PKC-θ modulator

Abstract

Disclosed are compounds, compositions and methods for treating diseases, syndromes, conditions and disorders affected by modulation of PKC-theta. Such compounds are represented herein by Formula I, wherein the variables are defined herein. TIFF2024518447000142.tif8164

Description

Technical Field

[0001] The present disclosure relates to novel compounds capable of regulating PKC-θ phosphorylation activity. Such phosphorylation activity can be inhibited by the compounds described herein. The invention further describes the synthesis of the compounds and their use as pharmaceuticals in diseases or disorders in which PKC-θ regulation may be beneficial.

Background Art

[0002] Protein kinases constitute a large family of structurally related enzymes and are responsible for controlling various intracellular signal transduction processes (see Hardie, G and Hanks, S. The Protein Kinase Facts Book, I and II, Academic Press, San Diego, CA:1995).

[0003] The association between abnormal protein phosphorylation and diseases is well known. Therefore, protein kinases are an important group of drug discovery targets (see, for example, Cohen, Nature, vol. 1 (2002), pp 309-315, Gaestel et al. Curr. Med. Chem, 2007, pp 2214-223; Grimminger et al. Nat. Rev. Drug Disc. vol. 9(12), 2010, pp 956-970).

[0004] Protein kinase C (hereinafter, PKC) is a family of protein kinases specific for serine and threonine. PKC family members are known to phosphorylate a wide variety of protein targets and are involved in diverse intracellular signal transduction pathways. Each member of the PKC family is thought to have a unique expression profile and to play a different role.

[0005] PKC members can be classified into three groups: Group I (Ca 2+and DAG (diacylglycerol) dependent: PKC-α, PKC-βI, PKC-βII and PKC-γ; Group II (Ca 2+ Independent): PKC-δ (hereafter, PKC-delta), PKC-e, PKC-η (or PKC-eta), and PKC-θ (hereafter, PKC-theta); Group III (Ca 2+ and DAG-independent): PKC-i, PKC-ζ, PKC-μ (Brezar et al., 2015, Frontiers Immunol).

[0006] The PKC-θ isoform of PKC is highly expressed in T lymphocytes and plays a crucial role in T cell activation induced by the T cell receptor (TCR). PKC-θ signals via transcription factors such as NF-κB, NFAT, and AP-1, leading to the release of cytokines such as IL-2 and IFN-γ, which then promote T cell proliferation, differentiation, and survival (Brezar et al., 2015, Front Immunol., 6:530). Unlike the broad-spectrum repressive mechanisms exhibited by calcineurin inhibitors, inhibition of PKC-θ shows selective effects on the immune system (Brezar et al., 2015, Front Immunol., 6:530). In mice lacking PKC-θ activity, the antiviral response remains intact (Zhang et al., Adv Pharm. 2013;66:267-31). In regulatory T cells (Tregs), PKC-θ signaling is not essential for activation and function (Zhang et al., Adv Pharm. 2013;66:267-31). - / - The mice showed a significant decrease in the proportion of circulating Tregs, and Prkcq - / -Tregs isolated from mice retained inhibitory activity (Gupta, et al., 2008). Pharmacological inhibition of PKC-θ protected Tregs from TNFα-induced inactivation and enhanced protection of mice from inflammatory colitis (Zanin-Zhorov, et al., 2010). In fact, there is evidence that PKC-θ is a negative regulator of Treg function (Zhang et al., Adv Pharm. 2013;66:267-31).

[0007] In human diseases, genome-wide association studies (GWAS; Brezar et al., 2015, Front Immunol., 6:530) have identified associations between single nucleotide polymorphisms (SNPs) specific to the Prkcq locus and type 1 diabetes mellitus (T1D), rheumatoid arthritis (RA), and celiac disease. Furthermore, pharmacological inhibition of PKC-θ rescued Treg activity deficiencies from rheumatoid arthritis patients (Zanin-Zhorov, et al., 2010).

[0008] PKC-θ activity is crucial in Th2 (allergic diseases) and Th17 (autoimmune diseases) responses and differentiation (Zhang et al., Adv Pharm., 2013;66:267-31). - / - Mice are protected in Th2 models of allergic pneumonia and parasitic infections. Similarly, inactivation of PKC-θ activity is protective in Th17-driven mouse models of experimental autoimmune encephalomyelitis (EAE), adjuvant-induced arthritis, and colitis.

[0009] PKC-θ is involved in various types of cancer, and PKC-θ-mediated signaling events control cancer development and progression. In these types of cancer, high expression of PKC-θ leads to abnormal cell proliferation, migration, and invasion, resulting in a malignant phenotype (Nicolle, A et al., Biomolecules, 2021, 11, 221). Inhibition of PKC-θ may also be useful in treating cancers in which PKC-θ is involved.

[0010] Small molecule inhibitors of PKC-θ are known. For example, inhibitors based on a pyrazolopyrimidine scaffold are described in WO 2011 / 139273, and PKC-θ inhibitors based on a diaminopyrimidine core are described in WO 2015 / 095679.

[0011] To date, there are no effective and approved medical treatments based on the inhibition of PKC-θ. The main reason is that it is difficult to ensure a strong inhibition that shows appropriate selectivity of the PKC-θ isoform over other isoforms, especially PKC-δ of the PKC family (group 2) and other kinases.

[0012] The present invention has been devised in consideration of the above points.

Summary of the Invention

[0013] In one aspect of the present invention, formula I:

Chemical formula

[0014] In embodiments, the compounds of the present disclosure are defined by structural formula II: [ka] It has.

[0015] In embodiments, the compounds of the present disclosure have structural formula IIa: [ka] It has the following characteristics, and R17 in the formula is as follows: [ka] (In the formula, R11 is selected from the group consisting of the following: hydrogen, halogens, and C1-2 alkyl groups; R12 is selected from the group consisting of the following: hydrogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkylhydroxyl, and C1-2 alkylnitrile; R13 is selected from the group consisting of the following: hydrogen, halogens, and C1-2 alkyl groups; R14 is selected from the group consisting of the following: hydrogen and C1-2 alkyl; R15 is selected from the group consisting of the following: hydrogen and C1-2 alkyl; R16 is selected from the group consisting of the following: hydrogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkylhydroxy, and C1-3 alkylalkoxy; n is selected from the group consisting of the following: 0 and 1; p is selected from the following groups: 1 and 2; X is selected from the group consisting of the following: CH2 and O; Y is selected from the group consisting of the following: CH2, O, NH, and NMe. It is selected from the group consisting of the following.

[0016] In an explicit manner: R1 is selected from the group consisting of the following: hydrogen, Me, Et, OMe, OEt, OH, NH2, NHMe, and NHEt; R2 is selected from the group consisting of the following: hydrogen, Me and Et; or R1 and R2 together form a optionally substituted 3- to 5-membered spirocarbocyclic or heterocyclic ring, particularly a optionally substituted 4- to 5-membered carbocyclic or heterocyclic spiroring; in one embodiment, the carbocyclic or heterocyclic spiroring is unsubstituted; in another embodiment, the carbocyclic or heterocyclic spiroring is substituted with one or more substituents selected from the group consisting of: C1-2 alkyl, halogen, C1-2 haloalkyl, hydroxyl, and C1-2 alkoxyl; A is selected from the group consisting of the following: CH, CF, C-Cl, and C-Br; B is selected from the group consisting of the following: N, CH, CF, C-Cl, and C-Br; R17 is described below: [ka] (In the formula, R18 is selected from the group consisting of the following: hydrogen and halogens; R19 is selected from the group consisting of the following: hydrogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkylhydroxy; m is selected from the following group: 0 and 1; R20 is selected from the group consisting of the following: hydrogen, halogen; X is selected from the group consisting of the following: CH2 and O; R21 and R22 are each independently selected from the group consisting of: hydrogen and C1-3 alkyl groups; Y is selected from the group consisting of the following: CH2, O, and NH; R23 is selected from the group consisting of the following: hydrogen, C1-3 alkyl, C1-3 haloalkyl. It is selected from the group consisting of the following.

[0017] In embodiments, the compounds of the present disclosure are defined by structural formula III: [ka] It is a compound having the following in the formula: D is selected from the following group: N, CH, and C-R3; R3 is selected from the group consisting of the following: C1-3 alkyl, C2-5 alkylalkoxy, C1-3 haloalkyl, and halogen; R4 is selected from the group consisting of the following: hydrogen, C1-3 alkyl, C2-5 alkylalkoxyl, C1-3 haloalkyl, and halogen.

[0018] In embodiments, the compounds of the present disclosure are structural formulas IIIa, IIIb, or IIIc: [ka] It has the following characteristics, in the formula, R17, see below: [ka] (In the formula, R11 is selected from the group consisting of the following: hydrogen, halogens, and C1-2 alkyl groups; R12 is selected from the group consisting of the following: hydrogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkylhydroxyl, and C1-2 alkylnitrile; R13 is selected from the group consisting of the following: hydrogen, halogens, and C1-2 alkyl groups; R14 is selected from the group consisting of the following: hydrogen and C1-2 alkyl; R15 is selected from the group consisting of the following: hydrogen and C1-2 alkyl; R16 is selected from the group consisting of the following: hydrogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkylhydroxyl, and C1-3 alkylalkoxyl; n is selected from the group consisting of the following: 0 and 1; p is selected from the following groups: 1 and 2; X is selected from the group consisting of the following: CH2 and O; Y is selected from the group consisting of the following: CH2, O, NH, and NMe. It is selected from the group consisting of the following.

[0019] In an explicit manner: R1 is selected from the group consisting of the following: hydrogen, Me, Et, OMe, OH, NH2, and NHMe; R2 is selected from the group consisting of the following: hydrogen, Me and Et; or R1 and R2 together form a 3- to 5-membered spirocarbon or heterocyclic ring, which may be substituted as desired; A is selected from the group consisting of the following: CH, CF, C-Cl, and C-Br; R17 is described below: [ka] (In the formula, R18 is selected from the group consisting of the following: hydrogen and halogens; R19 is selected from the group consisting of the following: hydrogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkyl, and hydroxyl; m is selected from the following group: 0 and 1; R20 is selected from the group consisting of the following: hydrogen and halogens; X is selected from the group consisting of the following: CH2 and O; R21 and R22 are each independently selected from the group consisting of: hydrogen and C1-3 alkyl groups; Y is selected from the group consisting of the following: CH2, O, and NH; R23 is selected from the group consisting of the following: hydrogen, C1-3 alkyl, and C1-3 haloalkyl. It is selected from the group consisting of the following.

[0020] In another aspect, the present invention provides pharmaceutical compositions comprising a compound according to the present disclosure, or a pharmaceutically acceptable salt, solvate, stereoisomer or mixture of stereoisomers, tautomer, isotopic form or pharmaceutically active metabolite or combination thereof, and one or more pharmaceutically acceptable carriers.

[0021] In another embodiment, the present invention provides compounds or pharmaceutical compositions according to the present disclosure for use in the treatment of a disease or disorder selected from autoimmune diseases and / or inflammatory diseases and / or neoplastic diseases and / or cancer and / or HIV infection and replication. Preferably, the disease or disorder is selected from the group consisting of rheumatoid arthritis, multiple sclerosis, psoriasis and atopic dermatitis.

[0022] In embodiments, the compound or pharmaceutical composition for use according to this disclosure is a PKC-θ inhibitor.

[0023] In embodiments, use refers to a method of administering the compound orally, topically, by inhalation or intranasal administration, or systemically by intravenous injection, intraperitoneal injection, subcutaneous injection or intramuscular injection. In embodiments, use refers to a method of administering the compound according to the disclosure in combination with one or more additional therapeutic agents. In embodiments, administration includes administering the compound according to the disclosure simultaneously, sequentially, or separately with one or more additional therapeutic agents.

[0024] In embodiments, use is characterized by administering an effective amount of the compound according to this disclosure to a subject, wherein the effective amount is approximately 5 nM to approximately 10 μM in the subject's blood.

[0025] In another aspect of the present invention, a method is provided for treating or preventing a PKC-θ-mediated disease or a condition that is treatable or preventable by inhibition of a kinase, such as PKC-θ. In embodiments, the disease may be an autoimmune, inflammatory disease, cancer and / or neoplastic disease and / or cancer and / or HIV infection and replication-related disease (in particular, autoimmune and inflammatory diseases) in a subject requiring it. Preferably, the disorder or disease is selected from the group consisting of: rheumatoid arthritis, multiple sclerosis, psoriasis, and atopic dermatitis.

[0026] In embodiments, the method comprises administering a compound or a pharmaceutical composition according to the disclosure. Preferably, the compound is a PKC-θ inhibitor, or the pharmaceutical composition comprises a PKC-θ inhibitor.

[0027] In embodiments, the method includes administering the compound or pharmaceutical composition or systemically by oral administration, topical administration, inhalation or intranasal administration, or by intravenous injection, intraperitoneal injection, subcutaneous injection or intramuscular injection. In embodiments, the method includes administering the compound or pharmaceutical composition according to the disclosure in combination with one or more additional therapeutic agents. In embodiments, administration includes administering the compound or pharmaceutical composition according to the disclosure with one or more additional therapeutic agents simultaneously, sequentially, or separately.

[0028] In embodiments, the method comprises administering an effective amount of the compound according to the disclosure to a subject, the effective amount being approximately 5 nM to approximately 10 μM in the subject's blood.

[0029] Within the scope of this application, the various aspects, embodiments, examples and alternatives described in the preceding paragraphs, claims and / or the following description and drawings, and in particular their individual features, are expressly intended to be independent or in any combination. That is, all embodiments and / or features of any embodiment can be in any way and / or combination, except where such features are incompatible. More specifically, it is particularly intended that any embodiment of any aspect may form an embodiment of any other aspect, and all such combinations are encompassed within the scope of the invention. The applicant reserves the right to amend the initially filed claims or to file new claims accordingly, including the right to amend the initially filed claims to depend on and / or incorporate features of other claims that were not originally claimed as such. Detailed Description of the Invention

[0030] This specification describes compounds and compositions (e.g., organic molecules, research tools, pharmaceutical formulations and therapeutic agents); uses of the compounds and compositions disclosed herein (in vitro and in vivo); and corresponding methods, whether for diagnostic, therapeutic or research purposes. The chemical synthesis and biological testing of the compounds disclosed herein are also described. Beneficially, the compounds, compositions, uses and methods are useful for the study and / or treatment of diseases or disorders in animals such as humans. Diseases or disorders that may benefit from PKC-θ modulation include, for example, autoimmune diseases, inflammatory diseases, cancer and / or neoplastic diseases and / or HIV infection and replication, such as rheumatoid arthritis, multiple sclerosis, psoriasis, asthma, atopic dermatitis and Crohn's disease.

[0031] The compound may also be useful as a lead molecule for the selection, screening, and development of further derivatives that may have one or more improved beneficial drug properties as desired. Such further selection and screening may be carried out, for example, using the proprietary evolutionary computation algorithm described in the applicant's prior published patent application WO 2011 / 061548, which is incorporated in its entirety herein by reference.

[0032] This disclosure also includes salts, solvates, and functional derivatives of the compounds described herein. These compounds may be useful in treating diseases or disorders that may benefit from PKC-θ modulation, such as autoimmune diseases, inflammatory diseases, cancer and / or neoplastic diseases and / or HIV infection and replication, as identified herein.

[0033] Unless otherwise specified, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art (e.g., organic chemistry, physical chemistry, or theoretical chemistry; biochemistry and molecular biology).

[0034] Unless otherwise stated, the implementation of the present invention utilizes prior art in chemistry and chemical methods, biochemistry, molecular biology, pharmaceutical formulation, and patient delivery and treatment regimens, which are within the scope of those skilled in the art. Such art is also described in the literature cited herein. All literature cited herein is incorporated herein by reference in its entirety.

[0035] Before giving a detailed description of the present invention, we provide several definitions to aid in understanding this disclosure.

[0036] In accordance with this disclosure, the term “molecule” is interchangeable with the term “compound,” and the term “chemical structure” may also be used. The term “agent” is typically used in the context of pharmaceuticals, pharmaceutical compositions, and medicinal products having known or predicted physiological or in vitro activity of medical importance, but such characteristics and properties are not excluded in the molecules or compounds of this disclosure. Accordingly, the term “agent” is also interchangeable with the other terms and phrases “therapeutic agent,” “pharmaceutical agent,” and “active agent.” The therapeutic agents of this disclosure also include compositions and pharmaceutical formulations containing the compounds of this disclosure.

[0037] Prodrugs and solvates of the compounds of this disclosure are also included within the scope of this disclosure. The term “prodrug” means a compound (e.g., a drug precursor) that is converted in vivo to obtain a compound of this disclosure or a pharmaceutically acceptable salt, solvate, or ester thereof. This conversion can occur by various mechanisms (e.g., metabolic or chemical processes), such as hydrolysis of hydrolyzable bonds, e.g., in the blood (see Higuchi & Stella (1987), “Pro-drugs as Novel Delivery Systems”, vol.14 of the ACS Symposium Series; (1987), “Bioreversible Carriers in Drug Design”, Roche, ed., American Pharmaceutical Association and Pergamon Press). Accordingly, the compositions and pharmaceuticals of this disclosure may include prodrugs of the compounds of this disclosure. In certain aspects and embodiments, the compounds of this disclosure may themselves be prodrugs and be metabolized in vivo to become therapeutically effective compounds.

[0038] The present invention also includes various deuterated forms of any compound of the formulas disclosed herein, each of formulas I, II, or III (including the corresponding sub-formulas defined herein), or pharmaceutically acceptable salts and / or their corresponding tautomer forms (including the sub-formulas defined above). Each available hydrogen atom bonded to a carbon atom may independently be substituted with a deuterium atom. Those skilled in the art will know how to synthesize any deuterated forms of any compound of the formulas disclosed herein, each of formulas (I), (II), or (III) (including the corresponding sub-formulas defined herein), or pharmaceutically acceptable salts and / or their corresponding tautomer forms (including the sub-formulas defined above). For example, deuterated materials (e.g., alkyl groups) can be produced by the prior art (see, e.g., methyl-d3-amine available from Aldrich Chemical Co., Milwaukee, WI, Cat. No. 489, 689-2).

[0039] The present invention also includes isotope-labeled compounds or pharmaceutically acceptable salts thereof and / or corresponding tautomer forms (including the subformulas defined above) that are identical to those described in any of the formulas disclosed herein, including formula (I), (II), or (III) (including the corresponding subformulas defined herein), except that one or more atoms are substituted with atoms having atomic masses or mass numbers different from those most commonly found in nature. Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, iodine, and chlorine, such as 3H, 11C, 14C, 18F, 123I, or 125I. Compounds of the present invention containing the aforementioned isotopes and / or isotopes of other atoms and pharmaceutically acceptable salts thereof are within the scope of the present invention. The isotope-labeled compounds of the present invention (e.g., compounds incorporating radioactive isotopes such as 3H or 14C) are useful in tissue distribution assays of drugs and / or substrates. Tritium isotopes (i.e., 3H) and carbon-14 isotopes (i.e., 14C) are particularly preferred because they are easy to prepare and detect. 11C and 18F isotopes are especially useful in PET (positron emission tomography).

[0040] In this disclosure, the terms “individual,” “subject,” or “patient” are used interchangeably to refer to an animal that may be suffering from a medical (pathological) condition and may respond to the molecules, pharmaceuticals, medical procedures, or therapeutic regimens of this disclosure. The animals are preferably mammals such as humans, cattle, sheep, pigs, dogs, cats, bats, mice, or rats. In particular, the subject may be human.

[0041] The term "alkyl" refers to a monovalent, optionally substituted, saturated aliphatic hydrocarbon group. Any number of carbon atoms may be present, but typically the number of carbon atoms in an alkyl group may be 1 to about 20, 1 to about 12, 1 to about 6, or 1 to about 4. Usefully, the number of carbon atoms is indicated; for example, C1-12 alkyl (or C1-12 alkyl) refers to any alkyl group containing 1 to 12 carbon atoms in the chain. Alkyl groups may be linear (i.e., linear), branched, or cyclic. "Lower alkyl" refers to an alkyl group having 1 to 6 carbon atoms in the chain, which may have 1 to 4 or 1 to 2 carbon atoms. Therefore, typical examples of lower alkyl groups include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, isobutyl, isopentyl, and amyl (C5H 11 Examples include sec-butyl, tert-butyl, sec-amyl, tert-pentyl, 2-ethylbutyl, and 2,3-dimethylbutyl. "Higher alkyl" refers to alkyl groups with 7 or more carbon atoms, such as n-heptyl, n-octyl, n-nonyl, n-decyl, n-dodecyl, n-tetradecyl, n-hexadecyl, n-octadecyl, and n-eicosyl, and also includes their branched chain forms. A linear carbon chain with 4 to 6 carbon atoms refers to the chain length excluding carbon atoms present on branched chains, and in branched chains, it refers to the total number of carbon atoms. Any substituents on alkyl groups and other groups will be described later.

[0042] The term "substituted" means that one or more hydrogen atoms (bonded to a carbon or heteroatom) are substituted with a group of choice from the group of substituents shown, provided that the valence does not exceed the normal valence of the specified atom in the present context. The group may optionally be substituted with specific substituents at a position where the substituent does not significantly adversely affect the biological activity or structural stability of the compound and does not significantly hinder the production of compounds within the scope of the present invention. The combination of substituents is acceptable only if a stable compound is obtained. "Stable compound" or "stable structure" means a compound that is robust enough to be isolated from the reaction mixture to a useful purity and / or formulated into an effective therapeutic agent. "Optionally substituted" means that the group is unsubstituted or at least one hydrogen atom is substituted with one of the specified substituents, groups, or sites.

[0043] Any substituent / group / site described herein that may be substituted (or may be substituted as desired) may be substituted with one or more substituents (e.g., 1, 2, 3, 4, or 5), which may be selected independently of the specified substituents. Therefore, unless otherwise stated, substituents may be selected from the following group: halogen (or "halo", e.g., F, Cl, and Br), hydroxyl (-OH), amino or aminyl (-NH2), thiol (-SH), cyano (-CN), (lower) alkyl, (lower) alkoxy, (lower) alkenyl, (lower) alkynyl, aryl, heteroaryl, (lower) alkylthio, oxo, haloalkyl, hydroxyalkyl, nitro (-NO2), phosphate, azide (-N3), alkoxycarbonyl, carboxy, alkylcarboxy, alkylamino, dialkylamino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, thioalkyl, alkylsulfonyl, arylsulfinyl, alkylaminosulfonyl, arylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, arylcarbamoyl, alkylcarbonylamino, arylcarbonylamino, cycloalkyl, heterocycloalkyl. Alternatively, if the substituent is in an aryl or other ring system, two adjacent atoms may be substituted with a methylenedioxy or ethylenedioxy group.More appropriately, the substituents are selected from the following: halogen, hydroxy, amino, thiol, cyano, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkenyl, (C1-C6)alkynyl, aryl, aryl(C1-C6)alkyl, aryl(C1-C6)alkoxy, heteroaryl, (C1-C6)alkylthio, oxo, halo(C1-C6)alkyl, hydroxy(C1-C6)alkyl, nitro, phosphate, azide, (C1-C6)alkoxycarbonyl, carboxy, (C1-C6)alkylcarboxy, (C1-C6)alkylamino, di(C1-C6)alkylamino, amino( C1-C6) alkyl, (C1-C6) alkylamino(C1-C6) alkyl, di(C1-C6) alkylamino(C1-C6) alkyl, thio(C1-C6) alkyl, (C1-C6) alkylsulfonyl, arylsulfinyl, (C1-C6) alkylaminosulfonyl, arylaminosulfonyl, (C1-C6) alkylsulfonylamino, arylsulfonylamino, carbamoyl, (C1-C6) alkylcarbamoyl, di(C1-C6) alkylcarbamoyl, arylcarbamoyl, (C1-C6) alkylcarbonylamino, arylcarbonylamino, (C1-C6) cycloalkyl and heterocycloalkyl. More preferably, the substituent is selected from one or more of the following groups: fluoro, chloro, bromo, hydroxy, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C5-C6)aryl, 5 or 6-membered heteroaryl, (C4-C6)cycloalkyl, 4-6 membered heterocycloalkyl, cyano, (C1-C6)alkylthio, amino, -NH(alkyl), -NH((C1-C6)cycloalkyl), -N((C1-C6)alkyl)2, -OC(O)-(C1-C6)alkyl, -OC(O)-(C5-C6)aryl, -OC(O)-(C1-C6)cycloalkyl, carboxy, and -C(O)O-(C1-C6)alkyl. Most appropriately, the substituents are selected from one or more of the following groups: fluoro, chloro, bromo, hydroxy, amino, (C1-C6)alkyl, and (C1-C6)alkoxy, where the alkyl and alkoxy groups may optionally be substituted with one or more chloro groups.Particularly preferred substituents are those listed below: chloro, methyl, ethyl, methoxy, and ethoxy.

