Compounds useful as RET inhibitors

Abstract

The present invention relates to compounds of formula I which act as inhibitors of RET (rearranged during transfection) kinase enzyme activity: wherein HET, bonds a, b, c and d, X 1 , X 2 , X 3 , X 4 , R 2 and R 3 Each is as defined herein. The present invention also relates to processes for the preparation of these compounds, pharmaceutical compositions comprising them, and their use in the treatment of proliferative disorders such as cancer and other diseases or conditions in which RET kinase activity is implicated.

Description

[0001] This application is a divisional application of the Chinese invention patent application with application number 2018800244337 (application date: April 13, 2018, invention name: compounds suitable for use as RET inhibitors).

[0002] introduction

[0003] The present invention relates to certain compounds that act as inhibitors of RET (rearranged during transfection) kinase enzyme activity. The present invention also relates to methods for preparing these compounds, pharmaceutical compositions containing them, and their use in treating proliferative disorders such as cancer and other diseases or conditions in which RET kinase activity is implicated. Background of the Invention

[0004] Cancer is caused by uncontrolled and unregulated cell proliferation. Exactly what causes cells to become malignant and to proliferate in an uncontrolled and unregulated manner has been the focus of intense research in recent decades. This research has led to the identification of many molecular targets associated with key metabolic pathways known to be associated with malignancy.

[0005] RET (REarranged during Transfection) is a receptor tyrosine kinase (RTK) that forms part of a macromolecular receptor complex containing a dimerized RET receptor, two co-receptors, and bound ligands. Ligands from the glial-derived neurotrophic factor (GDNF) family bind to RET in association with one of the four glycosylphosphatidylinositol (GPI)-anchored GDNF family alpha receptors (GFRα). Binding of ligands to the corresponding GFRα co-receptors triggers RET dimerization and subsequent transphosphorylation of intracellular signaling cascades. These downstream signaling networks play a key role in regulating cell survival, differentiation, proliferation, migration, and chemotaxis.

[0006] Activating mutations in RET have been identified in familial and sporadic forms of medullary thyroid carcinoma (MTC) (Santoro and Carlomagno 2006; Schulmberger et al. 2008; Wells and Santoro 2009), and these activating mutations are associated with aggressive disease progression (Elisei et al. 2008). Clinical benefits have been observed in MTC patients using vandetanib (Wells et al. 2011), a small molecule VEGFR2 / EGFR inhibitor recently approved by the FDA and EMEA. RET inhibition is a secondary pharmacological effect of this agent, which also targets VEGFR2 (vascular endothelial growth factor receptor, also known as KDR-kinase insert domain receptor) and EGFR (epidermal growth factor receptor). The clinical benefits in the case of MTC are believed to be attributed to RET inhibition, but unfortunately, due to the inhibition of EGFR and / or VEGFR, there are significant side effects (rash, hypertension, diarrhea). In addition, vandetanib also exhibits off-target activity against hERG. Taken together, all of these undesirable pharmacological activities may impair its use in the setting of advanced MTC and may also impair its extrapolation to earlier clinical settings, such as the adjuvant clinical setting.

[0007] In addition, several recent publications (Ju et al., 2012; Lipson et al., 2012; Kohno et al., 2012; Wang et al., 2012; Chao et al., 2012) describe various RET fusion translocations (e.g., KIF5B-RET and CCDC6-RET) present in approximately 1% of NSCLC (non-small cell lung cancer) patient samples, which may provide important alternative disease segments in which specific RET inhibitors would provide clinical benefit.

[0008] Therefore, there is a need to develop more selective RET inhibitors, particularly inhibitors that show less inhibition of KDR. It is expected that these more selective inhibitors will produce the desired therapeutic benefits associated with RET inhibition without the side effects associated with significant KDR inhibition. The inhibitors will provide the potential for better treatment of cancers such as MTC and NSCLC, and will broaden the scope of clinical use of RET inhibitors in early disease settings.

[0009] Therefore, an object of the present invention is to provide further inhibitors of RET kinase enzymatic activity.

[0010] Another object of the present invention is to provide an inhibitor of RET kinase enzymatic activity that exhibits greater selectivity for inhibition of RET kinase relative to inhibition of KDR. Summary of the invention

[0011] According to a first aspect of the present invention, there is provided a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof.

[0012] According to another aspect of the present invention, there is provided a pharmaceutical composition comprising a compound as defined herein or a pharmaceutically acceptable salt, hydrate or solvate thereof in admixture with a pharmaceutically acceptable diluent or carrier.

[0013] According to another aspect of the present invention, there is provided a method for inhibiting RET kinase enzymatic activity in vitro or in vivo, the method comprising contacting a cell with an effective amount of a compound as defined herein or a pharmaceutically acceptable salt, hydrate or solvate thereof.

[0014] According to another aspect of the present invention, there is provided a method for selectively inhibiting RET kinase enzymatic activity over KDR enzymatic activity in vitro or in vivo, the method comprising contacting a cell with an effective amount of a compound as defined herein or a pharmaceutically acceptable salt, hydrate or solvate thereof.

[0015] According to another aspect of the present invention, there is provided a method for inhibiting cell proliferation in vitro or in vivo, the method comprising contacting the cells with an effective amount of a compound as defined herein or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein.

[0016] According to another aspect of the present invention, there is provided a method for treating a disease or condition in which RET kinase activity is involved in a patient in need of 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.

[0017] According to another aspect of the present invention, there is provided a method of treating a proliferative disorder in a patient in need of 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.

[0018] According to another aspect of the present invention, there is provided a method of treating cancer in a patient in need of 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.

[0019] According to another aspect of the present invention there is provided a compound as defined herein or a pharmaceutically acceptable salt, hydrate or solvate thereof or a pharmaceutical composition for use in therapy.

[0020] According to another aspect of the present invention, there is provided a compound as defined herein or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein, for use in treating a proliferative disorder.

[0021] According to another aspect of the present invention, there is provided a compound as defined herein or a pharmaceutically acceptable salt, hydrate or solvate thereof or a pharmaceutical composition for use in treating cancer. In a particular embodiment, the cancer is a human cancer.

[0022] According to another aspect of the present invention, there is provided a compound as defined herein or a pharmaceutically acceptable salt, hydrate or solvate thereof for use in inhibiting RET kinase enzyme activity.

[0023] According to another aspect of the present invention, there is provided a compound as defined herein or a pharmaceutically acceptable salt, hydrate or solvate thereof for selectively inhibiting RET kinase enzymatic activity relative to inhibition of KDR enzymatic activity.

[0024] According to another aspect of the present invention there is provided a compound as defined herein or a pharmaceutically acceptable salt, hydrate or solvate thereof for use in treating a disease or disorder in which RET kinase activity is implicated.

[0025] According to another aspect of the present invention, there is provided the use of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, for the manufacture of a medicament for treating a proliferative disorder.

[0026] Suitably, the proliferative disorder is cancer, suitably a human cancer (eg medullary thyroid carcinoma (MTC)).

[0027] According to another aspect of the present invention, there is provided use of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, for the manufacture of a medicament for treating cancer.

[0028] According to another aspect of the present invention, there is provided use of a compound as defined herein or a pharmaceutically acceptable salt, hydrate or solvate thereof for the manufacture of a medicament for inhibiting RET kinase enzyme activity.

[0029] According to another aspect of the present invention, there is provided use of a compound as defined herein or a pharmaceutically acceptable salt, hydrate or solvate thereof for the manufacture of a medicament for selectively inhibiting RET kinase enzymatic activity relative to inhibition of KDR enzymatic activity.

[0030] According to another aspect of the present invention there is provided the use of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, for the manufacture of a medicament for treating a disease or disorder in which RET kinase activity is implicated.

[0031] According to another aspect of the present invention, there is provided a process for preparing a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof.

[0032] According to another aspect of the present invention there is provided a compound obtainable by, or by, or directly by a process for preparing a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof.

[0033] According to another aspect of the present invention there is provided a novel intermediate as defined herein suitable for use in any one of the synthetic methods described herein.

[0034] Features, including optional, suitable and preferred features, described in relation to one aspect of the present invention may also be features, including optional, suitable and preferred features, described in relation to any other aspect of the present invention. DETAILED DESCRIPTION

[0035] definition

[0036] Unless stated otherwise, the following terms used in the specification and claims have the following meanings set forth below.

[0037] It will be understood that references to "treating" or "treatment" include preventing and treating as well as alleviating established symptoms of a condition. Thus, "treating" a condition, disorder, or condition includes: (1) preventing the clinical symptoms of the condition, disorder, or condition from manifesting in a person who is susceptible to or predisposed to the condition, disorder, or condition but who does not yet experience or display clinical or subclinical symptoms of the condition, disorder, or condition, or delaying the clinical or subclinical symptoms of the condition, disorder, or condition, (2) inhibiting the condition, disorder, or condition, i.e., arresting, reducing, or delaying the development of the disease or its recurrence (in the case of maintenance therapy) or at least one clinical or subclinical symptom thereof, or (3) palliating or attenuating the disease, i.e., causing regression of the condition, disorder, or condition or at least one clinical or subclinical symptom thereof.

[0038] "Therapeutically effective amount" means the amount of a compound that, when administered to a mammal for treating a disease, is sufficient to effect said treatment for said disease. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity, and the age, weight, etc., of the mammal to be treated.

[0039] In this specification, the term "alkyl" includes both straight-chain alkyl and branched-chain alkyl. References to individual alkyl groups such as "propyl" are specific only to the straight-chain form, and references to individual branched-chain alkyl groups such as "isopropyl" are specific only to the branched form. For example, "(1-6C)alkyl" includes (1-4C)alkyl, (1-3C)alkyl, propyl, isopropyl, and tert-butyl. Similar conventions apply to other groups, for example, "phenyl(1-6C)alkyl" includes phenyl(1-4C)alkyl, benzyl, 1-phenylethyl, and 2-phenylethyl.

[0040] The term "(m-nC)" or "(m-nC) group" used alone or as a prefix refers to any group having from m to n carbon atoms.

[0041] "Alkylene", "alkenylene" or "alkynylene" is an alkyl, alkenyl or alkynyl group positioned between and used to connect two other chemical groups. Thus, "(1-6C)alkylene" means a straight chain saturated divalent hydrocarbon group having one to six carbon atoms or a branched chain saturated divalent hydrocarbon group having three to six carbon atoms, such as methylene, ethylene, propylene, 2-methylpropylene, pentylene, etc.

[0042] "(2-6C)alkenylene" means a straight chain divalent hydrocarbon group having two to six carbon atoms or a branched chain divalent hydrocarbon group having three to six carbon atoms containing at least one double bond, for example as in the case of vinylene, 2,4-pentadienylene, and the like.

[0043] "(2-6C)alkynylene" means a straight chain divalent hydrocarbon group having two to six carbon atoms or a branched chain divalent hydrocarbon group having three to six carbon atoms containing at least one triple bond, such as in the case of ethynylene, propynylene, butynylene and the like.

[0044] "(3-8C)cycloalkyl" means a hydrocarbon ring containing 3 to 8 carbon atoms, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or bicyclo[2.2.1]heptyl.

[0045] "(3-8C)cycloalkenyl" means a hydrocarbon ring containing at least one double bond, for example cyclobutenyl, cyclopentenyl, cyclohexenyl or cycloheptenyl, such as 3-cyclohexen-1-yl, or cyclooctenyl.

[0046] "(3-8C)cycloalkyl-(1-6C)alkylene" means a (3-8C)cycloalkyl group covalently linked to a (1-6C)alkylene group, both of which are defined herein.

[0047] The term "halo" or "halogen" refers to fluoro, chloro, bromo and iodo.

[0048] The term "heterocyclyl", "heterocyclic" or "heterocycle" means a non-aromatic saturated or partially saturated monocyclic, fused, bridged or spiro bicyclic heterocyclic ring system. The monocyclic heterocyclic ring contains about 3 to 12 (suitably 3 to 7) ring atoms in the ring, of which 1 to 5 (suitably 1, 2 or 3) heteroatoms are selected from nitrogen, oxygen or sulfur. The bicyclic heterocyclic ring contains 7 to 17 member atoms in the ring, suitably containing 7 to 12 member atoms. The bicyclic heterocyclic ring may be a fused ring system, a spiro ring system or a bridged ring system. Examples of heterocyclic groups include cyclic ethers such as oxirane, oxetane, tetrahydrofuranyl, dioxanyl and substituted cyclic ethers. Nitrogen-containing heterocyclic rings include, for example, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrotriazinyl, tetrahydropyrazolyl, etc. Typical sulfur-containing heterocycles include tetrahydrothienyl, dihydro-1,3-dithiolene, tetrahydro-2H-thiopyran and hexahydrothiocycloheptatriene.Other heterocycles include dihydro-oxathiolene, tetrahydro-oxazolyl, tetrahydro-oxadiazolyl, tetrahydro-dioxazolyl, tetrahydro-oxathiazolyl, hexahydrotriazinyl, tetrahydro-oxazinyl, morpholinyl, thiomorpholinyl, tetrahydropyrimidinyl, dioxadienyl, octahydrobenzofuranyl, octahydrobenzimidazolyl and octahydrobenzothiazolyl.For sulfur-containing heterocycles, also include oxidized sulfur heterocycles containing SO or SO2 groups.Examples include sulfoxide and sulfone forms of tetrahydrothienyl and thiomorpholinyl, such as tetrahydrothiophene 1,1-dioxide and thiomorpholinyl 1,1-dioxide. Suitable meanings of heterocyclyl carrying 1 or 2 oxo (=O) or thio (=S) groups are, for example, 2-oxopyrrolidinyl, 2-thiopyrrolidinyl, 2-oxoimidazolidinyl, 2-thioimidazolidinyl, 2-oxopiperidinyl, 2,5-dioxopyrrolidinyl, 2,5-dioxoimidazolidinyl or 2,6-dioxopiperidinyl. Particular heterocyclyl groups are saturated monocyclic 3- to 7-membered heterocyclyl groups containing 1, 2 or 3 heteroatoms selected from nitrogen, oxygen or sulfur, for example azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, tetrahydrothienyl, tetrahydrothienyl 1,1-dioxide, thiomorpholinyl, thiomorpholinyl 1,1-dioxide, piperidinyl, homopiperidinyl, piperazinyl or homopiperazinyl. As will be appreciated by the skilled person, any heterocycle may be linked to another group via any suitable atom, such as via a carbon or nitrogen atom. However, references herein to piperidino or morpholino refer to the piperidin-1-yl or morpholin-4-yl ring attached through the ring nitrogen.

[0049] By "bridged ring system" is meant a ring system in which two rings have more than two atoms in common, see, e.g., Advanced Organic Chemistry, Jerry March, 4th edition, Wiley Interscience, pp. 131-133, 1992. Examples of bridged heterocyclyl ring systems include aza-bicyclo[2.2.1]heptane, 2-oxa-5-azabicyclo[2.2.1]heptane, aza-bicyclo[2.2.2]octane, aza-bicyclo[3.2.1]octane and quinuclidine.

[0050] By "spiro bicyclic ring system" we mean that the two ring systems share one common spiro carbon atom, i.e. the heterocyclic ring is attached to another carbocyclic ring or heterocyclic ring via a single common spiro carbon atom. Examples of spiro ring 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.

[0051] "Heterocyclyl(1-6C)alkyl" means a heterocyclyl group covalently linked to a (1-6C)alkylene group, both of which are defined herein.

[0052] The term "heteroaryl" or "heteroaromatic" means an aromatic monocyclic, bicyclic or polycyclic ring having 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 species. Examples of heteroaryl are monocyclic and bicyclic groups containing five to twelve ring members, and more generally containing five to ten ring members. Heteroaryl can be, for example, a 5- or 6-membered monocyclic ring or a 9- or 10-membered bicyclic ring, such as a bicyclic structure formed by a fused five-membered ring and a six-membered ring or two fused six-membered rings. Each ring can contain up to about four heteroatoms, which are generally selected from nitrogen, sulfur and oxygen. Typically, the heteroaryl ring will contain up to 3 heteroatoms, more generally up to 2, such as a single heteroatom. In one embodiment, the heteroaryl ring contains at least one ring nitrogen atom. The nitrogen atom in the heteroaryl ring can be basic, such as in the case of imidazole or pyridine, or can be substantially non-basic, such as in the case of indole or pyrrole nitrogen. In general, the number of basic nitrogen atoms present in a heteroaryl group including any amino substituents of the ring will be less than five.

[0053] Examples of heteroaryl groups include furanyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazene, benzofuranyl, indolyl, isoindolyl, benzothiophenyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, benzothiazolyl, indazolyl, purinyl, benzofurazanyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, Cinoline, pteridinyl, naphthyridinyl, carbazolyl, phenazinyl, benzisoquinolinyl, pyridopyrazinyl, thieno[2,3-b]furanyl, 2H-furo[3,2-b]-pyranyl, 5H-pyrido[2,3-d]-oxazinyl, 1H-pyrazolo[4,3-d]-oxazolyl, 4H-imidazo[4,5-d]thiazolyl, pyrazino[2,3-d]pyridazinyl, imidazo[2,1-b]thiazolyl, imidazo[1,2-b][1,2,4]triazinyl. "Heteroaryl" also encompasses partially aromatic bicyclic or polycyclic ring systems in which at least one ring is aromatic 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, tetrahydroisoquinolyl, tetrahydroquinolyl, 2-oxo-1,2,3,4-tetrahydroquinolyl, dihydrobenzothienyl, dihydrobenzofuranyl, 2,3-dihydro-benzo[1,4]dioxinyl, benzo[1,3]dioxolyl, 2,2-dioxo-1,3-dihydro-2-benzothienyl, 4,5,6,7-tetrahydrobenzofuranyl, indolyl, 1,2,3,4-tetrahydro-1,8-naphthyridinyl, 1,2,3,4-tetrahydropyrido[2,3-b]pyrazinyl and 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl.

[0054] Examples of five-membered heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, and tetrazolyl.

[0055] Examples of six-membered heteroaryl groups include, but are not limited to, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, and triazinyl.

[0056] The bicyclic heteroaryl group may be, for example, a group selected from:

[0057] A benzene ring is fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms;

[0058] The pyridine ring is fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms;

[0059] The pyrimidine ring is fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms;

[0060] The pyrrole ring is fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms;

[0061] The pyrazole ring is fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms;

[0062] The pyrazine ring is fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms;

[0063] The imidazole ring is fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms;

[0064] The oxazole ring is fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms;

[0065] The isoxazole ring is fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms;

[0066] The thiazole ring is fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms;

[0067] The isothiazole ring is fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms;

[0068] The thiophene ring is fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms;

[0069] The furan ring is fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms;

[0070] The cyclohexyl ring is fused to a 5- or 6-membered heteroaromatic ring containing 1, 2 or 3 ring heteroatoms;

[0071] as well as

[0072] The cyclopentyl ring is fused to a 5- or 6-membered heteroaromatic ring containing 1, 2 or 3 ring heteroatoms.

[0073] Specific examples of bicyclic heteroaryl groups containing a six-membered ring fused to a five-membered ring include, but are not limited to, benzofuranyl, benzothiophenyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indolizinyl, indolyl, isoindolyl, purinyl (e.g., adeninyl, guaninyl), indazolyl, benzodioxolyl, and pyrazolopyridinyl.

[0074] 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, benzodioxanyl, quinolizinyl, benzoxazinyl, benzodiazinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl, and pteridinyl.

[0075] "Heteroaryl(1-6C)alkyl" means a heteroaryl group covalently linked to a (1-6C)alkylene group, both of which are defined herein. Examples of heteroaralkyl groups include pyridin-3-ylmethyl, 3-(benzofuran-2-yl)propyl, and the like.

[0076] The term "aryl" means a cyclic or polycyclic aromatic ring having 5 to 12 carbon atoms. The term aryl includes both monovalent and divalent species. Examples of aryl include, but are not limited to, phenyl, biphenyl, naphthyl, and the like. In a particular embodiment, aryl is phenyl.

[0077] The term "aryl(1-6C)alkyl" means an aryl group covalently linked to a (1-6C)alkylene group, both of which are defined herein. Examples of aryl-(1-6C)alkyl include benzyl, phenylethyl, and the like.

[0078] This specification also utilizes several composite terms to describe groups that contain more than one functional group. Such terms will be understood by those skilled in the art. For example, heterocyclyl (m-nC) alkyl includes (m-nC) alkyl substituted with a heterocyclyl.

[0079] The term "optionally substituted" refers to groups, structures or molecules that are substituted as well as groups, structures or molecules that are not substituted. 1 "Any CH, CH2, CH3 group or heteroatom (i.e. NH) in the group is optionally substituted" suitably means that R 1 (Any) one hydrogen radical of a group is replaced by the relevant specified group.

[0080] When optional substituents are selected from "one or more" groups, it is understood that this definition includes all substituents selected from one of the specified groups or substituents selected from two or more of the specified groups.

[0081] The phrase "compounds of the invention" refers to those compounds disclosed herein both generically as well as specifically.

[0082] Compounds of the present invention

[0083] In one aspect, the present invention relates to a compound having structural formula (I) shown below or a pharmaceutically acceptable salt, hydrate or solvate thereof:

[0084]

[0085] in:

[0086] HET is selected from one of the following:

[0087]

[0088] in Indicates a connection point;

[0089] R1 is selected from hydrogen, (1-4C)haloalkyl, (1-4C)haloalkoxy or a group having the formula:

[0090] -LYQ

[0091] in:

[0092] L is absent or (1-5C)alkylene optionally substituted by one or more substituents selected from (1-2C)alkyl or oxo;

[0093] Y does not exist, or is O, S, SO, SO2, N(R a ), C(O), C(O)O, OC(O), C(O)N(R a )、N(R a )C(O), N(R a )C(O)N(R b )、N(R a )C(O)O、OC(O)N(R a )、S(O)2N(R a ) or N(R a )SO2, where R a and R b are each independently selected from hydrogen or (1-4C)alkyl; and

[0094] Q is hydrogen, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, aryl, (3-10C)cycloalkyl, (3-10C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Q is optionally further substituted by one or more substituents independently selected from the group consisting of (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, amino, (1-4C)aminoalkyl, cyano, hydroxy, carboxyl, carbamoyl, sulfamoyl, thiol, urea, NR c R d , OR c 、C(O)R c 、C(O)OR c 、OC(O)R c 、C(O)N(R d )R c 、N(R d )C(O)R c 、S(O) y R c (where y is 0, 1 or 2), SO2N(R d )R c 、N(R d )SO2R c、Si(R d )(R c )R e or (CH2) z NR d R c (where z is 1, 2 or 3); where R c , R d and R e are each independently selected from hydrogen, (1-6C)alkyl or (3-6C)cycloalkyl; or R c and R d may be linked so that, together with the nitrogen atom to which they are attached, they form a 4-7 membered heterocyclic ring optionally substituted by one or more substituents selected from the group consisting of (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano or hydroxy; or

[0095] Q is optionally substituted with a group having the formula:

[0096] -L1-L Q1 -Z1

[0097] in:

[0098] L1 is absent or (1-3C)alkylene optionally substituted by one or more substituents selected from (1-2C)alkyl or oxo;

[0099] L Q1 is absent, or is selected from O, S, SO, SO2, N(R f ), C(O), C(O)O, OC(O), C(O)N(R f )、N(R f )C(O), N(R g )C(O)N(R f )、N(R f )C(O)O、OC(O)N(R f )、S(O)2N(R f ) or N(R f )SO2, where R f and R g are each independently selected from hydrogen or (1-2C)alkyl; and

[0100] Z1 is hydrogen, (1-6C)alkyl, aryl, aryl(1-2C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Z1 is optionally substituted by one or more substituents selected from the group consisting of (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano, hydroxy, carboxyl, carbamoyl, sulfamoyl, thiol, ureido, aryl, heteroaryl, heterocyclyl, (3-6C)cycloalkyl, NR h R i , OR h 、C(O)R h 、C(O)OR h 、OC(O)R h 、C(O)N(R i )R h 、N(R i )C(O)R h 、S(O) y R h (where y is 0, 1 or 2), SO2N(R i )R h 、N(R i )SO2R h or (CH2) z NR i R h (where z is 1, 2 or 3); where R h and R i are each independently selected from hydrogen, (1-4C)alkyl or (3-6C)cycloalkyl;

[0101] R 1a and R 1b are each selected from H, (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano, hydroxy, carboxyl, carbamoyl, sulfamoyl or thiol;

[0102] W is selected from O, S or NR 1 , where R 1 Selected from H or (1-2C)alkyl;

[0103] Bonds a, b, c and d are independently selected from single bonds or double bonds;

[0104] X1 and X2 are each independently selected from N or CR when bond a is a double bond j , or when bond a is a single bond, each independently selected from NR k or CR j R k ;

