PKC-theta modulators

Abstract

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

Description

[Technical field]

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

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

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

[0004] Protein kinase C (PKC) is a family of serine- and threonine-specific protein kinases. PKC family members are known to phosphorylate a wide variety of protein targets and are involved in a variety of intracellular signaling pathways. Each member of the PKC family has a unique expression profile and is thought to play a distinct role.

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

[0006] The PKC-θ isoform of PKC is highly expressed in T lymphocytes and plays a key role in T cell receptor (TCR)-driven T cell activation. PKC-θ signals through transcription factors such as NF-κB, NFAT, and AP-1, leading to the release of cytokines such as IL-2 and IFN-γ, which promote T cell proliferation, differentiation, and survival (Brezar et al., 2015, Front Immunol., 6:530). Unlike the broad biological suppressive mechanisms shown by calcineurin inhibitors, inhibition of PKC-θ has selective effects on the immune system (Brezar et al., 2015, Front Immunol., 6:530). Mice lacking PKC-θ activity maintain intact antiviral responses (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). - / - Mice have a significantly decreased percentage of circulating Tregs and Prkcq - / -Tregs isolated from mice retain suppressive activity (Gupta, et al., 2008). Pharmacological inhibition of PKC-θ protected Tregs from inactivation by TNFα and enhanced protection of mice from inflammatory bowel disease (Zanin-Zhorov, et al., 2010). Indeed, evidence exists that PKC-θ is a negative regulator of Treg function (Zhang et al., Adv Pharm. 2013 ;66:267-31).

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

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

[0009] PKC-θ is also involved in various types of cancer, and PKC-θ-mediated signaling events control the development and progression of cancer. 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-theta are known, for example inhibitors based on a pyrazolopyrimidine scaffold are described in WO 2011 / 139273, and PKC-theta inhibitors based on a diaminopyrimidine core are described in WO 2015 / 095679.

[0011] To date, there are no effective and approved medical treatments based on the inhibition of PKC-θ, mainly due to the difficulty in ensuring potent inhibition with adequate selectivity of the PKC-θ isoform over other isoforms, in particular PKC-δ and other kinases of the PKC family (group 2).

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

[0013] In one embodiment of the invention, a compound of formula I: [ka] [In the formula, A is selected from the group consisting of N, CR a (In the formula, R a is selected from hydrogen, halogen, C1-3 alkyl and CN; G is selected from the group consisting of: CR1R2, O and NR1; R1 and R2 are independently selected from the group consisting of 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 cPr), C2-6 alkylalkoxy (e.g., CHOMe), hydroxyl, C1-3 alkylhydroxyl (e.g., CH2OH), amino, C1-3 alkylamino (e.g., CH2NH2), C1-4 aminoalkyl (e.g., NHMe or N(Me)2), C2-7 alkylaminoalkyl (e.g., CH2NHMe or CH2N(Me)2), and C1-3 haloalkyl; or R1 and R2 together form an optionally substituted 3- to 5-membered spirocarbocyclic or heterocyclic ring; in particular an optionally substituted 4- to 5-membered carbocyclic or heterocyclic spiro ring; in an embodiment, said carbocyclic or heterocyclic spiro ring is unsubstituted; in another embodiment, said 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; B is selected from the group consisting of N, CH and C-halogen (e.g., CF, C-Cl, C-Br); D is selected from the group consisting of: N and C-R3; R3 is selected from the group consisting of hydrogen, C1-3 alkyl (e.g., Me, Et), C1-3 haloalkyl (e.g., CF2H, CF3, CH2CF3), C1-3 alkoxyl (e.g., OMe), C2-5 alkyl alkoxyl (e.g., CHOMe) and halogen (e.g., F, Cl, Br); R4 is selected from the group consisting of hydrogen, C1-3 alkyl, C1-3 haloalkyl (e.g., CF2H, CF3, CH2CF3), OMe, and halogen; or When D is C-R3, R3 and R4 join together to form the following: [ka] [In the formula, R7 is selected from the group consisting of hydrogen and halogen; R8 is selected from the group consisting of hydrogen and halogen; R9 is selected from the group consisting of hydrogen, C1-3 haloalkyl (e.g., CF2H, CF3, CH2CF3) and halogen; R10 is selected from the group consisting of hydrogen, halogen, C1-3 haloalkyl (e.g., CF2H, CF3, CH2CF3) and C1-3 haloalkoxy (e.g., OCFH2, OCF2H, OCF3)]. and forming an optionally substituted aryl or heteroaryl ring having a structure selected from the group consisting of: n is selected from the group consisting of: 0 and 1; E is selected from the group consisting of CH and CR a (In the formula, R a is selected from halogen, C1-3 alkyl, C1-3 alkyl hydroxyl (e.g., CH2OH), C1-3 haloalkyl (e.g., CH2F), C2-6 alkyl alkoxyl (e.g., CHOMe), and C2-4 alkyl nitrile (e.g., CH2CN); R5 and R6 taken together and linked to form an optionally substituted and optionally bridged 4-8 membered, preferably 5-7 membered, saturated carbocyclic or heterocyclic ring. or a pharma- ceutically acceptable salt, solvate, stereoisomer or mixture of stereoisomers, tautomer, isotopic form, or pharma- ceutical active metabolite thereof, or a combination thereof.

[0014] In embodiments, the compounds of the present disclosure have structural formula II: [ka] has.

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

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

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

[0018] In embodiments, the compounds of the present disclosure have structural formula IIIa, IIIb, or IIIc: [ka] wherein: R17, Postscript: [ka] (In the formula, R11 is selected from the group consisting of hydrogen, halogen and C1-2 alkyl; R12 is selected from the group consisting of hydrogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkylhydroxyl, and C1-2 alkylnitrile; R13 is selected from the group consisting of hydrogen, halogen and C1-2 alkyl; R14 is selected from the group consisting of: hydrogen and C1-2 alkyl; R15 is selected from the group consisting of: hydrogen and C1-2 alkyl; R16 is selected from the group consisting of hydrogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkylhydroxyl, and C1-3 alkylalkoxyl; n is selected from the group consisting of: 0 and 1; p is selected from the group consisting of: 1 and 2; X is selected from the group consisting of: CH2 and O; Y is selected from the group consisting of: CH2, O, NH and NMe. is selected from the group consisting of:

[0019] In embodiments: R1 is selected from the group consisting of hydrogen, Me, Et, OMe, OH, NH2 and NHMe; R2 is selected from the group consisting of: hydrogen, Me and Et; or R1 and R2 together form an optionally substituted 3-5 membered spiro carbocyclic or heterocyclic ring; A is selected from the group consisting of CH, CF, C-Cl and C-Br; R17: [ka] (In the formula, R18 is selected from the group consisting of hydrogen and halogen; R19 is selected from the group consisting of hydrogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkyl and hydroxyl; m is selected from the group consisting of: 0 and 1; R20 is selected from the group consisting of hydrogen and halogen; X is selected from the group consisting of: CH2 and O; R21 and R22 are each independently selected from the group consisting of hydrogen and C1-3 alkyl; Y is selected from the group consisting of: CH2, O, and NH; R23 is selected from the group consisting of hydrogen, C1-3 alkyl and C1-3 haloalkyl. is selected from the group consisting of:

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

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

[0022] In embodiments, the compound or pharmaceutical composition for use according to the present disclosure is an inhibitor of PKC-theta.

[0023] In an embodiment, the use refers to a method characterized by administering the compound by oral, topical, inhalation or intranasal administration, or systemically by intravenous, intraperitoneal, subcutaneous or intramuscular injection. In an embodiment, the use refers to a method characterized by administering a compound according to the present disclosure in combination with one or more additional therapeutic agents. In an embodiment, administration includes administering a compound according to the present disclosure simultaneously, sequentially or separately with one or more additional therapeutic agents.

[0024] In an embodiment, the use comprises administering to a subject an effective amount of a compound according to the present disclosure, said effective amount being from about 5 nM to about 10 μM in the subject's blood.

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

[0026] In an embodiment, the method comprises administering a compound according to the present disclosure or a pharmaceutical composition according to the present disclosure. Suitably, the compound is an inhibitor of PKC-theta or the pharmaceutical composition comprises an inhibitor of PKC-theta.

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

[0028] In an embodiment, the method includes administering to a subject an effective amount of a compound according to the present disclosure, the effective amount being from about 5 nM to about 10 μM in the subject's blood.

[0029] Within the scope of this application, it is expressly intended that 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, may be taken independently or in any combination. That is, all embodiments and / or features of any embodiment may be taken in any manner and / or combination, except where such features are incompatible. More particularly, it is specifically 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 present invention. The applicant reserves the right to modify the claims as originally filed or to file new claims accordingly, including the right to modify the claims as originally filed to rely on and / or incorporate features of other claims, even if not originally claimed as such. Detailed Description of the Invention

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

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

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

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

[0034] Unless otherwise stated, the implementation of the present invention uses conventional techniques in chemistry and chemical methods, biochemistry, molecular biology, pharmaceutical formulation, and patient delivery and treatment regimen, which are within the scope of the ability of those skilled in the art.Such techniques are also described in the documents cited herein.All documents cited in this disclosure are incorporated herein in their entirety by reference.

[0035] Before setting forth a detailed description of the present invention, a number of definitions are provided to aid in the understanding of this disclosure.

[0036] In accordance with the present disclosure, the term "molecule" is used interchangeably with the term "compound" and sometimes the term "chemical structure". The term "agent" is typically used in the context of a medicine, pharmaceutical composition, drug, etc., that has known or predicted physiological or in vitro activity of medical importance, but said characteristics and properties are not excluded in the molecules or compounds of the present disclosure. Thus, the term "agent" is used interchangeably with the other terms and phrases "therapeutic", "medicinal", and "active". Therapeutic agents according to the present disclosure also encompass compositions and pharmaceutical formulations that include the compounds of the present disclosure.