[0044] The term "halo" or "halogen" refers to a monovalent halogen group selected from chloro, bromo, iodine, and fluoro. A "halogenated" compound is one that is substituted with one or more halo substituents. Preferred halo groups are F, Cl, and Br, with F being the most preferred.

[0045] As used herein, with respect to the substitution of a parent moiety by one or more substituents, the term “independently” means that the parent moiety may be substituted individually or in combination with any of the substituents listed, and any number of chemically possible substituents may be used. In any embodiment, if the group is substituted, it may contain up to five, up to four, up to three, or one and two substituents. As non-limiting examples, useful substituents include phenyl or pyridine independently substituted with one or more lower alkyl, lower alkoxy, or halo substituents, such as chlorophenyl, dichlorophenyl, trichlorophenyl, tolyl, xylyl, 2-chloro-3-methylphenyl, and 2,3-dichloro-4-methylphenyl.

[0046] In this specification, the terms "alkylene" or "alkylenyl" mean a difunctional group obtained by removing a hydrogen atom from an alkyl group as defined above. Non-limiting examples of alkylenes include methylene, ethylene, and propylene. "Lower alkylene" means an alkylene having 1 to 6 carbon atoms in the chain, which may be linear or branched. The alkylene group may be substituted as desired.

[0047] The term "alkenyl" refers to a monovalent, optionally substituted, unsaturated aliphatic hydrocarbon group. Therefore, an alkenyl has at least one carbon-carbon double bond (C=C). The number of carbon atoms in an alkenyl group can be, for example, 2 to about 20. For example, a C2-12 alkenyl (or C2-12 alkenyl) refers to an alkenyl group containing 2 to 12 carbon atoms in its structure. An alkenyl group may be linear (i.e., linear), branched, or cyclic. A "lower alkenyl" refers to an alkenyl having 1 to 6 carbon atoms, which may have 1 to 4 carbon atoms, or 1 to 2 carbon atoms. Representative examples of lower alkenyl groups include ethenyl, 1-propenyl, 1-butenyl, 1-pentenyl, 1-hexenyl, isopropenyl, and isobutenyl. Higher alkenyls refer to alkenyls with 7 or more carbon atoms, such as 1-heptenyl, 1-octenyl, 1-nonenyl, 1-decenyl, 1-dodecenyl, 1-tetradecenyl, 1-hexadecenyl, 1-octadecenyl, and 1-eicocenyl, and their branched forms are also included. Any optional substituents are listed elsewhere.

[0048] "Alkenylene" refers to a difunctional group obtained by removing hydrogen from the alkenyl group as defined above. Non-restrictive examples of alkenylenes include -CH=CH-, -C(CH3)=CH-, and -CH=CHCH2-.

[0049] The terms "alkynyl" and "lower alkynyl" are defined similarly to the term "alkenyl," except that they contain at least one carbon-carbon triple bond.

[0050] The term "alkoxy" refers to the monovalent group of the formula RO-, where R is any alkyl, alkenyl, or alkynyl as defined herein. The alkoxy group may optionally be substituted with any substituent described herein. "Lower alkoxy" refers to the formula RO-, where R is a lower alkyl, alkenyl, or alkynyl. Typical alkoxy groups include methoxy, ethoxy, n-propoxy, n-butoxy, n-pentyloxy, n-hexyloxy, isopropoxy, isobutoxy, isopentyloxy, amyloxy, sec-butoxy, tert-butoxy, and tert-pentyloxy. Preferred alkoxy groups are methoxy and ethoxy.

[0051] As used herein, the term “aryl” refers to a substituted or unsubstituted aromatic carbocyclic group containing 5 to about 15 carbon atoms; preferably 5 or 6 carbon atoms. An aryl group may have only one carbocyclic ring or consist of one or more fused rings in which at least one ring is essentially aromatic. “Phenyl” is a group formed by removing a hydrogen atom from a benzene ring, and may be substituted or unsubstituted. Thus, the “phenoxy” group is the group of formula RO-, where R is the phenyl group. “Benzyl” is the group of formula R-CH2-, where R is phenyl, and “benzyloxy” is the group of formula RO-, where R is benzyl. Non-limiting examples of aryl groups include phenyl, naphthyl, benzyl, biphenyl, furanyl, pyridinyl, indanyl, anthraquinolyl, tetrahydronaphthyl, benzoic acid, and furan-2-carboxylic acid groups.

[0052] A "heteroaryl" group is defined herein as a substituted or unsubstituted "aryl" group in which one or more carbon atoms in the ring structure are substituted with a heteroatom such as nitrogen, oxygen, or sulfur. Generally, heteroaryl groups contain one or two heteroatoms. The preferred heteroatom is nitrogen. Examples of heteroaryl groups include furan, benzofuran, isobenzofuran, pyrrole, indole, isoindole, thiophene, benzothiophene, benzo[c]thiophene, imidazole, benzimidazole, purine, pyrazole, indazole, oxazole, benzoxazole, isoxazole, benzisoxazole, thiazole, benzothiazole, pyridine, quinoline, isoquinoline, pyrazine, quinoxaline, acridine, pyrimidine, quinazoline, pyridazine, and cinnoline.

[0053] As used herein, the terms “heterocyclic” or “heterocyclic” group refer to a monovalent group having about 4 to about 15 ring atoms, preferably 4-, 5- or 6-, or 7-ring members. Generally, heterocyclic groups contain 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. The preferred heteroatom is nitrogen. Heterocyclic groups may have only one ring, or they may consist of one or more fused rings in which at least one ring contains a heteroatom. They may be fully saturated or partially saturated, and may be substituted or unsubstituted, as in the case of aryl and heteroaryl groups. Representative examples of unsaturated 5-membered heterocyclic groups having only one heteroatom include 2- or 3-pyrrolyl, 2- or 3-furanyl, and 2- or 3-thiophenyl. Corresponding partially saturated or fully saturated groups include 3-pyrrolin-2-yl, 2- or 3-pyrrolindinyl, 2- or 3-tetrahydrofuranyl, and 2- or 3-tetrahydrothiophenyl. Representative unsaturated five-membered heterocyclic groups with two heteroatoms include imidazolyl, oxazolyl, thiazolyl, and pyrazolyl. Corresponding fully saturated and partially saturated groups are also included. Representative unsaturated six-membered heterocyclic groups with only one heteroatom include 2-,3-, or 4-pyridinyl, 2H-pyranyl, and 4H-pyranyl. Corresponding partially saturated or fully saturated groups include 2-,3-, or 4-piperidinyl and 2-,3-, or 4-tetrahydropyranyl. Representative unsaturated six-membered heterocyclic groups with two heteroatoms include 3-, or 4-pyridazinyl, 2-,4-, or 5-pyrimidinyl, 2-pyrazinyl, and morpholino. Corresponding fully saturated and partially saturated groups are also included, such as 2-piperazine. Heterocyclic groups are bonded either directly to the ring via available carbon atoms or heteroatoms within the heterocycle, or via linkers such as alkylenes, including methylene or ethylene.

[0054] Unless otherwise specified, “room temperature” is intended to mean a temperature of approximately 18–28°C, typically approximately 18–25°C, and more generally approximately 18–22°C. Where used herein, the term “room temperature” may be abbreviated as “rt” or “RT”.

[0055] Molecules and compounds What is disclosed in this specification is structural formula I: [ka] [In the formula, A is selected from the group consisting of the following: N, C-Ra (wherein Ra is selected from hydrogen, halogen, C1-3 alkyl, and CN); G is selected from the group consisting of the following: CR1R2, O, and NR1; R1 and R2 are independently selected from the group consisting of the following: hydrogen, halogen, C1-3 alkyl, C3-7 cycloalkyl (e.g., CH2 c Pr), C1-3 alkoxyl (e.g., OMe), C2-6 cycloalkoxyl (e.g., O c Pr), C2-6 alkylalkoxy (e.g., CH2OMe), hydroxyl, C1-3 alkylhydroxyl (e.g., CH2OH), amino, C1-3 alkylamino (e.g., CH2NH2), C1-4 aminoalkyl (e.g., NHMe or N(Me)2), C2-7 alkylaminoalkyl (e.g., CH2NHMe or CH2N(Me)2), C1-3 haloalkyl; or R1 and R2 together form a 3- to 5-membered spiro-carbocyclic or heterocyclic ring, which may be optionally substituted; in particular, they form a 4- to 5-membered carbocyclic or heterocyclic spiro-ring, which may be optionally substituted; in embodiments, the carbocyclic or heterocyclic spiro-ring is unsubstituted; in other embodiments, the carbocyclic or heterocyclic spiro-ring is substituted with one or more substituents selected from the group consisting of: C1-2 alkyl, halogen, C1-2 haloalkyl, hydroxyl, and C1-2 alkoxyl; B is selected from the group consisting of the following: N, CH, and C-halogens (e.g., CF, C-Cl, C-Br); D is selected from the following group: N and C-R3; R3 is selected from the group consisting of the following: hydrogen, C1-3 alkyl (e.g., Me, Et), C1-3 haloalkyl (e.g., CF2H, CF3, CH2CF3), C1-3 alkoxyl (e.g., OMe), C2-5 alkylalkoxyl (e.g., CH2OMe), and halogen (e.g., F, Cl, Br); R4 is selected from the group consisting of the following: hydrogen, C1-3 alkyl, C1-3 haloalkyl (e.g., CF2H, CF3, CH2CF3), OMe, and halogen; or If D is C-R3, then R3 and R4 combine together as follows: [ka] (In the formula, R7 is selected from the group consisting of the following: hydrogen and halogens; R8 is selected from the group consisting of the following: hydrogen and halogens; R9 is selected from the group consisting of the following: hydrogen, C1-3 haloalkyl (e.g., CF2H, CF3, CH2CF3), and halogens; R10 is selected from the group consisting of the following: hydrogen, halogens, C1-3 haloalkyls (e.g., CF2H, CF3, CH2CF3), and C1-3 haloalkoxys (e.g., OCFH2, OCF2H, OCF3)). Forming an aryl or heteroaryl ring having a structure selected from the group consisting of the following, which may optionally be substituted; and n is selected from the group consisting of the following: 0 and 1; E is selected from the following group: CH and CR a (In the formula, R aThis is selected from halogens, C1-3 alkyls, C1-3 alkylhydroxys (e.g., CH2OH), C1-3 haloalkyls (e.g., CH2F), C2-6 alkylalkoxys (e.g., CH2OMe), and C2-4 alkylnitriles (e.g., CH2CN). R5 and R6 bond together to form a 4-8 member, preferably 5-7 member saturated carbocyclic or heterocyclic ring, which may be optionally substituted and optionally bridged. The present invention provides compounds having the same properties, or pharmaceutically acceptable salts, solvates, stereoisomers or mixtures of stereoisomers, tautomers, isotopic forms or pharmaceutically active metabolites thereof, or combinations thereof.

[0056] In a particular embodiment of formula I, D is C-R3, and R3 and R4 are joined together to form the following structure: [ka] An aryl ring having which may be optionally substituted, i.e., general formula II: [ka] (In the formula, A, B, E, G, R1, R2, R5, R6, R7, R8, R9, R10, and n are as defined for formula I.) It forms a compound.

[0057] In a specific embodiment of formula II, the compound is formula IIa: [ka] [In the formula, A, B, E, R1, R2, R5, R6, R7, R8, R9, R10, and n are as defined with respect to formula I; R17 is described below: [ka] (In the formula, R11 is selected from the group consisting of the following: hydrogen, halogens (e.g., F), and C1-2 alkyls (e.g., Me); R12 is selected from the group consisting of the following: hydrogen, C1-3 alkyl (e.g., Me), C1-3 haloalkyl (e.g., CH2F), C1-3 alkylhydroxy (e.g., CH2OH), and C1-2 alkylnitrile (e.g., CH2CN); R13 is selected from the group consisting of the following: hydrogen, halogens (e.g., F), and C1-2 alkyls (e.g., Me); R14 is selected from the group consisting of the following: hydrogen and C1-2 alkyl (e.g., Me); R15 is selected from the group consisting of the following: hydrogen and C1-2 alkyl (e.g., Me); R16 is selected from the group consisting of the following: hydrogen, C1-3 alkyl (e.g., Me), C1-3 haloalkyl (e.g., -CH2CH2F, CH2CHF2, CH2CF3), C1-3 alkylhydroxy (e.g., CH2OH), and C1-3 alkylalkoxyl (e.g., CH2OMe); n is selected from the group consisting of the following: 0 and 1; p is selected from the following groups: 1 and 2; X is selected from the group consisting of the following: CH2 and O; Y is selected from the group consisting of the following: CH2, O, NH, and NMe. Selected from the group consisting of: It has the structure of [the object].

[0058] In a particular embodiment of formula IIa, E, R5, R6, R7, R8, R9, and R10 are as defined for formula I, R1 is selected from the group consisting of the following: hydrogen, Me, Et, OMe, OEt, OH, NH2, NHMe, and NHEt; R2 is selected from the group consisting of the following: hydrogen, Me and Et; or R1 and R2 together form a 3- to 5-membered spirocarbocyclic or heterocyclic ring, which may be optionally substituted; in particular, they form a 4- to 5-membered carbocyclic or heterocyclic spiroring, which may be optionally substituted; in one embodiment, the carbocyclic or heterocyclic spiroring is unsubstituted; in another embodiment, the carbocyclic or heterocyclic spiroring is substituted with one or more substituents selected from the group consisting of: C1-2 alkyl, halogen, C1-2 haloalkyl, hydroxyl, and C1-2 alkoxyl; A is selected from the group consisting of the following: CH, CF, C-Cl, and C-Br; B is selected from the group consisting of the following: N, CH, and C-halogens (e.g., CF, C-Cl, and C-Br); R17 is described below: [ka] (In the formula, R18 is selected from the group consisting of the following: hydrogen and halogens (e.g., F); R19 is selected from the group consisting of the following: hydrogen, C1-3 alkyl (e.g., Me), C1-3 haloalkyl (e.g., CH2F), and C1-3 alkylhydroxyl (e.g., CH2OH); m is selected from the following group: 0 and 1; R20 is selected from the group consisting of the following: hydrogen and halogens (e.g., F); X is selected from the group consisting of the following: CH2 and O; R21 and R22 are each independently selected from the group consisting of: hydrogen and C1-3 alkyl (e.g., Me); Y is selected from the group consisting of the following: CH2, O, and NH; R23 is selected from the group consisting of the following: hydrogen; C1-3 alkyl (e.g., Me) and C1-3 haloalkyl (e.g., -CH2CH2F, CH2CHF2, CH2CF3)). It is selected from the group consisting of the following.

[0059] In another embodiment of formula I, the compound is general formula III: [ka] [In the formula, A, B, E, G, R1, R2, R5, R6, and n are as defined for formulas I, II, or IIa; D is selected from the following group: N, CH, and C-R3; R3 is selected from the group consisting of the following: C1-3 alkyl, C2-5 alkylalkoxy (e.g., OMe), C1-3 haloalkyl (e.g., CF3), and halogen; R4 is selected from the group consisting of the following: hydrogen, C1-3 alkyl, C2-5 alkylalkoxyl (e.g., OMe), C1-3 haloalkyl (e.g., CF3), and halogen. It is a compound that has [a certain characteristic].

[0060] In a particular embodiment of formula III, G is CR1R2, one of B or D is N and the other is CH; or a compound in which B and D are CH, i.e., formula IIIa, IIIb, or IIIc: [ka] [In the formula, A, R1, R2, R3, R4, E, R5, R6, and n are as defined for Equation III; R17 is described below: [ka] (In the formula, R11 is selected from the group consisting of the following: hydrogen, halogens (e.g., F), and C1-2 alkyls (e.g., Me); R12 is selected from the group consisting of the following: hydrogen, C1-3 alkyl (e.g., Me), C1-3 haloalkyl (e.g., CH2F), C1-3 alkylhydroxy (e.g., CH2OH), and C1-2 alkylnitrile (e.g., CH2CN). R13 is selected from the group consisting of the following: hydrogen, halogens (e.g., F), and C1-2 alkyls (e.g., Me); R14 is selected from the group consisting of the following: hydrogen and C1-2 alkyl (e.g., Me); R15 is selected from the group consisting of the following: hydrogen and C1-2 alkyl (e.g., Me); R16 is selected from the group consisting of the following: hydrogen; C1-3 alkyl (e.g., Me), C1-3 haloalkyl (e.g., -CH2CH2F, CH2CHF2, CH2CF3), C1-3 alkylhydroxyl (e.g., CH2OH), and C1-3 alkylalkoxyl (e.g., CH2OMe); n is selected from the group consisting of the following: 0 and 1; p is selected from the following groups: 1 and 2; X is selected from the group consisting of the following: CH2 and O; Y is selected from the group consisting of the following: CH2, O, NH, and NMe. Selected from the group consisting of: It is a compound having the following structure.

[0061] In specific embodiments of formulas IIIa, IIIb, and IIIc, A and n are as defined for Equation III; R1 is selected from the group consisting of the following: hydrogen, Me, Et, OMe, OH, NH2 and NHMe; and R2 is selected from the group consisting of the following: hydrogen, Me and Et; or R1 and R2 together form a 3- to 5-membered spirocarbocyclic or heterocyclic ring, which may be optionally substituted; in particular, they form a 4- to 5-membered carbocyclic or heterocyclic spiroring (e.g., cyclobutene, cyclopentane, tetrahydrofuran), which may be optionally substituted; in one embodiment, the carbocyclic or heterocyclic spiroring is unsubstituted; in another embodiment, the carbocyclic or heterocyclic spiroring is substituted with one or more substituents selected from the group consisting of: C1-2 alkyl, halogen, C1-2 haloalkyl, hydroxy, and C1-2 alkoxy; A is selected from the group consisting of the following: CH, CF, C-Cl and C-Br; and R17 is described below: [ka] [In the formula, R18 is selected from the group consisting of the following: hydrogen and halogens (e.g., F); R19 is selected from the group consisting of the following: hydrogen, C1-3 alkyl (e.g., Me), C1-3 haloalkyl (e.g., CH2F), and C1-3 alkylhydroxy (e.g., CH2OH); m is selected from the following group: 0 and 1; R20 is selected from the group consisting of the following: hydrogen and halogens (e.g., F); X is selected from the group consisting of the following: CH2 and O; R21 and R22 are each independently selected from the group consisting of: hydrogen and C1-3 alkyl (e.g., Me); Y is selected from the group consisting of the following: CH2, O, and NH; R23 is selected from the group consisting of the following: hydrogen, C1-3 alkyl (e.g., Me), and C1-3 haloalkyl (e.g., -CH2CH2F, CH2CHF2, CH2CF3)). It is selected from the group consisting of the following.

[0062] In another aspect, the present invention provides a pharmaceutical composition comprising the compounds of the present disclosure.

[0063] The compounds of the present invention may have the following structures: [Table 1] [Table 2] [Table 3] [Table 4] [Table 5] [Table 6] [Table 7] [Table 8] [Table 9] [Table 10] [Table 11] [Table 12] [Table 13] [Table 14] Table 15 Table 16 Table 17 Table 18 Table 19 Table 20 Table 21 Table 22 Table 23 Table 24 Table 25 Table 26 Table 27 Table 28 Table 29 Table 30 Table 31 Table 32 Table 33 Table 34 Table 35 Table 36 Table 37 Table 38 Table 39 Table 40 Table 41 Table 42 Table 43 Table 44 Table 45 Table 46 Table 47 Table 48 Table 49 Table 50 Table 51 Table 52 Table 53 Table 54 Table 55 Table 56

[0064] PKC-θ activity of compounds, prodrugs and metabolites PKC-θ is selectively expressed in T lymphocytes and plays a crucial role in the activation of mature T cells initiated by the T cell antigen receptor (TCR), followed by the release of cytokines such as IL-2 and T cell proliferation (Isakov and Altman, Annu. Rev. Immunol., 2002, 20, 761-94). Therefore, a decrease in IL-2 levels represents a desirable response that can treat the diseases and disorders described herein, such as autoimmune diseases and neoplastic diseases.

[0065] Due to its involvement in T cell activation, selective inhibition of PKC-θ may reduce harmful inflammation mediated by Th17 (mediating autoimmune diseases) or Th2 (causing allergies) without impairing the T cell's ability to eliminate virus-infected cells (Madouri et al, Journal of Allergy and Clinical Immunology. 139 (5):2007, pp 1650-1666). Inhibitors may be used in T cell-mediated adaptive immune responses. Inhibition of PKC-θ downregulates transcription factors (NF-κB, NF-AT) and reduces IL-2 production. Animals lacking PKC-θ have been observed to be resistant to several autoimmune diseases (Zanin-Zhorov et al., Trends in Immunology. 2011, 32(8):358-363). Therefore, PKC-θ is an interesting target as a potential treatment for cancer and autoimmune diseases.

[0066] Studies using PKC-θ-deficient mice have demonstrated that the antiviral response is independent of PKC-θ activity, while the T cell response associated with autoimmune diseases is PKC-θ-dependent (Jimenez et al., J. Med. Chem. 2013, 56(5) pp 1799-1810). Therefore, it is expected that potent and selective inhibition of PKC-θ can block the autoimmune T cell response without impairing antiviral immunity. However, the similarity of PKC isoforms, particularly PKC-δ, and their selectivity for other protein kinases remain challenges in developing PKC inhibitors suitable for clinical use.

[0067] To address these concerns, in aspects and embodiments, the compounds of the Disclosure (or “Active Substances”) may advantageously provide potent and selective PKC-θ inhibition against other PKC-isoforms such as PKCδ and other kinases (having a selectivity of 5-fold or greater, preferably 20-fold or greater, on a suitable measure such as pIC50 in a suitable assay).

[0068] The active substance or compound of the present invention may be provided as a prodrug of the compound of the present disclosure.

[0069] The term “active substance” is typically used to refer to the compounds of this disclosure that have inhibitory activity against PKC-θ, particularly under physiological conditions. However, active substances are often difficult to administer or deliver to the relevant physiological site due to, for example, solubility, half-life, or many other chemical or biological reasons. Therefore, it is known that “prodrugs” of active substances are used to overcome physicochemical, biological, or other problems in pharmacokinetics and / or toxicity. Furthermore, prodrug strategies can be used to increase the selectivity of the drug to the intended target. Thus, according to this disclosure, prodrugs would be beneficial in targeting the active drug to the biological site of interest while favorably avoiding undesirable side effects such as those in the stomach (or lungs) due to local inhibition of PKC-θ activity.

[0070] The active substance may be formed from the compound or prodrug of this disclosure by in vivo metabolism of the active substance and / or by in vivo chemical or enzymatic cleavage of the prodrug. Typically, the prodrug may be a pharmacologically inactive compound and requires chemical or enzymatic transformation to become an active substance effective in the body to exert a therapeutic effect. On the other hand, in some embodiments, the prodrug may have a very close structural similarity to the active substance, and in some such embodiments, the prodrug may also have activity against PKC-θ targets. This would be particularly the case when the active substance is formed from a compound of the prodrug of this disclosure by metabolism or minor chemical transformation, and the metabolite is closely related to the parent compound / prodrug. Thus, the prodrug of this disclosure may be an inhibitor of PKC-θ activity. However, preferably, such a prodrug may have lower inhibitory activity against PKC-θ than the drug / active substance derived from the prodrug of this disclosure.

[0071] On the other hand, when the therapeutic effect arises from the release of active substances from a larger chemical structure, the final active substance / compound / drug may have significant structural differences compared to the prodrug derived from them. In such cases, the prodrug can effectively "mask" the form of the active substance, and in such cases, the prodrug may be completely (or essentially) inactive under physiological conditions.

[0072] Medication forms, pharmaceuticals, and pharmaceutical compositions The compounds, molecules, or agents of this disclosure may be used to treat (e.g., cure, alleviate, or prevent) one or more diseases, infections, or disorders. Accordingly, in accordance with this disclosure, the compounds and molecules may be manufactured into pharmaceuticals, incorporated into pharmaceutical compositions, or formulated.

[0073] The molecules, compounds, and compositions of this disclosure may be administered by any preferred route, such as intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, oral, sublingual, nasal, vaginal, transdermal, rectal, inhalation, or topical administration to the skin. Delivery systems include, for example, encapsulation in liposomes, microgels, microparticles, microcapsules, and capsules. The use of any other suitable delivery system known in the art is also conceivable. Administration may be systemic or topical. The mode of administration is at the discretion of those skilled in the art.

[0074] The dosage naturally varies depending on known factors such as the pharmacodynamic properties of the specific active substance, the chosen mode and route of administration, the recipient's age, health status and weight, the nature of the disease or disorder being treated, the severity of symptoms, concurrent or parallel treatment, the frequency of treatment, and the desired effect. Generally, the daily dose of the active substance can be considered to be approximately 0.001 to approximately 1,000 mg / kg relative to body weight. Depending on the application, the dosage may preferably be in the range of approximately 0.01 to approximately 100 mg / kg; approximately 0.1 to approximately 25 mg / kg; or approximately 0.5 to approximately 10 mg / kg.