[0105] in

[0106] R j is selected from hydrogen, halo, (1-4C)alkyl, (1-4C)alkoxy, amino, (1-4C)alkylamino, (1-4C)dialkylamino, cyano, (2C)alkynyl, C(O)R j1 、C(O)OR j1 、OC(O)R j1 、C(O)N(R j2 )R j1 、N(R j2 )C(O)R j1 、S(O) y R j1 (where y is 0, 1 or 2), SO2N(R j2 )R j1 、N(R j2 )SO2R j1 or (CH2) z NR j1 R j2 (wherein z is 1, 2 or 3); wherein the (1-4C)alkyl is optionally substituted with one or more substituents selected from the group consisting of amino, hydroxy, (1-2C)alkoxy or halo;

[0107] R k and R j are independently selected from hydrogen or (1-4C)alkyl; and

[0108] R j1 and R j2 are each independently selected from hydrogen or (1-4C)alkyl;

[0109] X3 is selected from N or CR when bond b is a double bond l , or when bond b is a single bond, selected from NR m or CR l R m ;

[0110] in

[0111] R1 is selected from hydrogen, halo, (1-4C)alkyl, (1-4C)alkoxy, amino, (1-4C)alkylamino, (1-4C)dialkylamino, cyano, (2C)alkynyl, C(O)R l1 、C(O)OR l1 、OC(O)R l1 、C(O)N(R l2 )R l1 、N(R l2 )C(O)R l1 、S(O) y Rl1 (where y is 0, 1 or 2), SO2N(R l2 )R l1 、N(R l2 )SO2R l1 or (CH2) z NR l2 R l1 (wherein z is 1, 2 or 3); wherein the (1-4C)alkyl is optionally substituted with one or more substituents selected from the group consisting of amino, hydroxy, (1-2C)alkoxy or halo;

[0112] R l and R m are independently selected from hydrogen or (1-4C)alkyl; and

[0113] R l1 and R l2 are each independently selected from hydrogen or (1-4C)alkyl;

[0114] X4 is selected from N or CR when bond d is a double bond n , or when bond d is a single bond, selected from NR o or CR n R o ;

[0115] in

[0116] R n is selected from hydrogen, halo, (1-4C)alkyl, (1-4C)alkoxy, amino, (1-4C)alkylamino, (1-4C)dialkylamino, cyano, (2C)alkynyl, C(O)R n1 、C(O)OR n1 、OC(O)R n1 、C(O)N(R n2 )R n1 、N(R n2 )C(O)R n1 、S(O) y R n1 (where y is 0, 1 or 2), SO2N(R n2 )R n1 、N(R n2 )SO2R n1 or (CH2) z NR n1 R n2 (wherein z is 1, 2 or 3); wherein the (1-4C)alkyl is optionally substituted with one or more substituents selected from the group consisting of amino, hydroxy, (1-2C)alkoxy or halo;

[0117] R n and R oare independently selected from hydrogen or (1-4C)alkyl; and

[0118] R n1 and R n2 are each independently selected from hydrogen or (1-4C)alkyl;

[0119] R2 is selected from hydrogen, (1-4C)alkyl or a group having the formula:

[0120] -L2-Y2-Q2

[0121] in:

[0122] L2 is absent or (1-3C)alkylene optionally substituted by one or more substituents selected from (1-2C)alkyl or oxo;

[0123] Y2 does not exist, or is C(O), C(O)O, C(O)N(R p ), where R p is selected from hydrogen or (1-4C)alkyl and

[0124] Q2 is hydrogen, (1-6C) alkyl, aryl, (3-8C) cycloalkyl, (3-8C) cycloalkenyl, heteroaryl or heterocyclyl; wherein Q2 is optionally further substituted by one or more substituents independently selected from the group consisting of (1-4C) alkyl, halo, (1-4C) haloalkyl, (1-4C) haloalkoxy, amino, cyano, hydroxy, carboxyl, carbamoyl, sulfamoyl, NR q R r , OR q , where R q and R r are each independently selected from hydrogen, (1-4C)alkyl or (3-6C)cycloalkyl;

[0125] R3 is selected from the group having the following formula:

[0126] -Y3-Q3

[0127] in:

[0128] Y3 is C(O), C(O)N(R s )、N(R s )(O)C、C(O)OR s 、OC(O)CR s , triazole, oxadiazole or tetrazole, wherein R s is selected from hydrogen or (1-2C)alkyl; and

[0129] Q3 is hydrogen, (1-6C)alkyl, (1-6C)alkoxy, aryl, aryl(1-2C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Q3 is optionally further substituted by one or more substituents independently selected from the group consisting of (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, amino, cyano, hydroxy, carboxyl, carbamoyl, sulfamoyl, NR t R u , OR t , where R t and R u are each independently selected from hydrogen, (1-4C)alkyl or (3-6C)cycloalkyl; or Q3 is optionally substituted with a group having the formula:

[0130] -L4-L Q4 -Z4

[0131] in:

[0132] L4 is absent or (1-3C)alkylene optionally substituted by one or more substituents selected from (1-2C)alkyl or oxo;

[0133] L Q4 is absent, or is selected from O, S, SO, SO2, N(R v ), C(O), C(O)O, OC(O), C(O)N(R v )、N(R v )C(O), N(R w )C(O)N(R v )、N(R v )C(O)O、OC(O)N(R v )、S(O)2N(R v ) or N(R v )SO2, where R v and R w are each independently selected from hydrogen or (1-2C)alkyl; and

[0134] Z4 is hydrogen, (1-6C)alkyl, aryl, aryl(1-2C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Z4 is optionally substituted by one or more substituents selected from the group consisting of (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano, hydroxy, carboxyl, carbamoyl, sulfamoyl, thiol, urea, aryl, heteroaryl, heterocyclyl, (3-6C)cycloalkyl, NR x R y , OR x、C(O)R x 、C(O)OR x 、OC(O)R x 、C(O)N(R y )R x 、N(R y )C(O)R x 、S(O) y R x (where y is 0, 1 or 2), SO2N(R y )R x 、N(R y )SO2R x or (CH2) z NR x R y (where z is 1, 2 or 3); where R x and R y are each independently selected from hydrogen, (1-4C)alkyl or (3-6C)cycloalkyl;

[0135] Provided that only one or two of X1, X2, X3 or X4 may be N.

[0136] Specific compounds of the present invention include, for example, compounds of Formula I or pharmaceutically acceptable salts, hydrates and / or solvates thereof, wherein unless otherwise stated, HET, R1, R 1a , R 1b , W, bonds a, b, c and d, X1, X2, X3, X4, R2 and R3 and any associated substituent groups each have any meaning as defined above or in any of paragraphs (1) to (44) below: -

[0137] (1) HET is selected from one of the following:

[0138]

[0139] (2) HET is selected from one of the following:

[0140]

[0141] (3) HET is:

[0142]

[0143] (4) R1 is selected from hydrogen, (1-4C)haloalkyl, (1-4C)haloalkoxy or a group having the following formula:

[0144] -LYQ

[0145] in:

[0146] L is absent or (1-5C)alkylene optionally substituted by one or more substituents selected from (1-2C)alkyl or oxo;

[0147] Y does not exist, or is O, S, SO, SO2, N(R a ), C(O), C(O)O, OC(O), C(O)N(R a )、N(R a )C(O), S(O)2N(R a ) or N(R a )SO2, where R a and R b are each independently selected from hydrogen or (1-4C)alkyl; and

[0148] Q is hydrogen, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, aryl, (3-10C)cycloalkyl, (3-10C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Q is optionally further substituted by one or more substituents independently selected from the group consisting of (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, amino, (1-4C)aminoalkyl, cyano, hydroxy, carboxyl, carbamoyl, sulfamoyl, thiol, urea, NR c R d , OR c 、C(O)R c 、C(O)OR c 、OC(O)R c 、C(O)N(R d )R c 、N(R d )C(O)R c 、S(O) y R c (where y is 0, 1 or 2), SO2N(R d )R c 、N(R d )SO2R c 、Si(R d )(R c )R e or (CH2) z NR d R c (where z is 1, 2 or 3); where R c , R d and R e are each independently selected from hydrogen, (1-6C)alkyl or (3-6C)cycloalkyl; or R c and R dmay be linked so that, together with the nitrogen atom to which they are attached, they form a 4-7 membered heterocyclic ring optionally substituted by one or more substituents selected from the group consisting of (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano or hydroxy; or

[0149] Q is optionally substituted with a group having the formula:

[0150] -L1-L Q1 -Z1

[0151] in:

[0152] L1 is absent or (1-3C)alkylene optionally substituted by one or more substituents selected from (1-2C)alkyl;

[0153] L Q1 is absent, or is selected from O, S, SO, SO2, N(R f ), C(O), C(O)O, OC(O), C(O)N(R f )、N(R f )C(O), N(R f )C(O)O、S(O)2N(R f ) or N(R f )SO2, where R f and R g are each independently selected from hydrogen or (1-2C)alkyl; and

[0154] Z1 is hydrogen, (1-6C)alkyl, aryl, aryl(1-2C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Z1 is optionally substituted by one or more substituents selected from the group consisting of (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano, hydroxy, carboxyl, carbamoyl, sulfamoyl, thiol, ureido, aryl, heteroaryl, heterocyclyl, (3-6C)cycloalkyl, NR h R i OR h , where R h and R i are each independently selected from hydrogen, (1-4C)alkyl or (3-6C)cycloalkyl;

[0155] (5) R1 is selected from hydrogen, (1-4C)haloalkyl, (1-4C)haloalkoxy or a group having the following formula:

[0156] -LYQ

[0157] in:

[0158] L is absent or (1-3C)alkylene optionally substituted by one or more substituents selected from (1-2C)alkyl or oxo;

[0159] Y does not exist, or is O, N (R a ), C(O), C(O)O, OC(O), C(O)N(R a )、N(R a )C(O), S(O)2N(R a ) or N(R a )SO2, where R a and R b are each independently selected from hydrogen or (1-4C)alkyl and

[0160] Q is hydrogen, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, aryl, (3-10C)cycloalkyl, (3-10C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Q is optionally further substituted by one or more substituents independently selected from the group consisting of (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, amino, (1-4C)aminoalkyl, cyano, hydroxy, carboxyl, carbamoyl, sulfamoyl, thiol, urea, NR c R d , OR c 、C(O)R c 、C(O)OR c 、OC(O)R c 、C(O)N(R d )R c 、N(R d )C(O)R c 、S(O) y R c (where y is 0, 1 or 2), SO2N(R d )R c 、N(R d )SO2R c 、Si(R d )(R c )R e or (CH2) z NR d R c (where z is 1, 2 or 3); where R c , R d and R e are each independently selected from hydrogen, (1-6C)alkyl or (3-6C)cycloalkyl; or R c and R dmay be linked so that, together with the nitrogen atom to which they are attached, they form a 4-7 membered heterocyclic ring optionally substituted by one or more substituents selected from the group consisting of (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano or hydroxy; or

[0161] Q is optionally substituted with a group having the formula:

[0162] -L1-L Q1 -Z1

[0163] in:

[0164] L1 is absent or (1-3C)alkylene optionally substituted by one or more substituents selected from (1-2C)alkyl;

[0165] L Q1 is not present, or is selected from or is N(R f ), C(O), C(O)O, OC(O), C(O)N(R f )、N(R f )C(O) or N(R f )C(O)O, where R f and R g are each independently selected from hydrogen or (1-2C)alkyl; and

[0166] Z1 is hydrogen, (1-6C)alkyl, aryl, aryl(1-2C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Z1 is optionally substituted by one or more substituents selected from the group consisting of (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano, hydroxy, (3-6C)cycloalkyl, NR h R i OR h , where R h and R i Each is independently selected from hydrogen, (1-4C)alkyl or cycloalkyl; (6) R1 is selected from hydrogen, (1-4C)haloalkyl, (1-4C)haloalkoxy or a group having the following formula:

[0167] -LYQ

[0168] in:

[0169] L is absent or (1-3C)alkylene optionally substituted by one or more substituents selected from (1-2C)alkyl or oxo;

[0170] Y does not exist, or is O, N (R a ), C(O), C(O)O, OC(O), C(O)N(R a )、N(R a )C(O), S(O)2N(R a ) or N(R a )SO2, where R a and R b are each independently selected from hydrogen or (1-4C)alkyl and

[0171] Q is hydrogen, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, aryl, (3-10C)cycloalkyl, (3-10C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Q is optionally further substituted by one or more substituents independently selected from the group consisting of (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, amino, (1-4C)aminoalkyl, cyano, hydroxy, carboxyl, carbamoyl, sulfamoyl, thiol, urea, NR c R d , OR c 、C(O)R c 、C(O)OR c 、OC(O)R c 、C(O)N(R d )R c 、N(R d )C(O)R c 、S(O) y R c (where y is 0, 1 or 2), SO2N(R d )R c 、N(R d )SO2R c 、Si(R d )(R c )R e or (CH2) z NR d R c (where z is 1, 2 or 3); where R c , R d and R e are each independently selected from hydrogen, (1-6C)alkyl or (3-6C)cycloalkyl; or R c and R d may be linked so that, together with the nitrogen atom to which they are attached, they form a 4-7 membered heterocyclic ring optionally substituted by one or more substituents selected from the group consisting of (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano or hydroxy;

[0172] (7) R1 is selected from hydrogen, (1-4C)haloalkyl, (1-4C)haloalkoxy or a group having the following formula:

[0173] -LYQ

[0174] in:

[0175] L is absent or (1-3C)alkylene optionally substituted by one or more substituents selected from (1-2C)alkyl or oxo;

[0176] Y does not exist, or is C(O), C(O)O, OC(O), C(O)N(R a ) or N(R a )C(O), where R a and R b are each independently selected from hydrogen or (1-4C)alkyl; and

[0177] Q is hydrogen, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, aryl, (3-10C)cycloalkyl, (3-10C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Q is optionally further substituted by one or more substituents independently selected from the group consisting of (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, amino, (1-4C)aminoalkyl, cyano, hydroxy, carboxyl, carbamoyl, sulfamoyl, thiol, urea, NR c R d , OR c 、C(O)R c 、C(O)OR c 、OC(O)R c 、C(O)N(R d )R c 、N(R d )C(O)R c 、S(O) y R c (where y is 0, 1 or 2), SO2N(R d )R c 、N(R d )SO2R c 、Si(R d )(R c )R e or (CH2) z NR d R c (where z is 1, 2 or 3); where R c , R d and R eare each independently selected from hydrogen, (1-6C)alkyl or (3-6C)cycloalkyl;

[0178] (8) R1 is selected from hydrogen, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, aryl, (3-10C)cycloalkyl, (3-10C)cycloalkenyl, heteroaryl or heterocyclyl; wherein each of the substituents is optionally further substituted by one or more substituents independently selected from the following: (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, amino, (1-4C)aminoalkyl, cyano, hydroxy, carboxyl, carbamoyl, sulfamoyl, thiol, urea, NR c R d , OR c 、C(O)R c 、C(O)OR c 、OC(O)R c 、C(O)N(R d )R c 、N(R d )C(O)R c 、S(O) y R c (where y is 0, 1 or 2), SO2N(R d )R c 、N(R d )SO2R c 、Si(R d )(R c )R e or (CH2) z NR d R c (where z is 1, 2 or 3); where R c , R d and R e are each independently selected from hydrogen, (1-6C)alkyl or (3-6C)cycloalkyl;

[0179] (9) R1 is selected from hydrogen, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-6C)alkyl, (3-10C)cycloalkyl or heterocyclyl; wherein each of the substituents is optionally further substituted by one or more substituents independently selected from the following: (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, amino, (1-4C)aminoalkyl, cyano, hydroxy, carboxyl, carbamoyl, sulfamoyl, mercapto, urea, NR c R d , OR c or Si(R d )(R c )Re ; where R c , R d and R e are each independently selected from hydrogen or (1-6C)alkyl;

[0180] (10) R1 is selected from hydrogen, (1-6C) alkyl or (3-10C) cycloalkyl; wherein each of the substituents is optionally further substituted by one or more substituents independently selected from the group consisting of (1-4C) alkyl, halo, amino, (1-4C) aminoalkyl, cyano, hydroxy, carboxyl, NR c R d , OR c or Si(R d )(R c )R e ; where R c , R d and R e are each independently selected from hydrogen or (1-4C)alkyl;

[0181] (11) R1 is selected from hydrogen, (1-6C)alkyl or (3-6C)cycloalkyl; wherein each of the substituents is optionally further substituted by one or more substituents independently selected from the following: (1-4C)alkyl, OR c or Si(R d )(R c )R e ; where R c , R d and R e are each independently selected from hydrogen or (1-2C)alkyl;

[0182] (12) R1 is tert-butyl;

[0183] (13)R 1a and R 1b are each selected from H, (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano or hydroxy;

[0184] (14)R 1a and R 1b are each selected from H, (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)alkoxy, amino, cyano or hydroxy;

[0185] (15)R 1a and R 1b are each selected from H or (1-4C)alkyl;

[0186] (16)R 1a and R 1b Each is H;

[0187] (17) W is selected from O or S;

[0188] (18)W is O;

[0189] (19) Bonds a, b, c, and d are all double bonds;

[0190] (20) Bonds a, b, c, and d are all single bonds;

[0191] (21) X1 and X2 are each independently selected from N or CR when bond a is a double bond j , or when bond a is a single bond, each independently selected from NR k or CR j R k ;

[0192] in

[0193] R j is selected from hydrogen, halo, (1-4C)alkyl, (1-4C)alkoxy, amino, (1-4C)alkylamino, (1-4C)dialkylamino, cyano, (2C)alkynyl, wherein the (1-4C)alkyl is optionally substituted with one or more substituents selected from amino, hydroxy, (1-2C)alkoxy or halo;

[0194] R k and R j independently selected from hydrogen or (1-4C)alkyl;

[0195] (22) X1 and X2 are each independently selected from N or CR when bond a is a double bond j , or when bond a is a single bond, each independently selected from NR k or CR j R k ;

[0196] in

[0197] R j is selected from hydrogen, halo, (1-4C)alkyl, (1-4C)alkoxy, amino, (1-4C)alkylamino, (1-4C)dialkylamino, cyano, (2C)alkynyl; and

[0198] R k and R j independently selected from hydrogen or (1-4C)alkyl;

[0199] (23) X1 and X2 are each independently selected from N or CR j , and bond a is a double bond, where R j is selected from hydrogen, halo, (1-4C)alkyl or amino;

[0200] (24) X1 and X2 are CRj, and bond a is a double bond, wherein R j is selected from hydrogen, halo or (1-4C)alkyl;

[0201] (25) X1 and X2 are CH, and bond a is a double bond;

[0202] (26) X3 is selected from N or CR when bond b is a double bond l , or when bond b is a single bond, selected from NR m or CR l R m ;

[0203] in

[0204] R l is selected from hydrogen, halo, (1-4C)alkyl, (1-4C)alkoxy, amino, (1-4C)alkylamino, (1-4C)dialkylamino, cyano, (2C)alkynyl, wherein the (1-4C)alkyl is optionally substituted with one or more substituents selected from amino, hydroxy, (1-2C)alkoxy or halo; and

[0205] R l and R m independently selected from hydrogen or (1-4C)alkyl;

[0206] (27) X3 is selected from N or CR when bond b is a double bond l , or when bond b is a single bond, selected from NR m or CR l R m ;

[0207] in

[0208] R l is selected from hydrogen, halo, (1-4C)alkyl, (1-4C)alkoxy, amino, (1-4C)alkylamino, (1-4C)dialkylamino, cyano, (2C)alkynyl; and

[0209] R l and R m independently selected from hydrogen or (1-4C)alkyl;

[0210] (28) X3 is selected from N or CR l , and bond b is a double bond, where R l is selected from hydrogen, halo, (1-4C)alkyl or amino;

[0211] (29) X3 is CR l , and bond b is a double bond, where R l is selected from hydrogen, halo, (1-4C)alkyl or amino;

[0212] (30) X3 is CH, and bond b is a double bond;

[0213] (31) X4 is selected from N or CR when bond d is a double bond n , or when bond d is a single bond, selected from NR o or CR n R o ;

[0214] in

[0215] R n is selected from hydrogen, halo, (1-4C)alkyl, (1-4C)alkoxy, amino, (1-4C)alkylamino, (1-4C)dialkylamino, cyano, (2C)alkynyl, wherein the (1-4C)alkyl is optionally substituted with one or more substituents selected from amino, hydroxy, (1-2C)alkoxy or halo;

[0216] R n and R o are independently selected from hydrogen or (1-4C)alkyl; and

[0217] (32) X4 is selected from N or CR when bond d is a double bond n , or when bond d is a single bond, selected from NR o or CR n R o ;

[0218] in

[0219] R n is selected from hydrogen, halo, (1-4C)alkyl, (1-4C)alkoxy, amino, (1-4C)alkylamino, (1-4C)dialkylamino, cyano, (2C)alkynyl; and

[0220] R n and R o independently selected from hydrogen or (1-4C)alkyl;

[0221] (33) X4 is selected from N or CR n , and bond d is a double bond, where R n is selected from hydrogen, halo, (1-4C)alkyl, (1-4C)alkoxy, amino, (1-4C)alkylamino, (1-4C)dialkylamino or cyano, (2C)alkynyl;

[0222] (34)X4 is CR n , and bond d is a double bond, where R n is selected from hydrogen, halo, (1-4C)alkyl or amino;

[0223] (35) R2 is selected from hydrogen, (1-4C)alkyl or a group having the following formula:

[0224] -L2-Y2-Q2

[0225] in:

[0226] L2 is absent or (1-3C)alkylene optionally substituted by one or more substituents selected from (1-2C)alkyl or oxo;

[0227] Y2 does not exist, or is C(O), C(O)O, C(O)N(R p ), where R p is selected from hydrogen or (1-4C)alkyl; and

[0228] Q2 is hydrogen, (1-6C)alkyl, aryl, (3-8C)cycloalkyl, heteroaryl or heterocyclyl; wherein Q2 is optionally further substituted by one or more substituents independently selected from the group consisting of (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, amino, cyano, hydroxy, NR q R r , OR q , where R q and R r are each independently selected from hydrogen or (1-4C)alkyl;

[0229] (36) R2 is selected from hydrogen, (1-4C)alkyl or a group having the following formula:

[0230] -Y2-Q2

[0231] in:

[0232] Y2 does not exist, or is C(O), C(O)O, C(O)N(R p ), where R p is selected from hydrogen or (1-4C)alkyl; and

[0233] Q2 is hydrogen, (1-6C)alkyl, aryl, (3-8C)cycloalkyl, heteroaryl or heterocyclyl; wherein Q2 is optionally further substituted by one or more substituents independently selected from the group consisting of (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, amino, cyano, hydroxy, NR q R r , OR q , where R q and R r are each independently selected from hydrogen or (1-4C)alkyl;

[0234] (37) R2 is selected from hydrogen, (1-4C)alkyl or a group having the following formula:

[0235] -Y2-Q2

[0236] in:

[0237] Y2 is C(O)N(R p ), where R p is selected from hydrogen or (1-4C)alkyl; and

[0238] Q2 is (1-6C)alkyl, aryl, (3-8C)cycloalkyl, heteroaryl or heterocyclyl; wherein Q2 is optionally further substituted by one or more substituents independently selected from the group consisting of (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, amino, cyano or hydroxy;

[0239] (38) R2 is selected from hydrogen or (1-4C)alkyl;

[0240] (39) R2 is hydrogen;

[0241] (40) R3 is selected from the group having the following formula:

[0242] -Y3-Q3

[0243] in:

[0244] Y3 is C(O), C(O)N(R s )、N(R s )(O)C、C(O)OR s 、OC(O)CR s , where R s is selected from hydrogen or (1-2C)alkyl; and

[0245] Q3 is hydrogen, (1-6C)alkyl, (1-6C)alkoxy, aryl, aryl(1-2C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Q3 is optionally further substituted by one or more substituents independently selected from the group consisting of (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, amino, cyano, hydroxy, carboxyl, carbamoyl, sulfamoyl, NR t R u , OR t , where R t and R u are each independently selected from hydrogen, (1-4C)alkyl or (3-6C)cycloalkyl; or Q3 is optionally substituted with a group having the formula:

[0246] -L4-LQ4-Z4

[0247] in:

[0248] L4 is absent or (1-3C)alkylene optionally substituted by one or more substituents selected from (1-2C)alkyl or oxo;

[0249] L Q4 is non-existent, or is selected from O, N(R v ), C(O), C(O)O, OC(O), C(O)N(R v )、N(R v )C(O), S(O)2N(R v ) or N(R v )SO2, where R v and R w are each independently selected from hydrogen or (1-2C)alkyl; and

[0250] Z4 is hydrogen, (1-6C)alkyl, aryl, aryl(1-2C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Z4 is optionally substituted by one or more substituents selected from the group consisting of (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano, hydroxy, carboxyl, carbamoyl, sulfamoyl, thiol, urea, aryl, heteroaryl, heterocyclyl, (3-6C)cycloalkyl, NR x R y , OR x 、C(O)R x 、C(O)OR x 、OC(O)R x 、C(O)N(R y )R x 、N(R y )C(O)R x 、S(O) y R x (where y is 0, 1 or 2), SO2N(R y )R x 、N(R y )SO2R x or (CH2) z NR x R y (where z is 1, 2 or 3); where R x and R y are each independently selected from hydrogen, (1-4C)alkyl or (3-6C)cycloalkyl;

