IKK inhibitors

Abstract

The invention relates to an IKK-alpha inhibitory compound or a pharmaceutically acceptable salt, hydrate or solvate thereof. The IKK-alpha inhibitory compound has the structural formula (I) shown in the specification, wherein R1, X, R3, R4 and X1 are each as defined in the specification. 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. # imgabs0 #

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 alterations in cell proliferation. For decades, the exact mechanisms that lead to cell malignancy and uncontrolled, regulated proliferation have been a focus of intensive research. This research enables the identification of 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, immune response regulation, cell growth, proliferation, apoptosis, and differentiation and development [1-5]. NF-κB signaling is now believed to occur via canonical (classical) or atypical (alternative) pathways mobilizing homodimeric complexes of these family members. Figure 1 [1-5] 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 inhibitory κB (IκB) proteins (including isoforms of IκBα, IκBβ, and IκBε), and in the case of p105 and p100 proteins, they maintain their self-binding inhibitory form through their intrinsic protein structure consisting of C-terminal IκB-like structures composed of ankyrin repeat sequences (IκBδ and IκBγ, respectively) [1-5]. Activation and release of NF-κB protein generally occur in response to a number of extracellular ligands and reagents that generate a DNA damage response (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 classic 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 suggests that receptor-mediated atypical NF-κB activation is established as a paradigm surrounding the activation of its homologous receptor by TNF superfamily ligands through the recruitment of 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. Figure 1 [1-5]

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

[16] . TRAF3 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 events in the signaling pathway toward 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 dimeric complex with RelB and generates a p52-RelB dimer upon stimulated degradation, which can translocate to the nucleus to initiate transcription of different genes ( Figure 1 ).

[0008] 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 downstream signaling mediated by IKKα

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

[23] . Based on these observations, further research revealed that NIK plays a key role in regulating p100 processing by recruiting IKKα and binding 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, many 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 protein inhibitors of activated STAT1 (PIAS1)

[36] , which act as transcriptional / inflammatory regulators; estrogen receptors (ER)

[37] and androgen receptors (AR)

[38] , which are steroid hormone family receptors, and their associated steroid receptor cofactors (SRC)-3 [37, 39, 40] and aurora kinase A [41, 42], which promotes mitotic processes. 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 events that initiate and / or maintain the development of acquired traits or phenotypes, which we now refer to as “hallmarks” the cancer features identified and defined by Hanahan and Weinberg [46, 47]. Using a variety of experimental methods such as gene deletion and reconstruction [48, 49], siRNA “depletion”

[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 proliferative 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 consolidating phenotypes associated with long-term tumor development: by modulating the expression of adhesion molecules (e.g., VCAM; [48-50]), mammary maspin [50; 53], and MMP

[50] under different cell / 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 activating invasion and metastasis.It is equally 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 possibility that tumors are “addicted” to IKKα-mediated atypical NF-κB signaling, thereby “realizing their 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 could have significant effects on tumor-matrix communication and matrix composition in the tumor microenvironment and define a better understanding of “tumor-promoted 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 mutation background. This drives p45 IKKα-mediated nuclear signaling to be delivered 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 a desire to identify potentially useful IKKα inhibitors.

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

[0013] References

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[0059] According to a first aspect of the invention, a compound as defined herein or a pharmaceutically acceptable salt, hydrate or solvate thereof is provided.

[0060] 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.

[0061] 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.

[0062] 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.

[0063] 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.

[0064] 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.

[0065] 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 therapeutic purposes.

[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 as pharmaceuticals.

[0067] 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.

[0068] According to another aspect of the invention, compounds as defined herein, or pharmaceutically acceptable salts, hydrates, or solvates thereof, or pharmaceutical compositions, are provided for the treatment of cancer. In one particular embodiment, the cancer is a human cancer.

[0069] 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.

[0070] 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.

[0071] 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.

[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 cancer 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 inhibiting IKKα activity is provided.

[0074] 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.

[0075] According to another aspect of the invention, a method for preparing compounds as defined herein or pharmaceutically acceptable salts, hydrates or solvates thereof is provided.

[0076] 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.

[0077] 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.

[0078] 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

[0079] definition

[0080] Unless otherwise stated, the following terms used in the specification and claims have the following meanings.

[0081] 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 a 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.

[0082] 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.

[0083] When 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.

[0084] 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).

[0085] 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, and 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.

[0086] The terms “(m-nC)” or “(m-nC) group” used alone or as a prefix refer to any group having m to n carbon atoms.

[0087] "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.

[0088] 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.

[0089] 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.

[0090] "(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.

[0091] The term "alkoxy" refers to O-linked straight-chain and branched alkyl groups. Examples of alkoxy groups include methoxy, ethoxy, and tert-butoxy.

[0092] 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.

[0093] 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.

[0094] 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 spiro[3.3]heptyl.

[0095] The terms "heterocyclic group," "heterocyclic," or "heterocyclic" refer to a non-aromatic, saturated or partially saturated monocyclic, fused, bridged, or spirobicyclic heterocyclic system. Monocyclic heterocycles contain about 3 to 12 (suitably 3 to 7) ring atoms, having 1 to 5 (suitably 1, 2, or 3) heteroatoms selected from nitrogen, oxygen, or sulfur. 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 ethylene oxide, oxetyl, tetrahydrofuranyl, dioxanyl, and substituted cyclic ethers. Nitrogen-containing heterocycles include, for example, oxetyl, 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.

[0096] 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.

[0097] 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 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.

[0098] 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. Aromatics 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.

[0099] 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 include and encompasses 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.

[0100] 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.

[0101] 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.

[0102] 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.

[0103] Examples of six-membered heteroaryl groups include, but are not limited to, pyridyl, pyrazinyl, pyridinyl, pyrimidinyl, and triazinyl.

[0104] The bicyclic heteroaryl group can be, for example, selected from the following groups:

[0105] A benzene ring fused with a 5- or 6-membered ring containing 1, 2, or 3 heteroatoms;

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

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

[0108] Pyrrole rings fused with 5- or 6-membered rings containing 1, 2, or 3 heteroatoms;

[0109] A pyrazole ring fused with a 5- or 6-membered ring containing 1 or 2 heteroatoms;

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

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

[0112] Oxazole rings fused with 5- or 6-membered rings containing 1 or 2 heteroatoms;

[0113] An isoxazole ring fused with a 5- or 6-membered ring containing 1 or 2 heteroatoms;

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

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

[0116] Thiophene rings fused with 5- or 6-membered rings containing 1, 2, or 3 heteroatoms;

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

[0118] Cyclohexyl rings fused with 5- or 6-membered heteroaromatic rings containing 1, 2, or 3 cyclic heteroatoms; and

[0119] A cyclopentyl ring fused with a 5- or 6-membered heteroaromatic ring containing 1, 2, or 3 cyclic heteroatoms.

[0120] 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), indazole, benzodioxanepentenyl, and pyrazolopyridyl.

[0121] 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.

[0122] 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.

[0123] 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.

[0124] 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.

[0125] 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.

[0126] The phrase “compounds of the present invention” refers to those compounds disclosed herein, including both general and specific ones.

[0127] 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.

[0128] compound

[0129] On the one hand, the present invention relates to compounds having structural formula (I) or pharmaceutically acceptable salts, hydrates or solvates thereof, as follows:

[0130]

[0131] in:

[0132] R1 is selected from hydrogen, halogen, (1-6C)alkyl, (2-6C)ynyl, (3-7C)cycloalkyl, aryl, heteroaryl, and heterocyclic groups.

[0133] And wherein the (1-6C)alkyl, (2-6C)ynyl, (3-7C)cycloalkyl, aryl, heteroaryl, and heterocyclic groups are optionally surrounded by one or more R 100 Substituent substitution;

[0134] Where R 100 Selected from halogens, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, (1-4C)alkyl, (1-4C)hydroxyalkyl, and (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) y 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 or (CH2) z Aryl;

[0135] And among them:

[0136] (i)R f and R g Each is independently selected from hydrogen, (1-6C)alkyl, or phenyl; and wherein R h and R j Each is independently selected from hydrogen, (1-6C)alkyl or phenyl, or R hand 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

[0137] (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) y 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;

[0138] X is N or CR2; where R2 is selected from hydrogen, halogen, (1-8C)alkyl, (2-8C)alkenyl, (2-8C)ynyl, (3-7C)cycloalkyl, aryl, heteroaryl, and heterocyclic groups.

[0139] The (1-8C)alkyl, (2-8C)alkenyl, (2-8C)ynyl, (3-7C)cycloalkyl, aryl, heteroaryl, and heterocyclic groups are optionally surrounded by one or more R groups. 200 Substituent substitution;

[0140] Where R 200 Selected from halogens, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, (1-4C)alkyl, (1-4C)hydroxyalkyl, and (CH2). z OR m (CH2) z C(O)R m (CH2) z C(O)OR m (CH2) zOC(O)R m (CH2) z C(O)N(R o )R p (CH2) z N(R n )C(O)R m (CH2) z S(O) y 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 or (CH2) z Aryl;

[0141] And among them:

[0142] (i)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 phenyl, or R o and R p 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

[0143] (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 qS(O) y 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;

[0144] R3 is selected from hydrogen, (1-8C)alkyl, (3-7C)cycloalkyl, and (CH2). 1-3 (3-7C)cycloalkyl, carbon-linked 4-7-membered heterocyclic, carbon-linked 5-6-membered heteroaryl, -C(O)-(1-8C)alkyl, -C(O)(3-7C)cycloalkyl, -C(O)[5 or 6-membered heteroaryl], -C(O)phenyl, -C(O)O(1-8C)alkyl, C(O)O(3-7C)cycloalkyl, C(O)O(CH2) 1-3 (3-7C)cycloalkyl, -C(O)NH2, -C(O)NH-(1-8C)alkyl,

[0145] -C(O)NH-(CH2) 0-3 (3-7C)cycloalkyl, -C(O)NH-(CH2) 0-3 Heterocyclic group, -C(O)NH-(CH2) 0-3 [5 or 6-membered heteroaryl], -C(O)NH-(CH2) 0-3 Phenyl, -S(O)2H or -S(O)2-(1-8C)alkyl;

[0146] Any alkyl, cycloalkyl, phenyl, heteroaryl, or heterocyclic moiety may optionally be represented by one or more R 300 Substituent substitution;

[0147] Where R 300 Selected from halogens, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, (1-4C)alkyl, (1-4C)hydroxyalkyl, and (CH2). z OR s (CH2) z C(O)R s (CH2) z C(O)OR s (CH2) z OC(O)R s (CH2) z C(O)N(R v )R u (CH2)z N(R t )C(O)R s (CH2) z N(R t )C(O)OR s (CH2) z S(O) y R s (CH2) z SO2N(R v )R u (CH2) z N(R t SO2R s (CH2) z NR u R v ;

[0148] And among them:

[0149] (i)R s and R t Each is independently selected from hydrogen, (1-6C)alkyl, or (CH2). z Phenyl; R u and R v Each is independently selected from hydrogen, (1-6C)alkyl, or (CH2). z Phenyl, or R u and R v 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 s R t R u and R v 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

[0150] (ii)R 300 Any alkyl, 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 w C(O)R w C(O)OR w OC(O)R w C(O)N(R) w )R x 、N(Rx )C(O)R w S(O) y R w SO2N(R) x )R w 、N(R x SO2R w or NR w R x Substituents of R, wherein R w It is hydrogen, (1-2C)alkyl, or phenyl, and R x Selected from hydrogen or (1-2C) alkyl;

[0151] Alternatively, R2 and R3 can be linked together to form a -CH=CQ- or -N=CQ- group;

[0152] Q is a hydrogen, halogen, cyano, or a group of the following formula:

[0153] -L1-Y1-L2-Q1

[0154] in:

[0155] L1 is absent or is a (1-3C) alkylene group;

[0156] Y1 does not exist or is O, S, SO, SO2, or N(R). y1 ), C(O), C(O)O, OC(O),

[0157] C(O)N(R y1 ) or N(R y1 )C(O), where R y1 Selected from hydrogen or (1-4C) alkyl;

[0158] L2 is absent or is a (1-3C) alkylene group; and

[0159] Q1 is hydrogen, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)ynyl, phenyl, (3-8C)cycloalkyl, heteroaryl, or heterocyclic.

[0160] Q may optionally be further selected by one or more independently from oxo, hydroxyl, (1-6C) groups.

[0161] Alkyl, halogen, (1-4C) haloalkyl, (1-4C) haloalkoxy, (1-4C) aminoalkyl

[0162] (1-4C) The hydroxyalkyl or cyano group is substituted, or it is substituted by one or more groups of the following formula:

[0163] -L3-Y2-L4-W1

[0164] in:

[0165] L3 is absent or is a (1-3C) alkylene group;

[0166] Y2 does not exist or is selected from O, S, SO, SO2, N(R) y2 ), C(O), C(O)O,

[0167] OC(O), C(O)N(R) y2 ) or N(R y2 C(O), S(O)2N(R) y2 ), N(R y2 SO2,

[0168] Where R y2 Selected from hydrogen or (1-3C) alkyl;

[0169] L4 is absent or is a (1-3C) alkylene group; and

[0170] W1 is hydrogen, (1-6C)alkyl, phenyl, (3-8C)cycloalkyl, heteroaryl, or heterocyclic.

[0171] W1 is optionally divided by one or more elements selected from oxo, (1-4C) alkyl, halogen, ...

[0172] (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,

[0173] (CH2) 0-3 - Substitution of heterocyclic or cyano groups;

[0174] R4 is selected from hydrogen, halogen, cyano or amino;

[0175] When R2 and R3 are linked together to form a -CH=CH- group, X1 is N; or X1 is CR5, where R5 is selected from hydrogen, halogen, cyano or amino.

[0176] y is independently selected from 0, 1, or 2;

[0177] z can be independently selected from 0, 1, 2, or 3;

[0178] The conditions are:

[0179] (i) When R2 and R3 are both hydrogen, R1 is not hydrogen;

[0180] (ii) When R1 and R3 are both hydrogen, R2 is not hydrogen;

[0181] (iii) When R2 and R3 are connected to form a -CH=CH- group, R1 is not hydrogen;

[0182] (iv) When X is N and R3 is hydrogen, R1 is not hydrogen; and

[0183] (v) When L1, Y1 and L2 are not present, Q1 is not aryl or heteroaryl.

[0184] In another aspect, the present invention relates to compounds of formula I as defined above, wherein R3 is selected from hydrogen, cyano, (1-8C)alkyl, (3-7C)cycloalkyl, and (CH2). 1-3 (3-7C)cycloalkyl, carbon-linked 4-7-membered heterocyclic groups, carbon-linked 5-6-membered heteroaryl groups, -C(O)-(1-8C)alkyl, -C(O)(CH2) 0-3 (3-7C)cycloalkyl, -C(O)[5 or 6-membered heteroaryl], -C(O)phenyl, -C(O)O(1-8C)alkyl, -C(O)O(3-7C)cycloalkyl, -C(O)O(CH2) 1-3 (3-7C)cycloalkyl, -C(O)NH2, -C(O)NH-(1-8C)alkyl, -C(O)NH-(CH2) 0-3 (3-7C)cycloalkyl, -C(O)NH-(CH2) 0-3 Heterocyclic group, -C(O)NH-(CH2) 0-3 [5 or 6-membered heteroaryl], -C(O)NH-(CH2) 0-3 Phenyl, -S(O)2H or -S(O)2-(1-8C)alkyl; wherein any alkyl, cycloalkyl, phenyl, heteroaryl or heterocyclic moiety is optionally surrounded by one or more R as defined herein. 300 Substituent substitution.

[0185] 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 structural formulas (Ia), (Ib), (Ic), (Id) or (Ie) shown below:

[0186]

[0187] R1, X, R3, R4, R5 and Q are each defined as described in this paper.

[0188] Specific compounds of the present invention include, for example, compounds of formula (I) [including sub-formulas (Ia), (Ib), (Ic), (Id), (Ie), or (If)], or pharmaceutically acceptable salts, hydrates, and / or solvates thereof, wherein, unless otherwise stated, R1, X, R2, R3, R4, X1, R5, and Q, and any associated substituents, each have any meaning as defined in any of paragraphs (1) to (43) above or below:

[0189] (1) R1 is selected from hydrogen, halogen, (1-6C)alkyl, (2-6C)ynyl, (3-7C)cycloalkyl, phenyl, 5- or 6-membered heteroaryl or 4-7-membered heterocyclic group.

[0190] The (2-6C) ynyl, (3-7C) cycloalkyl, phenyl, heteroaryl, and heterocyclic groups are optionally surrounded by one or more R groups. 100 Substituent substitution;

[0191] And R 100 Selected from halogens, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, (1-4C)alkyl, (1-4C)hydroxyalkyl, and (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) y 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 or (CH2) z Phenyl;

[0192] And among them:

[0193] (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 jTogether with the nitrogen atoms they are attached to, they form 3-7 membered rings, which may optionally include additional heteroatoms; and

[0194] (ii)R 100 Any (1-4C) alkyl, (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 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) y 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

[0195] (2) R1 is selected from hydrogen, halogen, (1-6C)alkyl, (2-6C)ynyl, phenyl, or 5- or 6-membered heteroaryl.

[0196] The (2-6C) alkynyl, phenyl, or heteroaryl group is optionally surrounded by one or more R groups. 100 Substituent substitution;

[0197] And R 100 Selected from halogens, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, (1-4C)alkyl, (1-4C)hydroxyalkyl, and (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) y 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 -[4-6 membered heterocyclic group], (CH2) z -[5 or 6-membered heteroaryl] or (CH2) z Phenyl;

[0198] And among them:

[0199] (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

[0200] (ii)R 100 Any (1-4C) alkyl, (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 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) y 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 lSelected from hydrogen or (1-2C)alkyl.

[0201] (3) R1 is selected from hydrogen, halogen, (1-6C)alkyl, (2-6C)ynyl, phenyl, or 5- or 6-membered heteroaryl.

[0202] The (2-6C) alkynyl, phenyl, or heteroaryl group is optionally surrounded by one or more R groups. 100 Substituent substitution;

[0203] And R 100 Selected from halogens, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, (1-4C)alkyl, (1-4C)hydroxyalkyl, and (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) y 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 -[4-6 membered heterocyclic group], (CH2) z -[5 or 6-membered heteroaryl] or (CH2) z Phenyl;

[0204] And among them:

[0205] (i)R f and R g Each is independently selected from hydrogen or (1-2C)alkyl; and

[0206] (ii)R 100Any (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;

[0207] (4) R1 is selected from hydrogen, (2-6C) ynyl, phenyl, or 5- or 6-membered heteroaryl.

[0208] The (2-6C) alkynyl, phenyl, or heteroaryl group is optionally surrounded by one or more R groups. 100 Substituent substitution;

[0209] And R 100 Selected from halogens, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, (1-4C)alkyl, (1-4C)hydroxyalkyl, and (CH2). z 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) y R f SO2N(R) j )R h 、N(R g SO2R f NR j R h (CH2) z -[4-6 membered heterocyclic group] or (CH2) z Phenyl;

[0210] And among them:

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

[0212] (ii)R 100 Any (1-4C) alkyl, heterocyclic, or phenyl moiety in the substituent may optionally be further selected from one or more halogens, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, (1-2C) alkyl, (1-2C) haloalkyl, (1-2C) hydroxyalkyl, or OR k Substituents of R, wherein R kSelected from hydrogen or (1-2C) alkyl;

[0213] (5) R1 is selected from:

[0214] (i)Hydrogen;

[0215] (ii) Halogens;

[0216] (iii) Methyl;

[0217] (iv)CF3;

[0218] (v) ethynyl group, i.e.

[0219]

[0220] Its optional use by R 100 replace;

[0221] (vi) Optionally subject to R 100 Substituted phenyl;

[0222] (vii) Optionally placed by R 100 Substituted 5- or 6-membered heteroaryl groups;

[0223] And R 100 Selected from halogens, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, (1-4C)alkyl, (1-4C)hydroxyalkyl, and (CH2). z 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) y R f SO2N(R) j )R h 、N(R g SO2R f NR j R h (CH2) z -[4-6 membered heterocyclic group] or (CH2) z Phenyl;

[0224] And among them:

[0225] (i)R f and R g Each is independently selected from hydrogen or (1-2C)alkyl; and

[0226] (ii)R 100Any (1-4C) alkyl, heterocyclic, or phenyl moiety in the substituent may optionally be further selected from one or more halogens, 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.

[0227] (6) R1 is selected from:

[0228] (i)Hydrogen;

[0229] (ii) Ethynyl group, i.e.

[0230]

[0231] Its optional use by R 100 replace;

[0232] (iii) Randomly selected by R 100 Substituted phenyl;

[0233] (iv) 5- or 6-membered heteroaryl groups;

[0234] And R 100 Selected from halogens, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, (1-4C)alkyl, (1-4C)hydroxyalkyl, and (CH2). z 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) y R f SO2N(R) j )R h 、N(R g SO2R f NR j R h (CH2) z -[4-6 membered heterocyclic group] or (CH2) z Phenyl;

[0235] And among them:

[0236] (i)R f and R g Each is independently selected from hydrogen or (1-2C)alkyl; and

[0237] (ii)R 100Any (1-4C) alkyl, heterocyclic, or phenyl moiety in the substituent may optionally be further selected from one or more halogens, 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;

[0238] (7) R1 is selected from:

[0239] (i)Hydrogen;

[0240] (ii) Ethynyl group, i.e.

[0241]

[0242] Its optional use by R 100 replace;

[0243] (iii) Randomly selected by R 100 Substituted phenyl;

[0244] (iv) 5- or 6-membered heteroaryl groups;

[0245] And R 100 Selected from halogens, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, (1-4C)alkyl, (1-4C)hydroxyalkyl, and (CH2). z 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) y R f SO2N(R) j )R h NR j R h (CH2) z -[4-6 membered heterocyclic group] or (CH2) z Phenyl;

[0246] And among them:

[0247] (i)R f and R g Each is independently selected from hydrogen or (1-2C)alkyl; and

[0248] (ii)R 100Any (1-4C) alkyl, heterocyclic, or phenyl moiety in the substituent may optionally be further selected from one or more halogens, 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;

[0249] (8) R1 is selected from:

[0250] (i)Hydrogen;

[0251] (ii) Ethynyl group, i.e.

[0252]

[0253] Its optional use by R 100 replace;

[0254] (iii) Randomly selected by R 100 Substituted phenyl;

[0255] (iv) 5- or 6-membered heteroaryl groups;

[0256] And R 100 Selected from halogens, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, (1-4C)alkyl, (1-4C)hydroxyalkyl, and (CH2). z OR f C(O)R f C(O)OR f C(O)N(R) j )R h S(O) y R f SO2N(R) j )R h NR j R h (CH2) z -[4-6 membered heterocyclic group] or (CH2) z Phenyl;

[0257] And among them:

[0258] (i)R f and R g Each is independently selected from hydrogen or (1-2C)alkyl; and

[0259] (ii)R 100Any (1-4C) alkyl, heterocyclic, or phenyl moiety in the substituent may optionally be further selected from one or more halogens, 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;

[0260] (9) R1 is selected from:

[0261] (i)Hydrogen;

[0262] (ii) Ethynyl group, i.e.

[0263]

[0264] Its optional use by R 100 replace;

[0265] (iii) Randomly selected by R 100 Substituted phenyl;

[0266] (iv) 5- or 6-membered heteroaryl groups;

[0267] And R 100 Selected from halogens, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, (1-4C)alkyl, (1-4C)hydroxyalkyl, and (CH2). z OR f C(O)R f C(O)OR f C(O)N(R) j )R h S(O) y R f SO2N(R) j )R h NR j R h (CH2) z -[4-6 membered heterocyclic group] or (CH2) z Phenyl;

[0268] And among them:

[0269] (i)R f and R g Each is independently selected from hydrogen or (1-2C)alkyl; and

[0270] (ii)R 100 Any (1-4C) alkyl, heterocyclic, or phenyl moiety in the substituent may optionally be further selected from one or more halogens, (1-2C) alkyl groups, or OR groups. k Substituents of R, wherein R kSelected from hydrogen or methyl;

[0271] (10) X is N or CR2; wherein R2 is selected from hydrogen, halogen, (1-8C)alkyl, (2-8C)alkenyl, (2-8C)ynyl, (3-7C)cycloalkyl, phenyl, 5- or 6-membered heteroaryl or 4-7-membered heterocyclic group.

[0272] The (1-6C)alkyl, (2-6C)alkenyl, (2-6C)ynyl, (3-7C)cycloalkyl, phenyl, 5- or 6-membered heteroaryl, or 4-7-membered heterocyclic group is optionally surrounded by one or more R 200 Substituent substitution;

[0273] And R 200 Selected from halogens, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, (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 S(O) y 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 or (CH2) z Phenyl;

[0274] And among them:

[0275] (i)R m and R n Each is independently selected from hydrogen, (1-6C)alkyl, or phenyl; R o and R pEach is independently selected from hydrogen, (1-6C)alkyl or phenyl, or R o and R p 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

[0276] (ii)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) y 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

[0277] (11) X is N or CR2; wherein R2 is selected from hydrogen, halogen, (1-8C)alkyl, (2-8C)ynyl, (3-7C)cycloalkyl, phenyl, 5- or 6-membered heteroaryl or 4-7-membered heterocyclic group.

[0278] The (2-6C) ynyl, (3-7C) cycloalkyl, phenyl, heteroaryl, and heterocyclic groups are optionally surrounded by one or more R groups. 200 Substituent substitution;

[0279] And R 200 Selected from halogens, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, (1-4C)alkyl, (1-4C)hydroxyalkyl, and (CH2). z OR m (CH2) z C(O)R m (CH2) z C(O)ORm (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 S(O) y 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 or (CH2) z Phenyl;

[0280] And among them:

[0281] (i)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 phenyl, or R o and R p 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

[0282] (ii)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(Rr )C(O)R q S(O) y 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

[0283] (12) X is N or CR2; where R2 is selected from hydrogen, fluorine, (1-8C)alkyl, (2-8C)alkynyl, (3-7C)cycloalkyl, phenyl, or 5- or 6-membered heteroaryl.

[0284] The (1-6C) ynyl, (3-7C) cycloalkyl, phenyl, heteroaryl, and heterocyclic groups are optionally surrounded by one or more R groups. 200 Substituent substitution;

[0285] And R 200 Selected from halogens, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, (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 S(O) y 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) zHeterocyclic group, (CH2) z heteroaryl or (CH2) z Phenyl;

[0286] And among them:

[0287] (i)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 phenyl, or R o and R p 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

[0288] (ii)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) y 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

[0289] (13) X is N or CR2; wherein R2 is selected from hydrogen, fluorine, (1-8C)alkyl, (3-7C)cycloalkyl, or (2-6C)alkynyl.

[0290] The (2-6C) ynyl group is optionally surrounded by one or more R groups. 200 Substituent substitution;

[0291] And R200 Selected from halogens, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, (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 S(O) y 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 or (CH2) z Phenyl;

[0292] And among them:

[0293] (i)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 phenyl, or R o and R p 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

[0294] (ii)R 200Any (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) y 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;

[0295] (14) X is N or CR2; where R2 is selected from:

[0296] (i)Hydrogen;

[0297] (ii) Fluorine;

[0298] (iii) Ethynyl group, i.e.

[0299]

[0300] Its optional use by R 200 replace;

[0301] (vi) Optionally subject to R 200 Substituted phenyl;

[0302] (vii) Optionally placed by R 200 Substituted 5- or 6-membered heteroaryl groups;

[0303] And R 200 Selected from halogens, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, (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)Rm (CH2) z C(O)N(R o )R p (CH2) z N(R n )C(O)R m (CH2) z S(O) y 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 or (CH2) z Phenyl;

[0304] And among them:

[0305] (i)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 phenyl, or R o and R p 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

[0306] (ii)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)y 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;

[0307] (15) X is N or CR2; where R2 is selected from:

[0308] (i) Hydrogen; or

[0309] (ii) Ethynyl group, i.e.

[0310]

[0311] Its optional use by R 200 replace;

[0312] And R 200 Selected from halogens, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, (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 S(O) y 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) zheteroaryl or (CH2) z Phenyl;

[0313] And among them:

[0314] (i)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 phenyl, or R o and R p 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

[0315] (ii)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) y 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;

[0316] (16) X is N or CR2; where R2 is selected from:

[0317] (i) Hydrogen; or

[0318] (ii) Ethynyl group, i.e.

[0319]

[0320] Its optional use by R 200 replace;

[0321] And R 200 Selected from halogens, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, (1-4C)alkyl, (1-4C)hydroxyalkyl, and (CH2). z OR m (CH2) z C(O)R m (CH2) z C(O)N(R o )R p (CH2) z N(R n )C(O)R m (CH2) z S(O) y R m (CH2) z NR o R p (CH2) z (3-7C)cycloalkyl, (CH2) z Heterocyclic group, (CH2) z heteroaryl or (CH2) z Phenyl;

[0322] And among them:

[0323] (i)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 phenyl, or R o and R p Together with the nitrogen atoms to which they are attached, they form a 3-6 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

[0324] (ii)R 200 Any (3-7C) cycloalkyl, heterocyclic, heteroaryl, or phenyl moiety in the substituent may optionally be further selected from one or more halogens, 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) y 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;

[0325] (17) X is N or CR2; where R2 is selected from:

[0326] (i) Hydrogen; or

[0327] (ii) Ethynyl group, i.e.

[0328]

[0329] Its optional use by R 200 replace;

[0330] And R 200 Selected from halogens, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, (1-4C)alkyl, (1-4C)hydroxyalkyl, and (CH2). z OR m (CH2) z NR o R p (CH2) z (3-7C)cycloalkyl, (CH2) z Heterocyclic group, (CH2) z heteroaryl or (CH2) z Phenyl;

[0331] And among them:

[0332] (i)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 phenyl, or R o and R p Together with the nitrogen atoms they are attached to, they form 3-6 membered rings; and

[0333] (ii)R 200Any (3-7C) cycloalkyl, heterocyclic, heteroaryl, or phenyl moiety in the substituent may optionally be further selected from one or more halogens, 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) y 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 methyl;

[0334] (18) X is CR2, and R2 is defined as in any of the paragraphs (10) to (17) above;

[0335] (19) R3 is selected from hydrogen, (1-8C)alkyl, (3-7C)cycloalkyl, carbon-linked 4-7-membered heterocyclic group, carbon-linked 5-6-membered heteroaryl group, (CH2) 1-3 (3-7C)cycloalkyl, -C(O)-(1-8C)alkyl, -C(O)(3-7C)cycloalkyl, -C(O)phenyl, -C(O)O(1-8C)alkyl, -C(O)NH2, -C(O)NH-(1-8C)alkyl, -C(O)NH-(CH2) 0-3 (3-7C)cycloalkyl, -C(O)NH-(CH2) 0-3 [5 or 6-membered heteroaryl], -C(O)NH-(CH2) 0-3 Phenyl, -S(O)2H or -S(O)2-(1-6C)alkyl;

[0336] Any alkyl, cycloalkyl, phenyl, or heteroaryl moiety may optionally be represented by one or more R 300 Substituent substitution;

[0337] Where R 300 Selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, (1-4C)alkyl, (1-4C)hydroxyalkyl, OR s C(O)R s C(O)ORs OC(O)R s C(O)N(R) v )R u 、N(R t )C(O)R s 、N(R t )C(O)OR s S(O) y R s SO2N(R) v )R u 、N(R t SO2R s (CH2) z NR u R v ;

[0338] And among them:

[0339] (i)R s and R t Each is independently selected from hydrogen, (1-6C)alkyl, or (CH2). z Phenyl; R u and R v Each is independently selected from hydrogen, (1-6C)alkyl, or (CH2). z Phenyl, or R u and R v 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 s R t R u and R v 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

[0340] (ii)R 300 Any cycloalkyl, heterocyclic, heteroaryl, or phenyl moiety in the substituent may optionally be further substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, or (1-2C)alkyl.

