IKK-alpha inhibitors

Abstract

The invention relates to IKK-alpha inhibitory compounds or pharmaceutically acceptable salts, hydrates or solvates thereof. The compounds have the structural formula (I) shown in the specification, wherein R1, R2, R3, R4 and X1 are each as defined herein. The invention also relates to processes for preparing these compounds, pharmaceutical compositions comprising them, and their use in the treatment of proliferative disorders, such as cancer, as well as other diseases or conditions involving IKK-alpha activity.

Description

Technical Field

[0001] This invention relates to certain compounds that act as inhibitors of inhibitory κB kinase (IKK) activity, particularly the α subunit of IKK (IKKα). Therefore, the compounds of this invention can be used to treat diseases or conditions mediated at least in part by abnormal or inappropriate IKK (especially IKKα) activity. Cancer is an example of a condition associated with abnormal or inappropriate IKK (especially IKKα) activity. This invention also relates to the use of said compounds for treating diseases or conditions involving IKK (especially IKKα) activity, methods for preparing these compounds, and pharmaceutical compositions comprising them. Background Technology

[0002] Cancer is caused by altered cell proliferation. For decades, the exact mechanisms that lead to cell malignancy and uncontrolled, regulated proliferation have been a focus of intensive research. This study has identified molecular targets associated with key pathways leading to this malignancy.

[0003] Nuclear factor κ-B (NF-κB) is derived from the nuclear factor κ-light chain enhancer of B cells and represents a family of five transcription factors involved in various biological responses supporting phenotypic outcomes related to inflammation, regulation of immune responses, cell growth, proliferation, apoptosis, and differentiation and development [1-5]. NF-κB signaling is now thought to occur via canonical (classical) or atypical (alternative) pathways that mobilize homodimeric complexes of these family members. In general, there are five distinct isoforms of NF-κB protein: RelA (p65), RelB, c-Rel, NF-κB1 (p105 / p50), and NF-κB2 (p100 / p52) [1-5]. In their inactive state, these proteins are typically associated with repressive κB (IκB) proteins (including isoforms of IκBα, IκBβ, and IκBε), and in the case of p105 and p100 proteins, they maintain their self-binding repressive form through their intrinsic protein structures composed of C-terminal IκB-like structures (IκBδ and IκBγ, respectively) formed by ankyrin repeat sequences [1-5]. Activation and release of NF-κB proteins generally occur in response to numerous extracellular ligands and mediators that generate DNA damage responses (DDR), leading to the nuclear localization of DNA-binding protein dimers after dissociation from IκB molecules [1-5].

[0004] Typical pathways are activated in response to cytokines such as TNFα and IL-1β and pathogen-associated molecular profiles (PAMPs) such as bacterial endotoxin lipopolysaccharide (LPS) [6, 7]. This response is typically rapid and transient, mediated by the classical inhibitory κB kinase (IKK) complex (IKKα / β / γ), requiring IKKβ-mediated phosphorylation of selected IκB proteins [6, 7]. In contrast, activation of the atypical NF-κB pathway is relatively slow, leading to IKKα-mediated release of the p52-RelB dimer after several hours, thereby driving gene transcription [1–7]. This slower response reflects a dependence on protein expression / stabilization in the upstream components of this pathway. While TNFα and IL-1β have the ability to activate the atypical NF-κB pathway, activation is typically driven by alternative members of the larger TNF superfamily [3, 4]. This includes lymphotoxin-β (LT-β), a member of the tumor necrosis factor superfamily known as LIGHT 14 (TNFSF14), a weak inducer of TNF-like apoptosis (TWEAK), CD40 ligand (CD40L), receptor activator of NF-κB ligand (RANKL), and B cell activator (BAFF) [1, 3, 4].

[0005] The combination of molecular and genetic studies has established a paradigm around which TNF superfamily ligands activate their homologous receptors by recruiting a series of recognizable adaptor molecules of the TNF receptor-associated factor (TRAF) family, particularly TRAF2 and TRAF3, regulators of ubiquitination and associated protein degradation in the form of cIAP inhibitors. These proteins induce the involvement and activation of cellular kinases NF-κB-inducible kinase (NIK) (the 14th member of the MAP kinase kinase (MAP3K) family) and IKKα to determine the release of the p52-RelB protein complex.

[0006] In the cellular environment, under resting, non-stimulated conditions, NIK expression remains low due to proteasome degradation focused on NIK. However, upon receptor activation, NIK is stabilized, and protein expression increases to activate the pathway

[16] . It is TRAF3 that acts as a key regulator of NIK expression by controlling the extent of its proteasome-mediated degradation

[16] . Upon receptor activation, the focus of proteasome-mediated protein degradation shifts from NIK to TRAF2 and TRAF3, which stabilize NIK expression, thereby initiating a series of signaling events leading to p100 processing [17-20]. The cIAP protein acts as a ubiquitin ligase, ubiquitinizing NIK and then targeting TRAF3 for degradation to increase NIK protein levels.

[0007] Once stabilized, NIK protein, as the first component of the atypical NF-κB pathway, catalyzes the phosphorylation of IKKα and supports IKKα recruitment and p100 phosphorylation to drive subsequent p100 ubiquitination and proteasome-mediated degradation, releasing p52

[16] . Under basal conditions, p100 is normally present in a dimer complex with RelB and generates a p52-RelB dimer upon stimulated degradation, which can translocate to the nucleus to initiate transcription of different genes.

[0008] Both NIK and IKKα play key roles in p100 phosphorylation to release the mature p52-RelB protein dimer. However, while IKKα is now considered a key regulator of p100 phosphorylation, it also co-dependently relies on NIK to deliver the coupled phosphorylation and processing of p100 to produce a transcriptionally active mature p52

[22] . In transfected cells, NIK can stimulate phosphorylation, ubiquitination, and processing of p100 [23, 24], however, recombinant NIK itself does not show any phosphorylation of p100 in vitro [24, 25]. In a cell-based setting, NIK leads to phosphorylation of the C-terminal region of p100 by participating in and activating IKKα-mediated downstream signaling

[25] , independent of other IKK isoforms β and γ associated with typical NF-κB activation [26, 27]. Although IKKα alone phosphorylates p100 and regulates atypical NF-κB activation, it is less effective than NIK in inducing p100 processing

[23] . Based on these observations, further studies have found that NIK plays a key role in regulating p100 processing by recruiting IKKα and binding it to p100 as a protein substrate

[22] . In general, the interaction between NIK-IKKα and p100 leads to phosphorylation of p100 at specific serine residues, primarily Ser868 / 870

[24] . These sites are components of the phosphorylation degradation determinant (phosphor-degron) within the p100 C-terminal NIK reactive domain (NRD), which, upon phosphorylation, leads to βTrCP binding as an SCF. βTrCP As part of the ubiquitin ligase complex, it drives the final processing of p100 to generate p52.

[0009] Independent of the atypical NF-κB pathway, numerous studies have identified examples of signal bifurcation at the NIK-IKKα kinase level. These may depend on different extracellular conditions

[29] and demonstrate that p100 is not the only substrate for IKKα-mediated phosphorylation. IKKα directly regulates many cellular proteins by catalytic phosphorylation, and then directly or indirectly regulates cellular transcription [6,7]. This includes transcription factors other than the NF-κB family, such as E2F1 [30, 31], β-catenin

[32] , CBP

[33] , as well as transcriptional repressors, such as retinoic acid and silencing mediators of thyroid hormone receptors (SMRT)

[34] and the cell cycle regulator cyclin D1

[35] . Other substrates include the protein inhibitor of activated STAT1 (PIAS1)

[36] , which acts as a transcriptional / inflammatory regulator; the estrogen receptor (ER)

[37] and androgen receptor (AR)

[38] , which are steroid hormone family receptors, and their associated steroid receptor cofactor (SRC)-3 [37, 39, 40]; and aurora kinase A [41, 42], which promotes mitosis. IKKα directly regulates the transcription of these protein states in connection with other regulatory proteins, such as p53 [43,44] and EZH2

[44] , as well as other mitotic kinases like Polo-like kinase (PLK) 4

[45] . Thus, IKKα acts as a key switch in the coordinated regulation of NF-κB-dependent and NF-κB-independent gene transcription, which reinforces outcomes associated with the initiation and / or maintenance of acquired traits or phenotypic development, which we now recognize as precisely the cancer “hallmarks” [46, 47] identified and defined by Hanahan and Weinberg. Using a variety of experimental methods such as gene deletion and reconstruction [48, 49], siRNA “run-down”

[35] and overexpression strategies

[50] , it has been revealed that IKKα-mediated signaling-driven transcriptional regulation may involve more than 200 genes, and these gene / protein induction / inhibition events support the acquisition of specific “markers”, particularly the tumor’s ability to “maintain proliferation signaling,” “resist cell death,” “evade growth inhibitors,” and promote “genomic instability and mutation.”More notably, IKKα plays a role in regulating genes / proteins that contribute to the consolidation of phenotypes associated with long-term tumor development: by inducing and regulating the expression of adhesion molecules (e.g., VCAM; [48-50]), mammary maspin [50; 53], and MMP

[50] under different cellular / tissue conditions through the regulation of cytokines (e.g., IL-1β, IL-6 [48, 49]) and chemokines (e.g., CCL19, CCL21, CXCL12, CXCL13, and BAFF [27, 51, 52]) and MMPs (e.g., CCL19, CCL21, CXCL12, CXCL13, and BAFF [27, 51, 52]) and MMPs (e.g., VCAM; [48-50]) under different cellular / tissue conditions, it “induces angiogenesis” and “activates invasion and metastasis.” It is also evident that, in certain cancer subtypes, the acquisition of a specific mutation, C250T, in the hTERT promoter

[54] that supports tumor reactivation has established the potential for tumor “addiction” to IKKα-mediated atypical NF-κB signaling, thereby “realizing replication potential.” In general, interference with this enzyme could have a wide range of effects on multiple markers of the aforementioned tumor cells. Furthermore, given the role of IKKα in regulating major cytokines, chemokines, and matrix metalloproteinase isoforms, intervention targeting this enzyme may have a significant impact on tumor-matrix communication and matrix composition in the tumor microenvironment and define a better understanding of "pro-tumor inflammation".

[0010] The additional complexity of IKKα-dependent, NF-κB-dependent, and independent gene transcriptional regulation is now evident in the cancer setting as we recognize that this transcriptional process is not entirely driven by receptor-mediated activation. In solid tumors (e.g., pancreatic adenocarcinoma) and hematologic conditions (e.g., multiple myeloma), constitutive activation of IKKα-mediated signaling has been reported due to the regulation of expression of upstream TRAF and cIAP components in the pathway, or mutations in these very similar components, ultimately leading to constitutive activation of the pathway even in the absence of agonists. Furthermore, truncated p45 forms of IKKα have been identified in numerous colorectal cancers [55, 56], particularly those with well-established B-Raf... V600E Colorectal cancer with a mutational background. This drives p45 IKKα-mediated nuclear signaling in a TNF superfamily member-independent manner, thus introducing additional mechanistic and transcriptional diversity into tumor development, which implies potential therapeutic interventions.

[0011] In recent years, the atypical NF-κB pathway and its component IKKα have played an increasingly important role in the development and progression of various solid tumors and hematologic malignancies. Therefore, there is a need and expectation to identify potentially useful IKKα inhibitors.

[0012] This invention was designed with the foregoing in mind.

[0013] References

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[0059]

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[0060] According to a first aspect of the invention, a compound as defined herein or a pharmaceutically acceptable salt, hydrate or solvate thereof is provided.

[0061] According to another aspect of the invention, a pharmaceutical composition is provided comprising a compound as defined herein or a pharmaceutically acceptable salt, hydrate or solvate thereof, and a pharmaceutically acceptable diluent or carrier.

[0062] According to another aspect of the invention, a method for inhibiting IKKα activity in vitro or in vivo is provided, the method comprising contacting cells with an effective amount of a compound as defined herein or a pharmaceutically acceptable salt, hydrate or solvate thereof.

[0063] According to another aspect of the invention, a method is provided for treating a disease or condition involving IKKα activity in a patient requiring such treatment, the method comprising administering to the patient a therapeutically effective amount of a compound as defined herein or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein.

[0064] According to another aspect of the invention, a method for treating proliferative disorders in a patient requiring such treatment is provided, the method comprising administering to the patient a therapeutically effective amount of a compound as defined herein or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein.

[0065] According to another aspect of the invention, a method for treating cancer in a patient requiring such treatment is provided, the method comprising administering to the patient a therapeutically effective amount of a compound as defined herein or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein.

[0066] According to another aspect of the invention, compounds as defined herein or pharmaceutically acceptable salts, hydrates or solvates thereof, or pharmaceutical compositions thereof, are provided for use in therapy.

[0067] According to another aspect of the invention, compounds as defined herein or pharmaceutically acceptable salts, hydrates or solvates thereof, or pharmaceutical compositions thereof, are provided for use as pharmaceuticals.

[0068] According to another aspect of the invention, compounds as defined herein or pharmaceutically acceptable salts, hydrates or solvates thereof, or pharmaceutical compositions as defined herein, are provided for the treatment of proliferative disorders.

[0069] According to another aspect of the invention, compounds, or pharmaceutically acceptable salts, hydrates, or solvates thereof, or pharmaceutical compositions, as defined herein, are provided for the treatment of cancer. In a particular embodiment, the cancer is a human cancer.

[0070] According to another aspect of the invention, compounds as defined herein or pharmaceutically acceptable salts, hydrates or solvates thereof are provided for inhibiting IKKα activity.

[0071] According to another aspect of the invention, compounds as defined herein or pharmaceutically acceptable salts, hydrates or solvates thereof are provided for the treatment of diseases or conditions involving IKKα activity.

[0072] According to another aspect of the invention, the use of a compound as defined herein or a pharmaceutically acceptable salt, hydrate or solvate thereof in the preparation of a medicament for treating proliferative disorders is provided.

[0073] According to another aspect of the invention, the use of a compound as defined herein or a pharmaceutically acceptable salt, hydrate or solvate thereof in the preparation of a medicament for treating cancer is provided.

[0074] According to another aspect of the invention, the use of a compound as defined herein or a pharmaceutically acceptable salt, hydrate or solvate thereof in the preparation of a medicament for inhibiting IKKα activity is provided.

[0075] According to another aspect of the invention, use is provided in the preparation of a medicament for treating a disease or condition involving IKKα activity, using a compound as defined herein or a pharmaceutically acceptable salt, hydrate or solvate thereof.

[0076] According to another aspect of the invention, a method for preparing a compound as defined herein or a pharmaceutically acceptable salt, hydrate or solvate thereof is provided.

[0077] According to another aspect of the invention, a compound or a pharmaceutically acceptable salt, hydrate or solvate thereof is provided, which can be obtained by a method for preparing a compound as defined herein, or by a method for preparing a compound as defined herein, or directly by a method for preparing a compound as defined herein.

[0078] According to another aspect of the invention, a novel intermediate as defined herein is provided, which is applicable to any of the synthetic methods listed herein.

[0079] Features associated with one aspect of the invention include optional, suitable, and preferred features, and can also be features associated with any other aspect of the invention, including optional, suitable, and preferred features. Detailed Implementation

[0080] Definitions

[0081] Unless otherwise stated, the following terms used in the specification and claims have the following meanings as listed below.

[0082] It should be understood that references to “treatment” or “management” include prevention and relief of established symptoms of a condition. Therefore, “treatment” or “management” of a state, condition or illness includes: (1) preventing or delaying the development of clinical symptoms of the state, condition or illness in a person who may have or is susceptible to the state, condition or illness but has not yet experienced or exhibited clinical or subclinical symptoms of the state, condition or illness; (2) suppressing the state, condition or illness, i.e., preventing, reducing or delaying the development of the disease or its recurrence (in the case of maintenance treatment) or at least one of its clinical or subclinical symptoms; or (3) alleviating or reducing the disease, i.e. causing the disappearance of the state, condition or illness or at least one of its clinical or subclinical symptoms.

[0083] A "therapeutic effective amount" refers to the amount of a compound that, when administered to a mammal to treat a disease, is sufficient to achieve therapeutic effect. Therapeutic effective amounts will vary depending on the compound, the disease and its severity, and the age, weight, etc., of the mammal being treated. It should be understood that, in humans or other mammals, therapeutic effective amounts can be determined experimentally in a laboratory or clinical setting, or they can be the amount required by guidelines from the U.S. Food and Drug Administration (FDA) or an equivalent foreign regulatory agency for a specific disease and the treated subject. It should be understood that determining the appropriate dosage form, dosage, and route of administration is within the realm of general pharmaceutical and medical expertise.

[0084] As used alone or in combination with one or more other terms in this document, “subject” and “patient” refer to animals (e.g., mammals), especially humans. Appropriately, “subject” and “patient” can refer to non-human animals (e.g., livestock and pets) or humans.

[0085] As used alone or in combination with one or more other terms in this document, “pharmaceutical acceptable” means a substance that is generally chemically and / or physically compatible with other components (e.g., in relation to the formulation) and / or generally physiologically compatible with its recipient (e.g., the subject).

[0086] In this specification, the term "alkyl" includes both straight-chain and branched alkyl groups. When referring to a single alkyl group such as "propyl", it refers only to the straight-chain form; when referring to a single branched alkyl group such as "isopropyl", it refers only to the branched form. For example, "(1-6C)alkyl" includes (1-4C)alkyl, (1-3C)alkyl, propyl, isopropyl, and tert-butyl.

[0087] The terms “(m-nC)” or “(m-nC) group” used alone or as a prefix refer to any group having m to n carbon atoms.

[0088] "Alkylene" is an alkyl group located between two other chemical groups and used to connect them. Therefore, "(1-6C)alkylene" refers to a straight-chain saturated divalent hydrocarbon group with 1-6 carbon atoms or a branched saturated divalent hydrocarbon group with 3-6 carbon atoms, such as methylene (-CH2-), ethylidene isomers (–CH(CH3)– and –CH2CH2–), propylidene isomers (–CH(CH3)CH2–, –CH(CH2CH3)–, –C(CH3)2– and –CH2CH2CH2–), pentylene (-CH2CH2CH2CH2CH2-), etc.

[0089] The term "alkenyl" refers to a straight-chain or branched alkyl group containing two or more carbon atoms, wherein at least one carbon-carbon double bond is present in the group. Examples of alkenyl groups include vinyl, propenyl, and but-2,3-alkenyl groups, and include all possible geometric (E / Z) isomers.

[0090] The term "alkynyl" refers to a straight-chain or branched alkyl group containing two or more carbon atoms, wherein at least one carbon-carbon triple bond is present in the group. Examples of alkynyl groups include ethynyl and propynyl.

[0091] "(m-nC)cycloalkyl" refers to a saturated hydrocarbon ring system containing m to n carbon atoms. Exemplary cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and bicyclic [2.2.1]heptyl.

[0092] The term "alkoxy" refers to O-linked straight-chain and branched alkyl groups. Examples of alkoxy groups include methoxy, ethoxy, and tert-butoxy.

[0093] As used herein, the term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by a halogen (e.g., fluorine) atom. Examples of haloalkyl groups include -CH2F, -CHF2, and -CF3.

[0094] The term "halogen" or "halogen group" refers to fluorine, chlorine, bromine, and iodine, more appropriately fluorine, chlorine, and bromine, and more appropriately fluorine and chlorine.

[0095] The terms “carbocyclic group,” “carbocyclic,” or “carbocyclic” refer to a non-aromatic, saturated, or partially saturated monocyclic, fused, bridged, or spirocyclic bicyclic system containing a carbon ring. A monocyclic carbocyclic ring contains about 3 to 12 (suitably 3 to 7) ring atoms. A bicyclic carbocyclic ring contains 6 to 17 member atoms, suitably 7 to 12 member atoms. Bicyclic carbocyclic rings can be fused, spirocyclic, or bridged ring systems. Examples of carbocyclic groups include cyclopropyl, cyclobutyl, cyclohexyl, cyclohexenyl, and spirocyclic [3.3]heptyl.

[0096] The terms "heterocyclic group," "heterocyclic," or "heterocyclic" refer to a non-aromatic, saturated, or partially saturated monocyclic, fused, bridged, or spirocyclic bicyclic heterocyclic system. Monocyclic heterocycles contain about 3 to 12 (suitably 3 to 7) ring atoms, with 1 to 5 (suitably 1, 2, or 3) heteroatoms selected from nitrogen, oxygen, or sulfur in the ring. Bicyclic heterocycles contain 7 to 17 member atoms, suitably 7 to 12 member atoms. Bicyclic heterocycles can be fused, spirocyclic, or bridged ring systems. Examples of heterocyclic groups include cyclic ethers, such as oxiranyl, oxetanyl, tetrahydrofuranyl, dioxanyl, and substituted cyclic ethers. Nitrogen-containing heterocycles include, for example, aza-butyl, pyrrolidinyl, piperidinyl, piperazineyl, tetrahydrotriazineyl, tetrahydropyrazolyl, etc. Typical sulfur-containing heterocycles include tetrahydrothiophene, dihydro-1,3-dithiol, tetrahydro-2H-thiaran, and hexahydrothiepine. Other heterocycles include dihydro-oxathiolyl, tetrahydrooxazolyl, tetrahydrooxadiazolyl, tetrahydrodioxazolyl, tetrahydro-oxathiazolyl, hexahydrotriazinyl, tetrahydrooxazinyl, morpholinyl, thiomorpholinyl, tetrahydropyrimidinyl, dioxolinyl, octahydrobenzofuranyl, octahydrobenzimidazolyl, and octahydrobenzothiazolyl. Sulfur-containing heterocycles also include sulfur oxide heterocycles containing SO or SO2 groups. Examples include the sulfoxide and sulfone forms of tetrahydrothiophene and thiomorpholinyl, such as tetrahydrothiophene 1,1-dioxide and thiomorpholinyl 1,1-dioxide. The heterocycle may contain one or two oxo (=O) or thio (=S) substituents. Suitable values ​​for heterocyclic groups with one or two oxo (=O) or thio (=S) substituents are, for example, 2-oxopyrrolyl, 2-thiopyrrolyl, 2-oxoimidazoyl, 2-thioimidazoyl, 2-oxopyridinyl, 2,5-dioxopyrrolyl, 2,5-dioxoimidazoyl, or 2,6-dioxopyridinyl. Specific heterocyclic groups are saturated monocyclic 3- to 7-membered heterocyclic groups containing one, two, or three heteroatoms selected from nitrogen, oxygen, or sulfur, such as azobutyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolyl, morpholinyl, tetrahydrothiophenyl, tetrahydrothiophenyl 1,1-dioxide, thiomorpholinyl, thiomorpholinyl 1,1-dioxide, piperidinyl, homopiperidinyl, piperazine, or homopiperazine. As those skilled in the art will understand, any heterocycle can be attached to another group by any suitable atom, such as a carbon or nitrogen atom. However, the piperidinyl or morpholino groups mentioned herein refer to piperidin-1-yl or morpholino-4-yl rings linked by a cyclic nitrogen atom.

[0097] A “bridged ring system” refers to a ring system in which two rings share two or more atoms, see, for example, Jerry March’s *Advanced Organic Chemistry*, 4th ed., Wiley Interscience, pp. 131-133, 1992. Examples of bridged heterocyclic ring systems include azabicyclo[2.2.1]heptane, 2-oxa-5-azabicyclo[2.2.1]heptane, azabicyclo[2.2.2]octane, azabicyclo[3.2.1]octane, and quinine rings.

[0098] A "spirocyclic bicyclic system" refers to a system in which two rings share a common spirocarbon atom, meaning that the heterocycle is connected to another carbon ring or heterocycle through a single common spirocarbon atom. Examples of spirocyclic systems include 6-azaspiro[3.4]octane, 2-oxa-6-azaspiro[3.4]octane, 2-azaspiro[3.3]heptane, 2-oxa-6-azaspiro[3.3]heptane, 7-oxa-2-azaspiro[3.5]nonane, 6-oxa-2-azaspiro[3.4]octane, 2-oxa-7-azaspiro[3.5]nonane, and 2-oxa-6-azaspiro[3.5]nonane.

[0099] As used alone or in combination with one or more other terms herein, “aromatic” refers to monocyclic and polycyclic systems containing 4n+2π electrons, where n is an integer. “Aromatic” should be understood to refer to and include ring systems containing only carbon atoms (i.e., “aryl”) and ring systems containing at least one heteroatom selected from N, O, or S (i.e., “hybrid aromatic” or “heteroaryl”). Aromatic ring systems can be substituted or unsubstituted.

[0100] As used alone or in combination with one or more other terms herein, “non-aromatic” refers to a monocyclic or polycyclic system having at least one double bond that is not part of an extended conjugated π system. As used herein, non-aromatic means and includes ring systems containing only carbon atoms and ring systems containing at least one heteroatom selected from N, O, or S. Non-aromatic ring systems can be substituted or unsubstituted.

[0101] The term "heteroaryl" or "heteroaromatic" refers to an aromatic monocyclic, bicyclic, or polycyclic ring containing one or more (e.g., 1-4, particularly 1, 2, or 3) heteroatoms selected from nitrogen, oxygen, or sulfur. The term heteroaryl includes both monovalent and divalent substances. Examples of heteroaryls are monocyclic and bicyclic groups containing 5-12 ring members, more typically 5-10 ring members. Heteroaryls can be, for example, 5- or 6-membered monocyclic or 9- or 10-membered bicyclic, such as a bicyclic structure formed by fused 5-membered and 6-membered rings or two fused 6-membered rings. Each ring may contain up to about 4 heteroatoms, typically selected from nitrogen, sulfur, and oxygen. Typically, a heteroaryl ring will contain up to 3 heteroatoms, more typically up to 2, such as a single heteroatom. In one embodiment, the heteroaryl ring contains at least one cyclic nitrogen atom. The nitrogen atom in the heteroaryl ring can be basic, as in the case of imidazole or pyridine, or substantially non-basic, as in the case of indole or pyrrole nitrogen. Typically, the number of basic nitrogen atoms present in a heteroaryl group, including any amino substituents on the ring, will be less than five.

[0102] Examples of heteroaryl groups include furanyl, pyrrolyl, thiophenyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, 1,3,5-triazenyl, benzofuranyl, indolyl, isoindolyl, benzothiophenyl, benzooxazolyl, benzoimidazolyl, benzothiazolyl, benzothiazolyl, indolyl, purinyl, benzofuranyl, quinolinyl, isoquinolinyl, and quinazolinyl. The terms "heteroaryl" also include partially aromatic bicyclic or polycyclic systems, wherein at least one ring is an aromatic ring and one or more other rings are non-aromatic saturated or partially saturated rings, provided that at least one ring contains one or more heteroatoms selected from nitrogen, oxygen, or sulfur. Examples of some aromatic heteroaryl groups include, for example, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 2-oxo-1,2,3,4-tetrahydroquinolinyl, dihydrobenzothiopheneyl, dihydrobenzofuranyl, 2,3-dihydro-benzo[1,4]dioxinyl, benzo[1,3]dioxolyl, 2,2-dioxo-1,3-dihydro-2-benzothiopheneyl, 4,5,6,7-tetrahydrobenzofuranyl, indololinyl, 1,2,3,4-tetrahydro-1,8-naphthidyl, 1,2,3,4-tetrahydropyrido[2,3-b]pyrazinyl, and 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl.

[0103] Examples of five-membered heteroaryl groups include, but are not limited to, pyrrole, furanyl, thiophene, imidazolyl, furazolidone, oxazolyl, oxadiazolyl, oxtriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, and tetrazolyl.

[0104] Examples of six-membered heteroaryl groups include, but are not limited to, pyridyl, pyrazinyl, pyridinyl, pyrimidinyl, and triazinyl.

[0105] The bicyclic heteroaryl group can be, for example, selected from the following groups:

[0106] A benzene ring fused with a 5- or 6-membered ring containing 1, 2, or 3 heteroatoms;

[0107] A pyridine ring fused with a 5- or 6-membered ring containing 1, 2, or 3 heteroatoms;

[0108] A pyrimidine ring fused with a 5- or 6-membered ring containing 1 or 2 heteroatoms;

[0109] Pyrrole rings fused with 5- or 6-membered rings containing 1, 2, or 3 heteroatoms;

[0110] A pyrazole ring fused with a 5- or 6-membered ring containing 1 or 2 heteroatoms;

[0111] A pyrazine ring fused with a 5- or 6-membered ring containing 1 or 2 heteroatoms;

[0112] An imidazole ring fused with a 5- or 6-membered ring containing 1 or 2 heteroatoms;

[0113] Oxazole rings fused with 5- or 6-membered rings containing 1 or 2 heteroatoms;

[0114] An isoxazole ring fused with a 5- or 6-membered ring containing 1 or 2 heteroatoms;

[0115] A thiazole ring fused with a 5- or 6-membered ring containing 1 or 2 heteroatoms;

[0116] An isothiazole ring fused with a 5- or 6-membered ring containing 1 or 2 heteroatoms;

[0117] Thiophene rings fused with 5- or 6-membered rings containing 1, 2, or 3 heteroatoms;

[0118] Furan rings fused with 5- or 6-membered rings containing 1, 2, or 3 heteroatoms;

[0119] Cyclohexyl rings fused with 5- or 6-membered heteroaromatic rings containing 1, 2, or 3 cyclic heteroatoms; and

[0120] A cyclopentyl ring fused with a 5- or 6-membered heteroaromatic ring containing 1, 2, or 3 cyclic heteroatoms.

[0121] Specific examples of bicyclic heteroaryl groups containing a six-membered ring fused with a five-membered ring include, but are not limited to, benzofuranyl, benzothiophenyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indolizinyl, indololinyl, isoindololinyl, purine (e.g., adenine, guanine), indazoleyl, benzodioxanepentenyl, and pyrazolopyridyl.

[0122] Specific examples of bicyclic heteroaryl groups containing two fused six-membered rings include, but are not limited to, quinolinyl, isoquinolinyl, chromanyl, thiochromanyl, chromenyl, isochromenyl, chromanyl, isochromanyl, benzodioxazinyl, quinolizinyl, benzoxazinyl, benzodiazinyl, pyridinylpyridinyl, quinoxolinyl, quinazolinyl, terpineyl, phthalazinyl, naphthidyl, and pteridylyl.

[0123] The term "aryl" refers to a cyclic or polycyclic aromatic ring having 5 to 12 carbon atoms. The term aryl includes both monovalent and divalent compounds. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, and naphthyl. In a particular embodiment, the aryl group is phenyl.

[0124] This specification also uses several compound terms to describe groups containing more than one functional group. Those skilled in the art will understand such terms. For example, (3-6C)cycloalkyl(m-nC)alkyl includes (m-nC)alkyl groups substituted with (3-6C)cycloalkyl groups.

[0125] The term "optionally substituted" refers to substituted and unsubstituted groups, structures, or molecules. The term "wherein R..." 1 "One or any CH, CH2, CH3 group or heteroatom (i.e., NH) is optionally substituted" appropriately represents R. 1 Any hydrogen group in the group is replaced by the relevant specified group.

[0126] When the optional substituents are selected from "one or more" groups, it should be understood that this definition includes all substituents selected from a particular group or substituents selected from two or more particular groups. In some embodiments, "one or more" means one, two, or three. In another embodiment, "one or more" means one or two. In a particular embodiment, "one or more" means one.

[0127] The phrase “compounds of the present invention” refers to those compounds disclosed herein, including both general and specific ones.

[0128] When used in this text in conjunction with a measurable value such as a quantity or a period of time, the word “about” is intended to include reasonable variations in that value, for example, taking into account experimental errors in the measurement of the value.

[0129] Compounds

[0130] On one hand, the present invention relates to compounds having the following structural formula (I) or pharmaceutically acceptable salts, hydrates or solvates thereof:

[0131]

[0132] in:

[0133] R1 is selected from hydrogen, halogen, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)ynyl, (3-7C)cycloalkyl, aryl, heteroaryl, and heterocyclic groups.

[0134] The (1-6C)alkyl, (2-6C)alkenyl, (2-6C)ynyl, (3-7C)cycloalkyl, aryl, heteroaryl, and heterocyclic groups are optionally surrounded by one or more R groups. 100 Substituent substitution;

[0135] Each R 100 Independently selected from halogens, (1-2C) haloalkyl (e.g., trifluoromethyl), (1-2C) haloalkoxy (e.g., trifluoromethoxy), cyano, hydroxyl, (1-4C) alkyl, (1-4C) hydroxyalkyl, (CH2) x OR f (CH2) x C(O)R f (CH2) x C(O)OR f (CH2) x OC(O)R f (CH2) x C(O)N(R j )R h (CH2) x N(R g )C(O)R f (CH2) x S(O) y1 R f (CH2) x SO2N(R j )R h (CH2) x N(R g SO2R f (CH2) x NR j R h (CH2) x (3-7C)cycloalkyl, (CH2) x Heterocyclic group, (CH2) x heteroaryl, (CH2) x Aryl;

[0136] And among them:

[0137] (i) R f and R g Each is independently selected from hydrogen, (1-6C)alkyl, or phenyl; and wherein R hand R j Each is independently selected from hydrogen, (1-6C)alkyl or phenyl, or R h and R j Together with the nitrogen atoms to which they are attached, they form a 3-7 membered ring, which may optionally include additional heteroatoms and may optionally be further substituted by one or more substituents selected from halogens, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, carboxyl, carbamoyl, aminosulfonyl, and (1-2C)alkyl groups; and

[0138] (ii) R 100 Any (1-4C) alkyl, (3-7C) cycloalkyl, heterocyclic, heteroaryl, or aryl group in the substituent may optionally be further composed of one or more elements selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, (1-2C) alkyl, (1-2C) haloalkyl, (1-2C) hydroxyalkyl, OR k C(O)R k C(O)OR k OC(O)R k C(O)N(R) l )R k 、N(R l )C(O)R k S(O) y2 R k SO2N(R) l )R k 、N(R l SO2R k or NR l R k Substituents of R, wherein R k and R l Selected from hydrogen or (1-2C) alkyl;

[0139] R2 is hydrogen;

[0140] R3 is selected from hydrogen, (1-8C)alkyl, (2-8C)alkenyl, (2-8C)ynyl, (3-7C)cycloalkyl, aryl, heteroaryl, heterocyclic, and (CH2). 0-3 (3-7C)cycloalkyl, (CH2) 0-3 Heterocyclic group, (CH2) 0-3 heteroaryl, (CH2) 0-3 Aryl, -C(O)-(CH2) 0-3 (3-7C)cycloalkyl, -C(O)-(CH2) 0-3 Heterocyclic group, -C(O)-(CH2) 0-3 heteroaryl, -C(O)-(CH2) 0-3 Aryl or -C(O)O(1-8C)alkyl, -C(O)NR 3a-(1-8C)alkyl, -C(O)NR 3a -(CH2) 0-3 (3-7C)cycloalkyl, -C(O)NR 3a -(CH2) 0-3 Heterocyclic groups, -C(O)NR 3a -(CH2) 0-3 heteroaryl, -C(O)NR 3a -(CH2) 0-3 Aryl;

[0141] Where R 3a It is hydrogen or (1-2C) alkyl;

[0142] Any (1-8C)alkyl, (2-8C)alkenyl, (2-8C)ynyl, (3-7C)cycloalkyl, aryl, heteroaryl, and heterocyclic moiety thereof is optionally surrounded by one or more R 200 Substituent substitution;

[0143] Where R 200 Selected from halogens, (1-2C) haloalkyl (e.g., trifluoromethyl), (1-2C) haloalkoxy (e.g., trifluoromethoxy), cyano, hydroxyl, nitro, (1-4C) alkyl, (1-4C) hydroxyalkyl, and (CH2). z OR m (CH2) z C(O)R m (CH2) z C(O)OR m (CH2) z OC(O)R m (CH2) z C(O)N(R o )R p (CH2) z N(R n )C(O)R m (CH2) z N(R n )C(O)OR m (CH2) z S(O) y3 R m (CH2) z SO2N(R o )R p (CH2) z N(R n SO2R m (CH2) z NR o R p (CH2) z(3-7C)cycloalkyl, (CH2) z Heterocyclic group, (CH2) z heteroaryl, (CH2) z Aryl;

[0144] And among them:

[0145] (i) R m and R n Each is independently selected from hydrogen, (1-6C)alkyl, or (CH2). 0-3 Phenyl; R o and R p Each is independently selected from hydrogen, (1-6C)alkyl or phenyl, or R o and R p Together with the nitrogen atoms they are attached to, they form 3-7 membered rings, which may optionally include additional heteroatoms, and wherein R o and R p Any 3-7 member ring formed, and for R m R n R o and R p Any alkyl or phenyl group present may optionally be further substituted with one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, carboxyl, carbamoyl, aminosulfonyl, and (1-2C)alkyl; and

[0146] (ii) R 200 Any (3-7C) cycloalkyl, heterocyclic, heteroaryl, or aryl moiety in the substituent may optionally be further selected from one or more of halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, (1-2C) alkyl, (1-2C) haloalkyl, (1-2C) hydroxyalkyl, OR q C(O)R q C(O)OR q OC(O)R q C(O)N(R) q )R r 、N(R r )C(O)R q S(O) y4 R q SO2N(R) r )R q 、N(R r SO2R q or NR r R q Substituents of R, wherein R q It is hydrogen, (1-2C)alkyl, or phenyl, and R r Selected from hydrogen or (1-2C) alkyl;

[0147] Alternatively, R2 and R3 can be linked together to form a -X2=CQ- group;

[0148] X2 is selected from N and CR. a ;where R a Selected from hydrogen, fluorine, chlorine, methyl, cyano, difluoromethyl, and trifluoromethyl; and

[0149] Q is a hydrogen, halogen, cyano, or a group of the following formula:

[0150] -L1-Y1-L2-Q1

[0151] in:

[0152] L1 is absent or is a (1-4C) alkylene group;

[0153] Y1 does not exist or is O, S, SO, SO2, or N(R). y1 ), C(O), C(O)O, OC(O), C(O)N(R y1 ) or N(R y1 )C(O), where R y1 Selected from hydrogen or (1-6C) alkyl;

[0154] L2 is absent or is a (1-3C) alkylene group; and

[0155] Q1 is hydrogen, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)ynyl, aryl, (3-8C)cycloalkyl, heteroaryl or heterocyclic;

[0156] Q may optionally be further substituted by one or more substituents independently selected from oxo, (1-6C) alkyl, halogen, (1-4C) haloalkyl, (1-4C) haloalkoxy, (1-4C) aminoalkyl, (1-4C) hydroxyalkyl, cyano, or substituted by one or more groups of the following formula:

[0157] -L3-Y2-L4-W1

[0158] in:

[0159] L3 is absent or is a (1-4C) alkylene group;

[0160] Y2 does not exist or is selected from O, S, SO, SO2, N(R) y2 ), C(O), C(O)O, OC(O), C(O)N(R y2 ), N(R y2 C(O) or S(O)2N(R) y2 ), N(R y2 SO2, where R y2 Selected from hydrogen or (1-4C) alkyl;

[0161] L4 is absent or is a (1-3C) alkylene group; and

[0162] W1 is hydrogen, (1-6C)alkyl, aryl, (3-8C)cycloalkyl, heteroaryl, or heterocyclic.

[0163] W1 is optionally composed of one or more compounds selected from oxo, (1-4C)alkyl, halogen, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, amino, (1-4C)alkylamino, di[(1-4C)alkyl]aminoC(O)OH, C(O)O(1-4C)alkyl, (CH2) 0-3 - Substitution of heterocyclic or cyano groups;

[0164] R4 is selected from hydrogen or halogen;

[0165] X1 is N or CR5, where R5 is selected from hydrogen, halogen, cyano or amino;

[0166] x is independently selected from 0, 1, 2, or 3;

[0167] y1, y2, y3, and y4 are each independently selected from 0, 1, or 2;

[0168] z can be independently selected from 0, 1, 2, or 3;

[0169] The conditions are:

[0170] When Q is hydrogen, X1 and X2 are only N;

[0171] When X1 and X2 are CR5 or CR a At that time, Q was not hydrogen;

[0172] When L1, Y1, and L2 are all absent, Q1 is not hydrogen;

[0173] And R1, Q, R a At least one of R4 or R5 is a substituent other than hydrogen.

[0174] Specific compounds of the present invention include, for example, compounds of formula (I), or pharmaceutically acceptable salts, hydrates and / or solvates thereof, defined herein as having one of the following structural formulas (Ia), (Ib) or (Ic):

[0175]

[0176] R1, R3, R4, R5, Q, X1, and X2 are each defined as described in this paper.

[0177] Specific compounds of the present invention include, for example, compounds of formula (I) [including sub-formulas (Ia), (Ib) or (Ic)], or pharmaceutically acceptable salts, hydrates and / or solvates thereof, wherein, unless otherwise stated, R1, R2, R3, R4, X1 and any associated substituents each have any meaning as defined in paragraphs (1) to (49) above or below:

[0178] (1) R1 is selected from hydrogen, halogen, (2-6C) ynyl, (3-7C) cycloalkyl, phenyl, 5- or 6-membered heteroaryl or 4- to 7-membered heterocyclic group.

