Indazole compounds

Abstract

The present invention provides novel compounds having the general formula (I) wherein R1 and A are as described herein, or a pharmaceutically acceptable salt thereof, compositions including the compounds and methods of using the compounds.

Description

[0001] Case P39558

[0002] Indazole compounds

[0003] FIELD OF THE INVENTION

[0004] The present invention relates to organic compounds, in particular to PKMYT1 (protein kinase, membrane-associated tyrosine and threonine kinase) kinase inhibitors, useful for treatment of cancers in a mammal. In particular, the present invention relates to indazole compounds that have PKMYT1 kinase inhibition activity, as well as their manufacture, pharmaceutical compositions containing them and their potential use as medicaments.

[0005] BACKGROUND OF THE INVENTION

[0006] Cells are frequently experiencing both intrinsic and extrinsic genotoxic stresses that cause DNA damage and impair the integrity of our genome. To counter the potential genetic alterations caused by these DNA-damaging factors, cells need to establish various mechanisms to detect DNA lesions and repair DNA damage to maintain genome stability. This sophisticated network, referred to as the DNA damage response (DDR), is orchestrated by multiple highly evolutionarily conserved and coordinated signaling pathways that can correct different types of DNA lesions. One essential component involved in DDR machinery is the activation of cell cycle checkpoints that arrest the cell cycle at a specific stage until damaged DNA has been repaired. At least two types of checkpoints, Gl / S and G2 / M, participate in DDR signaling. They sense DNA damage and pause the cell cycle before DNA replication and chromosome segregation respectively, thereby ensuring the fidelity of genetic information in the divided cells. In cancer cells, genome instability and replication stress are commonly observed due to the dysregulation of DDR machinery usually induced by endogenous genetic alterations of cancer cells or genotoxic agents. For example, Gl / S checkpoints such as p53, are frequently mutated and disrupted in cancer cells. As a result, the survival of cancer cells bearing replication stress and dysfunctional Gl / S checkpoints highly depends on G2 / M checkpoints for the processing of DNA damage repair. Therefore, disruption the G2 / M checkpoint via PKMYT1 kinase activity inhibition has become a promising therapeutic approach especially for genetically targeted cancer therapies. SUMMARY OF THE INVENTION

[0007] Objects of the present invention are novel compounds of formula (I), their manufacture, medicaments based on a compound in accordance with the invention and their production as well as the use of compounds of formula (I) as PKMYT1 kinase inhibitors for the treatment of a broad spectrum of cancers. The compounds of formula (I) show superior PKMYT1 kinase inhibition activity. In addition, the compounds of formula (I) also show good safety and good PK profiles, e.g., good microsome stability, hepatic clearance and safety margin.

[0008] One aspect of the invention pertains to a compound of formula (I), wherein

[0009] R1is H or halogen; and

[0010] R2and R3together with the atoms to which they are bonded form a 5 to 6 membered ring having 0 to 2 heteroatoms independently selected from N, O, and S, wherein the ring is optionally substituted with Ci-6alkyl;

[0011] R5is selected from the group consisting of H, halogen, Ci-6alkyl, and deuterated Ci-ealkyl; or

[0012] R3and R4together with the atoms to which they are bonded form a 5 to 6 membered ring having 0 to 2 heteroatoms independently selected from N, O, and S, R5is H; or

[0013] R3is H, R4and R5together with the atoms to which they are bonded form a 5 to 6 membered ring; or

[0014] (iii) A is

[0015] R6and R7together with the atoms to which they are bonded form a 5 to 6 membered ring having one N atom; or

[0016] (iv) A is

[0017] R8and R9together with the atoms to which they are bonded form a 5 to 6 membered ring having one N atom; or

[0018] (v) A is

[0019] R10and R11together with the atoms to which they are bonded form a 5 to 6 membered ring, or a pharmaceutically acceptable salt thereof.

[0020] Another aspect of the invention pertains to a process for the preparation of a compound of formula (I), as well as a compound of formula (I) or a pharmaceutically acceptable salt thereof when manufactured according to the process.

[0021] Another aspect of the invention pertains to a pharmaceutical composition comprising a compound of this invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0022] Another aspect of the invention pertains to a compound of this invention or a pharmaceutically acceptable salt thereof for use as therapeutically active substance.

[0023] Another aspect of the invention pertains to a compound of this invention or a pharmaceutically acceptable salt thereof for use in the treatment of cancer.

[0024] Another aspect of the invention pertains to the use of a compound of this invention or a pharmaceutically acceptable salt thereof for the treatment of cancer.

[0025] Another aspect of the invention pertains to the use of a compound of this invention or a pharmaceutically acceptable salt thereof for the inhibition of PKMYT1 kinase. Another aspect of the invention pertains to the use of a compound of this invention or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of cancer.

[0026] Another aspect of the invention pertains to the use of a compound of this invention or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the inhibition of PKMYT1 kinase.

[0027] Another aspect of the invention pertains to a method for the treatment of cancer, which method comprises administering an effective amount of a compound of this invention or a pharmaceutically acceptable salt thereof.

[0028] DETAILED DESCRIPTION OF THE INVENTION

[0029] DEFINITIONS

[0030] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Furthermore, the following definitions are set forth to illustrate and define the meaning and scope of the various terms used to describe the invention.

[0031] The nomenclature used in this application is based on IUPAC systematic nomenclature, unless indicated otherwise.

[0032] The term “compound(s) of this invention” and “compound(s) of the present invention” refers to compounds of formula (I), and stereoisomers, solvates or salts thereof (e.g., pharmaceutically acceptable salts).

[0033] The term “substituent” denotes an atom or a group of atoms replacing a hydrogen atom on the parent molecule.

[0034] As used herein, the term “Ci-6alkyl” alone or in combination signifies a saturated, linear- or branched chain alkyl group containing 1 to 6, particularly 2 to 6 or 1 to 4 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl and the like. Particular “Cn ealkyl” groups are methyl, ethyl, propyl, isopropyl, and isopentyl.

[0035] The term “Ci-6alkylene” denotes a linear or branched saturated divalent hydrocarbon group of 1 to 6 carbon atoms or a divalent branched saturated divalent hydrocarbon group of 3 to 6 carbon atoms. Examples of Ci-6alkylene groups include methylene, ethylene, propylene, 2- methylpropylene, butylene, 2-ethylbutylene, pentylene, hexylene.

[0036] The term “halogen” or “halo” denotes fluoro, chloro, bromo, or iodo. The compounds according to the present invention may exist in the form of their pharmaceutically acceptable salts. The term “pharmaceutically acceptable salt” refers to conventional acid-addition salts or base-addition salts that retain the biological effectiveness and properties of the compounds of this invention and are formed from suitable non-toxic organic or inorganic acids or organic or inorganic bases. Acid-addition salts include for example those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid, and those derived from organic acids such as p-tolucncsulfonic acid, trifluoroacetic acid, formic acid, salicylic acid, methanesulfonic acid, oxalic acid, succinic acid, citric acid, malic acid, lactic acid, fumaric acid, and the like. Base-addition salts include those derived from ammonium, potassium, sodium and, quaternary ammonium hydroxides, such as for example, tetramethyl ammonium hydroxide. The chemical modification of a pharmaceutical compound into a salt is a technique well known to pharmaceutical chemists in order to obtain improved physical and chemical stability, hygroscopicity, flowability and solubility of compounds. It is for example described in Bastin R .J., et al., Organic Process Research & Development 2000, 4, 427-435. Particular are the sodium salts of the compounds of this invention.

[0037] The term “therapeutically effective amount” denotes an amount of a compound or molecule of the present invention that, when administered to a subject, (i) treats or prevents the particular disease, condition or disorder, (ii) attenuates, ameliorates or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition or disorder described herein. The therapeutically effective amount will vary depending on the compound, the disease state being treated, the severity of the disease treated, the age and relative health of the subject, the route and form of administration, the judgement of the attending medical or veterinary practitioner, and other factors.

[0038] The term “pharmaceutical composition” denotes a mixture or solution comprising a therapeutically effective amount of an active pharmaceutical ingredient together with pharmaceutically acceptable excipients to be administered to a mammal, e.g., a human in need thereof.

[0039] INHIBITOR OF PKMYT1 KINASE

[0040] The present invention relates to (i) a compound of formula (I), wherein

[0041] R1is H or halogen; and

[0042] (i) A is

[0043] R2and R3together with the atoms to which they are bonded form a 5 to 6 membered ring having 0 to 2 heteroatoms independently selected from N, O, and S, wherein the ring is optionally substituted with Ci-6alkyl;

[0044] R5is selected from the group consisting of H, halogen, Ci-6alkyl, and deuterated Ci-ealkyl; or

[0045] (ii) A is

[0046] R3and R4together with the atoms to which they are bonded form a 5 to 6 membered ring having 0 to 2 heteroatoms independently selected from N, O, and S, R5is H; or

[0047] R3is H, R4and R5together with the atoms to which they are bonded form a 5 to 6 membered ring; or

[0048] (iii) A is

[0049] R6and R7together with the atoms to which they are bonded form a 5 to 6 membered ring having one N atom; or

[0050] (iv) A is

[0051] R8and R9together with the atoms to which they are bonded form a 5 to 6 membered ring having one N atom; or

[0052] R10and R11together with the atoms to which they are bonded form a 5 to 6 membered ring, or a pharmaceutically acceptable salt thereof.

[0053] A further embodiment of present invention is (ii) the compound according to (i), wherein R1is H or fluoro.

[0054] A further embodiment of present invention is (iii) the compound according to (i) or (ii), wherein

[0055] R2and R3together with the atoms to which they are bonded form a 5 to 6 membered ring having 0 to 2 heteroatoms independently selected from N, and O, wherein R2is selected from the group consisting of O, Ci-2alkylene, and -Ci-2alkylene-O-, R3is selected from the group consisting of Ci-3alkylene, -N(Ci-2alkyl)- Ci-2alkylene-, -O-Ci-2alkylene-, -Cn 2alkylene-O-, and O, or

[0056] A further embodiment of present invention is (iv) the compound according to any one of (i)

[0057] - (iii), wherein R5is selected from the group consisting of H, chloro, methyl, and trideuteriomethyl . A further embodiment of present invention is (v) the compound according to (i) or (ii),

[0058] R3and R4together with the atoms to which they are bonded form a 5 to 6 membered ring having 0 to 1 heteroatoms O, wherein R3is C2-3alkylene, R4is O or methylene, R5is H; or

[0059] R3is H, R4and R5together with the atoms to which they are bonded form a 5 to 6 membered ring, wherein R4is C2-3alkylene, R5is methylene.

[0060] A further embodiment of present invention is (vi) the compound according to (i) or (ii),

[0061] R6and R7together with the atoms to which they are bonded form a 5 to 6 membered ring having one N atom, wherein R6is C2-3alkylene, R7is methylene.

[0062] A further embodiment of present invention is (vii) the compound according to (i) or (ii), wherein

[0063] A is selected from the group consisting of

[0064] R5is selected from the group consisting of H, chloro, methyl, and trideuteriomethyl.

[0065] A further embodiment of present invention is (viii) the compound according to (i), wherein R1is halogen,

[0066] R2and R3together with the atoms to which they are bonded form a 5 to 6 membered ring having 1 heteroatom O, wherein R2is selected from the group consisting of O, Ci-2alkylene, and -Ci-2alkylene-O-, R3is selected from the group consisting of Ci-3alkylene and O,

[0067] R5is selected from the group consisting of Ci-6alkyl and deuterated Ci-6alkyl,

[0068] R6and R7together with the atoms to which they are bonded form a 5 to 6 membered ring having one N atom, wherein R6is C2-3alkylene, R7is methylene.

[0069] A further embodiment of present invention is (ix) the compound according to any one of (viii), wherein

[0070] R1is fluoro,

[0071] A is selected from the group consisting of

[0072] R5is selected from the group consisting of methyl, and trideuteriomethyl.

[0073] A further embodiment of present invention is (x) a compound selected from:

[0074] 3-Amino-4-(7-fluoro- lH-indazol-4-yl)- 1 ,7,8,9-tetrahydrocyclopenta[h] [ 1 ,5]naphthyridin-2- one,

[0075] 9-Amino-10-(7-fluoro-177-indazol-4-yl)-6-methyl-2,3,4,7-tetrahydropyrano[2,3- f] [ 1 ,7]naphthyridin-8-one,

[0076] 9-Amino-10-(7-fluoro-177-indazol-4-yl)-6-(trideuteriomethyl)-2, 3,4,7- tetrahydropyrano[2,3-f] [ 1 ,7]naphthyridin-8-one,

[0077] 7-amino-6-(7-fluoro-177-indazol-4-yl)-2,3,4,9-tetrahydropyrano[3,2-b][l,5]naphthyridin-8- one,

[0078] 9-amino-10-(7-fluoro-177-indazol-4-yl)-2,3,4,7-tetrahydropyrano[2,3-f][l,7]naphthyridin-8- one,

[0079] 3-amino-4-(7-fluoro-177-indazol-4-yl)-l,6,7,8-tetrahydrocyclopenta[b][l,5]naphthyridin-2- one,

[0080] 9-Amino-10-(7-fluoro-177-indazol-4-yl)-4-methyl-3,7-dihydro-277-[l,4]oxazino[2,3- f] [ 1 ,7]naphthyridin-8-one,

[0081] 9-Amino- 10-( 177-indazol-4-yl)-6-methyl-2,3,4,7-tetrahydropyrano[2,3-f] [ 1 ,7]naphthyridin-

[0082] 8-one,

[0083] 9-Amino-6-chloro-10-(7-fluoro-177-indazol-4-yl)-2,3,4,7-tetrahydropyrano[2,3- f] [ 1 ,7]naphthyridin-8-one,

[0084] 6-Amino-5-(7-fluoro-177-indazol-4-yl)-3,8-dihydro-277-furo[3,2-b][l,5]naphthyridin-7-one,

[0085] 8-Amino-9-(7-fluoro-177-indazol-4-yl)-5-methyl-3,6-dihydro-277-furo[2,3- f] [ 1 ,7]naphthyridin-7-one,

[0086] 9-Amino- 10-(7-fluoro-177-indazol-4-yl)-6-methyl-3,7-dihydro-277-[l,4]dioxino[2, 3- f] [ 1 ,7]naphthyridin-8-one, 9-Amino-6-chloro-10-(7-fluoro-177-indazol-4-yl)-4-methyl-3,7-dihydro-277-

[0087] [ 1 ,4]oxazino[2,3-f] [ 1 ,7]naphthyridin-8-one,

[0088] 8-amino-5-chloro-9-(7-fluoro-lH-indazol-4-yl)-6H-[l,3]dioxolo[4,5-f][l,7]naphthyridin-7- one,

[0089] 8-Amino-9-(7-fluoro-lH-indazol-4-yl)-5-methyl-6H-[l,3]dioxolo[4,5-f][l,7]naphthyridin-

[0090] 7-one,

[0091] 9-Amino-10-(7-fluoro-lH-indazol-4-yl)-4,6-dimethyl-3,7-dihydro-2H-[l,4]oxazino[2,3- f] [ 1 ,7]naphthyridin-8-one,

[0092] 9-Amino-6-chloro-10-(7-fluoro-177-indazol-4-yl)-l,3,4,7-tetrahydropyrano[3,4- f] [ 1 ,7]naphthyridin-8-one,

[0093] 9-Amino-10-(7-fluoro-177-indazol-4-yl)-6-methyl-l,3,4,7-tetrahydropyrano[3,4- f] [ 1 ,7]naphthyridin-8-one,

[0094] 8-Amino-5-chloro-9-(7-fluoro-177-indazol-4-yl)-2,6-dihydro-177-furo[3,2- f] [ 1 ,7]naphthyridin-7-one,

[0095] 8-Amino-5-chloro-9-(7-fluoro-177-indazol-4-yl)-l,2,3,6- tetrahydrocyclopenta[f] [ 1 ,7]naphthyridin-7-one,

