Kinase inhibitors

Abstract

This invention provides IH-indole-7-carboxamide derivatives as protein kinase inhibitors, particularly Bruton's tyrosine kinase (BTK) inhibitors, pharmaceutical compositions containing them, and the use of such protein kinase inhibitors for treating or preventing diseases, disorders, and conditions related to kinase function. [Solution] A compound having the structure of formula (II), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof is provided. JPEG2026048716000342.jpg4845

Description

[Technical Field]

[0001] The present invention generally relates to protein kinase inhibitors, particularly Bruton tyrosine kinase (BTK) inhibitors, pharmaceutical compositions containing them, processes for preparing them, and the use of such inhibitors for treating or preventing diseases, disorders, and conditions related to kinase function. [Background technology]

[0002] Protein kinases are a large group of intracellular and transmembrane signaling proteins in eukaryotic cells. These enzymes are responsible for the transfer of terminal (gamma) phosphate from ATP to specific amino acid residues of target proteins. Phosphorylation of specific amino acid residues in target proteins can modulate their activity, leading to significant changes in cellular signaling and metabolism. Protein kinases can be found in organelles such as the cell membrane, cytosol, and nucleus, and are responsible for mediating multiple cellular functions, including metabolism, cell growth and differentiation, cellular signaling, regulation of immune responses, and cell death. Serine kinases specifically phosphorylate serine or threonine residues in target proteins. Similarly, tyrosine kinases, including tyrosine receptor kinases, phosphorylate tyrosine residues in target proteins. The tyrosine kinase family includes TEC, SRC, ABL, JAK, CSK, FAK, SYK, FER, ACK, and the receptor tyrosine kinase subfamily, which includes ERBB, FGFR, VEGFR, RET, and EPH. Subclass I of the receptor tyrosine kinase superfamily includes the ERBB receptor and comprises four members: ErbB1 (also known as the epidermal growth factor receptor, EGFR), ErbB2, ErbB3, and ErbB4.

[0003] Kinases exert control over key biological processes related to health and disease. Furthermore, abnormal activation or overexpression of various protein kinases is involved in the mechanisms of multiple diseases and disorders characterized by benign and malignant proliferation, as well as diseases resulting from inappropriate activation of the immune system. Therefore, inhibitors of selective kinases or kinase families are considered useful in the treatment of cancer, vascular diseases, autoimmune diseases, and inflammatory conditions, including but not limited to solid tumors, hematological malignancies, thrombosis, arthritis, graft-versus-host disease, lupus erythematosus, psoriasis, colitis, ileitis, multiple sclerosis, uveitis, coronary artery disease, systemic sclerosis, atherosclerosis, asthma, transplant rejection, allergies, ischemia, dermatomyositis, and pemphigus.

[0004] Tec kinases are a family of non-receptor tyrosine kinases that are expressed primarily, though not exclusively, in hematopoietic cells. The Tec family includes TEC, Bruton's tyrosine kinase (BTK), inducible T-cell kinase (ITK), resting lymphocyte kinase (TXK in the case of RLK / tyrosine protein kinase), and bone marrow-expressed kinase (BMX / ETK).

[0005] BTK is important in regulating B cell receptor signaling and B cell development and activation. Mutations in the gene encoding BTK in humans lead to X-linked agammaglobulinemia, characterized by impaired immune function, including impaired B cell maturation, decreased levels of immunoglobulins and peripheral B cells, and reduced T cell-independent immune responses. BTK is activated by Src family kinases and phosphorylates PLC gamma, affecting B cell function and survival. Furthermore, BTK is important for the cellular function of mast cells, macrophages, and neutrophils, and BTK inhibition has been shown to be effective in treating diseases mediated by these cells and related cells, including inflammation, bone disorders, and allergic diseases. BTK inhibition is also important for the survival of lymphoma cells, and BTK inhibition has been shown to be useful in the treatment of lymphoma and other cancers. Therefore, inhibitors of BTK and related kinases are of great interest as anti-inflammatory and anticancer agents. BTK is also important for platelet function and thrombus formation, and BTK selective inhibitors have also been shown to be useful as antithrombotic agents. Furthermore, BTK is required for inflammasome activation, and inhibition of BTK may be used to treat inflammasome-related disorders, including stroke, gout, type 2 diabetes, obesity-induced insulin resistance, atherosclerosis, and Muckle-Wells syndrome. In addition, BTK is expressed in HIV-infected T cells, and treatment with BTK inhibitors sensitizes infected cells to apoptosis and leads to a decrease in viral production. Therefore, BTK inhibitors are considered useful in the treatment of HIV-AIDS and other viral infections.

[0006] Furthermore, BTK is important for neurological function. Specifically targeting BTK in the brain and CNS has the potential to significantly advance the treatment of neurological disorders such as progressive and relapsing MS and primary CNS lymphoma (PCNSL).

[0007] PCNSL is a rare brain tumor in the United States, with approximately 1,900 new cases reported annually, accounting for about 3% of newly diagnosed brain tumors.

[0008] PCNSL is highly invasive, and unlike other lymphomas outside the CNS, the prognosis remains poor despite improvements in state-of-the-art treatments. High-dose methotrexate remains the main component of treatment, used in combination with other cytotoxic agents, and more recently, rituximab has been added. From initial diagnosis, the 5-year survival rate improved from 19% to 30% between 1990 and 2000, but this improvement has not been seen in the elderly population (over 70 years), as more than 20% of these patients are considered unsuitable for chemotherapy. Tumor regression was observed in approximately 85% of patients, regardless of whether state-of-the-art treatment modalities were used, but about half of these patients experienced recurrent disease within 10–18 months after initial treatment, with the majority of relapses occurring within the first two years of diagnosis.

[0009] Therefore, the prognosis for patients with relapsed / refractory PCNSL (R / R PCNSL) remains poor, with a median survival time of approximately 2 months if no further treatment is given. Since there is no uniform standard treatment for R / R PCNSL, participation in clinical trials is encouraged. New, safe, and effective treatments are urgently needed.

[0010] Btk is involved in signaling in the B cell antigen receptor (BCR) signaling pathway and integrates BCR and Toll-like receptor (TLR) signaling. Genes in these pathways frequently carry mutations in diffuse large B-cell lymphoma (DLBCL), including CD79B and myelodifferentiation primary response 88 (MyD88). Ibrutinib, a first-generation irreversible selective inhibitor of Btk, is approved for chronic lymphocytic leukemia / small cell lymphocytic lymphoma (CLL / SLL), previously treated mantle cell lymphoma (MCL) and marginal zone lymphoma (MZL), Waldenstrom's macroglobulinemia, and previously treated chronic graft-versus-host disease. In clinical studies, the recommended dose of ibrutinib (480 mg / day for CLL and 560 mg / day for MCL) was escalated to 840 mg to achieve appropriate brain exposure in primary CNS lymphomas.

[0011] Abnormal activation of the NF-κB pathway in PCNSL is emerging as a potential mechanism for more targeted therapies. In particular, activating mutations in CARD11 and MyD88 (Toll-like receptor pathway) are involved. The leucine-to-proline activating exchange at position 265 of MyD88, which is reported to occur in 38% (11 / 29) to 50% (7 / 14) of patients, is the most frequent mutation identified to date in PCNSL. In addition, the coding region of CD79B, a component of the B cell receptor signaling pathway, appears to contain mutations in 20% of cases, suggesting that dysregulation of the B cell receptor and NF-κB pathway contributes to the pathogenesis of PCNSL. These data suggest that BCR pathway mutations and Btk dependence are particularly associated with PCNSL.

[0012] Recently, several clinical studies have reported substantial monotherapy clinical activity in the treatment of PCNSL with response rates of 70–77%. However, the majority of patients discontinued therapy by 9 months. Ibrutinib therapy has been reported to be generally well-tolerated with manageable adverse events, although there have been occasional reports of fatal fungal infections. Notably, escalating doses exceeding 560 mg–840 mg / day have been used to achieve higher brain exposure, and these higher doses may be associated with off-target effects mediated by ibrutinib's kinase selectivity profile. Finally, the combination of high-dose ibrutinib with high-dose steroids may contribute to increased exacerbation of fungal infections. Therefore, second-generation Btk inhibitors with improved efficacy and safety profiles due to greater brain penetration and Btk inactivation rates with greater kinase selectivity may be beneficial for PCNSL patients.

[0013] In addition, there is still a need for compounds that modulate protein kinases in general, as well as compounds that modulate specific protein kinases such as BTK, as well as compounds that modulate specific protein kinases and selectively cross the blood-brain barrier for related compositions, and methods for treating diseases, disorders, and conditions that would benefit from such modulation and selectivity. [Overview of the project]

[0014] In one embodiment, a compound having the structure of formula (I),

[0015] [ka] And in the formula,

[0016] [ka] However, it represents a single bond or a double bond, R 1is -H, -CH3, or -F, R 2 is -H, -CH3, or -F, or alternatively R 1 and R 2 together with the C atom to which they are attached form a C 3-6 membered carbocyclic ring, R I1 is -Cl, -F, -CN, -CH3, -CH2F, -CHF2, or -CF3, R I2 is -H or -F, R B is -CH=CH2, -C≡CH, or -C≡C-CH3, R I1 when is -CH3, R 1 and R 2 at least one of is -CH3 or -F, a compound, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof is provided. [[ID=3​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​3 Together they form an alkylene crosslink, R II1 However, it is Cl, F, -CH2F, -CHF2, -CF3, or -CN, R II2 However, it is H or F, R B The present invention provides compounds that are -CH=CH2, -C≡CH, or -C≡C-CH3, or pharmaceutically acceptable salts, solvates, hydrates, isomers, tautomers, racemates, or isotopes thereof.

[0019] In yet another embodiment, a compound having the structure of formula (III),

[0020] [ka] And in the formula, Z is -CH2-, -CHMe-, or a bond. Y, -CHR 4 -or combination, R 4 However, it is H, F, or OH, R 5 However, it is H, F, or Me, R 6 However, it is either H or Me, R 7 However, it is either H or Me, R 8 Is it H? Or R 5 and R 7 However, together they form a 5-membered or 6-membered heterogeneous ring, Or R 6 and R 7 However, when combined, they form a 4-member, 5-member, or 6-member complex ring, Or R 8 and R 7 However, together they form a 5-membered or 6-membered complex ring. a is 0, 1, or 2, R III1However, it is either Cl, F, -CH2F, -CHF2, -CF3, or -CN, R 4 When is F or OH, or R 5 When F, or R 5 and R 7 Or R 8 and R 7 However, when they come together to form a 5- or 6-membered heterocyclic ring, or R 6 and R 7 However, when they come together to form a 4, 5, or 6-membered complex ring, R III1 is -CH3, R III2 However, it is H or F, R B The present invention provides compounds that are -CH=CH2, -C≡CH, or -C≡C-CH3, or pharmaceutically acceptable salts, solvates, hydrates, isomers, tautomers, racemates, or isotopes thereof.

[0021] In one embodiment, a pharmaceutical composition is provided comprising a compound having the structure of formula (I), formula (II), or formula (III), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, and at least one pharmaceutically acceptable excipient.

[0022] In one embodiment, a method for modulating a protein kinase is provided, comprising contacting the protein kinase with an effective amount of a compound having the structure of formula (I), formula (II), or (III), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, isotope, or pharmaceutical composition thereof. In one embodiment, the protein kinase is BTK.

[0023] In one embodiment, a method is provided for treating a BTK-dependent condition, comprising administering to a subject in need an effective amount of a compound having the structure of formula (I), formula (II), or formula (III), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, isotope, or pharmaceutical composition thereof.

[0024] In one embodiment, the use of a compound having the structure of formula (I), formula (II), or formula (III), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, isotope, or pharmaceutical composition thereof in the manufacture of a pharmaceutical product is provided. [Modes for carrying out the invention]

[0025] Unless otherwise specified, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art in the field to which the subject matter described in the claims pertains. It should be understood that detailed descriptions are illustrative and descriptive only and do not limit any subject matter described in the claims. In this application, unless otherwise specified, the use of singular nouns includes plural nouns. It should be noted that, when used herein, the singular nouns "a," "an," and "the" refer to multiple objects unless otherwise explicitly indicated by the context. In this application, the use of "or" means "and / or" unless otherwise specified. Furthermore, the use of the term "including," as well as other forms such as "include," "includes," and "included," is not limited to these terms.

[0026] Various features of the present invention can be described in the context of a single embodiment, but these features can also be provided separately or in any preferred combination. Conversely, the present invention can be described herein in the context of separate embodiments for clarity, but the present invention can also be implemented in a single embodiment.

[0027] References to “several embodiments,” “embodiment,” “one embodiment,” or “other embodiments” in this specification mean that certain characteristics, structures, or features described in relation to an embodiment are included in at least some embodiments, but not necessarily in all embodiments.

[0028] As used herein, ranges and quantities can be expressed as "approximately" a specific value or range. "Approximately" also includes the exact quantity. Therefore, "approximately 100 μL" means both "approximately 100 μL" and "100 μL". In some embodiments, "approximately" means within 5% of the value. Therefore, "approximately 100 μL" means 95 to 105 μL. Generally, the term "approximately" includes quantities that would be expected to be within experimental error.

[0029] As used herein, “alkyl” means a linear or branched saturated hydrocarbon group. “Lower alkyl” means a linear or branched alkyl group having 1 to 8 carbon atoms, 1 to 6 carbon atoms in some embodiments, 1 to 4 carbon atoms in some embodiments, and 1 to 2 carbon atoms in some embodiments. Examples of linear lower alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl groups. Examples of branched lower alkyl groups include, but are not limited to, isopropyl, iso-butyl, sec-butyl, t-butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl groups.

[0030] The "alkenyl" group includes the linear and branched chains, as well as cyclic alkyl groups, as defined above, except that at least one double bond is present between two carbon atoms. Thus, alkenyl groups have 2 to about 20 carbon atoms, typically 2 to 12 carbon atoms, or in some embodiments 2 to 8 carbon atoms. Examples include, in particular, -CH=CH2, -CH=CH(CH3), -CH=C(CH3)2, -C(CH3)=CH2, -C(CH3)=CH(CH3), -C(CH2CH3)=CH2, -CH=CHCH2CH3, -CH=CH(CH2)2CH3, -CH=CH(CH2)3CH3, -CH=CH(CH2)4CH3, vinyl, cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, and hexadienyl.

[0031] The "alkynyl" group includes linear and branched alkyl groups, except that at least one triple bond exists between two carbon atoms. Thus, the alkynyl group has 2 to about 20 carbon atoms, typically 2 to 12 carbon atoms, or in some embodiments 2 to 8 carbon atoms. Examples include, but are not limited to, -C≡CH, -C≡C(CH3), -C≡C(CH2CH3), -CH2C≡CH, -CH2C≡C(CH3), and -CH2C≡C(CH2CH3).

[0032] As used herein, “alkylene” means a divalent alkyl group. Examples of linear lower alkylene groups include, but are not limited to, methylene (i.e., -CH2-), ethylene (i.e., -CH2CH2-), propylene (i.e., -CH2CH2CH2-), and butylene (i.e., -CH2CH2CH2CH2-). As used herein, “heteroalkylene” is an alkylene group in which one or more carbon atoms are replaced by heteroatoms such as (but not limited to) N, O, S, or P.

[0033] "Alkoxy" refers to alkyl groups, as defined above, that are bonded by an oxygen atom (i.e., -O-alkyl). Examples of lower alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, n-butoxy, isopropoxy, sec-butoxy, and tert-butoxy.

[0034] The terms "carbocyclic" and "carbocyclic" refer to a ring structure in which the ring atoms are carbon. A carbocyclic can be monocyclic or polycyclic. Carbocyclics include both saturated and unsaturated rings. Carbocyclics include both cycloalkyl groups and aryl groups. In some embodiments, a carbocyclic has 3 to 8 ring members, while in other embodiments, the number of ring carbon atoms is 4, 5, 6, or 7. Unless otherwise specifically indicated, a carbocyclic ring can be substituted with up to N substituents, where N is the size of the carbocyclic ring, and substitutions can be, for example, alkyl groups, amino groups, hydroxyl groups, cyano groups, carboxyl groups, nitro groups, thio groups, alkoxy groups, and halogen groups.

[0035] A "cycloalkyl" group is an alkyl group that forms a ring structure and may be substituted or unsubstituted. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In some embodiments, the cycloalkyl group has 3 to 8 ring members, while in other embodiments, the number of ring carbon atoms is in the range of 3 to 5, 3 to 6, or 3 to 7. Further examples of cycloalkyl groups include polycyclic cycloalkyl groups such as norbornyl, adamantyl, bornyl, camphenyl, isocamphenyl, and calenyl groups (but are not limited to these), as well as fused rings such as dekalinyl (but are not limited to these). Cycloalkyl groups also include rings substituted with linear or branched alkyl groups as defined above. Typical substituted cycloalkyl groups include monosubstituted or disubstituted cyclohexyl groups, such as 2,2-disubstituted, 2,3-disubstituted, 2,4-disubstituted, 2,5-disubstituted, or 2,6-disubstituted (but not limited to these), or monosubstituted, disubstituted, or trisubstituted norbornyl or cycloheptyl groups that can be substituted with, for example, amino groups, hydroxyl groups, cyano groups, carboxyl groups, nitro groups, thio groups, alkoxy groups, and halogen groups.

[0036] An "aryl" group is a cyclic aromatic hydrocarbon that does not contain heteroatoms. Therefore, examples of aryl groups include, but are not limited to, phenyl, azlenyl, heptarenyl, biphenyl, indacenyl, fluorenyl, phenantrenyl, triphenylenyl, pyrenyl, naphthacenyl, chrysenyl, biphenylenyl, anthracenyl, and naphthyl groups. In some embodiments, the aryl group contains 6 to 14 carbon atoms in the ring portion of the group. The terms "aryl" and "aryl group" include fusion rings in which at least one ring is aromatic, but which do not need to be entirely ring-abandoned groups, such as fusion aromatic aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, etc.).

[0037] A "carbocyclic alkyl group" refers to an alkyl group defined above in which one or more hydrogen atoms are replaced by a carbocyclic ring. Examples of carbocyclic alkyl groups include benzyl, but are not limited to these.

[0038] As used herein, a “heterocyclic” group refers to an aromatic and non-aromatic ring compound (heterocyclic) containing three or more ring members, wherein one or more of the ring members are heteroatoms such as (but not limited to) N, O, S, or P. A heterocyclic group as defined herein may be a heteroaryl group or a partially or fully saturated cyclic group containing at least one ring heteroatom. In some embodiments, a heterocyclic group contains 3 to 20 ring members, while other such groups have 3 to 15 ring members. At least one ring contains a heteroatom, but not all rings in a polycyclic system need to contain a heteroatom. For example, both the dioxolanyl ring and the benzodioxolanyl ring system (methylenedioxyphenyl ring system) are heterocyclic groups within the meaning of this specification. A heterocyclic group represented as a C2-heterocyclic ring can be a five-membered ring with two carbon atoms and three heteroatoms, a six-membered ring with two carbon atoms and four heteroatoms, and so on. Similarly, a C4-heterocyclic ring can be a five-membered ring with one heteroatom, a six-membered ring with two heteroatoms, and so on. The sum of the number of carbon atoms and the number of heteroatoms equals the total number of ring atoms. A saturated heterocyclic ring refers to a heterocyclic ring that does not contain unsaturated carbon atoms.

[0039] A "heteroaryl" group is an aromatic ring compound containing five or more ring members, wherein one or more of the ring members are heteroatoms such as N, O, and S (but not limited to these). A heteroaryl group designated as C2-heteroaryl may be a five-membered ring having two carbon atoms and three heteroatoms, a six-membered ring having two carbon atoms and four heteroatoms, etc. Similarly, a C4-heteroaryl may be a five-membered ring having one heteroatom, a six-membered ring having two heteroatoms, etc. The sum of the number of carbon atoms and the number of heteroatoms is equal to the total number of ring atoms. Examples of heteroaryl groups include, but are not limited to, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, prinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, quinoxalinyl, and quinazolinyl groups. The terms "heteroaryl" and "heteroaryl group" include fused ring compounds in which at least one ring is aromatic, such as tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolyl, and 2,3-dihydroindolyl, though not all rings are included.

[0040] A "heterocyclic alkyl" refers to an alkyl group defined above that has one or more hydrogen atoms substituted by a heterocycle. Examples of heterocyclic alkyl groups include, but are not limited to, morpholinoethyl.

[0041] "Halo" or "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0042] A "haloalkyl" refers to an alkyl group defined above in which one or more hydrogen atoms are substituted with halogens. Examples of lower haloalkyl groups include, but are not limited to, -CF3 and -CH2CF3.

[0043] A "haloalkoxy" refers to an alkoxy group defined above in which one or more hydrogen atoms are substituted with halogens. Examples of lower haloalkoxy groups include, but are not limited to, -OCF3 and -OCH2CF3.

[0044] "Hydroxyalkyl" refers to the alkyl group defined above, in which one or more hydrogen atoms are replaced by -OH groups. Examples of lower hydroxyalkyl groups include, but are not limited to, -CH2OH and -CH2CH2OH.

[0045] As used herein, the term “optionally substituted” refers to a group having 0, 1, or more substituents, e.g., 0 to 25, 0 to 20, 0 to 10, or 0 to 5 substituents (e.g., alkyl, carbocyclic, or heterocyclic). Substituents include -OR a , -NR a R b -S(O)2R a , or -S(O)2OR a Examples include, but are not limited to, halogens, cyano, alkyl, haloalkyl, alkoxy, carbocyclic, heterocyclic, carbocyclic alkyl, or heterocyclic alkyl, in the formula each R a and R b Independently, these are H, alkyl, haloalkyl, carbocyclic, or heterocyclic, or R a and R b These atoms, together with the atoms to which they are bonded, form a 3- to 8-membered carbon ring or heterocycle.

[0046] The term "isomer" is used herein to encompass all chiral, diastereomer, or racemic forms of a given structure unless a specific stereochemistry or isomeric form is specifically indicated. Such compounds may be optical isomers concentrated or decomposed at any or all chiral atoms, as is evident from the description, at any degree of enrichment. Both racemic and diastereomer mixtures, as well as individual optical isomers, can be synthesized such that they substantially do not contain their enantiomer or diastereomer partner, all of which are within the scope of the specific embodiments of this disclosure. Isomers arising from the presence of a chiral center include a pair of non-superimal isomers, called "enantiomers." A single enantiomer of a pure compound is optically active (i.e., they can rotate the plane of plane-polarized light and are called R or S).

[0047] "Isolated optical isomer" means a compound substantially purified from the corresponding optical isomer of the same formula. For example, the isolated isomer may have a purity of at least about 80%, at least 80%, or at least 85%. In other embodiments, the isolated isomer may have a purity of at least 90% by weight, at least 98% by weight, or at least 99% by weight.

[0048] "Substantially enantiomerically or diastereomerically" pure means a level of enantiomeric or diastereomeric enrichment of one enantiomer relative to the other enantiomer or diastereomer of at least about 80%, more specifically 80%, 85%, 90%, 95%, 98%, 99%, 99.5%, or 99.9%.

[0049] The terms "racemate" and "racemic mixture" refer to an equal mixture of two enantiomers. Racemates are labeled "(±)" because they are not optically active (i.e., their constituent enantiomers cancel each other out and therefore do not rotate plane-polarized light in any direction).

[0050] A "hydrate" is a compound that exists in combination with water molecules. This combination may contain a stoichiometric amount of water, such as a monohydrate or dihydrate, or a random amount of water. As used herein, "hydrate" refers to the solid form. That is, a compound in an aqueous solution can be hydrated, but it is not a hydrate in the sense as the term is used herein.

[0051] A “solvate” is similar to a hydrate, except that a solvent other than water is present. For example, methanol or ethanol can form an “alcoholic acid,” which can again be stoichiometric or non-stoichiometric. As used herein, “solvate” refers to the solid form. That is, a compound in a solvent solution can be solvated, but it is not a solvate as the term is used herein.

[0052] An "isotope" refers to an atom that has the same number of protons but a different number of neutrons. The isotopes of the compound in formula (I) include any such compound in which one or more atoms are replaced by isotopes of that atom. For example, carbon-12 (the most common form of carbon) has 6 protons and 6 neutrons, carbon-13 has 6 protons and 7 neutrons, and carbon-14 has 6 protons and 8 neutrons. Hydrogen has two stable isotopes: deuterium (1 proton and 1 neutron) and tritium (1 proton and 2 neutrons). Fluorine has several isotopes, but fluorine-19 is the longest-lived. Therefore, isotopes of compounds having the structure of formula (I) include, but are not limited to, compounds of formula (I) in which one or more carbon-12 atoms are replaced by carbon-13 and / or carbon-14 atoms, compounds of formula (I) in which one or more hydrogen atoms are replaced by deuterium and / or tritium, and / or compounds of formula (I) in which one or more fluorine atoms are replaced by fluorine-19.

[0053] The term "salt" generally refers to an organic compound in ionic form, combined with a counterion, such as a carboxylic acid or amine. For example, a salt formed between an anionic acid and a cation is called an "acid addition salt." Conversely, a salt formed between a cationic base and an anion is called a "base addition salt."

[0054] The term "medically acceptable" refers to a drug that is approved for human consumption and is generally non-toxic. For example, the term "medically acceptable salt" refers to a non-toxic inorganic or organic acid and / or base addition salt (see, e.g., Lit et al., Salt Selection for Basic Drugs, Int. J. Pharm., 33, 201-217, 1986) (this document is incorporated herein by reference).

[0055] pharmaceutically acceptable base addition salts of the compounds of this disclosure include metal salts, such as alkali metal salts, alkaline earth metal salts, and transition metal salts, such as calcium salts, magnesium salts, potassium salts, sodium salts, and zinc salts. Examples of pharmaceutically acceptable base addition salts include organic salts made from basic amines, such as N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine.

[0056] Medicinally acceptable acid addition salts can be prepared from inorganic or organic acids. Examples of inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, sulfuric acid, and phosphoric acid. Suitable organic acids can be selected from the aliphatic, alicyclic, aromatic, aromaticaliphatic, heterocyclic, carboxylic acid, and sulfonic acid classes of organic acids, examples of which include formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, glucuronic acid, maleic acid, fumaric acid, pyruvic acid, aspartic acid, glutamic acid, benzoic acid, anthranilic acid, 4-hydroxybenzoic acid, and f(x) Examples include phenylacetic acid, mandelic acid, hippuric acid, malonic acid, oxalic acid, embonic (pamoic acid), methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, pantothenic acid, trifluoromethanesulfonic acid, 2-hydroxyethanesulfonic acid, p-toluenesulfonic acid, sulfanilic acid, cyclohexylaminosulfonic acid, stearic acid, alginic acid, β-hydroxybutyric acid, salicylic acid, galactaric acid, and galacturonic acid.

[0057] While pharmaceutically unacceptable salts are generally not useful as pharmaceuticals, such salts may be useful, for example, as intermediates in the synthesis of the compounds described herein, or in their purification by recrystallization.

[0058] In certain embodiments, the Disclosure provides pharmaceutical compositions comprising a compound described herein, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, together with at least one pharmaceutically acceptable carrier, diluent, or excipient. For example, the active compound is typically mixed with a carrier, diluted by a carrier, or encapsulated in a carrier, which may be in the form of an ampoule, capsule, sachet, paper, or other container. When the active compound is mixed with a carrier, or when the carrier functions as a diluent, it may be a solid, semi-solid, or liquid material that functions as a vehicle, excipient, or medium for the active compound. The active compound may be adsorbed onto a granular solid carrier, for example, contained in a sachet. Some examples of suitable carriers include water, salt solutions, alcohol, polyethylene glycol, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, clay, sucrose, dextrin, magnesium carbonate, sugar, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid, or cellulose, silicic acid, fatty acids, fatty acid amines, lower alkyl ethers of fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose, and polyvinylpyrrolidone. Similarly, any sustained-release material known in the art, such as glyceryl monostearate or glyceryl distearate, can be used as a carrier or diluent, either alone or in combination with wax.

[0059] As used herein, the term “pharmaceutical composition” means a composition containing one or more of the compounds described herein, or their pharmaceutically acceptable isomers, racemates, hydrates, solvates, homologs, or salts, formulated with a pharmaceutically acceptable carrier (which may include other additives), and manufactured or marketed with the approval of a government regulatory body as part of a therapeutic regimen for the treatment of diseases in mammals. Pharmaceutical compositions may be formulated, for example, in unit dosage forms for oral administration (e.g., as tablets, capsules, caplets, gel caps, or syrups), for topical administration (e.g., as creams, gels, lotions, or ointments), for intravenous administration (e.g., in sterile solutions free of particulate embolisms and solvent systems suitable for intravenous use), or in any other formulations described herein. Conventional procedures and components for selecting and preparing suitable formulations are described, for example, in Remington: The Science and Practice of Pharmacy, 21st Ed., Gennaro, Ed., Lippencott Williams & Wilkins (2005) and the United States Pharmacopeia: The National Formulary (USP 36 NF31) (published in 2013).

[0060] In other embodiments, methods are provided for preparing compositions of the compounds described herein, comprising formulating the compounds of the disclosed herein using a pharmaceutically acceptable carrier or diluent. In some embodiments, the pharmaceutically acceptable carrier or diluent is suitable for oral administration. In some such embodiments, the method may further include the step of formulating the composition into tablets or capsules. In other embodiments, the pharmaceutically acceptable carrier or diluent is suitable for parenteral administration. In some such embodiments, the method may further include the step of lyophilizing the composition to form a lyophilized preparation.

[0061] As used herein, the term “pharmaceutically acceptable carrier” means any component other than the disclosed compound or its pharmaceutically acceptable isomers, racemates, hydrates, solvates, homologs, or salts (e.g., a carrier capable of suspending or dissolving the active compound) that has non-toxic and non-inflammatory properties in the patient. Examples of excipients include anti-tackifiers, antioxidants, binders, coatings, compression aids, disintegrants, dyes (pigments), emollients, emulsifiers, fillers (diluents), film-forming agents or coatings, flavoring agents, fragrances, lubricants (flow enhancers), preservatives, printing inks, adsorbents, suspending agents or dispersants, sweeteners, or hydration water. Examples of excipients include, but are not limited to, butylated hydroxytoluene (BHT), calcium carbonate, dibasic calcium phosphate, calcium stearate, croscarmellose, cross-linked polyvinylpyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methylparaben, microcrystalline cellulose, polyethylene glycol, polyvinylpyrrolidone, povidone, pregelatinized starch, propylparaben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethylcellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn starch), stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol.

[0062] The formulation can be mixed with auxiliary agents that do not react in a way that adversely affects the active compound. Such additives may include wetting agents, emulsifiers and suspending agents, salts to affect osmotic pressure, buffers and / or colorants, preservatives, sweeteners, or flavoring agents. The composition may also be sterilized as needed.

[0063] The route of administration may be any route that effectively delivers the active compound of this disclosure to an appropriate or desired site of action, such as orally, intranasally, in the lungs, in the cheeks, subdermally, intradermally, transdermally, or parenterally, for example, rectally, in a depot, subcutaneously, intravenously, intraurethrally, intramuscularly, intranasally, in ophthalmic solution, or ointment, but the oral route is preferred.

[0064] The dosage form may be administered once daily, or more than twice daily, for example, twice or three times daily. Alternatively, the dosage form may be administered less frequently than once daily, for example, once every two days or once a week, if the prescribing physician deems it appropriate. The administration regimen may include, for example, a dose setting that is necessary or useful for the indication being treated, thereby enabling the patient's body to adapt to the treatment and / or minimizing or avoiding undesirable side effects associated with the treatment. Other dosage forms include delayed-release or controlled-release forms. Suitable administration regimens and / or forms include, for example, those described in the latest edition of the Physicians' Desk Reference, which is incorporated herein by reference.

[0065] As used herein, the terms “administer” or “dosage” mean to provide a subject with a compound, or a pharmaceutical composition containing the compound, by any acceptable means or route, including (for example) oral, parenteral (for example) or intravenous, or topical administration.

[0066] As used herein, the term “treatment” refers to an intervention that improves the signs or symptoms of a disease or pathological condition. As used herein, the terms “treatment,” “to treat,” and “to treat” with respect to a disease, pathological condition, or symptoms also refer to any observable beneficial effect of such treatment. Beneficial effects may be demonstrated, for example, by delaying the onset of clinical symptoms of a disease in a susceptible subject, by reducing the severity of some or all clinical symptoms of the disease, by slower progression of the disease, by reducing the number of disease relapses, by improving the subject’s overall health or well-being, or by other parameters well known in the art that are specific to a particular disease. Preventive treatment is a treatment administered to a subject who shows no signs of the disease or only early signs, with the aim of reducing the risk of the symptoms developing and progressing. Therapeutic treatment is a treatment administered to a subject after the signs and symptoms of the disease have developed and progressed.

[0067] As used herein, the term “subject” refers to an animal (e.g., a mammal such as a human). Subjects treated according to the methods described herein may be subjects diagnosed with a neurodegenerative disease involving demyelination, myelin deficiency, or myelin developmental impairment, such as subjects diagnosed with multiple sclerosis or cerebral palsy, or subjects at risk of developing such conditions. Diagnosis may be performed by any method or technique known in the art. A person skilled in the art will understand that subjects treated according to this disclosure may be identified as at risk by standard testing or without testing due to the presence of one or more risk factors associated with the disease or condition.

[0068] As used herein, the term “effective dose” refers to an amount of a particular drug sufficient to achieve the desired effect in the subject being treated by that drug. Ideally, the effective dose of a drug is sufficient to inhibit or treat a disease without causing substantial toxicity in the subject. The effective dose of a drug varies depending on the subject being treated, the severity of the pain, and the method of administration of the pharmaceutical composition. Methods for determining an effective dose of a disclosed compound sufficient to achieve the desired effect in a subject will be understood by those skilled in the art in light of this disclosure.

[0069] As used herein, the terms “modulate” or “modulating” refer to the ability to increase or decrease the activity of one or more protein kinases. Therefore, the compounds of the present invention can be used in a manner that modulates protein kinases by contacting them with one or more of the compounds or compositions described herein. In some embodiments, the compounds can act as inhibitors of one or more protein kinases. In some embodiments, the compounds can act to stimulate the activity of one or more protein kinases. In further embodiments, the compounds of the present invention can be used to modulate the activity of protein kinases in individuals requiring receptor modulation by administering modulating amounts of the compounds described herein.

[0070] As used herein, the terms “BTK-mediated,” “BTK-modulated,” or “BTK-dependent” disease or disorder mean any disease or other adverse condition in which BTK or its variants are known to play a role. Therefore, another embodiment of this application relates to treating or reducing the severity of one or more diseases in which BTK or its variants are known to play a role. Specifically, this application relates to a method for treating or reducing the severity of a disease or condition selected from proliferative disorders or autoimmune diseases, comprising administering a compound or composition of formula (I) according to this application to a patient in need thereof.

[0071] compound A compound having the structure of formula (I),

[0072] [ka] And in the formula,

[0073] [ka] However, it represents a single bond or a double bond, R 1 However, it is -H, -CH3, or -F. R 2 However, is it -H, -CH3, or -F? Or R 1 and R 2 However, together with the C atoms to which they are bonded, 3-6 Forms a member carbon-cyclic ring, R I1 However, it is -Cl, -F, -CN, -CH3, -CH2F, -CHF2, or -CF3, R I2 However, it is -H or -F, R B However, -CH=CH2, -C≡CH, or -C≡C-CH3, R I1 When R is -CH3, 1 and R 2 at least one of them is -CH3 or -F, and a compound, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof is disclosed herein.

[0074] In some embodiments, --- represents a single bond. In other embodiments, --- represents a double bond.

[0075] In some embodiments, R 1 is -H. In other embodiments, R 1 is -CH3. In other embodiments, R 1 is -F. In some embodiments, R 1 is -H and R 2 is -H. In other embodiments, R 1 is -H and R 2 is -CH3. In other embodiments, R 1 is -H and R 2 is -F. In other embodiments, R 1 is -CH3 and R 2 is -CH3. In other embodiments, R 1 is -CH3 and R 2 is -F. In other embodiments, R 1 is -F and R 2 is -F.

[0076] In some embodiments, R 1 and R 2 together with the C atom to which they are attached form a C 3-6 membered carbocyclic ring. In some embodiments, R 1 and R 2 together with the C atom to which they are attached form a cyclopropyl ring. In some embodiments, R 1 and R 2 together with the C atom to which they are attached form a cyclopropyl ring. In some embodiments, R 1and R 2 together with the C atom to which they are attached form a cyclobutyl ring. In some embodiments, R 1 and R 2 together with the C atom to which they are attached form a cyclopentyl ring. In some embodiments, R 1 and R 2 together with the C atom to which they are attached form a cyclohexyl ring.

[0077] In some embodiments, R I1 is -Cl, -F, -CN, -CH2F, -CHF2, or -CF3. In other embodiments, R I1 is -Cl or -F. In other embodiments, R I1 is -Cl. In other embodiments, R I1 is -F. In other embodiments, R I1 is -CN. In other embodiments, R I1 is F, -CH2F, -CHF2, or -CF3.

[0078] In some embodiments, R I2 is -H. In some embodiments, R I2 is -F.

[0079] In some embodiments, R B is -CH=CH2. In other embodiments, R[[ID=4I]] B is -C≡CH. In other embodiments, R B is -C≡C-CH3.

[0080] In some embodiments, --- represents a single bond, R I2 is -H, R 1 is -H, R 2 is -H. In other embodiments, --- represents a single bond, R I2 is -F, R 1 is -H, R 2 is -H. In other embodiments, --- represents a single bond, R I1 is -Cl, R I2is -F, and R 1 is -H, and R 2 is -H.

[0081] In some embodiments, the compound has the structure of formula (IS) or (IR).

[0082] [ka]

[0083] In some embodiments, the compound has the structure shown below.

[0084] [ka]

[0085] In one embodiment, a compound of formula (I) having the structure of the compound shown in Table 1 below, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof is provided.

[0086] [Table 1-1]

[0087] [Table 1-2]

[0088] [Table 1-3]

[0089] [Table 1-4]

[0090] [Table 1-5]

[0091] In another embodiment, a compound of formula (I) having the structure of the compound shown in Table 2 below, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof is provided.

[0092] [Table 2-1]

[0093] [Table 2-2]

[0094] [Table 2-3]

[0095] Also, compounds having the structure of formula (II),

[0096] [ka] And in the formula, R 3 However, it is H, Me, or cyclopropyl, X is either -CH2CH2- or -CR x1 R x2 -and, R x1 However, it is H, F, or Me, R x2 However, is it H, F, or Me? Or R x1 and R x2 However, together with the C atoms to which they are bonded, 3-6 Forming a member-carbon ring, Or R x1 H is R x2 and R 3 Together they form an alkylene crosslink, R II1However, it is Cl, F, -CH2F, -CHF2, -CF3, or -CN, R II2 However, it is H or F, R B Compounds that are -CH=CH2, -C≡CH, or -C≡C-CH3, or pharmaceutically acceptable salts, solvates, hydrates, isomers, tautomers, racemates, or isotopes thereof are also disclosed herein.

[0097] In one embodiment, R 3 In another embodiment, R 3 In yet another embodiment, R 3 is cyclopropyl. In other embodiments, R 3 is either H or Me.

[0098] In one embodiment, X is -CH2CH2-.

[0099] [ka]

[0100] In one embodiment, X is -CR x1 R x2 - is

[0101] [ka]

[0102] In one embodiment, X is -CR x1 R x2 - and R x1 H is R X2 H is H.

[0103] [ka]

[0104] In one embodiment, X is -CR x1 R x2 - and Rx1 H is R X2 It is F.

[0105] [ka]

[0106] In one embodiment, X is -CR x1 R x2 - and R x1 F is R X2 It is F.

[0107] [ka]

[0108] In one embodiment, X is -CR x1 R x2 - and R x1 is Me, and R X2 It is F.

[0109] [ka]

[0110] In one embodiment, X is -CR x1 R x2 - and R x1 is Me, and R X2 This is Me.

[0111] [ka]

[0112] In one embodiment, X is -CR x1 R x2 - and R x1 and R x2 Together with the C atoms to which they are bonded, C 3-6 It forms a member-carbon ring. In some embodiments, R x1 and R x2These, together with the C atom to which they are bonded, form a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl ring.

[0113] [ka]

[0114] In one embodiment, X is -CR x1 R x2 - and R x1 H is R x2 and R 3 Together, they form an alkylene crosslink. In one embodiment, R X2 and R 3 They combine to form a methylene crosslink.

[0115] [ka]

[0116] In one embodiment, R B -CH=CH2.

[0117] [ka]

[0118] In one embodiment, R B -C ≡ CH.

[0119] [ka]

[0120] In one embodiment, R B -C≡C-CH3.

[0121] [ka]

[0122] In one embodiment, R II1 is Cl, F, or -CN. In one embodiment, R II1 In another embodiment, R II1 In another embodiment, R II1 is CN.

[0123] In one embodiment, R II1 is -CH2F, -CHF2, or -CF3. In one embodiment, R II1 is -CH2F. In another embodiment, R II1 is -CHF2. In another embodiment, R II1 It is -CF3.

[0124] In one embodiment, R II2 In another embodiment, R II2 It is F.

[0125] In one embodiment, a compound of formula (II) having the structure of the following compound is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof.

[0126] [ka]

[0127] In one embodiment, a compound of formula (II) having the structure of the compound shown in Table 3, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof is provided.

[0128] [Table 3-1]

[0129] [Table 3-2]

[0130] [Table 3-3]

[0131] [Table 3-4]

[0132] [Table 3-5]

[0133] [Table 3-6]

[0134] [Table 3-7]

[0135] In some embodiments, the compound of formula (II) comprises a mixture of two isomers. In other embodiments, the compound of formula (II) comprises a mixture of two atropisomers. In other embodiments, the compound of formula (II) comprises a racemic mixture of two atropisomers. In other embodiments, the compound of formula (II) comprises a single atropisomer. In other embodiments, the compound of formula (II) comprises a single (R)-atropisomer. In other embodiments, the compound of formula (II) comprises a single (S)-atropisomer. In some embodiments, the compound of formula (II-a) or (II-b) is provided.

