4]diazino A solution of [5',6':4,5]thieno[3,2-f]quinolin-8-one (300 mg, 0.520 mmol, 1.00 equiv) and 4-bromo-6-chloro-N,N-dimethyl-pyridazin-3-amine (150 mg, 0.638 mmol, 1.20 equiv) in 1,4-dioxane (10.0 mL) was added Pd(PPh3)4 (44 mg, 0.050 mmol, 0.10 equiv). The resulting solution was stirred overnight at 100 °C under a nitrogen atmosphere. LCMS showed the reaction was complete. The resulting solution was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using water (0.05% TFA) / MeCN (2:1) to give (R)-3-(6-chloro-3-(dimethylamino)pyridazin-4-yl)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino [5',6':4,5]thieno[3,2-f]quinolin-8-one (80 mg, 34%). LCMS (ESI, m / z): 439 [M+H] + .

[0266] Step 3: Synthesis of (R)-3-(3-(dimethylamino)-6-vinylpyridazin-4-yl)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino [5',6':4,5]thieno[3,2-f]quinolin-8-one

[0267] To (R)-3-(6-chloro-3-(dimethylamino)pyridazin-4-yl)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino A solution of [5',6':4,5]thieno[3,2-f]quinolin-8-one (30 mg, 0.070 mmol, 1.00 equiv) and tributyl(vinyl)stannane (65 mg, 0.210 mmol, 3.00 equiv) in 1,4-dioxane (2.0 mL) was added with Pd(PPh3)4 (5 mg, 0.010 mmol, 0.10 equiv). The resulting solution was stirred overnight at 100 °C under a nitrogen atmosphere. LCMS showed the reaction was complete. The resulting solution was concentrated under reduced pressure. The residue was purified by preparative HPLC using the following gradient conditions: column: SunFire Prep C18 OBD column, 19×150 mm, 5 μm; mobile phase A: water (0.05% TFA), mobile phase B: MeCN; flow rate: 20 mL / min; gradient: 20% B to 40% B in 5 min, 40% B; wavelength: 210 / 254 nm; RT1 (min): 5.13. The purification yielded the desired (R)-3-(3-(dimethylamino)-6-vinylpyridazin-4-yl)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino [5',6':4,5]thieno[3,2-f]quinolin-8-one (5.6 mg, 18%). LCMS (ESI, m / z): 431 [M+H] + . Analytical conditions: column: Shim-pack GIST C18-AQ column 4.6×100 mm, 3.0 μm; mobile phase A: 0.1% H3PO4 + H2O, mobile phase B: acetonitrile; flow rate: 1.5000 mL / min; gradient: 10% B to 95% B in 8.00 min; 254 nm; Rt: 4.889 min.

[0268] 1 1H NMR (400 MHz, DMSO-d6) δ 9.31 (d, J = 8.8 Hz, 1H), 8.21 (d, J = 8.8 Hz, 1H), 8.14 (d, J = 4.4 Hz, 1H), 8.12 - 8.01 (m, 2H), 7.97 (d, J = 8.8 Hz, 1H), 7.19 (s, 1H), 6.98 (dd, J = 18.0 Hz, 11.2 Hz, 1H), 6.29 (d, J = 18.0 Hz, 1H), 5.40 (d, J = 11.2 Hz, 1H), 3.62 - 3.60 (m, 1H), 3.51 - 3.48 (m, 2H), 2.83 (s, 6H), 1.21 (d, J = 6.8 Hz, 3H). Example 23: Synthesis of (R)-3-(5-(difluoromethyl)-2-ethenylpyridin-4-yl)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazeto and[5',6':4,5]thieno[3,2-f]quinolin-8-one

[0269] To a solution of (R)-3-(2-chloro-5-(difluoromethyl)pyridin-4-yl)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazeto and[5',6':4,5]thieno[3,2-f]quinolin-8-one (50 mg, 0.110 mmol, 1.00 equiv) in 1,4-dioxane (2.0 mL) was added tributyl(vinyl)stannane (106 mg, 0.340 mmol, 3.00 equiv) and Pd(PPh3)4 (9 mg, 0.010 mmol, 0.10 equiv). The resulting solution was stirred overnight at 100 °C under a nitrogen atmosphere. LCMS showed completion of the reaction. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using water (0.05% NH4HCO3) / MeCN (1:1). The purification gave (R)-3-(5-(difluoromethyl)-2-ethenylpyridin-4-yl)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazeto and[5',6':4,5]thieno[3,2-f]quinolin-8-one (8.3 mg, 16%) as a red solid. LCMS (ESI, m / z): 437 [M+H] + . Analytical conditions: Column: HALOWA C18 column 3.0×30 mm, 1.9 μm; Mobile phase A: water / 0.05% TFA, Mobile phase B: acetonitrile / 0.05% TFA; Flow rate: 1.2000 mL / min; Gradient: 5% B to 100% B in 2.40 min; 254 nm; Rt: 1.804 min.

[0270] 1H NMR(400MHz, DMSO-d6)δ9.36(d,J=8.8Hz,1H),8.97(s,1H),8.22(d,J=8.8Hz, 1H),8.13(d,J=8.8Hz,1H),8.05(d,J=8.8Hz,1H),7.75(t,J=54.4Hz,1H),7.21 (t,J=5.2Hz,1H),7.02(dd,J=17.2,10.8Hz,1H),6.50(d,J=17.2Hz,1H),5.68( d,J=11.2Hz,1H),3.63-3.62(m,1H),3.52-3.45(m,2H),1.20(d,J=6.8Hz,3H).

[0271] Example 24: (R)-10-methyl-3-(3-(2-morpholinoethoxy)-6-vinylpyridazin-4-yl)-9,10,11,12-tetrahydro-8H-[1,4]diazepine Synthesis of 5',6':4,5'-thieno[3,2-f]quinolin-8-one

[0272] Step 1: Synthesis of 4-[2-(4-bromo-6-chloro-pyridazin-3-yl)oxyethyl]morpholine

[0273] To a solution of 5-bromo-3-chloro-1H-pyridazin-6-one (1.5 g, 7.16 mmol), 2-morpholinoethanol (1.9 g, 14.320 mmol, 1.00 equiv), and PPh3 (5 g, 17.910 mmol) in THF (80 mL) was added dropwise DIAD (3.5 mL, 17.910 mmol, 1.30 equiv). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 h. LCMS showed the reaction was complete. The resulting solution was diluted with water (300 mL) and extracted with ethyl acetate (2 × 500 mL). The combined organic layers were washed with brine (2 × 300 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using water (0.05% TFA) / MeCN (1:2) to give the crude product. The crude product was purified by preparative HPLC using the following conditions: column: Welch Utimate AQ-C18, 50 × 250 mm × 10 μm; mobile phase A: water (0.05% TFA), mobile phase B: MeCN; flow rate: 100 mL / min; gradient: 3% B to 13% B in 22 min, hold at 13% B; wavelength: 210 / 254 nm; RT1 (min): 18.9. Purification gave the desired 4-[2-(4-bromo-6-chloro-pyridazin-3-yl)oxyethyl]morpholine as a white solid (200 mg, 8%). LCMS (ESI, m / z): 322 [M+H] + 。

[0274] Step 2: Synthesis of ((R)-3-(6-chloro-3-(2-morpholinoethoxy)pyridazin-4-yl)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazino and [5',6':4,5]thieno[3,2-f]quinolin-8-one

[0275] To 4-[2-(4-bromo-6-chloro-pyridazin-3-yl)oxyethyl]morpholine (30 mg, 0.090 mmol, 1.00 equiv) and (R)-10-methyl-3-(tributylstannyl)-9,10,11,12-tetrahydro-8H-[1,4]diazino A solution of benzo[5',6':4,5]thieno[3,2-f]quinolin-8-one (80 mg, 0.140 mmol, 1.50 equiv) in 1,4-dioxane (2.0 mL) was added with Pd2(dba)3 (17 mg, 0.020 mmol, 0.20 equiv) and P(o-Tol.)3 (6 mg, 0.020 mmol, 0.20 equiv). The resulting mixture was stirred at 90 °C under a nitrogen atmosphere for 2 h. LCMS showed the reaction was complete. The resulting solution was diluted with ethyl acetate (20 mL). The solid was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions: column: SunFire Prep C18 OBD column, 19 × 150 mm, 5 μm; mobile phase A: water (0.05% TFA), mobile phase B: MeCN; flow rate: 20 mL / min; gradient: 20% B to 40% B in 6 min, 40% B; wavelength: 210 / 254 nm; RT1 (min): 5.62. The purification gave the desired ((R)-3-(6-chloro-3-(2-morpholinoethoxy)pyridazin-4-yl)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino benzo[5',6':4,5]thieno[3,2-f]quinolin-8-one (9.6 mg, 19.5% yield). LCMS (ESI, m / z): 525 [M+H]+. Analytical conditions: column: HALO C18 column 3 × 30 mm, 2.7 □m; mobile phase A: water + 0.05% TFA, mobile phase B: acetonitrile + 0.05% TFA; flow rate: 1.5000 mL / min; gradient: 5% B to 65% B in 1.7 min; 254 nm; Rt: 1.300 min.

[0276] 1 1H NMR (400 MHz, DMSO-d6 + D2O) δ 9.30 (d, J = 8.8 Hz, 1H), 8.37 (s, 1H), 8.30 (d, J = 8.8 Hz, 1H), 8.24 (d, J = 8.8 Hz, 1H), 8.07 (d, J = 8.8 Hz, 1H), 4.97 (t, J = 4.4 Hz, 2H), 3.92 - 3.82 (m, 2H), 3.72 (t, J = 4.8 Hz, 3H), 3.69 - 3.59 (m, 3H), 3.52 - 3.44 (m, 3H), 3.31 - 3.20 (m, 2H), 1.22 (d, J = 6.8 Hz, 3H).

[0277] Step 3: Synthesis of (R)-10-methyl-3-(3-(2-morpholinoethoxy)-6-vinylpyridazin-4-yl)-9,10,11,12-tetrahydro-8H-[1,4]diazino [5',6':4,5]thieno[3,2-f]quinolin-8-one

[0278] To a solution of ((R)-3-(6-chloro-3-(2-morpholinoethoxy)pyridazin-4-yl)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazino [5',6':4,5]thieno[3,2-f]quinolin-8-one (20 mg, 0.040 mmol, 1.00 equiv) and tributyl(vinyl)stannane (36 mg, 0.110 mmol, 3.00 equiv) in 1,4-dioxane (2.0 mL) was added Pd(PPh3)4 (9 mg, 0.010 mmol, 0.20 equiv). The resulting mixture was stirred at 90 °C under a nitrogen atmosphere for 3 h. LCMS showed completion of the reaction. The resulting solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using dichloromethane / methanol (20:1) to give the crude product. The crude product was purified by preparative HPLC using the following conditions: column: SunFire Prep C18 OBD column, 19 × 150 mm, 5 μm; mobile phase A: water (0.05% TFA), mobile phase B: MeCN; flow rate: 20 mL / min; gradient: 20% B to 60% B in 6 min, 60% B; wavelength: 254 nm; RT1 (min): 5.56. Purification gave the desired (R)-10-methyl-3-(3-(2-morpholinoethoxy)-6-vinylpyridazin-4-yl)-9,10,11,12-tetrahydro-8H-[1,4]diazino [5',6':4,5]thieno[3,2-f]quinolin-8-one (4.5 mg, 22%). LCMS (ESI, m / z): 517 [M+H] + . Analytical conditions: column: HALO C18 column 3 × 30 mm, 2.7 □m; mobile phase A: water + 0.05% TFA, mobile phase B: acetonitrile + 0.05% TFA; flow rate: 1.5000 mL / min; gradient: 5% B to 65% B in 1.70 min; 254 nm; Rt: 1.307 min.

[0279] 1H NMR(400MHz, DMSO-d6+D2O)δ9.30(d,J=8.8Hz,1H),8.41(s,1H),8.27(d,J=8.8Hz,1H), 8.22(d,J=8.8Hz,1H),8.08(d,J=8.8Hz,1H),7.10(dd,J=18.0,11.2Hz,1H),6.37(d,J=1 8.0Hz,1H),5.72(d,J=11.2Hz,1H),4.99(t,J=4.4Hz,2H),4.03-3.83(m,2H),3.75-3.68 (m,3H),3.63-3.56(m,2H),3.56-3.43(m,4H),3.32-3.09(m,2H),1.22(d,J=6.8Hz,3H).

[0280] Example 25: (R)-3-(6-ethynyl-3-(2-morpholinoethoxy)pyridazin-4-yl)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepine Synthesis of 5',6':4,5'-thieno[3,2-f]quinolin-8-one

[0281] Step 1: (R)-10-methyl-3-(3-(2-morpholinoethoxy)-6-((trimethylsilyl)ethynyl)pyridazin-4-yl)-9,10,11,12-tetrahydro-8H-[1,4]diazepine Synthesis of 5',6':4,5'-thieno[3,2-f]quinolin-8-one

[0282] To ((R)-3-(6-chloro-3-(2-morpholinoethoxy)pyridazin-4-yl)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepine A solution of benzo[5',6':4,5]thieno[3,2-f]quinolin-8-one (30 mg, 0.060 mmol, 1.00 equiv) and trimethyl(2-tributylstannylethynyl)silane (66 mg, 0.170 mmol, 3.00 equiv) in 1,4-dioxane (2.0 mL) was added Pd(PPh3)4 (13 mg, 0.010 mmol, 0.20 equiv). The resulting mixture was stirred at 90 °C under a nitrogen atmosphere for 3 h. LCMS showed the reaction was complete. The resulting solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography using DCM / MeOH (20:1), to give (R)-10-methyl-3-(3-(2-morpholinoethoxy)-6-((trimethylsilyl)ethynyl)pyridazin-4-yl)-9,10,11,12-tetrahydro-8H-[1,4]diazepino benzo[5',6':4,5]thieno[3,2-f]quinolin-8-one (15 mg, 45%). LCMS (ESI, m / z): 587 [M+H] + .

[0283] Step 2: Synthesis of (R)-3-(6-ethynyl-3-(2-morpholinoethoxy)pyridazin-4-yl)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino benzo[5',6':4,5]thieno[3,2-f]quinolin-8-one

[0284] To (R)-10-methyl-3-(3-(2-morpholinoethoxy)-6-((trimethylsilyl)ethynyl)pyridazin-4-yl)-9,10,11,12-tetrahydro-8H-[1,4]diazepino A solution of [5',6':4,5]thieno[3,2-f]quinolin-8-one (13 mg, 0.020 mmol, 1.00 equiv) in DCM (2.0 mL) was added with Et3N-3HF (0.1 mL). The resulting mixture was stirred at room temperature for 1 h. LCMS showed the reaction was complete. The resulting solution was concentrated under reduced pressure and the residue was purified by preparative HPLC using the following conditions: column: SunFire Prep C18 OBD column, 19×150 mm, 5 μm; mobile phase A: water (0.05% TFA), mobile phase B: MeCN; flow rate: 25 mL / min; gradient: 15% B to 35% B in 5 min, 35% B; wavelength: 254 nm; RT1 (min): 5.56. The purification yielded the desired (R)-3-(6-ethynyl-3-(2-morpholinoethoxy)pyridazin-4-yl)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino [5',6':4,5]thieno[3,2-f]quinolin-8-one (1 mg, 8%). LCMS (ESI, m / z): 515 [M+H] + . Analytical conditions: column: HALO C18 column 3×30 mm, 2.7 □m; mobile phase A: water + 0.05% TFA, mobile phase B: acetonitrile + 0.05% TFA; flow rate: 1.5000 mL / min; gradient: 5% B to 60% B in 1.80 min; 254 nm; Rt: 1.383 min.

[0285] 1 1H NMR (400 MHz, DMSO-d6 + D2O) δ 9.29 (d, J = 8.8 Hz, 1H), 8.39 (s, 1H), 8.32 (d, J = 8.8 Hz, 1H), 8.23 (d, J = 8.8 Hz, 1H), 8.07 (d, J = 9.2 Hz, 1H), 4.96 (s, 2H), 4.68 (s, 1H), 3.80 - 3.60 (m, 5H), 3.52 - 3.36 (m, 6H), 3.22 - 3.03 (m, 2H), 1.24 (d, J = 6.4 Hz, 3H). Example 26: Synthesis of (R)-10-methyl-3-(3-methyl-6-vinylpyridazin-4-yl)-9,10,11,12-tetrahydro-8H-[1,4]diazepino [5',6':4,5]thieno[3,2-f]quinolin-8-one Step 1: Preparation of 4-chloro-3-methyl-6-vinylpyridazine:

[0286] A 20 mL reaction vial was charged with a stir bar, potassium vinyltrifluoroborate (82 mg, 0.613 mmol), 4,6-dichloro-3-methylpyridazine (100 mg, 0.613 mmol), Pd(dppf)Cl2, DCM adduct (50.1 mg, 0.061 mmol), cesium carbonate (500 mg, 1.534 mmol), dioxane (2454 μl) and water (613 μl) to give an orange suspension. The resulting mixture was degassed by bubbling nitrogen for 5 minutes and then stirred at 60 °C for 16 hours. LC MS indicated formation of a large amount of product. The reaction mixture was concentrated under reduced pressure, diluted in ethyl acetate and filtered through a pad of Celite. The filtrate was concentrated under reduced pressure to give the crude product, which was purified by flash chromatography (0 to 100% ethyl acetate / heptane; eluting approximately 50% of the desired product). The pure eluates were combined and concentrated to give 4-chloro-3-methyl-6-vinylpyridazine as a clear oil (26 mg, 0.168 mmol, 27.4% yield). MSESIm / z 155.2 and 157.2 (M+H) + Step 2: Preparation of (R)-10-methyl-3-(3-methyl-6-vinylpyridazin-4-yl)-9,10,11,12-tetrahydro-8H-[1,4]diazino and [5',6':4,5]thieno[3,2-f]quinolin-8-one:

[0287] A 4 mL reaction vial was charged with a stir bar, (R)-10-methyl-3-(tributylstannyl)-9,10,11,12-tetrahydro-8H-[1,4]diazino And [5',6':4,5]thieno[3,2-f]quinolin-8-one (33.3 mg, 0.058 mmol), 4-chloro-3-methyl-6-vinylpyridazine (9 mg, 0.058 mmol), PdCl2(dtbpf) (3.79 mg, 5.82 μmol) and dioxane (291 μl) were taken to obtain a brown solution. The reactants were degassed by evacuating and backfilling with nitrogen three times. The resulting mixture was stirred at 80 °C for 16 h. LC MS indicated exhaustion of a large amount of starting material. The reaction mixture was concentrated under reduced pressure, dissolved in ethyl acetate and filtered through a pad of diatomaceous earth. The crude product was concentrated under reduced pressure. The crude material was purified by preparative reverse-phase chromatography using the following conditions: column: XBridge C18, 19 mm × 200 mm, 5 μm particles; mobile phase A: 5:95 acetonitrile: water and 10 mM ammonium acetate; mobile phase B: 95:5 acetonitrile: water and 10 mM ammonium acetate; gradient: held at 7% B for 0 min, 7% to 47% B over 20 min, followed by holding at 100% B for 4 min; flow rate: 20 mL / min; column temperature: 25 °C. Eluate collection was triggered by UV (220 nm) and MS (ESI+). The eluates containing the desired product were combined and dried by centrifugal evaporation to give (R)-10-methyl-3-(3-methyl-6-vinylpyridazin-4-yl)-9,10,11,12-tetrahydro-8H-[1,4]diazepino [5',6':4,5]thieno[3,2-f]quinolin-8-one (1.4 mg, 0.003 mmol, 6% yield).