[0341] (19a) R3 is selected from hydrogen, cyano, (1-8C)alkyl, (3-7C)cycloalkyl, carbon-linked 4-7-membered heterocyclic group, carbon-linked 5-6-membered heteroaryl, (CH2). 1-3(3-7C)cycloalkyl, -C(O)-(1-8C)alkyl, -C(O)(3-7C)cycloalkyl, -C(O)phenyl, -C(O)O(1-8C)alkyl, -C(O)NH2, -C(O)NH-(1-8C)alkyl, -C(O)NH-(CH2) 0-3 (3-7C)cycloalkyl, -C(O)NH-(CH2) 0-3 [5 or 6-membered heteroaryl], -C(O)NH-(CH2) 0-3 Phenyl, -S(O)2H or -S(O)2-(1-6C)alkyl;

[0342] Any alkyl, cycloalkyl, phenyl, or heteroaryl moiety may optionally be represented by one or more R 300 Substituent substitution;

[0343] Where R 300 Selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, (1-4C)alkyl, (1-4C)hydroxyalkyl, OR s C(O)R s C(O)OR s OC(O)R s C(O)N(R) v )R u 、N(R t )C(O)R s 、N(R t )C(O)OR s S(O) y R s SO2N(R) v )R u 、N(R t SO2R s (CH2) z NR u R v ;

[0344] And among them:

[0345] (i)R s and R t Each is independently selected from hydrogen, (1-6C)alkyl, or (CH2). z Phenyl; R u and R v Each is independently selected from hydrogen, (1-6C)alkyl, or (CH2). z Phenyl, or R u and R v 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 pAny 3-7 member ring formed, and for R s R t R u and R v 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

[0346] (ii)R 300 Any cycloalkyl, heterocyclic, heteroaryl, or phenyl moiety in the substituent may optionally be further substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, or (1-2C)alkyl.

[0347] (20) R3 is selected from hydrogen, (1-8C)alkyl, (3-7C)cycloalkyl, (CH2) 1-3 (3-7C)cycloalkyl, carbon-linked 4-7-membered heterocyclic groups, carbon-linked 5-6-membered heteroaryl groups, -C(O)-(1-8C)alkyl, -C(O)(3-7C)cycloalkyl, -C(O)phenyl, -C(O)O(1-8C)alkyl, -C(O)NH2, -C(O)NH-(1-8C)alkyl, -C(O)NH-(CH2) 0-3 (3-7C)cycloalkyl, -C(O)NH-(CH2) 0-3 [5 or 6-membered heteroaryl], -C(O)NH-(CH2) 0-3 Phenyl, -S(O)2H or -S(O)2-(1-6C)alkyl;

[0348] Any alkyl, cycloalkyl, phenyl, or heteroaryl moiety may optionally be represented by one or more R 300 Substituent substitution;

[0349] Where R 300 Selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, (1-4C)alkyl, (1-4C)hydroxyalkyl, OR s C(O)N(R) v )R u S(O) y R s (CH2) z NR u R v ;

[0350] And among them:

[0351] (i)R s and R t Each is independently selected from hydrogen, (1-6C)alkyl, or (CH2). z Phenyl; Ru and R v Each is independently selected from hydrogen, (1-6C)alkyl, or (CH2). z Phenyl, or R u and R v Together with the nitrogen atoms they are attached to, they form 3-7 membered rings, which may optionally include additional heteroatoms; and

[0352] (ii)R 300 Any cycloalkyl, heterocyclic, heteroaryl, or phenyl moiety in the substituent may optionally be further substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, or (1-2C)alkyl.

[0353] (20a) R3 is selected from hydrogen, cyano, (1-8C)alkyl, (3-7C)cycloalkyl, (CH2). 1-3 (3-7C)cycloalkyl, carbon-linked 4-7-membered heterocyclic groups, carbon-linked 5-6-membered heteroaryl groups, -C(O)-(1-8C)alkyl, -C(O)(3-7C)cycloalkyl, -C(O)phenyl, -C(O)O(1-8C)alkyl, -C(O)NH2, -C(O)NH-(1-8C)alkyl, -C(O)NH-(CH2) 0-3 (3-7C)cycloalkyl, -C(O)NH-(CH2) 0-3 [5 or 6-membered heteroaryl], -C(O)NH-(CH2) 0-3 Phenyl, -S(O)2H or -S(O)2-(1-6C)alkyl;

[0354] Any alkyl, cycloalkyl, phenyl, or heteroaryl moiety may optionally be represented by one or more R 300 Substituent substitution;

[0355] Where R 300 Selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, (1-4C)alkyl, (1-4C)hydroxyalkyl, OR s C(O)N(R) v )R u S(O) y R s (CH2) z NR u R v ;

[0356] And among them:

[0357] (i)R s and R t Each is independently selected from hydrogen, (1-6C)alkyl, or (CH2). z Phenyl; R u and Rv Each is independently selected from hydrogen, (1-6C)alkyl, or (CH2). z Phenyl, or R u and R v Together with the nitrogen atoms they are attached to, they form 3-7 membered rings, which may optionally include additional heteroatoms; and

[0358] (ii)R 300 Any cycloalkyl, heterocyclic, heteroaryl, or phenyl moiety in the substituent may optionally be further substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, or (1-2C)alkyl.

[0359] (21) R3 is selected from hydrogen or acetyl;

[0360] (22) R4 is selected from hydrogen or fluorine;

[0361] (23) R4 is hydrogen;

[0362] (24) When R2 and R3 are connected together to form a -CH=CH- group, X1 is N; or X1 is CR5, where R5 is selected from hydrogen, halogen or cyano;

[0363] (25) When R2 and R3 are connected together to form a -CH=CH- group, X1 is N; or X1 is CR5, where R5 is selected from hydrogen, fluorine or cyano;

[0364] (26) When R2 and R3 are connected together to form a -CH=CH- group, X1 is N; or X1 is CR5, where R5 is selected from hydrogen or cyano;

[0365] (27) When R2 and R3 are connected together to form a -CH=CH- group, X1 is N;

[0366] (28)X1 is CR5, where R5 is selected from hydrogen, halogen or cyano;

[0367] (29)X1 is CR5, where R5 is selected from hydrogen, fluorine or cyano;

[0368] (30)X1 is CR5, where R5 is selected from hydrogen or cyano;

[0369] (31) R2 and R3 are linked together to form a -CH=CQ- group;

[0370] (32) Q is hydrogen or a group of the following formula:

[0371] -L1-Y1-L2-Q1

[0372] in:

[0373] L1 is absent or is a (1-3C) alkylene group;

[0374] Y1 does not exist or is O, S, SO, SO2, or N(R). y1 ), C(O), C(O)O, C(O)N(R) y1 )

[0375] or N(R) y1 )C(O), where R y1 Selected from hydrogen or (1-4C) alkyl;

[0376] L2 is absent or is a (1-3C) alkylene group; and

[0377] Q1 is hydrogen, (1-6C)alkyl, phenyl, (3-8C)cycloalkyl, heteroaryl, or heterocyclic; wherein Q is optionally further substituted by one or more substituents independently selected from oxo, hydroxyl, (1-6C)alkyl, halogen, (1-4C) haloalkyl, (1-4C) haloalkoxy, (1-4C) aminoalkyl, (1-4C) hydroxyalkyl, or cyano, or substituted by one or more groups of the following formula:

[0378] -L3-Y2-L4-W1

[0379] in:

[0380] L3 does not exist;

[0381] Y2 does not exist or is selected from O, S, SO, SO2, N(R) y2 ), C(O), C(O)O,

[0382] OC(O), C(O)N(R) y2 ) or N(R y2 C(O), S(O)2N(R) y2 ), N(R y2 SO2, where R y2 Selected from hydrogen or (1-3C) alkyl;

[0383] L4 is absent or is a (1-3C) alkylene group; and

[0384] W1 is hydrogen, (1-6C) alkyl, or phenyl;

[0385] W1 may optionally be substituted by one or more substituents selected from (1-2C) alkyl or halogen groups;

[0386] The condition is that Q1 is not aryl or heteroaryl when L1, Y1, and L2 are all absent;

[0387] (33) Q is hydrogen or a group of the following formula:

[0388] -L1-Y1-L2-Q1

[0389] in:

[0390] L1 is absent or is a (1-3C) alkylene group;

[0391] Y1 does not exist or is O, S, SO, SO2, or N(R). y1 ), C(O), C(O)O or C(O)N(R) y1 ), where R y1 Selected from hydrogen or (1-3C) alkyl;

[0392] L2 is absent or is a (1-3C) alkylene group; and

[0393] Q1 is hydrogen, (1-6C)alkyl, phenyl, (3-6C)cycloalkyl, 5- or 6-membered heteroaryl or 4- or 7-membered heterocyclic group;

[0394] Optionally, Q may be further substituted by one or more substituents independently selected from oxo, hydroxyl, (1-6C)alkyl, halogen, (1-4C) haloalkyl, (1-4C) haloalkoxy, (1-4C) aminoalkyl, (1-4C) hydroxyalkyl, cyano, or by one or more groups of the following formula:

[0395] -L3-Y2-L4-W1

[0396] in:

[0397] L3 does not exist;

[0398] Y2 does not exist or is selected from O, S, SO, SO2, N(R) y2 ), C(O), C(O)O,

[0399] OC(O), C(O)N(R) y2 ) or N(R y2 C(O), S(O)2N(R) y2 ), N(R y2 SO2, where R y2 Selected from hydrogen or (1-3C) alkyl;

[0400] L4 is absent or is a (1-3C) alkylene group; and

[0401] W1 is hydrogen, (1-6C) alkyl, or phenyl;

[0402] The condition is that Q1 is not phenyl or heteroaryl when L1, Y1, and L2 are all absent;

[0403] (34) Q is hydrogen or a group of the following formula:

[0404] -L1-Y1-L2-Q1

[0405] in:

[0406] L1 is absent or is a (1-3C) alkylene group;

[0407] Y1 does not exist or is 0 or N(R) y1 ), C(O), C(O)O or C(O)N(R) y1 ), where R y1 Selected from hydrogen or (1-3C) alkyl;

[0408] L2 is absent or is a (1-3C) alkylene group; and

[0409] Q1 is hydrogen, (1-6C)alkyl, phenyl, (3-6C)cycloalkyl, 5- or 6-membered heteroaryl or 4- or 7-membered heterocyclic group;

[0410] Q may optionally be further substituted by one or more substituents independently selected from oxo, hydroxyl, (1-6C)alkyl, halogen, (1-4C) haloalkyl, (1-4C) haloalkoxy, cyano, or by one or more groups of the following formula:

[0411] -L3-Y2-L4-W1

[0412] in:

[0413] L3 does not exist;

[0414] Y2 does not exist or is selected from O, N(R) y2 ), C(O), C(O)N(R) y2 ) or N(R y2 )C(O), where R y2 Selected from hydrogen or (1-3C) alkyl;

[0415] L4 is absent or is a (1-3C) alkylene group; and

[0416] W1 is hydrogen, (1-6C) alkyl, or phenyl;

[0417] The condition is that Q1 is not phenyl or heteroaryl when L1, Y1, and L2 are all absent;

[0418] (35) Q is hydrogen or a group of the following formula:

[0419] -L1-Y1-L2-Q1

[0420] in:

[0421] L1 is absent or is a (1-3C) alkylene group;

[0422] Y1 does not exist or is 0 or N(R) y1 ), C(O), C(O)O or C(O)N(R) y1 ), where Ry1 Selected from hydrogen or (1-3C) alkyl;

[0423] L2 is absent or is a (1-3C) alkylene group; and

[0424] Q1 is hydrogen, (1-6C)alkyl, phenyl, (3-6C)cycloalkyl, 5- or 6-membered heteroaryl or 4- or 7-membered heterocyclic group;

[0425] Q may optionally be further substituted by one or more substituents independently selected from oxo, hydroxyl, (1-6C) alkyl, halogen, cyano, or by one or more groups of the following formula:

[0426] -L3-Y2-L4-W1

[0427] in:

[0428] L3 does not exist;

[0429] Y2 does not exist or is selected from O or N(R) y2 ), where R y2 Selected from hydrogen or (1-3C) alkyl;

[0430] L4 is absent or is a (1-2C) alkylene group; and

[0431] W1 is hydrogen, (1-6C) alkyl, or phenyl;

[0432] The condition is that Q1 is not phenyl or heteroaryl when L1, Y1, and L2 are all absent;

[0433] (36) y is independently selected from 0, 1 or 2;

[0434] (37) y is 0;

[0435] (38) y is 1;

[0436] (39) y is 2;

[0437] (40) z is independently selected from 0, 1 or 2;

[0438] (41) z is 0;

[0439] (42) z is 1;

[0440] (43) z is 2;

[0441] Appropriately, R1 is defined as in any of the numbered paragraphs (1) to (9) above. More appropriately, R1 is defined as in any of the numbered paragraphs (5) to (9) above. Most appropriately, R1 is defined as in any of the numbered paragraphs (7) to (9) above.

[0442] Suitablely, X is defined as in any of the numbered paragraphs (10) to (18) above. More suitablely, X is defined as in any of the numbered paragraphs (14) to (18) above. Most suitablely, X is defined as in any of the numbered paragraphs (16) to (18) above.

[0443] Suitablely, R2 is defined as in any of paragraphs (10) to (17) above, R3 is defined as in any of paragraphs (19) to (21) above (inclusive of (19a) and (20a)), or R2 and R3 are joined together to form a -CH=CQ- group, and Q is defined as in any of paragraphs (31) to (35) above. More suitably, R2 is defined as in any of paragraphs (14) to (17) above, R3 is defined as in any of paragraphs (20) or (21) above, or R2 and R3 are joined together to form a -CH=CQ- group, and Q is defined as in any of paragraphs (33) to (35) above. Most preferably, R2 is defined as in paragraph (16) or (17) above numbered, R3 is defined as in paragraph (20) or (21) above numbered, or R2 and R3 are joined together to form a -CH=CQ- group, and Q is defined as in paragraph (34) or (35) above numbered.

[0444] Appropriately, R4 is defined as in paragraph (23) numbered above.

[0445] Suitablely, X1 is defined as in any of the numbered paragraphs (24) to (30) above. More suitablely, X1 is defined as in the numbered paragraphs (28) to (30) above. Most suitablely, X1 is defined as in any of the numbered paragraphs (29) or (30) above.

[0446] Appropriately, R5 is defined as in any of the numbered paragraphs (28) through (30) above. More appropriately, R5 is defined as in the numbered paragraphs (29) or (30) above. Most appropriately, R5 is defined as in the numbered paragraph (30) above.

[0447] Appropriately, y is as defined in paragraph (36) above.

[0448] Appropriately, x is as defined in paragraph (40) above numbered.

[0449] 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 structural formulas (Ia), (Ib), (Ic), (Id) or (Ie) shown below:

[0450]

[0451] R1, X, R3, R4, R5 and Q are each defined as described in this paper.

[0452] 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 X, R4 and R5 each have any of the definitions given herein.

[0453] In embodiments of compounds of formula Ia or their pharmaceutically acceptable salts, hydrates, and / or solvates:

[0454] X is defined as in any of the paragraphs (10) to (18) numbered above;

[0455] R4 is defined as in paragraph (23) above; and

[0456] R5 is defined as in any of the paragraphs numbered (28) to (30) above.

[0457] In embodiments of compounds of formula Ia or their pharmaceutically acceptable salts, hydrates, and / or solvates:

[0458] X is defined as in any of the numbered paragraphs (14) to (18) above;

[0459] R4 is defined as in paragraph (23) above; and

[0460] R5 is defined as in paragraphs (29) or (30) above numbered.

[0461] In embodiments of compounds of formula Ia or their pharmaceutically acceptable salts, hydrates, and / or solvates:

[0462] X is defined as in paragraph (14) above;

[0463] R4 is defined as in paragraph (23) above; and

[0464] R5 is defined in paragraph (28) above.

[0465] In embodiments of compounds of formula Ia or their pharmaceutically acceptable salts, hydrates, and / or solvates:

[0466] X is defined as in paragraph (15) above;

[0467] R4 is defined as in paragraph (23) above; and

[0468] R5 is defined in paragraph (28) above.

[0469] In embodiments of compounds of formula Ia or their pharmaceutically acceptable salts, hydrates, and / or solvates:

[0470] X is defined as in paragraph (16) above;

[0471] R4 is defined as in paragraph (23) above; and

[0472] R5 is defined in paragraph (29) above.

[0473] In embodiments of compounds of formula Ia or their pharmaceutically acceptable salts, hydrates, and / or solvates:

[0474] X is defined as in paragraph (17) above;

[0475] R4 is defined as in paragraph (23) above; and

[0476] R5 is defined in paragraph (30) above.

[0477] 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 R1, R3, R4 and R5 each have any of the definitions given herein.

[0478] In embodiments of compounds of formula Ib or their pharmaceutically acceptable salts, hydrates, and / or solvates:

[0479] R1 is defined as in any of the paragraphs (1) to (9) numbered above;

[0480] R3 is defined as any of the paragraphs numbered above (19) to (21) (inclusive of (19a) and (20a));

[0481] R4 is defined as in paragraph (23) above; and

[0482] R5 is defined as in any of the paragraphs numbered (28) to (30) above.

[0483] In embodiments of compounds of formula Ib or their pharmaceutically acceptable salts, hydrates, and / or solvates:

[0484] R1 is defined as in any of the paragraphs (5) to (9) numbered above;

[0485] R3 is defined as any of the paragraphs numbered above (19) to (21) (inclusive of (19a) and (20a));

[0486] R4 is defined as in paragraph (23) above; and

[0487] R5 is defined as in paragraphs (29) or (30) above numbered.

[0488] In embodiments of compounds of formula Ib or their pharmaceutically acceptable salts, hydrates, and / or solvates:

[0489] R1 is defined as in paragraph (5) above;

[0490] R3 is defined as in paragraph (19) above;

[0491] R4 is defined as in paragraph (23) above; and

[0492] R5 is defined in paragraph (28) above.

[0493] In embodiments of compounds of formula Ib or their pharmaceutically acceptable salts, hydrates, and / or solvates:

[0494] R1 is defined as in paragraph (6) above;

[0495] R3 is defined as in paragraph (20) above;

[0496] R4 is defined as in paragraph (23) above; and

[0497] R5 is defined in paragraph (29) above.

[0498] In embodiments of compounds of formula Ib or their pharmaceutically acceptable salts, hydrates, and / or solvates:

[0499] R1 is defined as in paragraph (7) above;

[0500] R3 is defined as in paragraph (20) above;

[0501] R4 is defined as in paragraph (23) above; and

[0502] R5 is defined in paragraph (29) above.

[0503] In embodiments of compounds of formula Ib or their pharmaceutically acceptable salts, hydrates, and / or solvates:

[0504] R1 is defined as in paragraph (8) above;

[0505] R3 is defined as in paragraph (21) above;

[0506] R4 is defined as in paragraph (23) above; and

[0507] R5 is defined in paragraph (30) above.

[0508] In embodiments of compounds of formula Ib or their pharmaceutically acceptable salts, hydrates, and / or solvates:

[0509] R1 is defined as in paragraph (9) above;

[0510] R3 is defined as in paragraph (21) above;

[0511] R4 is defined as in paragraph (23) above; and

[0512] R5 is defined in paragraph (30) above.

[0513] 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 and R5 each have any of the definitions given herein.

[0514] In embodiments of the compound of formula Ic or its pharmaceutically acceptable salts, hydrates and / or solvates:

[0515] R1 is defined as in any of the paragraphs (1) to (9) numbered above;

[0516] R4 is defined as in paragraph (23) above; and

[0517] R5 is defined as in any of the paragraphs numbered (28) to (30) above.

[0518] In embodiments of the compound of formula Ic or its pharmaceutically acceptable salts, hydrates and / or solvates:

[0519] R1 is defined as in any of the paragraphs (5) to (9) numbered above;

[0520] R4 is defined as in paragraph (23) above; and

[0521] R5 is defined as in paragraphs (29) or (30) above numbered.

[0522] In embodiments of the compound of formula Ic or its pharmaceutically acceptable salts, hydrates and / or solvates:

[0523] R1 is defined as in paragraph (5) above;

[0524] R4 is defined as in paragraph (23) above; and

[0525] R5 is defined in paragraph (28) above.

[0526] In embodiments of the compound of formula Ic or its pharmaceutically acceptable salts, hydrates and / or solvates:

[0527] R1 is defined as in paragraph (6) above;

[0528] R4 is defined as in paragraph (23) above; and

[0529] R5 is defined in paragraph (29) above.

[0530] In embodiments of the compound of formula Ic or its pharmaceutically acceptable salts, hydrates and / or solvates:

[0531] R1 is defined as in paragraph (7) above;

[0532] R4 is defined as in paragraph (23) above; and

[0533] R5 is defined in paragraph (29) above.

[0534] In embodiments of the compound of formula Ic or its pharmaceutically acceptable salts, hydrates and / or solvates:

[0535] R1 is defined as in paragraph (8) above;

[0536] R4 is defined as in paragraph (23) above; and

[0537] R5 is defined in paragraph (30) above.

[0538] In embodiments of the compound of formula Ic or its pharmaceutically acceptable salts, hydrates and / or solvates:

[0539] R1 is defined as in paragraph (9) above;

[0540] R4 is defined as in paragraph (23) above; and

[0541] R5 is defined in paragraph (30) above.

[0542] In a particular group of compounds of the present invention, the compounds have a structure according to formula Id (which is a sub-definition of formula I), or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, wherein R1, Q, R4 and R5 each have any of the definitions given herein.

[0543] In embodiments of the compound of formula Id or its pharmaceutically acceptable salts, hydrates and / or solvates:

[0544] R1 is defined as in any of the paragraphs (1) to (9) numbered above;

[0545] Q is defined as in any of the numbered paragraphs (32) to (35) above;

[0546] R4 is defined as in paragraph (23) above; and

[0547] R5 is defined as in any of the paragraphs numbered (28) to (30) above.

[0548] In embodiments of the compound of formula Id or its pharmaceutically acceptable salts, hydrates and / or solvates:

[0549] R1 is defined as in any of the paragraphs (5) to (9) numbered above;

[0550] Q is defined as in any of the numbered paragraphs (33) to (35) above;

[0551] R4 is defined as in paragraph (23) above; and

[0552] R5 is defined as in paragraphs (29) or (30) above numbered.

[0553] In embodiments of the compound of formula Id or its pharmaceutically acceptable salts, hydrates and / or solvates:

[0554] R1 is defined as in paragraph (5) above;

[0555] Q is defined as in paragraph (32) above;

[0556] R4 is defined as in paragraph (23) above; and

[0557] R5 is defined in paragraph (28) above.

[0558] In embodiments of the compound of formula Id or its pharmaceutically acceptable salts, hydrates and / or solvates:

[0559] R1 is defined as in paragraph (6) above;

[0560] Q is defined as in paragraph (33) above;

[0561] R4 is defined as in paragraph (23) above; and

[0562] R5 is defined in paragraph (29) above.

[0563] In embodiments of the compound of formula Id or its pharmaceutically acceptable salts, hydrates and / or solvates:

[0564] R1 is defined as in paragraph (7) above;

[0565] Q is defined as in paragraph (33) above;

[0566] R4 is defined as in paragraph (23) above; and

[0567] R5 is defined in paragraph (29) above.

[0568] In embodiments of the compound of formula Id or its pharmaceutically acceptable salts, hydrates and / or solvates:

[0569] R1 is defined as in paragraph (8) above;

[0570] Q is defined as in paragraph (34) above;

[0571] R4 is defined as in paragraph (23) above; and

[0572] R5 is defined in paragraph (30) above.

[0573] In embodiments of the compound of formula Id or its pharmaceutically acceptable salts, hydrates and / or solvates:

[0574] R1 is defined as in paragraph (9) above;

[0575] Q is defined as in paragraph (35) above;

[0576] R4 is defined as in paragraph (23) above; and

[0577] R5 is defined in paragraph (30) above.

[0578] In a particular group of compounds of the present invention, the compounds have a structure according to formula Ie (which is a sub-definition of formula I), or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, wherein X, R3, R4 and R5 each have any of the definitions given herein.

[0579] In embodiments of compounds of formula Ie or their pharmaceutically acceptable salts, hydrates, and / or solvates:

[0580] X is defined as in any of the paragraphs (10) to (18) numbered above;

[0581] R3 is defined as any of the paragraphs numbered above (19) to (21) (inclusive of (19a) and (20a));

[0582] R4 is defined as in paragraph (23) above; and

[0583] R5 is defined as in any of the paragraphs numbered (28) to (30) above.

[0584] In embodiments of compounds of formula Ie or their pharmaceutically acceptable salts, hydrates, and / or solvates:

[0585] X is defined as in any of the numbered paragraphs (14) to (18) above;

[0586] R3 is defined as any of the paragraphs numbered above (19) to (21) (inclusive of (19a) and (20a));

[0587] R4 is defined as in paragraph (23) above; and

[0588] R5 is defined as in paragraphs (29) or (30) above numbered.

[0589] In embodiments of compounds of formula Ie or their pharmaceutically acceptable salts, hydrates, and / or solvates:

[0590] X is defined as in paragraph (14) above;

[0591] R3 is defined as in paragraph (19) above;

[0592] R4 is defined as in paragraph (23) above; and

[0593] R5 is defined in paragraph (28) above.

[0594] In embodiments of compounds of formula Ie or their pharmaceutically acceptable salts, hydrates, and / or solvates:

[0595] X is defined as in paragraph (14) above;

[0596] R3 is defined as in paragraph (20) above;

[0597] R4 is defined as in paragraph (23) above; and

[0598] R5 is defined in paragraph (29) above.

[0599] In embodiments of compounds of formula Ie or their pharmaceutically acceptable salts, hydrates, and / or solvates:

[0600] X is defined as in paragraph (15) above;

[0601] R3 is defined as in paragraph (20) above;

[0602] R4 is defined as in paragraph (23) above; and

[0603] R5 is defined in paragraph (29) above.

[0604] In embodiments of compounds of formula Ie or their pharmaceutically acceptable salts, hydrates, and / or solvates:

[0605] X is defined as in paragraph (16) above;

[0606] R3 is defined as in paragraph (21) above;

[0607] R4 is defined as in paragraph (23) above; and

[0608] R5 is defined in paragraph (30) above.

[0609] In embodiments of compounds of formula Ie or their pharmaceutically acceptable salts, hydrates, and / or solvates:

[0610] X is defined as in paragraph (17) above;

[0611] R3 is defined as in paragraph (21) above;

[0612] R4 is defined as in paragraph (23) above; and

[0613] R5 is defined in paragraph (30) above.

[0614] In a particular group of compounds of the present invention, the compounds have a structure according to formula If (which is a sub-definition of formula I), or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, wherein R1, Q, R4 and R5 each have any of the definitions given herein.

[0615] In embodiments of compounds of formula If or their pharmaceutically acceptable salts, hydrates, and / or solvates:

[0616] R1 is defined as in any of the paragraphs (1) to (9) numbered above;

[0617] Q is defined as in any of the numbered paragraphs (32) to (35) above;

[0618] R4 is defined as in paragraph (23) above; and

[0619] R5 is defined as in any of the paragraphs numbered (28) to (30) above.

[0620] In embodiments of compounds of formula If or their pharmaceutically acceptable salts, hydrates, and / or solvates:

[0621] R1 is defined as in any of the paragraphs (5) to (9) numbered above;

[0622] Q is defined as in any of the numbered paragraphs (33) to (35) above;

[0623] R4 is defined as in paragraph (23) above; and

[0624] R5 is defined as in paragraphs (29) or (30) above numbered.

[0625] In embodiments of compounds of formula If or their pharmaceutically acceptable salts, hydrates, and / or solvates:

[0626] R1 is defined as in paragraph (5) above;

[0627] Q is defined as in paragraph (32) above;

[0628] R4 is defined as in paragraph (23) above; and

[0629] R5 is defined in paragraph (28) above.

[0630] In embodiments of compounds of formula If or their pharmaceutically acceptable salts, hydrates, and / or solvates:

[0631] R1 is defined as in paragraph (6) above;

[0632] Q is defined as in paragraph (33) above;

[0633] R4 is defined as in paragraph (23) above; and

[0634] R5 is defined in paragraph (29) above.

[0635] In embodiments of compounds of formula If or their pharmaceutically acceptable salts, hydrates, and / or solvates:

[0636] R1 is defined as in paragraph (7) above;

[0637] Q is defined as in paragraph (33) above;

[0638] R4 is defined as in paragraph (23) above; and

[0639] R5 is defined in paragraph (29) above.

[0640] In embodiments of compounds of formula If or their pharmaceutically acceptable salts, hydrates, and / or solvates:

[0641] R1 is defined as in paragraph (8) above;

[0642] Q is defined as in paragraph (34) above;

[0643] R4 is defined as in paragraph (23) above; and

[0644] R5 is defined in paragraph (30) above.

[0645] In embodiments of compounds of formula If or their pharmaceutically acceptable salts, hydrates, and / or solvates:

[0646] R1 is defined as in paragraph (9) above;

[0647] Q is defined as in paragraph (35) above;

[0648] R4 is defined as in paragraph (23) above; and

[0649] R5 is defined in paragraph (30) above.