[0179] The (2-6C) ynyl, (3-7C) cycloalkyl, phenyl, heteroaryl, and heterocyclic groups are optionally surrounded by one or more R groups. 100 Substituent substitution;

[0180] And each of R 100 Independently selected from halogens, (1-2C) haloalkyl (e.g., trifluoromethyl), (1-2C) haloalkoxy (e.g., trifluoromethoxy), cyano, hydroxyl, (1-4C) alkyl, (1-4C) hydroxyalkyl, (CH2) z OR f (CH2) z C(O)R f (CH2) z C(O)OR f (CH2) z OC(O)R f (CH2) z C(O)N(R j )R h (CH2) z N(R g )C(O)R f (CH2) z S(O) y1 R f (CH2) z SO2N(R j )R h (CH2) z N(R g SO2R f (CH2) z NR j R h (CH2) z (3-7C)cycloalkyl, (CH2) z Heterocyclic group, (CH2) z heteroaryl, (CH2) z Aryl;

[0181] And among them:

[0182] (i) R f and R g Each is independently selected from hydrogen or (1-2C)alkyl; and wherein R h and R j Each is independently selected from hydrogen or (1-2C)alkyl, or R h and R j Together with the nitrogen atoms they are attached to, they form 3-7 membered rings, which may optionally include additional heteroatoms; and

[0183] R 100 Any (1-4C) alkyl, (3-7C) cycloalkyl, heterocyclic, heteroaryl, or aryl moiety in the substituent may optionally be further composed of one or more elements selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, (1-2C) alkyl, (1-2C) haloalkyl, (1-2C) hydroxyalkyl, OR k C(O)R k C(O)OR k OC(O)R k C(O)N(R) l )R k 、N(R l )C(O)R k S(O) y2 R k SO2N(R) l )R k 、N(R l SO2R k or NR l R k Substituents of R, wherein R k and R l Selected from hydrogen or (1-2C)alkyl.

[0184] (2) R1 is selected from hydrogen, halogen, (2-6C) ynyl, phenyl, or 5- or 6-membered heteroaryl.

[0185] The (2-6C) alkynyl, phenyl, or heteroaryl group is optionally surrounded by one or more R groups. 100 Substituent substitution;

[0186] And each of R 100 Independently selected from halogens, (1-2C) haloalkyl (e.g., trifluoromethyl), (1-2C) haloalkoxy (e.g., trifluoromethoxy), cyano, hydroxyl, (1-4C) alkyl, (1-4C) hydroxyalkyl, (CH2) x OR f (CH2) x C(O)R f (CH2)x C(O)OR f (CH2) x OC(O)R f (CH2) x C(O)N(R j )R h (CH2) x N(R g )C(O)R f (CH2) x S(O) y1 R f (CH2) x SO2N(R j )R h (CH2) x N(R g SO2R f (CH2) x NR j R h (CH2) x (3-7C)cycloalkyl, (CH2) x -[4-6 membered heterocyclic group], (CH2) x -[5 or 6-membered heteroaryl] or (CH2) x Phenyl;

[0187] And among them:

[0188] (i) R f and R g Each is independently selected from hydrogen or (1-2C)alkyl; and wherein R h and R j Each is independently selected from hydrogen or (1-2C)alkyl, or R h and R j Together with the nitrogen atoms they are attached to, they form 3-7 membered rings, which may optionally include additional heteroatoms; and

[0189] R 100 Any (1-4C) alkyl, (3-7C) cycloalkyl, heterocyclic, heteroaryl, or aryl moiety in the substituent may optionally be further composed of one or more elements selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, (1-2C) alkyl, (1-2C) haloalkyl, (1-2C) hydroxyalkyl, OR k C(O)R k C(O)OR k OC(O)R k C(O)N(R) l )R k 、N(R l )C(O)R kS(O) y2 R k SO2N(R) l )R k 、N(R l SO2R k or NR l R k Substituents of R, wherein R k and R l Selected from hydrogen or (1-2C)alkyl.

[0190] (3) R1 is selected from hydrogen, halogen, (2-6C) ynyl, phenyl, or 5- or 6-membered heteroaryl.

[0191] The (2-6C) alkynyl, phenyl, or heteroaryl group is optionally surrounded by one or more R groups. 100 Substituent substitution;

[0192] And each of R 100 Independently selected from halogens, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, (1-4C)alkyl, (1-4C)hydroxyalkyl, and (CH2). x OR f (CH2) x C(O)R f (CH2) x C(O)OR f (CH2) x OC(O)R f (CH2) x C(O)N(R j )R h (CH2) x N(R g )C(O)R f (CH2) x S(O) y1 R f (CH2) x SO2N(R j )R h (CH2) x N(R g SO2R f (CH2) x NR j R h (CH2) x (3-7C)cycloalkyl, (CH2) x -[4-6 membered heterocyclic group], (CH2) x -[5 or 6-membered heteroaryl] or (CH2) x Phenyl;

[0193] And among them:

[0194] (i) R f and R g Each is independently selected from hydrogen or (1-2C)alkyl; and wherein R h and R j Each is independently selected from hydrogen or (1-2C)alkyl; and

[0195] R 100 Any (1-4C) alkyl, (3-7C) cycloalkyl, heterocyclic, heteroaryl, or aryl moiety in the substituent may optionally be further composed of one or more elements selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, (1-2C) alkyl, (1-2C) haloalkyl, (1-2C) hydroxyalkyl, or OR k Substituents of R, wherein R k Selected from hydrogen or (1-2C)alkyl.

[0196] (4) R1 is selected from hydrogen, halogen, (2-6C) ynyl, phenyl, or 5- or 6-membered heteroaryl.

[0197] The (2-6C) alkynyl, phenyl, or heteroaryl group is optionally surrounded by one or more R groups. 100 Substituent substitution;

[0198] And each of R 100 Independently selected from halogens, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, (1-4C)alkyl, (1-4C)hydroxyalkyl, and (CH2). x OR f C(O)R f C(O)OR f OC(O)R f C(O)N(R) j )R h 、N(R g )C(O)R f S(O) y1 R f SO2N(R) j )R h 、N(R g SO2R f NR j R h (CH2) x -[4-6 membered heterocyclic group] or (CH2) x Phenyl;

[0199] And among them:

[0200] (i) R f and R gEach is independently selected from hydrogen or (1-2C)alkyl; and wherein R h and R j Each is independently selected from hydrogen or (1-2C)alkyl; and

[0201] R 100 Any (1-4C) alkyl, (3-7C) cycloalkyl, heterocyclic, heteroaryl, or aryl moiety in the substituent may optionally be further composed of one or more elements selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, (1-2C) alkyl, (1-2C) haloalkyl, (1-2C) hydroxyalkyl, or OR k Substituents of R, wherein R k Selected from hydrogen or (1-2C)alkyl.

[0202] (5) R1 is selected from:

[0203] (i) Hydrogen or halogen;

[0204] (ii) Ethynyl group, i.e.

[0205]

[0206] Its optional use by R 100 replace;

[0207] (ii) Phenyl, which is optionally R 100 replace;

[0208] (iii) 5- or 6-membered heteroaryl groups, optionally bound by R 100 replace;

[0209] And each of R 100 Independently selected from halogens, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, (1-4C)alkyl, (1-4C)hydroxyalkyl, and (CH2). x OR f C(O)R f C(O)OR f OC(O)R f C(O)N(R) j )R h 、N(R g )C(O)R f S(O) y1 R f SO2N(R) j )R h 、N(R g SO2R f NR j R h (CH2) x -[4-6 membered heterocyclic group] or (CH2)x Phenyl;

[0210] And among them:

[0211] (i) R f and R g Each is independently selected from hydrogen or (1-2C)alkyl; and wherein R h and R j Each is independently selected from hydrogen or (1-2C)alkyl; and

[0212] (ii) R 100 Any (1-4C) alkyl, (3-7C) cycloalkyl, heterocyclic, heteroaryl, or aryl moiety in the substituent may optionally be further composed of one or more elements selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, (1-2C) alkyl, (1-2C) haloalkyl, (1-2C) hydroxyalkyl, or OR k Substituents of R, wherein R k Selected from hydrogen or (1-2C)alkyl.

[0213] (6) R1 is selected from:

[0214] (i) Hydrogen or halogen;

[0215] (ii) Ethynyl group, i.e.

[0216]

[0217] Its optional use by R 100 replace;

[0218] (iii) Phenyl, which is optionally R 100 replace;

[0219] And each of R 100 Independently selected from halogens, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, (1-4C)alkyl, (1-4C)hydroxyalkyl, and (CH2). x OR f C(O)R f C(O)OR f OC(O)R f C(O)N(R) j )R h 、N(R g )C(O)R f S(O) y1 R f SO2N(R) j )R h 、N(R g SO2R f NR j Rh (CH2) x -[4-6 membered heterocyclic group] or (CH2) x Phenyl;

[0220] And among them:

[0221] (i) R f and R g Each is independently selected from hydrogen or (1-2C)alkyl; and wherein R h and R j Each is independently selected from hydrogen or (1-2C)alkyl; and

[0222] R 100 Any (1-4C) alkyl, (3-7C) cycloalkyl, heterocyclic, heteroaryl, or aryl moiety in the substituent may optionally be further composed of one or more elements selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, (1-2C) alkyl, (1-2C) haloalkyl, (1-2C) hydroxyalkyl, or OR k Substituents of R, wherein R k Selected from hydrogen or (1-2C)alkyl.

[0223] (7) R1 is selected from:

[0224] (i) Hydrogen or halogen;

[0225] (ii) Ethynyl group, i.e.

[0226]

[0227] Its optional use by R 100 replace;

[0228] (iii) Phenyl, which is optionally R 100 replace;

[0229] And each of R 100 Independently selected from halogens, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, (1-4C)alkyl, (1-4C)hydroxyalkyl, and (CH2). x OR f C(O)R f C(O)N(R) j )R h S(O) y1 R f SO2N(R) j )R h 、N(R g SO2R f NR j R h (CH2) x-[4-6 membered heterocyclic group] or (CH2) x Phenyl;

[0230] And among them:

[0231] (i) R f and R g Each is independently selected from hydrogen or (1-2C)alkyl; and wherein R h and R j Each is independently selected from hydrogen or (1-2C)alkyl.

[0232] (8) R1 is selected from:

[0233] (i) Hydrogen or halogen;

[0234] (ii) Ethynyl group, i.e.

[0235]

[0236] Its optional use by R 100 replace;

[0237] (iii) Phenyl, which is optionally R 100 replace;

[0238] And each of R 100 It is independently selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy or (1-4C)alkyl.

[0239] (9) R3 is selected from hydrogen, (1-8C)alkyl, (2-8C)alkenyl, (2-8C)ynyl, (3-7C)cycloalkyl, phenyl, 5- or 6-membered heteroaryl, 4- to 7-membered heterocyclic, (CH2) 0-3 (3-7C)cycloalkyl, (CH2) 0-3 [4- to 7-membered heterocyclic groups], (CH2) 0-3 [5 or 6-membered heteroaryl], (CH2) 0-3 Phenyl, -C(O)-(CH2) 0-3 (3-7C)cycloalkyl, -C(O)-(CH2) 0-3 [4- to 7-membered heterocyclic groups], -C(O)-(CH2) 0-3 [5 or 6-membered heteroaryl], -C(O)-(CH2) 0-3 Phenyl, -C(O)O(1-8C)alkyl, -C(O)NR 3a -(1-8C)alkyl, -C(O)NR 3a -(CH2) 0-3 (3-7C)cycloalkyl, -C(O)NR 3a -(CH2) 0-3 [5- to 7-membered heterocyclic groups], -C(O)NR3a -(CH2) 0-3 [5 or 6-membered heteroaryl] or -C(O)NR 3a -(CH2) 0-3 Phenyl;

[0240] Where R 3a It is hydrogen or (1-2C) alkyl;

[0241] Any (1-8C)alkyl, (2-8C)alkenyl, (2-8C)ynyl, (3-7C)cycloalkyl, phenyl, 5- or 6-membered heteroaryl, or 4- to 7-membered heterocyclic moiety may optionally be composed of one or more R 200 Substituent substitution;

[0242] Where R 200 Selected from halogens, (1-2C) haloalkyl (e.g., trifluoromethyl), (1-2C) haloalkoxy (e.g., trifluoromethoxy), cyano, hydroxyl, nitro, (1-4C) alkyl, (1-4C) hydroxyalkyl, and (CH2). z OR m (CH2) z C(O)R m (CH2) z C(O)OR m (CH2) z C(O)N(R o )R p (CH2) z N(R n )C(O)R m (CH2) z N(R n )C(O)OR m (CH2) z S(O) y3 R m (CH2) z SO2N(R o )R p (CH2) z N(R n SO2R m (CH2) z NR o R p (CH2) z (3-7C)cycloalkyl, (CH2) z [4- to 7-membered heterocyclic groups], (CH2) z [5 or 6-membered heteroaryl], (CH2) z Phenyl;

[0243] And among them:

[0244] (i) R m and R n Each is independently selected from hydrogen, (1-6C)alkyl, or (CH2). 0-3 Phenyl; R o and R p Each is independently selected from hydrogen, (1-6C)alkyl or phenyl, or R o and R p Together with the nitrogen atoms they are attached to, they form 3-7 membered rings, which may optionally include additional heteroatoms, and wherein R o and R p Any 3-7 member ring formed, and for R m R n R o and R p Any alkyl or phenyl group present may optionally be further substituted with one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, carboxyl, carbamoyl, aminosulfonyl, and (1-2C)alkyl; and

[0245] R 200 Any (3-7C) cycloalkyl, heterocyclic, heteroaryl, or phenyl moiety in the substituent may optionally be further composed of one or more elements selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, (1-2C) alkyl, (1-2C) haloalkyl, (1-2C) hydroxyalkyl, OR q C(O)R q C(O)OR q OC(O)R q C(O)N(R) q )R r 、N(R r )C(O)R q S(O) y4 R q SO2N(R) r )R q 、N(R r SO2R q or NR r R q Substituents of R, wherein R q It is hydrogen, (1-2C)alkyl, or phenyl, and R r Selected from hydrogen or (1-2C)alkyl.

[0246] (10) R3 is selected from hydrogen, (1-8C)alkyl, (2-8C)alkenyl, (2-8C)ynyl, (3-7C)cycloalkyl, phenyl, 5- or 6-membered heteroaryl, 4- to 7-membered heterocyclic, (CH2) 0-3 (3-7C)cycloalkyl, (CH2) 0-3[4- to 7-membered heterocyclic groups], (CH2) 0-3 [5 or 6-membered heteroaryl], (CH2) 0-3 Phenyl, -C(O)-(CH2) 0-3 (3-7C)cycloalkyl, -C(O)-(CH2) 0-3 [4- to 7-membered heterocyclic groups], -C(O)-(CH2) 0-3 [5 or 6-membered heteroaryl], -C(O)-(CH2) 0-3 Phenyl, -C(O)O(1-8C)alkyl, -C(O)NR 3a -(1-8C)alkyl, -C(O)NR 3a -(CH2) 0-3 (3-7C)cycloalkyl, -C(O)NR 3a -(CH2) 0-3 [5- to 7-membered heterocyclic groups], -C(O)NR 3a -(CH2) 0-3 [5 or 6-membered heteroaryl] or -C(O)NH-(CH2) 0-3 Phenyl;

[0247] Where R 3a It is hydrogen or (1-2C) alkyl;

[0248] Any (1-8C)alkyl, (2-8C)alkenyl, (2-8C)ynyl, (3-7C)cycloalkyl, phenyl, 5- or 6-membered heteroaryl, or 4- to 7-membered heterocyclic moiety may optionally be composed of one or more R 200 Substituent substitution;

[0249] Where R 200 Selected from halogens, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, nitro, (1-4C)alkyl, (1-4C)hydroxyalkyl, and (CH2). z OR m (CH2) z C(O)R m (CH2) z C(O)OR m (CH2) z C(O)N(R o )R p (CH2) z N(R n )C(O)R m (CH2) z N(R n )C(O)OR m (CH2) z S(O) y3 R m (CH2)z SO2N(R o )R p (CH2) z N(R n SO2R m (CH2) z NR o R p (CH2) z (3-7C)cycloalkyl, (CH2) z [4- to 7-membered heterocyclic groups], (CH2) z [5 or 6-membered heteroaryl], (CH2) z Phenyl;

[0250] And among them:

[0251] (i) R m and R n Each is independently selected from hydrogen, (1-6C)alkyl, or (CH2). 0-3 Phenyl; R o and R p Each is independently selected from hydrogen, (1-6C)alkyl or phenyl, or R o and R p Together with the nitrogen atoms they are attached to, they form 3-7 membered rings, which may optionally include additional heteroatoms, and wherein R o and R p Any 3-7 member ring formed, and for R m R n R o and R p Any alkyl or phenyl groups present may optionally be further substituted with one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, carboxyl, carbamoyl, aminosulfonyl and (1-2C)alkyl.

[0252] (11) R3 is selected from hydrogen, (1-8C)alkyl, (2-8C)alkenyl, (2-8C)ynyl, (3-7C)cycloalkyl, phenyl, 5- or 6-membered heteroaryl, 4- to 7-membered heterocyclic, (CH2) 0-3 (3-7C)cycloalkyl, (CH2) 0-3 [4- to 7-membered heterocyclic groups], (CH2) 0-3 [5 or 6-membered heteroaryl], (CH2) 0-3 Phenyl, -C(O)-(CH2) 0-3 (3-7C)cycloalkyl, -C(O)-(CH2) 0-3 [4- to 7-membered heterocyclic groups], -C(O)-(CH2) 0-3 [5 or 6-membered heteroaryl], -C(O)-(CH2) 0-3Phenyl, -C(O)O(1-8C)alkyl, -C(O)NR 3a -(1-8C)alkyl, -C(O)NR 3a -(CH2) 0-3 (3-7C)cycloalkyl, -C(O)NR 3a -(CH2) 0-3 [5- to 7-membered heterocyclic groups], -C(O)NR 3a -(CH2) 0-3 [5 or 6-membered heteroaryl] or -C(O)NR 3a -(CH2) 0-3 Phenyl;

[0253] Where R 3a It is hydrogen or (1-2C) alkyl;

[0254] Any (1-8C)alkyl, (2-8C)alkenyl, (2-8C)ynyl, (3-7C)cycloalkyl, phenyl, 5- or 6-membered heteroaryl, or 4- to 7-membered heterocyclic moiety may optionally be composed of one or more R 200 Substituent substitution;

[0255] Where R 200 Selected from halogens, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, nitro, (1-4C)alkyl, (1-4C)hydroxyalkyl, and (CH2). z OR m (CH2) z C(O)R m (CH2) z C(O)OR m (CH2) z C(O)N(R o )R p (CH2) z N(R n )C(O)R m (CH2) z N(R n )C(O)OR m (CH2) z S(O) y3 R m (CH2) z SO2N(R o )R p (CH2) z N(R n SO2R m Or (CH2) z NR o R p ;

[0256] And among them:

[0257] R m and R n Each is independently selected from hydrogen, (1-6C)alkyl, or phenyl; R o and R p Each is independently selected from hydrogen, (1-6C)alkyl, or (CH2). 0-2 Phenyl, or R o and R p Together with the nitrogen atoms they are attached to, they form 3-7 membered rings, which may optionally include additional heteroatoms, and wherein R o and R p Any 3-7 member ring formed, and for R m R n R o and R p Any alkyl or phenyl groups present may optionally be further substituted with one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, carboxyl, carbamoyl, aminosulfonyl and (1-2C)alkyl.

[0258] (12) R3 is selected from hydrogen, (1-8C)alkyl, (2-8C)alkenyl, (2-8C)ynyl, (3-7C)cycloalkyl, phenyl, 5- or 6-membered heteroaryl, 4- to 7-membered heterocyclic, (CH2) 0-3 (3-7C)cycloalkyl, (CH2) 0-3 [4- to 7-membered heterocyclic groups], (CH2) 0-3 [5 or 6-membered heteroaryl], (CH2) 0-3 Phenyl, -C(O)-(CH2) 0-3 (3-7C)cycloalkyl, -C(O)-(CH2) 0-3 [5 or 6-membered heterocyclic group], -C(O)-(CH2) 0-3 Phenyl, -C(O)O(1-8C)alkyl, -C(O)NR 3a -(1-8C)alkyl, -C(O)NR 3a -(CH2) 0-3 (3-7C)cycloalkyl, -C(O)NR 3a -(CH2) 0-3 [5 or 6-membered heterocyclic group] or -C(O)NR 3a -(CH2) 0-3 Phenyl;

[0259] Where R 3a It is hydrogen or (1-2C) alkyl;

[0260] Any (1-8C)alkyl, (2-8C)alkenyl, (2-8C)ynyl, (3-7C)cycloalkyl, phenyl, 5- or 6-membered heteroaryl, or 4- to 7-membered heterocyclic moiety may optionally be composed of one or more R 200 Substituent substitution;

[0261] Where R 200 Selected from halogens, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, nitro, (1-4C)alkyl, (1-4C)hydroxyalkyl, and (CH2). z OR m (CH2) z C(O)R m (CH2) z C(O)OR m (CH2) z C(O)N(R o )R p (CH2) z N(R n )C(O)R m (CH2) z N(R n )C(O)OR m (CH2) z S(O) y3 R m (CH2) z SO2N(R o )R p (CH2) z N(R n SO2R m Or (CH2) z NR o R p ;

[0262] And among them:

[0263] R m and R n Each is independently selected from hydrogen, (1-6C)alkyl, or phenyl; R o and R p Each is independently selected from hydrogen, (1-6C)alkyl, or (CH2). 0-2 Phenyl, or R o and R p Together with the nitrogen atoms they are attached to, they form 3-7 membered rings, which may optionally include additional heteroatoms, and wherein R o and R p Any 3-7 member ring formed, and for R m R n R o and R pAny alkyl or phenyl groups present may optionally be further substituted with one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, carboxyl, carbamoyl, aminosulfonyl and (1-2C)alkyl.

[0264] (13) R3 is selected from hydrogen or a group of the following formula:

[0265] , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ;

[0266] Any of the above-mentioned cycloalkyl, heterocyclic, aryl, or heteroaryl groups may optionally be represented by one or more R groups. 200 Substituent substitution, where R 200 As defined in this article.

[0267] (14) R2 and R3 are linked together to form the -X2=CQ- group;

[0268] (15) X2 is selected from N and CR a ;where R a It is selected from hydrogen, fluorine, chlorine, methyl or cyano.

[0269] (16) X2 is selected from N and CR a ;where R a Selected from hydrogen, fluorine, chlorine or methyl.

[0270] (17) X2 is selected from N and CR a ;where R a Selected from hydrogen, fluorine, or chlorine.

[0271] (18) Q is a hydrogen, halogen, cyano, or a group of the following formula:

[0272] -L1-Y1-L2-Q1

[0273] in:

[0274] L1 is absent or is a (1-4C) alkylene group;

[0275] Y1 does not exist or is O, S, SO, SO2, or N(R). y1 ), C(O), C(O)O, OC(O), C(O)N(R y1 ) or N(R y1 )C(O), where R y1 Selected from hydrogen or (1-6C) alkyl;

[0276] L2 is absent or is a (1-3C) alkylene group; and

[0277] Q1 is hydrogen, (1-6C)alkyl, phenyl, (3-8C)cycloalkyl, 5- or 6-membered heteroaryl or 4- to 7-membered heterocyclic group;

[0278] Q may optionally be further substituted by one or more substituents independently selected from oxo, (1-6C) alkyl, halogen, (1-4C) haloalkyl, (1-4C) haloalkoxy, (1-4C) aminoalkyl, (1-4C) hydroxyalkyl, cyano, or substituted by one or more groups of the following formula:

[0279] -L3-Y2-L4-W1

[0280] in:

[0281] L3 is absent or is a (1-4C) alkylene group;

[0282] Y2 does not exist or is selected from O, S, SO, SO2, N(R) y2 ), C(O), C(O)O, OC(O), C(O)N(R y2 ), N(R y2 C(O) or S(O)2N(R) y2 ), N(R y2 SO2, where R y2 Selected from hydrogen or (1-4C) alkyl;

[0283] L4 is absent or is a (1-3C) alkylene group; and

[0284] W1 is hydrogen, (1-6C)alkyl, aryl, (3-8C)cycloalkyl, 5- or 6-membered heteroaryl or 4- to 7-membered heterocyclic group;

[0285] W1 is optionally composed of one or more compounds selected from oxo, (1-4C)alkyl, halogen, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, amino, (1-4C)alkylamino, di[(1-4C)alkyl]aminoC(O)OH, C(O)O(1-4C)alkyl, (CH2) 0-3 -Substitution with [4 to 7-membered heterocyclic groups] or cyano groups.

[0286] (19) Q is a hydrogen, halogen, cyano, or a group of the following formula:

[0287] -L1-Y1-L2-Q1

[0288] in:

[0289] L1 is absent or is a (1-4C) alkylene group;

[0290] Y1 does not exist or is O, S, SO, SO2, or N(R). y1 ), C(O), C(O)O, OC(O), C(O)N(R y1 ) or N(R y1 )C(O), where R y1 Selected from hydrogen or (1-4C) alkyl;

[0291] L2 is absent or is a (1-3C) alkylene group; and

[0292] Q1 is hydrogen, (1-6C)alkyl, phenyl, (3-8C)cycloalkyl, 5- or 6-membered heteroaryl or 4- to 7-membered heterocyclic group;

[0293] Q may optionally be further substituted by one or more substituents independently selected from oxo, (1-6C) alkyl, halogen, (1-4C) haloalkyl, (1-4C) haloalkoxy, (1-4C) aminoalkyl, (1-4C) hydroxyalkyl, cyano, or substituted by one or more groups of the following formula:

[0294] -L3-Y2-L4-W1

[0295] in:

[0296] L3 is absent or is a (1-3C) alkylene group;

[0297] Y2 does not exist or is selected from O, S, SO, SO2, N(R) y2 ), C(O), C(O)O, OC(O), C(O)N(R y2 ), N(R y2 C(O), S(O)2N(R) y2 ) or N(R y2 SO2, where R y2 Selected from hydrogen or (1-2C) alkyl;

[0298] L4 is absent or is a (1-3C) alkylene group; and

[0299] W1 is hydrogen, (1-6C)alkyl, aryl, (3-8C)cycloalkyl, 5- or 6-membered heteroaryl or 4- to 7-membered heterocyclic group;

[0300] W1 is optionally composed of one or more compounds selected from oxo, (1-4C)alkyl, halogen, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, amino, (1-4C)alkylamino, di[(1-4C)alkyl]aminoC(O)OH, C(O)O(1-4C)alkyl, (CH2) 0-3 -[4 to 7 membered heterocyclic group] or cyano substituents;

[0301] (20) Q is a group in the following formula:

[0302] -L1-Y1-L2-Q1

[0303] in:

[0304] L1 is absent or is a (1-3C) alkylene group;

[0305] Y1 does not exist or is O, S, N(R) y1 ), C(O), C(O)O, C(O)N(R) y1 ) or N(R y1 )C(O), where R y1 Selected from hydrogen or (1-4C) alkyl;

[0306] L2 is absent or is methylene; and

[0307] Q1 is hydrogen, (1-6C)alkyl, phenyl, (3-8C)cycloalkyl, 5- or 6-membered heteroaryl or 4- to 7-membered heterocyclic group;

[0308] Q may optionally be further substituted by one or more substituents independently selected from oxo, (1-6C)alkyl, halogen, (1-2C) haloalkyl, (1-2C) haloalkoxy, cyano, or substituted by one or more groups of the following formula:

[0309] -L3-Y2-L4-W1

[0310] in:

[0311] L3 is absent or is a (1-4C) alkylene group;

[0312] Y2 does not exist or is selected from O, SO2, N(R) y2 ), C(O), C(O)O, C(O)N(R) y2 ) or N(R y2 SO2, where R y2 Selected from hydrogen or (1-2C) alkyl;

[0313] L4 is absent or is a (1-3C) alkylene group; and

[0314] W1 is hydrogen, (1-6C)alkyl, aryl, (3-8C)cycloalkyl, 5- or 6-membered heteroaryl or 4- to 7-membered heterocyclic group;

[0315] W1 is optionally composed of one or more radicals selected from oxo, (1-4C)alkyl, halogen, (1-2C)haloalkyl, (1-2C)haloalkoxy, (1-4C)alkoxy, C(O)OH, C(O)O(1-4C)alkyl, (CH2). 0-3 -Substitution with [4 to 7-membered heterocyclic groups] or cyano groups.

[0316] (21) Q is a group selected from hydrogen, halogen, cyano, (1-6C)alkyl, (1-6C)alkoxy, (1-6C)haloalkyl, (1-6C)haloalkoxy, or a group selected from the following formula:

[0317] , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ;

[0318] Any of the above-mentioned cycloalkyl, heterocyclic, aryl, or heteroaryl rings may optionally be substituted by one or more substituents selected from oxo, (1-6C)alkyl, halogen, (1-2C) haloalkyl, (1-2C) haloalkoxy, cyano, or by one or more groups of the following formula:

[0319] -L3-Y2-L4-W1

[0320] L3, Y2, L4, and W1 are defined as described in this paper.

[0321] (22) R4 is hydrogen or fluorine.

[0322] (23) R4 is hydrogen.

[0323] (24) R4 is fluorine.

[0324] (25) X1 is N or CR5, where R5 is selected from hydrogen, halogen or cyano.

[0325] (26) x is independently selected from 0, 1 or 2;

[0326] (27) x is 0;

[0327] (28) x is 1;

[0328] (29) x is 2;

[0329] (30) y1 is independently selected from 0, 1 or 2;

[0330] (31) y1 is 0;

[0331] (32) y1 is 1;

[0332] (33) y1 is 2;

[0333] (34) y2 is independently selected from 0, 1 or 2;

[0334] (35) y2 is 0;

[0335] (36) y2 is 1;

[0336] (37) y2 is 2;

[0337] (38) y3 is independently selected from 0, 1 or 2;

[0338] (39) y3 is 0;

[0339] (40) y3 is 1;

[0340] (41) y3 is 2;

[0341] (42) y4 is independently selected from 0, 1 or 2;

[0342] (43) y4 is 0;

[0343] (44) y4 is 1;

[0344] (45) y4 is 2;

[0345] (46) z is independently selected from 0, 1 or 2;

[0346] (47) z is 0;

[0347] (48) z is 1;

[0348] (49) z is 2;

[0349] Appropriately, R1 is defined as in any of the numbered paragraphs (1) through (8) above. More appropriately, R1 is defined as in any of the numbered paragraphs (5) through (8) above. Most appropriately, R1 is defined as in either the numbered paragraph (7) or (8) above.

[0350] Suitable, is any of the following:

[0351] a) R2 hydrogen and R3 are as defined in any of the numbered paragraphs (9) to (13) above, or

[0352] b) R2 and R3 are connected together to form a -X2=CQ- group, where X2 is defined as in any of paragraphs (15) to (17) above, and Q is defined as in any of paragraphs (18) to (21) above.

[0353] More appropriately, any of the following:

[0354] a) R2 hydrogen and R3 are as defined in any of the numbered paragraphs (11) to (13) above, or

[0355] b) R2 and R3 are connected together to form a -X2=CQ- group, where X2 is as defined in paragraph (16) or (17) above, and Q is as defined in paragraph (19), (20) or (21) above.

[0356] The most suitable one is any of the following:

[0357] a) R2 hydrogen and R3 as defined in paragraph (13) above, or

[0358] b) R2 and R3 are connected together to form a -X2=CQ- group, where X2 is defined in paragraph (17) above and Q is defined in paragraph (20) or (21) above.

[0359] Appropriately, R4 is defined as in any of the paragraphs numbered (22) through (24) above. More appropriately, R4 is defined as in paragraphs numbered (23) or (24) above.

[0360] Appropriately, Q is defined as in any of the numbered paragraphs (18) through (21) above. More appropriately, Q is defined as in the numbered paragraphs (19), (20), or (21) above. Most appropriately, Q is defined as in the numbered paragraphs (20) or (21) above.

[0361] Appropriately, X1 is defined as in paragraph (24).

[0362] Suitablely, X2 is defined as in any of the numbered paragraphs (15) to (17) above. More suitablely, X2 is defined as in the numbered paragraphs (16) or (17) above. Most suitablely, X2 is defined as in the numbered paragraph (17) above.

[0363] Appropriately, x is defined as in any of the numbered paragraphs (26) to (29) above. More appropriately, x is defined as in the numbered paragraph (26) above.

[0364] Appropriately, y1 is defined as in any of the numbered paragraphs (30) to (33) above. More appropriately, y1 is defined as in the numbered paragraph (30) above.

[0365] Appropriately, y2 is defined as in any of the numbered paragraphs (34) to (37) above. More appropriately, y2 is defined as in the numbered paragraph (34) above.

[0366] Appropriately, y3 is defined as in any of the numbered paragraphs (38) to (41) above. More appropriately, y3 is defined as in the numbered paragraph (38) above.

[0367] Appropriately, y4 is defined as in any of the numbered paragraphs (42) to (45) above. More appropriately, y4 is defined as in the numbered paragraph (42) above.

[0368] Appropriately, z is defined as in any of the numbered paragraphs (46) to (49) above. More appropriately, z is defined as in the numbered paragraph (46) above.

[0369] As described above, specific compounds of the present invention include, for example, compounds of formula (I), or pharmaceutically acceptable salts, hydrates and / or solvates thereof, defined herein as having one of the following structural formulas (Ia), (Ib) or (Ic):

[0370]

[0371] R1, X1, X2, R3, R4, R5 and Q are each defined as described in this paper.

[0372] In a particular group of compounds of the present invention, the compounds have a structure according to formula Ia (which is a sub-definition of formula I), or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, wherein R1, X1, X2, R3, R4, R5 and Q each have any of the definitions given herein.

[0373] In embodiments of compounds of formula Ia or their pharmaceutically acceptable salts, hydrates, and / or solvates:

[0374] R1 is defined as any of the paragraphs (1) to (8) numbered above;

[0375] R3 is defined as any of the paragraphs numbered (9) to (13) above;

[0376] R4 is defined as in any of the numbered paragraphs (22) to (24) above; and

[0377] R5 is defined in paragraph (25) above.

[0378] In embodiments of compounds of formula Ia or their pharmaceutically acceptable salts, hydrates, and / or solvates:

[0379] R1 is defined as in any of the numbered paragraphs (5) to (8) above;

[0380] R3 is defined as any of the paragraphs (11) to (13) numbered above;

[0381] R4 is defined as in paragraphs (23) or (24) above; and

[0382] R5 is defined in paragraph (25) above.

[0383] In embodiments of compounds of formula Ia or their pharmaceutically acceptable salts, hydrates, and / or solvates:

[0384] R1 is defined as in paragraphs (7) or (8) above;

[0385] R3 is defined as in paragraph (13) above;

[0386] R4 is defined as in paragraphs (23) or (24) above; and

[0387] R5 is defined in paragraph (25) above.

[0388] In a particular group of compounds of the present invention, the compounds have a structure according to formula Ib (which is a sub-definition of formula I), or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, wherein R3, R4 and R5 each have any of the definitions given herein.

[0389] In embodiments of compounds of formula Ib or their pharmaceutically acceptable salts, hydrates, and / or solvates:

[0390] R3 is defined as any of the paragraphs numbered (9) to (13) above;

[0391] R4 is defined as in any of the numbered paragraphs (22) to (24) above; and

[0392] R5 is defined in paragraph (25) above.

[0393] In embodiments of compounds of formula Ib or their pharmaceutically acceptable salts, hydrates, and / or solvates:

[0394] R3 is defined as any of the paragraphs (11) to (13) numbered above;

[0395] R4 is defined as in paragraphs (23) or (24) above; and

[0396] R5 is defined in paragraph (25) above.

[0397] In embodiments of compounds of formula Ib or their pharmaceutically acceptable salts, hydrates, and / or solvates:

[0398] R3 is defined as in paragraph (13) above;

[0399] R4 is defined as in paragraphs (23) or (24) above; and

[0400] R5 is defined in paragraph (25) above.

[0401] In a particular group of compounds of the present invention, the compounds have a structure according to formula Ic (which is a sub-definition of formula I), or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, wherein R1, R4, X1, X2 and Q each have any of the definitions given herein.

[0402] In embodiments of the compound of formula Ic or its pharmaceutically acceptable salts, hydrates and / or solvates:

[0403] R1 is defined as any of the paragraphs (1) to (8) numbered above;

[0404] R4 is defined as in any of the paragraphs (22) to (24) numbered above;

[0405] X1 is defined as in paragraph (25) above;

[0406] X2 is defined as in any of the numbered paragraphs (15) to (17) above; and

[0407] Q is defined as in any of the paragraphs (18) to (21) numbered above.

[0408] In embodiments of the compound of formula Ic or its pharmaceutically acceptable salts, hydrates and / or solvates:

[0409] R1 is defined as in any of the numbered paragraphs (5) to (8) above;

[0410] R4 is defined as in paragraphs (23) or (24) above;

[0411] X1 is defined as in paragraph (25) above;

[0412] X2 is defined as in paragraphs (16) or (17) above; and

[0413] Q is defined as in paragraphs (19), (20) or (21) numbered above.

[0414] In embodiments of the compound of formula Ic or its pharmaceutically acceptable salts, hydrates and / or solvates:

[0415] R1 is defined as in paragraphs (7) or (8) above;

[0416] R4 is defined as in paragraphs (23) or (24) above;

[0417] X1 is defined as in paragraph (25) above;

[0418] X2 is defined as in paragraph (17) above; and

[0419] Q is defined as in paragraphs (20) or (21) above.