[0288] 1 H NMR (500 MHz, DMSO-d6) δ 9.35 (d, J = 8.9 Hz, 1H), 8.22 (d, J = 9.0 Hz, 1H), 8.12 (s, 2H), 8.08 (d, J = 8.8 Hz, 1H), 8.05 (d, J = 8.9 Hz, 1H), 7.21 (br s, 1H), 7.11 (dd, J = 17.9, 11.1 Hz, 1H), 6.48 (d, J = 17.8 Hz, 1H), 5.75 (d, J = 11.2 Hz, 1H), 3.63 (br s, 2H), 2.80 (s, 3H), 1.21 (d, J = 6.8 Hz, 3H). One proton was shielded by water. MS ESI m / z 402.1 (M+H) + Example 27: Synthesis of methyl (R)-4-(10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino [5',6':4,5]thieno[3,2-f]quinolin-3-yl)-6-vinylpyridazine-3-carboxylate Step 1: Preparation of methyl 4-chloro-6-vinylpyridazine-3-carboxylate:

[0289] Into 20mL reaction bottle, stir bar, potassium vinyl trifluoroborate (81mg, 0.604mmol), 4,6-dichloropyridazine-3-methyl formates (125mg, 0.604mmol), Pd (dppf) Cl , DCM adduct (49.3mg, 0.060mmol) and cesium carbonate (492mg, 1.510mmol), dioxane (2415 μ l) and water (604 μ l) are packed, obtain orange suspension.By nitrogen bubbling, the gained mixture is degassed 5 minutes and then stirred at 60 DEG C for 16 hours.LC-MS indicates the presence of a large amount of products.The reaction mixture is concentrated under reduced pressure, diluted in ethyl acetate and filtered through diatomaceous earth pad.The filtrate is concentrated under reduced pressure, obtains crude product.By flash chromatography (0 to 100% ethyl acetate / heptane) purification of crude product. The pure fractions were concentrated under reduced pressure to give methyl 4-chloro-6-vinylpyridazine-3-carboxylate (28 mg, 0.141 mmol, 23.35% yield). MS ESI m / z 199.2 (M+H)+ Step 2: (R)-4-(10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepine Preparation of methyl (5',6':4,5)thieno[3,2-f]quinolin-3-yl)-6-vinylpyridazine-3-carboxylate:

[0290] A 4 mL reaction vial was charged with a stir bar, (R)-10-methyl-3-(tributylstannyl)-9,10,11,12-tetrahydro-8H-[1,4]diazepine And [5',6':4,5]thieno[3,2-f]quinolin-8-one (25.9 mg, 0.045 mmol), methyl 4-chloro-6-vinylpyridazine-3-carboxylate (9 mg, 0.045 mmol), PdCl2(dtbpf) (29.5 mg, 0.045 mmol), and dioxane (227 μl). The reaction mixture was degassed by evacuation and backfilling with nitrogen three times. The vial was sealed and heated to 80 °C overnight. The crude reaction mixture was concentrated under reduced pressure, dissolved in ethyl acetate, and filtered through a pad of diatomaceous earth. The filtrate was concentrated under reduced pressure. The crude material was purified by preparative LC / MS using the following conditions: column: XBridge C18, 200 mm × 19 mm, 5-μm particles; mobile phase A: 5:95 acetonitrile:water and 0.1% trifluoroacetic acid; mobile phase B: 95:5 acetonitrile:water and 0.1% trifluoroacetic acid; gradient: hold at 9% B for 0 min, 9% to 49% B over 20 min, then hold at 100% B for 0 min; flow rate: 20 mL / min; column temperature: 25 °C. Eluate fractions were collected triggered by the MS signal. The eluate fractions containing the desired product were combined and dried by centrifugal evaporation. The material was further purified by preparative LC / MS using the following conditions: column: XBridge C18, 200 mm × 19 mm, 5-μm particles; mobile phase A: 5:95 acetonitrile:water and 10-mM ammonium acetate; mobile phase B: 95:5 acetonitrile:water and 10-mM ammonium acetate; gradient: hold at 9% B for 0 min, 9% to 49% B over 20 min, then hold at 100% B for 0 min; flow rate: 20 mL / min; column temperature: 25 °C. Eluate fractions were collected triggered by the UV signal. The eluate fractions containing the desired product were combined and dried by centrifugal evaporation to give (R)-4-(10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino [5',6':4,5]thieno[3,2-f]quinolin-3-yl)-6-vinylpyridazine-3-carboxylate (0.5 mg, 0.001 mmol, 2.5% yield). MS ESIm / z 446.1 (M+H)+. HPLC RT 1.34 min Example 28: Synthesis of (R)-10-methyl-3-(2-(morpholinomethyl)-6-vinylpyridin-4-yl)-9,10,11,12-tetrahydro-8H-[1,4]diazepino And [5',6':4,5]thieno[3,2-f]quinolin-8-one Step 1: Preparation of 4-((4,6-dichloropyridin-2-yl)methyl)morpholine:

[0291] A stir bar, morpholine (49.0 μl, 0.568 mmol), 4,6-dichloropyridine-2-carbaldehyde (100 mg, 0.568 mmol), acetic acid (65.1 μl, 1.136 mmol), and DCM (2841 μl) were charged into a 20 mL reaction vial to obtain a colorless solution. The reaction mixture was stirred at room temperature for 10 minutes. Sodium triacetoxyborohydride (241 mg, 1.136 mmol) was added, and the reactants were stirred overnight at room temperature. LC / MS indicated completion of the reaction. The reaction was quenched by washing with saturated sodium bicarbonate. The suspension was diluted in DCM and the layers were separated. The aqueous layer was extracted twice more with DCM. The organic layers were combined and washed with brine. The organic phase was concentrated under reduced pressure to give 4-((4,6-dichloropyridin-2-yl)methyl)morpholine as an oil (142 mg, 0.575 mmol, 101% yield). MS ESI m / z 328.5 (M+H) + Step 2: Preparation of 4-((4-chloro-6-vinylpyridin-2-yl)methyl)morpholine:

[0292] A stir bar, potassium vinyltrifluoroborate (72 mg, 0.538 mmol), 4-((4,6-dichloropyridin-2-yl)methyl)morpholine (140 mg, 0.567 mmol), Pd(dppf)Cl2·DCM adduct (46.3 mg, 0.057 mmol), cesium carbonate (461 mg, 1.416 mmol), dioxane (2261 μl), and water (567 μl) were charged into a 20 mL reaction vial to obtain an orange suspension. The resulting mixture was degassed by bubbling nitrogen for 5 minutes and then stirred at 60 °C for 16 hours. LC-MS indicated formation of a large amount of product. The reaction mixture was concentrated under reduced pressure, diluted in ethyl acetate, and filtered through a pad of celite. The filtrate was concentrated under reduced pressure to give the crude product, which was purified by flash chromatography (0 to 100% ethyl acetate / heptane; eluting approximately 50% of the desired product). The pure fractions were combined and concentrated to give 4-((4-chloro-6-vinylpyridin-2-yl)methyl)morpholine as a clear oil (89 mg, 0.373 mmol, 66% yield).

[0293] 1 1H NMR (400 MHz, chloroform-d) δ 7.40 (s, 1H), 7.28 - 7.25 (m, 1H), 6.78 (dd, J = 17.4, 10.8 Hz, 1H), 6.22 (dd, J = 17.4, 1.0 Hz, 1H), 5.55 (dd, J = 10.9, 1.1 Hz, 1H), 3.79 - 3.76 (m, 4H), 3.67 (s, 2H), 2.56 (br s, 4H). MS ESI m / z 239.3 and 241.3 (M+H)+ Step 3: Preparation of (2-(morpholinomethyl)-6-vinylpyridin-4-yl)boronic acid:

[0294] Charge a 20 mL reaction vial with a stir bar, bis(pinacolato)diboron (62.2 mg, 0.245 mmol), 4-((4-chloro-6-vinylpyridin-2-yl)methyl)morpholine (45 mg, 0.189 mmol), potassium acetate (27.8 mg, 0.283 mmol), Pd(dppf)Cl2·DCM adduct (15.39 mg, 0.019 mmol), and dioxane (1885 μl) to obtain an orange suspension. Degas the reaction mixture by bubbling nitrogen through it for 5 minutes. Seal the vial and heat to 80 °C for 16 hours. LC MS shows that the reaction is incomplete. Add PdCl2(dtbpf) (12.29 mg, 0.019 mmol), degas the reactants by evacuation and backfilling with nitrogen three times, and heat the reactants to 80 °C for 2 hours. LC / MS indicates depletion of the starting material. Concentrate the crude product under reduced pressure and dilute in ethyl acetate and water. Separate the layers and extract the aqueous layer with ethyl acetate two more times. Wash the combined organic layers with brine and concentrate under reduced pressure to obtain (2-(morpholinomethyl)-6-vinylpyridin-4-yl)boronic acid. The product will be used as the crude reaction mixture without further separation. MS ESI m / z 249.3 (M+H) + Step 4: Preparation of (R)-10-methyl-3-(2-(morpholinomethyl)-6-vinylpyridin-4-yl)-9,10,11,12-tetrahydro-8H-[1,4]diazepino and [5',6':4,5]thieno[3,2-f]quinolin-8-one:

[0295] Charge a 4 mL reaction vial with a stir bar, (R)-3-chloro-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino And [5',6':4,5]thieno[3,2-f]quinolin-8-one (20 mg, 0.063 mmol), (2-(morpholinomethyl)-6-vinylpyridin-4-yl)boronic acid (629 μl, in the form of a crude mixture in dioxane at 0.1 M, 0.094 mmol), and PdCl2(dtbpf) (4.10 mg, 6.29 μmol) were taken to give a brown solution. Aqueous potassium phosphate (94 μl, 0.189 mmol) was added. The reaction mixture was degassed by evacuation and backfilling with nitrogen three times. The vial was sealed and heated to 100 °C for 2 hours. LCMS indicated the presence of a large amount of product. The reaction mixture was concentrated under reduced pressure. The crude material was dissolved in ethyl acetate and water. The phases were separated. The aqueous layer was extracted twice more with ethyl acetate. The combined organic layers were washed with brine and dried over sodium sulfate. Ethyl acetate was removed in vacuo. The Boc-protected crude product was dissolved in 1 ml of DCM containing 10% TFA (v / v) and stirred overnight at room temperature. The crude material was purified by preparative LC / MS using the following conditions: column: XBridge C18, 200 mm × 19 mm, 5-μm particles; mobile phase A: 5:95 acetonitrile:water and 10-mM ammonium acetate; mobile phase B: 95:5 acetonitrile:water and 10-mM ammonium acetate; gradient: held at 16% B for 0 min, 16% to 56% B over 20 min, then held at 100% B for 0 min; flow rate: 20 mL / min; column temperature: 25 °C. Eluate fractions were collected triggered by the MS signal. The fractions containing the desired product were combined and dried by centrifugal evaporation to give (R)-10-methyl-3-(2-(morpholinomethyl)-6-vinylpyridin-4-yl)-9,10,11,12-tetrahydro-8H-[1,4]diazepino And [5',6':4,5]thieno[3,2-f]quinolin-8-one (5.1 mg, 0.11 mmol, 14% yield).

[0296] 1 H NMR (500 MHz, DMSO-d6) δ 9.32 (d, J = 8.8 Hz, 1H), 8.37 (d, J = 8.9 Hz, 1H), 8.24 - 8.18 (m, 3H), 8.10 (s, 2H), 7.20 (br t, J = 5.2 Hz, 1H), 6.98 (dd, J = 17.5, 10.8 Hz, 1H), 6.42 - 6.36 (m, 1H), 5.56 (d, J = 12.1 Hz, 1H), 3.74 (s, 2H), 3.69 - 3.61 (m, 6H), 3.50 (br s, 3H), 1.22 (br d, J = 6.8 Hz, 4H). One proton was obscured by the solvent peak. MS ESI m / z 486.2 (M+H) +

[0297] Table 1: The compounds in Table 1 were prepared in a manner similar to (R)-10-methyl-3-(2-(morpholinomethyl)-6-vinylpyridin-4-yl)-9,10,11,12-tetrahydro-8H-[1,4]diazepino [5',6':4,5]thieno[3,2-f]quinolin-8-one. Example 29: Synthesis of (15R)-5-(5-chloro-2-vinyl-4-pyridyl)-15-methyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one

[0298] Step 1: Synthesis of (15R)-5-(2,5-dichloro-4-pyridyl)-15-methyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one

[0299] To a solution of (15R)-15-methyl-5-tributylstannyl-11-thia-6,14,17-triazatricyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one (1.0 g, 1.750 mmol, 1.00 equiv) and 2,5-dichloro-4-iodopyridine (478 mg, 1.750 mmol, 1.00 equiv) in 1,4-dioxane (10.0 mL) was added Pd(dppf)Cl2 (285 mg, 0.350 mmol, 0.20 equiv). The resulting mixture was stirred overnight at 90 °C under a nitrogen atmosphere. LCMS showed completion of the reaction. The resulting solution was diluted with ethyl acetate (100 mL). The solid was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using water (0.05% TFA) / MeCN (2:1) to give (15R)-5-(2,5-dichloropyridin-4-yl)-15-methyl-11-thia-6,14,17-triazatricyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one as a yellow solid (350 mg, 46%). LCMS (ESI, m / z): 429 (M+H) + 。

[0300] Step 2: Synthesis of (15R)-5-(5-chloro-2-ethenylpyridin-4-yl)-15-methyl-11-thia-6,14,17-triazatricyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one

[0301] To a solution of (15R)-5-(2,5-dichloro-4-pyridyl)-15-methyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one (85 mg, 0.200 mmol, 1.00 equiv) and tributyl(vinyl)stannane (94 mg, 0.300 mmol, 1.50 equiv) in 1,4-dioxane (10.0 mL) was added Pd(dppf)Cl2 (32 mg, 0.040 mmol, 0.20 equiv). The resulting mixture was stirred at 90 °C under a nitrogen atmosphere for 8 h. LCMS showed completion of the reaction. The resulting solution was concentrated under reduced pressure. The residue was purified by preparative HPLC using the following gradient conditions: column: SunFire Prep C18 OBD column, 19 × 150 mm, 5 μm; mobile phase A: water (0.05% TFA), mobile phase B: MeCN; flow rate: 20 mL / min; gradient: 10% B to 40% B in 6 min, 40% B; wavelength: 210 / 254 nm; RT1 (min): array. Purification gave the desired (15R)-5-(5-chloro-2-ethenyl-4-pyridyl)-15-methyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one as a yellow solid (10.4 mg, 12%). LCMS (ESI, m / z): 421 (M+H) + Analytical conditions: column: HALO C18 column 3.0 × 30 mm, 2.7 μm; mobile phase A: water / 0.05% TFA, mobile phase B: acetonitrile / 0.05% TFA; flow rate: 1.5000 mL / min; gradient: 20% B to 70% B in 1.9 min; 254 nm; Rt: 1.364 min.

[0302] 11H NMR (400 MHz, DMSO-d6) δ 9.33 (d, J = 8.8 Hz, 1H), 8.78 (s, 1H), 8.22 (d, J = 9.2 Hz, 1H), 8.14 (d, J = 4.0 Hz, 1H), 8.09 - 8.01 (m, 2H), 7.89 (s, 1H), 7.21 (s, 1H), 6.96 (dd, J = 17.6 Hz, 10.8 Hz, 1H), 6.37 (dd, J = 17.6 Hz, 1.2 Hz, 1H), 5.59 (dd, J = 10.8 Hz, 1.2 Hz, 1H), 3.64 - 3.62 (s, 1H), 3.50 - 3.40 (m, 2H), 1.20 (d, J = 6.8 Hz, 3H). 19 19F NMR (376 MHz, DMSO-d6) δ -73.89. Example 30: Synthesis of (15R)-15-methyl-5-[5-(trideuteriomethyl)-2-ethenyl-4-pyridinyl]-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one

[0303] To a solution of (15R)-5-(5-chloro-2-ethenyl-4-pyridinyl)-15-methyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one (40 mg, 0.095 mmol, 1.00 equiv), 4,4,5,5-tetramethyl-2-(trideuteriomethyl)-1,3,2-dioxaborolane (14 mg, 0.190 mmol, 2.00 equiv) and K2CO3 (26 mg, 0.190 mmol, 2.00 equiv) in 1,4-dioxane (2.0 mL) and water (0.2 mL) was added Pd(dtbpf)Cl2 (15 mg, 0.019 mmol, 0.10 equiv). The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 3 h. LCMS showed completion of the reaction. The resulting solution was diluted with DMSO (3 mL). The solid was filtered off. The filtrate was purified by preparative HPLC using the following gradient conditions: column: Welch Utimate HS-C18, 21.2×250 mm, 7 μm; mobile phase A: water (0.05% TFA), mobile phase B: MeCN; flow rate: 25 mL / min; gradient: 15% B to 35% B in 6.3 min, hold at 35% B; wavelength: 254 / 210 nm; RT1 (min): 5.56. Purification gave the desired (15R)-15-methyl-5-[5-(trideuteriomethyl)-2-ethenyl-4-pyridinyl]-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one as a yellow solid (1.1 mg, 3%). LCMS (ESI, m / z): 404 (M+H) + Analytical conditions: column: HALO C18 column 3.0×30 mm, 2.7 μm; mobile phase A: water / 0.05% TFA, mobile phase B: acetonitrile / 0.05% TFA; flow rate: 1.5000 mL / min; gradient: 5% B to 60% B in 1.8 min; 254 nm; Rt: 1.249 min.

[0304] 11H NMR (400 MHz, DMSO-d6) δ 9.31 (d, J = 8.8 Hz, 1H), 8.59 (s, 1H), 8.19 (d, J = 8.8 Hz, 1H), 8.12 (d, J = 4.0 Hz, 1H), 8.03 (d, J = 8.8 Hz, 1H), 7.95 (d, J = 8.8 Hz, 1H), 7.74 (s, 1H), 7.20 (s, 1H), 6.93 (dd, J = 17.6 Hz, 11.2 Hz, 1H), 6.32 (d, J = 17.6 Hz, 1H), 5.52 (d, J = 11.2 Hz, 1H), 3.60 - 3.40 (m, 3H), 1.20 (d, J = 6.8 Hz, 3H). 19 19F NMR (376 MHz, DMSO-d6) δ -73.99. Example 31: Synthesis of (15R)-15-methyl-5-[5-(morpholinomethyl)-2-ethenyl-4-pyridinyl]-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one

[0305] Step 1: Synthesis of 4-[(4-bromo-6-chloro-3-pyridinyl)methyl]morpholine

[0306] To a solution of 4-bromo-6-chloro-pyridine-3-carbaldehyde (100 mg, 0.450 mmol, 1.00 equiv) in methanol (5.0 mL) was added morpholine (79 mg, 0.910 mmol, 2.00 equiv). The resulting mixture was stirred at room temperature for 0.5 h. Subsequently, NaBH3CN (116 mg, 1.81 mmol, 4.00 equiv) was added to the resulting mixture and stirred overnight at room temperature. LCMS showed the reaction was complete. The resulting solution was diluted with water (20 mL) and extracted with ethyl acetate (3 × 20 mL). The organic layer was washed with brine (2 × 20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using ethyl acetate / petroleum ether (1:2) to give 4-[(4-bromo-6-chloro-3-pyridinyl)methyl]morpholine as a white solid (80 mg, 60%). LCMS (ESI, m / z): 291 and 293 [M+H] + .

