Kinase inhibitors

Abstract

Disclosed herein are 1H-indole-7-carboxamide derivatives as protein kinase inhibitors, particularly Bruton's tyrosine kinase (BTK) inhibitors, pharmaceutical compositions comprising them, methods for preparing them, and uses of such protein kinase inhibitors for treating or preventing diseases, disorders, and conditions associated with kinase function. Specifically, the present invention relates to selective BTK inhibitors.

Description

Technical Field

[0001] The present invention relates generally to protein kinase inhibitors, particularly Bruton's tyrosine kinase (BTK) inhibitors, pharmaceutical compositions comprising them, methods for preparing them, and the use of such inhibitors for treating or preventing diseases, disorders, and conditions associated with kinase function. Background Art

[0002] Protein kinases are a large class of intracellular and transmembrane signal transduction proteins in eukaryotic cells. These enzymes are responsible for transferring terminal (γ) phosphate from ATP to specific amino acid residues of the target protein. The phosphorylation of specific amino acid residues in the target protein can regulate their activity, thereby causing significant changes in cell signal transduction and metabolism. Protein kinases are present in the cell membrane, cytosol and organelles (such as the nucleus) and are responsible for mediating a variety of cellular functions, including metabolism, cell growth and differentiation, cell signal transduction, immune response regulation and cell death. Serine kinases specifically phosphorylate serine or threonine residues in the target protein. Similarly, tyrosine kinases (including tyrosine receptor kinases) phosphorylate tyrosine residues in the target protein. The tyrosine kinase family includes: TEC, SRC, ABL, JAK, CSK, FAK, SYK, FER, ACK and receptor tyrosine kinase subfamily, these subfamilies include ERBB, FGFR, VEGFR, RET and EPH. Subclass I of the receptor tyrosine kinase superfamily includes the ERBB receptors and comprises four members: ErbBl (also known as epidermal growth factor receptor (EGFR)), ErbB2, ErbB3, and ErbB4.

[0003] Kinases control key biological processes associated with health and disease. Furthermore, aberrant activation or overexpression of various protein kinases has been implicated in the mechanisms of a wide range of diseases and conditions characterized by benign and malignant proliferation, as well as diseases caused by inappropriate activation of the immune system. Therefore, inhibitors targeting selected 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 vascular disease, systemic sclerosis, atherosclerosis, asthma, transplant rejection, allergic reactions, ischemia, dermatomyositis, pemphigus, and the like.

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

[0005] BTK is important in B cell receptor signaling and the regulation of B cell development and activation. Mutations in the gene encoding BTK in humans lead to X-linked agammaglobulinemia, which is characterized by reduced immune function, including impaired B cell maturation, reduced levels of immunoglobulins and peripheral B cells, and diminished T cell-independent immune responses. BTK is activated by Src family kinases and phosphorylates PLCγ, leading to effects on B cell function and survival. In addition, BTK is important for the cellular function of mast cells, macrophages, and neutrophils, suggesting that BTK inhibition is effective in treating diseases mediated by these and related cells, including inflammation, bone diseases, and allergic diseases. BTK inhibition is also important for the survival of lymphoma cells, suggesting that BTK inhibition may be useful in treating lymphomas and other cancers. Therefore, inhibitors of BTK and related kinases have received great attention as anti-inflammatory and anticancer agents. BTK is also important for platelet function and thrombosis, suggesting that BTK selective inhibitors may also be useful as antithrombotic agents. Furthermore, BTK is required for inflammasome activation, and inhibition of BTK could be used to treat inflammasome-associated conditions, including stroke, gout, type 2 diabetes, obesity-induced insulin resistance, atherosclerosis, and Muckle-Wells syndrome. Furthermore, BTK is expressed in HIV-infected T cells, and treatment with BTK inhibitors sensitizes infected cells to apoptotic death and leads to reduced viral production. Therefore, BTK inhibitors are considered useful for treating HIV-AIDS and other viral infections.

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

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

[0008] PCNSL is highly aggressive and, unlike other lymphomas outside of the CNS, has a poor prognosis despite improvements in treatment in the first-line setting. High-dose methotrexate remains the mainstay of treatment and is used in combination with other cytotoxic agents and, more recently, rituximab. The 5-year survival rate improved from 19% to 30% between 1990 and 2000 from the time of initial diagnosis, but it did not improve in the elderly population (>70 years) because 20% or more of these patients are considered ineligible for chemotherapy. Tumor regression is observed in ~85% of patients, regardless of the treatment modality in the first-line setting; however, approximately half of these patients will develop recurrent disease within 10–18 months of initial treatment, with most relapses occurring within the first 2 years of diagnosis.

[0009] Therefore, the prognosis for patients with relapsed / refractory PCNSL (R / R PCNSL) remains poor, with a median survival of approximately 2 months without further treatment. Because there is no unified standard of care for the treatment of R / R PCNSL, participation in clinical trials is encouraged. New, safe, and effective treatments are urgently needed.

[0010] Btk is involved in signal transduction within the B cell antigen receptor (BCR) signaling pathway and integrates BCR and Toll-like receptor (TLR) signaling. Genes in these pathways, including CD79B and myeloid differentiation primary response 88 (MyD88), are frequently mutated in diffuse large B-cell lymphoma (DLBCL). Ibrutinib, a first-generation, irreversible, selective Btk inhibitor, has been approved for use in 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 in CLL or 560 mg / day in MCL) was escalated to 840 mg to achieve adequate brain exposure in primary CNS lymphomas.

[0011] Aberrant activation of the NF-κB pathway in PCNSL is emerging as a potential mechanism for more targeted therapy. Specifically, activating mutations in CARD11 as well as MyD88 (Toll-like receptor pathway) are implicated. Activating exchange of leucine to proline at position 265 of MyD88, noted to occur in between 38% (11 / 29) and 50% (7 / 14) of patients, is the most common mutation found in PCNSL to date. 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 pathways contributes to the pathogenesis of PCNSL. These data suggest that BCR pathway mutations and Btk dependency are particularly relevant to PCNSL.

[0012] Recently, several clinical studies have reported significant single-agent clinical activity in the treatment of PCNSL, with response rates of 70–77%. However, most patients discontinued treatment at 9 months. Although ibrutinib treatment is reported to be generally well tolerated with manageable adverse events, there have been reports of sometimes fatal fungal infections. Notably, escalating doses exceeding 560 mg to 840 mg / day have been used to achieve higher brain exposure, and these higher doses may be associated with off-target effects mediated by the kinase selectivity of ibrutinib. Finally, the combination of high-dose ibrutinib with high-dose steroids may contribute to exacerbated 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 benefit patients with PCNSL.

[0013] Additionally, there remains a need for compounds that modulate protein kinases generally, as well as compounds that modulate specific protein kinases such as BTK, and compounds that modulate specific protein kinases and selectively cross the blood / brain barrier, for use in related compositions and methods for treating diseases, disorders, and conditions that would benefit from such modulation and selectivity. Summary of the Invention

[0014] In one aspect, provided are compounds having the structure of Formula (I):

[0015]

[0016] or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate or isotope thereof, wherein:

[0017] Indicates a single bond or a double bond;

[0018] R 1 is -H, -CH3 or -F;

[0019] R 2 is -H, -CH3 or -F;

[0020] or R 1 and R 2 Together with the C atoms to which they are attached, they form C 3-6 membered carbon ring;

[0021] R I1 is -Cl, -F, -CN, -CH3, -CH2F, -CHF2 or -CF3;

[0022] R I2 is -H or -F; and

[0023] R B-CH=CH2, -C≡CH or -C≡C-CH3;

[0024] And when R I1 When it is -CH3, R 1 and R 2 At least one of them is -CH3 or -F.

[0025] In another aspect, provided are compounds having the structure of Formula (II):

[0026]

[0027] or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate or isotope thereof, wherein:

[0028] R 3 is H, Me or cyclopropyl;

[0029] X is -CH2CH2- or -CR x1 R x2 -;

[0030] R x1 is H, F or Me;

[0031] R x2 is H, F or Me;

[0032] or R x1 and R x2 Together with the C atoms to which they are attached, they form C 3-6 membered carbon ring;

[0033] or R x1 is H, and R x2 and R 3 together to form an alkylene bridge;

[0034] R II1 is Cl, F, -CH2F, -CHF2, -CF3 or -CN;

[0035] R II2 is H or F; and

[0036] R B It is -CH=CH2, -C≡CH or -C≡C-CH3.

[0037] In another aspect, provided are compounds having the structure of Formula (III):

[0038]

[0039] or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate or isotope thereof, wherein:

[0040] Z is -CH2-, -CHMe- or a bond;

[0041] Y is -CHR 4 - or key;

[0042] R 4 is H, F or OH;

[0043] R 5 is H, F or Me;

[0044] R 6 is H or Me;

[0045] R 7 is H or Me;

[0046] R 8 is H;

[0047] or R 5 and R 7 Together they form a 5- or 6-membered heterocyclic ring;

[0048] or R 6 and R 7 Together they form a 4-, 5- or 6-membered heterocyclic ring;

[0049] or R 8 and R 7 Together they form a 5- or 6-membered heterocyclic ring;

[0050] a is 0, 1, or 2;

[0051] R III1 is Cl, F, -CH2F, -CHF2, -CF3 or -CN; or

[0052] When R 4 When F or OH, or when R 5 When F, or when R 5 and R 7 or R 8 and R 7 When combined to form a 5-membered or 6-membered heterocyclic ring, or when R 6 and R 7 When combined to form a 4-membered, 5-membered or 6-membered heterocyclic ring, R III1 is -CH3;

[0053] R III2 is H or F; and

[0054] R BIt is -CH=CH2, -C≡CH or -C≡C-CH3.

[0055] In one embodiment, a pharmaceutical composition is provided, comprising a compound having a 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.

[0056] In one embodiment, a method for regulating a protein kinase is provided, comprising contacting the protein kinase with an effective amount of a compound having a 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 one embodiment, the protein kinase is BTK.

[0057] In one embodiment, a method for treating a BTK-dependent disorder is provided, comprising administering to a subject in need thereof an effective amount of a compound having a structure of Formula (I), Formula (II) or Formula (III) or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, isotope or pharmaceutical composition thereof.

[0058] In one embodiment, provided is the use of a compound having a 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 medicament. DETAILED DESCRIPTION

[0059] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which the claimed subject matter belongs. It should be understood that the detailed description is exemplary and illustrative only and is not a limitation on any subject matter claimed. In this application, unless otherwise specifically stated, the use of the singular includes the plural. It must be noted that, as used in the specification, unless the context clearly indicates otherwise, the singular forms "a", "an", and "the / said" include multiple referents. In this application, unless otherwise stated, the use of "or" means "and / or". In addition, the use of the term "comprise" and other forms such as "comprises", "contains", and "having" is not restrictive.

[0060] Although the various features of the invention may be described in the context of a single embodiment, these features may also be provided separately or in any suitable combination. Conversely, although the invention may be described in the context of separate embodiments for clarity, the invention may also be implemented in a single embodiment.

[0061] Reference in the specification to "some embodiments," "an embodiment," "one embodiment," or "other embodiments" means that a particular feature, structure, or characteristic described in connection with the embodiments is included in at least some embodiments of the invention, but not necessarily in all embodiments of the invention.

[0062] As used herein, ranges and amounts may be expressed as "about" a particular value or range. About also includes the exact amount. Thus, "about 100 μL" means "about 100 μL" as well as "100 μL." In some embodiments, about means within 5% of the value. Thus, "about 100 μL" means 95 μL-105 μL. Generally speaking, the term "about" includes amounts that are expected to be within experimental error.

[0063] As used herein, "alkyl" means a straight or branched chain saturated hydrocarbon group. "Lower alkyl" means a straight or branched chain alkyl group having 1 to 8 carbon atoms, in some embodiments 1 to 6 carbon atoms, in some embodiments 1 to 4 carbon atoms, and in some embodiments 1 to 2 carbon atoms. Examples of straight chain 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, isobutyl, sec-butyl, tert-butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl groups.

[0064] "Alkenyl" includes straight chain, branched, and cyclic alkyl groups as defined above, except that there is at least one double bond between two carbon atoms. Thus, an alkenyl group has 2 to about 20 carbon atoms, and typically has 2 to 12 carbon atoms, or in some embodiments, has 2 to 8 carbon atoms. Examples include, but are not limited to, -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, etc.

[0065] "Alkynyl" includes straight and branched chain alkyl groups, except that at least one triple bond exists between two carbon atoms. Thus, an alkynyl group has 2 to about 20 carbon atoms, and typically has 2 to 12 carbon atoms, or in some embodiments, has 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), etc.

[0066] As used herein, "alkylene" refers to a divalent alkyl group. Examples of straight-chain 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 a heteroatom, such as, but not limited to, N, O, S, or P.

[0067] "Alkoxy" refers to an alkyl group as defined above attached through an oxygen atom (ie, -O-alkyl). Examples of lower alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, n-butoxy, isopropoxy, sec-butoxy, tert-butoxy, and the like.

[0068] The terms "carbocyclic" and "carbocycle" refer to ring structures in which the ring atoms are carbon. Carbocycles can be monocyclic or polycyclic. Carbocycles include saturated and unsaturated rings. Carbocycles include cycloalkyl and aryl groups. In some embodiments, carbocycles have 3 to 8 ring members, while in other embodiments, the number of ring carbon atoms is 4, 5, 6, or 7. Unless specifically stated to the contrary, carbocycles can be substituted with up to N substituents, where N is the size of the carbocycle, such as alkyl, amino, hydroxy, cyano, carboxyl, nitro, thiol, alkoxy, and halogen groups.

[0069] "Cycloalkyl" is an alkyl group that forms a ring structure, which may be substituted or unsubstituted. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. 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. Cycloalkyl groups further include, but are not limited to, polycyclic cycloalkyl groups such as norbornyl, adamantyl, bornyl, camphenyl, isocamphenyl, and carenyl, and fused rings such as, but not limited to, decalin. Cycloalkyl groups also include rings substituted with straight or branched alkyl groups as defined above. Representative substituted cycloalkyl groups can be monosubstituted or substituted more than once, such as, but not limited to, 2,2-, 2,3-, 2,4-, 2,5- or 2,6-disubstituted cyclohexyl groups or mono-, di- or tri-substituted norbornyl or cycloheptyl groups, which can be substituted with, for example, amino, hydroxy, cyano, carboxyl, nitro, thio, alkoxy and halo groups.

[0070] "Aryl" is a cyclic aromatic hydrocarbon containing no heteroatoms. Thus, aryl includes, but is not limited to, phenyl, azulenyl, heptalenyl, biphenyl, indacenyl, fluorenyl, phenanthrenyl, triphenylene, pyrenyl, naphthacene, In some embodiments, the aryl group contains 6 to 14 carbon atoms in the ring portion of the group. The terms "aryl" and "aryl groups" include fused rings in which at least one ring, but not necessarily all rings, are aromatic, such as fused aromatic-aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, etc.).

[0071] "Carbocycloalkyl" refers to an alkyl group as defined above in which one or more hydrogen atoms are replaced by a carbocyclic ring. Examples of carbocycloalkyl groups include, but are not limited to, benzyl and the like.

[0072] As used herein, "heterocycle" or "heterocyclyl" groups include aromatic and non-aromatic ring compounds (heterocycles) containing 3 or more ring members, one or more of which 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 comprising at least one ring heteroatom. In some embodiments, the heterocyclic group comprises 3 to 20 ring members, while other such groups have 3 to 15 ring members. At least one ring contains a heteroatom, but each ring in a polycyclic system need not contain a heteroatom. For example, dioxolanyl rings and benzodioxolanyl ring systems (methylenedioxyphenyl ring systems) are heterocyclic groups within the meaning of this article. A heterocyclic group designated as a C2 heterocycle can be a 5-membered ring with two carbon atoms and three heteroatoms, a 6-membered ring with two carbon atoms and four heteroatoms, etc. Similarly, a C4 heterocycle can be a 5-membered ring with one heteroatom, a 6-membered ring with two heteroatoms, etc. The sum of the number of carbon atoms plus the number of heteroatoms equals the total number of ring atoms. A saturated heterocycle is a heterocycle that does not contain unsaturated carbon atoms.

[0073] A "heteroaryl" group is an aromatic ring compound containing five or more ring members, one or more of which is a heteroatom such as, but not limited to, N, O, and S. A heteroaryl group designated as a C2 heteroaryl group 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 heteroaryl group 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 plus the number of heteroatoms equals the total number of ring atoms. Heteroaryl includes, but is not limited to, groups such as pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, thienyl, benzothienyl, benzofuranyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridyl, isoxazolopyridyl, thianaphthyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolyl, isoquinolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, quinoxalinyl, and quinazolinyl. The term "heteroaryl" includes fused ring compounds such as those in which at least one ring, but not necessarily all rings, are aromatic, including tetrahydroquinolyl, tetrahydroisoquinolyl, indolyl, and 2,3-dihydroindolinyl.

[0074] "Heterocycloalkyl" refers to an alkyl group as defined above in which one or more hydrogen atoms are replaced by a heterocycle. Examples of heterocycloalkyl groups include, but are not limited to, morpholinoethyl and the like.

[0075] "Halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.

[0076] "Haloalkyl" refers to an alkyl group as defined above in which one or more hydrogen atoms are replaced by a halogen. Examples of lower haloalkyl groups include, but are not limited to, -CF3, -CH2CF3, and the like.

[0077] "Haloalkoxy" refers to an alkoxy group as defined above in which one or more hydrogen atoms are replaced by a halogen. Examples of lower haloalkoxy groups include, but are not limited to, -OCF3, -OCH2CF3, and the like.

[0078] "Hydroxyalkyl" refers to an alkyl group as defined above in which one or more hydrogen atoms are replaced by -OH. Examples of lower hydroxyalkyl groups include, but are not limited to, -CH2OH, -CH2CH2OH, and the like.

[0079] As used herein, the term "optionally substituted" refers to a group (e.g., alkyl, carbocycle, or heterocycle) having 0, 1, or more substituents, such as 0-25, 0-20, 0-10, or 0-5 substituents. Substituents include, but are not limited to, -OR a 、-NR a R b 、-S(O)2R a or -S(O)2OR a , halogen, cyano, alkyl, haloalkyl, alkoxy, carbocyclic, heterocyclic, carbocycloalkyl or heterocycloalkyl, wherein each R a and R b are independently H, alkyl, haloalkyl, carbocyclic or heterocyclic, or R a and R b Together with the atoms to which they are attached, they form a 3-8 membered carbocyclic or heterocyclic ring.

[0080] "Isomer" is used herein to encompass all chiral forms, diastereomeric forms, or racemic forms of a structure, unless a specific stereochemistry or isomeric form is explicitly indicated. Such compounds can be enriched or resolved optical isomers at any or all asymmetric atoms to any degree of enrichment, as is apparent from the diagrams. Racemic and diastereomeric mixtures, as well as individual optical isomers, can be synthesized substantially free of their enantiomers or diastereomeric partners, and these are within the scope of certain embodiments of the present disclosure. The isomers produced by the presence of a chiral center include a pair of non-superimposable isomers referred to as "enantiomers." The single enantiomers of a pure compound are optically active (i.e., they can rotate the plane of plane polarized light and are designated as R or S).

[0081] An "isolated optical isomer" refers to a compound that has been substantially purified from the corresponding optical isomer of the same formula. For example, the isolated isomer may be at least about 80%, at least 80%, or at least 85% pure. In other embodiments, the isolated isomer is at least 90% pure, or at least 98% pure, or at least 99% pure by weight.

[0082] By "substantially enantiomerically or diastereomerically" pure is meant that the level of enantiomeric or diastereomeric enrichment of one enantiomer relative to the other enantiomer or diastereomer is at least about 80%, and more specifically greater than 80%, 85%, 90%, 95%, 98%, 99%, 99.5% or 99.9%.

[0083] The terms "racemate" and "racemic mixture" refer to a mixture of equal amounts of two enantiomers. A racemate is designated "(±)" because it is not optically active (i.e., does not rotate plane-polarized light in either direction because its constituent enantiomers cancel each other out).

[0084] A "hydrate" is a compound that exists in association with water molecules. The association may include a stoichiometric amount of water, such as a monohydrate or dihydrate, or it may include a random amount of water. As used herein, the term "hydrate" refers to the solid form; in other words, a compound in aqueous solution, while hydrated, is not a hydrate as the term is used herein.

[0085] A "solvate" is similar to a hydrate, except that a solvent other than water is present. For example, methanol or ethanol can form an "alcoholate," which can also be stoichiometric or non-stoichiometric. The term "solvate," as used herein, refers to a solid form; in other words, a compound in a solvent solution, although solvated, is not a solvate as the term is used herein.

[0086] "Isotope" refers to an atom with the same number of protons but different number of neutrons, and the isotope of a compound of formula (I) includes any such compound in which one or more atoms are replaced by an isotope of the atom. For example, carbon 12 is the most common form of carbon, with six protons and six neutrons, while carbon 13 has six protons and seven neutrons, and carbon 14 has six protons and eight neutrons. Hydrogen has two stable isotopes, deuterium (a proton and a neutron) and tritium (a proton and two neutrons). Although fluorine has several isotopes, fluorine 19 has the longest lifespan. Therefore, the isotope of a compound with a structure of formula (I) includes but is not limited to a compound of formula (I), wherein one or more carbon 12 atoms are replaced by carbon 13 and / or carbon 14 atoms, wherein one or more hydrogen atoms are replaced by deuterium and / or tritium, and / or wherein one or more fluorine atoms are replaced by fluorine 19.

[0087] "Salt" generally refers to an organic compound in ionic form, such as a carboxylic acid or an amine, associated with a counterion. For example, a salt formed between an acid in its anionic form and a cation is called an "acid addition salt." Conversely, a salt formed between a base in its cationic form and an anion is called a "base addition salt."

[0088] The term "pharmaceutically acceptable" refers to pharmaceutical agents that have been approved for human consumption and are generally non-toxic. For example, the term "pharmaceutically acceptable salt" refers to non-toxic inorganic or organic acid and / or base addition salts (see, e.g., Lit et al., Salt Selection for Basic Drugs, Int. J. Pharm., 33, 201-217, 1986) (incorporated herein by reference).

[0089] Pharmaceutically acceptable base addition salts of the compounds of the present disclosure include, for example, metal salts, including alkali metal salts, alkaline earth metal salts, and transition metal salts, such as calcium salts, magnesium salts, potassium salts, sodium salts, and zinc salts. Pharmaceutically acceptable base addition salts also include organic salts prepared from basic amines such as N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine.

[0090] Pharmaceutically 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 may be selected from aliphatic, alicyclic, aromatic, aromatic aliphatic, heterocyclic, carboxylic and sulfonic 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, phenylacetic acid, mandelic acid, hippuric acid, malonic acid, oxalic acid, pamoic acid (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, beta-hydroxybutyric acid, salicylic acid, galactaric acid and galacturonic acid.

[0091] 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, for example, in their purification by recrystallization.

[0092] In certain embodiments, the present disclosure provides a pharmaceutical composition comprising a compound as described herein or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, and at least one pharmaceutically acceptable carrier, diluent or excipient. For example, the active compound is typically mixed with a carrier or 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 a carrier is used as a diluent, the carrier may be a solid, semi-solid or liquid material that serves as a vehicle, excipient or medium for the active compound. The active compound may be adsorbed on a granular solid carrier, for example, contained in a sachet. Some examples of suitable carriers are water, saline solution, alcohol, polyethylene glycol, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, gum arabic, lower alkyl ethers of stearic acid or cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid mono- and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone. Similarly, the carrier or diluent may comprise any sustained-release material known in the art such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.

[0093] As used herein, the term "pharmaceutical composition" refers to a composition containing one or more compounds described herein or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, homolog or salt thereof, formulated with a pharmaceutically acceptable carrier, which may also include other additives, and manufactured or sold as part of a therapeutic regimen for treating a disease in a mammal with the approval of a governmental regulatory agency. The pharmaceutical composition can be formulated for oral administration, for example, in a unit dosage form (e.g., tablets, capsules, caplets, softgels or syrups); for topical administration (e.g., as a cream, gel, lotion or ointment); for intravenous administration (e.g., as a sterile solution free of particulate plugs and in a solvent system suitable for intravenous use); or in any other formulation described herein. Conventional procedures and ingredients for selecting and preparing suitable formulations are described, for example, in Remington: The Science and Practice of Pharmacy, 21st edition, Gennaro ed., Lippencott Williams & Wilkins (2005) and in The United States Pharmacopeia: The National Formulary (USP 36NF31), published in 2013.

[0094] In other embodiments, methods for preparing compositions having compounds described herein are provided, comprising formulating the compounds of the present disclosure with 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 comprise the step of formulating the composition into a tablet or capsule. In other embodiments, the pharmaceutically acceptable carrier or diluent is suitable for parenteral administration. In some such embodiments, the method further comprises the step of lyophilizing the composition to form a lyophilized formulation.

[0095] As used herein, the term "pharmaceutically acceptable carrier" refers to any ingredient other than a disclosed compound or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, homolog or salt thereof (e.g., a carrier capable of suspending or dissolving the active compound) and having non-toxic and non-inflammatory properties in the patient. Excipients may include, for example, anti-adherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colorants), emollients, emulsifiers, fillers (diluents), film formers or coatings, flavorings, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, adsorbents, suspending or dispersing agents, sweeteners or water of hydration. Exemplary excipients include, but are not limited to, butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, cross-linked carboxymethylcellulose, cross-linked polyvinyl pyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methylparaben, microcrystalline cellulose, polyethylene glycol, polyvinyl pyrrolidone, povidone, pregelatinized starch, propylparaben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethylcellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol.

[0096] The formulation may be mixed with auxiliary agents that do not adversely react with the active compound. Such additives may include wetting agents, emulsifying agents and suspending agents, salts that affect osmotic pressure, buffers and / or coloring substances, preservatives, sweeteners or flavorings. If desired, the composition may also be sterilized.

[0097] The route of administration may be any route that effectively transports the active compound of the present disclosure to the appropriate or desired site of action, such as oral, nasal, pulmonary, buccal, subcutaneous, intradermal, transdermal, or parenteral, e.g., rectal, depot, subcutaneous, intravenous, intraurethral, ​​intramuscular, intranasal, ophthalmic solution or ointment, with the oral route being preferred.

[0098] The dosage form can be administered once a day, or more than once a day, such as twice or three times a day. Alternatively, the dosage form can be administered less frequently than daily, such as every other day or weekly, if deemed appropriate by the prescribing physician. The dosage regimen includes, for example, titration of the dose to an extent necessary or useful for the indication to be treated, thereby allowing 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 or controlled release forms. Suitable dosage regimens and / or forms include, for example, those set forth in the latest edition of the Physicians' Desk Reference, which is incorporated herein by reference.

[0099] As used herein, the term "administering" refers to providing a compound, a pharmaceutical composition containing the compound, to a subject by any acceptable means or route, including, for example, by oral, parenteral (eg, intravenous), or topical administration.

[0100] 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 term "treatment" with respect to a disease, pathological condition, or symptom also refers to any observable beneficial effect of the treatment. A beneficial effect can be demonstrated, for example, by a delayed onset of clinical symptoms of the disease in susceptible subjects, a reduction in the severity of some or all of the clinical symptoms of the disease, a slowing of the progression of the disease, a reduction in the number of relapses of the disease, an improvement in the overall health or well-being of the subject, or by other parameters that are well known in the art and are specific for a particular disease. Prophylactic treatment is a treatment administered to a subject who does not show signs of the disease or who only shows early signs, with the aim of reducing the risk of developing the pathology. Therapeutic treatment is a treatment given to a subject after the signs and symptoms of the disease appear.

[0101] As used herein, the term "subject" refers to an animal (e.g., a mammal, such as a human). The subject to be treated according to the methods described herein can be a subject diagnosed with a neurodegenerative disease involving demyelination, hypomyelination or myelin sheath dysplasia, such as a subject diagnosed with multiple sclerosis or cerebral palsy, or a subject at risk of developing the disease. Diagnosis can be performed by any method or technology known in the art. It will be understood by those skilled in the art that the subject to be treated according to this disclosure may have been subjected to standard testing, or may be identified as being at risk due to the presence of one or more risk factors associated with the disease or condition without examination.

[0102] As used herein, the term "effective amount" refers to the amount of a given agent sufficient to achieve the desired effect in a subject being treated with the agent. Ideally, an effective amount of an agent is an amount sufficient to inhibit or treat a disease without causing significant toxicity in the subject. The effective amount of an agent will depend on the subject being treated, the severity of the ailment, and the mode of administration of the pharmaceutical composition. Based on this disclosure, one skilled in the art will understand methods for determining an effective amount of a disclosed compound sufficient to achieve the desired effect in a subject.

[0103] As used herein, the term "modulate" refers to the ability to increase or decrease the activity of one or more protein kinases. Thus, the compounds of the present invention can be used in methods for modulating protein kinases by contacting the protein kinases with any one or more 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 be used to stimulate the activity of one or more protein kinases. In other embodiments, the compounds of the present invention can be used to modulate the activity of protein kinases in individuals in need of receptor modulation by administering a modulating amount of a compound as described herein.

[0104] As used herein, the term "BTK-mediated" or "BTK-regulated" or "BTK-dependent" disease or condition means any disease or other harmful condition in which BTK or a mutant thereof is known to play a role. Therefore, another embodiment of the present application is directed to treating one or more diseases in which BTK or a mutant thereof is known to play a role or to reducing the severity thereof. Specifically, the present application relates to a method of treating a disease or condition selected from a proliferative disorder or an autoimmune disorder or reducing the severity thereof, wherein the method comprises administering a compound of formula (I) or a composition according to the present application to a patient in need thereof.

[0105] Compound

[0106] Disclosed herein are compounds having the structure of Formula (I):

[0107]

[0108] or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate or isotope thereof, wherein:

[0109] Indicates a single bond or a double bond;

[0110] R 1 is -H, -CH3 or -F;

[0111] R 2 is -H, -CH3 or -F;

[0112] or R1 and R 2 Together with the C atoms to which they are attached, they form C 3-6 membered carbon ring;

[0113] R I1 is -Cl, -F, -CN, -CH3, -CH2F, -CHF2 or -CF3;

[0114] R I2 is -H or -F; and

[0115] R B -CH=CH2, -C≡CH or -C≡C-CH3;

[0116] And when R I1 When it is -CH3, R 1 and R 2 At least one of them is -CH3 or -F.

[0117] In some embodiments, --- represents a single bond. In other embodiments, --- represents a double bond.

[0118] In some embodiments, R 1 In other embodiments, R 1 In other embodiments, R 1 In some embodiments, R 1 is -H, and R 2 In other embodiments, R 1 is -H, and R 2 In other embodiments, R 1 is -H, and R 2 In other embodiments, R 1 is -CH3, and R 2 In other embodiments, R 1 is -CH3, and R 2 In other embodiments, R 1 is -F, and R 2 is -F.

[0119] In some embodiments, R 1 and R 2 Together with the C atoms to which they are attached, they form C 3-6 In some embodiments, R 1 and R 2 Together with the C atoms to which they are attached, they form a cyclopropyl ring. 1 and R 2Together with the C atoms to which they are attached, they form a cyclopropyl ring. 1 and R 2 Together with the C atoms to which they are attached, they form a cyclobutyl ring. 1 and R 2 Together with the C atom to which they are attached, they form a cyclopentyl ring. 1 and R 2 Together with the C atoms to which they are attached they form a cyclohexyl ring.

[0120] In some embodiments, R I1 In other embodiments, R I1 In other embodiments, R I1 In other embodiments, R I1 In other embodiments, R I1 In other embodiments, R I1 is F, -CH2F, -CHF2 or -CF3.

[0121] In some embodiments, R I2 is -H. In some embodiments, R I2 is -F.

[0122] In some embodiments, R B is -CH=CH2. In other embodiments, R B In other embodiments, R B It is -C≡C-CH3.

[0123] In some embodiments, --- represents a single bond, R I2 -H, R 1 is -H; and R 2 In other embodiments, --- represents a single bond, R I2 -F, R 1 is -H; and R 2 In other embodiments, --- represents a single bond, R I1 -Cl, R I2 -F, R 1 is -H; and R 2 is -H.

[0124] In some embodiments are compounds having the structure of Formula (IS) or (IR):

[0125]

[0126] In some embodiments is a compound having the structure shown below:

[0127]

[0128] In one embodiment, a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate or isotope thereof is provided, which has the structure of the compound of Table 1 below:

[0129] Table 1: Representative compounds of formula (I)

[0130]

[0131]

[0132]

[0133]

[0134]

[0135]

[0136] In another embodiment, a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate or isotope thereof is provided, which has the structure of the compound of Table 2 below.