[0037] Prodrugs and solvates of the compounds of the present disclosure are also included within the scope of the present disclosure. The term "prodrug" refers to a compound (e.g., a drug precursor) that is converted in vivo to obtain the compound of the present disclosure or a pharma- ceutically acceptable salt, solvate, or ester thereof. This conversion can occur by various mechanisms (e.g., metabolic or chemical processes), such as hydrolysis of a hydrolyzable bond, e.g., in 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). Thus, the compositions and pharmaceuticals of the present disclosure can include prodrugs of the compounds of the present disclosure. In some aspects and embodiments, the compounds of the present disclosure are themselves prodrugs and can be metabolized in vivo to become therapeutically active compounds.

[0038] The present invention also includes various deuterated forms of any of the compounds of the formulas disclosed herein, including formula I, II or III (including the corresponding subformulas defined herein), or pharma- ceutically acceptable salts of the present invention and / or their corresponding tautomeric forms (including the subformulas defined above). Each available hydrogen atom bonded to a carbon atom may be independently replaced with a deuterium atom. Those skilled in the art will know how to synthesize deuterated forms of any of the compounds of the formulas disclosed herein, including formula (I), (II) or (III) (including the corresponding subformulas defined herein), or pharma-ceutically acceptable salts of the present invention and / or their corresponding tautomeric forms (including the subformulas defined above). For example, deuterated substances (e.g., alkyl groups) can be prepared by conventional techniques (see, for example: methyl-d3-amine available from Aldrich Chemical Co., Milwaukee, WI, Cat. No. 489,689-2).

[0039] The present invention also includes isotopically labeled compounds or pharma- ceutically acceptable salts thereof and / or corresponding tautomeric forms (including subformulas defined above) that are identical to those described in any of the formulas disclosed herein, including formulas (I), (II) or (III) (including corresponding subformulas defined herein), respectively, except for the fact that one or more atoms are replaced with an atom having an atomic mass or mass number different from the atomic mass or mass number 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 and pharma-ceutically acceptable salts of said compounds that contain the aforementioned isotopes and / or other isotopes of atoms are within the scope of the present invention. Isotopically labeled compounds of the present invention (e.g., compounds incorporating radioactive isotopes such as 3H or 14C) are useful in drug and / or substrate tissue distribution assays. Tritium, i.e., 3H, and carbon-14, i.e., 14C, isotopes are particularly preferred because of their ease of preparation and detectability, with 11C and 18F isotopes being particularly useful in PET (positron emission tomography).

[0040] In the context of the present 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 treatments or therapeutic treatment regimens of the present disclosure. The animal is preferably a mammal, such as a human, cow, sheep, pig, dog, cat, bat, mouse or rat. In particular, the subject may be a human.

[0041] The term "alkyl" refers to a monovalent, optionally substituted, saturated aliphatic hydrocarbon group. While there may be any number of carbon atoms, typically the number of carbon atoms in an alkyl group may be from 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 from 1 to 12 carbon atoms in the chain. The alkyl group may be straight-chained (i.e., linear), branched, or cyclic. "Lower alkyl" refers to an alkyl group having from 1 to 6 carbon atoms in the chain, and may have from 1 to 4 carbon atoms or 1 to 2 carbon atoms. Thus, representative examples of lower alkyl groups include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, isobutyl, isopentyl, amyl (C5H 11 ), sec-butyl, tert-butyl, sec-amyl, tert-pentyl, 2-ethylbutyl, 2,3-dimethylbutyl, etc. "Higher alkyl" refers to an alkyl having 7 or more carbon atoms, such as n-heptyl, n-octyl, n-nonyl, n-decyl, n-dodecyl, n-tetradecyl, n-hexadecyl, n-octadecyl, n-eicosyl, etc., including branched chain types. A straight carbon chain having 4 to 6 carbon atoms means a chain length that does not include carbons present on branched chains, and in the case of branched chains, means the total number. Optional substituents for alkyl groups and other groups will be described later.

[0042] The term "substituted" means that one or more hydrogen atoms (attached to carbon or heteroatoms) are replaced with a group selected from the indicated group of substituents, provided that the normal valence of the designated atom in the context of the group is not exceeded. The group may be optionally substituted with a particular substituent at a position where the substituent does not significantly adversely affect the biological activity or structural stability of the compound, and does not significantly interfere with the preparation of compounds within the scope of the present invention. Combinations of substituents are permissible only if they result in a stable compound. A "stable compound" or "stable structure" refers to a compound that is sufficiently robust to be isolated to a useful degree of purity from a reaction mixture and / or formulated into an effective therapeutic agent. "Optionally substituted" means that the group is unsubstituted or that at least one hydrogen atom is replaced with one of the specified substituents, groups, or sites.

[0043] Any substituents / groups / moieties described herein that are optionally substituted (or optionally substituted) may be substituted with one or more (e.g., 1, 2, 3, 4 or 5) substituents, which may be independently selected from the specified substituents. As such, the substituents, unless otherwise stated, may be selected from the group set forth below: 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, azido (-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, when substituents are present on an aryl or other ring system, two adjacent atoms may be substituted with methylenedioxy or ethylenedioxy groups.More suitably, 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, azido, (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. Even more suitably, the substituents are 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- to 6-membered heterocycloalkyl, cyano, (C1-C6)alkylthio, amino, -NH(alkyl), -NH((C1-C6)cycloalkyl), -N((C1-C6)alkyl), -OC(O)-(C1-C6)alkyl, -OC(O)-(C5-C6)aryl, -OC(O)-(C1-C6)cycloalkyl, carboxy, and -C(O)O-(C1-C6)alkyl. Most suitably, the substituents are selected from one or more of the following groups: fluoro, chloro, bromo, hydroxy, amino, (C1-C6)alkyl and (C1-C6)alkoxy, wherein the alkyl and alkoxy are optionally substituted with one or more chloro.Particularly preferred substituents are those set forth below: chloro, methyl, ethyl, methoxy and ethoxy.

[0044] The term "halo" or "halogen" refers to a monovalent halogen radical 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 most preferred.

[0045] As used herein, with respect to the substitution of a parent moiety with one or more substituents, the term "independently" means that the parent moiety may be substituted with any of the listed substituents individually or in combination, and any number of chemically possible substituents may be used. In any embodiment, when a group is substituted, it may contain up to 5, up to 4, up to 3, or 1 and 2 substituents. As a non-limiting example, 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, 2,3-dichloro-4-methylphenyl, and the like.

[0046] As used herein, the term "alkylene" or "alkylenyl" refers to a difunctional group obtained by removal of a hydrogen atom from an alkyl group, as defined above. Non-limiting examples of alkylene include methylene, ethylene and propylene. "Lower alkylene" refers to an alkylene having 1 to 6 carbon atoms in the chain and may be straight or branched. Alkylene groups may be optionally substituted.

[0047] The term "alkenyl" refers to a monovalent, optionally substituted, unsaturated aliphatic hydrocarbon group. Thus, 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, C2-12 alkenyl (or C2-12 alkenyl) refers to an alkenyl group containing 2 to 12 carbon atoms in the structure. An alkenyl group may be linear (i.e., straight-chained), branched, or cyclic. "Lower alkenyl" refers to an alkenyl group having 1 to 6 carbon atoms, and may have 1 to 4 carbon atoms, or may have 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 alkenyl refers to alkenyl having 7 or more carbon atoms, such as 1-heptenyl, 1-octenyl, 1-nonenyl, 1-decenyl, 1-dodecenyl, 1-tetradecenyl, 1-hexadecenyl, 1-octadecenyl, 1-eicosenyl, and the like, including branched forms thereof. Optional substituents include those described elsewhere.

[0048] "Alkenylene" means a difunctional group obtained by removal of a hydrogen from an alkenyl group that is defined above. Non-limiting examples of alkenylene include -CH=CH-, -C(CH3)=CH-, and -CH=CHCH2-.

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

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

[0051] The term "aryl" as used herein refers to a substituted or unsubstituted aromatic carbocyclic group containing from 5 to about 15 carbon atoms; preferably 5 or 6 carbon atoms. An aryl group may have only one carbon ring or may be composed of one or more fused rings in which at least one ring is aromatic in nature. "Phenyl" is a group formed by removing a hydrogen atom from a benzene ring, which may be substituted or unsubstituted. Thus, a "phenoxy" group is a group of formula RO- where R is a phenyl group. "Benzyl" is a group of formula R-CH2- where R is phenyl, and "benzyloxy" is a 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 group, furan-2-carboxylic acid group, and the like.

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

[0053] The term "heterocycle" or "heterocyclic" group as used herein refers to a monovalent group of about 4 to about 15 ring atoms, preferably 4-, 5-, 6-, or 7-ring members. Generally, heterocycle groups contain 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. The preferred heteroatom is nitrogen. Heterocycle groups may have only one ring or may be composed of one or more fused rings, at least one of which 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 heterocycles 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 5-membered heterocyclic groups having two heteroatoms include imidazolyl, oxazolyl, thiazolyl, pyrazolyl, etc. Corresponding fully saturated and partially saturated groups are also included. Representative unsaturated 6-membered heterocyclic groups having only one heteroatom include 2-, 3- or 4-pyridinyl, 2H-pyranyl and 4H-pyranyl, etc. Corresponding partially saturated or fully saturated groups include 2-, 3- or 4-piperidinyl, 2-, 3- or 4-tetrahydropyranyl, etc. Representative unsaturated 6-membered heterocyclic groups having two heteroatoms include 3- or 4-pyridazinyl, 2-, 4- or 5-pyrimidinyl, 2-pyrazinyl, morpholino, etc. Corresponding fully saturated and partially saturated groups are also included, such as 2-piperazine, etc. A heterocyclic group is attached directly to the ring through an available carbon atom or heteroatom in the heterocycle or through a linker such as an alkylene, such as methylene or ethylene.

[0054] Unless otherwise specified, "room temperature" is intended to mean a temperature of about 18-28° C., usually about 18-25° C., and more usually about 18-22° C. As used herein, the phrase "room temperature" may be abbreviated as "rt" or "RT."