[0096] 8-Amino-9-(7-fluoro-177-indazol-4-yl)-5-methyl-2,6-dihydro-177-furo[3,2- f] [ 1 ,7]naphthyridin-7-one,

[0097] 8-Amino-9-(7-fluoro-177-indazol-4-yl)-5-methyl-l,2,3,6- tetrahydrocyclopenta[f] [ 1 ,7]naphthyridin-7-one,

[0098] 10-Amino-9-(7-fluoro-177-indazol-4-yl)-6,7,12-triazatricyclo[6.4.0.02,6]dodeca-l,7,9-trien-

[0099] 11 -one,

[0100] 8-Amino-9-(7-fluoro-177-indazol-4-yl)-5-methyl-3,6-dihydro-177-furo[3,4- f] [ 1 ,7]naphthyridin-7-one,

[0101] 8-Amino-9-(7-fluoro-177-indazol-4-yl)-5-methyl-6H-furo[2,3-f][l,7]naphthyridin-7-one,

[0102] 5-Amino-6-(7-fluoro-177-indazol-4-yl)-8-oxa-3,12-diazatricyclo[7.4.0.02,7] trideca-

[0103] 1 (9) ,2(7), 5 , 10,12-pentaen-4-one,

[0104] 5-Amino-6-(7-fluoro-lH-indazol-4-yl)-3,8,9-triazatricyclo[7.4.0.02,7]trideca-l,5,7-trien-4- one,

[0105] 3-Amino-4-(7-fluoro-177-indazol-4-yl)-177-[l]benzofuro[2,3-b]pyridin-2-one,

[0106] 9-Amino-10-(7-fluoro-lH-indazol-4-yl)-777-pyrido[2,3-f][l,7]naphthyridin-8-one, or a pharmaceutically acceptable salt thereof. A further embodiment of present invention is (xi) a process for the preparation of a compound having the structure of formula (la), a) formation of compound of formula (la) via decomposition reaction of compound of formula (X), in the presence of hydrazine hydrate; b) formation of compound of formula (la) via cross coupling of compound of formula (XV), and compound of formula (XVI),

[0107] (XVI), in the presence of suitable catalyst, in particular Pd(dtbpf)Ch, Pd(dppf)Ch or Pd(PPh3)4, followed by deprotecting of PG3, in the presence a suitable acid, in particular TFA or HC1, wherein

[0108] Ring B together with the ring to which it is bonded form a tricyclic ring containing two to five heteroatoms selected from N, O, and S, in particular, ring B and the ring to which it is bonded form a tricyclic ring selected from the group consisting of

[0109] Rbis halogen, in particular bromo or iodide,

[0110] Rcis boronic acid, boronic ester or tributyltin,

[0111] PG3 is hydrogen, or a protecting group, in particular p-methoxybenzyl,

[0112] R1is as defined in any one of (i) to (ix).

[0113] A further embodiment of present invention is (xii) a pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof according to any one of (i) to (x), and a pharmaceutically acceptable excipient.

[0114] PHARMACEUTICAL COMPOSITIONS AND ADMINISTRATION

[0115] Another embodiment provides pharmaceutical compositions or medicaments containing the compounds of the invention and a therapeutically inert carrier, diluent or excipient, as well as methods of using the compounds of the invention to prepare such compositions and medicaments. In one example, compounds of this invention may be formulated by mixing at ambient temperature at the appropriate pH, and at the desired degree of purity, with physiologically acceptable carriers, i.e., carriers that are non-toxic to recipients at the dosages and concentrations employed into a galenical administration form. The pH of the formulation depends mainly on the particular use and the concentration of compound, but preferably ranges anywhere from about 3 to about 8. In one example, a compound of this invention is formulated in an acetate buffer, at pH 5. In another embodiment, the compounds of this invention are sterile. The compound may be stored, for example, as a solid or amorphous composition, as a lyophilized formulation or as an aqueous solution. Compositions are formulated, dosed, and administered in a fashion consistent with good medical practice. Factors for consideration in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the scheduling of administration, and other factors known to medical practitioners. The “effective amount” of the compound to be administered will be governed by such considerations, and is the minimum amount necessary to inhibit the growth of PKMYT1 dependent cancers (z.e., cancers whose survival depends on PKMYT1 kinase activity). For example, such amount may be below the amount that is toxic to normal cells, or the mammal as a whole.

[0116] In one example, the pharmaceutically effective amount of the compound of the invention administered parenterally per dose will be in the range of about 0.1 to 1000 mg / kg, alternatively about 0.1 to 1000 mg / kg of patient body weight per day, with the typical initial range of compound used being 0.3 to 15 mg / kg / day. In another embodiment, oral unit dosage forms, such as tablets and capsules, preferably contain from about 1 to about 1000 mg of the compound of the invention.

[0117] The compounds of the invention may be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal and epidural and intranasal, and, if desired for local treatment, intralesional administration. Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.

[0118] The compounds of the present invention may be administered in any convenient administrative form, e.g., tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions may contain components conventional in pharmaceutical preparations, e.g., diluents, carriers, pH modifiers, sweeteners, bulking agents, and further active agents.

[0119] A typical formulation is prepared by mixing a compound of the present invention and a carrier or excipient. Suitable carriers and excipients are well known to those skilled in the art and are described in detail in, e.g., Ansel, Howard C., et al., Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R., et al. Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. The formulations may also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents, diluents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present invention or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament).

[0120] An example of a suitable oral dosage form is a tablet containing about 1 to 1000 mg of the compound of the invention compounded with about 1 to 1000 mg anhydrous lactose, about 1 to 1000 mg sodium croscarmellose, about 1 to 1000 mg polyvinylpyrrolidone (PVP) K30, and about 1 to 1000 mg magnesium stearate. The powdered ingredients are first mixed together and then mixed with a solution of the PVP. The resulting composition can be dried, granulated, mixed with the magnesium stearate and compressed to tablet form using conventional equipment. An example of an aerosol formulation can be prepared by dissolving the compound, for example 5 to 400mg, of the invention in a suitable buffer solution, e.g. a phosphate buffer, adding a tonicifier, e.g. a salt such sodium chloride, if desired. The solution may be filtered, e.g., using a 0.2 micron filter, to remove impurities and contaminants.

[0121] An embodiment, therefore, includes a pharmaceutical composition comprising a compound of this invention, or a stereoisomer or pharmaceutically acceptable salt thereof. In a further embodiment includes a pharmaceutical composition comprising a compound of this invention, or a stereoisomer or pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or excipient.

[0122] Another embodiment includes a pharmaceutical composition comprising a compound of this invention for use in the treatment of PKMYT1 dependent cancers. Another embodiment includes a pharmaceutical composition comprising a compound of this invention for use in the treatment of PKMYT1 dependent cancers.

[0123] The following composition A and B illustrate typical compositions of the present invention, but serve merely as representative thereof.

[0124] Composition A

[0125] A compound of the present invention can be used in a manner known per se as the active ingredient for the production of tablets of the following composition:

[0126] Per tablet

[0127] Active ingredient 200 mg

[0128] Microcrystalline cellulose 155 mg Corn starch 25 mg

[0129] Talc 25 mg

[0130] Hydroxypropylmethylcellulose 20 mg

[0131] 425 mg

[0132] Composition B

[0133] A compound of the present invention can be used in a manner known per se as the active ingredient for the production of capsules of the following composition:

[0134] Per capsule

[0135] Active ingredient 100.0 mg

[0136] Corn starch 20.0 mg

[0137] Lactose 95.0 mg

[0138] Talc 4.5 mg

[0139] Magnesium stearate 0,5 mg

[0140] 220.0 mg

[0141] INDICATIONS AND METHODS OF TREATMENT

[0142] The compounds of the invention bind to the kinase domain of PKMYT1, inhibit its kinase activity and thereby reduce inhibitory CDK1 phosphorylation at Thrl4 without grossly affecting CDK1 phosphorylation at Tyrl5. Inhibition of PKMYT1, a negative regulator of CDK1, causes unscheduled CDK1 activation that forces cells to enter into mitosis. In cancer cells with high level of replication stress or DNA damage, e.g. cancer cells with amplification of cyclin El (CCNE1), inhibition of PKMYT1 further induces CDK1 imbalance and promotes early mitotic entry in cells undergoing DNA synthesis and DNA repair, which eventually results in accumulation of replication stress and leads to catastrophic genome instability. Therefore, the compounds of the invention are useful for treating cancers bearing high level of replication stress and genome instability. Alternatively, the compounds of the invention are useful for combinational therapeutic approaches with agents that induce DNA damage or perturb DNA replication or DNA damage repair process.

[0143] Another embodiment includes a method of treating cancer in a mammal in need of such treatment, wherein the method comprises administering to said mammal a therapeutically effective amount of a compound of formula (I), a stereoisomer, tautomer, prodrug or pharmaceutically acceptable salt thereof. Cancer includes but is not limited to sarcomas, adenocarcinomas, blastomas, and carcinomas, of the various organ systems, such as those affecting pancreas, liver, lung, breast, stomach, buliarintestinal (e.g. colon), genitourinary tract (e.g. renal urothelial cells) and ovary.

[0144] A further embodiment of present invention is (xxxii) a compound of the invention for use as therapeutically active substance.

[0145] A further embodiment of present invention is (xxxiii) a compound of the invention for use in the treatment or cancer.

[0146] A further embodiment of present invention is (xxxiv) the use of a compound of the invention for the treatment of cancer.

[0147] A further embodiment of present invention is (xxxv) the use of a compound of the invention for the inhibition of PKMYT1.

[0148] A further embodiment of present invention is (xxxvi) the use of a compound of the invention for the preparation of a medicament for the treatment of cancer.

[0149] A further embodiment of present invention is (xxxvii) the use of a compound of the invention for the preparation of a medicament for the inhibition of PKMYT1.

[0150] A further embodiment of present invention is (xxxviii) a method for the treatment of cancer, which method comprises administering an effective amount of a compound of the invention.

[0151] A further embodiment of present invention is (xxxix) the use of according to (xxxiv) or (xxxvi), or the method according to (xxxviii), wherein the cancer is a cancer in pancreas, liver, lung, breast, stomach, buliarintestinal, genitourinary tract, or ovary.

[0152] SYNTHESIS

[0153] The compounds of the present invention can be prepared by any conventional means. Suitable processes for synthesizing these compounds as well as their starting materials are provided in the schemes below and in the examples. All substituents, in particular, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, and R11are defined above. Furthermore, and unless explicitly otherwise stated, all reactions, reaction conditions, abbreviations and symbols have the meanings well known to a person of ordinary skill in organic chemistry.

[0154] General synthetic routes for preparing the compound of formula (la) are shown below.

[0155] Scheme 1:

[0156] Wherein

[0157] Rais halogen, such as Br or I;

[0158] PGi is a protecting group, such as tert-butoxycarbonyl,

[0159] PG2 is hydrogen, or a protecting group such as tetrahydropyranyl,

[0160] Ring B together with the ring to which it is bonded form a tricyclic ring containing two to five heteroatoms selected from N, O, and S; in particular, B and the ring to which it is bonded form a tricyclic ring selected from the group consisting of and

[0161] Compound of formula (VI) could be obtained from metal-halogen exchange reaction of compound of formula (II) in the presence of organometallic reagent, such as n-BuLi or z- PrMgBr, followed by nucleophilic addition reacting with compound of formula (III). Alternatively, compound of formula (VI) could be obtained from compound of formula (V) instead of compound of formula (II) and compound of formula (IV) instead of compound of formula (III). The oxidation of alcohol of the compound of formula (IV) with a suitable oxidant, such as Dess-Martin periodinane or MnCE, could afford compound of formula (VII). The deprotection of compound of formula (VII) in the presence of a suitable acid, such as TFA or HC1, could afford compound of formula (VIII). Compound of formula (IX) could be prepared from acylation of compound of formula (VIII) with 2-chloroacetyl chloride in the presence of a suitable base such as pyridine, DMAP, TEA or DIPEA. Cyclization of compound of formula (IX) in the presence of pyridine could afford compound of formula (X). Compound of formula (la) could be obtained by decomposition of pyridinium salts of formula (X) with hydrazine hydrate.

[0162] Scheme 2:

[0163] Wherein

[0164] Rbis halogen, such as bromo or iodide,

[0165] Rcis boronic acid, boronic ester or tributyltin,

[0166] PG3 is hydrogen, or a protecting group such as p-methoxybenzyl,

[0167] Ring B together with the ring to which it is bonded form a tricyclic ring containing two to five heteroatoms selected from N, O, and S; in particular, B and the ring to which it is bonded form a tricyclic ring selected from the group consisting of

[0168] and

[0169] Alternatively, the compound of formula (la) could also be prepared according to the scheme 2. The nitration of compound of formula (XI) in the presence a suitable nitrating reagent, such as nitric acid, could afford compound of formula (XII). Halogenation of compound of formula (XII) could afford compound of formula (XIII) in the presence of suitable reagent, such as POBi'3. The reduction of compound of formula (XIII) in the presence a suitable reduction reagent, such as iron powder, sodium dithionite or Pd / C with hydrogen, could afford compound of formula (XIV). The deprotecting of compound of formula (XIV) in the presence a suitable acid, such as methanesulfonic acid, could afford compound of formula (XV). Cross coupling reaction of compound of formula (XV) and compound of formula (XVI) in the presence of suitable catalyst, such as Pd(dtbpf)Ch, Pd(dppf)Ch or Pd(PPh3)4, could afford compound of formula (XVII). Compound of formula (la) could be obtained by deprotection of compound of formula (XVII) in the presence a suitable acid such as TFA or HC1.

[0170] Compounds of this invention can be obtained as mixtures of diastereomers or enantiomers, which can be separated by methods well known in the art, e.g. (chiral) HPLC or SFC.

[0171] This invention also relates to a process for the preparation of a compound of formula (la) comprising one of the following steps: a) formation of compound of formula (la), via decomposition reaction of compound of formula (X),

[0172] (X), in the presence of hydrazine hydrate; b) formation of compound of formula (la), via cross coupling of compound of formula (XV),

[0173] (XV), and compound of formula (XVI),

[0174] (XVI), in the presence of suitable catalyst, such as Pd(dtbpf)Ch, Pd(dppf)Ch or Pd(PPh3)4, followed by deprotecting of PG3 in the presence a suitable acid, such as TFA or HC1, wherein Rbis halogen, such as bromo or iodide; Rcis boronic acid, boronic ester or tributyltin, and PG3 is hydrogen, or a protecting group such as p-methoxybenzyl group.

[0175] EXAMPLES The invention will be more fully understood by reference to the following examples. They should not, however, be construed as limiting the scope of the invention.

[0176] ABBREVIATIONS

[0177] Abbreviations used herein are as follows: aq.: aqueous

[0178] Boc: tert-butoxycarbonyl group

[0179] CS2CO3: caesium carbonate

[0180] DCM: dichloromethane

[0181] DIPEA: 2V,iV-diisopropylethylamine

[0182] DMAP: 4-dimethylaminopyridine

[0183] DMF: V,V-dimcthylformamidc

[0184] EtOAc: ethyl acetate

[0185] K2CO3: potassium carbonate

[0186] MeCN: acetonitrile

[0187] MeOH: methanol

[0188] NCS: V-chlorosuccin imide

[0189] NBS: V-bromo succinimide

[0190] NMP: V-mcthyl-2-pyrrolidonc

[0191] NaHMDS: sodium bis(trimethylsilyl)amide

[0192] NADPH: reduced nicotinamide adenine dinucleotide phosphate

[0193] NaOH: sodium hydroxide

[0194] NaH: sodium hydride

[0195] Na2S2O3: sodium thiosulfate

[0196] Na2SO4: sodium sulfate

[0197] NH4HCO3: ammonium bicarbonate

[0198] NH4CI: ammonium chloride

[0199] HC1: hydrochloric acid

[0200] N2: nitrogen

[0201] THF: tetrahydrofuran

[0202] TFA: trifluoroacetic acid

[0203] TEA: triethylamine

[0204] THP: tetrahydropyran group

[0205] Pd(OAc)2: palladium(II) acetate Pd(dppf)C12: 1 , 1 '-bis(diphenylphosphino)ferrocene-palladium(II)dichloride

[0206] Pd(dtbpf)Ch: 1 , 1 '-bis(di-tert-butylphosphino)ferrocene palladium dichloride

[0207] PdC12(PPh3)2: dichlorobis(triphenylphosphine)palladium(II) z-PrMgBr: isopropylmagnesium bromide

[0208] Na2CO3: sodium carbonate

[0209] HEPES: 4-(2-hydroxyethyl)-l -piperazineethanesulfonic acid

[0210] EGTA: ethylene glycol-bis(P-aminoethyl ether)-N,N,N’,N’ -tetraacetic acid

[0211] DTT: dithiothreitol

[0212] IPA: isopropyl alcohol

[0213] Xphos: 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl rt: room temperature

[0214] IC50: the molar concentration of an inhibitor, which produces 50% of the maximum possible response for that inhibitor.

