Cbl-b inhibitors

Abstract

The present application relates to a heterocyclic compound or a pharmaceutically acceptable salt thereof as a Cbl-b inhibitor. Specifically, the present application relates to a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof. The present application also relates to a preparation method of the compound or the pharmaceutically acceptable salt thereof. The compound of the present application can be used for treating and / or preventing a Cbl-b mediated disease, particularly cancer.

Description

Technical Field

[0001] This invention relates to heterocyclic compounds suitable for modulating or inhibiting Cbl-b activity, or pharmaceutically acceptable salts thereof. The invention also relates to methods for preparing such heterocyclic compounds. Furthermore, the invention relates to methods for treating and / or preventing diseases mediated by this protein, particularly cancer. Background Technology

[0002] Cbl-b (Casitas B-lineage lymphoma proto-oncogene-b) is a RING E3 ligase, forming the Cbl family along with Cbl and Cbl-c. The Cbl-b protein comprises several structural regions: an N-terminal tyrosine kinase-binding (TKB) domain, a helical linker (L) domain, a ring finger (RF) domain, a proline-rich motif (PR) region, and a C-terminal ubiquitin-associated domain (UBA). Cbl-b interacts with activated tyrosine kinases through its TBK domain, phosphorylating the Y363 region of the L domain, resulting in a conformational change. In the activated conformation, the masking of the RF domain by the TKB domain is removed, allowing the RF domain to recruit E2 ubiquitin-binding enzymes and mediating substrate ubiquitination and degradation. Tyrosine kinases that interact with the TBK domain of Cbl-b are proteins essential for T cell receptor (TCR) signaling, such as ZAP70, PKCθ, and PI3K. Their degradation leads to the termination of TCR signaling, thereby inhibiting T cell activation. Cbl-b knockout mice exhibit overactive T cells with enhanced adaptive and innate anti-tumor immunity. Therefore, Cbl-b plays a negative regulatory role in TCR signaling, and its inhibitors hold promise for use in cancer immunotherapy.

[0003] Detailed description of the invention

[0004] definition

[0005] Unless otherwise stated, the following terms as used in this application shall have the following meanings.

[0006] “C x-y "" represents the range of carbon atoms, where x and y are both integers, for example, C 3-8 Cycloalkyl refers to cycloalkyl groups having 3-8 carbon atoms, that is, cycloalkyl groups having 3, 4, 5, 6, 7, or 8 carbon atoms. It should also be understood that "C..." 3-8 It also includes any subrange within it, such as C. 3-7 C 3-6C 4-7 C 4-6 C 5-6 wait.

[0007] "Alkyl" refers to a saturated straight-chain or branched hydrocarbon group containing 1 to 20 carbon atoms, such as 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, etc.

[0008] “Cycloalkyl” refers to a saturated cyclic hydrocarbon substituent containing 3 to 14 carbon ring atoms. A cycloalkyl group can be a monocyclic ring, typically containing 3 to 8, 3 to 7, or 3 to 6 carbon ring atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc. Cycloalkyl groups can also be fused, bridged, or spirocyclic bicyclic or tricyclic rings, such as decahydronaphthyl, bicyclo[2.2.2]octane, spiro[3.3]heptane, etc.

[0009] "Heterocyclic group or heterocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic group comprising 3 to 20 ring atoms, for example, 3 to 14, 3 to 12, 3 to 10, 3 to 8, 3 to 6, or 5 to 6 ring atoms, wherein one or more ring atoms are selected from nitrogen, oxygen, or S(O). m (Where m is an integer from 0 to 2), and the remaining ring atoms are carbon. Preferably, it includes 3 to 12 ring atoms, 3 to 10 ring atoms, 4 to 7 ring atoms, or 4 to 6 ring atoms, wherein 1 to 4 are heteroatoms, 1 to 3 are heteroatoms, or 1 to 2 are heteroatoms. Non-limiting examples of monocyclic heterocyclic groups include oxobutylcycloyl, tetrahydrofuranyl, tetrahydropyranyl, acridineyl, pyrrolylyl, piperidinyl, piperazinyl, morpholinyl, homopiperazinyl, 1,4-oxazazoleyl, pyrrolidoneyl, piperidinoneyl, 1,1-thiomorpholinyl, etc. Polycyclic heterocyclic groups include fused, bridged, or spiropolycyclic heterocyclic groups, such as octahydrocyclopentadien[c]pyrrole, octahydropyrrolo[1,2-a]pyrazine, 3,8-diazabicyclo[3.2.1]octane, 5-azaspiro[2.4]heptane, 2-oxa-7-azaspiro[3.5]nonane, etc.

[0010] "Aryl or aromatic ring" refers to an aromatic monocyclic or fused polycyclic group containing 6 to 14 carbon atoms, preferably 6 to 10 members, such as phenyl and naphthyl, with phenyl being the most preferred. The aryl ring may be fused to a heteroaryl, heterocyclic, or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring. Non-limiting examples include:

[0011] wait.

[0012] "Heteroaryl or heteroaryl ring" refers to a heteroaryl system containing 5 to 14 ring atoms, wherein 1 to 4 ring atoms are selected from heteroatoms including oxygen, sulfur, and nitrogen. The heteroaryl group is preferably 5 to 10-membered, more preferably 5- or 6-membered, such as furanyl, thiophene, pyridyl, pyrroleyl, pyrimidinyl, pyrazinyl, pyrazolyl, imidazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, quinolinyl, isoquinolinyl, indole, isoindole, etc. The heteroaryl ring may be fused to an aryl, heterocyclic, or cycloalkyl ring; non-limiting examples include:

[0013] wait.

[0014] "Halogen" refers to fluorine, chlorine, bromine, or iodine.

[0015] “Cyano” refers to -CN.

[0016] "Oxytochemical" means =O.

[0017] "Carbonyl" refers to the -C(O)- group.

[0018] "Sulfoyl" refers to the -S(O)2- group.

[0019] "Thionyl" refers to the -S(O)- group.

[0020] "Optional" means that the event or situation described below may, but does not have to, occur. For example, the description "one or more hydrogens of the phenyl may be substituted by a halogen" includes both cases where one or more hydrogens of the phenyl are substituted by a halogen and cases where they are not substituted by a halogen.

[0021] "Substitution" refers to one or more hydrogen atoms in a group, preferably 1 to 5, for example 1 to 3 hydrogen atoms, independently replaced by the corresponding number of substituents. Substituents are only located in chemical positions known to those skilled in the art. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (such as an alkene). Substituents include, but are not limited to, halogens, cyano groups, nitro groups, hydroxyl groups, amino groups, oxo groups, -SF5 groups, and C6 groups. 1-4 Alkyl, C 3-7 Cycloalkyl, 4-7 membered heterocyclic groups, phenyl, 5-6 membered heteroaryl, etc.

[0022] "Isomers" refer to compounds with the same molecular formula but different atomic positions or spatial arrangements. Isomers with different atomic spatial arrangements are called "stereoisomers." Stereoisomers include optical isomers, geometric isomers, and conformational isomers.

[0023] The compounds of this invention can exist as optical isomers. Optical isomers include enantiomers and diastereomers. Enantiomers are two stereoisomers that are non-overlapping and mirror images of each other. Racemic mixtures or racemates are mixtures of chiral molecules having equal numbers of levorotatory and dextrorotatory enantiomers. Diastereomers are two stereoisomers that are non-overlapping and not mirror images of each other. When an optical isomer is a single isomer and its absolute configuration is determined, it is called an "R" or "S" isomer based on the configuration of the substituents on the chiral atom; when its absolute configuration is not determined, it is called a (+) or (-) isomer based on its measured optical rotation value. Methods for preparing and separating optical isomers are known in the art.

[0024] The compounds of the present invention may also have geometric isomers with different distributions of substituents around carbon-carbon double bonds, carbon-nitrogen double bonds, cycloalkyl groups, or heterocyclic groups. Substituents around carbon-carbon double bonds or carbon-nitrogen bonds are designated as Z or E configurations, while substituents around cycloalkyl groups or heterocyclic groups are designated as cis or trans configurations.

[0025] The compounds of the present invention may also exhibit tautomerism, such as keto-enol tautomerism.

[0026] It should be understood that the present invention includes any tautomer or stereoisomer form and mixtures thereof, and is not limited to any one of the tautomer or stereoisomer forms used in the naming or chemical structural formula of the compound.

[0027] "Isotope" refers to all isotopes of atoms appearing in the compounds of this invention. Isotopes include atoms having the same atomic number but different mass numbers. Examples of isotopes suitable for inclusion in the compounds of this invention are hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, respectively, for example, but not limited to, [examples of isotopes]. 2 H(D), 3 H, 13 C 14 C 15 N、 17 O、 18 O、 31 P, 32 P, 35 S, 18 F and 36Cl. The isotope-labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by methods similar to those described in the appended examples, using a suitable isotope-labeled reagent instead of a non-isotope-labeled reagent. Such compounds have a variety of potential uses, for example as standards and reagents for determining biological activity. Regarding stable isotopes, for example, deuterium... 2 H(D), 13 C and 15 N, compounds containing this isotope have the potential to alter biological, pharmacological, or pharmacokinetic properties. Deuterium 2 H(D) is a preferred isotope of the present invention, for example, hydrogen in methyl, methylene or methine can be replaced by deuterium.

[0028] The compounds of the present invention can be administered in the form of prodrugs. A "prodrug" is a derivative which, under physiological conditions in vivo, is converted into the bioactive compounds of the present invention through processes such as oxidation, reduction, hydrolysis, etc. (each involving an enzyme or without enzyme involvement). Examples of prodrugs include compounds in which the amino group is acylated, alkylated, or phosphorylated, for example, eicosanoylamino, alanylamino, neopentanoyloxymethylamino; or in which the hydroxyl group is acylated, alkylated, phosphorylated, or converted to a borate, for example, acetoxy, palmitoyloxy, neopentanoyloxy, succinoxy, fumaroyloxy, alanyloxy; or in which the carboxyl group is esterified or amidated; or in which the thiol group is associated with a carrier molecule that selectively delivers a drug to a target and / or to the cytosol of cells. These compounds can be prepared from the compounds of the present invention according to known methods.

[0029] "Pharmaceutical-grade salt" or "pharmaceutically acceptable salt" refers to a salt made from a pharmaceutically acceptable base or acid, including inorganic bases or acids and organic bases or acids, in cases where the compounds of the present invention contain one or more acidic or basic groups. Therefore, compounds of the present invention containing acidic groups can exist in salt form, such as alkali metal salts, alkaline earth metal salts, or ammonium salts. More precise examples of such salts include sodium salts, potassium salts, calcium salts, magnesium salts, or salts with ammonia or organic amines, such as ethylamine, ethanolamine, triethanolamine, or amino acids. Compounds of the present invention containing basic groups can exist in the form of inorganic acids or organic acid salts. Examples of suitable acids include hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acid, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pentylamino acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, aminosulfonic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, and other acids known to those skilled in the art. If the compounds of the present invention contain both acidic and basic groups in the molecule, the present invention also includes internal salts or internal ammonium salts in addition to the salt forms mentioned. Each salt can be obtained by conventional methods known to those skilled in the art, for example by mixing the compound with an organic or inorganic acid or base in a solvent or dispersant, or by anion or cation exchange with other salts.

[0030] "Pharmaceutical composition" refers to a mixture containing one or more of the compounds of the present invention or their pharmaceutically acceptable salts, stable isotope derivatives, isomers, prodrugs, and mixtures thereof, as well as other components such as pharmaceutically acceptable carriers and excipients.

[0031] Therefore, when referring to “compound,” “compound of the present invention,” or “compound of the present invention” in this application, it includes all said compound forms, such as pharmaceutically usable salts, stable isotope derivatives, isomers, prodrugs, and mixtures thereof.

[0032] "Therapeutic effective amount" refers to the amount of the compound of the present invention that can effectively inhibit Cbl-b activity to treat or prevent diseases mediated thereunder.

[0033] "Patient" refers to mammals, especially humans.

[0034] This invention provides compounds that can be used as Cbl-b inhibitors. The compounds are shown in general formula (I), or their prodrugs, stable isotope derivatives, pharmaceutically acceptable salts, and isomers thereof:

[0035]

[0036] in:

[0037] Ring A is a benzene ring or a 6-membered heteroaromatic ring, wherein one or two hydrogens of the benzene ring and the heteroaromatic ring are optionally replaced by halogens, cyano groups, or -OC groups.1-6 Alkyl, C 1-6 Alkyl, C 3-8 The alkyl group is substituted with a cycloalkyl or 4-8 membered heterocyclic group, wherein one or more hydrogens of the alkyl group may optionally be further substituted with D or F;

[0038] Ring B is a benzene ring or a 5-6 membered heteroaromatic ring, wherein one or two hydrogens of the benzene ring or heteroaromatic ring are optionally replaced by halogens, cyano groups, -C(O)NH2, or -OC. 1-6 Alkyl, C 1-6 Alkyl or C 3-8 The alkyl group is substituted with a cycloalkyl group, wherein one or more hydrogen atoms of the alkyl group may optionally be further substituted with D or F;

[0039] The ring C is a 5-6 membered heteroaromatic ring, wherein one or two hydrogens of the heteroaromatic ring are optionally replaced by halogen, cyano, oxo, or -OC. 1-6 Alkyl, C 1-6 Alkyl or C 3-8 The alkyl group is substituted with a cycloalkyl group, wherein one or more hydrogen atoms of the alkyl group may optionally be further substituted with D or F;

[0040] X 1 and X 2 Each independently selected from CR 1 Or N;

[0041] Z 1 Z 2 Z 3 and Z 4 Each independently selected from CR 2 Or N;

[0042] L represents a bond, -O-, -NR 3 -or

[0043] R is a halogen, cyano group, R c -OR c -NR c R d ;

[0044] R 1 It can be halogen, cyano, R′ or -OR′;

[0045] R 2 It can be halogen, cyano, R′, -OR′ or -NR′R″;

[0046] R 3 For H, C 1-6 Alkyl or C 3-8 cycloalkyl;

[0047] R a and R bEach group is independently selected from H, D, halogens, cyano groups, -OH, and -OC. 1-6 Alkyl, C 1-6 Alkyl or C 3-8 cycloalkyl, or R a and R b Together with the carbon atoms attached to it, they can be optionally combined to form C. 3-6 Cycloalkanes or 4-8 membered heterocycles;

[0048] R c and R d Each is independently selected from H and C 1-6 Alkyl, C 3-8 Cycloalkyl or 4-10 membered heterocyclic group, wherein one or more hydrogens of the alkyl, cycloalkyl and heterocyclic group are optionally substituted with R′″;

[0049] R′ and R″ are each independently selected from H and C. 1-6 Alkyl, C 3-8 Cycloalkyl or 4-8 membered heterocyclic group, wherein one or more hydrogens of the alkyl, cycloalkyl, or heterocyclic group are optionally replaced by D, halogen, cyano, -OH, or -OC. 1-6 Alkyl groups are substituted; and

[0050] R″′ represents D, halogen, cyano, -OH, or -OC. 1-6 Alkyl, C 1-6 Alkyl, C 3-8 Cycloalkyl or 4-8 membered heterocyclic group, wherein one or more hydrogens of the alkyl, cycloalkyl, or heterocyclic group are optionally halogenated, cyano, -OH, or -OC. 1-6 Alkyl or C 1-6 Alkyl groups are substituted.

[0051] In some embodiments, ring A is a benzene ring, a pyridine ring, a pyridazine ring, or a pyrimidine ring, wherein one or two hydrogens of the benzene ring and the heteroaromatic ring are optionally replaced by a halogen, a cyano group, or an -OC group. 1-2 Alkyl, C 1-2 Alkyl or C 3-8 The alkyl group is substituted with a cycloalkyl group, wherein one or more hydrogen atoms of the alkyl group may optionally be further substituted with D or F.

[0052] In some embodiments, ring B is a benzene ring or a 6-membered heteroaromatic ring, such as a pyridine ring, a pyrimidine ring, a pyridazine ring, or a pyrazine ring, wherein one or two hydrogens of the benzene ring or heteroaromatic ring are optionally replaced by a halogen, a cyano group, -C(O)NH2, or -OC. 1-6 Alkyl, C 1-6 Alkyl or C 3-8 The alkyl group is substituted with a cycloalkyl group, wherein one or more hydrogen atoms of the alkyl group are optionally substituted with D or F.

[0053] In some embodiments, ring B is a 5-membered heteroaromatic ring, such as a pyrazole ring, a thiadiazole ring, or a triazole ring, wherein one hydrogen atom of the heteroaromatic ring is optionally replaced by C. 1-6 Alkyl or C 3-8 The alkyl group is substituted with a cycloalkyl group, wherein one or more hydrogen atoms of the alkyl group may optionally be further substituted with D or F.

[0054] In some embodiments, ring C is a 5-membered heteroaromatic ring containing 1-4 heteroatoms of N, O, and S, such as furan ring, pyrrole ring, thiophene ring, pyrazole ring, imidazole ring, oxazole ring, isoxazole ring, thiazole ring, isothiazole ring, triazole ring, oxadiazole ring, or thiadiazole ring, wherein one hydrogen atom of the heteroaromatic ring is optionally replaced by a halogen, cyano group, or -OC group. 1-6 Alkyl, C 1-6 Alkyl or C 3-8 The alkyl group is substituted with a cycloalkyl group, wherein one or more hydrogen atoms of the alkyl group may optionally be further substituted with D or F.

[0055] In some embodiments, ring C is a triazole ring, isoxazole ring, pyrazole ring, or thiadiazole ring, and one hydrogen atom of the heteroaromatic ring is optionally replaced by C. 1-6 Alkyl or C 3-8 The alkyl group is substituted with a cycloalkyl group, wherein one or more hydrogen atoms of the alkyl group may optionally be further substituted with D or F.

[0056] In some implementation schemes, X 1 and X 2 Each can be independently selected from CH or N.

[0057] In some implementation schemes, Z 1 Z 2 Z 3 and Z 4 For CR 2 In some implementation schemes, Z 1 For N, Z 2 Z 3 and Z 4 For CR 2 In some implementation schemes, Z 2 For N, Z 1 Z 3 and Z 4 For CR 2 In some implementation schemes, Z 3 For N, Z 1 Z 2 and Z 4 For CR 2 In some implementation schemes, Z 4 For N, Z 1 Z 2 and Z 3 For CR 2 In some implementation schemes, Z1 and Z 4 For N, Z 2 and Z 3 For CR 2 In some implementation schemes, Z 1 and Z 3 For N, Z 2 and Z 4 For CR 2 .