[0137] Table 2: Other representative compounds of formula (I)

[0138]

[0139]

[0140]

[0141]

[0142] Also disclosed herein are compounds having the structure of Formula (II):

[0143]

[0144] or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate or isotope thereof, wherein:

[0145] R 3 is H, Me or cyclopropyl;

[0146] X is -CH2CH2- or -CR x1 Rx2 -;

[0147] R x1 is H, F or Me;

[0148] R x2 is H, F or Me;

[0149] or R x1 and R x2 Together with the C atoms to which they are attached, they form C 3-6 membered carbon ring;

[0150] or R x1 is H, and R x2 and R 3 together to form an alkylene bridge; and

[0151] R II1 is Cl, F, -CH2F, -CHF2, -CF3 or -CN;

[0152] R II2 H or F;

[0153] R B It is -CH=CH2, -C≡CH or -C≡C-CH3.

[0154] In one embodiment, R 3 is H. In another embodiment, R 3 In another embodiment, R 3 In other embodiments, R 3 It is H or Me.

[0155] In one embodiment, X is -CH2CH2-:

[0156]

[0157] In one embodiment, X is -CR x1 R x2 -:

[0158]

[0159] In one embodiment, X is -CR x1 R x2 -, R x1 is H, and R X2 For H:

[0160]

[0161] In one embodiment, X is -CR x1 R x2-, R x1 is H, and R X2 For F:

[0162]

[0163] In one embodiment, X is -CR x1 R x2 -, R x1 is F, and R X2 For F:

[0164]

[0165] In one embodiment, X is -CR x1 R x2 -, R x1 For Me, and R X2 For F:

[0166]

[0167] In one embodiment, X is -CR x1 R x2 -, R x1 For Me, and R X2 For Me:

[0168]

[0169] In one embodiment, X is -CR x1 R x2 -, and R x1 and R x2 Together with the C atoms to which they are attached, they form C 3-6 In some embodiments, R x1 and R x2 Together with the C atom to which they are attached they form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl ring:

[0170]

[0171] In one embodiment, X is -CR x1 R x2 -, R x1 is H, and R x2 and R 3 Together they form an alkylene bridge. In one embodiment, R X2 and R 3 together to form a methylene bridge:

[0172]

[0173] In one embodiment, RB For -CH=CH2:

[0174]

[0175] In one embodiment, R B For -C≡CH:

[0176]

[0177] In one embodiment, R B For -C≡C-CH3:

[0178]

[0179] In one embodiment, R II1 In one embodiment, R II1 In another embodiment, R II1 is F. In another embodiment, R II1 For CN.

[0180] In one embodiment, R II1 In one embodiment, R II1 In another embodiment, R II1 In another embodiment, R II1 It is -CF3.

[0181] In one embodiment, R II2 is H. In another embodiment, R II2 For F.

[0182] In one embodiment, a compound of formula (II) or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate or isotope thereof is provided, which has the structure of the following compound:

[0183]

[0184] In one embodiment, a compound of formula (II) or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate or isotope thereof is provided, which has the structure of the compound of Table 3.

[0185] Table 3: Representative compounds of formula (II)

[0186]

[0187]

[0188]

[0189]

[0190]

[0191]

[0192]

[0193]

[0194] 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, compounds of formula (II-a) or (II-b) are provided:

[0195]

[0196] Also disclosed herein are compounds having the structure of Formula (III):

[0197]

[0198] or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate or isotope thereof, wherein:

[0199] Z is -CH2-, -CHMe- or a bond;

[0200] Y is -CHR 4 - or key;

[0201] R 4 is H, F or OH;

[0202] R 5 is H, F or Me;

[0203] R 6 is H or Me;

[0204] R 7 is H or Me;

[0205] R 8 is H;

[0206] or R 5 and R 7 Together they form a 5- or 6-membered heterocyclic ring;

[0207] or R 6 and R 7 Together they form a 4-, 5- or 6-membered heterocyclic ring;

[0208] or R 8 and R 7 Together they form a 5- or 6-membered heterocyclic ring;

[0209] a is 0, 1, or 2;

[0210] R III1 is Cl, F, -CH2F, -CHF2, -CF3 or -CN; or

[0211] When R 4 When F or OH, or when R 5 When F, or when R 5 and R 7 or R 8 and R 7 When combined to form a 5-membered or 6-membered heterocyclic ring, or when R 6 and R 7 When combined to form a 4-membered, 5-membered or 6-membered heterocyclic ring, R III1 is -CH3;

[0212] R III2 is H or F; and

[0213] R B It is -CH=CH2, -C≡CH or -C≡C-CH3.

[0214] In one embodiment of formula (III), Z is a bond, Y is a bond, and a compound having the structure of formula (IV) is provided:

[0215]

[0216] or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate or isotope thereof, wherein R III1 、R III2 、R B ,a,R 5 、R 6 、R 7 and R 8 As defined above in the context of formula (III).

[0217] In one embodiment of Formula (III), Z is -CH2-, Y is a bond, and a compound having the structure of Formula (Va) is provided:

[0218]

[0219] or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate or isotope thereof, wherein R III1 、R III2 、R B ,a,R 5 、R 6 、R 7 and R 8 As defined above in the context of formula (III).

[0220] In one embodiment of formula (III), Z is a bond and Y is -CHR 4 -, and provides a compound having a structure of Formula (Vb):

[0221]

[0222] or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate or isotope thereof, wherein R III1 、R III2 、R B ,a,R 4 、R 5 、R 6 、R 7 and R 8 As defined above in the context of formula (III). In one embodiment of formula (III-b), R 4 is H. In another embodiment of formula (III-b), R 4 is F. In another embodiment of formula (III-b), R 4 It is -OH.

[0223] In one embodiment of formula (III), Z is -CH2-, Y is -CHR 4 -, and provides a compound having a structure of formula (VI-a):

[0224]

[0225] or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate or isotope thereof, wherein R III1 、R III2 、R B ,a,R 4 、R 5 、R6 、R 7 and R 8 As defined above in the context of formula (III). In one embodiment of formula (VI-a), R 4 is F. In another embodiment of formula (VI-a), R 4 It is -OH.

[0226] In one embodiment of Formula (VI-a), R 4 is H, and provides a compound having the structure of formula (VI-a-1):

[0227]

[0228] or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate or isotope thereof, wherein R III1 、R III2 、R B ,a,R 5 、R 6 、R 7 and R 8 As defined above in the context of formula (III).

[0229] In one embodiment of formula (III), Z is -CHMe-, Y is -CHR 4 -, and provides a compound having a structure of formula (VI-b):

[0230]

[0231] or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate or isotope thereof, wherein R III1 、R III2 、R B ,a,R 4 、R 5 、R 6 、R 7 and R 8 As defined above in the context of formula (III). In one embodiment of formula (VI-b), R 4 is H. In another embodiment of formula (VI-b), R 4 is F. In another embodiment of formula (VI-b), R 4 It is -OH.

[0232] In one embodiment of formula (III), R 7 and R 8 Together they form a 5-membered heterocyclic ring, where a is 0 and R 5 H, R6 is H, and provides a compound having the structure of Formula (VII-a):

[0233]

[0234] or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate or isotope thereof, wherein R III1 、R III2 、R B , Z and Y are as defined above in the context of 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 .

[0235] In one embodiment of formula (III), R 7 and R 8 Together they form a 5-membered heterocyclic ring, where a is 1 and R 5 H, R 6 is H, and provides a compound having the structure of Formula (VII-b):

[0236]

[0237] or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate or isotope thereof, wherein R III1 、R III2 、R B , Z and Y are as defined above in the context of 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 .

[0238] In one embodiment of formula (III), R 7 and R 8 Together they form a 5-membered heterocyclic ring, a is 2, R 5 H, R 6 is H, and provides a compound having the structure of Formula (VII-c):

[0239]

[0240] or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate or isotope thereof, wherein R III1 、R III2 、R B , Z and Y are as defined above in the context of 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 .

[0241] In one embodiment of formula (III), R 7 and R 8 Together they form a 6-membered heterocyclic ring, a is 0, R 5 H, R 6 is H, and provides a compound having the structure of Formula (VIII-a):

[0242]

[0243] or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate or isotope thereof, wherein R III1 、R III2 、R B , Z and Y are as defined above in the context of 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 .

[0244] In one embodiment of formula (III), R 7 and R 8 Together they form a 6-membered heterocyclic ring, where a is 1 and R 5 H, R 6 is H, and provides a compound having the structure of Formula (VIII-b):

[0245]

[0246] or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate or isotope thereof, wherein R III1 、R III2 、R B , Z and Y are as defined above in the context of 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 .

[0247] In one embodiment of formula (III), R 7 and R 8 Together they form a 6-membered heterocyclic ring, a is 2, R 5 H, R 6 is H, and provides a compound having the structure of Formula (VIII-c):

[0248]

[0249] or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate or isotope thereof, wherein R III1 、R III2 、R B , Z and Y are as defined above in the context of 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 .

[0250] In one embodiment of formula (III), R 6 and R 7 Together they form a 4-membered heterocyclic ring, where a is 0 and R 5 H, R 8 is H, and provides a compound having the structure of Formula (IX-a):

[0251]

[0252] or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate or isotope thereof, wherein R III1 、R III2 、R B , Z and Y are as defined above in the context of 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 .

[0253] In one embodiment of formula (III), R 6 and R 7 Together they form a 4-membered heterocyclic ring, where a is 1 and R 5 H, R 8 is H, and provides a compound having the structure of Formula (IX-b):

[0254]

[0255] or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate or isotope thereof, wherein R III1 、R III2 、R B , Z and Y are as defined above in the context of 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 .

[0256] In one embodiment of formula (III), R 5 and R 7 Together they form a 5-membered heterocyclic ring, a is 2, R 6 H, R 8 is H, and provides a compound having the structure of Formula (Xa):

[0257]

[0258] or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate or isotope thereof, wherein R III1 、RIII2 、R B , Z and Y are as defined above in the context of 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 .

[0259] In one embodiment of formula (III), R 5 and R 7 Together they form a 5-membered heterocyclic ring, where a is 1 and R 6 H, R 8 is H, and provides a compound having a structure of Formula (Xb):

[0260]

[0261] or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate or isotope thereof, wherein R III1 、R III2 、R B , Z and Y are as defined above in the context of 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 .

[0262] In one embodiment of formula (III), R 5 and R 7 Together they form a 5-membered heterocyclic ring, where a is 0 and R 6 H, R 8 is H, and provides a compound having a structure of Formula (Xc):

[0263]

[0264] or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate or isotope thereof, wherein R III1 、R III2 、R B, Z and Y are as defined above in the context of 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 .

[0265] In one embodiment of formula (III), R 5 and R 7 Together they form a 6-membered heterocyclic ring, a is 2, R 6 is H, and provides a compound having the structure of Formula (XI-a):

[0266]

[0267] or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate or isotope thereof, wherein R III1 、R III2 、R B 、R 8 , Z and Y are as defined above in the context of 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 .

[0268] In one embodiment of formula (III), R 5 and R 7 Together they form a 6-membered heterocyclic ring, where a is 1 and R 6 is H, and provides a compound having the structure of Formula (XI-b):

[0269]

[0270] or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate or isotope thereof, wherein R III1 、R III2 、R B 、R 8, Z and Y are as defined above in the context of 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 .

[0271] In one embodiment of formula (III), R 5 and R 7 Together they form a 6-membered heterocyclic ring, a is 0, R 5 H, R 6 is H, and provides a compound having the structure of Formula (XI-c):

[0272]

[0273] or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate or isotope thereof, wherein R III1 、R III2 、R B 、R 8 , Z and Y are as defined above in the context of 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 .

[0274] In some embodiments of Formula (III), R 5 and R 7 Together they form a 6-membered heterocyclic ring, R 6 is H, Z is CH2, and provides a compound having a structure of one of Formula (XII-a), (XII-b) or (XII-c):

[0275]

[0276] or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate or isotope thereof, wherein R III1 、R III2 、R B 、R 8 and Y are as defined above in the context of formula (III).

[0277] In some embodiments of Formula (III), R 5 and R 7 Together they form a 6-membered heterocyclic ring, R 6 is H, Z is a bond, and provides a compound having a structure of one of Formula (XIII-a), (XIII-b) or (XIII-c):

[0278]

[0279] or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate or isotope thereof, wherein R III1 、R III2 、R B 、R 8 and Y are as defined above in the context of formula (III).

[0280] In some embodiments of Formula (III), R 5 H, R 6 H, R 7 H, R 8 is H, and provides a compound having the structure of Formula (XIV):

[0281]

[0282] or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate or isotope thereof, wherein R III1 、R III2 ,a,R B , Z and Y are as defined above in the context of 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 Formula (XIV), a is 0. In other embodiments of Formula (XIV), a is 1. In other embodiments of Formula (XIV), a is 2.

[0283] In some embodiments of Formula (III), R 5 H, R 6 H, R 7 H, R 8 is H, Z is CH2, and Y is CHR 4, and provides a compound having a structure of Formula (XV):

[0284]

[0285] or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate or isotope thereof, wherein R III1 、R III2 ,a,R 4 and R B As defined above in the context of formula (III).

[0286] In some embodiments of Formula (XV), a is 0, 1, or 2, and provided are compounds having the structure of one of Formula (XV-a), (XV-b), or (XV-c):

[0287]

[0288] or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate or isotope thereof, wherein R III1 、R III2 、R 4 and R B As defined above in the context of formula (III).

[0289] In some embodiments of Formula (III), and each more specific embodiment of any one 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)-(XV)”), R III1 Is Cl, F, -CN, -CH2F, -CHF2 or -CF3. In other embodiments of any one of Formulas (III)-(XV), R III1 is Cl or F. In other embodiments of any one of Formulas (III)-(XV), R III1 In other embodiments of any one of formulae (III)-(XV), R III1 is F. In other embodiments of any one of Formulas (III)-(XV), R III1In other embodiments of any one of Formulas (III)-(XV), R III1 is F, -CH2F, -CHF2 or -CF3.

[0290] In some embodiments of any one of Formulas (III)-(XV), when R 4 When it is F or OH, R III1 In other embodiments of any one of formulae (III)-(XV), when R 5 When F, R III1 In other embodiments of any one of formulae (III)-(XV), when R 5 and R 7 When combined to form a 5-membered or 6-membered heterocyclic ring, or when R 6 and R 7 When combined to form a 4-membered, 5-membered or 6-membered heterocyclic ring, or when R 8 and R 7 When combined to form a 5-membered or 6-membered heterocyclic ring, R III1 is -CH3.

[0291] In some embodiments of any one of Formulas (III)-(XV), R III2 is H. In some embodiments of any one of Formulas (III)-(XV), R III2 For F.

[0292] In one embodiment of any one of Formulas (III)-(XV), R B It is -CH=CH2.

[0293] In one embodiment of formula (III), R B is -CH=CH2, and provides a compound having the structure of Formula (XVI):

[0294]

[0295] or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate or isotope thereof, wherein R III1 、R III2 ,a,Z,Y,R 5 、R 6 、R 7 and R 8 As defined above in the context of formula (III).

[0296] In one embodiment of any one of Formulas (III)-(XIII), R Bis -C≡CH, and provides a compound having a structure of Formula (XVII):

[0297]

[0298] or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate or isotope thereof, wherein R III1 、R III2 ,a,Z,Y,R 5 、R 6 、R 7 and R 8 As defined above in the context of formula (III).

[0299] In one embodiment of any one of Formulas (III)-(XIII), R B is -C≡C-CH3, and provides a compound having a structure of formula (XVIII):

[0300]

[0301] or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate or isotope thereof, wherein R III1 、R III2 ,a,Z,Y,R 5 、R 6 、R 7 and R 8 As defined above in the context of formula (III).

[0302] In one embodiment, a compound of formula (III) or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate or isotope thereof is provided, which has the structure of the compound listed in Table 4.

[0303] Table 4: Representative compounds of formula (III)

[0304]

[0305]

[0306]

[0307]

[0308]

[0309]

[0310]

[0311]

[0312]

[0313]

[0314]

[0315]

[0316]

[0317] In additional embodiments, a pharmaceutically acceptable salt of a compound of Formula (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), (XII-b), (XII-c), (XIII-a), (XIII-b), (XIII-c), (XIII), (XIV), (XV-a), (XV-b), (XV-c), (XVI), (XVII), or (XVIII).

[0318] In other embodiments, it is a solvate of a compound of Formula (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), (XII-b), (XII-c), (XIII-a), (XIII-b), (XIII-c), (XIII), (XIV), (XV-a), (XV-b), (XV-c), (XVI), (XVII), or (XVIII).

[0319] In other embodiments, it is a hydrate of a compound of Formula (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), (XII-b), (XII-c), (XIII-a), (XIII-b), (XIII-c), (XIII), (XIV), (XV-a), (XV-b), (XV-c), (XVI), (XVII), or (XVIII).

[0320] In other embodiments, isomers of compounds of Formula (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), (XII-b), (XII-c), (XIII-a), (XIII-b), (XIII-c), (XIII), (XIV), (XV-a), (XV-b), (XV-c), (XVI), (XVII), or (XVIII).

[0321] In other embodiments, it is a tautomer of a compound of Formula (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), (XII-b), (XII-c), (XIII-a), (XIII-b), (XIII-c), (XIII), (XIV), (XV-a), (XV-b), (XV-c), (XVI), (XVII), or (XVIII).

[0322] In other embodiments, it is a racemate of a compound of Formula (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), (XII-b), (XII-c), (XIII-a), (XIII-b), (XIII-c), (XIII), (XIV), (XV-a), (XV-b), (XV-c), (XVI), (XVII), or (XVIII).

[0323] In other embodiments, are isotopic forms of compounds of Formula (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), (XII-b), (XII-c), (XIII-a), (XIII-b), (XIII-c), (XIII), (XIV), (XV-a), (XV-b), (XV-c), (XVI), (XVII), or (XVIII).

[0324] In another embodiment, the invention comprises formula (I), formula (II), formula (II-a), formula (II-b), formula (IV), formula (Va), formula (Vb), formula (VI-a), formula (VI-a-1), formula (VI-b), formula (VII-a), formula (VII-b), formula (VII-c), formula (VIII-a), formula (VIII-b), formula (VIII-c), formula (IX-a), formula (IX-b), formula (Xa), formula (Xb), formula (Xc), formula (XI-a), Pharmaceutical compositions of compounds of 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) and pharmaceutically acceptable salts, solvates, hydrates, isomers, tautomers, racemates or isotopes thereof.

[0325] In another embodiment, the invention comprises formula (I), formula (II), formula (II-a), formula (II-b), formula (IV), formula (Va), formula (Vb), formula (VI-a), formula (VI-a-1), formula (VI-b), formula (VII-a), formula (VII-b), formula (VII-c), formula (VIII-a), formula (VIII-b), formula (VIII-c), formula (IX-a), formula (IX-b), formula (Xa), formula (Xb), formula (Xc), formula (XI-a), formula (XI-b), A pharmaceutical composition comprising a compound of 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) or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate or isotope thereof and at least one pharmaceutically acceptable excipient.

[0326] In another embodiment, the invention comprises a compound comprising formula (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-b), (IX-c), (IX-d), (IX-e), (IX-f), (Xf), (Xf), (Xg ... (XIII-a), (XIII-b), (XIII-c), (XIII), (XIV), (XV-a), (XV-b), (XV-c), (XVI), (XVII) or (XVIII) and a pharmaceutical composition of a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate or isotope thereof, and a pharmaceutically acceptable carrier, adjuvant or vehicle.

[0327] disease

[0328] Described herein is a method of inhibiting a protein kinase, comprising contacting the protein kinase with 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. In some embodiments, the protein kinase is BTK.

[0329] Described herein are methods for treating BTK-dependent disorders comprising administering to a subject in need thereof 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.

[0330] In some embodiments, the BTK-dependent condition is cancer, an autoimmune disease, an inflammatory disease, or a 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 condition is cancer. In some embodiments, the BTK-dependent condition is an autoimmune disease. In some embodiments, the BTK-dependent condition is an inflammatory disease. In some embodiments, the BTK-dependent condition is a thromboembolic disease. In some embodiments, the BTK-dependent condition is multiple sclerosis. In some embodiments, the BTK-dependent condition is rheumatoid arthritis. In some embodiments, the BTK-dependent condition is psoriasis. In some embodiments, the BTK-dependent condition is Sjögren's syndrome. In some embodiments, the BTK-dependent condition is systemic lupus erythematosus. In some embodiments, the BTK-dependent condition is urticaria.

[0331] In some embodiments, 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, is used in the manufacture of a medicament. In some embodiments, the medicament is used to treat cancer. In some embodiments, the medicament is used to treat an autoimmune disease. In some embodiments, the medicament is used to treat an inflammatory disease. In some embodiments, the medicament is used to treat a thromboembolic disease. In some embodiments, the medicament is used to treat multiple sclerosis. In some embodiments, the medicament is used to treat rheumatoid arthritis. In some embodiments, the medicament is used to treat psoriasis. In some embodiments, the medicament is used to treat Sjögren's syndrome. In some embodiments, the medicament is used to treat systemic lupus erythematosus. In some embodiments, the medicament is used to treat urticaria.

[0332] Therefore, inhibition of BTK activity can be used to treat 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 I diabetes, membranous nephritis, inflammatory bowel disease, autoimmune hemolytic anemia, autoimmune thyroiditis, hot and cold agglutinin disease, Evans syndrome, hemolytic uremic syndrome / thrombotic thrombocytopenic purpura, sarcoidosis, Sjögren's syndrome, peripheral neuropathies (e.g., Guillain-Barré syndrome), pemphigus vulgaris, and asthma.

[0333] Furthermore, BTK has been reported to play a role in controlling 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, inhibiting BTK activity could be used to treat B-cell lymphomas and leukemias.

[0334] The compounds described herein, or pharmaceutically acceptable salts, solvates, hydrates or tautomers thereof, may optionally be used in combination with corticosteroids, non-corticosteroids, immunosuppressants and / or anti-inflammatory agents to treat the diseases listed above. In one embodiment, the immunosuppressant is selected from interferon alpha, interferon gamma, cyclophosphamide, tacrolimus, mycophenolate mofetil, methotrexate, dapsone, sulfasalazine, azathioprine, anti-CD20 agents (such as rituximab, ofatumumab, obinutuzumab or veltuzumab or their biosimilar forms), anti-TNFα agents (such as etanercept, infliximab, golimumab, adalimumab or certolizumab pegol or their biosimilar forms), anti-IL6 agents directed against a ligand or its receptor (such as tocilizumab, salimumab, olotuzumab, eselumab or silduzumab), anti-IL17 agents directed against a ligand or its receptor (such as secukinumab, ustekinumab, brolucizumab or ixekizumab), anti-TNFα agents (such as etanercept, infliximab, golimumab, adalimumab or certolizumab pegol or their biosimilar forms), anti-IL6 agents directed against a ligand or its receptor (such as tocilizumab, salimumab, olotuzumab, eselumab or silduzumab), anti-IL17 agents directed against a ligand or its receptor (such as secukinumab, ustekinumab, brolucizumab or ixekizumab), Anti-IL1 agents directed against a ligand or its receptor (such as rilocept, canakinumab or anakinra), anti-IL2 agents directed against a ligand or its receptor (such as basiliximab or daclizumab), anti-CD2 agents such as afacept, anti-cd3 agents such as muromonab-cd3, anti-CD80 / 86 agents such as abatacept or belatacept, anti-sphingosine-1-phosphate receptor agents such as fingolimod, anti-C5 agents such as eculizumab, anti-integrin α4 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 blisibimud), leflunomide and teriflunomide. Preferably, the immunosuppressant is rituximab, ofatumumab, obinutuzumab or veltuzumab or a biosimilar form thereof.

[0335] Synthesis of compounds

[0336] Reaction as herein described, process and synthetic method are not limited to the specific conditions described in the following experimental section, but are intended as guidance to a suitable technician in this area. For example, the reaction can be carried out in any suitable solvent or other reagent to carry out necessary conversion. Generally, suitable solvent is a proton or aprotic solvent, which is substantially not reacted with reactants, intermediates or products at the temperature (that is, the temperature that can be frozen to the boiling temperature range) where the reaction is carried out. A given reaction can be carried out in a solvent or a mixture of more than one solvent. Depending on specific reaction, a suitable solvent for specific post-processing after the reaction can be used.

[0337] Unless otherwise indicated, mass spectrometry (MS), liquid chromatography-mass spectrometry (LCMS), NMR, HPLC, protein chemistry, biochemistry, recombinant DNA technology and pharmacological conventional methods are used. Standard organic chemistry techniques, such as those described in, for example, March's Advanced Organic Chemistry, 7th edition, John Wiley and Sons, Inc (2013), are used to prepare compounds. Alternative reaction conditions for synthetic transformations described herein can be used, such as changing solvent, reaction temperature, reaction time and different chemical reagents and other reaction conditions. If necessary, it may be necessary to use appropriate protecting groups. The introduction and cracking of this group can be carried out using the standard method described in Peter G.M.Wuts and Theodora W.Green, Protecting Groups in Organic Synthesis, 4th edition, Wiley-Interscience. (2006). All starting materials and reagents are commercially available or easily prepared.

[0338] 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 the present disclosure can be synthesized using the general synthetic procedures set forth in Schemes 1-21.

[0339] Preparation of 4-bromo-1H-indole starting materials

[0340] Scheme 1: 4-Bromo-5-fluoro-2-methyl-1H-indole-7-carboxamide

[0341]

[0342] 4-Bromo-5-fluoro-2-nitrobenzoic acid is reacted with prop-1-en-2-ylmagnesium bromide to give 4-bromo-5-fluoro-2-methyl-1H-indole-7-carboxylic acid, which is amidated by treatment with ammonium chloride in the presence of HATU and DIEA to give 4-bromo-5-fluoro-2-methyl-1H-indole-7-carboxamide (R I2 、R II2 、R III2 =H).

[0343] Scheme 2: 4-Bromo-5,6-difluoro-2-methyl-1H-indole-7-carboxamide

[0344]

[0345] 1,4-dibromo-2,3-difluorobenzene is nitrated by treatment with a sulfuric acid solution of potassium nitrate, and the resulting nitro group is reduced to form 2,5-dibromo-3,4-difluoroaniline. Iodination is performed and then reacted with prop-1-yne to produce 4,7-dibromo-5,6-difluoro-2-methyl-1H-indole. The indole is then protected (e.g., Boc) and carboxylated at the 7-position by reaction with n-butyllithium and carbon dioxide to give 4-bromo-5,6-difluoro-2-methyl-1H-indole-7-carboxylic acid. The acid is amidated by treatment with ammonium chloride, and the indole is deprotected to give 4-bromo-5,6-difluoro-2-methyl-1H-indole-7-carboxamide (R I2 、R II2 、R III2 =F).

[0346] Synthesis of compounds having the structure of formula (I)

[0347] With 3-R 1 -3-R 2 -Coupling of 1,2,3,6-tetrahydropyridine

[0348] 4-Bromo-5-fluoro-6-R I2 -2-methyl-1H-indole-7-carboxamide is coupled with N-protected (e.g. Boc) 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine. Tetrahydropyridine can be R-protected at the 3-position. 1 / R 2 replace.

[0349] Scheme 3: N-protected 4-(5-R 1 -5-R 2 --1,2,5,6-tetrahydropyridin-3-yl)-5-fluoro-6-( ... I2 -2-methyl- 1H-Indole-7-carboxamide (---=double bond)

[0350]

[0351] 4-Bromo-5-fluoro-6-R I2 -2-methyl-1H-indole-7-carboxamide is coupled with N-protected (e.g. Boc) 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine. Tetrahydropyridine can be R-protected at the 3-position. 1 / R 2 replace.

[0352] Reduction to piperidine (optional)

[0353] Scheme 4: N-protected 4-(5-R 1 -5-R 2 -piperidin-3-yl)-5-fluoro-6-R I2 -2-methyl-1H-indole-7-carboxylate Amine (--- = single bond)

[0354]

[0355] N-protected-5-fluoro-6-R I2-2-methyl-4-(1,2,5,6-tetrahydropyridin-3-yl)-1H-indole-7-carboxamide ( = double bond) can be optionally reduced by treatment with a suitable reducing agent (e.g., Pd / C, H2) to afford N-protected-5-fluoro-6-R I2 -2-methyl-4-(piperidin-3-yl)-1H-indole-7-carboxamide, wherein the piperidine can be replaced by R at the 5 position 1 / R 2 replace.

[0356] Option 5: R I1 and R B Introduction

[0357]

[0358] N-protected-5-fluoro-6-R I2 -2-methyl-4-(1,2,5,6-tetrahydropyridin-3-yl)-1H-indole-7-carboxamide or N-protected-5-fluoro-6-R I2 -2-methyl-4-(piperidin-3-yl)-1H-indole-7-carboxamide (wherein tetrahydropyridine or piperidine can be R 1 / R 2 Substitution) is reacted as shown in Scheme 5, i.e., with:

[0359] N-chlorosuccinimide to obtain R I1 ;or

[0360] Phosphorus oxychloride to give the 3-formyl compound, which is then treated with diethylaminosulfur trifluoride (Et2NSF3; DAST) to give R as CHF2 I1 ;or

[0361] Phosphorus oxychloride is used to obtain a 3-formyl compound, which is reduced to a hydroxymethyl group and then treated with diethylaminosulfur trifluoride (Et2NSF3; DAST) to obtain R as CH2F. I1 .

[0362] From 3-R I1 -4-(5-R 1 -5-R 2 -piperidin-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-tetrahydropyridin-3-yl)-5-fluoro-6-R I2Removal of the protecting group on the piperidine or tetrahydropyridine nitrogen of -2-methyl-1H-indole-7-carboxamide (e.g., by treatment with HCl to remove the Boc protecting group) reveals the free amine, which is then reacted with R B Treatment with an acid chloride affords the final compound of formula (I):

[0363] 3-R I1 -4-(5-R 1 -5-R 2 -1-R B Carbonyl-piperidin-3-yl)-5-fluoro-6-(2-[ ... I2 -2-methyl-1H-indole-7-carboxamide; or

[0364] 3-R I1 -4-(5-R 1 -5-R 2 -1-R B Carbonyl-1,2,5,6-tetrahydropyridin-3-yl)-5-fluoro-6-(2-(2-nitro-1,2,5,6-tetrahydropyridin-3-yl) ...5-fluoro-6-(2-nitro-1,2,5,6-tetrahydropyridin-3-yl)-1,2,5,6-tetrahydropyridin-3- I2 -2-methyl-1H-indole-7-carboxamide.

[0365] It should be pointed out that The compound of formula (I) exists as a pair of isomers:

[0366]

[0367] Synthesis of compounds having the structure of formula (II)

[0368] Preparation of II-INT-B intermediate

[0369]

[0370] Scheme 6: Preparation of II-INT-B intermediate; X is CH2

[0371]

[0372] Intermediate II-INT-B is prepared by converting 2-(3-bromophenyl)ethan-1-amine to an amide by reaction with acetyl chloride, wherein X is CH2 and R 3 Me. Reaction with oxalyl chloride and ferric chloride followed by acid treatment gives 5-bromo-1-methyl-3,4-dihydroisoquinoline. Reduction with a suitable reducing agent (e.g., sodium borohydride) gives 5-bromo-1-methyl-1,2,3,4-tetrahydroisoquinoline. Tetrahydroisoquinoline can then be protected with a suitable protecting group (e.g., Boc) or by reacting with a suitable R B The acid chloride is reacted to convert to the desired final amide.

[0373] Scheme 7: Preparation of II-INT-B intermediate; X is CH2CH2

[0374]

[0375] Intermediate II-INT-B is prepared by converting 5-bromo-3,4-dihydronaphthalen-1(2H)-one to 6-bromo-2,3,4,5-tetrahydro-1H-benzo[c]azepin-1-one, wherein X is CH2CH2 and R 3 is H. Reduction with a suitable reducing agent (e.g. BH3) gives 6-bromo-2,3,4,5-tetrahydro-1H-benzo[c]azepine. The azepine can then be protected with a suitable protecting group (e.g. Boc) or by reacting with a suitable R B The acid chloride is reacted to convert to the desired final amide.