[0307] Step 2: Synthesis of (15R)-5-[2-chloro-5-(morpholinomethyl)-4-pyridinyl]-15-methyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one

[0308] To a solution of 4-[(4-bromo-6-chloro-3-pyridinyl)methyl]morpholine (60 mg, 0.210 mmol, 1.00 equiv) and (15R)-15-methyl-5-tributylstannyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one (141 mg, 0.250 mmol, 1.20 equiv) in 1,4-dioxane (2.0 mL) was added Pd(PPh3)4 (23 mg, 0.020 mmol, 0.10 equiv). The resulting mixture was stirred overnight at 110 °C under a nitrogen atmosphere. LCMS showed completion of the reaction. The resulting solution was diluted with ethyl acetate (10 mL). The solid was collected by filtration and washed with ethyl acetate (2 × 5 mL). The solid was dried to give (15R)-5-[2-chloro-5-(morpholinomethyl)-4-pyridinyl]-15-methyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one as a yellow solid (80 mg, 78%). LCMS (ESI, m / z): 494 [M+H] + 。

[0309] Step 3: Synthesis of (15R)-15-methyl-5-[5-(morpholinomethyl)-2-ethenyl-4-pyridinyl]-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one

[0310] To a solution of (15R)-5-[2-chloro-5-(morpholinomethyl)-4-pyridinyl]-15-methyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one (40 mg, mmol, 1.00 equiv) and tributyl(vinyl)stannane (30 mg, 0.100 mmol, 1.20 equiv) in 1,4-dioxane (5.0 mL) was added Pd(PPh3)4 (7 mg, 0.010 mmol, 0.10 equiv). The resulting mixture was stirred overnight at 100 °C under a nitrogen atmosphere. LCMS showed completion of the reaction. The resulting solution was concentrated under reduced pressure and the residue was purified by preparative HPLC using the following gradient conditions: column: X Bridge Prep C18 OBD column, 19×150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: MeCN; flow rate: 20 mL / min; gradient: 25% B to 27% B in 6 min, 27% B; wavelength: 254 nm; RT1 (min): 4.55. Purification gave the desired (15R)-15-methyl-5-[5-(morpholinomethyl)-2-ethenyl-4-pyridinyl]-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one (3.8 mg, 9%) as an orange solid. LCMS (ESI, m / z): 486 [M+H] + . Analytical conditions: column: HALO C18 100A column 3.0×33 mm, 3 μm; mobile phase A: water / 5 mM NH4HCO3, mobile phase B: MeCN / 0.05% TFA; flow rate: 1.5000 mL / min; gradient: 10% B to 95% B in 1.20 min; 254 nm; Rt: 0.880 min.

[0311] 11H NMR (400 MHz, DMSO-d6) δ 9.44 (d, J = 9.2 Hz, 1H), 8.85 (s, 1H), 8.29 (d, J = 8.8 Hz, 1H), 8.25 (d, J = 8.8 Hz, 1H), 8.17 (d, J = 3.2 Hz, 1H), 8.03 (d, J = 9.2 Hz, 1H), 7.99 (d, J = 8.8 Hz, 1H), 7.27 (s, 1H), 7.03 (dd, J = 17.2, 10.4 Hz, 1H), 6.48 (d, J = 17.6 Hz, 1H), 5.67 (d, J = 10.8 Hz, 1H), 4.64 (s, 2H), 4.10 - 3.90 (m, 3H), 3.80 - 3.62 (m, 4H), 3.56 - 3.45 (m, 4H), 1.21 (d, J = 6.8 Hz, 3H). 19 19F NMR (376 MHz, DMSO-d6) δ -73.83 Example 32: Synthesis of (15R)-5-[2-Ethynyl-5-(morpholinomethyl)-4-pyridinyl]-15-methyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one

[0312] Step 1: Synthesis of (15R)-15-Methyl-5-[5-(morpholinomethyl)-2-(2-trimethylsilylethynyl)-4-pyridinyl]-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one

[0313] To a solution of (15R)-5-[2-chloro-5-(morpholinomethyl)-4-pyridinyl]-15-methyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one (50 mg, 0.100 mmol, 1.00 equiv) and trimethyl(2-tributylstannylethynyl)silane (78.39 mg, 0.200 mmol, 2.00 equiv) in 1,4-dioxane (2.0 mL) was added Pd(PPh3)4 (11 mg, 0.010 mmol, 0.10 equiv). The resulting mixture was stirred overnight at 100 °C under a nitrogen atmosphere. LCMS showed completion of the reaction. The resulting solution was diluted with ethyl acetate (10 mL). The solid was collected by filtration and washed with ethyl acetate (3 × 50 mL). The solid was dried to give (15R)-15-methyl-5-[5-(morpholinomethyl)-2-(2-trimethylsilylethynyl)-4-pyridinyl]-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one (35 mg, 62%) as a yellow solid. LCMS (ESI, m / z): 556 [M+H] + 。

[0314] Step 2: Synthesis of (15R)-5-[2-ethynyl-5-(morpholinomethyl)-4-pyridinyl]-15-methyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one

[0315] To a solution of (15R)-15-methyl-5-[5-(morpholinomethyl)-2-(2-trimethylsilylethynyl)-4-pyridinyl]-11-thia-6,14,17-triazatricyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one (30 mg, 0.050 mmol, 1.00 equiv) in methanol (2.0 mL) was added K2CO3 (22 mg, 0.160 mmol, 3.00 equiv). The resulting mixture was stirred at room temperature for 30 min. LCMS showed completion of the reaction. The resulting solution was diluted with DMSO (2.0 mL). The solid was filtered off and the filtrate was purified by preparative HPLC using the following gradient conditions: column: XBridge Prep OBD C18 column, 30×150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: MeCN; flow rate: 20 mL / min; gradient: 35% B to 52% B in 4.7 min, 52% B; wavelength: 254 nm; RT1 (min): 4.58. Purification gave the desired (15R)-5-[2-ethynyl-5-(morpholinomethyl)-4-pyridinyl]-15-methyl-11-thia-6,14,17-triazatricyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one as a yellow solid (6.1 mg, 22%). LCMS (ESI, m / z): 484 [M+H] + . Analytical conditions: column: HALO C18 100A column 3.0×33 mm, 3.0 μm; mobile phase A: water / 5 mM NH4HCO3, mobile phase B: acetonitrile / 0.05% TFA; flow rate: 1.5000 mL / min; gradient: 10% B to 95% B in 1.20 min; 254 nm; Rt: 0.856 min.

[0316] 1H NMR (400MHz, DMSO-d6) δ9.28(d,J=8.8Hz,1H),8.72(s,1H),8.19(d,J=8.8Hz,1H),8.13(d,J=5.6Hz,1H),8.0 5(d,J=8.8Hz,1H),8.01(d,J=9.2Hz,1H),7.77(s,1H),7.18(t,J=5.2Hz,1H),4.41(s,1H),3.76(s,2H),3.65 -3.61(m,1H),3.55-3.45(m,2H),3.33 -3.31(m,4H),2.22(s,4H),1.21(d,J=6.8Hz,3H). Example 33: (R)-3-(5-((4-methoxypiperidin-1-yl)methyl)-2-vinylpyridin-4-yl)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepine Synthesis of 5',6':4,5'-thieno[3,2-f]quinolin-8-one Step 1: Synthesis of 4-((4,6-dichloropyridin-2-yl)methyl)morpholine:

[0317] A stirring bar, morpholine (49.0 μl, 0.568 mmol), 4,6-dichloropyridinecarboxaldehyde (100 mg, 0.568 mmol), acetic acid (65.1 μl, 1.136 mmol) and DCM (2841 μl) were loaded into a 20 mL reaction vial to give a colorless solution. The reaction mixture was stirred at room temperature for 10 minutes. Sodium triacetoxyborohydride (241 mg, 1.136 mmol) was added and the reactant was stirred at room temperature overnight. LC / MS indicated that the reaction was complete. The reactant was quenched by washing with saturated sodium bicarbonate. The suspension was diluted in DCM and the layers were separated. The aqueous layer was extracted twice with DCM. The organic layers were combined and washed with brine. The organic phase was concentrated under reduced pressure to give 4-((4,6-dichloropyridin-2-yl)methyl)morpholine (142 mg, 0.575 mmol, 101% yield) in an oily state. MS ESI m / z 328.5 (M+H) + Step 2: Synthesis of 4-((4-chloro-6-vinylpyridin-2-yl)methyl)morpholine:

[0318] A magnetic stir bar, potassium vinyltrifluoroborate (72 mg, 0.538 mmol), 4-((4,6-dichloropyridin-2-yl)methyl)morpholine (140 mg, 0.567 mmol), Pd(dppf)Cl2·DCM adduct (46.3 mg, 0.057 mmol), cesium carbonate (461 mg, 1.416 mmol), dioxane (2261 μl) and water (567 μl) were charged into a 20 mL reaction vial to give an orange suspension. The resulting mixture was degassed by bubbling nitrogen for 5 min and then stirred at 60 °C for 16 h. LC MS indicated formation of a major product. The reaction mixture was concentrated under reduced pressure, diluted in ethyl acetate and filtered through a pad of Celite. The filtrate was concentrated under reduced pressure to give the crude product, which was purified by flash chromatography (0 to 100% ethyl acetate / heptane; elution of approximately 50% of the desired product). The pure fractions were combined and concentrated to give 4-((4-chloro-6-vinylpyridin-2-yl)methyl)morpholine as a clear oil (89 mg, 0.373 mmol, 66% yield).

[0319] 1 H NMR (400 MHz, chloroform-d) δ 7.40 (s, 1H), 7.28 - 7.25 (m, 1H), 6.78 (dd, J = 17.4, 10.8 Hz, 1H), 6.22 (dd, J = 17.4, 1.0 Hz, 1H), 5.55 (dd, J = 10.9, 1.1 Hz, 1H), 3.79 - 3.76 (m, 4H), 3.67 (s, 2H), 2.56 (br s, 4H). MS ESI m / z 239.3 and 241.3 (M + H) + Step 3: Synthesis of (2-(morpholinomethyl)-6-vinylpyridin-4-yl)boronic acid:

[0320] Into a 20mL reaction vial was charged a stirring bar, bis(pinacolato)diboron (62.2mg, 0.245mmol), 4-((4-chloro-6-vinylpyridin-2-yl)methyl)morpholine (45mg, 0.189mmol), potassium acetate (27.8mg, 0.283mmol), Pd(dppf)Cl , DCM adduct (15.39mg, 0.019mmol) and dioxane (1885μl) to give an orange suspension. The reaction mixture was degassed for 5 minutes by bubbling with nitrogen. The vial was sealed and heated to 80°C for 16 hours. LCMS showed that the reaction was incomplete. PdCl (dtbpf) (12.29mg, 0.019mmol) was added, the reactants were degassed by evacuating and backfilling 3 times with nitrogen, and the reactants were heated to 80°C for 2 hours. LC / MS indicated that the starting material was exhausted. The crude product was concentrated under reduced pressure and diluted in ethyl acetate and water. The layers were separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic layer was washed with salt water and concentrated under reduced pressure to give (2-(morpholinomethyl)-6-vinylpyridine-4-yl)boronic acid. The product was used as a crude reaction mixture without further separation. MS ESI m / z 249.3 (M+H) + Step 4: (R)-3-(5-((4-methoxypiperidin-1-yl)methyl)-2-vinylpyridin-4-yl)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepine Synthesis of 5',6':4,5'-thieno[3,2-f]quinolin-8-one:

[0321] A 4 mL reaction vial was charged with a stir bar containing (R)-10-methyl-3-(tributylstannyl)-9,10,11,12-tetrahydro-8H-[1,4]diazepine And [5',6':4,5]thieno[3,2-f]quinolin-8-one (506 μl, 0.101 mmol), 4-chloro-5-((4-methoxypiperidin-1-yl)methyl)-2-vinylpyridine (27 mg, 0.101 mmol) and tetrakis(11.70 mg, 10.12 μmol) of tetrakis(11.70 mg, 10.12 μmol) to obtain a yellow solution. The reaction mixture was degassed by evacuating and backfilling with nitrogen three times. The vial was sealed and heated to 100 °C for 16 hours. LC MS indicated the presence of a large amount of product. The reaction mixture was concentrated under reduced pressure. The crude material was dissolved in ethyl acetate and water. The phases were separated. The aqueous layer was extracted twice more with ethyl acetate. The ethyl acetate was removed in vacuo. The crude material was purified by preparative LC / MS using the following conditions: column: XBridge C18, 200 mm × 19 mm, 5-μm particles; mobile phase A: 5:95 acetonitrile:water and 10-mM ammonium acetate; mobile phase B: 95:5 acetonitrile:water and 10-mM ammonium acetate; gradient: hold at 11% B for 0 minutes, 11% to 51% B over 20 minutes, then hold at 100% B for 0 minutes; flow rate: 20 mL / min; column temperature: 25 °C. Fractions were collected by triggering on the MS signal. The fractions containing the desired product were combined and dried by centrifugal evaporation to give (R)-3-(5-((4-methoxypiperidin-1-yl)methyl)-2-vinylpyridin-4-yl)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino [5',6':4,5]thieno[3,2-f]quinolin-8-one (0.9 mg, 0.002 mmol, 2% yield). HPLC retention time (TFA / AA): 1.23 m / 1.32 m. MS ESI m / z 514.2 (M+H) +

[0322] Table 2: The compounds in Table 2 were prepared in a manner similar to (R)-3-(5-((4-methoxypiperidin-1-yl)methyl)-2-vinylpyridin-4-yl)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino [5',6':4,5]thieno[3,2-f]quinolin-8-one. Example 34: Synthesis of (15R)-15-methyl-5-(2-morpholino-6-ethenyl-4-pyridyl)-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one

[0323] Step 1: Synthesis of (15R)-5-(2-chloro-6-morpholino-4-pyridyl)-15-methyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one

[0324] Morpholine (203 mg, 2.330 mmol, 5.00 equivalents) was added to a solution of (15R)-5-(2,6-dichloro-4-pyridyl)-15-methyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one (200 mg, 0.470 mmol, 1.00 equivalent) and K2CO3 (193 mg, 1.400 mmol, 3.00 equivalents) in DMF (5.0 mL). The resulting mixture was stirred overnight at 100 °C under a nitrogen atmosphere. LCMS showed that the reaction was complete. The resulting solution was diluted with water (50 mL) and extracted with dichloromethane (3 × 50 mL). The combined organic layers were washed with brine (2 × 20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 100 mg of the crude product. The crude product was used directly in the next step without further purification. LCMS (ESI, m / z): 480 (M+H) + 。

[0325] Step 2: Synthesis of (15R)-5-(2-chloro-6-morpholino-4-pyridyl)-15-methyl-13-oxo-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaene-14,17-dicarboxylic acid di-tert-butyl ester

[0326] To a solution of (15R)-5-(2-chloro-6-morpholino-4-pyridyl)-15-methyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one (100 mg, 0.210 mmol, 1.00 equiv) and Boc2O (182 mg, 0.830 mmol, 4.00 equiv) in 1,4-dioxane (5.0 mL) was added DMAP (3 mg, 0.020 mmol, 0.10 equiv). The resulting mixture was stirred at 60 °C under a nitrogen atmosphere for 2 h. LCMS showed completion of the reaction. The resulting solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography using dichloromethane / ethyl acetate (1:1) to give (15R)-5-(2-chloro-6-morpholino-4-pyridyl)-15-methyl-13-oxo-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaene-14,17-dicarboxylic acid di-tert-butyl ester (50 mg, 35%) as a yellow solid. LCMS (ESI, m / z): 680 (M+H) + 。

[0327] Step 3: Synthesis of (15R)-15-methyl-5-(2-morpholino-6-vinyl-4-pyridyl)-13-oxo-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaene-14,17-dicarboxylic acid di-tert-butyl ester

[0328] To a solution of di-tert-butyl (15R)-5-(2-chloro-6-morpholino-4-pyridyl)-15-methyl-13-oxo-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaene-14,17-dicarboxylate (50 mg, 0.070 mmol, 1.00 equiv) and tributyl(vinyl)stannane (35 mg, 0.110 mmol, 1.50 equiv) in 1,4-dioxane (1.0 mL) was added Pd(PPh3)4 (8 mg, 0.010 mmol, 0.10 equiv). The resulting mixture was stirred at 90 °C under a nitrogen atmosphere for 3 h. LCMS showed completion of the reaction. The resulting solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using dichloromethane / ethyl acetate (1:1) to afford di-tert-butyl (15R)-15-methyl-5-(2-morpholino-6-vinyl-4-pyridyl)-13-oxo-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaene-14,17-dicarboxylate (20 mg, 41%) as a yellow solid. LCMS (ESI, m / z): 672 (M+H) + 。

[0329] Step 4: Synthesis of (15R)-15-methyl-5-(2-morpholino-6-vinyl-4-pyridyl)-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one

[0330] To a solution of di-tert-butyl (15R)-15-methyl-5-(2-morpholino-6-ethenyl-4-pyridinyl)-13-oxo-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaene-14,17-dicarboxylate (20 mg, 0.030 mmol, 1.00 equiv) in DCM (1.0 mL) was added dropwise TFA (0.2 mL). The resulting mixture was stirred at room temperature for 1 h. LCMS showed completion of the reaction. The resulting solution was concentrated under reduced pressure. The residue was purified by preparative HPLC using the following gradient: column: Xselect CSH C18 OBD column 30×150 mm 5 μm; mobile phase A: water (0.05% TFA), mobile phase B: MeCN; flow rate: 60 mL / min; gradient: 26% B to 56% B in 10 min, 56% B; wavelength: 254 nm; RT1 (min): 5.17. Purification gave the desired (15R)-15-methyl-5-(2-morpholino-6-ethenyl-4-pyridinyl)-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one (3.3 mg, 23%) as an orange solid. LCMS (ESI, m / z): 472 (M+H) + Analytical conditions: column: HALO AQ-C18 100A column 3.0×30 mm, 2.0 μm; mobile phase A: water / 0.05% TFA, mobile phase B: acetonitrile / 0.05% TFA; flow rate: 1.2000 mL / min; gradient: 20% B to 70% B in 2.10 min; 254 nm; Rt: 1.299 min.

