PYRIMIDO[5,4,d]PYRIMIDINE COMPOUNDS, COMPOSITIONS COMPRISING THEM AND USES THEREOF

Abstract

Compounds, compositions, and their use in the treatment of proliferative disorders or conditions, such as those associated with RAF gene mutations and / or RAS gene mutations. The disclosed compounds have Formula I or a pharmaceutically acceptable salt or solvate thereof, wherein R... 1. R 2. R 3. X 1. X 2. X 3. X 4 and Y are defined below: .

Description

technical field

[0001] Related applications

[0002] This application claims priority under applicable law to U.S. Provisional Application No. 63 / 201,222, filed April 19, 2021, the disclosure of which is incorporated herein by reference in its entirety for all purposes.

[0003] The disclosure generally relates to pyrimido[5,4-d]pyrimidine compounds, pharmaceutical compositions comprising the same, and their use in the treatment and prevention of diseases characterized by dysregulation of the RAS-ERK pathway (e.g., cancer, RAS disease) . prior art

[0004] RAS-RAF-MEK-ERK (RAS: rat sarcoma; RAF: rapidly accelerating fibrosarcoma; MEK: mitogen-activated protein kinase; ERK: extracellular signal-regulated kinase) signaling pathway (hereinafter referred to as the RAS-ERK pathway ) play a crucial role in transmitting proliferative signals generated by growth factor receptors from the plasma membrane to the nucleus. Due to the activation of receptor tyrosine kinase (RTK) (such as ERBB1, ERBB2, FLT3, RET, KIT), the activation or inactivation of RAS regulatory factors (SOS1 and NF1), and the activation or inactivation of RAS genes (HRAS, KRAS and NRAS; a total of 30% of cancers) or persistent activating mutations in the BRAF gene (8% of cancers), a pathway that is dysregulated in most cancers. The prevalence of KRAS mutations is particularly high in pancreatic cancer (>90%), colorectal cancer (50%) and lung cancer (30%). For its part, BRAF mutations are found at very high frequency in malignant melanoma (70%), thyroid cancer (40%) and colorectal cancer (10%) (mutation frequency based on the 95th issue of November 24, 2021). Edition Catalog Of Somatic Mutations In Cancer (COSMIC; Wellcome Trust Sanger Institute)).

[0005] RAS proteins are small GTPases that transmit extracellular growth signals to effectors to control vital processes such as cell differentiation, proliferation and survival (Nat. Rev. Cancer 2003, 3, 459). Physiological activation of RAS occurs at the plasma membrane following PTK stimulation, which results in GTP loading of GTPases and thus activation of the RAS. Activated RAS interacts with and activates a series of effector molecules, among which RAF kinases are the most critical RAS interactors in the context of cancer development (Nature Rev. Drug Discov. 2014, 13, 828). Oncogenic mutations of glycine 12, glycine 13, or glutamine 61 in RAS isoforms lead to aberrant and persistent signaling in human cancers (Nat. Rev. Cancer2003, 3, 459) (2021 Nov 95th edition of COSMIC issued on 24th April).

[0006] Downstream of RAS, mammalian cells express three RAF paralogs (ARAF, BRAF, and CRAF) that share a conserved C-terminal kinase domain (KD) (Nat. Rev. Mol. Cell Biol. 2015, 16, 281) and the N-terminal regulatory domain (NTR) comprising the RAS-binding domain (RBD). In unstimulated cells, RAF proteins are sequestered in the cytoplasm as monomers. Binding of GTP-bound activated RAS to RBD induces membrane anchoring of RAF kinase (Nat. Rev. Mol. Cell Biol. 2015, 16, 281). At the same time, RAF protein undergoes side-to-side dimerization and catalytic activation of the kinase domain (Nature2009, 461, 542). Activated RAF proteins transmit a signal from RAF to MEK and subsequently from MEK to ERK via a phosphorylation cascade, causing ERK to phosphorylate a range of substrates that trigger cell-specific responses (Nat. Rev. Mol. Cell Biol .2020 October, 21(10), 607).

[0007] To date, activating RAF isoform mutations have been largely restricted to the BRAF gene, although rare variants have been observed in ARAF and CRAF, underscoring the functional importance of this isoform (version 95, November 24, 2021 COSMIC). The most common cancer mutation in BRAF, the substitution of valine for glutamic acid at position 600 (known as BRAF V600E), enhances BRAF activity by stabilizing its active form (Cell 2004, 116, 855). In addition to the V600E allele, a series of mutations at other residues (such as G466V, D594G, etc.) lead to increased RAF signaling through multiple mechanisms (Nat. Rev. Mol. Cell Biol. 2015, 16, 281). These mutations have been classified into three main categories (1 to 3) according to their dependence on RAS activity and RAF dimerization (Nature 2017-10-10, 548(7666), 234-238). The key role of wild-type BRAF and CRAF in mediating RAS-driven tumor formation by stimulating ERK signaling has been widely verified ( Cancer Cell2011, 19, 652; Cancer Discov.2012, 2, 685; Nat. Commun.2017 , 8, 15262). Thus, tumor cells depend on elevated and sustained signaling via the RAS-ERK pathway activated by RAS and RAF, providing strong support for the concept of targeting RAF family kinases in cancer.

[0008] To meet existing medical needs, the past decade has witnessed the development of a broad series of ATP-competitive RAF inhibitors (Nat. Rev. Cancer 2017, 17, 676). Efforts have largely focused on the most common RAS-independent BRAF mutation (BRAF V600E), leading to the development and FDA approval of sulfonamide derivatives such as vemurafenib and dabrafenib. Some of these RAF inhibitors have shown impressive efficacy against metastatic melanoma carrying repeated BRAF V600E alleles and have been approved for the treatment of this patient population (N. Engl. J. Med. 2011, 364, 2507; Lancet 2012, 380, 358). Clinical responses against BRAF V600E-dependent melanomas are induced by potent ATP-competitive inhibition of monomeric forms of this specific dimerization-independent BRAF mutein (Cancer Cell 2015, 28, 370). Unfortunately, acquired resistance to these agents invariably occurs, mainly through reactivation of the RAS-ERK pathway, partly through mechanisms that stimulate RAF dimerization. These include upregulation of RTK signaling, RAS mutations, and BRAF V600E amplification or truncation (Sci. Signal.2010, 3, ra84; Nature2010, 468, 973; Nature2011, 480, 387; Nature Commun.2012, 3, 724) .

[0009] At the same time, tumors exhibiting RAS activity (due to activating RAS mutations or elevated RTK signaling, but otherwise wild-type BRAF) exhibit major resistance to BRAF V600E inhibitors (Nature 2010, 464, 431). Conversely, RAF inhibitors were found to induce ERK signaling under conditions of elevated RAS activity and thus enhance cell proliferation (Nature 2010, 464, 431). This counterintuitive phenomenon, called the paradoxical effect, is also observed in normal tissues that depend on physiological RAS activity and is one of the adverse effects seen with RAF inhibitors in melanoma patients (such as new secondary tumors (e.g., squamous epithelial (Nat. Rev. Cancer2014, 14, 455). Thus, BRAF V600E is ineffective and even contraindicated against RAS-driven cancers. The underlying mechanism arises from the ability of the compound to promote dimerization of the RAF kinase domain in the presence of active RAS (Nature 2010, 464, 431). This event is not limited to BRAF, but also involves other RAF family members and is determined by compound binding mode and affinity ( Nat. Chem. Biol. 2013, 9, 428 ).

[0010] Two strategies have been recently implemented to circumvent the limitations of first-generation RAF inhibitors in RAS-mutated cancers. The first strategy relies on the observation that paradoxical ERK activation is a dose-dependent phenomenon, i.e., induction occurs at subsaturating inhibitor concentrations, but when the compound occupies both units of the RAF dimer, the pathway is activated at saturating concentrations. Down by suppression. Therefore, a first strategy focused on the development of molecules with higher binding affinity for all RAF paralogs in order to saturate RAF protein at lower drug concentrations, thereby reducing aberrant pathway induction (Bioorg. Med. Chem. Lett. 2012 , 22, 6237; Cancer Res.2013, 73, 7043; J. Med. Chem.2015, 58, 4165; Cancer Cell2017, 31, 466; J Med Chem.2020, 63, 2013; 27, 2061; Nature 2021, 594, 418). However, these compounds retain a strong RAF dimer-inducing capacity and thus paradoxically stimulate RAS-ERK signaling, albeit at a lower magnitude than previous generations of RAF inhibitors. Although this class of compounds exhibits improved properties, recent studies have shown that the majority of these compounds are free of the ARAF isoform that leads to activation of abnormal pathways and primary drug resistance, as well as acquisitions that occur in vitro and in clinical settings. Sexual drug resistance (Clin Cancer Res.2021, 27, 2061; Nature 2021, 594, 418). A second strategy consists in designing compounds that are conformationally biased towards the BRAF kinase domain in the inactive state and thus do not paradoxically induce ERK signaling. This resulted in the "Paradox Breaker" (PB) molecule PLX8394, which is a derivative of PLX4032 / vemurafenib (Nature 2015, 526, 583). These molecules retain high potency against BRAF V600E and should therefore prove useful in the treatment of BRAF V600E-dependent melanoma. However, although PLX8394 did not induce ERK signaling in the tested RAS mutant cell lines, it was still ineffective and inapplicable to RAS mutant tumors.

[0011] There remains a need for inhibitors that effectively and consistently block RAS-ERK signaling and intracellular proliferation in human tumor cells carrying multiple RAS and RAF genotypes. Importantly, it would be highly desirable to develop such inhibitors that are also not induced by aberrant pathways in a variety of RAS mutant tumor cell lines. Contents of the invention

[0012] According to one aspect, the technology relates to compounds of formula I: Formula I in: R 1 is selected from substituted or unsubstituted OR 3, SR 3, NH 2, NHR 3, N(R 3) 2, C 3-8 cycloalkyl, C 4-8 heterocycloalkyl, C 6- 10 aryl and C 5-10 heteroaryl; R 2 is selected from substituted C 6 aryl and C 5-10 heteroaryl, substituted or unsubstituted C 4-8 heterocycloalkyl and N(R 3) 2; Each occurrence of R is independently selected from substituted or unsubstituted C 1-8 alkyl, C 3-8 cycloalkyl, C 4-8 heterocycloalkyl, C 6-10 aryl and C 5-10 heteroaryl; X1 is a halogen group or an electron-withdrawing group; X2 is selected from H, halo and electron-withdrawing groups; X 3 and X 4 are each selected from H, halo, electron-withdrawing group, C 1-3 alkyl, C 3-4 cycloalkyl and OC 1-3 alkyl; Y is selected from H, halo, CN, OH, OC 1-8 alkyl, NH 2, NHC 1-8 alkyl, N(C 1-8 alkyl) 2 and substituted or unsubstituted C 1- 8 alkyl; or its pharmaceutically acceptable salt or solvate; The prerequisite is that the compound is not: .

[0013] Compounds of formula I are also defined according to any of the Examples and Examples described throughout this document.

[0014] According to another aspect, the technology relates to a pharmaceutical composition for use as defined in any one of the above-mentioned embodiments, the composition comprising a compound as defined herein and a pharmaceutically acceptable acceptable carrier, diluent or excipient.

[0015] In another aspect, the present technology relates to the use of a compound as defined herein for the treatment of a disease or disorder selected from the group consisting of proliferative diseases or disorders, dysplasia due to dysregulation of the RAS-ERK signaling cascade (RAS diseases), or inflammatory diseases or immune system disorders.

[0016] The present technology also further relates to methods for treating a disease or disorder selected from the group consisting of a proliferative disease or disorder, a dysregulation of the RAS-ERK signaling cascade (RAS disease), or an inflammatory disease or disorder of the immune system , the method comprising administering a compound as defined herein to a subject in need thereof. Also contemplated is a method for inhibiting abnormal cell proliferation comprising contacting such cells with a compound as defined herein.

[0017] In one embodiment of the above uses and methods, the disease or disorder is selected from neoplasms and dysplasia, such as diseases or disorders associated with RAF gene mutations (such as ARAF, BRAF or CRAF), diseases or disorders associated with RAS gene mutations (such as KRAS) or diseases or conditions associated with both RAF gene mutations and RAS gene mutations. In one embodiment, the disease or disorder is associated with a mutation or amplification of a receptor tyrosine kinase (e.g. EGFR, HER2) or a regulator of the RAS downstream of the receptor (e.g. SOS1 gain of function, NF1 loss of function) relevant.

[0018] For example, the disease or condition is a neoplasm, such as a neoplasm selected from the group consisting of melanoma, thyroid cancer (e.g., papillary thyroid cancer), colorectal cancer, ovarian cancer, breast cancer, endometrial cancer, liver cancer, sarcoma, Gastric cancer, pancreatic cancer, Barret's adenocarcinoma, glioma (eg, ependymoma), lung cancer (eg, non-small cell lung cancer), head and neck cancer, acute lymphoblastic leukemia, acute myeloid Leukemia, non-Hodgkin's lymphoma, and hairy cell leukemia. For example, the neoplasm is selected from colon or colorectal cancer, lung cancer, pancreatic cancer, thyroid cancer, breast cancer and melanoma. For example, any of the uses and methods include inhibiting the RAS-ERK signaling pathway without substantially inducing an aberrant pathway.

[0019] Additional objects and features of the present compounds, compositions, methods and uses will become more apparent upon reading the non-limiting description of the following illustrative examples and examples section, which should not be construed as limiting the present invention scope of invention. Brief description of the diagram

[0020] Figure 1 shows compounds that do not induce paradoxical induction (Y MIN >-20%) of pERK signaling in RAS mutant HCT116 cells (Examples 80 and 81) as described herein and elicit this in the same cell line Representative IC50 inhibitory dose-response curve of a compound (PLX4720; CAS# 918505-84-7) with strong induction of the pathway (Y MIN~-600%).

[0021] Figure 2 shows immunoblot analysis of RAS mutant HCT-116 cells treated with a representative compound (Example 80; upper panel) that did not induce paradoxical induction of pERK or pMEK signaling, and compared to Next, treated with a compound (PLX4720; lower panel) that induces the pathway in the same cell line. Implementation

[0022] All technical and scientific terms and expressions used herein have the same definitions as commonly understood by those skilled in the art to which this technology belongs. Nevertheless, definitions of some terms and expressions are provided below. To the extent definitions of terms in publications, patents and patent applications incorporated by reference herein are contrary to the definitions set forth in this specification, the definitions in this specification control. The section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter disclosed. i. Definition

[0023] Chemical structures described herein are drawn according to customary standards. Furthermore, when drawn atoms (such as carbon atoms) appear to include incomplete valences, it is assumed that the valences are satisfied by one or more hydrogen atoms, even if such hydrogen atoms are not necessarily drawn explicitly. A hydrogen atom should be inferred to be part of the compound.

[0024] The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. It should be noted that the singular forms "a" and "the" include the plural forms unless the context clearly dictates otherwise. Thus, for example, reference to a composition containing "a compound" also covers a mixture of two or more compounds. It should also be noted that the term "or" is generally employed in its sense including "and / or" unless the context clearly dictates otherwise. Furthermore, where the terms "including / includes", "having / has / with" or variations thereof are used in the embodiments and / or claims, such terms are intended to be used in conjunction with the term "comprising" and the like are inclusive.

[0025] The term "about" or "approximately" means within an acceptable range of error for a particular value, as determined by one of ordinary skill in the art, which will depend in part on how the value was measured or determined, i.e. Measurement system limitations. For example, "about" can mean within 1 standard deviation or greater than 1 standard deviation, depending on the practice in the art. Alternatively, "about" may mean a range of up to 20%, preferably up to 10%, more preferably up to 5%, and even more preferably up to 1% of a given value. Alternatively, especially with regard to biological systems or processes, the term may mean within an order of magnitude of a value, preferably within 5-fold and more preferably within 2-fold. Where specific values ​​are described in this application and claims, unless otherwise specified, the term "about" should be assumed to mean within an acceptable error range for the specific value.

[0026] As used herein, the terms "compound", "compound described herein", "compound of the application", "pyrimido[5,4-d]pyrimidine compound", "pyrimidopyrimidine compound" and equivalent expressions Refers to the compounds described in this application, such as those covered by structural formula I with reference to any of the applicable Examples as appropriate and also includes exemplary compounds, such as the compounds of Examples 1 to 114, and their pharmaceutical Above acceptable salts, solvates, esters and prodrugs (if applicable). Where a zwitterionic form is possible, a compound may for practical purposes be drawn in its neutral form, but the compound is understood to include its zwitterionic form. The embodiments herein may also exclude one or more compounds. A compound can be identified by its chemical structure or its chemical name. In case of conflict between chemical structure and chemical name, the chemical structure shall prevail.

[0027] Unless otherwise stated, structures described herein are also meant to include all isomeric (e.g., mirror-like, non-mirror-like, and geometric (or configurational)) forms of the structure (if applicable); R and S configurations. Accordingly, single stereochemical isomers as well as enantiomerically, diastereomerically and geometric (or configurational) mixtures of the compounds of the present invention are within the scope of this specification. Unless otherwise indicated, therapeutic compounds also encompass all possible tautomeric forms of the described compounds, if any. The term also includes isotopically labeled compounds in which one or more atoms have an atomic mass different from that most abundantly found in nature. Examples of isotopes that may be incorporated into compounds of the invention include, but are not limited to: any of 2H(D), 3H(T), 11C, 13C, 14C, 15N, 18O, 17O, isotopes of sulfur, and the like. The compounds may also exist in unsolvated forms as well as solvated forms, including hydrated forms. Compounds can exist in various crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated herein and are intended to be within the scope of the invention.

[0028] When a particular enantiomer is preferred, it may, in some embodiments, be provided substantially free of the corresponding enantiomer, and may also be enantiomerically enriched. "Enantiomerically enriched" means that a compound is composed of a significantly greater proportion of one enantiomer. In certain embodiments, the compounds consist of at least about 90% by weight of the preferred enantiomer. In other embodiments, the compounds consist of at least about 95%, 98%, or 99% by weight of the preferred enantiomer. The preferred enantiomer can be determined by any method known to those skilled in the art (including high-pressure liquid chromatography (HPLC) on a chiral support and formation and crystallization of chiral salts) Isolated from racemic mixtures, or prepared by asymmetric synthesis.

[0029] The expression "pharmaceutically acceptable salt" means, within the scope of reasonable medical diagnosis, suitable for use in contact with tissues of humans and lower animals without undue toxicity, irritation, allergic reactions and the like, and with reasonable These salts of the compounds of the invention have a commensurate benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977). Such salts can be prepared in situ during the final isolation and purification of the compounds of this specification, either by reacting the free base functionality of the compounds with a suitable organic or inorganic acid (acid addition salts) or by rendering the acidic Functional groups are prepared individually by reaction with suitable organic or inorganic bases (base addition salts).

[0030] The term "solvate" refers to the physical association of a compound of the present invention with one or more solvent molecules, including water molecules and non-aqueous solvent molecules. This physical association may include hydrogen bonding. In some cases, solvates will be able to be isolated, for example when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid. The term "solvate" encompasses both solution-phase and isolatable solvates. Exemplary solvates include, but are not limited to, hydrates, hemihydrates, ethanolates, hemiethanolates, n-propanolates, isopropanolates, 1-butanolates, 2-butanolates, and other physiologically acceptable Solvates of accepted solvents, such as Class 3 solvents described in International Conference on Harmonization (ICH), Guide for Industry, Q3C Impurities: Residual Solvents (1997). Accordingly, compounds as described herein also include each of their solvates and mixtures thereof.

[0031] As used herein, the expression "pharmaceutically acceptable ester" refers to an ester of a compound formed by the process of the invention which is hydrolyzable in vivo and includes those which break down readily in the human body to leave the parent compound or a salt thereof. Ester. Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, especially alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, Wherein each alkyl or alkenyl moiety preferably has not more than 6 carbon atoms. Examples of specific esters include, but are not limited to, formates, acetates, propionates, butyrates, acrylates, and ethylsuccinates with hydroxyl groups, and alkyl esters with acidic groups. Other ester groups include sulfonate or sulfate.

[0032] As used herein, the expression "pharmaceutically acceptable prodrugs" refers to those prodrugs of the compounds formed by the methods of the present invention, which are suitable for contact with tissues of humans and lower animals within the scope of rational medical diagnosis free from undue toxicity, irritation, allergic reactions and the like, commensurate with a reasonable benefit / risk ratio and valid for its intended use. "Prodrug" as used herein means a compound that can be transformed in vivo by metabolic means, for example by hydrolysis, to provide any compound described by the formulas of the present invention.

[0033] Abbreviations may also be used throughout this application, and unless otherwise indicated, such abbreviations are intended to have their commonly understood meanings in the art. Examples of such abbreviations include Me (methyl), Et (ethyl), Pr (propyl), i-Pr (isopropyl), Bu (butyl), t-Bu (tertiary butyl), i -Bu (isobutyl), s-Bu (secondary butyl), c-Bu (cyclobutyl), Ph (phenyl), Bn (benzyl), Bz (benzoyl), CBz or Cbz Or Z (benzyloxycarbonate), Boc or BOC (tertiary butoxycarbonyl) and Su or Suc (succinimide). For greater certainty, additional definitions of specific abbreviations are also included in the introduction to the Examples section.

[0034] The number of carbon atoms in a hydrocarbyl substituent can be indicated by the prefix "Cx-Cy" or "Cx-y", where x is the minimum number of carbon atoms in the substituent and y is the maximum number. However, when the prefix "Cx-Cy" or "Cx-y" is associated with a group which by definition contains one or more heteroatoms (e.g. heterocycloalkyl, heteroaryl, etc.), then x and y, respectively, are defined is the minimum and maximum number of atoms in the ring, including carbon atoms and one or more heteroatoms.

[0035] As used herein, the term "alkyl" refers to a saturated straight or branched chain hydrocarbon group usually containing 1 to 20 carbon atoms. For example, "C 1-8 alkyl" contains one to eight carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl, n-hexyl, heptyl, octyl, and the like.

[0036] As used herein, the term "alkenyl" refers to a straight or branched chain hydrocarbon group containing one or more double bonds and generally containing 2 to 20 carbon atoms. For example, "C 2-8 alkenyl" contains two to eight carbon atoms. Alkenyl groups include, but are not limited to, for example, vinyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, heptenyl, octenyl, and the like.

[0037] As used herein, the term "alkenyl" refers to a straight or branched chain hydrocarbon group containing one or more triple bonds and generally containing 2 to 20 carbon atoms. For example, "C 2-8 alkynyl" contains two to eight carbon atoms. Representative alkynyl groups include, but are not limited to, for example, ethynyl, 1-propynyl, 1-butynyl, heptynyl, octynyl, and the like.

[0038] The terms "cycloalkyl", "cycloaliphatic", "carbocycle", "carbocyclyl" and equivalent expressions refer to compounds containing saturated or partially unsaturated (non-aromatic) carbocycles in a monocyclic or polycyclic ring system Groups having three to fifteen ring members, the polycyclic ring system including spiro-connected (sharing one atom), fused (sharing at least one bond) or bridged (sharing two or more bonds) carbocycles system. Examples of cycloalkyl groups include, but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclopenten-1-yl, cyclopenten-2-yl, cyclopenten-3-yl, cyclohexyl, cyclo Hexen-1-yl, cyclohexen-2-yl, cyclohexen-3-yl, cycloheptyl, bicyclo[4,3,0]nonyl, norbornyl and similar cycloalkyl groups. The term cycloalkyl includes both unsubstituted and substituted cycloalkyl groups. For example, the term "C 3-n cycloalkyl" refers to a cycloalkyl group having from 3 to the indicated "n" number of carbon atoms in the ring structure. Unless otherwise indicated by the number of carbon atoms, a "lower cycloalkyl group" as used herein has at least 3 and equal to or less than 8 carbon atoms in its ring structure.

[0039] As used herein, the terms "heterocycle", "heterocycloalkyl", "heterocyclyl", "heterocyclic group" and "heterocyclic ring" are used interchangeably and mean saturated or partially unsaturated and except Chemically stable 3 to 7 membered monocyclic or 7-10 membered bicyclic heterocyclic moieties also having one or more, preferably one to four, heteroatoms as defined above in addition to carbon atoms. When used with reference to a ring atom of a heterocyclic ring, the term "nitrogen" includes substituted nitrogens. For example, in a saturated or partially unsaturated ring with 1-3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen can be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR (as in N-substituted pyrrolidinyl). A heterocycle can have its pendant groups attached at any heteroatom or carbon atom to give a chemically stable structure and any of the ring atoms can be optionally substituted. Examples of heterocycloalkyl groups include, but are not limited to: 1,3-dioxanyl, pyrrolidinyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl , piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, tetrahydrothiazolyl, isotetrahydrothiazolyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrobithiophene Base, tetrahydrothienyl, thiomorpholinyl, thioxyl, azetanyl, oxetanyl, thietanyl, homopiperidinyl, oxirane, thiepanyl, Oxazepinyl, diazrazyl, thiazepinyl, 1,2,3,6-tetrahydropyridyl, 2-pyrrolinyl, 3-pyrrolinyl, 2H-pyranyl, 4H- Pyranyl, dioxanyl, dithienyl, dithianyl, dihydropyranyl, dihydrothienyl, dihydrofuryl, 3-azabicyclo[3,1,0]hexyl, 3 - azabicyclo[4,1,0]heptyl, quinazinyl, quinuclidinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl and similar heterocycloalkyl groups. Heterocyclyl also includes groups fused to one or more aryl, heteroaryl or cycloaliphatic rings, such as indolinyl, 3H-indolyl, chromanyl, benzopiperyl pyranyl, phenanthridinyl, 2-azabicyclo[2.2.1]heptyl, octahydroindolyl or tetrahydroquinolinyl, wherein the radical or point of attachment is on the heterocyclyl ring. A heterocyclyl group can be monocyclic or bicyclic. The term "heterocyclylalkyl" refers to an alkyl group substituted with a heterocyclyl group, wherein the alkyl and heterocyclyl moieties are independently optionally substituted. For example, the term "C 3-n heterocycloalkyl" refers to a heterocycloalkyl group having from 3 to the indicated "n" number of atoms, including carbon atoms and heteroatoms, in the ring structure.