[0215] HPLC: high performance liquid chromatography

[0216] Prep-TLC: preparative thin layer chromatography

[0217] MS (ESI): mass spectroscopy (electron spray ionization) obsd: observed

[0218] PE: petroleum ether

[0219] 5: chemical shift

[0220] SFC: supercritical fluid chromatography

[0221] GENERAL EXPERIMENTAL CONDITIONS

[0222] Intermediates and final compounds were purified by flash chromatography using one of the following instruments: i) Biotage SP1 system and the Quad 12 / 25 Cartridge module, ii) ISCO combi-flash chromatography instrument. Silica gel brand and pore size: i) KP-SIL 60 A, particle size: 40-60 pm; ii) CAS registry NO: Silica Gel: 63231-67-4, particle size: 47-60 micron silica gel; iii) ZCX from Qingdao Haiyang Chemical Co., Ltd, pore: 200-300 or 300-400.

[0223] Alternatively, intermediates and final compounds were purified by preparative HPLC on reversed phase column using XBridge™ Prep-C18 (5 pm, OBDTM 30 x 100 mm) column, SunFire™ Prep-C18 (5 pm, OBD™ 30 x 100 mm) column, Phenomenex Synergi-C18 (10 pm, 25 x 150 mm) or Phenomenex Gemini-C18 (10 pm, 25 x 150 mm); Waters AutoP purification System (Sample Manager 2767, Pump 2525, Detector: Micromass ZQ and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water; acetonitrile and 0.1% FA in water or acetonitrile and 0.1% TFA in water); or Gilson-281 purification System (Pump 322, Detector: UV 156, solvent system: acetonitrile and 0.05% ammonium hydroxide in water; acetonitrile and 0.225% FA in water; acetonitrile and 0.05% HC1 in water; acetonitrile and 0.075% TFA in water; or acetonitrile and water).

[0224] For SFC chiral separation, intermediates and final compounds were separated by chiral column (Daicel chiralpak IC, 5 pm, 30 x 250 mm), AS (10 pm, 30 x 250 mm) or AD (10 pm, 30 x 250 mm) using Mettler Toledo Multigram III system SFC, Waters 80Q preparative SFC or Thar 80 preparative SFC, solvent system: CO2 and IPA (0.5% TEA in IPA) or CO2 and MeOH (0.1% NEp-EhO in MeOH), back pressure lOObar, detection UV @ 254 or 220 nm.

[0225] LC / MS spectra of compounds were obtained using a LC / MS (Waters™ Alliance 2795- Micromass ZQ, Shimadzu Alliance 2020-Micromass ZQ or Agilent Alliance 6110-Micromass ZQ), LC / MS conditions were as follows (running time 3 or 1.5 mins):

[0226] Acidic condition I: A: 0.1% TFA in H2O; B: 0.1% TFA in acetonitrile;

[0227] Acidic condition II: A: 0.0375% TFA in H2O; B: 0.01875% TFA in acetonitrile;

[0228] Basic condition I: A: 0.1% NH3 H2O in H2O; B: acetonitrile;

[0229] Basic condition II: A: 0.025% NH3 H2O in H2O; B: acetonitrile;

[0230] Neutral condition: A: H2O; B: acetonitrile.

[0231] Mass spectra (MS): generally only ions which indicate the parent mass are reported, and unless otherwise stated the mass ion quoted is the positive mass ion (MH)+.

[0232] NMR Spectra were obtained using Bruker Avance 400 / 500 MHz. The microwave assisted reactions were carried out in a Biotage Initiator Sixty microwave synthesizer. All reactions involving air-sensitive reagents were performed under an argon or nitrogen atmosphere. Reagents were used as received from commercial suppliers without further purification unless otherwise noted.

[0233] PREPARATIVE EXAMPLES

[0234] The following examples are intended to illustrate the meaning of the present invention but should by no means represent a limitation within the meaning of the present invention:

[0235] Intermediate 1: Tert-butyl (3-bromo-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl)carbamate

[0236] Int-1

[0237] Step 1: 2-Cyclopentylidenemalononitrile

[0238] Int-la

[0239] A mixture of cyclopentanone (10.5 mL, 118 mmol), malononitrile (11.7 g, 178 mmol), ammonium acetate (5.9 g, 77.2 mmol) and acetic acid (7.0 mL, 118 mmol) in toluene (100 mL) was stirred at 115 °C for 1.5 h under N2 protection. The mixture was filtered and the filtrate was concentrated under vacuum to give a residue, which was purified by silica-gel chromatography (elute with EtOAc: PE = 0-10%) to give Int-la (10.0 g, 63.6% yield) as a white gum. ’ H NMR (400 MHz, CDCI3-J) 8 ppm 2.81-2.78 (m, 4H), 1.94-1.90 (m, 4H).

[0240] Step 2: 2-(2-((Dimethylamino)methylene)cyclopentylidene)malononitrile

[0241] Int-lb

[0242] A solution of Int-la (9.0 g, 68.1 mmol), acetic anhydride (1.35 mL, 68.1 mmol) and N,N- dimethylformamide dimethyl acetal (9.7 g, 81.7 mmol) in toluene (100 mL) was stirred at 25 °C for 0.5 h. After completion, the reaction mixture was concentrated under reduced pressure to give crude Int-lb (12 g, crude) as a brown solid. MS (ESI+) obsd. [(M+H)+]: 188.1.

[0243] Step 3 : 3-Bromo-6,7 -dihyd ro-5H-cyclopenta[ c ] py ridine-4-carbonit ile

[0244] Int-lc

[0245] To a solution of Int-lb (5.0 g, 26.7 mmol) in acetic acid (50 mL) was added hydrobromic acid (41 g, 168 mmol) dropwise. The mixture was degassed under vacuum and purged with nitrogen several time, then stirred at 55 °C for 1 h. The mixture was filtered and washed with PE (100 ml). The filtrate was concentrated under vacuum to give compound Int-lc (5.7 g, 95.7% yield) as a yellow solid. MS (ESI+) obsd. [(M+H)+]: 223.2.

[0246] Step 4: 3-Bromo-6,7-dihydro-5H-cyclopenta[c]pyridine-4-carboxamide

[0247] Int-ld

[0248] A solution of Int-lc (5.7 g, 25.6 mmol) and NaOH (8.0 g, 200 mmol) in water (100 mL) was stirred at 100 °C for 12 h. After completion, the mixture was filtered and the filtrate was concentrated under vacuun to give Int-ld (5 g, 20.74 mmol) as a white solid. MS (ESI+) obsd. [(M+H)+]: 241.2.

[0249] Step 5: 3-Bromo-6,7-dihydro-5H-cyclopenta[c]pyridin-4-amine

[0250] Int-le

[0251] To a solution of NaOH (2.8 g, 71.1 mmol) and sodium hypochlorite (45 g, 30.2 mmol) in THF (30 mL) and water (30 mL) was added Int-ld (5.2 g, 21.5 mmol) at 0 °C. The mixture was stirred at 25 °C for 4 h. After completion, the mixture was quenched with saturated ammonium chloride (220 mL) and extracted with EtOAc (200 mL x 3). The combined organic layer was concentrated under vacuum to give a residue, which was purified by silica gel chromatography (elute with EtOAc: PE = 0-20%) to give compound Int-le (2.8 g, 60.1% yield) as a yellow solid. MS (ESI+) obsd. [(M+H)+]: 213.2. Step 6: Tert-butyl (3-bromo-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl)carbamate

[0252] Int-1

[0253] To a solution of Int-le (2.3 g, 10.9 mmol) in THF (30 mL) was added NaHMDS (21.5 mL, 21.5 mmol) dropwise at 0 °C and the mixture was stirred at 0 °C for 0.5 h. And then, a solution of di-t-butyldicarbonate (2.59 g, 11.8 mmol) in THF (8 mL) was added dropwise at 0 °C and the mixture was stirred for another 1 h at 0 °C. After completion, the mixture was quenched with saturated ammonium chloride (80 mL) and extracted with EtOAc (100 mL x 3). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to give Int-1 (3.3 g, 97.6% yield) as a yellow solid. MS (ESI+) obsd. [(M+H)+]: 315.3.

[0254] Intermediate 2: Tert-butyl (6-bromo-3,4-dihydro-2H-pyrano[3,2-b]pyridin-7-yl)carbamate

[0255] Int-2

[0256] Step 1: 5-Bromo-3-(3-bromopropoxy)-2-iodopyridine

[0257] Int-2a

[0258] A mixture of 1,3-dibromopropane (15.67 mL, 150.1 mmol), K2CO3 (8.3 g, 60.0 mmol) and 5-bromo-2-iodo-pyridin-3-ol (9.0 g, 30.01 mmol) in DMF (80 mL) was stirred at 60 °C for 2 h. After completion, the mixture was filtered and the filtrate was concentrated under vacuum to give a crude residue, which was purified by silica- gel chromatography (elute with EtOAc: PE = 0-20%) to give Int-2a (11.0 g, 87.1% yield) as a yellow solid. MS (ESI+) obsd. [(M+ H)+]: 421.8.

[0259] Step 2: 7-bromo-3,4-dihydro-2H-pyrano[3,2-b]pyridine

[0260] Int-2b To a solution of Int-2a (11.0 g, 26.1 mmol) in THF (150 mL) was added dropwise n-BuLi (11.0 mL, 27.4 mmol) at -78°C under nitrogen atmosphere. Then the mixture was stirred for 1 h. The reaction mixture was quenched with saturated ammonium chloride (300 mL) and the resulting mixture was extracted with ethyl acetate (300 mL x 3). The combined organic layer was washed with brine (300 mL), dried over anhydrous sodium sulfate and concentrated under vacuum to give a residue, which was purified by silica-gel chromatography (elute with EtOAc: PE = 0-20%) to give Int-2b (3.6 g, 64.3% yield) as a yellow solid. MS (ESI+) obsd. [(M+ H)+]: 213.9.

[0261] Step 3: Tert-butyl (3,4-dihydro-2H-pyrano[3,2-b]pyridin-7-yl)carbamate

[0262] Int-2c

[0263] A mixture of Int-2b (2.4 g, 20.2 mmol), Xphos (1.4 g, 3.3 mmol), Pd(OAc)2 (0.4 g, 1.7 mmol) and CS2CO3 (11.0 g, 33.6 mmol) in 1,4-dioxane (60 mL) was stirred at 100 °C for 6 h under N2 protection. After completion, the mixture was filtered and the filtrate was concentrated under vacuum to give a residue, which was purified by silica-gel chromatography (elute with EtOAc: PE = 0-20%) to give Int-2c (3.8 g, 90.3% yield) as a yellow solid. MS (ESI+) obsd. [(M+H)+]: 251.1

[0264] Step 4: Tert-butyl (6-bromo-3,4-dihydro-2H-pyrano[3,2-b]pyridin-7-yl)carbamate

[0265] Int-2

[0266] To a solution of Int-2c (1.8 g, 7.2 mmol) in MeCN (30 mL) was added NBS (2.6 g, 14.4 mmol) at rt. The mixture was stirred at 25 °C for 2 h. After completion, the reaction mixture was quenched with saturated sodium sulfite (80 mL) and extracted with ethyl acetate (120 mL x 3). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue, which was purified by silica-gel chromatography (elute with EtOAc: PE = 0-20%) to give Int-2 (2.2 g, 92.9% yield) as a yellow solid. MS (ESI+) obsd. [(M+H)+]: 329.0.

[0267] Intermediate 3: Tert-butyl (2-bromo-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl)carbamate

[0268] Int-3

[0269] Step 1: 6,7-Dihydro-5H-cyclopenta[b]pyridin-3-amine

[0270] Int-3a

[0271] To a solution of 3-nitro-6,7-dihydro-577-cyclopenta[b]pyridine (2.0 g, 12.2 mmol) and NH4CI (3.3 g, 61.0 mmol) in ethanol (50 mL) and water (10 mL) was added iron (2.1 g, 36.6 mmol), and the reaction mixture was stirred at 50 °C for 1 h. After completion, the mxiture was filtered and the filtrate was concentracted under vacuum to give a residue, which was purified by silica-gel chromatography (elute with EtOAc: PE = 0-100%) to give to Int-3a (1.6 g, 97.9% yield) as a yellow solid. MS (ESI+) obsd. [(M+H)+]: 135.2.

[0272] Step 2: 2-Bromo-6,7-dihydro-5H-cyclopenta[b]pyridin-3-amine

[0273] Int-3b

[0274] To a solution of Int-3a (1.5 g, 11.18 mmol) in MeCN (50 mL) was added NBS (2.19 g, 12.3 mmol) portionwise at 0 °C, and the reaction mixture was stirred at 0 °C for 1 h. After completion, the reaction mixture was concentrated under vacuum to give a residue, which was purified by silica-gel chromatography (elute with EtOAc: PE = 0-50%) to give Int-3b (1.5 g, 63.0% yield) as a light yellow solid. MS (ESI+) obsd. [(M+H)+]: 213.0

[0275] Step 3: Tert-butyl V-(2-bromo-6.7-dihydro-5 / / -cyclopenta|b|pyridin-3-yl)- V-tert- butoxy carbonyl-carbamate

[0276] Int-3c

[0277] To a solution of Int-3b (1.5 g, 7.1 mmol), DMAP (86.0 mg, 0.7 mmol) and TEA (3.6 g, 35.2 mmol) in THF (30 mL) was added di-t-butyldicarbonate (4.61 g, 21.12 mmol), and the reaction mixture was stirred at 50 °C for 4 h. After completion, the mixture was diluted with EtOAc (50 mL) and washed with brine (30 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to give crude product (3.0 g, crude) as a light brown solid, which was used in the next step directly. MS (ESI+) obsd. [(M+H)+]: 415.0.

[0278] Step 4: Tert-butyl (2-bromo-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl)carbamate

[0279] A mixture of Int-3c (3.0 g, 7.3 mmol) and NaOH (0.87 g, 21.8 mmol) in methanol (30 mL) and water (5 mL) was stirred at 50 °C for 8 h. After completion, the reaction mixture was concentrated under vacuum to give a residue, which was purified by silica-gel chromatography (elute with EtOAc: PE = 0-20%) to give Int-3 (1.2 g, 52.8% yield) as a yellow solid. MS (ESI+) obsd. [(M+H)+]: 313.0.

[0280] Intermediate 4: Tert-butyl (4-methyl-3,4-dihydro-2H-pyrido[3,2-b][l,4]oxazin-7- yl)carbamate

[0281] Step 1: 7-Bromo-4-methyl-3,4-dihydro-2H-pyrido[3,2-b][l,4]oxazine

[0282] Int-4a

[0283] To a solution of 7-bromo-3,4-dihydro-277-pyrido[3,2-b][l,4]oxazine (6.0 g, 27.9 mmol) in THF (60 mL) was added NaH (1.34 g, 33.48 mmol) at 0 °C, then the reaction mixture was stirred at 25 °C for 0.5 h. And then, iodomethane (3.47 mL, 55.8 mmol) was added to the above mixture and the mixture was stirred at 25 °C for 1 h. After completion, the reaction mixture was quenched with saturated ammonium chloride (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layer was concentrated under vacuum to give Int-4a (6.3 g, crude) as a yellow solid, which was used in the next step directly. MS (ESI+) obsd. [(M+H)+]: 230.9.