[0650] 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:

[0651] 5-(2-aminopyridin-4-yl)-7-chloro-1H-indazole-3-amine;

[0652] 5-(2-aminopyridin-4-yl)-7-methyl-1H-indazole-3-amine;

[0653] 5-(2-aminopyridin-4-yl)-7-(trifluoromethyl)-1H-indazole-3-amine;

[0654] 7-Chloro-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine;

[0655] 7-Bromo-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine;

[0656] 7-Ethynyl-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine;

[0657] 7-Phenyl-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine;

[0658] 5-(2-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine;

[0659] 5-(2-(tert-butyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine;

[0660] 4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid;

[0661] 7-Bromo-5-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-indazole-3-amine

[0662] 5-(2-(ethylamino)pyridin-4-yl)-1H-indazole-3-amine;

[0663] 5-(2-(propylamino)pyridin-4-yl)-1H-indazole-3-amine;

[0664] 5-(2-(isopropylamino)pyridin-4-yl)-1H-indazole-3-amine;

[0665] 5-(2-((cyclopropylmethyl)amino)pyridin-4-yl)-1H-indazole-3-amine;

[0666] 5-(2-(isopentylamino)pyridin-4-yl)-1H-indazole-3-amine;

[0667] 5-(2-(hexylamino)pyridin-4-yl)-1H-indazole-3-amine;

[0668] 5-(2-(cyclohexylamino)pyridin-4-yl)-1H-indazole-3-amine;

[0669] 5-{2-[(trans-4-methylcyclohexyl)amino]pyridin-4-yl}-1H-indazole-3-amine;

[0670] 2-((4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)amino)ethanol-1-ol;

[0671] 3-((4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)amino)prop-1-ol;

[0672] 4-((4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)amino)but-1-ol;

[0673] 5-((4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)amino)pentan-1-ol;

[0674] 5-{2-[(trans-4-hydroxycyclohexyl)amino]pyridin-4-yl}-1H-indazole-3-amine;

[0675] 5-(2-((2-methoxyethyl)amino)pyridin-4-yl)-1H-indazole-3-amine;

[0676] 5-(2-((3-methoxypropyl)amino)pyridin-4-yl)-1H-indazole-3-amine;

[0677] 5-(2-((3-isopropoxypropyl)amino)pyridin-4-yl)-1H-indazole-3-amine;

[0678] 3-((4-(3-amino-1H-indazol-5-yl)pyrimidin-2-yl)amino)prop-1-ol;

[0679] 3-((4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)(methyl)amino)prop-1-ol;

[0680] 5-(2-((2-morpholinoethyl)amino)pyridin-4-yl)-1H-indazole-3-amine;

[0681] 5-(2-((2-(piperidin-1-yl)ethyl)amino)pyridin-4-yl)-1H-indazole-3-amine;

[0682] N 1 -(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-N3-methylpropane-1,3-diamine;

[0683] N-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)cyclopropaneformamide;

[0684] N-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)benzamide;

[0685] (4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)carbamate;

[0686] 1-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-3-ethylurea;

[0687] 1-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-3-ethylurea;

[0688] 1-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-3-propylurea;

[0689] 1-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-3-isopentylurea;

[0690] 1-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-3-cyclopentylurea;

[0691] 1-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-3-cyclohexylurea;

[0692] 1-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-3-(2-hydroxyethyl)urea;

[0693] 1-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-3-(3-hydroxypropyl)urea;

[0694] 1-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-3-(2-methoxyethyl)urea;

[0695] 3-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-1-(2-hydroxyethyl)-1-methylurea;

[0696] 1-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-3-benzylurea;

[0697] 1-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-3-phenylethylurea;

[0698] 1-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-3-(pyridin-2-ylmethyl)urea;

[0699] 1-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-3-(pyridin-3-ylmethyl)urea;

[0700] 1-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-3-(pyridin-4-ylmethyl)urea;

[0701] 1-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-3-phenylurea;

[0702] 1-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-3-(3-fluorophenyl)urea;

[0703] 1-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-3-(3-chlorophenyl)urea;

[0704] 1-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-3-(3-isopropylphenyl)urea;

[0705] 1-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-3-(3-(hydroxymethyl)phenyl)urea;

[0706] 3-(3-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)ureo)benzamide;

[0707] 1-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-3-(3-phenoxyphenyl)urea;

[0708] 1-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-3-(3-(benzyloxy)phenyl)urea;

[0709] 1-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-3-(3-((4-fluorobenzyl)oxy)phenyl)urea;

[0710] 1-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-3-(3-((3-fluorobenzyl)oxy)phenyl)urea;

[0711] 1-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-3-(3-((2-fluorobenzyl)oxy)phenyl)urea;

[0712] 3-(3-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)ureo)-N-phenylbenzamide;

[0713] 1-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-3-(4-fluorophenyl)urea;

[0714] 1-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-3-(4-chlorophenyl)urea;

[0715] 1-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-3-(4-(tert-butyl)phenyl)urea;

[0716] 1-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-3-(4-(methanesulfonyl)phenyl)urea;

[0717] 1-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-3-(o-tolyl)urea;

[0718] 1-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-3-(2-ethylphenyl)urea;

[0719] 1-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-3-(2-isopropylphenyl)urea;

[0720] 1-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-3-(pyridin-3-yl)urea;

[0721] 5-(2-amino-3-ethynylpyridin-4-yl)-1H-indazole-3-amine;

[0722] 5-(2-amino-3-(cyclopropylethynyl)pyridin-4-yl)-1H-indazole-3-amine;

[0723] 5-(2-amino-3-(3,3-dimethylbut-1-yn-1-yl)pyridin-4-yl)-1H-indazole-3-amine;

[0724] 5-(2-amino-3-(cyclopentylethynyl)pyridin-4-yl)-1H-indazole-3-amine;

[0725] 5-(2-amino-3-(cyclohexylethynyl)pyridin-4-yl)-1H-indazole-3-amine;

[0726] 5-(2-amino-3-(phenylethynyl)pyridin-4-yl)-1H-indazole-3-amine;

[0727] 5-(2-amino-3-((4-aminophenyl)ethynyl)pyridin-4-yl)-1H-indazole-3-amine;

[0728] 5-(2-amino-3-((3-aminophenyl)ethynyl)pyridin-4-yl)-1H-indazole-3-amine;

[0729] 5-(2-amino-3-((2-aminophenyl)ethynyl)pyridin-4-yl)-1H-indazole-3-amine;

[0730] 3-((2-amino-4-(3-amino-1H-indazol-5-yl)pyridin-3-yl)ethynyl)methyl benzoate;

[0731] 4-((2-amino-4-(3-amino-1H-indazol-5-yl)pyridin-3-yl)ethynyl)methyl benzoate;

[0732] 5-(2-amino-3-((2-methoxyphenyl)ethynyl)pyridin-4-yl)-1H-indazole-3-amine;

[0733] 5-(2-amino-4-(3-amino-1H-indazol-5-yl)pyridin-3-yl)-1-phenylpent-4-yn-1-one;

[0734] 3-(2-amino-4-(3-amino-1H-indazol-5-yl)pyridin-3-yl)prop-2-yn-1-ol;

[0735] 4-(2-amino-4-(3-amino-1H-indazol-5-yl)pyridin-3-yl)but-3-yn-1-ol;

[0736] 5-(2-amino-4-(3-amino-1H-indazol-5-yl)pyridin-3-yl)pent-4-yn-1-ol;

[0737] 6-(2-amino-4-(3-amino-1H-indazol-5-yl)pyridin-3-yl)-2-methylhex-5-yn-2-ol;

[0738] 4-(2-amino-4-(3-amino-1H-indazol-5-yl)pyridin-3-yl)-2-methylbut-3-yn-2-ol;

[0739] 5-(2-amino-3-(3-(tert-butoxy)prop-1-yn-1-yl)pyridin-4-yl)-1H-indazole-3-amine;

[0740] 1-((2-amino-4-(3-amino-1H-indazol-5-yl)pyridin-3-yl)ethynyl)cyclopentan-1-ol;

[0741] 1-((2-amino-4-(3-amino-1H-indazol-5-yl)pyridin-3-yl)ethynyl)cyclohexane-1-ol;

[0742] 1-((2-amino-4-(3-amino-1H-indazol-5-yl)pyridin-3-yl)ethynyl)cycloheptane-1-ol;

[0743] 5-(2-amino-3-(3-amino-3-methylbut-1-yn-1-yl)pyridin-4-yl)-1H-indazole-3-amine;

[0744] 5-(2-amino-3-(4-(piperidin-1-yl)but-1-yn-1-yl)pyridin-4-yl)-1H-indazole-3-amine;

[0745] 5-(2-amino-3-(4-morpholinobut-1-yn-1-yl)pyridin-4-yl)-1H-indazole-3-amine;

[0746] 5-(2-amino-3-(5-(piperidin-1-yl)pent-1-yn-1-yl)pyridin-4-yl)-1H-indazole-3-amine;

[0747] 5-(2-amino-3-(5-morpholinopent-1-yn-1-yl)pyridin-4-yl)-1H-indazole-3-amine;

[0748] 5-(2-amino-3-(3-(piperidin-4-yl)prop-1-yn-1-yl)pyridin-4-yl)-1H-indazole-3-amine;

[0749] 3-(2-amino-4-(3-amino-1H-indazol-5-yl)pyridin-3-yl)-N-methylpropionamide;

[0750] 5-(2-amino-4-(3-amino-1H-indazol-5-yl)pyridin-3-yl)-1-morpholinopent-4-yn-1-one;

[0751] 5-(2-amino-3-cyclopropylpyridin-4-yl)-1H-indazole-3-amine;

[0752] 4-(2-amino-4-(3-amino-1H-indazol-5-yl)pyridin-3-yl)but-1-ol;

[0753] 1-(2-(2-amino-4-(3-amino-1H-indazol-5-yl)pyridin-3-yl)ethyl)cyclohexane-1-ol;

[0754] 5-(2-amino-4-(3-amino-1H-indazol-5-yl)pyridin-3-yl)pentan-1-ol;

[0755] 5-(2-aminopyridin-4-yl)-7-phenyl-1H-indazole-3-amine;

[0756] 5-(2-aminopyridin-4-yl)-7-(3-fluorophenyl)-1H-indazole-3-amine;

[0757] 5-(2-aminopyridin-4-yl)-7-(3-(trifluoromethyl)phenyl)-1H-indazole-3-amine;

[0758] 7-(3-aminophenyl)-5-(2-aminopyridin-4-yl)-1H-indazole-3-amine;

[0759] 3-(3-amino-5-(2-aminopyridin-4-yl)-1H-indazol-7-yl)phenol;

[0760] 5-(2-aminopyridin-4-yl)-7-(3-methoxyphenyl)-1H-indazole-3-amine;

[0761] (3-(3-amino-5-(2-aminopyridin-4-yl)-1H-indazol-7-yl)phenyl)methanol;

[0762] 3-(3-amino-5-(2-aminopyridin-4-yl)-1H-indazol-7-yl)benzaldehyde;

[0763] Ethyl 3-(3-amino-5-(2-aminopyridin-4-yl)-1H-indazol-7-yl)benzoate;

[0764] 3-(3-amino-5-(2-aminopyridin-4-yl)-1H-indazol-7-yl)benzamide;

[0765] 3-(3-amino-5-(2-aminopyridin-4-yl)-1H-indazol-7-yl)benzenesulfonamide;

[0766] 5-(2-aminopyridin-4-yl)-7-(3-(methanesulfonyl)phenyl)-1H-indazole-3-amine;

[0767] 5-(2-aminopyridin-4-yl)-7-(3-(morpholinomethyl)phenyl)-1H-indazole-3-amine;

[0768] 4-(3-amino-5-(2-aminopyridin-4-yl)-1H-indazol-7-yl)phenol;

[0769] (4-(3-amino-5-(2-aminopyridin-4-yl)-1H-indazol-7-yl)phenyl)methanol;

[0770] 5-(2-aminopyridin-4-yl)-7-(4-(dimethylamino)phenyl)-1H-indazole-3-amine;

[0771] 4-(3-amino-5-(2-aminopyridin-4-yl)-1H-indazol-7-yl)benzamide;

[0772] 4-(3-amino-5-(2-aminopyridin-4-yl)-1H-indazol-7-yl)benzenesulfonamide;

[0773] 5-(2-aminopyridin-4-yl)-7-(4-(morpholinomethyl)phenyl)-1H-indazole-3-amine;

[0774] 5-(2-aminopyridin-4-yl)-7-(4-(tert-butyl)phenyl)-1H-indazole-3-amine;

[0775] 5-(2-aminopyridin-4-yl)-7-(2-chlorophenyl)-1H-indazole-3-amine;

[0776] (2-(3-amino-5-(2-aminopyridin-4-yl)-1H-indazol-7-yl)phenyl)methanol;

[0777] 4-(3-amino-5-(2-aminopyridin-4-yl)-1H-indazol-7-yl)-3-methylbenzenesulfonamide;

[0778] 5-(2-aminopyridin-4-yl)-7-(pyridin-3-yl)-1H-indazole-3-amine;

[0779] 5-(2-aminopyridin-4-yl)-7-(pyridin-4-yl)-1H-indazole-3-amine;

[0780] 5-(2-aminopyridin-4-yl)-7-(furan-3-yl)-1H-indazole-3-amine;

[0781] 5-(2-aminopyridin-4-yl)-7-(thiophen-3-yl)-1H-indazole-3-amine;

[0782] 5-(2-aminopyridin-4-yl)-7-(thiophen-2-yl)-1H-indazole-3-amine;

[0783] 5-(2-aminopyridin-4-yl)-7-(thiazo-5-yl)-1H-indazole-3-amine;

[0784] 5-(2-aminopyridin-4-yl)-7-(1H-pyrazol-5-yl)-1H-indazole-3-amine;

[0785] 5-(2-aminopyridin-4-yl)-7-(3-methylbut-1-yn-1-yl)-1H-indazole-3-amine;

[0786] 5-(2-aminopyridin-4-yl)-7-(pent-1-yn-1-yl)-1H-indazole-3-amine;

[0787] 5-(2-aminopyridin-4-yl)-7-(cyclopropylethynyl)-1H-indazole-3-amine;

[0788] 5-(2-aminopyridin-4-yl)-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazole-3-amine;

[0789] 5-(2-aminopyridin-4-yl)-7-(phenylethynyl)-1H-indazole-3-amine;

[0790] 4-(3-amino-5-(2-aminopyridin-4-yl)-1H-indazol-7-yl)but-3-yn-1-ol;

[0791] 4-(3-amino-5-(2-aminopyridin-4-yl)-1H-indazol-7-yl)-2-methylbut-3-yn-2-ol;

[0792] 5-(2-aminopyridin-4-yl)-7-((3-methyloxetane-3-yl)ethynyl)-1H-indazole-3-amine;

[0793] 5-(2-aminopyridin-4-yl)-7-((tetrahydro-2H-pyran-4-yl)ethynyl)-1H-indazole-3-amine;

[0794] 5-(2-aminopyrimidin-4-yl)-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazole-3-amine;

[0795] 5-(2-aminopyridin-4-yl)-7-(3,3-dimethylbutyl)-1H-indazole-3-amine;

[0796] 5-(2-aminopyridin-4-yl)-7-(2-cyclohexylethyl)-1H-indazole-3-amine;

[0797] 5-(2-aminopyridin-4-yl)-7-(2-cyclopropylethyl)-1H-indazole-3-amine;

[0798] 5-(2-aminopyridin-4-yl)-7-phenethyl-1H-indazole-3-amine;

[0799] 5-(2-amino-5-fluoropyridin-4-yl)-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazole-3-amine;

[0800] 5-(2-amino-3-fluoropyridin-4-yl)-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazole-3-amine;

[0801] 5-(2-amino-6-fluoropyridin-4-yl)-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazole-3-amine;

[0802] 4-(3-amino-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazol-5-yl)pyridine-2,6-diamine;

[0803] 6-Amino-4-(3-Amino-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazol-5-yl)nicotinonitrile;

[0804] 5-(2-(cyclopropylamino)pyridin-4-yl)-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazole-3-amine;

[0805] 5-(2-(cyclobutanylamino)pyridin-4-yl)-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazole-3-amine;

[0806] 7-(3,3-Dimethylbut-1-yn-1-yl)-5-(2-(oxecyclobutan-3-ylamino)pyridin-4-yl)-1H-indazole-3-amine;

[0807] 5-(2-(cyclopentylamino)pyridin-4-yl)-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazole-3-amine;

[0808] 5-(2-((cyclopropylmethyl)amino)pyridin-4-yl)-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazole-3-amine;

[0809] 7-(3,3-Dimethylbut-1-yn-1-yl)-5-(2-((2,2,2-trifluoroethyl)amino)pyridin-4-yl)-1H-indazole-3-amine;

[0810] 3-((4-(3-amino-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazol-5-yl)pyridin-2-yl)amino)propionitrile;

[0811] 2-((4-(3-amino-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazol-5-yl)pyridin-2-yl)amino)ethanol;

[0812] N1-(4-(3-amino-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazol-5-yl)pyridin-2-yl)ethane-1,2-diamine;

[0813] 7-(3,3-Dimethylbut-1-yn-1-yl)-5-(2-((2-methoxyethyl)amino)pyridin-4-yl)-1H-indazole-3-amine;

[0814] 7-(3,3-Dimethylbut-1-yn-1-yl)-5-(2-((3-methoxypropyl)amino)pyridin-4-yl)-1H-indazole-3-amine;

[0815] N-(4-(3-amino-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazol-5-yl)pyridin-2-yl)acetamide;

[0816] N-(4-(3-amino-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazol-5-yl)pyridin-2-yl)propionamide;

[0817] N-(4-(3-amino-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazol-5-yl)pyridin-2-yl)-3,3,3-trifluoropropionamide;

[0818] N-(4-(3-amino-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazol-5-yl)pyridin-2-yl)cyclopropaneformamide;

[0819] N-(4-(3-amino-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazol-5-yl)pyridin-2-yl)isobutyramide;

[0820] N-(4-(3-amino-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazol-5-yl)pyridin-2-yl)neopentamide;

[0821] N-(4-(3-amino-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazol-5-yl)pyridin-2-yl)-2-cyclopropylacetamide;

[0822] N-(4-(3-amino-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazol-5-yl)pyridin-2-yl)-3-methylbutyramide;

[0823] N-(4-(3-amino-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazol-5-yl)pyridin-2-yl)cyclobutanecarboxamide;

[0824] N-(4-(3-amino-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazol-5-yl)pyridin-2-yl)cyclopentanecarboxamide;

[0825] N-(4-(3-amino-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazol-5-yl)pyridin-2-yl)-2-hydroxyacetamide;

[0826] N-(4-(3-amino-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazol-5-yl)pyridin-2-yl)-2-methoxyacetamide;

[0827] 5-(2-(cyclopropylamino)pyridin-4-yl)-7-((3-methyloxacyclobutane-3-yl)ethynyl)-1H-indazole-3-amine;

[0828] N-(4-(3-amino-7-((3-methyloxetane-3-yl)ethynyl)-1H-indazol-5-yl)pyridin-2-yl)acetamide;

[0829] N-(4-(3-amino-7-(phenylethynyl)-1H-indazol-5-yl)pyridin-2-yl)acetamide;

[0830] (4-(3-amino-7-(cyclopropylethynyl)-1H-indazol-5-yl)pyridin-2-yl)carbamate;

[0831] (4-(3-amino-7-(3-hydroxy-3-methylbut-1-yn-1-yl)-1H-indazol-5-yl)pyridin-2-yl)carbamate;

[0832] (4-(3-amino-7-(3-amino-3-methylbut-1-yn-1-yl)-1H-indazol-5-yl)pyridin-2-yl)carbamate;

[0833] (4-(3-amino-7-(3-methoxy-3-methylbut-1-yn-1-yl)-1H-indazol-5-yl)pyridin-2-yl)carbamate;

[0834] (4-(3-amino-7-(3-morpholinoprop-1-yn-1-yl)-1H-indazol-5-yl)pyridin-2-yl)carbamate;

[0835] (4-(3-amino-7-(4-morpholinobut-1-yn-1-yl)-1H-indazol-5-yl)pyridin-2-yl)carbamate;

[0836] 1-(4-(3-amino-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazol-5-yl)pyridin-2-yl)urea;

[0837] 1-(4-(3-amino-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazol-5-yl)pyridin-2-yl)-3-methylurea;

[0838] 1-(4-(3-amino-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazol-5-yl)pyridin-2-yl)-3-ethylurea;

[0839] 1-(4-(3-amino-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazol-5-yl)pyridin-2-yl)-3-propylurea;

[0840] 1-(4-(3-amino-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazol-5-yl)pyridin-2-yl)-3-phenylurea;

[0841] (4-(3-amino-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazol-5-yl)pyridin-2-yl)carbamate;

[0842] (4-(3-amino-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazol-5-yl)pyridin-2-yl)carbamate;

[0843] (4-(3-amino-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazol-5-yl)pyridin-2-yl)tert-butyl carbamate;

[0844] (4-(3-amino-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazol-5-yl)pyridin-2-yl)aminosulfonic acid;

[0845] N-(4-(3-amino-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazol-5-yl)pyridin-2-yl)methanesulfonamide;

[0846] N-(4-(3-amino-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazol-5-yl)-6-fluoropyridin-2-yl)acetamide;

[0847] N-(4-(3-amino-7-phenyl-1H-indazol-5-yl)pyridin-2-yl)acetamide;

[0848] N-(4-(3-amino-7-(pyridin-4-yl)-1H-indazol-5-yl)pyridin-2-yl)acetamide;

[0849] 7-(furan-3-yl)-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine;

[0850] 7-Ethynyl-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine;

[0851] 7-(3,3-Dimethylbut-1-yn-1-yl)-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine;

[0852] 7-(cyclopropylethynyl)-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine;

[0853] 7-(cyclopentylethynyl)-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine;

[0854] 7-(cyclohexylethynyl)-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine;

[0855] 3-(3-amino-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-7-yl)prop-2-yn-1-ol;

[0856] 4-(3-amino-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-7-yl)-2-methylbut-3-yn-2-ol;

[0857] 1-((3-amino-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-7-yl)ethynyl)cyclopentan-1-ol;

[0858] 1-((3-amino-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-7-yl)ethynyl)cyclohexane-1-ol;

[0859] 1-((3-amino-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-7-yl)ethynyl)cycloheptane-1-ol;

[0860] 7-(5-morpholinopent-1-yn-1-yl)-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine;

[0861] 7-(4-(piperidin-1-yl)but-1-yn-1-yl)-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine;

[0862] 7-(5-(piperidin-1-yl)pent-1-yn-1-yl)-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine;

[0863] 7-(6-(piperidin-1-yl)hex-1-yn-1-yl)-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine;

[0864] 6-(3-amino-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-7-yl)hex-5-ynyl acid;

[0865] 7-(3-amino-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-7-yl)hepta-6-ynyl acid;

[0866] 7-(4-phenoxybut-1-yn-1-yl)-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine;

[0867] 7-(6-phenoxyhexyl-1-yn-1-yl)-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine;

[0868] 5-(2-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine;

[0869] 5-(2-(tert-butyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine;

[0870] 5-(2-Cyclopropyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine;

[0871] 5-(2-cyclohexyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine;

[0872] 5-(2-neopentyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine;

[0873] 5-(2-(cyclohexylmethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine;

[0874] 5-(2-(2-cyclohexylethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine;

[0875] 5-(2-benzyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine;

[0876] (4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)methanol;

[0877] 2-(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)prop-2-ol;

[0878] 3-(4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)pentan-3-ol;

[0879] 5-(2-(tert-butoxymethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine;

[0880] 5-(2-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine;

[0881] 5-(2-(tetrahydro-2H-pyran-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine;

[0882] 5-(2-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine;

[0883] 4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid;

[0884] 4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid methyl ester;

[0885] 4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid ethyl ester;

[0886] 4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide;

[0887] (4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)(pyrrolidin-1-yl) methyl ketone;

[0888] 4-(3-amino-1H-indazol-5-yl)-N-cyclopentyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide;

[0889] 4-(3-amino-1H-indazol-5-yl)-N-cyclohexyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide;

[0890] 4-(3-amino-1H-indazol-5-yl)-N-isopentyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide;

[0891] 4-(3-amino-1H-indazol-5-yl)-N-phenethyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide;

[0892] 4-(3-amino-1H-indazol-5-yl)-N-(3-phenylpropyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide;

[0893] 4-(3-amino-1H-indazol-5-yl)-N-(2-methoxyethyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide;

[0894] 4-(3-amino-1H-indazol-5-yl)-N-(2-aminoethyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide;

[0895] 4-(3-amino-1H-indazol-5-yl)-N-(2-(dimethylamino)ethyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide;

[0896] (4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)(4-methylpiperazin-1-yl) methyl ketone;

[0897] 4-(3-amino-1H-indazol-5-yl)-N-(2-(piperidin-1-yl)ethyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide;

[0898] 4-(3-amino-1H-indazol-5-yl)-N-(2-(butyl(ethyl)amino)ethyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide;

[0899] 4-(3-amino-1H-indazol-5-yl)-N-(2-(diisopropylamino)ethyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide;

[0900] 4-(3-amino-1H-indazol-5-yl)-N-(3-(dimethylamino)propyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide;

[0901] 5-(2-((tert-butylamino)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine;

[0902] 5-(2-((isopentylamino)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine;

[0903] 5-(2-(piperidin-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine;

[0904] 5-(2-((cyclohexylamino)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine;

[0905] 5-(2-((phenylamino)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine;

[0906] 5-(2-(((2-(benzyloxy)phenyl)amino)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine;

[0907] 5-(2-(((2-methoxyethyl)amino)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine;

[0908] N 1 -((4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)-N 2 N 2 -Dimethylethane-1,2-diamine;

[0909] 5-(2-(((3-methoxypropyl)amino)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine;

[0910] 5-(2-(((3-isopropoxypropyl)amino)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine;

[0911] N 1 -((4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)-N 3 N 3 -Dimethylpropane-1,3-diamine;

[0912] 5-(2-((isopropyl(methyl)amino)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine;

[0913] 5-(2-(piperidin-1-ylmethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine;

[0914] 5-(2-((4,4-difluoropiperidin-1-yl)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine;

[0915] 5-(2-(morpholinomethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine;

[0916] 5-(2-((4-methylpiperazin-1-yl)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine;

[0917] 5-(2-((4-(tert-butyl)piperazin-1-yl)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine;

[0918] 5-(2-(azacycloheptane-1-ylmethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine;

[0919] 5-(2-((4-methyl-1,4-diazaphen-1-yl)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine;

[0920] 5-(2-(2-(piperidin-1-yl)ethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine;

[0921] 5-(2-(2-morpholinoethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine;

[0922] 5-(2-(3-(piperidin-1-yl)propyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine;

[0923] 5-(2-(3-(cyclohexylamino)propyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine;

[0924] 5-(2-(3-morpholinopropyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine;

[0925] 5-(2-(piperidin-4-ylmethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine;

[0926] 5-(2-((1-benzylpiperidin-4-yl)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine;

[0927] N-(4-(3-amino-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazol-5-yl)pyridin-2-yl)oxazol-2-amine;

[0928] 7-(3,3-Dimethylbut-1-yn-1-yl)-5-(2-((3,3,3-trifluoropropyl)amino)pyridin-4-yl)-1H-indazole-3-amine;

[0929] 7-(cyclopropylethynyl)-5-(2-(oxacyclobutane-3-ylamino)pyridin-4-yl)-1H-indazole-3-amine;

[0930] (4-(3-amino-7-((tetrahydro-2H-pyran-4-yl)ethynyl)-1H-indazol-5-yl)pyridin-2-yl)carbamate;

[0931] (4-(3-amino-7-((3-methyloxetane-3-yl)ethynyl)-1H-indazol-5-yl)pyridin-2-yl)carbamate;

[0932] 4-(3-amino-5-(2-(oxecyclobutan-3-ylamino)pyridin-4-yl)-1H-indazol-7-yl)-2-methylbut-3-yne-2-ol;

[0933] 5-(2-(oxacyclobutane-3-ylamino)pyridin-4-yl)-7-((tetrahydro-2H-pyran-4-yl)ethynyl)-1H-indazole-3-amine;

[0934] N-(4-(3-amino-7-(cyclopropylethynyl)-1H-indazol-5-yl)pyridin-2-yl)cyclopropaneformamide;

[0935] N-(4-(3-amino-7-(3-hydroxy-3-methylbut-1-yn-1-yl)-1H-indazol-5-yl)pyridin-2-yl)cyclopropaneformamide;

[0936] (4-(3-amino-7-(5-morpholinopent-1-yn-1-yl)-1H-indazol-5-yl)pyridin-2-yl)carbamate;

[0937] N-(4-(3-amino-7-(3-hydroxy-3-methylbutyl)-1H-indazol-5-yl)pyridin-2-yl)cyclopropaneformamide;

[0938] (4-(3-amino-7-(3,3-dimethylbutyl)-1H-indazol-5-yl)pyridin-2-yl)carbamate;

[0939] 5-(2-Cyclopropyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazole-3-amine;

[0940] 5-(2-cyclopentyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazole-3-amine;

[0941] 5-(2-(tert-butyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazole-3-amine;

[0942] (4-(3-amino-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)methanol;

[0943] 2-(4-(3-amino-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)prop-2-ol;

[0944] 4-(3-amino-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid methyl ester;

[0945] 5-(2-(difluoromethyl)-3H-imidazo[4,5-b]pyridin-7-yl)-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazole-3-amine;

[0946] 5-(2-Cyclobutyl-3H-imidazo[4,5-b]pyridin-7-yl)-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazole-3-amine;

[0947] N-(4-(3-amino-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazol-5-yl)pyridin-2-yl)aminocyano;

[0948] 5-(2-((1H-pyrazol-3-yl)amino)pyridin-4-yl)-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazole-3-amine;

[0949] 5-(2-((1H-pyrazol-4-yl)amino)pyridin-4-yl)-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazole-3-amine;

[0950] 7-(3,3-Dimethylbut-1-yn-1-yl)-5-(2-((5-methyl-1H-pyrazol-3-yl)amino)pyridin-4-yl)-1H-indazole-3-amine;

[0951] 7-(3,3-Dimethylbut-1-yn-1-yl)-5-(2-((3-methyl-1H-pyrazol-4-yl)amino)pyridin-4-yl)-1H-indazole-3-amine;

[0952] N-(4-(3-amino-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazol-5-yl)pyridin-2-yl)thiazolyl-2-amine;

[0953] N-(4-(3-amino-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazol-5-yl)pyridin-2-yl)-4-methyloxazol-2-amine;

[0954] N-(4-(3-amino-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazol-5-yl)pyridin-2-yl)-4-(trifluoromethyl)oxazol-2-amine;

[0955] N-(4-(3-amino-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazol-5-yl)pyridin-2-yl)-3,5-dimethylisoxazol-4-amine;

[0956] 5-(2-((1H-imidazol-4-yl)amino)pyridin-4-yl)-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazole-3-amine;

[0957] 5-(2-((4H-1,2,4-triazol-3-yl)amino)pyridin-4-yl)-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazol-3-amine;

[0958] 7-(3,3-Dimethylbut-1-yn-1-yl)-5-(2-((2-methyl-2H-tetrazol-5-yl)amino)pyridin-4-yl)-1H-indazol-3-amine;

[0959] 7-(3,3-Dimethylbut-1-yn-1-yl)-5-(2-(pyrimidin-2-ylamino)pyridin-4-yl)-1H-indazole-3-amine;

[0960] 7-(3,3-Dimethylbut-1-yn-1-yl)-5-(2-((tetrahydrofuran-3-yl)amino)pyridin-4-yl)-1H-indazole-3-amine;

[0961] Methyl (4-(3-amino-7-(4-hydroxyphenyl)-1H-indazol-5-yl)pyridin-2-yl)carbamate;

[0962] 4-(3-amino-5-(2-(oxetane-3-ylamino)pyridin-4-yl)-1H-indazol-7-yl)phenol;

[0963] Methyl (4-(3-amino-7-(4-aminophenyl)-1H-indazol-5-yl)pyridin-2-yl)carbamate;

[0964] Methyl (4-(7-(4-acetamidophenyl)-3-amino-1H-indazol-5-yl)pyridin-2-yl)carbamate;

[0965] Methyl (4-(3-amino-7-(4-carbamoylphenyl)-1H-indazol-5-yl)pyridin-2-yl)carbamate;

[0966] (4-(3-amino-7-(4-(morpholinomethyl)phenyl)-1H-indazol-5-yl)pyridin-2-yl)carbamate;

[0967] 5-(2-aminopyridin-4-yl)-7-(4-(2-morpholinoethyl)phenyl)-1H-indazole-3-amine;

[0968] Methyl (4-(3-amino-7-(4-(2-morpholinoethyl)phenyl)-1H-indazol-5-yl)pyridin-2-yl)carbamate;

[0969] Methyl (4-(3-amino-7-(4-(methanesulfonyl)phenyl)-1H-indazol-5-yl)pyridin-2-yl)carbamate;

[0970] Methyl (4-(3-amino-7-(3-hydroxyphenyl)-1H-indazol-5-yl)pyridin-2-yl)carbamate;

[0971] Methyl (4-(3-amino-7-(3-carbamoylphenyl)-1H-indazol-5-yl)pyridin-2-yl)carbamate;

[0972] Methyl (4-(3-amino-7-(3-(morpholinomethyl)phenyl)-1H-indazol-5-yl)pyridin-2-yl)carbamate;

[0973] N-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-2-cyclohexylacetamide; or

[0974] 6-Amino-4-(3-Amino-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazol-5-yl)nicotinonitrile.

[0975] Typically, various functional groups and substituents constituting the compounds of formula (I) or subformulas (Ia) to (Ie) are chosen 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.

[0976] 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.

[0977] 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."

[0978] 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 a particular compound in the specification and claims is intended to include its 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).

[0979] It should be understood that the present invention includes all active optical isomers, diastereomers and geometric isomers and mixtures thereof.

[0980] 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.

[0981] It should also be understood that certain compounds of formula (I) or sub-formulas (Ia) to (Ie) can 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.

[0982] It should also be understood that certain compounds of formula (I) or sub-formulas (Ia) to (Ie) may exhibit polymorphism, and the present invention includes all of these active forms.

[0983] Compounds of formula (I) or sub-forms (Ia) through (Ie) can exist in many different tautomeric forms, and all such forms are included when referring to compounds of formula (I) or sub-forms (Ia) through (Ie). For the avoidance of doubt, when a compound can exist in one of several tautomeric forms, and only one is specifically described or shown, all the others are included in formula (I) or sub-forms (Ia) through (Ie). Examples of tautomeric forms include ketone-, enol-, and enolate-forms, such as the following tautomeric pairs: ketone / enol (as shown below), imine / enamine, amide / imino alcohol, amidine / amidinium, nitroso / oxime, thionone / enthiol, and nitro / acidic nitro.

[0984]

[0985] Compounds of formula (I) or sub-formulas (Ia) to (Ie) containing amine functional groups can also form N-oxides. The compounds of formula (I) or sub-formulas (Ia) to (Ie) 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 using the LWDeady procedure (Syn. Comm. 1977, 7, 509-514), in which an amine compound reacts with m-chloroperoxybenzoic acid (mCPBA) in, for example, an inert solvent such as dichloromethane.

[0986] Compounds of formula (I) or sub-formulas (Ia) to (Ie) 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 properties 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, and the modifying groups can be attached to such groups or substituents. 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 (Ie), 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 (Ie).