[0075] Depending on the known factors described above, the required amount of the active substance may be administered once daily, or the total daily dose may be divided and administered, for example, two, three, or four times a day. Preferably, the treatment regimen according to this disclosure can be considered as once daily or divided into two daily doses.

[0076] Dosage forms of the pharmaceutical compositions of this disclosure suitable for administration may contain about 1 mg to about 2,000 mg of the active ingredient per unit. Typically, the daily dose of the compound may be at least about 10 mg and at most about 1,500 mg per human dose; for example, between about 25 and 1,250 mg, or preferably between about 50 and 1,000 mg. Typically, the daily dose of the compound may be at most about 1,000 mg. In such compositions, the compound of the present invention is typically present in an amount of about 0.5 to 95% by weight based on the total weight of the composition.

[0077] “Effective dose” or “therapeutic effective dose” means the amount of a compound or composition of the Disclosure that is effective in curing, suppressing, mitigating, reducing or preventing the side effects of a disease or disorder to be treated, or the amount required to achieve a physiologically or biochemically detectable effect. Thus, an effective dose of a compound or agent can produce a desired therapeutic, ameliorative, suppressive, or preventive effect with respect to a disease or disorder. Beneficially, an effective dose of a compound or composition of the Disclosure may have a PKC-θ inhibitory effect. Diseases or disorders that may benefit from PKC-θ inhibition include, for example, autoimmune diseases, inflammatory diseases, cancers and / or neoplastic diseases, such as rheumatoid arthritis, multiple sclerosis, psoriasis, Sjögren's syndrome and systemic lupus erythematosus or vasculitic diseases, hematopoietic cancers or solid tumors, including chronic myeloid leukemia, myeloid leukemia, non-Hodgkin lymphoma and other B-cell lymphomas.

[0078] For therapeutic applications, the effective or therapeutically effective amount of the compound / active substance of this disclosure may be at least about 50 nM or at least about 100 nM in the blood of the subject; typically at least about 200 nM or at least about 300 nM. The effective or therapeutically effective amount may be at most about 5 μM, at most about 3 μM, preferably at most about 2 μM, typically at most about 1 μM in the blood of the subject. For example, the therapeutically effective amount may be at most about 500 nM, for example, about 100 nM to 500 nM. In some embodiments, the amount of the compound for therapeutic use may be measured in the serum of the subject, and then the above concentrations may be applied to the serum concentration of the compound of this disclosure.

[0079] When administered to a target, the compounds of this disclosure are preferably administered as components of a composition containing a pharmaceutically acceptable carrier or vehicle. One or more additional pharmaceutically acceptable carriers (such as diluents, adjuvants, excipients, or vehicles) can be combined with the compounds of this disclosure in a pharmaceutical composition. Suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" by E.W. Martin. The pharmaceutical formulations and compositions of this disclosure are formulated to comply with regulatory standards and according to a selected route of administration.

[0080] Acceptable medicinal vehicles may be liquids of water and oil (e.g., of petroleum, animal, plant, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc.). Examples of medicinal vehicles include saline, acacia gum, gelatin, starch paste, talc, keratin, colloidal silica, and urea. Furthermore, adjuvants, stabilizers, thickeners, lubricants, and colorants may be used. When administered to a subject, pharmaceutically acceptable vehicles are generally sterile. Water is a suitable vehicle when administering compounds intravenously. Aqueous solutions of saline, dextrose, and glycerol can also be used as liquid vehicles, particularly for injection. Suitable medicinal vehicles may also include excipients such as starch, glucose, lactose, sucrose, gelatin, malt, rice, wheat flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene glycol, water, and ethanol. The compositions of the present invention may optionally contain small amounts of wetting agents, emulsifiers, or buffers.

[0081] The pharmaceuticals and pharmaceutical compositions of this disclosure may take the form of solutions, suspensions, emulsions, tablets, pills, pellets, powders, gels, capsules (e.g., capsules containing liquid or powder), sustained-release formulations (such as delayed-release or sustained-release formulations), suppositories, emulsions, aerosols, sprays, suspensions, or any other form suitable for use. For other examples of suitable pharmaceutical vehicles, see Remington's Pharmaceutical Sciences, Alfonso R. Gennaro ed., Mack Publishing Co. Easton, Pa., 19th ed., 1995 (e.g., pp. 1447–1676).

[0082] Preferably, the therapeutic compositions or pharmaceuticals of the present disclosure are formulated according to routine procedures as pharmaceutical compositions suitable for oral administration (more preferably to humans). Compositions for oral administration may be in the form of, for example, tablets, lozenges, aqueous or oily suspensions, granules, powders, emulsions, capsules, syrups, or elixirs. Thus, in one embodiment, the pharmaceutically acceptable vehicle is a capsule, tablet, or pill.

[0083] Orally administered compositions may contain one or more pharmaceutical components, such as sweeteners like fructose, aspartame, or saccharin; flavoring agents like peppermint, wintergreen, or cherry; colorants; and preservatives, to provide a pharmaceutically palatable formulation. If the composition is in the form of a tablet or cereal tablet, it may be coated to delay breakdown and absorption in the gastrointestinal tract to provide sustained release of the active substance over a longer period. Selectively permeable membranes surrounding an osmotically active driving compound are also suitable for orally administered compositions. In these dosage forms, fluids from the environment surrounding the capsule are absorbed by the driving compound, causing it to swell and exchange the drug or pharmaceutical composition through the opening. These dosage forms can provide an essentially zero-order delivery profile, in contrast to the spike profile of immediate-release formulations. Time-delaying substances such as glycerol monostearate or glycerol stearate may also be used. Oral compositions may contain standard vehicles such as mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, and magnesium carbonate. Such vehicles are preferably of pharmaceutical grade. In the case of oral formulations, the release site may be the stomach, small intestine (duodenum, jejunum, or ileum), or large intestine. Those skilled in the art can manufacture formulations that do not dissolve in the stomach but release the substance in the duodenum or other part of the intestine. Preferably, the release avoids adverse effects on the gastric environment by either protecting the compound (or composition) or releasing the compound (or composition) after it has passed through the gastric environment, for example, release in the intestines. To ensure complete gastric resistance, a coating that is impermeable to at least pH 5.0 would be essential.Examples of more common inert ingredients used as enteric coatings include cellulose acetate trimellitate (CAT), hydroxypropyl methylcellulose phthalate (HPMCP), HPMCP 50, HPMCP 55, polyvinyl acetate phthalate (PVAP), Eudragit L30D, Aquateric, cellulose acetate phthalate (CAP), Eudragit L, Eudragit S, and shellac, which can be used as mixed films.

[0084] Providing therapeutic compositions and / or compounds of the Disclosure in a form suitable for oral administration may be beneficial, for example, to improve patient compliance and facilitate administration. However, in some embodiments, compounds or compositions of the Disclosure may cause undesirable side effects, such as colitis, which may lead to premature termination of the treatment regimen. Therefore, in some embodiments, the treatment regimen is adapted to accommodate a “drug-free period,” for example, one or more non-administration days. For example, the treatment regimens and methods of treatment of the Disclosure may include a repeating process that involves administering a therapeutic composition or compound for a number of consecutive days, followed by a drug-free period of one or more consecutive days. For example, a therapeutic regimen of the present disclosure may include repeated cycles of administering a therapeutic composition or compound for 1 to 49 consecutive days, 2 to 42 consecutive days, 3 to 35 consecutive days, 4 to 28 consecutive days, 5 to 21 consecutive days, 6 to 14 consecutive days, or 7 to 10 consecutive days; followed by drug-free periods of 1 to 14 consecutive days, 1 to 12 consecutive days, 1 to 10 consecutive days, or 1 to 7 consecutive days (e.g., 1, 2, 3, 4, 5, 6, or 7 days).

[0085] To assist the therapeutic agent in dissolving in an aqueous environment, a surfactant may be added as a wetting agent. Anionic detergents such as sodium lauryl sulfate, sodium dioctyl sulfosuccinate, and sodium dioctyl sulfonate may be mentioned as surfactants. Cationic detergents may also be used, which include benzalkonium chloride and benzethonium chloride. Non-ionic detergents that may be included in the formulation as surfactants include lauromacrogol 400, polyoxyl 40 stearate, polyoxyethylene hydrogenated castor oil 10, 50 and 60, glyceryl monostearate, polysorbate 20, 40, 60, 65 and 80, sucrose fatty acid esters, methylcellulose and carboxymethylcellulose. When using these surfactants, they can be present alone or as a mixture in different ratios in the formulation of the compound or derivative.

[0086] Generally, compositions for intravenous administration contain a sterile isotonic aqueous buffer. If necessary, the composition may also contain a solubilizing agent.

[0087] Another suitable route of administration of the therapeutic composition of the present disclosure is pulmonary or nasal delivery.

[0088] Additives may be included to enhance the cellular uptake of the therapeutic agent of the present disclosure; for example, fatty acids, oleic acid, linolenic acid and linoleic acid.

[0089] The therapeutic agent of the present disclosure may be formulated into a composition for topical administration to the skin of a subject.

[0090] When providing one or more active compounds / drugs for combined use, generally, the drugs can be formulated separately or in a single dosage form according to the predetermined most appropriate dosing regimen for each of the drugs involved. When the therapeutic agents are formulated separately, the pharmaceutical compositions of the present invention can be used in therapeutic regimens including simultaneous administration, individual administration or sequential administration with one or more other therapeutic agents. The other therapeutic agent(s) may include the compounds of the present disclosure or therapeutic agents known in the art.

[0091] The compounds and / or pharmaceutical compositions of the present disclosure may be formulated and suitable for administration to the central nervous system (CNS) and / or for passing through the blood-brain barrier (BBB).

[0092] The present invention is illustrated by the following non-limiting examples.

Examples

[0093] Materials and Methods Sample preparation: The powder was dissolved in DMSO-d6 and vortexed thoroughly until the solution became clear, and then transferred to NMR for data acquisition.

[0094] NMR Spectroscopy: Liquid-phase NMR experiments were performed using a triple resonance 1 H, 15 N, 13 C CP-TCI 5mm cryoprobe (Bruker Biospin, Germany) on a 600 MHz (14.1 Tesla) Bruker Avance III NMR spectrometer ( 1 600 MHz for H, 13 151 MHz for C).

[0095] Liquid-phase NMR experiments were performed using a Dual Resonance BBI 5 mm probe (Bruker Biospin, Germany) on a 500 MHz (11.75 Tesla) Bruker Avance I NMR spectrometer ( 1H is 500 MHz, 13 The value of C was recorded at 125 MHz.

[0096] Liquid-phase NMR experiments were performed using an SEI 5 mm probe (Bruker Biospin, Germany) and a 400 MHz (9.4 Tesla) Bruker Avance NEO NMR spectrometer. 1 For H, it is 400 MHz. 13 The value of C was recorded at 100 MHz.

[0097] All experiments used in the resonance assignment procedure and the structural analysis of the product (1D) 1 H, 2D 1 H- 1 H-COSY, 2D 1 H- 1 H-ROESY, 2D 1 H- 13 C-HSQC, 2D 1 H- 13 C-HMBC was recorded at 300 K. 1 The H chemical shift is reported in δ (ppm) as s (singlet), d (doublet), t (triplet), q (quartet), dd (double doublet), m (multiplet), or brs (broad singlet).

[0098] LC-MS chromatography: LC-MS chromatography was recorded using the following equipment: -Waters HPLC:Alliance 2695, UV:PDA 996, MS:ZQ (simple Quad) ZQ2 -Waters UPLC:Acquity, UV:Acquity PDA, MS:Qda -Waters UPLC:Acquity, UV:Acquity TUV, MS:Qda -Waters UPLC:Acquity, UV:Acquity PDA, MS:QDa, ELSD.

[0099] For Waters HPLC, a Gemini NX-C18 Phenomenex (30 x 2 mm) 3 μm column was used, and for ULC Waters, a CSH C18 Waters (50 x 2.1 mm) 1.7 μm column was used. In both cases, the following component combinations were used: H2O + 0.05% TFA (v / v) and ACN + 0.035% TFA (v / v), with positive electrospray ES+ as the ionization mode. UV detection was set to 220 and 254 nm.

[0100] Temperatures are given in degrees Celsius (°C). The reaction mixtures used in the following examples can be obtained from commercially available raw materials, or they can be prepared from commercially available starting materials by methods as described herein or by methods known in the art. All compounds of the present invention are synthesized according to the examples described herein. The progress of the reactions described herein can be monitored as appropriate by, for example, LC, GC or TLC, and will be easily understood by those skilled in the art, but the reaction time and temperature can be adjusted as appropriate.

[0101] Chiral purification: Method A: Equipment:Waters Prep SFC80 Stationary phase: Chiralpak IC 5μm, 250 x 20mm Mobile phase: CO2 / (EtOH + 0.5% IPAm) 70 / 30 Flow rate: 50 mL / min UV detection: 220 nm Temperature: 40℃ Pressure: 100 bars Method B: Equipment: Waters Prep SFC80; Stationary phase: Chiralcel OJ-H 5μm, 250 x 20mm Mobile phase: CO2 / (EtOH + 0.5% IPAm) 70 / 30 Flow rate: 50 mL / min UV detection: λ = 254 nm Temperature: 40°C - Pressure: 100 bars

[0102] Abbreviations In addition to the above definitions, the following abbreviations are used in the above synthetic scheme and the following examples. If an abbreviation used in this specification is not defined, the abbreviation has its generally accepted meaning: [Table 57] TIFF0007874663000079.tif95153

[0103] Example 1 - Chemical synthesis route Scaffold Synthesis of dimethyl scaffolds Synthesis of 4-bromo-3,3-dimethyl-1H-pyrrolo[2,3-b]pyridin-2-one [Chemical formula] In a 250 mL three-necked round-bottom flask, 33 mL (33.4 mmol, 3.8 eq.) of 1 M lithium bis(trimethylsilyl)amide solution was added dropwise from a dropping funnel to a solution of 4-bromo-1,3-dihydro-2H-pyrrolo[2,3-b]pyridine-2-one (2.00 g, 8.92 mmol, 1 eq.) / anhydrous THF (44 mL, 0.2 N) at -78°C. The mixture was stirred at -78°C for 10 minutes. Next, iodomethane (1.4 mL, 22.3 mmol, 2.5 eq.) was added. The reaction mixture was warmed to room temperature and stirred at room temperature for 1 hour. Then, saturated aqueous solution of NH4Cl and ethyl acetate were added. The two phases were separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phase was dried over Na2SO4, filtered, and evaporated to obtain the crude product. The crude product was purified by flash chromatography on silica gel using a dichloromethane / ethyl acetate gradient. It was eluted through a solid phase of Dicalite. The relevant fractions were collected and concentrated under vacuum to obtain 4-bromo-3,3-dimethyl-1H-pyrrolo[2,3-b]pyridine-2-one as a pale yellow powder (yield 63%). 1 H NMR (DMSO-d6, 400 MHz):δ (ppm) 11.26 (s, 1H), 7.95 (d, J=5.7 Hz, 1H), 7.19 (d, J=5.7 Hz, 1H), 1.39 (s, 6H);m / z = 241.2, 243.2 [M+H]+.

[0104] Synthesis of 4-bromo-3,3-dimethyl-1-tetrahydropyran-2-ylpyrrolo[2,3-b]pyridine-2-one [ka] In a 20 mL microwave vial, 3,4-dihydro-2H-pyran (0.68 mL, 7.47 mmol, 3 eq) was added to a stirred solution of 4-bromo-3,3-dimethyl-1H-pyrrolo[2,3-b]pyridine-2-one (600 mg, 2.49 mmol) and p-toluenesulfonic acid hydrate (95 mg, 0.498 mmol, 0.2 eq.) / anhydrous toluene (12 mL, 0.2 N). The reaction mixture was stirred at 90°C for 5 hours. The solvent was removed under vacuum, and the crude product was obtained as an orange oil. The crude product was purified by flash chromatography on silica gel using a heptane / ethyl acetate gradient. The relevant fractions were collected and concentrated under vacuum to obtain 4-bromo-3,3-dimethyl-1-tetrahydropyran-2-yl-pyrrolo[2,3-b]pyridine-2-one (750 mg, 93% yield). 1 H NMR (DMSO-d6, 400 MHz):δ (ppm) 8.07 (d, J=5.6 Hz, 1H), 7.32 (d, J=5.6 Hz, 1H), 5.40 (dd, J=11.3, 2.1 Hz, 1H), 3.97 (d, J=10.8 Hz, 1H), 3.56 (qd, J=11.2, 10.8, 5.0 Hz, 1H), 2.85 (qd, J=13.7, 12.7, 3.8 Hz, 1H), 2.01 - 1.86 (m, 1H), 1.68 - 1.48 (m, 4H), 1.42 (s, 6H), m / z = 325.2, 327.0 [M+H]+.

[0105] Synthesis of 3,3-dimethyl-1-tetrahydropyran-2-yl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine-2-one [ka] In a sealed vial, under nitrogen, 4-bromo-3,3-dimethyl-1-tetrahydropyran-2-yl-pyrrolo[2,3-b]pyridine-2-one (0.75 g, 2.31 mmol), bis(pinacolato)diborone (0.88 g, 3.46 mmol, 1.5 eq.), potassium acetate (715 mg, 6.92 mmol, 3 eq.), and dichloromethane adduct of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (193 mg, 0.231 mmol, 0.1 eq.) were added in anhydrous dioxane (8 mL, 0.3 N). The vial was sealed and degassed with nitrogen. The reaction mixture was stirred overnight at 100°C. The reaction mixture was filtered through a Dycalite pad, and the filtrate was evaporated to dryness to obtain the crude product as a dark oil. The crude product was purified by flash chromatography on silica gel using a heptane / ethyl acetate gradient. The relevant fractions were collected and concentrated under vacuum to obtain 3,3-dimethyl-1-tetrahydropyran-2-yl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine-2-one (490 mg, yield 57%) as a yellow oil. 1 H NMR (DMSO-d6, 400 MHz):δ (ppm) 8.19 (d, J=5.1 Hz, 1H), 7.24 (d, J=5.1 Hz, 1H), 5.42 (dd, J=11.3, 2.0 Hz, 1H), 3.96 (d, J=11.1 Hz, 1H), 3.64 - 3.44 (m, 1H), 2.89 (d, J=11.4 Hz, 1H), 1.91 (s, 1H), 1.73 - 1.46 (m, 4H), 1.40 (s, 6H), 1.35 (s, 12H). m / z = 373.4 [M+H]+.

[0106] Ethyl / methyl scaffold synthesis Synthesis of 3,4-dibromo-3-methyl-1H-pyrrolo[2,3-b]pyridine-2-one [ka] To a stirred solution of 4-bromo-3-methyl-1H-pyrrolo[2,3-b]pyridine (460 mg, 2.07 mmol) / tert-butanol (16 mL, 0.13 N), bromide-pyridinium perbromide (1.46 g, 4.56 mmol, 2.2 eq.) was added in small increments over 10 minutes. The reaction mixture was stirred overnight at room temperature. t-butanol was removed under vacuum. After adding water, ethyl acetate was added. The two phases were separated, and the aqueous phase was extracted with ELISA. The combined organic phases were washed with water, dried over Na2SO4, and concentrated under high vacuum to obtain 3,4-dibromo-3-methyl-1H-pyrrolo[2,3-b]pyridine-2-one (660 mg, 96% yield) as a white solid. 1 ¹H NMR (DMSO-d6, 400 MHz): δ (ppm) 11.77 (s, 1H), 8.04 (d, J=5.7 Hz, 1H), 7.32 (d, J=5.7 Hz, 1H), 2.07 (s, 3H); (The product is unstable under LC-MS).

[0107] Synthesis of 4-bromo-3-methyl-1,3-dihydropyrrolo[2,3-b]pyridine-2-one [ka] In a 50 mL round-bottom flask, at room temperature, zinc powder (847 mg, 13.0 mmol, 2 eq.) was added in small amounts to a stirred suspension of 3,4-dibromo-3-methyl-1H-pyrrolo[2,3-b]pyridine-2-one (2.00 g, 6.01 mmol) in a mixed solvent of methanol (30 mL) and acetic acid (15 mL). The reaction mixture was stirred at room temperature for 10 minutes. The mixture was neutralized to pH=6 with aqueous NaHCO3. The solution was filtered, and the aqueous phase was extracted with ELISA. The combined organic phases were washed with brine, dried over Na2SO4, filtered, and evaporated to obtain 4-bromo-3-methyl-1,3-dihydropyrrolo[2,3-b]pyridine-2-one (1.08 g, yield 76%) as a white solid. 1H NMR (DMSO-d6, 400 MHz):δ (ppm) 11.22 (s, 1H), 7.95 (dd, J=5.7, 0.8 Hz, 1H), 7.18 (d, J=5.7 Hz, 1H), 3.66 - 3.49 (m, 1H), 1.43 (d, J=7.6 Hz, 3H);m / z = 227.1, 229.1 [M+H]+.

[0108] Synthesis of 4-bromo-3-ethyl-3-methyl-1H-pyrrolo[2,3-b]pyridine-2-one [ka] A 1M lithium [bis(trimethylsilyl)amide] solution (2.2 mL, 2.16 mmol, 2 eq.) was added dropwise to a solution of 4-bromo-3-methyl-1,3-dihydropyrrolo[2,3-b]pyridine-2-one (350 mg, 1.08 mmol) / anhydrous tetrahydrofuran (2.7 mL, 0.4 N) at -78°C under an argon stream. The reaction mixture was stirred at -78°C for 10 minutes. Then, iodoethane (0.087 mL, 1.08 mmol, 1 eq.) was added, and the mixture was stirred at room temperature under an argon stream for 1 hour. Then, 1N hydrochloric acid aqueous solution was slowly added until the pH reached 6-7, and ethyl acetate was added. The two phases were separated, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, dried using a phase separator, and evaporated to obtain the crude product as an orange solid. The crude substance was purified by flash chromatography on silica gel using a heptane / ethyl acetate gradient. It was eluted through the solid phase. The relevant fractions were collected and concentrated under vacuum to obtain 4-bromo-3-ethyl-3-methyl-1H-pyrrolo[2,3-b]pyridine-2-one (155 mg, 56% yield) as a flesh-colored powder. 1H NMR (400 MHz, DMSO-d6) δ 11.30 (s, 1H), 7.96 (d, J = 5.7 Hz, 1H), 7.21 (d, J = 5.7 Hz, 1H), 2.21 - 2.05 (m, 1H), 1.77 (dq, J = 14.7, 7.4 Hz, 1H), 1.38 (s, 3H), 0.50 (t, J = 7.4 Hz, 3H);m / z = 255.1, 257.1 [M+H]+.

[0109] Two enantiomers were obtained by chiral separation of a racemic mixture under SFC conditions. Equipment: Novasep SFC Superprep Stationary phase: ChiRalpak AD-H 20μm, 300 x 50mm Mobile phase: CO2 / MeOH 73 / 27 Flow rate: 1000 g / min UV detection: λ=295 nm Temperature: 45℃ Pressure: 130 bars Sample: Dissolved in MeOH rt(MeEt isomer 1) = 4.74 min and rt(MeEt isomer 2) = 7.06 min

[0110] The S-isomer was arbitrarily assigned as MeEt isomer 1, and the R-isomer was arbitrarily assigned as MeEt isomer 2. The same nomenclature was used to describe all related derivatives.

[0111] The following methods are the same for racemic mixtures and pure enantiomers. The synthesis of boronic acid esters describes the racemic mixture.

[0112] Synthesis of 4-bromo-3-ethyl-3-methyl-1-tetrahydropyran-2-ylpyrrolo[2,3-b]pyridine-2-one [ka] 4-bromo-3-ethyl-3-methyl-1H-pyrrolo[2,3-b]pyridine-2-one (2.14 g, 6.79 mmol), 3,4-dihydro-2H-pyran (1.9 mL, 20.4 mmol, 3 eq.), and p-toluenesulfonic acid hydrate (271 mg, 1.43 mmol, 0.2 eq.) / anhydrous toluene (34 mL, 0.2 N) were placed in a 50 mL vial. The reaction mixture was stirred overnight at 80°C. The reaction mixture was cooled to room temperature. Water was then added, and the reaction mixture was extracted with ELISA. The combined organic layers were dried using a phase separator and concentrated under vacuum to obtain the crude product as an orange solid. The crude product was purified by flash chromatography on silica gel using a cyclohexane / ELISA gradient. It was eluted through a solid phase of Dicalite. The relevant fractions were collected and concentrated under vacuum to obtain 4-bromo-3-ethyl-3-methyl-1-tetrahydropyran-2-yl-pyrrolo[2,3-b]pyridine-2-one (1.45 g, 62.951% yield) as a yellow oil. 1H NMR (400 MHz, DMSO-d6) δ 8.08 (d, J = 5.6 Hz, 1H), 7.33 (d, J = 5.7 Hz, 1H), 5.42 (dd, J = 11.4, 1.8 Hz, 1H), 3.97 (d, J = 10.9 Hz, 1H), 3.54 (tt, J = 11.2, 2.9 Hz, 1H), 2.86 (pd, J = 13.1, 3.9 Hz, 1H), 2.18 (ddh, J = 15.0, 7.5, 3.5 Hz, 1H), 1.93 (d, J = 10.8 Hz, 1H), 1.81 (dqd, J = 14.7, 7.3, m / z = 338.9, 340.8 [M+H]+.