[0284] Step 2: Tert-butyl (4-methyl-3,4-dihydro-2H-pyrido[3,2-b][l,4]oxazin-7-yl)carbamate

[0285] Int-4

[0286] A mixture of solution of Int-4a (6.3 g, 27.5 mmol), tert-butyl carbamate (6.4 g, 55.0 mmol), Xphos (2.6 g, 5.5 mmol), Pd(OAc)2 (0.62 g, 2.75 mmol) and CS2CO3 (17.9 g, 55.0 mmol) in 1,4- dioxane (100 mL) was stirred at 100 °C for 12 h under nitrogen atmosphere. The suspension was filtered and the filtrate was concentrated under vacuum to give a residue, which was purified by silica-gel chromatography (elute with THF: PE = 0-20%) to give Int-4 (7.0 g, 96.0% yield) as a yellow oil. MS (ESI+) obsd. [(M+ H)+]: 266.2.

[0287] Intermediate 5: Tert-butyl (6-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-7-yl)carbamate

[0288] Int-5

[0289] The title compound was prepared in analogy to the preparation of Int-2, replacing compound NBS with NCS in step 4. Int-5 (850 mg) was obtained as a yellow solid. MS (ESI+) obsd. [(M+H)+]: 285.0.

[0290] Intermediate 6: Tert-butyl (5-bromo-2,3-dihydrofuro[3,2-b]pyridin-6-yl)carbamate

[0291] Int-6

[0292] Step 1: Methyl 5-acetoxy-6-iodonicotinate

[0293] Int-6a

[0294] A mixture of methyl 5-hydroxy-6-iodo-pyridine-3-carboxylate (5.0g, 17.9 mmol), acetyl chloride (2.6 mL, 35.8 mmol) and TEA (7.3 g, 71.7 mmol) in DCM (5 mL) was stirred at 25 °C for 12 h. After completion, the reaction mixture was quenched with water (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layer was washed with brine (130 mL), dried over anhydrous sodium sulfate and concentrated under vacuum to give a residue, which was purified by silica-gel chromatography (elute with EtOAc: PE = 0-30%) to give Int-6a (4.9 g, 85.2% yield) as a yellow solid. MS (ESI+) obsd. [(M+H)+]: 322.1.

[0295] Step 2: Methyl 5-acetoxy-6-((trimethylsilyl)ethynyl)nicotinate

[0296] Int-6b

[0297] A smixture of Int-6a (4.9 g, 15.2 mmol), TEA (23.1 g, 228 mmol), copper(I) iodide (289 mg, 1.5 mmol), PdCh(PPh3)2 (642 mg, 0.9 mmol) and trimethylsilylacetylene (2.0 g, 19.8 mmol) in THF (100 mL) was stirred at 25 °C for 2 h under N2 protection. After completion, the mixture was filtered and the filtrate was concentrated under vacuum to give Int-6b (4.3 g, 96.7% yield) as a yellow solid. MS (ESI+) obsd. [(M+H)+]: 292.0.

[0298] Step 3: Methyl furo[3,2-b]pyridine-6-carboxylate

[0299] Int-6c

[0300] To a mixture of Int-6b (4.3 g, 14.8 mmol) in methanol (50 mL) was added potassium fluoride (2.6 g, 44.2 mmol), and the reaction mixture was stirred at 25 °C for 12 h. After completion, the suspension was filtered and the filtrate was concentrated under vacuum to give a residue, which was purified by silica-gel chromatography (elute with EtOAc: PE = 0-20%) to give Int-6c (1.95 g, 74.6% yield) as a yellow solid. MS (ESI+) obsd. [(M+H)+]: 178.0.

[0301] Step 4: Methyl 2,3-dihydrofuro[3,2-b]pyridine-6-carboxylate

[0302] Int-6d

[0303] A mixture of Int-6c (1.90 g, 10.72 mmol) and palladium on carbon (1.0 g, 10% wet) in methanol (30 mL) was stirred under H2 (50 psi) at 30 °C for 12 h. After completion, the mixture was filtered and the filtrate was concentrated under vacuum to give Int-6d (700.0 mg, 63.3% yield) as a yellow solid. MS (ESI+) obsd. [(M+H)+]: 180.3. Step 5: 2,3-Dihydrofuro[3,2-b]pyridine-6-carboxylic acid

[0304] A mixture of Int-6d (1.2 g, 6.7 mmol), lithium hydroxide (12.0 mL, 48.0 mmol) in methanol (2 mL) and water (2 mL) was stirred at 25 °C for 2 h. After completion, the mixture was dropped into HC1 (4M) (10 mL) and the suspention was collected by filtration to afford a solid Int-6e (0.7 g, 63.3% yield) as a yellow solid. MS (ESI+) obsd. [(M+H)+]: 166.0.

[0305] Step 6: Tert-butyl (2,3-dihydrofuro[3,2-b]pyridin-6-yl)carbamate

[0306] Int-6f

[0307] A mixture of Int-6e (625 mg, 3.8 mmol), TEA (458 mg, 4.54 mmol), diphenylphosphoryl azide (1.6 g, 5.7 mmol) and 2-methylpropan-2-ol (280 mg, 3.8 mmol) in toluene (2 mL) was stirred at 80 °C for 4 h. After completion, the reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layer was concentrated under vacuum to give a residue, which was purified by perp-HPLC (NH4HCO3 as additive) to give Int-6f (340.0 mg, 38.0% yield) as a yellow gum. MS (ESI+) obsd. [(M+H)+]: 237.2.

[0308] Step 7: Tert-butyl (5-bromo-2,3-dihydrofuro[3,2-b]pyridin-6-yl)carbamate

[0309] Int-6

[0310] To a mixture of Int-6f (340.0 mg, 1.4 mmol) in MeCN (2 mL) was added NBS (384 mg, 2.16 mmol), and the reaction mixture was stirred at 25 °C for 2 h. After completion, the reaction mixture was quenched with saturated sodium sulfite (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to give a residue, which was purified by silica-gel chromatography (elute with THF: PE = 0-20%) to give Int-6 (370.0 mg, 81.6% yield) as a white solid. MS (ESI+) obsd. [(M+H)+]: 317.0.

[0311] Intermediate 7: Tert-butyl (6-chloro-2,3-dihydro-[l,4]dioxino[2,3-b]pyridin-7-yl)carbamate

[0312] Int-7

[0313] Step 1: Tert-butyl (2,3-dihydro-[l,4]dioxino[2,3-b]pyridin-7-yl)carbamate

[0314] Int-7a

[0315] A mixture of 7-bromo-2,3-dihydro-[l,4]dioxino[2,3-b]pyridine (1.30 g, 11.1 mmol), tertbutyl carbamate (3.2 g, 27.5 mmol), Xphos (0.79 g, 1.85 mmol), Pd(0Ac)2 (0.21 g, 0.93 mmol) and CS2CO3 (6.03 g, 18.5 mmol) in 1,4-dioxane (20 mL) was stirred at 100 °C for 4 h. After completion, the suspension was filtered and the filtrate was concentrated under vacuum to give a residue, which was purified by silica-gel chromatography (elute with EtOAc: PE = 0-30%) to give Int-7a (1.60 g, 68.5% yield) as a yellow solid. MS (ESI+) obsd. [(M+H)+]: 253.1.

[0316] Step 2: Tert-butyl (6-chloro-2,3-dihydro-[l,4]dioxino[2,3-b]pyridin-7-yl)carbamate

[0317] Int-7

[0318] To a solution of Int-7a (800 mg, 3.2 mmol) in DMF (16 mL) was added NCS (508 mg, 3.8 mmol), and the mixture was stirred at 50 °C for 2 h. After completion, the mixture was extracted with EtOAc (15 mL x 3). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to give a residue, which was purified by silica-gel chromatography (elute with EtOAc: PE = 0-10%) to give Int-7 (800 mg, 88.0% yield) as a white solid. MS (ESI+) obsd. [(M+H)+]: 287.1.

[0319] Intermediate 8: Tert-butyl (6-chloro-4-methyl-3,4-dihydro-2H-pyrido[3,2-b][l,4]oxazin-7- yl)carbamate Step 1: 7-Bromo-6-chloro-3,4-dihydro-2H-pyrido[3,2-b][l,4]oxazine

[0320] H

[0321] .N N Cl o

[0322] Int-8a

[0323] To a solution of 6-chloro-3,4-dihydro-277-pyrido[3,2-b][l,4]oxazine (540.0 mg, 3.2 mmol) in MeCN (10 mL) was added NBS (619.7 mg, 3.5 mmol) at 0 °C. Then the mixture was stirred at 0 °C for 1 h. After completion, the reaction mixture was quenched with saturated sodium sulfite (10 mL) and saturated sodium bicarbonate (10 mL), then the resulting mixture was filtered and the filter cake was dried under vacum to give Int-8a (700.0 mg, crude) as a white solid. MS (ESP) obsd. [(M+H)+]: 250.9.

[0324] Step 2: 7-Bromo-6-chloro-4-methyl-3,4-dihydro-2H-pyrido[3,2-b][l,4]oxazine

[0325] Int-8b

[0326] To a solution of Int-8a (700.0 mg, 2.8 mmol) in THF (10 mL) was added NaH (134.7 mg, 3.4 mmol) at 0 °C, then the reaction mixture was stirred at 25 °C for 0.5 h. And then, iodomethane (0.35 mL, 5.61 mmol, 2.0 eq) was added to the above mixture and the mixture was stirred at 25 °C for 1 h. After completion, the mixture was quenched with saturated ammonium chloride (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to give Int-8a (0.7 g, crude) as a yellow solid. MS (ESI+) obsd. [(M+H)+]: 263.0.

[0327] Step 3: Tert-butyl (6-chloro-4-methyl-3,4-dihydro-2H-pyrido[3,2-b][l,4]oxazin-7- yl)carbamate

[0328] Int-8

[0329] The title compound was prepared in analogy to the preparation of In-4, replacing Int-4a with Int-8b in step 2. Int-8 (650 mg) was obtained as a yellow oil. MS (ESI+) obsd. [(M+H)+]: 300.1. Intermediate 9: Tert-butyl (5-chloro-[l,3]dioxolo[4,5-b]pyridin-6-yl)carbamate

[0330] Int-9

[0331] Step 1: 6-Bromo-[l,3]dioxolo[4,5-b]pyridine

[0332] Int-9a

[0333] A mixture of 5-bromopyridine-2,3-diol (25.0 g, 132 mmol), K2CO3 (54.4 g, 395 mmol) and dibromomethane (27.5 g, 158 mmol) in l-methyl-2-pyrrolidinone (250 mL) were heated to 90 °C for 16 h. After completion, the reaction mixture was diluted with ethyl acetate (250 mL) and filtered. The filtrate was washed with water (100 mL), and dried over anhydrous sodium sulfate and concentrated under vacuum to give a crude residue, which was purified by silica-gel chromatography (elute with EtOAc: PE = 0-15%) to give Int-9a (3.50 g, 13.2% yield) as a yellow solid. MS (ESI+) obsd. [(M+H)+]: 203.1.

[0334] Step 2: Tert-butyl [l,3]dioxolo[4,5-b]pyridin-6-ylcarbamate

[0335] Int-9b

[0336] The title compound was prepared in analogy to the preparation of In-4, replacing Int-4a with Int-9a in step 2. Int-9b (3.4 g) was obtained as a yellow oil. MS (ESI+) obsd. [(M+H)+]: 239.0.

[0337] Step 3: Tert-butyl (5-chloro-[l,3]dioxolo[4,5-b]pyridin-6-yl)carbamate

[0338] Cl

[0339] <OXXN'

[0340] HBOC

[0341] Int-9

[0342] The title compound was prepared in analogy to the preparation of In-7, replacing Int-7a with Int-9b in step 2. Int-9 (1.1 g) was obtained as a white solid. MS (ESI+) obsd. [(M+H)+]: 273.1. Intermediate 10: / ( / / -butyl 2V-(4-bromo-2-chloro-7,8-dihydro-5H-pyrano[4,3-b]pyridin-3- yl)carbamate

[0343] Int-10

[0344] Step 1: 2-Bromo-7,8-dihydro-5H-pyrano[4,3-b]pyridin-3-amine

[0345] Int-lOa

[0346] To a solution of 7,8-dihydro-577-pyrano[4,3-b]pyridin-3-amine (1.60 g, 10.6 mmol) in acetonitrile (80.0 mL) was added NBS (2.0 g, 11.2 mmol) at at 0 °C and stirred at 0 °C for 0.5 h. After completion, the mixture was quenched with NaiSiCh solution and extracted with EtOAc (20 mL x 3). The combined organic layers were dried over NaiSCU and concentrated under vacuum to give crude residue, which was purified by silica-gel chromatography (elute with EtOAc: PE = 0-50%) to give Int-lOa (3.1 g, 99.0% yield) as brown solid. MS (ESI+) obsd. [(M+H)+]: 229.0.

[0347] Step 2: 2-Chloro-7,8-dihydro-5H-pyrano[4,3-b]pyridin-3-amine

[0348] Int-lOb

[0349] A mixture of Int-lOa (630.0 mg, 2.8 mmol), L-proline (126.7 mg, 1.1 mmol), tetramethylammonium chloride (602.86 mg, 5.5 mmol) and copper(I) oxide (78.7 mg, 550.1 umol) in ethanol (12.6 mL) was heated at 110 °C for 2 h under N2 protection. After completion, the solvent was removed under vacuum and the residue was purified by silica-gel chromatography (elute with EtOAc: PE = 0-50%) to give Int-lOb (314.0 mg, 58.0% yield) as brown solid. MS (ESI+) obsd. [(M+H)+]: 185.0.

[0350] Step 3 : 4-Bromo-2-chloro-7,8-dihydro-5H-pyrano[4,3-b]pyridin-3-amine

[0351] Int-lOc To a solution of Int-lOc (350.0 mg, 1.9 mmol) in acetonitrile (7.78 mL) was added NBS (371.2 mg, 2.1 mmol) at rt. The mixture was stirred at rt for 0.5 h. After completion, the mixture was diluted with sat. NaiSiCh solution (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layer was dried over NaiSCL and concentrated under vacuum to give crude residue, which was purified by silica-gel chromatography (elute with EtOAc: PE = 0-50%) to give Int-lOc (475.0 mg, 95.0% yield) as brown solid. MS (ESI+) obsd. [(M+H)+]: 263.0.

[0352] Step 4: Tert-butyl 2V-(4-bromo-2-chloro-7,8-dihydro-5H-pyrano[4,3-b]pyridin-3- yl)carbamate

[0353] Int-10

[0354] The title compound was prepared in analogy to the preparation of In-1, replacing Int-le with Int-lOc in step 6. Int-10 (300 mg) was obtained as a yellow solid. MS (ESI+) obsd. [(M+H)+]: 363.1.

[0355] Intermediate 11: Tert-butyl V-( 6-chloro-2,3-dihyd rol'uro|2,3-b| pyridin-5-yl (carbamate

[0356] O^N ci YJ Y ^^s^xNHBoc

[0357] Int-11

[0358] Step 1: 6-Chloro-2,3-dihydrofuro[2,3-b]pyridin-5-amine

[0359] Int-lla

[0360] 2,3-Dihydrofuro[2,3-b]pyridin-5-amine (200.0 mg, 1.47 mmol) was dissolved in MeCN (10.0 mL) and NCS (235.38 mg, 1.76 mmol) were added at rt. The reaction mixture was stirred at rt for 1.5 h. After completion, the reaction mixture was diluted with sat. NaiSiCh solution and extracted with EtOAc (30 mL x 3). The organic layer was dried over NaiSO4 and concentrated under vacuum to give a residue, which was purified by silica-gel chromatography (elute with EtOAc: PE = 0-50%) to give Int-lla (45.0 mg, 18.0% yield) as yellow solid. MS (ESI+) obsd. [(M+H)+]: 171.0. Step 2: Tert-butyl 2V-(6-chloro-2,3-dihydrofuro[2,3-b]pyridin-5-yl)carbamate

[0361] Int-11

[0362] The title compound was prepared in analogy to the preparation of In-1, replacing Int-le with Int-lla in step 6. Int-11 (45 mg) was obtained as a white solid. MS (ESI+) obsd. [(M+H)+]: 271.2.