[0376] Scheme 8: Preparation of II-INT-B intermediate; X is cyclopropyl

[0377]

[0378] The intermediate II-INT-B was prepared starting from 3-bromo-2-hydroxybenzonitrile, wherein R 3 is H, and X is CR x1 R x2 , and R x1 and R x2 Together with the C atom to which they are attached, a cyclopropyl ring is formed. Reaction with 5-bromovaleronitrile followed by treatment with a strong base (e.g., KOtBu) affords 9-bromo-1,2-dihydrofuro[2,3-c]isoquinolin-5-amine. Treatment with an acid (e.g., HCl), a base (e.g., potassium carbonate), followed by heating and subsequent reduction affords 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) or by reacting with a suitable R B The acid chloride is reacted to convert to the desired final amide.

[0379] Scheme 9: Preparation of II-INT-B intermediate; R x2 and R 3 Formation of methylene bridges

[0380]

[0381] Preparation of intermediate II-INT-B starting from ethyl 2-(2-bromophenyl)acetate, wherein X is CR x1 R x2 , and R x1 is H, and R X2 and R 3Together they form a methylene bridge. Reaction with ethyl 2-bromoacetate followed by treatment with a base and then reaction with acid chloride / thionyl chloride gives 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 can be protected (for example, as an ester such as a methyl ester) and the oxo group is then converted to an amine by reaction with ammonium hydroxide to form a hydroxyimine, which is then reduced to an amine. Treatment with a base forms a bridged bicyclic compound, which is reduced with a suitable reducing agent (for example, BH3) to give 5-bromo-1,2,3,4-tetrahydro-1,4-methyleneisoquinoline. The methyleneisoquinoline can then be protected with a suitable protecting group (for example, Boc) or by reacting with a suitable R B The acid chloride is converted to the desired final amide.

[0382] 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 =F) coupling

[0383] Scheme 10: Suzuki coupling to form compounds of formula (II)

[0384] Pathway A

[0385]

[0386] Pathway B

[0387] Compounds of formula (II) can be prepared by conversion of 4-bromo-1H-indole to the corresponding dioxaborolanyl derivative followed by Suzuki coupling with II-INT-B (see Scheme 10, Route A).

[0388] Alternatively, compounds of formula (II) can be prepared by conversion of (I-INT-B) to the corresponding dioxaborolanyl derivative followed by Suzuki coupling with 4-bromo-1H-indole (see Scheme 10, Route B).

[0389] Scheme 11: Introducing R with Cl or F II1

[0390]

[0391] where R II1 The compound of formula (II) wherein R II1 The N-protected compound is treated with N-chlorosuccinimide or selective fluorine to introduce Cl or F, respectively. B Treatment with an acid chloride affords the final compounds. The order of these steps can be altered from that shown in Scheme 11 as desired.

[0392] Scheme 12: Introducing R with I or CN II1

[0393]

[0394] The N-protected compound is treated with N-iodosuccinimide to introduce I. This is accomplished by removing the protecting group and replacing it with an appropriate R B Treatment with an acid chloride afforded the final compound.

[0395] Scheme 13: Introduction of R with CHO, CHF2 or CH2F II1

[0396]

[0397] The N-protected compound is treated with POCl3 to introduce an aldehyde group. The aldehyde can be reduced to an alcohol by treatment with a suitable reducing agent (e.g., NaBH4). Treatment of the aldehyde with DAST yields a CF2H group, while treatment with the alcohol provides a CH2F group. The protecting group is removed and subsequently reacted with R B The acid chloride is reacted to give the final compound of formula (II).

[0398] Synthesis of compounds having the structure of formula (III)

[0399] Cyclic amine starting materials

[0400] Non-limiting examples of cyclic amines that can be used as starting materials are shown below and are commercially available or prepared via routes that will be apparent to one skilled in the art. Differential protection of the second amine group is performed as desired.

[0401]

[0402] Cyclic amine 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 =F) coupling

[0403] Scheme 14: General procedure for the preparation of compounds of formula (III)

[0404]

[0405] As a general procedure, compounds of formula (III) are prepared according to Scheme 14. Cyclic amine is coupled with bromoindole (e.g. using a Pd catalyst). The resulting amine-containing compound is then deprotected as needed and reacted with R B Reaction of the acid chloride affords the desired final compound.

[0406] Scheme 15: Preparation of compounds of formula (III) -R III1 is Cl, and R III2 H

[0407]

[0408] where R III1 is Cl and R III2Compounds of formula (III) wherein R is H are prepared as shown in Scheme 15. The carboxamide group is first protected, for example by treatment with phosphorus oxychloride to convert it into a nitrile group. The protected compound is then coupled with a cyclic amine and the carboxamide protecting group is removed, for example by hydration of the nitrile group. R is then introduced by treatment with N-chlorosuccinimide. III1 Finally, the second amine group is deprotected (e.g., the Boc group is removed) and the resulting amine is reacted with R B Reaction of the acid chloride affords the desired final compound.

[0409] Scheme 16: Preparation of compounds of formula (III)

[0410] R III1 is Cl, and R III2 、R 6 and R 7 H

[0411]

[0412] The formamide-protected bromoindole was reacted with cyclic amine (R 6 is H, and R 7 H) coupling, and removal of the formamide protecting group. The introduction of R by treatment with N-chlorosuccinimide III1 Finally, the second amine group is deprotected and reacted with R B Reaction of the acid chloride affords the desired final compound.

[0413] Scheme 17: Preparation of compounds of formula (III)

[0414] R 6 H, R 8 is H, a is 1, and R 5 and R 7 Together to form a 5-membered ring

[0415]

[0416] As shown in Scheme 17, indole bromide (R III1 and R III2 Both H) and cyclic amine (R 5 H, R 8 is H, a is 1, and R 5 and R 7 The R is introduced by treatment with N-chlorosuccinimide. III1 Finally, the second amine group is deprotected and reacted with R B Reaction of the acid chloride affords the desired final compound.

[0417] Scheme 18: Preparation of compounds of formula (III)

[0418] R III1 For Me, R 6 H, R 8 is H, a is 0, and R 5 and R 7 Together to form a 5-membered ring

[0419]

[0420] As shown in Scheme 18, indole bromide (R III1 and R III2 Both H) and dicycloamine (R 6 H, R 8 is H, a is 0, and R 5 and R 7 The R is introduced by treatment with N-chlorosuccinimide. III1 Finally, the second amine group is deprotected and reacted with R B Reaction of the acid chloride affords the desired final compound.

[0421] Scheme 19: Preparation of compounds of formula (III)

[0422] R III1 For Me, R 6 H, R 8 is H, a is 0, and R 5 and R 7 Together to form a 5-membered ring

[0423]

[0424] As shown in Scheme 19, indole bromide (R III1 For Me, and R III2 H) and dicyclic amine (R 6 H, R 8 is H, a is 0, and R 5 and R 7 The R is introduced by treatment with N-chlorosuccinimide. III1 Finally, the second amine group is deprotected and reacted with R B Reaction of the acid chloride affords the desired final compound.

[0425] Scheme 20: Preparation of compounds of formula (III)

[0426] Z is a bond, Y is CHR 4 , R 4 H, R 6 H, R 8 is H, a is 0, and R 5 and R 7 Together they form a 6-membered ring

[0427]

[0428] As shown in Scheme 20, indole bromide (R III1 and R III2 are H) and 1-PG-octahydro-1H-pyrrolo[3,4-b]pyridine (PG is a suitable protecting group, Z is a bond, Y is CR 4 , R 4 H, R 6 H, R 8 is H, a is 0, and R 5 and R 7The R is introduced by treatment with N-chlorosuccinimide. III1 Finally, the second amine group is deprotected and reacted with R B Reaction of the acid chloride affords the desired final compound.

[0429] Scheme 21: R III1 Introduction

[0430]

[0431] Where R III1 A compound of formula (III) is H and as shown in Scheme 21 is treated with:

[0432] Phosphorus oxychloride to give the 3-formyl compound, which is then treated with diethylaminosulfur trifluoride (Et2NSF3; DAST) to give R-CHF2 III1 ;or

[0433] Phosphorus oxychloride is used to obtain a 3-formyl compound, which is reduced to a hydroxymethyl group and then treated with diethylaminosulfur trifluoride (Et2NSF3; DAST) to obtain R-CH2F. III1 .

[0434] Then, the second amine group is deprotected and reacted with R B Reaction of the acid chloride affords the desired final compound.

[0435] Example

[0436] The following examples are provided for illustrative purposes only and are not intended to limit the scope of the claims provided herein. Although preferred embodiments of the present invention have been shown and described herein, it will be apparent to those skilled in the art that these embodiments are provided as examples only. Without departing from the present invention, those skilled in the art will now appreciate that many variations, changes, and substitutions may be made. It should be understood that various alternatives to the embodiments of the present invention described herein may be used for implementing the present invention. This means that the following claims define the scope of the present invention and therefore encompass methods and structures within the scope of these claims and their equivalents.

[0437] Preparation of compounds of formula (I)

[0438]

[0439] Example 1

[0440] 4-(1-Acryloyl-1,2,5,6-tetrahydropyridin-3-yl)-3-chloro-5-fluoro-2-methyl-1H-indole-7-carboxylate Synthesis of amine (compound 1)

[0441]

[0442] Step 1: 4-Bromo-5-fluoro-2-methyl-1H-indole-7-carboxylic acid

[0443]

[0444] To a stirred solution of 4-bromo-5-fluoro-2-nitrobenzoic acid (17 g, 64.4 mmol) in THF (200 mL) was added propane-1-en-2-ylmagnesium bromide (451 mL, 225 mmol, 0.5 M THF solution) at -70 ° C under nitrogen. After addition, the reaction mixture was stirred at -70 ° C for 3 h. 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 anhydrous sodium sulfate and concentrated in vacuo to give 4-bromo-5-fluoro-2-methyl-1H-indole-7-carboxylic acid (17.5 g) as a brown solid. The solid was used further without purification.

[0445] ESI-MS[MH] - Calculated value (C 10 H7BrFNO2)269.96, 271.96, measured values: 270.25, 272.25.

[0446] Step 2: 4-Bromo-5-fluoro-2-methyl-1H-indole-7-carboxamide

[0447]

[0448] To a stirred solution of 4-bromo-5-fluoro-2-methyl-1H-indole-7-carboxylic acid (17.5 g, 64.4 mmol), ammonia hydrochloride (5.17 g, 96.6 mmol) and HATU (29.4 g, 77.3 mmol) in DMF (200 mL) was added N-ethyl-N-isopropyl-propan-2-amine (25.0 g, 193 mmol). The reaction mixture was stirred at 25 ° C for 16 h, quenched with water (300 mL) and extracted with ethyl acetate (3×300 mL). The combined extracts were washed with water (200 mL), brine (200 mL), then dried over anhydrous sodium sulfate and concentrated in vacuo. The concentrate was purified by column chromatography (50% ethyl acetate in petroleum ether) to give 4-bromo-5-fluoro-2-methyl-1H-indole-7-carboxamide (3.8 g, 22%) as a yellow solid.

[0449] 1 H NMR (400MHz, DMSO-d6) δ11.26(s,1H),8.11(s,1H),7.63-7.53(m,2H),6.19(s,1H),2.42(s,3H).

[0450] ESI-MS[M+H] + Calculated value (C 10 H8BrFN2O)270.98, 272.98; measured values: 270.90, 272.90.

[0451] Step 3: 5-(7-Carbamoyl-5-fluoro-2-methyl-1H-indol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate Tert-butyl ester

[0452]

[0453] A mixture of 4-bromo-5-fluoro-2-methyl-1H-indole-7-carboxamide (250 mg, 0.922 mmol), tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (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 backfilled with nitrogen. The reaction mixture was stirred at 90°C under nitrogen for 2 h. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (3 x 20 mL). The combined extracts were washed with brine (20 mL), dried over sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography (50% ethyl acetate in petroleum ether) to give tert-butyl 5-(7-carbamoyl-5-fluoro-2-methyl-1H-indol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate (330 mg, 96%) as a yellow solid.

[0454] 1 H NMR(300MHz,DMSO-d6)δ7.46(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).

[0455] ESI-MS[M+H] + Calculated value (C 20 H 24 FN3O3)374.18, measured value: 374.15.

[0456] Step 4: 5-(7-Carbamoyl-3-chloro-5-fluoro-2-methyl-1H-indol-4-yl)-3,6-dihydropyridine-1 (2H)-tert-Butyl formate

[0457]

[0458] At 0 ° C, to a solution of tert-butyl 5-(7-carbamoyl-5-fluoro-2-methyl-1H-indol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate (150 mg, 0.40 mmol) in DMF (5 mL) was added N-chlorosuccinimide (54 mg, 0.40 mmol). The reaction mixture was stirred at 0 ° C for 1 h, 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 in vacuo. The residue was purified by reverse phase column chromatography, eluted with an aqueous solution of acetonitrile (10% to 60%) to give tert-butyl 5-(7-carbamoyl-3-chloro-5-fluoro-2-methyl-1H-indol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate (100 mg, 61%) as a yellow solid.

[0459] 1 H NMR (300MHz, DMSO-d6) δ7.55(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).

[0460] ESI-MS[M+H-tBu] + Calculated value (C 20 H 23 ClFN3O3)352.14, 352.14; measured values: 352.10, 352.10.

[0461] Step 5: 3-Chloro-5-fluoro-2-methyl-4-(1,2,5,6-tetrahydropyridin-3-yl)-1H-indole-7-carboxamide

[0462]

[0463] A mixture of tert-butyl 5-(7-carbamoyl-3-chloro-5-fluoro-2-methyl-1H-indol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate (100 mg, 0.245 mmol) and 4M hydrogen chloride in dioxane (3 mL) was stirred at 20 ° C for 2 h. The reaction mixture was concentrated in vacuo, diluted with saturated aqueous sodium bicarbonate (30 mL) and extracted with ethyl acetate (3×20 mL). The combined extracts were dried over sodium sulfate and concentrated in vacuo to give 3-chloro-5-fluoro-2-methyl-4-(1,2,5,6-tetrahydropyridin-3-yl)-1H-indole-7-carboxamide (70 mg) as a green solid.

[0464] ESI-MS[M+H] + Calculated value (C 15 H 15ClFN3O)308.09, 310.09; measured values: 308.05, 310.05.

[0465] Step 6: 4-(1-acryloyl-1,2,5,6-tetrahydropyridin-3-yl)-3-chloro-5-fluoro-2-methyl-1H-indole- 7-Formamide

[0466]

[0467] 4-(1-Acryloyl-1,2,5,6-tetrahydropyridin-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-tetrahydropyridin-3-yl)-1H-indole-7-carboxamide (70 mg, 0.23 mmol) in tetrahydrofuran (4.0 mL) and water (1.0 mL) at 0°C was added sodium bicarbonate (57 mg, 0.68 mmol) and acryloyl chloride (20 mg, 0.23 mmol). The reaction mixture was stirred at 0°C for 2 h. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 x 10 mL). The combined extracts were washed with brine (10 mL), dried over sodium sulfate, and concentrated in vacuo. The residue was purified by reverse phase column chromatography eluting with acetonitrile in water (10% to 35%) to give 4-(1-acryloyl-1,2,5,6-tetrahydropyridin-3-yl)-3-chloro-5-fluoro-2-methyl-1H-indole-7-carboxamide (42.3 mg, 51%) as a green solid.

[0468] 1 H NMR(300MHz,DMSO-d6)δ11.37(s,1H),8.12(s,1H),7.68-7.50(m,2H),6.93-6.69(m,1H),6.13 (d,J=17.4Hz,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).

[0469] ESI-MS[M+H] + Calculated value (C 18 H 17 ClFN3O2)362.10, 364.10; measured values: 362.05, 362.05.

[0470] Example 2

[0471] 4-(1-acryloylpiperidin-3-yl)-3-chloro-5-fluoro-2-methyl-1H-indole-7-carboxamide (Compound 2) synthesis

[0472]

[0473] Step 1: tert-Butyl 3-(7-carbamoyl-5-fluoro-2-methyl-1H-indol-4-yl)piperidine-1-carboxylate

[0474]

[0475] A mixture of tert-butyl 5-(7-carbamoyl-5-fluoro-2-methyl-1H-indol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate (prepared as described in Example 1 herein; 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 h. The reaction mixture was filtered. The filtrate was concentrated in vacuo to give tert-butyl 3-(7-carbamoyl-5-fluoro-2-methyl-1H-indol-4-yl)piperidine-1-carboxylate (340 mg, 87%) as a white solid.

[0476] ESI-MS[MH] - Calculated value (C 20 H 26 FN3O3)374.20, measured value: 374.15.

[0477] Step 2: tert-Butyl 3-(7-carbamoyl-3-chloro-5-fluoro-2-methyl-1H-indol-4-yl)piperidine-1-carboxylate

[0478]

[0479] tert-Butyl 3-(7-carbamoyl-3-chloro-5-fluoro-2-methyl-1H-indol-4-yl)piperidine-1-carboxylate: To a solution of tert-butyl 3-(7-carbamoyl-5-fluoro-2-methyl-1H-indol-4-yl)piperidine-1-carboxylate (340 mg, 0.91 mmol) in DMF (10 mL) was added NCS (133 mg, 0.996 mmol) at 0°C. The reaction mixture was stirred at 0°C for 1 h. The reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (3 x 30 mL). The combined extracts were washed with brine (3 x 20 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (0 to 50% ethyl acetate in petroleum ether) to give tert-butyl 3-(7-carbamoyl-3-chloro-5-fluoro-2-methyl-1H-indol-4-yl)piperidine-1-carboxylate (270 mg, 73%) as a white solid.

[0480] 1H NMR(400MHz,DMSO-d6)δ11.32(s,1H),8.10(s,1H),7.56-7.46(m,2H),4.14-3.96(m,3H),3.30-3.09(m,1 H),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).

[0481] ESI-MS [M+H-tBu]+ calculated value (C 20 H 25 ClFN3O3)354.16, 356.16; measured values: 354.15, 356.15.

[0482] Step 3: 3-Chloro-5-fluoro-2-methyl-4-(piperidin-3-yl)-1H-indole-7-carboxamide hydrochloride

[0483]

[0484] 3-Chloro-5-fluoro-2-methyl-4-(piperidin-3-yl)-1H-indole-7-carboxamide hydrochloride: A mixture of tert-butyl 3-(7-carbamoyl-3-chloro-5-fluoro-2-methyl-1H-indol-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 h. The reaction mixture was concentrated in vacuo to give 3-chloro-5-fluoro-2-methyl-4-(piperidin-3-yl)-1H-indole-7-carboxamide hydrochloride (260 mg) as a white solid.

[0485] ESI-MS [MH]-calculated (C 15 H 17 ClFN3O)308.10, 310.10; measured values: 308.00, 310.00.

[0486] Step 4: 4-(1-Acryloylpiperidin-3-yl)-3-chloro-5-fluoro-2-methyl-1H-indole-7-carboxamide

[0487]

[0488] 4-(1-Acryloylpiperidin-3-yl)-3-chloro-5-fluoro-2-methyl-1H-indole-7-carboxamide: To a mixture of 3-chloro-5-fluoro-2-methyl-4-(piperidin-3-yl)-1H-indole-7-carboxamide hydrochloride (260 mg, 0.76 mmol) in water (2 mL) and THF (8 mL) at 0° C., sodium bicarbonate (382 mg, 4.55 mmol) and acryloyl chloride (65 mg, 0.76 mmol) were added. The reaction mixture was stirred at 0° C. for 0.5 h, diluted with water (20 mL) and extracted with ethyl acetate (3×15 mL). The combined extracts were washed with brine (20 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative HPLC (column: XSelect CSH Prep C18 OBD column, 5 μm, 19×150 mm; mobile phase A: water (10 mmol / L NH 4 HCO 3 ), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: 10% B to 35% B, 7 min; 220 nm; retention time = 6.4 minutes) to give 4-(1-acryloylpiperidin-3-yl)-3-chloro-5-fluoro-2-methyl-1H-indole-7-carboxamide (165 mg, 60%) as a white solid.

[0489] 1 H NMR (300MHz, DMSO-d6) δ11.40(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).

[0490] ESI-MS [M+H]+ calculated values ​​(C 18 H 19 ClFN3O2)364.11, 366.11; measured values: 364.10, 366.10.

[0491] Step 5: Chiral separation (compounds 2a and 2b)

[0492]

[0493] The enantiomers of 4-(1-acryloylpiperidin-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 NH 3 -MeOH), mobile phase B: EtOH; flow rate: 17 mL / min; gradient: 50% B to 50% B in 14 min; 220 / 254 nm) to give compounds 2a (RT=7.106 min) and 2b (RT=11.312 min).

[0494] Compound 2a (retention time = 7.106 minutes) was obtained as 48.6 mg of a white solid.

[0495] 1 H NMR (300MHz, DMSO-d6) δ11.39(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).

[0496] ESI-MS [M+H]+ calculated values ​​(C 18 H 19 ClFN3O2)364.11, 366.11; measured values: 364.05, 366.05.

[0497] Compound 2b (retention time = 11.312 minutes) was obtained as 46.7 mg of a white solid.

[0498] 1 H NMR (300MHz, DMSO-d6) δ11.40(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).

[0499] ESI-MS [M+H]+ calculated values ​​(C18 H 19 ClFN3O2)364.11, 366.11; measured values: 364.10, 366.10.

[0500] Example 3

[0501] 4-(1-Acryloylpiperidin-3-yl)-3-chloro-5,6-difluoro-2-methyl-1H-indole-7-carboxamide (Compound 3) Synthesis

[0502]

[0503] Step 1: 1,4-Dibromo-2,3-difluoro-5-nitrobenzene

[0504]

[0505] To a solution of 1,4-dibromo-2,3-difluorobenzene (25.0 g, 91.95 mmol) in concentrated sulfuric acid (200 mL) was added potassium nitrate (11.0 g, 108.8 mmol) at 0°C. The reaction mixture was stirred at 25°C for 16 h. The reaction mixture was poured into ice water (1 L) and stirred at 0°C for 30 min. The resulting precipitate was filtered, and the filter cake was washed with water and dried under reduced pressure to give 1,4-dibromo-2,3-difluoro-5-nitrobenzene (27.0 g, 92%) as a yellow solid.

[0506] 1 H NMR (300MHz, DMSO-d6) δ8.47 (dd, J=6.0, 2.4Hz 1H).

[0507] Step 2: 2,5-Dibromo-3,4-difluoroaniline

[0508]

[0509] To a solution of 1,4-dibromo-2,3-difluoro-5-nitrobenzene (27.0 g, 85.21 mmol) in acetic acid (260 mL) was added iron powder (47.6 g, 852.0 mmol). The reaction mixture was stirred at 45 ° C for 5 h. 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 2,5-dibromo-3,4-difluoroaniline (23.0 g, 94% yield) as a yellow solid.

[0510] 1 H NMR (300MHz, DMSO-d6) δ6.88 (dd, J=6.0, 2.4Hz 1H), 5.74 (brs, 2H).

[0511] Step 3: 2,5-Dibromo-3,4-difluoro-6-iodoaniline

[0512]

[0513] To a solution of 2,5-dibromo-3,4-difluoroaniline (23.0 g, 80.17 mmol) in acetic acid (250 mL) was added N-iodosuccinimide (19.84 g, 88.18 mmol). The reaction mixture was stirred at 25 ° C for 2 h. The reaction mixture was poured into ice water (500 mL) and filtered. The filter cake was washed with water (100 mL) and dried under reduced pressure. The crude product was purified by silica gel column chromatography and eluted with a petroleum ether solution of ethyl acetate (0 to 5%) to give 2,5-dibromo-3,4-difluoro-6-iodoaniline (30.0 g, 90%) as an off-white solid.

[0514] 1 H NMR (300MHz, DMSO-d6) δ5.63 (s, 2H).

[0515] ESI-MS[MH] - Calculated values ​​(C6H2Br2F2IN) 409.76, 411.75, 413.75, found values: 409.75, 411.75, 413.70.

[0516] Step 4: 2,5-Dibromo-3,4-difluoro-6-(prop-1-yn-1-yl)aniline

[0517]

[0518] Under nitrogen, to 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 (PPh 3 ) 2 Cl 2 (5.12 g, 7.27 mmol) in triethylamine (365 mL) was added prop-1-yne (1 M THF solution, 364 mL). The reaction mixture was stirred at 50 ° C for 4 h in a sealed flask. The cooled reaction mixture was quenched with water (300 ml) and extracted with ethyl acetate (300 ml × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluted with a petroleum ether solution of ethyl acetate (0 to 10%) to give 2,5-dibromo-3,4-difluoro-6-(prop-1-yn-1-yl)aniline (20.0 g, 84%) as a yellow solid.

[0519] ESI-MS[MH] - Calculated values ​​(C9H5Br2F2N) 321.88, 323.87, 325.87, found values: 322.00, 324.00, 326.00.

[0520] 1 H NMR (300MHz, DMSO-d6) δ5.79 (s, 2H), 2.18 (s, 3H).

[0521] Step 5: 4,7-Dibromo-5,6-difluoro-2-methyl-1H-indole

[0522]

[0523] By 2,5-dibromo-3,4-difluoro-6-(prop-1-yn-1-yl)aniline (20.0g, 61.55mmol) and PdCl2(1.09g, 6.15mmol) in acetonitrile (400mL) mixture degassed and backfilled with nitrogen three times, and stirred at 85 DEG C for 5h.The cooled reaction mixture was concentrated in vacuo.The residue was purified by silica gel column chromatography, eluted with a solution of petroleum ether (0 to 10%) of ethyl acetate to give 4,7-dibromo-5,6-difluoro-2-methyl-1H-indole (17.0g, 85%) as a yellow solid.

[0524] 1 H NMR (300MHz, DMSO-d6) δ11.75(s,1H),6.28(s,1H),2.41(s,3H).

[0525] ESI-MS[MH] - Calculated values ​​(C9H5Br2F2N) 321.88, 323.87, 325.87, found values: 321.80, 323.80, 325.80.

[0526] Step 6: 4,7-Dibromo-5,6-difluoro-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- Indole

[0527]

[0528] 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) was added sodium hydride (1.60 g, 40.01 mmol, 60%) at 0°C. After stirring at this temperature for 1 h, 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 h. 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 in vacuo. The residue was purified by silica gel column chromatography eluting with ethyl acetate in petroleum ether (0 to 10%) to give 4,7-dibromo-5,6-difluoro-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole (12.3 g, 87%) as a yellow oil.

[0529] 1 H NMR (300MHz, DMSO-d6) δ6.42 (s, 1H), 5.78 (s, 2H), 3.55 (t, J = 7.8 Hz, 2H), 2.47 (s, 3H), 0.83 (t, J = 8.1 Hz, 2H), -0.08 (s, 9H).

[0530] Step 7: 4-Bromo-5,6-difluoro-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole Indole-7-carboxylic acid

[0531]

[0532] 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) was added n-butyllithium (2.5 M in n-hexane, 13 mL, 32.5 mmol) at -70°C under nitrogen. After stirring at this temperature for 0.5 h and at 0°C for 0.5 h, the reaction mixture was cooled to -70°C and bubbled with carbon dioxide for 30 min. After stirring at 25°C for 1.5 h, the reaction mixture was quenched with saturated aqueous ammonium chloride (100 mL) and extracted with dichloromethane (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to give 4-bromo-5,6-difluoro-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7-carboxylic acid (11.4 g, crude) as a yellow oil.

[0533] ESI-MS[MH] - Calculated value (C 16 H20 BrF2NO3Si)418.04, 420.03, measured values: 417.95, 419.95.

[0534] Step 8: 4-Bromo-5,6-difluoro-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole Indole-7-carboxamide

[0535]

[0536] 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) at 0° C., HATU (12.38 g, 32.55 mmol) and DIPEA (17.53 g, 135.61 mmol) were added. After stirring at 25° C. for 16 h, the reaction mixture was quenched with water (300 ml) and extracted with ethyl acetate (300 ml×3). The combined organic layers were washed with brine (200 ml×3), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with ethyl acetate in petroleum ether (0 to 50%) to give 4-bromo-5,6-difluoro-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7-carboxamide (6.3 g, 55%) as a yellow solid.

[0537] 1 H NMR (300MHz, DMSO-d6) δ8.34(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).

[0538] ESI-MS[M+H] + Calculated value (C 16 H 21 BrF2N2O2Si)419.05, 421.05, measured values: 419.20, 421.20.

[0539] Step 9: 4-Bromo-5,6-difluoro-2-methyl-1H-indole-7-carboxamide

[0540]

[0541] A 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) in THF (60 mL) was stirred at 75 ° C. for 40 h. The reaction mixture was cooled to 0 ° C. and acidified with 2M hydrochloric acid until pH = 4. The precipitate was collected by filtration, washed with water (100 mL) and dried under reduced pressure to give 4-bromo-5,6-difluoro-2-methyl-1H-indole-7-carboxamide (3.5 g, 80%) as a yellow solid.

[0542] ESI-MS [M+H]+ calculated values ​​(C 10 H7BrF2N2O)288.97, 290.97, measured values: 288.95, 290.95.

[0543] 1H NMR (300MHz, DMSO-d6) δ11.38(s,1H),7.97(s,1H),7.90(s,1H),6.20(s,1H),2.40(s,3H).

[0544] Step 10: 5-(7-Carbamoyl-5,6-difluoro-2-methyl-1H-indol-4-yl)-3,6-dihydropyridine-1 (2H)-tert-Butyl formate

[0545]

[0546] 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-carboxylic acid tert-butyl ester (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 and backfilled with nitrogen five times and stirred at 90 ° C for 2 h. 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 in vacuo. The residue was purified by silica gel column chromatography eluting with ethyl acetate in dichloromethane (0 to 7%) to give tert-butyl 5-(7-carbamoyl-5,6-difluoro-2-methyl-1H-indol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate (700 mg, 86%) as a yellow solid.

[0547] ESI-MS [MH]-calculated (C 20 H 23 F2N3O3)390.17, measured value: 390.05.

[0548] 1H NMR(400MHz,DMSO-d6)δ11.07(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).

[0549] Step 11: tert-Butyl 3-(7-carbamoyl-5,6-difluoro-2-methyl-1H-indol-4-yl)piperidine-1-carboxylate

[0550]

[0551] To a stirred solution of 5-(7-carbamoyl-5,6-difluoro-2-methyl-1H-indol-4-yl)-3,6-dihydropyridine-1(2H)-formic acid tert-butyl ester (450 mg, 1.15 mmol) in methanol (60 mL) and tetrahydrofuran (30 mL) was added Pd / C (300 mg, 10%). The reaction mixture was stirred at 25 ° C for 48 h under hydrogen (2 atm). The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography and eluted with a solution of ethyl acetate in dichloromethane (0 to 7%) to give tert-butyl 3-(7-carbamoyl-5,6-difluoro-2-methyl-1H-indol-4-yl) piperidine-1-formate (400 mg, 88%) as a yellow solid.

[0552] 1 H NMR (400MHz, DMSO-d6) δ11.02(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).

[0553] ESI-MS[M+H-tBu] + Calculated value (C 20 H 25 F2N3O3)338.19, measured value: 338.10.

[0554] Step 12: 3-(7-Carbamoyl-3-chloro-5,6-difluoro-2-methyl-1H-indol-4-yl)piperidine-1-carboxylic acid tert-Butyl ester

[0555]

[0556] At 0 ° C, to a stirred solution of tert-butyl 3- (7-carbamoyl-5,6-difluoro-2-methyl-1H-indol-4-yl) piperidine-1-carboxylate (400 mg, 1.02 mmol) in DMF (10 mL) was added NCS (136 mg, 1.02 mmol). The reaction mixture was stirred at 25 ° C for 3 h. The reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (3 × 40 mL). The combined organic layer was washed with brine (50 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluted with a solution of methanol in dichloromethane (0 to 8%) to give tert-butyl 3- (7-carbamoyl-3-chloro-5,6-difluoro-2-methyl-1H-indol-4-yl) piperidine-1-carboxylate (350 mg, 80%) as a yellow solid.

[0557] 1 H NMR(400MHz,DMSO-d6)δ11.45(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).

[0558] ESI-MS[M+H-tBu] + Calculated value (C 20 H 24 ClF2N3O3)372.15, 374.14, measured values: 372.10, 374.10.