[0987] Therefore, the present invention includes those compounds of formula (I) or sub-formulas (Ia) to (Ie) as defined above, when obtained by organic synthesis, and when obtained in a human or animal body by cleavage of their prodrugs. Thus, the present invention includes those compounds of formula (I) or sub-formulas (Ia) to (Ie) produced by organic synthesis methods, and such compounds produced in a human or animal body by metabolism of precursor compounds, i.e., compounds of formula (I) or sub-formulas (Ia) to (Ie) can be synthetically produced or metabolically produced compounds.

[0988] A suitable pharmaceutically acceptable prodrug of a compound of formula (I) or sub-formulas (Ia) to (Ie) is a drug based on reasonable medical judgment that is suitable for administration to humans or animals without undesirable pharmacological activity and excessive toxicity.

[0989] Various forms of prodrugs have been described, for example in the following documents:

[0990] a)Methods in Enzymology, Vol.42, p.309-396, edited by K. Widder, etal. (Academic Press, 1985);

[0991] b) Design of Pro-drugs, edited by H. Bundgaard, (Elsevier, 1985);

[0992] c)A Textbook of Drug Design and Development,edited by Krogsgaard-Larsen and

[0993] H.Bundgaard, Chapter 5 "Design and Application of Pro-drugs", by H.Bundgaard p.113-191 (1991);

[0994] d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992);

[0995] e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988);

[0996] f) N. Kakeya, et al., Chem. Pharm. Bull., 32, 692 (1984);

[0997] g)T.Higuchi and V.Stella, "Pro-Drugs as Novel Delivery Systems", ACSSymposium Series, Volume 14; and

[0998] h) E. Roche (editor), "Bioreversible Carriers in Drug Design", Pergamon Press, 1987.

[0999] Suitable pharmaceutically acceptable prodrugs of compounds of formula (I) or sub-formulas (Ia) to (Ie) 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 (Ie) 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 esters; (1-6C)alkyloxymethyl esters, such as neopentyloxymethyl esters; 3-phthalidyl esters; (3-8C)cycloalkylcarbonyloxy-(1-6C)alkyl esters, such as cyclopentylcarbonyloxymethyl esters and 1-cyclohexylcarbonyloxyethyl esters; 2-oxo-1,3-dioxolenylmethyl esters, such as 5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl esters; and (1-6C)alkoxycarbonyloxy-(1-6C)alkyl esters, such as methoxycarbonyloxymethyl esters and 1-methoxycarbonyloxyethyl esters.

[1000] Suitable pharmaceutically acceptable prodrugs of compounds of formula (I) or sub-formulas (Ia) to (Ie) 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 cyclic phosphoramide 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.

[1001] Suitable pharmaceutically acceptable prodrugs of compounds of formula (I) or sub-formulas (Ia) to (Ie) 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.

[1002] Suitable pharmaceutically acceptable prodrugs of compounds having an amino group of formula (I) or subforms (Ia) to (Ie) 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 acyl 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.

[1003] The in vivo effects of compounds of formula (I) or sub-formulas (Ia) to (Ie) may be exerted in part by one or more metabolites formed in the human or animal body following administration of a compound of formula (I) or sub-formulas (Ia) to (Ie). As described above, the in vivo effects of compounds of formula (I) or sub-formulas (Ia) to (Ie) may also be exerted by the metabolism of prodrugs (prodrugs).

[1004] While the invention may relate to any compound or particular group of compounds as defined herein by optional, preferred or suitable features or by 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.

[1005] Suitablely, the present invention excludes any single compound that does not have the biological activity defined herein.

[1006] synthesis

[1007] 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.

[1008] 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 procedures.

[1009] 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.

[1010] 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.

[1011] 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.

[1012] 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.

[1013] 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.

[1014] 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.

[1015] 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.

[1016] Resins can also be used as protecting groups.

[1017] The method for synthesizing compounds of formula (I) or sub-formulas (Ia) to (Ie) will be based on R 1 R 2 R 3 R 4 R 6 and R 10 The properties vary depending on the nature of any substituents or subunits associated with them. Suitable methods for preparing them are further described in the accompanying examples.

[1018] Once a compound of formula (I) or sub-formulas (Ia) to (Ie) has been synthesized by any of the methods defined herein, the method may further include additional steps:

[1019] (i) Remove any existing protecting groups;

[1020] (ii) Converting a compound of formula (I) into another compound of formula (I);

[1021] (iii) forming a pharmaceutically acceptable salt, hydrate, or solvate thereof; and / or

[1022] (iv) Formation of its prodrug.

[1023] An example of (ii) above is that when a compound of formula (I) is synthesized, one or more groups can then react further to change the properties of that group and provide an alternative compound of formula (I).

[1024] The obtained compounds of formula (I) or sub-formulas (Ia) to (Ie) can be separated and purified using techniques known in the art.

[1025] The compounds of formula (I) can be synthesized via the synthetic route shown in the following examples.

[1026] Bioactivity

[1027] The bioassays described in the Examples section of this document can be used to measure the pharmacological effects of the compounds of this invention.

[1028] 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 IKK-α assay described in the Examples section, with preferred compounds showing better selectivity for IKK-α than for IKK-β.

[1029] Pharmaceutical Composition

[1030] 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.

[1031] 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).

[1032] The compositions of the present invention can be obtained by conventional methods using conventional pharmaceutical excipients known in the art. Therefore, compositions for oral administration may contain, for example, one or more colorants, sweeteners, flavoring agents, and / or preservatives.

[1033] An effective amount of the compound of the present invention used for treatment is an amount sufficient to treat or prevent the proliferative condition referred to herein, slow its progression and / or alleviate the symptoms associated with the condition.

[1034] 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.

[1035] 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.

[1036] When the compounds of the present invention are used for therapeutic or preventative purposes, they are typically administered to obtain a daily dose, for example, ranging from 0.1 mg / kg to 75 mg / kg body weight (in fractions if necessary). Generally, a lower dose is administered when the administration is via a parenteral route. Thus, for example, for intravenous or intraperitoneal administration, a dose ranging from 0.1 mg / kg to 30 mg / kg body weight is typically used. Similarly, for inhalation administration, a dose ranging from, for example, 0.05 mg / kg to 25 mg / kg body weight is used. Oral administration is also suitable, especially 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.

[1037] Therapeutic uses and applications

[1038] 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 where inhibition of IKKα activity may be beneficial.

[1039] IKKα activity is known to play a role in cancer.

[1040] The role of IKKα in cancer

[1041] IKKα in solid tumors

[1042] 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.

[1043] 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] .

[1044] 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 in HER2-positive epithelial cells via p27

[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.

[1045] IKKα signaling in solid tumors that is independent of the NF-κB pathway

[1046] 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] .

[1047] 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 promotion of 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 truncated form of IKKα (p45 IKKα) that is persistently activated and 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 p45IKKα 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.

[1048] It has been consistently reported that the nuclear function of IKKα is independent of NF-κB and exerts its effects through the activation of 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 metastasis, delays the development of castration-resistant disease

[89] .

[1049] IKKα is associated with cancer markers in human tumors.

[1050] 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 peritoneal metastasis model, intraperitoneal injection of IκBα-inhibited colon cells induced an M1-like macrophage phenotype, resulting in reduced liver and peritoneal metastases in vivo. This is related to the activation of CD4+ within the tumor. + and CD8 + Increased T cells and decreased angiogenesis

[93] demonstrate 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] .

[1051] 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] .

[1052] The role of IKKα in hematological malignancies

[1053] 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 tumor microenvironment signaling, IKKα represents an attractive anticancer target.

[1054] Chronic lymphocytic leukemia (CLL) is the most common type of leukemia in Europe and North America. It is characterized by the accumulation of mature CD5+ / CD19+ B lymphocytes in peripheral blood, bone marrow, and lymphoid tissues

[105] . In many CLL patients, NF-κB is constitutively activated, which is associated with a more aggressive disease [106, 107]. Many relapsing gene mutations of NF-κB-related genes have been described in CLL. Among the most common are NFκBIE inactivating mutations encoding the negative NF-κB regulator IκBε. These NFKBIE 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 NFKBIE 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 (~4%) of CLL patients, but these mutations affect the atypical NF-κB pathway due to premature truncation of the protein product cIAP2 encoded by BIRC3, resulting in the loss of E3 ubiquitin ligase activity of cIAP2, which is essential for NIK proteasome degradation. Consequently, 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] .

[1055] 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] . Separating the tumor from sites of enhanced NF-κB signaling leads to durable remission, but this effect is reversed upon discontinuation of the drug.

[1056] Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma. They are classified into three molecular subtypes: 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 subtype. 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 subtype 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 subtypes, 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 tumor subpopulations that may be targeted by IKKα.

[1057] 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].

[1058] 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 interactions [130, 131]. CD40 is a cell surface marker that is not normally expressed on normal plasma cells but has been shown to be increased 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 contributes 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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[1141] 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.

[1142] 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.

[1143] 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.

[1144] 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.

[1145] 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 therapeutic purposes.

[1146] 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 medicines.

[1147] 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.

[1148] According to another aspect of the invention, compounds as defined herein, or pharmaceutically acceptable salts, hydrates, or solvates thereof, or pharmaceutical compositions, are provided for the treatment of cancer. In one particular embodiment, the cancer is a human cancer.

[1149] 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.

[1150] 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.

[1151] 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.

[1152] 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.

[1153] 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.

[1154] 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.

[1155] According to another aspect of the invention, a method for preparing compounds as defined herein or pharmaceutically acceptable salts, hydrates or solvates thereof is provided.

[1156] 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.

[1157] 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.

[1158] 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 tumors or proliferative growth, whether in vitro or in vivo, of unwanted excess or abnormal cells.

[1159] In the above aspects of the invention, the proliferative disease is suitably cancer, and the cancer is suitably human cancer. In particular, the compounds of the invention will be used to treat any cancer that is beneficial to mismatch repair inhibition. They can target any suitable cancer (e.g., adenoid cystic carcinoma, adrenal tumor, amyloidosis, anal cancer, appendiceal 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 tumors (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 cancer) Precellular lymphocytic leukemia, hairy cell leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic T-cell lymphocytic 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 cancer, nasal... Pharyngeal cancer, 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 cancer, osteosarcoma, ovarian / fallopian tube / peritoneal cancer, pancreatic cancer, parathyroid cancer, 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), skin cancer, small bowel 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.

[1160] 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).

[1161] 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 therapy, and improve survival. Furthermore, their application in hormone-sensitive new metastatic disease can significantly prolong the duration of benefit from conventional therapy and reduce the overall incidence (CRPC) of castration-resistant prostate cancer. Therefore, IKKα inhibitors can be used in the following clinical situations:

[1162] Last-line treatment for CRPC patients who have failed standard treatment

[1163] • Combination therapy with ADT to prevent the onset of CRPC / prolong sensitivity to ADT

[1164] • Combination therapy in CRPC patients to restore sensitivity to ADT / reduce the development of chemotherapy resistance

[1165] • Single-drug therapy for the prevention of CRPC

[1166] Application route

[1167] 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).

[1168] Routes of administration include, but are not limited to, oral (e.g., by ingestion); buccal; sublingual; transdermal (including, for example, by patches, plaster, etc.); transmucosal (including, for example, by patches, plaster, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eye drops); pulmonary (e.g., by inhalation or blowing therapy, 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, intraspinal, intracapsular, intraorbital, intraperitoneal, intratracheal, subcutaneous, intra-articular, subarachnoid, and intrasternal; and by implantation of a reservoir or depository, such as subcutaneous or intramuscular.

[1169] Combination therapy

[1170] 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 drugs. Such chemotherapy or targeted agents may include one or more of the following categories:

[1171] (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., anthracycline antibiotics, such as adriamycin). (Cin), bleomycin, doxorubicin, daunorubicin, epirubicin, idarubicin, mitomycin-C, sclerosingin, and sclerosingin); 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., epipodophyllotoxin such as etoposide and teniposide, acridine, topotecan, and camptothecin);

[1172] (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, nilutamide, 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 5-reductase inhibitors, such as finasteride;

[1173] (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.

[1174] (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]). TMAnti-EGFR antibody panitumumab, anti-erbB1 antibody cetuximab [Erbitux, C225], and any growth factor or growth factor receptor antibody disclosed by Stern et al. (Critical reviews in oncology / haematology, 2005, Vol. 54, pp11-29); 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;

[1175] (v) Anti-angiogenic agents, such as, but not limited to, those drugs that inhibit the action of vascular endothelial growth factor (VEGF), [e.g., the anti-VEGF antibody bevacizumab (Avastin)]. TM And, for example, VEGF receptor tyrosine kinase inhibitors, such as vandetanib (ZD6474), vastarani (PTK787), sunitinib (SU11248), axitinib (AG-013736) and pazopanib (GW 786034).

[1176] (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;

[1177] (vii) Endothelin receptor antagonists, such as zipotan (ZD4054) or atrasentan;

[1178] (viii) Antisense therapies, such as, but not limited to, those targeting the targets listed above, such as ISIS2503, an anti-ras antisense;

[1179] (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 bromine domain inhibitors; transduction of cancer antigens using microbial vectors; direct transduction of cancer antigens into 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.

[1180] 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).

[1181] This combination therapy can be achieved by administering the individual therapeutic components simultaneously, sequentially, or separately. This combination product uses compounds of the invention within the dosage range described above, and other pharmaceutically active agents within their approved dosage range.

[1182] 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.

[1183] 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.

[1184] 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.

[1185] 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.

[1186] 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.

[1187] 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, combined with an antitumor agent (optionally selected from one listed above) and a pharmaceutically acceptable diluent or carrier.

[1188] Example

[1189] Experimental Section

[1190] Unless otherwise specified, conventional methods 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 (Acros, Use silica gel or the Biotage SP4 automated chromatography system (SNAP KP-Sil) at a depth of 35-70 μm. Rapid chromatographic separation was performed using a 40-63 μm column; detection wavelength: 254 nm; monitoring wavelength: 280 nm. NMR spectroscopy (… 1 H and 13 C) 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. Low-resolution mass spectrometry was performed by direct injection onto a ThermoFinnigan LCQ Duo, followed by high-resolution mass spectrometry on an Exactive (thermoscientific) LCMS mass spectrometer. Reversed-phase HPLC purification was performed on a water HPLC system consisting of a Waters 1525 binary HPLC pump, a Waters 717 autosampler, and a Waters 2487 dual-λ absorbance detector (254 nm), using a semi-preparative (50 × 21.2 mm) Luna 5 μC 18 column (eluted with an acetonitrile / water gradient, each solvent containing 0.1% TFA, using the following gradient;

[1191] Time (min) Flow rate (mL / min) % water 0.1% TFA % Acetonitrile 0.1% TFA 0 6 90 10 25 6 50 50 30 6 30 70 35 6 90 10 40 0 90 10

[1192] Microwave reactions were performed using a Biotage Initiator-8 microwave synthesizer (operated at 2.45 GHz). Thin-layer chromatography (TLC) was performed on an aluminum-backed SiO2 plate (Merck, silica gel 60, F). 254 Spots 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.

[1193] General Procedure

[1194] All commercially available reagents and solvents used were purchased 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.

[1195] Microwave reactions were performed using the Biotage Initiator system.

[1196] Rapid chromatographic separations were performed using the Biotage SP4 automated chromatography system, which employs a silica stationary phase (Fisher Scientific). (35-70μm; detection wavelength: 254nm; monitoring: 280nm), the mobile phase used is described in detail in the main text.

[1197] Purification was performed by reversed-phase HPLC on a Shimadzu Prominence HPLC system at 40 °C using a semi-preparative (50 × 21.2 mm) Luna 5 μm C18 column; flow rate: 6 mL / min; detection wavelength: 254 nm; elution was performed using an acetonitrile / water gradient containing 0.1% TFA.

[1198] 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), doublets of doublets (dd), triplets (t), quartets (q), and multiplies (m).

[1199] 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 (Thermoscientific) or LTQ orbital trap (Thermo Scientific).

[1200] Section 1 - Compounds of the following formula:

[1201]

[1202] Example 1

[1203] 3-Chloro-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxoborhecyclopentan-2-yl)benzylnitrile

[1204]

[1205] 7.2 mL of a pre-prepared catalyst solution of [Ir(OMe)cod]2 (104 mg, 0.312 mmol [Ir]), bipinallodiborane (2644 mg, 10.4 mmol), and 4,4'-di-tert-butyl-2,2'-bipyridine (84 mg, 0.312 mmol) dissolved in tert-butyl methyl ether was transferred to a 10–20 mL microwave-safe vial. 3-Chloro-2-fluorobenzyl nitrile (934 mg, 6 mmol) was added, and the solution was heated to 90 °C and held at this temperature for 90 minutes under microwave conditions. The solution was filtered through diatomaceous earth using a 10:1 CH2Cl2:methanol solution, and the process was continued without further purification.

[1206] 5-(4,4,5,5-Tetramethyl-1,3,2-dioxoboronyl-2-yl)-7-chloro-3-amino-1H-indazole

[1207]

[1208] A crude mixture of 3-chloro-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)benzylnitrile was diluted in ethanol (20 mL), and hydrazine hydrate (50-60%, 1.46 mL, 30 mmol) was added. The solution was stirred at 90 °C for 28 hours. Water (75 mL) was added, and the resulting precipitate was filtered. The solid was washed with water (20 × 10 mL) and petroleum ether at 60-80 °C (10 × 10 mL), and dried under reduced pressure to give a brown solid (678 mg, 39% after two steps). 1 H(DMSO-d6,400MHz)δ1.30(s,12H),5.69(br s,2H),7.46(s,1H),8.17(s,1H),12.02(br s,1H); 13 C (DMSO-d6, 100MHz) δ 25.15 (4C), 84.03 (2C), 114.27, 116.70, 118.51, 128.10, 130.61, 140.38, 151.12; LR-MS ESI 294.13 (100%), 296.07 (32.6%).

[1209] 5-(2-aminopyridin-4-yl)-7-chloro-1H-indazole-3-amine

[1210]

[1211] 5-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-7-chloro-3-amino-1H-indazole (176.1 mg, 0.6 mmol), 2-amino-4-bromopyridine (86.5 mg, 0.5 mmol), and [1,1′-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride catalyst (16.3 mg, 0.025 mmol) were placed in 2–5 mL microwave-safe vials, which were then sealed and purged with nitrogen. Ethanol (1.5 mL) was added, and the suspension was brought to 90 °C with stirring. K₃PO₄ (1 M, 0.75 mL, O₂-free) was then added. Stirring continued for 24 hours. The resulting solution was diluted in EtOAc, washed with water, and adsorbed onto silica under reduced pressure. Chromatographic purification (Biotage SP4, 50g column, solvent system: EtOAc / methanol, 0%, 6CV; 0-2%, 1CV; 2%, 3CV; 2-10%, 1CV; 10%, 4CV) yielded the product as a yellow solid (42mg, 32%). 1 H(DMSO-d6,400MHz)δ5.65(s,2H),5.92(s,2H),6.71(s,1H),6.79(dd,J=5.4&1.1Hz,1H),7.57(s,1H),7.95(d,J=5.6Hz,1H),8.07(s,1H),12.01(br s,1H); 13 C(DMSO-d6, 100MHz)δ104.62,109.89,114.66,116.36,117.67,123.89,129.11,138.48,147.67,148.35,150.63,160.39; LR-MS ESI 260.13 (100%), 262.13 (33.7%). HRMS (ESI+ve): for C 12 H 11 The required N5Cl value is 260.0697, and the actual values ​​are 260.0696 (100%) and 262.0665 (32%).

[1212] Example 2

[1213] (E)-5-bromo-2-fluoro-3-methylbenzaldehyde oxime

[1214]

[1215] 5-Bromo-2-fluoro-3-methylbenzaldehyde (2.00 g, 9.30 mmol) was dissolved together with hydroxylamine hydrochloride (1.26 g, 18.12 mmol) and 6 mL of 50% w / w sodium hydroxide solution in ethanol:water (1:2) (180 mL). The solution was then stirred at room temperature for 1 hour. The solution was then neutralized to pH 7 with concentrated HCl. The solution was then extracted with dichloromethane (150 mL), the organic layer was washed with brine (50 mL), and dried over magnesium sulfate. The solvent was then removed to give the title compound as fine white needle-like substances (1.92 g, 8.35 mmol, 90% yield). 1 ¹H NMR (500MHz DMSO-d⁶): δ 2.23 (s, 3H), 7.52 (dd, J = 6.5, 2.0Hz, 1H), 7.64 (dd, J = 6.0, 2.5Hz, 1H), 8.16 (s, 1H), 11.74 (s, 1H). LRMS: Required 231.96 for C₈H₇BrFNO, measured 231.98 (M+H).

[1216] 5-Bromo-2-fluoro-3-methylbenzylnitrile

[1217]

[1218] (E)-5-bromo-2-fluoro-3-methylbenzaldehyde oxime (1.90 g, 8.26 mmol) was dissolved in acetic anhydride (10 mL), and the solution was heated to 140 °C and maintained for 3 hours. The solution was then cooled, and the solvent was removed under high vacuum to obtain the desired product, a light brown needle-like substance (1.55 g, 7.31 mmol, 86%). 1 H NMR (500MHz DMSO-d6): δ 2.28 (d, J = 2.0Hz, 3H), 7.93 (m, 1H), 8.04 (m, 1H), LRMS: 212.96 for C8H5BrFN, measured 213.97 (M+H).

[1219] 5-(2-aminopyridin-4-yl)-7-methyl-1H-indazole-3-amine

[1220]

[1221] 4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)pyridine-2-amine (0.352 g, 0.80 mmol), 5-bromo-2-fluoro-3-methylbenzylnitrile (0.085 g, 0.40 mmol), and sodium acetate (0.066 g, 0.80 mmol) were dissolved in a 10 mL microwave-safe vial in a 2:1 mixture of IPA and water (5 mL). The solution was then degassed with nitrogen for 15 min. Then, 0.040 g of [1,1′-bis(diphenylphosphine)ferrocene]palladium(II) dichloride catalyst was added, the vial was sealed, and the solution was microwaved to 160 °C for 40 min. Then, 1 mL of hydrazine hydrate was added, and the solution was heated to 100 °C for 1 hour. The solvent was then removed under reduced pressure, the residue was dissolved in DMF (1 mL), and purified by HPLC to obtain the desired product as a white solid (0.0054 g, 0.023 mmol, 6%). 1 ¹H NMR (500MHz DMSO-d⁶): δ 2.47 (s, 3H), 7.21 (m, 2H), 7.45 (s, 1H), 7.93 (s, 2H), 7.99 (d, J = 7.2Hz, 1H), 8.14 (d, J = 1.2Hz, 1H), 12.10 (s, 1H) LRMS: for C 13 H 13 N5 requires 239.12, actual measurement is 240.13 (M+H).

[1222] Example 3

[1223] 5-Bromo-2-fluoro-3-(trifluoromethyl)benzylnitrile

[1224]

[1225] 5-Bromo-2-fluoro-3-(trifluoromethyl)benzaldehyde oxime (1.5 g, 5.25 mmol) was dissolved in acetic anhydride (10 mL) and evenly distributed into two 2–5 mL microwave-safe vials, sealed, and purged with nitrogen. The vials were microwaved at 180 °C for 2 hours. The resulting solutions were combined, diluted in EtOAc (100 mL), and washed with saturated sodium carbonate (100 mL). The organic matter was dried over magnesium sulfate and adsorbed onto silica under reduced pressure. Chromatographic purification (Biotage SP4, 50 g column, solvent system: petroleum ether / EtOAc, isocratic, 5%, 8 CV) gave the title product as a white, waxy solid (920 mg, 65%). 1 H(DMSO-d6,500MHz)δ8.40(dd,J=6.3&2.2Hz,1H),8.64(dd,J=5.3&2.5Hz,1H); 13C(DMSO-d6,125MHz)δ105.00(d,J=15.6Hz),112.16,117.70(d,J=3.7Hz),119.67(dd,J=34 .1&11.1Hz), 121.43 (d, J = 273.9Hz), 135.80 (d, J = 3.7Hz), 141.23, 159.51 (d, J = 265.6Hz).

[1226] 5-Bromo-7-(trifluoromethyl)-3-amino-1H-indazole

[1227]

[1228] 5-Bromo-2-fluoro-3-(trifluoromethyl)benzyl nitrile (900 mg, 3.36 mmol), sodium bicarbonate (378 mg, 4.5 mmol), and ethanol (4 mL) were placed in a 10–20 mL microwave-safe vial, sealed, and purged with nitrogen. The solution was heated to 90 °C with stirring, at which point hydrazine hydrate (0.73 mL, 15 mmol) was added. The solution was stirred for 18 hours and then cooled to room temperature. Water (15 mL) was added, and the precipitate was filtered off. The product was washed with water (10 × 10 mL) and petroleum ether (5 × 10 mL) to give the title product as a crystalline white solid (840 mg, 89%). 1 H(DMSO-d6,500MHz)δ5.72(s,2H),7.69(s,1H),8.28(s,1H),12.17(s,1H); 13 C (DMSO-d6, 125MHz) δ 107.97, 112.40 (d, J = 34.8Hz), 118.28, 126.61 (d, J = 4.6Hz), 128.26 134.98, 149.73.

[1229] 5-(4,4,5,5-Tetramethyl-1,3,2-dioxoborhecyclopentan-2-yl)-7-(trifluoromethyl)-3-amino-1H-indazole

[1230]

[1231] 5-Bromo-7-(trifluoromethyl)-3-amino-1H-indazole (280 mg, 1 mmol), bis(pinacolyl)diborane (280 mg, 1.1 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride catalyst (36.6 mg, 0.05 mmol), and 1,4-dioxane (5 mL) were placed in 10–20 mL microwave-safe vials, sealed, and purged with nitrogen. A solution of potassium acetate (264 mg, 3 mmol) in water (0.5 mL) was added, and the solution was stirred at 100 °C for 24 hours. The resulting solution was suspended in EtOAc (150 mL) and methanol (10 mL) and washed with water (2 × 50 mL) and brine (50 mL). The organic matter was dried over magnesium sulfate and adsorbed onto silica under reduced pressure. Chromatographic purification (Biotage SP4, 50 g column, solvent system: petroleum ether / EtOAc, 30%, 5 CV; 30-70%, 1 CV; 70%, 3 CV) yielded the title product as a brown solid (190 mg, 58%). 1 H(DMSO-d6,500MHz)δ1.31(s,12H),5.80(s,2H),7.72(s,1H),8.45(s,1H),12.10(s,1H);

[1232] 5-(2-aminopyridin-4-yl)-7-(trifluoromethyl)-1H-indazole-3-amine

[1233]

[1234] Dissolved in ethanol (O2-free, 0.66 mL) in 128 mg (1 mmol), [1,1′-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride catalyst (12 mg, 0.019 mmol), and 5-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-7-(trifluoromethyl)-3-amino-1H-indazole (120 mg, 0.37 mmol) were placed in a 2–5 mL microwave-safe vial, sealed, and purged with nitrogen. Another 0.84 mL of ethanol (O2-free) was added, and the solution was heated to 100 °C. K₃PO₄ (1 M, 0.74 mL) was then added, and the solution was stirred for 24 hours. The solution was cooled, suspended in EtOAc (100 mL), and washed with water (2 × 50 mL) and brine (50 mL). The organic matter was dried with magnesium sulfate and adsorbed onto silica under reduced pressure. Chromatographic purification (Biotage SP4, 50 g column, solvent system: EtOAc / methanol, 0%, 4CV; 0-2%, 3CV; 2%, 2CV; 2-10%, 1CV; 10%, 4CV) yielded a product as a pale yellow solid (47 mg, 44%). 1H(DMSO-d6,500MHz)δ5.77(s,2H),5.96(s,2H),6.75(d,J=0.9Hz,1H),6.75(dd,J =5.3&1.6Hz,1H),7.79(s,1H),7.97(d,J=5.3Hz,1H),8.40(s,1H),12.09(s,1H); 19 F(DMSO-d6, 376MHz)δ-60.34; 13 C(DMSO-d6, 100MHz)δ105.09,110.26,117.43,119.28(d,J=245.8Hz),122.72(d,J=4.4Hz),123.21,123.88,125.90,127.84,147.87,149.00,150.88,160.97; HRMS(ESI+ve): for C 13 H 11 F3N5 requires a value of 294.0961, and the measured value is 294.0961.

[1235] Section 2 - Compounds of the following formula:

[1236]

[1237] Example 4

[1238] 7-Chloro-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[1239]

[1240] 4-Bromo-1H-pyrrolo[2,3-b]pyridine (0.291 g, 1.50 mmol) was mixed with 7-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-1H-indazole-3-amine (0.502 g, 1.5 mmol), dioxane (8 mL), and potassium phosphate (4 mL, 1 M solution) in a 20 mL microwave-safe vial. The solution was then degassed with N2 for 10 min. Then, [1,1′-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride catalyst (118) (0.118 g, 0.17 mmol, 5 mol%) was added, the vial was sealed, and the solution was heated to 90 °C and maintained for 16 h. The solution was then cooled, and the solvent was removed under reduced pressure to obtain a crude product. This crude product was purified by rapid chromatography to obtain the desired product. (321 mg, 0.98 mmol, 65%), δ H(d6-DMSO): 5.57(s, 1H), 5.69(s, 2H), 6.70(q, J = 1.72 1H), 7.21(d, J = 5.00, 1H), 7.56(t, J = 2.76, 1H), 7.84(d, J = 1.24, 1H), 8.22(d, J = 1.28Hz, 1H), 8.27(d, J = 5.00Hz, 1H), 11.76(s, 1H), 11.96(s, 1H). LRMS: Measured: 283.2(M+1), calculated as C. 14 H 10 ClN5: 284.2.

[1241] Example 5

[1242] 7-Bromo-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[1243]

[1244] 4-Bromo-1H-pyrrolo[2,3-b]pyridine (0.291 g, 1.50 mmol) was placed in a 20 mL microwave-safe vial with 7-bromo-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-1H-indazole-3-amine (0.502 g, 1.5 mmol), dioxane (8 mL), and potassium phosphate (4 mL, 1 M solution). The solution was then degassed with N2 for 10 min. Then, [1,1′-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride catalyst (0.118 g, 0.17 mmol, 5 mol%) was added, the vial was sealed, and the solution was heated to 90 °C for 16 h. The solution was then cooled, and the solvent was removed under reduced pressure to obtain a crude product. This crude product was purified by rapid chromatography to obtain the desired product. (321 mg, 0.98 mmol, 65%) H (d6-DMSO): 5.57(s, 1H), 5.69(s, 2H), 6.70(q, J = 1.72 1H), 7.21(d, J = 5.00, 1H), 7.56(t, J = 2.76, 1H), 7.84(d, J = 1.24, 1H), 8.22(d, J = 1.28Hz, 1H), 8.27(d, J = 5.00Hz, 1H), 11.76(s, 1H), 11.96(s, 1H). LRMS: Measured: 328.17(M+1), calculated as C. 14 H 10 BrN5: 327.01.

[1245] Example 6

[1246] 7-Ethynyl-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[1247]

[1248] 7-Bromo-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine (0.200 g, 0.61 mmol) and ethynyltrimethylsilane (0.169 mL, 1.2 mmol) were added to a sealable vial containing triethylamine (2 mL) and DMF (2 mL), and the solution was degassed with N2 for 10 min. [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride catalyst (0.064 g, 0.08 mmol) and CuI (0.017 g, 0.08 mmol) were added, the vial was sealed, and the solution was heated to 60 °C and maintained for 16 h. The solution was then cooled, and the solvent was removed under reduced pressure to obtain a crude product. This crude product was purified by rapid chromatography to obtain the desired product. (64 mg, 0.23 mmol, 38%), δ H (d6-DMSO): 5.10(s, 1H), 5.66(s, 2H), 6.69(q, J = 1.48 1H), 7.20(d, J = 4.76, 1H), 7.55(t, J = 3.28, 1H), 7.75(d, J = 1.48, 1H), 8.25(m, 2H), 11.76(s, 1H), 11.96(s, 1H). LRMS: Measured: 274.2(M+1), calculated as C. 14 H 10 BrN5: 273.1.

