Thienyl and cycloalkylaminopyrimidine compounds as inhibitors of NUAK kinase, compositions and uses thereof

Abstract

This application relates to compounds of formula (I) or their pharma- ceutically acceptable salts, solvates and / or prodrugs, to compositions comprising these compounds or their pharma- ceutically acceptable salts, solvates and / or prodrugs, and to various uses in the treatment of diseases, disorders or conditions treatable by inhibiting or blocking NUAK kinase, such as cancer and fibrosis. JPEG2024502174000190.jpg86130

Description

[Technical field]

[0001] The present application relates to thienyl and cycloalkylaminopyrimidine compounds, methods for preparing the same, compositions comprising the same, and uses of the same in therapy. More particularly, the present application relates to thienyl and cycloalkylaminopyrimidine compounds useful in the treatment of diseases, disorders or conditions treatable by inhibiting or blocking NUAK kinase, such as cancer and fibrosis. [Background technology]

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 134,739, filed January 7, 2021, the disclosure of which is incorporated herein by reference in its entirety.

[0003] The Hippo signaling pathway, also known as the Salvador / Warts / Hippo pathway, controls organ size in animals by regulating cell proliferation and apoptosis. The pathway is named after one of its major signaling components identified in Drosophila, the protein kinase Hippo (Hpo), known in vertebrates as MST1 / 2. Mutations in this gene result in abnormal tissue growth, or a "hippo"-like phenotype. The Hippo signaling pathway regulates tissue growth and organogenesis in response to diverse extracellular cues, including cell contact and cytoskeletal rearrangements (Cell 2015,163,811; Cancer Cell 2016,29,783). Mechanistically, the transcriptional effectors YAP and TAZ are phosphorylated and thereby inhibited by a core cassette consisting of the tumor suppressor kinases MST and LATS. In most solid tumors, YAP / TAZ are uncoupled from the Hippo kinase cassette and thus constitutively present in the nucleus, driving a pro-oncogenic transcriptional program. YAP / TAZ activity promotes proliferation, migration, invasion, and maintenance of cancer stem cell traits (Cell 2015,163,811). Although active YAP / TAZ is a hallmark of cancer, pathway components are rarely mutated, and therefore there is an urgent need to identify new, targetable nodes. Compounds that restore pathway activity in vitro or in vivo have not been previously described.

[0004] Using systematic physical and functional screens, NUAK2 (previously called SNARK), a poorly studied AMPK family kinase but most closely related to NUAK1, was identified as a cancer-associated negative regulator of the Hippo pathway [Nat Commun. 2018,9(1):3510; Nat Commun. 2018,9(1):4834]. NUAK isoforms are ubiquitously expressed and have an N-terminal kinase domain (residues 55-306, NUAK1) followed by a C-terminal region that, although similar between NUAK1 and NUAK2, does not share distinct domains or homology with other proteins. Both NUAK1 and NUAK2 isoforms phosphorylate MYPT1 (myosin phosphatase target subunit 1) at Ser445. Suppressing NUAK2 expression using siRNA, shRNA, and CRISPR or pharmacologically inhibiting NUAK activity using commercially available tool compounds (WZ4003 or ON123300) in several cancer cell lines (1) results in blocking YAP / TAZ nuclear localization as determined using manual or automated immunofluorescence confocal microscopy (IF) and (2) attenuates transcriptional function as measured by PCR analysis of target gene expression [Nat Commun. 2018, 9(1):3510; Nat Commun. 2018, 9(1):4834]. Interestingly, YAP / TAZ can transcriptionally activate NUAK2 expression, revealing a feed-forward loop in which NUAK2 positively enhances the oncogenic activity of YAP / TAZ. Disrupting this oncogenic loop by inhibiting NUAK2 is therefore an attractive therapeutic target.

[0005] Recently, it has also been demonstrated that MYC-driven tumors are dependent on NUAK activity, and that intact function of the spliceosome is associated with their survival [Mol Cell. 2020, 77(6):1322-1339]. MYC drives gene expression required for cell growth and division and is deregulated in many tumors. MYC itself has been shown to be refractory to small molecule-based pharmacological intervention, shifting much of the focus of drug discovery efforts to other potential targets, specifically proteins or pathways that contribute to survival in cancer cells that have MYC amplification or that contain otherwise deregulated MYC. Depletion of NUAK1 by RNA interference (RNAi) induced apoptosis, particularly in osteosarcoma cells that overexpress MYC [Nature. 2012, 483(7391):608-12]. Reduced NUAK1 activity appears to impair splicing and lead to the accumulation of unspliced ​​transcripts by deregulating PNUTS-PP1β. These results suggest that deregulated MYC overrides checkpoint controls on transcription elongation, thereby bypassing splicing defects due to NUAK1 dysfunction that would otherwise lead to elongation arrest and / or premature termination, leading to the trapping of RNAP II in non-productive elongation complexes. Thus, in addition to regulating the hippo pathway in cancer, inhibition of NUAK activity may also play an important role in inhibiting MYC-driven tumor growth.

[0006] Accumulating evidence also indicates that YAP / TAZ functions in a cooperative manner with other established signaling pathways, in particular crosstalk with the TGFβ and Wnt signaling pathways (Am. J. Physiol. Lung Cell. Mol. Physiol. 2015, 309, L756-L767; Cell 2012, 151, 1443-1456). Importantly, in the context of cancer immunology, TGFβ has been shown to have a key role in regulating anti-tumor immune responses and contribute to resistance to anti-PD-1-PD-L1 treatment in cancer patients (ACS Med. Chem. Lett. 2018, 9, 1117). Thus, targeting the TGFβ pathway (by NUAK-YAP / TAZ inhibition) in combination with anti-PD1 or anti-PD-L1 antibodies may help overcome resistance and obtain more effective anti-tumor responses.

[0007] Another indication that could potentially benefit from inhibiting the NUAK-YAP / TAZ-TGFβ signaling axis is fibrosis. Fibrosis is a response to tissue or organ injury, such as chronic inflammation or chemical and mechanical injury. In pathological conditions, fibrosis progresses to an uncontrolled process characterized by the progressive accumulation of extracellular matrix (ECM), mainly collagen, which ultimately destroys normal organ architecture and leads to loss of organ function. A key step in fibrosis is the conversion of quiescent fibroblasts into active myofibroblasts that deposit extracellular matrix (ECM) and secrete TGFβ, the main driver of this activation process (Science 2002,296:1646-1647). Fibrosis, which affects several organs such as the liver, lungs, and kidneys, is responsible for up to 45% of deaths in industrialized societies (J.Clin.Invest.2007,117,524-529; Front.Pharmacol.2017,8,855). Current treatments are mostly supportive rather than curative, and there is an urgent need to identify agents with therapeutic potential to address this disease. NUAK inhibition, which regulates YAP / TAZ and TGFβ signaling, is a novel approach to treat fibrosis.

[0008] Previously reported NUAK inhibitor drugs lack potency and selectivity and are not ideal. This suggests that new, potent and selective NUAK inhibitor drugs are needed. Design efforts to identify compounds that bind to specific kinases such as NUAK may result in the inhibition of multiple kinase targets and may have therapeutic implications for compound safety. One such off-target kinase is Aurora kinase A (AurA), whose inhibition leads to undesirable adverse effects such as neutropenia and hematologic toxicity (Semin. Oncol. 2015, 42(6), 832-848). Thus, identifying compounds that are potent against NUAK kinase and more selective than AurA is a means to find ligands with reduced side effects.

[0009] For example, there remains a need to provide potent NUAK kinase inhibitors for the treatment of cancer and fibrosis. Additionally, there is a need to provide NUAK kinase inhibitors that have selectivity over other kinases, such as Aurora A kinase. Summary of the Invention

[0010] This application describes certain inhibitors of NUAK kinase (NUAK2 and / or NUAK1) and their use for the treatment of cancer and fibrosis by regulating the Hippo pathway. In addition, this application describes NUAK inhibitors that are selective compared to Aurora A inhibitors and therefore have improved safety and therapeutic potential.

[0011] Thus, this application encompasses compounds of formula I, or pharma- ceutically acceptable salts, solvates and / or prodrugs thereof. [ka] During the ceremony: A is, [ka] Selected from; * is the point of attachment for A in compounds of formula I; R 1 is selected from H, halo, C1-4 alkyl, OC1-4 alkyl, C1-4 haloalkyl, OC1-4 haloalkyl, CN, C1-4 hydroxyalkyl, and OC1-4 hydroxyalkyl; R 2 is selected from H, halo, CN, C1-4 alkyl, C1-4 haloalkyl, OC1-4 alkyl, and OC1-4 haloalkyl; R 3 is selected from C1-4 fluoroalkyl and OC1-4 fluoroalkyl; R 4 is selected from H, C1-4 alkyl, and C1-4 haloalkyl; R 5 and R 6 is independently selected from H, halo, CN, C1-4 alkyl, and C1-4 haloalkyl; X is CR a and N; Y is CR b and N; R a and R b is independently selected from H, halo, C1-4 alkyl, and C1-4 haloalkyl; Z is C1-6 alkylene NR 7 R 8 , OC1~6 alkylene NR 7 R 8 , N.R. 8 C1-6 alkylene NR 7 R 8 , N.R. 8 C1~6 alkylene OR 7 and N.R. 7 R 8 or Z and R 2and are bonded together with the atoms therebetween to form ring B selected from C3-13 cycloalkyl and C3-12 heterocycloalkyl, said ring B being selected from halo, =O, OH, C1-6 alkyl, C3-6 cycloalkyl, aryl, C5-6 heteroaryl, C3-6 heterocycloalkyl, C1-6 alkyleneC3-6 cycloalkyl, C1-6 alkylenearyl, C1-6 alkyleneC5-6 heteroaryl, C1-6 alkyleneC3-6 heterocycloalkyl, C(O)C1-6 alkyl, OC1-6 alkyl, OC1-6 alkyleneOC1-6 alkyl, C(O)NH2, C(O)NH(C1-6 alkyl), C(O)N(C1-6 alkyl)(C1-6 alkyl), NHC(O) optionally substituted by one or more substituents selected from C1-6 alkyl, N(C1-6 alkyl)C(O)C1-6 alkyl, NH2, NH(C1-6 alkyl), N(C1-6 alkyl)(C1-6 alkyl), SC1-6 alkyl, S(O)C1-6 alkyl and SO2C1-6 alkyl, and all alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups of the optional substituents on ring B are also optionally substituted by one or more of halo, C1-6 alkyl, OC1-6 alkyl, C1-6 haloalkyl and OC1-6 haloalkyl; R 7 is H, C1-6 alkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkylene C3-10 cycloalkyl, C1-6 alkylene C3-10 heterocycloalkyl, C1-6 alkyl alkylene OR 10 and C1-6 alkyl alkylene NR 10 R 11 Selected from R 7 all alkyl, alkenyl, alkynyl, alkylene, heterocycloalkyl and cycloalkyl groups are optionally substituted with one or more of halo, C1-6 alkyl and C1-6 haloalkyl; R 8is selected from H, C1-6 alkyl, and C1-6 haloalkyl; or R 7 and R 8 and are bonded together with the atoms therebetween to form a C3-12 heterocycloalkyl, and the C3-12 heterocycloalkyl is NR 12 , O, S, S(O) and SO2, and optionally containing one further hetero moiety selected from halo, =O, OH, C1-6 alkyl, C3-6 cycloalkyl, aryl, C5-6 heteroaryl, C3-6 heterocycloalkyl, C1-6 alkyleneC3-6 cycloalkyl, C1-6 alkylenearyl, C1-6 alkyleneC5-6 heteroaryl, C1-6 alkyleneC3-6 heterocycloalkyl, C(O)C1-6 alkyl, OC1-6 alkyl, OC1-6 alkylene, optionally substituted by one or more substituents selected from OC1-6 alkyl, C(O)NH2, C(O)NH(C1-6 alkyl), C(O)N(C1-6 alkyl)(C1-6 alkyl), NHC(O)C1-6 alkyl, N(C1-6 alkyl)C(O)C1-6 alkyl, NH2, NH(C1-6 alkyl), N(C1-6 alkyl)(C1-6 alkyl), SC1-6 alkyl, S(O)C1-6 alkyl and SO2C1-6 alkyl; R 7 and R 8 all alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups of the optional substituents on the C3-12 heterocycloalkyl formed by are also optionally substituted with one or more of halo, C1-6 alkyl, OC1-6 alkyl, C1-6 haloalkyl and OC1-6 haloalkyl; and R 9 , R 10 , R 11 and R 12 is independently selected from H, C1-6 alkyl, and C1-6 haloalkyl.

[0012] The present application also encompasses compositions comprising one or more compounds of the present application and a carrier and / or diluent, in some embodiments, the composition is a pharmaceutical composition comprising one or more compounds of the present application and a pharma- ceutically acceptable carrier and / or diluent.

[0013] In some embodiments, the compounds of the present application are used as a pharmaceutical. Thus, the present application also encompasses one or more compounds of the present application for use as a pharmaceutical.

[0014] The compounds of the present application have been shown to inhibit or block NUAK2 and / or NUAK1 (including NUAK2 and / or NUAK1 promoting the cytoplasmic localization of YAP / TAZ) and attenuate the transcriptional function of YAP / TAZ target gene expression. Thus, the compounds of the present application are useful for inhibiting NUAK2 and / or NUAK1 (more particularly NUAK2). Thus, the present application also encompasses a method of inhibiting NUAK2 and / or NUAK1, comprising administering an effective amount of one or more compounds of the present application to a cell or subject in need of inhibiting NUAK2 and / or NUAK1.

[0015] The present application also includes the use of one or more compounds of the present application for inhibiting NUAK2 and / or NUAK1 in a cell or a subject. The present application further includes one or more compounds of the present application for use in inhibiting NUAK2 and / or NUAK1 in a cell or a subject.

[0016] In some embodiments, the compounds of the present application are useful for treating a disease, disorder, or condition treatable by inhibiting NUAK2 and / or NUAK1 (more particularly NUAK2). Accordingly, the present application also encompasses a method of treating a disease, disorder, or condition treatable by inhibiting NUAK2 and / or NUAK1, comprising administering to a cell or subject in need of treatment a therapeutically effective amount of one or more compounds of the present application.

[0017] The present application also encompasses the use of one or more compounds of the present application for the treatment of a disease, disorder or condition treatable by inhibiting NUAK2 and / or NUAK 1, as well as the use of one or more compounds of the present application for the preparation of a medicament for the treatment of a disease, disorder or condition treatable by inhibiting NUAK2 and / or NUAK 1. The present application further encompasses one or more compounds of the present application for use in the treatment of a disease, disorder or condition treatable by inhibiting NUAK2 and / or NUAK1.

[0018] In some embodiments, the disease, disorder, or condition treatable by inhibiting NUAK2 and / or NUAK1 is a neoplastic disorder. In some embodiments, the treatment comprises the administration or use of one or more compounds of the present application in an amount effective to alleviate at least one symptom of the neoplastic disorder, e.g., reduce cell proliferation or reduce tumor burden, in a subject in need of treatment.

[0019] In some embodiments, the disease, disorder or condition treatable by inhibiting NUAK2 and / or NUAK1 is cancer, hi some embodiments, the cancer is selected from solid cancers such as breast cancer, colon cancer, bladder cancer, skin cancer, head and neck cancer, liver cancer, bone cancer and glioblastoma.

[0020] In some embodiments, the disease, disorder or condition treatable by inhibiting NUAK2 and / or NUAK1 is fibrosis. Fibrosis is a response to tissue or organ injury, such as chronic inflammation or chemical and mechanical injury. In pathological conditions, fibrosis progresses to an uncontrolled process characterized by progressive accumulation of extracellular matrix (ECM), mainly collagen, that eventually destroys normal organ architecture and leads to loss of organ function. The relevant step in fibrosis is the conversion of quiescent fibroblasts into active myofibroblasts that deposit extracellular matrix (ECM) and secrete TGFβ, the main driver of this activation process (Science 2002,296:1646-1647). Fibrosis affects several organs, such as the liver, lungs, and kidneys.

[0021] In some embodiments, the fibrosis is selected from fibrotic diseases such as renal fibrosis, pulmonary fibrosis, and hepatic fibrosis.

[0022] In some embodiments, the treatment involves administration or use of one or more compounds of the present application in an amount effective to alleviate at least one symptom of fibrosis, e.g., reduce accumulation of extracellular matrix (ECM), such as collagen, in a subject in need of treatment.

[0023] In some embodiments, the disease, disorder or condition treatable by inhibiting NUAK2 and / or NUAK1 is a disease, disorder or condition associated with unregulated and / or abnormal cellular activity that is affected directly or indirectly by inhibiting NUAK2 and / or NUAK1. In certain other embodiments, the unregulated and / or abnormal cellular activity that is affected directly or indirectly by inhibiting NUAK2 and / or NUAK1 is proliferative activity in cells.

[0024] In some embodiments, the present application also encompasses a method of inhibiting proliferative activity in a cell, comprising administering to the cell an effective amount of one or more compounds of the present application.

[0025] In some embodiments, the disease, disorder or condition treatable by inhibiting NUAK2 and / or NUAK1 is cancer and / or fibrosis, and one or more compounds of the present application are administered or used in combination with one or more additional cancer and / or anti-fibrosis therapies, hi certain other embodiments, the additional therapies are selected from one or more of radiation therapy, chemotherapy, targeted therapies such as antibody therapy (including anti-PD1 and / or anti-PD-L1 antibodies), and small molecule therapies such as tyrosine kinase inhibitor therapy, immunotherapy, hormonal therapy, and anti-angiogenic therapy.

[0026] The present application further includes methods of preparing the compounds of the present application, the general and specific processes being described in more detail in the Examples below.

[0027] In some embodiments, the present application provides: (a) under basic conditions, a substituted dichloropyrimidine of formula A, 1 is as defined in formula I or a protected version thereof) with an ortho-aminocarboxamide of formula B, 4 and ring A is as defined in formula I or a protected version thereof) to provide a compound of formula D: [ka] (b) reacting a compound of formula D with an aniline of formula E, where R 2 , R 3 wherein X, Y and Z are as defined in formula I or a protected version thereof, to give, after removal of the protecting groups if necessary, a compound of formula I: [ka] The present invention also includes a method for preparing the compounds of the present application, comprising:

[0028] Other features and advantages of the present application will become apparent from the following detailed description. However, the detailed description and specific examples, although showing embodiments of the present application, are given only as examples, and it should be understood that the claims should not be limited by these embodiments, but should be given the broadest interpretation consistent with the entire specification. [Brief description of the drawings]

[0029] The present application will now be described in more detail with reference to the accompanying drawings, in which:

[0030] [Figure 1] FIG. 1 shows the results of YAP / TAZ nuclear localization in cellular assays performed for exemplary compound I-1 and prior art compound WZ-4003.

[0031] [Diagram 2] FIG. 2 shows the results of a cellular pMYPT1 assay performed on exemplary compound I-1. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0032] I. Definition Unless otherwise stated, the definitions and embodiments described in this section and other sections are intended to be applicable to all embodiments and aspects of the present application described in this disclosure as understood by those of skill in the art to be suitable.

[0033] This application makes reference to many chemical terms and abbreviations used by those of skill in the art. Nonetheless, for clarity and consistency, definitions of selected terms are provided.

[0034] As used in this disclosure, the words "comprising" (and any form of comprising, such as "comprising" (present tense) (with or without s attached to the third person singular)), "having" (and any form of having, such as "having" (present tense) (with or without s attached to the third person singular)), "including" (and any form of including, such as "including" (present tense) (with or without s attached to the third person singular)), and "containing" (and any form of containing, such as "including" (present tense) (with or without s attached to the third person singular)) are inclusive and open-ended and do not exclude additional, unrecited elements or process / method steps.

[0035] As used in this disclosure, the word "consisting of" and its derivatives are intended to be closed terminology that specifies the presence of stated features, elements, components, groups, integers, and / or steps and excludes the presence of other, unrecited features, elements, components, groups, integers, and / or steps.

