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. TIFF2024517861000178.tif84160

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] It is well known that abnormal protein phosphorylation is associated with diseases. 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 diacylglycerol (DAG)-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., 6:530).

[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, Frontiers 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, Frontiers 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., Mol Immunol., 2008, 46(2):213-24). Pharmacological inhibition of PKC-θ protected Tregs from inactivation by TNFα and enhanced protection of mice from inflammatory bowel disease (Zanin-Zhorov, et al., Science, 2010, 328 (5976):372-6). Indeed, evidence exists that PKC-θ is a negative regulator of Tregs function (Zhang et al., Adv Pharm. 2013;66:267-31).

[0007] In human disease, genome-wide association studies (GWAS; Brezar et al., 2015, Frontiers 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., Science, 2010, 328 (5976):372-6).

[0008] PKC-θ activity is crucial in Th2 (allergic diseases) and Th17 (autoimmune diseases) responses and differentiation (Zhang et al., Adv Pharm., 2013;66:267-31). - / - Mice are protected in Th2 models of allergic 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 present invention, a compound of structural 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 (e.g., Me, Et) and CN; B is selected from the group consisting of N, CH, CF, and C-(C1-3 alkyl) (e.g., C-Me, C-Et); D is selected from the group consisting of N, CH, CRb (In the formula, R b is halogen (e.g., F, Cl, Br), C1-3 alkyl (e.g., Me, Et) and C1-3 haloalkyl (e.g., CHF 2 , C.F. 3 ) selected from); G is selected from the group consisting of: CR1R2, NR1 and O; R1 and R2 are independently selected from the group consisting of hydrogen, halogen (e.g., F, Cl, Br), C1-3 alkyl (e.g., Me, Et), C3-7 cycloalkyl (e.g., c Pr, c Hex), C1-3 alkoxyl (e.g., OMe, OEt), C2-6 cycloalkoxyl (e.g., oxetane, furan), C2-6 alkylalkoxyl (e.g., CH 2 OMe, (CH 2 ) 2 OMe), hydroxyl, C1-3 alkyl hydroxyl (e.g., CH 2 OH, (CH 2 ) 2 OH), amino, C1-3 alkylamino (e.g., CH 2 NH 2 , (CH 2 ) 2 NH 2 ), C1-4 aminoalkyl (e.g., NMe 2 , NMeEt), C2-7 alkylaminoalkyl (e.g., CH 2 NMe 2 , (CH 2 ) 2 NEt 2 ), C1-3 haloalkyl (e.g., CHF 2 , C.F. 3 , C.H. 2 CHF 2 ), aryl (e.g., phenyl), heteroaryl (e.g., pyridine, thiazole), alkylaryl (e.g., benzyl) and alkylheteroaryl (e.g., CH 2 -Pyridine, CH 2 -thiazole); or R1 and R2 together form an optionally substituted 3-5 membered spiro carbocyclic or heterocyclic ring (e.g., cyclopropane, cyclobutene, cyclopentane, oxetane, furan, pyrrolidine, piperidine); R3 is selected from the group consisting of hydrogen, C1-2 alkyl (e.g., Me, Et), OMe, and halogen (e.g., F, Cl, Br); R4 is selected from the group consisting of hydrogen, C1-5 alkyl (e.g., Me, Et), C3-7 cycloalkyl (e.g., c Pr, c Hex), C1-5 haloalkyl (e.g., CHF 2 , C.F. 3 , C.F. 2 Me, C.H. 2 CHF 2 ), C1-5 alkoxyl (e.g., OMe, OEt), C1-5 haloalkoxyl (e.g., OCHF 2 , OCF 3 , O.C.H. 2 CHF 2 ), alkylalkoxy (e.g., CH 2 OMe, (CH 2 ) 2 OMe), C2-6 heterocycloalkyl (e.g., piperidine, piperazine), CN and halogen (e.g., F, Cl, Br); E is selected from the group consisting of N, CH, CR c (In the formula, R c is halogen (e.g., F, Cl, Br), hydroxyl, C1-3 alkyl hydroxyl (e.g., CH 2 OH, (CH 2 ) 2 OH), C1-3 alkylamino (e.g., CH 2 NH 2 , (CH 2 ) 2 NH 2 ), C1-3 haloalkyl (e.g., CH 2 F, CHF 2 , C.F. 3 , C.H. 2 CHF 2 ), C2-6 alkyl alkoxyl (e.g., CH2 OMe, (CH 2 ) 2 CN) and CN; R5 and R6 are each independently selected from the group consisting of hydrogen, C2-5 alkyl (e.g., Me, Et), C1-C5 amino alkyl (e.g., NMe 2 , NMeEt), 4-8 membered aminoalkyl rings (e.g., piperidine, piperazine), C1-9 alkylalkoxy (e.g., (CH 2 ) 2 OEt, C.H. 2 OMe), C1-9 alkylaminoalkyl (e.g., (CH 2 ) 2 NMe 2 , C.H. 2 NHMe); or R5 and R6 are joined together to form an optionally substituted and optionally bridged ring Z, where ring Z is a C3-10 heterocycloalkyl monocyclic or bicyclic ring, such as c Pr, oxetane, c Hex, piperidine, piperazine, 1,4-diazacycloheptane); E, R5 and R6 together form J, where J is selected from the group consisting of: NR d , C(=O)R d , S.O. 2 R d , OR d , where R d is a 4- to 8-membered aminoalkyl ring (e.g., piperidine, piperazine)] 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 an embodiment, ring Z has the general formula Ia; [ka] [wherein R7 is selected from the group consisting of hydrogen, C1-3 alkyl (e.g., Me, Et) and C1-3 haloalkyl (e.g., CH 2 CHF, CH 2 CHF 2 )] and optionally substituted and optionally bridged, 4-8 membered aminoalkyl ring having the formula:

[0015] In an embodiment, ring Z is: [ka] [In the formula, R8, R9, R10, R11, R13 and R21 are each independently selected from the group consisting of hydrogen, C1-3 alkyl (e.g., Me, Et), C1-3 alkylalkoxy (e.g., CH 2 OMe), C1-3 alkyl hydroxyl (e.g., CH 2 OH), amino, C1-3 alkylamino (e.g., CH 2 NH 2 ), C1-6 alkylaminoalkyl (e.g., CH 2 NMe 2 ), C1-3 haloalkyl (e.g., CHF 2 , C.F. 3 , C.H. 2 CHF 2 ), alkylheteroaryl (e.g., CH 2 -Pyridine, CH 2 -thiazole); R12 is selected from the group consisting of hydrogen, C1-3 alkyl (e.g., Me, Et) and C1-3 haloalkyl (e.g., CH 2 CHF, CH 2 CHF 2 );or any one of R8, R9, R10, R11, R12, R13 and R21 may be joined to another different R8, R9, R10, R11, R12, R13 or R21 to form a 3-7 membered spiro or bicyclic carbocyclic or heterocyclic ring structure and / or a 3-6 membered bridged carbocyclic or heterocyclic ring structure; n is selected from the group consisting of 0, 1 and 2, preferably n is 1 or 2. It is of the following.

[0016] In an embodiment, when n=0, E is selected from N, CH and CR. c where R c is halogen (e.g., F, Cl, Br), hydroxy, C1-3 alkylhydroxy (e.g., CH 2 OH), C1-3 haloalkyl (e.g., CHF 2 , C.F. 3 , C.H. 2 CHF 2 ), C2-5 alkylalkoxy (e.g., CH 2 OMe), C2-5 alkylnitriles (e.g., CH 2 CN).

[0017] In an embodiment, ring Z has the following structure: [ka] It is.

[0018] In one embodiment, G is CR1R2 and ring Z has the following structure: [ka] The A is selected from the group consisting of CH, CF, C-Cl and C-Br; B and D are each independently selected from the group consisting of: N and CH; E is selected from the group consisting of N, CF and CH; R1 is selected from the group consisting of hydrogen, Et, OMe, OEt, OH, NH 2 and NHMe; R2 is selected from the group consisting of hydrogen, Me and Et; or R1 and R2 together form a 3- to 6-membered spiro carbocyclic or heterocyclic ring; R3 is hydrogen or halogen; R4 is selected from the group consisting of hydrogen, Me, Et, CF 2 H, C.F. 3 , C.F. 2 Me, OMe, OEt, OCF 2 H, OCF 3 , CN, Cl and F; R8 and R9 are each independently selected from the group consisting of hydrogen, Me, Et, CH 2 OH, CHMeOH, CMe 2 OH, CH 2 OMe, C.H. 2 F and halogens; R10 and R11 are each independently selected from the group consisting of hydrogen, Me, Et, CH 2 OH, CHMeOH, CMe 2 OH, CH 2 OMe, C.H. 2 F, CHF 2 , C.H. 2 CF 3 and C.H. 2 -heteroaryl; R12 is selected from the group consisting of hydrogen and Me; R13 is selected from the group consisting of hydrogen and Me; R21 is selected from the group consisting of hydrogen and Me; or Any one of R8, R9, R10, R11, R12, R13 and R21 together with another different R8, R9, R10, R11, R21, R13 or R21 forms a 3-7 membered spiro bicyclic carbocyclic or heterocyclic ring structure and / or a 3-6 membered bridged carbocyclic or heterocyclic ring structure.

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

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

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

[0022] In another embodiment of formula I, G is CR1R2 and ring Z is: [ka] The A is selected from the group consisting of CH, CF, C-Cl and C-Br; B and D are each independently selected from the group consisting of: N and CH; E is selected from the group consisting of N, CH and CF; R1 is selected from the group consisting of hydrogen, Me, Et, OMe, OEt, OH, NH 2 and NHMe; and R2 is selected from the group consisting of: hydrogen, Me and Et; or R1 and R2 together form a 3- to 6-membered spiro carbocyclic or heterocyclic ring; in particular a 4- to 5-membered carbocyclic or heterocyclic spiro ring; R3 is hydrogen or F; R4 is selected from the group consisting of Me, Et, CF 2 H, C.F. 3 , C.F. 2 Me, OMe, OEt, OCF 2 H, CN, Cl and F; R14, R15, R17, R18, R19 and R20 are each independently selected from the group consisting of hydrogen, Me and F; and R16 is selected from the group consisting of hydrogen and Me.

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

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

[0025] In an embodiment, when G is NH, B is N.

[0026] In a second aspect, the present invention provides a compound according to Table 1 herein, 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.

[0027] In a third aspect, the present invention provides pharmaceutical compositions comprising one or more compounds of the first or second aspect of the invention, 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.

[0028] In a fourth aspect, the present invention provides a compound of the first or second aspect or a pharmaceutical composition of the third aspect for use in the treatment of a disorder or disease selected from an autoimmune disease and / or an inflammatory disease and / or a neoplastic disease and / or cancer and / or HIV infection and replication.

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

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

[0031] In embodiments, the use includes administering the compound orally, topically, by inhalation or intranasally; or systemically by intravenous, intraperitoneal, subcutaneous or intramuscular injection.

[0032] In an embodiment, use includes administering one or more compounds according to the first or second aspect, optionally in combination with one or more additional therapeutic agents. Suitably, administration includes simultaneous, sequential or separate administration of one or more compounds according to any one of the first or second embodiments with one or more additional therapeutic agents.

[0033] In an embodiment, the use comprises administering to a subject an effective amount of a compound according to the first or second aspect, the effective amount being from about 5 nM to about 10 μM in the subject's blood or a component thereof.

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

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

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

[0037] 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

[0038] 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.

[0039] 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.

[0040] 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.

[0041] 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).

[0042] 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.

[0043] Before setting forth a detailed description of the present invention, a number of definitions are provided to aid in the understanding of this disclosure.

[0044] 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.

[0045] 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.

[0046] 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).

[0047] 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. Tritiated (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).

[0048] 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.

[0049] 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. Alkyl groups may be straight-chained (i.e., linear), branched, or cyclic. "Lower alkyl" refers to an alkyl having from 1 to 6 carbon atoms in the chain, and may have from 1 to 4 carbon atoms or from 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 (C 5 H 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.

[0050] 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.