[0113] Synthesis of 3-ethyl-3-methyl-1-tetrahydropyran-2-yl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine-2-one [ka] In a 20 mL microwave vial, bis(pinacolato)diborone (2.19 g, 8.61 mmol, 2 eq.), potassium acetate (1.33 g, 12.9 mmol, 3 eq.), 4-bromo-3-ethyl-3-methyl-1-tetrahydropyran-2-yl-pyrrolo[2,3-b]pyridine-2-one (1460 mg, 4.30 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (352 mg, 0.430 mmol, 0.1 eq.) were added in anhydrous dioxane (43 mL, 0.1 N). The mixture was degassed with nitrogen and stirred at 100°C for 2 hours. The reaction mixture was allowed to return to room temperature and filtered through a dikalite pad. The dikalite was washed with ELISA. The combined organic layers were concentrated under vacuum to obtain the crude substance as a brown oil. The crude substance was purified by flash chromatography on silica gel using a cyclohexane / siRNA gradient. It was eluted through a solid phase of dikalite. The relevant fractions were collected and concentrated under vacuum to obtain 3-ethyl-3-methyl-1-tetrahydropyran-2-yl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine-2-one (1.08 g, 52% yield) as a pale yellow oil. 1H NMR (DMSO-d6, 400 MHz):δ (ppm) 8.19 (d, J=5.2 Hz, 1H), 7.25 (d, J=5.1 Hz, 1H), 5.43 (dd, J=11.4, 2.0 Hz, 1H), 3.96 (d, J=11.1 Hz, 1H), 3.64 - 3.49 (m, 1H), 3.01 - 2.79 (m, 1H), 2.33 - 2.16 (m, 1H), 1.93 (d, J=11.0 Hz, 1H), 1.87 - 1.73 (m, 2H), 1.71 - 1.43 (m, 6H), 1.34 (s, 12 H), 0.38 (t, J=7.4 Hz, 3H); m / z = 387.0 [M+H]+.

[0114] Me / OH scaffold synthesis Synthesis of 4-bromo-3-hydroxy-3-methyl-1H-pyrrolo[2,3-b]pyridine-2-one [ka] Sodium hydride (60%, 203 mg, 5.09 mmol, 1.1 eq) / THF (10 mL) was placed in a round-bottom flask. The mixture was cooled to 0°C, and 4-bromo-3-methyl-1,3-dihydropyrrolo[2,3-b]pyridine-2-one (1.05 g, 4.62 mmol) / THF (13 mL) was added dropwise. The reaction mixture was then exposed to air at room temperature overnight. Subsequently, a 1N aqueous HCl solution was added. The aqueous phase was extracted with ethyl acetate. The combined organic phases were dried and evaporated using a phase separator to obtain the crude product. The product was triturated in DCM to obtain 4-bromo-3-hydroxy-3-methyl-1H-pyrrolo[2,3-b]pyridine-2-one (697 mg, yield 62%) as a pale yellow solid. 1 H NMR (DMSO-d6, 400 MHz):δ (ppm) 11.11 (s, 1H), 7.95 (d, J=5.7 Hz, 1H), 7.18 (d, J=5.7 Hz, 1H), 6.11 (s, 1H), 1.50 (s, 3H);m / z = 243.1, 245.1 [M+H]+.

[0115] Two enantiomers were obtained by chiral separation of a racemic mixture under SFC conditions. Equipment: Waters prep SFC Supersep Stationary phase: Chiralpak AD-H 20μm, 250 x 50mm Mobile phase: CO2 / MeOH 87 / 13 Flow rate: 1000 g / min UV detection: λ = 290 nm Temperature: 40℃ Pressure: 150 bars Sample: Dissolved in MeOH rt (OHMe isomer 1) = 6.05 min and rt (OHMe isomer 2) = 8.34 min

[0116] The S-isomer was arbitrarily assigned as OHMe isomer 1, and the R-isomer was arbitrarily assigned as OHMe isomer 2. The same nomenclature was used to describe all related derivatives.

[0117] The following method is the same for racemic mixtures and pure enantiomers. Boronic acid ester synthesis is described for enantiomer 1.

[0118] Synthesis of (3R)-4-bromo-3-hydroxy-3-methyl-1-tetrahydropyran-2-ylpyrrolo[2,3-b]pyridine-2-one [ka] In a sealed vial, 3,4-dihydro-2H-pyran (3.0 mL, 32.9 mmol, 4 eq.) was added to a stirred solution of (3R)-4-bromo-3-hydroxy-3-methyl-1H-pyrrolo[2,3-b]pyridine-2-one (2.00 g, 8.23 ​​mmol) and p-toluenesulfonic acid hydrate (313 mg, 1.65 mmol, 0.2 eq.) / anhydrous toluene (27 mL, 0.3 N). The reaction mixture was stirred overnight at 90°C. The mixture was then cooled to 0°C, and 4M hydrogen chloride (4.1 mL, 16.5 mmol, 2 eq.) was added. The mixture was stirred at room temperature for 2 hours. The solution was concentrated under vacuum. Dichloromethane and saturated aqueous solutions of NaHCO3 were added. The aqueous phase was extracted with dichloromethane. The organic phase was dried using a phase separator and concentrated under vacuum. The crude material was purified by flash chromatography on silica gel using a heptane / siRNA gradient. The associated fractions were recovered and evaporated to obtain (3R)-4-bromo-3-hydroxy-3-methyl-1-tetrahydropyran-2-ylpyrrolo[2,3-b]pyridine-2-one (1.02 g, 36% yield). 1 H NMR (DMSO-d6, 400 MHz):δ (ppm) 8.07 (dd, J=5.6, 1.2 Hz, 1H), 7.31 (dd, J=5.7, 0.8 Hz, 1H), 6.28 (d, J=6.8 Hz, 1H), 5.37 (dd, J=11.3, 1.9 Hz, 1H), 4.02 - 3.90 (m, 1H), 3.54 (td, J=11.0, 10.6, 3.2 Hz, 1H), 2.90 - 2.73 (m, 1H), 1.93 (d, J=10.0 Hz, 1H), 1.69 - 1.44 (m, 7H);m / z = 327.0, 328.9 [M+H]+.

[0119] Synthesis of (3R)-3-hydroxy-3-methyl-1-tetrahydropyran-2-yl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine-2-one [ka] In a vial, bis(pinacolato)diborone (640 mg, 2.52 mmol, 1.5 eq), potassium acetate (521 mg, 5.04 mmol, 3 eq), (3R)-4-bromo-3-hydroxy-3-methyl-1-tetrahydropyran-2-yl-pyrrolo[2,3-b]pyridine-2-one (0.55 g, 1.68 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (140 mg, 0.168 mmol, 0.1 eq.) were placed in anhydrous dioxane (5.6 mL, 0.3 N). The vial was sealed and degassed with nitrogen. The reaction mixture was stirred at 100°C for 2 hours. The reaction mixture was filtered through a dicalite pad, and the filtrate was evaporated to dryness to obtain the crude product as a dark-colored oil. The crude substance was purified by flash chromatography on silica gel using a dichloromethane / ethyl acetate gradient. It was eluted through a solid phase of dicalite. The fractions were collected and concentrated under vacuum to obtain (3R)-3-hydroxy-3-methyl-1-tetrahydropyran-2-yl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine-2-one (211 mg, yield 28%) as a yellow gum. 1 H NMR (DMSO-d6, 400 MHz):δ (ppm) 8.18 (d, J=5.0 Hz, 1H), 7.14 (d, J=5.1 Hz, 1H), 5.92 (d, J=6.4 Hz, 1H), 5.38 (d, J=9.9 Hz, 1H), 3.96 (d, m / z = 293.2 [M+H]+.

[0120] Me / OMe scaffold synthesis Synthesis of (3R)-4-bromo-3-methoxy-3-methyl-1-tetrahydropyran-2-ylpyrrolo[2,3-b]pyridine-2-one [ka] In a 50 mL round-bottom flask under a nitrogen atmosphere at 0°C, sodium hydride (60%, 378 mg, 9.44 mmol, 1.5 eq.) was added to a stirred solution of (3R)-4-bromo-3-hydroxy-3-methyl-1-tetrahydropyran-2-ylpyrrolo[2,3-b]pyridine-2-one (2.06 g, 6.30 mmol) / anhydrous DMF (32 mL, 0.2 N). The reaction mixture was stirred at room temperature for 30 minutes. Then, 2 M iodomethane (6.3 mL, 12.6 mmol, 2 eq.) / tert-butylmethyl ether was added dropwise at 0°C. The reaction mixture was stirred at 0°C for 15 minutes and then raised to room temperature. After 45 minutes at room temperature, the reaction was quenched with water and ethyl acetate. The two phases were separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water, dried using a phase separator, and evaporated to obtain (3R)-4-bromo-3-methoxy-3-methyl-1-tetrahydropyran-2-ylpyrrolo[2,3-b]pyridine-2-one as an orange gum (1.49 g, yield 63%). 1 H NMR (DMSO-d6, 400 MHz):δ (ppm) 8.16 (d, J=5.6 Hz, 1H), 7.40 (dd, J=5.6, 0.8 Hz, 1H), 5.42 (dt, J=11.4, 2.6 Hz, 1H), 4.00 - 3.93 (m, 1H), 3.61 - 3.49 (m, 1H), 2.91 (s, 3H), 2.87 - 2.75 (m, 1H), 1.94 (d, J=10.9 Hz, 1H), 1.70 - 1.41 (m, 7H);m / z = 341.1, 343.1 [M+H]+.

[0121] Synthesis of (3R)-3-methoxy-3-methyl-1-tetrahydropyran-2-yl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine-2-one [ka] Tricyclohexylphosphan (459 μL, 0.290 mmol, 0.075 eq.), bis(pinacolato)diborone (1.96 g, 7.73 mmol, 4 eq.), (3R)-4-bromo-3-methoxy-3-methyl-1-tetrahydropyran-2-ylpyrrolo[2,3-b]pyridine-2-one (1.45 g, 3.87 mmol), and anhydrous dioxane (19 mL, 0.2 N) were added to a Reacti-vial under a nitrogen atmosphere. Then, potassium acetate (767 mg, 7.73 mmol, 4 eq.) and tris(dibenzylideneacetone)dipalladium(0) (186 mg, 0.193 mmol, 0.05 eq.) were added. The reaction mixture was stirred at 100°C for 2 hours. The solvent was removed by distillation. Subsequently, water and dichloromethane were added. The two phases were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phase was dried using a phase separator and evaporator to obtain the crude material as an orange gum. The crude material was purified by flash chromatography on silica gel using a heptane / ethyl acetate gradient. It was eluted through the solid phase. The relevant fractions were collected and concentrated under vacuum to obtain (3R)-3-methoxy-3-methyl-1-tetrahydropyran-2-yl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine-2-one (665 mg, 43% yield) as an orange gum. 1H NMR (DMSO-d6, 400 MHz):δ (ppm) 8.26 (d, J=5.1 Hz, 1H), 7.22 (dd, J=5.1, 1.7 Hz, 1H), 5.42 (ddd, J=11.4, 5.4, 2.1 Hz, 1H), 4.01 - 3.94 (m, m / z = 307.2 [M+H]+ (acid form).

[0122] Et / OH scaffold synthesis Synthesis of 3-bromo-4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridine-2-one [ka] To a stirred solution of 4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridine hydrochloride (3.00 g, 13.8 mmol) / tert-butanol (106 mL, 0.13 N), bromide-pyridinium perbromide (11.05 g, 34.5 mmol) was added in small amounts. The reaction mixture was stirred at room temperature for 3 hours. Tert-butanol was removed by vacuum. The product was triturated in water and filtered to obtain 3-bromo-4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridine-2-one (2.95 g, 77% yield) as a flesh-colored solid. 1H NMR (DMSO-d6, 400 MHz):δ (ppm) 11.89 (s, 1H), 8.18 (d, J=5.7 Hz, 1H), 7.21 (d, J=5.7 Hz, 1H), 2.84 - 2.56 (m, 1H), 2.47 - 2.23 (m, 1H), 0.62 (t, J=7.4Hz, 3H)

[0123] Synthesis of 4-chloro-3-ethyl-1,3-dihydropyrrolo[2,3-b]pyridine-2-one [ka] To a stirred suspension of 3-bromo-4-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridine-2-one (2.95 g, 10.7 mmol) / THF (33 mL, 0.3 N), zinc (1.05 g, 16.1 mmol) was added at room temperature, followed by dropwise addition of water (0.58 mL, 32.1 mmol). The mixture was stirred at room temperature for 2 hours. The solution was then filtered under Dicalite to remove all zinc residue. The filtrate was concentrated under vacuum to obtain 4-chloro-3-ethyl-1,3-dihydropyrrolo[2,3-b]pyridine-2-one (2.1 g, 98% yield) as a yellow solid; m / z = 197.1, 199.1 [M+H]+.

[0124] Synthesis of 4-chloro-3-ethyl-3-hydroxy-1H-pyrrolo[2,3-b]pyridine-2-one [ka] A 10N sodium hydroxide aqueous solution (2.7 mL, 26.7 mmol) was added to a solution of 4-chloro-3-ethyl-1,3-dihydropyrrolo[2,3-b]pyridine-2-one (2.10 g, 10.7 mmol) / ethanol (49 mL, 0.2 N). The mixture was stirred overnight at room temperature. The mixture was concentrated under vacuum and a mixed aqueous solution of NH4Cl and MeTHF was added. The phases were separated, the organic phase was dried and concentrated under vacuum to obtain 4-chloro-3-ethyl-3-hydroxy-1H-pyrrolo[2,3-b]pyridine-2-one (2.2 g, 94% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.07 (d, J = 5.7 Hz, 1H), 7.06 (d, J = 5.7 Hz, 1H), 6.19 (s, 1H), 2.13 (tt, J = 14.3, 7.8 Hz, 1H), 2.03 - 1.87 (m, 1H), 0.55 (t, J = 7.5 Hz, 3H);m / z = 213.1, 215.1 [M+H]+.

[0125] Two enantiomers, SFC conditions: Equipment: Waters prep SFC200 Stationary phase: Chiralpak IC 5μm, 250 x 30mm Mobile phase: CO2 / MeOH 80 / 20 Flow rate: 100 mL / min UV detection: λ=210 nm Temperature: 40℃ Pressure: 100 bars Sample: Dissolved in MeOH rt(OHEt isomer 1) = 4.82 min and rt(OHEt isomer 2) = 6.74 min It was obtained by chiral separation of a racemic mixture.

[0126] The S-isomer was arbitrarily assigned as OHEt isomer 1, and the R-isomer was arbitrarily assigned as OHEt isomer 2. The same nomenclature was used to describe all related derivatives.

[0127] Et / OMe scaffold synthesis Synthesis of 4-chloro-3-ethyl-3-hydroxy-1-tetrahydropyran-2-ylpyrrolo[2,3-b]pyridine-2-one [ka] In a sealed vial, 3,4-dihydro-2H-pyran (0.79 mL, 8.67 mmol, 4 eq.) was added to a stirred solution of 4-chloro-3-ethyl-3-hydroxy-1H-pyrrolo[2,3-b]pyridine-2-one (614 mg, 2.89 mmol) and p-toluenesulfonic acid hydrate (110 mg, 0.578 mmol) / anhydrous toluene (12 mL, 0.2 N). The reaction mixture was stirred overnight at 90°C. The mixture was then cooled to 0°C and 4M hydrogen chloride (1.4 mL, 5.78 mmol, 2 eq.) was added. The mixture was stirred at room temperature for 3 hours. The solution was concentrated under vacuum. Ethyl acetate and aqueous solutions of NaHCO3 were added. The aqueous phase was extracted with ethyl acetate. The organic phase was dried using a phase separator and concentrated under vacuum. The crude substance was purified by flash chromatography on silica gel using a heptane / siRNA gradient. The relevant fractions were collected and evaporated to obtain 4-chloro-3-ethyl-3-hydroxy-1-tetrahydropyran-2-yl-pyrrolo[2,3-b]pyridine-2-one (446 mg, yield 52%) as a yellow oil. 1H NMR (DMSO-d6, 400 MHz):δ (ppm) 8.19 (d, J=5.7 Hz, 1H), 7.18 (d, J=5.7 Hz, 1H), 6.34 (d, J=4.5 Hz, 1H), 5.39 (d, J=11.3 Hz, 1H), 3.97 (d, J=10.5 Hz, 1H), 3.55 (t, J=11.2 Hz, 1H), 2.92 - 2.73 (m, 1H), 2.17 (dtd, J=15.4, 7.7, 3.5 Hz, 1H), 1.99 - 1.88 (m, 2H), 1.64 - 1.44 (m, 4H), 0.50 (t, J=7.6 Hz, 3H);m / z = 297.1, 299.1 [M+H]+.

[0128] Synthesis of 4-chloro-3-ethyl-3-methoxy-1-tetrahydropyran-2-ylpyrrolo[2,3-b]pyridine-2-one [ka] To a solution of 4-chloro-3-ethyl-3-hydroxy-1-tetrahydropyran-2-yl-pyrrolo[2,3-b]pyridine-2-one (220 mg, 0.741 mmol) in anhydrous DMF (3.7 mL, 0.2 N), sodium hydride (60%, 44 mg, 1.11 mmol) was added at 0°C under N2. The resulting mixture was stirred at 0°C for 20 minutes. Then, iodomethane (0.092 mL, 1.48 mmol) was added dropwise at 0°C. The mixture was stirred at 0°C for 5 minutes and then heated to RT. The resulting mixture was stirred at RT under N2 for 30 minutes. The mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried on a phase separator, and concentrated under vacuum to obtain 4-chloro-3-ethyl-3-methoxy-1-tetrahydropyran-2-yl-pyrrolo[2,3-b]pyridine-2-one (213 mg, 90% yield) as a yellow oil. 1H NMR (DMSO-d6, 400 MHz):δ (ppm) 8.29 (d, J=5.7 Hz, 1H), 7.29 (dd, J=5.7, 1.2 Hz, 1H), 5.43 (d, J=11.3 Hz, 1H), 3.98 (d, J=11.0 Hz, 1H), 3.55 (t, J=11.1 Hz, 1H), 3.28 (d, J=4.8 Hz, 1H), 2.95 (d, J=1.2 Hz, 3H), 2.81 (d, J=11.4 Hz, 1H), 2.18 (ddd, J=13.2, 7.7, 2.4 Hz, 1H), 1.98 (dd, J=13.3, 7.5 Hz, 1H), 1.57 (d, J=45.7 Hz, 4H), 0.55 (t, J=7.5 Hz, 3H), m / z = 311.2 - 313.2 [M+H]+.

[0129] Scaffold Me / NMe Synthesis of 4-bromo-3-methyl-3-(methylamino)-1H-pyrrolo[2,3-b]pyridine-2-one [ka] In a reaction vial, a solution of methanamine / THF (6.0 mL, 8.04 mmol 1,34N) (cooled to -30°C) was added to 3,4-dibromo-3-methyl-1H-pyrrolo[2,3-b]pyridine-2-one (500 mg, 1.63 mmol) at -30°C. The mixture was raised to 0°C and stirred at 0°C for 7 hours. The solution was concentrated to dryness to obtain a yellow gum. The crude material was purified by flash chromatography on silica gel using a heptane / siRNA gradient. It was eluted by liquid injection / DCM on a 24 g Redisep column. The relevant fractions were collected and concentrated under vacuum to obtain 4-bromo-3-methyl-3-(methylamino)-1H-pyrrolo[2,3-b]pyridine-2-one as a white solid (179 mg, 43%); 1H NMR (400 MHz, DMSO-d6) δ 11.23 (s, 1H), 7.96 (d, J = 5.7 Hz, 1H), 7.20 (d, J = 5.7 Hz, 1H), 1.90 (s, 3H), 1.41 (s, 3H); m / z = 256.0, 258.0 [M+H]+

[0130] Other scaffolds Synthesis of 7-bromo-1,3-dihydroimidazo[4,5-b]pyridine-2-one [ka] 4-Bromopyridine-2,3-diamine (5.00 g, 25.3 mmol) and 1,1'-carbonyldiimidazole (8.19 g, 50.5 mmol) were placed in a sealed vial. 140 mL of THF was added, and the mixture was stirred overnight at 60°C. The flask was cooled for 5 minutes using an ice bath. The precipitate was filtered through glass frit, washed once with cold THF, and then washed with water. The solid was vacuum-dried. 7-Bromo-1,3-dihydroimidazo[4,5-b]pyridine-2-one was obtained as a brown powder (5.14 g, 94%). 1H NMR (DMSO-d6, 400 MHz):δ (ppm) 11.60 (s, 1H), 11.39 (s, 1H), 7.74 (d, J=5.7 Hz, 1H), 7.17 (d, J=5.7 Hz, 1H);m / z = 214.0, 216.0 [M+H]+.

[0131] Synthesis of 7-bromo-3-tetrahydropyran-2-yl-1H-imidazo[4,5-b]pyridine-2-one [ka] To a solution of 7-bromo-1,3-dihydroimidazo[4,5-b]pyridine-2-one (500 mg, 2.34 mmol) / anhydrous THF (17.5 mL, 0.1 N), 3,4-dihydro-2H-pyran (0.64 mL, 7.01 mmol, 3 eq.) and p-toluenesulfonic acid hydrate (89 mg, 0.467 mmol, 0.2 eq.) were added. The mixture was stirred overnight at 75°C. 3,4-dihydro-2H-pyran (0.64 mL, 7.01 mmol, 3 eq.) was added, and the reaction mixture was stirred at 75°C for 3 hours. The reaction mixture was allowed to return to room temperature and quenched with water. ELISA was added, and the two layers were separated. The aqueous layer was extracted with ELISA. The combined organic layers were dried over Na2SO4, filtered, and vacuum concentrated to obtain the crude product as brown oil. The crude mixture was purified by flash chromatography using a cyclohexane / siRNA gradient. It was eluted through a solid phase of dichalite. The relevant fractions were collected and concentrated under vacuum to obtain 7-bromo-3-tetrahydropyran-2-yl-1H-imidazo[4,5-b]pyridine-2-one (452 ​​mg, 65% yield) as a yellow solid. 1H NMR (DMSO-d6, 400 MHz):δ (ppm) 11.77 (s, 1H), 7.84 (d, J=5.6 Hz, 1H), 7.28 (d, J=5.7 Hz, 1H), 5.41 (dd, J=11.3, 2.2 Hz, 1H), 4.02 - 3.92 m / z = 298.0;300.0 [M+H]+.

[0132] Synthesis of 3-tetrahydropyran-2-yl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-imidazo[4,5-b]pyridine-2-one [ka] To a solution of 7-bromo-3-tetrahydropyran-2-yl-1H-imidazo[4,5-b]pyridine-2-one (300 mg, 1.01 mmol) / anhydrous dioxane (10 mL, 0.1 N), potassium acetate (420 mg, 4.02 mmol, 4 eq.) and bis(pinacorato)diborone (767 mg, 3.02 mmol, 3 eq.) were added. The mixture was degassed using N2, and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (78 mg, 0.101 mmol, 0.1 eq.) was added. The resulting mixture was stirred at 95°C for 2 hours under N2. The mixture was filtered through dikalite and concentrated to obtain 3-tetrahydropyran-2-yl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-imidazo[4,5-b]pyridine-2-one (1.1 g, 57% yield) as a dark oil. The crude product was used in the next step without further purification. m / z = 264.1 [M+H]+. (boronic acid).

[0133] Synthesis of 7-bromo-1-methyl-3-tetrahydropyran-2-ylimidazo[4,5-b]pyridine-2-one [ka] To a solution of 7-bromo-3-tetrahydropyran-2-yl-1H-imidazo[4,5-b]pyridine-2-one (502 mg, 1.63 mmol) in anhydrous DMF (8.3 mL, 0.1 N), sodium hydride (78 mg, 1.95 mmol, 1.2 eq., 60%) was added at 0°C. The mixture was stirred for 15 minutes, and iodomethane (125 μL, 2.01 mmol, 1.2 eq.) was added at the same temperature. The reaction mixture was stirred for 1 hour. Water was added, the resulting precipitate was filtered, and washed with water. The solid was vacuum-dried at 40°C to obtain 7-bromo-1-methyl-3-tetrahydropyran-2-yl-imidazo[4,5-b]pyridine-2-one (0.40 g, 77% yield) as a pink solid. 1 H NMR (DMSO-d6, 400 MHz):δ (ppm) 7.86 (d, J=5.6 Hz, 1H), 7.32 (d, J=5.6 Hz, 1H), 5.49 (dd, J=11.3, 2.2 Hz, 1H), 3.97 (dd, J=11.2, 2.0 Hz, m / z = 312.1, 314.1 [M+H]+.

