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. TIFF2024517861000178.tif84160

Description

[Technical Field]

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

[0002] Protein kinases constitute a large family of structurally related enzymes and are responsible for regulating various intracellular signaling 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 protein phosphorylation abnormalities and disease is well known. Therefore, protein kinases are an important group of drug 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 (PKC) is a family of protein kinases specific to serine and threonine. Members of the PKC family are known to phosphorylate a wide variety of protein targets and are involved in diverse intracellular signaling pathways. Each member of the PKC family is thought to have a unique expression profile and a distinct role.

[0005] PKC members can be classified into three groups: Group I (Ca 2+(and diacylglycerol (DAG) 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., 6:530).

[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, Frontiers 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, Frontiers 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., Mol Immunol., 2008, 46(2):213-24). Pharmacological inhibition of PKC-θ protected Tregs from TNFα-induced inactivation and enhanced protection of mice from inflammatory colitis (Zanin-Zhorov, et al., Science, 2010, 328 (5976):372-6). 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, Frontiers 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., Science, 2010, 328 (5976):372-6).

[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 pyrazolopyrimidine scaffolds are described in WO 2011 / 139273, and PKC-θ inhibitors based on diaminopyrimidine cores are described in WO 2015 / 095679.

[0011] To date, there are no effective and approved medical therapies based on PKC-θ inhibition, primarily because it is difficult to ensure potent inhibition of the PKC-θ isoform with appropriate selectivity for other isoforms, particularly PKC-δ of the PKC family (group 2) and other kinases.

[0012] This invention was devised in consideration of the above points. [Overview of the Initiative]

[0013] In one embodiment of the present invention, structural formula I: [ka] [In the formula, A is selected from the following groups: N, CR a (In the formula, R a This is selected from hydrogen, halogens, C1-3 alkyl groups (e.g., Me, Et), and CN; B is selected from the group consisting of the following: N, CH, CF, and C-(C1-3 alkyl) (e.g., C-Me, C-Et); D is selected from the following group: N, CH, CRb (wherein, R b is selected from halogen (e.g., F, Cl, Br), C1-3 alkyl (e.g., Me, Et) and C1-3 haloalkyl (e.g., CHF2, CF3)); G is selected from the group consisting of: CR1R2, NR1 and O; R1 and R2 are independently selected from the group consisting of: hydrogen, halogen (e.g., F, Cl, Br), C1-3 alkyl (e.g., Me, Et), C3-7 cycloalkyl (e.g., c Pr, c Hex), C1-3 alkoxyl (e.g., OMe, OEt), C2-6 cycloalkoxyl (e.g., oxetane, furan), C2-6 alkylalkoxyl (e.g., CH2OMe, (CH2)2OMe), hydroxyl, C1-3 alkylhydroxyl (e.g., CH2OH, (CH2)2OH), amino, C1-3 alkylamino (e.g., CH2NH2, (CH2)2NH2), C1-4 aminoalkyl (e.g., NMe2, NMeEt), C2-7 alkylaminoalkyl (e.g., CH2NMe2, (CH2)2NEt2), C1-3 haloalkyl (e.g., CHF2, CF3, CH2CHF2), aryl (e.g., phenyl), heteroaryl (e.g., pyridine, thiazole), alkylaryl (e.g., benzyl) and alkylheteroaryl (e.g., CH2-pyridine, CH2-thiazole); or R1 and R2 together form a 3- to 5-membered spiro carbocyclic or heterocyclic ring (e.g., cyclopropane, cyclobutene, cyclopentane, oxetane, furan, pyrrolidine, piperidine) which may be optionally substituted; R3 is selected from the group consisting of: hydrogen, C1-2 alkyl (e.g., Me, Et), OMe and halogen (e.g., F, Cl, Br); R4 is selected from the group consisting of: hydrogen, C1-5 alkyl (e.g., Me, Et), C3-7 cycloalkyl (e.g., c Pr, cHex), C1-5 haloalkyls (e.g., CHF2, CF3, CF2Me, CH2CHF2), C1-5 alkoxyls (e.g., OMe, OEt), C1-5 haloalkoxyls (e.g., OCHF2, OCF3, OCH2CHF2), alkylalkoxys (e.g., CH2OMe, (CH2)2OMe), C2-6 heterocycloalkyls (e.g., piperidine, piperazine), CN and halogens (e.g., F, Cl, Br); E is selected from the following group: N, CH, CR c (In the formula, R c This is selected from the group consisting of halogens (e.g., F, Cl, Br), hydroxyl, C1-3 alkylhydroxyl (e.g., CH2OH, (CH2)2OH), C1-3 alkylamino (e.g., CH2NH2, (CH2)2NH2), C1-3 haloalkyl (e.g., CH2F, CHF2, CF3, CH2CHF2), C2-6 alkylalkoxyl (e.g., CH2OMe, (CH2)2OMe), and CN); R5 and R6 are each independently selected from the group consisting of the following: hydrogen, C2-5 alkyl (e.g., Me, Et), C1-C5 aminoalkyl (e.g., NMe2, NMeEt), 4-8 membered aminoalkyl ring (e.g., piperidine, piperazine), C1-9 alkylalkoxy (e.g., (CH2)2OEt, CH2OMe), C1-9 alkylaminoalkyl (e.g., (CH2)2NMe2, CH2NHMe); or R5 and R6 are bonded together to form a ring Z, which may optionally be substituted and optionally crosslinked, where ring Z is a C3-10 heterocycloalkyl monocycle or dicycle (e.g., c Pr, oxetane, c Hex, piperidine, piperazine, 1,4-diazacycloheptane) are; E, R5, and R6 together form J, where J is selected from the group consisting of the following: NR d , C(=O)R d SO2R d , OR d Here, R d(e.g., piperidine, piperazine) The present invention provides compounds thereof, or pharmaceutically acceptable salts, solvates, stereoisomers or mixtures of stereoisomers, tautomers, isotopic forms or pharmaceutically active metabolites thereof, or combinations thereof.

[0014] In this embodiment, ring Z is given by general formula Ia; [ka] [In the formula, R7 is selected from the group consisting of the following: hydrogen, C1-3 alkyl (e.g., Me, Et), and C1-3 haloalkyl (e.g., CH2CHF, CH2CHF2)] It is a 4- to 8-membered aminoalkyl ring having the following properties, which may optionally be substituted or crosslinked.

[0015] In this embodiment, ring Z is as follows: [ka] [In the formula, R8, R9, R10, R11, R13, and R21 are each independently selected from the group consisting of the following: hydrogen, C1-3 alkyl (e.g., Me, Et), C1-3 alkylalkoxy (e.g., CH2OMe), C1-3 alkylhydroxyl (e.g., CH2OH), amino, C1-3 alkylamino (e.g., CH2NH2), C1-6 alkylaminoalkyl (e.g., CH2NMe2), C1-3 haloalkyl (e.g., CHF2, CF3, CH2CHF2), and alkyl heteroaryl (e.g., CH2-pyridine, CH2-thiazole); R12 is selected from the group consisting of the following: hydrogen, C1-3 alkyl (e.g., Me, Et), and C1-3 haloalkyl (e.g., CH2CHF, CH2CHF2); or Any one of R8, R9, R10, R11, R12, R13, and R21 may bond to another different R8, R9, R10, R11, R12, R13, or R21 to form a 3- to 7-membered spiro or bicyclic carbocyclic or heterocyclic ring structure and / or a 3- to 6-membered bridging carbocyclic or heterocyclic ring structure; n is selected from the group consisting of 0, 1, and 2, and preferably n is 1 or 2. It belongs to them.

[0016] In this embodiment, when n=0, E is N, CH and CR c A group consisting of R is selected, where R c The element is selected from the group consisting of halogens (e.g., F, Cl, Br), hydroxy, C1-3 alkylhydroxy (e.g., CH2OH), C1-3 haloalkyl (e.g., CHF2, CF3, CH2CHF2), C2-5 alkylalkoxy (e.g., CH2OMe), and C2-5 alkylnitrile (e.g., CH2CN).

[0017] In this embodiment, ring Z has the following structure: [ka] That is the case.

[0018] In this embodiment, G is CR1R2, and ring Z has the following structure: [ka] It is, A is selected from the group consisting of the following: CH, CF, C-Cl, and C-Br; B and D are each independently selected from the following groups: N and CH; E is selected from the group consisting of the following: N, CF, and CH; R1 is selected from the group consisting of the following: hydrogen, Et, OMe, OEt, 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 6-membered spirocarbon or heterocyclic ring; R3 is either hydrogen or a halogen; R4 is selected from the group consisting of the following: hydrogen, Me, Et, CF2H, CF3, CF2Me, OMe, OEt, OCF2H, OCF3, CN, Cl, and F; R8 and R9 are each independently selected from the group consisting of: hydrogen, Me, Et, CH2OH, CHMeOH, CMe2OH, CH2OMe, CH2F, and halogens; R10 and R11 are each independently selected from the group consisting of: hydrogen, Me, Et, CH2OH, CHMeOH, CMe2OH, CH2OMe, CH2F, CHF2, CH2CF3, and CH2-heteroaryl; R12 is selected from the group consisting of the following: hydrogen and Me; R13 is selected from the group consisting of the following: hydrogen and Me; R21 is selected from the group consisting of the following: hydrogen and Me; is; or Any one of R8, R9, R10, R11, R12, R13, and R21 combines with another different R8, R9, R10, R11, R21, R13, or R21 to form a 3- to 7-membered spirodicyclic carbocyclic or heterocyclic ring structure and / or a 3- to 6-membered bridging carbocyclic or heterocyclic ring structure.

[0019] In this embodiment, a) One of R8 and R9 combines with one of R10 and R11 to form a [6,3]-, [6,4]-, [6,5]-, [6,7]-, or [6,8]-bicyclic structure; b) One of R8 and R9 bonds with R13 to form a [6,5,5]-, [6,6,6]-, [6,7,7]-, or [6,8,8]-bridged structure; c) One of R10 and R11 bonds with R13 to form a [6,6,4]-, [6,7,5]-, or [6,8,6]-bridged structure; d) One of R10 and R11 may bond with R21 to form a [6,5,5]-, [6,6,6]-, [6,7,7]-, [6,8,8]-bridged structure; e) One of R8 and R9 may bond with R21 to form a [6,6,4]-, [6,7,5]-, [6,8,6]-bridged structure; f) R8 may bind with R9 to form a [6,3]-, [6,4-], [6,5]-, [6,6]- or [6,7]-spirostructure; or g) R10 binds to R11 to form a [6,3]-, [6,4-], [6,5]-, [6,6]- or [6,7]-spiro structure.

[0020] In this embodiment, ring Z is selected from the group consisting of the following: [ka] [ka] [ka] [ka] .

[0021] In this embodiment, ring Z is selected from the group consisting of the following: [ka] .

[0022] In another embodiment of formula I, G is CR1R2, and ring Z is as follows: [ka] It is, A is selected from the group consisting of the following: CH, CF, C-Cl, and C-Br; B and D are each independently selected from the following groups: N and CH; E is selected from the group consisting of the following: N, CH, and CF; R1 is selected from the group consisting of the following: hydrogen, Me, Et, OMe, OEt, 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 6-membered spirocarbocyclic or heterocyclic ring; in particular, they form a 4- to 5-membered carbocyclic or heterocyclic spiroring; R3 is either hydrogen or F; R4 is selected from the group consisting of the following: Me, Et, CF2H, CF3, CF2Me, OMe, OEt, OCF2H, CN, Cl, and F; R14, R15, R17, R18, R19, and R20 are each independently selected from the group consisting of: hydrogen, Me, and F; and R16 is selected from the group consisting of the following: hydrogen and Me.

[0023] In this embodiment, a) Each of R14, R15, R16, R17, R18, R19, and R20 is hydrogen; b) If one of R14, R15, R17, R18, and R20 is Me, then R16 and R19 are hydrogen; c) If R18 is F, then R14, R15, R16, R17, R19 and R20 are hydrogen; d) If R18 is F and R19 is Me, then R14, R15, R16, R17 and R19 are hydrogen; e) R18 and R19 are both F, and R14, R15, R17 and R20 are hydrogen; or f) If E is CH, then R14 or R20 is F.

[0024] In this embodiment, ring Z is selected from the group consisting of the following: [ka] .

[0025] In this embodiment, if G is NH, then B is N.

[0026] In a second aspect, the present invention provides compounds according to Table 1 herein, or pharmaceutically acceptable salts, solvates, stereoisomers or mixtures of stereoisomers thereof, tautomers, isotopic forms or pharmaceutically active metabolites or combinations thereof.

[0027] In a third aspect, the present invention provides a pharmaceutical composition comprising one or more compounds of the first or second aspect of the present invention, or a pharmaceutically acceptable salt, solvate, stereoisomer or mixture of stereoisomers thereof, tautomer, isotopic form or pharmaceutically active metabolite or combination thereof, and one or more pharmaceutically acceptable carriers.

[0028] In a fourth aspect, the present invention provides compounds of the first or second aspect or pharmaceutical compositions of the third aspect for use in the treatment of disorders or diseases selected from autoimmune diseases and / or inflammatory diseases and / or neoplastic diseases and / or cancer and / or HIV infection and replication.

[0029] In this embodiment, the disorder or disease is selected from the group consisting of the following: rheumatoid arthritis, multiple sclerosis, psoriasis, and atopic dermatitis.

[0030] In this embodiment, the compound is an inhibitor of PKC-θ.

[0031] In this embodiment, use includes administering the compound orally, topically, by inhalation or intranasal administration; or systemically by intravenous injection, intraperitoneal injection, subcutaneous injection or intramuscular injection.

[0032] In this embodiment, use includes administering one or more compounds relating to the first or second aspect in combination with one or more additional therapeutic agents, if desired. Preferably, administration includes administering one or more compounds relating to either the first or second embodiment, together with one or more additional therapeutic agents, simultaneously, sequentially, or separately.

[0033] In this embodiment, use involves administering an effective amount of the compound according to the first or second embodiment to a subject, the effective amount being about 5 nM to about 10 μM in the subject's blood or its components.

[0034] In a fifth aspect, the present invention provides a method for treating a disorder or disease selected from autoimmune diseases and / or inflammatory diseases and / or neoplastic diseases and / or cancer and / or HIV infection and replication, using a compound from the first or second aspect or a pharmaceutical composition from the third aspect.

[0035] In this embodiment, the disorder or disease is selected from the group consisting of the following: rheumatoid arthritis, multiple sclerosis, psoriasis, and atopic dermatitis.

[0036] In this embodiment, the compound is an inhibitor of PKC-θ.

[0037] 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

[0038] 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.

[0039] 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.

[0040] 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.

[0041] 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).

[0042] 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.

[0043] Before giving a detailed description of the present invention, we provide several definitions to aid in understanding this disclosure.

[0044] 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.

[0045] 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.

[0046] 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).

[0047] 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).

[0048] 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.

[0049] 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.

[0050] 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.

[0051] 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.

[0052] 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.

[0053] 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.

[0054] 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.

[0055] 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.

[0056] "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-.

[0057] The terms "alkynyl" and "lower alkynyl" are defined similarly to the term "alkenyl," except that they contain at least one carbon-carbon triple bond.

[0058] 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.

[0059] 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.

[0060] 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.

[0061] 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.

[0062] 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”.