[0251] (41) R3 is selected from the group having the following formula:

[0252] -Y3-Q3

[0253] in:

[0254] Y3 is C(O)N(R s ), where R s is selected from hydrogen or (1-2C)alkyl; and

[0255] Q3 is hydrogen, (1-6C)alkyl, (1-6C)alkoxy, aryl, aryl(1-2C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Q3 is optionally further substituted by one or more substituents independently selected from the group consisting of (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, amino, cyano, hydroxy, carboxyl, carbamoyl, sulfamoyl, NR t R u , OR t , where R t and R u are each independently selected from hydrogen, (1-4C)alkyl or (3-6C)cycloalkyl; or Q3 is optionally substituted with a group having the formula:

[0256] -L4-L Q4 -Z4

[0257] in:

[0258] L4 is absent or (1-3C)alkylene optionally substituted by one or more substituents selected from (1-2C)alkyl or oxo;

[0259] L Q4 is absent, or is selected from O, S, SO, SO2, N(R v ), C(O), C(O)O, OC(O), C(O)N(R v )、N(R v )C(O), N(R w )C(O)N(R v )、N(R v )C(O)O、OC(O)N(R v )、S(O)2N(R v ) or N(R v )SO2, where R v and R w are each independently selected from hydrogen or (1-2C)alkyl; and

[0260] Z4 is hydrogen, (1-6C)alkyl, aryl, aryl(1-2C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Z4 is optionally substituted by one or more substituents selected from the group consisting of (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano, hydroxy, carboxyl, carbamoyl, sulfamoyl, thiol, urea, aryl, heteroaryl, heterocyclyl, (3-6C)cycloalkyl, NR x R y , OR x 、C(O)R x 、C(O)OR x 、OC(O)R x 、C(O)N(R y )R x 、N(R y )C(O)R x 、S(O) y R x (where y is 0, 1 or 2), SO2N(R y )R x 、N(R y )SO2R x or (CH2) z NR x R y (where z is 1, 2 or 3); where R x and R y are each independently selected from hydrogen, (1-4C)alkyl or (3-6C)cycloalkyl;

[0261] (42) R3 is selected from the group having the following formula:

[0262] -Y3-Q3

[0263] in:

[0264] Y3 is C(O)NH; and

[0265] Q3 is hydrogen, (1-6C)alkyl, (1-6C)alkoxy, aryl, aryl(1-2C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Q3 is optionally further substituted by one or more substituents independently selected from the group consisting of (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, amino, cyano, hydroxy, carboxyl, carbamoyl, sulfamoyl, NR t R u , OR t , where R t and R uare each independently selected from hydrogen, (1-4C)alkyl or (3-6C)cycloalkyl; or Q3 is optionally substituted with a group having the formula:

[0266] -L4-LQ4-Z4

[0267] in:

[0268] L4 is absent or (1-3C)alkylene optionally substituted by one or more substituents selected from (1-2C)alkyl or oxo;

[0269] L Q4 is non-existent, or is selected from O, N(R v ), C(O), C(O)O, OC(O), C(O)N(R v )、N(R v )C(O), S(O)2N(R v ) or N(R v )SO2, where R v and R w are each independently selected from hydrogen or (1-2C)alkyl; and

[0270] Z4 is hydrogen, (1-6C)alkyl, aryl, aryl(1-2C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Z4 is optionally substituted by one or more substituents selected from the group consisting of (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano, hydroxy, carboxyl, carbamoyl, sulfamoyl, thiol, urea, aryl, heteroaryl, heterocyclyl, (3-6C)cycloalkyl, NR x R y , OR x ; where R x and R y are each independently selected from hydrogen or (1-4C)alkyl;

[0271] (43) R3 is selected from the group having the following formula:

[0272] -Y3-Q3

[0273] in:

[0274] Y3 is C(O)NH; and

[0275] Q3 is hydrogen, (1-6C)alkyl, (1-6C)alkoxy, aryl, aryl(1-2C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Q3 is optionally further substituted by one or more substituents independently selected from the group consisting of (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, amino, cyano, hydroxy, carboxyl, carbamoyl, sulfamoyl, NR t R u , OR r , where R t and R u are each independently selected from hydrogen, (1-4C)alkyl or (3-6C)cycloalkyl; or Q3 is optionally substituted with a group having the formula:

[0276] -L4-L Q4 -Z4

[0277] in:

[0278] L4 is absent or (1-3C)alkylene optionally substituted by one or more substituents selected from (1-2C)alkyl;

[0279] L Q4 is non-existent, or is selected from O, N(R v ), where R v is selected from hydrogen or (1-2C)alkyl; and

[0280] Z4 is hydrogen, (1-6C) alkyl, (3-8C) cycloalkyl; wherein Z4 is optionally substituted by one or more substituents selected from the group consisting of (1-4C) alkyl, halo, (1-4C) haloalkyl, (1-4C) haloalkoxy, (1-4C) alkoxy, (1-4C) alkylamino, amino, cyano, hydroxy, (3-6C) cycloalkyl, NR x R y , OR x ; where R x and R y are each independently selected from hydrogen or (1-4C)alkyl;

[0281] (44) R3 is selected from the group having the following formula:

[0282] -Y3-Q3

[0283] in:

[0284] Y3 is C(O)NH; and

[0285] Q3 is hydrogen, (1-6C)alkyl, (1-6C)alkoxy, aryl, aryl(1-2C)alkyl, (3-8C)cycloalkyl, heteroaryl or heterocyclyl; wherein Q3 is optionally further substituted by one or more substituents independently selected from the group consisting of (1-4C)alkyl, halo, (1-4C)haloalkyl, amino, cyano, hydroxy, NR t R u , OR t , where R t and R u are each independently selected from hydrogen or (1-4C)alkyl; or Q3 is optionally substituted with a group having the formula:

[0286] -L4-L Q4 -Z4

[0287] in:

[0288] L4 is absent or is (1-2C)alkylene;

[0289] L Q4 is non-existent, or is selected from or is O; and

[0290] Z4 is hydrogen, (1-6C) alkyl, (3-8C) cycloalkyl; wherein Z4 is optionally substituted by one or more substituents selected from the group consisting of (1-4C) alkyl, halo, (1-4C) haloalkyl, (1-4C) alkoxy, amino, hydroxy, (3-6C) cycloalkyl, NR x R y , OR x ; where R x and R y Each is independently selected from hydrogen or (1-4C)alkyl.

[0291] Suitably, the heteroaryl or heterocyclyl as defined herein is a monocyclic heteroaryl or heterocyclyl comprising one, two or three heteroatoms selected from N, O or S.

[0292] Suitably, the heteroaryl group is a 5 or 6 membered heteroaryl ring comprising one, two or three heteroatoms selected from N, O or S.

[0293] Suitably, the heterocyclyl group is a 4, 5 or 6 membered heterocyclyl ring comprising one, two or three heteroatoms selected from N, O or S. Most suitably, the heterocyclyl group is a 5, 6 or 7 membered ring comprising one, two or three heteroatoms selected from N, O or S [e.g. morpholinyl (e.g. 4-morpholinyl), pyridinyl, piperazinyl, homopiperazinyl or pyrrolidonyl].

[0294] Suitably, aryl is phenyl.

[0295] Suitably, HET is as defined in any one of paragraphs (1) to (3). Most preferably, HET is as defined in paragraph (3).

[0296] Suitably, R1 is as defined in any one of paragraphs (4) to (12). More suitably, R1 is as defined in any one of paragraphs (8) to (12). Most suitably, R1 is as defined in paragraph (12).

[0297] Suitably, R 1a and R 1b As defined in any of paragraphs (13) to (16). Most preferably, R 1a and R 1b As defined in paragraph (16).

[0298] Suitably, W is as defined in any one of paragraphs (17) to (18). Most preferably, W is as defined in paragraph (18).

[0299] Suitably, bonds a, b, c and d are as defined in any one of paragraphs (19) to (20). Suitably, bonds a, b, c and d are as defined in paragraph (19).

[0300] Suitably, X1 and X2 are as defined in any one of paragraphs (21) to (25). Most preferably, X1 and X2 are as defined in paragraph (25).

[0301] Suitably, X3 is as defined in any one of paragraphs (26) to (30). Most preferably, X3 is as defined in paragraph (30).

[0302] Suitably, X4 is as defined in any one of paragraphs (31) to (34). Most preferably, X4 is as defined in paragraph (34).

[0303] Suitably, R2 is as defined in any one of paragraphs (35) to (39). More suitably, R2 is as defined in any one of paragraphs (37) to (39). Most suitably, R2 is as defined in paragraph (39).

[0304] Suitably, R3 is as defined in any one of paragraphs (40) to (44). Most preferably, R3 is as defined in paragraph (44).

[0305] In a specific group of compounds of the present invention, the compound has the structural formula Ia (subdefinition of formula (I)) shown below or a pharmaceutically acceptable salt, hydrate and / or solvate thereof:

[0306]

[0307] Among them, HET, R1, R 1a, R 1b , keys a, b, c and d, X1, X2, X3, X4, R2, Q3 and R s Each has any meaning as defined herein.

[0308] In one embodiment of the compound of formula Ia:

[0309] HET is as defined in any of paragraphs (1) to (3) above;

[0310] R1 is as defined in any of the above paragraphs (4) to (12);

[0311] R 1a and R 1b As defined in any of paragraphs (13) to (16) above;

[0312] Bonds a, b, c and d are as defined in any of paragraphs (19) to (20) above;

[0313] X1 and X2 are as defined in any of paragraphs (21) to (25) above;

[0314] X3 is as defined in any of the above paragraphs (26) to (30);

[0315] X4 is as defined in any of the above paragraphs (31) to (34);

[0316] R2 is as defined in any of the above paragraphs (35) to (39);

[0317] R s As defined in any of paragraphs (40) to (41) above; and

[0318] Q3 is as defined in any of paragraphs (40) to (44).

[0319] In another embodiment of the compounds of Formula Ia:

[0320] HET is as defined in paragraph (3) above;

[0321] R1 is as defined in paragraph (12) above;

[0322] R 1a and R 1b As defined in paragraph (16) above;

[0323] Bonds a, b, c and d are as defined in paragraph (20) above;

[0324] X1 and X2 are as defined in paragraph (25) above;

[0325] X3 is as defined in paragraph (30) above;

[0326] X4 is as defined in paragraph (34) above;

[0327] R2 is as defined in paragraph (39) above; and

[0328] R3 is as defined in paragraph (44) above.

[0329] In a specific group of compounds of the present invention, the compound has the structural formula Ib (subdefinition of formula (I)) shown below or a pharmaceutically acceptable salt, hydrate and / or solvate thereof:

[0330]

[0331] Where R1, bonds a, b, c and d, X1, X2, X3, X4, R2, Q3 and R s Each has any meaning as defined herein.

[0332] In one embodiment of the compound of formula Ib:

[0333] R1 is as defined in any of the above paragraphs (4) to (12);

[0334] Bonds a, b, c and d are as defined in any of paragraphs (19) to (20) above;

[0335] X1 and X2 are as defined in any of paragraphs (21) to (25) above;

[0336] X3 is as defined in any of the above paragraphs (26) to (30);

[0337] X4 is as defined in any of the above paragraphs (31) to (34);

[0338] R2 is as defined in any of paragraphs (35) to (39) above; and

[0339] R s As defined in any of paragraphs (40) to (41) above;

[0340] Q3 is as defined in any of paragraphs (40) to (44).

[0341] In another embodiment of the compound of Formula Ib:

[0342] R1 is as defined in paragraph (12) above;

[0343] Bonds a, b, c and d are as defined in paragraph (20) above;

[0344] X1 and X2 are as defined in paragraph (25) above;

[0345] X3 is as defined in paragraph (30) above;

[0346] X4 is as defined in paragraph (34) above;

[0347] R2 is as defined in paragraph (39) above;

[0348] R s as defined in paragraph (41) above; and

[0349] Q3 is as defined in paragraph (44) above.

[0350] In a specific group of compounds of the present invention, the compound has the structural formula Ic (subdefinition of formula (I)) shown below or a pharmaceutically acceptable salt, hydrate and / or solvate thereof:

[0351]

[0352] Among them, R1, X1, X2, X3, X4, R2, Q3 and R s Each has any meaning as defined herein.

[0353] In one embodiment of the compound of formula Ic:

[0354] R1 is as defined in any of the above paragraphs (4) to (12);

[0355] X1 and X2 are as defined in any of paragraphs (23) to (25) above;

[0356] X3 is as defined in any of the above paragraphs (28) to (30);

[0357] X4 is as defined in any of the above paragraphs (33) to (34);

[0358] R2 is as defined in any of the above paragraphs (35) to (39);

[0359] R s As defined in any of paragraphs (40) to (41) above; and

[0360] Q3 is as defined in any of paragraphs (40) to (44).

[0361] In another embodiment of the compound of Formula Ic:

[0362] R1 is as defined in paragraph (12) above;

[0363] X1 and X2 are as defined in paragraph (25) above;

[0364] X3 is as defined in paragraph (30) above;

[0365] X4 is as defined in paragraph (34) above;

[0366] R2 is as defined in paragraph (39) above;

[0367] R s as defined in paragraph (41) above; and

[0368] Q3 is as defined in paragraph (44) above.

[0369] In a specific group of compounds of the present invention, the compound has the structural formula Id (subdefinition of formula (I)) shown below or a pharmaceutically acceptable salt, hydrate and / or solvate thereof:

[0370]

[0371] wherein R1, X4, R2 and Q3 each have any meaning as defined herein.

[0372] In one embodiment of the compound of formula Id:

[0373] R1 is as defined in any of the above paragraphs (4) to (12);

[0374] X4 is as defined in any of the above paragraphs (33) to (34);

[0375] R2 is as defined in any of paragraphs (35) to (39) above; and

[0376] Q3 is as defined in any of paragraphs (40) to (44) above.

[0377] In another embodiment of the compound of Formula Id:

[0378] R1 is as defined in paragraph (12) above;

[0379] X4 is as defined in paragraph (34) above;

[0380] R2 is as defined in paragraph (39) above; and

[0381] Q3 is as defined in paragraph (44) above.

[0382] Specific compounds of the present invention include any compound exemplified in the present application or a pharmaceutically acceptable salt or solvate thereof, and specifically include any of the following:

[0383] 6-(4-amino-1-cyclopropyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-methyl-1H-indole-2-carboxamide;

[0384] 6-(4-amino-1-ethyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-methyl-1H-indole-2-carboxamide;

[0385] 6-(4-amino-1-isopropyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-methyl-1H-indole-2-carboxamide;

[0386] 6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(2,5-dimethylpyrazol-3-yl)-1H-indole-2-carboxamide;

[0387] 6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N,3-dimethyl-1H-indole-2-carboxamide;

[0388] 6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-3-fluoro-N-methyl-1H-indole-2-carboxamide;

[0389] 6-(4-amino-1-(tert-butyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-1H-indole-2-carboxamide;

[0390] 6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-cyclobutyl-1H-indole-2-carboxamide;

[0391] 6-(4-amino-1-(tert-butyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-ethyl-1H-indole-2-carboxamide;

[0392] 6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-cyclopropyl-1H-indole-2-carboxamide;

[0393] 6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-methyl-1H-indole-2-carboxamide;

[0394] 6-(4-amino-1-isopropyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(1,3,4-thiadiazol-2-yl)-1H-indole-2-carboxamide;

[0395] 6-(4-amino-1-isopropyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(1-methylpyrazol-3-yl)-1H-indole-2-carboxamide;

[0396] 6-(4-amino-1-isopropyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-thiazol-2-yl-1H-indole-2-carboxamide;

[0397] 6-(4-amino-1-isopropyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-ethoxy-1H-indole-2-carboxamide;

[0398] 6-(4-amino-1-isopropyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(2-fluoroethyl)-1H-indole-2-carboxamide;

[0399] 6-(4-amino-1-isopropyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-cyclopropyl-1H-indole-2-carboxamide;

[0400] 6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-3-chloro-N-methyl-1H-indole-2-carboxamide;

[0401] 6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-[1-(2-hydroxyethyl)pyrazol-3-yl]-1H-indole-2-carboxamide;

[0402] 6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-pyridinyl)-1H-indole-2-carboxamide;

[0403] 6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(3-pyridinyl)-1H-indole-2-carboxamide;

[0404] 6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-[1-(2-fluoroethyl)pyrazol-3-yl]-1H-indole-2-carboxamide;

[0405] 6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-[1-(2-methoxyethyl)pyrazol-3-yl]-1H-indole-2-carboxamide;

[0406] 6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(1-ethylpyrazol-3-yl)-1H-indole-2-carboxamide;

[0407] 6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-methylthiazol-2-yl)-1H-indole-2-carboxamide;

[0408] 6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-isoxazol-4-yl-1H-indole-2-carboxamide;

[0409] 6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-thiazol-5-yl-1H-indole-2-carboxamide;

[0410] 6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(3-thienyl)-1H-indole-2-carboxamide;

[0411] 6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(1,2,4-thiadiazol-5-yl)-1H-indole-2-carboxamide;

[0412] 6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)-1H-indole-2-carboxamide;

[0413] 6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(2-hydroxyethyl)-1H-indole-2-carboxamide;

[0414] 6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-phenyl-1H-indole-2-carboxamide;

[0415] 6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(2-methylpyrazol-3-yl)-1H-indole-2-carboxamide;

[0416] 6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(2-methoxyethoxy)-1H-indole-2-carboxamide;

[0417] 6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(1-methylpyrazol-3-yl)-1H-indole-2-carboxamide;

[0418] 6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(1,3,4-thiadiazol-2-yl)-1H-indole-2-carboxamide;

[0419] 6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(cyclopropylmethoxy)-1H-indole-2-carboxamide;

[0420] 6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-ethoxy-1H-indole-2-carboxamide;

[0421] 6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(2,2-difluoroethyl)-1H-indole-2-carboxamide;

[0422] 6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(2,2,2-trifluoroethyl)-1H-indole-2-carboxamide;

[0423] 6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(cyclopropylmethyl)-1H-indole-2-carboxamide;

[0424] 6-(4-amino-1-(tert-butyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-phenethyl-1H-indole-2-carboxamide;

[0425] 6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-benzyl-1H-indole-2-carboxamide;

[0426] 6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-isobutyl-1H-indole-2-carboxamide;

[0427] 6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(2-fluoroethyl)-1H-indole-2-carboxamide;

[0428] 6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-methoxy-1H-indole-2-carboxamide;

[0429] 6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-propyl-1H-indole-2-carboxamide;

[0430] 6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(2-methoxyethyl)-1H-indole-2-carboxamide;

[0431] 6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-butyl-1H-indole-2-carboxamide;

[0432] 6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-thiazol-2-yl-1H-indole-2-carboxamide;

[0433] 6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-isopropyl-1H-indole-2-carboxamide;

[0434] 6-[4-amino-1-(3-hydroxy-3-methyl-cyclopentyl)pyrazolo[3,4-d]pyrimidin-3-yl]-N-methyl-1H-indole-2-carboxamide;

[0435] 6-(4-amino-1-isopropyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N,3-dimethyl-1H-indole-2-carboxamide;

[0436] 6-[4-amino-1-(3-methoxypropyl)pyrazolo[3,4-d]pyrimidin-3-yl]-N-methyl-1H-indole-2-carboxamide;

[0437] 6-(4-amino-1-cyclobutyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-methyl-1H-indole-2-carboxamide; or

[0438] Tert-butyl 3-[4-amino-3-[2-(methylcarbamoyl)-1H-indol-6-yl]pyrazolo[3,4-d]pyrimidin-1-yl]azetidine-1-carboxylate.

[0439] The various functional groups and substituents making up the compounds of formula (I) are typically selected so that the molecular weight of the compounds 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, and for example is 550 or less.

[0440] Suitable pharmaceutically acceptable salts of the compounds of this invention are, for example, acid addition salts of the compounds of this invention with sufficient alkalinity, for example, acid addition salts obtained 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. In addition, suitable pharmaceutically acceptable salts of the compounds of this invention with sufficient acidity are alkali metal salts such as sodium salts or potassium salts, alkaline earth metal salts such as calcium salts or magnesium salts, ammonium salts, or salts obtained with organic bases providing pharmaceutically acceptable cations, for example, salts obtained with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.

[0441] Compounds that have the same molecular formula but differ in the nature or order of bonding of their atoms or the arrangement of their atoms in space are termed "isomers". Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers". Stereoisomers that are not mirror images of one another are termed "diastereomers", and those that are non-superimposable mirror images of one another are termed "enantiomers". When a compound has an asymmetric center, for example one bonded to four different groups, it is possible to have a pair of enantiomers. An enantiomer can be characterized by the absolute configuration of its asymmetric center and described by the R and S ordering rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light, and is designated as right-handed or left-handed (i.e., as a (+)-isomer or a (-)-isomer, respectively). Chiral compounds can exist as individual enantiomers or as mixtures thereof. A mixture containing equal proportions of enantiomers is termed a "racemic mixture".

[0442] The compounds of the present invention may have one or more asymmetric centers; therefore, the compounds may be produced in individual (R)-stereoisomer or (S)-stereoisomer form or in the form of a mixture thereof. Unless otherwise indicated, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and their racemic mixtures or other mixtures. The stereochemistry of the determination of stereoisomers and the method for separating stereoisomers are well known in the art (see "Advanced Organic Chemistry", 4th edition J. March, John Wiley and Sons, New York, 2001, Chapter 4, discussion), for example, by synthesizing from optically active starting materials or by splitting racemic forms. Some compounds of the present invention may have geometric isomer centers (E-isomers and Z-isomers). It should be understood that the present invention encompasses all optical isomers, diastereomers and geometric isomers and mixtures thereof with antiproliferative activity.

[0443] The present invention also encompasses compounds of the present invention as defined herein that contain one or more isotopic substitutions. For example, H may be in any isotopic form, including 1H, 2H (D) and 3H (T); C may be in any isotopic form, including 12C, 13C and 14C; and O may be in any isotopic form, including 16O and 18O; and so on.

[0444] It will also be appreciated that certain compounds of formula (I) may exist in solubilized as well as unsolubilized forms, such as, for example, hydrated forms. It will be appreciated that the present invention encompasses all such solubilized forms which possess antiproliferative activity.

[0445] It will also be appreciated that certain compounds of Formula I may exhibit polymorphism and that the present invention encompasses all such forms which possess antiproliferative activity.

[0446] Compounds of formula I can exist in many different tautomeric forms, and reference to compounds of formula I includes all such forms. For the avoidance of doubt, when a compound can exist in one of several tautomeric forms, and only one tautomeric form is specifically described or shown, all other tautomeric forms are still included by formula I. Examples of tautomeric forms include keto, enol and enolate forms, such as in the form of, for example, the following tautomeric pairs: keto / enol (described below), imine / enamine, amide / imino alcohol, amidine / amidine, nitroso / oxime, thione / enethiol, and nitro / acid nitro.

[0447]

[0448] Compounds of formula I containing amine functions can also form N-oxides. Mention herein that compounds of formula I containing amine functions also include N-oxides. When a compound contains several amine functions, one or more than one nitrogen atom may be oxidized to form an N-oxide. A specific example of an N-oxide is an N-oxide of a nitrogen atom of a tertiary amine or a nitrogen-containing heterocycle. N-oxides can be formed by treating the corresponding amine with an oxidant such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid), see, for example, Advanced Organic Chemistry, Jerry March, 4th edition, Wiley Interscience, multiple pages. More specifically, N-oxides can be prepared by the procedure of LW Deady (Syn. Comm. 1977, 7, 509-514), wherein an amine compound is reacted with meta-chloroperoxybenzoic acid (mCPBA), for example, in an inert solvent such as dichloromethane.

[0449] The compounds of formula (I) can be administered in the form of prodrugs, which are decomposed in the human or animal body to release the compounds of the invention. Prodrugs can be used to change the physical properties and / or pharmacokinetic properties of the compounds of the invention. Prodrugs can be formed when the compounds of the invention contain a suitable group or substituent to which a modifying group can be attached. Examples of prodrugs include ester derivatives that can be cleaved in vivo, which can be formed at a carboxyl or hydroxyl group in the compounds of formula (I); and amide derivatives that can be cleaved in vivo, which can be formed at a carboxyl or amino group in the compounds of formula (I).

[0450] Therefore, the present invention includes those compounds of formula (I) as defined above when they can be obtained by organic synthesis and when they can be obtained in the human or animal body by cleavage of their prodrugs. Therefore, the present invention includes those compounds of formula I produced by organic synthesis and those compounds produced in the human or animal body by metabolism of precursor compounds, that is, compounds of formula (I) can be synthetically produced compounds or metabolically produced compounds.

[0451] Suitable pharmaceutically acceptable prodrugs of the compounds of formula (I) are prodrugs that are suitable, based on sound medical judgment, for administration to the human or animal body without undesirable pharmacological activity and without excessive toxicity.