[0051] 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. Thus, 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 (-NH 2 ), thiol (-SH), cyano (-CN), (lower) alkyl, (lower) alkoxy, (lower) alkenyl, (lower) alkynyl, aryl, heteroaryl, (lower) alkylthio, oxo, haloalkyl, hydroxyalkyl, nitro (-NO 2 ), phosphate, azide (-N 3), 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 a substituent is present on an aryl or other ring system, two adjacent atoms may be substituted with methylenedioxy or ethylenedioxy groups. More suitably, the substituent is selected from the following: halogen, hydroxy, amino, thiol, cyano, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) alkenyl, (C 1 -C 6 ) Alkynyl, aryl, aryl (C 1 -C 6 ) Alkyl, aryl (C 1 -C 6 ) alkoxy, heteroaryl, (C 1 -C 6 ) alkylthio, oxo, halo(C 1 -C 6 ) alkyl, hydroxy (C 1 -C 6 ) Alkyl, nitro, phosphate, azide, (C 1 -C 6 ) alkoxycarbonyl, carboxy, (C 1 -C 6 ) alkyl carboxy, (C 1 -C 6 ) alkylamino, di(C 1 -C 6 ) Alkylamino, Amino(C 1 -C 6 ) alkyl, (C 1 -C 6 ) Alkylamino(C1 -C 6 ) alkyl, di(C 1 -C 6 ) Alkylamino(C 1 -C 6 ) alkyl, thio (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkylsulfonyl, arylsulfinyl, (C 1 -C 6 ) alkylaminosulfonyl, arylaminosulfonyl, (C 1 -C 6 ) alkylsulfonylamino, arylsulfonylamino, carbamoyl, (C 1 -C 6 ) alkylcarbamoyl, di(C 1 -C 6 ) alkylcarbamoyl, arylcarbamoyl, (C 1 -C 6 ) alkylcarbonylamino, arylcarbonylamino, (C 1 -C 6 ) cycloalkyl and heterocycloalkyl. Even more suitably, the substituents are selected from one or more of the following groups: fluoro, chloro, bromo, hydroxy, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, (C 5 -C 6 ) aryl, 5- or 6-membered heteroaryl, (C 4 -C 6 ) cycloalkyl, 4-6 membered heterocycloalkyl, cyano, (C 1 -C 6 ) alkylthio, amino, -NH(alkyl), -NH((C 1 -C 6 )cycloalkyl), -N((C 1 -C 6 )Alkyl) 2 , -OC(O)-(C 1 -C 6 ) alkyl, -OC(O)-(C5 -C 6 )aryl, -OC(O)-(C 1 -C 6 )cycloalkyl, carboxy and -C(O)O-(C 1 -C 6 ) alkyl. Most suitably, the substituents are selected from one or more of the following groups: fluoro, chloro, bromo, hydroxy, amino, (C 1 -C 6 ) alkyl and (C 1 -C 6 ) alkoxy, where alkyl and alkoxy may be optionally substituted with one or more chloro. Particularly preferred substituents are those set forth below: chloro, methyl, ethyl, methoxy and ethoxy.

[0052] 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.

[0053] 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.

[0054] 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.

[0055] 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.

[0056] "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(CH 3 )=CH- and -CH=CHCH 2 -- are some examples.

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

[0058] The term "alkoxy" refers to 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.

[0059] 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-CH 2 "Benzyloxy" is a group of the formula RO- where R is benzyl. Non-limiting examples of aryl groups include phenyl, naphthyl, benzyl, biphenyl, furanyl, pyridinyl, indanyl, anthraquinolyl, tetrahydronaphthyl, benzoic acid, furan-2-carboxylic acid, and the like.

[0060] A "heteroaryl" group is defined herein as a substituted or unsubstituted "aryl" group in which one or more carbon atoms in the ring structure are 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.

[0061] 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.

[0062] 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."

[0063] Molecules and Compounds The present disclosure provides compounds of structural 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; B is selected from the group consisting of N, CH, CF, and C-(C1-3 alkyl); D is selected from the group consisting of N, CH, CR b (In the formula, R b is selected from halogen, C1-3 alkyl, C1-3 haloalkyl; G is selected from the group consisting of: CR1R2, NR1 and O; R1 and R2 are independently selected from the group consisting of hydrogen, halogen, C1-3 alkyl, C3-7 cycloalkyl (e.g., CH 2 c Pr), C1-3 alkoxyl (e.g., OMe), C2-6 cycloalkoxyl (e.g., O c Pr), C2-6 alkylalkoxy (e.g., CH 2 OMe), hydroxyl, C1-3 alkyl hydroxyl (e.g., CH 2 OH), amino, C1-3 alkylamino (e.g., CH 2 NH 2 ), C1-4 aminoalkyl (e.g., NHMe or N(Me) 2 ), C2-7 alkylaminoalkyl (e.g., CH 2 NHMe or CH 2 NH(Me) 2), C1-3 haloalkyl, aryl (e.g., phenyl), heteroaryl (e.g., pyridine), alkylaryl (e.g., benzyl), and alkylheteroaryl; or R1 and R2 together form an optionally substituted 3- to 5-membered spiro carbocyclic or heterocyclic ring; in particular an optionally substituted 4- to 5-membered carbocyclic or heterocyclic spiro ring; wherein in an embodiment, said carbocyclic or heterocyclic spiro ring is unsubstituted; wherein 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; R3 is selected from the group consisting of hydrogen, C1-2 alkyl, -OMe, and halogen; R4 is selected from the group consisting of hydrogen, C1-5 alkyl (e.g., Me, Et), C3-7 cycloalkyl (e.g., c Pr, c Hex), C1-5 haloalkyl (e.g., CHF 2 , C.F. 3 , C.F. 2 Me, C.H. 2 CHF 2 ), C1-5 alkoxyl (e.g., OMe, OEt), C1-5 haloalkoxyl (e.g., OCHF 2 , OCF 3 , O.C.H. 2 CHF 2 ), alkylalkoxy (e.g., CH 2 OMe, (CH 2 ) 2 OMe), C2-6 heterocycloalkyl (e.g., piperidine, piperazine), CN and halogen (e.g., F, Cl, Br); E is selected from the group consisting of N, CH, CR c (In the formula, R c is halogen (e.g., F, Cl, Br), hydroxyl, C1-3 alkyl hydroxyl (e.g., CH 2 OH, (CH 2 ) 2OH), C1-3 alkylamino (e.g., CH 2 NH 2 , (CH 2 ) 2 NH 2 ), C1-3 haloalkyl (e.g., CH 2 F, CHF 2 , C.F. 3 , C.H. 2 CHF 2 ), C2-6 alkyl alkoxyl (e.g., CH 2 OMe, (CH 2 ) 2 CN) and CN; R5 and R6 are each independently selected from the group consisting of hydrogen, C2-5 alkyl, C1-C5 aminoalkyl (e.g., -(CH 2 ) 2 NH 2 ), 4- to 8-membered aminoalkyl ring (e.g., piperidine, preferably 4-piperidine), C1-9 alkylalkoxy (e.g., -CH 2 OMe), C1-9 alkylaminoalkyl (e.g., -(CH 2 ) 2 NHMe or -(CH 2 ) 2 N(Me) 2 );or R5 and R6 together form an optionally substituted and optionally bridged C3-10 heterocycloalkyl monocyclic or bicyclic ring (defined herein above as ring Z); or E, R5 and R6 together form J, where J is NR d , C(=O)R d , S.O. 2 R d , OR d (In the formula, R d is a 4- to 8-membered aminoalkyl 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.

[0064] In certain embodiments, R5 and R6 are joined together to form an optionally substituted and optionally bridged 4-8 membered, preferably 5-7 membered, aminoalkyl ring (described above as ring Z) and have the general formula Ia; [ka] [In the formula, R7 is selected from the group consisting of hydrogen, C1-3 alkyl (e.g., Me) and C1-3 haloalkyl (e.g., CH 2 CHF, CH 2 CHF 2 ) selected from the group consisting of has.

[0065] In certain embodiments of formula I, formula Ia represents an optionally substituted and optionally bridged aminoalkyl ring, i.e., a ring having the general formula II: [ka] [In the formula, A, B, D, E, G and R3 and R4 are as for formula I; R8, R9, R10, R11, R13 and R21 are each independently selected from the group consisting of: Hydrogen, C1-3 alkyl, C1-3 alkylalkoxy (e.g., CH 2 OMe), C1-3 alkyl hydroxyl (e.g., CH 2 OH, CHMeOH, CMe 2 OH), amino, C1-3 alkylamino (e.g., CH 2 NH 2 , CHMeNH 2 , CMe 2 NH 2 ), C1-6 alkylaminoalkyl (e.g., CH 2 NHMe or CH 2 NH(Me) 2 ), C1-3 haloalkyl (e.g., CH 2 F), alkylheteroaryl (e.g., CH2 -pyridyl, preferably CH 2 -3-pyridyl, or CH 2 -thiazole); R12 is selected from the group consisting of: hydrogen, C1-3 alkyl, and C1-3 haloalkyl; or any one of R8, R9, R10, R11, R12, R13 and R21 may be joined to another different R8, R9, R10, R11, R12, R13 or R21 to form a 3-7 membered spiro or bicyclic carbocyclic or heterocyclic ring structure and / or a 3-6 membered bridged carbocyclic or heterocyclic ring structure; n is selected from the group consisting of 0, 1 and 2, preferably n is 1 or 2. It is.

[0066] In an embodiment, when n=0, E is preferably selected from the group consisting of N, CH, CR d (In the formula, R d is halogen, alkoxy, C1-3 alkylhydroxy (e.g., CH 2 OH), C1-3 haloalkyl (e.g., CH 2 F), C2-5 alkylalkoxy (e.g., CH 2 OMe), C2-5 alkylnitriles (e.g., CH 2 CN).

[0067] In certain embodiments of formula I or II, the ring defined above as ring Z is: [ka] where R in this context may be: [ka] The remaining structural moieties of formula I or II are as follows:

[0068] In certain embodiments of formula II, G is CR1R2 and n is 1, i.e., formula IIa: [ka] [In the formula, A is selected from the group consisting of CH, CF, C-Cl and C-Br; B and D are each independently selected from the group consisting of: N and CH; E is selected from the group consisting of N, CF and CH; R1 is selected from the group consisting of hydrogen, Me, Et, OMe, OEt, OH, NH 2 , N.H.Me; R2 is selected from the group consisting of hydrogen, Me, Et; preferably Me; or R1 and R2 together form a 3- to 6-membered spiro carbocyclic or heterocyclic ring, in particular a 4- to 5-membered carbocyclic or heterocyclic spiro ring; R3 is hydrogen or halogen; R4 is selected from the group consisting of hydrogen, Me, Et, CF 2 H, C.F. 3 , C.F. 2 Me, OMe, OEt, OCF 2 H, OCF 3 , CN, Cl and F; and R8 and R9 are each independently selected from the group consisting of hydrogen, Me, Et, CH 2 OH, CHMeOH, CMe 2 OH, CH 2 OMe, C.H. 2 F and halogens (e.g., F when E is CH); R10 and R11 are each independently selected from the group consisting of H, Me, Et, CH 2 OH, CHMeOH, CMe 2 OH, CH 2 OMe, C.H. 2 F, CHF 2 , C.H. 2-heteroaryl (e.g., pyridyl and thiazole) and CH 2 CF 3 ; R12 is selected from the group consisting of hydrogen and Me; R13 is selected from the group consisting of hydrogen and Me; R21 is selected from the group consisting of: hydrogen and methyl; or any one of R8, R9, R10, R11, R12, R13 and R21 is linked to another different R8, R9, R10, R11, R21, R13 or R21 to form a 3-7 membered spiro or bicyclic carbocyclic or heterocyclic ring structure and / or a 3-6 membered bridged carbocyclic or heterocyclic ring structure. It is a compound of the formula:

[0069] In certain embodiments of formula I or II, the ring defined above as ring Z is: [ka] [ka] wherein R in this context may be selected from the group consisting of: [ka] The remaining structural moiety of formula II (or formula IIa; where G is CR1R2) is as follows:

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

[0071] Suitable bicyclic, bridged or spiro structures include the following: [ka] wherein R in this context may be selected from the group consisting of: [ka] (or formula IIa; where G is CR1R2) defined as follows:

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

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

[0074] In certain embodiments of formula IIb, the ring defined herein before ring Z is: [ka] wherein in the present context R may be selected from the group consisting of: [ka] (or formula IIb; where G is R1R2) as defined above.

[0075] In other specific embodiments of formula I, II and / or III, when G is NH, then B is N.

[0076] In certain embodiments of formula I, G is CR1R2, and E, R5 and R6 together form J, wherein J is selected from the group consisting of: NR d , C(=O)R d , S.O.2 R d , OR d (In the formula, R d is a 4-8 membered aminoalkyl ring, for example, of formula III: [ka] (In the formula, R1, R2, R3 and R4 are as for formula I, II, IIa or IIb; and K is selected from the group consisting of N and CH; When K is N, J is selected from the group consisting of: CH 2 , CHMe, CMe 2 , CO and SO 2 ;or When K is CH, J is selected from the group consisting of O and NR e ;where R e is hydrogen, Me, Et, propyl, CH 2 CF 3 , C.H. 2 CH 2 F, C.H. 2 CH 2 OMe, C.H. 2 - selected from the group consisting of oxetanes; R22, R23, R24, R25, and R26 are each independently selected from the group consisting of hydrogen, fluoro, and Me. It is a compound having the structure:

[0077] In certain embodiments, R22, R23, R24, R25, R26 are each independently selected from the group consisting of hydrogen, Me, and fluoro (wherein J is CH and E is NR e (only if R22, R23, R24, R25, R26 are each independently selected from the group consisting of hydrogen and Me.