[0559] Step 13: 3-Chloro-5,6-difluoro-2-methyl-4-(piperidin-3-yl)-1H-indole-7-carboxamide hydrochloride

[0560]

[0561] To a stirred solution of tert-butyl 3-(7-carbamoyl-3-chloro-5,6-difluoro-2-methyl-1H-indol-4-yl)piperidine-1-carboxylate (350 mg, 0.82 mmol) in methanol (1 mL) was added hydrogen chloride (4 M in dioxane, 5 mL). The reaction mixture was stirred at 25 ° C for 1 h. The mixture was concentrated in vacuo to give 3-chloro-5,6-difluoro-2-methyl-4-(piperidin-3-yl)-1H-indole-7-carboxamide hydrochloride (280 mg, 94%) as a yellow solid.

[0562] ESI-MS[M+H] + Calculated value (C 15 H 16 ClF2N3O)328.09, 330.09, measured values: 328.15, 330.15.

[0563] Step 14: 4-(1-Acryloylpiperidin-3-yl)-3-chloro-5,6-difluoro-2-methyl-1H-indole-7-carboxamide

[0564]

[0565] To a stirred solution of 3-chloro-5,6-difluoro-2-methyl-4-(3-piperidinyl)-1H-indole-7-carboxamide (280 mg, 0.76 mmol) in THF (4 mL) was added DIEA (294 mg, 2.28 mmol) and acryloyl chloride (98 mg, 0.76 mmol) at -70 ° C. The reaction mixture was stirred at -70 ° C for 1 h. 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 in vacuo. 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 NH 4 HCO 3 + 0.1% NH 3 .H 2 O), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 30% B to 52% B in 7 min; 220 nm; Rt: 6.32 min to give 4-(1-acryloylpiperidin-3-yl)-3-chloro-5,6-difluoro-2-methyl-1H-indole-7-carboxamide (123.7 mg, 42%) as an off-white solid.

[0566] 1 H NMR (400MHz, DMSO-d6) δ11.46(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,0.5 H),2.35(s,3H),2.13-1.91(m,2H),1.89-1.77(m,1H),1.64-1.40(m,1H).

[0567] ESI-MS[M+H] + Calculated value (C 18 H 18ClF2N3O2)382.11, 384.11, measured values: 382.25, 384.25.

[0568] Example 4

[0569] 4-(1-Acryloyl-1,2,5,6-tetrahydropyridin-3-yl)-3-chloro-5,6-difluoro-2-methyl-1H-indole-7-yl Synthesis of formamide (compound 4)

[0570]

[0571] Step 1: 5-(7-Carbamoyl-3-chloro-5,6-difluoro-2-methyl-1H-indol-4-yl)-3,6-dihydropyridine tert-Butylpyridine-1(2H)-carboxylate

[0572]

[0573] At 0 ° C, to a stirred solution of 5- (7-carbamoyl-5,6-difluoro-2-methyl-1H-indol-4-yl) -3,6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (150 mg, 0.38 mmol) was added NCS (52 mg, 0.38 mmol). The reaction mixture was stirred at 25 ° C for 4 h. The reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic layer was washed with brine (30 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by alumina column chromatography and eluted with a solution of methanol in dichloromethane (0 to 10%) to give 5- (7-carbamoyl-3-chloro-5,6-difluoro-2-methyl-1H-indol-4-yl) -3,6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (140 mg, 85%) as a yellow solid.

[0574] 1 H NMR (400MHz, DMSO-d6) δ11.46(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).

[0575] ESI-MS[M+H] + Calculated value (C 20 H 22 ClF2N3O3)426.13, 426.13, measured values: 426.15, 428.15.

[0576] Step 2: 3-Chloro-5,6-difluoro-2-methyl-4-(1,2,5,6-tetrahydropyridin-3-yl)-1H-indole-7-carboxamide hydrochloride

[0577]

[0578] To a stirred solution of tert-butyl 5-(7-carbamoyl-3-chloro-5,6-difluoro-2-methyl-1H-indol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate (140 mg, 0.33 mmol) in methanol (1 mL) was added hydrogen chloride (4 M in dioxane, 2 mL). The reaction mixture was stirred at 25 ° C for 1 h. The mixture was concentrated in vacuo to give 3-chloro-5,6-difluoro-2-methyl-4-(1,2,5,6-tetrahydropyridin-3-yl)-1H-indole-7-carboxamide hydrochloride (125 mg, crude material) as a yellow solid.

[0579] ESI-MS[M+H] + Calculated value (C 15 H 14 ClF2N3O)326.08, 328.08, measured values: 326.10, 328.10.

[0580] Step 3: 4-(1-acryloyl-1,2,5,6-tetrahydropyridin-3-yl)-3-chloro-5,6-difluoro-2-methyl-1H-indole Indole-7-carboxamide

[0581]

[0582] To a stirred solution of 3-chloro-5,6-difluoro-2-methyl-4-(1,2,5,6-tetrahydropyridin-3-yl)-1H-indole-7-carboxamide hydrochloride (125 mg, 0.34 mmol) in THF (4 mL) was added DIEA (140 mg, 1.08 mmol) and acryloyl chloride (33 mg, 0.36 mmol) at -78 ° C. The reaction mixture was stirred at -78 ° C for 1 h. 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 in vacuo. 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 NH 4 HCO 3 + 0.1% NH 3 .H 2 O), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 33% B to 53% B in 7 min; 220 nm; Rt: 5.53 min to give 4-(1-acryloyl-1,2,5,6-tetrahydropyridin-3-yl)-3-chloro-5,6-difluoro-2-methyl-1H-indole-7-carboxamide (66.3 mg, 48%) as an off-white solid.

[0583] 1H NMR(400MHz,DMSO-d6)δ11.47(s,1H),7.99(s,1H),7.93(s,1H),6.95-6.68(m,1H),6.19-6.08(m,1 H),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).

[0584] ESI-MS[M+H] + Calculated value (C 18 H 16 ClF2N3O2)380.09, 382.09, measured values: 380.05, 382.05.

[0585] Example 5

[0586] 4-(1-acryloyl-1,2,5,6-tetrahydropyridin-3-yl)-3-cyano-5,6-difluoro-2-methyl-1H-indole- Synthesis of 7-formamide (Compound 5)

[0587]

[0588] Step 1: 5-(3-Bromo-7-carbamoyl-5,6-difluoro-2-methyl-1H-indol-4-yl)-3,6-dihydropyridine tert-Butylpyridine-1(2H)-carboxylate

[0589]

[0590] To a stirred solution of tert-butyl 5-(7-carbamoyl-5,6-difluoro-2-methyl-1H-indol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate (600 mg, 1.53 mmol) in DMF (15 mL) at 0° C. was added N-bromosuccinimide (273 mg, 1.53 mmol). After stirring at 0° C. for 2 h, 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 in vacuo. The residue was purified by column chromatography on silica gel eluting with ethyl acetate in petroleum ether (0 to 33%) to give tert-butyl 5-(3-bromo-7-carbamoyl-5,6-difluoro-2-methyl-1H-indol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate (530 mg, 73%) as a yellow solid.

[0591] 1H NMR(400MHz,DMSO-d6)δ11.57(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).

[0592] ESI-MS[M+H-Boc] + Calculated value (C 20 H 22 BrF2N3O3)370.08, 372.08, measured values: 370.10, 372.10.

[0593] Step 2: 5-(7-Carbamoyl-3-cyano-5,6-difluoro-2-methyl-1H-indol-4-yl)-3,6-dihydropyridine tert-Butylpyridine-1(2H)-carboxylate

[0594]

[0595] A mixture of tert-butyl 5-(3-bromo-7-carbamoyl-5,6-difluoro-2-methyl-1H-indol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate (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 backfilled with nitrogen five times. The reaction mixture was heated at 120 ° C for 2 h. 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 in vacuo. The residue was purified by column chromatography on silica gel eluting with ethyl acetate in petroleum ether (0 to 43%) to give tert-butyl 5-(7-carbamoyl-3-cyano-5,6-difluoro-2-methyl-1H-indol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate (220 mg, 46%) as a yellow solid.

[0596] ESI-MS[M+H-Boc] + Calculated value (C 21 H 22 F2N4O3)317.17, measured value: 317.15.

[0597] Step 3: 3-cyano-5,6-difluoro-2-methyl-4-(1,2,5,6-tetrahydropyridin-3-yl)-1H-indole-7-carboxamide Amine hydrochloride

[0598]

[0599] To a stirred solution of tert-butyl 5-(7-carbamoyl-3-cyano-5,6-difluoro-2-methyl-1H-indol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate (220 mg, 0.528 mmol) in MeOH (2 mL) was added a 4M solution of hydrogen chloride in dioxane (5.00 mL). The reaction mixture was stirred at 25 ° C. for 1 h. The resulting mixture was concentrated in vacuo to give 3-cyano-5,6-difluoro-2-methyl-4-(1,2,5,6-tetrahydropyridin-3-yl)-1H-indole-7-carboxamide hydrochloride (182 mg, crude) as a brown solid.

[0600] ESI-MS[M+H] + Calculated value (C 16 H 14 F2N4O)317.11, measured value: 317.15.

[0601] Step 4: 4-(1-acryloyl-1,2,5,6-tetrahydropyridin-3-yl)-3-cyano-5,6-difluoro-2-methyl-1H- Indole-7-carboxamide

[0602]

[0603] To a solution of 3-cyano-5,6-difluoro-2-methyl-4-(1,2,5,6-tetrahydropyridin-3-yl)-1H-indole-7-carboxamide hydrochloride (160 mg, 0.453 mmol) in THF (6 mL) was added DIEA (293 mg, 2.27 mmol) and acryloyl chloride (41 mg, 0.453 mmol) at -70 ° C. The reaction mixture was stirred at -70 ° C for 1 h. 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 in vacuo. 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 NH 4 HCO 3 ), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 5% B to 95% B in 12 min; 254 nm; RT: 4.33 min to give 4-(1-acryloyl-1,2,5,6-tetrahydropyridin-3-yl)-3-cyano-5,6-difluoro-2-methyl-1H-indole-7-carboxamide (88 mg, 52%) as a white solid.

[0604] 1H NMR(400MHz,DMSO-d6)δ12.19(s,1H),8.16-7.94(m,2H),6.98-6.70(m,1H),6.17-6.01(m,2 H),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).

[0605] ESI-MS[M+H] + Calculated value (C 19 H 16 F2N4O2)371.12, measured value: 371.05.

[0606] Example 6

[0607] (S)-4-(1-acryloylpiperidin-3-yl)-3,5,6-trifluoro-2-methyl-1H-indole-7-carboxamide and (R)-4-(1-Acryloylpiperidin-3-yl)-3,5,6-trifluoro-2-methyl-1H-indole-7-carboxamide (Compounds 6a and 6b) Synthesis

[0608]

[0609] Step 1: tert-Butyl 3-(7-carbamoyl-3,5,6-trifluoro-2-methyl-1H-indol-4-yl)piperidine-1-carboxylate ester

[0610]

[0611] At 15 ° C, to a stirred solution of 3- (7-carbamoyl -5,6- difluoro -2- methyl -1H- indol -4- bases) piperidine -1- carboxylic acid tert-butyl ester (500 mg, 1.27 mmol) in acetonitrile (8 mL) and DMSO (2 mL) was added selective fluorine II (407 mg, 1.27 mmol) in batches. The reaction mixture was stirred for 1 h at 15 ° C. The reaction mixture was quenched with water (30 mL) and extracted with dichloromethane (3 × 30 mL). The combined organic layer was washed with brine (30 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluted with a petroleum ether solution of ethyl acetate (0 to 53%) to give 3- (7-carbamoyl -3,5,6- trifluoro -2- methyl -1H- indol -4- bases) piperidine -1- carboxylic acid tert-butyl ester (300 mg, crude material) as a yellow solid.

[0612] ESI-MS[M+H-tBu] + Calculated value (C 20 H 24 F3N3O3)356.18, measured value: 356.10.

[0613] Step 2: 3,5,6-Trifluoro-2-methyl-4-(piperidin-3-yl)-1H-indole-7-carboxamide hydrochloride

[0614]

[0615] To a stirred solution of tert-butyl 3-(7-carbamoyl-3,5,6-trifluoro-2-methyl-1H-indol-4-yl)piperidine-1-carboxylate (300 mg, crude material) in methanol (1 mL) was added hydrogen chloride (4 M in dioxane, 4 mL). The reaction mixture was stirred at 25 ° C for 1 h. The reaction mixture was concentrated in vacuo to give 3,5,6-trifluoro-2-methyl-4-(3-piperidinyl)-1H-indole-7-carboxamide (220 mg, crude material) as a yellow solid.

[0616] ESI-MS[M+H] + Calculated value (C 15 H 16 F3N3O)312.12, measured value: 312.10.

[0617] Step 3: 4-(1-acryloylpiperidin-3-yl)-3,5,6-trifluoro-2-methyl-1H-indole-7-carboxamide

[0618]

[0619] To a stirred solution of 3,5,6-trifluoro-2-methyl-4-(3-piperidinyl)-1H-indole-7-carboxamide (200 mg, crude material) in THF (6 mL) was added DIEA (223 mg, 1.73 mmol) and acryloyl chloride (52 mg, 0.58 mmol) at -70 ° C. The reaction mixture was stirred at -70 ° C for 1 h. 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 in vacuo. 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 NH 4 HCO 3 + 0.1% NH 3 .H 2 O), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 32% B to 53% B in 7 min; 220 nm; RT: 5.43 min to give 4-(1-acryloylpiperidin-3-yl)-3,5,6-trifluoro-2-methyl-1H-indole-7-carboxamide (107 mg, 23% over three steps) as an off-white solid.

[0620] 1H NMR(400MHz,DMSO-d6)δ10.96(s,1H),7.92(s,1H),7.84(s,1H),6.96-6.71(m,1H),6.1 9-6.03(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=12.4Hz,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).

[0621] ESI-MS[M+H] + Calculated value (C 18 H 18 F3N3O2)366.14, measured value: 366.15.

[0622] Step 4: (S)-4-(1-acryloylpiperidin-3-yl)-3,5,6-trifluoro-2-methyl-1H-indole-7-carboxamide and (R)-4-(1-acryloylpiperidin-3-yl)-3,5,6-trifluoro-2-methyl-1H-indole-7-carboxamide

[0623]

[0624] 4-(1-Acryloylpiperidin-3-yl)-3,5,6-trifluoro-2-methyl-1H-indole-7-carboxamide (90 mg) was separated by preparative chiral HPLC under the following conditions: column: CHIRALPAK IG, 2×25 cm, 5 μm; mobile phase A: hexane (0.5% 2M NH 3 -MeOH)--HPLC, mobile phase B: EtOH--HPLC; flow rate: 20 mL / min; gradient: 50% B to 50% B in 26 min; 220 / 254 nm.

[0625] Retention time: 12.231 min

[0626] 1H NMR(300MHz,DMSO-d6)δ10.96(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=1 3.2Hz,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).

[0627] ESI-MS[M+H] + Calculated value (C 18 H 18 F3N3O2)366.14, measured value: 366.15.

[0628] Retention time: 20.421 min

[0629] 1 H NMR(300MHz,DMSO-d6)δ10.96(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=1 3.2Hz,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).

[0630] ESI-MS[M+H] + Calculated value (C 18 H 18 F3N3O2)366.14, measured value: 366.15.

[0631] (S)-4-(1-Acryloylpiperidin-3-yl)-3,5,6-trifluoro-2-methyl-1H-indole-7-carboxamide (32.6 mg, 36%) as a white solid; (R)-4-(1-Acryloylpiperidin-3-yl)-3,5,6-trifluoro-2-methyl-1H-indole-7-carboxamide (32.2 mg, 36%) as a white solid.

[0632] Examples 7-19

[0633] Synthesis of compound 7-19

[0634] Compounds 7-19 shown in Table 5 below were prepared according to similar methods as described in the aforementioned schemes and examples by using the corresponding appropriate starting materials.

[0635] Table 5: Compounds 7-19

[0636]

[0637]

[0638]

[0639] Preparation of compounds of formula (II)

[0640]

[0641] Preparation of compounds of formula (II) wherein X is CH2, R 3 H and R II2 H

[0642]

[0643] Example 20

[0644] 4-(2-Acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-3-chloro-5-fluoro-2-methyl-1H-indole-7-carboxylate Synthesis of amide (Compound 20a)

[0645]

[0646] Step 1: 5-(7-Carbamoyl-5-fluoro-2-methyl-1H-indol-4-yl)-3,4-dihydroisoquinoline-2(1H)- tert-Butyl formate

[0647]

[0648] 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)-carboxylate (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 backfilled with nitrogen. The reaction mixture was stirred at 30° C. under nitrogen for 16 h, then diluted 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 in vacuo. The residue was purified by silica gel column chromatography (45% ethyl acetate in petroleum ether) to give tert-butyl 5-(7-carbamoyl-5-fluoro-2-methyl-1H-indol-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (2.50 g, 80%) as a yellow solid.

[0649] 1 H NMR(300MHz,DMSO-d6)δ11.03(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).

[0650] ESI-MS [M+H]+ calculated values ​​(C 24 H 26 FN3O3)424.20, measured value: 424.15.

[0651] Step 2: 5-(7-Carbamoyl-3-chloro-5-fluoro-2-methyl-1H-indol-4-yl)-3,4-dihydroisoquinoline-2 (1H)-tert-Butyl formate

[0652]

[0653] To a solution of tert-butyl 5-(7-carbamoyl-5-fluoro-2-methyl-1H-indol-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (3.0 g, 7.08 mmol) in N,N-dimethylformamide (30.0 mL) at 0°C was added N-chlorosuccinimide (1.00 g, 7.79 mmol). The reaction mixture was stirred at 0°C for 2 h. The reaction mixture was quenched with water (80 mL) and extracted with ethyl acetate (3 x 60 mL). The combined extracts were washed with brine (60 mL), dried over sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography (45% ethyl acetate in petroleum ether) to give tert-butyl 5-(7-carbamoyl-3-chloro-5-fluoro-2-methyl-1H-indol-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (2.30 g, 71%) as a yellow solid.

[0654] 1 H NMR(400MHz,DMSO-d6)δ11.42(s,1H),8.16(s,1H),7.70-7.56(m,2H),7.28-7.20(m,2 H),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).

[0655] ESI-MS [M+H-Boc] + calculated value (C 24 H 25 ClFN3O3)358.16, 360.16; Measured values: 358.05, 360.05

[0656] Step 3: 3-Chloro-5-fluoro-2-methyl-4-(1,2,3,4-tetrahydroisoquinolin-5-yl)-1H-indole-7-carboxamide

[0657]

[0658] A mixture of tert-butyl 5-(7-carbamoyl-3-chloro-5-fluoro-2-methyl-1H-indol-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (2.30 g, 5.02 mmol) and 4.0 M hydrogen chloride in dioxane (20 mL) was stirred at 20 ° C for 2 h. The reaction mixture was concentrated in vacuo. The residue was diluted with saturated aqueous sodium bicarbonate solution (150 mL) and extracted with ethyl acetate (3×100 mL). The combined extracts were dried over sodium sulfate and concentrated in vacuo to give 3-chloro-5-fluoro-2-methyl-4-(1,2,3,4-tetrahydroisoquinolin-5-yl)-1H-indole-7-carboxamide (1.70 g) as a brown solid.

[0659] ESI-MS [M+H]+ calculated values ​​(C19 H 17 ClFN3O)358.16, 360.16; measured values: 358.10, 360.10.

[0660] Step 4: 4-(2-Acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-3-chloro-5-fluoro-2-methyl-1H-indole Indole-7-carboxamide (Compound 20a)

[0661]

[0662] To a mixture of 3-chloro-5-fluoro-2-methyl-4-(1,2,3,4-tetrahydroisoquinolin-5-yl)-1H-indole-7-carboxamide (1.70 g, 4.75 mmol) in tetrahydrofuran (16 mL) and water (4.0 mL) at 0°C was added sodium bicarbonate (1.20 g, 14.3 mmol) and acryloyl chloride (430 mg, 4.75 mmol). The reaction mixture was stirred at 0°C for 2 h. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined extracts were washed with brine (50 mL), dried over sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography (75% ethyl acetate in petroleum ether) to give 4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-3-chloro-5-fluoro-2-methyl-1H-indole-7-carboxamide (1.20 g, 51%) as a white solid.

[0663] 1 H NMR (300MHz, DMSO-d6) δ11.45(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).

[0664] ESI-MS [M+H]+ calculated values ​​(C 22 H 19 ClFN3O2)412.11, 414.11; measured values: 412.05, 414.05.

[0665] Step 5: Separation of isomers

[0666] (R)-4-(2-Acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-3-chloro-5-fluoro-2-methyl-1H-indole- 7-Formamide (Compound 20b) and

[0667] (S)-4-(2-Acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-3-chloro-5-fluoro-2-methyl-1H-indole- 7-Formamide (Compound 20c) :

[0668]

[0669] 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% 2 M NH 3 -MeOH), mobile phase B: EtOH; flow rate: 20 mL / min; gradient: 30% B, isocratic, 16 min; 220 / 254 nm).

[0670] Compound 20b: retention time = 9.807 minutes (530 mg)

[0671] 1H NMR (400MHz, DMSO-d6) δ11.45(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).

[0672] ESI-MS [M+H]+ calculated values ​​(C 22 H 19 ClFN3O2)412.11, 414.11; measured values: 412.10, 414.10.

[0673] Compound 20c: retention time = 12.634 minutes (515 mg)

[0674] 1H NMR (400MHz, DMSO-d6) δ11.45(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).

[0675] ESI-MS [M+H]+ calculated values ​​(C 22 H 19 ClFN3O2)412.11, 414.11; measured values: 412.10, 414.10.

[0676] Compounds 20d-20i

[0677] The following compounds 20d-20i were prepared according to analogous procedures as described in the preceding schemes and examples by employing the corresponding appropriate starting materials (NA = not available).

[0678] Table 6: Compounds 20d-20i

[0679]

[0680]

[0681] Compound 20j: 5-fluoro-2,3-dimethyl-4-(2-propioloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-1H- Indole-7-carboxamide

[0682]

[0683] Compound 1j was prepared according to a similar procedure using propioloyl chloride instead of acryloyl chloride.

[0684] 1 H NMR (400MHz, DMSO-d6) δ10.84(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).

[0685] ESI-MS [M+H] + m / z = 390.15

[0686] Preparation of compounds of formula (II) wherein X is CH2, R 3 H and R II2 F

[0687]

[0688] Example 21

[0689] 4-(2-Acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-3-chloro-5,6-difluoro-2-methyl-1H-indole- Preparation of 7-formamide (Compound 21a)

[0690]

[0691] Step 1: 1,4-Dibromo-2,3-difluoro-5-nitrobenzene

[0692]

[0693] To a solution of 1,4-dibromo-2,3-difluorobenzene (25.0 g, 91.95 mmol) in concentrated sulfuric acid (200 mL) was added potassium nitrate (11.0 g, 108.8 mmol) at 0°C. The reaction mixture was stirred at 25°C for 16 h. The reaction mixture was poured into ice water (1 L) and stirred at 0°C for 30 min. The resulting precipitate was filtered, and the filter cake was washed with water and dried under reduced pressure to give 1,4-dibromo-2,3-difluoro-5-nitrobenzene (27.0 g, 92%) as a yellow solid.

[0694] 1 H NMR (300MHz, DMSO-d6) δ8.47 (dd, J=6.0, 2.4Hz 1H).

[0695] Step 2: 2,5-Dibromo-3,4-difluoroaniline

[0696]

[0697] To a solution of 1,4-dibromo-2,3-difluoro-5-nitrobenzene (27.0 g, 85.21 mmol) in acetic acid (260 mL) was added iron powder (47.6 g, 852.0 mmol). The reaction mixture was stirred at 45 ° C for 5 h. 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 2,5-dibromo-3,4-difluoroaniline (23.0 g, 94% yield) as a yellow solid.

[0698] 1 H NMR (300MHz, DMSO-d6) δ6.88 (dd, J=6.0, 2.4Hz 1H), 5.74 (brs, 2H).

[0699] Step 3: 2,5-Dibromo-3,4-difluoro-6-iodoaniline

[0700]

[0701] To a solution of 2,5-dibromo-3,4-difluoroaniline (23.0 g, 80.17 mmol) in acetic acid (250 mL) was added N-iodosuccinimide (19.84 g, 88.18 mmol). The reaction mixture was stirred at 25 ° C for 2 h. The reaction mixture was poured into ice water (500 mL) and filtered. The filter cake was washed with water (100 mL) and dried under reduced pressure. The crude product was purified by silica gel column chromatography and eluted with a petroleum ether solution of ethyl acetate (0 to 5%) to give 2,5-dibromo-3,4-difluoro-6-iodoaniline (30.0 g, 90%) as an off-white solid.

[0702] 1H NMR (300MHz, DMSO-d6) δ5.63 (s, 2H).

[0703] ESI-MS[MH] - Calculated values ​​(C6H2Br2F2IN) 409.76, 411.75, 413.75, found values: 409.75, 411.75, 413.70.

[0704] Step 4: 2,5-Dibromo-3,4-difluoro-6-(prop-1-yn-1-yl)aniline

[0705]

[0706] Under nitrogen, to 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 (PPh 3 ) 2 Cl 2 (5.12 g, 7.27 mmol) in triethylamine (365 mL) was added prop-1-yne (1 M THF solution, 364 mL). The reaction mixture was stirred at 50 ° C in a sealed flask for 4 h. The cooled reaction mixture was quenched with water (300 ml) and extracted with ethyl acetate (300 ml × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluted with a petroleum ether solution of ethyl acetate (0 to 10%) to give 2,5-dibromo-3,4-difluoro-6-(prop-1-yn-1-yl)aniline (20.0 g, 84%) as a yellow solid.

[0707] 1 H NMR (300MHz, DMSO-d6) δ5.79 (s, 2H), 2.18 (s, 3H).

[0708] ESI-MS[MH] - Calculated values ​​(C9H5Br2F2N) 321.88, 323.87, 325.87, found values: 322.00, 324.00, 326.00.

[0709] Step 5: 4,7-Dibromo-5,6-difluoro-2-methyl-1H-indole

[0710]

[0711] By 2,5-dibromo-3,4-difluoro-6-(prop-1-yn-1-yl)aniline (20.0g, 61.55mmol) and PdCl2(1.09g, 6.15mmol) in acetonitrile (400mL) mixture degassed and backfilled with nitrogen three times, and stirred at 85 DEG C for 5h.The cooled reaction mixture was concentrated in vacuo.The residue was purified by silica gel column chromatography, eluted with a solution of petroleum ether (0 to 10%) of ethyl acetate to give 4,7-dibromo-5,6-difluoro-2-methyl-1H-indole (17.0g, 85%) as a yellow solid.

[0712] 1 H NMR (300MHz, DMSO-d6) δ11.75(s,1H),6.28(s,1H),2.41(s,3H).

[0713] ESI-MS[MH] - Calculated values ​​(C9H5Br2F2N) 321.88, 323.87, 325.87, found values: 321.80, 323.80, 325.80.

[0714] Step 6: 4,7-Dibromo-5,6-difluoro-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- Indole

[0715]

[0716] 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) was added sodium hydride (1.60 g, 40.01 mmol, 60%) at 0°C. After stirring at this temperature for 1 h, 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 h. 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 in vacuo. The residue was purified by silica gel column chromatography eluting with ethyl acetate in petroleum ether (0 to 10%) to give 4,7-dibromo-5,6-difluoro-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole (12.3 g, 87%) as a yellow oil.

[0717] 1H NMR (300MHz, DMSO-d6) δ6.42 (s, 1H), 5.78 (s, 2H), 3.55 (t, J = 7.8 Hz, 2H), 2.47 (s, 3H), 0.83 (t, J = 8.1 Hz, 2H), -0.08 (s, 9H).

[0718] Step 7: 4-Bromo-5,6-difluoro-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole Indole-7-carboxylic acid

[0719]

[0720] 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) was added n-butyllithium (2.5 M in n-hexane, 13 mL, 32.5 mmol) at -70°C under nitrogen. After stirring at this temperature for 0.5 h and at 0°C for 0.5 h, the reaction mixture was cooled to -70°C and bubbled with carbon dioxide for 30 min. After stirring at 25°C for 1.5 h, the reaction mixture was quenched with saturated aqueous ammonium chloride (100 mL) and extracted with dichloromethane (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to give 4-bromo-5,6-difluoro-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7-carboxylic acid (11.4 g, crude) as a yellow oil.

[0721] ESI-MS[MH] - Calculated value (C 16 H 20 BrF2NO3Si)418.04, 420.03, measured values: 417.95, 419.95.

[0722] Step 8: 4-Bromo-5,6-difluoro-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole Indole-7-carboxamide

[0723]

[0724] 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) at 0° C., HATU (12.38 g, 32.55 mmol) and DIPEA (17.53 g, 135.61 mmol) were added. After stirring at 25° C. for 16 h, the reaction mixture was quenched with water (300 ml) and extracted with ethyl acetate (300 ml×3). The combined organic layers were washed with brine (200 ml×3), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with ethyl acetate in petroleum ether (0 to 50%) to give 4-bromo-5,6-difluoro-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7-carboxamide (6.3 g, 55%) as a yellow solid.

[0725] 1 H NMR (300MHz, DMSO-d6) δ8.34(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).

[0726] ESI-MS[M+H] + Calculated value (C 16 H 21 BrF2N2O2Si)419.05, 421.05, measured values: 419.20, 421.20.

[0727] Step 9: 4-Bromo-5,6-difluoro-2-methyl-1H-indole-7-carboxamide

[0728]

[0729] A 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) in THF (60 mL) was stirred at 75 ° C. for 40 h. The reaction mixture was cooled to 0 ° C. and acidified with 2M hydrochloric acid until pH = 4. The precipitate was collected by filtration, washed with water (100 mL) and dried under reduced pressure to give 4-bromo-5,6-difluoro-2-methyl-1H-indole-7-carboxamide (3.5 g, 80%) as a yellow solid.

[0730] 1 H NMR (300MHz, DMSO-d6) δ11.38(s,1H),7.97(s,1H),7.90(s,1H),6.20(s,1H),2.40(s,3H).

[0731] ESI-MS[M+H] + Calculated value (C 10 H7BrF2N2O)288.97, 290.97, measured values: 288.95, 290.95.

[0732] Step 10: 5-(7-Carbamoyl-5,6-difluoro-2-methyl-1H-indol-4-yl)-3,4-dihydroisoquinoline-2 (1H)-tert-Butyl formate

[0733]

[0734] A mixture of 4-bromo-5,6-difluoro-2-methyl-1H-indole-7-carboxamide (250 mg, 0.864 mmol), tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (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 and backfilled with nitrogen five times and stirred at 90 ° C for 2 h. 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 in vacuo. The residue was purified by silica gel column chromatography eluting with ethyl acetate in petroleum ether (0 to 38%) to give tert-butyl 5-(7-carbamoyl-5,6-difluoro-2-methyl-1H-indol-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (340 mg, 89%) as a white solid.

[0735] 1 H NMR (300MHz, DMSO-d6) δ11.11(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).

[0736] ESI-MS[M+H-tBu] + Calculated value (C 24 H 25 F2N3O3)386.19, measured value: 386.15.

[0737] Step 11: 5-(7-Carbamoyl-3-chloro-5,6-difluoro-2-methyl-1H-indol-4-yl)-3,4-dihydroisothiazolinone tert-Butyl quinoline-2(1H)-carboxylate

[0738]

[0739] To a solution of tert-butyl 5-(7-carbamoyl-5,6-difluoro-2-methyl-1H-indol-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (250 mg, 0.566 mmol) in DMF (5 mL) was added NCS (91 mg, 0.679 mmol) at 0 ° C. After stirring at 10 ° C for 2 h, 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 in vacuo. The residue was purified by preparative TLC (30% ethyl acetate in petroleum ether) to give tert-butyl 5-(7-carbamoyl-3-chloro-5,6-difluoro-2-methyl-1H-indol-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (200 mg, 74%) as a yellow solid.

[0740] 1 H NMR(300MHz,DMSO-d6)δ11.52(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).

[0741] ESI-MS[M+H-tBu] + Calculated value (C 24 H 24 ClF2N3O3)420.15, 422.15, measured values: 420.05, 422.05.