[0063] Molecules and compounds This disclosure is based on structural formula I: [ka] [In the formula, A is selected from the following groups: N, CR a (In the formula, R a (Selected from hydrogen, halogens, C1-3 alkyl, and CN); B is selected from the group consisting of the following: N, CH, CF, and C-(C1-3 alkyl); D is selected from the following group: N, CH, CR b (In the formula, R b (Selected from halogens, C1-3 alkyls, and C1-3 haloalkyls); G is selected from the group consisting of the following: CR1R2, NR1, and O; 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 CH2NH(Me)2), C1-3 haloalkyl, aryl (e.g., phenyl), heteroaryl (e.g., pyridine), alkylaryl (e.g., benzyl), and alkylheteroaryl; or R1 and R2 together form a 3- to 5-membered spiro-carbocyclic or heterocyclic ring, which may be optionally substituted; in particular, a 4- to 5-membered carbocyclic or heterocyclic spiro-ring, which may be optionally substituted; here, in an embodiment, the carbocyclic or heterocyclic spiro-ring is unsubstituted; here, in another embodiment, 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, hydroxy, and C1-2 alkoxy; R3 is selected from the group consisting of hydrogen, C1-2 alkyl, -OMe, and halogens; R4 is selected from the group consisting of the following: hydrogen, C1-5 alkyl (e.g., Me, Et), C3-7 cycloalkyl (e.g., c Pr, c Hex), C1-5 haloalkyls (e.g., CHF2, CF3, CF2Me, CH2CHF2), C1-5 alkoxyls (e.g., OMe, OEt), C1-5 haloalkoxyls (e.g., OCHF2, OCF3, OCH2CHF2), alkylalkoxys (e.g., CH2OMe, (CH2)2OMe), C2-6 heterocycloalkyls (e.g., piperidine, piperazine), CN and halogens (e.g., F, Cl, Br); E is selected from the following group: N, CH, CR c (In the formula, R c This is selected from the group consisting of halogens (e.g., F, Cl, Br), hydroxyl, C1-3 alkylhydroxyl (e.g., CH2OH, (CH2)2OH), C1-3 alkylamino (e.g., CH2NH2, (CH2)2NH2), C1-3 haloalkyl (e.g., CH2F, CHF2, CF3, CH2CHF2), C2-6 alkylalkoxyl (e.g., CH2OMe, (CH2)2OMe), and CN); R5 and R6 are each independently selected from the group consisting of the following: hydrogen, C2-5 alkyl, C1-C5 aminoalkyl (e.g., -(CH2)2NH2), 4- to 8-membered aminoalkyl ring (e.g., piperidine, preferably 4-piperidine), C1-9 alkylalkoxy (e.g., -CH2OMe), C1-9 alkylaminoalkyl (e.g., -(CH2)2NHMe or -(CH2)2N(Me)2); or R5 and R6 together form a C3-10 heterocycloalkyl monocycle or dicycle (defined herein as ring Z), which may be optionally substituted and optionally crosslinked; or E, R5 and R6 together form J, where J is NR d , C(=O)R d SO2R d , OR d (In the formula, R d [Selected from the group consisting of 4-8 membered aminoalkyl rings] Compounds having [the specified characteristic], or pharmaceutically acceptable salts, solvates, stereoisomers or mixtures of stereoisomers thereof, tautomers, isotopic forms or pharmaceutically active metabolites, or combinations thereof.

[0064] In certain embodiments, R5 and R6 are bonded together to form a 4- to 8-membered, preferably 5- to 7-membered aminoalkyl ring (referred to as ring Z above), which may optionally be substituted and optionally crosslinked, and the general formula is Ia; [ka] [In the formula, R7 is selected from the group consisting of hydrogen, C1-3 alkyl (e.g., Me), and C1-3 haloalkyl (e.g., CH2CHF, CH2CHF2). It has.

[0065] In a particular embodiment of formula I, formula Ia may optionally be substituted and optionally crosslinked, i.e., general formula II: [ka] [In the formula, A, B, D, E, G and R3 and R4 are as shown in formula I; R8, R9, R10, R11, R13, and R21 were each independently selected from the following group: Hydrogen, C1-3 alkyl, C1-3 alkylalkoxy (e.g., CH2OMe), C1-3 alkylhydroxyl (e.g., CH2OH, CHMeOH, CMe2OH), amino, C1-3 alkylamino (e.g., CH2NH2, CHMeNH2, CMe2NH2), C1-6 alkylaminoalkyl (e.g., CH2NHMe or CH2NH(Me)2), C1-3 haloalkyl (e.g., CH2F), alkyl heteroaryl (e.g., CH2-pyridyl, preferably CH2-3-pyridyl, or CH2-thiazole); R12 is selected from the group consisting of the following: hydrogen, C1-3 alkyl and C1-3 haloalkyl; or Any one of R8, R9, R10, R11, R12, R13, and R21 may bond to another different R8, R9, R10, R11, R12, R13, or R21 to form a 3- to 7-membered spiro or bicyclic carbocyclic or heterocyclic ring structure and / or a 3- to 6-membered bridging carbocyclic or heterocyclic ring structure; n is selected from the group consisting of 0, 1, and 2, and preferably n is 1 or 2. That is the case.

[0066] In this embodiment, when n=0, E is preferably selected from the group consisting of: N, CH, CR d (In the formula, R d (These are selected from halogens, alkoxys, C1-3 alkylhydroxys (e.g., CH2OH), C1-3 haloalkyls (e.g., CH2F), C2-5 alkylalkoxys (e.g., CH2OMe), and C2-5 alkylnitriles (e.g., CH2CN).

[0067] In a particular embodiment of formula I or II, the ring defined above as ring Z is as follows: [ka] It may also be the case that, in the formula, R in this context is as follows: [ka] This relates to the remaining structural parts of formula I or II, such as those shown.

[0068] In a particular embodiment of Equation II, G is CR1R2 and n is 1, i.e., Equation IIa: [ka] [In the formula, A is selected from the group consisting of the following: CH, CF, C-Cl, and C-Br; B and D are each independently selected from the following groups: N and CH; E is selected from the group consisting of the following: N, CF, and CH; R1 is selected from the group consisting of the following: hydrogen, Me, Et, OMe, OEt, OH, NH2, NHMe; R2 is selected from the group consisting of the following: hydrogen, Me, Et; preferably Me; or R1 and R2 together form a 3- to 6-membered spirocarbocyclic or heterocyclic ring, and in particular, a 4- to 5-membered carbocyclic or heterocyclic spiroring; R3 is either hydrogen or a halogen; R4 is selected from the group consisting of the following: hydrogen, Me, Et, CF2H, CF3, CF2Me, OMe, OEt, OCF2H, OCF3, CN, Cl and F; and R8 and R9 are each independently selected from the group consisting of: hydrogen, Me, Et, CH2OH, CHMeOH, CMe2OH, CH2OMe, CH2F, and halogens (for example, if E is CH, then F); R10 and R11 are each independently selected from the following group: H, Me, Et, CH2OH, CHMeOH, CMe2OH, CH2OMe, CH2F, CHF2, CH2-heteroaryl (e.g., pyridyl and thiazole), and CH2CF3; R12 is selected from the group consisting of the following: hydrogen and Me; R13 is selected from the group consisting of the following: hydrogen and Me; R21 is selected from the group consisting of the following: hydrogen and methyl; or One of R8, R9, R10, R11, R12, R13, and R21 is bonded to another different R8, R9, R10, R11, R21, R13, or R21 to form a 3- to 7-membered spiro or bicyclic carbocyclic or heterocyclic ring structure and / or a 3- to 6-membered bridging carbocyclic or heterocyclic ring structure. It is a compound of [the compound].

[0069] In a particular embodiment of formula I or II, the ring defined above as ring Z is: [ka] [ka] The group may be selected from the following, where R in this context is: [ka] This is the remaining structural part of equation II (or equation IIa; when G is CR1R2).

[0070] In further specific embodiments of formula II or IIa, one of R8-R13 or R21 may bond with another different R8-R13 or R21 to form a 3-7 membered carbocyclic or heterocyclic ring and / or a 3-6 membered bridging carbocyclic or heterocyclic ring structure. In embodiments, one of R8 and R9 may bond with one of R10 and R11 to form a [6,3]-, [6,4]-, [6,5]-, [6,7]-, [6,8]- bicyclic structure. In other embodiments, one of R8 and R9 may bond with R13 to form a [6,5,5]-, [6,6,6]-, [6,7,7]-, [6,8,8]- bridging structure. In another embodiment, one of R10 and R11 may bond to R13 to form a [6,6,4]-, [6,7,5]-, [6,8,6]- crosslinking structure. In another embodiment, one of R10 and R11 may bond to R21 to form a [6,5,5]-, [6,6,6]-, [6,7,7]-, [6,8,8]- crosslinking structure. In another embodiment, one of R8 and R9 may bond to R21 to form a [6,6,4]-, [6,7,5]-, [6,8,6]- crosslinking structure. In other embodiments, R8 and R9 may be bonded to form a [6,3]-, [6,4]-, [6,5]-, [6,6]-, [6,7]- spiro structure, or R10 and R11 may be bonded to form a [6,3]-, [6,4]-, [6,5]-, [6,6]-, [6,7]- spiro structure.

[0071] Suitable biring, cross-linked, or spiro structures are as follows: [ka] The group may be selected from the following, where R in this context is: [ka] This is part of formula II (or formula IIa; when G is CR1R2) as defined above.

[0072] In a particular embodiment of Equation II, G is CR1R2 and n is 2, i.e., Equation IIb: [ka] [In the formula, A is selected from the group consisting of the following: CH, CF, C-Cl, and C-Br; B and D are each independently selected from the following groups: N and CH; E is selected from the group consisting of the following: N, CH, and CF; R1 is selected from the group consisting of the following: hydrogen, Me, Et, OMe, OEt, OH, NH2, NHMe; R2 is selected from the group consisting of the following: hydrogen, Me, Et; preferably Me; or R1 and R2 together form a 3- to 6-membered spirocarbocyclic or heterocyclic ring; in particular, a 4- to 5-membered carbocyclic or heterocyclic spiroring; R3 is selected from the group consisting of the following: hydrogen or halogen (e.g., F); R4 is selected from the group consisting of the following: Me, Et, CF2H, CF3, CF2Me, OMe, OEt, CN, OCF2H, OCF3, Cl, F; R14, R15, R17, R18, R19, and R20 are each independently selected from the group consisting of: hydrogen, methyl, and fluoro; R16 is selected from the group consisting of the following: hydrogen and Me] It is a compound having the following structure.

[0073] In a particular embodiment of formula IIb, R14, R15, R16, R17, R18, R19, and R20 are each H. In another particular embodiment of formula IIb, R14, R15, R17, R18, R19, and R20 are each independently selected from the group consisting of: hydrogen and methyl (when E is N). In another particular embodiment of formula IIb, if one of R14, R15, R17, R18, and R20 is Me, then R16 and R19 are hydrogen. In a further specific embodiment of formula IIb, if R18 is F, then R14, R15, R16, R17, R19, and R20 are H. In another specific embodiment of formula IIb, if R18 is F and R19 is Me, then R14, R15, R16, R17, and R19 are hydrogen. In another specific embodiment of formula IIb, R18 and R19 are both fluoro, and R14, R15, R17, and R20 are hydrogen. In another specific embodiment of formula IIb, if E is CH, then R14 or R20 is fluoro.

[0074] In a particular embodiment of formula IIb, the ring defined herein prior to ring Z is as follows: [ka] The group may be selected from the following, wherein the formula, R is as follows: [ka] It is part of formula II (or formula IIb; when G is R1R2) as defined in [reference].

[0075] In another specific embodiment of formulas I, II, and / or III, if G is NH, then B is N.

[0076] In a particular embodiment of formula I, G is CR1R2, and E, R5 and R6 together form J, which is selected from the group consisting of the following: NR d , C(=O)R d SO2Rd , OR d (In the formula, R d This is a 4-8 membered aminoalkyl ring, for example, formula III: [ka] (In the formula, R1, R2, R3 and R4 are as per formula I, II, IIa or IIb; and K is selected from the group consisting of the following: N and CH; If K is N, then J is selected from the following group: CH2, CHMe, CMe2, CO and SO2; or If K is CH, J is selected from the following group: O and NR e ; Here R e This is selected from the group consisting of hydrogen, Me, Et, propyl, CH2CF3, CH2CH2F, CH2CH2OMe, and CH2-oxetane; R22, R23, R24, R25, and R26 are each independently selected from the group consisting of: hydrogen, fluorocarbon, and mesopropyl alcohol. It is a compound having the following structure.

[0077] In a particular embodiment, R22, R23, R24, R25, and R26 are each independently selected from the group consisting of the following: hydrogen, Me, and fluoro(J is CH and E is NR). e (Only if) or R22, R23, R24, R25, and R26 are each independently selected from the group consisting of the following: hydrogen and Me.

[0078] 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 Table 57 Table 58 Table 59 Table 60 [Table 61] [Table 62] [Table 63] [Table 64] [Table 65] [Table 66] [Table 67] [Table 68] [Table 69] [Table 70]

[0079] In another aspect, the present invention provides a pharmaceutical composition comprising a compound.

[0080] PKC-θ activity of compounds, prodrugs and metabolites PKC-θ is selectively expressed in T lymphocytes and plays an important role in the activation of mature T cells initiated by the T cell antigen receptor (TCR), subsequent cytokine release such as IL-2, and T cell proliferation (Isakov and Altman, Annu.Rev. Immunol., 2002, 20, 761-94). Thus, a decrease in IL-2 levels represents a desirable response that can treat the diseases and disorders described herein, such as autoimmune and neoplastic diseases.

[0081] Due to its involvement in T cell activation, selective inhibition of PKC-θ can reduce harmful inflammation mediated by Th17 (mediating autoimmune diseases) or Th2 (causing allergies) without reducing the ability of T cells to eliminate virus-infected cells (Madouri et al, Journal of Allergy and Clinical Immunology. 139 (5):2007, pp 1650-1666). The inhibitor may be useful for adaptive immune responses mediated by T cells. Inhibition of PKC-θ downregulates transcription factors (NF-κB, NF-AT) and reduces the production of IL-2. Animals lacking PKC-θ have been observed to be resistant to some autoimmune diseases (Zanin-Zhorov et al., Trends in Immunology. 2011, 32(8):358-363). Thus, PKC-θ is an interesting target as a potential for cancer and autoimmune therapy.

[0082] 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.

[0083] 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).

[0084] The active substance or compound of the present invention may be provided as a prodrug of the compound of the present disclosure.

[0085] 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.

[0086] 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.

[0087] 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.

[0088] 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.

[0089] 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.

[0090] 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.

[0091] 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.

[0092] 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.

[0093] “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.

[0094] 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 therapeutic compound 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.

[0095] 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.

[0096] 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.

[0097] 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).

[0098] 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.

[0099] 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.

[0100] 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).

[0101] To help therapeutic agents dissolve in an aqueous environment, surfactants may be added as wetting agents. Examples of surfactants include anionic detergents such as sodium lauryl sulfate, sodium dioctyl sulfosuccinate, and sodium dioctyl sulfonate. Cationic detergents may also be used, including benzalkonium chloride and benzethonium chloride. Nonionic detergents that may be included in formulations as surfactants include lauromacrogol 400, polyoxyl stearate 40, 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 these surfactants are used, they may be present in the compound or derivative formulation alone or in mixtures of different proportions.

[0102] Generally, intravenous administration compositions contain a sterile isotonic aqueous buffer. If necessary, the composition may also contain a solubilizer.

[0103] Another preferred route of administration of the therapeutic compositions disclosed herein is transpulmonary or transnasal delivery.

[0104] 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.

[0105] The therapeutic agents disclosed herein may be formulated into compositions for topical administration to the skin of a target.

[0106] When the present invention provides one or more active compounds / agents for use in combination, the agents can generally be formulated separately or in single dosage forms, depending on the most appropriate dosage regimen for each agent involved. When the therapeutic agents are formulated separately, the pharmaceutical compositions of the present invention can be used in therapeutic regimens including co-administration, individual administration, or sequential administration with one or more other therapeutic agents. The other therapeutic agents may include the compounds of the present disclosure or therapeutic agents known in the art.

[0107] The compounds and / or pharmaceutical compositions of this disclosure may be formulated and suitable for administration to the central nervous system (CNS) and / or cross the blood-brain barrier (BBB).

[0108] The present invention will be illustrated by the following non-limiting embodiments. [Examples]

[0109] material and method Sample preparation: The powder was dissolved in DMSO-d6, vortexed thoroughly until the solution became clear, and then transferred to NMR for data acquisition.

[0110] NMR spectroscopy: Liquid-phase NMR experiments use triple resonance 1 H, 15 N, 13 Using a C CP-TCI 5mm cryoprobe (Bruker Biospin, Germany), a 600MHz (14.1 Tesla) Bruker Avance III NMR spectrometer was used. 1 For H, 600MHz, 13 The value of C was recorded at 151MHz.

[0111] Liquid-phase NMR experiments were performed using a Dual Resonance BBI 5 mm probe (Bruker Biospin, Germany) and 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.

[0112] 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.

[0113] 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).

[0114] 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.

[0115] 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.

[0116] 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.

[0117] Chiral purification: Method A: Equipment: Waters Prep SFC80; Stationary phase: Chiralcel OJ-H 5μm, 250 x 21mm Mobile phase: CO2 / (EtOH + 0.5% IPAm) 80 / 20 Flow rate: 50 mL / min UV detection: λ = 210 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 = 210 nm Temperature: 40℃ - Pressure: 100 bars

[0118] Abbreviation In addition to the definitions above, the following abbreviations are used in the above synthesis scheme and the following examples. If an abbreviation is not defined herein, it has its generally accepted meaning: [Table 71] TIFF0007871296000099.tif139153

[0119] Example 1 - Chemical Synthesis Route Scaffold Synthesis of dimethyl scaffolds Synthesis of 4-bromo-3,3-dimethyl-1H-pyrrolo[2,3-b]pyridine-2-one [ka] 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 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) via a dropping funnel 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]+.