[0136] [ka]

[0137] Also, compounds having the structure of formula (III),

[0138] [ka] And in the formula, Z is -CH2-, -CHMe-, or a bond. Y, -CHR 4 -or combination, R 4 However, it is H, F, or OH, R 5 However, it is H, F, or Me, R 6 However, it is either H or Me, R 7 However, it is either H or Me, R 8 Is it H? Or R 5 and R 7 However, together they form a 5-membered or 6-membered heterogeneous ring, Or R 6 and R 7 However, when combined, they form a 4-member, 5-member, or 6-member complex ring, Or R 8 and R 7 However, together they form a 5-membered or 6-membered complex ring. a is 0, 1, or 2, R III1 However, it is either Cl, F, -CH2F, -CHF2, -CF3, or -CN, R 4 When is F or OH, or R 5 When F, or R 5 and R 7 Or R 8 and R 7 However, when they come together to form a 5- or 6-membered heterocyclic ring, or R 6 and R 7 However, when they come together to form a 4, 5, or 6-membered complex ring, R III1 is -CH3, R III2 However, it is H or F, R B Compounds that are -CH=CH2, -C≡CH, or -C≡C-CH3, or pharmaceutically acceptable salts, solvates, hydrates, isomers, tautomers, racemates, or isotopes thereof are also disclosed herein.

[0139] In one embodiment of formula (III), Z is a bond, Y is a bond, and the compound has the structure of formula (IV).

[0140] [ka] Or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemic mixture, or isotope thereof is provided, where R III1 , R III2 , R B , a, R 5 , R 6 , R 7 , and R 8 This is defined above in reference to equation (III).

[0141] In one embodiment of formula (III), Z is -CH2- and Y is a bond, and the compound has the structure of formula (Va).

[0142] [ka] Or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemic mixture, or isotope thereof is provided, where R III1 , R III2 , R B , a, R 5 , R 6 , R 7 , and R 8 This is defined above in reference to equation (III).

[0143] In one embodiment of formula (III), Z is a bond and Y is -CHR 4 - and a compound having the structure of formula (Vb),

[0144] [ka] Or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemic mixture, or isotope thereof is provided, where R III1 , R III2 , R B , a, R 4 , R 5 , R 6 , R 7 , and R 8 This is defined above in reference to equation (III). In one embodiment of equation (III-b), R 4 is H. In another embodiment of equation (III-b), R 4 is F. In another embodiment of equation (III-b), R 4 It is -OH.

[0145] In one embodiment of formula (III), Z is -CH2- and Y is -CHR 4 - and a compound having the structure of formula (VI-a),

[0146] [ka] Or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemic mixture, or isotope thereof is provided, where R III1 , R III2 , R B , a, R 4 , R 5 , R 6 , R 7 , and R 8 This is defined above in reference to equation (III). In one embodiment of equation (VI-a), R 4 is F. In another embodiment of equation (VI-a), R 4 It is -OH.

[0147] In one embodiment of formula (VI-a), R 4 is H, and the compound has the structure of formula (VI-a-1),

[0148] [ka] Or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemic mixture, or isotope thereof is provided, where R III1 , R III2 , R B , a, R 5 , R 6 , R 7 , and R 8 This is defined above in reference to equation (III).

[0149] In one embodiment of equation (III), Z is -CHMe- and Y is -CHR 4 - and a compound having the structure of formula (VI-b),

[0150] [ka] Or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemic mixture, or isotope thereof is provided, where R III1 , R III2 , R B , a, R 4 , R 5 , R 6 , R 7 , and R 8 This is defined above in reference to equation (III). In one embodiment of equation (VI-b), R 4 is H. In another embodiment of equation (VI-b), R 4 is F. In another embodiment of equation (VI-b), R 4 It is -OH.

[0151] In one embodiment of formula (III), R 7 and R 8 Together they form a 5-membered complex ring, where a is 0 and R 5 H is R 6 is H, and the compound has the structure of formula (VII-a),

[0152] [ka] Or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemic mixture, or isotope thereof is provided, where R III1 , R III2 , R B Z, Y, and , are defined above in reference to formula (III). In some embodiments of formula (VII-a), Z is CH2. In some embodiments of formula (VII-a), Y is CH2. In some embodiments of formula (VII-a), Z is CH2 and Y is CH2. In some embodiments of formula (VII-a), Z is CHMe and Y is CH2. In some embodiments of formula (VII-a), Z is CH2 and Y is CHR 4 That is the case.

[0153] In one embodiment of formula (III), R 7 and R 8 Together they form a 5-membered hetero ring, where a is 1 and R 5 H is R 6 is H, and the compound has the structure of formula (VII-b),

[0154] [ka] Or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemic mixture, or isotope thereof is provided, where R III1 , R III2 , R B Z, Y, and , are defined above in reference to formula (III). In some embodiments of formula (VII-b), Z is CH2. In some embodiments of formula (VII-b), Y is CH2. In some embodiments of formula (VII-b), Z is CH2 and Y is CH2. In some embodiments of formula (VII-b), Z is CHMe and Y is CH2. In some embodiments of formula (VII-b), Z is CH2 and Y is CHR 4 That is the case.

[0155] In one embodiment of formula (III), R 7 and R8 Together they form a 5-membered heterocycle, where a is 2 and R 5 H is R 6 is H, and the compound has the structure of formula (VII-c),

[0156] [ka] Or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemic mixture, or isotope thereof is provided, where R III1 , R III2 , R B Z, Y, and , are defined above in reference to formula (III). In some embodiments of formula (VII-c), Z is CH2. In some embodiments of formula (VII-c), Y is CH2. In some embodiments of formula (VII-c), Z is CH2 and Y is CH2. In some embodiments of formula (VII-c), Z is CHMe and Y is CH2. In some embodiments of formula (VII-c), Z is CH2 and Y is CHR 4 That is the case.

[0157] In one embodiment of formula (III), R 7 and R 8 Together they form a 6-membered complex ring, where a is 0 and R 5 H is R 6 is H, and the compound has the structure of formula (VIII-a),

[0158] [ka] Or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemic mixture, or isotope thereof is provided, where R III1 , R III2 , R BZ, Y, and Z are defined above in reference to formula (III). In some embodiments of formula (VIII-a), Z is CH2. In some embodiments of formula (VIII-a), Y is CH2. In some embodiments of formula (VIII-a), Z is CH2 and Y is CH2. In some embodiments of formula (VIII-a), Z is CHMe and Y is CH2. In some embodiments of formula (VIII-a), Z is CH2 and Y is CHR 4 That is the case.

[0159] In one embodiment of formula (III), R 7 and R 8 Together they form a 6-membered complex ring, where a is 1 and R 5 H is R 6 is H, and the compound has the structure of formula (VIII-b),

[0160] [ka] Or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemic mixture, or isotope thereof is provided, where R III1 , R III2 , R B Z, Y, and , are defined above in reference to formula (III). In some embodiments of formula (VIII-b), Z is CH2. In some embodiments of formula (VIII-b), Y is CH2. In some embodiments of formula (VIII-b), Z is CH2 and Y is CH2. In some embodiments of formula (VIII-b), Z is CHMe and Y is CH2. In some embodiments of formula (VIII-b), Z is CH2 and Y is CHR 4 That is the case.

[0161] In one embodiment of formula (III), R 7 and R 8 Together they form a 6-membered heteroring, where a is 2 and R 5 H is R 6 is H, and the compound has the structure of formula (VIII-b),

[0162] [ka] Or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemic mixture, or isotope thereof is provided, where R III1 , R III2 , R B Z, Y, and , are defined above in reference to formula (III). In some embodiments of formula (VIII-c), Z is CH2. In some embodiments of formula (VIII-c), Y is CH2. In some embodiments of formula (VIII-c), Z is CH2 and Y is CH2. In some embodiments of formula (VIII-c), Z is CHMe and Y is CH2. In some embodiments of formula (VIII-c), Z is CH2 and Y is CHR 4 That is the case.

[0163] In one embodiment of formula (III), R 6 and R 7 Together they form a 4-membered complex ring, where a is 0 and R 5 H is R 8 is H, and the compound has the structure of formula (IX-a),

[0164] [ka] Or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemic mixture, or isotope thereof is provided, where R III1 , R III2 , R BZ, Y, and , are defined above in reference to formula (III). In some embodiments of formula (IX-a), Z is CH2. In some embodiments of formula (IX-a), Y is CH2. In some embodiments of formula (IX-a), Z is CH2 and Y is CH2. In some embodiments of formula (IX-a), Z is CHMe and Y is CH2. In some embodiments of formula (IX-a), Z is CH2 and Y is CHR 4 That is the case.

[0165] In one embodiment of formula (III), R 6 and R 7 Together they form a 4-membered heterocycle, where a is 1 and R 5 H is R 8 is H, and the compound has the structure of formula (IX-b),

[0166] [ka] Or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemic mixture, or isotope thereof is provided, where R III1 , R III2 , R B Z, Y, and , are defined above in reference to formula (III). In some embodiments of formula (IX-b), Z is CH2. In some embodiments of formula (IX-b), Y is CH2. In some embodiments of formula (IX-b), Z is CH2 and Y is CH2. In some embodiments of formula (IX-b), Z is CHMe and Y is CH2. In some embodiments of formula (IX-b), Z is CH2 and Y is CHR 4 That is the case.

[0167] In one embodiment of formula (III), R 5 and R 7 Together they form a 5-membered heterocycle, where a is 2 and R 6 H is R 8 is H, and the compound has the structure of formula (Xa),

[0168] [ka] Or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemic mixture, or isotope thereof is provided, where R III1 , R III2 , R B Z, Y, and , are defined above in reference to formula (III). In some embodiments of formula (Xa), Z is CH2. In some embodiments of formula (Xa), Y is CH2. In some embodiments of formula (Xa), Z is CH2 and Y is CH2. In some embodiments of formula (Xa), Z is CHMe and Y is CH2. In some embodiments of formula (Xa), Z is CH2 and Y is CHR 4 That is the case.

[0169] In one embodiment of formula (III), R 5 and R 7 Together they form a 5-membered hetero ring, where a is 1 and R 6 H is R 8 is H, and the compound has the structure of formula (Xb),

[0170] [ka] Or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemic mixture, or isotope thereof is provided, where R III1 , R III2 , R B Z, Y, and Z are defined above in reference to formula (III). In some embodiments of formula (Xb), Z is CH2. In some embodiments of formula (Xb), Y is CH2. In some embodiments of formula (Xb), Z is CH2 and Y is CH2. In some embodiments of formula (Xb), Z is CHMe and Y is CH2. In some embodiments of formula (Xb), Z is CH2 and Y is CHR 4 That is the case.

[0171] In one embodiment of formula (III), R 5 and R 7 Together they form a 5-membered complex ring, where a is 0 and R 6 H is R 8 is H, and the compound has the structure of formula (Xc),

[0172] [ka] Or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemic mixture, or isotope thereof is provided, where R III1 , R III2 , R B Z, Y, and Z are defined above in reference to formula (III). In some embodiments of formula (Xc), Z is CH2. In some embodiments of formula (Xc), Y is CH2. In some embodiments of formula (Xc), Z is CH2 and Y is CH2. In some embodiments of formula (Xc), Z is CHMe and Y is CH2. In some embodiments of formula (Xc), Z is CH2 and Y is CHR 4 That is the case.

[0173] In one embodiment of formula (III), R 5 and R 7 Together they form a 6-membered heteroring, where a is 2 and R 6 is H, and the compound has the structure of formula (XI-a),

[0174] [ka] Or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemic mixture, or isotope thereof is provided, where R III1 , R III2 , R B , R 8Z, Y, and , are defined above in reference to formula (III). In some embodiments of formula (XI-a), Z is CH2. In some embodiments of formula (XI-a), Y is CH2. In some embodiments of formula (XI-a), Z is CH2 and Y is CH2. In some embodiments of formula (XI-a), Z is CHMe and Y is CH2. In some embodiments of formula (XI-a), Z is CH2 and Y is CHR 4 That is the case.

[0175] In one embodiment of formula (III), R 5 and R 7 Together they form a 6-membered complex ring, where a is 1 and R 6 is H, and the compound has the structure of formula (XI-b),

[0176] [ka] Or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemic mixture, or isotope thereof is provided, where R III1 , R III2 , R B , R 8 Z, Y, and , are defined above in reference to formula (III). In some embodiments of formula (XI-b), Z is CH2. In some embodiments of formula (XI-b), Y is CH2. In some embodiments of formula (XI-b), Z is CH2 and Y is CH2. In some embodiments of formula (XI-b), Z is CHMe and Y is CH2. In some embodiments of formula (XI-b), Z is CH2 and Y is CHR 4 That is the case.

[0177] In one embodiment of formula (III), R 5 and R 7 Together they form a 6-membered complex ring, where a is 0 and R 5 H is R 6 H is a compound having the structure of formula (XI-c),

[0178] [ka] Or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemic mixture, or isotope thereof is provided, where R III1 , R III2 , R B , R 8 Z, Y, and , are defined above in reference to formula (III). In some embodiments of formula (XI-c), Z is CH2. In some embodiments of formula (XI-c), Y is CH2. In some embodiments of formula (XI-c), Z is CH2 and Y is CH2. In some embodiments of formula (XI-c), Z is CHMe and Y is CH2. In some embodiments of formula (XI-c), Z is CH2 and Y is CHR 4 That is the case.

[0179] In some embodiments of equation (III), R 5 and R 7 Together they form a 6-membered heteroring, R 6 A is H, Z is CH2, and the compound has one of the structures of formula (XII-a), (XII-b), or (XII-c).

[0180] [ka] Or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemic mixture, or isotope thereof is provided, where R III1 , R III2 , R B , R 8 , and Y are defined above in reference to equation (III).

[0181] In some embodiments of equation (III), R 5 and R 7 Together they form a 6-membered heteroring, R 6is H, Z is a bond, and the compound has one of the structures of formula (XIII-a), (XIII-b), or (XIII-c).

[0182] [ka] Or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemic mixture, or isotope thereof is provided, where R III1 , R III2 , R B , R 8 , and Y are defined above in reference to equation (III).

[0183] In some embodiments of equation (III), R 5 H is R 6 H is R 7 H is R 8 is H, and the compound has the structure of formula (XIV),

[0184] [ka] Or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemic mixture, or isotope thereof is provided, where R III1 , R III2 , a, R B Z, Y, and Z are defined above in reference to formula (III). In some embodiments of formula (XIV), Z is CH2. In some embodiments of formula (XIV), Y is CH2. In some embodiments of formula (XIV), Z is CH2 and Y is CH2. In some embodiments of formula (XIV), Z is CHMe and Y is CH2. In some embodiments of formula (XIV), Z is CH2 and Y is CHR 4 In some embodiments of equation (XIV), a is 0. In other embodiments of equation (XIV), a is 1. In other embodiments of equation (XIV), a is 2.

[0185] In some embodiments of equation (III), R 5 H, R 6 H is R 7 H is R 8 H is H, Z is CH2, and Y is CHR 4 The compound having the structure of formula (XV)

[0186] [ka] Or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemic mixture, or isotope thereof is provided, where R III1 , R III2 , a, R 4 , and R B This is defined above in reference to equation (III).

[0187] In some embodiments of formula (XV), a is 0, 1, or 2, and the compound has one of the structures of formula (XV-a), (XV-b), or (XV-c).

[0188] [ka] Or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemic mixture, or isotope thereof is provided, where R III1 , R III2 , R 4 , and R B This is defined above in reference to equation (III).

[0189] In several embodiments of formula (III), and in each of any one more specific embodiment of formulas (IV), (Va), (Vb), (VI-a), (VI-a-1), (VI-b), (VII-a), (VII-b), (VII-c), (VIII-a), (VIII-b), (VIII-c), (IX-a), (IX-b), (Xa), (Xb), (Xc), (XI-a), (XI-b), (XI-c), (XII-a), (XII-b), (XII-c), (XIII-a), (XIII-b), (XIII-c), (XIV), (XV-a), (XV-b), and (XV-c) (hereinafter referred to as "formulas (III) to (XV)"), R III1 is Cl, F, -CN, -CH2F, -CHF2, or -CF3. In any other embodiment of any one of formulas (III) to (XV), R III1 is Cl or F. In any other embodiment of any one of formulas (III) to (XV), R III1 is Cl. In any other embodiment of any one of equations (III) to (XV), R III1 is F. In any other embodiment of any one of equations (III) to (XV), R III1 -CN. In any other embodiment of equations (III) to (XV), R III1 These are F, -CH2F, -CHF2, or -CF3.

[0190] In some embodiments of any one of equations (III) to (XV), R 4 When is F or OH, R III1 is -CH3. In any other embodiment of any one of equations (III) to (XV), R 5 When F, R III1 is -CH3. In any other embodiment of any one of equations (III) to (XV), R 5 and R 7 They come together to form a 5- or 6-membered heterocycle, or R 6 and R 7 They come together to form a 4, 5, or 6-membered heteroring, or R 8 and R 7When they come together to form a 5- or 6-membered heteroring, R III1 It is -CH3.

[0191] In some embodiments of any one of equations (III) to (XV), R III2 is H. In some embodiments of any one of equations (III) to (XV), R III2 It is F.

[0192] In any one embodiment of equations (III) to (XV), R B -CH=CH2.

[0193] In one embodiment of formula (III), R B The compound is -CH=CH2 and has the structure of formula (XVI).

[0194] [ka] Or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemic mixture, or isotope thereof is provided, where R III1 , R III2 a, Z, Y, R 5 , R 6 , R 7 , and R 8 This is defined above in reference to equation (III).

[0195] In any one embodiment of equations (III) to (XIII), R B The compound is -C≡CH and has the structure of formula (XVII).

[0196] [ka]

[0197] Or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemic mixture, or isotope thereof is provided, where R III1 , R III2a, Z, Y, R 5 , R 6 , R 7 , and R 8 This is defined above in reference to equation (III).

[0198] In any one embodiment of equations (III) to (XIII), R B The compound is -C≡C-CH3 and has the structure of formula (XVIII).

[0199] [ka] Or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemic mixture, or isotope thereof is provided, where R III1 , R III2 a, Z, Y, R 5 , R 6 , R 7 , and R 8 This is defined above in reference to equation (III).

[0200] In one embodiment, a compound of formula (III) having the structure of the compound listed in Table 4 is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof.

[0201] [Table 4-1]

[0202] [Table 4-2]

[0203] [Table 4-3]

[0204] [Table 4-4]

[0205] Table 4-5

[0206] Table 4-6

[0207] Table 4-7

[0208] Table 4-8

[0209] Table 4-9

[0210] Table 4-10

[0211] Table 4-11

[0212] Table 4-12

[0213] In further embodiments, equations (I), (II), (II-a), (II-b), (IV), (Va), (Vb), (VI-a), (VI-a-1), (VI-b), (VII-a), (VII-b), (VII-c), (VIII-a), (VIII-b), (VIII-c), (IX-a), (IX-b), (Xa), (Xb), and These are pharmaceutically acceptable salts of the compounds of formula (Xc), formula (XI-a), formula (XI-b), formula (XI-c), formula (XII-a), formula (XII-b), formula (XII-c), formula (XIII-a), formula (XIII-b), formula (XIII-c), formula (XIII), formula (XIV), formula (XV-a), formula (XV-b), formula (XV-c), formula (XVI), formula (XVII), or formula (XVIII).

[0214] In other embodiments, formulas (I), (II), (II-a), (II-b), (IV), (Va), (Vb), (VI-a), (VI-a-1), (VI-b), (VII-a), (VII-b), (VII-c), (VIII-a), (VIII-b), (VIII-c), (IX-a), (IX-b), (Xa), (Xb) It is a solvate of a compound of formula (Xc), formula (XI-a), formula (XI-b), formula (XI-c), formula (XII-a), formula (XII-b), formula (XII-c), formula (XIII-a), formula (XIII-b), formula (XIII-c), formula (XIII), formula (XIV), formula (XV-a), formula (XV-b), formula (XV-c), formula (XVI), formula (XVII), or formula (XVIII).

[0215] In other embodiments, formulas (I), (II), (II-a), (II-b), (IV), (Va), (Vb), (VI-a), (VI-a-1), (VI-b), (VII-a), (VII-b), (VII-c), (VIII-a), (VIII-b), (VIII-c), (IX-a), (IX-b), (Xa), (Xb) It is a hydrate of the compound of formula (Xc), formula (XI-a), formula (XI-b), formula (XI-c), formula (XII-a), formula (XII-b), formula (XII-c), formula (XIII-a), formula (XIII-b), formula (XIII-c), formula (XIII), formula (XIV), formula (XV-a), formula (XV-b), formula (XV-c), formula (XVI), formula (XVII), or formula (XVIII).

[0216] In other embodiments, formulas (I), (II), (II-a), (II-b), (IV), (Va), (Vb), (VI-a), (VI-a-1), (VI-b), (VII-a), (VII-b), (VII-c), (VIII-a), (VIII-b), (VIII-c), (IX-a), (IX-b), (Xa), (Xb) They are isomers of the compounds of formula (Xc), formula (XI-a), formula (XI-b), formula (XI-c), formula (XII-a), formula (XII-b), formula (XII-c), formula (XIII-a), formula (XIII-b), formula (XIII-c), formula (XIII), formula (XIV), formula (XV-a), formula (XV-b), formula (XV-c), formula (XVI), formula (XVII), or formula (XVIII).

[0217] In other embodiments, formulas (I), (II), (II-a), (II-b), (IV), (Va), (Vb), (VI-a), (VI-a-1), (VI-b), (VII-a), (VII-b), (VII-c), (VIII-a), (VIII-b), (VIII-c), (IX-a), (IX-b), (Xa), (Xb) These are tautomers of compounds of formula (Xc), formula (XI-a), formula (XI-b), formula (XI-c), formula (XII-a), formula (XII-b), formula (XII-c), formula (XIII-a), formula (XIII-b), formula (XIII-c), formula (XIII), formula (XIV), formula (XV-a), formula (XV-b), formula (XV-c), formula (XVI), formula (XVII), or formula (XVIII).

[0218] In other embodiments, formulas (I), (II), (II-a), (II-b), (IV), (Va), (Vb), (VI-a), (VI-a-1), (VI-b), (VII-a), (VII-b), (VII-c), (VIII-a), (VIII-b), (VIII-c), (IX-a), (IX-b), (Xa), (Xb) It is a racemic mixture of the compounds of formula (Xc), formula (XI-a), formula (XI-b), formula (XI-c), formula (XII-a), formula (XII-b), formula (XII-c), formula (XIII-a), formula (XIII-b), formula (XIII-c), formula (XIII), formula (XIV), formula (XV-a), formula (XV-b), formula (XV-c), formula (XVI), formula (XVII), or formula (XVIII).

[0219] In other embodiments, formulas (I), (II), (II-a), (II-b), (IV), (Va), (Vb), (VI-a), (VI-a-1), (VI-b), (VII-a), (VII-b), (VII-c), (VIII-a), (VIII-b), (VIII-c), (IX-a), (IX-b), (Xa), (Xb) These are isotopic forms of the compounds of formula (Xc), formula (XI-a), formula (XI-b), formula (XI-c), formula (XII-a), formula (XII-b), formula (XII-c), formula (XIII-a), formula (XIII-b), formula (XIII-c), formula (XIII), formula (XIV), formula (XV-a), formula (XV-b), formula (XV-c), formula (XVI), formula (XVII), or formula (XVIII).

[0220] In further embodiments, equations (I), (II), (II-a), (II-b), (IV), (Va), (Vb), (VI-a), (VI-a-1), (VI-b), (VII-a), (VII-b), (VII-c), (VIII-a), (VIII-b), (VIII-c), (IX-a), (IX-b), (Xa), (Xb), (Xc), (XI-a), (XI-b), (X A pharmaceutical composition comprising a compound of formula (I-c), formula (XII-a), formula (XII-b), formula (XII-c), formula (XIII-a), formula (XIII-b), formula (XIII-c), formula (XIII), formula (XIV), formula (XV-a), formula (XV-b), formula (XV-c), formula (XVI), formula (XVII), or formula (XVIII), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof.

[0221] In further embodiments, equations (I), (II), (II-a), (II-b), (IV), (Va), (Vb), (VI-a), (VI-a-1), (VI-b), (VII-a), (VII-b), (VII-c), (VIII-a), (VIII-b), (VIII-c), (IX-a), (IX-b), (Xa), (Xb), (Xc), (XI-a), (XI-b), (XI-c), (XII-a A pharmaceutical composition comprising a compound of formula (XII-b), formula (XII-c), formula (XIII-a), formula (XIII-b), formula (XIII-c), formula (XIII), formula (XIV), formula (XV-a), formula (XV-b), formula (XV-c), formula (XVI), formula (XVII), or formula (XVIII), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, and at least one pharmaceutically acceptable excipient.

[0222] In another embodiment, equations (I), (II), (II-a), (II-b), (IV), (Va), (Vb), (VI-a), (VI-a-1), (VI-b), (VII-a), (VII-b), (VII-c), (VIII-a), (VIII-b), (VIII-c), (IX-a), (IX-b), (Xa), (Xb), (Xc), (XI-a), (XI-b), (XI-c), (XII-a), A pharmaceutical composition comprising a compound of formula (XII-b), formula (XII-c), formula (XIII-a), formula (XIII-b), formula (XIII-c), formula (XIII), formula (XIV), formula (XV-a), formula (XV-b), formula (XV-c), formula (XVI), formula (XVII), or formula (XVIII), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0223] disease This specification describes a method for inhibiting a protein kinase, comprising contacting the protein kinase with an effective amount of a compound of formula (I), formula (II), or (III), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, isotope, or pharmaceutical composition thereof. In some embodiments, the protein kinase is BTK.

[0224] This specification describes a method for treating a BTK-dependent condition, comprising administering to a subject in need an effective amount of a compound of formula (I), formula (II), or formula (III), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, isotope, or pharmaceutical composition thereof.

[0225] In some embodiments, the BTK-dependent state is cancer, autoimmune disease, inflammatory disease, or thromboembolic disease. In some embodiments, the autoimmune disease is multiple sclerosis, rheumatoid arthritis, psoriasis, Sjögren's syndrome, or systemic lupus erythematosus. In some embodiments, the inflammatory disease is urticaria. In some embodiments, the BTK-dependent state is cancer. In some embodiments, the BTK-dependent state is an autoimmune disease. In some embodiments, the BTK-dependent state is an inflammatory disease. In some embodiments, the BTK-dependent state is a thromboembolic disease. In some embodiments, the BTK-dependent state is multiple sclerosis. In some embodiments, the BTK-dependent state is rheumatoid arthritis. In some embodiments, the BTK-dependent state is psoriasis. In some embodiments, the BTK-dependent state is Sjögren's syndrome. In some embodiments, the BTK-dependent state is systemic lupus erythematosus. In some embodiments, the BTK-dependent state is urticaria.

[0226] In some embodiments, the use of compounds of formula (I), formula (II), or formula (III), or pharmaceutically acceptable salts, solvates, hydrates, isomers, tautomers, racemates, isotopes, or pharmaceutical compositions thereof, in the manufacture of pharmaceuticals. In some embodiments, the pharmaceuticals are for the treatment of cancer. In some embodiments, the pharmaceuticals are for the treatment of autoimmune diseases. In some embodiments, the pharmaceuticals are for the treatment of inflammatory diseases. In some embodiments, the pharmaceuticals are for the treatment of thromboembolic diseases. In some embodiments, the pharmaceuticals are for the treatment of multiple sclerosis. In some embodiments, the pharmaceuticals are for the treatment of rheumatoid arthritis. In some embodiments, the pharmaceuticals are for the treatment of psoriasis. In some embodiments, the pharmaceuticals are for the treatment of Sjögren's syndrome. In some embodiments, the pharmaceuticals are for the treatment of systemic lupus erythematosus. In some embodiments, the pharmaceuticals are for the treatment of urticaria.

[0227] Therefore, inhibition of BTK activity may be useful in the treatment of allergic disorders and / or autoimmune and / or inflammatory diseases, including but not limited to SLE, rheumatoid arthritis, polyangiitis, idiopathic thrombocytopenic purpura (ITP), myasthenia gravis, allergic rhinitis, multiple sclerosis (MS), transplant rejection, type 1 diabetes mellitus, membranous nephritis, inflammatory bowel disease, autoimmune hemolytic anemia, autoimmune thyroiditis, cold and warm agglutinin disorders, Evans syndrome, hemolytic uremic syndrome / thrombotic thrombocytopenic purpura, sarcoidosis, Sjögren's syndrome, peripheral neuropathy (e.g., Guillain-Barré syndrome), pemphigus vulgaris, and asthma.

[0228] In addition, BTK has been reported to play a role in regulating B-cell survival in certain B-cell cancers. For example, BTK has been shown to be important for the survival of BCR-Abl-positive B-cell acute lymphoblastic leukemia cells. Therefore, inhibition of BTK activity may be useful in the treatment of B-cell lymphomas and leukemias.

[0229] The compounds described herein, or their pharmaceutically acceptable salts, solvates, hydrates, or tautomers, may be optionally combined with corticosteroids, non-corticosteroids, immunosuppressants, and / or anti-inflammatory agents to be useful in the treatment of the diseases listed above. In one embodiment, the immunosuppressant is interferon alpha, interferon gamma, cyclophosphamide, tacrolimus, mycophenolmofetil, methotrexate, dapsone, sulfasalazine, azathioprine, anti-CD20 agents (rituximab, ofatumumab, obinutuzumab, or bertuzumab, or their biosimilar versions, etc.), anti-TNF alpha agents (entanercept, infliximab, gorilumab, adalimumab, or certolizumab pegol, or their biosimilar versions, etc.), anti-IL6 agents against ligands or their receptors (tocilizumab, sarilumab, orokizumab, erusilumab, or siltuximab, etc.), anti-IL17 agents against ligands or their receptors (secukinumab, ustekinumab, bro Anti-IL1 agents targeting ligands or their receptors (such as darumab or isekizumab), anti-IL2 agents targeting ligands or their receptors (such as lilonacept, canakinumab, or anakinra), anti-IL2 agents targeting ligands or their receptors (such as basiliximab or daclizumab), anti-CD2 agents such as alefacept, anti-CD3 agents such as muromonab-cd3, anti-CD80 / 86 agents such as abatacept or beratacept, anti-sulfamethoxazole such as fingolimod The immunosuppressant is selected from ingosine-1-phosphate receptor agents, anti-C5 agents such as eculizumab, anti-integrin alpha-4 agents such as natalizumab, anti-α4β7 agents such as vedolizumab, anti-mTOR agents such as sirolimus or everolimus, anti-calcineurin agents such as tacrolimus, and anti-BAFF / BlyS agents (such as belimumab, VAY736, or bricibimod), leflunomide, and teriflunomide. Preferably, the immunosuppressant is rituximab, ofatumumab, obinutuzumab, or bertuzumab, or a biosimilar version thereof.

[0230] Compound Synthesis The reactions, processes, and synthesis methods described herein are not limited to the specific conditions described in the following experimental sections, but are intended as a guide to those skilled in the art. For example, reactions may be carried out in any suitable solvent or other reagent to carry out the necessary transformations. Generally, suitable solvents are protic or aprotic solvents that are substantially inactive with the reactants, intermediates, or products at the temperature in which the reaction is carried out (i.e., a temperature that may range from freezing to boiling). A given reaction may be carried out in one solvent or a mixture of two or more solvents. Depending on the particular reaction, a solvent suitable for the specific post-reaction work may be used.

[0231] Unless otherwise specified, conventional methods of mass spectrometry (MS), liquid chromatography-mass spectrometry (LCMS), NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques, and pharmacology are used. Compounds are prepared using standard organic chemistry techniques, such as those described in March's Advanced Organic Chemistry, 7th Edition, John Wiley and Sons, Inc. (2013). Alternative reaction conditions for the synthetic transformations described herein may be used, such as a variety of solvents, reaction temperatures, reaction times, and different chemical reagents and other reaction conditions. Where necessary, the use of appropriate protecting groups may be required. The incorporation and cleavage of such groups can be performed using standard methods described in Peter GMWuts and Theodora W. Green, Protecting Groups in Organic Synthesis, 4th Edition, Wiley-Interscience. (2006). All starting materials and reagents are commercially available or readily prepared.

[0232] Compounds having the structure of formula (I), formula (II), or formula (III) can be synthesized using standard synthetic techniques known to those skilled in the art. For example, the compounds of this disclosure can be synthesized using the general synthetic procedures described in schemes 1 to 21.

[0233] Preparation of 4-bromo-1H-indole starting material

[0234] [ka]

[0235] 4-Bromo-5-fluoro-2-nitrobenzoic acid is reacted with propane-1-en-2-ylmagnesium bromide to obtain 4-bromo-5-fluoro-2-methyl-1H-indole-7-carboxylic acid, which is then amidated by treatment with ammonium chloride in the presence of HATU and DIEA to obtain 4-bromo-5-fluoro-2-methyl-1H-indole-7-carboxamide (R I2 , R II2 , R III2 We obtain =H).

[0236] [ka]

[0237] 1,4-dibromo-2,3-difluorobenzene is nitrated by treatment with potassium nitrate in sulfuric acid, and the resulting nitro group is reduced to form 2,5-dibromo-3,4-difluoroaniline. Iodination, followed by reaction with propane-1-yne, yields 4,7-dibromo-5,6-difluoro-2-methyl-1H-indole. Then, the indole is protected (e.g., with Boc), and carboxylated at position 7 by reaction with n-butyllithium and carbon dioxide to obtain 4-bromo-5,6-difluoro-2-methyl-1H-indole-7-carboxylic acid. This acid is amidated by treatment with ammonium chloride, and the indole is deprotected to obtain 4-bromo-5,6-difluoro-2-methyl-1H-indole-7-carboxamide (RI2 , R II2 , R III2 We obtain =F).

[0238] Synthesis of compounds having the structure of formula (I) 3-R 1 -3-R 2 Coupling with -1,2,3,6-tetrahydropyridine 4-Bromo-5-fluoro-6-R I2 -2-methyl-1H-indole-7-carboxamide is coupled to N-protected (e.g., Boc) 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine. Tetrahydropyridine is coupled at position 3. 1 / R 2 You can also substitute it with this.

[0239] [ka]

[0240] 4-Bromo-5-fluoro-6-R I2 -2-methyl-1H-indole-7-carboxamide is coupled to N-protected (e.g., Boc) 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine. Tetrahydropyridine is coupled at position 3. 1 / R 2 You can also substitute it with this.

[0241] Reduction to piperidine (optional)

[0242] [ka]

[0243] N-protected 5-fluoro-6-R I2 -2-methyl-4-(1,2,5,6-tetrahydropyridine-3-yl)-1H-indole-7-carboxamide

[0244] [ka] The 5-fluoro-6-R is reduced by treatment with a suitable reducing agent (e.g., Pd / C,H2) of any choice, thereby obtaining N-protected 5-fluoro-6-R I2 -2-methyl-4-(piperidine-3-yl)-1H-indole-7-carboxamide may also be obtained, where piperidine is at position 5. 1 / R 2 You can also substitute it with this.

[0245] [ka]

[0246] [ka]

[0247] N-protected 5-fluoro-6-R I2 -2-methyl-4-(1,2,5,6-tetrahydropyridine-3-yl)-1H-indole-7-carboxamide, or N-protected 5-fluoro-6-R I2 -2-methyl-4-(piperidine-3-yl)-1H-indole-7-carboxamide (where tetrahydropyridine or piperidine is R) 1 / R 2 (which may be substituted with) as shown in Scheme 5, i.e., Reacting with N-chlorosuccinimide to R I1 You can obtain it as Cl, or It is reacted with phosphorus oxychloride to obtain a 3-formyl compound, which is then treated with diethylaminosulfur trifluoride, (Et2NSF3;DAST), and R I1 You can obtain it as CHF2, or It is reacted with phosphorus oxychloride to obtain a 3-formyl compound, which is then reduced to hydroxymethyl, and subsequently treated with diethylaminosulfur trifluoride, (Et2NSF3;DAST), R I1 This is obtained as CH2F.

[0248] 3-R I1 -4-(5-R 1 -5-R 2 (-piperidine-3-yl)-5-fluoro-6-R 1 -2-methyl-1H-indole-7-carboxamide or 3-R I1 -4-(5-R 1 -5-R 2 (-1,2,5,6-tetrahydropyridine-3-yl)-5-fluoro-6-R I2 The protecting group of -2-methyl-1H-indole-7-carboxamide is removed from the piperidine or tetrahydropyridine nitrogen (e.g., by treatment with HCl to remove the Boc protecting group), which then yields a free amine, which is then converted to R B Treatment with an acid chloride yields the final compound of formula (I). 3-R I1 -4-(5-R 1 -5-R 2 -1-R B Carbonyl-piperidine-3-yl)-5-fluoro-6-R I2 -2-methyl-1H-indole-7-carboxamide, or 3-R I1 -4-(5-R 1 -5-R 2 -1-R B Carbonyl-1,2,5,6-tetrahydropyridine-3-yl)-5-fluoro-6-R I2 -2-methyl-1H-indole-7-carboxamide is obtained.

[0249] [ka] Note that compounds of formula (I), where the bond is a single bond, exist as a pair of isomers.

[0250] [ka]

[0251] Synthesis of compounds having the structure of formula (II) Preparation of II-INT-B intermediate

[0252] [ka]

[0253] X is CH2, R 3 Intermediate II-INT-B, in which is Me, is prepared by converting 2-(3-bromophenyl)ethane-1-amine to an amide by reaction with acetyl chloride. 5-bromo-1-methyl-3,4-dihydroisoquinoline is obtained by reaction with oxalic acid dichloride and iron chloride, followed by acid treatment. 5-bromo-1-methyl-1,2,3,4-tetrahydroisoquinoline is obtained by reduction with a suitable reducing agent (e.g., sodium borohydride). Tetrahydroisoquinoline may then be protected with a suitable protecting group (e.g., Boc), and appropriate R B The desired final amide may be converted by reaction with an acid chloride.

[0254] [ka]

[0255] X is CH2CH2, and R 3 Intermediate II-INT-B, in which is H, is prepared by converting 5-bromo-3,4-dihydronaphthalene-1(2H)-one to 6-bromo-2,3,4,5-tetrahydro-1H-benzo[c]azepine-1-one. Reducing with a suitable reducing agent (e.g., BH3) yields 6-bromo-2,3,4,5-tetrahydro-1H-benzo[c]azepine. The azepine may then be protected with a suitable protecting group (e.g., Boc), and appropriate R B The desired final amide may be converted by reaction with an acid chloride.

[0256] [ka]

[0257] R 3 H is and X is CR x1 R x2 And R x1 and R x2 However, intermediate II-INT-B, which forms a cyclopropyl ring together with the C atoms to which they are bonded, is prepared starting from 3-bromo-2-hydroxybenzonitrile. It is reacted with 5-bromopentannitrile and subsequently treated with a strong base (e.g., KOtBu) to obtain 9-bromo-1,2-dihydroflou[2,3-c]isoquinoline-5-amine. Treatment with an acid (e.g., HCl), a base (e.g., potassium carbonate), then heat, followed by reduction, yields 5'-bromo-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline]. The isoquinoline may then be protected with a suitable protecting group (e.g., Boc), and appropriate R B The desired final amide may be converted by reaction with an acid chloride.

[0258] [ka]

[0259] X is CR x1 R x2 And R x1 H is R x2 and R 3Intermediate II-INT-B, which forms a methylene crosslink together, is prepared starting from ethyl 2-(2-bromophenyl)ethyl acetate. Reaction with ethyl 2-bromoethyl acetate, followed by treatment with a base, and then reaction with acyl chloride / thionyl chloride yields 3-(2-bromophenyl)dihydrofuran-2,5-dione. Treatment with aluminum chloride forms 7-bromo-3-oxo-2,3-dihydro-1H-indene-1-carboxylic acid. The acid group may be protected (e.g., as an ester such as a methyl ester), and then the oxo group may be reacted with ammonium hydroxide to form a hydroxyimine, which is then reduced to an amine. Treatment with a base forms a crosslinked bicyclic compound, which is then reduced with a suitable reducing agent (e.g., BH3) to obtain 5-bromo-1,2,3,4-tetrahydro-1,4-methanoisoquinoline. Methanoisoquinoline may then be protected with a suitable protecting group (e.g., Boc), and appropriate R B The desired final amide may be converted by reaction with an acid chloride.

[0260] II-INT-B and 4-bromo-5-fluoro-2-methyl-3-R II1 -1H-indole-7-carboxamide (R II2 =H) or 4-bromo-5,6-difluoro-2-methyl-3-R II1 -1H-indole-7-carboxamide (R II2 Coupling with =F)

[0261] [ka]

[0262] The compound of formula (II) may also be prepared by converting 4-bromo-1H-indole to the corresponding dioxaboloranil derivative, followed by Suzuki coupling with II-INT-B (see Scheme 10, Route A).

[0263] Alternatively, the compound of formula (II) may be prepared by converting (I-INT-B) to the corresponding dioxaboloranil derivative, followed by Suzuki coupling with 4-bromo-1H-indole (see Scheme 10, Route B).

[0264] [ka]

[0265] R II1 A compound of formula (II) where is H, R II1 The H group may be converted to a compound that is not H. The N-protected compound is treated with N-chlorosuccinimide or selectfluor to introduce Cl or F, respectively. The protecting group is removed, and the appropriate R group is added. B The final compound is obtained by treatment with an acid chloride. The order of these steps may be changed as necessary from the order shown in Scheme 11.

[0266] [ka]

[0267] The N-protected compound is treated with N-iodosuccinimide to introduce I. The protecting group is removed, and the appropriate R is added. B The final compound is obtained by treatment with an acid chloride.

[0268] [ka]

[0269] The N-protected compound is treated with POCl3 to introduce an aldehyde group. This aldehyde may be reduced to an alcohol by treatment with a suitable reducing agent (e.g., NaBH4). By treating the aldehyde with DAST, a CF2H group is obtained, and by treating the alcohol, a CH2F group is obtained. The protecting group is removed, followed by R B By reacting it with an acid chloride, the final compound of formula (II) is obtained.

[0270] Synthesis of compounds having the structure of formula (III) Cyclic amine starting materials The following are some non-limiting examples of cyclic amines that may be used as starting materials, which are commercially available or can be prepared by routes obvious to those skilled in the art. If necessary, differential protection of the secondary amine group may be performed.