[0742] Step 12: 3-Chloro-5,6-difluoro-2-methyl-4-(1,2,3,4-tetrahydroisoquinolin-5-yl)-1H-indole-7-carboxylate Amide hydrochloride

[0743]

[0744] A mixture of tert-butyl 5-(7-carbamoyl-3-chloro-5,6-difluoro-2-methyl-1H-indol-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (240 mg, 0.504 mmol) and hydrogen chloride (4 M in dioxane, 5 mL) was stirred for 2 h at 20° C. The mixture was concentrated in vacuo to give 3-chloro-5,6-difluoro-2-methyl-4-(1,2,3,4-tetrahydroisoquinolin-5-yl)-1H-indole-7-carboxamide hydrochloride (200 mg, crude) as a brown solid.

[0745] ESI-MS[M+H] + Calculated value (C 19 H 16 ClF2N3O)376.09, 378.09, measured values: 376.05, 378.05.

[0746] Step 13: 4-(2-Acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-3-chloro-5,6-difluoro-2-methyl- 1H-Indole-7-carboxamide

[0747]

[0748] To a mixture of 3-chloro-5,6-difluoro-2-methyl-4-(1,2,3,4-tetrahydroisoquinolin-5-yl)-1H-indole-7-carboxamide hydrochloride (200 mg, 0.485 mmol) in tetrahydrofuran (4 mL) and water (1 mL) at 0°C was added sodium bicarbonate (204 mg, 2.43 mmol) and acryloyl chloride (44 mg, 0.485 mmol). After stirring at 0°C for 1 h, the reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, and concentrated in vacuo. 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 NH 4 HCO 3 + 0.1% NH 3 .H 2 O), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 30% B to 60% B in 7 min; 220 nm; Rt: 6.32 min to give 4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-3-chloro-5,6-difluoro-2-methyl-1H-indole-7-carboxamide (80 mg, 38%) as a white solid.

[0749] 1H NMR(400MHz,DMSO-d6)δ11.54(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).

[0750] ESI-MS[M+H] + Calculated value (C 22 H 18 ClF2N3O2)430.11, 432.11, measured values: 430.05, 432.05.

[0751] Step 14: Separation of isomers:

[0752] (R)-4-(2-Acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-3-chloro-5,6-difluoro-2-methyl-1H-indole-7-carboxamide (Compound 21b) and (S)-4-(2-Acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-3-chloro-5,6-difluoro-2-methyl-1H-indole-7-carboxamide (Compound 21c):

[0753]

[0754] Two atropisomers of 4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-3-chloro-5,6-difluoro-2-methyl-1H-indole-7-carboxamide were prepared by preparative chiral HPLC according to the procedure as described herein:

[0755] 1 H NMR(300MHz,DMSO-d6)δ11.54(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,

[0756] 3H). LC-MS: m / z=430.05,432.05[M+H] + .

[0757] 1 H NMR (300MHz, DMSO-d6) δ11.54(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,

[0758] 1H),5.75-5.66(m,1H),4.88-4.77(m,2H),3.77-3.62(m,2H),2.46-2.36(m,

[0759] 2H),2.31(s,3H). LC-MS: m / z=430.05,432.05[M+H] + .

[0760] Compounds 21d-21e

[0761] Compounds 21d and 21e were prepared according to analogous methods as described in the previous schemes and examples by employing the corresponding appropriate starting materials.

[0762] Table 7-1: Compounds 21D and 21E

[0763]

[0764]

[0765] Preparation of compounds of formula (II) wherein X is CH2, R 3 For Me

[0766]

[0767] Example 22

[0768] 4-(2-Acryloyl-1-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-3-chloro-5-fluoro-2-methyl-1H-indole Synthesis of Indole-7-carboxamide (Compound 22a)

[0769]

[0770] Step 1: N-(2-bromophenethyl)acetamide

[0771]

[0772] To a stirred solution of 2-(2-bromophenyl)ethyl-1-amine (5.0 g, 25.0 mmol) in DCM (25 mL) and pyridine (50 mL) was added acetyl chloride (1.96 g, 24.99 mmol) at 0 ° C. After addition, the reaction mixture was stirred at 25 ° C for 1.5 h. 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 in vacuo. The concentrate was purified by silica gel column chromatography (5% methanol in dichloromethane) to give N-(2-bromophenethyl)acetamide (4.8 g, 79%) as a yellow oil.

[0773] 1 H NMR (300MHz, DMSO-d6) δ7.96 (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).

[0774] ESI-MS[M+H] + Calculated value (C 10 H 12 BrNO) 242.01, 244.01; measured values: 242.10, 244.10.

[0775] Step 2: 7-Bromo-10b-methyl-6,10b-dihydro-5H-oxazolo[2,3-a]isoquinoline-2,3-dione

[0776]

[0777] To a solution of N-(2-bromophenethyl)acetamide (5.0 g, 20.7 mmol) in DCM (70 mL) was added oxalyl chloride (4.72 g, 37.2 mmol) dropwise at 0 ° C. The mixture was stirred at 0 ° C for 2 h and then at 25 ° C for 3 h. The reaction mixture was cooled to 0 ° C and FeCl3 (4.02 g, 24.8 mmol) was added in batches. The reaction mixture was warmed to 25 ° C and stirred for 16 h. The reaction mixture was diluted with 12M aqueous ammonia (50 mL) and extracted with DCM (3×30 mL). The combined extracts were washed with brine (50 mL), dried over sodium sulfate and concentrated in vacuo to give 7-bromo-10b-methyl-6,10b-dihydro-5H-oxazolo[2,3-a]isoquinoline-2,3-dione (6.0 g) as a brown solid, which was used without purification.

[0778] ESI-MS[M+H] + Calculated value (C 12 H 10BrNO3)295.98, 297.98; measured values: 296.05, 298.05.

[0779] Step 3: 5-Bromo-1-methyl-3,4-dihydroisoquinoline

[0780]

[0781] To 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 added concentrated sulfuric acid (1.99 g, 20.3 mmol). The reaction mixture was heated at 65 ° C for 20 h. The reaction mixture was diluted with 12M aqueous ammonia at 0 ° C. The 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 in vacuo to give 5-bromo-1-methyl-3,4-dihydroisoquinoline (3.9 g, 86%) as a brown oil.

[0782] 1 H NMR (400MHz, DMSO-d6) δ7.68 (d, J = 8.0 Hz, 1H), 7.59 (d, J = 8.0 Hz, 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).

[0783] ESI-MS[M+H] + Calculated value (C 12 H 10 BrNO3)224.00, 226.00; measured values: 224.10, 226.10.

[0784] Step 4: 5-Bromo-1-methyl-1,2,3,4-tetrahydroisoquinoline

[0785]

[0786] To a solution of 5-bromo-1-methyl-3,4-dihydroisoquinoline (3.9 g, 17.4 mmol) in ethanol (100 mL) at 0° C. was added sodium borohydride (658 mg, 17.4 mmol). The reaction mixture was stirred at 0° C. for 2 h, diluted with water (100 mL) and extracted with DCM (3×100 mL). The combined extracts were washed with brine (100 mL), dried over sodium sulfate and concentrated in vacuo to give 5-bromo-1-methyl-1,2,3,4-tetrahydroisoquinoline (2.75 g, 70%) as a brown solid.

[0787] 1H NMR (300MHz, DMSO-d6) δ7.40(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).

[0788] ESI-MS[M+H] + Calculated value (C 10 H 12 BrN)226.02, 228.02; measured values: 226.15, 228.11.

[0789] Step 5: tert-Butyl 5-bromo-1-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate

[0790]

[0791] 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) was added di-tert-butyl dicarbonate (2.65 g, 12.2 mmol). The reaction mixture was stirred at 25 ° C for 3 h, quenched with water (50 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 in vacuo. The residue was purified by silica gel column chromatography (7% ethyl acetate in petroleum ether) to give tert-butyl 5-bromo-1-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (3.1 g, 78%) as a white solid.

[0792] 1 H NMR (300MHz, DMSO-d6) δ7.48(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).

[0793] ESI-MS[M+H-Boc] + Calculated value (C 15 H 20 BrNO2)226.07, 228.07; measured values: 226.05, 228.05.

[0794] Step 6: 1-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisothiazolinone tert-Butyl quinoline-2(1H)-carboxylate

[0795]

[0796] A mixture of tert-butyl 5-bromo-1-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (3.5 g, 10.7 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(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 backfilled with nitrogen. The reaction mixture was heated at 100 ° C. under nitrogen for 2 h. 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 in vacuo. The residue was purified by silica gel column chromatography (60% ethyl acetate in petroleum ether) to give tert-butyl 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylate (4.0 g, 89%) as a yellow oil.

[0797] 1 H NMR(300MHz, DMSO-d6)δ7.52(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).

[0798] ESI-MS[M+H-Boc] + Calculated value (C 21 H 32 BNO4)274.24, measured value: 274.25.

[0799] Step 7: 4-Bromo-5-fluoro-2-methyl-1H-indole-7-carboxylic acid

[0800]

[0801] To a stirred solution of 4-bromo-5-fluoro-2-nitrobenzoic acid (17 g, 64.4 mmol) in THF (200 mL) was added propane-1-en-2-ylmagnesium bromide (451 mL, 225 mmol, 0.5 M THF solution) at -70 ° C under nitrogen. After addition, the reaction mixture was stirred at -70 ° C for 3 h. 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 anhydrous sodium sulfate and concentrated in vacuo to give 4-bromo-5-fluoro-2-methyl-1H-indole-7-carboxylic acid (17.5 g) as a brown solid. The solid was used further without purification.

[0802] ESI-MS[MH] - Calculated value (C 10 H7BrFNO2)269.96, 271.96; measured values: 270.25, 272.25.

[0803] Step 8: 4-Bromo-5-fluoro-2-methyl-1H-indole-7-carboxamide

[0804]

[0805] To a stirred solution of 4-bromo-5-fluoro-2-methyl-1H-indole-7-carboxylic acid (17.5 g, 64.4 mmol), ammonia hydrochloride (5.17 g, 96.6 mmol) and HATU (29.4 g, 77.3 mmol) in DMF (200 mL) was added N-ethyl-N-isopropyl-propan-2-amine (25.0 g, 193 mmol). The reaction mixture was stirred at 25 ° C for 16 h. 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), brine (200 mL), then dried over anhydrous sodium sulfate and concentrated in vacuo. The concentrate was purified by column chromatography (50% ethyl acetate in petroleum ether) to give 4-bromo-5-fluoro-2-methyl-1H-indole-7-carboxamide (3.8 g, 22%) as a yellow solid.

[0806] 1 H NMR (400MHz, DMSO-d6) δ11.26(s,1H),8.11(s,1H),7.63-7.53(m,2H),6.19(s,1H),2.42(s,3H).

[0807] ESI-MS[M+H] + Calculated value (C 10 H8BrFN2O)270.98, 272.98; measured values: 270.90, 272.90.

[0808] Step 9: 5-(7-Carbamoyl-5-fluoro-2-methyl-1H-indol-4-yl)-1-methyl-3,4-dihydroisoquinoline tert-Butyl 2(1H)-methylenecarboxylate

[0809]

[0810] 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-carboxylic acid tert-butyl ester (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 backfilled with nitrogen. The reaction mixture was stirred at 30 ° C. under nitrogen for 16 h, 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 in vacuo. The concentrate was purified by silica gel column chromatography (55% ethyl acetate in petroleum ether) to give tert-butyl 5-(7-carbamoyl-5-fluoro-2-methyl-1H-indol-4-yl)-1-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (500 mg, 78%) as a yellow solid.

[0811] 1 H NMR(300MHz,DMSO-d6)δ11.05(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).

[0812] ESI-MS[M+H] + Calculated value (C 25 H 28 FN3O3)438.21, measured value: 438.30.

[0813] Step 10: 5-Fluoro-2-methyl-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-1H-indole-7-carboxamide amine

[0814]

[0815] A mixture of tert-butyl 5-(7-carbamoyl-5-fluoro-2-methyl-1H-indol-4-yl)-1-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (500 mg, 1.14 mmol) and hydrogen chloride (4 M in dioxane, 10 mL) was stirred at 25 ° C for 1 h. The reaction mixture was concentrated in vacuo. 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 in vacuo to give 5-fluoro-2-methyl-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-1H-indole-7-carboxamide (370 mg, 89%) as a yellow solid.

[0816] ESI-MS[M+H] + Calculated value (C 20 H 20 FN3O)338.16, measured value: 338.15.

[0817] Step 11: 4-(2-Acryloyl-1-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-2-methyl-1H- Indole-7-carboxamide

[0818]

[0819] To a stirred mixture of 5-fluoro-2-methyl-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-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) at 0°C was added acryloyl chloride (99 mg, 1.10 mmol). The reaction mixture was stirred at 0°C for 0.5 h. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (3 x 30 mL). The combined extracts were washed with brine (30 mL), dried over sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography (75%-100% ethyl acetate in petroleum ether) to give 4-(2-acryloyl-1-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-2-methyl-1H-indole-7-carboxamide (290 mg, 67%) as a yellow solid.

[0820] 1H NMR(300MHz,DMSO-d6)δ11.09-11.00(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).

[0821] ESI-MS[M+H] + Calculated value (C 23 H 22 FN3O2)392.17, measured value: 392.15.

[0822] Step 12: 4-(2-Acryloyl-1-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-3-chloro-5-fluoro-2-methylpropane 1H-indole-7-carboxamide

[0823]

[0824] To a stirred solution of 4-(2-acryloyl-1-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-2-methyl-1H-indole-7-carboxamide (230 mg, 0.59 mmol) in DMF (5.0 mL) at 0°C was added 1-chloropyrrolidine-2,5-dione (78 mg, 0.59 mmol). The reaction mixture was stirred at 0°C for 1 h. The reaction mixture was diluted with water (25 mL) and extracted with ethyl acetate (3 x 20 mL). The combined extracts were washed with brine (30 mL), dried over sodium sulfate, and concentrated in vacuo. 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 NH 4 HCO 3 + 0.1% NH 3 · H 2 O), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: 40% B to 60% B in 7 min; 220 nm; RT: 6.00 minutes) to give 4-(2-acryloyl-1-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-3-chloro-5-fluoro-2-methyl-1H-indole-7-carboxamide (110 mg, 44%) as a white solid.

[0825] 1H NMR (400MHz, DMSO-d6) δ11.55-11.40(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).

[0826] ESI-MS[M+H] + Calculated value (C 23 H 21 ClFN3O2)426.13, found: 426.25.

[0827] Step 13: Separation of isomers

[0828]

[0829] 4-(2-Acryloyl-1-methyl-1,2,3,4-tetrahydroisoquinolin-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 material was passed through a CHIRALPAKIG (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 min; 220 / 254 nm to obtain four compounds with the following retention times:

[0830] Compound 22b: retention time = 11.342 minutes (16.4 mg)

[0831] 1 H NMR (400MHz, methanol-d4) δ7.55 (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).

[0832] ESI-MS[M+H] + Calculated value (C 23 H 21 ClFN3O2)426.13, measured value: 426.05.

[0833] Compound 22c: retention time = 18.98 minutes (19.5 mg)

[0834] 1 H NMR (400MHz, methanol-d4) δ7.51 (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) ,4.36-3.92(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).

[0835] ESI-MS[M+H] + Calculated value (C 23 H 21 ClFN3O2)426.13, measured value: 426.05.

[0836] Compound 22d

[0837] The material eluting at 14.331 minutes was then chromatographed on a CHIRAL ART Cellulose-SC (2×25 cm, 5 μm); mobile phase A: hexane (0.5% 2M NH 3 -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).

[0838] 1H NMR (400MHz, methanol-d4) δ7.51 (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).

[0839] ESI-MS[M+H] + Calculated value (C 23 H 21 ClFN3O2)426.13, measured value: 426.05.

[0840] Compound 22e

[0841] The material eluting at 15.677 minutes was then chromatographed on a CHIRAL ART Cellulose-SC (2×25 cm, 5 μm); mobile phase A: hexane (0.5% 2M NH 3 -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).

[0842] 1 H NMR (400MHz, methanol-d4) δ7.51 (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).

[0843] ESI-MS [M+H]+ calculated values ​​(C 23 H 21 ClFN3O2)426.13, measured value: 426.05.

[0844] Compounds 22f-22i

[0845] The compounds listed in Table 8-1 were prepared according to similar methods as described in the aforementioned schemes and examples by using the corresponding appropriate starting materials.

[0846] Table 8-1: Compounds 22F-22I

[0847]

[0848] Preparation of compounds of formula (II) wherein X is CH2, R 3 Cyclopropyl

[0849]

[0850] Example 23

[0851] 4-(2-Acryloyl-1-cyclopropyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-2-methyl-1H-indole- Synthesis of 7-formamide (Compound 23)

[0852]

[0853] Compound 23 was prepared according to similar procedures as described herein.

[0854] 1 H NMR(400MHz,DMSO-d6)δ11.18-10.92(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).

[0855] LC-MS: m / z = 418.15 [M+H] + .

[0856] Preparation of compounds of formula (II) wherein X is -CR x1 R x2 -, and R x1 and R x2 and the C atoms to which they are attached Form C 3-6 carbon ring

[0857]

[0858] Example 24

[0859] 4-(2'-Acryloyl-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinolin]-5'-yl)-3-chloro-5- Synthesis of Fluoro-2-methyl-1H-indole-7-carboxamide (Compound 24a)

[0860]

[0861] Step 1: 3-Bromo-2-(3-cyanopropoxy)benzonitrile

[0862]

[0863] A mixture of 3-bromo-2-hydroxybenzonitrile (10 g, 50.5 mmol), 4-bromobutyronitrile (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 h. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (3×100 mL). The combined extracts were washed with brine (120 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (0 to 40% ethyl acetate in petroleum ether) to give 3-bromo-2-(3-cyanopropoxy)benzonitrile (12.0 g, 89%) as a colorless oil.

[0864] 1 H NMR(300MHz,DMSO-d6)δ8.03(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).

[0865] Step 2: 9-Bromo-1,2-dihydrofuro[2,3-c]isoquinolin-5-amine

[0866]

[0867] A mixture of 3-bromo-2-(3-cyanopropoxy)benzonitrile (1.0 g, 3.77 mmol) and potassium 2-methylpropan-2-ol (847 mg, 7.54 mmol) in dioxane (30 mL) was heated at 95 ° C for 1 h. The reaction mixture was diluted 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 in vacuo. The residue was purified by silica gel column chromatography (0 to 50% ethyl acetate in petroleum ether) to give 9-bromo-1,2-dihydrofuro[2,3-c]isoquinolin-5-amine (300 mg, 30%) as a yellow solid.

[0868] 1H NMR (400MHz, DMSO-d6) δ8.11 (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).

[0869] ESI-MS[M+H] + Calculated value (C 11 H9BrN2O) 265.11, 267.11; measured values: 265.10, 267.10.

[0870] Step 3: 5'-Bromo-1'H-spiro[cyclopropane-1,4'-isoquinoline]-1',3'(2'H)-dione

[0871]

[0872] A mixture of 5'-bromo-1'H-spiro[cyclopropane-1,4'-isoquinoline]-1',3'(2'H)-dione and 9-bromo-1,2-dihydrofuro[2,3-c]isoquinolin-5-amine (1.80 g, 6.78 mmol) in concentrated hydrochloric acid (100 mL) was heated at 100°C for 3 h. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (3 x 150 mL). The combined extracts were washed with brine (150 mL), dried over sodium sulfate, and concentrated in vacuo. 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 h. The reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (3 x 40 mL). The combined extracts were washed with brine (50 mL), dried over sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography (0 to 60% ethyl acetate in petroleum ether) to provide 5'-bromo-l'H-spiro[cyclopropane-l,4'-isoquinoline]-l',3'(2'H)-dione (1.0 g, 55%) as a white solid.

[0873] 1 H NMR (300MHz, DMSO-d6) δ7.43 (d, J = 8.1 Hz, 1H), 7.20 (d, J = 8.4 Hz, 1H), 7.11-7.01 (m, 1H), 1.93-1.81 (m, 2H), 0.86-0.77 (m, 2H).

[0874] ESI-MS [MH]-calculated (C 11 H8BrNO2)263.97, 265.97; measured values: 264.00, 266.00.

[0875] Step 4: 5'-Bromo-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline]

[0876]

[0877] To a mixture of sodium borohydride (600 mg, 15.8 mmol) in THF (30 mL) at 0°C was added BF3.Et2O (3.00 g, 21.1 mmol). After stirring at this temperature for 1 h, 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 h. The reaction mixture was quenched with water (60 mL) and extracted with ethyl acetate (3 x 50 mL). The combined extracts were washed with brine (50 mL), dried over sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography (80% ethyl acetate in petroleum ether) to give 5'-bromo-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline (480 mg, 38%) as a white solid.

[0878] ESI-MS [M+H]+ calculated values ​​(C 11 H 12 BrN) 238.02, 240.02; measured values: 238.10, 240.10.

[0879] Step 5: 1-(5'-Bromo-1'H-spiro[cyclopropane-1,4'-isoquinolinyl]-2'(3'H)-yl)prop-2-en-1-one

[0880]

[0881] At 0 ° C, sodium bicarbonate (850 mg, 10.1 mmol) and acryloyl chloride (180 mg, 2.02 mmol) were added 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). The reaction mixture was stirred at 0 ° C for 1.5 h. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (3×25 mL). The combined extracts were washed with brine (30 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (40% ethyl acetate in petroleum ether) to give 1-(5'-bromo-1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-yl)prop-2-en-1-one (350 mg, 59%) as a yellow solid.

[0882] 1H NMR (400MHz, DMSO-d6) δ7.47(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 ),5.76-5.67(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).

[0883] ESI-MS [M+H]+ calculated values ​​(C 14 H 14 BrNO) 292.03, 294.03; measured values: 292.00, 294.00.

[0884] Step 6: 4-(2'-Acryloyl-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinolin]-5'-yl)-5- Fluoro-2-methyl-1H-indole-7-carboxamide (Compound 5b)

[0885]

[0886] 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'-isoquinolin]-2'(3'H)-yl)prop-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 backfilled with nitrogen. The reaction mixture was heated at 80° C. under nitrogen for 16 h. 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 in vacuo. The residue was purified by silica gel column chromatography (80% ethyl acetate in petroleum ether) to give 4-(2'-acryloyl-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinolin]-5'-yl)-5-fluoro-2-methyl-1H-indole-7-carboxamide (170 mg, 56%) as a green solid.

[0887] 1H NMR(400MHz,DMSO-d6)δ11.06(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 ),6.22-6.10(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).

[0888] ESI-MS[M+H] + Calculated value (C 24 H 22 FN3O2)404.17, measured value: 404.30.

[0889] Step 7: 4-(2'-Acryloyl-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinolin]-5'-yl)-3- Chloro-5-fluoro-2-methyl-1H-indole-7-carboxamide (Compound 5a)

[0890]

[0891] To a solution of 4-(2'-acryloyl-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinolin]-5'-yl)-5-fluoro-2-methyl-1H-indole-7-carboxamide (170 mg, 0.421 mmol) in DMF (6.0 mL) at 0°C was added NCS (56.0 mg, 0.421 mmol). The reaction mixture was stirred at 0°C for 2 h. The reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (3 x 15 mL). The combined extracts were washed with brine (3 x 20 mL), dried over sodium sulfate, and concentrated in vacuo. The residue was purified by preparative HPLC (column: Xselect CSH OBD column, 30×150 mm, 5 μm; mobile phase A: water (10 mmol / L NH 4 HCO 3 + 0.1% NH 3 .H 2 O), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 38% B to 58% B, 7 min; 220 nm; retention time = 5.32 minutes) to give 4-(2′-acryloyl-2′,3′-dihydro-1′H-spiro[cyclopropane-1,4′-isoquinolin]-5′-yl)-3-chloro-5-fluoro-2-methyl-1H-indole-7-carboxamide (32.6 mg, 17%) as a white solid.

[0892] 1H NMR(400MHz,DMSO-d6)δ11.43(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).

[0893] ESI-MS[M+H] + Calculated value (C 24 H 21 ClN3O2)438.13, measured value: 438.15.

[0894] Step 8: Separation of isomers

[0895] (R)-4-(2'-Acryloyl-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinolin]-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'-isoquinolin]-5'-yl)-3-chloro-5-fluoro-2-methyl-1H-indole-7-carboxamide (Compound 24d):

[0896]

[0897] The two atropisomers were separated by preparative chiral HPLC (sample amount = 24 mg, column: CHIRALPAK IE, 2 x 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):

[0898] Compound 24c: retention time = 8.078 minutes (7.9 mg)

[0899] 1H NMR (400 MHz, methanol-d4) δ 7.50 (d, J = 10.0 Hz, 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).

[0900] ESI-MS[M+H] + Calculated value (C 24 H 21 ClN3O2) 438.13, measured value: 438.10

[0901] Compound 24d: retention time = 9.991 minutes (7.6 mg)

[0902] 1 H NMR (400 MHz, methanol-d4) δ 7.50 (d, J = 10.0 Hz, 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).

[0903] ESI-MS[M+H] + Calculated value (C 24 H 21 ClN3O2)438.13, measured value: 438.10.

[0904] Preparation of compounds of formula (II) wherein X is -CH2CH2-

[0905]

[0906] Example 25

[0907] 4-(2-Acryloyl-2,3,4,5-tetrahydro-1H-benzo[c]azepin-6-yl)-3-chloro-5-fluoro-2-methyl- Synthesis of 1H-indole-7-carboxamide (Compound 25a)

[0908]

[0909] Step 1: 5-Fluoro-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole Indole-7-carboxamide

[0910]

[0911] 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'-bis(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 backfilled with nitrogen. The reaction mixture was heated at 100° C. under nitrogen for 2 h. The cooled reaction mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (0 to 30% ethyl acetate in petroleum ether) to give 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.

[0912] ESI-MS[M+H] + Calculated value (C 16 H 20 BFN2O3)319.16, measured value: 319.25.

[0913] Step 2: 6-Bromo-2,3,4,5-tetrahydro-1H-benzo[c]azepin-1-one

[0914]

[0915] A mixture of 5-bromonetalin-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 at 90° C. for 2 h under nitrogen. 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 (100 mL), dried over sodium sulfate and concentrated in vacuo. The residue was dissolved in polyphosphoric acid (100 mL) and stirred at 100° C. for 2 h. The cooled reaction mixture was basified with aqueous sodium hydroxide solution and extracted with ethyl acetate (4×150 mL). The combined extracts were washed with brine (200 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (0 to 10% ethyl acetate in petroleum ether) to give 6-bromo-2,3,4,5-tetrahydro-2-benzazepin-1-one (2.7 g, 48%) as a brown solid.

[0916] ESI-MS[M+H] + Calculated value (C 10 H10 BrNO)239.99, 241.99; measured values: 240.00, 242.00.

[0917] Step 3: 6-Bromo-2,3,4,5-tetrahydro-1H-benzo[c]azepine

[0918]

[0919] To 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 added borane (1 M in THF, 112 mL, 112 mmol). The reaction mixture was heated at 70 ° C for 3 h. The cooled reaction mixture was diluted with methanol (100 mL) and concentrated in vacuo. The residue was purified by silica gel column chromatography (0 to 12% ethyl acetate in petroleum ether) to give 6-bromo-2,3,4,5-tetrahydro-1H-benzo [c] azepine (2.4 g, 94%) as a colorless oil.

[0920] 1 H NMR(400MHz,DMSO-d6)δ6.96(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).

[0921] ESI-MS[M+H] + Calculated value (C 10 H 12 BrN)226.02, 228.02; measured values: 226.15, 228.15.

[0922] Step 4: 1-(6-Bromo-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)prop-2-en-1-one

[0923]

[0924] To 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 added 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 h. Water (20 mL) was added. The mixture was extracted with ethyl acetate (3 × 20 mL). The combined extracts were washed with brine (40 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (0 to 15% ethyl acetate in petroleum ether) to give 1-(6-bromo-4,5-dihydro-1H-benzo[c]azepine-2(3H)-yl)prop-2-en-1-one (1.6 g, 80%) as a white solid.

[0925] 1 H NMR (300MHz, DMSO-d6) δ7.63(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).

[0926] ESI-MS[M+H] + Calculated value (C 13 H 14 BrNO) 280.03, 282.03; measured values: 280.10, 282.10.

[0927] Step 5: 4-(2-Acryloyl-2,3,4,5-tetrahydro-1H-benzo[c]azepin-6-yl)-5-fluoro-2-methyl- 1H-Indole-7-carboxamide (Compound 25b)

[0928]

[0929] A mixture of 1-(6-bromo-1,3,4,5-tetrahydro-2-benzazepin-2-yl)prop-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 backfilled with nitrogen. The reaction mixture was heated at 80° C. under nitrogen for 16 h. 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 in vacuo. The residue was purified by silica gel column chromatography (0 to 70% ethyl acetate in petroleum ether) to give 5-fluoro-2-methyl-4-(2-prop-2-enoyl-1,3,4,5-tetrahydro-2-benzazepin-6-yl)-1H-indole-7-carboxamide (500 mg, 61%) as a white solid.

[0930] 1 H NMR (400MHz, DMSO-d6) δ11.08(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).

[0931] ESI-MS[M+H] + Calculated value (C 23 H 22 FN3O2)392.17, measured value: 392.30.

[0932] Step 6: 4-(2-Acryloyl-2,3,4,5-tetrahydro-1H-benzo[c]azepin-6-yl)-3-chloro-5-fluoro-1H- Indole-7-carboxamide (Compound 25a)

[0933]

[0934] To a stirred solution of 5-fluoro-2-methyl-4-(2-prop-2-enoyl-1,3,4,5-tetrahydro-2-benzazepin-6-yl)-1H-indole-7-carboxamide (150 mg, 0.38 mmol) in N,N-dimethylformamide (5.0 mL) at 0°C was added N-chlorosuccinimide (51 mg, 0.38 mmol). The reaction mixture was stirred at 0°C for 1 h. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (3 x 25 mL). The combined extracts were washed with brine (30 mL), dried over sodium sulfate, and concentrated in vacuo. 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 NH 4 HCO 3 + 0.1% NH 3 .H 2 O), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 40% B to 60% B in 7 min; 220 nm; RT: 5.45 min) to give 3-chloro-5-fluoro-2-methyl-4-(2-prop-2-enoyl-1,3,4,5-tetrahydro-2-benzazepin-6-yl)-1H-indole-7-carboxamide (80 mg, 49%) as a mixture of atropisomers.

[0935] 1 H NMR (400MHz, DMSO-d6) δ11.46(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).

[0936] ESI-MS[M+H] + Calculated value (C 23 H 21 ClFN3O2)426.13, 428.13; measured values: 426.25, 428.25.

[0937] Step 7: Separation of isomers

[0938] (R)-3-Chloro-5-fluoro-2-methyl-4-(2-prop-2-enoyl-1,3,4,5-tetrahydro-2-benzazepin-6-yl)-1H-indole-7-carboxamide (Compound 25c) and (S)-3-Chloro-5-fluoro-2-methyl-4-(2-prop-2-enoyl-1,3,4,5-tetrahydro-2-benzazepin-6-yl)-1H-indole-7-carboxamide (Compound 25d):

[0939]

[0940] The two atropisomers were separated by chiral HPLC (sample amount = 45 mg, CHIRAL ART Cellulose-SB, 2 x 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).

[0941] Compound 25c: retention time = 8.502 minutes (19.1 mg)

[0942] 1 H NMR (400MHz, DMSO-d6) δ11.44(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).

[0943] ESI-MS [M+H]+ calculated values ​​(C 23 H 21 ClFN3O2)426.13, 428.13; measured values: 426.10, 428.10.

[0944] Compound 25d: retention time = 11.588 minutes (19.3 mg)

[0945] 1H NMR (400MHz, DMSO-d6) δ11.44(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).

[0946] ESI-MS [M+H]+ calculated values ​​(C 23 H 21 ClFN3O2)426.13, 428.13; measured values: 426.05, 428.05.

[0947] 4-(2-Acryloyl-2,3,4,5-tetrahydro-1H-benzo[c]azepin-6-yl)-3,5-difluoro-2-methyl-1H- Synthesis of indole-7-carboxamide (Compound 25e)

[0948]

[0949] To a stirred solution of 4-(2-acryloyl-2,3,4,5-tetrahydro-1H-benzo[c]azepin-6-yl)-5-fluoro-2-methyl-1H-indole-7-carboxamide (80 mg, 0.20 mmol) in dichloromethane (10 mL) was added N-fluorobenzenesulfonimide (126 mg, 0.51 mmol). The reaction mixture was stirred at 25°C for 36 h. The reaction mixture was diluted with water (30 mL) and extracted with dichloromethane (3 x 30 mL). The combined extracts were washed with brine (100 mL), dried over sodium sulfate, and concentrated in vacuo. The residue was purified by preparative HPLC (column: YMC-Actus Triart C18, 30×250 mm, 5 μm; mobile phase A: water (10 mmol / L NH 4 HCO 3 + 0.1% NH 3 .H 2 O), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 40% B to 50% B, 8 min; 254 nm; retention time = 7.95) to give 4-(2-acryloyl-2,3,4,5-tetrahydro-1H-benzo[c]azepin-6-yl)-3,5-difluoro-2-methyl-1H-indole-7-carboxamide (8.0 mg, 9%) as a white solid.