[0120] 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]+.

[0121] 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 Dicalite 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]+.

[0122] 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).

[0123] 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]+.

[0124] Synthesis of 4-bromo-3-ethyl-3-methyl-1H-pyrrolo[2,3-b]pyridine-2-one (MeEt) [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 via 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, yield 56%) 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]+.

[0125] 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

[0126] 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.

[0127] The following steps are the same for racemic mixtures and pure enantiomers. The boronic acid ester synthesis describes the racemic mixture.

[0128] Synthesis of 4-bromo-3-ethyl-3-methyl-1-tetrahydropyran-2-ylpyrrolo[2,3-b]pyridine-2-one [ka] A 50 mL vial contained a solution of 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). 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 substance as an orange solid. The crude substance 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]+.

[0129] 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.) / anhydrous dioxane (43 mL, 0.1 N) were added. 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 Dicalite pad. The Dicalite 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 Dicalite. 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]+.

[0130] Me / OH scaffold synthesis Synthesis of 4-bromo-3-hydroxy-3-methyl-1H-pyrrolo[2,3-b]pyridine-2-one (OHMe) [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 overnight at room temperature. 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. 1H 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]+.

[0131] 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

[0132] 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.

[0133] The following steps are identical for racemic mixtures and pure enantiomers. Boronic acid ester synthesis is described starting with OHMe isomer 1.

[0134] 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, yield 36%). 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]+.

[0135] 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 substance as a dark 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]+.

[0136] 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]+.

[0137] 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] In a Reacti vial, under a nitrogen atmosphere, 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. 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 via 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).

[0138] 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), pyridinium perbromide (11.05 g, 34.5 mmol) was added in small increments. 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)

[0139] 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]+.

[0140] Synthesis of 4-chloro-3-ethyl-3-hydroxy-1H-pyrrolo[2,3-b]pyridine-2-one [ka] A 10N aqueous sodium hydroxide 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) in ethanol (49 mL, 0.2 N). The mixture was stirred overnight at room temperature. The mixture was concentrated under vacuum, and a mixed 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]+.

[0141] 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.

[0142] 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.

[0143] The following protocol describes racemic mixtures.

[0144] Synthesis of 4-bromo-3-ethyl-3-hydroxy-1-tetrahydropyran-2-ylpyrrolo[2,3-b]pyridine-2-one [ka] 3,4-dihydro-2H-pyran (0.59 mL, 6.50 mmol) was added to a stirred solution of 4-bromo-3-ethyl-3-hydroxy-1H-pyrrolo[2,3-b]pyridine-2-one (0.56 g, 2.17 mmol) and p-toluenesulfonic acid (82 mg, 0.433 mmol) / anhydrous toluene (11 mL, 0.2 N) in a sealed vial. The reaction mixture was stirred overnight at 90°C. The mixture was then cooled to 0°C and 4M hydrogen chloride (1.1 mL, 4.33 mmol) was added. The mixture was stirred at room temperature for 3 hours. The solution was concentrated under vacuum. Aqueous solutions of DCM and NaHCO3 were added. The compounds were redissolved in free base form, and the aqueous phase was extracted with DCM. The organic phase was dried on a phase separator and concentrated under vacuum. The crude substance was purified by flash chromatography on silica gel using a heptane / AcOEt gradient. It was eluted through a 24g column of Dicalite solid phase. The fraction was recovered and evaporated to obtain 4-bromo-3-ethyl-3-hydroxy-1-tetrahydropyran-2-yl-pyrrolo[2,3-b]pyridine-2-one (200 mg, 26% yield) as an orange oil. m / z = 341.0, 343.0 [M+H]+.

[0145] Synthesis of 3-ethyl-3-hydroxy-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, bis(pinacolato)diborone (223 mg, 0.879 mmol, 4 eq.), 4-bromo-3-ethyl-3-hydroxy-1-tetrahydropyran-2-ylpyrrolo[2,3-b]pyridine-2-one (200 mg, 0.586 mmol), and anhydrous dioxane (1.9 mL, 0.3 N) were added. Then, potassium acetate (182 mg, 1.76 mmol, 4 eq.) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (49 mg, 0.0586 mmol, 0.1 eq.) were added. The reaction mixture was stirred at 100°C for 3 hours. The mixture was filtered through a Dicalite pad and the solvent was evaporated. The crude substance was purified by flash chromatography on silica gel using a DCM / ethyl acetate gradient. It was eluted via the solid phase. The relevant fractions were collected and concentrated under vacuum to obtain 3-ethyl-3-hydroxy-1-tetrahydropyran-2-yl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine-2-one (97 mg, 42.62% yield) as a yellow gum-like substance. m / z = 307.1 [M+H]+ (acid form).

[0146] 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%). 1 H 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]+.

[0147] 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 Dicalite. 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. 1 H 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]+.

[0148] 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(pinacolato)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 Dicalite 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).

[0149] 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. 1H 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]+.

[0150] Synthesis of 7-bromo-3H-oxazolo[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 dried under vacuum 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).

[0151] Synthesis of 4,5-dibromo-3,3-dimethyl-1H-pyrrolo[2,3-b]pyridine-2-one [ka] In a 25 mL round-bottom flask at room temperature, N-bromosuccinimide (236 mg, 1.33 mmol, 1.6 eq.) was added to a stirred suspension of 4-bromo-3,3-dimethyl-1H-pyrrolo[2,3-b]pyridine-2-one (200 mg, 0.830 mmol) and sodium acetate (34 mg, 0.415 mmol, 0.5 eq.) / acetic acid (1 mL, 0.8 N). The reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with water and quenched with a 1 M aqueous solution of Na2S2O3. The resulting solid was filtered through glass frit to obtain 4,5-dibromo-3,3-dimethyl-1H-pyrrolo[2,3-b]pyridine-2-one (223.1 mg, 82% yield) 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), 8.35 (s, 1H), 1.40 (s, 6H).

[0152] 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 using a phase separator and evaporated to obtain the crude product as an oil. The crude product was purified by flash chromatography on silica gel using a heptane / EtOAC gradient. It was eluted through the solid phase on silica. 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%). 1 H 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]+.

[0153] 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 by 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). 1 H 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]+.

[0154] 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] A vial was charged with bis(pinacolato)diboron (258 mg, 1.02 mmol, 1.5 eq.), potassium acetate (210 mg, 2.03 mmol, 3 eq.), 4'-bromo-1'-tetrahydropyran-2-yl-spiro[cyclopentane-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.) in anhydrous dioxane (2.2 mL, 0.3 N). The vial was sealed and degassed with nitrogen. The reaction mixture was stirred at 100 °C overnight. The reaction mixture was filtered through a pad of celite, and the filtrate was evaporated to dryness to afford the crude material as a dark oil. This crude material was purified by flash chromatography on silica gel using a gradient of dichloromethane / ethyl acetate. It was eluted through a solid phase of Dicalite. The relevant fractions were collected and concentrated under vacuum to give 1'-tetrahydropyran-2-yl-4'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[cyclopentane-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); m / z = 399.4 [M+H]+.

[0155] Synthesis of 3,3-dibromo-4-chloro-2-oxo-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile

Chemical Structure

[0156] Synthesis of 4-chloro-2-oxo-1,3-dihydropyrrolo[2,3-b]pyridine-5-carbonitrile [ka] 3,3-dibromo-4-chloro-2-oxo-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile (1.90 g, 3.84 mmol) was placed in a flask, to which methanol (18 mL) and acetic acid (18 mL) were added. Zinc (628 mg, 9.60 mmol, 2.5 eq.) was added in small amounts over 3 minutes. The suspension was stirred at room temperature for 1.5 hours. The solution was diluted with toluene and slowly neutralized with saturated aqueous NaHCO3 solution. The aqueous layer was separated, and the organic layer was washed with water and brine and dried on anhydrous MgSO4. After filtration, the organic layer was concentrated until dry to obtain a yellow solid. This solid was made into an aqueous suspension and filtered through a Buchner funnel. The obtained solid was triturated with cold ether and heptane, and then dried in an oven for 1 hour. The final product was obtained as a flesh-colored solid (494 mg, 53%). 1H NMR (400 MHz, DMSO-d6) δ 11.81 (br. s, 1H), 8.65 (s, 1H), 3.70 (s, 2H);m / z = 192.1, 194.1 [MH]-

[0157] Synthesis of 4-chloro-3,3-dimethyl-2-oxo-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile [ka] 4-chloro-2-oxo-1,3-dihydropyrrololo[2,3-b]pyridine-5-carbonitrile (494 mg, 2.04 mmol) was placed in a flask, and anhydrous THF (7 mL, 0.3 N) was added under a nitrogen atmosphere. The suspension was cooled to -78°C and stirred for 5 minutes. 1 M lithium [bis(trimethylsilyl)amide] solution (7.7 mL, 7.66 mmol, 3.75 eq.) / THF was slowly added over 3 minutes, and the resulting solution was stirred for 10 minutes. Iodomethane (0.31 mL, 4.90 mmol, 2.4 eq.) was added dropwise, and the solution was stirred at -78°C for 30 minutes. The solution was warmed to room temperature and stirred for a further 3 hours. The solution was cooled to 0°C and quenched by dropwise addition of saturated ammonium chloride aqueous solution. The solution was diluted with ELISA and washed with water and brine. Subsequently, the organic matter was separated, dried (MgSO4), and concentrated to dryness. The crude material was purified by flash column chromatography using a TBME / heptane gradient. The target fraction was vacuum concentrated to dryness, and the target compound was obtained as a yellow solid (195 mg, 43%). ¹H NMR (500 MHz, CDCl3) δ 8.71 (s, ¹H), 8.44 (s, ¹H), 1.58 (s, ⁶H); m / z = 222.0-224.0 [M+H]+

[0158] 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, 82% yield) 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]+

[0159] 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 triturated in 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]+

[0160] Synthesis of 4-chloro-5-fluoro-3,3-dimethyl-1-tetrahydropyran-2-ylpyrrolo[2,3-b]pyridine-2-one [ka] In a 20 mL vial, 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, and the reaction mixture was stirred overnight at 90°C. Then, 3,4-dihydro-2H-pyran (0.5 mL) was added, and the reaction was stirred overnight at 90°C. The solvent was evaporated, and the crude product was obtained as a brown oil. The crude product was purified by flash chromatography on silica gel using a heptane / ethyl acetate gradient. It was eluted via 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]+

[0161] 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-ylpyrrolo[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 Dicalite 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]+

[0162] Synthesis of 5-fluoro-3-methyl-1,3-dihydropyrrolo[2,3-b]pyridine-2-one hydrochloride [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.1 H 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]+

[0163] 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]+

[0164] 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]+.

[0165] 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 vials sealed 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 Dicalite. The solvent was partially evaporated under a nitrogen stream, and the solution was extracted with 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 RINKAN. 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)

[0166] Scaffold coupling - General method (pyridine) [ka] TIFF0007871296000139.tif54120

[0167] This scheme includes cross-linked piperidine structures and bicyclic piperidine structures, and includes diazacycloheptane instead of piperidine.

[0168] 1. Replacement Piperazine I' (1.08 mmol, 1 eq.), pyridine I (1.08 mmol, 1 eq.), sodium bicarbonate (1.08 mmol, 1 eq.), and anhydrous DMF (3 mL, 0.35 N) were placed in a microwave tube. The resulting mixture was heated overnight at 110°C. Water was added, and the mixture was extracted with toluene. The combined organic layers were washed with water and brine, dried on a phase separator, and concentrated under vacuum to obtain a brown solid. The crude product was purified by a cyclohexane / toluene gradient on a silica gel column held in solid phase. The relevant fractions were collected and concentrated under vacuum to obtain the desired product II.

[0169] Example 1: Synthesis of tert-butyl (3R)-4-(6-bromo-4-chloro-2-pyridyl)-3-methylpiperazine-1-carboxylate (R1=Cl, R2=, R4=, R5=H; R3=Me, X=Br) Beige solid; yield 48% 1 H NMR (400 MHz, DMSO-d6) δ 6.92 (d, J = 21.3 Hz, 2H), 4.44 (s, 1H), 3.88 (dd, J = 79.1, 12.8 Hz, 3H), 3.19 - 2.81 (m, 3H), 1.43 (s, 9H), 1.05 (d, J = 6.6 Hz, 3H);m / z=390.0, 392.0 [M+H]+

[0170] 2. Suzuki Coupling A reaction vial was filled with a mixed solution of substituted pyridine II (0.201 mmol, 1 eq.), boronic acid ester II' (0.201 mmol, 1 eq.), and disodium carbonate (0.604 mmol, 3 eq.) in a mixed solvent of DMF (1.6 mL) and water (0.4 mL). The reaction mixture was degassed, and tetrakistriphenylphosphine palladium (0.0201 mmol, 0.1 eq.) was added. The resulting mixture was stirred overnight at 95°C under a nitrogen atmosphere. Water was added to the mixture. The precipitate was filtered and dissolved in DCM. The organic phase was dried on a phase separator and evaporated to obtain the crude product. It was then purified using a heptane / siRNA gradient on a silica gel column. The relevant fractions were collected and concentrated under vacuum to obtain product III by Suzuki coupling.

[0171] Example 1: Synthesis of tert-butyl (3R)-4-[4-chloro-6-(3,3-dimethyl-2-oxo-1-tetrahydropyran-2-yl-pyrrolo[2,3-b]pyridine-4-yl)-2-pyridyl]-3-methylpiperazine-1-carboxylate (R1=Cl, R2=, R4=, R5=H; R3=Me, G=CMe2, X=Br) White foamy substance; yield 46%; 1 H NMR (400 MHz, DMSO-d6) δ 8.24 (d, J = 5.3 Hz, 1H), 7.02 (d, J = 5.3 Hz, 1H), 6.98 (s, 1H), 6.80 (s, 1H), 5.52 - 5.40 (m, 1H), 4.57 (s, 1H), 4.08 - 3.84 (m, 3H), 3.78 (d, J = 13.4 Hz, 1H), 3.63 - 3.49 (m, 1H), 3.19 - 3.00 (m, 2H), 3.00 - 2.83 (m, 2H), 1.97 (d, J = 22.9 Hz, 1H), 1.68 - 1.47 (m, 4H), 1.42 (s, 9H), 1.24 - 1.19 (m, 6H), 1.05 (d, J = 6.5 Hz, 3H);m / z = 556.2, 558.1 [M+H]+

[0172] 3. Deprotection To a solution of Suzuki coupling product III (0.093 mmol) in anhydrous methanol (0.46 mL, 0.2 N), 4 M hydrogen chloride (3.70 mmol, 40 eq.) was added. The resulting mixture was stirred overnight at 60°C under a nitrogen atmosphere. The mixture was concentrated under vacuum. The product was dissolved in water. This aqueous phase was then washed with DCM and evaporated to obtain the desired final product IV in salt form.

[0173] Example 1: Synthesis of 4-[4-chloro-6-[(2R)-2-methylpiperazin-1-yl]-2-pyridyl]-3,3-dimethyl-1H-pyrrolo[2,3-b]pyridine-2-one; dihydrochloride (R1=Cl, R2=, R4=, R5=H; R3=Me, G=CMe2) Green powder; yield 79%, 1H NMR (500 MHz, DMSO-d6) Shift 11.13 (s, 1H), 9.42 (br d, J=9.05 Hz, 1H), 8.98 (br d, J=9.05 Hz, 1H), 8.13 (d, J=5.72 Hz, 1H), 7.08 (s, 1H), 6.91 (d, J=5.70 Hz, 1H), 6.87 (s, 1H), 4.74-4.83 (m, 1H), 4.28 (br d, J=13.45 Hz, 1H), 3.12-3.32 (m, 4H), 2.92-3.02 (m, 1H), 1.25 (d, J=6.85 Hz, 3H), 1.19 (d, J=6.11 Hz, 6H);m / z = 372.1, 374.1

[0174] Scaffold Coupling - Specific Examples Pyridine I was obtained from a commercial source or synthesized by standard techniques according to the following methods.

[0175] Synthesis of 2,6-dichloro-4-(1,1-difluoroethyl)pyridine (specific pyridine 1) [ka] At room temperature, 1-(2,6-dichloro-4-pyridyl)ethanone (300 mg, 1.50 mmol) was added to a stirred solution of triethylamine (0.21 mL, 1.50 mmol, 1 eq.), N,N-diethylethaneamine trihydrofluoride (0.50 mL, 3.00 mmol, 2 eq.), and Xtal fluor (687 mg, 3.00 mmol, 2 eq.) / anhydrous DCE (4.5 mL, 0.3 N). The reaction mixture was stirred overnight at 60°C. The reaction was quenched with a saturated aqueous solution of NaHCO3. Dichloromethane was added to separate the two phases. The combined organic phases were dried using a phase separator and evaporated to obtain the crude product as a yellow 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 2,6-dichloro-4-(1,1-difluoroethyl)pyridine (124 mg, 38% yield) as a yellow oil. ¹H NMR (DMSO-d6, 400 MHz): δ (ppm) 7.81 (s, 2H), 2.01 (t, J=19.3 Hz, 3H); m / z = 212.1, 214.1.