[0040] As used herein, the term "partially unsaturated" refers to a portion of a ring that includes at least one double or triple bond between ring atoms, but is not aromatic. The term "partially unsaturated" is intended to encompass rings having multiple sites of unsaturation but is not intended to include aryl or heteroaryl moieties as defined herein.

[0041] The term "aryl" used alone or as part of a larger moiety such as "aralkyl", "aralkoxy", "aryloxy" or "aryloxyalkyl" refers to groups having a total of six Monocyclic moieties of up to 15 ring members or aromatic groups having 4n+2 conjugated π(pi) electrons in a bicyclic or tricyclic fused ring system, where n is an integer from 1 to 3, wherein the At least one ring is aromatic and wherein each ring in the system contains from three to seven ring members. The term "aryl" is used interchangeably with the term "aryl ring". In certain embodiments of the present invention, "aryl" refers to an aromatic ring system that may bear one or more substituents, including but not limited to phenyl, biphenyl, naphthyl, azulenyl, anthracenyl, and the like group. The term "aralkyl" or "arylalkyl" refers to an alkyl residue attached to an aromatic ring. Examples of aralkyl groups include, but are not limited to, benzyl, phenethyl, and the like. Also included within the scope of the term "aryl" as used herein are groups in which an aromatic ring is fused to one or more non-aromatic rings, such as indenyl, indenyl, phthalimino, naphthalene Naphthimidyl, fenyl, phenanthryl or tetrahydronaphthyl and similar groups. For example, the term "C 6-n aryl" refers to an aryl group having from 6 to the indicated "n" number of atoms in the ring structure.

[0042] The term "heteroaryl" used alone or as part of a larger moiety such as "heteroaralkyl" or "heteroaralkoxy" refers to an aromatic group having 4n+2 conjugated π(pi) electrons. Groups wherein n is an integer from 1 to 3 (e.g. having 5 to 18 ring atoms, preferably 5, 6 or 9 ring atoms; sharing 6, 10 or 14 π electrons in the ring array); except carbon atoms In addition, with one to five heteroatoms. The term "heteroatom" includes, but is not limited to, nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternary ammonium form of a basic nitrogen. A heteroaryl group can be a single ring, or two or more fused rings. As used herein, the term "heteroaryl" also includes groups in which a heteroaryl ring is fused to one or more aryl, cycloaliphatic, or heterocyclic rings, wherein the radical or point of attachment is on the heteroaryl ring. Non-limiting examples of heteroaryl include thienyl, furanyl / furyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazole Base, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyrazinyl, triazinyl, indolyl, 3H-indolyl, isoindolyl, indoxazinyl benzothienyl / benzothiophenyl, benzofuryl, dibenzofuryl, indazolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, pyrrole Pyridyl (such as pyrrolo[3,2-b]pyridyl or pyrrolo[3,2-c]pyridyl), pyrazolopyridyl (such as pyrazolo[1,5-a]pyridyl) , furopyridyl, purinyl, imidazopyrazinyl (eg imidazo[4,5-b]pyrazinyl), quinolyl / quinolinyl, isoquinolyl / isoquinolinyl, quinoline Ketone, isoquinolinone, cinnolinyl, oxazinyl, quinazolinyl, quinoxalinyl, 4H-quinazinyl, naphthyridinyl and pteridylcarbazolyl, acridinyl, phenanthridinyl, phenythiazinyl, phenythiazinyl, phenythiazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl and pyrido[2,3-b]-l,4-oxazin-3(4H)-one . Heteroaryl groups can be monocyclic or bicyclic. Heteroaryl includes optionally substituted rings. The term "heteroaralkyl" refers to a heteroaryl-substituted alkyl group, wherein the alkyl and heteroaryl portions independently are optionally substituted. Examples include, but are not limited to, pyridylmethyl, pyrimidinylethyl, and the like. For example, the term "C 5-n heteroaryl" refers to a heteroaryl group having from 5 to the indicated "n" number of atoms, including carbon atoms and heteroatoms, in the ring structure.

[0043] As described herein, compounds of the invention may contain "optionally substituted" moieties. In general, the term "substituted", whether preceded by the term "optionally" or not, means that one or more hydrogens of the designated moiety are replaced by a suitable substituent. Unless otherwise indicated, "optionally substituted" groups may have suitable substituents at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one selected from the specified group When substituting a group, the substituents at each position may be the same or different. Combinations of substituents envisaged under the present invention are preferably those that result in the formation of chemically stable or chemically feasible compounds. As used herein, the term "chemically stable" means that a compound is not substantially altered when subjected to conditions that permit its production, detection, and in certain embodiments, its recovery, purification, and use for one or more of the purposes disclosed herein .

[0044] The term "halo" denotes a halogen atom, ie a fluorine, chlorine, bromine or iodine atom, preferably fluorine or chlorine.

[0045] The term "optionally substituted" refers to a group that is substituted or unsubstituted by independently replacing one, two or three or more hydrogen atoms thereon with substituents including, but not limited to: F, CI, Br, I, OH, CO 2H, alkoxy, pendant oxy, thio pendant oxy, NO 2, CN, CF 3, NH 2, NH alkyl, NH alkenyl, NH alkynyl, NH ring Alkyl, NH aryl, NH heteroaryl, NH heterocycle, dialkylamino, diarylalkyl, diheteroarylamino, O-alkyl, O-alkenyl, O-alkynyl, O-cycloalkyl, O-aryl, O-heteroaryl, O-haloalkyl, O-heterocycle, C(O)alkyl, C(O)alkenyl, C(O)alkynyl, C (O)cycloalkyl, C(O)aryl, C(O)heteroaryl, C(O)heterocycloalkyl, CO2alkyl, CO2alkenyl, CO2alkynyl, CO2cycloalkane radical, CO2aryl, CO2heteroaryl, CO2heterocycloalkyl, OC(O)alkyl, OC(O)alkenyl, OC(O)alkynyl, OC(O)cycloalkyl, OC (O)aryl, OC(O)heteroaryl, OC(O)heterocycloalkyl, C(O)NH2, C(O)NHalkyl, C(O)NHalkenyl, C(O) NH alkynyl, C(O)NH cycloalkyl, C(O)NH aryl, C(O)NH heteroaryl, C(O)NH heterocycloalkyl, OCO 2 alkyl, OCO 2 alkenyl, OCO 2 alkynyl, OCO 2 cycloalkyl, OCO 2 aryl, OCO 2 heteroaryl, OCO 2 heterocycloalkyl, OC(O)NH 2 , OC(O)NH alkyl, OC(O)NH alkene radical, OC(O)NH alkynyl, OC(O)NH cycloalkyl, OC(O)NH aryl, OC(O)NH heteroaryl, OC(O)NH heterocycloalkyl, NHC(O) Alkyl, NHC(O)alkenyl, NHC(O)alkynyl, NHC(O)cycloalkyl, NHC(O)aryl, NHC(O)heteroaryl, NHC(O)heterocycloalkyl, NHCO 2 Alkyl, NHCO 2 Alkenyl, NHCO 2 Alkynyl, NHCO 2 Cycloalkyl, NHCO 2 Aryl, NHCO 2 Heteroaryl, NHCO 2 Heterocycloalkyl, NHC(O)NH 2 , NHC(O)NH Alkyl, NHC(O)NHalkenyl, NHC(O)NHalkenyl, NHC(O)NHcycloalkyl, NHC(O)NHaryl, NHC(O)NHheteroaryl, NHC(O)NH Heterocycloalkyl, NHC(S)NH2, NHC(S)NHalkyl, NHC(S)NHalkenyl, NHC(S)NHalkynyl, NHC(S)NHcycloalkyl, NHC(S)NH Aryl, NHC(S)NHheteroaryl, NHC(S)NHheterocycloalkyl, NHC(NH)NH2, NHC(NH)NHalkyl, NHC(NH)NHalkenyl, NHC(NH)NH Alkenyl, NHC(NH)NHcycloalkyl, NHC(NH)NHaryl, NHC(NH)NHheteroaryl, NHC(NH)NHheterocycloalkyl, NHC(NH)alkyl, NHC(NH) Alkenyl, NHC(NH)alkenyl, NHC(NH)cycloalkyl, NHC(NH)aryl, NHC(NH)heteroaryl, NHC(NH)heterocycloalkyl, C(NH)NHalkyl, C(NH)NH alkenyl, C(NH)NH alkynyl, C(NH)NH cycloalkyl, C(NH)NH aryl, C(NH)NH heteroaryl, C(NH)NH heterocycloalkane radical, P(O)(alkyl)2, P(O)(alkenyl)2, P(O)(alkynyl)2, P(O)(cycloalkyl)2, P(O)(aryl ) 2, P(O)(heteroaryl) 2, P(O)(heterocycloalkyl) 2, P(O)(Oalkyl) 2, P(O)(OH) 2, P(O) (Oalkenyl)2, P(O)(Oalkynyl)2, P(O)(Ocycloalkyl)2, P(O)(Oaryl)2, P(O)(Oheteroaryl ) 2. P(O)(O heterocycloalkyl) 2. S(O)alkyl, S(O)alkenyl, S(O)alkynyl, S(O)cycloalkyl, S(O)aryl radical, S(O)2alkyl, S(O)2alkenyl, S(O)2alkynyl, S(O)2cycloalkyl, S(O)2aryl, S(O)heteroaryl , S(O)heterocycloalkyl, SO 2NH 2 , SO 2NH alkyl, SO 2NH alkenyl, SO 2NH alkynyl, SO 2NH cycloalkyl, SO 2NH aryl, SO 2NH heteroaryl, SO 2NH heterocycle Alkyl, NHSO2alkyl, NHSO2alkenyl, NHSO2alkynyl, NHSO2cycloalkyl, NHSO2aryl, NHSO2heteroaryl, NHSO2heterocycloalkyl, CH2NH2, CH2SO2CH3 , alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, cycloalkyl, carbocycle, heterocycle, polyalkoxyalkyl, Polyalkoxy, methoxymethoxy, methoxyethoxy, SH, S-alkyl, S-alkenyl, S-alkynyl, S-cycloalkyl, S-aryl, S-hetero Aryl, S-heterocycloalkyl or methylthiomethyl. ii. Compound

[0046] The recitation of a listing of chemical groups in any definition of a variable herein includes definitions of that variable as any single group or combination of listed groups. The recitation herein of an embodiment of a variant includes that embodiment as any single embodiment or in combination with any other embodiment or portion thereof. The recitation herein of an embodiment includes that embodiment as any single embodiment or in combination with any other embodiment or portion thereof. Accordingly, the following examples are presented individually or in combination, where applicable.

[0047] The compounds of the present invention exhibit a pyrimido[5,4-d]pyrimidine core structure to which defined substituents are attached to achieve favorable activity of the product. Examples of pyrimidopyrimidine compounds as defined herein are shown by the general formula I: Formula I in: R 1 is selected from substituted or unsubstituted OR 3, SR 3, NH 2, NHR 3, N(R 3) 2, C 3-8 cycloalkyl, C 4-8 heterocycloalkyl, C 6- 10 aryl and C 5-10 heteroaryl; R 2 is selected from substituted C 6 aryl and C 5-10 heteroaryl, substituted or unsubstituted C 4-8 heterocycloalkyl and N(R 3) 2; Each occurrence of R is independently selected from substituted or unsubstituted C 1-8 alkyl, C 3-8 cycloalkyl, C 4-8 heterocycloalkyl, C 6-10 aryl and C 5-10 heteroaryl; X1 is a halogen group or an electron-withdrawing group; X2 is selected from H, halo and electron-withdrawing groups; X 3 and X 4 are each selected from H, halo, electron-withdrawing group, C 1-3 alkyl, C 3-4 cycloalkyl and OC 1-3 alkyl; Y is selected from H, halo, CN, OH, OC 1-8 alkyl, NH 2, NHC 1-8 alkyl, N(C 1-8 alkyl) 2 and substituted or unsubstituted C 1- 8 alkyl; or its pharmaceutically acceptable salt or solvate; The prerequisite is that the compound is not: .

[0048] For example, the electron withdrawing group is selected from the group consisting of perhaloalkyl (e.g. CF3 or CCl3), CN, NO2, sulfonate, alkylsulfonyl (e.g. SO2Me or SO2CF3), alkylcarbonyl (eg C(O)Me), carboxylate, alkoxycarbonyl (eg C(O)OMe) and aminocarbonyl (eg C(O)NH2). In one embodiment, X 1 is Cl and X 2 is F, or X 1 is F and X 2 is H, or both X 1 and X 2 are F. In another embodiment, each of X3 and X4 is H. In yet another embodiment, X3 is F and X4 is H.

[0049] According to one example, Y is H and all other groups are as defined herein. According to another example, Y is NH and all other groups are as defined herein.

[0050] For example, the aminoarylsulfonamide moiety in Formula I is designated L and is selected from: The dotted line (---) indicates a key.

[0051] In another embodiment, R 2 is a substituted C aryl or C 5-10 heteroaryl, for example R 2 is a C aryl substituted by at least one group selected from the group consisting of F, Cl, Br, CN, NO 2 and substituted or unsubstituted C 1-3 alkyl, C 3-4 cycloalkyl or OC 1-3 alkyl. For example, R is a group having the formula: in: R 4 is selected from H, F, Cl, Br, CN and substituted or unsubstituted C 1-3 alkyl, C 3-4 cycloalkyl or OC 1-3 alkyl, for example R 4 is selected from H, F, Cl, Br, Me, Et, CN, CHF 2 and CF 3; R 5 is selected from H, F, Cl, CN and substituted or unsubstituted C 1-3 alkyl, C 3-4 cycloalkyl or OC 1-3 alkyl, for example R 5 is selected from H, F, Me, CF3, CN and Cl; R 6 is selected from H, F, Cl, Br, NO 2 , NH 2 , and substituted or unsubstituted C 1-3 alkyl, C 3-4 cycloalkyl or OC 1-3 alkyl, for example R 6 is selected from H, F, Cl, Br and substituted or unsubstituted C 1-3 alkyl, C 3-4 cycloalkyl or OC 1-3 alkyl, or R 6 is selected from H, F, Cl , Me, Et and OMe; R 7 is selected from H, F, Cl and substituted or unsubstituted C 1-3 alkyl, for example R 7 is selected from H, Me, F and Cl; R 8 is selected from H, F and substituted or unsubstituted C 1-3 alkyl, for example R 8 is selected from H, Me and F; Or R 4 and R 5 or R 5 and R 6 together with their adjacent carbon atoms form a substituted or unsubstituted carbocyclic or heterocyclic ring, provided that the heterocyclic ring (R 2) is not a benzoxazoline ketones; and (---) means a key; Wherein when R 4 is H or F, then at least one of R 5 , R 6 , R 7 or R 8 is not H or F; and Wherein when R 5 is CN, at least one of R 4 , R 6 , R 7 or R 8 is not H.

[0052] In one embodiment, R 8 is H. In another embodiment, R4 is selected from F, Cl, Et and Me, R5, R7 and R8 are each H, and R6 is selected from H, Cl, Me and OMe. In another embodiment, R4 is selected from F, Cl and Me, R6, R7 and R8 are each H, and R5 is selected from F and Cl.

[0053] In one embodiment, R 4 is selected from Cl and substituted or unsubstituted C 1-3 alkyl (such as Me); preferably, R 4 is Cl or Me; R 5 is selected from H, F, Cl And substituted or unsubstituted C 1-3 alkyl (such as Me); R 6 is selected from H and substituted or unsubstituted OC 1-3 alkyl (such as OCH 3); and R 7 and R 8 Each is H.

[0054] In yet another embodiment, R is selected from H, Cl, Br and methyl; R is selected from H, F and Cl; R is selected from H, F, Cl, Me and OMe; and R and R 8 are H each.

[0055] In another embodiment, R 4 is selected from Cl and substituted or unsubstituted C 1-3 alkyl (such as Me), preferably, R 4 is Cl or Me; R 5 is selected from H, F, Cl and substituted or unsubstituted C 1-3 alkyl (such as Me), preferably, R 5 is F, Cl or Me; R 6 is selected from H, F, Cl, substituted or unsubstituted C 1-3 alkyl (eg Me) and substituted or unsubstituted OC 1-3 alkyl (eg OCH 3 ), preferably, R 6 is H or F, or R 6 is Cl or substituted or Unsubstituted C 1-3 alkyl or substituted or unsubstituted OC 1-3 alkyl, or CH 3 or OCH 3 ; and R 7 and R 8 are each H. In yet another embodiment, R 6 is substituted C 1-3 alkyl.

[0056] In another embodiment, R is a substituted C heteroaryl, such as a group having the formula: in: X 5 is selected from NH, NC 1-3 alkyl, NC 3-4 cycloalkyl, O and S; R 9 , R 10 , R 11 are each independently selected from H, F, Cl, CN, and substituted or unsubstituted C 1-3 alkyl, C 3-4 cycloalkyl, C(O)OC 1- 3 alkyl or OC 1-3 alkyl, provided that one of R 9 and R 11 is H and the other is not H; and (---) indicates a key.

[0057] Alternatively, R is a group having the formula: in: X 5 is selected from NH, NC 1-3 alkyl, NC 3-4 cycloalkyl, O and S; R 9 is selected from F, Cl, CN and substituted or unsubstituted C 1-3 alkyl, C 3-4 cycloalkyl, C(O)OC 1-3 alkyl or OC 1-3 alkyl; R 10 and R 12 are each independently selected from H, F, Cl, CN, and substituted or unsubstituted C 1-3 alkyl, C 3-4 cycloalkyl, C(O)OC 1-3 alkyl or OC 1-3 alkyl; and (---) indicates a key.

[0058] In a preferred embodiment, R 9 and R 10 are each independently selected from F, Cl, CN and substituted or unsubstituted C 1-3 alkyl, C 3-4 cycloalkyl, C(O) OC 1-3 alkyl or OC 1-3 alkyl, preferably Cl and substituted or unsubstituted C 1-3 alkyl, more preferably, both R 9 and R 10 are Cl. In another embodiment, X is O or S, preferably S.

[0059] In another embodiment, R is a substituted C5-10 heteroaryl, such as a group having the formula: in: X 9 , X 10 , X 11 , X 12 and X 13 are independently selected from N and C, wherein at least one of X 9 , X 10 , X 11 , X 12 and X 13 and at most both are N; and R 19, R 20, R 21, R 22 and R 23 are selected from H, F, Cl, Br, CN, NO 2, NH 2 and substituted or unsubstituted C 1-3 alkyl, C 3-4 Cycloalkyl or OC 1-3 alkyl, or when X 9 , X 10 , X 11 , X 12 and X 13 to which it is attached is N, it does not exist; wherein at least one of X9 and X13 is not N; and Wherein when one of X9 and X13 is N, the other is not N or CH.

[0060] In another example, R 2 is C 5 heterocycloalkyl. For example, R is a group having the formula: in: R 13 is independently selected from F, Cl and substituted or unsubstituted C 1-3 alkyl, C 3-4 cycloalkyl or C 1-3 alkoxy at each occurrence; n is an integer selected from 0 to 8; or n is between 2 and 8, and two R 13 together with their adjacent carbon atoms form a C 3-4 cycloalkyl; and (---) indicates a key.

[0061] In one embodiment, R 13 is in the 3-position. In another embodiment, R 13 is selected from F, Me, OMe and CH 2 OMe, and n is 1 or 2. For example, R 13 is methoxy at the 3-position, and n is 1.

[0062] In another example, R 2 is N(R 3 ) 2 . For example, R 2 is N(R 3 ) 2 and R 3 is selected from substituted or unsubstituted C 1-8 alkyl or C 3-8 cycloalkyl.

[0063] In yet another embodiment, the compound of formula I is a compound of formula II, or a pharmaceutically acceptable salt or solvate thereof: Formula II Wherein R 1 , R 4 , R 5 and R 6 are each independently as defined herein, preferably, R 4 is selected from Cl, Br and methyl; R 5 is selected from H, F, Cl and methyl; R 6 selected from H, F, Cl, Me and OMe.

[0064] In another embodiment, the compound of formula I is a compound of formula III, or a pharmaceutically acceptable salt or solvate thereof: Formula III wherein R 1 , R 9 , R 10 , R 12 and X 5 are each independently as defined herein.

[0065] Exemplary R are illustrated by B1 to B77 as defined below: B1 B2 B3 B4 B5 B6 B7 B8 B9 B10 B11 B12 B13 B14 B15 B16 B17 B18 B19 B20 B21 B22 B23 B24 B25 B26 B27 B28 B29 B30 B31 B32 B33 B34 B35 B36 B37 B38 B39 B40 B41 B42 B43 B44 B45 B46 B47 B48 B49 B50 B51 B52 B53 B54 B55 B56 B57 B58 B59 B60 B61 B62 B63 B64 B65 B66 B67 B68 B69 B70 B71 B72 B73 B74 B75 B76 B77 Among them (---) represents a key.

[0066] In one embodiment, R 2 is selected from groups B1 to B37, B41 to B44, B49, B51 to B55, B57, B59, B62 to B67, B71 to B74, B76 and B77, or preferably, R 2 is selected from From the group B1-B33, B36, B41, B42, B51 to B54, B59, B65, B73 and B77, or more preferably, R2 is selected from the group B1, B2, B6, B8, B11, B12, B15, B20, B21, B36, B41, B42, B53, B54, B59, B65 and B73, or most preferably, R is selected from the group B21, B36, B41, B42, B52, B53, B54, B59, B65 and B73 .

[0067] In one embodiment of the compound of formula I, R 1 is OR 3 or SR 3 , for example R 1 is SR 3 . In various embodiments, R 3 is substituted or unsubstituted C 1-8 alkyl (eg, C 1-3 alkyl).

[0068] In another embodiment, R is a substituted or unsubstituted C aryl. In another embodiment, R 1 is a substituted or unsubstituted C 4-6 heterocycloalkyl. For example, R 1 is C 4-5 heterocycloalkyl optionally substituted with one or two groups selected from the group consisting of halo, OH, C 1-6 alkyl and OC 1-6 alkyl. For example, R is N-pyrrolidinyl optionally substituted with one or two groups selected from F and OH.

[0069] In another embodiment, R 1 is a substituted or unsubstituted C 5-6 heteroaryl or a substituted or unsubstituted C 9 heteroaryl. In another embodiment, R is a substituted or unsubstituted group selected from the group consisting of thienyl, imidazolyl, pyrazolyl, triazolyl, thiazolyl, pyridyl, pyrimidinyl, indolyl , indazolyl, benzimidazolyl, benzotriazolyl, pyrrolopyridyl (such as pyrrolo[3,2-b]pyridyl or pyrrolo[3,2-c]pyridyl), pyrazolo Pyridyl (e.g. pyrazolo[1,5-a]pyridinyl), purinyl, imidazopyrazinyl (e.g. imidazo[4,5-b]pyrazinyl) and quinolyl (quinolyl / quinolinyl) , preferably, R is a substituted or unsubstituted group selected from the group consisting of imidazolyl, pyrazolyl, triazolyl, indolyl, indazolyl, benzimidazolyl, benzotriazole base, pyrrolopyridyl (such as pyrrolo[3,2-b]pyridyl or pyrrolo[3,2-c]pyridyl), pyrazolopyridyl (such as pyrazolo[1,5-a] pyridyl), purinyl and imidazopyrazinyl (eg imidazo[4,5-b]pyrazinyl), more preferably attached to the pyrimidopyrimidine core via a nitrogen atom.

[0070] Examples of R include groups selected from the following groups: ; wherein (---) represents a bond, and wherein the group is optionally further substituted.

[0071] For example, R is a substituted or unsubstituted group selected from: ; Among them (---) represents a key.

[0072] In one embodiment, R 1 is one of the above groups, which is further substituted by at least one substituent selected from: OH, halo, CN, NO 2 , C 1-6 alkyl, C 2- 6 alkenyl, C 2-6 alkynyl, OC 1-6 alkyl, C 5-10 heteroaryl, C 3-10 cycloalkyl, C 4-10 heterocycloalkyl, C(O)R 15, C(O)N(R 14) 2, SO 2R 15, SO 2N(R 14) 2, N(R 16)C(O)R 15, N(R 16)SO 2R 15, N(R 16)C (O)N(R 14) 2, N(R 16)SO 2N(R 14) 2, N(R 14) 2, P(O)(R 15) 2, CH 2C(O)R 15, CH 2C (O)N(R 14) 2, CH 2SO 2R 15, CH 2SO 2N(R 14) 2, CH 2N(R 16)C(O)R 15, CH 2N(R 16)SO 2R 15, CH 2N( R 16)C(O)N(R 14) 2, CH 2N(R 16)SO 2N(R 14) 2 and CH 2N(R 14) 2; in: R 14 is independently selected from each occurrence of H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 4-10 heterocycloalkyl , C 6 aryl and C 5-10 heteroaryl, or two R 14 and their adjacent nitrogen atoms together form a C 4-10 heterocycloalkyl; R 15 is independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C aryl and C 5-10 hetero aryl; and R 16 is independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6 aryl and C 5- 10 heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl included in R (included in the definitions of R, R, and R) is optionally further replaced.

