3-AZA-bicyclo[3.3.0]octane compounds, preparation and therapeutic uses thereof

Abstract

Compounds are provided which can inhibit ERK5. Also provided are pharmaceutical compositions and medical uses of the same, including the use in treating or preventing conditions such as cancers.

Description

[0001] 3-AZA-BICYCLO [3.3.0] OCTANE COMPOUNDS, PREPARATION AND THERAPEUTIC USES THEREOF

[0002] Compounds are provided which can inhibit ERK5. Also provided are pharmaceutical compositions, methods of making the compounds and compositions, and medical uses of the same, including the use in treating or preventing conditions such as cancers.

[0003] The mitogen-activated protein kinase (MAPK) cascade is a highly -conserved cellular pathway which transmits signals from the cell surface to the nucleus. The pathway plays an important role in cell proliferation, differentiation, and migration and it is well known to be involved in the development of cancer. Proteins in the pathway include the extracellular signal-regulated kinase (ERK) proteins; among those, ERK5 (expressed from the MAPK7 gene) plays an important role in cell proliferation, as well as epithelial development and neural differentiation. ERK5 is unique among the ERK proteins, having a large C-terminal domain which contains a transcriptional activation domain (TAD) as well as a nuclear localization signal and two proline-rich regions. Autophosphorylation of the TAD is required for transcriptional activation.

[0004] ERK5 plays an important role in controlling cell proliferation and cell cycle progression, for example via direct or indirect phosphorylation of MEF2C, cMYC, SGK1, RSK, FOS, and FRA1 among others. The involvement of ERK5 in numerous biological pathways means that its activity is associated with many aspects of cancer progression, including tumour angiogenesis, metastasis, inflammation, sustained proliferation, and evasion of growth suppression. It therefore presents an attractive target for modulating disease pathology and treatment in a wide range of conditions. In previous studies, ERK5 inhibition or downregulation has been shown to block tumorigenesis in murine leukaemia cells, reduce growth of chronic myeloid leukaemia cells, inhibit growth of breast cancer and multiple myeloma cells, suppress colon cancer cell proliferation, and have to have an impact on renal cell carcinoma, mesothelioma, adenocarcinoma, neuroblastoma and hepatocellular carcinoma cell growth or survival, among others.

[0005] ERK5 inhibition thus represents a promising approach to tackle a broad range of cancers. Despite recent progress in cancer treatment with the development of targeted therapies and immunotherapies, not all cancer patients can be offered an efficient therapeutic solution. There is therefore a need to identify and develop new drugs. The present disclosure seeks to address this need by providing novel compounds, which comprise a 3-aza- bicyclo[3.3.0]octane core for use as ERK5 inhibitors and for the treatment of ERK5 related diseases and conditions.

[0006] Accordingly, herein is provided a compound of Formula (I):

[0007]

[0008] or a pharmaceutically acceptable salt thereof, wherein the dotted line represents an optional unsaturation and wherein:

[0009] R1 represents a hydrogen atom or a -NH2 group;

[0010] R2 is selected from the groups (a) and (b):

[0011]

[0012] wherein R3 represents a hydrogen atom or a fluorine atom;

[0013] X represents a nitrogen atom or a -CH= group;

[0014] R4 represents a saturated cycloalkyl or heterocycloalkyl group selected from groups (al), (a2), (a3) and (a4); and R5 represents a saturated cycloalkyl or heterocycloalkyl group selected from groups (al), (a2) and (a5), wherein R6 represents an -OH or -OCH3 group:

[0015]

[0016] (a5) A further aspect provides a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein R1 and R2 are defined as in formula (I):

[0017]

[0018] (II)

[0019] Formula (II) corresponds to formula (I), wherein the bicyclic core is fully saturated.

[0020] In an embodiment of formula (II), the stereochemistry of the piperidine ring is cis, as represented by formula (II- 1 ):

[0021]

[0022] In other embodiments of formulae (II) and (II- 1), R2 represents a group of formula (a) as defined in formula (I).

[0023] In another embodiment, when R2 represents a group of formula (a) in formulae (II) and (II-1), then R3 represents a fluorine atom.

[0024] In other embodiments of formulae (II) and (II- 1), R2 represents a group of formula (b) as defined in formula (I). A further aspect provides a compound of formula (III), or a pharmaceutically acceptable salt thereof, wherein R1 and R2 are defined as in formula (I):

[0025]

[0026] (III)

[0027] Formula (III) corresponds to formula (I), wherein the bicyclic core bears an unsaturation.

[0028] In an embodiment of formula (III), the stereochemistry of the piperidine ring is cis, as represented by formula (III-l):

[0029]

[0030] (III-l)

[0031] In other embodiments of formulae (III) and (III-l), R1 represents an amino group.

[0032] In other embodiments of formulae (III) and (III-l), R2 represents a group of formula (b) as defined in formula (I). In another embodiment, when R2 represents a group of formula (b) in formulae (III) and (III-l), then R5 represents a group of formula (al) or (a5).

[0033] A further aspect provides a compound selected from: (cis, cis)-[5-[5-fluoro-2-((trans)-4-methoxycyclohexyl)-lH-pyrrolo[2,3-b]pyridin-4-yl]-3, 3a, 4,5,6, 6a-hexahy dro-lH-cy clopenta[ c]pyrrol-2 -yl]-[4-(trifluoromethoxy)phenyl]methanone;

[0034] (cis, cis)-[5-[5-fluoro-2-((cis)-4-methoxycyclohexyl)-lH-pyrrolo[2,3-b]pyridin-4-yl]-3,3a,4,5,6,6a-hexahydro-lH-cyclopenta[c]pyrrol-2-yl]-[4-(trifluoromethoxy)phenyl]methanone;

[0035] (cis, cis)-[5-[5-fluoro-2-((cis)-4-methoxycyclohexyl)-lH-pyrrolo[2,3-b]pyridin-4-yl]-3,3a,4,5,6,6a-hexahydro-lH-cyclopenta[c]pyrrol-2-yl]-[2-amino-4-(trifluoromethoxy)phenyl]methanone;

[0036] (cis, cis)-[5-[5-fluoro-2-((trans)-4-methoxycyclohexyl)-lH-pyrrolo[2,3-b]pyridin-4-yl]-3,3a,4,5,6,6a-hexahydro-lH-cyclopenta[c]pyrrol-2-yl]-[2-amino-4-(trifluoromethoxy)phenyl]methanone;

[0037] (cis, cis)-[5-[5-fluoro-2-((cis)-4-hydroxycyclohexyl)-lH-pyrrolo[2,3-b]pyridin-4-yl]-3,3a,4,5,6,6a-hexahydro-lH-cyclopenta[c]pyrrol-2-yl]-[4-(trifluoromethoxy)phenyl]methanone;

[0038] (cis, cis)-[5-[5-fluoro-2-((trans)-4-hydroxycyclohexyl)-lH-pyrrolo[2,3-b]pyridin-4-yl]-3, 3a, 4,5,6, 6a-hexahy dro-lH-cy clopenta[ c]pyrrol-2 -yl]-[4-(trifluoromethoxy)phenyl]methanone;

[0039] (cis, cis)-[5-[5-fluoro-2-((cis)-4-hydroxycyclohexyl)-lH-pyrrolo[2,3-b]pyridin-4-yl]-3,3a,4,5,6,6a-hexahydro-lH-cyclopenta[c]pyrrol-2-yl]-[2-amino-4-(trifluoromethoxy)phenyl]methanone;

[0040] (cis, cis)-[5-[5-fluoro-2-((trans)-4-hydroxycyclohexyl)-lH-pyrrolo[2,3-b]pyridin-4-yl]-3,3a,4,5,6,6a-hexahydro-lH-cyclopenta[c]pyrrol-2-yl]-[2-amino-4-(trifluoromethoxy)phenyl]methanone;

[0041] (cis, cis)-[5-(5-tetrahydropyran-4-yl-lH-pyrrolo[2,3-b]pyridin-3-yl)-3,3a,4,5,6,6a-hexahydro-lH-cyclopenta[c]pyrrol-2-yl]-[2-amino-4-(trifluoromethoxy)phenyl]methanone;

[0042] (cis, cis)-[5-[6-fluoro-2-(3-methoxy-l-bicyclo[l.l.l]pentanyl)-3H-imidazo[4,5-b]pyri din-7-yl]-3, 3a, 4,5,6, 6a-hexahy dro-lH-cy clopenta[c]pyrrol-2 -yl]-[4-(trifluoromethoxy)phenyl]methanone;

[0043] (cis, cis)-[5-[6-fluoro-2-(3-methoxy-l-bicyclo[l.l.l]pentanyl)-3H-imidazo[4,5-b]pyri din-7-yl]-3, 3a, 4,5,6, 6a-hexahy dro-lH-cy clopenta[c]pyrrol-2-yl]-[2-amino-4-(trifluoromethoxy)phenyl]methanone; (cis, cis)-[5-[5-((cis)-4-hydroxycyclohexyl)-lH-pyrrolo[2,3-b]pyridin-3-yl]- 3,3a,4,5,6,6a-hexahydro-lH-cyclopenta[c]pyrrol-2-yl]-[4- (trifluoromethoxy)phenyl]methanone;

[0044] (cis, cis)-[5-[5-((trans)-4-hydroxycyclohexyl)-lH-pyrrolo[2,3-b]pyridin-3-yl]- 3,3a,4,5,6,6a-hexahydro-lH-cyclopenta[c]pyrrol-2-yl]-[4- (trifluoromethoxy)phenyl]methanone;

[0045] (cis, cis)-[5-(5-morpholino-lH-pyrrolo[2,3-b]pyridin-3-yl)-3, 3a, 4,5,6, 6a-hexahydro- lH-cyclopenta[c]pyrrol-2-yl]-[2-amino-4-(trifluoromethoxy)phenyl]methanone; (cis, cis)-[5-[5-((cis)-4-hydroxycyclohexyl)-lH-pyrrolo[2,3-b]pyridin-3-yl]- 3,3a,4,5,6,6a-hexahydro-lH-cyclopenta[c]pyrrol-2-yl]-[2-amino-4- (trifluoromethoxy)phenyl]methanone;

[0046] (cis, cis)-[5-[5-((trans)-4-hydroxycyclohexyl)-lH-pyrrolo[2,3-b]pyridin-3-yl]- 3,3a,4,5,6,6a-hexahydro-lH-cyclopenta[c]pyrrol-2-yl]-[2-amino-4- (trifluoromethoxy)phenyl]methanone;

[0047] (cis)-[5-(5-tetrahydropyran-4-yl-lH-pyrrolo[2,3-b]pyridin-3-yl)-3,3a,6,6a-tetrahydro- lH-cyclopenta[c]pyrrol-2-yl]-[2-amino-4-(trifluoromethoxy)phenyl]methanone; (cis)-[5-(5-morpholino-lH-pyrrolo[2,3-b]pyridin-3-yl)-3,3a,6,6a-tetrahydro-lH- cyclopenta[c]pyrrol-2-yl]-[2-amino-4-(trifluoromethoxy)phenyl] methanone;

[0048] (cis, cis)-[5-[5-fluoro-2-[(2S)-morpholin-2-yl]-lH-pyrrolo[2,3-b]pyridin-4-yl]- 3,3a,4,5,6,6a-hexahydro-lH-cyclopenta[c]pyrrol-2-yl]-[4- (trifluoromethoxy)phenyl]methanone;

[0049] (cis, cis)-[5-[5-fluoro-2-[(2R)-morpholin-2-yl]-lH-pyrrolo[2,3-b]pyridin-4-yl]- 3,3a,4,5,6,6a-hexahydro-lH-cyclopenta[c]pyrrol-2-yl]-[4- (trifluoromethoxy)phenyl]methanone;

[0050] (cis, cis)-[5-(5-fluoro-2-tetrahydropyran-4-yl-lH-pyrrolo[2,3-b]pyridin-4-yl)- 3,3a,4,5,6,6a-hexahydro-lH-cyclopenta[c]pyrrol-2-yl]-[2-amino-4- (trifluoromethoxy)phenyl]methanone;

[0051] and the pharmaceutically acceptable salts thereof.

[0052] Definitions

[0053] Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, exemplary methods, devices, and materials are now described. All technical and patent publications cited herein are incorporated herein by reference in their entirety.

[0054] All numerical designations, e.g., pH, temperature, time, concentration, molecular weight, etc., including ranges, are approximations which are varied ( + ) or ( - ) by increments of, e.g., 0.1 or 1.0, where appropriate. It is to be understood, although not always explicitly stated, that all numerical designations are preceded by the term “about”, which is used to denote a conventional level of variability. For example, a numerical designation which is “about” a given value may vary by ± 10% of said value; alternatively, the variation may be ± 5%, ± 2%, or ± 1% of the value. It also is to be understood, although not always explicitly stated, that the reagents described herein are merely exemplary and that equivalents of such are known in the art.

[0055] As used in the specification and claims, the singular forms “a”, “an”, and “the” include plural references unless the context clearly dictates otherwise. For example, the term “a cell” includes a plurality of cells, including mixtures thereof. Unless specifically stated or obvious from context, as used herein, the term “or” is understood to be inclusive. The term “including” is used herein to mean, and is used interchangeably with, the phrase “including but not limited to”.

[0056] As used herein, the term “comprising” or “comprises” is intended to mean that the compositions and methods include the recited elements, without excluding other elements. “Consisting essentially of’ when used to define compositions and methods, shall mean excluding other elements of any essential significance for the stated purpose. Thus, a composition consisting essentially of the elements as defined herein would not exclude trace contaminants from the isolation and purification method and pharmaceutically acceptable carriers, such as phosphate buffered saline, preservatives, and the like. “Consisting of’ shall mean excluding more than trace elements of other ingredients and substantial method steps for administering the compositions of this disclosure or process steps to produce a composition or achieve an intended result. Embodiments defined by each of these transition terms are within the scope of this disclosure. Use of the term “comprising” herein is intended to encompass, and to disclose, the corresponding statements in which the term “comprising” is replaced by “consisting essentially of’ or “consisting of’. A “subject,” “individual”, or “patient” is used interchangeably herein, and refers to a vertebrate, such as a mammal. Mammals include, but are not limited to, rodents, farm animals, sport animals, pets, and primates; for example murines, rats, rabbit, simians, bovines, ovines, porcines, canines, felines, equines, and humans. In a particular embodiment, the mammal is a human.

[0057] “Administering” is defined herein as a means of providing an agent or a composition containing the agent to a subject in a manner that results in the agent being contacted with (e.g., being inside) the subject’s body. Such an administration can be by any route including, without limitation, oral, transdermal (e.g., by the vagina, rectum, or oral mucosa), by injection (e.g., subcutaneous, intravenous, parenteral, intraperitoneal, or into the central nervous system), or by inhalation (e.g., oral or nasal). Administration may also involve providing a substance or composition to a part of the surface of the subject’s body, for example by topical administration to the skin. Pharmaceutical preparations are, of course, given by forms suitable for each administration route.

[0058] “Treating” or “treatment” of a disease includes: (1) preventing the disease, i.e. causing the clinical symptoms of the disease not to develop in a patient that may be predisposed to the disease but does not yet experience or display symptoms of the disease; (2) inhibiting the disease, i.e. arresting or reducing the development of the disease or its clinical symptoms; and / or (3) relieving the disease, i.e. causing regression of the disease or its clinical symptoms. The term “suffering” as it relates to the term “treatment” refers to a patient or individual who has been diagnosed with or is predisposed to the disease. A patient may also be referred to being “at risk of suffering” from a disease because of a history of disease in their family lineage or because of the presence of genetic mutations associated with the disease. A patient at risk of a disease has not yet developed all or some of the characteristic pathologies of the disease.

[0059] An “effective amount” or “therapeutically effective amount” is an amount sufficient to effect beneficial or desired results. An effective amount can be administered in one or more administrations, applications, or dosages. Such delivery is dependent on a number of variables including the time period for which the individual dosage unit is to be used, the bioavailability of the therapeutic agent, the route of administration, etc. It is understood, however, that specific dose levels of the therapeutic agents of the present disclosure for any particular subject depends upon a variety of factors including, for example, the activity of the specific compound employed, the age, body weight, general health, sex, and diet of the subject, the time of administration, the rate of excretion, the drug combination, the severity of the particular disorder being treated and the form of administration. Treatment dosages generally may be titrated to optimize safety and efficacy. Typically, dosage-effect relationships from in vitro and / or in vivo tests initially can provide useful guidance on the proper doses for patient administration. In general, one will desire to administer an amount of the compound that is effective to achieve a serum level commensurate with the concentrations found to be effective in vitro. Determination of these parameters is well within the skill of the art. These considerations, as well as effective formulations and administration procedures are well known in the art and are described in standard textbooks. Consistent with this definition, as used herein, the term “therapeutically effective amount” is an amount sufficient to treat (e.g., improve) one or more symptoms associated with the condition. The total daily dose may be administered in single or divided doses and may, at the physician's discretion, fall outside of the typical range given herein.

[0060] As used herein, the terms "increased" and "elevated" are used interchangeably and encompass any measurable increase in a biological function and / or a biological activity and / or a concentration. For example, an increase can be by at least about 10%, e.g. at least about 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%, such as at least about 95%, 96%, 97%, 98%, 99%, or 100%. Thus, an increase can be by at least about 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, or 10-fold, such as at least about 20-fold, 25-fold, 50-fold, 100-fold, or higher, relative to a control or baseline amount or function, or activity, or concentration.

[0061] As used herein, the terms "increased expression" and / or "increased activity" of a substance, such as ERK5, in a sample or cancer or patient, typically refers to an increase in the amount of the substance (e.g., of the MAPK7 gene product or ERK5 protein), although it may also denote an increase in the biological activity of the substance (e.g., constitutive activation of phosphorylation and / or reduced discrimination of phosphorylation sites of ERK5). For example, an increase can be by an amount of about 5%, e.g., about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%, such as about 96%, 97%, 98%, 99%, or 100%. Thus, the increase can be about 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, or 10-fold, such as about 20-fold, 25-fold, 50-fold, 100-fold, or higher, relative to the amount (or activity) of the substance, such as ERK5, in a control sample or control samples, such as an individual or group of individuals who are not suffering from the disease or disorder (e.g. cancer) or an internal control, as determined by techniques known in the art. A subject can also be determined to have an "increased expression” or "increased activity" of ERK5 if the expression and / or activity of ERK5 is increased by one standard deviation, two standard deviations, three standard deviations, four standard deviations, five standard deviations, or more, relative to the mean (average) or median amount of ERK5 in a control group of samples or a baseline group of samples or a retrospective analysis of patient samples. As practiced in the art, such control or baseline expression levels can be previously determined or measured prior to the measurement in the sample or cancer or subject, or can be obtained from a database of such control samples. As used herein, the term “pharmaceutically acceptable excipient” encompasses any of the standard pharmaceutical excipients. Such excipients include carriers such as a phosphate buffered saline solution, water, and emulsions, such as an oil / water or water / oil emulsion, and various types of wetting agents. Pharmaceutical compositions also can include stabilizers, preservatives, adjuvants, fillers, binders, lubricants, and the like.

[0062] As used herein, the term “cycloalkyl group” means a saturated cyclic group, which may contain a single ring or bicyclic bridged rings, such as a cyclohexyl group or a

[0063] bi cyclofl.1.1 ]pentanyl group.

[0064] As used herein, the term “heterocycloalkyl group” means a saturated cyclic group comprising one or two heteroatoms selected from nitrogen and oxygen, such as a tetrahydropyranyl or morpholinyl group.

[0065] The compounds of the present disclosure are described, inter alia, by way of structural formulae. It will be appreciated that these formulae typically show only one resonance or tautomeric form of the compound, whereas certain compounds may exist in more than one such form. This will be readily apparent to the skilled reader. The present disclosure includes all possible resonance or tautomer forms of the compounds characterized by the structural formulae herein, including as single forms, or as any mixture thereof in any ratio.

[0066] It will also be appreciated that certain of the present compounds may exist in one or more isomeric (e.g., stereoisomeric) forms. The present disclosure includes all possible stereoisomers, enantiomers, diastereomers, etc. of the compounds described herein, as well as cis- and trans- forms and conformers of the same. The purification and the separation of isomers may be accomplished by methods described hereinafter, as well as by techniques known in the art. For example, optical isomers of the compounds can be obtained by resolution of the racemic mixture of diastereoisomeric salts thereof (e.g., using an optically active acid or base, or by the formation of covalent diastereomers). A different process for separation of optical isomers involves the use of chiral chromatography (e.g., HPLC columns using a chiral phase), with or without conventional derivatization. Enzymatic separation, with or without derivatization, may also be useful, and optically active compounds of the present disclosure can likewise be obtained by chiral syntheses utilizing optically active starting materials. The present disclosure includes all possible stereoisomers of the compounds described herein as single stereoisomers, or as any mixture of said stereoisomers, e.g. (R)- or (S)- isomers, in any ratio.

[0067] The compounds of the disclosure may exist in the form of free acids or bases or may exist as addition salts with suitable acids or bases.

[0068] As used herein, the term “pharmaceutically acceptable” when used in connection with salts means a salt of a currently disclosed compound that may be administered without any resultant substantial undesirable biological effect(s) or any resultant deleterious interaction(s) with any other component of a pharmaceutical composition in which it may be contained. The recitation of a listing of chemical groups in any definition of a variable herein includes definitions of that variable as any single group or combination of listed groups. The recitation of an embodiment for a variable or aspect herein includes that embodiment as any single embodiment or in combination with any other embodiments or portions thereof.