[0452] Various forms of prodrugs have been described, for example, in the following documents:-

[0453] a) Methods in Enzymology, Vol. 42, pp. 309-396, edited by K. Widder et al. (Academic Press, 1985);

[0454] b) Design of Pro-drugs, edited by H.Bundgaard, (Elsevier, 1985);

[0455] c) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 "Design and Application of Pro-drugs", H. Bundgaard, pp. 113-191 (1991);

[0456] d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992);

[0457] e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988);

[0458] f) N. Kakeya, et al., Chem. Pharm. Bull., 32, 692 (1984);

[0459] g) T. Higuchi and V. Stella, "Pro-Drugs as Novel Delivery Systems", ACSSymposium Series, Vol. 14; and

[0460] h) E. Roche (editor), "Bioresible Carriers in Drug Design", Pergamon Press, 1987.

[0461] Suitable pharmaceutically acceptable prodrugs of compounds of formula I having a carboxyl group are, for example, in vivo cleavable esters thereof. An in vivo cleavable ester of a compound of formula I containing a carboxyl group is, for example, a pharmaceutically acceptable ester which is cleaved in the human or animal body to produce the parent acid. Suitable pharmaceutically acceptable esters of carboxyl groups include C1-6 alkyl esters such as methyl, ethyl and tert-butyl, C1-6 alkoxymethyl esters such as methoxymethyl, C1-6 alkanoyloxymethyl esters such as pivaloyloxymethyl, 3-phthalyl esters, C3-8 cycloalkylcarbonyloxy-C1-6 alkyl esters such as cyclopentylcarbonyloxymethyl and 1-cyclohexylcarbonyloxyethyl, 2-oxo-1,3-dioxolylmethyl esters such as 5-methyl-2-oxo-1,3-dioxol-4-ylmethyl ester, and C1-6 alkoxycarbonyloxy-C1-6 alkyl esters such as methoxycarbonyloxymethyl and 1-methoxycarbonyloxyethyl.

[0462] The suitable pharmaceutically acceptable prodrug of the formula (I) compound with hydroxyl group is for example its ester or ether that can be decomposed in vivo.The ester or ether that can be decomposed in vivo of the formula I compound containing hydroxyl group is for example cleaved in human body or animal body to produce the pharmaceutically acceptable ester or ether of parent hydroxyl compound.The suitable pharmaceutically acceptable ester forming group of hydroxyl group includes inorganic ester such as phosphate ester (including amino phosphoric acid cyclic ester).Other suitable pharmaceutically acceptable ester forming groups of hydroxyl group include C1-10 alkanoyl such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, C1-10 alkoxycarbonyl such as ethoxycarbonyl, N, N-(C1-6)2 formamyl, 2-dialkylaminoacetyl and 2-carboxyacetyl. Examples of ring substituents on phenylacetyl and benzoyl include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl and 4-(C1-4alkyl)piperazin-1-ylmethyl. Suitable pharmaceutically acceptable ether-forming groups for hydroxyl include α-acyloxyalkyl such as acetoxymethyl and pivaloyloxymethyl.

[0463] Suitable pharmaceutically acceptable prodrugs of compounds of formula (I) having a carboxyl group are, for example, amides thereof which are cleavable in vivo, for example amides formed with amines such as ammonia, C1-4 alkylamines such as methylamine, (C1-4 alkyl)2 amines such as dimethylamine, N-ethyl-N-methylamine or diethylamine, C1-4 alkoxy-C2-4 alkylamines such as 2-methoxyethylamine, phenyl-C1-4 alkylamines such as benzylamine, and amino acids such as glycine or their esters.

[0464] Suitable pharmaceutically acceptable prodrugs of compounds of formula I with amino groups are, for example, amide derivatives thereof that can be cleaved in vivo. Suitable pharmaceutically acceptable amides obtained from amino groups include, for example, amides formed with C1-10 alkanoyl groups such as acetyl, benzoyl, phenylacetyl, and substituted benzoyl and phenylacetyl groups. Examples of ring substituents on phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazine-1-ylmethyl, and 4-(C1-4alkyl)piperazine-1-ylmethyl.

[0465] The in vivo effects of the compounds of formula (I) may be exerted in part by one or more metabolites formed in the human or animal body after administration of the compounds of formula (I). As stated above, the in vivo effects of the compounds of formula (I) may also be exerted by the metabolism of the precursor compounds (prodrugs).

[0466] Although the present invention may relate to any compound or specific group of compounds defined herein by way of optional, preferred or suitable features or otherwise defined with respect to specific embodiments, the present invention may also relate to any compound or specific group of compounds that explicitly excludes such optional, preferred or suitable features or specific embodiments.

[0467] Suitably, the present invention excludes any individual compound that does not possess the biological activity defined herein.

[0468] synthesis

[0469] 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 accompanying examples.

[0470] In describing the synthetic methods described herein, as well as in any reference to synthetic methods for preparing starting materials, it is understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of experiments and workup procedures, can be selected by one skilled in the art.

[0471] Those skilled in the art of organic synthesis will appreciate that the functionality present on the various portions of the molecule must be compatible with the reagents and reaction conditions utilized.

[0472] It will be appreciated that during the synthesis of the compounds of the invention in the methods defined herein, or during the synthesis of certain starting materials, it may be desirable to protect certain substituent groups to prevent their undesired reactions. A skilled chemist will understand when such protection is required and how such protecting groups may be placed in place and later removed.

[0473] For examples of protecting groups, see one of the many general textbooks on the subject, for example 'Protective Groups in Organic Synthesis', by Theodora Green, (Publisher: John Wiley & Sons). Protecting groups may be removed by any suitable method described in the literature or known to the skilled chemist as suitable for removing the protecting group in question, the method being selected so as to effect removal of the protecting group with minimal disturbance of groups elsewhere in the molecule.

[0474] Thus, if reactants include, for example, groups such as amino, carboxyl or hydroxy, it may be desirable to protect the group in some of the reactions mentioned herein.

[0475] For example, the suitable protecting group of amino or alkylamino is, for example, acyl, for example, alkanoyl such as acetyl, alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl or tert-butoxycarbonyl, arylmethoxycarbonyl such as benzyloxycarbonyl or aroyl such as benzoyl. The deprotection conditions for the above protecting groups must vary with the selection of the protecting groups. Therefore, for example, acyl such as alkanoyl or alkoxycarbonyl or aroyl 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 such as tert-butoxycarbonyl 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 such as benzyloxycarbonyl can be removed, for example, by hydrogenation through a catalyst such as palladium / charcoal, or by treatment with Lewis acid such as tri(trifluoroacetic acid) boron. A suitable alternative protecting group for primary amino is, for example, phthaloyl, which can be removed by treatment with an alkylamine such as dimethylaminopropylamine or with hydrazine.

[0476] Suitable protecting groups for hydroxyl groups are, for example, acyl groups, for example, alkanoyl groups such as acetyl, aroyl groups such as benzoyl, or arylmethyl groups such as benzyl. The deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting groups. Thus, for example, acyl groups such as alkanoyl or aroyl groups can be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide (e.g., lithium hydroxide, sodium hydroxide) or ammonia. Alternatively, arylmethyl groups such as benzyl groups can be removed, for example, by hydrogenation over a catalyst such as palladium / carbon.

[0477] A suitable protecting group for a carboxyl group is, for example, an esterifying group such as a methyl or ethyl group, which can be removed, for example, by hydrolysis with a base such as sodium hydroxide, or such as a tert-butyl group, which can be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or such as a benzyl group, which can be removed, for example, by hydrogenation over a catalyst such as palladium on carbon.

[0478] Resins can also serve as protecting groups.

[0479] The method for synthesizing the compounds of formula (I) will vary depending on the nature of HET, X1, X2, X3, X4, R2, R3 and any substituent groups associated therewith. Suitable methods for their preparation are further described in the accompanying examples.

[0480] Once a compound of formula (I) has been synthesized by any of the methods defined herein, the method may then further comprise the following additional step:

[0481] (i) removing any protecting groups present;

[0482] (ii) converting a compound of formula (I) into another compound of formula (I);

[0483] (iii) forming a pharmaceutically acceptable salt, hydrate or solvate thereof; and / or

[0484] (iv) forming a prodrug thereof.

[0485] An example of (ii) above is when a compound of formula (I) is synthesized, then one or more of the groups HET, X1, X2, X3, X4, R2, R3 can be further reacted to change the nature of the group and provide an alternative compound of formula (I). For example, the compound can be reacted to convert any R group into a substituent group other than hydrogen.

[0486] The resulting compound of formula (I) can be isolated and purified using techniques well known in the art.

[0487] Biological Activity

[0488] The bioassay described in Example 51 herein can be used to measure the pharmacological effects of the compounds of the invention.

[0489] Although the pharmacological properties of compounds of Formula I vary as a function of structure, compounds of the invention were found to be active in the RET assay described in Example 51, as expected.

[0490] In general, compounds of the invention exhibited IC values ​​of 1 μM or less in the RET assay described in Example 51. 50 , wherein preferably the compounds of the present invention show an IC of 200 nM or less 50 , and most preferably the compounds of the present invention show an IC of 50 nM or less 50 .

[0491] Suitably, the ratio of RET activity to KDR activity measured in the RET and KDR assay set forth in Example 51 herein is greater than 5, more suitably greater than 10, more suitably greater than 25, and most suitably greater than 100.

[0492] In the RET cell assay described herein in Example 51, the compounds of Formula I suitably have an activity of less than 1 μM, with preferred compounds showing an activity of 500 nM or less, and most preferably compounds of the invention showing an IC of 200 nM or less. 50 .

[0493] The following compounds were tested in the assay described in Example 51, but did not exhibit the desired activity:

[0494] 6-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-1H-indole-2-carboxylic acid;

[0495] N-ethyl-6-[1-[(1S,3R)-3-hydroxycyclopentyl]-4-(methylamino)pyrazolo[3,4-d]pyrimidin-3-yl]-1H-indole-2-carboxamide;

[0496] 6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-1H-indole-2-carboxamide;

[0497] 6-(4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-methyl-1H-indole-2-carboxamide;

[0498] 6-[4-amino-1-(2-hydroxyethyl)pyrazolo[3,4-d]pyrimidin-3-yl]-N-methyl-1H-indole-2-carboxamide;

[0499] 6-[4-amino-1-[2-(dimethylamino)-2-oxo-ethyl]pyrazolo[3,4-d]pyrimidin-3-yl]-N-methyl-1H-indole-2-carboxamide; and

[0500] 6-[4-Amino-1-[3-(dimethylamino)-3-oxo-propyl]pyrazolo[3,4-d]pyrimidin-3-yl]-N-methyl-1H-indole-2-carboxamide.

[0501] Pharmaceutical composition

[0502] According to another aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of the present invention as defined above or a pharmaceutically acceptable salt, hydrate or solvate thereof in combination with a pharmaceutically acceptable diluent or carrier.

[0503] The compositions of the invention may be in a form suitable for oral use (e.g., in the form of tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (e.g., in the form of creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (e.g., in the form of finely divided powders or liquid aerosols), for administration by insufflation (e.g., in the form of finely divided powders), or for parenteral administration (e.g., in the form of sterile aqueous or oily solutions for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular administration or in the form of suppositories for rectal administration).

[0504] The compositions of the present invention can be obtained by conventional procedures using conventional pharmaceutical excipients well known in the art. Thus, compositions intended for oral use may contain, for example, one or more coloring agents, sweeteners, flavoring agents and / or preservatives.

[0505] An effective amount of a compound of the invention for use in therapy is an amount sufficient to treat or prevent the proliferative disorders mentioned herein, slow its progression and / or alleviate the symptoms associated with said disorders.

[0506] 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 particular route of administration. For example, a formulation intended for oral administration to humans will typically contain, for example, 0.5 mg to 0.5 g of active agent (more suitably 0.5 to 100 mg, e.g. 1 to 30 mg) compounded with an appropriate and suitable amount of excipients that may vary from about 5 to about 98% by weight of the total composition.

[0507] The size of the dose of the compound of formula I for therapeutic or prophylactic purposes will of course vary according to the nature and severity of the disorder, the age and sex of the animal or patient, and the route of administration, in accordance with well-known medical principles.

[0508] When using the compounds of this invention for treatment or prevention purposes, it will be generally applied so that a daily dose in the range of, for example, 0.1mg to 75mg per kg body weight is accepted, if necessary, so the daily dose is given in divided doses. In general, when parenteral route is adopted, a lower dose will be applied. Therefore, for example, for intravenous or intraperitoneal administration, a dose in the range of, for example, 0.1mg to 30mg per kg body weight will be generally used. Similarly, for administration by suction, a dose in the range of, for example, 0.05mg to 25mg per kg body weight will be used. Oral administration may also be suitable, particularly in tablet form. Generally, a unit dosage form will contain about 0.5mg to 0.5g of the compounds of this invention.

[0509] Therapeutic uses and applications

[0510] The present invention provides compounds that act as inhibitors of RET. Furthermore, the compounds of the present invention show improved selectivity for RET relative to selectivity for KDR (ie, they are potent inhibitors of RET and poor inhibitors of KDR).

[0511] Thus, the present invention provides a method of inhibiting RET kinase enzymatic activity in vitro or in vivo, the method comprising contacting a cell with an effective amount of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof.

[0512] The present invention also provides a method for selectively inhibiting RET kinase enzymatic activity over KDR enzymatic activity in vitro or in vivo, the method comprising contacting a cell with an effective amount of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof.

[0513] The present invention also provides a method of treating a disease or condition in which RET kinase activity is implicated in a patient in need of 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 thereof.

[0514] The present invention provides a method of inhibiting cell proliferation in vitro or in vivo, the method comprising contacting the cell with an effective amount of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof.

[0515] The present invention provides a method of treating a proliferative disorder in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition thereof.

[0516] The present invention provides a method of treating cancer in a patient in need of 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 thereof.

[0517] The present invention provides a compound as defined herein or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition for use in therapy.

[0518] The present invention provides a compound as defined herein or a pharmaceutically acceptable salt, hydrate or solvate thereof or a pharmaceutical composition for use in treating a proliferative disorder.

[0519] The present invention provides a compound as defined herein or a pharmaceutically acceptable salt, hydrate or solvate thereof or a pharmaceutical composition for use in the treatment of cancer. In a particular embodiment, the cancer is a human cancer.

[0520] The present invention provides a compound as defined herein or a pharmaceutically acceptable salt, hydrate or solvate thereof for use in inhibiting RET kinase enzyme activity.

[0521] The present invention provides a compound as defined herein or a pharmaceutically acceptable salt, hydrate or solvate thereof for use in selectively inhibiting RET kinase enzymatic activity over KDR enzymatic activity.

[0522] The present invention provides a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, for use in treating a disease or disorder in which RET kinase activity is implicated.

[0523] The present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, for the manufacture of a medicament for the treatment of a proliferative disorder.

[0524] The present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, for the manufacture of a medicament for the treatment of cancer. Suitably, the medicament is for the treatment of human cancer.

[0525] The present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, for the manufacture of a medicament for inhibiting RET kinase enzyme activity.

[0526] The present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, for the manufacture of a medicament for selectively inhibiting RET kinase enzymatic activity over KDR enzymatic activity.

[0527] The present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, for the manufacture of a medicament for the treatment of a disease or disorder in which RET kinase activity is implicated.

[0528] The term "proliferative disorder" is used interchangeably herein and relates to the unwanted or uncontrolled undesirable cell proliferation of excess or abnormal cells, such as neoplastic or hyperplastic growth, whether in vitro or in vivo. Examples of proliferative disorders include, but are not limited to, premalignant and malignant cell proliferation, including, but not limited to, malignant neoplasms and tumors, cancer, leukemia, psoriasis, bone diseases, fibroproliferative disorders (e.g., connective tissue fibroproliferative disorders), and atherosclerosis. Any type of cell can be treated, including, but not limited to, lung, colon, breast, ovarian, prostate, liver, pancreas, brain, and skin cells.

[0529] The antiproliferative effects of the compounds of the invention have particular application in the treatment of human cancers (by virtue of their inhibition of RET kinase enzymatic activity, and / or selective inhibition of RET kinase enzymatic activity over that of KDR).

[0530] The anti-cancer effects may occur through one or more mechanisms including, but not limited to, modulation of cell proliferation, inhibition of angiogenesis (formation of new blood vessels), inhibition of metastasis (spread of a tumor from its origin), inhibition of invasion (spread of tumor cells into adjacent normal structures), or promotion of apoptosis (programmed cell death).

[0531] In a specific embodiment of the invention, the proliferative disorder to be treated is cancer, such as medullary thyroid carcinoma (MTC) or non-small cell lung cancer (NSCLC).

[0532] Route of administration

[0533] The compounds of the invention or pharmaceutical compositions comprising these compounds may be administered to a subject by any suitable systemic / peripheral or topical (ie, at the desired site of action) administration route.

[0534] Routes of administration include, but are not limited to, oral (e.g., by ingestion); buccal; sublingual; transdermal (including, for example, by patches, plasters, etc.); transmucosal (including, for example, by patches, plasters, etc.); intranasal (e.g., by nasal sprays); ocular (e.g., by eye drops); pulmonary (e.g., by inhalation or insufflation therapy, such as by aerosol, such as through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, such as by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcutaneous, intraarticular, subarachnoid, and intrasternal injection; by implantation of a reservoir or reservoir, such as subcutaneously or intramuscularly.

[0535] Combination therapy

[0536] The antiproliferative therapy defined above may be used as the sole therapy or may involve conventional surgery or radiotherapy or chemotherapy in addition to the compounds of the invention. The chemotherapy may include one or more of the following antineoplastic agent classes:-

[0537] (i) other anti-proliferative / antineoplastic drugs and combinations thereof as used in medical oncology, such as alkylating agents (e.g., cis-platin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan, temozolamide, and nitrosourea); antimetabolites (e.g., gemcitabine and antifolates such as fluoropyrimidines, e.g., 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside, cytosine arabinoside, cytosine pyrimidine ... arabinoside and hydroxyurea); antitumor antibiotics (e.g., anthracyclines such as adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin, and mithramycin); antimitotic agents (e.g., vinca alkaloids such as vincristine (vincristine, vinblastine, vindesine and vinorelbine and taxoids such as taxol and taxotere and polo kinase inhibitors); and topoisomerase inhibitors (e.g. epipodophyllotoxins such as etoposide and teniposide, amsacrine, topotecan and camptothecin);

[0538] (ii) cytostatic agents such as antiestrogens (e.g. tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene), antiandrogens (e.g. bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (e.g. goserelin, leuprorelin and buserelin), progestins (e.g. megestrol acetate), acetate), aromatase inhibitors (e.g. in the form of anastrozole, letrozole, vorazole and exemestane) and 5α-reductase inhibitors such as finasteride;

[0539] (iii) anti-invasive agents [e.g., inhibitors of the c-Src kinase family such as 4-(6-chloro-2,3-methylenedioxyanilino)-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}thiazole-5-carboxamide (dasatinib, BMS-354825); J. Med. Chem. , 2004, 47 , 6658-6661) and bosutinib (SKI-606), as well as metalloproteinase inhibitors such as marimastat, inhibitors of urokinase plasminogen activator receptor function or antibodies against heparanase];

[0540] (iv) Inhibitors of growth factor function: For example, the inhibitors include growth factor antibodies and growth factor receptor antibodies (such as the anti-erbB2 antibody trastuzumab [Herceptin TM], the anti-EGFR antibody panitumumab, the anti-erbB1 antibody cetuximab [Erbitux, C225]) and by Stern et al. (Critical reviews in any growth factor or growth factor receptor antibody disclosed in (oncology / haematology, 2005, volume 54, pages 11-29); the inhibitor also includes tyrosine kinase inhibitors, for example inhibitors of the epidermal growth factor family (for example, EGFR family tyrosine kinase inhibitors such as N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine (gefitinib, ZD1839), N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) and 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)-quinazolin-4-amine (CI 1033), erbB2 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 farnesyl transferase inhibitors, for example sorafenib (BAY 43-9006), tipifarnib (R115777) and lonafarnib (SCH66336)), inhibitors of cell signaling through 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 (e.g., AZD1152, PH739358, VX-680, MLN8054, R763, MP235, MP529, VX-528 and AX39459) and cyclin-dependent kinase inhibitors such as CDK2 and / or CDK4 inhibitors;

[0541] (v) Anti-angiogenic agents such as those that inhibit the action of vascular endothelial growth factor [e.g., the anti-vascular endothelial growth factor antibody bevacizumab (Avastin TM) and, for example, VEGF receptor tyrosine kinase inhibitors such as vandetanib (ZD6474), vatalanib (PTK787), sunitinib (SU11248), axitinib (AG-013736), pazopanib (GW 786034) and 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline (AZD2171; Example 240 in WO 00 / 47212), such as International Patent Applications WO 97 / 22596, WO 97 / 30035, WO Compounds disclosed in WO 97 / 32856 and WO 98 / 13354 and compounds acting through other mechanisms (e.g., linomide, inhibitors of integrin αvβ3 function and angiostatin];

[0542] (vi) Vascular damaging agents such as Combretastatin 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;

[0543] (vii) endothelin receptor antagonists, for example zibotentan (ZD4054) or atrasentan;

[0544] (viii) antisense therapies, e.g., those directed against the targets listed above, such as the anti-ras antisense ISIS 2503;

[0545] (ix) gene therapy approaches, including, for example, approaches to replace abnormal genes such as abnormal p53 or abnormal BRCA1 or BRCA2, GDEPT (gene-directed enzyme prodrug therapy) approaches such as those using cytosine deaminase, thymidine kinase or bacterial nitroreductase, and approaches to increase a patient's tolerance to chemotherapy or radiation therapy such as multidrug resistance gene therapy; and

[0546] (x) Immunotherapeutic methods, including, for example, ex vivo and in vivo methods for increasing the immunogenicity of a patient's tumor cells, such as transfection with cytokines such as interleukin 2, interleukin 4, or granulocyte-macrophage colony stimulating factor, methods for reducing T cell anergy, methods using transfected immune cells such as dendritic cells transfected with cytokines, methods using tumor cell lines transfected with cytokines, and methods using anti-idiotypic antibodies.

[0547] In a particular embodiment, the antiproliferative therapy defined above may also involve, in addition to the compounds of the invention, conventional surgery or radiotherapy or chemotherapy, wherein the chemotherapy may comprise one or more antineoplastic agents selected from the group consisting of procarbazine, carmustine, lomustine, irinotecan, temozolomide, cisplatin, carboplatin, methotrexate, etoposide, cyclophosphamide, ifosfamide and vincristine.

[0548] Such conjoint treatment may be achieved by way of simultaneous, sequential or separate dosing of the individual components of the treatment.The combination products employ the compounds of this invention within the dosage range described above and the other pharmaceutically active agent within its approved dosage range.

[0549] According to this aspect of the invention there is provided a combination for use in the treatment of cancer (eg cancer involving solid tumours) comprising a compound of the invention as defined above or a pharmaceutically acceptable salt, hydrate or solvate thereof and another anti-tumour agent.

[0550] According to this aspect of the invention there is provided a combination for use in the treatment of a proliferative disorder such as cancer (e.g. cancer involving solid tumours) comprising a compound of the invention as defined above or a pharmaceutically acceptable salt, hydrate or solvate thereof and any one of the anti-tumour agents listed herein above.

[0551] In another aspect of the present invention, there is provided a compound of the present invention or a pharmaceutically acceptable salt, hydrate or solvate thereof for use in treating cancer in combination with another anti-tumor agent optionally selected from the anti-tumor agents listed herein above.

[0552] In this document, when the term "combination" is used, it should be understood that this involves simultaneous, separate or sequential administration. In one aspect of the invention, "combination" involves simultaneous administration. In another aspect of the invention, "combination" involves separate administration. In another aspect of the invention, "combination" involves sequential administration. When administration is sequential or separate, the delay in administering the second component should not be such as to lose the beneficial effects of the combination.

[0553] According to another aspect of the present invention, a pharmaceutical composition is provided, which comprises a compound of the present invention or a pharmaceutically acceptable salt, hydrate or solvate thereof in combination with an anti-tumor agent (optionally selected from the anti-tumor agents listed above in this document) and a pharmaceutically acceptable diluent or carrier.