[0950] 1H NMR(400MHz,DMSO-d6)δ10.87(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).

[0951] ESI-MS [M+H]+ calculated values ​​(C 23 H 21 F2N3O2)410.16, measured value: 410.30.

[0952] Preparation of compounds of formula (II) wherein X is -CR x1 R x2 -, and R x1 is H, and R x2 and R 3 Together to form alkylene Base Bridge

[0953]

[0954] Example 26

[0955] 4-(2-Acryloyl-1,2,3,4-tetrahydro-1,4-methyleneisoquinolin-5-yl)-3-chloro-5-fluoro-2-methyl- Synthesis of 1H-indole-7-carboxamide (Compound 26)

[0956]

[0957] Step 1: 4-Ethyl 1-methyl 2-(2-bromophenyl)succinate

[0958]

[0959] At -78 ° C under nitrogen, to a stirred solution of 2- (2- bromophenyl) methyl acetate (10.0 g, 43.7 mmol) in THF (120 mL) was added potassium bis (trimethylsilyl) amide (1.0 M, 65.5 mL, 65.5 mmol). After stirring for 1 h at this temperature, ethyl 2-bromoacetate (50.00 g, 299 mmol) was added dropwise. The reaction mixture was stirred at -78 ° C for 1 h and then at -40 ° C for 3 h. 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 in vacuo. The residue was purified by silica gel column chromatography (0 to 30% ethyl acetate in petroleum ether) to obtain 4-ethyl 1-methyl 2- (2- bromophenyl) succinate (11.9 g, 86%) as a white solid.

[0960] 1H NMR(400MHz,DMSO-d6)δ7.63-7.59(m,1H),7.38-7.28(m,2H),7.24-7.19(m,1H),4.52-4.45(m,1 H), 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).

[0961] ESI-MS [M+H]+ calculated values ​​(C 13 H 15 BrO4)315.02, 317.02; measured values: 314.95, 316.95.

[0962] Step 2: 2-(2-bromophenyl)succinic acid

[0963]

[0964] To a stirred mixture of 4-ethyl 1-methyl 2-(2-bromophenyl)succinate (11.9 g, 37.8 mmol) in water (150 mL) was added potassium hydroxide (21.2 g, 378 mmol). The reaction mixture was heated under reflux for 20 h. The pH of the cooled reaction mixture was adjusted to 3-4 with a 1 M aqueous HCl solution. The solid was collected by filtration and dried under reduced pressure to give 2-(2-bromophenyl)succinic acid (9.80 g) as a white solid.

[0965] 1 H NMR (300MHz, DMSO-d6) δ12.49(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).

[0966] ESI-MS [M+H]+ calculated values ​​(C 10 H9BrO4)272.97, 274.97; measured values: 272.85, 274.85.

[0967] Step 3: 3-(2-bromophenyl)dihydrofuran-2,5-dione

[0968]

[0969] 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 at reflux for 3 h. The cooled reaction mixture was concentrated in vacuo to give 3-(2-bromophenyl)dihydrofuran-2,5-dione (9.0 g) as a yellow solid.

[0970] 1 H NMR (400MHz, DMSO-d6) δ7.67 (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).

[0971] ESI-MS [MH]-calculated (C 10 H7BrO3)252.96, 254.96; measured values: 252.85, 254.85.

[0972] Step 4: 7-Bromo-3-oxo-2,3-dihydro-1H-indene-1-carboxylic acid

[0973]

[0974] To a solution of 3-(2-bromophenyl)dihydrofuran-2,5-dione (9.0 g) in 1,2-dichloroethane (125 mL) was added 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 h. The reaction mixture was diluted with water (100 mL) and extracted with DCM (3×100 mL). The combined extracts were washed with brine (100 mL), dried over sodium sulfate and concentrated in vacuo to give 7-bromo-3-oxo-2,3-dihydro-1H-indene-1-carboxylic acid (8.30 g) as a yellow solid.

[0975] 1 H NMR(300MHz,DMSO-d6)δ12.81(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).

[0976] Step 5: 7-bromo-3-oxo-2,3-dihydro-1H-indene-1-carboxylic acid methyl ester

[0977]

[0978] To 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 added concentrated sulfuric acid (4.0 mL). The reaction mixture was heated under reflux for 5 h. The reaction mixture was concentrated in vacuo. 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 in vacuo. The residue was purified by silica gel column chromatography (0 to 20% ethyl acetate in petroleum ether) to give 7-bromo-3-oxo-2,3-dihydro-1H-indene-1-carboxylic acid methyl ester (7.30 g, 86%) as a yellow solid.

[0979] 1 H NMR(300MHz,DMSO-d6)δ7.99(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).

[0980] ESI-MS [M+H+ACN] + calculated value (C 11 H9BrO3)309.97, 311.97; measured values: 309.95, 311.95.

[0981] Step 6: (Z)-methyl 7-bromo-3-(hydroxyimino)-2,3-dihydro-1H-indene-1-carboxylate

[0982]

[0983] To a solution of 7-bromo-3-oxo-2,3-dihydro-1H-indene-1-carboxylic acid methyl ester (7.30 g, 27.1 mmol) in MeOH (50 mL) was added hydroxylamine hydrochloride (2.60 g, 36.8 mmol). The reaction mixture was stirred at reflux for 3 h. 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 in vacuo to give (Z)-7-bromo-3-(hydroxyimino)-2,3-dihydro-1H-indene-1-carboxylic acid methyl ester (7.5 g) as a yellow solid.

[0984] 1H NMR(300MHz,DMSO-d6)δ11.32(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).

[0985] ESI-MS [M+H]+ calculated values ​​(C 11 H 10 BrNO3)283.98, 285.98; measured values: 284.00, 286.00.

[0986] Step 7: 3-Amino-7-bromo-2,3-dihydro-1H-indene-1-carboxylic acid methyl ester

[0987]

[0988] To a solution of (Z)-7-bromo-3-(hydroxyimino)-2,3-dihydro-1H-indene-1-carboxylic acid methyl ester (1.0 g, 3.52 mmol) in acetic acid (30 mL) was added zinc powder (2.30 g, 35.2 mmol) and ammonium chloride (1.88 g, 35.2 mmol). The reaction mixture was stirred at 30 ° C for 16 h. The reaction mixture was basified with saturated aqueous NaHCO3 solution and extracted with ethyl acetate (3×60 mL). The combined extracts were washed with brine (50 mL), dried over sodium sulfate and concentrated in vacuo to give 3-amino-7-bromo-2,3-dihydro-1H-indene-1-carboxylic acid methyl ester (700 mg) as a white solid.

[0989] ESI-MS [M+H]+ calculated values ​​(C 11 H 12 BrNO2)270.01, 272.01; measured values: 270.00, 272.00.

[0990] Step 8: 3-Amino-7-bromo-2,3-dihydro-1H-indene-1-carboxylic acid

[0991]

[0992] A mixture of methyl 3-amino-7-bromo-2,3-dihydro-1H-indene-1-carboxylate (6.00 g, 22.2 mmol) in 2M hydrochloric acid (300 mL) was heated under reflux for 5 h. The pH of the cooled reaction mixture was adjusted to 7 with saturated aqueous sodium bicarbonate solution, and the mixture was extracted with ethyl acetate (4 × 150 mL). The combined extracts were washed with brine (150 mL), dried over sodium sulfate and concentrated in vacuo to give 3-amino-7-bromo-2,3-dihydro-1H-indene-1-carboxylic acid (5.50 g) as a white solid.

[0993] 1 H NMR(300MHz,DMSO-d6)δ12.94(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).

[0994] ESI-MS [M+H]+ calculated values ​​(C 10 H 10 BrNO2)255.99, 257.99; measured values: 255.95, 257.95.

[0995] Step 9: 5-Bromo-1,4-dihydro-1,4-methyleneisoquinolin-3(2H)-one

[0996]

[0997] To a solution of 3-amino-7-bromo-2,3-dihydro-1H-indene-1-carboxylic acid (5.50 g, crude material) and pyridine (9.30 g, 117 mmol) in acetonitrile (150 mL) was added dicyclohexylcarbodiimide (5.3 g, 25.8 mmol). The reaction mixture was heated under reflux for 1 h. The cooled reaction mixture was quenched with water (200 mL) and extracted with ethyl acetate (3 × 150 mL). The combined extracts were washed with brine (100 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (0 to 50% ethyl acetate in petroleum ether) to give 5-bromo-1,4-dihydro-1,4-methyleneisoquinolin-3 (2H) -one (2.40 g, 43%) as a yellow solid.

[0998] ESI-MS [M+H]+ calculated values ​​(C 10 H8BrNO)237.98, 239.98; measured values: 238.00, 240.00.

[0999] Step 10: 5-Bromo-1,2,3,4-tetrahydro-1,4-methyleneisoquinoline

[1000]

[1001] To a solution of sodium borohydride (596 mg, 15.8 mmol) in THF (10 mL) was added BF3.Et2O (2.98 g, 21.0 mmol) at 0 ° C. After stirring at this temperature for 1 h, a solution of 5-bromo-1,4-dihydro-1,4-methyleneisoquinolin-3 (2H) -one (1.25 g, 5.25 mmol) in THF (10 mL) was added dropwise. The reaction mixture was stirred at reflux for 16 h. 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 in vacuo to give 5-bromo-1,2,3,4-tetrahydro-1,4-methyleneisoquinoline (1.00 g) as a yellow solid.

[1002] ESI-MS [M+H]+ calculated values ​​(C 10 H 10 BrN)224.00, 226.00; measured values: 224.00, 226.00.

[1003] Step 11: 1-(5-Bromo-3,4-dihydro-1,4-methyleneisoquinolin-2(1H)-yl)prop-2-en-1-one

[1004]

[1005] To a mixture of 5-bromo-1,2,3,4-tetrahydro-1,4-methyleneisoquinoline (800 mg, 3.57 mmol) in water (2 mL) and THF (8 mL) was added 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 h. The 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 anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (0 to 50% ethyl acetate in petroleum ether) to give 1-(5-bromo-3,4-dihydro-1,4-methyleneisoquinolin-2(1H)-yl)prop-2-en-1-one (400 mg, 40%) as a white solid.

[1006] ESI-MS [M+H]+ calculated values ​​(C 13 H 12 BrNO)278.01, 280.01; measured values: 277.95, 279.95.

[1007] Step 12: 4-(2-Acryloyl-1,2,3,4-tetrahydro-1,4-methyleneisoquinolin-5-yl)-5-fluoro-2-methyl- 1H-Indole-7-carboxamide

[1008]

[1009] A mixture of 1-(5-bromo-3,4-dihydro-1,4-methyleneisoquinolin-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 under nitrogen for 16 h. The cooled reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (3 x 30 mL). The combined extracts were washed with brine (50 mL), dried over sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography (0 to 10% methanol in dichloromethane) to give 4-(2-acryloyl-1,2,3,4-tetrahydro-1,4-methyleneisoquinolin-5-yl)-5-fluoro-2-methyl-1H-indole-7-carboxamide (440 mg, 52%) as a green solid.

[1010] 1 H NMR(300MHz,DMSO-d6)δ11.09(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).

[1011] ESI-MS [M+H]+ calculated values ​​(C 23 H 20 FN3O2)390.15, measured value: 390.30.

[1012] Step 13: 4-(2-Acryloyl-1,2,3,4-tetrahydro-1,4-methyleneisoquinolin-5-yl)-3-chloro-5-fluoro-2- Methyl-1H-indole-7-carboxamide (Compound 26)

[1013]

[1014] To a solution of 4-(2-acryloyl-1,2,3,4-tetrahydro-1,4-methyleneisoquinolin-5-yl)-5-fluoro-2-methyl-1H-indole-7-carboxamide (200 mg, 0.51 mmol) in DMF (6 mL) was added NCS (83 mg, 0.62 mmol) at 0°C. The reaction mixture was stirred at 0°C for 1 h. The reaction mixture was quenched with water (15 mL) and extracted with ethyl acetate (3 x 15 mL). The combined extracts were washed with brine (3 x 20 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by preparative HPLC (column: Xselect CSH OBD column, 30×150 mm, 5 μm; mobile phase A: water (10 mmol / L NH 4 HCO 3 + 0.1% NH 3 .H 2 O), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 38% B to 58% B, 7 min; 220 nm; retention time = 5.32 minutes) to give 4-(2-acryloyl-1,2,3,4-tetrahydro-1,4-methyleneisoquinolin-5-yl)-3-chloro-5-fluoro-2-methyl-1H-indole-7-carboxamide (91 mg, 42%) as a white solid.

[1015] 1 H NMR(300MHz,DMSO-d6)δ11.49(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).

[1016] ESI-MS [M+H]+ calculated values ​​(C 23 H 19 ClN3O2)424.11, measured value: 424.10.

[1017] Preparation of compounds of formula (III)

[1018]

[1019] Example 27

[1020] 4-((3S,5R)-3-(but-2-ynylamino)-5-fluoropiperidin-1-yl)-3-chloro-5-fluoro-2-methyl-1H-indole- Synthesis of 7-formamide (Compound 27)

[1021]

[1022] Step 1: 4-Bromo-5-fluoro-2-methyl-1H-indole-7-carboxylic acid

[1023]

[1024] To a stirred solution of 4-bromo-5-fluoro-2-nitrobenzoic acid (17 g, 64.4 mmol) in THF (200 mL) was added propane-1-en-2-ylmagnesium bromide (451 mL, 225 mmol, 0.5 M THF solution) at -70 ° C under nitrogen. After addition, the reaction mixture was stirred at -70 ° C for 3 h. 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 anhydrous sodium sulfate and concentrated in vacuo to give 4-bromo-5-fluoro-2-methyl-1H-indole-7-carboxylic acid (17.5 g) as a brown solid. The solid was used further without purification.

[1025] ESI-MS[MH] - Calculated value (C 10 H7BrFNO2)269.96, 271.96, measured values: 270.25, 272.25.

[1026] Step 2: 4-Bromo-5-fluoro-2-methyl-1H-indole-7-carboxamide

[1027]

[1028] To a stirred solution of 4-bromo-5-fluoro-2-methyl-1H-indole-7-carboxylic acid (17.5 g, 64.4 mmol), ammonia hydrochloride (5.17 g, 96.6 mmol) and HATU (29.4 g, 77.3 mmol) in DMF (200 mL) was added N-ethyl-N-isopropyl-propan-2-amine (25.0 g, 193 mmol). The reaction mixture was stirred at 25 ° C for 16 h. 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), brine (200 mL), then dried over anhydrous sodium sulfate and concentrated in vacuo. The concentrate was purified by column chromatography (50% ethyl acetate in petroleum ether) to give 4-bromo-5-fluoro-2-methyl-1H-indole-7-carboxamide (3.8 g, 22%) as a yellow solid.

[1029] 1 H NMR (400MHz, DMSO-d6) δ11.26(s,1H),8.11(s,1H),7.63-7.53(m,2H),6.19(s,1H),2.42(s,3H).

[1030] ESI-MS[M+H]+ Calculated value (C 10 H8BrFN2O)270.98, 272.98, measured values: 270.90, 272.90.

[1031] Step 3: 4-Bromo-5-fluoro-2-methyl-1H-indole-7-carbonitrile

[1032]

[1033] At 0 ° C, pyridine (1.46 g, 18.4 mmol) and phosphorus oxychloride (1.70 g, 11.1 mmol) were added to a mixture of 4-bromo-5-fluoro-2-methyl-1H-indole-7-carboxamide (2.00 g, 7.38 mmol) in DCM (40 mL). The reaction mixture was stirred for 2 h at 25 ° C. The reaction mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (0-10% ethyl acetate in petroleum ether) to give 4-bromo-5-fluoro-2-methyl-1H-indole-7-carbonitrile (1.50 g, 80%) as a white solid.

[1034] 1 H NMR (400MHz, DMSO-d6) δ12.26 (s, 1H), 7.63 (d, J = 9.2Hz, 1H), 6.34-6.31 (m, 1H), 2.42 (s, 3H).

[1035] ESI-MS[MH] - Calculated value (C 10 H6BrFN2)250.97, 252.97; measured values: 250.95, 252.95.

[1036] Step 4: ((3S,5R)-1-(7-cyano-5-fluoro-2-methyl-1H-indol-4-yl)-5-fluoropiperidin-3-yl)amino tert-Butyl formate

[1037]

[1038] A mixture of 4-bromo-5-fluoro-2-methyl-1H-indole-7-carbonitrile (500 mg, 1.74 mmol), tert-butyl ((3S, 5R)-5-fluoropiperidin-3-yl)carbamate (418 mg, 1.91 mmol), benzyl-[1-[2-[benzyl(phenyl)phosphanyl]-1-naphthyl]-2-naphthyl]-phenyl-phosphane (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 backfilled with nitrogen. The reaction mixture was heated at 100 ° C. under nitrogen for 16 h. The cooled reaction mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (0 to 16% ethyl acetate in petroleum ether) to give tert-butyl ((3S,5R)-1-(7-cyano-5-fluoro-2-methyl-1H-indol-4-yl)-5-fluoropiperidin-3-yl)carbamate (380 mg) as a yellow solid.

[1039] ESI-MS[M+H] + Calculated value (C 20 H 24 F2N4O2)391.19, measured value: 391.15.

[1040] Step 5: ((3S,5R)-1-(7-Carbamoyl-5-fluoro-2-methyl-1H-indol-4-yl)-5-fluoropiperidin-3-yl)- tert-Butyl)carbamate

[1041]

[1042] To a mixture of tert-butyl ((3S, 5R)-1-(7-cyano-5-fluoro-2-methyl-1H-indol-4-yl)-5-fluoropiperidin-3-yl)carbamate (350 mg, 0.89 mmol) in ethanol (16 mL) and water (4 mL) was added Parkin catalyst (19 mg, 0.045 mmol). The reaction was stirred at 90 ° C for 2 h. 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 silica gel column chromatography (0 to 50% ethyl acetate in petroleum ether) to give tert-butyl ((3S, 5R)-1-(7-carbamoyl-5-fluoro-2-methyl-1H-indol-4-yl)-5-fluoropiperidin-3-yl)carbamate (320 mg) as a yellow solid.

[1043] ESI-MS[M+H] + Calculated value (C 20 H 26 F2N4O3)409.20, measured value: 409.10.

[1044] Step 6: ((3S,5R)-1-(7-Carbamoyl-3-chloro-5-fluoro-2-methyl-1H-indol-4-yl)-5-fluoropiperidin tert-Butyl pyridin-3-yl)carbamate

[1045]

[1046] Tert-Butyl ((3S,5R)-1-(7-carbamoyl-3-chloro-5-fluoro-2-methyl-1H-indol-4-yl)-5-fluoropiperidin-3-yl)carbamate: To a solution of tert-butyl ((3S,5R)-1-(7-carbamoyl-5-fluoro-2-methyl-1H-indol-4-yl)-5-fluoropiperidin-3-yl)carbamate (250 mg, 0.61 mmol) in N,N-dimethylformamide (8 mL) was added N-chlorosuccinimide (82 mg, 0.61 mmol) at 0°C. The reaction mixture was stirred at 0°C for 2 h. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (3 x 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 eluting with (0 to 50% ethyl acetate in petroleum ether) to give tert-butyl ((3S,5R)-1-(7-carbamoyl-3-chloro-5-fluoro-2-methyl-1H-indol-4-yl)-5-fluoropiperidin-3-yl)carbamate (240 mg).

[1047] ESI-MS[M+H] + Calculated value (C 15 H 17 ClF2N4O) 443.16, 445.16; Measured values: 443.15, 445.15

[1048] Step 7: 4-((3S,5R)-3-amino-5-fluoropiperidin-1-yl)-3-chloro-5-fluoro-2-methyl-1H-indole-7-carboxylate Amide hydrochloride

[1049]

[1050] A mixture of tert-butyl ((3S,5R)-1-(7-carbamoyl-3-chloro-5-fluoro-2-methyl-1H-indol-4-yl)-5-fluoropiperidin-3-yl)carbamate (200 mg, 0.45 mmol) and 4M hydrogen chloride in dioxane (10 mL) was stirred at 20° C. for 2 h. The reaction mixture was concentrated in vacuo to give 4-((3S,5R)-3-amino-5-fluoropiperidin-1-yl)-3-chloro-5-fluoro-2-methyl-1H-indole-7-carboxamide hydrochloride (170 mg).

[1051] ESI-MS[M+H] + Calculated value (C 15 H 17ClF2N4O)343.11, 345.11; measured values: 343.05, 345.05.

[1052] Step 8: 4-((3S,5R)-3-(but-2-ynylamino)-5-fluoropiperidin-1-yl)-3-chloro-5-fluoro-2-methyl- 1H-Indole-7-carboxamide

[1053]

[1054] To a mixture of 4-((3S,5R)-3-amino-5-fluoropiperidin-1-yl)-3-chloro-5-fluoro-2-methyl-1H-indole-7-carboxamide hydrochloride (170 mg, 0.49 mmol), but-2-ynoic acid (42 mg, 0.49 mmol) and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (207 mg, 0.55 mmol) in N,N-dimethylformamide (8 mL) was added N,N-diisopropylethylamine (321 mg, 2.48 mmol). The reaction mixture was stirred at 20 ° C for 2 h. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (3×30 mL). The combined extracts were washed with brine (3×30 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative HPLC (column: YMC-Actus Triart C18, 30×250 mm, 5 μm; mobile phase A: water (10 MMOL / L NH 4 HCO 3 + 0.1% NH 3 .H 2 O), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 36% B to 47% B in 8 min; 254 nm; RT1: 7.5 min) to give 4-((3S,5R)-3-(but-2-ynylamino)-5-fluoropiperidin-1-yl)-3-chloro-5-fluoro-2-methyl-1H-indole-7-carboxamide (14.4 mg) as an off-white solid.

[1055] 1H NMR (400MHz, DMSO-d6) δ11.27(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,1 H),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).

[1056] ESI-MS[M+H] + Calculated value (C 19 H 19 ClF2N4O2) 409.12, 411.12; Measured values: 409.05, 411.05

[1057] Example 28

[1058] 4-((3S,5S)-3-(but-2-ynylamino)-5-fluoropiperidin-1-yl)-3-chloro-5-fluoro-2-methyl-1H-indole- Synthesis of 7-formamide (Compound 28)

[1059]

[1060] Step 1: ((3S,5S)-1-(7-cyano-5-fluoro-2-methyl-1H-indol-4-yl)-5-fluoropiperidin-3-yl)amino tert-Butyl formate

[1061]

[1062] A mixture of 4-bromo-5-fluoro-2-methyl-1H-indole-7-carbonitrile (500 mg, 1.74 mmol), tert-butyl ((3S, 5S)-5-fluoropiperidin-3-yl)carbamate (418 mg, 1.91 mmol), benzyl-[1-[2-[benzyl(phenyl)phosphanyl]-1-naphthyl]-2-naphthyl]-phenyl-phosphane (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) is degassed and backfilled with nitrogen. The reaction mixture is heated at 100 ° C under nitrogen for 16 h. The cooled reaction mixture is concentrated in vacuo. The residue was purified by silica gel column chromatography (0 to 16% ethyl acetate in petroleum ether) to give tert-butyl ((3S,5S)-1-(7-cyano-5-fluoro-2-methyl-1H-indol-4-yl)-5-fluoropiperidin-3-yl)carbamate (320 mg) as a yellow solid.

[1063] ESI-MS[M+H] + Calculated value (C 20 H 24 F2N4O2)391.19, measured value: 391.10.

[1064] Step 2: ((3S,5S)-1-(7-Carbamoyl-5-fluoro-2-methyl-1H-indol-4-yl)-5-fluoropiperidine -3-yl)carbamic acid tert-butyl ester

[1065]

[1066] To a mixture of tert-butyl ((3S, 5S) -1- (7-cyano-5-fluoro-2-methyl-1H-indol-4-yl) -5-fluoropiperidin-3-yl) carbamate (320 mg, 0.82 mmol) in water (4 mL) and ethanol (16 mL) was added Parkin catalyst (18 mg, 0.041 mmol). The reaction mixture was heated at 90 ° C for 2 h. 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 silica gel column chromatography (0 to 50% ethyl acetate in petroleum ether) to give tert-butyl ((3S, 5S) -1- (7-carbamoyl-5-fluoro-2-methyl-1H-indol-4-yl) -5-fluoropiperidin-3-yl) carbamate (350 mg) as a yellow solid.

[1067] ESI-MS[M+H] + Calculated value (C 20 H 26 F2N4O3)409.20, measured value: 409.10.

[1068] Step 3: ((3S,5S)-1-(7-Carbamoyl-3-chloro-5-fluoro-2-methyl-1H-indol-4-yl)-5-fluoropiperidin tert-Butyl pyridin-3-yl)carbamate

[1069]

[1070] To a solution of tert-butyl ((3S,5S)-1-(7-carbamoyl-5-fluoro-2-methyl-1H-indol-4-yl)-5-fluoropiperidin-3-yl)carbamate (250 mg, 0.61 mmol) in DMF (6 mL) at 0°C was added N-chlorosuccinimide (82 mg, 0.61 mmol). The reaction mixture was stirred at 0°C for 2 h. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (3×30 mL). The combined extracts were washed with brine (5 mL), dried over sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 0 to 50% ethyl acetate in petroleum ether to give tert-butyl ((3S,5S)-1-(7-carbamoyl-3-chloro-5-fluoro-2-methyl-1H-indol-4-yl)-5-fluoropiperidin-3-yl)carbamate (250 mg).

[1071] ESI-MS[M+H] + Calculated value (C 20 H 25 ClF2N4O3)443.16, 445.16; measured values: 443.15, 445.15.

[1072] Step 4: 4-((3S,5S)-3-amino-5-fluoropiperidin-1-yl)-3-chloro-5-fluoro-2-methyl-1H-indole-7-carboxylate Amide hydrochloride

[1073]

[1074] A mixture of tert-butyl (3S,5S)-1-(7-carbamoyl-3-chloro-5-fluoro-2-methyl-1H-indol-4-yl)-5-fluoropiperidin-3-ylcarbamate (250 mg, crude) and 4M hydrogen chloride in dioxane (10 mL) was stirred for 2 h at 20° C. The reaction mixture was concentrated in vacuo to give 4-((3S,5S)-3-amino-5-fluoropiperidin-1-yl)-3-chloro-5-fluoro-2-methyl-1H-indole-7-carboxamide hydrochloride (200 mg).

[1075] ESI-MS[M+H] + Calculated value (C 15 H 17 ClF2N4O) 343.11, 345.11; Measured values: 343.10, 345.10

[1076] Step 5: 4-((3S,5S)-3-(but-2-ynylamino)-5-fluoropiperidin-1-yl)-3-chloro-5-fluoro-2-methyl- 1H-Indole-7-carboxamide

[1077]

[1078] To a solution of 4-((3S,5S)-3-amino-5-fluoropiperidin-1-yl)-3-chloro-5-fluoro-2-methyl-1H-indole-7-carboxamide hydrochloride (200 mg, 0.527 mmol), but-2-ynoic 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) was added N,N-diisopropylethylamine (341 mg, 2.64 mmol). The mixture was stirred at 20 ° C for 2 h. 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 in vacuo. 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 NH 4 HCO 3 + 0.1% NH 3 .H 2 O), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: 38% B to 58% B in 7 min; 220 nm; RT: 5.12 min) to give 4-((3S,5S)-3-but-2-ynamido-5-fluoropiperidin-1-yl)-3-chloro-5-fluoro-2-methyl-1H-indole-7-carboxamide (34.9 mg, 16%) as a white solid.

[1079] 1 H NMR (400MHz, DMSO-d6) δ11.28(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).

[1080] Example 29

[1081] 4-(1-Acryloyloctahydro-6H-pyrrolo[2,3-c]pyridin-6-yl)-3-chloro-5-fluoro-2-methyl-1H-indole Synthesis of Indole-7-carboxamide (Compound 29)

[1082]

[1083] Step 1: 6-(7-cyano-5-fluoro-2-methyl-1H-indol-4-yl)octahydro-1H-pyrrolo[2,3-c]pyridine-1- tert-Butyl formate

[1084]

[1085] A mixture of 4-bromo-5-fluoro-2-methyl-1H-indole-7-carbonitrile (500 mg, 1.74 mmol), tert-butyl octahydro-1H-pyrrolo[2,3-c]pyridine-1-carboxylate (cis enantiomer mixture, 433 mg, 1.91 mmol), benzyl-[1-[2-[benzyl(phenyl)phosphanyl]-1-naphthyl]-2-naphthyl]-phenyl-phosphane (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 backfilled with nitrogen. The reaction mixture was heated at 100 ° C. under nitrogen for 16 h. The cooled reaction mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with (0 to 16% ethyl acetate in petroleum ether) to give tert-butyl 6-(7-cyano-5-fluoro-2-methyl-1H-indol-4-yl)octahydro-1H-pyrrolo[2,3-c]pyridine-1-carboxylate (400 mg) as a yellow solid.

[1086] ESI-MS[M+H] + Calculated value (C 22 H 27 FN4O2)399.21, measured value: 399.20.

[1087] Step 2: 6-(7-Carbamoyl-5-fluoro-2-methyl-1H-indol-4-yl)octahydro-1H-pyrrolo[2,3-c] tert-Butyl pyridine-1-carboxylate

[1088]

[1089] To a mixture of tert-butyl 6-(7-cyano-5-fluoro-2-methyl-1H-indol-4-yl)octahydro-1H-pyrrolo[2,3-c]pyridine-1-carboxylate (350 mg, 0.88 mmol) in water (4 mL) and ethanol (16 mL) was added Parkin catalyst (19 mg, 0.044 mmol). The reaction mixture was stirred at 90 ° C for 2 h. The cooled reaction mixture was diluted 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 in vacuo. The residue was purified by silica gel column chromatography, eluted with (0 to 50% ethyl acetate in petroleum ether) to give tert-butyl 6-(7-carbamoyl-5-fluoro-2-methyl-1H-indol-4-yl)octahydro-1H-pyrrolo[2,3-c]pyridine-1-carboxylate (350 mg) as a yellow solid.

[1090] ESI-MS[M+H] + Calculated value (C 22 H 29 FN4O3)417.22, measured value: 417.20.

[1091] Step 3: 6-(7-Carbamoyl-3-chloro-5-fluoro-2-methyl-1H-indol-4-yl)octahydro-1H-pyrrolo[2, tert-Butyl 3-c]pyridine-1-carboxylate

[1092]

[1093] To a solution of tert-butyl 6-(7-carbamoyl-5-fluoro-2-methyl-1H-indol-4-yl)octahydro-1H-pyrrolo[2,3-c]pyridine-1-carboxylate (330 mg, 0.792 mmol) in DMF (6 mL) at 0°C was added N-chlorosuccinimide (106 mg, 0.792 mmol). The reaction mixture was stirred at 0°C for 2 h. The reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (3 x 30 mL). The combined extracts were washed with brine (50 mL), dried over sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography (0 to 50% ethyl acetate in petroleum ether) to give tert-butyl 6-(7-carbamoyl-3-chloro-5-fluoro-2-methyl-1H-indol-4-yl)octahydro-1H-pyrrolo[2,3-c]pyridine-1-carboxylate (350 mg).

[1094] ESI-MS[M+H] + Calculated value (C 22 H 28ClFN4O3)451.18, 453.18; measured values: 451.05, 453.05.

[1095] Step 4: 3-Chloro-5-fluoro-2-methyl-4-(octahydro-6H-pyrrolo[2,3-c]pyridin-6-yl)-1H-indole-7-yl Formamide 2,2,2-trifluoroacetate

[1096]

[1097] To a solution of tert-butyl 6-(7-carbamoyl-3-chloro-5-fluoro-2-methyl-1H-indol-4-yl)octahydro-1H-pyrrolo[2,3-c]pyridine-1-carboxylate (300 mg, 0.665 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (5 mL). The reaction mixture was stirred at 25° C. for 2 h. The reaction mixture was concentrated in vacuo to afford 3-chloro-5-fluoro-2-methyl-4-(octahydro-6H-pyrrolo[2,3-c]pyridin-6-yl)-1H-indole-7-carboxamide 2,2,2-trifluoroacetate (310 mg).