[0363] Intermediate 12: Tert-butyl 2V-(2-chloro-6,7-dihydro-5H-cyclopenta[b]pyridin-3- yl)carbamate

[0364] Int-12

[0365] Step 1: 2-Bromo-6,7-dihydro-5H-cyclopenta[b]pyridin-3-amine

[0366] Int-12a

[0367] The title compound was prepared in analogy to the preparation of Int-3b, replacing Int-3a with 6,7-dihydro-577-cyclopenta[b]pyridin-3-amine. Int-12a (2.2 g) was obtained as a white solid. MS (ESI+) obsd. [(M+H)+]: 212.8.

[0368] Step 2: 2-Chloro-6,7-dihydro-5H-cyclopenta[b]pyridin-3-amine

[0369] Int-12b

[0370] A mixture of Int-12a (540.00 mg, 2.53 mmol), L-proline (116.71 mg, 1.01 mmol), tetramethylammonium chloride (555.5 mg, 5.1 mmol) and CirO (72.5 mg, 506.9 umol) in ethanol (12 mL) was stirred at 110 °C for 3 h under N2 protection. After completion, the solvent was removed under vacuum to give a residue, which was purified by silica-gel chromatography (elute with EtOAc: PE = 0-50%) to give Int-12b (1.54 g, 90.0% yield) as white solid. MS (ESI+) obsd. [(M+H)+]: 169.9.

[0371] Step 3: Tert-butyl 2V-(2-chloro-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl)carbamate

[0372] Int-12

[0373] The title compound was prepared in analogy to the preparation of In-1, replacing Int-le with Int-12b in step 6. Int-12 (45 mg) was obtained as a white solid. MS (ESI+) obsd. [(M+H)+]: 269.0.

[0374] Intermediate 13: Tert-butyl (2-chloro-5,7-dihydrofuro[3,4-b]pyridin-3-yl)carbamate

[0375] Int-13

[0376] Step 1: Dimethyl 5-bromopyridine-2,3-dicarboxylate

[0377] Int-13a

[0378] A mixture of 5-bromopyridine-2,3-dicarboxylic acid (5.0 g, 20.3 mmol), DMF (0.31 mL, 4.06 mmol) and thionyl chloride (8.9 mL, 122.0 mmol) in methanol (50.0 mL, 20.3 mmol) was stirred at 60 °C for 12 h. After completion, the reaction mixture was concentrated under vacuum to give Int-13a (5.1 g, crude) as a yellow solid. MS (ESI+) obsd. [(M+Na)+]: 298.0.

[0379] Step 2: (5-Bromopyridine-2,3-diyl)dimethanol Int-13b

[0380] To a solution of Int-13a (5.0 g, 18.2 mmol) and calcium dichloride (1.8 g, 16.4 mmol) in ethanol (80 mL) was added sodium borohydride (3.4 g, 90.9 mmol) slowly at 25 °C at rt. And the resulting mixture was stirred at 25 °C for 12 h. After completion, the reaction mixture was quenched with 2M HC1 (60 mL) at 0°. After stirring for 2 h, the mixture was concentrated under vacuum to give crude residue, which was purified by silica-gel chromatography (elute with MeOH: EtOAc = 0-15%) to give Int-13b (2.2 g, 55.3% yield) as a light yellow solid. MS (ESI+) obsd. [(M+H)+]: 218.0.

[0381] Step 3: 3-Bromo-5,7-dihydrofuro[3,4-b]pyridine

[0382] Int-13c

[0383] To a solution of Int-13b (1.0 g, 4.6 mmol) in 1,4-dioxane (10 mL) was added NaH (405.0 mg, 10.1 mmol) at 25 °C. Then l-(4-methylphenyl) sulfonylimidazole (2.1 g, 9.2 mmol) was added. The mixture was stirred at 25 °C for 2 h. After completion, the mixture was quenched with saturated ammonium chloride (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to give a residue which was purified silica-gel chromatography (elute with EtOAc:PE = 0-20%) to give Int-13c (400.0 mg, 43.6% yield) as a white solid. MS (ESI+) obsd. [(M+H)+]: 199.9.

[0384] Step 4: 3-Bromo-5,7-dihydrofuro[3,4-b]pyridine 1-oxide

[0385] Int-13d

[0386] To a solution of Int-13c (400.0 mg, 2.0 mmol) in DCM (5 mL) was added metachloroperoxybenzoic acid (608.0 mg, 3.0 mmol) at 0 °C. The mixture was stirred at 25 °C for 1 h. After completion, the reaction mixture was quenched with saturated sodium sulfite (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to give Int-13d (400.0 mg, crude) as a yellow solid. MS (ESI+) obsd. [(M+H)+]: 218.1.

[0387] Step 5: 3-Bromo-2-chloro-5,7-dihydrofuro[3,4-b]pyridine

[0388] Int-13e

[0389] A solution of Int-13d (300.0 mg, 1.39 mmol) in phosphorus oxychloride (3.0 mL) was stirred at 100 °C for 1 h. After completion, the reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (20 mLx3). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to give a residue, which was purified by silica-gel chromatography (elute with EtOAc:PE = 0-30%) to give Int-13e (140.0 mg, 44.0% yield) as a white solid. MS (ESI+) obsd. [(M+H)+]: 236.0.

[0390] Step 6: Tert-butyl (2-chloro-5,7-dihydrofuro[3,4-b]pyridin-3-yl)carbamate

[0391] Int-13

[0392] The title compound was prepared in analogy to the preparation of In-4, replacing Int-4a with Int-13e in step 2. Int-13 (60.0 mg) was obtained as a yellow solid. MS (ESI+) obsd. [(M+H)+]: 271.1.

[0393] Intermediate 14: Tert-butyl (2-formylfuro[3,2-c]pyridin-3-yl)carbamate

[0394] Int-14

[0395] Step 1: Ethyl 3-aminofuro[3,2-c]pyridine-2-carboxylate

[0396] Int-14a

[0397] A suspension of 4-chloronicotinonitrile (1.0 g, 7.2 mmol), CS2CO3 (7.1 g, 21.7 mmol) and ethyl glycolate (0.9 g, 8.7 mmol) in A-methyl-2-pyrrolidone (30 mL) was stirred at 70 °C for 12 h. After completion, the suspension was filtered and the filtrate was diluted with ethyl acetate (20 mL) and washed with water (100 mL). The organic layer was concentrated under vacuum to give a crude, which was purified by silica-gel chromatography (elute with EtOAc: PE = 0-50%) to give Int-14a (880 mg, 59.1% yield) as a yellow solid. MS (ESI+) obsd. [(M+H)+]: 207.1.

[0398] Step 2: Ethyl 3-[ / s(tert-butoxycarbonyl)amino]furo[3,2-c]pyridine-2-carboxylate

[0399] Int-14b

[0400] The title compound was prepared in analogy to the preparation of In-3c, replacing Int-3b with Int-14a. Int-14b (170 mg) was obtained as a yellow solid. MS (ESI+) obsd. [(M+H)+]: 407.1.

[0401] Step 3: Tert-butyl (2-(hydroxymethyl)furo[3,2-c]pyridin-3-yl)carbamate

[0402] Int-14c

[0403] To a solution of Int-14b (170 mg, 0.4 mmol) in THF (2 mL) was added diisobutylaluminium hydride (1.4 mL, 1.4 mmol) dropwise at 0 °C and stirred at 0 °C for 2 h. After completion, the reaction mixture was quenched with 0.5 g sodium sulfate decahydrate in 5 portions at 0°C. The suspension was filtered and the filtrate was concentrated under vacuum to give Int-14c (110 mg, crude) as a yellow gum. MS (ESI+) obsd. [(M+H)+]: 265.1.

[0404] Step 4: Tert-butyl (2-formylfuro[3,2-c]pyridin-3-yl)carbamate

[0405] Int-14

[0406] A suspension of Int-14c (1.3 g, 4.9 mmol) and MnOi (4. 4 g, 50.0 mmol) in 1,2- dichloroethylene (30 mL) was stirred at 70 °C for 2 h. After completion, the suspension was filtered and the filtrate was concentrated under vacuum to give a crude residue, which was purified by silica-gel chromatography (elute with EtOAc: PE = 0-20%) to give Int-14 (650 mg, 49.6% yield) as a yellow gum. MS (ESI+) obsd. [(M+H)+]: 263.1.

[0407] Intermediate 15: Tert-butyl (4-iodo-l,5-naphthyridin-3-yl)carbamate

[0408] Int-15

[0409] Step 1: 4-iodo-l,5-naphthyridin-3-amine

[0410] Int-15a

[0411] To a solution of l,5-naphthyridin-3-amine (963 mg, 6.63 mmol) in MeCN (20 mL) was added A-iodo succinimide (1.6 g, 7.3 mmol) at rt. The mixture was stirred at 50 °C for 12 h. After completion, the mixture was quenched with saturated sodium sulfite (15 mL) and extracted with EtOAc (10 mL x 3). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to give a residue which was purified by silica-gel chromatography (elute with EtOAc: PE = 0 to 20%) to give Int-15a (1.6 g, 89.0% yield) as a yellow solid. MS (ESI+) obsd. [(M+H)+]: 272.0.

[0412] Step 2: Tert-butyl (4-iodo-l,5-naphthyridin-3-yl)carbamate

[0413] Int-15 The title compound was prepared in analogy to the preparation of In-1, replacing Int-le with Int-15a in step 6. Int-15 (54 mg) was obtained as a yellow solid. MS (ESI+) obsd. [(M+H)+]: 372.0.

[0414] Example 001: 3-Amino-4-(7-fluoro-lH-indazol-4-yl)-l,7,8,9-tetrahydrocyclopenta[h] [l,5]naphthyridin-2-one

[0415] 001

[0416] Step 1: Tert-butyl (3-((7-fluoro-l-(tetrahydro-2H-pyran-2-yl)-lH-indazol-4- yl)(hydroxy)methyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl)carbamate

[0417] 001a

[0418] To a solution of Int-1 (1.4 g, 4.5 mmol) in THF (20 mL) was added n-butyllithium (3.8 mL, 9.4 mmol) dropwise at 0 °C. After stirred at 0 °C for 0.5 h, a solution of 7-fluoro-l- tetrahydropyran-2-yl-indazole-4-carbaldehyde (1.2 g, 4.9 mmol) in THF (5 mL) was added to the above mixture at -78 °C, and stirred at -78 °C for another 0.5 h. After completion, the reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL) and extracted with EtOAc (80 mL x 3). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to give a residue, which purified by silica-gel chromatography (elute with EtOAc:PE = 0-50%) to give 001a (1.3 g, 60.3% yield) as a yellow solid. MS (ESI+) obsd. [(M+H)+]: 483.4.

[0419] Step 2: Tert-butyl (3-(7-fluoro-l-(tetrahydro-2H-pyran-2-yl)-lH-indazole-4-carbonyl)-6,7- dihydro-5H-cyclopenta[c]pyridin-4-yl)carbamate

[0420]

[0421] 001b

[0422] To a solution of 001a (1.3 g, 2.7 mmol) in chloroform (20 mL) was added manganese dioxide (2.6 g, 26.9 mmol) portionwise. The mixture was stirred at 80 °C for 2 h. After completion, the suspension was filtered and the filtrate was concentrated under vacuum to give a residue, which was purified by silica-gel chromatography (elute with EtOAc: PE = 0-50%) to give 001b (600 mg, 46.4% yield) as a yellow solid. MS (ESI+) obsd. [(M+H)+]: 481.4.

[0423] Step 3: (4-Amino-6,7-dihydro-5H-cyclopenta[c]pyridin-3-yl)(7-fluoro-lH-indazol-4- yl)methanone

[0424] 001c

[0425] A solution of 001b (630.0 mg, 1.3 mmol) in HCl / EtOAc (6.0 mL, 4 M) was stirred at 25 °C for 1 h. After completion, the reaction mixture was concentrated under vacuum to give a residue, which was purified by silica-gel chromatography (elute with EtOAc: PE = 0-50%) to give 001c (350.0 mg, 90.1% yield) as a yellow solid. MS (ESI+) obsd. [(M+H)+]: 297.3.

[0426] Step 4: 2-Chloro-A^-(3-(7-fluoro-lH-indazole-4-carbonyl)-6,7-dihydro-5H- cyclopenta[c]pyridin-4-yl)acetamide OOld

[0427] To a solution of 001c (175 mg, 0.6 mmol) in toluene (5 mL) was added chloroacetyl chloride (100 mg, 0.89 mmol). The mixture was stirred at 100 °C for 1 h. After completion, the reaction mixture was concentrated under reduced pressure to give OOld (200 mg, crude) as a brown solid, which was used in the next step directly. MS (ESI+) obsd. [(M+H)+]: 373.3.

[0428] Step 5: l-(4-(7-Fluoro-lH-indazol-4-yl)-2-oxo-2,7,8,9-tetrahydro-lH-cyclopenta[c][l,5] naphthyridin-3-yl)pyridin-l-ium chloride

[0429] OOle

[0430] A mixture of OOld (200 mg, 0.5 mmol) in pyridine (2.4 mL, 30.1 mmol) was stirred at 100 °C for 5 h. After completion, the reaction mixture was concentrated under vacuum to give OOle (200 mg, crude) as a brown solid. MS (ESI+) obsd. [(M-C1)+]: 398.3.

[0431] Step 6: 3-Amino-4-(7-fluoro-lH-indazol-4-yl)-l,7,8,9-tetrahydrocyclopenta[h]

[0432] [l,5]naphthyridin-2-one

[0433] 001

[0434] A mixture of OOle (200 mg, 0.5 mmol) in ethanol (2 mL) and hydrazine monohydrate (3.0 mL) was stirred at 70 °C for 1 h. After completion, the mixture was poured into water (10 mL) and extracted with EtOAc (10 mLx 3). The combined organic layer was concentrated under vacuum to give a residue, which was purified by perp-HPLC (ammonia hydroxide as additive) to afford Example 001 (61.5 mg, 38.3% yield) as a light yellow solid. MS (ESI+) obsd. [(M+H)+]: 336.3. Example 001: ‘ H NMR (400 MHz, DMSO-tfe) 6 ppm 8.02 (s, 1H), 7.58 (d, J= 3.2 Hz, 1H), 7.27 (dd, J = 8.0, 11.2 Hz, 1H), 6.97 (dd, 7= 4.4, 7.6 Hz, 1H), 5.08 (s, 2H), 3.07 (t, 7= 7.6 Hz, 2H), 2.92 (t, 7 = 7.2 Hz, 2H), 214-2.08 (m, 2H).19F NMR (376 MHz, DMSO-76) 8 ppm - 133.01 (s, IF).