[0078] The compounds of the invention may have the structure as 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

Table 57

Table 58

Table 59

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

[0080] 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.

[0081] 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.

[0082] 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.

[0083] 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.

[0084] The active agents or compounds of the present invention may be provided as prodrugs of the compounds of the present disclosure.

[0085] The term "active substance" is usually used to refer to compounds of the present disclosure that have inhibitory activity against PKC-theta, especially under physiological conditions. However, active substances 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 substances to overcome physicochemical, biological or other problems in efficacy and / or toxicity.

[0086] 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.

[0087] 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.

[0088] 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.

[0089] 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.

[0090] 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.

[0091] 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.

[0092] 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.

[0093] "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.

[0094] 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.

[0095] 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.

[0096] 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.

[0097] 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).

[0098] 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.

[0099] 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.

[0100] 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).

[0101] 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.

[0102] Compositions for intravenous administration generally comprise sterile isotonic aqueous buffer.Optionally, the composition may also include a solubilizing agent.

[0103] Another suitable route of administration of the therapeutic compositions of the present disclosure is pulmonary or nasal delivery.

[0104] 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.

[0105] The therapeutic agents of the present disclosure may be formulated into compositions for topical administration to the skin of a subject.

[0106] 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.

[0107] 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).

[0108] The invention is illustrated by the following non-limiting examples. EXAMPLES

[0109] material and method Sample preparation: Powder was dissolved in DMSO-d 6 The solution was dissolved in 0.5% ethanol and vortexed vigorously until the solution was clear and transferred to the NMR for data acquisition.

[0110] 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.

[0111] Liquid-phase NMR experiments were performed on a 500 MHz (11.75 Tesla) Bruker Avance I NMR spectrometer (1 500 MHz for H, 13 C was recorded at 125 MHz.

[0112] Liquid-phase NMR experiments were performed using a SEI 5 mm probe (Bruker Biospin, Germany) on a 400 MHz (9.4 Tesla) Bruker Avance NEO NMR spectrometer ( 1 400 MHz for H, 13 C was recorded at 100 MHz.

[0113] 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).

[0114] 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.

[0115] The instrument was tested using a Gemini NX-C18 Phenomenex (30 x 2 mm) 3 μm column for the Waters HPLC and a CSH C18 Waters (50 x 2.1 mm) 1.7 μm column for the UPLC Waters, both with the following combination of components: 2 O + 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.

[0116] 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.

[0117] Chiral purification: Method A: Equipment: Waters Prep SFC80; Stationary phase: Chiralcel OJ-H 5μm, 250 x 21mm Mobile phase: CO 2 / (EtOH + 0.5% IPAm) 80 / 20 Flow rate: 50 mL / min UV detection: λ = 210 nm Temperature: 40℃ - Pressure: 100 bars Method B: Equipment: Waters Prep SFC80; Stationary phase: Chiralcel OJ-H 5μm, 250 x 20mm Mobile phase: CO 2 / (EtOH + 0.5% IPAm) 70 / 30 Flow rate: 50 mL / min UV detection: λ = 210 nm Temperature: 40℃ - Pressure: 100 bars

[0118] Abbreviation In addition to the 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 71] TIFF2024517861000100.tif139153

[0119] 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, 1M lithium bis(trimethylsilyl)amide solution (33 mL, 33.4 mmol, 3.8 eq.) was added dropwise via 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, NH 4 A saturated aqueous solution of Cl and ethyl acetate were added. The two phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with Na 2 SO 4The 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-d 6 , 400 MHz):δ (ppm) 11.26 (s, 1H), 7.95 (d, J=5.7 Hz, 1H), 7.19 (d, J=5.7 Hz, 1H), 1.39 (s, 6H);m / z = 241.2, 243.2 [M+H]+.

[0120] Synthesis of 4-bromo-3,3-dimethyl-1-tetrahydropyran-2-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 heptane / ethyl acetate gradient. 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-d 6, 400 MHz):δ (ppm) 8.07 (d, J=5.6 Hz, 1H), 7.32 (d, J=5.6 Hz, 1H), 5.40 (dd, J=11.3, 2.1 Hz, 1H), 3.97 (d, J=10.8 Hz, 1H), 3.56 (qd, J=11.2, 10.8, 5.0 Hz, 1H), 2.85 (qd, J=13.7, 12.7, 3.8 Hz, 1H), 2.01 - 1.86 (m, 1H), 1.68 - 1.48 (m, 4H), 1.42 (s, 6H), m / z = 325.2, 327.0 [M+H]+.

[0121] Synthesis of 3,3-dimethyl-1-tetrahydropyran-2-yl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]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 (715 mg, 6.92 mmol, 3 eq.) and the dichloromethane adduct of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (193 mg, 0.231 mmol, 0.1 eq.) in anhydrous dioxane (8 mL, 0.3 N) 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-d 6 , 400 MHz):δ (ppm) 8.19 (d, J=5.1 Hz, 1H), 7.24 (d, J=5.1 Hz, 1H), 5.42 (dd, J=11.3, 2.0 Hz, 1H), 3.96 (d, J=11.1 Hz, 1H), 3.64 - 3.44 (m, 1H), 2.89 (d, J=11.4 Hz, 1H), 1.91 (s, 1H), 1.73 - 1.46 (m, 4H), 1.40 (s, 6H), 1.35 (s, 12H). m / z = 373.4 [M+H]+.

[0122] Ethyl / methyl scaffold synthesis Synthesis of 3,4-dibromo-3-methyl-1H-pyrrolo[2,3-b]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. tert-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 and concentrated with Na 2 SO 4 Drying over rt and concentration under high vacuum gave 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-d 6 , 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)

[0123] 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 diluted with NaHCO 3 The solution was neutralized to pH = 6 with aqueous solution. The solution was filtered and the aqueous phase was extracted with EtOAc. The combined organic phase was washed with brine and added Na 2 SO 4Drying on ethyl acetate, filtration and evaporation gave 4-bromo-3-methyl-1,3-dihydropyrrolo[2,3-b]pyridin-2-one (1.08 g, 76% yield) as a white solid. 1 H NMR (DMSO-d 6 , 400 MHz):δ (ppm) 11.22 (s, 1H), 7.95 (dd, J=5.7, 0.8 Hz, 1H), 7.18 (d, J=5.7 Hz, 1H), 3.66 - 3.49 (m, 1H), 1.43 (d, J=7.6 Hz, 3H);m / z = 227.1, 229.1 [M+H]+.

[0124] Synthesis of 4-bromo-3-ethyl-3-methyl-1H-pyrrolo[2,3-b]pyridin-2-one (MeEt) [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 pooled 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]+.

[0125] 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: CO 2 / MeOH 73 / 27 Flow rate: 1000 g / min UV detection: λ=295 nm Temperature: 45℃ Pressure: 130 bars Sample: Dissolved in MeOH rt(MeEt isomer 1) = 4.74 min and rt(MeEt isomer 2) = 7.06 min

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

[0127] The following steps are the same for the racemic mixture and the pure enantiomers. The boronic ester synthesis is as described for the racemic mixture.

[0128] 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 a solution of 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]+.

[0129] Synthesis of 3-ethyl-3-methyl-1-tetrahydropyran-2-yl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]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. 1 H NMR (DMSO-d 6, 400 MHz):δ (ppm) 8.19 (d, J=5.2 Hz, 1H), 7.25 (d, J=5.1 Hz, 1H), 5.43 (dd, J=11.4, 2.0 Hz, 1H), 3.96 (d, J=11.1 Hz, 1H), 3.64 - 3.49 (m, 1H), 3.01 - 2.79 (m, 1H), 2.33 - 2.16 (m, 1H), 1.93 (d, J=11.0 Hz, 1H), 1.87 - 1.73 (m, 2H), 1.71 - 1.43 (m, 6H), 1.34 (s, 12 H), 0.38 (t, J=7.4 Hz, 3H);m / z = 387.0 [M+H]+.

[0130] Me / OH scaffold synthesis Synthesis of 4-bromo-3-hydroxy-3-methyl-1H-pyrrolo[2,3-b]pyridin-2-one (OHMe) [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-d 6 , 400 MHz):δ (ppm) 11.11 (s, 1H), 7.95 (d, J=5.7 Hz, 1H), 7.18 (d, J=5.7 Hz, 1H), 6.11 (s, 1H), 1.50 (s, 3H);m / z = 243.1, 245.1 [M+H]+.

[0131] 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: CO 2 / 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

[0132] The S-isomer was arbitrarily assigned as OHMe isomer 1, and the R-isomer was arbitrarily assigned as OHMe isomer 2. The same nomenclature was used to describe all related derivatives.

[0133] The following steps are identical for the racemic mixture and the pure enantiomers. The boronic ester synthesis is described starting from OHMe isomer 1.

[0134] 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 NaHCO 3 A saturated aqueous solution of was 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-d 6 , 400 MHz):δ (ppm) 8.07 (dd, J=5.6, 1.2 Hz, 1H), 7.31 (dd, J=5.7, 0.8 Hz, 1H), 6.28 (d, J=6.8 Hz, 1H), 5.37 (dd, J=11.3, 1.9 Hz, 1H), 4.02 - 3.90 (m, 1H), 3.54 (td, J=11.0, 10.6, 3.2 Hz, 1H), 2.90 - 2.73 (m, 1H), 1.93 (d, J=10.0 Hz, 1H), 1.69 - 1.44 (m, 7H);m / z = 327.0, 328.9 [M+H]+.

[0135] Synthesis of (3R)-3-hydroxy-3-methyl-1-tetrahydropyran-2-yl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]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-d 6 , 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, J=11.0 Hz, m / z = 293.2 [M+H]+.

[0136] 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-d 6 , 400 MHz):δ (ppm) 8.16 (d, J=5.6 Hz, 1H), 7.40 (dd, J=5.6, 0.8 Hz, 1H), 5.42 (dt, J=11.4, 2.6 Hz, 1H), 4.00 - 3.93 (m, 1H), 3.61 - 3.49 (m, 1H), 2.91 (s, 3H), 2.87 - 2.75 (m, 1H), 1.94 (d, J=10.9 Hz, 1H), 1.70 - 1.41 (m, 7H);m / z = 341.1, 343.1 [M+H]+.

[0137] Synthesis of (3R)-3-methoxy-3-methyl-1-tetrahydropyran-2-yl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]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. 1 H NMR (DMSO-d 6, 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, 1H), 3.62 - 3.48 (m, 1H), 2.89 - 2.76 (m, 4H), 1.94 (d, J=11.4 Hz, 1H), 1.73 - 1.46 (m, 7H), 1.33 (d, J=2.6 Hz, 12H);m / z = 307.2 [M+H]+ (acid form).

[0138] Et / OH scaffold synthesis Synthesis of 3-bromo-4-chloro-3-ethyl-1H-pyrrolo[2,3-b]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 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)

[0139] 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]+.

[0140] 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 diluted with NH 4 A mixture of Cl 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-d 6 ) δ 8.07 (d, J = 5.7 Hz, 1H), 7.06 (d, J = 5.7 Hz, 1H), 6.19 (s, 1H), 2.13 (tt, J = 14.3, 7.8 Hz, 1H), 2.03 - 1.87 (m, 1H), 0.55 (t, J = 7.5 Hz, 3H);m / z = 213.1, 215.1 [M+H]+.

[0141] The two enantiomers were separated under the SFC conditions: Equipment: Waters prep SFC200 Stationary phase: Chiralpak IC 5μm, 250 x 30mm Mobile phase: CO 2 / 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

[0142] The S-isomer was arbitrarily assigned as OHEt isomer 1 and the R-isomer was arbitrarily assigned as OHEt isomer 2. The same nomenclature was used to describe all related derivatives.

[0143] The following protocol describes a racemic mixture.