[0069] Compositions and methods provided herein may be combined with one or more of any of the other compositions and methods provided herein.

[0070] The following abbreviations and empirical formulae are used herein:

[0071] °C degree Celsius

[0072] pm micrometer

[0073] Ac Acetyl

[0074] BOC tert-butoxycarbonyl

[0075] cat. catalytic amount

[0076] DCM dichloromethane

[0077] DiPEA Diisopropylethylamine

[0078] DMF dimethylformamide DMSO dimethylsulfoxide

[0079] Dppf (diphenylphosphino)ferrocene

[0080] EDC1 1 -ethyl-3-(3-dimethylaminopropyl)carbodiimide

[0081] Et Ethyl

[0082] G gram

[0083] hrs hours

[0084] i-Pr iso-propyl

[0085] LC / MS Liquid chromatography / mass spectrometry

[0086] LDA lithium diisopropylamide

[0087] LiHMDS Lithium bis(trimethylsilyl)amide

[0088] Me Methyl

[0089] Mg milligram

[0090] Min minute

[0091] mL milliliter

[0092] mm millimeter

[0093] mmol millimoles

[0094] MW microwave

[0095] NBS N-bromosuccinimide

[0096] NMP N-methyl-2-pyrrolidone

[0097] NMR Nuclear Magnetic Resonance

[0098] Pd Palladium

[0099] Pd / C Palladium on charcoal

[0100] PG protective group

[0101] Ph phenyl

[0102] PMB para-methoxybenzyl

[0103] r.t. room temperature

[0104] SCX strong cation exchange

[0105] TBTU O-(Benzotriazol- 1 -y l)-N,N,N',N'-tetramethyluronium tetrafluoroborate t-Bu tert-Butyl

[0106] TEA triethylamine

[0107] TFA trifluoroacetic acid

[0108] THF tetrahydrofuran

[0109] Ts Tosyl

[0110] UV ultra-violet General synthetic schemes

[0111] The following scheme, Scheme 1, illustrates an exemplary way of preparing compounds in accordance with the present disclosure and examples:

[0112] STEP 1

[0113] Compound 1A Compound 1B

[0114]

[0115] SCHEME 1

[0116] According to Scheme 1 (in which X may be Cl or Br, or I; PG a protective group such as for example a tosyl group; Y is O, -CH(OH)-, -CH(OMe)-; R1is -H or -NH2), Compound IB can be obtained in STEP 1 by protection of Compound 1 A with TsCl using a base such as sodium hydride for example. Compound 1C can be obtained by iodination of compound IB in STEP 2 using I2 and a base such as LDA, for example. Compound IE can be obtained by Suzuki coupling in STEP 3 between Compound 1C and Compound ID using, for example, a catalyst such as [l,T-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex, in a mixture of dioxane and water and in the presence of a base, such as potassium carbonate, by heating to reflux. Compound 1G can be obtained by an additional Suzuki coupling in STEP 4 between Compound IE and Compound IF using, for example, a catalyst such as [l,r-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex in a mixture of dioxane and water and in the presence of a base, such as potassium carbonate, by heating to reflux. Compound 1G can then be converted to Compound 1H in STEP 5 using NaOH in i-PrOH as solvent. Compound 1H can be deprotected to compound II in STEP 6 using TFA or HC1 in DCM for example. Compound IK can then be prepared from Compound 1H in STEP 7 with carboxylic acid and Compound 1J, using conditions known by the person skilled in the art such as TBTU in a solvent like DMF in presence of a base such as DIPEA. Compound I can be obtained by hydrogenation of compound IK in STEP 8 using Pd / C with H2 for example. STEP 8 may optionally further comprise cis / trans mixture separation, for example, with compounds in which Y is -CH(OMe)- or -CH(OH)-substituents.

[0117] The preparation of compound I (in which PG is a protective group such as for example a tosyl group; Y is O, -CH(OH)-, -CH(OMe)-; R1is -H or -NH2), may be also effected according to the alternative following scheme, Scheme 2:

[0118]

[0119] SCHEME 2

[0120] According to Scheme 2 (in which PG is a protective group such as for example a tosyl group; Y is O, -CH(OH)-, -CH(OMe)-; R1is -H or -NH2), compound IL can be obtained by hydrogenation of compound 1G in STEP 1 using Pd / C with H2 for example. Compound IL can be converted to Compound IM in STEP 2 by deprotection using TFA or HC1 in DCM for example. Compound IN can then be prepared from Compound IM in STEP 3 with carboxylic acid Compound 1 J, using conditions known by the person skilled in the art such as TBTU in a solvent like DMF in presence of a base such as DIPEA. Compound IN can be then deprotected in STEP 4 to give compound I, using NaOH in i-PrOH as solvent, for example. STEP 4 may optionally further comprise cis / trans mixture separation, for example, with compounds in which Y is -CH(OMe)- or -CH(OH)- substituents.

[0121] The preparation of compound I (in which R4 represents a saturated cycloalkyl or heterocycloalkyl group; R1 is -H or -NH2), may be also effected according to the alternative following scheme, Scheme 3:

[0122]

[0123] SCHEME 3

[0124] According to Scheme 3 (in which R4 represents a saturated cycloalkyl or heterocycloalkyl group; R1 is -H or -NH2), compound 10 can be oxidized in STEP 1 to give compound IP, using conditions known by the person skilled in the art such as oxalyl chloride and DMSO, for example. Compound IP can be converted to Compound 1R in STEP 2 using compound IQ in the presence of a base such as potassium carbonate in MeOH for example. Compound IT can then be prepared from Compound IS by Sonogashira coupling in STEP 3 with Compound IS, using a palladium catalyst in a solvent like DMF in presence of a base such as TEA. Intramolecular cyclization of compound IT in STEP 4 can be performed, to give compound 1U, by using a base such t-BuOK, in NMP as solvent, for example. Compound 1W can be obtained by Suzuki coupling in STEP 5 between Compound 1U and Compound IV using, for example, a catalyst such as [l,r-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex, in a mixture of dioxane and water and in the presence of a base, such as potassium carbonate, by heating to reflux. Compound I can be obtained by hydrogenation of compound 1W in STEP 6 using Pd / C with H2 for example. STEP 6 may optionally further comprise a -N-BOC deprotection, and / or a chiral separation, for example, with compounds in which R4 is a (N-(BOC))-morpholin-2-yl substituent.

[0125] The preparation of compound I (in which X is Cl, Br or I; Y is O, -CH(OH)-, -CH(OMe)-; R1is -H or -NH2), may be also effected according to the alternative following scheme, Scheme 4:

[0126] STEP 1

[0127] STEP 3

[0128]

[0129] SCHEME 4

[0130] According to Scheme 4 (in which X is Cl, Br or I; Y is O, -CH(OH)-, -CH(OMe)-; R1is -H or -NH2), compound 2C can be obtained in STEP 1 by condensation of compound 2A with compound 2B using a base such as potassium hydroxide in MeOH for example. Compound 2D can be obtained by Suzuki coupling in STEP 2 between Compound 2C and Compound ID using, for example, a catalyst such as [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex, in a mixture of dioxane and water and in the presence of a base, such as potassium carbonate, by heating to reflux. Compound 2D can be converted to Compound 2E in STEP 3 by deprotection using TFA or HCI in DCM for example. Compound 2F can then be prepared from Compound 2E in STEP 4 with carboxylic acid Compound 1 J, using conditions known by the person skilled in the art such as TBTU in a solvent like DMF in presence of a base such as DIPEA. Compound I can be obtained by hydrogenation of compound 2F in STEP 5 using Pd / C with H2 for example. STEP 5 may optionally further comprise cis / trans mixture separation, for example, with compounds in which Y is -CH(OMe)- or -CH(OH)- substituents.

[0131] The preparation of compound I (in which X is Cl, Br or I; Y is O, -CH(OH)-, -CH(OMe)-; W is C, N; Z is H, (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl); R1is -H or -NH2), may be also effected according to the alternative following scheme, Scheme 5:

[0132] STEP 1 STEP 2

[0133] Compound 2B Compound 2G KOH, MeOH Base, Pd Catalyst solvent Compound 2A Compound 2H STEP 3 HCI or TFA solvent, 2 hrs

[0134]

[0135] Compound 2J SCHEME 5

[0136] According to Scheme 5 (in which X is Cl, Br or I; Y is O, -CH(OH)-, -CH(OMe)-; W is C, N; Z is H, (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl); R1is -H or -NH2), Compound 2H can be obtained in STEP 1 by Suzuki or Hartwig-Buchwald-like coupling reaction of Compound 2A with compound 2G, using, for example, a catalyst such as XphosPdG4, in the presence of a base, such as LiHMDS, by heating at 90 °C. Compound 21 can be then prepared in STEP 2 by condensation of compound 2H with compound 2B using a base such as potassium hydroxide in MeOH for example. Compound 21 can be converted to Compound 2J in STEP 3 by deprotection using TFA or HC1 in DCM for example. Compound 2F can be prepared from Compound 2J in STEP 4 with carboxylic acid Compound 1J, using conditions known by the person skilled in the art such as TBTU in a solvent like DMF in presence of a base such as DIPEA. Compound I can be then obtained by hydrogenation of compound 2F in STEP 5 using Pd / C with H2 for example.

[0137] The preparation of compound I (in which R4 is a saturated cycloalkyl or heterocycloalkyl group; R1is -H, -NO2 or -NH2), may be also effected according to the alternative following scheme, Scheme 6:

[0138] STEP 1 STEP 2 STEP 3

[0139] PMB-NH2, Et3N, CuBr2, t-BuONO DMSO, 150 °C MeCN, 45 °C, 1 hr sealed tube 3 hrs Compound 3A Compound 3B Compound 3C Compound 3D STEP 4 Pd Catalyst base, solvent, STEP 7 STEP 6 100 °C, 6 hrs

[0140] Compound 3G Compound 3F Compound 3E

[0141]

[0142] Compound I SCHEME 6 According to Scheme 6 (in which R4 is a saturated cycloalkyl or heterocycloalkyl group; R1is -H, -NO2 or -NH2), Compound 3B can be obtained in STEP 1 by nitration of Compound 3A using, nitric acid and sulfuric acid. Compound 3B can be converted in STEP 2 into compound 3C by nucleophilic aromatic substitution using PMB-NH2, in DMSO in the presence of base such as EtsN at 150 °C in sealed tube. Compound 3D can be prepared from compound 3C in STEP 3, using CuBn, t-BuONO in acetonitrile. Compound 3E can be obtained by Suzuki coupling in STEP 4 between Compound 3D and Compound IF using, for example, a catalyst such as [l,r-bis(diphenylphosphino)ferrocene]dichloropalladium(II) di chloromethane complex, in a mixture of dioxane and water and in the presence of a base, such as potassium carbonate, by heating to reflux. Compound 3F can be then obtained by hydrogenation of compound 3E in STEP 5 using Pd / C with H2 for example. Compound 3F can be converted to Compound 3G in STEP 6 by deprotection using TFA or HC1 in DCM for example. Compound 3H can be prepared from Compound 3G in STEP 7 with carboxylic acid Compound 1J, using conditions known by the person skilled in the art such as TBTU in a solvent like DMF in presence of a base such as DIPEA. Compound I can be then obtained in STEP 8 via a two steps sequence by coupling with compound 31 using EDC1 and a base such as pyridine for example, followed by an intramolecular cyclocondensation using a base such as potassium carbonate in i-PrOH for example. STEP 8 may optionally further comprise a subsequent hydrogenation step using iron and ammonium chloride in ethanol, for example, with compounds in which R1 is -NO2.

[0143] Pharmaceutical compositions, uses

[0144] A further aspect provides a pharmaceutical composition comprising a compound of formula (I), (II), (II- 1), (III) or (III- 1) and at least one pharmaceutically acceptable excipient or carrier.

[0145] The pharmaceutical compositions of the disclosure may be formulated for administration in solid or liquid form, e.g., using conventional carriers or excipients. Compositions may be adapted for, e.g., oral administration (e.g., as a solution, suspension, tablet, or capsule), parenteral administration (e.g., as a solution, dispersion, suspension, or emulsion, or as a dry powder for reconstitution), or topical application (e.g., as a cream, ointment, patch, or spray to be applied to the skin) using techniques known in the art. Compounds of the present disclosure act as inhibitors of ERK5, which gives them utility in the treatment of ERK5 -associated disorders and conditions. In particular, compounds of the disclosure are useful in the treatment of cancers.

[0146] Viewed from this aspect, the disclosure provides a method of treatment comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the disclosure (e.g., a compound of Formula (I), (II), (II- 1 ), (III), (III-l) or a pharmaceutically acceptable salt thereof). In a related aspect, the disclosure provides the use of a compound of the disclosure (e.g., a compound of Formula (I), (II), (II-l), (III), (III- 1) or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament. In a further related aspect, the disclosure provides a compound of the disclosure (e.g., a compound of Formula (I), (II), (II-l), (III), (III- 1 ) or a pharmaceutically acceptable salt thereof) for use in therapy.

[0147] Compounds of the present disclosure are useful for treating or preventing: diseases or deleterious conditions in which ERK5, or a variant or mutant thereof, is known to play a role; diseases or disorders associated with increased MAPK7 (i.e., ERK5 gene) expression and / or increased ERK5 activity; and diseases or disorders in which inhibition or antagonism of ERK5 activity is beneficial.

[0148] In one aspect, the present disclosure provides a method of treating or preventing a disease or disorder mediated by ERK5, or a disease or disorder in which ERK5 is implicated, in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of the disclosure (e.g., a compound of Formula (I), (II), (II-l), (III), (III- 1) or a pharmaceutically acceptable salt thereof). In a related aspect, the disclosure provides the use of a compound of the disclosure (e.g., a compound of Formula (I), (II), (II-1), (III), (III-l) or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for the treatment or prevention of a disease or disorder mediated by ERK5, or a disease or disorder in which ERK5 is implicated. In a further related aspect, the disclosure provides a compound of the disclosure (e.g., a compound of Formula (I), (II), (II-l), (III), (III-l) or a pharmaceutically acceptable salt thereof) for use in the treatment or prevention of a disease or disorder mediated by ERK5, or a disease or disorder in which ERK5 is implicated.

[0149] In another aspect, the present disclosure provides a method of treating or preventing a disease or disorder associated with ERK5 (e.g., cancer) in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of the disclosure (e.g., a compound of Formula (I), (II), (II-l), (III), (III-l) or a pharmaceutically acceptable salt thereol). In a related aspect, the disclosure provides the use of a compound of the disclosure (e.g., a compound of Formula (I), (II), (II-l), (III), (III-l) or a pharmaceutically acceptable salt thereol) in the manufacture of a medicament for the treatment or prevention of a disease or disorder associated with ERK5 (e.g., cancer). In a further related aspect, the disclosure provides a compound of the disclosure (e.g., a compound of Formula (I), (II), (II-1), (III), (III-l) or a pharmaceutically acceptable salt thereol) for use in the treatment or prevention of a disease or disorder associated with ERK5 (e.g., cancer).

[0150] In another aspect, the present disclosure provides a method of treating or preventing cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of the disclosure (e.g., a compound of Formula (I), (II), (II-l), (III), (III-l) or a pharmaceutically acceptable salt thereol). In a related aspect, the disclosure provides the use of a compound of the disclosure (e.g., a compound of Formula (I), (II), (II-l), (III), (III-l) or a pharmaceutically acceptable salt thereol) in the manufacture of a medicament for the treatment or prevention of cancer. In a further related aspect, the disclosure provides a compound of the disclosure (e.g., a compound of Formula (I), (II), (II-l), (III), (III-l) or a pharmaceutically acceptable salt thereol) for use in the treatment or prevention of cancer.

[0151] In embodiments, the compound reduces angiogenesis, reduces or prevents metastasis, reduces inflammation, blocks tumorigenesis (e.g., in part or completely), reduces evasion of growth suppression, reduces or inhibits growth of cancerous or pre-cancerous cells, supresses proliferation of cancerous or pre-cancerous cells, and / or reduces the survival of cancerous or pre-cancerous cells.

[0152] In embodiments, the cancer is characterized by increased MAPK7 (i.e., ERK5 gene) expression and / or increased ERK5 activity. In embodiments, the cancer has elevated ERK5 activity. In embodiments, the cancer overexpresses ERK5. In embodiments, the cancer is characterised by MAPK7 genomic amplification and / or constitutively active ERK5 signalling. In embodiments, the cancer has genomically amplified ERK5. In embodiments, the cancer has constitutively active ERK5 signalling. In embodiments, the cancer is a solid tumour (e.g., a melanoma, carcinoma, or blastoma). In other embodiments, the cancer is leukaemia (e.g., chronic lymphocytic leukaemia, CLL; acute myelogenous leukaemia, AML; or chronic myelogenous leukaemia, CML).

[0153] In embodiments, the cancer is a primary tumour. In other embodiments, the cancer is a secondary tumour (e.g., a metastatic tumour).

[0154] In embodiments, the cancer is selected from breast cancer (e.g., ductal breast carcinoma, or breast adenocarcinoma), liver cancer, kidney cancer (e.g., hepatocellular carcinoma), prostate cancer, colorectal cancer (CRC), lung cancer (e.g., non-small cell lung cancer, NSCLC; lung adenocarcinoma; or lung squamous cell carcinoma), pancreatic cancer (e.g., adenocarcinoma), ovarian cancer, brain cancer (e.g., glioblastoma), cervical cancer (e.g., adenocarcinoma), gastric cancer, skin cancer (e.g., melanoma), bile duct cancer (e.g., cholangiocarcinoma), nervous system cancer (e.g., neuroblastoma), and melanoma.

[0155] In embodiments, the cancer is selected from leukaemia (e.g., acute leukaemia, acute lymphocytic leukaemia, acute myelocytic leukaemia, acute myeloblastic leukaemia, acute promyelocytic leukaemia, acute myelomonocytic leukaemia, acute monocytic leukaemia, acute erythroleukemia, chronic leukaemia, chronic myelocytic leukaemia, or chronic lymphocytic leukaemia), polycythaemia vera, lymphoma (e.g., Hodgkin's disease or nonHodgkin's disease), Waldenstrom macroglobulinemia, and multiple myeloma.

[0156] In embodiments, the cancer is selected from leukaemia (e.g., chronic myeloid leukaemia), breast cancer, multiple myeloma, colon cancer, colorectal cancer, lung cancer, pancreatic cancer, renal cell carcinoma, mesothelioma, adenocarcinoma, neuroblastoma, melanoma, and hepatocellular carcinoma.

[0157] In embodiments, the cancer is selected from leukaemia (e.g., chronic myeloid leukaemia), breast cancer, multiple myeloma, colon cancer, renal cell carcinoma, mesothelioma, adenocarcinoma, neuroblastoma, and hepatocellular carcinoma.

[0158] In another aspect, the disclosure provides a method of inhibiting ERK5 activity, the method comprising contacting ERK5 (e.g., a cell comprising ERK5) with a compound of the present disclosure (e.g., a compound of Formula (I), (II), (II-l), (III), (III-l) or a pharmaceutically acceptable salt thereof). In embodiments, the method is an in vitro or ex vivo method. In other embodiments the method is an in vivo method. In a related aspect, the disclosure provides an in vitro method of inhibiting ERK5 activity in a cell, the method comprising contacting the cell with a compound of the present disclosure (e.g., a compound of Formula (I), (II), (II-l ), (III), (III- 1 ) or a pharmaceutically acceptable salt thereof).

[0159] The compounds of the disclosure may be used alone (e.g., as a monotherapy) or in combination with one or more cancer therapies.

[0160] Having been generally described herein, the follow non-limiting examples are provided to further illustrate this disclosure.

[0161] Although specific embodiments of the present disclosure will now be described with reference to the description and examples, it should be understood that such embodiments are by way of example only and merely illustrative of but a small number of the many possible specific embodiments which can represent applications of the principles of the present disclosure. Various changes and modifications will be obvious to those of skill in the art given the benefit of the present disclosure and are deemed to be within the spirit and scope of the present disclosure as further defined in the appended claims.

[0162] EXAMPLES

[0163] Examples 1 to 21 - Compounds

[0164] All synthetic reactions were performed under an inert atmosphere, unless otherwise stated. In the following examples, when the source of the starting products is not specified, it should be understood that said products are known compounds (e.g., commercially available compounds from suppliers such as Sigma- Aldrich).

[0165] Analytical data have been obtained as follows:

[0166] Proton NMR: 'H NMR Spectra at 400 and 500 MHz were performed on a Bruker Avance DRX-400 and Bruker Avance DPX-500 spectrometer, respectively, with the chemical shifts (6 in ppm) in the solvent dimethyl sulfoxide-de (DMSO-de) referenced at 2.5 ppm at the quoted temperatures. Coupling constants (J) are given in Hertz.

[0167] LC-MS: The liquid chromatography / mass spectra (LC / MS) were obtained on a UPLC Acquity Waters instrument, light scattering detector Sedere and SQD Waters mass spectrometer using UV detection DAD 210<l<400 nm and column Acquity BEH Cl 8, 1.7 pm, dimension 2.1x50 mm, flow 0.8 ml / min, 40°C, mobile phase H2O + 0.1% HCO2H (A) / CH3CN + 0.1% HCO2H (B), gradient (time vs. % B) of 0.0 / 5, 0.3 / 5, 0.5 / 100, 1.8 / 100, 2.0 / 5, 3.0 / 5. Mass spectra: MSDl-Positive mode / MSD2-Negative mode.