[1249] Example 7

[1250] 7-Phenyl-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[1251]

[1252] A mixture of 7-chloro-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine (Example 4) (57 mg, 0.2 mmol, 1 equivalent), phenylboronic acid (49 mg, 1.2 equivalent, 2 equivalent), and [1,1′-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride catalyst (6.5 mg, 5 mol%) in 1,4-dioxane (1.2 mL) was loaded into a 2–5 mL MW tube and stirred under argon atmosphere. Then, an aqueous solution of 1 M K₃PO₄ (0.6 mL, 3 equivalent) was added. The reaction mixture was heated to 50 °C and held for 10 minutes under a gentle argon atmosphere, then heated to 110 °C and held for 17 hours, during which time the initially orange solution became a suspension. The stirred reaction mixture was then cooled to room temperature, slowly diluted with water (15 mL), and filtered. The filtered solid was washed with water (3 × 5 mL) and hexane (3 × 5 mL) to give a crude product (63 mg). Purification by rapid chromatography (80–100% AcOEt in hexane) yielded the title compound as a beige solid (19 mg). 1 H NMR (400MHz, DMSO-D6) δ5.60(s,2H),6.76(dd,J=3.5,1.8Hz,1H),7.28(d,J=5.1Hz,1H),7.39–7.47(m,1H),7.49–7.58(m ,3H),7.69(d,J=1.7Hz,1H),7.75–7.81(m,2H),8.20(d,J=1.6Hz,1H),8.27(d,J=5.1Hz,1H),11.71(s,1H),11.74(s,1H).

[1253] Example 8

[1254] 5-(2-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazole-3-amine

[1255]

[1256] A suspension of 4-chloro-2-methyl-7-azaindole (0.058 g, 0.35 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-1H-indazole-3-amine (0.136 g, 0.53 mmol), 1M potassium phosphate solution (0.87 mL, 0.87 mmol), and [1,1′-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride catalyst (0.011 g, 0.0175 mmol) in 1.5 mL of ethanol / water (1:1) was deoxygenated with nitrogen in a sealed tube, and the mixture was stirred at 90–100 °C for 18 hours. After cooling the reaction mixture to room temperature, EtOAc and water were added. The extracted organic layer was dried over magnesium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (80-90% EtOAc and 1% triethylamine in 60-80% petroleum ether) to give the title compound as a white solid (35 mg, 38%). 1 ¹H NMR (400MHz, DMSO-d⁶) δppm 2.63 (s, 3H) 5.53 (s, 2H) 6.37 (d, J = 2.20Hz, 1H) 7.12 (d, J = 4.83Hz, 1H) 7.37 (d, J = 8.35Hz, 1H) 7.62 (dd, J = 8.79, 1.76Hz, 1H) 8.12 (s, 1H) 8.17 (d, J = 5.27Hz, 1H) 11.53 (s, 1H) 11.62 (s, 1H). m / z (ESI-HRMS) calculated as C 15 H 14 N5(M+H + )264.1249 Measured = 264.1253 (M+H) + ).

[1257] Example 9

[1258] 2-(tert-butyl)-7-oxide-7-azaindole

[1259]

[1260] To an ice-cold EtOAc solution of 0.1 g (0.57 mmol) of 2-tert-butylazaindole, m-chloroperoxybenzoic acid (0.16 g, 0.91 mmol) was slowly added. The reaction mixture was then heated to room temperature and stirred for 1 hour. After the reaction was complete, the solvent was evaporated, treated with 1 M sodium carbonate solution, and extracted with EtOAc. The residue was then concentrated under vacuum to give the product as a yellow solid (68.4 mg, 63%). 1H NMR(400MHz,DMSO-d6)δppm 1.36 (s, 9H) 6.26 (d, J = 1.76Hz, 1H) 7.01 (dd, J = 7.91, 6.15Hz, 1H) 7.51 (d, J = 7.91Hz, 1H) 8.04 (d, J = 6.15Hz, 1H) 12.25 (br.s., 1H). 13 C NMR (100MHz, DMSO-d6) δppm 29.93, 32.67, 97.14, 116.54, 119.27, 124.58, 130.97, 139.38, 151.47. m / z(ESI-MS)[M] + 191.1.

[1261] 2-(tert-butyl)-4-(3-amino-1H-indazol-5-yl)-7-azaindole

[1262]

[1263] A suspension of 2-(tert-butyl)-4-chloro-7-azaindole (0.052 g, 0.28 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxoboronacyclopentan-2-yl)-1H-indazole-3-amine (0.096 g, 0.37 mmol), 1M potassium phosphate solution (0.49 mL, 0.49 mmol), and [1,1′-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride catalyst (0.008 g, 0.0124 mmol) in 1.4 mL of ethanol was deoxygenated with nitrogen in a sealed tube, and the mixture was stirred at 90–100 °C for 18 hours. After cooling the reaction mixture to room temperature, EtOAc and water were added. The extracted organic layer was dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (80-90% EtOAc and 1% triethylamine in 60-80% petroleum ether) to give the title compound as a white solid (33.5 mg, 44%). 1 H NMR(400MHz,DMSO-d6)δppm 1.38(s,9H)5.52(s,2H)6.35(d,J=2.20Hz,1H)7.10(d,J=4.83Hz,1H)7.38(d,J=8.35Hz,1H) 7.63(dd,J=8.79,1.76Hz,1H)8.12(s,1H)8.17(d,J=5.27Hz,1H)11.53(s,1H)11.62(s,1H). 13C NMR (100MHz, DMSO-d6) 30.21, 32.51, 94.00, 110.37, 114.49, 115.12, 118.15, 120.67, 127.23, 128.74, 140.07, 140.93, 141.62, 142.34, 150.40, 150.62. m / z (ESI-HRMS) calculated as C 18 H 20 N5 = 306.1713, measured = 306.1710.

[1264] Example 10

[1265] 4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid

[1266]

[1267] The reactants used to synthesize 4-(3-amino-1H-indazol-5-yl)-N-isopentyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (Example 237) were purified by HPLC, yielding the title compound as a yellow solid (0.0091 g, 0.0175 mmol, 22%). 1 ¹H NMR (400MHz, DMSO-d⁶) δ 7.27 (d, J = 5.0Hz, 1H), 7.34 (s, 1H), 7.43 (d, J = 8.8Hz, 1H), 7.70 (dd, J = 8.7, 1.6Hz, 1H), 8.24 (s, 1H), 8.43 (d, J = 5.0Hz, 1H), 12.45 (s, 1H). HRMS: calculated as C 15 H 12 O2N5(M+H + =294.0986; Actual measurement: 294.0987.

[1268] Section 3 - Compounds of the following formula:

[1269]

[1270] Example 11

[1271] 7-Bromo-5-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-indazole-3-amine

[1272]

[1273] 4-Bromo-7H-pyrrolo[2,3-d]pyrimidine (0.200 g, 1.02 mmol) was mixed with 7-bromo-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-1H-indazole-3-amine (0.401 g, 1.20 mmol), dioxane (6 mL), and potassium phosphate (3 mL, 1 M solution) in a 20 mL microwave-safe vial. The solution was then degassed with N2 for 10 min. Then, [1,1′-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride catalyst (0.118 g, 0.17 mmol) was added, the vial was sealed, and the solution was heated to 90 °C and maintained for 16 h. The solution was then cooled, and the solvent was removed under reduced pressure to obtain the crude product. This crude product was purified by rapid chromatography to obtain the desired product. (180 mg, 0.55 mmol, 53%) H (d6-DMSO): 5.85(s, 2H), 7.14(d, J = 3.5, 1H), 7.67(d, J = 2.90, 1H), 8.40(s, 1H), 8.67(s, 1H), 8.79(s, 1H), 12.07(s, 1H), 12.22(s, 1H). LRMS: Measured: 329.15(M+1), calculated as C. 13 H9BrN6: 328.01.

[1274] Section 4 - Compounds of the following formula:

[1275]

[1276] Example 12

[1277] 5-[2-(ethylamino)pyridin-4-yl]-1H-indazole-3-amine

[1278]

[1279] A suspension of 4-chloro-N-ethylpyridin-2-amine (0.179 g, 1.15 mmol), 3-cyano-4-fluorophenylboronic acid (0.446 g, 1.81 mmol), and [1,1′-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride catalyst (0.062 g, 0.095 mmol) in IPA / H₂O (3:1.5 mL) was degassed with nitrogen. Then, tert-butylamine (0.60 mL, 5.71 mmol) was added, and the mixture was degassed with nitrogen. The reaction mixture was placed in a microwave oven and irradiated at 160 °C for 40 min. Once cooled to room temperature, the reaction mixture was concentrated under reduced pressure and then suspended in EtOH (4.5 mL). Hydrazine hydrate (0.30 mL, 5.71 mmol) was added to this suspension, and the reaction mixture was placed in a microwave oven and irradiated at 165 °C for 30 min. The reaction mixture was diluted with MeOH and concentrated under reduced pressure. The resulting solid was purified by column chromatography (100% EtOAc to 20% MeOH / EtOAc). The solid was then ground with Et2O and hexane and filtered under reduced pressure to give the title compound as a pale yellow solid (0.075 g, 0.296 mmol). 1 H NMR (400MHz, DMSO-d6): δ1.16 (t, 3H, J = 7.2, 14.4Hz), 3.29 (q, 2H, J = 10.1Hz), 5.48 (br s,2H),6.45(t,1H,J=5.6,10.8Hz),6.68(s,1H),6.76(dd,1H,J=1.2,5.2Hz),7.30(d,1 H, J=8.4Hz),7.52(dd,1H,J=1.6,8.8Hz),8.00(d,1H,J=5.2Hz),8.07(s,1H),11.51(br s,1H). HRMS: For C 14 H 16 N5 requires 254.1400, actual measurement is 254.1407.

[1280] Example 13

[1281] 5-(2-(propylamino)pyridin-4-yl)-1H-indazole-3-amine

[1282]

[1283] A suspension of 4-bromo-N-propylpyridine-2-amine (0.094 g, 0.44 mmol), 3-cyano-4-fluorophenylboronic acid (0.122 g, 0.54 mmol), tert-butylamine (138 μL, 1.31 mmol), [1,1′-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride catalyst (0.024 g, 0.04 mmol), isopropanol (2 mL), and H₂O (1 mL) was degassed with nitrogen. The reactants were placed in a microwave oven and irradiated at 160 °C for 40 min. Once cooled to room temperature, the reaction mixture was concentrated under reduced pressure and then suspended in EtOH (2 mL). Hydrazine hydrate (57 μL, 1.17 mmol) and NaHCO₃ (0.030 g) were added to this suspension. The resulting suspension was heated to 80°C and maintained for 2 days, during which time hydrazine hydrate (28.5 μL, 2.5 equivalents) and EtOH (1 mL) were added. Heating was continued for 1.5 days. The reaction mixture was then cooled to 40°C, diluted with water (6 mL), stirred at room temperature for 30 minutes, and placed in a refrigerator overnight. The resulting precipitate was collected by filtration and washed with cold H2O (2 × 20 mL) and 1:1 EtOH / H2O (2 × 20 mL). The aqueous filtrates were combined and extracted with EtOAc (50 mL). The organic layer was combined with the initial precipitate, concentrated onto silica gel, and purified by rapid chromatography (Biotage SP4, 50 g SiO4, EtOAc to remove impurities, followed by addition of 7% MeOH-1% triethylamine in EtOAc) to give the title compound as a pale yellow solid (0.028 g, 0.105 mmol, 45%). 1 H NMR (400MHz, DMSO-d6): δ0.93(t,J=7.4Hz,1H),1.50–1.61(m,1H),3.18–3.28(m,1H),5.47(s,1H),6.49(t,J=5.7Hz,1H),6.69(s, 1H),6.75(dd,J=5.4,1.6Hz,1H),7.30(d,J=8.8Hz,1H),7.52(dd,J=8.7,1.9Hz,1H),7.98(d,J=5.4Hz,1H),8.06(s,1H),11.50(br s,1H).

[1284] Example 14

[1285] 5-(2-(isopropylamino)pyridin-4-yl)-1H-indazole-3-amine

[1286]

[1287] A suspension of 4-bromo-N-isopropylpyridine-2-amine (0.050 g, 0.23 mmol), 3-cyano-4-fluorophenylboronic acid pinacol ester (0.115 g, 0.5 mmol), and [1,1′-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride catalyst (0.030 g, 0.05 mmol) in IPA / H₂O (2:1 mL) was degassed with nitrogen. Tert-butylamine (0.25 mL, 2.32 mmol) was added, and the mixture was heated in a microwave oven at 160 °C for 40 min. The reaction mixture was concentrated and dissolved in EtOH (4 mL), and degassed with nitrogen. Hydrazine hydrate (0.34 mL, 7.0 mmol) was added, and the mixture was heated in a microwave oven at 165 °C for 30 min. The reaction mixture was concentrated and purified by rapid column chromatography (silica gel with EtOAc (50-100%) in hexane) to give the title compound as a grayish-white solid. 1 H NMR(400MHz,DMSO-d6):1.16(s,3H),1.17(s,3H),3.98-4.08(m,1H),5.46(br s,2H),6.30(d,J=7.6Hz,1H),6.67(s,1H),6.74(dd,J=5.4,1.0Hz,1H),7.30(d,J=8.7H z, 1H), 7.51 (dd, J = 8.7, 1.5Hz, 1H), 7.98 (d, J = 5.4Hz, 1H), 8.05 (s, 1H), 11.50 (brs, 1H). HRMS:C 15 H 18 N5 requires 268.1557, actual measured 268.1553 (M+H) + .

[1288] Example 15

[1289] 5-(2-((cyclopropylmethyl)amino)pyridin-4-yl)-1H-indazole-3-amine

[1290]

[1291] A suspension of 4-bromo-N-(cyclopropylmethyl)pyridine-2-amine (0.020 g, 0.09 mmol), 3-cyano-4-fluorophenylboronic acid (0.04, 0.16 mmol), and [1,1′-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride catalyst (0.010 g, 0.02 mmol) in IPA / H₂O (3:1.5 mL) was degassed with nitrogen. Then, tert-butylamine (0.25 mL, 2.38 mmol) was added, and the mixture was degassed with nitrogen. The reaction mixture was placed in a microwave oven and irradiated at 160 °C for 40 min. The reaction mixture was diluted with EtOAc and concentrated under reduced pressure. EtOH (4 mL) was added, followed by hydrazine hydrate (0.20 mL, 5.00 mmol), and the mixture was irradiated at 165 °C for 30 min. The reaction mixture was then concentrated under reduced pressure and purified by column chromatography (100% EtOAc) to give the desired product as a yellow solid (0.004 g, 0.02 mmol, 17%). 1 H NMR (400MHz, DMSO-d6): δ0.22(d,J=4.4Hz,2H),0.44(d,J=8.0Hz,2H),1.07(br s,1H),3.17(t,J=5.8Hz,2H),5.47(br s,2H),6.57(br s,1H),6.73(s,1H),6.77(d,J=5.2Hz,1H),7.30(d,J=8.8Hz,1H),7.52(d,J=8.8Hz,1H),7.98(d,J=4.8Hz,1H),8.06(s,1H),11.51(br s,1H).

[1292] Example 16

[1293] 5-(2-(isopentylamino)pyridin-4-yl)-1H-indazole-3-amine

[1294]

[1295] A suspension of 4-bromo-N-isopentylpyridin-2-amine (0.05 g, 0.23 mmol), 3-cyano-4-fluorophenylboronic acid pinacol ester (0.115 g, 0.50 mmol), and [1,1′-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride catalyst (0.030 g, 0.05 mmol) in IPA / H₂O (3:1.5 mL) was degassed with nitrogen. Tert-butylamine (0.25 mL, 2.32 mmol) was added, and the mixture was heated in a microwave oven at 160 °C for 40 min. The reaction mixture was concentrated and dissolved in EtOH (4 mL), and degassed with nitrogen. Hydrazine hydrate (0.34 mL, 7.00 mmol) was added, and the mixture was heated in a microwave oven at 165 °C for 30 min. The reaction mixture was concentrated and purified by rapid column chromatography (silica gel with EtOAc (50-100%) in hexane) to give the title compound as a grayish-white solid (0.011 g, 0.04 mmol, 16%). 1 H NMR (400MHz, DMSO-d6):0.91(s,3H),0.93(s,3H),1.64-1.72(m,1H),3.24-3.30(m,2H),5.47(br s,2H),6.42(t,J=5.5Hz,1H),6.68(s,1H),6.76(dd,J=4.7,1.3Hz,1H),7.30(d,J= 8.5Hz,1H),7.52(dd,J=7.3,1.6Hz,1H),7.99(d,J=5.3,1H),8.06(s,1H),11.50(br s,1H). HRMS:C 17 H 22 The N5 requires a resolution of 296.1870, but the actual measured value is 296.1867 (M+H). + .

[1296] Example 17

[1297] 5-(2-(hexylamino)pyridin-4-yl)-1H-indazole-3-amine

[1298]

[1299] A suspension of 4-bromo-N-hexylpyridin-2-amine (0.090 g, 0.35 mmol), 3-cyano-4-fluorophenylboronic acid (0.148 g, 0.60 mmol), and [1,1′-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride catalyst (0.028 g, 0.04 mmol) in IPA / H₂O (3:1.5 mL) was degassed with nitrogen. Then, tert-butylamine (0.25 mL, 2.38 mmol) was added, and the mixture was degassed with nitrogen. The reaction mixture was placed in a microwave oven and irradiated at 160 °C for 40 min. The reaction mixture was diluted with EtOAc and concentrated under reduced pressure. EtOH (4 mL) was added, followed by hydrazine hydrate (0.2 mL, 5.0 mmol), and the mixture was irradiated at 165 °C for 30 min. The reaction mixture was then concentrated under reduced pressure and purified by column chromatography (100% hexane-100% EtOAc). The solid obtained by grinding with diethyl ether was filtered and dried to give the title compound as a grayish-white solid (0.061 g, 0.20 mmol, 56.2%). 1 H NMR (400MHz, DMSO-d6): δ0.88(br s,3H),1.30-1.35(m,6H),1.54(br s,2H),3.26(br s,2H),5.47(br s,2H),6.46(br s,1H),6.68(br s,1H),6.75(br s,1H),7.29-7.31(m,1H),7.50-7.53(m,1H),7.99(m,1H),8.06(s,1H),11.50(br s,1H). HRMS: For C 18 H 24 N5 requires 310.2026, actual measurement is 310.2023.

[1300] Example 18

[1301] 5-(2-(cyclohexylamino)pyridin-4-yl)-1H-indazole-3-amine

[1302]

[1303] A suspension of 4-bromo-N-cyclohexylpyridin-2-amine (0.108 g, 0.43 mmol), 3-cyano-4-fluorophenylboronic acid (0.168 g, 0.68 mmol), and [1,1′-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride catalyst (0.029 g, 0.04 mmol) in IPA / H₂O (3:1.5 mL) was degassed with nitrogen. Then, tert-butylamine (0.25 mL, 2.38 mmol) was added, and the mixture was degassed with nitrogen. The reaction mixture was placed in a microwave oven and irradiated at 160 °C for 40 min. The reaction mixture was diluted with EtOAc and concentrated under reduced pressure. EtOH (4 mL) was added, followed by hydrazine hydrate (0.25 mL, 5.5 mmol), and the mixture was irradiated at 165 °C for 30 min. The reaction mixture was then concentrated under reduced pressure and purified by column chromatography (100% EtOAc). The solid obtained by grinding with diethyl ether was filtered and dried to give the title compound as a grayish-white solid (0.059 g, 0.19 mmol, 45%). 1 H NMR (400MHz, DMSO-d6): δ1.16-1.24(m,3H),1.29-1.38(m,2H),1.58-1.61(m,1H),1.71-1.74(m,2H),1.92-1.95(m,2H),3.70-3.77(m,1H),5.47(br s,1H),6.33(d,J=8.0Hz,1H),6.69(s,1H),6.71(dd,J=1.6,5.6Hz,1H),7.30(d,J=8 .8Hz,1H),7.50(dd,J=1.6,8.8Hz,1H),7.97(d,J=5.6Hz,1H),8.04(s,1H),11.50(br s,1H).

[1304] Example 19

[1305] 4-Bromo-N-(trans-4-methylcyclohexyl)pyridine-2-amine

[1306]

[1307] 4-Bromo-2-fluoropyridine (0.1 mL, 0.98 mmol), triethylamine (0.50 mL, 3.59 mmol), and trans-4-methylcyclohexylamine (0.4 mL, 2.98 mmol) in 2.5 mL of 1,4-dioxane were heated in a microwave oven at 160 °C for 30 min. Once cooled to room temperature, the reaction mixture was concentrated under reduced pressure. Purification by column chromatography (100% hexane-75 / 25 hexane / EtOAc-100% EtOAc) gave the title compound as a grayish-white solid (0.22 g, 0.82 mmol, 83.8%). 1¹H NMR (DMSO-d⁶): δ 0.87 (d, J = 6.4 Hz, 3H), 1.01 (2H, m), 1.13 (2H, m), 1.34 (1H, m), 1.68 (d, J = 12.4 Hz, 2H), 1.91 (d, J = 10.0 Hz, 2H), 3.58 (1H, m), 6.61 (3H, m), 7.82 (d, J = 5.6 Hz, 1H). HRMS: For C 12 H 18 The required N2Br concentration is 269.0648, and the actual measured concentration is 269.0648.

[1308] 5-{2-[(trans-4-methylcyclohexyl)amino]pyridin-4-yl}-1H-indazole-3-amine

[1309]

[1310] A suspension of 4-bromo-N-(trans-4-methylcyclohexyl)pyridine-2-amine (0.118 g, 0.44 mmol), 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)benzylnitrile (0.169 g, 0.68 mmol), and [1,1′-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride catalyst (0.026 g, 0.04 mmol) in IPA / H₂O (3:1.5 mL) was degassed for 5 min under a stable stream of nitrogen. Tert-butylamine (0.25 mL, 2.38 mmol) was added, and the mixture was degassed for 5 min under nitrogen. The reaction mixture was reacted in a microwave at 160 °C for 40 min, then cooled to room temperature and concentrated under reduced pressure. The reaction mixture was suspended in EtOH (4.5 mL), and hydrazine hydrate (0.3 mL, 6.00 mmol) was added. The mixture was then reacted in a microwave oven at 165 °C for 30 min. Once cooled to room temperature, the reaction mixture was concentrated under reduced pressure. Purification was performed by column chromatography (100% EtOAc – 10% MeOH / EtOAc), followed by grinding with Et2O and filtration to give the desired compound as a grayish-white solid (0.11 g, 0.34 mmol, 78%). 1H NMR(DMSO-d6): δ0.90(d,J=6.8Hz,3H),1.05(2H,m),1.18(2H,m),1.36(1H,m),5.46(2H,br s),6.30(d,J=8.0Hz,1H),6.67(1H,s),6.71(dd,J=5.2,1.2Hz,1H),7.30(d,J=8.4H z,1H),7.50(dd,J=1.6,8.8Hz,1H),7.97(d,J=5.6Hz,1H),8.04(1H,s),11.50(1H,br s). HRMS: For C 19 H 24 N5 requires 322.2024, but the actual value is 322.2026.

[1311] Example 20

[1312] 2-((4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)amino)ethanol-1-ol

[1313]

[1314] A suspension of 2-((4-bromopyridin-2-yl)amino)ethanol (0.117 g, 0.54 mmol), 3-cyano-4-fluorophenylboronic acid (0.218 g, 0.88 mmol), and [1,1′-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride catalyst (0.032 g, 0.049 mmol) in IPA / H₂O (3:1.5 mL) was degassed with nitrogen. Then, tert-butylamine (0.30 mL, 2.85 mmol) was added, and the mixture was degassed with nitrogen. The reaction mixture was placed in a microwave oven and irradiated at 160 °C for 40 min. The reaction mixture was diluted with EtOAc and concentrated under reduced pressure. EtOH (4 mL) was added, followed by hydrazine hydrate (0.3 mL, 6.00 mmol), and the mixture was irradiated at 165 °C for 30 min. The reaction mixture was then concentrated under reduced pressure and purified by column chromatography (100% EtOAc – 20% MeOH / EtOAc). The resulting solid was ground with Et2O, filtered, and dried to give the title compound as a grayish-white solid (0.128 g, 0.48 mmol, 88%). 1HNMR (400MHz, DMSO-d6): δ3.41 (q, J=10.0Hz, 2H), 3.59 (t, J=5.6, Hz, 2H), 5.60 (br s,2H),6.94(t,J=3.8Hz,2H),7.21(s,1H),7.33(d,J=8.8Hz,1H),7.58(dd ,1H,J=1.6,8.8Hz),7.98(d,1H,J=5.6Hz),8.16(d,1H,J=1.2Hz),11.59(br s,1H). HRMS: For C 14 H 16 ON5 requires 270.1349, but the measured value is 270.1346.

[1315] Example 21

[1316] 3-((4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)amino)prop-1-ol

[1317]

[1318] A suspension of 3-((-4-bromopyridin-2-yl)amino)prop-1-ol (0.116 g, 0.72 mmol), 3-cyano-4-fluorophenylboronic acid (0.246 g, 1.00 mmol), and [1,1′-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride catalyst (0.037 g, 0.057 mmol) in IPA / H₂O (3:1.5 mL) was degassed with nitrogen. Then, tert-butylamine (0.38 mL, 3.62 mmol) was added, and the mixture was degassed with nitrogen. The reaction mixture was placed in a microwave oven and irradiated at 160 °C for 40 min. The reaction mixture was diluted with EtOAc and concentrated under reduced pressure. EtOH (4 mL) was added, followed by hydrazine hydrate (0.25 mL, 5.0 mmol), and the mixture was irradiated at 165 °C for 30 min. The reaction mixture was then concentrated under reduced pressure and purified by column chromatography (100% EtOAc – 20% MeOH / EtOAc). The resulting solid was ground with Et2O, filtered, and dried to give the title compound as a grayish-white solid (0.0676 g, 0.239 mmol, 47.3%). 1H NMR (400MHz, DMSO-d6): δ1.79(qt,2H,J=6.4Hz), 3.45(q,2H,J=6.4Hz), 3.55(t,2H,J=6.0Hz), 7.18(d,1H,J=6 .8Hz),7.24(s,1H),7.39(d,1H,J=8.8Hz),7.67(d,1H,J=8.4Hz),7.98(d,1H,J=6.8Hz),8.33(s,1H),8.51(br s,1H),11.80(br s,1H). HRMS: For C 15 H 18 ON5 requires 284.1506, but the measured value is 284.1504.

[1319] Example 22

[1320] 4-(4-(3-amino-1H-indazol-5-yl)pyridin-2-ylamino)but-1-ol

[1321]

[1322] A suspension of 4-((3-bromopyridin-2-yl)amino)but-1-ol (0.093 g, 0.38 mmol), pinacol ester of 3-cyano-4-fluorophenylboronic acid (0.187 g, 0.76 mmol), and [1,1′-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride catalyst (0.040 g, 0.061 mmol) in IPA / H₂O (3:1.5 mL) was degassed with nitrogen. Tert-butylamine (0.4 mL, 3.8 mmol) was added, and the mixture was heated in a microwave oven at 160 °C for 45 min. The reaction mixture was concentrated and dissolved in EtOH (4 mL), and degassed with nitrogen. Hydrazine hydrate (0.55 mL, 11.38 mmol) was added, and the mixture was heated in a microwave oven at 165 °C for 30 min. The reaction mixture was concentrated and purified by rapid column chromatography (silica gel, with 50% EtOAc in hexane and 10% MeOH in EtOAc) to give the title compound as a light-colored solid (0.070 g, 0.24 mmol, 62%). 1H NMR(400MHz, DMSO-d6):1.57(m,4H),3.28(q,J=6.8Hz,2H),3.44(q,J=6.4Hz,2H),4.39(t,J=5.2Hz,1H),5.45(br s,2H),6.45(t,J=5.2Hz,1H),6.70(s,1H),6.76(dd,J=1.6,5.6Hz,1H),7.31(d,J=8.4H z, 1H), 7.53 (dd, J = 1.6, 8.8Hz, 1H), 7.99 (d, J = 5.6Hz, 1H), 8.07 (s, 1H), 11.49 (brs, 1H).

[1323] Example 23

[1324] 5-((4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)amino)pentan-1-ol

[1325]

[1326] A suspension of 5-[(4-bromopyridin-2-yl)amino]pentan-1-ol (0.150 g, 0.58 mmol), 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboronylpentan-2-yl)benzylnitrile (0.240 g, 0.96 mmol), and [1,1′-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride catalyst (0.047 g, 0.072 mmol) in IPA / H₂O (3:1.5 mL) was degassed for 5 min under a stable stream of nitrogen. Tert-butylamine (0.3 mL, 2.9 mmol) was added, and the mixture was degassed for 5 min under nitrogen. The reaction mixture was reacted in a microwave at 160 °C for 40 min, then cooled to room temperature and concentrated under reduced pressure. The reaction mixture was suspended in EtOH (4.5 mL), and hydrazine hydrate (0.3 mL, 5.99 mmol) was added. The mixture was then reacted in a microwave oven at 165 °C for 30 min. Once cooled to room temperature, the reaction mixture was concentrated under reduced pressure. It was purified by column chromatography (100% EtOAc-15% MeOH / EtOAc), recrystallized from MeOH (15 mL) and hexane (150 mL), and filtered to give the desired compound as a yellow solid (0.099 g, 0.32 mmol, 55%). 1H NMR(DMSO-d6): δ1.37-1.40(2H,m),1.41-1.5(2H,m),1.52-1.59(2H,m),3.2 6(q,J=6.5Hz,2H),3.40(q,J=6.0Hz,2H),4.37(t,J=5.2Hz,1H),5.48(2H,br s),6.55(1H,br s),6.77(d,J=5.2Hz,1H,),7.30(d,J=8.8Hz,1H),7.53(dd,J=8.8,1.6Hz,1H),7.98(d,J=5.6Hz,1H),8.07(1H,s),11.52(1H,br s). HRMS: For C 17 H 22 ON5 requires 312.1813, but the actual measured value is 312.1819.

[1327] Example 24

[1328] 4-Bromo-N-(trans-4-hydroxycyclohexyl)pyridine-2-amine

[1329]

[1330] 4-Bromo-2-fluoropyridine (0.5 mL, 4.52 mmol), (1r,4r)-4-aminocyclohexanol (1.200 g, 10.60 mmol), and triethylamine (0.7 mL, 5.02 mmol) were placed in a round-bottom flask containing n-butanol (15 mL), and the solution was heated for 16 hours. The solvent was then removed under reduced pressure, and the residue was dissolved in EtOAc (50 mL) and extracted with water (2 × 50 mL). The organic layer was then dried over (Mg2SO4), and the solvent was removed under reduced pressure. The residue was then purified by rapid chromatography using hexane-hexane:ethyl acetate (2:1) to give the desired product. (0.879 g, 3.2 mmol, 72.3%), δ H (d6-DMSO):1.19(4H,m),1.82(4H,m),3.40(1H,m),3.57(1H,m),4.51(d,J=4.0Hz,1H ),6.58(2H,m),6.62(d,J=1.6Hz,1H),7.82(d,J=5.5Hz,1H),9.32(t,J=5.1Hz,1H).δ C (d6-DMSO): 30.8, 34.4, 49.0, 68.8, 110.7, 114.2, 131.9, 149.5, 159.7, LRMS: Measured: 273.00, 275.00 (M+1), calculated as C 11 H 15BrN2O: 270.03.

[1331] 5-{2-[(trans-4-hydroxycyclohexyl)amino]pyridin-4-yl}-1H-indazole-3-amine

[1332]

[1333] 4-Bromo-N-(trans-4-hydroxycyclohexyl)pyridine-2-amine (0.143 g, 0.53 mmol) was placed in a 5 mL microwave-safe vial with 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)benzylnitrile (0.132 g, 0.53 mmol) and tert-butylamine (150 μl). IPA:H₂O (2:1) (4 mL) was added. The solution was then degassed with N₂ for 10 minutes. Then, [1,1′-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride catalyst (0.020 g, 0.03 mmol, 5 mol%) was added, the vial was sealed, and the solution was heated to 140 °C and maintained for 40 minutes. The solution was then allowed to cool, and hydrazine hydrate (1 mL) was added. The solution was then heated in a microwave-safe environment to 100 °C and maintained for 1 hour. The solution was then cooled, and the solvent was removed under reduced pressure to obtain the crude product, which was then purified by HPLC to obtain the desired product. (0.029 g, 0.09 mmol, 16.9%) δ H (d6-DMSO):1.32(4H,m),1.88(4H,m),3.47(1H,m),3.64(1H,m),7.15(dd,J=6.9,1.7Hz,1H),7.21(d,J=1 .0Hz,1H),7.40(d,J=8.8Hz,1H),7.67(d,J=8.65Hz,1H),7.96(d,J=6.9Hz,1H),8.30(1H,s),8.55(1H,s). HRMS:C 18 H 21 The required N5O value is 323.1746, and the actual measured value is 324.1819 (M+H).