[0176] Synthesis of tert-butyl 3-[6-chloro-4-(trifluoromethyl)-2-pyridyl]-3-(hydroxymethyl)pyrrolidine-1-carboxylate (2-step process) (specific pyridine 2) [ka] Step 1: Synthesis of O1-tert-butyl O3-ethyl 3-[6-chloro-4-(trifluoromethyl)-2-pyridyl]pyrrolidine-1,3-dicarboxylate O1-tert-butylO3-ethylpyrrolidine-1,3-dicarboxylate (436 mg, 1.70 mmol, 1.5 eq.), 2,6-dichloro-4-(trifluoromethyl)pyridine (250 mg, 1.13 mmol), anhydrous THF (6.25 mL, 0.18 N), and 1 M lithium [bis(trimethylsilyl)amide] solution (2.3 mL, 2.27 mmol, 2 eq.) were added sequentially at 0°C to a 2-6 mL microwave vial. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was placed in a saturated aqueous solution of NH4Cl. Dichloromethane was added to separate the two phases. The aqueous phase was extracted with dichloromethane. The combined organic phases were washed with water, dried using a phase separator, and evaporated to obtain the crude material as an orange gum. The crude substance was purified by flash chromatography on silica gel using a heptane / ethyl acetate gradient. It was eluted through a solid phase of Isolute HM-N. O1-tert-butyl O3-ethyl 3-[6-chloro-4-(trifluoromethyl)-2-pyridyl]pyrrolidine-1,3-dicarboxylate (408 mg, yield 82%) was obtained as a colorless gum. 1H NMR (400 MHz, DMSO-d6) δ 8.01 (s, 1H), 7.85 (d, J = 5.6 Hz, 1H), 4.12 (q, J = 7.1 Hz, 2H), 4.07 (d, J = 11.2 Hz, 1H), 3.76 (dd, J = 11.1, 6.9 Hz, 1H), 3.35 (dd, J = 13.8, 7.2 Hz, 2H), 2.66 (dd, J = 12.3, 6.0 Hz, 1H), 2.51 (dt, J = 3.7, 1.9 Hz, 1H), 1.40 (d, J = 5.0 Hz, 9H), 1.11 (t, J = 7.1 Hz, 3H). m / z = 323.2, 325.2 [M+H-Boc]+

[0177] Step 2: Synthesis of tert-butyl 3-[6-chloro-4-(trifluoromethyl)-2-pyridyl]-3-(hydroxymethyl)pyrrolidine-1-carboxylate O1-tert-butyl O3-ethyl 3-[6-chloro-4-(trifluoromethyl)-2-pyridyl]pyrrolidine-1,3-dicarboxylate (200 mg, 0.421 mmol) was dissolved in anhydrous THF (2 mL, 0.2 N). The mixture was cooled to 0°C. 2M lithium borohydride solution (0.42 mL, 0.842 mmol, 2 eq.) was added dropwise, and the reaction mixture was stirred at room temperature for 2 hours. The reaction was quenched with Rochelle salt solution, and dichloromethane was added. The two phases were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried using a phase separator and evaporated to obtain tert-butyl 3-[6-chloro-4-(trifluoromethyl)-2-pyridyl]-3-(hydroxymethyl)pyrrolidine-1-carboxylate as a colorless gum. 1H NMR (400 MHz, DMSO-d6) δ 7.88 (s, 1H), 7.69 (d, J = 6.4 Hz, 1H), 5.00 (t, J = 5.5 Hz, 1H), 3.71 - 3.51 (m, 3H), 3.35 (d, J = 7.8 Hz, m / z = 325-327[M+H-tBu]+.

[0178] Synthesis of tert-butyl rac-(4aR,8aR)-6-[6-bromo-4-(trifluoromethyl)-2-pyridyl]-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazine-4-carboxylate (specific pyridine 3) [ka] Step 1: Synthesis of rac-(4aR,8aR)-6-[6-bromo-4-(trifluoromethyl)-2-pyridyl]-2,3,4,4a,5,7,8,8a-octahydropyrido[4,3-b][1,4]oxazine Into a microwave tube, 2,6-dibromo-4-(trifluoromethyl)pyridine (150 mg, 0.467 mmol), (4aR,8aR)-octahydro-2H-pyrido[4,3-b]morpholine (70 mg, 0.467 mmol) and sodium hydrogen carbonate (39 mg, 0.467 mmol) / anhydrous DMF (1.4 mL, 0.34 N) were added. The resulting mixture was heated at 140 °C for 15 minutes under microwave irradiation. Water was added and the mixture was extracted with AcOEt. The combined organic layers were washed with water and brine, dried on a phase separator and concentrated to give a brown oil. The crude product was purified by silica gel column with a gradient of DCM / MeOH. The relevant fractions were collected and concentrated under vacuum to give rac-(4aR,8aR)-6-[6-bromo-4-(trifluoromethyl)-2-pyridyl]-2,3,4,4a,5,7,8,8a-octahydropyrido[4,3-b][1,4]oxazine (124 mg, yield 72%) as a beige solid. 1 1H NMR (DMSO-d6, 500 MHz): δ (ppm) 7.08 (s, 1H), 6.97 (s, 1H), 3.83 - 3.95 (m, 2H), 3.67 - 381 (m, 2H), 3.62 (dd, J = 13.2 , 10.0 Hz, 1H), <3.46 (td, J = <10.5, 2.8 Hz, 1H), 3.20 - <3.28 (m, 1H), <293 (ddd, J = <12.7, 9.8, 3.4 Hz, 1H), <2.67 - <2.78 (m, 1H), <2.49 - <2.53 (m, 1H), <1.80 - <1.88 (m, 1H), <1.53 - <1.69 (m, 1H); m / z = 366.0, 368.0 [M+H]+.

[0179] Step 2: Synthesis of tert-butyl rac-(4aR,8aR)-6-[6-bromo-4-(trifluoromethyl)-2-pyridyl]-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazine-4-carboxylate To a solution of tert-butoxycarbonyl tert-butyl carbonate (111 mg, 0.51 mmol) and N,N-dimethylpyridine-4-amine (4.2 mg, 0.0339 mmol) in anhydrous DCM (1.7 mL, 0.2 N), rac-(4aR,8aR)-6-[6-bromo-4-(trifluoromethyl)-2-pyridyl]-2,3,4,4a,5,7,8,8a-octahydropyrido[4,3-b][1,4]oxazine (124 mg, 0.339 mmol) was added. The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. Water was added, and the mixture was extracted with AcOEt. The combined organic layers were washed with water and brine, dried on a phase separator, and concentrated to obtain a brown gum. The crude product was purified by a heptane / AcOEt gradient using a silica gel column. The relevant fractions were collected and concentrated under vacuum to obtain tert-butylrac-(4aR,8aR)-6-[6-bromo-4-(trifluoromethyl)-2-pyridyl]-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazine-4-carboxylate (126 mg, yield 77%) as a colorless gum. 1 H NMR (400 MHz, DMSO-d6) δ 7.16 - 6.97 (m, 2H), 4.40 - 3.77 (m, 4H), 3.68 (d,J= 14.5 Hz, 2H), 3.64 - 3.54 (m, 1H), 3.49 (t,J= 10.5 Hz, 1H), 3.20 - 2.90 (m, 2H), 1.80 (s, 2H), 1.45 (d,J= 6.6 Hz, 9H);m / z = 466.0, 468.0 [M+H]+.

[0180] Synthesis of 3-[[6-bromo-4-(trifluoromethyl)-2-pyridyl]amino]pyrrolidine-1-carboxylate (specific pyridine 4) [ka] A microwave tube was filled with 2,6-dibromo-4-(trifluoromethyl)pyridine (145 mg, 0.45 mmol), tert-butyl 3-aminopyrrolidine-1-carboxylate (84 mg, 0.452 mmol), and sodium bicarbonate (38 mg, 0.452 mmol) / anhydrous DMF (1.3 mL, 0.34 M) solution. The resulting mixture was heated under microwave irradiation at 150°C for 10 minutes. The mixture was stirred under microwave irradiation at 150°C for a further 15 minutes. The mixture was stirred under microwave irradiation at 150°C for a further 15 minutes. 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 brown oil. The crude product was purified by a heptane / RINKAN gradient using a silica gel column. The relevant fractions were collected and concentrated under vacuum to obtain tert-butyl 3-[[6-bromo-4-(trifluoromethyl)-2-pyridyl]amino]pyrrolidine-1-carboxylate (108 mg, yield 57%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 7.78 (d, J = 6.6 Hz, 1H), 6.97 (s, 1H), 6.78 (s, 1H), 4.32 (d, J = 17.4 Hz, 1H), 3.62 - 3.51 (m, 1H), 3.45 - 3.34 (m, 2H), 3.11 (dd, J = 11.0, 4.2 Hz, 1H), 2.13 (s, 1H), 1.82 (s, 1H), 1.41 (d, J = 2.6 Hz, 9H);m / z = 353.9, 355.9 [M+H]+.

[0181] Synthesis of tert-butyl 4-[4-(3,3-dimethyl-2-oxo-1-tetrahydropyran-2-yl-pyrrolo[2,3-b]pyridine-4-yl)-6-(trifluoromethyl)pyrimidine-2-yl]piperazine-1-carboxylate (2-step process) (pyrimidine) [ka] Step 1: Synthesis of tert-butyl 4-[4-chloro-6-(trifluoromethyl)pyrimidine-2-yl]piperazine-1-carboxylate In a 10 mL Reactivial vial, 2,4-dichloro-6-(trifluoromethyl)pyrimidine (16 mL, 1.11 mmol), tert-butylpiperazine-1-carboxylate (0.21 g, 1.11 mmol), and triethylamine (0.46 mL, 3.32 mmol, 3 eq.) / anhydrous DMF (2.9 mL, 0.4 M) were added. The reaction mixture was stirred overnight at 100°C. After the reaction mixture returned to room temperature, water was added, followed by ethyl acetate. The two layers were separated, and the aqueous layer was extracted with ethyl acetate. The combined organic phases were washed with water, dried using a phase separator, and concentrated under vacuum to obtain the crude substance as a brown oil. This crude substance was purified by flash chromatography on silica gel using a cyclohexane / ethyl acetate gradient. It was eluted by liquid injection / cyclohexane. The relevant fractions were collected and concentrated under vacuum to obtain tert-butyl 4-[4-chloro-6-(trifluoromethyl)pyrimidine-2-yl]piperazine-1-carboxylate (295 mg, yield 73%) as a white solid. 1 H NMR (500 MHz, DMSO-d6) δ ppm 7.32 (s, 1 H), 3.57 - 3.95 (m, 4 H), 3.36 - 3.52 (m, 4 H), 1.42 (s, 9 H);m / z = 367.1 [M+H]+

[0182] Step 2: Synthesis of tert-butyl 4-[4-(3,3-dimethyl-2-oxo-1-tetrahydropyran-2-yl-pyrrolo[2,3-b]pyridine-4-yl)-6-(trifluoromethyl)pyrimidine-2-yl]piperazine-1-carboxylate A 5 mL Reactivial was filled with a solution 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 (81 mg, 0.218 mmol), tetrakis-triphenylphosphine palladium (50 mg, 0.0436 mmol, 0.1 eq), tert-butyl 4-[4-chloro-6-(trifluoromethyl)pyrimidine-2-yl]piperazine-1-carboxylate (80 mg, 0.218 mmol), and disodium carbonate (69 mg, 0.65 mmol, 3 eq.) in DMF (1.9 mL) and water (0.4 mL). The reaction mixture was stirred at 100 °C for 2 hours. The reaction mixture was allowed to return to room temperature. Water was then added. The obtained solid was filtered through glass frit and washed with water to obtain the crude substance as a brown solid. This crude substance was purified by flash chromatography on silica gel using a cyclohexane / siRNA gradient. It was eluted through a solid phase of Dicalite. The relevant fractions were collected and concentrated under vacuum to obtain tert-butyl 4-[4-(3,3-dimethyl-2-oxo-1-tetrahydropyran-2-yl-pyrrolo[2,3-b]pyridine-4-yl)-6-(trifluoromethyl)pyrimidine-2-yl]piperazine-1-carboxylate (66.4 mg, 52% yield) as a pale yellow powder. 1H NMR(400 MHz, DMSO-d6) δ 8.34 (d, J = 5.5 Hz, 1H), 7.69 (d, J = 5.5 Hz, 1H), 7.38 (s, 1H), 5.49 (dd, J = 11.3, 2.0 Hz, 1H), 3.99 (d, J = 10.8 Hz, 1H), 3.84 (s, 3H), 3.56 (td, J = 11.3, 3.4 Hz, 1H), 3.51 - 3.45 (m, 4H), 3.00 - 2.83 (m, 1H), 1.94 (s, 1H), 1.70 - 1.48 (m, 5H), 1.48 - 1.37 (m, 15H). m / z = 577.2 [M+H]+

[0183] Step 3: Synthesis of 3,3-dimethyl-4-[2-piperazin-1-yl-6-(trifluoromethyl)pyrimidine-4-yl]-1H-pyrrolo[2,3-b]pyridine-2-one dihydrochloride A microvial was filled with tert-butyl 4-[4-(3,3-dimethyl-2-oxo-1-tetrahydropyran-2-yl-pyrrolo[2,3-b]pyridine-4-yl)-6-(trifluoromethyl)pyrimidine-2-yl]piperazine-1-carboxylate (66 mg, 0.113 mmol) and 4M hydrogen chloride / dioxane (0.85 mL, 3.39 mmol, 30 eq.) / methanol (0.56 mL, 0.2 N). The reaction mixture was stirred overnight at 60°C. The solvent was removed under vacuum. Water was then added. The aqueous layer was extracted with ELISA. The aqueous layer was concentrated under vacuum to obtain 3,3-dimethyl-4-[2-piperazin-1-yl-6-(trifluoromethyl)pyrimidine-4-yl]-1H-pyrrolo[2,3-b]pyridine-2-one dihydrochloride (42.5 mg, 77% yield) as a pale yellow powder. 1H NMR (500 MHz, DMSO-d6):δ ppm 11.19 (s, 1 H), 8.85 - 9.93 (m, 2 H), 8.22 (d, J=5.38 Hz, 1 H), 7.61 (d, J=5.62 Hz, 1 H), 7.47 (s, 1 H), 3.95 - 4.16 (m, 4 H), 3.16 - 3.30 (m, 4 H), 1.45 (s, 6 H);m / z = 393.0 [M+H]+.

[0184] Scaffold coupling - General method (Phenyl 1) [ka] TIFF0007871296000146.tif15156 Suzuki Coupling In a microwave vial, bromine scaffold I (0.467 mmol, 1 eq.), dipotassium carbonate (1.40 mmol, 3 eq.), and boronic acid ester I' (0.701 mmol, 1.5 eq.) were sequentially added to a mixed solvent of dioxane (4 mL) and water (0.5 mL). The mixture was degassed, and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (95%, 0.0467 mmol, 0.1 eq.) was added. The reaction solution was irradiated with microwaves and stirred at 140°C for 1 hour and 30 minutes. The reaction mixture was filtered through a Daicalite pad, the filtrate was diluted with dichloromethane, and water was removed by passing it through a phase separator. The organic layer was concentrated under vacuum to obtain the crude material as a black solid. The crude material was purified by flash chromatography on silica gel using a dichloromethane / ethyl acetate gradient. It was eluted through the solid phase of Dicalite. The relevant fractions were collected and concentrated under vacuum. The resulting product was triturated with THF or diethyl ether, filtered, and dried under vacuum at 40°C to obtain compound II.