[0168] Table 1 below lists the compounds of formula (I) synthesized as in the previous general schemes or in the following synthetic examples. Table 1:

[0169] Example No. Structure Name

[0170] F F(cis, cis)-[5-[5-fluoro-2-((trans)-4- N methoxycyclohexyl)-lH-pyrrolo[2,3- 1 b]pyri din-4-yl]-3, 3a, 4,5,6, 6a-hexahydro-lH- cyclopenta[c]pyrrol-2-yl]-[4- „ ..<0 yF(trifluoromethoxy)phenyl]methanone / W N-^N>

[0171] H

[0172] F F(cis, cis)-[5-[5-fluoro-2-((cis)-4- N methoxycyclohexyl)-lH-pyrrolo[2,3- 2 b]pyri din-4-yl]-3, 3a, 4,5,6, 6a-hexahydro-lH- cyclopenta[c]pyrrol-2-yl]-[4- (trifluoromethoxy)phenyl]methanone o.-0 . mF

[0173] HFT L0O (cis, cis)-[5-[5-fluoro-2-((cis)-4- N methoxycyclohexyl)-lH-pyrrolo[2,3- 3 b]pyri din-4-yl]-3, 3a, 4,5,6, 6a-hexahydro-lH- cyclopenta[c]pyrrol-2-yl]-[2-amino-4- / o<0 yF(trifluoromethoxy)phenyl]methanone HFT 00 (cis, cis)-[5-[5-fluoro-2-((trans)-4- N methoxycyclohexyl)-lH-pyrrolo[2,3- 4 b]pyri din-4-yl]-3, 3a, 4,5,6, 6a-hexahydro-lH- cyclopenta[c]pyrrol-2-yl]-[2-amino-4- / O...O0F(trifluoromethoxy)phenyl]methanone / \ — f N-^N>

[0174] H

[0175] F F(cis, cis)-[5-[5-fluoro-2-((cis)-4- N hydroxycyclohexyl)-lH-pyrrolo[2,3-b]pyridin 5 4-yl]-3, 3a, 4,5,6, 6a-hexahydro-lH- cyclopenta[c]pyrrol-2-yl]-[4- HO— / \— |] (trifluoromethoxy)phenyl]methanone \ — f N-^N>

[0176] H

[0177]

[0178] Example No. Structure Name

[0179] F F(cis, cis)-[5-[5-fluoro-2-((trans)-4- N hydroxycyclohexyl)-lH-pyrrolo[2,3-b]pyridin 6 4-yl]-3, 3a, 4,5,6, 6a-hexahy dro-1 Iley clopenta[c]pyrrol-2-yl] -[4- I HO - / \— |] (trifluoromethoxy)phenyl]methanone O \ — f N-^N>

[0180] H

[0181] 0

[0182] (cis, cis)-[5-[5-fluoro-2-((cis)-4- w hydroxycyclohexyl)-lH-pyrrolo[2,3-b]pyridin 7 \ J( o=- 4-yl]-3, 3a, 4,5,6, 6a-hexahy dro-lH- cyclopenta[c]pyrrol-2-yl]-[2-amino-4- (trifluoromethoxy)phenyl]methanone

[0183] F O^ / ^ NH2

[0184] FT TJ^O (cis, cis)-[5-[5-fluoro-2-((trans)-4- N hydroxycyclohexyl)-lH-pyrrolo[2,3-b]pyridin 8 4-yl]-3, 3a, 4,5,6, 6a-hexahy dro-lH- cyclopenta[c]pyrrol-2-yl]-[2-amino-4- HO - / \— < | || (trifluoromethoxy)phenyl]methanone X — f N-^N^

[0185] H NH2

[0186] FT XX^ (cis, cis)- [5 -(5 -tetrahy dropy ran-4-y 1- 1 H- N pyrrolo[2,3-b]pyridin-3-yl)-3,3a,4,5,6,6a- 9 hexahydro-lH-cyclopenta[c]pyrrol-2-yl]-[2- amino-4-(trifluoromethoxy)phenyl]methanone vXfQ

[0187] ^=N H

[0188] F F(cis, cis)-[5-[6-fluoro-2-(3-methoxy-l- N bicyclo[l.l.l]pentanyl)-3H-imidazo[4,5- 10 b]pyri din-7-yl]-3, 3a, 4,5,6, 6a-hexahy dro-1 Iley clopenta[c]pyrrol-2-yl] -[4- (trifluoromethoxy)phenyl]methanone J J H

[0189] F^°^X^^N H2

[0190] FT VY° (cis, cis)-[5-[6-fluoro-2-(3-methoxy-l- N bicyclo[l.l.l]pentanyl)-3H-imidazo[4,5- 11 b]pyri din-7-yl]-3, 3a, 4,5,6, 6a-hexahy dro-1 Iley clopenta[c]pyrrol-2-yl]-[2-amino-4- (trifluoromethoxy)phenyl]methanone o^v^ / Xf T

[0191] / VN-^N^

[0192]

[0193] H Example No. Structure Name

[0194] F F(cis, cis)-[5-[5-((cis)-4-hydroxycyclohexyl)- N lH-pyrrolo[2,3-b]pyridin-3-yl]-3,3a,4,5,6,6a- 12 hexahydro-lH-cyclopenta[c]pyrrol-2-yl]-[4- (trifluoromethoxy)phenyl]methanone uXp

[0195] ^=N H

[0196] F F(cis, cis)-[5-[5-((trans)-4-hydroxycyclohexyl)- N lH-pyrrolo[2,3-b]pyridin-3-yl]-3,3a,4,5,6,6a- 13 hexahydro-lH-cyclopenta[c]pyrrol-2-yl]-[4- (trifluoromethoxy)phenyl]methanone HO„.Z^\

[0197] IXX

[0198] ^=N H

[0199] NH?

[0200] FT XX^ (cis, cis)-[5-(5-morpholino-lH-pyrrolo[2,3- N b]pyridin-3-yl)-3, 3a, 4,5,6, 6a-hexahydro-l Il14 ey clopenta[c]pyrrol-2-yl]-[2-amino-4- (trifluoromethoxy)phenyl]methanone O' / ---As

[0201] ' — / \ V-N

[0202] ^=N H

[0203] F^O. / \ NH2

[0204] FT XX^ (cis, cis)-[5-[5-((cis)-4-hydroxycyclohexyl)- N lH-pyrrolo[2,3-b]pyridin-3-yl]-3,3a,4,5,6,6a- 15 hexahydro-lH-cyclopenta[c]pyrrol-2-yl]-[2- amino-4-(trifluoromethoxy)phenyl]methanone

[0205] ^=N H

[0206] F^O ^. NH?

[0207] FT XX^O (cis, cis)-[5-[5-((trans)-4-hydroxycyclohexyl)- N lH-pyrrolo[2,3-b]pyridin-3-yl]-3,3a,4,5,6,6a- 16 hexahydro-lH-cyclopenta[c]pyrrol-2-yl]-[2- amino-4-(trifluoromethoxy)phenyl]methanone HO,,.Z*X

[0208] OXX-N

[0209] ^=N H

[0210] LX^O (cis)- [5 -(5-tetrahy dropyran-4-yl- 1 H- N pyrrolo[2,3-b]pyridin-3-yl)-3,3a,6,6a- 17 tetrahydro-lH-cyclopenta[c]pyrrol-2-yl]-[2- amino-4-(trifluoromethoxy)phenyl]methanone 0Z'X / --zAs

[0211] O-fX-N

[0212] ^=N H

[0213]

[0214] Example No. Structure Name

[0215] F F(cis)-[5-(5-morpholino-lH-pyrrolo[2,3- N b]pyridin-3-yl)-3,3a,6,6a-tetrahydro-lH- 18 cyclopenta[c]pyrrol-2-yl]-[2-amino-4- (trifluoromethoxy)phenyl]methanone O -n -nv— / \ >-N

[0216] ^=N H

[0217] o

[0218] (cis, cis)- [5- [5-fluoro-2- [morpholin-2-yl] - 1H- pyrrolo[2,3-b]pyridin-4-yl]-3,3a,4,5,6,6a- 19 hexahydro-lH-cyclopenta[c]pyrrol-2-yl]-[4- (trifluoromethoxy)phenyl] methanone isomer 1

[0219] F^o\x^

[0220] F F(cis, cis)- [5- [5-fluoro-2- [morpholin-2-yl] - 1H- N pyrrolo[2,3-b]pyridin-4-yl]-3,3a,4,5,6,6a- 20 hexahydro-lH-cyclopenta[c]pyrrol-2-yl]-[4- (trifluoromethoxy)phenyl] methanone isomer 2 V P

[0221] O . Co

[0222] ^0

[0223] 6 P - N H-^N^

[0224] (cis, cis)-[5-(5-fluoro-2-tetrahydropyran-4-yl- lH-pyrrolo[2,3-b]pyridin-4-yl)-3,3a,4,5,6,6a- 21 hexahydro-lH-cyclopenta[c]pyrrol-2-yl]-[2- amino-4-(trifluoromethoxy)phenyl]methanone

[0225]

[0226] Examples 1 & 2: (cis, cis)-[5-[5-fluoro-2-((trans)-4-methoxycyclohexyl)-lH-pyrrolo[2,3-b]pyridin-4-yl]-3,3a,4,5,6,6a-hexahydro-lH-cyclopenta[c]pyrrol-2-yl]-[4-(trifluoromethoxy)phenyl]methanone & (cis, cis)-[5-[5-fluoro-2-((cis)-4-methoxycyclohexyl)-lH-pyrrolo[2,3-b]pyridin-4-yl]-3,3a,4,5,6,6a-hexahydro-lH-cyclopenta[c]pyrrol-2-yl]-[4-(trifluoromethoxy)phenyl]methanone

[0227]

[0228] METHOD A (Scheme 1) STEP 1: 4-chloro-5-fluoro-l-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridine

[0229] ci

[0230]

[0231] To a stirred solution of 4-chloro-5-fluoro-lH-pyrrolo[2,3-b]pyridine (5 g, 29.3 mmol) in DMF (40 mL), were added NaH (60 % dispersion in oil, 1.76 g, 44 mmol) at 0 °C and TsCl (8.38 g, 44 mmol) at room temperature and the resulting reaction mixture was stirred for 16 hours at room temperature. Then, the whole mixture was quenched with water (100 mL), a solid precipitated which was filtered and this residue was triturated to give 8.5 g (89% yield) of 4-chloro-5-fluoro-l-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridine as a white solid. LC / MS (m / z, M+H): calc. 325.0, found 325.1.

[0232] STEP 2: 4-chloro-5-fluoro-2-iodo-l-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridine

[0233] ci

[0234]

[0235] To a stirred solution of 4-chloro-5-fluoro-l-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridine (5 g, 15.4 mmol) in THF (100 mL) ,was added LDA (2 M, 11.5 mL, 23 mmol) at -78 °C and the resulting reaction mixture was stirred for one hour at -78 °C. , Then, molecular h (3.91 g, 15.4 mmol) was added at -78 °C and the reaction mixture was warmed up to room temperature and stirred for 2 hours. Then, the whole mixture was quenched with an aqueous saturated solution of NH4CI (50 ml) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under vacuum. The resulting residue was purified by flash chromatography on silica gel eluting with ethyl acetate / hexane (1 / 1) to give 2.5 g (purity 59%, 21% yield) of 4-chloro-5-fluoro-2-iodo-l-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridine as a brown solid. LC / MS (m / z, M+H): calc. 450.9, found 450.8.

[0236] STEP 3: (rac)-4-chl oro-5 -fluoro-2-(4-methoxy cy cl ohexen- 1 -yl)- 1 -(p-tolylsulfonyl)pyrrolo[2,3-b]pyridine

[0237]

[0238] To a stirred solution of 4-chloro-5-fluoro-2-iodo-l-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridine (1.5 g, 3.33 mmol) and 2-(4-methoxycyclohexen-l-yl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (1.19 g, 4.99 mmol) in 1,4-dioxane / water (20 / 5 mL), was added K2CO3 (1.38 g, 9.99 mmol) at room temperature, and the resulting reaction mixture was bubbled with Argon for 10 minutes. After 10 minutes, PdCh(dppf)DCM complex (272 mg, 0.33 mmol) was added, and the whole mixture was stirred for 16 hours at 70 °C, then diluted with ethyl acetate, filtered through celite bed and the filtrate was concentrated under vacuum. The resulting residue was purified by flash chromatography on silica gel eluting with 30% of EtOAc in hexane to give 1 g (61% yield) of (rac)-4-chl oro-5 -fluoro-2-(4-methoxycy cl ohexen-l-yl)-l-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridine as a brown sticky solid. LC / MS (m / z, M+H): calc. 435.1, found 434.9.

[0239] STEP 4: (rac)-tert-butyl 5-[5-fluoro-2-(4-methoxycyclohexen-l-yl)-l-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-4-yl]-(cis)-3,3a,6,6a-tetrahydro-lH-cyclopenta[c]pyrrole-2-carboxylate

[0240]

[0241] To a stirred solution of (rac)-4-chloro-5-fluoro-2-(4-methoxycyclohexen-l-yl)-l-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridine (900 mg, 2.3 mmol) and tert-butyl (cis)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,3a,6,6a-tetrahydro-lH-cyclopenta[c]pyrrole-2-carboxylate (1.16 g, 3.45 mmol) in 1,4-dioxane / water( 10 / 2mL), was added K2CO3 (953 mg, 6.9 mmol) at room temperature, and the resulting reaction mixture was bubbled with argon for 10 minutes. After 10 minutes, was added PdCh(dppf)DCM complex (188 mg, 0.23 mmol), and the whole mixture was stirred for 16 hours at 100 °C then cooled down to room temperature, diluted with ethyl acetate, filtered through celite bed and filtrate was concentrated under vacuum. The resulting residue was purified by Has chromatography on silica gel eluting with 50% of EtOAc in Hexane to give 550 mg (35% yied) of (rac)-tert-butyl (cis, cis)-5-[5-fluoro-2-(4-methoxycyclohexen-l-yl)-l-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-4-yl]-3,3a,6,6a-tetrahydro-lH-cyclopenta[c]pyrrole-2-carboxylate as a brown sticky solid. LC / MS (m / z, M+H): calc. 608.2, found 608.1.

[0242] STEP 5: (rac)-tert-butyl (cis)-5-[5-fluoro-2-(4-methoxycyclohexen-l-yl)-lH-pyrrolo[2,3-b]pyridin-4-yl]-3,3a,6,6a-tetrahydro-lH-cyclopenta[c]pyrrole-2-carboxylate

[0243]

[0244] To a stirred solution of tert-butyl (cis)-5-[5-fluoro-2-(4-methoxycyclohexen-l-yl)-l-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-4-yl]-3,3a,6,6a-tetrahydro-lH-cyclopenta[c]pyrrole-2-carboxylate (550 mg, 0.91 mmol) in methanol (2 mL) was added NaOH (109 mg, 2.71 mmol) in water, and the resulting recti on mixture was stirred for 2 hours at 70 °C. Then, the whole mixture was diluted with water (20 mL), extracted with ethyl acetate (2x50 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under vacuum to give 350 mg (81% purity, 69% yield) of (rac)-tert-butyl (cis)-5-[5-fhioro-2-(4-methoxycyclohexen-l-yl)-lH-pyrrolo[2,3-b]pyridin-4-yl]-3,3a,6,6a-tetrahydro-lH-cyclopenta[c]pyrrole-2-carboxylate. LC / MS (m / z, M+H): calc. 454.2, found 454.1.

[0245] STEP 6: (rac)-4-[(cis)-l,2,3,3a,6,6a-hexahydrocyclopenta[c]pyrrol-5-yl]-5-fluoro-2-(4-methoxycyclohexen-l-yl)-lH-pyrrolo[2,3-b]pyridine hydrochloride

[0246] H

[0247] N.

[0248] N

[0249]

[0250] H

[0251] A stirred solution of tert-butyl (rac)-(cis)-5-[5-fluoro-2-(4-methoxycyclohexen-l-yl)-lH-pyrrolo[2,3-b]pyridin-4-yl]-3,3a,6,6a-tetrahydro-lH-cyclopenta[c]pyrrole-2-carboxylate (350 mg, 0.77 mmol) in DCM (5 mL) was cooled to 0 °C, and a 4M solution of HC1 in 1,4-dioxane (0.97 mL, 3.86 mmol) was added and the resulting reaction mixture was stirred for 1 hour at room temperature. Then, the whole mixture was concentrated under vacuum and the resulting residue was triturated with hexane to give 300 mg (100% yield) of (rac)-4-[4-[(cis)-l,2,3,3a,6,6a-hexahydrocyclopenta[c]pyrrol-5-yl]-5-fluoro-lH-pyrrolo[2,3-b]pyridin-2-yl] cyclohex-3 -en-l-ol hydrochloride as a yellow solid. LC / MS (m / z, M+H -HC1): calc. 354.2, found 354.1.

[0252] STEP 7: Trans / cis mixture of [(cis, cis)-5-[5-fluoro-2-(4-methoxycyclohexyl)-l-(p-tolylsulfonyl)pyrrolo[2, 3-b]pyridin-4-yl]-3, 3a, 4,5,6, 6a-hexahy dro-lH-cy clopenta[c]pyrrol-2-yl]-[4-(trifluoromethoxy)phenyl]methanone

[0253]

[0254] To a stirred solution of (rac)-4-[4-[(cis)-l,2,3,3a,6,6a-hexahydrocyclopenta[c]pyrrol-5-yl]-5-fluoro-lH-pyrrolo[2,3-b]pyridin-2-yl]cyclohex-3-en-l-ol hydrochloride (270 mg, 0.69 mmol) and 4-(trifluoromethoxy)benzoic acid (164 mg, 0.8 mmol) in DMF (5 mL), was added N,N-diethylethanamine (241 mg, 2.39 mmol) at 0 °C and then [benzotriazol- 1-yloxy(dimethylamino)methylene]-dimethyl-ammonium;tetrafluoroborate (383 mg, 1.19 mmol) and the resulting reaction mixture was stirred for 1 hour at room temperature. Then, the reaction mixture was poured into crushed ice, a solid precipitated which was triturated with hexane, filtered and dried under vacuum to give 250 mg (67% yield) of (rac)-[(cis)-5-[5-fluoro-2-(4-methoxycyclohexen-l-yl)-lH-pyrrolo[2,3-b]pyridin-4-yl]-3,3a,6,6a-tetrahydro-lH-cyclopenta[c]pyrrol-2-yl]-[4-(trifluoromethoxy)phenyl]methanone as an off white solid. LC / MS (m / z, M+H): calc. 542.2, found 542.2.

[0255] STEP 8i: (cis, cis)-[5-[5-fluoro-2-((trans)-4-methoxycyclohexyl)-lH-pyrrolo[2,3-b]pyridin-4-yl]-3, 3a, 4,5,6, 6a-hexahydro-lH-cyclopenta[c]pyrrol-2-yl]-[4-(trifluoromethoxy)phenyl]methanone & (cis, cis)-[5-[5-fluoro-2-((cis)-4-methoxycyclohexyl)-lH-pyrrolo[2,3-b]pyridin-4-yl]-3,3a,4,5,6,6a-hexahydro-lH-cyclopenta[c]pyrrol-2-yl]-[4-(trifluoromethoxy)phenyl]methanone

[0256]

[0257] To a stirred solution of (rac)-[(cis)-5-[5-fluoro-2-(4-methoxycyclohexen-l-yl)-lH-pyrrolo[2,3-b]pyridin-4-yl]-3,3a,6,6a-tetrahydro-lH-cyclopenta[c]pyrrol-2-yl]-[4-(trifluoromethoxy)phenyl]methanone (240 mg, 0.44 mmol) in methanol / ethanol (3 / 3 mL) , were added palladium (141 mg, 1.33 mmol) and dihydroxypalladium (187 mg, 1.3 mmol) at room temperature, under one atmosphere of hydrogen and the resulting reaction mixture was stirred for 16 hours at room temperature. Then, the reaction mixture was diluted with MeOH, filtered through celite bed and filtrate was concentrated under vacuum.

[0258] STEP 8ii: The resulting residue was purified by preparative HPLC, to give

[0259] 16 mg (7% yield) of (cis, cis)-[5-[5-fluoro-2-((trans)-4-methoxycyclohexyl)-lH-pyrrolo[2,3-b]pyri din-4-yl]-3, 3a, 4,5,6, 6a-hexahydro-lH-cyclopenta[c]pyrrol -2-yl]-[4- (trifluoromethoxy)phenyl]methanone as a off-white solid.JH NMR (400 MHz, DMSO-c ) 6 ppm 11.57 (s, 1 H), 7.98 (d, J= 3.2 Hz, 1 H), 7.67 (dd, J= 6.8, 1.9 Hz, 2 H), 7.45 (d, J= 8.0 Hz, 2 H), 6.22 (d, J= 1.2 Hz, 1 H), 3.81 (s, 1 H), 3.64 (s, 2 H), 3.51-3.47 (m, 1 H), 3.27 (s, 3 H), 3.17-3.11 (m, 1 H), 2.83 (s, 2 H), 2.70-2.64 (m, 1 H), 2.26 (d, J= 4.8 Hz, 1 H), 2.11-2.04 (m, 6 H), 1.90 (s, 1 H), 1.72 (s, 1 H), 1.57-1.48 (m, 2 H), 1.29-1.25 (m, 2 H). LC / MS (m / z, M+H): calc. 546.2, found 546.3.