[0144] Synthesis of 4-bromo-3-ethyl-3-hydroxy-1-tetrahydropyran-2-yl-pyrrolo[2,3-b]pyridin-2-one [ka] In a sealed vial, 3,4-dihydro-2H-pyran (0.59 mL, 6.50 mmol) was added to a stirred solution of 4-bromo-3-ethyl-3-hydroxy-1H-pyrrolo[2,3-b]pyridin-2-one (0.56 g, 2.17 mmol) and para-toluenesulfonic acid (82 mg, 0.433 mmol) in anhydrous toluene (11 mL, 0.2 N). The reaction mixture was stirred at 90° C. overnight. The mixture was then cooled to 0° C. and 4M hydrogen chloride (1.1 mL, 4.33 mmol) was added. The mixture was stirred at room temperature for 3 hours. The solution was concentrated in vacuo. DCM and NaHCO 3 An aqueous solution of was added. The compound was redissolved in the free base form and the aqueous phase was extracted with DCM. 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 / AcOEt. It was eluted through a 24 g column of Dicalite solid phase. The fractions were collected and evaporated to give 4-bromo-3-ethyl-3-hydroxy-1-tetrahydropyran-2-yl-pyrrolo[2,3-b]pyridin-2-one (200 mg, 26% yield) as an orange oil. m / z = 341.0, 343.0 [M+H]+.

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

[0146] 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%). 1 H NMR (DMSO-d 6 , 400 MHz):δ (ppm) 11.60 (s, 1H), 11.39 (s, 1H), 7.74 (d, J=5.7 Hz, 1H), 7.17 (d, J=5.7 Hz, 1H);m / z = 214.0, 216.0 [M+H]+.

[0147] Synthesis of 7-bromo-3-tetrahydropyran-2-yl-1H-imidazo[4,5-b]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 washed with Na 2 SO 4The mixture was dried over hexane, 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. It was eluted through a Dicalite solid phase. The relevant fractions were collected 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. 1 H NMR (DMSO-d 6 , 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 / z = 298.0;300.0 [M+H]+.

[0148] Synthesis of 3-tetrahydropyran-2-yl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-imidazo[4,5-b]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 heated at 37° C. for 1 hour at 4° C. for 2 hours at 4° C. for 1 hour at 4° C. 2 The mixture was degassed using 0.1% NaOH and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (78 mg, 0.101 mmol, 0.1 eq.) was added. The resulting mixture was heated under reduced pressure with N 2The mixture was stirred at 95° C. for 2 hours under reduced pressure. 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).

[0149] 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-d 6 , 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, 1H), 3.59 (s, 4H), 2.92 (qd, J=13.5, 13.0, 4.4 Hz, 1H), 2.03 - 1.89 (m, 1H), 1.79 - 1.41 (m, 4H);m / z = 312.1, 314.1 [M+H]+.

[0150] Synthesis of 7-bromo-3H-oxazolo[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-d 6 , 400 MHz):δ (ppm) 7.85 (d, J=5.8 Hz, 1H), 7.25 (d, J=5.8 Hz, 1H).

[0151] Synthesis of 4,5-dibromo-3,3-dimethyl-1H-pyrrolo[2,3-b]pyridin-2-one [ka] In a 25 mL round bottom flask at room temperature, N-bromosuccinimide (236 mg, 1.33 mmol, 1.6 eq.) was added to a stirred suspension of 4-bromo-3,3-dimethyl-1H-pyrrolo[2,3-b]pyridin-2-one (200 mg, 0.830 mmol) and sodium acetate (34 mg, 0.415 mmol, 0.5 eq.) in acetic acid (1 mL, 0.8 N). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with water and added Na 2 S 2 O 3The reaction mixture was quenched with a 1M aqueous solution of 4,5-dibromo-3,3-dimethyl-1H-pyrrolo[2,3-b]pyridin-2-one (223.1 mg, 82% yield) as a yellow powder, which was used in the next step without further purification. 1 H NMR (DMSO-d 6 , 400 MHz):δ (ppm) 11.41 (s, 1H), 8.35 (s, 1H), 1.40 (s, 6H).

[0152] Synthesis of 4-bromospiro[1H-pyrrolo[2,3-b]pyridine-3,1'-cyclopentan]-2-one [ka] A solution of 4-bromo-1,3-dihydro-2H-pyrrolo[2,3-b]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 NH 4 The mixture was quenched with saturated aqueous Cl and extracted with EtOAc. The organic phase was dried on a phase separator and evaporated 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, which was eluted through the silica gel column. The relevant fractions were collected 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]+.

[0153] 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). 1 H NMR (400 MHz, DMSO-d 6) 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, m / z = 351.2-353.2 [M+H]+.

[0154] Synthesis of 1'-tetrahydropyran-2-yl-4'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[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);m / z = 399.4 [M+H]+.

[0155] Synthesis of 3,3-dibromo-4-chloro-2-oxo-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile [ka] To a flask containing 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile (1.00 g, 5.35 mmol) was added tert-butanol (62 mL). Pyridinium bromide (4.84 mg, 15.1 mmol, 3.5 eq.) was added in portions over 10 min. Pyridine (1.24 mL) was added to aid in dissolution. The resulting solution was stirred at 40° C. for 6 h. The solution was concentrated to dryness under reduced pressure. Water was added to the resulting yellow solid to give a yellow suspension. The organic product was extracted into EtOAc. The combined organic extracts were washed with brine, separated and diluted with anhydrous MgSO. 4 The mixture was dried over ice. After filtration, the organic material was concentrated. The crude material was purified by flash column chromatography using a gradient of EtOAc / heptane. The relevant fractions were combined and concentrated to give the final compound as an off-white solid of sufficient purity to proceed to the next step of the synthesis. m / z = 347.7, 349.7 [MH]-

[0156] Synthesis of 4-chloro-2-oxo-1,3-dihydropyrrolo[2,3-b]pyridine-5-carbonitrile [ka] To a flask containing 3,3-dibromo-4-chloro-2-oxo-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile (1.90 g, 3.84 mmol) was added methanol (18 mL) and acetic acid (18 mL). Zinc (628 mg, 9.60 mmol, 2.5 eq.) was added in portions over 3 min. The suspension was stirred at room temperature for 1.5 h. The solution was diluted with EtOAc and saturated NaHCO 3 The aqueous solution was slowly neutralized by adding water. The aqueous layer was separated, and the organic layer was washed with water and brine, and anhydrous MgSO 4The mixture was dried over ice. After filtration, the organic layer was concentrated to dryness to give a yellow solid. This solid was suspended in water and filtered through a Buchner funnel. The solid was triturated with cold ether, heptane, and then dried in an oven for 1 hour. The final product was obtained as a flesh-colored solid (494 mg, 53%). 1H NMR (400 MHz, DMSO-d6) δ 11.81 (br. s, 1H), 8.65 (s, 1H), 3.70 (s, 2H);m / z = 192.1, 194.1 [MH]-

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

[0158] Synthesis of 4-bromo-5-chloro-3,3-dimethyl-1H-pyrrolo[2,3-b]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 hours. 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 diluted with 1M Na 2 S 2 O 3 Quenched with aqueous 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. This product was used in the next step without further purification. 1 H NMR (DMSO-d 6 , 400 MHz):δ (ppm) 11.41 (s, 1H), 8.27 (s, 1H), 1.41 (s, 6H);m / z = 275.0, 277.0 [M+H]+

[0159] Synthesis of 4-chloro-5-fluoro-3,3-dimethyl-1H-pyrrolo[2,3-b]pyridin-2-one [ka] In a round-bottom flask, at 0° C., 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). The mixture was stirred at 0° C. for 10 min. 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. NH 4 A saturated aqueous solution of Cl was slowly added. 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 purified by diisopropyl ether / Et 2 Trituration in a mixture of 0 (50 / 50) and filtration gave 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-d 6 , 400 MHz):δ (ppm) 11.32 (s, 1H), 8.24 (d, J=2.2 Hz, 1H), 1.41 (s, 6H). m / z = 215.2, 217.2 [M+H]+

[0160] Synthesis of 4-chloro-5-fluoro-3,3-dimethyl-1-tetrahydropyran-2-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.) in that order, and the reaction mixture was stirred at 90° C. overnight. Then, 3,4-dihydro-2H-pyran (0.5 mL) was added and the reaction 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]+

[0161] Synthesis of 5-fluoro-3,3-dimethyl-1-tetrahydropyran-2-yl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]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]+

[0162] Synthesis of 5-fluoro-3-methyl-1,3-dihydropyrrolo[2,3-b]pyridin-2-one hydrochloride [ka] To a solution of tert-butyl 5-fluoro-3-methyl-2-oxo-3H-pyrrolo[2,3-b]pyridine-1-carboxylate (210 mg, 0.752 mmol) 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.1 H NMR (500 MHz, DMSO-d 6 ) δ 11.01 (br s, 1H), 8.03 (t, J=1.83 Hz, 1H), 7.69 (dd, J=2.20, 8.31 Hz, 1H), 3.54-3.61 (m, 1H), 1.35 (d, J=7.58 Hz, 3H);m / z = 167.1 [M+H]+

[0163] Synthesis of 3-ethyl-5-fluoro-3-methyl-1H-pyrrolo[2,3-b]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]+

[0164] 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-d 6 , 600 MHz):δ (ppm) 8.17-8.18 (m, 1H), 7.85 (dd, J = 8.2, 2.8 Hz, 1H), 5.36 (d, J = 10.4 Hz, 1H), 3.95 (dt, J = 11.4, 2.0 Hz, 1H), 3.53 (tt, J = 11.4, 2.8 Hz, 1H), 2.79-2.94 (m, 1H), 1.89-1.95 (m, 1H), 1.74-1.86 (m, 2H), 1.53-1.65 (m, 2H), 1.45-1.55 (m, 2H), 1.29 (s, 3H), 0.51 (td, J = 7.4, 3.4 Hz, 3H) ;m / z = 279.2 [M+H]+.

[0165] Synthesis of 5-ethyl-3-fluoro-5-methyl-7-tetrahydropyran-2-yl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7H-cyclopenta[b]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 at 0°C with dropwise addition of 3N hydrochloric acid 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).

[0166] Scaffold Coupling - General Method (Pyridine) [ka] TIFF2024517861000140.tif54120

[0167] This scheme includes bridged piperidine structures, bicyclic piperidine structures, and diazacycloheptane in place of piperidine.

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

[0169] Example 1: tert-Butyl (3R)-4-(6-bromo-4-chloro-2-pyridyl)-3-methyl-piperazine-1-carboxylate (R 1 = Cl, R 2 = R 4 = R 5 = H;R 3 Synthesis of 1,2-dichlorophenyl ether (X=Me, X=Br) Beige solid; yield 48%, 1 H NMR (400 MHz, DMSO-d 6 ) δ 6.92 (d, J = 21.3 Hz, 2H), 4.44 (s, 1H), 3.88 (dd, J = 79.1, 12.8 Hz, 3H), 3.19 - 2.81 (m, 3H), 1.43 (s, 9H), 1.05 (d, J = 6.6 Hz, 3H);m / z=390.0, 392.0 [M+H]+

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

[0171] Example 1: tert-Butyl (3R)-4-[4-chloro-6-(3,3-dimethyl-2-oxo-1-tetrahydropyran-2-yl-pyrrolo[2,3-b]pyridin-4-yl)-2-pyridyl]-3-methyl-piperazine-1-carboxylate (R 1 = Cl, R 2 = R 4 = R 5 = H;R 3 = Me, G= CMe 2 Synthesis of Br White foam; Yield 46%; 1 H NMR (400 MHz, DMSO-d 6) δ 8.24 (d, J = 5.3 Hz, 1H), 7.02 (d, J = 5.3 Hz, 1H), 6.98 (s, 1H), 6.80 (s, 1H), 5.52 - 5.40 (m, 1H), 4.57 (s, 1H), 4.08 - 3.84 (m, 3H), 3.78 (d, J = 13.4 Hz, 1H), 3.63 - 3.49 (m, 1H), 3.19 - 3.00 (m, 2H), 3.00 - 2.83 (m, 2H), 1.97 (d, J = 22.9 Hz, 1H), 1.68 - 1.47 (m, 4H), 1.42 (s, 9H), 1.24 - 1.19 (m, 6H), 1.05 (d, J = 6.5 Hz, 3H);m / z = 556.2, 558.1 [M+H]+

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

[0173] Example 1: 4-[4-chloro-6-[(2R)-2-methylpiperazin-1-yl]-2-pyridyl]-3,3-dimethyl-1H-pyrrolo[2,3-b]pyridin-2-one; dihydrochloride (R 1 = Cl, R 2 = R 4 = R 5 = H;R 3 = Me, G= CMe 2 Synthesis of Green powder; yield 79%, 1H NMR (500 MHz, DMSO-d6) Shift 11.13 (s, 1H), 9.42 (br d, J=9.05 Hz, 1H), 8.98 (br d, J=9.05 Hz, 1H), 8.13 (d, J=5.72 Hz, 1H), 7.08 (s, 1H), 6.91 (d, J=5.70 Hz, 1H), 6.87 (s, 1H), 4.74-4.83 (m, 1H), 4.28 (br d, J=13.45 Hz, 1H), 3.12-3.32 (m, 4H), 2.92-3.02 (m, 1H), 1.25 (d, J=6.85 Hz, 3H), 1.19 (d, J=6.11 Hz, 6H);m / z = 372.1, 374.1

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

[0175] Synthesis of 2,6-dichloro-4-(1,1-difluoroethyl)pyridine (specific pyridine 1) [ka] 1-(2,6-Dichloro-4-pyridyl)ethanone (300 mg, 1.50 mmol) was added to a stirred solution of triethylamine (0.21 mL, 1.50 mmol, 1 eq.), N,N-diethylethanamine trihydrofluoride (0.50 mL, 3.00 mmol, 2 eq.) and Xtal fluor (687 mg, 3.00 mmol, 2 eq.) in anhydrous DCE (4.5 mL, 0.3 N) at room temperature. The reaction mixture was stirred at 60 °C overnight. The reaction was concentrated by centrifugation with NaHCO 3Quenched with saturated aqueous solution of 1,2-dichloromethane. Dichloromethane was added and the two phases were separated. The combined organic phases were dried using a phase separator and evaporated to give the crude material as a yellow oil. The crude material was purified by flash chromatography on silica gel using a heptane / ethyl acetate gradient. Relevant fractions were combined and concentrated in vacuo to give 2,6-dichloro-4-(1,1-difluoroethyl)pyridine (124 mg, 38% yield) as a yellow oil. 1H NMR (DMSO-d6, 400 MHz): δ (ppm) 7.81 (s, 2H), 2.01 (t, J=19.3 Hz, 3H); m / z = 212.1, 214.1.