[0271] [ka]

[0272] [ka]

[0273] Cyclic amines and 4-bromo-5-fluoro-2-methyl-3-R II1 -1H-indole-7-carboxamide (R II2 =H) or 4-bromo-5,6-difluoro-2-methyl-3-R II1 -1H-indole-7-carboxamide (R II2 Coupling with =F)

[0274] [ka]

[0275] As a general procedure, the compound of formula (III) is prepared according to scheme 14. The cyclic amine is coupled with bromoindole (e.g., using a Pd catalyst). The resulting compound containing the amine group is then deprotected as needed, and R B The desired final compound is obtained by reacting it with an acid chloride.

[0276] [ka]

[0277] R III1 Cl is and RIII2 A compound of formula (III) where is H is prepared as shown in scheme 15. The carboxamide group is first protected by converting it to a nitrile group, for example by treatment with phosphoryl chloride. The protected compound is then coupled with a cyclic amine to remove the carboxamide protecting group, for example by hydration of the nitrile group. The compound is then treated with N-chlorosuccinimide to R III1 Introducing chloroform. Finally, the second amine group is deprotected (e.g., removal of the Boc group), and the resulting amine is R B The desired final compound is obtained by reacting it with an acid chloride.

[0278] [ka]

[0279] Carboxamide-protected bromoindole is coupled with a cyclic amine (R 6 H is R 7 (is H), the carboxamide protecting group is removed. By treating with N-chlorosuccinimide, R III1 Introducing chloroform. Finally, deprotect the second amine group, R B The desired final compound is obtained by reacting it with an acid chloride.

[0280] [ka]

[0281] Indole bromide (R III1 and R III2 (both are H) as shown in Scheme 17, a cyclic amine (R 5 H is R 8 H is H, a is 1, R 5 and R 7 The two molecules are coupled together to form a protected 5-membered ring containing N, and then the carboxamide is deprotected as needed. By treating with N-chlorosuccinimide, R III1Introducing chloroform. Finally, deprotect the second amine group and R B The desired final compound is obtained by reacting it with an acid chloride.

[0282] [ka]

[0283] Indole bromide (R III1 and R III2 (both are H) as shown in Scheme 18, a bicyclic amine (R 6 H is R 8 H is H, a is 0, and R 5 and R 7 The two molecules are coupled together to form a protected 5-membered ring containing N, and then the carboxamide is deprotected as needed. By treating with N-chlorosuccinimide, R III1 Introducing chloroform. Finally, deprotect the second amine group, R B The desired final compound is obtained by reacting it with an acid chloride.

[0284] [ka]

[0285] Indole bromide (R III1 is Me, and R III2 (where is H), as shown in Scheme 19, a bicyclic amine (R 6 H is R 8 H is H, a is 0, and R 5 and R 7 The two molecules are coupled together to form a protected 5-membered ring containing N, and then the carboxamide is deprotected as needed. By treating with N-chlorosuccinimide, R III1 Introducing chloroform. Finally, deprotect the second amine group and R B The desired final compound is obtained by reacting it with an acid chloride.

[0286] [ka]

[0287] Indole bromide (R III1 and R III2 (both are H) as shown in Scheme 20, 1-PG-octahydro-1H-pyrrolo[3,4-b]pyridine (PG is a preferred protecting group, Z is a bond, and Y is CR) 4 And R 4 H is R 6 H is R 8 H is H, a is 0, and R 5 and R 7 The two molecules are coupled together to form a protected 6-membered ring containing N, and then the carboxamide is deprotected as needed. By treating with N-chlorosuccinimide, R III1 Introducing chloroform. Finally, deprotect the second amine group, R B The desired final compound is obtained by reacting it with an acid chloride.

[0288] [ka]

[0289] R III1 Since is H, the compound of formula (III) as shown in scheme 21, It is reacted with phosphorus oxychloride to obtain a 3-formyl compound, which is then treated with diethylaminosulfur trifluoride, (Et2NSF3;DAST), and R III1 You can obtain it as -CHF2, or It is reacted with phosphorus oxychloride to obtain a 3-formyl compound, which is then reduced to hydroxymethyl, and subsequently treated with diethylaminosulfur trifluoride, (Et2NSF3;DAST), R III1 This is obtained as -CH2F.

[0290] Next, the second amine group is deprotected, R B The desired final compound is obtained by reacting it with an acid chloride. [Examples]

[0291] The following embodiments are provided for illustrative purposes only and are not intended to limit the scope of the claims provided herein. While preferred embodiments of the present invention have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided only as examples. Those skilled in the art will be able to conceive of numerous variations, modifications, and substitutions without departing from the present invention. It should be understood that various alternatives to the embodiments of the present invention described herein may be used in carrying out the invention. The following claims define the scope of the present invention and are intended to thereby cover methods and structures within the scope of these claims, as well as their equivalents.

[0292] Preparation of the compound of formula (I)

[0293] [ka]

[0294] Example 1 Synthesis of 4-(1-acryloyl-1,2,5,6-tetrahydropyridine-3-yl)-3-chloro-5-fluoro-2-methyl-1H-indole-7-carboxamide (compound 1)

[0295] [ka] Step 1: 4-Bromo-5-fluoro-2-methyl-1H-indole-7-carboxylic acid

[0296] [ka] To a stirred solution of 4-bromo-5-fluoro-2-nitrobenzoic acid (17 g, 64.4 mmol) in THF (200 mL), propane-1-en-2-ylmagnesium bromide (451 mL, 225 mmol, 0.5 M in THF) was added dropwise under nitrogen at -70°C. After addition, the reaction mixture was stirred at -70°C for 3 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (500 mL) and extracted with ethyl acetate (2 × 500 mL). The combined extracts were washed with brine (300 mL), dried over sodium sulfate, and concentrated under vacuum to obtain a brown solid of 4-bromo-5-fluoro-2-methyl-1H-indole-7-carboxylic acid (17.5 g). The solid was retained without purification.

[0297] ESI-MS[MH] - (C 10 Calculated values ​​for H7BrFNO2: 269.96, 271.96. Measured values: 270.25, 272.25.

[0298] Step 2: 4-Bromo-5-fluoro-2-methyl-1H-indole-7-carboxamide

[0299] [ka] N-ethyl-N-isopropyl-propan-2-amine (25.0 g, 193 mmol) was added to a stirred solution of 4-bromo-5-fluoro-2-methyl-1H-indole-7-carboxylic acid (17.5 g, 64.4 mmol), ammonium hydrochloride (5.17 g, 96.6 mmol), and HATU (29.4 g, 77.3 mmol) in DMF (200 mL). The reaction mixture was stirred at 25°C for 16 hours, quenched with water (300 mL), and extracted with ethyl acetate (3 × 300 mL). The combined extract was washed with water (200 mL) and brine (200 mL), then dried over anhydrous sodium sulfate and concentrated under vacuum. The concentrate was purified by column chromatography (50% ethyl acetate in petroleum ether) to obtain 4-bromo-5-fluoro-2-methyl-1H-indole-7-carboxamide (3.8 g, 22%) as a yellow solid.

[0300] 1 H NMR(400MHz,DMSO-d6)δ 11.26(s,1H),8.11(s,1H),7.63-7.53(m,2H),6.19(s,1H),2.42(s,3H).

[0301] ESI-MS[M+H] + (C 10 Calculated values ​​for H8BrFN2O: 270.98, 272.98; measured values: 270.90, 272.90.

[0302] Step 3: 5-(7-carbamoyl-5-fluoro-2-methyl-1H-indole-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate tert-butyl

[0303] [ka] A mixture of 4-bromo-5-fluoro-2-methyl-1H-indole-7-carboxamide (250 mg, 0.922 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate tert-butyl (314 mg, 1.01 mmol), Pd(dppf)Cl2 (67 mg, 0.092 mmol), and potassium carbonate (382 mg, 2.77 mmol) in 1,4-dioxane (8 mL) and water (2 mL) was degassed and backpacked with nitrogen. The reaction mixture was stirred under nitrogen at 90°C for 2 hours. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (3 × 20 mL). The combined extract was washed with brine (20 mL), dried over sodium sulfate, and concentrated under vacuum. The residue was purified by column chromatography using silica gel (50% ethyl acetate in petroleum ether) to obtain a yellow solid 5-(7-carbamoyl-5-fluoro-2-methyl-1H-indole-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate tert-butyl (330 mg, 96%).

[0304] 1H NMR(300MHz,DMSO-d6)δ 7.46(d,J=11.7Hz,1H),6.17(s,1H),5.98(s,1H),4.12-4.06(m,2H),3.58-3.46(m,2H),2.38(s,3H),2.34-2.21(m,2H),1.40(s,9H).

[0305] ESI-MS[M+H] + (C 20 H 24 The calculated value for FN3O3 is 374.18, and the measured value is 374.15.

[0306] Step 4: tert-butyl 5-(7-carbamoyl-3-chloro-5-fluoro-2-methyl-1H-indole-4-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid

[0307] [ka] To a solution of tert-butyl 5-(7-carbamoyl-5-fluoro-2-methyl-1H-indole-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate (150 mg, 0.40 mmol) in DMF (5 mL), N-chlorosuccinimide (54 mg, 0.40 mmol) was added at 0°C. The reaction mixture was stirred at 0°C for 1 hour, quenched with water (20 mL), and extracted with ethyl acetate (3 × 20 mL). The combined extracts were washed with brine (30 mL), dried over sodium sulfate, and concentrated under vacuum. The residue was purified by reverse-phase column chromatography using acetonitrile (10% to 60%) in water to obtain a yellow solid 5-(7-carbamoyl-3-chloro-5-fluoro-2-methyl-1H-indole-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate tert-butyl (100 mg, 61%).

[0308] 1H NMR(300MHz,DMSO-d6)δ 7.55(d,J=10.8Hz,1H),5.78(s,1H),4.04-3.97(m,2H),3.63-3.43(m,2H),2.37(s,3H),2.33-2.18(m,2H),1.39(s,9H).

[0309] ESI-MS[M+H-tBu] + (C 20 H 23 Calculated values ​​for ClFN3O3: 352.14, 352.14; measured values: 352.10, 352.10.

[0310] Step 5: 3-Chloro-5-fluoro-2-methyl-4-(1,2,5,6-tetrahydropyridine-3-yl)-1H-indole-7-carboxamide

[0311] [ka] A mixture of 5-(7-carbamoyl-3-chloro-5-fluoro-2-methyl-1H-indole-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate tert-butyl (100 mg, 0.245 mmol) and 4M hydrogen chloride in dioxane (3 mL) was stirred at 20°C for 2 hours. The reaction mixture was concentrated under vacuum, diluted with saturated aqueous sodium bicarbonate (30 mL), and extracted with ethyl acetate (3 × 20 mL). The combined extract was dried over sodium sulfate and concentrated under vacuum to obtain the green solid 3-chloro-5-fluoro-2-methyl-4-(1,2,5,6-tetrahydropyridine-3-yl)-1H-indole-7-carboxamide (70 mg).

[0312] ESI-MS[M+H] + (C 15 H 15 Calculated values ​​for ClFN3O: 308.09, 310.09; measured values: 308.05, 310.05.

[0313] Step 6: 4-(1-acryloyl-1,2,5,6-tetrahydropyridine-3-yl)-3-chloro-5-fluoro-2-methyl-1H-indole-7-carboxamide

[0314] [ka] 4-(1-acryloyl-1,2,5,6-tetrahydropyridine-3-yl)-3-chloro-5-fluoro-2-methyl-1H-indole-7-carboxamide: To a mixture of 3-chloro-5-fluoro-2-methyl-4-(1,2,5,6-tetrahydropyridine-3-yl)-1H-indole-7-carboxamide (70 mg, 0.23 mmol) in tetrahydrofuran (4.0 mL) and water (1.0 mL), sodium bicarbonate (57 mg, 0.68 mmol) and acryloyl chloride (20 mg, 0.23 mmol) were added at 0°C. The reaction mixture was stirred at 0°C for 2 hours. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 × 10 mL). The combined extract was washed with brine (10 mL), dried over sodium sulfate, and concentrated under vacuum. The residue was purified by reverse-phase column chromatography using acetonitrile (10% to 35%) in water to obtain a green solid 4-(1-acryloyl-1,2,5,6-tetrahydropyridine-3-yl)-3-chloro-5-fluoro-2-methyl-1H-indole-7-carboxamide (42.3 mg, 51%).

[0315] 1 H NMR(300MHz,DMSO-d6)δ 11.37(s,1H),8.12(s,1H),7.68-7.50(m,2H),6.93-6.69(m,1H),6.13(d,J=17.4H) z,1H),5.83-5.62(m,2H),4.35-4.05(m,2H),3.90-3.60(m,2H),2.41-2.27(m,5H).

[0316] ESI-MS[M+H] + (C 18 H 17Calculated values ​​for ClFN3O2: 362.10, 364.10; measured values: 362.05, 362.05.

[0317] Example 2 Synthesis of 4-(1-acryloylpiperidine-3-yl)-3-chloro-5-fluoro-2-methyl-1H-indole-7-carboxamide (compound 2)

[0318] [ka] Step 1: 3-(7-carbamoyl-5-fluoro-2-methyl-1H-indole-4-yl)piperidine-1-carboxylate tert-butyl

[0319] [ka] A mixture of 5-(7-carbamoyl-5-fluoro-2-methyl-1H-indole-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate tert-butyl (prepared as described in Example 1 of this specification; 390 mg, 1.04 mmol) and Pd / C (10%, 500 mg) in methanol (20 mL) was stirred at 25°C under hydrogen (2 atm) for 16 hours. The reaction mixture was filtered. The filtrate was concentrated under vacuum to obtain a white solid 3-(7-carbamoyl-5-fluoro-2-methyl-1H-indole-4-yl)piperidine-1-carboxylate tert-butyl (340 mg, 87%).

[0320] ESI-MS[MH] - (C 20 H 26 The calculated value for FN3O3 is 374.20, and the measured value is 374.15.

[0321] Step 2: 3-(7-carbamoyl-3-chloro-5-fluoro-2-methyl-1H-indole-4-yl)piperidine-1-carboxylate tert-butyl

[0322] [ka] To a solution of 3-(7-carbamoyl-3-chloro-5-fluoro-2-methyl-1H-indole-4-yl)piperidine-1-carboxylate tert-butyl (340 mg, 0.91 mmol) in DMF (10 mL), NCS (133 mg, 0.996 mmol) was added at 0°C. The reaction mixture was stirred at 0°C for 1 hour. The reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (3 × 30 mL). The combined extracts were washed with brine (3 × 20 mL), dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography (0 to 50% ethyl acetate in petroleum ether) to obtain a white solid tert-butyl 3-(7-carbamoyl-3-chloro-5-fluoro-2-methyl-1H-indole-4-yl)piperidine-1-carboxylate (270 mg, 73%).

[0323] 1 H NMR(400MHz,DMSO-d6)δ 11.32(s,1H),8.10(s,1H),7.56-7.46(m,2H),4.14-3.96(m,3H),3.30-3.09(m,1H),2.91-2. 62(m,1H),2.39(s,3H),1.94-1.87(m,2H),1.79-1.69(m,1H),1.47-1.38(m,1H),1.38(s,9H).

[0324] ESI-MS[M+H-tBu]+(C 20 H 25 Calculated values ​​for ClFN3O3: 354.16, 356.16; measured values: 354.15, 356.15.

[0325] Step 3: 3-Chloro-5-fluoro-2-methyl-4-(piperidine-3-yl)-1H-indole-7-carboxamide hydrochloride

[0326] [ka] A mixture of 3-chloro-5-fluoro-2-methyl-4-(piperidine-3-yl)-1H-indole-7-carboxamide hydrochloride, tert-butyl 3-(7-carbamoyl-3-chloro-5-fluoro-2-methyl-1H-indole-4-yl)piperidine-1-carboxylate (312 mg, 0.76 mmol), and hydrogen chloride (4 M in dioxane, 6.0 mL) was stirred at 25°C for 1 hour. The reaction mixture was concentrated under vacuum to obtain a white solid, 3-chloro-5-fluoro-2-methyl-4-(piperidine-3-yl)-1H-indole-7-carboxamide hydrochloride (260 mg).

[0327] ESI-MS[MH]-(C 15 H 17 Calculated values ​​for ClFN3O: 308.10, 310.10; measured values: 308.00, 310.00.

[0328] Step 4: 4-(1-acryloylpiperidine-3-yl)-3-chloro-5-fluoro-2-methyl-1H-indole-7-carboxamide

[0329] [ka] A mixture of 4-(1-acryloylpiperidine-3-yl)-3-chloro-5-fluoro-2-methyl-1H-indole-7-carboxamide:3-chloro-5-fluoro-2-methyl-4-(piperidine-3-yl)-1H-indole-7-carboxamide hydrochloride (260 mg, 0.76 mmol) in water (2 mL) and THF (8 mL) was mixed with sodium bicarbonate (382 mg, 4.55 mmol) and acryloyl chloride (65 mg, 0.76 mmol) at 0°C. The reaction mixture was stirred at 0°C for 0.5 hours, diluted with water (20 mL), and extracted with ethyl acetate (3 × 15 mL). The combined extract was washed with brine (20 mL), dried over sodium sulfate, and concentrated under vacuum. The residue was purified by preparative HPLC (column: XSelect CSH Prep C18 OBD Column, 5um, 19×150mm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: 10% B to 35% B, 7 min; 220 nm; retention time = 6.4 min) to obtain a white solid 4-(1-acryloylpiperidine-3-yl)-3-chloro-5-fluoro-2-methyl-1H-indole-7-carboxamide (165 mg, 60%).

[0330] 1 H NMR(300MHz,DMSO-d6)δ 11.40(s,1H),8.12(s,1H),7.62-7.48(m,2H),6.84-6.76(m,1H),6.16-6.07(m,1H),5.66-5.60(m,1H),4.57(d,J=12.6Hz,1H),4. 23-3.94(m,2H),3.55-3.51(m,0.5H),3.12-3.08(m,1H),2.78-2.60(m,0.5H),2.40(s,3H),2.17-1.77(m,3H),1.60-1.38(m,1H).

[0331] ESI-MS[M+H]+(C 18 H 19 Calculated values ​​for ClFN3O2: 364.11, 366.11; measured values: 364.10, 366.10.

[0332] Step 5: Chiral separation (compounds 2a and 2b)

[0333] [ka] The enantiomers of 4-(1-acryloylpiperidine-3-yl)-3-chloro-5-fluoro-2-methyl-1H-indole-7-carboxamide were separated by preparative chiral HPLC (120 mg sample, column: CHIRALPAK IG, 2 × 25 cm, 5 μm; mobile phase A: hexane (0.5% 2M NH3-MeOH), mobile phase B: EtOH; flow rate: 17 mL / min; gradient: 50% B to 50% B in 14 mins; 220 / 254 nm) to obtain compounds 2a (RT=7.106 min) and 2b (RT=11.312 min).

[0334] A white solid of compound 2a (retention time = 7.106 minutes) was obtained in a volume of 48.6 mg. 1 H NMR(300MHz,DMSO-d6)δ 11.39(s,1H),8.11(s,1H),7.64-7.50(m,2H),6.84-6.80(m,1H),6.11-6.07(m,1H),5.66-5.61(m,1H),4.57(d,J=12.8Hz,1H),4. 26-3.91(m,2H),3.57-3.54(m,0.5H),3.12-3.18(m,1H),2.68-2.64(m,0.5H),2.40(s,3H),1.95-1.83(m,3H),1.70-1.50(m,1H).

[0335] ESI-MS[M+H]+(C 18 H 19 Calculated values ​​for ClFN3O2: 364.11, 366.11; measured values: 364.05, 366.05.

[0336] A white solid of 46.7 mg of compound 2b (retention time = 11.312 minutes) was obtained. 1H NMR(300MHz,DMSO-d6)δ 11.40(s,1H),8.11(s,1H),7.63-7.46(m,2H),6.84-6.80(m,1H),6.11-5.95(m,1H),5.66-5.41(m,1H),4.57(d,J=12.7Hz,1H),4. 23-3.95(m,2H),3.57-3.54(m,0.5H),3.12-3.01(m,1H),2.68-2.55(m,0.5H),2.40(s,3H),1.95-1.73(m,3H),1.70-1.50(m,1H).

[0337] ESI-MS[M+H]+(C 18 H 19 Calculated values ​​for ClFN3O2: 364.11, 366.11; measured values: 364.10, 366.10.

[0338] Example 3 Synthesis of 4-(1-acryloylpiperidine-3-yl)-3-chloro-5,6-difluoro-2-methyl-1H-indole-7-carboxamide (compound 3)

[0339] [ka] Step 1: 1,4-dibromo-2,3-difluoro-5-nitrobenzene

[0340] [ka] Potassium nitrate (11.0 g, 108.8 mmol) was added at 0°C to a solution of 1,4-dibromo-2,3-difluorobenzene (25.0 g, 91.95 mmol) in concentrated sulfuric acid (200 mL). The reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was poured into ice water (1 L) and stirred at 0°C for 30 minutes. The resulting precipitate was filtered, the filter cake was washed with water, and dried under reduced pressure to obtain a yellow solid of 1,4-dibromo-2,3-difluoro-5-nitrobenzene (27.0 g, 92%).

[0341] 1 H NMR(300MHz,DMSO-d6)δ 8.47(dd,J=6.0,2.4 Hz 1H).

[0342] Step 2: 2,5-dibromo-3,4-difluoroaniline

[0343] [ka] To a solution of 1,4-dibromo-2,3-difluoro-5-nitrobenzene (27.0 g, 85.21 mmol) in acetic acid (260 mL), iron powder (47.6 g, 852.0 mmol) was added. The reaction mixture was stirred at 45°C for 5 hours. The cooled reaction mixture was filtered. The filtrate was poured into ice water (500 mL) and filtered. The filter cake was washed with water (300 mL) and dried under reduced pressure to obtain a yellow solid of 2,5-dibromo-3,4-difluoroaniline (23.0 g, yield 94%).

[0344] 1 H NMR(300MHz,DMSO-d6)δ 6.88(dd,J=6.0,2.4 Hz 1H),5.74(brs,2H).

[0345] Step 3: 2,5-dibromo-3,4-difluoro-6-iodoaniline

[0346] [ka] To a solution of 2,5-dibromo-3,4-difluoroaniline (23.0 g, 80.17 mmol) in acetic acid (250 mL), N-iodosuccinimide (19.84 g, 88.18 mmol) was added. The reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was poured into ice water (500 mL) and filtered. The filtered cake was washed with water (100 mL) and dried under reduced pressure. The crude product was purified by silica gel column chromatography eluted with ethyl acetate (0 to 5%) in petroleum ether to obtain a grayish-white solid of 2,5-dibromo-3,4-difluoro-6-iodoaniline (30.0 g, 90%).

[0347] 1 H NMR(300MHz,DMSO-d6)δ 5.63(s,2H).

[0348] ESI-MS[MH] - Calculated values ​​for (C6H2Br2F2IN): 409.76, 411.75, 413.75. Measured values: 409.75, 411.75, 413.70.

[0349] Step 4: 2,5-dibromo-3,4-difluoro-6-(propa-1-in-1-yl)aniline

[0350] [ka] A mixture of 2,5-dibromo-3,4-difluoro-6-iodoaniline (30.0 g, 72.68 mmol), copper(II) iodide (2.77 g, 14.54 mmol), and Pd(PPh3)2Cl2 (5.12 g, 7.27 mmol) in triethylamine (365 mL) was mixed with propane-1-yne (1 M in THF, 364 mL) under nitrogen. The reaction mixture was stirred in a sealed flask at 50°C for 4 hours. The cooled reaction mixture was quenched with water (300 mL) and extracted with ethyl acetate (300 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by column chromatography on silica gel eluted with ethyl acetate (0 to 10%) in petroleum ether to obtain 2,5-dibromo-3,4-difluoro-6-(propa-1-in-1-yl)aniline (20.0 g, 84%) as a yellow solid.

[0351] ESI-MS[MH] - Calculated values ​​for (C9H5Br2F2N) are 321.88, 323.87, and 325.87. Measured values ​​are 322.00, 324.00, and 326.00.

[0352] 1 H NMR(300MHz,DMSO-d6)δ 5.79(s,2H),2.18(s,3H).

[0353] Step 5: 4,7-dibromo-5,6-difluoro-2-methyl-1H-indole

[0354] [ka] A mixture of 2,5-dibromo-3,4-difluoro-6-(propa-1-in-1-yl)aniline (20.0 g, 61.55 mmol) and PdCl2 (1.09 g, 6.15 mmol) in acetonitrile (400 mL) was degassed, backpacked three times with nitrogen, and stirred at 85°C for 5 hours. The cooled reaction mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography eluted with ethyl acetate (0 to 10%) in petroleum ether to obtain a yellow solid of 4,7-dibromo-5,6-difluoro-2-methyl-1H-indole (17.0 g, 85%).

[0355] 1 H NMR(300MHz,DMSO-d6)δ 11.75(s,1H),6.28(s,1H),2.41(s,3H).

[0356] ESI-MS[MH] - Calculated values ​​for (C9H5Br2F2N): 321.88, 323.87, 325.87. Measured values: 321.80, 323.80, 325.80.

[0357] Step 6: 4,7-dibromo-5,6-difluoro-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole

[0358] [ka] To a stirred solution of 4,7-dibromo-5,6-difluoro-2-methyl-1H-indole (10.0 g, 30.77 mmol) in THF (200 mL), sodium hydride (1.60 g, 40.01 mmol, 60%) was added at 0°C. After stirring at this temperature for 1 hour, 2-(trimethylsilyl)ethoxymethyl chloride (7.70 g, 46.16 mmol) was added at 0°C. The reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was quenched with water (200 mL) and extracted with ethyl acetate (150 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by column chromatography using silica gel with ethyl acetate (0 to 10%) in petroleum ether to obtain yellow oily 4,7-dibromo-5,6-difluoro-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole (12.3 g, 87%).

[0359] 1 H NMR(300MHz,DMSO-d6)δ 6.42(s,1H),5.78(s,2H),3.55(t,J=7.8Hz,2H),2.47(s,3H),0.83(t,J=8.1Hz,2H),-0.08(s,9H).

[0360] Step 7: 4-Bromo-5,6-difluoro-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7-carboxylic acid

[0361] [ka] To a solution of 4,7-dibromo-5,6-difluoro-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole (12.3 g, 27.03 mmol) in THF (130 mL), n-butyllithium (2.5 M in n-hexane, 13 mL, 32.5 mmol) was added under nitrogen at -70°C. After stirring at this temperature for 0.5 hours and then at 0°C for 0.5 hours, the reaction mixture was cooled to -70°C and bubbling with carbon dioxide for 30 minutes. After stirring at 25°C for 1.5 hours, the reaction mixture was quenched with saturated aqueous ammonium chloride (100 mL) and extracted with dichloromethyl (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain a yellow, oily 4-bromo-5,6-difluoro-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7-carboxylic acid (11.4 g, crude).

[0362] ESI-MS[MH] - (C 16 H 20 Calculated values ​​for BrF2NO3Si: 418.04, 420.03. Measured values: 417.95, 419.95.

[0363] Step 8: 4-bromo-5,6-difluoro-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7-carboxamide

[0364] [ka] To a stirred mixture of 4-bromo-5,6-difluoro-2-methyl-1-(2-trimethylsilylethoxymethyl)indole-7-carboxylic acid (11.4 g, 27.12 mmol) and ammonium chloride (2.18 g, 40.68 mmol) in DMF (100 mL), HATU (12.38 g, 32.55 mmol) and DIPEA (17.53 g, 135.61 mmol) were added at 0°C. After stirring at 25°C for 16 hours, the reaction mixture was quenched with water (300 ml) and extracted with ethyl acetate (300 ml x 3). The combined organic layers were washed with brine (200 ml x 3), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography using ethyl acetate (0 to 50%) in petroleum ether to obtain a yellow solid, 4-bromo-5,6-difluoro-2-methyl-1-((2-(trimehyalsilyl)ethoxy)methyl)-1H-indole-7-carboxamide (6.3 g, 55%).

[0365] 1 H NMR(300MHz,DMSO-d6)δ 8.34(s,1H),8.10(s,1H),6.40(s,1H),5.50(s,2H),3.42(t,J=8.1Hz,2H),2.46(s,3H),0.81(t,J=8.1Hz,2H),-0.06(s,9H).

[0366] ESI-MS[M+H] + (C 16 H 21 Calculated values ​​for BrF2N2O2Si: 419.05, 421.05. Measured values: 419.20, 421.20.

[0367] Step 9: 4-bromo-5,6-difluoro-2-methyl-1H-indole-7-carboxamide

[0368] [ka] The mixture of 4-bromo-5,6-difluoro-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7-carboxamide (6.3 g, 15.02 mmol), TBAF (1 M in THF, 150 mL, 150.2 mmol), and ethane-1,2-diamine (30 mL, 450.6 mmol) was stirred at 75°C for 40 hours. The reaction mixture was cooled to 0°C and acidified to pH=4 with 2 M hydrochloric acid. The precipitate was collected by filtration, washed with water (100 mL), and dried under reduced pressure to obtain a yellow solid of 4-bromo-5,6-difluoro-2-methyl-1H-indole-7-carboxamide (3.5 g, 80%).

[0369] ESI-MS[M+H]+(C 10 Calculated values ​​for H7BrF2N2O: 288.97, 290.97. Measured values: 288.95, 290.95.

[0370] 1H NMR(300MHz,DMSO-d6)δ 11.38(s,1H),7.97(s,1H),7.90(s,1H),6.20(s,1H),2.40(s,3H).

[0371] Step 10: 5-(7-carbamoyl-5,6-difluoro-2-methyl-1H-indole-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate tert-butyl

[0372] [ka] A mixture of 4-bromo-5,6-difluoro-2-methyl-1H-indole-7-carboxamide (600 mg, 2.1 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate tert-butyl (706 mg, 2.3 mmol), Pd(dppf)Cl2.DCM (169 mg, 0.21 mmol), and potassium carbonate (860 mg, 6.23 mmol) in dioxane (12 mL) and water (3 mL) was degassed, backpacked five times with nitrogen, and stirred at 90°C for 2 hours. The cooled reaction mixture was diluted with water (60 mL) and extracted with dichloromethane (3 × 50 mL). The combined organic layers were washed with brine (60 mL), dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography eluted with ethyl acetate (0 to 7%) in dichloromethane to obtain a yellow solid 5-(7-carbamoyl-5,6-difluoro-2-methyl-1H-indole-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate tert-butyl (700 mg, 86%).

[0373] ESI-MS[MH]-(C 20 H 23 Calculated value for F2N3O3: 390.17; Measured value: 390.05.

[0374] 1H NMR(400MHz,DMSO-d6)δ 11.07(s,1H),7.86(s,1H),7.77(s,1H),6.18(s,1H),6.08-5.98(m,1H),4.17-4 .07(m,2H),3.55(t,J=5.8Hz,2H),2.37(s,3H),2.35-2.27(m,2H),1.42(s,9H).

[0375] Step 11: 3-(7-carbamoyl-5,6-difluoro-2-methyl-1H-indole-4-yl)piperidine-1-carboxylate tert-butyl

[0376] [ka] To a stirred solution of 5-(7-carbamoyl-5,6-difluoro-2-methyl-1H-indole-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate tert-butyl (450 mg, 1.15 mmol) in methanol (60 mL) and tetrahydrofuran (30 mL), Pd / C (300 mg, 10%) was added. The reaction mixture was stirred at 25°C under hydrogen (2 atm) for 48 hours. The reaction mixture was filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography eluted with ethyl acetate (0 to 7%) in dichloromethane to obtain a yellow solid of 3-(7-carbamoyl-5,6-difluoro-2-methyl-1H-indole-4-yl)piperidine-1-carboxylate tert-butyl (400 mg, 88%).

[0377] 1 H NMR(400MHz,DMSO-d6)δ 11.02(s,1H),7.82(s,1H),7.71(s,1H),6.38(s,1H),4.04-3.82(m,2H),3.31-3.04(m,2H),3.01 -2.63(m,1H),2.38(s,3H),2.14-1.99(m,1H),1.90-1.68(m,2H),1.59-1.44(m,1H),1.40(s,9H).

[0378] ESI-MS[M+H-tBu] + (C 20 H 25 The calculated value for F2N3O3 is 338.19, while the measured value is 338.10.

[0379] Step 12: 3-(7-carbamoyl-3-chloro-5,6-difluoro-2-methyl-1H-indole-4-yl)piperidine-1-carboxylate tert-butyl

[0380] [ka] To a stirred solution of 3-(7-carbamoyl-5,6-difluoro-2-methyl-1H-indole-4-yl)piperidine-1-carboxylate tert-butyl (400 mg, 1.02 mmol) in DMF (10 mL), NCS (136 mg, 1.02 mmol) was added at 0°C. The reaction mixture was stirred at 25°C for 3 hours. The reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (3 × 40 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography eluted with methanol (0 to 8%) in dichloromethane to obtain a yellow solid of 3-(7-carbamoyl-3-chloro-5,6-difluoro-2-methyl-1H-indole-4-yl)piperidine-1-carboxylate tert-butyl (350 mg, 80%).

[0381] 1 H NMR(400MHz,DMSO-d6)δ 11.45(s,1H),7.92(s,1H),7.85(s,1H),4.13-4.04(m,2H),3.27-3.06(m,2H),2.90-2.65( m,1H),2.36(s,3H),1.98-1.88(m,2H),1.80-1.71(m,1H),1.57-1.42(m,1H),1.39(s,9H).

[0382] ESI-MS[M+H-tBu] + (C 20 H 24 Calculated values ​​for ClF2N3O3: 372.15, 374.14. Measured values: 372.10, 374.10.

[0383] Step 13: 3-Chloro-5,6-difluoro-2-methyl-4-(piperidine-3-yl)-1H-indole-7-carboxamide hydrochloride

[0384] [ka] To a stirred solution of tert-butyl 3-(7-carbamoyl-3-chloro-5,6-difluoro-2-methyl-1H-indole-4-yl)piperidine-1-carboxylate (350 mg, 0.82 mmol) in methanol (1 mL), hydrogen chloride (4 M in dioxane, 5 mL) was added. The reaction mixture was stirred at 25°C for 1 hour. The mixture was concentrated under vacuum to obtain a yellow solid, 3-chloro-5,6-difluoro-2-methyl-4-(piperidine-3-yl)-1H-indole-7-carboxamide hydrochloride (280 mg, 94%).

[0385] ESI-MS[M+H] + (C 15 H 16 Calculated values ​​for ClF2N3O: 328.09, 330.09; Measured values: 328.15, 330.15.

[0386] Step 14: 4-(1-acryloylpiperidine-3-yl)-3-chloro-5,6-difluoro-2-methyl-1H-indole-7-carboxamide

[0387] [ka] To a stirred solution of 3-chloro-5,6-difluoro-2-methyl-4-(3-piperidyl)-1H-indole-7-carboxamide (280 mg, 0.76 mmol) in THF (4 mL), DIEA (294 mg, 2.28 mmol) and acryloyl chloride (98 mg, 0.76 mmol) were added at -70°C. The reaction mixture was stirred at -70°C for 1 hour. The reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, and concentrated under vacuum. The residue was analyzed by preparative HPLC under the following conditions: Column: XBridge Prep OBD C18 Column, 30 × 150 mm 5 μm; Mobile phase A: Water (10 mmol / L NH4HCO3 + 0.1%) The mixture was purified using NH3 (H2O), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 30% B to 52% B over 7 mins; 220 nm; Rt: 6.32 mins to obtain a grayish-white solid of 4-(1-acryloylpiperidine-3-yl)-3-chloro-5,6-difluoro-2-methyl-1H-indole-7-carboxamide (123.7 mg, 42%).

[0388] 1 H NMR(400MHz,DMSO-d6)δ 11.46(s,1H),7.95(s,1H),7.88(s,1H),6.96-6.70(m,1H),6.20-6.03(m,1H),5.81-5.57(m,1H),4.74-4.45(m,1H),4.28-3.94(m,2H) ),3.60-3.45(m,0.5H),3.19-3.00(m,1H),2.77-2.63(m,0.5H),2.35(s,3H),2.13-1.91(m,2H),1.89-1.77(m,1H),1.64-1.40(m,1H).

[0389] ESI-MS[M+H] + (C 18 H 18 Calculated values ​​for ClF2N3O2: 382.11, 384.11. Measured values: 382.25, 384.25.

[0390] Example 4 Synthesis of 4-(1-acryloyl-1,2,5,6-tetrahydropyridine-3-yl)-3-chloro-5,6-difluoro-2-methyl-1H-indole-7-carboxamide (compound 4)

[0391] [ka] Step 1: 5-(7-carbamoyl-3-chloro-5,6-difluoro-2-methyl-1H-indole-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate tert-butyl

[0392] [ka] To a stirred solution of 5-(7-carbamoyl-5,6-difluoro-2-methyl-1H-indole-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate tert-butyl (150 mg, 0.38 mmol), NCS (52 mg, 0.38 mmol) was added at 0°C. The reaction mixture was stirred at 25°C for 4 hours. The reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, and concentrated under vacuum. The residue was purified by column chromatography with aluminum oxide, eluted with methanol (0 to 10%) in dichloromethane, to obtain a yellow solid of 5-(7-carbamoyl-3-chloro-5,6-difluoro-2-methyl-1H-indole-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate tert-butyl (140 mg, 85%).

[0393] 1 H NMR(400MHz,DMSO-d6)δ 11.46(s,1H),7.95(s,1H),7.89(s,1H),5.85(s,1H),4.16-3.91(m,2H),3.60-3.46(m,2H),2.35(s,3H),2.31-2.24(m,2H),1.40(s,9H).

[0394] ESI-MS[M+H] + (C 20 H 22 Calculated values ​​for ClF2N3O3: 426.13, 426.13. Measured values: 426.15, 428.15.

[0395] Step 2: 3-Chloro-5,6-difluoro-2-methyl-4-(1,2,5,6-tetrahydropyridine-3-yl)-1H-indole-7-carboxamide hydrochloride

[0396] [ka] To a stirred solution of tert-butyl 5-(7-carbamoyl-3-chloro-5,6-difluoro-2-methyl-1H-indole-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate (140 mg, 0.33 mmol) in methanol (1 mL), hydrogen chloride (4 M in dioxane, 2 mL) was added. The reaction mixture was stirred at 25°C for 1 hour. The mixture was concentrated under vacuum to obtain a yellow solid, 3-chloro-5,6-difluoro-2-methyl-4-(1,2,5,6-tetrahydropyridine-3-yl)-1H-indole-7-carboxamide hydrochloride (125 mg, crude).

[0397] ESI-MS[M+H] + (C 15 H 14 For ClF2N3O, the calculated values ​​are 326.08 and 328.08, while the measured values ​​are 326.10 and 328.10.

[0398] Step 3: 4-(1-acryloyl-1,2,5,6-tetrahydropyridine-3-yl)-3-chloro-5,6-difluoro-2-methyl-1H-indole-7-carboxamide

[0399] [ka] To a stirred solution of 3-chloro-5,6-difluoro-2-methyl-4-(1,2,5,6-tetrahydropyridine-3-yl)-1H-indole-7-carboxamide hydrochloride (125 mg, 0.34 mmol) in THF (4 mL), DIEA (140 mg, 1.08 mmol) and acryloyl chloride (33 mg, 0.36 mmol) were added at -78°C. The reaction mixture was stirred at -78°C for 1 hour. The reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, and concentrated under vacuum. The residue was purified by preparative HPLC under the following conditions: column: Xselect CSH OBD Column 30×150mm 5um; mobile phase A: water (10MMOL / L NH4HCO3 + 0.1% NH3.H2O), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 33% B to 53% B in 7 mins; 220 nm; Rt: 5.53 mins to obtain a grayish-white solid of 4-(1-acryloyl-1,2,5,6-tetrahydropyridine-3-yl)-3-chloro-5,6-difluoro-2-methyl-1H-indole-7-carboxamide (66.3 mg, 48%).

[0400] 1 H NMR(400MHz,DMSO-d6)δ 11.47(s,1H),7.99(s,1H),7.93(s,1H),6.95-6.68(m,1H),6.19-6.08(m,1H),5.95-5. 84(m,1H),5.75-5.61(m,1H),4.40-4.09(m,2H),3.93-3.57(m,2H),2.44-2.16(m,5H).

[0401] ESI-MS[M+H] + (C 18 H 16 Calculated values ​​for ClF2N3O2: 380.09, 382.09. Measured values: 380.05, 382.05.

[0402] Example 5 Synthesis of 4-(1-acryloyl-1,2,5,6-tetrahydropyridine-3-yl)-3-cyano-5,6-difluoro-2-methyl-1H-indole-7-carboxamide (compound 5)

[0403] [ka] Step 1: 5-(3-bromo-7-carbamoyl-5,6-difluoro-2-methyl-1H-indole-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate tert-butyl

[0404] [ka] To a stirred solution of 5-(7-carbamoyl-5,6-difluoro-2-methyl-1H-indole-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate tert-butyl (600 mg, 1.53 mmol) in DMF (15 mL), N-bromosuccinimide (273 mg, 1.53 mmol) was added at 0°C. After stirring at 0°C for 2 hours, the reaction mixture was quenched with water (60 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography with elution in ethyl acetate (0 to 33%) in petroleum ether to obtain a yellow solid 5-(3-bromo-7-carbamoyl-5,6-difluoro-2-methyl-1H-indole-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate tert-butyl (530 mg, 73%).

[0405] 1 H NMR(400MHz,DMSO-d6)δ 11.57(s,1H),7.94(s,1H),7.89(s,1H),5.90-5.82(m,1H),4.15-3.86( m,2H),3.72-3.44(m,2H),2.36(s,3H),2.32-2.24(m,2H),1.41(s,9H).

[0406] ESI-MS[M+H-Boc] + (C 20 H 22 Calculated values ​​for BrF2N3O3: 370.08, 372.08. Measured values: 370.10, 372.10.

[0407] Step 2: 5-(7-carbamoyl-3-cyano-5,6-difluoro-2-methyl-1H-indole-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate tert-butyl

[0408] [ka] A mixture of 5-(3-bromo-7-carbamoyl-5,6-difluoro-2-methyl-1H-indole-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate tert-butyl (530 mg, 1.13 mmol), Pd(PPh3)4 (130 mg, 0.112 mmol), and Zn(CN)2 (132 mg, 1.13 mmol) in DMF (15 mL) was degassed and backpacked five times with nitrogen. The reaction mixture was heated at 120 °C for 2 hours. The cooled reaction mixture was quenched with water (60 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography with elution in ethyl acetate (0 to 43%) in petroleum ether to obtain a yellow solid 5-(7-carbamoyl-3-cyano-5,6-difluoro-2-methyl-1H-indole-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate tert-butyl (220 mg, 46%).