[1098] ESI-MS[M+H] + Calculated value (C 17 H 20 ClFN4O) 351.13, 353.13; Measured values: 351.05, 353.05

[1099] Step 5: 4-(1-acryloyloctahydro-6H-pyrrolo[2,3-c]pyridin-6-yl)-3-chloro-5-fluoro-2-methyl- 1H-Indole-7-carboxamide

[1100]

[1101] To a mixture of 3-chloro-5-fluoro-2-methyl-4-(octahydro-6H-pyrrolo[2,3-c]pyridin-6-yl)-1H-indole-7-carboxamide 2,2,2-trifluoroacetate (310 mg, 0.667 mmol) in tetrahydrofuran (3 mL) at -78°C was added N,N-diisopropylethylamine (517 mg, 4.00 mmol) and acryloyl chloride (66 mg, 0.734 mmol). The reaction mixture was stirred at -78°C for 0.5 h. The reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (3 x 30 mL). The combined extracts were washed with brine (50 mL), dried over sodium sulfate, and concentrated in vacuo. The residue was purified by preparative HPLC (column: XBridgePrep OBD C18 column, 19×250 mm, 5 μm; mobile phase A: water (10 MMOL / L NH 4 HCO 3 + 0.1% NH 3 .H 2 O), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: 40% B to 60% B in 7 min; 220 nm; retention time = 5.78 minutes) to give 4-(1-acryloyloctahydro-6H-pyrrolo[2,3-c]pyridin-6-yl)-3-chloro-5-fluoro-2-methyl-1H-indole-7-carboxamide (110 mg, 40%) as a white racemic mixture.

[1102] 1 H NMR (400MHz, DMSO-d6) δ11.26 (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 ),2.58-2.52(m,0.5H),2.39(d,J=5.2Hz,3H),2.28-2.06(m,2H),1.95-1.63(m,2H).

[1103] ESI-MS[M+H] + Calculated value (C 20 H 22 ClFN4O2) 405.14, 407.14; Measured values: 405.10, 407.10

[1104] Step 6: Separation of isomers

[1105] Racemic 4-(1-acryloyloctahydro-6H-pyrrolo[2,3-c]pyridin-6-yl)-3-chloro-5-fluoro-2-methyl-1H-indole-7-carboxamide was separated into its corresponding enantiomers by preparative chiral HPLC (sample amount = 90 mg; column: Chiralpak IA, 2×25 cm, 5 μm; mobile phase A: MTBE (0.5% 2 M NH 3 -MeOH), mobile phase B: EtOH; flow rate: 18 mL / min; gradient: 50% B, isocratic; 220 / 254 nm).

[1106]

[1107] Compound 29a: Retention time = 8.163 minutes (29.1 mg). Isolated as a white solid

[1108] 1 H NMR(400MHz,DMSO-d6)δ11.27(d,J=12.0Hz,1H),8.02(s,1H),7.58-7.39(m,2H),6.65-6 .48(m,1H),6.16-6.06(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] + Calculated value (C 20 H 22 ClFN4O2)405.14, 407.14; measured values: 405.10, 407.10.

[1109] Compound 29b: Retention time = 11.102 minutes (30.9 mg). Isolated as a white solid

[1110] 1H NMR (400MHz, DMSO-d6) δ11.27 (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 ),2.60-2.51(m,0.5H),2.39(d,J=5.2Hz,3H),2.28-2.06(m,2H),1.93-1.65(m,2H).

[1111] ESI-MS[M+H] + Calculated value (C 20 H 22 ClFN4O2)405.14, 407.14; measured values: 405.10, 407.10.

[1112] Example 30

[1113] 4-((3S,4S)-3-Acrylamido-4-fluoropiperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxylate Synthesis of amine (Compound 30)

[1114]

[1115] Step 1: ((3S,4S)-1-(7-cyano-5-fluoro-2,3-dimethyl-1H-indol-4-yl)-4-fluoropiperidin-3-yl) tert-Butyl carbamate

[1116]

[1117] At 20 ° C under a nitrogen atmosphere, to a mixture of 4-bromo-5-fluoro-2,3-dimethyl-1H-indole-7-carbonitrile (250 mg, 0.94 mmol) and tert-butyl ((3S, 4S)-4-fluoropiperidin-3-yl)carbamate (225 mg, 1.03 mmol) in 1,4-dioxane (10 mL) was added 1.1'-binaphthyl-2,2'-diphenylphosphine (61 mg, 0.09 mmol), tris(dibenzylideneacetone)dipalladium (86 mg, 0.09 mmol) and cesium carbonate (457 mg, 1.40 mmol). The mixture was degassed and backfilled with nitrogen three times and stirred at 100 ° C for 16 hours. The cooled mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL×3). The combined extracts were washed with water (50 mL × 2) and brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (0 to 25% ethyl acetate in petroleum ether) to give tert-butyl ((3S, 4S)-1-(7-cyano-5-fluoro-2,3-dimethyl-1H-indol-4-yl)-4-fluoropiperidin-3-yl)carbamate (290 mg, 77%) as a light yellow solid.

[1118] 1 H NMR (400MHz, DMSO-d6) δ11.59(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),3.1 8-3.04(m,3H),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).

[1119] Step 2: ((3S,4S)-1-(7-Carbamoyl-5-fluoro-2,3-dimethyl-1H-indol-4-yl)-4-fluoropiperidin tert-Butyl pyridin-3-yl)carbamate

[1120]

[1121] To a mixture of tert-butyl ((3S,4S)-1-(7-cyano-5-fluoro-2,3-dimethyl-1H-indol-4-yl)-4-fluoropiperidin-3-yl)carbamate (290 mg, 0.72 mmol) and potassium carbonate (297 mg, 2.15 mmol) in DMSO (5 mL) was added hydrogen peroxide (30%, 813 mg, 7.17 mmol). The reaction mixture was stirred at 60° C. for 30 min. The cooled mixture was diluted with water (50 mL) and extracted with ethyl acetate (40 mL×3). The combined extracts were washed with water (50 mL x 3) and brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give tert-butyl ((3S,4S)-1-(7-carbamoyl-5-fluoro-2,3-dimethyl-1H-indol-4-yl)-4-fluoropiperidin-3-yl)carbamate (300 mg, 99%) as a yellow solid.

[1122] 1 H NMR (400MHz, DMSO-d6) δ10.64(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),3.85-3.6 9(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).

[1123] Step 3: 4-((3S,4S)-3-amino-4-fluoropiperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide Amine hydrochloride

[1124]

[1125] To a solution of tert-butyl ((3S,4S)-1-(7-carbamoyl-5-fluoro-2,3-dimethyl-1H-indol-4-yl)-4-fluoropiperidin-3-yl)carbamate (300 mg, 0.71 mmol) in methanol (5 mL) was added hydrogen chloride (10 mL, 4 M in 1,4-dioxane). The reaction mixture was stirred at 20 ° C for 2 hours. The resulting mixture was concentrated in vacuo to give 4-((3S,4S)-3-amino-4-fluoropiperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide hydrochloride (320 mg, crude material) as a yellow solid.

[1126] ESI-MS [M+H]+ calculated values ​​(C 16 H 20F2N4O)323.16, measured value: 323.25.

[1127] Step 4: 4-((3S,4S)-3-Acrylamido-4-fluoropiperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole- 7-carboxamide

[1128]

[1129] To 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 acryloyl chloride (81 mg, 0.89 mmol) at 0°C. The reaction mixture was stirred for 1 h, 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 μm; mobile phase A: water (10 mmol / L NH 4 HCO 3 + 0.1% NH 3 .H 2 O), mobile phase B: acetonitrile; flow rate: 45 mL / min; gradient: 35% B to 45% B in 7 min; 254, 220 nm, retention time = 6.48 min) to give 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.

[1130] 1 H NMR (300MHz, DMSO-d6) δ (ppm): 10.65 (s, 1H), 8.31 (s, 1H), 7.92 (s, 1H), 7.41 (d, J = 14.1Hz, 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).

[1131] ESI-MS [M+H]+ calculated values ​​(C 19 H 22 F2N4O2)377.17, measured value: 377.25.

[1132] Example 31

[1133] Synthesis of 4-((3S,4R)-3-Acrylamido-4-fluoropiperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (Compound 31) Step 1: tert-Butyl ((3S,4R)-1-(7-cyano-5-fluoro-2,3-dimethyl-1H-indol-4-yl)-4-fluoropiperidin-3-yl)carbamate

[1134]

[1135] Step 2: tert-Butyl ((3S,4R)-1-(7-carbamoyl-5-fluoro-2,3-dimethyl-1H-indol-4-yl)-4-fluoropiperidin-3-yl)carbamate Step 3: 4-((3S,4R)-3-Amino-4-fluoropiperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide hydrochloride

[1136]

[1137] To a mixture of 4-bromo-5-fluoro-2,3-dimethyl-1H-indole-7-carbonitrile (250 mg, 0.94 mmol) and tert-butyl ((3S,4R)-4-fluoropiperidin-3-yl)carbamate (225 mg, 1.03 mmol) in 1,4-dioxane (10 mL) was added 1.1'-binaphthyl-2,2'-diphenylphosphine (61 mg, 0.09 mmol), tris(dibenzylideneacetone)dipalladium (86 mg, 0.09 mmol), and cesium carbonate (610 mg, 1.87 mmol). The reaction mixture was degassed and backfilled with nitrogen, then stirred at 100°C for 16 hours. The cooled mixture was diluted with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined extracts were washed with water (2 x 50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (0 to 25% ethyl acetate in petroleum ether) to give tert-butyl ((3S,4R)-1-(7-cyano-5-fluoro-2,3-dimethyl-1H-indol-4-yl)-4-fluoropiperidin-3-yl)carbamate (238 mg, 63%) as a light yellow solid.

[1138] 1 H NMR (400MHz, DMSO-d6) δ11.58(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),3.25-3.14(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).

[1139] ESI-MS [M+H]+ calculated values ​​(C 21 H 26 F2N4O2)405.20, measured value: 405.25.

[1140] Step 4: 4-((3S,4R)-3-Acrylamido-4-fluoropiperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide

[1141]

[1142] To a mixture of tert-butyl ((3S,4R)-1-(7-cyano-5-fluoro-2,3-dimethyl-1H-indol-4-yl)-4-fluoropiperidin-3-yl)carbamate (238 mg, 0.59 mmol) and potassium carbonate (244 mg, 1.77 mmol) in DMSO (5 mL) was added hydrogen peroxide (30%, 667 mg, 5.88 mmol). The reaction mixture was stirred at 60° C. for 30 min. 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 x 30 mL) and brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford tert-butyl ((3S,4R)-1-(7-carbamoyl-5-fluoro-2,3-dimethyl-1H-indol-4-yl)-4-fluoropiperidin-3-yl)carbamate (240 mg, 97%) as a light yellow solid.

[1143] 1 H NMR (400MHz, DMSO-d6) δ10.64(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 ),3.91-3.74(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).

[1144] ESI-MS [M+H]+ calculated values ​​(C 21 H 28 F2N4O3)423.21, measured value: 423.15.

[1145] Example 32 Synthesis of 4-(1-Acryloyloctahydro-6H-pyrrolo[2,3-c]pyridin-6-yl)-5-fluoro-2,3-dimethyl-1H-indole-

[1146]

[1147] To a solution of tert-butyl ((3S,4R)-1-(7-carbamoyl-5-fluoro-2,3-dimethyl-1H-indol-4-yl)-4-fluoropiperidin-3-yl)carbamate (240 mg, 0.57 mmol) in methanol (5 mL) was added hydrogen chloride (10 mL, 4 M in 1,4-dioxane). The reaction mixture was stirred at 20 ° C for 2 hours. The resulting mixture was concentrated in vacuo to give 4-((3S,4R)-3-amino-4-fluoropiperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide hydrochloride (260 mg, crude material) as a light yellow solid.

[1148] ESI-MS [M+H]+ calculated values ​​(C 16 H20F2N4O)323.16, measured value: 323.25

[1149] 7-carboxamide (Compound 32) Step 1: tert-Butyl 6-(7-cyano-5-fluoro-2,3-dimethyl-1H-indol-4-yl)octahydro-1H-pyrrolo[2,3-c]pyridine-1-carboxylate

[1150]

[1151] To a mixture of 4-((3S,4R)-3-amino-4-fluoropiperidin-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) was added acryloyl chloride (66 mg, 0.72 mmol) at 0°C. 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 extracts were 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 NH 4 HCO 3 ), mobile phase B: acetonitrile; flow rate: 50 mL / min; gradient: 40% B to 70% B in 7 min; 220 nm; retention time = 6.08 minutes to give 4-((3S,4R)-3-acrylamido-4-fluoropiperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (5.0 mg, 1.8%) as an off-white solid.

[1152] 1H 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).

[1153] ESI-MS [M+H]+ calculated values ​​(C 19 H 22 F2N4O2)377.17, measured value: 377.25.

[1154] Step 2: tert-Butyl 6-(7-carbamoyl-5-fluoro-2,3-dimethyl-1H-indol-4-yl)octahydro-1H-pyrrolo[2,3-c]pyridine-1-carboxylate

[1155] Step 3: 5-Fluoro-2,3-dimethyl-4-(octahydro-6H-pyrrolo[2,3-c]pyridin-6-yl)-1H-indole-7-carboxamide 2,2,2-trifluoroacetate Step 4: 4-(1-Acryloyloctahydro-6H-pyrrolo[2,3-c]pyridin-6-yl)-5-fluoro-2,3-dimethyl-

[1156]

[1157] 1H-indole-7-carboxamide Step 5: Separation of isomers

[1158]

[1159] To a mixture of 4-bromo-5-fluoro-2,3-dimethyl-1H-indole-7-carbonitrile (650 mg, 2.43 mmol) and racemic cis-octahydropyrrolo[2,3-c]pyridine-1-carboxylic acid tert-butyl ester (606 mg, 2.68 mmol) in 1,4-dioxane (20 mL) was added 1,1'-binaphthyl-2,2'-diphenylphosphine (152 mg, 0.24 mmol), tris(dibenzylideneacetone)dipalladium (223 mg, 0.24 mmol) and cesium carbonate (1.59 g, 4.86 mmol). The reaction mixture was degassed and backfilled with nitrogen three times and stirred at 100 ° C under a nitrogen atmosphere 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 x 100 mL) and brine (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with (0 to 20% ethyl acetate in petroleum ether) to afford tert-butyl 6-(7-cyano-5-fluoro-2,3-dimethyl-1H-indol-4-yl)octahydro-1H-pyrrolo[2,3-c]pyridine-1-carboxylate (410 mg, 41%) as a light yellow solid.

[1160] ESI-MS [M+H]+ calculated values ​​(C 23 H 29 FN4O2) 413.23, measured value: 413.20

[1161] Compound 32a: Retention time = 4.826 min (55 mg). A pale gray solid was isolated Compound 32b: Retention time = 6.483 min (52 mg). A pale gray solid was isolated

[1162]

[1163] To a mixture of 6- (7- cyano -5- fluoro -2,3- dimethyl -1H- indol -4- bases) octahydro -1H- pyrrolo [2,3-c] pyridine -1- carboxylic acid tert-butyl ester (410 mg, 0.99 mmol) in ethanol (16 mL) and water (4.0 mL) was added 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 give 6- (7- carbamoyl -5- fluoro -2,3- dimethyl -1H- indol -4- bases) octahydro -1H- pyrrolo [2,3-c] pyridine -1- carboxylic acid tert-butyl ester (330 mg, 77%) as a light yellow solid.

[1164] ESI-MS [M+H]+ calculated values ​​(C 23 H 31 FN4O3)431.24, measured value: 431.15.

[1165] Example 33 Synthesis of 4-((3S,5R)-3-(but-2-ynoylamido)-5-fluoropiperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-

[1166]

[1167] To a solution of tert-butyl 6-(7-carbamoyl-5-fluoro-2,3-dimethyl-1H-indol-4-yl)octahydro-1H-pyrrolo[2,3-c]pyridine-1-carboxylate (330 mg, 0.77 mmol) in dichloromethane (8 mL) was added trifluoroacetic acid (2.0 mL). The reaction mixture was stirred at 20 ° C. for 1 hour. The reaction mixture was concentrated in vacuo to give 5-fluoro-2,3-dimethyl-4-(octahydro-6H-pyrrolo[2,3-c]pyridin-6-yl)-1H-indole-7-carboxamide 2,2,2-trifluoroacetate (400 mg) as a brown solid.

[1168] ESI-MS [M+H]+ calculated values ​​(C 18 H 23 FN4O)331.19, measured value: 331.15

[1169] 7-carboxamide (Compound 7) Step 1: 4-Bromo-5-fluoro-2,3-dimethyl-1H-indole-7-carbonitrile

[1170]

[1171] To a solution of 5-fluoro-2,3-dimethyl-4-(octahydro-6H-pyrrolo[2,3-c]pyridin-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) at -78°C was added acryloyl chloride (70 mg, 0.77 mmol). 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 x 30 mL). The combined extracts were washed with water (2 x 30 mL) and brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative TLC (silica gel, eluent: dichloromethane / methanol = 20:1) to give 4-(1-acryloyloctahydro-6H-pyrrolo[2,3-c]pyridin-6-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (130 mg, 44% over two steps) as an off-white solid.

[1172] 1 H 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).

[1173] ESI-MS[M+H] + Calculated value (C 21 H 25 FN4O2)385.20, measured value: 385.30.

[1174] Step 2: tert-Butyl ((3S,5R)-1-(7-cyano-5-fluoro-2,3-dimethyl-1H-indol-4-yl)-5-fluoropiperidin-3-yl)carbamate

[1175] The isomers of 4-(1-acryloyloctahydro-6H-pyrrolo[2,3-c]pyridin-6-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide were separated by preparative chiral HPLC (sample = 130 mg, column: CHIRALPAK IA, 2×25 cm, 5 μm; mobile phase A: MTBE (0.5% 2M NH 3 -MeOH), mobile phase B: IPA-HPLC; flow rate: 18 mL / min; gradient: 45% B, isocratic; 220 / 254 nm).

[1176]

[1177] Step 3: tert-Butyl ((3S,5R)-1-(7-carbamoyl-5-fluoro-2,3-dimethyl-1H-indol-4-yl)-5-fluoropiperidin-3-yl)carbamate .

[1178] 1 H NMR(300MHz,DMSO-d6)δ(ppm):10.65(d,J=6.1Hz,1H),7.93(s,1H),7.42(dd,J=14.2,4.0Hz,1H),7 .35(s,1H),6.54(dd,J=16.9,10.5Hz,1H),6.10(dd,J=16.7,2.5Hz,1H),5.63(dd,J=10.3,2.5Hz,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).

[1179] ESI-MS[M+H] + Calculated value (C 21 H 25 FN4O2)385.20, measured value: 385.15.

[1180] ​ .

[1181] 1H NMR(300MHz,DMSO-d6)δ(ppm):10.65(d,J=6.1Hz,1H),7.93(s,1H),7.42(dd,J=14.2,4.0Hz,1H),7 .35(s,1H),6.54(dd,J=16.8,10.2Hz,1H),6.10(dd,J=16.7,2.5Hz,1H),5.63(dd,J=10.3,2.5Hz,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).

[1182] ESI-MS[M+H] + Calculated value (C 21 H 25 FN4O2)385.20, measured value: 385.15.

[1183] ​

[1184] ​ ​

[1185]

[1186] ​

[1187]

[1188] To a solution of 4-bromo-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (600 mg, 2.10 mmol) in dichloromethane (12 mL) was added pyridine (416 mg, 5.26 mmol) and phosphorus oxychloride (484 mg, 3.16 mmol). The reaction mixture was stirred at 20 ° C for 0.5 hours. After completion, the reaction mixture was concentrated in vacuo. The residue was washed with water, filtered and dried under reduced pressure to give 4-bromo-5-fluoro-2,3-dimethyl-1H-indole-7-carbonitrile (520 mg, 92%) as a red solid.

[1189] 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).

[1190] ​ ​

[1191]

[1192] To a mixture of 4-bromo-5-fluoro-2,3-dimethyl-1H-indole-7-carbonitrile (400mg, 1.50mmol) and ((3S, 5R)-5-fluoropiperidin-3-yl) tert-butyl carbamate (360mg, 1.65mmol) in dioxane (8mL) was added tris(dibenzylideneacetone)dipalladium (137mg, 0.15mmol), 1.1'-binaphthyl-2,2'-diphenylphosphine (93mg, 0.15mmol) and cesium carbonate (732mg, 2.25mmol). The reaction mixture was evacuated and purged with a nitrogen atmosphere three times and stirred at 100°C under nitrogen for 16 hours. The cooled reaction mixture was quenched with water (20ml) and extracted with ethyl acetate (3×20ml). The combined extracts were washed with brine (30ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (0 to 20% ethyl acetate in petroleum ether) to give tert-butyl ((3S,5R)-1-(7-cyano-5-fluoro-2,3-dimethyl-1H-indol-4-yl)-5-fluoropiperidin-3-yl)carbamate (350 mg, 58%) as a white solid.

[1193] 1 H NMR (300MHz, DMSO-d6) δ11.60(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,1 H),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).

[1194] ESI-MS[M+H] + Calculated value (C 21 H 26 F2N4O2)405.20, measured value: 405.10.

[1195] ​ ​

[1196]

[1197] To a solution of tert-butyl ((3S,5R)-1-(7-cyano-5-fluoro-2,3-dimethyl-1H-indol-4-yl)-5-fluoropiperidin-3-yl)carbamate (320 mg, 0.79 mmol) in dimethyl sulfoxide (6.0 mL) was added potassium carbonate (328 mg, 2.37 mmol) and hydrogen peroxide (30%, 1.34 g, 11.87 mmol). 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 x 20 mL). The combined extracts were washed with brine (30 ml), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (0 to 80% ethyl acetate in petroleum ether) to give tert-butyl ((3S,5R)-1-(7-carbamoyl-5-fluoro-2,3-dimethyl-1H-indol-4-yl)-5-fluoropiperidin-3-yl)carbamate (250 mg, 75%) as a yellow solid.

[1198] 1 H NMR (300MHz, DMSO-d6) δ10.62(s,1H),7.92(s,1H),7.40(d,J=14.1Hz,1H),7.34(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),2.74-2.65(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).

[1199] ESI-MS[M+H] + Calculated value (C 21 H 28 F2N4O3)423.21, measured value: 423.30.

[1200] Step 4: 4-((3S,5R)-3-amino-5-fluoropiperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide Amine hydrochloride

[1201]

[1202] A mixture of tert-butyl ((3S,5R)-1-(7-carbamoyl-5-fluoro-2,3-dimethyl-1H-indol-4-yl)-5-fluoropiperidin-3-yl)carbamate (250 mg, 0.59 mmol) and hydrogen chloride (4M in dioxane, 5.0 mL) was stirred at 20° C. for 2 hours. The reaction mixture was concentrated in vacuo to give 4-((3S,5R)-3-amino-5-fluoropiperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide hydrochloride (240 mg) as a yellow solid.

[1203] ESI-MS[M+H] + Calculated value (C 16 H 20 F2N4O)323.16, measured value: 323.15.

[1204] Step 5: 4-((3S,5R)-3-amino-5-fluoropiperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide Amine hydrochloride

[1205]

[1206] To a solution of but-2-ynoic acid (28 mg, 0.33 mmol) in N,N-dimethylformamide (3 mL) was added HATU (148 mg, 0.39 mmol), 4-((3S,5R)-3-amino-5-fluoropiperidin-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). 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 extracts were washed with brine (30 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. 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 NH 4 HCO 3 ), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: 35% B to 46% B, 9 min; 254 nm; retention time = 8.03 minutes) to give 4-((3S,5R)-3-(but-2-ynylamino)-5-fluoropiperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (46 mg, 42%) as an off-white solid.

[1207] 1H NMR (400MHz, DMSO-d6) δ10.63(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).

[1208] ESI-MS[M+H] + Calculated value (C 20 H 22 F2N4O2)389.17, measured value: 389.05.

[1209] Example 34

[1210] 4-((3S,5R)-3-Acrylamido-5-fluoropiperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide Synthesis of amine (Compound 34)

[1211]

[1212] 4-((3S,5R)-3-Acrylamido-5-fluoropiperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide: To a mixture of 4-[(3S,5R)-3-amino-5-fluoropiperidin-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) at 0°C was added sodium bicarbonate (70 mg, 0.84 mmol) and acryloyl chloride (30 mg, 0.33 mmol). 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 x 20 mL). The combined extracts were washed with brine (30 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (column: X Bridge Shield RP18OBD column, 19×250 mm, 10 μm; mobile phase A: water (10 mmol / L NH 4 HCO 3 ), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: 30% B to 50% B, 8 minutes; 254 nm; retention time = 7.77 minutes) to give 4-((3S,5R)-3-acrylamido-5-fluoropiperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (42.7 mg, 41%) as a white solid.

[1213] 1 H NMR (400MHz, DMSO-d6) δ10.63(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).

[1214] ESI-MS[M+H] + Calculated value (C 19 H 22 F2N4O2)377.17, measured value: 377.10.

[1215] Example 35

[1216] 4-((3S,5S)-3-(but-2-ynylamino)-5-fluoropiperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole- Synthesis of 7-formamide (Compound 35)

[1217]

[1218] Step 1: ((3S,5S)-1-(7-cyano-5-fluoro-2,3-dimethyl-1H-indol-4-yl)-5-fluoropiperidin-3-yl) tert-Butyl carbamate

[1219]

[1220] To a mixture of 4-bromo-5-fluoro-2,3-dimethyl-1H-indole-7-carbonitrile (600 mg, 2.25 mmol) and tert-butyl ((3S, 5S)-5-fluoropiperidin-3-yl)carbamate (539 mg, 2.47 mmol) in 1,4-dioxane (10 mL) was added tris(dibenzylideneacetone)-dipalladium (206 mg, 0.22 mmol), 1.1'-binaphthyl-2,2'-diphenylphosphine (140 mg, 0.22 mmol) and cesium carbonate (1.10 g, 3.37 mmol). The reaction mixture was evacuated and purged with nitrogen three times 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). The combined extracts were then washed with brine (30 ml), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (0 to 20% ethyl acetate in petroleum ether) to give tert-butyl ((3S,5S)-1-(7-cyano-5-fluoro-2,3-dimethyl-1H-indol-4-yl)-5-fluoropiperidin-3-yl)carbamate (450 mg, 50%) as a white solid.

[1221] 1 H NMR (400MHz, DMSO-d6) δ11.58(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,1 H),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).

[1222] ESI-MS[M+H] + Calculated value (C 21 H 26 F2N4O2)405.20, measured value: 405.25.

[1223] Step 2: ((3S,5S)-1-(7-Carbamoyl-5-fluoro-2,3-dimethyl-1H-indol-4-yl)-5-fluoropiperidin tert-Butyl pyridin-3-yl)carbamate

[1224]

[1225] To a solution of tert-butyl ((3S,5S)-1-(7-cyano-5-fluoro-2,3-dimethyl-1H-indol-4-yl)-5-fluoropiperidin-3-yl)carbamate (450 mg, 1.11 mmol) in dimethyl sulfoxide (6.0 mL) was added potassium carbonate (461 mg, 3.34 mmol) and hydrogen peroxide (30%, 1.89 g, 16.69 mmol). 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 x 20 ml). The combined organic layers were washed with brine (30 ml), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (0 to 80% ethyl acetate in petroleum ether) to give tert-butyl ((3S,5S)-1-(7-carbamoyl-5-fluoro-2,3-dimethyl-1H-indol-4-yl)-5-fluoropiperidin-3-yl)carbamate (420 mg, 89%) as a yellow solid.

[1226] 1 H NMR (300MHz, DMSO-d6) δ10.64(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).

[1227] ESI-MS[M+H] + Calculated value (C 21 H 28 F2N4O3)423.21, measured value: 423.25

[1228] Step 3: 4-((3S,5S)-3-amino-5-fluoropiperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide Amine hydrochloride

[1229]

[1230] A mixture of tert-butyl ((3S,5S)-1-(7-carbamoyl-5-fluoro-2,3-dimethyl-1H-indol-4-yl)-5-fluoropiperidin-3-yl)carbamate (420 mg, 0.99 mmol) and hydrogen chloride (4M in dioxane, 8 mL) was stirred at 20° C. for 2 hours. The reaction mixture was concentrated in vacuo to give 4-((3S,5S)-3-amino-5-fluoropiperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide hydrochloride (350 mg) as a yellow solid.

[1231] ESI-MS[M+H] + Calculated value (C 16 H 20 F2N4O)323.16, measured value: 323.15.

[1232] Step 4: 4-((3S,5S)-3-(but-2-ynylamino)-5-fluoropiperidin-1-yl)-5-fluoro-2,3-dimethyl-1H- Indole-7-carboxamide

[1233]

[1234] To a solution of but-2-ynoic acid (47 mg, 0.56 mmol) in N,N-dimethylformamide (5 mL) was added HATU (248 mg, 0.65 mmol), 4-((3S,5S)-3-amino-5-fluoropiperidin-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). 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 extracts were washed with brine (30 ml), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (column: Xselect CSH OBD column, 30×150 mm, 5 μm, mobile phase A: water (10 mmol / L NH 4 HCO 3 + 0.1% NH 3 .H 2 O), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 25% B to 52% B in 7 min; 220 nm; retention time = 6.17 minutes) to give 4-[(3S,5S)-3-(but-2-ynylamino)-5-fluoropiperidin-1-yl]-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (57.2 mg, 32%) as an off-white solid.

[1235] 1H NMR (300MHz, DMSO-d6) δ10.63(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),3.28-3.13(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).

[1236] ESI-MS[M+H] + Calculated value (C 20 H 22 F2N4O2)389.17, measured value: 389.25.

[1237] Example 36

[1238] 4-((3S,5R)-3-Acrylamido-5-fluoropiperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide Synthesis of amine (Compound 36)

[1239]

[1240] 4-((3S,5S)-3-Acrylamido-5-fluoropiperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide: To a mixture of 4-[(3S,5S)-3-amino-5-fluoropiperidin-1-yl]-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide hydrochloride (220 mg, 0.62 mmol) in tetrahydrofuran (4.0 mL) and water (1.0 mL) at 0°C was added sodium bicarbonate (156 mg, 1.86 mmol) and acryloyl chloride (67 mg, 0.74 mmol). 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 x 25 mL). The combined extracts were washed with brine (30 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. 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 NH 4 HCO 3 + 0.1% NH 3 .H 2 O), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 28% B to 48% B, 7 min; 220 nm; retention time = 5.33 minutes) to give 4-((3S,5S)-3-acrylamido-5-fluoropiperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (82.4 mg, 35%) as a white solid.

[1241] 1 H NMR(300MHz,DMSO-d6)δ10.64(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),2.8 2-2.75(m,1H),2.43(s,3H),2.32(s,3H),2.28-2.21(m,1H),1.78-1.53(m,1H).

[1242] ESI-MS[M+H] + Calculated value (C 19 H 22 F2N4O2)377.17, measured value: 377.30.

[1243] Example 37

[1244] 4-((3S,5R)-3-Acrylamido-5-hydroxypiperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxylate Synthesis of amide (Compound 37)

[1245]

[1246] Step 1: ((3S,5R)-1-(7-Carbamoyl-5-fluoro-2,3-dimethyl-1H-indol-4-yl)-5-hydroxypiperidin tert-Butyl pyridin-3-yl)carbamate

[1247]

[1248] To a mixture of 4-bromo-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (250 mg, 0.88 mmol) and ((3S, 5R)-5-hydroxypiperidin-3-yl) tert-butyl carbamate (228 mg, 1.05 mmol) in 1,4-dioxane (5.0 mL) was added tris(dibenzylideneacetone)dipalladium (80 mg, 0.088 mmol), 1.1'-binaphthyl-2,2'-diphenylphosphine (109 mg, 0.17 mmol) and cesium carbonate (429 mg, 1.32 mmol). The reaction mixture was evacuated and purged with nitrogen three times and stirred at 110 ° C for 40 hours under nitrogen. 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 concentrated in vacuo. The residue was purified by silica gel column chromatography (0 to 60% ethyl acetate in petroleum ether) to give tert-butyl ((3S,5R)-1-(7-carbamoyl-5-fluoro-2,3-dimethyl-1H-indol-4-yl)-5-hydroxypiperidin-3-yl)carbamate (150 mg, 41%) as a yellow solid.