[0058] In some implementation schemes, R 2 It can be halogen, cyano, R′, -OR′ or -NR′R″; R′ and R″ are each independently selected from H, C 1-6 Alkyl or C 3-8 Cycloalkyl, wherein the alkyl group and one or more hydrogens of the cycloalkyl group are optionally replaced by D, halogen, cyano, -OH or -OC. 1-6 Alkyl groups are substituted.

[0059] In some implementations, L represents a bond; R represents H, halogen, cyano, or C. 3-8 Cycloalkyl or 4-10 membered heterocyclic group, wherein one or more hydrogens of the cycloalkyl or heterocyclic group are optionally halogenated, cyano, -OH, or -OC. 1-6 Alkyl or C 1-6 Alkyl groups are substituted.

[0060] In some implementations, L is -O- or -NR 3 -;R 3 For H, C 1-6 Alkyl or C 3-8 Cycloalkyl; R is H or C 1-6 Alkyl, C 3-8 Cycloalkyl or 4-10 membered heterocyclic group, wherein one or more hydrogens of the alkyl, cycloalkyl, or heterocyclic group are optionally substituted by R″′; R″′ is D, halogen, cyano, -OH, -OC. 1-6 Alkyl, C 1-6 Alkyl, C 3-8 Cycloalkyl, 4-8 membered heterocyclic groups, wherein one or more hydrogens of the alkyl, cycloalkyl, or heterocyclic group are optionally halogenated, cyano, -OH, or -OC. 1-6 Alkyl or C 1-6 Alkyl groups are substituted.

[0061] In some implementations, L is R a and R b Each group is independently selected from H, D, halogens, cyano groups, -OH, and -OC. 1-6 Alkyl, C 1-6 Alkyl or C 3-8 cycloalkyl, or R a and Rb Together with the carbon atoms attached to it, they can be optionally combined to form C. 3-6 Cycloalkanes or 4-8 membered heterocycles; R is a cyano group, R c -OR c -NR c R d ;R c and R d Each is independently selected from H and C 1-6 Alkyl, C 3-8 Cycloalkyl or 4-10 membered heterocyclic group, wherein one or more hydrogens of the alkyl, cycloalkyl, or heterocyclic group are optionally substituted by R″′; R″′ is D, halogen, cyano, -OH, -OC. 1-6 Alkyl, C 1-6 Alkyl, C 3-8 Cycloalkyl or 4-8 membered heterocyclic group, wherein one or more hydrogens of the alkyl, cycloalkyl, or heterocyclic group are optionally halogenated, cyano, -OH, or -OC. 1-6 Alkyl or C 1-6 Alkyl groups are substituted.

[0062] In some embodiments, the compounds of the present invention are shown as general formula (II):

[0063]

[0064] in:

[0065] R a and R b Each element is independently selected from H, D, halogens, or C. 1-6 alkyl;

[0066] R 11 For H, C 1-6 Alkyl, C 3-8 Cycloalkyl or 4-8 membered heterocyclic group, wherein one or more hydrogens of the alkyl, cycloalkyl and heterocyclic group are optionally substituted with R″′;

[0067] R 12 For H, C 1-6 Alkyl or C 3-8 cycloalkyl;

[0068] R 11 and R 12 Together with the nitrogen atom attached thereto, they optionally form 4-10 membered heterocycles optionally containing an additional O or N heteroatom, including but not limited to aziridine, pyrrolidine, piperidine, aziridine-heptane, morpholine, piperazine, etc. One or more hydrogen atoms of the heterocycle may be optionally replaced by D, halogen, cyano, -OH, or -OC. 1-6 Alkyl, C 1-6 Alkyl or C3-8 The alkyl group is replaced by a cycloalkyl group, wherein one or more hydrogen atoms of the alkyl group may optionally be further replaced by a halogen, cyano, -OH, or -OC group. 1-6 Alkyl or C 1-6 Alkyl groups are substituted.

[0069] Ring A, Ring B, Ring C, X 1 X 2 Z 1 Z 2 Z 3 Z 4 And R″′ are as defined in general formula (I).

[0070] In some embodiments, the compounds of the present invention are shown as general formula (III):

[0071]

[0072] in:

[0073] Y 1 Y 2 and Y 3 Each can be independently selected from CH or N;

[0074] R 13 H, halogen, cyano, -C(O)NH2, -OC 1-6 Alkyl, C 1-6 Alkyl or C 3-8 Cycloalkyl, wherein one or more hydrogens of the alkyl group are optionally replaced by D or F;

[0075] Ring A, Ring C, X 1 X 2 Z 1 Z 2 Z 3 Z 4 R 11 R 12 R a R b As defined in general formula (II).

[0076] In some implementations, ring C is a five-membered heteroaromatic ring, including but not limited to... Preferred R 14 For H, C 1-6 Alkyl or C 3-8 Cycloalkyl, wherein one or more hydrogens of the alkyl group are optionally substituted with D;

[0077] This invention also relates to the following compounds, or pharmaceutically acceptable salts, stable isotope derivatives, isomers, prodrugs, and mixtures thereof:

[0078]

[0079]

[0080]

[0081]

[0082]

[0083]

[0084]

[0085]

[0086]

[0087]

[0088]

[0089]

[0090]

[0091]

[0092]

[0093] The present invention also relates to pharmaceutical compositions comprising a compound of general formula (I) or a pharmaceutically acceptable salt, stable isotope derivative, isomer, and prodrug thereof, and one or more pharmaceutically acceptable carriers or excipients. The pharmaceutical compositions can inhibit the activity of Cbl-b, affecting its biological function, thereby achieving therapeutic or preventative effects against Cbl-b-mediated diseases.

[0094] The present invention also provides a method for treating or preventing Cbl-b-mediated diseases, the method comprising administering to a patient in need a therapeutically effective amount of a compound of general formula (I) or a pharmaceutically acceptable salt, stable isotope derivative, isomer, prodrug, or pharmaceutical composition thereof; wherein the “effective amount” is an effective dose for treating the disease by improving the pathological state of the disease or alleviating the symptoms of the disease; the diseases include, but are not limited to, hematologic malignancies (such as leukemia, lymphoma, myeloma, etc.) and solid tumors (such as glioma, thyroid cancer, head and neck cancer, pancreatic cancer, lung cancer, colon cancer, liver cancer, bile duct cancer, gastric cancer, esophageal cancer, kidney cancer, prostate cancer, bladder cancer, breast cancer, ovarian cancer, cervical cancer, uterine cancer, endometrial cancer, urothelial carcinoma, muscle cancer, bone cancer, etc.).

[0095] The present invention also provides a pharmaceutical composition comprising the compound of any one of claims 1-8 or a pharmaceutically acceptable salt thereof, a stable isotope derivative, an isomer thereof, and at least one additional drug, wherein the additional drug includes, but is not limited to, chemotherapeutic agents, kinase inhibitors, synthetic lethal agents, immune and / or inflammatory modulators, neurological disease modulators, etc.

[0096] According to the present invention, the drug can be any dosage form, including but not limited to tablets, capsules, solutions, lyophilized preparations, and injections.

[0097] The pharmaceutical formulations of the present invention can be administered in dose units of a predetermined amount of the active ingredient. Depending on the condition being treated, the method of administration, and the patient's age, weight, and condition, such units contain from 1 mg to 1000 mg of the compound of the present invention. Furthermore, the pharmaceutical formulations can be prepared using methods well-known in the pharmaceutical field, for example by formulating the active ingredient together with one or more excipients or adjuvants.

[0098] The pharmaceutical formulations of the present invention are suitable for administration by any desired and appropriate method, such as oral (including oral cavity or sublingual), rectal, nasal, local (including oral cavity, sublingual or transdermal) or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) methods.

[0099] This invention also provides a method for preparing the compound. The compound can also be synthesized using synthetic techniques known to those skilled in the art. The products obtained from each reaction step are obtained using separation techniques known in the art. The starting materials and chemical reagents required for the synthesis can be routinely synthesized or purchased from literature (available on SciFinder).

[0100] Synthesis method

[0101] The heterocyclic compound of general formula (I) of the present invention can be synthesized according to the following route: P-1 is protected by Boc and then converted to P-3 by palladium-catalyzed coupling reaction; P-3 is halogenated to obtain P-4, and then further substituted to obtain P-5; P-5 and O-1 are coupled by palladium-catalyzed coupling reaction to obtain I.

[0102]

[0103] The intermediate P-5 can also be synthesized via the following route: P-1 is directly obtained by a palladium-catalyzed cross-coupling reaction.

[0104]

[0105] Intermediate P-1 can be synthesized via the following route: P-11 is brominated to obtain P-12, P-12 is substituted to obtain P-13, and then P-1 is obtained through a rearrangement reaction.

[0106]

[0107] Intermediate O-1 can be synthesized via the following route: carboxylic acid O-11 undergoes a condensation reaction to give O-12, and O-12 can be further cyclized to give O-13. O-13 undergoes a reduction reaction and a cross-coupling reaction to give O-15, and O-15 can be further derivatized to give O-1.

[0108]

[0109] The following examples further illustrate the present invention. These examples are intended to illustrate the invention only and should not be considered as limiting the scope of the invention. Example

[0110] The starting materials of this invention can be synthesized according to methods known in the art, or can be purchased from chemical companies such as ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc., Beijing Ouhe, Bid Pharmaceutical, and Zesheng Technology.

[0111] The structures of the compounds of this invention were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR measurements were performed using a Bruker ASCEND-400 NMR spectrometer, with solvents such as deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), or deuterated methanol (CD3OD), and tetramethylsilane (TMS) as the internal standard. Chemical shifts were expressed as 10⁻⁶. -6 (ppm) are given as the unit. MS determinations were performed using an Agilent SQD (ESI) mass spectrometer (Agilent 6120).

[0112] HPLC was performed using an Agilent 1260DAD high-performance liquid chromatograph (Poroshell 120EC-C18, 50×3.0mm, 2.7μm column) or a Waters Arc high-performance liquid chromatograph (Sunfire C18, 150×4.6mm, 5μm column).

[0113] Unless otherwise specified in the examples, the reaction temperature is room temperature (20℃-30℃).

[0114] Unless otherwise specified in the examples, the reactions were carried out under an argon or nitrogen atmosphere. An argon or nitrogen atmosphere refers to a reaction flask that has been evacuated and then refilled with argon or nitrogen (repeated 3 times) and then connected to an argon or nitrogen balloon with a volume of approximately 1L.

[0115] A hydrogen atmosphere refers to a reaction flask that has been evacuated and then refilled with hydrogen (repeated 3 times) and then connected to a hydrogen balloon with a volume of about 1L.

[0116] The microwave reaction used a CEM Discover-SP type microwave reactor.

[0117] The reaction process in the examples was monitored using an Agilent liquid chromatography-mass spectrometry (LC-MS) system (1260 / 6120), or thin-layer chromatography (TLC) with a silica gel plate thickness of 0.15–0.2 mm (Qingdao Ocean GF254).

[0118] The compounds were purified by column chromatography or thin-layer chromatography. For column chromatography, 200-300 mesh silica gel from Qingdao Ocean was used, and for thin-layer chromatography, GF254 silica gel plates with a thickness of 0.4-0.5 mm from Qingdao Ocean were used.

[0119] The solvent systems used for column chromatography or thin-layer chromatography typically include a) dichloromethane and methanol, b) petroleum ether and ethyl acetate, or as shown in the examples. The volume ratio of the solvent is adjusted according to the polarity of the compound, and can also be further adjusted by adding a small amount of triethylamine or other acidic or basic reagents.

[0120] The compounds were purified using a Waters mass spectrometry-guided automated preparation system (mass spectrometer detector: SQD2, abbreviated as prep-HPLC). Elution was performed on a reversed-phase high-pressure column (XBridge-C18, 19×150mm, 5μm) using an appropriate acetonitrile / water gradient (containing 0.1% trifluoroacetic acid or formic acid, or 0.05% ammonia) at a flow rate of 20 mL / min, depending on the compound's polarity. In some examples, after purification using the automated preparation system, 1N dilute hydrochloric acid was added, followed by solvent removal under reduced pressure to obtain the hydrochloride salt.

[0121] The abbreviation DMF stands for N,N-dimethylformamide.

[0122] The abbreviation DMA stands for N,N-dimethylacetamide.

[0123] The abbreviation NMP refers to N-methylpyrrolidone.

[0124] The abbreviation THF stands for tetrahydrofuran.

[0125] The abbreviation DIPEA refers to N,N-diisopropylethylamine.

[0126] The abbreviation DMAP refers to para-N,N-dimethylaminopyridine.

[0127] The abbreviation NBS refers to N-bromosuccinimide.

[0128] The abbreviation NIS stands for N-iodosuccinimide.

[0129] The abbreviation HATU refers to 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate.

[0130] The abbreviation Xantphos refers to 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene.

[0131] The abbreviation XPhos refers to 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl.

[0132] The abbreviation Pd(dtbpf)Cl2 refers to [1,1'-bis(di-tert-butylphosphine)ferrocene]palladium dichloride.

[0133] Example 1

[0134] 4-(2-Cyclopropyl-6-(4-Methyl-2-oxobenzo[cd]indol-1(2H)-yl)pyridin-4-yl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)benzonitrile (Compound 1)

[0135]

[0136] first step

[0137] 2-Bromo-5-cyanobenzoic acid (1b)

[0138] Methyl 2-bromo-5-cyanobenzoate 1a (4.80 g, 25 mmol) and LiOH·H₂O (4.20 g, 100 mmol) were dissolved in a mixed solvent of THF (50 mL) and water (50 mL). After stirring for 2 hours, dilute hydrochloric acid (2N, 100 mL) was added to the mixture, followed by extraction with ethyl acetate (200 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to give the target product 1b (4.52 g). This product was used directly in the next reaction without further purification.

[0139] MS m / z(ESI): 226,228[M+1]

[0140] Step 2

[0141] 2-(2-Bromo-5-cyanobenzoyl)-N-methylhydrazine-1-thiocarboxamide (1c)

[0142] To a DMF (50 mL) solution of 1b (4.52 g, crude product, approximately 25 mmol), N-methylhydrazine carbosulfan (2.89 g, 27.5 mmol), HATU (11.41 g, 30 mmol), and DIPEA (13 mL, 75 mmol) were added sequentially, followed by stirring for 1 hour. This product was used directly in the next reaction without further purification.

[0143] MS m / z(ESI): 313,315[M+1]

[0144] Step 3

[0145] 4-Bromo-3-(4-methyl-5-thio-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzonitrile (1d)

[0146] Add 50 mL of saturated sodium bicarbonate solution to the reaction solution from the second step, then heat to 80 °C and stir for 14 hours. After cooling to room temperature, add dilute hydrochloric acid (2 N, 100 mL) and then filter. Collect the precipitate and dry it to obtain the target product 1d (4.83 g, 65%).

[0147] MS m / z(ESI): 295, 297 [M+1]

[0148] Step 4

[0149] 4-Bromo-3-(4-methyl-4H-1,2,4-triazol-3-yl)benzonitrile (1e)

[0150] Acetic acid (9 mL) and hydrogen peroxide solution (30%, 7.5 mL) were added to a 60 mL solution of dichloromethane (4.72 g, 16 mmol) at 0 °C. The resulting mixture was stirred at 0 °C for 1 hour, then saturated sodium bicarbonate solution (100 mL) was added, followed by extraction with dichloromethane (3 × 100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to give the target product 1e (3.95 g). This product was used directly in the next reaction without further purification.

[0151] MS m / z(ESI): 263,265 [M+1]

[0152] Step 5

[0153] 4-(2,6-Dichloropyridin-4-yl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)benzonitrile (1f)

[0154] 1e (3.95 g, crude product, approximately 15 mmol) was dissolved in 1,4-dioxane (60 mL) and water (15 mL), and Pd(dppf)Cl2 (1.10 g, 1.5 mmol), potassium carbonate (6.22 g, 45 mmol), and (2,6-dichloropyridin-4-yl)boronic acid (3.45 g, 18 mmol) were added. The mixture was heated to 60 °C and stirred for 13 hours under nitrogen protection. After cooling to room temperature, water (100 mL) was added, followed by extraction with ethyl acetate (200 mL). The filtrate was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 1 / 0 to 9 / 1) to give the target product 1f (1.64 g, 33%).

[0155] MS m / z(ESI): 330[M+1]

[0156] Step 6

[0157] (R)-4-(4-(1-(4-(chloromethyl)phenyl)ethyl)piperazin-1-yl)-3-fluorobenzyl nitrile (1g)

[0158] 1 f (1.65 g, 5 mmol) was dissolved in 1,4-dioxane (20 mL) and water (5 mL), and Pd(dppf)Cl2 (366 mg, 6 mmol), potassium carbonate (2.07 g, 15 mmol), and cyclopropylboronic acid (515 mg, 18 mmol) were added. The mixture was heated to 100 °C and stirred for 16 hours under nitrogen protection. After cooling to room temperature, water (100 mL) was added, followed by extraction with ethyl acetate (200 mL). The filtrate was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 1 / 0 to 9 / 1) to give 1 g (1.46 g, 87%) of the target product.

[0159] MS m / z(ESI): 336[M+1]

[0160] Step 7

[0161] 5-Bromo-1H,3H-benzo[de]isochrome-1,3-dione (1i)

[0162] Br2 (10.16 g, 63.6 mmol) was added to a mixture of 1H,3H-benzo[de]1,3-dione isochromene 1h (10 g, 50.5 mmol), silver sulfate (7.84 g, 25.1 mmol), and concentrated sulfuric acid (200 mL) at room temperature. The resulting mixture was heated to 60 °C and stirred for 12 hours. After cooling to room temperature, the filtrate was collected by filtration. The filtrate was added to ice water and stirred for 20 minutes. The solid was collected by filtration to give the target product 1i (12.5 g, 90%).

[0163] MS m / z(ESI): 277,279 [M+1]

[0164] Step 8

[0165] 5-Bromo-1,3-dioxo-1H-benzo[de]isoquinoline-2(3H)-yl 4-methylbenzenesulfonic acid ester (1j)

[0166] Hydroxylamine hydrochloride (3.1 g, 46.1 mmol) was added to a pyridine (100 mL) solution of product 1i (12.5 g, 46.1 mmol), and the mixture was heated to 90 °C and stirred for 3 hours. After cooling to 80 °C, p-toluenesulfonyl chloride (10.6 g, 57.2 mmol) was slowly added, and the mixture was heated to 90 °C and stirred for 3 hours. After cooling to room temperature, the reaction mixture was concentrated to dryness under reduced pressure to give the target product 1j (20.5 g). This product was used directly in the next reaction without further purification.