[0055] Molecules and Compounds Disclosed herein is a compound of structural formula I: [ka] [In the formula, A is selected from the group consisting of: N, C-Ra, where Ra is selected from hydrogen, halogen, C1-3 alkyl, and CN; G is selected from the group consisting of: CR1R2, O and NR1; R1 and R2 are independently selected from the group consisting of 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., CHOMe), hydroxyl, C1-3 alkylhydroxyl (e.g., CH2OH), amino, C1-3 alkylamino (e.g., CH2NH2), C1-4 aminoalkyl (e.g., NHMe or N(Me)2), C2-7 alkylaminoalkyl (e.g., CH2NHMe or CH2N(Me)2), C1-3 haloalkyl; or R1 and R2 together form an optionally substituted 3- to 5-membered spirocarbocyclic or heterocyclic ring; in particular an optionally substituted 4- to 5-membered carbocyclic or heterocyclic spiro ring; in an embodiment, said carbocyclic or heterocyclic spiro ring is unsubstituted; in another embodiment, said carbocyclic or heterocyclic spiro ring is substituted with one or more substituents selected from the group consisting of C1-2 alkyl, halogen, C1-2 haloalkyl, hydroxyl and C1-2 alkoxyl; B is selected from the group consisting of N, CH and C-halogen (e.g., CF, C-Cl, C-Br); D is selected from the group consisting of: N and C-R3; R3 is selected from the group consisting of hydrogen, C1-3 alkyl (e.g., Me, Et), C1-3 haloalkyl (e.g., CF2H, CF3, CH2CF3), C1-3 alkoxyl (e.g., OMe), C2-5 alkylalkoxyl (e.g., CHOMe) and halogen (e.g., F, Cl, Br); R4 is selected from the group consisting of hydrogen, C1-3 alkyl, C1-3 haloalkyl (e.g., CF2H, CF3, CH2CF3), OMe, and halogen; or When D is C-R3, R3 and R4 join together to form the following: [ka] (In the formula, R7 is selected from the group consisting of hydrogen and halogen; R8 is selected from the group consisting of hydrogen and halogen; R9 is selected from the group consisting of hydrogen, C1-3 haloalkyl (e.g., CF2H, CF3, CH2CF3) and halogen; R10 is selected from the group consisting of hydrogen, halogen, C1-3 haloalkyl (e.g., CF2H, CF3, CH2CF3), C1-3 haloalkoxy (e.g., OCFH2, OCF2H, OCF3)). and forming an optionally substituted aryl or heteroaryl ring having a structure selected from the group consisting of: n is selected from the group consisting of: 0 and 1; E is selected from the group consisting of CH and CR a (In the formula, R ais selected from halogen, C1-3 alkyl, C1-3 alkylhydroxy (e.g., CH2OH), C1-3 haloalkyl (e.g., CH2F), C2-6 alkylalkoxy (e.g., CHOMe), and C2-4 alkylnitrile (e.g., CH2CN); R5 and R6 taken together and linked to form an optionally substituted and optionally bridged 4-8 membered, preferably 5-7 membered, saturated carbocyclic or heterocyclic ring. or a pharma- ceutically acceptable salt, solvate, stereoisomer or mixture of stereoisomers, tautomer, isotopic form, or pharma- ceutically active metabolite thereof, or a combination thereof.

[0056] In certain embodiments of formula I, D is C-R3, and R3 and R4 join together to form the following structure: [ka] Optionally substituted aryl rings having the general formula II: [ka] (wherein A, B, E, G, R1, R2, R5, R6, R7, R8, R9, R10 and n are as defined for formula I). to form a compound of the formula:

[0057] In certain embodiments of formula II, the compound has formula IIa: [ka] [In the formula, A, B, E, R1, R2, R5, R6, R7, R8, R9, R10 and n are as defined for formula I; R17: [ka] (In the formula, R11 is selected from the group consisting of hydrogen, halogen (e.g., F) and C1-2 alkyl (e.g., Me); R12 is selected from the group consisting of hydrogen, C1-3 alkyl (e.g., Me), C1-3 haloalkyl (e.g., CH2F), C1-3 alkylhydroxy (e.g., CH2OH), and C1-2 alkylnitrile (e.g., CH2CN); R13 is selected from the group consisting of hydrogen, halogen (e.g., F) and C1-2 alkyl (e.g., Me); R14 is selected from the group consisting of: hydrogen and C1-2 alkyl (e.g., Me); R15 is selected from the group consisting of hydrogen and C1-2 alkyl (e.g., Me); R16 is selected from the group consisting of hydrogen, C1-3 alkyl (e.g., Me), C1-3 haloalkyl (e.g., -CH2CH2F, CH2CHF2, CH2CF3), C1-3 alkylhydroxy (e.g., CH2OH), and C1-3 alkylalkoxyl (e.g., CHOMe); n is selected from the group consisting of: 0 and 1; p is selected from the group consisting of: 1 and 2; X is selected from the group consisting of: CH2 and O; Y is selected from the group consisting of: CH2, O, NH and NMe. selected from the group consisting of It has the structure:

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

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

[0060] In certain embodiments of formula III, G is CR1R2, one of B or D is N and the other is CH; or B and D are CH, i.e., compounds of formula IIIa, IIIb, or IIIc: [ka] [In the formula, A, R1, R2, R3, R4, E, R5, R6 and n are as defined for formula III; R17: [ka] (In the formula, R11 is selected from the group consisting of hydrogen, halogen (e.g., F) and C1-2 alkyl (e.g., Me); R12 is selected from the group consisting of hydrogen, C1-3 alkyl (e.g., Me), C1-3 haloalkyl (e.g., CH2F), C1-3 alkylhydroxy (e.g., CH2OH), and C1-2 alkylnitrile (e.g., CH2CN). R13 is selected from the group consisting of hydrogen, halogen (e.g., F) and C1-2 alkyl (e.g., Me); R14 is selected from the group consisting of: hydrogen and C1-2 alkyl (e.g., Me); R15 is selected from the group consisting of hydrogen and C1-2 alkyl (e.g., Me); R16 is selected from the group consisting of hydrogen; C1-3 alkyl (e.g., Me), C1-3 haloalkyl (e.g., -CH2CH2F, CH2CHF2, CH2CF3), C1-3 alkyl hydroxyl (e.g., CH2OH) and C1-3 alkyl alkoxyl (e.g., CHOMe); n is selected from the group consisting of: 0 and 1; p is selected from the group consisting of: 1 and 2; X is selected from the group consisting of: CH2 and O; Y is selected from the group consisting of: CH2, O, NH and NMe. selected from the group consisting of It is a compound having the structure:

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

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

[0063] The compounds of the invention may have the structure depicted 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

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

[0065] Due to its involvement in T cell activation, selective inhibition of PKC-θ may reduce harmful inflammation mediated by Th17 (which mediates autoimmune diseases) or Th2 (which causes 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). Inhibitors could potentially be used in T cell-mediated adaptive immune responses. Inhibition of PKC-θ downregulates transcription factors (NF-κB, NF-AT) and reduces the production of IL-2. It has been observed that animals lacking PKC-θ are resistant to several autoimmune diseases (Zanin-Zhorov et al., Trends in Immunology. 2011, 32(8):358-363). PKC-θ is therefore an interesting target for potential cancer and autoimmune therapy.

[0066] Studies using PKC-θ-deficient mice demonstrated that antiviral responses are independent of PKC-θ activity, whereas T cell responses associated with autoimmune diseases are PKC-θ-dependent (Jimenez et al., J. Med. Chem. 2013, 56(5) pp 1799-1810). Thus, potent and selective inhibition of PKC-θ is expected to block autoimmune T cell responses without compromising antiviral immunity. However, the similarity of PKC isoforms, especially PKC-δ, and their selectivity over other protein kinases pose a challenge in developing PKC inhibitors suitable for clinical use.

[0067] To address such concerns, in aspects and embodiments, the compounds (or "active agents") of the present disclosure may advantageously provide potent and selective inhibition of PKC-theta (having 5-fold or greater selectivity, preferably 20-fold or greater selectivity, as measured by a suitable measure, such as pIC50 in a suitable assay) over other PKC-isoforms, such as PKCδ, and other kinases.

[0068] The active agents or compounds of the present invention may be provided as prodrugs of the compounds of the present disclosure.

[0069] The term "active agent" is usually used to refer to compounds of the present disclosure that have inhibitory activity against PKC-theta, especially under physiological conditions. However, active agents are often difficult to administer or deliver to the relevant physiological site, for example, due to solubility, half-life, or many other chemical or biological reasons. Therefore, it is known to use "prodrugs" of active agents to overcome physicochemical, biological or other problems in efficacy and / or toxicity. Furthermore, prodrug strategies can be used to increase the selectivity of drugs to their intended targets. Thus, according to the present disclosure, prodrugs would be beneficial to target active agents to the desired biological site, while advantageously avoiding sites such as the stomach (or lungs), where adverse side effects are problematic due to local inhibition of PKC-theta activity.

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

[0071] On the other hand, if the therapeutic effect results from the release of an active agent from a larger chemical structure, the final active agent / compound / drug may have significant structural differences compared to the prodrug from which it is derived. In such cases, the prodrug may effectively "mask" a form of the active agent, and in such cases, the prodrug may be completely (or essentially) inactive under physiological conditions.

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

[0073] The molecules, compounds and compositions of the present disclosure may be administered by any suitable route, for example, administration methods include intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, oral, sublingual, intranasal, intravaginal, transdermal, rectal, inhalation or topical administration to the skin. Delivery systems are also known, for example, encapsulation in liposomes, microgels, microparticles, microcapsules, capsules, etc. The use of any other suitable delivery system known in the art is also envisioned. Administration can be systemic or local. The mode of administration can be left to the discretion of the skilled artisan.