[0260] And 50 mg (21% yield) of (cis, cis)-[5-[5-fluoro-2-((cis)-4-methoxycyclohexyl)-lH-pyrrolo[2, 3-b]pyridin-4-yl]-3, 3a, 4,5,6, 6a-hexahy dro-lH-cy clopenta[c]pyrrol-2-yl]-[4-(trifluoromethoxy)phenyl]methanone as a off-white solid. 'H NMR (400 MHz, DMSO- e) 8 ppm 11.52 (s, 1 H), 7.97 (d, J= 3.2 Hz, 1 H), 7.68-7.66 (m, 2 H), 7.45 (d, J= 8.0 Hz, 2 H), 6.19 (d, J= 1.2 Hz, 1 H), 3.82 (d, J= 11.2 Hz, 1 H), 3.64 (s, 2 H), 3.52-3.46 (m, 2 H), 3.38 (s, 1 H), 3.23 (d, J= 16.8 Hz, 3 H), 2.82-2.73 (m, 3 H), 2.33-2.28 (m, 1 H), 2.14 (d, J= 21.2 Hz, 1 H), 1.91 (d, J= 12.8 Hz, 3 H), 1.75 (s, 5 H), 1.57-1.50 (m, 2 H). LC / MS (m / z, M+H): calc.

[0261] 546.2, found 546.3.

[0262] Examples 3 & 4: (cis, cis)-[5-[5-fluoro-2-((cis)-4-methoxycyclohexyl)-lH-pyrrolo[2,3-b]pyridin-4-yl]-3,3a,4,5,6,6a-hexahydro-lH-cyclopenta[c]pyrrol-2-yl]-[2-amino-4- (trifluoromethoxy)phenyl]methanone & (cis, cis)-[5-[5-fluoro-2-((trans)-4-methoxycyclohexyl)-lH-pyrrolo[2,3-b]pyridin-4-yl]-3,3a,4,5,6,6a-hexahydro-lH-cyclopenta[c]pyrrol-2-yl]-[2-amino-4-(trifluoromethoxy)phenyl]methanone

[0263]

[0264] STEP 1: (rac)-tert-butyl (cis)-5-[5-fluoro-2-(4-methoxycyclohexen-l-yl)-lH-pyrrolo[2,3-b]pyridin-4-yl]-3,3a,6,6a-tetrahydro-lH-cyclopenta[c]pyrrole-2-carboxylate

[0265]

[0266] STEP 1 of examples 3 & 4 was performed following the procedure described in STEP 5 of examples 1 & 2 (Method A) to give 300 mg (100% yield) of (rac)-tert-butyl (cis)-5-[5-fluoro-2-(4-methoxycyclohexen-l-yl)-lH-pyrrolo[2,3-b]pyridin-4-yl]-3,3a,6,6a-tetrahydro-lH-cyclopenta[c]pyrrole-2-carboxylate as a yellow gum. LC / MS (m / z, M+H): calc. 454.3, found 454.1.

[0267] STEP 2: (rac)-4-[(cis)-l,2,3,3a,6,6a-hexahydrocyclopenta[c]pyrrol-5-yl]-5-fluoro-2-(4-methoxycyclohexen-l-yl)-lH-pyrrolo[2,3-b]pyridine hydrochloride

[0268]

[0269] STEP 2 of examples 3 & 4 was performed following the procedure described in STEP 6 of examples 1 & 2 (Method A) to give 250 mg (98% yield) of (rac)-4-[(cis)-l,2,3,3a,6,6a-hexahydrocyclopenta[c]pyrrol-5-yl]-5-fluoro-2-(4-methoxycyclohexen-l-yl)-lH-pyrrolo[2,3-b]pyridine hydrochloride as a pale yellow solid. LC / MS (m / z, M+H): calc. 354.3, found 354.2. STEP 3: (rac)-[(cis)-5-[5-fluoro-2-(4-methoxycyclohexen-l-yl)-lH-pyrrolo[2,3-b]pyridin-4-yl]-3,3a,6,6a-tetrahydro-lH-cyclopenta[c]pyrrol-2-yl]-[2-amino-4- (trifluoromethoxy)phenyl]methanone

[0270]

[0271] STEP 3 of examples 3 & 4 was performed following the procedure described in STEP 7 of examples 1 & 2 (Method A) to give 200 mg (56% yield) of (rac)-[(cis)-5-[5-fluoro-2-(4-methoxycyclohexen-l-yl)-lH-pyrrolo[2,3-b]pyridin-4-yl]-3,3a,6,6a-tetrahydro-lH-cyclopenta[c]pyrrol-2-yl]-[2-amino-4-(trifluoromethoxy)phenyl]methanone as a yellow solid. LC / MS (m / z, M+H): calc. 557.2, found 557.0.

[0272] STEP 4: cis / trans mixture of [(cis, cis)-5-[5-fluoro-2-(4-methoxycyclohexyl)-lH-pyrrolo[2,3-b]pyridin-4-yl]-3,3a,4,5,6,6a-hexahydro-lH-cyclopenta[c]pyrrol-2-yl]-[2-amino-4-(trifluoromethoxy)phenyl]methanone

[0273]

[0274] To a stirred solution of [(cis)-5-[5-fluoro-2-(4-methoxycyclohexen-l-yl)-lH-pyrrolo[2,3-b]pyridin-4-yl]-3,3a,6,6a-tetrahydro-lH-cyclopenta[c]pyrrol-2-yl]-[2-amino-4-(trifluoromethoxy)phenyl]methanone (200 mg, 0.36 mmol) in methanol / ethanol (3 / 3mL) , was added palladium (115 mg, 1.08 mmol) and palladium (II) hydroxyde (151 mg, 1.08 mmol) at room temperature, and the resulting reaction mixture was stirred under one atmosphere of hydrogen for 16 hours. Then, the whole mixture was diluted with MeOH, filtered through celite bed and filtrate was concentrated under vacuum and the resulting residue was engaged in the next step.

[0275] STEP 5 : (cis, cis)-[5-[5-fluoro-2-((cis)-4-methoxycyclohexyl)-lH-pyrrolo[2,3-b]pyridin-4-yl]-3, 3a, 4,5,6, 6a-hexahydro-lH-cyclopenta[c]pyrrol-2-yl]-[2-amino-4- (trifluoromethoxy)phenyl|methanone & (cis, cis)-[5-[5-fluoro-2-((trans)-4-methoxycyclohexyl)-lH-pyrrolo[2,3-b]pyridin-4-yl]-3,3a,4,5,6,6a-hexahydro-lH-cyclopenta[c]pyrrol-2-yl]-[2-amino-4-(trifluoromethoxy)phenyl]methanone

[0276]

[0277] The above obtained residue was purified by preparative HPLC to give 1.5 mg (0.75% yield) of [(cis, cis)-5-[5-fluoro-2-(cis)-(4-methoxycyclohexyl)-lH-pyrrolo[2,3-b]pyridin-4-yl]-3,3a,4,5,6,6a-hexahydro-lH-cyclopenta[c]pyrrol-2-yl]-[2-amino-4-(trifluoromethoxy)phenyl]methanone as a solid. LC / MS (m / z, M+H): calc. 561.2, found 561.1. H NMR (400 MHz, DMSO-d6) 8 ppm 11.56 (s, 1 H), 7.99 (d, J= 2.8 Hz, 1 H), 7.21 (d, J= 8.4 Hz, 1 H), 6.67 (s, 1 H), 6.47 (d, J= 8.0 Hz, 1 H), 6.21 (s, 1 H), 5.75 (s, 2 H), 3.62 (s, 2 H), 3.48 (d, J = 5.6 Hz, 2 H), 3.26 (s, 3 H), 3.14 (d, J= 10.8 Hz, 1 H), 2.83 (s, 2 H), 2.67 (s, 1 H), 2.20 (s, 2 H), 2.11 - 2.04 (m, 4 H), 1.82 (s, 2 H), 1.53 (d, J= 12.4 Hz, 2 H), 1.27 (t, J= 10.8 Hz, 3 H).

[0278] And 12 mg (6% yield) of [(cis, cis)-5-[5-fluoro-2-(trans)-(4-methoxycyclohexyl)-lH-pyrrolo[2,3-b]pyridin-4-yl]-3,3a,4,5,6,6a-hexahydro-lH-cyclopenta[c]pyrrol-2-yl]-[2-amino-4-(trifluoromethoxy)phenyl]methanone as a solid. LC / MS (m / z, M+H): calc. 561.2, found 561.1. ‘HNMR (400 MHz, DMSO-d6) 8 ppm 11.54 (s, 1 H), 7.96 (d, J= 3.2 Hz, 1 H), 7.22 (d, J= 8.4 Hz, 1 H), 6.66 (s, 1 H), 6.48 (d, J= 8.4 Hz, 1 H), 6.23 (s, 1 H), 5.75 (s, 2 H), 3.61 (d, J = 3.6 Hz, 2 H), 3.49 (s, 3 H), 3.22 (s, 3 H), 2.79 (s, 3 H), 2.43 (s, 1 H), 2.19 (s, 2 H), 1.92 (s, 2 H), 1.79 - 1.76 (m, 6 H), 1.57 - 1.53 (m, 2 H).

[0279] Examples 5 & 6: (cis, cis)-[5-[5-fluoro-2-((cis)-4-hydroxycyclohexyl)-lH-pyrrolo[2,3-b]pyri din-4-yl]-3, 3a, 4,5,6, 6a-hexahy dro-lH-cy clopenta[c]pyrrol-2 -yl]-[4-(trifluoromethoxy)phenyl]methanone and (cis, cis)-[5-[5-fluoro-2-((trans)-4-hy droxycy clohexyl)-lH-pyrrolo[2,3-b]pyridin-4-yl]-3, 3a, 4,5,6, 6a-hexahydro-lH-cyclopenta[c]pyrrol-2-yl]-[4-(trifluoromethoxy)phenyl]methanone

[0280]

[0281] STEP 1: (rac)-4-[4-chloro-5-fluoro-l-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-2-yl]cyclohex-3-en-l-ol

[0282]

[0283] STEP 1 of examples 5 and 6 was performed following the protocol described in STEP 3 of examples 1 & 2, using 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)cyclohex-3-en-l-ol (746 mg, 3.33 mmol) to give 700 mg (71% yield) of (rac)-4-[4-chloro-5-fluoro-l-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-2-yl]cyclohex-3-en-l-ol as a solid. LC / MS (m / z, M+H): calc. 421.1, found 421.00.

[0284] STEP 2: (rac)-tert-butyl (cis)-5-[5-fluoro-2-(4-hydroxycyclohexen-l-yl)-l-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-4-yl]-3,3a,6,6a-tetrahydro-lH-cyclopenta[c]pyrrole-2-carboxylate

[0285]

[0286] STEP 2 of examples 5 and 6 was performed following the protocol described in STEP 4 of examples 1 & 2, to give 680 mg (57% yield) of (rac)-tert-butyl (cis)-5-[5-fluoro-2-(4-hydroxycyclohexen-l-yl)-l-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-4-yl]-3,3a,6,6a-tetrahydro-lH-cyclopenta[c]pyrrole-2-carboxylate as a yellow solid. LC / MS (m / z, M+H): calc. 594.2, found 594.2. STEP 3: (rac)-tert-butyl (cis)-5-[5-fluoro-2-(4-hydroxycyclohexen-l-yl)-lH-pyrrolo[2,3-b]pyridin-4-yl]-3,3a,6,6a-tetrahydro-lH-cyclopenta[c]pyrrole-2-carboxylate

[0287]

[0288] STEP 3 of examples 5 and 6 was performed following the protocol described in STEP 5 of examples 1 & 2, usingNaOH (236 mg, 5.9 mmol) in amixture of MeOH / water to give 517 mg (100% yield) of crude (rac)-tert-butyl (cis)-5-[5-fluoro-2-(4-hydroxycyclohexen-l-yl)-lH-pyrrolo[2,3-b]pyridin-4-yl]-3,3a,6,6a-tetrahydro-lH-cyclopenta[c]pyrrole-2-carboxylate as a solid. LC / MS (m / z, M+H): calc. 440.2, found 440.1.

[0289] STEP 4: (rac)-4-[4-[(cis)-l,2,3,3a,6,6a-hexahydrocyclopenta[c]pyrrol-5-yl]-5-fluoro-lH-pyrrolo[2,3-b]pyridin-2-yl]cyclohex-3-en-l-ol hydrochloride

[0290]

[0291] STEP 4 of examples 5 and 6 was performed following the protocol described in STEP 6 of examples 1 & 2, to give 570 mg (96% yield) of (rac)-4-[4-[(cis)-l,2,3,3a,6,6a-hexahydrocyclopenta[c]pyrrol-5-yl]-5-fluoro-lH-pyrrolo[2,3-b]pyridin-2-yl]cyclohex-3-en-l-ol hydrochloride as a yellow solid. LC / MS (m / z, M+H): calc. 340.2, found 340.1.

[0292] STEP 5: (rac)-[(cis)-5-[5-fluoro-2-(4-hydroxycyclohexen-l-yl)-lH-pyrrolo[2,3-b]pyridin-4-yl]-3,3a,6,6a-tetrahydro-lH-cyclopenta[c]pyrrol-2-yl]-[4-(trifluoromethoxy)phenyl]methanone

[0293]

[0294] STEP 5 of examples 5 and 6 was performed following the protocol described in STEP 7 of examples 1 & 2, to give 216 mg (57% yield) of (rac)-[(cis)-5-[5-fluoro-2-(4-hy droxycy clohexen-l-yl)-lH-pyrrolo[2,3-b]pyridin-4-yl]-3, 3a, 6, 6a-tetrahy dro-lH-cyclopenta[c]pyrrol-2-yl]-[4-(trifluoromethoxy)phenyl]methanone as a white solid. LC / MS (m / z, M-H): calc. 526.2, found 526.1.

[0295] STEP 6: cis / trans mixture of [(cis, cis)-5-[5-fluoro-2-(4-hydroxycyclohexyl)-lH-pyrrolo[2,3-b]pyri din-4-yl]-3, 3a, 4,5,6, 6a-hexahy dro-lH-cy clopenta[c]pyrrol-2 -yl]-[4-(trifluoromethoxy)phenyl]methanone

[0296]

[0297] STEP 6 of examples 5 and 6 was performed following the protocol described in STEP 8i of examples 1 & 2, to give a crude cis / trans mixture of [(cis, cis)-5-[5-fluoro-2-(4-hy droxycy clohexyl)-lH-pyrrolo[2,3-b]pyridin-4-yl]-3, 3a, 4,5,6, 6a-hexahydro-lH-cyclopenta[c]pyrrol-2-yl]-[4-(trifluoromethoxy)phenyl]methanone which was engaged in the next step.

[0298] STEP 7: (cis, cis)-[5-[5-fluoro-2-((cis)-4-hy droxycy clohexyl)-lH-pyrrolo[2, 3-b]pyridin-4-yl]-3, 3a, 4,5,6, 6a-hexahy dro-lH-cy clopenta[c]pyrrol-2 -yl]-[4-(trifluoromethoxy)phenyl]methanone and (cis, cis)-[5-[5-fluoro-2-((trans)-4-hy droxycy clohexyl)-lH-pyrrolo[2,3-b]pyridin-4-yl]-3, 3a, 4,5,6, 6a-hexahydro-lH-cyclopenta[c]pyrrol-2-yl]-[4-(trifluoromethoxy)phenyl]methanone

[0299]

[0300] STEP 7 of examples 5 and 6 was performed following the protocol described in STEP 8ii of examples 1 & 2, to give 24 mg (9% yield on the last two steps) of (cis, cis)-[5-[5-fluoro-2-((cis)-4-hydroxycyclohexyl)-lH-pyrrolo[2,3-b]pyridin-4-yl]-3,3a,4,5,6,6a-hexahydro-lH- cyclopenta[c]pyrrol-2-yl]-[4-(trifluoromethoxy)phenyl]methanone as a solid. 'H NMR (400 MHz, DMSO-O 8 ppm 11.54 (s, 1 H), 7.97 (d, J = 3.2 Hz, 1 H), 7.67 (d, J= 8.8 Hz, 2 H), 7.45 (d, J= 8.0 Hz, 2 H), 6.19 (d,J= 1.6 Hz, 1 H), 4.61 (d,J = 4.4Hz, 1 H) (-OH proton), 3.81 (d, J= 10.8 Hz, 1 H), 3.62 (s, 2 H), 3.52-3.43 (m, 2 H), 2.84 (s, 2 H), 2.66-2.59 (m, 1 H), 2.26 (d, J= 10.4 Hz, 1 H), 2.13 (s, 1 H), 2.02-1.91 (m, 6 H), 1.72 (s, 1 H), 1.52 (td, J= 13.1, 10.5 Hz, 2 H), 1.32-1.26 (m, 2 H). LC / MS (m / z, M-H): calc. 530.2, found 530.2.

[0301] And 55g (20% yield) of (cis, cis)-[5-[5-fluoro-2-((trans)-4-hydroxycyclohexyl)-lH-pyrrolo[2, 3-b]pyridin-4-yl]-3, 3a, 4,5,6, 6a-hexahy dro-lH-cy clopenta[c]pyrrol-2-yl]-[4-(trifluoromethoxy)phenyl]methanone as a white solid. 'H NMR (400 MHz, DMSO- / >) 8 ppm 11.53 (s, 1 H), 7.97 (d, J= 3.2 Hz, 1 H), 7.69 (d, J= 8.8 Hz, 2 H), 7.46 (d, J= 8.0 Hz, 2 H), 6.21 (s, 1 H), 4.38 (d, J= 3.2 Hz, 1 H) ) (-OH proton), 3.85 (d, J= 16.8 Hz, 2 H), 3.64 (s, 2 H), 3.53-3.47 (m, 1 H), 2.85 (s, 2 H), 2.72 (t, J= 10.5 Hz, 1 H), 2.26 (s, 1 H), 2.15 (s, 1 H), 1.92 (s, 3H), 1.75-1.69 (m, 6 H), 1.59-1.53 (m, 2 H). LC / MS (m / z, M-H): calc. 530.2, found 530.2.

[0302] Examples 7 & 8: (cis, cis)-[5-[5-fluoro-2-((cis)-4-hydroxycyclohexyl)-lH-pyrrolo[2,3-b]pyridin-4-yl]-3,3a,4,5,6,6a-hexahydro-lH-cyclopenta[c]pyrrol-2-yl]-[2-amino-4-(trifluoromethoxy)phenyl|methanone and (cis, cis)-[5-[5-fluoro-2-((trans)-4-hydroxycyclohexyl)-lH-pyrrolo[2,3-b]pyridin-4-yl]-3,3a,4,5,6,6a-hexahydro-lH-cyclopenta[c]pyrrol-2-yl]-[2-amino-4-(trifluoromethoxy)phenyl]methanone

[0303]

[0304] Examples 7 and 8 were prepared following the protocols described for the preparation of examples 1 and 2, using 2-amino-4-(trifluoromethoxy)benzoic acid (176 mg, 0.8 mmol) in STEP 7, to give in STEP 8ii, 16 mg (8% purity, 0.5% yield) of (cis, cis)-[5-[5-fluoro-2-((cis)-4-hydroxy cyclohexyl)-lH-pyrrolo[2,3-b]pyridin-4-yl]-3, 3a, 4,5,6, 6a-hexahydro-lH-cyclopenta[c]pyrrol-2-yl]-[2-amino-4-(trifluoromethoxy)phenyl]methanone as a white solid. H NMR (400 MHz, DMSO-6) 8 ppm 11.56 (s, 1 H), 7.98 (d, J= 3.2 Hz, 1 H), 7.22 (d, J= 8.4 Hz, 1 H), 6.65 (s, 1 H), 6.45 (d, J= 8.4 Hz, 1 H), 6.23 (s, 1 H), 5.73 (s, 2 H), 4.61 (s, 1 H), 3.61-3.44 (m, 6 H), 2.81 (s, 2H), 2.67-2.61 (m, 1 H), 2.20 (s, 2 H), 2.01-1.91 (m, 4H), 1.76 (s, 2 H), 1.57-1.49 (m, 2 H), 1.32-1.26 (m, 2 H). LC / MS (m / z, M+H): calc. 547.2, found 574.3. And 47 mg (17% yield) of (cis, cis)-[5-[5-fluoro-2-((trans)-4-hydroxycyclohexyl)-lH-pyrrolo[2,3-b]pyridin-4-yl]-3,3a,4,5,6,6a-hexahydro-lH-cyclopenta[c]pyrrol-2-yl]-[2-amino-4-(trifluoromethoxy)phenyl]methanone as a white solid. ‘HNMR (400 MHz, DMSO-t / >) 6 ppm 11.52 (s, 1 H), 7.95 (d, J= 3.2 Hz, 1 H), 7.22 (d, J= 8.4 Hz, 1 H), 6.65 (s, 1 H), 6.48 (d, J = 7.2 Hz, 1 H), 6.24 (s, 1 H), 5.77 (s, 2 H), 4.42 (d, J= 2.4 Hz, 1 H), 3.87 (s, 1 H), 3.63-3.47 (m, 4 H), 2.82 (s, 2 H), 2.72 (s, 1 H), 2.20 (s, 2 H), 1.97-1.81 (m, 4 H), 1.73-1.69 (m, 5 H), 1.59-1.53 (m, 2 H). LC / MS (m / z, M+H): calc. 547.2, found 574.3.