[0185] Example 1: Synthesis of 7-[3-[(dimethylamino)methyl]phenyl]-1,3-dihydroimidazo[4,5-b]pyridine-2-one (R1=H, G=NH) Skin-colored powder; 32% yield; 1 H NMR (DMSO-d6, 500 MHz):δ (ppm) 11.42 (s, 1H), 11.03 (s, 1H), 7.93 (d, J = 5.4 Hz, 1H), 7.44-7.53 (m, 3H), 7.37 (d, J = 7.3 Hz, 1H), 7.05 (d, J = 5.4 Hz, 1H), 3.48 (s, 2H), 2.17 (s, 6H);m / z = 269.2 [M+H]+

[0186] Scaffold coupling - General method (phenyl2) [ka] Synthesis of boronic acid esters (only in Example 32 (X=C, R1=F, R=CH2), other products are commercially available) To a solution of tert-butyl 4-[(3-bromo-5-fluorophenyl)methyl]piperazine-1-carboxylate (200 mg, 0.536 mmol) I / anhydrous dioxane (5.4 mL, 0.1 N), potassium acetate (158 mg, 1.61 mmol, 3 eq.) and bis(pinacolato)diborone (275 mg, 1.07 mmol, 2 eq.) were added. The solution was degassed with N2. [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (39 mg, 0.0536 mmol, 0.1 eq.) was added to the mixture. The mixture was then stirred overnight at 95°C. The solution was filtered on Dicalite, and the filtrate was concentrated under vacuum to obtain tert-butyl 4-[[3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]piperazine-1-carboxylate II as a black oil. The crude product was used in the next step without further purification. m / z = 421.5 [M+H]+

[0187] Suzuki Coupling To a solution of boronic acid ester II (481 mg, 0.458 mmol, 1.2 eq) / DMF (3 mL) and water (0.8 mL), bromine scaffold I' (90 mg, 0.373 mmol) and disodium carbonate (119 mg, 1.12 mmol, 3 eq) were added. The mixture was degassed with N2, and then tetrakistriphenylphosphine palladium (43 mg, 0.0373 mmol, 0.1 eq) was added. The solution was stirred overnight at 95°C. The mixture was filtered through a Dicalite pad, washed with Âi, and the solvent was evaporated under vacuum. The product was purified by silica gel column and solid precipitation using a DCM / MeOH gradient. The relevant fractions were collected and concentrated under vacuum to obtain Suzuki coupling product III.

[0188] Example 32: Synthesis of tert-butyl 4-[[3-(3,3-dimethyl-2-oxo-1H-pyrrolo[2,3-b]pyridine-4-yl)-5-fluorophenyl]methyl]piperazine-1-carboxylate (X=C, R1=F, R=CH2, A=CMe2) Yellow oil; 15% yield. 1 H NMR (chloroform-d, 400 MHz):δ (ppm) 8.13 (t, J=5.3 Hz, 2H), 7.15 (d, J=9.4 Hz, 1H), 7.07 (s, 1H), 6.89 (d, J=8.9 Hz, 1H), 6.78 (d, J=5.4 Hz, m / z = 455.4 [M+H]+

[0189] Deprotection To a solution of dioxane (0.11 mL, 0.447 mmol, 10 eq.) in 4M hydrogen chloride, Suzuki coupling product III (0.0447 mmol) / methanol (0.22 mL, 0.2N) was added. The mixture was stirred overnight at room temperature. The solvent was removed by distillation, and the product was vacuum-dried at 40°C. The final compound was obtained as hydrogen chloride salt IV.

[0190] Example 32: Synthesis of 4-[3-fluoro-5-(piperazine-1-ylmethyl)phenyl]-3,3-dimethyl-1H-pyrrolo[2,3-b]pyridine-2-one; dihydrochloride (X=C, R1=F, R=CH2, A=CMe2) Yellow solid; 93% yield; 1H NMR (DMSO-d6, 500 MHz): δ (ppm) 11.81-12.85 (m, 1H), 11.19 (s, 1H), 9.52 (br s, 2H), 8.13 (d, J = 5.4 Hz, 1H), 7.61-7.78 (m, 1H), 7.45 (br s, 1H), 7.33 (br d, J = 8.6 Hz, 1H), 6.83 (d, J = 5.4 Hz, 1H), 3.95-4.33 (m, 7H), 3.11-3.34 (m, 3H), 1.10 (s, 6H);M / Z = 355.1 [M+H]+

[0191] Scaffold coupling - General method (phenyl 3) [ka]

[0192] Buchwald reaction Xantphos (0.022 mmol, 0.03 eq.), Pd(OAc)2 (7.5 μmol, 0.01 eq.), and NaOtBu (1.12 mmol, 1.5 eq.) were added to a Reacti vial under N2 conditions. After adding anhydrous toluene (1.9 mL, 0.4 M), dibromobenzene product I (0.786 mmol, 1.05 eq.) and the corresponding piperazine I' (0.749 mmol, 1 eq.) were added. The reaction mixture was heated overnight at 80°C. Water was added, and the mixture was extracted by DCM. 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. This was eluted by liquid injection. The relevant fractions were collected and concentrated under vacuum to obtain the target compound II.

[0193] Example: Synthesis of tert-butyl (3S)-4-(3-bromophenyl)-3-methylpiperazine-1-carboxylate (R1= R2= R4= R5= R5= H; R3= Me) Yellow oil; 72% yield.1 H NMR(DMSO-d6, 400 MHz):δ (ppm) 7.15 (t, J=8.1 Hz, 1H), 7.02 (t, J=2.1 Hz, 1H), 6.93 - 6.86 (m, 2H), 4.03 (dd, J=6.6, 3.5 Hz, 1H), 3.93 (s, 1H), 3.75 (d, J=13.1 Hz, 1H), 3.29-3.33 (m, 2H), 3.18 (s, 1H), 3.05 - 2.83 (m, 2H), 1.43 (s, 9H), 0.92 (d, J=6.5 Hz, 3H); 357.1 [M+H]+

[0194] 1. Synthesis of boronic acid esters Compound II (0.538 mmol, 1 eq.), bis(pinacolato)diborone (0.645 mmol, 1.2 eq.), and potassium acetate (1.62 mmol, 3 eq.) / anhydrous dioxane (1.8 mL, 0.3 M) were placed in a 10 mL Reacti vial. The mixture was degassed with N2 and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.0538 mmol, 0.1 eq.) was added. The solution was heated overnight at 100°C. The mixture was filtered and concentrated under vacuum. Crude material III was used in the next step without purification.

[0195] Example: Synthesis of tert-butyl (3S)-3-methyl-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperazine-1-carboxylate (R1= R2= R4= R5= R5= H; R3= Me) Black oil; m / z = 403.2 [M+H]+

[0196] 2. Suzuki Coupling A solution of bromine scaffold II' (0.327 mmol, 1 eq.), boronic acid ester III (0.523 mmol, 1.6 eq.), Na2CO3 (0.981 mmol, 3 eq.) / DMF (2.6 mL), and water (0.5 mL) was placed in a 10 mL Reacti vial. The mixed solution was degassed, and tetrakistriphenylphosphine palladium (0.0327 mmol, 0.1 eq.) was added. The reaction mixture was heated overnight at 100 °C. The solution was filtered on Dicalite and 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. The product was tritulated in DCM and dried overnight at 40 °C under vacuum to obtain the target compound IV.

[0197] Example: Synthesis of tert-butyl (3S)-3-methyl-4-[3-(2-oxo-1,3-dihydroimidazo[4,5-b]pyridine-7-yl)phenyl]piperazine-1-carboxylate (G=NH; R=X=H; R1=R2=R4=R5=R5=H; R3=Me) Pink powder; 22% yield; 1 H NMR(DMSO-d6, 400 MHz):δ (ppm) 11.39 (s, 1H), 10.96 (s, 1H), 7.92 (d, J=5.4 Hz, 1H), 7.35 (t, J=7.9 Hz, 1H), 7.06 - 6.96 (m, 4H), 4.10 (s, 1H), 3.95 (s, 1H), 3.76 (d, J=12.9 Hz, 1H), 3.42 (d, J=11.0 Hz, 1H), 3.25 (br s, 1H), 3.01 (s, 2H), 1.43 (s, 9H), 0.95 (d, J=6.4 Hz, 3H);m / z = 410.2 [M+H]+

[0198] 3.Deprotection A 4M hydrogen chloride solution (0.366 mmol, 5 eq.) / dioxane was added to a solution of Suzuki coupling product IV (0.0733 mmol, 1 eq.) / methanol (0.7 mL, 0.1 M). The mixture was stirred overnight at room temperature. The solution was concentrated under vacuum, the product was tritulated in DCM, filtered, and vacuum-dried at 40°C to obtain the target product V in hydrochloride form.

[0199] Example 8: Synthesis of 7-[3-[(2S)-2-methylpiperazin-1-yl]phenyl]-1,3-dihydroimidazo[4,5-b]pyridine-2-one dihydrochloride (G=NH;R= X= H;R1= R2= R4= R5= H;R3= Me) Brown powder; yield 80%; 1H NMR (DMSO-d6, 500 MHz): δ (ppm) 11.53 (br s, 1H), 11.07 (s, 1H), 9.49 (br s, 1H), 9.03 (br s, 1H), 7.93 (d, J = 5.6 Hz, 1H), 7.41 (t, J = 8.1 Hz, 1H), 7.08-7.16 (m, 3H), 7.06 (d, J = 5.6 Hz, 1H), 5.58 (br s, 1H), 4.17-4.41 (m, 1H), 3.63 (br d, J = 13.0 Hz, 1H), 3.18-3.37 (m, 4H), 3.03-3.13 (m, 1H), 1.11 (d, J = 6.8 Hz, 3H);m / z = 310.2 [M+H]+

[0200] Scaffold coupling - specific method (specific phenyl 1) [ka] Synthesis of tert-butyl 4-[3-(2-oxo-1,3-dihydropyrrolo[2,3-b]pyridine-4-yl)phenyl]piperazine-1-carboxylate In a Reacti vial, tetrakis-triphenylphosphine palladium (103 mg, 0.0892 mmol, 0.1 eq), Na2CO3 (284 mg, 2.68 mmol, 3 eq.), and tert-butyl 4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperazine-1-carboxylate (433 mg, 1.07 mmol, 1.2 eq) were dissolved in a solution of DMF (7.2 mL) and water (1.4 mL). The mixture was degassed, and 4-bromo-1,3-dihydro-2H-pyrrolo[2,3-b]pyridine-2-one (200 mg, 0.892 mmol) was added. The reaction mixture was heated overnight at 100°C. This solution was filtered on Dicalite and concentrated under vacuum. The crude substance was purified by flash chromatography on silica gel using a DCM / siRNA gradient. The relevant fractions were collected and evaporated to obtain tert-butyl 4-[3-(2-oxo-1,3-dihydropyrrolo[2,3-b]pyridine-4-yl)phenyl]piperazine-1-carboxylate (266 mg, 75% yield) as a beige solid. m / z = 395.2 [M+H]+.

[0201] Synthesis of tert-butyl 4-[3-(3-ethyl-2-oxo-1,3-dihydropyrrolo[2,3-b]pyridine-4-yl)phenyl]piperazine-1-carboxylate Iodoethane (0.085 mL, 1.05 mmol, 3 eq) was added dropwise to a solution of N,N,N',N'-tetramethylethylenediamine (0.16 mL, 1.05 mmol, 3 eq) / anhydrous THF (0.88 mL) at -78°C, and then 1.6 M butyllithium solution (0.66 mL, 1.05 mmol, 3 eq) was added. The reaction was stirred at -78°C for 30 minutes. Next, tert-butyl 4-[3-(2-oxo-1,3-dihydropyrrolo[2,3-b]pyridine-4-yl)phenyl]piperazine-1-carboxylate (140 mg, 0.351 mmol) was added, and the mixture was allowed to stand until it reached room temperature. The reaction mixture was stirred at room temperature for 2 hours. Water was added, and the mixture was extracted with DCM. The organic phase was dried and concentrated under vacuum. The crude substance 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 and concentrated under vacuum to obtain tert-butyl 4-[3-(3-ethyl-2-oxo-1,3-dihydropyrrolo[2,3-b]pyridine-4-yl)phenyl]piperazine-1-carboxylate (20 mg, 32% yield) as a white oil. 1 H NMR (400 MHz, DMSO-d6) δ 11.05 (s, 1H), 8.11 (d, J = 5.7 Hz, 1H), 7.40 - 7.32 (m, 1H), 7.14 (s, 1H), 7.07 - 6.97 (m, 3H), 4.21 - 4.11 (m, 1H), 3.54 - 3.36 (m, 4H), 3.11-3.20 (m, 4H), 1.79 - 1.62 (m, 1H), 1.42 (s, 9H), 1.31 - 1.40 (m, 1H), 0.41 (t, J = 7.4 Hz, 3H). m / z = 423.3 [M+H]+.

[0202] Synthesis of 3-ethyl-4-(3-piperazin-1-ylphenyl)-1,3-dihydropyrrolo[2,3-b]pyridine-2-one; dihydrochloride A 4M hydrogen chloride (0.05 mL, 0.2 mmol, 4 eq.) / dioxane solution was added to a tert-butyl 4-[3-(3-ethyl-2-oxo-1,3-dihydropyrrolo[2,3-b]pyridine-4-yl)phenyl]piperazine-1-carboxylate (21 mg, 0.050 mmol) / methanol (0.5 mL, 0.1 N) solution. The mixture was stirred overnight at room temperature. The solution was concentrated under vacuum and dried overnight at 40°C to obtain 3-ethyl-4-(3-piperazine-1-ylphenyl)-1,3-dihydropyrrolo[2,3-b]pyridine-2-one; dihydrochloride (11.8 mg, 60% yield) as a yellow powder. 1H NMR (DMSO-d6, 500 MHz):δ (ppm) 11.10 (s, 1H), 9.10 (br s, 2H), 8.12 (d, J = 5.4 Hz, 1H), 7.38 (t, J = 7.9 Hz, 1H), 7.18 (t, J = 1.8 Hz, 1H), 7.05-7.10 (m, 2H), 7.00 (d, J = 5.4 Hz, 1H), 4.14-4.20 (m, 1H), 4.11 (br s, 1H), 3.44 (br d, J = 4.9 Hz, 4H), 3.18-3.26 (m, 4H), 1.68 (ddd, J = 13.8, 7.4, 4.0 Hz, 1H), 1.31-1.44 (m, 1H), 0.41 (t, J = 7.3 Hz, 3H);m / z = 323.2 [M+H]+.

[0203] Scaffold coupling - specific method (specific phenyl 2) [ka] Synthesis of tert-butyl 4-[3-(5-methyl-6-oxo-5,7-dihydropyrrolo[2,3-d]pyrimidine-4-yl)phenyl]piperazine-1-carboxylate In a Reacti vial, tert-butyl 4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperazine-1-carboxylate (264 mg, 0.654 mmol, 1.5 eq), 4-chloro-5-methyl-5H,6H,7H-pyrrolo[2,3-d]pyrimidine-6-one (80 mg, 0.436 mmol), disodium carbonate (139 mg, 1.31 mmol), and tetrakis-triphenylphosphine palladium (51 mg, 0.0436 mmol, 0.1 eq) were placed in a mixture of DMF (4.2 mL) and water (0.8351 mL). The vial was sealed, degassed with nitrogen, and then stirred at 120°C for 1 hour under microwave irradiation. The reaction was quenched, the reaction mixture was filtered through a Dicalite pad, and washed with ELISA. The solvent was removed under vacuum, and the crude substance was obtained as a red oil. This crude substance was purified by flash chromatography on silica gel using a cyclohexane / acetone gradient. It was eluted through the solid phase on Dicalite. The relevant fractions were collected and concentrated under vacuum to obtain tert-butyl 4-[3-(5-methyl-6-oxo-5,7-dihydropyrrolo[2,3-d]pyrimidine-4-yl)phenyl]piperazine-1-carboxylate (53.1 mg, 30% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.53 (s, 1H), 8.76 (d, J = 9.9 Hz, 1H), 7.44 (s, 3H), 7.12 (d, J = 9.4 Hz, 1H), 4.26 (q, J = 7.4 Hz, 1H), 3.49 (t, J = 5.0 Hz, 4H), 3.22 - 3.12 (m, 4H), 1.43 (s, 9H), 1.12 (d, J = 7.6 Hz, 3H);m / z = 410.3 [M+H]+.

[0204] Synthesis of 3-ethyl-4-(3-piperazine-1-ylphenyl)-1,3-dihydropyrrolo[2,3-b]pyridine-2-one; dihydrochloride 4M hydrogen chloride solution / dioxane (0.32 mL, 1.3 mmol, 10 eq) was added to a solution of tert-butyl 4-[3-(5-methyl-6-oxo-5,7-dihydropyrrolo[2,3-d]pyrimidine-4-yl)phenyl]piperazine-1-carboxylate (53 mg, 0.13 mmol) / methanol (1.2 mL, 0.1 N). The mixture was stirred overnight at room temperature. The solution was concentrated under vacuum. The product was triturated in DCM and dried overnight under vacuum at 40°C to obtain 5-methyl-4-(3-piperazine-1-ylphenyl)-5,7-dihydropyrrolo[2,3-d]pyrimidine-6-one dihydrochloride (34.3 mg, 66% yield) as a pale yellow solid. 1H NMR (DMSO-d6, 500 MHz):δ (ppm) 11.69 (br s, 1H), 9.24 (br s, 2H), 8.79 (s, 1H), 7.36-7.49 (m, 3H), 7.17 (br dd, J = 7.8, 1.5 Hz, 1H), 5.73 (br s, 1H), 4.29 (q, J = 7.6 Hz, 1H), 3.45 (br d, J = 2.2 Hz, 4H), 3.23 (br s, 4H), 1.11 (d, J = 7.6 Hz, 3H);m / z = 310.3 [M+H]+.