[0331] 11H NMR (400 MHz, DMSO-d6) δ 9.28 (d, J = 8.8 Hz, 1H), 8.36 (d, J = 8.8 Hz, 1H), 8.18 (d, J = 9.2 Hz, 1H), 8.13 (d, J = 4.4 Hz, 1H), 8.07 (d, J = 8.8 Hz, 1H), 7.62 (d, J = 12.4 Hz, 2H), 7.23 (s, 1H), 6.86 (dd, J = 17.2, 10.8 Hz, 1H), 6.32 (dd, J = 17.2, 2.0 Hz, 1H), 5.47 (dd, J = 10.8, 2.0 Hz, 1H), 3.78 (t, J = 4.8 Hz, 4H), 3.80 - 3.70 (m, 1H), 3.64 (t, J = 4.8 Hz, 4H), 3.66 - 3.63 (m, 4H), 3.49 (s, 2H), 1.21 (d, J = 6.4 Hz, 3H). 19 19F NMR (376 MHz, DMSO-d6) δ -74.70 Example 35: Synthesis of (15R)-5-[2-Ethynyl-6-(4-methoxy-1-piperidinyl)-4-pyridinyl]-15-methyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one

[0332] Step 1: Synthesis of Di-tert-butyl (15R)-5-[2-(4-methoxy-1-piperidinyl)-6-(2-trimethylsilylethynyl)-4-pyridinyl]-15-methyl-13-oxo-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaene-14,17-dicarboxylate

[0333] To a solution of di-tert-butyl (15R)-5-[2-chloro-6-(4-methoxy-1-piperidinyl)-4-pyridinyl]-15-methyl-13-oxo-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaene-14,17-dicarboxylate (50 mg, 0.070 mmol, 1.00 equiv) and trimethyl(2-tributylstannylethynyl)silane (41 mg, 0.110 mmol, 1.50 equiv) in 1,4-dioxane (2.0 mL) was added Pd(PPh3)4 (8 mg, 0.010 mmol, 0.10 equiv). The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 6 h. LCMS showed completion of the reaction. The resulting solution was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using ethyl acetate / petroleum ether (2:1) to afford di-tert-butyl (15R)-5-[2-(4-methoxy-1-piperidinyl)-6-(2-trimethylsilylethynyl)-4-pyridinyl]-15-methyl-13-oxo-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaene-14,17-dicarboxylate (50 mg, 92%) as a brown solid. LCMS (ESI, m / z): 771 (M+H) + 。

[0334] Step 2: Synthesis of (15R)-5-[2-ethynyl-6-(4-methoxy-1-piperidinyl)-4-pyridinyl]-15-methyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one

[0335] To a solution of di-tert-butyl (15R)-5-[2-(4-methoxypiperidin-1-yl)-6-(2-trimethylsilylethynyl)-4-pyridinyl]-15-methyl-13-oxo-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaene-14,17-dicarboxylate (50 mg, 0.060 mmol, 1.00 equiv) in DCM (2.5 mL) was added dropwise TFA (0.5 mL). The mixture was stirred at room temperature for 2 h. LCMS showed completion of the reaction. The resulting solution was concentrated under reduced pressure. The residue was dissolved in MeOH (2.0 mL), and K2CO3 (11 mg, 0.080 mmol, 1.50 equiv) was added. The resulting mixture was stirred at room temperature for 2 h. LCMS showed completion of the reaction. The resulting solution was diluted with DMSO (3 mL). The solid was filtered off. The filtrate was purified by preparative HPLC using the following gradient conditions: column: SunFire Prep C18 OBD column, 19×150 mm, 5 μm; mobile phase A: water (0.05% TFA), mobile phase B: MeCN; flow rate: 20 mL / min; gradient: 50% B to 50% B in 6 min, 50% B; wavelength: 254 nm; RT1 (min): 5.12. Purification gave the desired (15R)-5-[2-ethynyl-6-(4-methoxypiperidin-1-yl)-4-pyridinyl]-15-methyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one as an orange solid (9.0 mg, 33%). LCMS (ESI, m / z): 498 (M+H) + Analytical conditions: column: HALO AQ-C18 100A column 3.0×30 mm, 2.0 μm; mobile phase A: water / 0.05% TFA, mobile phase B: acetonitrile / 0.05% TFA; flow rate: 1.2000 mL / min; gradient: 5% B to 100% B in 1.30 min; 254 nm; Rt: 1.196 min.

[0336] 11H NMR (400 MHz, DMSO-d6) δ 9.27 (d, J = 8.8 Hz, 1H), 8.37 (d, J = 8.8 Hz, 1H), 8.18 (d, J = 8.8 Hz, 1H), 8.12 - 8.03 (m, 2H), 7.71 (s, 1H), 7.68 (s, 1H), 7.19 (s, 1H), 4.23 (s, 1H), 4.11 - 4.03 (m, 2H), 3.55 - 3.42 (m, 4H), 3.33 - 3.28 (m, 5H), 2.02 - 1.89 (m, 2H), 1.54 - 1.42 (m, 2H), 1.21 (d, J = 6.8 Hz, 3H). 19 19F NMR (376 MHz, DMSO-d6) δ -74.63 Example 36: Synthesis of (15R)-5-[2-ethynyl-6-(morpholinomethyl)-4-pyridyl]-15-methyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one

[0337] Step 1: Synthesis of methyl (4-bromo-6-chloro-2-pyridyl)methanesulfonate

[0338] At 0 °C under a nitrogen atmosphere, methanesulfonyl chloride (185 mg, 1.620 mmol, 1.50 equiv) was added dropwise to a solution of (4-bromo-6-chloro-2-pyridyl)methanol (300 mg, 1.350 mmol, 1.00 equiv) and TEA (0.7 mL, 4.050 mmol, 3.00 equiv) in DCM (15.0 mL). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 h. LCMS showed completion of the reaction. The resulting solution was diluted with water (50 mL) and extracted with dichloromethane (2 × 70 mL). The combined organic layers were washed with brine (2 × 30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product methyl (4-bromo-6-chloro-2-pyridyl)methanesulfonate (350 mg, 87%). The crude product was used directly in the next step without further purification. LCMS (ESI, m / z): 300 (M+H) + .

[0339] Step 2: Synthesis of 4-[(4-bromo-6-chloro-2-pyridyl)methyl]morpholine

[0340] To a solution of 4-bromo-6-chloro-2-pyridyl)methyl methanesulfonate (300 mg, 1.000 mmol, 1.00 equiv) and K2CO3 (413 mg, 2.990 mmol, 3.00 equiv) in MeCN (10.0 mL) was added dropwise morpholine (130 mg, 1.500 mmol, 1.50 equiv). The resulting mixture was stirred at room temperature for 2 h. LCMS showed completion of the reaction. The resulting solution was diluted with ethyl acetate (30 mL). The solid was filtered off. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate (1:5) to give 4-[(4-bromo-6-chloro-2-pyridyl)methyl]morpholine as a pale yellow solid (280 mg, 96%). LCMS (ESI, m / z): 291 (M+H) + .

[0341] Step 3: Synthesis of (15R)-5-[2-chloro-6-(morpholinomethyl)-4-pyridyl]-15-methyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one

[0342] To a solution of 4-[(4-bromo-6-chloro-2-pyridinyl)methyl]morpholine (100 mg, 0.340 mmol, 1.00 equiv) and (15R)-15-methyl-5-tributylstannyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one (235 mg, 0.410 mmol, 1.20 equiv) in 1,4-dioxane (4.0 mL) was added P(o-Tol.)3 (21 mg, 0.070 mmol, 0.20 equiv) and Pd2(dba)3 (63 mg, 0.070 mmol). The resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 2 h. LCMS showed completion of the reaction. The resulting solution was diluted with water (20 mL) and extracted with ethyl acetate (2 × 30 mL). The combined organic layers were washed with brine (2 × 20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using water (0.05% TFA) / MeCN (1:1) to afford (15R)-5-[2-chloro-6-(morpholinomethyl)-4-pyridinyl]-15-methyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one (110 mg, 65%) as a pale yellow solid. LCMS (ESI, m / z): 494 (M+H) + 。

[0343] Step 4: Synthesis of (15R)-15-methyl-5-[2-(morpholinomethyl)-6-(2-trimethylsilylethynyl)-4-pyridinyl]-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one

[0344] To a solution of (15R)-5-[2-chloro-6-(morpholinomethyl)-4-pyridinyl]-15-methyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one (70 mg, 0.140 mmol, 1.00 equiv) and trimethyl(2-tributylstannylethynyl)silane (274 mg, 0.710 mmol, 5.00 equiv) in 1,4-dioxane (2.0 mL) was added Pd(PPh3)4 (24 mg, 0.030 mmol, 0.20 equiv). The resulting solution was stirred at 80 °C under a nitrogen atmosphere for 2 h. LCMS showed completion of the reaction. The resulting solution was diluted with water (20 mL) and extracted with ethyl acetate (2 × 20 mL). The combined organic layers were washed with brine (2 × 20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using water (0.05% TFA) / MeCN (1:2) to give (15R)-15-methyl-5-[2-(morpholinomethyl)-6-(2-trimethylsilylethynyl)-4-pyridinyl]-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one (50 mg, 63%) as a pale yellow solid. LCMS (ESI, m / z): 556 (M+H) + 。

[0345] Step 5: Synthesis of (15R)-5-[2-ethynyl-6-(morpholinomethyl)-4-pyridinyl]-15-methyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one

[0346] To a solution of (15R)-15-methyl-5-[2-(morpholinomethyl)-6-(2-trimethylsilylethynyl)-4-pyridinyl]-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one (50 mg, 0.090 mmol, 1.00 equiv) in methanol (1.0 mL) was added K2CO3 (37 mg, 0.270 mmol, 3.00 equiv). The resulting solution was stirred at room temperature for 1 h. LCMS showed completion of the reaction. The resulting solution was diluted with DMSO (3 mL). The solid was filtered off. The filtrate was purified by preparative HPLC using the following conditions: column: SunFire Prep C18 OBD column, 19×150 mm, 5 μm; mobile phase A: water (0.05% TFA), mobile phase B: MeCN; flow rate: 20 mL / min; gradient: 20% B to 35% B in 6 min, 35% B; wavelength: 254 nm; RT1 (min): 4.98. Purification gave the desired (15R)-5-[2-ethynyl-6-(morpholinomethyl)-4-pyridinyl]-15-methyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one as a yellow solid (21.1 mg, 48%). LCMS (ESI, m / z): 484 [M+H] + . Analytical conditions: column: HALO C18 100A column 3.0×30 mm, 2.0 μm; mobile phase A: water / 0.05% TFA, mobile phase B: acetonitrile / 0.05% TFA; flow rate: 1.2000 mL / min; gradient: 5% B to 100% B in 1.30 min; 254 nm; Rt: 0.968 min.

[0347] 1 H NMR (400 MHz, DMSO-d6) δ 10.47 (s, 1H), 9.35 (d, J = 9.2 Hz, 1H), 8.53 (d, J = 8.8 Hz, 1H), 8.46 (d, J = 8.8 Hz, 1H), 8.24 (d, J = 8.8 Hz, 1H), 8.15 (d, J = 4.0 Hz, 1H), 8.07 (d, J = 8.8 Hz, 1H), 7.22 (t, J = 4.4 Hz, 1H), 4.65 (s, 2H), 4.61 (s, 1H), 4.12 - 3.78 (m, 5H), 3.71 - 3.51 (m, 6H), 1.21 (d, J = 6.8 Hz, 3H). 1919F NMR (376 MHz, DMSO-d6) δ -73.80. Example 37: Synthesis of (15R)-15-methyl-5-[2-[[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl]-6-vinyl-4-pyridinyl]-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one

[0348] Step 1: Synthesis of methyl (4-bromo-6-chloro-2-pyridinyl) methanesulfonate

[0349] To a solution of (4-bromo-6-chloro-2-pyridinyl)methanol (300 mg, 1.350 mmol, 1.00 equiv) and TEA (0.7 mL, 4.050 mmol, 3.00 equiv) in DCM (15.0 mL) at 0 °C was added dropwise methanesulfonyl chloride (185 mg, 1.620 mmol, 1.50 equiv). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 h. LCMS showed completion of the reaction. The resulting solution was diluted with water (50 mL) and extracted with dichloromethane (2 × 50 mL). The combined organic layers were washed with brine (2 × 30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product methyl (4-bromo-6-chloro-2-pyridinyl) methanesulfonate (350 mg, 87%). The crude product was used directly in the next step without further purification. LCMS (ESI, m / z): 300 (M+H) + .

[0350] Step 2: Synthesis of (2R,6S)-4-[(4-bromo-6-chloro-2-pyridinyl)methyl]-2,6-dimethyl-morpholine

[0351] To a solution of methyl (4-bromo-6-chloro-2-pyridyl)methanesulfonate (100 mg, 0.330 mmol, 1.00 equiv) and K2CO3 (137 mg, 1.000 mmol, 3.00 equiv) in MeCN (3.0 mL) was added (2S,6R)-2,6-dimethylmorpholine (38 mg, 0.330 mmol, 1.00 equiv). The mixture was stirred for 1 h at room temperature under a nitrogen atmosphere. LCMS showed completion of the reaction. The resulting solution was diluted with ethyl acetate (30 mL). The solid was filtered off. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography using ethyl acetate to give (2R,6S)-4-[(4-bromo-6-chloro-2-pyridyl)methyl]-2,6-dimethylmorpholine as a yellow solid (80 mg, 75%). LCMS (ESI, m / z): 319 (M+H) + .

[0352] Step 3: Synthesis of (15R)-5-[2-chloro-6-[[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl]-4-pyridyl]-15-methyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one

[0353] To a solution of (2R,6S)-4-[(4-bromo-6-chloro-2-pyridinyl)methyl]-2,6-dimethyl-morpholine (100 mg, 0.310 mmol, 1.00 equiv) and (15R)-15-methyl-5-tributylstannyl-11-thia-6,14,17-triazatricyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one (215 mg, 0.380 mmol, 1.20 equiv) in 1,4-dioxane (5.0 mL) was added P(o-Tol.)3 (19 mg, 0.060 mmol, 0.20 equiv) and Pd2(dba)3 (57 mg, 0.060 mmol, 0.20 equiv). The resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 2 h. LCMS showed completion of the reaction. The resulting solution was diluted with water (20 mL) and extracted with ethyl acetate (2 × 20 mL). The combined organic layers were washed with brine (2 × 20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification of the residue by reverse-phase flash chromatography using water (0.05% TFA) / MeCN (1:2) afforded (15R)-5-[2-chloro-6-[[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl]-4-pyridinyl]-15-methyl-11-thia-6,14,17-triazatricyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one (120 mg, 73%) as a pale yellow solid. LCMS (ESI, m / z): 522 (M+H) + 。

[0354] Step 4: Synthesis of (15R)-15-methyl-5-[2-[[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl]-6-ethenyl-4-pyridinyl]-11-thia-6,14,17-triazatricyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one

[0355] Racemic-(15R)-5-[2-chloro-6-[[racemic-(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl]-4-pyridinyl]-15-methyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one (60 mg, 0.110 mmol, 1.00 equiv) and tributyl(vinyl)stannane (182 mg, 0.5700 mmol, 5.00 equiv) were added to a solution of Pd(PPh3)4 (27 mg, 0.020 mmol, 0.20 equiv) in 1,4-dioxane (2.0 mL). The resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 2 h. LCMS showed completion of the reaction. The resulting solution was concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions: column: SunFire Prep C18 OBD column, 19 × 150 mm, 5 μm; mobile phase A: water (0.05% TFA), mobile phase B: MeCN; flow rate: 20 mL / min; gradient: 28% B to 32% B, 32% B in 6 min; wavelength: 254 nm; RT1 (min): 6.15. Purification gave the desired (15R)-15-methyl-5-[2-[[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl]-6-vinyl-4-pyridinyl]-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one (34.1 mg, 56%) as a pale yellow solid. LCMS (ESI, m / z): 514 [M+H] + . Analytical conditions: column: HALO C18 100A column 3.0 × 30 mm, 2.0 μm; mobile phase A: water / 0.05% TFA, mobile phase B: acetonitrile / 0.05% TFA; flow rate: 1.2000 mL / min; gradient: 5% B to 60% B in 2.10 min; 254 nm; Rt: 1.730 min.

[0356] 11H NMR (400 MHz, DMSO-d6) δ 9.35 (d, J = 8.8 Hz, 1H), 8.45 (s, 1H), 8.43 (d, J = 9.2 Hz, 1H), 8.35 (s, 1H), 8.23 (d, J = 8.8 Hz, 1H), 8.15 (d, J = 4.4 Hz, 1H), 8.07 (d, J = 9.2 Hz, 1H), 7.22 (t, J = 4.4 Hz, 1H), 7.07 (dd, J = 17.6, 10.8 Hz, 1H), 6.52 (dd, J = 17.6, 1.2 Hz, 1H), 5.70 (dd, J = 10.8, 1.2 Hz, 1H), 4.65 (s, 2H), 3.96 - 3.92 (m, 2H), 3.63 - 3.45 (m, 5H), 2.91 - 2.85 (m, 2H), 1.21 (d, J = 6.8 Hz, 3H), 1.15 (d, J = 9.2 Hz, 6H). 19 19F NMR (376 MHz, DMSO-d6) δ -73.98. Example 38: Synthesis of (15R)-5-[2-[[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl]-6-ethynyl-4-pyridinyl]-15-methyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one

[0357] Step 1: Synthesis of (15R)-15-methyl-5-[2-[[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl]-6-(2-trimethylsilylethynyl)-4-pyridinyl]-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one

[0358] Racemic-(15R)-5-[2-chloro-6-[[racemic-(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl]-4-pyridinyl]-15-methyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one (70 mg, 0.130 mmol, 1.00 equiv) and trimethyl(2-tributylstannylethynyl)silane (259 mg, 0.670 mmol, 5.00 equiv) were added to a solution of Pd(PPh3)4 (31 mg, 0.030 mmol, 0.20 equiv) in 1,4-dioxane (2.0 mL). The resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 2 h. LCMS showed completion of the reaction. The resulting solution was concentrated under reduced pressure and the residue was purified by reverse-phase flash chromatography using water (0.05% TFA) / MeCN (1:2) to give racemic-(15R)-15-methyl-5-[2-[[racemic-(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl]-6-(2-trimethylsilylethynyl)-4-pyridinyl]-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one (60 mg, 77%). LCMS (ESI, m / z): 584 (M+H) + 。

[0359] Step 2: Synthesis of (15R)-5-[2-[[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl]-6-ethynyl-4-pyridinyl]-15-methyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one To a solution of (15R)-15-methyl-5-[2-[[(2R)-2-methylmorpholin-4-yl]methyl]-6-(2-trimethylsilylethynyl)-4-pyridinyl]-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one (60 mg, 0.110 mmol, 1.00 equiv) in methanol (2.0 mL) was added K2CO3 (58 mg, 0.4200 mmol, 4.00 equiv). The resulting mixture was stirred at room temperature for 1 h. LCMS showed completion of the reaction. The resulting solution was diluted with DMSO (3 mL). The solid was filtered off. The filtrate was purified by preparative HPLC using the following conditions: column: Welch Utimate HS-C18, 21.2×250 mm, 7 μm; mobile phase A: water (0.05% TFA), mobile phase B: MeCN; flow rate: 25 mL / min; gradient: 29% B to 30% B in 5 min, then 30% B; wavelength: 254 / 210 nm; RT1 (min): 4.45. Purification gave the desired (15R)-5-[2-[[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl]-6-ethynyl-4-pyridinyl]-15-methyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one as a pale yellow solid (32.1 mg, 59%). LCMS (ESI, m / z): 512 [M+H] + . Analytical conditions: column: HALO C18 100A column 3.0×30 mm, 2.0 μm; mobile phase A: water / 0.05% TFA, mobile phase B: acetonitrile / 0.05% TFA; flow rate: 1.2000 mL / min; gradient: 5% B to 65% B in 2.10 min; 254 nm; Rt: 1.607 min.

[0360] 11H NMR (400 MHz, DMSO-d6) δ 9.34 (d, J = 9.2 Hz, 1H), 8.53 (s, 1H), 8.49 (s, 1H), 8.44 (d, J = 8.8 Hz, 1H), 8.24 (d, J = 8.8 Hz, 1H), 8.10 (d, J = 8.8 Hz, 1H), 4.62 (s, 2H), 4.57 (s, 1H), 3.93 - 3.85 (m, 2H), 3.61 - 3.43 (m, 3H), 2.86 (t, J = 12.0 Hz, 2H), 1.21 (d, J = 6.8 Hz, 3H), 1.15 (d, J = 6.4 Hz, 6H). 19 19F NMR (376 MHz, DMSO-d6) δ -74.01. Example 39: Synthesis of (15R)-5-[2-[[(2R,6R)-2,6-dimethylmorpholin-4-yl]methyl]-6-ethenyl-4-pyridinyl]-15-methyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one

[0361] Step 1: Synthesis of methyl (4-bromo-6-chloro-2-pyridyl) methanesulfonate

[0362] Methanesulfonyl chloride (309 mg, 2.700 mmol, 1.20 equiv) was added dropwise to a solution of (4-bromo-6-chloro-2-pyridyl)methanol (500 mg, 2.250 mmol, 1.00 equiv) and TEA (871 mg, 6.740 mmol, 3.00 equiv) in DCM (10.0 mL). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 h. LCMS showed completion of the reaction. The resulting solution was diluted with water (50 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine (2 × 50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 450 mg of the crude product. The crude product was used directly in the next step without further purification. LCMS (ESI, m / z): 300 (M+H) + .