[0409] ESI-MS[M+H-Boc] + (C 21 H 22 Calculated value for F2N4O3: 317.17; Measured value: 317.15.

[0410] Step 3: 3-Cyano-5,6-difluoro-2-methyl-4-(1,2,5,6-tetrahydropyridine-3-yl)-1H-indole-7-carboxamide hydrochloride

[0411] [ka] To a stirred solution of 5-(7-carbamoyl-3-cyano-5,6-difluoro-2-methyl-1H-indole-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate tert-butyl (220 mg, 0.528 mmol) in MeOH (2 mL), 4 M hydrogen chloride in dioxane (5.00 mL) was added. The reaction mixture was stirred at 25°C for 1 hour. The resulting mixture was concentrated under vacuum to obtain a brown solid, 3-cyano-5,6-difluoro-2-methyl-4-(1,2,5,6-tetrahydropyridine-3-yl)-1H-indole-7-carboxamide hydrochloride (182 mg, crude).

[0412] ESI-MS[M+H] + (C 16 H 14 Calculated value for F2N4O: 317.11; Measured value: 317.15.

[0413] Step 4: 4-(1-acryloyl-1,2,5,6-tetrahydropyridine-3-yl)-3-cyano-5,6-difluoro-2-methyl-1H-indole-7-carboxamide

[0414] [ka] To a solution of 3-cyano-5,6-difluoro-2-methyl-4-(1,2,5,6-tetrahydropyridine-3-yl)-1H-indole-7-carboxamide hydrochloride (160 mg, 0.453 mmol) in THF (6 mL), DIEA (293 mg, 2.27 mmol) and acryloyl chloride (41 mg, 0.453 mmol) were added at -70°C. The reaction mixture was stirred at -70°C for 1 hour. The reaction mixture was quenched with water (40 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, and concentrated under vacuum. The residue was purified by preparative HPLC under the following conditions: column: XBridge Prep OBD C18 Column, 30 × 150 mm 5 μm; mobile phase A: water (50 mmol / L NH4HCO3), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 5% B to 95% B in 12 mins; 254 nm; RT: 4.33 mins to obtain a white solid 4-(1-acryloyl-1,2,5,6-tetrahydropyridine-3-yl)-3-cyano-5,6-difluoro-2-methyl-1H-indole-7-carboxamide (88 mg, 52%).

[0415] 1 H NMR(400MHz,DMSO-d6)δ 12.19(s,1H),8.16-7.94(m,2H),6.98-6.70(m,1H),6.17-6.01(m,2H),5.80-5. 63(m,1H),4.41-4.20(m,2H),3.88-3.67(m,2H),2.54(s,3H),2.44-2.28(m,2H).

[0416] ESI-MS[M+H] + (C 19 H 16 Calculated value for F2N4O2: 371.12; Measured value: 371.05.

[0417] Example 6 (S)-4-(1-acryloylpiperidine-3-yl)-3,5,6-trifluoro-2-methyl-1H-indole-7-carboxamide and (R)-4-(1-acryloylpiperidine-3-yl)-3,5,6-trifluoro-2-methyl-1H-indole-7-carboxamide Synthesis of compounds 6a and 6b

[0418] [ka] Step 1: 3-(7-carbamoyl-3,5,6-trifluoro-2-methyl-1H-indole-4-yl)piperidine-1-carboxylate tert-butyl

[0419] [ka] To a stirred solution of tert-butyl 3-(7-carbamoyl-5,6-difluoro-2-methyl-1H-indole-4-yl)peridin-1-carboxylate (500 mg, 1.27 mmol) in acetonitrile (8 mL) and DMSO (2 mL), selectfluor II (407 mg, 1.27 mmol) was added in fractions at 15°C. The reaction mixture was stirred at 15°C for 1 hour. The reaction mixture was quenched with water (30 mL) and extracted with dichloromethane (3 × 30 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography eluted with ethyl acetate (0 to 53%) in petroleum ether to obtain a yellow solid of tert-butyl 3-(7-carbamoyl-3,5,6-trifluoro-2-methyl-1H-indole-4-yl)peridin-1-carboxylate (300 mg, crude).

[0420] ESI-MS[M+H-tBu] + (C 20 H 24 Calculated value for F3N3O3: 356.18; Measured value: 356.10.

[0421] Step 2: 3,5,6-trifluoro-2-methyl-4-(piperidine-3-yl)-1H-indole-7-carboxamide hydrochloride

[0422] [ka] To a stirred solution of tert-butyl 3-(7-carbamoyl-3,5,6-trifluoro-2-methyl-1H-indole-4-yl)piperidine-1-carboxylate (300 mg, crude) in methanol (1 mL), hydrogen chloride (4 M in dioxane, 4 mL) was added. The reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was concentrated under vacuum to obtain a yellow solid, 3,5,6-trifluoro-2-methyl-4-(3-piperidyl)-1H-indole-7-carboxamide (220 mg, crude).

[0423] ESI-MS[M+H] + (C 15 H 16 Calculated value for F3N3O: 312.12; Measured value: 312.10.

[0424] Step 3: 4-(1-acryloylpiperidine-3-yl)-3,5,6-trifluoro-2-methyl-1H-indole-7-carboxamide

[0425] [ka] To a stirred solution of 3,5,6-trifluoro-2-methyl-4-(3-piperidyl)-1H-indole-7-carboxamide (200 mg, crude) in THF (6 mL), DIEA (223 mg, 1.73 mmol) and acryloyl chloride (52 mg, 0.58 mmol) were added at -70°C. The reaction mixture was stirred at -70°C for 1 hour. The reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, and concentrated under vacuum. The residue was purified by preparative HPLC under the following conditions: column: Xselect CSH OBD Column 30×150mm 5um; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 32% B to 53% B in 7 mins; 220 nm; RT: 5.43 mins to obtain a grayish-white solid of 4-(1-acryloylpiperidine-3-yl)-3,5,6-trifluoro-2-methyl-1H-indole-7-carboxamide (107 mg, 23% in 3 steps).

[0426] 1 H NMR(400MHz,DMSO-d6)δ 10.96(s,1H),7.92(s,1H),7.84(s,1H),6.96-6.71(m,1H),6.19-6.03(m,1H),5. 78-5.52(m,1H),4.54(t,J=12.4Hz,1H),4.15(d,J=13.2Hz,1H),3.49(t,J=12.4H z,0.5H),3.31-3.22(m,1H),3.16-2.97(m,1H),2.64(t,J=13.4Hz,0.5H),2.31(s ,3H),2.12-1.97(m,1H),1.96-1.87(m,1H),1.86-1.76(m,1H),1.56-1.36(m,1H).

[0427] ESI-MS[M+H] + (C 18 H 18 Calculated value for F3N3O2: 366.14; Measured value: 366.15.

[0428] Step 4: (S)-4-(1-acryloylpiperidine-3-yl)-3,5,6-trifluoro-2-methyl-1H-indole-7-carboxamide and (R)-4-(1-acryloylpiperidine-3-yl)-3,5,6-trifluoro-2-methyl-1H-indole-7-carboxamide

[0429] [ka] 4-(1-acryloylpiperidine-3-yl)-3,5,6-trifluoro-2-methyl-1H-indole-7-carboxamide (90 mg) was purified by preparative chiral HPLC under the following conditions: Column: CHIRALPAK IG, 2 × 25 cm, 5 μm; Mobile phase A: Hexane (0.5% 2M NH3-MeOH)--HPLC, Mobile phase B: EtOH--HPLC; Flow rate: 20 mL / min; Gradient: 50% B to 50% B over 26 mins; Purified at 220 / 254 nm.

[0430] Retention time: 12.231 minutes 1 H NMR(300MHz,DMSO-d6)δ 10.96(s,1H),7.92(s,1H),7.84(s,1H),7.00-6.72(m,1H),6.22-6.05 (m,1H),5.79-5.58(m,1H),4.67-4.47(m,1H),4.17(d,J=13.2Hz,1H), 3.50(t,J=12.6Hz,0.5H),3.31-3.22(m,1H),3.18-2.98(m,1H),2.66( t,J=12.6Hz,0.5H),2.33(s,3H),2.17-1.79(m,3H),1.62-1.41(m,1H).

[0431] ESI-MS[M+H] + (C 18 H 18 Calculated value for F3N3O2: 366.14; Measured value: 366.15. Retention time: 20.421;min 1H NMR(300MHz,DMSO-d6)δ 10.96(s,1H),7.92(s,1H),7.84(s,1H),6.97-6.63(m,1H),6.24-6.01 (m,1H),5.80-5.55(m,1H),4.66-4.45(m,1H),4.17(d,J=13.2Hz,1H), 3.51(t,J=12.6Hz,0.5H),3.30-3.21(m,1H),3.19-2.97(m,1H),2.66( t,J=12.6Hz,0.5H),2.33(s,3H),2.16-1.77(m,3H),1.65-1.41(m,1H).

[0432] ESI-MS[M+H] + (C 18 H 18 Calculated value for F3N3O2: 366.14; Measured value: 366.15.

[0433] White solid (S)-4-(1-acryloylpiperidine-3-yl)-3,5,6-trifluoro-2-methyl-1H-indole-7-carboxamide (32.6 mg 36%); White solid (R)-4-(1-acryloylpiperidine-3-yl)-3,5,6-trifluoro-2-methyl-1H-indole-7-carboxamide (32.2 mg 36%)

[0434] Examples 7-19 Synthesis of compounds 7-19 Compounds 7-19, shown in Table 5 below, were prepared by following a method similar to that described in the preceding scheme and examples, using appropriate starting materials accordingly.

[0435] [Table 5-1]

[0436] [Table 5-2]

[0437] [Table 5-3]

[0438] Preparation of the compound of formula (II)

[0439] [ka] × is CH2, R 3 H is R II2 Preparation of the compound of formula (II) where is H

[0440] [ka]

[0441] Example 20 Synthesis of 4-(2-acryloyl-1,2,3,4-tetrahydroisoquinoline-5-yl)-3-chloro-5-fluoro-2-methyl-1H-indole-7-carboxamide (compound 20a)

[0442] [ka] Step 1: 5-(7-carbamoyl-5-fluoro-2-methyl-1H-indole-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate tert-butyl

[0443] [ka] A mixture of 4-bromo-5-fluoro-2-methyl-1H-indole-7-carboxamide (2.0 g, 7.38 mmol), tert-butyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylic acid (2.70 g, 7.38 mmol), potassium phosphate (4.70 g, 22.1 mmol), and Pd(dppf)Cl2 (540 mg, 0.738 mmol) in tetrahydrofuran (16 mL) and water (4.0 mL) was degassed and backpacked with nitrogen. The reaction mixture was stirred under nitrogen at 30°C for 16 hours, then diluted with water (50 mL) and extracted with ethyl acetate (3 × 50 mL). The combined extract was washed with brine (50 mL), dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography (45% ethyl acetate in petroleum ether) to obtain a yellow solid 5-(7-carbamoyl-5-fluoro-2-methyl-1H-indole-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate tert-butyl (2.50 g, 80%).

[0444] 1 H NMR(300MHz,DMSO-d6)δ 11.03(s,1H),8.10(s,1H),7.60-7.47(m,2H),7.32-7.23(m,2H),7.16-7.13(m,1H) ,5.71(s,1H),4.64-4.49(m,2H),3.55-3.43(m,2H),2.39-2.30(m,5H),1.05(s,9H).

[0445] ESI-MS[M+H]+(C 24 H 26 The calculated value for FN3O3 was 424.20, while the measured value was 424.15.

[0446] Step 2: 5-(7-carbamoyl-3-chloro-5-fluoro-2-methyl-1H-indole-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate tert-butyl

[0447] [ka] To a solution of 5-(7-carbamoyl-5-fluoro-2-methyl-1H-indole-4-yl)-3,4-dihydro-isoquinoline-2(1H)-carboxylate tert-butyl (3.0 g, 7.08 mmol) in N,N-dimethylformamide (30.0 mL), N-chlorosuccinimide (1.00 g, 7.79 mmol) was added at 0°C. The reaction mixture was stirred at 0°C for 2 hours. The reaction mixture was quenched with water (80 mL) and extracted with ethyl acetate (3 × 60 mL). The combined extracts were washed with brine (60 mL), dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography (45% ethyl acetate in petroleum ether) to obtain a yellow solid 5-(7-carbamoyl-3-chloro-5-fluoro-2-methyl-1H-indole-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate tert-butyl (2.30 g, 71%).

[0448] 1 H NMR(400MHz,DMSO-d6)δ 11.42(s,1H),8.16(s,1H),7.70-7.56(m,2H),7.28-7.20(m,2H),7.09-7. 06(m,1H),4.56(s,2H),3.49-3.34(m,2H),2.40-2.22(m,5H),1.38(s,9H).

[0449] ESI-MS[M+H-Boc]+(C 24 H 25 Calculated values ​​for ClFN3O3: 358.16, 360.16; Measured values: 358.05, 360.05

[0450] Step 3: 3-Chloro-5-fluoro-2-methyl-4-(1,2,3,4-tetrahydroisoquinoline-5-yl)-1H-indole-7-carboxamide

[0451] [ka] A mixture of 5-(7-carbamoyl-3-chloro-5-fluoro-2-methyl-1H-indole-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate tert-butyl (2.30 g, 5.02 mmol) and 4.0 M hydrogen chloride in dioxane (20 mL) was stirred at 20°C for 2 hours. The reaction mixture was concentrated under vacuum. The residue was diluted with saturated aqueous sodium bicarbonate (150 mL) and extracted with ethyl acetate (3 × 100 mL). The combined extracts were dried over sodium sulfate and concentrated under vacuum to obtain the brown solid 3-chloro-5-fluoro-2-methyl-4-(1,2,3,4-tetrahydroisoquinoline-5-yl)-1H-indole-7-carboxamide (1.70 g).

[0452] ESI-MS[M+H]+(C 19 H 17 Calculated values ​​for ClFN3O: 358.16, 360.16; measured values: 358.10, 360.10.

[0453] Step 4: 4-(2-acryloyl-1,2,3,4-tetrahydroisoquinoline-5-yl)-3-chloro-5-fluoro-2-methyl-1H-indole-7-carboxamide (compound 20a)

[0454] [ka] A mixture of 3-chloro-5-fluoro-2-methyl-4-(1,2,3,4-tetrahydroisoquinoline-5-yl)-1H-indole-7-carboxamide (1.70 g, 4.75 mmol) in tetrahydrofuran (16 mL) and water (4.0 mL) was mixed with sodium bicarbonate (1.20 g, 14.3 mmol) and acryloyl chloride (430 mg, 4.75 mmol) at 0°C. The reaction mixture was stirred at 0°C for 2 hours. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3 × 50 mL). The combined extract was washed with brine (50 mL), dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography (75% ethyl acetate in petroleum ether) to obtain a white solid 4-(2-acryloyl-1,2,3,4-tetrahydroisoquinoline-5-yl)-3-chloro-5-fluoro-2-methyl-1H-indole-7-carboxamide (1.20 g, 51%).

[0455] 1 H NMR(300MHz,DMSO-d6)δ 11.45(s,1H),8.19(s,1H),7.73-7.56(m,2H),7.38-7.22(m,2H),7.17-7.08(m,1H),6.98-6.75(m,1H),6 .17-6.11(m,1H),5.78-5.62(m,1H),4.87(s,0.8H),4.76(s,1.2H),3.77-3.56(m,2H),2.43-2.35(m,5H).

[0456] ESI-MS[M+H]+(C 22 H 19 Calculated values ​​for ClFN3O2: 412.11, 414.11; measured values: 412.05, 414.05.

[0457] Step 5: Isomer (R)-4-(2-acryloyl-1,2,3,4-tetrahydroisoquinoline-5-yl)-3-chloro-5-fluoro-2-methyl-1H-indole-7-carboxamide (compound 20b) and Separation of (S)-4-(2-acryloyl-1,2,3,4-tetrahydroisoquinoline-5-yl)-3-chloro-5-fluoro-2-methyl-1H-indole-7-carboxamide (compound 20c):

[0458] [ka] The two atropisomers were separated by preparative chiral HPLC (sample amount = 1.2 g, column: CHIRALPAK IC (2 × 25 cm, 5 μm); mobile phase A: hexane (0.5% 2M NH3-MeOH), mobile phase B: EtOH; flow rate: 20 mL / min; gradient: 30% B, isocratic, 16 min; 220 / 254 nm).

[0459] Compound 20b: Retention time = 9.807 minutes (530 mg) 1H NMR(400MHz,DMSO-d6)δ 11.45(s,1H),8.19(s,1H),7.67-7.63(m,2H),7.32-7.25(m,2H),7.13-7.11(m,1H),6.98-6.75(m,1H),6 .17-6.11(m,1H),5.75-5.65(m,1H),4.87(s,0.8H),4.76(s,1.2H),3.78-3.59(m,2H),2.41-2.35(m,5H).

[0460] ESI-MS[M+H]+(C 22 H 19 Calculated values ​​for ClFN3O2: 412.11, 414.11; measured values: 412.10, 414.10.

[0461] Compound 20c: Retention time = 12.634 minutes (515 mg) 1H NMR(400MHz,DMSO-d6)δ 11.45(s,1H),8.19(s,1H),7.68-7.64(m,2H),7.30-7.25(m,2H),7.13-7.11(m,1H),6.94-6.75(m,1H),6 .17-6.11(m,1H),5.75-5.65(m,1H),4.87(s,0.8H),4.76(s,1.2H),3.76-3.59(m,2H),2.41-2.35(m,5H).

[0462] ESI-MS[M+H]+(C 22 H 19 Calculated values ​​for ClFN3O2: 412.11, 414.11; measured values: 412.10, 414.10.

[0463] Compound 20d~20i The compounds listed below, 20d to 20i, were prepared using appropriate starting materials according to a method similar to that described in the preceding scheme and examples (NA = not applicable).

[0464] [Table 6-1]

[0465] [Table 6-2]

[0466] Compound 20j: 5-Fluoro-2,3-dimethyl-4-(2-propioloyl-1,2,3,4-tetrahydroisoquinoline-5-yl)-1H-indole-7-carboxamide

[0467] [ka] Compound 1j was prepared using a similar procedure, but with propioloyl chloride instead of acryloyl chloride.

[0468] 1H NMR(400MHz,DMSO-d6)δ 10.84(s,1H),8.08(s,1H),7.60-7.45(m,2H),7.38-7.28(m,2H),7.17-7.10(m,1H),4.97(s,1H),4.81 -4.70(m,1H),4.68-4.50(m,1H),4.00-3.51(m,2H),2.47-2.32(m,2H),2.29(s,3H),1.46-1.35(m,3H).

[0469] ESI-MS[M+H]+m / z=390.15

[0470] × is CH2, R 3 H is R II2 Preparation of the compound of formula (II) where F is

[0471] [ka]

[0472] Example 21 Preparation of 4-(2-acryloyl-1,2,3,4-tetrahydroisoquinoline-5-yl)-3-chloro-5,6-difluoro-2-methyl-1H-indole-7-carboxamide (compound 21a)

[0473] [ka] Step 1: 1,4-dibromo-2,3-difluoro-5-nitrobenzene

[0474] [ka] Potassium nitrate (11.0 g, 108.8 mmol) was added at 0°C to a solution of 1,4-dibromo-2,3-difluorobenzene (25.0 g, 91.95 mmol) in concentrated sulfuric acid (200 mL). The reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was poured into ice water (1 L) and stirred at 0°C for 30 minutes. The resulting precipitate was filtered, the filter cake was washed with water, and dried under reduced pressure to obtain a yellow solid of 1,4-dibromo-2,3-difluoro-5-nitrobenzene (27.0 g, 92%).

[0475] 1 H NMR(300MHz,DMSO-d6)δ 8.47(dd,J=6.0,2.4Hz 1H).

[0476] Step 2: 2,5-dibromo-3,4-difluoroaniline

[0477] [ka] To a solution of 1,4-dibromo-2,3-difluoro-5-nitrobenzene (27.0 g, 85.21 mmol) in acetic acid (260 mL), iron powder (47.6 g, 852.0 mmol) was added. The reaction mixture was stirred at 45°C for 5 hours. The cooled reaction mixture was filtered. The filtrate was poured into ice water (500 mL) and filtered. The filter cake was washed with water (300 mL) and dried under reduced pressure to obtain a yellow solid of 2,5-dibromo-3,4-difluoroaniline (23.0 g, yield 94%).

[0478] 1 H NMR(300MHz,DMSO-d6)δ 6.88(dd,J=6.0,2.4Hz 1H),5.74(brs,2H).

[0479] Step 3: 2,5-dibromo-3,4-difluoro-6-iodoaniline

[0480] [ka] To a solution of 2,5-dibromo-3,4-difluoroaniline (23.0 g, 80.17 mmol) in acetic acid (250 mL), N-iodosuccinimide (19.84 g, 88.18 mmol) was added. The reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was poured into ice water (500 mL) and filtered. The filtered cake was washed with water (100 mL) and dried under reduced pressure. The crude product was purified by silica gel column chromatography eluted with ethyl acetate (0 to 5%) in petroleum ether to obtain a grayish-white solid of 2,5-dibromo-3,4-difluoro-6-iodoaniline (30.0 g, 90%).

[0481] 1 H NMR(300MHz,DMSO-d6)δ 5.63(s,2H).

[0482] ESI-MS[MH] - Calculated values ​​for (C6H2Br2F2IN): 409.76, 411.75, 413.75. Measured values: 409.75, 411.75, 413.70.

[0483] Step 4: 2,5-dibromo-3,4-difluoro-6-(propa-1-in-1-yl)aniline

[0484] [ka] A mixture of 2,5-dibromo-3,4-difluoro-6-iodoaniline (30.0 g, 72.68 mmol), copper(I) iodide (2.77 g, 14.54 mmol), and Pd(PPh3)2Cl2 (5.12 g, 7.27 mmol) in triethylamine (365 mL) was mixed with propane-1-yne (1 M in THF, 364 mL) under nitrogen. The reaction mixture was stirred in a sealed flask at 50°C for 4 hours. The cooled reaction mixture was quenched with water (300 mL) and extracted with ethyl acetate (300 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by column chromatography on silica gel eluted with ethyl acetate (0 to 10%) in petroleum ether to obtain 2,5-dibromo-3,4-difluoro-6-(propa-1-in-1-yl)aniline (20.0 g, 84%) as a yellow solid.

[0485] 1 H NMR(300MHz,DMSO-d6)δ 5.79(s,2H),2.18(s,3H).

[0486] ESI-MS[MH] - Calculated values ​​for (C9H5Br2F2N) are 321.88, 323.87, 325.87. Measured values ​​are 322.00, 324.00, 326.00.

[0487] Step 5: 4,7-dibromo-5,6-difluoro-2-methyl-1H-indole

[0488] [ka] A mixture of 2,5-dibromo-3,4-difluoro-6-(propa-1-in-1-yl)aniline (20.0 g, 61.55 mmol) and PdCl2 (1.09 g, 6.15 mmol) in acetonitrile (400 mL) was degassed, backpacked three times with nitrogen, and stirred at 85°C for 5 hours. The cooled reaction mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography eluted with ethyl acetate (0 to 10%) in petroleum ether to obtain a yellow solid of 4,7-dibromo-5,6-difluoro-2-methyl-1H-indole (17.0 g, 85%).

[0489] 1 H NMR(300MHz,DMSO-d6)δ 11.75(s,1H),6.28(s,1H),2.41(s,3H).

[0490] ESI-MS[MH] - For (C9H5Br2F2N), the calculated values ​​were 321.88, 323.87, and 325.87. The measured values ​​were 321.80, 323.80, and 325.80.

[0491] Step 6: 4,7-dibromo-5,6-difluoro-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole

[0492] [ka] To a stirred solution of 4,7-dibromo-5,6-difluoro-2-methyl-1H-indole (10.0 g, 30.77 mmol) in THF (200 mL), sodium hydride (1.60 g, 40.01 mmol, 60%) was added at 0°C. After stirring at this temperature for 1 hour, 2-(trimethylsilyl)ethoxymethyl chloride (7.70 g, 46.16 mmol) was added at 0°C. The reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was quenched with water (200 mL) and extracted with ethyl acetate (150 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by column chromatography using silica gel with ethyl acetate (0 to 10%) in petroleum ether to obtain yellow oily 4,7-dibromo-5,6-difluoro-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole (12.3 g, 87%).

[0493] 1 H NMR(300MHz,DMSO-d6)δ 6.42(s,1H),5.78(s,2H),3.55(t,J=7.8Hz,2H),2.47(s,3H),0.83(t,J=8.1Hz,2H),-0.08(s,9H).

[0494] Step 7: 4-Bromo-5,6-difluoro-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7-carboxylic acid

[0495] [ka] To a solution of 4,7-dibromo-5,6-difluoro-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole (12.3 g, 27.03 mmol) in THF (130 mL), n-butyllithium (2.5 M in n-hexane, 13 mL, 32.5 mmol) was added under nitrogen at -70°C. After stirring at this temperature for 0.5 hours and then at 0°C for 0.5 hours, the reaction mixture was cooled to -70°C and bubbling with carbon dioxide for 30 minutes. After stirring at 25°C for 1.5 hours, the reaction mixture was quenched with saturated aqueous ammonium chloride (100 mL) and extracted with dichloromethyl (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain a yellow, oily 4-bromo-5,6-difluoro-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7-carboxylic acid (11.4 g, crude).

[0496] ESI-MS[MH] - (C 16 H 20 Calculated values ​​for BrF2NO3Si: 418.04, 420.03; Measured values: 417.95, 419.95.

[0497] Step 8: 4-bromo-5,6-difluoro-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7-carboxamide

[0498] [ka] To a stirred mixture of 4-bromo-5,6-difluoro-2-methyl-1-(2-trimethylsilylethoxymethyl)indole-7-carboxylic acid (11.4 g, 27.12 mmol) and ammonium chloride (2.18 g, 40.68 mmol) in DMF (100 mL), HATU (12.38 g, 32.55 mmol) and DIPEA (17.53 g, 135.61 mmol) were added at 0°C. After stirring at 25°C for 16 hours, the reaction mixture was quenched with water (300 ml) and extracted with ethyl acetate (300 ml x 3). The combined organic layers were washed with brine (200 ml x 3), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography using ethyl acetate (0 to 50%) in petroleum ether to obtain a yellow solid, 4-bromo-5,6-difluoro-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7-carboxamide (6.3 g, 55%).

[0499] 1 H NMR(300MHz,DMSO-d6)δ 8.34(s,1H),8.10(s,1H),6.40(s,1H),5.50(s,2H),3.42(t,J=8.1Hz,2H),2.46(s,3H),0.81(t,J=8.1Hz,2H),-0.06(s,9H).

[0500] ESI-MS[M+H] + (C 16 H 21 Calculated values ​​for BrF2N2O2Si: 419.05, 421.05. Measured values: 419.20, 421.20.

[0501] Step 9: 4-bromo-5,6-difluoro-2-methyl-1H-indole-7-carboxamide

[0502] [ka] The mixture of 4-bromo-5,6-difluoro-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7-carboxamide (6.3 g, 15.02 mmol), TBAF (1 M in THF, 150 mL, 150.2 mmol), and ethane-1,2-diamine (30 mL, 450.6 mmol) was stirred at 75°C for 40 hours. The reaction mixture was cooled to 0°C and acidified to pH=4 with 2 M hydrochloric acid. The precipitate was collected by filtration, washed with water (100 mL), and dried under reduced pressure to obtain a yellow solid of 4-bromo-5,6-difluoro-2-methyl-1H-indole-7-carboxamide (3.5 g, 80%).

[0503] 1 H NMR(300MHz,DMSO-d6)δ 11.38(s,1H),7.97(s,1H),7.90(s,1H),6.20(s,1H),2.40(s,3H).

[0504] ESI-MS[M+H] + (C 10 Calculated values ​​for H7BrF2N2O: 288.97, 290.97. Measured values: 288.95, 290.95.

[0505] Step 10: 5-(7-carbamoyl-5,6-difluoro-2-methyl-1H-indole-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate tert-butyl

[0506] [ka] A mixture of 4-bromo-5,6-difluoro-2-methyl-1H-indole-7-carboxamide (250 mg, 0.864 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate tert-butyl (373 mg, 1.04 mmol), potassium carbonate (359 mg, 2.59 mmol), and Pd(dppf)Cl2.DCM (71 mg, 0.086 mmol) in dioxane (8 mL) and water (2 mL) was degassed, backpacked five times with nitrogen, and stirred at 90°C for 2 hours. The cooled reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography eluted with ethyl acetate (0 to 38%) in petroleum ether to obtain a white solid 5-(7-carbamoyl-5,6-difluoro-2-methyl-1H-indole-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate tert-butyl (340 mg, 89%).

[0507] 1 H NMR(300MHz,DMSO-d6)δ 11.11(s,1H),7.90(s,1H),7.82(s,1H),7.40-7.22(m,2H),7.17(dd,J=6.9,2.1Hz,1H),5.70(s,1H),4.70-4 .44(m,2H),3.91(s,1H),3.56-3.44(m,1H),3.40-3.35(m,1H),2.43-2.38(m,1H),2.32(s,3H),1.41(s,9H).

[0508] ESI-MS[M+H-tBu] + (C 24 H 25 The calculated value for F2N3O3 is 386.19, while the measured value is 386.15.

[0509] Step 11: 5-(7-carbamoyl-3-chloro-5,6-difluoro-2-methyl-1H-indole-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate tert-butyl

[0510] [ka] To a solution of 5-(7-carbamoyl-5,6-difluoro-2-methyl-1H-indole-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate tert-butyl (250 mg, 0.566 mmol) in DMF (5 mL), NCS (91 mg, 0.679 mmol) was added at 0°C. After stirring at 10°C for 2 hours, the reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, and concentrated under vacuum. The residue was purified by preparative TLC (30% ethyl acetate in petroleum ether) to obtain a yellow solid 5-(7-carbamoyl-3-chloro-5,6-difluoro-2-methyl-1H-indole-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate tert-butyl (200 mg, 74%).

[0511] 1 H NMR(300MHz,DMSO-d6)δ 11.52(s,1H),8.01-7.95(m,2H),7.32-7.28(m,2H),7.17-7.11(m,1H),4.66- 4.52(m,2H),3.52-3.43(m,2H),2.45-2.34(m,2H),2.31(s,3H),1.41(s,9H).

[0512] ESI-MS[M+H-tBu] + (C 24 H 24 Calculated values ​​for ClF2N3O3: 420.15, 422.15. Measured values: 420.05, 422.05.

[0513] Step 12: 3-Chloro-5,6-difluoro-2-methyl-4-(1,2,3,4-tetrahydroisoquinoline-5-yl)-1H-indole-7-carboxamide hydrochloride

[0514] [ka] A mixture of 5-(7-carbamoyl-3-chloro-5,6-difluoro-2-methyl-1H-indole-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate tert-butyl (240 mg, 0.504 mmol) and hydrogen chloride (4 M in dioxane, 5 mL) was stirred at 20°C for 2 hours. The mixture was concentrated under vacuum to obtain a brown solid, 3-chloro-5,6-difluoro-2-methyl-4-(1,2,3,4-tetrahydroisoquinoline-5-yl)-1H-indole-7-carboxamide hydrochloride (200 mg, crude).

[0515] ESI-MS[M+H] + (C 19 H 16 Calculated values ​​for ClF2N3O: 376.09, 378.09. Measured values: 376.05, 378.05.

[0516] Step 13: 4-(2-acryloyl-1,2,3,4-tetrahydroisoquinoline-5-yl)-3-chloro-5,6-difluoro-2-methyl-1H-indole-7-carboxamide

[0517] [ka] A mixture of 3-chloro-5,6-difluoro-2-methyl-4-(1,2,3,4-tetrahydroisoquinoline-5-yl)-1H-indole-7-carboxamide hydrochloride (200 mg, 0.485 mmol) in tetrahydrofuran (4 mL) and water (1 mL) was to be mixed with sodium bicarbonate (204 mg, 2.43 mmol) and acryloyl chloride (44 mg, 0.485 mmol) at 0°C. After stirring at 0°C for 1 hour, the reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic layer was washed with brine (30 mL), dried over sodium sulfate, and concentrated under vacuum. The residue was purified by preparative HPLC under the following conditions: column: XBridge Prep OBD C18 Column, 30 × 150 mm 5 μm; mobile phase A: water (10 MMOL / L NH4HCO3 + 0.1% NH3.H2O), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 30% B to 60% B in 7 mins; 220 nm; Rt: 6.32 mins to obtain a white solid 4-(2-acryloyl-1,2,3,4-tetrahydroisoquinoline-5-yl)-3-chloro-5,6-difluoro-2-methyl-1H-indole-7-carboxamide (80 mg, 38%).

[0518] 1 H NMR(400MHz,DMSO-d6)δ 11.54(s,1H),8.03(s,1H),7.99(s,1H),7.35-7.29(m,2H),7.17-7.14(m,1H),6.97-6.77(m,1H),6.15(dd,J =17.2,1.6Hz,1H),5.74-5.66(m,1H),4.89-4.75(m,2H),3.78-3.60(m,2H),2.46-2.34(m,2H),2.31(s,3H).

[0519] ESI-MS[M+H] + (C 22 H 18 Calculated values ​​for ClF2N3O2: 430.11, 432.11; Measured values: 430.05, 432.05.

[0520] Step 14: Separation of isomers: (R)-4-(2-acryloyl-1,2,3,4-tetrahydroisoquinoline-5-yl)-3-chloro-5,6-difluoro-2-methyl-1H-indole-7-carboxamide (compound 21b) and (S)-4-(2-acryloyl-1,2,3,4-tetrahydroisoquinoline-5-yl)-3-chloro-5,6-difluoro-2-methyl-1H-indole-7-carboxamide (compound 21c):

[0521] [ka]

[0522] Two atropisomers of 4-(2-acryloyl-1,2,3,4-tetrahydroisoquinoline-5-yl)-3-chloro-5,6-difluoro-2-methyl-1H-indole-7-carboxamide were separated by preparative chiral HPLC according to the procedure described herein:

[0523] 1 H NMR(300MHz,DMSO-d6)δ 11.54(s,1H),8.05-7.96(m,2H),7.37-7.29(m,2H),7.18-7.13(m,1H),6.98-6.75(m,1H),6.20-6.10(m,1H),5.75- 5.65(m,1H),4.95-4.67(m,2H),3.81-3.57(m,2H),2.46-2.36(m,2H),2.31(s,3H).LC-MS:m / z=430.05,432.05[M+H] + .

[0524] 1H NMR(300MHz,DMSO-d6)δ 11.54(s,1H),8.02-7.97(m,2H),7.37-7.29(m,2H),7.18-7.13(m,1H),6.98-6.76(m,1H),6.15(dd,J=16.5,1.8Hz,1H),5 .75-5.66(m,1H),4.88-4.77(m,2H),3.77-3.62(m,2H),2.46-2.36(m,2H),2.31(s,3H).LC-MS:m / z=430.05,432.05[M+H] + .

[0525] Compounds 21d~21e Compounds 21d and 21e were prepared by following a method similar to that described in the preceding scheme and examples, using appropriate starting materials accordingly.

[0526] [Table 7]

[0527] × is CH2, R 3 Preparation of the compound of formula (II) where ME is

[0528] [ka]

[0529] Example 22 Synthesis of 4-(2-acryloyl-1-methyl-1,2,3,4-tetrahydroisoquinoline-5-yl)-3-chloro-5-fluoro-2-methyl-1H-indole-7-carboxamide (compound 22a)

[0530] [ka] Step 1: N-(2-bromophenethyl)acetamide

[0531] [ka] To a stirred solution of 2-(2-bromophenyl)ethane-1-amine (5.0 g, 25.0 mmol) in DCM (25 mL) and pyridine (50 mL), acetyl chloride (1.96 g, 24.99 mmol) was added dropwise at 0°C. After addition, the reaction mixture was stirred at 25°C for 1.5 hours. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3 × 20 mL). The combined extracts were washed with water (30 mL) and brine (30 mL), dried over sodium sulfate, and concentrated under vacuum. The concentrate was purified by silica gel column chromatography (5% methanol in dichloromethane) to obtain yellow oily N-(2-bromophenethyl)acetamide (4.8 g, 79%).

[0532] 1 H NMR(300MHz,DMSO-d6)δ 7.96(s,1H),7.59(d,J=6.0Hz,1H),7.35-7.28(m,2H),7.19-7.13(m,1H),3.31-3.20(m,2H),2.84-2.80(m,2H),1.78(s,3H).

[0533] ESI-MS[M+H] + (C 10 H 12 Calculated values ​​for BrNO: 242.01, 244.01; measured values: 242.10, 244.10.

[0534] Step 2: 7-Bromo-10b-methyl-6,10b-dihydro-5H-oxazolo[2,3-a]isoquinoline-2,3-dione

[0535] [ka] To a solution of N-(2-bromophenethyl)acetamide (5.0 g, 20.7 mmol) in DCM (70 mL), oxalyl chloride (4.72 g, 37.2 mmol) was added dropwise at 0°C. The mixture was stirred at 0°C for 2 hours, then at 25°C for 3 hours. The reaction mixture was cooled to 0°C, and FeCl3 (4.02 g, 24.8 mmol) was added in fractions. The reaction mixture was warmed to 25°C and stirred for 16 hours. The reaction mixture was diluted with 12 M aqueous ammonia (50 mL) and extracted with DCM (3 × 30 mL). The combined extract was washed with brine (50 mL), dried over sodium sulfate, and concentrated under vacuum to obtain the brown solid 7-bromo-10b-methyl-6,10b-dihydro-5H-oxazolo[2,3-a]isoquinoline-2,3-dione (6.0 g), which was used without purification.

[0536] ESI-MS[M+H] + (C 12 H 10 Calculated values ​​for BrNO3: 295.98, 297.98; measured values: 296.05, 298.05.

[0537] Step 3: 5-Bromo-1-methyl-3,4-dihydroisoquinoline

[0538] [ka] A solution of 7-bromo-10b-methyl-6,10b-dihydro-5H-oxazolo[2,3-a]isoquinoline-2,3-dione (6.0 g, 20.3 mmol) in methanol (150 mL) was mixed with concentrated sulfuric acid (1.99 g, 20.3 mmol). The reaction mixture was heated at 65 C for 20 hours. The reaction mixture was diluted at 0 C with 12 M aqueous ammonia. Methanol was removed under reduced pressure. The residue was diluted with water (30 mL) and extracted with DCM (3 × 50 mL). The combined extracts were washed with brine (50 mL), dried over sodium sulfate, and concentrated under vacuum to obtain brown oily 5-bromo-1-methyl-3,4-dihydroisoquinoline (3.9 g, 86%).

[0539] 1 H NMR(400MHz,DMSO-d6)δ 7.68(d,J=8.0Hz,1H),7.59(d,J=8.0Hz,1H),7.32-7.28(m,1H),3.58-3.54(m,2H),2.71-2.67(m,2H),2.31-2.30(m,3H).

[0540] ESI-MS[M+H] + (C 12 H 10 Calculated values ​​for BrNO3: 224.00, 226.00; measured values: 224.10, 226.10.

[0541] Step 4: 5-Bromo-1-methyl-1,2,3,4-tetrahydroisoquinoline

[0542] [ka] To a solution of 5-bromo-1-methyl-3,4-dihydroisoquinoline (3.9 g, 17.4 mmol) in ethanol (100 mL), sodium borohydride (658 mg, 17.4 mmol) was added at 0°C. The reaction mixture was stirred at 0°C for 2 hours, diluted with water (100 mL), and extracted with DCM (3 × 100 mL). The combined extract was washed with brine (100 mL), dried over sodium sulfate, and concentrated under vacuum to obtain a brown solid of 5-bromo-1-methyl-1,2,3,4-tetrahydroisoquinoline (2.75 g, 70%).

[0543] 1 H NMR(300MHz,DMSO-d6)δ 7.40(d,J=7.8Hz,1H),7.18(d,J=7.5Hz,1H),7.12-7.01(mf,1H),3.93-3.87(m,1H),3.30 (brs,1H),3.15-3.11(m,1H),2.88-2.76(m,1H),2.61-2.57(m,2H),1.33(d,J=6.6Hz,3H).

[0544] ESI-MS[M+H] + (C 10 H12 Calculated values ​​for BrN: 226.02, 228.02; measured values: 226.15, 228.11.

[0545] Step 5: 5-Bromo-1-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate tert-butyl

[0546] [ka] Di-tert-butyl dicarbonate (2.65 g, 12.2 mmol) was added to a solution of 5-bromo-1-methyl-1,2,3,4-tetrahydroisoquinoline (2.75 g, 12.2 mmol) and triethylamine (3.69 g, 36.5 mmol) in DCM (75 mL). The reaction mixture was stirred at 25°C for 3 hours, quenched with water (50 mL), and extracted with ethyl acetate (3 × 50 mL). The combined organic layer was washed with brine (50 mL), dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography (7% ethyl acetate in petroleum ether) to obtain a white solid 5-bromo-1-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate tert-butyl (3.1 g, 78%).

[0547] 1 H NMR(300MHz,DMSO-d6)δ 7.48(d,J=7.8Hz,1H),7.28(d,J=7.5Hz,1H),7.21-7.10(m,1H),5.24-4.96(m,1H),4.13- 3.97(m,1H),3.27-3.06(m,1H),2.86-2.73(m,1H),2.69-2.57(m,1H),1.46-1.37(m,12H).

[0548] ESI-MS[M+H-Boc] + (C 15 H 20 Calculated values ​​for BrNO2: 226.07, 228.07; measured values: 226.05, 228.05.