[0305] Example 9: (cis, cis)-[5-(5-tetrahydropyran-4-yl-lH-pyrrolo[2,3-b]pyridin-3-yl)-3,3a,4,5,6,6a-hexahydro-lH-cyclopenta[c]pyrrol-2-yl]-[2-amino-4-(trifluoromethoxy)phenyl]methanone

[0306]

[0307] STEP 1: 5-(3,6-dihydro-2H-pyran-4-yl)-lH-pyrrolo[2,3-b]pyridine

[0308]

[0309] To a solution of 5 -bromo- IH-pyrrolo [2, 3 -b] pyridine (10 g, 50.8 mmol) and 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (16 g, 76.1 mmol) in 1,4-dioxane (200 mL) and water (30 mL) was added K2CO3 (14 g, 102 mmol) and the resulting reaction mixture was bubbled with argon for 15 minutes. Then, PdC12(dppl). DCM complex (3.71 g, 50.8 mmol) was added and the whole mixture was stirred at 90°C for 4 hours, cooled down to room temperature and then filtered through celite bed. The filtrate was diluted with ethyl acetate (500 mL), washed with water (500 mL), and the organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue (30 g) was absorbed over silica gel and purified by Gravity column to give 9 g (89% yield) of 5-(3,6-dihydro-2H-pyran-4-yl)-lH-pyrrolo[2,3-b]pyridine as an off white solid. LC / MS (m / z, M+H): calc. 201.1, found 201.1.

[0310] STEP 2: 5-tetrahydropyran-4-yl-lH-pyrrolo[2,3-b]pyridine

[0311]

[0312] To a stirred solution of 5-(3,6-dihydro-2H-pyran-4-yl)-lH-pyrrolo[2,3-b]pyridine (8 g, 40 mmol) in methanol (50 mL) and ethanol (50 mL) was added palladium (6.38 g, 59.9 mmol) under an inert atmosphere and the reaction mixture was stirred overnight under hydrogen atmosphere in parr shaker ( 100 psi ) at room temperature for 16 hours. Then, the reaction mixture was filtered through celite bed and washed with ethanol (2 x 20 mL) and concentrated to dryness. The crude compound (9 g) was adsorbed over silica gel and purified by gravity column to give 5 g (62% yield) of 5-tetrahydropyran-4-yl-lH-pyrrolo[2,3-b]pyridine as a yellow solid. LC / MS (m / z, M+H): calc. 203.1, found 203.0.

[0313] STEP 3: 1 -(p-tolylsulfonyl)-5-tetrahydropyran-4-yl-pyrrolo[2,3-b]pyridine

[0314]

[0315] To a stirred solution of 5-tetrahydropyran-4-yl-lH-pyrrolo[2,3-b]pyridine (5 g, 24.7 mmol) and 4-methylbenzenesulfonyl chloride (7.07 g, 37.1 mmol) in DMF (60 mL) was added NaH 60% dispersion in oil (1.19 g, 49.4 mmol) at 0 °C and the resulting reaction mixture was stirred at room temperature for 1 hour under argon atmosphere. Then, the whole mixture was diluted with chilled water (100 mL) and extracted with ethyl acetate ( 2 x 100 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated. The resulting residue was purified by flash chromatography on silica gel to give 5 g (57% yield) of l-(p-tolylsulfonyl)- 5-tetrahydropyran-4-yl-pyrrolo[2,3-b]pyridine as an off white solid. LC / MS (m / z, M+H): calc.

[0316] 357.1, found 357.0.

[0317] STEP 4: tert-butyl (cis)-5-(5-tetrahydropyran-4-yl-lH-pyrrolo[2,3-b]pyridin-3-yl)-3,3a,6,6a-tetrahydro-lH-cyclopenta[c]pyrrole-2-carboxylate

[0318]

[0319] To a solution of l-(p-tolylsulfonyl)-5-tetrahydropyran-4-yl-pyrrolo[2,3-b]pyridine (500 mg, 1.40 mmol) and tert-butyl (cis)-5-oxo-l,3,3a,4,6,6a-hexahydrocyclopenta[c]pyrrole-2-carboxylate (632 mg, 2.81 mmol) in methanol (10 mL) was added KOH (118 mg, 2.1 mmol) at 0° C , and the resulting reaction mixture was stirred for 16 hours at 70 °C. Then, the whole mixture was diluted with chilled water (100 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic layers were dried over Na2SO4, filtered concentrated under reduced pressure. The resulting residue was purified by flash chromatography on silica gel to give 148 mg (26% yield) tert-butyl (cis)-5-(5-tetrahydropyran-4-yl-lH-pyrrolo[2,3-b]pyridin-3-yl)-3,3a,6,6a-tetrahydro-lH-cyclopenta[c]pyrrole-2-carboxylate as an off white solid. LC / MS (m / z, M+H): calc. 410.2, found 410.1.

[0320] STEP 5: 3-[(cis)-l,2,3 ,3a,6,6a-hexahydrocyclopenta[c]pyrrol-5-yl]-5-tetrahydropyran-4-yl-lH-pyrrolo[2,3-b]pyridine hydrochloride

[0321]

[0322] To a solution of tert-butyl (cis)-5-(5-tetrahydropyran-4-yl-lH-pyrrolo[2,3-b]pyridin-3-yl)-3,3a,6,6a-tetrahydro-lH-cyclopenta[c]pyrrole-2-carboxylate (140 mg, 0.34 mmol) in DCM (2 mL) was added a 4M solution of hydrogen chloride in 1,4-dioxane (0.86 mL, 3.42 mmol) at 0 °C, and the resulting reaction mixture was stirred for 1 hour at room temperature. The whole mixture was then concentrated under reduced pressure and the resulting residue was triturated with diethyl ether (10 mL) to give 117 mg (100% yield) of crude 3-[(cis)-l,2,3,3a,6,6a-hexahydrocyclopenta[c]pyrrol-5-yl]-5-tetrahydropyran-4-yl-lH-pyrrolo[2,3-b]pyridine hydrochloride as a yellow solid. LC / MS (m / z, M+H): calc. 310.2, found 310.0. STEP 6 (example 17): [(cis)-5-(5-tetrahydropyran-4-yl-lH-pyrrolo[2,3-b]pyridin-3-yl)- 3,3a,6,6a-tetrahydro-lH-cyclopenta[c]pyrrol-2-yl]-[2-amino-4- (trifluoromethoxy)phenyl]methanone

[0323]

[0324] To a stirred solution of 2-amino-4-(trifluoromethoxy)benzoic acid (140 g, 0.63 mmol) and 3-[(cis)-l,2,3,3a,6,6a-hexahydrocyclopenta[c]pyrrol-5-yl]-5-tetrahydropyran-4-yl-lH-pyrrolo[2,3-b]pyridine hydrochloride (117 mg g, 0.34 mmol) in DMF (5 mL) was added N,N-diethylethanamine (192 mg, 1.9 mmol) and [benzotriazol- 1-yloxy (dimethylamino)methylene] -dimethyl-ammonium;tetrafluoroborate (305 mg, 0.95 mmol) at 0 °C. The resulting reaction mixture was stirred at room temperature for 1 hour. The whole mixture was then diluted with chilled water (100 mL) and extracted with ethyl acetate (100 mL x 2). The combined organic layers were dried over Na2SO4, filtered and concentrate under reduced pressure. The resulting residue was purified by flash chromatography on silica gel to give 110 mg (63% yield) of [(cis)-5-(5-tetrahydropyran-4-yl-lH-pyrrolo[2,3-b]pyridin-3-yl)-3,3a,6,6a-tetrahydro-lH-cyclopenta[c]pyrrol-2-yl]-[2-amino-4-(trifluoromethoxy)phenyl]methanone as a yellow solid. LC / MS (m / z, M+H): calc. 513.2, found 513.5.

[0325] STEP 7: [(cis, cis)-5-(5-tetrahydropyran-4-yl-lH-pyrrolo[2,3-b]pyridin-3-yl)-3,3a,4,5,6,6a-hexahydro-lH-cyclopenta[c]pyrrol-2-yl]-[2-amino-4-(trifluoromethoxy)phenyl]methanone

[0326]

[0327] To a stirred solution of [(cis)-5-(5-tetrahydropyran-4-yl-lH-pyrrolo[2,3-b]pyridin-3-yl)-3,3a,6,6a-tetrahydro-lH-cyclopenta[c]pyrrol-2-yl]-[2-amino-4- (trifluoromethoxy)phenyl]methanone (110 mg, 0.22 mmol) in methanol (10 mL) were added palladium (114 mg, 1.07 mmol) and a catalytic amount of acetic acid (1.3 mg, 0.2 mmol) under an inert atmosphere and the resulting mixture was stirred under one atmosphere of hydrogen at room temperature for 16 hours. Then, the reaction mixture was filtered through celite bed and washed with ethanol (2 x 10 mL) and concentrated to dryness. The resulting residue was purified by preparative HPLC to give 10 mg (9% yield) of [(cis, cis)-5-(5-tetrahydropyran-4-yl-lH-pyrrolo[2, 3-b]pyridin-3-yl)-3, 3a, 4,5,6, 6a-hexahy dro-lH-cy clopenta[c]pyrrol-2-yl]-[2-amino-4-(trifluoromethoxy)phenyl]methanone as an off white solid. 'H NMR (400 MHz, DMSO-O 8 ppm 11.10-11.22 (m, 1 H), 8.09 (d, J=1.9Hz, 1 H), 7.78 (d, J=1.9Hz, 1 H), 7.13-7.23 (m, 2 H), 6.63 (d, J=1.0 Hz, 1 H), 6.35-6.50 (m, 1 H), 5.69 (s, 2 H), 3.87-4.02 (m, 2 H), 3.57 (br s, 2 H), 3.43-3.50 (m, 3 H), 3.20-3.31 (m, 2 H), 2.80-2.92 (m, 1 H), 2.71-2.80 (m, 2 H), 2.31-2.43 (m, 2 H), 1.68-1.80 (m, 4 H), 1.33-1.55 (m, 2 H). LC / MS (m / z, M+H): calc.

[0328] 515.2, found 515.5.

[0329] Example 10: (cis, cis)-[5-[6-fhroro-2-(3-methoxy-l-bicyclo[l.l.l]pentanyl)-3H-imidazo[4,5-b]pyri din-7-yl]-3, 3a, 4,5,6, 6a-hexahy dro-lH-cy clopenta[c]pyrrol-2 -yl]-[4-(trifluoromethoxy)phenyl]methanone

[0330]

[0331] METHOD B (Scheme 6)

[0332] STEP 1: 2-chloro-5-fluoro-3-nitro-pyridin-4-amine

[0333] NH2

[0334]

[0335] To a stirred solution of 2-chloro-5-fluoro-pyridin-4-amine (2 g, 13.6 mmol) in sulfuric acid (20 mL) was added potassium nitrate (2.76 g, 27.3 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 1 hour. Then, the reaction mixture was carefully diluted with water, extracted with ethyl acetate (200 mL x 2). The combined organic layers were separated, dried over Na2SO4, filtered and concentrated under reduced pressure to give 2 g (76% yield) of 2-chloro-5-fluoro-3-nitro-pyridin-4-amine as a gummy liquid. LC / MS (m / z, M+H): calc. 192.0, found 192.1.

[0336] STEP 2: 5-fluoro-N2-[(4-methoxyphenyl)methyl]-3-nitro-pyridine-2,4-diamine

[0337]

[0338] To a stirred solution of 2-chloro-5-fluoro-3-nitro-pyridin-4-amine (15 g, 78.3 mmol) and (4-methoxyphenyl)methanamine (10.7 g, 78.3 mmol) in DMSO (150 mL) was added DIPEA (23.8 g, 235 mmol) at room temperature. The resulting reaction mixture was stirred at 150 °C for 1 hour. Then, the whole reaction mixture was cooled down to room temperature, concentrated under reduced pressure and the resulting residue was diluted water (100 mL) and extracted with EtOAc (300 mL x 2). The combined organic layers were dried over Na2SO4, filtered, concentrated under reduced pressure. The resulting residue was purified by flash chromatography on silica gel eluting with 30% of EtOAc in Hexane to give 15 g (65% yield) of 5-fluoro-N2-[(4-methoxyphenyl)methyl]-3-nitro-pyridine-2,4-diamine as a yellow color solid.. LC / MS (m / z, M+H): calc. 293.1, found 292.9.

[0339] STEP 3: 4-bromo-5-fluoro-N-[(4-methoxyphenyl)methyl]-3-nitro-pyridin-2-amine

[0340] Br

[0341]

[0342] To a stirred solution of tert-butyl nitrite (5.29 g, 51.3 mmol) and copper(II)bromide (11.5 g, 51.3 mmol) in acetonitrile (150 mL) was added 5-fluoro-N2-[(4-methoxyphenyl)methyl]-3-nitro-pyridine-2,4-diamine (15 g, 51.3 mmol) at room temperature. The reaction mixture was then stirred at 45 °C for 1 hour. The whole mixture was then concentrated under reduced pressure and the thus obtained residue was diluted with water (50 mL) and extracted with ethyl acetate (100 mL). The organic layer was separated, dried over Na2SO4, filtered and concentrated. The resulting residue was purified flash chromatography on silica gel to give 15 g (82% yield) of 4-bromo-5-fluoro-N-[(4-methoxyphenyl)methyl]-3-nitro-pyridin-2-amine as ayellow solid. LC / MS (m / z, M-H): calc. 354.0, found 354.1.

[0343] STEP 4: tert-butyl (cis)-5-[5-fluoro-2-[(4-methoxyphenyl)methylamino]-3-nitro-4-pyridyl]- 3,3a,6,6a-tetrahydro-lH-cyclopenta[c]pyrrole-2-carboxylate

[0344]

[0345] To a stirred solution of 4-bromo-5-fluoro-N-[(4-methoxyphenyl)methyl]-3-nitro-pyridin-2-amine (3 g, 8.42 mmol) and tert-butyl 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,3a,6,6a-tetrahydro-lH-cyclopenta[c]pyrrole-2-carboxylate (4.24 g, 12.6 mmol) and potassium carbonate (3.49 g, 25.3 mmol) in 1,4-dioxane (40 mL) and water (10 mL) was added [l,l'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (616 mg, 0.84 mmol) at room temperature, and the whole mixture was bubbled with argon for 5 minutes then was stirred at 80 °C for 4 hours. The reaction mixture was then concentrated under reduced pressure. The resulting residue was diluted with water (500 mL) and extracted with ethyl acetate (500 mL). The organic layer was separated, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography on silica gel to give 1.5 g (37% yield) of tert-butyl (cis)-5-[5-fluoro-2-[(4-methoxyphenyl)methylamino]-3-nitro-4-pyridyl]-3,3a,6,6a-tetrahydro-lH-cyclopenta[c]pyrrole-2-carboxylate as a yellow solid. LC / MS (m / z, M+H): calc. 485.2, found 485.2.

[0346] STEP 5: tert-butyl (cis, cis)-5-(2,3-diamino-5-fluoro-4-pyridyl)-3,3a,4,5,6,6a-hexahydro-lH-cyclopenta[c]pyrrole-2-carboxylate

[0347]

[0348] To a stirred solution of tert-butyl tert-butyl (cis)-5-[5-fluoro-2-[(4-methoxyphenyl)methylamino] -3-nitro-4-pyridyl] -3,3a,6,6a-tetrahydro- 1H-cyclopenta[c]pyrrole-2-carboxylate (500 mg, 1.03 mmol) in methanol (20 mL) was added palladium on carbon ( 1.10 g, 1.03 mmol) and a catalytic amount of acetic acid (6 mg, 0.1 mmol) under inert atmosphere and then the reaction mixture was stirred in an autoclave overnight under one atmosphere of hydrogen at 70 °C for 16 hours. Then, the reaction mixture was filtered through celite bed and washed with ethanol and concentrated. The resulting residue was purified by flash chromatography on silica gel to give 250 mg (72% yield) of tert-butyl (cis, cis)-5-(2,3-diamino-5-fluoro-4-pyridyl)-3,3a,4,5,6,6a-hexahydro-lH-cyclopenta[c]pyrrole-2-carboxylate as a yellow solid. LC / MS (m / z, M+H): calc. 337.2, found 337.1.

[0349] STEP 6: 4-[(cis, cis)-l,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrol-5-yl]-5-fluoro-pyridine-2,3-diamine trihydrochloride

[0350] N H-CI

[0351] O H-Cl

[0352] O H-Cl

[0353] F^ JL .NH2

[0354]

[0355] X ^NI^NH2

[0356] To a stirred solution of (cis, cis)-5-(2,3-diamino-5-fluoro-4-pyridyl)-3, 3a, 4,5,6, 6a-hexahydro-lH-cyclopenta[c]pyrrole-2-carboxylate (250 mg, 0.74 mmol) in DCM (5 mL) was added a 4M solution of HC1 in 1,4-dioxane (1.86 mL, 7.43 mmol) at 0 °C .The reaction mixture was then stirred at room temperature for 1 hour. Then, the reaction mixture was concentrated and the resulting residue was triturated with diethyl ether (10 mL) to give 250 mg (98% yield) of 4-[(cis, cis)-l,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrol-5-yl]-5-fluoro-pyridine-2,3-diamine trihydrochloride as a yellow solid. LC / MS (m / z, M+H -3 HC1): calc. 237.2, found 237.0.

[0357] STEP 7: [(cis, cis)-5-(2,3-diamino-5-fluoro-4-pyridyl)-3, 3a, 4,5,6, 6a-hexahydro-lH-cyclopenta[c]pyrrol-2-yl]-[4-(trifluoromethoxy)phenyl]methanone

[0358]

[0359] To a stirred solution of 4-[(cis, cis)-l,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrol-5-yl]-5-fluoro-pyridine-2,3-diamine trihydrochloride (250 mg, 0.73 mmol) and 4-(trifluoromethoxy)benzoic acid (262 mg, 1.27 mmol) in DMF (2 mL) were added N,N-diethylethanamine (321 mg, 3.17 mmol) and [benzotriazol- 1-yloxy(dimethylamino)methylene]-dimethyl-ammonium;tetrafluoroborate (408 mg, 1.27 mmol) at 0 °C .The reaction mixture was stirred at room temperature for one hour and then was diluted with chilled water (50 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic layers were separated, dried over Na2SO4, filtered and evaporated under reduced pressure. The resulting residue was purified by flash chromatography on silica gel to give 250 mg (81% yield) of [(cis, cis)-5-(2,3-diamino-5-fluoro-4-pyridyl)-3, 3a, 4,5,6, 6a-hexahydro-lH-cyclopenta[c]pyrrol-2-yl]-[4-(trifluoromethoxy)phenyl]methanone as a light yellow solid. LC / MS (m / z, M+H): calc. 425.2, found 425.1.

[0360] STEP 8: (cis, cis)-[5-[6-fluoro-2-(3-methoxy-l-bicyclo[l.l.l]pentanyl)-3H-imidazo[4,5-b]pyri din-7-yl]-3, 3a, 4,5,6, 6a-hexahy dro-lH-cy clopenta[c]pyrrol-2 -yl]-[4-(trifluoromethoxy)phenyl]methanone

[0361]

[0362] To a stirred solution of [(cis, cis)-5-(2,3-diamino-5-fluoro-4-pyridyl)-3,3a,4,5,6,6a-hexahydro-lH-cyclopenta[c]pyrrol-2-yl]-[4-(trifluoromethoxy)phenyl]methanone (250 mg, 0.59 mmol) and 3-methoxy bi cyclofl .1. l]pentane-l -carboxylic acid (84 mg, 0.59 mmol) in pyridine (5 mL) was added 3-(ethyliminomethyleneamino)-N,N-dimethyl-propan-l-amine;hydrochloride (169 mg, 0.88 mmol) at 0 °C .The reaction mixture was then stirred at room temperature for one hour and then diluted with chilled water (50 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic layers were separated and dried over Na2SO4, filtered and evaporated under reduced pressure. The resulting residue was purified by flash chromatography on silica gel to give 250 mg (77% yield) of N-[4-[(cis, cis)-2-[4-(trifluoromethoxy)benzoyl]-3,3a,4,5,6,6a-hexahydro-lH-cyclopenta[c]pyrrol-5-yl]-3-amino-5-fluoro-2-pyridyl]-3-methoxy-bicyclo[l.l.l]pentane-l-carboxamide as a yellow solid. LC / MS (m / z, M-H): calc.

[0363] 547.2, found 547.1.

[0364] A solution of N-[4-[(cis, cis)-2-[4-(trifluoromethoxy)benzoyl]-3,3a,4,5,6,6a-hexahydro-lH-cy clopenta[c]pyrrol-5-yl] -3-amino-5-fluoro-2-pyridyl] -3-methoxy-bicy clo[ 1.1.1 ]pentane- 1 -carboxamide (250 mg, 0.46 mmol) and potassium carbonate (189 mg, 1.37 mmol) in propan-2-ol (5 mL) was stirred at 100 °C for 4 hours. The reaction mixture was then concentrated under reduced pressure and the resulting residue was diluted with chilled water (50 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic layers were dried over Na2SO4, filtered and evaporated under the reduced pressure. The resulting residue was purified by preparative HPLC (Mobile Phase: A= 0.1% Formic acid in water, B= CAN 30 to 70% of B; Column: x-select (Cl 8, 19 mm x 250 mm); flow rate: 15mL / min) to give 110 mg (45% yield) of (cis, cis)-[5-[6-fluoro-2-(3-methoxy-l-bicyclo[l.l.l]pentanyl)-3H-imidazo[4,5-b]pyridin-7-yl]-3, 3a, 4,5,6, 6a-hexahydro-lH-cyclopenta[c]pyrrol-2-yl]-[4- (trifluoromethoxy)phenyl]methanone as a yellow solid. 'H NMR (400 MHz, DMSO-t / e) 6 ppm 13.18 (s, 1 H), 8.48 (s, 1 H), 7.66 (d, J=8.80 Hz, 2 H), 7.44 (d, J=8.80 Hz, 2 H), 3.84-3.82 (m, 1 H), 3.62-3.45 (m, 3 H), 3.42-3.31 (m, 1 H), 3.26 (s, 3 H), 2.86-2.76 (m, 2 H), 2.32-2.23 (m, 7 H), 2.18-2.07 (m, 3 H). LC / MS (m / z, M+H): calc. 531.2, found 531.2.