[0435] Example 002: 9-Amino-10-(7-fluoro-lH-indazol-4-yl)-6-methyl-2,3,4,7- tetrahydropyrano[2,3-f][l,7]naphthyridin-8-one

[0436] 002

[0437] Step 1: Tert-butyl (6-bromo-8-((7-fluoro-l-(tetrahydro-2H-pyran-2-yl)-lH-indazol-4- yl)(hydroxy)methyl)-3,4-dihydro-2H-pyrano[3,2-b]pyridin-7-yl)carbamate

[0438] 002a

[0439] To a solution of Int-2 (1.7 g, 5.2 mmol) in THF (40 mL) was added dropwise n- butyllithium (5.2 mL, 12.9 mmol) at -78 °C and the mixture was stirred at -78 °for 2 h. And then, a solution of 7-fluoro-l -tetrahydrop yran-2-yl-indazole-4-carbaldehyde (1.4 g, 5.7 mmol) in THF (5 mL) was added to the above mixture at -78 °C, and the mixture was stirred -78 °C for another 0.5 h. After completion, the mixture was quenched with saturated ammonium chloride (200 mL) and extracted with EtOAc (300 mL x 3). The combined organic layer was concentrated under reduced pressure to give a residue, which was purified by slica-gel chromatography (elute with EtOAc: PE= 0 to 50%) to give 002a (1.0 g, 1.7 mmol) as a yellow solid. MS (ESI+) obsd. [(M+H)+]: 579.2. Step 2: Tert-butyl (6-bromo-8-(7-fluoro-l-(tetrahydro-2H-pyran-2-yl)-lH-indazole-4- carbonyl)-3,4-dihydro-2H-pyrano[3,2-b]pyridin-7-yl)carbamate

[0440] 002b

[0441] The title compound was prepared in analogy to the preparation of 001b, replacing 001a with 002a. 002b (410 mg) was obtained as a white solid. MS (ESI+) obsd. [(M+H)+]: 577.2. Step 3: (7-Amino-6-bromo-3,4-dihydro-2H-pyrano[3,2-Z>]pyridin-8-yl)(7-fluoro-lH- indazol-4-yl)methanone

[0442] 002c

[0443] The title compound was prepared in analogy to the preparation of 001c, replacing 001b with 002b. 002c (270 mg) was obtained as a white solid. MS (ESI+) obsd. [(M+H)+]: 391.0.

[0444] Step 4: 2V-(6-bromo-8-(7-fluoro-lH-indazole-4-carbonyl)-3,4-dihydro-2H-pyrano[3,2- / >]pyridin-7-yl)-2-chloroacetamide

[0445] 002d

[0446] The title compound was prepared in analogy to the preparation of OOld, replacing 001c with 002c. 002d (320 mg) was obtained as a yellow solid. MS (ESI+) obsd. [(M+H)+]: 466.9. Step 5: l-(6-Bromo-10-(7-fluoro-lH-indazol-4-yl)-8-oxo-3,4,7,8-tetrahydro-2H-pyrano[2,3-

[0447] / || 1.7|naphthyridin-9-yl)pyridin- 1-ium chloride

[0448] 002e

[0449] The title compound was prepared in analogy to the preparation of OOle, replacing OOld with 002d. 002e (360 mg) was obtained as a brown solid. MS (ESI+) obsd. [(M-C1)+]: 492.1.

[0450] Step 6: 9-Amino-6-bromo-10-(7-fluoro-lH-indazol-4-yl)-2,3,4,7-tetrahydro-8H-pyrano[2,3- / || l,7|naphthyridin-8-one

[0451] 002f

[0452] The title compound was prepared in analogy to the preparation of 001, replacing OOle with 002e in step 6. 002f (280 mg) was obtained as a brown solid. MS (ESI+) obsd. [(M+H)+]: 430.0. Step 7 : 9-Amino-10-(7-fluoro-lH-indazol-4-yl)-6-methyl-2,3,4,7-tetrahydropyrano[2,3- f] [ 1 ,7] naphthyridin-8-one

[0453] 002

[0454] A mixture of 002f (240.0 mg, 0.55 mmol), trimethylboroxine (0.24 mL, 0.83 mmol), Pd(dppf)Ch (42.7 mg, 0.06 mmol) and CS2CO3 (271.8 mg, 0.83 mmol) in 1,4-dioxane (4 mL) was stirred at 80 °C for 6 h under N2 protection. After completion, the mixture was filtered and the filtrate was concentrated under vacuum to give a residue, which was purified by silica-gel chromatography (elute with EtOAc: PE = 0 to 30%) to afford Example 002 (110.0 mg, 53.7% yield) as a yellow solid. MS (ESI+) obsd. [(M+H)+]: 366.1

[0455] Example 002:1H NMR (400 MHz, DMSO-tfe) 6 ppm 7.70 (d, J = 3.2 Hz, 1H), 7.22 (dd, J = 8.0, 11.2 Hz, 1H), 6.90 (dd, J= 4.0, 8.0 Hz, 1H), 3.45-3.38 (m, 1H), 3.27-3.20 (m, 1H), 2.78 (t, J= 6.4 Hz, 2H), 2.69 (s, 3H), 1.77-1.61 (m, 2H).19F NMR (376 MHz, DMSO-tfe) 6 ppm -132.28 (s, IF).

[0456] Example 003: 9-Amino-10-(7-fluoro-lH-indazol-4-yl)-6-(trideuteriomethyl)-2,3,4,7- tetrahydropyrano[2,3-f][l,7]naphthyridin-8-one

[0457] 003

[0458] To a solution of 002f (200.0 mg, 0.46 mmol) and iron(III)-acetylacetonate (32.8 mg, 0.09 mmol) in THF (3 mL) was added iodo(trideuteriomethyl)magnesium (3.72 mL, 3.72 mmol) dropwise at 0 °C, and the reaction mixture was stirred at 25 °C for 2 h. After completion, the reaction mixture was quenched with saturated ammonium chloride (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to give a crude residue, which was purified by prep-HPLC (HC1 as additive) to afford Example 003 (6.75 mg, 3.6% yield) as a yellow solid. MS (ESI+) obsd. [(M+H)+]: 369.1.

[0459] Example 003:1H NMR (400 MHz, MeOD-d4) 6 ppm 7.74 (d, J = 3.6 Hz, 1H), 7.22 (dd, J = 8.0, 11.2 Hz, 1H), 7.00 (dd, J = 4.0, 8.0 Hz, 1H), 3.6-3.55 (m, 1H), 3.46-3.40 (m, 1H), 2.91 (t, J= 6.8 Hz, 2H), 1.91-1.81 (m, 2H).19F NMR (376 MHz, McOD-4) 6 ppm -134.74 (s, IF).

[0460] The following Examples 004 to 007, 009, 010, 013, 014, 017, 019 and 020 were prepared in analogy to the procedure described for the preparation of Example 001, replacing compound Int-2 with PYCPD indicated in Table 1 in stepl. Table 1: Compound synthesis and characterization

[0461] Example 008: 9-Amino-10-(lH-indazol-4-yl)-6-methyl-2,3,4,7-tetrahydropyrano[2,3- f] [ 1 ,7] naphthyridin-8-one

[0462] 008

[0463] The title compound was prepared in analogy to the preparation of 002, replacing 7-fluoro-l- tetrahydropyran-2-yl-indazole-4-carbaldehyde with 1 -tetrahydrop yran-2-ylindazole-4- carbaldehyde in stepl. Example 008 (20 mg) was obtained as a yellow solid. MS (ESI+) obsd. [(M+H)+]: 348.2.

[0464] Example 008: ’ H NMR (400 MHz, MeOD-74) 8 ppm 7.84 (s, 1H), 7.69-7.63 (m, 1H), 7.60-7.53 (m, 1H), 7.12 (d, J= 6.8 Hz, 1H), 3.58-3.50 (m, 1H), 3.40 (m, 1H), 2.92 (t, J= 6.4 Hz, 2H), 2.82 (s, 3H), 1.91 (m, 2H).

[0465] Example Oil: 8-Amino-9-(7-fluoro-lH-indazol-4-yl)-5-methyl-3,6-dihydro-2H-furo[2,3- f] [ 1 ,7] naphthyridin-7-one

[0466]

[0467] Oil

[0468] The title compound was prepared in analogy to the preparation of 002, replacing Int-2 with Int-6 in stepl. Example 011 (20 mg) was obtained as a yellow solid. MS (ESI+) obsd. [(M+H)+]: 352.2.

[0469] Example Oil: ’ H NMR (400 MHz, MeOD-d4) 6 ppm 7.76 (d, J= 3.2 Hz, 1H), 7.22 (dd, J = 7.6, 10.8 Hz, 1H), 7.05 (dd, J = 4.0, 7.6 Hz, 1H), 4.44-4.37 (m, 1H), 4.30-4.22 (m, 1H), 3.35 (d, J = 10.4 Hz, 2H), 2.79 (s, 3H).19F NMR (376 MHz, MeOD-d4) 8 ppm -133.94 (s, IF).

[0470] Example 012: 9-Amino-10-(7-fluoro-lH-indazol-4-yl)-6-methyl-3,7-dihydro-2H-

[0471] [l,4]dioxino[2,3-f][l,7]naphthyridin-8-one

[0472] 012

[0473] Step 1: Tert-butyl (6-chloro-8-((7-fluoro-l-(tetrahydro-2H-pyran-2-yl)-lH-indazol-4- yl)(hydroxy)methyl)-2,3-dihydro-[l,4]dioxino[2,3-b]pyridin-7-yl)carbamate

[0474] 012a The title compound was prepared in analogy to the preparation of 001a, replacing Int-2 with Int-7. 012a (720 mg) was obtained as a yellow solid. MS (ESI+) obsd. [(M+Na)+]: 557.2.

[0475] Step 2: Tert-butyl (6-chloro-8-(7-fluoro-l-(tetrahydro-2H-pyran-2-yl)-lH-indazole-4- carbonyl)-2,3-dihydro-[l,4]dioxino[2,3-b]pyridin-7-yl)carbamate

[0476] 012b

[0477] The title compound was prepared in analogy to the preparation of 001b, replacing 001a with 012a. 012b (200 mg) was obtained as a yellow solid. MS (ESI+) obsd. [(M+H)+]: 533.2. Step 3: Tert-butyl (8-(7-fluoro-l-(tetrahydro-2H-pyran-2-yl)-lH-indazole-4-carbonyl)-6- methyl-2,3-dihydro-[l,4]dioxino[2,3-b]pyridin-7-yl)carbamate

[0478] 012c

[0479] A mxiture of 012b (130 mg, 0.24 mmol), trimethylboroxine (0.06 mL, 0.73 mmol), CS2CO3 (159 mg, 0.49 mmol), Pd(dppf)Ch (17.9 mg, 0.02 mmol) in 1,4-dioxane (3 mL) was stirred at 100 °C for 2 h under N2 proteciton. After completion, the mixture was filtered and the filtrate was concentrated under vacuum to give a residue, which was purified by silica-gel chromatography (elute with EtOAc: PE = 0 to 30%) to give 012c (124 mg, 99.9% yield) as a yellow solid. MS (ESI+) obsd. [(M+H)+]: 513.2.

[0480] Step 4: (7-Amino-6-methyl-2,3-dihydro-[ l,4]dioxino[2,3-b]pyridin-8-yl)(7-fluoro- 1H- indazol-4-yl)methanone

[0481]

[0482] 012d

[0483] The title compound was prepared in analogy to the preparation of 001c, replacing 001b with 012c. 012d (88 mg) was obtained as a yellow solid. MS (ESI+) obsd. [(M+H)+]: 329.0.

[0484] Step 5: 2-Chloro-2V-(8-(7-fluoro-lH-indazole-4-carbonyl)-6-methyl-2,3-dihydro- [l,4]dioxino[2,3-b]pyridin-7-yl)acetamide

[0485] 012e

[0486] The title compound was prepared in analogy to the preparation of OOld, replacing 001c with 012d. 012e (102 mg) was obtained as a yellow solid. MS (ESI+) obsd. [(M+H)+]: 405.0.

[0487] Step 6: l-(10-(7-Fluoro-lH-indazol-4-yl)-6-methyl-8-oxo-2,3,7,8-tetrahydro- [l,4]dioxino[2,3-f][l,7]naphthyridin-9-yl)pyridin-l-ium chloride

[0488] 012f

[0489] The title compound was prepared in analogy to the preparation of OOle, replacing OOld with 012e. 012f (110 mg) was obtained as a red solid. MS (ESI+) obsd. [(M-C1)+]: 430.1. Step 7: 9-Amino-10-(7-fluoro-lH-indazol-4-yl)-6-methyl-3,7-dihydro-2H-[l,4]dioxino[2,3- f] [ 1 ,7] naphthyridin-8-one

[0490] The title compound was prepared in analogy to the preparation of Example 001, replacing OOle with 012f in step 6. Example 012 (20 mg) was obtained as a yellow solid. MS (ESI+) obsd. [(M+H)+]: 368.1.

[0491] Example 012: ’ H NMR (400 MHz, DMSO-76) 5 ppm 11.47 (s, 1H), 7.73 (d, J= 3.6 Hz, 1H), 7.21 (dd, J= 8.0, 11.2 Hz, 1H), 6.90 (dd, J= 4.0, 8.0 Hz, 1H), 4.12 - 4.06 (m, 2H), 3.42 - 3.38 (m, 2H), 2.55 (s, 3H).19F NMR (377 MHz, DMSO-d6) 5 ppm -133.14 (s, IF).

[0492] The following Examples 015, 016, 018, 021, 022 and 024 were prepared in analogy to the procedure described for the preparation of Example 0012, replacing compound Int-7 with CHLOROCPD indicated in Table 2 in stepl.

[0493] Table 2: Compound synthesis and characterization

[0494] Example 023: 10-Amino-9-(7-fluoro-lH-indazol-4-yl)-6,7,12- triazatricyclo[6.4.0.02,6] dodeca- 1 ,7,9- trien- 11 -one

[0495] 023

[0496] Step 1: Ethyl 3-nitro-4H,5H,6H-pyrrolo[l,2-b]pyrazole-2-carboxylate

[0497] 023a

[0498] Ethyl 477,577,677-pyrrolo[l,2-b]pyrazole-2-carboxylate (20.0 g, 111.0 mmol) was added to a solution of HNO3 (150.0 mL) in sulfuric acid (150 mL) at 0°C in portions. The light yellow solution was stirred for 2 h at rt. After completion, the mixture was poured to ice water (1000 mL) and the precipitated solids were collected by filtration and washed with water (500 mL x 3) to afford 023a (24.0 g, yield 96.0%) as a white solid. MS (ESI+) obsd. [(M+H)+]: 226.1.

[0499] Step 2: Ethyl 3-amino-4H,5H,6H-pyrrolo[l,2-b]pyrazole-2-carboxylate

[0500] 023b

[0501] To a solution of 023a (18.0 g, 79.9 mmol) in MeOH (350 mL) was added palladium on carbon (10%, 5.0 g) in a pressure tank. The mixture was hydrogenated at rt with a hydrogen balloon for 24 h. After completion, the mixture was filtered and concentrated under vacuum to give 023b (15.0 g, yield 96.1%) as grey solid. MS (ESI+) obsd. [(M+H)+]: 196.2.

[0502] Step 3: Ethyl 3-acetamido-4H,5H,6H-pyrrolo[l,2-b]pyrazole-2-carboxylate

[0503] 023c

[0504] To a solution of 023b (15.0 g, 76.8 mmol) in DCM (300 mL) was added TEA (23.3 g, 230.5 mmol) and acetyl chloride (7.2 g, 92.2 mmol) sequentially at 0°C. The reaction mixture was stirred for 2 h at rt. After completion, the resulting mixture was filtered and the filtrate was concentrated under vacuum to give 023c (14.0 g, yield 76.8%) as a white solid. MS (ESI+) obsd. [(M+H)+]: 238.2.

[0505] Step 4: Ethyl 3-{2V-[(4-methoxyphenyl)methyl]acetamido}-4H,5H,6H-pyrrolo[ 1,2- b]pyrazole-2-carboxylate

[0506] 023d

[0507] To a solution of 023c (13.0 g, 54.8 mmol) in dimethylsulfoxide (130 mL) was added 4- methoxybenzyl chloride (12.9 g, 82.2 mmol) at 0°C. The reaction mixture was stirred at 60°C for 8 h. After completion, the mixture was poured into water (150 mL) and extracted with EtOAc (200 mL x 3). The combined organic layer was dried over anhydrous NaiSCU and concentrated under vacuum to give a residue, which was purified by silica-gel chromatography (elute with EtOAc: PE = 0 to 25%) to afford 023d (13.0 g, yield 66.4%) as a light yellow solid. MS (ESI+) obsd. [(M+H)+]: 358.2.