[0549] Step 6: 1-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate tert-butyl

[0550] [ka] A mixture of 5-bromo-1-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylic acid (3.5 g, 10.7 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (3.27 g, 12.9 mmol), Pd(dppf)Cl2.DCM (876 mg, 1.07 mmol), and potassium acetate (3.16 g, 32.2 mmol) in 1,4-dioxane (100 mL) was degassed and backpacked under nitrogen. The reaction mixture was heated under nitrogen at 100°C for 2 hours. The cooled reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (3 × 50 mL). The combined extracts were washed with brine (50 mL), dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography (60% ethyl acetate in petroleum ether) to obtain a yellow oily 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylate tert-butyl (4.0 g, 89%).

[0551] 1 H NMR(300MHz,DMSO-d6)δ 7.52(d,J=7.5Hz,1H),7.30(d,J=7.2Hz,1H),7.21-7.14(m,1H),5.12-4.96(m,1H),3.97-3.81( m,1H),3.29-3.03(m,2H),2.93-2.88(m,1H),1.43(s,9H),1.36(d,J=6.0Hz,3H),1.29(s,12H).

[0552] ESI-MS[M+H-Boc] + (C 21 H 32The calculated value for BNO4 is 274.24, and the measured value is 274.25.

[0553] Step 7: 4-Bromo-5-fluoro-2-methyl-1H-indole-7-carboxylic acid

[0554] [ka] To a stirred solution of 4-bromo-5-fluoro-2-nitrobenzoic acid (17 g, 64.4 mmol) in THF (200 mL), propane-1-en-2-ylmagnesium bromide (451 mL, 225 mmol, 0.5 M in THF) was added dropwise under nitrogen at -70°C. After addition, the reaction mixture was stirred at -70°C for 3 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (500 mL) and extracted with ethyl acetate (2 × 500 mL). The combined extracts were washed with brine (300 mL), dried over sodium sulfate, and concentrated under vacuum to obtain a brown solid of 4-bromo-5-fluoro-2-methyl-1H-indole-7-carboxylic acid (17.5 g). The solid was retained without purification.

[0555] ESI-MS[MH] - (C 10 Calculated values ​​for H7BrFNO2: 269.96, 271.96; measured values: 270.25, 272.25.

[0556] Step 8: 4-bromo-5-fluoro-2-methyl-1H-indole-7-carboxamide

[0557] [ka] N-ethyl-N-isopropyl-propan-2-amine (25.0 g, 193 mmol) was added to a stirred solution of 4-bromo-5-fluoro-2-methyl-1H-indole-7-carboxylic acid (17.5 g, 64.4 mmol), ammonium hydrochloride (5.17 g, 96.6 mmol), and HATU (29.4 g, 77.3 mmol) in DMF (200 mL). The reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was quenched with water (300 mL) and extracted with ethyl acetate (3 × 300 mL). The combined extracts were washed with water (200 mL) and brine (200 mL), then dried over anhydrous sodium sulfate and concentrated under vacuum. The concentrate was purified by column chromatography (50% ethyl acetate in petroleum ether) to obtain 4-bromo-5-fluoro-2-methyl-1H-indole-7-carboxamide (3.8 g, 22%) as a yellow solid.

[0558] 1 H NMR(400MHz,DMSO-d6)δ 11.26(s,1H),8.11(s,1H),7.63-7.53(m,2H),6.19(s,1H),2.42(s,3H).

[0559] ESI-MS[M+H] + (C 10 Calculated values ​​for H8BrFN2O: 270.98, 272.98; measured values: 270.90, 272.90.

[0560] Step 9: 5-(7-carbamoyl-5-fluoro-2-methyl-1H-indole-4-yl)-1-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate tert-butyl

[0561] [ka] A mixture of 4-bromo-5-fluoro-2-methyl-1H-indole-7-carboxamide (400 mg, 1.47 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylate tert-butyl (550 mg, 1.47 mmol), potassium phosphate (938 mg, 4.42 mmol), and Pd(dppf)Cl2 (108 mg, 0.147 mmol) in THF (12 mL) and water (3 mL) was degassed and backpacked with nitrogen. The reaction mixture was stirred under nitrogen at 30°C for 16 hours, quenched with water (60 mL), and extracted with ethyl acetate (3 × 50 mL). The combined extracts were washed with brine (30 mL), dried over sodium sulfate, and concentrated under vacuum. The concentrate was purified by silica gel column chromatography (55% ethyl acetate in petroleum ether) to obtain a yellow solid 5-(7-carbamoyl-5-fluoro-2-methyl-1H-indole-4-yl)-1-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate tert-butyl (500 mg, 78%).

[0562] 1 H NMR(300MHz,DMSO-d6)δ 11.05(s,1H),7.62-7.52(m,2H),7.36-7.26(m,3H),7.17-7.11(m,1H),5.78-5.76(m,1H),5.18-5.13(m,1H), 3.92-3.61(m,1H),3.19-2.98(m,1H),2.43-2.40(m,1H),2.39-2.33(m,3H),2.30-2.24(m,1H),1.43(s,12H).

[0563] ESI-MS[M+H] + (C 25 H 28 The calculated value for FN3O3 was 438.21, and the measured value was 438.30.

[0564] Step 10: 5-Fluoro-2-methyl-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-5-yl)-1H-indole-7-carboxamide

[0565] [ka] A mixture of 5-(7-carbamoyl-5-fluoro-2-methyl-1H-indole-4-yl)-1-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate tert-butyl (500 mg, 1.14 mmol) and hydrogen chloride (4 M in dioxane, 10 mL) was stirred at 25°C for 1 hour. The reaction mixture was concentrated under vacuum. The residue was diluted with saturated aqueous sodium bicarbonate (50 mL) and extracted with ethyl acetate (3 × 50 mL). The combined extracts were dried over sodium sulfate and concentrated under vacuum to obtain a yellow solid 5-fluoro-2-methyl-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-5-yl)-1H-indole-7-carboxamide (370 mg, 89%).

[0566] ESI-MS[M+H] + (C 20 H 20 The calculated value for FN3O is 338.16, and the measured value is 338.15.

[0567] Step 11: 4-(2-acryloyl-1-methyl-1,2,3,4-tetrahydroisoquinoline-5-yl)-5-fluoro-2-methyl-1H-indole-7-carboxamide

[0568] [ka] Acryloyl chloride (99 mg, 1.10 mmol) was added at 0°C to a stirred mixture of 5-fluoro-2-methyl-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-5-yl)-1H-indole-7-carboxamide (370 mg, 1.10 mmol) and sodium bicarbonate (276 mg, 3.29 mmol) in THF (8 mL) and water (2 mL). The reaction mixture was stirred at 0°C for 0.5 hours. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (3 × 30 mL). The combined extract was washed with brine (30 mL), dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography (75 to 100% ethyl acetate in petroleum ether) to obtain a yellow solid 4-(2-acryloyl-1-methyl-1,2,3,4-tetrahydroisoquinoline-5-yl)-5-fluoro-2-methyl-1H-indole-7-carboxamide (290 mg, 67%).

[0569] 1 H NMR(300MHz,DMSO-d6)δ 11.09-11.00(m,1H),8.11(s,1H),7.63-7.49(m,2H),7.43-7.28(m,2H),7.19-7.14(m,1H),7.03-6.71(m,1H),6.25-6.08 (m,1H),5.83-5.55(m,3H),4.36-3.85(m,1H),3.54-3.36(m,1H),2.76-2.53(m,1H),2.46-2.23(m,4H),1.56-1.47(m,3H).

[0570] ESI-MS[M+H] + (C 23 H 22 The calculated value for FN3O2 was 392.17, while the measured value was 392.15.

[0571] Step 12: 4-(2-acryloyl-1-methyl-1,2,3,4-tetrahydroisoquinoline-5-yl)-3-chloro-5-fluoro-2-methyl-1H-indole-7-carboxamide

[0572] [ka] To a stirred solution of 4-(2-acryloyl-1-methyl-1,2,3,4-tetrahydroisoquinoline-5-yl)-5-fluoro-2-methyl-1H-indole-7-carboxamide (230 mg, 0.59 mmol) in DMF (5.0 mL), 1-chloropyrrolidine-2,5-dione (78 mg, 0.59 mmol) was added at 0°C. The reaction mixture was stirred at 0°C for 1 hour. The reaction mixture was diluted with water (25 mL) and extracted with ethyl acetate (3 × 20 mL). The combined extracts were washed with brine (30 mL), dried over sodium sulfate, and concentrated under vacuum. The concentrate was purified by preparative HPLC (column: XBridge Prep OBD C18 Column, 19 × 250 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3·H2O), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: 40% B to 60% B in 7 mins; 220 nm; RT: 6.00 min) to obtain a white solid 4-(2-acryloyl-1-methyl-1,2,3,4-tetrahydroisoquinoline-5-yl)-3-chloro-5-fluoro-2-methyl-1H-indole-7-carboxamide (110 mg, 44%).

[0573] 1 H NMR(400MHz,DMSO-d6)δ 11.55-11.40(m,1H),8.19(s,1H),7.72-7.59(m,2H),7.38-7.24(m,2H),7.15-7.07(m,1H),7.01-6.73(m,1H),6 .18-6.11(m,1H),5.77-5.36(m,2H),4.31-3.93(m,1H),3.48-3.05(m,1H),2.44-2.18(m,5H),1.54-1.43(m,3H).

[0574] ESI-MS[M+H] + (C 23 H 21 The calculated value for ClFN3O2 was 426.13, and the measured value was 426.25.

[0575] Step 13: Separation of isomers

[0576] [ka] 4-(2-acryloyl-1-methyl-1,2,3,4-tetrahydroisoquinoline-5-yl)-3-chloro-5-fluoro-2-methyl-1H-indole-7-carboxamide (100 mg) was separated into four isomers by preparative chiral HPLC. The crude product was electrophoresed through CHIRALPAK IG (2 × 25 cm, 5 μm); mobile phase A: hexane (0.5% 2M NH3-MeOH), mobile phase B: EtOH; flow rate: 20 mL / min; gradient: 25% B, isocratic, 24 minutes; 220 / 254 nm to obtain the four compounds. The retention times were as follows.

[0577] Compound 22b: Retention time = 11.342 minutes (16.4 mg) 1 H NMR(400MHz, methanol-d4)δ 7.55(d,J=10.4Hz,1H),7.38-7.28(m,2H),7.19-7.10(m,1H),6.96-6. 73(m,1H),6.34-6.24(m,1H),5.83-5.68(m,1.6H),5.42-5.37(m,0.4H ),4.42-3.96(m,1H),3.61-3.54(m,0.6H),3.28-3.21(m,0.4H),2.70- 2.35(m,2H),2.38(s,3H),1.66(d,J=6.8Hz,1H),1.58(d,J=6.8Hz,2H).

[0578] ESI-MS[M+H] + (C 23 H 21 The calculated value for ClFN3O2 was 426.13, while the measured value was 426.05.

[0579] Compound 22c: Retention time = 18.98 minutes (19.5 mg) 1H NMR(400MHz, methanol-d4)δ 7.51(d,J=10.4Hz,1H),7.30-7.28(m,2H),7.14-7.11(m,1H),6.96-6.73(m,1H),6.29-6.20(m,1H),5.82-5.35(m,2H),4.36-3.9 2(m,1H),3.59-3.52(m,0.6H),3.25-3.18(m,0.4H),2.65-2.47(m,2H),2.38(s,3H),1.62(d,J=6.8Hz,1H),1.54(d,J=6.8Hz,2H).

[0580] ESI-MS[M+H] + (C 23 H 21 The calculated value for ClFN3O2 was 426.13, while the measured value was 426.05.

[0581] compound 22d Subsequently, the substance eluted at 14.331 minutes was subjected to chromatography using CHIRAL ART Cellulose-SC (2×25cm, 5um); mobile phase A: hexane (0.5% 2M NH3-MeOH), mobile phase B: EtOH; flow rate: 20 mL / min; gradient: 25% B, isocratic, 18 minutes; 220 / 254 nm. Retention time = 10.855 minutes (14.9 mg).

[0582] 1 H NMR(400MHz, methanol-d4)δ 7.51(d,J=10.4Hz,1H),7.30-7.29(m,2H),7.14-7.11(m,1H),6.96-6. 72(m,1H),6.29-6.19(m,1H),5.81-5.66(m,1.6H),5.39-5.34(m,0.4H ),4.35-3.92(m,1H),3.59-3.52(m,0.6H),3.24-3.18(m,0.4H),2.55- 2.47(m,2H),2.38(s,3H),1.62(d,J=6.8Hz,1H),1.54(d,J=6.8Hz,2H).

[0583] ESI-MS[M+H] + (C 23 H 21The calculated value for ClFN3O2 was 426.13, and the measured value was 426.05.

[0584] compound 22e Subsequently, the substance eluted after 15.677 minutes was subjected to chromatography using CHIRAL ART Cellulose-SC (2×25cm, 5um); mobile phase A: hexane (0.5% 2M NH3-MeOH), mobile phase B: EtOH; flow rate: 20 mL / min; gradient: 25% B, isocratic, 18 minutes; 220 / 254 nm. Retention time = 14.665 minutes (19.0 mg).

[0585] 1 H NMR(400MHz, methanol-d4)δ 7.51(d,J=10.4Hz,1H),7.31-7.28(m,2H),7.14-7.11(m,1H),6.96-6. 72(m,1H),6.29-6.18(m,1H),5.82-5.65(m,1.6H),5.39-5.32(m,0.4H ),4.36-3.90(m,1H),3.60-3.50(m,0.6H),3.24-3.18(m,0.4H),2.55- 2.47(m,2H),2.37(s,3H),1.62(d,J=6.4Hz,1H),1.54(d,J=6.8Hz,2H).

[0586] ESI-MS[M+H]+(C 23 H 21 The calculated value for ClFN3O2 was 426.13, and the measured value was 426.05.

[0587] Compounds 22f~22i The compounds listed in Table 8 were prepared by following a method similar to that described in the preceding scheme and examples, using appropriate starting materials accordingly.

[0588] [Table 8]

[0589] × is CH2, R 3 Preparation of the compound of formula (II) in which is cyclopropyl

[0590] [ka]

[0591] Example 23 Synthesis of 4-(2-acryloyl-1-cyclopropyl-1,2,3,4-tetrahydroisoquinoline-5-yl)-5-fluoro-2-methyl-1H-indole-7-carboxamide (compound 23)

[0592] [ka] Compound 23 was prepared according to a similar procedure described herein.

[0593] 1 H NMR(400MHz,DMSO-d6)δ 11.18-10.92(m,1H),8.12(s,1H),7.63-7.49(m,2H),7.48-7.37(m,1H ),7.36-7.27(m,1H),7.23-7.11(m,1H),7.04-6.68(m,1H),6.23-6.04 (m,1H),5.85-5.58(m,2H),5.02-4.67(m,1H),4.41-3.85(m,1H),3.75 -3.15(m,1H),2.70-2.28(m,5H),1.48-1.19(m,1H),0.99-0.32(m,4H).

[0594] LC-MS: m / z = 418.15 [M + H] + .

[0595] × is -CR x1 R x2 - and R x1 and R x2 However, together with the C atoms to which they are bonded, 3-6 Preparation of a compound of formula (II) that forms a membered carbocyclic ring.

[0596] [ka]

[0597] Example 24 Synthesis of 4-(2'-acryloyl-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline]-5'-yl)-3-chloro-5-fluoro-2-methyl-1H-indole-7-carboxamide (compound 24a)

[0598] [ka] Step 1: 3-Bromo-2-(3-cyanopropoxy)benzonitrile

[0599] [ka] A mixture of 3-bromo-2-hydroxybenzonitrile (10 g, 50.5 mmol), 4-bromobutanenitrile (11.2 g, 75.8 mmol), and potassium carbonate (10.5 g, 75.8 mmol) in DMF (100 mL) was stirred at 25°C for 16 hours. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (3 × 100 mL). The combined extract was washed with brine (120 mL), dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography (0 to 40% ethyl acetate in petroleum ether) to obtain colorless oily 3-bromo-2-(3-cyanopropoxy)benzonitrile (12.0 g, 89%).

[0600] 1 H NMR(300MHz,DMSO-d6)δ 8.03(dd,J=8.1,1.5Hz,1H),7.88(dd,J=7.8,1.5Hz,1H),7.28-6.98(m,1H),4.22(t,J=6.0Hz,2H),2.77(t,J=7.2Hz,2H),2.20-2.06(m,2H).

[0601] Step 2: 9-Bromo-1,2-dihydrofl[2,3-c]isoquinoline-5-amine

[0602] [ka] A mixture of 3-bromo-2-(3-cyanopropoxy)benzonitrile (1.0 g, 3.77 mmol) and potassium 2-methylpropane-2-oleate (847 mg, 7.54 mmol) in dioxane (30 mL) was stirred at 95°C for 1 hour. The reaction mixture was diluted with water (60 mL) and extracted with ethyl acetate (3 × 50 mL). The combined extract was washed with brine (50 mL), dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography (0 to 50% ethyl acetate in petroleum ether) to obtain a yellow solid 9-bromo-1,2-dihydrofl[2,3-c]isoquinoline-5-amine (300 mg, 30%).

[0603] 1 H NMR(400MHz,DMSO-d6)δ 8.11(d,J=8.4Hz,1H),7.79(d,J=7.6Hz,1H),7.09(s,2H),7.06-6.95(m,1H),4.50(t,J=6.6Hz,2H),3.73(t,J=6.6Hz,2H).

[0604] ESI-MS[M+H] + (C 11 Calculated values ​​for H9BrN2O: 265.11, 267.11; measured values: 265.10, 267.10.

[0605] Step 3: 5'-bromo-1'H-spiro[cyclopropane-1,4'-isoquinoline]-1',3'(2'H)-dione

[0606] [ka] A mixture of 5'-bromo-1'H-spiro[cyclopropane-1,4'-isoquinoline]-1',3'(2'H)-dione and 9-bromo-1,2-dihydroflou[2,3-c]isoquinoline-5-amine (1.80 g, 6.78 mmol) in concentrated hydrochloric acid (100 mL) was stirred at 100°C for 3 hours. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (3 × 150 mL). The combined extract was washed with brine (150 mL), dried over sodium sulfate, and concentrated under vacuum. The residue was dissolved in DMF (25 mL) and potassium carbonate (1.90 g, 13.9 mmol) was added. The reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (3 × 40 mL). The combined extract was washed with brine (50 mL), dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography (0 to 60% ethyl acetate in petroleum ether) to obtain a white solid 5'-bromo-1'H-spiro[cyclopropane-1,4'-isoquinoline]-1',3'(2'H)-dione (1.0 g, 55%).

[0607] 1 H NMR(300MHz,DMSO-d6)δ 7.43(d,J=8.1Hz,1H),7.20(d,J=8.4Hz,1H),7.11-7.01(m,1H),1.93-1.81(m,2H),0.86-0.77(m,2H).

[0608] ESI-MS[MH]-(C 11 Calculated values ​​for H8BrNO2: 263.97, 265.97; measured values: 264.00, 266.00.

[0609] Step 4: 5'-Bromo-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline

[0610] [ka] A mixture of sodium borohydride (600 mg, 15.8 mmol) in THF (30 mL) was mixed with BF3.Et2O (3.00 g, 21.1 mmol) at 0°C. After stirring at this temperature for 1 hour, a solution of 5'-bromo-1'H-spiro[cyclopropane-1,4'-isoquinoline]-1',3'(2'H)-dione (1.40 g, 5.26 mmol) in THF (50 mL) was added dropwise. The reaction mixture was heated at 70°C for 16 hours. The reaction mixture was quenched with water (60 mL) and extracted with ethyl acetate (3 × 50 mL). The combined extracts were washed with brine (50 mL), dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography (80% ethyl acetate in petroleum ether) to obtain a white solid 5'-bromo-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline (480 mg, 38%).

[0611] ESI-MS[M+H]+(C 11 H 12 Calculated values ​​for BrN: 238.02, 240.02; Measured values: 238.10, 240.10.

[0612] Step 5: 1-(5'-bromo-1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-yl)propane-2-ene-1-one

[0613] [ka] To a stirred mixture of 5'-bromo-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline] (480 mg, 2.02 mmol) in water (2.0 mL) and THF (8.0 mL), sodium bicarbonate (850 mg, 10.1 mmol) and acryloyl chloride (180 mg, 2.02 mmol) were added at 0°C. The reaction mixture was stirred at 0°C for 1.5 hours. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (3 × 25 mL). The combined extract was washed with brine (30 mL), dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography (40% ethyl acetate in petroleum ether) to obtain a yellow solid 1-(5'-bromo-1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-yl)propa-2-en-1-one (350 mg, 59%).

[0614] 1 H NMR(400MHz,DMSO-d6)δ 7.47(d,J=8.4Hz,1H),7.39-7.31(m,1H),7.18-7.10(m,1H),7.00-6.59(m,1H),6.19-6.13(m,1H),5.76-5.6 7(m,1H),4.87(s,0.8H),4.78(s,1.2H),3.49(s,1.2H),3.33(s,0.8H),1.58-1.54(m,2H),1.08-1.02(m,2H).

[0615] ESI-MS[M+H]+(C 14 H 14 Calculated values ​​for BrNO: 292.03, 294.03; measured values: 292.00, 294.00.

[0616] Step 6: 4-(2'-acryloyl-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline]-5'-yl)-5-fluoro-2-methyl-1H-indole-7-carboxamide (compound 5b)

[0617] [ka] A mixture of 5-fluoro-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-7-carboxamide (350 mg, 1.10 mmol), 1-(5'-bromo-1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-yl)propa-2-en-1-one (230 mg, 0.787 mmol), potassium phosphate (500 mg, 2.36 mmol), and Pd(PPh3)4 (90 mg, 0.078 mmol) in water (2.5 mL) and dioxane (10 mL) was degassed and backpacked with nitrogen. The reaction mixture was heated under nitrogen at 80°C for 16 hours. The cooled reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (3 × 30 mL). The combined extracts were washed with brine (30 mL), dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography (80% ethyl acetate in petroleum ether) to obtain the green solid 4-(2'-acryloyl-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline]-5'-yl)-5-fluoro-2-methyl-1H-indole-7-carboxamide (170 mg, 56%).

[0618] 1 1H NMR (400MHz, DMSO-d6)δ 11.06(s,1H),8.13(s,1H),7.65-7.48(m,2H),7.46-7.36(m,1H),7.35-7.29( m,1H),7.19-7.10(m,1H),7.06-6.96(m,0.5H),6.67-6.58(m,0.5H),6.22-6.1 0(m,1H),5.82-5.60(m,2H),5.09-4.96(m,1H),4.85-4.55(m,1H),3.65-3.42 (m,1H),3.37-3.13(m,1H),2.38(s,3H),0.72-0.59(m,2H),0.32-0.14(m,2H).

[0619] ESI-MS[M+H] + (C 24 H 22 The calculated value for FN3O2 was 404.17, while the measured value was 404.30.

[0620] Step 7: 4-(2'-acryloyl-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline]-5'-yl)-3-chloro-5-fluoro-2-methyl-1H-indole-7-carboxamide (compound 5a)

[0621] [ka] To a solution of 4-(2'-acryloyl-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline]-5'-yl)-5-fluoro-2-methyl-1H-indole-7-carboxamide (170 mg, 0.421 mmol) in DMF (6.0 mL), NCS (56.0 mg, 0.421 mmol) was added at 0°C. The reaction mixture was stirred at 0°C for 2 hours. The reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (3 × 15 mL). The combined extracts were washed with brine (3 × 20 mL), dried over sodium sulfate, and concentrated under vacuum. The residue was purified by preparative HPLC (column: Xselect CSH OBD Column 30×150mm 5um; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 38% B to 58% B in 7 mins; 220 nm; retention time = 5.32 mins) to obtain the white solid 4-(2'-acryloyl-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline]-5'-yl)-3-chloro-5-fluoro-2-methyl-1H-indole-7-carboxamide (32.6 mg, 17%).

[0622] 1H NMR(400MHz,DMSO-d6)δ 11.43(s,1H),8.18(s,1H),7.68-7.56(m,2H),7.38-7.35(m,1H),7.24-7.21(m,1H),7.05-6.54(m,2H),6.14-6.08( m,1H),5.69-5.60(m,1H),4.98-4.65(m,2H),3.42-3.20(m,2H),2.34(s,3H),0.67-0.53(m,2H),0.36-0.22(m,2H).

[0623] ESI-MS[M+H]+(C 24 H 21 The calculated value for ClN3O2 was 438.13, and the measured value was 438.15.

[0624] Step 8: Separation of isomers (R)-4-(2'-acryloyl-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline]-5'-yl)-3-chloro-5-fluoro-2-methyl-1H-indole-7-carboxamide (compound 24c) and (S)-4-(2'-acryloyl-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline]-5'-yl)-3-chloro-5-fluoro-2-methyl-1H-indole-7-carboxamide (compound 24d):

[0625] [ka]

[0626] The two atropisomers were separated by preparative chiral HPLC (sample amount = 24 mg, column: CHIRALPAK IE, 2 × 25 cm, 5 μm; mobile phase A: MTBE (0.5% 2M NH3-MeOH), mobile phase B: EtOH; flow rate: 20 mL / min; gradient: 5% B, 12 min; 220 / 254 nm):

[0627] Compound 24c: Retention time = 8.078 minutes (7.9 mg) 1H NMR(400MHz, methanol-d4)δ 7.50(d,J=10.0Hz,1H),7.36-7.34(m,1H),7.27-7.25(m,1H),7.09-7.07(m,1H),6.99-6.55(m,1H),6.26-6.23(m ,1H),5.83-5.72(m,1H),5.03-4.78(m,2H),3.59-3.37(m,2H),2.38(s,3H),0.68-0.58(m,2H),0.48-0.40(m,2H).

[0628] ESI-MS[M+H] + (C 24 H 21 Calculated value for ClN3O2: 438.13, Measured value: 438.10

[0629] Compound 24d: Retention time = 9.991 minutes (7.6 mg) 1 H NMR(400MHz, methanol-d4)δ 7.50(d,J=10.0Hz,1H),7.36-7.34(m,1H),7.30-7.25(m,1H),7.09-7.07(m,1H),6.98-6.56(m,1H),6.26-6.23(m ,1H),5.77-5.72(m,1H),5.02-4.78(m,2H),3.56-3.41(m,2H),2.38(s,3H),0.66-0.58(m,2H),0.47-0.41(m,2H).

[0630] ESI-MS[M+H] + (C 24 H 21 The calculated value for ClN3O2 was 438.13, and the measured value was 438.10.

[0631] Preparation of the compound of formula (II) where × is -CH2CH2-

[0632] [ka]

[0633] Example 25 Synthesis of 4-(2-acryloyl-2,3,4,5-tetrahydro-1H-benzo[c]azepine-6-yl)-3-chloro-5-fluoro-2-methyl-1H-indole-7-carboxamide (compound 25a)

[0634] [ka] Step 1: 5-Fluoro-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-7-carboxamide

[0635] [ka] A mixture of 4-bromo-5-fluoro-2-methyl-1H-indole-7-carboxamide (prepared as described in Example 1, 1.30 g, 4.80 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.34 g, 5.28 mmol), potassium acetate (941 mg, 9.59 mmol), and Pd(dppf)Cl2.DCM (196 mg, 0.24 mmol) in dioxane (16 mL) was degassed and backpacked with nitrogen. The reaction mixture was heated at 100°C for 2 hours under nitrogen. The cooled reaction mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography (0 to 30% ethyl acetate in petroleum ether) to obtain 5-fluoro-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-7-carboxamide (660 mg) as a yellow solid.

[0636] ESI-MS[M+H] + (C 16 H 20 The calculated value for BFN2O3 was 319.16, and the measured value was 319.25.

[0637] Step 2: 6-bromo-2,3,4,5-tetrahydro-1H-benzo[c]azepine-1-one

[0638] [ka] A mixture of 5-bromotetralin-1-one (5.2 g, 23.10 mmol), hydroxylamine hydrochloride (2.41 g, 34.7 mmol), and sodium acetate (2.84 g, 34.7 mmol) in ethanol (100 mL) and water (40 mL) was heated under nitrogen at 90°C for 2 hours. The cooled reaction mixture was diluted with water (150 mL) and extracted with ethyl acetate (3 × 100 mL). The combined extract was washed with brine (100 mL), dried over sodium sulfate, and concentrated under vacuum. The residue was dissolved in polyphosphate (100 mL) and stirred at 100°C for 2 hours. The cooled reaction mixture was basicized with aqueous sodium hydroxide and extracted with ethyl acetate (4 × 150 mL). The combined extract was washed with brine (200 mL), dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography (0 to 10% ethyl acetate in petroleum ether) to obtain 6-bromo-2,3,4,5-tetrahydro-2-benzazepine-1-one (2.7 g, 48%) as a brown solid.

[0639] ESI-MS[M+H] + (C 10 H 10 Calculated values ​​for BrNO: 239.99, 241.99; measured values: 240.00, 242.00.

[0640] Step 3: 6-bromo-2,3,4,5-tetrahydro-1H-benzo[c]azepine

[0641] [ka] A solution of 6-bromo-2,3,4,5-tetrahydro-2-benzazepine-1-one (2.7 g, 11.3 mmol) in THF (54 mL) was mixed with borane (1 M in THF, 112 mL, 112 mmol). The reaction mixture was heated at 70°C for 3 hours. The cooled reaction mixture was diluted with methanol (100 mL) and concentrated under vacuum. The residue was purified by silica gel column chromatography (0 to 12% ethyl acetate in petroleum ether) to obtain a colorless oily 6-bromo-2,3,4,5-tetrahydro-1H-benzo[c]azepine (2.4 g, 94%).

[0642] 1 H NMR(400MHz,DMSO-d6)δ 6.96(dd,J=7.6,1.2Hz,1H),6.87-6.75(m,2H),5.44(s,1H),2.97-2.90(m,2H),2.89-2.82(m,2H),1.70-1.60(m,2H),1.59-1.49(m,2H).

[0643] ESI-MS[M+H] + (C 10 H 12 Calculated values ​​for BrN: 226.02, 228.02; Measured values: 226.15, 228.15.

[0644] Step 4: 1-(6-bromo-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-yl)propa-2-en-1-one

[0645] [ka] A mixture of 6-bromo-2,3,4,5-tetrahydro-1H-benzo[c]azepine (1.6 g, 7.08 mmol) in THF (8 mL) and water (2 mL) was mixed with sodium bicarbonate (1.78 g, 21.2 mmol) and acryloyl chloride (769 mg, 8.49 mmol) at 0°C. The reaction mixture was stirred at 0°C for 0.5 hours. Water (20 mL) was added. The mixture was extracted with ethyl acetate (3 × 20 mL). The combined extract was washed with brine (40 mL), dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography (0 to 15% ethyl acetate in petroleum ether) to obtain the white solid 1-(6-bromo-4,5-dihydro-1H-benzo[c]azepine-2(3H)-yl)propa-2-en-1-one (1.6 g, 80%).

[0646] 1 H NMR(300MHz,DMSO-d6)δ 7.63(dd,J=7.5,2.1Hz,1H),7.27-7.11(m,2H),6.25-6.13(m,1H),6.07-5.92(m,1H),5.58(dd,J=10.2,2.4Hz,1H) ,4.58-4.46(m,1H),3.27-3.14(m,1H),2.79-2.55(m,2H),1.99-1.85(m,1H),1.82-1.63(m,2H),1.45-1.14(m,1H).

[0647] ESI-MS[M+H] + (C 13 H 14 Calculated values ​​for BrNO: 280.03, 282.03; measured values: 280.10, 282.10.

[0648] Step 5: 4-(2-acryloyl-2,3,4,5-tetrahydro-1H-benzo[c]azepine-6-yl)-5-fluoro-2-methyl-1H-indole-7-carboxamide (compound 25b)

[0649] [ka] A mixture of 1-(6-bromo-1,3,4,5-tetrahydro-2-benzazepine-2-yl)propa-2-en-1-one (581 mg, 2.07 mmol), 5-fluoro-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-7-carboxamide (660 mg, 2.07 mmol), potassium phosphate (1.32 g, 6.22 mmol), and tetrakis(triphenylphosphine)palladium (240 mg, 0.21 mmol) in dioxane (8 mL) and water (2 mL) was degassed and backpacked with nitrogen. The reaction mixture was heated under nitrogen at 80°C for 16 hours. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (3 × 30 mL). The combined extracts were washed with brine (40 mL), dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography (0 to 70% ethyl acetate in petroleum ether) to obtain a white solid 5-fluoro-2-methyl-4-(2-propa-2-enoyl-1,3,4,5-tetrahydro-2-benzazepine-6-yl)-1H-indole-7-carboxamide (500 mg, 61%).

[0650] 1 H NMR(400MHz,DMSO-d6)δ 11.08(s,1H),8.12(s,1H),7.65-7.48(m,2H),7.42-7.36(m,1H),7.29-7.18(m,2H),6.25-6.15(m,1H),6.14-6.00(m,1H),5.88 -5.68(m,1H),5.67-5.59(m,1H),4.69-4.52(m,1H),2.82-2.66(m,1H),2.45-2.25(m,5H),1.89-1.55(m,3H),1.48-1.08(m,1H).

[0651] ESI-MS[M+H] + (C 23 H 22 The calculated value for FN3O2 was 392.17, and the measured value was 392.30.

[0652] Step 6: 4-(2-acryloyl-2,3,4,5-tetrahydro-1H-benzo[c]azepine-6-yl)-3-chloro-5-fluoro-1H-indole-7-carboxamide (compound 25a)

[0653] [ka] N-chlorosuccinimide (51 mg, 0.38 mmol) was added at 0°C to a stirred solution of 5-fluoro-2-methyl-4-(2-propa-2-enoyl-1,3,4,5-tetrahydro-2-benzazepine-6-yl)-1H-indole-7-carboxamide (5.0 mL) in N,N-dimethylformamide (5.0 mL). The reaction mixture was stirred at 0°C for 1 hour. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (3 × 25 mL). The combined extract was washed with brine (30 mL), dried over sodium sulfate, and concentrated under vacuum. The residue was purified by preparative HPLC under the following conditions: column: Xselect CSH OBD Column 30×150 mm 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 40% B to 60% B in 7 mins; 220 nm; RT: 5.45 mins) to obtain a mixture of atropisomers, 3-chloro-5-fluoro-2-methyl-4-(2-propa-2-enoyl-1,3,4,5-tetrahydro-2-benzazepine-6-yl)-1H-indole-7-carboxamide (80 mg, 49%).

[0654] 1 H NMR(400MHz,DMSO-d6)δ 11.46(s,1H),8.19(s,1H),7.70-7.57(m,2H),7.43-7.29(m,1H),7.28-7.19(m,2H),6.28-5.96(m,2H),5.68 -5.57(m,1H),4.66-4.52(m,1H),2.80-2.65(m,1H),2.45-2.25(m,5H),1.77-1.51(m,3H),1.33-1.10(m,1H).

[0655] ESI-MS[M+H] + (C 23 H 21 Calculated values ​​for ClFN3O2: 426.13, 428.13; measured values: 426.25, 428.25.

[0656] Step 7: Separation of isomers (R)-3-chloro-5-fluoro-2-methyl-4-(2-propa-2-enoyl-1,3,4,5-tetrahydro-2-benzazepine-6-yl)-1H-indole-7-carboxamide (compound 25c) and (S)-3-chloro-5-fluoro-2-methyl-4-(2-propa-2-enoyl-1,3,4,5-tetrahydro-2-benzazepine-6-yl)-1H-indole-7-carboxamide (compound 25d):

[0657] [ka]

[0658] The two atrop isomers were separated by chiral HPLC (sample amount = 45 mg, CHIRAL ART Cellulose-SB, 2 × 25 cm, 5 μm; mobile phase A: MTBE (0.5% 2M NH3-MeOH), mobile phase B: IPA; flow rate: 20 mL / min; gradient: 5% B, 14 min; 220 / 254 nm).

[0659] Compound 25c: Retention time = 8.502 minutes (19.1 mg) 1 H NMR(400MHz,DMSO-d6)δ 11.44(s,1H),8.18(s,1H),7.70-7.54(m,2H),7.40-7.29(m,1H),7.29-7.16(m,2H),6.26-5.98(m,2H),5.67 -5.55(m,1H),4.64-4.53(m,1H),2.80-2.65(m,1H),2.45-2.25(m,5H),1.81-1.62(m,3H),1.32-1.14(m,1H).

[0660] ESI-MS[M+H]+(C 23 H 21 Calculated values ​​for ClFN3O2: 426.13, 428.13; measured values: 426.10, 428.10.

[0661] Compound 25d: Retention time = 11.588 minutes (19.3 mg) 1 H NMR(400MHz,DMSO-d6)δ 11.44(s,1H),8.18(s,1H),7.70-7.60(m,2H),7.38-7.29(m,1H),7.27-7.17(m,2H),6.26-6.00(m,2H),5.67 -5.56(m,1H),4.64-4.53(m,1H),2.80-2.65(m,1H),2.43-2.30(m,5H),1.77-1.65(m,3H),1.33-1.15(m,1H).

[0662] ESI-MS[M+H]+(C 23 H 21 Calculated values ​​for ClFN3O2: 426.13, 428.13; measured values: 426.05, 428.05.

[0663] Synthesis of 4-(2-acryloyl-2,3,4,5-tetrahydro-1H-benzo[c]azepine-6-yl)-3,5-difluoro-2-methyl-1H-indole-7-carboxamide (compound 25e)

[0664] [ka] N-fluorobenzenesulfonimide (126 mg, 0.51 mmol) was added to a stirred solution of 4-(2-acryloyl-2,3,4,5-tetrahydro-1H-benzo[c]azepine-6-yl)-5-fluoro-2-methyl-1H-indole-7-carboxamide (80 mg, 0.20 mmol) in dichloromethane (10 mL). The reaction mixture was stirred at 25°C for 36 hours. The reaction mixture was diluted with water (30 mL) and extracted with dichloromethane (3 × 30 mL). The combined extract was washed with brine (100 mL), dried over sodium sulfate, and concentrated under vacuum. The residue was purified by preparative HPLC (column: YMC-Actus Triart C18, 30 × 250 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 40% B to 50% B, 8 min; 254 nm; retention time = 7.95) to obtain a white solid 4-(2-acryloyl-2,3,4,5-tetrahydro-1H-benzo[c]azepine-6-yl)-3,5-difluoro-2-methyl-1H-indole-7-carboxamide (8.0 mg, 9%).

[0665] 1 H NMR(400MHz,DMSO-d6)δ 10.87(s,1H),8.09(s,1H),7.65-7.43(m,2H),7.37-7.12(m,3H),6.20-6.05(m,1H),6.03-5.80(m,1H),5.59-5.52( m,1H),4.60-4.45(m,1H),2.75-2.58(m,1H),2.42-2.28(m,2H),2.24(s,3H),1.75-1.52(m,3H),1.30-1.05(m,1H).

[0666] ESI-MS[M+H]+(C 23 H 21 The calculated value for F2N3O2 is 410.16, and the measured value is 410.30.

[0667] × is -CR x1 R x2 - and R x1 H is R x2and R 3 Preparation of the compound of formula (II) in which these elements combine to form an alkylene bridge.

[0668] [ka]

[0669] Example 26 Synthesis of 4-(2-acryloyl-1,2,3,4-tetrahydro-1,4-methanoisoquinoline-5-yl)-3-chloro-5-fluoro-2-methyl-1H-indole-7-carboxamide (compound 26)

[0670] [ka] Step 1: 4-ethyl 1-methyl 2-(2-bromophenyl)succinate

[0671] [ka] To a stirred solution of methyl 2-(2-bromophenyl)acetate (10.0 g, 43.7 mmol) in THF (120 mL), potassium bis(trimethylsilyl)amide (1.0 M, 65.5 mL, 65.5 mmol) was added dropwise under nitrogen at -78°C. After stirring at this temperature for 1 hour, 2-bromoacetic acid (50.00 g, 299 mmol) was added dropwise. The reaction mixture was stirred at -78°C for 1 hour, then at -40°C for 3 hours. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (3 × 100 mL). The combined extracts were washed with brine (100 mL), dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography (0 to 30% ethyl acetate in petroleum ether) to obtain a white solid 4-ethyl 1-methyl 2-(2-bromophenyl)succinate (11.9 g, 86%).

[0672] 1H NMR(400MHz,DMSO-d6)δ 7.63-7.59(m,1H),7.38-7.28(m,2H),7.24-7.19(m,1H),4.52-4.45(m,1H),4.03-4. 00(m,2H),3.59(s,3H),3.03-2.99(m,1H),2.69-2.66(m,1H),1.12(t,J=6.8Hz,3H).

[0673] ESI-MS[M+H]+(C 13 H 15 Calculated values ​​for BrO4: 315.02, 317.02; measured values: 314.95, 316.95.

[0674] Step 2: 2-(2-bromophenyl)succinate

[0675] [ka] Potassium hydroxide (21.2 g, 378 mmol) was added to a stirred mixture of 4-ethyl 1-methyl 2-(2-bromophenyl)succinate (11.9 g, 37.8 mmol) in water (150 mL). The reaction mixture was heated under reflux for 20 hours. The pH of the cooled reaction mixture was adjusted to 3-4 with 1 M aqueous HCl. The solid was collected by filtration and dried under reduced pressure to obtain a white solid of 2-(2-bromophenyl)succinate (9.80 g).

[0676] 1 H NMR(300MHz,DMSO-d6)δ 12.49(brs,2H),7.63(dd,J=8.1,1.5Hz,1H),7.40-7.13(m,3H),4.35-4.30(m,1H),2.89-2.85(m,1H),2.59-2.50(m,1H).

[0677] ESI-MS[M+H]+(C 10 Calculated values ​​for H9BrO4: 272.97, 274.97; measured values: 272.85, 274.85.

[0678] Step 3: 3-(2-bromophenyl)dihydrofuran-2,5-dione

[0679] [ka] A mixture of 2-(2-bromophenyl)succinic acid (9.80 g, crude) and sulfur dichloride (4.30 g, 35.9 mmol) in acetyl chloride (84.0 g) was stirred under reflux for 3 hours. The cooled reaction mixture was concentrated under vacuum to obtain 3-(2-bromophenyl)dihydrofuran-2,5-dione (9.0 g) as a yellow solid.

[0680] 1 H NMR(400MHz,DMSO-d6)δ 7.67(dd,J=8.0,1.2Hz,1H),7.55(dd,J=7.6,1.6Hz,1H),7.48-7.36(m,1H), 7.34-7.24(m,1H),5.00-4.87(m,1H),3.51-3.35(m,1H),3.21-3.09(m,1H).