[0420] Specific compounds of this invention include any compound exemplified in this application, or a pharmaceutically acceptable salt or solvate thereof, particularly any of the following compounds:

[0421] 5-(2-aminopyridin-4-yl)-7-chloro-1H-indazole-3-amine

[0422] 5-(2-aminopyridin-4-yl)-7-methyl-1H-indazole-3-amine

[0423] 5-(2-aminopyridin-4-yl)-7-(trifluoromethyl)-1H-indazole-3-amine

[0424] 5-(2-(ethylamino)pyridin-4-yl)-1H-indazole-3-amine

[0425] 5-(2-(propylamino)pyridin-4-yl)-1H-indazole-3-amine

[0426] 5-(2-(isopropylamino)pyridin-4-yl)-1H-indazole-3-amine

[0427] 5-(2-((cyclopropylmethyl)amino)pyridin-4-yl)-1H-indazole-3-amine

[0428] 5-(2-(isopentylamino)pyridin-4-yl)-1H-indazole-3-amine

[0429] 5-(2-(hexylamino)pyridin-4-yl)-1H-indazole-3-amine

[0430] 5-(2-(cyclohexylamino)pyridin-4-yl)-1H-indazole-3-amine

[0431] 5-{2-[(trans-4-methylcyclohexyl)amino]pyridin-4-yl}-1H-indazole-3-amine

[0432] 2-((4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)amino)ethanol-1-ol

[0433] 3-((4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)amino)prop-1-ol

[0434] 4-((4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)amino)but-1-ol

[0435] 5-((4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)amino)pentan-1-ol

[0436] 5-{2-[(trans-4-hydroxycyclohexyl)amino]pyridin-4-yl}-1H-indazole-3-amine

[0437] 5-(2-((2-methoxyethyl)amino)pyridin-4-yl)-1H-indazole-3-amine

[0438] 5-(2-((3-methoxypropyl)amino)pyridin-4-yl)-1H-indazole-3-amine

[0439] 5-(2-((3-isopropoxypropyl)amino)pyridin-4-yl)-1H-indazole-3-amine

[0440] 3-((4-(3-amino-1H-indazol-5-yl)pyrimidin-2-yl)amino)prop-1-ol

[0441] 3-((4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)(methyl)amino)prop-1-ol

[0442] 5-(2-((2-morpholinoethyl)amino)pyridin-4-yl)-1H-indazole-3-amine

[0443] 5-(2-((2-(piperidin-1-yl)ethyl)amino)pyridin-4-yl)-1H-indazole-3-amine

[0444] N1-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-N3-methylpropane-1,3-diamine

[0445] 5-(2-(benzylamino)pyridin-4-yl)-1H-indazole-3-amine

[0446] 3-(((4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)amino)methyl)benzonitrile

[0447] 5-(2-((3-methoxybenzyl)amino)pyridin-4-yl)-1H-indazole-3-amine

[0448] 2-(3-(((4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)amino)methyl)phenyl)prop-2-ol

[0449] 5-(2-((4-(trifluoromethyl)benzyl)amino)pyridin-4-yl)-1H-indazole-3-amine

[0450] 4-(((4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)amino)methyl)benzonitrile

[0451] 5-(2-((4-(tert-butyl)benzyl)amino)pyridin-4-yl)-1H-indazole-3-amine

[0452] 2-(4-(((4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)amino)methyl)phenyl)prop-2-ol

[0453] 5-(2-((4-(methanesulfonyl)benzyl)amino)pyridin-4-yl)-1H-indazole-3-amine

[0454] 5-(2-((furan-3-ylmethyl)amino)pyridin-4-yl)-1H-indazole-3-amine

[0455] 5-(2-((pyridin-2-ylmethyl)amino)pyridin-4-yl)-1H-indazole-3-amine

[0456] 5-(2-(phenylethylamino)pyridin-4-yl)-1H-indazole-3-amine

[0457] 5-(2-((2-(pyridin-2-yl)ethyl)amino)pyridin-4-yl)-1H-indazole-3-amine

[0458] 5-(2-((2-(pyridin-3-yl)ethyl)amino)pyridin-4-yl)-1H-indazole-3-amine

[0459] 5-(2-((2-(pyridin-4-yl)ethyl)amino)pyridin-4-yl)-1H-indazole-3-amine

[0460] 5-(2-((2-(1H-indol-3-yl)ethyl)amino)pyridin-4-yl)-1H-indazole-3-amine

[0461] 5-(2-((4-fluorophenylethyl)amino)pyridin-4-yl)-1H-indazole-3-amine

[0462] 5-(2-((4-chlorophenylethyl)amino)pyridin-4-yl)-1H-indazole-3-amine

[0463] 4-(2-((4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)amino)ethyl)phenol

[0464] 5-(2-((4-methoxyphenethyl)amino)pyridin-4-yl)-1H-indazole-3-amine

[0465] 5-(2-((4-(tert-butyl)phenethyl)amino)pyridin-4-yl)-1H-indazole-3-amine

[0466] 4-(2-((4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)amino)ethyl)benzenesulfonamide

[0467] 5-(2-((3-chlorophenylethyl)amino)pyridin-4-yl)-1H-indazole-3-amine

[0468] 5-(2-((2-(trifluoromethyl)phenethyl)amino)pyridin-4-yl)-1H-indazole-3-amine

[0469] 5-(2-((3-phenylpropyl)amino)pyridin-4-yl)-1H-indazole-3-amine

[0470] 5-(2-((2-phenoxyethyl)amino)pyridin-4-yl)-1H-indazole-3-amine

[0471] N-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)cyclopropaneformamide

[0472] N-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)benzamide

[0473] N-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-2-phenylacetamide

[0474] N-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-2-(3-fluorophenyl)acetamide

[0475] N-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-2-(3-tolyl)acetamide

[0476] N-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-2-(3-(trifluoromethyl)phenyl)acetamide

[0477] N-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-2-(3-chlorophenyl)acetamide

[0478] N-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-2-(3-aminophenyl)acetamide

[0479] N-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-2-(3-nitrophenyl)acetamide

[0480] N-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-2-(3-(methanesulfonyl)phenyl)acetamide

[0481] N-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-2-(3-methoxyphenyl)acetamide

[0482] N-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-2-(3-(benzyloxy)phenyl)acetamide

[0483] (3-(2-((4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)amino)-2-oxoethyl)phenyl)tert-butyl carbamate

[0484] N-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-2-(4-fluorophenyl)acetamide

[0485] N-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-2-(p-tolyl)acetamide

[0486] N-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-2-(4-(trifluoromethyl)phenyl)acetamide

[0487] N-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-2-(4-chlorophenyl)acetamide

[0488] N-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-2-(4-(methylthio)phenyl)acetamide

[0489] N-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-2-(4-(methanesulfonyl)phenyl)acetamide

[0490] N-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-2-(4-methoxyphenyl)acetamide

[0491] N-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-2-(4-aminophenyl)acetamide

[0492] (4-(2-((4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)amino)-2-oxoethyl)phenyl)tert-butyl carbamate

[0493] N-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-2-(2-fluorophenyl)acetamide

[0494] N-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-2-(o-tolyl)acetamide

[0495] N-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-2-(2-(trifluoromethyl)phenyl)acetamide

[0496] N-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-2-(2-chlorophenyl)acetamide

[0497] N-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-2-(2-methoxyphenyl)acetamide

[0498] N-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-2-(pyridin-2-yl)acetamide

[0499] N-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-2-(pyridin-3-yl)acetamide

[0500] N-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-2-(pyridin-4-yl)acetamide

[0501] N-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-3-phenylpropionamide

[0502] (4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)carbamate

[0503] 1-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-3-ethylurea

[0504] 1-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-3-propylurea

[0505] 1-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-3-isopentylurea

[0506] 1-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-3-cyclopentylurea

[0507] 1-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-3-cyclohexylurea

[0508] 1-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-3-(2-hydroxyethyl)urea

[0509] 1-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-3-(3-hydroxypropyl)urea

[0510] 1-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-3-(2-methoxyethyl)urea

[0511] 3-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-1-(2-hydroxyethyl)-1-methylurea

[0512] 1-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-3-benzylurea

[0513] 1-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-3-phenylethylurea

[0514] 1-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-3-(pyridin-2-ylmethyl)urea

[0515] 1-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-3-(pyridin-3-ylmethyl)urea

[0516] 1-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-3-(pyridin-4-ylmethyl)urea

[0517] 1-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-3-phenylurea

[0518] 1-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-3-(3-fluorophenyl)urea

[0519] 1-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-3-(3-chlorophenyl)urea

[0520] 1-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-3-(3-isopropylphenyl)urea

[0521] 1-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-3-(3-(hydroxymethyl)phenyl)urea

[0522] 3-(3-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)ureo)benzamide

[0523] 1-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-3-(3-phenoxyphenyl)urea

[0524] 1-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-3-(3-(benzyloxy)phenyl)urea

[0525] 1-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-3-(3-((4-fluorobenzyl)oxy)phenyl)urea

[0526] 1-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-3-(3-((3-fluorobenzyl)oxy)phenyl)urea

[0527] 1-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-3-(3-((2-fluorobenzyl)oxy)phenyl)urea

[0528] 3-(3-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)ureo)-N-phenylbenzamide

[0529] 1-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-3-(4-fluorophenyl)urea

[0530] 1-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-3-(4-chlorophenyl)urea

[0531] 1-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-3-(4-(tert-butyl)phenyl)urea

[0532] 1-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-3-(4-(methanesulfonyl)phenyl)urea

[0533] 1-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-3-(o-tolyl)urea

[0534] 1-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-3-(2-ethylphenyl)urea

[0535] 1-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-3-(2-isopropylphenyl)urea

[0536] 1-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-3-(pyridin-3-yl)urea

[0537] 5-(2-(phenylamino)pyridin-4-yl)-1H-indazole-3-amine

[0538] 5-(2-((3-isopropylphenyl)amino)pyridin-4-yl)-1H-indazole-3-amine

[0539] 3-((4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)amino)phenol

[0540] (3-((4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)amino)phenyl)methanol

[0541] 3-((4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)amino)benzoic acid

[0542] Ethyl 3-((4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)amino)benzoate

[0543] 3-((4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)amino)benzamide

[0544] 3-((4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)amino)-N-(2-hydroxyethyl)benzamide

[0545] N1-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)phenyl-1,3-diamine

[0546] N-(3-((4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)amino)phenyl)acetamide

[0547] N-(3-((4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)amino)phenyl)benzamide

[0548] 5-(2-((3-phenoxyphenyl)amino)pyridin-4-yl)-1H-indazole-3-amine

[0549] 5-(2-((3-(benzyloxy)phenyl)amino)pyridin-4-yl)-1H-indazole-3-amine

[0550] 5-(2-((4-fluorophenyl)amino)pyridin-4-yl)-1H-indazole-3-amine

[0551] 5-(2-((4-chlorophenyl)amino)pyridin-4-yl)-1H-indazole-3-amine

[0552] 4-((4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)amino)phenol

[0553] 5-(2-((4-methoxyphenyl)amino)pyridin-4-yl)-1H-indazole-3-amine

[0554] 5-(2-((4-(trifluoromethoxy)phenyl)amino)pyridin-4-yl)-1H-indazole-3-amine

[0555] 5-(2-((4-propoxyphenyl)amino)pyridin-4-yl)-1H-indazole-3-amine

[0556] 2-((4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)amino)phenol

[0557] 4-((4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)amino)-2-methylphenol

[0558] 5-((4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)amino)-2-methylphenol

[0559] 4-((4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)amino)-3-methylphenol

[0560] 5-(2-((3,4-dichlorophenyl)amino)pyridin-4-yl)-1H-indazole-3-amine

[0561] N-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)thiazolyl-2-amine

[0562] 5-(2-(pyrimidin-2-ylamino)pyridin-4-yl)-1H-indazole-3-amine

[0563] 5-(2-(pyridin-4-ylamino)pyridin-4-yl)-1H-indazole-3-amine

[0564] 5-(2-(pyridin-3-ylamino)pyridin-4-yl)-1H-indazole-3-amine

[0565] 5-(2-(pyridin-2-ylamino)pyridin-4-yl)-1H-indazole-3-amine

[0566] N2-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)pyridin-2,6-diamine

[0567] N2-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-N6-benzylpyridin-2,6-diamine

[0568] 5-(7H-pyrrolo[2,3-b]pyrimidin-4-yl)-1H-indazole-3-amine

[0569] 2-Amino-4-(3-Amino-1H-indazol-5-yl)-7H-pyrrolo[2,3-b]pyrimidin-5-nitrile

[0570] 5-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-indazole-3-amine

[0571] 5-(3-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0572] 5-(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0573] 4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-nitrile

[0574] 5-(2-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0575] 5-(2-(tert-butyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0576] 5-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0577] 4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid

[0578] 5-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0579] 5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0580] 4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridine-5-nitrile

[0581] 5-(7H-pyrrolo[2,3-b]pyrimidin-4-yl)-1H-indazole-3-amine

[0582] 7-Bromo-5-(7H-pyrrolo[2,3-b][2,3-b]pyrimidin-4-yl)-1H-indazole-3-amine

[0583] 5-(2-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0584] 5-(2-(tert-butyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0585] 5-(2-Cyclopropyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0586] 5-(2-cyclohexyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0587] 5-(2-neopentyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0588] 5-(2-(cyclohexylmethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0589] 5-(2-(2-cyclohexylethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0590] 5-(2-benzyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0591] (4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)methanol

[0592] 2-(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)prop-2-ol

[0593] 3-(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)pentan-3-ol

[0594] 5-(2-(tert-butoxymethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0595] 5-(2-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0596] 5-(2-(tetrahydro-2H-pyran-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0597] 5-(2-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0598] 4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid

[0599] 4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid methyl ester

[0600] 4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid ethyl ester

[0601] (4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)(pyrrolidin-1-yl)methyl ketone

[0602] 4-(3-amino-1H-indazol-5-yl)-N-cyclopentyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide

[0603] 4-(3-amino-1H-indazol-5-yl)-N-cyclohexyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide

[0604] 4-(3-amino-1H-indazol-5-yl)-N-isopentyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide

[0605] 4-(3-amino-1H-indazol-5-yl)-N-phenethyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide

[0606] 4-(3-amino-1H-indazol-5-yl)-N-(3-phenylpropyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide

[0607] 4-(3-amino-1H-indazol-5-yl)-N-(2-methoxyethyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide

[0608] 4-(3-amino-1H-indazol-5-yl)-N-(2-aminoethyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide

[0609] 4-(3-amino-1H-indazol-5-yl)-N-(2-(dimethylamino)ethyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide

[0610] (4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)(4-methylpiperazin-1-yl)methyl ketone

[0611] 4-(3-amino-1H-indazol-5-yl)-N-(2-(piperidin-1-yl)ethyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide

[0612] 4-(3-amino-1H-indazol-5-yl)-N-(2-(butyl(ethyl)amino)ethyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide

[0613] 4-(3-amino-1H-indazol-5-yl)-N-(2-(diisopropylamino)ethyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide

[0614] 4-(3-amino-1H-indazol-5-yl)-N-(3-(dimethylamino)propyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide

[0615] 5-(2-((tert-butylamino)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0616] 5-(2-((isopentylamino)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0617] 5-(2-(piperidin-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0618] 5-(2-((cyclohexylamino)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0619] 5-(2-((phenylamino)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0620] 5-(2-(((2-(benzyloxy)phenyl)amino)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0621] 5-(2-(((2-methoxyethyl)amino)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0622] N1-((4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)-N2,N2-dimethylethane-1,2-diamine

[0623] 5-(2-(((3-methoxypropyl)amino)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0624] 5-(2-(((3-isopropoxypropyl)amino)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0625] N1-((4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)-N3,N3-dimethylpropane-1,3-diamine

[0626] 5-(2-((isopropyl(methyl)amino)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0627] 5-(2-(piperidin-1-ylmethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0628] 5-(2-((4,4-difluoropiperidin-1-yl)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0629] 5-(2-(morpholinomethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0630] 5-(2-((4-methylpiperazin-1-yl)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0631] 5-(2-((4-(tert-butyl)piperazin-1-yl)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0632] 5-(2-(azacycloheptan-1-ylmethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0633] 5-(2-((4-methyl-1,4-diazacycloheptane-1-yl)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0634] 5-(2-(2-(piperidin-1-yl)ethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0635] 5-(2-(2-morpholinoethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0636] 5-(2-(3-(piperidin-1-yl)propyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0637] 5-(2-(3-(cyclohexylamino)propyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0638] 5-(2-(3-morpholinopropyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0639] 5-(2-(piperidin-4-ylmethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0640] 5-(2-((1-benzylpiperidin-4-yl)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0641] 5-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0642] 5-(2-(3-(trifluoromethyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0643] 3-(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)benzonitrile

[0644] 3-(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)phenol

[0645] 5-(2-(3-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0646] 3-(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)benzoic acid

[0647] 3-(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)benzamide

[0648] 3-(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-N-(2-methoxyethyl)benzamide

[0649] 3-(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-N-(2-(piperidin-1-yl)ethyl)benzamide

[0650] (3-(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)phenyl)(4-methylpiperazin-1-yl)methyl ketone

[0651] 5-(2-(3-(morpholinomethyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0652] 5-(2-(3-(methanesulfonyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0653] 5-(2-(3-(morpholinosulfonyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0654] 5-(2-(3-aminophenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0655] N-(3-(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)phenyl)-3-methoxypropionamide

[0656] N-(3-(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)phenyl)-3-(piperidin-1-yl)propionamide

[0657] 4-((3-(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)phenyl)amino)-4-oxobutyric acid

[0658] N-(3-(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)phenyl)methanesulfonamide

[0659] N-(3-(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)phenyl)-4-methylbenzenesulfonamide

[0660] 5-(2-(4-(morpholinomethyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0661] N-(4-(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)phenyl)-4-methylbenzenesulfonamide

[0662] 2-(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)phenol

[0663] 5-(2-(2-ethoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0664] 5-(2-(2-ethylphenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0665] 5-(2-(benzo[d][1,3]dioxacyclopenten-5-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0666] 4-(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-fluorobenzonitrile

[0667] 5-(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-(pyrrolidin-1-yl)benzonitrile

[0668] 5-(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-(4-methylpiperazin-1-yl)benzonitrile

[0669] 5,5'-(1H-pyrrolo[2,3-b]pyridine-2,4-diyl)bis(1H-indazole-3-amine)

[0670] 5-(2-(3,5-difluorophenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0671] 5-(2-(2,3,5-trifluorophenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0672] 5-(2-(pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0673] 5-(2-(pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0674] 5-(2-(pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0675] 5-(2-(pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0676] 4-(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)pyridin-2(1H)-one

[0677] 5-(2-(2-fluoropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0678] 5-(2-(2-fluoro-6-methylpyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0679] 5-(2-(2,6-difluoropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0680] 5-(2-(2-(piperidin-1-yl)pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0681] 5-(2-(2-(piperazin-1-yl)pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0682] 5-(2-(2-morpholinopyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0683] 5-(2-(2-(4-(tert-butyl)piperazin-1-yl)pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0684] 4-(4-(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)pyridin-2-yl)thiomorpholine 1,1-dioxide

[0685] 5-(2-(2,6-dimorpholinopyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0686] 4-(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1-(4-(piperidin-1-ylmethyl)benzyl)pyridin-2(1H)-one

[0687] 4-(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1-(3-(piperidin-1-ylmethyl)benzyl)pyridin-2(1H)-one

[0688] 4-(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1-(2-(piperidin-1-ylmethyl)benzyl)pyridin-2(1H)-one

[0689] 5-(2-(5-methoxypyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0690] 5-(2-(6-morpholinopyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0691] 5-(2-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0692] 5-(2-(6-((2-morpholinoethyl)amino)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0693] 5-(2-(2-fluoropyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0694] 5-(2-(2-morpholinopyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0695] 5-(2-(3-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0696] 5-(2-(3-isobutoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0697] 5-(2-(3-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0698] 5-(2-(3-(2-morpholinoethoxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0699] 5-(2-(3-(benzyloxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0700] 5-(2-(3-((4-methoxybenzyl)oxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0701] 5-(2-(3-((3,5-dimethoxybenzyl)oxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0702] 5-(2-(3-((4-fluorobenzyl)oxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0703] 5-(2-(3-((2-fluorobenzyl)oxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0704] 5-(2-(3-(pyridin-2-ylmethoxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0705] 3-(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-fluorophenol

[0706] 5-(2-(3-fluoro-5-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0707] 5-(2-(3-fluoro-5-(2-methoxyethoxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0708] 5-(2-(3-fluoro-5-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0709] 5-(2-(3-(benzyloxy)-5-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0710] 5-(2-(3-(benzyloxy)-5-(trifluoromethoxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0711] Methyl 3-(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(benzyloxy)benzoate

[0712] 5-(2-(3-(benzyloxy)-5-((2-methoxyethoxy)methyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0713] 5-(2-(3-(benzyloxy)-5-((2-methoxyethyl)amino)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0714] 5-(2-(3-(benzyloxy)-5-((2-morpholinoethyl)amino)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0715] 5-(2-(2-(benzyloxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0716] 5-(2-(4-(benzyloxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0717] 5-(2-(5-(benzyloxy)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0718] 5-(2-(2-(benzyloxy)pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0719] 5-(2-(6-(benzyloxy)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0720] 5-(2-(4-(benzyloxy)pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0721] 5-(2-(2-(pyrimidin-5-ylmethoxy)pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0722] 5-(2-(2-(pyridin-4-ylmethoxy)pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0723] 5-(2-(2-(pyridin-3-ylmethoxy)pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0724] 5-(2-(2-(pyridin-2-ylmethoxy)pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0725] 5-(2-(6-(benzylamino)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0726] 5-(2-(2-(benzylamino)pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0727] 5-(2-(2-(benzyl(methyl)amino)pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0728] 5-(2-(2-(benzylthio)pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0729] 5-(2-(2-(benzylthio)-6-morpholinopyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0730] 5-(2-(3-phenylethylphenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0731] 5-(2-(2-phenethoxypyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0732] 5-(2-(3-((phenylamino)methyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0733] 5-(2-(3-((tert-butylamino)methyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0734] 5-(2-(3-((cyclopentylamino)methyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0735] 5-(2-(3-((cyclohexylamino)methyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0736] 5-(2-(3-((butanoamino)methyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0737] 5-(2-(3-((isopentylamino)methyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0738] 5-(2-(3-((butyl(ethyl)amino)methyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0739] 5-(2-(3-((dibutylamino)methyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0740] 5-(2-(2-fluoro-6-(piperidin-1-ylmethyl)pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0741] 5-(2-(2-fluoro-6-(piperazin-1-ylmethyl)pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0742] 5-(2-(2-fluoro-6-((4-methylpiperazin-1-yl)methyl)pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0743] 4-((4-(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-6-fluoropyridin-2-yl)methyl)piperazine-1-carboxylic acid tert-butyl ester

[0744] 5-(2-(2-((tert-butylamino)methyl)-6-fluoropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0745] 5-(2-(2-((cyclohexylamino)methyl)-6-fluoropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0746] 5-(2-(2-fluoro-6-((phenylamino)methyl)pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0747] 4-(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-2,6-difluorobenzamide

[0748] 5-(2-(4-((dimethylamino)methyl)-3,5-difluorophenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0749] 5-(2-(3,5-difluoro-4-(piperidin-1-ylmethyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0750] 5-(2-(3,5-difluoro-4-((isopropyl(methyl)amino)methyl)-phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0751] 5-(2-(4-((butyl(ethyl)amino)methyl)-3,5-difluorophenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0752] 5-(2-(4-((dibutylamino)methyl)-3,5-difluorophenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0753] 5-(2-(3,5-difluoro-4-(3-morpholinopropyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0754] 5-(2-(3,5-difluoro-4-(3-(piperidin-1-yl)propyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0755] 5-(2-(4-(3-(diethylamino)propyl)-3,5-difluorophenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0756] 5-(2-(4-(3-(dibutylamino)propyl)-3,5-difluorophenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0757] 7-Chloro-5-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0758] 7-Chloro-5-(2-(3-(morpholinomethyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0759] 7-Chloro-5-(2-(4-(morpholinomethyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0760] 7-Chloro-5-(2-(2-fluoro-6-(piperazin-1-ylmethyl)pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0761] 4-(3-amino-7-chloro-1H-indazol-5-yl)-N-(2-(piperidin-1-yl)ethyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide

[0762] 7-Chloro-5-(2-(cyclohexylmethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0763] 7-Chloro-5-(2-(morpholinomethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0764] 7-Chloro-5-(2-(2-morpholinoethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0765] 7-Phenyl-5-(2-Phenyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[0766] 5-(2-(3-(morpholinomethyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-7-phenyl-1H-indazole-3-amine

[0767] 5-(2-(4-(morpholinomethyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-7-phenyl-1H-indazole-3-amine

[0768] 5-(2-(cyclohexylmethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazole-3-amine

[0769] 5-(2-(2-(benzylthio)-6-fluoropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine.

[0770] Typically, various functional groups and substituents are chosen to constitute compounds of formula (I) or subformulas (Ia) to (Ic) such that the molecular weight of the compound of formula (I) does not exceed 1000. More typically, the molecular weight of the compound will be less than 900, for example less than 800, or less than 750, or less than 700, or less than 650. More preferably, the molecular weight is less than 600, for example 550 or less.

[0771] Suitable pharmaceutically acceptable salts of the compounds of the present invention are, for example, acid addition salts of the compounds of the present invention having sufficient basicity, such as acid addition salts with, for example, inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, formic acid, citric acid, methanesulfonic acid, or maleic acid. Furthermore, suitable pharmaceutically acceptable salts of the compounds of the present invention having sufficient acidity are alkali metal salts, such as sodium or potassium salts, alkaline earth metal salts, such as calcium or magnesium salts, ammonium salts, or salts formed with organic bases providing pharmaceutically acceptable cations, such as salts formed with methylamine, dimethylamine, trimethylamine, piperidine, morpholine, or tri-(2-hydroxyethyl)amine.

[0772] Compounds with the same molecular formula but different atomic bonding properties, sequences, or spatial arrangements are called "isomers." Isomers with different spatial atomic arrangements are called "stereoisomers." Stereoisomers that are not mirror images of each other are called "diastereomers," while those that are non-overlapping mirror images of each other are called "enantiomers." When a compound has an asymmetry center, for example, if it is bonded to four different groups, a pair of enantiomers may exist. Enantiomers can be characterized by the absolute configuration of their asymmetry center and by the R- and S-sequence rules of Cahn and Prelog, or by the way in which the molecule rotates the plane of polarization and is designated as dextrorotatory or levorotatory (i.e., as (+) or (-)- isomers, respectively). Chiral compounds can exist as individual enantiomers or as mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture."

[0773] The compounds of the present invention may have one or more asymmetric centers; therefore, such compounds may be produced as individual (R)- or (S)- stereoisomers or mixtures thereof. Unless otherwise stated, the description or naming of particular compounds in the specification and claims is intended to include individual enantiomers and mixtures thereof, racemic or other forms. Methods for determining stereochemistry and separating stereoisomers are well known in the art (see discussion in Chapter 4 of "Advanced Organic Chemistry," 4th edition, J. March, John Wiley and Sons, New York, 2001), for example by synthesis from optically active raw materials or by resolving racemic forms. Some compounds of the present invention may have geometric isomeric centers (E- and Z-isomers).

[0774] It should be understood that the present invention includes all active optical isomers, diastereomers and geometric isomers and mixtures thereof.

[0775] The present invention also includes compounds of the invention comprising one or more isotopic substitutions as defined herein. For example, H can be any isotopic form, including 1H, 2H(D), and 3H(T); C can be any isotopic form, including 12C, 13C, and 14C; and O can be any isotopic form, including 16O and 18O; etc.

[0776] It should also be understood that certain compounds of formula (I) or sub-formulas (Ia) to (Ic) may exist in solvated and non-solvated forms, such as hydrated forms. It should be understood that the present invention includes all such active solvated forms.

[0777] It should also be understood that certain compounds of formula (I) or sub-formulas (Ia) to (Ic) may exhibit polymorphism, and the present invention includes all of these active forms.

[0778] Compounds of formula (I) or sub-forms (Ia) through (Ic) can exist in many different tautomer forms, and all such forms are included when referring to compounds of formula (I) or sub-forms (Ia) through (Ic). To avoid ambiguity, when a compound can exist in one of several tautomer forms, and only one is specifically described or shown, all other forms are included in formula (I) or sub-forms (Ia) through (Ic). Examples of tautomer forms include ketone, enol, and enol salt forms, such as the following tautomer pairs: ketone / enol (as shown below), imine / enamine, amide / imino alcohol, amidine / amidinium, nitroso / oxime, thionone / enthiol, and nitro / acidic nitro.

[0779]

[0780] Compounds of formula (I) or sub-formulas (Ia) to (Ic) containing amine functional groups can also form N-oxides. The compounds of formula (I) or sub-formulas (Ia) to (Ic) containing amine functional groups mentioned herein also include N-oxides. When a compound contains several amine functional groups, one or more nitrogen atoms can be oxidized to form N-oxides. Specific examples of N-oxides are N-oxides of tertiary amines or nitrogen atoms in nitrogen-containing heterocycles. N-oxides can be formed by treating the corresponding amine with an oxidizing agent such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid), see, for example, Jerry March's *Advanced Organic Chemistry*, 4th ed., Wiley Interscience, pages. More specifically, N-oxides can be prepared by the steps of LW Deady (Syn. Comm. 1977, 7, 509-514), in which an amine compound is reacted with m-chloroperoxybenzoic acid (mCPBA) in, for example, an inert solvent such as dichloromethane.

[0781] Compounds of formula (I) or sub-formulas (Ia) to (Ic) can be administered as prodrugs, which decompose in the human or animal body to release the compounds of the present invention. Prodrugs can be used to modify the physical and / or pharmacokinetic properties of the compounds of the present invention. Prodrugs can be formed when the compounds of the present invention contain suitable groups or substituents to which a modifying group can be attached. Examples of prodrugs include in vivo cleavable ester derivatives that can be formed from the carboxyl or hydroxyl groups of compounds of formula (I) or sub-formulas (Ia) to (Ic), and in vivo cleavable amide derivatives that can be formed from the carboxyl or amino groups of compounds of formula (I) or sub-formulas (Ia) to (Ic).

[0782] Therefore, when obtained by organic synthesis, and when obtained in humans or animals by cleavage of its prodrug, the present invention includes those compounds of formula (I) or sub-formulas (Ia) to (Ic) as defined above. Thus, the present invention includes those compounds of formula (I) or sub-formulas (Ia) to (Ic) produced by organic synthesis methods, and such compounds produced in humans or animals by metabolism of precursor compounds, i.e., compounds of formula (I) or sub-formulas (Ia) to (Ic) can be synthetically produced or metabolically produced compounds.

[0783] A suitable pharmaceutically acceptable prodrug of a compound of formula (I) or sub-formulas (Ia) to (Ic) is a drug based on reasonable medical judgment that is suitable for administration to humans or animals without undesirable pharmacological activity and excessive toxicity.

[0784] Various forms of prodrugs have been described, for example in the following documents:

[0785] a) Methods in Enzymology, Vol. 42, p. 309 - 396, edited by K. Widder, etal. (Academic Press, 1985);

[0786] b) Design of Pro - drugs, edited by H. Bundgaard, (Elsevier, 1985);

[0787] c) A Textbook of Drug Design and Development, edited by Krogsgaard - Larsen and H. Bundgaard, Chapter 5 “Design and Application of Pro - drugs”, by H. Bundgaard p. 113 - 191 (1991);

[0788] d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1 - 38 (1992);

[0789] e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285(1988);

[0790] f) N. Kakeya, et al., Chem. Pharm. Bull., 32, 692 (1984);

[0791] g) T. Higuchi and V. Stella, “Pro - Drugs as Novel Delivery Systems”, A.C.S. Symposium Series, Volume 14; and

[0792] h) E. Roche (editor), “Bioreversible Carriers in Drug Design”, Pergamon Press, 1987.

[0793] Suitable pharmaceutically acceptable prodrugs of compounds of formula (I) or sub-formulas (Ia) to (Ic) containing a carboxyl group are, for example, esters that are cleavable in vivo. Cleavable esters of compounds of formula (I) or sub-formulas (Ia) to (Ic) containing a carboxyl group are, for example, pharmaceutically acceptable esters that cleave in the human or animal body to produce a parent acid or parent alcohol. Suitable pharmaceutically acceptable esters with carboxyl groups include (1-6C)alkyl esters, such as methyl, ethyl, and tert-butyl esters; (1-6C)alkoxymethyl esters, such as methoxymethyl ester; (1-6C)alkyloxymethyl esters, such as neopentyloxymethyl ester; 3-phthalidylester; (3-8C)cycloalkylcarbonyloxy-(1-6C)alkyl esters, such as cyclopentylcarbonyloxymethyl ester and 1-cyclohexylcarbonyloxyethyl ester; 2-oxo-1,3-dioxolenylmethyl ester, such as 5-methyl-2-oxo-1,3-dioxolen-4-yl ester; and (1-6C)alkoxycarbonyloxy-(1-6C)alkyl esters, such as methoxycarbonyloxymethyl ester and 1-methoxycarbonyloxyethyl ester.

[0794] Suitable pharmaceutically acceptable prodrugs of compounds of formula (I) or sub-formulas (Ia) to (Ic) containing a hydroxyl group are, for example, esters or ethers that are cleavable in vivo. Suitable pharmaceutically acceptable esterifying groups of the hydroxyl group include inorganic esters, such as phosphate esters (including cyclophosphamide esters). Other suitable pharmaceutically acceptable esterifying groups of the hydroxyl group include (1-10C) alkyl acyl groups, such as acetyl, benzoyl, phenylacetyl, and substituted benzoyl and phenylacetyl groups; (1-10C) alkoxycarbonyl groups, such as ethoxycarbonyl; N,N-(1-6C)2-carbamoyl, 2-dialkylaminoacetyl, and 2-carboxyacetyl. Examples of cyclic substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazine-1-ylmethyl, and 4-(1-4C)alkylpiperazine-1-ylmethyl. Suitable pharmaceutically acceptable etherifying groups for the hydroxyl group include α-acyloxyalkyl, such as acetoxymethyl and neopentyloxymethyl.

[0795] Suitable pharmaceutically acceptable prodrugs of compounds of formula (I) or sub-formulas (Ia) to (Ic) having a carboxyl group are, for example, amides that are cleavable in vivo, such as amides formed with amines, such as ammonia, 1-4C alkylamines such as methylamine, [(1-4C)alkyl]2amines such as dimethylamine, N-ethyl-N-methylamine or diethylamine, (1-4C)alkoxy-(2-4C)alkylamines such as 2-methoxyethylamine, phenyl-(1-4C)alkylamines such as benzylamine, and amino acids such as glycine or esters thereof.

[0796] Suitable pharmaceutically acceptable prodrugs of compounds having an amino group of formula (I) or subforms (Ia) to (Ic) are, for example, amide derivatives that are cleavable in vivo. Suitable pharmaceutically acceptable amides of the amino group include, for example, amides formed from (1-10C) alkyl groups such as acetyl, benzoyl, phenylacetyl, and substituted benzoyl and phenylacetyl groups. Examples of cyclic substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazine-1-ylmethyl, and 4-(1-4C)alkyl)piperazine-1-ylmethyl.

[0797] The in vivo effects of compounds of formula (I) or sub-formulas (Ia) to (Ic) may be exerted in part by one or more metabolites formed in the human or animal body following administration of the compound of formula (I) or sub-formulas (Ia) to (Ic). As mentioned above, the in vivo effects of compounds of formula (I) or sub-formulas (Ia) to (Ic) may also be exerted by the metabolism of prodrugs (prodrugs).

[0798] While the invention may relate to any compound or particular group of compounds as defined herein by means of optional, preferred or suitable features or by means of particular embodiments, the invention may also relate to any compound or particular group of compounds that explicitly excludes the optional, preferred or suitable features or particular embodiments.

[0799] Suitablely, the present invention excludes any single compound that does not have biological activity as defined herein.

[0800] Synthesis

[0801] The compounds of the present invention can be prepared by any suitable technique known in the art. Specific methods for preparing these compounds are further described in the appended examples.

[0802] In the description of the synthetic methods described herein and in any reference synthetic methods used to prepare the raw materials, it should be understood that those skilled in the art can choose all the proposed reaction conditions, including the choice of solvent, reaction atmosphere, reaction temperature, experimental duration, and post-treatment steps.

[0803] Those skilled in the field of organic synthesis can understand that the functionality present in different parts of a molecule must be adapted to the reagents and reaction conditions used.

[0804] It should be understood that during the synthesis of the compounds of this invention using the methods defined herein, or during the synthesis of certain starting materials, it may be necessary to protect certain substituents to prevent them from undergoing undesirable reactions. A skilled chemist will understand when such protection is needed and how to place such protecting groups in the appropriate positions before removing them.

[0805] For examples of protecting groups, see one of the many general texts on the subject, such as Theodora Green's *Protective Groups in Organic Synthesis* (published by John Wiley & Sons). Protecting groups can be removed by any convenient method described in the literature or known to a skilled chemist suitable for removing the protecting group in question, chosen so as to achieve the removal of the protecting group with minimal interference to other groups in the molecule.

[0806] Therefore, if the reactants include groups such as amino, carboxyl, or hydroxyl, it may be necessary to protect these groups in some of the reactions mentioned herein.

[0807] For example, suitable protecting groups for amino or alkylamino groups are, for example, acyl groups, such as alkanoyl groups, such as acetyl groups, alkoxycarbonyl groups, such as methoxycarbonyl, ethoxycarbonyl, or tert-butyloxycarbonyl groups, arylmethoxycarbonyl groups, such as benzyloxycarbonyl groups, or aromatic acyl groups, such as benzoyl groups. The deprotection conditions for these protecting groups necessarily vary depending on the choice of protecting group. Therefore, for example, acyl groups such as alkanoyl, alkoxycarbonyl, or aromatic acyl groups can be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide such as lithium hydroxide or sodium hydroxide. Alternatively, acyl groups such as tert-butyloxycarbonyl groups can be removed, for example, by treatment with a suitable acid such as hydrochloric acid, sulfuric acid, or phosphoric acid or trifluoroacetic acid, and arylmethoxycarbonyl groups such as benzyloxycarbonyl groups can be removed, for example, by hydrogenation on a catalyst such as a carbon-supported palladium, or by treatment with a Lewis acid such as tri(trifluoroacetic acid)borane. Suitable alternative protecting groups for primary amino groups are, for example, phthalyl groups, which can be removed by treatment with an alkylamine, such as dimethylaminopropylamine, or with hydrazine.

[0808] Suitable protecting groups for the hydroxyl group are, for example, acyl groups, such as alkanoyl groups like acetyl, aromatic acyl groups like benzoyl, or arylmethyl groups like benzyl. The deprotection conditions for these protecting groups will necessarily vary depending on the choice of protecting group. Therefore, for example, acyl groups like alkanoyl or aromatic acyl groups can be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide like lithium hydroxide, sodium hydroxide, or ammonia. Alternatively, arylmethyl groups like benzyl can be removed, for example, by hydrogenation on a catalyst such as a carbon-supported palladium.

[0809] Suitable protecting groups for the carboxyl group are, for example, esterification groups, such as methyl or ethyl groups that can be removed by hydrolysis with a base such as sodium hydroxide, or tert-butyl groups that can be removed by treatment with an acid such as an organic acid such as trifluoroacetic acid, or benzyl groups that can be removed by hydrogenation on a catalyst such as a carbon-supported palladium.

[0810] Resins can also be used as protecting groups.

[0811] The method for synthesizing compounds of formula (I) or sub-formulas (Ia) to (Ic) will be based on R 1 R 2 R 3 R 4 The properties of X1 and any substituents or subunits associated therewith vary. Suitable methods for preparing them are further described in the accompanying examples.

[0812] Once a compound of formula (I) or sub-formulas (Ia) to (Ic) has been synthesized by any of the methods defined herein, the method may further include the following additional steps:

[0813] (i) Remove any existing protecting groups;

[0814] (ii) Converting a compound of formula (I) into another compound of formula (I);

[0815] (iii) forming a pharmaceutically acceptable salt, hydrate, or solvate thereof; and / or

[0816] (iv) Formation of its prodrug.

[0817] An example of (ii) above is when a compound of formula (I) is synthesized, then one or more groups can be further reacted to change the properties of that group and provide an alternative compound of formula (I).

[0818] The obtained compounds of formula (I) or sub-formulas (Ia) to (Ic) can be isolated and purified using techniques known in the art.

[0819] The compounds of formula (I) can be synthesized via the synthetic route shown in the following examples.

[0820] Biological activity

[0821] The bioassays described in the Examples section of this document can be used to measure the pharmacological effects of the compounds of this invention.

[0822] Although, as expected, the pharmacological properties of the compounds of formula (I) vary with structural changes, the compounds of the present invention have been found to be active in the in vitro assay of IKK-α described in the Examples section, with preferred compounds showing better selectivity for IKK-α than for IKK-β.

[0823] Pharmaceutical compositions

[0824] According to another aspect of the invention, a pharmaceutical composition is provided comprising the compound of the invention as defined above, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, and a pharmaceutically acceptable diluent or carrier.

[0825] The compositions of the present invention may be in forms suitable for oral use (e.g., as tablets, lozenges, hard capsules or soft capsules, aqueous suspensions or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), in forms suitable for topical use (e.g., as creams, ointments, gels or aqueous or oily solutions or suspensions), in forms suitable for inhalation (e.g., as fine powders or liquid aerosols), in forms suitable for inhalation (e.g., as fine powders), or in forms suitable for parenteral administration (e.g., as sterile aqueous or oily solutions for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular administration, or as suppositories for rectal administration).

[0826] The compositions of the present invention can be obtained by conventional steps using conventional pharmaceutical excipients known in the art. Therefore, compositions for oral use may contain, for example, one or more colorants, sweeteners, flavoring agents, and / or preservatives.

[0827] An effective amount of the compound of the invention used in a therapy is an amount sufficient to treat or prevent the proliferative condition referred to herein, slow its progression, and / or alleviate symptoms associated with the condition.

[0828] The amount of active ingredient combined with one or more excipients to produce a single dosage form will necessarily vary depending on the individual being treated and the specific route of administration. For example, formulations for oral administration in humans typically contain, for example, 0.5 mg to 0.5 g of the active ingredient (more suitably 0.5 to 100 mg, e.g., 1 to 30 mg), mixed with an appropriate and convenient amount of excipients, which may comprise about 5% to about 98% of the total composition by weight.

[0829] According to well-known medical principles, the dosage of Formula I compounds used for therapeutic or preventative purposes will naturally vary depending on the nature and severity of the condition, the age and sex of the animal or patient, and the route of administration.

[0830] When the compounds of the present invention are used for therapeutic or preventative purposes, they are typically administered in a daily dose, for example, ranging from 0.1 mg / kg to 75 mg / kg body weight (provided in fractions if necessary). Generally, lower doses are administered when administered via a parenteral route. Thus, for example, for intravenous or intraperitoneal administration, doses ranging from 0.1 mg / kg to 30 mg / kg body weight are typically used. Similarly, for inhalation administration, doses ranging from, for example, 0.05 mg / kg to 25 mg / kg body weight are used. Oral administration is also suitable, particularly in tablet form. Typically, a unit dosage form will contain about 0.5 mg to 0.5 g of the compounds of the present invention.

[0831] Therapeutic uses and applications

[0832] This invention provides compounds that can be used as inhibitors of IKK activity, particularly IKKα activity. Therefore, the compounds of this invention are suitable for treating any disease or condition in which inhibition of IKKα activity may be beneficial.

[0833] IKKα activity is known to play a role in cancer.

[0834] The role of IKKα in cancer

[0835] IKKα in solid tumors

[0836] In recent years, the role of the atypical NF-κB pathway and its component IKKα in the development and progression of various solid tumors has become increasingly apparent. The atypical NF-κB pathway is associated with poor prognosis in glioblastoma

[57] , and upregulation of this pathway has been demonstrated in mouse orthotopic models as being associated with aggressive glioblastoma subtypes

[57] . In prostate cancer, nuclear localization of RelB is associated with higher-grade tumors

[58] , and androgen therapy in prostate cancer cells induces the accumulation of nuclear p52

[59] . Furthermore, silencing of IKKα reduces androgen receptor activity and gene expression, providing evidence that IKKα is associated with prostate cancer growth

[58] . Therefore, IKKα is an attractive target for prostate cancer because androgen receptors are major drivers of prostate cancer proliferation and inhibition of cell death.

[0837] In pancreatic cancer, the atypical NF-κB pathway is constitutively activated and associated with increased cell proliferation

[60] . NIK is elevated in pancreatic cancer and associated with increased proliferation [61, 62], and upregulation of RelB and p52 is associated with mutant KRAS pancreatic cancer

[63] , with IKKα-dependent gene expression observed. In gastrointestinal tumors, NF-κB2... DCT / DCT Spontaneous tumor formation in mice provides evidence that p100 / p52 drives tumorigenesis in this context

[64] . In renal cell carcinoma, members of the atypical NF-κB pathway are associated with poor prognosis, increased disease stage, and reduced local inflammation

[65] . In lung cancer, RelB is associated with shorter overall survival, differentiation, tumor invasion, lymph node metastasis, distant metastasis, and tumor-lymph node-metastasis (TNM) stage

[68] . In bladder cancer, upregulation of RelB and p52 is associated with histological grade, stage, and lymph node metastasis

[69] .

[0838] Numerous studies have investigated the role of IKKα in breast cancer. IKKα, RelB, and p52 are associated with decreased cancer-specific survival in ER-positive breast disease [70, 71]. Bcl3 can form a DNA-binding complex with p52 and has been observed to be overexpressed in breast cancer samples. IKKα has been shown to play an important role in the proliferation of mammary epithelial cells, so the aberrant IKKα signaling reported in breast cancer is not surprising

[72] . Yang et al. (2013) reported that nuclear IKKα can promote tumorigenesis progression via p27 in HER2-positive epithelial cells

[73] . In transgenic mice, overexpression of p100 / 52 leads to delayed mammary development, accompanied by overexpression of cyclin D1, MMP2, MMP9, and COX-2, and results in multiple tumors in mice

[74] . Furthermore, constitutive RANK signaling leads to increased atypical NF-κB signaling in breast cancer cell lines, which subsequently stimulates cell proliferation through increased cyclin D1 transcription [75-77], and nuclear IKKα expression has been observed in invasive ductal carcinoma and is associated with disease-free survival. Immunohistochemical studies have demonstrated that the p52 subunit is expressed at higher levels in breast cancer tissues compared to normal adjacent tissues

[78] , and Western blots of nuclear portions extracted from cancerous and adjacent normal breast tissues have confirmed increased p52 levels in tumor cells

[78] . This is accompanied by increased mRNA levels of p52, Bcl-3, and cyclin D1, all of which are regulated by IKKα

[78] . In addition, IKKα has been shown to regulate mTORC1 and mTORC2, which control tumor cell proliferation, in cervical, lung, prostate, and pancreatic cell lines

[79] . In summary, there is now substantial evidence supporting the role of the IKKα-NF-κB atypical pathway in the development and progression of solid tumors.