[0167] MS m / z(ESI): 446,448 [M+1]

[0168] Step 9

[0169] 4-Bromobenzo[cd]indol-2(1H)-one(1k)

[0170] Sodium hydroxide (5.5 g, 138 mmol) was added to a mixture of 1j (20.5 g, crude product, approximately 41.6 mmol) and water (150 mL). The resulting mixture was heated to 90 °C and stirred for 2 hours. After cooling to room temperature, the pH was adjusted to 5 with 1 N hydrochloric acid, and then filtered. The resulting solid was dried at 50 °C for 2 hours to give the target product 1k (9.78 g, 86%).

[0171] MS m / z(ESI): 248,250 [M+1]

[0172] Step 10

[0173] 4-Methylbenzo[cd]indol-2(1H)-one (1l)

[0174] 1kJ (150 mg, 0.61 mmol) was dissolved in THF (10 mL), and then trimethylcyclotriboroxane (3.5 M THF solution) (0.35 mL, 1.22 mmol), Pd(dppf)Cl2·CH2Cl2 (99 mg, 0.12 mmol), potassium carbonate (334 mg, 2.44 mmol), and water (0.5 mL) were added sequentially. The resulting mixture was heated to 100 °C and stirred for 12 hours under a nitrogen atmosphere. After cooling to room temperature, it was extracted with ethyl acetate (3 × 15 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 0 to 2 / 1) to give 1 L (90 mg, 81%) of the target product.

[0175] MS m / z(ESI): 184[M+1]

[0176] Step 11

[0177] 4-(2-Cyclopropyl-6-(4-Methyl-2-oxobenzo[cd]indol-1(2H)-yl)pyridin-4-yl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)benzonitrile(1)

[0178] 1 L (60 mg, 0.33 mmol) and 1 g (110 mg, 0.33 mmol) were dissolved in toluene (20 mL), followed by the sequential addition of Pd2(dba)3 (30 mg, 0.033 mmol), Xantphos (57 mg, 0.99 mmol), and cesium carbonate (213 mg, 0.65 mmol). The resulting mixture was heated to 110 °C and stirred for 12 hours under a nitrogen atmosphere. After cooling to room temperature, the reaction mixture was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 0 to 40 / 1), followed by prep-HPLC purification to give target product 1 (55 mg, 35%).

[0179] MS m / z(ESI): 483[M+1]

[0180] 1H NMR (400MHz, DMSO-d6) δ8.55(s,1H),8.29–8.19(m,2H),8.10(s,1H),8.02(s,1H),7.93(d,J=8.5Hz,1H),7.85(d,J=7.2Hz,1H),7.69(dd,J=9. 0,4.8Hz,2H),7.61(dd,J=8.3,7.3Hz,1H),7.03(d,J=1.3Hz,1H),3.45(s,3H),2.64(s,3H),2.16(dd,J=8.7,3.9Hz,1H),1.10–0.93(m,4H).

[0181] Example 2

[0182] (S)-4-(2-cyclopropyl-6-(4-((3-methylpiperidin-1-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)pyridin-4-yl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)benzonitrile (Compound 2)

[0183]

[0184] first step

[0185] (S)-4-((3-methylpiperidin-1-yl)methyl)benzo[cd]indol-2(1H)-one (2a)

[0186] Cesium carbonate (2.76 g, 8.46 mmol) was added to a THF (32 mL) solution of potassium (bromomethyl)trifluoroborate (850 mg, 4.23 mmol) and (S)-3-methylpiperidine hydrochloride (574 mg, 4.23 mmol). The resulting mixture was heated to 80 °C and stirred for 5 hours. After cooling to room temperature, 1kJ (350 mg, 1.41 mmol), Pd(OAc)₂ (317 mg, 1.41 mmol), XPhos (1.34 g, 2.82 mmol), and water (8 mL) were added sequentially to the reaction mixture. The resulting mixture was heated to 90 °C and stirred for 12 hours under a nitrogen atmosphere. After cooling to room temperature, the mixture was extracted with ethyl acetate (3 × 15 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 0 to 40 / 1) to give the target product 2a (270 mg, 68%).

[0187] MS m / z(ESI): 281[M+1]

[0188] Step 2

[0189] (S)-4-(2-cyclopropyl-6-(4-(((3-methylpiperidin-1-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)pyridin-4-yl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)benzonitrile(2)

[0190] To a solution of 2a (135 mg, 0.48 mmol) and 1 g (162 mg, 0.48 mmol) in 20 mL of toluene, Pd2(dba)3 (66 mg, 0.072 mmol), Xantphos (84 mg, 0.15 mmol), and cesium carbonate (393 mg, 1.21 mmol) were added sequentially. The resulting mixture was heated to 110 °C and stirred for 12 hours. After cooling to room temperature, the reaction mixture was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 0 to 20 / 1), and then purified again by prep-HPLC to give target product 2 (100 mg, 36%, containing 0.35 equivalents of formic acid).

[0191] MS m / z(ESI): 580 [M+1]

[0192] 1 H NMR (400MHz, DMSO-d6) δ8.56(s,1H),8.29–8.21(m,2H),8.19(s,1H),8.14(s,0.35H,HCOOH),8.10(s,1H),7.93(d ,J=8.6Hz,1H),7.88(d,J=7.3Hz,1H),7.77(d,J=8.4Hz,1H),7.67(d,J=1.0Hz,1H),7.66–7.60(m,1H),7.04(d ,J=1.0Hz,1H),3.76(d,J=2.4Hz,2H),3.46(s,3H),2.78(t,J=12.1Hz,2H),2.22–2.12(m,1H),1.97(t,J=10.0 Hz,1H),1.73–1.41(m,5H),1.11–1.02(m,2H),1.02–0.94(m,2H),0.86(d,J=7.4Hz,1H),0.81(d,J=6.2Hz,3H).

[0193] Example 3

[0194] (S)-1-(6-cyclopropyl-4-(1-methyl-4-(4-methyl-4H-1,2,4-triazol-3-yl)-1H-pyrazol-5-yl)pyridin-2-yl)-4-((3-methylpiperidin-1-yl)methyl)benzo[cd]indol-2(1H)-one (Compound 3)

[0195]

[0196] first step

[0197] ethyl 5-bromo-1-methyl-1H-pyrazole-4-carboxylate (3b)

[0198] At 0 °C, tert-butyl nitrite (24.7 g, 240 mmol) was added to ethyl 5-amino-1-methyl-1H-pyrazole-4-carboxylate 3a (34 g, 200 mmol), copper bromide (66.9 g, 300 mmol), and acetonitrile (400 mL). The mixture was stirred at room temperature for 1 hour, then 6N hydrochloric acid (860 mL) was added and stirred. The mixture was then extracted once with dichloromethane (300 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50 / 1 to 20 / 1) to give the target product 3b (41.6 g, 89%).

[0199] MS m / z(ESI): 233,235[M+1]

[0200] Step 2

[0201] Ethyl 5-(2,6-dichloropyridin-4-yl)-1-methyl-1H-pyrazole-4-carboxylate (3c)

[0202] Pd(dppf)Cl₂·CH₂Cl₂ (3.76 g, 5.15 mmol) was added to a mixture of 3b (12 g, 51.5 mmol), (2,6-dichloropyridin-4-yl)boric acid (9.9 g, 51.5 mmol), potassium carbonate (21.32 g, 154.5 mmol), 1,4-dioxane (430 mL), and water (86 mL). The resulting mixture was heated to 60 °C and stirred for 5 hours under a nitrogen atmosphere. After cooling to room temperature, the mixture was extracted with ethyl acetate (3 × 200 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 30 / 1 to 10 / 1) to give the target product 3c (10.62 g, 69%).

[0203] MS m / z(ESI): 300[M+1]

[0204] Step 3

[0205] 5-(2,6-Dichloropyridin-4-yl)-1-methyl-1H-pyrazole-4-carboxylic acid (3d)

[0206] 3c (6.8 g, 22.8 mmol) was dissolved in THF (91 mL) and water (91 mL), and then lithium hydroxide (2.9 g, 68.5 mmol) was added. The mixture was heated to 50 °C and stirred for 2 hours. After cooling to room temperature, it was concentrated to 100 mL under reduced pressure and adjusted to pH 4 with 2N hydrochloric acid. The precipitate was collected by filtration and dried in a drying oven at 50 °C to obtain the target product 3d (4 g, 64%).

[0207] MS m / z(ESI): 272[M+1]

[0208] Step 4

[0209] 2-(5-(2,6-dichloropyridin-4-yl)-1-methyl-1H-pyrazole-4-carbonyl)-N-methylhydrazine-1-thiocarboxamide (3e)

[0210] HATU (6.1 g, 16.2 mmol) was added to a mixture of 3d (4 g, 14.7 mmol), DIPEA (3.8 g, 29.4 mmol), 4-methylaminothiourea (1.7 g, 16.2 mmol), and DMF (60 mL). The resulting mixture was stirred at room temperature for 1 hour, water (100 mL) was added, and then extracted with ethyl acetate (3 × 200 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1 to 3 / 1) to give the target product 3e (4.5 g, 86%).

[0211] MS m / z(ESI): 359[M+1]

[0212] Step 5

[0213] 5-(5-(2,6-dichloropyridin-4-yl)-1-methyl-1H-pyrazol-4-yl)-4-methyl-4H-1,2,4-triazol-3-thiol (3f)

[0214] Dissolve 3e (4.5 g, 12.5 mmol) in water (125 mL), cool to 0 °C, and then add sodium hydroxide (5 g, 12.5 mmol). Stir the mixture at room temperature for 12 hours. Adjust the pH to 4 with 2N hydrochloric acid. Collect the precipitate by filtration and dry it in a drying oven at 50 °C to obtain the target product 3f (3.25 g, 76%).

[0215] MS m / z(ESI): 341[M+1]

[0216] Step 6

[0217] 2,6-Dichloro-4-(1-methyl-4-(4-methyl-4H-1,2,4-triazol-3-yl)-1H-pyrazol-5-yl)pyridine (3g)

[0218] Hydrogen peroxide (30%, 3.2 g, 95 mmol) was added to a 3f (3.25 g, 9.5 mmol) solution of dichloromethane (35 mL). The resulting mixture was stirred at room temperature for 2 hours, then concentrated to dryness. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 50 / 1 to 10 / 1) to give 3 g (1.6 g, 54%) of the target product.

[0219] MS m / z(ESI): 309[M+1]

[0220] Step 7

[0221] 2-Chloro-6-cyclopropyl-4-(1-methyl-4-(4-methyl-4H-1,2,4-triazol-3-yl)-1H-pyrazole-5-yl)pyridine (3h)

[0222] Pd(dppf)Cl2·CH2Cl2 (210 mg, 0.26 mmol) was added to a mixture of 3 g (0.8 g, 2.6 mmol), cyclopropylboronic acid (379 mg, 4.41 mmol), potassium phosphate (1.1 g, 5.2 mmol), and 1,4-dioxane (26 mL). The mixture was heated to 100 °C and stirred for 12 hours under a nitrogen atmosphere. After cooling to room temperature, it was extracted with ethyl acetate (3 × 200 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 50 / 1 to 10 / 1) to give the target product 3 h (460 mg, 56%).

[0223] MS m / z(ESI): 315[M+1]

[0224] Step 8

[0225] (S)-1-(6-cyclopropyl-4-(1-methyl-4-(4-methyl-4H-1,2,4-triazol-3-yl)-1H-pyrazol-5-yl)pyridin-2-yl)-4-((3-methylpiperidin-1-yl)methyl)benzo[cd]indol-2(1H)-one(3)

[0226] 3h (31.5 mg, 0.1 mmol), 2a (28.1 mg, 0.1 mmol), palladium acetate (1.7 mg, 0.01 mmol), Xantphos (11.5 mg, 0.02 mmol), cesium carbonate (98 mg, 0.3 mmol), and 1,4-dioxane (2 mL) were mixed in a 10-mL microwave-safe tube. The air in the system was replaced with nitrogen, the tube was capped, and the mixture was heated at 100 °C for 1 hour in a microwave-safe reactor. After cooling to room temperature, the reaction mixture was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 0 to 20 / 1), and then purified again by prep-HPLC to obtain target product 3 (6.7 mg, 12%).

[0227] MS m / z(ESI): 559 [M+1]

[0228] 1 H NMR (400MHz, CD3OD) δ8.68(s,1H),8.39(s,1H),8.24(s,1H),8.05(d,J=7.2Hz,1H),7.99(s,1H),7.91(d,J=1.1Hz,1H),7. 82(d,J=8.4Hz,1H),7.72(t,J=7.8Hz,1H),7.32(d,J=1.1Hz,1H),4.64(s,2H),4.10(s,3H),3.63(s,3H),3.58–3.53(m,1H) ,3.49–3.43(m,1H),3.00(dd,J=12.7,10.1Hz,1H),2.82–2.66(m,1H),2.26(tt,J=7.5,5.5Hz,1H),2.04–1.95(m,1H),1.8 9(d,J=10.6Hz,2H),1.77(dd,J=27.5,13.2Hz,1H),1.21(dd,J=12.7,5.6Hz,1H),1.17–1.11(m,4H),1.00(d,J=6.4Hz,3H).

[0229] Example 4

[0230] 3-(2,6-Difluorophenyl)-1-((4-(morpholino-4-carbonyl)phenyl)amino)imidazo[1,5-a]pyrazin-8(7H)-one (compound 4)

[0231]

[0232] first step

[0233] 4-Bromo-6-fluorobenzo[cd]indol-2(1H)-one (4a)

[0234] To a solution of 1k (600 mg, 2.42 mmol) of DMF (18 mL), a fluorine reagent (Selectfluor, 1.03 g, 2.90 mmol) and glacial acetic acid (174 mg, 2.90 mmol) were added sequentially. The resulting mixture was heated to 90 °C and stirred for 12 hours. After cooling to room temperature, the reaction mixture was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 0 to 4 / 1) to give the target product 4a (150 mg, 23%).

[0235] MS m / z(ESI): 267,269 [M+1]

[0236] Step 2

[0237] (S)-6-fluoro-4-((3-methylpiperidin-1-yl)methyl)benzo[cd]indol-2(1H)-one (4b)

[0238] Cesium carbonate (1.10 g, 3.38 mmol) was added to a THF (16 mL) solution of potassium (bromomethyl)trifluoroborate (340 mg, 1.69 mmol) and (S)-3-methylpiperidine hydrochloride (230 mg, 1.69 mmol). The mixture was heated to 80 °C and stirred for 5 hours. After cooling to room temperature, 4a (150 mg, 0.56 mmol), Pd(OAc)₂ (25 mg, 0.11 mmol), XPhos (108 mg, 0.23 mmol), and water (4 mL) were added sequentially to the mixture. The resulting mixture was heated to 90 °C and stirred for 12 hours under a nitrogen atmosphere. After cooling to room temperature, it was extracted with ethyl acetate (3 × 15 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 0 to 2 / 1) to give the target product 4b (135 mg, 80%).

[0239] MS m / z(ESI): 299[M+1]

[0240] Step 3

[0241] (S)-4-(2-cyclopropyl-6-(6-fluoro-4-((3-methylpiperidin-1-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)pyridin-4-yl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)benzonitrile(2)

[0242] To a mixture of 4b (100 mg, 0.34 mmol), 1 g (113 mg, 0.34 mmol), and toluene (20 mL), Pd2(dba)3 (46 mg, 0.05 mmol), Xantphos (58 mg, 0.10 mmol), and cesium carbonate (273 mg, 0.84 mmol) were added sequentially. The resulting mixture was heated to 110 °C and stirred for 12 hours under a nitrogen atmosphere. After cooling to room temperature, the reaction mixture was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 0 to 20 / 1), and then purified again by prep-HPLC to give target product 4 (19 mg, containing 0.2 equivalents of formic acid, 9.5%).

[0243] MS m / z(ESI): 598 [M+1]

[0244] 1 H NMR (400MHz, DMSO-d6) δ8.56 (s, 1H), 8.24 (dd, J = 5.8, 4.0Hz, 3H), 8.21 (s, 0.2H, HCOOH), 8.19 (s, 1H),7.93(d,J=8.6Hz,1H),7.85(dd,J=8.1,3.2Hz,1H),7.69(s,1H),7.44(dd,J=11.6,8.1Hz,1H ),7.04(s,1H),3.78(s,2H),3.46(s,3H),2.75(d,J=10.2Hz,2H),2.17(s,1H),2.01–1.93(m,1H) ,1.66(d,J=10.0Hz,5H),1.06(d,J=7.9Hz,2H),0.98(s,2H),0.85(s,1H),0.81(d,J=6.1Hz,3H).

[0245] Example 5

[0246] (S)-1-(4-(4-cyano-2-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-6-cyclopropylpyridin-2-yl)-4-((3-methylpiperidin-1-yl)methyl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-nitrile (Compound 5)

[0247]

[0248] first step

[0249] 4-Bromo-6-iodobenzo[cd]indol-2(1H)-one (5a)

[0250] NIS (2.27 g, 10.1 mmol) was added to a 20 mL solution of DMF containing 1 kJ (1.00 g, 4.03 mmol). The resulting mixture was heated to 120 °C and stirred for 12 hours. After cooling to room temperature, the mixture was concentrated to dryness under reduced pressure, and then anhydrous ethanol (20 mL) was added and stirred for 0.5 hours. After filtration, the filter cake was collected to give the target product 5a (1.20 g, 80%).

[0251] MS m / z(ESI): 374,376 [M+1]

[0252] Step 2

[0253] 4-Bromo-2-oxo-1,2-dihydrobenzo[cd]indole-6-nitrile (5b)

[0254] 5a (500 mg, 1.34 mmol), Zn(CN)₂ (166 mg, 1.41 mmol), Pd(PPh)₄ (77 mg, 0.067 mmol), and DMF (20 mL) were placed in a 100-mL sealed tube, and the air was purged with nitrogen. The mixture was heated to 80 °C and stirred for 12 hours. After cooling to room temperature, ethyl acetate (50 mL) and water (50 mL) were added, and the mixture was stirred and separated. The organic phase was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 0 to 2 / 1) to obtain the target product 5b (270 mg, 74%).

[0255] MS m / z(ESI): 273,275 [M+1]

[0256] Step 3

[0257] (S)-4-((3-methylpiperidin-1-yl)methyl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-nitrile (5c)

[0258] Potassium (bromomethyl)trifluoro-4-borane (296 mg, 1.98 mmol), (S)-3-methylpiperidine hydrochloride (398 mg, 1.98 mmol), cesium carbonate (1.29 g, 3.96 mmol), and THF (15 mL) were mixed and heated to 80 °C with stirring for 16 hours. After cooling to room temperature, 5b (270 mg, 0.99 mmol), Pd(OAc)₂ (17 mg, 0.099 mmol), Xphos (94 mg, 0.198 mmol), and water (2 mL) were added to the mixture. The resulting mixture was heated to 80 °C with stirring for 16 hours. After cooling to room temperature, the mixture was filtered and then separated. The organic phase was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 0 to 6 / 1) to give the target product 5c (170 mg, 56%).