[0554] Example

[0555] abbreviation

[0556] B2(OH)4 Tetrahydroxydiboron

[0557] br s broad single peak

[0558] d Doublet

[0559] dd double peak

[0560] CDCl3 Chloroform

[0561] DMAP 4-(dimethylamino)pyridine

[0562] DCM Dichloromethane

[0563] DIPEA N,N,-diisopropylethylamine, Hunig's base

[0564] DMF N,N-Dimethylformamide

[0565] DMSO Dimethyl sulfoxide

[0566] EDCI.HCl 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride

[0567] EtBr Ethyl bromide

[0568] EtOAc Ethyl acetate

[0569] EtOH

[0570] HATU 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium hexafluorophosphate 3-oxide

[0571] HCl

[0572] HPLC High Pressure Liquid Chromatography

[0573] Hz Hertz

[0574] J coupling constant

[0575] K2CO3 Potassium carbonate

[0576] KOAc Potassium acetate

[0577] LCMS liquid chromatography-mass spectrometry

[0578] LiOH.H2O Lithium hydroxide monohydrate

[0579] m multiplet

[0580] MeOH Methanol

[0581] MgSO4 Magnesium sulfate

[0582] MHz Megahertz

[0583] N2 Nitrogen

[0584] NaHCO3 Sodium bicarbonate

[0585] Na2SO4 Sodium sulfate

[0586] NH4Cl Ammonium chloride

[0587] NMR Nuclear Magnetic Resonance

[0588] POCl3 Phosphorus oxychloride

[0589] q quartet

[0590] s Single peak

[0591] t Triplet

[0592] tt triple triplet

[0593] THF Tetrahydrofuran

[0594] XPhos 2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl

[0595] XPhos-Pd-G2 Chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)

[0596] method

[0597] General Experiments

[0598] Flash chromatography was performed using pre-packed silica gel cartridges. 254Thin layer chromatography was performed on 5×10 cm plates coated with silica gel to a thickness of 0.25 mm. All reagents obtained from commercial sources were used without further purification. Anhydrous solvents were obtained from Sigma-Aldrich Chemical Company Ltd. or Fisher Chemicals Ltd. and used without further drying. HPLC grade solvents were obtained from Fisher Chemicals Ltd.

[0599] Unless otherwise indicated, all compounds were >90% pure as determined by inspection of both LC-MS and 1H NMR spectra. When Cl or Br were present, the expected isotopic distribution pattern was observed.

[0600] NMR

[0601] Protons were recorded on a 300 MHz or 400 MHz Bruker spectrometer ( 1 H) NMR spectroscopy. Solutions are usually prepared in deuterated chloroform (CDCl3) or deuterated dimethyl sulfoxide (DMSO-d6), with chemical shifts referenced to tetramethylsilane (TMS) as an internal standard or to deuterated solvents. Report indicated chemical shifts (δ), integrals (e.g. 1 H), multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad; dd, doublet of doublets, etc.) and coupling constant (J) in Hz (app implies apparent coupling of broadened signals) 1 H NMR data. Deuterated solvents were obtained from Sigma-Aldrich Chemical Company, Goss or Fluorochem.

[0602] LCMS method

[0603] Analytical LC-MS

[0604] LC-MS analysis was performed on a Waters Acquity UPLC system equipped with a BEH C18 1.7 μM column (2.1×50 mm or 2.1×100 mm) and UV diode array detection (210-400 nm). Positive and negative mass ion detection was performed using a Waters SQD detector. Analyses were performed using buffered acidic or basic solvents and gradients as detailed below.

[0605] Low pH:

[0606] Solvent A-water + 10 mM ammonium formate + 0.1% formic acid

[0607] Solvent B-acetonitrile + 5% water + 0.1% formic acid

[0608] High pH:

[0609] Solvent A-water + 10 mM ammonium bicarbonate + 0.1% ammonia solution

[0610] Solvent B-acetonitrile + 0.1% ammonia solution

[0611] gradient:

[0612]

[0613] Preparative HPLC

[0614] Some compounds were purified by preparative HPLC on a Waters FractionLynx MS automated purification system, using a Waters XBridge 5 μm C18 100 mm×19 mm i.d. column, operating at a flow rate of 20 mL / min, with UV diode array detection (210-400 nm) and mass-directed collection using both positive and negative mass ion detection.

[0615] Purification was performed using either buffered acidic or basic solvent systems as appropriate.Retention times of compounds on the system were routinely assessed using 30-50 μL test injections and a standard gradient, followed by purification using an appropriately selected focused gradient as detailed below based on the observed retention times.

[0616] Low pH:

[0617] Solvent A-water + 10 mM ammonium formate + 0.1% formic acid

[0618] Solvent B-acetonitrile + 5% water + 0.1% formic acid

[0619] High pH:

[0620] Solvent A-water + 10 mM ammonium formate + 0.1% ammonia solution

[0621] Solvent B-acetonitrile + 5% water + 0.1% ammonia solution

[0622] Standard gradient:

[0623]

[0624] Focusing Gradient:

[0625]

[0626] Synthesis method

[0627] Several methods for chemically synthesizing the compounds of the present invention are described herein. These and / or other well-known methods can be modified and / or adapted in a known manner to facilitate the synthesis of additional compounds within the scope of the present invention.

[0628] Intermediates

[0629] 6-(4-amino-1-(tert-butyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-1H-indole-2-carboxylic acid

[0630]

[0631] A mixture of 6-chloro-1H-indole-2-carboxylic acid (1.92 g, 9.8 mmol), XPhos-Pd-G2 (155 mg, 0.2 mmol), XPhos (187 mg, 0.4 mmol), B2(OH)4 (2.59 g, 29.5 mmol) and KOAc (2.89 g, 29.5 mmol) in EtOH (80 ml) was heated at 80° C. under N2 for 2 h. A solution of K2CO3 (4.07 g, 29.8 mmol) in water (20 ml) and a solution of 3-bromo-1-(tert-butyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1.96 g, 7.3 mmol) in 1,4-dioxane (25 ml) were added and the mixture was heated at 80° C. for 15 h. The reaction was cooled to room temperature, concentrated under reduced pressure to remove organics, then acidified to pH 5 with 1 M aqueous HCl to afford a solid, which was collected by filtration, washed with water, and dried under vacuum at 50 °C to afford 6-(4-amino-1-(tert-butyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-1H-indole-2-carboxylic acid (2.92 g, 85%) as an off-white solid.

[0632] LCMS: [M+H] + 351.2

[0633] 1 H NMR: (300MHz, DMSO-d6) δ11.91 (s, 1H), 8.25 (s, 1H), 7.80 (d, J=8.29Hz, 1H), 7.71 (s, 1H), 7.37 (dd, J=1.32, 8.10Hz, 1H), 7.17 (d, J=1.51Hz, 1H), 6.51 (s, 2H), 1.77 (s, 9H).

[0634] 6-(4-amino-1-(tert-butyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-3-chloro-1H-indole-2-carboxylic acid

[0635]

[0636] To a solution of 6-(4-amino-1-(tert-butyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-1H-indole-2-carboxylic acid (793 mg, 2.3 mmol) in DMF (10 mL) was added N-chlorosuccinimide (302.23 mg, 2.3 mmol) at room temperature. The reaction was stirred for 18 hours and then diluted with water (50 ml). The resulting suspension was stirred for 10 minutes, filtered, washed with water, and dried in vacuo to afford 6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-3-chloro-1H-indole-2-carboxylic acid (518 mg, 1.3 mmol, 60%) as a purple solid. The material was used without further purification.

[0637] LCMS: purity 58%, [MH]-383.2.

[0638] 1 H NMR (300MHz, DMSO-d6) δ 12.18 (s, 1H), 8.27 (s, 1H), 7.69-7.80 (m, 2H), 7.48 (dd, J=1.41, 8.38Hz, 1H), 1.77 (s, 9H).

[0639] 6-(4-amino-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-1H-indole-2-carboxylic acid

[0640]

[0641] Prepared as described for 6-(4-amino-1-(tert-butyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-1H-indole-2-carboxylic acid using 3-bromo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine in place of 3-bromo-1-(tert-butyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine to obtain an off-white solid (2.88 g, 86%).

[0642] LCMS: [M+H] + 337.2.

[0643] 6-Bromo-N-methyl-1H-indole-2-carboxamide

[0644]

[0645] To a solution of 6-bromo-1H-indole-2-carboxylic acid (1.0 g, 4.2 mmol) in DMF (25 ml) was added DIPEA (1.7 ml, 10.0 mmol), methylamine hydrochloride (338 mg, 5.0 mmol) and HATU (1.9 g, 5.0 mmol). The mixture was stirred at room temperature for 18 hours and then partitioned between water and EtOAc. The organic layer was separated and washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (40 g column, 0-100% EtOAc in isohexane) to afford 6-bromo-N-methyl-1H-indole-2-carboxamide (657 mg, 63%) as a brown solid.

[0646] LCMS: [M+H] + 253.0 / 254.9

[0647] 1 H NMR: (400MHz, DMSO-d6)δ11.71(br s, 1H), 8.52 (q, J=4.09Hz, 1H), 7.59 (d, J=6.55Hz, 2H), 7.58 (s, 1H), 7.13-7.18 (m, 1H), 7.08 (s, 1H), 2.81 (d, J=4.64Hz, 3H).

[0648] 6-Bromo-N-cyclopropyl-1H-indole-2-carboxamide

[0649]

[0650] Prepared as described for 6-bromo-N-methyl-1H-indole-2-carboxamide using cyclopropylamine in place of methylamine hydrochloride to obtain as a white solid (181 mg, 62%).

[0651] LCMS: [M+H] + 278.9 / 280.9.

[0652] 6-Bromo-N-ethyl-1H-indole-2-carboxamide

[0653]

[0654] Prepared as described for 6-bromo-N-methyl-1H-indole-2-carboxamide using ethylamine in place of methylamine hydrochloride to obtain as a white solid (144 mg, 52%).

[0655] LCMS: [M+H] + 266.9 / 268.9.

[0656] 1 H NMR: (400MHz, chloroform-d) δ9.51 (br s, 1H), 7.61 (s, 1H), 7.50 (d, J=8.54Hz, 1H), 7.24 (dd, J=1.71, 8.54Hz, 1H), 6.77 (dd, J=0.70, 2.04Hz, 1H), 6.13 (br s, 1H), 3.55 (dq, J=5.89, 7.23Hz, 2H), 1.30 (t, J=7.29Hz, 3H).

[0657] 6-Bromo-N-cyclobutyl-1H-indole-2-carboxamide

[0658]

[0659] Prepared as described for 6-bromo-N-methyl-1H-indole-2-carboxamide using cyclobutylamine in place of methylamine hydrochloride to obtain as a beige solid (268 mg, 73%).

[0660] LCMS: [M+H]+ 293.1 / 295.1.

[0661] 1 H NMR (400MHz, DMSO-d6) δ11.66 (s, 1H), 8.67 (d, J = 7.75Hz, 1H), 7.58 (s, 1H), 7.59 (d, J = 8.94Hz, 1H), 7 .11-7.19 (m, 2H), 4.44 (sxt, J=8.17Hz, 1H), 2.17-2.30 (m, 2H), 2.01-2.14 (m, 2H), 1.60-1.77 (m, 2H).

[0662] 6-Bromo-N-methoxy-1H-indole-2-carboxamide

[0663]

[0664] Prepared as described for 6-bromo-N-methyl-1H-indole-2-carboxamide using O-methylhydroxylamine hydrochloride in place of methylamine hydrochloride to obtain as an off-white solid (300 mg, 89%).

[0665] LCMS: [M+H] + 269.0 / 271.0.

[0666] 6-Bromo-3-fluoro-N-methyl-1H-indole-2-carboxamide

[0667]

[0668] Step 1: To a suspension of ethyl 6-bromo-1H-indole-2-carboxylate (688 mg, 2.6 mmol) in acetonitrile (30 mL) was added saturated aqueous NaHCO3 (5.6 ml). The mixture was cooled with ice and Selectfluor TM To 6-bromo-3-fluoro-1H-indole-2-formic acid ethyl ester (362mg) in 4% paraformaldehyde (1g, 2.8mmol) was added to 4% paraformaldehyde (1g, 2.8mmol). (1g, 2.8mmol). The solution was warmed to room temperature, then heated at 80 ° C for 4 hours. The solution was cooled to room temperature, then Selectfluor (1g, 2.8mmol) was added, and heated at 80 ° C for 1 hour. The mixture was cooled to room temperature, and diluted with water, then extracted with ethyl acetate (x3). The combined organic phase was dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography (cyclohexane containing 0-50% ethyl acetate) to obtain 6-bromo-3-fluoro-1H-indole-2-formic acid ethyl ester (362mg) in a light yellow solid. The product is impure, but used in the next step.

[0669] Step 2: To a solution of 6-bromo-3-fluoro-1H-indole-2-carboxylic acid ethyl ester (362 mg) in THF (10 mL), a solution of LiOH.HO (213 mg, 5.1 mmol) in water (6.4 mL) was added. The mixture was stirred at room temperature for 3 hours. The charge of LiOH.HO (213 mg, 5.1 mmol) in water (6.4 mL) was added, and the mixture was heated at 60 ° C for 2 hours. The mixture was cooled to room temperature and then concentrated under reduced pressure. The residue was acidified with 1M HCl aqueous solution and extracted with EtOAc (x3). The combined organic phases were dried over NaSO and evaporated under reduced pressure to produce 6-bromo-3-fluoro-1H-indole-2-carboxylic acid (322 mg) as a light yellow solid. The impure product was used without further purification.

[0670] Step 3: The impure acid (322 mg) was subjected to amide coupling conditions as described for 6-bromo-N-methyl-1H-indole-2-carboxamide to afford 6-bromo-3-fluoro-N-methyl-1H-indole-2-carboxamide (52 mg, 7% over 3 steps) as a light yellow solid. The material was carried forward despite being impure.

[0671] 6-Bromo-N,3-dimethyl-1H-indole-2-carboxamide

[0672]

[0673] Step 1: POCl3 (1.67 g, 10.9 mmol) was added to a solution of 6-bromo-N-methyl-1H-indole-2-carboxamide (2.3 g, 9.1 mmol) in DMF (10 mL) at 0 ° C. The mixture was stirred at room temperature for 15 minutes, then stirred at 100 ° C for 5 hours. The mixture was poured into ice water (100 mL), and the product was extracted with EtOAc (4x100 mL). The combined organic phase was washed with brine (100 mL), dried over MgSO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography to obtain 6-bromo-3-formyl-N-methyl-1H-indole-2-carboxamide (2.1 g). The material was impure, but it was advanced to the next stage.

[0674] Step 2: Triethylsilane (608 mg, 5.2 mmol) was added to a solution of 6-bromo-3-formyl-N-methyl-1H-indole-2-carboxamide (2.1 g) in trifluoroacetic acid (15 mL) at 0 ° C. The mixture was stirred at room temperature for 18 hours, then poured into a saturated Na2CO3 aqueous solution (100 ml) and extracted with EtOAc (5x100 ml). The combined organic phases were washed with brine (100 mL), dried over MgSO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography to obtain 6-bromo-N, 3-dimethyl-1H-indole-2-carboxamide (388 mg, 16% over 2 steps). The material was advanced despite being impure.

[0675] 6-Bromo-N-(1,3-dimethyl-1H-pyrazol-5-yl)-1H-indole-2-carboxamide

[0676]

[0677] 6-bromo-1H-indole-2-carbonyl chloride (200 mg, 0.8 mmol) was added to a solution of 1,3-dimethyl-1H-pyrazole-5-amine (86 mg, 0.8 mmol) in pyridine (5 ml). The mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure. The residue was diluted with saturated NaHCO3 aqueous solution and then extracted with EtOAc (3x20 ml). The combined organic phase was concentrated under reduced pressure. The residue was purified by flash column chromatography (1: 1 EtOAc: petroleum ether) to obtain 6-bromo-N-(1,3-dimethyl-1H-pyrazole-5-yl)-1H-indole-2-carboxamide (50 mg, 19%).

[0678] LCMS: [M+H] + 333.0 / 335.0.

[0679] 3-Bromo-1-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine

[0680]

[0681] A mixture of 3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1 g, 4.7 mmol) and KCO (1.29 g, 9.3 mmol) in DMF (10 mL) was heated at 60 °C under nitrogen for 30 min. The solution was cooled to room temperature before EtBr (0.42 mL, 5.6 mmol) was added. The mixture was heated at 60 °C under nitrogen for 4 h, then cooled to room temperature and concentrated under reduced pressure. The residue was partitioned between water and EtOAc. The organic layer was dried over MgSO, filtered, and concentrated under reduced pressure to obtain the crude product (980 mg, 87%) as a yellow solid, which was used directly in the next reaction without further purification.

[0682] LCMS: [M+H] + 242.0 / 244.0.

[0683] 3-Bromo-1-cyclopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine

[0684]

[0685] To the solution of 3-bromo-1H-pyrazolo[3,4-d]pyrimidine-4-amine (1.2g, 5mmol) in 1,2-dichloroethane (50mL), cyclopropylboric acid (860mg, 10mmol), copper (II) acetate (908mg, 5mmol), 2,2'-bipyridine (780mg, 5mmol) and NaHCO (1.1g, 10mmol) are added. The mixture is stirred under air at 70°C for 2 hours, then cooled to room temperature. The reaction mixture is quenched with saturated NH4Cl aqueous solution (100mL), and extracted with dichloromethane (3x50mL). The organic phases merged are washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (0-100% EtOAc in isohexane) to afford 3-bromo-1-cyclopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (121 mg, 9%) as a white solid.

[0686] LCMS: [M+H] + 254.0 / 256.0.

[0687] 1H NMR (400 MHz, chloroform-d) δ 8.38 (s, 1H), 5.89 (br s, 2H), 3.73 (tt, J=3.71, 7.28 Hz, 1H), 1.27-1.34 (m, 2H), 1.12-1.19 (m, 2H).

[0688] Final compound

[0689] Example 1-6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-thiazol-2-yl-1H-indole-2-carboxamide

[0690]

[0691] To a mixture of 6-(4-amino-1-(tert-butyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-1H-indole-2-carboxylic acid (50 mg, 0.14 mmol) and HATU (65 mg, 0.17 mmol) in DMF (1 ml) was added DIPEA (0.07 ml, 0.42 mmol). The mixture was stirred for 5 minutes, followed by the addition of 2-aminothiazole (17 mg, 0.17 mmol). The mixture was stirred at room temperature for 18 hours, then diluted with water and extracted with EtOAc (3x). The combined extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC to obtain 6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-thiazole-2-yl-1H-indole-2-carboxamide (14 mg, 0.03 mmol, 23%) as a yellow solid.

[0692] LCMS: purity > 95%, [M+H] + 433.1.

[0693] 1 H NMR(400MHz, DMSO-d6)δ12.04(br s, 1H), 8.36 (s, 1H), 8.25 (s, 1H), 7.84 (d, J=7.89Hz, 1H), 7.75 (s, 1H), 7.71 (s, 1H), 7.5 7 (d, J=3.55Hz, 1H), 7.39 (dd, J=1.47, 8.25Hz, 1H), 7.27 (d, J=3.61Hz, 1H), 1.78 (s, 9H).

[0694] Example 2-6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-butyl-1H-indole-2-carboxamide

[0695]

[0696] Prepared as described for Example 1 using n-butylamine in place of 2-aminothiazole to obtain as a white solid (26 mg, 51%).

[0697] LCMS: purity > 95%, [M+H] + 406.2.

[0698] 1 H NMR (400MHz, DMSO-d6) δ11.66-11.76 (m, 1H), 8.50 (t, J=5.72Hz, 1H), 8.24 (s, 1H), 7.77 (d, J=8.25Hz, 1H), 7.69 (s, 1H), 7.33 (dd, J=1.47, 8.25Hz, 1H), 7.19 (d, J=1.28Hz, 1H), 3.30 (br s, 2H), 1.77 (s, 9H), 1.54 (quin, J=7.20Hz, 2H), 1.36 (sxt, J=7.70Hz, 2H), 0.93 (t, J=7.34Hz, 3H).

[0699] Example 3-6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(2-methoxyethyl)-1H-indole-2-carboxamide

[0700]

[0701] Prepared as described for Example 1 using 2-methoxyethylamine in place of 2-aminothiazole to obtain as a white solid (30 mg, 53%).

[0702] LCMS: purity > 95%, [M+H] + 408.2.

[0703] 1 H NMR (400MHz, DMSO-d6) δ11.65-11.82 (m, 1H), 8.53-8.66 (m, 1H), 8.24 (s, 1H), 7.77 (d, J=8.25Hz, 1H), 7.70 ( s, 1H), 7.34 (dd, J=1.47, 8.25Hz, 1H), 7.21 (d, J=1.34Hz, 1H), 3.43-3.55 (m, 5H), 3.30 (s, 2H), 1.77 (s, 9H).

[0704] Example 4-6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-propyl-1H-indole-2-carboxamide

[0705]

[0706] Prepared as described for Example 1 using n-propylamine in place of 2-aminothiazole to obtain as a white solid (33 mg, 60%).

[0707] LCMS: purity > 95%, [M+H] + 392.2.

[0708] 1 H NMR (400MHz, DMSO-d6) δ11.70-11.74 (m, 1H), 8.53 (t, J=5.72Hz, 1H), 8.24 (s, 1H), 7.77 (d, J=8.25Hz, 1H), 7.69 (s, 1H), 7. 33 (dd, J=1.50, 8.22Hz, 1H), 7.19 (s, 1H), 3.24-3.27 (m, 2H), 1.77 (s, 9H), 1.57 (sxt, J=7.34Hz, 2H), 0.92 (t, J=7.40Hz, 3H)

[0709] Example 5-6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-methoxy-1H-indole-2-carboxamide

[0710]

[0711] Prepared as described for Example 1 using O-methylhydroxylamine hydrochloride in place of 2-aminothiazole to obtain as a white solid (51 mg, 47%).

[0712] LCMS: purity > 95%, [M+H] + 380.2.

[0713] 1 H NMR(400MHz, DMSO-d6)δ11.84(br s, 1H), 8.24 (s, 1H), 7.77 (d, J=8.25Hz, 1H), 7.70 (s, 1H), 7.34 (dd, J=1.44, 8.22Hz, 1H), 7.06 (s, 1H), 3.76 (s, 3H), 1.77 (s, 9H)

[0714] Example 6-6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(2-fluoroethyl)-1H-indole-2-carboxamide

[0715]

[0716] Prepared as described for Example 1 using 2-fluoroethylamine hydrochloride in place of 2-aminothiazole to obtain as a white solid (32 mg, 28%).

[0717] LCMS: purity > 95%, [M+H] + 396.3.

[0718] 1 H NMR (300MHz, DMSO-d6) δ11.80 (br s, 1H), 8.82 (br t, J=5.04Hz, 1H), 8.25 (s, 1H), 7.79 (br d, J=8.19Hz, 1H), 7.71 (s, 1H), 7.35 (br d, J=8.01Hz, 1H), 7.25 (s, 1H), 4.66 (br t, J=4.76Hz, 1H), 4.50 (br t, J=4.66Hz, 1H), 3.66 (br d, J=4.80Hz, 1H), 3.57 (br d, J=4.80Hz, 1H), 1.77(s, 9H)

[0719] Example 7-6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-isobutyl-1H-indole-2-carboxamide

[0720]

[0721] Prepared as described for Example 1 using isobutylamine in place of 2-aminothiazole to obtain as a white solid (51 mg, 43%).

[0722] LCMS: purity > 95%, [M+H] + 406.3.

[0723] 1 H NMR (400MHz, DMSO-d6) δ11.72-11.82 (m, 1H), 8.56 (t, J=5.93Hz, 1H), 8.31 (s, 1H), 7.79 (d, J=8.25Hz, 1H), 7.69 (s, 1H), 7.34 (dd, J =1.53, 8.25Hz, 1H), 7.23 (d, J = 1.34Hz, 1H), 3.13 (t, J = 6.67Hz, 2H), 1.87 (spt, J = 7.09Hz, 1H), 1.77 (s, 9H), 0.92 (d, J = 6.66Hz, 6H)

[0724] Example 8-6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-benzyl-1H-indole-2-carboxamide

[0725]

[0726] Prepared as described for Example 1 using benzylamine in place of 2-aminothiazole to obtain as a white solid (34 mg, 32%).

[0727] LCMS: purity > 95%, [M+H] + 440.3.

[0728] 1 H NMR (400MHz, DMSO-d6) δ11.75-11.85 (m, 1H), 9.13 (t, J=6.08Hz, 1H), 8.25 (s, 1H), 7.79 (d, J=8.25Hz, 1H), 7.70 (s, 1H), 7.24-7.38 (m, 7H), 4.54 (d, J=6.05Hz, 2H), 1.77 (s, 9H)

[0729] Example 9-6-(4-amino-1-(tert-butyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-phenethyl-1H-indole-2-carboxamide

[0730]

[0731] Prepared as described for Example 1 using phenethylamine in place of 2-aminothiazole to obtain as a white solid (39 mg, 36%).

[0732] LCMS: purity > 95%, [M+H] + 454.3.

[0733] 1 H NMR (400MHz, DMSO-d6) δ11.72-11.81 (m, 1H), 8.68 (t, J=5.69Hz, 1H), 8.32 (s, 1H), 7.79 (d, J=8.31Hz, 1H), 7.69 (s, 1H), 7.25-7.36 (m, 5H), 7.17-7.25 (m, 2H), 3.49-3.57 (m, 2H), 2.89 (t, J=7.37Hz, 2H), 1.77 (s, 9H)

[0734] Example 10-6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(cyclopropylmethyl)-1H-indole-2-carboxamide

[0735]

[0736] Prepared as described for Example 1 using cyclopropylmethylamine in place of 2-aminothiazole to obtain as a beige solid (64 mg, 55%).