[0073] In another embodiment, R is a group having the formula: in: R 17 is selected from H, OH, halo, CN, NO 2, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, OC 1-6 alkyl, C 5-10 heteroaryl base, C 3-10 cycloalkyl, C 4-10 heterocycloalkyl, C(O)R 15, C(O)N(R 14) 2, SO 2R 15, SO 2N(R 14) 2, N (R 16)C(O)R 15, N(R 16)SO 2R 15, N(R 16)C(O)N(R 14) 2, N(R 16)SO 2N(R 14) 2,N (R 14) 2, P(O)(R 15) 2, CH 2C(O)R 15, CH 2C(O)N(R 14) 2, CH 2SO 2R 15, CH 2SO 2N(R 14) 2, CH 2N(R 16)C(O)R 15, CH 2N(R 16)SO 2R 15, CH 2N(R 16)C(O)N(R 14) 2, CH 2N(R 16)SO 2N(R 14) 2 and CH 2N(R 14) 2; X6 is N or CH; and X 7 is N and R 18 is absent; or X 7 is C and R 18 is selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, OC 1-6 alkyl, C 5-10 heteroaryl, C 3-10 ring Alkyl, C 4-10 heterocycloalkyl, C(O)R 15, C(O)N(R 14) 2, SO 2R 15, SO 2N(R 14) 2, N(R 16)C(O )R15, N(R16)SO2R15, N(R16)C(O)N(R14)2, N(R16)SO2N(R14)2, N(R14)2, P (O)(R 15) 2, CH 2C(O)R 15, CH 2C(O)N(R 14) 2, CH 2SO 2R 15, CH 2SO 2N(R 14) 2, CH 2N(R 16)C (O)R 15, CH 2N(R 16)SO 2R 15, CH 2N(R 16)C(O)N(R 14) 2, CH 2N(R 16)SO 2N(R 14) 2 and CH 2N( R 14) 2; wherein R 14, R 15 and R 16 are as defined above; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl or heteroaryl included in R (included in the definition of R 14, R 15, R 16, R 17 and R 18) further superseded as appropriate; and Among them (---) represents a key.

[0074] In another embodiment, R is a group having the formula: in: X 15, X 16, X 17 and X 18 are independently selected from O, N, S and CR 17, wherein R 17 is as previously defined; Wherein at most two of X 15, X 16, X 17 and X 18 are O, N or S.

[0075] In one embodiment, the compound of formula I is a compound of formula IV or V, or a pharmaceutically acceptable salt or solvate thereof: Formula IV Formula V wherein R 4 , R 5 , R 6 , R 17 , R 18 , X 6 , X 7 , X 15 , X 16 , X 17 and X 18 are each independently as defined herein, preferably, R 4 is selected from Cl , Br and methyl; R is selected from H, F, Cl and methyl; R is selected from H, F, Cl, Me and OMe.

[0076] In another embodiment, the compound of formula I is a compound of formula VI or VII, or a pharmaceutically acceptable salt or solvate thereof: Formula VI Formula VII wherein R 9 , R 10 , R 12 , R 17 , R 18 , X 5 , X 6 , X 7 , X 15 , X 16 , X 17 and X 18 are each independently as defined herein.

[0077] In one embodiment of the above chemical formula, X 6 is N. In another embodiment, X6 is CH.

[0078] In another embodiment, X 7 is N, and R 17 is selected from H, OH, CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, OC 1-6 alkyl, C 5-10 heteroaryl, C 3-10 cycloalkyl, C 4-10 heterocycloalkyl, C(O)R 15, C(O)N(R 14) 2, SO 2R 15, SO 2N( R 14) 2, N(R 16)C(O)R 15, N(R 16)SO 2R 15, N(R 16)C(O)N(R 14) 2, N(R 16)SO 2N( R 14) 2, N(R 14) 2, P(O)(R 15) 2, CH 2C(O)R 15, CH 2C(O)N(R 14) 2, CH 2SO 2R 15, CH 2SO 2N (R 14) 2, CH 2N(R 16)C(O)R 15, CH 2N(R 16)SO 2R 15, CH 2N(R 16)C(O)N(R 14) 2, CH 2N(R 16) SO 2N(R 14) 2 and CH 2N(R 14) 2, and R 18 does not exist, wherein the alkyl, alkenyl, alkynyl, cycloalkane in R 14, R 15, R 16 or R 17 The group, heterocycloalkyl or heteroaryl is further substituted as appropriate, preferably, R 17 is selected from C 1-6 alkyl, C 5-10 heteroaryl, C 4-10 heterocycloalkyl, N( R 14) 2, N(R 16)C(O)R 15, N(R 16)SO 2R 15, C(O)N(R 14) 2 and SO 2N(R 14) 2, wherein R 14, R 15. The alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl or heteroaryl in R 16 or R 17 is optionally further substituted. For example, R 17 is selected from R 17 is H, NH 2 and optionally substituted C 5-10 heteroaryl or C 4-10 heterocycloalkyl, preferably, R 17 is optionally substituted C 5-10 heteroaryl or C 4-10 heterocycloalkyl.

[0079] In another embodiment, R 17 is optionally substituted C 4-10 heterocycloalkyl, wherein the heterocycloalkyl can be monocyclic or bicyclic and includes 1 to 3 heteroatoms, preferably, wherein X 7 is N. In a preferred embodiment, the heterocycloalkyl is, for example, substituted by at least one group selected from the group consisting of F, OH, pendant oxy, CN, C 1-4 alkyl and OC 1-4 alkyl, wherein the C 1-4 alkyl is optionally further substituted (eg, substituted with F, OH, OC 1-3 alkyl, etc.). For example, heterocycloalkyl groups can be selected from optionally substituted piperidine groups, piperazine groups, thiomorpholine groups and morpholine groups, or contain piperidine, piperazine, thiomorpholine groups Or the ring structure of morpholine ring (bridged or spiro ring).

[0080] In another embodiment, X 7 is C, for example X 7 is C and R 18 is selected from C 1-6 alkyl, C 5-10 heteroaryl, C 3-10 cycloalkyl, C 4-10 hetero Cycloalkyl, C(O)R 15, C(O)N(R 14) 2, SO 2R 15, SO 2N(R 14) 2, N(R 16)C(O)R 15, N(R 16 )SO 2R 15, N(R 16)C(O)N(R 14) 2, N(R 16)SO 2N(R 14) 2, N(R 14) 2, P(O)(R 15) 2 , CH 2C(O)R 15, CH 2C(O)N(R 14) 2, CH 2SO 2R 15, CH 2SO 2N(R 14) 2, CH 2N(R 16)C(O)R 15, CH 2N (R 16)SO 2R 15, CH 2N(R 16)C(O)N(R 14) 2, CH 2N(R 16)SO 2N(R 14) 2 and CH 2N(R 14) 2, wherein R 14 , the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, or heteroaryl in R 15, R 16 or R 18 are optionally further substituted, preferably, R 18 is selected from C( O)N(R 14) 2, SO 2R 15 and SO 2N(R 14) 2. In a subclass of these embodiments, R 17 is selected from H, OH, C 1-6 alkyl, N(R 14 ) 2 and optionally substituted C 5-10 heteroaryl. For example, R 17 is selected from H, NH 2 , and optionally substituted C 5-10 heteroaryl, preferably H or NH 2 .

[0081] In yet another embodiment, each occurrence of R 14 is independently selected from H, optionally substituted C 1-6 alkyl, optionally substituted C 3-10 cycloalkyl, optionally substituted A C 4-10 heterocycloalkyl group and an optionally substituted C 5-6 heteroaryl group, or two R 14 together with their adjacent nitrogen atoms form a C 4-10 heterocycloalkyl group.

[0082] In another embodiment, R 17 is N(R 14) 2, wherein the R 14 forms a C 4-10 heterocycloalkyl together with its adjacent nitrogen atom, wherein the heterocycloalkyl can be monocyclic or bicyclic And include 1 to 3 heteroatoms, preferably, wherein X 7 is N. In a preferred embodiment, the heterocycloalkyl is, for example, substituted by at least one group selected from the group consisting of F, OH, pendant oxy, CN, C 1-4 alkyl and OC 1-4 alkyl, wherein the C 1-4 alkyl is optionally further substituted (eg, substituted with F, OH, OC 1-3 alkyl, etc.). For example, heterocycloalkyl groups can be selected from optionally substituted piperidine groups, piperazine groups, thiomorpholine groups and morpholine groups, or contain piperidine, piperazine, thiomorpholine groups Or the ring structure of morpholine ring (bridged or spiro ring).

[0083] In another embodiment, R is selected from: wherein R 14 is as defined herein and (---) represents a bond.

[0084] In another example, R is selected from: ; wherein R 14 is as defined herein and (---) represents a bond.

[0085] Other subclass embodiments are also presented in the Examples section, where the respective substituents R 1 (C group), R 2 (B group), Y and L are defined. Examples of combinations are also set forth further below and in Tables 2-5. Representative preferred compounds of Examples 1-163 are also described herein.

[0086] More specifically, exemplary R groups are shown as C1 to C493 as defined below: MeS-- C1 C2 C3 C4 C5 C6 C7 C8 C9 C10 C11 C12 C13 MeO-- C14 C15 C16 C17 C18 C19 C20 C21 C22 C23 C24 C25 C26 C27 C28 C29 C30 C31 C32 C33 C34 C35 C36 C37 C38 C39 C40 C41 C42 C43 C44 C45 C46 C47 C48 C49 C50 C51 C52 C53 C54 C55 C56 C57 C58 C59 C60 C61 C62 C63 C64 C65 C66 C67 C68 C69 C70 C71 C72 C73 C74 C75 C76 C77 C78 C79 C80 C81 C82 C83 C84 C85 C86 C87 C88 C89 C90 C91 C92 C93 C94 C95 C96 C97 C98 C99 C100 C101 C102 C103 C104 C105 C106 C107 C108 C109 C110 C111 C112 C113 C114 C115 C116 C117 C118 C119 C120 C121 C122 C123 C124 C125 C126 C127 C128 C129 C130 C131 C132 C133 C134 C135 C136 C137 C138 C139 C140 C141 C142 C143 C144 C145 C146 C147 C148 C149 C150 C151 C152 C153 C154 C155 C156 C157 C158 C159 C160 C161 C162 C163 C164 C165 C166 C167 C168 C169 C170 C171 C172 C173 C174 C175 C176 C177 C178 C179 C180 C181 C182 C183 C184 C185 C186 C187 C188 C189 C190 C191 C192 C193 C194 C195 C196 C197 C198 C199 C200 C201 C202 C203 C204 C205 C206 C207 C208 C209 C210 C211 C212 C213 C214 C215 C216 C217 C218 C219 C220 C221 C222 C223 C224 C225 C226 C227 C228 C229 C230 C231 C232 C233 C234 C235 C236 C237 C238 C239 C240 C241 C242 C243 C244 C245 C246 C247 C248 C249 C250 C251 C252 C253 C254 C255 C256 C257 C258 C259 C260 C261 C262 C263 C264 C265 C266 C267 C268 C269 C270 C271 C272 C273 C274 C275 C276 C277 C278 C279 C280 C281 C282 C283 C284 C285 C286 C287 C288 C289 C290 C291 C292 C293 C294 C295 C296 C297 C298 C299 C300 C301 C302 C303 C304 C305 C306 C307 C308 C309 C310 C311 C312 C313 C314 C315 C316 C317 C318 C319 C320 C321 C322 C323 C324 C325 C326 C327 C328 C329 C330 C331 C332 C333 C334 C335 C336 C337 C338 C339 C340 C341 C342 C343 C344 C345 C346 C347 C348 C349 C350 C351 C352 C353 C354 C355 C356 C357 C358 C359 C360 C361 C362 C363 C364 C365 C366 C367 C368 C369 C370 C371 C372 C373 C374 C375 C376 C377 C378 C379 C380 C381 C382 C383 C384 C385 C386 C387 C388 C389 C390 C391 C392 C393 C394 C395 C396 C397 C398 C399 C400 C401 C402 C403 C404 C405 C406 C407 C408 C409 C410 C411 C412 C413 C414 C415 C416 C417 C418 C419 C420 C421 C422 C423 C424 C425 C426 C427 C428 C429 C430 C431 C432 C433 C434 C435 C436 C437 C438 C439 C440 C441 C442 C443 C444 C445 C446 C447 C448 C449 C450 C451 C452 C453 C454 C455 C456 C457 C458 C459 C460 C461 C462 C463 C464 C465 C466 C467 C468 C469 C470 C471 C472 C473 C474 C475 C476 C477 C478 C479 C480 C481 C482 C483 C484 C485 C486 C487 C488 C489 C490 C491 C492 C493 Among them (---) represents a key.

[0087] In one embodiment, R is selected from groups C1 to C493 or R is selected from groups C1 to C23, C27, C60, C69, C71 to C73, C81 to C83, C88, C114, C182 to C184, C196, C220, C223 to C226, C275, C292, C310, C312, C313, C323, C346, C376, C402, C404, C414, C418, C419, C434, C435, C438, C440, C441, C472, C483, C488 and C4 90, For example R is selected from groups C1, C3, C5, C7, C22, C23, C27, C60, C69, C73, C81 to C83, C88, C182 to C184, C196, C224-C226, C313, C323, C376, C402 , C404, C414, C418, C419, C438 and C488 are for example selected from C7, C22, C23 and C60 or selected from C183, C323, C376, C414, C418, C419, C438 and C488.

[0088] The following examples depict combinations of R (C1 to C493), R (B1 to B77) and L (L1 to L4) groups that can be combined to produce compounds of formula I, wherein Y is H or NH 2: C1-L-B1;C1-L-B2;C1-L-B3;C1-L-B4 to 70;C1-L-B71;C1-L-B72;C1-L-B73;C1-L-74; C1-L-B75 to B77; C2-L-B1;C2-L-B2;C2-L-B3;C2-L-B4 to 70;C2-L-B71;C2-L-B72;C2-L-B73;C2-L-B74; C2-L-B75 to B77; C3-L-B1;C3-L-B2;C3-L-B3;C3-L-B4 to 70;C3-L-B71;C3-L-B72;C3-L-B73;C3-L-B74; C3-L-B75 to B77; C4 to C488-L-B1;C4 to C488-L-B2;C4 to C488-L-B3;C4 to C488-L-B4 to 70;C4 to C488-L-B71;C4 to C488-L-B72; C4 to C488-L-B73; C4 to C488-L-B74; C4 to C488-L-B75 to B77; C489-L-B1;C489-L-B2;C489-L-B3;C489-L-B4 to B70;C489-L-B71;C489-L-B72;C489-L-B73;C489-L-B74; C489-L-B75 to B77; C490-L-B1;C490-L-B2;C490-L-B3;C490-L-B4 to B70;C490-L-B71;C490-L-B72;C490-L-B73;C490-L-B74; C490-L-B75 to B77; C491 to C493-L-B1;C491 to C493-L-B2;C491 to C493-L-B3;C491 to C493-L-B4 to B70;C491 to C493-L-B71;C491 to C493-L-B72; C491 to C493-L-B73; C491 to C493-L-B74; or C491 to C493-L-B75 to B77.

[0089] In one embodiment, the compound is as defined in Formula I, wherein: - R1 is selected from the groups C1 to C493 or R1 is selected from the groups C1 to C23, C27, C60, C69, C71 to C73, C81 to C83, C88, C114, C182 to C184, C196, C220, C223 to C226 , C275, C292, C310, C312, C313, C323, C346, C376, C402, C404, C414, C418, C419, C434, C435, C438, C440, C441, C472, C483, C488 and C490, for example R is selected from Groups C1, C3, C5, C7, C22, C23, C27, C60, C69, C73, C81 to C83, C88, C182 to C184, C196, C224-C226, C313, C323, C376, C402, C404, C414, C418, C419, C438 and C488; - R is selected from B1, B2, B8, B11, B12, B20 to B23, B34 to B37, B41 to B44, B49, B51 to B54, B57, B59, B62 to B67, B71 to B74 and B77; and - L is a group selected from L1 to L4, and Y is H or NH 2 , preferably, Y is H.

[0090] In another embodiment, the compound is as defined in formula I, wherein R is selected from C7, C22, C23, C60, C73, C81, C83, C183, C376, C404, C414, C418, C419, C438 and C488, R 2 is selected from B12, B21, B36, B41, B42, B52 to B54, B59, B65 and B73, L is a group selected from L1 to L4, and Y is H or NH 2 , preferably Y is H.

[0091] Exemplary compounds as defined herein include each single compound covered in Tables 2, 3, 4 and 5 under Examples 1-163.

[0092] Examples of preferred compounds are i.e. examples 31, 36, 40, 51, 55 to 60, 69, 72, 80 to 83, 88, 93, 94, 96 to 122, 124 to 147, from Tables 3, 4 and 5 149, 151 to 160, 162 and 163. Examples of more preferred compounds include examples 80 to 83, 93, 94, 96, 98 to 101, 104, 106, 111, 112, 114 to 116, 119, 120, 122, 125, 128 to 134 from Tables 3 and 5 , 139, 142, 144 to 146, 153, 155, 157, 159 and 162.

[0093] It should be understood that any of the above compounds may be in any amorphous, crystalline or polymorphic form, including any salt or solvate form, or mixtures thereof. The compounds of the present invention can be further modified by adding various functions through any of the synthetic means described herein to enhance selective biological properties. Such modifications are known in the art and include increasing biopenetration into a given biological system (e.g., blood, lymphatic system, central nervous system), increasing oral availability, increasing solubility to allow administration by injection, altering metabolism And those modifications that change the rate of excretion.

[0094] These compounds can be prepared by conventional chemical syntheses, such as those exemplified in the Schemes and Examples of this disclosure. Other methods of synthesizing compounds of the formulas herein will be apparent to those of ordinary skill in the art, as can be understood by those skilled in the art. Additionally, the various synthetic steps may be performed in an alternating sequence or sequence to give the desired compounds. iii. Methods, uses, formulations and administration

[0095] As used herein, the term "effective amount" means the amount of a drug or pharmaceutical agent that elicits, for example, a biological or medical response in a tissue, system, animal or human being sought by a researcher or clinician. Furthermore, the term "therapeutically effective amount" means any amount that results in the treatment, cure, prevention, or amelioration of a disease, disorder, or symptoms thereof, or reduces the rate of progression of a disease or disorder, compared to a corresponding subject that has not received such amount. . The term also includes within its scope amounts effective to enhance normal physiological function.

[0096] As used herein, the terms "treatment / treat / treating" refer to reversing, alleviating, delaying onset or inhibiting progression of a disease or disorder as described herein, or one or more symptoms thereof. In some embodiments, treatment may be administered after one or more symptoms have manifested. In other embodiments, treatment can be administered in the absence of symptoms. For example, treatment can be administered to susceptible individuals prior to the onset of symptoms (eg, in view of history of symptoms and / or in view of genetic or other predisposition factors). Treatment can also be continued after symptoms have resolved, eg, to prevent or delay their recurrence.

[0097] In one embodiment, the disease or condition to be treated is a proliferative disease or disorder or a kinase-mediated disease or disorder. More specifically, the diseases or conditions to be treated include proliferative diseases or conditions, developmental abnormalities due to dysregulation of the RAS-ERK signaling cascade (RAS diseases), inflammatory diseases or disorders of the immune system.

[0098] According to some examples, the proliferative disease or disorder to be treated is a neoplasm, an inflammatory disease or condition or dysplasia involving persistent activating mutations in the RAS and / or RAF genes (e.g. KRAS and / or ARAF, BRAF or CRAF mutations) . Diseases or conditions may further be associated with mutations or amplifications of receptor tyrosine kinases (eg EGFR, HER2) or mutations of regulators of the RAS downstream of the receptor (eg SOS1 gain-of-function, NF1 loss-of-function). For example, compounds as defined herein are inhibitors of signaling enzymes (such as BRAF and CRAF), which are not only involved in the control of cell proliferation in tumors carrying RAF mutations (such as BRAF V600E), but importantly also in the mutated RAS-driven Cancer cell proliferation. Thus, the compounds of the invention are useful, for example, in the treatment of diseases associated with the activity of these signaling enzymes and characterized by excessive or abnormal cell proliferation.

[0099] According to one embodiment, the disease or disorder is characterized by uncontrolled cell proliferation, ie a "proliferative disorder" or "proliferative disease". More specifically, these diseases and disorders are associated with cells that have the ability to grow autonomously, that is, an abnormal condition characterized by rapid proliferation of cells, often in the form of Coordinated pronounced lumps.

[0100] For example, a proliferative disorder or disease is defined as "neoplastic," "neoplastic disorder," "neoplastic," "cancer," and "tumour," and these terms collectively encompass hematopoietic neoplasms (such as lymphoma or leukemia) and solid neoplasms (such as sarcomas or carcinomas), including precancerous and cancerous growths, or all types of oncogenic processes, metastatic tissue, or malignantly transformed cells, tissues, or organs, regardless of histopathological type or invasive stage how. Hematopoietic neoplasms are malignant neoplasms that affect hematopoietic structures (structures associated with blood cell formation) and components of the immune system, including leukemias (related to white blood cells (leukocytes) and their precursors) of the myeloid, lymphoid, or erythroid lineage associated), and lymphoma (associated with lymphocytes). Solid neoplasms include sarcomas, which are malignant neoplasms derived from connective tissue, such as muscle, cartilage, blood vessels, fibrous tissue, fat, or hard bone. Solid neoplasms also include carcinomas, which are malignant neoplasms arising from epithelial structures, including the outer epithelium (such as the skin and linings of the gastrointestinal tract, lungs, and cervix), and the linings of various glands (such as breast, pancreas, , thyroid) inner epithelium. Examples of neoplasms include leukemia and hepatocellular carcinoma, sarcoma, vascular endothelial carcinoma, breast cancer, central nervous system cancers such as astrocytoma, gliosarcoma, neuroblastoma, oligodendroglioma, and glioma cancer), prostate cancer, lung and bronchial cancer, laryngeal cancer, esophageal cancer, colon cancer, colorectal cancer, gastrointestinal cancer, melanoma, ovarian cancer and endometrial cancer, kidney cancer and bladder cancer, liver cancer, endocrine cancer (e.g. thyroid) and pancreatic cancer. For example, the disease or condition is selected from colon cancer, lung cancer, pancreatic cancer, thyroid cancer, breast cancer and skin cancer. Examples of neoplasms include melanoma, papillary thyroid cancer, colorectal cancer, ovarian cancer, breast cancer, endometrial cancer, liver cancer, sarcoma, gastric cancer, Barrett's adenocarcinoma, glioma (including ependymoma ), lung cancer (including non-small cell lung cancer), head and neck cancer, acute lymphoblastic leukemia, acute myeloid leukemia, non-Hodgkin's lymphoma and hairy cell leukemia.

[0101] In one embodiment, patients presenting with one of the above-mentioned hematopoietic or solid neoplasms have previously been treated with inhibitors targeting the RAS-ERK pathway, including RTK, RAF, MEK or ERK inhibitors , but have developed resistance to the inhibitor. Inhibitors include standard of care treatments such as vemurafenib, dabrafenib, cobimetinib, trametinib, YERVOY, OPDIVO, or any combination of these pharmaceutical agents.

[0102] In one embodiment, the disease to be treated is defined as a developmental abnormality caused by a dysregulation of the RAS-ERK signaling cascade (RAS disease: e.g. Noonan syndrome, Costello syndrome, LEOPARD syndrome, Cardiofaciocutaneous syndrome and hypertrophic cardiomyopathy).

[0103] In one embodiment, the disease to be treated is defined as an inflammatory disease or a disorder of the immune system. Examples of such inflammatory diseases or disorders of the immune system include inflammatory bowel disease, Crohn's disease, ulcerative colitis, systemic lupus erythematosis (SLE), rheumatoid arthritis , multiple sclerosis, thyroiditis, type 1 diabetes, sarcoidosis, psoriasis, allergic rhinitis, asthma, chronic obstructive pulmonary disease (chronic obstructive pulmonary disease; COPD).

[0104] In one embodiment, a compound as defined herein is an inhibitor of RAS-ERK signaling and cell proliferation in tumor cells carrying at least one mutated RAS or RAF genotype, without inducing or substantially not inducing aberrant pathways.

[0105] As used herein, the term "patient or subject" refers to an animal, such as a mammal. Thus, a subject may refer to, for example, mice, rats, dogs, cats, horses, cows, pigs, guinea pigs, primates including humans, and the like. The subject is preferably a human.

[0106] Accordingly, the present invention further relates to a method of treating a subject, such as a human subject, suffering from a proliferative disease or disorder, eg RAF mutation and / or mutated RAS driven cancer. The method comprises administering to a subject in need of such treatment a therapeutically effective amount of a compound as defined herein.

[0107] In certain embodiments, the invention provides a method of treating a condition (as described herein) in a subject comprising administering to a subject identified in need thereof a compound of the invention. It is well within the ability and knowledge of those skilled in the art to identify those patients in need of treatment for the conditions described above. Certain methods for identifying patients at risk of developing the above-mentioned conditions treatable by the subject methods are recognized in the medical field, such as family history, and the presence of risk factors associated with the development of the subject patient's disease state. A clinician skilled in the art can readily identify such candidate patients by using, for example, clinical tests, physical exams, medical / family history, and genetic testing.

[0108] Methods of assessing the efficacy of treatment in a subject include determining pre-treatment symptoms of a disorder by methods well known in the art, and then administering to the subject a therapeutically effective amount of a compound of the invention. Symptoms of the disorder are again determined after an appropriate period of time (eg, 1 week, 2 weeks, one month, six months) after administration of the compound. Modulation (eg, reduction) of a symptom of a disorder and / or a biomarker (eg, pERK or pMEK) is indicative of efficacy of the treatment. Symptoms and / or biomarkers of a disorder can be determined periodically throughout the course of treatment. For example, symptoms and / or biomarkers of a disorder can be detected every few days, weeks or months to assess further efficacy of the treatment. A reduction in symptoms and / or biomarkers of a disorder indicates that the treatment is effective.

[0109] In some embodiments, a therapeutically effective amount of a compound as defined herein may be administered to a patient alone or in a composition in admixture with a pharmaceutically acceptable carrier, adjuvant or vehicle.