[0363] Step 2: Synthesis of (2R,6R)-4-[(4-bromo-6-chloro-2-pyridyl)methyl]-2,6-dimethyl-morpholine

[0364] To a solution of methyl (4-bromo-6-chloro-2-pyridyl)methanesulfonate (400 mg, 1.330 mmol, 1.00 equiv) and (2R,6R)-2,6-dimethylmorpholine (184 mg, 1.600 mmol, 1.20 equiv) in MeCN (10.0 mL) was added K2CO3 (551 mg, 3.990 mmol, 3.00 equiv). The resulting mixture was stirred at room temperature for 3 h. LCMS showed completion of the reaction. The resulting solution was diluted with water (100 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine (2 × 50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using ethyl acetate / petroleum ether (1:2) to afford (2R,6R)-4-[(4-bromo-6-chloro-2-pyridyl)methyl]-2,6-dimethyl-morpholine as an off-white solid (400 mg, 94%). LCMS (ESI, m / z): 319 (M+H) + .

[0365] Step 3: Synthesis of (15R)-5-[2-chloro-6-[[(2R,6R)-2,6-dimethylmorpholin-4-yl]methyl]-4-pyridyl]-15-methyl-11-thia-6,14,17-triazatricyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one

[0366] To a solution of (2R,6R)-4-[(4-bromo-6-chloro-2-pyridinyl)methyl]-2,6-dimethyl-morpholine (380 mg, 1.190 mmol, 1.00 equiv) and (15R)-15-methyl-5-tributylstannyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one (1.0 g, 1.780 mmol, 1.50 equiv) in 1,4-dioxane (10.0 mL) was added Pd(PPh3)4 (137 mg, 0.120 mmol, 0.10 equiv). The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 3 h. LCMS showed completion of the reaction. The resulting solution was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using dichloromethane / ethyl acetate (1:1) to give (15R)-5-[2-chloro-6-[[(2R,6R)-2,6-dimethylmorpholin-4-yl]methyl]-4-pyridinyl]-15-methyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one (450 mg, 73%) as a yellow solid. LCMS (ESI, m / z): 522 (M+H) + 。

[0367] Step 4: Synthesis of (15R)-5-[2-[[(2R,6R)-2,6-dimethylmorpholin-4-yl]methyl]-6-ethenyl-4-pyridinyl]-15-methyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one

[0368] To a solution of (15R)-5-[2-chloro-6-[[(2R,6R)-2,6-dimethylmorpholin-4-yl]methyl]-4-pyridinyl]-15-methyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one (100 mg, 0.190 mmol, 1.00 equiv) and tributyl(vinyl)stannane (91 mg, 0.290 mmol, 1.50 equiv) in 1,4-dioxane (5.0 mL) was added Pd(PPh3)4 (22 mg, 0.020 mmol, 0.10 equiv). The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 3 h. LCMS showed completion of the reaction. The resulting solution was concentrated under reduced pressure. The residue was purified by preparative HPLC using the following gradient conditions: column: Xselect CSH C18 OBD column 30 × 150 mm 5 μm; mobile phase A: water (0.1% FA), mobile phase B: MeCN; flow rate: 60 mL / min; gradient: 7% B to 37% B in 10 min, 37% B; wavelength: 254 nm; RT1 (min): 9.05. Purification gave the desired (15R)-5-[2-[[(2R,6R)-2,6-dimethylmorpholin-4-yl]methyl]-6-vinyl-4-pyridinyl]-15-methyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one as a yellow solid (6.1 mg, 6%). LCMS (ESI, m / z): 514 (M+H) + Analytical conditions: column: HALO AQ-C18 100A column 3.0 × 30 mm, 2.0 μm; mobile phase A: water / 0.05% TFA, mobile phase B: acetonitrile / 0.05% TFA; flow rate: 1.2000 mL / min; gradient: 5% B to 65% B in 2.10 min; 254 nm; Rt: 1.621.

[0369] 11H NMR (300 MHz, DMSO-d6) δ 9.32 (d, J = 9.0 Hz, 1H), 8.37 (d, J = 8.4 Hz, 1H), 8.30 - 8.22 (m, 3H), 8.19 (s, 1H), 8.05 (d, J = 9.0 Hz, 1H), 6.98 (dd, J = 17.4, 10.5 Hz, 1H), 6.39 (d, J = 17.1 Hz, 1H), 5.57 (d, J = 12.0 Hz, 1H), 4.02 (s, 3H), 3.89 - 3.62 (m, 3H), 3.52 - 3.47 (m, 3H), 2.77 - 2.61 (m, 1H), 2.46 - 2.22 (m, 2H), 1.23 - 1.20 (m, 9H). Example 40: Synthesis of (R)-3-(2,3-dimethyl-6-vinylpyridin-4-yl)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino [5',6':4,5]thieno[3,2-f]quinolin-8-one Step 1: Synthesis of 4-chloro-2,3-dimethyl-6-vinylpyridine:

[0370] A 20 mL reaction vial was charged with a stir bar, potassium vinyltrifluoroborate (76 mg, 0.568 mmol), 4,6-dichloro-2,3-dimethylpyridine (100 mg, 0.568 mmol), Pd(dppf)Cl2·DCM adduct (46.4 mg, 0.057 mmol), cesium carbonate (463 mg, 1.420 mmol), dioxane (2272 μl) and water (568 μl) to give an orange suspension. The resulting mixture was degassed by bubbling N2 for 5 minutes and then sealed and stirred at 60 °C for 16 hours. LC-MS indicated the desired product as the major product. The reaction mixture was concentrated under reduced pressure, diluted in ethyl acetate and filtered through a pad of celite. The filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by flash chromatography (0 to 100% ethyl acetate / heptane gradient; the product eluted at 50% ethyl acetate) to give 4-chloro-2,3-dimethyl-6-vinylpyridine as a clear oil (53 mg, 0.316 mmol, 55.7% yield).

[0371] 1H NMR (400 MHz, chloroform-d) δ 8.98 (d, J = 8.6 Hz, 1H), 8.38 (s, 1H), 8.22-8.05 (m, 2H), 7.72-7.48 (m, 2H), 5.23-5.07 (m, 1H), 4.95 (br dd, J = 13.8, 8.2 Hz, 1H), 3.25 (br dd, J = 13.9, 4.6 Hz, 1H), 2.47-2.36 (m, 3H), 1.65-1.45 (m, 18H), 1.31-1.20 (m, 3H). MS ESI m / z 168.3 and 170.3 (M+H) + Step 2: (R)-3-(2,3-Dimethyl-6-vinylpyridin-4-yl)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepine Synthesis of 5',6':4,5'-thieno[3,2-f]quinolin-8-one: A 4 mL reaction vial was charged with a stir bar, (R)-10-methyl-3-(tributylstannyl)-9,10,11,12-tetrahydro-8H-[1,4]diazepine To the product was added [5', 6': 4, 5] thieno [3, 2-f] quinoline -8- one (44.4 mg, 0.078 mmol), 4-chloro-2,3-dimethyl-6-vinylpyridine (13 mg, 0.078 mmol) and tetrakis (8.96 mg, 7.75 μmol) and dioxane (388 μl) to give a yellow solution. The reaction mixture was degassed by evacuating and backfilling with nitrogen 3 times. The vial was sealed and heated to 100 ° C for 16 hours. LC MS indicated that a large amount of product was formed. The reaction mixture was diluted with potassium fluoride aqueous solution and stirred at room temperature for 2 hours. The reactant was diluted in DMF and filtered through a celite pad. The crude material was purified by preparative reverse phase chromatography using the following conditions: Column: XBridge C18, 19 mm × 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% TFA; Mobile phase B: 95:5 acetonitrile:water with 0.1% TFA; Gradient: 2% B for 0 min, 2% to 42% B over 20 min, then 100% B for 4 min; Flow rate: 20 mL / min; Column temperature: 25°C. Fraction collection was performed by UV (220 nm) and MS (ESI+) triggering. Gradient: Fractions containing the desired product were combined and dried by centrifugal evaporation to yield (R)-3-(2,3-dimethyl-6-vinylpyridin-4-yl)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepine. And [5',6':4,5]thieno[3,2-f]quinolin-8-one (7.3 mg, 0.018 mmol, 23% yield). 1 H NMR (500 MHz, DMSO-d6) δ 9.35 (d, J = 8.8 Hz, 1H), 8.22 (d, J = 8.9 Hz, 1H), 8.12 (brd, J = 4.1 Hz, 1H), 8.03 (d, J = 8.8 Hz, 1H), 7.90 (d, J = 8.7 Hz, 2H), 7.30 - 7.01 (m, 2H), 6.94 (dd, J = 17.5, 11.0 Hz, 1H), 6.47 (br d, J = 17.6 Hz, 1H), 5.74 (br d, J = 11.2 Hz, 1H), 2.69 (s, 3H), 2.34 (s, 3H), 1.21 (d, J = 6.8 Hz, 3H). Three protons are shielded by the solvent peak. MS ESI m / z 415.2 (M + H) + Example 41: Synthesis of (15R)-5-[3-Fluoro-2-(morpholinomethyl)-6-ethenyl-4-pyridinyl]-15-methyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one

[0372] Step 1: Synthesis of 4-[(6-Chloro-3-fluoro-2-pyridinyl)methyl]morpholine

[0373] To a solution of 6-chloro-3-fluoropyridine-2-carbaldehyde (500 mg, 3.130 mmol, 1.00 equiv) in methanol (10.0 mL) was added morpholine (409 mg, 4.7 mmol, 1.50 equiv) and the pH of the resulting solution was adjusted to 5 - 6 with acetic acid. After 0.5 h, a solution of NaBH3CN (592 mg, 9.390 mmol, 3.00 equiv) in methanol (5.0 mL) was added to the resulting solution and the mixture was stirred at room temperature for 1 h. LCMS showed completion of the reaction. The resulting solution was diluted with water (40 mL) and extracted with ethyl acetate (3 × 40 mL). The combined organic layers were washed with brine (2 × 30 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate (2:1) to give 4-[(6-chloro-3-fluoro-2-pyridinyl)methyl]morpholine as an off-white solid (480 mg, 66%). LCMS (ESI, m / z): 231 (M + H)+ 。

[0374] Step 2: Synthesis of 4-[(6-chloro-3-fluoro-4-iodo-2-pyridinyl)methyl]morpholine

[0375] At -78 °C under a nitrogen atmosphere, LDA (2 M in THF) (0.65 mL, 1.300 mmol, 1.50 equivalents) was added dropwise to a solution of 4-[(6-chloro-3-fluoro-2-pyridinyl)methyl]morpholine (200 mg, 0.870 mmol, 1.00 equivalent) in THF (5.0 mL). After 0.5 h, a solution of I2 (242 mg, 0.950 mmol, 1.10 equivalents) in THF (4.0 mL) was added to the resulting solution and stirred at -78 °C under a nitrogen atmosphere for 15 minutes. After 15 minutes at -78 °C, the resulting solution was warmed to room temperature. LCMS showed that the reaction was complete. The resulting solution was quenched with saturated aqueous ammonium chloride (30 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic layers were washed with saturated aqueous sodium thiosulfate (2 × 30 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate (2:1) to give 4-[(6-chloro-3-fluoro-4-iodo-2-pyridinyl)methyl]morpholine as an off-white solid (280 mg, 90%). LCMS (ESI, m / z): 357 [M+H] + 。

[0376] Step 3: Synthesis of (15R)-5-[6-chloro-3-fluoro-2-(morpholinomethyl)-4-pyridinyl]-15-methyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one

[0377] To a solution of (15R)-15-methyl-5-tributylstannyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one (150 mg, 0.260 mmol, 1.00 equiv) and 4-[(6-chloro-3-fluoro-4-iodo-2-pyridinyl)methyl]morpholine (93 mg, 0.260 mmol, 1.00 equiv) in 1,4-dioxane (5.0 mL) was added Pd2(dba)3 (27 mg, 0.0300 mmol, 0.10 equiv) and P(o-Tol.)3 (8 mg, 0.030 mmol, 0.10 equiv). The resulting solution was stirred at 90 °C under a nitrogen atmosphere for 6 h. LCMS showed completion of the reaction. The resulting solution was diluted with ethyl acetate / petroleum ether (1:1) (20 mL). The precipitated solid was collected by filtration and washed with ethyl acetate / petroleum ether (1:1) (2 × 20 mL). The solid was dried to give (15R)-5-[6-chloro-3-fluoro-2-(morpholinomethyl)-4-pyridinyl]-15-methyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one (110 mg, 81%) as a pale yellow solid. LCMS (ESI, m / z): 512 (M+H) + .

[0378] Step 4: Synthesis of (15R)-5-[3-fluoro-2-(morpholinomethyl)-6-ethenyl-4-pyridinyl]-15-methyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one

[0379] To a solution of (15R)-5-[6-chloro-3-fluoro-2-(morpholinomethyl)-4-pyridinyl]-15-methyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one (105 mg, 0.210 mmol, 1.00 equiv), K2CO3 (56 mg, 0.410 mmol, 2.00 equiv) and potassium trifluoro(vinyl)borate (82 mg, 0.620 mmol, 3.00 equiv) in 1,4-dioxane (5.0 mL) and water (0.5 mL) was added Pd(dppf)Cl2 (16 mg, 0.020 mmol, 0.10 equiv). The resulting mixture was stirred at 90 °C under a nitrogen atmosphere for 4 h. LCMS showed completion of the reaction. The resulting solution was diluted with water (30 mL). The solid was collected by filtration and washed with water (2 × 30 mL). The solid was purified by reverse-phase flash chromatography using water (0.5% TFA) / MeCN (4:1) to give (15R)-5-[3-fluoro-2-(morpholinomethyl)-6-vinyl-4-pyridinyl]-15-methyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one as a yellow solid (35.9 mg, 34%). LCMS (ESI, m / z): 504 [M+H] + Analytical conditions: Column: HALO C18 100A column 3.0×30 mm, 2.0 μm; Mobile phase A: water / 0.05% TFA, Mobile phase B: acetonitrile / 0.05% TFA; Flow rate: 1.2000 mL / min; Gradient: 5% B to 60% B in 2.10 min; 254 nm; Rt: 1.602 min.

[0380] 1 H NMR (400 MHz, DMSO-d6) δ 10.80 - 10.60 (m, 1H), 9.37 (d, J = 9.2 Hz, 1H), 8.32 - 8.23 (m, 2H), 8.16 - 8.07 (m, 3H), 7.22 (s, 1H), 7.04 (dd, J = 17.2, 10.8 Hz, 1H), 6.41 (d, J = 17.6 Hz, 1H), 5.65 (d, J = 11.2 Hz, 1H), 4.78 (s, 2H), 4.10 - 3.70 (m, 4H), 3.70 - 3.30 (m, 7H), 1.21 (d, J = 6.8 Hz, 3H), 19 F NMR (376 MHz, DMSO-d6) δ -74.65, 131.37. Example 42: Synthesis of (15R)-15-methyl-5-(5-vinyl-1,2,4-triazol-1-yl)-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one

[0381] Step 1: Synthesis of (NE)-N-(dimethylaminomethylene)prop-2-enamide

[0382] To a solution of prop-2-enamide (100 mg, 1.407 mmol, 1.00 equiv) in DCM (4.0 mL) was added 1,1-dimethoxy-N,N-dimethyl-methanamine (251 mg, 2.110 mmol, 1.50 equiv). The resulting mixture was stirred at 40 °C under a nitrogen atmosphere for 1 h. LCMS showed completion of the reaction. The resulting solution was concentrated under reduced pressure. The residue was used in the next step without further purification. LCMS (ESI, m / z): 127 (M+H) + 。

[0383] Step 2: Synthesis of (15R)-15-methyl-5-(5-vinyl-1,2,4-triazol-1-yl)-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one

[0384] To a solution of (15R)-5-hydrazino-15-methyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one (100 mg, 0.319 mmol, 1.00 equiv) in 1,4-dioxane (2.0 mL) and acetic acid (2.0 mL) was added (NE)-N-(dimethylaminomethylene)prop-2-enamide (60 mg, 0.479 mmol, 1.50 equiv). The resulting mixture was stirred at 90 °C under a nitrogen atmosphere for 1.5 h. LCMS showed completion of the reaction. The resulting solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using dichloromethane / methanol (15:1) to give 40 mg of the crude product. The crude product was purified by reverse-phase flash chromatography using water (0.05% TFA) / MeCN (3:1) to give (15R)-15-methyl-5-(5-vinyl-1,2,4-triazol-1-yl)-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one as a yellow solid (11.8 mg, 10%). LCMS (ESI, m / z): 377 (M+H) + . Analytical conditions: Column: ACE Excel 2C18 column 3.0×30 mm, 2.0 μm; Mobile phase A: water + 0.05% TFA, Mobile phase B: acetonitrile + 0.05% TFA; Flow rate: 1.2000 mL / min; Gradient: 5% B to 70% B in 1.70 min; 254 nm; Rt: 1.351 min.

[0385] 1 H NMR (300 MHz, DMSO-d6+D2O) δ 9.42 (d, J = 9.3 Hz, 1H), 8.27 (s, 1H), 8.25 (d, J = 9.0 Hz, 1H), 8.11 (d, J = 9.3 Hz, 1H), 8.03 (d, J = 9.0 Hz, 1H), 7.88 (dd, J = 17.1, 11.1 Hz, 1H), 6.47 (dd, J = 17.4, 1.8 Hz, 1H), 5.84 (dd, J = 11.1, 1.8 Hz, 1H), 3.70 - 3.60 (m, 1H), 3.50 - 3.45 (m, 2H), 1.20 (d, J = 6.6 Hz, 3H). 19 F NMR (376 MHz, DMSO-d6) δ -74.89. Example 43: Synthesis of (15R)-5-(2-ethynyl-1H-imidazol-1-yl)-15-methyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one

[0386] Step 1: Synthesis of (15R)-5-(2-chloro-1H-imidazol-1-yl)-15-methyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one

[0387] To a solution of (15R)-5-chloro-15-methyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one (300 mg, 0.940 mmol, 1.00 equiv) and 2-chloro-1H-imidazole (290 mg, 2.830 mmol, 3.00 equiv) in DMSO (5.0 mL) was added Cs2CO3 (920 mg, 2.83 mmol, 3.00 equiv). The reaction mixture was stirred at 100 °C under a nitrogen atmosphere for 48 h. LCMS showed that the major product was the desired one. The resulting solution was diluted with water (30 mL). The solid was collected by filtration. The solid was purified by reverse-phase flash chromatography using water (0.05% TFA) / MeCN (1:1) to give (15R)-5-(2-chloro-1H-imidazol-1-yl)-15-methyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one as a yellow solid (150 mg, 41%). LCMS (ESI, m / z): 384 [M+H] + 。

[0388] Step 2: Synthesis of (15R)-15-methyl-5-[2-(trimethylsilylethynyl)-1H-imidazol-1-yl]-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one

[0389] To a solution of (15R)-5-(2-chloroimidazol-1-yl)-15-methyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one (75 mg, 0.200 mmol, 1.00 equiv) and trimethyl(2-tributylstannylethynyl)silane (91 mg, 0.230 mmol, 1.20 equiv) in 1,4-dioxane (5.0 mL) was added Pd(PPh3)4 (18 mg, 0.020 mmol, 0.10 equiv). The reaction mixture was stirred at 100 °C under a nitrogen atmosphere for 3 h. LCMS showed completion of the reaction. The resulting solution was diluted with petroleum ether (50 mL). The solid was collected by filtration and washed with petroleum ether (2 × 10 mL). The crude product was used directly in the next step without further purification. LCMS (ESI, m / z): 446 [M+H] + 。

[0390] Step 3: Synthesis of (15R)-5-(2-ethynylimidazol-1-yl)-15-methyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one

[0391] To a solution of (15R)-15-methyl-5-[2-(2-trimethylsilylethynyl)imidazol-1-yl]-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one (50 mg, 0.110 mmol, 1.00 equiv) in methanol (2.0 mL) was added K2CO3 (46 mg, 0.340 mmol, 3.00 equiv). The resulting mixture was stirred at room temperature for 30 minutes. LCMS showed completion of the reaction. The reaction solution was diluted with ethyl acetate (50 mL). The solid was filtered off. The filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC using the following gradient conditions: column: XBridge Prep OBD C18 column, 19×250 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: MeCN; flow rate: 25 mL / min; gradient: 35% B to 39% B in 5 min, 39% B; wavelength: 254 nm; RT1 (min): 4.62. Purification gave the desired (15R)-5-(2-ethynylimidazol-1-yl)-15-methyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one as a yellow solid (6.7 mg, 15%). LCMS (ESI, m / z): 374 [M+H] + . Analytical conditions: column: Shim-pack ScepterC18 column 3.0×33 mm, 3.0 μm; mobile phase A: water / 5 mM NH4HCO3, mobile phase B: acetonitrile; flow rate: 1.5000 mL / min; gradient: 10% B to 60% B in 1.85 min; 254 nm; Rt: 1.359 min.