[0074] The dosage will of course vary depending on known factors such as the pharmacodynamic properties of the particular active agent, the selected mode and route of administration, the age, health and weight of the recipient, the nature of the disease or disorder being treated, the severity of symptoms, simultaneous or concurrent treatments, frequency of treatment, and the desired effect. In general, the daily dosage of the active agent may be considered to be about 0.001 to about 1,000 mg / kg of body weight. Depending on the application, the dosage may suitably be within the range of about 0.01 to about 100 mg / kg; about 0.1 to about 25 mg / kg; or about 0.5 to about 10 mg / kg.

[0075] Depending on known factors such as those mentioned above, the required amount of active agent may be administered once a day, or the total daily dosage may be divided and administered, for example, two, three or four times a day. Suitably, the treatment regimen according to the present disclosure is contemplated as a once a day administration or a divided twice a day administration.

[0076] A dosage form of the pharmaceutical composition of the present disclosure suitable for administration may contain about 1 mg to about 2,000 mg of active ingredient per unit. Typically, the daily dosage of the compound may be at least about 10 mg and at most about 1,500 mg per human; for example, between about 25 and 1,250 mg, or preferably between about 50 and 1,000 mg. Typically, the daily dosage of the compound may be at most about 1000 mg. In such compositions, the compound of the present invention is typically present in an amount of about 0.5 to 95% by weight based on the total weight of the composition.

[0077] "Effective amount" or "therapeutically effective amount" refers to an amount of a compound or composition of the present disclosure that is effective for curing, suppressing, alleviating, reducing or preventing the side effects of the disease or disorder to be treated, or an amount required to achieve a physiologically or biochemically detectable effect. Thus, an effective amount of a compound or agent can produce a desired therapeutic, ameliorative, suppressive or preventive effect on a disease or disorder. Beneficially, an effective amount of a compound or composition of the present disclosure can have an effect of inhibiting PKC-theta. Diseases or disorders that can benefit from PKC-theta inhibition include, for example, autoimmune diseases, inflammatory diseases, cancer and / or neoplastic diseases, such as rheumatoid arthritis, multiple sclerosis, psoriasis, Sjogren's syndrome and systemic lupus erythematosus or vasculitic diseases, hematopoietic origin cancers or solid tumors, including chronic myelogenous leukemia, myeloid leukemia, non-Hodgkin's lymphoma and other B-cell lymphomas.

[0078] For therapeutic use, the effective amount or therapeutically effective amount of the compound / active agent of the present disclosure may be at least about 50 nM or at least about 100 nM; typically at least about 200 nM or at least about 300 nM in the blood of a subject. The effective amount 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 a subject. For example, the therapeutically effective amount may be at most about 500 nM, for example, about 100 nM to 500 nM. In some embodiments, the amount of the compound for treatment may be measured in the serum of a subject, and then the above concentration may be applied to the serum concentration of the compound of the present disclosure.

[0079] When administered to a subject, the compound of the present disclosure is preferably administered as a component of a composition that includes a pharma- ceutically acceptable carrier or vehicle.One or more additional pharma- ceutically acceptable carriers (such as diluents, adjuvants, excipients or vehicles) can be combined with the compound of the present disclosure in a pharmaceutical composition.Suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" by EW Martin.The pharmaceutical preparations and compositions of the present disclosure are formulated to comply with regulatory standards and according to the selected route of administration.

[0080] Acceptable pharmaceutical vehicles can be liquids such as water and oils (e.g., petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc.). Pharmaceutical vehicles can include saline, gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea, etc. In addition, auxiliary agents, stabilizers, thickeners, lubricants and colorants can be used. When administered to a subject, pharma-ceutically acceptable vehicles are generally sterile. When the compound is administered intravenously, water is a suitable vehicle. Aqueous solutions of saline, dextrose and glycerol can also be used as liquid vehicles, particularly for injections. Suitable pharmaceutical vehicles also include excipients such as starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol, etc. The compositions of the present invention, if desired, can also contain minor amounts of wetting agents, emulsifying agents, or buffers.

[0081] The pharmaceutical agents and pharmaceutical compositions of the present disclosure can be in the form of a solution, suspension, emulsion, tablet, pill, pellet, powder, gel, capsule (e.g., capsule containing liquid or powder), sustained release formulation (such as delayed or sustained release formulation), suppository, emulsion, aerosol, spray, suspension 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., pages 1447-1676).

[0082] Preferably, the therapeutic composition or medicament of the present disclosure is formulated according to routine procedures as a pharmaceutical composition adapted for oral administration (more preferably for humans).Compositions for oral administration can 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 capsules, tablets or pills.

[0083] Orally administered compositions may contain one or more pharmaceutical ingredients, such as, for example, sweeteners, such as fructose, aspartame, or saccharin; flavorings, such as peppermint, wintergreen, or cherry; colorings; and preservatives, to provide a medicament that is medicamentically palatable. When the composition is in the form of a tablet or pill, the composition may be coated to delay disintegration and absorption in the digestive tract, so as to provide sustained release of the active agent over an extended period of time. A selectively permeable membrane surrounding an osmotically active driving compound is also suitable for orally administered compositions. In these dosage forms, fluid from the environment surrounding the capsule is imbibed by the driving compound, causing the driving compound to swell and exchange the drug or drug composition through an opening. These dosage forms can provide an essentially zero order delivery profile, as opposed to the spiked profiles of immediate release formulations. Time-delay materials, such as glycerol monostearate or glycerol stearate, may also be used. Oral compositions may include standard vehicles, such as mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, and the like. Such vehicles are preferably of pharmaceutical grade. For oral formulations, the release location may be the stomach, the small intestine (duodenum, jejunum or ileum) or the large intestine. Those skilled in the art can prepare formulations that do not dissolve in the stomach but release the substance in the duodenum or other places in the intestine. Suitably, the release avoids harmful effects on the stomach environment, either by protecting the compound (or composition) or by releasing the compound (or composition) after passing through the stomach environment, for example, in the intestine. To ensure full gastric resistance, a coating that is impermeable to at least pH 5.0 may be essential.Examples of more common inactive ingredients used as enteric coatings are 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 blend films.

[0084] Providing the therapeutic composition and / or the compound of the present disclosure in a form suitable for oral administration may be beneficial, for example, to improve patient compliance and facilitate administration, but in some embodiments, the compound or composition of the present disclosure may cause undesirable side effects, such as enteritis, which may lead to early termination of the therapeutic regimen.Thus, in some embodiments, the therapeutic regimen is adapted to accommodate a "drug holiday", for example, one or more days of non-administration.For example, the therapeutic regimen and method of the present disclosure may include an iterative process that includes administering the therapeutic composition or compound on consecutive days, followed by one or more consecutive days of drug holiday. For example, a treatment regimen of the present disclosure may include repeated cycles of administration of 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 a rest period of 1 to 14 consecutive days, 1 to 12 consecutive days, 1 to 10 consecutive days, or 1 to 7 consecutive days (e.g., 1, 2, 3, 4, 5, 6, or 7 days).

[0085] To help dissolve the therapeutic agent in the aqueous environment, surfactants may be added as wetting agents.Surfactants include anionic detergents such as sodium lauryl sulfate, dioctyl sodium sulfosuccinate, dioctyl sodium sulfonate, etc.Cationic detergents may also be used, including benzalkonium chloride and benzethonium chloride.Nonionic detergents that may be included in the formulation as surfactants include lauromacrogol 400, polyoxyl 40 stearate, polyoxyethylene hydrogenated castor oil 10, 50 and 60, glyceryl monostearate, polysorbate 20, 40, 60, 65 and 80, sucrose fatty acid esters, methylcellulose and carboxymethylcellulose.When these surfactants are used, they can be present alone or as a mixture of different ratios in the formulation of the compound or derivative.

[0086] Compositions for intravenous administration generally comprise sterile isotonic aqueous buffer.Optionally, the composition may also include a solubilizing agent.

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

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

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

[0090] When the present invention provides one or more active compounds / drugs for use in combination, generally, the drugs can be formulated separately or in a single dosage form, depending on the most appropriate administration regimen determined for each drug involved.When the therapeutic agent is formulated separately, the pharmaceutical composition of the present invention can be used in a therapeutic regimen that includes simultaneous administration, separate administration or sequential administration with one or more other therapeutic agents.The other therapeutic agent(s) can include the compounds of the present disclosure or therapeutic agents known in the art.

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

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

[0093] material and method Sample preparation: The powder was dissolved in DMSO-d6, vortexed vigorously until the solution was clear, and transferred to NMR for data acquisition.

[0094] NMR spectroscopy: Liquid-phase NMR experiments are triple-resonance 1 H, 15 N, 13 C CP-TCI 5 mm cryoprobe (Bruker Biospin, Germany) was used on a 600 MHz (14.1 Tesla) Bruker Avance III NMR spectrometer ( 1 H is 600MHz, 13 C was recorded at 151 MHz.

[0095] Liquid-phase NMR experiments were performed on a 500 MHz (11.75 Tesla) Bruker Avance I NMR spectrometer ( 1500 MHz for H, 13 C was recorded at 125 MHz.

[0096] Liquid-phase NMR experiments were performed on a 400 MHz (9.4 Tesla) Bruker Avance NEO NMR spectrometer ( 1 400 MHz for H, 13 C was recorded at 100 MHz.

[0097] All experiments (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 H chemical shifts are reported in δ (ppm) as s (singlet), d (doublet), t (triplet), q (quartet), dd (double doublet), m (multiplet) or brs (broad singlet).

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

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

[0100] Temperatures are given in degrees Celsius (°C). The reaction mixtures used in the following examples can be obtained from commercially available materials or can be prepared from commercially available starting materials by methods as described herein or 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 suitably followed, for example, by LC, GC or TLC, and reaction times and temperatures can be adjusted as appropriate, as would be readily understood by one of ordinary skill in the art.