[0365] Example 11: (cis, cis)-[5-[6-fluoro-2-(3-methoxy-l-bicyclo[l.l.l]pentanyl)-3H-imidazo[4,5-b]pyridin-7-yl]-3,3a,4,5,6,6a-hexahydro-lH-cyclopenta[c]pyrrol-2-yl]-[2-amino-4- (trifluoromethoxy)phenyl]methanone

[0366]

[0367] Example 11 was prepared following the protocols described in Method B using 2-nitro-4-(trifluoromethoxy)benzoic acid (319 mg, 1.27 mmol) in STEP 7, and an additional STEP 9 for the reduction of the nitro substituent, described as follows:

[0368] STEP 9: (cis, cis)-[5-[6-fluoro-2-(3-methoxy-l-bicyclo[l.l.l]pentanyl)-3H-imidazo[4,5-b]pyridin-7-yl]-3,3a,4,5,6,6a-hexahydro-lH-cyclopenta[c]pyrrol-2-yl]-[2-amino-4- (trifluoromethoxy)phenyl]methanone

[0369]

[0370] To a stirred solution of [(cis, cis)-5-[6-fhroro-2-(3-methoxy-l-bicyclo[l.l.l]pentanyl)-3H-imidazo[4,5-b]pyri din-7-yl]-3, 3a, 4,5,6, 6a-hexahy dro-lH-cy clopenta[c]pyrrol-2-yl]-[2-nitro-4-(trifluoromethoxy)phenyl]methanone (200 mg, 0.35 mmol) in EtOH (5 mL) cooled to 0 °C, were added Fe (97 mg, 1.74 mmol) and NH4CI (93 mg, 1.74 mmol) in H2O (1 mL). The reaction mixture was then stirred at 100 °C for 1 hour, then cooled down to room temperature, concentrated under reduced pressure. The resulting residue was diluted with ice water (10 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC to give 86 mg (45% yield) of (cis, cis)-[5-[6-fluoro-2-(3-methoxy-l-bicyclofl.1. l]pentanyl)-3H-imi dazo[4,5-b]pyri din-7-yl]-3, 3a, 4,5,6, 6a-hexahydro-lH-cyclopenta[c]pyrrol-2-yl]-[2-amino-4-(trifluoromethoxy)phenyl]methanone as an off white solid. 'HNMR (400 MHz, DMSO-t / e) 6 ppm 13.07 (s, 1 H), 8.15 (d, J= 3.2 Hz, 1 H), 7.23 (d, J= 8.4 Hz, 1 H), 6.65 (s, 1 H), 6.46 (d, J= 8.4 Hz, 1 H), 5.72 (s, 2 H), 3.68 (d, J= 11.2 Hz, 2 H), 3.59 (s, 2 H), 3.26 (s, 3 H), 2.82 (s, 2 H), 2.28 (s, 7 H), 2.15-2.09 (m, 4 H). LC / MS (m / z, M+H): calc. 546.2, found 546.2.

[0371] Examples 12 & 13: (cis, cis)-[5-[5-((cis)-4-hydroxycyclohexyl)-lH-pyrrolo[2,3-b]pyridin-3-yl]-3, 3a, 4,5,6, 6a-hexahy dro-lH-cy clopenta[c]pyrrol-2 -yl]-[4-(trifluoromethoxy)phenyl|methanone & (cis, cis)-[5-[5-((trans)-4-hydroxycyclohexyl)-lH-pyrrolo[2, 3-b]pyridin-3-yl]-3, 3a, 4,5,6, 6a-hexahy dro-lH-cy clopenta[c]pyrrol-2-yl]-[4-(trifluoromethoxy)phenyl]methanone

[0372]

[0373] METHOD C (Scheme 4)

[0374] STEP 1: tert-butyl (cis)-5-(5-bromo-lH-pyrrolo[2,3-b]pyridin-3-yl)-3,3a,6,6a-tetrahydro-lH-cyclopenta[c]pyrrole-2-carboxylate

[0375]

[0376] To a stirred solution of tert-butyl (cis)-5-oxo-l,3,3a,4,6,6a-hexahydrocyclopenta[c]pyrrole-2-carboxylate (3 g, 13.3 mmol) and 5-bromo-lH-pyrrolo[2,3-b]pyridine (2.62 g, 13.3 mmol) in methanol (30 mL), was added KOH (747 mg, 13.3 mmol) at room temperature. The resulting reaction mixture was stirred for 24 hours at 80 °C. Then, the whole mixture was diluted with cold water (50 mL) and extracted with ethyl acetate (100 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography on silica gel eluting with 70% of EtOAc in Hexane to give 3 g (56% yield) of tert-butyl (cis)-5-(5-bromo-lH-pyrrolo[2,3-b]pyridin-3-yl)-3,3a,6,6a-tetrahydro-lH-cyclopenta[c]pyrrole-2-carboxylate (as an off white solid. LC / MS (m / z, M+H): calc. 404.1, found 404.1.

[0377] STEP 2: (rac)-tert-butyl (cis)-5-[5-(4-hydroxycyclohexen-l-yl)-lH-pyrrolo[2,3-b]pyridin-3-yl]-3,3a,6,6a-tetrahydro-lH-cyclopenta[c]pyrrole-2-carboxylate

[0378] N

[0379]

[0380] H

[0381] To a stirred solution of 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)cyclohex-3-en-l-ol (1 g, 4.46 mmol) and tert-butyl (cis)-5-(5-bromo-lH-pyrrolo[2,3-b]pyridin-3-yl)-3,3a,6,6a-tetrahydro-lH-cyclopenta[c]pyrrole-2-carboxylate (1.8 g, 4.46 mmol) in 1,4-dioxane (40 mL) and water (10 mL) was added K2CO3 (1.85 g, 13.4 mmol) and the resulting reaction mixture was bubbled with argon for 15 minutes. Then, PdCh(dppf) (327 mg, 0.45 mmol) was added and the reaction mixture was stirred at 90 °C for 16 hours. Then, the whole mixture was cooled down to room temperature, concentrated under reduced pressure and the resulting residue was diluted with water (50 mL) and extracted with ethyl acetate (500 mL x 2). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography on silica gel eluting with 70% of EtOAc in hexane to give 400 mg (21% yield) of (rac)-tert-butyl (cis)-5-[5-(4-hydroxycyclohexen-l-yl)-lH-pyrrolo[2,3-b]pyridin-3-yl]-3,3a,6,6a-tetrahydro-lH-cyclopenta[c]pyrrole-2-carboxylate as a yellow solid.

[0382] STEP 3: (rac)-4-[3-[(cis)-l,2,3,3a,6,6a-hexahydrocyclopenta[c]pyrrol-5-yl]-lH-pyrrolo[2,3-b]pyridin-5-yl]cyclohex-3-en-l-ol hydrochloride

[0383]

[0384] To a stirred solution of (rac)-tert-butyl (cis)-5-[5-(4-hydroxycyclohexen-l-yl)-lH-pyrrolo[2,3-b]pyridin-3-yl]-3,3a,6,6a-tetrahydro-lH-cyclopenta[c]pyrrole-2-carboxylate (350 mg, 0.83 mmol) in DCM (10 mL) was added at 0 °C, a 4M solution of HC1 in 1,4-dioxane (2.08 mL, 8.30 mol). The resulting reaction mixture was stirred for 1 hour at room temperature. Then, the whole mixture was concentrated under reduced pressure and the resulting residue was triturated with diethyl ether (10 mL), filtered and dried to give 300 mg (101% yield) of (rac)-4-[3-[(cis)-l,2,3,3a,6,6a-hexahydrocyclopenta[c]pyrrol-5-yl]-lH-pyrrolo[2,3-b]pyridin-5-yl]cyclohex-3-en-l-ol hydrochloride as ayellow solid. LC / MS (m / z, M+H-HC1): calc. 322.2, found 322.1.

[0385] STEP 4: (rac)-[(cis)-5-[5-(4-hydroxycyclohexen-l-yl)-lH-pyrrolo[2,3-b]pyridin-3-yl]- 3,3a,6,6a-tetrahydro-lH-cyclopenta[c]pyrrol-2-yl]-[4-(trifluoromethoxy)phenyl]methanone

[0386]

[0387] To a stirred solution of (rac)-4-[3-[(cis)-l,2,3,3a,6,6a-hexahydrocyclopenta[c]pyrrol-5-yl]-lH-pyrrolo[2,3-b]pyridin-5-yl]cyclohex-3-en-l-ol hydrochloride (0.300 g, 0.84 mmol) and 2-amino-4-(trifluoromethoxy)benzoic acid (206 mg, 0.93 mmol) in DMF (5 mL). were added DIPEA (94 mg, 0.93 mmol) and TBTU (450 mg, 01.4 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 1 hour, then diluted with chilled water (50 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure .The resulting residue was purified by flash chromatography on silica gel to give 200 mg (47% yield) of (rac)-[(cis)-5-[5-(4-hydroxycyclohexen-l-yl)-lH-pyrrolo[2,3-b]pyridin-3-yl]-3,3a,6,6a-tetrahydro-lH-cyclopenta[c]pyrrol-2-yl]-[4-(trifluoromethoxy)phenyl]methanone as a light yellow solid. LC / MS (m / z, M+H): calc. 510.2, found 510.3. STEP 5: (cis, cis)-[5-[5-((cis)-4-hydroxycyclohexyl)-lH-pyrrolo[2,3-b]pyridin-3-yl]-3,3a,4,5,6,6a-hexahydro-lH-cyclopenta[c]pyrrol-2-yl]-[4-(trifluoromethoxy)phenyl]methanone & (cis, cis)-[5-[5-((trans)-4-hydroxycyclohexyl)-lH-pyrrolo[2, 3-b]pyridin-3-yl]-3, 3a, 4,5,6, 6a-hexahy dro-lH-cy clopenta[c]pyrrol-2-yl]-[4-(trifluoromethoxy)phenyl]methanone

[0388]

[0389] To a stirred solution of (rac)-[(cis)-5-[5-(4-hydroxycyclohexen-l-yl)-lH-pyrrolo[2,3-b]pyridin-3-yl]-3,3a,6,6a-tetrahydro-lH-cyclopenta[c]pyrrol-2-yl]-[4- (trifluoromethoxy)phenyl] methanone (300 mg, 0.59 mmol) in methanol (10 mL), were added palladium (627 mg, 5.89 mmol) and a catalytic amount of acetic acid (3.5 mg, 0.06 mmol) under an inert atmosphere. The reaction mixture was then stirred under one atmosphere of hydrogen at room temperature for 16 hours. Then, the reaction mixture was filtered through celite bed and washed with ethanol. The resulting filtrate was concentrated and the resulting residue was purified by preparative HPLC to give

[0390] 6 mg (2% yield) of (cis, cis)-[5-[5-((cis)-4-hydroxycyclohexyl)-lH-pyrrolo[2,3-b]pyridin-3-yl]-3, 3a, 4,5,6, 6a-hexahy dro-lH-cy clopenta[c]pyrrol-2 -yl]-[4- (trifluoromethoxy)phenyl]methanone as an off white solid. 'H NMR (400 MHz, DMSO-t / >) 6 ppm 11.16 (s, 1 H), 8.06 (d, J= 1.6 Hz, 1 H), 7.73 (s, 1 H), 7.64 (d, J= 8.8 Hz, 2 H), 7.42 (d, J= 8.0 Hz, 2 H), 7.21 (d, J= 1.6 Hz, 1 H), 3.91 (d, J= 3.2 Hz, 1 H), 3.68-3.62 (m, 3 H), 3.30-3.22 (m, 3 H), 2.79 (br, s, 2 H), 2.66-2.60 (m, 1 H), 2.45-2.32 (m, 2 H), 1.96-1.82 (m, 2 H), 1.78-1.75 (m, 2 H), 1.60-1.53 (m, 5 H), 1.41-1.39 (m, 1 H). LC-MS: tRA= 1.62 min, LC / MS (m / z, M+H): calc. 514.2, found 514.2.

[0391] And 5 mg (1.7% yield) of (cis, cis)-[5-[5-((trans)-4-hydroxycyclohexyl)-lH-pyrrolo[2,3-b]pyri din-3-yl]-3, 3a, 4,5,6, 6a-hexahy dro-lH-cy clopenta[c]pyrrol-2 -yl]-[4-(trifluoromethoxy)phenyl]methanone. 'H NMR (400 MHz, DMSO-t / e) 6 ppm 11.17 (s, 1 H), 8.05 (d, J= 2.0 Hz, 1 H), 7.74 (d, J= 1.6 Hz, 1 H), 7.64-7.62 (m, 2 H), 7.41 (d, J= 8.0 Hz, 2 H), 7.20 (d, J= 2.0 Hz, 1 H), 4.56 (d, J= 4.4 Hz, 1 H), 3.63 (s, 3 H), 3.53-3.46 (m, 2 H), 3.24-3.21 (m, 2 H), 2.81 (s, 2 H), 2.57-2.54 (m, 1 H), 2.44 (s, 1 H), 2.30 (d, J= 1.6 Hz, 1 H), 1.99- 1.92 (m, 2 H), 1.80 (d, J= 12.4 Hz, 2 H), 1.56 (td, J= 12.3, 10.2 Hz, 3 H), 1.32 (t, J= 13.2 Hz, 2 H). LC-MS: tRA= 1.70 min, LC / MS (m / z, M+H): calc. 514.2, found 514.2.

[0392] Example 14: (cis, cis)-[5-(5-morpholino-lH-pyrrolo[2,3-b]pyridin-3-yl)-3,3a,4,5,6,6a-hexahydro-lH-cyclopenta[c]pyrrol-2-yl]-[2-amino-4-(trifluoromethoxy)phenyl]methanone

[0393]

[0394] METHOD D (Scheme 5)

[0395] STEP 1: 4-(lH-pyrrolo[2,3-b]pyridin-5-yl)morpholine

[0396]

[0397] To a stirred solution of 5-bromo-lH-pyrrolo[2,3-b]pyridine (1.5 g, 7.61 mmol) and morpholine (663 mg, 7.61 mmol) in tetrahydrofuran (15 mL) was added LiHMDS (12.7 g, 76.1 mmol) and degassed with argon for 15 minutes. Then, RuPhosPdG3 (320 mg, 0.38 mmol) and dicyclohexyl-[2-(2,6-diisopropoxyphenyl)phenyl]phosphane (355 mg, 0.76 mmol) were added and the reaction mixture was stirred at 90 °C for 16 hours. Then, the reaction mixture was concentrated under reduced pressure and the resulting residue was diluted with an aqueous saturated solution of NH4CI (100 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic layers were separated, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was adsorbed over silica gel and purified by gravity column to give 1.5 g (97% yield) of 4-(lH-pyrrolo[2,3-b]pyridin-5-yl)morpholine as an off white solid. LC / MS (m / z, M+H): calc. 204.1, found 204.2.

[0398] STEP 2: tert-butyl (cis)-5-(5-morpholino-lH-pyrrolo[2,3-b]pyridin-3-yl)-3,3a,6,6a-tetrahydro-lH-cyclopenta[c]pyrrole-2-carboxylate

[0399] °y0

[0400] _N

[0401] 0i

[0402] I ^N.

[0403]

[0404] To a stirred solution of 4-(lH-pyrrolo[2,3-b]pyridin-5-yl)morpholine (900 mg, 4.43 mmol) and tert-butyl (cis)-5-oxo-l,3,3a,4,6,6a-hexahydrocyclopenta[c]pyrrole-2-carboxylate (998 mg, 4.43 mmol) in methanol (15 mL) was added KOH (497 mg, 8.86 mmol) at 0 °C, and the resulting reaction mixture was stirred for 16 hours at 70 °C. The resulting reaction mixture was diluted with chilled water (100 mL) and extracted with ethyl acetate (100 mL x 2). The combined organic layers were separated, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography on silica gel to give 300 mg (16% yield) of tert-butyl (cis)-5-(5-morpholino-lH-pyrrolo[2,3-b]pyridin-3-yl)-3,3a,6,6a-tetrahydro-lH-cyclopenta[c]pyrrole-2-carboxylate as an off white solid. LC / MS (m / z, M+H): calc. 411.2, found 411.1.

[0405] STEP 3: 4-[3-[(cis)-l,2,3,3a,6,6a-hexahydrocyclopenta[c]pyrrol-5-yl]-lH-pyrrolo[2,3-b]pyri din-5 -yl] morpholine dihydrochloride

[0406] H

[0407] N

[0408]

[0409] To a stirred solution of tert-butyl (cis)-5-(5-morpholino-lH-pyrrolo[2,3-b]pyridin-3-yl)-3,3a,6,6a-tetrahydro-lH-cyclopenta[c]pyrrole-2-carboxylate (300 mg, 0.73 mmol) in DCM (4 mL) , was added a 4M solution of HC1 in 1,4-dioxane (1.83 mL, 7.31 mmol) at 0 °C, and the resulting reaction mixture was stirred for 1 hour at room temperature. Then, the whole mixture was concentrated under reduced pressure and the resulting residue was triturated with diethyl ether (10 mL) to give 278 mg (100% yield) 4-[3-[(cis)-l,2,3,3a,6,6a-hexahydrocyclopenta[c]pyrrol-5-yl]-lH-pyrrolo[2,3-b]pyridin-5-yl]morpholine dihydrochloride as a yellow solid. LC / MS (m / z, M+H -2 HC1): calc. 311.2, found 311.1.

[0410] STEP 4 (example 18): [(cis)-5-(5-morpholino-lH-pyrrolo[2,3-b]pyridin-3-yl)-3,3a,6,6a-tetrahydro-lH-cyclopenta[c]pyrrol-2-yl]-[2-amino-4-(trifluoromethoxy)phenyl]methanone

[0411]

[0412] To a stirred solution of 4-[3-[(cis)-l,2,3,3a,6,6a-hexahydrocyclopenta[c]pyrrol-5-yl]-lH-pyrrolo[2,3-b]pyridin-5-yl]morpholine dihydrochloride (278 mg, 0.73 mmol) and 2-amino-4-(trifluoromethoxy)benzoic acid (214 mg, 0.97 mmol) in DMF (5 mL) were added N,N-diethylethanamine (293 mg, 2.9 mmol) and [benzotriazol- 1-yloxy (dimethylamino)methylene] -dimethyl-ammonium;tetrafluoroborate (465 mg, 1.45 mmol) at 0 °C and the resulting reaction mixture was stirred at room temperature for 1 hour. Then, the whole mixture was diluted with chilled water (50 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC to give 210 mg (56% yield) ([(cis)-5-(5-morpholino-lH-pyrrolo[2,3-b]pyridin-3-yl)-3,3a,6,6a-tetrahydro-lH-cyclopenta[c]pyrrol-2-yl]-[2-amino-4-(trifluoromethoxy)phenyl]methanone as an off white solid. 'H NMR (400 MHz, DMSO-t / e) 6 ppm 11.50 (s, 1 H), 8.52 (s, 1 H), 7.66 (s, 1 H), 7.42 (s, 1 H), 7.15 (d, J= 7.6Hz, 1 H), 6.64 (s, 1 H), 6.44 (d, J= 8.4Hz, 1 H), 6.03 (s, 1 H), 5.71 (d, J= 33.2 Hz, 2 H), 3.77 (t, J= 4.4 Hz, 6 H), 3.57 (s, 2 H), 3.13 (d, J= 3.2 Hz, 4 H), 2.98-2.82 (m, 2 H), 2.01-1.92 (m, 2 H). LC / MS (m / z, M+H): calc. 514.2, found 514.1.

[0413] STEP 5: (cis, cis)-[5-(5-morpholino-lH-pyrrolo[2,3-b]pyridin-3-yl)-3, 3a, 4,5,6, 6a-hexahydro-lH-cyclopenta[c]pyrrol-2-yl]-[2-amino-4-(trifluoromethoxy)phenyl]methanone

[0414]

[0415] To a stirred solution of [(cis)-5-(5-morpholino-lH-pyrrolo[2,3-b]pyridin-3-yl)-3,3a,6,6a-tetrahydro-lH-cyclopenta[c]pyrrol-2-yl]-[2-amino-4-(trifluoromethoxy)phenyl]methanone (200 mg, 0.39 mmol) in methanol (10 mL) were added palladium (207 mg, 1.95 mmol) and catalytic amount of acetic acid (2.3 mg, 0.04 mmol) under an inert atmosphere and the resulting reaction mixture was stirred under one atmosphere of hydrogen at room temperature for 16 hours. Then, the reaction mixture was filtered through celite bed and washed with ethanol and concentrated to dryness. The resulting residue was purified by preparative HPLC to give 54 mg (27% yield) of [(cis, cis)-5-(5-morpholino-lH-pyrrolo[2,3-b]pyridin-3-yl)-3,3a,4,5,6,6a-hexahydro-lH-cyclopenta[c]pyrrol-2-yl]-[2-amino-4-(trifluoromethoxy)phenyl]methanone as an off white solid. H NMR (400 MHz, DMSO-A) 8 ppm 11.05 (s, 1 H), 8.04 (d, J= 2.4 Hz, 1 H), 7.46 (d, J= 2.4 Hz, 1 H), 7.16 (d, J = 8.4 Hz, 2 H), 6.64 (d, J= 1.2 Hz, 1 H), 6.44 (dd, J = 8.4, 1.1 Hz, 1 H), 5.70 (s, 2 H), 3.78-3.57 (m, 8 H), 3.22 (s, 1 H), 3.07 (t, J= 4.6 Hz, 4 H), 2.76 (s, 2 H), 2.37 (d, J= 1.6 Hz, 2 H), 1.49 (s, 2 H). LC / MS (m / z, M+H): calc. 516.2, found 516.5.