[0134] Synthesis of 7-bromo-3H-oxazole[4,5-b]pyridine-2-one [ka] 2-amino-4-bromopyridine-3-ol (200 mg, 1.01 mmol) and 1,1'-carbonyldiimidazole (0.33 g, 2.01 mmol, 2 eq.) were placed in a sealed vial. THF (6 mL, 0.2 N) was added, and the mixture was stirred overnight at 60°C. The solution was evaporated under vacuum, and the crude product was triturated in DCM. The resulting solid was filtered and vacuum-dried to obtain 7-bromo-3H-oxazolo[4,5-b]pyridine-2-one as a brown powder (140 mg, yield 32%). 1 H NMR (DMSO-d6, 400 MHz): δ (ppm) 7.85 (d, J=5.8 Hz, 1H), 7.25 (d, J=5.8 Hz, 1H).

[0135] Synthesis of 4-bromospiro[1H-pyrrolo[2,3-b]pyridine-3,1'-cyclopentan]-2-one [ka] A solution of 4-bromo-1,3-dihydro-2H-pyrrolo[2,3-b]pyridine-2-one (500 mg, 2.35 mmol) / anhydrous THF (7.8 mL, 0.3 N) was cooled to -78°C, and 1 M lithium [bis(trimethylsilyl)amide] solution (8.2 mL, 8.21 mmol, 3.5 eq.) was added. After stirring for 30 minutes, 1,4-diiodobutane (371 μL, 2.82 mmol, 1.2 eq.) was added dropwise. The reaction mixture was warmed to room temperature and stirred overnight. The reaction was quenched with saturated aqueous NH4Cl solution and extracted with ELISA. The organic phase was dried and evaporated using a phase separator to obtain the crude product as oil. The crude product was purified by flash chromatography on silica gel using a heptane / EtOAC gradient. It was eluted through the solid silica phase. The relevant fractions were collected and concentrated to obtain 4-bromospiro[1H-pyrrolo[2,3-b]pyridine-3,1'-cyclopentan]-2-one (258 mg, yield 41%). 1H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 7.91 (d, J = 5.7 Hz, 1H), 7.19 (d, J = 5.7 Hz, 1H), 2.15 (dd, J = 8.1, 5.5 Hz, 2H), 2.08 - 1.82 (m, 6H);m / z = 267.1, 269.1 [M+H]+.

[0136] Synthesis of 4'-bromo-1'-tetrahydropyran-2-yl-spiro[cyclopentan-1,3'-pyrrolo[2,3-b]pyridine]-2'-one [ka] 3,4-Dihydro-2H-pyran (0.26 mL, 2.90 mmol, 3 eq.) was added to a stirred solution of 4-bromospiro[1H-pyrrolo[2,3-b]pyridine-3,1'-cyclopentan]-2-one (258 mg, 0.966 mmol) and p-toluenesulfonic acid hydrate (37 mg, 0.193 mmol, 0.2 eq.) / anhydrous toluene (4.8 mL, 0.2 N). The reaction mixture was stirred overnight at 90°C. The solvent was removed under vacuum. The crude product was purified by flash chromatography on silica gel using a heptane / ethyl acetate gradient. The relevant fractions were collected and concentrated under vacuum to obtain 4'-bromo-1'-tetrahydropyran-2-yl-spiro[cyclopentan-1,3'-pyrrolo[2,3-b]pyridine]-2'-one (238 mg, 70% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.04 (d,J= 5.6 Hz, 1H), 7.32 (d,J= 5.7 Hz, 1H), 5.37 (dd,J= 11.3, 2.1 Hz, 1H), 3.96 (d,J= 11.3 Hz, 1H), 3.53 (td,J= 11.2, 4.0 Hz, 1H), 2.95 - 2.76 (m, 1H), 2.17 (dd,J= 13.2, 5.9 Hz, 2H), 2.04 - 1.87 (m, 7H), 1.69 - 1.50 (m, 4H);m / z = 351.2-353.2 [M+H]+.

[0137] Synthesis of 1'-tetrahydropyran-2-yl-4'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[cyclopentan-1,3'-pyrrolo[2,3-b]pyridine]-2'-one [ka] In a vial, bis(pinacolato)diborone (258 mg, 1.02 mmol, 1.5 eq.), potassium acetate (210 mg, 2.03 mmol, 3 eq.), 4'-bromo-1'-tetrahydropyran-2-yl-spiro[cyclopentan-1,3'-pyrrolo[2,3-b]pyridine]-2'-one (238 mg, 0.68 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (57 mg, 0.068 mmol, 0.1 eq.) were added in anhydrous dioxane (2.2 mL, 0.3 N). The vial was sealed and degassed with nitrogen. The reaction mixture was stirred overnight at 100°C. The reaction mixture was filtered through a Celite pad, and the filtrate was evaporated to dryness to obtain the crude substance as a dark oil. This crude substance was purified by flash chromatography on silica gel using a dichloromethane / ethyl acetate gradient. It was eluted through a solid phase of Dicalite. The relevant fractions were collected and concentrated under vacuum to obtain 1'-tetrahydropyran-2-yl-4'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[cyclopentan-1,3'-pyrrolo[2,3-b]pyridine]-2'-one (190 mg, 35% yield). 1 H NMR (chloroform-d, 400 MHz):δ (ppm) 8.16 (d, J=5.2 Hz, 1H), 7.28 (d, J=5.1 Hz, 1H), 5.52 (dd, J=11.3, 2.2 Hz, 1H), 4.21 - 4.10 (m, 1H), 3.69 (td, J=11.9, 2.2 Hz, 1H), 3.00 (qd, J=13.1, 12.6, 4.1 Hz, 1H), 2.29 - 1.95 (m, 9H), 1.85 - 1.60 (m, 4H), 1.35 (s, 12H); 399.4 [M+H]+.

[0138] Synthesis of 4-bromo-5-chloro-3,3-dimethyl-1H-pyrrolo[2,3-b]pyridine-2-one [ka] In a 50 mL round-bottom flask at room temperature, N-chlorosuccinimide (133 mg, 0.996 mmol, 1.6 eq.) was added to a stirred suspension of 4-bromo-3,3-dimethyl-1H-pyrrolo[2,3-b]pyridine-2-one (150 mg, 0.622 mmol) and sodium acetate (26 mg, 0.311 mmol, 0.5 eq.) / acetic acid (0.8 mL, 0.8 N). The mixture was heated at 60°C for 2 hours. N-chlorosuccinimide (133 mg, 0.996 mmol, 1.6 eq.) was added, and the solution was stirred overnight at 80°C. The reaction mixture was diluted with water and quenched with 1 M Na2S2O3 aqueous solution. The resulting solid was filtered through glass frit to obtain 4-bromo-5-chloro-3,3-dimethyl-1H-pyrrolo[2,3-b]pyridine-2-one (143 mg, yield 82%) as a yellow powder. This product was used in the next step without further purification. 1 H NMR (DMSO-d6, 400 MHz):δ (ppm) 11.41 (s, 1H), 8.27 (s, 1H), 1.41 (s, 6H);m / z = 275.0, 277.0 [M+H]+

[0139] Synthesis of 4-chloro-5-fluoro-3,3-dimethyl-1H-pyrrolo[2,3-b]pyridine-2-one [ka] In a round-bottom flask, at 0°C, 38 mL (37.7 mmol, 3.7 eq.) of 1 M lithium [bis(trimethylsilyl)amide] solution was added dropwise to a stirred solution of 4-chloro-5-fluoro-1H,2H,3H-pyrrolo[2,3-b]pyridine-2-one (2.00 g, 10.2 mmol) / 2-methyltetrahydrofuran anhydride (26 mL, 0.4 N). The mixture was stirred at 0°C for 10 minutes. Then, 1.6 mL (25.5 mmol, 2.5 eq.) was added dropwise at 0°C, and the mixture was stirred at this temperature for 3 hours. A saturated aqueous solution of NH4Cl was slowly added. Water was added, and the mixture was extracted with RINKAN. The combined organic layers were washed with water and brine, dried on a phase separator, and concentrated to obtain a green solid. The crude product was transferred to a mixture of diisopropyl ether / Et2O(50 / 50) and filtered to obtain 4-chloro-5-fluoro-3,3-dimethyl-1H-pyrrolo[2,3-b]pyridine-2-one (1.8 g, yield 78%) as a green solid. 1 H NMR (DMSO-d6, 400 MHz):δ (ppm) 11.32 (s, 1H), 8.24 (d, J=2.2 Hz, 1H), 1.41 (s, 6H). m / z = 215.2, 217.2 [M+H]+

[0140] Synthesis of 4-chloro-5-fluoro-3,3-dimethyl-1-tetrahydropyran-2-ylpyrrolo[2,3-b]pyridine-2-one [ka] 4-chloro-5-fluoro-3,3-dimethyl-1H-pyrrolo[2,3-b]pyridine-2-one (830 mg, 3.87 mmol), anhydrous toluene (13 mL, 0.3 N), p-toluenesulfonic acid hydrate (147 mg, 0.773 mmol, 0.2 eq.), and 3,4-dihydro-2H-pyran (1.1 mL, 11.6 mmol, 3 eq.) were added sequentially to a 20 mL vial. The reaction mixture was stirred overnight at 90°C. Then, 3,4-dihydro-2H-pyran (0.5 mL) was added, and the reaction mixture was stirred overnight at 90°C. The solvent was evaporated, and the crude substance was obtained as a brown oil. The crude substance was purified by flash chromatography on silica gel using a heptane / ethyl acetate gradient. It was eluted through the solid phase. The relevant fractions were collected and concentrated under vacuum to obtain 4-chloro-5-fluoro-3,3-dimethyl-1-tetrahydropyran-2-yl-pyrrolo[2,3-b]pyridine-2-one (785 mg, yield 67%) as an orange gum. 1H NMR (400 MHz, DMSO-d6) δ 8.37 (d, J = 2.0 Hz, 1H), 5.38 (dd, J = 11.3, 2.1 Hz, 1H), 3.97 (d, J = 10.7 Hz, 1H), 3.55 (td, J = 11.3, 4.0 Hz, 1H), 2.82 (qd, J = 13.7, 12.9, 4.1 Hz, 1H), 1.97 - 1.88 (m, 1H), 1.69 - 1.48 (m, 4H), 1.44 (s, 6H), m / z = 299.2, 301.2 [M+H]+

[0141] Synthesis of 5-fluoro-3,3-dimethyl-1-tetrahydropyran-2-yl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine-2-one [ka] In a Reacti-vial, under a nitrogen atmosphere, tricyclohexylphosphan (284 μL, 0.180 mmol, 0.075 eq.), bis(pinacolato)diborone (1.22 g, 4.79 mmol, 2 eq.), 4-chloro-5-fluoro-3,3-dimethyl-1-tetrahydropyran-2-yl-pyrrolo[2,3-b]pyridine-2-one (715 mg, 2.39 mmol), and anhydrous dioxane (12 mL, 0.2 N) were added. Then, potassium acetate (475 mg, 4.79 mmol, 2 eq.) and tris(dibenzylideneacetone)dipalladium(0) (115 mg, 0.120 mmol, 0.05 eq.) were added. The reaction mixture was stirred overnight at 100°C. The mixture was filtered and concentrated on dikalite to obtain the crude substance as a black oil. The crude substance was purified by flash chromatography on silica gel using a heptane / ethyl acetate gradient. 5-Fluoro-3,3-dimethyl-1-tetrahydropyran-2-yl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine-2-one (670 mg, yield 22%) was obtained as a yellow solid (a mixture of the product and the debrominated product). m / z = 391.4 [M+H]+

[0142] Synthesis of 5-fluoro-3-methyl-1,3-dihydropyrrolo[2,3-b]pyridine-2-one; hydrochloride salt [ka] To a solution of tert-butyl 5-fluoro-3-methyl-2-oxo-3H-pyrrolo[2,3-b]pyridine-1-carboxylate (210 mg, 0.752 mmol) / anhydrous dioxane (2 mL, 0.3 N), 4 M hydrogen chloride (1.0 mL, 4.00 mmol, 5 eq.) / dioxane was added. The vial was sealed and the reaction mixture was stirred at 60°C for 1 hour. The solution was concentrated to dryness to obtain 5-fluoro-3-methyl-1,3-dihydropyrrolo[2,3-b]pyridine-2-one hydrochloride (139 mg, yield 84%) as a white solid. 1H NMR (500 MHz, DMSO-d6) δ 11.01 (br s, 1H), 8.03 (t, J=1.83 Hz, 1H), 7.69 (dd, J=2.20, 8.31 Hz, 1H), 3.54-3.61 (m, 1H), 1.35 (d, J=7.58 Hz, 3H);m / z = 167.1 [M+H]+

[0143] Synthesis of 3-ethyl-5-fluoro-3-methyl-1H-pyrrolo[2,3-b]pyridine-2-one [ka] In a 2-5 mL vial, 1.7 mL, 1.71 mmol, 3.8 eq. of 1 M lithium [bis(trimethylsilyl)amide] solution was added dropwise to a stirred suspension of 5-fluoro-3-methyl-1,3-dihydropyrrolo[2,3-b]pyridine-2-one hydrochloride (98 mg, 0.445 mmol) / 2-methyltetrahydrofuran anhydride (1.5 mL, 0.3 N) at 0°C. The reaction mixture was stirred at 0°C for 10 minutes. Iodoethane (0.065 mL, 0.813 mmol, 1.8 eq.) was added dropwise at 0°C, and the reaction mixture was stirred at room temperature over the weekend. Water was added, and the mixture was acidified to pH=5 with aqueous hydrochloric acid. Ether was added. The two phases were separated, and the aqueous phase was extracted with Ether. The combined organic phases were washed with brine, dried using a phase separator, and evaporated to obtain 3-ethyl-5-fluoro-3-methyl-1H-pyrrolo[2,3-b]pyridine-2-one (104 mg, 90% yield) as an orange solid. ¹H NMR (400 MHz, DMSO-d6) δ 11.05 (s, 1H), 8.05 (dd, J = 2.7, 1.9 Hz, 1H), 7.75 (dd, J = 8.3, 2.8 Hz, 1H), 1.86 - 1.69 (m, 2H), 1.28 (s, 3H), 0.57 (t, J = 7.4 Hz, 3H). m / z = 195.2 [M+H]+

[0144] Synthesis of 3-ethyl-5-fluoro-3-methyl-1-tetrahydropyran-2-ylpyrrolo[2,3-b]pyridine-2-one [ka] 3-ethyl-5-fluoro-3-methyl-1H-pyrrolo[2,3-b]pyridine-2-one (126 mg, 0.519 mmol), 3,4-dihydro-2H-pyran (0.14 mL, 1.56 mmol, 3 eq), and p-toluenesulfonic acid hydrate (20 mg, 0.104 mmol, 0.2 N) were placed in 2-5 mL vials in anhydrous toluene (1.7 mL, 0.3 N). The resulting mixture was stirred overnight at 95 °C and concentrated to dryness. The crude product was purified by flash chromatography on silica gel using a heptane / siRNA gradient to obtain 3-ethyl-5-fluoro-3-methyl-1-tetrahydropyran-2-yl-pyrrolo[2,3-b]pyridine-2-one (80 mg, yield 51%). 1 H NMR (DMSO-d6, 600 MHz):δ (ppm) 8.17-8.18 (m, 1H), 7.85 (dd, J = 8.2, 2.8 Hz, 1H), 5.36 (d, J = 10.4 Hz, 1H), 3.95 (dt, J = 11.4, 2.0 Hz, 1H), 3.53 (tt, J = 11.4, 2.8 Hz, 1H), 2.79-2.94 (m, 1H), 1.89-1.95 (m, 1H), 1.74-1.86 (m, 2H), 1.53-1.65 (m, 2H), 1.45-1.55 (m, 2H), 1.29 (s, 3H), 0.51 (td, J = 7.4, 3.4 Hz, 3H) ;m / z = 279.2 [M+H]+.

[0145] Synthesis of 5-ethyl-3-fluoro-5-methyl-7-tetrahydropyran-2-yl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7H-cyclopenta[b]pyridine-6-one [ka] In 2-5 mL sealed vials at -60°C under a nitrogen atmosphere, 1 M lithium diisopropylamide solution (0.60 mL, 0.600 mmol, 2.3 eq.) was added dropwise to a stirred solution of 3-ethyl-5-fluoro-3-methyl-1-tetrahydropyran-2-yl-pyrrolo[2,3-b]pyridine-2-one (78 mg, 0.256 mmol) / anhydrous THF (2 mL, 0.1 N). The reaction mixture was stirred at -60°C for 30 minutes. Triisopropyl borate (0.15 mL, 0.650 mmol, 2.5 eq.) was added dropwise at -60°C. The reaction mixture was stirred at -60°C for 30 minutes and then raised to room temperature over 4 hours. 2,3-dimethylbutane-2,3-diol (0.60 mL, 0.512 mmol, 2 eq.) was added to the mixture, and after stirring for 10 minutes, acetic acid (0.015 mL, 0.269 mmol, 1.05 eq.) was added. The reaction mixture was stirred overnight at room temperature. The mixture was filtered through dichalite. The solvent was partially evaporated under a nitrogen stream, and the solution was extracted with a 5% NaOH aqueous solution. The resulting aqueous layer was collected, acidified to pH=6 at 0°C by adding 3N hydrochloric acid dropwise, and extracted with ELISA. The combined organic phases were washed with brine, dried using a phase separator, and evaporated to obtain 5-ethyl-3-fluoro-5-methyl-7-tetrahydropyran-2-yl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7H-cyclopenta[b]pyridine-6-one (50 mg, yield 26%) as a brown gum. m / z = 323.2 [M+H]+ (acid form) (impurity)

[0146] Scaffold coupling - General method (indole) [ka]

[0147] 1. Mitsunobu reaction To a stirred mixture of indole I (1.66 mmol) and anhydrous toluene (8 mL, 0.2 N), cyanomethylenetributylphosphorane (3.31 mmol, 2 eq.) and alcohol I' (2.48 mmol, 1.5 eq.) were added. The reaction mixture was stirred overnight at 80°C. After adding cyanomethylenetributylphosphorane (3.31 mmol, 2 eq.) and alcohol I' (2.48 mmol, 1.5 eq.), the mixture was stirred further at 80°C for 4 hours. The reaction mixture was concentrated to dryness, and the crude product was purified by flash chromatography using an toluene / cyclohexane gradient column. The relevant fractions were collected and concentrated under vacuum to obtain the desired product II.

[0148] Example: Synthesis of tert-butyl 4-indole-1-ylpiperidine-1-carboxylate (n=1, G=CMe2) White oil, yield 82%, 1 H NMR (DMSO-d6, 400 MHz):δ (ppm) 7.60 - 7.52 (m, 2H), 7.50 (d, J=3.2 Hz, 1H), 7.13 (t, J=7.8 Hz, 1H), 7.02 (t, J=7.4 Hz, 1H), 6.45 (d, J=3.2 Hz, 1H), 4.58 (ddt, J=11.7, 7.7, 3.8 Hz, 1H), 4.13 (d, J=12.2 Hz, 2H), 2.98 (s, 2H), 1.94 (d, J=10.4 Hz, 2H), 1.83 (qd, J=12.3, 4.3 Hz, 2H), 1.44 (s, 9H);m / z = 245.3 [M+H-tBu]+

[0149] 2. Bromination N-bromosuccinimide (1.45 mmol, 1.05 eq.) was added to a solution of substituted indole II (1.38 mmol) / anhydrous DMF (13.8 mL, 0.1 N). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 6 hours. N-bromosuccinimide (1 eq.) was added, and the reaction mixture was stirred overnight at room temperature under N2. Water was added, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried on a phase separator, and concentrated under vacuum. The crude product was purified by silica gel column using a heptane / ethyl acetate gradient. The relevant fractions were collected and concentrated under vacuum to obtain brominated product III.

[0150] Example: Synthesis of tert-butyl 4-(3-bromoindol-1-yl)piperidine-1-carboxylate (n=1, G=CMe2) White oil, yield 83%, 1 H NMR (DMSO-d6, 400 MHz):δ (ppm) 7.77 (s, 1H), 7.65 (d, J=8.3 Hz, 1H), 7.42 (d, J=7.9 Hz, 1H), 7.28 - 7.20 (m, 1H), 7.16 (t, J=7.4 Hz, m / z = 323.1, 325.1 [M+H-tBu]+

[0151] 3. Boronic acid formation To a solution of bromoindole III (0.854 mmol) / anhydrous THF (4.3 mL, 0.2 N), 1.2 M butyllithium solution (1.1 mL, 1.28 mmol, 1.5 eq.) was added dropwise at -78°C. The resulting mixture was stirred under N2 at -78°C for 20 minutes. Then, triisopropyl borate (0.59 mL, 2.56 mmol, 3 eq.) was added, and the solution was stirred for 4 hours and 30 minutes while raising the temperature to room temperature. The reaction was quenched by adding a mixture of water / MeOH (1:1.3 mL). Water was added, and the mixture was extracted with diethyl ether. The organic phase was washed with brine, dried on a phase separator, and concentrated to obtain the desired boronic acid IV.

[0152] Example: Synthesis of [1-(1-tert-butoxycarbonyl-4-piperidyl)indole-3-yl]boronic acid (n=1, G=CMe2) Green solid, yield 51%, m / z = 245.3 [M+H-Boc]+

[0153] 4. Suzuki Coupling In a Reacti vial, a mixture of DMF (1.5 mL) and water (0.5 mL) was used to add boronic acid IV (0.218 mmol, 1.05 eq.), bromine scaffold II' (0.207 mmol), and disodium carbonate (0.622 mmol, 3 eq.). The mixture was degassed, and tetrakistriphenylphosphine palladium (0.0207 mmol, 0.1 eq.) was added. The resulting mixture was stirred overnight at 90°C under N2. The mixture was filtered on dichalite and evaporated under vacuum. The crude product was purified using a heptane / siRNA gradient with a silica gel column. The relevant fractions were collected and concentrated under vacuum to obtain Suzuki coupling product V.

[0154] Example: Synthesis of tert-butyl 4-[3-(3,3-dimethyl-2-oxo-1H-pyrrolo[2,3-b]pyridine-4-yl)indole-1-yl]piperidine-1-carboxylate (n=1, G=CMe2) Skin-colored solid; yield 20%; m / z = 461.4 [M+H]+

[0155] 5. Deprotection To a solution of Suzuki coupling compound V (0.041 mmol) in anhydrous methanol (0.2 mL, 0.2 eq.), a solution of 4 M hydrogen chloride / dioxane (0.16 mmol, 4 eq.) was added. The reaction mixture was stirred overnight at room temperature. Diisopropyl ether was added to the mixture, and the precipitate was filtered to obtain a gum. The precipitate was diluted with MeOH, and this solution was concentrated under vacuum to obtain the final compound as a hydrochloride salt.

[0156] Example 7: Synthesis of 3,3-dimethyl-4-[1-(4-piperidyl)indole-3-yl]-1H-pyrrolo[2,3-b]pyridine-2-one dihydrochloride (n = 1, G = CMe2) Orange solid; 95% yield, 1H NMR (DMSO-d6, 500 MHz): δ (ppm) 11.09 (s, 1H), 8.55-9.02 (m, 2H), 8.11 (d, J = 5.4 Hz, 1H), 7.71 (d, J = 8.3 Hz, 1H), 7.51 (s, 1H), 7.35 (d, J = 7.8 Hz, 1H), 7.26 (td, J = 7.6, 1.0 Hz, 1H), 7.10 (td, J = 7.3, 0.5 Hz, 1H), 6.92 (d, J = 5.4 Hz, 1H), 4.85 (tt, J = 11.5, 4.7 Hz, 1H), 3.48 (br d, J = 13.4 Hz, 3H), 3.10-3.23 (m, 2H), 2.17-2.29 (m, 4H), 1.13 (s, 6H);m / z = 361.1

[0157] Scaffold Coupling - Specific Examples Indole I was obtained from a commercially available source or synthesized using standard techniques according to the following method.

[0158] Scaffold coupling - specific method (specific indole 1) [ka] 1. Suzuki Coupling Bromine scaffold I' (1.12 mmol), tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indole-1-carboxylate I (1.58 mmol, 1.4 eq.), disodium carbonate (3.35 mmol, 3 eq.), and tetrakistriphenylphosphine palladium (0.112 mmol, 0.1 eq.) were placed in a Reacti-vial in a mixed solvent of DMF (9 mL) and water (1.9 mL). The vial was sealed, evacuated under vacuum, and refilled with argon. The reaction mixture was stirred overnight at 100°C. The reaction mixture was diluted with ethyl acetate, filtered, washed with water, dried over Na2SO4, and evaporated. The crude product was purified by flash chromatography on silica gel using a heptane / ethyl acetate gradient. The relevant fractions were collected and concentrated under vacuum to obtain the desired Suzuki coupling product II.