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

[0102] Abbreviation In addition to the above definitions, the following abbreviations are used in the synthetic schemes above and in the examples below. If an abbreviation used herein is not defined, it has its generally accepted meaning: [Table 57] TIFF2024518447000080.tif95153

[0103] Example 1 - Chemical synthesis route Scaffold Synthesis of dimethyl scaffolds Synthesis of 4-bromo-3,3-dimethyl-1H-pyrrolo[2,3-b]pyridin-2-one [ka] In a 250 mL three-neck round-bottom flask, a 1M solution of lithium bis(trimethylsilyl)amide (33 mL, 33.4 mmol, 3.8 eq.) was added dropwise from a dropping funnel to a solution of 4-bromo-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (2.00 g, 8.92 mmol, 1 eq.) in anhydrous THF (44 mL, 0.2N) at -78 °C. The mixture was stirred at -78 °C for 10 min. Then, iodomethane (1.4 mL, 22.3 mmol, 2.5 eq.) was added. The reaction mixture was allowed to warm to room temperature and stirred at room temperature for 1 h. Then, a 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 give 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 Dicalite solid phase. The relevant fractions were collected and concentrated in vacuo to give 4-bromo-3,3-dimethyl-1H-pyrrolo[2,3-b]pyridin-2-one as a pale yellow powder (63% yield). 1 H NMR (DMSO-d6, 400 MHz):δ (ppm) 11.26 (s, 1H), 7.95 (d, J=5.7 Hz, 1H), 7.19 (d, J=5.7 Hz, 1H), 1.39 (s, 6H);m / z = 241.2, 243.2 [M+H]+.

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

[0105] Synthesis of 3,3-dimethyl-1-tetrahydropyran-2-yl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridin-2-one [ka] A sealed vial was charged with 4-bromo-3,3-dimethyl-1-tetrahydropyran-2-yl-pyrrolo[2,3-b]pyridin-2-one (0.75g, 2.31mmol), bis(pinacolato)diboron (0.88g, 3.46mmoL, 1.5eq.), potassium acetate (715mg, 6.92mmol, 3eq.) and the dichloromethane adduct of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (193mg, 0.231mmol, 0.1eq.) in anhydrous dioxane (8mL, 0.3N) under nitrogen. 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 dicalite and the filtrate was evaporated to dryness to give 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 pooled and concentrated in vacuo to give 3,3-dimethyl-1-tetrahydropyran-2-yl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridin-2-one (490 mg, 57% yield) as a yellow oil. 1 H NMR (DMSO-d6, 400 MHz):δ (ppm) 8.19 (d, J=5.1 Hz, 1H), 7.24 (d, J=5.1 Hz, 1H), 5.42 (dd, J=11.3, 2.0 Hz, 1H), 3.96 (d, J=11.1 Hz, 1H), 3.64 - 3.44 (m, 1H), 2.89 (d, J=11.4 Hz, 1H), 1.91 (s, 1H), 1.73 - 1.46 (m, 4H), 1.40 (s, 6H), 1.35 (s, 12H). m / z = 373.4 [M+H]+.

[0106] Ethyl / methyl scaffold synthesis Synthesis of 3,4-dibromo-3-methyl-1H-pyrrolo[2,3-b]pyridin-2-one [ka] To a stirred solution of 4-bromo-3-methyl-1H-pyrrolo[2,3-b]pyridine (460 mg, 2.07 mmol) in tert-butanol (16 mL, 0.13N) was added bromide-pyridinium perbromide (1.46 g, 4.56 mmol, 2.2 eq.) in portions over 10 min. The reaction mixture was stirred at room temperature overnight. t-butanol was removed under vacuum. Water was added followed by ethyl acetate. The two phases were separated and the aqueous phase was extracted with EtOAc. The combined organic phase was washed with water, dried over Na2SO4 and concentrated under high vacuum to give 3,4-dibromo-3-methyl-1H-pyrrolo[2,3-b]pyridin-2-one (660 mg, 96% yield) as a white solid. 1 H 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); (product unstable by LCMS)

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

[0108] Synthesis of 4-bromo-3-ethyl-3-methyl-1H-pyrrolo[2,3-b]pyridin-2-one [ka] A 1M solution of lithium[bis(trimethylsilyl)amide] (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]pyridin-2-one (350 mg, 1.08 mmol) in 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 min. 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 h. Then, 1N aqueous hydrochloric acid was added slowly until the pH was 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 on a phase separator and evaporated to give the crude material as an orange solid. The crude material was purified by flash chromatography on silica gel using a gradient of heptane / ethyl acetate that was eluted through the solid phase. The relevant fractions were collected and concentrated in vacuo to give 4-bromo-3-ethyl-3-methyl-1H-pyrrolo[2,3-b]pyridin-2-one (155 mg, 56% yield) as a flesh-colored powder. 1H NMR (400 MHz, DMSO-d6) δ 11.30 (s, 1H), 7.96 (d, J = 5.7 Hz, 1H), 7.21 (d, J = 5.7 Hz, 1H), 2.21 - 2.05 (m, 1H), 1.77 (dq, J = 14.7, 7.4 Hz, 1H), 1.38 (s, 3H), 0.50 (t, J = 7.4 Hz, 3H);m / z = 255.1, 257.1 [M+H]+.

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

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

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

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

[0113] Synthesis of 3-ethyl-3-methyl-1-tetrahydropyran-2-yl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridin-2-one [ka] A 20 mL microwave vial was charged with bis(pinacolato)diboron (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]pyridin-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.) in anhydrous dioxane (43 mL, 0.1 N). The mixture was degassed with nitrogen and stirred at 100 °C for 2 h. The reaction mixture was allowed to warm to room temperature and filtered through a pad of dicalite. The dicalite was washed with EtOAc. The combined organic layers were concentrated in vacuo to give the crude material as a brown oil. The crude material was purified by flash chromatography on silica gel using a gradient of cyclohexane / EtOAc. It was eluted through a dicalite solid phase. The relevant fractions were collected and concentrated under vacuum to give 3-ethyl-3-methyl-1-tetrahydropyran-2-yl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridin-2-one (1.08 g, 52% yield) as a pale yellow oil. 1H NMR (DMSO-d6, 400 MHz):δ (ppm) 8.19 (d, J=5.2 Hz, 1H), 7.25 (d, J=5.1 Hz, 1H), 5.43 (dd, J=11.4, 2.0 Hz, 1H), 3.96 (d, J=11.1 Hz, 1H), 3.64 - 3.49 (m, 1H), 3.01 - 2.79 (m, 1H), 2.33 - 2.16 (m, 1H), 1.93 (d, J=11.0 Hz, 1H), 1.87 - 1.73 (m, 2H), 1.71 - 1.43 (m, 6H), 1.34 (s, 12 H), 0.38 (t, J=7.4 Hz, 3H);m / z = 387.0 [M+H]+.

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

[0115] The two enantiomers were obtained from chiral separation of the 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: 1000g / min UV detection: λ=290 nm Temperature: 40℃ Pressure: 150 bars Sample: Dissolved in MeOH rt (OHMe isomer 1) = 6.05 min and rt(OHMe isomer 2) = 8.34 min

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

[0117] The following methods are identical for the racemic mixture and the pure enantiomers. The boronic ester synthesis is described for enantiomer 1.

[0118] Synthesis of (3R)-4-bromo-3-hydroxy-3-methyl-1-tetrahydropyran-2-yl-pyrrolo[2,3-b]pyridin-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]pyridin-2-one (2.00 g, 8.23 ​​mmol) and p-toluenesulfonic acid hydrate (313 mg, 1.65 mmol, 0.2 eq.) in anhydrous toluene (27 mL, 0.3 N). The reaction mixture was stirred at 90° C. overnight. 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 in vacuo. Dichloromethane and a saturated aqueous solution of NaHCO3 were added. The aqueous phase was extracted with dichloromethane. The organic phase was dried on a phase separator and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel using a gradient of heptane / EtOAc. The relevant fractions were collected and evaporated to give (3R)-4-bromo-3-hydroxy-3-methyl-1-tetrahydropyran-2-yl-pyrrolo[2,3-b]pyridin-2-one (1.02 g, 36% yield). 1 H NMR (DMSO-d6, 400 MHz):δ (ppm) 8.07 (dd, J=5.6, 1.2 Hz, 1H), 7.31 (dd, J=5.7, 0.8 Hz, 1H), 6.28 (d, J=6.8 Hz, 1H), 5.37 (dd, J=11.3, 1.9 Hz, 1H), 4.02 - 3.90 (m, 1H), 3.54 (td, J=11.0, 10.6, 3.2 Hz, 1H), 2.90 - 2.73 (m, 1H), 1.93 (d, J=10.0 Hz, 1H), 1.69 - 1.44 (m, 7H);m / z = 327.0, 328.9 [M+H]+.

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

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

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

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

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

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

[0125] The two enantiomers were separated under the 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 from chiral separation of the racemic mixture in

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

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

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

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

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

[0131] Synthesis of 7-bromo-3-tetrahydropyran-2-yl-1H-imidazo[4,5-b]pyridin-2-one [ka] To a solution of 7-bromo-1,3-dihydroimidazo[4,5-b]pyridin-2-one (500 mg, 2.34 mmol) in anhydrous THF (17.5 mL, 0.1 N) was added 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.). The mixture was stirred at 75° C. overnight. 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 h. The reaction mixture was allowed to warm to room temperature and quenched with water. EtOAc was added and the two layers were separated. The aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give the crude material as a brown oil. The crude mixture was purified by flash chromatography using a gradient of cyclohexane / EtOAc, which was eluted through a dicalite solid phase. The relevant fractions were pooled and concentrated in vacuo to give 7-bromo-3-tetrahydropyran-2-yl-1H-imidazo[4,5-b]pyridin-2-one (452 ​​mg, 65% yield) as a yellow solid. 1H NMR (DMSO-d6, 400 MHz):δ (ppm) 11.77 (s, 1H), 7.84 (d, J=5.6 Hz, 1H), 7.28 (d, J=5.7 Hz, 1H), 5.41 (dd, J=11.3, 2.2 Hz, 1H), 4.02 - 3.92 (m, 1H), 3.58 (td, J=11.3, 3.4 Hz, 1H), 2.94 (qd, J=12.6, 4.1 Hz, 1H), 1.99 - 1.90 (m, 1H), 1.76 - 1.45 (m, 4H), [M+H]+.