[1249] 1 H NMR (400MHz, DMSO-d6) δ10.65(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).

[1250] ESI-MS[M+H] + Calculated value (C 21 H 29 F N4O4)421.22, measured value: 421.25.

[1251] Step 2: 4-((3S,5R)-3-amino-5-hydroxypiperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxylate Amide hydrochloride

[1252]

[1253] A mixture of tert-butyl ((3S,5R)-1-(7-carbamoyl-5-fluoro-2,3-dimethyl-1H-indol-4-yl)-5-hydroxypiperidin-3-yl)carbamate (140 mg, 0.33 mmol) and hydrogen chloride (4M in dioxane, 5.0 mL) was stirred at 20° C. for 2 hours. Upon completion, the reaction mixture was concentrated in vacuo to give 4-((3S,5R)-3-amino-5-hydroxypiperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide hydrochloride (130 mg) as a yellow solid.

[1254] ESI-MS[M+H] + Calculated value (C 16 H 21 N4O2F)321.16, measured value: 321.25.

[1255] Step 3: 4-((3S,5R)-3-acrylamido-5-hydroxypiperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole Indole-7-carboxamide

[1256]

[1257] To a mixture of 4-((3S,5R)-3-amino-5-hydroxypiperidin-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 added sodium bicarbonate (95 mg, 1.13 mmol) and acryloyl chloride (41 mg, 451 umol) at 0°C. The reaction mixture was stirred at 0°C for 1 hour. Upon completion, 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 anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (column: XBridgePrep OBD C18 column, 30×150 mm, 5 μm; mobile phase A: water (10 mmol / L NH 4 HCO 3 + 0.1% NH 3 .H 2 O), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 5% B to 35% B in 7 min; 220 nm; retention time = 5.48 minutes) to give 4-((3S,5R)-3-acrylamido-5-hydroxypiperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (32.3 mg, 23%) as an off-white solid.

[1258] 1H NMR (300MHz, DMSO-d6) δ10.64(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).

[1259] ESI-MS[M+H] + Calculated value (C 19 H 23 F N4O3)375.18, measured value: 375.25.

[1260] Example 38

[1261] 4-((3S,5S)-3-Acrylamido-5-hydroxypiperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxylate Synthesis of amide (Compound 38)

[1262]

[1263] Step 1: ((3S,5S)-1-(7-Carbamoyl-5-fluoro-2,3-dimethyl-1H-indol-4-yl)-5-hydroxypiperidin tert-Butyl pyridin-3-yl)carbamate

[1264]

[1265] To a mixture of 4-bromo-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (380 mg, 1.33 mmol) and ((3S, 5S)-5-hydroxypiperidin-3-yl) tert-butyl carbamate (240 mg, 1.11 mmol) in 1,4-dioxane (7.0 mL) was added tris(dibenzylideneacetone)dipalladium (102 mg, 0.11 mmol), 1.1'-binaphthyl-2,2'-diphenylphosphine (138 mg, 0.22 mmol) and cesium carbonate (542 mg, 1.66 mmol). The reaction mixture was evacuated and purged with nitrogen three times and stirred at 110 ° C for 60 hours under nitrogen. 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 concentrated in vacuo. The residue was purified by preparative TLC (100% ethyl acetate, Rf = 0.6) to give tert-butyl ((3S,5S)-1-(7-carbamoyl-5-fluoro-2,3-dimethyl-1H-indol-4-yl)-5-hydroxypiperidin-3-yl)carbamate (110 mg) as a yellow solid.

[1266] ESI-MS[M+H] + Calculated value (C 21 H 29 F N4O4)421.22, measured value: 421.35.

[1267] Step 2: 4-((3S,5S)-3-amino-5-hydroxypiperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxylate Amide hydrochloride

[1268]

[1269] A mixture of tert-butyl ((3S,5S)-1-(7-carbamoyl-5-fluoro-2,3-dimethyl-1H-indol-4-yl)-5-hydroxypiperidin-3-yl)carbamate (110 mg, 0.33 mmol) and hydrogen chloride (4M in dioxane, 5.0 mL) was stirred at 20° C. for 2 hours. Upon completion, the reaction mixture was concentrated in vacuo to give 4-((3S,5S)-3-amino-5-hydroxypiperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide hydrochloride (80 mg) as a yellow solid.

[1270] ESI-MS [M+H]+ calculated values ​​(C 16 H 21 F N4O2)321.16, measured value: 321.15.

[1271] Step 3: 4-((3S,5S)-3-Acrylamido-5-hydroxypiperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole Indole-7-carboxamide

[1272]

[1273] To a solution of 4-((3S,5S)-3-amino-5-hydroxypiperidin-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) was added sodium bicarbonate (47 mg, 0.56 mmol) and acryloyl chloride (20 mg, 0.22 mmol) at 0°C. The reaction mixture was stirred at 0°C for 1 hour. Upon completion, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3×15 mL). The combined extracts were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (column: XBridgePrep OBD C18 column, 30×150 mm, 5 μm; mobile phase A: water (10 mmol / L NH 4 HCO 3 + 0.1% NH 3 .H 2 O), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 15% B to 30% B, 7 minutes; 220 nm; retention time = 6.02 minutes) to give 4-((3S,5S)-3-acrylamido-5-hydroxypiperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (13.1 mg, 19%) as a white solid.

[1274] 1 H NMR (400MHz, DMSO-d6) δ10.60(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).

[1275] ESI-MS[M+H] + Calculated value (C 19 H 23 F N4O3)375.18, measured value: 375.15.

[1276] Example 39

[1277] 4-(trans-2-acryloyloctahydro-5H-pyrrolo[3,4-c]pyridin-5-yl)-3-chloro-5-fluoro-2-methyl- Synthesis of 1H-indole-7-carboxamide (Compound 39)

[1278]

[1279] Step 1: trans-5-(7-cyano-5-fluoro-2-methyl-1H-indol-4-yl)octahydro-2H-pyrrolo[3,4-c]pyrrolidone tert-Butylpyridine-2-carboxylate

[1280]

[1281] To a mixture of 4-bromo-5-fluoro-2-methyl-1H-indole-7-carbonitrile (600 mg, 2.37 mmol) and trans-octahydro-2H-pyrrolo[3,4-c]pyridine-2-carboxylic acid tert-butyl ester (536 mg, 2.37 mmol) in 1,4-dioxane (10 mL) was added tris(dibenzylideneacetone)dipalladium (217 mg, 0.24 mmol), 1.1'-binaphthyl-2,2'-diphenylphosphine (295 mg, 0.47 mmol) and cesium carbonate (2.32 g, 7.11 mmol). The reaction mixture was evacuated and purged with nitrogen three times 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 concentrated in vacuo. The residue was purified by column chromatography (silica gel, 0-30% ethyl acetate in petroleum ether) to give trans-tert-butyl 5-(7-cyano-5-fluoro-2-methyl-1H-indol-4-yl)octahydro-2H-pyrrolo[3,4-c]-pyridine-2-carboxylate (500 mg, 53%) as a yellow solid.

[1282] 1 H NMR(300MHz,DMSO-d6)δ7.36(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),2.91-2.79(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).

[1283] ESI-MS [M+H]+ calculated values ​​(C 22 H 27 FN4O2)399.21, measured value: 399.15.

[1284] Step 2: trans-5-(7-carbamoyl-5-fluoro-2-methyl-1H-indol-4-yl)octahydro-2H-pyrrolo[3, 4-c] tert-Butyl pyridine-2-carboxylate

[1285]

[1286] To a mixture of trans-5-(7-cyano-5-fluoro-2-methyl-1H-indol-4-yl)octahydro-2H-pyrrolo[3,4-c]pyridine-2-carboxylic acid tert-butyl ester (500 mg, 1.11 mmol) in ethanol (12 mL) and water (3.0 mL) was added 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 extracts were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 0-60% ethyl acetate in petroleum ether) to give tert-butyl trans-5-(7-carbamoyl-5-fluoro-2-methyl-1H-indol-4-yl)octahydro-2H-pyrrolo[3,4-c]pyridine-2-carboxylate (420 mg, 80%) as a yellow solid.

[1287] 1 H NMR (300MHz, DMSO-d6) δ10.83(s,1H),7.89(s,1H),7.46(d,J=14.4Hz,1H),7.27(s,1H),6.22(s,1H),3.72-3.4 3(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).

[1288] ESI-MS[M+H] + Calculated value (C 22 H 29 FN4O3)417.22, measured value: 417.15.

[1289] Step 3: trans-5-(7-carbamoyl-3-chloro-5-fluoro-2-methyl-1H-indol-4-yl)octahydro-2H-pyrrole tert-Butyl 2-[3,4-c]pyridine-2-carboxylate

[1290]

[1291] To a mixture of tert-butyl trans-5-(7-carbamoyl-5-fluoro-2-methyl-1H-indol-4-yl)octahydro-2H-pyrrolo[3,4-c]pyridine-2-carboxylate (400 mg, 0.96 mmol) in dichloromethane (10 mL) at 0°C was added N-chlorosuccinimide (128 mg, 0.96 mmol). The reaction mixture was stirred at 0°C for 1 hour. Upon completion, the reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (3 x 20 mL). The combined extracts were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 0-60% ethyl acetate in petroleum ether) to give tert-butyl trans-5-(7-carbamoyl-3-chloro-5-fluoro-2-methyl-1H-indol-4-yl)octahydro-2H-pyrrolo[3,4-c]pyridine-2-carboxylate (400 mg, 92%) as a yellow solid.

[1292] ESI-MS[M+H] + Calculated value (C 22 H 28 ClFN4O3)451.18, 453.18; measured values: 451.10, 453.10.

[1293] Step 4: 3-chloro-5-fluoro-2-methyl-4-(trans-octahydro-5H-pyrrolo[3,4-c]pyridin-5-yl)-1H-indole Indole-7-carboxamide hydrochloride

[1294]

[1295] A mixture of tert-butyl trans-5-(7-carbamoyl-3-chloro-5-fluoro-2-methyl-1H-indol-4-yl)octahydro-2H-pyrrolo[3,4-c]pyridine-2-carboxylate (400 mg, 0.89 mmol) and hydrogen chloride (4 M in dioxane, 8.0 mL) was stirred at 20° C. for 2 h. Upon completion, the reaction mixture was concentrated in vacuo to afford 3-chloro-5-fluoro-2-methyl-4-(trans-octahydro-5H-pyrrolo[3,4-c]pyridin-5-yl)-1H-indole-7-carboxamide hydrochloride (420 mg) as a yellow solid.

[1296] ESI-MS[M+H] + Calculated value (C 17 H 20 ClFN4O)351.13, 353.13; measured values: 351.05, 353.05.

[1297] Step 5: 4-(trans-2-acryloyloctahydro-5H-pyrrolo[3,4-c]pyridin-5-yl)-3-chloro-5-fluoro-2- Methyl-1H-indole-7-carboxamide

[1298]

[1299] To a mixture of 3-chloro-5-fluoro-2-methyl-4-(trans-octahydro-5H-pyrrolo[3,4-c]pyridin-5-yl)-1H-indole-7-carboxamide hydrochloride (300 mg, 0.77 mmol) in tetrahydrofuran (5.0 mL) was added N,N-diisopropylethylamine (500 mg, 3.87 mmol). After 10 min, 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 h. Upon completion, the reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (3×20 mL). The combined extracts were washed with brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (column: Xselect CSH OBD column, 30×150 mm, 5 μm, mobile phase A: water (10 mmol / L NH 4 HCO 3 + 0.1% NH 3 .H 2 O), mobile phase B: acetonitrile, flow rate: 60 mL / min, gradient: 35% B to 55% B in 7 min, 220 nm, retention time = 5.27 minutes) to give 4-(trans-2-acryloyloctahydro-5H-pyrrolo[3,4-c]pyridin-5-yl)-3-chloro-5-fluoro-2-methyl-1H-indole-7-carboxamide (78.6 mg, 25%, mixture of trans enantiomers) as a white solid.

[1300] 1 H NMR (400MHz, DMSO-d6) δ11.24(s,1H),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).

[1301] ESI-MS [M+H]+ calculated values ​​(C 20 H 22 ClFN4O2)405.14, 407.14; measured values: 405.10, 407.10.

[1302] Example 40

[1303] 4-(1-(But-2-ynyl)octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-3-chloro-5-fluoro-2-methyl- Synthesis of 1H-indole-7-carboxamide (Compound 40)

[1304]

[1305] Step 1: 6-(7-cyano-5-fluoro-2-methyl-1H-indol-4-yl)octahydro-1H-pyrrolo[3,4-b]pyridine-1- tert-Butyl formate

[1306]

[1307] To a mixture of 4-bromo-5-fluoro-2-methyl-1H-indole-7-carbonitrile (600 mg, 2.37 mmol) and tert-butyl octahydro-1H-pyrrolo[3,4-b]pyridine-1-carboxylate (643 mg, 2.85 mmol) in 1,4-dioxane (10 mL) was added 1.1'-binaphthyl-2,2'-diphenylphosphine (295 mg, 0.47 mmol), tris(dibenzylideneacetone)dipalladium (217 mg, 0.23 mmol) and cesium carbonate (2.32 g, 7.11 mmol). The reaction mixture was degassed and backfilled with nitrogen five times and stirred at 100 ° C for 16 h. 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 concentrated in vacuo. The residue was purified by column chromatography (silica gel, 25% ethyl acetate in petroleum ether) to give tert-butyl 6-(7-cyano-5-fluoro-2-methyl-1H-indol-4-yl)octahydro-1H-pyrrolo[3,4-b]pyridine-1-carboxylate (720 mg, 76%) as a yellow solid.

[1308] 1H NMR (300MHz, DMSO-d6) δ11.49(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),3.6 7-3.56(m,1H),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).

[1309] ESI-MS [M+H]+ calculated values ​​(C 22 H 27 FN4O2)399.21, measured value: 399.30.

[1310] Step 2: 6-(7-Carbamoyl-5-fluoro-2-methyl-1H-indol-4-yl)octahydro-1H-pyrrolo[3,4-b] tert-Butyl pyridine-1-carboxylate

[1311]

[1312] To a mixture of tert-butyl 6-(7-cyano-5-fluoro-2-methyl-1H-indol-4-yl)octahydro-1H-pyrrolo[3,4-b]pyridine-1-carboxylate (720 mg, 1.81 mmol) in ethanol (8 mL) and water (2.0 mL) was added Parkin catalyst (38 mg, 0.09 mmol). The reaction mixture was stirred at 90°C for 2 h. The cooled mixture was diluted with water (40 mL) and extracted with ethyl acetate (3 x 40 mL). The combined extracts were washed with water (2 x 30 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 50% ethyl acetate in petroleum ether) to give tert-butyl 6-(7-carbamoyl-5-fluoro-2-methyl-1H-indol-4-yl)octahydro-1H-pyrrolo[3,4-b]pyridine-1-carboxylate (600 mg, 79%) as a yellow solid.

[1313] ESI-MS [M+H]+ calculated values ​​(C 22 H 29 FN4O3)417.22, measured value: 417.20.

[1314] Step 3: 6-(7-Carbamoyl-3-chloro-5-fluoro-2-methyl-1H-indol-4-yl)octahydro-1H-pyrrolo[3, 4-b] tert-Butyl pyridine-1-carboxylate

[1315]

[1316] To a solution of tert-butyl 6-(7-carbamoyl-5-fluoro-2-methyl-1H-indol-4-yl)octahydro-1H-pyrrolo[3,4-b]pyridine-1-carboxylate (600 mg, 1.44 mmol) in DMF (10 mL) at 0°C was added 1-chloropyrrolidine-2,5-dione (192 mg, 1.44 mmol). The reaction mixture was stirred at 0°C for 1 h. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (3 x 30 mL). The combined extracts were washed with water (2 x 30 mL) and brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 40% ethyl acetate in petroleum ether) to give tert-butyl 6-(7-carbamoyl-3-chloro-5-fluoro-2-methyl-1H-indol-4-yl)octahydro-1H-pyrrolo[3,4-b]pyridine-1-carboxylate (600 mg, 92%) as a yellow solid.

[1317] ESI-MS [M+H]+ calculated values ​​(C 22 H 28 ClFN4O3)451.18, 453.18; measured values: 451.20, 453.20.

[1318] Step 4: 3-Chloro-5-fluoro-2-methyl-4-(octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-1H-indole-7-yl Formamide 2,2,2-trifluoroacetate

[1319]

[1320] To a solution of tert-butyl 6-(7-carbamoyl-3-chloro-5-fluoro-2-methyl-1H-indol-4-yl)octahydro-1H-pyrrolo[3,4-b]pyridine-1-carboxylate (600 mg, 1.33 mmol) in dichloromethane (5.0 mL) was added trifluoroacetic acid (5.0 mL). The reaction mixture was stirred at 20 ° C for 2 h. The resulting mixture was concentrated in vacuo to give 3-chloro-5-fluoro-2-methyl-4-(octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-1H-indole-7-carboxamide 2,2,2-trifluoroacetate (600 mg) as a yellow solid.

[1321] ESI-MS [M+H]+ calculated values ​​(C 17 H 20 ClFN4O)351.13, 353.13; measured values: 351.10, 353.10.

[1322] Step 5: 4-(1-(But-2-ynyl)octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-3-chloro-5-fluoro-2- Methyl-1H-indole-7-carboxamide

[1323]

[1324] To a mixture of 3-chloro-5-fluoro-2-methyl-4-(octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-1H-indole-7-carboxamide 2,2,2-trifluoroacetate (600 mg, 1.33 mmol) in DMF (10 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (757 mg, 1.99 mmol), but-2-ynoic acid (134 mg, 1.60 mmol), and N,N-diisopropylethylamine (663 mg, 5.13 mmol). The reaction mixture was stirred at 20°C for 2 h. The resulting mixture was diluted with water (30 mL) and extracted with ethyl acetate (2 x 30 mL). The combined extracts were washed with water (2 x 30 mL) and brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (column: Xselect CSH OBD column, 30×150 mm, 5 μm, mobile phase A: water (10 M NH 4 HCO 3 + 0.1% NH 3 .H 2 O); mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 40% B to 60% B, 7 min; 220 nm; retention time = 6.02 minutes) to give 4-(1-(but-2-ynyl)octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-3-chloro-5-fluoro-2-methyl-1H-indole-7-carboxamide (28.6 mg, 5%) as an off-white solid.

[1325] 1 H NMR (300MHz, DMSO-d6) δ11.26(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).

[1326] ESI-MS [M+H]+ calculated values ​​(C 21 H 22 ClFN4O2)417.14, 419.14; measured values: 417.10, 419.10.

[1327] Example 41

[1328] Compounds 41a-41t shown in Table 7-2 were prepared according to similar methods as described in the aforementioned schemes and examples by using corresponding appropriate starting materials.

[1329] Table 7-2: Compounds 41A-41T

[1330]

[1331]

[1332]

[1333]

[1334]

[1335]

[1336] Example 42

[1337] Synthesis of compounds 42a-42x

[1338] Compounds 42a-42x shown in Table 8-2 were prepared according to similar methods as described in the aforementioned schemes and examples by using corresponding appropriate starting materials.

[1339] Table 8-2: Compounds 42A-42X

[1340]

[1341]

[1342]

[1343]

[1344]

[1345]

[1346]

[1347] Example 43

[1348] Assays to determine activity against BTK

[1349] Compounds (test or control) were prepared in DMSO at the desired concentration and serially diluted to 11 concentrations by 3-fold dilution in 384pp plates using a TECAN EVO 200. 20 nL of the stock solution was transferred to the 384 plate using an Echo 550. DMSO was used as a vehicle control.

[1350] 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 uM), 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; FLPeptide2 was obtained from PerkinElmer, and ibrutinib was obtained from Selleck. 5 μL of ATP solution was added to each well, followed by 15 μL of BTK solution to initiate the reaction. (Note that the final volume of each well is 20 μL, containing 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 uM), ATP (1 mM) and BTK (2 nM)).

[1351] The plate was incubated at room temperature for 90 minutes, and then stop buffer (75 μL, containing 0.5 M EDTA) was added to terminate the reaction. Samples from each well were analyzed using an EZ plate reader. The remaining activity % was calculated using the conversion rate (CR) reading according to the following formula:

[1352]

[1353] Calculate IC by floating bottoms and tops using XLFit (Equation 201) 50 .

[1354] BTK IC of representative compounds of the present invention 50 The values ​​are provided below in Table 9. With respect to BTK activity, Table 9 lists the following activities:

[1355] "A" indicates an IC value less than 10 nM 50 ,

[1356] "B" indicates an IC of 10 nM to less than 100 nM 50 ;and

[1357] "C" indicates an IC of 100 nM or greater 50 .

[1358] Example 44

[1359] Assay to determine BTK activity in RAMOS B cells

[1360] 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 manual of the FLIRP Calcium 6 Assay Kit: the dye was diluted with assay buffer (1× HBSS solution of 20 mM HEPES, pH 7.4); probenecid was added to a final concentration of 5 mM; and vigorous vortexing was performed for 1-2 minutes. The 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 cells / ml. An equal volume of 2× dye solution was added to the cell suspension. The cells were then seeded into 384-well poly-D-lysine-coated plates at 20 μl / well. The plates were centrifuged at 1000 rpm for 3 minutes, then incubated at 37°C for 2 hours, and then incubated at 25°C for another 15 minutes. Compounds were prepared at 3X concentration in dilution buffer (20 mM HEPES and 0.1% BSA in 1X HBSS, pH 7.4). Serially diluted compounds were transferred from the source plate to a 384-well compound plate using an Echo 550 (Labcyte). 20 μl / well compound dilution buffer was added to the compound plate and mixed on a plate shaker for 2 minutes. 4X EC was prepared in dilution buffer. 80 Anti-IgM (Jackson ImmunoResearch) was added to a new 384-well compound plate at 20 μl / well. After incubation at 25°C in the dark for 60 minutes, the cell plate containing 4X EC 80 The anti-IgM compound plate and FLIPR terminal were placed in FLIPR (Molecular Devices). 10 μl / well of 4X EC 80 Anti-IgM was transferred to the cell plate and the plate was read at 1 second intervals for 160 seconds.

[1361] IC of representative compounds of the present invention 50 The values ​​are provided below in Table 9. With respect to Ramos activity, Table 9 lists the following activities:

[1362] "A" indicates an IC value less than 10 nM 50 ;

[1363] "B" indicates an IC of 10 nM to less than 100 nM 50 ;and

[1364] "C" indicates an IC of 100 nM or greater 50 .

[1365] Table 9 :

[1366] Activity of representative compounds

[1367]

[1368]

[1369]

[1370] Example 45

[1371] Assay to determine the rate of BTK inactivation in human whole blood

[1372] Human whole blood compound processing and lysis

[1373] Human whole blood was purchased from StemExpress and stored at ambient temperature until the time of the experiment. 1× lysis buffer was prepared by using 10× lysis buffer (Cell Signaling Technology, #9083S), distilled water, 100× protease and phosphatase inhibitor cocktail (ThermoFisher, #78440) and GBD-1066 probe (final: 0.4 μM). This was prepared fresh on each experimental day. Lysis buffer was added to all wells in a v-bottom plate (GreinerBio, #651261) in a volume of 30 μL in preparation for time point collection. The compounds were reconstituted as a 10 mM stock solution and diluted in DMSO in two-fold serial dilutions to generate an 8-point curve, with the last point being DMSO only, forming a 100× dilution series. A working 10× dilution series was formed using 1.0 μL of prepared DMSO titrated (100×) into 300 μL 1× PBS to keep DMSO constant. Human whole blood was added to a new 96-well v-bottom plate at a volume of 225 μL / well, where eight wells in a column were sufficient to test one compound. For compound treatment, 25 μL of 10× serial dilutions in PBS were added to 225 μL of whole blood and then briefly pipetted up and down twice. The plate was covered with a lid and incubated at 37°C for 5, 15, 30, and 60 minutes. At each time point, 30 μL of treated blood was drawn from each column and added to a preloaded collection plate containing 30 μL of supplemented lysis buffer and briefly mixed. The collected and lysed samples were shaken on a rotator at room temperature for 60 minutes. These samples were freshly used for detection via ELISA, and if repeated, the remaining samples were frozen at -80°C.

[1374] ELISA: Determine the amount of unoccupied BTK

[1375] When lysing the samples, all streptavidin pre-coated plates (R&D Systems, #CP004) were brought to room temperature. Assay buffer 1, 1X PBS+0.05% Tween 20+1% BSA was prepared and stored at 4°C when not in use. Using this assay buffer, assay buffer+1× protease / phosphatase inhibitor cocktail (PIC) was prepared in the amount required for all samples. Assay buffer+PIC was added to the ELISA plate in a volume of 90 μL / well. The lysed blood sample (10 μL) was added to the ELISA plate. BTK recombinant protein dilutions were prepared in assay buffer+PICS and used in μM. Standards were loaded into the ELISA plate at 100 μL / well in duplicate. These samples and standards were retained in the plate, sealed, and stored at 4°C overnight. The next day, the plate was washed four times with 1X wash buffer (1X PBS+0.05% Tween 20) using a plate washer. Each time the plate was inverted to drain all fluid and blotted on a clean paper towel to remove the remaining liquid. Prepare assay buffer 2 (1X PBS+0.05% Tween 20+0.05% BSA) and store at 4°C when not in use. Antibody α-BTK (clone D3H5, Cell Signaling Technology#8547S) was diluted 1:500 in assay buffer 2. Diluted α-BTK antibody was added at 100 μl / well. Cover the plate with an 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. Each time the plate was inverted to drain all fluid and blotted on a clean paper towel to remove the remaining liquid. The third antibody (Jackson Immuno Research, #711-005-152) was diluted 1:2,500 with assay buffer 2. Add the diluted antibody at 100 μl / well. Cover the plate with an adhesive film and incubate for one hour at room temperature. Wash the plate four times with 1X wash buffer using a plate washer. Each time the plate is inverted to drain all fluid and blotted on a clean paper towel to remove the remaining liquid. Preheated TMB substrate (ThermoFisher, #34029) is added to the plate at 100 μl / well. The plate is incubated in the dark at room temperature for about 5-10 minutes. The reaction is stopped by adding 50 μl / well of 2N sulfuric acid (H2SO4) (R&D Systems, #DY994). Read the plate at a wavelength of 460nm and 570nm (calibration wavelength) in a plate reader. Use GraphpadPrism to create an XY table + graph, listing 0-60 minutes as the X-axis and concentration as the Y-axis. A one-phase decay model fit is applied to the data. Check the result table, obtain the K value and create a new XY table + graph. Assign the concentration to the X-axis and enter the K value from the first analysis.The Michaelis-Menten formula was applied to the data. From the results table, Vmax(Kinact) and Km(KI) values ​​were used to calculate Kinact / Ki 10-4 nM-1 min-1 by dividing by Vmax,Km*10000.

[1376] Regarding the inactivation rate, the Kinact / Ki values ​​of representative compounds of the present disclosure are provided in Table 10 below. Likewise, Table 10 lists the following activities:

[1377] “A” means Kinact / Ki>10×10 -4 nM -1 min -1 ,

[1378] “B” means Kinact / Ki is 10×10 -4 nM -1 min -1 to 1×10 -4 nM -1 min -1 ,and

[1379] “C” means Kinact / Ki<1×10 -4 nM -1 min -1 .

[1380] Table 10 :

[1381] BTK inactivation activity of representative compounds

[1382]

[1383] Example 46

[1384] Plasma and total brain concentrations were determined 1 hour after a single oral administration of test compound to female C57BL / 6 mice.

[1385] Test products

[1386] Acalabrutinib, ibrutinib, and brevitinib were used as comparative control compounds .

[1387] Acalabrutinib It is a BTK inhibitor approved for the treatment of non-Hodgkin lymphomas called mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL), or small lymphocytic leukemia (SLL).

[1388] Ibrutinib It is a BTK inhibitor approved for the treatment of mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL) / small lymphocytic lymphoma (SLL), Waldenstrom's macroglobulinemia (WM), marginal zone lymphoma (MZL) and chronic graft-versus-host disease (cGVHD).

[1389] Britinib is a BTK inhibitor approved for the treatment of mantle cell lymphoma (MCL) and is in clinical trials for the treatment of rheumatoid arthritis, systemic lupus erythematosus, and primary Sjögren's syndrome.

[1390] Test article preparation

[1391] The appropriate amount of test article was dissolved in a 10% dimethylacetamide (DMA) / 90% (20% hydroxypropyl-b-cyclodextrin (HP-B-CD) w / v) aqueous solution to obtain a final concentration of 1 mg / mL for oral administration. Ultrasonication, vortexing, and homogenization were used as needed. Three female C57BL / 6 mice aged 7-9 weeks (20 g-30 g) were administered 10 mg / kg of the test article solution by gavage.

[1392] Sample collection and processing

[1393]

[1394] Sample analysis

[1395] The concentrations of representative test compounds in plasma and brain samples were analyzed using LC-MS / MS (plasma and brain homogenate standard curves were used for all samples as appropriate). Regarding brain: plasma ratios, Table 11 lists the following results:

[1396] “A” indicates a ratio > 0.5;

[1397] "B" indicates a ratio between 0.1 and 0.5; and

[1398] “C” indicates a ratio < 0.1.

[1399] Table 11:

[1400] Brain and plasma drug levels

[1401]

[1402] The various embodiments described above can be combined to provide additional embodiments. All U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications, and non-patent publications mentioned in this specification and / or listed in the patent application data sheet are incorporated herein by reference in their entirety. If necessary, various aspects of the embodiments can be modified to adopt the concepts of the various patents, applications, and publications to provide further embodiments.

[1403] These and other changes can be made to the embodiments in light of the above detailed description. In general, in the following claims, the terms used should not be construed to limit the claims to the specific embodiments disclosed in the specification and claims, but should be construed to include all possible embodiments and the full scope of equivalents to which such claims are entitled. Therefore, the claims are not limited by this disclosure.

[1404] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

Claims

1. A compound having a structure of formula (I): or a pharmaceutically acceptable salt, chiral isomer, tautomer or racemate thereof, wherein: --- Represents a single bond; R 1 is -H; R 2 is -H; R I1 is -Cl, -F or -CN; R I2 is -F; and R B It is -CH=CH2, -C≡CH or -C≡C-CH3.

2. The compound according to claim 1, wherein R B It is -CH=CH2.

3. The compound according to claim 1, wherein R I1 It is -Cl.

4. The compound according to claim 1, which has the structure of formula (IS) or (IR):

5. The compound according to claim 1, having the following structure: or a pharmaceutically acceptable salt, chiral isomer, tautomer or racemate thereof.

6. The compound according to claim 1, having the following structure: or a pharmaceutically acceptable salt, chiral isomer, tautomer or racemate thereof.

7. The compound according to claim 5, having the following structure: or a pharmaceutically acceptable salt, chiral isomer, tautomer or racemate thereof.

8. The compound according to claim 5, having the following structure: or a pharmaceutically acceptable salt, chiral isomer, tautomer or racemate thereof.

9. A pharmaceutically acceptable salt of a compound according to any one of claims 1 to 8. 10 . A pharmaceutical composition comprising the compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt, chiral isomer, tautomer or racemate thereof.

11. The pharmaceutical composition according to claim 10, further comprising a pharmaceutically acceptable carrier, adjuvant or vehicle.

12. Use of the compound according to any one of claims 1 to 8 or its pharmaceutically acceptable salt, chiral isomer, tautomer or racemate, or the pharmaceutical composition according to claim 10 or 11 in the preparation of a medicament for inhibiting protein kinase.

13. The use according to claim 12, wherein the protein kinase is BTK.

14. Use of the compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt, chiral isomer, tautomer or racemate thereof, or the pharmaceutical composition according to claim 10 or 11 in the preparation of a medicament for treating a BTK-dependent disorder.

15. The use according to claim 14, wherein the BTK-dependent disorder is primary CNS lymphoma.

16. The use according to claim 14, wherein the BTK-dependent disorder is cancer, an autoimmune disease, an inflammatory disease or a thromboembolic disease.

17. The use according to claim 16, wherein the autoimmune disease is multiple sclerosis, rheumatoid arthritis, psoriasis, Sjögren's syndrome or systemic lupus erythematosus.

18. The use according to claim 16, wherein the inflammatory disease is urticaria.

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