[0110] The expression "pharmaceutically acceptable carrier, adjuvant or vehicle" and equivalent expressions mean a non-toxic carrier, adjuvant or vehicle which does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants, and vehicles that can be used in the compositions of the present disclosure include, but are not limited to: ion exchangers, aluminum oxide, aluminum stearate, lecithin, serum albumin ( such as human serum albumin), buffer substances (such as phosphate), glycine, sorbic acid, potassium sorbate, mixtures of partial glycerides of saturated vegetable fatty acids, water, salts or electrolytes (such as protamine sulfate ), disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon dioxide, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, carboxymethyl cellulose sodium sulfate, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol, and lanolin.

[0111] The compositions described herein can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally or via an implanted reservoir. As used herein, the term "parenteral" includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Other modes of administration also include intradermal or transdermal administration.

[0112] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compound, liquid dosage forms may also contain inert diluents commonly used in the art, such as water or other solvents; solubilizers and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzene; Methanol, Benzyl Benzoate, Propylene Glycol, 1,3-Butanediol, Dimethylformamide, Oils (specifically, Cottonseed Oil, Peanut Oil, Corn Oil, Germ Oil, Olive Oil, Castor Oil, and Sesame Oil) , glycerin, tetrahydrofurfuryl alcohol, polyethylene glycol and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, surface-active agents, sweetening, flavoring, and perfuming agents.

[0113] Injectable preparations such as sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Acceptable vehicles and solvents that may be employed include water, U.S.P. Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0114] Injectable formulations can be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use. agent to sterilize.

[0115] In order to prolong the effect of a provided compound, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of poorly water soluble crystalline or amorphous material. The rate of absorption of the compound then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled.

[0116] Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions which are compatible with body tissues.

[0117] Compositions for rectal administration are preferably suppositories, which can be obtained by combining a compound of the invention with a suitable non-irritating formulation that is solid at ambient temperature but liquid at body temperature and therefore melts in the rectum and releases the active compound. It is prepared by mixing with a sexual excipient or carrier such as cocoa butter, polyethylene glycol or suppository wax.

[0118] Solid dosage forms for oral administration include capsules, lozenges, pills, powders, and granules. In such solid dosage forms, the active compound is admixed with at least one inert pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate and / or a) a filler or extender dosing agents such as starch, lactose, sucrose, glucose, mannitol and silicic acid, b) binders such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone (PVP), sucrose and acacia , c) humectants, such as glycerin, d) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate, e) solution retarders, such as paraffin, f) Absorption accelerators, such as quaternary ammonium compounds, g) humectants, such as cetyl alcohol and glyceryl monostearate, h) adsorbents, such as kaolin and bentonite, and i) lubricants, such as talc, calcium stearate , magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate and mixtures thereof. In the case of capsules, lozenges and pills, the dosage form may also comprise buffering agents.

[0119] Solid compositions of a similar type can also be used as fillers in soft and hard-filled gelatin capsules using such excipients as lactose (milk sugar) and high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain devitrification agents and may also be of a composition such that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type can also be used as fillers in soft and hard-filled gelatin capsules using such excipients as lactose (milk sugar) and high molecular weight polyethylene glycols and the like.

[0120] The composition can also be in microencapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms, the active compound may be admixed with at least one inert diluent, such as sucrose, lactose or starch. Such dosage forms may also contain substances other than inert diluents, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose, as is normal practice. In the case of capsules, lozenges and pills, the dosage form may also comprise buffering agents. They may optionally contain devitrification agents and may also be of a composition such that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0121] Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active ingredient is admixed under sterile conditions with a pharmaceutically acceptable carrier and, if desired, any required preservatives or buffers. Ophthalmic formulations, ear drops, and eye drops are also within the scope of this invention. Additionally, the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of the compound to the body. Such dosage forms can be prepared by dissolving or dispersing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0122] The pharmaceutically acceptable compositions provided herein can also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the pharmaceutical compounding art and may be prepared using benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons and / or other conventional solvents or dispersants into a solution in saline.

[0123] The pharmaceutically acceptable compositions provided herein can be formulated for oral administration. Such formulations can be administered with or without food. In some embodiments, the pharmaceutically acceptable compositions of the disclosure are administered without food. In other embodiments, the pharmaceutically acceptable compositions of the disclosure are administered with food.

[0124] The amount of compound that can be combined with a carrier material to produce a composition in a single dosage form will vary depending upon the patient being treated and the particular mode of administration. The provided compositions may be formulated so that doses of between 0.01-100 mg per kilogram body weight per day of the inhibitor can be administered to patients receiving such compositions.

[0125] It is also understood that the particular dosage and treatment regimen for any particular patient will depend on a variety of factors, including age, weight, general health, sex, diet, time of administration, rate of excretion, drug combination, diagnosis of the treating physician, and contact with the patient. Severity of symptoms associated with a proliferative disease or disorder. The amount of compound provided in the composition will also depend on the particular compound in the composition.

[0126] A compound or composition described herein may be administered using any amount and any route of administration effective to treat or lessen the severity of a symptom contemplated herein. The precise amount required will vary from subject to subject, depending on the species, age, and general condition of the subject; the severity of the infection; the particular agent; its mode of administration, and the like. Provided compounds are preferably formulated in unit dosage form for ease of administration and uniformity of dosage. As used herein, the expression "unit dosage form" refers to a physically discrete unit of pharmaceutical agent suitable for the patient to be treated. It should be understood, however, that the total daily dosage of the compounds and compositions of the disclosure will be at the discretion of the attending physician within the scope of sound medical diagnosis.

[0127] Depending on the severity of the infection being treated, the pharmaceutically acceptable compositions of the disclosure can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intraperitoneally, topically (e.g., by powder, ointment or drops), buccally (in the form of an oral or nasal spray), or the like. In certain embodiments, the provided compound can be administered orally or parenterally one or more times a day at a dose of about 0.01 mg to about 50 mg per kilogram of subject body weight per day, and preferably about 1 mg to about 25 mg. Enteral administration is used to obtain the desired therapeutic effect.

[0128] It is to be understood that the total daily dosage of the compounds and compositions of this invention will be determined by the attending physician within the scope of sound medical diagnosis. The total daily inhibitory dose of a compound of the invention administered to a subject in a single dose or in divided doses may be, for example, in an amount of 0.01 mg to 50 mg per kilogram body weight, or more usually 0.1 mg to 25 mg per kilogram body weight. Single dose compositions may contain such amounts or submultiples thereof to make up the daily dose. In one embodiment, a treatment regimen according to the invention comprises administering to a patient in need of such treatment from about 10 mg to about 1000 mg of one or more compounds of the invention per day in single or multiple doses.

[0129] Depending on the disease or condition being treated, additional therapeutic agents may also be present in the compositions of the present disclosure or administered separately as part of a dosage regimen, such as additional chemotherapeutic agents. Non-limiting examples of additional therapeutic agents that may be used in combination with the compounds of the invention include antiproliferative compounds, such as aromatase inhibitors; antiestrogens; antiandrogens; sex release hormone agonists; topoisomerase I inhibitors; Puisomerase II inhibitors; microtubule activators; alkylating agents; retinoids, carotenoids, tocopherols; cyclooxygenase inhibitors; MMP inhibitors; antimetabolites; platinum compounds; methionine aminopeptides Enzyme Inhibitors; Bisphosphonates; Antiproliferative Antibodies; Heparanase Inhibitors; Ras Oncogenic Isoform Inhibitors; Telomerase Inhibitors; Proteasome Inhibitors; Compounds for Hematological Malignancies; Drivers Protein spindle protein inhibitors; Hsp90 inhibitors; mTOR inhibitors; PI3K inhibitors; Flt-3 inhibitors; CDK4 / 6 inhibitors; HER2 inhibitors (Herceptin, Trastuzumab )); EGFR inhibitors (Iressa, Tarceva, Neratinib, Lapatinib (Tykerb), Erbitux); RAS inhibitors; MEK Inhibitors (trametinib, binimetinib, cobimetinib); ERK inhibitors (ulixertinib); anti-PD-1 antibodies (Opdivo, Keytruda); anti-CTLA4 Antibody (Yervoy); antineoplastic antibody; nitrosourea; compound that targets / reduces protein or lipid kinase activity, compound that targets / reduces protein or lipid phosphatase activity, or any other anti-angiogenic compound.

[0130] Treatment may also be supplemented by other treatments or interventions such as surgery, radiation therapy (such as gamma radiation, neutron beam radiation therapy, electron beam radiation therapy, proton therapy, brachytherapy, and systemic radioisotopes), biological response modifiers (such as interference hormone, interleukin, tumor necrosis factor (tumor necrosis factor; TNF)) and agents for alleviating adverse reactions.

[0131] The recitation herein of an embodiment of a variant includes that embodiment as any single embodiment or in combination with any other embodiment or portion thereof. The recitation herein of an embodiment includes that embodiment as any single embodiment or in combination with any other embodiment or portion thereof. example

[0132] List of abbreviations: Ac: Acetyl AcOEt: ethyl acetate AcOH: acetic acid Ar: aryl ATCC: American Type Culture Collection ATP: adenosine triphosphate BINOL:[1,1'-binaphthyl]-2,2'-diol Boc: tertiary butoxycarbonyl BOP:(Benzotriazol-1-yloxy)paraffin(dimethylamino)phosphonium hexafluorophosphate br: broadband BSA: bovine serum albumin CCL: cancer cell line DCE:1,2-dichloroethane DCM: dichloromethane DIEA (or DIPEA): N,N-Diisopropylethylamine (Huenig’s base) DME:1,2-Dimethoxyethane DMF:N,N-Dimethylformamide DMSO: Dimethyroxide DTT: dithiothreitol EA: ethyl acetate EC 50: half maximum effective concentration ECL: enhanced chemiluminescence EDTA: ethylenediaminetetraacetic acid Et2O: diethyl ether EtOH: ethanol Eu: Europium FBS: Fetal Bovine Serum GST: glutathione S-transferase HATU: O-(7-Azabenzotriazol-1-yl)-N,N,N’,N’,-tetramethyluronium hexafluorophosphate HEPES: 4-(2-Hydroxyethyl)-1-piperazineethanesulfonic acid Het: Heterocycle Hex: hexane HRMS: High Resolution Mass Spectrometry HPLC: High Performance Liquid Chromatography HRP: Horseradish Peroxidase IC 50: half maximal inhibitory concentration IPA or iPrOH: Isopropanol LCMS: Liquid Chromatography Mass Spectrometry MeCN:Acetonitrile MS: mass spectrometry NMP:N-Methylpyrrolidone NMR: nuclear magnetic resonance ON: Overnight PBS: Phosphate Buffered Saline pERK: Phosphorylated extracellular signal-regulated kinase PMB: p-Methoxybenzyl PMSF: phenylmethylsulfonyl fluoride Rf: retention factor RPMI-1640: Roswell Park Memorial Institute Medium RT: room temperature SDS: sodium dodecyl sulfate SDS-PAGE: Sodium Dodecyl Sulfate-Polyacrylamide Gel Electrophoresis SEM: Trimethylsilylethoxymethyl SNAr: nucleophilic aromatic substitution TBST: Tris-buffered saline with 0.2% Tween-20 TBTU: O-(benzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluoroborate TEV: Tobacco etch virus protease TFA: Trifluoroacetic acid THF: Tetrahydrofuran TLC: silica gel thin layer chromatography TR-FRET: Time-resolved fluorescence resonance energy transfer Ts: p-toluenesulfonate Y MIN: the minimum data point of the dose-activity curve

[0133] The following non-limiting examples are illustrative embodiments and should not be construed as further limiting the scope of the invention. Such examples will be better understood with reference to the figures.

[0134] The examples set forth below provide synthetic and experimental results obtained for certain exemplary compounds. Reactions are carried out under an inert atmosphere (nitrogen or argon) where it is necessary to protect the reaction components from air and moisture, as is well known to those skilled in the art. Temperatures are given in degrees Celsius (°C). Unless otherwise stated, solution percentages and ratios express a volume-to-volume relationship. The reactants used in the following examples can be obtained as described herein or, if not described herein, are commercially available as such or can be prepared from commercially available materials by methods known in the art. Flash chromatography was performed on silica (SiO2) using commercial normal phase silica at 254 nm using a Teledyne Isco Rf Combiflash instrument. Mass spectrometry was recorded using electrospray mass spectrometry. NMR was recorded on a 400 MHz Varian instrument.

[0135] Preparative HPLC was performed using an Agilent instrument using a Phenomenex-Kinetex C18 (21×100 mm, 5 µm) column at a flow rate (RT) of 20 mL / min and UV detection at 220 nm and 254 nm. Unless otherwise stated, the mobile phase consisted of solvent A (5% MeOH, 95% water + 0.1% formic acid) and solvent B (95% MeOH, 5% water + 0.1% formic acid). Occasionally use 0.05% TFA or 0.1% AcOH or other additives instead of 0.1% formic acid as additives in both solvents, as described in the text. As described in the text, MeCN was also used instead of MeOH in both mobile phases for more challenging separations. Specific gradient conditions are also provided in the examples, but the following are representative: T(0)→T(3 min) isocratic, depending on compound polarity, using between 10% and 50% solvent B, followed by 12 Minute gradient to 100% solvent B. Use 100% solvent B for the last 5 minutes.

[0136] LCMS analysis was performed on an Agilent instrument. Liquid chromatography was performed on a Phenomenex Kinetex C18 column (2.6 µm; 100 Å; 3 x 30 mm) at a flow rate (RT) of 1.5 mL / min with UV detection at 220 nm and 254 nm. The mobile phase consisted of solvent A (95% HO / 5% MeOH / 0.1% AcOH) and solvent B (95% MeOH / 5% HO / 0.1% AcOH) using the following gradient: T(0) 100% A → T(0.5 min) 100% B → isocratic 100% B to T(2 min). MS detection was performed in parallel using APCI detection in positive and negative modes.

[0137] Unless otherwise indicated, all numbers expressing amounts of ingredients, reaction conditions, concentrations, properties, stability, etc. used in this specification and claims are to be understood as being modified in all instances by the term "about". At the very least, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Accordingly, unless indicated to the contrary, the numerical parameters set forth in this specification and the accompanying claims are approximations that may vary depending upon the properties sought to be obtained. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the examples are approximations, the numerical values ​​set forth in the specific examples are reported as precisely as possible. Any numerical value, however, inherently contains certain errors resulting from variation in experimentation, test measurements, statistical analysis, and the like. Synthesis, Biological Activity and Characterization of Examples:

[0138] All compounds described herein were prepared according to the methods shown in Tables 2-5. Characterization data from mass spectrometry and NMR are provided for each of the examples. Compounds were tested in the assays described in the Biological Assays section. The conventions used to report biological data are provided as footnotes in the respective tables. General Synthesis Method A:

[0139] Commercially available 2,6-difluoro-3-nitrobenzoic acid A-1 (Scheme A) can be reacted via the Curtius reaction according to the procedure described in J. Med. Chem. 2003, 46, 1905 ) into carbamate A-2. The hydrogenolysis of nitroarenes A-2 to aniline A-3 is catalyzed using hydrogen gas and a catalyst such as palladium metal on carbon or palladium hydroxide on carbon (Pearlman's catalyst). Aniline A-3 with a sulfonylating agent (such as sulfonyl chloride) in the presence of an organic base (such as pyridine, which can be used as a solvent), with or without a catalyst (such as 4-dimethylaminopyridine), and Reaction in the presence or absence of additional solvents such as dichloromethane or tetrahydrofuran leads to the sulfonamide intermediate A-4, which can be deprotected as the aniline salt using a strong acid such as anhydrous hydrochloric acid in dioxane , such as A-5. Alternatively, 2,6-difluoroaniline A-6 can be converted to its acetaniline A-7 using an acetylating agent such as acetic anhydride and to monoprotected diphenylamine A-7 as described in WO 2012 / 101238A1 8. Sulfonylation to sulfonylamide A-9 is used in the presence of an organic base such as pyridine, with or without a catalyst such as 4-dimethylaminopyridine and a solvent such as dichloromethane or tetrahydrofuran, using a sulfonylating reagent. The conversion of carbamate A-3 to sulfonamide A-4 is achieved under similar conditions without solvent. Treatment of acetaniline A-9 with aqueous hydrochloric acid in the presence of a co-solvent such as alcohol affords aniline salt A-5. Process A

[0140] 8-Chloro-2-(methylthio)pyrimidopyrimidine A-10 is commercially available or can be prepared as described in WO 2012 / 101238A1. Inhibitors of general formula I were prepared by nucleophilic substitution between A-10 and aniline derivative A-5 following a procedure similar to that described in WO 2012 / 101238A1. Inhibitors of general formula II are prepared from inhibitors of general formula I by a two-step procedure involving first the oxidation of the thiomethyl group generally to the corresponding formazine and a mixture of formazines which are then followed by A similar procedure to the procedure described in WO 2012 / 101238A1 reacts with nucleophiles such as 1° amines or 2° amines, alcohols, phenols or NH-containing heterocycles, etc. The latter step is usually carried out in the presence of a base (eg organic bases such as DIEA, trimethylamine, pyridine and the like) in a solvent such as DMSO or NMP at a temperature in the range of 70°C to 140°C. General Synthesis Method B:

[0141] An alternative method for preparing the inhibitors of the invention is described in Scheme B. As shown in Scheme B, intermediate A-2 (described in Scheme A and prepared as described in J. Med. Chem. 2003, 46, 1905) was prepared under acidic conditions (HCl in dioxane or TFA ) is converted to nitroaniline hydrochloride B-1 by cleavage of the carbamate protecting group. Chloropyrimidopyrimidine A-10 (prepared as described in Scheme A (WO 2012 / 101238A1)) is treated with an aniline salt such as B-1 or preferably Nucleophilic substitution with aniline free base affords intermediate B-2. This is followed by methods well known to those skilled in the art, such as tin(II) chloride, Iron powder or zinc powder reduces the nitro functional group of the intermediate B-2 to the corresponding aniline B-3. Subsequent sulfonylation of p-aniline B-3 using sulfonyl chloride under basic conditions as described in Scheme A provides inhibitors of general formula I. Subsequently, inhibitors of general formula I are converted to inhibitors of general formula II as described in Scheme A. Process B General Synthesis Method C:

[0142] An alternative method of preparing inhibitors of the invention having general formulas III and IV is described in Scheme C. As shown in Scheme C, intermediate B3, prepared as described in Scheme B, can be converted to chlorine by treatment with sulfonyl chloride in the presence of an organic base such as a 3° amine (e.g., trimethylamine, DIEA, and similar amines). Sulfonylaniline C-1. Reaction of intermediate C-1 with 1° or 2° amines such as pyrrolidine derivatives provides inhibitors of general formula III. Inhibitors of general formula IV are then obtained by a two-step procedure involving oxidation of the thiomethyl group to a mixture of arone and aridine, followed by reaction with a nucleophile as described in Scheme A. Process C General Synthetic Method D:

[0143] Examples of inhibitors of general formula V are prepared according to the sequence shown in Scheme D. Process D

[0144] 2,4,8-Trichloropyrimidopyrimidine D-1 was prepared by the procedure described in ACS Med.Chem.Lett.2011, 2,538 and by treatment with ammonia as described in WO 2010 / 026262A1 And converted to 4-amino-2,8-dichloropyrimidopyrimidine D-2. Regioselective nucleophilic displacement of dichloropyrimidopyrimidine D-2 with an aniline salt of general formula A-5 under the general conditions described in Scheme A provides 8-chloropyrimidopyrimidine intermediate D-3. Chloropyrimidopyrimidine D-3 is second displaced by a nucleophile such as a 2° amine or an NH-containing heterocycle following a scheme similar to that described in WO 2012 / 101238A1 to provide a compound of general formula V Inhibitors. The latter step is usually carried out at a temperature in the range of 70°C to 140°C in the presence of a base (eg organic bases such as DIEA, trimethylamine, pyridine and the like) in a solvent such as DMSO or NMP. Alternatively, intermediate D-3 reacts with a heteroaryl such as a 2° amine or an NH-containing heteroaryl in the presence of an organic ligand (e.g., racemic BINOL) and an inorganic base such as cesium carbonate under copper-catalyzed cross-coupling conditions. Nucleophiles react with groups such as imidazole, benzimidazole, and similar heteroaryls. These reactions are typically carried out in solvents such as DMSO or NMP at temperatures ranging from 80°C to 140°C. Other methods of coupling chloropyrimidines to such nucleophiles involving metal catalyzed processes are well known to those skilled in the art and can be used to obtain inhibitors of general formula V. General Synthetic Method E:

[0145] Inhibitors of general formula VI were prepared as described in Scheme E. Intermediates of general formula I are first prepared according to general method A or B and then oxidized as described in general method A to formazine and a mixture of formazine. Intermediate I was subsequently combined with 3-indole carboxylate (e.g. methyl ester, X=CH) or 3-indazole carboxylate (e.g. methyl ester, X=CH) following a protocol similar to that described in WO 2012 / 101238 A1. =N) coupling. The latter step is typically a base (e.g. an organic or inorganic base such as Cs2CO3, KOtBu, DIEA, trimethylamine, pyridine and in the presence of a similar base). Esters are protected using an inorganic base such as NaOH or KOH in a mixture of water and a miscible organic solvent such as methanol, ethanol, THF, dioxane, and the like at temperatures ranging from ambient to 100°C Group deprotection, followed by acidification with minerals (e.g. aqueous hydrochloric or sulfuric acid), inorganic salt solutions (e.g. aqueous NH4Cl or KHSO4) or organic acids (e.g. aqueous citric or acetic acid) provides the corresponding carboxylic acid intermediate E- 1. Intermediate E-1 is coupled with amines using standard amide coupling reagents such as TBTU, HATU, DCC, EDC and the like to provide amide derivatives of general formula VI. Process E General Synthetic Method F:

[0146] Following the general procedure described in Scheme F, thiomethyl intermediate I, prepared as described in general method A or B, was oxidized in step 1 to a mixture of formazan and formazan as described in general method A . Respectively, in step 2, 2,3-indosulfonyl chloride is prepared as described in Org. Lett. 2011, 13, 3588 and an organic base (such as DIEA, trimethylamine and Condensation with amine in the presence of similar base) to provide intermediate 3-indolesulfonamide intermediate F-1. Alternatively, N-tosyl-protected indole-3-sulfonyl chloride (prepared by the procedure described in Chemical and Pharmaceutical Bulletin 2009, 57, 591 ) in a solvent such as THF and in a tertiary base ( Reaction with a primary or secondary amine in the presence of such as DIEA or triethylamine) to provide the intermediate sulfonamide F-1 after removal of the tosyl protecting group following treatment with an aqueous inorganic base such as KOH. Subsequently, intermediate F-1 was condensed with the oxidation mixture of intermediate I from step 1 following a protocol similar to that described in WO 2012 / 101238 A1. The latter step is usually carried out in the presence of a base (e.g., an organic base such as DIEA, trimethylamine, pyridine, and the like) in a solvent such as DMSO or NMP at a temperature in the range of 70°C to 140°C to provide general Inhibitors of formula VII. Process F General synthetic method G:

[0147] 3-Indole thiocyanate G-1 (prepared according to the procedure described in Phosphorus, Sulfur and Silicon and the Related Elements 2014, 189, 1378) was reduced to the corresponding sulfide using a reducing agent such as sodium sulfide nonahydrate salt, and direct alkylation without isolation from the alkyl halide to provide the sulfide intermediate G-2. Subsequently, sulfide intermediate G-2 is converted to sulfide intermediate G-3 using an oxidizing agent such as 3-chloroperoxybenzoic acid. Subsequently, the final inhibitor of general structure VIII was obtained in the usual manner as described. Process G General synthetic method H:

[0148] A bright red solution of commercially available 3-fluoro-2-nitroaniline H-1 in a solvent such as MeCN, DMSO or NMP in the presence of an inorganic base such as potassium carbonate or an organic base such as DIEA Reaction with primary or secondary amines to provide intermediate H-2 upon heating under thermal or microwave conditions at temperatures ranging from 40°C to 120°C. Reduction of the nitro group of intermediate H-2 can be achieved using a metal such as Fe or Zn in the presence of ammonium chloride in an alcoholic solvent such as isopropanol at a temperature in the range of 40°C to 80°C. Subsequently, the 1,2-phenylenediamine intermediate was directly converted to the desired benzimidazole intermediate H-3 after heating with formic acid at temperatures ranging from 40 °C to 80 °C. Subsequently, the final inhibitor of general structure IX was obtained from intermediate benzimidazoles H-3 and I under usual conditions as described previously. Process H General synthetic method I:

[0149] Nitroaniline H obtained as described following the general synthetic method H using a metal such as Fe or Zn in an alcoholic solvent such as isopropanol in the presence of ammonium chloride at temperatures ranging from 40°C to 80°C -2 is reduced to 1,2-phenylenediamine I-1. Subsequently, 1,2-phenylenediamine intermediate I-1 is converted to the desired benzotriazole intermediate I-2 after treatment with an inorganic nitrite such as sodium nitrite under acidic conditions (e.g. AcOH) . Subsequently, the final inhibitor of general structure X was obtained from intermediates 1-2 and I under conditions as previously described. Process I Sulfonyl chloride:

[0150] The following sulfonyl chlorides were obtained from commercial sources and used as received: 4-methoxybenzenesulfonyl chloride, 2,4-dichlorobenzenesulfonyl chloride, 2,4-xylenesulfonyl chloride, 2-chlorobenzenesulfonyl chloride Chlorine, 2-toluenesulfonyl chloride, 4-ethylbenzenesulfonyl chloride, 2-cyanobenzenesulfonyl chloride, 2,4-dimethoxybenzenesulfonyl chloride, 2-trifluorotoluenesulfonyl chloride, 3-chlorobenzene Sulfonyl chloride, 3-toluenesulfonyl chloride, 2,3-dichlorobenzenesulfonyl chloride, 3-chloro-2-toluenesulfonyl chloride, 2-bromobenzenesulfonyl chloride, 2-chloro-4-fluorobenzenesulfonyl chloride Acyl chloride, 2-chloro-6-fluorobenzenesulfonyl chloride, 2,5-dichlorobenzenesulfonyl chloride, 2,5-xylenesulfonyl chloride, 2-chloro-6-toluenesulfonyl chloride, 3-fluoro -2-toluenesulfonyl chloride, 2-chloro-4-toluenesulfonyl chloride, 1,3-benzodioxer-5-sulfonyl chloride, 2-chloro-4-(trifluoromethyl)-benzenesulfonyl Acyl chloride, 2-methyl-4-nitrobenzenesulfonyl chloride, 2-(difluoromethyl)benzenesulfonyl chloride.