[0508] Step 5 : 9-Hydroxy- 12-[(4-methoxyphenyl)methyl] - 12-azatricyclo[6.4.0.02,6]dodeca- 1,7,9- trien-ll-one

[0509] 023e To a solution of ethyl 023d (13.0 g, 36.4 mmol) in THF (10 mL) was added lithium Z?z5(trimethylsilyl)amide (58.2 mL, 1 M in THF) at -78°C dropwise slowly. The reaction mixture was stirred at -78°C for 0.5 h. After completion, the resulting mixture was poured into ice-water (1000 mL) and extracted with EtOAc (2000 mL x 3). The combined organic layer was dried over anhydrous NaiSCL and concentrated under vacuum to give a residue, which was purified by silica-gel chromatography (elute with MeOH: DCM = 0 to 10%) to afford 023e (4.5 g, yield 40.0%) as a light yellow solid. MS (ESI+) obsd. [(M+H)+]: 312.2.

[0510] Step 6: 9-Hydroxy-12-[(4-methoxyphenyl)methyl]-10-nitro-12-azatricyclo[6.4.0.02,6]dodeca- 1 ,7,9-trien- 11 -one

[0511] 023f

[0512] To a solution of 023e (4.5 g, 14.5 mmol) in AcOH (50 mL) was added NaNCh (0.20 g, 2.9 mmol) and nitric acid (1.0 g, 16.0 mmol) at 0°C dropwise slowly. The reaction mixture was stirred at rt for 1 h. After completion, the mixture was poured into ice water (150 mL) and the precipitated solids were collected by filtration to afford 023f (3.5 g, yield 67.9%) as a yellow solid. MS (ESI+) obsd. [(M+H)+]: 357.2.

[0513] Step 7: 9-Bromo-12-[(4-methoxyphenyl)methyl]-10-nitro-12-azatricyclo[6.4.0.02,6]dodeca- 1 ,7,9-trien- 11 -one

[0514] 023g

[0515] To a solution 023f (3.5 g, 9.9 mmol) in DCM (60 mL) was added phosphoryl bromide (3.4 g, 11.9 mmol) and DMF (0.04 g, 0.5 mmol) at 0°C dropwise slowly. The reaction mixture was stirred at rt for 3 h. After completion, the mixture was washed with water (50 mL x 3), dried over anhydrous NaiSCL. The organic layer was concentrated under vacuum to give a residue, which was purified by silica-gel chromatography (elute with MeOH: DCM = 0 to 10%) to afford 023g (2.0 g, 48.5%yield) as a light yellow solid. MS (ESI+) obsd. [(M+H)+]: 419.0. Step 8: 10-Amino-9-bromo-12-[(4-methoxyphenyl)methyl]-12-azatricyclo[6.4.0.02,6]dodeca- 1 ,7,9-trien- 11 -one

[0516] 023h

[0517] To a solution of 023g (2.0 g, 5.6 mmol) in DMF (20 mL) was added bipyridine (0.04 g, 0.28 mmol) and then B2(OH)4 (1.5 g, 16.9 mmol) in portions at 0°C, and the reaction mixture was stirred at 0°C for 0.5 g. After completion, the precipitated solids were collected by filtration and washed with water (30 mL x3) to give 023h (1.2 g, yield 54.9%) as a light brown solid. MS (ESP) obsd. [(M+H)+]: 389.2.

[0518] Step 9: 10-amino-9-bromo-6,7,12-triazatricyclo[6.4.0.02’6]dodeca-l,7,9-trien-ll-one

[0519] 023i

[0520] A mixture of 023h (1.2 g, 3.1 mmol) in methanesulfonic acid (4 mL) was stirred at rt for 15 h. After completion, the mixture was poured onto ice- water (10 mL) and neutralized to pH=7 with NaHCOa a.q. The precipitated solid was collected by filtration and washed with water, DCM / diethylether (2 mL / 20 mL) and diethylether in sequential to give 023i (448.3 mg, 51.4% yield) as a brown solid MS (ESI+) obsd. [(M+H)+]: 268.9.

[0521] Step 10: 10-Amino-9-(7-fluoro-l-tetrahydropyran-2-yl-indazol-4-yl)-6,7,12- triazatricyclo[6.4.0.02’6]dodeca-l,7,9-trien-ll-one

[0522] 023j

[0523] A mixture of 7-fluoro-l-tetrahydropyran-2-yl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)indazole (212.3 mg, 613.2 umol), 023i (150.0 mg, 557.4 umol), K2CO3 (192.6 mg, 1.4 mmol) and Pd(dtbpf)Ch (45.5 mg, 55.7 umol) in 1,4-dioxane (5 mL) and water (1 mL) was stirred in sealed tube at 90°C for 2 h under N2 atmosphere. After completion, the mixture was poured into water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers was concentrated under vacuum to give a residue, which was purified by silica-gel chromatography (elute with MeOH: DCM = 0 to 5%) to give 023j (100 mg, yield 43.9%) as yellow solid. MS (ESI+) obsd. [(M+H)+]: 409.3.

[0524] Step 11: 10-Amino-9-(7-fluoro-lH-indazol-4-yl)-6,7,12-triazatricyclo[6.4.0.02,6]dodeca- 1 ,7,9-trien- 11 -one

[0525] 023

[0526] To a solution of 023j (100.0 mg, 0.25 mmol) in dichloromethane (5 mL) was added TFA(5 mL). The mixture was stirred at rt for 3 hr. After completion, the mixture was concentrated under vacuum to give a residue, which was purified by pre-HPLC (NH4HCO3 as additive) to give Example 023 (27.6 mg, 34.4%) as white powder. MS (ESI+) obsd. [(M+H)+]: 325.0. Example 023: ’ H NMR (400 MHz, DMSO-76) 5 ppm 13.64 (s, 1H), 11.59 (s, 1H), 7.75 (d, J = 2.1 Hz, 1H), 7.28 (dd, 7 = 7.9, 11.1 Hz, 1H), 7.15 (dd, J = 4.2, 7.8 Hz, 1H), 4.77 (s, 2H), 4.06 - 3.94 (m, 2H), 2.91 (t, J = 7.2 Hz, 2H), 2.58 - 2.51 (m, 2H).

[0527] Example 025: 8-Amino-9-(7-fluoro-lH-indazol-4-yl)-5-methyl-6H-furo[2,3- f] [ 1 ,7] naphthyridin-7-one

[0528] 025

[0529] To a solution of Example 011 (40.0 mg, 0.10 mmol) in THF (2 mL) was added 2,3- dichloro-5,6-dicyano-l,4-benzoquinone (70.2 mg, 0.31 mmol), then the reaction was heated to 100 °C for 4 h. After completion, the reaction mixture was concentrated under vacuum to give a crude residue, which was purified by prep-HPLC (NH4HCO3 as additive) to give Example 025 (1.7 mg, 7.0% yield) as a yellow solid. MS (ESI+) obsd. [(M+H)+]: 350.1.

[0530] Example 025: ’ H NMR (400 MHz, McOD-4) 6 ppm 7.69 (s, 1H), 7.42 (d, J= 2.0 Hz, 1H), 7.32 - 7.27 (m, 1H), 7.16 (dd, J= 4.4, 8.0 Hz, 1H), 6.76 (d, J= 2.0 Hz, 1H), 2.83 (s, 3H).19F NMR (377 MHz, McOD-4) 6 ppm -130.22 (s, IF).

[0531] Example 026: 5-Amino-6-(7-fluoro-lH-indazol-4-yl)-8-oxa-3,12-diazatricyclo[7.4.0.02,7] trideca-l(9),2(7),5,10,12-pentaen-4-one

[0532] 026

[0533] The title compound was prepared in analogy to the preparation of Example 001, replacing Int-1 with 7-fluoro-4-iodo-l -tetrahydrop yran-2-yl-indazole and 7-fluoro-l -tetrahydrop yran-2-yl- indazole-4-carbaldehyde with Int-14 in stepl. Example 026 (1.6 mg) was obtained as a yellow solid. MS (ESI+) obsd. [(M+H)+]: 336.0.

[0534] Example 026: ‘ H NMR (400 MHz, DMSO-tfe) 6 ppm 13.8 l(s, 1H), 12.83 (s, 1H), 9.09 (s, 1H), 8.39 (d, J = 5.6 Hz, 1H), 7.90 (s, 1H), 7.54 (dd, J = 0.8, 5.6 Hz, 1H), 7.37 (dd, J = 8.0, 10.8 Hz, 1H), 7.27 (dd, J = 4.4, 8.0 Hz, 1H), 5.48 (br s, 2H).19F NMR (377 MHz, DMSO-tfe) 6 ppm - 131.04 (s, IF).

[0535] Example 027: 5-Amino-6-(7-fluoro-lH-indazol-4-yl)-3,8,9-triazatricyclo[7.4.0.02,7]trideca- l,5,7-trien-4-one

[0536] 027 The title compound was prepared in analogy to the preparation of Example 023, replacing ethyl 477,577,677-pyrrolo[l,2-b]pyrazole-2-carboxylate with ethyl 4,5,6,7-tetrahydropyrazolo[l,5- a]pyridine-2-carboxylate in stepl. Example 027 (4.9 mg) was obtained as a yellow solid. MS (ESI+) obsd. [(M+H)+]: 339.2.

[0537] Example 027: ’ H NMR (400 MHz, McOD-4) 6 ppm 7.84 (d, J= 3.2 Hz, 1H), 7.32-7.23 (m, 2H), 4.11 (t, J= 6.0 Hz, 2H), 2.98 (t, J = 6.4 Hz, 2H), 2.13-2.06 (m, 2H), 2.00-1.92 (m, 2H).19F NMR (376 MHz, McOD-4) 6 ppm -133.50 (s, IF).

[0538] Example 028: 3-Amino-4-(7-fluoro-lH-indazol-4-yl)-lH-[l]benzofuro[2,3-b]pyridin-2-one

[0539] Step 1: 2-(Cyanomethyl)phenyl 7-fluoro-l-(tetrahydro-2H-pyran-2-yl)-l H-indazole-4- carboxylate

[0540] 028a

[0541] To a solution of 2- (2-hydroxyphenyl) acetonitrile (1.0 g, 7.5 mmol), 7-fluoro-4-bromo-l- tetrahydropyran-2-yl-indazole (2.7 g, 9.0 mmol) and TEA (1.57 mL, 11.3 mmol) in DMF (20 mL) was added tetrakis(triphenylphosphine)palladium (173.49 mg, 0.15 mmol). The flask was then evacuated and backfilled with nitrogen and CO. Then the reaction mixture was stirred at 100 °C under carbon monoxide (15 Psi) for 4 h. After completion, the mixture was concentrated under vacuum to give a residue, which was purified by silica-gel chromatography (elute with

[0542] EtOAc: PE = 0 to 30%) to give 028a (2.0 g, 70.2% yield) as a yellow oil. MS (ESI+) obsd. [(M- THP)+]: 296.0. Step 2: (2-Aminobenzofuran-3-yl)(7-fluoro-l-(tetrahydro-2H-pyran-2-yl)-lH-indazol-4- yl)methanone

[0543] 028b

[0544] A mixture of 028a (1.0 g, 2.64 mmol), palladium(II) acetate (59.17 mg, 0.26 mmol) and I,r-Z?z5(diphenylphosphino)ferrocene (292.1 mg, 0.53 mmol) in DMF (10 mL) was stirred at 140 °C for 8 h under N2 atmosphere. After completion, the reaction was concentrated under vacuum to give a crude residue, which was purified by silica-gel chromatography (elute with EtOAc: PE = 0 to 30%) to give 028b (190.0 mg, 19.0% yield) as a yellow solid. MS (ESI+) obsd. [(M+H)+]: 380.1.

[0545] Step 3: 2-Chloro-2V-(3-(7-fluoro-l-(tetrahydro-2H-pyran-2-yl)-lH-indazole-4- carbonyl)benzofuran-2-yl)acetamide

[0546] 028c

[0547] To a solution of 028b (190.0 mg, 0.5 mmol) and TEA (0.28 mL, 2.0 mmol) in DCM (10 mL) was added chloroacetyl chloride (0.12 mL, 1.5 mmol) dropwise, and the reaction mixture was stirred at 25 °C for 8 h. After completion, the reaction mixture was concentrated under vacuum to give 028c (300 mg, crude) as a dark brown solid, which was used in the next step directly. MS (ESI+) obsd. [(M-THP)+]: 372.0.

[0548] Step 4: l-(4-(7-Fluoro-l-(tetrahydro-2H-pyran-2-yl)-lH-indazol-4-yl)-2-oxo-l,2- dihydrobenzofuro[2,3-b]pyridin-3-yl)pyridin-l-ium chloride

[0549]

[0550] 028d

[0551] A mixture of 028c (300.0 mg, 0.66 mmol) in pyridine (4.0 mL) was stirred at 70 °C for 1 h.

[0552] After completion, the mixture was concentrated under vacuum to give crude 028d (340 mg, crude) as a dark brown solid. MS (ESI+) obsd. [(M-C1)+]: 481.3.

[0553] Step 5: 3-Amino-4-(7-fluoro-l-(tetrahydro-2H-pyran-2-yl)-lH-indazol-4-yl)benzofuro[2,3- b]pyridin-2(lH)-one

[0554] 028e

[0555] To a solution of 028d (340.0 mg, 0.66 mmol) in ethanol (2 mL) was added hydrazine monohydrate (2.0 mL, 0.66 mmol), and the reaction mixture was stirred at 90 °C for 24 h. After completion, the mixture was concentrated under vacuum to give a residue, which concentrated under vacuum to give a crude residue, which was purified silica-gel chromatography (elute with MeOH: DCM = 0 to 20%) to give 028e (200.0 mg, 72.7% yield) as a yellow solid. MS (ESI+) obsd. [(M+H)+]: 419.2.

[0556] Step 6: 3-Amino-4-(7-fluoro-lH-indazol-4-yl)-lH-[l]benzofuro[2,3-b]pyridin-2-one

[0557] 028 A mixture of 028e (200.0 mg, 0.48 mmol) in HC1 / dioxane (5 mL) was stirred at 25 °C for 2 h. After completion, the mixture was concentrated under vacuum to give a crude residue, which was purified by prep-HPLC (HC1 as additive) to give Example 028 (20.7 mg, 11.6% yield) as a brown solid. MS (ESI+) obsd. [(M+H)+]: 335.1.

[0558] Example 028:1H NMR (400 MHz, MeOD-d4) 8 ppm 7.76 (d, J = 3.2 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.45 - 7.40 (m, 1H), 7.36 - 7.30 (m, 2H), 7.02 - 6.98 (m, 1H), 6.41 (d, J= 8.0 Hz, 1H).19F NMR (376 MHz, MeOD-d4) 6 = -131.06 (s, IF).

[0559] Example 029: 9-Amino-10-(7-fluoro-lH-indazol-4-yl)-7H-pyrido[2,3-f][l,7]naphthyridin-8- one

[0560] 029

[0561] The title compound was prepared in analogy to the preparation of Example 001, replacing Int-1 with Int-15 in stepl. Example 029 (17 mg) was obtained as a yellow solid. MS (ESI+) obsd. [(M+H)+]: 347.0.

[0562] Example 029:1H NMR (400 MHz, MeOD-d4) 6 ppm 8.90 (s, 1H), 8.36-8.26 (m, 2H), 7.68 (d, J = 3.2 Hz, 1H), 7.61 (dd, J = 4.4, 8.4 Hz, 1H), 7.28 (dd, 7 = 7.6, 10.8 Hz, 1H), 7.02 (dd, J = 4.0, 7.6 Hz, 1H).19F NMR (377 MHz, McOD / 4) 6 ppm -134.82 (s, IF).