[0205] Scaffold coupling - specific method (specific phenyl 3) (Method for obtaining the 4-aminopiperidine variant. The 3-aminopiperidine variant was prepared by the same method.) [ka] Synthesis of tert-butyl 4-(3-bromoanilino)piperidine-1-carboxylate Diacetoxypalladium (3.3 mg, 0.0145 mmol, 0.01 eq), Xantphos (25 mg, 0.0436 mmol, 0.03 eq), and potassium tert-butyrate (245 mg, 2.18 mmol, 1.5 eq) / anhydrous toluene (3.63 mL, 0.4 N) were placed in a Reacti vial and stirred at room temperature for 5 minutes. 1,3-Dibromobenzene (360 mg, 1.53 mmol, 1.05 eq) and tert-butyl 4-aminopiperidine-1-carboxylate (300 mg, 1.45 mmol) were sequentially added to the reaction mixture. The resulting mixture was heated to 80°C under N2. Diacetoxypalladium (0.01 eq), xanthos (0.03 eq), tert-potassium butyrate (1 eq), and tert-butyl 4-aminopiperidine-1-carboxylate (1.5 eq) were added again, and the mixture was stirred overnight at 80°C. Water was added, and the mixture was extracted with DCM. The combined organic layer was washed with water and brine, filtered through a phase separator, and concentrated under vacuum to obtain a yellow liquid. The crude product was purified by silica gel column solid phase using a heptane / siRNA gradient. The relevant fractions were collected and concentrated under vacuum to obtain tert-butyl 4-(3-bromoanilino)piperidine-1-carboxylate (304 mg, 58% yield) as a white solid. 1 H NMR(DMSO-d6, 400 MHz):δ (ppm) 6.99 (t, J=8.0 Hz, 1H), 6.75 (t, J=2.0 Hz, 1H), 6.66 - 6.61 (m, 1H), 6.57 (dd, J=8.3, 1.6 Hz, 1H), 5.81 (d, J=8.2 Hz, 1H), 3.86 (d, J=13.1 Hz, 2H), 3.50 - 3.34 (m, 1H), 2.92 (s, 2H), 1.85 (dd, J=12.8, 3.0 Hz, 2H), 1.41 (s, 9H), 1.31 - 1.12 (m, 2H);m / z = 355.0 [M+H]+

[0206] Synthesis of tert-butyl 4-[3-bromo-N-(oxetan-3-ylmethyl)anilino]piperidine-1-carboxylate In a Reacti vial, tert-butyl 4-(3-bromoanilino)piperidine-1-carboxylate (293 mg, 0.808 mmol), oxetane-3-carbaldehyde (110 mg, 1.21 mmol, 1.5 eq), and acetic acid (0.046 mL, 0.808 mmol, 1 eq) / anhydrous methanol (4 mL, 0.2 N) were added. The mixture was stirred for 30 minutes, and sodium cyanoborohydride (1010 mg, 2.02 mmol, 2.5 eq) (resin) was added. The resulting mixture was stirred at 50°C for 7 days, with oxetane-3-carbaldehyde being added in several batches. The resin was filtered and washed with MeOH. The filtrate was concentrated under vacuum to obtain a colorless oil. The crude product was purified from the solid-phase retained material on a silica gel column using a heptane / siRNA gradient. The relevant fractions were collected and concentrated under vacuum to obtain tert-butyl 4-[3-bromo-N-(oxetane-3-ylmethyl)anilino]piperidine-1-carboxylate (194 mg, yield 56%) as a colorless gum. 1 H NMR (DMSO-d6, 400 MHz):δ (ppm) 7.11 (t, J=8.1 Hz, 1H), 6.96 (t, J=2.0 Hz, 1H), 6.82 (ddd, J=13.8, 8.2, 1.7 Hz, 2H), 4.55 (dd, J=7.9, 5.9 Hz, 2H), 4.31 (t, J=6.2 Hz, 2H), 4.02 (d, J=11.2 Hz, 2H), 3.72 (td, J=9.7, 7.9, 5.9 Hz, 1H), 3.43 (d, J=6.9 Hz, 2H), 3.11 (hept, J=6.8 Hz, 1H), 2.83 (s, 2H), 1.62 (d, J=10.3 Hz, 2H), 1.49 (qd, J=12.1, 4.3 Hz, 2H), 1.42 (s, 9H);m / z = 425.1, 427.1 [M+H]+

[0207] The next step was the same as the general procedure for phenyl 3. Scaffold coupling - specific method (specific phenyl 4) [ka] Synthesis of tert-butyl 4-(3-bromo-5-fluorophenyl)piperazine-1-carboxylate Xantphos (17 mg, 0.0300 mmol, 0.03 eq.), Pd(OAc)2 (2.3 mg, 9.98 μmol, 0.01 eq.), and NaOtBu (107 mg, 0.474 mmol, 1.5 eq.) were added to a vial under nitrogen. After adding anhydrous toluene (118 mL, 0.4N), 1,3-dibromo-5-fluorobenzene (12.6 g, 49.7 mmol, 1.05 eq.) and tert-butylpiperazine-1-carboxylate (9 g, 47.3 mmol) were added. The reaction mixture was heated overnight at 80°C. Water was added, and the mixture was extracted with DCM. The organic phase was washed with an aqueous MgCl2 solution, dried on a phase separator, and concentrated under vacuum to obtain tert-butyl 4-(3-bromo-5-fluorophenyl)piperazine-1-carboxylate as an orange oil (20.8 g, quantitative yield). This crude material was used directly in the next reaction. 1 H NMR (DMSO-d6, 400 MHz):δ (ppm) 6.95 - 6.92 (m, 1H), 6.84 - 6.76 (m, 2H), 3.47 - 3.36 (m, 4H), 3.24 - 3.14 (m, 4H), 1.42 (s, 9H);m / z = 305.0 [M+H-tBu]+

[0208] Synthesis of tert-butyl 4-[3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperazine-1-carboxylate In a 500 mL sealed vial, tert-butyl 4-(3-bromo-5-fluorophenyl)piperazine-1-carboxylate (81%, 20.81 g, 46.9 mmol), bis(pinacolato)diborone (14.3 g, 56.3 mmol, 1.2 eq.), and potassium acetate (14.69 g, 0.141 mol, 3 eq.) / anhydrous dioxane (156 mL, 0.3 N) were added. The mixture was degassed with nitrogen, and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (3.84 g, 4.69 mmol, 0.1 eq.) was added. The solution was heated overnight at 100°C. The mixture was filtered and concentrated under vacuum. The crude material was purified by flash chromatography on silica gel using a heptane / siRNA gradient. It was eluted through a solid phase of silica. The relevant fractions were collected and concentrated under vacuum to obtain tert-butyl 4-[3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperazine-1-carboxylate as a brown foam (8.67 g, 46%). 1H NMR (400 MHz, chloroform-d) δ 7.12 (d, J = 2.2 Hz, 1H), 6.98 (dd, J = 8.3, 2.3 Hz, 1H), 6.67 (dt, J = 11.9, 2.3 Hz, 1H), 3.58 - 3.54 (m, 4H), 3.20 - 3.13 (m, 4H), 1.56 (s, 6H), 1.48 (s, 9H), 1.33 (s, 12H);m / z = 407.1 [M+H]+

[0209] Synthesis of tert-butyl 4-[3-fluoro-5-(2-oxo-1,3-dihydropyrrolo[2,3-b]pyridine-4-yl)phenyl]piperazine-1-carboxylate A 50 mL sealed tube was filled with a solution of 4-bromo-1,3-dihydro-2H-pyrrolo[2,3-b]pyridine-2-one (500 mg, 2.35 mmol), tert-butyl 4-[3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperazine-1-carboxylate (1.05 g, 2.58 mmol, 1.1 eq.), disodium carbonate (746 mg, 7.04 mmol, 3 eq.) / DMF (17.5 mL), and water (5 mL). The mixture was degassed, and tetrakis(triphenylphosphine)palladium (542 mg, 0.469 mmol, 0.1 N) was added. The reaction mixture was heated overnight at 100 °C. The reaction mixture was diluted with water, filtered, and the residue was obtained as a yellowish powder to obtain the crude substance. The crude substance 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 tert-butyl 4-[3-fluoro-5-(2-oxo-1,3-dihydropyrrolo[2,3-b]pyridine-4-yl)phenyl]piperazine-1-carboxylate as an orange powder (631 mg, 42%). 1 H NMR(DMSO-d6, 400 MHz):δ (ppm) 11.08 (s, 1H), 8.12 (d, J=5.5 Hz, 1H), 7.09 (d, J=5.5 Hz, 1H), 6.97 (s, 1H), 6.88 (s, 1H), 6.85 (dd, M / z = 413.2 [M+H]+

[0210] Identification method (specific phenyl 4a) Synthesis of tert-butyl 4-[3-fluoro-5-(2-oxospiro[1H-pyrrolo[2,3-b]pyridine-3,1'-cyclopropane]-4-yl)phenyl]piperazine-1-carboxylate (n=1) In a 9 mL Reactivial vial, tert-butyl 4-[3-fluoro-5-(2-oxo-1,3-dihydropyrrolo[2,3-b]pyridine-4-yl)phenyl]piperazine-1-carboxylate (166 mg, 0.36 mmol), diphenylvinylsulfonium triflate (127 mg, 0.33 mmol, 0.9 eq.), zinc trifluoromethanesulfonate (276 mg, 0.74 mmol, 2 eq.), and molecular sieve (100 mg) / anhydrous DMF (2.1 mL, 0.2 N) were added. The mixture was stirred at room temperature for 10 minutes, and then 1,8-diazabicyclo[5.4.0]-7-undecene (167 μL, 1.11 mmol, 3 eq.) was added. The mixture was stirred for 3 hours, quenched with water, and then extracted with ELISA. The combined organic layers were washed with brine, dried using a phase separator, and evaporated to obtain the crude oil. The crude was purified by preparative HPLC under TFA conditions (preparative HPLC with trifluoroacetic acid mobile phase). The relevant fractions were combined and concentrated under vacuum to obtain tert-butyl 4-[3-fluoro-5-(2-oxospiro[1H-pyrrolo[2,3-b]pyridine-3,1'-cyclopropane]-4-yl)phenyl]piperazine-1-carboxylate (89 mg, 54%) as a yellowish powder. m / z = 439.1 [M+H]+.

[0211] Synthesis of 4-(3-fluoro-5-piperazine-1-ylphenyl)spiro[1H-pyrrolo[2,3-b]pyridine-3,1'-cyclopropane]-2-one; 2,2,2-trifluoroacetic acid (n=1) In a Reactivial vial, trifluoroacetic acid (0.15 mL, 2.03 mmol, 10 eq.) was added to a stirred solution in tert-butyl 4-[3-fluoro-5-(2-oxospiro[1H-pyrrolo[2,3-b]pyridine-3,1'-cyclopropane]-4-yl)phenyl]piperazine-1-carboxylate (89 mg, 0.203 mmol) / anhydrous DCM (2 mL, 0.1 N). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was evaporated to dryness under vacuum, and the product was obtained as a yellow powder. The crude material was purified by preparative HPLC under TFA conditions (preparative HPLC with trifluoroacetic acid as the mobile phase). The relevant fractions were combined and concentrated to obtain a yellow oil. This oil was incorporated into a DCM / MeOH mixture, and resin PL-HCO3 was added while stirring until the pH of the mixture reached 8. The solution was filtered, concentrated, and dried overnight under vacuum to obtain 4-(3-fluoro-5-piperazine-1-ylphenyl)spiro[1H-pyrrolo[2,3-b]pyridine-3,1'-cyclopropane]-2-one;2,2,2-trifluoroacetic acid (13.2 mg, yield 14%). 1H NMR (DMSO-d6, 500 MHz):δ (ppm) 11.32 (s, 1H), 8.72 (br s, 2H), 8.07 (d, J = 5.4 Hz, 1H), 6.91 (br dt, J = 12.5, 2.2 Hz, 1H), 6.74 (d, J = 5.4 Hz, 1H), 6.72 (t, J = 1.5 Hz, 1H), 6.60 (dt, J = 8.6, 1.2 Hz, 1H), 3.42-3.46 (m, 4H), 3.18-3.23 (m, 4H), 1.28-1.37 (m, 2H), 1.22 (q, J = 4.0 Hz, 2H). m / z = 339.1 [M+H]+.

[0212] A specific method (specific phenyl 4b) Synthesis of tert-butyl 4-[3-fluoro-5-(2-oxospiro[1H-pyrrolo[2,3-b]pyridine-3,1'-cyclobutane]-4-yl)phenyl]piperazine-1-carboxylate (n=2) To a solution of tert-butyl 4-[3-fluoro-5-(2-oxo-1,3-dihydropyrrolo[2,3-b]pyridine-4-yl)phenyl]piperazine-1-carboxylate (327 mg, 0.64 mmol) / anhydrous THF (6.4 mL, 0.1 N), 1.4 mL of 1 M lithium [bis(trimethylsilyl)amide] solution (1.4 mL, 1.41 mmol, 2.2 eq.) was added dropwise at -78°C under a nitrogen atmosphere. The mixture was stirred at this temperature for 5 minutes. Next, 1,3-diiodopropane (0.098 mL, 0.835 mmol, 1.3 eq.) was added dropwise at -78°C, and the resulting mixture was stirred for 1 hour while increasing the temperature to room temperature. The mixture was quenched with aqueous NH4Cl solution. Water was added, and the mixture was extracted with ELISA. The organic layer was washed with water and brine, dried on a phase separator, and concentrated to obtain a brown oil. The crude product was purified by preparative HPLC under TFA conditions (preparative HPLC with trifluoroacetic acid mobile phase). The relevant fractions were combined and concentrated to obtain tert-butyl 4-[3-fluoro-5-(2-oxospiro[1H-pyrrolo[2,3-b]pyridine-3,1'-cyclobutane)-4-yl)phenyl]piperazine-1-carboxylate (39 mg, 12%) as a brown solid. 1 H NMR(DMSO-d6, 400 MHz):δ (ppm) 11.00 (s, 1H), 8.06 (d, J=5.4 Hz, 1H), 6.89 - 6.86 (m, 2H), 6.81 (d, J=5.3 Hz, 1H), 6.73 (d, J=9.2 Hz, 1H), 3.49 - 3.40 (m, 4H), 3.28 - 3.16 (m, 4H), 2.42 - 2.29 (m, 2H), 2.28 - 2.17 (m, 2H), 1.79-1.89 (m, 1H), 1.42 (d, J=3.8 Hz, 9H), 1.30 - 1.17 (m, 1H);m / z = 453.2 [M+H]+

[0213] Synthesis of 4-(3-fluoro-5-piperazine-1-ylphenyl)spiro[1H-pyrrolo[2,3-b]pyridine-3,1'-cyclobutan]-2-one (n=2) To a solution of tert-butyl 4-[3-fluoro-5-(2-oxospiro[1H-pyrrolo[2,3-b]pyridine-3,1'-cyclobutane]-4-yl)phenyl]piperazine-1-carboxylate (39 mg, 0.0767 mmol) / anhydrous DCM (0.4 mL, 0.2 N), trifluoroacetic acid (57 μL, 0.767 mmol, 10 eq.) was added. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 8 hours. The solution was then concentrated under vacuum. The crude product was purified by preparative HPLC under TFA conditions (preparative HPLC with trifluoroacetic acid as the mobile phase). The relevant fractions were combined and concentrated under vacuum. The product was incorporated into a DCM / MeOH mixture, and resin PL-HCO3 was added until the pH reached 8. The solution was filtered and concentrated under vacuum to obtain 4-(3-fluoro-5-piperazine-1-ylphenyl)spiro[1H-pyrrolo[2,3-b]pyridine-3,1'-cyclobutan]-2-one (11 mg, 34%) as an orange solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 10.48 - 11.39 (m, 1 H), 8.04 (d, J=5.38 Hz, 1 H), 6.81 - 6.87 (m, 2 H), 6.80 (d, J=5.38 Hz, 1 H), 6.61 - 6.67 (m, 1 H), 3.24 - 3.30 (m, 1 H), 3.10 - 3.14 (m, 4 H), 2.76 - 2.81 (m, 4 H), 2.21 - 2.37 (m, 4 H), 1.73 - 1.90 (m, 1 H), 1.12 - 1.31 (m, 1 H);m / z = 353.1 [M+H]+