[0681] ESI-MS[MH]-(C 10 Calculated values ​​for H7BrO3: 252.96, 254.96; measured values: 252.85, 254.85.

[0682] Step 4: 7-Bromo-3-oxo-2,3-dihydro-1H-indene-1-carboxylic acid

[0683] [ka] A solution of 3-(2-bromophenyl)dihydrofuran-2,5-dione (9.0 g) in 1,2-dichloroethane (125 mL) was mixed with a solution of aluminum chloride (11.0 g, 82.5 mmol) in 1,2-dichloroethane (32 mL) at 0°C. The reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was diluted with water (100 mL) and extracted with DCM (3 × 100 mL). The combined extract was washed with brine (100 mL), dried over sodium sulfate, and concentrated under vacuum to obtain a yellow solid 7-bromo-3-oxo-2,3-dihydro-1H-indene-1-carboxylic acid (8.30 g).

[0684] 1 H NMR(300MHz,DMSO-d6)δ 12.81(brs,1H),7.96(dd,J=7.8,1.2Hz,1H),7.70(dd,J=7.5,0.9Hz,1H),7 .48-7.42(m,1H),4.18-4.09(m,1H),3.23-3.10(m,1H),2.72-2.67(m,1H).

[0685] Step 5: 7-Bromo-3-oxo-2,3-dihydro-1H-indene-1-carboxylate methyl

[0686] [ka] A solution of 7-bromo-3-oxo-2,3-dihydro-1H-indene-1-carboxylic acid (8.00 g, 31.4 mmol) in methanol (130 mL) was mixed with concentrated sulfuric acid (4.0 mL). The reaction mixture was heated under reflux for 5 hours. The reaction mixture was concentrated under vacuum. The residue was diluted with water (150 mL) and extracted with ethyl acetate (3 × 100 mL). The combined extracts were washed with brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography (0 to 20% ethyl acetate in petroleum ether) to obtain a yellow solid methyl 7-bromo-3-oxo-2,3-dihydro-1H-indene-1-carboxylic acid (7.30 g, 86%).

[0687] 1 H NMR(300MHz,DMSO-d6)δ 7.99(d,J=7.8,1.2Hz,1H),7.74(dd,J=7.5,1.2Hz,1H),7.64-7.49(m,1H),4.33(dd,J=8 .7,2.9Hz,1H),3.67(s,3H),3.17(dd,J=19.1,8.7Hz,1H),2.79(dd,J=19.1,2.9Hz,1H).

[0688] ESI-MS[M+H+ACN]+(C 11 Calculated values ​​for H9BrO3: 309.97, 311.97; measured values: 309.95, 311.95.

[0689] Step 6: (Z)-7-bromo-3-(hydroxyimino)-2,3-dihydro-1H-indene-1-carboxylate methyl

[0690] [ka] To a solution of methyl 7-bromo-3-oxo-2,3-dihydro-1H-indene-1-carboxylate (7.30 g, 27.1 mmol) in MeOH (50 mL), hydroxylamine hydrochloride (2.60 g, 36.8 mmol) was added. The reaction mixture was stirred under reflux for 3 hours. The cooled reaction mixture was diluted with water (150 mL) and extracted with ethyl acetate (3 × 100 mL). The combined extracts were washed with brine (2 × 100 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain a yellow solid (Z)-7-bromo-3-(hydroxyimino)-2,3-dihydro-1H-indene-1-carboxylate (7.5 g).

[0691] 1 H NMR(300MHz,DMSO-d6)δ 11.32(s,1H),7.66-7.58(m,2H),7.39-7.31(m,1H),4.21(dd,J=9.6,3.3Hz, 1H),3.65(s,3H),3.23(dd,J=18.9,9.6Hz,1H),2.88(dd,J=18.9,3.3Hz,1H).

[0692] ESI-MS[M+H]+(C 11 H 10 Calculated values ​​for BrNO3: 283.98, 285.98; measured values: 284.00, 286.00.

[0693] Step 7: 3-amino-7-bromo-2,3-dihydro-1H-indene-1-carboxylate methyl

[0694] [ka] To a solution of (Z)-7-bromo-3-(hydroxyimino)-2,3-dihydro-1H-indene-1-carboxylate methyl (1.0 g, 3.52 mmol) in acetic acid (30 mL), zinc powder (2.30 g, 35.2 mmol) and ammonium chloride (1.88 g, 35.2 mmol) were added. The reaction mixture was stirred at 30°C for 16 hours. The reaction mixture was basicized with saturated aqueous solution NaHCO3 and extracted with ethyl acetate (3 × 60 mL). The combined extract was washed with brine (50 mL), dried over sodium sulfate, and concentrated under vacuum to obtain a white solid of 3-amino-7-bromo-2,3-dihydro-1H-indene-1-carboxylate methyl (700 mg).

[0695] ESI-MS[M+H]+(C 11 H 12 Calculated values ​​for BrNO2: 270.01, 272.01; measured values: 270.00, 272.00.

[0696] Step 8: 3-amino-7-bromo-2,3-dihydro-1H-indene-1-carboxylic acid

[0697] [ka] A mixture of methyl 3-amino-7-bromo-2,3-dihydro-1H-indene-1-carboxylic acid (6.00 g, 22.2 mmol) in 2M hydrochloric acid (300 mL) was heated under reflux for 5 hours. The pH of the cooled reaction mixture was adjusted to 7 with saturated aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate (4 × 150 mL). The combined extract was washed with brine (150 mL), dried over sodium sulfate, and concentrated under vacuum to obtain a white solid of 3-amino-7-bromo-2,3-dihydro-1H-indene-1-carboxylic acid (5.50 g).

[0698] 1 H NMR(300MHz,DMSO-d6)δ 12.94(s,1H),8.57(s,2H),7.69-7.62(m,2H),7.36-7.32(m,1H),4.92 -4.74(m,1H),3.99-3.94(m,1H),2.95-2.85(m,1H),2.14-2.08(m,1H).

[0699] ESI-MS[M+H]+(C 10 H 10 Calculated values ​​for BrNO2: 255.99, 257.99; measured values: 255.95, 257.95.

[0700] Step 9: 5-Bromo-1,4-dihydro-1,4-methanoisoquinoline-3(2H)-one

[0701] [ka] Dicyclohexylcarbodiimide (5.3 g, 25.8 mmol) was added to a solution of 3-amino-7-bromo-2,3-dihydro-1H-indene-1-carboxylic acid (5.50 g, crude) and pyridine (9.30 g, 117 mmol) in acetonitrile (150 mL). The reaction mixture was heated under reflux for 1 hour. The cooled reaction mixture was quenched with water (200 mL) and extracted with ethyl acetate (3 × 150 mL). The combined extract was washed with brine (100 mL), dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography (0 to 50% ethyl acetate in petroleum ether) to obtain 5-bromo-1,4-dihydro-1,4-methanoisoquinoline-3(2H)-one (2.40 g, 43%) as a yellow solid.

[0702] ESI-MS[M+H]+(C 10 Calculated values ​​for H8BrNO: 237.98, 239.98; measured values: 238.00, 240.00.

[0703] Step 10: 5-Bromo-1,2,3,4-tetrahydro-1,4-methanoisoquinoline

[0704] [ka] To a solution of sodium borohydride (596 mg, 15.8 mmol) in THF (10 mL), BF3.Et2O (2.98 g, 21.0 mmol) was added at 0°C. After stirring at this temperature for 1 hour, a solution of 5-bromo-1,4-dihydro-1,4-methanoisoquinoline-3(2H)-one (1.25 g, 5.25 mmol) in THF (10 mL) was added dropwise. The reaction mixture was stirred under reflux for 16 hours. The cooled reaction mixture was quenched with water (40 mL) and extracted with ethyl acetate (3 × 30 mL). The combined extracts were washed with brine (40 mL), dried over sodium sulfate, and concentrated under vacuum to obtain a yellow solid of 5-bromo-1,2,3,4-tetrahydro-1,4-methanoisoquinoline (1.00 g).

[0705] ESI-MS[M+H]+(C 10 H 10 Calculated values ​​for BrN: 224.00, 226.00; Measured values: 224.00, 226.00.

[0706] Step 11: 1-(5-bromo-3,4-dihydro-1,4-methanoisoquinoline-2(1H)-yl)propa-2-en-1-one

[0707] [ka] A mixture of 5-bromo-1,2,3,4-tetrahydro-1,4-methanoisoquinoline (800 mg, 3.57 mmol) in water (2 mL) and THF (8 mL) was mixed with sodium bicarbonate (1.50 g, 17.9 mmol) and acryloyl chloride (323 mg, 3.57 mmol) at 0°C. The reaction mixture was stirred at 0°C for 0.5 hours. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (3 × 30 mL). The combined extract was washed with brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography (0 to 50% ethyl acetate in petroleum ether) to obtain a white solid 1-(5-bromo-3,4-dihydro-1,4-methanoisoquinoline-2(1H)-yl)prop-2-en-1-one (400 mg, 40%).

[0708] ESI-MS[M+H]+(C 13 H 12 Calculated values ​​for BrNO: 278.01, 280.01; measured values: 277.95, 279.95.

[0709] Step 12: 4-(2-acryloyl-1,2,3,4-tetrahydro-1,4-methanoisoquinoline-5-yl)-5-fluoro-2-methyl-1H-indole-7-carboxamide

[0710] [ka] A mixture of 1-(5-bromo-3,4-dihydro-1,4-methanoisoquinolin-2(1H)-yl)prop-2-en-1-one (755 mg, 2.37 mmol), 5-fluoro-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-7-carboxamide (600 mg, 2.16 mmol), potassium phosphate (1.37 g, 6.47 mmol), and Pd(PPh3)4 (250 mg, 0.216 mmol) in water (3.0 mL) and dioxane (12 mL) was degassed and backfilled with nitrogen. The reaction mixture was heated at 80 °C for 16 h under nitrogen. The cooled reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (3 × 30 mL). The combined extracts were washed with brine (50 mL), dried over sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (0 to 10% methanol in dichloromethane) to afford 4-(2-acryloyl-1,2,3,4-tetrahydro-1,4-methanoisoquinolin-5-yl)-5-fluoro-2-methyl-1H-indole-7-carboxamide (440 mg, 52%) as a green solid.

[0711] 1 H NMR (300 MHz, DMSO-d6) δ 11.09 (s, 1H), 8.14 (s, 1H), 7.67 - 7.21 (m, 5H), 7.08 - 6.24 (m, 1H), 6.17 - 5.43 (m, 4H), 3.94 - 3.45 (m, 2H), 3.03 - 2.60 (m, 1H), 2.46 - 2.34 (m, 3H), 2.05 - 1.92 (m, 2H).

[0712] ESI-MS [M + H]+ (C 23 H 20 FN3O2) calcd for 390.15, found: 390.30.

[0713] Step 13: 4-(2-Acryloyl-1,2,3,4-tetrahydro-1,4-methanoisoquinolin-5-yl)-3-chloro-5-fluoro-2-methyl-1H-indole-7-carboxamide (Compound 26)

[0714] [ka] To a solution of 4-(2-acryloyl-1,2,3,4-tetrahydro-1,4-methanoisoquinoline-5-yl)-5-fluoro-2-methyl-1H-indole-7-carboxamide (200 mg, 0.51 mmol) in DMF (6 mL), NCS (83 mg, 0.62 mmol) was added at 0°C. The reaction mixture was stirred at 0°C for 1 hour. The reaction mixture was quenched with water (15 mL) and extracted with ethyl acetate (3 × 15 mL). The combined extracts were washed with brine (3 × 20 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by preparative HPLC (column: Xselect CSH OBD Column 30×150mm 5um; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 38% B to 58% B, 7 min; 220 nm; retention time = 5.32 min) to obtain a white solid 4-(2-acryloyl-1,2,3,4-tetrahydro-1,4-methanoisoquinoline-5-yl)-3-chloro-5-fluoro-2-methyl-1H-indole-7-carboxamide (91 mg, 42%).

[0715] 1 H NMR(300MHz,DMSO-d6)δ 11.49(s,1H),8.21(s,1H),7.71-7.66(m,2H),7.40-7.32(m,1H),7.26-6.20(m,3H),6.18-6.01(m,1H),5.75 -5.47(m,2H),3.79-3.40(m,1H),3.31-3.20(m,1H),2.81-2.76(m,1H),2.40-2.31(m,3H),1.96-1.88(m,2H).

[0716] ESI-MS[M+H]+(C 23 H 19 The calculated value for ClN3O2 was 424.11, while the measured value was 424.10.

[0717] Preparation of the compound of formula (III)

[0718]

Chem.

[0719] Example 27 Synthesis of 4-((3S,5R)-3-(but-2-ynamide)-5-fluoropiperidin-1-yl)-3-chloro-5-fluoro-2-methyl-1H-indole-7-carboxamide (Compound 27)

[0720]

Chem.

[0721]

Chem.

[0722] ESI-MS [M-H] - (C 10 H7BrFNO2) Calculated for 269.96, 271.96; Found: 270.25, 272.25.

[0723] Step 2: 4-Bromo-5-fluoro-2-methyl-1H-indole-7-carboxamide

[0724] [ka] N-ethyl-N-isopropyl-propan-2-amine (25.0 g, 193 mmol) was added to a stirred solution of 4-bromo-5-fluoro-2-methyl-1H-indole-7-carboxylic acid (17.5 g, 64.4 mmol), ammonium hydrochloride (5.17 g, 96.6 mmol), and HATU (29.4 g, 77.3 mmol) in DMF (200 mL). The reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was quenched with water (300 mL) and extracted with ethyl acetate (3 × 300 mL). The combined extracts were washed with water (200 mL) and brine (200 mL), then dried over anhydrous sodium sulfate and concentrated under vacuum. The concentrate was purified by column chromatography (50% ethyl acetate in petroleum ether) to obtain 4-bromo-5-fluoro-2-methyl-1H-indole-7-carboxamide (3.8 g, 22%) as a yellow solid.

[0725] 1 H NMR(400MHz,DMSO-d6)δ 11.26(s,1H),8.11(s,1H),7.63-7.53(m,2H),6.19(s,1H),2.42(s,3H).

[0726] ESI-MS[M+H] + (C 10 Calculated values ​​for H8BrFN2O: 270.98, 272.98. Measured values: 270.90, 272.90.

[0727] Step 3: 4-Bromo-5-fluoro-2-methyl-1H-indole-7-carbonitrile

[0728] [ka] A mixture of 4-bromo-5-fluoro-2-methyl-1H-indole-7-carboxamide (2.00 g, 7.38 mmol) in DCM (40 mL) was mixed with pyridine (1.46 g, 18.4 mmol) and phosphorus oxychloride (1.70 g, 11.1 mmol) at 0°C. The reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography (0 to 10% ethyl acetate in petroleum ether) to obtain a white solid of 4-bromo-5-fluoro-2-methyl-1H-indole-7-carbonitrile (1.50 g, 80%).

[0729] 1 H NMR(400MHz,DMSO-d6)δ 12.26(s,1H),7.63(d,J=9.2Hz,1H),6.34-6.31(m,1H),2.42(s,3H).

[0730] ESI-MS[MH] - (C 10 Calculated values ​​for H6BrFN2: 250.97, 252.97; measured values: 250.95, 252.95.

[0731] Step 4: ((3S,5R)-1-(7-cyano-5-fluoro-2-methyl-1H-indole-4-yl)-5-fluoropiperidine-3-yl) tert-butyl carbamate

[0732] [ka] A mixture of 4-bromo-5-fluoro-2-methyl-1H-indole-7-carbonitride (500 mg, 1.74 mmol), ((3S,5R)-5-fluoropiperidine-3-yl)carbamate tert-butyl (418 mg, 1.91 mmol), benzyl-[1-[2-[benzyl(phenyl)phosphanyl]-1-naphthyl]-2-naphthyl]-phenylphosphan (453 mg, 696 μmol), tris(dibenzylideneacetone)dipalladium (360 mg, 348 μmol), and cesium carbonate (1.70 g, 5.22 mmol) in dioxane (10 mL) was degassed and backpacked with nitrogen. The reaction mixture was heated under nitrogen at 100°C for 16 hours. The cooled reaction mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography (0 to 16% ethyl acetate in petroleum ether) to obtain a yellow solid ((3S,5R)-1-(7-cyano-5-fluoro-2-methyl-1H-indole-4-yl)-5-fluoropiperidine-3-yl)carbamate tert-butyl (380 mg).

[0733] ESI-MS[M+H] + (C 20 H 24 The calculated value for F2N4O2 is 391.19, and the measured value is 391.15.

[0734] Step 5: ((3S,5R)-1-(7-carbamoyl-5-fluoro-2-methyl-1H-indole-4-yl)-5-fluoropiperidine-3-yl) tert-butyl carbamate

[0735] [ka] A mixture of tert-butyl ((3S,5R)-1-(7-cyano-5-fluoro-2-methyl-1H-indole-4-yl)-5-fluoropiperidine-3-yl)carbamate (350 mg, 0.89 mmol) in ethanol (16 mL) and water (4 mL) was mixed with Parkin catalyst (19 mg, 0.045 mmol). The reaction mixture was stirred at 90°C for 2 hours. The cooled reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (3 × 30 mL). The combined extracts were washed with brine (50 mL), dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography (0 to 50% ethyl acetate in petroleum ether) to obtain a yellow solid ((3S,5R)-1-(7-carbamoyl-5-fluoro-2-methyl-1H-indole-4-yl)-5-fluoropiperidine-3-yl)carbamate tert-butyl (320 mg).

[0736] ESI-MS[M+H] + (C 20 H 26 The calculated value for F2N4O3 is 409.20, and the measured value is 409.10.

[0737] Step 6: ((3S,5R)-1-(7-carbamoyl-3-chloro-5-fluoro-2-methyl-1H-indole-4-yl)-5-fluoropiperidine-3-yl) tert-butyl carbamate

[0738] [ka] To a solution of ((3S,5R)-1-(7-carbamoyl-3-chloro-5-fluoro-2-methyl-1H-indole-4-yl)-5-fluoropiperidine-3-yl)carbamate tert-butyl (250 mg, 0.61 mmol) in N,N-dimethylformamide (8 mL), N-chlorosuccinimide (82 mg, 0.61 mmol) was added at 0°C. The reaction mixture was stirred at 0°C for 2 hours. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (3 × 30 mL). The combined extracts were washed with brine (50 mL), dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography with elution in (0 to 50% ethyl acetate in petroleum ether) to obtain ((3S,5R)-1-(7-carbamoyl-3-chloro-5-fluoro-2-methyl-1H-indole-4-yl)-5-fluoropiperidine-3-yl)carbamate tert-butyl (240 mg).

[0739] ESI-MS[M+H] + (C 15 H 17 Calculated values ​​for ClF2N4O: 443.16, 445.16; measured values: 443.15, 445.15

[0740] Step 7: 4-((3S,5R)-3-amino-5-fluoropiperidine-1-yl)-3-chloro-5-fluoro-2-methyl-1H-indole-7-carboxamide hydrochloride

[0741] [ka] A mixture of ((3S,5R)-1-(7-carbamoyl-3-chloro-5-fluoro-2-methyl-1H-indole-4-yl)-5-fluoropiperidine-3-yl)carbamate tert-butyl (200 mg, 0.45 mmol) and 4M hydrogen chloride in dioxane (10 mL) was stirred at 20°C for 2 hours. The reaction mixture was concentrated under vacuum to obtain 44-((3S,5R)-3-amino-5-fluoropiperidine-1-yl)-3-chloro-5-fluoro-2-methyl-1H-indole-7-carboxamide hydrochloride (170 mg).

[0742] ESI-MS[M+H] + (C 15 H 17 Calculated values ​​for ClF2N4O: 343.11, 345.11; measured values: 343.05, 345.05.

[0743] Step 8: 4-((3S,5R)-3-(bute-2-inamide)-5-fluoropiperidine-1-yl)-3-chloro-5-fluoro-2-methyl-1H-indole-7-carboxamide

[0744] [ka] N,N-Diisopropylethylamine (321 mg, 2.48 mmol) was added to a mixture of 4-((3S,5R)-3-amino-5-fluoropiperidine-1-yl)-3-chloro-5-fluoro-2-methyl-1H-indole-7-carboxamide hydrochloride (170 mg, 0.49 mmol), bute-2-inoic acid (42 mg, 0.49 mmol), and N,N,N',N'-tetramethyl-O-(7-azabenzotriazole-1-yl)uronium hexafluorophosphate (207 mg, 0.55 mmol) in N,N-dimethylformamide (8 mL). The reaction mixture was stirred at 20°C for 2 hours. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (3 × 30 mL). The combined extract was washed with brine (3 × 30 mL), dried over sodium sulfate, and concentrated under vacuum. The residue was purified by preparative HPLC (column: YMC-Actus Triart C18, 30 × 250 mm, 5 μm; mobile phase A: water (10 MMOL / L NH4HCO3 + 0.1% NH3.H2O), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 36% B to 47% B in 8 mins; 254 nm; RT1: 7.5 mins) to obtain a grayish-white solid of 4-((3S,5R)-3-(bute-2-inamide)-5-fluoropiperidine-1-yl)-3-chloro-5-fluoro-2-methyl-1H-indole-7-carboxamide (14.4 mg).

[0745] 1H NMR(400MHz,DMSO-d6)δ 11.27(s,1H),8.43(s,1H),8.03(s,1H),7.61-7.42(m,2H),5.15-4.85(m,1H),4.49(s,1H),3.32-3. 15(m,2H),2.90-2.70(m,1H),2.45-2.35(m,4H),2.20-2.08(m,1H),1.94(s,3H),1.75-1.50(m,1H).

[0746] ESI-MS[M+H] + (C 19 H 19 Calculated values ​​for ClF2N4O2: 409.12, 411.12; Measured values: 409.05, 411.05

[0747] Example 28 Synthesis of 4-((3S,5S)-3-(bute-2-inamide)-5-fluoropiperidine-1-yl)-3-chloro-5-fluoro-2-methyl-1H-indole-7-carboxamide (compound 28)

[0748] [ka] Step 1: ((3S,5S)-1-(7-cyano-5-fluoro-2-methyl-1H-indole-4-yl)-5-fluoropiperidine-3-yl) tert-butyl carbamate

[0749] [ka] A mixture of 4-bromo-5-fluoro-2-methyl-1H-indole-7-carbonitride (500 mg, 1.74 mmol), tert-butyl ((3S,5S)-5-fluoropiperidine-3-yl)carbamate (418 mg, 1.91 mmol), benzyl-[1-[2-[benzyl(phenyl)phosphanyl]-1-naphthyl]-2-naphthyl]-phenylphosphan (453 mg, 0.696 mmol), tris(dibenzylideneacetone)dipalladium (360 mg, 0.348 mmol), and cesium carbonate (1.70 g, 5.22 mmol) in dioxane (10 mL) was degassed and backpacked with nitrogen. The reaction mixture was heated under nitrogen at 100°C for 16 hours. The cooled reaction mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography (0 to 16% ethyl acetate in petroleum ether) to obtain a yellow solid ((3S,5S)-1-(7-cyano-5-fluoro-2-methyl-1H-indole-4-yl)-5-fluoropiperidine-3-yl)carbamate tert-butyl (320 mg).

[0750] ESI-MS[M+H] + (C 20 H 24The calculated value for F2N4O2 is 391.19, while the measured value is 391.10.

[0751] Step 2: ((3S,5S)-1-(7-carbamoyl-5-fluoro-2-methyl-1H-indole-4-yl)-5-fluoropiperidine-3-yl) tert-butyl carbamate

[0752] [ka] A mixture of ((3S,5S)-1-(7-cyano-5-fluoro-2-methyl-1H-indole-4-yl)-5-fluoropiperidine-3-yl)carbamate tert-butyl (320 mg, 0.82 mmol) in water (4 mL) and ethanol (16 mL) was mixed with Parkin catalyst (18 mg, 0.041 mmol). The reaction mixture was heated at 90°C for 2 hours. The cooled reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (3 × 30 mL). The combined extract was washed with brine (50 mL), dried over sodium sulfate, and concentrated under vacuum. The residue was purified by column chromatography using silica gel (0 to 50% ethyl acetate in petroleum ether) to obtain a yellow solid ((3S,5S)-1-(7-carbamoyl-5-fluoro-2-methyl-1H-indole-4-yl)-5-fluoropiperidine-3-yl)carbamate tert-butyl (350 mg).

[0753] ESI-MS[M+H] + (C 20 H 26 The calculated value for F2N4O3 is 409.20, and the measured value is 409.10.

[0754] Step 3: ((3S,5S)-1-(7-carbamoyl-3-chloro-5-fluoro-2-methyl-1H-indole-4-yl)-5-fluoropiperidine-3-yl) tert-butyl carbamate

[0755] [ka] To a solution of tert-butyl ((3S,5S)-1-(7-carbamoyl-5-fluoro-2-methyl-1H-indole-4-yl)-5-fluoropiperidine-3-yl)carbamate (250 mg, 0.61 mmol) in DMF (6 mL), N-chlorosuccinimide (82 mg, 0.61 mmol) was added at 0°C. The reaction mixture was stirred at 0°C for 2 hours. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (3 × 30 mL). The combined extract was washed with brine (5 mL), dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography with elution in (0 to 50% ethyl acetate in petroleum ether) to obtain ((3S,5S)-1-(7-carbamoyl-3-chloro-5-fluoro-2-methyl-1H-indole-4-yl)-5-fluoropiperidine-3-yl)carbamate tert-butyl (250 mg).

[0756] ESI-MS[M+H] + (C 20 H 25 Calculated values ​​for ClF2N4O3: 443.16, 445.16; measured values: 443.15, 445.15.

[0757] Step 4: 4-((3S,5S)-3-amino-5-fluoropiperidine-1-yl)-3-chloro-5-fluoro-2-methyl-1H-indole-7-carboxamide hydrochloride

[0758] [ka] A mixture of (3S,5S)-1-(7-carbamoyl-3-chloro-5-fluoro-2-methyl-1H-indole-4-yl)-5-fluoropiperidine-3-ylcarbamate tert-butyl (250 mg, crude) and 4M hydrogen chloride in dioxane (10 mL) was stirred at 20°C for 2 hours. The reaction mixture was concentrated under vacuum to obtain 4-((3S,5S)-3-amino-5-fluoropiperidine-1-yl)-3-chloro-5-fluoro-2-methyl-1H-indole-7-carboxamide hydrochloride (200 mg).

[0759] ESI-MS[M+H] + (C 15 H 17 Calculated values ​​for ClF2N4O: 343.11, 345.11; measured values: 343.10, 345.10

[0760] Step 5: 4-((3S,5S)-3-(bute-2-inamide)-5-fluoropiperidine-1-yl)-3-chloro-5-fluoro-2-methyl-1H-indole-7-carboxamide

[0761] [ka] N,N-diisopropylethylamine (341 mg, 2.64 mmol) was added to a solution of 4-((3S,5S)-3-amino-5-fluoropiperidine-1-yl)-3-chloro-5-fluoro-2-methyl-1H-indole-7-carboxamide hydrochloride (200 mg, 0.527 mmol), bute-2-inoic acid (44 mg, 0.527 mmol), and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (221 mg, 0.58 mmol) in N,N-dimethylformamide (8 mL). The mixture was stirred at 20°C for 2 hours. The reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (3 × 30 mL). The combined extract was washed with brine (50 mL), dried over sodium sulfate, and concentrated under vacuum. The residue was purified by preparative HPLC (column: XBridge Prep OBD C18 Column, 19 × 250 mm, 5 μm; mobile phase A: water (10 MMOL / L NH4HCO3 + 0.1% NH3.H2O), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: 38% B to 58% B in 7 mins; 220 nm; RT: 5.12 mins) to obtain a white solid 4-((3S,5S)-3-bute-2-inamide-5-fluoropiperidine-1-yl)-3-chloro-5-fluoro-2-methyl-1H-indole-7-carboxamide (34.9 mg, 16%).

[0762] 1 H NMR(400MHz,DMSO-d6)δ 11.28(s,1H),8.45(s,1H),8.03(s,1H),7.62-7.44(m,2H),5.12-4.88(m,1H),4.62-4.40(m,1H),3.51-3.35( m,1H),3.32-3.15(m,2H),2.90-2.70(m,1H),2.37(s,3H),2.21-2.03(m,1H),1.94(s,3H),1.78-1.44(m,1H).

[0763] Example 29 Synthesis of 4-(1-acryloyloctahydro-6H-pyrrolo[2,3-c]pyridine-6-yl)-3-chloro-5-fluoro-2-methyl-1H-indole-7-carboxamide (compound 29)

[0764] [ka] Step 1: 6-(7-cyano-5-fluoro-2-methyl-1H-indole-4-yl)octahydro-1H-pyrrolo[2,3-c]pyridine-1-carboxylate tert-butyl

[0765] [ka] A mixture of 4-bromo-5-fluoro-2-methyl-1H-indole-7-carbonitride (500 mg, 1.74 mmol), octahydro-1H-pyrrolo[2,3-c]pyridine-1-carboxylate tert-butyl (cis-enantiomer mixture, 433 mg, 1.91 mmol), benzyl-[1-[2-[benzyl(phenyl)phosphanyl]-1-naphthyl]-2-naphthyl]-phenylphosphan (453 mg, 0.696 mmol), tris(dibenzylideneacetone)dipalladium (360 mg, 0.348 mmol), and cesium carbonate (1.70 g, 5.22 mmol) in dioxane (15 mL) was degassed and backpacked with nitrogen. The reaction mixture was heated under nitrogen at 100°C for 16 hours. The cooled reaction mixture was concentrated under vacuum. The residue was purified by column chromatography on silica gel with elution (0 to 16% ethyl acetate in petroleum ether) to obtain 400 mg of yellow solid 6-(7-cyano-5-fluoro-2-methyl-1H-indole-4-yl)octahydro-1H-pyrrolo[2,3-c]pyridine-1-carboxylate tert-butyl.

[0766] ESI-MS[M+H] + (C 22 H 27 The calculated value for FN4O2 is 399.21, and the measured value is 399.20.

[0767] Step 2: 6-(7-carbamoyl-5-fluoro-2-methyl-1H-indole-4-yl)octahydro-1H-pyrrolo[2,3-c]pyridine-1-carboxylate tert-butyl

[0768] [ka] A mixture of 6-(7-cyano-5-fluoro-2-methyl-1H-indole-4-yl)octahydro-1H-pyrrolo[2,3-c]pyridine-1-carboxylate tert-butyl (350 mg, 0.88 mmol) in water (4 mL) and ethanol (16 mL) was mixed with Parkin catalyst (19 mg, 0.044 mmol). The reaction mixture was stirred at 90°C for 2 hours. The cooled reaction mixture was diluted with water (60 mL) and extracted with ethyl acetate (3 × 50 mL). The combined extract was washed with brine (50 mL), dried over sodium sulfate, and concentrated under vacuum. The residue was purified by column chromatography on silica gel with elution in (0 to 50% ethyl acetate in petroleum ether) to obtain a yellow solid, 6-(7-carbamoyl-5-fluoro-2-methyl-1H-indole-4-yl)octahydro-1H-pyrrolo[2,3-c]pyridine-1-carboxylate tert-butyl (350 mg).

[0769] ESI-MS[M+H] + Calculated value (C 22 H 29 For FN4O3, the measured value was 417.22, while the actual measured value was 417.20.

[0770] Step 3: 6-(7-carbamoyl-3-chloro-5-fluoro-2-methyl-1H-indole-4-yl)octahydro-1H-pyrrolo[2,3-c]pyridine-1-carboxylate tert-butyl

[0771] [ka] To a solution of 6-(7-carbamoyl-5-fluoro-2-methyl-1H-indole-4-yl)octahydro-1H-pyrrolo[2,3-c]pyridine-1-carboxylate tert-butyl (330 mg, 0.792 mmol) in DMF (6 mL), N-chlorosuccinimide (106 mg, 0.792 mmol) was added at 0°C. The reaction mixture was stirred at 0°C for 2 hours. The reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (3 × 30 mL). The combined extracts were washed with brine (50 mL), dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography (0 to 50% ethyl acetate in petroleum ether) to obtain 6-(7-carbamoyl-3-chloro-5-fluoro-2-methyl-1H-indole-4-yl)octahydro-1H-pyrrolo[2,3-c]pyridine-1-carboxylate tert-butyl (350 mg).

[0772] ESI-MS[M+H] + (C 22 H 28 Calculated values ​​for ClFN4O3: 451.18, 453.18; measured values: 451.05, 453.05.

[0773] Step 4: 3-Chloro-5-fluoro-2-methyl-4-(octahydro-6H-pyrrolo[2,3-c]pyridine-6-yl)-1H-indole-7-carboxamide 2,2,2-trifluoroacetate

[0774] [ka] Trifluoroacetic acid (5 mL) was added to a solution of 6-(7-carbamoyl-3-chloro-5-fluoro-2-methyl-1H-indole-4-yl)octahydro-1H-pyrrolo[2,3-c]pyridine-1-carboxylate tert-butyl (300 mg, 0.665 mmol) in dichloromethane (5 mL). The reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was concentrated under vacuum to obtain 3-chloro-5-fluoro-2-methyl-4-(octahydro-6H-pyrrolo[2,3-c]pyridine-6-yl)-1H-indole-7-carboxamide 2,2,2-trifluoroacetate (310 mg).

[0775] ESI-MS[M+H] + (C 17 H 20 Calculated values ​​for ClFN4O: 351.13, 353.13; Measured values: 351.05, 353.05

[0776] Step 5: 4-(1-acryloyloctahydro-6H-pyrrolo[2,3-c]pyridin-6-yl)-3-chloro-5-fluoro-2-methyl-1H-indole-7-carboxamide

[0777] [ka] A mixture of 3-chloro-5-fluoro-2-methyl-4-(octahydro-6H-pyrrolo[2,3-c]pyridine-6-yl)-1H-indole-7-carboxamide 2,2,2-trifluoroacetate (310 mg, 0.667 mmol) in tetrahydrofuran (3 mL) was mixed with N,N-diisopropylethylamine (517 mg, 4.00 mmol) and acryloyl chloride (66 mg, 0.734 mmol) at -78°C. The reaction mixture was stirred at -78°C for 0.5 hours. The reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (3 × 30 mL). The combined extracts were washed with brine (50 mL), dried over sodium sulfate, and concentrated under vacuum. The residue was purified by preparative HPLC (column: XBridge Prep OBD C18 Column, 19 × 250 mm, 5 μm; mobile phase A: water (10 MMOL / L NH4HCO3 + 0.1% NH3.H2O), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: 40% B to 60% B in 7 mins; 220 nm; retention time = 5.78 mins) to obtain a white racemic mixture of 4-(1-acryloyloctahydro-6H-pyrrolo[2,3-c]pyridine-6-yl)-3-chloro-5-fluoro-2-methyl-1H-indole-7-carboxamide (110 mg, 40%).

[0778] 1 1H NMR (400MHz, DMSO-d6)δ 11.26(d,J=12.0Hz,1H),8.01(s,1H),7.60-7.35(m,2H),6.63-6.48(m,1H),6 .15-6.05(m,1H),5.69-5.58(m,1H),4.38-4.27(m,1H),3.77-3.69(m,0.5H),3 .58-3.49(m,1H),3.49-3.36(m,1H),3.32-3.10(m,2H),3.05-2.87(m,2H),2.5 8-2.52(m,0.5H),2.39(d,J=5.2Hz,3H),2.28-2.06(m,2H),1.95-1.63(m,2H).

[0779] ESI-MS[M+H] + (C 20 H 22Calculated values ​​for ClFN4O2: 405.14, 407.14; Measured values: 405.10, 407.10

[0780] Step 6: Separation of isomers Racemic 4-(1-acryloyloctahydro-6H-pyrrolo[2,3-c]pyridine-6-yl)-3-chloro-5-fluoro-2-methyl-1H-indole-7-carboxamide was separated into its respective enantiomers by preparative chiral HPLC (sample volume = 90 mg; column: Chiralpak IA, 2 × 25 cm, 5 μm; mobile phase A: MTBE (0.5% 2M NH3-MeOH), mobile phase B: EtOH; flow rate: 18 mL / min; gradient: 50% B, isocratic; 220 / 254 nm).

[0781] [ka]

[0782] Compound 29a: Retention time = 8.163 minutes (29.1 mg). Isolated as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 11.27(d,J=12.0Hz,1H),8.02(s,1H),7.58-7.39(m,2H),6.65-6.48(m,1H),6.16-6.0 6(m,1H),5.69-5.59(m,1H),4.39-4.23(m,1H),3.77-3.69(m,0.5H),3.58-3.49(m,1H) ,3.49-3.35(m,1H),3.32-3.10(m,2H),3.06-2.88(m,2H),2.58-2.54(m,0.5H),2.39( d,J=5.2Hz,3H),2.27-2.06(m,2H),1.95-1.76(m,1H),1.75-1.61(m,1H).ESI-MS[M+H] + (C 20 H 22 Calculated values ​​for ClFN4O2: 405.14, 407.14; measured values: 405.10, 407.10.

[0783] Compound 29b: Retention time = 11.102 minutes (30.9 mg). Isolated as a white solid. 1 1H NMR (400MHz, DMSO-d6)δ 11.27(d,J=12.0Hz,1H),8.02(s,1H),7.61-7.31(m,2H),6.64-6.48(m,1H),6 .15-6.07(m,1H),5.69-5.57(m,1H),4.41-4.24(m,1H),3.77-3.69(m,0.5H),3 .61-3.49(m,1H),3.48-3.37(m,1H),3.31-3.11(m,2H),3.06-2.85(m,2H),2.6 0-2.51(m,0.5H),2.39(d,J=5.2Hz,3H),2.28-2.06(m,2H),1.93-1.65(m,2H).

[0784] ESI-MS[M+H] + (C 20 H 22 Calculated values ​​for ClFN4O2: 405.14, 407.14; measured values: 405.10, 407.10.

[0785] Example 30 Synthesis of 4-((3S,4S)-3-acrylamido-4-fluoropiperidine-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (compound 30)

[0786] [ka] Step 1: ((3S,4S)-1-(7-cyano-5-fluoro-2,3-dimethyl-1H-indole-4-yl)-4-fluoropiperidine-3-yl) tert-butyl carbamate

[0787] [ka] To a mixture of 4-bromo-5-fluoro-2,3-dimethyl-1H-indole-7-carbonitride (250 mg, 0.94 mmol) and tert-butyl ((3S,4S)-4-fluoropiperidine-3-yl)carbamate (225 mg, 1.03 mmol) in 1,4-dioxane (10 mL), 1,1'-binaphthyl-2,2'-difemylphosphine (61 mg, 0.09 mmol), tris(dibenzylidene-acetone)dipalladium (86 mg, 0.09 mmol), and cesium carbonate (457 mg, 1.40 mmol) were added at 20°C under a nitrogen atmosphere. The mixture was degassed, backpacked three times under nitrogen, and stirred at 100°C for 16 hours. The cooled mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined extracts were washed with water (50 ml x 2) and brine (50 ml), dried over anhydrous sodium sulfate, filtered, and vacuum concentrated. The residue was purified by silica column chromatography (0 to 25% ethyl acetate in petroleum ether) to obtain a pale yellow solid of ((3S,4S)-1-(7-cyano-5-fluoro-2,3-dimethyl-1H-indole-4-yl)-4-fluoropiperidine-3-yl) tert-butyl carbamate (290 mg, 77%).

[0788] 1 H NMR(400MHz,DMSO-d6)δ 11.59(s,1H),7.36(d,J=12.7Hz,1H),7.12(s,1H),4.64-4.35(m,1H),3.85-3.67(m,1H),3.18-3.04(m,3 H),2.83(t,J=11.0Hz,1H),2.37(s,3H),2.30(s,3H),2.21-2.08(m,1H),1.91-1.74(m,1H),1.34(s,9H).

[0789] Step 2: ((3S,4S)-1-(7-carbamoyl-5-fluoro-2,3-dimethyl-1H-indole-4-yl)-4-fluoropiperidine-3-yl) tert-butyl carbamate

[0790] [ka] Hydrogen peroxide (30%, 813 mg, 7.17 mmol) was added to a mixture of ((3S,4S)-1-(7-cyano-5-fluoro-2,3-dimethyl-1H-indole-4-yl)-4-fluoropiperidine-3-yl)carbamate tert-butyl (290 mg, 0.72 mmol) and potassium carbonate (297 mg, 2.15 mmol) in DMSO (5 mL). The reaction mixture was stirred at 60°C for 30 minutes. The cooled mixture was diluted with water (50 mL) and extracted with ethyl acetate (40 mL x 3). The combined extracts were washed with water (50 mL x 3) and brine (50 mL), dried over anhydrous sodium sulfate, filtered, and vacuum concentrated to obtain a yellow solid ((3S,4S)-1-(7-carbamoyl-5-fluoro-2,3-dimethyl-1H-indole-4-yl)-4-fluoropiperidine-3-yl)carbamate tert-butyl (300 mg, 99%).

[0791] 1 H NMR(400MHz,DMSO-d6)δ 10.64(s,1H),7.91(s,1H),7.39(d,J=14.0Hz,1H),7.34(s,1H),7.10(s,1H),4.63-4.36(m,1H),3.85-3.69(m,1H),3. 19-3.01(m,3H),2.84(t,J=1.09Hz,1H),2.37(s,3H),2.31(s,3H),2.20-2.09(m,1H),1.91-1.76(m,1H),1.34(s,9H).

[0792] Step 3: 4-((3S,4S)-3-amino-4-fluoropiperidine-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide hydrochloride

[0793] [ka] To a solution of tert-butyl ((3S,4S)-1-(7-carbamoyl-5-fluoro-2,3-dimethyl-1H-indole-4-yl)-4-fluoropiperidine-3-yl)carbamate (300 mg, 0.71 mmol) in methanol (5 mL), hydrogen chloride (10 mL, 4 M in 1,4-dioxane) was added. The reaction mixture was stirred at 20°C for 2 hours. The resulting mixture was concentrated under vacuum to obtain a yellow solid, 4-((3S,4S)-3-amino-4-fluoropiperidine-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide hydrochloride (320 mg, crude).

[0794] ESI-MS[M+H]+(C 16 H 20 The calculated value for F2N4O is 323.16, and the measured value is 323.25.