[0151] Other sulfonyl chlorides were prepared by using or adapting literature procedures as described below. 2-Fluoro-4-methoxybenzenesulfonyl chloride:

[0152] Following the procedure described in EP2752410A1, 2-fluoro-4-methoxyaniline (1.00 g, 7.1 mmol) was dissolved in acetonitrile (25 mL) and concentrated HCl (10 mL) was added. The mixture was cooled to 0°C in an ice-salt bath. A solution of NaNO2 (0.59 g, 8.5 mmol) in water (1 mL) was then added in portions and the mixture was stirred at 0 °C for 1.5 h (light brown solution with a small amount of white solid suspended). AcOH (12 mL) was added to the resulting mixture and NaHSO 3 (7.37 g, 10 equiv, 71 mmol) was added after stirring at 0 °C for 10 min. After stirring for 5 min, copper(II) chloride (0.96 g, 1 equiv) and CuCl (70 mg, 0.1 equiv) were added and the green suspension was stirred in an ice bath, allowing the temperature to rise to RT within 1 h, The suspension was then stirred for another 18 h at RT (in 2:1 hexane / EtOAc, TLC R f: 0.45). The reaction mixture was then poured into water (100 mL) and extracted with EtOAc. The extract was washed with water, dried over MgSO 4 and filtered through a pad of silica gel (15 mL) using 1:1 hexane / EA as eluent. Removal of volatile components under reduced pressure gave 1.22 g of a clear beige oil (TLC showed more polar unidentified impurities after aqueous workup). 1H NMR (CDCl 3 ) δ: 7.88 (t, J = 8.6 Hz, 1H), 6.76 - 6.93 (m, 2H), 3.93 (s, 3H). The homogeneity by 1H NMR is about 70%.

[0153] Prepare the following sulfonyl chlorides using a similar procedure: 2-Cyano-4-fluorobenzenesulfonyl chloride: Prepared using 2-cyano-4-fluoroaniline as starting material. The crude material was highly impure, but was used successfully in the sulfonylation reaction. 4-Methoxy-2-trifluorotoluenesulfonyl chloride: Prepared using 4-methoxy-2-trifluoromethylaniline: 1H NMR (CDCl 3 ) δ: 8.30 (d, J = 9.0 Hz, 1H) , 7.42 (d, J = 2.3 Hz, 1H), 7.19 (dd, J = 9.0, 2.7 Hz, 1H), 3.99 (s, 3H). 4-Chloro-2-toluenesulfonyl chloride:

[0154] Prepared by chlorosulfonylation of m-chlorotoluene following the procedure described in Acta Crystallographica Section E2009, 65(4), o800. m-Chlorotoluene (1 mL) was dissolved in CHCl 3 (4 mL) and the solution was cooled in an ice bath. Chlorosulfonic acid (2.5 mL) was added dropwise over 15 min as HCl gas slowly evolved. After completion, the reaction mixture was allowed to warm to RT. TLC showed no more starting material (Rf = 0.8 in 8:2 hexanes / EA) and slightly behind new spots (Rf = 0.7 in 8:2 hexanes / EA). The reaction mixture was poured onto ice (50 mL), DCM (15 mL) was added and the product organic phase was separated, washed with cold water, dried (MgSO 4 ) and concentrated to a colorless oil (0.87 g) without further purification Even with: 1H NMR (CDCl 3 ) δ: 8.01 (d, J = 8.6 Hz, 1H), 7.43 (s, 1H), 7.40 (dd, J = 8.6, 2.0 Hz, 1H), 2.78 (s, 3H) .

[0155] The following sulfonyl chlorides were prepared using a similar procedure with some modifications as described below: 4-Methoxy-2-toluenesulfonyl chloride:

[0156] 3-Methoxytoluene (6.00 g) was dissolved in CHCl 3 (30 mL) and the solution was cooled to -35 °C (bath temperature). Over 20 min, chlorosulfonic acid (15 mL) was added dropwise (no significant HCl / SO gas evolution). The clear solution was then stirred at -30°C to -25°C for 15 min (no gas evolution noted). The reaction mixture was carefully poured onto ice (50 mL), DCM (50 mL) was added and the slightly milky product organic phase was separated, washed with cold water, dried (MgSO 4 ) and concentrated to a colorless oil which was extracted in vacuo (8.28 g, 76% yield). NMR showed the presence of a single isomer: 1H NMR (CDCl 3 ) δ: 8.01 (d, J = 8.6 Hz, 1H), 6.72 - 6.95 (m, 2H), 3.90 (s, 3H), 2.75 (s, 3H) . 2-Chloro-4-methoxybenzenesulfonyl chloride:

[0157] 3-Chlorophenylmethyl ether (1.00 g) was dissolved in CHCl 3 (4 mL) and the solution was cooled to about -35 °C. Chlorosulfonic acid (2.5 mL) in CHCl 3 (2 mL) was added dropwise over 15 min. After completion, TLC (SM Rf = 0.8 in 8:2 hexane / EA) detected only baseline material. Once the reaction mixture was warmed to RT, gas evolution was noted and isomeric products were noted by TLC (Rf = 0.30 and 0.25 in 8:2 hexane / EA). After stirring for 30 min at RT, a white precipitate started to form. The reaction mixture was poured onto ice (50 mL), DCM (15 mL) was added and the organic product phase was separated, washed with cold water, dried (MgSO 4 ) and concentrated to a colorless oil which crystallized as white needles on standing material (0.89 g). 1H NMR showed a mixture of 2 isomers in a 60:40 ratio, which were separated by flash chromatography on silica gel using 8:2 hexane / EtOAc as eluent. Desired isomer (more polar): 1H NMR (CDCl 3 ) δ: 7.90 (d, J = 8.6 Hz, 1H), 7.04 - 7.19 (m, 2H), 4.08 (s, 3H). 2,3-Xylenesulfonyl chloride:

[0158] Isolation as the minor isomer after o-xylene chlorosulfonylation as described in WO2003 / 055478. 1H NMR (CDCl 3 ) δ: 7.96 (d, J = 7.8 Hz, 1H), 7.52 (d, J = 7.4 Hz, 1H), 7.30 (t, J = 7.8 Hz, 1H), 2.71 (s, 3H) , 2.41 (s, 3H). 3-fluoro-2-methyl-4-methoxybenzenesulfonyl chloride:

[0159] Step 1: To a solution of 2-fluoro-3-methylphenol (4.32 mL, 39.7 mmol) in acetone (50 mL) was added potassium carbonate (6.58 g, 47.6 mmol), followed by iodomethane (2.75 mL, 43.7 mmol). Subsequently, the reaction mixture was refluxed overnight at 60 °C. The reaction mixture was then cooled to RT, filtered (2 x 10 mL acetone for rinse) and concentrated under reduced pressure. The crude product was extracted from water (30 mL) and EtOAc (2 x 50 mL). The organic layer was then separated, dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using 0 to 5% EtOAc / hexanes to give 2-fluoro-3-tolylmethyl ether as a clear colorless liquid (5.30 g, 95% yield ): 1H NMR (CDCl 3 ) δ: 6.95 (td, J = 8.0, 1.4 Hz, 1H), 6.85 – 6.71 (m, 2H), 3.87 (s, 3H), 2.28 (d, J = 2.3 Hz, 3H ).

[0160] Step 2: To a solution of 2-fluoro-3-tolylmethyl ether (1.00 g, 7.13 mmol) from step 1 in DCM (5.6 mL) was added chlorosulfonic acid (1.13 mL, 16.5 mmol) over a period of 5 minutes ) in DCM (5.6 mL). The beige reaction mixture containing a viscous liquid layer was stirred at RT for 10 min and then quenched by pouring into a mixture of water (10 mL) and ice (5 g). The aqueous phase was extracted with DCM (2×10 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give the desired sulfonyl chloride (1.70 g, 100% yield) as a colorless liquid. The material was used without further purification: 1H NMR (CDCl 3 ) δ: 7.87 (dd, J = 9.0, 1.8 Hz, 1H), 6.97 – 6.86 (m, 1H), 3.97 (s, 3H), 2.66 (d , J = 2.8 Hz, 3H). 3-Chloro-2-methyl-4-methoxybenzenesulfonyl chloride:

[0161] Following a similar procedure to 3-fluoro-2-methyl-4-methoxybenzenesulfonyl chloride (step 1), and starting from 2-chloro-3-methylphenol, was obtained as a colorless liquid in quantitative yield 2-Chloro-3-tolyl methyl ether: 1H NMR (CDCl 3 ) δ:7.12 (t, J = 7.9 Hz, 1H), 6.87 – 6.83 (m, 1H), 6.79 (d, J = 8.2 Hz, 1H ), 3.89 (s, 3H), 2.38 (s, 3H).

[0162] Treatment with chlorosulfonic acid as described for 3-fluoro-2-methyl-4-methoxybenzenesulfonyl chloride (step 2) afforded the desired 3-chloro-2 as a colorless liquid in 96% yield. -Methyl-4-methoxybenzenesulfonyl chloride: 1H NMR (CDCl 3 ) δ:8.02 (d, J = 9.1 Hz, 1H), 6.90 (d, J = 9.1 Hz, 1H), 4.00 (s, 3H ), 2.83 (s, 3H). 2-Ethylbenzenesulfonyl chloride:

[0163] 2-Ethylbenzenethiol (1.46 mL, 10.3 mmol) and KCl (776 mg, 10.3 mmol) were dissolved in water (38 mL) and oxone® (15.8 g, 25.8 mmol) was added in small portions. After stirring at RT for 1 h, the reaction was considered complete by LCMS analysis and the reaction mixture was extracted with EtOAc (4×5 mL). The extract was dried (Na 2 SO 4 ) and concentrated under reduced pressure to give a white crystalline solid (1.43 g, 68% yield), which was used as received: 1H NMR (CDCl 3 ) δ: 8.07 (dd, J=8.1 , 1.3 Hz, 1H), 7.66 (td, J= 7.6, 1.3 Hz, 1H), 7.49 (d, J= 7.7 Hz, 1H), 7.45 – 7.38 (m, 1H), 3.20 (q, J= 7.5 Hz ), 1.36 (t, J= 7.5 Hz). 3-Fluoro-2-ethylbenzenesulfonyl chloride

[0164] Step 1: 2-Bromo-6-fluorobenzaldehyde (6.00 g, 29.5 mmol) was dissolved in anhydrous THF (60 mL) and the solution was cooled to -78 °C under argon atmosphere. Methylmagnesium bromide (3.0 M solution in diethyl ether, 13.4 mL, 40.3 mmol) was added dropwise and the mixture was stirred at -78 °C for 30 min. The reaction was then quenched with 10% hydrochloric acid (50 mL) and the product was extracted into diethyl ether (2 x 50 mL). The extract was dried (MgSO 4 ) and concentrated, and the residue was purified by Combiflash® on silica gel using 10%-30% EtOAc / hexanes as eluent to give the desired alcohol as a colorless oil Derivative (6.20 g, 96% yield): 1H NMR (CDCl 3 ) δ:7.35 (ddd, J = 7.9, 3.1, 2.0 Hz, 1H), 7.16 – 6.99 (m, 2H), 5.35 (q, J = 6.7 Hz, 1H), 1.61 (dd, J = 6.8, 1.1 Hz, 3H).

[0165] Step 2: Indium(III) chloride (412 mg, 1.83 mmol) was suspended in DCM (40 mL) and chlorodiisopropylsilane (8.42 mL, 49.3 mmol) was added. Alcohol (4.00 g, 18.3 mmol) from step 1 in DCM (8 mL) was added and the mixture was stirred at RT for 3 h to give a clear solution. The reaction mixture was quenched with water (50 mL), extracted with diethyl ether (3×20 mL), washed with brine and dried (MgSO 4 ). Concentration and purification by flash chromatography using hexane as eluent provided the silylated ether of the starting alcohol.

[0166] This material was dissolved in DCE (41 mL) and chlorodiisopropylsilane (0.78 mL, 4.6 mmol) and indium(III) chloride (103 mg, 4.6 mmol) were added. The mixture was stirred at 80 °C for 3 h. After cooling to ambient temperature, the reaction mixture was diluted with hexane (100 mL), washed with water (100 mL) and the aqueous phase was back extracted with hexane (2×50 mL). The combined organic phases were dried (Na2SO4) and concentrated to give a colorless oil, which was purified by flash chromatography on silica gel using hexane as eluent to give 2- as a colorless oil. Bromo-6-fluoro-ethylbenzene (3.71 g, 100%): 1H-NMR (CDCl 3 ) δ: 7.32 (d, J = 7.8 Hz, 1H), 7.11 – 6.91 (m, 2H), 2.82 (dq, J = 7.5, 2.2 Hz, 2H), 1.20 – 1.15 (m, 3H).

[0167] Step 3: The aryl bromide (3.71 g, 18.3 mmol) from Step 2 was dissolved in toluene (60 mL) and N,N-diisopropylethylamine (6.40 mL, 36.5 mmol) was added. The solution was then degassed by 3 cycles of evacuation and backfilling with nitrogen. Add ginseng(dibenzylideneacetone)-dipalladium(0) (836 mg, 0.9 mmol), 4,4-bis(diphenylphosphino)-9,9-dimethyldibenzopyran (1.08 g , 1.83 mmol) and 2-ethylhexyl-3-mercaptopropionate (4.59 mL, 19.2 mmol) and the mixture was degassed twice more, then refluxed overnight under nitrogen atmosphere. The reaction mixture was then cooled to RT, quenched with water (50 mL), and extracted with EtOAc (2×50 mL). The combined organic phases were washed with 10% aqueous HCl (75 mL) and dried (Na 2 SO 4 ). Concentrate under reduced pressure and purify the residue by flash chromatography using 0-15% EtOAc / hexanes as eluent to give the desired thiol as an orange oil contaminated with some unreacted starting thiol Intermediate (4.00 g). This material was used as such in the next step.

[0168] Step 4: The crude sulfide derivative from Step 3 (4.00 g, assumed to be 11.7 mmol) was dissolved in THF (41 mL) and potassium tert-butoxide (1.0 M in THF, 14.1 mL, 14.1 mmol). The resulting solution was stirred at RT for 1 h. Then, the reaction was quenched by adding saturated aqueous NH 4 Cl (40 mL) and extracted with EtOAc (2×30 mL). The combined organic phases were concentrated and the dark orange residue was washed through a small pad of silica gel with hexane to give a mixture of thiol and disulfide (1.50 g), which was used as such in the next step ( CAUTION: Foul smell).

[0169] Step 5: The crude mixture of thiophenols and disulfides from Step 4 (1.50 g, assumed to be 9.6 mmol) and KCl (723 mg, 9.6 mmol) were suspended in water (40 mL) and oxone® was added in portions ( 14.8 g, 24 mmol). After stirring at RT for 1 h, the reaction mixture was extracted with EtOAc (2×20 mL), and the extract was dried (Na 2 SO 4 ) and concentrated under reduced pressure to give crude sulfonyl chloride, which was used as such in the preparation of Corresponding fragment A-5 and aniline A-8 (see Table 1). 3-Chloro-2-ethylbenzenesulfonyl chloride:

[0170] Follow the same procedure as for 3-fluoro-2-ethylbenzenesulfonyl chloride, but starting from 2-bromo-6-chlorobenzaldehyde to prepare sulfonyl chloride: Step 1 (white solid, 98% yield): 1H NMR (CDCl 3 ) δ: 7.49 (dd, J= 8.0, 1.2 Hz, 1H), 7.33 (dd, J= 8.0, 1.2 Hz, 1H), 7.05 (t, J= 8.0 Hz, 1H), 5.58 (q, J= 6.9 Hz, 1H), 1.64 (d, J= 6.9 Hz, 3H).

[0171] Step 2 (as colorless oil, 100% yield): 1H-NMR (CDCl 3 ) δ: 7.43 (dd, J= 8.0, 1.2 Hz, 1H), 7.29 (dd, J= 8.0, 1.2 Hz, 1H ), 6.96 (t, J= 8.0 Hz, 1H), 2.97 (q, J= 7.5 Hz, 2H), 1.17 (t, J= 7.5 Hz, 3H).

[0172] Step 3 (orange oil, 81% yield): 1H-NMR (CDCl 3 ) δ: 7.24 – 7.18 (m, 2H), 7.08 (t, J= 7.9 Hz, 1H), 4.07 – 3.96 (m , 2H), 3.17 (t, J= 7.4 Hz, 2H), 2.96 (q, J= 7.5 Hz, 2H), 2.64 (t, J= 7.4 Hz, 2H), 1.56 (dd, J= 11.9, 5.8 Hz , 2H), 1.40 – 1.21 (m, 9H), 1.16 (t, J= 7.5 Hz, 3H), 0.89 (t, J= 7.4 Hz, 6H).

[0173] Step 4 (colorless liquid, 99% yield): 1H-NMR (CDCl 3 ) δ: 7.15 (d, J= 7.9 Hz, 2H), 6.97 – 6.92 (m, 1H), 3.41 (s, 1H) , 2.87 (q, J= 7.5 Hz, 2H), 1.18 (t, J= 7.5 Hz, 3H).

[0174] Step 5 (crude material used without further purification): 1H-NMR (CDCl 3 ) δ: 8.03 (dd, J= 8.2, 1.3 Hz, 1H), 7.73 (dd, J= 8.0.1.3 Hz, 1H) , 7.37 (t, J= 8.1 Hz, 1H), 3.30 (q, J= 7.4 Hz, 2H), 1.33 (t, J= 7.4 Hz, 3H). 2-Methyl-3-(trifluoromethyl)benzenesulfonyl chloride:

[0175] The sulfonyl chloride was prepared following the same procedure as for 3-fluoro-2-ethylbenzenesulfonyl chloride, but starting from commercially available 2-methyl-3-(trifluoromethyl)bromobenzene:

[0176] Step 3 (Orange oil, 100% yield): 1H-NMR (CDCl 3 ) δ: 7.49 (d, J= 7.9 Hz, 2H), 7.26 – 7.19 (m, 1H), 4.06 – 4.00 (m , 2H), 3.18 (dd, J= 9.1, 5.6 Hz, 2H), 2.65 (dd, J= 9.2, 5.6 Hz, 2H), 2.50 (d, J= 1.3Hz, 3H), 1.33 – 1.23 (m, 11H ), 0.88 (td, J= 7.4, 2.3 Hz, 6H).

[0177] Step 4 (colorless oil, quantitative yield): 1H-NMR (CDCl 3 ) δ: 7.43 (dd, J= 7.9, 2.2 Hz, 2H), 7.12 (t, J= 7.8 Hz, 1H), 3.42 (s, 1H), 2.43 (s, 3H).

[0178] Step 5 (white solid, quantitative yield): 1H-NMR (CDCl 3 ) δ: 8.31 (d, J= 8.1 Hz, 1H), 8.00 (t, J= 7.7 Hz, 1H), 7.55 (dd, J= 15.6, 7.6 Hz, 1H), 2.93 (s, 3H). General procedure for the preparation of sulfonyl chlorides from aryl bromides:

[0179] Step 1: Aryl bromide 1 (1.00 mmol) was dissolved in toluene (1.70 mL). The mixture was degassed by bubbling nitrogen through the solution for 5 min. Add ginseng(dibenzylideneacetone)-dipalladium(0) (0.02 mmol), 4,4-bis(diphenylphosphino)-9,9-dimethyldibenzopyran (0.04 mmol) and N , N-diisopropylethylamine (2.0 mmol) and then the mixture was degassed again for 5 min. Benzylthiol (1 mmol) was then added and the resulting mixture was heated at reflux overnight (oil bath T=115°C). After completion, the reaction was cooled to room temperature, diluted with EtOAc (20 mL) and quenched with H 2 O (20 mL). The aqueous layer was extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine (50.0 mL), dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure. The crude material was further purified by flash chromatography (0-10% EtOAc / hexanes, 35 mL / min, product eluted in 100% hexanes). Fractions of interest were collected and concentrated under reduced pressure to afford the title compound 2.

[0180] Step 2: Compound 2 (1.00 mmol) was dissolved in acetic acid (1.90 mL) and H 2 O (0.65 mL) was added to obtain a heterogeneous solution. N-chlorosuccinimide (4.00 mmol) was added in portions. The reaction was stirred and monitored by LCMS (sample was quenched with N-methylpiperazine). After the reaction was completed, the mixture was concentrated under reduced pressure. The resulting mixture was slowly poured into saturated aqueous NaHCO 3 with gas evolution. The mixture was extracted with EtOAc (2 x 75 mL). The combined organic layers were washed with brine, dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure. The crude compound was further purified by normal phase chromatography (0-40% EtOAc / hexanes, 60 mL / min, product separated on 100% hexanes). Fractions of interest were collected and concentrated under reduced pressure to afford the title compound 3. 2-Chloro-3-toluenesulfonyl chloride:

[0181] Sulfonyl chloride was prepared following the general procedure starting from commercially available 1-bromo-2-chloro-3-toluene:

[0182] (2-Chloro-3-methylphenyl)benzylsulfide: yellow solid, 51% yield, 95% purity (at 220 nm). (ES -) M-H =247.2; 1H NMR (400 MHz, CDCl 3 ) δ 7.39 – 7.35 (m, 2H), 7.33 – 7.28 (m, 2H), 7.28 – 7.23 (m, 1H + CDCl 3 ), 7.11 – 7.03 (m, 3H), 4.15 (s, 2H), 2.38 (s, 3H).

[0183] 2-Chloro-3-toluenesulfonyl chloride: Pale yellow oil, 70% yield, 60% purity (at 254 nm). LCMS: LCMS sample was quenched with N-methylpiperazine (resulting sulfonamide MW = 288.8) (ES+) M+H = 289.2. Used as a crude substance. 3-Fluoro-2-(trifluoromethyl)benzenesulfonyl chloride:

[0184] Sulfonyl chloride was prepared following the general procedure starting from commercially available 1-bromo-3-fluoro-2-(trifluoromethyl)benzene:

[0185] (3-Fluoro-2-(trifluoromethyl)phenyl)benzyl sulfide: yellow oil, 66% yield, 98% purity (at 254 nm). (ES -) M-H = 285.2.

[0186] 3-Fluoro-2-(trifluoromethyl)benzenesulfonyl chloride: Pale yellow oil, 93% yield, 98% purity (at 254 nm). The LCMS sample was quenched with N-methylpiperazine (resulting sulfonamide MW = 326.1) (ES+) M+H = 327.1. 3-Chloro-2-(trifluoromethyl)benzenesulfonyl chloride:

[0187] Sulfonyl chloride was prepared following the general procedure starting from commercially available 1-bromo-3-chloro-2-(trifluoromethyl)benzene:

[0188] (3-Chloro-2-(trifluoromethyl)phenyl)benzyl sulfide: white solid, 59% yield, 90% purity (at 220 nm). (ES -) M-H =301.2; 1H NMR (400 MHz, CDCl 3 ) δ 7.46 – 7.14 (m, 8H + CDCl 3 ), 4.16 (s, 2H).

[0189] 3-Chloro-2-(trifluoromethyl)benzenesulfonyl chloride: colorless oil, 66% yield. LCMS: LCMS sample was quenched with N-methylpiperazine (resulting sulfonamide MW = 343.5) (ES+) M+H = 343.2. Used as a crude substance. 3,4-Difluoro-2-toluenesulfonyl chloride:

[0190] Sulfonyl chloride was prepared following the general procedure starting from commercially available 1-bromo-3-chloro-2-(trifluoromethyl)benzene:

[0191] (3,4-Dichloro-2-methylphenyl)benzylsulfide: orange oil, 96% yield, 96% purity (at 254 nm). (ES -) M-H = 249.2; 1H NMR (400 MHz, DMSO-d 6) δ 7.32 – 7.17 (m, 7H), 4.16 (s, 2H), 2.18 (d, J = 2.7 Hz, 3H). 3,4-Difluoro-2-toluenesulfonyl chloride: Pale yellow oil, 49% yield. LCMS: LCMS sample was quenched with N-methylpiperazine (obtained sulfonamide MW=290.3) (ES+) M+H=291.2; 1H NMR (400 MHz, DMSO-d 6) δ 7.56 (ddd, J = 8.4, 5.5, 1.8 Hz, 1H), 7.15 (dd, J = 18.4, 8.4 Hz, 1H), 2.46 (d, J = 2.8 Hz, 3H). 2,4-Dimethyl-3-fluorobenzenesulfonyl chloride:

[0192] Sulfonyl chloride was prepared following the general procedure starting from commercially available 1-bromo-2,4-dimethyl-3-fluorobenzene:

[0193] (3-Fluoro-2,4-xylyl)benzylsulfide: orange oil, 95% yield of crude material, 80% purity (at 254 nm), used as crude material.

[0194] 3-Fluoro-2,4-dimethylbenzene-1-sulfonyl chloride: orange oil, 89% crude yield, 74% purity (at 254 nm). LCMS: LCMS sample was quenched with N-methylpiperazine (resulting sulfonamide MW = 286.4) (ES+) M+H = 287.1. Used as a crude substance. 2-picoline-3-sulfonyl chloride:

[0195] Sulfonyl chloride was prepared following the general procedure starting from commercially available 3-bromo-2-picoline:

[0196] 3-(Benzylthio)-2-picoline: orange liquid, 88% yield, 94% purity (at 220 nm). (ES +) M + H = 215.8, (ES -) M - H = 214.1. 1H NMR (400 MHz, DMSO-d 6) δ 8.30 (dd, J = 4.9, 1.5 Hz, 1H), 7.57 – 7.45 (m, 1H), 7.31 – 7.27 (m, 5H), 7.07 (dd, J = 7.6, 5.1 Hz, 1H), 4.09 (s, 2H), 2.58 (s, 3H).