[0176] Synthesis of tert-butyl 3-[6-chloro-4-(trifluoromethyl)-2-pyridyl]-3-(hydroxymethyl)pyrrolidine-1-carboxylate (2 steps) (specific pyridine 2) [ka] Step 1: Synthesis of O1-tert-butyl O3-ethyl 3-[6-chloro-4-(trifluoromethyl)-2-pyridyl]pyrrolidine-1,3-dicarboxylate To a 2-6 mL microwave vial were added O1-tert-butyl O3-ethylpyrrolidine-1,3-dicarboxylate (436 mg, 1.70 mmol, 1.5 eq.), 2,6-dichloro-4-(trifluoromethyl)pyridine (250 mg, 1.13 mmol), anhydrous THF (6.25 mL, 0.18 N), and 1 M lithium [bis(trimethylsilyl)amide] solution (2.3 mL, 2.27 mmol, 2 eq.) in sequence at 0° C. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with NH 4The mixture was poured into a saturated aqueous solution of Cl. Dichloromethane was added and the two phases were separated. The aqueous phase was extracted with dichloromethane. The combined organic phases were washed with water, dried using a phase separator and evaporated 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 of Isolute HM-N. O1-tert-butyl O3-ethyl 3-[6-chloro-4-(trifluoromethyl)-2-pyridyl]pyrrolidine-1,3-dicarboxylate (408 mg, 82% yield) was obtained as a colorless gum. 1H NMR (400 MHz, DMSO-d6) δ 8.01 (s, 1H), 7.85 (d, J = 5.6 Hz, 1H), 4.12 (q, J = 7.1 Hz, 2H), 4.07 (d, J = 11.2 Hz, 1H), 3.76 (dd, J = 11.1, 6.9 Hz, 1H), 3.35 (dd, J = 13.8, 7.2 Hz, 2H), 2.66 (dd, J = 12.3, 6.0 Hz, 1H), 2.51 (dt, J = 3.7, 1.9 Hz, 1H), 1.40 (d, J = 5.0 Hz, 9H), 1.11 (t, J = 7.1 Hz, 3H). m / z = 323.2, 325.2 [M+H-Boc]+

[0177] Step 2: Synthesis of tert-butyl 3-[6-chloro-4-(trifluoromethyl)-2-pyridyl]-3-(hydroxymethyl)pyrrolidine-1-carboxylate O1-tert-Butyl O3-ethyl 3-[6-chloro-4-(trifluoromethyl)-2-pyridyl]pyrrolidine-1,3-dicarboxylate (200 mg, 0.421 mmol) was dissolved in anhydrous THF (2 mL, 0.2 N). The mixture was cooled to 0° C. 2M lithium borohydride solution (0.42 mL, 0.842 mmol, 2 eq.) was added dropwise and the reaction mixture was stirred at room temperature for 2 hours. The reaction was quenched with Rochelle's salt solution and dichloromethane was added. The two phases were separated and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried using a phase separator and evaporated to give tert-butyl 3-[6-chloro-4-(trifluoromethyl)-2-pyridyl]-3-(hydroxymethyl)pyrrolidine-1-carboxylate as a colorless gum. 1H NMR (400 MHz, DMSO-d6) δ 7.88 (s, 1H), 7.69 (d, J = 6.4 Hz, 1H), 5.00 (t, J = 5.5 Hz, 1H), 3.71 - 3.51 (m, 3H), 3.35 (d, J = 7.8 Hz, m / z = 325-327[M+H-tBu]+.

[0178] Synthesis of tert-butyl rac-(4aR,8aR)-6-[6-bromo-4-(trifluoromethyl)-2-pyridyl]-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazine-4-carboxylate (specific pyridine 3) [ka] Step 1: Synthesis of rac-(4aR,8aR)-6-[6-bromo-4-(trifluoromethyl)-2-pyridyl]-2,3,4,4a,5,7,8,8a-octahydropyrido[4,3-b][1,4]oxazine A microwave tube was charged with 2,6-dibromo-4-(trifluoromethyl)pyridine (150 mg, 0.467 mmol), (4aR,8aR)-octahydro-2H-pyrido[4,3-b]morpholine (70 mg, 0.467 mmol) and sodium bicarbonate (39 mg, 0.467 mmol) in anhydrous DMF (1.4 mL, 0.34 N). The resulting mixture was heated at 140° C. for 15 min under microwave irradiation. Water was added and the mixture was extracted with AcOEt. The combined organic layers were washed with water, brine, dried on a phase separator and concentrated to give a brown oil. The crude product was purified on a silica gel column with a gradient of DCM / MeOH. The relevant fractions were combined and concentrated in vacuo to give rac-(4aR,8aR)-6-[6-bromo-4-(trifluoromethyl)-2-pyridyl]-2,3,4,4a,5,7,8,8a-octahydropyrido[4,3-b][1,4]oxazine (124 mg, 72% yield) as a beige solid. 1 H NMR (DMSO-d 6 , 500 MHz):δ (ppm) 7.08 (s, 1H), 6.97 (s, 1H), 3.83-3.95 (m, 2H), 3.67-3.81 (m, 2H), 3.62 (dd, J = 13.2, 10.0 Hz, 1H), 3.46 (td, J = 10.5, 2.8 Hz, 1H), 3.20-3.28 (m, 1H), 2.93 (ddd, J = 12.7, 9.8, 3.4 Hz, 1H), 2.67-2.78 (m, 1H), 2.49-2.53 (m, 1H), 1.80-1.88 (m, 1H), 1.53-1.69 (m, 1H);m / z = 366.0, 368.0 [M+H]+.

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

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

[0181] Synthesis of tert-butyl 4-[4-(3,3-dimethyl-2-oxo-1-tetrahydropyran-2-yl-pyrrolo[2,3-b]pyridin-4-yl)-6-(trifluoromethyl)pyrimidin-2-yl]piperazine-1-carboxylate (2 steps) (pyrimidine) [ka] Step 1: Synthesis of tert-butyl 4-[4-chloro-6-(trifluoromethyl)pyrimidin-2-yl]piperazine-1-carboxylate A 10 mL reaction vial was charged with 2,4-dichloro-6-(trifluoromethyl)pyrimidine (16 mL, 1.11 mmol), tert-butyl piperazine-1-carboxylate (0.21 g, 1.11 mmol) and triethylamine (0.46 mL, 3.32 mmol, 3 eq.) in anhydrous DMF (2.9 mL, 0.4 M). The reaction mixture was stirred at 100° C. overnight. After the reaction mixture was allowed to warm to room temperature, water was added followed by EtOAc. The two layers were separated and the aqueous layer was extracted with EtOAc. The combined organic phases were washed with water, dried using a phase separator 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 cyclohexane / EtOAc. It was eluted with liquid injection / cyclohexane. The relevant fractions were combined and concentrated in vacuo to give tert-butyl 4-[4-chloro-6-(trifluoromethyl)pyrimidin-2-yl]piperazine-1-carboxylate (295 mg, 73% yield) as a white solid. 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 7.32 (s, 1 H), 3.57 - 3.95 (m, 4 H), 3.36 - 3.52 (m, 4 H), 1.42 (s, 9 H);m / z = 367.1 [M+H]+

[0182] Step 2: Synthesis of tert-butyl 4-[4-(3,3-dimethyl-2-oxo-1-tetrahydropyran-2-yl-pyrrolo[2,3-b]pyridin-4-yl)-6-(trifluoromethyl)pyrimidin-2-yl]piperazine-1-carboxylate A 5 mL reaction vial was charged with 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 (81 mg, 0.218 mmol), tetrakis-triphenylphosphine palladium (50 mg, 0.0436 mmol, 0.1 eq), tert-butyl 4-[4-chloro-6-(trifluoromethyl)pyrimidin-2-yl]piperazine-1-carboxylate (80 mg, 0.218 mmol) and disodium carbonate (69 mg, 0.65 mmol, 3 eq.) in DMF (1.9 mL) and water (0.4 mL). The reaction mixture was stirred at 100° C. for 2 hours. The reaction mixture was allowed to warm to room temperature. Water was then added. The resulting solid was filtered through a glass frit and washed with water to give the crude material as a brown solid. 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 tert-butyl 4-[4-(3,3-dimethyl-2-oxo-1-tetrahydropyran-2-yl-pyrrolo[2,3-b]pyridin-4-yl)-6-(trifluoromethyl)pyrimidin-2-yl]piperazine-1-carboxylate (66.4 mg, 52% yield) as a pale yellow powder. 1H NMR(400 MHz, DMSO-d6) δ 8.34 (d, J = 5.5 Hz, 1H), 7.69 (d, J = 5.5 Hz, 1H), 7.38 (s, 1H), 5.49 (dd, J = 11.3, 2.0 Hz, 1H), 3.99 (d, J = 10.8 Hz, 1H), 3.84 (s, 3H), 3.56 (td, J = 11.3, 3.4 Hz, 1H), 3.51 - 3.45 (m, 4H), 3.00 - 2.83 (m, 1H), 1.94 (s, 1H), 1.70 - 1.48 (m, 5H), 1.48 - 1.37 (m, 15H). m / z = 577.2 [M+H]+

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

[0184] Scaffold Coupling – General Method (Phenyl 1) [ka] TIFF2024517861000147.tif15156 Suzuki Coupling A microwave vial was charged with the bromine scaffold I (0.467 mmol, 1 eq.), dipotassium carbonate (1.40 mmol, 3 eq.) and boronate ester I' (0.701 mmol, 1.5 eq.) in the mixture of dioxane (4 mL) and water (0.5 mL). The mixture was degassed and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (95%, 0.0467 mmol, 0.1 eq.) was added. The reaction solution was stirred at 140° C. for 1 h 30 min under microwave irradiation. The reaction mixture was filtered through a Daicalite pad and the filtrate was diluted with dichloromethane and passed through a phase separator to remove water. The organic layer was concentrated under vacuum to give the crude material as a black solid. The crude material was purified by flash chromatography on silica gel using a gradient of dichloromethane / ethyl acetate. It was eluted through the Dicalite solid phase. The relevant fractions were collected and concentrated under vacuum. The resulting product was triturated with THF or diethyl ether, filtered and dried under vacuum at 40° C. to give compound II.