[1334] Example 25

[1335] 5-(2-((2-methoxyethyl)amino)pyridin-4-yl)-1H-indazole-3-amine;

[1336]

[1337] A suspension of 4-bromo-N-(2-methoxyethyl)pyridine-2-amine (0.040 g, 0.17 mmol), 3-cyano-4-fluorophenylboronic acid (0.075 g, 0.30 mmol), and [1,1′-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride catalyst (0.015 g, 0.02 mmol) in IPA / H₂O (3:1.5 mL) was degassed with nitrogen. Then, tert-butylamine (0.15 mL, 1.43 mmol) was added, and the mixture was degassed with nitrogen. The reaction mixture was placed in a microwave oven and irradiated at 160 °C for 40 min. The reaction mixture was diluted with EtOAc and concentrated under reduced pressure. EtOH (4 mL) was added, followed by hydrazine hydrate (0.2 mL, 5.0 mmol), and the mixture was irradiated at 165 °C for 30 min. The reaction mixture was then concentrated under reduced pressure and purified by column chromatography (100% EtOAc – 20% MeOH / EtOAc). The resulting solid was recrystallized from methanol and hexane, filtered, and dried to give the title compound as a grayish-white solid (0.037 g, 0.13 mmol, 49%). 1 H NMR (400MHz, DMSO-d6): δ3.28(s,3H),3.48(br s,2H),5.47(br s,2H),6.55(br s,1H),6.76(s,1H),6.78(d,J=5.6Hz,1H),7.31(d,J=8.8Hz,1H),7.51(dd,J=1.2,8.4Hz,1H),7.99(d,J=5.6Hz,1H),8.06(s,1H),11.51(br s,1H).

[1338] Example 26

[1339] 5-(2-((3-methoxypropyl)amino)pyridin-4-yl)-1H-indazole-3-amine

[1340]

[1341] A suspension of 4-bromo-N-(3-methoxypropyl)pyridine-2-amine (0.030 g, 0.12 mmol), 3-cyano-4-fluorophenylboronic acid (0.056 g, 0.23 mmol), and [1,1′-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride catalyst (0.013 g, 0.02 mmol) in IPA / H₂O (3:1.5 mL) was degassed with nitrogen. Then, tert-butylamine (0.15 mL, 1.43 mmol) was added, and the mixture was degassed with nitrogen. The reaction mixture was placed in a microwave oven and irradiated at 160 °C for 40 min. The reaction mixture was diluted with EtOAc and concentrated under reduced pressure. EtOH (4 mL) was added, followed by hydrazine hydrate (0.20 mL, 5.0 mmol), and the mixture was irradiated at 165 °C for 30 min. The reaction mixture was then concentrated under reduced pressure and purified by column chromatography (100% EtOAc – 20% MeOH / EtOAc). The resulting solid was recrystallized from methanol and EtOAc, filtered, and dried under reduced pressure to give the title compound as a grayish-white solid (0.022 g, 0.07 mmol, 60%). 1 H NMR (400MHz, DMSO-d6): δ1.79(qt,J=6.6Hz,2H),3.25(s,3H),3.42(t,J=6.3Hz,2H),5.45(br s,2H),6.48(t,J=5.3Hz,1H),6.69(s,1H),6.77(dd,J=1.4,5.4Hz,1H),7.30(d,J=8 .6Hz,1H),7.52(dd,J=1.6,8.7Hz,1H),7.99(d,J=5.4Hz,1H),8.06(s,1H),11.49(br s,1H). HRMS: For C 16 H 19 ON5 requires 298.1662, but the measured value is 298.1661.

[1342] Example 27

[1343] 4-Bromo-N-[3-(propyl-2-yloxy)propyl]pyridine-2-amine

[1344]

[1345] A solution of 4-bromo-2-fluoropyridine (0.1 mL, 0.98 mmol), triethylamine (0.55 mL, 3.95 mmol), and 3-(propyl-2-yloxy)propyl-1-amine (0.68 mL, 4.90 mmol) in 1,4-dioxane (2.5 mL) was heated in a microwave at 160 °C for 30 min. Once cooled to room temperature, the reaction mixture was concentrated under reduced pressure. Purification by column chromatography (100% hexane – 75 / 25 hexane / EtOAc) gave the title compound as a grayish-white solid (0.21 g, 0.77 mmol, 79%). 1 ¹H NMR (DMSO-d⁶): δ 1.07 (d, J = 6.0 Hz, 6H), 1.69 (2H, m), 3.24 (q, J = 6.5 Hz, 2H), 3.41 (t, J = 2.8 Hz, 2H), 3.49 (2H, m), 6.63 (dd, J = 5.2, 1.6 Hz, 1H), 6.66 (d, J = 1.6 Hz, 1H), 6.73 (t, J = 10.8 Hz, 1H), 7.83 (d, J = 5.6 Hz, 1H). LRMS: Measured: 273.00, 274.93 (M+1), calculated as C. 11 H 17 BrN2O: 272.05.

[1346] 5-(2-((3-isopropoxypropyl)amino)pyridin-4-yl)-1H-indazole-3-amine

[1347]

[1348] A suspension of 4-bromo-N-[3-(propyl-2-yloxy)propyl]pyridine-2-amine (0.196 g, 0.72 mmol), 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)benzylnitrile (0.280 g, 1.14 mmol), and [1,1′-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride catalyst (0.050 g, 0.08 mmol) in IPA / H₂O (3:1.5 mL) was degassed for 5 min under a stable stream of nitrogen. Tert-butylamine (0.38 mL, 3.6 mmol) was added, and the mixture was degassed under nitrogen for 5 min. The reaction mixture was reacted in a microwave at 160 °C for 40 min, then cooled to room temperature and concentrated under reduced pressure. The reaction mixture was suspended in EtOH (4.5 mL), and hydrazine hydrate (0.38 mL, 7.60 mmol) was added. The mixture was then reacted in a microwave oven at 165 °C for 30 min. Once cooled to room temperature, the reaction mixture was concentrated under reduced pressure. It was purified by column chromatography (100% hexane-50 / 50 hexane / EtOAc-100% EtOAc-10% MeOH / EtOAc), recrystallized from MeOH (15 mL) and hexane (150 mL), and filtered to give the desired compound as a yellow solid (0.114 g, 0.35 mmol, 48.7%). 1 H NMR (DMSO-d6): δ1.09(d,J=6.0Hz,6H),1.77(qt,J=6.5Hz,2H),3.46(t,J=12.4Hz,2H),3.53(qt,J=6.1Hz,1H),5.50(1H,br s),6.81(1H,s),6.89(d,J=3.2Hz,1H),7.32(d,J=8.4Hz,1H),7.56(d,J=8.8Hz,1H),7.99(d,J=5.6Hz,1H),8.12(1H,s).11.56(1H,br s). HRMS: For C 18 H 24 ON5 requires 326.1977, but the actual measured value is 326.1975.

[1349] Example 28

[1350] 3-((4-chloropyrimidin-2-yl)amino)prop-1-ol

[1351]

[1352] 2,4-Dichloropyrimidine (2 g, 13.42 mmol) and triethylamine (1.5 mL, 21.21 mmol) were placed in a round-bottom flask containing dichloromethane (30 mL). Then, 3-aminoprop-1-ol (2.5 mL, 33.50 mmol) was added dropwise, and the solution was stirred overnight at room temperature. Water (20 mL) was then added, and the organic layer was dried over sodium sulfate. The mixture was filtered, and the solvent was removed under reduced pressure to obtain the crude product. The crude product was purified by rapid chromatography (100% hexane-50 / 50 hexane / EtOAc) to give the desired products (I) and (II) (0.562 g, 3.00 mmol, 22%). H (d6-DMSO): 1.65(q, J = 6.5 Hz, 2H), 3.28(2H, m), 3.44(t, J = 6.5 Hz, 2H), 4.43(1H, s), 6.61(d, J = 5.0 Hz, 1H), 7.58(t, J = 5.5 Hz, 1H), 8.21(1H, s). LRMS: Measured: 188.00(M+1), calculated as C7H. 10 ClN3O: 187.05.

[1353] 3-((4-(3-amino-1H-indazol-5-yl)pyrimidin-2-yl)amino)prop-1-ol

[1354]

[1355] 3-((4-chloropyrimidin-2-yl)amino)prop-1-ol (0.103 g, 0.53 mmol) was placed in a 5 mL microwave-safe vial with 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)benzylnitrile (0.132 g, 0.53 mmol) and tert-butylamine (150 μl). IPA:H₂O (2:1) (4 mL) was added. The solution was then degassed with N₂ for 10 minutes. Then, [1,1′-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride catalyst (0.020 g, 0.03 mmol, 5 mol%) was added, the vial was sealed, and the solution was heated to 140 °C and maintained for 40 minutes. The solution was then allowed to cool, and hydrazine hydrate (1 mL) was added. The solution was then heated in a microwave-safe vial to 100 °C and maintained for 1 hour. The solution was then cooled, and the solvent was removed under reduced pressure to obtain the crude product. The crude product was then purified by HPLC to obtain the desired product. (32 mg, 0.1 mmol, 20.8%) δ H(d6-DMSO):1.77(t,J=6.1Hz,2H),3.53(4H,m),4.48(1H,s),7.27(1H,s),7.39 (d,J=6.2Hz,1H),8.06(1H,s),8.16(1H,m),8.35(d,J=6.2Hz,1H),8.73(1H,s). HRMS:C 14 H 16 The required N6O value is 284.1386, but the actual measured value is 285.1458 (M+H). + .

[1356] Example 29

[1357] 3-((4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)(methyl)amino)prop-1-ol

[1358]

[1359] A suspension of 3-((4-bromopyridin-2-yl)(methyl)amino)prop-1-ol (0.027 g, 0.11 mmol), pinacol ester of 3-cyano-4-fluorophenylboronic acid (0.054 g, 0.22 mmol), and [1,1′-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride catalyst (0.014 g, 0.02 mmol) in IPA / H₂O (3:1.5 mL) was degassed with nitrogen. Tert-butylamine (0.12 mL, 1.10 mmol) was added, and the mixture was heated in a microwave oven at 160 °C for 45 min. The reaction mixture was concentrated and dissolved in EtOH (4 mL), and degassed with nitrogen. Hydrazine hydrate (0.16 mL, 3.30 mmol) was added, and the mixture was heated in a microwave oven at 165 °C for 30 min. The reaction mixture was concentrated and purified by rapid column chromatography (silica gel, with 50% EtOAc in hexane – 10% MeOH in EtOAc) to give the title compound as a grayish-white solid (0.008 g, 0.03 mmol, 24%). 1 H NMR–(500MHz, DMSO-d6):1.72(m,2H),3.06(m,3H),3.44(q,J=6.0Hz,2H),3.62(t,J=7.1Hz,2H),6.81(s,1H),6.83(d d,J=1.5,5.5Hz,1H),7.29(d,J=9.0Hz,1H),7.61(dd,J=1.5,8.5Hz,1H),8.08(d,J=5.0Hz,1H),8.12(s,1H),11.49(br s,1H). HRMS:C 16 H 19ON5 requires 297.1590, actual measured 298.1662 (M+H) + .

[1360] Example 30

[1361] 5-(2-((2-morpholinoethyl)amino)pyridin-4-yl)-1H-indazole-3-amine

[1362]

[1363] A suspension of 4-bromo-N-(2-morpholinoethyl)pyridine-2-amine (0.100 g, 0.35 mmol), 3-cyano-4-fluorophenylboronic acid (0.151 g, 0.61 mmol), and [1,1′-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride catalyst (0.021 g, 0.032 mmol) in IPA / H₂O (3:1.5 mL) was degassed with nitrogen. Then, tert-butylamine (0.20 mL, 1.90 mmol) was added, and the mixture was degassed with nitrogen. The reaction mixture was placed in a microwave oven and irradiated at 160 °C for 40 min. The reaction mixture was diluted with EtOAc and concentrated under reduced pressure. EtOH (4.5 mL) was added, followed by hydrazine hydrate (0.3 mL, 6.0 mmol), and the mixture was irradiated at 165 °C for 30 min. The reaction mixture was then concentrated under reduced pressure and purified by column chromatography (100% EtOAc – 20% MeOH / EtOAc). The resulting solid was ground with Et2O, filtered, and dried to give the title compound as a grayish-white solid (0.0379 g, 0.11 mmol, 32.1%). 1 H NMR (400MHz, DMSO-d6): δ2.40-2.44(m,4H),3.41(q,J=6.4,12.4Hz,2H),3.59(m,4H),5.48(br s,2H),6.35(t,1H),6.74(s,1H),6.78(dd,J=1.2,5.2Hz,1H),7.30(d,J=8.8Hz ,1H),7.54(dd,J=1.6,8.8Hz,1H),7.99(d,J=5.6Hz,1H),8.08(s,1H),11.52(br s,1H). HRMS: For C 18 H 23 ON6 requires 339.1928, but the measured value is 339.1927.

[1364] Example 31

[1365] 5-(2-((2-(piperidin-1-yl)ethyl)amino)pyridin-4-yl)-1H-indazole-3-amine

[1366]

[1367] A suspension of 4-bromo-N-(2-(piperidin-1-yl)ethyl)pyridine-2-amine (0.110 g, 0.39 mmol), 3-cyano-4-fluorophenylboronic acid (0.155 g, 0.63 mmol), and [1,1′-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride catalyst (0.030 g, 0.05 mmol) in IPA / H₂O (3:1.5 mL) was degassed with nitrogen. Then, tert-butylamine (0.15 mL, 1.43 mmol) was added, and the mixture was degassed with nitrogen. The reaction mixture was placed in a microwave oven and irradiated at 160 °C for 40 min. The reaction mixture was diluted with EtOAc and concentrated under reduced pressure. EtOH (4 mL) was added, followed by hydrazine hydrate (0.2 mL, 4.0 mmol), and the mixture was irradiated at 165 °C for 30 min. The reaction mixture was then concentrated under reduced pressure and purified by column chromatography (100% EtOAc – 20% MeOH / EtOAc). The resulting solid was recrystallized from methanol and hexane, filtered, and dried to give the title compound as a grayish-white solid (0.011 g, 0.003 mmol, 8.7%). 1 H NMR (400MHz, DMSO-d6): δ1.39-1.40(m,2H),150-1.53(m,4H),2.39-2.47(m,4H),3.38(q,J=6.2Hz,2H),5.47(br s,2H),6.29(t,J=4.8Hz,1H),6.73(s,1H),6.77(dd,J=5.2,11.2Hz,1H),7.30(d, J=8.8Hz,1H),7.54(d,J=8.4Hz,1H),7.99(d,J=5.2Hz,1H),8.08(s,1H),11.51(br s,1H). HRMS: For C 19 H 24 N6 requires 337.2135, but the measured value is 337.2133.

[1368] Example 32

[1369] 3-(3-(3-amino-1H-indazol-5-yl)phenylamino)propyl(methyl)carbamate tert-butyl

[1370]

[1371] A suspension of tert-butyl 3-(3-bromophenylamino)propyl(methyl)carbamate (0.105 g, 0.31 mmol), pinacol 3-cyano-4-fluorophenylboronic acid (0.150 g, 0.61 mmol), and [1,1′-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride catalyst (0.040 g, 0.06 mmol) in IPA / H₂O (3:1.5 mL) was degassed with nitrogen. Tert-butylamine (0.32 mL, 3.05 mmol) was added, and the mixture was heated in a microwave oven at 160 °C for 45 minutes. The reaction mixture was concentrated and dissolved in EtOH (4 mL), and degassed with nitrogen. Hydrazine hydrate (0.44 mL, 9.15 mmol) was added, and the mixture was heated in a microwave oven at 165 °C for 30 minutes. The reaction mixture was concentrated and purified by rapid column chromatography (silica gel, with 50% EtOAc in hexane – 10% MeOH in EtOAc) to give the title compound as a grayish-white solid (0.032 g, 0.08 mmol, 26%). 1 HNMR(400MHz,DMSO-d6):1.37(br s,9H),1.75(m,2H),2.80(s,3H),3.26(m,4H),5.45(br s,2H),6.45(br s,1H),6.69(s,1H),6.78(dd,J=1.6,5.6Hz,1H),7.31(d,J=8.4Hz,1H),7.53(d,J=8.8Hz,1H),8.0(d,J=5.2Hz,1H),8.07(s,1H),11.50(br s,1H). HRMS:C 21 H 28 The required O2N5 value is 396.2274, and the actual measured value is 397.2347 (M+H).

[1372] N 1 -(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-N 3 1,3-Methylpropane-1,3-diamine

[1373]

[1374] At 0 °C, TFA (0.1 mL, 1.31 mmol) was added to a mixture of tert-butyl 3-(3-(3-amino-1H-indazol-5-yl)phenylamino)propyl(methyl)carbamate (0.02 g, 0.05 mmol) in anhydrous dichloromethane (0.1 mL). The reaction mixture was stirred at 0 °C for 1 hour, then at room temperature for 1 hour. 2 M NaOH (0.7 mL) was added and stirring was continued for 10 minutes. The reaction mixture was extracted and washed with dichloromethane (1 mL x 2). 1HNMR(400MHz, DMSO-d6):1.91(tt,J=7.2Hz,2H),2.60(t,J=5.4Hz,3H),3.01(m,2H),3.47(m,2H),7.19(br s,2H),7.39(d,J=8.8Hz),7.70(d,J=9.5Hz,1H),8.05(d,J=7.2Hz,1H),8.32(s,1H),8.48br s,1H),11.80(br s,1H).

[1375] Section 5 - Compounds of the following formula:

[1376]

[1377] Example 33

[1378] N-[4-(3-amino-1H-indazol-5-yl)pyridin-2-yl]cyclopropaneformamide

[1379]

[1380] A suspension of N-(4-chloropyridin-2-yl)cyclopropaneformamide (0.133 g, 0.678 mmol), 3-cyano-4-fluorophenylboronic acid (0.205 g, 0.791 mmol), and [1,1′-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride catalyst (0.043 g, 0.066 mmol) in IPA / H₂O (3:1.5 mL) was degassed with nitrogen. Then, tert-butylamine (0.60 mL, 5.71 mmol) was added, and the mixture was degassed with nitrogen. The reaction mixture was placed in a microwave oven and irradiated at 160 °C for 40 min. The reaction mixture was diluted with EtOAc, concentrated under reduced pressure, and ethanol (5 mL) and hydrazine hydrate (0.25 mL, 5.0 mmol) were added to the residue. The reaction mixture was then placed in a microwave oven and irradiated at 165 °C for 30 min. Purification was performed by HPLC as described in the General Experiments section. A peak value was reached at 9 min. (0.01229g, 0.04mmol, 6.2%). 1 ¹H NMR (400MHz, DMSO-d⁶): δ 0.83–0.86 (m, 4H), 2.04–2.07 (m, 1H), 7.36–7.40 (m, 2H), 7.63 (d, J = 8.4Hz, 1H), 8.19 (s, 1H), 8.34 (d, J = 5.2Hz, 1H), 8.43 (s, 1H), 10.84 (s, 1H), 11.72 (br s, 1H). LRMS: Measured: 294.13 (M+1), calculated as C. 16 H 15 N5O: 293.13.

[1381] Example 34

[1382] N-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)benzamide

[1383]

[1384] K₃PO₄ (1M, 0.88mL) was added to a suspension of N-(4-bromopyridin-2-yl)benzamide (0.097g, 0.35mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-1H-indazole-3-amine (0.136g, 0.525mmol), and tetra(triphenylphosphine)palladium(O) catalyst (0.02g, 0.0175mmol) in EtOH / water (1:1; 1.5mL, degassed under nitrogen), and the reaction mixture was heated to 80°C and maintained for 24 hours. The reaction mixture was cooled to room temperature, filtered, and the resulting solid was washed with water (10mL) and Et₂O (8mL) and then dried. The title compound was purified by column chromatography (100% hexane-2 / 1 hexane / EtOAc-100% EtOAc) and ground with MeOH and hexane to give a gray solid (0.05 g, 43%). 1 HNMR(500MHz,DMSO)δ11.60(s,1H),10.81(s,1H),8.57(d,J=1.7Hz,1H),8.43(d,J=5.3Hz,1H),8.24(d,J=1.7Hz,1H),8.11–8.0 6(m,2H),7.70–7.62(m,1H),7.61(s,1H),7.55(t,J=7.6Hz,2H),7.48(dd,J=5.2,1.8Hz,1H),7.39(d,J=8.7Hz,1H),5.56(s,2H).

[1385] LRMS: Measured value: 330.13(M+1), calculated as C 19 H 16 N5O: 330.14(M+1).

[1386] Example 35

[1387] (4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)carbamate

[1388]

[1389] Ethyl (4-bromopyridin-2-yl)carbamate (0.437 g, 1.82 mmol) was placed in a 5 mL microwave-safe vial containing EtOH (10 mL) along with 5-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-1H-indazole-3-amine (0.722 g, 2.16 mmol) and potassium phosphate (945 mg in 4 mL of water). The solution was then degassed with N2 for 10 min. [1,1′-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride catalyst (118) (0.060 g, 0.10 mmol, 5 mol%) was then added, the vial was sealed, and the solution was heated to 90 °C and maintained for 16 h. The solution was then cooled, and the solvent was removed under reduced pressure to obtain the crude product. The crude product was purified by HPLC to obtain the desired product (569 mg, 1.70 mmol, 94%). H (d6-DMSO): 1.25(t, J = 7.0 Hz, 3H), 4.02(q, J = 7.0 Hz, 2H), 5.52(s, 2H), 7.32(m, 2H), 7.59(dd, J = 8.5 and 1.5 Hz, 1H), 8.15(m, 2H), 8.27(d, J = 5.5 Hz, 1H), 10.08(s, 1H), 11.56(s, 1H). LRMS: Measured: 298.10(M+1), calculated as C. 15 H 15 N5O2: 297.12.

[1390] Example 36

[1391] 1-(4-chloropyridin-2-yl)-3-ethylurea

[1392]

[1393] 4-Chloropyridine-2-amine (437 mg, 3.40 mg, 1 equivalent) and chloroform (1.6 mL) were placed in 2–5 mL microwave-safe vials, and isocyanate ethane (483 mg, 538 μL, 6.80 mmol, 2 equivalents) was added to the resulting suspension. The reaction mixture was heated to 100 °C and held for 1 hour under microwave irradiation. The resulting pale yellow solution was cooled to room temperature, diluted dropwise with hexane (8 mL), and allowed to stand overnight. The white precipitate was then filtered and washed with hexane (8 mL × 3) to give the title compound (480 mg, 71%) as a white solid. 1H NMR(DMSO-D6)δ:1.07(t,J=7.2Hz,3H),3.21–3.12(m,2H),7.04(dd,J=5.5,1.9Hz,1H),7.59(d,J=1.6Hz,1H),7.62(br s, 1H), 8.16 (d, J = 5.5Hz, 1H), 9.30 (s, 1H).

[1394] 1-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-3-ethylurea

[1395]

[1396] 1-(4-chloropyridin-2-yl)-3-ethylurea (200 mg, 1 mol, 1 equivalent), 5-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-1H-indazole-3-amine (259 mg, 1.2 mmol, 1.2 equivalent), and [1,1′-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride catalyst (33 mg, 0.05 mmol, 5 mol%) were packaged into 2–5 mL microwave-safe vials, sealed with aluminum caps fitted with disposable PTFE / silicone diaphragms, and purged with nitrogen. Ethanol (4 mL) was added, and the mixture was stirred under nitrogen for several minutes, followed by the addition of 2.0 mL of 1 M K₃PO₄ aqueous solution (oxygen-free). The mixture was heated to approximately 50 °C, purged with nitrogen for 10 minutes, and then stirred at 60 °C for 24 hours. The reaction mixture was then diluted with EtOAc (200 mL), washed with water (40 mL × 3), dried (MgSO4), and purified by rapid chromatography (Biotage SP4, 50 g SiO4, 5% MeOH in EtOAc) to give the title compound (53 mg, 18%) as a grayish-white solid. 1 ¹H NMR (DMSO-D6) δ: 1.11 (t, J = 7.2 Hz, 3H), 3.25–3.17 (m, 2H), 5.53 (s, 2H), 7.20 (dd, J = 5.4, 1.6 Hz, 1H), 7.34 (d, J = 8.7 Hz, 1H), 7.54 (dd, J = 8.7, 1.6 Hz, 1H), 7.67 (s, 1H), 8.12 (s, 1H), 8.15 (br s, 1H), 8.20 (d, J = 5.4 Hz, 1H), 9.17 (s, 1H), 11.58 (s, 1H). HRMS: calculated as C 15 H 17 ON6(M+H + ): 297.1458; Actual measurement: 297.1450.

[1397] Example 37

[1398] 1-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-3-propylurea

[1399]

[1400] 1-(4-bromopyridin-2-yl)-3-propylurea (0.136 g, 0.53 mmol) was placed in a 5 mL microwave-safe vial with 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)benzylnitrile (0.132 g, 0.53 mmol) and tert-butylamine (150 μl). IPA:H₂O (2:1) (4 mL) was added. The solution was then degassed with N₂ for 10 minutes. Then, [1,1′-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride catalyst (0.020 g, 0.03 mmol, 5 mol%) was added, the vial was sealed, and the solution was heated to 140 °C and maintained for 40 minutes. The solution was then allowed to cool, and hydrazine hydrate (1 mL) was added. The solution was then heated in a microwave-safe environment to 100 °C and maintained for 1 hour. The solution was then cooled, and the solvent was removed under reduced pressure to obtain the crude product. The crude product was then purified by HPLC to obtain the desired product. (0.052 g, 0.17 mmol, 32.8%) δ H (d6-DMSO):0.91(t,J=7.4Hz,3H),1.50(h,J=7.25Hz,2H),3.16(q,J=6.9Hz,2H),7 .36(d,J=4.8Hz,1H),7.43(d,J=8.8Hz,1H),7.67(m,2H),7.93(s,1H),8.26(m,2H). HRMS:C 16 H 18 The required N6O value is 310.1542, but the actual measured value is 311.1615 (M+H). + .

[1401] Example 38

[1402] 1-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-3-isopentylurea

[1403]

[1404] To a 0.5–2 mL microwave-safe vial, add ethyl 4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)carbamate (Example 35) (0.030 g, 0.10 mmol, 1 equivalent), 3-methylbut-1-amine (0.264 g, 352 μL, 3.03 mmol, 30 equivalent), and dioxane (650 μL), seal with an aluminum cap fitted with a disposable PTFE / silicone diaphragm, and purge with nitrogen. Heat the reaction mixture to 180 °C under microwave irradiation and maintain for 30 minutes. Then cool the reaction mixture to approximately 40 °C and dilute with water (5 mL) dropwise using a syringe. Stir and sonicate the mixture for 30 minutes, then cool to room temperature. Remove the cap, filter out the solid, wash with water (2 × 4 mL), and dry to give the title compound (32 mg, 0.09 mmol, 94%). 1 ¹H NMR (DMSO-D6) δ: 0.91 (d, J = 6.6 Hz, 6H), 1.39 (dd, J = 14.3, 7.1 Hz, 2H), 1.67–1.57 (m, 1H), 3.26–3.15 (m, 2H), 5.53 (s, 2H), 7.20 (d, J = 5.5 Hz, 1H), 7.34 (d, J = 8.7 Hz, 1H), 7.54 (d, J = 8.6 Hz, 1H), 7.67 (s, 1H), 8.23–8.09 (m, 3H), 9.16 (s, 1H), 11.58 (s, 1H), HRMS: calculated as C 18 H 23 ON6(M+H + ): 339.1928; Actual measurement: 339.1925.

[1405] Example 39

[1406] 1-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-3-cyclopentylurea

[1407]

[1408] 1-(4-bromopyridin-2-yl)-3-cyclopentylurea (0.149 g, 0.53 mmol) was placed in a 5 mL microwave-safe vial with 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)benzylnitrile (0.132 g, 0.53 mmol) and tert-butylamine (150 μl). IPA:H₂O (2:1) (4 mL) was added. The solution was then degassed with N₂ for 10 minutes. Then, [1,1′-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride catalyst (0.020 g, 0.03 mmol, 5 mol%) was added, the vial was sealed, and the solution was heated to 140 °C and maintained for 40 minutes. The solution was then allowed to cool, and hydrazine hydrate (1 mL) was added. The solution was then heated in a microwave-safe environment to 100 °C and maintained for 1 hour. The solution was then cooled, and the solvent was removed under reduced pressure to obtain the crude product. The crude product was then purified by HPLC to obtain the desired product. (0.028 g, 0.08 mmol, 16%) δ H (d6-DMSO):1.43(m,2H),1.56(m,2H),1.66(m,2H),1.89(m,2H),4.02(h,J=6.5Hz,1H) ,7.29(s,1H),7.39(d,J=9.0Hz,1H),7.62(d,J=8.8Hz,1H),7.72(s,1H),8.22(m,2H). HRMS:C 18 H 20 The required N6O value is 336.1699, but the actual measured value is 337.1771 (M+H). + .

[1409] Example 40

[1410] 1-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-3-cyclohexylurea

[1411]

[1412] 1-(4-bromopyridin-2-yl)-3-cyclopentylurea (0.157 g, 0.53 mmol) was placed in a 5 mL microwave-safe vial with 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)benzylnitrile (0.132 g, 0.53 mmol) and tert-butylamine (150 μl). IPA:H₂O (2:1) (4 mL) was added. The solution was then degassed with N₂ for 10 minutes. Then, [1,1′-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride catalyst (0.020 g, 0.03 mmol, 5 mol%) was added, the vial was sealed, and the solution was heated to 140 °C and maintained for 40 minutes. The solution was then allowed to cool, and hydrazine hydrate (1 mL) was added. The solution was then heated in a microwave-safe environment to 100 °C and maintained for 1 hour. The solution was then cooled, and the solvent was removed under reduced pressure to obtain the crude product. The crude product was then purified by HPLC to obtain the desired product. (0.043 g, 0.12 mmol, 22%)δ H (d6-DMSO):1.18(m,6H),1.67(m,2H),1.86(m,2H),3.58(m,1H),7.32(s,1H), 7.42 (d, J = 8.7Hz, 1H), 7.62 (dd, J = 8.8 and 1.4Hz, 1H), 7.71 (s, 1H), 8.24 (m, 2H). HRMS:C 19 H 22 The N6O specification requires 350.1855, but the actual measured value is 351.1928 (M+H). + .

[1413] Example 41

[1414] 1-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-3-(2-hydroxyethyl)urea

[1415]

[1416] Ethyl 4-(3-amino-2H-indazol-5-yl)pyridin-2-yl)carbamate (Example 35) (0.030 g, 0.10 mmol, 1 equivalent), 2-aminoethanol (0.025 g, 24.4 μL, 0.40 mmol, 4 equivalents), and dioxane (650 μL) were loaded into 0.5–2 mL microwave-safe vials, sealed with an aluminum cap fitted with a disposable PTFE / silicone diaphragm, and purged with nitrogen. The reaction mixture was heated to 160 °C and held at this temperature for 90 minutes under microwave irradiation. The reaction mixture was then concentrated under vacuum, and the resulting crude product was dissolved in water (3 mL). The mixture was stirred and sonicated for 30 minutes, then the solid was filtered off, washed with water (2 × 3 mL), and dried to give the title compound (27 mg, 0.08 mmol, 84%). 1¹H NMR (400MHz, DMSO-D6) δ 3.25 (app q, J = 5.6Hz, 2H), 3.48 (m, 2H), 4.78 (t, J = 5.1Hz, 1H), 5.53 (s, 2H), 7.20 (dd, J = 5.4, 1.5Hz, 1H), 7.34 (d, J = 8.7Hz, 1H), 7.54 (dd, J = 8.7, 1.5Hz, 1H), 7.68 (s, 1H), 8.12 (s, 1H), 8.20 (d, J = 5.4Hz, 1H), 8.27 (br s, 1H), 9.24 (s, 1H), 11.58 (s, 1H). HRMS: calculated as C 15 H 17 O2N6(M+H + ): 313.1408; Actual measurement: 313.1400.