[0839] IKKα signaling in solid tumors that is independent of the NF-κB pathway

[0840] In addition to its role in the NF-κB pathway, IKKα has been reported to have effects independent of both typical and atypical NF-κB pathways. IKKα accumulates in the nucleus, where it can phosphorylate a variety of substrates, including histone H3, SMRT, and nuclear co-repressor (NCoR)

[80] . In colorectal cancer, IKKα phosphorylates SMRT, leading to increased Notch-dependent gene expression

[80] . Furthermore, IKKα has been reported to be associated with NOTCH activation in the presence of anti-estrogens in breast cancer, leading to upregulation of ER-dependent gene expression and providing a mechanism for hormone resistance in an NF-κB-independent manner [81, 82]. Bennett et al. reported that IKKα expression (rather than NIK or RelB) was associated with recurrence in Luminal A breast cancer, suggesting that it is independent of the atypical NF-κB pathway

[71] . In the second group of patients treated with tamoxifen, the authors reported that cytoplasmic IKKα was associated with disease-free and recurrence-free survival in Luminal A disease after tamoxifen treatment, which may indicate that patients may develop resistance to tamoxifen or IKKα-targeted therapy

[71] , further supporting the role of IKKα in tamoxifen-resistant breast cancer. However, in contrast, Roseweir et al. reported in a multinational (TEAM) clinical trial cohort of tamoxifen and exemestane adjuvant therapy that low IKKα expression was associated with an increased risk of recurrence with sequential tamoxifen / exemestane treatment, suggesting that the role of IKKα in hormone therapy resistance may vary depending on the mechanism of action of the treatment received by the patient

[83] .

[0841] In gastric cancer, Helicobacter pylori-mediated NF-κB activation is thought to occur through an IKKα-related pathway that is independent of the atypical NF-κB pathway but involves IKKα and NIK upregulation of inflammatory invasion and promotes tumorigenesis

[84] . Studies on IKKα in colorectal cancer and squamous cell carcinoma of the skin that are independent of the atypical NF-κB pathway have focused on a persistently active truncated form of IKKα (p45 IKKα) that is specifically localized to the nucleus [55, 56]. Bennett et al. observed that nuclear IKKα had a stronger predictive power than cytoplasmic IKKα in breast cancer and suggested that this might be due to the detection of the truncated activated form of p45 IKKα, since the antibody used could not distinguish between full-length IKKα and the truncated p45 IKKα form

[71] . Further studies on IKKα signaling in colorectal cancer that is independent of the atypical NF-κB pathway provide additional evidence that IKKα binds to Notch-dependent gene promoters, upregulates them, and releases chromatin-bound SMRT, which can be restored by inhibiting IKKα and leads to a reduction in colorectal cancer xenograft size

[56] . Truncated p45 IKKα has been reported to form a complex with full-length IKKα and NEMO and is responsible for regulating SMRT and histone H3 phosphorylation in an NF-κB-independent manner. Furthermore, in BRAF… V600E In mutant colorectal tumors, p45 IKKα may be phosphorylated in a TAK1-dependent but NF-κB-independent manner

[56] , thus supporting the role of nuclear IKKα in atypical NF-κB signaling.

[0842] It has been consistently reported that the nuclear function of IKKα is independent of NF-κB and exerts its effects by activating alternative pathways such as NOTCH

[85] . This has been observed in breast cancer, skin cancer, and osteosarcoma

[86] . In hepatocellular carcinoma, hepatitis B virus X protein downregulates maspin expression via nuclear IKKα, leading to chemotherapeutic resistance, suggesting that targeting IKKα can resensitize HCC tumors to chemotherapy

[87] . In a transgenic mouse model of prostate adenocarcinoma (TRAMP), IKKα can translocate to the nucleus and promote the metastasis and development of castration-resistant disease in a maspin-dependent manner, accompanied by a local inflammatory response

[88] . Similar to breast cancer, nuclear IKKα appears to provide a mechanism for hormone resistance in prostate cancer, as IKKα is associated with the development of castration-resistant prostate cancer

[53] , and the loss of BAG3, which is required for IKKα nuclear translocation, delays the development of castration-resistant disease

[89] .

[0843] IKKα is associated with cancer markers in human tumors.

[0844] The NF-κB pathway regulates the transcription of a variety of genes involved in inflammation, proliferation, and apoptosis. Many of these processes are hallmarks of cancer [46, 47], and NF-κB is hypothesized to be a link between inflammation and tumorigenesis. Whether IKKα functions as a member of the atypical NF-κB pathway or as an NF-κB-independent agent, it is clear that it is associated with multiple cancer hallmarks, including key roles in innate and adaptive immune responses, cell survival, cell death, and inflammation [90, 91]. The atypical NF-κB pathway plays a key role in regulating processes including the production of lymphoid organs (responsible for B and T lymphocyte production), B cell development and survival, dendritic cell function, and bone metabolism

[92] , and has been reported to promote cancer development and progression by facilitating inflammatory infiltration. Mouse model studies have shown that mice with dominant-negative, non-catalytically active IKKα, when treated with carcinogens, exhibit reduced adenoma formation, smaller colorectal tumors, and lower proliferation indices, which are associated with increased recruitment of macrophages and other immune cell types

[93] . In skin cancer research, IKKα has been shown to induce inflammation-related genes

[94] . In another study using an immunocompetent mouse model of peritoneal metastasis, intraperitoneal injection of IκBα-inhibited colon cells induced an M1-like macrophage phenotype and reduced liver and peritoneal metastases in vivo. This was associated with an increase in activated CD4+ and CD8+ T cells and a decrease in angiogenesis within the tumor

[93] , demonstrating that the NF-κB pathway, along with local inflammatory infiltration, promotes colorectal cancer progression. In renal cell carcinoma, the inflammatory effects of the NF-κB pathway are primarily attributed to the typical p65 / p50 subunit that binds to STAT3. However, NIK and RelB have previously been shown to be crucial for B cell development[2], indicating that the atypical NF-κB pathway also plays a role, and that RelB can regulate local inflammatory infiltration in renal cell carcinoma. IKKα is also associated with promoting the expression of pro-inflammatory cytokines such as IL-8 in prostate cancer

[95] .

[0845] Kong et al. proposed that IKKα can be phosphorylated by deletion in breast cancer 1 (DBC1), thereby regulating B cell activation through RelB activity and leading to increased cell proliferation in mice

[96] . In addition, gene transcription profiling experiments based on polymerase chain reaction (PCR) arrays demonstrated that reduced cellular IKKα expression significantly affected the increased expression of apoptosis-inducing genes (especially BAK1 and BBC3), providing evidence that IKKα is involved in regulating the proliferation and apoptosis of ER-positive breast cancer cells. Dan et al. demonstrated that IKKα can induce cell proliferation in cervical, lung, prostate, and pancreatic cell lines via mTORC

[79] , and that in basal cell carcinoma, IKKα is associated with proliferation and EMT

[94] . In vitro studies have also shown that the proliferation, migration, and invasive phenotype of ovarian cancer epithelial cells are promoted by upregulation of IKKα. Furthermore, NIK levels are associated with the regulation of cell proliferation and apoptosis in colorectal cancer, suggesting that the atypical NF-κB pathway is involved in cell viability and tumor growth

[97] .

[0846] The role of IKKα in hematological malignancies

[0847] Aberrant NF-κB signaling and associated gene transcription, regulating cellular processes involved in the occurrence, maintenance, and progression of human malignancies, are also common in hematologic cells and cancers. In this regard, many B-cell leukemias and lymphomas exhibit aberrant NF-κB activation, suggesting that this family of transcription factors is associated with these diseases and hinting that the regulation of these proteins may be a promising therapeutic target. Furthermore, it is now recognized that conventional cytotoxic agents can increase NF-κB activation, promoting the development of drug resistance through many different mechanisms. Therefore, inhibitors targeting NIK-IKKα-mediated signaling may prove useful clinically as single agents and could also resensitize patients to chemotherapy drugs. Given the frequency of gene mutations in the atypical NF-κB pathway and their crucial role in signal transduction in the tumor microenvironment, IKKα represents an attractive anticancer target.

[0848] Chronic lymphocytic leukemia (CLL) is the most common type of leukemia in Europe and North America. It is characterized by the presence of mature CD5+ cells in peripheral blood, bone marrow, and lymphoid tissues. + / CD19 +The accumulation of B lymphocytes

[105] . In many CLL patients, NF-κB is constitutively activated, which is associated with a more aggressive disease [106, 107]. Recurrent gene mutations in many NF-κB-related genes have been described in CLL. The most common of these is the NFκBIE inactivation mutation encoding the negative NF-κB regulator IκBε. These NFκBIE abnormalities are found in approximately 7% of CLL cases and occur primarily in subgroups with poor prognosis. This may be causally related, as mutations in NFκBIE lead to increased nuclear translocation of RelA

[108] . In CLL, NOTCH1 mutations occur even more frequently (~11%). These activating mutations are associated with adverse responses to chemotherapy

[109] , which may be due to NOTCH1-mediated activation of the NF-κB pathway [110-112]. BIRC3 mutations have been found in a small percentage of CLL patients (~4%), but these mutations affect the atypical NF-κB pathway due to premature truncation of the protein product cIAP2 encoded by BIRC3, leading to the loss of E3 ubiquitin ligase activity of cIAP2, which is essential for NIK proteasome degradation. As a result, increased NIK levels lead to phosphorylation of IKKα and NF-κB2, p100-p52 processing, and constitutive activation of atypical NF-κB signaling

[113] . Importantly, BIRC3 mutations are associated with loss of chemosensitivity and poor prognosis

[114] .

[0849] In addition to the genetic causes of NF-κB dysregulation in CLL, the lymph node microenvironment is now known to play a crucial role in regulating the natural pathology of the disease. A pro-survival, pro-proliferative niche mediated by NF-κB activation is created through signaling from B-cell receptors (BCR), toll-like receptors (TLR), and CD40, as well as the involvement of BAFF and proliferation-inducing ligand (APRIL) receptors TACI, BAFF-R, and BCMA [116, 117]. The remarkable clinical efficacy of the Bruton's tyrosine kinase inhibitor ibrutinib is perhaps the best illustration of the importance of this microenvironment. Treatment with this drug produces a significant tissue redistribution effect, excluding leukemia cells from lymphoid tissues

[118] . Separation of the tumor from sites of enhanced NF-κB signaling leads to durable remission, but this effect is reversed upon discontinuation of the drug.

[0850] Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma. They are classified into three molecular isoforms: ABC (activated B cells), GCB (germinal center B cells), and PMBL (primary mediastinal B-cell lymphoma). The initial evidence for the role of the canonical NF-κB pathway in DLBCL came from gene expression profiling studies showing enrichment of NF-κB target genes in the ABC isoform. This group had the worst prognosis, suggesting that NF-κB is a regulator of clinical outcomes in DLBCL

[123] . Constitutive NF-κB activation in the ABC isoform can be caused by mutations in components of the BCR signaling cascade, leading to chronic BCR activation. These mutations typically occur in the immune receptor tyrosine motif (ITAM), but also in the coiled-coil domain of the CARD11 / CARMA1 gene

[124] . Finally, mutations in the MYD88 gene have been found in approximately 30% of the ABC isoforms, leading to spontaneous activation of the downstream IRAK complex and NF-κB activation

[125] . Due to TRAF2 and TRAF3 mutations, the atypical NF-κB pathway is also abnormally dysregulated in 10-15% of DLBCL cases

[126] , thus identifying a tumor subpopulation that may be targeted by IKKα.

[0851] Multiple myeloma (MM) is an incurable plasma cell malignancy, accounting for approximately 13% of all blood cancers. Disease progression involves clonal expansion of transformed plasma cells in the bone marrow. Overall, genetic abnormalities leading to constitutive NF-κB activity have been found in approximately 20% of MM patients and 40% of MM cell lines [127-129]. Most genetic abnormalities associated with NF-κB dysregulation in MM involve atypical NF-κB pathways, including aberrant expression of NIK, CD40, TRAF2, TRAF3, transmembrane activator and CAML interactor (TACI), and cIAP1 / 2 [127, 128]. In these studies, most MM cases showed overexpression of positive NF-κB regulators NIK, TACI, and CD40, or decreased or silenced activity of negative NF-κB regulators TRAF2, TRAF3, and cIAP1 / 2. All of these phenotypes contribute to increased NF-κB signaling, with atypical NF-κB signaling being preferentially represented [128, 129]. In addition, other less common genetic abnormalities have been found that also contribute to constitutive NF-κB signaling in MM. These include overexpression of the NFκB1 gene (p105) and abnormalities in the NFκB2 gene (p100), which lead to increased typical and atypical NFκB signaling, respectively [127-129].

[0852] While genetic abnormalities may explain the high NF-κB activity in MM to some extent, it is likely that most NF-κB signaling in this disease is due to interactions within the bone marrow microenvironment

[129] . One mechanism of NF-κB activation is through CD40-CD40L interaction [130, 131]. CD40 is a cell surface marker that is not normally expressed on normal plasma cells but has been shown to increase in early MM

[132] . Furthermore, blocking the CD40-CD40L interaction reduces NF-κB activation

[127] . This leads to inhibition of IL-6 and vascular endothelial growth factor (VEGF) secretion, which in turn leads to growth arrest and cell death in MM cells

[133] . In addition, high levels of NF-κB activation have been found in bone marrow stromal cells (BMSCs) found in the MM tumor microenvironment, which may contribute to the proliferation, survival, and drug resistance of malignant plasma cells within the bone marrow microenvironment

[134] . MM cell adhesion to BMSCs induces NF-κB-dependent cytokine transcription and secretion of TNFα, IL-6, VEGF, RANKL and BAFF, which promote MM cell survival and growth through NF-κB activation [135, 136].

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[0935] Therefore, according to another aspect of the invention, a method for inhibiting IKKα activity in vitro or in vivo is provided, the method comprising contacting cells with an effective amount of a compound as defined herein or a pharmaceutically acceptable salt, hydrate or solvate thereof.

[0936] According to another aspect of the invention, a method is provided for treating a disease or condition involving IKKα activity in a patient requiring such treatment, the method comprising administering to the patient a therapeutically effective amount of a compound as defined herein or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein.

[0937] According to another aspect of the invention, a method for treating proliferative disorders in a patient requiring such treatment is provided, the method comprising administering to the patient a therapeutically effective amount of a compound as defined herein or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein.

[0938] According to another aspect of the invention, a method for treating cancer in a patient requiring such treatment is provided, the method comprising administering to the patient a therapeutically effective amount of a compound as defined herein or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein.

[0939] According to another aspect of the invention, compounds as defined herein or pharmaceutically acceptable salts, hydrates or solvates thereof, or pharmaceutical compositions thereof, are provided for use in therapy.

[0940] According to another aspect of the invention, compounds as defined herein or pharmaceutically acceptable salts, hydrates or solvates thereof, or pharmaceutical compositions thereof, are provided for use as pharmaceuticals.

[0941] According to another aspect of the invention, compounds as defined herein or pharmaceutically acceptable salts, hydrates or solvates thereof, or pharmaceutical compositions as defined herein, are provided for the treatment of proliferative disorders.

[0942] According to another aspect of the invention, compounds, or pharmaceutically acceptable salts, hydrates, or solvates thereof, or pharmaceutical compositions, as defined herein, are provided for the treatment of cancer. In a particular embodiment, the cancer is a human cancer.

[0943] According to another aspect of the invention, compounds as defined herein or pharmaceutically acceptable salts, hydrates or solvates thereof are provided for inhibiting IKKα activity.

[0944] According to another aspect of the invention, compounds as defined herein or pharmaceutically acceptable salts, hydrates or solvates thereof are provided for the treatment of diseases or conditions involving IKKα activity.

[0945] According to another aspect of the invention, the use of a compound as defined herein or a pharmaceutically acceptable salt, hydrate or solvate thereof in the preparation of a medicament for treating proliferative disorders is provided.

[0946] According to another aspect of the invention, the use of a compound as defined herein or a pharmaceutically acceptable salt, hydrate or solvate thereof in the preparation of a medicament for treating cancer is provided.

[0947] According to another aspect of the invention, the use of a compound as defined herein or a pharmaceutically acceptable salt, hydrate or solvate thereof in the preparation of a medicament for inhibiting IKKα activity is provided.

[0948] According to another aspect of the invention, use is provided in the preparation of a medicament for treating a disease or condition involving IKKα activity, using a compound as defined herein or a pharmaceutically acceptable salt, hydrate or solvate thereof.

[0949] According to another aspect of the invention, a method for preparing a compound as defined herein or a pharmaceutically acceptable salt, hydrate or solvate thereof is provided.

[0950] According to another aspect of the invention, a compound or a pharmaceutically acceptable salt, hydrate or solvate thereof is provided, which can be obtained by a method for preparing a compound as defined herein, or by a method for preparing a compound as defined herein, or directly by a method for preparing a compound as defined herein.

[0951] According to another aspect of the invention, a novel intermediate as defined herein is provided, which is applicable to any of the synthetic methods listed herein.

[0952] The terms “proliferative disorder,” “proliferative condition,” and “proliferative disease” are used interchangeably in this document and refer to unwanted or uncontrolled cell proliferation, such as neoplastic or proliferative growth, whether in vitro or in vivo, of unwanted excess or abnormal cells.

[0953] In the above aspects of the invention, the proliferative condition is suitably cancer, and said cancer is suitably human cancer. In particular, the compounds of the invention will be used to treat any cancer in which mismatch repair is beneficially inhibited.It can target any suitable cancer (e.g., adenoid cystic carcinoma, adrenal tumor, amyloidosis, anal cancer, appendix cancer, astrocytoma, ataxia-telangiectasia, Beckwith-Wiedemann syndrome, cholangiocarcinoma, Birt-Hogg-Dubé syndrome, bladder cancer, bone cancer, brainstem glioma, brain tumor, breast cancer, Carney syndrome, central nervous system tumors, cervical cancer, colorectal cancer, Cowden syndrome, craniopharyngioma, connective tissue proliferative infantile ganglion glioma, ependymoma, esophageal cancer, Ewing sarcoma, eye cancer, eyelid cancer, familial adenomatous polyposis, familial GIST, familial malignant melanoma, familial non-VHL clear cell renal cell carcinoma, familial pancreatic cancer, gallbladder cancer, gastrointestinal stromal tumor (GIST), germ cell tumors, gestational trophoblastic disease). Head and neck cancer, hereditary breast and ovarian cancer, hereditary diffuse gastric cancer, hereditary leiomyomatosis and renal cell carcinoma, hereditary mixed polyposis syndrome, hereditary pancreatitis, hereditary papillary renal cell carcinoma, juvenile polyposis syndrome, kidney cancer, lacrimal gland tumors, laryngeal and hypopharyngeal cancer, leukemia (acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), B-cell prolymphoblastic leukemia, hairy cell leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic T-cell lymphoblastic leukemia, eosinophilic leukemia), Li-Fraumeni syndrome, liver cancer, lung cancer (non-small cell lung cancer, small cell lung cancer), lymphoma (Hodgkin's, non-Hodgkin's), Lynch syndrome, mastocytosis, medulloblastoma, melanoma, meningioma, mesothelioma, type 1 and 2 multiple endocrine tumors, multiple myeloma, MUTYH (or MYH) related polyposis, myelodysplastic syndrome (MDS), nasal and sinus carcinoma, nasopharyngeal carcinoma, neuroblastoma, neuroendocrine tumors (e.g., tumors of the gastrointestinal tract, lung, or pancreas), neurofibromatosis type 1 and 2, nevus-like basal cell carcinoma syndrome, oral and oropharyngeal carcinoma, osteosarcoma, ovarian / fallopian tube / abdominal cancer, pancreatic cancer, parathyroid carcinoma, penile cancer, Peutz-Jeghers syndrome, pheochromocytoma, paraganglioma, pituitary tumor, pleural pulmonary blastoma, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma (e.g., Kaposi's sarcoma or soft tissue sarcoma), skin cancer, small intestine cancer, gastric cancer, testicular cancer, thymoma and thymic carcinoma, thyroid cancer, tuberous sclerosis, uterine cancer, vaginal cancer, Von Hippel-Lindau syndrome, vulvar cancer, Waldenstrom macroglobulinemia, Werner syndrome, Wilms' tumor, and xeroderma pigmentosum.Specific cancers of interest include blood cancers such as lymphomas (including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), Burkitt lymphoma (BL), and angioimmunoblastic T-cell lymphoma (AITL)), leukemias (including acute lymphoblastic leukemia (ALL) and chronic myeloid leukemia (CML)), multiple myeloma, breast cancer, non-small cell lung cancer (NSCLC), colorectal cancer, endometrial cancer, gastroesophageal cancer, neuroendocrine cancer, osteosarcoma, prostate cancer, pancreatic cancer, small bowel cancer, bladder cancer, rectal cancer, bile duct cancer, central nervous system cancers, thyroid cancer, head and neck cancer, esophageal cancer, and ovarian cancer.

[0954] Specific cancers for which IKKα is expected to be beneficial include advanced prostate cancer, multiple myeloma, pancreatic cancer, colorectal cancer (especially metastatic colorectal cancer), and breast cancer (especially triple-negative breast cancer).

[0955] Prostate cancer is of particular interest as a potential therapeutic target for IKKα inhibitors. Without being bound by any particular theory, effective targeting of IKKα in prostate cancer can enhance the response to androgen deprivation therapy (ADT) by simultaneously inhibiting androgen-driven androgen-independent AR (androgen receptor) activity. IKKα inhibition can also eliminate inflammatory microenvironment signaling and eliminate pro-tumor stimulation from adjacent stroma and infiltrating monocytes. Therefore, IKKα inhibitors have the potential to alter disease course, restore / prolong sensitivity to AR-targeted therapies, and improve survival. Furthermore, their application in hormone-sensitive new metastatic disease can significantly prolong the duration of benefit from conventional therapies and reduce the overall incidence of castration-resistant prostate cancer (CRPC). Therefore, IKKα inhibitors can be used in clinical situations such as:

[0956] - Last-line treatment for CRPC patients who have failed standard treatment;

[0957] - Use ADT in combination therapy to prevent the onset of CRPC / prolong sensitivity to ADT;

[0958] - Combination therapy in CRPC patients to restore sensitivity to ADT / reduce the development of resistance to chemotherapy;

[0959] - Single-drug therapy to prevent CRPC.

[0960] Routes of administration

[0961] The compounds of the present invention or pharmaceutical compositions comprising these compounds may be administered to a subject via any convenient route of administration, whether systemic, peripheral or local (i.e., at the site of desired action).

[0962] Routes of administration include, but are not limited to, oral (e.g., by ingestion); buccal; sublingual; transdermal (including, for example, by patches, plasters, etc.); transmucosal (including, for example, by patches, plasters, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eye drops); pulmonary (e.g., by inhalation or blowing therapy using, for example, aerosols, such as through the mouth or nose); rectal (e.g., by suppositories or enemas); vaginal (e.g., by vaginal suppositories); parenteral, such as by injection, including intratumoral, subcutaneous, intradermal, intramuscular, intravenous, intraarticular, intracardiac, intrasheathal, spinal, intracapsular, intraorbital, intraperitoneal, intratracheal, subepidermal, intra-articular, subarachnoid, and intrasternal; and by implantation of a reservoir or depository, for example, subcutaneously or intramuscularly.

[0963] Combination therapy

[0964] The compounds of the present invention can be administered as a monotherapy, or, in addition to the compounds of the present invention, may include conventional surgery, radiotherapy, chemotherapy, or targeted agents. Such chemotherapy or targeted agents may include one or more of the following categories:

[0965] (i) Antiproliferative / antitumor drugs and combinations thereof used in medical oncology, such as, but not limited to, alkylating agents (e.g., cisplatin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulfan, temozolomide, and nitrosourea); antimetabolites (e.g., gemcitabine and antifolate drugs, such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytarabine, and hydroxyurea); and antitumor antibiotics (e.g., anthracyclines like adriamycin). (Cin), bleomycin, doxorubicin, daunorubicin, epirubicin, idarubicin, mitomycin-C, sclerosingmycin, and sclerosingmycin; antimitotic agents (e.g., vinblastine alkaloids such as vincristine, vinblastine, vinorelbine, and vinorelbine, as well as taxanes such as paclitaxel and docetaxel, and multi-kinase inhibitors); and topoisomerase inhibitors (e.g., epipodophyllotoxins such as etoposide and teniposide, acridine, topotecan, and camptothecin);

[0966] (ii) Cell growth inhibitors, such as, but not limited to, anti-estrogens (e.g., tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene, and iodoxyfene), anti-androgens (e.g., bicalutamide, flutamide, nilumethoxazole, and cyproterone acetate), LHRH antagonists or LHRH agonists (e.g., goserelin, leuprorelin, and buserelin), steroid hormones, including progestins (e.g., megestrol acetate) and corticosteroids (e.g., dexamethasone, prednisone, and prednisolone), aromatase inhibitors (e.g., anastrozole, letrozole, vorazole, and exemestane), and 5α-reductase inhibitors, such as finasteride;

[0967] (iii) Anti-invasive agents, such as, but not limited to, c-Src kinase family inhibitors 4-(6-chloro-2,3-methylenedioxyaniline)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-tetrahydropyran-4-yloxyquinazoline (AZD0530; International Patent Application WO 01 / 94341), N-(2-chloro-6-methylphenyl)-2-{6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4-ylamino}thiazolyl-5-carboxamide (dasatinib, BMS-354825; J. Med. Chem., 2004, 47 , 6658-6661), bosutinib (SKI-606) and metalloproteinase inhibitors such as marimasitol, urokinase plasminogen activator receptor function inhibitors or heparanase antibodies.

[0968] (iv) Inhibitors of growth factor function, such as, but not limited to, growth factor antibodies and growth factor receptor antibodies (e.g., anti-erbB2 antibody trastuzumab [Herceptin™], anti-EGFR antibody panitumumab, anti-erbB1 antibody cetuximab [Erbitux, C225], and Stern et al. (Critical reviews in oncology / haematology, 2005, Vol. 54, Any growth factor or growth factor receptor antibody disclosed in pp. 11-29; such inhibitors also include tyrosine kinase inhibitors, such as inhibitors of the epidermal growth factor family (e.g., EGFR family tyrosine kinase inhibitors, such as N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazoline-4-amine (gefitinib, ZD1839), N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazoline-4-amine (erlotinib, OSI-774) and 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)quinazoline-4-amine (CI) 1033), ERB2 tyrosine kinase inhibitors such as lapatinib; inhibitors of the hepatocyte growth factor family; inhibitors of the insulin growth factor family; inhibitors of the platelet-derived growth factor family, such as imatinib and / or nilotinib (AMN107); inhibitors of serine / threonine kinases (e.g., Ras / Raf signaling inhibitors, such as farnesyltransferase inhibitors, such as sorafenib (BAY 43-9006), tilpifanib (R115777), and lonafanib (SCH66336)), inhibitors of cell signaling via MEK and / or AKT kinases, c-kit inhibitors, abl kinase inhibitors, PI3 kinase inhibitors, Plt3 kinase inhibitors, CSF-1R kinase inhibitors, IGF receptor (insulin-like growth factor) kinase inhibitors; aurora kinase inhibitors and cyclin-dependent kinase inhibitors, such as CDK2 and / or CDK4 inhibitors;

[0969] (v) Anti-angiogenic agents, such as, but not limited to, those that inhibit the action of vascular endothelial growth factor, [e.g., the anti-vascular endothelial growth factor antibody bevacizumab (Avastin™), and VEGF receptor tyrosine kinase inhibitors, such as vandetanib (ZD6474), vastarani (PTK787), sunitinib (SU11248), axitinib (AG-013736), and pazopanib (GW 786034).

[0970] (vi) Vascular damaging agents, such as, but not limited to, Compressor A4 and compounds disclosed in international patent applications WO 99 / 02166, WO 00 / 40529, WO 00 / 41669, WO 01 / 92224, WO 02 / 04434 and WO 02 / 08213;

[0971] (vii) Endothelin receptor antagonists, such as zipotan (ZD4054) or atrasentan;

[0972] (viii) Antisense therapies, such as, but not limited to, those targeting the targets listed above, such as ISIS 2503, an anti-ras antisense;

[0973] (ix) Immunotherapy, including, for example, cancer vaccines, antibodies, viruses (oncolytic viruses), and small molecule or cell therapies, to increase the immunogenicity of a patient's tumor cells and / or promote cell-mediated anti-tumor responses. This therapy may include, but is not limited to, OX40 agonists, cGAS-STING agonists, A2a receptor antagonists, PI3 kinase inhibitors, TLR7 / 8 agonists, IDO inhibitors, arginase inhibitors, BTK inhibitors, and bromodomain inhibitors; transduction using microbial vectors of cancer antigens; direct transduction of cancer antigens to antigen-presenting cells; treatment with cancer antigen-specific immune cells (e.g., CAR-T); and treatment with antibodies, antibody fragments, and antibody-drug conjugates that enable the immune system to recognize tumor cells.

[0974] The compounds of the present invention are expected to be particularly useful in combination with androgen deprivation therapy (ADT) and standard chemotherapy for the treatment of prostate cancer, particularly castration-resistant prostate cancer (CRPC).

[0975] This combination therapy can be achieved by administering the individual components simultaneously, sequentially, or separately. This combination product uses compounds of the present invention within the dosage range described above, and other pharmaceutically active agents within the approved dosage range.

[0976] According to this aspect of the invention, a combination for treating cancer (e.g., cancer involving solid tumors) is provided, comprising the compound of the invention as defined above or a pharmaceutically acceptable salt or solvate thereof, and an antitumor agent.

[0977] According to this aspect of the invention, a combination for treating proliferative conditions such as cancer (e.g., cancer involving solid tumors) is provided, comprising the compound of the invention as defined above or a pharmaceutically acceptable salt or solvate thereof, and any of the antitumor agents listed above.

[0978] In another aspect of the invention, compounds of the invention or pharmaceutically acceptable salts or solvates thereof are provided for use in combination with another antitumor agent, optionally selected from one listed above, to treat cancer.

[0979] In another aspect of the invention, compounds of the invention or pharmaceutically acceptable salts or solvates thereof are provided for use in combination with tyrosine kinase inhibitors optionally selected from one listed above for the treatment of cancer.

[0980] In this document, when the term "combination" is used, it should be understood to mean simultaneous, separate, or sequential application. In one aspect of the invention, "combination" means simultaneous application. In another aspect of the invention, "combination" means separate application. In yet another aspect of the invention, "combination" means sequential application. When applied sequentially or separately, the delayed application of the second component should not result in the loss of the beneficial effects of the combination.

[0981] According to another aspect of the invention, a pharmaceutical composition is provided comprising the compound of the invention or a pharmaceutically acceptable salt or solvate thereof, in combination with an antitumor agent (optionally selected from one listed above), and a pharmaceutically acceptable diluent or carrier.

[0982] Examples

[0983] Inhibitor design and structure-activity relationship

[0984] To design ligands selective for IKKα over IKKβ, their ATP-binding sites were superimposed and compared to determine the specific differences that could be exploited between the two isoforms. When comparing the primary sequences of this region (residues 6–180, IKKα; and 1–180, IKKβ), the level of homology between the two isoforms was striking: 62.8% sequence identity and 77.2% sequence similarity. Both use Met as the GK residue, and GK+1 / GK+3 are Glu and Cys, respectively. Figure 1 However, given the number of structurally diverse compounds reported to bind at or near the ATP-binding site with selectivity for IKKβ over IKKα [1-3], there are significant differences at the two ATP-binding sites that confer this selectivity. To explore these differences, we superimposed the kinase domain of IKKβ with the equivalent domain of IKKα taken from 5EBZ.pdb coordinates using the 4KIK.pdb chain B crystal structure containing two phosphorylated Ser residues in the activation ring [4]. Figure 1To date, no team has been able to successfully crystallize IKKα and report a high-resolution structure, but Polley and colleagues [5] combined X-ray crystallography and single-particle cryo-electron microscopy to generate IKKα structures in both dimer (~150 kDa) and hexamer (~450 kDa) forms at a resolution of 4.5 Å. This was achieved using a recombinant form of the protein in which two Ser amino acids in the activation loop were mutated to Glu residues, thus representing a constitutively activated form of the kinase that can be superimposed on the IKKβ 4KIK crystal structure. Although the resolution of the IKKα structure is lower than that of IKKβ, it is encouraging that it fits very well with our previously reported homology model and successfully guides the design of structure-based inhibitors [6].

[0985] Figure 1 The images show the superposition of IKKα (light gray) and IKKβ (dark gray) ATP-binding sites, taken from 5EBZ.pdb and 4KIK.pdb, respectively. A, Top view of IKKα superimposed on the IKKβ binding site, showing the displacement of the Thr 23 (dark gray) IKKβ G loop from the IKKα position (light gray), indicated by a double-headed red arrow; B, Front view rotated 90° to show the two superimposed isoforms, with the distorted Thr 23-containing G loop of IKKβ shifted towards the N-lobes above the ATP-binding site (double arrows); C, Sequence alignment of amino acid residues at the ATP-binding sites of IKKα and IKKβ (rmsd 1.393), with similarity levels color-coded, as shown in the figure.

[0986] Despite high sequence homology, a key difference between the two isoforms involves the Thr 23-containing G-loop opposite the hinge-binding region, which imposes different topological structures at the site by employing different positions. Figure 1 In IKKα, this G-ring forms a complete wall, surrounding the site on three sides (the third side involves...). Figure 1 The Met 95 GK residues shown on the left of A provide additional binding sites for the ligand ( Figure 2 A, B). In IKKβ, the sequence is twisted and shifted to the upper half of the binding pocket ( Figure 2 C), this removes the wall from the opposite side of the hinge-binding region seen in IKKα, exposing the site to the solvent on both sides. While hydrophilic groups may be accommodated in the solvent region to facilitate binding with IKKβ, the closed wall in IKKα provides a presumed interaction site that can be used to facilitate binding with this isoform. Furthermore, the twisting of the G ring in IKKβ opens the site to the solvent, causing Thr 23 to invade the site itself, creating a barrier protrusion through which any ligand portion entering the solvent region must pass ( Figure 2D). Finally, because IKKβ is exposed to the solvent on both sides, it has only one accessible residue (Asp 102, Figure 2 Compared to IKKα (B), IKKβ has more residues near the site available for ligand binding (Asn 28, Asp 103, Asp 145, Lys 147, Asn 150, and Asp 166). Figure 2 C). In summary, IKKα has a more closed site, opening to the solvent only on the side closest to the hinge, while IKKβ is more open to the solvent on both sides, although the Thr 23 protrusion interrupts the continuous solvent channel from both sides ( Figure 2 D).

[0987] Figure 2 The 3D crystal structures of the ATP binding sites of IKKα and IKKβ are shown (PDB IDs: 5EBZ and 4KIK, respectively). A, Top view of the IKKα binding site, showing the hinge region at the bottom, highlighting GK, GK+1, and GK+3 (Met 95, Glu 96, and Cys 98, respectively) and the top G-ring segment forming the wall opposite the hinge, highlighting Thr 23 and Glu 148; B, Front view of the IKKα binding site rotated 90° from the solvent-accessible region, with the hinge region at the bottom. Asp 102 is the main residue at the edge of this region available for ligand binding; C, Top view of the IKKβ binding site, showing the hinge region at the bottom, in the same position as IKKα, highlighting Met 96, Glu 97, and Cys 99. Thr 23 and Asn 28 from the G-ring are labeled, as are residues along the lips of the two solvent-exposed regions. D, rotated 90° to show a front view of the IKKβ binding site, with the hinge region also at the bottom. The black dashed circle highlights the obstructive protrusion from Thr 23, through which the solvent region shown must be reached, as well as the numerous residues present at the lip edges of the two solvent-exposed regions (Asn 28, Asp 103, Asp 145, Lys 147, Asn 150, and Asp 166). The black circles in B and D show that the equivalent site of Thr 23 in IKKα does not protrude into the site but forms a posterior wall to completely block solvent entry from the top.

[0988] In 2008, an aminoinazole-pyrrolo[2,3-b]pyridine (AIPP) core scaffold was identified as an inhibitor of both IKKα and IKKβ, but its potency was not revealed except for submicromolar activity against both isoforms in cell-free time-resolved FRET assays [7]. In 2017, we identified compound 1 SU909 (pyrrolo[2,3-d]pyrimidine) as a selective inhibitor of IKKα, which summarizes this difference in U2OS cells [6]. To test pyrrolo[2,3-b]pyridine as an alternative scaffold, we used the AIPP core because it has a similar size to 1 SU909, with the HBD / HBA motif located at the scaffold tip, interacting with the hinge region and G ring wall of IKKα, which is the basis for the selective effect we previously proposed. A preliminary set of AIPP derivatives was designed to explore their utility as IKK-targeting scaffolds, while introducing additional functionality that introduces selectivity for IKKα isoforms (2-4 SU1087, SU1266 and SU1253). Figure 3 This was achieved initially through two different approaches: either by attaching the hydrophobic moiety as a fused form to the pyrrolo[2,3-b]pyridine motif to provide tricyclic derivatives 2 and 3 SU1266 and SU1087, or as a phenyl substituent to introduce the flexibility of the central pyrrolo[2,3-b]pyridine motif into 4 SU1253. When IKKα and IKKβ were evaluated using our in-house DELFIA kinase assay [6] (Table 1), all three compounds exhibited excellent inhibitory activity against IKKα (K i 2-3 nM), which is significantly more potent than our previous hit compound 1SU909 (80 nM). However, unlike 1SU909, they exhibit poor selectivity, inhibiting IKKβ (K) at low nanomolar concentrations. i 5-77 nM). This comparable activity against the two isoforms can be explained by our docking studies, in which all three compounds adopted similar postures at the ATP-binding sites of both IKKs. Pyrrolo[2,3-b]pyridine binds to the hinge region of the classic HBA / HBD motif via the GK+3 NH and C=O backbone, while aminoinazole protrudes to the top of the pocket and interacts with the G ring ( Figure 4 A). Notably, in IKKα, the aminoinazole ring forms two HBD / HBA interactions with Thr 23 and Glu 148 in the closed wall at this site, while in IKKβ, these interactions do not exist because the G ring is rotatable and has no equivalent wall. Furthermore, in IKKβ, the entire scaffold clearly shifts towards the solvent-exposed region ( Figure 4B) This allows aminoinazole to form hydrogen bonds with Asp 103, which may compensate for the lack of interaction with the G ring wall and increase the activity to a level comparable to IKKα. In both isoforms, the 2-phenyl moiety is oriented from the hinge toward the exposed solvent region.

[0989] Figure 3 The design principles of the preliminary AIPP test set used in this study are shown. Tricyclic derivatives of AIPP-based scaffolds with fused hydrophobic groups were designed to investigate the effect of coplanarity on bonding (5a, b SU1266 and SU1087). Derivatives with σ-bond spacers separating the hydrophobic groups from the AIPP were designed to evaluate their flexibility (5c SU1253).

[0990] Table 1. K values ​​for the preliminary test sets (5a-c) of IKKα and IKKβ i Value (nM).

[0991]

[0992] Figure 4 4. SU1253 and the predicted binding postures of IKKα (A) and IKKβ (B). A, the pyrrolo[2,3-b]pyridine binding motif points to the hinge region and exhibits two hydrogen bond interactions with Cys 98 (2.02 and 2.14 Å). The aminoindazole binding motif is anchored to the G ring via two hydrogen bond interactions with Thr 23 (2.38 Å) and Glu 148 (2.21 Å), which form the closed wall. The 2-phenyl ring is exposed to the solvent region and exhibits hydrophobic interactions with the nonpolar amino acid residues (Leu 21 and Val 151) at this site; B, 4SU1253 at the IKKβ active site shows the same binding posture as IKKα. The pyrrolo[2,3-b]pyridine ring interacts with Cys 99 in two locations (2.58 and 2.72 Å) in the hinge region, but although the aminoinazole is oriented toward the G ring, it interacts with Asp 103 only in the solvent-exposed region (2.48 Å), which is blocked in IKKα.

[0993] To shift the selectivity spectrum toward IKKα, we opted for structural optimization of 4SU1253 based on the assumption that the σ-bond rotation between the benzene ring and pyrrolo[2,3-b]pyridine would impart the necessary flexibility, allowing it to engage with a neighboring three-dimensional array of residues, thus leveraging the difference between the two isoforms. Furthermore, this would enable the inclusion of portions that can also extend into the solvent, addressing solubility concerns. Small groups (NH2, OH, OMe, OEt, and F) were initially introduced into the benzene ring to evaluate their impact on the selectivity spectra of the two IKKs (5a-g SU1354–SU1373, Table 2). Our goal was to achieve a selectivity ratio of 1:50 for IKKα to IKKβ, with minimal IKKβ inhibition K. i It is 500 nM.

[0994] Table 2. Ka of series 1 compound (5a-aa) to IKKα and IKKβ i value.