[0392] 1 1H NMR (400 MHz, DMSO-d6) δ 9.42 (d, J = 9.2 Hz, 1H), 8.25 (d, J = 8.8 Hz, 1H), 8.17 (d, J = 9.2 Hz, 1H), 8.17 (s, 1H), 8.03 (s, 1H), 7.97 (d, J = 8.8 Hz, 1H), 7.24 (s, 1H) 7.22 (t, J = 5.2 Hz, 1H), 4.67 (s, 1H), 3.68 - 3.60 (m, 1H), 3.51 - 3.44 (m, 2H), 1.19 (d, J = 6.8 Hz, 3H). Example 44: Synthesis of (15R)-15-methyl-5-(3-methyl-5-ethenyl-1,2,4-triazol-4-yl)-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one

[0393] Step 1: Synthesis of di-tert-butyl (15R)-5-[(E)-1-(dimethylamino)ethylideneamino]-15-methyl-13-oxo-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaene-14,17-dicarboxylate

[0394] To a solution of di-tert-butyl (15R)-5-amino-15-methyl-13-oxo-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaene-14,17-dicarboxylate (200 mg, 0.400 mmol, 1.00 equiv) in DCM (5.0 mL) was added 1,1-dimethoxy-N,N-dimethyl-ethanamine (160 mg, 1.200 mmol, 3.00 equiv). The resulting mixture was stirred at 50 °C for 4 h. LCMS showed completion of the reaction. The resulting solution was concentrated under reduced pressure. The residue was used directly in the next step without further purification. LCMS (ESI, m / z): 568 (M+H) + 。

[0395] Step 2: Synthesis of di-tert-butyl (15R)-5-[3-(hydroxymethyl)-5-methyl-1,2,4-triazol-4-yl]-15-methyl-13-oxo-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaene-14,17-dicarboxylate

[0396] To a solution of (15R)-5-[(E)-1-(dimethylamino)ethylideneamino]-15-methyl-13-oxo-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaene-14,17-dicarboxylic acid di-tert-butyl ester (200 mg, 0.350 mmol, 1.00 equiv) in 1,4-dioxane (2.0 mL) and AcOH (2.0 mL) was added 2-hydroxyacetohydrazide (190 mg, 2.110 mmol, 6.00 equiv). The resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 6 h. LCMS showed formation of 50% of the desired product. The resulting solution was diluted with saturated aqueous sodium carbonate (50 ml) and extracted with ethyl acetate (3 × 30 mL). The combined organic layers were washed with brine (2 × 20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel using dichloromethane / methanol (15:1) to give (15R)-5-[3-(hydroxymethyl)-5-methyl-1,2,4-triazol-4-yl]-15-methyl-13-oxo-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaene-14,17-dicarboxylic acid di-tert-butyl ester (80 mg, 38%) as an orange solid. LCMS (ESI, m / z): 595 (M+H) + 。

[0397] Step 3: Synthesis of (15R)-5-(3-formyl-5-methyl-1,2,4-triazol-4-yl)-15-methyl-13-oxo-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaene-14,17-dicarboxylic acid di-tert-butyl ester

[0398] To a solution of di-tert-butyl (15R)-5-[3-(hydroxymethyl)-5-methyl-1,2,4-triazol-4-yl]-15-methyl-13-oxo-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaene-14,17-dicarboxylate (80 mg, 0.130 mmol, 1.00 equiv) in DCM (5.0 mL) was added Dess-Martin periodinane (68 mg, 0.160 mmol, 1.20 equiv). The resulting mixture was stirred at room temperature for 1 h. LCMS showed completion of the reaction. The resulting mixture was diluted with water (30 mL) and extracted with ethyl acetate (3 × 15 mL). The combined organic layers were washed with saturated aqueous sodium thiosulfate (2 × 20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was used directly in the next step without further purification. LCMS (ESI, m / z): 593 (M+H) + .

[0399] Step 4: Synthesis of Di-tert-butyl (15R)-15-methyl-5-(3-methyl-5-vinyl-1,2,4-triazol-4-yl)-13-oxo-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaene-14,17-dicarboxylate

[0400] At -70 °C under a nitrogen atmosphere, DBU (33 mg, 0.220 mmol, 2.00 equivalents) was added dropwise to a solution of CH3PPh3I (132 mg, 0.330 mmol, 3.00 equivalents) in THF (3.0 mL). After 30 min, a solution of (15R)-5-(3-formyl-5-methyl-1,2,4-triazol-4-yl)-15-methyl-13-oxo-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaene-14,17-dicarboxylic acid di-tert-butyl ester (65 mg, 0.110 mmol, 1.00 equivalent) in THF (3 mL) was added dropwise to the resulting mixture. The reaction mixture was stirred at -70 °C for 1 h and then allowed to warm to room temperature. LCMS showed completion of the reaction. The resulting mixture was diluted with water (30 mL) and extracted with ethyl acetate (3 × 15 mL). The combined organic layers were washed with brine (2 × 15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel using dichloromethane / methanol (15:1) to give (15R)-15-methyl-5-(3-methyl-5-vinyl-1,2,4-triazol-4-yl)-13-oxo-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaene-14,17-dicarboxylic acid di-tert-butyl ester (20 mg, 30%) as a brown oil. LCMS (ESI, m / z): 591 (M+H) + .

[0401] Step 5: Synthesis of (15R)-15-methyl-5-(3-methyl-5-vinyl-1,2,4-triazol-4-yl)-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one

[0402] To a solution of di-tert-butyl (15R)-15-methyl-5-(3-methyl-5-vinyl-1,2,4-triazol-4-yl)-13-oxo-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaene-14,17-dicarboxylate (20 mg, 0.030 mmol, 1.00 equiv) in DCM (1.0 mL) was added dropwise TFA (0.2 mL). The reaction mixture was stirred at room temperature for 2 h. LCMS showed completion of the reaction. The resulting solution was concentrated under reduced pressure. The residue was purified by preparative HPLC using the following gradient conditions: column: XSelect CSH Prep C18 OBD column, 19×150 mm, 5 μm; mobile phase A: water (0.05% TFA), mobile phase B: MeCN; flow rate: 25 mL / min; gradient: 21% B to 27% B in 6.5 min, hold at 27% B; wavelength: 254 / 210 nm; RT1 (min): 5.95. Purification gave the desired (15R)-15-methyl-5-(3-methyl-5-vinyl-1,2,4-triazol-4-yl)-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one as a yellow solid (6.4 mg, 46%). LCMS (ESI, m / z): 391 (M+H) + . Analytical conditions: column: XSelect HSS T3 100A column 2.1×30 mm, 2.5 μm; mobile phase A: water / 0.05% TFA, mobile phase B: acetonitrile / 0.05% TFA; flow rate: 1.2000 mL / min; gradient: 5% B to 50% B in 2.00 min; 254 nm; Rt: 1.429.

[0403] 1 H NMR (400 MHz, CD3OD-d4) δ 9.50 (d, J = 8.8 Hz, 1H), 8.24 - 8.12 (m, 1H), 8.07 - 7.99 (m, 1H), 7.80 (d, J = 8.8 Hz, 1H), 6.58 (dd, J = 17.6, 11.2 Hz, 1H), 6.22 (d, J = 17.2 Hz, 1H), 5.72 (d, J = 11.6 Hz, 1H), 3.82 - 3.72 (m, 1H), 3.72 - 3.45 (m, 2H), 2.54 (s, 3H), 1.33 (d, J = 6.8 Hz, 3H). 19 F NMR (376 MHz, CD3OD-d4) δ -77.36. Example 45: Synthesis of (15R)-15-methyl-5-(3-methyl-5-vinyl-1,2,4-triazol-1-yl)-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one

[0404] Step 1: Synthesis of (15R)-5-hydrazino-15-methyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one

[0405] To a solution of (15R)-5-chloro-15-methyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one (1.0 g, 3.150 mmol, 1.00 equivalent) and K2CO3 (1.3 g, 9.440 mmol, 3.00 equivalents) in DMSO (10.0 mL) was added N2H4.H2O (630 mg, 12.590 mmol, 4.00 equivalents). The resulting mixture was stirred overnight at 100 °C under a nitrogen atmosphere. LCMS showed completion of the reaction. The resulting solution was purified by reverse-phase flash chromatography using water (0.05% TFA) / MeCN (8:2) to give (15R)-5-hydrazino-15-methyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one as a pale yellow solid (950 mg, 96%). LCMS (ESI, m / z): 314 (M+H) + 。

[0406] Step 2: Synthesis of (NE)-N-[1-(dimethylamino)ethylidene]prop-2-enamide

[0407] To a solution of acrylamide (100 mg, 1.410 mmol, 1.00 equiv) in DCM (2.0 mL) was added 1,1-dimethoxy-N,N-dimethylethan-1-amine (281 mg, 2.110 mmol, 1.50 equiv). The resulting mixture was stirred at 40 °C under a nitrogen atmosphere for 1 h. LCMS showed completion of the reaction. The resulting solution was concentrated under reduced pressure. The residue was used directly in the next step without further purification. LCMS (ESI, m / z): 141 (M+H) + .

[0408] Step 3: Synthesis of (15R)-15-methyl-5-(3-methyl-5-vinyl-1,2,4-triazol-1-yl)-11-thia-6,14,17-triazatricyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one

[0409] To a solution of (15R)-5-hydrazino-15-methyl-11-thia-6,14,17-triazatricyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one (100 mg, 0.320 mmol, 1.00 equiv) in 1,4-dioxane (2.0 mL) and acetic acid (2.0 mL) was added (NE)-N-[1-(dimethylamino)ethylidene]acrylamide (89 mg, 0.640 mmol, 2.00 equiv). The resulting mixture was stirred at 90 °C for 1 h. LCMS showed completion of the reaction. The pH of the resulting mixture was adjusted to 7 - 8 with NaHCO3 and extracted with dichloromethane (3 × 15 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel using dichloromethane / methanol (15:1) to give 30 mg of crude product. The crude product was purified by reverse-phase flash chromatography using water (0.05% TFA) / MeCN (7:3) to give (15R)-15-methyl-5-(3-methyl-5-vinyl-1,2,4-triazol-1-yl)-11-thia-6,14,17-triazatricyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one as a yellow solid (16.5 mg, 13%). LCMS (ESI, m / z): 391 (M+H) +Analysis conditions: Column: HALO C18 100A column, 3.0×30 mm, 2.7 μm; Mobile phase A: water / 0.05% TFA, Mobile phase B: acetonitrile / 0.05% TFA; Flow rate: 1.5000 mL / min; Gradient: 5% B to 60% B in 1.80 min; 254 nm; Rt: 1.512.

[0410] 1 H NMR (400 MHz, DMSO-d6 + D2O) δ 9.39 (d, J = 8.8 Hz, 1H), 8.23 (d, J = 9.2 Hz, 1H), 8.06 (d, J = 9.2 Hz, 1H), 8.01 (d, J = 9.2 Hz, 1H), 7.87 (dd, J = 17.2, 11.2 Hz, 1H), 6.42 (dd, J = 17.6, 2.0 Hz, 1H), 5.80 (dd, J = 11.2, 2.0 Hz, 1H), 3.64 - 3.61 (m, 1H), 3.50 - 3.40 (m, 2H), 2.41 (s, 3H), 1.21 (d, J = 6.8 Hz, 3H). 19 F NMR (376 MHz, DMSO-d6) δ -74.85. Example 46: Synthesis of (R)-10-methyl-3-(5-(methyl-d3)-2-ethenylpyridin-4-yl-3-d)-9,10,11,12-tetrahydro-8H-[1,4]diazepino and [5',6':4,5]thieno[3,2-f]quinolin-8-one Step 1: Synthesis of (R)-(10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino and [5',6':4,5]thieno[3,2-f]quinolin-3-yl)boronic acid:

[0411] Charge a stir bar into a 40 mL reaction vial, containing (R)-3-chloro-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino [5',6':4,5]Thieno[3,2-f]quinolin-8-one (2g, 6.29 mmol), bis(pinacolato)diboron (1.758 g, 6.92 mmol), tricyclohexylphosphine (0.176 g, 0.629 mmol), bis(dibenzylideneacetone)palladium(0) (0.181 g, 0.315 mmol) and potassium acetate (0.926 g, 9.44 mmol) in DMA (25.2 ml) gave a yellow suspension. The resulting mixture was degassed by bubbling nitrogen for 5 minutes and then stirred at 80 °C for 16 hours. LC-MS indicated that the desired product was the major product, with a ratio of 2:1 to the original deborylated byproduct. (R)-(10-Methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino [5',6':4,5]thieno[3,2-f]quinolin-3-yl)boronic acid will be used as a crude solution without further purification. MS ESI m / z 328.5 (M+H) + Step 2: Synthesis of 4-bromo-2-chloro-5-(methyl-d3)pyridine-3-d:

[0412] A 40 mL reaction vial was charged with a stir bar, 4-bromo-2-chloro-5-methylpyridine (1 g, 4.84 mmol) and d6-DMSO (9.69 ml) to give a colorless solution. Potassium tert-butoxide (0.272 g, 2.422 mmol) was added and the solution immediately turned wine red. The reaction was heated to 50 °C for 15 minutes. LC MS indicated completion of the reaction. The reaction mixture was quenched by slow addition of saturated aqueous ammonium chloride, leaving a brown suspension. The suspension was diluted with water and ethyl acetate. The layers were separated and the aqueous layer was extracted twice more with ethyl acetate. The combined organic layers were washed with water and concentrated under reduced pressure to give the crude product as a brown oil. The crude product was dissolved in dichloromethane and purified by flash chromatography to give 4-bromo-2-chloro-5-(methyl-d3)pyridine-3-d as a clear oil (368 mg, 1.748 mmol, 36% yield).

[0413] 1 1H NMR (400 MHz, DMSO-d6) δ 8.38 - 8.34 (m, 1H) MS ESI m / z 209.8, 211.8 and 213.7 (M+H) + Step 3: Synthesis of (R)-3-(2-chloro-5-(methyl-d3)pyridin-4-yl-3-d)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino [5',6':4,5]thieno[3,2-f]quinolin-8-one: A stir bar, 4-bromo-2-chloro-5-(methyl-d3)pyridine-3-d (65 mg, 0.309 mmol), (R)-(10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino [5',6':4,5]thieno[3,2-f]quinolin-3-yl)boronic acid (1.853 mL of a DMA solution, 0.463 mmol), copper(I) chloride (30.6 mg, 0.309 mmol), and PdCl2(dtbpf) (20.13 mg, 0.031 mmol) were placed into a 20 mL reaction vial to give a brown suspension. Aqueous tripotassium phosphate (0.463 mL, 0.926 mmol) was added. The reaction mixture was degassed by evacuation and backfilling with nitrogen three times. The vial was sealed and heated to 80 °C for 2 h. After 2 h, LC / MS indicated near-complete conversion to the product. The reaction mixture was cooled to room temperature and filtered through a 0.45 μm PTFE frit. The frit was washed with DMSO. The crude product was purified by reverse-phase HPLC. The pure eluate was concentrated under reduced pressure to give (R)-3-(2-chloro-5-(methyl-d3)pyridin-4-yl-3-d)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino [5',6':4,5]thieno[3,2-f]quinolin-8-one (42 mg, 0.102 mmol, 32.9% yield). MS ESIm / z 413.1 and 415.1 (M+H) +

[0414] Due to the presence of two rotamers, 1 1H NMR was not integrated. Step 4: Synthesis of (R)-10-methyl-3-(5-(methyl-d3)-2-ethenylpyridin-4-yl-3-d)-9,10,11,12-tetrahydro-8H-[1,4]diazepino [5',6':4,5]thieno[3,2-f]quinolin-8-one:

[0415] A stir bar and (R)-3-(2-chloro-5-(methyl-d3)pyridin-4-yl-3-d)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino And [5',6':4,5]thieno[3,2-f]quinolin-8-one (42 mg, 0.102 mmol), PdCl2(dtbpf) (6.63 mg, 10.17 μmol), potassium trifluoro(vinyl)borate (27.2 mg, 0.203 mmol) and DMA (1017 μl) were taken to obtain a brown solution. Aqueous potassium phosphate solution (153 μl, 0.305 mmol) was added. The reaction mixture was degassed by evacuation and backfilling with nitrogen three times. The vial was sealed and heated to 80 °C for 16 h. LCMS indicated incomplete conversion. Potassium trifluoro(vinyl)borate (27.2 mg, 0.203 mmol) was added. The reaction mixture was degassed by evacuation and backfilling with nitrogen three times. The vial was sealed and heated to 80 °C for 3 h. LC MS indicated significant conversion. The reaction mixture was concentrated under reduced pressure. The crude material was purified by preparative reverse-phase chromatography using the following conditions: column: XBridge C18, 19 mm × 200 mm, 5 μm particles; flow rate: 20 mL / min; column temperature: 25 °C. Eluate fractions were collected triggered by UV (220 nm) and MS (ESI+). The eluate fractions containing the desired product were combined and dried by centrifugal evaporation to give (R)-10-methyl-3-(5-(methyl-d3)-2-vinylpyridin-4-yl-3-d)-9,10,11,12-tetrahydro-8H-[1,4]diazepino And [5',6':4,5]thieno[3,2-f]quinolin-8-one (12.3 mg, 0.03 mmol, 30% yield).