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

[0186] Scaffold Coupling – General Method (Phenyl 2) [ka] Synthesis of boronic esters (only in the case of Example 32 (X=C, R1=F, R=CH 2 ), others are commercially available) To a solution of tert-butyl 4-[(3-bromo-5-fluorophenyl)methyl]piperazine-1-carboxylate (200 mg, 0.536 mmol) I in anhydrous dioxane (5.4 mL, 0.1 N) was added potassium acetate (158 mg, 1.61 mmol, 3 eq.) and bis(pinacolato)diboron (275 mg, 1.07 mmol, 2 eq.). The solution was diluted with N 2 The mixture was degassed at 40° C. [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (39 mg, 0.0536 mmol, 0.1 eq) was added to the mixture. It was then stirred at 95° C. overnight. The solution was filtered over Dicalite and the filtrate was concentrated in vacuo to give tert-butyl 4-[[3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]piperazine-1-carboxylate II as a black oil. The crude product was used in the next step without further purification. m / z = 421.5 [M+H]+

[0187] Suzuki Coupling To a solution of boronic ester II (481 mg, 0.458 mmol, 1.2 eq) in DMF (3 mL) and water (0.8 mL) was added bromine scaffold I' (90 mg, 0.373 mmol) and disodium carbonate (119 mg, 1.12 mmol, 3 eq). The mixture was cooled to room temperature under reduced pressure with N 2 After degassing at 30° C., tetrakistriphenylphosphine palladium (43 mg, 0.0373 mmol, 0.1 eq) was added. The solution was stirred at 95° C. overnight. The mixture was filtered through a Dicalite pad, washed with EtOAc, and the solvent was evaporated under vacuum. The product was purified by silica gel column and solid precipitation with a gradient of DCM / MeOH. The relevant fractions were collected and concentrated under vacuum to give the Suzuki coupling product III.

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

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

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

[0191] Scaffold Coupling – General Method (Phenyl 3) [ka]

[0192] Buchwald reaction In a reaction vial, add Xantphos (0.022mmol, 0.03 eq.), Pd(OAc) 2 (7.5 μmol, 0.01 eq.) and NaOtBu (1.12 mmol, 1.5 eq.) were dissolved in N 2 The mixture was added under reduced pressure. Anhydrous toluene (1.9 mL, 0.4 M) was added followed by the dibromobenzene product I (0.786 mmol, 1.05 eq.) and the corresponding piperazine I' (0.749 mmol, 1 eq.). The reaction mixture was heated at 80° C. overnight. Water was added and the mixture was extracted with DCM. The organic phase was dried on a phase separator and concentrated under vacuum. The crude material was purified by flash chromatography on silica gel using a gradient of heptane / EtOAc, which was eluted by liquid injection. The relevant fractions were collected and concentrated under vacuum to give the desired compound II.

[0193] Example: tert-Butyl (3S)-4-(3-bromophenyl)-3-methyl-piperazine-1-carboxylate (R 1 = R 2 = R4 = R 5 = R 5 = H;R 3 = Me) Yellow oil; 72% yield, 1 H NMR (DMSO-d 6 , 400 MHz):δ (ppm) 7.15 (t, J=8.1 Hz, 1H), 7.02 (t, J=2.1 Hz, 1H), 6.93 - 6.86 (m, 2H), 4.03 (dd, J=6.6, 3.5 Hz, 1H), 3.93 (s, 1H), 3.75 (d, J=13.1 Hz, 1H), 3.29-3.33 (m, 2H), 3.18 (s, 1H), 3.05 - 2.83 (m, 2H), 1.43 (s, 9H), 0.92 (d, J=6.5 Hz, 3H);M / Z = 357.1 [M+H]+

[0194] 1. Synthesis of boronic esters A 10 mL reaction vial was charged with compound II (0.538 mmol, 1 eq.), bis(pinacolato)diboron (0.645 mmol, 1.2 eq.), and potassium acetate (1.62 mmol, 3 eq.) in anhydrous dioxane (1.8 mL, 0.3 M). The mixture was diluted with N 2 The mixture was degassed at 40° C. and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.0538 mmol, 0.1 eq.) was added. The solution was heated at 100° C. overnight. The mixture was filtered and concentrated in vacuo. The crude material III was used in the next step without purification.

[0195] Example: tert-Butyl (3S)-3-methyl-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperazine-1-carboxylate (R 1 = R 2 = R 4 = R 5 = R 5 = H;R 3 = Me) Black oil; m / z = 403.2 [M+H]+

[0196] 2. Suzuki Coupling In a 10 mL reaction vial, add bromine scaffold II' (0.327 mmol, 1 eq.), boronate ester III (0.523 mmol, 1.6 eq.), and Na 2 CO 3 (0.981 mmol, 3 eq.) in DMF (2.6 mL) and water (0.5 mL) was charged. The mixture was degassed and tetrakistriphenylphosphine palladium (0.0327 mmol, 0.1 eq.) was added. The reaction mixture was heated at 100° C. overnight. The solution was filtered over Dicalite and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel using a heptane / EtOAc gradient. The relevant fractions were collected and concentrated in vacuo. The product was triturated in DCM and dried under vacuum at 40° C. overnight to give the desired compound IV.

[0197] Example: tert-Butyl (3S)-3-methyl-4-[3-(2-oxo-1,3-dihydroimidazo[4,5-b]pyridin-7-yl)phenyl]piperazine-1-carboxylate (G = NH; R = X = H; R 1 = R 2 = R 4 = R 5 = R 5 = H;R 3 = Me) Pink powder; 22% yield; 1 H NMR (DMSO-d 6, 400 MHz):δ (ppm) 11.39 (s, 1H), 10.96 (s, 1H), 7.92 (d, J=5.4 Hz, 1H), 7.35 (t, J=7.9 Hz, 1H), 7.06 - 6.96 (m, 4H), 4.10 (s, 1H), 3.95 (s, 1H), 3.76 (d, J=12.9 Hz, 1H), 3.42 (d, J=11.0 Hz, 1H), 3.25 (br s, 1H), 3.01 (s, 2H), 1.43 (s, 9H), 0.95 (d, J=6.4 Hz, 3H);m / z = 410.2 [M+H]+

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

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

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

[0201] Synthesis of tert-butyl 4-[3-(3-ethyl-2-oxo-1,3-dihydropyrrolo[2,3-b]pyridin-4-yl)phenyl]piperazine-1-carboxylate Iodoethane (0.085mL, 1.05mmol, 3 eq) was added dropwise to a solution of N,N,N',N'-tetramethylethylenediamine (0.16mL, 1.05mmol, 3 eq) in anhydrous THF (0.88mL) at -78°C, followed by 1.6M butyllithium solution (0.66mL, 1.05mmol, 3 eq). The reaction was stirred at -78°C for 30 minutes. Then, tert-butyl 4-[3-(2-oxo-1,3-dihydropyrrolo[2,3-b]pyridin-4-yl)phenyl]piperazine-1-carboxylate (140 mg, 0.351 mmol) was added and the mixture was allowed to warm to room temperature. The reaction mixture was stirred at room temperature for 2 hours. Water was added and the mixture was extracted with DCM. The organic phase was dried and concentrated under vacuum. The crude material was purified by flash chromatography on silica gel using a gradient of DCM / EtOAc eluted with Liquid Injection / DCM. The relevant fractions were collected and concentrated in vacuo to give tert-butyl 4-[3-(3-ethyl-2-oxo-1,3-dihydropyrrolo[2,3-b]pyridin-4-yl)phenyl]piperazine-1-carboxylate (20 mg, 32% yield) as a white oil. 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.05 (s, 1H), 8.11 (d, J = 5.7 Hz, 1H), 7.40 - 7.32 (m, 1H), 7.14 (s, 1H), 7.07 - 6.97 (m, 3H), 4.21 - 4.11 (m, 1H), 3.54 - 3.36 (m, 4H), 3.11-3.20 (m, 4H), 1.79 - 1.62 (m, 1H), 1.42 (s, 9H), 1.31 - 1.40 (m, 1H), 0.41 (t, J = 7.4 Hz, 3H). m / z = 423.3 [M+H]+.

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

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

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

[0205] Scaffold Coupling - Specific Method (Specific Phenyl 3) (Method for obtaining 4-aminopiperidine variants. 3-aminopiperidine variants were prepared by the same method) [ka] Synthesis of tert-butyl 4-(3-bromoanilino)piperidine-1-carboxylate A reaction vial was charged with diacetoxypalladium (3.3 mg, 0.0145 mmol, 0.01 eq), Xantphos (25 mg, 0.0436 mmol, 0.03 eq) and potassium tert-butylate (245 mg, 2.18 mmol, 1.5 eq) in anhydrous toluene (3.63 mL, 0.4 N) and stirred at room temperature for 5 min. 1,3-Dibromobenzene (360 mg, 1.53 mmol, 1.05 eq) and tert-butyl 4-aminopiperidine-1-carboxylate (300 mg, 1.45 mmol) were added sequentially to the reaction mixture. The resulting mixture was diluted with N 2 The mixture was heated to 80° C. under reduced pressure. Diacetoxypalladium (0.01 eq), Xantphos (0.03 eq), potassium tert-butylate (1 eq) and tert-butyl 4-aminopiperidine-1-carboxylate (1.5 eq) were added again and the mixture was stirred at 80° C. for another night. Water was added and the mixture was extracted with DCM. The combined organic layers were washed with water and brine, filtered through a phase separator and concentrated under vacuum to give a yellow liquid. The crude product was purified on a silica gel column solid phase using a heptane / EtOAc gradient. The relevant fractions were collected and concentrated under vacuum to give tert-butyl 4-(3-bromoanilino)piperidine-1-carboxylate (304 mg, 58% yield) as a white solid. 1 H NMR (DMSO-d 6 , 400 MHz):δ (ppm) 6.99 (t, J=8.0 Hz, 1H), 6.75 (t, J=2.0 Hz, 1H), 6.66 - 6.61 (m, 1H), 6.57 (dd, J=8.3, 1.6 Hz, 1H), 5.81 (d, J=8.2 Hz, 1H), 3.86 (d, J=13.1 Hz, 2H), 3.50 - 3.34 (m, 1H), 2.92 (s, 2H), 1.85 (dd, J=12.8, 3.0 Hz, 2H), 1.41 (s, 9H), 1.31 - 1.12 (m, 2H);m / z = 355.0 [M+H]+

[0206] Synthesis of tert-butyl 4-[3-bromo-N-(oxetan-3-yl methyl)anilino]piperidine-1-carboxylate A reaction vial was charged with tert-butyl 4-(3-bromoanilino)piperidine-1-carboxylate (293 mg, 0.808 mmol), oxetane-3-carbaldehyde (110 mg, 1.21 mmol, 1.5 eq) and acetic acid (0.046 mL, 0.808 mmol, 1 eq) in anhydrous methanol (4 mL, 0.2 N). The mixture was stirred for 30 min and sodium cyanoborohydride (1010 mg, 2.02 mmol, 2.5 eq) (resin) was added. The resulting mixture was stirred at 50° C. for 7 days while adding oxetane-3-carbaldehyde in several portions. The resin was filtered and washed with MeOH. The filtrate was concentrated in vacuo to give a colorless oil. The crude product was purified from the solid phase retentate of a silica gel column using a gradient of heptane / EtOAc. The relevant fractions were pooled and concentrated in vacuo to give tert-butyl 4-[3-bromo-N-(oxetan-3-ylmethyl)anilino]piperidine-1-carboxylate (194 mg, 56% yield) as a colorless gum. 1 H NMR (DMSO-d 6 , 400 MHz):δ (ppm) 7.11 (t, J=8.1 Hz, 1H), 6.96 (t, J=2.0 Hz, 1H), 6.82 (ddd, J=13.8, 8.2, 1.7 Hz, 2H), 4.55 (dd, J=7.9, 5.9 Hz, 2H), 4.31 (t, J=6.2 Hz, 2H), 4.02 (d, J=11.2 Hz, 2H), 3.72 (td, J=9.7, 7.9, 5.9 Hz, 1H), 3.43 (d, J=6.9 Hz, 2H), 3.11 (hept, J=6.8 Hz, 1H), 2.83 (s, 2H), 1.62 (d, J=10.3 Hz, 2H), 1.49 (qd, J=12.1, 4.3 Hz, 2H), 1.42 (s, 9H);m / z = 425.1, 427.1 [M+H]+

[0207] The next step was similar to the general procedure-phenyl 3. Scaffold Coupling - Specific Method (Specific Phenyl 4) [ka] Synthesis of tert-butyl 4-(3-bromo-5-fluoro-phenyl)piperazine-1-carboxylate In a vial, add Xantphos (17 mg, 0.0300 mmol, 0.03 eq.), Pd(OAc) 2 (2.3 mg, 9.98 μmol, 0.01 eq.) and NaOtBu (107 mg, 0.474 mmol, 1.5 eq.) were charged under nitrogen. Anhydrous toluene (118 mL, 0.4N) was added, followed by 1,3-dibromo-5-fluorobenzene (12.6 g, 49.7 mmol, 1.05 eq.) and tert-butyl piperazine-1-carboxylate (9 g, 47.3 mmol). The reaction mixture was heated at 80° C. overnight. Water was added and the mixture was extracted with DCM. The organic phase was washed with MgCl 2 Washing with aqueous solution, drying on a phase separator and concentration in vacuo gave tert-butyl 4-(3-bromo-5-fluoro-phenyl)piperazine-1-carboxylate as an orange oil (20.8 g, quantitative yield). This crude material was used directly in the next reaction. 1 H NMR (DMSO-d 6 m / z = 305.0 [M+H-tBu]+