[0159] Example: Synthesis of 4-(1H-indole-3-yl)-3,3-dimethyl-1-tetrahydropyran-2-yl-pyrrolo[2,3-b]pyridine-2-one (G=CMe2) Brown gum; yield 37%, 1 H NMR(DMSO-d6, 400 MHz):δ (ppm) 11.47 (s, 1H), 8.21 (d, J=5.4 Hz, 1H), 7.51 (d, J=2.5 Hz, 1H), 7.48 (d, J=8.2 Hz, 1H), 7.30 (d, J=8.0 Hz, 1H), 7.22 - 7.11 (m, 1H), 7.06 - 6.97 (m, 2H), 5.48 (dd, J=11.3, 2.0 Hz, 1H), 3.99 (d, J=11.7 Hz, 1H), 3.65 - 3.51 (m, 1H), 3.08 - 2.87 (m, 1H), 1.95 (s, 1H), 1.71 - 1.45 (m, 4H), 1.14 (d, J=4.1 Hz, 6H);m / z = 362.1 [M+H]+

[0160] 2. Michael's reaction In a 4 mL Reacti-vial, cyclobutylidene acetonitrile (0.387 mmol, 2 eq.), Suzuki coupling product II (0.194 mmol, 1 eq.) / anhydrous acetonitrile (0.95 mL, 0.2 N), and DBU (0.387 mmol, 2 eq.) were added in sequence. The reaction mixture was stirred overnight at 85°C. Then, 1 equivalent of cyclobutylidene acetonitrile was added, and the reaction mixture was stirred for 2 hours. The reaction mixture was filtered, and the precipitate was washed with acetonitrile to obtain product III.

[0161] Example: Synthesis of 2-[1-[3-(3,3-dimethyl-2-oxo-1-tetrahydropyran-2-yl-pyrrolo[2,3-b]pyridine-4-yl)indole-1-yl]cyclobutyl]acetonitrile (G= CMe2) White powder; yield 29%, 1 H NMR(DMSO-d6, 400 MHz):δ (ppm) 8.22 (d, J=5.4 Hz, 1H), 7.46 (s, 1H), 7.43 (d, J=8.3 Hz, 1H), 7.33 (d, J=7.8 Hz, 1H), 7.22 (t, J=7.7 Hz, 1H), 7.11 (t, J=7.2 Hz, 1H), 6.99 (d, J=5.3 Hz, 1H), 5.52 - 5.41 (m, 1H), 3.99 (d, J=10.9 Hz, 1H), 3.58 (t, J=11.1 Hz, 1H), 3.48 (s, 2H), 2.95 (d, J=11.4 Hz, 1H), 2.76 (t, J=11.2 Hz, 2H), 2.63 (t, J=9.2 Hz, 2H), 2.28 - 2.12 (m, 1H), 1.97 (d, J=11.4 Hz, 2H), 1.73 - 1.40 (m, 4H), 1.16 (d, J=3.7 Hz, 6H);m / z = 455.4 [M+H]+

[0162] 3. Deprotection A 4M hydrogen chloride solution (1.14 mmol, 20 eq.) / dioxane was added to a solution of compound III (0.057 mmol) / dioxane (0.2 mL, 0.3 N). The reaction mixture was stirred overnight at 45°C. Then, 4M hydrogen chloride solution (1.14 mmol, 20 eq.) / dioxane was added, and the mixture was stirred overnight at 50°C. The solvent was evaporated. The crude material was purified by preparative HPLC under neutral conditions. The relevant fractions were combined and concentrated to obtain the target compound IV.

[0163] Example 21: Synthesis of 2-[1-[3-(3,3-dimethyl-2-oxo-1H-pyrrolo[2,3-b]pyridine-4-yl)indole-1-yl]cyclobutyl]acetonitrile (G= CMe2) White powder; yield 37%, 1H NMR (DMSO-d6, 600 MHz): δ (ppm) 11.04 (s, 1H), 8.09 (d, J = 5.4 Hz, 1H), 7.43 (s, 1H), 7.42 (d, J = 8.4 Hz, 1H), 7.34 (d, J = 7.9 Hz, 1H), 7.21 (td, J = 7.7, 1.0 Hz, 1H), 7.07-7.12 (m, 1H), 6.89 (d, J = 5.3 Hz, 1H), 3.46 (s, 2H), 2.72-2.81 (m, 2H), 2.58-2.66 (m, 2H), 2.13-2.26 (m, 1H), 1.92-2.03 (m, 1H), 1.15 (s, 6H);m / z = 371.0 [M+H]+.

[0164] Scaffold coupling - General method (Indazole 1) [ka]

[0165] 1. Mitsunobu reaction In a sealed vial under a nitrogen atmosphere, bromoindazole I (1.23 mmol), anhydrous toluene (4 mL, 0.3 M), hydroxypiperidine-1-carboxylate I' (2.46 mmol, 2 eq.), and cyanomethylenetributylphosphoran (2.46 mmol, 2 eq.) were added sequentially. The reaction mixture was stirred overnight at 90°C. The solvent was evaporated to obtain the crude product as a brown liquid. The crude product was purified by flash chromatography on silica gel using a heptane / ethyl acetate gradient. It was eluted through a solid phase of dicalite. The fraction was collected and concentrated under vacuum. A mixture of two diastereoisomers II was obtained. This mixture was used in the next step.

[0166] Example: Synthesis of tert-butyl rac-(3R,4R)-4-(3-bromoindazole-1-yl)-3-fluoropiperidine-1-carboxylate (R1= R2= R3= R5= H; R4= F; n = 0; m = p = 1) Yellow oil; diastereomer, quantitative yield, 1H NMR (400 MHz, DMSO-d6) δ 7.81 (d, J = 8.6 Hz, 1H), 7.60 (d, J = 8.2 Hz, 1H), 7.57 - 7.50 (m, 1H), 7.32 - 7.26 (m, 1H), 5.09 (dd, J = 18.2, 9.2 Hz, 1H), 4.90 - 4.68 (m, 1H), 4.35 (s, 1H), 4.09 - 4.01 (m, 1H), 3.06 (s, 2H), 2.07 (qd, J = 10.0, 3.8 Hz, 2H), 1.45 (s, 9H);m / z = 342.0, 344.0 [M-tBu+H]+

[0167] 2. Boronic acid ester formation A 10 mL Reacti-vial contained substituted bromoindazole II (0.753 mmol), bis(pinacolato)diborone (1.13 mmol, 1.5 eq), and bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.0753 mmol, 0.1 eq.) / anhydrous dioxane (2.5 mL, 0.3 N). The mixture was degassed under N2 and stirred overnight at 100°C. The mixture was filtered on dicalite and concentrated under vacuum to obtain the crude substance as a dark oil. Crude substance III was used in the next step without further purification.

[0168] Example: Synthesis of tert-butyl rac-(3R,4R)-3-fluoro-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazole-1-yl]piperidine-1-carboxylate (R1= R2= R3= R5= H; R4= F; n = 0; m = p = 1) Black oil; m / z = 364.0 [M+H]+ (boronic acid form)

[0169] 3. Suzuki Coupling In a 10 mL vial, bromine scaffold II' (0.332 mmol), boronic acid ester III (0.602 mmol, 1.8 eq.), and disodium carbonate (0.996 mmol, 3 eq.) were added in a mixed solvent of DMF (3 mL) and water (0.6 mL). The mixture was degassed, and tetrakistriphenylphosphine palladium (0.033 mmol, 0.1 eq.) was added. The reaction mixture was heated at 100 °C for 4 hours. Water was added. The precipitated product was filtered. It was dissolved in DCM, the organic phase was dried on a phase separator, and concentrated under vacuum. The crude material was purified by flash chromatography on silica gel using a heptane / siRNA gradient. The fractions were collected and concentrated under vacuum to obtain the target Suzuki coupling compound IV.

[0170] Example: Synthesis of tert-butyl rac-(3R,4R)-4-[3-(3,3-dimethyl-2-oxo-1H-pyrrolo[2,3-b]pyridine-4-yl)indazole-1-yl]-3-fluoropiperidine-1-carboxylate (R1= R2= R3= R5= H; R4= F, n = 0; m = p = 1; G = CMe2; L = H) Skin-colored powder; yield 63%; 1 H NMR (DMSO-d6, 500 MHz):δ (ppm) 11.13 (s, 1H), 8.24 (d, J = 5.6 Hz, 1H), 7.80-7.90 (m, 2H), 7.47-7.57 (m, 1H), 7.36 (d, J = 5.4 Hz, 1H), 7.23-7.31 (m, 1H), 5.20-5.36 (m, 1H), 4.71-4.98 (m, 1H), 4.26-4.49 (m, 1H), 4.03-4.12 (m, 1H), 2.94-3.23 (m, 2H), 2.03-2.27 (m, 2H), 1.44 (s, 9H), 1.34 (d, J = 8.3 Hz, 6H);m / z = 480.2 [M+H]+

[0171] 4. Deprotection 4M hydrogen chloride (1.04 mmol, 5 eq.) / dioxane was added to a solution of Suzuki coupling product IV (0.21 mmol) in methanol (2 mL, 0.1 N). The mixture was stirred overnight at room temperature. The mixture was concentrated under vacuum. The product was tritulated in diethyl ether and filtered. This was vacuum-dried at 40°C to obtain the final product V in the form of a salt.

[0172] Synthesis of the racemic mixture of Example 36: 3,3-dimethyl-4-[1-[rac-(3R,4R)-3-fluoro-4-piperidyl]indazole-3-yl]-1H-pyrrolo[2,3-b]pyridine-2-one; dihydrochloride (R1= R2= R3= R5=H; R4= F, n = 0; m = p = 1; G = CMe2) Yellow powder; yield 91%, 1H NMR (500 MHz, DMSO-d6) δ ppm 11.16 (s, 1 H);8.97 - 10.01 (m, 2 H), 8.24 (d, J=5.38 Hz, 1 H);7.84 (dd, J=8.31, 5.62 Hz, 2 H), 7.50 - 7.59 (m, 1 H), 7.34 (d, J=5.62 Hz, 1 H), 7.27 - 7.32 (m, 1 H), 5.37 - 5.48 (m, 1 H), 5.19 - 5.37 (m, 1 H);3.85 (br s, 1 H);3.46 - 3.54 (m, 1 H), 3.24 - 3.34 (m, m / z = 380.0

[0173] Scaffold coupling - General method (Indazole 2) [ka]

[0174] 1. Mitsunobu To a stirred mixture of bromoindazole I (1.97 mmol) and anhydrous toluene (8 mL, 0.25 N), cyanomethylenetributylphosphorane (5.91 mmol, 3 eq.) and hydroxypyrrolidine I' (3.94 mmol, 2 eq.) were added. The reaction mixture was stirred overnight at 100°C. The reaction mixture was concentrated to dryness, and the crude product was purified by flash chromatography using an toluene / cyclohexane gradient column. The relevant fractions were collected and concentrated under vacuum to obtain the desired product II.

[0175] Example: Synthesis of tert-butyl (3S)-3-(3-bromoindazole-1-yl)pyrrolidine-1-carboxylate (n=0, R1= R2= R3= R4= H) Colorless oil, yield 44%, 1H NMR (DMSO-d6, 500 MHz):δ (ppm) 7.80 (d, J = 8.6 Hz, 1H), 7.59 (d, J = 8.1 Hz, 1H), 7.52 (ddd, J = 8.4, 7.0, 1.0 Hz, 1H), 7.20-7.33 (m, 1H), 5.35-5.60 (m, 1H), 3.69-3.83 (m, 1H), 3.55 (dd, J = 11.0, 4.9 Hz, 2H), 3.43 (br d, J = 6.6 Hz, 1H), 2.20-2.45 (m, 2H), 1.32-1.50 (m, 9H);M / Z = 366.2-368.2 [M+H]+

[0176] 2. Suzuki Coupling In a 6-20 mL Reacti vial, substituted bromoindazole II (0.41 mmol), disodium carbonate (1.23 mmol, 3 eq.), and boronic acid ester II' (0.491 mmol, 1.2 eq.) were sequentially added in a mixed solution of DMF (2.6 mL) and water (0.7 mL). The mixture was degassed, and tetrakistriphenylphosphine palladium (0.0410 mmol, 0.01 eq.) was added. The reaction mixture was stirred overnight at 100°C. The reaction mixture was poured into water. The precipitate was filtered. The filtrate was dissolved in dichloromethane. The organic phase was dried on a phase separator and evaporated to obtain the crude product. The crude product was then purified by flash chromatography on silica gel using a heptane / siRNA gradient. The relevant fractions were collected and concentrated under vacuum to obtain the target product III.

[0177] Example: Synthesis of tert-butyl (3S)-3-[3-(3,3-dimethyl-2-oxo-1-tetrahydropyran-2-yl-pyrrolo[2,3-b]pyridine-4-yl)indazole-1-yl]pyrrolidine-1-carboxylate (n=0, R1= R2= R3= R4= H, G= CMe2) Flesh-colored foam; yield 56%; 1H NMR (400 MHz, DMSO-d6) δ 8.35 (d, J = 5.4 Hz, 1H), 7.87 (dd, J = 13.2, 8.4 Hz, 2H), 7.54 (ddd, J = 8.3, 6.9, 0.9 Hz, 1H), 7.43 (d, J = 5.4 Hz, 1H), 7.32 - 7.27 (m, 1H), 5.62 (s, 1H), 5.51 - 5.47 (m, 1H), 4.00 (d, J = 11.3 Hz, 1H), 3.89 (s, 1H), 3.73 (d, J = 10.6 Hz, 1H), 3.62 - 3.46 (m, 3H), 2.94 (d, J = 11.4 Hz, 1H), 2.49-2.52 (m, 1H), 2.33 (s, 1H), 1.95 (s, 1H), 1.71 - 1.49 (m, 4H), 1.40 (d, J = 5.2 Hz, 9H), 1.37 (s, 3H), 1.31 (d, J = 3.6 Hz, 3H), m / z = 532.4 [M+H]+

[0178] 3. Deprotection A 4M hydrogen chloride solution (9.18 mmol, 40 eq.) / dioxane was added to a solution of Suzuki coupling compound III (0.229 mmol) / anhydrous methanol (0.5 mL, 0.5 N). The reaction mixture was stirred overnight at 65°C. The reaction mixture was filtered to obtain the final compound IV (60 mg, 62% yield) as its hydrochloride salt.

[0179] Example 16: Synthesis of 3,3-dimethyl-4-[1-[(3S)-pyrroridine-3-yl]indazole-3-yl]-1H-pyrrolo[2,3-b]pyridine-2-one dihydrochloride (R1= R2= R3= R4= H, G= CMe2) White powder; yield 62%, 1H NMR (DMSO-d6, 500 MHz): δ (ppm) 11.14 (br s, 1H), 8.23 ​​(d, J = 5.4 Hz, 1H), 7.87 (d, J = 8.6 Hz, 1H), 7.82 (d, J = 8.3 Hz, 1H), 7.53 (t, J = 7.7 Hz, 1H), 7.28 (q, J = 4.8 Hz, 2H), 5.60 (s, 1H), 3.51-3.72 (m, 2H), 3.37 (br s, 4H), 2.44-2.48 (m, 1H), 2.33 (br d, J = 5.9 Hz, 1H), 1.91 (s, 1H), 1.36 (s, 3H), 1.31 (s, 3H);m / z = 348.0

[0180] Scaffold coupling - Common method (Indazole 3) [ka]

[0181] 1. Michael's reaction 3-bromo-1H-indazole I (2.46 mmol), reactant I' (2.46 mmol), and 1,8-diazabicyclo[5.4.0]undec-7-ene (4.92 mmol, 2 eq.) / anhydrous acetonitrile (12 mL, 0.2 N) were sequentially added to a 20 mL Biotage vial. The mixture was stirred overnight at 85°C. The mixture was concentrated under vacuum. The crude product was purified by flash chromatography using a heptane / siRNA gradient. The relevant fractions were collected and concentrated under vacuum to obtain the corresponding product II.

[0182] Example: Synthesis of 2-[1-(3-bromoindazole-1-yl)cyclobutyl]acetonitrile (Y=CH, R1=H, Z=CH2) White solid, yield 83%, 1H NMR (DMSO-d6, 500 MHz):δ (ppm) 7.60-7.64 (m, 2H), 7.47-7.52 (m, 1H), 7.26-7.32 (m, 1H), 3.38 (s, 2H), 2.80-2.94 (m, 2H), 2.52-2.61 (m, 2H), 2.17 (dquin, J = 11.3, 9.0 Hz, 1H), 1.95 (dtt, J = 11.2, 9.8, 3.2 Hz, 1H);m / z = 290.1-292.1 [M+H]+

[0183] 2. Suzuki Coupling In a 20 mL vial of Biotage, substituted bromoindazole II (0.59 mmol, 1.1 eq.) was dissolved in a mixed solvent of DMF (4 mL) and water (1.3 mL), followed by the addition of boronic acid ester II' (0.53 mmol) and disodium carbonate (1.60 mmol, 3 eq.). The solution was degassed with N2, and tetrakistriphenylphosphine palladium (0.053 mmol, 0.01 eq.) was added. The mixture was heated to 75°C over 3 hours. The solution was cooled, and water was added. The product was extracted several times with ethyl acetate. The organic phase was collected, filtered through a phase separator, and concentrated under vacuum to obtain the crude product. The crude product was then purified by flash chromatography using a heptane / ethyl acetate gradient. The relevant fractions were collected and concentrated under vacuum to obtain the target compound III.

[0184] Example: Synthesis of 2-[1-[3-(3-hydroxy-3-methyl-2-oxo-1-tetrahydropyran-2-yl-pyrrolo[2,3-b]pyridine-4-yl)indazole-1-yl]cyclobutyl]acetonitrile (Y=CH, R1=H, G=COHMe, Z=CH2) Pale yellow solid; yield 15%; 1H NMR(DMSO-d6, 400 MHz):δ (ppm) 8.40 (dd, J=5.5, 0.9 Hz, 1H), 8.09 (d, J=8.4 Hz, 1H), 7.72 (d, J=8.6 Hz, 1H), 7.61 (dd, J=5.5, 2.0 Hz, 1H), 7.58 - 7.51 (m, 1H), 7.40 - 7.34 (m, 1H), 6.11 (d, J=5.3 Hz, 1H), 5.47 (d, J=11.2 Hz, 1H), 4.00 (d, J=8.7 Hz, 1H), 3.54-3.62 (m, 1H), 3.50 (s, 2H), 3.28-3.31 (m, 1H), 3.05 - 2.81 (m, 3H), 2.71 - 2.58 (m, 2H), 2.31 - 2.17 (m, 1H), 1.94-2.06 (d, J=1.8 Hz, 1H), 1.59 (d, J=50.3 Hz, 4H), 1.51 (d, J=1.4 Hz, 3H);m / z = 458.4 [M+H]+

[0185] 3. Deprotection A 4M hydrogen chloride solution (1.5 mmol, 20 eq.) / dioxane was added to a solution of Suzuki coupling compound III (0.075 mmol) / anhydrous methanol (0.5 mL, 0.3N). The reaction mixture was stirred overnight at room temperature, and then stirred overnight at 50°C. The mixture was made basic with an aqueous NaHCO3 solution, extracted by DCM, and the solvent was evaporated to obtain the crude product. The crude product was then purified in reverse phase using an H2O / acetonitrile gradient. The fraction containing the product was collected and concentrated to obtain the target product IV.

[0186] Example 25: Synthesis of 2-[1-[3-(3-hydroxy-3-methyl-2-oxo-1H-pyrrolo[2,3-b]pyridine-4-yl)indazole-1-yl]cyclobutyl]acetonitrile (Y = CH, R1 = H, G = COHMe, Z = CH2) White powder; yield 26%, 1H NMR (DMSO-d6, 500 MHz):δ (ppm) 11.09 (br s, 1H), 8.27 (d, J = 5.4 Hz, 1H), 8.09 (d, J = 8.3 Hz, 1H), 7.70 (d, J = 8.6 Hz, 1H), 7.54 (ddd, J = 8.4, 7.2, 1.0 Hz, 1H), 7.51 (d, J = 5.6 Hz, 1H), 7.36 (dd, J = 7.8, 6.8 Hz, 1H), 5.98 (s, 1H), 3.49 (d, J = 2.2 Hz, 2H), 2.79-3.05 (m, 2H), 2.64 (ddd, J = 12.2, 8.9, 2.7 Hz, 2H), 1.93-2.30 (m, 2H), 1.48 (s, 3H);m / z = 374.2 [M+H]+

[0187] Scaffold coupling - Common method (Indazole 4) [ka]

[0188] 1. Mitsunobu In a 10 mL vial, at room temperature, cyanomethylenetributylphosphoran (0.68 mL, 2.49 mmol, 2 eq.) was added to a stirred solution of bromoindazole I (1.24 mmol, 1 eq.) and alcohol (1.24 mmol, 1 eq.) in anhydrous toluene (3.7 mL, 0.3 N). The reaction mixture was stirred at 80°C for 5 hours. The reaction mixture was allowed to return to room temperature and concentrated under vacuum to obtain the crude substance as a brown oil. The crude substance was purified by flash chromatography on silica gel using a heptane / siRNA gradient. It was eluted by liquid injection / DCM. The relevant fractions were collected and concentrated under vacuum to obtain the target compound II.

[0189] Example: Synthesis of 4-benzyl-3-[(3-bromoindazole-2-yl)methyl]-3-methylmorpholine (R1=H, R2=Me) Colorless galvanic acid, 45% yield, ¹H NMR (400 MHz, DMSO-d⁶) δ 7.82 (d, J = 8.6 Hz, 1H), 7.60 (d, J = 8.2 Hz, 1H), 7.54 - 7.41 (m, 1H), 7.40 - 7.16 (m, 6H), 4.83 (d, J = 14.7 Hz, 1H), 4.54 (d, J = 14.7 Hz, 1H), 3.93 - 3.79 (m, 1H), 3.75 (d, J = 13.9 Hz, 1H), 3.63 (dd, J = 9.8, 5.0 Hz, 1H), 3.51 (ddd, J = 11.2, 8.2, 3.2 Hz, 1H), 3.43 (d, J = 11.3 Hz, 1H), 3.26 (d, J = 11.3 Hz, 1H), 2.69 (ddd, J = 11.7, 8.2, 3.3 Hz, 1H), 2.43 - 2.28 (m, 1H), 1.06 (s, 3H);m / z = 400.3, 402.3[M+H]+.

[0190] 2. Suzuki Karin In a 6-20 mL Reacti-vial, substituted bromoindazole II (0.532 mmol), 3,3-dimethyl-1-tetrahydropyran-2-yl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine-2-one (0.532 mmol, 1 eq.), tripotassium phosphate (229 mg, 1.06 mmol, 3 eq.), Xphos (10 mg, 0.021 mmol, 0.04 eq.), tris(dibenzylideneacetone)dipalladium(0) (0.011 mmol, 0.02 eq.), dioxane (2.2 mL), and water (0.4 mL) were added in sequence. The vial was sealed, evacuated under vacuum, and refilled with argon. The reaction mixture was stirred overnight at 95°C. Water and toluene were added. The two phases were separated, and the aqueous phase was extracted with toluene. The combined organic phase was dried using a phase separator and evaporated to obtain the crude product. The crude product was purified by flash chromatography on silica gel using a heptane / toluene gradient. It was eluted by liquid injection / DCM. The relevant fractions were collected and concentrated under vacuum to obtain the desired product III.

[0191] Example: Synthesis of 4-[1-[(4-benzyl-3-methyl-morpholine-3-yl)methyl]indazole-3-yl]-3,3-dimethyl-1-tetrahydropyran-2-yl-pyrrolo[2,3-b]pyridine-2-one (R1=H, R2=Me) White foamy substance; 67% yield; 1H NMR (500 MHz, DMSO-d6) δ 8.34 (d, J=5.38 Hz, 1H), 7.90 (d, J=8.56 Hz, 1H), 7.79 (d, J=8.31 ​​Hz, 1H), 7.50 (t, J=7.61 Hz, 1H), 7.39 (d, J=5.38 Hz, 1H), 7.19-7.32 (m, 6H), 5.47-5.50 (m, 1H), 4.95 (d, J=14.43 Hz, 1H), 4.65 (d, J=14.67 Hz, 1H), 3.91-4.01 (m, 2H), 3.68-3.78 (m, 2H), 3.51-3.64 (m, 3H), 3.26-3.29 (m, 1H), 2.90-2.99 (m, 1H), 2.75 (br t, J=8.80 Hz, 1H), 2.37-2.42 (m, 1H), 1.96 (br d, J=11.49 Hz, 1H), 1.49-1.69 (m, 4H), 1.31-1.39 (m, 6H), 1.11 (s, 3H);m / z = 566.5 [M+H]+

[0192] 3. Deprotection of benzyl Suzuki coupling product III (0.09 mmol) was dissolved in anhydrous methanol (2.2 mL, 0.04 N). Ammonium formate (0.62 mmol, 7 eq.) and Pd / C 10% Engelhard (0.09 mmol, 1 eq.) were added. The reactor vial was sealed, evacuated under vacuum, and refilled with argon. The suspension was stirred at 110°C for 3 hours. The reaction mixture was filtered, washed with MeOH, and concentrated to obtain the benzyl deprotection product.