[0197] 2-picoline-3-sulfonyl chloride: Pale yellow oil, 100% yield, 95% purity (at 254 nm). The LCMS sample was diluted with H 2 O (obtained sulfonic acid MW=173.1) (ES -) M-H = 171.9; 1H NMR (400 MHz, CDCl 3 ) δ 8.80 (dd, J = 4.8, 1.6 Hz, 1H), 8.33 (dd , J = 8.1, 1.7 Hz, 1H), 7.43 – 7.36 (m, 1H), 3.02 (s, 3H). 6-Methoxy-4-picoline-3-sulfonyl chloride:

[0198] The preparation of 3-((6-methoxyl-4-picoline-3-yl)thio)propanoic acid 2-ethylhexyl ester (2): 5-bromo-2-methoxyl-4-formyl Pyridine (6.00 g, 29.7 mmol) was dissolved in toluene (100 mL) and N,N-diisopropylethylamine (10.4 mL, 59.4 mmol) was added. The mixture was degassed by bubbling nitrogen through the solution for 5 min. Add ginseng(dibenzylideneacetone)dipalladium(0) (1.36 g, 1.49 mmol), 4,4-bis(diphenylphosphino)-9,9-dimethyldibenzopyran (1.75 g, 2.97 mmol) and 2-ethylhexyl-3-mercaptopropionate (7.47 mL, 31.2 mmol). The mixture was degassed again for 5 min. The mixture was heated at reflux overnight (oil bath T=117°C). The reaction was cooled to room temperature, diluted with EtOAc (100 mL) and quenched with H 2 O (100 mL). The organic and aqueous layers were separated, and the aqueous layer was extracted with EtOAc (2×50.0 mL). The combined organic layers were washed with HCl (10% in H 2 O, 50.0 mL), dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography (330 g silica gel column, EtOAc-hexane, 0-20%) to give the title compound (10.0 g, 99% yield) as an orange oil. (ES +) M+H = 340.2; 1H NMR (400 MHz, CDCl 3 ) δ 8.19 (s, 1H), 6.64 (s, 1H), 3.99 (dd, J = 5.9, 2.4 Hz, 2H), 3.93 ( s, 3H), 2.96 (t, J = 7.3 Hz, 2H), 2.55 (t, J = 7.3 Hz, 2H), 2.42 (d, J = 0.5 Hz, 3H), 1.56 (dt, J = 12.1, 6.0 Hz, 1H), 1.39 – 1.22 (m, 8H), 0.88 (m, 6H).

[0199] Preparation of 6-methoxy-4-picoline-3-thiol (3): To a solution of 2 (10.0 g, 29.5 mmol) in THF (105 mL) at -78 °C was added dropwise tertiary butanol Potassium (1.00 M in THF, 35.3 mL, 35.3 mmol) and a precipitate formed. The resulting suspension was stirred at -78°C for 30 minutes. The reaction was quenched by the addition of NH 4 Cl (50.0 mL) and the mixture was extracted with CH 2 Cl 2 (2×50.0 mL). The combined organic layers were dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure to give a dark orange liquid. The crude material was purified by flash chromatography (100% hexanes) to give a mixture of the title compound and its disulfide (4.56 g), which was used in the next step without further purification. LCMS: Thiol 3: (ES+) M+H = 156.9 and Disulfide: (ES+) M+H = 309.0.

[0200] Preparation of 6-methoxy-4-picoline-3-sulfonyl chloride (4): To a mixture of thiol 3 (4.56 g, 29.4 mmol) in H2O (123 mL) was added potassium chloride (2.21 g, 29.3 mmol), followed by adding Oxone® (45.2 g, 73.5 mmol) in portions. After the reaction was complete (1 h), the mixture was extracted with EtOAc (2×20.0 mL) and the combined organic layers were dried (Na 2 SO 4 ) and concentrated under reduced pressure. The crude product obtained was used without further purification. 3-picoline-4-sulfonyl chloride:

[0201] Step 1: 4-Bromopyridine (1.00 mmol) was dissolved in toluene (1.70 mL) and N,N-diisopropylethylamine (2.00 mmol) was added. The mixture was degassed by bubbling nitrogen through the solution for 5 min. Add ginseng(dibenzylideneacetone)-dipalladium(0) (0.02 mmol), 4,4-bis(diphenylphosphino)-9,9-dimethyldibenzopyran (0.04 mmol) and benzene Methyl mercaptan / benzyl mercaptan (1.00 mmol). The mixture was degassed again for 5 min. The mixture was heated at reflux for 18 h (oil bath T=115 °C). The reaction was cooled to room temperature, diluted with EtOAc (10.0 mL) and quenched with H 2 O (10.0 mL). The aqueous and organic layers were separated and the aqueous layer was extracted with EtOAc (2×10.0 mL), and the combined organic phases were washed with brine HCl (10% in H 2 O, 10.0 mL), dried (Na 2 SO 4 ), filtered and washed at Concentrate under reduced pressure. The crude material was purified by flash chromatography (EtOAc-hexanes, 10% to 35%) to afford sulfide 2: (90% yield). (ES +) M+H = 216.1; 1H NMR (400 MHz, CDCl 3 ) δ 8.28 (d, J = 4.6, 1H), 8.24 (s, 1H), 7.43 – 7.27 (m, 5H), 7.20 (t , J = 5.4 Hz, 1H), 4.25 (s, 2H), 2.28 (s, 3H).

[0202] Step 2: Compound 2 (1.00 mmol) was dissolved in CH 2 Cl 2 (11.5 mL) and cooled to -10 °C. HCl (1.00 M in H 2 O, 5.70 mL) was added and stirred at -10 °C for 5 min. Sodium hypochlorite (10% solution in water, 3.00 mmol) was added over 10 min, keeping the temperature below 0°C. The mixture was stirred at 0 °C for 10 min. The organic and aqueous layers were separated. The organic layer was dried (Na2SO4). The crude sulfonyl chloride was used in the next step without further purification or evaporation: the LCMS sample was quenched with N-methylpiperazine (obtained sulfonamide MW = 255.3); (ES+) M+H+= 256.2 . 2,3-Lutidine-4-sulfonyl chloride:

[0203] Starting with 2,3-dimethyl-4-bromopyridine, use the same procedure as for 3-picoline-4-sulfonyl chloride:

[0204] Step 1: 4-(Benzylthio)-2,3-lutidine (2): (92% yield). LCMS: (ES +) M+H = 230.2; 1H NMR (400 MHz, CDCl 3 ) δ: 8.17 (d, J = 5.5 Hz, 1H), 7.42 – 7.28 (m, 5H), 6.99 (d, J = 5.5 Hz, 1H), 4.18 (s, 2H), 2.53 (s, 3H), 2.24 (s, 3H).

[0205] Step 2: 2,3-Lutidine-4-sulfonyl chloride (3): Quench the LCMS sample with N-methylpiperazine (obtained sulfonamide MW=269.3); (ES +) M + H + = 270.2. Protected sulfonyl chloride against fragment B69:

[0206] Step 1: To a solution of commercially available aminopyridine (1.00 g, 4.27 mmol) and N-benzylcarbamoyl chloride (0.9421 g, 5.5546 mmol) in EtOAc (20 mL) was added 20 mL of saturated aqueous NaHCO3 . The solution was stirred at RT for 16 h. Once complete, EtOAc was added to the reaction mixture and the organic layer was separated, washed with brine, dried over MgSO 4 , then filtered and concentrated. The residue was adsorbed on SiO2 followed by purification on SiO2 by EtOAc / hexanes to give the desired protected aminopyridine (1.00 g, 2.72 mmol, 64%). 1H NMR (400 MHz, DMSO-d 6) δ:10.35 (s, 1H), 8.09 (d, J= 8.61 Hz, 1H), 7.47 (d, J= 9.00 Hz, 1H), 7.23 - 7.44 (m, 4H), 5.16 (s, 2H), 2.53 (s, 3H) MS m / z 369.2 (MH+).

[0207] Step 2: Iodopyridine (0.61 g, 1.66 mmol) from Step 1, ginseng(dibenzylideneacetone)-dipalladium(0) chloroform adduct (86 mg, 0.0828 mmol), 9,9-dimethyl -9h-dibenzopyran-4,5-diyl-bis(diphenylphosphine) (96 mg, 0.166 mmol), DIPEA (0.576 mL, 3.31 mmol) and benzylthiol (0.233 mL, 1.99 mmol) in A degassed solution in toluene (15 mL) was stirred at 115 °C for 3 h under N2. Once complete, SiO2 was added to the reaction mixture and concentrated under vacuum. The residue was purified on a SiO 2 column with EtOAc / hexanes to provide the expected sulfide (560 mg, 93%). 1H NMR (400 MHz, CDCl 3 ) δ:7.71 (d, J= 8.61 Hz, 1H), 7.54 (d, J= 8.61 Hz, 1H), 7.46 (br s, 1H), 7.31 - 7.43 (m, 5H ), 7.19 - 7.26 (m, 2H), 7.12 - 7.19 (m, 2H), 5.22 (s, 2H), 3.96 (s, 2H), 2.41 (s, 3H). MS m / z 365.2 (MH+).

[0208] Step 3: To a solution of the sulfide from Step 2 (300 mg, 0.823 mmol) in 90% AcOH in water (16 mL) was added N-chlorosuccinimide (330 mg, 2.47 mmol). The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was evaporated to dryness then diluted in EtOAc and washed with water followed by brine. The organic layer was dried over MgSO 4 , filtered and concentrated under vacuum to give the desired sulfonyl chloride of group B49 (282 mg, 99%) which was used as received: 1H NMR (400 MHz, CDCl 3 ) δ: 8.28 (d, J= 9.00 Hz, 1H), 8.02 (d, J= 9.00 Hz, 1H), 7.72 (br s, H), 7.34 - 7.60 (m, 5H), 5.27 (s, 2H), 2.86 ( s, 3H). MS m / z 341.2 (MH+). 2,2-Difluorobenzo[d][1,3]dioxer-4-sulfonyl chloride:

[0209] Thionyl chloride (5.96 mL) was added dropwise to water (30 mL) over 20 min and the mixture was stirred at RT for 48 h to generate a solution containing sulfur dioxide. In a separate vessel, 2,2-difluorobenzo[d][1,3]dioxer-4-amine (1.00 g, 5.78 mmol) was added dropwise to ice-cooled HCl (7 mL) , to form a white precipitate. A solution of sodium nitrite (523 mg, 7.5 mmol) in water (2 mL) was added dropwise to aniline hydrochloride over 5 min to generate an orange reaction mixture. Subsequently, the orange suspension was gradually added at 5 °C to the sulfur dioxide solution from above to which 10 mg of cuprous chloride had been added previously. The mixture was stirred for another 2 h in the ice bath (gas evolution was observed and an orange liquid was deposited at the bottom of the flask). After completion as determined by LCMS analysis, the reaction mixture was extracted with DCM (2 x 20 mL), dried (Na2SO4), filtered and concentrated to give the desired sulfonyl chloride as an orange oil (100% crude material yield), which was used without further purification: 1H-NMR (400 MHz, CDCl 3 ) δ 7.65 (dd, J=8.4, 1.1 Hz, 1H), 7.44 (dd, J=8.1, 1.1 Hz, 1H ), 7.32 (t, J= 8.2 Hz, 1H). 4-Chloro-3-fluoro-2-toluenesulfonyl chloride:

[0210] Preparation of N-(3-fluoro-2-methylphenyl)trimethylacetamide (2): Add 3-fluoro-2-toluidine (10.9 mL, 93.0 mmol) at 0°C for 10 min To a solution in THF (240 mL) was added triethylamine (14.9 mL, 106 mmol), followed by trimethylacetyl chloride (13.1 mL, 105 mmol). The mixture was warmed to room temperature and stirred for 2 h. The volatile components were evaporated under reduced pressure and the residue was partitioned between H 2 O (250 mL) and EtOAc (150 mL). The organic and aqueous layers were separated. The aqueous layer was extracted with EtOAc (4 x 60 mL). The combined organic layers were washed with brine (60 mL), dried (Na 2 SO 4 ) and concentrated under reduced pressure to give the title compound 2 (18.5 g, 95% yield) as a solid. (ES +) M + H = 210.2.

[0211] Preparation of N-(4-chloro-3-fluoro-2-methylphenyl)trimethylacetamide (3): Add compound 2 (4.20 g, 20.1 mmol) to DMF (50.0 mL) solution was added N-chlorosuccinimide (2.76 g, 20.1 mmol) in 3 portions. At 80 °C, the mixture was heated for 90 min. Additional N-chlorosuccinimide (541 mg, 4.01 mmol) was added and it was stirred at 80 °C for 45 min. The mixture was cooled to room temperature and diluted with EtOAc (30 mL) and water (60 mL). The organic and aqueous layers were separated. The aqueous layer was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with H 2 O (3×30 mL), brine (20.0 mL), dried (Na 2 SO 4 ) and concentrated under reduced pressure to give crude compound (5.20 g). The crude material was dissolved in cyclohexane (30 mL) and heated at 45°C-50°C until all solids were dissolved. The solution was cooled to room temperature. The precipitated white solid was filtered off and washed with cyclohexane (3 x 5 mL) to give the title compound 3 (1.95 g, 40% yield) as a solid. (ES +) M + H = 244.1.

[0212] Preparation of 4-chloro-3-fluoro-2-toluidine (4): To a solution of compound 3 (1.60 g, 6.57 mmol) in dioxane (18 mL) was added HCl (6.00 M in water, 23 mL, 138 mmol). The mixture was heated at 100 °C for 20 h. The mixture was cooled to room temperature. Solid K2CO3 was added portionwise (exotherm) until pH = 8-9 was obtained. The mixture was extracted with EtOAc (4 x 20 mL). The combined organic layers were washed with brine (20 mL), dried (Na2SO4) and concentrated under reduced pressure to give 1.6 g of crude material which was dried under vacuum for 24 h to give the title compound as an oil 4 (850 mg, 81% yield). It was used in the next reaction without further purification. 1H NMR (400 MHz, CDCl 3 ) δ 6.99 (t, J = 8.3 Hz, 1H), 6.40 (d, J = 8.6 Hz, 1H), 2.22 – 2.06 (m, 3H).

[0213] Preparation of 4-chloro-3-fluoro-2-toluene-1-sulfonyl chloride (5): Add thionyl chloride (29.1 mL, 395 mmol) dropwise to H2O ( 92.1 mL). This solution containing sulfur dioxide was stirred at 0 °C for 2 h and at room temperature for 18 h. Separately, HCl (conc.) (23 mL) was added portionwise to compound 4 (3.00 g, 18.8 mmol) at 0 °C to give a beige precipitate. It was stirred at 0 °C for 5 min. A solution of sodium nitrite (1.70 g, 24.4 mmol) in H 2 O (2 mL) was added dropwise over approximately 10 min. The above-mentioned sulfur dioxide solution containing copper(I) chloride (38.4 mg, 376 μmol) was gradually added to the reaction mixture at 5 °C over 40 min. The mixture was further stirred for 2 h under ice cooling and then at room temperature for 4 days. The mixture was diluted with CH 2 Cl 2 (20 mL). The aqueous and organic layers were separated. The aqueous layer was extracted with CH 2 Cl 2 (3×20 mL). The combined organic layers were dried (Na 2 SO 4 ), filtered and concentrated to give crude Compound 5 (1.95 g, 30% yield, 70% purity) as an oil. Crude material 5 was used as such without further purification. LCMS: LCMS samples were quenched with N-methylpiperazine (obtained sulfonamide MW=306.784); (ES +) M+H = 307.1; 1H NMR (400 MHz, CDCl 3 ) δ 7.81 (d, J = 8.4 Hz, 1H), 7.46 (t, J = 7.5 Hz, 1H), 2.69 (s, 3H). 3-Methyl-2-phenylthiosulfonyl chloride:

[0214] Prepared by chlorosulfonylation of 3-methylthiophene as described in US Patent 3,991,081. 1H NMR (CDCl 3 ) δ: 7.67 (d, J = 5.1 Hz, 1H), 7.03 (d, J = 5.1 Hz, 1H), 2.63 (s, 3H). 3-Chloro-2-phenylthiosulfonyl chloride:

[0215] 3-Chlorothiophene (1.00 g) was dissolved in CHCl 3 (10 mL) and the solution was cooled to -30°C. Over 5 min, chlorosulfonic acid (2.4 mL) was added dropwise (no significant gas evolution). Subsequently, the orange-brown solution was stirred for 30 min, and the temperature was raised to −10 °C for another 30 min, then to RT. Subsequently, the reaction mixture was stirred at RT for 2 h (no gas evolution was found, and TLC showed product formation (Rf=0.4 in 8:2 hexane / EA)). The reaction mixture was poured onto ice (50 mL), DCM (25 mL) was added and the milky organic phase was separated, washed with cold water, dried (MgSO 4 ) and concentrated to a yellow oil (0.55 g), which was extracted under vacuum Dried and used without further purification. 1H NMR (CDCl 3 ) δ: 7.76 (d, J = 5.7 Hz, 1H), 7.16 (d, J = 5.7 Hz, 1H). 4-Chloro-3-methylthiophene-2-sulfonyl chloride:

[0216] Preparation of 3-chloro-4-methylthiophene: In a 100 mL flask, copper(I) chloride (5.76 g, 56.5 mmol) was added to 3-bromo-4-methylthiophene (3.16 mL, 28.2 mmol) in DMF (20.1 mL). It was heated at 160 °C in an oil bath for 24 h. The crude material was poured onto H2O (50 mL). The resulting mixture was stirred at room temperature for 10 min. The resulting brown-green solid was filtered, washed with water (3×10.0 mL) and Et 2 O (4×10.0 mL). The filtrate was extracted with Et 2 O (3×25.0 mL). The combined organic layers were washed with H2O (2 x 20.0 mL), brine (20.0 mL), dried (Na2SO4) and concentrated under reduced pressure to give an orange oil (0.890 g, 59% crude yield ). 1H NMR (400 MHz, CDCl3) δ 7.09 (d, J = 3.5 Hz, 1H), 6.99 – 6.95 (m, 1H), 2.22 – 2.21 (m, 3H).

[0217] Preparation of 4-chloro-3-methylthiophene-2-sulfonyl chloride: 3-chloro-4-methylthiophene (1.00 g, 7.54 mmol) was dissolved in CHCl 3 (4.43 mL), and at room temperature for 5 min, a solution of chlorosulfonic acid (1.19 mL, 17.3 mmol) in CHCl 3 (1.48 mL) was added. The mixture was stirred for 10 min. Phosphorus pentachloride (4.13 g, 18.9 mmol) was added to the reaction mixture followed by CHCl 3 (7.50 mL). It was heated at 50 °C for 1 h. The reaction mixture was slowly added to aqueous NaHCO 3 + ice (30 mL). It was stirred for 10 min. Extract with CH 2 Cl 2 (4×10 mL). The combined organic layers were dried (Na 2 SO 4 ), concentrated under reduced pressure to give the title compound (1.30 g, 30% yield, 40% purity) as an oil. It was used in the next reaction without further purification. LCMS: LCMS sample was quenched with N-methylpiperazine; (ES+) M+H = 295.1; 1H NMR (400 MHz, CDCl 3 ) δ 7.57 (s, 1H), 2.57 (s, 3H). 3,4-Dichlorothiophene-2-sulfonyl chloride:

[0218] Preparation of 3,4-dichlorothiophene: Add copper(I) chloride (13.9 g, 137 mmol) to 3,4-dibromothiophene (5.03 mL, 45.5 mmol) in a 100 mL flask at room temperature ) in DMF (32 mL). It was heated at 160 °C in an oil bath for 24 h. The crude material was poured on H 2 O (100 mL) and diluted with Et 2 O (60 mL). The mixture was stirred at room temperature for 10 min. The resulting brown-green solid was filtered, washed with H 2 O (3×20 mL), followed by Et 2 O (4×20 mL). The filtrate was extracted with Et 2 O (4×30 mL). The combined organic layers were washed with H 2 O (2×30 mL), brine (30 mL), dried (MgSO 4 ) and concentrated under reduced pressure to give the title compound 2 (5.50 g, 79% Yield). 1H NMR (400 MHz, CDCl 3 ) δ 7.21 (s, 2H).

[0219] Preparation of 3,4-dichlorothiophene-2-sulfonyl chloride: To a solution of compound 2 (1.61 g, 10.5 mmol) in CHCl (5.98 mL) was added chlorosulfonic acid (757 µL, 11.0 mmol) over 5 min Solution in CHCl 3 (2 mL). The mixture was stirred at room temperature for 20 min. Phosphorus pentachloride (5.77 g, 26.3 mmol) was added to the mixture in 4 portions. The mixture was heated at 50 °C for 18 h. The volatile components were removed under reduced pressure, and the residue was dissolved in CH 2 Cl 2 (25 mL), washed with saturated aqueous NaHCO 3 (3×15 mL), H 2 O (3×10 mL) and brine (10 mL) washing. The organic layer was dried (Na 2 SO 4 ) and concentrated under reduced pressure to give the title compound 3 (2.32 g, 88% yield). LCMS: LCMS sample was quenched with N-methylpiperazine (resulting sulfonamide MW = 315.240); (ES+) M+H = 315.1. (3 R)-3-methoxyl-pyrrolidinesulfonyl chloride:

[0220] Following the procedure described in US Patent Application US 2011 / 0311474A1, (R)-3-methoxypyrrolidine hydrochloride (0.30 g, 2.1 mmol) was suspended in a mixture of 4 mL of toluene and 2 mL of DCM. Triethylamine (0.64 mL, 4.6 mmol) was added and the mixture was sonicated for 4-5 min to give a fine white suspension. In a separate flask, cool 4 mL of toluene to -40 °C in an acetonitrile / dry ice bath. Thioyl chloride (0.71 mL, 8.7 mmol) was added and the solution was stirred for 5 min. Subsequently, the pyrrolidine suspension was added dropwise to the cold (-40 °C) sulfonyl chloride solution over a period of 10 min. The resulting suspension was stirred at the same temperature for 1 hour and then allowed to warm to room temperature. The solid was filtered off and rinsed with toluene. The filtrate was concentrated to give 400 mg of the desired product (0.40 g) as a light brown oil which was used without further purification. 1H NMR (CDCl 3 ) δ:4.07 (tt, J = 4.6, 2.1 Hz, 1H), 3.48 - 3.69 (m, 4H), 3.36 (s, 3H), 2.12 - 2.23 (m, 1H), 1.98 - 2.12 (m, 1H). (3 S)-3-methoxyl-pyrrolidinesulfonyl chloride:

[0221] Prepared in a similar manner to the (R)-isomer, but starting from (S)-3-methoxypyrrolidine hydrochloride.

[0222] Other sulfonyl chlorides were prepared in a similar manner using commercially available 2° amines and the procedure described in US 2011 / 0311474A1, including: (S)-3-fluoropyrrolidine-1-sulfonyl chloride: Obtained from (S)-3-fluoropyrrolidine hydrochloride as a white solid: 1H NMR (DMSO-d 6) δ: 4.54 (dt, J = 52.6, 3.2 Hz, 1H), 2.72 - 3.03 (m, 5H), 1.34 - 1.58 (m, 2H) 3,3-Difluoropyrrolidine-1-sulfonyl chloride: obtained from 3,3-difluoropyrrolidine hydrochloride as a white solid: 1H NMR (CDCl 3 ) δ: 3.81 (t, J = 12.3 Hz, 2H), 3.74 (t, J = 7.4 Hz, 2H), 2.53 (tt, J = 13.0, 7.5 Hz, 2H).

[0223] 3-Methoxyacridine-1-sulfonyl chloride: Obtained from 3-methoxyacridine hydrochloride: 1H NMR (CDCl 3 ) δ: 4.22 - 4.33 (m, 3H), 3.97 - 4.09 (m, 2H), 3.33 (s, 3H). (R)-3-(Chloromethyl)pyrrolidine-1-sulfonyl chloride:

[0224] A solution of (R)-3-(hydroxymethyl)pyrrolidine (200 mg, 2 mmol) and triethylamine (0.61 mL, 4.35 mmol) in anhydrous DCM (15 mL) was separated at -78°C Added dropwise to a stirred solution of thionyl chloride (0.48 mL, 5.9 mmol) in DCM (5 mL). The reaction was stirred at -78°C for 30 minutes. And then allowed to warm to room temperature over 1 h. Subsequently, the reaction mixture was washed with 1 M aqueous hydrochloric acid (5 mL) and brine (5 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound as a colorless oil, which was used as such in the preparation of Example 28. Preparation of difluoroaniline hydrochloride intermediate A-5 from tertiary butyl carbamate A-2 (Ar=4-methoxyphenyl).

[0225] Preparation of step 1-aniline intermediate A-3: Nitroarene A-2 (5.00 g, 18 mmol, prepared according to the procedure described in J.Med.Chem.2003, 46, 1905) and 20% Pd ( OH)2 / C (130 mg) was suspended in MeOH (50 mL) and when the reduction was shown to be complete by TLC analysis (Rf = 0.45 in 2:1 hexane / EtOAc), the mixture was placed under a balloon containing hydrogen Stir for 18 h. The suspension was filtered through a pad of celite® to remove the catalyst, washed with MeOH and the solvent was evaporated under reduced pressure. Upon exposure to air, the originally colorless solution rapidly turns an extremely dark blue-green. The crude intermediate Aniline A-3 was obtained as a dark purple-green foam, which was used immediately in the next step without further purification: 1H NMR (DMSO-d 6 ) δ: 8.58 (s, 1H), 6.77 ( td, J = 9.4, 2.0 Hz, 1H), 6.60 (td, J = 9.4, 5.5 Hz, 1H), 4.97 (s, 2H), 1.43 (s, 9H).