[0036] As used in this disclosure, the term "consisting essentially of" is intended to specify the presence of stated features, elements, components, groups, integers, and / or steps, and that do not materially affect the basic and novel characteristic(s) of those features, elements, components, groups, integers, and / or steps.

[0037] As used in this disclosure, terms of degree such as "substantially," "about," and "approximately" refer to a reasonable amount of deviation from the modified word such that the end result is not significantly changed. These terms of degree should be construed to include deviations of at least ±5% from the modified word, provided that the deviation does not negate the meaning of the word it modifies.

[0038] As used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. For example, an embodiment including "a compound" should be understood to present an aspect having one compound, or an aspect having two or more additional compounds. In an embodiment including an "additional" or "second" component, e.g., an additional or second compound, the second component, as referred to in this disclosure, is chemically distinct from the other components or the first component. A "third" component is distinct from the other first and second components, and further listed or "additional" components are similarly distinct.

[0039] As used in this disclosure, the term "and / or" means that the listed items are present or used either individually or in any combination. In effect, the term means that "at least one" or "one or more" of the listed items are used or present.

[0040] Unless otherwise noted herein or understood otherwise by one of ordinary skill in the art, the nomenclature used herein generally follows the examples and rules set forth in "Nomenclature of Organic Chemistry" (Pergamon Press, 1979), Sections A, B, C, D, E, F, and H. Optionally, compound names may be generated using the chemical naming program ACD / ChemSketch, version 5.09 / September 2001 (Advanced Chemistry Development, Inc., Toronto, Canada).

[0041] As used in this disclosure, the term "compounds of the present application" and similar terms refer to compounds of Formula I, including pharma- ceutically acceptable salts, solvates, and / or prodrugs thereof.

[0042] As used in this disclosure, the term "composition of the present application" and like terms refer to a composition that includes one or more compounds of the present application and at least one additional component.

[0043] As used in this disclosure, the term "suitable" ("preferred") means that the selection of a particular compound or condition will depend on the particular synthetic operation to be performed and the species to be converted, but that the selection is well within the skill of the skilled artisan. All chemical synthesis method steps described in this disclosure are to be performed under conditions sufficient to provide the desired product. Those skilled in the art will understand, and it is within the skill of the skilled artisan to do so, that all reaction conditions, such as reaction solvent, reaction time, reaction temperature, reaction pressure, reactant ratios, whether the reaction should be performed in anhydrous or inert atmosphere, etc., can be varied to maximize the yield of the desired product.

[0044] The compounds described in this disclosure may have at least one asymmetric center. When a compound has two or more asymmetric centers, the compound may exist as diastereomers. It should be understood that all such isomers and their mixtures in any ratio are encompassed within the scope of this application. The stereochemistry of a compound may be as shown in a given compound listed in this disclosure, but it should be further understood that the compound may contain a certain amount (e.g., less than 20%, suitably less than 10%, more suitably less than 5%) of the same compound of this application having an alternative stereochemistry. Any optical isomer as a separated, pure or partially purified optical isomer, or a racemic mixture thereof, is intended to be encompassed within the scope of this application.

[0045] The compounds of the present application may exist in various tautomeric forms, and any tautomeric forms that the compounds form are intended to be included within the scope of the present application.

[0046] The compounds of the present application may exist in different polymorphic forms, and all such polymorphic forms are intended to be included within the scope of the present application.

[0047] As used in this disclosure, the term "protecting group" or "PG" and similar terms refer to a chemical moiety that protects or masks reactive portions of a molecule to prevent side reactions at those reactive portions of the molecule while manipulating or reacting different portions of the molecule. After the manipulation or reaction is complete, the protecting group is removed under conditions that do not destroy or degrade the remaining portions of the molecule. Selection of an appropriate protecting group can be made by one of ordinary skill in the art. Many conventional protecting groups are known in the art and can be found, for example, in "Protective Groups in Organic Chemistry" McOmie, JFW Ed., Plenum Press, 1973, in Greene, TW and Wuts, PGM, "Protective Groups in Organic Synthesis", John Wiley & Sons, 3 rd Edition, 1999 and in Kocienski, P. Protecting Groups, 3rd Edition, 2003, Georg Thieme Verlag (The Americas).

[0048] As used in this disclosure, the term "cell" refers to a single cell or multiple cells, including cells in cell culture or in a subject.

[0049] As used in this disclosure, the term "subject" includes all members of the animal kingdom, including mammals, and thus the methods and uses of the present application are applicable to both human therapeutic applications and veterinary applications.

[0050] The term "pharmaceutical acceptable" means compatible with the treatment of a subject.

[0051] The term "pharmaceutical acceptable carrier" refers to a non-toxic solvent, dispersant, excipient, adjuvant or other material with which an active ingredient (e.g., one or more compounds of the present application) can be mixed to form a pharmaceutical composition, i.e., a dosage form that can be administered to a subject.

[0052] The term "pharmaceutical acceptable salt" means an acid addition salt or a base addition salt which is suitable or compatible with the treatment of a subject.

[0053] Suitable or compatible acid addition salts for the treatment of subjects are any non-toxic organic or inorganic acid addition salts of any basic compound. Basic compounds that form acid addition salts include, for example, compounds that contain amine groups. Exemplary inorganic acids that form suitable salts include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid, as well as acid metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate. Exemplary organic acids that form suitable salts include monocarboxylic acids, dicarboxylic acids, and tricarboxylic acids. Examples of such organic acids are, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, mandelic acid, salicylic acid, 2-phenoxybenzoic acid, p-toluenesulfonic acid, and other sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, and 2-hydroxyethanesulfonic acid. Monoacid salts may be formed, or diacid salts may be formed, or such acids may be present in either hydrated, solvated, or substantially anhydrous form. In general, acid addition salts are more soluble in water and various hydrophilic organic solvents than their free base forms, and generally exhibit higher melting points. The criteria for selecting an appropriate salt will be known to those skilled in the art. Other pharma-ceutically unacceptable salts, such as, but not limited to, oxalates, may be used, for example, in the isolation of compounds of the present application for experimental use, or for subsequent conversion to a pharma-ceutically acceptable acid addition salt.

[0054] Suitable or compatible base addition salts for the treatment of subjects are any non-toxic organic or inorganic base addition salts of any acidic compound. Acidic compounds that form base addition salts include, for example, compounds containing a carboxylic acid group. Exemplary inorganic bases that form suitable salts include lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, or barium hydroxide, as well as ammonia. Exemplary organic bases that form suitable salts include aliphatic, alicyclic, or aromatic organic amines such as isopropylamine, methylamine, trimethylamine, picoline, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, EGFRaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. Exemplary organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine [see, for example, S. M. Berge, et al., "Pharmaceutical Salts," J. Pharm. Sci. 1977, 66, 1-19]. Selection of an appropriate salt can be useful in preventing the hydrolysis of ester functional groups, if any, on other parts of the compound. The criteria for selecting an appropriate salt will be known to those skilled in the art.

[0055] Prodrugs of the compounds of the present application may be, for example, conventional esters formed with available hydroxy, thiol, amino, or carboxyl groups. Some common esters that have been utilized as prodrugs are phenyl esters, aliphatic (C1-C24) esters, acyloxymethyl esters, carbamates, and amino acid esters.

[0056] As used in this disclosure, the term "solvate" refers to a compound or a salt or prodrug of a compound, in which molecules of a suitable solvent are incorporated into the crystal lattice. A suitable solvent is physiologically acceptable at the administered dosage. Examples of suitable solvents are ethanol, water, etc. When water is the solvent, the molecule is referred to as a "hydrate."

[0057] As used in this disclosure, the term "inert organic solvent" refers to a solvent that is generally considered to be non-reactive with the functional groups present in the compounds being coupled in any given reaction, and thus does not interfere with or inhibit the desired synthetic transformation. Organic solvents are typically non-polar and will dissolve compounds that are insoluble in aqueous solutions.

[0058] As used herein, the term "alkyl" refers to a saturated straight or branched chain alkyl group, whether used alone or as part of another group. The number of possible carbon atoms in the alkyl group of interest is represented by the prefix "Cn1-Cn2". For example, the term "C1-6 alkyl" refers to an alkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms. Unless otherwise noted, all alkyl groups are optionally fluoro-substituted.

[0059] The term "alkylene", whether used alone or as part of another group, refers to a linear or branched saturated alkylene group, i.e., a saturated carbon chain containing substituents at two of its termini. The possible number of carbon atoms in the alkylene group in question is indicated by the prefix "Cn1-n2". For example, the term "C1-10 alkylene" refers to an alkylene group having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.

[0060] As used herein, the term "alkenyl", whether used alone or as part of another group, refers to a straight or branched chain unsaturated alkyl group containing at least one double bond. The number of possible carbon atoms in the alkylene group of interest is represented by the prefix "Cn1-n2". Thus, for example, the term "C2-6 alkenyl" refers to an alkenyl group having 2, 3, 4, 5, or 6 carbon atoms and at least one double bond.

[0061] As used herein, the term "alkynyl", whether used alone or as part of another group, refers to a straight or branched chain unsaturated alkynyl group containing at least one triple bond. The number of possible carbon atoms in the alkyl group of interest is represented by the prefix "Cn1-n2". For example, the term C2-6 alkynyl refers to an alkynyl group having 2, 3, 4, 5, or 6 carbon atoms.

[0062] As used herein, the term "cycloalkyl", whether used alone or as part of another group, refers to a saturated carbocyclic group containing 3-10 carbon atoms and one or more rings. The number of possible carbon atoms in a given cycloalkyl group is represented by the prefix "Cn1-n2". For example, the term C3-10 cycloalkyl refers to a cycloalkyl group having 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms.

[0063] As used herein, the term "aryl," whether used alone or as part of another group, refers to a carbocyclic group containing at least one aromatic ring and containing from 6 to 10 carbon atoms.

[0064] As used herein, the term "heterocycloalkyl", whether used alone or as part of another group, refers to a cyclic group that includes at least one non-aromatic ring containing 3-10 atoms, one or more of which are heteroatoms selected from O, S, and N, and the remaining atoms are C. Heterocycloalkyl groups can be saturated or unsaturated (i.e., containing one or more double bonds). When a heterocycloalkyl group includes the prefix Cn1-n2, the prefix represents the number of carbon atoms in the corresponding carbocyclic group, where one or more, preferably 1-5, of the ring atoms are replaced by a heteroatom as defined above. Heterocycloalkyl groups are optionally benzo-fused.

[0065] As used herein, the term "heteroaryl", whether used alone or as part of another group, refers to a cyclic group containing at least one heteroaromatic ring containing 5-10 atoms, one or more of which are heteroatoms selected from O, S, and N, and the remaining atoms are C. When a heteroaryl group contains the prefix Cn1-n2, the prefix represents the number of carbon atoms in the corresponding carbocyclic group, where one or more, preferably 1-5, of the ring atoms are replaced by a heteroatom as defined above. The heteroaryl group is optionally benzo-fused.

[0066] All cyclic groups, including aryl, heteroaryl, heterocycloalkyl, and cycloalkyl groups, contain one ring (i.e., monocyclic) or multiple rings (i.e., polycyclic). When a cyclic group contains multiple rings, the multiple rings can be fused, bridged, or spiro-fused.

[0067] As used in this disclosure, the term "benzo-fused" refers to a polycyclic group in which a benzene ring is fused to other rings.

[0068] A first ring is "fused" to a second ring means that the first ring and the second ring share two adjacent atoms between each other.

[0069] A first ring is "bridged" to a second ring means that the first ring and the second ring share two non-adjacent atoms between each other.

[0070] A first ring is "spirofused" to a second ring means that the first ring and the second ring share one atom between each other.

[0071] The term "fluoro-substituted" means that one or more, including all, of the available hydrogen atoms in the group in question have been replaced with fluorine.

[0072] The term "halo-substituted" means that one or more, including all, of the available hydrogen atoms in the group in question have been replaced with a halogen.

[0073] The term "hydroxy-substituted" means that one or more, including all, of the available hydrogen atoms in the group in question have been replaced with a hydroxyl (OH).

[0074] As used in this disclosure, the terms "halo" or "halogen," whether used alone or as part of another group, refer to a halogen atom and include fluoro, chloro, bromo, and iodo.

[0075] The term "available" in "available hydrogen atom" or "available atom" refers to an atom that would be known to one of ordinary skill in the art to be replaceable by another atom or group.

[0076] As used in this disclosure, the term "optionally substituted" means that the group it refers to is unsubstituted or substituted.

[0077] As used in this disclosure, the term "atm" refers to standard atmosphere.

[0078] As used in this disclosure, the term "MS" stands for mass spectrometry.

[0079] As used in this disclosure, the term "LCMS" refers to liquid chromatography mass spectrometry.

[0080] As used in this disclosure, the term "LRMS" stands for low resolution mass spectrometry.

[0081] As used in this disclosure, the term "NMR" stands for nuclear magnetic resonance.

[0082] As used in this disclosure, the term "aq." stands for aqueous.

[0083] As used in this disclosure, the term "N", for example in "4N", represents the unit symbol for normality indicating "equivalents / L".

[0084] As used in this disclosure, the term "M," such as in "4M," represents the unit symbol for molar concentration indicating "moles / L."

[0085] As used in this disclosure, the term "DCM" refers to dichloromethane.

[0086] As used in this disclosure, the term "DIPEA" refers to N,N-diisopropylethylamine.

[0087] As used in this disclosure, the term "DMF" refers to dimethylformamide.

[0088] As used in this disclosure, the term "THF" refers to tetrahydrofuran.

[0089] As used in this disclosure, the term "DMSO" refers to dimethylsulfoxide.

[0090] As used in this disclosure, the term "EtOAc" refers to ethyl acetate.

[0091] As used in this disclosure, the term "MeOH" refers to methanol.

[0092] As used in this disclosure, the term "EtOH" refers to ethanol.

[0093] As used in this disclosure, the term "AcOH" refers to acetic acid.

[0094] As used in this disclosure, the term "MeCN" or "ACN" refers to acetonitrile.

[0095] As used in this disclosure, the term "HCl" refers to hydrochloric acid.

[0096] As used in this disclosure, the term "TFA" refers to trifluoroacetic acid.

[0097] As used in this disclosure, the term "TFAA" stands for trifluoroacetic anhydride.

[0098] As used in this disclosure, the term "TfO" refers to trifluoromethanesulfonic anhydride, also known as triflic anhydride.

[0099] As used in this disclosure, the term "CV" stands for column volume.

[0100] As used in this disclosure, the term "Hex" refers to hexane.

[0101] As used in this disclosure, the term "PBS" refers to phosphate buffered saline.

[0102] As used in this disclosure, the term "IPA" refers to isopropyl alcohol.

[0103] As used in this disclosure, the term "HATU" refers to 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate, also known as azabenzotriazole tetramethyluronium hexafluorophosphate.

[0104] As used in this disclosure, the term "N-Boc" refers to a tert-butoxycarbonyl protecting group.

[0105] As used in this disclosure, the term "dba" refers to dibenzyl acetone.

[0106] As used in this disclosure, the term "dppf" refers to 1,1'-bis(diphenylphosphino)ferrocene.

[0107] As used in this disclosure, the term "RT" refers to room temperature.

[0108] As used in this disclosure, the term "DCE" refers to 1,2-dichloroethane.

[0109] As used in this disclosure, the term "TPP" refers to triphenylphosphine.

[0110] As used in this disclosure, the term "TLC" stands for thin layer chromatography.

[0111] As used in this disclosure, the term "HPLC" refers to high performance liquid chromatography.

[0112] As used in this disclosure, the term "PPA" refers to polyphosphoric acid.

[0113] As used in this disclosure, the term "TEA" or "Et3N" refers to triethylamine.

[0114] As used in this disclosure, the term "DMAP" refers to 4-dimethylaminopyridine.

[0115] As used in this disclosure, the term "MOPS" refers to 3-(N-morpholino)propanesulfonic acid.

[0116] As used in this disclosure, the term "EDTA" refers to ethylenediaminetetraacetic acid.

[0117] As used in this disclosure, the term "ATP" refers to adenosine triphosphate.

[0118] As used in this disclosure, the term "FBS" refers to fetal bovine serum.

[0119] As used in this disclosure, the term "MEM" stands for minimum essential medium.

[0120] As used in this disclosure, the term "treat" or "treatment" refers to an approach for obtaining beneficial or desired results, such as clinical results, as is well known in the art. Beneficial or desired clinical results may include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, reduction in the severity of a disease, disorder or condition, a stabilized (i.e., not worsening) state of a disease, disorder or condition, prevention of the spread of a disease, disorder or condition, delay or slowing of the progression of a disease, disorder or condition, improvement or palliation of the state of a disease, disorder or condition, reduction in recurrence of a disease, disorder or condition, and remission (whether partial or complete), which may be detectable or undetectable. "Treat" and "treatment" may also refer to an increased survival time compared to the expected survival time in the absence of treatment. As used in this disclosure, "treat" and "treatment" also encompass prophylactic measures.

[0121] "Palliating" a disease, disorder, or condition means that the severity and / or undesirable clinical manifestations of the disease, disorder, or condition are reduced and / or the time course of progression is slowed or prolonged compared to if the disease, disorder, or condition is not treated.

[0122] As used in this disclosure, the term "prevention" or "prophylaxis," or synonyms thereof, as used in this disclosure, refers to a reduction in the risk or probability of a patient suffering from a disease, disorder, or condition treatable by inhibition of NUAK2 and / or NUAK1, or the risk or probability of exhibiting symptoms associated with a disease, disorder, or condition treatable by inhibition of NUAK2 and / or NUAK1.

[0123] As used in this disclosure, the term "effective amount" or "therapeutically effective amount" means an amount of a compound of the present application, or one or more compounds of the present application, effective, at dosages and for periods of time necessary, to achieve the desired result.

[0124] As used in this disclosure, the phrase "inhibiting NUAK2 and / or NUAK1" refers to inhibiting, blocking, and / or disrupting the kinase activity or function of NUAK2 and / or NUAK1 in a cell, which inhibits, blocks, and / or disrupts, causing a therapeutic effect in the cell.

[0125] By "inhibiting, blocking and / or destroying" is meant any detectable inhibition, blocking and / or destruction in the presence of a compound compared to otherwise identical conditions in the absence of the compound.

[0126] As used in this disclosure, the term "NUAK" refers to the NUAK family SNF1-like kinases 1 and 2, also known as AMPK-related protein kinase 5 (ARK5) or SNARK, respectively, or any functional mutant or analog thereof.

[0127] As used in this disclosure, the term "administered" means administration of a therapeutically effective amount of a compound of the present application, or one or more compounds of the present application, or a composition of the present application, to a cell or a subject.

[0128] As used in this disclosure, the term "neoplastic disorder" refers to a disease, disorder, or condition characterized by cells capable of autonomous growth or replication, e.g., an abnormal state or condition characterized by proliferative cell growth. As used in this disclosure, the term "neoplasm" refers to a mass of tissue resulting from the abnormal proliferation and / or division of cells in a subject with a neoplastic disorder. Tumors can be benign (such as uterine fibroids and pigmented nevi), potentially malignant (carcinoma in situ), or malignant (i.e., cancer).

[0129] As used in this disclosure, the term "fibrosis" refers to a disease, disorder or condition that is the thickening and scarring of connective tissue, usually resulting from injury.