[0193] Example: Synthesis of 3,3-dimethyl-4-[1-[(3-methylmorpholine-3-yl)methyl]indazole-3-yl]-1-tetrahydropyran-2-yl-pyrrolo[2,3-b]pyridine-2-one (R1=H, R2=Me) Brown gum; 61% yield; 1H NMR (600 MHz, DMSO-D6, 300 K) δ (ppm) = 8.33 (d, J = 5.3 Hz, 1H), 7.84 (d, J = 8.5 Hz, 1H), 7.78 (d, J = 8.2 Hz, 1H), 7.50 (ddd, J = 0.9, 7.1, 8.3 Hz, 1H), 7.38 (d, J = 5.4 Hz, 1H), 7.27 - 7.20 (m, 1H), 5.49 (dd, J = 2.1, 11.4 Hz, 1H), 4.69 (d, J = 14.5 Hz, 1H), 4.54 (d, J = 14.5 Hz, 1H), 3.99 (td, J = 1.9, 11.4 Hz, 1H), 3.65 (td, J = 3.8, 11.0 Hz, 1H), 3.61 - 3.46 (m, 3H), 3.13 - 3.06 (m, 1H), 3.04 - 2.83 (m, 1H), 2.78 - 2.70 (m, 1H), 2.37 - 2.14 (m, 1H), 1.96 (br dd, J = 2.5, 10.0 Hz, 1H), 1.72 - 1.44 (m, 5H), 1.37 (d, J = 1.0 Hz, 6H), 0.94 (s, 3H); 476.5 [M+H]+

[0194] 4. Deprotection of THP A 4M hydrogen chloride / dioxane (8 mmol, 8 eq.) solution was added to the compound (0.17 mmol) / anhydrous methanol (0.8 mL, 0.2 N). The reaction mixture was stirred overnight at 65°C. After cooling, an aqueous solution of NaHCO3 was added, and the mixture was extracted with dimethylammonium sulfate. The organic layers were combined, dried over Na2SO4, filtered, and evaporated to obtain the target compound IV as its hydrochloride salt.

[0195] Synthesis of the racemic precursor of Example 31: 3,3-dimethyl-4-[1-[(3-methylmorpholine-3-yl)methyl]indazole-3-yl]-1H-pyrrolo[2,3-b]pyridine-2-one (R1=H, R2=Me) White powder; yield 62%, 1H NMR (DMSO-d6, 600 MHz): δ (ppm) 11.10 (s, 1H), 8.21 (d, J = 5.4 Hz, 1H), 7.83 (d, J = 8.7 Hz, 1H), 7.80 (d, J = 8.2 Hz, 1H), 7.49 (ddd, J = 8.3, 7.0, 1.0 Hz, 1H), 7.29 (d, J = 5.4 Hz, 1H), 7.22-7.26 (m, 1H), 4.69 (d, J = 14.5 Hz, 1H), 4.53 (d, J = 14.5 Hz, 1H), 3.65 (dt, J = 10.8, 3.8 Hz, 1H), 3.58 (d, J = 11.2 Hz, 1H), 3.49 (ddd, J = 10.8, 8.3, 2.9 Hz, 1H), 3.28-3.30 (m, 1H), 3.10 (ddd, J = 12.3, 8.6, 3.2 Hz, 1H), 2.71-2.78 (m, 1H), 2.33 (br s, 1H), 1.36 (d, J = 1.6 Hz, 6H), 0.94 (s, 3H);m / z = 392.1 [M+H]+

[0196] The enantiomer compound was obtained after chiral purification.

[0197] Example 63 was obtained as a byproduct in benzyl deprotection / methanol.

[0198] Scaffold coupling - Common method (Indazole 5) [ka]

[0199] 1. Synthesis of O1-tert-butyl O3-methyl 3-methylsulfonyloxypyrrolidine-1,3-dicarboxylate At room temperature, methanesulfonyl chloride (1.2 mL, 14.9 mmol, 2 eq.) was added to a stirred suspension of triethylamine (2.1 mL, 14.9 mmol, 2 eq.) and 1-tert-butyl 3-methyl 3-hydroxypyrrolidine-1,3-dicarboxylate (1.90 g, 7.44 mmol, 2 eq.) in anhydrous dichloroethane (62 mL, 0.12 N). The reaction mixture was stirred overnight at 55 °C. Water was added, and the mixture was extracted by DCE. The organic phase was dried and concentrated under vacuum. The crude product was purified by flash chromatography using a heptane / siRNA gradient. The relevant fractions were collected and concentrated under vacuum to obtain O1-tert-butyl O3-methylsulfonyloxypyrrolidine-1,3-dicarboxylate (1.5 g, yield 63%) as a yellow oil. ¹H NMR (chloroform-d, 400 MHz): δ (ppm) 3.92 (t, J=14.9 Hz, 5H), 3.69 - 3.49 (m, 2H), 3.18 (s, 3H), 2.66 - 2.41 (m, 2H), 1.46 (s, 9H).

[0200] 2. Replacement Sodium hydride (1.99 mmol, 1.5 eq.) and anhydrous THF (0.05 mL) were placed in a Reacti vial. Bromoindazole I (300 mg, 1.33 mmol) / anhydrous THF (0.1 mL) was then added. O1-tert-butyl O3-methyl 3-methylsulfonyloxypyrrolidine-1,3-dicarboxylate (1.99 mmol, 2 eq.) / anhydrous THF (0.35 mL) was added dropwise at room temperature. The reaction mixture was stirred overnight at room temperature. Sodium hydride (1.5 eq.) was added, and the reaction mixture was stirred overnight at room temperature. The solvent was evaporated. The residue was dissolved in ethyl acetate, and water was added. The two phases were separated. The aqueous phases were combined, neutralized with 1N HCl aqueous solution, and extracted with dichloromethane. The organic phases were combined, dried using a phase separator, and evaporated to obtain product II.

[0201] Example: Synthesis of 3-(3-bromo-6-fluoroindazole-1-yl)-1-tert-butoxycarbonylpyrrolidine-3-carboxylic acid (R1=F) Colorless gum, 37% yield, 1H NMR (400 MHz, DMSO-d6) δ 13.72 (s, 1H), 7.69 (dd, J = 8.9, 5.2 Hz, 1H), 7.46 (s, 1H), 7.26 - 7.17 (m, 1H), 4.37 - 4.10 (m, 2H), 3.02 - 2.83 (m, 2H), 2.42 (s, 1H), 2.15 (s, 1H), 1.42 (s, 9H);m / z = 400.3, 402.3 [M+H]+.

[0202] 3. Reduction Substituted indazole II (0.487 mmol) was placed in a 2 mL Reacti-vial, and a 1 M boranetetrahydrofuran (0.974 mmol, 2 eq.) solution was added. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into a saturated aqueous solution of NH4Cl and extracted with dichloromethane. The combined organic phase was dried on a phase separator and evaporated to obtain the crude product as a brown solid. The crude product was purified by flash chromatography on silica gel using a dichloromethane / ethyl acetate gradient. It was eluted through an isolute HM-N solid phase. The relevant fractions were collected and concentrated under vacuum to obtain the desired product III.

[0203] Example: Synthesis of tert-butyl 3-(3-bromo-6-fluoroindazole-1-yl)-3-(hydroxymethyl)pyrrolidine-1-carboxylate (R1=F) White foamy substance; 44% yield; m / z = 358, 360 [M+H-tBu]+

[0204] 4. Suzuki Compound III (0.222 mmol), boronic acid ester I' (0.222 mmol, 1 eq.), and tetrakistriphenylphosphine palladium (0.0222 mmol, 0.1 eq.) were placed in a 12 mL Reacti vial in a mixed solvent of DMF (1.7 mL) and water (0.6 mL). The mixture was degassed with N2, and disodium carbonate (0.666 mmol, 3 eq.) was added. The mixture was again degassed with N2 and stirred at 90°C for 3 hours. Water was added to the cold mixture, the precipitate was filtered, washed with water, and dissolved in DCM. The organic phase was filtered through a phase separator and concentrated under vacuum. The crude product was purified with a heptane / siRNA gradient, the relevant fractions were collected, and concentrated under vacuum to obtain the target compound IV.

[0205] Example: Synthesis of tert-butyl 3-[6-fluoro-3-(2'-oxo-1'-tetrahydropyran-2-yl-spiro[cyclopentan-1,3'-pyrrolo[2,3-b]pyridine]-4'-yl)indazole-1-yl]-3-(hydroxymethyl)pyrrolidine-1-carboxylate (R1=F, G=C cyclopentyl) Skin-colored solid, 24% yield, m / z = 606.3 [M+H]+

[0206] 5. Deprotection A 4M hydrogen chloride solution (1.9 mmol, 40 eq) / dioxane was added to a solution of compound IV (0.05 mmol) / anhydrous methanol (0.1 mL, 0.5 N). The reaction mixture was stirred overnight at 65°C. The solution was concentrated. The product was dissolved in water, and impurities were extracted with ethyl acetate. The aqueous phase was concentrated under vacuum to obtain the target compound IV as its hydrochloride salt.

[0207] Example 55: Synthesis of 4-[6-fluoro-1-[3-(hydroxymethyl)pyrrolidine-3-yl]indazole-3-yl]spiro[1H-pyrrololo[2,3-b]pyridine-3,1'-cyclopentane]-2-one dihydrochloride (R1=F, G=C cyclopentyl) Yellow powder; 57% yield; 1H NMR (DMSO-d6, 500 MHz): δ (ppm) 11.02 (s, 1H), 9.18-9.66 (m, 2H), 8.19 (d, J = 5.4 Hz, 1H), 7.65-7.84 (m, 2H), 7.17 (td, J = 9.0, 2.1 Hz, 1H), 7.11 (d, J = 5.4 Hz, 1H), 4.10 (dt, J = 12.0, 6.0 Hz, 2H), 3.80-3.97 (m, 3H), 3.40-3.52 (m, 1H), 3.23-3.34 (m, 1H), 2.66-2.93 (m, 2H), 2.10-2.28 (m, 2H), 1.77-1.90 (m, 4H), 1.60 (br d, J = 2.7 Hz, 2H);m / z = 422.1 [M+H]+

[0208] To obtain Example 77, one or more steps were performed before deprotection: [ka]

[0209] Synthesis of tert-butyl 3-[3-(3,3-dimethyl-2-oxo-1-tetrahydropyran-2-yl-pyrrolo[2,3-b]pyridine-4-yl)indazole-1-yl]-3-(fluoromethyl)pyrrolidine-1-carboxylate In a 5 mL Reacti-vial, DAST (0.019 mL, 0.142 mmol, 1.5 eq) was added dropwise to a stirred solution of tert-butyl 3-[3-(3,3-dimethyl-2-oxo-1-tetrahydropyran-2-yl-pyrrolo[2,3-b]pyridine-4-yl)indazole-1-yl]-3-(hydroxymethyl)pyrrolidine-1-carboxylate (53 mg, 0.0944 mmol) / anhydrous DCM (1.2 mL, 0.08 N) at 0°C. The reaction mixture was allowed to return to room temperature and stirred overnight at room temperature. DAST (0.019 mL, 0.142 mmol, 3 eq) was added, and the reaction mixture was stirred at room temperature over the weekend. The reaction mixture was quenched with 1 M aqueous NaOH until pH=12, extracted with dichloromethane, and dried on a phase separator. The solvent was evaporated to obtain tert-butyl 3-[3-(3,3-dimethyl-2-oxo-1-tetrahydropyran-2-yl-pyrrolo[2,3-b]pyridine-4-yl)indazole-1-yl]-3-(fluoromethyl)pyrrolidine-1-carboxylate (35.3 mg, 66% yield) as a pale yellow gum. This was subjected to the next step without further purification. 1 H NMR (400 MHz, DMSO-d6) δ 8.36 (d,J = 5.4 Hz, 1H), 7.94 - 7.77 (m, 2H), 7.58 - 7.48 (m, 1H), 7.41 (d,J = 6.3 Hz, 1H), 7.37 - 7.27 (m, 1H), 5.49 (d,J = 11.1 Hz, 1H), 5.10 - 4.78 (m, 2H), 4.09 - 3.95 (m, 1H), 3.57 (d, J = 10.2 Hz, 2H), 2.97 (dq, J = 13.7, 6.9 Hz, 3H), 2.75 (q, J = 7.2 Hz, 3H), 1.95 (s, 1H), 1.71 - 1.45 (m, 4H), 1.38 (d, J = 12.7 Hz, 6H), 1.07 (dt, J = 20.1, 7.2 Hz, 9H);m / z = 564.2 [M+H]+.

[0210] Scaffold coupling - specific method (specific indazole 1) [ka] Step 1: Synthesis of tert-butyl-(1H-indazole-7-yloxy)-diphenyl-silane To a solution of 7-hydroxy-1H-indazole (95%, 1.44 g, 10.2 mmol) in anhydrous DMF (14 mL, 0.5 N), tert-butylchlorodiphenylsilane (6.8 mL, 25.5 mmol, 2.5 eq) was added at room temperature. The resulting mixture was stirred overnight at room temperature. Further stirring of the mixture at 80°C overnight was performed. The reaction mixture was poured into an aqueous solution of NaHCO3 and extracted with ethyl acetate. The two phases were separated, the organic phase was washed with water, dried over Na2SO4, filtered, and evaporated. The crude material was purified by flash chromatography on silica gel using a heptane / ethyl acetate gradient. It was eluted by liquid injection / DCM. The relevant fractions were collected and concentrated under vacuum to obtain tert-butyl-(1H-indazole-7-yloxy)-diphenylsilane (1.4 g, yield 37%) as a white foam. 1 H NMR (DMSO-d6, 500 MHz):δ (ppm) 13.36 (s, 1H), 8.07 (s, 1H), 7.71-7.74 (m, 4H), 7.40-7.51 (m, 6H), 7.23 (d, J = 8.1 Hz, 1H), 6.63 (t, J = 7.8 Hz, 1H), 6.13 (d, J = 7.3 Hz, 1H), 1.09 (s, 9H);m / z = 373.4 [M+H]+

[0211] Step 2: Synthesis of 4-[7-[tert-butyl(diphenyl)silyl]oxyindazole-1-yl]piperidine-1-carboxylate To a stirred mixture of tert-butyl-(1H-indazole-7-yloxy)-diphenylsilane (650 mg, 1.74 mmol) / anhydrous toluene (5 mL, 0.3 N), cyanomethylenetributylphospholane (0.91 mL, 3.49 mmol, 2 eq) and tert-butyl 4-hydroxypiperidine-1-carboxylate (0.70 g, 3.49 mmol, 2 eq) were added. The mixture was then stirred overnight at 85°C. The reaction mixture was concentrated to dryness, and the crude product was purified by flash chromatography using an siRNA / cyclohexane gradient column. The relevant fractions were collected and concentrated under vacuum to obtain tert-butyl 4-[7-[tert-butyl(diphenyl)silyl]oxyindazole-1-yl]piperidine-1-carboxylate (180 mg, 18%). 1H NMR (600 MHz, DMSO-d6) shift 8.09 (s, 1H), 7.71-7.76 (m, 4H), 7.38-7.52 (m, 6H), 7.23 (d, J=8.02 Hz, 1H), 6.64 (t, J=7.85 Hz, 1H), 6.21 (d, J=7.63 Hz, 1H), 5.57 (tt, J=5.28, 10.27 Hz, 1H), 4.14 (br d, J=12.03 Hz, 2H), 2.78 (br s, 2H), 2.02-2.11 (m, 4H), 1.38-1.45 (m, 9H),1.11 (s, 9H);m / z = 556.4 [M+H]+.

[0212] Step 3: Synthesis of tert-butyl 4-(7-hydroxyindazole-1-yl)piperidine-1-carboxylate In a 50 mL round-bottom flask, 0.49 mL, 0.486 mmol, 1.5 eq. of 1 M tetrabutylammonium fluoride solution was added at room temperature to a stirred solution of tert-butyl 4-[7-[tert-butyl(diphenyl)silyl]oxyindazole-1-yl]piperidine-1-carboxylate (180 mg, 0.324 mmol) / anhydrous THF (1.6 mL, 0.2 N). The reaction mixture was stirred at room temperature for 1 hour. The reaction was quenched with brine and siRNA was added. The two phases were separated, the organic phase was washed with water and brine, dried over Na2SO4, and evaporated to dryness. The crude product was triturated with DCM. The solid was filtered and dried under high vacuum to obtain tert-butyl 4-(7-hydroxyindazole-1-yl)piperidine-1-carboxylate (70 mg, 68% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.20 (s, 1H), 7.95 (s, 1H), 7.14 (dd, J = 8.0, 0.6 Hz, 1H), 6.96 - 6.82 (m, 1H), 6.69 (dd, J = 7.4, 0.6 Hz, m / z = 318.1 [M+H]+

[0213] Step 4: Synthesis of tert-butyl 4-[7-(difluoromethoxy)indazole-1-yl]piperidine-1-carboxylate In a 2-5 mL sealed tube, at -78°C, diethyl[bromo(difluoro)methyl]phosphonate (0.080 mL, 0.429 mmol, 2 eq) was added in one step to a chilled solution of tert-butyl 4-(7-hydroxyindazole-1-yl)piperidine-1-carboxylate (68 mg, 0.214 mmol) and potassium hydroxide (240 mg, 4.29 mmol, 20 eq) in a mixed solvent of acetonitrile (1.1 mL) and water (1.1 mL). The reaction mixture was heated to room temperature and stirred for 1 hour. The reaction mixture was diluted with ethyl acetate. The two phases were separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with brine and water, dried on Na2SO4, and evaporated to obtain tert-butyl 4-[7-(difluoromethoxy)indazole-1-yl]piperidine-1-carboxylate as a brown gum. 1 H NMR (600 MHz, DMSO-d6) δ ppm 8.17 (s, 1 H), 7.63 - 7.67 (m, 1 H), 7.27 - 7.53 (m, 1 H), 7.16 - 7.19 (m, 1 H), 7.11 - 7.15 (m, 1 H), 4.95 - 5.04 (m, 1 H), 4.03 - 4.18 (m, 2 H), 2.71 - 3.11 (m, 2 H), 1.83 - 2.06 (m, 4 H), 1.43 (s, 9 H);m / z = 312.2 [M+H]+

[0214] Step 5: Synthesis of tert-butyl 4-[3-bromo-7-(difluoromethoxy)indazole-1-yl]piperidine-1-carboxylate To a solution of tert-butyl 4-[7-(difluoromethoxy)indazole-1-yl]piperidine-1-carboxylate (64 mg, 0.122 mmol) in acetonitrile (0.3 mL, 0.4 N), N-bromosuccinimide (23 mg, 0.128 mmol, 1.05 eq.) was added. The mixture was stirred overnight at room temperature. The solvent was removed under vacuum, and the residue was dissolved in ethyl acetate. The organic solution was washed with aqueous NaOH solution and water, dried over Na2SO4, and concentrated under vacuum to obtain tert-butyl 4-[3-bromo-7-(difluoromethoxy)indazole-1-yl]piperidine-1-carboxylate (69 mg, yield 85%) as a purple gum. 1 H NMR (DMSO-d6, 500 MHz):δ (ppm) 7.15-7.71 (m, 4H), 4.89-5.07 (m, 1H), 3.99-4.19 (m, 2H), 2.75-3.10 (m, 2H), 1.72-2.15 (m, 4H), 1.36-1.46 (m, 9H) ;m / z = 390.2, 392.2 [M+H-tBu]+

[0215] The next step was similar to the general method—indazole 2.

[0216] Scaffold coupling - specific method (specific indazole 2) [ka] In a 6 ml sealed vial, under a nitrogen atmosphere, 3-bromo-1H-indazole (120 mg, 0.59 mmol), (tributyl-lambda-5-phosphanylidene)acetonitrile (0.31 mL, 1.18 mmol), and compound I' were sequentially added in anhydrous toluene (2 mL). The reaction mixture was stirred overnight at 80°C. The solvent was evaporated to obtain the crude product. The crude product was purified by flash chromatography on silica gel using a heptane / ethyl acetate gradient. It was eluted through an isolute HM-N solid phase of a 12 g Redisep Gold column. The relevant fractions were collected and concentrated under vacuum to obtain compound II.

[0217] Example: Synthesis of tert-butyl N-[rac-(1R,2R,4R)-4-(3-bromoindazole-1-yl)-2-fluorocyclohexyl]carbamate (R1=F) Flesh-colored solid, 58% yield, 1H NMR (400 MHz, DMSO-d6) δ 7.88 (d, J = 8.6 Hz, 1H), 7.58 (d, J = 8.2 Hz, 1H), 7.29 - 7.23 (m, 1H), 7.13 - 7.03 (m, 1H), 4.81 (s, 1H), 4.63 (s, 1H), 4.50 (s, 1H), 3.57 (s, 1H), 2.42 (d, J = 5.2 Hz, 1H), 2.21 - 2.08 (m, 1H), 1.91 (d, J = 7.3 Hz, 2H), 1.45 (d, J = 7.0 Hz, 2H), 1.42 (s, 9H).

[0218] Scaffold coupling - specific method (specific indazole 3) [ka] Process 1 Synthesis of 2-[1-(3-bromoindazole-1-yl)cyclobutyl]acetonitrile In a 20 ml vial of Biotage, 3-bromo-1H-indazole (500 mg, 2.46 mmol), cyclobutylidene acetonitrile (0.25 mL, 2.46 mmol), and 1,8-diazabicyclo[5.4.0]undeca-7-ene (0.73 mL, 4.92 mmol) were sequentially added in anhydrous acetonitrile (12 mL). The mixture was stirred at 85 °C for 48 hours. The mixture was concentrated under vacuum. An orange oil was obtained and purified by a 12 g silica gel column with a heptane / siRNA gradient. The relevant fractions were collected and concentrated under vacuum to obtain 2-[1-(3-bromoindazole-1-yl)cyclobutyl]acetonitrile (600 mg, yield 83%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.63 (d, J = 9.1 Hz, 2H), 7.57 - 7.42 (m, 1H), 7.30 (dd, J = 8.7, 7.0 Hz, 1H), 3.39 (s, 2H), 2.87 (dt, J = 12.5, m / z = 290.0, 292.0 [M+H]+

[0219] Process 2 Synthesis of 2-[1-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazole-1-yl]cyclobutyl]acetonitrile In a vial, bis(pinacol)diborane (1.5 g, 6.00 mmol), potassium acetate (589 mg, 6.00 mmol), 2-[1-(3-bromoindazole-1-yl)cyclobutyl]acetonitrile (580 mg, 2.00 mmol), and bis(diphenylphosphino)ferrocene]dichloropalladium(II) (147 mg, 0.200 mmol) were added in anhydrous dioxane (20 mL). The vial was sealed, evacuated under vacuum, and refilled with argon. The reaction mixture was stirred at 110 °C for 2 hours, then allowed to cool to room temperature, filtered, washed with ethyl acetate, and concentrated under vacuum to obtain the crude substance as a brown oil. The crude substance was purified by flash chromatography on silica gel using a heptane / ethyl acetate gradient. It was eluted by liquid injection / DCM on a 70 g column. The relevant fractions were collected and concentrated under vacuum to obtain 2-[1-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazole-1-yl]cyclobutyl]acetonitrile as an orange solid. 1H NMR (400 MHz, DMSO-d6) δ 7.96 (d, J = 8.1 Hz, 1H), 7.62 (d, J = 8.5 Hz, 1H), 7.41 - 7.36 (m, 1H), 7.26 - 7.21 (m, 1H), 3.42 (s, 2H), 2.90 (dt, J = 12.4, 9.8 Hz, 2H), 2.66 - 2.56 (m, 2H), 2.28 - 2.11 (m, 1H), 2.01 - 1.88 (m, 1H), 1.36 (s, 12H);m / z = 256.3 [M+H]+

[0220] Scaffold coupling - Common method (pyrazole) [ka]

[0221] First step: Alkylation or Mitsunori 1a. Alkylation (X = Br) In a Reacti vial, cesium carbonate (532 mg, 1.63 mmol, 1.2 eq) was added to a solution of 3-bromo-1H-pyrazole I (200 mg, 1.36 mmol) and tert-butyl 4-bromopiperidine-1-carboxylate (431 mg, 1.63 mmol, 1.2 eq) in anhydrous DMF (14 mL, 0.1 N). Then, tert-butyl 4-bromopiperidine-1-carboxylate (431 mg, 1.63 mmol, 2 eq.) and cesium carbonate (532 mg, 1.63 mmol, 2 eq.) were added, and the mixture was heated overnight at 70°C. Then, tert-butyl 4-bromopiperidine-1-carboxylate (2 eq.) and cesium carbonate (2 eq.) were added again, and the mixture was heated further at 80°C for 4 hours. Water was added, and the mixture was extracted with ethyl acetate. The organic phase was dried and concentrated under vacuum to obtain the crude product. The crude product was purified by flash chromatography on silica gel using a DCM / siRNA gradient. It was eluted by liquid injection / DCM. The relevant fractions were collected (invisible under UV) and concentrated under vacuum to obtain tert-butyl 4-(3-bromopyrazole-1-yl)piperidine-1-carboxylate II (266 mg, yield 54%) as a pale oil. 1 H NMR(DMSO-d6, 400 MHz):δ (ppm) 7.83 (d, J=2.4 Hz, 1H), 6.38 (d, J=2.3 Hz, 1H), 4.35 (tt, J=11.5, 4.0 Hz, 1H), 4.03 (d, J=12.3 Hz, 2H), 2.88 (s, 2H), 2.04 - 1.92 (m, 2H), 1.73 (qd, J=12.4, 4.4 Hz, 2H), 1.42 (s, 9H);m / z = 276.1 [M+H]+

[0222] 1b. Mitsunobu reaction (X=OH) Cyanomethylenetributylphosphoran (1.7 mL, 6.12 mmol, 3 eq.) was added to a solution of 3-bromo-1H-pyrazole I (300 mg, 2.04 mmol) and tert-butylcis-4-hydroxycyclohexyl carbamate (1.32 g, 6.12 mmol, 3 eq.) in anhydrous toluene (10 mL, 0.2 N). The reaction mixture was stirred overnight at 90°C. The solution was concentrated under vacuum. The crude product was purified by flash chromatography on silica gel using a heptane / siRNA gradient. The relevant fractions were collected and concentrated under vacuum to obtain tert-butyl N-[4-(3-bromopyrazole-1-yl)cyclohexyl]carbamate II (288 mg, yield 41%) as a yellow solid. 1 H NMR(DMSO-d6, 400 MHz):δ (ppm) 7.79 (d, J=2.3 Hz, 1H), 6.80 (d, J=7.9 Hz, 1H), 6.34 (d, J=2.3 Hz, 1H), 4.09 (tt, J=11.9, 3.9 Hz, 1H), 3.22-3.30 (m, 1H), 2.04 - 1.65 (m, 6H), 1.51 - 1.20 (m, 11H), m / z = 288.1-290.1 ​​[M+H-tBu]+

[0223] The same synthesis applies to the following steps as well. 2. Boronic acid esters Substituted bromopyrazole II (0.806 mmol), bis(pinacolato)diborone (1.21 mmol, 1.5 eq.), and potassium acetate (2.42 mmol, 3 eq.) / anhydrous dioxane (2.7 mL, 0.3 N) were placed in a Reacti-vial. The mixture was degassed with N2, and bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.081 mmol, 0.1 eq.) was added. The reaction mixture was stirred overnight at 100°C. The mixture was filtered on a dicalite and concentrated under vacuum to obtain crude product III. The crude product was used in the next step without further purification.