[0737] LCMS: purity > 95%, [M+H] + 404.2.

[0738] 1 H NMR (400MHz, DMSO-d6) δ11.73 (s, 1H), 8.63 (t, J=5.78Hz, 1H), 8.24 (s, 1H), 7.78 (d, J=8.25Hz, 1H), 7.70 (s, 1H), 7.34 (dd, J=1. 47, 8.25Hz, 1H), 7.22 (d, J=1.22Hz, 1H), 3.19 (t, J=6.27Hz, 2H), 1.77 (s, 9H), 1.06 (s, 1H), 0.43-0.50 (m, 2H), 0.23-0.30 (m, 2H)

[0739] Example 11-6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(2,2,2-trifluoroethyl)-1H-indole-2-carboxamide

[0740]

[0741] Prepared as described for Example 1 using 2,2,2-trifluoroethan-1-amine in place of 2-aminothiazole to obtain as a beige solid (68 mg, 54%).

[0742] LCMS: purity > 95%, [M+H] + 432.2.

[0743] 1 H NMR (400MHz, DMSO-d6) δ11.85-11.95 (m, 1H), 9.17 (t, J=6.39Hz, 1H), 8.32 (s, 1H), 7.82 (d, J=8.31Hz , 1H), 7.71 (s, 1H), 7.37 (dt, J=1.59, 8.00Hz, 1H), 7.33-7.35 (m, 1H), 4.09-4.20 (m, 2H), 1.78 (s, 9H).

[0744] Example 12-6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(2,2-difluoroethyl)-1H-indole-2-carboxamide

[0745]

[0746] Prepared as described for Example 1 using 2,2-difluoroethan-1-amine in place of 2-aminothiazole to obtain as a yellow solid (41 mg, 34%).

[0747] LCMS: purity > 95%, [M+H] + 414.2.

[0748] 1 H NMR (400MHz, DMSO-d6) δ11.77-11.88 (m, 1H), 8.93 (t, J=5.99Hz, 1H), 8.25 (s, 1H), 7.80 (d, J=8.25Hz, 1H), 7.71 (s, 1H), 7.36 (dd, J=1.47, 8.25Hz, 1H), 7.28 (d, J=1.34Hz, 1H), 6.16 (tt, J=3.91, 55.80Hz, 1H), 3.63-3.93 (m, 2H), 1.77 (s, 9H).

[0749] Example 13-6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-ethoxy-1H-indole-2-carboxamide

[0750]

[0751] Prepared as described for Example 1 using O-ethylhydroxylamine hydrochloride in place of 2-aminothiazole to obtain as a yellow solid (56 mg, 49%).

[0752] LCMS: purity > 95%, [M+H] + 394.2.

[0753] 1 H NMR (400MHz, DMSO-d6) δ11.85 (br s, 1H), 11.75 (br s, 1H), 8.24 (s, 1H), 7.78 (d, J=8.25Hz, 1H), 7.70 (s, 1H), 7.35 (dd, J=1.47, 8.25H z, 1H), 7.10 (s, 1H), 3.98 (q, J=7.00Hz, 2H), 1.77 (s, 9H), 1.25 (t, J=7.00Hz, 3H).

[0754] Example 14-6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(cyclopropylmethoxy)-1H-indole-2-carboxamide

[0755]

[0756] Prepared as described for Example 1 using O-(cyclopropylmethyl)hydroxylamine hydrochloride in place of 2-aminothiazole to obtain as a yellow solid (68 mg, 56%).

[0757] LCMS: purity > 95%, [M+H] + 420.2.

[0758] 1 H NMR (400MHz, DMSO-d6) δ11.84 (s, 1H), 11.77 (br s, 1H), 8.28 (s, 1H), 7.78 (d, J=8.25Hz, 1H), 7.70 (s, 1H), 7.35 (dd, J=1.44, 8.28Hz, 1H), 7.10 (s, 1H), 3.76 ( d, J=7.15Hz, 2H), 1.77 (s, 9H), 1.14 (ddd, J=2.90, 4.65, 7.79Hz, 1H), 0.52-0.60 (m, 2H), 0.25-0.34 (m, 2H).

[0759] Example 15-6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(1,3,4-thiadiazol-2-yl)-1H-indole-2-carboxamide

[0760]

[0761] Prepared as described for Example 1 using 1,3,4-thiadiazol-2-amine in place of 2-aminothiazole to obtain as a yellow solid (22 mg, 18%).

[0762] LCMS: purity 90-95%, [M+H] + 434.2.

[0763] 1 H NMR(400MHz, DMSO-d6)δ12.04(br s, 1H), 9.16 (s, 1H), 8.25 (s, 1H), 8.17 (s, 1H), 7.85 (d, J=8.31Hz, 1H), 7.75 (s, 1H), 7.69 (s, 1H), 7.39 (dd, J=1.44, 8.28Hz, 1H), 1.78 (s, 9H).

[0764] Example 16-6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(1-methylpyrazol-3-yl)-1H-indole-2-carboxamide

[0765]

[0766] Prepared as described for Example 1 using 1-methyl-1H-pyrazol-3-amine in place of 2-aminothiazole to obtain as a white solid (46 mg, 37%).

[0767] LCMS: purity > 95%, [M+H] + 430.3.

[0768] 1 H NMR (400MHz, DMSO-d6) δ11.80-11.89 (m, 1H), 10.95 (s, 1H), 8.26 (s, 1H), 7.80 (d, J=8.25Hz, 1H), 7.73 (s, 1H), 7.60-7.6 6 (m, 1H), 7.56 (d, J=1.34Hz, 1H), 7.36 (dd, J=1.50, 8.22Hz, 1H), 6.63 (d, J=2.20Hz, 1H), 3.79-3.83 (m, 3H), 1.78 (s, 9H).

[0769] Example 17-6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(2-methoxyethoxy)-1H-indole-2-carboxamide

[0770]

[0771] Prepared as described for Example 1 using O-(2-methoxyethyl)hydroxylamine in place of 2-aminothiazole to obtain as a white solid (31 mg, 25%).

[0772] LCMS: purity 90-95%, [M+H] + 424.3.

[0773] 1 H NMR (400MHz, DMSO-d6) δ11.86 (br s, 2H), 8.24 (s, 1H), 7.78 (d, J=8.25Hz, 1H), 7.70 (s, 1H), 7.35 (dd, J=1.47, 8.25Hz, 1H), 7.12 (br s, 1H), 4.02-4.11 (m, 2H), 3.49-3.66 (m, J=3.70, 5.30Hz, 2H), 3.31 (br s, 3H), 1.77 (s, 9H).

[0774] Example 18-6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(2-methylpyrazol-3-yl)-1H-indole-2-carboxamide

[0775]

[0776] Prepared as described for Example 1 using 1-methyl-1H-pyrazol-5-amine in place of 2-aminothiazole to obtain as a beige solid (25 mg, 20%).

[0777] LCMS: purity 90-95%, [M+H] + 430.3.

[0778] 1 H NMR (400MHz, DMSO-d6) δ12.02 (br s, 1H), 10.42 (br s, 1H), 8.25 (s, 1H), 7.85 (d, J=8.25Hz, 1H), 7.66-7.79 (m, 1H), 7.47 (br s, 1H), 7.43 (d, J=1.90Hz, 1H), 7.39 (dd, J=1.47, 8.25Hz, 1H), 6.28 (d, J=1.96Hz, 1H), 3.74 (s, 3H), 1.75-1.80 (m, 9H).

[0779] Example 19-6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-phenyl-1H-indole-2-carboxamide

[0780]

[0781] Prepared as described for Example 1 using aniline instead of 2-aminothiazole to obtain as a beige solid (30 mg, 24%).

[0782] LCMS: purity > 95%, [M+H] + 426.2.

[0783] 1 H NMR (400MHz, DMSO-d6) δ11.89-11.98 (m, 1H), 10.28 (s, 1H), 8.29 (s, 1H), 7.83-7.90 (m, 2H), 7.82 (d, J=0.92 Hz, 1H), 7.74 (s, 1H), 7.52 (d, J=1.41Hz, 1H), 7.32-7.46 (m, 3H), 7.13 (tt, J=0.90, 7.20Hz, 1H), 1.78 (s, 9H).

[0784] Example 20-6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(2-hydroxyethyl)-1H-indole-2-carboxamide

[0785]

[0786] To a mixture of 6-(4-amino-1-(tert-butyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-1H-indole-2-carboxylic acid (100 mg, 0.28 mmol) and PyBOP (148 mg, 0.28 mmol) in DMF (2 ml) was added triethylamine (0.12 ml, 0.84 mmol) and ethanolamine (17 μL, 0.17 mmol). The mixture was stirred at room temperature for 18 hours, then diluted with water and extracted with EtOAc (3x). The combined extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (10% MeOH in DCM) to afford 6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(2-hydroxyethyl)-1H-indole-2-carboxamide (32 mg, 0.08 mmol, 28%) as a beige solid.

[0787] LCMS: purity > 95%, [M+H] + 394.4.

[0788] 1 H NMR (400MHz, DMSO-d6) δ11.66-11.80 (m, 1H), 8.53 (t, J=5.90Hz, 1H), 8.24 (s, 1H), 7.77 (d, J=8.25Hz, 1H), 7.69 (s, 1H), 7. 33 (dd, J=1.47, 8.19Hz, 1H), 7.13-7.26 (m, 1H), 4.78 (s, 1H), 3.55 (q, J=5.80Hz, 2H), 3.37 (q, J=5.80Hz, 2H), 1.77 (s, 9H).

[0789] Example 21-6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)-1H-indole-2-carboxamide

[0790]

[0791] Prepared as described for Example 1 using 5-methyl-1,3,4-thiadiazol-2-amine in place of 2-aminothiazole to obtain as a white solid (9 mg, 7%).

[0792] LCMS: purity > 95%, [M+H] + 448.3.

[0793] 1H NMR(400MHz, DMSO-d6)δ12.05(br s, 1H), 8.25 (s, 1H), 8.19 (s, 1H), 7.84 (d, J=8.25Hz, 1H), 7.74 (s, 1H), 7.68 (s, 1H), 7.39 (dd, J=1.44, 8.28Hz, 1H), 2.64 (s, 3H), 1.78 (s, 9H).

[0794] Example 22-6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(1,2,4-thiadiazol-5-yl)-1H-indole-2-carboxamide

[0795]

[0796] To a suspension of 6-(4-amino-1-(tert-butyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-1H-indole-2-carboxylic acid (175 mg, 0.5 mmol) in DCM (5 mL) was added oxalyl chloride (51 μL, 0.6 mmol) and a drop of DMF. The mixture was stirred at room temperature for 1 hour, then concentrated under reduced pressure, and azeotroped with toluene to obtain a yellow solid. This was redissolved in DCM (5 ml), followed by the addition of 1,2,4-thiadiazole-5-amine (56 mg, 0.5 mmol), DIPEA (0.1 ml, 0.6 mmol), and DMAP (3 mg, 5 mol%). The reaction was stirred at room temperature for 24 hours, then concentrated under reduced pressure. The residue was partitioned between EtOAc and water, then filtered to remove the solids. The organic phase was separated and washed with saturated NaHCO and brine, dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (0-100% EtOAc in isohexane) to give the crude product. This was further purified by preparative HPLC to afford 6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(1,2,4-thiadiazol-5-yl)-1H-indole-2-carboxamide (16 mg, 0.03 mmol, 7%) as a white solid.

[0797] LCMS: purity 90-95%, [M+H] + 434.2.

[0798] 1H NMR (400MHz, DMSO-d6) δ12.10 (br s, 1H), 8.48 (s, 1H), 8.25 (s, 1H), 8.15 (s, 1H), 7.85 (d, J=8.25Hz, 1H), 7.75 (s, 1H), 7.67 (br s, 1H), 7.40 (dd, J=1.41, 8.31Hz, 1H), 1.75-1.82 (m, 9H).

[0799] Example 23-6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(3-thienyl)-1H-indole-2-carboxamide

[0800]

[0801] Prepared as described for Example 1 using 3-aminothiophene oxalate in place of 2-aminothiazole to obtain as a white solid (45 mg, 36%).

[0802] LCMS: purity > 95%, [M+H] + 432.2.

[0803] 1 H NMR (400MHz, DMSO-d6) δ11.90-12.01 (m, 1H), 10.80 (s, 1H), 8.25 (s, 1H), 7.84 (d, J=8.25Hz, 1H), 7.71 -7.77 (m, 2H), 7.52 (dd, J=3.21, 5.17Hz, 1H), 7.45 (d, J=1.34Hz, 1H), 7.34-7.41 (m, 2H), 1.78 (s, 9H).

[0804] Example 24-6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-thiazol-5-yl 1H-indole-2-carboxamide

[0805]

[0806] Prepared as described for Example 1 using thiazol-5-amine in place of 2-aminothiazole, obtained as a white solid (14 mg, 11%).

[0807] LCMS: purity > 95%, [M+H] + 433.2.

[0808] 1H NMR(400MHz, DMSO-d6)δ12.07(br s, 1H), 11.74-12.01 (m, 1H), 8.65 (d, J = 0.73Hz, 1H), 8.21-8.28 (m, 1H), 7.88 (d, J = 8.46Hz, 1 H), 7.83 (s, 1H), 7.75 (s, 1H), 7.50 (s, 1H), 7.40 (dd, J=1.44, 8.28Hz, 1H), 1.73-1.83 (m, 9H).

[0809] Example 25-6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-isoxazol-4-yl-1H-indole-2-carboxamide

[0810]

[0811] A mixture of 6-(4-amino-1-(tert-butyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-1H-indole-2-carboxylic acid (100 mg, 0.28 mmol), EDCI.HCl (109 mg, 0.57 mmol) and HOBt.HO (87 mg, 0.57 mmol) in DMF (4 ml) was stirred at room temperature for 1 hour before isoxazol-4-amine (34 mg, 0.28 mmol) was added. After 1 hour, DIPEA (0.14 ml, 0.86 mmol) was added and the mixture was stirred for 3 hours. Additional DIPEA (0.1 ml, 0.6 mmol) was added and the reaction was stirred at room temperature for 18 hours before being concentrated under reduced pressure. The residue was partitioned between DCM and water, separated, and the organic phase was dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (0-5% MeOH in DCM) to give the crude product. This was further purified by preparative HPLC to afford 6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-isoxazol-4-yl-1H-indole-2-carboxamide (7 mg, 0.02 mmol, 6%) as a white solid.

[0812] LCMS: purity > 95%, [M+H] + 417.2.

[0813] 1H NMR (400MHz, DMSO-d6) δ12.01 (s, 1H), 10.88 (s, 1H), 9.28 (s, 1H), 8.78 (s, 1H), 8.25 (s, 1H), 7.86 (d, J=8.31Hz, 1H), 7.75 (s, 1H), 7.40 (d, J=1.47Hz, 1H), 7.38-7.39 (m, 1H), 1.78 (s, 9H)

[0814] Example 26-6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-methylthiazol-2-yl)-1H-indole-2-carboxamide

[0815]

[0816] Prepared as described for Example 1 using 4-methylthiazol-2-amine in place of 2-aminothiazole to obtain as a beige solid (5 mg, 1%).

[0817] LCMS: purity > 95%, [M+H] + 447.2.

[0818] 1 H NMR (400MHz, DMSO-d6) δ12.70 (br s, 1H), 12.02 (br s, 1H), 8.25 (s, 1H), 7.83 (d, J=8.01Hz, 1H), 7.74 (s, 1H), 7.69 (s, 1H), 7.39 (dd, J=1.44, 8.28Hz, 1H), 6.82 (s, 1H), 2.33 (d, J=0.92Hz, 3H), 1.78 (s, 9H).

[0819] Example 27-6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(1-ethylpyrazol-3-yl)-1H-indole-2-carboxamide

[0820]

[0821] Prepared as described for Example 1 using 1-ethyl-1H-pyrazol-3-amine in place of 2-aminothiazole to obtain as an off-white solid (26 mg, 20%).

[0822] LCMS: purity > 95%, [M+H] + 444.3.

[0823] 1H NMR (400MHz, DMSO-d6) δ11.77-11.90 (m, 1H), 10.98 (s, 1H), 8.25 (s, 1H), 7.79 (d, J=8.31Hz, 1H), 7.72 (s, 1H), 7.68 (s, 1H), 7.57 (d, J=1.28Hz, 1H), 7.36 (dd, J=1.50, 8.22Hz, 1H), 6.63 (d, J=2.26Hz, 1H), 4.10 (q, J=7.25Hz, 2H), 1.77 (s, 9H), 1.40 (t, J=7.24Hz, 3H).

[0824] Example 28-6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-[1-(2-methoxyethyl)pyrazol-3-yl]-1H-indole-2-carboxamide

[0825]

[0826] Prepared as described for Example 1 using 1-(2-methoxyethyl)-1H-pyrazol-3-amine in place of 2-aminothiazole to obtain as a white solid (29 mg, 21%).

[0827] LCMS: purity > 95%, [M+H] + 474.3.

[0828] 1 H NMR (400MHz, DMSO-d6) δ 11.81-11.88 (m, 1H), 10.99 (s, 1H), 8.22-8.26 (m, 1H), 7.79 (d, J = 8.25Hz, 1H), 7.72 (s, 1H), 7.66 (d, J = 2.26Hz, 1H), 7.57 ( d, J=1.28Hz, 1H), 7.36 (dd, J=1.47, 8.25Hz, 1H), 6.64 (d, J=2.26Hz, 1H), 4.22 (t, J=5.32Hz, 2H), 3.70 (t, J=5.32Hz, 2H), 3.25 (s, 3H), 1.77 (s, 9H).

[0829] Example 29-6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-[1-(2-fluoroethyl)pyrazol-3-yl]-1H-indole-2-carboxamide

[0830]

[0831] Prepared as described for Example 1 using 1-(2-fluoroethyl)-1H-pyrazol-3-amine in place of 2-aminothiazole to obtain as a white solid (32 mg, 24%).

[0832] LCMS: purity > 95%, [M+H] + 462.3.

[0833] 1 H NMR (400MHz, DMSO-d6) δ11.81-11.90 (m, 1H), 11.03 (s, 1H), 8.24 (s, 1H), 7.8 0 (d, J=8.25Hz, 1H), 7.72 (d, J=2.02Hz, 2H), 7.58 (d, J=1.41Hz, 1H), 7.36 (dd, J=1.50, 8.28Hz, 1H), 6.68(d, J=2.26Hz, 1H), 4.84(t, J=4.71Hz, 1H), 4.72(t , J=4.71Hz, 1H), 4.43 (t, J=4.71Hz, 1H), 4.36 (t, J=4.71Hz, 1H), 1.77 (s, 9H).

[0834] Example 30-6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(3-pyridinyl)-1H-indole-2-carboxamide

[0835]

[0836] Prepared as described for Example 1 using 3-aminopyridine instead of 2-aminothiazole to obtain as a yellow solid (25 mg, 100%).

[0837] LCMS: purity >95%, [MH] - 427.3.

[0838] 1 H NMR (400MHz, DMSO-d6) δ11.93-12.04 (m, 1H), 10.50 (s, 1H), 8.99 (d, J=2.20Hz, 1H), 8.34 (dd, J=1.44, 4.68Hz, 1H) , 8.21-8.27 (m, 2H), 7.87 (d, J=8.25Hz, 1H), 7.75 (s, 1H), 7.54 (d, J=1.41Hz, 1H), 7.37-7.47 (m, 2H), 1.78 (s, 9H).

[0839] Example 31-6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-pyridinyl)-1H-indole-2-carboxamide

[0840]

[0841] Prepared as described for Example 1 using 4-aminopyridine in place of 2-aminothiazole to obtain as a yellow solid (22 mg, 9%).

[0842] LCMS: purity >95%, [MH] - 427.3.

[0843] 1 H NMR (400MHz, DMSO-d6) δ11.98-12.05 (m, 1H), 10.60 (s, 1H), 8.48-8.53 (m, 2H), 8.25 (s, 1H), 7.88 (d, J=8.31 Hz, 1H), 7.81-7.85 (m, 2H), 7.75 (s, 1H), 7.58 (d, J=1.34Hz, 1H), 7.40 (dd, J=1.44, 8.28Hz, 1H), 1.78 (s, 9H).

[0844] Example 32-6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-[1-(2-hydroxyethyl)pyrazol-3-yl]-1H-indole-2-carboxamide

[0845]

[0846] Prepared as described for Example 1 using 2-(3-amino-1H-pyrazol-1-yl)ethan-1-ol in place of 2-aminothiazole to obtain as a beige solid (15 mg, 7%).

[0847] LCMS: purity >95%, [MH] - 460.3.

[0848] 1H NMR (400MHz, DMSO-d6) δ11.81-11.88 (m, 1H), 10.99 (s, 1H), 8.26 (s, 1H), 7.80 (d, J=8.25Hz, 1H), 7.72 (s, 1H), 7.65 (d, J=2.20Hz, 1H), 7. 57 (d, J=1.41Hz, 1H), 7.36 (dd, J=1.47, 8.25Hz, 1H), 6.64 (d, J=2.26Hz, 1H), 4.10 (t, J=5.65Hz, 2H), 3.75 (t, J=5.59Hz, 2H), 1.78 (s, 9H).

[0849] Example 33-6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-3-chloro-N-methyl-1H-indole-2-carboxamide

[0850]

[0851] Prepared as described for Example 1, using 6-(4-amino-1-(tert-butyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-3-chloro-1H-indole-2-carboxylic acid and methylamine hydrochloride in place of 6-(4-amino-1-(tert-butyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-1H-indole-2-carboxylic acid and 2-aminothiazole to obtain as a white solid (14 mg, 14%).

[0852] LCMS: purity >95%, [MH]-396.2.

[0853] 1 H NMR(300MHz, DMSO-d6)δ12.07(br s, 1H), 8.25 (s, 1H), 7.97 (q, J=4.43Hz, 1H), 7.70-7.78 (m, 2H), 7.47 (d, J=8.18Hz, 1H), 2.90 (d, J=4.62Hz, 3H), 1.75-1.90 (m, 9H).

[0854] Example 34-6-(4-amino-1-isopropyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-cyclopropyl-1H-indole-2-carboxamide

[0855]

[0856] Prepared as described for Example 1, using 6-(4-amino-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-1H-indole-2-carboxylic acid and cyclopropylmethylamine in place of 6-(4-amino-1-(tert-butyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-1H-indole-2-carboxylic acid and 2-aminothiazole to obtain as a white solid (20 mg, 9%).

[0857] LCMS: purity > 95%, [M+H] + 376.3.

[0858] 1 H NMR (400MHz, DMSO-d6) δ8.25 (s, 1H), 7.80 (d, J=8.25Hz, 1H), 7.74 (s, 1H), 7.36 (dd, J=1.53, 8.25Hz, 1H), 7.19 (s , 1H), 5.08 (spt, J=6.63Hz, 1H), 2.82-2.91 (m, 1H), 1.51 (d, J=6.72Hz, 6H), 0.70-0.83 (m, 2H), 0.59-0.68 (m, 2H).

[0859] Example 35-6-(4-amino-1-isopropyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(2-fluoroethyl)-1H-indole-2-carboxamide

[0860]

[0861] Prepared as described for Example 1, using 6-(4-amino-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-1H-indole-2-carboxylic acid and 2-fluoroethylamine hydrochloride in place of 6-(4-amino-1-(tert-butyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-1H-indole-2-carboxylic acid and 2-aminothiazole to obtain as a tan solid (172 mg, 51%).

[0862] LCMS: purity > 95%, [M+H] + 382.2.

[0863] 1H NMR (400MHz, DMSO-d6) δ11.72-11.83 (m, 1H), 8.79 (t, J=5.62Hz, 1H), 8.24 (s, 1H), 7.79 (d, J=8.31Hz, 1H), 7.73 (s, 1H), 7.36 (dd, J=1.53, 8.25Hz, 1H), 7.24 (dd, J=0.67, 2.02Hz, 1H), 5.08 (spt, J=6.70Hz, 1H), 4.64 (t, J=5.07Hz, 1H), 4 .52 (t, J=5.04Hz, 1H), 3.62 (qd, J=5.32, 26.78Hz, 2H), 1.51 (d, J=6.72Hz, 6H).

[0864] Example 36-6-(4-amino-1-isopropyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-ethoxy-1H-indole-2-carboxamide

[0865]

[0866] Prepared as described for Example 1, using 6-(4-amino-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-1H-indole-2-carboxylic acid and O-ethylhydroxylamine in place of 6-(4-amino-1-(tert-butyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-1H-indole-2-carboxylic acid and 2-aminothiazole to obtain as a beige solid (68 mg, 60%).

[0867] LCMS: purity > 95%, [M+H] + 380.2.

[0868] 1 H NMR (400MHz, DMSO-d6) δ11.85 (s, 1H), 11.74 (br s, 1H), 8.25 (s, 1H), 7.79 (d, J=8.31Hz, 1H), 7.72 (s, 1H), 7.37 (dd, J=1.47, 8.25Hz, 1H), 7.10 (s, 1H), 5.08 (spt, J=6.71Hz, 1H), 3.98 (q, J=6.97Hz, 2H), 1.51 (d, J=6.66Hz, 6H), 1.23-1.27 (m, 3H).