[0795] Step 4: 4-((3S,4S)-3-acrylamido-4-fluoropiperidine-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide

[0796] [ka] A mixture of 4-((3S,4S)-3-amino-4-fluoropiperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide hydrochloride (320 mg, 0.89 mmol) and sodium bicarbonate (749 mg, 8.92 mmol) in water (3.0 mL) and THF (12 mL) was added with acryloyl chloride (81 mg, 0.89 mmol) at 0 °C. The reaction mixture was stirred for 1 hour, and the resulting mixture was diluted with water (30 mL) and extracted with ethyl acetate (2×30 mL). The combined extracts were washed with water and brine, then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: YMC-Actus Triart C18, 30×250 mm, 5 um; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), mobile phase B: acetonitrile; flow rate: 45 mL / min; gradient: 35% B to 45% B in 7 minutes; 254, 220 nm, retention time = 6.48 minutes) to obtain 4-((3S,4S)-3-acrylamido-4-fluoropiperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (50.2 mg, 15%) as an off-white solid.

[0797] 1 H NMR (300 MHz, DMSO-d6) δ (ppm): 10.65 (s, 1H), 8.31 (s, 1H), 7.92 (s, 1H), 7.41 (d, J = 14.1 Hz, 1H), 7.34 (s, 1H), 6.32 - 6.00 (m, 2H), 5.61 (dd, J = 9.8, 2.5 Hz, 1H), 4.79 - 4.45 (m, 1H), 4.30 - 4.06 (m, 1H), 3.26 - 3.05 (m, 3H), 3.01 - 2.85 (m, 1H), 2.42 (s, 3H), 2.33 (s, 3H), 2.28 - 2.15 (m, 1H), 2.03 - 1.82 (m, 1H).

[0798] ESI-MS [M+H]+ (C 19 H 22 F2N4O2) calculated value 377.17, measured value: 377.25.

[0799] Example 31 Synthesis of 4-((3S,4R)-3-acrylamido-4-fluoropiperidine-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (compound 31)

[0800] [ka] Step 1: ((3S,4R)-1-(7-cyano-5-fluoro-2,3-dimethyl-1H-indole-4-yl)-4-fluoropiperidine-3-yl) tert-butyl carbamate

[0801] [ka] To a mixture of 4-bromo-5-fluoro-2,3-dimethyl-1H-indole-7-carbonitride (250 mg, 0.94 mmol) and tert-butyl ((3S,4R)-4-fluoropiperidine-3-yl)carbamate (225 mg, 1.03 mmol) in 1,4-dioxane (10 mL), 1,1'-binaphthyl-2,2'-difemylphosphine (61 mg, 0.09 mmol), tris(dibenzylidene-acetone)dipalladium (86 mg, 0.09 mmol), and cesium carbonate (610 mg, 1.87 mmol) were added. The reaction mixture was degassed, backpacked with nitrogen, and then stirred at 100°C for 16 hours. The cooled mixture was diluted with water (50 mL) and extracted with ethyl acetate (3 × 50 mL). The combined extracts were washed with water (2 × 50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (0 to 25% ethyl acetate in petroleum ether) to obtain a pale yellow solid of ((3S,4R)-1-(7-cyano-5-fluoro-2,3-dimethyl-1H-indole-4-yl)-4-fluoropiperidine-3-yl) tert-butyl carbamate (238 mg, 63%).

[0802] 1H NMR(400MHz,DMSO-d6)δ 11.58(s,1H),7.37(d,J=12.8Hz,1H),7.01(s,1H),4.97-4.78(m,1H),3.91-3.72(m,1H),3.2 5-3.14(m,2H),3.00-2.79(m,2H),2.34(s,3H),2.29(s,3H),2.09-1.87(m,2H),1.35(s,9H).

[0803] ESI-MS[M+H]+(C 21 H 26 The calculated value for F2N4O2 was 405.20, and the measured value was 405.25.

[0804] Step 2: ((3S,4R)-1-(7-carbamoyl-5-fluoro-2,3-dimethyl-1H-indole-4-yl)-4-fluoropiperidine-3-yl) tert-butyl carbamate

[0805] [ka] Hydrogen peroxide (30%, 667 mg, 5.88 mmol) was added to a mixture of ((3S,4R)-1-(7-cyano-5-fluoro-2,3-dimethyl-1H-indole-4-yl)-4-fluoropiperidine-3-yl)carbamate tert-butyl (238 mg, 0.59 mmol) and potassium carbonate (244 mg, 1.77 mmol) in DMSO (5 mL). The reaction mixture was stirred at 60°C for 30 minutes. The cooled mixture was diluted with water (30 mL) and extracted with ethyl acetate (3 × 30 mL). The combined extracts were washed with water (3 × 30 mL) and brine (30 mL), dried over anhydrous sodium sulfate, filtered, and vacuum concentrated to obtain a pale yellow solid ((3S,4R)-1-(7-carbamoyl-5-fluoro-2,3-dimethyl-1H-indole-4-yl)-4-fluoropiperidine-3-yl)carbamate tert-butyl (240 mg, 97%).

[0806] 1H NMR(400MHz,DMSO-d6)δ 10.64(s,1H),7.91(s,1H),7.40(d,J=14.0Hz,1H),7.33(s,1H),6.99(s,1H),4.97-4.77(m,1H),3.91-3.7 4(m,1H),3.28-3.14(m,2H),2.94-2.79(m,2H),2.34(s,3H),2.30(s,3H),2.06-1.95(m,2H),1.36(s,9H).

[0807] ESI-MS[M+H]+(C 21 H 28 The calculated value for F2N4O3 is 423.21, and the measured value is 423.15.

[0808] Step 3: 4-((3S,4R)-3-amino-4-fluoropiperidine-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide hydrochloride

[0809] [ka] To a solution of tert-butyl ((3S,4R)-1-(7-carbamoyl-5-fluoro-2,3-dimethyl-1H-indole-4-yl)-4-fluoropiperidine-3-yl)carbamate (240 mg, 0.57 mmol) in methanol (5 mL), hydrogen chloride (10 mL, 4 M in 1,4-dioxane) was added. The reaction mixture was stirred at 20°C for 2 hours. The resulting mixture was concentrated under vacuum to obtain a pale yellow solid, 4-((3S,4R)-3-amino-4-fluoropiperidine-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide hydrochloride (260 mg, crude).

[0810] ESI-MS[M+H]+(C 16 Calculated value for H2OF2N4O: 323.16, measured value: 323.25

[0811] Step 4: 4-((3S,4R)-3-acrylamido-4-fluoropiperidine-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide

[0812] [ka] Acryloyl chloride (66 mg, 0.72 mmol) was added at 0°C to a mixture of 4-((3S,4R)-3-amino-4-fluoropiperidine-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide hydrochloride (260 mg, 0.72 mmol) and sodium bicarbonate (609 mg, 7.25 mmol) in a mixed solvent of water (3 mL) and THF (12 mL). The reaction mixture was stirred at 0°C for 1 hour. The resulting mixture was diluted with water (30 mL) and extracted with ethyl acetate (2 × 30 mL). The combined extract was washed with water (3 × 30 mL) and brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: YMC-Actus Triart C18, 30 × 250 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: acetonitrile; flow rate: 50 mL / min; gradient: 40% B to 70% B in 7 minutes; 220 nm; retention time = 6.08 minutes) to obtain a grayish-white solid of 4-((3S,4R)-3-acrylamido-4-fluoropiperidine-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (5.0 mg, 1.8%).

[0813] 1 H NMR(300MHz,DMSO-d6)δ(ppm):10.64(s,1H),8.29(s,1H),7.93(s,1H),7.42(d,J=14.1Hz,1H),7.34(s,1H),6.42-6.31(m,1H),6. 14-6.07(m,1H),5.62-5.56(m,1H),5.03-4.84(m,1H),4.30-4.19(m,1H),3.05-2.86(m,2H),2.44-2.28(m,8H),2.20-1.96(m,2H).

[0814] ESI-MS[M+H]+(C 19 H 22 The calculated value for F2N4O2 was 377.17, while the measured value was 377.25.

[0815] Example 32 Synthesis of 4-(1-acryloyloctahydro-6H-pyrrolo[2,3-c]pyridine-6-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (compound 32)

[0816] [ka] Step 1: 6-(7-cyano-5-fluoro-2,3-dimethyl-1H-indole-4-yl)octahydro-1H-pyrrolo[2,3-c]pyridine-1-carboxylate tert-butyl

[0817] [ka] To a mixture of 4-bromo-5-fluoro-2,3-dimethyl-1H-indole-7-carbonitride (650 mg, 2.43 mmol) and racemic cis-tert-butyloctahydropyrrolo[2,3-c]pyridine-1-carboxylic acid (606 mg, 2.68 mmol) in 1,4-dioxane (20 mL), 1,1'-binaphthyl-2,2'-difemylphosphine (152 mg, 0.24 mmol), tris(dibenzylideneacetone)dipalladium (223 mg, 0.24 mmol), and cesium carbonate (1.59 g, 4.86 mmol) were added. The reaction mixture was degassed, backpacked three times under nitrogen, and stirred at 100°C under nitrogen for 16 hours. The cooled mixture was diluted with water (150 mL) and extracted with ethyl acetate (3 × 100 mL). The combined extracts were washed with water (2 × 100 mL) and brine (150 mL), dried over anhydrous sodium sulfate, filtered, and vacuum concentrated. The residue was purified by silica gel column chromatography eluted with (0 to 20% ethyl acetate in petroleum ether) to obtain a pale yellow solid of 6-(7-cyano-5-fluoro-2,3-dimethyl-1H-indole-4-yl)octahydro-1H-pyrrolo[2,3-c]pyridine-1-carboxylate tert-butyl (410 mg, 41%).

[0818] ESI-MS[M+H]+(C 23 H 29 Calculated value for FN4O2: 413.23, Measured value: 413.20

[0819] Step 2: 6-(7-carbamoyl-5-fluoro-2,3-dimethyl-1H-indole-4-yl)octahydro-1H-pyrrolo[2,3-c]pyridine-1-carboxylate tert-butyl

[0820] [ka] A mixture of 6-(7-cyano-5-fluoro-2,3-dimethyl-1H-indole-4-yl)octahydro-1H-pyrrolo[2,3-c]pyridine-1-carboxylate tert-butyl (410 mg, 0.99 mmol) in ethanol (16 mL) and water (4.0 mL) was mixed with Parkin catalyst (22 mg, 0.05 mmol). The reaction mixture was stirred at 90°C for 1 hour. The cooled mixture was poured into water (50 mL). The precipitate was collected by filtration, washed with water (20 mL), and dried under reduced pressure to obtain a pale yellow solid of 6-(7-carbamoyl-5-fluoro-2,3-dimethyl-1H-indole-4-yl)octahydro-1H-pyrrolo[2,3-c]pyridine-1-carboxylate tert-butyl (330 mg, 77%).

[0821] ESI-MS[M+H]+(C 23 H 31 The calculated value for FN4O3 was 431.24, while the measured value was 431.15.

[0822] Step 3: 5-Fluoro-2,3-dimethyl-4-(octahydro-6H-pyrrolo[2,3-c]pyridine-6-yl)-1H-indole-7-carboxamide 2,2,2-trifluoroacetate

[0823] [ka] A solution of 6-(7-carbamoyl-5-fluoro-2,3-dimethyl-1H-indole-4-yl)octahydro-1H-pyrrolo[2,3-c]pyridine-1-carboxylate tert-butyl (330 mg, 0.77 mmol) in dichloromethane (8 mL) was mixed with trifluoroacetic acid (2.0 mL). The reaction mixture was stirred at 20°C for 1 hour. The reaction mixture was concentrated under vacuum to obtain a brown solid, 5-fluoro-2,3-dimethyl-4-(octahydro-6H-pyrrolo[2,3-c]pyridine-6-yl)-1H-indole-7-carboxamide 2,2,2-trifluoroacetate (400 mg).

[0824] ESI-MS[M+H]+(C18 H 23 Calculated value for FN4O: 331.19, measured value: 331.15

[0825] Step 4: 4-(1-acryloyloctahydro-6H-pyrrolo[2,3-c]pyridine-6-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide

[0826] [ka] Acryloyl chloride (70 mg, 0.77 mmol) was added at -78°C to a solution of 5-fluoro-2,3-dimethyl-4-(octahydro-6H-pyrrolo[2,3-c]pyridine-6-yl)-1H-indole-7-carboxamide 2,2,2-trifluoroacetate (400 mg, crude) and N,N-diisopropylethylamine (995 mg, 7.70 mmol) in tetrahydrofuran (15 mL). The reaction mixture was stirred at -78°C for 1 hour. The reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (3 × 30 mL). The combined extracts were washed with water (2 × 30 mL) and brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by preparative TLC (silica gel, eluent: dichloromethane / methanol = 20:1) to obtain a grayish-white solid of 4-(1-acryloyloctahydro-6H-pyrrolo[2,3-c]pyridine-6-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (130 mg, 44% in two steps).

[0827] 1H NMR(300MHz,DMSO-d6)δ(ppm):10.67-10.59(m,1H),7.91(s,1H),7.47-7.32(m,2H), 6.60-6.46(m,1H),6.14-6.04(m,1H),5.69-5.55(m,1H),4.42-4.13(m,1H),3.78-3. 64(m,1H),3.61-3.48(m,1H),3.46-3.35(m,2H),3.25-3.12(m,1H),3.11-2.84(m,2H) ),2.41(s,3H),2.33(s,3H),2.22-2.02(m,2H),1.97-1.81(m,1H),1.78-1.66(m,1H).

[0828] ESI-MS[M+H] + (C 21 H 25 The calculated value for FN4O2 was 385.20, and the measured value was 385.30.

[0829] Step 5: Isomers of 4-(1-acryloyloctahydro-6H-pyrrolo[2,3-c]pyridine-6-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide were purified by preparative chiral HPLC (sample = 130 mg, column: CHIRALPAK IA, 2 × 25 cm, 5 μm; mobile phase A: MTBE (0.5% 2M NH3-MeOH), mobile phase B: IPA-HPLC; flow rate: 18 mL / min; gradient: 45% B, isocratic; 220 / 254 nm).

[0830] [ka]

[0831] Compound 32a: Retention time = 4.826 minutes (55 mg). Isolated as a grayish-white solid. 11H NMR (300 MHz, DMSO-d6) δ (ppm): 10.65 (d, J = 6.1 Hz, 1H), 7.93 (s, 1H), 7.42 (dd, J = 14.2, 4.0 Hz, 1H), 7.35 (s, 1H), 6.54 (dd, J = 16.9, 10.5 Hz, 1H), 6.10 (dd, J = 16.7, 2.5 Hz, 1H), 5.63 (dd, J = 10.3, 2.5 Hz, 1H), 4.42 - 4.16 (m, 1H), 3.81 - 3.67 (m, 1H), 3.61 - 3.47 (m, 1H), 3.46 - 3.37 (m, 2H), 3.27 - 3.14 (m, 1H), 3.10 - 2.74 (m, 2H), 2.42 (s, 3H), 2.33 (s, 3H), 2.25 - 2.01 (m, 2H), 1.95 - 1.79 (m, 1H), 1.78 - 1.68 (m, 1H).

[0832] ESI-MS [M + H] + (C 21 H 25 Calculated value for (C

[0833] Compound 32b: Retention time = 6.483 min (52 mg). Isolated as a pale gray solid. 1 1H NMR (300 MHz, DMSO-d6) δ (ppm): 10.65 (d, J = 6.1 Hz, 1H), 7.93 (s, 1H), 7.42 (dd, J = 14.2, 4.0 Hz, 1H), 7.35 (s, 1H), 6.54 (dd, J = 16.8, 10.2 Hz, 1H), 6.10 (dd, J = 16.7, 2.5 Hz, 1H), 5.63 (dd, J = 10.3, 2.5 Hz, 1H), 4.42 - 4.17 (m, 1H), 3.79 - 3.67 (m, 1H), 3.61 - 3.48 (m, 1H), 3.46 - 3.37 (m, 2H), 3.28 - 3.13 (m, 1H), 3.10 - 2.72 (m, 2H), 2.42 (s, 3H), 2.33 (s, 3H), 2.26 - 2.02 (m, 2H), 1.96 - 1.79 (m, 1H), 1.78 - 1.66 (m, 1H).

[0834] ESI-MS [M + H] + (C 21 H<The calculated value for FN4O2 is 385.20, and the measured value is 385.15.

[0835] Example 33 Synthesis of 4-((3S,5R)-3-(bute-2-inamide)-5-fluoropiperidine-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (compound 7)

[0836] [ka] Step 1: 4-bromo-5-fluoro-2,3-dimethyl-1H-indole-7-carbonitrine

[0837] [ka] To a solution of 4-bromo-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (600 mg, 2.10 mmol) in dichloromethane (12 mL), pyridine (416 mg, 5.26 mmol) and phosphorus oxychloride (484 mg, 3.16 mmol) were added. The mixture was stirred at 20°C for 0.5 hours. After completion, the reaction mixture was concentrated under vacuum. The residue was washed with water, filtered, and dried under reduced pressure to obtain a red solid of 4-bromo-5-fluoro-2,3-dimethyl-1H-indole-7-carbonitrile (520 mg, 92%).

[0838] 1 H NMR(300MHz,DMSO-d6)δ 11.96(s,1H),7.58(d,J=9.3Hz,1H),2.38(s,3H),2.33(s,3H).

[0839] Step 2: ((3S,5R)-1-(7-cyano-5-fluoro-2,3-dimethyl-1H-indole-4-yl)-5-fluoropiperidine-3-yl) tert-butyl carbamate

[0840] [ka] To a mixture of 4-bromo-5-fluoro-2,3-dimethyl-1H-indole-7-carbonitride (400 mg, 1.50 mmol) and tert-butyl ((3S,5R)-5-fluoropiperidine-3-yl)carbamate (360 mg, 1.65 mmol) in dioxane (8 mL), tris(dibenzylideneacetone)dipalladium (137 mg, 0.15 mmol), 1,1'-binaphthyl-2,2'-difemylphosphine (93 mg, 0.15 mmol), and cesium carbonate (732 mg, 2.25 mmol) were added. The reaction mixture was evacuated, flushed three times under a nitrogen atmosphere, and stirred at 100°C under nitrogen for 16 hours. The cooled reaction mixture was quenched with water (20 ml) and extracted with ethyl acetate (3 × 20 ml). The combined extracts were washed with brine (30 ml), dried over anhydrous sodium sulfate, filtered, and vacuum concentrated. The residue was purified by silica gel column chromatography (with 0 to 20% ethyl acetate in petroleum ether) to obtain a white solid ((3S,5R)-1-(7-cyano-5-fluoro-2,3-dimethyl-1H-indole-4-yl)-5-fluoropiperidine-3-yl) tert-butyl carbamate (350 mg, 58%).

[0841] 1 H NMR(300MHz,DMSO-d6)δ 11.60(s,1H),7.39(d,J=12.6Hz,1H),6.94(d,J=8.1Hz,1H),5.11-4.88(m,1H),4.05-3.96(m,1H),3.29-3. 15(m,3H),2.76-2.66(m,1H),2.41(s,3H),2.32(s,3H),2.19-2.07(m,1H),1.77-1.52(m,1H),1.36(s,9H).

[0842] ESI-MS[M+H] + (C 21 H 26 Calculated value for F2N4O2: 405.20; Measured value: 405.10.

[0843] Step 3: ((3S,5R)-1-(7-carbamoyl-5-fluoro-2,3-dimethyl-1H-indole-4-yl)-5-fluoropiperidine-3-yl) tert-butyl carbamate

[0844] [ka] To a solution of tert-butyl ((3S,5R)-1-(7-cyano-5-fluoro-2,3-dimethyl-1H-indole-4-yl)-5-fluoropiperidine-3-yl)carbamate (320 mg, 0.79 mmol) in dimethyl sulfoxide (6.0 mL), potassium carbonate (328 mg, 2.37 mmol) and hydrogen peroxide (30%, 1.34 g, 11.87 mmol) were added. The reaction mixture was stirred at 60°C for 2 hours and then cooled to room temperature. The reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (3 × 20 mL). The combined extract was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (0 to 80% ethyl acetate in petroleum ether) to obtain a yellow solid ((3S,5R)-1-(7-carbamoyl-5-fluoro-2,3-dimethyl-1H-indole-4-yl)-5-fluoropiperidine-3-yl) tert-butyl carbamate (250 mg, 75%).

[0845] 1 H NMR(300MHz,DMSO-d6)δ 10.62(s,1H),7.92(s,1H),7.40(d,J=14.1Hz,1H),7.3 4(s,1H),6.88(d,J=8.1Hz,1H),5.10-4.85(m,1H),4.00-3.93(m,1H),3.24-3.13(m,3H),2.7 4-2.65(m,1H),2.38(s,3H),2.30(s,3H),2.19-2.05(m,1H),1.72-1.48(m,1H),1.34(s,9H).

[0846] ESI-MS[M+H] + (C 21 H28 The calculated value for F2N4O3 is 423.21, and the measured value is 423.30.

[0847] Step 4: 4-((3S,5R)-3-amino-5-fluoropiperidine-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide hydrochloride

[0848] [ka] ((3S,5R)-1-(7-carbamoyl-5-fluoro-2,3-dimethyl-1H-indole-4-yl)-5-fluoropiperidine-3-yl)carbamate tert-butyl (250 mg, 0.59 mmol) and hydrogen chloride (4 M in dioxane, 5.0 mL) were stirred at 20°C for 2 hours. The reaction mixture was concentrated under vacuum to obtain the yellow solid 4-((3S,5R)-3-amino-5-fluoropiperidine-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide hydrochloride (240 mg).

[0849] ESI-MS[M+H] + (C 16 H 20 The calculated value for F2N4O is 323.16, and the measured value is 323.15.

[0850] Step 5: 4-((3S,5R)-3-amino-5-fluoropiperidine-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide hydrochloride

[0851] [ka] To a solution of bute-2-inoic acid (28 mg, 0.33 mmol) in N,N-dimethylformamide (3 mL), HATU (148 mg, 0.39 mmol), 4-((3S,5R)-3-amino-5-fluoropiperidine-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide hydrochloride (100 mg, 0.28 mmol), and N,N-diisopropylethylamine (108 mg, 0.84 mmol) were added. The reaction mixture was stirred at 20°C for 2 hours. The reaction mixture was quenched with water (15 ml) and extracted with ethyl acetate (3 × 10 mL). The combined extract was washed with brine (30 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by preparative HPLC (column: X Bridge Shield RP18 OBD Column, 19 × 250 mm, 10 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: 35% B to 46% B, 9 min; 254 nm; retention time = 8.03 min) to obtain a grayish-white solid of 4-((3S,5R)-3-(bute-2-inamide)-5-fluoropiperidine-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (46 mg, 42%).

[0852] 1 H NMR(400MHz,DMSO-d6)δ 10.63(s,1H),8.51(d,J=8.4Hz,1H),7.93(s,1H),7.41(d,J=14.0Hz,1H),7.35(s,1H),5.05-4.93(m,1H),4.39-4.23(m, 1H),3.27-3.13(m,3H),2.82-2.77(m,1H),2.38(s,3H),2.31(s,3H),2.25-2.14(m,1H),1.94(s,3H),1.76-1.56(m,1H).

[0853] ESI-MS[M+H] + (C 20 H 22 The calculated value for F2N4O2 is 389.17, and the measured value is 389.05.

[0854] Example 34 Synthesis of 4-((3S,5R)-3-acrylamido-5-fluoropiperidine-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (compound 34)

[0855] [ka] 4-((3S,5R)-3-acrylamido-5-fluoropiperidine-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide: A mixture of 4-[(3S,5R)-3-amino-5-fluoropiperidine-1-yl]-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide hydrochloride (100 mg, 0.28 mmol) in tetrahydrofuran (2.0 mL) and water (0.5 mL) was mixed with sodium bicarbonate (70 mg, 0.84 mmol) and acryloyl chloride (30 mg, 0.33 mmol) at 0°C. The reaction mixture was stirred at 0°C for 1 hour. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 × 20 mL). The combined extract was washed with brine (30 mL), dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by preparative HPLC (column: X Bridge Shield RP18 OBD Column, 19 × 250 mm, 10 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: 30% B to 50% B, 8 min; 254 nm; retention time = 7.77 min) to obtain a white solid 4-((3S,5R)-3-acrylamido-5-fluoropiperidine-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (42.7 mg, 41%).

[0856] 1H NMR(400MHz,DMSO-d6)δ 10.63(s,1H),8.07(d,J=8.0Hz,1H),7.93(s,1H),7.42(d,J=14.0Hz,1H), 7.35(s,1H),6.25-6.03(m,2H),5.58(dd,J=9.6,2.4Hz,1H),5.08-4.95(m, 1H),4.45-4.32(m,1H),3.40-3.36(m,1H),3.27-3.20(m,2H),2.79(t,J=9 .6Hz,1H),2.42(s,3H),2.32(s,3H),2.25-2.15(m,1H),1.75-1.56(m,1H).

[0857] ESI-MS[M+H] + (C 19 H 22 The calculated value for F2N4O2 is 377.17, and the measured value is 377.10.

[0858] Example 35 Synthesis of 4-((3S,5S)-3-(bute-2-inamide)-5-fluoropiperidine-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (compound 35)

[0859] [ka] Step 1: ((3S,5S)-1-(7-cyano-5-fluoro-2,3-dimethyl-1H-indole-4-yl)-5-fluoropiperidine-3-yl) tert-butyl carbamate

[0860] [ka] To a mixture of 4-bromo-5-fluoro-2,3-dimethyl-1H-indole-7-carbonitride (600 mg, 2.25 mmol) and tert-butyl ((3S,5S)-5-fluoropiperidine-3-yl)carbamate (539 mg, 2.47 mmol) in 1,4-dioxane (10 mL), tris(dibenzylideneacetone)dipalladium (206 mg, 0.22 mmol), 1,1'-binaphthyl-2,2'-difemylphosphine (140 mg, 0.22 mmol), and cesium carbonate (1.10 g, 3.37 mmol) were added. The reaction mixture was evacuated, flushed three times with nitrogen, and stirred at 100°C for 16 hours. The cooled reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (3 × 30 mL). Subsequently, the combined extracts were washed with brine (30 ml), dried with sodium sulfate, filtered, and vacuum concentrated. The residue was purified by silica gel column chromatography (with 0 to 20% ethyl acetate in petroleum ether) to obtain a white solid ((3S,5S)-1-(7-cyano-5-fluoro-2,3-dimethyl-1H-indole-4-yl)-5-fluoropiperidine-3-yl) tert-butyl carbamate (450 mg, 50%).

[0861] 1 H NMR(400MHz,DMSO-d6)δ 11.58(s,1H),7.39(d,J=12.4Hz,1H),6.92(d,J=8.0Hz,1H),5.08-4.91(m,1H),4.04-3.97(m,1H),3.27-3. 16(m,3H),2.77-2.69(m,1H),2.41(s,3H),2.32(s,3H),2.18-2.08(m,1H),1.74-1.54(m,1H),1.36(s,9H).

[0862] ESI-MS[M+H] + (C 21 H 26 The calculated value for F2N4O2 was 405.20, and the measured value was 405.25.

[0863] Step 2: ((3S,5S)-1-(7-carbamoyl-5-fluoro-2,3-dimethyl-1H-indole-4-yl)-5-fluoropiperidine-3-yl) tert-butyl carbamate

[0864] [ka] To a solution of tert-butyl ((3S,5S)-1-(7-cyano-5-fluoro-2,3-dimethyl-1H-indole-4-yl)-5-fluoropiperidine-3-yl)carbamate (450 mg, 1.11 mmol) in dimethyl sulfoxide (6.0 mL), potassium carbonate (461 mg, 3.34 mmol) and hydrogen peroxide (30%, 1.89 g, 16.69 mmol) were added. The reaction mixture was stirred at 60°C for 2 hours. The reaction mixture was diluted with water (25 ml) and extracted with ethyl acetate (3 × 20 ml). The combined organic layers were washed with brine (30 ml), dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by column chromatography using silica gel (0 to 80% ethyl acetate in petroleum ether) to obtain a yellow solid ((3S,5S)-1-(7-carbamoyl-5-fluoro-2,3-dimethyl-1H-indole-4-yl)-5-fluoropiperidine-3-yl) tert-butyl carbamate (420 mg, 89%).

[0865] 1 H NMR(300MHz,DMSO-d6)δ 10.64(s,1H),7.94(s,1H),7.42(d,J=13.8Hz,1H),7.36(s,1H),6.90(d,J=7.8Hz,1H),5.12-4.86(m,1H),4.03-3.95(m, 1H),3.26-3.15(m,3H),2.77-2.68(m,1H),2.40(s,3H),2.32(s,3H),2.21-2.07(m,1H),1.75-1.48(m,1H),1.36(s,9H).

[0866] ESI-MS[M+H] + (C 21 H 28Calculated value for F2N4O3: 423.21, Measured value: 423.25

[0867] Step 3: 4-((3S,5S)-3-amino-5-fluoropiperidine-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide hydrochloride

[0868] [ka] ((3S,5S)-1-(7-carbamoyl-5-fluoro-2,3-dimethyl-1H-indole-4-yl)-5-fluoropiperidine-3-yl)carbamate tert-butyl (420 mg, 0.99 mmol) and hydrogen chloride (4 M in dioxane, 8 mL) were stirred at 20°C for 2 hours. The reaction mixture was concentrated under vacuum to obtain the yellow solid 4-((3S,5S)-3-amino-5-fluoropiperidine-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide hydrochloride (350 mg).

[0869] ESI-MS[M+H] + (C 16 H 20 The calculated value for F2N4O is 323.16, and the measured value is 323.15.

[0870] Step 4: 4-((3S,5S)-3-(bute-2-inamide)-5-fluoropiperidine-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide

[0871] [ka] To a solution of bute-2-inoic acid (47 mg, 0.56 mmol) in N,N-dimethylformamide (5 mL), HATU (248 mg, 0.65 mmol), 4-((3S,5S)-3-amino-5-fluoropiperidine-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide hydrochloride (165 mg, 0.46 mmol), and N,N-diisopropylethylamine (180 mg, 1.40 mmol) were added. The reaction mixture was stirred at 20°C for 2 hours. The reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (3 × 20 mL). The combined extract was washed with brine (30 mL), dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by preparative HPLC (column: Xselect CSH OBD Column 30×150mm, 5um, mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 25% B to 52% B in 7 minutes; 220 nm; retention time = 6.17 minutes) to obtain a grayish-white solid of 4-[(3S,5S)-3-(bute-2-inoylamino)-5-fluoropiperidine-1-yl]-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (57.2 mg, 32%).

[0872] 1 H NMR(300MHz,DMSO-d6)δ 10.63(s,1H),8.51(d,J=8.1Hz,1H),7.93(s,1H),7.45-7.35(m,2H),5.07-4.91(m,1H),4.42-4.24(m,1H),3.2 8-3.13(m,3H),2.82-2.75(m,1H),2.38(s,3H),2.31(s,3H),2.20-2.09(m,1H),1.94(s,3H),1.78-1.53(m,1H).

[0873] ESI-MS[M+H] + (C 20 H 22 The calculated value for F2N4O2 is 389.17, and the measured value is 389.25.

[0874] Example 36 Synthesis of 4-((3S,5R)-3-acrylamido-5-fluoropiperidine-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (compound 36)

[0875] [ka] A mixture of 4-[(3S,5S)-3-amino-5-fluoropiperidine-1-yl]-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide:tetrahydrofuran (4.0 mL) and water (1.0 mL) containing 4-[(3S,5S)-3-amino-5-fluoropiperidine-1-yl]-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide hydrochloride (220 mg, 0.62 mmol) was prepared by adding sodium bicarbonate (156 mg, 1.86 mmol) and acryloyl chloride (67 mg, 0.74 mmol) at 0°C. The reaction mixture was stirred at 0°C for 1 hour. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (3 × 25 mL). The combined extract was washed with brine (30 mL), dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by preparative HPLC (column: X select CSH OBD Column 30×150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 28% B to 48% B in 7 mins; 220 nm; retention time = 5.33 mins) to obtain a white solid 4-((3S,5S)-3-acrylamido-5-fluoropiperidine-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (82.4 mg, 35%).

[0876] 1H NMR(300MHz,DMSO-d6)δ 10.64(s,1H),8.09(d,J=7.8Hz,1H),7.94(s,1H),7.42(d,J=14.1Hz,1H) ,7.36(s,1H),6.28-6.02(m,2H),5.58(dd,J=9.6,2.7Hz,1H),5.10-4.93( m,1H),4.48-4.34(m,1H),3.43-3.38(m,1H),3.26-3.21(m,2H),2.82-2.7 5(m,1H),2.43(s,3H),2.32(s,3H),2.28-2.21(m,1H),1.78-1.53(m,1H).

[0877] ESI-MS[M+H] + (C 19 H 22 The calculated value for F2N4O2 is 377.17, and the measured value is 377.30.

[0878] Example 37 Synthesis of 4-((3S,5R)-3-acrylamido-5-hydroxypiperidine-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (compound 37)

[0879] [ka] Step 1: ((3S,5R)-1-(7-carbamoyl-5-fluoro-2,3-dimethyl-1H-indole-4-yl)-5-hydroxypiperidine-3-yl) tert-butyl carbamate

[0880] [ka] A mixture of 4-bromo-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (250 mg, 0.88 mmol) and tert-butyl ((3S,5R)-5-hydroxypiperidine-3-yl)carbamate (228 mg, 1.05 mmol) in 1,4-dioxane (5.0 mL) was mixed with tris(dibenzylideneacetone)dipalladium (80 mg, 0.088 mmol), 1,1'-binaphthyl-2,2'-difemylphosphine (109 mg, 0.17 mmol), and cesium carbonate (429 mg, 1.32 mmol). The reaction mixture was evacuated, flushed three times with nitrogen, and stirred at 110°C under nitrogen for 40 hours. The cooled reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (3 × 20 mL). The combined extracts were washed with brine (30 ml), dried over anhydrous sodium sulfate, filtered, and vacuum concentrated. The residue was purified by silica gel column chromatography (0 to 60% ethyl acetate in petroleum ether) to obtain a yellow solid ((3S,5R)-1-(7-carbamoyl-5-fluoro-2,3-dimethyl-1H-indole-4-yl)-5-hydroxypiperidine-3-yl)carbamate tert-butyl (150 mg, 41%).

[0881] 1 H NMR(400MHz,DMSO-d6)δ 10.65(s,1H),7.94(s,1H),7.41(d,J=14.0Hz,1H),7.36(s,1H),6.93(d,J=8.0Hz,1H),4.91(s,1H),3.72-3.63(m,2H) ),3.13-3.07(m,2H),2.77-2.58(m,2H),2.34(s,3H),2.32(s,3H),2.07-2.04(m,1H),1.35(s,9H),1.26-1.23(m,1H).

[0882] ESI-MS[M+H] + (C 21 H 29 The calculated value for F N4O4 is 421.22, and the measured value is 421.25.

[0883] Step 2: 4-((3S,5R)-3-amino-5-hydroxypiperidine-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide hydrochloride

[0884] [ka] A mixture of ((3S,5R)-1-(7-carbamoyl-5-fluoro-2,3-dimethyl-1H-indole-4-yl)-5-hydroxypiperidine-3-yl)carbamate tert-butyl (140 mg, 0.33 mmol) and hydrogen chloride (4 M in dioxane, 5.0 mL) was stirred at 20°C for 2 hours. After completion, the reaction mixture was concentrated under vacuum to obtain the yellow solid 4-((3S,5R)-3-amino-5-hydroxypiperidine-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide hydrochloride (130 mg).

[0885] ESI-MS[M+H] + (C 16 H 21 The calculated value for N4O2F was 321.16, and the measured value was 321.25.

[0886] Step 3: 4-((3S,5R)-3-acrylamido-5-hydroxypiperidine-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide

[0887] [ka] A mixture of 4-((3S,5R)-3-amino-5-hydroxypiperidine-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide hydrochloride (130 mg, 0.37 mmol) in tetrahydrofuran (2.0 mL) and water (0.5 mL) was mixed with sodium bicarbonate (95 mg, 1.13 mmol) and acryloyl chloride (41 mg, 451 mmol) at 0°C. The reaction mixture was stirred at 0°C for 1 hour. After completion, the reaction mixture was diluted with water (25 mL) and extracted with ethyl acetate (3 × 20 mL). The combined extract was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by preparative HPLC (column: XBridge Prep OBD C18 Column, 30 × 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 5% B to 35% B in 7 minutes; 220 nm; retention time = 5.48 min) to obtain a grayish-white solid of 4-((3S,5R)-3-acrylamido-5-hydroxypiperidine-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (32.3 mg, 23%).

[0888] 1 H NMR(300MHz,DMSO-d6)δ 10.64(s,1H),8.10(d,J=7.8Hz,1H),7.92(s,1H),7.41(d,J=14.1Hz,1H), 7.34(s,1H),6.28-6.01(m,2H),5.57(dd,J=9.6,2.7Hz,1H),4.97(d,J=4. 8Hz,1H),4.12-4.03(m,1H),3.79-3.75(m,1H),3.19-3.15(m,2H),2.81-2 .68(m,2H),2.36(s,3H),2.32(s,3H)2.16-2.11(m,1H),1.30-1.23(m,1H).

[0889] ESI-MS[M+H] + (C 19 H 23 The calculated value for F (N4O3) is 375.18, and the measured value is 375.25.

[0890] Example 38 Synthesis of 4-((3S,5S)-3-acrylamido-5-hydroxypiperidine-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (compound 38)

[0891] [ka] Step 1: ((3S,5S)-1-(7-carbamoyl-5-fluoro-2,3-dimethyl-1H-indole-4-yl)-5-hydroxypiperidine-3-yl) tert-butyl carbamate

[0892] [ka] A mixture of 4-bromo-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (380 mg, 1.33 mmol) and tert-butyl ((3S,5S)-5-hydroxypiperidine-3-yl)carbamate (240 mg, 1.11 mmol) in 1,4-dioxane (7.0 mL) was to be mixed with tris(dibenzylideneacetone)dipalladium (102 mg, 0.11 mmol), 1,1'-binaphthyl-2,2'-difemylphosphine (138 mg, 0.22 mmol), and cesium carbonate (542 mg, 1.66 mmol). The reaction mixture was evacuated, flushed three times with nitrogen, and stirred at 110°C under nitrogen for 60 hours. After completion, the cooled reaction mixture was quenched with water (30 mL) and extracted with dichloromethane (3 × 30 mL). The combined extracts were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and vacuum concentrated. The residue was purified by preparative TLC (100% ethyl acetate, Rf=0.6) to obtain a yellow solid ((3S,5S)-1-(7-carbamoyl-5-fluoro-2,3-dimethyl-1H-indole-4-yl)-5-hydroxypiperidine-3-yl)carbamate tert-butyl (110 mg).

[0893] ESI-MS[M+H] + (C 21 H 29 The calculated value for F N4O4 is 421.22, and the measured value is 421.35.

[0894] Step 2: 4-((3S,5S)-3-amino-5-hydroxypiperidine-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide hydrochloride

[0895] [ka] A mixture of ((3S,5S)-1-(7-carbamoyl-5-fluoro-2,3-dimethyl-1H-indole-4-yl)-5-hydroxypiperidine-3-yl)carbamate tert-butyl (110 mg, 0.33 mmol) and hydrogen chloride (4 M in dioxane, 5.0 mL) was stirred at 20°C for 2 hours. After completion, the reaction mixture was concentrated under vacuum to obtain the yellow solid 4-((3S,5S)-3-amino-5-hydroxypiperidine-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide hydrochloride (80 mg).

[0896] ESI-MS[M+H]+(C 16 H 21 The calculated value for F (N4O2) is 321.16, and the measured value is 321.15.

[0897] Step 3: 4-((3S,5S)-3-acrylamido-5-hydroxypiperidine-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide

[0898] [ka] To a solution of 4-((3S,5S)-3-amino-5-hydroxypiperidine-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide hydrochloride (68 mg, 0.19 mmol) in tetrahydrofuran (2.0 mL) and water (0.5 mL), sodium bicarbonate (47 mg, 0.56 mmol) and acryloyl chloride (20 mg, 0.22 mmol) were added at 0°C. The reaction mixture was stirred at 0°C for 1 hour. After completion, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 × 15 mL). The combined extract was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by preparative HPLC (column: XBridge Prep OBD C18 Column, 30 × 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 15% B to 30% B, 7 min; 220 nm; retention time = 6.02 min) to obtain a white solid 4-((3S,5S)-3-acrylamido-5-hydroxypiperidine-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (13.1 mg, 19%).

[0899] 1 H NMR(400MHz,DMSO-d6)δ 10.60(s,1H),7.98-7.92(m,2H),7.43-7.33(m,2H),6.40-6.14(m,1H),6.04(dd,J=17.2,2.0Hz,1H),5.55(dd,J=10 .0,2.0Hz,1H),4.90-3.95(m,3H),3.21-2.95(m,3H),2.68-2.63(m,1H),2.49-2.30(m,6H),2.08-1.91(m,1H),1.60- 1.40(m,1H).

[0900] ESI-MS[M+H] + (C 19 H 23 The calculated value for F (N4O3) is 375.18, and the measured value is 375.15.

[0901] Example 39 Synthesis of 4-(trans-2-acryloyloctahydro-5H-pyrrolo[3,4-c]pyridine-5-yl)-3-chloro-5-fluoro-2-methyl-1H-indole-7-carboxamide (compound 39)

[0902] [ka] Step 1: Trans-5-(7-cyano-5-fluoro-2-methyl-1H-indole-4-yl)octahydro-2H-pyrrolo[3,4-c]pyridine-2-carboxylate tert-butyl

[0903] [ka] To a mixture of 4-bromo-5-fluoro-2-methyl-1H-indole-7-carbonitride (600 mg, 2.37 mmol) and trans-octahydro-2H-pyrrolo[3,4-c]pyridine-2-carboxylate tert-butyl (536 mg, 2.37 mmol) in 1,4-dioxane (10 mL), tris(dibenzylideneacetone)dipalladium (217 mg, 0.24 mmol), 1,1'-binaphthyl-2,2'-difemylphosphine (295 mg, 0.47 mmol), and cesium carbonate (2.32 g, 7.11 mmol) were added. The reaction mixture was evacuated, flushed three times with nitrogen, and stirred at 100°C under nitrogen for 16 hours. After completion, the cooled reaction mixture was quenched with water (40 mL) and extracted with ethyl acetate (3 × 30 mL). The combined extracts were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and vacuum concentrated. The residue was purified by column chromatography (silica gel, 0 to 30% ethyl acetate in petroleum ether) to obtain a yellow solid trans-5-(7-cyano-5-fluoro-2-methyl-1H-indole-4-yl)octahydro-2H-pyrrolo[3,4-c]-pyridine-2-carboxylate tert-butyl (500 mg, 53%).