[0416] 1 H NMR (500 MHz, DMSO-d6) δ 9.31 (d, J = 8.9 Hz, 1H), 8.57 (s, 1H), 8.19 (d, J = 8.9 Hz, 1H), 8.11 (d, J = 4.6 Hz, 1H), 8.03 (d, J = 8.9 Hz, 1H), 7.94 (d, J = 8.7 Hz, 1H), 7.19 (t, J = 5.3 Hz, 1H), 6.96 - 6.89 (m, 1H), 6.29 (dd, J = 17.4, 1.6 Hz, 1H), 5.50 - 5.46 (m, 1H), 3.63 (brs, 1H), 3.53 - 3.45 (m, 2H), 1.21 (d, J = 6.8 Hz, 3H). MS ESI m / z 405.1 (M + H) + Example 47: (R)-3-(2-Bromo-4,5-dichloro-1H-imidazol-1-yl)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino Synthesis of [5',6':4,5]thieno[3,2-f]quinolin-8-one

[0417] A stir bar was placed into a 4 mL reaction vial, and DCE (1 mL) containing 2-bromo-4,5-dichloro-1H-imidazole (38.9 mg, 0.180 mmol), DIPEA (0.052 mL, 0.300 mmol) and tosyl chloride (28.6 mg, 0.150 mmol) was added. The mixture was stirred at room temperature for 10 min to obtain a pink solution. (R)-9,12-Bis(tert-butoxycarbonyl)-10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino [5',6':4,5]thieno[3,2-f]quinoline 4-oxide (30 mg, 0.060 mmol) was added and the resulting mixture was stirred at 100 °C overnight. The reaction mixture was diluted with DCM (10 mL) and washed with 1N aqueous HCl (3 mL) and brine. The organic layer was separated, dried over Na2SO4, filtered and concentrated. The crude product obtained above was dissolved in dioxane (1.5 mL) and HCl (0.225 mL, 0.901 mmol) (4N in dioxane) was added. After 4 h, 4N HCl in dioxane (200 μL) was added again. After a total of 20 h, the reaction mixture was concentrated. The crude material was purified by preparative reverse-phase chromatography using the following conditions: column: XBridge C18, 19 mm × 200 mm, 5 μm particles; mobile phase A: 5:95 acetonitrile:water and 10 mM ammonium acetate; mobile phase B: 95:5 acetonitrile:water and 10 mM ammonium acetate; gradient: hold at 30% B for 0 min, 30% to 70% B over 20 min, then hold at 100% B for 4 min; flow rate: 20 mL / min; column temperature: 25 °C. Eluate fractions were collected triggered by UV (220 nm) and MS (ESI+). The fractions containing the desired product were combined and dried by centrifugal evaporation to give (R)-3-(2-bromo-4,5-dichloro-1H-imidazol-1-yl)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino [5',6':4,5]thieno[3,2-f]quinolin-8-one (12.4 mg, 42% yield). MS ESI m / z 495.9 (M+H) + Example 48: (R)-3-(4,5-Dichloro-2-ethenyl-1H-imidazol-1-yl)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino Synthesis of [5',6':4,5]thieno[3,2-f]quinolin-8-one

[0418] A stir bar was placed into a 4 mL reaction vial, and DCE (1 mL) containing 4,5-dichloro-2-vinyl-1H-imidazole (31.0 mg, 0.190 mmol), DIPEA (66.4 μL, 0.380 mmol), and tosyl chloride (31.9 mg, 0.167 mmol) was added. The mixture was stirred at room temperature for 10 min to obtain a pale yellow solution. (R)-9,12-Bis(tert-butoxycarbonyl)-10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepino [5',6':4,5]thieno[3,2-f]quinoline 4-oxide (38 mg, 0.076 mmol) was added and the resulting reddish brown mixture was stirred at 100 °C for 3 h. The reaction mixture was cooled to RT, diluted with DCM (10 mL), and washed with 1 N aqueous HCl (3 mL) and brine. The organic layer was separated, dried over Na2SO4, filtered, and concentrated to give the crude product as a dark red oil. The crude product obtained above was dissolved in DCM (2 mL), and trifluoroacetic acid (400 μL, 5.19 mmol) was added. After stirring for 2 h, the reaction mixture was concentrated. Purification by preparative HPLC on ACCQ Prep (10% to 95% ACN-H2O, 0.1% TFA, 25 min) yielded BMS-A2E65-95-1 (R)-3-(4,5-dichloro-2-vinyl-1H-imidazol-1-yl)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino [5',6':4,5]thieno[3,2-f]quinolin-8-one (14 mg, 0.025 mmol, 32.6% yield) as a yellow solid.

[0419] 1 H NMR (400 MHz, DMSO-d6) δ 9.49 (d, J = 8.9 Hz, 1H), 8.30 (d, J = 8.9 Hz, 1H), 8.18 (d, J = 4.4 Hz, 1H), 8.03 - 7.95 (m, 2H), 7.23 (br s, 1H), 6.38 (dd, J = 17.2, 11.1 Hz, 1H), 6.04 (dd, J = 17.2, 1.6 Hz, 1H), 5.47 - 5.41 (m, 1H), 3.68 - 3.58 (m, 1H), 3.56 - 3.42 (m, 2H), 1.20 (d, J = 6.8 Hz, 3H). MS ESI m / z 444.2 (M+H) + Example 49: Synthesis of (R)-3-(5-(hydroxymethyl)-2-ethenylpyridin-4-yl)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazeto and[5',6':4,5]thieno[3,2-f]quinolin-8-one Step 1: Synthesis of (4-bromo-6-chloropyridin-3-yl)methanol:

[0420] A stir bar, 4-bromo-6-chloronicotinaldehyde (417 mg, 1.892 mmol), and ethanol (7566 μl) were charged into a 20 mL reaction vial to obtain a colorless solution. Sodium borohydride (75 mg, 1.986 mmol) was added in portions, allowing some gas to escape. The reaction mixture was stirred at room temperature for 15 minutes. LC-MS indicated complete conversion. The reaction mixture was quenched by slow addition of saturated ammonium chloride. Ethyl acetate was added and the layers were separated. The aqueous layer was extracted twice more with ethyl acetate. The combined organic layers were washed with water and then with brine. The organic layer was concentrated under reduced pressure to give a crude product, which was purified by flash chromatography to give (4-bromo-6-chloropyridin-3-yl)methanol as a white crystalline solid (216 mg, 0.971 mmol, 51.3% yield).

[0421] 1 1H NMR (400 MHz, chloroform-d) δ 8.47 (s, 1H), 7.59 (s, 1H), 4.81 (s, 2H). MS ESI m / z 221.7, 223.7, and 225.7 (M+H) + Step 2: Synthesis of (R)-3-(2-chloro-5-(hydroxymethyl)pyridin-4-yl)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazeto and[5',6':4,5]thieno[3,2-f]quinolin-8-one:

[0422] A stir bar, (R)-(10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazeto And [5',6':4,5]thieno[3,2-f]quinolin-3-yl)boronic acid (2248 μl, 0.2 M solution in DMA, 0.450 mmol), (4-bromo-6-chloropyridin-3-yl)methanol (50 mg, 0.225 mmol), copper(I) chloride (22.25 mg, 0.225 mmol) and PdCl2(dtbpf) (14.65 mg, 0.022 mmol) to give a yellow suspension. Aqueous tripotassium phosphate solution (337 μl, 0.674 mmol) was added. The reaction mixture was degassed by evacuation and backfilling with nitrogen three times. The vial was sealed and heated to 80 °C for 2.5 h. LC-MS indicated completion of the reaction. The reaction was cooled to room temperature and filtered through a 0.45 μm PTFE frit. The frit was washed with additional DMF. The crude material was purified by reverse phase HPLC (water and acetonitrile as mobile phases, with 0.1% TFA added) to give (R)-3-(2-chloro-5-(hydroxymethyl)pyridin-4-yl)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino [5',6':4,5]thieno[3,2-f]quinolin-8-one (15 mg, 0.035 mmol, 15.71% yield). MS ESI m / z 425.3 (M+H) + Step 3: Synthesis of (R)-3-(5-(hydroxymethyl)-2-ethenylpyridin-4-yl)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino [5',6':4,5]thieno[3,2-f]quinolin-8-one:

[0423] A 4 mL reaction vial was charged with a stir bar, (R)-3-(2-chloro-5-(hydroxymethyl)pyridin-4-yl)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino And [5',6':4,5]thieno[3,2-f]quinolin-8-one (15 mg, 0.035 mmol), potassium trifluoro(vinyl)borate (23.64 mg, 0.177 mmol), and PdCl2(dtbpf) (2.301 mg, 3.53 μmol) and DMA (353 μl) were taken to obtain a yellow suspension. Tripotassium phosphate (53.0 μl, 0.106 mmol) was added. The reaction mixture was degassed by evacuation and backfilling with nitrogen three times. The resulting mixture was stirred at 80 °C for 16 h. LC MS indicated the presence of a large amount of product. The reaction mixture was filtered and the precipitate was washed with DMF. The crude material was purified by preparative reverse-phase chromatography using the following conditions: column: XBridge C18, 19 mm × 200 mm, 5 μm particles; mobile phase A: 5:95 acetonitrile:water and 10 mM ammonium acetate; mobile phase B: 95:5 acetonitrile:water and 10 mM ammonium acetate; gradient: held at 0% B for 0 min, 0 to 53% B over 20 min, then held at 100% B for 4 min; flow rate: 20 mL / min; column temperature: 25 °C. Eluate fractions were collected by triggering with UV (220 nm) and MS (ESI+). The eluate fractions containing the desired product were combined and dried by centrifugal evaporation to obtain (R)-3-(5-(hydroxymethyl)-2-ethenylpyridin-4-yl)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino And [5',6':4,5]thieno[3,2-f]quinolin-8-one (3.8 mg, 0.009 mmol, 25% yield).

[0424] 1 H NMR (500 MHz, DMSO-d6) δ 9.33 (d, J = 9.1 Hz, 1H), 8.79 (s, 1H), 8.21 (d, J = 8.9 Hz, 1H), 8.14 - 8.08 (m, 2H), 8.02 (d, J = 8.9 Hz, 1H), 7.80 (s, 1H), 7.20 (br s, 1H), 6.96 (dd, J = 17.5, 10.8 Hz, 1H), 6.36 (d, J = 17.4 Hz, 1H), 5.54 (d, J = 12.1 Hz, 1H), 4.73 (s, 2H), 3.63 (br s, 1H), 3.51 - 3.48 (m, 2H), 1.21 (d, J = 6.8 Hz, 3H). MS ESI m / z 417.0 (M+H) + Example 50: (R)-3-(5-(methoxymethyl)-2-ethenylpyridin-4-yl)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino Synthesis of [5',6':4,5]thieno[3,2-f]quinolin-8-one Step 1: Synthesis of (4,6-dichloropyridin-3-yl)methanol:

[0425] A stir bar, 4,6-dichloronicotinaldehyde (1 g, 5.68 mmol), acetic acid (0.651 ml, 11.36 mmol), and DCM (22.73 ml) were charged into a 40 mL reaction vial to obtain a yellow solution. Sodium triacetoxyborohydride (2.408 g, 11.36 mmol) was added portionwise at room temperature, resulting in an opaque mixture. The reaction mixture was heated to 40 °C on a heating block and maintained for 2 hours. After 2 hours, LC / MS indicated the completion of the reaction. The vial was cooled to room temperature. The reactant was quenched with saturated sodium bicarbonate (added slowly) such that vigorous gas evolution occurred. After the gas evolution ceased, the mixture was transferred to a separatory funnel and additional saturated sodium bicarbonate and dichloromethane were added. The layers were separated after mixing irregularly for one hour to ensure the removal of any remaining borohydride. The aqueous layer was extracted twice with dichloromethane. The combined organic layers were washed with water and brine and then concentrated under reduced pressure to obtain the crude product. The crude product was dissolved in a minimal amount of dichloromethane and purified by flash chromatography (120 g silica column, 0 to 100% heptane / ethyl acetate). The pure eluates were combined and concentrated under reduced pressure to obtain (4,6-dichloropyridin-3-yl)methanol as a white powder (1.1 g, 6.18 mmol, 109% yield).

[0426] 1 H NMR (400 MHz, chloroform-d) δ 8.51 (s, 1H), 7.41 (s, 1H), 4.84 (d, J = 5.9 Hz, 2H), 1.96 (t, J = 6.0 Hz, 1H). MS ESI m / z 178.2 and 180.2 (M+H) + Step 2: Synthesis of 2,4-dichloro-5-(methoxymethyl)pyridine:

[0427] A magnetic stir bar was placed into a 20 mL reaction vial, and THF (2809 μL) containing (4,6-dichloropyridin-3-yl)methanol (100 mg, 0.562 mmol) was added to give a colorless solution. Sodium hydride (67.4 mg, 1.685 mmol) was added portionwise and the mixture was stirred at room temperature for 15 minutes. Gas evolution ceased rapidly. Methyl iodide (105 μL, 1.685 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 3 days. LC-MS indicated completion of the reaction. The remaining sodium hydride was quenched by the slow addition of saturated ammonium chloride. The mixture was extracted three times with DCM. The combined DCM layers were washed with water and brine and concentrated under reduced pressure to give the crude product. The crude product was purified by flash chromatography to give 2,4-dichloro-5-(methoxymethyl)pyridine (74 mg, 0.385 mmol, 68.6% yield).

[0428] 1 1H NMR (400 MHz, Chloroform-d) δ 8.45 (s, 1H), 7.40 (s, 1H), 4.56 (s, 2H), 3.52 - 3.46 (m, 3H). MS ESI m / z 191.8 (M+H) + Step 3: Synthesis of 4-chloro-5-(methoxymethyl)-2-vinylpyridine:

[0429] A magnetic stir bar was placed into a 20 mL reaction vial, and dioxane (1541 μL) and water (385 μL) containing 2,4-dichloro-5-(methoxymethyl)pyridine (74 mg, 0.385 mmol), trifluoro(vinyl)borate, K+ (51.6 mg, 0.385 mmol), Pd(dppf)Cl2, DCM adduct (31.5 mg, 0.039 mmol) and cesium carbonate (314 mg, 0.963 mmol) were added to give an orange suspension. The reaction mixture was degassed by evacuation and backfilling with nitrogen three times. The vial was sealed and heated to 70 °C for 16 h. LC-MS indicated completion of the reaction. The aqueous layer was removed and the organic layer was concentrated under reduced pressure. The crude product was purified by flash chromatography to give 4-chloro-5-(methoxymethyl)-2-vinylpyridine as a colorless oil (48 mg, 0.261 mmol, 67.8% yield). MS ESI m / z 184.0 (M+H) + Step 4: Synthesis of (5-(methoxymethyl)-2-vinylpyridin-4-yl)boronic acid:

[0430] A 20 mL reaction vial was charged with a stirring bar, dioxane (2614 μl) containing 4-chloro-5-(methoxymethyl)-2-vinylpyridine (48 mg, 0.261 mmol), bis(pinacolato)diboron (73.0 mg, 0.288 mmol), bis(dibenzylideneacetone)palladium(0) (15.03 mg, 0.026 mmol), tricyclohexylphosphine (14.66 mg, 0.052 mmol) and potassium acetate (38.5 mg, 0.392 mmol) to give a dark suspension. The reaction mixture was degassed by evacuating and backfilling with nitrogen 3 times. The vial was sealed and heated to 80 ° C for 3 hours. LC-MS indicated that the starting material was converted in large quantities to give (5-(methoxymethyl)-2-vinylpyridin-4-yl)boronic acid in the form of a crude reaction mixture, which was used without further purification (the conversion rate estimated by LC MS was 50%). MS ESI m / z 193.8 (M+H) + Step 5: (R)-3-(5-(methoxymethyl)-2-vinylpyridin-4-yl)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepine Synthesis of 5',6':4,5'-thieno[3,2-f]quinolin-8-one:

[0431] A 4 mL reaction vial was charged with a stir bar, (R)-3-chloro-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepine And [5',6':4,5]thieno[3,2-f]quinolin-8-one (65.9 mg, 0.207 mmol), (5-(methoxymethyl)-2-vinylpyridin-4-yl)boronic acid (259 μl, 0.2 M in dioxane crude reaction mixture, 0.052 mmol) and PdCl2(dtbpf) (6.75 mg, 10.36 μmol) were taken to give a dark suspension. Tripotassium phosphate in aqueous solution (155 μl, 0.311 mmol) was added. The reaction mixture was degassed by evacuation and backfilling with nitrogen three times. The resulting mixture was stirred at 60 °C for 16 h. LC MS indicated the presence of a large amount of product. The reactants were concentrated under reduced pressure and the crude product was dissolved in DMSO. The crude product was purified by reverse-phase preparative HPLC under acidic conditions to give 12 mg of product. The substance was purified by preparative reverse-phase chromatography using the following conditions: column: XBridge C18, 19 mm × 200 mm, 5 μm particles; mobile phase A: 5:95 acetonitrile:water and 10 mM ammonium acetate; mobile phase B: 95:5 acetonitrile:water and 10 mM ammonium acetate; gradient: hold at 19% B for 0 min, 19% to 59% B over 20 min, then hold at 100% B for 4 min; flow rate: 20 mL / min; column temperature: 25 °C. Eluate collection was triggered by UV (220 nm) and MS (ESI+). The eluates containing the desired product were combined and dried by centrifugal evaporation to give (R)-3-(5-(methoxymethyl)-2-vinylpyridin-4-yl)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino [5',6':4,5]thieno[3,2-f]quinolin-8-one (7.2 mg, 0.017 mmol, 32% yield).

[0432] 1 H NMR (500 MHz, DMSO-d6) δ 9.28 (br d, J = 8.8 Hz, 1H), 8.70 (s, 1H), 8.17 (d, J = 8.9 Hz, 1H), 8.10 - 8.05 (m, 1H), 8.02 (d, J = 9.2 Hz, 1H), 7.98 (br d, J = 8.9 Hz, 1H), 7.76 (s, 1H), 7.18 (br t, J = 5.1 Hz, 1H), 6.94 (dd, J = 17.2, 10.9 Hz, 1H), 6.37 - 6.28 (m, 1H), 5.61 - 5.46 (m, 1H), 4.67 (s, 2H), 3.23 - 3.19 (m, 3H), 1.19 (d, J = 6.7 Hz, 3H). Three protons were obscured by the water peak. MS ESI m / z 431.1 (M+H) +

[0433] Table 3: The compounds in Table 3 were prepared in a manner similar to (R)-3-(5-(methoxymethyl)-2-ethenylpyridin-4-yl)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino [5',6':4,5]thieno[3,2-f]quinolin-8-one. Example 51: Synthesis of (15R)-15-methyl-5-[5-[2,2,2-trideuterio-1-hydroxy-1-(trideuteriomethyl)ethyl]-2-ethenyl-4-pyridinyl]-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one

[0434] Step 1: Synthesis of 2-(4-bromo-6-chloro-3-pyridinyl)-1,1,1,3,3,3-hexadeuterio-propan-2-ol

[0435] At -78 °C under a nitrogen atmosphere, a solution of methyl 4-bromo-6-chloropyridine-3-carboxylate (200 mg, 0.800 mmol, 1.00 equivalent) in THF (8.0 mL) was added dropwise to a solution of THF (8.0 mL, 8.000 mmol, 10.00 equivalents) containing 1 M magnesium iodide (trideuteriomethyl). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. LCMS showed completion of the reaction. The resulting solution was quenched with saturated aqueous ammonium chloride (20 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with brine (2 × 10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate (1:1) to give 2-(4-bromo-6-chloro-3-pyridinyl)-1,1,1,3,3,3-hexadeuterio-propan-2-ol (200 mg, 97%) as a pale yellow solid. LCMS (ESI, m / z): 256 [M+H] +

[0436] Step 2: Synthesis of (15R)-5-[2-chloro-5-[2,2,2-trideuterio-1-hydroxy-1-(trideuteriomethyl)ethyl]-4-pyridinyl]-15-methyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one

[0437] To a solution of 2-(4-bromo-6-chloro-3-pyridinyl)-1,1,1,3,3,3-hexadeuterio-propan-2-ol (100 mg, 0.390 mmol, 1.00 equiv) and (15R)-15-methyl-5-tributylstannyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one (268 mg, 0.470 mmol, 1.20 equiv) in 1,4-dioxane (4.0 mL) was added Pd2(dba)3 (81 mg, 0.080 mmol, 0.20 equiv) and P(o-Tol.)3 (24 mg, 0.080 mmol, 0.20 equiv). The resulting mixture was stirred at 90 °C under a nitrogen atmosphere for 4 h. LCMS showed completion of the reaction. The resulting solution was diluted with ethyl acetate (20 mL). The solid was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using water (0.05% TFA) / MeCN (1:3) to give (15R)-5-[2-chloro-5-[2,2,2-trideuterio-1-hydroxy-1-(trideuteriomethyl)ethyl]-4-pyridinyl]-15-methyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one as a yellow solid (80 mg, 44%). LCMS (ESI, m / z): 459 [M+H] + 。

[0438] Step 3: Synthesis of (15R)-15-methyl-5-[5-[2,2,2-trideuterio-1-hydroxy-1-(trideuteriomethyl)ethyl]-2-ethenyl-4-pyridinyl]-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one

[0439] To a solution of (15R)-5-[2-chloro-5-[2,2,2-trideuterio-1-hydroxy-1-(trideuteriomethyl)ethyl]-4-pyridinyl]-15-methyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one (70 mg, 0.150 mmol, 1.00 equiv) and tributyl(vinyl)stannane (145 mg, 0.450 mmol, 3.00 equiv) in 1,4-dioxane (3.0 mL) was added Pd(PPh3)4 (28 mg, 0.030 mmol, 0.20 equiv). The resulting mixture was stirred at 90 °C under a nitrogen atmosphere for 2 h. LCMS showed completion of the reaction. The resulting solution was diluted with ethyl acetate (10 mL). The solid was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using water (0.05% TFA) / MeCN (1:2) to give 40 mg of the crude product. The crude product was purified by preparative HPLC using the following conditions: column: Welch Utimate HS-C18, 21.2×250 mm, 7 μm; mobile phase A: water (0.05% TFA), mobile phase B: MeCN; flow rate: 25 mL / min; gradient: 30% B to 30% B over 6.5 min, then 30% B; wavelength: 254 / 210 nm; RT1 (min): 5.68. Purification gave the desired (15R)-15-methyl-5-[5-[2,2,2-trideuterio-1-hydroxy-1-(trideuteriomethyl)ethyl]-2-ethenyl-4-pyridinyl]-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one as a yellow solid (21.1 mg, 29%). LCMS (ESI, m / z): 451 [M+H] + Analytical conditions: column: HALO C18 column 2.1×30 mm, 2.5 □m; mobile phase A: water + 0.05% TFA, mobile phase B: acetonitrile + 0.05% TFA; flow rate: 1.2000 mL / min; gradient: 5% B to 50% B over 2.00 min at 254 nm; RT: 1.475 min.