[0869] Example 37-6-(4-amino-1-isopropyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-thiazol-2-yl-1H-indole-2-carboxamide

[0870]

[0871] Prepared as described for Example 1 using 6-(4-amino-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-1H-indole-2-carboxylic acid in place of 6-(4-amino-1-(tert-butyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-1H-indole-2-carboxylic acid to obtain as a yellow solid (42 mg, 10%).

[0872] LCMS: purity > 95%, [M+H] + 419.2.

[0873] 1 H NMR (400MHz, DMSO-d6) δ12.76 (br s, 1H), 12.06 (br s, 1H), 8.25 (s, 1H), 7.85 (d, J=8.31Hz, 1H), 7.77 (s, 1H), 7.75 (br s, 1H), 7.58 (d, J=3.55Hz, 1H), 7.42 (dd, J=1.47, 8.25Hz, 1H), 7.30 (d, J=3.48Hz, 1H), 5.09 (spt, J=6.70Hz, 1H), 1.52 (d, J=6.66Hz, 6H).

[0874] Example 38-6-(4-amino-1-isopropyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(1-methylpyrazol-3-yl)-1H-indole-2-carboxamide

[0875]

[0876] Prepared as described for Example 1, using 6-(4-amino-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-1H-indole-2-carboxylic acid and 1-methyl-1H-pyrazol-3-amine in place of 6-(4-amino-1-(tert-butyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-1H-indole-2-carboxylic acid and 2-aminothiazole to obtain as a white solid (49 mg, 26%).

[0877] LCMS: purity > 95%, [M+H] + 416.2.

[0878] 1H NMR (400MHz, DMSO-d6) δ11.81-11.88 (m, 1H), 10.96 (s, 1H), 8.25 (s, 1H), 7.80 (d, J=7.94Hz, 1H), 7.74 (s, 1H), 7.63 (d, J=2.14Hz, 1H), 7.5 6 (d, J=1.34Hz, 1H), 7.38 (dd, J=1.50, 8.28Hz, 1H), 6.63 (d, J=2.20Hz, 1H), 5.08 (spt, J=6.70Hz, 1H), 3.81 (s, 3H), 1.51 (d, J=6.66Hz, 6H).

[0879] Example 39-6-(4-amino-1-isopropyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(1,3,4-thiadiazol-2-yl)-1H-indole-2-carboxamide

[0880]

[0881] Prepared as described for Example 1, using 6-(4-amino-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-1H-indole-2-carboxylic acid and 1,3,4-thiadiazol-2-amine in place of 6-(4-amino-1-(tert-butyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-1H-indole-2-carboxylic acid and 2-aminothiazole to obtain as a tan solid (3 mg, 2%).

[0882] LCMS: purity > 95%, [M+H] + 420.1.

[0883] 1 H NMR (400MHz, DMSO-d6) δ11.94 (br s, 1H), 9.08 (br s, 1H), 8.25 (s, 1H), 8.21 (s, 1H), 7.83 (d, J=8.31Hz, 1H), 7.77 (s, 1H), 7.58 (br s, 1H), 7.39 (br d, J=8.25Hz, 1H), 5.08 (quin, J=6.71Hz, 1H), 1.52 (d, J=6.72Hz, 6H).

[0884] Example 40-6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-methyl-1H-indole-2-carboxamide

[0885]

[0886] A mixture of 6-bromo-N-methyl-1H-indole-2-carboxamide (253 mg, 1 mmol), XPhos-Pd-G2 (16 mg, 0.02 mmol), XPhos (19 mg, 0.04 mmol), B2(OH)4 (269 mg, 3 mmol) and KOAc (294 mg, 3 mmol) in EtOH (10 ml) was degassed with argon for 5 min and then heated at 80° C. for 2 h. A degassed aqueous solution of K2CO3 (1.8 M, 1.7 ml, 3.0 mmol) and a degassed solution of 3-bromo-1-(tert-butyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (270 mg, 1.0 mmol) in THF (2 ml) were added and the mixture was heated at 80° C. for 18 h. The reaction was cooled to room temperature, diluted with water, and extracted with EtOAc (3×). The combined organic phases were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue, which was purified by flash column chromatography to obtain 204 mg of a solid, which was further purified by preparative HPLC to obtain 6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-methyl-1H-indole-2-carboxamide (76 mg, 21%) as a white solid.

[0887] LCMS: purity >95%, [MH] - 362.2.

[0888] 1 H NMR (400MHz, DMSO-d6) δ11.74 (s, 1H), 8.52 (q, J = 4.42Hz, 1H), 8.24 (s, 1H), 7.77 (d, J = 8.25Hz, 1H), 7. 70 (s, 1H), 7.33 (dd, J=1.50, 8.22Hz, 1H), 7.14 (d, J=1.28Hz, 1H), 2.84 (d, J=4.65Hz, 3H), 1.77 (s, 9H).

[0889] Example 41-6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-cyclopropyl-1H-indole-2-carboxamide

[0890]

[0891] Prepared as described for Example 40 using 6-bromo-N-cyclopropyl-1H-indole-2-carboxamide in place of 6-bromo-N-methyl-1H-indole-2-carboxamide to obtain as a white solid (78 mg, 31%).

[0892] LCMS: purity >95%, [MH]- 390.2.

[0893] 1 H NMR (400MHz, DMSO-d6) δ11.71 (s, 1H), 8.52 (d, J = 4.10Hz, 1H), 8.24 (s, 1H), 7.76 (d, J = 8.25Hz, 1H), 7.69 (s, 1H), 7.33 (dd, J = 1.47, 8.25Hz, 1H), 7.17 (d, J=1.28Hz, 1H), 2.87 (qq, J=3.90, 7.30Hz, 1H), 1.77 (s, 9H), 0.67-0.77 (m, 2H), 0.57-0.67 (m, 2H).

[0894] Example 42-6-(4-amino-1-(tert-butyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-ethyl-1H-indole-2-carboxamide

[0895]

[0896] Prepared as described for Example 40 using 6-bromo-N-ethyl-1H-indole-2-carboxamide instead of 6-bromo-N-methyl-1H-indole-2-carboxamide to obtain as a white solid (77 mg, 31%).

[0897] LCMS: purity >95%, [MH]-378.2.

[0898] 1 H NMR (400MHz, DMSO-d6) δ 11.66-11.77 (m, 1H), 8.54 (t, J = 5.59Hz, 1H), 8.20-8.26 (m, 1H), 7.77 (d, J = 8.25Hz, 1H), 7.69 ( s, 1H), 7.33 (dd, J=1.50, 8.22Hz, 1H), 7.17 (d, J=1.28Hz, 1H), 3.33-3.38 (m, 2H), 1.77 (s, 9H), 1.16 (t, J=7.21Hz, 3H).

[0899] Example 43-6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-cyclobutyl-1H-indole-2-carboxamide

[0900]

[0901] Prepared as described for Example 40 using 6-bromo-N-cyclobutyl-1H-indole-2-carboxamide in place of 6-bromo-N-methyl-1H-indole-2-carboxamide to obtain as a white solid (93 mg, 30%).

[0902] LCMS: purity 85-90%, [MH] - 404.3.

[0903] 1 H NMR(400MHz, DMSO-d6)δ11.71(br s, 1H), 8.69 (d, J = 7.76Hz, 1H), 8.24 (s, 1H), 7.78 (d, J = 8.25Hz, 1H), 7.69 (s, 1H), 7.34 (dd, J = 1.50, 8.22Hz, 1H), 7.24 (d, J = 1.00Hz, 1H), 4.47 (br d, J=8.31Hz, 1H), 2.21-2.32(m, 2H), 2.03-2.16(m, 2H), 1.77(s, 9H), 1.67-1.75(m, 2H).

[0904] Example 44-6-(4-amino-1-(tert-butyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-1H-indole-2-carboxamide

[0905]

[0906] Prepared as described for Example 40 using 6-bromo-N-methoxy-1H-indole-2-carboxamide in place of 6-bromo-N-methyl-1H-indole-2-carboxamide to afford not the expected 6-(4-amino-1-(tert-butyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-1H-indole-2-carboxamide, but 6-(4-amino-1-(tert-butyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-1H-indole-2-carboxamide as a white solid (17 mg, 5%).

[0907] LCMS: purity >95%, [MH] - 350.2.

[0908] 1H NMR (400MHz, DMSO-d6) δ11.66-11.75 (m, 1H), 8.24 (s, 1H), 8.02 (br s, 1H), 7.77 (d, J=8.25Hz, 1H), 7.69 (s, 1H), 7.42 (br s, 1H), 7.33 (dd, J=1.50, 8.22Hz, 1H), 7.20 (d, J=1.34Hz, 1H), 1.77 (s, 9H).

[0909] Example 45-6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-3-fluoro-N-methyl-1H-indole-2-carboxamide

[0910]

[0911] Prepared as described for Example 40 using 6-bromo-3-fluoro-N-methyl-1H-indole-2-carboxamide in place of 6-bromo-N-methyl-1H-indole-2-carboxamide to obtain as a white solid (12 mg, 17%).

[0912] LCMS: purity > 95%, [M+H] + 382.2.

[0913] 1 H NMR (400MHz, DMSO-d6) δ11.62 (s, 1H), 8.24 (s, 1H), 7.85-7.97 (m, 1H), 7.77 (d, J=8.38H z, 1H), 7.65 (s, 1H), 7.40 (dd, J=1.34, 8.38Hz, 1H), 2.86 (d, J=4.58Hz, 3H), 1.77 (s, 9H).

[0914] Example 46-6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N,3-dimethyl-1H-indole-2-carboxamide

[0915]

[0916] Prepared as described for Example 40 using 6-bromo-N,3-dimethyl-1H-indole-2-carboxamide in place of 6-bromo-N-methyl-1H-indole-2-carboxamide to obtain as a white solid (28 mg, 20%).

[0917] LCMS: purity > 95%, [M+H] + 378.2.

[0918] 1H NMR (400MHz, DMSO-d6) δ11.38 (s, 1H), 8.24 (s, 1H), 7.89 (q, J=4.30Hz, 1H), 7.75 (d, J=8.19Hz, 1H), 7.63 (s, 1H), 7.33 (dd, J=1.47, 8.25Hz, 1H), 2.84 (d, J=4.58Hz, 3H), 2.52-2.55 (m, 3H), 1.77 (s, 9H).

[0919] Example 47-6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(2,5-dimethylpyrazol-3-yl)-1H-indole-2-carboxamide

[0920]

[0921] Prepared as described for Example 40 using 6-bromo-N-(1,3-dimethyl-1H-pyrazol-5-yl)-1H-indole-2-carboxamide in place of 6-bromo-N-methyl-1H-indole-2-carboxamide to obtain as a white solid (27 mg, 5%).

[0922] LCMS: purity >95%, [MH] - 444.3.

[0923] 1 H NMR(400MHz, DMSO-d6)δ12.01(br s, 1H), 10.25-10.45 (m, 1H), 8.25 (s, 1H), 7.85 (d, J=8.18Hz, 1H), 7.73 (s, 1H), 7.46 (s, 1H), 7.39 (dd, J=1.43, 8.27Hz, 1H), 6.06 (s, 1H), 3.65 (s, 3H), 2.15 (s, 3H), 1.77 (s, 9H).

[0924] Example 48-6-(4-amino-1-isopropyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-methyl-1H-indole-2-carboxamide

[0925]

[0926] Prepared as described for Example 40 using 3-bromo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine in place of 3-bromo-1-(tert-butyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine to obtain as a white solid (81 mg, 39%).

[0927] LCMS: purity > 95%, [M+H] +350.3.

[0928] 1 H NMR (400MHz, DMSO-d6) δ11.68-11.81 (m, 1H), 8.53 (q, J=4.44Hz, 1H), 8.24 (s, 1H), 7.77 (s, 1H), 7.72 (s, 1H), 7.35 (dd, J=1.50, 8.22Hz, 1H), 7.15 (d, J=1.28Hz, 1H), 5.08 (spt, J=6.69Hz, 1H), 2.84 (d, J=4.65Hz, 3H), 1.51 (d, J=6.66Hz, 6H).

[0929] Example 49-6-(4-amino-1-ethyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-methyl-1H-indole-2-carboxamide

[0930]

[0931] Prepared as described for Example 40 using 3-bromo-1-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine in place of 3-bromo-1-(tert-butyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine to obtain as a white solid (23 mg, 17%).

[0932] LCMS: purity > 95%, [M+H] + 336.2.

[0933] 1 H NMR (400MHz, DMSO-d6) δ11.72-11.82 (m, 1H), 8.53 (q, J=4.44Hz, 1H), 8.25 (s, 1H), 7.78 (d, J=8.43Hz, 1H), 7.72 (s, 1H), 7.3 5 (dd, J=1.50, 8.22Hz, 1H), 7.14 (d, J=1.34Hz, 1H), 4.39 (q, J=7.21Hz, 2H), 2.84 (d, J=4.58Hz, 3H), 1.43 (t, J=7.21Hz, 3H).

[0934] Example 50-6-(4-amino-1-cyclopropyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-methyl-1H-indole-2-carboxamide

[0935]

[0936] Prepared as described for Example 40 using 3-bromo-1-cyclopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine in place of 3-bromo-1-(tert-butyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine to obtain as a white solid (36 mg, 23%).

[0937] LCMS: purity > 95%, [M+H] + 348.3.

[0938] 1 H NMR (400MHz, DMSO-d6) δ11.71-11.81 (m, 1H), 8.53 (q, J=4.52Hz, 1H), 8.26 (s, 1H), 7.77 (d, J=8.25Hz, 1H), 7.69 (s, 1H), 7.32 (dd, J=1. 53, 8.25Hz, 1H), 7.14 (d, J=1.34Hz, 1H), 3.87 (tt, J=3.77, 7.35Hz, 1H), 2.83 (d, J=4.58Hz, 3H), 1.16-1.27 (m, 2H), 1.03-1.16 (m, 2H).

[0939] The following compounds were prepared in a manner analogous to those described above using synthetic procedures analogous to those detailed for Example 40:

[0940]

[0941]

[0942]

[0943] Example 60 - Biological Data

[0944] RET and KDR enzyme assays

[0945] Kinase activity was detected using the CisBio HTRF kinEASE kit based on time-resolved fluorescence transfer (FRET). For RET, the assay was performed in a 384-well white plate (Corning #3574) with a 10 μL reaction volume containing 1X CisBio enzyme buffer supplemented with a final concentration of 5 mM MgCl2, 1 mM DTT, 10 nM SEB, and 0.01% Triton X100. The same buffer was used for the KDR biochemical assay with the addition of 2 mM MnCl2.

[0946] Inhibitors were pre-incubated in the plate for 15 minutes with 5 μL of kinase and assay buffer at the following concentrations; 13 pM RET (Carna Biosciences; 08-159) and 150 pM KDR (Millipore; 14-630). Reactions were initiated by adding 5 μL of ATP and substrate at 2X final reaction concentrations. For RET, this was 18 μM and 2 μM, respectively; for KDR, this was 16 μM and 1 μM, respectively. Reactions were performed at ATP K of each target. m The measurement was carried out at room temperature for 20 minutes, and then supplemented with Eu 3 + - Termination was performed with cryptate-labeled TK antibody (1:100 dilution) and streptavidin-XL665 (128 nM) in 10 μL HTRF detection buffer containing EDTA. After incubation for 1 hour at room temperature, the FRET signal was measured using a Pherastar FS microplate reader.

[0947] The activity data (IC50) of the compounds of the present invention against RET and KDR enzymes are shown in Table 1 below.

[0948] Table 1 - RET and KDR enzyme activity data

[0949]

[0950]

[0951] BaF3 cell assay

[0952] Used originally by Daley and Baltimore 16 A system was developed whereby IL3-dependent BaF3 cells were modified to express an activated recombinant kinase. After removal of IL3, the modified cells were dependent on the activity of the recombinant kinase for survival and proliferation. KIF5B-RET expressing cells (from PasiJanne) were maintained in RPMI-1640 medium containing 10% FBS and appropriate antibiotics. 7BaF3 cell lines were obtained from BaF3 (a gift from R&D Systems) and KDR (Advanced Cellular Dynamics, San Diego). Non-modified BaF3 cells (WT) were maintained in RPMI-1640 medium containing 10% FBS and supplemented with 10 ng / mL recombinant mouse IL3 (R&D systems). For evaluation of compound IC50s, cells were plated in 384-well plates at 1500 or 3000 cells per well in 30 μL of medium and compounds were dispensed using an acoustic liquid handling platform (LABCYTE). After incubation of cells for 48 hours at 37°C in a humidified 5% CO2 atmosphere, viability was determined by adding 10 μL of CellTiter-Glo reagent (Promega) and measuring luminescence.

[0953] Cell viability data are presented in Table 2 below.

[0954] Table 2 - Cell viability data

[0955]

[0956]

[0957] In summary, this application includes but is not limited to the following:

[0958] 1. A compound having the structural formula (I) shown below or a pharmaceutically acceptable salt, hydrate or solvate thereof:

[0959]

[0960] in:

[0961] HET is selected from one of the following:

[0962]

[0963] in Indicates a connection point;

[0964] R1 is selected from hydrogen, (1-4C)haloalkyl, (1-4C)haloalkoxy or a group having the formula:

[0965] -LYQ

[0966] in:

[0967] L is absent or (1-5C)alkylene optionally substituted by one or more substituents selected from (1-2C)alkyl or oxo;

[0968] Y does not exist, or is O, S, SO, SO2, N(R a), C(O), C(O)O, OC(O), C(O)N(R a )、N(R a )C(O), N(R a )C(O)N(R b )、N(R a )C(O)O、OC(O)N(R a )、S(O)2N(R a ) or N(R a )SO2, where R a and R b are each independently selected from hydrogen or (1-4C)alkyl; and

[0969] Q is hydrogen, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, aryl, (3-10C)cycloalkyl, (3-10C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Q is optionally further substituted by one or more substituents independently selected from the group consisting of (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, amino, (1-4C)aminoalkyl, cyano, hydroxy, carboxyl, carbamoyl, sulfamoyl, thiol, urea, NR c R d , OR c 、C(O)R c 、C(O)OR c 、OC(O)R c 、C(O)N(R d )R c 、N(R d )C(O)R c 、S(O) y R c (where y is 0, 1 or 2), SO2N(R d )R c 、N(R d )SO2R c 、Si(R d )(R c )R e or (CH2) z NR d R c (where z is 1, 2 or 3); where R c , R d and R e are each independently selected from hydrogen, (1-6C)alkyl or (3-6C)cycloalkyl; or R c and R dmay be linked so that, together with the nitrogen atom to which they are attached, they form a 4-7 membered heterocyclic ring optionally substituted by one or more substituents selected from the group consisting of (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano or hydroxy; or

[0970] Q is optionally substituted with a group having the formula:

[0971] -L1-L Q1 -Z1

[0972] in:

[0973] L1 is absent or (1-3C)alkylene optionally substituted by one or more substituents selected from (1-2C)alkyl or oxo;

[0974] L Q1 is absent, or is selected from O, S, SO, SO2, N(R f ), C(O), C(O)O, OC(O), C(O)N(R f )、N(R f )C(O), N(R g )C(O)N(R f )、N(R f )C(O)O、OC(O)N(R f )、S(O)2N(R f ) or N(R f )SO2, where R f and R g are each independently selected from hydrogen or (1-2C)alkyl; and

[0975] Z1 is hydrogen, (1-6C)alkyl, aryl, aryl(1-2C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Z1 is optionally substituted by one or more substituents selected from the group consisting of (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano, hydroxy, carboxyl, carbamoyl, sulfamoyl, thiol, ureido, aryl, heteroaryl, heterocyclyl, (3-6C)cycloalkyl, NR h R i , OR h 、C(O)R h 、C(O)OR h 、OC(O)R h 、C(O)N(R i )R h 、N(R i)C(O)R h 、S(O) y R h (where y is 0, 1 or 2), SO2N(R i )R h 、N(R i )SO2R h or (CH2) z NR i R h (where z is 1, 2 or 3); where R h and R i are each independently selected from hydrogen, (1-4C)alkyl or (3-6C)cycloalkyl;

[0976] R 1a and R 1b are each selected from H, (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano, hydroxy, carboxyl, carbamoyl, sulfamoyl or thiol;

[0977] W is selected from O, S or NR 1 , where R 1 Selected from H or (1-2C)alkyl;

[0978] Bonds a, b, c and d are independently selected from single bonds or double bonds;

[0979] X1 and X2 are each independently selected from N or CR when bond a is a double bond j , or when bond a is a single bond, each independently selected from NR k or CR j R k ;

[0980] in

[0981] R j is selected from hydrogen, halo, (1-4C)alkyl, (1-4C)alkoxy, amino, (1-4C)alkylamino, (1-4C)dialkylamino, cyano, (2C)alkynyl, C(O)R j1 、C(O)OR j1 、OC(O)R j1 、C(O)N(R j2 )R j1 、N(R j2 )C(O)R j1 、S(O) y R j1 (where y is 0, 1 or 2), SO2N(R j2 )R j1 、N(R j2 )SO2Rj1 or (CH2) z NR j1 R j2 (wherein z is 1, 2 or 3); wherein the (1-4C)alkyl is optionally substituted with one or more substituents selected from the group consisting of amino, hydroxy, (1-2C)alkoxy or halo;

[0982] R k and R j are independently selected from hydrogen or (1-4C)alkyl; and

[0983] R j1 and R j2 are each independently selected from hydrogen or (1-4C)alkyl;

[0984] X3 is selected from N or CR when bond b is a double bond l , or when bond b is a single bond, selected from NR m or CR l R m ;

[0985] in

[0986] R l is selected from hydrogen, halo, (1-4C)alkyl, (1-4C)alkoxy, amino, (1-4C)alkylamino, (1-4C)dialkylamino, cyano, (2C)alkynyl, C(O)R l1 、C(O)OR l1 、OC(O)R l1 、C(O)N(R l2 )R l1 、N(R l2 )C(O)R l1 、S(O) y R l1 (where y is 0, 1 or 2), SO2N(R l2 )R l1 、N(R l2 )SO2R l1 or (CH2) z NR l2 R l1 (wherein z is 1, 2 or 3); wherein the (1-4C)alkyl is optionally substituted with one or more substituents selected from the group consisting of amino, hydroxy, (1-2C)alkoxy or halo;

[0987] R l and R m are independently selected from hydrogen or (1-4C)alkyl; and

[0988] R l1 and R l2are each independently selected from hydrogen or (1-4C)alkyl;

[0989] X4 is selected from N or CR when bond d is a double bond n , or when bond d is a single bond, selected from NR o or CR n R o ;

[0990] in

[0991] R n is selected from hydrogen, halo, (1-4C)alkyl, (1-4C)alkoxy, amino, (1-4C)alkylamino, (1-4C)dialkylamino, cyano, (2C)alkynyl, C(O)R n1 、C(O)OR n1 、OC(O)R n1 、C(O)N(R n2 )R n1 、N(R n2 )C(O)R n1 、S(O) y R n1 (where y is 0, 1 or 2), SO2N(R n2 )R n1 、N(R n2 )SO2R n1 or (CH2) z NR n1 R n2 (wherein z is 1, 2 or 3); wherein the (1-4C)alkyl is optionally substituted with one or more substituents selected from the group consisting of amino, hydroxy, (1-2C)alkoxy or halo;

[0992] R n and R o are independently selected from hydrogen or (1-4C)alkyl; and

[0993] R n1 and R n2 are each independently selected from hydrogen or (1-4C)alkyl;

[0994] R2 is selected from hydrogen, (1-4C)alkyl or a group having the formula:

[0995] -L2-Y2-Q2

[0996] in:

[0997] L2 is absent or (1-3C)alkylene optionally substituted by one or more substituents selected from (1-2C)alkyl or oxo;

[0998] Y2 does not exist, or is C(O), C(O)O, C(O)N(Rp ), where R p is selected from hydrogen or (1-4C)alkyl and

[0999] Q2 is hydrogen, (1-6C) alkyl, aryl, (3-8C) cycloalkyl, (3-8C) cycloalkenyl, heteroaryl or heterocyclyl; wherein Q2 is optionally further substituted by one or more substituents independently selected from the group consisting of (1-4C) alkyl, halo, (1-4C) haloalkyl, (1-4C) haloalkoxy, amino, cyano, hydroxy, carboxyl, carbamoyl, sulfamoyl, NR q R r , OR q , where R q and R r are each independently selected from hydrogen, (1-4C)alkyl or (3-6C)cycloalkyl;

[1000] R3 is selected from the group having the following formula:

[1001] -Y3-Q3

[1002] in:

[1003] Y3 is C(O), C(O)N(R s )、N(R s )(O)C、C(O)OR s 、OC(O)CR s , triazole, oxadiazole or tetrazole, wherein R s is selected from hydrogen or (1-2C)alkyl; and

[1004] Q3 is hydrogen, (1-6C)alkyl, (1-6C)alkoxy, aryl, aryl(1-2C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Q3 is optionally further substituted by one or more substituents independently selected from the group consisting of (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, amino, cyano, hydroxy, carboxyl, carbamoyl, sulfamoyl, NR t R u , OR t , where R t and R u are each independently selected from hydrogen, (1-4C)alkyl or (3-6C)cycloalkyl; or Q3 is optionally substituted with a group having the formula:

[1005] -L4-L Q4 -Z4

[1006] in:

[1007] L4 is absent or (1-3C)alkylene optionally substituted by one or more substituents selected from (1-2C)alkyl or oxo;

[1008] L Q4 is absent, or is selected from O, S, SO, SO2, N(R v ), C(O), C(O)O, OC(O), C(O)N(R v )、N(R v )C(O), N(R w )C(O)N(R v )、N(R v )C(O)O、OC(O)N(R v )、S(O)2N(R v ) or N(R v )SO2, where R v and R w are each independently selected from hydrogen or (1-2C)alkyl; and

[1009] Z4 is hydrogen, (1-6C)alkyl, aryl, aryl(1-2C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Z4 is optionally substituted by one or more substituents selected from the group consisting of (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano, hydroxy, carboxyl, carbamoyl, sulfamoyl, thiol, urea, aryl, heteroaryl, heterocyclyl, (3-6C)cycloalkyl, NR x R y , OR x 、C(O)R x 、C(O)OR x 、OC(O)R x 、C(O)N(R y )R x 、N(R y )C(O)R x 、S(O) y R x (where y is 0, 1 or 2), SO2N(R y )R x 、N(R y )SO2R x or (CH2) z NR x R y (where z is 1, 2 or 3); where R x and R y are each independently selected from hydrogen, (1-4C)alkyl or (3-6C)cycloalkyl;

[1010] Provided that only one or two of X1, X2, X3 or X4 may be N.