[0416] Examples 15 & 16: (cis, cis)-[5-[5-((cis)-4-hydroxycyclohexyl)-lH-pyrrolo[2,3-b]pyridin-3-yl]-3, 3a, 4,5,6, 6a-hexahydro-lH-cyclopenta[c]pyrrol-2-yl]-[2-amino-4-(trifluoromethoxy)phenyl]methanone and (cis, cis)-[5-[5-((trans)-4-hydroxycyclohexyl)-lH-pyrrolo[2,3-b]pyridin-3-yl]-3,3a,4,5,6,6a-hexahydro-lH-cyclopenta[c]pyrrol-2-yl]-[2-amino-4-(trifluoromethoxy)phenyl]methanone

[0417]

[0418] Examples 15 & 16 were prepared following the protocols described in Method C using in STEP 4, 2-amino-4-(trifluoromethoxy)benzoic acid (206 mg, 0.93 mmol) to give in the last step, 15 mg (7% yield) of (cis, cis)-[5-[5-((cis)-4-hydroxycyclohexyl)-lH-pyrrolo[2,3-b]pyridin-3-yl]-3,3a,4,5,6,6a-hexahydro-lH-cyclopenta[c]pyrrol-2-yl]-[2-amino-4-(trifluoromethoxy)phenyl]methanone as a white solid. 'H NMR (400 MHz, DMSO- / >) 6 ppm 11.21-11.11 (m, 1 H), 8.05 (d, J=1.91 Hz, 1 H), 7.73 (d, J=1.61 Hz, 1 H), 7.26-7.13 (m, 2 H), 6.64 (d, J=1.17 Hz, 1 H), 6.54-6.38 (m, 1 H), 5.71 (s, 2 H), 4.34-4.43 (m, 1 H), 3.98 (s, 1 H), 3.64-3.54 (m, 3 H), 3.30-3.15 (m, 1 H), 2.85-2.71 (m, 2 H), 2.62-2.55 (m, 1 H), 2.32-2.43 (m, 2 H), 2.00-1.85 (m, 2 H), 1.85-1.71 (m, 3 H), 1.41-1.66 (m, 6 H).

[0419] And 19 mg (8% yield) of (cis, cis)-[5-[5-((trans)-4-hydroxycyclohexyl)-lH-pyrrolo[2,3-b]pyridin-3-yl]-3,3a,4,5,6,6a-hexahydro-lH-cyclopenta[c]pyrrol-2-yl]-[2-amino-4-(trifluoromethoxy)phenyl]methanone as an off-white solid. 'H NMR (400 MHz, DMSO- / >) 6 ppm 11.16 (s, 1 H), 8.05 (d, J= 2.0 Hz, 1 H), 7.73 (d, J= 1.6 Hz, 1 H), 7.20-7.17 (m, 2 H), 6.64 (d, J= 1.2 Hz, 1 H), 6.45 (dd, J= 8.4, 1.2 Hz, 1 H), 5.72 (s, 2 H), 4.40 (d, J= 3.6 Hz, 1 H), 3.92 (s, 1 H), 3.57 (s, 2 H), 3.27-3.20 (m, 1 H), 2.77 (d, J= 13.6 Hz, 2 H), 2.60 (t, J= 12.2 Hz, 1 H), 2.35-2.33 (m, 2 H), 2.02-1.86 (m, 3 H), 1.77 (d, J= 10.8 Hz, 3 H), 1.60-1.46 (m, 6 H). LC / MS (m / z, M+H): calc. 529.2, found 529.2.

[0420] Example 17: (cis)-[5-(5-tetrahydropyran-4-yl-lH-pyrrolo[2,3-b]pyridin-3-yl)-3,3a,6,6a-tetrahydro-lH-cyclopenta[c]pyrrol-2-yl]-[2-amino-4-(trifluoromethoxy)phenyl]methanone

[0421]

[0422] Prepared according to STEP 6 of example 9.

[0423] Example 18: (cis)-[5-(5-morpholino-lH-pyrrolo[2,3-b]pyridin-3-yl)-3,3a,6,6a-tetrahydro-lH-cyclopenta[c]pyrrol-2-yl]-[2-amino-4-(trifluoromethoxy)phenyl]methanone

[0424]

[0425] Prepared according to STEP 4 of example 14.

[0426] Examples 19 & 20: (cis, cis)-[5-[5-fluoro-2-[morpholin-2-yl]-lH-pyrrolo[2,3-b]pyridin-4-yl]-3, 3a, 4,5,6, 6a-hexahy dro-lH-cy clopenta[c]pyrrol-2 -yl]-[4-(trifluoromethoxy)phenyl]methanone isomer 1 and (cis, cis)-[5-[5-fluoro-2-[morpholin-2-yl]-lH-pyrrolo[2, 3-b]pyridin-4-yl]-3, 3a, 4,5,6, 6a-hexahy dro-lH-cy clopenta[c]pyrrol-2 -yl]-[4-(trifluoromethoxy)phenyl]methanone isomer 2

[0427]

[0428] METHOD E (Scheme 3)

[0429] STEP 1: (rac)-tert-butyl 2-formylmorpholine-4-carboxylate

[0430]

[0431] To a stirred solution of DMSO (4 g, 51.2 mmol) in DCM (100 mL) was added oxalyl dichloride (3.2 g, 25.2 mmol) at -78 °C and the resulting mixture was stirred for 30 minutes at -78 °C. Then, tert-butyl 2-(hydroxymethyl)morpholine-4-carboxylate (5 g, 23 mmol) was added at -78 °C and the mixture was stirred at -78 °C for 1 hour under argon atmosphere. Then, N,N-diethylethanamine (11.6 g, 115 mmol) was added. After completion, the reaction mixture was quenched with ice water (250 mL) and extracted with DCM (3 x 80 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give 5 g of crude (rac)-tert-butyl 2-formylmorpholine-4-carboxylate as a yellow gummy liquid.

[0432] STEP 2: (rac)-tert-butyl 2-ethynylmorpholine-4-carboxylate

[0433]

[0434] To a stirred solution of (rac)-tert-butyl 2-formylmorpholine-4-carboxylate (5 g, 23.2 mmol) and K2CO3 (5 g, 36.2 mmol) in methanol (15 mL) was added 1 -diazo- 1 -dimethoxyphosphoryl-propan-2-one (6 g, 31.2 mmol) in methanol (35 mL) at 0 °C and the resulting reaction mixture was stirred at room temperature for 16 hours under argon atmosphere. Then, the whole reaction mixture was concentrated under reduced pressure. The resulting residue was diluted with ice water (250 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography on silica gel to give 2.6 g (39% yield) of (rac)-tert-butyl 2-ethynylmorpholine-4-carboxylate as an off white solid.

[0435] STEP 3: (rac)-tert-butyl 2-[2-(2-amino-4-bromo-5-fluoro-3-pyridyl)ethynyl]morpholine-4-carboxylate

[0436]

[0437] To a stirred solution of (rac)-tert-butyl 2-ethynylmorpholine-4-carboxylate (1.1 g, 5.21 mmol) and 4-bromo-5-fluoro-3-iodo-pyridin-2-amine (1.1 g, 3.47 mmol) in DMF (15 mL), was added N,N-diethylethanamine (1.58 g, 15.6 mmol) and copper iodide (99 mg, 0.52 mmol) and the resulting mixture was bubbled with argon 15 minutes. Then, PdCh(PPh3)2 (365 mg, 0.52 mmol) purge with argon for 5 minutes, was added and the reaction mixture was stirred at 75 °C for 6 hours. Then, the whole mixture was cooled down to room temperature, diluted with ice water (25 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure to give 1 g (48% yield) of (rac)-tert-butyl 2-[2-(2-amino-4-bromo-5-fluoro-3-pyridyl)ethynyl]morpholine-4-carboxylate as a yellow solid. LC / MS (m / z, M+H): calc. 400.0, found 399.9.

[0438] STEP 4: (rac)-tert-butyl 2-(4-bromo-5-fluoro-lH-pyrrolo[2,3-b]pyridin-2-yl)morpholine-4-carboxylate

[0439]

[0440] To a stirred solution of (rac)-tert-butyl 2-[2-(2-amino-4-bromo-5-fluoro-3-pyridyl)ethynyl]morpholine-4-carboxylate (1.1 g, 2.75 mmol) in 1 -methylpyrrolidin-2-one (11 mL), was added t-BuOK (600 mg, 5.35 mmol) at room temperature under nitrogen atmosphere and the resulting reaction mixture was stirred at room temperature for 4 hours. Then, the whole mixture was diluted with ice water (50 mL) and extracted with ethyl acetate (2 x 25 mL). The combined organic layers were separated, dried over Na2SO4, filtered, concentrated under reduced pressure. The resulting residue was purified by flash chromatography on silica gel to give 500 mg (45% yield) of (rac)-tert-butyl 2-(4-bromo-5-fluoro-lH-pyrrolo[2,3-b]pyridin-2-yl)morpholine-4- as a yellow solid. LC / MS (m / z, M+H): calc. 400.0, found 400.0.

[0441] STEP 5: (rac)-tert-butyl 2-[4-[(cis)-2-[4-(trifluoromethoxy)benzoyl]-3,3a,6,6a-tetrahydro-lH-cyclopenta[c]pyrrol-5-yl]-5-fluoro-lH-pyrrolo[2,3-b]pyridin-2-yl]morpholine-4-carboxylate

[0442]

[0443] To a stirred solution of tert-butyl (rac)-2-(4-bromo-5-fluoro-lH-pyrrolo[2,3-b]pyridin-2-yl)morpholine-4-carboxylate (700 mg, 1.75 mmol) and [(cis)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,3a,6,6a-tetrahydro-lH-cyclopenta[c]pyrrol-2-yl]-[4-(trifluoromethoxy)phenyl]methanone (intermediate IV, 800 mg, 1.89 mmol, for its preparation see the following section) in 1,4-dioxane (8 mL) and water (2 mL) was added K2CO3 (1.4 g, 10.1 mmol) and the whole mixture was bubbled with argon for 15 minutes. Then, PdC12(dppf).DCM complex (250 mg, 0.31 mmol) was added and reaction mixture was stirred at 90 °C for 6 hours. Then, the reaction mixture was cooled down to room temperature and filtered through celite bed. The filtrate was diluted with ethyl acetate (lOmL), washed with water (5mL) and the organic layer was separated, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography on silica gel to give 600 mg (56% yield) of tert-butyl (rac)-2-[4-[(cis)-2-[4-(trifluoromethoxy)benzoyl]-3,3a,6,6a-tetrahydro-lH-cyclopenta[c]pyrrol-5-yl]-5-fluoro-lH-pyrrolo[2,3-b]pyridin-2-yl]morpholine-4-carboxylate as a yellow solid. LC / MS (m / z, M-H): calc. 615.2, found 615.1.

[0444] STEP 6: (rac)-tert-butyl 2-[4-[(cis, cis)-2-[4-(trifluoromethoxy)benzoyl]-3,3a,4,5,6,6a-hexahydro-lH-cyclopenta[c]pyrrol-5-yl]-5-fluoro-lH-pyrrolo[2,3-b]pyridin-2-yl]morpholine-4-carboxylate

[0445]

[0446] To a stirred solution of tert-butyl (rac)-2-[4-[(cis)-2-[4-(trifluoromethoxy)benzoyl]-3,3a,6,6a-tetrahydro-lH-cyclopenta[c]pyrrol-5-yl]-5-fluoro-lH-pyrrolo[2,3-b]pyridin-2-yl]morpholine-4-carboxylate (600 mg, 0.97 mmol) in ethanol (10 mL) and methanol (10 mL) was added palladium / carbon (1.04 g, 9.73 mmol) and a catalytic amount off acetic acid (58 mg, 0.97 mmol) at room temperature and the resulting reaction mixture was stirred under one atmosphere of hydrogen for 3 hours. Then, the whole mixture was filtered through celite and washed with ethanol (2 x 10 mL), concentrated under reduced pressure to give 400 mg (66% yield) of (rac)-tert-butyl 2-[4-[(cis, cis)-2-[4-(trifluoromethoxy)benzoyl]-3,3a,4,5,6,6a-hexahydro-lH-cyclopenta[c]pyrrol-5-yl]-5-fluoro-lH-pyrrolo[2,3-b]pyridin-2-yl]morpholine-4-carboxylate as ayellow solid. LC / MS (m / z, M+H): calc. 619.2, found 619.1.

[0447] STEP 7: (rac)-[(cis, cis)-5-(5-fluoro-2-morpholin-2-yl-lH-pyrrolo[2,3-b]pyridin-4-yl)-3,3a,4,5,6,6a-hexahydro-lH-cyclopenta[c]pyrrol-2-yl]-[4-(trifluoromethoxy)phenyl]methanone

[0448]

[0449] To a stirred solution of tert-butyl (rac)-2-[4-[(cis)-2-[4-(trifluoromethoxy)benzoyl]-3,3a,4,5,6,6a-hexahydro-lH-cyclopenta[c]pyrrol-5-yl]-5-fluoro-lH-pyrrolo[2,3-b]pyridin-2-yl]morpholine-4-carboxylate (400 mg, 0.65 mmol) in DCM (5 mL) was added a 4M solution of HC1 in 1,4-di oxane (281 mg, 7.71 mmol) under argon atmosphere at 0 °C and the resulting reaction mixture was stirred at room temperature for 1 hour. Then, the whole mixture was concentrated under reduced pressure and the resulting residue was triturated with diethyl ether (5 mL), filtered to give (rac)-[(cis, cis)-5-(5-fluoro-2-morpholin-2-yl-lH-pyrrolo[2,3-b]pyridin-4-yl)-3, 3a, 4,5,6, 6a-hexahydro-lH-cyclopenta[c]pyrrol -2-yl]-[4-(trifluoromethoxy)phenyl]methanone as an off white solid which was purified by preparative HPLC, to give 100 mg (30% yield) of (rac)-[(cis, cis)-5-(5-fluoro-2-morpholin-2-yl-lH-pyrrolo[2,3-b]pyridin-4-yl)-3,3a,4,5,6,6a-hexahydro-lH-cyclopenta[c]pyrrol-2-yl]-[4-(trifluoromethoxy)phenyl] methanone as an off white solid. LC / MS (m / z, M+H): calc. 519.2, found 519.5.

[0450] STEP 8: (cis, cis)-[5-[5-fluoro-2-[morpholin-2-yl]-lH-pyrrolo[2,3-b]pyridin-4-yl]-3,3a,4,5,6,6a-hexahydro-lH-cyclopenta[c]pyrrol-2-yl]-[4-(trifluoromethoxy)phenyl]methanone isomer 1 and (cis, cis)-[5-[5-fluoro-2-[morpholin-2-yl]- lH-pyrrolo[2, 3-b]pyridin-4-yl]-3, 3a, 4,5,6, 6a-hexahy dro-lH-cy clopenta[c]pyrrol-2 -yl]-[4-(trifluoromethoxy)phenyl]methanone isomer 2

[0451]

[0452] The above obtained (rac)-[(cis, cis)-5-(5-fluoro-2-morpholin-2-yl-lH-pyrrolo[2,3-b]pyridin-4-yl)-3, 3a, 4,5,6, 6a-hexahy dro-lH-cy clopenta[c]pyrrol-2 -yl]-[4- (trifluoromethoxy)phenyl]methanone (100 mg, 0.19 mmol) was purified by SFC separation to give 23 mg (23% yield) of [(cis, cis)-5-(5-fluoro-2-morpholin-2-yl-lH-pyrrolo[2,3-b]pyridin-4-yl)-3, 3a, 4,5,6, 6a-hexahydro-lH-cyclopenta[c]pyrrol-2-yl]-[4- (trifluoromethoxy)phenyl]methanone isomer 1 as an off-white solid. 'H NMR (400 MHz, DMSO-t / e) 8 ppm 11.72-11.83 (m, 1 H), 8.02-8.11 (m, 1 H), 7.67-7.75 (m, 2H), 7.35-7.51 (m, 2 H), 6.37-6.48 (m, 1 H), 4.51-4.64 (m, 1 H), 3.77-3.92 (m, 2 H), 3.55-3.69 (m, 4 H), 3.45-3.55 (m, 1 H), 3.01-3.12 (m, 1 H), 2.71-2.89 (m, 6 H), 2.25-2.36 (m, 1 H), 2.08-2.21 (m, 1 H), 1.82-1.98 (m, 1 H), 1.63-1.78 (m, 1 H). LC / MS (m / z, M+H): calc. 519.2, found 519.0.

[0453] And 25 mg (25% yield) of [(3aS,6aR)-5-(5-fluoro-2-morpholin-2-yl-lH-pyrrolo[2,3-b]pyridin-4-yl)-3, 3a, 4,5,6, 6a-hexahy dro-lH-cy clopenta[c]pyrrol-2 -yl]-[4- (trifluoromethoxy)phenyl]methanone isomer 2 as an off white solid. 'H NMR (400 MHz, DMSO-<76) 8 ppm 11.75 (br s, 1 H), 8.01-8.12 (m, 1 H), 7.65-7.78 (m, 2 H), 7.38-7.53 (m, 2 H), 6.35-6.49 (m, 1 H), 4.46-4.65 (m, 1 H), 3.74-3.92 (m, 2 H), 3.47-3.67 (m, 4 H), 3.00-3.12 (m, 1 H), 2.67-2.92 (m, 6 H), 2.12-2.38 (m, 3 H), 1.61-1.96 (m, 2 H). LC / MS (m / z, M+H): calc. 519.2, found 519.0.

[0454] Preparation of compound IV: [(cis)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,3a,6,6a-tetrahydro-lH-cyclopenta[c]pyrrol-2-yl]-[4-(trifluoromethoxy)phenyl]methanone F

[0455]

[0456] STEP 1: (cis)-2,3,3a,4,6,6a-hexahydro-lH-cyclopenta[c]pyrrol-5-one hydrochloride

[0457]

[0458] To a stirred solution of tert-butyl (cis)-5-oxo-l,3,3a,4,6,6a-hexahydrocyclopenta[c]pyrrole-2-carboxylate (4 g, 17.8 mmol) in DCM (40 mL) was added a 4M solution of HC1 in 1,4-dioxane (40 g, 1.10 mol) under argon atmosphere and then the reaction mixture was stirred at room temperature for 1 hour. The whole mixture was then concentrated under reduced pressure and the resulting residue was triturated with diethyl ether (50 mL), filtered, to give 2.867 g (100% yield) of (cis)-2,3,3a,4,6,6a-hexahydro-lH-cyclopenta[c]pyrrol-5-one hydrochloride as an off white solid.

[0459] STEP 2: (cis)-2-[4-(trifluoromethoxy)benzoyl]-l,3,3a,4,6,6a-hexahydrocyclopenta[c]pyrrol- 5-one

[0460]

[0461] To a stirred solution of (cis)-2,3,3a,4,6,6a-hexahydro-lH-cyclopenta[c]pyrrol-5-one hydrochloride (2.867 g, 17.8 mmol), 4-(trifluoromethoxy)benzoic acid (3 g, 14.6 mmol) and N,N-diethylethanamine (4.5 g, 44.5 mmol) in DMF (30 mL) was added [benzotriazol- 1-yloxy(dimethylamino)methylene]-dimethyl-ammonium;tetrafluoroborate (6 g, 18.7 mmol) at 0 °C and the resulting reaction mixture was stirred at room temperature for 1 hour under argon atmosphere. Then, the whole mixture was diluted with chilled water (100 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography on silica gel to give 3 g (65% yield) of (cis)-2-[4-(trifluoromethoxy)benzoyl]-l,3,3a,4,6,6a-hexahydrocyclopenta[c]pyrrol-5-one as a yellow solid. LC / MS (m / z, M+H): calc. 314.1, found 314.0.

[0462] STEP 3: [(cis)-2-[4-(trifluoromethoxy)benzoyl]-3,3a,6,6a-tetrahydro-lH-cyclopenta[c]pyrrol-5-yl] trifluoromethanesulfonate

[0463]

[0464] To a stirred solution of (cis)-2-[4-(trifluoromethoxy)benzoyl]-l,3,3a,4,6,6a-hexahydrocyclopenta[c]pyrrol-5-one (3 g, 9.6 mmol) in THF (30 mL) at -78 °C, was added dropwise LiHMDS (16.5 g, 9.86 mmol, 1.0 M in THF) under argon atmosphere and the resulting reaction mixture was stirred for 1 hour. Then, 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (3.42 g, 9.6 mmol) was added and the resulting reaction mixture was stirred for 1 hour at -78 °C and then warmed up to room temperature and stirred for 16 hours. The whole mixture was then quenched with an aqueous saturated solution ofNH4Cl (100 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography on silica gel to give 2.5 g, (59% yield) of [(cis)-2-[4-(trifluoromethoxy)benzoyl]-3,3a,6,6a-tetrahydro-lH-cyclopenta[c]pyrrol-5-yl] trifluoromethanesulfonate as ayellow oil. LC / MS (m / z, M+H): calc. 446.0, found 446.1.