[0130] I. Compound The present application encompasses compounds of Formula I, or pharma- ceutically acceptable salts, solvates and / or prodrugs thereof. [ka] During the ceremony: A is, [ka] Selected from; * is the point of attachment for A in compounds of formula I; R 1 is selected from H, halo, C1-4 alkyl, OC1-4 alkyl, C1-4 haloalkyl, OC1-4 haloalkyl, CN, C1-4 hydroxyalkyl, and OC1-4 hydroxyalkyl; R 2is selected from H, halo, CN, C1-4 alkyl, C1-4 haloalkyl, OC1-4 alkyl, and OC1-4 haloalkyl; R 3 is selected from C1-4 fluoroalkyl and OC1-4 fluoroalkyl; R 4 is selected from H, C1-4 alkyl, and C1-4 haloalkyl; R 5 and R 6 is independently selected from H, halo, CN, C1-4 alkyl, and C1-4 haloalkyl; X is CR a and N; Y is CR b and N; R a and R b is independently selected from H, halo, C1-4 alkyl, and C1-4 haloalkyl; Z is C1-6 alkylene NR 7 R 8 , OC1~6 alkylene NR 7 R 8 , N.R. 9 C1-6 alkylene NR 7 R 8 , N.R. 9 C1~6 alkylene OR 7 and N.R. 7 R 8 or Z and R 2and are bonded together with the atoms therebetween to form ring B selected from C3-12 cycloalkyl and C3-12 heterocycloalkyl, said ring B being selected from halo, =O, OH, C1-6 alkyl, C3-6 cycloalkyl, aryl, C5-6 heteroaryl, C3-6 heterocycloalkyl, C1-6 alkylene C3-6 cycloalkyl, C1-6 alkylene aryl, C1-6 alkylene C5-6 heteroaryl, C1-6 alkylene C3-6 heterocycloalkyl, C(O)C1-6 alkyl, OC1-6 alkyl, OC1-6 alkylene OC1-6 alkyl, C(O)NH2, C(O)NH(C1-6 alkyl), C(O)N(C1-6 alkyl)(C1-6 alkyl), NHC(O) optionally substituted by one or more substituents selected from C1-6 alkyl, N(C1-6 alkyl)C(O)C1-6 alkyl, NH2, NH(C1-6 alkyl), N(C1-6 alkyl)(C1-6 alkyl), SC1-6 alkyl, S(O)C1-6 alkyl and SO2C1-6 alkyl, and all alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups of the optional substituents on ring B are also optionally substituted by one or more of halo, C1-6 alkyl, OC1-6 alkyl, C1-6 haloalkyl and OC1-6 haloalkyl; R 7 is H, C1-6 alkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkylene C3-10 cycloalkyl, C1-6 alkylene C3-10 heterocycloalkyl, C1-6 alkyl alkylene OR 10 and C1-6 alkyl alkylene NR 10 R 11 Selected from R 7 all alkyl, alkenyl, alkynyl, alkylene, heterocycloalkyl and cycloalkyl groups are optionally substituted with one or more of halo, C1-6 alkyl and C1-6 haloalkyl; R 8is selected from H, C1-6 alkyl, and C1-6 haloalkyl; or R 7 and R 8 and are bonded together with the atoms therebetween to form a C3-12 heterocycloalkyl, and the C3-12 heterocycloalkyl is NR 12 , O, S, S(O) and SO2, and optionally containing one further hetero moiety selected from halo, =O, OH, C1-6 alkyl, C3-6 cycloalkyl, aryl, C5-6 heteroaryl, C3-6 heterocycloalkyl, C1-6 alkyleneC3-6 cycloalkyl, C1-6 alkylenearyl, C1-6 alkyleneC5-6 heteroaryl, C1-6 alkyleneC3-6 heterocycloalkyl, C(O)C1-6 alkyl, OC1-6 alkyl, OC1-6 alkylene, optionally substituted by one or more substituents selected from OC1-6 alkyl, C(O)NH2, C(O)NH(C1-6 alkyl), C(O)N(C1-6 alkyl)(C1-6 alkyl), NHC(O)C1-6 alkyl, N(C1-6 alkyl)C(O)C1-6 alkyl, NH2, NH(C1-6 alkyl), N(C1-6 alkyl)(C1-6 alkyl), SC1-6 alkyl, S(O)C1-6 alkyl and SO2C1-6 alkyl; R 7 and R 8 all alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups of the optional substituents on the C3-12 heterocycloalkyl formed by are also optionally substituted with one or more of halo, C1-6 alkyl, OC1-6 alkyl, C1-6 haloalkyl and OC1-6 haloalkyl; and R 9 , R 10 , R 11 and R 12 is independently selected from H, C1-6 alkyl, and C1-6 haloalkyl.

[0131] In some embodiments, R 1is selected from H, Cl, F, Br, I, CN, CH, CHOH, OCH, OCF, OCFH, OCHF, CF, CFH, and CHF. In some embodiments, R 1 is selected from Cl, CH3, and CF3. In some embodiments, R 1 is selected from Cl and CF3.

[0132] In some embodiments, R 2 is selected from H, F, Cl, CN, and CH3. In some embodiments, R 2 is selected from H and F.

[0133] In some embodiments, R 3 is selected from CF, CFH, CHF, OCF, OCHF, and OCHF. In some embodiments, R 3 is selected from CF3 and OCHF2. In some embodiments, R 3 is OCHF2.

[0134] In some embodiments, R 4 is selected from H and CH. In some embodiments, R 4 is H.

[0135] In some embodiments, R 5 and R 6 is independently selected from H and CH. In some embodiments, R 5 and R 6 is H.

[0136] In some embodiments, X is selected from CH, N, CF, and CCH. In some embodiments, X is CH.

[0137] In some embodiments, Y is selected from CH, N, CF, and CCH. In some embodiments, Y is selected from CH and CF.

[0138] In some embodiments, Z is C alkyleneNR 7 R 8 , OC1~4 alkylene NR 7 R 8 , N.R. 9 C1-4 alkylene NR 7 R 8 , N.R. 9 C1~4 alkylene OR 7 and N.R. 7 R 8 Selected from R 7 , R 8 and R 9 is independently selected from H and C1-6 alkyl.

[0139] In some embodiments, Z is C alkyleneNR 7 R 8 , OC1~4 alkylene NR 7 R 8 , N.R. 9 C1-4 alkylene NR 7 R 8 , N.R. 9 C1~4 alkylene OR 7 and N.R. 7 R 8 Selected from R 7 and R 8 and are bonded together with the atoms therebetween to form a C4-12 heterocycloalkyl, and the C4-12 heterocycloalkyl is NR 12 , O and S, and is optionally substituted by one or more of halo and C1-6 alkyl.

[0140] In some embodiments, Z is NR 7 R 8 and R 7 and R 8 and are bonded together with the atoms therebetween to form a C4-12 heterocycloalkyl, and the C4-12 heterocycloalkyl is NR 12, O, and S, and optionally substituted by one or two substituents selected from halo, ═O, C alkyl, C cycloalkyl, C heterocycloalkyl, NH(C alkyl), N(C alkyl)(C alkyl), SC alkyl, S(O)C alkyl, and SO2C alkyl; R 7 and R 8 All alkyl, cycloalkyl, and heterocycloalkyl groups of the optional substituents on the C4-12 heterocycloalkyl formed by are also optionally substituted by one or more of halo, C1-6 alkyl, OC1-6 alkyl, C1-6 haloalkyl, and OC1-6 haloalkyl.

[0141] In some embodiments, Z is NR 7 R 8 and R 7 and R 8 and are bonded together with the atoms therebetween to form a C5-11 heterocycloalkyl, and the C5-11 heterocycloalkyl is NR 12 and O, and optionally substituted by one substituent selected from halo, ═O, C1-4 alkyl, C3-6 cycloalkyl, C3-6 heterocycloalkyl, NH(C1-4 alkyl) and N(C1-4 alkyl)(C1-4 alkyl); R 7 and R 8 All alkyl, cycloalkyl, and heterocycloalkyl groups of the optional substituents on the C5-11 heterocycloalkyl formed by are also optionally substituted with 1 to 3 of fluoro, C1-4 alkyl, OC1-4 alkyl, C1-4 fluoroalkyl, and OC1-4 fluoroalkyl.

[0142] In some embodiments, Z is [ka] wherein R c is selected from H and C1-6 alkyl, and * is the point of attachment for Z in compounds of formula I.

[0143] In some embodiments, R 7 is selected from H, CH3, CH2CH3, CH(CH3)2, C(CH3)3, CF3, CH2CF3, and (CH2)2OCH3.

[0144] In some embodiments, R 8 is selected from H and CH3.

[0145] In some embodiments, R 9 , R 10 , R 11 and R 12 is independently selected from H and CH3.

[0146] In some embodiments, Z and R 2and form, together with the atoms therebetween, a ring B selected from a C5-10 cycloalkyl and a C5-10 heterocycloalkyl, said ring B being selected from halo, ═O, C1-4 alkyl, C3-6 cycloalkyl, aryl, C5-6 heteroaryl, C3-6 heterocycloalkyl, C1-4 alkyleneC3-6 cycloalkyl, C1-4 alkylenearyl, C1-4 alkyleneC5-6 heteroaryl, C1-4 alkyleneC3-6 heterocycloalkyl, C(O)C1-4 alkyl, OC1-4 alkyleneOC1-4 alkyl, C(O)NH2, C(O)NH(C1-4 alkyl), C(O)N(C1-4 alkyl)(C1-4 alkyl), NHC(O)C1 1-4 alkyl, N(C1-4 alkyl)C(O)C1-4 alkyl, NH2, NH(C1-4 alkyl), N(C1-4 alkyl)(C1-4 alkyl), SC1-4 alkyl, S(O)C1-4 alkyl, and SO2C1-4 alkyl, and all alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups of the optional substituents on ring B are also optionally substituted with one or more of halo, C1-4 alkyl, OC1-4 alkyl, C1-4 fluoroalkyl, and OC1-4 fluoroalkyl. In some embodiments, ring B is selected from C5-7 cycloalkyl and C5-8 heterocycloalkyl optionally substituted with one or more substituents selected from halo, ═O, and C1-4 alkyl.

[0147] In some embodiments, ring B is [ka] wherein R d is selected from H and C1-6 alkyl, and * is the point of attachment for ring B in compounds of formula I.

[0148] In some embodiments, [ka] teeth, [ka] is selected from the group consisting of [ka] is the point of attachment for this group in compounds of formula I.

[0149] In some embodiments, the compound of formula I is [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9]

Table 1-10

Table 1-11

Table 1-12

Table 1-13

Table 1-14

Table 1-15

Table 1-16

Table 1-17

Table 1-18

Table 1-19

Table 1-20

Table 1-21

Table 1-22

Table 1-23

[0150] In some embodiments, the compound of formula I is [Table 1-30] [Table 1-31] [Table 1-32] [Table 1-33] [Table 1-34] [Table 1-35] [Table 1-36] [Table 1-37] [Table 1-38] or a pharma- ceutically acceptable salt, solvate and / or prodrug thereof.

[0151] In some embodiments, the compound of formula I is [Table 1-39] [Table 1-40] [Table 1-41] [Table 1-42] or a pharma- ceutically acceptable salt, solvate and / or prodrug thereof.

[0152] In some embodiments, the compound of formula I is a compound of formula IA, or a pharma- ceutically acceptable salt, solvate, and / or prodrug thereof: [ka] During the ceremony: A is, [ka] Selected from; * is the point of attachment for A in compounds of formula I; R 1 is selected from H, halo, CN, C1-4 alkyl, OC1-4 alkyl, C1-4 haloalkyl, OC1-4 haloalkyl, CN; R 2 is selected from H, halo, CN, C1-4 alkyl, C1-4 haloalkyl, OC1-4 alkyl, and OC1-4 haloalkyl; R 3 is selected from C1-4 fluoroalkyl and OC1-4 fluoroalkyl; R 5 and R 6 is independently selected from H, halo, CN, C1-4 alkyl, and C1-4 haloalkyl; X is CR a and N; Y is CR b and N; R a and R b is independently selected from H, halo, C1-4 alkyl, and C1-4 haloalkyl; Z is NR 7 R 8 or Z and R 2and bond together with the atoms therebetween to form ring B selected from C3-12 cycloalkyl and C3-12 heterocycloalkyl, said ring B being selected from halo, =O, OH, C1-6 alkyl, C3-6 cycloalkyl, aryl, C5-6 heteroaryl, C3-6 heterocycloalkyl, C1-6 alkyleneC3-6 cycloalkyl, C1-6 alkylenearyl, C1-6 alkyleneC5-6 heteroaryl, C1-6 alkyleneC3-6 heterocycloalkyl, OC1-6 alkyl, OC1-6 alkyleneOC1-6 alkyl, NH(C1-6 alkyl), N optionally substituted by one or more substituents selected from (C1-6 alkyl)(C1-6 alkyl), SC1-6 alkyl, S(O)C1-6 alkyl and SO2C1-6 alkyl, and all alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups of the optional substituents on ring B are also optionally substituted by one or more of halo, C1-6 alkyl, OC1-6 alkyl, C1-6 haloalkyl and OC1-6 haloalkyl; R 7 is C1-6 alkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-6 alkylene C3-10 cycloalkyl, C1-6 alkylene C3-10 heterocycloalkyl, C1-6 alkyl alkylene OR 10 and C1-6 alkyl alkylene NR 10 R 11 Selected from R 7 all alkyl, alkylene, heterocycloalkyl and cycloalkyl groups are also optionally substituted with one or more of halo, C1-6 alkyl and C1-6 haloalkyl; R 8 is selected from H, C1-6 alkyl, and C1-6 haloalkyl; or R 7 and R 8 and are bonded together with the atoms therebetween to form a C3-12 heterocycloalkyl, and the C3-12 heterocycloalkyl is NR 12, O, S, S(O) and SO2, and optionally substituted by one or more substituents selected from halo, ═O, OH, C1-6 alkyl, C3-6 cycloalkyl, C3-6 heterocycloalkyl, C1-6 alkyleneC3-6 cycloalkyl, C1-6 alkyleneC3-6 heterocycloalkyl, NH(C1-6 alkyl), N(C1-6 alkyl)(C1-6 alkyl), SC1-6 alkyl, S(O)C1-6 alkyl and SO2C1-6 alkyl; 7 and R 8 all alkyl, alkylene, cycloalkyl and heterocycloalkyl groups of the optional substituents on the C3-12 heterocycloalkyl formed by are also optionally substituted by one or more of halo, C1-6 alkyl, OC1-6 alkyl, C1-6 haloalkyl and OC1-6 haloalkyl; and R 9 , R 10 , R 11 and R 12 is independently selected from H, C1-6 alkyl, and C1-6 haloalkyl.

[0153] In some embodiments, the compound of formula I is a compound of formula IB, or a pharma- ceutically acceptable salt, solvate, and / or prodrug thereof: [ka] During the ceremony: A is, [ka] Selected from; * is the point of attachment for A in compounds of formula I; R 1 is selected from H, halo, CN, C1-4 alkyl, OC1-4 alkyl, C1-4 haloalkyl, OC1-4 haloalkyl, CN; R 2 is selected from H, halo, CN, C1-4 alkyl, C1-4 haloalkyl, OC1-4 alkyl, and OC1-4 haloalkyl; R 3 is selected from C1-4 fluoroalkyl and OC1-4 fluoroalkyl; R 5 and R 6 is independently selected from H, halo, CN, C1-4 alkyl, and C1-4 haloalkyl; X is CR a and N; Y is CR b and N; R a and R b is independently selected from H, halo, C1-4 alkyl, and C1-4 haloalkyl; Z is NR 7 R 8 or Z and R 2 and bond together with the atoms therebetween to form ring B selected from C3-12 cycloalkyl and C3-12 heterocycloalkyl, said ring B being selected from halo, =O, OH, C1-6 alkyl, C3-6 cycloalkyl, aryl, C5-6 heteroaryl, C3-6 heterocycloalkyl, C1-6 alkyleneC3-6 cycloalkyl, C1-6 alkylenearyl, C1-6 alkyleneC5-6 heteroaryl, C1-6 alkyleneC3-6 heterocycloalkyl, OC1-6 alkyl, OC1-6 alkyleneOC1-6 alkyl, NH(C1-6 alkyl), N optionally substituted by one or more substituents selected from (C1-6 alkyl)(C1-6 alkyl), SC1-6 alkyl, S(O)C1-6 alkyl and SO2C1-6 alkyl, and all alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups of the optional substituents on ring B are also optionally substituted by one or more of halo, C1-6 alkyl, OC1-6 alkyl, C1-6 haloalkyl and OC1-6 haloalkyl; R 7 is C1-6 alkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-6 alkylene C3-10 cycloalkyl, C1-6 alkylene C3-10 heterocycloalkyl, C1-6 alkyl alkylene OR 10 and C1-6 alkyl alkylene NR 10 R 11 Selected from R 7 all alkyl, alkylene, heterocycloalkyl and cycloalkyl groups are also optionally substituted with one or more of halo, C1-6 alkyl and C1-6 haloalkyl; R 8 is selected from H, C1-6 alkyl, and C1-6 haloalkyl; or R 7 and R 8 and are bonded together with the atoms therebetween to form a C3-12 heterocycloalkyl, and the C3-12 heterocycloalkyl is NR 12 , O, S, S(O) and SO2, and optionally substituted by one or more substituents selected from halo, ═O, OH, C1-6 alkyl, C3-6 cycloalkyl, C3-6 heterocycloalkyl, C1-6 alkyleneC3-6 cycloalkyl, C1-6 alkyleneC3-6 heterocycloalkyl, NH(C1-6 alkyl), N(C1-6 alkyl)(C1-6 alkyl), SC1-6 alkyl, S(O)C1-6 alkyl and SO2C1-6 alkyl; 7 and R 8 all alkyl, alkylene, cycloalkyl and heterocycloalkyl groups of the optional substituents on the C3-12 heterocycloalkyl formed by are also optionally substituted by one or more of halo, C1-6 alkyl, OC1-6 alkyl, C1-6 haloalkyl and OC1-6 haloalkyl; and R 9 , R 10 , R 11and R 12 is independently selected from H, C1-6 alkyl, and C1-6 haloalkyl.

[0154] In some embodiments, the compound of formula I is a compound of formula IC, or a pharma- ceutically acceptable salt, solvate, and / or prodrug thereof: [ka] During the ceremony, A is, [ka] Selected from; * is the point of attachment for A in compounds of formula I; R 1 is selected from H, halo, CN, C1-4 alkyl, OC1-4 alkyl, C1-4 haloalkyl, OC1-4 haloalkyl, CN; R 2 is selected from H, halo, CN, C1-4 alkyl, C1-4 haloalkyl, OC1-4 alkyl, and OC1-4 haloalkyl; R 3 is selected from C1-4 fluoroalkyl and OC1-4 fluoroalkyl; R 5 and R 6 is independently selected from H, halo, CN, C1-4 alkyl, and C1-4 haloalkyl; X is CR a and N; Y is CR b and N; R a and R b is independently selected from H, halo, C1-4 alkyl, and C1-4 haloalkyl; R 7is C1-6 alkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-6 alkylene C3-10 cycloalkyl, C1-6 alkylene C3-10 heterocycloalkyl, C1-6 alkyl alkylene OR 10 and C1-6 alkyl alkylene NR 10 R 11 Selected from R 7 all alkyl, alkylene, heterocycloalkyl and cycloalkyl groups are also optionally substituted with one or more of halo, C1-6 alkyl and C1-6 haloalkyl; R 8 is selected from H, C1-6 alkyl, and C1-6 haloalkyl; or R 7 and R 8 and are bonded together with the atoms therebetween to form a C3-12 heterocycloalkyl, and the C3-12 heterocycloalkyl is NR 12 , O, S, S(O) and SO2, and optionally substituted by one or more substituents selected from halo, ═O, OH, C1-6 alkyl, C3-6 cycloalkyl, C3-6 heterocycloalkyl, C1-6 alkyleneC3-6 cycloalkyl, C1-6 alkyleneC3-6 heterocycloalkyl, NH(C1-6 alkyl), N(C1-6 alkyl)(C1-6 alkyl), SC1-6 alkyl, S(O)C1-6 alkyl and SO2C1-6 alkyl; 7 and R 8 all alkyl, alkylene, cycloalkyl and heterocycloalkyl groups of the optional substituents on the C3-12 heterocycloalkyl formed by are also optionally substituted by one or more of halo, C1-6 alkyl, OC1-6 alkyl, C1-6 haloalkyl and OC1-6 haloalkyl; and R 9 , R 10 , R 11 and R 12is independently selected from H, C1-6 alkyl, and C1-6 haloalkyl.