[0259] MS m / z(ESI): 306[M+1]

[0260] Step 4

[0261] (S)-1-(4-(4-cyano-2-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-6-cyclopropylpyridin-2-yl)-4-((3-methylpiperidin-1-yl)methyl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-onitrile(5)

[0262] 5c (70 mg, 0.23 mmol), Pd2(dba)3 (21 mg, 0.023 mmol), Xantphos (27 mg, 0.046 mmol), cesium carbonate (225 mg, 0.69 mmol), 1 g (77 mg, 0.23 mmol), and toluene (5 mL) were mixed and heated to 110 °C and stirred for 16 hours under a nitrogen atmosphere. After cooling to room temperature, the mixture was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 0 to 5 / 1) and then purified by prep-HPLC to obtain the target product 5 (19 mg, 14%).

[0263] MS m / z(ESI): 605 [M+1]

[0264] 1 H NMR (400MHz, CD3OD) δ8.53(s,1H),8.25(d,J=13.4Hz,2H),8.12(ddd,J=22.7,1 1.5,4.7Hz,3H),7.97(dd,J=10.4,7.9Hz,2H),7.66(d,J=1.3Hz,1H),7.14(d,J= 1.3Hz,1H),3.93(s,2H),3.49(s,3H),2.93(s,2H),2.23–2.11(m,2H),1.88(t,J =10.2Hz,1H),1.74(t,J=13.2Hz,4H),1.12–0.93(m,5H),0.89(d,J=6.4Hz,3H).

[0265] Example 6

[0266] 4-(2-Cyclopropyl-6-(4-(hydroxymethyl)-2-oxobenzo[cd]indol-1(2H)-yl)pyridin-4-yl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)benzonitrile (Compound 6)

[0267]

[0268] first step

[0269] (R)-4-(1-(4-(4-cyano-2-fluorophenyl)piperazin-1-yl)ethyl)methyl benzoate (6a)

[0270] Boc₂O (1.05 g, 50.7 mmol) was added to an acetonitrile solution of 1 kJ (9.78 g, 39.4 mmol) and DMAP (561 mg, 4.6 mmol) at room temperature. The mixture was stirred for 2 hours, and the reaction mixture was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50 / 1 to 30 / 1) to give the target product 6a (7.45 g, 54%).

[0271] MS m / z(ESI): 348, 350 [M+1]

[0272] Step 2

[0273] 4-(hydroxymethyl)-2-oxobenzo[cd]indole-1(2H)-carboxylic acid tert-butyl ester (6b)

[0274] Pd(PPh3)2Cl2 (100 mg, 0.144 mmol) was added to a DMF (10 mL) solution of 6a (500 mg, 1.44 mmol) and (tributyltin)methanol (695 mg, 2.16 mmol), and the mixture was heated to 100 °C and stirred for 12 hours. After cooling to room temperature, the solution was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1 to 10 / 1) to give the target product 6b (329 mg, 77%).

[0275] MS m / z(ESI): 300[M+1]

[0276] Step 3

[0277] 4-(hydroxymethyl)-1H-benzo[cd]indol-2-one (6c)

[0278] 6b (20 mg, 0.67 mmol) was dissolved in an ethanol solution of hydrogen chloride (2 mL, 2N), and then stirred for 2 hours. The resulting mixture was concentrated to dryness under reduced pressure to give the target product 6c. This product was used directly in the next reaction without further purification.

[0279] MS m / z(ESI): 200[M+1]

[0280] Step 4

[0281] 4-(2-Cyclopropyl-6-(4-(hydroxymethyl)-2-oxobenzo[cd]indol-1(2H)-yl)pyridin-4-yl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)benzonitrile(6)

[0282] A mixture of 6c (20 mg, crude product, approximately 0.1 mmol), 1 g (38 mg, 0.1 mmol), Pd2(dba)3 (8 mg, 0.01 mmol), XantPhos (12 mg, 0.02 mmol), cesium carbonate (100 mg, 0.3 mmol), and 1,4-dioxane (2 mL) was heated to 100 °C and stirred for 18 hours under a nitrogen atmosphere. After cooling to room temperature, the mixture was concentrated to dryness under reduced pressure, and the residue was purified by prep-HPLC to give target product 6 (0.88 mg, 17%).

[0283] MS m / z(ESI): 499[M+1]

[0284] 1 H NMR(400MHz,DMSO-d6)δ8.56(s,1H),8.27–8.22(m,2H),8.12(s,1H),7.94 (d,J=8.6Hz,1H),7.89(d,J=7.2Hz,1H),7.78(d,J=8.4Hz,1H),7.69(s,1H) ,7.68–7.61(m,1H),7.42–7.35(m,1H),7.03(s,1H),5.61–5.53(m,1H),4. 82(d,J=5.5Hz,2H),3.46(s,3H),2.17(d,J=4.3Hz,1H),1.11–0.95(m,4H).

[0285] Example 7

[0286] (R)-4-(2-cyclopropyl-6-(4-((4,4-difluoro-3-methylpiperidin-1-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)pyridin-4-yl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)benzonitrile (Compound 7)

[0287]

[0288] first step

[0289] (4-(chloromethyl)benzo[cd]indol-2(1H)-one (7a)

[0290] Thionyl chloride (69 mg, 0.58 mmol) was added to a solution of 6b (329 mg, 1.1 mmol) in dichloromethane (5 mL). The resulting mixture was stirred at room temperature for 2 hours and concentrated to dryness to give the target product 7a (240 mg, 1.1 mmol).

[0291] MS m / z(ESI): 218[M+1]

[0292] Step 2

[0293] (R)-4-((4,4-difluoro-3-methylpiperidin-1-yl)methyl)benzo[cd]indol-2(1H)-one (7b)

[0294] To a DMF (1 mL) solution of 7a (31 mg, 0.14 mmol), (R)-4,4-difluoro-3-methylpiperidine (27 mg, 0.16 mmol) and cesium carbonate (137 mg, 0.42 mmol) were added sequentially. The resulting mixture was heated to 60 °C and stirred for 1 hour. After cooling to room temperature, the precipitate was removed by filtration. The filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 0 to 9 / 1) to give the target product 7b (25 mg, 57%).

[0295] MS m / z(ESI): 317[M+1]

[0296] Step 3

[0297] (R)-4-(2-cyclopropyl-6-(4-((4,4-difluoro-3-methylpiperidin-1-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)pyridin-4-yl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)benzonitrile(7)

[0298] 7b (25 mg, 0.08 mmol), 1 g (50 mg, 0.15 mmol), Pd2(dba)3 (14 mg, 0.015 mmol), Xantphos (17 mg, 0.03 mmol), cesium carbonate (147 mg, 0.45 mmol), and 1,4-dioxane (4 mL) were mixed in a 10-mL microwave-safe tube. The air in the system was replaced with nitrogen, the tube was capped, and the mixture was heated at 100 °C for 1 hour in a microwave-safe reactor. After cooling to room temperature, the reaction mixture was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 0 to 9 / 1) and further purified by prep-HPLC to give the target product 7 (26.2 mg, 54%).

[0299] MS m / z(ESI): 616[M+1]

[0300] 1 H NMR (400MHz, DMSO-d6) δ8.55 (s, 1H), 8.24 (d, J = 6.6Hz, 3H), 8.13 (s, 1H), 7. 93(d,J=8.6Hz,1H),7.89(d,J=7.3Hz,1H),7.79(d,J=8.2Hz,1H),7.67(s,2H ),7.05(s,1H),3.84(s,2H),3.46(s,3H),2.78(s,3H),2.33(s,1H),2.12–1. 91(m,4H),1.05(dd,J=10.6,6.0Hz,2H),0.98(s,2H),0.92(d,J=5.8Hz,3H).

[0301] The following compounds were synthesized following the experimental procedure of Example 7, but different compounds were used instead of (R)-4,4-difluoro-3-methylpiperidine.

[0302]

[0303]

[0304]

[0305] The following compounds were synthesized following the experimental procedure of Example 7, but different compounds were used instead of (R)-4,4-difluoro-3-methylpiperidine and 1g.

[0306]

[0307] The NMR data for these compounds are as follows:

[0308]

[0309]

[0310]

[0311]

[0312] Example 8

[0313] 4-(2-Cyclopropyl-6-(2-oxo-4-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)benzo[cd]indol-1(2H)-yl)pyridin-4-yl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)benzonitrile (Compound 11)

[0314]

[0315] first step

[0316] 4-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)benzo[cd]indol-2(1H)-one (11a)

[0317] Sodium hydride (4.4 mg, 0.11 mmol) was added to a DMF (1 mL) solution of tetrahydropyran-4-ol (6 mg, 0.66 mmol) at 0 °C. After stirring at 0 °C for 20 min, 7a (7 mg, 0.02 mmol) was added to the mixture. After stirring at room temperature for 2 hours, the mixture was diluted with ethyl acetate (20 mL) and then washed with saturated brine (2 × 20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 0 to 1 / 4) to give the target product 11a (15 mg).

[0318] MS m / z(ESI): 284[M+1]

[0319] Step 2

[0320] 4-(2-Cyclopropyl-6-(2-oxo-4-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)benzo[cd]indol-1(2H)-yl)pyridin-4-yl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)benzonitrile (11)

[0321] 11a (10 mg, 0.04 mmol), 1 g (13 mg, 0.04 mmol), Pd2(dba)3 (3 mg, 0.004 mmol), Xantphos (5 mg, 0.008 mmol), potassium carbonate (17 mg, 0.12 mmol), and 1,4-dioxane (0.5 mL) were mixed and then heated to 100 °C and stirred for 3 hours under a nitrogen atmosphere. After cooling to room temperature, the mixture was concentrated to dryness under reduced pressure, and the residue was purified by prep-HPLC to give the target product 11 (1.9 mg, 8%).

[0322] MS m / z(ESI): 583 [M+1]

[0323] 1H NMR (400MHz, CD3OD) δ8.44 (s, 1H), 8.05 (dd, J=19.1, 12.5Hz, 3H), 7.86 (dd, J=7 .6,4.8Hz,2H),7.69–7.61(m,2H),7.54–7.47(m,2H),6.99(s,1H),4.78(d,J=3 .4Hz,2H),3.91–3.79(m,2H),3.73–3.61(m,3H),3.41(dd,J=16.2,4.6Hz,4H), 2.10–2.00(m,1H),1.98–1.85(m,2H),1.65–1.46(m,2H),0.99(d,J=6.2Hz,3H).

[0324] The following compounds were synthesized following the experimental procedure of Example 8, but different compounds were used instead of tetrahydropyran-4-ol.

[0325]

[0326] The NMR data for these compounds are as follows:

[0327]

[0328]

[0329] Example 9

[0330] 4-(2-Cyclopropyl-6-(4-(((((1-hydroxycyclobutyl)methyl)(methyl)amino)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)pyridin-4-yl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)benzonitrile (Compound 19)

[0331]

[0332] first step

[0333] 4-((((1-hydroxycyclobutyl)methyl)amino)methyl)benzo[cd]indol-2(1H)-one (19a)

[0334] To a DMF (5 mL) solution of 7a (200 mg, 0.92 mmol), 1-(aminomethyl)cyclobutane-1-ol (140 mg, 1.38 mmol) and K₂CO₃ (506 mg, 3.68 mmol) were added sequentially. The resulting mixture was heated to 70 °C and stirred for 2 hours. After cooling to room temperature, the precipitate was removed by filtration. The filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 0 to 20 / 1) to give the target product 19a (86 mg, 33%).

[0335] MS m / z(ESI): 283[M+1]

[0336] Step 2

[0337] 4-((((1-hydroxycyclobutyl)methyl)(methyl)amino)methyl)benzo[cd]indol-2(1H)-one (19b)

[0338] Triethylamine (0.5 mL) and sodium triacetoxyborohydride (259 mg, 1.22 mmol) were added sequentially to a solution of 19a (86 mg, 0.31 mmol) and paraformaldehyde (73 mg, 2.48 mmol) in dichloromethane (10 mL). The resulting mixture was heated to 30 °C and stirred for 12 hours. After cooling to room temperature, it was diluted with water (10 mL) and then extracted with dichloromethane (3 × 10 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 0 to 20 / 1) to give the target product 19b (68 mg, 75%).

[0339] MS m / z(ESI): 297[M+1]

[0340] Step 3

[0341] 4-(2-Cyclopropyl-6-(4-(((((1-hydroxycyclobutyl)methyl)(methyl)amino)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)pyridin-4-yl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)benzonitrile (19)

[0342] To a mixture of 19b (45 mg, 0.15 mmol), 1 g (51 mg, 0.15 mmol), and toluene (8 mL), Pd2(dba)3 (21 mg, 0.023 mmol), Xantphos (27 mg, 0.046 mmol), and cesium carbonate (124 mg, 0.38 mmol) were added sequentially. The resulting mixture was heated to 110 °C and stirred for 11 hours under a nitrogen atmosphere. After cooling to room temperature, the reaction mixture was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 0 to 30 / 1), and then purified again by prep-HPLC to give the target product 19 (8.5 mg, 9.4%).

[0343] MS m / z(ESI): 596 [M+1]

[0344] 1 H NMR (400MHz, DMSO) δ8.56(s,1H),8.29–8.14(m,4H),7.93(d,J=8.6Hz,1H),7.88(d,J=7.3Hz,1H),7.77(d, J=8.4Hz,1H),7.67(d,J=1.3Hz,1H),7.64(t,J=7.9Hz,1H),7.05(s,1H),4.93(s,1H),3.90(s,2H),3.46(s ,3H),2.54(s,2H),2.27(s,3H),2.17(ddd,J=12.9,8.6,4.6Hz,1H),2.03(dt,J=8.9,4.9Hz,2H),1.92(dd, J=19.4,9.8Hz,2H),1.66–1.56(m,1H),1.32(dd,J=18.6,9.4Hz,1H),1.10–1.02(m,2H),1.01–0.93(m,2H).

[0345] The following compounds were synthesized following the experimental procedure of Example 9, but different compounds were used instead of 1-(aminomethyl)cyclobutane-1-ol.

[0346]

[0347] The NMR data of the compound are as follows:

[0348]

[0349] Example 10

[0350] (S)-2'-cyclopropyl-3-(4-methyl-4H-1,2,4-triazol-3-yl)-6'-(4-((3-methylpiperidin-1-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)-[2,4'-bipyridine]-5-nitrile (compound 24) and (S)-2'-cyclopropyl-3-(4-methyl-4H-1,2,4-triazol-3-yl)-6'-(4-((3-methylpiperidin-1-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)-[2,4'-bipyridine]-5-carboxamide (compound 23).

[0351]

[0352] first step

[0353] 6-Amino-5-bromonicornitrile (23b)

[0354] NBS (8.87 g, 49.9 mmol) was added to a solution of 6-aminonicotinamide 23a (4.95 g, 41.6 mmol) in acetonitrile (100 mL). After stirring at room temperature for 2 hours, the mixture was diluted with water (200 mL) and then extracted with ethyl acetate (3 × 200 mL). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 0 to 19 / 1) to give the target product 23b (8.23 g, 100%).

[0355] MS m / z(ESI): 198,200 [M+1]

[0356] Step 2

[0357] 2-Amino-5-cyanonic acid methyl ester (23c)

[0358] Triethylamine (5.75 g, 56.8 mmol) and Pd(dppf)Cl2 (693 mg, 0.95 mmol) were added to a methanol (50 mL) solution of 23b (3.75 g, 18.9 mmol). The mixture was sealed in a 100 mL autoclave and then heated to 100 °C and stirred for 5 hours under a carbon monoxide atmosphere (4 atm). Another batch of 23b (3.45 g, 17.4 mmol) was reacted in the same manner. After cooling to room temperature, the two batches of reactants were mixed, concentrated to dryness, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 0 to 19 / 1) to give the target product 23c (5.64 g, 88%).

[0359] MS m / z(ESI): 178 [M+1]

[0360] Step 3

[0361] 2-Bromo-5-cyanonic acid methyl ester (23d)

[0362] Copper bromide (8.39 g, 37.6 mmol) was added to a THF (125 mL) solution of tert-butyl nitrite (3.88 g, 37.6 mmol) at 0 °C, followed by the addition of a THF (125 mL) solution of 23c (4.44 g, 25 mmol) to the mixture. The resulting mixture was heated to room temperature and stirred for 1.5 h, then heated to 50 °C and stirred for 2 h. After cooling to room temperature, the mixture was concentrated to dryness under reduced pressure. The residue was suspended in dichloromethane (200 mL) and water (200 mL), stirred for 30 min, and filtered. The filtrate was allowed to stand and separate into layers; the organic phase was separated, and the aqueous phase was extracted with dichloromethane (200 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 0 to 4 / 1) to give the target product 23d (2.54 g, 42%).

[0363] MS m / z(ESI): 241[M+1]

[0364] Step 4

[0365] 2',6'-Dichloro-5-cyano-[2,4'-bipyridine]-3-carboxylic acid (23e)

[0366] A mixture of 23d (2.54 g, 10.5 mmol), (2,6-dichloropyridin-4-yl)boric acid (2.02 g, 10.5 mmol), potassium carbonate (5.83 g, 42.2 mmol), Pd(dppf)Cl2 (463 mg, 0.63 mmol), 1,4-dioxane (200 mL), and water (4 mL) was heated to 100 °C and stirred for 20 hours. After cooling to room temperature, the reaction mixture was filtered through diatomaceous earth. The filtrate was diluted with water (100 mL), adjusted to pH 3 with 1 N HCl, and extracted with ethyl acetate (3 × 200 mL). The combined organic phases were washed with saturated brine (100 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / ethyl acetate = 100 / 0 to 3 / 2) to give the target product 23e (1.04 g, 34%).

[0367] MS m / z(ESI): 294[M+1]

[0368] Step 5

[0369] 2',6'-Dichloro-3-(4-methyl-5-thio-4,5-dihydro-1H-1,2,4-triazol-3-yl)-[2,4'-bipyridine]-5-onitrile (23f)

[0370] To a solution of 23e (1.04 g, 3.54 mmol) and N-methylhydrazine carbosulfan (558 mg, 5.30 mmol) in NMP (7 mL), DIPEA (458 mg, 3.54 mmol) and HATU (1.75 g, 4.60 mmol) were added. After stirring at room temperature for 1 hour, KHCO3 (3.5 g, 35.0 mmol) and water (7 mL) were added to the reaction mixture, which was then heated to 100 °C and stirred for 9 hours. After cooling to room temperature, the reaction mixture was filtered, and the filter cake was washed with dichloromethane (3 × 50 mL). The combined filtrates were concentrated to dryness under reduced pressure, and the residue was dispersed in dichloromethane (200 mL) and filtered again to remove insoluble matter. The fresh filtrate was dried over anhydrous sodium sulfate, filtered, and used directly for the next reaction.