[0995]

[0996]

[0997]

[0998] Unsurprisingly, this minor structural change did not improve the selectivity profile, as supported by docking studies. 5a-g SU1354–SU1373 all adopted a similar binding posture to 4 SU1253, with no differential interactions between these substituents and key amino acid residues aligned in the solvent-exposed region. However, crucially, they did not impair activity and provided a handle for further derivatization to introduce substituents containing appropriately positioned HBD and HBA, which could exploit the differences between each isoform (5h-o SU1303–SU1367; Table 2). In this case, a significant difference in activity emerged between the two isoforms, which appeared to be related to the size of the substituents. Docking studies showed that in IKKα, the AIPP core scaffold adopted a new posture as the spatial volume of the substituents attached to the benzene ring increased, essentially a 180° flip from the 4 SU1253 posture, as exemplified by 5o SU1367 (…). Figure 5 A). In this paper, aminoinazole is now located in the hinge region, forming two hydrogen bonds with GK+1, penetrating deep into the binding site ( Figure 5 A), and pyrrolo[2,3-b]pyridine forms hydrogen bonds with Thr 23 and Glu 148 in the G ring wall. The benzene ring and its side substituents point towards the solvent-exposed region and acquire additional HB interactions between the ether handle and Asp 102, potentially demonstrating this reversal (Figure 5 A). It appears that the large substituent attached to the phenyl handle does not allow for the 4 SU1253 posture because the solvent opening near the hinge in IKKα is too narrow to accommodate the large volume. Docking this larger series with IKKβ can explain why the activity decreases but the selectivity increases for this isoform. Notably, no posture is generated where aminoinazole or pyrrolo[2,3-b]pyridine forms a hydrogen bond with GK+1 or GK+3. We attribute this to the Thr 23 protrusion in IKKβ preventing the 5o SU1367 ( Figure 5 A) The inverted posture shown in the example either prevents 4 SU1253 ( Figure 4 The posture B) was adopted. This protrusion prevents the phenyl group and its large side substituents from oriented towards the solvent into the channel while simultaneously binding the HBD / HBA motif to the hinge via conventional kinase binding. The only posture identified for IKKβ involves a hook conformation around the displaced Thr23 protrusion, where the aminoinazole is accessible to the solvent below the G ring, and the phenyl substituent is accessible to the solvent from the hinge, but does not form any HBD / HBA interaction with the hinge region itself. Figure 5 B), which might explain its decline.

[0999] Figure 5 The proposed binding orientation of 5o SU1367 is shown to explain its superior selectivity for IKKα compared to IKKβ (KKα and IKKβ, respectively). i19 and 458 nM). A, Compared to 4 SU1253 in IKKα, a reversed binding orientation was observed. The aminoinazole binding motif points towards the hinge region and shows two interactions with Cys 98 (1.89 and 2.43 Å). The pyrrolo[2,3-b]pyridine ring shows two interactions with Thr 23 and Glu 148 in the opposite closed wall (2.05 and 2.25 Å). The HBA-containing side substituent interacts via hydrogen bonding Asp 102 in the solvent-exposed region (3.31 Å); B, 5o SU1367 did not show any posture of forming conventional hydrogen bonds with the hinge residues through the aminoinazole or pyrrolo[2,3-b]pyridine moiety in IKKβ. Instead, a novel orientation was generated, showing a hook-like posture around the Thr 23 G ring protrusion characteristic of IKKβ. Here, the aminoinazole is oriented towards the solvent on one side of the Thr 23 protrusion, while the bulky side substituent is oriented towards the solvent on the other side of the protrusion, thus forming a hydrogen bond between the ether and Asp 103 (3.34 Å). C, 2D diagram of 5o SU1367 at the IKKα active site, showing the closed wall in the G ring region, which provides additional interaction with the pyrrolo[2,3-b]pyridine binding motif. Hydrogen bonds with key residues are shown as dashed lines; D, 2D diagram of 5o SU1367 at the IKKβ active site, illustrating the hook-like posture around the Thr 23 protrusion, which separates the two solvent-exposed regions. In this posture, there are no hydrogen bonds on the hinge residues, which could explain the poor affinity of the compound with the bulky hydrophobic substituent for IKKβ.

[1000] Since compounds with larger phenyl-side substituents (5n, o SU1550 and SU1367) tend to exhibit improved selectivity, we began to explore whether increasing the steric volume could further enhance the window. We integrated a series of moieties with different saturations, each with a different HBA and HBD (5p-aa SU1278 – SU1283), to further develop SAR and selectivity spectra. With increasing steric volume, the observed overall trend was a more pronounced decrease in IKKβ activity, while the potency of IKKα generally remained unchanged, resulting in a significant improvement in selectivity across the entire series. The docking results for these compounds are consistent with our earlier observations: binding to IKKα inevitably reverts to a flipped posture, where the aminoinazole is coupled with the hinge region of each more sterically hindered analogue (5r SU1261, ...). Figure 6A) Binding. Furthermore, increasing the volume of the phenyl substituent generally prevents any effective binding of the aminoinazole or pyrrolo[2,3-b]pyridine in IKKβ to the hinge region, except for the unfavorable hook conformation observed in 5o SU1367 around the displaced Thr 23 protrusion, and the absence of hydrogen bonding with the hinge region. This posture is consistent with those compounds exhibiting the lowest activity towards IKKβ (5o-r, t, w SU1367, SU1278, SU1549, SU1353, SU1324, and SU1261).

[1001] Figure 6 The predicted 3D binding postures of 5r SU1261 with IKKα (A) and 5x SU1335 with IKKβ (B) are shown. In A, the aminoindazole binding motif of 5r SU1261 is located in the hinge region of IKKα, exhibiting two key interactions with Cys 98 (1.99 and 2.56 Å), while pyrrolo[2,3-B]pyridine is located on the opposite G ring, exhibiting two key interactions with Thr 23 (2.04 Å) and Glu 148 (2.39 Å). Similar to 5o SU1367, the side benzene ring is located in the solvent-exposed region, and the benzyl ether oxygen atom is hydrogen-bonded to Asp 102 (2.52 Å); B, in IKKβ, 5x SU1335 is observed to exhibit a hook-like binding posture, with the aminoindazole moiety interacting with Thr 23 (2.65 Å), Gly 24 (3.04 Å), and Asn 28 (2.00 Å). Notably, an additional interaction (2.99 Å) is observed between the terminal polar pyran group and Lys 106, which compensates for the lack of hydrogen bonding with the hinge region in IKKβ.

[1002] Despite increased steric hindrance, many analogues do indeed exhibit good IKKβ inhibition, such as 5l, m, x, y SU1317, SU1316, SU1335, and SU1336. Notably, these derivatives all possess terminal polar groups in their side phenyl substituents, although docking studies consistently revert to the hook-like posture described in IKKβ for 5o, t, p, q, w SU1367, SU1278, SU1549, SU1353, SU1324, and SU1261 (and in... Figure 5 (Taking 5o SU1367 as an example in B), but these terminal groups can form additional hydrogen bond interactions: for 5x SU1335, it is a hydrogen bond interaction with the protonated Lys106 residue ( Figure 6B); for 5y SU1336 located in the solvent-exposed region, it interacts with the Tyr98 side chain via hydrogen bonding. We propose that these additional interactions can compensate for those not observed in the hinges of 5o, t, p, q, w SU1367, SU1278, SU1549, SU1353, SU1324, and SU1261, to explain the enhanced activity against IKKβ.

[1003] Shifting the phenyl-side substituent to the para position (e.g., 5s, u SU1334, and SU1283) tends to increase the activity of IKKβ, thereby reducing selectivity, and is therefore not widely adopted. From a docking perspective, the change in ligand geometry caused by para-substitution produces a new posture in IKKβ, which can explain the increase in activity. Here, the aminoinazole is positioned along the hinge region, forming a hydrogen bond with GK+1, the pyrrolo[2,3-b]pyridine is close to the solvent near the hinge, and the para-substituted benzene ring extends upward into the solvent-exposed region below the G ring, forming additional hydrogen bonds with the Thr 23 protrusion via ether (5s SU1334) or sulfonamide (5u SU1283). Both compounds adopt the inverted posture commonly observed in this series for IKKα.

[1004] Having established the basic principles of selectivity, our next step was to attempt to improve the physicochemical properties of this series (6a–l SU1371–1621, Table 3) by introducing solubilizing groups and additional heteroatoms into the central benzene ring. 5r SU1261 was chosen as the starting point for optimizing this series because its activity and selectivity can be reproduced in cells. The introduction of polar functional groups and additional nitrogen atoms was explored to reduce lipophilicity and improve water solubility. Modifications such as linker length extension, heteroatom selection, and arrangement were also explored to see if the potency and specificity of the ligands could be further improved.

[1005] Table 3. Ki of series 2 compounds (6a–l) to IKKα and IKKβ i value.

[1006]

[1007]

[1008]

[1009] The addition of heteroatoms and polar moieties generally maintains the potency against IKKα and reduces the inhibition against IKKβ, which ultimately improves the selectivity of these analogues. Again, similar to previous docking results, the large meta-substituents on the benzene ring are located in the same solvent-exposed orientation in IKKα, allowing for significant interactions between the AIPP core and the hinge and G ring walls in the flipped posture to promote efficient inhibition (6 g SU1349, Figure 7 A). Furthermore, most analogues exhibit poor activity towards IKKβ, which can usually be explained by computer simulations: such as Figure 5 The common, unfavorable hook conformation shown in 5o SU1367 in B and D is mainly reproduced in IKKβ and is not hydrogen-bonded with the hinge.

[1010] Figure 7 The 3D interaction between the proposed 6g SU1349 (A) and 6c SU1365 (B) and the IKKα active site is shown. A, 6g SU1349 has an aminoinazole motif located in the hinge region, showing two hydrogen bond interactions with Cys 98 (2.00 and 2.62 Å), pyrrolo[2,3-b]pyridine is hydrogen bonded to Thr 23 (2.04 Å) and Glu 148 (2.46 Å), and the ether shows an HB interaction between the oxygen atom and Asp 102 (2.49 Å); B, 6c SU1365 has an aminoinazole motif located in the hinge region, showing two interactions with Cys 98 (1.90 and 2.39 Å), pyrrolo[2,3-b]pyridine interacts with the G ring wall through Thr 23 (2.02 Å) and Glu 148 (2.26 Å). The side benzene ring is located in the solvent-exposed region and forms a π-anionic interaction (2.52 Å) with Asp 102, while the benzyl ether oxygen atom is hydrogen-bonded to Asp 102 (2.75 Å). Additional solubilizing alkyl ether substituents are accommodated in the solvent-exposed region.

[1011] Compounds with auxiliary solubilizing long-chain polar groups (6b, c SU1358 and SU1365) exhibit similar selectivity spectra, which can be explained by our model. The solvent exposure region in IKKα is large enough to allow them to consistently adopt a standard flipped posture in the inhibition-related series (6c SU1365, ...). Figure 7 B). In IKKβ, the increased spatial volume resulting from the double substitution arrangement in the two orbitals cannot accommodate the Thr 23 protrusion under any conditions, and no feasible bonding posture is produced.

[1012] While the addition of heteroatoms and polar moieties generally preserves selectivity for these analogues, there is one exception: 6k SU1628 exhibits effective suppression of IKKβ despite a large substituent on the benzene ring. However, this substituent is a polar pyridyl group, which reproduces the poor selectivity observed in 5l, m, x, y SU1317, SU1316, SU1335, and SU1336, all of which contain hydrogen-bonded side groups. Furthermore, 6k SU1628 exhibits a similar docking posture and additional hydrogen-bonded interactions with Lys 106 are observed, which helps improve the affinity for the unfavorable hook posture. Figure 8 These data suggest that to maintain selectivity, bulky substituents with terminal polar functional groups (which can form hydrogen bonds with IKKβ isoforms) should be avoided. Finally, the para-substituted analog 6d SU1350 also showed reduced selectivity and reproduced the docking posture observed in 5s, u SU1334, and SU1283.

[1013] Figure 8 The 3D binding posture of 6kSU1628 with IKKβ is shown. A common hook-like binding posture is observed, with the aminoindazole moiety hydrogen-bonded to Thr 23 (2.64 Å) and Asn 28 (2.12 Å), but without interaction with the hinge residues. However, an additional interaction (2.44 Å) is observed between the terminal pyridinyl nitrogen and Lys 106, which compensates for the lack of hydrogen bonding with the hinge.

[1014] Chemical

[1015] The synthetic strategy for obtaining the compounds described herein begins with the organoiridium (I)-catalyzed CH activation of commercially available fluorobenzonitrile 7 to produce borate intermediate 8 (Scheme 1) [8]. Cyclic closure is then performed using hydrazine, which is carried out by nucleophilic aromatic substitution at the aryl fluoride and nucleophilic attack at the nitrile carbon, to obtain the key aminoindazole intermediate 9 (Scheme 1). The final step in the preparation of the first group of AIPP derivatives 2–4 is the Suzuki-Miyaura cross-coupling between borate intermediate 9 and commercially available pyrrolo[2,3-b]pyridine aryl chlorides 10–12 (Scheme 1) [9].

[1016]

[1017] Scheme 1. Reagents and conditions. a, B2Pin2, dtbbpy, [Ir(OMe)(1,5-cod)]2, MTBE, 80℃, 18h; b, hydrazine hydrate, EtOH, reflux, 30h; c, PdCl2(dtbpf), K3PO4, EtOH / H2O, 120℃, 20h.

[1018] Compound 5 was prepared via the same route as in the first group of compounds 2–4 (Scheme 2). Aryl chloride 15 was prepared by an additional Suzuki reaction of 4-chloro-2-iodo-pyrrolo[2,3-b]pyridine (13) with a series of borates 14 (Scheme 2), achieving selectivity at the 2-position of pyrrolo[2,3-b]pyridine by leveraging the reduced reactivity of aryl chlorides within the same skeleton compared to aryl iodides

[10] . By carefully selecting catalytic systems with different activities, namely triphenylphosphine palladium catalysis at the iodide site followed by chlorine-directed palladium catalysis using ferrocene ligands, the two Suzuki coupling reactions were carried out sequentially and selectively. Many of these pyrrolo[2,3-b]pyridines were further functionalized prior to final coupling; specifically, anilines 15c and 15ac underwent alkylation conditions to provide amide and sulfonamide intermediates 15l, 15t, and 15u, carboxylic acid 15h was functionalized by forming an amide bond to provide intermediate 15m, and the benzaldehyde functionalized handle of 15ab underwent reductive amination to produce amines 15n and 15p. As previously described, final coupling was carried out between the synthesized aryl halide 15 and borate 9 to give the final compound 5 shown in Table 3, with varying degrees of steric volume (Scheme 2).

[1019]

[1020] Option 2. Reagents and conditions. a, K2CO3, PdCl2(PPh3)2, dioxane / H2O, 100℃, 20 h; b, (15l) 3-methoxypropionic acid, HCTU, Et3N, DMF, rt, 18 h; (15m) 2-methoxyethylamine, HCTU, Et3N, DMF, rt, 18 h; (15n) cyclopentylamine, STAB, AcOH, DMA, rt, 48 h; (15p) aniline, STAB, AcOH, DMA, rt, 48 h; (15t) TsCl, Et3N, DCM, 0℃ – rt; (15u) TsCl, Et3N, DCM, 0℃ – rt, 18 h; c, PdCl2(dtbpf), K3PO4, EtOH / H2O, 120℃, 20 h.

[1021] Considering the design of analogs 6a–i aimed at improving solubility, their synthesis followed a similar route as described above. The selected phenyl and pyridylboronic acid 16a–i was coupled to the aryl iodine moiety of 13 to give intermediate 17. Subsequently, by coupling with the Suzuki of the key intermediate 9, the scaffold was modified at the chlorine moiety to obtain compound 6 (Scheme 3).

[1022]

[1023] Scheme 3. Reagents and conditions. a, K2CO3, PdCl2(PPh3)2, dioxane / H2O, 100℃, 20 h; b, PdCl2(dtbpf), K3PO4, EtOH / H2O, 120℃, 20 h.

[1024] The intermediates in the route for synthesizing compound 6j–l require custom synthesis, which begins with commercially available disubstituted pyridine 18 (Scheme 4). In the case of 20a, via benzyl bromide S… N Intermediate 20 was prepared by 2-halogen substitution, or by nucleophilic aromatic substitution of aromatic fluorides in the cases of 20b and 20c, and then subjected to Suzuki-Miyaura borylation conditions to give intermediate 21 (Scheme 4)

[11] . Intermediate 23 was obtained by using a protecting group strategy to aid purification, and then iodinated with methoxymethyl (MOM) chloride or tert-butoxycarbonyl (Boc) anhydride, followed by lithium-halogen exchange with n-butyllithium to give protected intermediate 24. These compounds were then sequentially Suzuki coupled with borate ester 21 at the 2- and 4-halogen moieties to first generate intermediate 25, and then borate ester 9 to generate the final target compound 6j–l (Scheme 4).

[1025]

[1026] Scheme 4. Reagents and conditions. a, (20a) Cs2CO3, DMF, 0℃ – rt, 4 h; (20b,c) KOt-Bu, THF, 0℃ – rt, 4 h; b, B2Pin 2、 Pd(dppf)Cl2, KOAc, dioxane / H2O, 110℃, 18 h. c, (23a) K2CO3, MOMCl, DMF, 0℃ – rt, 18 h; (23b) DMAP, Boc2O, DMF, rt, 18 h; d, n-BuLi, I2, THF, -78℃ – rt, 2 h; e, PdCl2(dtbpf), Cs2CO3, dioxane / H2O, 80℃, 18 h; f, Compound 9, PdCl2(dtbpf), Cs2CO3, dioxane / H2O, 110℃, 18 h; (6j) HCl / MeOH, reflux, 8 h; (6k,l) TBAF, THF, reflux, 8 h.

[1027] Physicochemical / DMPK Analysis

[1028] Next, we studied a series of compounds using the open-source software package Datawarrior, which can be used to generate and analyze physicochemical properties. First, according to IKKα K... i < 40 nM and IKKβ K i >500 nM plotted inhibition maps of compounds on IKKα and IKKβ, including the initial dataset filter ( Figure 9 A).

[1029] Figure 9 Graphical correlations between activity and calculated physicochemical properties are shown. A, IKKα vs. IKKβ selectivity analysis. Compounds with superior potency and selectivity spectra are highlighted in dark gray; B, physicochemical property analysis. Compounds with superior potency and selectivity spectra are highlighted in blue.

[1030] By applying an initial filter based on potency and selectivity, the data can be sorted according to the following key physicochemical properties: CLog P, topological polar surface area (tPSA), and ligand efficiency (LE), with compounds exhibiting sufficient potency and selectivity highlighted in dark gray. Figure 9 B).

[1031] After removing compounds with poor selectivity spectra, the filtered data points fall within a narrow region of chemical space, with CLog P values ​​of approximately 3.5 to 4.5 and 100 to 120 Å. 2 tPSA (at 90 and 140 Å) 2 There were two outliers), and the LE value was close to the ideal baseline of 0.3 required for further development. All compounds that met our selectivity and potency criteria had large hydrophobic meta-substituents, and seven of the nine derivatives contained benzyl ethers or thioethers and pyridinyl groups. The most notable example was 6g SU1349, which showed 209 times greater selectivity for IKKα than for IKKβ. Figure 10 ).

[1032] Figure 10 The physicochemical properties analysis is shown.

[1033] Modify 5r SU1261 to Figure 10The derivatives in this series, while generally improving selectivity, only slightly improved solubility (Table 4), despite the introduction of solubilizing ether groups used in the development of erlotinib (6b, c SU1358, and SU1365). The problem for further research on this series lies here: to date, introducing polar functional groups into side groups exposed to solvents has improved solubility but significantly impaired the in vitro biochemical selectivity of IKKα (see above). This is clearly demonstrated by comparing 6g SU1349 and 6k SU1628—the latter possessing the necessary solubility but equal potency for both isoforms, while the former exhibits a basic selectivity profile but poorer solubility. However, despite its lower solubility compared to 6k SU1628, 6g SU1349 has the highest solubility among the series exhibiting selectivity, and furthermore, it has a sufficiently low in vitro mouse clearance for in vivo PK evaluation (Table 5).

[1034] Table 4. Turbidity solubility and mouse hepatocyte clearance of compounds selected from the series.

[1035]

[1036] Table 5. In vivo mouse PK parameters of 6g SU1349.

[1037]

[1038] We performed kinaseomic analysis on three compounds in this series. Figure 11 Our initial pan-IKK inhibitor, 4 SU1253, proved highly promiscuous, exhibiting >80% inhibition against 44 of the 231 kinase groups at 1 μM. The introduction of a side benzyloxy substituent into 5r SU1261 significantly reduced off-target kinase inhibition against 10 kinases (>80% at 1 μM), most notably CDK5, CDK9, haspin, and the activating kinases MKK7β and PRAK. Interestingly, replacing the 2-phenylpyrrolo[2,3-b]pyridine substituent in 5r SU1261 with the 2-pyridin-4-yl group in 6g SU1349 not only improved solubility and scavenging but also significantly reduced off-target inhibition of MKK7β and PRAK, although not CDK5 and CDK9. To determine the structural drivers of CDK inhibition, we obtained the X-ray crystal structures of 5y and 6g SU1336 and SU1349 with CDK-2. Figure 12A) to potentially identify possible pathways for introducing selectivity for IKKα compared to CDK enzymes and IKKβ. The active sites of CDK2 and CDK9 are comparable to those of IKKβ; in a sense, they have accessible pockets that are readily open to the solvent on both sides. Furthermore, they lack an equivalent Thr 23 protrusion, resulting in a larger volume to accommodate bulky substituents while allowing hydrogen bonding to the hinge residues ( Figure 13 All three derivatives form a complex with CDK2, with pyrrolo[2,3-b]pyridine hydrogen-bonded to GK+3 (Leu 83), and aminoinazole protruding toward the G ring ( Figure 12 A), forming hydrogen bonds with Glu 51 and Lys 33 at the rear of the pocket. π stacking between aminoinazole and GK residues may contribute to the 4 SU1253 orientation, rather than the flipped posture observed in IKKα, which is Phe instead of Met in CDK. Notably, the position of the side chain changes significantly depending on the nature of the substituents and potential interactions. For 6g SU1349, the hydrophobic side chain benzyloxy group points towards the solvent but can engage in edge-facing π-π interactions with the hinge's Phe 82 and His 84. Replacing the hydrophobic side chain benzyloxy group in 5y SU1336 with a substituent containing a morpholinoethyl eliminates any direct interaction with these hinge residues, instead favoring a position more exposed to the solvent. This posture change is consistent with the characteristics of basic side chains protonated at physiological pH. Figure 12 B).

[1039] Figure 11 The images show the kinases that exhibited significant % inhibition against a group of 253 kinases at 1 μM, represented by 4 SU1253, 5r SU1261, and 6g SU1349. Black represents 4 SU1253; gray represents 5r SU1261; and diagonal stripes represent 6g SU1349. 4 SU1253 showed >80% inhibition against all 46 kinases shown. Compared to 6g SU1253, 5r SU1261 inhibited fewer kinases (showing >80% inhibition against 10 kinases). 6g SU1349 showed significantly reduced off-target inhibition (>80% inhibition against only 4 kinases). All compounds tested (4 SU1253, 5r SU1261, and 6g SU1349) inhibited CDK5 and CDK9 by >80%.

[1040] Figure 12Display: A, Crystal structure of 15g SU1349 containing CDK2. The aminoinazole moiety points to the G ring, forming HB with Glu51 and Lys33 (3.09 and 2.92 Å, respectively). The pyrrolo[2,3-b]pyridine in the hinge region is hydrogen-bonded to Leu83 (2.94 Å). The side benzyl ether is located in the solvent-exposed region flat along the protein wall, forming π-π interactions with Phe82 and His84. B, Overlapping crystal structures of 13k SU1336 and 15g SU1349 with CDK2. Although the AIPP motif occupies a similar position within the ATP of both compounds, the morpholinoethyl side chain of 13k SU1336 occupies a completely different position than the benzyloxy group of 15g SU1349. In the former case, this basic side chain is fully exposed to the solvent, rather than interacting with specific residues in the kinase.

[1041] Figure 13 The sequence alignment of amino acid residues at the ATP-binding sites of IKKα (residues 10-180), CDK2 (residues 5-150), and CDK9 (residues 20-180) is shown (RMSD 1.081 and 1.634). Homology analysis revealed 16.3% sequence identity and 40.1% sequence similarity among the three kinases (IKKα, CDK2, and CDK9), with similarity levels color-coded as shown in the figure.

[1042] A key observation about these CDK complexes is the presence of lipophilic pocket side chains between the hinge and the adjacent solvent-exposed region, consisting of side chains from Ile 10, Phe 82, and Leu 134. In CDK9, an equivalent hydrophobic pocket is formed by Ile 25, Phe 105, and Leu 156. The spatial positioning of these residues is highly ideal, allowing for π-alkyl and π-σ interactions with the central 2-phenyl / pyridyl ring in this series of compounds. These additional interactions are possible in our compound series and, when combined with hydrogen-bonded interactions that anchor the central AIPP core to the hinge region, provide a potential explanation for the observed off-target activity against CDK isoforms.

[1043] Experimental Section

[1044] Routine. Unless otherwise specified, all commercially available reagents and solvents used were obtained from Sigma-Aldrich, Fluorochem Fisher Scientific, Acros, Alfa Aesar, Apollo Scientific, and AdvancedChemBlocks and were ready for use without further purification. Reactions sensitive to air or moisture were carried out under an argon or nitrogen atmosphere. Microwave reactions were performed using the Biotage initiator system. Thin-layer chromatography (TLC) was performed on aluminum-backed SiO2 plates (Merck, silica gel 60, F). 254Spots were visualized using ultraviolet light (254 nm) or by staining with potassium permanganate. Unless otherwise specified, all tested compounds were determined to be ≥95% pure by LC-MS and analytical HPLC. Rapid chromatography was performed using a Biotage SP4 automated chromatography system with a silica stationary phase (Fisher Scientific, 60 Å, 35–70 μm; detection wavelength: 254 nm; monitoring: 280 nm), and the mobile phase used is described in detail in the text. Reversed-phase HPLC purification was performed at 40 °C on a Shimadzu Prominence HPLC system using a semi-preparative (50 × 21.2 mm) Luna 5 µm C18 column; flow rate: 6 ml / min; detection wavelength: 254 nm; elution with an acetonitrile / water gradient containing 0.1% TFA. NMR spectra were recorded on Bruker Avance3 / DPX400 (400 MHz), Bruker DRX500 (500 MHz), Bruker AV400 (400 MHz), Bruker AV500HD (500 MHz), or Bruker AV600 (600 MHz) instruments and analyzed using Advanced Chemistry Development Labs (ACD / labs) NMR Processor 12.00 or MestReNova 10.0 software. Chemical shifts (δ) were recorded in parts per million (ppm) relative to an internal solvent reference (tetramethylsilane), and coupling constants (J) were recorded in Hertz (Hz). Splitting modes were represented as singlets (s), broad singlets (br s), doublets (d), twin doublets (dd), triplets (t), quartets (q), and multiplets (m). LCMS was performed in ESI / APCI mode on an Agilent Technologies 1220 series LC system and an Agilent 6100 series quadrupole mass spectrometer. Separation was achieved using an Agilent Eclipse C18 4.6 x 50 mm column; flow rate: 1 ml / min; detection: 254 nm; sample volume: 10 µl; mobile phase: acetonitrile / 5 mM ammonium acetate: water / 5 mM ammonium acetate; 5%, 1.48 min; 5–100%, 8 min; 100%, 13.5 min; 100–5%, 16.5 min; 18 min. HRMS was performed on an Exactive (Thermo Scientific) or LTQ orbital trap (Thermo Scientific).

[1045] Synthesis of 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)benzonitrile (8). A solution of bis(pinacolyl)diboron (1.3 g, 5.2 mmol), 4,4'-di-tert-butyl-2,2'-bipyridine (43 mg, 0.16 mmol), and (1,5-cyclooctadiene)(methoxy)iridium(I) dimer (106 mg, 0.16 mmol) in an anhydrous MTBE (10 mL) solution in a sealed vial (20 mL) was stirred at room temperature for 1 hour. A solution of 2-fluorobenzonitrile (1, 0.6 g, 5 mmol) in anhydrous MTBE (1 mL) was added. The reaction mixture was stirred at 80 °C for 18 hours. The reaction mixture was cooled, filtered through diatomaceous earth, and evaporated under reduced pressure. The crude residue was used in the next step without further purification.

[1046] Synthesis of 5-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-1H-indazole-3-amine (9). Hydrazine hydrate (2.4 mL, 2.47 g, 39 mmol, 50-60%) was added to a solution of compound 8 (1.98 g, 8 mmol) in ethanol (100 mL), and the reaction was refluxed for 30 hours. The solvent was evaporated under reduced pressure. The residue was prepared with a mixture of ethyl acetate and petroleum ether (1:1, 12 mL), filtered, and washed with water and 60-80% petroleum ether to give title product 3 as a yellow solid (1.4 g, 67%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 12.70 (s, 1 H), 8.17 (s, 1 H), 7.49 (d, J=8.35 Hz, 1 H), 7.18 (d, J=7.91 Hz, 1 H), 5.46 (s, 2 H), 1.30 (s, 12 H). 13 CNMR (100 MHz, DMSO-d6) δ ppm 150.34, 143.38, 132.01, 129.35, 114.66, 109.23,83.74, 25.31. LC-MS: C 13 H 18 The calculated exact mass of BN3O2 is 259.12, while the measured mass is 260.1 (M+1). + .

[1047] General procedure for the synthesis of 5-(substituted pyridin-4-yl)-1H-indazole-3-amine (2–4). A solution of K3PO4 (1 M, 0.88 mL) was added to a suspension of 4-chloro-pyridine derivative (10–12, 0.35 mmol), compound 9 (0.136 g, 0.525 mmol), and [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) catalyst (0.011 g, 0.0175 mmol) in EtOH (1 mL) and water (1 mL). The reaction mixture was heated to 120 °C and maintained for 20 h. The reaction mixture was cooled, diluted with EtOAc, and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude residue was purified by column chromatography (10% methanol in ethyl acetate) to give the title product (2–4).

[1048] 5-(6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl)-1H-indazole-3-amine (2). Beige solid (73 mg, 69%). 1 H NMR (400 MHz, DMSO-d6) δ 11.46 (s, 1H), 11.27 (s, 1H), 8.07 (d,J = 4.9 Hz, 1H), 7.78 (s, 1H), 7.33 (d, J = 8.6 Hz, 1H), 7.29 (d, J = 8.6 Hz,1H), 6.86 (d, J = 4.9 Hz, 1H), 5.43 (s, 2H), 2.71 (t, J = 5.8 Hz, 2H), 2.20(t, J = 5.2 Hz, 2H), 1.81 – 1.77 (m, 2H), 1.66 – 1.50 (m, 2H). HRMS (ESI):C 18 H 17 The calculated exact mass of N5 is 303.1552, while the measured mass is 304.1557 (M+1). + .

[1049] 5-(9H-pyrido[2,3-b]indol-4-yl)-1H-indazole-3-amine (3). White powder (36 mg, 35%). 1HNMR (400 MHz, DMSO-d6): δ 11.90 (br s, 1H), 11.62 (br s, 1H), 8.44 (d, J = 5.0Hz, 1H), 8.05 (s, 1H), 7.57 (d, J = 8.1 Hz, 1H), 7.54 (dd, J = 8.7, 1.4 Hz, 1H), 7.51 (d, J = 8.1 Hz, 1H), 7.44 (d, J = 8.5 Hz, 1H), 7.42-7.38 (m, 1H), 7.11 (d, J= 5.0 Hz, 1H), 7.02-6.98 (m, 1H), 5.47 (br s, 2H). LC-MS: C 18 H 13 The calculated precise mass of N5 is 299.12, while the actual measured mass is 300.3 (M+1). + .

[1050] 5-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine (4). Grayish-white solid (50 mg, 44%). 1 H NMR (500 MHz, DMSO-d6) δ 12.27 (s, 1H), 12.05 (s, 1H), 8.27 – 8.24(m, 2H), 7.99 (d, J = 8.5 Hz, 1H), 7.74 (s, 1H), 7.55 – 7.49 (m, 2H), 7.40 –7.34 (m, 3H), 7.22 (d, J = 8.5 Hz, 1H), 7.17 (d, J = 1.9 Hz, 1H), 5.73 (s, 2H).

[1051] General procedure for the synthesis of 4-chloro-2-(substituted phenyl)-1H-pyrrolo[2,3-b]pyridine (15a–ac). A suspension of 4-chloro-2-iodo-7-azaindole (0.343 g, 1.23 mmol), substituted phenylboronic acid (14a–ac, 1.52 mmol), K₂CO₃ (0.483 g, 3.49 mmol), and bis(triphenylphosphine)palladium(II) chloride (0.074 g, 0.105 mmol) in dioxane (3 mL) and water (2 mL) was degassed under nitrogen. The reaction mixture was stirred at 100 °C for 20 h. The reaction mixture was cooled to room temperature and extracted between EtOAc (5 mL) and water (3 mL). The organic layer was washed with brine (2 × 3 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Unless otherwise stated below, the crude residue was used for the next step without further purification.

[1052] 4-Chloro-2-(2-ethoxyphenyl)-1H-pyrrolo[2,3-b]pyridine (15b). The solid obtained was purified by recrystallization using DCM and hexane to give the title compound as an orange solid (207 mg, 62%). 1 H NMR (DMSO-d6): δ 12.13(br s, 1H), 8.17 (d, J = 5.2 Hz, 1H), 7.89 (dd, J = 1.6, .6 Hz, 1H), 7.39 –7.36 (m, 1H), 7.19 (d, J = 5.2 Hz, 1H), 7.16 (s, 1H), 7.08 – 7.06 (m, 2H), 4.21 (q, J = 6.9 Hz, 2H), 1.46 (t, J = 7.0 Hz, 3H).

[1053] 3-(4-chloro-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-fluorophenol (15f). The resulting solid was purified by column chromatography (90% EtOAc in petroleum ether) to give the title compound as a yellow solid (69 mg, 21.5%). 1 H NMR(DMSO-d6): δ 12.50 (br s, 1H), 10.13 (s, 1H), 8.19 (d, J = 4.8 Hz, 1H), 7.30 (dt, J = 1.8, 10.0 Hz, 1H), 7.23 – 7.21 (m, 2H), 6.98 (d, J = 2.4 Hz, 1H), 6.59 (dt, J = 2.2, 10.4 Hz, 1H). LC-MS: C 13 H835 The calculated exact mass of ClFN2O is 262.03, while the measured mass is 263.13 (M+1). + .

[1054] N-(3-(4-chloro-1H-pyrrolo[2,3-b]pyridin-2-yl)phenyl)methanesulfonamide (15j). The crude solid was purified by column chromatography (90% EtOAc in petroleum ether) to give the title compound as a pale yellow solid (0.216 g, 64.7%). 1 HNMR (DMSO-d6): δ 12.62 (br s, 1H), 9.88 (br s, 1H), 8.19 (d, J = 5.2 Hz, 1H), 7.75 – 7.71 (m, 2H), 7.45 (t, J = 16.0 Hz, 1H), 7.22 – 7.20 (m, 2H), 6.88 (d,J= 2.0 Hz, 1H), 3.10 (s, 3H). HRMS (ESI):C 14 H 13 O2N3 35 The exact mass calculated by ClS is 322.0412, while the measured mass is 322.0410 (M+1). + .

[1055] 4-Chloro-2-(3-(methanesulfonyl)phenyl)-1H-pyrrolo[2,3-b]pyridine (15k). The resulting solid was purified by column chromatography (90% EtOAc in petroleum ether) to give the title compound as a grayish-white solid (245 mg, 62%). 1 H NMR(DMSO-d6): δ 12.73 (br s, 1H), 8.56 (t, J = 1.6 Hz, 1H), 8.35 (dt, J = 1.2,8.2 Hz, 1H), 8.24 (d, J = 5.3 Hz, 1H), 7.92 (dt, J = 1.2, 8.2 Hz, 1H), 7.77(t, J = 7.8 Hz, 1H), 7.26 (dd, J = 5.0 Hz, 1H), 7.24 (s, 1H), 3.33 (s, 3H). LC-MS: C 14 H 12 35 The calculated precise mass of ClN3O2S is 321.03, while the measured mass is 322.3 (M+1). + .

[1056] 4-Chloro-2-(3-isobutoxyphenyl)-1H-pyrrolo[2,3-b]pyridine (15°). The solid obtained was purified by recrystallization using DCM and hexane to give the title compound as an orange solid (166 mg, 45%). 1 H NMR (DMSO-d6): δ12.48 (br s, 1H), 8.17 (d, J = 5.2 Hz, 1H), 7.58 (s, 1H), 7.56 (s, 1H), 7.37(t, J = 8.0 Hz, 1H), 7.20 (d, J = 5.2 Hz, 1H), 7.04 (d, J = 2.4 Hz, 1H), 6.94– 6.92 (m, 1H), 3.85 (d, J = 6.4 Hz, 2H), 2.08 – 2.05 (m, 1H), 1.02 (d, J =6.4 Hz, 6H).

[1057] 2-(2-(benzyloxyphenyl)-4-chloro-1H-pyrrolo[2,3-b]pyridine (15q). The resulting solid was prepared with hexane and Et2O to give the title compound as a light-colored solid (378 mg, 92%). 1 H NMR (DMSO-d6): δ 12.19 (br s,1H), 8.18 (d, J = 7.5 Hz, 1H), 7.92 (dd, J = 2.0, 8.8 Hz, 1H), 7.54 (d, J =7.5 Hz, 1H), 7.42 (t, J = 7.0 Hz, 1H), 7.36 – 7.34 (m, 2H), 7.28 (d, J = 8.5Hz, 1H), 7.17 (d, J = 5.0 Hz, 1H), 7.09 (t, J = 7.5 Hz, 1H), 7.06 (s, 1H), 5.32 (s, 2H).

[1058] 3-(4-chloro-1H-pyrrolo[2,3-b]pyridin-2-yl)phenyl)(4-methylpiperazin-1-yl)methyl ketone (15 v). The resulting solid was prepared with hexane and filtered through a diatomaceous earth pad, concentrated under reduced pressure and dried to give the title compound as a light-colored solid (405 mg, 93%). 1H NMR (DMSO-d6): δ 12.57 (br s, 1H), 8.19 (d, J = 4.0 Hz, 1H), 8.08 (d, J = 6.8 Hz, 1H), 8.00 (s, 1H), 7.55 (t, J = 6.2 Hz, 1H), 7.37 (d, J= 6.0 Hz, 1H), 7.22 (d, J = 4.0 Hz, 1H), 7.11 (s, 1H), 3.66 (br s, 2H), 3.36(br s, 2H), 2.39 (br s, 2H), 2.23 (br s, 2H), 2.21 (s, 3H).

[1059] 4-Chloro-2-(3-(pyridin-2-ylmethoxy)phenyl)-1H-pyrrolo[2,3-b]pyridine (15w). The crude residue was purified by column chromatography (90% EtOAc in petroleum ether) to give the title compound as a brown solid (380 mg, 92%). 1 HNMR (400 MHz, DMSO-d6) δ 12.52 (s, 1H), 8.60 (d, J = 4.6 Hz, 1H), 8.18 (d, J= 5.2 Hz, 1H), 7.88 – 7.84 (m, 1H), 7.73 (s, 1H), 7.61 (d, J = 7.7 Hz, 1H),7.58 (d, J = 7.8 Hz, 1H), 7.45 – 7.37 (m, 1H), 7.36 (d, J = 7.2 Hz, 1H), 7.21(d, J = 5.2 Hz, 1H), 7.06 – 7.03 (m, 2H), 5.30 (s, 2H). LC-MS: C 19 H 14 35 The calculated exact mass of ClN3O is 335.08, while the measured mass is 336.1 (M+1). + .

[1060] 2-(3-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)-4-chloro-1H-pyrrolo[2,3-b]pyridine (15x). The crude residue was prepared with a petroleum ether solution of 50% EtOAc to give the title product as a brown solid (336 mg, 80%). 1HNMR (400 MHz, DMSO-d6) δ 12.51 (s, 1H), 8.17 (d, J = 5.2 Hz, 1H), 7.58 – 7.56 (m, 2H), 7.39 – 7.35 (m, 1H), 7.20 (d, J = 5.2 Hz, 1H), 7.05 (d, J = 2.0 Hz,1H), 6.94 (d, J = 7.2 Hz, 1H), 3.93 (d, J = 6.8 Hz, 2H), 3.89 (dd, J = 11.2,2.8 Hz, 2H), 3.37 (dd, J = 12.4, 1.6 Hz, 2H), 2.08 – 2.00 (m, 1H), 1.72 (d, J= 11.6 Hz, 2H), 1.42 – 1.31 (m, 2H). LC-MS: C 19 H 19 35 The calculated exact mass of ClN2O2 is 342.11, while the measured mass is 343.3 (M+1). + .

[1061] 4-(2-(3-(4-chloro-1H-pyrrolo[2,3-b]pyridin-2-yl)phenoxy)ethyl)morpholine (15y). The crude residue was purified by rapid chromatography (10% methanol in EtOAc) to give the title compound as a beige solid (136 mg, 31%). 1 HNMR (400 MHz, DMSO-d6) δ 12.49 (s, 1H), 8.17 (d, J = 5.2 Hz, 1H), 7.60 (s,1H), 7.58 (d, J = 8.0 Hz, 1H), 7.39 – 7.35 (m, 1H), 7.20 (d, J = 5.2 Hz, 1H), 7.06 (d, J = 2.0 Hz, 1H), 6.95 (dd, J = 8.1, 2.0 Hz, 1H), 4.19 (t, J = 5.8Hz, 2H), 3.61 – 3.58 (m, 4H), 2.73 (t, J = 5.8 Hz, 2H), 2.51-2.48 (m, 4H). LC-MS: C 19 H 20 35 The calculated exact mass of ClN3O2 is 357.12, while the measured mass is 358.1 (M+H). + .

[1062] 4-Chloro-2-(3-((4-methoxybenzyl)oxy)phenyl)-1H-pyrrolo[2,3-b]pyridine (15z). The resulting solid was purified by column chromatography (90% EtOAc in petroleum ether) and prepared with Et2O to give the title compound as an orange solid (228 mg, 51%). 1 H NMR (DMSO-d6): δ 12.48 (br s, 1H), 8.17 (d, J = 5.2 Hz, 1H), 7.68 (t, J = 2.0 Hz, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.43 – 7.41 (m, 3H), 7.21(d, J = 5.2 Hz, 1H), 7.05 (s, 1H), 6.98 – 6.96 (m, 3H), 5.13 (s, 2H), 3.75(s, 3H).