[0155] In some embodiments, the compound of formula I is a compound of formula ID, or a pharma- ceutically acceptable salt, solvate, and / or prodrug thereof: [ka] In the formula, A is [ka] Selected from; * is the point of attachment for A in compounds of formula I; R 1 is selected from H, halo, CN, C1-4 alkyl, OC1-4 alkyl, C1-4 haloalkyl, OC1-4 haloalkyl, CN; R 2 is selected from H, halo, CN, C1-4 alkyl, C1-4 haloalkyl, OC1-4 alkyl, and OC1-4 haloalkyl; R 3 is selected from C1-4 fluoroalkyl and OC1-4 fluoroalkyl; R 5 and R 6 is independently selected from H, halo, CN, C1-4 alkyl, and C1-4 haloalkyl; X is CR a and N; Y is CR b and N; R a and R b is independently selected from H, halo, C1-4 alkyl, and C1-4 haloalkyl; Ring B is selected from C3-12 cycloalkyl and C3-12 heterocycloalkyl, and said ring B is selected from halo, ═O, OH, C1-6 alkyl, C3-6 cycloalkyl, aryl, C5-6 heteroaryl, C3-6 heterocycloalkyl, C1-6 alkylene C3-6 cycloalkyl, C1-6 alkylene aryl, C1-6 alkylene C5-6 heteroaryl, C1-6 alkylene C3-6 heterocycloalkyl, OC1-6 alkyl, OC1-6 alkylene OC1-6 alkyl, NH(C1-6 alkyl), N(C1-6 alkyl)(C1-6 alkyl), and all alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups of the optional substituents on ring B are also optionally substituted with one or more of halo, C1-6 alkyl, OC1-6 alkyl, C1-6 haloalkyl and OC1-6 haloalkyl.

[0156] R for compounds of formula I 1 ~R 12 , R a , R b The above embodiments of X, Y, Z, Ring A and Ring B also apply to compounds of formula IA, formula IB, formula IC and formula ID.

[0157] The compounds of the present application are suitably formulated into compositions using one or more carriers and / or diluents in a conventional manner.Thus, the present application also includes compositions comprising one or more compounds of the present application and carriers.The compounds of the present application are suitably formulated into pharmaceutical compositions for administration to subjects in a biologically compatible form suitable for in vivo administration.Thus, the present application also includes pharmaceutical compositions comprising one or more compounds of the present application and pharma- ceutical acceptable carriers.

[0158] The compounds of the present application may be administered to a subject in various forms depending on the selected administration route, as will be understood by those skilled in the art. For example, the compounds of the present application may be administered, for example, orally, parenterally, bucally, sublingually, nasally, rectally, by patch, pump (for periodic or continuous delivery) or transdermally, and the pharmaceutical composition may be formulated accordingly. Conventional procedures and ingredients for the selection and preparation of suitable compositions are described, for example, in Remington's Pharmaceutical Sciences (2000 - 20th edition) and The United States Pharmacopeia: The National Formulary (USP 24 NF19), published in 1999.

[0159] Parenteral administration includes intravenous, intraarterial, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, pulmonary (e.g., by use of an aerosol), intrathecal, rectal, and topical (including use of a patch or other transdermal delivery device) modes of administration. Parenteral administration may also be by continuous infusion over a selected period of time.

[0160] The compounds of the present application may be administered orally, for example, with an inert diluent or an assimilable edible carrier, or may be enclosed in hard or soft shell gelatin capsules, or may be compressed into tablets, or may be directly incorporated with dietary food. For oral therapeutic administration, the compounds may be incorporated with a formulation excipient and used in the form of ingestible tablets, buccal tablets, troches, capsules, caplets, pellets, granules, lozenges, chewing gums, powders, syrups, elixirs, wafers, aqueous solutions, aqueous suspensions, and the like. For tablets, the carriers used include lactose, corn starch, sodium citrate, and salts of phosphoric acid. Pharmaceutically acceptable formulation additives include binders (e.g., pregelatinized corn starch, polyvinylpyrrolidone, or hydroxypropylmethylcellulose); fillers (e.g., lactose, microcrystalline cellulose, or calcium phosphate); lubricants (e.g., magnesium stearate, talc, or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulfate). Tablets may be coated by methods well known in the art. For tablets, capsules, caplets, pellets, or granules for oral administration, pH-sensitive enteric coatings such as Eudragits®, which are designed to control the release of the active ingredient, are optionally used. Oral dosage forms also include modified release formulations, such as immediate release formulations and timed-release formulations.Examples of modified release formulations include, for example, sustained release (SR), extended-release (ER, XR, or XL), time-release or timed-release, controlled release (CR), or continuous-release (CR or Contin) formulations, for example, in the form of coated tablets, osmotic delivery devices, coated capsules, microencapsulated microspheres, agglomerated particles (e.g., agglomerates of molecular sieve-type particles), or bundles of fine hollow permeable fibers, or chopped hollow permeable fibers that are assembled or held together in a fibrous packet. Timed release compositions may be formulated, for example, as liposomes, or formulations in which the compounds of the present application are protected by differentially degradable coatings (e.g., by microencapsulation, multilayer coatings, etc.). Liposomal delivery systems include, for example, small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes may be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholine. For oral administration in capsule form, useful carriers or diluents include lactose and dried cornstarch.

[0161] Liquid preparations for oral administration may take the form of, for example, solutions, syrups, or suspensions, or may be suitably presented as a dry product for constitution with water or other suitable vehicle before use. When aqueous suspensions and / or emulsions are administered orally, the compounds of the present application are suitably suspended or dissolved in an oily phase combined with an emulsifying and / or suspending agent. If desired, certain sweetening and / or flavoring and / or coloring agents may be added. Such liquid preparations for oral administration are prepared in a conventional manner using pharmaceutically acceptable additives. Pharmaceutically acceptable additives include, for example, suspending agents (e.g., sorbitol syrup, methylcellulose, or edible hydrogenated fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters, or ethyl alcohol); and preservatives (e.g., methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, or sorbic acid). Useful diluents include lactose and high molecular weight polyethylene glycols.

[0162] It is also possible to lyophilize the compounds of the present application and use the resulting lyophilizates, for example for the preparation of injectable products.

[0163] The compounds of the present application may be administered parenterally. For example, solutions of the compounds of the present application in water, suitably mixed with a surfactant such as hydroxypropylcellulose, may be prepared. Dispersions may also be prepared in glycerol, liquid polyethylene glycols, DMSO, and mixtures thereof (with or without alcohol), and in oils. Under normal storage and use conditions, these preparations contain a preservative to prevent the growth of microorganisms. Those skilled in the art know how to prepare suitable formulations. For parenteral administration, a sterile solution of the compounds of the present application is usually prepared, and the pH of the solution is appropriately adjusted and buffered. For intravenous use, the total concentration of solutes should be controlled so that the preparation is isotonic. For ocular administration, ointments or droppable liquids may be delivered by ocular delivery systems known in the art, such as applicators or droppers. Such compositions may contain mucosal mimetics such as hyaluronic acid, chondroitin sulfate, hydroxypropylmethylcellulose, or polyvinyl alcohol, preservatives such as sorbic acid, EDTA, or benzyl chromium chloride, as well as conventional amounts of diluents or carriers. For pulmonary administration, the diluent or carrier will be selected to be suitable to allow the formation of an aerosol.

[0164] The compounds of the present application may be formulated for parenteral administration by injection, including conventional catheter insertion techniques or infusion. Formulations for injection are provided, for example, in unit dosage form, for example, in ampoules or in multi-dose containers, with added preservatives. The compositions may take the form of a sterile suspension, solution, or emulsion in an oily or aqueous vehicle, and may contain formulatory agents such as suspending, stabilizing, and / or dispersing agents. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. Alternatively, the compounds of the present application are preferably in sterile powder form for reconstitution before use with a suitable vehicle, for example, sterile pyrogen-free water.

[0165] Compositions for nasal administration may conveniently be formulated as aerosols, drops, gels, and powders.

[0166] For intranasal administration or administration by inhalation, the compounds of the present application are conveniently delivered in the form of a solution, dry powder formulation, or suspension from a pump spray container that is squeezed or pumped by the subject patient, or as an aerosol spray from a pressurized container or nebulizer. The aerosol formulation typically comprises a solution or fine suspension of the compounds of the present application in a physiologically acceptable aqueous or non-aqueous solvent, and is usually provided as a single or multiple doses in a sterile form in a sealed container. The container may take the form of a cartridge or refill for use with a nebulizer device. Alternatively, the sealed container may be a unitary dispensing device, such as a single-dose nasal inhaler or an aerosol dispenser fitted with a metering valve intended to be discarded after use. When the dosage form comprises an aerosol dispenser, it will also comprise a propellant. The propellant may be a compressed gas, such as compressed air or an organic propellant, such as fluorochlorohydrocarbons. Suitable propellants include, but are not limited to, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, heptafluoroalkanes, carbon dioxide, or other suitable gases. In the case of a pressurized aerosol, the dosage unit is suitably determined by providing a valve to dispense a metered amount. The pressurized container or nebulizer may contain a solution or suspension of the active compound. Capsules and cartridges (made, for example, of gelatin) for use in an inhaler or insufflator may be formulated, for example, containing a powder mix of the compound of the present application and a suitable powder base, such as lactose or starch. The aerosol dosage form may take the form of a pump-atomizer.

[0167] Compositions suitable for buccal or sublingual administration include tablets, lozenges, and pastilles, wherein the compound of the present application is formulated with a carrier such as sugar, acacia, tragacanth, or gelatin and glycerin. Compositions for rectal administration are conveniently in the form of suppositories containing a conventional suppository base such as cocoa butter.

[0168] The compounds of the present application in suppository form are useful for vaginal, urethral, ​​and rectal administration. Such suppositories are generally composed of a mixture of materials that are solid at room temperature but melt at body temperature. Materials commonly used to make such vehicles include, but are not limited to, cacao fat (also known as cocoa butter), glycerinated gelatin, other glycerides, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights, and fatty acid esters of polyethylene glycol. For further description of suppository dosage forms, see, for example, Remington's Pharmaceutical Sciences, 16th Ed., Mack Publishing, Easton, PA, 1980, pp. 1530-1533.

[0169] The compounds of the present application may be coupled to soluble polymers as targetable drug carriers. Such polymers may include polyvinylpyrrolidone, pyran copolymers, polyhydroxypropylmethacrylamide-phenol, polyhydroxy-ethylaspartamide-phenol, or polyethylene oxide-polylysine substituted with palmitoyl residues. In addition, the compounds of the present application may be coupled to a class of biodegradable polymers useful for achieving controlled release of drugs, such as polylactic acid, polyglycolic acid, copolymers of polylactic acid and polyglycolic acid, poly-ε-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and crosslinked or amphiphilic block copolymers of hydrogels.

[0170] Although the compounds of the present application, including their pharma- ceutically acceptable salts, solvates and / or prodrugs, are suitably used alone, they are generally administered in the form of a pharmaceutical composition in which one or more compounds of the present application (active ingredients) are administered in association with a pharma- ceutically acceptable carrier. Depending on the mode of administration, the pharmaceutical composition may contain about 0.05% to about 99% by weight or about 0.10% to about 70% by weight of the active ingredient (one or more compounds of the present application) and about 1% to about 99.95% by weight or about 30% to about 99.90% by weight of the pharma- ceutically acceptable carrier, where all weight percentages are based on the total composition.

[0171] The compounds of the present application may be used alone or in combination with other known agents useful for treating diseases, disorders or conditions treatable by inhibiting NUAK2 and / or NUAK1. When used in combination with other agents useful for treating diseases, disorders or conditions treatable by inhibiting NUAK2 and / or NUAK1, it is an embodiment to administer the compounds of the present application simultaneously with such agents. In the present disclosure, "concurrent administration" of two substances to a subject means providing each of the two substances such that they are biologically active in the individual at the same time. The exact details of administration depend on the pharmacokinetics of the two substances in the presence of each other, but may include administering the two substances within a few hours of each other, or even administering one substance within 24 hours of the other, if the pharmacokinetics are suitable. Designing an appropriate dosing regimen is routine for one of ordinary skill in the art. In certain embodiments, the two substances are administered substantially simultaneously, i.e., within minutes of each other, or in a single composition containing both substances. It is a further embodiment of the present invention that the combination of agents is administered to a subject asynchronously. In some embodiments, the compound of the present application is administered simultaneously or sequentially with other therapeutic agents in separate unit dosage forms, or together in a single unit dosage form. Thus, the present application provides a single unit dosage form that includes one or more compounds of the present application (i.e., compounds of formula I), additional therapeutic agents, and a pharma- ceutically acceptable carrier.

[0172] The dosage of the compounds of the present application varies depending on many factors, including, for example, the pharmacokinetic properties of the compound, the mode of administration, the age, health, and weight of the recipient, the nature and extent of symptoms, the frequency of treatment, and the type of concurrent treatment (if any), and the clearance rate of the compound in the subject being treated. Those skilled in the art can determine the appropriate dosage based on the above factors. The compounds of the present application may be initially administered at an appropriate dosage, which may be adjusted as necessary depending on the clinical response. The dosage is generally selected to maintain a serum level of the compounds of the present application between about 0.01 μg / cc and about 1000 μg / cc, or between about 0.1 μg / cc and about 100 μg / cc. As a representative example, the oral dosage of one or more compounds of the present application for an adult is in the range of about 0.05 mg / kg to about 1000 mg / kg per day, preferably about 0.1 mg / kg to about 500 mg / kg per day, more preferably about 1 mg / kg to about 200 mg / day. In the case of parenteral administration, a representative amount is about 0.001 mg / kg to about 10 mg / kg, about 0.01 mg / kg to about 10 mg / kg, about 0.01 mg / kg to about 1 mg / kg, or about 0.1 mg / kg to about 1 mg / kg. In the case of oral administration, a representative amount is about 0.001 mg / kg to about 10 mg / kg, about 0.1 mg / kg to about 10 mg / kg, about 0.01 mg / kg to about 1 mg / kg, or about 0.1 mg / kg to about 1 mg / kg. When administered in suppository form, typical amounts are from about 0.1 mg / kg to about 10 mg / kg or from about 0.1 mg / kg to about 1 mg / kg. The compounds of the present application may be administered in a once-daily, once-weekly, or once-monthly dose, or the total daily dose may be divided into two-, three-, or four-times-daily doses.

[0173] For clarity, in the above, the term "compound" includes embodiments in which one or more compounds are referred to. Similarly, the term "compound of the present application" includes embodiments in which only one compound is referred to.

[0174] III. Methods and Uses The compounds of the present application have been shown to be capable of inhibiting or blocking NUAK2 and / or NUAK1 in cells, and have been shown to inhibit tumor cell proliferation and also inhibit YAP / TAZ localization to the nucleus of cells.

[0175] Thus, the present application also includes a method of inhibiting NUAK2 and / or NUAK1 in a cell in a biological sample or in a subject, comprising administering to said cell an effective amount of one or more compounds of the present application. The present application also includes the use of one or more compounds of the present application for inhibiting NUAK2 and / or NUAK1 in a cell, as well as the use of one or more compounds of the present application for the preparation of a medicament for inhibiting NUAK2 and / or NUAK1 in a cell. The present application further includes one or more compounds of the present application for use in inhibiting NUAK2 and / or NUAK1.

[0176] The compounds of the present application have been shown to inhibit NUAK2 and / or NUAK1, and therefore are useful for treating a disease, disorder, or condition by inhibiting NUAK2 and / or NUAK1. The compounds of the present application are therefore useful as pharmaceuticals. Thus, the present application encompasses one or more compounds of the present application for use as a pharmaceutical.

[0177] The present application also includes a method of treating a disease, disorder, or condition treatable by inhibiting NUAK2 and / or NUAK1, comprising administering to a subject in need of treatment a therapeutically effective amount of one or more compounds of the present application.

[0178] The present application also encompasses the use of one or more compounds of the present application for the treatment of a disease, disorder or condition treatable by inhibiting NUAK2 and / or NUAK 1, as well as the use of one or more compounds of the present application for the preparation of a medicament for the treatment of a disease, disorder or condition treatable by inhibiting NUAK2 and / or NUAK 1. The present application further encompasses one or more compounds of the present application for use in the treatment of a disease, disorder or condition treatable by inhibiting NUAK2 and / or NUAK1.

[0179] As mentioned above, "NUAK" is a protein kinase belonging to the NUAK family SNF1-like kinases 1 and 2, also known as AMPK-related protein kinase 5 (ARK5) or SNARK, respectively. In some embodiments, these serine / threonine-protein kinases are enzymes encoded in humans by the NUAK1 (Gene ID: 9891) and NUAK2 (Gene ID: 81788) genes, which comprise the amino acid sequences disclosed in Journal of Biological Chemistry 2003, 278(1):48-53.

[0180] In one embodiment, the disease, disorder or condition treatable by inhibiting NUAK2 and / or NUAK1 is a neoplastic disorder. Thus, the present application also encompasses a method for treating a neoplastic disorder, comprising administering to a subject in need of treatment a therapeutically effective amount of one or more compounds of the present application. The present application also encompasses the use of one or more compounds of the present application for treating a neoplastic disorder, as well as the use of one or more compounds of the present application for preparing a medicament for treating a neoplastic disorder. The present application further encompasses one or more compounds of the present application for use in treating a neoplastic disorder. In one embodiment, the treatment is in an amount effective to alleviate at least one symptom of a neoplastic disorder, in particular, for example, to reduce cell proliferation or reduce tumor burden, in a subject in need of such treatment.

[0181] The compounds of the present application have been demonstrated to inhibit the proliferation of cancer cells. Thus, in certain other embodiments of the present application, the disease, disorder, or condition treatable by inhibiting NUAK2 and / or NUAK1 is cancer. Thus, the present application also encompasses a method of treating cancer, comprising administering to a subject in need of treatment a therapeutically effective amount of one or more compounds of the present application. The present application also encompasses the use of one or more compounds of the present application for the treatment of cancer, as well as the use of one or more compounds of the present application for the preparation of a medicament for the treatment of cancer. The present application further encompasses one or more compounds of the present application for use in treating cancer. In certain embodiments, the compounds are administered or used for the prevention of cancer in a subject predisposed to cancer, such as a mammal predisposed to cancer.

[0182] In some embodiments, the cancer is any cancer whose cells exhibit increased expression of genes encoding NUAK1 and / or NUAK2. By "increased expression" is meant any increase in expression of genes encoding NUAK1 and / or NUAK2 in said cells compared to expression of genes encoding NUAK1 and / or NUAK2 in corresponding normal or healthy cells.

[0183] In some embodiments, the cancer is selected from one or more of a solid tumor, breast cancer, colon cancer, bladder cancer, skin cancer, head and neck cancer, liver cancer, lung cancer, pancreatic cancer, ovarian cancer, prostate cancer, bone cancer, and glioblastoma. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is skin cancer. In some embodiments, the cancer is head and neck cancer. In some embodiments, the cancer is colorectal cancer (CRC). In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is glioblastoma. In some embodiments, the cancer is osteosarcoma.

[0184] As described above, MYC-driven tumors are dependent on NUAK activity and the full function of the spliceosome is important for their survival [Mol Cell. 2020, 77(6):1322-1339]. MYC drives gene expression required for cell growth and cell division and is deregulated in many tumors. Thus, in some embodiments, the cancer treated with one or more compounds of the present application is a cancer in which MYC family cancer genes are amplified or otherwise deregulated (see, e.g., Signal Transduction and Targeted Therapy, 2018, vol. 3, Article 5).

[0185] In some embodiments, the compounds of the present application have been found to inhibit YAP / TAZ from localizing to the nucleus of a cell. Accordingly, the present application also encompasses a method of inhibiting YAP / TAZ localization to the nucleus of a cell, comprising administering an effective amount of one or more compounds of the present application to a cell in need of inhibiting YAP / TAZ localization to the nucleus of a cell. Also encompassed are the use of one or more compounds of the present application for inhibiting YAP / TAZ localization to the nucleus of a cell, the use of one or more compounds of the present application for the preparation of a medicament for inhibiting YAP / TAZ localization to the nucleus of a cell, and one or more compounds of the present application for use in inhibiting YAP / TAZ localization to the nucleus of a cell.