[0371] Step 6

[0372] 2',6'-Dichloro-3-(4-methyl-4H-1,2,4-triazol-3-yl)-[2,4'-bipyridine]-5-onitrile (24a) and 2',6'-dichloro-3-(4-methyl-4H-1,2,4-triazol-3-yl)-[2,4'-bipyridine]-5-carboxamide (23g)

[0373] The 23f solution in dichloromethane (200 mL) obtained in step 5 was cooled to 0 °C, and then glacial acetic acid (5 mL) and 30% hydrogen peroxide (2 mL) were added. After stirring at room temperature for 1 hour, the solution was concentrated to dryness under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile / water = 5 / 95 to 3 / 7) to give the target products 24a (244 mg, 21%) and 23g (185 mg, 15%).

[0374] 24a, MS m / z (ESI): 331 [M+1]

[0375] 23g, MS m / z (ESI): 349 [M+1]

[0376] Step 7

[0377] 2'-Chloro-6'-cyclopropyl-3-(4-methyl-4H-1,2,4-triazol-3-yl)-[2,4'-bipyridine]-5-onitrile (24b)

[0378] 24a (175 mg, 0.53 mmol), cyclopropylboronic acid (91 mg, 1.06 mmol), potassium carbonate (293 mg, 2.12 mmol), Pd(dppf)Cl2 (39 mg, 0.053 mmol), 1,4-dioxane (20 mL), and water (0.5 mL) were mixed in a 30 mL microwave-safe tube, and the air in the system was purged with nitrogen. The mixture was heated to 100 °C and stirred for 2 hours in a microwave reactor. Cyclopropylboronic acid (45 mg, 0.53 mmol) and Pd(dppf)Cl2 (39 mg, 0.053 mmol) were added to the mixture again, and the mixture was heated to 100 °C and stirred for 2 hours in a microwave reactor. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 0 to 9 / 1) to give the target product 24b (60 mg, 34%).

[0379] MS m / z(ESI): 337[M+1]

[0380] Step 8

[0381] (S)-2'-cyclopropyl-3-(4-methyl-4H-1,2,4-triazol-3-yl)-6'-(4-((3-methylpiperidin-1-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)-[2,4'-bipyridine]-5-nitrile (24)

[0382] 24b (60 mg, 0.18 mmol), 2a (50 mg, 0.18 mmol), cesium carbonate (176 mg, 0.54 mmol), Pd2(dba)3 (18 mg, 0.02 mmol), Xantphos (23 mg, 0.04 mmol), and 1,4-dioxane (4 mL) were mixed in a 10-mL microwave-safe tube, and the air in the system was purged with nitrogen. The mixture was heated to 100 °C and stirred in a microwave reactor for 2 hours. After cooling to room temperature, the mixture was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 0 to 9 / 1) and further purified by prep-HPLC to give the target product 24 (47.8 mg, 46%).

[0383] MS m / z(ESI): 581 [M+1]

[0384] 1H NMR (400MHz, CD3OD) δ9.28(d,J=2.0Hz,1H),8.62(s,1H),8.57(d,J=2.0Hz,1H),8.14(d,J=2.8Hz, 2H),7.97(d,J=7.2Hz,1H),7.86(d,J=1.3Hz,1H),7.70(d,J=8.4Hz,1H),7.61–7.56(m,1H),7.31( d,J=1.3Hz,1H),3.81(s,2H),3.52(s,3H),2.96–2.83(m,2H),2.21–2.15(m,1H),2.06–2.01(m,1H) ),1.71(ddd,J=10.7,10.0,6.7Hz,6H),1.11(d,J=2.1Hz,2H),1.09(s,2H),0.87(d,J=6.0Hz,3H).

[0385] Compound 23 can be synthesized according to Example 10, but 23g is used instead of 24a in step 6.

[0386] The characterization data of compound 23 are as follows:

[0387] MS m / z(ESI): 599[M+1]

[0388] 1 H NMR (400MHz, CD3OD) δ9.39(d,J=2.2Hz,1H),8.60(s,1H),8.54(d,J=2.2Hz,1H),8.16(d,J=2.3Hz,2H),7 .97(d,J=7.2Hz,1H),7.87(d,J=1.3Hz,1H),7.71(d,J=8.4Hz,1H),7.62–7.57(m,1H),7.32(d,J=1.3Hz,1 H),3.90(s,2H),3.50(s,3H),3.02–2.87(m,2H),2.21–2.17(m,1H),2.03(dd,J=12.2,6.5Hz,1H),1.87– 1.80(m,1H),1.78–1.68(m,4H),1.64(d,J=12.9Hz,1H),1.11(s,2H),1.09(s,2H),0.88(d,J=6.3Hz,3H).

[0389] Example 11

[0390] 4-(2-Cyclopropyl-6-(4-(1-((2-methoxyethyl)amino)ethyl)-2-oxobenzo[cd]indol-1(2H)-yl)pyridin-4-yl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)benzonitrile (Compound 27)

[0391]

[0392] first step

[0393] 4-Acetyl-2-oxobenzo[cd]indole-1(2H)-carboxylic acid tert-butyl ester (27a)

[0394] A mixture of 6a (100 mg, 0.28 mmol), Pd(PPh3)2Cl2 (25 mg, 0.028 mmol), tributyl(1-ethoxyethylene)tin (200 mg, 0.56 mmol), and 1,4-dioxane (4 mL) was heated to 100 °C and stirred for 12 hours. After cooling to room temperature, the mixture was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 0 to 9 / 1) to give the target product 27a (20 mg, 34%).

[0395] MS m / z(ESI): 212[M+1-100]

[0396] Step 2

[0397] 4-Acetylbenzo[cd]indol-2(1H)-one (27b)

[0398] 27a (110 mg, 0.52 mmol) was dissolved in an ethanol solution of hydrogen chloride (5 mL, 2N) and stirred at room temperature for 2 hours. The mixture was concentrated to dryness under reduced pressure to give the target product 3a (100 mg, 96%). This product was used directly in the next reaction without further purification.

[0399] MS m / z(ESI): 212[M+1]

[0400] Step 3

[0401] 4-(1-hydroxyethyl)benzo[cd]indol-2(1H)-one (27c)

[0402] Sodium borohydride (46 mg, 1 mmol) was added to a methanol (2 mL) solution of 27b (100 mg, 0.5 mmol). The resulting mixture was stirred at room temperature for 3 hours and then concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 0 to 9 / 1) to give the target product 27c (70 mg, 70%).

[0403] MS m / z(ESI): 214[M+1]

[0404] Step 4

[0405] 4-(1-Chloroethyl)benzo[cd]indol-2(1H)-one (27d)

[0406] Thionyl chloride (140 mg, 1.3 mmol) was added to a solution of 27c (70 mg, 0.33 mmol) in dichloromethane (2 mL). The resulting mixture was stirred at room temperature for 5 hours, and then concentrated to dryness under reduced pressure to give the target product 27d (70 mg, crude). This product was used directly in the next reaction without further purification.

[0407] MS m / z(ESI): 232[M+1]

[0408] Step 5

[0409] 4-(1-((2-methoxyethyl)amino)ethyl)benzo[cd]indol-2(1H)-one(27e)

[0410] A mixture of 27d (15 mg, 0.065 mmol), 2-methoxyethylamine (7 mg, 0.097 mmol), DIPEA (25 mg, 0.2 mmol), and acetonitrile (1 mL) was heated to 90 °C and stirred for 12 hours. After cooling to room temperature, the mixture was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 0 to 0 / 100) to give the target product 27e (20 mg).

[0411] MS m / z(ESI): 271[M+1]

[0412] Step 6

[0413] 4-(2-Cyclopropyl-6-(4-(1-((2-methoxyethyl)amino)ethyl)-2-oxobenzo[cd]indol-1(2H)-yl)pyridin-4-yl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)benzonitrile (27)

[0414] A mixture of 27e (10 mg, 0.037 mmol), 1 g (20 mg, 0.073 mmol), Pd2(dba)3 (5 mg, 0.007 mmol), Xantphos (9 mg, 0.014 mmol), potassium carbonate (15 mg, 0.11 mmol), and 1,4-dioxane (2 mL) was heated to 90 °C and stirred for 12 hours. After cooling to room temperature, the mixture was concentrated to dryness under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography to obtain the target product 27 (4.9 mg, 23%).

[0415] MS m / z(ESI): 570 [M+1]

[0416] 1 H NMR(400MHz,DMSO-d6)δ8.55(s,1H),8.33–8.20(m,4H),7.96–7.91(m,1H) ,7.89(d,J=7.2Hz,1H),7.77(d,J=8.3Hz,1H),7.69–7.63(m,2H),7.06(d, J=1.2Hz,1H),3.46(s,3H),3.42–3.37(m,2H),3.29–3.26(m,2H),3.22(s, 3H),2.23–2.14(m,1H),1.44(s,3H),1.26–1.20(m,1H),1.10–0.95(m,5H).

[0417] The following compounds were synthesized following the experimental procedure of Example 11, but different compounds were used instead of 1g and 2-methoxyethylamine.

[0418]

[0419] The NMR data for these compounds are as follows:

[0420]

[0421]

[0422] Example 12

[0423] (S)-4-(2-cyclopropyl-6-(4-(((3-methylpiperidin-1-yl)methyl)-2-oxopyrrolo[4,3,2-de]quinoline-1(2H)-yl)pyridin-4-yl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)benzonitrile (Compound 32)

[0424]

[0425] first step

[0426] 4-Nitroindoline-2-one (32b)

[0427] 4-Nitroindole 32a (2.4 g, 14.8 mmol), pyridine tribromide (5.68 g, 17.8 mmol), glacial acetic acid (10 mL), and water (1 mL) were added to a 30 mL sealed tube. The resulting mixture was heated to 80 °C and stirred for 15 hours. After cooling to room temperature, the reaction mixture was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50 / 1 to 1 / 2) to give the target product 32b (1.1 g, 41%).

[0428] MS m / z(ESI): 179 [M+1]

[0429] Step 2

[0430] 2-(4-nitro-2-oxoindoline-3-yl)ethyl acetate (32c)

[0431] Sodium hydride (60%, 54.3 mg, 13.6 mmol) was slowly added to a DMF (10 mL) solution of 32b (1.1 g, 6.2 mmol) at 0 °C. After stirring at 0 °C for half an hour, ethyl bromoacetate (2.28 g, 13.6 mmol) was slowly added, and stirring was continued at 0 °C for two hours. A saturated ammonium chloride solution (50 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (2 × 100 mL). The combined organic phases were washed with a saturated sodium chloride solution (50 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 1 to 1 / 1) to give the target product 32c (450 mg, 27%).

[0432] MS m / z(ESI): 265[M+1]

[0433] Step 3

[0434] 2-(4-amino-2-oxoindoline-3-yl)ethyl acetate (32d)

[0435] A mixture of 32c (450 mg, 1.7 mmol), palladium on carbon (10%, 200 mg), and methanol (30 mL) was stirred for 15 hours under a hydrogen atmosphere and then filtered. The filtrate was concentrated to dryness under reduced pressure to give the target product 32d (400 mg). This product was used directly in the next reaction without further purification.

[0436] MS m / z(ESI): 235[M+1]

[0437] Step 4

[0438] 2a,5-Dihydropyrrolo[4,3,2-de]quinoline-2,4(1H,3H)-dione(32e)

[0439] 32d (400 mg, crude product), p-toluenesulfonic acid monohydrate (32 mg, 0.17 mmol), acetic acid (1 mL), and toluene (10 mL) were mixed and then heated to 130 °C and stirred for 15 hours. After cooling to room temperature, the reaction solution was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 15 to 1 / 1) to give the target product 32e (140 mg, 43%).

[0440] MS m / z(ESI): 189[M+1]

[0441] Step 5

[0442] Pyrrolo[4,3,2-de]quinoline-2,4(1H,5H)-dione (32f)

[0443] To a solution of 32e (140 mg, 0.74 mmol) in toluene (20 mL), activated manganese dioxide (323 mg, 3.72 mmol) was added, and the resulting mixture was heated to 120 °C and stirred for 15 hours. After cooling to room temperature, the reaction mixture was diluted with dichloromethane / methanol (30 mL, 10:1) and stirred for 10 minutes, then filtered. The filtrate was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 1 to 20 / 1) to give the target product 32f (80 mg, 58%).

[0444] MS m / z(ESI): 187[M+1]

[0445] Step 6

[0446] 4-Chloropreno[4,3,2-de]quinoline-2(1H)-one (32g)

[0447] Phosphorus oxychloride (1 mL) was added to a 32g (80 mg, 0.43 mmol) solution of acetonitrile (10 mL). The resulting mixture was heated to 85°C and stirred for 2 hours. After cooling to room temperature, the reaction mixture was concentrated to dryness under reduced pressure. The residue was dissolved in dichloromethane (50 mL), washed with saturated sodium bicarbonate solution (15 mL), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50 / 1 to 1 / 1) to give 32g (50 mg, 57%) of the target product.

[0448] MS m / z(ESI): 205 [M+1]

[0449] Step 7

[0450] 4-(hydroxymethyl)pyrrolo[4,3,2-de]quinoline-2(1H)-one (32h)

[0451] A mixture of 32 g (140 mg, 0.68 mmol), (tributyltinyl)methanol (439 mg, 1.37 mmol), Pd(dppf)Cl2 (95 mg, 0.14 mmol), and 1,4-dioxane (5 mL) was heated to 110 °C and stirred for 2 hours. After cooling to room temperature, the reaction mixture was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50 / 1 to 1 / 2) to give the target product 32 h (60 mg, 44%).

[0452] MS m / z(ESI): 201[M+1]

[0453] Step 8

[0454] 4-(bromomethyl)pyrrolo[4,3,2-de]quinoline-2(1H)-one(32i)

[0455] Triphenylphosphine (94 mg, 0.36 mmol) was added to a solution of dichloromethane (10 mL) containing 60 mg (0.3 mmol) and carbon tetrabromide (120 mg, 0.36 mmol) for 32 h at 0 °C, and then the mixture was heated to room temperature and stirred for 3 h. The reaction mixture was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50 / 1 to 1 / 1) to give the target product 32i (35 mg, 44%).

[0456] MS m / z(ESI): 263,265 [M+1]

[0457] Step 9

[0458] (S)-4-((3-methylpiperidin-1-yl)methyl)pyrrolo[4,3,2-de]quinoline-2(1H)-one (32j) was prepared by mixing 32i (15 mg, 0.057 mmol), DIPEA (29 mg, 0.23 mmol), (S)-3-methylpiperidin hydrochloride (12 mg, 0.085 mmol), and DMA (2 mL), then heating to 90 °C and stirring for 1 hour. After cooling to room temperature, the reaction mixture was directly purified by prep-HPLC to give the target product 32j (10 mg, 62%).

[0459] MS m / z(ESI): 282[M+1]

[0460] Step 10

[0461] (S)-5-((4-(4-cyano-2-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-6-cyclopropylpyridin-2-yl)amino)-2-((3-methylpiperidin-1-yl)methyl)quinoline-4-carboxylic acid (32k)

[0462] 32kJ (10 mg, 0.035 mmol), 1 g (18 mg, 0.053 mmol), cesium carbonate (23 mg, 0.07 mmol), Xantphos (16 mg, 0.028 mmol), and Pd2(dba)3 (13 mg, 0.014 mmol) were added to toluene (2 mL), and the mixture was heated to 110 °C and stirred for 1.5 h under a nitrogen atmosphere. After cooling to room temperature, glacial acetic acid (6 mg) was added to the reaction mixture, and the mixture was concentrated to dryness under reduced pressure. The residue was purified by prep-HPLC to give the target product 32k (10 mg, 47%).

[0463] MS m / z(ESI): 599[M+1]

[0464] Step 11

[0465] (S)-4-(2-cyclopropyl-6-(4-(((3-methylpiperidin-1-yl)methyl)-2-oxopyrrolo[4,3,2-de]quinoline-1(2H)-yl)pyridin-4-yl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)benzonitrile (32)

[0466] Carbonyl diimidazole (27 mg, 0.16 mmol) was added to a 1 mL solution of DMF containing 32 kJ (10 mg, 0.016 mmol). The resulting mixture was stirred at room temperature for 3 hours and then purified directly by prep-HPLC to give the target product 32 (2.4 mg, 26%).

[0467] MS m / z(ESI): 581.3 [M+1]

[0468] 1H NMR (400MHz, CD3OD) δ8.53 (s, 1H), 8.14 (t, J = 7.1Hz, 3H), 7.97 (dd, J = 12.8, 7.0Hz, 2H),7.81(d,J=5.8Hz,2H),7.73(s,1H),7.14(s,1H),4.10(s,2H),3.49(d,J=7.3H z,3H),2.98(d,J=12.7Hz,2H),2.28(s,1H),2.21–2.10(m,2H),2.05–1.96(m,2H), 1.82–1.66(m,3H),1.59(d,J=6.9Hz,1H),1.10(d,J=7.9Hz,3H),0.93–0.87(m,3H).

[0469] Example 13

[0470] 4-(2-Cyclopropyl-6-(4-(((((1-hydroxycyclobutyl)methyl)amino)methyl)-2-oxopyrrolo[4,3,2-de]quinoline-1(2H)-yl)pyridin-4-yl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)benzonitrile (Compound 33)

[0471]

[0472] first step

[0473] 4-((((1-hydroxycyclobutyl)methyl)amino)methyl)pyrrolo[4,3,2-de]quinoline-2(1H)-one (33a)

[0474] 32i (30 mg, 0.11 mmol), DIPEA (43 mg, 0.33 mmol), and 1-(aminomethyl)cyclobutane-1-ol (29 mg, 0.29 mmol) were added to DMA (2 mL), and the resulting mixture was heated to 90 °C and stirred for 1 hour. After cooling to room temperature, the reaction mixture was purified by prep-HPLC to give the target product 33a (30 mg, 96%).

[0475] MS m / z(ESI): 284[M+1]

[0476] Step 2

[0477] 4-(2-Cyclopropyl-6-(4-(((((1-hydroxycyclobutyl)methyl)amino)methyl)-2-oxopyrrolo[4,3,2-de]quinoline-1(2H)-yl)pyridin-4-yl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)benzonitrile (33)

[0478] 33a (25 mg, 0.088 mmol), 1 g (45 mg, 0.13 mmol), cesium carbonate (57 mg, 0.176 mmol), Xantphos (40 mg, 0.07 mmol), and Pd2(dba)3 (32 mg, 0.035 mmol) were added to toluene (5 mL). The resulting mixture was heated to 110 °C and stirred for 1.5 hours under a nitrogen atmosphere. After cooling to room temperature, the reaction solution was concentrated to dryness under reduced pressure. The residue was purified by prep-HPLC to give the target product 33 (1 mg, 2%).