[0132] Synthesis of 3-tetrahydropyran-2-yl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-imidazo[4,5-b]pyridin-2-one [ka] To a solution of 7-bromo-3-tetrahydropyran-2-yl-1H-imidazo[4,5-b]pyridin-2-one (300 mg, 1.01 mmol) in anhydrous dioxane (10 mL, 0.1 N) was added potassium acetate (420 mg, 4.02 mmol, 4 eq.) and bis(pinacolato)diboron (767 mg, 3.02 mmol, 3 eq.). The mixture was degassed with 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 under N2 for 2 h. The mixture was filtered through dicalite and concentrated to give 3-tetrahydropyran-2-yl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-imidazo[4,5-b]pyridin-2-one (1.1 g, 57% yield) as a dark oil. The crude material was used in the next step without further purification. m / z = 264.1 [M+H]+. (boronic acid).

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

[0134] Synthesis of 7-bromo-3H-oxazol[4,5-b]pyridin-2-one [ka] 2-Amino-4-bromopyridin-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 at 60° C. overnight. The solution was evaporated in vacuum and the crude product was triturated in DCM. The resulting solid was filtered and dried in vacuum to give 7-bromo-3H-oxazolo[4,5-b]pyridin-2-one as a brown powder (140 mg, 32% yield). 1 H NMR (DMSO-d6, 400 MHz): δ (ppm) 7.85 (d, J=5.8 Hz, 1H), 7.25 (d, J=5.8 Hz, 1H).

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

[0136] Synthesis of 4'-bromo-1'-tetrahydropyran-2-yl-spiro[cyclopentane-1,3'-pyrrolo[2,3-b]pyridin]-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.) in anhydrous toluene (4.8 mL, 0.2 N). The reaction mixture was stirred at 90° C. overnight. The solvent was removed in vacuo. The crude material was purified by flash chromatography on silica gel using a heptane / ethyl acetate gradient. The relevant fractions were combined and concentrated in vacuo to give 4'-bromo-1'-tetrahydropyran-2-yl-spiro[cyclopentane-1,3'-pyrrolo[2,3-b]pyridin]-2'-one (238 mg, 70% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.04 (d,J= 5.6 Hz, 1H), 7.32 (d,J= 5.7 Hz, 1H), 5.37 (dd,J= 11.3, 2.1 Hz, 1H), 3.96 (d,J= 11.3 Hz, 1H), 3.53 (td,J= 11.2, 4.0 Hz, 1H), 2.95 - 2.76 (m, 1H), 2.17 (dd,J= 13.2, 5.9 Hz, 2H), 2.04 - 1.87 (m, 7H), 1.69 - 1.50 (m, 4H);m / z = 351.2-353.2 [M+H]+.

[0137] Synthesis of 1'-tetrahydropyran-2-yl-4'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[cyclopentane-1,3'-pyrrolo[2,3-b]pyridin]-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]pyridin]-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 give the crude material as a dark oil. The crude material was purified by flash chromatography on silica gel using a gradient of dichloromethane / ethyl acetate. It was eluted through a Dicalite solid phase. 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]pyridin]-2'-one (190 mg, 35% yield). 1 H NMR (chloroform-d, 400 MHz):δ (ppm) 8.16 (d, J=5.2 Hz, 1H), 7.28 (d, J=5.1 Hz, 1H), 5.52 (dd, J=11.3, 2.2 Hz, 1H), 4.21 - 4.10 (m, 1H), 3.69 (td, J=11.9, 2.2 Hz, 1H), 3.00 (qd, J=13.1, 12.6, 4.1 Hz, 1H), 2.29 - 1.95 (m, 9H), 1.85 - 1.60 (m, 4H), 1.35 (s, 12H); 399.4 [M+H]+.

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

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

[0140] Synthesis of 4-chloro-5-fluoro-3,3-dimethyl-1-tetrahydropyran-2-yl-pyrrolo[2,3-b]pyridin-2-one [ka] A 20 mL vial was charged with 4-chloro-5-fluoro-3,3-dimethyl-1H-pyrrolo[2,3-b]pyridin-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.). The reaction mixture was stirred at 90° C. overnight. Then, 3,4-dihydro-2H-pyran (0.5 mL) was added and the reaction mixture was stirred at 90° C. for another night. The solvent was evaporated to give the crude material as a brown oil. The crude material was purified by flash chromatography on silica gel using a heptane / ethyl acetate gradient. It was eluted through the solid phase. Relevant fractions were combined and concentrated in vacuo to give 4-chloro-5-fluoro-3,3-dimethyl-1-tetrahydropyran-2-yl-pyrrolo[2,3-b]pyridin-2-one (785 mg, 67% yield) as an orange gum. 1H NMR (400 MHz, DMSO-d6) δ 8.37 (d, J = 2.0 Hz, 1H), 5.38 (dd, J = 11.3, 2.1 Hz, 1H), 3.97 (d, J = 10.7 Hz, 1H), 3.55 (td, J = 11.3, 4.0 Hz, 1H), 2.82 (qd, J = 13.7, 12.9, 4.1 Hz, 1H), 1.97 - 1.88 (m, 1H), 1.69 - 1.48 (m, 4H), 1.44 (s, 6H), m / z = 299.2, 301.2 [M+H]+

[0141] Synthesis of 5-fluoro-3,3-dimethyl-1-tetrahydropyran-2-yl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridin-2-one [ka] To a reaction vial, under nitrogen atmosphere, was added tricyclohexylphosphane (284 μL, 0.180 mmol, 0.075 eq), bis(pinacolato)diboron (1.22 g, 4.79 mmol, 2 eq.), 4-chloro-5-fluoro-3,3-dimethyl-1-tetrahydropyran-2-yl-pyrrolo[2,3-b]pyridin-2-one (715 mg, 2.39 mmol) and anhydrous dioxane (12 mL, 0.2 N). 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 at 100 °C overnight. The mixture was filtered over dicalite and concentrated to give the crude material as a black oil. The crude material was purified by flash chromatography on silica gel using a gradient of heptane / ethyl acetate. 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]pyridin-2-one (670 mg, 22% yield) was obtained as a yellow solid (mixture of product and debrominated product). m / z = 391.4 [M+H]+

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

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

[0144] Synthesis of 3-ethyl-5-fluoro-3-methyl-1-tetrahydropyran-2-yl-pyrrolo[2,3-b]pyridin-2-one [ka] A 2-5 mL vial was charged with 3-ethyl-5-fluoro-3-methyl-1H-pyrrolo[2,3-b]pyridin-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) in anhydrous toluene (1.7 mL, 0.3 N). The resulting mixture was stirred at 95° C. overnight and concentrated to dryness. The crude material was purified by flash chromatography on silica gel using a heptane / EtOAc gradient to give 3-ethyl-5-fluoro-3-methyl-1-tetrahydropyran-2-yl-pyrrolo[2,3-b]pyridin-2-one (80 mg, 51% yield). 1 H NMR (DMSO-d6, 600 MHz):δ (ppm) 8.17-8.18 (m, 1H), 7.85 (dd, J = 8.2, 2.8 Hz, 1H), 5.36 (d, J = 10.4 Hz, 1H), 3.95 (dt, J = 11.4, 2.0 Hz, 1H), 3.53 (tt, J = 11.4, 2.8 Hz, 1H), 2.79-2.94 (m, 1H), 1.89-1.95 (m, 1H), 1.74-1.86 (m, 2H), 1.53-1.65 (m, 2H), 1.45-1.55 (m, 2H), 1.29 (s, 3H), 0.51 (td, J = 7.4, 3.4 Hz, 3H) ;m / z = 279.2 [M+H]+.

[0145] Synthesis of 5-ethyl-3-fluoro-5-methyl-7-tetrahydropyran-2-yl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7H-cyclopenta[b]pyridin-6-one [ka] A 1M solution of lithium diisopropylamide (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]pyridin-2-one (78 mg, 0.256 mmol) in anhydrous THF (2 mL, 0.1 N) in a sealed 2-5 mL vial under nitrogen at -60°C. The reaction mixture was stirred at -60°C for 30 min. 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 min and allowed to warm to room temperature over 4 h. 2,3-Dimethylbutane-2,3-diol (0.60 mL, 0.512 mmol, 2 eq.) was added to the mixture, which was then stirred for 10 min, followed by the addition of acetic acid (0.015 mL, 0.269 mmol, 1.05 eq.). The reaction mixture was stirred at room temperature overnight. The mixture was filtered through dicalite. The solvent was partially evaporated under a stream of nitrogen, and the solution was extracted with 5% aqueous NaOH. The resulting aqueous layer was collected and acidified to pH=6 by dropwise addition of 3N hydrochloric acid at 0° C., and extracted with EtOAc. The combined organic phases were washed with brine, dried using a phase separator and evaporated to give 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]pyridin-6-one (50 mg, 26% yield) as a brown gum. m / z = 323.2 [M+H]+ (acid form) (impurity).

[0146] Scaffold Coupling - General Method (Indoles) [ka]

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

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

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

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

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

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

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

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

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

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

[0157] Scaffold Coupling - Specific Examples Indole I was either obtained commercially or synthesized by standard techniques according to the following methods.

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

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

[0160] 2. Michael reaction A 4 mL reaction vial was charged with cyclobutylideneacetonitrile (0.387 mmol, 2 eq.), Suzuki coupling product II (0.194 mmol, 1 eq.) in anhydrous acetonitrile (0.95 mL, 0.2 N), and DBU (0.387 mmol, 2 eq.) in that order. The reaction was stirred at 85° C. overnight. One equivalent of cyclobutylideneacetonitrile was then added and the reaction mixture was stirred for 2 h. The reaction mixture was filtered and the precipitate was washed with acetonitrile to give product III.