[0186] The present application also includes a method for treating a disease, disorder, or condition by inhibiting the localization of YAP / TAZ to the nucleus of a cell, comprising administering to a subject in need of treatment an effective amount of one or more compounds of the present application. Also included are the use of one or more compounds of the present application for treating a disease, disorder, or condition by inhibiting the localization of YAP / TAZ to the nucleus of a cell, the use of one or more compounds of the present application for the preparation of a medicament for treating a disease, disorder, or condition by inhibiting the localization of YAP / TAZ to the nucleus of a cell, and one or more compounds of the present application for use in treating a disease, disorder, or condition by inhibiting the localization of YAP / TAZ to the nucleus of a cell.

[0187] As described above, accumulating evidence also indicates that YAP / TAZ functions in a cooperative manner with other established signaling pathways, in particular crosstalk with the TGFβ and Wnt signaling pathways (Am. J. Physiol. Lung Cell. Mol. Physiol. 2015, 309, L756-L767; Cell 2012, 151, 1443-1456). Thus, in some embodiments, the disease, disorder, or condition treated by inhibiting YAP / TAZ localization to the nucleus of a cell is one that would benefit from inhibition, whether direct or indirect, of the TGFβ and Wnt signaling pathways.

[0188] In some embodiments, the disease, disorder or condition treated by inhibiting YAP / TAZ localization to the cell nucleus is any cancer or fibrosis in which cells exhibit increased activation of TAZ and / or YAP. "Increased activation" refers to any increase in activation of TAZ and / or YAP in said cells compared to activation of TAZ and / or YAP in corresponding normal or healthy cells. In some embodiments, the cancer is selected from one or more of breast cancer, bladder cancer, liver cancer, human melanoma, colorectal cancer, hepatocellular carcinoma, cholangiocarcinoma, mesothelioma, osteosarcoma, and glioblastoma. In some embodiments, the fibrosis is liver fibrosis, pulmonary fibrosis, and / or renal fibrosis.

[0189] Another indication that could potentially benefit from inhibiting the NUAK-YAP / TAZ-TGFβ signaling axis is fibrosis. Fibrosis is a response to tissue or organ injury, such as chronic inflammation or chemical and mechanical injury. In pathological conditions, fibrosis progresses to an uncontrolled process characterized by progressive accumulation of extracellular matrix (ECM), mainly collagen, that ultimately destroys normal organ architecture and leads to loss of organ function. A key step in fibrosis is the conversion of quiescent fibroblasts into active myofibroblasts that deposit extracellular matrix (ECM) and secrete TGFβ, the main driver of this activation process (Science 2002,296:1646-1647). Fibrosis, which affects several organs such as the liver, lungs, and kidneys, is responsible for up to 45% of deaths in industrialized societies (J.Clin.Invest.2007,117,524-529;Front.Pharmacol.2017,8,855). Current therapies are mostly supportive rather than curative, and there is an urgent need to identify agents with therapeutic potential to address this disease. NUAK inhibition, which regulates YAP / TAZ and TGFβ signaling, is a novel approach to treat fibrosis.

[0190] In some embodiments, the disease, disorder or condition treatable by inhibiting NUAK2 and / or NUAK1 is a disease, disorder or condition associated with unregulated and / or abnormal cellular activity that is directly or indirectly affected by inhibiting NUAK2 and / or NUAK1. In certain other embodiments, the unregulated and / or abnormal cellular activity that is directly or indirectly affected by inhibiting NUAK2 and / or NUAK1 is proliferative activity in a cell. Thus, the present application also encompasses a method of inhibiting proliferative activity in a cell, comprising administering to the cell an effective amount of one or more compounds of the present application. The present application also encompasses the use of one or more compounds of the present application for inhibiting proliferative activity in a cell, as well as the use of one or more compounds of the present application for the preparation of a medicament for inhibiting proliferative activity in a cell. The present application further encompasses one or more compounds of the present application for use in inhibiting proliferative activity in a cell.

[0191] The present application also includes a method of inhibiting unregulated and / or abnormal cellular activity that is directly or indirectly affected by inhibiting NUAK2 and / or NUAK1 in a cell in a biological sample or in a subject, comprising administering to the cell an effective amount of one or more compounds of the present application. The present application also includes the use of one or more compounds of the present application for inhibiting unregulated and / or abnormal cellular activity that is directly or indirectly affected by inhibiting NUAK2 and / or NUAK1 in a cell, as well as the use of one or more compounds of the present application for the preparation of a medicament for inhibiting unregulated and / or abnormal cellular activity that is directly or indirectly affected by inhibiting NUAK2 and / or NUAK1 in a cell. The present application further includes one or more compounds of the present application for use in inhibiting unregulated and / or abnormal cellular activity that is directly or indirectly affected by inhibiting NUAK2 and / or NUAK1 in a cell.

[0192] The present application also encompasses methods of treating a disease, disorder, or condition treatable by inhibiting NUAK2 and / or NUAK1, comprising administering to a subject in need of treatment a therapeutically effective amount of one or more compounds of the present application in combination with other agents useful for the treatment of a disease, disorder, or condition treatable by inhibiting NUAK2 and / or NUAK1. The present application also encompasses the use of one or more compounds of the present application in combination with other known agents useful for the treatment of a disease, disorder, or condition treatable by inhibiting NUAK2 and / or NUAK1 for the treatment of a disease, disorder, or condition treatable by inhibiting NUAK2 and / or NUAK1, as well as the use of one or more compounds of the present application in combination with other known agents useful for the treatment of a disease, disorder, or condition treatable by inhibiting NUAK2 and / or NUAK1 for the preparation of a medicament for the treatment of a disease, disorder, or condition treatable by inhibiting NUAK2 and / or NUAK1. The present application further encompasses one or more compounds of the present application for use in treating a disease, disorder, or condition treatable by inhibiting NUAK2 and / or NUAK 1 in combination with other known agents useful in treating a disease, disorder, or condition treatable by inhibiting NUAK2 and / or NUAK 1. In certain embodiments, the disease, disorder, or condition treatable by inhibiting NUAK2 and / or NUAK1 is cancer and / or fibrosis.

[0193] In a further embodiment, the disease, disorder or condition treatable by inhibiting NUAK2 and / or NUAK1 is cancer and the one or more compounds are administered in combination with one or more additional cancer therapies, hi certain other embodiments, the additional cancer therapies are selected from targeted therapies such as radiation therapy, chemotherapy, antibody therapy, and small molecule therapies such as tyrosine kinase inhibitor therapy, immunotherapy, hormonal therapy, and anti-angiogenic therapy.

[0194] As mentioned above, accumulating evidence also indicates that YAP / TAZ functions in a cooperative manner with other established signaling pathways, in particular crosstalk with the TGFβ and Wnt signaling pathways (Am. J. Physiol. Lung Cell. Mol. Physiol. 2015, 309, L756-L767; Cell 2012, 151, 1443-1456). Importantly, in the context of cancer immunology, TGFβ has been shown to have a key role in regulating anti-tumor immune responses and contribute to resistance to anti-PD-1-PD-L1 treatment in cancer patients (ACS Med. Chem. Lett. 2018, 9, 1117). Thus, targeting the TGFβ pathway (by NUAK-YAP / TAZ inhibition) in combination with anti-PD1 or anti-PD-L1 antibodies may help overcome resistance and obtain more effective anti-tumor responses. Thus, in some embodiments, one or more compounds of the present application are administered in combination with treatment with, or use of, anti-PDI and / or anti-PD-L1 antibodies.

[0195] In some embodiments, both NUAK2 and NUAK1 are inhibited in the uses and methods of the present application. In some embodiments, in the uses and methods of the present application, inhibition of NUAK2 is greater than inhibition of NUAK1. In some embodiments, inhibition of NUAK2 and / or NUAK1 is selective relative to inhibition of one or more other kinases in a cell or subject. In some embodiments, the other kinase is Aurora A kinase.

[0196] In some embodiments, the subject is a mammal, hi some embodiments, the subject is a human.

[0197] Those skilled in the art will appreciate that the therapeutic methods and uses of the present application typically involve administering or using an effective amount of one or more of the compounds of the present application in a pharmaceutical composition of the present application. For example, in the context of treating a disease, disorder, or condition treatable by inhibition of NUAK2 and / or NUAK1, an effective amount is, for example, an amount that inhibits NUAK2 / NUAK1 compared to the inhibition in the absence of administration of the compound or compounds. An effective amount may vary depending on factors such as the disease state, age, sex, and / or weight of the subject. The amount of a given compound that will correspond to an effective amount will vary depending on a variety of factors, such as the given drug or compound, pharmaceutical formulation, route of administration, type of disease state, disease or disorder, identity of the subject being treated, etc., but can nevertheless be routinely determined by one of skill in the art. An effective amount is one that is manifested as an improvement or reduction in disease, disorder, or condition symptoms following treatment with that amount. In some embodiments, when the disease is cancer, an amount that is effective causes a reduction in the number, growth rate, size, and / or distribution of tumors.

[0198] The method of treatment includes administering to a subject a therapeutically effective amount of one or more compounds of the present application, optionally consisting of a single dose or including a series of doses, and optionally including the concurrent administration or use of one or more other therapeutic agents. For example, in some embodiments, the compounds of the present application may be administered more than once a week. In some embodiments, for a given treatment, the compounds may be administered to a subject about once every two or three weeks, or about once a week to about once a day. In other embodiments, the compounds are administered once, twice, three times, four times, five times, or six times a day. The length of the treatment period depends on various factors, such as the severity of the disease, disorder, or condition, the age of the subject, the concentration and / or activity of the compounds of the present application, and / or combinations thereof. It will also be understood that the effective dosage of the compounds used for treatment may increase or decrease over the course of a particular treatment regimen. Modifications in dosage may occur and be evident from standard diagnostic assays known in the art. In some cases, chronic administration may be necessary. For example, the compound is administered to the subject in an amount and for a period of time sufficient to treat the subject. In some embodiments, treatment includes prophylactic treatment. For example, a subject with early stage cancer can be treated to prevent progression, or a subject in remission can be treated with a compound or composition of the present application to prevent recurrence.

[0199] IV. Methods of Preparing the Compounds of the Present Application The compounds of the present application can be prepared by various synthetic processes. The selection of certain structural features and / or substituents may affect the selection of one process over another. It is within the scope of the skilled artisan to select a particular process for preparing a given compound of formula I. Some starting materials for preparing the compounds of the present application are available from commercial chemical suppliers. Other starting materials, such as those described below, are easily prepared from available precursors using simple transformations well known to those skilled in the art.

[0200] Compounds of formula I can generally be prepared by the process depicted in the scheme below. In the structures depicted below, the variables are as defined in formula I unless otherwise noted. 3 Comparative compounds in which C1-4 fluoroalkyl and OC1-4 fluoroalkyl are not were also prepared by a similar process. These comparative compounds are identified in this disclosure as formula "C" compounds. Those skilled in the art will appreciate that many of the reactions depicted in the schemes below are oxygen and water sensitive and will know to carry out the reactions under an anhydrous, inert atmosphere, if necessary. Reaction temperatures and reaction times are given for illustrative purposes only and may be varied to optimize yields as will be appreciated by those skilled in the art.

[0201] Thus, in some embodiments, a compound of formula I and a comparator compound of formula C are prepared as shown in Scheme 1. [ka]

[0202] Thus, in some embodiments, the substituted dichloropyrimidine A (R 1 is as defined in formula I or a protected version thereof) with an ortho-aminocarboxamide, B (R 4 and ring A is as defined in formula I or a protected version thereof) under basic conditions to give compound D, which can then be coupled with various anilines of formula E (R 2 , R 3 , X, Y and Z are as defined in formula I or a protected version thereof), under acidic or basic conditions to give, after removal of the protecting groups, a compound of formula I or formula C, if necessary. [ka]

[0203] In an alternative embodiment, intermediate D(R 1 , R 4 and ring A is as defined in formula I or a protected version thereof) can be reacted with various amino-isoquinolines or amino-aza-isoquinolines of formula F (R 3 and Ring B is as defined in formula I or a protected version thereof) under acidic or basic conditions to give, after removal of the protecting groups if necessary, a compound of formula I or formula C.

[0204] In some embodiments, X and Y are both carbon and R 1 is Cl, ring A is a 3-amino substituted thiophene, and R 2 and R 4 are both H and R 3 Compounds of formula I, where is OCF2H, are prepared as shown in Scheme 3. [ka]

[0205] Thus, commercially available 2,4,5-trichloropyrimidine A-1 can be treated with, for example, 3-amino-2-thiophenecarboxamine B-1 to give intermediate D-1. Coupling of D-1 with aniline E-1 (Z is as defined in formula I or a protected version thereof) gives, after removal of protecting groups if necessary, compounds of formula I.

[0206] In an alternative embodiment, compounds of formula I can be prepared as shown in Scheme 4. [ka]

[0207] Thus, treatment of 2,4,5-trichloropyrimidine A-1 with the protected carboxamide t-octyl 3-amino-2-thiophenecarboxamine B-1 (prepared from HATU-mediated coupling of 3-amino-2-thiophenecarboxylic acid and t-octylamine) provides intermediate D-2. As shown in Scheme 4, treatment of D-2 with aniline E-2, where Z is as defined in formula I or a protected version thereof, under acidic or basic conditions (e.g., TfO, EtN, CHCl) provides intermediate G, which is then subjected to acid-mediated deprotection conditions (e.g., TFA) to remove other protecting groups, if necessary, also to provide compounds of formula I.

[0208] Generally, the reaction is carried out in a suitable inert organic solvent at a temperature and for a time that will optimize the yield of the desired compound. Examples of suitable inert organic solvents include, but are not limited to, 2-propanol, dimethylformamide (DMF), dioxane, methylene chloride, chloroform, tetrahydrofuran (THF), toluene, and the like.

[0209] The salts of the compounds of the present application are generally formed by dissolving the neutral compound in an inert organic compound, adding either the desired acid or base, and isolating the resulting salt by filtration or other known means.

[0210] The formation of solvates of the compounds of the present application will vary depending on the compound and the solvate. In general, solvates are formed by dissolving the compound in a suitable solvent and isolating the solvate by cooling or by using an anti-solvent. The solvate is typically dried or azeotroped under ambient conditions. The selection of suitable conditions for forming a particular solvate can be made by one of ordinary skill in the art.

[0211] Prodrugs of the compounds of the present application may be, for example, conventional esters formed between available hydroxy, thiol, amino or carboxyl groups. For example, available hydroxy or amino groups may be acylated with an activated acid in the presence of a base, and optionally in an inert solvent (e.g., an acid chloride in pyridine). EXAMPLES

[0212] The following non-limiting examples are illustrative of the present application: Compound synthesis and characterization A general method for aniline coupling under acidic conditions.

[0213] To a mixture of aniline (1.1-1.5 equiv.) and chloropyrimidine (1 equiv.) in a microwave vial, IPA (0.05M-1M) and a few drops of concentrated HCl (1-1.6 drops / mmol) were added. The resulting mixture was irradiated in a microwave apparatus at 130-140°C for 2-4 h (mostly 3 h at 140°C). After evaporation of the solvent, the residue was dissolved in DCM and basified with aqueous NaHCO3. After extraction with DCM, the combined extracts were concentrated and triturated with MeOH or EtOAc to give the desired product. Alternatively, the crude mixture was purified by preparative HPLC to give the desired product.

[0214] When the aniline had an N-Boc moiety on the more basic amine, de-Boc occurred simultaneously as a one-pot reaction. Synthesis of 3-((5-chloro-2-((2-difluoromethoxy)-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)thiophene-2-carboxamide (compound I-1) [ka] Step 1: Synthesis of 3-((2,5-dichloropyrimidin-4-yl)amino)thiophene-2-carboxamide [ka]

[0215] To a solution of 3-aminothiophene-2-carboxamide ([Aldrich], 0.500 g, 3.52 mmol) in 2-propanol (10 ml) at room temperature was added 2,4,5-trichloropyrimidine ([Aldrich], 0.366 ml, 3.20 mmol) and N,N-diisopropylethylamine ([Aldrich], 0.668 ml, 3.84 mmol). The resulting solution was heated to 80° C. for 16 hours and then cooled to room temperature. The observed precipitate was collected by filtration and washed repeatedly with 2-propanol to give the desired product as a white powder. The product was dried under vacuum for 16 hours before being used in subsequent reactions. (Yield=0.569 g, 62%). LRMS: 289.2 / 293.4 (+ve) Step 2: Synthesis of 3-((5-chloro-2-((2-difluoromethoxy)-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)thiophene-2-carboxamide [ka]

[0216] To a solution of 3-((2,5-dichloropyrimidin-4-yl)amino)thiophene-2-carboxamide (see above, 0.100 g, 0.346 mmol) in 2-propanol (3 ml) at room temperature was added 2-(difluoromethoxy)-4-(4-methylpiperazin-,1-yl)aniline ([Enamine], 0.089 g, 0.346 mmol) and hydrochloric acid (III [Aldrich], 0.058 ml, 0.692 mmol). The resulting solution was heated to 120° C. for 16 hours (monitor the reaction as it may be complete after several hours; especially if using microwave), then cooled to room temperature and diluted with water (50 ml) and 1N NaOH solution (5 mL, ensure pH>8). The aqueous layer was extracted with EtOAc (3×40 ml) and the combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a dark solid which was purified by silica chromatography (Biotage SNAP 25 g column, 0-40% MeOH / EtOAc as eluent, 26 CV) to give a white powder (further recovered by trituration from EtOAc with hexanes) which was dried in vacuum for 16 h. (Yield=0.153 g, 87%). 1 H NMR(500MHz,MeOD-d4)δ 8.04(s,1H),7.56(d,J=8.8Hz,1H),7.44(d,J=5.3Hz,1H),6.94(d,J=8.8Hz,1H),6.86 (s,1H),6.73(t,J=74.2Hz,1H),3.29(s,4H),3.10(s,1H),2.72(s,4H),2.43(s,3H);MS (ESI)m / z 510.3[M+H] + ;LRMS:508.42(-ve) and 510.55(+ve).

[0217] In a similar manner, the following compounds of formula I or comparative compounds of formula C were synthesized: [Table 1-43] [Table 1-44]

Table 1-45

Table 1-46

Table 1-47

Table 1-48

Table 1-49

Table 1-50

Table 1-51

Table 1-52

Table 1-53

Table 1-54

Table 1-55

Table 1-56

Table 1-57

Table 1-58

Table 1-59

Table 1-60

Table 1-61

Table 1-62

Table 1-63

Table 1-64

Table 1-65

Table 1-66

Table 1-67

Table 1-68

Table 1-69

Table 1-70

Table 1-71

Table 1-72

[0218] Preparation of intermediates The following intermediate compounds were synthesized in a similar manner to Step 1 above: [Table 1-80] [Table 1-81] Synthesis of 4-((5-chloro-2-((2-difluoromethoxy)-4-(4-ethylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)thiophene-3-carboxamide (compound I-14) [ka] Step 1: Synthesis of methyl 4-((2,5-dichloropyrimidin-4-yl)amino)thiophene-3-carboxylate [ka]

[0219] To a solution of methyl 4-aminothiophene-3-carboxylate (0.566 g, 3.60 mmol) in 2-propanol (10 ml) at room temperature was added 2,4,5-trichloropyrimidine (0.413 ml, 3.60 mmol) and N,N-diisopropylethylamine (0.752 ml, 4.32 mmol). The resulting solution was heated to 80° C. for 16 h and then cooled to room temperature. The observed precipitate was collected by filtration and washed repeatedly with 2-propanol to give a light brown powder which was dried in vacuum for 16 h to give the title compound in 56% yield, which was used directly in the subsequent reaction. LRMS: 304.29 (+ve) Step 2: Synthesis of methyl 4-((5-chloro-2-((2-difluoromethoxy)-4-(4-ethylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)thiophene-3-carboxylate [ka]

[0220] To a solution of methyl 4-((2,5-dichloropyrimidin-4-yl)amino)thiophene-3-carboxylate (0.350 g, 1.151 mmol) in 2-propanol (7 ml) at room temperature was added 2-(difluoromethoxy)-4-(4-ethylpiperazin-1-yl)aniline (0.312 g, 1.151 mmol) and hydrochloric acid (0.096 ml, 1.151 mmol). The resulting solution was heated to 120° C. for 16 h, then cooled to room temperature and diluted with 1N NaOH solution (50 mL). The aqueous layer was extracted with EtOAc (3×40 mL) and the combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a black solid. The solid was dissolved in a minimum amount of EtOAc and triturated with hexane to give a beige solid (83% yield) which was dried under vacuum for 24 h. LRMS: 539.50 (+ve) Step 3: Synthesis of 4-((5-chloro-2-((2-difluoromethoxy)-4-(4-ethylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)thiophene-3-carboxamide [ka]

[0221] To a solution of methyl 4-((5-chloro-2-((2-difluoromethoxy)-4-(4-ethylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)thiophene-3-carboxylate (0.150 g, 0.278 mmol) in methanol (MeOH) (2 ml) at room temperature was added 7N ammonia solution in methanol (3.98 ml, 27.8 mmol). The resulting solution was heated to 75° C. for 16 h, then cooled to room temperature and diluted with 1N NaOH solution (40 mL). The aqueous layer was extracted with EtOAc (3×40 mL) and the combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a black solid. The solid was purified by silica chromatography (Biotage SNAP25 g column, 0-30% MeOH / EtOAc as eluent, 26 CV) to give a beige powder (further triturated from EtOAc with hexanes) which was dried in vacuum for 24 h. LRMS: 522.33 (-ve) 524.58 (+ve) 1 H NMR(500MHz,MeOD-d4)δ 8.15(d,J=3.4Hz,7H),7.99(s,7H),7.76(s,7H),7.54(d,J=8.8Hz,7H),6.95(dd,J=8.8,2.5Hz,8H),6.88-6.84(m ,9H),6.70(s,4H),6.56(s,2H),3.32-3.29(m,27H),2.79(s,27H),2.64(q,J=7.2Hz,15H),1.22(t,J=7.2Hz,21H).