[0563] BIOLOGICAL EXAMPLES

[0564] Example 30: ADP-Glo Assay:

[0565] Detection of Mytl kinase activity utilized a recombinant human Mytl kinase assay measuring the hydrolysis of ATP using a commercially available ADP-Glo Assay (ADP-Glo™ Kinase Assay from Promega, 10000 assays, #V9102). Briefly, 50 nL of compounds (diluted in DMSO) was added to the microplate by ECHO Eiquid Handler. After this, 2.5 pL recombinant human Mytl (full length PKMYT1 recombinant human protein expressed in insect cells) was prepared in reaction buffer (50 mM HEPES (A-2-hydroxyethylpiperazine-N-2-ethane sulfonic acid), 10 mM MgCh, ImM EGTA (ethylene glycol-bis(P-aminoethyl ether)-A,A,M,M -tetraacetic acid) , O.lmg / ml BSA (bovine serum albumin), 1 mM DTT (Dithio threitol)) and added to 384 well white microplate (Corning #4512) and incubated at 22 °C for 15 minutes. Ultra- Pure Adenosine Triphosphate (ATP) solution (ADP-Glo kit from Promega) was diluted in reaction buffer and 2.5 pL was added to the microplate, spun down briefly and incubated for 60 minutes at 30 °C. The final Mytl enzyme concentration was 20 nM and the final ATP concentration was 300 pM. After the 60-minute incubation, 5 pL of ADP-Glo reagent was added and the plate was spun briefly and sealed and incubated in the dark for 60 minutes at 22 °C. Following this, 10 pL of kinase detection reagent was added per well and the plate was spun briefly, sealed and incubated for 30 minutes at 22 °C in the dark. Luminescence was read using the Envision (250 ms integration). The IC50 and the % max inhibition were calculated for each inhibitor compound tested.

[0566] Exemplary prepared compounds and their activities were shown in Table 3 below.

[0567] Table 3: ADP-Glo assay potency

[0568] Example 31: Human microsome stability assay

[0569] The human microsomal stability assay is used for early assessment of metabolic stability of compounds of present invention in human liver microsomes. Human liver microsomes (Cat.NO.: 452117, Coming, USA) were pre-incubated with test compound for 10 minutes at 37°C in 100 mM potassium phosphate buffer, pH 7.4. The reactions were initiated by adding NADPH regenerating system. The final incubation mixtures contained 1 pM compound, 0.5 mg / mL liver microsomal protein, 1 mM MgCh and 1 mM NADPH in 100 mM potassium phosphate buffer, pH 7.4. After incubation times of 0, 3, 6, 9, 15 and 30 minutes at 37°C, 300 pL of cold acetonitrile (including internal standard) was added to 100 pL incubation mixture to terminate the reaction. Following precipitation and centrifugation, the amount of compound remaining in the samples were determined by LC-MS / MS. Controls of no NADPH regenerating system at zero and 30 minutes were also prepared and analyzed. The compounds of present invention showed good human liver microsome stability determined in the above assay, results are shown in Table 4 below.

[0570] Clint* protein / liver (mg / g)* liver / body weight (g / kg) / 1000* liver blood flow CLh(mL / min / kg)= -

[0571] Liver blood flow+Clint* protein / liver (mg / g)* liver / body weight (g / kg) / 1OOO

[0572] Table 4: Human microsome clearance values of the compounds of this invention

[0573] Example 32: Human hepatocyte stability assay

[0574] Warm the Thawing Media and incubation Media to 37°C. Thaw Human CryoHepatocytes (Product No. X008001, BioreclamationIVT) and measure cell viability and density, cell suspension is adjusted to 2*106cells / mL in incubation medium (William’s E media containing 10% FBS (Fetal bovine serum), 50U / mL pen strep, 0.004mg / mL insulin and 0.4 mM L- Glutamine). Fill incubation plate (Thermo 96 deep well PP plate Cat#260251) with 50pl of cell suspension. Pre-incubate incubation plate minimum 30min at 37°C in CO2 incubator with appropriate shaking speed (standard 900rpm). Dilute compound in incubation medium in order to obtain incubation concentration x2 (1 pM incubation should prepare compound at 2 pM). After pre-incubation, start kinetics by addition of 50pl of compound. The 100 pL incubations contained l*106cells / mL and IpM compound. Samples are in Single (one compound in one well for each time point). Stop reaction by addition of 200pl of acetonitrile containing an internal standard directly in well at appropriate sampling time. Single copy at t = 2, 10, 20, 40, 60 and 120 min. Samples centrifuge at 4000 rpm for 10 min. The samples were assayed by LC / MS / MS. The compounds of present invention showed good human hepatocyte stability determined in the above assay, results are shown in Table 5 below.

[0575] Table 5: Human hepatocyte clearance values of the compounds of this invention

[0576] Example 33: GSH Adduct Screening Assay

[0577] All compounds including positive control (Such as: diclofenac, troglitazone and nefazodone) and solvent control (pure DMSO) are incubated using a 96-deep-well plate (Eppendorf) at 20 pM (addition of 1 pl of 10 mM DMSO stock solution) in 450 pl of 0.1 M sodium phosphate buffer at pH 7.4 containing human liver microsomes (HLM). Microsomal protein concentration is 1 mg / ml. Pipetting is performed using a TECAN pipetting robot. After 5 minutes of preincubation at 37°C the reaction is started by adding 50 pl of buffer containing GSH (100 mM) and NADPH (20 mM). Fresh stock solutions of GSH and NADPH are prepared before each experiment. The final concentrations are 5 mM for GSH and 1 mM for NADPH. After 60 minutes of incubation at 37°C (shaking at 800 rpm) the reaction is quenched with 500 pl of cold acetonitrile and centrifuged at 5000 x g at 25°C for 11 minutes. Before analysis the supernatant is split to two fractions, 450 and 400 pl each followed by evaporation using a N2 stream at 35°C to a volume of approximately 150 pl.

[0578] The analysis was performed on UPLC with Quadrupole Time-of-Flight of mass spectrometer. Data analysis and evaluation is achieved in an automated approach with software (Mass-MetaSite and WebMetaBase) to extract and identify GSH conjugates based on the presence of multiple collision-induced neutral losses and fragment ions specific of glutathione conjugates in the MS spectra. The GSH assay provides a qualitative end point. The assay readout is binary, i.e., GSH adducts found (Flag) or not (No Flag). Results from the above assay are shown in Table 6 below.

[0579] Table 6: GSH adducts of this invention

Claims

CLAIMS1. A compound of formula (I),whereinR1i H or halogen; and(i) A isR2and R3together with the atoms to which they are bonded form a 5 to 6 membered ring having 0 to 2 heteroatoms independently selected from N, O, and S, wherein the ring is optionally substituted with Ci-6alkyl;R5is selected from the group consisting of H, halogen, Ci-6alkyl, and deuterated Ci-ealkyl; or(ii) A isR3and R4together with the atoms to which they are bonded form a 5 to 6 membered ring having 0 to 2 heteroatoms independently selected from N, O, and S, R5is H; orR3is H, R4and R5together with the atoms to which they are bonded form a 5 to 6 membered ring; or(iii) A isR6and R7together with the atoms to which they are bonded form a 5 to 6 membered ring having one N atom; orR10and R11together with the atoms to which they are bonded form a 5 to 6 membered ring, or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, wherein R1is H or fluoro.

3. The compound according to claim 1 or claim 2, whereinR2and R3together with the atoms to which they are bonded form a 5 to 6 membered ring having 0 to 2 heteroatoms independently selected from N, and O, wherein R2is selected from the group consisting of O, Ci-2alkylene, and -Ci-2alkylene-O-, R3is selected from the group consisting of Ci-3alkylene, -N(Ci-2alkyl)- Ci-2alkylene-, -O-Ci-2alkylene-, -Cn2alkylene-O-, and O, or4. The compound according to any one of claims 1 - 3, wherein R5is selected from the group consisting of H, chloro, methyl, and trideuteriomethyl.

5. The compound according to claim 1 or claim 2, whereinR3and R4together with the atoms to which they are bonded form a 5 to 6 membered ring having 0 to 1 heteroatoms O, wherein R3is C2-3alkylene, R4is O or methylene, R5is H; orR3is H, R4and R5together with the atoms to which they are bonded form a 5 to 6 membered ring, wherein R4is C2-3alkylene, R5is methylene.

6. The compound according to claim 1 or claim 2, whereinR6and R7together with the atoms to which they are bonded form a 5 to 6 membered ring having one N atom, wherein R6is C2-3alkylene, R7is methylene.

7. The compound according to claim 1 or claim 2, whereinA is selected from the group consisting ofR5is selected from the group consisting of H, chloro, methyl, and trideuteriomethyl.

8. The compound according to claim 1, whereinR1is halogen,A isR2and R3together with the atoms to which they are bonded form a 5 to 6 membered ring having 1 heteroatom O, wherein R2is selected from the group consisting of O, Ci-2alkylene, and -Ci-2alkylene-O-, R3is selected from the group consisting of Ci-3alkylene and O,R5is selected from the group consisting of Ci-6alkyl and deuterated Ci-6alkyl,R6and R7together with the atoms to which they are bonded form a 5 to 6 membered ring having one N atom, wherein R6is C2-3alkylene, R7is methylene.

9. The compound according to claim 8, whereinR1is fluoro,A is selected from the group consisting ofR5is selected from the group consisting of methyl, and trideuteriomethyl.

10. A compound selected from:3-Amino-4-(7-fluoro- l / T-indazol-4-yl)- 1 ,7,8,9-tetrahydrocyclopenta[h] [ 1 ,5]naphthyridin-2- one,9-Amino-10-(7-fluoro-177-indazol-4-yl)-6-methyl-2,3,4,7-tetrahydropyrano[2,3- f] [ 1 ,7]naphthyridin-8-one,9-Amino-10-(7-fluoro-177-indazol-4-yl)-6-(trideuteriomethyl)-2, 3,4,7- tetrahydropyrano[2,3-f] [ 1 ,7]naphthyridin-8-one,7-amino-6-(7-fluoro-177-indazol-4-yl)-2,3,4,9-tetrahydropyrano[3,2-b][l,5]naphthyridin-8- one,9-amino-10-(7-fluoro-177-indazol-4-yl)-2,3,4,7-tetrahydropyrano[2,3-f][l,7]naphthyridin-8- one,3-amino-4-(7-fluoro- 177-indazol-4-yl)- 1 ,6,7,8-tetrahydrocyclopenta[b] [ 1 ,5]naphthyridin-2- one,9-Amino-10-(7-fluoro-177-indazol-4-yl)-4-methyl-3,7-dihydro-277-[l,4]oxazino[2,3- f] [ 1 ,7]naphthyridin-8-one,9-Amino- 10-( 177-indazol-4-yl)-6-methyl-2,3,4,7-tetrahydropyrano[2,3-f] [ 1 ,7]naphthyridin-8-one,9-Amino-6-chloro-10-(7-fluoro-177-indazol-4-yl)-2,3,4,7-tetrahydropyrano[2,3- f] [ 1 ,7]naphthyridin-8-one,6-Amino-5-(7-fluoro-177-indazol-4-yl)-3,8-dihydro-277-furo[3,2-b][l,5]naphthyridin-7-one,8-Amino-9-(7-fluoro-177-indazol-4-yl)-5-methyl-3,6-dihydro-277-furo[2,3- f] [ 1 ,7]naphthyridin-7-one,9-Amino-10-(7-fluoro-177-indazol-4-yl)-6-methyl-3,7-dihydro-277-[l,4]dioxino[2,3- f] [ 1 ,7]naphthyridin-8-one,9-Amino-6-chloro-10-(7-fluoro-177-indazol-4-yl)-4-methyl-3,7-dihydro-277-[ 1 ,4]oxazino[2,3-f] [ 1 ,7]naphthyridin-8-one,8-amino-5-chloro-9-(7-fluoro-177-indazol-4-yl)-677-[l,3]dioxolo[4,5-f][l,7]naphthyridin-7- one,8-Amino-9-(7-fluoro-177-indazol-4-yl)-5-methyl-677-[l,3]dioxolo[4,5-f][l,7]naphthyridin-7-one,9-Amino-10-(7-fluoro-177-indazol-4-yl)-4,6-dimethyl-3,7-dihydro-277-[l,4]oxazino[2,3- f] [ 1 ,7]naphthyridin-8-one,9-Amino-6-chloro-10-(7-fluoro-177-indazol-4-yl)-l,3,4,7-tetrahydropyrano[3,4- f] [ 1 ,7]naphthyridin-8-one,9-Amino-10-(7-fluoro-177-indazol-4-yl)-6-methyl-l,3,4,7-tetrahydropyrano[3,4- f] [ 1 ,7]naphthyridin-8-one,8-Amino-5-chloro-9-(7-fluoro-177-indazol-4-yl)-2,6-dihydro-177-furo[3,2- f] [ 1 ,7]naphthyridin-7-one,8-Amino-5-chloro-9-(7-fluoro-177-indazol-4-yl)-l,2,3,6- tetrahydrocyclopenta[f] [ 1 ,7]naphthyridin-7-one,8-Amino-9-(7-fluoro-177-indazol-4-yl)-5-methyl-2,6-dihydro-177-furo[3,2- f] [ 1 ,7]naphthyridin-7-one,8-Amino-9-(7-fluoro-177-indazol-4-yl)-5-methyl-l,2,3,6- tetrahydrocyclopenta[f] [ 1 ,7]naphthyridin-7 -one,10-Amino-9-(7-fluoro-177-indazol-4-yl)-6,7,12-triazatricyclo[6.4.0.02,6]dodeca-l,7,9-trien-11 -one,8-Amino-9-(7-fluoro-177-indazol-4-yl)-5-methyl-3,6-dihydro-177-furo[3,4- f] [ 1 ,7]naphthyridin-7-one,8-Amino-9-(7-fluoro-177-indazol-4-yl)-5-methyl-6H-furo[2,3-f][l,7]naphthyridin-7-one,5-Amino-6-(7-fluoro-177-indazol-4-yl)-8-oxa-3,12-diazatricyclo[7.4.0.02,7] trideca-1 (9) ,2(7), 5 , 10,12-pentaen-4-one,5-Amino-6-(7-fluoro-lH-indazol-4-yl)-3,8,9-triazatricyclo[7.4.0.02,7]trideca-l,5,7-trien-4- one,3-Amino-4-(7-fluoro-177-indazol-4-yl)-177-[l]benzofuro[2,3-b]pyridin-2-one,9-Amino-10-(7-fluoro-lH-indazol-4-yl)-7H-pyrido[2,3-f][l,7]naphthyridin-8-one, or a pharmaceutically acceptable salt thereof.

11. A process for the preparation of a compound having the structure of formula (la),a) formation of compound of formula (la) via decomposition reaction of compound of formula (X),in the presence of hydrazine hydrate; b) formation of compound of formula (la) via cross coupling of compound of formula (XV),(XV), and compound of formula (XVI),(XVI), in the presence of suitable catalyst, in particular Pd(dtbpf)Ch, Pd(dppf)Ch or Pd(PPh3)4, followed by deprotecting of PG3, in the presence a suitable acid, in particular TFA or HC1,whereinRing B together with the ring to which it is bonded form a tricyclic ring containing two to five heteroatoms selected from N, O, and S, in particular, ring B and the ring to which it is bonded form a tricyclic ring selected from the group consisting ofRbis halogen, in particular bromo or iodide,Rcis boronic acid, boronic ester or tributyltin,PG3 is hydrogen, or a protecting group, in particular p-methoxybenzyl, R1is as defined in any one of claims 1 to 9.

12. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, when manufactured according to the process of claim 11.

13. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, and a pharmaceutically acceptable excipient.

14. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10 for use as therapeutically active substance.

15. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10 for use in the treatment or cancer.

16. The use of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10 for the treatment of cancer.

17. The use of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10 for the inhibition of PKMYT1.

18. The use of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10 for the preparation of a medicament for the treatment of cancer.

19. The use of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10 for the preparation of a medicament for the inhibition of PKMYT1.

20. A method for the treatment of cancer, which method comprises administering an effective amount of a compound or a pharmaceutically acceptable salt thereof as defined in any one of claims 1 to 10.

21. The use of according to claim 16 or 19, or the method according to claim 20, wherein the cancer is a cancer in pancreas, liver, lung, breast, stomach, buliarintestinal, genitourinary tract, or ovary.

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