[0226] Step 2 - Preparation of sulfonamide A-4 (Ar = 4-methoxyphenyl): The crude aniline A-3 (assumed to be 18 mmol) from step 1 was dissolved in THF (30 mL) and an excess of 4-Methoxyphenylsulfonyl chloride (7.53 g, 36 mmol), followed by pyridine (6 mL). The mixture was stirred at 50 °C for 18 h. THF was removed under reduced pressure and the residue was partitioned between EtOAc and water. The extract was washed with saturated aqueous NaHCO 3 and brine, and dried over MgSO 4 . Pass the desiccant slurry through a 75 mL pad of silica gel and wash with EtOAc to remove the desiccant and baseline material. Removal of solvent gave a brown oil, which was purified by flash chromatography on silica (ca. 250 mL) using 20%-50% EtOAc / hexanes as eluent. After drying under vacuum, the product A-4 (8.16 g) was obtained as a brown foam, which was contaminated with unreacted sulfonyl chloride in a 2:1 ratio by 1H NMR. The material was used directly in the next step as received: 1H NMR (CDCl3) δ: 7.68 (d, J = 9.0 Hz, 2H), 7.41 (td, J = 8.8, 5.5 Hz, 1H), 6.85 - 6.98 ( m, 3H), 6.57 (br s, 1H), 5.85 (br s, 1H), 3.85 (s, 3H), 1.46 (s, 9H). MS m / z 413.0 (M-H), m / z 313.0 (M-H-Boc).

[0227] Step 3 - Preparation of aniline hydrochloride A-5 (Ar=4-methoxyphenyl): Crude carbamate A-4 (8.16 g) from step 3 was dissolved in 4 N HCl at RT. Oxane (25 mL) was stirred for 1.5 h, during which time a beige solid gradually precipitated. After 1.5 h, another 10 mL of 4 N HCl in dioxane was added and stirring was continued for another 1 h. Subsequently, the reaction mixture was diluted with 50 mL diethyl ether and the beige precipitate was collected by filtration, washed with diethyl ether and dried under vacuum. Aniline salt A-5 (4.38 g) was obtained in pure form from nitroarene A-2 in 68% overall yield: 1H NMR (DMSO-d 6 ) δ: 9.73 (s, 1H), 7.62 (d, J = 8.6 Hz, 2H), 7.06 (d, J = 9.0 Hz, 2H), 6.69 - 6.88 (m, 1H), 6.30 (td, J = 8.6, 5.5 Hz, 1H), 3.81 (s, 3H). MS m / z 313.0 (M-H). Preparation of difluoroaniline hydrochloride intermediate A-5 (Ar=2,3-dichlorophenyl) from acetaniline A-8.

[0228] Preparation of Acetylaniline A-8: Acetylaniline A-7 can be prepared by acetylating 2,6-difluoroaniline A with acetic anhydride according to the literature procedure described in Bioorg.Med.Chem.2016, 24, 2215 -6 to prepare. Intermediate A-7 was converted to acetaniline A-8 by sequential nitration followed by reduction of the nitro group to aniline as described in WO 2012 / 101238A1.

[0229] Step 1 - Preparation of sulfonamide A-9 (Ar = 2,3-dichlorophenyl): Aniline A-8 (8.50 g, 45.5 mmol) was dissolved in THF (145 mL) and pyridine (4 eq. , 14.7 mL) was added to the brown solution, followed by 2,3-dichlorobenzenesulfonyl chloride (1.2 equiv, 13.45 g). The resulting reaction mixture was stirred at 45°C for 3.5 hours after which time the conversion was complete as judged by LCMS monitoring. The reaction mixture was cooled to room temperature, then partitioned between EtOAc and 2-Me-THF (1:1) and water. Add 1 N HCl solution until a slightly acidic pH is obtained. A significant amount of off-white solid was present in the biphasic mixture and was filtered off (first crop). The filtrate layers were separated, and the aqueous layer was extracted two more times with EtOAc. The combined organic extracts were washed once with water, then brine, dried over MgSO 4 , filtered and concentrated to about 20 mL. The resulting suspension was sonicated and the solid was collected by filtration and washed with EtOH (crop 2). The two batches were combined and dried under reduced pressure. A-9 (15.3 g, 85% yield) was obtained as a beige solid, which was used without further purification: 1H NMR (DMSO-d 6 ) δ: 10.61 (s, 1H), 9.67 (s, 1H), 7.95 (dd, J = 8.0, 1.4 Hz, 1H), 7.85 (dd, J = 8.0, 1.4 Hz, 1H), 7.51 (t, J = 8.0 Hz, 1H), 7.05 - 7.18 (m, 2H), 2.00 (s, 3H). MS m / z 395.0 (MH+).

[0230] Step 2 – Preparation of aniline hydrochloride A-5 (Ar=2,3-dichlorophenyl): In a 500 mL round bottom flask, suspend acetaniline A-9 (7.00 g, 17.7 mmol) in ethanol (65 mL) and a 1:1 mixture of concentrated HCl and water (65 mL) was added. The flask was equipped with a stoppered reflux condenser and heated at 80 °C with stirring. After 24 hours, the conversion was -70% as judged by LCMS monitoring. Additional EtOH (65 mL) and 6 N HCl (65 mL) were added to the suspension and stirred at 80 °C for over 7 h, after which LCMS indicated complete conversion to the desired aniline. The reaction mixture was diluted with 50 mL of water while still warm, and filtered through a cotton plug to remove a small amount of insoluble material. It was then concentrated to dryness under reduced pressure. The residue was azeotropically dried by evaporating toluene under reduced pressure 3 times, followed by drying under vacuum to give 7.2 g of the desired product A-5 as its HCl salt in the form of a yellow solid: 1H NMR (DMSO-d 6) δ:10.30 (s, 1H), 7.93 (dd, J = 8.2, 1.2 Hz, 1H), 7.83 (dd, J = 8.0, 1.4 Hz, 1H), 7.49 (t, J = 8.0 Hz, 1H) , 6.68 - 6.96 (m, 1H), 6.31 (td, J = 8.6, 5.5 Hz, 1H). MS m / z 350.9 (M-H). Table 1 A-5 SM MS m / z (M-H) 1H NMR (400 MHz) A-2 331.0 Not determined A-2 327.0 1H NMR (DMSO-d 6) d: 9.77 (s, 1H), 7.60 (d, J = 9.0 Hz, 1H), 6.93 (d, J = 2.3 Hz, 1H), 6.81 (dd, J = 8.8, 2.5 Hz, 1H), 6.72 - 6.79 (m, 1H), 6.32 (td, J = 8.6, 5.5 Hz, 1H), 3.78 (s, 3H), 2.56 (s, 3H). A-2 308.0 1H NMR (DMSO-d 6) δ: 10.34 (s, 1H), 8.07 (dd, J = 7.4, 1.2 Hz, 1H), 7.77 - 7.95 (m, 3H), 6.67 - 6.90 (m, 1H), 6.30 (td, J = 8.4, 5.5 Hz, 1H). A-2 322.9 Not determined A-8 317.0 1H NMR (DMSO-d 6) δ: 10.12 (s, 1H), 7.85 (dd, J = 7.8, 1.6 Hz, 1H), 7.59 - 7.71 (m, 2H), 7.46 (td, J = 7.5, 1.4 Hz , 1H), 6.74 - 6.82 (m, 1H), 6.31 (td, J = 8.6, 5.5 Hz, 1H) A-8 331.0 1H NMR (CDCl 3 ) δ: 7.84 (d, J = 7.8 Hz, 1H), 7.58 (d, J = 7.8 Hz, 1H), 7.21 (t, J = 8.0 Hz, 1H), 6.68 - 6.74 (m, 2H), 6.63 (br s, 1H), 2.75 (s, 3H) A-8 315.0 1H NMR (DMSO-d 6) δ: 10.10 (s, 1H), 7.54 (d, J= 7.8 Hz, 1H), 7.46 (td, J= 9.0, 1.2 Hz, 1H), 7.35 (td, J= 8.2 , 5.5 Hz, 1H), 6.79 (ddd, J= 10.9, 9.1, 2.0 Hz, 1H), 6.32 (td, J= 8.6, 5.5 Hz, 1H), 2.49 (d, J= 2.0 Hz, 3H A-2 346.9 1H NMR (CDCl 3 ) δ: 7.84 (d, J = 8.2 Hz, 1H), 7.74 (br s, 1H), 6.95 (s, 1H), 6.89 (br s, 1H), 6.76 (br. d, J = 7.8 Hz, 1H), 6.53 - 6.72 (m, 1H), 5.52 (br s, 3H), 3.78 (s, 3H) A-8 347.1 1H NMR (DMSO-d 6) δ: 9.94 (s, 1H), 7.48 (dd, J = 8.9, 1.5 Hz, 1H), 7.07 (t, J = 8.6 Hz, 1H), 6.78 (ddd, J = 10.8 , 9.0, 1.9 Hz, 1H), 6.33 (td, J = 8.6, 5,5 Hz, 1H), 3.86 (s, 3H), 2.48 (d, J = 2.7 Hz, 3H) A-8 363.2 1H NMR (DMSO-d 6) δ: 10.00 (s, 1H), 7.67 (d, J = 8.9 Hz, 1H), 7.07 (d, J = 9.0 Hz, 1H), 6.78 (ddd, J = 9.0, 6.5 , 1.9 Hz, 1H), 6.33 (td (J = 8.7, 5.5 Hz, 1H), 3.89 (s, 3H), 2.65 (s, 3H) A-8 313.0 1H NMR (CDCl 3 ) δ: 7.86 (dd, J = 8.0, 1.3 Hz, 1H), 7.49 (td, J = 7.6, 1.3 Hz, 1H), 7.38 – 7.29 (m, J = 7.7 Hz, 1H), 7.24 – 7.19 (m, 1H), 6.72 – 6.62 (m, 2H), 6.54 (brs, 1H), 3.04 (q, J = 7.5 Hz, 2H), 1.30 (t, J = 7.5 Hz, 3H) A-8 331.0 1H-NMR (CDCl 3 ) δ: 7.70 – 7.64 (m, 1H), 7.24 – 7.19 (m, 2H), 6.73 – 6.65 (m, 2H), 6.63 (s, 1H), 3.01 (qd, J = 7.4 , 2.1 Hz, 2H), 1.25 (t, J = 7.4 Hz, 3H) A-8 346.8 1H-NMR (DMSO-d 6) δ: 10.21 (s, 1H), 7.71 (ddd, J= 8.0, 4.9, 1.2 Hz, 1H), 7.35 (t, J= 8.0 Hz, 1H), 7.02 – 6.92 ( m, 1H), 6.87 – 6.75 (m, 1H), 6.60 (bs, 1H), 6.28 (td, J= 8.6, 5.6 Hz, 1H), 3.12 (q, J= 7.2 Hz, 2H), 1.18 (t , J= 7.3 Hz, 3H) A-8 366.3 1H-NMR (CDCl 3 ) δ: 8.12 (d, J= 8.1 Hz, 1H), 7.84 (d, J= 8.0 Hz, 1H), 7.37 (t, J= 8.0 Hz, 1H), 6.74 – 6.64 (m , 2H), 6.61 (s, 1H), 3.88 – 3.62 (bs), 2.83 (s, 3H) A-8 364.3 1H-NMR (DMSO-d 6) δ 10.38 (s, 1H), 7.70 (dd, J= 7.6, 1.6 Hz, 1H), 7.44 – 7.26 (m, 2H), 6.82 (ddd, J= 10.7, 9.0, 1.9 Hz, 1H), 6.32 (td, J= 8.6, 5.5 Hz, 1H), 5.27 (s, 2H). A-8 333.1 1H NMR (400 MHz, DMSO-d 6) δ 10.06 (s, 1H), 7.72 (dd,J = 7.9, 1.1 Hz, 1H), 7.65 – 7.61 (m, 1H), 7.36 (t,J = 7.7 Hz , 1H), 6.76 (ddd,J = 10.7, 9.0, 1.9 Hz, 1H), 6.28 (td,J = 8.6, 5.4 Hz, 1H), 2.42 (s, 3H) A-8 344.2 1H NMR (DMSO-d 6) δ: 10.33 (s, 1 H), 8.29 (d, J=2.35 Hz, 1 H), 8.13 (dd, J=8.61, 2.35 Hz, 1 H), 7.91 (d, J=8.61 Hz, 1 H), 2.72 (s, 2 H), 6.88 - 7.01 (m, 1 H), 6.70 - 6.86 (m, 1 H), 6.60 (td, J=8.41, 5.09 Hz, 1 H ), 6.32 (td, J=8.51, 5.67 Hz, 1 H) A-8 338.2 1H NMR (DMSO-d 6) δ: 10.38 (s, 1H), 8.59 (s, 1H), 7.92 - 8.39 (m, 4H), 7.45 - 7.66 (m, 1H) A-8 385.2 1H NMR (400 MHz, DMSO-d 6) δ 10.27 (s, 1H), 8.00 (dd,J = 8.0, 4.5 Hz, 2H), 7.81 (t,J = 8.1 Hz, 1H), 6.83 (ddd,J = 10.7, 9.1, 1.8 Hz, 1H), 6.35 (td,J = 8.6, 5.5 Hz, 1H), 5.31 (s, 2H) A-8 388.2 1H NMR (400 MHz, DMSO-d 6) δ 10.25 (s, 1H), 7.96 – 7.70 (m, 3H), 6.83 (m, 1H), 6.37 (m, 1H), 5.30 (s, 2H) A-8 335.2 1H NMR (400 MHz, DMSO-d 6) δ 10.15 (s, 1H), 7.54 (ddd, J = 8.8, 5.0, 1.3 Hz, 1H), 7.40 (dd, J = 17.3, 9.1 Hz, 1H), 6.80 (ddd, J = 10.7, 9.1, 1.8 Hz, 1H), 6.32 (td, J = 8.6, 5.5 Hz, 1H), 5.28 (s, 2H), 2.54 (d, J = 2.5 Hz, 3H) A-8 329.1 1H NMR (400 MHz, DMSO-d 6) δ 10.03 (s, 1H), 7.43 (d, J = 8.1 Hz, 1H), 7.22 (t, J = 7.8 Hz, 1H), 6.78 (ddd, J = 10.8 , 9.0, 1.9 Hz, 1H), 6.33 (td,J = 8.6, 5.5 Hz, 1H), 2.48 (d,J = 2.4 Hz, 3H), 2.26 (d,J = 1.9 Hz, 3H) A-8 349.1 1H NMR (400 MHz, DMSO-d 6) δ 10.21 (s, 1H), 7.60 – 7.55 (m, 1H), 7.55 – 7.50 (m, 1H), 6.81 (ddd,J = 10.7, 9.0, 1.8 Hz, 1H), 6.32 (td, J = 8.6, 5.5 Hz, 1H), 2.53 (d, J = 2.6 Hz, 3H) A-8 330.0 Not determined A-8 449.2 1H NMR (DMSO-d 6) δ: 10.71 (s, 1H), 10.02 (s, 1H), 7.91 - 8.07 (m, 1H), 7.74 (d, J= 8.61 Hz, 1H), 7.28 - 7.47 (m , 4H), 6.80 (t, J= 8.80Hz, 1H), 6.33 (dt, J= 5.48, 8.61 Hz, 1H), 5.76 (s, 1H), 5.24 (s, 1H), 5.18 (s, 2H) , 2.63 - 2.66 (m, 3H) A-8 314.2 1H NMR (400 MHz, DMSO-d 6) δ 10.59 (s, 1H), 8.57 (d, J = 5.6 Hz, 1H), 7.72 (d, J = 5.6 Hz, 1H), 6.97 (br s, 3H) , 6.80 (ddd, J = 10.7, 9.1, 1.8 Hz, 1H), 6.30 (td, J = 8.6, 5.4 Hz, 1H), 2.69 (s, 3H), 2.58 (s, 3H) A-8 337.2 1H NMR (400 MHz, DMSO-d 6) δ 10.27 (s, 1H), 7.92 (s, 1H), 6.93 – 6.75 (m, 1H), 6.35 (td,J = 8.5, 5.5 Hz, 1H), 5.32 (s, 2H), 2.22 (s, 3H) A-8 337.2 1H NMR (400 MHz, CDCl 3 ) δ 7.20 (m, 1H), 7.03 (br s, 1H), 6.87 (td, J = 8.8, 5.4 Hz, 1H), 6.73 (td, J = 9.8, 2.0 Hz, 1H), 2.21 (s, 3H) A-8 357.2 1H NMR (400 MHz, DMSO-d 6) δ 10.59 (s, 1H), 8.15 (s, 1H), 6.98 – 6.71 (m, 1H), 6.35 (td,J = 8.5, 5.5 Hz, 1H), 5.34 (s, 2H) A-8 319.1 Not determined A-8 337.2 1H NMR (400 MHz, DMSO-d 6) δ 10.27 (s, 1H), 7.92 (s, 1H), 6.93 – 6.75 (m, 1H), 6.35 (td, J = 8.5, 5.5 Hz, 1H), 5.32 (s, 2H), 2.22 (s, 3H). General Synthetic Method A - Preparation of Inhibitors I and II from Intermediate A-5 (Examples 1 and 36):

[0231] Step 1 (Preparation 1 of Example): Dissolve chloropyrimidine A-10 (0.546 g, 1.25 equiv) and aniline hydrochloride A-5 (Ar=4-methoxyphenyl; 0.750 g, 1 equiv) in AcOH ( 10 mL) and the brown solution was stirred at 50 °C for 1 h. LCMS showed complete conversion to the desired crude product (Example 1). The reaction mixture was cooled to RT and diluted with water (50 mL), resulting in a gray precipitate which was collected by filtration, washed with water and dried under vacuum. A 100 mg sample of crude material was purified by passing through a small pad of silica gel (3 mL) using 1:1 hexane / EA as the eluent to remove colored baseline material. After removal of volatile components from the mauve solution, the material was lyophilized from MeCN-water to provide the inhibitor of Example 1 (73 mg).

[0232] Steps 2 and 3 (preparation of Example 36): To a solution of the crude thiomethyl derivative (Example 1; 355 mg, 0.72 mmol, 1 equiv) in 7 mL of DCM was added m-CPBA (185 mg , 1.07 mmol, 1.5 equiv). The mixture was stirred at this temperature for 1 h. LCMS showed complete conversion to an 80:20 mixture of arginine and arginine. The mixture was concentrated to remove most of the DCM, then poured into EtOAc and washed 3 times with NaHCO 3 solution. The combined aqueous layers were back extracted with EtOAc and the combined organic layers were washed once with water followed by brine. The organic layer was then dried over MgSO 4 , filtered and concentrated to give 356 mg of a yellow foam which was used as such without further purification: MS m / z 507 and 523 (MH+).

[0233] A crude mixture of arginine and arginine (25 mg, 0.05 mmol) and benzimidazole (12 mg, 0.1 mmol, 2 equiv) from above was charged to a 4 mL vial and dissolved in NMP (1 mL). Then DIEA (43 µL, 0.25 mmol, 5 eq) was added and the resulting mixture was stirred at 60 °C for 19 h (LCMS showed complete reaction). The reaction was quenched by adding 0.2 mL of AcOH, then diluted to 2 mL with methanol. The solution was filtered and then purified by preparative HPLC (MeOH / H 2 O / 0.1% HCO 2H conditions, 10%-100% methanol gradient). Fractions containing the main peak were combined and partially concentrated to remove methanol. The resulting suspension was dissolved by adding a few milliliters of acetonitrile, then the solution was frozen and lyophilized. 8.1 mg of the desired product were obtained as a pink solid (Example 36).

[0234] Further examples of inhibitors of general formulas I and II prepared in a similar manner are listed in Tables 1 and 2 together with characterization data. Inhibitors I and II were synthesized using General Synthetic Method B (Examples 12 and 56):

[0235] Step 1: Carbamate A-2 (1.50 g) was dissolved in DCM (5 mL) and TFA (2 mL) was added. After stirring at room temperature for 2 h, deprotection (LCMS) was completed and the reaction mixture was concentrated and dried under reduced pressure.

[0236] Step 2: Although the crude TFA salt from Step 1 (above) can be used directly in Step 2, solvolysis of the desired intermediate B-2 from A-10 produces varying amounts of 8-hydroxy-2-thiomethan pyrimidopyrimidine contamination. This side reaction can be minimized and a cleaner intermediate B-2 obtained if the aniline TFA salt is neutralized to free aniline prior to reaction with A-10. The crude TFA from step 1 was dissolved in DCM and the solution was washed with NaHCO 3 . After drying (MgSO 4 ), removal of volatile components afforded free aniline B-1 (0.85 g) as a brown sticky solid: 1H NMR (DMSO-d 6 ) δ: 7.22 - 7.38 (m, 1H), 7.06 - 7.19 (m, 1H), 5.92 (br s, 2H).

[0237] Chloropyrimidopyrimidine A-10 (550 mg. 2.6 mmol) and B-1 aniline free base (0.39 g, 2.25 mmol) were dissolved in acetic acid (7 mL) and the mixture was stirred at 55 °C for 1 h. LCMS showed complete conversion to desired product. The reaction mixture was cooled to RT and diluted with three volumes of water, resulting in precipitation of the product as a cream solid. Material was collected by filtration, washed with water and dried under vacuum (0.58 g): 1H NMR (DMSO-d 6 ) δ: 10.28 (s, 1H), 9.35 (s, 1H), 8.60 (s, 1H), 8.23 - 8.49 (m, 1H), 7.58 (t, J = 8.8 Hz, 1H), 2.71 (s, 3H). MS m / z 350.1 (MH+).

[0238] Step 3: Suspend nitroarene B-2 (0.86 g, 2.45 mmol) and tin(II) chloride hydrate (2.7 equivalents, 6.6 mmol, 1.49 g) in absolute ethanol (10 mL) and dissolve the mixture in Stir at 65 °C for 3 h. The reaction mixture was partitioned between 1 N NaOH and EtOAc. The organic extracts were washed with NaHCO 3 , brine and dried (MgSO 4 ). Subsequently, the desiccant was separated from the extract by filtration through a pad of silica gel (40 mL) using EtOAc as the eluent to remove baseline material. The filtrate was concentrated and the residue was triturated with EtOAc / hexanes to give aniline B-3 as an orange solid which was collected by filtration, washed with diethyl ether and dried (0.438 g): 1H NMR (DMSO-d 6 ) δ: 9.98( s, 1H), 9.28 (s, 1H), 8.53 (s, 1H), 6.93 (td, J = 9.4, 1.6 Hz, 1H), 6.77 (td, J = 9.4, 5.5 Hz, 1H), 5.12 (br s, 2H), 2.73 (s, 3H). MS m / z 321.1 (MH+).

[0239] The mother liquor was purified by flash chromatography (30 mL) using 10%-70% EtOAc / hexane (Rf=0.3 in 1:2 hexane-EA) to provide an additional 96 mg of aniline B-3.

[0240] Step 4 (Example 12): Aniline B-3 (25 mg, 0.078 mmol) and 4-methoxy-2-toluenesulfonyl chloride (100 mg, 0.23 mmol, 3 equivalents) were dissolved in THF (1 mL) And pyridine (40 µL) was added. The mixture was stirred at 45 °C for 1 h (50% conversion by LCMS). Another portion of sulfonyl chloride (100 mg) was added and stirred at 45 °C for an assumed 18 h (LCMS showed complete conversion). The reaction mixture was acidified with TFA (100 µL) and diluted to 1.8 mL with DMSO. The product was isolated by preparative HPLC using a 30%-100% MeOH+0.1% HCOOH gradient (13 mg) (Example 12).

[0241] Steps 5 and 6 (Example 56): To a suspension of thiomethylpyrimidine (Example 12, 300 mg, 0.59 mmol) in DCM (5 mL) was added 1.2 equivalents of m-CPBA (160 mg, 0.71 mmol) at room temperature ). The mixture turned into a yellow solution within 10 minutes. It was allowed to stir at room temperature for a total of 45 minutes, at which point LCMS revealed that the reaction was complete. The mixture was concentrated to remove most of the DCM, then partitioned between EtOAc and aqueous NaHCO 3 . The layers were separated, and the organic layer was washed two more times with NaHCO 3 solution. The combined aqueous layers were back extracted with EtOAc and the combined organic layers were washed with brine, then dried over MgSO 4 and filtered. The filtrate was concentrated to dryness and then dried under vacuum to give 295 mg of a mixture of argon and arginine (~80:20 ratio by LCMS). The material was used as such in the next step without further purification.

[0242] 4,5-Dimethyl-1H-imidazole hydrochloride (19 mg, 0.14 mmol, 3 equiv) and the aridine-thridine mixture from above (25 mg, 0.048 mmol, 1 equiv) were charged to a 4 mL vial , followed by NMP (o, 5 mL) and DIEA (42 µL, 0.24 mmol, 5 equiv). The resulting mixture was stirred at 60 °C for 4 h (LCMS showed complete conversion). The reaction mixture was acidified with AcOH (0.2 mL), and the product (Example 56) was isolated by preparative HPLC (MeOH / H 2 O / 0.1% formic acid, 30%-100% methanol gradient). Fractions containing the main peak were combined and partially concentrated to remove methanol. The resulting suspension was dissolved by adding a few milliliters of acetonitrile, then the solution was frozen and lyophilized. 14 mg of yellow powder was obtained, the purity of which was only 88% by HPLC. This material was repurified by flash chromatography on a 3 g silica gel cartridge using a gradient of 100% DCM to 7% isopropanol / DCM. Appropriate fractions were combined, concentrated, co-evaporated once with acetonitrile, and subsequently poured into a 1:1 MeCN / water mixture. After lyophilization, 7.5 mg of the desired product was obtained as a yellow solid (Example 56).