[0214] Scaffold coupling - specific method (specific phenyl 5) Synthesis of tert-butyl 3-(3-bromophenyl)-3-(hydroxymethyl)pyrrolidine-1-carboxylate [ka] In a microwave flask under a nitrogen atmosphere at 0°C, lithium aluminum hydride (0.68 mL, 1.35 mmol, 2 eq.) was added to a stirred solution of 3-(3-bromophenyl)-1-tert-butoxycarbonylpyrrolidine-3-carboxylic acid (250 mg, 0.675 mmol) / anhydrous THF (6.8 mL, 0.1 N). The reaction mixture was stirred overnight at 0°C. The reaction mixture was diluted with ethyl acetate. The organic phase was washed with aqueous solutions of 20% Rochelle salt and 2% NaHCO3, dried using a phase separator, and evaporated to obtain the crude substance as a colorless syrup. The crude substance was purified by flash chromatography on silica gel using a DCM / MeOH gradient. It was eluted by liquid injection / DCM. The relevant fractions were collected and concentrated under vacuum to obtain tert-butyl 3-(3-bromophenyl)-3-(hydroxymethyl)pyrrolidine-1-carboxylate (169 mg, 38%) as a colorless syrup. m / z = 300.0, 302.0 [M+H-tBu]+

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

[0216] Scaffold coupling - specific method (specific phenyl 6) Synthesis of tert-butyl N-[[3-(3-bromophenyl)oxetan-3-yl]methyl]carbamate [ka] In a round-bottom flask, at room temperature, 4-dimethylaminopyridine (0.13 g, 1.03 mmol, 1 eq.) was added to a stirred solution of [3-(3-bromophenyl)oxetan-3-yl]methaneamine (0.25 g, 1.03 mmol, 2 eq.) and tert-butoxycarbonyl tert-butyl carbonate (0.34 g, 1.55 mmol, 2 eq.) / DCM (5 mL, 0.2 N). The reaction mixture was stirred overnight at room temperature. Water was added, and the mixture was extracted with DCM. The organic phase was dried and concentrated under vacuum. The crude product was purified by flash chromatography on silica gel using a DCM / MeOH gradient. It was eluted through a solid phase of dichalite. The relevant fractions were collected and concentrated under vacuum to obtain tert-butyl N-[[3-(3-bromophenyl)oxetan-3-yl]methyl]carbamate (0.166 g, yield 47%) as a colorless oil. 1 H NMR (DMSO-d6, 400 MHz):δ (ppm) 7.43 (d, J=7.8 Hz, 1H), 7.34 - 7.26 (m, 2H), 7.12 (d, J=7.9 Hz, 1H), 4.62-4.77 (m, 4H), 3.44 (d, J=6.3 Hz, 2H), 1.31 (s, 9H);m / z = 286.1, 288.1 [M+H-tBu]+.

[0217] The next step was similar to the general method—phenyl 2. Scaffold coupling - specific method (specific phenyl 7) [ka] Synthesis of tert-butyl 4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperidine-1-carboxylate To a solution of tert-butyl 4-(3-bromophenyl)piperidine-1-carboxylate (200 mg, 0.58 mmol) / anhydrous dioxane (5.8 mL, 0.1 N), bis(pinacolato)diborone (293 mg, 1.15 mmol, 1.5 eq.) and potassium acetate (171 mg, 1.73 mmol, 3 eq.) were added. The mixture was degassed with nitrogen, and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (42 mg, 0.0576 mmol) was added. The resulting mixture was stirred overnight at 95°C under a nitrogen atmosphere. The mixture was filtered over Dicalite and concentrated under vacuum to obtain tert-butyl 4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperidine-1-carboxylate (501 mg, 88% yield) as a dark oil. The crude product was used in the following reaction: m / z = 332.3 [M+H-tBu]+

[0218] Synthesis of tert-butyl 4-[3-(3-methyl-2-oxo-1,3-dihydropyrrolo[2,3-b]pyridine-4-yl)phenyl]piperidine-1-carboxylate In a Reactivial vial, tert-butyl 4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperidine-1-carboxylate (39%, 501 mg, 0.506 mmol, 1.2 eq.), 4-chloro-3-methyl-1H,2H,3H-pyrrolo[2,3-b]pyridine-2-one (81 mg, 0.421 mmol), and disodium carbonate (134 mg, 1.26 mmol, 3 eq.) were added in a mixture of DMF (3.3 mL) and water (0.9 mL). The mixture was degassed, and tetrakistriphenylphosphine palladium (49 mg, 0.0421 mmol, 0.1 eq.) was added. The resulting mixture was stirred at 95°C for 4 hours under a nitrogen atmosphere. The mixture was filtered over Dicalite and concentrated to obtain a brown oil. The crude product was purified from the solid phase retained on a silica gel column using a heptane / siRNA gradient. The relevant fractions were collected and concentrated under vacuum to obtain tert-butyl 4-[3-(3-methyl-2-oxo-1,3-dihydropyrrolo[2,3-b]pyridine-4-yl)phenyl]piperidine-1-carboxylate (150 mg, yield 65%) as a yellow oil. m / z = 408.4 [M+H]+

[0219] Synthesis of tert-butyl 4-[3-(3,3-dimethyl-2-oxo-1H-pyrrolo[2,3-b]pyridine-4-yl)phenyl]piperidine-1-carboxylate A 1 M lithium [bis(trimethylsilyl)amide] solution (0.88 mL, 0.885 mmol, 3.3 eq.) / anhydrous THF (1.4 mL, 0.2 N) was placed in a Reacti vial. The mixture was cooled to -78°C under a nitrogen atmosphere, and iodomethane (0.034 mL, 0.541 mmol, 2 eq.) was added dropwise. The resulting mixture was stirred at -78°C for 15 minutes, and tert-butyl 4-[3-(3-methyl-2-oxo-1,3-dihydropyrrolo[2,3-b]pyridine-4-yl)phenyl]piperidine-1-carboxylate (74%, 149 mg, 0.271 mmol) was added. The mixture was heated to RT and stirred for 1 hour. The mixture was quenched with saturated aqueous NaHCO3 solution and water. The mixture was extracted with DCM. The combined organic layers were washed with water and brine, dried on a phase separator, and concentrated to obtain an orange oil. The crude product was purified from the solid-phase retained material on a silica gel column using a heptane / siRNA gradient. The relevant fractions were collected and concentrated under vacuum to obtain tert-butyl 4-[3-(3,3-dimethyl-2-oxo-1H-pyrrolo[2,3-b]pyridine-4-yl)phenyl]piperidine-1-carboxylate (25 mg, yield 21%) as a yellowish solid. 1 H NMR (chloroform-d, 400 MHz):δ (ppm) 8.09 (d, J=5.6 Hz, 1H), 7.40 (t, J=7.6 Hz, 1H), 7.30 (d, J=7.8 Hz, 1H), 7.15 - 7.07 (m, 2H), 6.84 (d, J=5.6 Hz, 1H), 4.25 (s, 2H), 2.89 - 2.63 (m, 3H), 1.86 (d, J=13.7 Hz, 2H), 1.64 (tt, J=12.9, 6.8 Hz, 2H), 1.47 (s, 9H), 1.23 (s, 6H);m / z = 422.4 [M+H]+.

[0220] Synthesis of 3,3-dimethyl-4-[3-(4-piperidyl)phenyl]-1H-pyrrolo[2,3-b]pyridine-2-one dihydrochloride To a solution of tert-butyl 4-[3-(3,3-dimethyl-2-oxo-1H-pyrrolo[2,3-b]pyridine-4-yl)phenyl]piperidine-1-carboxylate (25 mg, 0.0575 mmol) / methanol (0.3 mL, 0.2 N), 4M hydrogen chloride solution (0.14 mL, 0.575 mmol, 10 eq.) / dioxane was added. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 days. The mixture was concentrated under vacuum to obtain 3,3-dimethyl-4-[3-(4-piperidyl)phenyl]-1H-pyrrolo[2,3-b]pyridine-2-one dihydrochloride (21.3 mg, 90% yield) as a yellow solid. 1H NMR (DMSO-d6, 600 MHz):δ (ppm) 11.13 (s, 1H), 8.55-8.87 (m, 2H), 8.09 (d, J = 5.3 Hz, 1H), 7.41-7.48 (m, 1H), 7.33 (dt, J = 7.8, 1.5 Hz, 1H), 7.19 (dt, J = 7.6, 1.3 Hz, 1H), 7.15 (t, J = 1.5 Hz, 1H), 6.77 (d, J = 5.3 Hz, 1H), 4.65 (br s, 1H), 3.36 (br d, J = 12.6 Hz, 2H), 2.95-3.03 (m, 2H), 2.92 (tt, J = 12.0, 3.5 Hz, 1H), 1.96 (br d, J = 13.2 Hz, 2H), 1.80-1.90 (m, 2H), 1.06 (s, 6H);m / z = 322.1 [M+H]+.

[0221] Scaffold coupling - specific method (specific phenyl 8) [ka] Synthesis of tert-butyl 4-[3-(3-methyl-2-oxo-1,3-dihydropyrrolo[2,3-b]pyridine-4-yl)phenyl]piperazine-1-carboxylate In a microwave flask, tetrakis-triphenylphosphine palladium (509 mg, 0.440 mmol, 0.1 eq) was added at room temperature to a stirred mixture of tert-butyl 4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperazine-1-carboxylate (214 mg, 0.528 mmol, 1.2 eq) and 4-bromo-3-methyl-1,3-dihydropyrrolo[2,3-b]pyridine-2-one (100 mg, 0.440 mmol) / DMF (3.6 mL) and water (0.70 mL). The reaction mixture was purged with argon for 15 minutes. Disodium carbonate (140 mg, 1.32 mmol, 3 eq.) was added under argon, and the reaction mixture was stirred overnight at 100°C. The reaction mixture was diluted with ethyl acetate. The organic phase was washed with water, dried using a phase separator, and evaporated to obtain the crude substance as a yellow solid. The crude substance was purified by flash chromatography on silica gel using a cyclohexane / siRNA gradient. It was eluted by liquid injection / DCM. The relevant fractions were collected and concentrated under vacuum to obtain tert-butyl 4-[3-(3-methyl-2-oxo-1,3-dihydropyrrolo[2,3-b]pyridine-4-yl)phenyl]piperazine-1-carboxylate (132 mg, yield 56%) as a yellow solid. m / z = 409.4 [M+H]+

[0222] Synthesis of tert-butyl 4-[3-(3-benzyl-3-methyl-2-oxo-1H-pyrrolo[2,3-b]pyridine-4-yl)phenyl]piperazine-1-carboxylate In a microwave flask, under nitrogen at -78°C, 1.5 mL, 1.50 mmol, 4.7 eq. of 1 M lithium [bis(trimethylsilyl)amide] solution was added to a stirred solution of tert-butyl 4-[3-(3-methyl-2-oxo-1,3-dihydropyrrolo[2,3-b]pyridine-4-yl)phenyl]piperazine-1-carboxylate (130 mg, 0.318 mmol) / anhydrous THF (3.2 mL, 0.1 N). The reaction mixture was stirred at -78°C for 10 minutes, then bromomethylbenzene (0.045 mL, 0.382 mmol, 1.2 eq.) was added, and the reaction mixture was warmed to room temperature and stirred for 6 hours. The reaction mixture was diluted with RINKAN. The organic phase was washed with saturated NH4Cl aqueous solution, dried using a phase separator, and evaporated to obtain the crude substance as a dark yellow syrup. The crude substance was purified by flash chromatography on silica gel using a toluene / acetone gradient. It was eluted by liquid injection / DCM. The relevant fractions were collected and concentrated under vacuum to obtain tert-butyl 4-[3-(3-benzyl-3-methyl-2-oxo-1H-pyrrolo[2,3-b]pyridine-4-yl)phenyl]piperazine-1-carboxylate (128 mg, yield 74%) as a yellowish foam. m / z = 499.2 [M+H]+.

[0223] Synthesis of 3-benzyl-3-methyl-4-(3-piperazine-1-ylphenyl)-1H-pyrrolo[2,3-b]pyridine-2-one dihydrochloride 4M hydrogen chloride solution (0.6 mL, 2.5 mmol, 10 eq.) / dioxane was added to a solution of tert-butyl 4-[3-(3-benzyl-3-methyl-2-oxo-1H-pyrrolo[2,3-b]pyridine-4-yl)phenyl]piperazine-1-carboxylate (125 mg, 0.251 mmol) / methanol (2.5 mL, 0.1 eq.). The mixture was stirred overnight at room temperature. The precipitate was filtered, washed with cold isopropanol, and dried overnight under high vacuum at 40°C to obtain 3-benzyl-3-methyl-4-(3-piperazine-1-ylphenyl)-1H-pyrrolo[2,3-b]pyridine-2-one dihydrochloride (58.6 mg, 49.337% yield) as a white powder. 1H NMR (DMSO-d6, 500 MHz):δ (ppm) 10.91 (s, 1H), 9.28 (br s, 2H), 8.00 (d, J = 5.4 Hz, 1H), 7.44 (t, J = 8.1 Hz, 1H), 7.14 (dd, J = 8.3, 2.0 Hz, 1H), 7.07-7.11 (m, 3H), 6.95-6.99 (m, 2H), 6.79 (d, J = 5.4 Hz, 1H), 6.76 (dd, J = 6.6, 2.9 Hz, 2H), 5.25 (br s, 1H), 3.36-3.50 (m, 4H), 3.22 (br s, 4H), 2.84 (d, J = 13.2 Hz, 1H), 2.56 (d, J = 13.2 Hz, 1H), 1.38 (s, 3H);m / z = 399.1 [M+H]+.

[0224] Scaffold coupling - specific method (specific phenyl 9) [ka] Synthesis of tert-butyl 3-oxo-1-(3-pyridyl)-5,6,8,8a-tetrahydro-1H-oxazolo[3,4-a]pyrazine-7-carboxylate In a 50 mL round-bottom flask, 14.9 mL (23.86 mmol) of 1.6 M tert-butylilixine solution was slowly added at -78°C to a stirred solution of 3-bromopyridine (1.17 mL, 11.93 mmol, 5 eq.) / anhydrous THF (20 mL). This solution was then added dropwise at -78°C to a solution of ditert-butyl 2-formylpiperazine-1,4-dicarboxylate (750 mg, 2.39 mmol) / anhydrous THF (20 mL). The reaction mixture was stirred at -78°C for 15 minutes. The reaction was quenched with a saturated aqueous solution of NH4Cl. The two phases were separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over Na2SO4, filtered, and evaporated to obtain the crude product as an orange gum. Subsequently, the residue was solubilized in anhydrous THF (8 mL) and slowly added to a heterogeneous mixture of 60% sodium hydride (95 mg, 2.38 mmol, 1 eq.) / anhydrous THF (20 mL). The reaction mixture was stirred overnight at 60°C. This reaction was quenched with water and ethyl acetate was added. The two phases were separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over Na2SO4, filtered, and evaporated to obtain the crude substance as an orange gum. The crude substance was purified by flash chromatography on silica gel using a dichloromethane / ethyl acetate gradient. It was eluted by liquid injection / DCM. The relevant fractions were collected and concentrated under vacuum to obtain tert-butyl 3-oxo-1-(3-pyridyl)-5,6,8,8a-tetrahydro-1H-oxazolo[3,4-a]pyrazine-7-carboxylate (220 mg, 19% yield) as a pale orange gum in two diastereomer forms. m / z = 394[M+H]+.

[0225] Synthesis of tert-butyl 3-(3-pyridylmethyl)piperazine-1-carboxylate In a 4 mL vial, ammonium formate (57 mg, 0.909 mmol, 2 eq.), tert-butyl 3-oxo-1-(3-pyridyl)-5,6,8,8a-tetrahydro-1H-oxazolo[3,4-a]pyrazine-7-carboxylate (220 mg, 0.455 mmol) / anhydrous ethanol (4.5 mL, 0.1 N), and dihydroxypalladium (20%, 32 mg, 0.0455 mmol, 0.1 eq.) were added in sequence. The reaction mixture was stirred at 80°C for 5 hours. Then, dihydroxypalladium (20%, 16 mg) and ammonium formate (29 mg) were added, and the reaction mixture was stirred overnight at 80°C. The reaction mixture was filtered through a Dicalite pad, and the filtrate was evaporated to dryness to obtain tert-butyl 3-(3-pyridylmethyl)piperazine-1-carboxylate (185 mg, 94% yield) as a colorless gum. 1 H NMR(DMSO-d6, 400 MHz):δ (ppm) 8.45 - 8.40 (m, 2H), 7.65 (d, J=7.8 Hz, 1H), 7.32 (dd, J=7.6, 4.8 Hz, 1H), 3.68 (d, J=12.6 Hz, 2H), 2.83 (d, J=12.1 Hz, 1H), 2.76 - 2.56 (m, 4H), 2.49 - 2.36 (m, 2H), 1.37 (d, J=17.4 Hz, 9H);m / z = 278.3 [M+H]+.