[0222] Compound I-51 was prepared in a similar manner in 23% overall yield. 1H NMR(500MHz,DMSO-d6)δ 11.40(s,1H),8.64(s,1H),8.33(d,J=3.0Hz,1H),8.19(br s,1H),8.06 (s,1H),7.81(br s,1H),7.59(br s,1H),7.33(d,J=8.7 Hz,1H),7.04(t,J=74.1Hz,1H),6.85(dd,J=8.9,2.5Hz,1H),6.76(d,J=2.1Hz,1H),3.73(d,J=12.3Hz,2H),2.73(t,J=11.4Hz,2H),2.40-2.25(br m,6H),2.15(s,3H),1.86(d,J=11.6Hz,2H),1.58-1.47(m,2H);MS(ESI) m / z 593.5[M+H] + . Commercially available anilines as reagents in the synthesis of compounds

[0223] Below is a list of commercially available anilines that have been coupled to a pyrimidine core in the above manner. [Table 1-82] Preparation of anilines as reagents in the synthesis of compounds Method A: [ka]

[0224] To a 30 mL vial containing 2-(difluoromethoxy)-4-fluoro-1-nitrobenzene (414 mg, 2 mmol, 1 equiv.) and cis-1,2,6-trimethylpiperazine (282 mg, 2.2 mmol, 1.1 equiv.) was added DMF (5 mL) and K2CO3 (415 mg, 3 mmol, 1.5 equiv.). The resulting mixture was stirred at 60 °C for 30 min. H2O (25 mL) was added slowly to the reaction mixture and the resulting yellow precipitate was collected by suction filtration, washed with H2O, and air-dried to give a yellow solid. LC-MS calculated [C 14 H 19 F2N3O3+H] +316.1; Actual value 316.4

[0225] The yellow solid was redissolved in MeOH (40 mL). Hydrazine monohydrate (0.39 mL, 8 mmol, 4 equiv) was added followed by Raney Nickel 2800 (137 mg, 1.6 mmol, 0.7 equiv). The resulting mixture was heated at 50° C. for 20 min. Hydrazine monohydrate (0.19 mL, 4 mmol, 2 equiv) was added followed by Raney Nickel 2800 (69 mg, 0.8 mmol). The resulting mixture was heated at 50° C. for 15 min. The mixture was filtered, rinsed with MeOH (10 mL), and the filtrate was concentrated and dried to give a dark purple oil (14.762-14.223 g = 539 mg, 94% yield over two steps). [C 14 H 21 F2N3O+H] + LC-MS calculated: 286.17; found: 286.36. Method B (reductive amination followed by reduction) [ka]

[0226] To a 50 mL vial containing 2-(difluoromethoxy)-4-fluoro-1-nitrobenzene (1.41 mL, 10 mmol) and piperidin-4-one HCl (1.424 g, 10.5 mmol) was added DMF (20 mL) and K2CO3 (2.90 g, 21 mmol). The resulting mixture was stirred at 60 °C for 1 h. The reaction was quenched with HO (100 mL) while stirring, and the resulting precipitate was collected by filtration, rinsed with HO (20 mL), air-dried and dried to give 1-(3-(difluoromethoxy)-4-nitrophenyl)piperidin-4-one (yellow solid, 2.784 g, 95%). MS (ESI) m / z 287.2 [M+H] + .

[0227] To a 50 mL vial charged with 1-(3-(difluoromethoxy)-4-nitrophenyl)piperidin-4-one (859 mg, 3 mmol) and an amine (e.g., 1-ethylpiperazine; 360 mg, 3.15 mmol) was added DCE (10 mL) and sodium triacetoxyborohydride (954 mg, 4.5 mmol), followed by 2 drops of HOAc. The resulting mixture was stirred at room temperature for 2 h. Aqueous workup was performed using DCM to give a yellow oil.

[0228] The yellow oil was redissolved in MeOH (20 mL). Hydrazine monohydrate (0.58 mL, 12 mmol) was added followed by Raney Nickel 2800 (129 mg, 1.5 mmol). The mixture was stirred at room temperature for 1 h. An additional 129 mg of Raney Nickel 2800 (1.5 mmol) was added and the mixture was stirred at room temperature for 30 min, filtered and rinsed with MeOH (20 mL). The filtrate was concentrated and dried to give 2-(difluoromethoxy)-4-(4-(4-ethylpiperazin-1-yl)piperidin-1-yl)aniline (brown crystalline solid, 934 mg, 80% over two steps, 91.32% pure). MS(ESI) m / z 355.5[M+H] + .

[0229] Similarly, the following compounds were prepared: [Table 1-83] [Table 1-84] [Table 1-85] [Table 1-86] [Table 1-87] [Table 1-88] [Table 1-89] General Method C: Synthesis of Anilines (Amine Displacement Followed by Nitro Reduction) [ka]

[0230] To a mixture of fluoro-nitrobenzene / pyridine (1 equiv.) and substituted piperazine or its HCl or di-HCl salt (1 equiv.-1.1 equiv.) in DMF (0.4 M) was added K2CO3 (3 equiv. relative to free base; 3.5 equiv.-4 equiv. relative to HCl, di-HCl salt). The resulting mixture was stirred at 60°C-70°C for 30 min-1 h. After cooling to room temperature, H2O (25 mL) was added slowly to the reaction mixture and the resulting precipitate was collected by suction filtration, washed with H2O, and air-dried to give the nitro intermediate as a solid. If no precipitate was formed, a standard aqueous workup by EtOAc extraction was performed to give the nitro intermediate as an oil or solid.

[0231] A solution or suspension of the above nitro intermediate in MeOH (0.2-0.5 M) was treated with hydrazine monohydrate (4 equiv.) and Raney Nickel 2800 (0.5 equiv.-0.8 equiv.). The resulting mixture was stirred at room temperature or heated at 50° C. for 15 min-1 h. If not complete, additional hydrazine monohydrate (1 equiv.-2 equiv.) and Raney Nickel 2800 (0.1 equiv.-0.4 equiv.) were added and the resulting mixture was heated at 50° C. for 15-30 min. After filtration and rinsing with MeOH, the filtrate was concentrated and dried to give the desired aniline as a solid or oil.

[0232] The following anilines were prepared using general procedure C: [Table 1-90] Synthesis of (1S,4S)-2-isopropyl-2,5-diazabicyclo[2.2.1]heptane [ka]

[0233] To a solution of (1S,4S)-(-)-2-Boc-2,5-diazabicyclo[2.2.1]heptane (991 mg, 5 mmol) in DCE (20 ml) was added acetone (1.11 mL, 15 mmol), sodium triacetoxyborohydride (1.70 g, 8 mmol) and 2 drops of HOAc. The resulting mixture was stirred at room temperature overnight. All solvent was removed and the resulting residue was treated with TFA (18 mL) and heated at 50° C. for 1.5 h. All solvent was removed and the resulting pale beige slurry was dried in vacuum to give crude (1S,4S)-2-isopropyl-2,5-diazabicyclo[2.2.1]heptane. Synthesis of 2-(difluoromethoxy)-3-fluoro-4-(4-methylpiperazin-1-yl)aniline [ka]

[0234] A mixture of 2,3-difluoro-6-nitrophenol (3.50 g, 20 mmol), 1-methylpiperazine (4.66 mL, 21 mmol) and acetonitrile (50 mL) in a 150 mL glass bomb was heated at 110° C. for 4.5 h. It was diluted with HO (50 mL), basified with saturated aqueous NaHCO until pH was about 8, and extracted with DCM (200 mL×2). The solvent was removed to give an orange solid, which was triturated with DCM / MeOH (2 mL / 20 mL) to give 2-fluoro-3-(4-methylpiperazin-1-yl)-6-nitrophenol (orange solid, 2.216 g). MS(ESI) m / z 256.2[M+H] + .

[0235] The orange solid was redissolved in DMF (10 mL) and treated with sodium chlorodifluoroacetate (1.525 g, 10 mmol) and potassium carbonate (2.76 g, 20 mmol). The resulting mixture was heated at 100° C. for 3 h. Aqueous workup gave a dark brown oil.

[0236] The crude dark brown oil (from the previous step) (estimated 8.33 mmol) was redissolved in MeOH (50 mL). Hydrazine monohydrate (1.21 mL, 25 mmol) was added followed by Raney Nickel 2800 (428 mg, 5 mmol). The resulting mixture was stirred at room temperature for 15 min, then heated at 50° C. for 45 min, filtered and rinsed with MeOH (20 mL). The filtrate was concentrated and dried to give 2-(difluoromethoxy)-3-fluoro-4-(4-methylpiperazin-1-yl)aniline (dark brown oil, 1.984 g, 24% over 3 steps, 65.87% pure). MS(ESI) m / z 276.3[M+H] + . In a similar manner, the following compounds were prepared: [Table 1-91] Synthesis of 2-(difluoromethoxy)-4-(4-ethylpiperazin-1-yl)aniline (8-6) [ka]

[0237] Step 1: Synthesis of 4-bromo-2-methoxy-1-nitrobenzene (8-2) To a solution of compound 8-1 (1 g, 4.5 mmol) in methanol (10 ml), 30% NaOMe in MeOH (1.36 ml) was added under argon atmosphere while stirring the solution and heated to 40° C. for 5 min. After 5 min, the reaction mixture was evaporated to dryness under reduced pressure. The crude product was then dissolved in EtOAc (50 mL) and washed with cold water (3×10 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give crude compound 8-2 (0.87 g, 83%) as a light brown solid, which was pure enough to be used in the next step; LCMS [M+H] + 232.1.

[0238] Step 2: Synthesis of 1-ethyl-4-(3-methoxy-4-nitrophenyl)piperazine (8-3) To a solution of crude compound 8-2 (0.5 g, 2.2 mmol) in DMF (5 ml) was added K2CO3 (0.899 g, 6.5 mmol) and 1-ethylpiperazine (0.552 mL, 4.4 mmol) under argon atmosphere while stirring the solution. The reaction mixture was heated to 80 °C for 16 h and then cooled to room temperature. The reaction mixture was poured into ice-cold water (10 mL), extracted with ethyl acetate (3 x 15 mL) and washed with ice-cold brine (2 x 10 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude product as a brown gummy liquid; this was then purified using a Grace Reveleris™ R silica flash cartridge (12 g column) using 2%-3% methanol in DCM as the eluent to give compound 8-3 (0.34 g, 60%) as a yellow oil; LCMS [M+H] + 266.1.

[0239] Step 3: Synthesis of 5-(4-ethylpiperazin-1-yl)-2-nitrophenol (8-4) To a solution of 47% aqueous HBr (42 mL) was added compound 8-3 (4.03 g, 15.2 mmol) while stirring the solution, and the mixture was heated to 105° C. for 18 h, then cooled to room temperature. The reaction mixture was poured into ice-cold saturated NaHCO3 solution (50 mL), adjusted to pH 8, and extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give crude compound 8-4 (3.8 g, quantitative), which was pure enough to be used in the next step. LCMS [M+H] + 252.

[0240] Step 4: Synthesis of 1-(3-(difluoromethoxy)-4-nitrophenyl)-4-ethylpiperazine (8-5) To a solution of crude compound 8-4 (3.44 g, 13.7 mmol) in DMF (35 ml), K2CO3 (2.0825 g, 15.1 mmol) and 2-chloro-2,2-difluoroacetic acid Na salt (2.506 g, 16.4 mmol) were added under argon atmosphere while stirring the solution. The reaction mixture was then heated to 90 °C for 9 h, and then cooled to room temperature. The reaction mixture was diluted with ethyl acetate (100 mL), washed with cold water (3 x 25 mL), and then washed with brine (2 x 25 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give crude compound 8-5 (3.8 g, 92%) as a brown oil, which was pure enough to be used in the next step. LCMS [M+H] + 302.

[0241] Step 5: Synthesis of 2-(difluoromethoxy)-4-(4-ethylpiperazin-1-yl)aniline 8-6 To a solution of crude compound 5 (1 g, 3.3 mmol) in ethanol (10 ml) was added 10% Pd / C (0.1 g, 10% w / w) under argon while stirring the solution, then stirred at room temperature under H2 atmosphere (balloon pressure) for 16 h. The reaction mixture was then filtered through a bed of Celite™; this was washed with MeOH (200 mL). The filtrate was concentrated under vacuum to give a crude residue; this was purified by column chromatography (basic alumina) using 10%-30% ethyl acetate in petroleum ether as eluent to give 2-(difluoromethoxy)-4-(4-ethylpiperazin-1-yl)aniline (0.64 g, 71%) as a dark red oil. LCMS [M+H] + 272.1. Synthesis of 4-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)aniline (9-5) [ka]

[0242] Step 1: Synthesis of tert-butyl (4-bromo-2-(trifluoromethoxy)phenyl)carbamate (9-2): A solution of compound 9-1 (6 g, 23.4 mmol) in DCM (60 mL) was treated with TEA (4.8 mL, 35.1 mmol) and di-tert-butyl dicarbonate (7.6 mL, 35.1 mmol) while stirring the solution, followed by DMAP (0.572 g, 35.1 mmol) at 0° C. to room temperature for 1 h. The reaction mixture was poured into ice water (1×200 mL) and extracted with DCM (1×200 mL). The separated organic layer was dried over Na2SO4 and concentrated under reduced pressure to give crude compound 9-2 (7 g, quantitative) as an off-white solid; LCMS [M+H] + 356.2.

[0243] Step 2: Synthesis of tert-butyl (4-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl)carbamate (9-4): A solution of compound 9-2 (7 g, 19.7 mmol) in toluene (70 mL) was treated with compound 9-3 (3.5 mL, 31.6 mmol), NaO-t-Bu (2.3 g, 23.6 mmol), and then Davephos (0.75 g, 2.0 mmol), while stirring the solution, degassed for 15 minutes, and then added Pd2(dba)3 (0.365 g, 2.0 mmol). The reaction mixture was heated to 120° C. for 16 hours, and then cooled to room temperature. The reaction mixture was then filtered through a Celite bed, which was washed with 5% methanol in DCM (300 mL). The combined filtrate was then concentrated under reduced pressure to give a crude residue, which was purified by column chromatography (neutral alumina) using 100% petroleum ether as the eluent to give compound 9-4 (4 g (33% pure by LCMS), 30%) as a brown liquid; LCMS [M+H] + 376.4.

[0244] Step 3: Synthesis of 4-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)aniline (9-5) A solution of compound 9-4 (4 g (33% pure by LCMS), 4.8 mmol) in 4M dioxane·HCl (20 mL) was allowed to stand at room temperature for 5 h. The solvent was concentrated under reduced pressure and the reaction mixture was poured into ice water (1×100 mL), basified with saturated sodium bicarbonate and extracted with DCM (1×200 mL). The separated organic layer was dried over Na2SO4 and concentrated under reduced pressure to give a crude residue which was purified by preparative HPLC to give 4-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)aniline (0.5 g, 50%) as a brown gummy liquid. LCMS [M+H] + 276.1. Synthesis of 2-(difluoromethoxy)-4-morpholinoaniline (10-8) [ka]

[0245] Step 1: Synthesis of 4-bromo-2-methoxy-1-nitrobenzene (10-2) To a solution of compound 10-1 (15 g, 68.5 mmol) in methanol (150 mL), 30% NaOMe in MeOH (18.5 mL) was added at room temperature while stirring the solution, and stirred at 40° C. for 20 min. The reaction mixture was then diluted with ice water (500 mL); the resulting precipitate was filtered, washed with water (100 mL), and dried under vacuum to obtain crude compound 10-2 (15 g, 95%) as a pale yellow solid. The crude compound was used for the next step without further purification; LCMS [M+H] + 232.1.

[0246] Step 2: Synthesis of 4-(3-methoxy-4-nitrophenyl)morpholine (10-4) To a solution of compound 10-3 (15 g, 65 mmol) in DMF (150 mL), potassium carbonate (35.84 g, 260 mmol) was added while stirring the solution, and then compound 3 (16.8 mL, 195 mmol) was added, and the reaction mixture was stirred at 85° C. for 18 hours, and then cooled to room temperature. The reaction mixture was diluted with ice water (300 mL); the resulting precipitate was filtered, washed with water (200 mL), and dried under vacuum to obtain compound 10-4 (11 g, 71%) as a pale yellow solid. The crude compound was used for the next step without further purification; LCMS [M+H] + 239.

[0247] Step 3: Synthesis of 5-morpholino-2-nitrophenol (10-5) To a solution of compound 10-4 (3 g, 12.6 mmol) in stirred 47% aqueous HBr (30 mL), the reaction mixture was heated at 120° C. for 12 h and then cooled to room temperature. The reaction mixture was poured into ice water, basified with NaHCO3, and extracted with EtOAc (3×300 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give crude compound 10-5 (1.5 g, 53%) as a green solid. The crude compound was used for the next step without further purification. LCMS [M+H] + 225.

[0248] Step 4: Synthesis of 4-(3-(difluoromethoxy)-4-nitrophenyl)morpholine (10-7) To a solution of compound 10-5 (1.5 g, 6.7 mmol) in DMF (25 mL), cesium carbonate (6.52 g, 20.1 mmol) was added while stirring the solution, followed by compound 10-6 (1.11 g, 7.35 mmol), and the resulting reaction mixture was stirred at 90° C. for 3 h and then cooled to room temperature. The reaction mixture was poured into ice water and extracted with EtOAc (2×200 mL). The combined organic layers were washed with chilled water (200 mL), dried over Na2SO4, and concentrated under reduced pressure to give the crude compound. The crude product was triturated with 10% diethyl ether in n-pentane (50 mL), and the resulting precipitate was filtered and dried in vacuum to give compound 10-7 (1.3 g, 71%) as a green solid. LCMS [M+H] + 275.