[1011] 2. The compound according to item 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein HET is selected from one of the following:

[1012]

[1013] Where R1, W and R 1b Each is as defined in item 1.

[1014] 3. The compound according to item 1 or 2, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein the compound has the structural formula Ib shown below:

[1015]

[1016] Where R1, bonds a, b, c and d, X1, X2, X3, X4, R2, Q3 and R s Each is as defined in item 1.

[1017] 4. A compound according to any one of items 1 to 3, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein X1 and X2 are each independently selected from N or CR j , and bond a is a double bond, where R j is selected from hydrogen, halo, (1-4C)alkyl or amino.

[1018] 5. A compound according to any one of items 1 to 4, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein X3 is selected from N or CR1, and bond b is a double bond, wherein R1 is selected from hydrogen, halo, (1-4C)alkyl or amino.

[1019] 6. A compound according to any one of items 1 to 5, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein X4 is selected from N or CR n , and bond d is a double bond, where R n is selected from hydrogen, halo, (1-4C)alkyl, (1-4C)alkoxy, amino, (1-4C)alkylamino, (1-4C)dialkylamino or cyano, (2C)alkynyl.

[1020] 7. The compound according to any preceding item or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein the compound has the structural formula Id shown below:

[1021]

[1022] wherein R1, X4, R2 and Q3 are each as defined in item 1.

[1023] 8. The compound according to item 7 or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein X4 is CR n , and where R n is selected from hydrogen, halo, (1-4C)alkyl or amino.

[1024] 9. A compound according to any preceding item, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R1 is selected from hydrogen, (1-4C)haloalkyl, (1-4C)haloalkoxy or a group having the formula:

[1025] -LYQ

[1026] in:

[1027] L is absent or (1-3C)alkylene optionally substituted by one or more substituents selected from (1-2C)alkyl or oxo;

[1028] Y does not exist, or is C(O), C(O)O, OC(O), C(O)N(R a ) or N(R a )C(O), where R a and R b are each independently selected from hydrogen or (1-4C)alkyl; and

[1029] Q is hydrogen, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, aryl, (3-10C)cycloalkyl, (3-10C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Q is optionally further substituted by one or more substituents independently selected from the group consisting of (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, amino, (1-4C)aminoalkyl, cyano, hydroxy, carboxyl, carbamoyl, sulfamoyl, thiol, urea, NR c R d , OR c 、C(O)R c 、C(O)OR c 、OC(O)R c 、C(O)N(R d )R c 、N(R d )C(O)R c 、S(O) y R c (where y is 0, 1 or 2), SO2N(R d )R c 、N(R d )SO2R c 、Si(R d )(Rc )R e or (CH2) z NR d R c (where z is 1, 2 or 3); where R c , R d and R e Each is independently selected from hydrogen, (1-6C)alkyl or (3-6C)cycloalkyl.

[1030] 10. A compound according to any preceding clause, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R1 is selected from hydrogen, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, aryl, (3-10C)cycloalkyl, (3-10C)cycloalkenyl, heteroaryl or heterocyclyl; wherein each of the substituents is optionally further substituted by one or more substituents independently selected from the group consisting of (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, amino, (1-4C)aminoalkyl, cyano, hydroxy, carboxyl, carbamoyl, sulfamoyl, thiol, urea, NR c R d , OR c 、C(O)R c 、C(O)OR c 、OC(O)R c 、C(O)N(R d )R c 、N(R d )C(O)R c 、S(O) y R c (where y is 0, 1 or 2), SO2N(R d )R c 、N(R d )SO2R c 、Si(R d )(R c )R e or (CH2) z NR d R c (where z is 1, 2 or 3); where R c , R d and R e Each is independently selected from hydrogen, (1-6C)alkyl or (3-6C)cycloalkyl.

[1031] 11. A compound according to any preceding clause, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R1 is selected from hydrogen, (1-6C) alkyl or (3-10C) cycloalkyl; wherein each of the substituents is optionally further substituted by one or more substituents independently selected from the group consisting of (1-4C) alkyl, halo, amino, (1-4C) aminoalkyl, cyano, hydroxy, carboxyl, NR c R d , OR c or Si(R d )(R c )R e ; where R c , R d and R e Each is independently selected from hydrogen or (1-4C)alkyl.

[1032] 12. A compound according to any preceding clause, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R2 is selected from hydrogen, (1-4C)alkyl or a group having the formula:

[1033] -Y2-Q2

[1034] in:

[1035] Y2 is C(O)N(R p ), where R p is selected from hydrogen or (1-4C)alkyl; and

[1036] Q2 is (1-6C)alkyl, aryl, (3-8C)cycloalkyl, heteroaryl or heterocyclyl; wherein Q2 is optionally further substituted by one or more substituents independently selected from the following: (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, amino, cyano or hydroxy.

[1037] 13. A compound according to any preceding item, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R2 is hydrogen.

[1038] 14. A compound according to any preceding clause, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein Q3 is hydrogen, (1-6C)alkyl, (1-6C)alkoxy, aryl, aryl(1-2C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Q3 is optionally further substituted by one or more substituents independently selected from the group consisting of (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, amino, cyano, hydroxy, carboxyl, carbamoyl, sulfamoyl, NR t R u , OR t , where Rt and R u are each independently selected from hydrogen, (1-4C)alkyl or (3-6C)cycloalkyl; or Q3 is optionally substituted with a group having the formula:

[1039] -L4-L Q4 -Z4

[1040] in:

[1041] L4 is absent or (1-3C)alkylene optionally substituted by one or more substituents selected from (1-2C)alkyl or oxo;

[1042] L Q4 is non-existent, or is selected from O, N(R v ), C(O), C(O)O, OC(O), C(O)N(R v )、N(R v )C(O), S(O)2N(R v ) or N(R v )SO2, where R v and R w are each independently selected from hydrogen or (1-2C)alkyl; and

[1043] Z4 is hydrogen, (1-6C)alkyl, aryl, aryl(1-2C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl; wherein Z4 is optionally substituted by one or more substituents selected from the group consisting of (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano, hydroxy, carboxyl, carbamoyl, sulfamoyl, thiol, urea, aryl, heteroaryl, heterocyclyl, (3-6C)cycloalkyl, NR x R y , OR x ; where R x and R y Each is independently selected from hydrogen or (1-4C)alkyl.

[1044] 15. A compound according to any preceding clause, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein Q3 is hydrogen, (1-6C)alkyl, (1-6C)alkoxy, aryl, aryl(1-2C)alkyl, (3-8C)cycloalkyl, heteroaryl or heterocyclyl; wherein Q3 is optionally further substituted by one or more substituents independently selected from the group consisting of (1-4C)alkyl, halo, (1-4C)haloalkyl, amino, cyano, hydroxy, NR t R u , OR t , where R t and Ru are each independently selected from hydrogen or (1-4C)alkyl; or Q3 is optionally substituted with a group having the formula:

[1045] -L4-L Q4 -Z4

[1046] in:

[1047] L4 is absent or is (1-2C)alkylene;

[1048] L Q4 is non-existent, or is selected from or is O; and

[1049] Z4 is hydrogen, (1-6C) alkyl, (3-8C) cycloalkyl; wherein Z4 is optionally substituted by one or more substituents selected from the group consisting of (1-4C) alkyl, halo, (1-4C) haloalkyl, (1-4C) alkoxy, amino, hydroxy, (3-6C) cycloalkyl, NR x R y , OR x ; where R x and R y Each is independently selected from hydrogen or (1-4C)alkyl.

[1050] 16. A compound or a pharmaceutically acceptable salt, hydrate or solvate thereof, which is selected from any one of the following:

[1051] 6-(4-amino-1-cyclopropyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-methyl-1H-indole-2-carboxamide;

[1052] 6-(4-amino-1-ethyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-methyl-1H-indole-2-carboxamide;

[1053] 6-(4-amino-1-isopropyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-methyl-1H-indole-2-carboxamide;

[1054] 6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(2,5-dimethylpyrazol-3-yl)-1H-indole-2-carboxamide;

[1055] 6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N,3-dimethyl-1H-indole-2-carboxamide;

[1056] 6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-3-fluoro-N-methyl-1H-indole-2-carboxamide;

[1057] 6-(4-amino-1-(tert-butyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-1H-indole-2-carboxamide;

[1058] 6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-cyclobutyl-1H-indole-2-carboxamide;

[1059] 6-(4-amino-1-(tert-butyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-ethyl-1H-indole-2-carboxamide;

[1060] 6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-cyclopropyl-1H-indole-2-carboxamide;

[1061] 6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-methyl-1H-indole-2-carboxamide;

[1062] 6-(4-amino-1-isopropyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(1,3,4-thiadiazol-2-yl)-1H-indole-2-carboxamide;

[1063] 6-(4-amino-1-isopropyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(1-methylpyrazol-3-yl)-1H-indole-2-carboxamide;

[1064] 6-(4-amino-1-isopropyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-thiazol-2-yl-1H-indole-2-carboxamide;

[1065] 6-(4-amino-1-isopropyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-ethoxy-1H-indole-2-carboxamide;

[1066] 6-(4-amino-1-isopropyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(2-fluoroethyl)-1H-indole-2-carboxamide;

[1067] 6-(4-amino-1-isopropyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-cyclopropyl-1H-indole-2-carboxamide;

[1068] 6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-3-chloro-N-methyl-1H-indole-2-carboxamide;

[1069] 6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-[1-(2-hydroxyethyl)pyrazol-3-yl]-1H-indole-2-carboxamide;

[1070] 6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-pyridinyl)-1H-indole-2-carboxamide;

[1071] 6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(3-pyridinyl)-1H-indole-2-carboxamide;

[1072] 6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-[1-(2-fluoroethyl)pyrazol-3-yl]-1H-indole-2-carboxamide;

[1073] 6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-[1-(2-methoxyethyl)pyrazol-3-yl]-1H-indole-2-carboxamide;

[1074] 6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(1-ethylpyrazol-3-yl)-1H-indole-2-carboxamide;

[1075] 6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-methylthiazol-2-yl)-1H-indole-2-carboxamide;

[1076] 6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-isoxazol-4-yl-1H-indole-2-carboxamide;

[1077] 6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-thiazol-5-yl-1H-indole-2-carboxamide;

[1078] 6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(3-thienyl)-1H-indole-2-carboxamide;

[1079] 6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(1,2,4-thiadiazol-5-yl)-1H-indole-2-carboxamide;

[1080] 6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)-1H-indole-2-carboxamide;

[1081] 6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(2-hydroxyethyl)-1H-indole-2-carboxamide;

[1082] 6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-phenyl-1H-indole-2-carboxamide;

[1083] 6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(2-methylpyrazol-3-yl)-1H-indole-2-carboxamide;

[1084] 6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(2-methoxyethoxy)-1H-indole-2-carboxamide;

[1085] 6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(1-methylpyrazol-3-yl)-1H-indole-2-carboxamide;

[1086] 6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(1,3,4-thiadiazol-2-yl)-1H-indole-2-carboxamide;

[1087] 6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(cyclopropylmethoxy)-1H-indole-2-carboxamide;

[1088] 6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-ethoxy-1H-indole-2-carboxamide;

[1089] 6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(2,2-difluoroethyl)-1H-indole-2-carboxamide;

[1090] 6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(2,2,2-trifluoroethyl)-1H-indole-2-carboxamide;

[1091] 6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(cyclopropylmethyl)-1H-indole-2-carboxamide;

[1092] 6-(4-amino-1-(tert-butyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-phenethyl-1H-indole-2-carboxamide;

[1093] 6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-benzyl-1H-indole-2-carboxamide;

[1094] 6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-isobutyl-1H-indole-2-carboxamide;

[1095] 6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(2-fluoroethyl)-1H-indole-2-carboxamide;

[1096] 6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-methoxy-1H-indole-2-carboxamide;

[1097] 6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-propyl-1H-indole-2-carboxamide;

[1098] 6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(2-methoxyethyl)-1H-indole-2-carboxamide;

[1099] 6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-butyl-1H-indole-2-carboxamide;

[1100] 6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-thiazol-2-yl-1H-indole-2-carboxamide;

[1101] 6-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-isopropyl-1H-indole-2-carboxamide;

[1102] 6-[4-amino-1-(3-hydroxy-3-methyl-cyclopentyl)pyrazolo[3,4-d]pyrimidin-3-yl]-N-methyl-1H-indole-2-carboxamide;

[1103] 6-(4-amino-1-isopropyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N,3-dimethyl-1H-indole-2-carboxamide;

[1104] 6-[4-amino-1-(3-methoxypropyl)pyrazolo[3,4-d]pyrimidin-3-yl]-N-methyl-1H-indole-2-carboxamide;

[1105] 6-(4-amino-1-cyclobutyl-pyrazolo[3,4-d]pyrimidin-3-yl)-N-methyl-1H-indole-2-carboxamide; or

[1106] Tert-butyl 3-[4-amino-3-[2-(methylcarbamoyl)-1H-indol-6-yl]pyrazolo[3,4-d]pyrimidin-1-yl]azetidine-1-carboxylate.

[1107] 17. A compound according to any one of the preceding clauses, or a pharmaceutically acceptable salt or hydrate thereof, for use in therapy.

[1108] 18. A pharmaceutical preparation comprising the compound according to any one of items 1 to 16 or a pharmaceutically acceptable salt or hydrate thereof and a pharmaceutically acceptable carrier or excipient.

[1109] 19. The compound according to any one of items 1 to 16 or a pharmaceutically acceptable salt, hydrate or solvate thereof, or the pharmaceutical composition according to item 18, for use in treating cancer.

[1110] 20. The compound or pharmaceutical composition according to claim 19, wherein the cancer is medullary thyroid carcinoma or non-small cell lung cancer.

[1111] 21. A method for treating cancer in a subject in need of such treatment, the method comprising administering a therapeutically effective amount of a compound according to any one of items 1 to 16 or a pharmaceutically acceptable salt or hydrate thereof, or a pharmaceutical composition according to item 18.

[1112] 22. The method of claim 21, wherein the cancer is medullary thyroid carcinoma or non-small cell lung cancer.

[1113] While specific embodiments of the present invention have been described herein for purposes of illustration and description, various modifications will become apparent to those skilled in the art without departing from the scope of the invention as defined by the following claims.

[1114] References

[1115] [1]Carlomagno, F., Guida, T., Anagantil, S., Vecchio, G., Fusco, A., Ryan, A., Billaud, M., Santoro, M. (2004).Disease associated mutations at valine 804 in the RET receptor tyrosine kinase confer resistance to selective kinaseinhibitors.Oncogene 23, 6056-6063

[1116] [2]Chao,B.,Briesewitz,R.,Villalona-Calero,M.(2012)RET fusion genes inNon-Small-Cell Lung Cancer.JCO 30,4439-4441.

[1117] [3]Dinér,P.,Alao,J., J.,Sunnerhagen,P.Grotli,M.(2012)J MedChem 2012 55(10)4872-6

[1118] [4]Elisei,R.,Cosci,B.,Romei,C.,Bottici,V.,Renzini,G.,Molinaro,E.,Agate,L.,Vivaldi,A.,Faviana,P.,Basolo,F.,Miccoli,P.,Berti,P.,Pacini,F.,Pinchera,A.(2008)RET genetic screening in patients with medullary thyroidcancer and their relatives:experience with 807 individuals at onecenter.Journal of Clinical Endocrinology and Metabolism 93,682-687.

[1119] [5]Ju,Y.,Lee,W.,Shin,J.,Lee,S.,Bleazard,T.,Won,J.,Kim,Y.,Kim,J.,Kang,J.,Seo,J.(2011).A transforming KIF5B and RET gene fusion in lungadenocarcinoma revealed from whole-genome and transcriptome sequencing.GenomeRes.3.436-445.

[1120] [6]Kohno,T.,Ichikawa,H.,Totoki,Y.,Yasuda,K.,Hiramoto,M.,Nammo,T.,Sakamoto,H.,T suta,K.,Furuta,K.,Shimada,Y.,Iwakawa,R.,Ogiwara,H.,Oike,T.,Enari,M.,Schetter, A.,Okayama,H.,Haugen,A.,Skaug,V.Chiku,S.,Yamanaka,I.,Arai,Y.,Watanabe,S.,Sekin e,I.,Ogawa,S.,Harris,C.,Tsuda,H.,Yoshida,T.,Yokota,J.,Shibata,T.(2012)KIF5B-RET fusions in lung adenocarcinoma.Nat Med.12,375-377.

[1121] [7]Lipson,D.,Capelletti,M.,Yelensky,R.,Otto,G.,Parker,A.,Jaroszi,M.,Curran,J.,Ba lasubramanian,S.,Bloom,T.,Brennan,K.,Donahue,A.,Downing,S.,Frampton,G.,Garcia,L. ,Juhn,F.,Mitchell,K.,White,E.,White,J.,Zwirko,Z.,Peretz,T.,Nechushtan,H.,Soussan -Gutman, L., Kim, J., Sasaki, H., Kim, H., Park, S., Ercan, D., Sheehan, C., Ross, J. Cronin, M. P.,Stephens,P.(2012)lidentification of newALK and RET gene fusions from colorectal and lung cancer biopsies.Nat Med.12,382-384.

[1122] [8]Matsubara,D.,Kanai,Y.,Ishikawa,S.,Ohara,S.,Yoshimoto,T.,Sakatani,T.,Oguni,S.,Tamura, T.,Kataoka,H.,Endo,S.,Muraakami,Y.,Aburatani,H.,Fukayama,M.,Niki,T.(2012).ldentification of CCDC6-RET fusion in the human lung adenocarcinoma cell line,LC-2 / ad.J Thorac Oncol.12,1872-6.

[1123] [9]Nagilla,M.,Brown,R.,Cohen,E.(2012).Cabozantinib for the treatment of advanced medullary thyroid cancer.Adv Ther 11,925-934.

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[10] Santoro,M.and Carlomagno,F.(2006).Small-molecule inhibitors of protein kinases in the treatment of thyroid cancer.NatureClinical Practice:Endocrinology and Metabolism 2,42-52.

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[11] Verbeek.HH,Alves,MM,de Groot,JW,Osinga J,Plukker,JT,Links,TP,Hofstra,R,M.(2011).The effects of four different tyrosine kinase inhibitors on medullary and papillary thyroid cancer cells.J Clin EndocrinolMetab.96,2010-2381.

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[12] Vitagliano,D.,De Falco,V.,Tamburrino,A.,Coluzzi,S.,Troncone,G.,Chiappetta,G.,Ciardi ello,F.Tortora,G.,Fagin,J.,Ryan,A.,Carlomagno,F.,Santoro,(2011)The The tyrosine inhibitor ZD6474 blocks proliferation of RET mutantmedullary thyroid carcinoma cells.Endocrine-related Cancer 18,1-11.

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[13] Wang, R., Hu, H., Pan, Y., Li, Y., Ye, T. Li, C., Luo, X., Wang, L., Li, H., Zhang, Y., Li, F.S .,Lu,Y.,Lu,Q.,Xu,J.,Garfield,D.,Shen,L.Ji,H.,Pao,W.,Sun,Y.,Chen,H.(2012).RET Fusions define a unique molecular and clinicopathologicsubtype of non-small-cell young cancer.JCO 30,4352-4359.

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[14] Wells,S.and Santoro,M.(2009)Targeting the RET pathway in thyroid cancer.

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[15] Wells,S.,Gosnell,J.,Gagel,R.,Moley,J.,Pfister,D.,Sosa,J.,S kinner,M.,Krebs,A.,Vasselli,J.,Schlumberger,M.(2012).Vandetanib in patients withIocally advanced or metastatic medullary thyroid cancer:a randomized,double-blind phasellI thal.JCO 10,134-141.

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Claims

1. A compound of formula Id or a pharmaceutically acceptable salt thereof: in: R1 is a group having the formula: -LYQ L does not exist; Y does not exist; and Q is for C 1-6 Alkyl or C 3-10 wherein Q is optionally substituted by one or more substituents independently selected from the following: 1-4 Alkyl and OR c ; where R c Each is hydrogen; X4 for CR n ; R n is hydrogen or halogen; R2 is hydrogen; Q3 is hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 wherein Q3 is optionally substituted by one or more substituents independently selected from the following: 1-4 Alkyl, halogen, C 1-4 Haloalkyl and OR t , where R t are each hydrogen; or Q3 is optionally substituted with a group having the formula: -L4-L Q4 -Z4 L4 does not exist, or C 1-3 Alkylene; L Q4 is non-existent, or is O; and Z4 is hydrogen, C 1-6 Alkyl or C 3-8 Cycloalkyl; The term "heteroaryl" refers to a 5- or 6-membered monocyclic ring having 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R1 is C 1-6 Alkyl or C 3-6 Cycloalkyl, which is optionally substituted by one or more groups independently selected from the following: 1-4 Alkyl and OR c ; where R c Each is hydrogen.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R1 is C 1-6 alkyl.

4. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R1 is tert-butyl.

5. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein: X4 is CR n ;and R n It's hydrogen.

6. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein Q3 is hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 wherein Q3 is optionally substituted by one or more substituents independently selected from the following: 1-4 Alkyl, halogen, C 1-4 Haloalkyl and OR t , where R t are each hydrogen; or Q3 is optionally substituted with a group having the formula: -L4-L Q4 -Z4 L4 does not exist, or C 1-2 Alkylene; L Q4 is non-existent, or is O; and Z4 is hydrogen, C 1-6 Alkyl or C 3-8 Cycloalkyl.

7. A pharmaceutical preparation comprising a compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.

8. Use of the compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof or the pharmaceutical preparation according to claim 7 in the preparation of a medicament for treating cancer associated with RET kinase activity.

9. The use according to claim 8, wherein the cancer is leukemia, lung cancer, colon cancer, breast cancer, ovarian cancer, prostate cancer, liver cancer, pancreatic cancer, brain cancer, skin cancer, medullary thyroid cancer or non-small cell lung cancer.

10. The use according to claim 8, wherein the cancer is a malignant neoplasm, a malignant tumor or a solid tumor.

11. The use according to any one of claims 8 to 10, wherein the cancer comprises a RET mutation.

12. The use according to claim 11, wherein the RET mutation is a RET fusion translocation.

13. The use according to claim 12, wherein the RET fusion translocation is KIF5B-RET or CCDC6-RET.

14. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from: 6-(4-amino-1-(tert-butyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-1H-indole-2-carboxylic acid; 6-(4-amino-1-(tert-butyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-3-chloro-1H-indole-2-carboxylic acid; 6-(4-amino-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-1H-indole-2-carboxylic acid; 6-Bromo-N-methyl-1H-indole-2-carboxamide; 6-Bromo-N-cyclopropyl-1H-indole-2-carboxamide; 6-Bromo-N-ethyl-1H-indole-2-carboxamide; 6-Bromo-N-cyclobutyl-1H-indole-2-carboxamide; 6-Bromo-N-methoxy-1H-indole-2-carboxamide; 6-Bromo-3-fluoro-N-methyl-1H-indole-2-carboxamide; 6-Bromo-N,3-dimethyl-1H-indole-2-carboxamide; 6-bromo-N-(1,3-dimethyl-1H-pyrazol-5-yl)-1H-indole-2-carboxamide; and 3-Bromo-1-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine.

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