[0479] MS m / z(ESI): 583 [M+1]

[0480] 1 H NMR (400MHz, CD3OD) δ8.52(s,1H),8.18–8.11(m,2H),7.99(dd,J=26.1,12.8Hz,3H),7.85(s,2H),7.72(s,1H),7.15(s,1H),4.61(s,2H),3.48(s,3 H),3.15(d,J=16.8Hz,2H),2.20(dd,J=20.5,10.2Hz,4H),2.03(d,J=4.9 Hz,1H),1.80(d,J=10.6Hz,2H),1.63–1.56(m,1H),1.10(d,J=8.4Hz,3H).

[0481] Compound 46 can be synthesized in step 2 of Example 13, but 32j and 24b are used instead of 33a and 1g.

[0482] The characterization data of compound 46 are as follows:

[0483] MS m / z(ESI): 582 [M+1]

[0484] 1 H NMR(400MHz,CD3OD)δ9.28(d,J=2.0Hz,1H),8.62(s,1H),8.58(d,J=2.0Hz,1H), 8.13(s,1H),7.99(d,J=6.0Hz,1H),7.86–7.73(m,3H),7.34(s,1H),4.01(s,2H) ,3.51(s,3H),2.93(t,J=13.2Hz,2H),2.24–2.14(m,2H),1.90(t,J=10.8Hz,1H) ,1.81–1.66(m,4H),1.04(ddd,J=16.8,10.8,6.7Hz,5H),0.89(d,J=6.4Hz,3H).

[0485] Example 14

[0486] 2'-(4-((5-azaspiro[2.4]hept-5-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)-6'-cyclopropyl-3-(4-methyl-4H-1,2,4-triazol-3-yl)-[2,4'-bipyridine]-5-nitrile (compound 34)

[0487]

[0488] first step

[0489] 2-Oxo-4-vinylbenzo[cd]indole-1(2H)-carboxylic acid tert-butyl ester (34a)

[0490] A mixture of 6a (2.52 g, 7.24 mmol), potassium trifluoroborate (1.92 g, 14.5 mmol), and 1,4-dioxane (36 mL) was added to potassium phosphate (4.61 g, 21.7 mmol), water (6 mL), and Pd(dtbpf)Cl2 (280 mg, 0.43 mmol). The resulting mixture was heated to 100 °C and stirred for 30 min in a microwave reactor under a nitrogen atmosphere. After cooling to room temperature, the mixture was filtered, the filtrate was diluted with water (100 mL), and then extracted with ethyl acetate (2 × 100 mL). The combined organic phases were washed with saturated brine (50 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to dryness under reduced pressure to give the target product 34a (2.14 g, 100%).

[0491] MS m / z (ESI): 613 [2M+Na]

[0492] Step 2

[0493] 4-Formyl-2-oxobenzo[cd]indole-1(2H)-tert-butyl formate (34b)

[0494] To a solution of 34a (2.14 g, 7.24 mmol) in 1,4-dioxane (72 mL), an aqueous solution of sodium periodate (7.74 g, 36.2 mmol) was added dropwise (72 mL), followed by potassium osmium tetroxide dihydrate (451 mg, 1.45 mmol). The resulting mixture was stirred for 3 hours, diluted with water (100 mL), and extracted with ethyl acetate (2 × 100 mL). The combined organic phases were washed with saturated brine (100 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / ethyl acetate = 100 / 0-0 / 100) to give the target product 34b (1.04 g, 48%).

[0495] MS m / z(ESI): 617[2M+23]

[0496] Step 3

[0497] 2-Oxo-1,2-dihydrobenzo[cd]indole-4-carboxaldehyde (34c)

[0498] A solution of 1,4-dioxane (4 M, 10 mL) of hydrogen chloride was added to a solution of 34b (1.04 g, 3.50 mmol) in dichloromethane (20 mL). The resulting mixture was stirred at room temperature for 2 hours and then concentrated to dryness under reduced pressure to give the target product 34c (690 mg, 100%).

[0499] MS m / z(ESI): 198[M+1]

[0500] Step 4

[0501] 2'-Cyclopropyl-6'-(4-formyl-2-oxobenzo[cd]indol-1(2H)-yl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)-[2,4'-bipyridine]-5-carboxynitrile (34d)

[0502] Cesium carbonate (1.98 g, 6.09 mmol), Pd2(dba)3 (93 mg, 0.10 mmol), and Xantphos (118 mg, 0.20 mmol) were added to 20 mL of 1,4-dioxane solution of 34c (420 mg, 2.13 mmol) and 24b (690 mg, 2.03 mmol). The resulting mixture was heated to 100 °C and stirred for 2 hours in a microwave reactor. The above operation was repeated once, and then the two batches of reaction mixtures of the same size were combined and filtered. The filtrate was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 0-94 / 6) to give the target product 34d (1.04 g, 51%).

[0503] MS m / z(ESI): 498[M+1]

[0504] Step 5

[0505] 2'-(4-((5-azaspiro[2.4]hept-5-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)-6'-cyclopropyl-3-(4-methyl-4H-1,2,4-triazol-3-yl)-[2,4'-bipyridine]-5-nitrile (34)

[0506] Triethylamine (0.2 mL) and NaBH(OAc)3 (13 mg, 0.06 mmol) were added to a mixture of 34d (10 mg, 0.02 mmol), 5-azaspiro[2,4]heptane hydrochloride (11 mg, 0.08 mmol), and dichloromethane (2 mL). The resulting mixture was stirred at room temperature for 2 hours, then concentrated to dryness under reduced pressure. The residue was purified by prep-HPLC to give the target product 34 (5.6 mg, 48%).

[0507] MS m / z(ESI): 579 [M+1]

[0508] 1 H NMR(400MHz,DMSO-d6)δ9.41(d,J=2.0Hz,1H),8.77(d,J=2.0Hz,1H),8.66(s,1H),8.23(s,1H), 8.12(s,1H),7.91(dd,J=7.6,4.3Hz,2H),7.78(d,J=8.4Hz,1H),7.68–7.61(m,1H),7.09(d,J=1 .3Hz,1H),3.90(s,2H),3.50(s,3H),2.73(d,J=6.3Hz,2H),2.49–2.47(m,2H),2.24–2.15(m,1H ),1.78(t,J=6.8Hz,2H),1.10–1.03(m,2H),0.98(dt,J=7.1,3.9Hz,2H),0.50(d,J=4.3Hz,4H).

[0509] The following compounds were synthesized following the experimental procedure of Example 14, but different compounds were used instead of 5-azaspiro[2,4]heptane hydrochloride.

[0510]

[0511]

[0512] The NMR data for these compounds are as follows:

[0513]

[0514]

[0515] Example 15

[0516] (S)-5-(4-methyl-4H-1,2,4-triazol-3-yl)-6-(3-(4-((3-methylpiperidin-1-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)phenyl)nicotinonitrile (Compound 41)

[0517]

[0518] first step

[0519] 2-Chloro-5-cyanonicotinic acid methyl ester (41b)

[0520] Molecular sieves (10 g), zinc cyanide (3.16 g, 26.9 mmol), and Pd(PPh3)4 (3.88 g, 3.36 mmol) were added to a DMF (70 mL) solution of methyl 2-chloro-5-iodonicotinate 41a (10 g, 33.6 mmol). The resulting mixture was heated to 100 °C and stirred for 18 hours, then cooled to room temperature. The reaction mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 0-4 / 1) to give the target product 41b (1.86 g, 28%).

[0521] MS m / z(ESI): 197[M+1]

[0522] Step 2

[0523] 2-(3-Bromophenyl)-5-cyanonicotinic acid methyl ester (41c)

[0524] A mixture of 1b (1.86 g, 9.46 mmol), (3-bromophenyl)boronic acid (1.71 g, 8.52 mmol), 1,4-dioxane (45 mL), water (1.5 mL), potassium carbonate (3.92 g, 28.4 mmol), and Pd(dppf)Cl2 (415 mg, 0.57 mmol) was heated to 80 °C and stirred for 30 minutes. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 0-1 / 1) to give the target product 41c (2.71 g, 90%).

[0525] MS m / z(ESI): 317,319 [M+1]

[0526] Step 3

[0527] 2-(3-Bromophenyl)-5-cyanonic acid (41d)

[0528] Water (25 mL) and lithium hydroxide monohydrate (1.07 g, 25.6 mmol) were added to a THF (25 mL) solution of 41c (2.71 g, 8.52 mmol). The resulting mixture was stirred for 1 hour, then adjusted to pH 3 with dilute hydrochloric acid (2 N), and extracted with ethyl acetate (3 × 100 mL). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure to give the target product 1e (2.58 g, 100%).

[0529] MS m / z(ESI): 303, 305 [M+1]

[0530] Step 4

[0531] 2-(2-(3-bromophenyl)-5-cyanoconicoyl)-N-methylhydrazine-1-thiocarboxamide (41e)

[0532] To a 17 mL NMP solution (2.58 g, 8.52 mmol), N-methylhydrazine thiocarboxamide (1.34 g, 12.8 mmol), DIPEA (1.10 g, 8.52 mmol), and HATU (4.21 g, 11.1 mmol) were added. The resulting reaction solution was stirred at room temperature for 1 hour and then used directly in the next step.

[0533] MS m / z(ESI): 390, 392 [M+1]

[0534] Step 5

[0535] 5-(4-(2-chloro-6-cyclopropylpyridin-4-yl)-1,2,5-thiadiazol-3-yl)-4-methyl-4H-1,2,4-triazol-3-thiol (41f)

[0536] Water (34 mL) and sodium bicarbonate (4.29 g, 51.1 mmol) were added to the reaction mixture from the previous step, and the mixture was then heated to 100 °C and stirred for 3 hours. After cooling to room temperature, the reaction mixture was adjusted to pH 3 with dilute hydrochloric acid (2 N) and then extracted with ethyl acetate (3 × 100 mL). The combined organic phases were dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated to dryness under reduced pressure, and the residue was used directly in the next reaction step.

[0537] MS m / z(ESI): 372,374 [M+1]

[0538] Step 6

[0539] 6-(3-Bromophenyl)-5-(4-methyl-4H-1,2,4-triazol-3-yl)nicotinonitrile (41g)

[0540] The crude 41f product obtained in the previous step was dissolved in dichloromethane (80 mL), acetic acid (7.67 g, 128 mmol) was added, and the mixture was cooled to 0 °C. Then, hydrogen peroxide (34%, 2.90 g, 25.6 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 1 hour, adjusted to pH 8 with saturated sodium bicarbonate, and then extracted with dichloromethane (3 × 50 mL). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure, and the residue was purified by C18 column chromatography (acetonitrile / water = 5 / 95–3 / 7) to give 41 g (1.16 g, 40%) of the target product.

[0541] MS m / z(ESI): 340, 342 [M+1]

[0542] Step 7

[0543] (S)-5-(4-methyl-4H-1,2,4-triazol-3-yl)-6-(3-(4-((3-methylpiperidin-1-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)phenyl)nicotinonitrile carboxylate (41)

[0544] Potassium phosphate (32 mg, 0.15 mmol), cuprous iodide (10 mg, 0.05 mmol), and (1R,2R)-N were added to 41 g (17 mg, 0.05 mmol) and 2a (14 mg, 0.05 mmol) solutions of DMA (0.2 mL). 1 N 2 -Dimethylcyclohexane-1,2-diamine (7 mg, 0.05 mmol). The resulting mixture was heated to 100 °C and stirred for 1 hour in a microwave reactor. After cooling to room temperature, the mixture was filtered, and the filtrate was directly purified by prep-HPLC to give the target product 41 (8.5 mg, 29%, formate).

[0545] MS m / z(ESI): 540 [M+1]

[0546] 1H NMR (400MHz, DMSO-d6) δ9.35(d,J=2.0Hz,1H),8.65(d,J=2.1Hz,1H),8.64(s,1H),8.17(s, 1H),8.10(s,1H),7.74–7.69(m,3H),7.63(d,J=7.9Hz,1H),7.60–7.56(m,2H),7.56–7.53( m,1H),7.38–7.34(m,1H),6.80(d,J=7.1Hz,1H),3.76(d,J=3.3Hz,2H),3.27(s,3H),2.83– 2.74(m,3H),2.00–1.91(m,2H),1.62(ddd,J=11.1,9.6,6.3Hz,4H),0.81(d,J=6.1Hz,3H).

[0547] Example 16

[0548] (S)-1-(6-cyclopropyl-4-(4-(4-methyl-4H-1,2,4-triazol-3-yl)-1,2,5-thiadiazol-3-yl)pyridin-2-yl)-4-((3-methylpiperidin-1-yl)methyl)benzo[cd]indol-2(1H)-one (Compound 43)

[0549]

[0550] first step

[0551] 2-Chloro-6-cyclopropylpyridine (43b)

[0552] 2-Bromo-6-chloropyridine 43a (10.0 g, 52.0 mmol) and cyclopropylboronic acid (4.46 g, 52.0 mmol) were dissolved in 1,4-dioxane / H₂O (200 mL, 5 / 1 v / v) under a nitrogen atmosphere. Then, Pd(dppf)Cl₂ (2.12 g, 2.60 mmol) and potassium carbonate (21.5 g, 156 mmol) were added sequentially. The mixture was heated to 100 °C and stirred for 16 hours. After cooling to room temperature, water (100 mL) was added to the mixture, followed by extraction with ethyl acetate (3 × 80 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 0 to 100 / 1) to give the target product 43b (3.50 g, 44%).

[0553] MS m / z (ESI): 154, 156 [M+1]

[0554] Step 2

[0555] 2-Chloro-6-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)pyridine (43c)

[0556] To a solution of 43b (2.00 g, 13.0 mmol) in methyl tert-butyl ether (50 mL), bis-pinacol borate (4.96 g, 19.5 mmol), methoxy(cyclooctadiene)iridium dimer (432 mg, 0.651 mmol), and 4,4'-di-tert-butyl-2,2'-dipyridine (349 mg, 1.30 mmol) were added sequentially. The resulting mixture was heated to 80 °C and stirred for 12 hours under a nitrogen atmosphere. After cooling to room temperature, the reaction mixture was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 0 to 100 / 1) to give the target product 43c (3.20 g, 88%).

[0557] MS m / z (ESI): 280, 282 [M+1]

[0558] Step 3

[0559] 4-(2-chloro-6-cyclopropylpyridin-4-yl)-1,2,5-thiadiazole-3-carboxylic acid methyl ester (43d)

[0560] Methyl 4-bromo-1,2,5-thiadiazole-3-carboxylate (223 mg, 1 mmol) and 43c (280 mg, 1 mmol) were dissolved in 1,4-dioxane (20 mL) and water (0.5 mL), followed by the addition of potassium carbonate (415 mg, 3 mmol) and Pd(dppf)Cl2 (73 mg, 0.1 mmol). The resulting mixture was heated to 80 °C and stirred for 30 minutes, then cooled to room temperature and filtered. The filtrate was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 0-7 / 3) to give the target product 43d (213 mg, 72%).

[0561] MS m / z (ESI): 296 [M+1]

[0562] Steps 4 to 8

[0563] (S)-1-(6-cyclopropyl-4-(4-(4-methyl-4H-1,2,4-triazol-3-yl)-1,2,5-thiadiazol-3-yl)pyridin-2-yl)-4-((3-methylpiperidin-1-yl)methyl)benzo[cd]indole-2(1H)-one hydrochloride (43)

[0564] 43 is synthesized according to steps three through seven of Example 15, but 43d is used instead of 41c in the operation.

[0565] MS m / z(ESI): 563 [M+1]

[0566] 1 H NMR(400MHz,DMSO-d6)δ9.95(s,1H),8.77(s,1H),8.47(s,1H),8.40(s,1H),8.18(d,J=1.1Hz,1H),8 .00(d,J=7.3Hz,1H),7.87(d,J=8.4Hz,1H),7.79–7.71(m,1H),7.53(d,J=1.0Hz,1H),4.60(s,2H),3. 87(s,3H),2.86(s,2H),2.27–2.20(m,1H),1.99(dt,J=12.9,6.6Hz,3H),1.83(d,J=13.2Hz,2H),1.73 (d,J=8.7Hz,2H),1.46(d,J=6.8Hz,1H),1.12–1.07(m,2H),1.07–1.03(m,2H),0.87(d,J=6.5Hz,3H).

[0567] Example 17

[0568] (S)-6-(6-cyclopropyl-2-(4-(((3-methylpiperidin-1-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)pyrimidin-4-yl)-5-(4-methyl-4H-1,2,4-triazol-3-yl)nicotinonitrile (Compound 44)

[0569]

[0570] first step

[0571] 2,4-Dichloro-6-cyclopropylpyrimidine (44b)

[0572] Cuprous iodide (248 mg, 1.3 mmol) was added to a THF (25 mL) solution of 2,4,6-trichloropyrimidine 44a (4.78 g, 26 mmol) under a nitrogen atmosphere. The resulting mixture was cooled to -15 °C, and cyclopropylmagnesium bromide (1 M THF solution, 26 mL, 26 mmol) was added dropwise. The mixture was heated to 0 °C and stirred for 1 hour, then stirred at room temperature for two days. Cuprous iodide (248 mg, 1.3 mmol) was added to the mixture again, and the mixture was cooled to 0 °C, and cyclopropylmagnesium bromide (1 M THF solution, 15 mL, 15 mmol) was added dropwise. After stirring for 1 hour, cyclopropylmagnesium bromide (1 M THF solution, 10 mL, 10 mmol) was added again. The resulting mixture was stirred at 0 °C for another 1 hour, then a saturated ammonium chloride solution (200 mL) was added, and the mixture was extracted with ethyl acetate (3 × 100 mL). The combined organic phases were washed successively with water (100 mL) and saturated brine (100 mL), and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 0-94 / 6) to give the target product 44b (1.77 g, 36%).

[0573] MS m / z(ESI): 189[M+1]

[0574] 1 H NMR (400MHz, CDCl3) δ7.09 (s, 1H), 1.94–1.86 (m, 1H), 1.11 (dt, J = 10.5, 4.8Hz, 4H).