[0226] The next step was similar to the general method—phenyl3. Scaffold coupling - specific method (specific phenyl 10) [ka] Synthesis of 2-[4-(3-bromophenyl)piperazine-2-yl]propan-2-ol Diacetoxypalladium (2.4 mg, 0.0106 mmol, 0.01 eq.), Xantphos (19 mg, 0.0318 mmol, 0.03 eq.), and potassium tert-butoxide (178 mg, 1.59 mmol, 1.5 eq.) / anhydrous toluene (2.6 mL, 0.4 N) were added to a Reacti vial. Then, 1,3-dibromobenzene (128 μL, 1.06 mmol, 1 eq.) and tert-butyl 2-(1-hydroxy-1-methyl-ethyl)piperazine-1-carboxylate (259 mg, 1.06 mmol) were added sequentially. The resulting mixture was stirred overnight at 95°C under nitrogen. Water was added, and the mixture was extracted with ELISA. The combined organic layers were washed with water and brine, dried on a phase separator, and concentrated under vacuum to obtain a brown liquid. The crude product was purified from the solid-phase retained material on a silica gel column using a DCM / MeOH gradient. The relevant fractions were collected and concentrated under vacuum to obtain 2-[4-(3-bromophenyl)piperazin-2-yl]propan-2-ol (163 mg, yield 51%) as an orange oil. 1 H NMR(DMSO-d6, 400 MHz):δ (ppm) 7.17 - 7.10 (m, 1H), 7.04 (t, J=2.1 Hz, 1H), 6.90 (ddd, J=12.9, 8.1, 1.8 Hz, 2H), 4.39 (s, 1H), 3.66 - 3.49 (m, 2H), 3.07 - 2.94 (m, 1H), 2.73 (td, J=11.8, 3.1 Hz, 1H), 2.59 - 2.52 (m, 1H), 2.48 (d, J=2.7 Hz, 1H), 2.34 (t, J=11.0 Hz, 1H), 2.14 (s, 1H), 1.14 (d, J=6.7 Hz, 6H);m / z = 299.1;301.0 [M+H]+

[0227] Synthesis of 7-(3-bromophenyl)-1,1-dimethyl-5,6,8,8a-tetrahydrooxazolo[3,4-a]pyrazine-3-one To a solution of 2-[4-(3-bromophenyl)piperazin-2-yl]propan-2-ol (239 mg, 0.799 mmol) / anhydrous DCM (4 mL, 0.2 N), dimethylaminopyridine (197 mg, 1.60 mmol, 2 eq.) and tert-butoxycarbonyl tert-butyl carbonate (349 mg, 1.60 mmol, 2 eq.) were sequentially added. The resulting mixture was stirred overnight at room temperature under nitrogen. 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 to obtain the crude product. This was purified from the solid phase retained on a silica gel column using a heptane / ethyl acetate gradient. The relevant fractions were collected and concentrated under vacuum to obtain 7-(3-bromophenyl)-1,1-dimethyl-5,6,8,8a-tetrahydrooxazolo[3,4-a]pyrazine-3-one (190 mg, yield 73%) as a colorless oil. 1 H NMR (DMSO-d6, 400 MHz):δ (ppm) 7.21 - 7.14 (m, 2H), 7.01 (dd, J=8.1, 2.1 Hz, 1H), 6.96 (dd, J=7.8, 1.1 Hz, 1H), 3.84 (ddd, J=12.2, 3.5, 1.6 Hz, 1H), 3.74 - 3.66 (m, 1H), 3.65 - 3.58 (m, 1H), 3.49 (dd, J=11.2, 3.6 Hz, 1H), 3.07 (td, J=12.5, 3.8 Hz, 1H), 2.75 - 2.62 (m, 2H), 1.43 (s, 3H), 1.34 (s, 3H);m / z = 325.0;327.0 [M+H]+

[0228] The next step was similar to the general method—phenyl3.

[0229] 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 2).

[0230] 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).

[0231] 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). [Table 72] [Table 73] [Table 74] [Table 75] [Table 76] [Table 77]

[0232] 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 between 9.0 and 9.5; 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.

[0233] 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.

[0234] 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 of 0:1.

[0235] 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 or CR a (In the formula, R a (These are selected from hydrogen, halogens, C1-3 alkyls, and CN); B is selected from N, CH, CF, and C-(C1-3 alkyl); D is N, CH, CR b (In the formula, R b (Selected from halogens, C1-3 alkyls, and C1-3 haloalkyls); G is selected from CR1R2, NR1, and O; 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, C1-3 haloalkyl, aryl, heteroaryl, alkylaryl and alkylheteroaryl; or R1 and R2 together form a 3- to 5-membered spirocarbon or heterocyclic ring, which may be substituted as desired; R3 is selected from hydrogen, C1-2 alkyl, OMe, and halogen; R4 is selected from hydrogen, C1-5 alkyl, C3-7 cycloalkyl, C1-5 haloalkyl, C1-5 alkoxyl, C1-5 haloalkoxyl, alkylalkoxy, C2-6 heterocycloalkyl, CN, and halogen; E is N, CH, CR c (In the formula, R c (Selected from the group consisting of halogens, hydroxyls, C1-3 alkylhydroxyls, C1-3 alkylaminos, C1-3 haloalkyls, C2-6 alkylalkoxyls, and CN; R5 and R6 are joined together to form a ring Z which may be substituted as desired and may be bridged as desired, where ring Z is General formula Ia: 【Chemistry 2】 (In the formula, R7 is selected from hydrogen, C1-3 alkyl, and C1-3 haloalkyl.) [A 4- to 8-membered aminoalkyl ring, which may optionally be substituted and optionally crosslinked] Compounds thereof, or their pharmaceutically acceptable salts, solvates, stereoisomers or mixtures of stereoisomers, tautomers and / or isotopes.

2. Ring Z is as follows: 【Transformation 3】 [In the formula, R8, R9, R10, R11, R13, and R21 are each independently selected from hydrogen, C1-3 alkyl, C1-3 alkylalkoxy, C1-3 alkylhydroxyl, amino, C1-3 alkylamino, C1-6 alkylaminoalkyl, C1-3 haloalkyl, and alkylheteroaryl; R12 is selected from hydrogen, C1-3 alkyl, and C1-3 haloalkyl; or Any one of R8, R9, R10, R11, R12, R13, and R21 may bond to another different R8, R9, R10, R11, R12, R13, or R21 to form a 3- to 7-membered spiro or bicyclic carbocyclic or heterocyclic ring structure and / or a 3- to 6-membered bridging carbocyclic or heterocyclic ring structure; n is selected from 0, 1, and 2. The compound according to claim 1, or a pharmaceutically acceptable salt, solvate, stereoisomer or mixture of stereoisomers, tautomer and / or isotope thereof.

3. n is 0; E is N, CH and CR d (In the formula, R d (Selected from halogens, alkoxys, C1-3 alkylhydroxys, C1-3 haloalkyls, C2-5 alkylalkoxys, and C2-5 alkylnitriles) The compound according to claim 2, or a pharmaceutically acceptable salt, solvate, stereoisomer or mixture of stereoisomers, tautomer and / or isotope thereof.

4. Ring Z is 【Chemistry 4】 The compound according to claim 2, or a pharmaceutically acceptable salt, solvate, stereoisomer or mixture of stereoisomers, tautomer and / or isotope thereof.

5. G is CR1R2, and ring Z is as follows: 【Transformation 5】 It is, A is CH, CF, C-Cl, and C-Br; B and D are, independently of N and CH; E is N, CF and CH; R1 is selected from hydrogen, Me, Et, OMe, OEt, OH, NH 2 and NHMe; R2 is selected from hydrogen, Me, and Et; or R1 and R2 together form a 3- to 6-membered spirocarbon or heterocyclic ring; R3 is either hydrogen or a halogen; R4 is hydrogen, Me, Et, CF 2 H, CF 3 , CF 2 Me, OMe, OEt, OCF 2 H, OCF 3 Selected from CN, Cl, and F; R8 and R9 independently produce hydrogen, Me, Et, and CH4, respectively. 2 OH, CHMeOH, CMe 2 OH, CH 2 OMe, CH 2 Selected from F and halogen; R10 and R11 independently produce hydrogen, Me, Et, and CH4, respectively. 2 OH, CHMeOH, CMe 2 OH, CH 2 OMe, CH 2 FCHF 2 CH 2 CF 3 and CH 2 - Selected from heteroaryls; R12 is selected from hydrogen and Me; R13 is selected from hydrogen and Me; R21 is selected from hydrogen and Me; or The compound according to claim 2, or a pharmaceutically acceptable salt, solvate, stereoisomer or mixture of stereoisomers, tautomers and / or isotopes thereof, wherein one of R8, R9, R10, R11, R21, R12, R13 and R21 may bond to another different R8, R9, R10, R11, R21, R13 or R21 to form a 3- to 7-membered spiro or bicyclic carbocyclic or heterocyclic ring structure and / or a 3- to 6-membered bridging carbocyclic or heterocyclic ring structure.

6. a) One of R8 and R9 binds to one of R10 and R11 to form a [6,3]-, [6,4]-, [6,5]-, [6,7]-, or [6,8]-bicyclic structure; b) One of R8 and R9 bonds to R13 to form a [6,5,5]-, [6,6,6]-, [6,7,7]-, or [6,8,8]-bridged structure; c) One of R10 and R11 bonds to R13 to form a [6,6,4]-, [6,7,5]-, or [6,8,6]-bridged structure; d) Whether one of R10 and R11 may bond to R21 to form a [6,5,5]-, [6,6,6]-, [6,7,7]-, or [6,8,8]-bridged structure; e) Whether one of R8 and R9 can bond to R21 to form a [6,6,4]-, [6,7,5]-, or [6,8,6]-bridged structure; f) R8 binds to R9 to form a [6,3]-, [6,4-], [6,5]-, [6,6]- or [6,7]-spirostructure; or g) The compound according to claim 5, or a pharmaceutically acceptable salt, solvate, stereoisomer or mixture of stereoisomers, tautomer and / or isotope thereof, wherein R10 is bonded to R11 to form a [6,3]-, [6,4-], [6,5]-, [6,6]- or [6,7]-spiro structure.

7. Ring Z is 【Transformation 6】 【Transformation 7】 【Transformation 8】 【Chemistry 9】 【Chemistry 10】 A compound according to claim 5, selected from the group consisting of the following, or a pharmaceutically acceptable salt thereof, solvate, stereoisomer or mixture of stereoisomers, tautomer and / or isotope.

8. Ring Z is 【Chemistry 11】 A compound according to claim 5, selected from the group consisting of the following, or a pharmaceutically acceptable salt thereof, solvate, stereoisomer or mixture of stereoisomers, tautomer and / or isotope.

9. G is CR1R2, and ring Z is as follows: 【Chemistry 12】 It is, A is selected from CH, CF, C-Cl, and C-Br; B and D are independently selected from N and CH, respectively; E is selected from N, CH, and CF; R1 is hydrogen, Me, Et, OMe, OEt, OH, NH 2 and selected from NHMe; and R2 is selected from hydrogen, Me and Et; or R1 and R2 together form a 3- to 6-membered spirocarbocyclic or heterocyclic ring; in particular, they form a 4- to 5-membered carbocyclic or heterocyclic spiroring; R3 is selected from hydrogen and F; R4 is Me, Et, CF 2 H, CF 3 , CF 2 Me, OMe, OEt, OCF 2 H, CN, Cl, and F; R14, R15, R17, R18, R19, and R20 are each independently selected from hydrogen, Me, and F; R16 is selected from hydrogen and Me. The compound according to claim 2, or a pharmaceutically acceptable salt, solvate, stereoisomer or mixture of stereoisomers, tautomer and / or isotope thereof.

10. a) Each of R14, R15, R16, R17, R18, R19, and R20 is hydrogen; b) If one of R14, R15, R17, R18, and R20 is Me, then R16 and R19 are hydrogen; c) If R18 is F, then R14, R15, R16, R17, R19 and R20 are hydrogen; d) If R18 is F and R19 is Me, then R14, R15, R16, R17 and R19 are hydrogen; e) R18 and R19 are both F, and R14, R15, R17, and R20 are hydrogen; f) If E is CH, then R14 or R20 is F. The compound according to claim 9, or a pharmaceutically acceptable salt, solvate, stereoisomer or mixture of stereoisomers, tautomer and / or isotope thereof.

11. Ring Z, see below: 【Chemistry 13】 A compound according to claim 9, or a pharmaceutically acceptable salt, solvate, stereoisomer or mixture of stereoisomers, tautomer and / or isotope thereof, selected from the above.

12. The compound according to claim 11, or a pharmaceutically acceptable salt, solvate, stereoisomer or mixture of stereoisomers, tautomer and / or isotope thereof, wherein G is NH and B is N.

13. 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 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 Table 57 Table 58 Table 59 Table 60 Table 61 Table 62 Table 63 Table 64 Table 65 Table 66 Table 67 Table 68 Table 69 Table 70 Compounds selected from, or their pharmaceutically acceptable salts, solvates, stereoisomers or mixtures of stereoisomers, tautomers and / or isotopes.

14. The compound has the following structure: 【Chemistry 14】 The compound according to claim 13, or a pharmaceutically acceptable salt, solvate, stereoisomer or mixture of stereoisomers, tautomer and / or isotope thereof.

15. The compound has the following structure: 【Chemistry 15】 The compound according to claim 13, or a pharmaceutically acceptable salt, solvate, stereoisomer or mixture of stereoisomers, tautomer and / or isotope thereof.

16. The compound has the following structure: 【Chemistry 16】 The compound according to claim 13, or a pharmaceutically acceptable salt, solvate, stereoisomer or mixture of stereoisomers, tautomer and / or isotope thereof.

17. The compound has the following structure: 【Chemistry 17】 The compound according to claim 13, or a pharmaceutically acceptable salt, solvate, stereoisomer or mixture of stereoisomers, tautomer and / or isotope thereof.

18. The compound has the following structure: [Chemistry 18] The compound according to claim 13, or a pharmaceutically acceptable salt, solvate, stereoisomer or mixture of stereoisomers, tautomer and / or isotope thereof.

19. The compound has the following structure: 【Chemistry 19】 The compound according to claim 13, which is the same as the compound according to claim 13.

20. The compound has the following structure: 【Chemistry 20】 The compound according to claim 13, which is the same as the compound according to claim 13.

21. The compound has the following structure: 【Chemistry 21】 The compound according to claim 13, which is the same as the compound according to claim 13.

22. The compound has the following structure: 【Chemistry 22】 The compound according to claim 13, which is the same as the compound according to claim 13.

23. The compound has the following structure: 【Chemistry 23】 The compound according to claim 13, which is the same as the compound according to claim 13.

24. The compound has the following structure: 【Chemistry 24】 The compound according to claim 13, which is the same as the compound according to claim 13.

25. The compound has the following structure: 【Chemistry 25】 The compound according to claim 13, which is the same as the compound according to claim 13.

26. One or more compounds as described in any one of claims 1 to 25, or pharmaceutically acceptable salts, solvates, stereoisomers or mixtures of stereoisomers, tautomers and / or isotopes thereof.

27. A pharmaceutical composition comprising any one of the compounds described in claims 1 to 25, or a pharmaceutically acceptable salt, solvate, stereoisomer or mixture of stereoisomers, tautomer and / or isotope thereof, 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 / or replication.

28. The pharmaceutical composition according to claim 27, wherein the disease or disorder is selected from the group consisting of rheumatoid arthritis, multiple sclerosis, psoriasis, and atopic dermatitis.

29. The pharmaceutical composition according to claim 27, wherein the compound is an inhibitor of PKC-θ.

30. The pharmaceutical composition according to claim 27, 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.

31. A combination pharmaceutical comprising a compound according to any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, solvate, stereoisomer or mixture of stereoisomers, tautomer and / or isotope, and one or more additional therapeutic agents.

32. The combination pharmacopoeia according to claim 31, wherein a compound according to any one of claims 1 to 25, or a pharmaceutically acceptable salt, solvate, stereoisomer or mixture of stereoisomers, tautomer and / or isotope thereof, is administered simultaneously, sequentially, or separately with one or more additional therapeutic agents.

33. The pharmaceutical composition according to claim 27, characterized by administering an effective amount of a compound according to any one of claims 1 to 25, 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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