[0904] 1H NMR(300MHz,DMSO-d6)δ 7.36(d,J=12.9Hz,1H),6.35(s,1H),3.77-3.66(m,2H),3.57-3.43(m,2H),3.15-3.03(m,2H),2.9 1-2.79(m,2H),2.37(s,3H),1.92-1.85(m,2H),1.75-1.63(m,1H),1.58-1.49(m,1H),1.41(s,9H).

[0905] ESI-MS[M+H]+(C 22 H 27 The calculated value for FN4O2 was 399.21, while the measured value was 399.15.

[0906] Step 2: Trans-5-(7-carbamoyl-5-fluoro-2-methyl-1H-indole-4-yl)octahydro-2H-pyrrolo[3,4-c]pyridine-2-carboxylate tert-butyl

[0907] [ka] A mixture of trans-5-(7-cyano-5-fluoro-2-methyl-1H-indole-4-yl)octahydro-2H-pyrrolo[3,4-c]pyridine-2-carboxylate tert-butyl (500 mg, 1.11 mmol) in ethanol (12 mL) and water (3.0 mL) was mixed with Parkin catalyst (47 mg, 0.11 mmol). The reaction mixture was stirred at 90°C for 2 hours. After completion, the cooled reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (3 × 30 mL). The combined extract was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by column chromatography (silica gel, petroleum ether with 0 to 60% ethyl acetate) to obtain a yellow solid trans-5-(7-carbamoyl-5-fluoro-2-methyl-1H-indole-4-yl)octahydro-2H-pyrrolo[3,4-c]pyridine-2-carboxylate tert-butyl (420 mg, 80%).

[0908] 1 H NMR(300MHz,DMSO-d6)δ 10.83(s,1H),7.89(s,1H),7.46(d,J=14.4Hz,1H),7.27(s,1H),6.22(s,1H),3.72-3.43(m,4H),3. 18-3.00(m,2H),2.94-2.77(m,2H),2.39(s,3H),1.95-1.79(m,2H),1.75-1.50(m,2H),1.41(s,9H).

[0909] ESI-MS[M+H] + (C 22 H 29 The calculated value for FN4O3 was 417.22, and the measured value was 417.15.

[0910] Step 3: Trans-5-(7-carbamoyl-3-chloro-5-fluoro-2-methyl-1H-indole-4-yl)octahydro-2H-pyrrolo[3,4-c]pyridine-2-carboxylate tert-butyl

[0911] [ka] A mixture of trans-5-(7-carbamoyl-5-fluoro-2-methyl-1H-indole-4-yl)octahydro-2H-pyrrolo[3,4-c]pyridine-2-carboxylate tert-butyl (400 mg, 0.96 mmol) in dichloromethane (10 mL) was mixed with N-chlorosuccinimide (128 mg, 0.96 mmol) at 0°C. The reaction mixture was stirred at 0°C for 1 hour. After completion, the reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (3 × 20 mL). The combined extract was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by column chromatography (silica gel, petroleum ether with 0 to 60% ethyl acetate) to obtain a yellow solid trans-5-(7-carbamoyl-3-chloro-5-fluoro-2-methyl-1H-indole-4-yl)octahydro-2H-pyrrolo-[3,4-c]pyridine-2-carboxylate tert-butyl (400 mg, 92%).

[0912] ESI-MS[M+H] + (C 22 H 28 Calculated values ​​for ClFN4O3: 451.18, 453.18; measured values: 451.10, 453.10.

[0913] Step 4: 3-Chloro-5-fluoro-2-methyl-4-(trans-octahydro-5H-pyrrolo[3,4-c]pyridine-5-yl)-1H-indole-7-carboxamide hydrochloride

[0914] [ka] A mixture of trans-5-(7-carbamoyl-3-chloro-5-fluoro-2-methyl-1H-indole-4-yl)octahydro-2H-pyrrolo[3,4-c]pyridine-2-carboxylate tert-butyl (400 mg, 0.89 mmol) and hydrogen chloride (4 M in dioxane, 8.0 mL) was stirred at 20°C for 2 hours. After completion, the reaction mixture was concentrated under vacuum to obtain the yellow solid 3-chloro-5-fluoro-2-methyl-4-(trans-octahydro-5H-pyrrolo[3,4-c]pyridine-5-yl)-1H-indole-7-carboxamide hydrochloride (420 mg).

[0915] ESI-MS[M+H] + (C 17 H 20 Calculated values ​​for ClFN4O: 351.13, 353.13; measured values: 351.05, 353.05.

[0916] Step 5: 4-(trans-2-acryloyloctahydro-5H-pyrrolo[3,4-c]pyridin-5-yl)-3-chloro-5-fluoro-2-methyl-1H-indole-7-carboxamide

[0917] [ka] N,N-diisopropylethylamine (500 mg, 3.87 mmol) was added to a mixture of 3-chloro-5-fluoro-2-methyl-4-(trans-octahydro-5H-pyrrolo[3,4-c]pyridine-5-yl)-1H-indole-7-carboxamide hydrochloride (300 mg, 0.77 mmol) in tetrahydrofuran (5.0 mL). After 10 minutes, acryloyl chloride (84 mg, 0.93 mmol) was added to the stirred solution at -70°C. The reaction mixture was stirred at -70°C for 1 hour. After completion, the reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (3 × 20 mL). The combined extract was washed with brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by preparative HPLC (column: Xselect CSH OBD Column 30×150mm 5um, mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), mobile phase B: acetonitrile, flow rate: 60 mL / min, gradient: 35% B to 55% B in 7 mins, 220 nm, retention time = 5.27 mins) to obtain a white solid 4-(trans-2-acryloyloctahydro-5H-pyrrolo[3,4-c]pyridine-5-yl)-3-chloro-5-fluoro-2-methyl-1H-indole-7-carboxamide (78.6 mg, 25%, mixture of trans-enantiomers).

[0918] 1 H NMR(400MHz,DMSO-d6)δ 11.24(s,1 H),8.00(s,1H),7.54(d,J=14.0Hz,1H),7.43(s,1H),6.62-6.51(m,1H),6.14(dd,J=16.8,2.4Hz,1H),5.69-5.64(m,1H),3. 86-3.65(m,2H),3.41-3.38(m,1H),3.30-3.20(m,1H),3.19-3.08(m,3H),2.93-2.90(m,1H),2.38(s,3H),2.10-1.68(m,4H).

[0919] ESI-MS[M+H]+(C 20 H 22Calculated values ​​for ClFN4O2: 405.14, 407.14; measured values: 405.10, 407.10.

[0920] Example 40 Synthesis of 4-(1-(bute-2-inoyl)octahydro-6H-pyrrolo[3,4-b]pyridine-6-yl)-3-chloro-5-fluoro-2-methyl-1H-indole-7-carboxamide (compound 40)

[0921] [ka] Step 1: 6-(7-cyano-5-fluoro-2-methyl-1H-indole-4-yl)octahydro-1H-pyrrolo[3,4-b]pyridine-1-carboxylate tert-butyl

[0922] [ka] To a mixture of 4-bromo-5-fluoro-2-methyl-1H-indole-7-carbonitride (600 mg, 2.37 mmol) and octahydro-1H-pyrrolo[3,4-b]pyridine-1-carboxylate tert-butyl (643 mg, 2.85 mmol) in 1,4-dioxane (10 mL), 1,1'-binaphthyl-2,2'-bifemylphosphine (295 mg, 0.47 mmol), tris(dibenzylideneacetone)dipalladium (217 mg, 0.23 mmol), and cesium carbonate (2.32 g, 7.11 mmol) were added. The reaction mixture was degassed, backpacked five times with nitrogen, and stirred at 100°C for 16 hours. The cooled mixture was diluted with water (30 mL) and extracted with ethyl acetate (3 × 30 mL). The combined extracts were washed with water (2 × 30 mL) and brine (30 mL), dried over anhydrous sodium sulfate, filtered, and vacuum concentrated. The residue was purified by column chromatography (silica gel, 25% ethyl acetate in petroleum ether) to obtain a yellow solid 6-(7-cyano-5-fluoro-2-methyl-1H-indole-4-yl)octahydro-1H-pyrrolo[3,4-b]pyridine-1-carboxylate tert-butyl (720 mg, 76%).

[0923] 1H NMR(300MHz,DMSO-d6)δ 11.49(s,1H),7.26(d,J=14.7Hz,1H),6.62(s,1H),4.73-4.54(m,1H),4.17-4.07(m,1H),3.98-3.82(m,2H),3.67-3.56(m,1 H),3.54-3.46(m,1H),2.95-2.81(m,1H),2.33(s,3H),2.26-2.10(m,1H),1.79-1.61(m,2H),1.42(s,9H),1.40-1.30(m,2H).

[0924] ESI-MS[M+H]+(C 22 H 27 The calculated value for FN4O2 was 399.21, while the measured value was 399.30.

[0925] Step 2: 6-(7-carbamoyl-5-fluoro-2-methyl-1H-indole-4-yl)octahydro-1H-pyrrolo[3,4-b]pyridine-1-carboxylate tert-butyl

[0926] [ka] A mixture of 6-(7-cyano-5-fluoro-2-methyl-1H-indole-4-yl)octahydro-1H-pyrrolo[3,4-b]pyridine-1-carboxylate tert-butyl (720 mg, 1.81 mmol) in ethanol (8 mL) and water (2.0 mL) was mixed with Parkin catalyst (38 mg, 0.09 mmol). The reaction mixture was stirred at 90°C for 2 hours. The cooled mixture was diluted with water (40 mL) and extracted with ethyl acetate (3 × 40 mL). The combined extract was washed with water (2 × 30 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by column chromatography (silica gel, 50% ethyl acetate in petroleum ether) to obtain a yellow solid 6-(7-carbamoyl-5-fluoro-2-methyl-1H-indole-4-yl)octahydro-1H-pyrrolo[3,4-b]pyridine-1-carboxylate tert-butyl (600 mg, 79%).

[0927] ESI-MS[M+H]+(C 22 H 29 The calculated value for FN4O3 is 417.22, and the measured value is 417.20.

[0928] Step 3: 6-(7-carbamoyl-3-chloro-5-fluoro-2-methyl-1H-indole-4-yl)octahydro-1H-pyrrolo[3,4-b]pyridine-1-carboxylate tert-butyl

[0929] [ka] To a solution of 6-(7-carbamoyl-5-fluoro-2-methyl-1H-indole-4-yl)octahydro-1H-pyrrolo[3,4-b]pyridine-1-carboxylate tert-butyl (600 mg, 1.44 mmol) in DMF (10 mL), 1-chloropyrrolidine-2,5-dione (192 mg, 1.44 mmol) was added at 0°C. The reaction mixture was stirred at 0°C for 1 hour. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (3 × 30 mL). The combined extracts were washed with water (2 × 30 mL) and brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by column chromatography (silica gel, 40% ethyl acetate in petroleum ether) to obtain a yellow solid 6-(7-carbamoyl-3-chloro-5-fluoro-2-methyl-1H-indole-4-yl)octahydro-1H-pyrrolo[3,4-b]pyridine-1-carboxylate tert-butyl (600 mg, 92%).

[0930] ESI-MS[M+H]+(C 22 H 28 Calculated values ​​for ClFN4O3: 451.18, 453.18; measured values: 451.20, 453.20.

[0931] Step 4: 3-Chloro-5-fluoro-2-methyl-4-(octahydro-6H-pyrrolo[3,4-b]pyridine-6-yl)-1H-indole-7-carboxamide 2,2,2-trifluoroacetate

[0932] [ka] A solution of 6-(7-carbamoyl-3-chloro-5-fluoro-2-methyl-1H-indole-4-yl)octahydro-1H-pyrrolo[3,4-b]pyridine-1-carboxylate tert-butyl (600 mg, 1.33 mmol) in dichloromethane (5.0 mL) was mixed with trifluoroacetic acid (5.0 mL). The reaction mixture was stirred at 20°C for 2 hours. The resulting mixture was concentrated under vacuum to obtain a yellow solid, 3-chloro-5-fluoro-2-methyl-4-(octahydro-6H-pyrrolo[3,4-b]pyridine-6-yl)-1H-indole-7-carboxamide 2,2,2-trifluoroacetate (600 mg).

[0933] ESI-MS[M+H]+(C 17 H 20 Calculated values ​​for ClFN4O: 351.13, 353.13; measured values: 351.10, 353.10.

[0934] Step 5: 4-(1-(bute-2-inoyl)octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-3-chloro-5-fluoro-2-methyl-1H-indole-7-carboxamide

[0935] [ka] To a mixture of 3-chloro-5-fluoro-2-methyl-4-(octahydro-6H-pyrrolo[3,4-b]pyridine-6-yl)-1H-indole-7-carboxamide 2,2,2-trifluoroacetate (600 mg, 1.33 mmol) in DMF (10 mL), O-(7-azabenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (757 mg, 1.99 mmol), bute-2-inoic acid (134 mg, 1.60 mmol), and N,N-diisopropylethylamine (663 mg, 5.13 mmol) were added. The reaction mixture was stirred at 20°C for 2 hours. The resulting mixture was diluted with water (30 mL) and extracted with ethyl acetate (2 × 30 mL). The combined extracts were washed with water (2 × 30 mL) and brine (30 mL), dried over anhydrous sodium sulfate, filtered, and vacuum concentrated. The residue was purified by preparative HPLC (column: Xselect CSH OBD Column 30 × 150 mm 5 μm, mobile phase A: water (10 M NH4HCO3 + 0.1% NH3.H2O); mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 40% B to 60% B, 7 min; 220 nm; retention time = 6.02 min) to obtain a grayish-white solid of 4-(1-(bute-2-inoyl)octahydro-6H-pyrrolo[3,4-b]pyridine-6-yl)-3-chloro-5-fluoro-2-methyl-1H-indole-7-carboxamide (28.6 mg, 5%).

[0936] 1 H NMR(300MHz,DMSO-d6)δ 11.26(d,J=4.8Hz,1H),8.03(s,1H),7.65-7.40(m,2H),5.19-5.03(m,1H),4.32-4.17(m,1H),3.65-3.40(m,2H),3.31 -3.02(m,2.4H),2.78-2.65(m,0.6H),2.43-2.16(m,4H),2.05(d,J=5.7Hz,3H),1.91-1.70(m,3H),1.52-1.24(m,1H).

[0937] ESI-MS[M+H]+(C 21 H 22Calculated values ​​for ClFN4O2: 417.14, 419.14; measured values: 417.10, 419.10.

[0938] Example 41 Compounds 41a to 41t shown in Table 7 below are prepared by following a method similar to that described in the preceding scheme and examples, using appropriate starting materials accordingly.

[0939] [Table 9-1]

[0940] [Table 9-2]

[0941] [Table 9-3]

[0942] [Table 9-4]

[0943] Example 42 Compounds 42a~42x Compounds 42a to 42x shown in Table 8 below are prepared by following a method similar to that described in the preceding scheme and examples, using appropriate starting materials accordingly.

[0944] [Table 10-1]

[0945] [Table 10-2]

[0946] [Table 10-3]

[0947] [Table 10-4]

[0948] [Table 10-5]

[0949] [Table 10-6]

[0950] [Table 10-7]

[0951] Example 43 Assay for determining activity against BTK Solutions of compounds (test or control) in DMSO were prepared at the desired concentration and serially diluted 3-fold in 384 pp plates using a TECAN EVO200 to 11 concentrations. 20 nL of stock was transferred to a 384 pp plate using an Echo550. DMSO was used as the vehicle control.

[0952] Two separate solutions were prepared: an ATP solution containing MgCl2 (10 mM), Brij-35 (0.01%), DTT (2 mM), BSA (0.05%), EGTA (1 mM), HEPE (pH 7.5) (50 mM), FLPeptide (6 μM), and ATP (4 mM); and a BTK solution containing MgCl2 (10 mM), Brij-35 (0.01%), DTT (2 mM), BSA (0.05%), EGTA (1 mM), HEPE (pH 7.5) (50 mM), and BTK (2.67 nM). (BTK was obtained from Carna, FLPeptide 2 from PerkinElmer, and ibrutinib from Selleck.) 5 μL of the ATP solution was added to each well, followed by 15 μL of the BTK solution to initiate the reaction. (Note that the final volume of each well was 20 μL and contained MgCl2 (10 mM), Brij-35 (0.01%), DTT (2 mM), BSA (0.05%), EGTA (1 mM), HEPE (pH 7.5) (50 mM), FLPeptide (1.5 μM), ATP (1 mM), and BTK (2 nM).)

[0953] The plate was incubated at room temperature for 90 minutes, then the reaction was terminated by adding stop buffer (75 μL, containing 0.5 M EDTA). Samples from each well were analyzed using an EZ reader. The residual activity % was calculated using the read conversion rate (CR) according to the following formula.

[0954]

number

[0955] By using XLFit (Equation 201), both the lower and upper parts of the IC are floated. 50 I calculated it.

[0956] BTK IC for representative compounds of the present invention 50 The values ​​are provided in Table 9 below. Regarding BTK activity, Table 4 lists the activities as follows. "A" refers to ICs with a minimum impedance of 10 nM.50 Show, "B" refers to ICs with a impedance of 10nM to less than 100nM. 50 Show, "C" indicates an IC with a impedance of 100 nM or higher. 50 This indicates.

[0957] Example 44 Assay for determining BTK activity in RAMOS B cells On the day before the assay, Ramos B cells were seeded in seeding medium (RPMI1640 medium containing 1% FBS and 1× penicillin-streptomycin). On the day of the assay, a 2× dye solution was prepared according to the FLIRP Calcium 6 Assay Kit manual: the dye was diluted with assay buffer (20 mM HEPES in 1× HBSS, pH 7.4), probenecid was added to a final concentration of 5 mM, and the mixture was vortexed vigorously for 1-2 minutes. Cells were collected by centrifugation, and the pellet was resuspended in seeding medium. After counting, the cells were resuspended in seeding medium at a density of 3×10⁶ / ml. An equal volume of 2× dye solution was added to the cell suspension. Cells were then seeded at 20 μl / well into a 384-well poly-D-lysine coated plate. The plate was centrifuged at 1000 rpm for 3 minutes, then incubated at 37°C for 2 hours, followed by incubation at 25°C for a further 15 minutes. The compound was prepared at a 3-fold concentration in dilution buffer (1×HBSS, pH 7.4, 20 mM HEPES and 0.1% BSA). The serially diluted compound was transferred from the source plate to a 384-well compound plate using an Echo550 (Labcyte). 20 μl / well of compound dilution buffer was added to the compound plate and mixed on a plate shaker for 2 minutes. 4×EC 80 The anti-IgM (Jackson ImmunoResearch) was prepared in dilution buffer, and 20 μl / well was added to a new 384-well compound plate. After incubation in the dark at 25°C for 60 minutes, the cells were plated and 4×EC2 were collected. 80 Compound plates containing anti-IgM and FLIPR tips were placed in FLIPR (Molecular Devices). 10 µl / well 4 × EC 80The anti-IgM cells were transferred to a cell plate using FLIPR. The plate was read at 1-second intervals for 160 seconds.

[0958] IC for representative compounds of the present invention 50 The values ​​are provided in Table 9 below. Regarding Ramos activity, Table 9 lists the activities as follows: "A" refers to ICs with a minimum impedance of 10 nM. 50 Show, "B" refers to ICs with a impedance of 10nM to less than 100nM. 50 Show, "C" indicates an IC with a impedance of 100 nM or higher. 50 This indicates.

[0959] [Table 11-1]

[0960] [Table 11-2]

[0961] Example 45 Assay for determining the BTK inactivation rate in human whole blood Treatment and dissolution of human whole blood compounds Human whole blood is obtained from StemExpress and maintained at ambient temperature until the experiment. A 1x lysis buffer is prepared using 10x lysis buffer (Cell Signaling Technology, #9083S), distilled water, a 100x protease and phosphatase inhibitor cocktail (ThermoFisher, #78440), and a GBD-1066 probe (final: 0.4 μM). This is prepared fresh each experimental day. The lysis buffer is added in a volume of 30 μL to all wells in a v-bottom plate (GreinerBio, #651261) in preparation for time point collection. The compound is reconstituted to a 10 mM stock, diluted with 2x serial dilutions, and an 8-point curve is generated with the last point being DMSO only, creating a 100x dilution series. To maintain a constant DMSO level, use 1.0 μL of prepared DMSO titration (100-fold) to create a working 10-fold dilution series in 300 μL of 1x PBS. Add human whole blood in a new 96w v-bottom plate at a volume of 225 μL per well; in this plate, one column in 8 wells is sufficient to test one compound. For compound processing, add the 10-fold dilution series in 25 μL of PBS to 225 μL of whole blood, followed by two brief up-and-down pipettes. Cover the plate with a lid and incubate at 37°C for 5, 15, 30, and 60 minutes. At each time point, withdraw 30 μL of processed blood from each column and add it to a pre-loaded collection plate containing 30 μL of supplemented lysis buffer, and mix briefly. Shake the collected and lysed samples on a rotating apparatus at room temperature for 60 minutes. These samples should be used fresh for ELISA detection, and if repetition is required, the remaining samples should be frozen at -80°C.

[0962] ELISA: Determines the amount of BTK that is not occupied. Allow all streptavidin-coated plates (R&D Systems, #CP004) to reach room temperature while the samples are lysed. Prepare assay buffer 1, 1×PBS + 0.05% Tween 20 + 1% BSA, and store at 4°C when not in use. Using this assay buffer, prepare assay buffer + 1x protease / phosphatase inhibitor cocktail (PIC) in the required amounts for all samples. Add 90 μL / well of assay buffer + PIC to the ELISA plate. Add lysed blood sample (10 μL) to the ELISA plate. Prepare BTK recombinant protein dilutions (μM) in assay buffer + PICS for use. Load standards into the ELISA plate in double decans at 100 μL / well. Leave these samples and standards in the plate and seal it overnight at 4°C. The next day, wash the plate four times with 1x wash buffer (1x PBS + 0.05% Tween 20) using a plate washer. Invert the plate to drain all fluid each time, and wipe with a clean paper towel to remove any remaining liquid. Prepare Assay Buffer 2 (1x PBS + 0.05% Tween 20 + 0.05% BSA) and maintain at 4°C when not in use. Dilute antibody α-BTK (clone D3H5, Cell Signaling Technology #8547S) to 1:500 in Assay Buffer 2. Add the diluted α-BTK antibody at a rate of 100 μl / well. Cover the plate with adhesive film and incubate at room temperature for 90 minutes. Wash the plate four times with 1x wash buffer (1x PBS + 0.05% Tween 20) using a plate washer. Invert the plate to drain all fluid each time, and wipe with a clean paper towel to remove any remaining liquid. Dilute tertiary antibody (Jackson Immuno Research, #711-005-152) to 1:2,500 in Assay Buffer 2. Add the diluted antibody at a rate of 100 μl / well. Cover the plate with adhesive film and incubate at room temperature for 1 hour. Wash the plate four times with 1x wash buffer using a plate washer. Invert the plate each time to drain all fluid, and wipe with a clean paper towel to remove any remaining liquid.Add preheated TMB substrate (ThermoFisher, #34029) to the plate at 100 μl / well. Incubate the plate in the dark at room temperature for approximately 5-10 minutes. Stop the reaction by adding 50 μl / well of 2N sulfuric acid (H2SO4) (R&D Systems, #DY994). Read the plate with a plate reader at wavelengths of 460 nm and 570 nm (corrected wavelength). Create an XY table + graph using Graphpad Prism, listing 0-60 minutes on the X axis and concentration on the Y axis. Apply a One Phase Decay model fit to the data. Obtain the K value by checking the Results table and create a new XY table + graph. Assign concentration to the X axis and enter the K value from the initial analysis. Apply the Michaelis-Menten equation to the data. Use the Vmax (Kinact) and Km (KI) values ​​from the Results table to calculate Vmax, Km. * By dividing by 10000, we calculate Kinact / Ki 10⁻⁴ nM⁻¹ min⁻¹.

[0963] Regarding the inactivation rate, the Kinact / Ki values ​​for representative compounds in this disclosure are provided in Table 10 below. Similarly, Table 10 lists the activities as follows. "A" is Kinact / Ki>10×10 -4 nM -1 minutes -1 Show, "B" is 10 x 10 -4 nM -1 minutes -1 ~1 × 10 -4 nM -1 minutes -1 This shows Kinact / Ki, "C" is Kinact / Ki<1×10 -4 nM -1 minutes -1 This indicates.

[0964] [Table 12]

[0965] Example 46 Determination of plasma and total brain concentrations 1 hour after single oral administration of the test compound to female C57BL / 6 mice. Test item Acalabrutinib, ibrutinib, and branebrutinib were used as comparator compounds.

[0966] Acalabrutinib (CALQUENCE®) is a BTK inhibitor approved for the treatment of non-Hodgkin lymphoma, also known as mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL), or small lymphocytic leukemia (SLL).

[0967] Ibrutinib (IMBRUVICA®) is a BTK inhibitor approved for the treatment of mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL) / small lymphocytic lymphoma (SLL), Waldenström macroglobulinemia (WM), marginal zone lymphoma (MZL), and chronic graft-versus-host disease (cGVHD).

[0968] Branebrutinib is a BTK inhibitor approved for the treatment of mantle cell lymphoma (MCL) and is currently in clinical trials for the treatment of rheumatoid arthritis, systemic lupus erythematosus, and primary Sjögren's syndrome.

[0969] Preparation of test specimens An appropriate amount of the test material was dissolved in 10% dimethylacetamide (DMA) / 90% (20% hydroxypropyl-β-cyclodextrin (HP-B-CD) w / v) water to obtain a final concentration of 1 mg / mL for oral administration. Sonication, vortexing, and homogenization were used as necessary. Three female C57BL / 6 mice, aged 7–9 weeks (20–30 grams), were administered a 10 mg / kg solution of the test material by forced oral administration.

[0970] [Table 13]

[0971] Sample analysis The concentrations of representative test compounds in plasma and brain samples (using appropriate plasma and brain homogenate standard curves for all samples) were analyzed using LC-MS / MS. The results for the brain:plasma ratio are listed in Table 11 below. "A" indicates a ratio > 0.5. "B" represents a ratio between 0.1 and 0.5. "C" indicates a ratio < 0.1.

[0972] [Table 14]

[0973] Further embodiments can be provided by combining the various embodiments described above. All U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications, and non-patent publications mentioned herein and / or listed in the application datasheet are incorporated herein by reference in their entirety. The aspects of the embodiments can be further provided by modifying them as necessary using concepts from various patents, applications, and publications.

[0974] In consideration of the details described above, these and other modifications can be made to the embodiments. In general, the terms used in the following claims should not be interpreted as limiting the claims to the specific embodiments disclosed in the specification and claims, but rather as including all possible embodiments along the entire scope of equivalents to which such claims are granted. Accordingly, the claims are not limited by the disclosure herein.

[0975] All publications, patents, and patent applications referenced herein are incorporated by reference to the same extent that each individual publication, patent, or patent application is specifically and individually indicated as being incorporated by reference.

Claims

1. A compound having the structure of formula (I), 【Chemistry 1】 And in the formula, 【Chemistry 2】 However, it represents a single bond or a double bond, R １ However, -H, -CH ３ , or -F, R ２ However, -H, -CH ３ , or -F, Or R １ and R ２ However, together with the C atoms to which they are bonded, ３－６ Forms a member carbon-cyclic ring, R Ｉ１ is -Cl, -F, -CN, -CH ３ , -CH ２ F, -CHF ２ , or -CF ３ and R Ｉ２ However, it is -H or -F, R Ｂ However, -CH=CH ２ -C≡CH, or -C≡C-CH ３ And, R Ｉ１ ga-CH ３ When R １ and R ２ At least one of them is -CH ３ A compound that is -F, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof. 【Request Item 2】 【Chemistry 3】 The compound according to claim 1, wherein represents a single bond. 【Request Item 3】 【Chemistry 4】 The compound according to claim 1, wherein represents a double bond.

4. R １ is -H, and R ２ The compound according to claim 1, wherein is -H.

5. R １ is -H, and R ２ The compound according to claim 1, wherein is -F.

6. R １ ga-CH ３ And R ２ ga-CH ３ The compound according to claim 1.

7. R １ and R ２ However, together with the C atoms to which they are bonded, ３－６ The compound according to claim 1, which forms a member-carbon ring.

8. R １ and R ２ The compound according to claim 1, wherein they combine with the C atom to which they are bonded to form a cyclopropyl ring.

9. R Ｉ２ The compound according to any one of claims 1 to 8, wherein is -H.

10. R Ｉ２ A compound according to any one of claims 1 to 8, wherein is -F.

11. R Ｂ -CH=CH ２ The compound according to any one of claims 1 to 10.

12. R Ｂ The compound according to any one of claims 1 to 10, wherein -C≡CH.

13. R Ｂ -C ≡ C - CH ３ The compound according to any one of claims 1 to 10. 【Request Item 14】 【Chemistry 5】 This represents a single bond, R Ｉ２ is -H, R １ is -H, R ２ The compound according to claim 1, wherein is -H.

15. R Ｉ１ The compound according to claim 14, wherein is -Cl. 【Request Item 16】 【Chemistry 6】 This represents a single bond, R Ｉ２ is -F, R １ is -H, R ２ The compound according to claim 1, wherein is -H.

17. R Ｉ１ The compound according to claim 16, wherein is -Cl.

18. The compound according to claim 1, having the structure of formula (I-S) or (I-R). 【Transformation 7】

19. Compounds having the structures listed in Table 1, or their pharmaceutically acceptable salts, solvates, hydrates, isomers, tautomers, racemates, or isotopes.

20. Compounds having the structures listed in Table 2, or their pharmaceutically acceptable salts, solvates, hydrates, isomers, tautomers, racemates, or isotopes.

21. A pharmaceutically acceptable salt of the compound according to any one of claims 1 to 20.

22. A pharmaceutical composition comprising a compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemic mixture, or isotope thereof.

23. The pharmaceutical composition according to claim 22, further comprising a pharmaceutically acceptable carrier, adjuvant, or vehicle.

24. A method for inhibiting a protein kinase, comprising contacting the protein kinase with an effective amount of a compound described in any one of claims 1 to 20, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, isotope, or pharmaceutical composition thereof.

25. The method according to claim 24, wherein the protein kinase is BTK.

26. A method for treating a BTK-dependent condition, comprising administering to a subject in need of such treatment an effective amount of a compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, isotope, or pharmaceutical composition thereof.

27. The method according to claim 26, wherein the BTK-dependent state is primary CNS lymphoma.

28. The method according to claim 26, wherein the BTK-dependent state is cancer, autoimmune disease, inflammatory disease, or thromboembolic disease.

29. The method according to claim 28, wherein the autoimmune disease is multiple sclerosis, rheumatoid arthritis, psoriasis, Sjögren's syndrome, or systemic lupus erythematosus.

30. The method according to claim 28, wherein the inflammatory disease is urticaria.

31. Use of a compound described in any one of claims 1 to 20, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, isotope, or pharmaceutical composition thereof, in the manufacture of a pharmaceutical product.

32. The use according to claim 30, wherein the pharmaceutical product is for the treatment of cancer, autoimmune diseases, inflammatory diseases, or thromboembolic diseases.

33. The use according to claim 32, wherein the autoimmune disease is multiple sclerosis, rheumatoid arthritis, psoriasis, Sjögren's syndrome, or systemic lupus erythematosus.

34. The use according to claim 32, wherein the inflammatory disease is urticaria.

35. A compound having the structure of formula (II), 【Transformation 8】 And in the formula, R ＩＩ１ However, Cl, F, -CH ２ F, -CHF ２ , -CF ３ , or -CN, R ＩＩ２ However, it is H or F, R ３ However, it is H, Me, or cyclopropyl, X is -CH ２ CH ２ - or -CR ｘ１ R ｘ２ - and R ｘ１ However, it is H, F, or Me, R ｘ２ However, is it H, F, or Me? Or R ｘ１ and R ｘ２ However, together with the C atoms to which they are bonded, ３－６ Forming a member-carbon ring, Or R ｘ１ H is R ｘ２ and R ３ Together they form an alkylene crosslink, R Ｂ However, -CH=CH ２ -C≡CH, or -C≡C-CH ３ A compound, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof.

36. R ３ The compound according to claim 35, wherein is H, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemic mixture, or isotope thereof.

37. R ３ The compound according to claim 35, wherein is Me, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemic mixture, or isotope thereof.

38. X is -CH ２ - The compound according to any one of claims 35 to 37, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemic mixture, or isotope thereof.

39. X is -CH ２ CH ２ - The compound according to any one of claims 35 to 37, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemic mixture, or isotope thereof.

40. X is -CR ｘ１ R ｘ２ - and R ｘ１ H is R ｘ２ A compound according to any one of claims 35 to 37, wherein F is present, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemic mixture, or isotope thereof.

41. X is -CR ｘ１ R ｘ２ - and R ｘ１ and R ｘ２ However, together with the C atoms to which they are bonded, ３－６ A compound according to any one of claims 35 to 37 that forms a carbocyclic ring, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemic mixture, or isotope thereof.

42. R ｘ１ and R ｘ２ The compound according to claim 41, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemic mixture, or isotope thereof, wherein these compounds, together with the C atom to which they are bonded, form a cyclopropyl ring.

43. X is -CR ｘ１ R ｘ２ is -, and R ｘ１ is H, and R ｘ２ and R １ together form an alkylene bridge, the compound according to claim 35, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof.

44. R ｘ２ and R ３ The compound according to claim 43, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemic mixture, or isotope thereof, wherein the compounds together form a methylene crosslink.

45. R ＩＩ１ The compound according to any one of claims 35 to 44, wherein the compound is Cl, F, or -CN, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof.

46. R ＩＩ１ is -CH ２ F, -CHF ２ or -CF ３ and is a compound according to any one of claims 35 to 44, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate or isotope thereof.

47. R ＩＩ２ A compound according to any one of claims 35 to 46, wherein is H, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemic mixture, or isotope thereof.

48. R ＩＩ２ A compound according to any one of claims 35 to 46, wherein F is present, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemic mixture, or isotope thereof.

49. R Ｂ -CH=CH ２ The compound described in any one of claims 35 to 48, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemic mixture, or isotope thereof.

50. R Ｂ A compound according to any one of claims 35 to 48, wherein -C≡CH, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemic mixture, or isotope thereof.

51. R Ｂ -C ≡ C - CH ３ The compound described in any one of claims 35 to 48, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemic mixture, or isotope thereof.

52. A compound according to any one of claims 35 to 51, comprising two isomers, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemic mixture, or isotope thereof.

53. A compound according to any one of claims 35 to 51, comprising two atropisomers, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof.

54. A compound according to any one of claims 35 to 51, comprising a racemic mixture of two atrop isomers, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemic mixture, or isotope thereof.

55. The compound according to claim 35, having the structure of formula (II-a) or (II-b), 【Chemistry 9】 or its pharmaceutically acceptable salts, solvates, hydrates, isomers, tautomers, racemates, or isotopes. 【Request Item 56】 【Chemistry 10】 The compound according to claim 35, having the structure.

57. Compounds having the structures listed in Table 3, or their pharmaceutically acceptable salts, solvates, hydrates, isomers, tautomers, racemates, or isotopes.

58. A pharmaceutically acceptable salt of the compound according to any one of claims 35 to 57.

59. An isomer or racemic mixture of the compound according to any one of claims 35 to 57.

60. an atropisomer of the compound according to any one of claims 35 to 57.

61. A pharmaceutical composition comprising a compound according to any one of claims 35 to 60, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemic mixture, or isotope thereof.

62. The pharmaceutical composition according to claim 61, further comprising a pharmaceutically acceptable carrier, adjuvant, or vehicle.

63. A method for inhibiting a protein kinase, comprising contacting the protein kinase with an effective amount of a compound according to any one of claims 35 to 60, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, isotope, or pharmaceutical composition thereof.

64. The method according to claim 63, wherein the protein kinase is BTK.

65. A method for treating a BTK-dependent condition, comprising administering to a subject in need of such treatment an effective amount of a compound according to any one of claims 35 to 60, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, isotope, or pharmaceutical composition thereof.

66. The method according to claim 65, wherein the BTK-dependent state is primary CNS lymphoma.

67. The method according to claim 65, wherein the BTK-dependent state is cancer, autoimmune disease, inflammatory disease, or thromboembolic disease.

68. The method according to claim 67, wherein the autoimmune disease is multiple sclerosis, rheumatoid arthritis, psoriasis, Sjögren's syndrome, or systemic lupus erythematosus.

69. The method according to claim 67, wherein the inflammatory disease is urticaria.

70. Use in the manufacture of pharmaceuticals of a compound described in any one of claims 35 to 60, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, isotope, or pharmaceutical composition thereof.

71. The use according to claim 70, wherein the pharmaceutical product is for the treatment of cancer, autoimmune diseases, inflammatory diseases, or thromboembolic diseases.

72. The use according to claim 71, wherein the autoimmune disease is multiple sclerosis, rheumatoid arthritis, psoriasis, Sjögren's syndrome, or systemic lupus erythematosus.

73. The use according to claim 71, wherein the inflammatory disease is urticaria.

74. A compound having the structure of formula (III), 【Chemistry 11】 And in the formula, Z is -CH ２ -, -CHMe-, or a bond, Y is -CHR ４ - or combination, R ４ However, it is H, F, or OH, R ５ However, it is H, F, or Me, R ６ However, it is H or Me, R ７ However, it is H or Me, R ８ Is it H? Or R ５ and R ７ However, together they form a 5-membered or 6-membered complex ring, Or R ６ and R ７ However, when combined, they form a 4-member, 5-member, or 6-member complex ring, Or R ８ and R ７ However, together they form a 5-member or 6-member complex ring. a is 0, 1, or 2, R ＩＩＩ１ However, Cl, F, -CH ２ F, -CHF ２ , -CF ３ , or -CN, or R ４ When is F or OH, or R ５ When F, or R ５ and R ７ Or R ８ and R ７ However, when they come together to form a 5- or 6-membered heterogeneous ring, or R ６ and R ７ However, when they come together to form a 4, 5, or 6-member complex ring, R ＩＩＩ１ ga-CH ３ And, R ＩＩＩ２ However, it is H or F, R Ｂ However, -CH=CH ２ -C≡CH, or -C≡C-CH ３ A compound, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof.

75. The compound according to claim 74, wherein Z is a bond, Y is a bond, and the compound has the structure of formula (IV), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof. 【Chemistry 12】

76. Z is -CH ２ The compound according to claim 74, wherein Y is a bond and the compound has the structure of formula (V-a), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof. 【Chemistry 13】

77. X is -CH ２ - and Y is -CHR ４ - and R ４ The compound according to claim 74, wherein is H and the compound has the structure of formula (VI-a-1), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof. 【Chemistry 14】

78. R ７ and R ８ The compound according to claim 74, wherein the compounds combine to form a five-membered heterocycle, and the compound has one structure from formula (VII-a), formula (VII-b), or formula (VII-c), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof. 【Chemistry 15】

79. R ７ and R ８ The compound according to claim 74, wherein the compounds combine to form a six-membered heterocycle, and the compound has one structure from formula (VIII-a), formula (VIII-b), or formula (VIII-c), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof. 【Chemistry 16】

80. R ６ and R ７ The compound according to claim 74, wherein the compounds combine to form a four-membered heterocycle, and the compound has the structure of either formula (IX-a) or formula (IX-b), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof. 【Chemistry 17】

81. R ５ and R ７ The compound according to claim 74, wherein the compounds combine to form a five-membered heterocycle, and the compound has one structure from formula (X-a), (X-b), or formula (X-c), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof. [Chemistry 18]

82. R ５ and R ７ The compound according to claim 74, wherein the compounds combine to form a six-membered heterocycle, and the compound has one structure from formula (XI-a), formula (XI-b), or formula (XI-c), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof. 【Chemistry 19】

83. Z is -CH ２ - The compound according to any one of claims 74 and 78 to 82, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemic mixture, or isotope thereof.

84. A compound according to any one of claims 74 and 78-82, wherein Z is a bond, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof.

85. A compound having one of the structures listed in Table 4, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof.

86. The compound according to any one of claims 74 to 85, in a pharmaceutically acceptable salt form.

87. A pharmaceutical composition comprising a compound according to any one of claims 74 to 86, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemic mixture, or isotope thereof, and at least one pharmaceutically acceptable excipient.

88. A method for inhibiting a protein kinase, comprising contacting the protein kinase with an effective amount of a compound according to any one of claims 74 to 85, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, isotope, or pharmaceutical composition thereof.

89. The method according to claim 88, wherein the protein kinase is BTK.

90. A method for treating a BTK-dependent condition, comprising administering to a subject in need of such treatment an effective amount of a compound according to any one of claims 74 to 85, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, isotope, or pharmaceutical composition thereof.

91. The method according to claim 90, wherein the BTK-dependent state is primary CNS lymphoma.

92. The method according to claim 90, wherein the BTK-dependent state is cancer, autoimmune disease, inflammatory disease, or thromboembolic disease.

93. The method according to claim 92, wherein the autoimmune disease is multiple sclerosis, rheumatoid arthritis, psoriasis, Sjögren's syndrome, or systemic lupus erythematosus.

94. The method according to claim 92, wherein the inflammatory disease is urticaria.

95. Use in the manufacture of pharmaceuticals of a compound described in any one of claims 74 to 85, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, isotope, or pharmaceutical composition thereof.

96. The use according to claim 95, wherein the pharmaceutical product is for the treatment of cancer, autoimmune diseases, inflammatory diseases, or thromboembolic diseases.

97. The use according to claim 96, wherein the autoimmune disease is multiple sclerosis, rheumatoid arthritis, psoriasis, Sjögren's syndrome, or systemic lupus erythematosus.

98. The use according to claim 96, wherein the inflammatory disease is urticaria.

Images