[0575] Step 2

[0576] 2-Chloro-4-cyclopropyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)pyrimidine (44c)

[0577] 44b (1.58 g, 8.36 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxoboronane) (2.33 g, 9.19 mmol) were dissolved in 1,4-dioxane (40 mL), followed by the addition of potassium acetate (1.64 g, 16.7 mmol) and Pd(dppf)Cl2 (612 mg, 0.84 mmol). The resulting mixture was heated to 100 °C and stirred for 20 hours, then cooled to room temperature and filtered. The filtrate was used directly for the next step.

[0578] MS m / z(ESI): 199[M+1-82]

[0579] Step 3

[0580] 2-(2-chloro-6-cyclopropylpyrimidin-4-yl)-5-cyanonic acid methyl ester (44d)

[0581] Add water (1 mL), 41b (1.64 g, 8.36 mmol), potassium carbonate (3.47 g, 25.08 mmol), and Pd(dppf)Cl2 (612 mg, 0.836 mmol) to the filtrate from the previous step. Heat the resulting mixture to 70 °C and stir for 30 minutes, then raise the temperature to 100 °C and stir for another hour. After cooling to room temperature, filter the mixture. Concentrate the filtrate to dryness under reduced pressure. Purify the residue by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 0-2 / 3) to give the target product 44d (340 mg, 13% in two steps).

[0582] MS m / z(ESI): 315[M+1]

[0583] Steps 4 to 8

[0584] (S)-6-(6-cyclopropyl-2-(4-(((3-methylpiperidin-1-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)pyrimidin-4-yl)-5-(4-methyl-4H-1,2,4-triazol-3-yl)nicotinonitrile(44)

[0585] 44 is synthesized according to steps three through seven of Example 15, but 44d is used instead of 41c in the operation.

[0586] MS m / z(ESI): 582.4 [M+1]

[0587] 1 H NMR (400MHz, DMSO-d6) δ9.41(d,J=2.0Hz,1H),8.80(d,J=2.0Hz,1H),8.42(s,1H),8.18(s,1H ),8.08(s,1H),8.01(s,1H),7.76(d,J=8.4Hz,1H),7.61–7.54(m,1H),7.32(d,J=7.3Hz,1H),3 .79–3.69(m,2H),3.61(s,3H),2.78(t,J=10.7Hz,2H),2.42(dd,J=12.5,6.2Hz,1H),2.03–1. 89(m,2H),1.71–1.56(m,4H),1.56–1.47(m,1H),1.23(d,J=5.7Hz,4H),0.82(d,J=6.0Hz,3H).

[0588] Example 18

[0589] 2'-Cyclopropyl-3-(4-Methyl-4H-1,2,4-triazol-3-yl)-6'-(4-(1-methylpiperidin-3-yl)-2-oxobenzo[cd]indol-1(2H)-yl)-[2,4'-bipyridine]-5-carboxynitrile (Compound 45)

[0590]

[0591] first step

[0592] 4-(1-((benzyloxy)carbonyl)-1,2,5,6-tetrahydropyridin-3-yl)-2-oxobenzo[cd]indole-1(2H)-carboxylic acid tert-butyl ester (45a)

[0593] Under a nitrogen atmosphere, 6a (400 mg, 1.15 mmol), Pd(dppf)Cl2 (49 mg, 0.06 mmol), and potassium carbonate (477 mg, 3.45 mmol) were added sequentially to a solution of 5-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (436 mg, 1.27 mmol) in 1,4-dioxane / H2O (22 mL, 20 / 1 v / v). The mixture was heated to 100 °C and stirred for 12 hours. After cooling to room temperature, water (20 mL) was added to the mixture, followed by extraction with ethyl acetate (3 × 30 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 0 to 10 / 1) to give the target product 45a (200 mg, 36%).

[0594] MS m / z(ESI): 485[M+1]

[0595] Step 2

[0596] 2-O-4-(piperidin-3-yl)benzo[cd]indole-1(2H)-carboxylic acid tert-butyl ester (45b)

[0597] Pd / C (40 mg, 20% wt) was added to a 10 mL solution of 45a (200 mg, 0.41 mmol) in THF. The resulting mixture was heated to 50 °C and stirred for 12 hours under a hydrogen atmosphere. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure to give the target product 45b (145 mg, 100%).

[0598] MS m / z(ESI): 353[M+1]

[0599] Step 3

[0600] 4-(1-Methylpiperidin-3-yl)-2-oxobenzo[cd]indole-1(2H)-carboxylic acid tert-butyl ester (45c)

[0601] To a solution of 45b (145 mg, 0.41 mmol) in 15 mL of dichloromethane, paraformaldehyde (98 mg, 3.28 mmol), sodium triacetoxyborohydride (348 mg, 1.64 mmol), and triethylamine (0.5 mL) were added sequentially. The resulting mixture was stirred at room temperature for 12 hours and then concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 0 to 50 / 1) to give the target product 45c (90 mg, 60%).

[0602] MS m / z (ESI): 367 [M+1]

[0603] Step 4

[0604] 4-(1-Methylpiperidin-3-yl)benzo[cd]indol-2(1H)-one (45d)

[0605] A 1,4-dioxane solution (4M, 5 mL) of hydrogen chloride was added to a 2 mL solution of 1,4-dioxane (90 mg, 0.25 mmol) of 45c. After stirring for 1 hour, the reaction solution was concentrated to dryness under reduced pressure. The residue was purified by prep-HPLC to obtain the target product 45d (65 mg, 100%).

[0606] MS m / z (ESI): 267 [M+1]

[0607] Step 5

[0608] 2'-Cyclopropyl-3-(4-methyl-4H-1,2,4-triazol-3-yl)-6'-(4-(1-methylpiperidin-3-yl)-2-oxobenzo[cd]indol-1(2H)-yl)-[2,4'-bipyridine]-5-carboxynitrile (45)

[0609] Pd₂(dba)₃ (19 mg, 0.021 mmol), Xantphos (24 mg, 0.042 mmol), and cesium carbonate (228 mg, 0.70 mmol) were added sequentially to toluene (8 mL) solutions of 24b (47 mg, 0.14 mmol) and 45d (37 mg, 0.14 mmol). The resulting mixture was heated to 110 °C and stirred for 12 hours. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by prep-HPLC to give the target product 45 (8 mg, 13%).

[0610] MS m / z (ESI): 567 [M+1]

[0611] 1 H NMR (400MHz, DMSO-d6) δ9.40(d,J=2.0Hz,1H),8.77(d,J=2.0Hz,1H),8.64(s,1H),8.20(s ,1H),8.11(s,1H),7.90(t,J=4.0Hz,2H),7.75(d,J=8.3Hz,1H),7.67–7.60(m,1H),7.09( d,J=1.3Hz,1H),3.49(s,3H),3.13(s,1H),2.88(d,J=38.5Hz,2H),2.24(s,3H),2.21–2.1 5(m,1H),1.99(dd,J=17.7,10.2Hz,2H),1.79–1.54(m,4H),1.02(dd,J=34.0,5.3Hz,4H).

[0612] Example 19

[0613] (S)-2'-cyclopropyl-3-(4-(methyl-d3)-4H-1,2,4-triazol-3-yl)-6'-(4-((3-methylpiperidin-1-yl))methyl)-2-oxobenzo[cd]indol-1(2H)-yl)-[2,4'-bipyridine]-5-nitrile (Compound 47)

[0614]

[0615] first step

[0616] Methyl deuterated isothiocyanate (47b)

[0617] Triphosgene (29.6 g, 100 mmol) was added to a mixture of deuterated methylamine 47a (2.11 g, 30 mmol), triethylamine (6.06 g, 60 mmol), carbon disulfide (3.04 g, 40 mmol), and dichloromethane (50 mL) at 0 °C. The resulting mixture was stirred for 2 hours and then extracted with dichloromethane (200 mL). The organic phase was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to dryness under reduced pressure to give the target product 47b (1.68 g, 73%).

[0618] MS m / z(ESI): 77[M+1]

[0619] Step 2

[0620] Methyl 2'-chloro-5-cyano-6'-cyclopropyl-[2,4'-bipyridine]-3-carboxylate (47d)

[0621] To a mixture of 47b (1 g, 5.1 mmol), 1,4-dioxane (20 mL), and water (4 mL), 43c (1.4 g, 5.1 mmol), potassium carbonate (1.4 g, 10 mmol), and Pd(dppf)Cl2 (416 mg, 0.51 mmol) were added. The resulting mixture was heated to 75 °C and stirred for 13 hours. After cooling to room temperature, water (100 mL) was added to the mixture, followed by extraction with ethyl acetate (200 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 1 / 0 to 20 / 1) to give the target product 47d (1.22 g, 76%).

[0622] MS m / z(ESI): 314[M+1]

[0623] Step 3

[0624] 2'-Chloro-5-cyano-6'-cyclopropyl-[2,4'-bipyridine]-3-carbazide (47e)

[0625] Hydrazine hydrate (80%, 2 mL) was added to an ethanol solution (10 mL) of 47d (4.72 g, 16 mmol) at 0 °C, and then heated to 80 °C and stirred for 2 hours. After cooling to room temperature, the mixture was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 0 to 20 / 1) to give the target product 47e (760 mg, 62%).

[0626] MS m / z(ESI): 314[M+1]

[0627] Step 4

[0628] 2-(2'-Chloro-5-cyano-6'-cyclopropyl-[2,4'-bipyridine]-3-carbonyl)-N-(methyl-d3)hydrazine-1-thiocarboxamide (47f)

[0629] Triethylamine (733 mg, 7.3 mmol) and 47b (186 mg, 2.4 mmol) were added to a 10 mL solution of THF containing 760 mg (2.4 mmol) of 47e at 0 °C. The resulting mixture was stirred at 0 °C for 1 hour, then concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 1 / 0 to 20 / 1) to give the target product 47f (0.76 g, 80%).

[0630] MS m / z(ESI): 390[M+1]

[0631] Step 5

[0632] 2'-Chloro-6'-cyclopropyl-3-(5-mercapto-4-(methyl-d3)-4H-1,2,4-triazol-3-yl)-[2,4'-bipyridine]-5-onitrile (47g)

[0633] Triethylamine (590 mg, 5.84 mmol) was added to a 10 mL solution of 47 g (760 mg, 1.95 mmol) of THF, and the mixture was heated to 50 °C and stirred for 12 hours. After cooling to room temperature, the reaction mixture was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 0 to 10 / 1) to give 47 g (520 mg, 72%) of the target product.

[0634] MS m / z(ESI): 372[M+1]

[0635] Step 6

[0636] 2'-Chloro-6'-cyclopropyl-3-(4-(methyl-d3)-4H-1,2,4-triazol-3-yl)-[2,4'-bipyridine]-5-carboxynitrile (47h)

[0637] Acetic acid (3 mL) and hydrogen peroxide solution (30%, 2.5 mL) were added to 47 g (520 mg, 1.4 mmol) of dichloromethane (10 mL) at 0 °C. After stirring the resulting mixture for 1 hour, saturated sodium bicarbonate solution (100 mL) was added, followed by extraction with dichloromethane (3 × 100 mL). The combined organic phases were dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 0 to 10 / 1) to give the target product 47 h (320 mg, 67%).

[0638] MS m / z(ESI): 340[M+1]

[0639] Step 7

[0640] (S)-2'-cyclopropyl-3-(4-(methyl-d3)-4H-1,2,4-triazol-3-yl)-6'-(4-((3-methylpiperidin-1-yl))methyl)-2-oxobenzo[cd]indol-1(2H)-yl)-[2,4'-bipyridine]-5-carboxynitrile (47)

[0641] Under a nitrogen atmosphere, palladium acetate (2.3 mg, 0.02 mmol), Xantphos (23 mg, 0.04 mmol), cesium carbonate (125 mg, 0.4 mmol), and 1,4-dioxane (2 mL) were added to a mixture of 47h (65 mg, 0.2 mmol), 2a (54 mg, 0.2 mmol), cesium carbonate (125 mg, 0.4 mmol), and 1,4-dioxane (2 mL). The resulting mixture was heated to 100 °C and stirred for 3 hours. After cooling to room temperature, the reaction mixture was extracted with ethyl acetate (3 × 150 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50 / 1 to 1 / 1), and then purified again by prep-HPLC to give the target product 47 (53.8 mg, 39%).

[0642] MS m / z(ESI): 584 [M+1]

[0643] 1 H NMR (400MHz, CD3OD) δ9.33(d,J=2.0Hz,1H),8.65(s,1H),8.61(d,J=2.0Hz,1H),8.40(s,1H),8.26(s,1H),8 .09(d,J=7.3Hz,1H),7.90(d,J=1.3Hz,1H),7.84(d,J=8.4Hz,1H),7.77–7.70(m,1H),7.38(d,J=1.3Hz,1H), 4.66(s,2H),3.53(dd,J=31.4,12.0Hz,2H),3.02(dd,J=12.8,9.9Hz,1H),2.76(t,J=12.0Hz,1H),2.24(dq,J =7.8,5.1Hz,1H),2.00–1.81(m,4H),1.24(dt,J=13.5,9.9Hz,1H),1.17–1.11(m,4H),1.03(d,J=6.4Hz,3H).

[0644] Example 20

[0645] (S)-1-(6-cyclopropyl-4-(6-methyl-4-(4-methyl-4H-1,2,4-triazol-3-yl)pyridin-3-yl)pyridin-2-yl)-4-((3-methylpiperidin-1-yl)methyl)benzo[cd]indol-2(1H)-one (Compound 51)

[0646]

[0647] first step

[0648] Methyl 6-methyl-3-oxo-2,3-dihydropyridazine-4-carboxylate (52b)

[0649] A 1,4-dioxane solution (30 g, 4 mol / L) of hydrogen chloride was added to a methanol (20 mL) solution of 52a (5.00 g, 32.44 mmol), and the mixture was then heated to 50 °C and stirred for 5 hours. After cooling to room temperature, the reaction mixture was concentrated to dryness under reduced pressure to give the target product 52b (5.45 g, 100%).

[0650] MS m / z (ESI): 169 [M+1]

[0651] Step 2

[0652] methyl 3-chloro-6-methylpyridazine-4-carboxylate (52c)

[0653] Phosphorus oxychloride (19.88 g, 129.6 mmol) was added to a solution of 52b (5.45 g, 32.41 mmol) in acetonitrile (50 mL), and the mixture was heated to 90 °C and stirred for 8 hours. After cooling to room temperature, the reaction mixture was concentrated to dryness under reduced pressure, and then ethyl acetate (50 mL) was added. The organic phase was washed with saturated sodium bicarbonate solution (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 0 to 5 / 1) to give the target product 52c (4.70 g, 78%).

[0654] MS m / z (ESI): 187, 189 [M+1]

[0655] Step 3

[0656] Methyl 3-(2-chloro-6-cyclopropylpyridin-4-yl)-6-methylpyridazine-4-carboxylate (52d)

[0657] 52c (1.00 g, 5.36 mmol) and 43c (1.50 g, 5.36 mmol) were dissolved in 1,4-dioxane / H₂O (27.5 mL, 10 / 1), followed by the sequential addition of Pd(dppf)Cl₂ (220 mg, 0.27 mmol) and potassium carbonate (2.22 g, 16.1 mmol). The resulting mixture was heated to 100 °C and stirred for 0.5 h under a nitrogen atmosphere. After cooling to room temperature, water (20 mL) was added to the mixture, followed by extraction with ethyl acetate (3 × 50 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 0 to 3 / 1) to give the target product 52d (1.71 g, 100%).

[0658] MS m / z (ESI): 304, 306 [M+1]

[0659] Steps 4 to 8

[0660] (S)-1-(6-cyclopropyl-4-(6-methyl-4-(4-methyl-4H-1,2,4-triazol-3-yl)pyridin-3-yl)pyridin-2-yl)-4-((3-methylpiperidin-1-yl)methyl)benzo[cd]indol-2(1H)-one (52)

[0661] 52 is synthesized according to steps three through seven of Example 15, but 41c is replaced by 52d in the operation.

[0662] MS m / z (ESI): 571 [M+1]

[0663] 1 H NMR(400MHz,DMSO-d6)δ8.66(s,1H),8.19(s,1H),8.10(s,1H),8.02(s,1H),7.91(dd,J=4.2,2.9Hz ,2H),7.78(d,J=8.4Hz,1H),7.65(dd,J=8.3,7.4Hz,1H),7.20(d,J=1.3Hz,1H),3.74(d,J=3.0Hz,2 H),3.48(s,3H),2.83(s,3H),2.76(d,J=8.6Hz,2H),2.25–2.18(m,1H),1.96(s,1H),1.62(ddd,J=1 3.3,9.7,6.7Hz,4H),1.51(s,1H),1.13–0.96(m,4H),0.86(d,J=6.8Hz,1H),0.81(d,J=6.1Hz,3H).

[0664] Compound 54 can be synthesized according to steps 2 to 8 of Example 20, but 52b is replaced with methyl 6-methyl-3-oxo-2,3-dihydropyridazine-4-carboxylate.

[0665] The characterization data of compound 54 are as follows:

[0666] MS m / z (ESI): 557 [M+1]

[0667] 1H NMR (400MHz, DMSO-d6) δ9.59(d,J=5.2Hz,1H),8.67(s,1H),8.19(s,1H),8.15(d,J=5.2Hz,1H),8.11(s,1 H),7.94(d,J=1.3Hz,1H),7.92(d,J=7.3Hz,1H),7.78(d,J=8.4Hz,1H),7.70–7.62(m,1H),7.24(d,J=1.3H z,1H),3.76(d,J=13.6Hz,2H),3.51(d,J=1.3Hz,3H),2.78(t,J=11.5Hz,2H),2.23(ddd,J=12.8,8.2,4.9H z,1H),2.03–1.90(m,1H),1.73–1.43(m,5H),1.14–0.95(m,4H),0.93–0.84(m,1H),0.81(d,J=6.1Hz,3H).

[0668] Example 21

[0669] (S)-2'-(1-hydroxycyclopropyl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)-6'-(4-((3-methylpiperidin-1-yl))methyl)-2-oxobenzo[cd]indol-1(2H)-yl)-[2,4'-bipyridine]-5-carboxynitrile (Compound 55)

[0670]

[0671] Step 1

[0672] 2-Bromo-6-(1-((tert-butyldimethylsilyl)oxy)vinyl)pyridine (55b)

[0673] Triethylamine (15.2 g, 150 mmol) and trimethylsilyl trifluoromethanesulfonate (14.5 g, 55.0 mmol) were added sequentially to a solution of 1-(6-bromopyridin-2-yl)ethane-1-one 55a (10.0 g, 50.0 mmol) in 100 mL of dichloromethane at 0 °C. After stirring at 0 °C for 1 hour, the mixture was diluted with water (100 mL) and then extracted with dichloromethane (3 × 50 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 0 to 20 / 1) to give the target product 55b (15.00 g, 95%).