[1417] Example 42

[1418] 1-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-3-(3-hydroxypropyl)urea

[1419]

[1420] To a 0.5–2 mL microwave-safe vial, add ethyl 4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)carbamate (Example 35) (0.030 g, 0.10 mmol, 1 equivalent), 3-aminoprop-1-ol (0.030 g, 30.9 μL, 0.40 mmol, 4 equivalents), and dioxane (650 μL), seal with an aluminum cap fitted with a disposable PTFE / silicone diaphragm, and purge with nitrogen. Heat the reaction mixture to 180 °C under microwave irradiation and maintain for 40 minutes. Then cool the reaction mixture to approximately 40 °C and dilute with water (5 mL) dropwise using a syringe. Stir and sonicate the mixture for 30 minutes, then cool to room temperature. Remove the cap, filter out the solid, wash with water (2 × 4 mL), and dry to give the title compound (17 mg, 0.05 mmol, 52%). 1 ¹H NMR (400MHz, DMSO-D6) δ 1.72–1.55 (m, 2H), 3.28–3.21 (m, 2H), 3.52–3.44 (m, 2H), 4.51 (t, J = 5.1Hz, 1H), 5.53 (s, 2H), 7.21 (d, J = 5.5Hz, 1H), 7.34 (d, J = 8.8Hz, 1H), 7.54 (d, J = 8.8Hz, 1H), 7.66 (s, 1H), 8.12 (s, 1H), 8.28–8.15 (m, 2H), 9.20 (s, 1H), 11.58 (s, 1H). HRMS: calculated as C16 H 19 O2N6(M+H + ): 327.1564; Actual measurement: 327.1558.

[1421] Example 43

[1422] 1-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-3-(2-methoxyethyl)urea

[1423]

[1424] To a 0.5–2 mL microwave-safe vial, ethyl 4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)carbamate (Example 35) (0.030 g, 0.10 mmol, 1 equivalent), 2-methoxyethylamine (0.264 g, 352 μL, 3.03 mmol, 30 equivalent), and dioxane (650 μL) were placed, sealed with an aluminum cap fitted with a disposable PTFE / silicone diaphragm, and purged with nitrogen. The reaction mixture was heated to 180 °C and held for 30 minutes under microwave irradiation. The reaction mixture was then cooled to approximately 40 °C and diluted dropwise with water (5 mL) using a syringe. The mixture was stirred and sonicated for 30 minutes, then cooled to room temperature. The cap was then removed, the solid was filtered off, washed with water (2 × 4 mL), and dried to give the title compound (0.029 g, 0.09 mmol, 88%). 1 H NMR(DMSO-D6)δ:3.29(s,3H),3.38–3.34(m,2H),3.45–3.40(m,2H),5.53(s,2H),7.21(d,J=5.3Hz,1H) ,7.34(d,J=8.7Hz,1H),7.54(d,J=8.8Hz,1H),7.70(s,1H),8.12(s,1H),8.20(d,J=5.4Hz,1H),8.24(br s,1H),9.24(s,1H),11.58(s,1H).

[1425] Example 44

[1426] 3-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-1-(2-hydroxyethyl)-1-methylurea

[1427]

[1428] Ethyl (4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)carbamate (Example 35) (0.030 g, 0.10 mmol) and 2-(methylamino)ethanol (0.5 mL) were placed in a 0.5–2 mL microwave-safe vial, sealed, and heated to 140 °C for 40 minutes. The solution was then cooled, and the solvent was removed under reduced pressure. The crude residue was then dissolved in DMF (0.5 mL) and purified by HPLC to obtain the desired product. (0.007 g, 0.02 mmol, 16%) H (d6-DMSO):3.04(s,3H),3.48(t,J=5.3Hz,2H),3.62(t,J=5.4Hz,2H)7.42(d,J=8.8Hz,2H),7.52(d,J=5.3 Hz, 1H), 7.68 (dd, J = 8.5 and 1.5 Hz, 1H), 8.02 (d, J = 1.3 Hz, 1H), 8.27 (d, J = 6.1 Hz, 1H), 8.32 (s, 1H), 9.85 (s, 1H). HRMS:C 16 H 18 The required N6O2 concentration is 326.1491, but the actual measured concentration is 327.1564 (M+H). + .

[1429] Example 45

[1430] 1-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-3-benzylurea

[1431]

[1432] 1-Benzyl-3-(4-bromopyridin-2-yl)urea (0.161 g, 0.53 mmol) was placed in a 5 mL microwave-safe vial with 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)benzylnitrile (0.132 g, 0.53 mmol) and tert-butylamine (150 μl). IPA:H₂O (2:1) (4 mL) was added. The solution was then degassed with N₂ for 10 minutes. Then, [1,1′-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride catalyst (0.020 g, 0.03 mmol, 5 mol%) was added, the vial was sealed, and the solution was heated to 140 °C and maintained for 40 minutes. The solution was then allowed to cool, and hydrazine hydrate (1 mL) was added. The solution was then heated in a microwave-safe environment to 100 °C and maintained for 1 hour. The solution was then cooled, and the solvent was removed under reduced pressure to obtain the crude product. The crude product was then purified by HPLC to obtain the desired product. (0.034 g, 0.10 mmol, 18%)δ H(d6-DMSO):4.41(d,J=5.5Hz,2H),7.23(m,1H),7.26(m,5H),7.42(d,J=9.0Hz,1H) ,7.64(dd,J=8.8 and 1.4Hz,1H),7.72(s,1H),8.22(m,2H),8.38(s,1H),9.70(s,1H). HRMS:C 20 H 18 The required N6O value is 358.1542, but the actual measured value is 359.1615 (M+H). + .

[1433] Example 46

[1434] 1-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-3-phenylethylurea

[1435]

[1436] 1-(4-bromopyridin-2-yl)-3-phenylethylurea (0.169 g, 0.53 mmol) was placed in a 5 mL microwave-safe vial with 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)benzylnitrile (0.132 g, 0.53 mmol) and tert-butylamine (150 μl). IPA:H₂O (2:1) (4 mL) was added. The solution was then degassed with N₂ for 10 minutes. Then, [1,1′-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride catalyst (0.020 g, 0.03 mmol, 5 mol%) was added, the vial was sealed, and the solution was heated to 140 °C and maintained for 40 minutes. The solution was then allowed to cool, and hydrazine hydrate (1 mL) was added. The solution was then heated in the microwave to 100 °C and maintained for 1 hour. The solution was then cooled, and the solvent was removed under reduced pressure to obtain the crude product. The crude product was then purified by HPLC to obtain the desired product. (0.023 g, 0.06 mmol, 12%) δ H (d6-DMSO):2.81(t,J=7.0Hz,2H),3.44(q,J=5.5Hz,2H),7.27(m,6H),7.44(d,J=9.0Hz,1H),7.68(m,2H),8.19(d,J=7.5Hz,1H),8.27(s,1H),HRMS: C 21 H 20 The required N6O value is 372.1699, but the actual measured value is 373.1771 (M+H). + .

[1437] Example 47

[1438] 1-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-3-(pyridin-2-ylmethyl)urea

[1439]

[1440] Ethyl 4-(3-amino-2H-indazol-5-yl)pyridin-2-yl)carbamate (Example 35) (0.030 g, 0.10 mmol, 1 equivalent), pyridin-2-ylmethylamine (0.044 g, 41.6 μL, 0.40 mmol, 4 equivalents), and dioxane (650 μL) were loaded into 0.5–2 mL microwave-safe vials, sealed with an aluminum cap fitted with a disposable PTFE / silicone diaphragm, and purged with nitrogen. The reaction mixture was heated to 180 °C and held for 40 minutes under microwave irradiation. The reaction mixture was then concentrated under vacuum, and the resulting crude product was dissolved in water (3 mL). The mixture was stirred and sonicated for 30 minutes, then the solid was filtered off, washed with water (2 × 3 mL), and dried to give the title compound (30 mg, 0.08 mmol, 83%). 1 ¹H NMR (400MHz, DMSO-D6) δ 4.52 (d, J = 5.5Hz, 2H), 5.53 (s, 2H), 7.23 (d, J = 5.5Hz, 1H), 7.31–7.25 (m, 1H), 7.35 (t, J = 7.7Hz, 2H), 7.55 (d, J = 8.8Hz, 1H), 7.72 (s, 1H), 7.78 (t, J = 7.7Hz, 1H), 8.13 (br s, 1H), 8.23 ​​(d, J = 5.4Hz, 1H), 8.54 (s, 1H), 8.78 (s, 1H), 9.41 (s, 1H), 11.58 (s, 1H). HRMS: calculated as C 19 H 18 ON7 360.1567(M+H + Actual measurement: 360.1564.

[1441] Example 48

[1442] 1-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-3-(pyridin-3-ylmethyl)urea

[1443]

[1444] Ethyl 4-(3-amino-2H-indazole-5-yl)pyridin-3-yl)carbamate (Example 35) (0.030 g, 0.10 mmol, 1 equivalent), pyridin-2-ylmethylamine (0.044 g, 41.6 μL, 0.40 mmol, 4 equivalents), and dioxane (650 μL) were loaded into 0.5–2 mL microwave-safe vials, sealed with an aluminum cap fitted with a disposable PTFE / silicone diaphragm, and purged with nitrogen. The reaction mixture was heated to 180 °C and held for 40 minutes under microwave irradiation. The reaction mixture was then cooled to approximately 40 °C and diluted dropwise with water (5 mL) using a syringe. The mixture was stirred and sonicated for 30 minutes, then cooled to room temperature. The cap was then removed, the solid was filtered off, washed with water (2 × 4 mL), and dried to give the title compound (29 mg, 0.08 mmol, 81%). 1 ¹H NMR (400MHz, DMSO-D6) δ 4.45 (d, J = 5.9Hz, 2H), 5.53 (s, 2H), 7.23 (d, J = 5.4Hz, 1H), 7.42–7.30 (m, 2H), 7.54 (d, J = 8.7Hz, 1H), 7.69 (s, 1H), 7.74 (d, J = 7.7Hz, 1H), 8.12 (s, 1H), 8.21 (d, J = 5.4Hz, 1H), 8.47 (d, J = 4.7Hz, 1H), 8.56 (s, 1H), 8.69 (br s, 1H), 9.37 (s, 1H), 11.59 (s, 1H). HRMS: calculated as C 19 H 18 ON7(M+H + ): 360.1567; Actual measurement: 360.1564.

[1445] Example 49

[1446] 1-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-3-(pyridin-4-ylmethyl)urea

[1447]

[1448] To a 0.5–2 mL microwave-safe vial, ethyl (4-(3-amino-2H-indazole-5-yl)pyridin-2-yl)carbamate (Example 35) (0.030 g, 0.101 mmol, 1 equivalent), pyridin-4-ylmethylamine (0.044 g, 41.6 μL, 0.40 mmol, 4 equivalents), and dioxane (650 μL) were placed, sealed with an aluminum cap fitted with a disposable PTFE / silicone diaphragm, and purged with nitrogen. The reaction mixture was heated to 180 °C and held for 40 minutes under microwave irradiation. The reaction mixture was then cooled to approximately 40 °C and diluted dropwise with water (5 mL) using a syringe. The mixture was stirred and sonicated for 30 minutes, then cooled to room temperature. The cap was then removed, the solid was filtered off, washed with water (2 × 4 mL), and dried to give the title compound (32 mg, 0.09 mmol, 89%). 1 H NMR (400MHz, DMSO-D6) δ4.46(d,J=6.0Hz,2H),5.53(s,2H),7.24(d,J=5.3Hz,1H),7.38–7.28(m,3H), 7.54(d,J=9.5Hz,1H),7.69(s,1H),8.12(s,1H),8.23(d,J=5.4Hz,1H),8.51(d,J=5.8Hz,2H),8.77(br s,1H),9.44(s,1H),11.58(s,1H).

[1449] Example 50

[1450] 1-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-3-phenylurea

[1451]

[1452] Ethyl 4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)carbamate (Example 35) (0.050 g, 0.17 mmol) and aniline (16 μl, 0.20 mmol, 1.2 equivalences) were placed together in a 0.5–2 mL microwave-safe vial containing 2 mL of dioxane. The solution was then degassed with nitrogen for 5 min, followed by th...

Claims

1. A compound or a pharmaceutically acceptable salt, hydrate or solvate thereof having the structural formula (I) shown below: in: R1 is selected from hydrogen, halogen, (1-6C)alkyl, (2-6C)alkynyl, (3-7C)cycloalkyl, aryl, heteroaryl and heterocyclyl, and wherein the (1-6C)alkyl, (2-6C)alkynyl, (3-7C)cycloalkyl, aryl, heteroaryl and heterocyclyl are optionally substituted by one or more R 100 Substituent substitution; Where R 100 is selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, (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) y 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 or (CH2) z Aryl; And among them: (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, they form a 3-7 membered ring which may optionally include additional heteroatoms and which is optionally further substituted with one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, carboxyl, carbamoyl, sulfamoyl and (1-2C)alkyl; and (ii) R 100 Any (1-4C)alkyl, (3-7C)cycloalkyl, heterocyclyl, heteroaryl or aryl in the substituent is optionally further substituted by one or more 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) y R k SO2N(R l )R k 、N(R l )SO2R k or NR l R k Substituents, where R k and R l is selected from hydrogen or (1-2C)alkyl; X is N or CR2; wherein R2 is selected from hydrogen, halogen, (1-8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (3-7C)cycloalkyl, aryl, heteroaryl and heterocyclyl, wherein the (1-8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (3-7C)cycloalkyl, aryl, heteroaryl and heterocyclyl are optionally substituted by one or more R 200 Substituent substitution; Where R 200 is selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, (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 S(O) y 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 or (CH2) z Aryl; And among them: (i)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 phenyl, or R o and R p Together with the nitrogen atom to which they are attached, they form a 3-7 membered ring which may optionally include additional heteroatoms and which is optionally further substituted with one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, carboxyl, carbamoyl, sulfamoyl and (1-2C)alkyl; and (ii) R 200 Any (3-7C)cycloalkyl, heterocyclyl, heteroaryl or aryl moiety in the substituent is optionally further substituted by one or more 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) y R q SO2N(R r )R q 、N(R r )SO2R q or NR r R q Substituents, where R q is hydrogen, (1-2C)alkyl or phenyl, and R r is selected from hydrogen or (1-2C)alkyl; R3 is selected from hydrogen, cyano, (1-8C) alkyl, (3-7C) cycloalkyl, (CH2) 1-3 (3-7C)cycloalkyl, carbon-linked 4-7 membered heterocyclyl, carbon-linked 5-6 membered heteroaryl, -C(O)-(1-8C)alkyl, -C(O)(CH2) 0-3 (3-7C)cycloalkyl, -C(O)[5- or 6-membered heteroaryl], -C(O)phenyl, -C(O)O(1-8C)alkyl, -C(O)O(3-7C)cycloalkyl, -C(O)O(CH2) 1-3 (3-7C)cycloalkyl, -C(O)NH2, -C(O)NH-(1-8C)alkyl, -C(O)NH-(CH2) 0-3 (3-7C)cycloalkyl, -C(O)NH-(CH2) 0-3 Heterocyclic group, -C(O)NH-(CH2) 0-3 [5- or 6-membered heteroaryl], -C(O)NH-(CH2) 0-3 Phenyl, -S(O)2H or -S(O)2-(1-8C)alkyl; wherein any alkyl, cycloalkyl, phenyl, heteroaryl or heterocyclyl moiety is optionally replaced by one or more R 300 Substituent substitution; Where R 300 is selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, (1-4C)alkyl, (1-4C)hydroxyalkyl, (CH2) z OR s 、(CH2) z C(O)R s 、(CH2) z C(O)OR s 、(CH2) z OC(O)R s 、(CH2) z C(O)N(R v )R u 、(CH2) z N(R t )C(O)R s 、(CH2) z N(R t )C(O)OR s 、(CH2) z S(O) y R s 、(CH2) z SO2N(R v )R u 、(CH2) z N(R t )SO2R s 、(CH2) z NR u R v ; And among them: (i)R s and R t are each independently selected from hydrogen, (1-6C)alkyl or (CH2) z Phenyl; R u and R v are each independently selected from hydrogen, (1-6C)alkyl or (CH2) z Phenyl, or R u and R v Together with the nitrogen atom to which they are attached, they form a 3-7 membered ring which may optionally include additional heteroatoms, and wherein R o and R p Any 3-7 membered ring formed, and for R s , R t , R u and R v Any alkyl or phenyl groups present are optionally further substituted with one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, carboxy, carbamoyl, sulfamoyl and (1-2C)alkyl; and (ii) R 300 Any alkyl, cycloalkyl, heterocyclyl, heteroaryl or phenyl moiety in the substituent is optionally further substituted by one or more selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, (1-2C)alkyl, (1-2C)haloalkyl, (1-2C)hydroxyalkyl, OR w 、C(O)R w 、C(O)OR w 、OC(O)R w 、C(O)N(R w )R x 、N(R x )C(O)R w 、S(O) y R w SO2N(R x )R w 、N(R x )SO2R w or NR w R x Substituents, where R w is hydrogen, (1-2C)alkyl or phenyl, and R x is selected from hydrogen or (1-2C)alkyl; Or R2 and R3 are linked together to form a -CH=CQ- or -N=CQ- group; Q is hydrogen, halogen, cyano or a group of the formula: -L1-Y1-L2-Q1 in: L1 is absent or is (1-3C)alkylene; Y1 does not exist or is 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), where R y1 is selected from hydrogen or (1-4C)alkyl; L2 is absent or is (1-3C)alkylene; and Q1 is hydrogen, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, phenyl, (3-8C)cycloalkyl, heteroaryl or heterocyclyl; wherein Q is optionally further substituted by one or more substituents independently selected from oxo, hydroxy, (1-6C)alkyl, halogen, (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 in: L3 is absent or is (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 ) or N(R y2 )C(O), S(O)2N(R y2 )、N(R y2 )SO2, where R y2 is selected from hydrogen or (1-3C)alkyl; L4 is absent or is (1-3C)alkylene; and W1 is hydrogen, (1-6C)alkyl, phenyl, (3-8C)cycloalkyl, heteroaryl or heterocyclyl; wherein W1 is optionally replaced by one or more selected from oxo, (1-4C)alkyl, halogen, (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 - Substitution with a heterocyclic group or a cyano group; R4 is selected from hydrogen, halogen, cyano or amino; When R2 and R3 are linked together to form a -CH=CH- group, X1 is N; or X1 is CR5, wherein R5 is selected from hydrogen, halogen, cyano or amino; y is independently selected from 0, 1 or 2; z is independently selected from 0, 1, 2 or 3; The conditions are: (i) when R2 and R3 are both hydrogen, R1 is not hydrogen; (ii) when R1 and R3 are both hydrogen, R2 is not hydrogen; (iii) when R2 and R3 are linked to form a -CH=CH- group, R1 is not hydrogen; (iv) when X is N and R3 is hydrogen, R1 is not hydrogen; and (v) When L1, Y1 and L2 are absent, Q1 is not aryl or heteroaryl.

2. The compound according to claim 1 or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is a compound having the following structural formula (Ia), (Ib), (Ic), (Id) or (Ie): wherein R1, X, R3, R4, R5 and Q are each as defined in claim 1.

3. A compound according to claim 1 or claim 2, or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is selected from hydrogen, halogen, (1-6C) alkyl, (2-6C) alkynyl, (3-7C) cycloalkyl, phenyl, 5- or 6-membered heteroaryl or 4-7-membered heterocyclyl, wherein the (2-6C)alkynyl, (3-7C)cycloalkyl, phenyl, heteroaryl and heterocyclyl are optionally substituted by one or more R 100 Substituent substitution; And where R 100 is selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, (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) y 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 or (CH2) z Phenyl; And among them: (i)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, or R h and R j Together with the nitrogen atom to which they are attached, they form a 3-7 membered ring which may optionally include additional heteroatoms; and (ii) R 100 Any (1-4C)alkyl, (3-7C)cycloalkyl, heterocyclyl, heteroaryl or phenyl moiety in the substituent is optionally further substituted by one or more 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) y R k SO2N(R l )R k 、N(R l )SO2R k or NR l R k Substituents, where R k and R l is selected from hydrogen or (1-2C)alkyl.

4. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is selected from hydrogen, halogen, (1-6C) alkyl, (2-6C) alkynyl, phenyl or 5- or 6-membered heteroaryl, wherein the (2-6C) alkynyl, phenyl or heteroaryl is optionally substituted by one or more R 100 Substituent substitution; And where R 100 is selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, (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) y 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 -[4-6 membered heterocyclic group], (CH2) z -[5- or 6-membered heteroaryl] or (CH2) z Phenyl; And among them: (i)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, or R h and R j Together with the nitrogen atom to which they are attached, they form a 3-7 membered ring which may optionally include additional heteroatoms; and (ii) R 100 Any (1-4C)alkyl, (3-7C)cycloalkyl, heterocyclyl, heteroaryl or phenyl moiety in the substituent is optionally further substituted by one or more 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) y R k SO2N(R l )R k 、N(R l )SO2R k or NR l R k Substituents, where R k and R l is selected from hydrogen or (1-2C)alkyl.

5. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is selected from hydrogen, halogen, (1-6C)alkyl, (2-6C)alkynyl, phenyl or 5- or 6-membered heteroaryl, wherein the (2-6C)alkynyl, phenyl or heteroaryl is optionally substituted by one or more R 100 Substituent substitution; And where R 100 is selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, (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) y 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 -[4-6 membered heterocyclic group], (CH2) z -[5- or 6-membered heteroaryl] or (CH2) z Phenyl; And among them: (i)R f and R g are each independently selected from hydrogen or (1-2C)alkyl; and (ii) R 100 Any (1-4C)alkyl, (3-7C)cycloalkyl, heterocyclyl, heteroaryl or aryl moiety in the substituent is optionally further substituted with one or more halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, (1-2C)alkyl, (1-2C)haloalkyl, (1-2C)hydroxyalkyl or OR k Substituents, where R k is 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, (2-6C)alkynyl, phenyl or 5 or 6 membered heteroaryl, wherein the (2-6C)alkynyl, phenyl or heteroaryl is optionally substituted by one or more R 100 Substituent substitution; And where R 100 is selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, (1-4C)alkyl, (1-4C)hydroxyalkyl, (CH2) z 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) y R f SO2N(R j )R h 、N(R g )SO2R f NR j R h 、(CH2) z -[4-6 membered heterocyclyl] or (CH2) z Phenyl; And among them: (i)R f and R g are each independently selected from hydrogen or (1-2C)alkyl; and (ii) R 100 Any (1-4C)alkyl, heterocyclyl or phenyl moiety in the substituent is optionally further substituted by one or more selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, (1-2C)alkyl, (1-2C)haloalkyl, (1-2C)hydroxyalkyl or OR k Substituents, where 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; (ii) halogen; (iii) methyl; (iv) CF3; (v) ethynyl, i.e. It is optionally replaced by R 100 replace; (vi) optionally R 100 Substituted phenyl; (vii) optionally R 100 substituted 5- or 6-membered heteroaryl; And where R 100 is selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, (1-4C)alkyl, (1-4C)hydroxyalkyl, (CH2) z 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) y R f SO2N(R j )R h 、N(R g )SO2R f NR j R h 、(CH2) z -[4-6 membered heterocyclyl] or (CH2) z Phenyl; And among them: (i)R f and R g are each independently selected from hydrogen or (1-2C)alkyl; and (ii) R 100 Any (1-4C)alkyl, (3-7C)cycloalkyl, heterocyclyl, heteroaryl or aryl moiety in the substituent is optionally further substituted with one or more halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, (1-2C)alkyl, (1-2C)haloalkyl, (1-2C)hydroxyalkyl or OR k Substituents, where 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) halogen; (iii) methyl; (iv) CF3; (v) ethynyl, i.e. It is optionally replaced by R 100 replace; (vi) optionally R 100 Substituted phenyl; (vii) optionally R 100 substituted 5- or 6-membered heteroaryl; And where R 100 is selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, (1-4C)alkyl, (1-4C)hydroxyalkyl, (CH2) z 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) y R f SO2N(R j )R h 、N(R g )SO2R f NR j R h 、(CH2) z -[4-6 membered heterocyclyl] or (CH2) z Phenyl; And among them: (i)R f and R g are each independently selected from hydrogen or (1-2C)alkyl; and (ii) R 100 Any (1-4C)alkyl, heterocyclyl or phenyl moiety in the substituent is optionally further substituted by one or more selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, (1-2C)alkyl, (1-2C)haloalkyl, (1-2C)hydroxyalkyl or OR k Substituents, where 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; (ii) ethynyl, i.e. It is optionally replaced by R 100 replace; (iii) optionally R 100 Substituted phenyl; (iv) a 5- or 6-membered heteroaryl group; And where R 100 is selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, (1-4C)alkyl, (1-4C)hydroxyalkyl, (CH2) z 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) y R f SO2N(R j )R h 、N(R g )SO2R f NR j R h 、(CH2) z -[4-6 membered heterocyclyl] or (CH2) z Phenyl; And among them: (i)R f and R g are each independently selected from hydrogen or (1-2C)alkyl; and (ii) R 100 Any (1-4C)alkyl, heterocyclyl or phenyl moiety in the substituent is optionally further substituted by one or more selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, (1-2C)alkyl, (1-2C)haloalkyl, (1-2C)hydroxyalkyl or OR k Substituents, where R k is selected from hydrogen or (1-2C)alkyl.

10. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt or solvate thereof, wherein X is N or CR2; wherein R2 is selected from hydrogen, halogen, (1-8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (3-7C)cycloalkyl, phenyl, 5- or 6-membered heteroaryl or 4-7-membered heterocyclyl, wherein the (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (3-7C)cycloalkyl, phenyl, 5- or 6-membered heteroaryl or 4-7-membered heterocyclyl is optionally substituted by one or more R 200 Substituent substitution; And where R 200 is selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, (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 S(O) y 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 or (CH2) z Phenyl; And among them: (i)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 phenyl, or R o and R p Together with the nitrogen atom to which they are attached, they form a 3-7 membered ring which may optionally include additional heteroatoms and which is optionally further substituted with one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, carboxyl, carbamoyl, sulfamoyl and (1-2C)alkyl; and (ii) R 200 Any (3-7C)cycloalkyl, heterocyclyl, heteroaryl or phenyl moiety in the substituent is optionally further substituted by one or more 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) y R q SO2N(R r )R q 、N(R r )SO2R q or NR r R q Substituents, where R q is hydrogen, (1-2C)alkyl or phenyl, and R r is selected from hydrogen or (1-2C)alkyl.

11. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt or solvate thereof, wherein X is N or CR2; wherein R2 is selected from hydrogen, halogen, (1-8C) alkyl, (2-8C) alkynyl, (3-7C) cycloalkyl, phenyl, 5- or 6-membered heteroaryl or 4-7-membered heterocyclyl, wherein the (2-6C)alkynyl, (3-7C)cycloalkyl, phenyl, heteroaryl and heterocyclyl are optionally substituted by one or more R 200 Substituent substitution; And where R 200 is selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, (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 S(O) y 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 or (CH2) z Phenyl; And among them: (i)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 phenyl, or R o and R p Together with the nitrogen atom to which they are attached, they form a 3-7 membered ring which may optionally include additional heteroatoms and which is optionally further substituted with one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, carboxyl, carbamoyl, sulfamoyl and (1-2C)alkyl; and (ii) R 200 Any (3-7C)cycloalkyl, heterocyclyl, heteroaryl or phenyl moiety in the substituent is optionally further substituted by one or more 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) y R q SO2N(R r )R q 、N(R r )SO2R q or NR r R q Substituents, where R q is hydrogen, (1-2C)alkyl or phenyl, and R r is selected from hydrogen or (1-2C)alkyl.

12. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt or solvate thereof, wherein X is N or CR2; wherein R2 is selected from hydrogen, fluorine, (1-8C) alkyl, (2-8C) alkynyl, (3-7C) cycloalkyl, phenyl or 5- or 6-membered heteroaryl, wherein the (1-6C)alkynyl, (3-7C)cycloalkyl, phenyl, heteroaryl and heterocyclyl are optionally substituted by one or more R 200 Substituent substitution; And where R 200 is selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, (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 S(O) y 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 or (CH2) z Phenyl; And among them: (i)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 phenyl, or R o and R p Together with the nitrogen atom to which they are attached, they form a 3-7 membered ring which may optionally include additional heteroatoms and which is optionally further substituted with one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, carboxyl, carbamoyl, sulfamoyl and (1-2C)alkyl; and (ii) R 200 Any (3-7C)cycloalkyl, heterocyclyl, heteroaryl or phenyl moiety in the substituent is optionally further substituted by one or more 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) y R q SO2N(R r )R q 、N(R r )SO2R q or NR r R q Substituents, where R q is hydrogen, (1-2C)alkyl or phenyl, and R r is selected from hydrogen or (1-2C)alkyl.

13. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt or solvate thereof, wherein X is N or CR2; wherein R2 is selected from hydrogen, fluorine, (1-8C) alkyl, (3-7C) cycloalkyl or (2-6C) alkynyl, wherein the (2-6C)alkynyl group is optionally substituted by one or more R 200 Substituent substitution; And where R 200 is selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, (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 S(O) y 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 or (CH2) z Phenyl; And among them: (i)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 phenyl, or R o and R p Together with the nitrogen atom to which they are attached, they form a 3-7 membered ring which may optionally include additional heteroatoms and which is optionally further substituted with one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, carboxyl, carbamoyl, sulfamoyl and (1-2C)alkyl; and (ii) R 200 Any (3-7C)cycloalkyl, heterocyclyl, heteroaryl or phenyl moiety in the substituent is optionally further substituted by one or more 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) y R q SO2N(R r )R q 、N(R r )SO2R q or NR r R q Substituents, where R q is hydrogen, (1-2C)alkyl or phenyl, and R r is selected from hydrogen or (1-2C)alkyl.

14. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt or solvate thereof, wherein X is N or CR2; wherein R2 is selected from: (i)Hydrogen; (ii) fluorine; (iii) ethynyl, i.e. It is optionally replaced by R 200 replace; (iv) optionally R 200 Substituted phenyl; (v) optionally R 200 substituted 5- or 6-membered heteroaryl; And where R 200 is selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, (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 S(O) y 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 or (CH2) z Phenyl; And among them: (i)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 phenyl, or R o and R p Together with the nitrogen atom to which they are attached, they form a 3-7 membered ring which may optionally include additional heteroatoms and which is optionally further substituted with one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, carboxyl, carbamoyl, sulfamoyl and (1-2C)alkyl; and R 200 Any (3-7C)cycloalkyl, heterocyclyl, heteroaryl or phenyl moiety in the substituent is optionally further substituted by one or more 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) y R q SO2N(R r )R q 、N(R r )SO2R q or NR r R q Substituents, where R q is hydrogen, (1-2C)alkyl or phenyl, and R r is selected from hydrogen or (1-2C)alkyl.

15. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt or solvate thereof, wherein X is N or CR2; wherein R2 is selected from: (i) hydrogen; or (ii) ethynyl, i.e. It is optionally replaced by R 200 replace; And where R 200 is selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, (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 S(O) y 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 or (CH2) z Phenyl; And among them: (i)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 phenyl, or R o and R p Together with the nitrogen atom to which they are attached, they form a 3-7 membered ring which may optionally include additional heteroatoms and which is optionally further substituted with one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, carboxyl, carbamoyl, sulfamoyl and (1-2C)alkyl; and (ii) R 200 Any (3-7C)cycloalkyl, heterocyclyl, heteroaryl or phenyl moiety in the substituent is optionally further substituted by one or more 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) y R q SO2N(R r )R q 、N(R r )SO2R q or NR r R q Substituents, where R q is hydrogen, (1-2C)alkyl or phenyl, and R r is selected from hydrogen or (1-2C)alkyl.

16. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt or solvate thereof, wherein X is CR2.

17. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is selected from hydrogen, cyano, (1-8C) alkyl, (3-7C) cycloalkyl, a carbon-linked 4-7 membered heterocyclyl, a carbon-linked 5-6 membered heteroaryl, -(CH2) 1-3 (3-7C)cycloalkyl, -C(O)-(1-8C)alkyl, -C(O)-(CH2) 0-3 (3-7C)cycloalkyl, -C(O)phenyl, -C(O)O(1-8C)alkyl, -C(O)NH2, -C(O)NH-(1-8C)alkyl, -C(O)NH-(CH2) 0-3 (3-7C)cycloalkyl, -C(O)NH-(CH2) 0-3 [5- or 6-membered heteroaryl], -C(O)NH-(CH2) 0-3 Phenyl, -S(O)2H or -S(O)2-(1-6C)alkyl; wherein any alkyl, cycloalkyl, phenyl or heteroaryl moiety is optionally replaced by one or more R 300 Substituent substitution; Where R 300 is selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, (1-4C)alkyl, (1-4C)hydroxyalkyl, OR s 、C(O)R s 、C(O)OR s 、OC(O)R s 、C(O)N(R v )R u 、N(R t )C(O)R s 、N(R t )C(O)OR s 、S(O) y R s SO2N(R v )R u 、N(R t )SO2R s 、(CH2) z NR u R v ; And among them: (i)R s and R t are each independently selected from hydrogen, (1-6C)alkyl or (CH2) z Phenyl; R u and R v are each independently selected from hydrogen, (1-6C)alkyl or (CH2) z Phenyl, or R u and R v Together with the nitrogen atom to which they are attached, they form a 3-7 membered ring which may optionally include additional heteroatoms, and wherein R o and R p Any 3-7 membered ring formed, and for R s , R t , R u and R v Any alkyl or phenyl groups present are optionally further substituted with one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, carboxy, carbamoyl, sulfamoyl and (1-2C)alkyl; and (ii) R 300 Any cycloalkyl, heterocyclyl, heteroaryl or phenyl moiety in the substituents is optionally further substituted with one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy or (1-2C)alkyl.

18. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is selected from hydrogen, cyano, (1-8C) alkyl, (3-7C) cycloalkyl, -(CH2) 1-3 (3-7C)cycloalkyl, carbon-linked 4-7 membered heterocyclyl, carbon-linked 5-6 membered heteroaryl, -C(O)-(1-8C)alkyl, -C(O)(3-7C)cycloalkyl, -C(O)phenyl, -C(O)O(1-8C)alkyl, -C(O)NH2, -C(O)NH-(1-8C)alkyl, -C(O)NH-(CH2) 0-3 (3-7C)cycloalkyl, -C(O)NH-(CH2) 0-3 [5- or 6-membered heteroaryl], -C(O)NH-(CH2) 0-3 Phenyl, -S(O)2H or -S(O)2-(1-6C)alkyl; wherein any alkyl, cycloalkyl, phenyl or heteroaryl moiety is optionally replaced by one or more R 300 Substituent substitution; Where R 300 is selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, (1-4C)alkyl, (1-4C)hydroxyalkyl, OR s 、C(O)N(R v )R u 、S(O) y R s 、(CH2) z NR u R v ; And among them: (i)R s and R t are each independently selected from hydrogen, (1-6C)alkyl or (CH2) z Phenyl; R u and R v are each independently selected from hydrogen, (1-6C)alkyl or (CH2) z Phenyl, or R u and R v Together with the nitrogen atom to which they are attached, they form a 3-7 membered ring which may optionally include additional heteroatoms; and (ii) R 300 Any cycloalkyl, heterocyclyl, heteroaryl or phenyl moiety in the substituents is optionally further substituted with one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy or (1-2C)alkyl.

19. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is selected from hydrogen or acetyl.

20. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is selected from hydrogen or fluorine.

21. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is selected from hydrogen, cyano or fluoro.

22. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt or solvate thereof, wherein Q is hydrogen or a group of the formula: -L1-Y1-L2-Q1 in: L1 is absent or is (1-3C)alkylene; Y1 does not exist or is O, S, SO, SO2, N(R y1 )、C(O)、C(O)O、C(O)N(R y1 ) or N(R y1 )C(O), where R y1 is selected from hydrogen or (1-4C)alkyl; L2 is absent or is (1-3C)alkylene; and Q1 is hydrogen, (1-6C)alkyl, phenyl, (3-8C)cycloalkyl, heteroaryl or heterocyclyl; wherein Q is optionally further substituted by one or more substituents independently selected from oxo, hydroxy, (1-6C)alkyl, halogen, (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 in: L3 does not exist; 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 ) or N(R y2 )C(O), S(O)2N(R y2 )、N(R y2 )SO2, where R y2 is selected from hydrogen or (1-3C)alkyl; L4 is absent or is (1-3C)alkylene; and W1 is hydrogen, (1-6C)alkyl or phenyl; wherein W1 is optionally substituted with one or more substituents selected from (1-2C)alkyl or halogen; Provided that when L1, Y1 and L2 are absent, Q1 is not aryl or heteroaryl.

23. A 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-indazol-3-amine; 5-(2-aminopyridin-4-yl)-7-methyl-1H-indazol-3-amine; 5-(2-aminopyridin-4-yl)-7-(trifluoromethyl)-1H-indazol-3-amine; 7-Chloro-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine; 7-Bromo-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine; 7-ethynyl-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine; 7-phenyl-5-(1H-pyrrolo[2,3-b]pyridin-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; 4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid; 7-Bromo-5-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-indazol-3-amine 5-(2-(Ethylamino)pyridin-4-yl)-1H-indazol-3-amine; 5-(2-(Propylamino)pyridin-4-yl)-1H-indazol-3-amine; 5-(2-(Isopropylamino)pyridin-4-yl)-1H-indazol-3-amine; 5-(2-((Cyclopropylmethyl)amino)pyridin-4-yl)-1H-indazol-3-amine; 5-(2-(Isopentylamino)pyridin-4-yl)-1H-indazol-3-amine; 5-(2-(Hexylamino)pyridin-4-yl)-1H-indazol-3-amine; 5-(2-(Cyclohexylamino)pyridin-4-yl)-1H-indazol-3-amine; 5-{2-[(trans-4-methylcyclohexyl)amino]pyridin-4-yl}-1H-indazol-3-amine; 2-((4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)amino)ethan-1-ol; 3-((4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)amino)propan-1-ol; 4-((4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)amino)butan-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-indazol-3-amine; 5-(2-((2-methoxyethyl)amino)pyridin-4-yl)-1H-indazol-3-amine; 5-(2-((3-methoxypropyl)amino)pyridin-4-yl)-1H-indazol-3-amine; 5-(2-((3-isopropoxypropyl)amino)pyridin-4-yl)-1H-indazol-3-amine; 3-((4-(3-amino-1H-indazol-5-yl)pyrimidin-2-yl)amino)propan-1-ol; 3-((4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)(methyl)amino)propan-1-ol; 5-(2-((2-morpholinoethyl)amino)pyridin-4-yl)-1H-indazol-3-amine; 5-(2-((2-(piperidin-1-yl)ethyl)amino)pyridin-4-yl)-1H-indazol-3-amine; N 1 -(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-N3-methylpropane-1,3-diamine; N-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)cyclopropanecarboxamide; N-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)benzamide; Ethyl (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-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-1H-indazol-5-yl)pyridin-2-yl)-3-(3-fluorophenyl)urea; 1-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-3-(3-chlorophenyl)urea; 1-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-3-(3-isopropylphenyl)urea; 1-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-3-(3-(hydroxymethyl)phenyl)urea; 3-(3-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)ureido)benzamide; 1-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-3-(3-phenoxyphenyl)urea; 1-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-3-(3-(benzyloxy)phenyl)urea; 1-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-3-(3-((4-fluorobenzyl)oxy)phenyl)urea; 1-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-3-(3-((3-fluorobenzyl)oxy)phenyl)urea; 1-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-3-(3-((2-fluorobenzyl)oxy)phenyl)urea; 3-(3-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)ureido)-N-phenylbenzamide; 1-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-3-(4-fluorophenyl)urea; 1-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-3-(4-chlorophenyl)urea; 1-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-3-(4-(tert-butyl)phenyl)urea; 1-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-3-(4-(methylsulfonyl)phenyl)urea; 1-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-3-(o-tolyl)urea; 1-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-3-(2-ethylphenyl)urea; 1-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-3-(2-isopropylphenyl)urea; 1-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-3-(pyridin-3-yl)urea; 5-(2-amino-3-ethynylpyridin-4-yl)-1H-indazol-3-amine; 5-(2-amino-3-(cyclopropylethynyl)pyridin-4-yl)-1H-indazol-3-amine; 5-(2-amino-3-(3,3-dimethylbut-1-yn-1-yl)pyridin-4-yl)-1H-indazol-3-amine; 5-(2-amino-3-(cyclopentylethynyl)pyridin-4-yl)-1H-indazol-3-amine; 5-(2-amino-3-(cyclohexylethynyl)pyridin-4-yl)-1H-indazol-3-amine; 5-(2-amino-3-(phenylethynyl)pyridin-4-yl)-1H-indazol-3-amine; 5-(2-amino-3-((4-aminophenyl)ethynyl)pyridin-4-yl)-1H-indazol-3-amine; 5-(2-amino-3-((3-aminophenyl)ethynyl)pyridin-4-yl)-1H-indazol-3-amine; 5-(2-amino-3-((2-aminophenyl)ethynyl)pyridin-4-yl)-1H-indazol-3-amine; Methyl 3-((2-amino-4-(3-amino-1H-indazol-5-yl)pyridin-3-yl)ethynyl)benzoate; Methyl 4-((2-amino-4-(3-amino-1H-indazol-5-yl)pyridin-3-yl)ethynyl)benzoate; 5-(2-amino-3-((2-methoxyphenyl)ethynyl)pyridin-4-yl)-1H-indazol-3-amine; 5-(2-amino-4-(3-amino-1H-indazol-5-yl)pyridin-3-yl)-1-phenylpent-4-yn-1-one; 3-(2-amino-4-(3-amino-1H-indazol-5-yl)pyridin-3-yl)prop-2-yn-1-ol; 4-(2-amino-4-(3-amino-1H-indazol-5-yl)pyridin-3-yl)but-3-yn-1-ol; 5-(2-amino-4-(3-amino-1H-indazol-5-yl)pyridin-3-yl)pent-4-yn-1-ol; 6-(2-amino-4-(3-amino-1H-indazol-5-yl)pyridin-3-yl)-2-methylhex-5-yn-2-ol; 4-(2-amino-4-(3-amino-1H-indazol-5-yl)pyridin-3-yl)-2-methylbut-3-yn-2-ol; 5-(2-amino-3-(3-(tert-butoxy)prop-1-yn-1-yl)pyridin-4-yl)-1H-indazol-3-amine; 1-((2-amino-4-(3-amino-1H-indazol-5-yl)pyridin-3-yl)ethynyl)cyclopentan-1-ol; 1-((2-amino-4-(3-amino-1H-indazol-5-yl)pyridin-3-yl)ethynyl)cyclohexan-1-ol; 1-((2-amino-4-(3-amino-1H-indazol-5-yl)pyridin-3-yl)ethynyl)cycloheptan-1-ol; 5-(2-amino-3-(3-amino-3-methylbut-1-yn-1-yl)pyridin-4-yl)-1H-indazol-3-amine; 5-(2-amino-3-(4-(piperidin-1-yl)but-1-yn-1-yl)pyridin-4-yl)-1H-indazol-3-amine; 5-(2-amino-3-(4-morpholinobut-1-yn-1-yl)pyridin-4-yl)-1H-indazol-3-amine; 5-(2-amino-3-(5-(piperidin-1-yl)pent-1-yn-1-yl)pyridin-4-yl)-1H-indazol-3-amine; 5-(2-amino-3-(5-morpholinopent-1-yn-1-yl)pyridin-4-yl)-1H-indazol-3-amine; 5-(2-amino-3-(3-(piperidin-4-yl)prop-1-yn-1-yl)pyridin-4-yl)-1H-indazol-3-amine; 3-(2-amino-4-(3-amino-1H-indazol-5-yl)pyridin-3-yl)-N-methylpropanamide; 5-(2-amino-4-(3-amino-1H-indazol-5-yl)pyridin-3-yl)-1-morpholinopent-4-yn-1-one; 5-(2-amino-3-cyclopropylpyridin-4-yl)-1H-indazol-3-amine; 4-(2-amino-4-(3-amino-1H-indazol-5-yl)pyridin-3-yl)butan-1-ol; 1-(2-(2-amino-4-(3-amino-1H-indazol-5-yl)pyridin-3-yl)ethyl)cyclohexan-1-ol; 5-(2-amino-4-(3-amino-1H-indazol-5-yl)pyridin-3-yl)pentan-1-ol; 5-(2-aminopyridin-4-yl)-7-phenyl-1H-indazol-3-amine; 5-(2-aminopyridin-4-yl)-7-(3-fluorophenyl)-1H-indazol-3-amine; 5-(2-aminopyridin-4-yl)-7-(3-(trifluoromethyl)phenyl)-1H-indazol-3-amine; 7-(3-aminophenyl)-5-(2-aminopyridin-4-yl)-1H-indazol-3-amine; 3-(3-amino-5-(2-aminopyridin-4-yl)-1H-indazol-7-yl)phenol; 5-(2-aminopyridin-4-yl)-7-(3-methoxyphenyl)-1H-indazol-3-amine; (3-(3-amino-5-(2-aminopyridin-4-yl)-1H-indazol-7-yl)phenyl)methanol; 3-(3-amino-5-(2-aminopyridin-4-yl)-1H-indazol-7-yl)benzaldehyde; Ethyl 3-(3-amino-5-(2-aminopyridin-4-yl)-1H-indazol-7-yl)benzoate; 3-(3-amino-5-(2-aminopyridin-4-yl)-1H-indazol-7-yl)benzamide; 3-(3-amino-5-(2-aminopyridin-4-yl)-1H-indazol-7-yl)benzenesulfonamide; 5-(2-aminopyridin-4-yl)-7-(3-(methylsulfonyl)phenyl)-1H-indazol-3-amine; 5-(2-aminopyridin-4-yl)-7-(3-(morpholinomethyl)phenyl)-1H-indazol-3-amine; 4-(3-amino-5-(2-aminopyridin-4-yl)-1H-indazol-7-yl)phenol; (4-(3-amino-5-(2-aminopyridin-4-yl)-1H-indazol-7-yl)phenyl)methanol; 5-(2-aminopyridin-4-yl)-7-(4-(dimethylamino)phenyl)-1H-indazol-3-amine; 4-(3-amino-5-(2-aminopyridin-4-yl)-1H-indazol-7-yl)benzamide; 4-(3-amino-5-(2-aminopyridin-4-yl)-1H-indazol-7-yl)benzenesulfonamide; 5-(2-aminopyridin-4-yl)-7-(4-(morpholinomethyl)phenyl)-1H-indazol-3-amine; 5-(2-aminopyridin-4-yl)-7-(4-(tert-butyl)phenyl)-1H-indazol-3-amine; 5-(2-aminopyridin-4-yl)-7-(2-chlorophenyl)-1H-indazol-3-amine; (2-(3-amino-5-(2-aminopyridin-4-yl)-1H-indazol-7-yl)phenyl)methanol; 4-(3-amino-5-(2-aminopyridin-4-yl)-1H-indazol-7-yl)-3-methylbenzenesulfonamide; 5-(2-aminopyridin-4-yl)-7-(pyridin-3-yl)-1H-indazol-3-amine; 5-(2-aminopyridin-4-yl)-7-(pyridin-4-yl)-1H-indazol-3-amine; 5-(2-aminopyridin-4-yl)-7-(furan-3-yl)-1H-indazol-3-amine; 5-(2-aminopyridin-4-yl)-7-(thiophen-3-yl)-1H-indazol-3-amine; 5-(2-aminopyridin-4-yl)-7-(thiophen-2-yl)-1H-indazol-3-amine; 5-(2-aminopyridin-4-yl)-7-(thiazol-5-yl)-1H-indazol-3-amine; 5-(2-aminopyridin-4-yl)-7-(1H-pyrazol-5-yl)-1H-indazol-3-amine; 5-(2-aminopyridin-4-yl)-7-(3-methylbut-1-yn-1-yl)-1H-indazol-3-amine; 5-(2-aminopyridin-4-yl)-7-(pent-1-yn-1-yl)-1H-indazol-3-amine; 5-(2-aminopyridin-4-yl)-7-(cyclopropylethynyl)-1H-indazol-3-amine; 5-(2-aminopyridin-4-yl)-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazol-3-amine; 5-(2-aminopyridin-4-yl)-7-(phenylethynyl)-1H-indazol-3-amine; 4-(3-amino-5-(2-aminopyridin-4-yl)-1H-indazol-7-yl)but-3-yn-1-ol; 4-(3-amino-5-(2-aminopyridin-4-yl)-1H-indazol-7-yl)-2-methylbut-3-yn-2-ol; 5-(2-aminopyridin-4-yl)-7-((3-methyloxetan-3-yl)ethynyl)-1H-indazol-3-amine; 5-(2-aminopyridin-4-yl)-7-((tetrahydro-2H-pyran-4-yl)ethynyl)-1H-indazol-3-amine; 5-(2-aminopyrimidin-4-yl)-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazol-3-amine; 5-(2-aminopyridin-4-yl)-7-(3,3-dimethylbutyl)-1H-indazol-3-amine; 5-(2-aminopyridin-4-yl)-7-(2-cyclohexylethyl)-1H-indazol-3-amine; 5-(2-aminopyridin-4-yl)-7-(2-cyclopropylethyl)-1H-indazol-3-amine; 5-(2-aminopyridin-4-yl)-7-phenethyl-1H-indazol-3-amine; 5-(2-amino-5-fluoropyridin-4-yl)-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazol-3-amine; 5-(2-amino-3-fluoropyridin-4-yl)-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazol-3-amine; 5-(2-amino-6-fluoropyridin-4-yl)-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazol-3-amine; 4-(3-amino-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazol-5-yl)pyridine-2,6-diamine; 6-amino-4-(3-amino-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazol-5-yl)nicotinonitrile; 5-(2-(Cyclopropylamino)pyridin-4-yl)-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazol-3-amine; 5-(2-(Cyclobutylamino)pyridin-4-yl)-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazol-3-amine; 7-(3,3-dimethylbut-1-yn-1-yl)-5-(2-(oxetan-3-ylamino)pyridin-4-yl)-1H-indazol-3-amine; 5-(2-(Cyclopentylamino)pyridin-4-yl)-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazol-3-amine; 5-(2-((Cyclopropylmethyl)amino)pyridin-4-yl)-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazol-3-amine; 7-(3,3-dimethylbut-1-yn-1-yl)-5-(2-((2,2,2-trifluoroethyl)amino)pyridin-4-yl)-1H-indazol-3-amine; 3-((4-(3-amino-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazol-5-yl)pyridin-2-yl)amino)propionitrile; 2-((4-(3-amino-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazol-5-yl)pyridin-2-yl)amino)ethan-1-ol; N1-(4-(3-amino-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazol-5-yl)pyridin-2-yl)ethane-1,2-diamine; 7-(3,3-dimethylbut-1-yn-1-yl)-5-(2-((2-methoxyethyl)amino)pyridin-4-yl)-1H-indazol-3-amine; 7-(3,3-dimethylbut-1-yn-1-yl)-5-(2-((3-methoxypropyl)amino)pyridin-4-yl)-1H-indazol-3-amine; N-(4-(3-amino-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazol-5-yl)pyridin-2-yl)acetamide; N-(4-(3-amino-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazol-5-yl)pyridin-2-yl)propanamide; N-(4-(3-amino-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazol-5-yl)pyridin-2-yl)-3,3,3-trifluoropropanamide; N-(4-(3-amino-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazol-5-yl)pyridin-2-yl)cyclopropanecarboxamide; N-(4-(3-amino-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazol-5-yl)pyridin-2-yl)isobutyramide; N-(4-(3-amino-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazol-5-yl)pyridin-2-yl)pivalamide; N-(4-(3-amino-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazol-5-yl)pyridin-2-yl)-2-cyclopropylacetamide; N-(4-(3-amino-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazol-5-yl)pyridin-2-yl)-3-methylbutanamide; N-(4-(3-amino-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazol-5-yl)pyridin-2-yl)cyclobutanecarboxamide; N-(4-(3-amino-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazol-5-yl)pyridin-2-yl)cyclopentanecarboxamide; N-(4-(3-amino-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazol-5-yl)pyridin-2-yl)-2-hydroxyacetamide; N-(4-(3-amino-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazol-5-yl)pyridin-2-yl)-2-methoxyacetamide; 5-(2-(Cyclopropylamino)pyridin-4-yl)-7-((3-methyloxetan-3-yl)ethynyl)-1H-indazol-3-amine; N-(4-(3-amino-7-((3-methyloxetan-3-yl)ethynyl)-1H-indazol-5-yl)pyridin-2-yl)acetamide; N-(4-(3-amino-7-(phenylethynyl)-1H-indazol-5-yl)pyridin-2-yl)acetamide; Methyl (4-(3-amino-7-(cyclopropylethynyl)-1H-indazol-5-yl)pyridin-2-yl)carbamate; Methyl (4-(3-amino-7-(3-hydroxy-3-methylbut-1-yn-1-yl)-1H-indazol-5-yl)pyridin-2-yl)carbamate; Methyl (4-(3-amino-7-(3-amino-3-methylbut-1-yn-1-yl)-1H-indazol-5-yl)pyridin-2-yl)carbamate; Methyl (4-(3-amino-7-(3-methoxy-3-methylbut-1-yn-1-yl)-1H-indazol-5-yl)pyridin-2-yl)carbamate; Methyl (4-(3-amino-7-(3-morpholinoprop-1-yn-1-yl)-1H-indazol-5-yl)pyridin-2-yl)carbamate; Methyl (4-(3-amino-7-(4-morpholinobut-1-yn-1-yl)-1H-indazol-5-yl)pyridin-2-yl)carbamate; 1-(4-(3-amino-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazol-5-yl)pyridin-2-yl)urea; 1-(4-(3-amino-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazol-5-yl)pyridin-2-yl)-3-methylurea; 1-(4-(3-amino-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazol-5-yl)pyridin-2-yl)-3-ethylurea; 1-(4-(3-amino-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazol-5-yl)pyridin-2-yl)-3-propylurea; 1-(4-(3-amino-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazol-5-yl)pyridin-2-yl)-3-phenylurea; Methyl (4-(3-amino-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazol-5-yl)pyridin-2-yl)carbamate; Ethyl (4-(3-amino-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazol-5-yl)pyridin-2-yl)carbamate; tert-Butyl (4-(3-amino-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazol-5-yl)pyridin-2-yl)carbamate; (4-(3-amino-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazol-5-yl)pyridin-2-yl)aminosulfonic acid; N-(4-(3-amino-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazol-5-yl)pyridin-2-yl)methanesulfonamide; N-(4-(3-amino-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazol-5-yl)-6-fluoropyridin-2-yl)acetamide; N-(4-(3-amino-7-phenyl-1H-indazol-5-yl)pyridin-2-yl)acetamide; N-(4-(3-amino-7-(pyridin-4-yl)-1H-indazol-5-yl)pyridin-2-yl)acetamide; 7-(Furan-3-yl)-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine; 7-ethynyl-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine; 7-(3,3-dimethylbut-1-yn-1-yl)-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine; 7-(Cyclopropylethynyl)-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine; 7-(Cyclopentylethynyl)-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine; 7-(Cyclohexylethynyl)-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine; 3-(3-amino-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-7-yl)prop-2-yn-1-ol; 4-(3-amino-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-7-yl)-2-methylbut-3-yn-2-ol; 1-((3-amino-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-7-yl)ethynyl)cyclopentan-1-ol; 1-((3-amino-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-7-yl)ethynyl)cyclohexane-1-ol; 1-((3-amino-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-7-yl)ethynyl)cycloheptan-1-ol; 7-(5-morpholinopent-1-yn-1-yl)-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine; 7-(4-(Piperidin-1-yl)but-1-yn-1-yl)-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine; 7-(5-(piperidin-1-yl)pent-1-yn-1-yl)-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine; 7-(6-(Piperidin-1-yl)hex-1-yn-1-yl)-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine; 6-(3-amino-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-7-yl)hex-5-ynoic acid; 7-(3-amino-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-7-yl)hept-6-ynoic acid; 7-(4-phenoxybut-1-yn-1-yl)-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine; 7-(6-phenoxyhex-1-yn-1-yl)-5-(1H-pyrrolo[2,3-b]pyridin-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]pyridine-2-carboxamide; (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-indazol-3-amine; 5-(2-((Isopentylamino)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine; 5-(2-(Piperidin-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine; 5-(2-((Cyclohexylamino)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine; 5-(2-((phenylamino)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine; 5-(2-(((2-(Benzyloxy)phenyl)amino)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine; 5-(2-(((2-methoxyethyl)amino)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine; N 1 -((4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)-N 2 ,N 2 -dimethylethane-1,2-diamine; 5-(2-(((3-methoxypropyl)amino)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine; 5-(2-(((3-isopropoxypropyl)amino)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine; N 1 -((4-(3-amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)-N 3 ,N 3 -Dimethylpropane-1,3-diamine; 5-(2-((isopropyl(methyl)amino)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine; 5-(2-(Piperidin-1-ylmethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine; 5-(2-((4,4-difluoropiperidin-1-yl)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine; 5-(2-(Morpholinomethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine; 5-(2-((4-methylpiperazin-1-yl)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine; 5-(2-((4-(tert-butyl)piperazin-1-yl)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine; 5-(2-(Azepan-1-ylmethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine; 5-(2-((4-methyl-1,4-diazepin-1-yl)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine; 5-(2-(2-(Piperidin-1-yl)ethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine; 5-(2-(2-morpholinoethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine; 5-(2-(3-(piperidin-1-yl)propyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine; 5-(2-(3-(cyclohexylamino)propyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine; 5-(2-(3-morpholinopropyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine; 5-(2-(Piperidin-4-ylmethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine; 5-(2-((1-benzylpiperidin-4-yl)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine; N-(4-(3-amino-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazol-5-yl)pyridin-2-yl)oxazol-2-amine; 7-(3,3-dimethylbut-1-yn-1-yl)-5-(2-((3,3,3-trifluoropropyl)amino)pyridin-4-yl)-1H-indazol-3-amine; 7-(Cyclopropylethynyl)-5-(2-(oxetan-3-ylamino)pyridin-4-yl)-1H-indazol-3-amine; Methyl (4-(3-amino-7-((tetrahydro-2H-pyran-4-yl)ethynyl)-1H-indazol-5-yl)pyridin-2-yl)carbamate; Methyl (4-(3-amino-7-((3-methyloxetan-3-yl)ethynyl)-1H-indazol-5-yl)pyridin-2-yl)carbamate; 4-(3-amino-5-(2-(oxetan-3-ylamino)pyridin-4-yl)-1H-indazol-7-yl)-2-methylbut-3-yn-2-ol; 5-(2-(Oxetane-3-ylamino)pyridin-4-yl)-7-((tetrahydro-2H-pyran-4-yl)ethynyl)-1H-indazol-3-amine; N-(4-(3-amino-7-(cyclopropylethynyl)-1H-indazol-5-yl)pyridin-2-yl)cyclopropanecarboxamide; N-(4-(3-amino-7-(3-hydroxy-3-methylbut-1-yn-1-yl)-1H-indazol-5-yl)pyridin-2-yl)cyclopropanecarboxamide; Methyl (4-(3-amino-7-(5-morpholinopent-1-yn-1-yl)-1H-indazol-5-yl)pyridin-2-yl)carbamate; N-(4-(3-amino-7-(3-hydroxy-3-methylbutyl)-1H-indazol-5-yl)pyridin-2-yl)cyclopropanecarboxamide; Methyl (4-(3-amino-7-(3,3-dimethylbutyl)-1H-indazol-5-yl)pyridin-2-yl)carbamate; 5-(2-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazol-3-amine; 5-(2-cyclopentyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazol-3-amine; 5-(2-(tert-butyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazol-3-amine; (4-(3-amino-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)methanol; 2-(4-(3-amino-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)propan-2-ol; 4-(3-amino-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid methyl ester; 5-(2-(Difluoromethyl)-3H-imidazo[4,5-b]pyridin-7-yl)-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazol-3-amine; 5-(2-cyclobutyl-3H-imidazo[4,5-b]pyridin-7-yl)-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazol-3-amine; N-(4-(3-amino-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazol-5-yl)pyridin-2-yl)cyanamide; 5-(2-((1H-pyrazol-3-yl)amino)pyridin-4-yl)-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazol-3-amine; 5-(2-((1H-pyrazol-4-yl)amino)pyridin-4-yl)-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazol-3-amine; 7-(3,3-dimethylbut-1-yn-1-yl)-5-(2-((5-methyl-1H-pyrazol-3-yl)amino)pyridin-4-yl)-1H-indazol-3-amine; 7-(3,3-dimethylbut-1-yn-1-yl)-5-(2-((3-methyl-1H-pyrazol-4-yl)amino)pyridin-4-yl)-1H-indazol-3-amine; N-(4-(3-amino-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazol-5-yl)pyridin-2-yl)thiazol-2-amine; N-(4-(3-amino-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazol-5-yl)pyridin-2-yl)-4-methyloxazol-2-amine; N-(4-(3-amino-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazol-5-yl)pyridin-2-yl)-4-(trifluoromethyl)oxazol-2-amine; N-(4-(3-amino-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazol-5-yl)pyridin-2-yl)-3,5-dimethylisoxazol-4-amine; 5-(2-((1H-imidazol-4-yl)amino)pyridin-4-yl)-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazol-3-amine; 5-(2-((4H-1,2,4-triazol-3-yl)amino)pyridin-4-yl)-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazol-3-amine; 7-(3,3-dimethylbut-1-yn-1-yl)-5-(2-((2-methyl-2H-tetrazol-5-yl)amino)pyridin-4-yl)-1H-indazol-3-amine; 7-(3,3-dimethylbut-1-yn-1-yl)-5-(2-(pyrimidin-2-ylamino)pyridin-4-yl)-1H-indazol-3-amine; 7-(3,3-dimethylbut-1-yn-1-yl)-5-(2-((tetrahydrofuran-3-yl)amino)pyridin-4-yl)-1H-indazol-3-amine; Methyl (4-(3-amino-7-(4-hydroxyphenyl)-1H-indazol-5-yl)pyridin-2-yl)carbamate; 4-(3-amino-5-(2-(oxetan-3-ylamino)pyridin-4-yl)-1H-indazol-7-yl)phenol; Methyl (4-(3-amino-7-(4-aminophenyl)-1H-indazol-5-yl)pyridin-2-yl)carbamate; Methyl (4-(7-(4-acetylaminophenyl)-3-amino-1H-indazol-5-yl)pyridin-2-yl)carbamate; Methyl (4-(3-amino-7-(4-carbamoylphenyl)-1H-indazol-5-yl)pyridin-2-yl)carbamate; Methyl (4-(3-amino-7-(4-(morpholinomethyl)phenyl)-1H-indazol-5-yl)pyridin-2-yl)carbamate; 5-(2-aminopyridin-4-yl)-7-(4-(2-morpholinoethyl)phenyl)-1H-indazol-3-amine; Methyl (4-(3-amino-7-(4-(2-morpholinoethyl)phenyl)-1H-indazol-5-yl)pyridin-2-yl)carbamate; Methyl (4-(3-amino-7-(4-(methylsulfonyl)phenyl)-1H-indazol-5-yl)pyridin-2-yl)carbamate; Methyl (4-(3-amino-7-(3-hydroxyphenyl)-1H-indazol-5-yl)pyridin-2-yl)carbamate; Methyl (4-(3-amino-7-(3-carbamoylphenyl)-1H-indazol-5-yl)pyridin-2-yl)carbamate; Methyl (4-(3-amino-7-(3-(morpholinomethyl)phenyl)-1H-indazol-5-yl)pyridin-2-yl)carbamate; N-(4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)-2-cyclohexylacetamide; 6-amino-4-(3-amino-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazol-5-yl)nicotinonitrile.

24. A pharmaceutical composition comprising a compound according to any one of claims 1 to 23 or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

25. A compound according to any one of claims 1 to 23 or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical preparation according to claim 24: (i) for therapeutic purposes; (ii) for treating a disease or condition responsive to IKKα modulation; (iii) for the treatment of a proliferative disorder (such as cancer); or (iv) For the treatment of inflammation.

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