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

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

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

[0164] Scaffold Coupling – General Method (Indazole 1) [ka]

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

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

[0167] 2. Boronate formation A 10 mL reaction vial was charged with substituted bromoindazole II (0.753 mmol), bis(pinacolato)diboron (1.13 mmol, 1.5 eq) and bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.0753 mmol, 0.1 eq.) in anhydrous dioxane (2.5 mL, 0.3 N). The mixture was degassed under N2 and stirred at 100° C. overnight. The mixture was filtered over dicalite and concentrated in vacuo to give the crude material as a dark oil. The crude material III was used in the next step without further purification.

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

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

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

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

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

[0173] Scaffold Coupling – General Method (Indazole 2) [ka]

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

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

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

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

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

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

[0180] Scaffold Coupling – General Method (Indazole 3) [ka]

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

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

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

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

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

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

[0187] Scaffold Coupling – General Method (Indazole 4) [ka]

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

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

[0190] 2. Suzuki Coupling A 6-20 mL reaction vial was charged with substituted bromoindazole II (0.532 mmol), 3,3-dimethyl-1-tetrahydropyran-2-yl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridin-2-one (0.532 mmol, 1 eq.), potassium phosphate tripotassium (229 mg, 1. 06 mmol, 3 eq.), Xphos (10 mg, 0.021 mmol, 0.04 eq.), tris(dibenzylideneacetone)dipalladium(0) (0.011 mmol, 0.02 eq.), dioxane (2.2 mL) and water (0.4 mL) in sequence. The vial was sealed, evacuated under vacuum and backfilled with argon. The reaction mixture was stirred at 95 °C overnight. Water and EtOAc were added. The two phases were separated and the aqueous phase was extracted with EtOAc. The combined organic phases were dried using a phase separator and evaporated to give the crude material. The crude material was purified by flash chromatography on silica gel using a gradient of heptane / EtOAc. It was eluted with Liquid Injection / DCM. The relevant fractions were collected and concentrated under vacuum to give the desired product III.

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

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

[0193] Example: Synthesis of 3,3-dimethyl-4-[1-[(3-methylmorpholin-3-yl)methyl]indazol-3-yl]-1-tetrahydropyran-2-yl-pyrrolo[2,3-b]pyridin-2-one (R1=H, R2=Me) Brown gum; 61% yield; 1H NMR (600 MHz, DMSO-D6, 300 K) δ (ppm) = 8.33 (d, J = 5.3 Hz, 1H), 7.84 (d, J = 8.5 Hz, 1H), 7.78 (d, J = 8.2 Hz, 1H), 7.50 (ddd, J = 0.9, 7.1, 8.3 Hz, 1H), 7.38 (d, J = 5.4 Hz, 1H), 7.27 - 7.20 (m, 1H), 5.49 (dd, J = 2.1, 11.4 Hz, 1H), 4.69 (d, J = 14.5 Hz, 1H), 4.54 (d, J = 14.5 Hz, 1H), 3.99 (td, J = 1.9, 11.4 Hz, 1H), 3.65 (td, J = 3.8, 11.0 Hz, 1H), 3.61 - 3.46 (m, 3H), 3.13 - 3.06 (m, 1H), 3.04 - 2.83 (m, 1H), 2.78 - 2.70 m / z = 476.5 [M+H]+

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

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

[0196] The enantiomeric compounds were obtained after chiral purification.

[0197] Example 63 was obtained as a by-product by benzyl deprotection / methanol.

[0198] Scaffold Coupling – General Method (Indazole 5) [ka]

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

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

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

[0202] 3. Reduction Substituted indazole II (0.487 mmol) was placed in a 2 mL reaction vial and a 1 M solution of borane in tetrahydrofuran (0.974 mmol, 2 eq.) was added. The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was poured into saturated aqueous NH4Cl and extracted with dichloromethane. The combined organic phases were dried on a phase separator and evaporated to give the crude material as a brown 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 Isolute HM-N. The relevant fractions were collected and concentrated under vacuum to give the desired product III.

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

[0204] 4. Suzuki A 12 mL reaction vial was charged with compound III (0.222 mmol), boronate ester I' (0.222 mmol, 1 eq.) and tetrakistriphenylphosphine palladium (0.0222 mmol, 0.1 eq.) in a mixture of DMF (1.7 mL) and water (0.6 mL). The mixture was degassed with N2, followed by the addition of disodium carbonate (0.666 mmol, 3 eq.). The mixture was again degassed with N2 and stirred at 90 °C for 3 h. Water was added to the cold mixture and the precipitate was filtered, washed with water and dissolved in DCM. The organic phase was filtered through a phase separator and concentrated under vacuum. The crude product was purified with a heptane / EtOAc gradient and the relevant fractions were collected and concentrated under vacuum to give the desired compound IV.

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

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

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

[0208] To obtain Example 77, one more step was performed before deprotection: [ka]

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

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

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

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

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

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

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

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

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

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

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

[0220] Scaffold Coupling – General Method (Pyrazole) [ka]

[0221] First step: Alkylation or Mitsunobu 1a. Alkylation (X= Br) In a reacti-vial, cesium carbonate (532 mg, 1.63 mmol, 1.2 eq) was added to a solution of 3-bromo-1H-pyrazole I (200 mg, 1.36 mmol) and tert-butyl 4-bromopiperidine-1-carboxylate (431 mg, 1.63 mmol, 1.2 eq) in anhydrous DMF (14 mL, 0.1 N). tert-Butyl 4-bromopiperidine-1-carboxylate (431 mg, 1.63 mmol, 2 eq.) and cesium carbonate (532 mg, 1.63 mmol, 2 eq.) were added and the mixture was heated to 70° C. overnight. tert-Butyl 4-bromopiperidine-1-carboxylate (2 eq.) and cesium carbonate (2 eq.) were added again and the mixture was heated to 80° C. for another 4 hours. Water was added and the mixture was extracted with ethyl acetate. The organic phase was dried and concentrated under vacuum to give the crude material. The crude material was purified by flash chromatography on silica gel using a gradient of DCM / EtOAc. It was eluted with Liquid Injection / DCM. Relevant fractions were collected (not visible by UV) and concentrated under vacuum to give tert-butyl 4-(3-bromopyrazol-1-yl)piperidine-1-carboxylate II (266 mg, 54% yield) as a pale oil. 1 H NMR(DMSO-d6, 400 MHz):δ (ppm) 7.83 (d, J=2.4 Hz, 1H), 6.38 (d, J=2.3 Hz, 1H), 4.35 (tt, J=11.5, 4.0 Hz, 1H), 4.03 (d, J=12.3 Hz, 2H), 2.88 (s, 2H), 2.04 - 1.92 (m, 2H), 1.73 (qd, J=12.4, 4.4 Hz, 2H), 1.42 (s, 9H);m / z = 276.1 [M+H]+

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

[0223] The same synthesis is used for the following steps. 2. Boronic esters Substituted bromopyrazole II (0.806 mmol), bis(pinacolato)diboron (1.21 mmol, 1.5 eq.) and potassium acetate (2.42 mmol, 3 eq.) in anhydrous dioxane (2.7 mL, 0.3 N) were placed in a reaction vial. The mixture was degassed with N2 and bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.081 mmol, 0.1 eq.) was added. The reaction mixture was stirred at 100° C. overnight. The mixture was filtered over dicalite and concentrated in vacuo to give crude material III. The crude material was used in the next step without further purification.

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

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

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

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

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

[0229] Scaffold Coupling - General Method (Pyrrole)

change

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

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

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

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

[0234] Example 2 - Biological Assays PKC-θ and PKC-δ inhibition assays Biochemical activity of PKC-θ and PKC-δ was measured using the PKC-θ HTRF KinEASEkit kit (Cisbio, Cat. No. 61ST1PEJ) according to the manufacturer's instructions. Briefly, the kinase buffer components of the kit were supplemented with 10 mM MgCl2, 1 mM DTT, and 0.1% Tween 20. For PKC-θ assays, STK substrate and ATP were added to final assay concentrations of 525 nM and 6.5 μM, respectively. For PKCδ assays, 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 reagents were mixed according to the manufacturer's instructions. Test compounds were diluted in DMSO into 10 serial semi-logarithmic 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 test compounds for 30 min on ice. Reactions were initiated by addition of substrate and ATP and incubated at 25°C for 30 or 20 min for PKC-θ and PKC-δ assays, respectively. Detection reagent was added and plates were incubated in the dark for 2 h. Fluorescence was measured using an Envision 2103 plate reader in HTRF mode with excitation at 665 nM and emission at 620 nM. The acceptor to donor emission signal ratio was calculated for each well. The % inhibition was calculated from the HTRF ratios at different doses and fitted to a 4-parameter logistic curve to determine IC50 values ​​(see Table 1).

[0235] IL-2 release assay of effector memory T cells NFκB signal inhibition in T cells by test compounds was evaluated by quantifying IL-2 secretion by human effector memory T cells (TEM) upon treatment and stimulation. Human TEM cells were isolated from buffy coats of healthy donors obtained from a French blood bank. First, peripheral blood mononuclear cells (PBMCs) were purified by Pancoll (PAN BIOTECH, cat#P04-60500) density gradient centrifugation (400×g, 20 min) from buffy coats diluted 1:1 with DPBS (Gibco, cat#14190-094). TEM cells were further enriched by negative immunomagnetic cell sorting using a human CD4+ effector memory T cell isolation kit (Miltenyi, cat#130-094-125) according to the manufacturer's instructions. Aliquots of 3x10E6 purified TEM cells were stored frozen in Cryo-SFM medium (PromoCelL, cat#C-29912) in nitrogen gas phase until use. Cell purity was confirmed by flow cytometric analysis of 200,000 PFA-fixed cells pre-labeled with monoclonal antibodies anti-CD4-PeRCP-Cy5.5 (BD Pharmigen, cat#332772), anti-CD8-V500 (BD Biosciences, cat#561617), anti-CD14-Pacific Blue (Biolegend, cat#325616), anti-CD45 RA-FITC (Biolegend, cat#304106) and anti-CCR7-APC (CD4+ Effector Memory T Cell Isolation Kit, Miltenyi, cat#130-094-125).