[0249] Step 5: Synthesis of 2-(difluoromethoxy)-4-morpholinoaniline (10-8) To a solution of compound 10-7 (1.3 g, 4.7 mmol) in ethanol (30 mL) was added 10% Pd / C (0.7 g) at room temperature under hydrogen balloon pressure for 5 h. The reaction mixture was filtered through a Celite pad and washed with methanol (100 mL). The filtrate was concentrated under vacuum to give the crude compound, which was purified by column chromatography (neutral alumina) using 10%-20% EtOAc in petroleum ether as eluent to give 2-(difluoromethoxy)-4-morpholinoaniline (0.9 g, 78% yield) as a brown solid. LCMS [M+H] + 245. Synthesis of 2-(difluoromethoxy)-5-fluoro-4-(4-methylpiperazin-1-yl)aniline (11-9) [ka]

[0250] Step 1: Synthesis of 1-bromo-2,5-difluoro-4-nitrobenzene (11-2) To a solution of compound 11-1 (6 g, 31.2 mmol) in concentrated H2SO4 (60 ml) cooled to 0°C, potassium nitrate (3.1 g, 31.2 mmol) was added while stirring the solution. The reaction mixture was then stirred at room temperature for 30 min. The reaction mixture was diluted with water and extracted with EtOAc (2 x 200 mL). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, and concentrated under reduced pressure to give crude compound 11-2 (7 g, quantitative) as an off-white solid. LC-MS: m / z 312.17 (M+H);

[0251] Step 2: Synthesis of 1-bromo-2-fluoro-5-methoxy-4-nitrobenzene (11-3) To a solution of compound 11-2 (7 g, 29.5 mmol) in methanol (70 ml), 30% NaOMe in MeOH (8.8 ml) was added at room temperature while stirring the solution, and stirred at 40° C. for 10 min. The reaction mixture was diluted with ice water (500 mL); the resulting precipitate was filtered, washed with water (100 mL), and dried to obtain crude compound 11-3 (6 g, quantitative) as an off-white solid. The crude compound was used for the next step without further purification.

[0252] Step 3: Synthesis of 1-(2-fluoro-5-methoxy-4-nitrophenyl)-4-methylpiperazine (11-5) To a solution of compound 11-3 (6 g (quantitative), 24.0 mmol) in DMF (60 ml) cooled to 0° C., potassium carbonate (9.9 g, 72.0 mmol) was added while stirring the solution, and then compound 11-4 (5.3 mL, 48.1 mmol) was added, and the resulting reaction mixture was stirred at 80° C. for 16 hours, and then cooled to room temperature. The reaction mixture was diluted with ice water (300 mL); the resulting precipitate was filtered, washed with water (100 mL), and dried to give crude compound 11-5 (6.2 g, quantitative) as a yellow solid. The crude compound was used for the next step without further purification. LC-MS: m / z 270.4 (M+H);

[0253] Step 4: Synthesis of 4-fluoro-5-(4-methylpiperazin-1-yl)-2-nitrophenol (11-6): To a solution of compound 11-5 (6.2 g, 23.0 mmol) in 48% aqueous HBr (300 ml), the reaction mixture was heated at 120° C. for 6 h while stirring the solution, then cooled to room temperature. The reaction mixture was poured into ice water, basified with aqueous NaHCO3, and extracted with EtOAc (2×500 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give crude compound 11-6 (5 g, (quantitative)) as a brown solid. The crude compound was used for the next step without further purification. LCMS: m / z 256.4 ([M+H] + );

[0254] Step 5: Synthesis of 1-(5-difluoromethoxy)-2-fluoro-4-nitrophenyl)-4-methylpiperazine (11-8) To a solution of compound 11-6 (5 g, 19.6 mmol) in DMF (50 ml) cooled to 0° C., potassium carbonate (2.7 g, 19.6 mmol) was added while stirring the solution, followed by compound 11-7 (3.2 g, 21.5 mmol), and the resulting mixture was stirred at 90° C. for 2 h and then cooled to room temperature. The reaction mixture was poured into ice water and extracted with EtOAc (2×200 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give the crude compound. The crude product was purified by column chromatography (silica gel, 100-200 mesh) using 70% EtOAc in petroleum ether as eluent to give compound 11-8 (3.5 g, 59% yield) as a brown liquid. LC-MS: m / z 306.4 (M+H).

[0255] Step 6: Synthesis of 2-(difluoromethoxy)-5-fluoro-4-(4-methylpiperazin-1-yl)aniline (11-9): To a solution of compound 11-8 (3.5 g, 11.4 mmol) in EtOH (40 ml) was added 10% Pd / C (0.6 g) at room temperature under hydrogen balloon pressure for 6 h. The reaction mixture was filtered through a Celite pad and washed with methanol (100 mL). The filtrate was concentrated under vacuum to give the crude compound; this was purified by column chromatography (basic alumina) using 10% EtOAc in petroleum ether as eluent to give 2-(difluoromethoxy)-5-fluoro-4-(4-methylpiperazin-1-yl)aniline (1.4 g, 45% yield) as a brown liquid. 1 H NMR (400MHz,DMSO-d6):δ 6.95(t,J=74.4Hz,1H),δ 6.7(d,J=8.4Hz,1H),δ 6.55(d,J=14Hz,1H),δ 4.94(br s,2H),δ 2.83(t,J=4.4Hz,4H),δ 2.42(s,4H),δ 2.19(s,3H); LC-MS: m / z276.2(M+H). Synthesis of 2-(difluoromethoxy)-4-(1-methylpiperidin-4-yl)aniline (14-8) [ka]

[0256] Step 1: Synthesis of 5-chloro-2-nitrophenol (14-2): To a solution of compound 14-1 (10 g, 53.3 mmol) in DCM (100 ml) was added AlCl3 (14.2 g, 106.6 mmol) in portions at 0° C., then stirred at room temperature for 16 h. The reaction mixture was poured into ice water (200 mL) and extracted with ethyl acetate (2×200 mL). The separated organic layer was dried over Na2SO4 and concentrated under reduced pressure to give compound 14-2 (8 g, quantitative) as a pale yellow solid, which was pure enough to be used in the next step.

[0257] Step 2: Synthesis of 4-chloro-2-(difluoromethoxy)-1-nitrobenzene (14-4): To a solution of compound 14-2 (5 g, 29.0 mmol) in DMF (50 ml) cooled to 0° C., cesium carbonate (9.4 g, 29.0 mmol) was added while stirring the solution, and then compound 14-3 (4.8 g, 31.9 mmol) was added, and the resulting reaction mixture was stirred at 90° C. for 2 h, and then cooled to room temperature. The reaction mixture was poured into ice water and extracted with EtOAc (2×200 mL). The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure to give compound 14-4 (4 g, quantitative) as a pale yellow liquid, which was pure enough to be used in the next step.

[0258] Step 3: Synthesis of 4-(3-(difluoromethoxy)-4-nitrophenyl)pyridine (14-6): To a degassed suspension of compound 14-4 (6 g, 26.9 mmol), compound 14-5 (3.9 g, 32.2 mmol), and cesium carbonate (21.9 g, 67.2 mmol) in dioxane:HO (48 mL:12 ml), Pd(dppf)Cl2·DCM (0.7 g, 0.9 mmol) was added, and the reaction mixture was then degassed again with argon for 10 min. The reaction mixture was heated at 100 °C for 16 h and then cooled to room temperature. The reaction mixture was filtered through a bed of Celite, which was washed with 10% methanol in DCM (600 mL). The combined filtrate was then concentrated under reduced pressure to give a crude residue, which was purified by column chromatography (silica gel 100-200 mesh) using 5-10% methanol in DCM as the eluent to give compound 14-6 (5 g, 70%) as a brown solid.

[0259] Step 4: Synthesis of 4-(3-(difluoromethoxy)-4-nitrophenyl)-1-methylpyridin-1-ium (14-7): To a solution of compound 14-6 (3 g, 11.2 mmol) in acetone (30 ml), iodomethane (3.5 mL, 56.3 mmol) was added while stirring the solution and stirred at room temperature for 16 h. The solid was removed, filtered, and dried in vacuum to give compound 14-7 (3.5 g, quantitative) as a yellow solid, which was pure enough to be used in the next step.

[0260] Step 5: Synthesis of 2-(difluoromethoxy)-4-(1-methylpiperidin-4-yl)aniline (14-8) To a solution of compound 14-7 (3.5 g, 12.4 mmol) in methanol (105 ml) was added platinum oxide (1.1 g, 4.98 mmol) under argon and then stirred at room temperature under H2 atmosphere (balloon pressure) for 16 h. The reaction mixture was then filtered through a bed of Celite, which was washed with methanol (300 mL). The filtrate was concentrated under vacuum to give the crude compound, which was purified by column chromatography (neutral alumina) using 70%-80% ethyl acetate in petroleum ether as eluent to give 2-(difluoromethoxy)-4-(1-methylpiperidin-4-yl)aniline (1 g, 32%) as a brown liquid. 1 H NMR(400MHz,DMSO-d6):δ 7.18-6.80(m,3H),δ 6.7(d,J=8.8Hz,1H),δ 4.83(br s,2H),δ 2.8(d,J=11.2Hz,2H),δ 2.30-2.18(m,1H),δ 2.10(s,3H), δ1.93-1.87(m,2H),δ 1.65(d,J=10.8Hz,2H),δ1.67-1.49(m,2H);LCMS m / z 257.47([M+H] + ): Synthesis of 2-(difluoromethoxy)-4-(1-methylpiperidin-4-yl)aniline [ka]

[0261] LiCl (1400 mg, 33.0 mmol) was added to a solution of 6-methoxy-2-methyl-7-nitro-3,4-dihydroisoquinolin-1(2H)-one (1300 mg, 5.50 mmol) in anhydrous DMF (12 ml). The mixture was stirred at 140° C. for 16 h (TLC). The solution was concentrated in vacuo, the residue was dissolved in CHCl (40 mL) and this solution was washed with 1N HCl (aq). The organic layer was dried over MgSO and concentrated in vacuo to give the title compound (1.20 g, 98%) as a yellow-orange solid, which was used directly in the next step.

[0262] A 20 mL vial was charged with 6-hydroxy-2-methyl-7-nitro-3,4-dihydroisoquinolin-1(2H)-one (1.10 g, 4.95 mmol, 1.0 equiv), acetonitrile (15.0 mL) and 6 M aqueous KOH (9.9 mL). The mixture was stirred rapidly at room temperature and HCF2OTf (1.876, 14.85 mmol, 3.0 equiv) was added in one portion. Note: The reaction is exothermic. The mixture was stirred vigorously for 2 min. The reaction product was diluted with H2O (8 mL) and extracted with DCM (2 x 25 mL). The combined organic layers were dried over MgSO4, concentrated and purified by silica gel chromatography (hexanes / EtOAc 0-100%) to give the title compound as a pale yellow solid (933 mg, 69%).

[0263] To a solution of 6-(difluoromethoxy)-2-methyl-7-nitro-3,4-dihydroisoquinolin-1(2H)-one (240 mg, 2.1 mmol) in THF (5 ml) was added borane dimethylsulfide complex (2.0 M, 3 mL). The resulting mixture was stirred at reflux for 14 h, then quenched by slow addition of MeOH at room temperature and stirred at reflux for 2 h. Volatiles were removed under reduced pressure and the residue was purified by silica gel flash chromatography eluting with 0%-10% MeOH / DCM to give 7-methoxy-2-methyl-8-nitro-2,3,4-S-tetrahydro-1H-benzo[c]azepine as a yellowish brown solid (240 mg, 97%).

[0264] To a solution of 6-(difluoromethoxy)-2-methyl-7-nitro-1,2,3,4-tetrahydroisoquinolin-7-amine (230 mg, 0.891 mmol) in MeOH (5 mL) and AcOH (1 ml) was added zinc powder (582 mg, 8.91 mmol). The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was filtered and the solvent was removed under vacuum. The residue was neutralized with NH4OH and extracted with DCM. The volatile compounds were removed under reduced pressure to give 6-(difluoromethoxy)-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-amine as a light brown solid (162 mg, 80%). The crude product was used in the next step without further purification.

[0265] Biological assays NUAK2 enzyme assay To identify small molecule NUAK inhibitors, a biochemical NUAK2 enzyme assay was outsourced to Eurofins. The assay was performed radiometrically using the full-length recombinant enzyme. NUAK2(h) was incubated with 8 mM MOPS pH 7.0, 0.2 mM EDTA, 300 μM KKKVSRSGLYRSPSMPENLNRPR, 10 mM magnesium acetate and [9-33P]-ATP (specific activity and concentration as required). The reaction was started by the addition of the Mg / ATP mix. After 40 min of incubation at room temperature, the reaction was stopped by adding phosphoric acid to a concentration of 0.5%. 10 μL of the reaction product was then spotted onto a P30 filtermat and washed four times for 4 min with 0.425% phosphoric acid and once with methanol before drying and scintillation counting. Compounds were routinely counterscreened against Aurora A and NUAK1. The results are shown in Table 1, where IC 50 are reported in the following ranges: For compounds of formula I), A: 0.1 nM-10 nM; B: 11 nM-100 nM; C: 101 nM-1000 nM; D: >1000 nM. Table 1: IC of representative compounds of the present application and comparative compounds for inhibition of NUAK2, NUAK1 and Aurora A 50 (nM) [Table 1-92] [Table 1-93] [Table 1-94] [Table 1-95] [Table 1-96]

[0266] R 3 is selected from C1-4 fluoroalkyl and OC1-4 fluoroalkyl, 3 showed a trend towards improved selectivity for inhibition of NUAK2, particularly relative to Aurora A kinase, compared to corresponding compounds containing other similar groups such as non-fluorinated alkyl or Cl (see Table 2). Table 2: NUAK2 selectivity for compounds of the present application compared to corresponding comparison compounds. [Table 2]

[0267] Cell-based YAP / TAZ localization assay Compounds of the present application were tested for their ability to inhibit YAP / TAZ from localizing to the nucleus of cells using the assay outlined in Nature Communications, 2018, 9:3510. Live cell imaging of MDA-MB-231 expressing clover YAP was performed using a custom WAVE-FX-X1 spinning disk confocal system (Quorum Technologies) with a modified Yokogawa CSU-X1 scanhead on an AxioObserver Z1 inverted microscope (Carl Zeiss) equipped with a ×40, NA 1.2 Plan Apochromat (Carl Zeiss) objective. Cells were plated on 35 mm glass bottom dishes (Mat-Tek, P35G-1.5-14-C) and maintained in a stage-top incubator at 37°C and 5% CO2 during imaging. Cells were cultured in phenol red-free RPMI medium (Thermo Fisher Scientific, 11835030) containing 5% FBS, and 200 nM SiR-DNA (Spirochrom, SC007) was added 1 h before imaging to visualize the nuclei. Clover YAP localization was monitored every 10 min for 2 h. Velocity software was used for image acquisition and processing. Compound 1-1 showed a significant improvement in the inhibition of YAP / TAZ localization (see Figure 1).

[0268] Cell-based phospho-MYPT1 assay: Compounds with sufficient activity in the biochemical NUAK assay were evaluated in cell-based assays to confirm their targeting activity.An antibody against MYPT1, a NUAK2 substrate, was utilized because it specifically recognizes the phosphorylated Ser445 epitope in the endogenous MYPT1 protein, allowing direct evaluation of target engagement by NUAK2 inhibitors in cells (Biochem J.2014 457(Pt1):215-225;Biochem J.201 461(Pt2):233-245). MDA-MB-231 cells were incubated in the absence (DMSO) or presence of compound I-1 (500 nM) for 1 h. Cells were lysed in RIPA buffer (50 mM Tris-HCl, 150 mM NaCl, 1 mM EDTA, 0.1% SDS, 1% NP-40, 0.5% sodium deoxycholate) containing protease and phosphatase inhibitors for 30 min at 4°C. Samples were separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), transferred to nitrocellulose, and pSer 445 Immunoblotting was performed to detect MYPT1 or ACTIN. The results of this assay are shown in Figure 2, where inhibition of NUAK2 by exemplary compound I-1 inhibits the formation of p-MYPT1 in cells.

[0269] (c) Tumor cell proliferation inhibition assay MDA-MB-231 cells were seeded at 1,000 cells / well in 50 μl of medium (alpha-MEM containing 10% FBS, 100 mg / ml Normocin (Invivogen) and 50 mg / ml Gentamicin (Invitrogen)) in 384-well plates. Plates were then incubated overnight to allow cells to attach. Cells were dosed with DMSO or test compounds over a 16-point concentration range (high dose 10 μM to low dose 5 nM) using an HP D300 digital dispenser. Plates were incubated at 37°C in a humidified 5% CO2 incubator. After 5 days, plates were removed from the incubator and allowed to equilibrate to room temperature. An equal volume of ATPlite assay reagent was then added to each well and samples were processed according to the manufacturer's instructions (Perkin Elmer). Luminescence signals were then measured using an Envision plate reader equipped with an ultrasensitive (US) luminescence detector.

[0270] The results for representative compounds of the present application are shown in Table 3. Table 3: Antiproliferative activity of representative NUAK inhibitors for compounds of the present application in breast tumor cell line MDA-MB-231 [Table 3]

[0271] While the present application has been described with reference to what are presently considered to be the preferred examples, it is to be understood that the present application is not limited to the disclosed examples. On the contrary, the present application is intended to cover various modifications and equivalent arrangements included within the spirit and scope of the appended claims.

[0272] All publications, patents, and patent applications are incorporated by reference in their entirety into this disclosure to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference in its entirety. If any term in this application is found to have a different definition in a document incorporated by reference into this disclosure, the definition provided in this disclosure shall control for said term.

Claims

1. A compound of formula I, or a pharma- ceutically acceptable salt, solvate and / or prodrug thereof: [Formula 1] During the ceremony: A is, [chemical 2] Selected from: * is the point of attachment for A in compounds of formula I; R １ is selected from H, halo, C1-4 alkyl, OC1-4 alkyl, C1-4 haloalkyl, OC1-4 haloalkyl, CN, C1-4 hydroxyalkyl, and OC1-4 hydroxyalkyl; R ２ is selected from H, halo, CN, C1-4 alkyl, C1-4 haloalkyl, OC1-4 alkyl, and OC1-4 haloalkyl; R ３ is selected from C1-4 fluoroalkyl and OC1-4 fluoroalkyl; R ４ is selected from H, C1-4 alkyl, and C1-4 haloalkyl; R ５ and R ６ is independently selected from H, halo, CN, C1-4 alkyl, and C1-4 haloalkyl; X is CR ａ and N; Y is CR ｂ and N; R ａ and R ｂ is independently selected from H, halo, C1-4 alkyl, and C1-4 haloalkyl; Z is C1-6 alkyleneNR ７ R ８ , OC1-6 alkyleneNR ７ R ８ , N.R. ９ C1-6 alkylene NR ７ R ８ , N.R. ９ C1-6 alkylene OR ７ and N.R. ７R ８ or Z and R ２ and are bonded together with the atoms therebetween to form a ring B selected from C3-12 cycloalkyl and C3-12 heterocycloalkyl, said ring B being selected from halo, ═O, OH, C1-6 alkyl, C3-6 cycloalkyl, aryl, C5-6 heteroaryl, C3-6 heterocycloalkyl, C1-6 alkylene C3-6 cycloalkyl, C1-6 alkylene aryl, C1-6 alkylene C5-6 heteroaryl, C1-6 alkylene C3-6 heterocycloalkyl, C(O)C1-6 alkyl, OC1-6 alkyl, OC1-6 alkylene OC1-6 alkyl, C(O)NH ２ , C(O)NH(C1-6 alkyl), C(O)N(C1-6 alkyl)(C1-6 alkyl), NHC(O)C1-6 alkyl, N(C1-6 alkyl)C(O)C1-6 alkyl, NH ２ , NH(C1-6 alkyl), N(C1-6 alkyl)(C1-6 alkyl), SC1-6 alkyl, S(O)C1-6 alkyl and SO ２ Optionally substituted by one or more substituents selected from C1-6 alkyl, and all alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups of said optional substituents on said ring B are also optionally substituted by one or more of halo, C1-6 alkyl, OC1-6 alkyl, C1-6 haloalkyl and OC1-6 haloalkyl; R ７ is H, C1-6 alkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkylene C3-10 cycloalkyl, C1-6 alkylene C3-10 heterocycloalkyl, C1-6 alkyl alkylene OR １０ and C1-6 alkyl alkylene NR １０ R １１ is selected from R ７all alkyl, alkenyl, alkynyl, alkylene, heterocycloalkyl and cycloalkyl groups are optionally substituted with one or more of halo, C1-6 alkyl and C1-6 haloalkyl; R ８ is selected from H, C1-6 alkyl, and C1-6 haloalkyl; or R ７ and R ８ and are bonded together with the atoms therebetween to form a C3-12 heterocycloalkyl, the C3-12 heterocycloalkyl being NR １２ , O, S, S(O) and SO ２ and optionally containing one further hetero moiety selected from halo, ═O, OH, C1-6 alkyl, C3-6 cycloalkyl, aryl, C5-6 heteroaryl, C3-6 heterocycloalkyl, C1-6 alkylene C3-6 cycloalkyl, C1-6 alkylene aryl, C1-6 alkylene C5-6 heteroaryl, C1-6 alkylene C3-6 heterocycloalkyl, C(O)C1-6 alkyl, OC1-6 alkyl, OC1-6 alkylene OC1-6 alkyl, C(O)NH ２ , C(O)NH(C1-6 alkyl), C(O)N(C1-6 alkyl)(C1-6 alkyl), NHC(O)C1-6 alkyl, N(C1-6 alkyl)C(O)C1-6 alkyl, NH ２ , NH(C1-6 alkyl), N(C1-6 alkyl)(C1-6 alkyl), SC1-6 alkyl, S(O)C1-6 alkyl and SO ２ Optionally substituted by one or more substituents selected from C1-6 alkyl; R ７ and R ８all alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups of the optional substituents on the C3-12 heterocycloalkyl formed by are also optionally substituted with one or more of halo, C1-6 alkyl, OC1-6 alkyl, C1-6 haloalkyl and OC1-6 haloalkyl; and R ９ , R １０ , R １１ and R １２ is independently selected from H, C1-6 alkyl, and C1-6 haloalkyl.