[0208] Synthesis of tert-butyl 4-[3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperazine-1-carboxylate A 500 mL sealed vial was charged with tert-butyl 4-(3-bromo-5-fluoro-phenyl)piperazine-1-carboxylate (81%, 20.81 g, 46.9 mmol), bis(pinacolato)diboron (14.3 g, 56.3 mmol, 1.2 eq.) and potassium acetate (14.69 g, 0.141 mol, 3 eq.) in anhydrous dioxane (156 mL, 0.3 N). The mixture was degassed with nitrogen and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (3.84 g, 4.69 mmol, 0.1 eq.) was added. The solution was heated to 100° C. overnight. The mixture was filtered and concentrated under vacuum. 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 collected and concentrated in vacuo to give tert-butyl 4-[3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperazine-1-carboxylate as a brown foam (8.67 g, 46%). 1H NMR (400 MHz, chloroform-d) δ 7.12 (d, J = 2.2 Hz, 1H), 6.98 (dd, J = 8.3, 2.3 Hz, 1H), 6.67 (dt, J = 11.9, 2.3 Hz, 1H), 3.58 - 3.54 (m, 4H), 3.20 - 3.13 (m, 4H), 1.56 (s, 6H), 1.48 (s, 9H), 1.33 (s, 12H);m / z = 407.1 [M+H]+

[0209] Synthesis of tert-butyl 4-[3-fluoro-5-(2-oxo-1,3-dihydropyrrolo[2,3-b]pyridin-4-yl)phenyl]piperazine-1-carboxylate A 50 mL sealed tube was charged with a solution of 4-bromo-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (500 mg, 2.35 mmol), tert-butyl 4-[3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperazine-1-carboxylate (1.05 g, 2.58 mmol, 1.1 eq.), disodium carbonate (746 mg, 7.04 mmol, 3 eq.) in DMF (17.5 mL) and water (5 mL). The mixture was degassed and tetrakis(triphenylphosphine)palladium (542 mg, 0.469 mmol, 0.1 N) was added. The reaction mixture was heated at 100° C. overnight. The reaction mixture was diluted with water, filtered, and the residue was obtained as a yellowish powder. 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 tert-butyl 4-[3-fluoro-5-(2-oxo-1,3-dihydropyrrolo[2,3-b]pyridin-4-yl)phenyl]piperazine-1-carboxylate as an orange powder (631 mg, 42%). 1 H NMR (DMSO-d 6 , 400 MHz):δ (ppm) 11.08 (s, 1H), 8.12 (d, J=5.5 Hz, 1H), 7.09 (d, J=5.5 Hz, 1H), 6.97 (s, 1H), 6.88 (s, 1H), 6.85 (dd, J=3.8, 1.7 m / z = 413.2 [M+H]+

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

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

[0212] Specific Method (Specific Phenyl 4b) Synthesis of tert-butyl 4-[3-fluoro-5-(2-oxospiro[1H-pyrrolo[2,3-b]pyridine-3,1'-cyclobutan]-4-yl)phenyl]piperazine-1-carboxylate (n=2) To a solution of tert-butyl 4-[3-fluoro-5-(2-oxo-1,3-dihydropyrrolo[2,3-b]pyridin-4-yl)phenyl]piperazine-1-carboxylate (327 mg, 0.64 mmol) in anhydrous THF (6.4 mL, 0.1 N) was added dropwise 1M lithium[bis(trimethylsilyl)amide] solution (1.4 mL, 1.41 mmol, 2.2 eq.) at -78°C under nitrogen atmosphere. The mixture was stirred at this temperature for 5 min. Then, 1,3-diiodopropane (0.098 mL, 0.835 mmol, 1.3 eq.) was added dropwise at -78°C, and the resulting mixture was stirred for 1 h while warming to room temperature. The mixture was diluted with NH 4 The mixture was quenched with aqueous Cl. Water was added and the mixture was extracted with EtOAc. The organic layer was washed with water and brine, dried on a phase separator and concentrated to give a brown oil. The crude product was purified by preparative HPLC in TFA conditions (preparative HPLC with trifluoroacetic acid mobile phase). Relevant fractions were combined and concentrated to give tert-butyl 4-[3-fluoro-5-(2-oxospiro[1H-pyrrolo[2,3-b]pyridine-3,1'-cyclobutan)-4-yl)phenyl]piperazine-1-carboxylate (39 mg, 12%) as a brown solid. 1 H NMR (DMSO-d 6 , 400 MHz):δ (ppm) 11.00 (s, 1H), 8.06 (d, J=5.4 Hz, 1H), 6.89 - 6.86 (m, 2H), 6.81 (d, J=5.3 Hz, 1H), 6.73 (d, J=9.2 Hz, 1H), 3.49 - 3.40 (m, 4H), 3.28 - 3.16 (m, 4H), 2.42 - 2.29 (m, 2H), 2.28 - 2.17 (m, 2H), 1.79-1.89 (m, 1H), 1.42 (d, J=3.8 Hz, 9H), 1.30 - 1.17 (m, 1H);m / z = 453.2 [M+H]+

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

[0214] Scaffold Coupling - Specific Method (Specific Phenyl 5) Synthesis of tert-butyl 3-(3-bromophenyl)-3-(hydroxymethyl)pyrrolidine-1-carboxylate [ka] Lithium aluminum hydride (0.68 mL, 1.35 mmol, 2 eq.) was added to a stirred solution of 3-(3-bromophenyl)-1-tert-butoxycarbonyl-pyrrolidine-3-carboxylic acid (250 mg, 0.675 mmol) in anhydrous THF (6.8 mL, 0.1 N) in a microwave flask under nitrogen at 0° C. The reaction mixture was stirred overnight at 0° C. The reaction mixture was diluted with EtOAc. The organic phase was washed with 20% Rochelle's salt and 2% NaHCO 3 The crude material was purified by flash chromatography on silica gel using a gradient of DCM / MeOH. It was eluted with Liquid Injection / DCM. The relevant fractions were collected and concentrated in vacuo to give tert-butyl 3-(3-bromophenyl)-3-(hydroxymethyl)pyrrolidine-1-carboxylate (169 mg, 38%) as a colorless syrup. m / z = 300.0, 302.0 [M+H-tBu]+

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

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

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

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

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

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

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

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

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

[0224] Scaffold Coupling - Specific Method (Specific Phenyl 9) [ka] Synthesis of tert-butyl 3-oxo-1-(3-pyridyl)-5,6,8,8a-tetrahydro-1H-oxazolo[3,4-a]pyrazine-7-carboxylate In a 50 mL round bottom flask, 1.6 M tert-butyl lithium solution (14.9 mL, 23.86 mmol) was slowly added to a stirred solution of 3-bromopyridine (1.17 mL, 11.93 mmol, 5 eq.) in anhydrous THF (20 mL) at −78° C. This solution was then added dropwise to a solution of di-tert-butyl 2-formylpiperazine-1,4-dicarboxylate (750 mg, 2.39 mmol) in anhydrous THF (20 mL) at −78° C. The reaction mixture was stirred at −78° C. for 15 min. The reaction was then cooled to −78° C. using NH 4 The mixture was quenched with a saturated aqueous solution of NaCl. The two phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with Na 2 SO 4 The mixture was dried over 1000 ml, filtered and evaporated to give the crude material as an orange gum. The residue was then solubilized in anhydrous THF (8 mL) and slowly added to a heterogeneous mixture of sodium hydride 60% (95 mg, 2.38 mmol, 1 eq.) in anhydrous THF (20 mL). The reaction mixture was stirred at 60° C. overnight. The reaction was quenched with water and ethyl acetate was added. The two phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phase was diluted with Na 2 SO 4 The crude material was purified by flash chromatography on silica gel using a gradient of dichloromethane / ethyl acetate. It was eluted with Liquid Injection / DCM. The relevant fractions were collected and concentrated in vacuo to give tert-butyl 3-oxo-1-(3-pyridyl)-5,6,8,8a-tetrahydro-1H-oxazolo[3,4-a]pyrazine-7-carboxylate (220 mg, 19% yield) as a pale orange gum in two diastereomeric forms. m / z = 394[M+H]+.

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

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

[0227] Synthesis of 7-(3-bromophenyl)-1,1-dimethyl-5,6,8,8a-tetrahydrooxazolo[3,4-a]pyrazin-3-one To a solution of 2-[4-(3-bromophenyl)piperazin-2-yl]propan-2-ol (239 mg, 0.799 mmol) in anhydrous DCM (4 mL, 0.2 N) were added sequentially dimethylaminopyridine (197 mg, 1.60 mmol, 2 eq.) and tert-butoxycarbonyl tert-butyl carbonate (349 mg, 1.60 mmol, 2 eq.). The resulting mixture was stirred overnight at room temperature under nitrogen. Water was added and the mixture was extracted with EtOAc. The combined organic layers were washed with water and brine, dried over a phase separator and concentrated in vacuo to give the crude material, which was purified from the solid retentate of a silica gel column using a heptane / EtOAc gradient. The relevant fractions were combined and concentrated in vacuo to give 7-(3-bromophenyl)-1,1-dimethyl-5,6,8,8a-tetrahydrooxazolo[3,4-a]pyrazin-3-one (190 mg, 73% yield) as a colourless oil. 1 H NMR (DMSO-d 6 , 400 MHz):δ (ppm) 7.21 - 7.14 (m, 2H), 7.01 (dd, J=8.1, 2.1 Hz, 1H), 6.96 (dd, J=7.8, 1.1 Hz, 1H), 3.84 (ddd, J=12.2, 3.5, 1.6 Hz, 1H), 3.74 - 3.66 (m, 1H), 3.65 - 3.58 (m, 1H), 3.49 (dd, J=11.2, 3.6 Hz, 1H), 3.07 (td, J=12.5, 3.8 Hz, 1H), 2.75 - 2.62 (m, 2H), 1.43 (s, 3H), 1.34 (s, 3H);m / z = 325.0;327.0 [M+H]+

[0228] The next step was similar to the general method-phenyl 3.

[0229] 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 (Cisbio, Cat. No. 61ST1PEJ) according to the manufacturer's instructions. Briefly, the kinase buffer component of the kit was supplemented with 10 mM MgCl 2 , 1 mM DTT and 0.1% Tween 20 were added. For PKC-θ assay, STK substrate and ATP were added to a final assay concentration of 525 nM and 6.5 μM, respectively. For PKCδ assay, STK substrate and ATP were added to a final assay concentration 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 to 10 consecutive 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 the test compounds for 30 min on ice. Reactions were initiated by the 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 ratio of acceptor to donor emission signals 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 2).

[0230] 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).

[0231] 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 4°C for 24 hours at 4°C for 1 h at 25°C for 30 min at 5% CO 2 The cells were incubated at 37°C for 24 hours under ambient conditions. After incubation, the cell suspension was centrifuged at 400 x g 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 an HTRF human IL-2 detection kit (Cisbio, cat# 62HIL02PEH). The IL-2 data at different compound doses were fitted with a four-parameter logistic curve to determine the IC, which corresponds to the compound concentration that reduces 50% of the maximum IL-2 levels 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). [Table 72] [Table 73] [Table 74] [Table 75] [Table 76] [Table 77]

[0232] 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 measured pIC50 is 9.0-9.5; 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.

[0233] 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.

[0234] 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 of 0:1.

[0235] 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 or CR a (In the formula, R a is selected from hydrogen, halogen, C1-3 alkyl and CN; B is selected from N, CH, CF and C—(C alkyl); D is N, CH, CR b (In the formula, R b is selected from halogen, C1-3 alkyl and C1-3 haloalkyl; G is selected from CR1R2, NR1 and O; R1 and R2 are independently selected from hydrogen, halogen, C1-3 alkyl, C3-7 cycloalkyl, C1-3 alkoxyl, C2-6 cycloalkoxyl, C2-6 alkylalkoxy, hydroxyl, C1-3 alkylhydroxyl, amino, C1-3 alkylamino, C1-4 aminoalkyl, C2-7 alkylaminoalkyl, C1-3 haloalkyl, aryl, heteroaryl, alkylaryl and alkylheteroaryl; or R1 and R2 together form an optionally substituted 3- to 5-membered spirocarbocyclic or heterocyclic ring; R3 is selected from hydrogen, C1-2 alkyl, OMe, and halogen; R4 is selected from hydrogen, C1-5 alkyl, C3-7 cycloalkyl, C1-5 haloalkyl, C1-5 alkoxyl, C1-5 haloalkoxyl, alkylalkoxy, C2-6 heterocycloalkyl, CN, and halogen; E is N, CH, CR c (In the formula, R c is selected from the group consisting of halogen, hydroxyl, C alkylhydroxyl, C alkylamino, C haloalkyl, C alkylalkoxyl, and CN; R5 and R6 together join to form an optionally substituted and optionally bridged ring Z, wherein ring Z is General formula Ia: 【Chemistry 2】 wherein R7 is selected from hydrogen, C1-3 alkyl and C1-3 haloalkyl. an optionally substituted and optionally bridged 4- to 8-membered aminoalkyl ring represented by the formula: or a pharmaceutically acceptable salt, solvate, stereoisomer or mixture of stereoisomers, tautomer, isotopic form or pharmaceutically active metabolite thereof, or a combination thereof.