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

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

[0238] Table 2: Biochemical data for representative compounds of the present disclosure In the columns provided, the data are classified into categories A to H according to the measured values ​​as shown below. About PKC-θ HTRF: A means a measured pIC50 of 9.0 or more; B means measured pIC50 is 8.5-9.0; C means measured pIC50 is 8.0-8.5; D means measured pIC50 is 7.5-8.0; E means measured pIC50 is 7.0-7.5; F means measured pIC50 is 6.5-7.0; G means measured pIC50 is 6.0-6.5; H means the measured pIC50 is <6.0.

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

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

[0241] Changes may be made to the above examples without departing from the scope of the invention as defined in the appended claims.

Claims

1. Structural formula I: 【Chemistry 1】 [In the formula, A is N, CR a (In the formula, R a is selected from hydrogen, halogen, C alkyl and CN; G is selected from CR1R2, O, and NR1; R1 and R2 are independently selected from hydrogen, halogen, C1-3 alkyl, C3-7 cycloalkyl, C1-3 alkoxyl, C2-6 cycloalkoxyl, C2-6 alkylalkoxy, hydroxyl, C1-3 alkylhydroxyl, amino, C1-3 alkylamino, C1-4 aminoalkyl, C2-7 alkylaminoalkyl and C1-3 haloalkyl; or R1 and R2 together form an optionally substituted 3- to 5-membered spirocarbocyclic or heterocyclic ring; B is selected from N, CH and C-halogen; D is selected from N, and C-R3; R3 is selected from hydrogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C2-5 alkylalkoxy and halogen; R4 is selected from hydrogen, C1-3 alkyl, C1-3 haloalkyl, OMe, and halogen; or When D is C-R3, R3 and R4 are bonded together to form: 【Chemistry 2】 (In the formula, R7 is selected from hydrogen and halogen; R8 is selected from hydrogen and halogen; R9 is selected from hydrogen, C1-3 haloalkyl, and halogen; R10 is selected from hydrogen, halogen, C1-3 haloalkyl, C1-3 haloalkoxy. forming an optionally substituted aryl or heteroaryl ring having a structure selected from: n is 0 or 1; E is CH or CR a (In the formula, R a is selected from halogen, C alkyl, C alkylhydroxy, C haloalkyl, C alkylalkoxy and C alkylnitrile; R5 and R6 taken together and joined to form an optionally substituted and optionally bridged 4-8 membered saturated carbocyclic or heterocyclic ring. or a pharmaceutically acceptable salt, solvate, stereoisomer or mixture of stereoisomers, tautomer, isotopic form or pharmaceutically active metabolite thereof, or a combination thereof.

2. Structural formula II: 【Transformation 3】 or a pharmaceutically acceptable salt, solvate, stereoisomer or mixture of stereoisomers, tautomer, isotopic form or pharmaceutically active metabolite thereof, or a combination thereof.

3. Structural formula IIa: 【Chemistry 4】 2. The compound of claim 1, wherein R17 is 【Transformation 5】 【Transformation 6】 (In the formula, R11 is selected from hydrogen, halogen, and C1-2 alkyl; R12 is selected from hydrogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkylhydroxyl, and C1-2 alkylnitrile; R13 is selected from hydrogen, halogen, and C1-2 alkyl; R14 is hydrogen or C1-2 alkyl; R15 is hydrogen or C1-2 alkyl; R16 is selected from hydrogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkylhydroxy, and C1-3 alkylalkoxy; R21 and R22 are each independently hydrogen and C1-3 alkyl; n is 0 or 1; p is 1 or 2; X is CH 2 or O; Y is CH 2 , O, NH and NMe) 10. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, stereoisomer or mixture of stereoisomers, tautomer, isotopic form or pharmaceutically active metabolite thereof, selected from:

4. R1 is hydrogen, Me, Et, OMe, OEt, OH, NH 2 , NHMe, and NHEt; R2 is selected from hydrogen, Me and Et; or R1 and R2 together form an optionally substituted 3- to 5-membered spirocarbocyclic or heterocyclic ring; in particular, an optionally substituted 4- to 5-membered carbocyclic or heterocyclic spiro ring; in embodiments, the carbocyclic or heterocyclic spiro ring is unsubstituted; in other embodiments, the carbocyclic or heterocyclic spiro ring is substituted with one or more substituents selected from C1-2 alkyl, halogen, C1-2 haloalkyl, hydroxyl, and C1-2 alkoxyl; A is selected from CH, CF, C—Cl, and C—Br; B is selected from N, CH, CF, C—Cl, and C—Br; R17, Postscript: 【Transformation 6】 (In the formula, R18 is selected from hydrogen and halogen; R19 is selected from hydrogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkylhydroxy; m is 0 or 1; R20 is hydrogen or halogen; X is CH 2 or O; R21 and R22 are each independently selected from hydrogen and C1-3 alkyl; Y is CH 2 , O and NH; R23 is selected from hydrogen, C1-3 alkyl, C1-3 haloalkyl 4. The compound of claim 3, or a pharmaceutically acceptable salt, solvate, stereoisomer or mixture of stereoisomers, tautomer, isotopic form or pharmaceutically active metabolite thereof, selected from:

5. Structural formula III: 【Transformation 7】 (In the formula, D is selected from N, CH and C-R; R3 is selected from C1-3 alkyl, C2-5 alkylalkoxy, C1-3 haloalkyl, and halogen; R4 is selected from hydrogen, C1-3 alkyl, C2-5 alkylalkoxyl, C1-3 haloalkyl and halogen. or a pharmaceutically acceptable salt, solvate, stereoisomer or mixture of stereoisomers, tautomer, isotopic form or pharmaceutically active metabolite thereof, or a combination thereof.

6. Structural Formula IIIa, IIIb, or IIIc: 【Transformation 8】 6. The compound of claim 5, wherein R17 is as defined below: 【Chemistry 9】 【Chemistry 11】 (In the formula, R11 is selected from hydrogen, halogen, and C1-2 alkyl; R12 is selected from hydrogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkylhydroxyl, and C1-2 alkylnitrile; R13 is selected from hydrogen, halogen, and C1-2 alkyl; R14 is selected from hydrogen and C1-2 alkyl; R15 is selected from hydrogen and C1-2 alkyl; R16 is selected from hydrogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkylhydroxyl, and C1-3 alkylalkoxyl; R21 and R22 are each independently hydrogen or C1-3 alkyl; n is 0 or 1; p is 1 or 2; X is CH 2 or O; Y is CH 2 , O, NH and NMe) 6. The compound of claim 5, or a pharmaceutically acceptable salt, solvate, stereoisomer or mixture of stereoisomers, tautomer, isotopic form or pharmaceutically active metabolite thereof, selected from:

7. R1 is hydrogen, Me, Et, OMe, OH, NH 2 and NHMe; R2 is selected from hydrogen, Me and Et; or R1 and R2 together form an optionally substituted 3- to 5-membered spirocarbocyclic or heterocyclic ring; A is selected from CH, CF, C—Cl, and C—Br; R17, Postscript: 【Chemistry 10】 (In the formula, R18 is selected from hydrogen and halogen; R19 is selected from hydrogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkyl and hydroxyl; m is 0 or 1; R20 is hydrogen or halogen; X is CH 2 or O; R21 and R22 are each independently selected from hydrogen and C1-3 alkyl; Y is CH 2 , O and NH; R23 is selected from hydrogen, C1-3 alkyl and C1-3 haloalkyl 7. The compound of claim 6, or a pharmaceutically acceptable salt, solvate, stereoisomer or mixture of stereoisomers, tautomer, isotopic form or pharmaceutically active metabolite thereof, selected from:

8. A compound having the following structure: 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 or a pharmaceutically acceptable salt, solvate, stereoisomer or mixture of stereoisomers, tautomer, isotopic form or pharmaceutically active metabolite thereof, or a combination thereof.

9. 10. A pharmaceutical composition comprising one or more compounds of any one of claims 1 to 8, or a pharmaceutically acceptable salt, solvate, stereoisomer or mixture of stereoisomers, tautomer, isotopic form, or pharmaceutically active metabolite thereof, or a combination thereof, and one or more pharmaceutically acceptable carriers.

10. 10. A pharmaceutical composition comprising the compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt, solvate, stereoisomer or mixture of stereoisomers, tautomer, isotopic form or pharmaceutically active metabolite thereof, or a combination thereof, for use in the treatment of a disease or disorder selected from an autoimmune disease, an inflammatory disease, a neoplastic disease, cancer and HIV infection.

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

12. 11. The pharmaceutical composition of claim 10, wherein the compound is an inhibitor of PKC-theta.

13. 11. The pharmaceutical composition of claim 10, for use in a method comprising administering the compound orally, topically, by inhalation, intranasally, or systemically by intravenous, intraperitoneal, subcutaneous, or intramuscular injection.

14. 10. A pharmaceutical combination comprising one or more compounds of any one of claims 1 to 8, or a pharmaceutically acceptable salt, solvate, stereoisomer or mixture of stereoisomers, tautomer, isotopic form or pharmaceutically active metabolite thereof, or a combination thereof, and one or more additional therapeutic agents.

15. 15. The pharmaceutical combination of claim 14, wherein one or more compounds according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, solvate, stereoisomer or mixture of stereoisomers, tautomer, isotopic form or pharmaceutically active metabolite thereof, or a combination thereof, is administered simultaneously, sequentially or separately with one or more additional therapeutic agents.

16. 11. The pharmaceutical composition of claim 10, comprising administering to a subject an effective amount of the compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt, solvate, stereoisomer or mixture of stereoisomers, tautomer, isotopic form, or pharmaceutically active metabolite thereof, wherein the effective amount is about 5 nM to about 10 μM in the blood of the subject.

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