2. R １ are H, Cl, F, Br, I, CN, and CH ３ , C.H. ２ O.H., O.C.H. ３ , O.C.F. ３ , O.C.F. ２ H, O.C.H. ２ F, C.F. ３ , C.F. ２ H and CH ２ F as claimed in claim 1. The compounds listed above.

3. R ２ is H, F, Cl, CN and CH ３ 2. The compound of claim 1 , selected from:

4. R ３ CF ３ , C.F. ２ H, C.H. ２ F, O.C.F. ３ , O.C.H.F. ２ and O.C.H. ２ The compound according to any one of claims 1 to 3, wherein the compound is selected from: F.

5. R ４ is H and CH ３ The compound according to any one of claims 1 to 4, selected from:

6. R ５ and R ６is H and CH ３ The compound according to any one of claims 1 to 5, independently selected from:

7. The compound according to any one of claims 1 to 6, wherein X is CH and Y is selected from CH, N, CF and CCH 3 .

8. Z is C1-4 alkyleneNR ７ R ８ , OC1-4 alkyleneNR ７ R ８ , N.R. ９ C1-4 alkylene NR ７ R ８ , N.R. ９ C1-4 alkylene OR ７ and N.R. ７ R ８ is selected from R ７ and R ８ is independently selected from H and C1-6 alkyl, or is joined together with the atoms therebetween to form a C4-12 heterocycloalkyl, said C4-12 heterocycloalkyl being selected from NR １２ 8. The compound of any one of claims 1 to 7, optionally comprising one further heteromoiety selected from: O and S, and optionally substituted by one or more substituents selected from halo, ═O, C1-6 alkyl, C3-6 cycloalkyl, C3-6 heterocycloalkyl, NH(C1-6 alkyl), N(C1-6 alkyl)(C1-6 alkyl), SC1-6 alkyl, S(O)C1-6 alkyl and SO 2 C1-6 alkyl, where all alkyl, cycloalkyl and heterocycloalkyl groups of optional substituents on the C4-12 heterocycloalkyl formed by R 7 and R 8 are also optionally substituted by one or more of halo, C1-6 alkyl, OC1-6 alkyl, C1-6 haloalkyl and OC1-6 haloalkyl.

9. Z is: [C3] wherein R ｃ A compound according to any one of claims 1 to 8, wherein is selected from H and C1-6 alkyl, and * is the point of attachment for Z in the compound of formula I.

10. R ７ is H, CH ３ , C.H. ２ CH ３ , CH(CH ３ ) ２ , C(CH ３ ) ３ , C.F. ３ , C.H. ２ CF ３ and (CH ２ ) ２ OCH ３ The compound according to any one of claims 1 to 9, selected from:

11. R ８ , R ９ , R １０ , R １１ and R １２ is H and CH ３ The compound according to any one of claims 1 to 10, independently selected from:

12. Z and R ２ and are linked together with the atoms therebetween to form ring B selected from C5-10 cycloalkyl and C5-10 heterocycloalkyl, said ring B being selected from halo, =O, C1-4 alkyl, C3-6 cycloalkyl, aryl, C5-6 heteroaryl, C3-6 heterocycloalkyl, C １～５ Alkylene C3-6 cycloalkyl, C1-4 alkylene aryl, C1-4 alkylene C5-6 heteroaryl, C1-4 alkylene C3-6 heterocycloalkyl, C(O)C1-4 alkyl, OC1-4 alkyl, OC1-4 alkylene OC1-4 alkyl, C(O)NH ２ , C(O)NH(C1-4 alkyl), C(O)N(C1-4 alkyl)(C1-4 alkyl), NHC(O)C1-4 alkyl, N(C1-4 alkyl)C(O)C1-4 alkyl, NH ２ , NH(C1-4 alkyl), N(C1-4 alkyl)(C1-4 alkyl), SC1-4 alkyl, S(O)C1-4 alkyl and SO ２ The compound according to any one of claims 1 to 7, wherein all alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups of said optional substituents on Ring B are also optionally substituted with one or more of halo, C1-4 alkyl, OC1-4 alkyl, C1-4 fluoroalkyl and OC1-4 fluoroalkyl.

13. Ring B is: [C4] wherein R ｄ The compound of claim 1, wherein is selected from H and C1-6 alkyl and is the point of attachment for ring B in the compound of formula I.

14.

5. teeth: [C6] is selected from the group consisting of [C7] A compound according to any one of claims 1 to 13, wherein is the point of attachment of this group in the compound of formula I.

15. The compound is [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13] [Table 1-14] [Table 1-15] [Table 1-16] [Table 1-17] [Table 1-18] [Table 1-19] [Table 1-20] [Table 1-21] [Table 1-22] [Table 1-23] [Table 1-24] [Table 1-25] [Table 1-26] [Table 1-27] [Table 1-28] [Table 1-29] [Table 1-30] [Table 1-31] [Table 1-32] 2. The compound of claim 1, selected from:

16. A compound of formula IA, or a pharma- ceutically acceptable salt, solvate and / or prodrug thereof: [C8] During the ceremony: A is, [C9] Selected from: * is the point of attachment for A in compounds of formula I; R １ is selected from H, halo, CN, C1-4 alkyl, OC1-4 alkyl, C1-4 haloalkyl, OC1-4 haloalkyl, CN; R ２ is selected from H, halo, CN, C1-4 alkyl, C1-4 haloalkyl, OC1-4 alkyl, and OC1-4 haloalkyl; R ３ is selected from C1-4 fluoroalkyl and OC1-4 fluoroalkyl; R ５ and R ６ is independently selected from H, halo, CN, C1-4 alkyl, and C1-4 haloalkyl; X is CR ａ and N; Y is CR ｂ and N; R ａ and R ｂ is independently selected from H, halo, C1-4 alkyl, and C1-4 haloalkyl; Z is NR ７ R ８ or Z and R ２ and, together with the atoms therebetween, form a C3-12 cycloalkyl group. and C3-12 heterocycloalkyl, said Ring B being selected from halo, ═O, OH, C1-6 alkyl, C3-6 cycloalkyl, aryl, C5-6 heteroaryl, C3-6 heterocycloalkyl, C1-6 alkylene C3-6 cycloalkyl, C1-6 alkylene aryl, C1-6 alkylene C5-6 heteroaryl, C1-6 alkylene C3-6 heterocycloalkyl, OC1-6 alkyl, OC1-6 alkylene OC1-6 alkyl, NH(C1-6 alkyl), N(C1-6 alkyl)(C1-6 alkyl), SC1-6 alkyl, S(O)C1-6 alkyl, and SO ２ C1-6 alkyl, and all alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups of said optional substituents on said ring B are also optionally substituted with one or more of halo, C1-6 alkyl, OC1-6 alkyl, C1-6 haloalkyl and OC1-6 haloalkyl; R ７ is C1-6 alkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-6 alkylene C3-10 cycloalkyl, C1-6 alkylene C3-10 heterocycloalkyl, C1-6 alkyl alkylene OR １０ and C1-6 alkyl alkylene NR １０ R １１ is selected from R ７ all alkyl, alkylene, heterocycloalkyl and cycloalkyl groups are also optionally substituted with one or more of halo, C1-6 alkyl and C1-6 haloalkyl; R ８ is selected from H, C1-6 alkyl, and C1-6 haloalkyl; or R ７ and R ８ and are bonded together with the atoms therebetween to form a C3-12 heterocycloalkyl, the C3-12 heterocycloalkyl being NR １２ , O, S, S(O) and SO ２ and optionally including one further hetero moiety selected from halo, OH, ═O, C1-6 alkyl, C3-6 cycloalkyl, C3-6 heterocycloalkyl, C1-6 alkylene C3-6 cycloalkyl, C1-6 alkylene C3-6 heterocycloalkyl, NH(C1-6 alkyl), N(C1-6 alkyl)(C1-6 alkyl), SC1-6 alkyl, S(O)C1-6 alkyl, and SO ２ Optionally substituted by one or more substituents selected from C1-6 alkyl; R ７ and R ８ all alkyl, alkylene, cycloalkyl and heterocycloalkyl groups of the optional substituents on the C3-12 heterocycloalkyl formed by are also optionally substituted with one or more of halo, C1-6 alkyl, OC1-6 alkyl, C1-6 haloalkyl and OC1-6 haloalkyl; and R ９ , R １０ , R １１ and R １２ are independently selected from H, C1-6 alkyl, and C1-6 haloalkyl, or A compound of formula I-B, or a pharma- ceutically acceptable salt, solvate and / or prodrug thereof: [C10] wherein: A is, [C11] Selected from: * is the point of attachment for A in compounds of formula I; R 1 is selected from H, halo, CN, C1-4 alkyl, OC1-4 alkyl, C1-4 haloalkyl, OC1-4 haloalkyl, CN; R 2 is selected from H, halo, CN, C1-4 alkyl, C1-4 haloalkyl, OC1-4 alkyl, and OC1-4 haloalkyl; R 3 is selected from C1-4 fluoroalkyl and OC1-4 fluoroalkyl; R 5 and R 6 are independently selected from H, halo, CN, C1-4 alkyl, and C1-4 haloalkyl; X is selected from CR a and N; Y is selected from CR b and N; R a and R b are independently selected from H, halo, C1-4 alkyl, and C1-4 haloalkyl; Z is selected from NR 7 R 8 ; or Z and R 2 are joined together with the atoms therebetween to form ring B selected from C3-12 cycloalkyl and C3-12 heterocycloalkyl, said ring B being selected from halo, ═O, OH, C1-6 alkyl, C3-6 cycloalkyl, aryl, C5-6 heteroaryl, C3-6 heterocycloalkyl, C1-6 alkylene C3-6 cycloalkyl, C1-6 alkylene aryl, C1-6 alkylene C5-6 heteroaryl, C1-6 alkylene C3-6 heterocycloalkyl, OC1-6 alkyl, OC1-6 alkylene OC1-6 alkyl, NH(C1-6 alkyl), N(C1-6 alkyl)(C1-6 alkyl), SC1-6 alkyl, S(O)C1-6 alkyl, and SO 2 C1-6 alkyl, and all alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups of said optional substituents on said ring B are also optionally substituted with one or more of halo, C1-6 alkyl, OC1-6 alkyl, C1-6 haloalkyl and OC1-6 haloalkyl; R 7 is selected from C1-6 alkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-6 alkylene C3-10 cycloalkyl, C1-6 alkylene C3-10 heterocycloalkyl, C1-6 alkylalkylene OR 10 , and C1-6 alkylalkylene NR 10 R 11 , all alkyl, alkylene, heterocycloalkyl, and cycloalkyl groups of R 7 are also optionally substituted with one or more of halo, C1-6 alkyl, and C1-6 haloalkyl; R 8 is selected from H, C1-6 alkyl, and C1-6 haloalkyl; or R 7 and R 8 are joined together with the atoms therebetween to form a C3-12 heterocycloalkyl, which optionally contains one further hetero moiety selected from NR 12 , O, S, S(O) and SO 2 , and is optionally substituted by one or more substituents selected from halo, ═O, OH, C1-6 alkyl, C3-6 cycloalkyl, C3-6 heterocycloalkyl, C1-6 alkylene C3-6 cycloalkyl, C1-6 alkylene C3-6 heterocycloalkyl, NH(C1-6 alkyl), N(C1-6 alkyl)(C1-6 alkyl), SC1-6 alkyl, S(O)C1-6 alkyl and SO 2 C1-6 alkyl; all alkyl, alkylene, cycloalkyl and heterocycloalkyl groups of the optional substituents on the C3-12 heterocycloalkyl formed by are also optionally substituted with one or more of halo, C1-6 alkyl, OC1-6 alkyl, C1-6 haloalkyl and OC1-6 haloalkyl; and R 9 , R 10 , R 11 and R 12 are independently selected from H, C1-6 alkyl and C1-6 haloalkyl; or A compound of formula IC, or a pharma- ceutically acceptable salt, solvate and / or prodrug thereof: [C12] During the ceremony: A is, [C13] Selected from: * is the point of attachment for A in compounds of formula I; R 1 is selected from H, halo, CN, C1-4 alkyl, OC1-4 alkyl, C1-4 haloalkyl, OC1-4 haloalkyl, CN; R 2 is selected from H, halo, CN, C1-4 alkyl, C1-4 haloalkyl, OC1-4 alkyl, and OC1-4 haloalkyl; R 3 is selected from C1-4 fluoroalkyl and OC1-4 fluoroalkyl; R 5 and R 6 are independently selected from H, halo, CN, C1-4 alkyl, and C1-4 haloalkyl; X is selected from CR a and N; Y is selected from CR b and N; R a and R b are independently selected from H, halo, C1-4 alkyl, and C1-4 haloalkyl; R 7 is selected from C1-6 alkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-6 alkylene C3-10 cycloalkyl, C1-6 alkylene C3-10 heterocycloalkyl, C1-6 alkylalkylene OR 10 , and C1-6 alkylalkylene NR 10 R 11 , all alkyl, alkylene, heterocycloalkyl, and cycloalkyl groups of R 7 are also optionally substituted with one or more of halo, C1-6 alkyl, and C1-6 haloalkyl; R 8 is selected from H, C1-6 alkyl, and C1-6 haloalkyl; or R 7 and R 8 are bonded together with the atoms therebetween to form a C3-12 heterocycloalkyl group. and R 7 and R 8 form an alkyl group, the C3-12 heterocycloalkyl optionally containing one further hetero moiety selected from NR 12 , O, S, S(O) and SO 2 , and optionally substituted by one or more substituents selected from halo, ═O, OH, C1-6 alkyl, C3-6 cycloalkyl, C3-6 heterocycloalkyl, C1-6 alkylene C3-6 cycloalkyl, C1-6 alkylene C3-6 heterocycloalkyl, NH(C1-6 alkyl), N(C1-6 alkyl)(C1-6 alkyl), SC1-6 alkyl, S(O)C1-6 alkyl and SO 2 C1-6 alkyl; all alkyl, alkylene, cycloalkyl and heterocycloalkyl groups of the optional substituents on the C3-12 heterocycloalkyl formed by are also optionally substituted with one or more of halo, C1-6 alkyl, OC1-6 alkyl, C1-6 haloalkyl and OC1-6 haloalkyl; and R 9 , R 10 , R 11 and R 12 are independently selected from H, C1-6 alkyl and C1-6 haloalkyl; or A compound of formula ID, or a pharma- ceutically acceptable salt, solvate and / or prodrug thereof: [C14] During the ceremony: A is, [C15] Selected from: * is the point of attachment for A in compounds of formula I; R 1 is selected from H, halo, CN, C1-4 alkyl, OC1-4 alkyl, C1-4 haloalkyl, OC1-4 haloalkyl, CN; R 2 is H, halo, CN, C1-4 alkyl, C1-4 haloalkyl, OC1-4 aralkyl, is selected from OC1-4 haloalkyl; R 3 is selected from C1-4 fluoroalkyl and OC1-4 fluoroalkyl; R 5 and R 6 are independently selected from H, halo, CN, C1-4 alkyl, and C1-4 haloalkyl; X is selected from CR a and N; Y is selected from CR b and N; R a and R b are independently selected from H, halo, C1-4 alkyl, and C1-4 haloalkyl; Ring B is selected from C3-12 cycloalkyl and C3-12 heterocycloalkyl, said Ring B being selected from halo, ═O, OH, C1-6 alkyl, C3-6 cycloalkyl, aryl, C5-6 heteroaryl, C3-6 heterocycloalkyl, C1-6 alkylene C3-6 cycloalkyl, C1-6 alkylene aryl, C1-6 alkylene C5-6 heteroaryl, C1-6 alkylene C3-6 heterocycloalkyl, OC1-6 alkyl, OC1-6 alkylene OC1-6 alkyl, NH(C1-6 alkyl), N(C1-6 alkyl)(C1-6 alkyl), SC1-6 alkyl, S(O)C1-6 alkyl, and SO2. and all alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups of said optional substituents on said ring B are also optionally substituted with one or more of halo, C1-6 alkyl, OC1-6 alkyl, C1-6 haloalkyl and OC1-6 haloalkyl.

17. A pharmaceutical composition comprising one or more compounds according to any one of claims 1 to 16 and a pharma- ceutically acceptable carrier and / or diluent.

18. A pharmaceutical for inhibiting NUAK2 and / or NUAK1 in cells in a biological sample or in a subject, comprising one or more compounds described in any one of claims 1 to 16 or the composition described in claim 17.

19. A pharmaceutical for treating a disease, disorder or condition treatable by inhibiting NUAK2 and / or NUAK1, comprising one or more compounds according to any one of claims 1 to 16 or a composition according to claim 17.

20. 20. The method of claim 19, wherein the disease, disorder or condition treatable by inhibiting NUAK2 and / or NUAK1 is cancer or fibrosis.

21. A pharmaceutical for treating a disease, disorder or condition treatable by inhibiting NUAK2 and / or NUAK1 comprising one or more compounds according to any one of claims 1 to 16 or the composition according to claim 17 in combination with another agent useful for the treatment of a treatable disease, disorder or condition treatable by inhibiting NUAK2 and / or NUAK1.

22. 22. The method of claim 21, wherein the disease, disorder or condition treatable by inhibiting NUAK2 and / or NUAK1 is cancer, and the one or more compounds are administered in combination with one or more additional cancer treatments selected from one or more of: radiation therapy, chemotherapy, antibody therapy, small molecule therapy, immunotherapy, hormonal therapy and anti-angiogenic therapy.

23. A pharmaceutical for inhibiting localization of YAP / TAZ in a cell nucleus, comprising one or more compounds described in any one of claims 1 to 16 or the composition described in claim 17.

24. A pharmaceutical for treating a disease, disorder or condition by inhibiting localization of YAP / TAZ to the cell nucleus, comprising one or more compounds described in any one of claims 1 to 16 or the composition described in claim 17.

25. (a) R １ is as defined in formula I or a protected version thereof, ４ and Ring A is defined in Formula I or a protected version thereof. and reacting with arylaminocarboxamide under basic conditions to give a compound of formula D: [C16] (b) reacting a compound of formula D with R ２ , R ３ , an aniline of formula E, wherein X, Y and Z are as defined in formula I or a protected version thereof, and or basic conditions to give, after removal of protecting groups if necessary, a compound of formula I: [C17] A method for preparing a compound according to any one of claims 1 to 16, comprising:

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