2. Ring Z is: 【Transformation 3】 [In the formula, R8, R9, R10, R11, R13 and R21 are each independently selected from hydrogen, C1-3 alkyl, C1-3 alkylalkoxy, C1-3 alkylhydroxyl, amino, C1-3 alkylamino, C1-6 alkylaminoalkyl, C1-3 haloalkyl and alkylheteroaryl; R12 is selected from hydrogen, C1-3 alkyl and C1-3 haloalkyl; or any one of R8, R9, R10, R11, R12, R13 and R21 may be joined to another different R8, R9, R10, R11, R12, R13 or R21 to form a 3- to 7-membered spiro or bicyclic carbocyclic or heterocyclic ring structure and / or a 3- to 6-membered bridged carbocyclic or heterocyclic ring structure; n is selected from 0, 1 and 2. or a pharmaceutically acceptable salt, solvate, stereoisomer or mixture of stereoisomers, tautomer, isotopic form or pharmaceutically active metabolite thereof, or a combination thereof, wherein

3. n is 0; E is N, CH and CR d (In the formula, R d is selected from halogen, alkoxy, C1-3 alkylhydroxy, C1-3 haloalkyl, C2-5 alkylalkoxy, C2-5 alkylnitrile), 10. The compound of claim 2, or a pharmaceutically acceptable salt, solvate, stereoisomer or mixture of stereoisomers, tautomer, isotopic form, or pharmaceutically active metabolite thereof, or a combination thereof.

4. Ring Z is 【Chemistry 4】 3. The compound of claim 2, wherein:

5. G is CR1R2 and ring Z is: 【Transformation 5】 It is A is CH, CF, C-Cl and C-Br; B and D are each independently N and CH; E is N, CF and CH; R1 is hydrogen, Me, Et, OMe, OEt, OH, NH 2 and NHMe; R2 is selected from hydrogen, Me and Et; or R1 and R2 together form a 3- to 6-membered spirocarbocyclic or heterocyclic ring; R3 is hydrogen or halogen; R4 is hydrogen, Me, Et, CF 2 H, CF 3 , C.F. 2 Me, OMe, OEt, OCF 2 H, OCF 3 , CN, Cl, and F; R8 and R9 are each independently hydrogen, Me, Et, CH 2 OH, CHMeOH, CMe 2 OH, CH 2 OMe, CH 2 selected from F and halogen; R10 and R11 are each independently hydrogen, Me, Et, CH 2 OH, CHMeOH, CMe 2 OH, CH 2 OMe, CH 2 FCHF 2 , C.H. 2 CF 3 and C.H. 2 -heteroaryl; R12 is selected from hydrogen and Me; R13 is selected from hydrogen and Me; R21 is selected from hydrogen and Me; or 4. The compound of claim 2 or 3, wherein any one of R8, R9, R10, R11, R12, R13 and R21 may be joined to another different R8, R9, R10, R11, R21, R13 or R21 to form a 3- to 7-membered spiro or bicyclic carbocyclic or heterocyclic ring structure and / or a 3- to 6-membered bridged carbocyclic or heterocyclic ring structure, or a pharmaceutically acceptable salt, solvate, stereoisomer or mixture of stereoisomers, tautomer, isotopic form or pharmaceutically active metabolite thereof, or a combination thereof.

6. a) one of R8 and R9 is bonded to one of R10 and R11 to form a [6,3]-, [6,4]-, [6,5]-, [6,7]- or [6,8]-bicyclic ring structure; b) one of R8 and R9 is linked to R13 to form a [6,5,5]-, [6,6,6]-, [6,7,7]- or [6,8,8]-bridged structure; c) one of R10 and R11 is bonded to R13 to form a [6,6,4]-, [6,7,5]- or [6,8,6]-bridged structure; d) one of R10 and R11 may be bonded to R21 to form a [6,5,5]-, [6,6,6]-, [6,7,7]-, or [6,8,8]-bridged structure; e) one of R8 and R9 can be bonded to R21 to form a [6,6,4]-, [6,7,5]-, or [6,8,6]-bridged structure; f) R8 is joined to R9 to form a [6,3]-, [6,4-], [6,5]-, [6,6]- or [6,7]-spiro structure; or g) The compound of claim 6, wherein R10 is bonded to R11 to form a [6,3]-, [6,4-], [6,5]-, [6,6]- or [6,7]-spiro structure, or a pharmaceutically acceptable salt, solvate, stereoisomer or mixture of stereoisomers, tautomer, isotopic form or pharmaceutically active metabolite thereof, or a combination thereof.

7. Ring Z is 【Transformation 6】 【Transformation 7】 【Transformation 8】 【Chemistry 9】 【Chemistry 10】 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 the group consisting of:

8. Ring Z is 【Chemistry 11】 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 the group consisting of:

9. G is CR1R2 and ring Z is: 【Chemistry 12】 It is A is selected from CH, CF, C—Cl, and C—Br; B and D are each independently selected from N and CH; E is selected from N, CH and CF; R1 is hydrogen, Me, Et, OMe, OEt, OH, NH 2 and NHMe; and R2 is selected from hydrogen, Me and Et; or R1 and R2 together form a 3- to 6-membered spirocarbocyclic or heterocyclic ring; in particular a 4- to 5-membered carbocyclic or heterocyclic spiro ring; R3 is selected from hydrogen and F; R4 is Me, Et, CF 2 H, CF 3 , C.F. 2 Me, OMe, OEt, OCF 2 H, CN, Cl and F; R14, R15, R17, R18, R19 and R20 are each independently selected from hydrogen, Me and F; R16 is selected from hydrogen and Me; 10. The compound of claim 2, or a pharmaceutically acceptable salt, solvate, stereoisomer or mixture of stereoisomers, tautomer, isotopic form, or pharmaceutically active metabolite thereof, or a combination thereof.

10. a) each of R14, R15, R16, R17, R18, R19 and R20 is hydrogen; b) when one of R14, R15, R17, R18 and R20 is Me, R16 and R19 are hydrogen; c) when R18 is F, R14, R15, R16, R17, R19 and R20 are hydrogen; d) when R18 is F and R19 is Me, then R14, R15, R16, R17 and R19 are hydrogen; e) R18 and R19 are both F, and R14, R15, R17 and R20 are hydrogen; f) when E is CH, R14 or R20 is F; 10. The compound of claim 9, or a pharmaceutically acceptable salt, solvate, stereoisomer or mixture of stereoisomers, tautomer, isotopic form, or pharmaceutically active metabolite thereof, or a combination thereof.

11. Ring Z is as follows: 【Chemistry 13】 10. The compound of claim 9, or a pharmaceutically acceptable salt, solvate, stereoisomer or mixture of stereoisomers, tautomer, isotopic form or pharmaceutically active metabolite thereof, selected from:

12. 12. The compound of claim 11, wherein when G is NH, then B is N, or a pharmaceutically acceptable salt, solvate, stereoisomer or mixture of stereoisomers, tautomer, isotopic form, or pharmaceutically active metabolite thereof, or a combination thereof.

13. 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 Table 39 Table 40 Table 41 Table 42 Table 43 Table 44 Table 45 Table 46 Table 47 Table 48 Table 49 Table 50 Table 51 Table 52 Table 53 Table 54 Table 55 Table 56 Table 57 Table 58 Table 59 Table 60 Table 61 Table 62 Table 63 Table 64 Table 65 Table 66 Table 67 Table 68 Table 69 Table 70 or a pharmaceutically acceptable salt, solvate, stereoisomer or mixture of stereoisomers, tautomer, isotopic form or pharmaceutically active metabolite thereof, or a combination thereof.

14. The compound of claim 1, wherein the compound has the structure: 【Chemistry 14】 or a pharmaceutically acceptable salt, solvate, stereoisomer or mixture of stereoisomers, tautomer, isotopic form or pharmaceutically active metabolite thereof, or a combination thereof, wherein 15. The compound of claim 1, wherein the compound has the structure: 【Chemistry 15】 or a pharmaceutically acceptable salt, solvate, stereoisomer or mixture of stereoisomers, tautomer, isotopic form or pharmaceutically active metabolite thereof, or a combination thereof, wherein 16. The compound of claim 1, wherein the compound has the structure: 【Chemistry 16】 or a pharmaceutically acceptable salt, solvate, stereoisomer or mixture of stereoisomers, tautomer, isotopic form or pharmaceutically active metabolite thereof, or a combination thereof, wherein 17. The compound of claim 1, wherein the compound has the structure: 【Chemistry 17】 or a pharmaceutically acceptable salt, solvate, stereoisomer or mixture of stereoisomers, tautomer, isotopic form or pharmaceutically active metabolite thereof, or a combination thereof, wherein 18. The compound of claim 1, wherein the compound has the structure: [Chemistry 18] or a pharmaceutically acceptable salt, solvate, stereoisomer or mixture of stereoisomers, tautomer, isotopic form or pharmaceutically active metabolite thereof, or a combination thereof, wherein 19. The compound of claim 19, wherein the compound has the structure: 【Chemistry 19】 or a pharmaceutically acceptable salt, solvate, stereoisomer or mixture of stereoisomers, tautomer, isotopic form or pharmaceutically active metabolite thereof, or a combination thereof, wherein 20. The compound of claim 1, wherein the compound has the structure: 【Chemistry 20】 or a pharmaceutically acceptable salt, solvate, stereoisomer or mixture of stereoisomers, tautomer, isotopic form or pharmaceutically active metabolite thereof, or a combination thereof, wherein 21. The compound of claim 20, wherein the compound has the structure: 【Chemistry 21】 or a pharmaceutically acceptable salt, solvate, stereoisomer or mixture of stereoisomers, tautomer, isotopic form or pharmaceutically active metabolite thereof, or a combination thereof, wherein 22. The compound of claim 21, wherein the compound has the structure: 【Chemistry 22】 or a pharmaceutically acceptable salt, solvate, stereoisomer or mixture of stereoisomers, tautomer, isotopic form or pharmaceutically active metabolite thereof, or a combination thereof, wherein 23. The compound of claim 22, wherein the compound has the structure: 【Chemistry 23】 or a pharmaceutically acceptable salt, solvate, stereoisomer or mixture of stereoisomers, tautomer, isotopic form or pharmaceutically active metabolite thereof, or a combination thereof, wherein 24. The compound of claim 24, wherein the compound has the structure: 【Chemistry 24】 or a pharmaceutically acceptable salt, solvate, stereoisomer or mixture of stereoisomers, tautomer, isotopic form or pharmaceutically active metabolite thereof, or a combination thereof, wherein 25. The compound of claim 25, wherein the compound has the structure: 【Chemistry 25】 or a pharmaceutically acceptable salt, solvate, stereoisomer or mixture of stereoisomers, tautomer, isotopic form or pharmaceutically active metabolite thereof, or a combination thereof, wherein

26. 26. A pharmaceutical composition comprising one or more compounds of any one of claims 1 to 25, 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.

27. 26. A pharmaceutical composition comprising a compound according to any one of claims 1 to 25 for use in the treatment of a disease or disorder selected from autoimmune diseases and / or inflammatory diseases and / or neoplastic diseases and / or cancer and / or HIV infection and / or replication.

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

29. 28. The pharmaceutical composition of claim 27, wherein the compound is an inhibitor of PKC-theta.

30. 28. The pharmaceutical composition of claim 27, for use in a method comprising administering the compound orally, topically, by inhalation, intranasally, or systemically by intravenous, intraperitoneal, subcutaneous, or intramuscular injection.

31. 26. A pharmaceutical combination comprising a compound according to any one of claims 1 to 25, 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.

32. 32. The pharmaceutical combination of claim 31, wherein the compound of any one of claims 1 to 25, 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.

33. 28. The pharmaceutical composition of claim 27, comprising administering to a subject an effective amount of the compound of any one of claims 1 to 25, or a pharmaceutically acceptable salt, solvate, stereoisomer or mixture of stereoisomers, tautomer, isotopic form, or pharmaceutically active metabolite thereof, wherein the effective amount is from about 5 nM to about 10 μM in the blood of the subject.

Images