[1063] 4-((3-(4-chloro-1H-pyrrolo[2,3-b]pyridin-2-yl)phenyl)sulfonyl)morpholine (15aa). The solid obtained by preparation with boiling MeOH was filtered and dried to give the title compound as a brown solid (88 mg, 19%). 1 H NMR(DMSO-d6): δ 12.83 (br s, 1H), 8.37 – 8.35 (m, 1H), 8.23 ​​(d, J = 4.8 Hz, 1H), 7.78 – 7.75 (m, 4H), 7.25 (d, J = 5.2 Hz, 1H), 7.23 (d, J = 2.0 Hz, 1H), 3.66–3.65 (m, 4H), 2.96–2.94 (m, 4H).

[1064] 2-(4-(benzyloxy)phenyl)-4-chloro-1H-pyrrolo[2,3-b]pyridine (15s). The crude residue was purified by column chromatography (90% EtOAc in petroleum ether) and then prepared into a solid by a hexane / Et2O mixture to give the title compound as a grayish-white solid (177 mg, 43%). 1H NMR (DMSO-d6): δ 12.38 (br s, 1H), 8.13 (d, J = 5.5Hz, 1H), 7.94 (d, J = 8.5 Hz, 1H), 7.47 (d, J = 7.0 Hz, 2H), 7.41 (t, J = 7.5Hz, 2H), 7.35 (d, J = 7.5 Hz, 1H), 7.18 (d, J = 5.0 Hz, 1H), 7.12 (d, J = 8.5Hz, 1H), 6.87 (d, J = 2.0 Hz, 1H), 5.19 (s, 2H).

[1065] Synthesis of N-(3-(4-chloro-1H-pyrrolo[2,3-b]pyridin-2-yl)phenyl)-3-methoxypropionamide (15l). A solution of compound 15c (0.10 g, 0.4 mmol) and 3-methoxypropionic acid (37 μL, 0.4 mmol) in DMF (5 mL) was stirred at room temperature for 5 min. HCTU (495 mg, 1.2 mmol) and trimethylamine (168 µL, 1.2 mmol) were added, and the solution was stirred at room temperature for 18 h. The reaction mixture was cooled and extracted between ethyl acetate and water. The organic layer was dried over anhydrous sodium sulfate and removed under reduced pressure. The resulting residue was purified by column chromatography (EtOAc solution of 1% Et3N and 10% MeOH) to give the title product as a pale yellow solid (95 mg, 72%). 1 H NMR (500 MHz, DMSO-d6) δ 12.54 (s, 1H), 10.04 (s, 1H), 7.89 – 7.86 (m, 2H), 7.66 (d, J = 7.8 Hz, 1H), 7.57 (d, J =7.8 Hz, 1H), 7.47 (t, J = 10.0 Hz, 1H), 7.22 (d, J = 6.5 Hz, 1H), 6.81 (d, J= 1.8 Hz, 1H), 3.65 (t, J = 8.0 Hz, 2H), 3.27 (s, 3H), 2.04 (t, J = 8.0 Hz, 2H). LC-MS: C 17 H 16 35 The calculated exact mass of ClN3O2 is 329.09 g / L, while the measured mass is 330.3 g / L (M+H). + .

[1066] Synthesis of N-(3-(4-chloro-1H-pyrrolo[2,3-b]pyridin-2-yl)phenyl)-4-methylbenzenesulfonamide (15t). Toluenesulfonyl chloride (136 µL, 1 mmol) was added to a solution of compound 15c (0.244 g, 1.04 mmol) and triethylamine (0.3 mL, 2 mmol) in anhydrous DCM (5 mL) at 0 °C. The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was washed with saturated sodium bicarbonate solution (5 mL) and brine (5 mL), dried over anhydrous sodium sulfate, and removed under reduced pressure. The crude residue was purified by column chromatography (90% EtOAc in petroleum ether) to give the title compound as a pale yellow solid (301 mg, 73%). 1 H NMR (DMSO-d6): δ 12.57 (br s, 1H), 10.36 (br s, 1H), 8.19 (d, J= 5.2 Hz, 1H), 7.71 (d, J = 8.4 Hz, 2H), 7.65 – 7.64 (m, 2H), 7.38 – 7.36 (m,3H), 7.22 (d, J = 5.2 Hz, 1H), 7.08 – 7.05 (m, 1H), 6.74 (d, J = 2.0 Hz, 1H), 2.33 (s, 3H).

[1067] Synthesis of 3-(4-chloro-1H-pyrrolo[2,3-b]pyridin-2-yl)-N-(2-methoxyethyl)benzamide (15m). A solution of compound 15h (0.11 g, 0.4 mmol) and 2-methoxyethylamine (35 µL, 0.4 mmol) in DMF (5 mL) was stirred at room temperature for 5 min. HCTU (495 mg, 1.2 mmol) and trimethylamine (168 µL, 1.2 mmol) were added. The reaction mixture was stirred at room temperature for 18 h. The solvent was then removed under high vacuum, and the resulting residue was ready for use in the next step without further purification.

[1068] General procedure for the synthesis of N-(3-(4-chloro-1H-pyrrolo[2,3-b]pyridin-2-yl)benzyl)-N-substituted amines (15n,p). A solution of compound 15ab (0.12 g, 0.46 mmol), a suitable amine (0.6 mmol), sodium triacetoxyborohydride (0.14 g, 0.69 mmol), and acetic acid (0.036 mL, 0.59 mmol) in dimethylacetamide (2 mL) was maintained at room temperature for 48 hours. The reaction mixture was poured into a 1 M sodium carbonate solution, stirred in an ice bath for 3 hours, and filtered.

[1069] N-[3-(4-chloro-7-azaindole)benzyl]-N-cyclopentanamine (15n). The collected solid was purified by column chromatography (10% MeOH in EtOAc) to give the desired compound as a white solid (102 mg, 68%). 1 H NMR (400 MHz, DMSO-d6) δ 12.49 (br s, 1 H), 8.17 (d, J=5.27 Hz, 1 H), 7.97 (s, 1 H), 7.84 (d, J=7.47 Hz, 1 H), 7.41 (t, J=7.69 Hz, 1 H), 7.35 (d, J=7.91 Hz, 1 H), 7.21 (d, J= 5.27 Hz, 1 H), 6.99 (s, 1 H), 3.74 (s, 2 H), 3.03 – 3.01 (m, 1 H), 1.73 – 1.71 (m, 2 H), 1.64 – 1.62 (m, 2 H), 1.47 – 1.44 (m, 2 H), 1.37 – 1.35(m, 2H). LC-MS: C 19 H 20 35 The calculated exact mass of ClN3 is 325.13, while the measured mass is 326.2 (M+1). + .

[1070] N-[3-(4-chloro-7-azaindole)benzyl]-N-aniline (15p). The collected solid was purified by column chromatography (60% EtOAc in petroleum ether) to give the desired compound as a white solid (118 mg, 77%). 1 H NMR (400 MHz, DMSO-d6) δ 12.54 (br s, 1 H), 8.17 (d, J = 5.27 Hz, 1 H), 8.04 (s, 1 H), 7.85 (d, J = 7.47 Hz, 1 H), 7.43 (t, J = 7.69 Hz, 1 H), 7.38 (d, J = 7.91 Hz, 1H), 7.21 (d, J = 5.27 Hz, 1 H), 7.08-7.02 (m, 2 H), 6.97(s, 1 H), 6.62 (d, J= 7.47 Hz, 2 H), 6.51 (t, J = 7.25 Hz, 1 H), 6.27 (t, J = 5.93 Hz, 1 H), 4.32(d, J= 6.15 Hz, 2 H).13 C NMR (100 MHz, DMSO-d6) δ 150.07, 149.17, 144.36,143.96, 141.78, 140.04, 134.03, 131.42, 129.53, 129.41, 128.02, 125.38,124.48, 120.44, 116.43, 112.94, 95.56, 47.05. LC-MS: C 20 H 16 35 The calculated exact mass of ClN3 is 333.10, while the measured mass is 334.1 (M+1). + .

[1071] Synthesis of N-(4-(4-chloro-1H-pyrrolo[2,3-b]pyridin-2-yl)phenyl)-4-methylbenzenesulfonamide (15u). Toluenesulfonyl chloride (136 µL, 1 mmol) was added to a solution of compound 15ac (0.244 g, 1 mmol) and triethylamine (0.3 mL, 2 mmol) in anhydrous DCM (5 mL) at 0 °C. The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was quenched with saturated sodium bicarbonate solution (5 mL). The organic layer was washed with brine (5 mL), dried over anhydrous sodium sulfate, and removed under reduced pressure. The crude residue was purified by column chromatography (90% EtOAc in petroleum ether) to give the title compound as a grayish-white solid (199 mg, 50%). 1 H NMR (DMSO-d6): δ 12.39 (br s, 1H), 10.47 (br s, 1H), 8.13 (d, J = 5.2 Hz, 1H), 7.85 (dd, J = 2.0, 6.8 Hz, 2H), 7.69 (dd, J = 1.6, 6.4Hz, 2H), 7.36 (d, J = 8.0 Hz, 2H), 7.17 (dd, J = 0.8, 6.4 Hz, 3H), 6.87 (d, J= 2.4 Hz, 1H), 2.33 (s, 3H).

[1072] The general procedure for synthesizing 5-(2-(substituted phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine (5a–aa) was followed. K3PO4 (1 M, 1.2 mL) was added to a suspension of compound 15 (0.37 mmol), compound 9 (0.146 g, 0.56 mmol), and [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) catalyst (0.028 g, 0.04 mmol) in EtOH (3 mL). The reaction mixture was heated to 120 °C and maintained for 20 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc, and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure.

[1073] 2-(4-(3-amino-1H-indazole-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)phenol (5a). The crude residue was purified by column chromatography (80% EtOAc in petroleum ether) to give the title product as a grayish-white solid (10 mg, 8%). 1 HNMR (DMSO-d6): δ 11.67 (br s, 1H), 11.54 (br s, 1H), 10.17 (br s, 1H), 8.23 ​​(d, J = 5.2 Hz, 1H), 8.19 (s, 1H), 7.85 (dd, J = 1.6, 7.6 Hz, 1H), 7.69 (dd,J = 1.6, 8.4 Hz, 1H), 7.40 (d, J = 8.8 Hz, 1H), 7.28 (s, 1H), 7.17 – 7.15 (m,2H), 6.98 – 6.96 (m, 1H), 6.92 – 6.89 (m, 1H), 5.50 (br s, 2H). HRMS (ESI): C 20 H 15 ON5 calculated precise mass: 341.1349, actual measured mass: 342.1346 (M+1) + .

[1074] 5-(2-(2-ethoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine (5b). The crude residue was purified by column chromatography (90% EtOAc in petroleum ether) to give the title compound as a grayish-white solid (56 mg, 41%). 1H NMR (DMSO-d6): δ 11.81 (br s, 1H), 11.54 (br s, 1H), 8.25 (d, J = 5.0Hz, 1H), 8.22 (s, 1H), 7.92 (dd, J = 2.0, 8.0 Hz, 1H), 7.72 (dd, J = 1.5, 9.0Hz, 1H), 7.39 – 7.37 (m, 2H), 7.34 – 7.32 (m, 1H), 7.18 (d, J = 5.0 Hz, 1H), 7.14 (d, J = 6.4 Hz, 1H), 7.05 (t, J = 5.8 Hz, 1H), 5.50 (br s, 2H), 4.18 (q,J = 5.5 Hz, 2H), 1.44 (t, J = 7.0 Hz, 3H). HRMS (ESI):C 22 H 19 The calculated exact mass of N5O is 369.1662, while the measured mass is 370.1660 (M+1). + .

[1075] 5-(2-(3-aminophenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine (5c). The crude residue was purified by rapid chromatography (90% EtOAc in petroleum ether) to give the title product as a beige solid (21 mg, 17%). 1 HNMR (500 MHz, DMSO-d6) δ 12.45 (s, 1H), 8.37 (s, 1H), 8.30 (d, J = 7.8 Hz,1H), 7.84 (d, J = 8.0 Hz 2H), 7.54 – 7.47 (m, 3H), 7.34 (t, J = 8.0 Hz, 1H), 7.26 (d, J = 5.0 Hz, 1H), 7.15 (s, 1H), 5.57 (s, 2H). LC-MS: C 20 H 16 The calculated exact mass of N6 is 340.14, while the measured mass is 341.20 (M+1). + .

[1076] 3-(4-(3-amino-1H-indazole-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)phenol (5d). The crude residue was purified by column chromatography (10% methanol in EtOAc) to give the title product as a brown solid (49 mg, 39%). 1H NMR(400 MHz, DMSO-d6) δ 12.16 (s, 1H), 11.56 (s, 1H), 9.56 (s, 1H), 8.25 – 8.24(m, 2H), 7.71 (dd, J = 8.5, 2.1 Hz, 1H), 7.34 (s, 1H), 7.44 – 7.38 (m, 2H), 7.28 – 7.24 (m, 1H), 7.19 (d, J = 5.3 Hz, 1H), 6.77 (d, J = 8.0 Hz, 1H), 7.09 (d, J = 2.2 Hz, 1H), 5.57 (s, 2H). HRMS (ESI):C 19 H 15 The calculated exact mass of N5O is 341.1301, while the measured mass is 341.1401 (M+1). + .

[1077] 5-(2-(3-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine (5e). The crude residue was purified by column chromatography (10% methanol in EtOAc) to give the title compound as a brown solid (58 mg, 44%). 1 HNMR (500 MHz, DMSO) δ 12.43 (s, 1H), 8.39 (s, 1H), 8.33 (d, J = 5.1 Hz, 1H), 7.89 (d, J = 8.7 Hz, 1H), 7.61 – 7.57 (m, 2H), 7.53 (d, J = 8.7 Hz, 1H), 7.41(t, J = 8.2 Hz, 1H), 7.28 (d, J = 5.2 Hz, 1H), 7.26 (s, 1H), 6.96 (dd, J =8.2, 2.4 Hz, 1H), 3.87 (s, 3H). LC-MS: C 21 H 17 The calculated exact mass of N5O is 355.14, while the measured mass is 356.14 (M+1). + .

[1078] 3-(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-fluorophenol (5f). The crude residue was purified by column chromatography (10% methanol in EtOAc) to give the title compound as a yellow solid (29 mg, 21.9%). 1H NMR (DMSO-d6): δ 12.35 (br s, 1H), 10.11 (s, 1H), 8.35 (s, 1H), 8.32 (d, J = 4.8 Hz, 1H), 7.85 (dd, J = 1.6, 8.8 Hz, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.29 – 7.26 (m, 1H), 7.26 (d, J = 4.8 Hz, 1H), 7.24 (t, J = 1.6 Hz, 1H), 7.20 (d, J = 2.0 Hz, 1H). HRMS (ESI):C 20 H 14 The calculated exact mass of FN5O is 359.1255, while the measured mass is 360.1252 (M+1). + .

[1079] 5-(2-(3-fluoro-5-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine (5 g). The crude solid was purified by column chromatography (90% EtOAc in petroleum ether) to give the title compound as a yellow solid (62 mg, 45%). 1 H NMR (400 MHz, DMSO-d6) δ 12.31 (s, 1H), 11.59 (s, 1H), 8.29 (d, J =4.9 Hz, 1H), 8.24 (s, 1H), 7.73 (d, J = 8.7 Hz, 1H), 7.50 – 7.43 (m, 2H), 7.40 (d, J = 8.7 Hz, 1H), 7.32 (s, 1H), 7.22 (d, J = 5.0 Hz, 1H), 6.85 – 6.77(m, 1H), 5.58 (s, 2H), 3.86 (s, 3H). LC-MS: C 21 H 16 The calculated exact mass of FN5O is 373.13, while the measured mass is 374.3 (M+1). + .

[1080] 3-(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)benzoic acid (5 h). The crude residue was purified by column chromatography (90% EtOAc in petroleum ether) to give the title compound as a beige solid (34 mg, 25%). 1H NMR (500 MHz, DMSO-d6) δ 12.48 (s, 1H), 8.53 (s, 1H), 8.34 (s, 1H), 8.30 (d, J = 5.0 Hz, 1H), 8.23 ​​(d, J = 8.1 Hz, 1H), 7.92 (d, J = 7.0 Hz, 1H), 7.85(d, J = 8.5 Hz 1H), 7.61 (t, J = 7.8 Hz, 1H), 7.49 (d, J = 8.7 Hz, 1H), 7.26– 7.24 (m, 2H), 5.54 (s, 2H). LC-MS: C 21 H 15 The calculated exact mass of N5O2 is 369.12, while the measured mass is 370.2 (M+1). + .

[1081] 3-(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)benzamide (5i). The crude solid was purified by column chromatography (10% methanol in EtOAc) to give the title compound as a beige solid (23 mg, 17%). 1 HNMR (500 MHz, DMSO-d6) δ 12.48 (s, 1H), 8.53 (s, 1H), 8.34 (s, 1H), 8.30 (d,J = 5.0 Hz, 1H), 8.23 ​​(d, J = 8.1 Hz, 1H), 7.92 (d, J = 7.0 Hz, 1H), 7.85 (d,J = 8.5 Hz 1H), 7.61 (t, J = 7.8 Hz, 1H), 7.49 (d, J = 8.7 Hz, 1H), 7.26 –7.23 (m, 2H), 5.54 (s, 2H). LC-MS: C 21 H 16 The calculated exact mass of N6O is 368.12, while the measured mass is 369.2 (M+1). + .

[1082] N-(3-(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)phenyl)methanesulfonamide (5j). The crude residue was purified by column chromatography (10% MeOH in EtOAc) and prepared with Et2O to give the title compound as a grayish-white solid (14 mg, 9%). 1H NMR (DMSO-d6): δ 12.32 (br s, 1H), 11.57 (br s, 1H), 9.83 (br s, 1H), 8.27 (d, J = 5.2 Hz, 1H), 7.70 – 7.68 (m, 3H), 8.23 ​​(s, 1H), 7.42 (q, J = 8.3 Hz, 2H), 7.19 – 7.16 (m, 2H), 7.07 (d, J = 2.0 Hz, 1H), 5.56(br s, 2H), 3.09 (s, 3H). HRMS (ESI):C 21 H 18 The calculated exact mass of N6O2S is 418.1285, while the measured mass is 419.1287 (M+1). + .

[1083] 5-(2-(3-(methanesulfonyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine (5k). The crude solid was purified by column chromatography (10% MeOH / EtOAc) to give the title compound as a grayish-white solid (34 mg, 23%). 1 H NMR (DMSO-d6): δ 12.43 (br s, 1H), 11.57 (br s, 1H), 8.27 (t, J = 1.2 Hz,1H), 8.32 – 8.30 (m, 2H), 8.25 (s, 1H), 7.87 (d, J = 6.4 Hz, 1H), 7.75 – 7.73(m, 2H), 7.42 (d, J = 6.8 Hz, 1H), 7.37 (d, J = 1.6 Hz, 1H), 7.23 (d, J = 4.0Hz, 1H), 3.31 (s, 3H). HRMS (ESI):C 21 H 17 The calculated exact mass of N5O2S is 403.1132, while the measured mass is 404.1172 (M+1). + .

[1084] N-(3-(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)phenyl)-3-methoxypropionamide (5l). The crude residue was purified by column chromatography (90% EtOAc in petroleum ether) to give the title compound as a beige solid (27 mg, 17%). 1H NMR (500 MHz, DMSO-d6) δ 12.45 (s, 1H), 10.08 (s, 1H), 8.32 (d, J = 6.50 Hz, 1H), 8.15 (s, 1H), 7.88 – 7.85 (m, 1H), 7.67 (d, J =7.8 Hz, 1H), 7.60 (d, J = 7.8 Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.43 (t, J =10.0 Hz, 1H), 7.25 (d, J = 6.5 Hz, 1H), 7.06 (d, J = 1.8 Hz, 1H), 3.63 (t, J= 8.0 Hz, 2H), 3.25 (s, 3H), 2.58 (t, J = 8.0 Hz, 2H). LC-MS: C 24 H 22 The calculated exact mass of N6O2 is 426.18, while the measured mass is 427.20 (M+1). + .

[1085] 3-(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-N-(2-methoxyethyl)benzamide (5m). The resulting residue was purified by column chromatography (EtOAc solution of 1% Et3N and 10% MeOH) to give the title product as a grayish-white solid (139 mg, 88%). 1 H NMR (500 MHz, DMSO-d6) δ 12.35 (s, 1H), 8.59 (s, 1H), 8.44 (d, J = 5.0 Hz, 1H), 8.31 (d, J = 8.1 Hz, 1H), 8.12 (d, J= 7.0 Hz, 1H), 7.79 (d, J = 8.5 Hz 1H), 7.57 (t, J = 7.8 Hz, 1H), 7.49 (d, J= 8.7 Hz, 1H), 7.25 – 7.23 (m, 2H), 5.54 (s, 2H), 3.48 (bs, 2H), 3.28 (bs,2H), 2.08 (s,3H). LC-MS: C 24 H 22 The calculated exact mass of N6O2 is 426.18, while the measured mass is 427.20 (M+1). + .

[1086] 5-(2-(3-((cyclopentylamino)methyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine (5n). The crude solid was purified by column chromatography (EtOAc solution of 1% Et3N and 20% MeOH) to give the title compound as a brown solid (12.5 mg, 8%). 1 H NMR (400 MHz, DMSO-d6) δ 12.20 (br s, 1H), 8.28 – 8.21(m, 2 H), 7.94 (s, 1 H), 7.84 (d, J=7.47 Hz, 1 H), 7.72 (d, J=8.79 Hz, 1 H),7.44 – 7.37 (m, 2 H), 7.32 (d, J= 7.47 Hz, 1 H), 7.21 – 7.15 (m, 2 H), 5.56 (s, 2 H), 3.74 (s, 2 H), 3.04 – 3.01 (m, 1 H), 1.74 – 1.72 (m, 2 H), 1.65 –1.64 (m, 2 H), 1.46 – 1.45 (m, 2 H), 1.38 – 1.36 (m, 2 H). 13 C NMR (100 MHz, DMSO-d6) δ 151.02, 150.43, 147.82, 143.71, 141.65, 141.75, 139.06, 131.98,129.18, 128.35, 127.27, 125.70, 124.17, 120.91, 119.11, 115.07, 115.05,110.53, 109.70, 97.35, 59.11, 52.20, 33.02, 24.18. HRMS (ESI): C 26 H 26 The calculated exact mass of N6 is 422.2292, while the measured mass is 423.2289 (M+1). + .

[1087] 5-(2-(3-isobutoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine (5o). The crude residue was purified by column chromatography (90% EtOAc in petroleum ether) to give the title compound as a grayish-white solid (28 mg, 19%). 1H NMR (DMSO-d6): δ 12.19 (br s, 1H), 11.55 (br s, 1H), 8.26 (d, J = 4.8Hz, 1H), 8.24 (s, 1H), 7.72 (dd, J = 1.6, 8.8 Hz, 1H), 7.57 – 7.54 (m, 2H),7.39 – 7.37 (m, 2H), 7.20 – 7.18 (m, 2H), 6.91 – 6.89 (m, 1H), 5.54 (br s,2H), 3.85 (d, J = 6.4 Hz, 2H), 2.06 – 2.04 (m, 1H), 1.02 (d, J = 6.8 Hz, 6H). HRMS (ESI): C 24 H 23 The calculated exact mass of N5O is 397.1975, while the measured mass is 398.1970 (M+1). + .

[1088] N-(3-(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)phenyl)-4-methylbenzenesulfonamide (5t). The crude residue was purified by column chromatography (10% MeOH in EtOAc) and prepared with Et2O to give the title compound as a grayish-white solid (53 mg, 29%). 1 H NMR (DMSO-d6): δ 12.25 (br s, 1H), 11.58 (br s,1H), 10.32 (s, 1H), 8.27 (d, J = 5.2 Hz, 1H), 8.22 (s, 1H), 7.69 – 7.66 (m,3H), 7.61 – 7.59 (m, 2H), 7.42 (d, J = 8.4 Hz, 1H), 7.32 (t, J = 8.0 Hz, 3H), 7.18 (d, J = 4.8 Hz, 1H), 7.05 (dd, J = 1.2, 8.0 Hz, 1H), 6.92 (d, J = 2.0Hz, 1H), 5.57 (br s, 2H), 3.33 (s, 3H). HRMS (ESI):C 27 H 22 The calculated exact mass of N6O2S is 494.1598, while the measured mass is 495.1592 (M+1). + .

[1089] 5-(2-(3-((phenylamino)methyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine (5p). The crude residue was purified by column chromatography (90% EtOAc in petroleum ether) followed by HPLC to give the title compound as a yellow solid (25 mg, 16%). 1 H NMR (400 MHz, DMSO-d6) δ 12.22 (br s, 1 H), 8.26(d, J=5.27 Hz, 1 H), 7.85 (d, J=7.47 Hz, 1 H), 7.71 (d, J=9.67 Hz, 1 H), 7.41(d, J=7.91 Hz, 2 H), 7.36 – 7.32 (m, 1 H), 7.19 (d, J=4.83 Hz, 1 H), 7.16 (d,J=1.32 Hz, 1 H), 7.04 (t, J=7.69 Hz, 3 H), 6.61 (d, J= 7.91 Hz, 3 H), 6.54 –6.48 (m, 1 H), 6.26 – 6.20 (m, 1 H), 5.56 (s, 2 H), 4.31 (d, J= 5.71 Hz, 2H). HRMS (ESI):C 27 H 22 The calculated exact mass of N6 is 430.199, while the measured mass is 431.1978 (M+1). + .

[1090] 5-(2-(2-(benzyloxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine (5q). The crude solid was purified by column chromatography (10% MeOH in EtOAc) and prepared with Et2O to give the title compound as a grayish-white solid (46 mg, 29%). 1H NMR (DMSO-d6): δ 11.85 (br s, 1H), 11.54 (br s, 1H), 8.24 (d, J= 4.8 Hz, 1H), 8.16 (s, 1H), 7.92 (dd, J = 1.6, 7.6 Hz, 1H), 7.57 (dd, J =1.6, 8.8 Hz, 1H), 7.53 – 7.52 (m, 2H), 7.35 – 7.30 (m, 1H), 7.27 – 7.24 (m,6H), 7.22 (d, J = 4.8 Hz, 1H), 7.11 – 6.98 (m, 1H), 5.50 (br s, 2H), 5.24 (s, 2H). HRMS (ESI): C 27 H 21 The calculated exact mass of N5O is 431.1719, while the measured mass is 432.1814 (M+1). + .

[1091] (3-(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)phenyl)(4-methylpiperazin-1-yl)methyl ketone (5v). The solid obtained by washing with hot DCM gave the title compound as a brown solid (125 mg, 75%). 1 HNMR (DMSO-d6): δ 12.29 (br s, 1H), 11.59 (br s, 1H), 8.28 (d, J = 4.8 Hz, 1H), 8.26 (s, 1H), 8.06 – 8.03 (m, 1H), 8.00 (s, 1H), 7.73 – 7.70 (m, 1H), 7.54(t, J = 7.8 Hz, 1H), 7.40 – 7.38 (m, 1H), 7.28 (d, J = 2.0 Hz, 1H), 7.21 (d,J = 5.2 Hz, 1H), 5.58 (s, 2H), 3.65 – 3.62 (m, 2H), 2.41 – 2.38 (m, 2H), 2.30– 2.27 (m, 2H), 2.20 (s, 3H). HRMS (ESI):C 26 H 25 The calculated exact mass of N7O is 451.2193, while the measured mass is 452.2191 (M+1). + .

[1092] 5-(2-(3-(pyridin-2-ylmethoxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine (5w). The crude residue was purified by column chromatography (5% methanol in EtOAc) to give the title compound as a beige solid (58 mg, 36%). 1 H NMR (400 MHz, DMSO-d6) δ 12.24 (s, 1H), 11.57 (s, 1H), 8.60 (d, J =4.3 Hz, 1H), 8.26 (d, J = 5.0 Hz, 1H), 8.24 (s, 1H), 7.88 – 7.84 (m, 1H),7.75 – 7.69 (m, 2H), 7.62 – 7.57 (m, 2H), 7.44 – 7.32 (m, 3H), 7.22 (d, J =1.9 Hz, 1H), 7.20 (d, J = 4.9 Hz, 1H), 7.02 (d, J = 8.0 Hz, 1H), 5.57 (s,2H), 5.29 (s, 2H). HRMS (ESI):C 26 H 20 The calculated exact mass of N6O is 432.1777, while the measured mass is 433.1767 (M+1). + .

[1093] 5-(2-(3-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine (5x). The title compound was obtained as a white solid (26 mg, 16%) by column chromatography (10% methanol in EtOAc). 1H NMR (400 MHz, DMSO-d6) δ 12.22 (s, 1H), 11.57 (s, 1H), 8.26 (d, J = 5.0 Hz, 1H), 8.24 (s, 1H), 7.72 (dd, J = 8.8, 1.2 Hz, 1H), 7.58 –7.56 (m, 2H), 7.40 (d, J = 8.8 Hz, 1H), 7.38 – 7.34 (m, 1H), 7.21 – 7.18 (m,2H), 6.92 (d, J = 7.1 Hz, 1H), 5.56 (s, 2H), 3.94 (d, J = 6.4 Hz, 2H), 3.90(dd, J = 11.5, 3.4 Hz, 2H), 3.42 – 3.34 (m, 2H), 2.12 – 1.95 (m, 1H), 1.72(d, J = 11.2 Hz, 2H), 1.41 – 1.32 (m, 2H). LC-MS: C 26 H 25 The calculated exact mass of N5O2 is 439.20, while the measured mass is 440.3 (M+1). + .

[1094] 5-(2-(3-(2-morpholinoethoxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine (5y). The crude solid was purified by column chromatography (10% methanol in EtOAc) to give the title compound as a white solid (123 mg, 73%). 1H NMR (400 MHz, DMSO-d6) δ 12.20 (s, 1H), 11.57 (s, 1H), 8.26 (d, J =5.0 Hz, 1H), 8.24 (s, 1H), 7.73 (d, J = 8.8 Hz, 1H), 7.59 – 7.56 (m, 2H), 7.40 (d, J = 8.4 Hz, 1H), 7.38 – 7.34 (m, 1H), 7.22 (d, J = 2.1 Hz, 1H), 7.20 (d, J = 4.9 Hz, 1H), 6.92 (d, J = 8.4 Hz, 1H), 5.56 (s, 2H), 4.19 (t, J = 5.7Hz, 2H), 3.63 – 3.56 (m, 4H), 2.73 (t, J = 5.7 Hz, 2H), 2.48-2.51 (m, 4H). LC-MS: C 26 H 26 The calculated exact mass of N6O2 is 454.21, while the measured mass is 455.3 (M+1). + .

[1095] 5-(2-(3-(benzyloxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine (5r). The crude residue was purified by column chromatography (90% EtOAc in petroleum ether) to give the title compound as a grayish-white solid (92 mg, 58%). 1 H NMR (500 MHz, DMSO-d6) δ 12.23 (s, 1H), 11.59 (s, 1H), 8.31 – 8.25 (m,2H), 7.75 (dd, J = 8.6, 1.6 Hz, 1H), 7.71 (t, J = 2.0 Hz, 1H), 7.61 (d, J =7.8 Hz, 1H), 7.52 (d, J = 7.5 Hz, 2H), 7.41 (dt, J = 14.4, 8.0 Hz, 4H), 7.35(t, J = 7.4 Hz, 1H), 7.28 – 7.18 (m, 2H), 7.01 (dd, J = 8.2, 2.4 Hz, 1H),5.58 (s, 2H), 5.22 (s, 2H). 13C NMR (126 MHz, DMSO-d6) δ 159.35, 150.94,143.82, 141.71, 138.56, 137.53, 133.50, 130.46, 128.36, 127.20, 120.86,118.9, 114.99, 112.13, 110.47, 97.79, 69.86. LC-MS: C 27 H 21 The calculated exact mass of N5O is 431.17, while the measured mass is 432.3 (M+1). + .

[1096] 5-(2-(3-((4-methoxybenzyl)oxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine (5z). The crude residue was purified by recrystallization using MeOH / DCM and hexane to give the title compound as a grayish-white solid (109 mg, 64%). 1 H NMR (DMSO-d6): δ 12.19 (br s, 1H), 11.55 (br s, 1H), 8.26 (d, J= 5.2 Hz, 1H), 8.24 (s, 1H), 7.72 (dd, J = 1.2, 8.4 Hz, 1H), 7.66 (s, 1H),7.58 (d, J = 8.0 Hz, 1H), 7.39 – 7.34 (m, 4H), 7.20 – 7.16 (m, 2H), 6.98 –6.95 (m, 3H), 5.54 (br s, 2H), 5.11 (s, 2H), 3.75 (s, 3H). HRMS (ESI):C 28 H 23 The calculated exact mass of N5O2 is 461.1925, while the measured mass is 462.1922 (M+1). + .

[1097] 5-(2-(3-(morpholinosulfonyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine (5aa). The resulting solid was suspended in EtOAc, filtered through a diatomaceous earth mat, and concentrated under reduced pressure to give the title compound as a pale yellow solid (17.5 mg, 10%). 1H NMR (DMSO-d6): δ 12.53 (br s, 1H), 11.58 (br s, 1H), 8.32 – 8.28 (m, 2H), 8.26 (s, 1H), 7.74 – 7.69 (m, 4H), 7.41 (d, J = 8.8 Hz, 1H), 7.34 (s, 1H), 7.23 (d, J = 4.8 Hz, 1H), 5.55 (br s, 2H), 3.65 – 3.61 (m,4H), 2.96 – 2.92 (m, 4H). HRMS (ESI):C 24 H 22 Precise mass of N6O3S: 474.1547, measured mass: 475.1548 (M+1) + .

[1098] 5-(2-(4-benzyloxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine (5s). The resulting solid was prepared with hexane and Et2O to give the title compound as a pale yellow solid (75 mg, 47%). 1 H NMR (DMSO-d6): δ12.09 (br s, 1H), 11.53 (br s, 1H), 8.22 – 8.18 (m, 2H), 7.92 (d, J = 8.8 Hz, 1H), 7.71 (d, J = 1.6, 8.8 Hz, 1H), 7.49 – 7.43 (m, 2H), 7.41 – 7.37 (m, 3H), 7.34 – 7.30 (m, 1H), 7.18 (d, J = 4.8 Hz, 1H), 7.12 (d, J = 8.8 Hz, 2H), 7.07(d, J = 2.4 Hz, 1H), 5.53 (br s, 2H), 5.18 (s, 2H). HRMS (ESI): C 27 H 21 The calculated exact mass of N5O is 431.1719, while the measured mass is 432.1813 (M+1). + .

[1099] N-(4-(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)phenyl)-4-methylbenzenesulfonamide (5u). The crude residue was purified by column chromatography (10% MeOH in EtOAc) and prepared with Et2O to give the title compound as a grayish-white solid (51 mg, 28%). 1H NMR (DMSO-d6): δ 12.10 (br s, 1H), 11.55 (br s,1H), 10.40 (br s, 1H), 8.22 (d, J = 4.8 Hz, 1H), 8.20 (s, 1H), 7.83 (d, J =8.8 Hz, 2H), 7.68 (dd, J = 2.0, 8.8 Hz, 3H), 7.37 (t, J = 9.2 Hz, 3H), 7.17(s, 1H), 7.15 (d, J = 4.0 Hz, 1H), 7.06 (d, J = 2.0 Hz, 1H), 5.54 (br s, 2H),2.32 (s, 3H). HRMS (ESI):C 27 H 22 The calculated N6O2S content is 494.1598, while the actual measured content is 495.1592 (M+1). + .

[1100] General procedure for the synthesis of 4-chloro-2-(substituted aryl)-1H-pyrrolo[2,3-b]pyridine (17a-i).

[1101] Follow the general procedure for synthesizing compound 15a-ac. Unless otherwise stated below, the crude residue can be used for the next step without further purification.

[1102] 2-(6-(benzyloxy)pyridin-3-yl)-4-chloro-1H-pyrrolo[2,3-b]pyridine (17d). The crude residue was purified by column chromatography (70% EtOAc in petroleum ether) to give the title compound as a white solid (181 mg, 44%). 1 H NMR(400 MHz, DMSO-d6) δ 12.55 (s, 1H), 8.82 (d, J = 2.3 Hz, 1H), 8.33 (dd, J =8.7, 2.3 Hz, 1H), 8.17 (d, J = 5.2 Hz, 1H), 7.48 (d, J = 7.0 Hz, 2H), 7.42 –7.38 (m, 2H), 7.35 (d, J = 7.1 Hz, 1H), 7.21 (d, J = 5.1 Hz, 1H), 7.05 – 6.99(m, 2H), 5.42 (s, 2H). LC-MS: C 19 H 14 35 The calculated exact mass of ClN3O is 335.0825, while the measured mass is 336.1 (M+1).+ .

[1103] 2-(5-(benzyloxy)pyridin-3-yl)-4-chloro-1H-pyrrolo[2,3-b]pyridine (17e). The crude residue was suspended in EtOAc, filtered through a diatomaceous earth mat, and evaporated to give the title product as a brown solid (383 mg, 93%). 1 H NMR(400 MHz, DMSO-d6) δ 12.67 (s, 1H), 8.84 (d, J = 1.6 Hz, 1H), 8.34 (d, J =2.6 Hz, 1H), 8.22 (d, J = 5.2 Hz, 1H), 8.11 (dd, J = 2.6, 1.6 Hz, 1H), 7.52(d, J = 7.1 Hz, 2H), 7.43 – 7.41 (m, 2H), 7.39 – 7.35 (m, 1H), 7.25 – 7.24(m, 2H), 5.29 (s, 2H). LC-MS: C 19 H 14 35 The calculated exact mass of ClN3O is 335.0825, while the measured mass is 336.1 (M+1). + .

[1104] 2-(2-(benzyloxy)pyridin-4-yl)-4-chloro-1H-pyrrolo[2,3-b]pyridine (17 g). The crude solid was purified by column chromatography (90% EtOAc in petroleum ether) to give the title product as a brown solid (371 mg, 90%). 1 H NMR (400MHz, DMSO-d6) δ 12.72 (s, 1H), 8.26 – 8.24 (m, 2H), 7.63 (d, J = 5.7 Hz, 1H), 7.52 – 7.47 (m, 3H), 7.42 – 7.38 (m, 2H), 7.35 (d, J = 7.5 Hz, 1H), 7.33 (d, J = 1.8 Hz, 1H), 7.26 (d, J = 5.3 Hz, 1H), 5.41 (s, 2H). LC-MS: C 19 H 14 35 The calculated exact mass of ClN3O is 335.0825, while the measured mass is 336.1 (M+1). + .

[1105] The general procedure for the synthesis of 5-(2-substituted aryl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine (6a–i) is followed. The general procedure for the synthesis of compound 5 is adopted.

[1106] 5-(2-(3-(benzyloxy)-5-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine (6a). The crude solid was recrystallized from EtOAc to give the title compound as a beige solid (88 mg, 53%). 1 H NMR (400MHz, DMSO-d6) δ 12.27 (s, 1H), 11.58 (s, 1H), 8.29 (d, J = 4.9 Hz, 1H), 8.23(s, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.61 – 7.31 (m, 9H), 7.22 (d, J = 4.9 Hz, 1H), 6.90 (d, J = 10.7 Hz, 1H), 5.56 (s, 2H), 5.22 (s, 2H). LC-MS: C 27 H 20 The calculated exact mass of FN5O is 449.1652, while the measured mass is 450.3 (M+1). + .

[1107] 5-(2-(3-(benzyloxy)-5-((2-methoxyethoxy)methyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine (6b). The crude solid was washed with water (3 mL) and hexane (3 × 3 mL) to give the title compound as a grayish-white solid (146 mg, 76%). 1H NMR (400 MHz, DMSO-d6) δ 12.23 (s, 1H), 11.57 (s,1H), 8.26 (d, J = 4.9 Hz, 1H), 8.23 ​​(s, 1H), 7.72 (d, J = 8.8 Hz, 1H), 7.61(s, 1H), 7.55 (s, 1H), 7.51 (d, J = 7.5 Hz, 2H), 7.46 – 7.38 (m, 3H), 7.38 –7.32 (m, 1H), 7.22 – 7.17 (m, 2H), 6.97 (s, 1H), 5.57 (s, 2H), 5.20 (s, 2H),4.52 (s, 2H), 3.60 – 3.55 (m, 2H), 3.53 – 3.46 (m, 2H), 3.25 (s, 3H). LC-MS: C 31 H 29 The calculated exact mass of N5O3 is 519.2270, while the measured mass is 520.3 (M+1). + .

[1108] 5-(2-(3-(benzyloxy)-5-((2-methoxyethyl)amino)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine (6c). The crude product was purified by HPLC to give the title compound as a pale yellow solid (26 mg, 14%). 1 H NMR (500 MHz, DMSO-d6) δ 12.23 (s, 1H), 8.31 (s, 1H), 8.27 (d, J = 4.9Hz, 1H), 7.82 (d, J = 8.4 Hz, 1H), 7.49 – 7.32 (m, 6H), 7.21 (d, J = 4.9 Hz,1H), 7.07 (d, J = 1.7 Hz, 1H), 6.90 (s, 1H), 6.83 (s, 1H), 5.11 (s, 2H), 3.52– 3.48 (m, 2H), 3.38 – 3.25 (m, 7H). LC-MS: C 20 H 28 The calculated exact mass of N6O2 is 504.2274, while the measured mass is 505.30 (M+1). + .

[1109] 5-(2-(6-(benzyloxy)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine (6d). The crude solid was purified by column chromatography (10% methanol in EtOAc) to give the title compound as a beige solid (43 mg, 27%). 1 H NMR (400 MHz, DMSO-d6) δ 12.27 (s, 1H), 11.57 (s, 1H), 8.81 (d, J =2.3 Hz, 1H), 8.32 (dd, J = 8.4, 2.3 Hz, 1H), 8.25 (d, J = 5.0 Hz, 1H), 8.23(s, 1H), 7.72 (d, J = 8.9 Hz, 1H), 7.50 – 7.46 (m, 2H), 7.42 – 7.36 (m, 3H), 7.34 (d, J = 7.4 Hz, 1H), 7.21 – 7.19 (m, 2H), 7.01 (d, J = 8.9 Hz, 1H), 5.56(s, 2H), 5.42(s, 2H). HRMS (ESI):C 26 H 20 The calculated exact mass of N6O is 432.1699, while the measured mass is 433.1777 (M+1). + .