[0674] MS m / z(ESI): 314,316[M+1]

[0675] Step 2

[0676] 2-Bromo-6-(1-((tert-butyldimethylsilyl)oxy)cyclopropyl)pyridine(55c)

[0677] A toluene solution of diethylzinc (64.0 mL, 127 mmol, 2 mol / L) was dissolved in dichloromethane (100 mL), then cooled to 0 °C and chloroiodomethane (44.9 g, 255 mmol) was slowly added dropwise. The resulting mixture was stirred at 0 °C for 0.5 h, and then a solution of 55b (15.2 g, 150 mmol) in dichloromethane (50 mL) was added dropwise. The resulting mixture was heated to room temperature and stirred for 12 hours, then a saturated aqueous solution of ammonium chloride (100 mL) was added, followed by extraction with dichloromethane (3 × 80 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 0 to 100 / 1) to give the target product 55c (6.50 g, 62%).

[0678] MS m / z(ESI): 328, 330 [M+1]

[0679] Step 3

[0680] 2-Bromo-6-(1-((tert-butyldimethylsilyl)oxy)cyclopropyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)pyridine (55d)

[0681] To a solution of MTBE (50 mL) containing 55c (2.70 g, 8.22 mmol), bis-pinacolborate (4.17 g, 16.4 mmol), methoxy(cyclooctadiene)iridium dimer (545 mg, 0.82 mmol), and 4,4'-di-tert-butyl-2,2'-dipyridine (441 mg, 1.64 mmol) were added sequentially. The resulting mixture was heated to 80 °C and stirred for 12 hours under a nitrogen atmosphere. After cooling to room temperature, the reaction mixture was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 0 to 100 / 1) to give the target product 55d (3.20 g, 86%).

[0682] MS m / z(ESI): 454,456 [M+1]

[0683] Step 4

[0684] 2-(2-chloro-5-iodonicotinyl)-N-methylhydrazine-1-thiocarboxamide (55f)

[0685] To a DMF (40 mL) solution of 2-chloro-5-iodonicotinic acid 55e (5.72 g, 20.1 mmol), N-methylhydrazine thioformamide (5.31 g, 50.4 mmol) and DIPEA (3.91 g, 30.3 mmol) were added sequentially. After stirring at room temperature for 10 minutes, HATU (8.44 g, 20.2 mmol) was added to the mixture. After stirring for 1 hour, water (60 mL) was added, and the mixture was then filtered. The filter cake was purified by prep-HPLC to give the target product 55f (4.50 g, 60%).

[0686] MS m / z(ESI): 371[M+1]

[0687] Step 5

[0688] 5-(2-chloro-5-iodopyridin-3-yl)-4-methyl-2,4-dihydro-3H-1,2,4-triazol-3-thione (55g)

[0689] A sodium hydroxide aqueous solution (2N, 24 mL) was added to a 55 g (4.50 g, 12.1 mmol) NMP (15 mL) solution. The resulting mixture was heated to 80 °C and stirred for 2 hours. After cooling to 0 °C, the mixture was adjusted to pH 2 with dilute hydrochloric acid (1 N) and then extracted with ethyl acetate (3 × 30 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to give 55 g (3.60 g, 84%) of the target product.

[0690] MS m / z(ESI): 353[M+1]

[0691] Step 6

[0692] 2-Chloro-5-iodo-3-(4-methyl-4H-1,2,4-triazol-3-yl)pyridine (55h)

[0693] At 0°C, glacial acetic acid (18.39 g, 306 mmol) and hydrogen peroxide (30%, 5.79 g, 51.1 mmol) were added sequentially to 55 g (3.60 g, 10.2 mmol) of dichloromethane (50 mL). The resulting mixture was heated to 35°C and stirred for 2 hours, then concentrated to dryness under reduced pressure. The residue was purified by prep-HPLC to give the target product 55 h (1.85 g, 57%).

[0694] MS m / z(ESI): 321[M+1]

[0695] Step 7

[0696] 6-Chloro-5-(4-methyl-4H-1,2,4-triazol-3-yl)nicotinonitrile (55i)

[0697] Zn(CN)₂ (407 mg, 3.46 mmol) and Pd(PPh₃)₄ (1.33 g, 1.15 mmol) were added sequentially to a 40 mL solution of DMF containing 55 h (1.85 g, 5.77 mmol). The resulting mixture was heated to 110 °C and stirred for 3 hours. After cooling to room temperature, the reaction mixture was concentrated to dryness under reduced pressure. The residue was purified by prep-HPLC to give the target product 55i (930 mg, 73%).

[0698] MS m / z(ESI): 220[M+1]

[0699] Step 8

[0700] 2'-Bromo-6'-(1-((tert-butyldimethylsilyl)oxy)cyclopropyl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)-[2,4'-[bipyridine]-5-carboxynitrile (55j)

[0701] To a mixture of 55i (675 mg, 3.07 mmol), 55d (1.67 g, 3.68 mmol), 1,4-dioxane (24 mL), and water (0.3 mL), Pd(dppf)Cl2 (251 mg, 0.31 mmol) and potassium carbonate (1.27 g, 9.21 mmol) were added sequentially. The resulting mixture was heated to 100 °C and stirred for 12 hours under a nitrogen atmosphere. After cooling to room temperature, it was diluted with water (10 mL) and then extracted with ethyl acetate (3 × 10 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 0 to 3 / 1) to give the target product 55j (420 mg, 27%).

[0702] MS m / z(ESI): 511,513[M+1]

[0703] Step 9

[0704] (S)-2'-(1-((tert-butyldimethylsilyl)oxy)cyclopropyl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)-6'-(4-((3-methylpiperidin-1-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)-[2,4'-bipyridine]-5-carboxynitrile (55k)

[0705] 55kJ (114 mg, 0.22 mmol) and 2a (80 mg, 0.20 mmol) were dissolved in 1,4-dioxane (3 mL), followed by the sequential addition of Pd2(dba)3 (28 mg, 0.031 mmol), Xantphos (35 mg, 0.061 mmol), and cesium carbonate (265 mg, 0.81 mmol). The resulting mixture was heated to 100 °C and stirred for 1 hour under a nitrogen atmosphere in a microwave reactor. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure to give the target product 55k (144 mg, crude). This product was used directly in the next reaction without purification.

[0706] MS m / z(ESI): 711[M+1]

[0707] Step 10

[0708] (S)-2'-(1-hydroxycyclopropyl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)-6'-(4-((3-methylpiperidin-1-yl))methyl)-2-oxobenzo[cd]indol-1(2H)-yl)-[2,4'-bipyridine]-5-carboxynitrile (55)

[0709] A TBAF THF solution (2 mL, 1 mol / mL) was added dropwise to a 55k (144 mg, 0.20 mmol) THF solution. The mixture was stirred for 2 hours, and the reaction solution was concentrated to dryness under reduced pressure. The residue was purified by prep-HPLC to obtain the target product 55 (35 mg, 29%).

[0710] MS m / z(ESI): 597[M+1]

[0711] 1 H NMR(400MHz,DMSO-d6)δ9.42(d,J=1.8Hz,1H),8.78(d,J=1.8Hz,1H),8.64(s,1H) ,8.19(d,J=33.5Hz,2H),7.87–7.75(m,3H),7.70(s,1H),7.64(t,J=7.7Hz,1H),6 .33(s,1H),3.97–3.68(m,2H),3.53(s,3H),3.01–2.74(m,2H),2.16–1.92(m,1H) ,1.80–1.46(m,5H),1.38–1.19(m,4H),0.97–0.87(m,1H),0.83(d,J=6.1Hz,3H).

[0712] Biological experiments

[0713] Example 14

[0714] Assay for human IL-2-driven reporter gene expression activity

[0715] Jurkat IL-2-Luc cells were constructed from the human acute T-cell leukemia cell line Jurkat, stably expressing a firefly luciferase reporter gene driven by the human IL-2 promoter. By detecting the activity of firefly luciferase, the transcriptional activation of the human IL-2-driven reporter gene under stimulation conditions can be tested. Jurkat IL-2-Luc cells were purchased from BPSBioscience (catalog number 60481).

[0716] The test compound was dissolved and diluted to 2.5 mM in DMSO (Sigma, catalog number D5879), and then serially diluted 3-fold with DMSO to a minimum concentration of 0.38 μM. Each concentration point was then diluted 62.5-fold with RPMI 1640 medium (Thermo Fisher, catalog number 11995073). If the compound EC 50 A low value can reduce the initial concentration of the compound.

[0717] Jurkat IL-2-Luc cells were cultured at 37°C in RPMI 1640 medium supplemented with a mixture of 10% FBS (ExCellBio, FSP500) and 100 units / mL penicillin-streptomycin (ThermoFisher, 15140122), and then seeded into 384-well plates (ThermoFisher, 164610) containing 30 μL of RPMI 1640 medium (1 × 10⁶ cells per well). 6 Cells / mL). After overnight culture, add 5 μL of compound solution to each well, and after 30 minutes, add 5 μL of antibody mixture [containing CD3 antibody (ThermoFisher, catalog number 16-0037-85) at a final concentration of 10 μg / mL and CD28 antibody (ThermoFisher, catalog number 16-0289-85) at a final concentration of 5 μg / mL]. Continue culturing the cells in a 37°C, 5% CO2 incubator for 6 hours, and then follow the instructions of the ONE-Glo luciferase kit (Promega, catalog number E6120): remove the cell culture plate and equilibrate to room temperature, add 20 μL of ONE-Glo reagent and mix thoroughly. After incubating at room temperature for 10 minutes, read the cold light signal at a emission wavelength of 560 nm using a microplate reader (EnVision, Perkin Elmer).

[0718] In this experiment, stimulation with a mixture of CD3 and CD28 antibodies served as the stimulation control group, while stimulation without the antibody mixture served as the baseline control group. XLfit software was used to plot the compound-induced IL-2 activation fold increase curve and calculate the corresponding EC50. 50 The values ​​and experimental results are shown in Table 1.

[0719] Table 1

[0720]

[0721]

[0722] The compounds in the embodiments of the present invention have an inhibitory effect on the activity of Cbl-b, preferably with an IC50 concentration of 100 mg / L. 50 Less than 100 nM.

Claims

1. A compound of general formula (I), or a pharmaceutically acceptable salt or stable isotopic derivative thereof: （I） in: Ring A is a benzene ring or a 6-membered heteroaromatic ring, wherein one or two hydrogens of the benzene ring and the heteroaromatic ring are optionally replaced by halogens, cyano groups, or -OC groups. 1-6 Alkyl, C 1-6 Alkyl, C 3-8 The alkyl group is substituted with a cycloalkyl or 4-8 membered heterocyclic group, wherein one or more hydrogens of the alkyl group may optionally be further substituted with D or F; Ring B is a benzene ring or a 5-6 membered heteroaromatic ring, wherein one or two hydrogens of the benzene ring or heteroaromatic ring are optionally replaced by halogens, cyano groups, -C(O)NH2, or -OC. 1-6 Alkyl, C 1-6 Alkyl or C 3-8 The alkyl group is substituted with a cycloalkyl group, wherein one or more hydrogen atoms of the alkyl group may optionally be further substituted with D or F; The ring C is a 5-6 membered heteroaromatic ring, wherein one or two hydrogens of the heteroaromatic ring are optionally replaced by halogen, cyano, oxo, or -OC. 1-6 Alkyl, C 1-6 Alkyl or C 3-8 The alkyl group is substituted with a cycloalkyl group, wherein one or more hydrogen atoms of the alkyl group may optionally be further substituted with D or F; X 1 and X 2 Each independently selected from CR 1 Or N; Z 1 Z 2 Z 3 and Z 4 Each independently selected from CR 2 Or N; L represents a bond, -O-, -NR 3 -or ; R is a halogen, cyano group, R c -OR c -NR c R d ; R 1 Halogen, cyano, R or -OR ; R 2 Halogen, cyano, R -OR or -NR R ; R 3 For H, C 1-6 Alkyl or C 3-8 cycloalkyl; R a and R b Each group is independently selected from H, D, halogens, cyano groups, -OH, and -OC. 1-6 Alkyl, C 1-6 Alkyl or C 3-8 cycloalkyl, or R a and R b Together with the carbon atoms attached to it, they can be optionally combined to form C. 3-6 Cycloalkanes or 4-8 membered heterocycles; R c and R d Each is independently selected from H and C 1-6 Alkyl, C 3-8 Cycloalkyl or 4-10 membered heterocyclic group, wherein one or more hydrogens of the alkyl, cycloalkyl, and heterocyclic group are optionally R Replaced; R and R Each is independently selected from H and C 1-6 Alkyl, C 3-8 Cycloalkyl or 4-8 membered heterocyclic group, wherein one or more hydrogens of the alkyl, cycloalkyl, or heterocyclic group are optionally replaced by D, halogen, cyano, -OH, or -OC. 1-6 Alkyl groups are substituted; and R For D, halogen, cyano, -OH, -OC 1-6 Alkyl, C 1-6 Alkyl, C 3-8 Cycloalkyl or 4-8 membered heterocyclic group, wherein one or more hydrogens of the alkyl, cycloalkyl, or heterocyclic group are optionally halogenated, cyano, -OH, or -OC. 1-6 Alkyl or C 1-6 Alkyl groups are substituted.

2. The compound according to claim 1, or its pharmaceutically acceptable salt or stable isotope derivative, wherein ring A is a benzene ring, pyridine ring, pyridazine ring, or pyrimidine ring, wherein one hydrogen atom of the benzene ring, pyridine ring, pyridazine ring, or pyrimidine ring is optionally replaced by a halogen, cyano group, CHF2, CF3, or -OC group. 1-2 Alkyl or C 1-2 Alkyl groups are substituted.

3. The compound according to any one of claims 1-2, or its pharmaceutically acceptable salt or stable isotope derivative, wherein X 1 and X 2 Each can be independently selected from CH or N.

4. The compound according to claim 1, or its pharmaceutically usable salt or stable isotope derivative, wherein Z 1 Z 2 Z 3 and Z 4 For CR 2 ; or Z 1 For N, Z 2 Z 3 and Z 4 For CR 2 ; or Z 2 For N, Z 1 Z 3 and Z 4 For CR 2 ; or Z 3 For N, Z 1 Z 2 and Z 4 For CR 2 ; or Z 4 For N, Z 1 Z 2 and Z 3 For CR 2 ; or Z 1 and Z 4 For N, Z 2 and Z 3 For CR 2 ; or Z 1 and Z 3 For N, Z 2 and Z 4 For CR 2 R 2 Halogen, cyano, R -OR or -NR R ;R and R Each is independently selected from H and C 1-6 Alkyl or C 3-8 Cycloalkyl, wherein one or more hydrogens of the alkyl or cycloalkyl group are optionally replaced by D, halogen, cyano, -OH or -OC. 1-6 Alkyl groups are substituted.

5. The compound according to claim 1, or its pharmaceutically usable salt or stable isotope derivative, wherein L is... ;R a and R b Each element is independently selected from H, D, halogens, or C. 1-6 Alkyl; R is R c -OR c -NR c R d ;R c and R d Each is independently selected from H and C 1-6 Alkyl, C 3-8 Cycloalkyl or 4-10 membered heterocyclic group, wherein one or more hydrogens of the alkyl, cycloalkyl, and heterocyclic group are optionally R Replaced; R For D, halogen, cyano, -OH, -OC 1-6 Alkyl, C 1-6 Alkyl, C 3-8 Cycloalkyl, 4-8 membered heterocyclic groups, wherein one or more hydrogens of the alkyl, cycloalkyl, or heterocyclic group are optionally halogenated, cyano, -OH, or -OC. 1-6 Alkyl or C 1-6 Alkyl groups are substituted.

6. The compound according to claim 1, or its pharmaceutically usable salt or stable isotope derivative, wherein the compound is a compound represented by general formula (II): (II) in: R 11 For H, C 1-6 Alkyl, C 3-8 Cycloalkyl or 4-8 membered heterocyclic group, wherein one or more hydrogens of the alkyl, cycloalkyl, and heterocyclic group are optionally R Replaced; R 12 For H, C 1-6 Alkyl or C 3-8 cycloalkyl; R 11 and R 12 Together with the nitrogen atom attached thereto, they optionally form 4-10 membered heterocycles optionally containing an additional O or N heteroatom, including but not limited to aziridine, pyrrolidine, piperidine, aziridine-heptane, morpholine, piperazine, etc. , , , or One or more hydrogen atoms of the heterocycle may be optionally replaced by D, halogen, cyano, -OH, or -OC. 1-6 Alkyl, C 1-6 Alkyl or C 3-8 The alkyl group is replaced by a cycloalkyl group, wherein one or more hydrogen atoms of the alkyl group may optionally be further replaced by a halogen, cyano, -OH, or -OC group. 1-6 Alkyl or C 1-6 Alkyl groups are substituted. Ring A, Ring B, Ring C, X 1 X 2 Z 1 Z 2 Z 3 Z 4 R a R b and R As defined in any one of claims 1-5.

7. The compound according to claim 1, or its pharmaceutically usable salt or stable isotope derivative, wherein it is a compound represented by general formula (III): (III) in: Ring C is a five-membered heteroaryl ring, including but not limited to , , , or ; Y 1 Y 2 and Y 3 Each can be independently selected from CH or N; R 13 H, halogen, cyano, -C(O)NH2, -OC 1-6 Alkyl, C 1-6 Alkyl or C 3-8 Cycloalkyl, wherein one or more hydrogens of the alkyl group are optionally replaced by D or F; R 14 For H, C 1-6 Alkyl or C 3-8 Cycloalkyl, wherein one or more hydrogens of the alkyl group are optionally substituted with D; Rings A and X 1 X 2 Z 1 Z 2 Z 3 Z 4 R 11 R 12 R a R b As defined in any one of claims 1-6.

8. The compound according to claim 1, wherein the compound is selected from the following compounds or their pharmaceutically acceptable salts: ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， 。 9. A pharmaceutical composition comprising the compound of any one of claims 1-8 or a pharmaceutically acceptable salt thereof, a stable isotope derivative thereof, and a pharmaceutically acceptable carrier or excipient.

10. Use of the compound or its pharmaceutically usable salt or stable isotope derivative according to any one of claims 1-8 in the preparation of a medicament for the prevention or treatment of Cbl-b-mediated diseases, wherein the Cbl-b-mediated diseases are leukemia, lymphoma, myeloma, glioma, thyroid cancer, head and neck cancer, pancreatic cancer, lung cancer, colon cancer, liver cancer, bile duct cancer, gastric cancer, esophageal cancer, kidney cancer, prostate cancer, bladder cancer, breast cancer, ovarian cancer, cervical cancer, uterine cancer, endometrial cancer, urothelial carcinoma, muscle cancer, or bone cancer.

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