[0440] 11H NMR (400 MHz, DMSO-d6) δ 9.35 (d, J = 8.8 Hz, 1H), 8.53 (s, 1H), 8.26 (d, J = 9.2 Hz, 1H), 7.97 (d, J = 8.8 Hz, 1H), 7.90 (d, J = 8.8 Hz, 1H), 7.85 (s, 1H), 6.97 (dd, J = 17.2, 10.8 Hz, 1H), 6.40 (d, J = 17.2, 1H), 5.63 (d, J = 12.0 Hz, 1H), 3.65 - 3.62 (m, 1H), 3.51 - 3.43 (m, 2H), 1.20 (d, J = 6.8 Hz, 3H). 19 19F NMR (376 MHz, DMSO-d6) δ -74.26. Example 52: Synthesis of (15R)-15-methyl-5-[5-(2,2,2-trideuterio-1-hydroxy-ethyl)-2-ethenyl-4-pyridyl]-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one

[0441] Step 1: Synthesis of 1-(4-bromo-6-chloro-3-pyridyl)-2,2,2-trideuterio-ethanol

[0442] To a solution of 4-bromo-6-chloro-pyridine-3-carbaldehyde (330 mg, 1.500 mmol, 1.00 equivalent) in THF (10.0 mL) at -40 °C was added dropwise a solution of THF (7.5 mL, 7.480 mmol, 5.00 equivalents) containing 1 M CD3MgI. The reaction mixture was stirred at 40 °C for 1 h and allowed to warm to 0 °C under a nitrogen atmosphere. LCMS showed completion of the reaction. The resulting solution was quenched with saturated aqueous ammonium chloride (20 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with brine (2 × 10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate (4:1) to give 1-(4-bromo-6-chloro-3-pyridyl)-2,2,2-trideuterio-ethanol as a colorless oil (245 mg, 63%). LCMS (ESI, m / z): 240 (M + H) + .

[0443] Step 2: Synthesis of 1-(4-bromo-6-chloro-3-pyridyl)-2,2,2-trideuterio-ethanol

[0444] The racemate (245 mg, purity: 97%) was separated by chiral preparative HPLC using the following gradient conditions: column: CHIRAL ART Cellulose-SA, 2 × 25 cm, 5 μm; mobile phase A: hexane (0.1% 2M NH3-MeOH), mobile phase B: EtOH; flow rate: 20 mL / min; gradient: 5% B to 5% B in 16 min; 220 / 254 nm; RT1: 10.62; RT2: 13.304. Purification yielded the front peak: (1-(4-bromo-6-chloro-3-pyridyl)-2,2,2-trideutero-ethanol as a colorless oil (125 mg, 51.02%, RT: 1.87 min). LCMS (ESI, m / z): 240 [M+H] + 。

[0445] Step 3: Synthesis of (15R)-5-[2-chloro-5-(2,2,2-trideutero-1-hydroxy-ethyl)-4-pyridyl]-15-methyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one

[0446] To a solution of 1-(4-bromo-6-chloro-3-pyridyl)-2,2,2-trideutero-ethanol (110 mg, 0.460 mmol, 1.00 equiv) and (15R)-15-methyl-5-tributylstannyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one (315 mg, 0.550 mmol, 1.20 equiv) in 1,4-dioxane (3.0 mL) was added Pd2(dba)3 (95 mg, 0.090 mmol, 0.20 equiv) and P(o-Tol.)3 (56 mg, 0.180 mmol, 0.40 equiv). The resulting mixture was stirred at 90 °C under a nitrogen atmosphere for 3 h. LCMS showed completion of the reaction. The resulting solution was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using water (0.05% TFA) / MeCN (3:2) to afford (15R)-5-[2-chloro-5-(2,2,2-trideutero-1-hydroxy-ethyl)-4-pyridyl]-15-methyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one (80 mg, 39%) as a red solid. LCMS (ESI, m / z): 442 (M+H) + 。

[0447] Step 4: Synthesis of (15R)-15-methyl-5-[5-(2,2,2-trideutero-1-hydroxy-ethyl)-2-ethenyl-4-pyridyl]-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one

[0448] To a solution of (15R)-5-[2-chloro-5-(2,2,2-trideuterio-1-hydroxy-ethyl)-4-pyridyl]-15-methyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one (80 mg, 0.180 mmol, 1.00 equiv) and tributyl(vinyl)stannane (176 mg, 0.540 mmol, 3.00 equiv) in 1,4-dioxane (2.0 mL) was added Pd(dppf)Cl2 (59 mg, 0.070 mmol, 0.40 equiv). The resulting mixture was stirred at 90 °C under a nitrogen atmosphere for 3 h. LCMS showed completion of the reaction. The resulting solution was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using water (0.05% TFA) / MeCN (2:1) to afford (15R)-15-methyl-5-[5-(2,2,2-trideuterio-1-hydroxy-ethyl)-2-vinyl-4-pyridyl]-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one (33.9 mg, 42%) as an orange solid. LCMS (ESI, m / z): 434 (M+H) + . Analytical conditions: Column: HALO C18 column 3.0×30 mm, 2.7 μm; Mobile phase A: water / 0.05% TFA, Mobile phase B: acetonitrile / 0.05% TFA; Flow rate: 1.5000 mL / min; Gradient: 5% B to 50% B in 1.70 min; 254 nm; Rt: 1.254 min.

[0449] 1 H NMR (400 MHz, DMSO-d6) δ 9.35 (d, J = 8.8 Hz, 1H), 8.91 (s, 1H), 8.22 (d, J = 8.8 Hz, 1H), 8.15 (d, J = 4.4 Hz, 1H), 8.01 (d, J = 9.2 Hz, 1H), 7.98 (d, J = 9.2 Hz, 1H), 7.81 (s, 1H), 7.22 (s, 1H), 6.96 (dd, J = 17.2 Hz, 10.8 Hz, 1H), 6.41 (d, J = 17.2 Hz, 1H), 5.63 (d, J = 11.2 Hz, 1H), 5.16 (s, 1H), 3.68 - 3.60 (m, 1H), 3.53 - 3.45 (m, 2H), 1.20 (d, J = 6.8 Hz, 3H). 19 FNMR (376 MHz, DMSO-d6) δ -74.69. Example 53: Synthesis of (15R)-15-methyl-5-[5-(2,2,2-trideuterio-1-hydroxy-ethyl)-2-ethenyl-4-pyridinyl]-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one

[0450] Step 1: Synthesis of (1-(4-bromo-6-chloro-3-pyridinyl)-2,2,2-trideuterio-ethanol

[0451] The racemate (245 mg, purity: 99%) was separated by chiral preparative HPLC using the following gradient conditions: column: CHIRAL ART Cellulose-SA, 2 × 25 cm, 5 μm; mobile phase A: hexane (0.1% 2M NH3-MeOH), mobile phase B: EtOH; flow rate: 20 mL / min; gradient: 5% B to 5% B in 16 min; 220 / 254 nm; RT1: 10.62; RT2: 13.304; purification gave the second peak: (1-(4-bromo-6-chloro-3-pyridinyl)-2,2,2-trideuterio-ethanol as an off-white semi-oily substance (120 mg, 49%, RT: 2.40 min). LCMS (ESI, m / z): 240 [M+H] + .

[0452] Step 2: Synthesis of (15R)-5-[2-chloro-5-(2,2,2-trideuterio-1-hydroxy-ethyl)-4-pyridinyl]-15-methyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one

[0453] To a solution of 1-(4-bromo-6-chloro-3-pyridyl)-2,2,2-trideutero-ethanol (120 mg, 0.500 mmol, 1.00 equiv) and (15R)-15-methyl-5-tributylstannanyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one (344 mg, 0.600 mmol, 1.20 equiv) in 1,4-dioxane (10.0 mL) was added Pd2(dba)3 (103 mg, 0.100 mmol, 0.20 equiv) and P(o-Tol.)3 (61 mg, 0.200 mmol, 0.40 equiv). The resulting mixture was stirred at 90 °C under a nitrogen atmosphere for 3 h. LCMS showed completion of the reaction. The resulting solution was diluted with DMF (3.0 ml). The solid was filtered off and the filtrate was purified by reverse phase flash chromatography using water (0.05% TFA) / MeCN (3:2) to give (15R)-5-[2-chloro-5-(2,2,2-trideutero-1-hydroxy-ethyl)-4-pyridyl]-15-methyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one as a red solid (90 mg, 40%). LCMS (ESI, m / z): 442 (M+H) + 。

[0454] Step 3: Synthesis of (15R)-15-methyl-5-[5-(2,2,2-trideutero-1-hydroxy-ethyl)-2-ethenyl-4-pyridyl]-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one

[0455] To a solution of (15R)-5-[2-chloro-5-(2,2,2-trideuterio-1-hydroxy-ethyl)-4-pyridyl]-15-methyl-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one (80 mg, 0.180 mmol, 1.00 equiv) and tributyl(vinyl)stannane (176 mg, 0.540 mmol, 3.00 equiv) in 1,4-dioxane (5.0 mL) was added Pd(dppf)Cl2 (60 mg, 0.070 mmol, 0.40 equiv). The resulting mixture was stirred at 90 °C under a nitrogen atmosphere for 3 h. LCMS showed completion of the reaction. The resulting solution was diluted with DMF (3.0 ml). The solid was filtered off and the filtrate was purified by reverse-phase flash chromatography using water (0.05% TFA) / MeCN (2:1) to give (15R)-15-methyl-5-[5-(2,2,2-trideuterio-1-hydroxy-ethyl)-2-vinyl-4-pyridyl]-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one as a yellow solid (31.4 mg, 39%). LCMS (ESI, m / z): 434 (M+H) + Analytical conditions: Column: HALO C18 column 3.0×30 mm, 2.7 μm; Mobile phase A: water / 0.05% TFA, Mobile phase B: acetonitrile / 0.05% TFA; Flow rate: 1.5000 mL / min; Gradient: 5% B to 50% B in 1.70 min; 254 nm; Rt: 1.246 min.

[0456] 1 H NMR (400 MHz, DMSO-d6) δ 9.34 (d, J = 8.8 Hz, 1H), 8.90 (s, 1H), 8.22 (d, J = 8.8 Hz, 1H), 8.15 (d, J = 4.4 Hz, 1H), 8.00 (d, J = 8.8 Hz, 1H), 7.97 (d, J = 8.8 Hz, 1H), 7.75 (s, 1H), 7.22 (s, 1H), 6.96 (dd, J = 17.2 Hz, 10.8 Hz, 1H), 6.39 (d, J = 17.2 Hz, 1H), 5.60 (d, J = 11.2 Hz, 1H), 5.12 (s, 1H), 3.70 - 3.60 (m, 1H), 3.55 - 3.45 (m, 2H), 1.20 (d, J = 6.8 Hz, 3H). 19 FNMR (376 MHz, DMSO-d6) δ -74.54. Example 54: Synthesis of (15R)-15-methyl-5-(5-vinylpyridazin-3-yl)-11-thia-6,14,17-triazatetracyclo[8.8.0.0^2,7.0^12,18]octadeca-1(10),2,4,6,8,12(18)-hexaen-13-one

[0457] Step 1: Synthesis of 3-chloro-5-vinyl-pyridazine

[0458] To a solution of 5-bromo-3-chloro-pyridazine (500 mg, 2.580 mmol, 1.00 equiv), potassium trifluoro(vinyl)borate (693 mg, 5.170 mmol, 2.00 equiv) and K2CO3 (1.1 g, 7.750 mmol, 3.00 equiv) in 1,4-dioxane (10.0 mL) and water (1.0 mL) was added Pd(dtbpf)Cl2 (168 mg, 0.260 mmol, 0.10 equiv). The resulting mixture was stirred at 60 °C under a nitrogen atmosphere for 3 h. LCMS showed completion of the reaction. The resulting solution was diluted with water (80 mL) and extracted with ethyl acetate (3 × 25 mL). Th...

Claims

1. A compound of formula I: or a pharmaceutically acceptable salt thereof, wherein: Ring A is a 5- to 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, provided that when Ring A is a 6-membered heteroaryl ring, the 1 to 3 heteroatoms are each nitrogen; R 1 and R 1' each independently selected from hydrogen and C x aliphatic which is substituted with 0 to 3 R 1-4 groups, or: R 1 and R 1' may together with the intervening atoms to which they are attached form an optionally substituted 3- to 6-membered saturated or partially unsaturated heterocyclic, carbocyclic or aryl ring having from 0 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; R x is -CN, -NO2, halogen, -OR, -SR, -N(R)2, -C(O)N(R)2, -C(O)OR, -C(O)R, -N(R)C(O)R, -SO2N(R)2 or -N(R)SO2; R 2 is halogen, -(CH2) q -CN, C2-C6 alkenyl or C2-C6 alkynyl, wherein the alkenyl or alkynyl is optionally substituted with m R y substituents; Each R y is independently selected from D, halogen, -CN, -CO2R, -N(R)2, and a 3- to 6-membered saturated or partially unsaturated heterocycle having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R 3 is independently selected from D, C 1-6 aliphatic, -CN, halogen, -(CH2) q -OR 4 , -N(R)2, -C(O)OR, -(CH2) r -Cy or -O-(CH2) t -R 5 , wherein said C 1-6 aliphatic is optionally substituted with one or more substituents independently selected from D, halogen and -OR; or: Two Rs 3 groups together with the intervening atom(s) to which they are attached form a 5- to 6-membered saturated, partially unsaturated heterocyclic, carbocyclic or aryl ring having from 0 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein said heterocyclic, carbocyclic or aryl ring is optionally substituted with one or more substituents independently selected from halogen, C 1-6 aliphatic and -OR; Each R 4 is independently selected from hydrogen, C 1-6 aliphatic and -Cy, where the C 1-6 aliphatic is optionally substituted with one or more substituents each independently selected from D, halogen, and -OR; Each R 5 is independently selected from -OR and -Cy; Each Cy is independently a ring selected from: a 3- to 9-membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3- to 9-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; phenyl; a 5- to 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 7- to 12-membered saturated or partially unsaturated fused, spirofused, or bridged bicyclic carbocyclic ring; or a 7- to 12-membered saturated or partially unsaturated fused, spirofused, or bridged bicyclic heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said ring is optionally substituted with one or more substituents independently selected from D, halogen, oxo, R, and -(CH2) q -OR; Each R is independently hydrogen, or C 1-6 aliphatic optionally substituted with one or more substituents each independently selected from D, halogen, -OH, and -O-(C 1-6 aliphatic), or: Two R groups on the same nitrogen together with the nitrogen form a 3- to 7-membered saturated or partially unsaturated heterocycle having 1 to 3 heteroatoms selected from nitrogen, oxygen, or sulfur; n, q, and r are each independently 0 to 4; and t is 1 to 4.

2. The compound according to claim 1, wherein Ring A is selected from:

3. The compound according to claim 1, wherein the compound is selected from any one of formula II, III, IV, or V: or a pharmaceutically acceptable salt thereof.

4. The compound according to any one of claims 1 to 3, wherein R 2 is a halogen.

5. The compound according to any one of claims 1 to 3, wherein R 2 is -CN.

6. The compound according to any one of claims 1 to 3, wherein R 2 is an aliphatic C y substituted with m R 2-6 groups, wherein the aliphatic C 2-6 group has at least one unsaturated unit.

7. The compound according to claim 6, wherein n is 0.

8. The compound according to claim 7, wherein R 2 is selected from:

9. The compound according to claim 1, wherein R 2 is selected from:

10. The compound according to claim 1, wherein R 2 is selected from 11. The compound according to claim 1, wherein the compound is selected from formula II-a, II-b, II-c, III-a, III-b, IV-a, IV-b, IV-c, V-a, V-b, or V-c: or a pharmaceutically acceptable salt thereof.

12. The compound according to claim 1, wherein the compound is selected from formula II-a-i, II-a-ii, II-b-i, II-b-ii, II-c-i, II-c-ii, III-a-i, III-b-i, IV-a-i, IV-a-ii, IV-b-i, IV-b-ii, IV-c-i, IV-c-ii, V-a-i, V-b-i, or V-c-i: or a pharmaceutically acceptable salt thereof.

13. The compound according to claim 1, wherein R 3 is selected from -CH3, -CD3, -CF2H, -CF3, -CH2CH3, 14. The compound according to claim 1, wherein R 3 is selected from -OCH3, -OCF2H, -OCF3, -O(CH2)2CH3, -O(CH2)2OCH2CH3, -CH2OH, -CH2OCH3, -CH2OCH2CH3, 15. The compound according to claim 1, wherein R 3 is -(CH2) r -Cy.

16. The compound according to claim 1, wherein R 3 is selected from 17. The compound according to claim 1, wherein R 3 is selected from 18. The compound according to any one of claims 1 to 17, selected from the group consisting of:

19. A pharmaceutically acceptable composition, the pharmaceutically acceptable composition comprising the compound according to any one of claims 1 to 18 and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

20. A method for inhibiting the activity of MK2 kinase or a mutant thereof in a biological sample, the method comprising the step of contacting the biological sample with the compound according to any one of claims 1 to 18.

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