[1110] 5-(2-(5-(benzyloxy)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine (6e). The crude solid was purified by column chromatography (EtOAc solution of 1% Et3N and 10% MeOH) to give the title compound as a beige solid (86 mg, 54%). 1 H NMR (400 MHz, DMSO-d6) δ 12.37 (s, 1H), 11.58 (s, 1H), 8.85 (d, J = 1.6 Hz, 1H), 8.34 – 8.27 (m, 2H), 8.24 (s, 1H), 8.08 (s, 1H), 7.74(d, J = 8.6 Hz, 1H), 7.52 (d, J = 7.5 Hz, 2H), 7.47 – 7.35 (m, 5H), 7.23 (d,J = 5.0 Hz, 1H), 5.57 (s, 2H), 5.28 (s, 2H). HRMS (ESI):C 26 H 20The calculated exact mass of N6O is 432.1699, while the measured mass is 433.1777 (M+1). + .

[1111] 5-(2-(2-fluoro-6-((phenylamino)methyl)pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine (6f). The crude product was purified by HPLC to give the title compound as a pale yellow solid (65 mg, 39%). 1 HNMR (500 MHz, DMSO-d6) δ 12.38 (s, 1H), 8.49 (t, J = 5.6 Hz, 1H), 8.35 (d, J= 5.6 Hz, 1H), 8.29 (s, 1H), 7.80 (d, J = 8.4 Hz, 1H), 7.51 (d, J = 8.5 Hz, 1H), 7.49 (d, J = 8.5 Hz, 1H), 7.26 (d, J = 8.5 Hz, 1H), 7.17 (s, 1H), 7.07(t, J = 8.5 Hz, 1H), 6.62 – 6.56 (m, 3H), 4.37 (s, 2H). LR-MS:C 26 H 20 The calculated exact mass using FN7 is 449.1764, while the measured mass is 450.20 (M+1). + .

[1112] 5-(2-(2-(benzyloxy)pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine (6 g). The crude product was purified by column chromatography (10% methanol in EtOAc) to give the title compound as a white solid (78 mg, 49%). 1 H NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H), 11.58 (s, 1H), 8.33 (d, J =5.0 Hz, 1H), 8.27 – 8.20 (m, 2H), 7.73 (dd, J = 8.7, 1.6 Hz, 1H), 7.62 (dd, J= 5.4, 1.6 Hz, 1H), 7.53 – 7.45 (m, 4H), 7.42 – 7.38 (m, 3H), 7.34 (d, J =7.3 Hz, 1H), 7.25 (d, J = 5.0 Hz, 1H), 5.57 (s, 2H), 5.41 (s, 2H). HRMS (ESI):C26 H 20 The calculated exact mass of N6O is 432.1699, while the measured mass is 433.1777 (M+1). + .

[1113] 5-(2-(2-(benzylthio)pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine (6h). The crude solid was purified by HPLC to give the title compound as a yellow solid (33 mg, 20%). 1 H NMR (500 MHz, DMSO-d6) δ 12.51 (s, 1H), 8.51 (d, J = 5.3 Hz, 1H), 8.36 (d, J = 4.9 Hz, 1H), 8.32 (d, J = 1.5 Hz, 1H) 7.92 (s, 1H), 7.85 – 7.80 (m, 1H), 7.72 (dd, J =5.3, 1.6 Hz, 1H), 7.50 (d, J = 2.2 Hz, 1H), 7.48 (d, J = 8.7 Hz, 1H), 7.46 –7.43 (m, 2H), 7.33 – 7.29 (m, 2H), 7.27 (d, J = 5.0 Hz, 1H), 7.26 – 7.21 (m,1H), 4.50 (s, 2H). LR-MS:C 26 H 20 The calculated precise mass using N6S is 448.1470, while the measured mass is 449.2 (M+1). + .

[1114] 5-(2-(2-(benzylthio)-6-fluoropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine (6i). The crude solid was purified by HPLC to give the title compound as a yellow (29 mg, 17%). 1H NMR (500 MHz, DMSO-d6) δ 12.56 (s, 1H), 8.40 (d, J = 4.9 Hz, 1H), 8.33 (s, 1H), 7.91 (s,1H), 7.84 (dd, J = 8.7, 1.7 Hz, 1H), 7.61 (d, J = 1.8 Hz, 1H), 7.51 (d, J =2.5 Hz, 3H), 7.50 – 7.46 (m, 2H), 7.34 (t, J = 7.5 Hz, 2H), 7.31 – 7.23 (m,2H), 4.47 (s, 2H). LR-MS:C 26 H 19 The precise mass calculated by FN6S is 466.1376, while the actual measured mass is 467.1 (M+1). + .

[1115] Synthesis of 4-(benzyloxy)-2-bromopyridine (20a). Compound 19a (0.436 g, 0.303 mL, 2.5 mmol) was added to a mixture of compound 18a (0.376 g, 2.16 mmol) and cesium carbonate (1.037 g, 3.182 mmol) in DMF (5 mL) at 0 °C under argon. The reaction mixture was warmed to room temperature and stirred for 4 hours. The reaction mixture was poured into ice / water (20 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (3 × 20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (50% EtOAc in petroleum ether) to give the title compound as a light brown solid (466 mg, 82%). 1 H NMR (400 MHz, DMSO-d6) δ 8.20 (d, J = 5.8 Hz, 1H), 7.54 – 7.34 (m, 6H), 7.11 (dd, J = 5.8, 2.3 Hz, 1H), 5.24 (s, 2H). LR-MS:C 12 H 10 79 BrNO calculated precise mass: 262.9946, measured mass: 264.0 (M+1) + .

[1116] General procedure for the synthesis of 4-bromo-2-(aryloxy)pyridine (20b,c). At 0 °C, a solution of potassium tert-butoxide (0.58 g, 1.36 mmol) in anhydrous THF (10 mL) was added to a solution of compound 18b (0.2 g, 1.136 mmol) in anhydrous THF (5 mL). Then, compound 19b,c (1.36 mmol) was added, and the resulting mixture was warmed to room temperature and stirred for 4 hours. The reaction mixture was poured into ice / water (20 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (3 × 20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Unless otherwise stated below, the crude residue was ready for use in the next step without further purification.

[1117] 4-Bromo-2-(pyridin-4-ylmethoxy)pyridine (20b). The crude residue was purified by column chromatography (50% EtOAc in petroleum ether) to give the title compound as a light brown oil (240 mg, 80%). 1 H NMR (500 MHz, DMSO-d6)δ 8.56 (ddd, J = 4.8, 1.8, 0.9 Hz, 1H), 8.07 (d, J = 5.4 Hz, 1H), 7.81 (td, J= 7.7, 1.8 Hz, 1H), 7.45 (dt, J = 7.9, 1.0 Hz, 1H), 7.33 (ddd, J = 7.6, 4.9,1.2 Hz, 1H), 7.29 – 7.24 (m, 2H), 5.44 (s, 2H). LR-MS:C 11 H9 79 The calculated exact mass of BrN2O is 263.9898, while the measured mass is 265.0 (M+1). + .

[1118] General procedure for the synthesis of 2-(substituted aryl)-4,4,5,5-tetramethyl-1,3,2-dioxoborhecyclopentane (21a-c). A suspension of 20a-c (6.3747 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.238 g, 0.325 mmol), potassium acetate (1.918 g, 19.541 mmol), and bis(pinacolyl)diboron (2.15 g, 8.466 mmol) in dioxane (9 mL) and water (1 mL) was stirred at 110 °C for 18 h under argon. The reaction mixture was cooled and diluted with EtOAc (30 mL), and washed with water (3 × 20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Unless otherwise stated below, the crude residue was ready for use in the next step without further purification.

[1119] 2-(pyridin-4-ylmethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)pyridine (21b). The crude residue was purified by column chromatography (70% EtOAc in petroleum ether) to give the title compound as a brown solid (978 mg, 49%). 1 H NMR (500 MHz, DMSO-d6) δ 8.64 (s, 2H), 8.18 (dd, J = 5.0, 0.8Hz, 1H), 7.45 (s, 2H), 7.17 (dd, J = 5.0, 0.8 Hz, 1H), 7.11 (s, 1H), 5.43 (s,2H), 1.30 (s,12H). LR-MS:C 17 H 21 The calculated exact mass of BN2O3 is 312.1645, while the measured mass is 313.0 (M+1). + .

[1120] 2-Phenylacetoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborhecyclopentan-2-yl)pyridine (21c). The crude residue was purified by column chromatography (50% EtOAc in petroleum ether) to give the title compound as a brown solid (832 mg, 40%). 1H NMR (500 MHz, DMSO-d6) δ 8.19 (dd, J = 4.9, 0.9 Hz, 1H), 7.31 (d, J =4.9 Hz, 4H), 7.22 (d, J = 4.3 Hz, 1H), 7.12 (dd, J = 4.9, 0.9 Hz, 1H), 6.91(d, J = 1.0 Hz, 1H), 4.46 (t, J = 6.8 Hz, 2H), 3.02 (t, J = 6.8 Hz, 2H), 1.30(s, 12H). LR-MS:C 19 H 24 The calculated exact mass of BNO3 is 325.1849, while the measured mass is 326.1 (M+1). + .

[1121] Synthesis of 4-chloro-1-(methoxymethyl)-1H-pyrrolo[2,3-b]pyridine (23b). Methoxymethyl chloride (3.1659 g, 39.33 mmol) was added to a solution of 4-chloro-1H-pyrrolo[2,3-b]pyridine (22, 5.0 g, 32.77 mmol) and potassium carbonate (6.793 g, 49.15 mmol) in DMF (20 mL) at 0 °C. The reaction mixture was warmed to room temperature and stirred for 18 hours. The reaction mixture was poured into ice / water and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (3 × 20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude residue was purified by column chromatography (90% EtOAc in petroleum ether) to give the title compound as a beige solid (4.62 g, 72%). 1 H NMR (500 MHz, DMSO-d6) δ8.26 (d, J = 5.2 Hz, 1H), 7.78 (d, J = 3.6 Hz, 1H), 7.29 (d, J = 5.2 Hz, 1H), 6.61 (d, J = 3.6 Hz, 1H), 5.62 (s, 2H), 3.22 (s, 3H). LR-MS:C9H9 35 The calculated exact mass of ClN2O is 196.0403, while the measured mass is 197.3 (M+1). + .

[1122] Synthesis of tert-butyl 4-chloro-1H-pyrrolo[2,3-b]pyridine-1-carboxylic acid (23a). Ditert-butyl dicarbonate (20.70 g, 21.81 mL, 94.85 mmol) was added to a solution of 4-chloro-1H-pyrrolo[2,3-b]pyridine (22, 9.6 g, 62.92 mmol) and 4-dimethylaminopyridine (11.59 g, 94.85 mmol) in DMF (10 mL) at room temperature under argon. The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was extracted between EtOAc and water. The combined organic layers were washed with brine (3 × 20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude residue was purified by column chromatography (50% EtOAc in petroleum ether) to give the title product as a beige solid (15.69 g, 99%). 1 H NMR (500 MHz, DMSO-d6) δ8.36 (d, J = 5.2 Hz, 1H), 7.89 (d, J = 4.0 Hz, 1H), 7.44 (dd, J = 5.2, 1.1Hz, 1H), 6.74 (dd, J = 4.1, 1.2 Hz, 1H), 1.62 (s, 9H). LR-MS:C 12 H 13 35 The calculated exact mass of ClN2O2 is 252.0666, while the measured mass is 253.3 (M+1). + .

[1123] General procedure for the synthesis of N-protected 4-chloro-2-iodo-1H-pyrrolo[2,3-b]pyridine (24a,b). Butyllithium (8.7 mL, 8.70 mmol, 1 M THF solution) was slowly added to a solution of compounds 23a,b (7.253 mmol) in anhydrous THF at -78 °C under argon. The reaction mixture was stirred at 0 °C for 30 min. Iodine (1.0125 g, 7.978 mmol) in THF (10 mL) was slowly added at -78 °C. The reaction mixture was warmed to room temperature and stirred for 2 h. The reaction mixture was poured into ice / H₂O and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with saturated ammonium chloride (20 mL), water (20 mL), and brine (20 mL). The organic layers were dried over anhydrous sodium sulfate and removed under reduced pressure.

[1124] 4-Chloro-2-iodo-1-(methoxymethyl)-1H-pyrrolo[2,3-b]pyridine (24b). The crude residue was purified by column chromatography (90% EtOAc in petroleum ether) to give the title compound as a light brown solid (1 g, 43%). 1 H NMR (500MHz, DMSO-d6) δ 8.21 (d, J = 5.2 Hz, 1H), 7.29 (d, J = 5.2 Hz, 1H), 7.01 (s,1H), 5.61 (s, 2H), 3.23 (s, 3H). LR-MS:C9H8 35 The calculated exact mass of ClIN2O is 321.9370, while the measured mass is 323.0 (M+1). + .

[1125] 4-Chloro-2-iodo-1H-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester (24a). The crude solid was purified by column chromatography (50% EtOAc in petroleum ether) to give the title compound as a light brown solid (1.8 g, 65%). 1 H NMR (500 MHz, DMSO-d6) δ 8.19 (t, J = 1.0 Hz, 1H), 7.53 (t, J = 1.4 Hz, 1H), 7.05 (dd, J =1.7, 0.9 Hz, 1H), 1.58 (s, 9H). LR-MS:C 12 H 12 35 The calculated exact mass of ClIN2O2 is 377.9632, while the measured mass is 379.4 (M+1). + .

[1126] General procedure for the synthesis of N-protected 4-chloro-2-(substituted aryl)-1H-pyrrolo[2,3-b]pyridine (25a-c). Under argon, a mixture of compounds 21a-c (3.139 mmol), compounds 24a,b (2.64 mmol), bis(triphenylphosphine)palladium(II) dichloride (0.0926 g, 0.132 mmol), and cesium carbonate (2.58 g, 7.9 mmol) was suspended in dioxane (9 mL) and water (1 mL). The reaction mixture was stirred at 80 °C for 18 hours. The reaction mixture was cooled, diluted with EtOAc, and washed with water (3 × 20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Unless otherwise stated below, the crude residue was ready for use in the next step without further purification.

[1127] 2-(4-(benzyloxy)pyridin-2-yl)-4-chloro-1-(methoxymethyl)-1H-pyrrolo[2,3-b]pyridine (25a). The crude residue was purified by column chromatography (1% Et3N and 50% EtOAc in petroleum ether) to give the title compound as a brown solid (990 mg, 99%). 1 H NMR (500 MHz, DMSO-d6) δ 8.54 (d, J = 5.7 Hz, 1H), 8.34 (d, J = 5.2 Hz, 1H), 7.73 (d, J = 2.4 Hz, 1H), 7.54 – 7.48 (m, 2H), 7.44(td, J = 7.3, 6.3, 1.5 Hz, 2H), 7.38 (dd, J = 8.0, 6.2 Hz, 2H), 7.25 (s, 1H), 7.10 (dd, J = 5.8, 2.4 Hz, 1H), 6.21 (s, 2H), 5.33 (s, 2H), 3.08 (s, 3H). LR-MS:C 21 H 18 35 The calculated exact mass of ClN3O2 is 379.1088, while the measured mass is 380.3 (M+1). + .

[1128] General procedure for the synthesis of 5-(2-substituted aryl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine (6j–l). A mixture of compound 25a-c (2.373 mmol), compound 9 (0.0676 g, 0.261 mmol), [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichlorocatalyst (0.0154 g, 0.0236 mmol), and cesium carbonate (0.232 g, 0.712 mmol) was suspended in dioxane (9 mL) and water (1 mL). The reaction mixture was stirred at 110 °C for 18 h. The reaction mixture was cooled, diluted with EtOAc, and washed with water (3 × 20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude residue was then dissolved in concentrated hydrochloric acid / methanol (4:1, 5 mL) (for 6kJ) or in TBAF (5 mL, 1 M THF solution) (for 6kJ) and refluxed for 8 hours. The reaction mixture was cooled and concentrated under reduced pressure.

[1129] 5-(2-(4-(benzyloxy)pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine (6j). The crude residue was purified by HPLC to give the title compound as an orange solid (35 mg, 31%). 1 H NMR (500MHz, DMSO-d6) δ 12.60 (s, 2H), 8.57 (d, J = 5.9 Hz, 1H), 8.41 (d, J = 5.1 Hz, 1H), 8.35 (d, J = 1.5 Hz, 1H), 7.95 (d, J = 2.4 Hz, 1H), 7.85 (dd, J = 8.7,1.7 Hz, 1H), 7.63 (s, 1H), 7.57 – 7.51 (m, 4H), 7.48 – 7.44 (m, 2H), 7.43 –7.38 (m, 1H), 7.32 (d, J = 5.0 Hz, 1H), 7.17 (dd, J = 6.2, 2.4 Hz, 1H), 5.37(s, 2H). LR-MS:C 26 H 20 The calculated exact mass of N6O is 432.1699, while the measured mass is 433.3 (M+1). + .

[1130] 5-(2-(2-(pyridin-4-ylmethoxy)pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine (6k). The crude residue was purified by HPLC to give the title compound as a bright yellow solid (11 mg, 10%). 1 HNMR (500 MHz, DMSO-d6) δ 12.60 (s, 1H), 8.83 (d, J = 5.7 Hz, 2H), 8.43 – 8.38 (m, 2H), 8.21 (d, J = 5.5 Hz, 1H), 7.92 – 7.88 (m, 3H), 7.69 – 7.65 (m, 2H), 7.54 (d, J = 7.5 Hz, 2H), 7.31 (d, J = 5.0 Hz, 1H), 5.69 (s, 2H). LR-MS:C 25 H 19 The calculated exact mass of N7O is 433.1651, while the measured mass is 434.3 (M+1). + .

[1131] 5-(2-(2-phenylethoxypyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine (6l). The crude residue was purified by HPLC to give the title compound as a bright yellow solid (13 mg, 11%). 1 H NMR (400MHz, DMSO-d6) δ 12.56 – 12.13 (m, 1H), 11.58 (s, 1H), 8.34 (d, J = 5.0 Hz, 1H), 8.27 – 8.23 ​​(m, 1H), 8.22 (d, J = 5.5 Hz, 1H), 7.74 (dd, J = 8.7, 1.6Hz, 1H), 7.59 (dd, J = 5.4, 1.5 Hz, 1H), 7.47 (d, J = 1.9 Hz, 1H), 7.44 –7.39 (m, 2H), 7.37 – 7.30 (m, 4H), 7.25 (dd, J = 5.6, 2.1 Hz, 2H), 5.56 (s,2H), 4.54 (t, J = 6.9 Hz, 2H), 3.08 (t, J = 6.8 Hz, 2H). LR-MS:C 27 H 22 The calculated exact mass of N6O is 446.1855, while the measured mass is 446.3 (M+1). + .

[1132] Pharmacokinetic studies

[1133] Pharmacokinetic studies were conducted by Sygnature Discovery Ltd. Intrinsic clearance and half-life were determined using cryopreserved mixed mouse CD1 hepatocytes. The pharmacokinetics were analyzed in 1 µM Williams Media E buffer (0.01% DMSO) at a concentration of 0.5 x 10⁻⁶ cells / mL. 6 mL of cells –1 Cell density analysis was performed to test for the compounds. Cells were incubated with shaking at 37°C for 1 hour, and compound consumption was measured by LC-MS / MS at 6 time points (0.25, 5, 10, 20, 40, and 60 min).

[1134] In vivo pharmacokinetic studies were conducted on CD1 mice in triplicate, with each dose being 1 mg / kg. -1 Intravenous injection, and a dose of 10 mg / kg -1Intraperitoneal injection was administered. Previous formulation / solubility assessments were performed using standard excipients (e.g., DMSO:cyclodextrin or HMPC / Tween 80). Intravenous injection timepoints were at 5 min, 15 min, 30 min, 1, 2, 4, 8, and 24 hours, while intraperitoneal injection timepoints were at 15 min, 30 min, 1, 2, 4, 6, 8, and 24 hours. Blood samples were prepared by protein precipitation with the addition of methanol or acetonitrile containing an internal standard, followed by quantitative bioanalysis using LC-MS / MS.

[1135] References

[1136] 1.Gamble, C., et al., Inhibitory kappa B Kinases as targets for pharmaceutical regulation. British journal of pharmacology, 2012. 165(4): p.802-819.

[1137] 2.Cohen, MS, et al., Structural bioinformatics-based design ofselective, irreversible kinase inhibitors. Science, 2005. 308(5726): p. 1318-1321.

[1138] 3.Paul, A., et al., Inhibitory-κB kinase (IKK) α and nuclear factor-κB (NFκB)-inducing kinase (NIK) as anti-cancer drug targets. Cells, 2018. 7(10): p. 176.

[1139] 4.Liu, S., et al., Crystal structure of a human IκB kinase βasymmetric dimer. Journal of Biological Chemistry, 2013. 288(31): p. 22758-22767.

[1140] 5.Polley, S., et al., Structural Basis for the Activation of IKK1 / α.Cell reports, 2016. 17(8): p. 1907-1914.

[1141] 6.Anthony, N.G., et al., Inhibitory kappa B kinase α (IKKα)inhibitors that recapitulate their selectivity in cells against isoform-related biomarkers. Journal of medicinal chemistry, 2017. 60(16): p. 7043-7066.

[1142] 7.Christopher John Andrew, J.D.K., Lackey Karen Elizabeth, LH-indazole-3-amine compounds as IKK1 inhibitors, S.B.C. Glaxo group LTD,Editor. 2008.

[1143] 8.Ishiyama, T., et al., A Stoichiometric Aromatic C H BorylationCatalyzed by Iridium (i) / 2, 2’‐Bipyridine Complexes at Room Temperature.Angewandte Chemie International Edition, 2002. 41(16): p. 3056-3058.

[1144] 9.Miyaura, N., K. Yamada, and A. Suzuki, A new stereospecific cross-coupling by the palladium-catalyzed reaction of 1-alkenylboranes with 1-alkenyl or 1-alkynyl halides. Tetrahedron Letters, 1979. 20(36): p. 3437-3440.

[1145] 10.D'Alterio, MC, et al., Mechanistic Aspects of the Palladium‐Catalyzed Suzuki‐Miyaura Cross‐Coupling Reaction. Chemistry–A EuropeanJournal, 2021. 27(54): p. 13481-13493.

[1146] 11.Ishiyama, T., M. Murata, and N. Miyaura, Palladium (0)-catalyzed cross-coupling reaction of alkoxydiboron with haloarenes: a direct procedure for arylboronic esters. The Journal of Organic Chemistry, 1995. 60(23): p.7508-7510.

[1147] Additional experimental section

[1148] General method. Unless otherwise specified, use commercially available materials that have not undergone further purification. Reactions sensitive to air or moisture are carried out under a nitrogen atmosphere. Anhydrous solvents are obtained from Sigma-Aldrich. (In standard techniques) 1 Rapid chromatography was performed using silica gel or a Biotage SP4 automated chromatography system (SNAP KP-Sil, 60 Å, 35-70 μm column; detection wavelength: 254 nm; monitoring wavelength: 280 nm) at Acros, 60 Å, 35-70 μm. NMR spectroscopy ( 1 H and 13C) Recordings were performed on a JEOL ECX-400 (400 MHz); Bruker Avance3 / DPX400 (400 MHz); or Bruker Avance / DPX500 (500 MHz) instrument. Chemical shifts (δ) were cited in parts per million (ppm) relative to an internal solvent reference. Coupling constants (J) were recorded in Hertz. High-resolution mass spectrometry was performed on an Exactive (thermoscientific) LCMS mass spectrometer by low-resolution mass spectrometry via direct injection onto a ThermoFinnigan LCQ Duo. Reversed-phase HPLC purification was performed on a Water HPLC system, which included a Waters 1525 binary HPLC pump, a Waters 717 autosampler, and a Waters 2487 dual-λ absorbance detector (254 nm). A semi-preparative (50 × 21.2 mm) Luna 5µ C18 column was used for elution with an acetonitrile / water gradient, each solvent containing 0.1% TFA, using the following gradient.

[1149]

[1150] Microwave reactions were performed using a Biotage Initiator-8 microwave synthesizer (operating at 2.45 GHz). The reaction was carried out on an aluminum-based SiO2 plate (Merck, silicone 60, F). 254 Thin-layer chromatography (TLC) was performed on the sample using ultraviolet light (254 nm) or by staining with potassium permanganate to visualize the spots. Unless otherwise specified, all tested compounds were determined to be ≥95% pure by LC-MS and analytical HPLC.

[1151] General Procedure

[1152] All commercially available reagents and solvents used were obtained from Sigma-Aldrich, Fluorochem Fisher Scientific, Acros, Alfa Aesar, Apollo Scientific, and Advanced ChemBlocks, and were ready for use without further purification. Reactions sensitive to air or moisture were carried out under an argon or nitrogen atmosphere.

[1153] Microwave reactions were performed using the Biotage Initiator system.

[1154] Rapid chromatography was performed using the Biotage SP4 automated chromatography ...

Claims

1. A compound, or a pharmaceutically acceptable salt or solvate thereof, having the structural Formula (I) shown below: ， wherein: R1is selected from hydrogen, halo, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (3-7C)cycloalkyl, aryl, heteroaryl and heterocyclyl, wherein said (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (3-7C)cycloalkyl, aryl, heteroaryl and heterocyclyl are optionally substituted by one or more R 100 substituents; Each R 100 Independently selected from halogens, (1-2C) haloalkyl (e.g., trifluoromethyl), (1-2C) haloalkoxy (e.g., trifluoromethoxy), cyano, hydroxyl, (1-4C) alkyl, (1-4C) hydroxyalkyl, (CH2) x OR f (CH2) x C(O)R f (CH2) x C(O)OR f (CH2) x OC(O)R f (CH2) x C(O)N(R j )R h (CH2) x N(R g )C(O)R f (CH2) x S(O) y1 R f (CH2) x SO2N(R j )R h (CH2) x N(R g SO2R f (CH2) x NR j R h (CH2) x (3-7C)cycloalkyl, (CH2) x Heterocyclic group, (CH2) x heteroaryl or (CH2) x Aryl; and wherein: (i) R f and R g are each independently selected from hydrogen, (1-6C)alkyl or phenyl; and wherein R h and R j are each independently selected from hydrogen, (1-6C)alkyl or phenyl, or R h and R j together with the nitrogen atom to which they are attached form a 3-7 membered ring which can optionally include a further heteroatom, and is optionally further substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl and (1-2C)alkyl; and (ii) R 100 Any (1-4C)alkyl, (3-7C)cycloalkyl, heterocyclyl, heteroaryl or aryl in a substituent is optionally further substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, (1-2C)alkyl, (1-2C)haloalkyl, (1-2C)hydroxyalkyl, OR k , C(O)R k , C(O)OR k , OC(O)R k , C(O)N(R l )R k , N(R l )C(O)R k , S(O) y2 R k , SO2N(R l )R k , N(R l )SO2R k or NR l R k wherein R k and R l are selected from hydrogen or (1-2C)alkyl; R2is hydrogen; R3is selected from hydrogen, (1-8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (3-7C)cycloalkyl, aryl, heteroaryl, heterocyclyl, (CH2) 0-3 (3-7C)cycloalkyl, (CH2) 0-3 heterocyclyl, (CH2) 0-3 heteroaryl, (CH2) 0-3 aryl, -C(O)-(CH2) 0-3 (3-7C)cycloalkyl, -C(O)-(CH2) 0-3 heterocyclyl, -C(O)-(CH2) 0-3 heteroaryl, -C(O)-(CH2) 0-3 aryl or -C(O)O(1-8C)alkyl, -C(O)NR 3a -(1-8C)alkyl, -C(O)NR 3a -(CH2) 0-3 (3-7C)cycloalkyl, -C(O)NR 3a -(CH2) 0-3 heterocyclyl, -C(O)NR 3a -(CH2) 0-3 heteroaryl, -C(O)NR 3a -(CH2) 0-3 aryl; wherein R is hydrogen or (1-2C)alkyl; and 3a is hydrogen or (1-2C)alkyl; wherein any (1-8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (3-7C)cycloalkyl, aryl, heteroaryl and heterocyclyl moieties are optionally substituted by one or more R 200 substituents; wherein R 200 is selected from halo, (1-2C)haloalkyl (e.g. trifluoromethyl), (1-2C)haloalkoxy (e.g. trifluoromethoxy), cyano, hydroxy, nitro, (1-4C)alkyl, (1-4C)hydroxyalkyl, (CH2) z OR m , (CH2) z C(O)R m , (CH2) z C(O)OR m , (CH2) z OC(O)R m , (CH2) z C(O)N(R o )R p , (CH2) z N(R n )C(O)R m , (CH2) z N(R n )C(O)OR m , (CH2) z S(O) y3 R m , (CH2) z SO2N(R o )R p , (CH2) z N(R n )SO2R m , (CH2) z NR o R p , (CH2) z (3-7C)cycloalkyl, (CH2) z heterocyclyl, (CH2) z heteroaryl, (CH2) z aryl; and wherein: (i) R m and R n are each independently selected from hydrogen, (1-6C)alkyl or (CH2) 0-3 phenyl; R o and R p are each independently selected from hydrogen, (1-6C)alkyl or phenyl, or R o and R p together with the nitrogen atom to which they are attached form a 3-7 membered ring which can optionally include a further heteroatom, and wherein R o and R p form any 3-7 membered ring, and any alkyl or phenyl present for R m , R n , R o and R p is optionally further substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl and (1-2C)alkyl; and (ii) R 200 Any (3-7C)cycloalkyl, heterocyclyl, heteroaryl or aryl moiety in a substituent is optionally further substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, (1-2C)alkyl, (1-2C)haloalkyl, (1-2C)hydroxyalkyl, OR q , C(O)R q , C(O)OR q , OC(O)R q , C(O)N(R q )R r , N(R r )C(O)R q , S(O) y4 R q , SO2N(R r )R q , N(R r )SO2R q or NR r R q wherein R q is hydrogen, (1-2C)alkyl or phenyl and R r is selected from hydrogen or (1-2C)alkyl; or R2and R3are linked together to form a -X2=CQ- group; X2is selected from N and CR a ; wherein R a is selected from hydrogen, fluorine, chlorine, methyl, cyano, difluoromethyl, and trifluoromethyl; and Q is hydrogen, halo, cyano or a group of the formula: -L1-Y1-L2-Q1 wherein: L1is absent or (1-4C)alkylene; Y1is absent, O, S, SO, SO2, N(R y1 ), C(O), C(O)O, OC(O), C(O)N(R y1 ), or N(R y1 )C(O), wherein R y1 is selected from hydrogen or (1-6C)alkyl; L2is absent or (1-3C)alkylene; and Q1is hydrogen, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, aryl, (3-8C)cycloalkyl, heteroaryl or heterocyclyl; wherein Q is optionally further substituted by one or more substituents independently selected from oxo, (1-6C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)aminoalkyl, (1-4C)hydroxyalkyl, cyano, or by one or more groups of the formula: -L3-Y2-L4-W1 wherein: L3is absent or (1-4C)alkylene; Y2 is absent or selected from O, S, SO, SO2, N(R y2 ), C(O), C(O)O, OC(O), C(O)N(R y2 ), N(R y2 )C(O) or S(O)2N(R y2 ), N(R y2 )SO2, wherein R y2 is selected from hydrogen or (1-4C)alkyl; L4is absent or (1-3C)alkylene; and W1is hydrogen, (1-6C)alkyl, aryl, (3-8C)cycloalkyl, heteroaryl or heterocyclyl; wherein W1is optionally substituted with one or more substituents selected from oxo, (1- 4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, amino, (1-4C)alkylamino, di[(1-4C)alkyl]amino C(O)OH, C(O)O(1-4C)alkyl, (CH2) 0-3 - heterocyclyl or cyano; R4is selected from hydrogen or halo; X1is N or CR5, wherein R5is selected from hydrogen, halo, cyano or amino; x is independently selected from 0, 1, 2 or 3; y1, y2, y3and y4are independently selected from 0, 1 or 2; z is independently selected from 0, 1, 2 or 3; with the provisos that: when Q is hydrogen, X1and X2are only N; when X1and X2are CR5or CR a Q is not hydrogen; when L1, Y1and L2are all absent, Q1is not hydrogen; and at least one of R1, Q, R a R4or R5is a substituent other than hydrogen.

2. A compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is a compound having the structural Formula (la), (lb) or (Ic) shown below: ， wherein R1, X1, X2, R3, R4and R5are each as defined in claim 1.

3. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from hydrogen, halo, (2-6C)alkynyl, (3-7C)cycloalkyl, phenyl, 5 or 6 membered heteroaryl or 4 to 7 membered heterocyclyl, wherein said (2-6C)alkynyl, (3-7C)cycloalkyl, phenyl, heteroaryl and heterocyclyl are optionally substituted by one or more R 100 substituted by one or more R and wherein R 100 selected from halo, (1-2C)haloalkyl (e.g. trifluoromethyl), (1-2C)haloalkoxy such as trifluoromethoxy, cyano, hydroxy, (1-4C)alkyl, (1-4C)hydroxyalkyl, (CH2) x OR f , (CH2) x C(O)R f , (CH2) x C(O)OR f , (CH2) x OC(O)R f , (CH2) x C(O)N(R j )R h , (CH2) x N(R g )C(O)R f , (CH2) x S(O) y1 R f , (CH2) x SO2N(R j )R h , (CH2) x N(R g )SO2R f , (CH2) x NR j R h , (CH2) x (3-7C)cycloalkyl, (CH2) x heterocyclyl, (CH2) x heteroaryl, (CH2) x aryl; and wherein: (i) x and y1are as defined in claim 1; (ii) R f and R g each independently is selected from hydrogen or (1-2C)alkyl; and wherein R h and R j each independently is selected from hydrogen or (1-2C)alkyl, or R h and R j together with the nitrogen atom to which they are attached form a 3-7 membered ring which can optionally include an additional heteroatom; and (iii) R 100 Any (1-4C)alkyl, (3-7C)cycloalkyl, heterocyclyl, heteroaryl or aryl moiety in a substituent is optionally further substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, (1-2C)alkyl, (1-2C)haloalkyl, (1-2C)hydroxyalkyl, OR k , C(O)R k , C(O)OR k , OC(O)R k , C(O)N(R l )R k , N(R l )C(O)R k , S(O) y2 R k , SO2N(R l )R k , N(R l )SO2R k or NR l R k wherein R k and R l are selected from hydrogen or (1-2C)alkyl and y2 is independently selected from 0, 1 or 2.

4. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from hydrogen, halo, (2-6C)alkynyl, phenyl or 5 or 6 membered heteroaryl, wherein said (2-6C)alkynyl, phenyl or heteroaryl is optionally substituted with one or more R 100 substituted with one or more R and wherein R 100 is selected from halo, (1-2C)haloalkyl (e.g. trifluoromethyl), (1-2C)haloalkoxy e.g. (trifluoromethoxy), cyano, hydroxy, (1-4C)alkyl, (1-4C)hydroxyalkyl, (CH2) x OR f , (CH2) x C(O)R f , (CH2) x C(O)OR f , (CH2) x OC(O)R f , (CH2) x C(O)N(R j )R h , (CH2) x N(R g )C(O)R f , (CH2) x S(O) y1 R f , (CH2) x SO2N(R j )R h , (CH2) x N(R g )SO2R f , (CH2) x NR j R h , (CH2) x (3-7C)cycloalkyl, (CH2) x -[4-6 membered heterocyclyl], (CH2) x -[5 or 6 membered heteroaryl] or (CH2) x phenyl; and wherein: (i) x and y1are as defined in claim 1; (ii) R f and R g each independently is selected from hydrogen or (1-2C)alkyl; and wherein R h and R j each independently is selected from hydrogen or (1-2C)alkyl, or R h and R j together with the nitrogen atom to which they are attached form a 3-7 membered ring which can optionally include an additional heteroatom; and (iii) R 100 Any (1-4C)alkyl, (3-7C)cycloalkyl, heterocyclyl, heteroaryl or aryl moiety in a substituent is optionally further substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, (1-2C)alkyl, (1-2C)haloalkyl, (1-2C)hydroxyalkyl, OR k , C(O)R k , C(O)OR k , OC(O)R k , C(O)N(R l )R k , N(R l )C(O)R k , S(O) y2 R k , SO2N(R l )R k , N(R l )SO2R k or NR l R k wherein R k and R l are selected from hydrogen or (1-2C)alkyl and y2 is independently selected from 0, 1 or 2.

5. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from hydrogen, halo, (2-6C)alkynyl, phenyl or 5 or 6 membered heteroaryl, wherein said (2-6C)alkynyl, phenyl or heteroaryl is optionally substituted with one or more R 100 substituted with one or more R and wherein R 100 is selected from halo, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, (1-4C)alkyl, (1-4C)hydroxyalkyl, (CH2) x OR f , (CH2) x C(O)R f , (CH2) x C(O)OR f , (CH2) x OC(O)R f , (CH2) x C(O)N(R j )R h , (CH2) x N(R g )C(O)R f , (CH2) x S(O) y1 R f , (CH2) x SO2N(R j )R h , (CH2) x N(R g )SO2R f , (CH2) x NR j R h , (CH2) x (3-7C)cycloalkyl, (CH2) x -[4-6 membered heterocyclyl], (CH2) x -[5 or 6 membered heteroaryl] or (CH2) x phenyl; and wherein: (i) x and y1are as defined in claim 1; (ii) R f and R g each independently is selected from hydrogen or (1-2C)alkyl; and wherein R h and R j each independently is selected from hydrogen or (1-2C)alkyl; and (iii) R 100 Any (1-4C)alkyl, (3-7C)cycloalkyl, heterocyclyl, heteroaryl or aryl moiety in a substituent is optionally further substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, (1-2C)alkyl, (1-2C)haloalkyl, (1-2C)hydroxyalkyl or OR k k selected from hydrogen or (1-2C)alkyl.​ 6. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is selected from hydrogen, halo, (2-6C)alkynyl, phenyl or 5 or 6 membered heteroaryl, wherein said (2-6C)alkynyl, phenyl or heteroaryl is optionally substituted with one or more R 100 substituted with one or more R and wherein R 100 selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, (1-4C)alkyl, (1-4C)hydroxyalkyl, (CH2) x OR f , C(O)R f , C(O)OR f , OC(O)R f , C(O)N(R j )R h , N(R g )C(O)R f , S(O) y1 R f , SO2N(R j )R h , N(R g )SO2R f , NR j R h , (CH2) x -[4-6 membered heterocyclyl] or (CH2) x phenyl; and wherein: (i) x and y1 are as defined in claim 1 ; (ii) R f and R g each independently is selected from hydrogen or (1-2C)alkyl; and wherein R h and R j each independently is selected from hydrogen or (1-2C)alkyl; and (iii) R 100 Any (1-4C)alkyl, (3-7C)cycloalkyl, heterocyclyl, heteroaryl or aryl moiety in a substituent is optionally further substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, (1-2C)alkyl, (1-2C)haloalkyl, (1-2C)hydroxyalkyl or OR k wherein R k is selected from hydrogen or (1-2C)alkyl.

7. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is selected from: (i) hydrogen or halo; (ii) ethynyl, i.e. ， which is optionally substituted with R 100 substituted; (iv) phenyl, which is optionally substituted with R 100 substituents; (v) 5- or 6-membered heteroaryl, which is optionally substituted by R 100 substituents; and wherein R 100 selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, (1-4C)alkyl, (1-4C)hydroxyalkyl, (CH2) x OR f , C(O)R f , C(O)OR f , OC(O)R f , C(O)N(R j )R h , N(R g )C(O)R f , S(O) y1 R f , SO2N(R j )R h , N(R g )SO2R f , NR j R h , (CH2) x -[4-6 membered heterocyclyl] or (CH2) x phenyl; and wherein: (i) x is independently selected from 0, 1 or 2; (ii) y1 is independently selected from 0, 1 or 2; (iii) R f and R g each independently is selected from hydrogen or (1-2C)alkyl; and wherein R h and R j each independently is selected from hydrogen or (1-2C)alkyl; and (iv) R 100 Any (1-4C)alkyl, (3-7C)cycloalkyl, heterocyclyl, heteroaryl or aryl moiety in a substituent is optionally further substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, (1-2C)alkyl, (1-2C)haloalkyl, (1-2C)hydroxyalkyl or OR k wherein R k is selected from hydrogen or (1-2C)alkyl.

8. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is selected from: (i) hydrogen; (ii) ethynyl, i.e. ， which is optionally substituted with R 100 substituted; (v) phenyl, which is optionally substituted with R 100 substituents; (vi) 5 or 6 membered heteroaryl; and wherein R 100 selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, (1-4C)alkyl, (1-4C)hydroxyalkyl, (CH2) x OR f , C(O)R f , C(O)OR f , OC(O)R f , C(O)N(R j )R h , N(R g )C(O)R f , S(O) y1 R f , SO2N(R j )R h , N(R g )SO2R f , NR j R h , (CH2) x -[4-6 membered heterocyclyl] or (CH2) x phenyl; and wherein: (i) x is independently selected from 0, 1 or 2; (ii) y1 is independently selected from 0, 1 or 2; (iii) R f and R g are each independently selected from hydrogen or (1-2C)alkyl; and wherein R h and R j are each independently selected from hydrogen or (1-2C)alkyl; and (iv) R 100 Any (1-4C)alkyl, (3-7C)cycloalkyl, heterocyclyl, heteroaryl or aryl moiety in a substituent is optionally further substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, (1-2C)alkyl, (1-2C)haloalkyl, (1-2C)hydroxyalkyl or OR k wherein R k is selected from hydrogen or (1-2C)alkyl.

9. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is selected from: (i) hydrogen or halo; (ii) ethynyl, i.e. ， which is optionally substituted with R 100 substituted with R (iii) phenyl, which is optionally substituted with R 100 substituents; and wherein R 100 selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy or (1-4C)alkyl.

10. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is selected from hydrogen, (1-8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (3-7C)cycloalkyl, phenyl, 5- or 6-membered heteroaryl, 4- to 7-membered heterocyclyl, (CH2) 0-3 (3-7C)cycloalkyl, (CH2) 0-3 [4- to 7-membered heterocyclyl], (CH2) 0-3 [5- or 6-membered heteroaryl], (CH2) 0-3 phenyl, -C(O)-(CH2) 0-3 (3-7C)cycloalkyl, -C(O)-(CH2) 0-3 [4- to 7-membered heterocyclyl], -C(O)-(CH2) 0-3 [5- or 6-membered heteroaryl], -C(O)-(CH2) 0-3 phenyl, -C(O)O(1-8C)alkyl, -C(O)NR 3a -(1-8C)alkyl, -C(O)NR 3a -(CH2) 0-3 (3-7C)cycloalkyl, -C(O)NR 3a -(CH2) 0-3 [5- to 7-membered heterocyclyl], -C(O)NR 3a -(CH2) 0-3 [5- or 6-membered heteroaryl], or -C(O)NR 3a -(CH2) 0-3 phenyl; Where R 3a It is hydrogen or (1-2C) alkyl; wherein any (1-8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (3-7C)cycloalkyl, phenyl, 5 or 6 membered heteroaryl or 4 to 7 membered heterocyclyl moiety is optionally substituted by one or more R 200 substituents; wherein R 200 is selected from halo, (1-2C)haloalkyl (e.g. trifluoromethyl), (1-2C)haloalkoxy (e.g. trifluoromethoxy), cyano, hydroxy, nitro, (1-4C)alkyl, (1-4C)hydroxyalkyl, (CH2) z OR m , (CH2) z C(O)R m , (CH2) z C(O)OR m , (CH2) z C(O)N(R o )R p , (CH2) z N(R n )C(O)R m , (CH2) z N(R n )C(O)OR m , (CH2) z S(O) y3 R m , (CH2) z SO2N(R o )R p , (CH2) z N(R n )SO2R m , (CH2) z NR o R p , (CH2) z (3-7C)cycloalkyl, (CH2) z [4 to 7 membered heterocyclyl], (CH2) z [5 or 6 membered heteroaryl], (CH2) z phenyl; and wherein: (i) z and y3 are as defined in claim 1 ; (ii) R m and R n each independently is selected from hydrogen, (1-6C)alkyl or (CH2) 0-3 phenyl; R o and R p each independently is selected from hydrogen, (1-6C)alkyl or phenyl, or R o and R p together with the nitrogen atom to which they are attached form a 3-7 membered ring which can optionally include a further heteroatom, and wherein R o and R p any 3-7 membered ring formed by R m , R n , R o and R p any alkyl or phenyl present is optionally further substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl and (1-2C)alkyl; and (iii) R 200 Any (3-7C)cycloalkyl, heterocyclyl, heteroaryl or phenyl moiety in a substituent is optionally further substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, (1-2C)alkyl, (1-2C)haloalkyl, (1-2C)hydroxyalkyl, OR q , C(O)R q , C(O)OR q , OC(O)R q , C(O)N(R q )R r , N(R r )C(O)R q , S(O) y4 R q , SO2N(R r )R q , N(R r )SO2R q or NR r R q , wherein R q is hydrogen, (1-2C)alkyl or phenyl, R r is selected from hydrogen or (1-2C)alkyl; and y4 is independently selected from 0, 1 or 2.

11. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is selected from hydrogen, (1-8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (3-7C)cycloalkyl, phenyl, 5- or 6-membered heteroaryl, 4- to 7-membered heterocyclyl, (CH2) 0-3 (3-7C)cycloalkyl, (CH2) 0-3 [4- to 7-membered heterocyclyl], (CH2) 0-3 [5- or 6-membered heteroaryl], (CH2) 0-3 phenyl, -C(O)-(CH2) 0-3 (3-7C)cycloalkyl, -C(O)-(CH2) 0-3 [4- to 7-membered heterocyclyl], -C(O)-(CH2) 0-3 [5- or 6-membered heteroaryl], -C(O)-(CH2) 0-3 phenyl, -C(O)O(1-8C)alkyl, -C(O)NR 3a -(1-8C)alkyl, -C(O)NR 3a -(CH2) 0-3 (3-7C)cycloalkyl, -C(O)NR 3a -(CH2) 0-3 [5- to 7-membered heterocyclyl], -C(O)NR 3a -(CH2) 0-3 [5- or 6-membered heteroaryl] or -C(O)NH-(CH2) 0-3 phenyl; wherein R is hydrogen or (1-2C)alkyl; and 3a is hydrogen or (1-2C)alkyl; wherein any (1-8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (3-7C)cycloalkyl, phenyl, 5 or 6 membered heteroaryl or 4 to 7 membered heterocyclyl moiety is optionally substituted by one or more R 200 substituents; wherein R 200 is selected from halo, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, nitro, (1-4C)alkyl, (1-4C)hydroxyalkyl, (CH2) z OR m , (CH2) z C(O)R m , (CH2) z C(O)OR m , (CH2) z C(O)N(R o )R p , (CH2) z N(R n )C(O)R m , (CH2) z N(R n )C(O)OR m , (CH2) z S(O) y3 R m , (CH2) z SO2N(R o )R p , (CH2) z N(R n )SO2R m , (CH2) z NR o R p , (CH2) z (3-7C)cycloalkyl, (CH2) z [4- to 7-membered heterocyclyl], (CH2) z [5- or 6-membered heteroaryl], (CH2) z phenyl; and wherein: (i) z and y3 are as defined in claim 1 ; and (ii) R m and R n are each independently selected from hydrogen, (1-6C)alkyl or (CH2) 0-3 phenyl; R o and R p are each independently selected from hydrogen, (1-6C)alkyl or phenyl, or R o and R p together with the nitrogen atom to which they are attached form a 3-7 membered ring which can optionally include a further heteroatom, and wherein R o and R p form any 3-7 membered ring, and any alkyl or phenyl present for R m , R n , R o and R p is optionally further substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl and (1-2C)alkyl.

12. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is selected from hydrogen, (1-8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (3-7C)cycloalkyl, phenyl, 5- or 6-membered heteroaryl, 4- to 7-membered heterocyclyl, (CH2) 0-3 (3-7C)cycloalkyl, (CH2) 0-3 [4- to 7-membered heterocyclyl], (CH2) 0-3 [5- or 6-membered heteroaryl], (CH2) 0-3 phenyl, -C(O)-(CH2) 0-3 (3-7C)cycloalkyl, -C(O)-(CH2) 0-3 [4- to 7-membered heterocyclyl], -C(O)-(CH2) 0-3 [5- or 6-membered heteroaryl], -C(O)-(CH2) 0-3 phenyl, -C(O)O(1-8C)alkyl, -C(O)NR 3a -(1-8C)alkyl, -C(O)NR 3a -(CH2) 0-3 (3-7C)cycloalkyl, -C(O)NR 3a -(CH2) 0-3 [5- to 7-membered heterocyclyl], -C(O)NR 3a -(CH2) 0-3 [5- or 6-membered heteroaryl], or -C(O)NR 3a -(CH2) 0-3 phenyl; wherein R is hydrogen or (1-2C)alkyl; and 3a is hydrogen or (1-2C)alkyl; wherein any (1-8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (3-7C)cycloalkyl, phenyl, 5 or 6 membered heteroaryl or 4 to 7 membered heterocyclyl moiety is optionally substituted by one or more R 200 substituents; wherein R 200 is selected from halo, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, nitro, (1-4C)alkyl, (1-4C)hydroxyalkyl, (CH2) z O m , (CH2) z C(O)R m , (CH2) z C(O)OR m , (CH2) z C(O)N(R o )R p , (CH2) z N(R n )C(O)R m , (CH2) z N(R n )C(O)OR m , (CH2) z S(O) y3 R m , (CH2) z SO2N(R o )R p , (CH2) z N(R n )SO2R m or (CH2) z NR o R p ; and wherein: R m and R n are each independently selected from hydrogen, (1-6C)alkyl or phenyl; R o and R p are each independently selected from hydrogen, (1-6C)alkyl or (CH2) 0-2 phenyl, or R o and R p together with the nitrogen atom to which they are attached form a 3-7 membered ring which can optionally include a further heteroatom, and wherein R o and R p form any 3-7 membered ring, and any alkyl or phenyl present for R m , R n , R o and R p is optionally further substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl and (1-2C)alkyl; and y3 is as defined in claim 1.

13. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is hydrogen or is selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ； wherein any of the above cycloalkyl, heterocyclyl, aryl or heteroaryl groups are optionally substituted with one or more R 200 substituted with one or more R 200 as defined in any of the preceding claims.

14. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is a compound of formula (la): ， wherein R1, R3, R4 and R5 are each as defined in any one of claims 1 to 13.

15. A compound according to claim 14, or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is hydrogen and R1 is a substituent as defined in any one of claims 1 and 3 to 9 other than hydrogen.

16. A compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is a compound of formula (lb): ， wherein R3 is a substituent as defined in any one of claims 1 or 10 to 13 other than hydrogen and R4 and R5 are each as defined in claim 1.

17. A compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is a compound of formula (lc): ， wherein R1, R4, X1, X2 and Q are each as defined in any one of claims 1 to 13.

18. The compound of claim 17, or a pharmaceutically acceptable salt or solvate thereof, wherein X2 is selected from N and CR a ; wherein R5 is selected from hydrogen, fluoro, chloro, methyl, or cyano.

19. A compound according to claim 17 or 18, or a pharmaceutically acceptable salt or solvate thereof, wherein Q is hydrogen, halo, cyano or a group of the formula: -L1-Y1-L2-Q1 wherein: L1 is absent or (1-4C)alkylene; L2 is absent or (1-3C)alkylene; and Y1is absent, O, S, SO, SO2, N(R y1 ), C(O), C(O)O, OC(O), C(O)N(R y1 ), or N(R y1 )C(O), wherein R y1 is selected from hydrogen or (1-6C)alkyl; Q1 is hydrogen, (1-6C)alkyl, phenyl, (3-8C)cycloalkyl, 5 or 6 membered heteroaryl or 4 to 7 membered heterocyclyl; ​ wherein Q is optionally further substituted by one or more substituents independently selected from oxo, (1-6C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)aminoalkyl, (1-4C)hydroxyalkyl, cyano, or by one or more groups of the formula: -L3-Y2-L4-W1 wherein: L3 is absent or (1-4C)alkylene; Y2 is absent or selected from O, S, SO, SO2, N(R y2 ), C(O), C(O)O, OC(O), C(O)N(R y2 ), N(R y2 )C(O) or S(O)2N(R y2 ), N(R y2 )SO2, wherein R y2 is selected from hydrogen or (1-4C)alkyl; L4 is absent or (1-3C)alkylene; and W1 is hydrogen, (1-6C)alkyl, aryl, (3-8C)cycloalkyl, 5- or 6-membered heteroaryl, or 4- to 7-membered heterocyclyl; wherein W1is optionally substituted with one or more substituents selected from oxo, (1- 4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, amino, (1-4C)alkylamino, di[(1-4C)alkyl]amino C(O)OH, C(O)O(1-4C)alkyl, (CH2) 0-3 -[4 to 7 membered heterocyclyl] or cyano; Optionally, wherein Q is a group of the formula: -L1-Y1-L2-Q1 wherein: L1 is absent or (1-4C)alkylene; Y1is absent, O, S, SO, SO2, N(R y1 ), C(O), C(O)O, OC(O), C(O)N(R y1 ), or N(R y1 )C(O), wherein R y1 is selected from hydrogen or (1-4C)alkyl; L2 is absent or (1-3C)alkylene; and Q1 is hydrogen, (1-6C)alkyl, phenyl, (3-8C)cycloalkyl, 5- or 6-membered heteroaryl, or 4- to 7-membered heterocyclyl; wherein Q is optionally further substituted by one or more substituents independently selected from oxo, (1-6C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)aminoalkyl, (1-4C)hydroxyalkyl, cyano, or by one or more groups of the formula: -L3-Y2-L4-W1 wherein: L3 is absent or (1-3C)alkylene; Y2 is absent or selected from O, S, SO, SO2, N(R y2 ), C(O), C(O)O, OC(O), C(O)N(R y2 ), N(R y2 )C(O), S(O)2N(R y2 ), or N(R y2 )SO2, wherein R y2 is selected from hydrogen or (1-2C)alkyl; L4 is absent or (1-3C)alkylene; and W1 is hydrogen, (1-6C)alkyl, aryl, (3-8C)cycloalkyl, 5- or 6-membered heteroaryl, or 4- to 7-membered heterocyclyl; wherein W1is optionally substituted with one or more substituents selected from oxo, (1- 4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, amino, (1-4C)alkylamino, di[(1-4C)alkyl]amino C(O)OH, C(O)O(1-4C)alkyl, (CH2) 0-3 -[4 to 7 membered heterocyclyl] or cyano; Further optionally, wherein: L1 is absent or (1-3C)alkylene; Y1is absent, O, S, N(R y1 ), C(O), C(O)O, C(O)N(R y1 ), or N(R y1 )C(O), wherein R y1 is selected from hydrogen or (1-4C)alkyl; L2 is absent or methylene; and Q1 is hydrogen, (1-6C)alkyl, phenyl, (3-8C)cycloalkyl, 5- or 6-membered heteroaryl, or 4- to 7-membered heterocyclyl; wherein Q is optionally further substituted by one or more substituents independently selected from oxo, (1-6C)alkyl, halo, (1-2C)haloalkyl, (1-2C)haloalkoxy, cyano, or by one or more groups of the formula: -L3-Y2-L4-W1 wherein: L3 is absent or (1-4C)alkylene; Y2 is absent or selected from O, SO2, N(R y2 ), C(O), C(O)O, C(O)N(R y2 ), or N(R y2 )SO2, wherein R y2 is selected from hydrogen or (1-2C)alkyl; L4 is absent or (1-3C)alkylene; and W1 is hydrogen, (1-6C)alkyl, aryl, (3-8C)cycloalkyl, 5- or 6-membered heteroaryl, or 4- to 7-membered heterocyclyl; W1 is optionally composed of one or more radicals selected from oxo, (1-4C)alkyl, halogen, (1-2C)haloalkyl, (1-2C)haloalkoxy, (1-4C)alkoxy, C(O)OH, C(O)O(1-4C)alkyl, (CH2). 0-3 Substitution with [4 to 7-membered heterocyclic groups] or cyano groups.

20. The compound of any one of claims 17-19, or a pharmaceutically acceptable salt or solvate thereof, wherein Q is a group selected from hydrogen, halo, cyano, (1-6C)alkyl, (1-6C)alkoxy, (1-6C)haloalkyl, (1-6C)haloalkoxy, or a group of the formula: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ； wherein any of the aforementioned cycloalkyl, heterocyclyl, aryl, or heteroaryl rings can be optionally substituted by one or more substituents selected from oxo, (1-6C)alkyl, halo, (1-2C)haloalkyl, (1-2C)haloalkoxy, cyano, or by one or more groups of the formula: -L3-Y2-L4-W1 L3, Y2, L4 and W1 are as defined in any of the preceding claims.

21. The compound according to any one of claims 17-20, or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is selected from hydrogen or fluorine.

22. The compound or a pharmaceutically acceptable salt or solvate thereof according to any one of claims 17-21, wherein X1 is N or CR5; wherein R5 is selected from hydrogen, halogen or cyano.

23. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt or solvate thereof, selected from: 5-(2-aminopyridin-4-yl)-7-chloro-1H-indazole-3-amine; 5-(2-aminopyridin-4-yl)-7-methyl-1H-indazole-3-amine; 5-(2-aminopyridin-4-yl)-7-(trifluoromethyl)-1H-indazole-3-amine; 5-(2-(ethylamino)pyridin-4-yl)-1H-indazole-3-amine; 5-(2-(propylamino)pyridin-4-yl)-1H-indazole-3-amine; 5-(2-(isopropylamino)pyridin-4-yl)-1H-indazole-3-amine; 5-(2-((cyclopropylmethyl)amino)pyridin-4-yl)-1H-indazole-3-amine; 5-(2-(isopentylamino)pyridin-4-yl)-1H-indazole-3-amine; 5-(2-(hexylamino)pyridin-4-yl)-1H-indazole-3-amine; 5-(2-(cyclohexylamino)pyridin-4-yl)-1H-indazole-3-amine; 5-{2-[(trans-4-methylcyclohexyl)amino]pyridin-4-yl}-1H-indazole-3-amine; 2-((4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)amino)ethanol-1-ol; 3-((4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)amino)prop-1-ol; 4-((4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)amino)but-1-ol; 5-((4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)amino)pentan-1-ol; 5-{2-[(trans-4-hydroxycyclohexyl)amino]pyridin-4-yl}-1H-indazole-3-amine; 5-(2-((2-methoxyethyl)amino)pyridin-4-yl)-1H-indazole-3-amine; 5-(2-((3-methoxypropyl)amino)pyridin-4-yl)-1H-indazole-3-amine; 5-(2-((3-isopropoxypropyl)amino)pyridin-4-yl)-1H-indazole-3-amine; 3-((4-(3-amino-1H-indazol-5-yl)pyrimidin-2-yl)amino)prop-1-ol; 3-((4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)(methyl)amino)prop-1-ol; 5-(2-((2-morpholinoethyl)amino)pyridin-4-yl)-1H-indazole-3-amine; 5-(2-((2-(piperidin-1-yl)ethyl)amino)pyridin-4-yl)-1H-indazole-3-amine; N 1 - N-(4-(3-amino-1 H-indol-6-yl)-N3-methylpropane-1,3-diamine; 5-(2-(benzylamino)pyridin-4-yl)-1H-indazole-3-amine; 3-(((4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)amino)methyl)benzonitrile; 5-(2-((3-methoxybenzyl)amino)pyridin-4-yl)-1H-indazole-3-amine; 2-(3-(((4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)amino)methyl)phenyl)propan-2-ol; 5-(2-((4-(trifluoromethyl)benzyl)amino)pyridin-4-yl)-1H-indazole-3-amine; 4-(((4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)amino)methyl)benzonitrile; 5-(2-((4-(tert-butyl)benzyl)amino)pyridin-4-yl)-1H-indazole-3-amine; 2-(4-(((4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)amino)methyl)phenyl)propan-2-ol; 5-(2-((4-(methylsulfonyl)benzyl)amino)pyridin-4-yl)-1H-indazole-3-amine; 5-(2-((furan-3-ylmethyl)amino)pyridin-4-yl)-1H-indazole-3-amine; 5-(2-((pyridin-2-ylmethyl)amino)pyridin-4-yl)-1H-indazole-3-amine; 5-(2-(phenethylamino)pyridin-4-yl)-1H-indazole-3-amine; 5-(2-((2-(pyridin-2-yl)ethyl)amino)pyridin-4-yl)-1H-indazole-3-amine; 5-(2-((2-(pyridin-3-yl)ethyl)amino)pyridin-4-yl)-1H-indazole-3-amine; 5-(2-((2-(pyridin-4-yl)ethyl)amino)pyridin-4-yl)-1H-indazole-3-amine; 5-(2-((2-(1H-indol-3-yl)ethyl)amino)pyridin-4-yl)-1H-indazole-3-amine; 5-(2-((4-fluorophenethyl)amino)pyridin-4-yl)-1H-indazole-3-amine; 5-(2-((4-chlorophenethyl)amino)pyridin-4-yl)-1H-indazole-3-amine; 4-(2-((4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)amino)ethyl)phenol; 5-(2-((4-methoxyphenethyl)amino)pyridin-4-yl)-1H-indazole-3-amine; 5-(2-((4-(tert-butyl)phenethyl)amino)pyridin-4-yl)-1H-indazole-3-amine; 4-(2-((4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)amino)ethyl)benzenesulfonamide; 5-(2-((3-chlorophenethyl)amino)pyridin-4-yl)-1H-indazole-3-amine; 5-(2-((2-(trifluoromethyl)phenethyl)amino)pyridin-4-yl)-1H-indazole-3-amine; 5-(2-((3-phenylpropyl)amino)pyridin-4-yl)-1H-indazole-3-amine; 5-(2-((2-phenoxyethyl)amino)pyridin-4-yl)-1H-indazol-3-amine; N-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)cyclopropanecarboxamide; N-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)benzamide; N-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-2-phenylacetamide; N-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-2-(3-fluorophenyl)acetamide; N-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-2-(3-methylphenyl)acetamide; N-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-2-(3-(trifluoromethyl)phenyl)acetamide; N-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-2-(3-chlorophenyl)acetamide; N-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-2-(3-aminophenyl)acetamide; N-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-2-(3-nitrophenyl)acetamide; N-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-2-(3-(methylsulfonyl)phenyl)acetamide; N-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-2-(3-methoxyphenyl)acetamide; N-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-2-(3-(benzyloxy)phenyl)acetamide; tert-butyl (3-(2-((4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)amino)-2-oxoethyl)phenyl)carbamate; N-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-2-(4-fluorophenyl)acetamide; N-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-2-(p-tolyl)acetamide; N-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-2-(4-(trifluoromethyl)phenyl)acetamide; N-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-2-(4-chlorophenyl)acetamide; N-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-2-(4-(methylthio)phenyl)acetamide; N-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-2-(4-(methylsulfonyl)phenyl)acetamide; N-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-2-(4-methoxyphenyl)acetamide; N-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-2-(4-aminophenyl)acetamide; tert-butyl (4-(2-((4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)amino)-2-oxoethyl)phenyl)carbamate; N-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-2-(2-fluorophenyl)acetamide; N-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-2-(o-tolyl)acetamide; N-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-2-(2-(trifluoromethyl)phenyl)acetamide; N-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-2-(2-chlorophenyl)acetamide; N-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-2-(2-methoxyphenyl)acetamide; N-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-2-(pyridin-2-yl)acetamide; N-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-2-(pyridin-3-yl)acetamide; N-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-2-(pyridin-4-yl)acetamide; N-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-3-phenylpropionamide; (4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)carbamate; 1-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-3-ethylurea; 1-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-3-propylurea; 1-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-3-isopentylurea; 1-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-3-cyclopentylurea; 1-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-3-cyclohexylurea; 1-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-3-(2-hydroxyethyl)urea; 1-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-3-(3-hydroxypropyl)urea; 1-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-3-(2-methoxyethyl)urea; 3-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-1-(2-hydroxyethyl)-1-methylurea; 1-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-3-benzylurea; 1-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-3-phenylethylurea; 1-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-3-(pyridin-2-ylmethyl)urea; 1-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-3-(pyridin-3-ylmethyl)urea; 1-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-3-(pyridin-4-ylmethyl)urea; 1-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-3-phenylurea; 1 -(4-(3-amino- 1 H-indazol-5-yl)pyridin-2-yl)-3-(3-fluorophenyl)urea; 1 -(4-(3-amino- 1 H-indazol-5-yl)pyridin-2-yl)-3-(3-fluorophenyl)urea; 1 -(4-(3-amino- 1 H-indazol-5-yl)pyridin-2-yl)-3-(3-fluorophenyl)urea; 1 -(4-(3-amino- 1 H-indazol-5-yl)pyridin-2-yl)-3-(3-fluorophenyl)urea; 3 -(3 -(4-(3 -amino- 1 H-indazol-5 -yl)pyridin-2-yl)ureido)-N-phenylbenzamide; 1 -(4-(3-amino- 1 H-indazol-5-yl)pyridin-2-yl)-3-(3-fluorophenyl)urea; 1 -(4-(3-amino- 1 H-indazol-5-yl)pyridin-2-yl)-3-(3-fluorophenyl)urea; 1 -(4-(3-amino- 1 H-indazol-5-yl)pyridin-2-yl)-3-(3-fluorophenyl)urea; 1 -(4-(3-amino- 1 H-indazol-5-yl)pyridin-2-yl)-3-(3-fluorophenyl)urea; 1 -(4-(3-amino- 1 H-indazol-5-yl)pyridin-2-yl)-3-(3-fluorophenyl)urea; 3 -(3 -(4-(3 -amino- 1 H-indazol-5 -yl)pyridin-2-yl)ureido)-N-phenylbenzamide; 1 -(4-(3-amino- 1 H-indazol-5-yl)pyridin-2-yl)-3-(3-fluorophenyl)urea; 1 -(4-(3-amino- 1 H-indazol-5-yl)pyridin-2-yl)-3-(3-fluorophenyl)urea; 1 -(4-(3-amino- 1 H-indazol-5-yl)pyridin-2-yl)-3-(3-fluorophenyl)urea; 1 -(4-(3-amino- 1 H-indazol-5-yl)pyridin-2-yl)-3-(3-fluorophenyl)urea; 1 -(4-(3-amino- 1 H-indazol-5-yl)pyridin-2-yl)-3-(3-fluorophenyl)urea; 1 -(4-(3-amino- 1 H-indazol-5-yl)pyridin-2-yl)-3-(3-fluorophenyl)urea; 5 -(2-((3 -isopropylphenyl)amino)pyridin-4-yl)- 1 H-indazol-3 -amine; 3 -((4-(3 -amino- 1 H-indazol-5 -yl)pyridin-2-yl)amino)phenol; (3 -((4-(3 -amino- 1 H-indazol-5 -yl)pyridin-2-yl)amino)phenyl)methanol; 3 -((4-(3 -amino- 1 H-indazol-5 -yl)pyridin-2-yl)amino)benzoic acid; ​ ​ ​ 3-((4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)amino)benzoic acid ethyl ester; 3-((4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)amino)benzamide; 3-((4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)amino)-N-(2-hydroxyethyl)benzamide; N1-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)benzene-1,3-diamine; N-(3-((4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)amino)phenyl)acetamide; N-(3-((4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)amino)phenyl)benzamide; 5-(2-((3-phenoxyphenyl)amino)pyridin-4-yl)-1H-indazol-3-amine; 5-(2-((3-(benzyloxy)phenyl)amino)pyridin-4-yl)-1H-indazol-3-amine; 5-(2-((4-fluorophenyl)amino)pyridin-4-yl)-1H-indazol-3-amine; 5-(2-((4-chlorophenyl)amino)pyridin-4-yl)-1H-indazol-3-amine; 4-((4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)amino)phenol; 5-(2-((4-methoxyphenyl)amino)pyridin-4-yl)-1H-indazol-3-amine; 5-(2-((4-(trifluoromethoxy)phenyl)amino)pyridin-4-yl)-1H-indazol-3-amine; 5-(2-((4-propoxyphenyl)amino)pyridin-4-yl)-1H-indazol-3-amine; 2-((4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)amino)phenol; 4-((4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)amino)-2-methylphenol; 5-((4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)amino)-2-methylphenol; 4-((4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)amino)-3-methylphenol; 5-(2-((3,4-dichlorophenyl)amino)pyridin-4-yl)-1H-indazol-3-amine; N-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)thiazol-2-amine; 5-(2-(pyrimidin-2-ylamino)pyridin-4-yl)-1H-indazol-3-amine; 5-(2-(pyridin-4-ylamino)pyridin-4-yl)-1H-indazol-3-amine; 5-(2-(pyridin-3-ylamino)pyridin-4-yl)-1H-indazol-3-amine; 5-(2-(pyridin-2-ylamino)pyridin-4-yl)-1H-indazol-3-amine; N2-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)pyridine-2,6-diamine; N2-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-N6-benzylpyridine-2,6-diamine; 5-(7H-pyrrolo[2,3-b]pyrimidin-4-yl)-1H-indazol-3-amine; 2-amino-4-(3-amino-1H-indazol-5-yl)-7H-pyrrolo[2,3-b]pyrimidine-5-carbonitrile; 5-(3H-imidazo[4,5-b]pyridin-7-yl)-1H-indazol-3-amine; 5-(3-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine; 5-(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine; 4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile; 5-(2-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine; 5-(2-(tert-butyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine; 5-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine; 4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid; 5-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine; 5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine; 4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile; 5-(7H-pyrrolo[2,3-b]pyrimidin-4-yl)-1H-indazol-3-amine; 7-bromo-5-(7H-pyrrolo[2,3-b]pyrimidin-4-yl)-1H-indazol-3-amine; 5-(2-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine; 5-(2-(tert-butyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine; 5-(2-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine; 5-(2-cyclohexyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine; 5-(2-neopentyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine; 5-(2-(cyclohexylmethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine; 5-(2-(2-cyclohexylethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine; 5-(2-benzyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine; (4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)methanol; 2-(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)propan-2-ol; 3-(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)pentan-3-ol; 5-(2-(tert-butoxymethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine; 5-(2-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine; 5-(2-(tetrahydro-2H-pyran-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine; 5-(2-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine; 4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid; 4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid methyl ester; 4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid ethyl ester; (4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)(pyrrolidin-1-yl)methanone; 4-(3-amino-1H-indazol-5-yl)-N-cyclopentyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide; 4-(3-amino-1H-indazol-5-yl)-N-cyclohexyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide; 4-(3-amino-1H-indazol-5-yl)-N-isopentyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide; 4-(3-amino-1H-indazol-5-yl)-N-phenethyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide; 4-(3-amino-1H-indazol-5-yl)-N-(3-phenylpropyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide; 4-(3-amino-1H-indazol-5-yl)-N-(2-methoxyethyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide; 4-(3-amino-1H-indazol-5-yl)-N-(2-aminoethyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide; 4-(3-amino-1H-indazol-5-yl)-N-(2-(dimethylamino)ethyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide; (4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)(4-methylpiperazin-1-yl)methanone; 4-(3-amino-1H-indazol-5-yl)-N-(2-(piperidin-1-yl)ethyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide; 4-(3-amino-1H-indazol-5-yl)-N-(2-(butyl(ethyl)amino)ethyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide; 4-(3-amino-1H-indazol-5-yl)-N-(2-(diisopropylamino)ethyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide; 4-(3-amino-1H-indazol-5-yl)-N-(3-(dimethylamino)propyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide; 5-(2-((tert-butylamino)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine; 5-(2-((isopentylamino)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine; 5-(2-(piperidin-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine; 5-(2-((cyclohexylamino)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine; 5-(2-((phenylamino)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine; 5-(2-(((2-(benzyloxy)phenyl)amino)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine; 5-(2-(((2-methoxyethyl)amino)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine; N1-((4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)-N2,N2-dimethylethane-1,2-diamine; 5-(2-(((3-methoxypropyl)amino)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine; 5-(2-(((3-isopropoxypropyl)amino)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine; N1-((4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)-N3,N3-dimethylpropane-1,3-diamine; 5-(2-((isopropyl(methyl)amino)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine 5-(2-(piperidin-1-ylmethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine; 5-(2-((4,4-difluoropiperidin-1-yl)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine 5-(2-(morpholinomethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine; 5-(2-((4-methylpiperazin-1-yl)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine; 5-(2-((4-(tert-butyl)piperazin-1-yl)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3- amine; 5-(2-(azepan-1-ylmethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine; 5-(2-((4-methyl-1,4-diazepan-1-yl)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3- amine; 5-(2-(2-(piperidin-1-yl)ethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine; 5-(2-(2-morpholinoethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine; 5-(2-(3-(piperidin-1-yl)propyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine; 5-(2-(3-(cyclohexylamino)propyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine; 5-(2-(3-morpholinopropyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine; 5-(2-(piperidin-4-ylmethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine; 5-(2-((1-benzylpiperidin-4-yl)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3- amine 5-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine; 5-(2-(3-(trifluoromethyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine; 3-(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)benzonitrile; 3-(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)phenol; 5-(2-(3-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine; 3-(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)benzoic acid; 3-(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)benzamide; 3-(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-N-(2-methoxyethyl)benzamide; 3-(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-N-(2-(piperidin-1- yl)ethyl)benzamide; (3-(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)phenyl)(4- methylpiperazin-1-yl)methanone; 5-(2-(3-(morpholinosulfonyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3- amine; 5-(2-(3-(morpholinosulfonyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3- amine; 5-(2-(3-(morpholinosulfonyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3- amine; 5-(2-(3-(morpholinosulfonyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3- amine; 5-(2-(3-(morpholinosulfonyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3- amine; N-(3-(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)phenyl)-3- methoxypropanamide; N-(3-(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)phenyl)-3- methoxypropanamide; 4-((3-(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)phenyl)amino)-4- oxobutanoic acid; N-(3-(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)phenyl)-3- methoxypropanamide; N-(3-(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)phenyl)-3- methoxypropanamide; 5-(2-(3-(morpholinosulfonyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3- amine; N-(3-(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)phenyl)-3- methoxypropanamide; 2-(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)phenol; 5-(2-(3-(morpholinosulfonyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3- amine; 5-(2-(3-(morpholinosulfonyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3- amine; 5-(2-(3-(morpholinosulfonyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3- amine; 4-(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-fluorobenzonitrile; 5-(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-(pyrrolidin-1- yl)benzonitrile; 5-(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-(4-methylpiperazin-1-yl)benzonitrile; 5,5'-(1H-pyrrolo[2,3-b]pyridine-2,4-diyl)bis(1H-indazol-3-amine); 5-(2-(3,5-difluorophenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine; 5-(2-(2,3,5-trifluorophenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine; 5-(2-(pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine; 5-(2-(pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine; 5-(2-(pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine; 5-(2-(pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine; 4-(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)pyridin-2(1H)-one; 5-(2-(2-fluoropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine; 5-(2-(2-fluoro-6-methylpyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine; 5-(2-(2,6-difluoropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine; 5-(2-(2-(piperidin-1-yl)pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine; 5-(2-(2-(piperazin-1-yl)pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine; 5-(2-(2-morpholinopyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine; 5-(2-(2-(4-(tert-butyl)piperazin-1-yl)pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine; 4-(4-(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)pyridin-2-yl)thiomorpholine 1,1-dioxide; 5-(2-(2,6-dimorpholinopyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine; 4-(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1-(4-(piperidin-1-ylmethyl)benzyl)pyridin-2(1H)-one; 4-(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1-(3-(piperidin-1-ylmethyl)benzyl)pyridin-2(1H)-one; 4-(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1-(2-(piperidin-1-ylmethyl)benzyl)pyridin-2(1H)-one; 5-(2-(5-methoxypyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine; 5-(2-(6-morpholinopyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine; 5-(2-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine; 5-(2-(6-((2-morpholinoethyl)amino)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine; 5-(2-(2-fluoropyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine; 5-(2-(2-morpholinopyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine; 5-(2-(3-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine; 5-(2-(3-isobutoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine; 5-(2-(3-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine; 5-(2-(3-(2-morpholinoethoxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine; 5-(2-(3-(benzyloxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine; 5-(2-(3-((3,5-dimethoxybenzyl)oxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine; 5-(2-(3-((4-fluorobenzyl)oxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine; 5-(2-(3-((2-fluorobenzyl)oxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine; 5-(2-(3-(pyridin-2-ylmethoxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine; 3-(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-fluorophenol; 5-(2-(3-fluoro-5-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine; 5-(2-(3-fluoro-5-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine; 5-(2-(3-fluoro-5-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine; 5-(2-(3-fluoro-5-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine; 5-(2-(3-fluoro-5-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine; 3-(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-5-(benzyloxy)benzoic acid methyl ester 5-(2-(3-(benzyloxy)-5-((2-methoxyethoxy)methyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine; 5-(2-(3-(benzyloxy)-5-((2-methoxyethoxy)methyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine; 5-(2-(3-(benzyloxy)-5-((2-methoxyethoxy)methyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine; 5-(2-(2-(benzyloxy)pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine; 5-(2-(2-(benzyloxy)pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine; 5-(2-(2-(benzyloxy)pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine; 5-(2-(2-(benzyloxy)pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine; 5-(2-(2-(benzyloxy)pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine; 5-(2-(2-(benzyloxy)pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine; 5-(2-(2-(benzyloxy)pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine; 5-(2-(2-(benzyloxy)pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine; 5-(2-(2-(benzyloxy)pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine; 5-(2-(2-(pyridin-3-ylmethoxy)pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine; 5-(2-(2-(pyridin-2-ylmethoxy)pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine; 5-(2-(6-(benzylamino)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine; 5-(2-(2-(benzylamino)pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine; 5-(2-(2-(benzyl(methyl)amino)pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine; 5-(2-(2-(benzylthio)pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine; 5-(2-(2-(benzylthio)-6-morpholinopyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine; 5-(2-(3-phenylethylphenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine; 5-(2-(2-phenethoxypyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine; 5-(2-(3-((phenylamino)methyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine; 5-(2-(3-((tert-butylamino)methyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine; 5-(2-(3-((cyclopentylamino)methyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine; 5-(2-(3-((cyclohexylamino)methyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine; 5-(2-(3-((butanoamino)methyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine; 5-(2-(3-((isopentylamino)methyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine 5-(2-(3-((butyl(ethyl)amino)methyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine; 5-(2-(3-((dibutylamino)methyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine; 5-(2-(2-fluoro-6-(piperidin-1-ylmethyl)pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine; 5-(2-(2-fluoro-6-(piperazin-1-ylmethyl)pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine; 5-(2-(2-fluoro-6-((4-methylpiperazin-1-yl)methyl)pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine; 4-((4-(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-6-fluoropyridin-2-yl)methyl)piperazine-1-carboxylic acid tert-butyl ester; 5-(2-(2-((tert-butylamino)methyl)-6-fluoropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine; 5-(2-(2-((cyclohexylamino)methyl)-6-fluoropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine; 5-(2-(2-fluoro-6-((phenylamino)methyl)pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine; 4-(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-2,6-difluorobenzamide 5-(2-(4-((dimethylamino)methyl)-3,5-difluorophenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine; 5-(2-(3,5-difluoro-4-(piperidin-1-ylmethyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine; 5-(2-(3,5-difluoro-4-((isopropyl(methyl)amino)methyl)-phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine 5-(2-(4-((butyl(ethyl)amino)methyl)-3,5-difluorophenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine; 5-(2-(4-((dibutylamino)methyl)-3,5-difluorophenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine; 5-(2-(3,5-difluoro-4-(3-morpholinopropyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine; 5-(2-(3,5-difluoro-4-(3-(piperidin-1-yl)propyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine; 5-(2-(4-(3-(diethylamino)propyl)-3,5-difluorophenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine; 5-(2-(4-(3-(dibutylamino)propyl)-3,5-difluorophenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine; 7-chloro-5-(2-(3-(morpholinomethyl)phenyl)-lH-pyrrolo[2,3-b]pyridin-4-yl)-lH- indazol-3-amine; 7-chloro-5-(2-(3-(morpholinomethyl)phenyl)-lH-pyrrolo[2,3-b]pyridin-4-yl)-lH- indazol-3-amine; 7-chloro-5-(2-(3-(morpholinomethyl)phenyl)-lH-pyrrolo[2,3-b]pyridin-4-yl)-lH- indazol-3-amine; 7-chloro-5-(2-(3-(morpholinomethyl)phenyl)-lH-pyrrolo[2,3-b]pyridin-4-yl)-lH- indazol-3-amine; 4-(3-amino-7-chloro-lH-indazol-5-yl)-N-(2-(piperidin-l-yl)ethyl)-lH-pyrrolo[2,3- b]pyridine-2-carboxamide; 7-chloro-5-(2-(3-(morpholinomethyl)phenyl)-lH-pyrrolo[2,3-b]pyridin-4-yl)-lH- indazol-3-amine; 7-chloro-5-(2-(3-(morpholinomethyl)phenyl)-lH-pyrrolo[2,3-b]pyridin-4-yl)-lH- indazol-3-amine; 7-chloro-5-(2-(3-(morpholinomethyl)phenyl)-lH-pyrrolo[2,3-b]pyridin-4-yl)-lH- indazol-3-amine; 7-chloro-5-(2-(3-(morpholinomethyl)phenyl)-lH-pyrrolo[2,3-b]pyridin-4-yl)-lH- indazol-3-amine; 7-chloro-5-(2-(3-(morpholinomethyl)phenyl)-lH-pyrrolo[2,3-b]pyridin-4-yl)-lH- indazol-3-amine; 7-chloro-5-(2-(3-(morpholinomethyl)phenyl)-lH-pyrrolo[2,3-b]pyridin-4-yl)-lH- indazol-3-amine; 7-chloro-5-(2-(3-(morpholinomethyl)phenyl)-lH-pyrrolo[2,3-b]pyridin-4-yl)-lH- indazol-3-amine; 5-(2-(3-(morpholinomethyl)phenyl)-lH-pyrrolo[2,3-b]pyridin-4-yl)-7-phenyl-lH- indazol-3-amine; 5-(2-(3-(morpholinomethyl)phenyl)-lH-pyrrolo[2,3-b]pyridin-4-yl)-7-phenyl-lH- indazol-3-amine; 5-(2-(3-(morpholinomethyl)phenyl)-lH-pyrrolo[2,3-b]pyridin-4-yl)-7-phenyl-lH- indazol-3-amine; or 5-(2-(3-(morpholinomethyl)phenyl)-lH-pyrrolo[2,3-b]pyridin-4-yl)-7-phenyl-lH- indazol-3-amine.

24. A pharmaceutical composition comprising a compound according to any one of claims 1-23, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

25. A compound according to any one of claims 1-23, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical formulation according to claim 24: (i) for use in therapy; (ii) for use in the treatment of a disease or condition responsive to IKK a modulation; (ii) for use in the treatment of a proliferative disorder (e.g. cancer); or (iii) for use in the treatment of inflammation.

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