[0465] STEP 4: [(cis)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,3a,6,6a-tetrahydro-lH-cyclopenta[c]pyrrol-2-yl]-[4-(trifluoromethoxy)phenyl]methanone

[0466]

[0467] To a stirred solution of [(cis)-2-[4-(trifluoromethoxy)benzoyl]-3,3a,6,6a-tetrahydro-lH-cyclopenta[c]pyrrol-5-yl] trifluoromethanesulfonate (1 g, 2.25 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (2.5 g, 9.84 mmol) in 1,4-dioxane (15 mL) and was added CH3CO2K (1.5 g, 15.3 mmol) and the resulting mixture was bubbled with argon for 15 minutes. Then, PdC12(dppf).DCM complex (250 mg, 0.31 mmol) was added, and the reaction mixture was stirred at 90 °C for 16 hours. Then, the whole mixture was cooled down to room temperature and filtered through celite bed. The filtrate was diluted with ethyl acetate (50 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography on silica gel to give 900 mg (95% yield) of[(cis)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,3a,6,6a-tetrahydro-lH-cyclopenta[c]pyrrol-2-yl]-[4- (trifluoromethoxy)phenyl]methanone as ayellow solid. LC / MS (m / z, M+H): calc. 424.2, found 424.1.

[0468] Example 21: (cis, cis)-[5-(5-fluoro-2-tetrahydropyran-4-yl-lH-pyrrolo[2,3-b]pyridin-4-yl)- 3,3a,4,5,6,6a-hexahydro-lH-cyclopenta[c]pyrrol-2-yl]-[2-amino-4- (trifluoromethoxy)phenyl]methanone

[0469]

[0470] METHOD F (Scheme 2)

[0471] STEP 1: 4-chloro-2-(3,6-dihydro-2H-pyran-4-yl)-5-fluoro-l-(p-tolylsulfonyl)pyrrolo[2,3-b] pyridine

[0472]

[0473] STEP 1 of example 21 was performed following the protocol described in STEP 3 of Method A (examples 1 & 2) using 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (1.12 g, 5.33 mmol), to give 1100 mg (60% yield) of 4-chloro-2-(3,6-dihydro-2H-pyran-4-yl)-5-fluoro-l-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridine as a solid. LC / MS (m / z, M-H): calc. 405.0, found 405.00.

[0474] STEP 2: tert-butyl (cis)-5-[2-(3,6-dihydro-2H-pyran-4-yl)-5-fluoro-l-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-4-yl]-3,3a,6,6a-tetrahydro-lH-cyclopenta[c]pyrrole-2-carboxylate

[0475]

[0476] STEP 2 of example 21 was performed following the protocol described in STEP 4 of Method A (examples 1 & 2) to give 350 mg (49% yield) of tert-butyl (cis)-5-[2-(3,6-dihydro-2H-pyran-4-yl)-5-fluoro-l-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-4-yl]-3,3a,6,6a-tetrahydro-lH-cyclopenta[c]pyrrole-2-carboxylate as a gum. LC / MS (m / z, M+H): calc. 580.2, found 580.3.

[0477] STEP 3: tert-butyl (cis, cis)-5-[5-fluoro-l-(p-tolylsulfonyl)-2-tetrahydropyran-4-yl-pyrrolo[2,3-b]pyridin-4-yl]-3,3a,4,5,6,6a-hexahydro-lH-cyclopenta[c]pyrrole-2-carboxylate

[0478]

[0479] STEP 3 of example 21 was performed following the protocol described in STEP 8i of Method A (examples 1 & 2) to give 200 mg (50% yield) of tert-butyl (cis, cis)-5-[5-fluoro-l-(p-tolylsulfonyl)-2-tetrahydropyran-4-yl-pyrrolo[2,3-b]pyridin-4-yl]-3, 3a, 4,5,6, 6a-hexahydro-lH-cyclopenta[c]pyrrole-2-carboxylate as a gum. LC / MS (m / z, M+H): calc. 584.2, found 584.1.

[0480] STEP 4: 4-[(cis, cis)-l,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrol-5-yl]-5-fluoro-l-(p-tolylsulfonyl)-2-tetrahydropyran-4-yl-pyrrolo[2,3-b]pyridine hydrochloride

[0481]

[0482] STEP 4 of example 21 was performed following the protocol described in STEP 6 of Method A (examples 1 & 2) to give 150 mg (84% yield) of 4-[(cis, cis)-l,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrol-5-yl]-5-fluoro-l-(p-tolylsulfonyl)-2-tetrahydropyran-4-yl-pyrrolo[2,3-b]pyridine hydrochloride as a brown solid. LC / MS (m / z, M-H -HC1): calc. 482.2, found 482.1.

[0483] STEP 5: [(cis, cis)-5-[5-fluoro-l-(p-tolylsulfonyl)-2-tetrahydropyran-4-yl-pyrrolo[2,3-b]pyridin-4-yl]-3,3a,4,5,6,6a-hexahydro-lH-cyclopenta[c]pyrrol-2-yl]-[2-amino-4-(trifluoromethoxy)phenyl]methanone

[0484]

[0485] STEP 5 of example 21 was performed following the protocol described in STEP 7 of Method A (examples 1 & 2) using 2-amino-4-(trifluoromethoxy)benzoic acid (150 mg, 0.68 mmol) to give 250 mg (purity 25%, 13% yield) of 4-[(cis, cis)-l,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrol-5-yl]-5-fluoro-l-(p-tolylsulfonyl)-2-tetrahydropyran-4-yl-pyrrolo[2,3-b]pyridine as a yellow gum which was engaged in the next step without further purification. LC / MS (m / z, M+H): calc. 687.2, found 687.1.

[0486] STEP 6: (cis, cis)-[5-(5-fluoro-2-tetrahydropyran-4-yl-lH-pyrrolo[2,3-b]pyridin-4-yl)-3,3a,4,5,6,6a-hexahydro-lH-cyclopenta[c]pyrrol-2-yl]-[2-amino-4-(trifluoromethoxy)phenyl]methanone

[0487]

[0488] STEP 6 of example 21 was performed following the protocol described in STEP 5 of Method A (examples 1 & 2) to give 32 mg (67% yield) of (cis, cis)-[5-(5-fluoro-2-tetrahydropyran-4-yl-lH-pyrrolo[2, 3-b]pyridin-4-yl)-3, 3a, 4,5,6, 6a-hexahy dro-lH-cy clopenta[c]pyrrol-2-yl]-[2-amino-4-(trifluoromethoxy)phenyl]methanone as a white solid. 'H NMR (400 MHz, DMSO-6) 8 ppm 11.63 (s, 1 H), 7.93-8.04 (m, 1 H), 7.13-7.30 (m, 1 H), 6.64-6.72 (m, 1 H), 6.40-6.50 (m, 1 H), 6.23-6.28 (m, 1 H), 5.72-5.81 (m, 2 H), 3.91-4.01 (m, 2 H), 3.56-3.66 (m, 2 H), 3.40-3.54 (m, 5 H), 2.89-3.02 (m, 1 H), 2.73-2.85 (m, 2 H), 2.13-2.29 (m, 2 H), 1.85-1.96 (m, 3 H), 1.67-1.83 (m, 3 H). LC / MS (m / z, M-H): calc. 531.2, found 531.1. ERK5 inhibitory activity of compounds

[0489] Two assays were performed to assess the ERK5 inhibitory activity of compounds of the Examples, a cell-based assay and a cell-free biochemical assay. Results of the assays are shown below in Table 2. Where repeat measurements were taken, the value reported is a mean average.

[0490] Inhibition of cellular ERK5 activity

[0491] The renal cancer cell line SN12C was transduced by a lentivirus pGreenFirel MEF2 EFl Neo (ref TR030VA-N) from SBI using standard infection protocol. pGreenFirel MEF2 EFl Neo allows the expression of luciferase gene under the control of minimal promoter with MEF2 transcriptional response elements. Cells harboring the reporter construct were selected by geneticin treatment. The selected cells were then transposed by a piggyback based plasmid pCM4007 allowing the expression of constitutively activated MEK5DD under control of TREG3 promoter, a doxycycline regulated promoter. Transposed cells were selected by puromycin treatment. Upon doxycycline treatment (Ipg / ml) MEK5DD was expressed.

[0492] MEK5DD activates ERK5 that phosphorylates MEF2C protein. Activated MEF2C protein can bind to its transcriptional response elements. Then the luciferase is expressed. In a 96-well plate (96F nuncleon refl37101 thermofisher), 50,000 cells were inoculated in 142.5pl of RPMI medium containing 10% fetal calf serum, 1% glutamine, and Ipg / ml doxycycline. After 24 hours, compounds were added in 7.5 pl culture medium (with 2% DMSO to give a final concentration of 0.1%) in order to obtain the desired concentration (0.3-10000nM). The luciferase activity was measured using the Kit Bright Gio Luminescent Cell Assay Cat E2610 (Promega) according to the manufacturer’s protocol. Luminescence was determined using 0.2 second reading / well using a Tecan SPARK. ICso values were calculated using XLFIT5 for Microsoft Excel using method 205. The ICso values represent the concentration of compound which inhibits the measurable luminescence signal by 50% as compared to DMSO-treated control cells.

[0493] Cell-free assay of ERK5 inhibition

[0494] An assay was performed to measure the capacity of each compound to inhibit ERK5 enzymatic activity. Compound potency was evaluated by Time-Resolved Forster Resonance Energy Transfer (FRET system). The activated catalytic domain of protein ERK5 (CamaBiosciences #04-146) was mixed at 4 nM with varying concentrations of compound and incubated for 30 minutes at room temperature. A mixture of ImM ATP and IpM biotinylated synthetic peptide was added (Biosyntan GmbH). This synthetic peptide represents amino acids 30-52 of Eukaryotic translation initiation factor 4E-binding protein 1 (see, e.g., the sequence under accession No. NP_004086.1) biotinylated at the N-terminus. After 30 minutes at 37°C, the peptide phosphorylation by ERK5 was measured by addition of FRET reagents consisting of 12.5 pg / ml Streptavidin-XL665, 1 nM Anti-P-4EBP1 antibody and 300ng / ml Anti-rabbit-K antibody. Following 90 minutes at room temperature fluorescent signals were read on the Pherastar FSX multimod detector from BMG Labtech (Exc° 340 nm, Eml 620 nm, Em2665 nm). The ICso values represent the concentration of compound which inhibits the measurable fluorescence signal by 50% as compared to the DMSO only control.

[0495] Table 2: Results of cell-based and cell-free assays

[0496] Compound Cell-free assay Cell-based assay (Example No.) (IC50 in nM) (IC50 in nM)

[0497] 1 27 57

[0498] 2 Inactive* 368

[0499] 3 Inactive* 283

[0500] 4 24020 85

[0501] 5 67 75

[0502] 6 26 46

[0503] 7 115 112

[0504] 8 60 55

[0505] 9 32 - 10 46 119

[0506] 11 98 107

[0507] 12 76 182

[0508] 13 10 29

[0509] 14 79 64

[0510] 15 111 118

[0511] 16 44 37

[0512] 17 3351 251

[0513] 18 1716 390

[0514] 19 22 53

[0515] 20 42 140

[0516]

[0517] 21 202 113

[0518] ” denotes that the values were not measured

[0519] * “Inactive ’’denotes an IC50 above 30000 nM

[0520] The data in Table 2 indicate that the compounds synthesised are active in the micromolar or nanomolar concentration range in cell-based and / or cell-free systems. All of the compounds synthesised have an ICso value below 400 nM in at least one of the cell-based and cell-free assays.

Claims

CLAIMS1. A compound of Formula (I):wherein the dotted line represents an optional unsaturation and wherein:R1 represents a hydrogen atom or a -NH2 group;R2 is selected from the groups (a) and (b):wherein:R3 represents a hydrogen atom or a fluorine atom;X represents a nitrogen atom or a -CH= group;R4 represents a saturated cycloalkyl or heterocycloalkyl group selected from groups (al), (a2), (a3) and (a4); and R5 represents a saturated cycloalkyl or heterocycloalkyl group selected from groups (al), (a2) and (a5), wherein R6 represents an -OH or -OCH3 group:(a1) (a2) (a3) (a4) (a5) or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1, which is represented by formula (II):(II)or a pharmaceutically acceptable salt thereof.

3. A compound according to claim 1 or claim 2, which is represented by formula (IM):(II-l)or a pharmaceutically acceptable salt thereof.

4. A compound according to claim 2 or claim 3, wherein R2 represents a group of formula (a),or a pharmaceutically acceptable salt thereof.

5. A compound according to claim 4, wherein R3 represents a fluorine atom, or a pharmaceutically acceptable salt thereof.

6. A compound according to claim 2 or claim 3, wherein R2 represents a group of formula (b),or a pharmaceutically acceptable salt thereof.

7. A compound according to claim 1, which is represented by formula (III):(III)or a pharmaceutically acceptable salt thereof.

8. A compound according to claim 1 or claim 7, which is represented by formula (III-l):(III-l)or a pharmaceutically acceptable salt thereof.

9. A compound according to claim 7 or claim 8, wherein R1 represents an amino group,or a pharmaceutically acceptable salt thereof.

10. A compound according to any of claims 7 to 9, wherein R2 represents a group of formula (b),or a pharmaceutically acceptable salt thereof.

11. A compound according to claim 10, wherein R5 represents a group of formula (al) or (a5),or a pharmaceutically acceptable salt thereof.

12. A compound according to claim 1, which is selected from:(cis, cis)-[5-[5-fluoro-2-((trans)-4-methoxycyclohexyl)-lH-pyrrolo[2,3-b]pyridin-4- yl]-3, 3a, 4,5,6, 6a-hexahy dro-lH-cy clopenta[ c]pyrrol-2 -yl]-[4- (trifluoromethoxy)phenyl]methanone;(cis, cis)-[5-[5-fluoro-2-((cis)-4-methoxycyclohexyl)-lH-pyrrolo[2,3-b]pyridin-4-yl]- 3,3a,4,5,6,6a-hexahydro-lH-cyclopenta[c]pyrrol-2-yl]-[4- (trifluoromethoxy)phenyl]methanone;(cis, cis)-[5-[5-fluoro-2-((cis)-4-methoxycyclohexyl)-lH-pyrrolo[2,3-b]pyridin-4-yl]- 3,3a,4,5,6,6a-hexahydro-lH-cyclopenta[c]pyrrol-2-yl]-[2-amino-4- (trifluoromethoxy)phenyl]methanone;(cis, cis)-[5-[5-fluoro-2-((trans)-4-methoxycyclohexyl)-lH-pyrrolo[2,3-b]pyridin-4- yl]-3,3a,4,5,6,6a-hexahydro-lH-cyclopenta[c]pyrrol-2-yl]-[2-amino-4- (trifluoromethoxy)phenyl]methanone;(cis, cis)-[5-[5-fluoro-2-((cis)-4-hydroxycyclohexyl)-lH-pyrrolo[2,3-b]pyridin-4-yl]- 3,3a,4,5,6,6a-hexahydro-lH-cyclopenta[c]pyrrol-2-yl]-[4- (trifluoromethoxy)phenyl]methanone;(cis, cis)-[5-[5-fluoro-2-((trans)-4-hydroxycyclohexyl)-lH-pyrrolo[2,3-b]pyridin-4- yl]-3, 3a, 4,5,6, 6a-hexahy dro-lH-cy clopenta[ c]pyrrol-2 -yl]-[4- (trifluoromethoxy)phenyl]methanone;(cis, cis)-[5-[5-fluoro-2-((cis)-4-hydroxycyclohexyl)-lH-pyrrolo[2,3-b]pyridin-4-yl]- 3,3a,4,5,6,6a-hexahydro-lH-cyclopenta[c]pyrrol-2-yl]-[2-amino-4- (trifluoromethoxy)phenyl]methanone;(cis, cis)-[5-[5-fluoro-2-((trans)-4-hydroxycyclohexyl)-lH-pyrrolo[2,3-b]pyridin-4- yl]-3,3a,4,5,6,6a-hexahydro-lH-cyclopenta[c]pyrrol-2-yl]-[2-amino-4- (trifluoromethoxy)phenyl]methanone;(cis, cis)-[5-(5-tetrahydropyran-4-yl-lH-pyrrolo[2,3-b]pyridin-3-yl)-3,3a,4,5,6,6a-hexahydro-lH-cyclopenta[c]pyrrol-2-yl]-[2-amino-4-(trifluoromethoxy)phenyl]methanone;(cis, cis)-[5-[6-fluoro-2-(3-methoxy-l-bicyclo[l.l.l]pentanyl)-3H-imidazo[4,5-b]pyri din-7-yl]-3, 3a, 4,5,6, 6a-hexahy dro-lH-cy clopenta[c]pyrrol-2 -yl]-[4-(trifluoromethoxy)phenyl]methanone;(cis, cis)-[5-[6-fluoro-2-(3-methoxy-l-bicyclo[l.l.l]pentanyl)-3H-imidazo[4,5-b]pyri din-7-yl]-3, 3a, 4,5,6, 6a-hexahy dro-lH-cy clopenta[c]pyrrol-2-yl]-[2-amino-4-(trifluoromethoxy)phenyl]methanone;(cis, cis)-[5-[5-((cis)-4-hydroxycyclohexyl)-lH-pyrrolo[2,3-b]pyridin-3-yl]-3,3a,4,5,6,6a-hexahydro-lH-cyclopenta[c]pyrrol-2-yl]-[4-(trifluoromethoxy)phenyl]methanone;(cis, cis)-[5-[5-((trans)-4-hydroxycyclohexyl)-lH-pyrrolo[2,3-b]pyridin-3-yl]-3,3a,4,5,6,6a-hexahydro-lH-cyclopenta[c]pyrrol-2-yl]-[4-(trifluoromethoxy)phenyl]methanone;(cis, cis)-[5-(5-morpholino-lH-pyrrolo[2,3-b]pyridin-3-yl)-3, 3a, 4,5,6, 6a-hexahydro-lH-cyclopenta[c]pyrrol-2-yl]-[2-amino-4-(trifluoromethoxy)phenyl]methanone (cis, cis)-[5-[5-((cis)-4-hydroxycyclohexyl)-lH-pyrrolo[2,3-b]pyridin-3-yl]-3,3a,4,5,6,6a-hexahydro-lH-cyclopenta[c]pyrrol-2-yl]-[2-amino-4-(trifluoromethoxy)phenyl]methanone;(cis, cis)-[5-[5-((trans)-4-hydroxycyclohexyl)-lH-pyrrolo[2,3-b]pyridin-3-yl]-3,3a,4,5,6,6a-hexahydro-lH-cyclopenta[c]pyrrol-2-yl]-[2-amino-4-(trifluoromethoxy)phenyl]methanone;(cis)-[5-(5-tetrahydropyran-4-yl-lH-pyrrolo[2,3-b]pyridin-3-yl)-3,3a,6,6a-tetrahydro-lH-cyclopenta[c]pyrrol-2-yl]-[2-amino-4-(trifluoromethoxy)phenyl]methanone (cis)-[5-(5-morpholino-lH-pyrrolo[2,3-b]pyridin-3-yl)-3,3a,6,6a-tetrahydro-lH-cyclopenta[c]pyrrol-2-yl]-[2-amino-4-(trifluoromethoxy)phenyl] methanone;(cis, cis)-[5-[5-fluoro-2-[(2S)-morpholin-2-yl]-lH-pyrrolo[2,3-b]pyridin-4-yl]- 3,3a,4,5,6,6a-hexahydro-lH-cyclopenta[c]pyrrol-2-yl]-[4-(trifluoromethoxy)phenyl]methanone;(cis, cis)-[5-[5-fluoro-2-[(2R)-morpholin-2-yl]-lH-pyrrolo[2,3-b]pyridin-4-yl]-3,3a,4,5,6,6a-hexahydro-lH-cyclopenta[c]pyrrol-2-yl]-[4-(trifluoromethoxy)phenyl]methanone;(cis, cis)-[5-(5-fluoro-2-tetrahydropyran-4-yl-lH-pyrrolo[2,3-b]pyridin-4-yl)- 3,3a,4,5,6,6a-hexahydro-lH-cyclopenta[c]pyrrol-2-yl]-[2-amino-4- (trifluoromethoxy)phenyl]methanone;and pharmaceutically acceptable salts thereof.

13. A pharmaceutical composition comprising the compound of any one of claims 1-12, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient or carrier.

14. A compound according to any of claims 1 to 12, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 13, for use in therapy.

15. A compound according to any of claims 1 to 12, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 13, for use in the treatment or prevention of cancer.

16. The compound or pharmaceutical composition for use according to claim 15, wherein the cancer is characterized by increased MAPK7 expression and / or increased ERK5 activity.

17. The compound or pharmaceutical composition for use according to claim 15 or claim 16, wherein the cancer is selected from leukaemia, breast cancer, multiple myeloma, colon cancer, colorectal cancer, lung cancer, pancreatic cancer, renal cell carcinoma, mesothelioma, adenocarcinoma, neuroblastoma, melanoma, and hepatocellular carcinoma.

18. A method of treating cancer comprising administering to a subject in need thereof a therapeutically effective amount of the compound of formula (I) according to any of claims 1 to 12, or a pharmaceutically acceptable salt thereof.

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