[0224] Example: Synthesis of tert-butyl 4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole-1-yl]piperidine-1-carboxylate (R=NHBoc, R2=H) Dark oil, m / z = 240.3 [M+H-tBu]+ (acid form)

[0225] 3. Suzuki Coupling In a Reacti vial, boronic acid ester III (0.709 mmol, 2 eq.), bromine scaffold I' (0.332 mmol), disodium carbonate (0.996 mmol, 3 eq.), and tetrakistriphenylphosphine palladium (0.0332 mmol, 0.1 eq.) were added in a mixed solution of DMF (3.2 mL) and water (0.6 mL). The vial was degassed with nitrogen and stirred at 100°C for 4 hours. Water was added, the precipitate was filtered, and dissolved in DCM. The organic phase was dried using a phase separator and concentrated under vacuum. The crude product was purified by flash chromatography on silica gel using a cyclohexane / siRNA gradient. The relevant fractions were collected and concentrated under vacuum to obtain Suzuki coupling product IV.

[0226] Example: Synthesis of tert-butyl 4-[3-(3,3-dimethyl-2-oxo-1H-pyrrolo[2,3-b]pyridine-4-yl)pyrazole-1-yl]piperidine-1-carboxylate (R=NHBoc, R2=H, G = CMe2) Yellow solid, 54% yield. 1H NMR (DMSO-d6, 400 MHz):δ (ppm) 11.01 (s, 1H), 8.07 (d, J=5.5 Hz, 1H), 7.95 (d, J=2.4 Hz, 1H), 7.24 (d, J=5.6 Hz, 1H), 6.83 (d, J=2.4 Hz, 1H), 4.49 (ddt, J=11.4, 7.9, 4.0 Hz, 1H), 4.13 - 3.99 (m, 2H), 2.91 (d, J=14.5 Hz, 2H), 2.06 (d, J=10.0 Hz, 2H), 1.86 (qd, J=12.4, 4.2 Hz, 2H), 1.45 (d, J=14.7 Hz, 15H);m / z = 412.4 [M+H]+

[0227] 4. Deprotection To a solution of Suzuki coupling compound IV (0.18 mmol) in anhydrous methanol (0.16 mL, 0.1 N), 4 M hydrogen chloride solution / dioxane (0.73 mmol, 4 eq.) was added. The reaction mixture was stirred overnight at room temperature. The solution was concentrated under vacuum. The product was tritulated in DCM and dried overnight at 40°C under vacuum to obtain the final compound IV as its hydrochloride salt.

[0228] Example: Synthesis of 3,3-dimethyl-4-[1-(4-piperidyl)pyrazole-3-yl]-1H-pyrrolo[2,3-b]pyridine-2-one dihydrochloride (R=NH, R2=H, G = CMe2) White powder, 73% purity, 1H NMR (DMSO-d6, 500 MHz): δ (ppm) 11.06 (s, 1H), 8.62–9.21 (m, 2H), 8.08 (d, J = 5.6 Hz, 1H), 7.93 (d, J = 2.4 Hz, 1H), 7.25 (d, J = 5.6 Hz, 1H), 6.86 (d, J = 2.4 Hz, 1H), 4.59 (tt, J = 10.3, 5.0 Hz, 1H), 4.25 (br s, 1H), 3.43 (br d, J = 13.0 Hz, 2H), 3.02–3.14 (m, 2H), 2.13–2.29 (m, 4H), 1.48 (s, 6H);m / z = 312.1 [M+H]+

[0229] Scaffold coupling - a common method (pyrrole)

change

[0230] 2. Suzuki Coupling In a Reacti-vial, tert-butyl 4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrole-1-yl]piperidine-1-carboxylate II (0.282 mmol, 1.1 eq.), bromine scaffold I' (0.256 mmol), disodium carbonate (81 mg, 0.768 mmol), and tetrakistriphenylphosphine palladium (30 mg, 0.0256 mmol, 0.1 eq.) were added in a mixture of DMF (2.5 mL) and water (0.5 mL). The vial was sealed, degassed with nitrogen, and stirred overnight at 100°C. The reaction was stopped, the reaction mixture was filtered through a dikalite pad, and washed with DCM. The solvent was removed under vacuum to obtain the crude product. The crude product was purified by flash chromatography on silica gel using a cyclohexane / siRNA gradient followed by a toluene / acetone gradient. The relevant fractions were collected and concentrated under vacuum to obtain the desired product III.

[0231] Example: Synthesis of tert-butyl 4-[3-(2-oxo-1,3-dihydroimidazo[4,5-b]pyridine-7-yl)pyrrole-1-yl]piperidine-1-carboxylate (G = NH) White solid; yield 13%; 1 H NMR(DMSO-d6, 400 MHz):δ (ppm) 11.22 (s, 1H), 10.63 (s, 1H), 7.86 (dd, J=5.2, 1.4 Hz, 1H), 7.79 (d, J=5.6 Hz, 1H), 7.66 (s, 1H), 7.12 (d, J=5.6 Hz, 1H), 6.59 (s, 1H), 4.12 (s, 3H), 2.86 (s, 2H), 2.05 - 1.69 (m, 4H), 1.44 (s, 9H);m / z = 384.5 [M+H]+

[0232] 3. Deprotection To a solution of Suzuki coupling compound III (0.032 mmol) in anhydrous methanol (0.16 mL, 0.2 N), 4 M hydrogen chloride solution (0.36 mmol, 10 eq.) in dioxane was added. The reaction mixture was stirred overnight at room temperature. The reaction mixture was filtered, the product was washed with pentane, and then vacuum-dried at 40°C to obtain the final compound as a hydrochloride salt.

[0233] Example 6: Synthesis of 7-[1-(4-piperidyl)pyrrole-3-yl]-1,3-dihydroimidazo[4,5-b]pyridine-2-one; dihydrochloride (G = NH) White powder; yield 50%, 1H NMR (DMSO-d6, 500 MHz): δ (ppm) 11.77 (br s, 1H), 10.97 (br s, 1H), 9.08 (br s, 1H), 8.89 (br s, 1H), 7.82 (d, J = 5.9 Hz, 1H), 7.64 (s, 1H), 7.22 (d, J = 5.9 Hz, 1H), 7.00 (t, J = 2.2 Hz, 1H), 6.70 (br s, 1H), 4.28 (tt, J = 11.4, 3.6 Hz, 1H), 3.53 (br s, 1H), 3.36-3.46 (m, 2H), 3.05 (q, J = 12.1 Hz, 2H), 2.23 (br d, J = 12.5 Hz, 2H), 2.06-2.18 (m, 2H);m / z = 284.2 [M+H]+

[0234] Example 2 - Biological Assay PKC-θ and PKC-δ Inhibition Assays The biochemical activities of PKC-θ and PKC-δ were measured using the PKC-θ HTRF KinEASEkit kit (Cisbio, catalog number 61ST1PEJ) according to the manufacturer's instructions. In short, 10 mM MgCl2, 1 mM DTT, and 0.1% Tween 20 were added to the kinase buffer component of the kit. For the PKC-θ assay, STK substrate and ATP were added to final assay concentrations of 525 nM and 6.5 μM, respectively. For the PKCδ assay, STK substrate and ATP were added to final assay concentrations of 243 nM and 5.7 μM, respectively. Streptavidin XL665 and STK antibody-cryptate detection reagent were mixed according to the manufacturer's instructions. The test compounds were diluted with DMSO in 10 consecutive semi-logarithmic stepwise doses, and 10 nL of each compound dose was dispensed into a 384-well plate. Recombinant human PKC-θ (His-tagged 362-706) or PKC-δ (His-tagged 345-676) were diluted in kinase buffer to a final assay concentration of 10 ng / mL and added to the test compound, then incubated on ice for 30 minutes. The reaction was initiated by adding the substrate and ATP, and incubated at 25°C for 30 minutes or 20 minutes for the PKC-θ and PKC-δ assays, respectively. The detection reagent was added, and the plate was incubated in the dark for 2 hours. Fluorescence was measured using an Envision 2103 plate reader in HTRF mode, set to excitation 665 nM and emission 620 nM. For each well, the emission signal ratio of acceptor to donor was calculated. Inhibition % was calculated from the HTRF ratio at different doses, and the IC50 value was determined by fitting it to a 4-parameter logistic curve (see Table 1).

[0235] IL-2 release assay of effector memory T cells The inhibition of NFκB signaling in T cells by the test compound was evaluated by quantifying IL-2 secretion by human effector memory T cells (TEMs) induced by treatment and stimulation. Human TEM cells were isolated from the buffy coat of healthy donors obtained from a French blood bank. First, peripheral blood mononuclear cells (PBMCs) were purified from buffy coats diluted 1:1 with DPBS (Gibco, cat#14190-094) by density gradient centrifugation (400 × g, 20 minutes) using Pancoll (PAN BIOTECH, cat#P04-60500). TEM cells were further enriched by negative immunomagnetic cell sorting according to the manufacturer's instructions using a human CD4+ effector memory T cell isolation kit (Miltenyi, cat#130-094-125). Aliquots of 3×10E6 purified TEM cells were cryopreserved in Cryo-SFM medium (PromoCelL, cat#C-29912) in a nitrogen gas phase until use. Cell purity was confirmed by flow cytometry analysis of 200,000 PFA-fixed cells pre-labeled with the monoclonal antibodies anti-CD4-PeRCP-Cy5.5 (BD Pharmigen, cat#332772), anti-CD8-V500 (BD Biosciences, cat#561617), anti-CD14-Pacific Blue (Biolegend, cat#325616), anti-CD45 RA-FITC (Biolegend, cat#304106), and anti-CCR7-APC (CD4+ Effector Memory T Cell Isolation Kit, Miltenyi, cat#130-094-125).

[0236] TEM cells were resuspended in complete RPMI medium consisting of: RPMI1640 (Gibco, cat#31870-025), 10% thermo-inactivated fetal bovine serum (Sigma, cat#F7524), 2 mM GlutaMAX (Gibco, cat#35050-038), 1 mM sodium pyruvate 100X (Gibco, cat#11360-039), 1% MEM non-essential amino acid solution (Gibco, cat#11140-035), 100 U / mL penicillin, and 100 μg / mL streptomycin (Sigma-Aldrich, cat#11074440001). 5,000 cells per well were plated into clear flat-bottomed 384-well plates (Corning, cat#3770). Cell stimulation was performed by adding 5,000 Dynabeads Human T-Activator CD3 / CD28 (Gibco, cat#11132D) to each well. Finally, 10 doses of the test compound, prepared by sequential semi-logarithmic serial dilution with DMSO, were added to cells in a triple well. The final DMSO concentration in the well was 0.1%, and the total volume of medium was 100 μL. The plate was incubated at 37°C for 24 hours under a 5% CO2 atmosphere. After incubation, the cell suspension was centrifuged at 400 xg, and the culture supernatant was collected and stored at -80°C. Cell viability was evaluated by flow cytometry after staining with Fixable Viability Dye eFluor 780 (Invitrogen, cat# 65-0865-14). IL-2 levels were measured in cell supernatant using the HTRF Human IL-2 Detection Kit (Cisbio, cat# 62HIL02PEH). IL-2 data at different compound doses were fitted to a 4-parameter logistic curve to determine the IC2 concentration that reduces the IL-2 level to 50% of the maximum IL-2 level observed in each experiment. 50 The values ​​were determined. To eliminate cytotoxicity that causes IL-2 reduction, survival rate data were analyzed in the same manner (see Table 1).

[0237] [Table 58] [Table 59] [Table 60]

[0238] Table 2: Biochemical data of representative compounds in this disclosure In the fields provided, the data is categorized into categories A through H as shown below, based on the measured values. About PKC-θHTRF: A means that the measured pIC50 is 9.0 or higher; B means that the measured pIC50 is between 8.5 and 9.0; C means that the measured pIC50 is between 8.0 and 8.5; D means that the measured pIC50 is between 7.5 and 8.0; E means that the measured pIC50 is between 7.0 and 7.5; F indicates a measured pIC50 of 6.5-7.0; G indicates a measured pIC50 of 6.0-6.5; H indicates that the measured value of pIC50 is <6.0.

[0239] Regarding PKC-θCD4Tc IL-2: A means that the measured pIC50 is between 8.5 and 9.0; B means that the measured pIC50 is between 8.0 and 8.5; C means that the measured pIC50 is between 7.5 and 8.0; D means that the measured pIC50 is between 7.0 and 7.5; E means that the measured pIC50 is between 6.5 and 7.0; F indicates a measured pIC50 of 6.0 to 6.5; G indicates that the measured value of pIC50 is <6.0.

[0240] Regarding the selection of PKC-θ / PKC-δ: A represents a ratio of 50 to 120; B represents a ratio of 30 to 50; C represents a ratio of 20-30; D represents a ratio of 10 to 20; E represents a ratio of 5 to 10; F represents a ratio between 1 and 5; G represents a ratio between 0 and 1.

[0241] Modifications can be made to the above embodiments without departing from the scope of the present invention as defined in the attached claims.

Claims

1. Structural formula I: 【Chemistry 1】 [In the formula, A is N, CR a (In the formula, R a (Selected from hydrogen, halogens, C1-3 alkyl and CN); G is selected from CR1R2, O, and NR1; R1 and R2 are independently selected from hydrogen, halogen, C1-3 alkyl, C3-7 cycloalkyl, C1-3 alkoxyl, C2-6 cycloalkoxyl, C2-6 alkylalkoxy, hydroxyl, C1-3 alkylhydroxyl, amino, C1-3 alkylamino, C1-4 aminoalkyl, C2-7 alkylaminoalkyl and C1-3 haloalkyl; or R1 and R2 together form a 3- to 5-membered spirocarbon or heterocyclic ring, which may be optionally substituted; B is selected from N, CH, and C-halogens; D is selected from N and C-R3; R3 is selected from hydrogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C2-5 alkylalkoxy, and halogen; R4 is selected from hydrogen, C1-3 alkyl, C1-3 haloalkyl, OMe, and halogen; or If D is C-R3, then R3 and R4 are combined together as follows: 【Chemistry 2】 (In the formula, R7 is selected from hydrogen and halogen; R8 is selected from hydrogen and halogen; R9 is selected from hydrogen, C1-3 haloalkyl, and halogen; R10 is selected from hydrogen, halogen, C1-3 haloalkyl, and C1-3 haloalkoxy. Forming an aryl or heteroaryl ring having a structure selected from the following, which may be optionally substituted; n is either 0 or 1; E is CH or CR a (In the formula, R a (These are selected from halogens, C1-3 alkyls, C1-3 alkylhydroxys, C1-3 haloalkyls, C2-6 alkylalkoxys, and C1-3 alkylnitriles); R5 and R6 bond together to form a 4- to 8-membered saturated carbocyclic or heterocyclic ring, which may optionally be substituted and optionally bridged. Compounds thereof, or pharmaceutically acceptable salts, solvates, stereoisomers or mixtures of stereoisomers, tautomers and / or isotopes thereof.

2. Structural formula II: 【Transformation 3】 A compound according to claim 1, or a pharmaceutically acceptable salt, solvate, stereoisomer or mixture of stereoisomers, tautomer and / or isotope thereof.

3. Structural formula IIa: 【Chemistry 4】 A compound according to claim 1, wherein R17 in the formula is as follows: 【Transformation 5】 【Transformation 6】 (In the formula, R11 is selected from hydrogen, halogens, and C1-2 alkyl groups; R12 is selected from hydrogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkylhydroxyl, and C1-2 alkylnitrile; R13 is selected from hydrogen, halogens, and C1-2 alkyl groups; R14 is hydrogen or a C1-2 alkyl group; R15 is hydrogen or a C1-2 alkyl group; R16 is selected from hydrogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkylhydroxy, and C1-3 alkylalkoxy; R21 and R22 are, independently, hydrogen and C1-3 alkyl, respectively; n is either 0 or 1; p is either 1 or 2; X is CH 2 or O; Y is CH 2 (Selected from O, NH, and NMe) A compound according to claim 1, or a pharmaceutically acceptable salt, solvate, stereoisomer or mixture of stereoisomers, tautomer and / or isotope thereof, selected from the above.

4. R1 is hydrogen, Me, Et, OMe, OEt, OH, NH 2 , selected from NHMe and NHEt; R2 is selected from hydrogen, Me and Et; or R1 and R2 together form a 3- to 5-membered spirocarbocyclic or heterocyclic ring, which may be optionally substituted; in particular, they form a 4- to 5-membered carbocyclic or heterocyclic spiroring, which may be optionally substituted; in one embodiment, the carbocyclic or heterocyclic spiroring is unsubstituted; in another embodiment, the carbocyclic or heterocyclic spiroring is substituted with one or more substituents selected from C1-2 alkyl, halogen, C1-2 haloalkyl, hydroxyl, and C1-2 alkoxyl; A is selected from CH, CF, C-Cl, and C-Br; B is selected from N, CH, CF, C-Cl, and C-Br; R17, see below: 【Transformation 6】 (In the formula, R18 is selected from hydrogen and halogen; R19 is selected from hydrogen, C1-3 alkyl, C1-3 haloalkyl, and C1-3 alkylhydroxy; m is either 0 or 1; R20 is hydrogen or halogen; X is CH 2 or O; R21 and R22 are independently selected from hydrogen and C1-3 alkyl groups, respectively; Y is CH 2 , O or NH; and is selected from R23 is selected from hydrogen, C1-3 alkyl, and C1-3 haloalkyl. A compound according to claim 3, or a pharmaceutically acceptable salt, solvate, stereoisomer or mixture of stereoisomers, tautomer and / or isotope thereof, selected from the above.

5. Structural formula III: 【Transformation 7】 (In the formula, D is selected from N, CH, and C-R3; R3 is selected from C1-3 alkyl, C2-5 alkylalkoxy, C1-3 haloalkyl, and halogen; R4 is selected from hydrogen, C1-3 alkyl, C2-5 alkylalkoxyl, C1-3 haloalkyl, and halogen. A compound according to claim 1, or a pharmaceutically acceptable salt, solvate, stereoisomer or mixture of stereoisomers and / or isotope thereof.

6. Structural formulas IIIa, IIIb, or IIIc: 【Transformation 8】 A compound according to claim 5, wherein R17 in the formula is as follows: 【Chemistry 9】 【Chemistry 11】 (In the formula, R11 is selected from hydrogen, halogens, and C1-2 alkyl groups; R12 is selected from hydrogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkylhydroxyl, and C1-2 alkylnitrile; R13 is selected from hydrogen, halogens, and C1-2 alkyl groups; R14 is selected from hydrogen and C1-2 alkyl; R15 is selected from hydrogen and C1-2 alkyl; R16 is selected from hydrogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkylhydroxyl, and C1-3 alkylalkoxyl; R21 and R22 are each independently hydrogen or a C1-3 alkyl group; n is either 0 or 1; p is either 1 or 2; X is CH 2 or O; Y is CH 2 (Selected from O, NH, and NMe) A compound according to claim 5, or a pharmaceutically acceptable salt, solvate, stereoisomer or mixture of stereoisomers, tautomer and / or isotope thereof, selected from the above.

7. R1 is hydrogen, Me, Et, OMe, OH, NH 2 and selected from NHMe; R2 is selected from hydrogen, Me and Et; or R1 and R2 together form a 3- to 5-membered spirocarbon or heterocyclic ring, which may be substituted as desired; A is selected from CH, CF, C-Cl, and C-Br; R17, see below: 【Chemistry 10】 (In the formula, R18 is selected from hydrogen and halogen; R19 is selected from hydrogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkyl, and hydroxyl; m is either 0 or 1; R20 is hydrogen or halogen; X is CH 2 or O; R21 and R22 are independently selected from hydrogen and C1-3 alkyl groups, respectively; Y is CH 2 Selected from O and NH; R23 is selected from hydrogen, C1-3 alkyl, and C1-3 haloalkyl. A compound according to claim 6, or a pharmaceutically acceptable salt, solvate, stereoisomer or mixture of stereoisomers, tautomer and / or isotope thereof, selected from the above.

8. Structure below: Table 1 Table 2 Table 3 Table 4 Table 5 Table 6 Table 7 Table 8 Table 9 Table 10 Table 11 Table 12 Table 13 Table 14 Table 15 Table 16 Table 17 Table 18 Table 19 Table 20 Table 21 Table 22 Table 23 Table 24 Table 25 Table 26 Table 27 Table 28 Table 29 Table 30 Table 31 Table 32 Table 33 Table 34 Table 35 Table 36 Table 37 Table 38 Compounds selected from, or their pharmaceutically acceptable salts, solvates, stereoisomers or mixtures of stereoisomers, tautomers and / or isotopes.

9. A pharmaceutical composition comprising one or more compounds according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, solvate, stereoisomer or mixture of stereoisomers thereof, tautomer and / or isotope, and one or more pharmaceutically acceptable carriers.

10. A pharmaceutical composition comprising a compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, solvate, stereoisomer or mixture of stereoisomers, tautomers and / or isotopes thereof, for use in the treatment of a disease or disorder selected from autoimmune diseases, inflammatory diseases, neoplastic diseases, cancer and HIV infection.

11. The pharmaceutical composition according to claim 10, wherein the disease or disorder is selected from the group consisting of rheumatoid arthritis, multiple sclerosis, psoriasis, and atopic dermatitis.

12. The pharmaceutical composition according to claim 10, wherein the compound is an inhibitor of PKC-θ.

13. The pharmaceutical composition according to claim 10, which is used in a method characterized by administering the compound orally, topically, by inhalation, by intranasal administration, or systemically by intravenous injection, intraperitoneal injection, subcutaneous injection, or intramuscular injection.

14. A combination pharmaceutical comprising one or more compounds according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, solvate, stereoisomer or mixture of stereoisomers, tautomer and / or isotope thereof, and one or more additional therapeutic agents.

15. The combination pharmacopoeia according to claim 14, wherein one or more compounds according to any one of claims 1 to 8, or pharmaceutically acceptable salts, solvates, stereoisomers or mixtures of stereoisomers, tautomers and / or isotopes thereof, are administered simultaneously, sequentially, or separately with one or more additional therapeutic agents.

16. The pharmaceutical composition according to claim 10, characterized by administering an effective amount of a compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, solvate, stereoisomer or mixture of stereoisomers, tautomer and / or isotope thereof, wherein the effective amount is about 5 nM to about 10 μM in the blood of the subject.

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