[0243] Further examples of inhibitors of general formulas I and II prepared in a similar manner are listed in Tables 2 and 3 together with characterization data. Inhibitors III and IV (Examples 29 and 73) were synthesized using General Synthetic Method C:

[0244] Step 1: Thioyl chloride (0.051 ml, 0.624 mmol) was dissolved in DCM (2 ml) and the solution was cooled to -78°C. A solution of aniline B-3 (50 mg, 0.156 mmol) and triethylamine (0.11 ml, 0.78 mmol) in DCM (5 mL) was added dropwise over 5 min. The reaction mixture was stirred at -78 °C for 90 min to obtain a solution of intermediate C-1.

[0245] Step 2 (Example 29): (R)-3-Methylpyrrolidine hydrochloride (76 mg, 0.62 mmol) in DCM (3 mL) was added to the cold solution on Intermediate C-1, followed by Pyridine (0.5 mL) was added. The reaction mixture was allowed to warm to RT, then stirred for 2 h (LCMS indicated the mass of the product and the reaction was complete). The reaction mixture was evaporated to dryness and azeotroped with toluene to remove pyridine. The residue was purified on an ISCO using a RediSep 24 g column (DCM / EtOAc) to provide the inhibitor of Example 29 (25 mg) as a tan solid.

[0246] Steps 3 and 4 (Example 73): Thiomethylpyrimidine from Step 1 (Example 29, 20 mg, 0.043 mmol) was dissolved in DCM (5 mL) and m-CPBA (11.5 mg, 0.051 mmol) was added. The mixture was stirred at RT for 30 min (LCMS showed no more starting material). The reaction mixture was diluted with dichloromethane (25 mL) and washed with saturated NaHCO 3 solution. The organic layer was separated and dried over anhydrous Na2SO4 and filtered. The filtrate was evaporated to dryness to afford a mixture of arginine and arginine (18 mg) as a brown foamy solid, which was used in the next step without any further purification.

[0247] The crude material from above (18 mg, 0.037 mmol) was dissolved in NMP (2 mL), and DIEA (0.033 ml, 0.186 mmol) and benzimidazole (13.2 mg, 0.112 mmol) were added. The reaction mixture was heated at 60 °C for 3 h (LCMS showed complete conversion). The reaction mixture was diluted with MeOH (1 mL), acidified with a few drops of acetic acid and the product was isolated by preparative HPLC using a 30%-100% MeOH-Water-0.1% TFA gradient. The product fractions were partially evaporated, dissolved in ACN and water and lyophilized to provide Example 73 (12 mg).

[0248] Further examples of inhibitors of general formulas I and II prepared in a similar manner are listed in Tables 2 and 3 together with characterization data. Inhibitor V was synthesized using General Synthetic Method D (Example 88):

[0249] Step 1: Dissolve amino-dichloropyrimidopyrimidine D-2 (50 mg, 0.23 mmol, 1 equiv) and aniline hydrochloride A-5 (85 mg, 0.23 mmol, 1 equiv) in AcOH (1.5 mL) and the mixture was stirred at 55 °C for 1 h (LCMS showed conversion to product, but still a small amount of aniline). Another 10 mg of dichloro derivative D-2 was added and stirring was continued for 30 min at 55°C. Cool to RT, dilute with 3 volumes of water, collect the creamy precipitate, wash with water and dry under vacuum (120 mg): 1H NMR (DMSO-d 6 ) δ: 10.10 (s, 1H), 9.78 (s, 1H), 8.61 (br s, 1H), 8.39 (br s, 1H), 8.37 (s, 1H), 7.66 (d, J = 9.0 Hz, 1H), 7.17 - 7.26 (m, 1H), 7.13 (t , J = 9.4 Hz, 1H), 6.94 (d, J = 2.0 Hz, 1H), 6.86 (dd, J = 9.0, 2.0 Hz, 1H), 3.80 (s, 3H), 2.56 (s, 3H). MS m / z 508.0 (MH+).

[0250] Step 2: Suspend amino-chloropyrimidine (25 mg, 0.05 mmol, 1 equiv) and benzimidazole (10.5 mg, 0.09 mmol, 1.8 equiv) in DMSO (0.7 mL) and add cesium carbonate (37 mg, 0.11 mmol, 2.3 equiv), followed by Cu powder (0.3 mg, 0.1 equiv) and rac-BINOL (1.5 mg, 0.1 equiv). The mixture was stirred at 110 °C for 2 h (LCMS showed complete conversion to the desired mass). The brown reaction mixture was acidified with TFA (100 μL) and the product was separated by preparative HPLC using a 30%-100% MeOH / 0.1% HCOOH gradient. The inhibitor of Example 88 (10 mg) was isolated as a beige solid after lyophilization. Examples 85, 86 and 87 were prepared in a similar manner.

[0251] In the case of Example 84, as described in the last step of schemes A and B, the product was obtained under basic conditions (intermediate D-3, 4 equivalents of DIEA and 2 equivalents of 3-fluoropyrrolidine hydrochloride in Formation using nucleophilic displacement under heating in NMP at 100 °C for 1.5 h).

[0252] Further examples of inhibitors of general formula V prepared in a similar manner are listed in Table 4 together with characterization data. Inhibitor VI was synthesized using General Synthetic Method E:

[0253] Step 1: Oxidation of Intermediate I (Ar = 3-fluoro-2-methylphenyl, Example 90) prepared from the appropriate Intermediate A-5 as described in Steps 1 and 2 of General Synthetic Method A to arone and A mixture of porridge.

[0254] Steps 2 and 3 (X=CH): Cesium carbonate (1.16 g, 3.51 mmol) and methylindole-3-carboxylate (X=CH; 0.554 g, 3.1 mmol) were suspended in DMSO (62 mL) And the mixture was stirred at RT for 10 min. The mixture of arginine and arginine from step 1 (1.55 g, 2.95 mmol) was added and the mixture was stirred at 80 °C for 18 h, at which point the conversion was complete as judged by LCMS analysis.

[0255] NaOH (236 mg, 5.9 mmol) was added to the reaction mixture from step 2 and the mixture was stirred at RT until complete conversion to the desired carboxylic acid intermediate E-1 (X=CH) as determined by LCMS analysis. Citric acid solution (1 M) was then added to precipitate the product, which was filtered, washed with water and dried to give E-1 (X=CH) (1.67 g, 93% yield) as a brown solid: 1H NMR (DMSO- d 6) δ 12.70 (br, 1H), 10.56 (s, 1H), 10.50 (s, 1H), 9.64 (s, 1H), 9.43 (s, 1H), 8.89 (d, J = 8.3 Hz, 1H) , 8.55 (s, 1H), 8.20 – 8.12 (m, 1H), 7.61 (d, J = 7.8 Hz, 1H), 7.53 – 7.45 (m, 1H), 7.45 – 7.33 (m, 3H), 7.27 (t , J = 9.2 Hz, 1H), 2.49 – 2.48 (m, 3H). MS m / z 620.3 (MH+).

[0256] Steps 2 and 3 (X=N): Sodium tert-butoxide (341 mg, 3.54 mmol) was added to methyl 1H-indazole-3-carboxylate (573 mg, 3.19 mmol) in anhydrous THF (6.2 mL). ), and the mixture was stirred at RT for 10 min. The argon / throne mixture from step 1 (1.55 g, 2.95 mmol) was added and the mixture was stirred at RT for 18 h, at which point the conversion was complete as judged by LCMS analysis. The reaction mixture was concentrated under reduced pressure to a volume of 20 mL and a solution of NaOH (236 mg, 5.9 mmol) in water (20 mL) was added. The mixture was stirred at RT for 4 h, at which time the conversion to the desired carboxylic acid was complete by LCMS analysis. The reaction mixture tended to be concentrated under reduced pressure to remove THF and the aqueous residue was acidified with 1 M citric acid to precipitate the product, which was collected by filtration, washed with water and dried to give a brownish color in quantitative yield. Solid E-1 (X=N): 1H NMR (DMSO-d 6) δ 10.53 (br, 1H), 10.03 (s, 1H), 9.69 (s, 1H), 8.89 (d, J = 8.6 Hz, 1H), 8.61 (s, 1H), 8.26 (d, J = 8.1 Hz, 1H), 7.72 – 7.67 (m, 1H), 7.62 (d, J = 7.8 Hz, 1H), 7.55 (dt, J = 8.0 , 1.5 Hz, 1H), 7.48 (d, J = 8.5 Hz, 1H), 7.41 (td, J = 8.0, 5.6 Hz, 1H), 7.33 (td, J = 8.6, 5.9 Hz, 1H), 7.25 (t , J = 9.3 Hz, 1H), 2.50 – 2.49 (m, 3H). MS m / z 607.2 (MH+).

[0257] Step 4 (Preparation of Example 103, X=CH): Combine carboxylic acid E-1 (X=CH; 61 mg, 0.1 mmol) and (S)-3-hydroxypiperidine hydrochloride (17 mg, 0.12 mmol) Dissolved in DMF (0.5 mL) and added DIPEA (61 µL, 0.35 mmol), followed by HATU (58 mg, 0.15 mmol). The mixture was stirred at ambient temperature for 18 h. The reaction mixture was then directly purified by preparative reverse phase HPLC to provide the compound of Example 103 as a yellow powder after lyophilization.

[0258] Other examples listed in Table 3 (X=CH or N) and using method E were prepared in a similar manner. Inhibitor VII was synthesized using General Synthetic Method F (Example 95):

[0259] Step 1: 3-Indosulfonyl chloride was prepared as described in Org. Lett. 2011, 13, 3588. Sulfonyl chloride (200 mg, 0.9 mmol) was charged into a 25 mL flask, THF (4 mL) was added to the flask, followed by dimethylamine hydrochloride (2 equiv, 150 mg, 1.9 mmol) and DIEA ( 4 equivalents, 0.65 mL, 3.7 mmol). The solution quickly turned pale yellow, and a yellow gummy oil settled to the bottom. After stirring at RT for 20 minutes (LCMS showed complete consumption of sulfonyl chloride). The mixture was partitioned between EtOAc and saturated NH 4 Cl solution. The aqueous layer was extracted with EtOAc and the combined organic layers were washed once more with saturated NH 4 Cl solution, followed by brine. Then, it was dried over MgSO 4 , filtered and concentrated to dryness to give 65 mg beige crystalline solid which was used as received without further purification: 1H NMR (DMSO-d 6 ) δ: 12.17 (br s, 1H), 7.96 (d, J = 3.1 Hz, 1H), 7.81 (d, J = 7.8 Hz, 1H), 7.49 - 7.57 (m, 1H), 7.22 - 7.28 (m, 1H), 7.16 - 7.22 (m, 1H) , 2.58 (s, 6H). MS m / z 225.1 (MH+).

[0260] Step 2: Oxidation of thiomethyl derivative I (Ar = 3-fluoro-2-tolyl; Example 90) to a mixture of aridine and aridine was carried out as described in General Method A.

[0261] Step 3 (Example 95): Prepared using general method A from indosulfonamide from step 1 and the argon / throne mixture from step 2.

[0262] The other examples listed in Table 3 were prepared in a similar manner using General Method F. Inhibitor VIII was synthesized using General Synthetic Method G (Example 142):

[0263] Step 1: To a solution of 1H-indol-3-yl-thiocyanate (Phosphorus, Sulfur and Silicon and the Related Elements 2014, 189, 1378) (100 mg, 0.57 mmol) in iPrOH (5 mL) was added Sodium sulfide nonahydrate (414 mg, 1.72 mmol) was dissolved in 0.5 mL of water, and the resulting mixture was stirred at 50 °C for 2 h. After this time, 4-chlorotetrahydropyranan (0.19 mL, 1.72 mmol) was added and stirred overnight at 50 °C. The reaction mixture was diluted with EtOAc (30 mL) and separated. The organic layer was washed with water (15 mL) followed by brine (15 mL), dried over MgSO 4 and then concentrated under vacuum to give the crude sulfide which was used directly in the next step without further purification.

[0264] Step 2: The sulfide from step 1 was dissolved in DCM and 3-chloroperoxybenzoic acid (297 mg, 1.72 mmol) was added and stirred at room temperature for 2 h. After completion, the reaction was quenched by adding 10 mL of a 1:1 solution of saturated aqueous NaHCO 3 and 10% aqueous Na 2 SO 3 . The resulting suspension was stirred at room temperature for 15 min. EtOAc was added and the organic layer was separated. The organic layer was washed with water (15 mL), followed by saturated brine solution (15 mL). The organic layer was separated, dried (MgSO 4 ) and filtered, then concentrated to dryness to provide the expected sulfide (154 mg, 98%), which was dissolved in DMSO and used directly in the next step without further purification. MS m / z 266.2 (MH+).

[0265] Step 3 (Example 142): Using the procedure described in General Method A, the indole from Step 2 was coupled with Intermediate I (Ar = 2,3-dichloromethyl).

[0266] Additional examples of inhibitors prepared in a similar manner in Step 1 using the appropriate alkylating agent are listed in Table 3 under Method F. Inhibitor IX was synthesized using General Synthetic Method H (Example 130):

[0267] In step 2, iron was used as reducing agent (Example 130):

[0268] Step 1: Add 4-methylpiperidin-4-ol (0.24 g, 1.84 mmol) and potassium carbonate (0.49 g, 3.52 mmol) to 3-fluoro-2-nitro-aniline (0.25 g, 1.60 mmol) in in solution in MeCN (2.6 mL). The resulting mixture was stirred at 85 °C for 10 h. MeCN was removed under reduced pressure and EtOAc was added. The suspension was centrifuged and poured into a flask. The solution was concentrated and the crude 1-(3-amino-2-nitro-phenyl)-4-methyl-piperidin-4-ol (0.40 g, 94% yield) was used without further purification in the following in one step. MS m / z 252.2 (MH+).

[0269] Step 2 (using iron as reducing agent): Add iron (0.37 g, 6.70 mmol) and ammonium chloride (0.36 g, 6.70 mmol) to 1-(3-amino-2-nitro-phenyl)-4 -Methyl-piperidin-4-ol (0.34 g, 1.34 mmol) in a mixture of iPrOH (6.5 mL) and formic acid (1.9 mL, 49.6 mmol). The resulting mixture was heated to 90 °C and stirred for 10 h. The reaction mixture was cooled to room temperature and filtered through Celite®. The solution was concentrated and the crude material was purified by column chromatography (silica gel, 0%-15% MeOH / DCM) to give 1-(1H-benzimidazol-4-yl)-4 as a reddish foamy solid -Methyl-piperidin-4-ol (0.17 g, 55% yield). MS m / z 232.2 (MH+). 1H NMR (400 MHz, DMSO-d 6)δ:12.21 (br s, 1H), 8.02 (s, 1H), 6.85 - 7.20 (m, 2H), 6.33 - 6.67 (m, 1H), 4.24 (s, 1H), 3.15 - 3.26 (m, 2H), 2.48 (td, J= 1.66, 3.72 Hz, 2H), 1.41 - 1.74 (m, 4H), 1.16 (s, 3H).

[0270] Step 3 (Example 130): Using the procedure described in General Method A, the benzimidazole from Step 2 was coupled with Intermediate I (Ar = 2,3-dichloromethyl). In step 2, zinc is used as reducing agent (preparation of benzimidazole fragment C328):

[0271] Step 1: 4-Mepiperidin-4-ol is replaced by (R)-3-methoxypiperidine hydrochloride. The nitroarene from step 1 was obtained in 88% yield as a red solid and used directly in step 2 without further purification: MS m / z 252.1 (MH+). 1H NMR (400 MHz, CDCl 3 )δ: 1.2 - 1.35 (m, 1 H), 1.58 - 1.73 (m, 1 H), 1.74 - 1.85 (m, 1 H), 2.06 - 2.17 (m, 1 H) , 2.53 - 2.61 (m, 1 H), 2.70 (td, J=11.5, 3.0 Hz, 1 H), 3.12 (dt, J=12.0, 3.8 Hz, 1 H), 3.35 - 3.45 (m, 2 H) , 3.40 (s, 3 H), 4.79 (br s, 2 H), 6.38 (dd, J=8.25, 1.13 Hz, 1 H), 6.41 (dd, J=8.13, 1.13 Hz, 1 H), 7.12 ( t, J=8.13 Hz, 1 H).

[0272] Step 2: The crude product from Step 1 (1.37 g, 5.45 mmol) and ammonium chloride (4.08 g, 76.3 mmol) in methanol (18 mL) and 2-methyltetrahydrofuran (36 mL) was treated with an added portion of zinc dust (2.7 g, 38.16 mmol). An exotherm was observed and after about 10 min the reaction mixture became colorless. The reaction mixture was stirred for 1 h and LCMS indicated complete conversion to 1,2-diaminobenzene. The reaction mixture was filtered through a small pad of celite and washed with DCM:isopropanol (9:1, 30 mL). The filtrate was diluted with DCM-isopropanol (9:1, 100 mL) and washed with 10% aqueous potassium carbonate (30 mL, pH~10). The organic phase was collected and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 1.2 g: MS m / z 222.2 (MH+). 1H NMR (400 MHz, CDCl 3 )δ: 1.4 - 1.6 (br s, 1 H), 1.61 - 1.74 (m, 1 H), 1.81 - 1.94 (m, 1 H), 2.0 (br s, 1 H) , 2.65 (br s, 1 H), 2.95 (br s, 1 H), 3.17 (br s, 1 H), 3.37 (br s, 2 H), 3.4 - 3.5 (m, 2 H), 3.41 (s , 3 H), 3.79 (br s, 2 H), 6.53 (dd, J=7.63, 1.45 Hz, 1 H), 6.61 (dd, J=7.94, 1.45 Hz, 1 H), 6.68 (t, J= 7.8 Hz, 1H).

[0273] Crude 1,2-diphenylamine was cyclized to the desired benzimidazole as follows: A 100 mL round bottom flask equipped with a Teflon-coated magnetic stir bar, a reflux condenser, and under nitrogen was charged with 2-propane Alcohol (20 mL) and the above crude product (1.20 g, 5.42 mmol). Subsequently, formic acid (5 mL, 132 mmol) was added in one portion and the resulting solution was heated at 60 °C for 16 h. LCMS indicated complete formation of the desired benzimidazole (m / z 232). The cooled reaction mixture was diluted with DCM: 2-propanol (9:1, 200 ml) was washed with 10% aqueous potassium carbonate (40 mL, pH 10), brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give a brown solid. The solid was chromatographed on silica gel (3×12 cm), eluting with ethyl acetate-2-propanol (90:5 to 9:1 ) to afford 1.01 g (81% yield). Trituration with ethyl acetate (10 mL) gave 0.88 g of a light orange-brown solid: MS m / z 232.1 (MH+). 1H NMR (400 MHz, CDCl 3 )δ: 1.47 (br s, 1 H) 1.80 (br s, 1 H) 1.94 (br s, 1 H), 2.13 (br s, 1 H), 2.92 (br s, 2 H), 3.47 (s, 3 H), 3.53 - 3.63 (m, 1 H), 4.1 (br s, 2 H), 6.72 (br s, 1 H), 7.07 (br s, 1 H), 7.19 (t, J=7.9 Hz, 1 H), 7.98 (s, 1 H), 9.43 and 9.7 (two br s, ratio 2:1, 1 H).

[0274] Further examples of inhibitors prepared in a similar manner using the appropriate amine in step 1 and iron or zinc as reducing agent in step 2 are listed in Table 3 under method H. Inhibitor X was synthesized using General Synthetic Method I (Example 138):

[0275] Step 1: Add 1-oxo-8-azaspiro[4.5]decane hydrochloride (188 mg, 1.06 mmol) and potassium carbonate (2.20 equivalents, 292 mg, 2.11 mmol) to 3-fluoro-2-nitrate A bright red solution of di-aniline (150 mg, 0.961 mmol) in ACN (4.5 mL). The resulting mixture was stirred at 90 °C for 16 h. Once complete, the reaction mixture was diluted with ACN and centrifuged. The supernatant was separated and used as such in the next step. MS m / z 278.3 (MH+).

[0276] Step 2: To 2-nitro-3-(1-oxo-8-azaspiro[4.5]dec-8-yl)aniline (250 mg, 0.901 mmol) in ACN was added ammonium chloride (1028 mg , 19.2 mmol) and zinc (628 mg, 9.61 mmol). The resulting suspension was stirred at 40 °C for 1 h. Once complete, the reaction mixture was diluted with EtOAc and centrifuged. The supernatant was separated and evaporated under vacuum. The residual 3-(1-oxo-8-azaspiro[4.5]dec-8-yl)benzene-1,2-diamine (194 mg, 0.784 mmol, 82% yield) was used as such in the next step middle. MS m / z 248.2 (MH+).

[0277] Step 3: Dissolve 3-(1-oxo-8-azaspiro[4.5]dec-8-yl)benzene-1,2-diamine (194 mg, 0.78 mmol) in AcOH (6 mL), followed by Sodium nitrite (54 mg, 0.78 mmol) was added and stirred at room temperature for 1 h. Once complete, EtOAc and aqueous NaHCO 3 were added and the organic layer was separated. The organic layer was washed with aqueous NaHCO 3 , then brine, dried over MgSO 4 , filtered and concentrated under vacuum to afford 8-(1H-benzotriazol-4-yl)-1-oxo-8-aza Spiro[4.5]decane (165 mg, 0.64 mmol, 67% yield), which was used without purification. MS m / z 259.2 (MH+).

[0278] Step 4 (Example 138): Using the procedure described in General Method A, the benzotriazole from Step 3 was coupled with Intermediate I (Ar = 2,3-dichlorophenyl).

[0279] Additional examples of inhibitors prepared in a similar manner using the appropriate amine in Step 1 are listed in Table 3 under Method I. Preparation of Example 114:

[0280] Step 1 - Preparation of 4-(pyridin-3-yl)-1 H-benzo[d]imidazole: bromobenzimidazole (70 mg, 0.355 mmol), potassium carbonate (196 mg, 1.42 mmol) and 3- Pyridylboronic acid (57 mg, 0.46 mmol) was charged to a 4 mL vial and dioxane (2 mL) and water (0.7 mL) were added. Argon was bubbled through the mixture for 1 min and tetrakis(triphenylphosphine)palladium(0) (16.4 mg, 0.014 mmol) was then added. Argon was bubbled through the solution again for 3 min, the vial was sealed and heated at 100 °C for 2 h (conversion to the desired product was complete as judged by LCMS analysis). The reaction mixture was cooled to RT, diluted with EtOAc and washed with brine. After drying over MgSO 4 , the extract was concentrated under reduced pressure and the residue was purified by flash chromatography using Et 3N pretreated silica and a DCM-20% iPrOH / DCM gradient to provide the desired benzo Imidazole intermediate (58 mg, 84% yield): 1H NMR (DMSO-d 6)δ: 12.71 (broadband s, 1H), 9.24 (s. 1H), 8.57 (dd, J = 5.1, 1.6 Hz, 1H), 8.43 (broad d, J = 5.5 Hz, 1H), 8.31 (s, 1H), 7.61 (d, J = 7.8 Hz, 1H), 7.52 (ddd, J = 7.8, 4.7, 0.8 Hz, 1H) , 7.47 (d, J = 7.4 Hz, 1H), 7.34 (t, J = 7.8 Hz, 1H). MS m / z 196.1 (MH+).

[0281] Step 2: Oxidation of thiomethyl derivative I (Ar = 3-fluoro-2-tolyl; Example 90) to a mixture of aridine and aridine was carried out as described in General Method A.

[0282] Step 3 (Example 114): Prepared using general method A from the benzimidazole derivative described in Step 1 and the argon / throne mixture from Step 2. Preparation of (R)-3-(difluoromethoxy)pyrrolidine hydrochloride:

[0283] (R)-N-Boc-3-hydroxypyrrolidine was difluoromethylated using 2-fluorosulfonyl-2,2-difluoroacetic acid and copper(I) iodide as a catalyst, as described in J.Org.Chem .2016, 81, 5803, followed by removal of the N-Boc protecting group with 4 N HCl in dioxane. The preparation of (S)-3-ethylpyrrolidine hydrochloride:

[0284] Step 1: Dissolve commercially available (R)-2-(1-(tertiary butoxycarbonyl)pyrrolidin-3-yl)acetic acid (2.0 g, 8.72 mmol) in anhydrous THF (25 mL) and Add 1 M BH 3.THF (17.45 mL, 17.45 mmol). The reaction mixture was stirred at RT for 3 h. Then, it was cooled in an ice-water bath and quenched by slow addition of 1 N HCl. The product was extracted into EtOA and washed with saturated aqueous NaHCO 3 and brine. The organic layer was dried over anhydrous NaSO and evaporated to dryness to afford (R)-tert-butyl 3-(2-hydroxyethyl)pyrrolidine-1-carboxylate (1.50 g, 6.98 mmol) as an oil ,80% yield): 1H NMR (CDCl 3 ) δ: 3.62 - 3.70 (m, 2H), 3.37 - 3.60 (m, 2H), 3.15 - 3.33 (m, 1H), 2.88 (dt, J = 18.4, 9.6 Hz, 1H), 2.13 - 2.35 (m, 1H), 1.94 - 2.08 (m, 1H), 1.47 - 1.69 (m, 3H), 1.45 (s, 9H), 1.30 - 1.43 (m, 1H), 0.93 (t, J = 7.4 Hz, 1H).

[0285] Step 2: 3-(2-Hydroxyethyl)pyrrolidine-1-carboxylic acid (R)-tert-butyl ester (1.0 g, 4.64 mmol) from step 1 was dissolved in DCM (15 mL) and triethyl was added Amine (1.55 mL, 11 mmol). The mixture was cooled to 0 °C, and a solution of methanesulfonyl chloride (0.58 mL, 7.4 mmol) in DCM (2 mL) was added dropwise. The reaction mixture was stirred at 0 °C for 1 h. Then the reaction mixture was diluted with DCM (15 mL) and washed with saturated NaHCO 3 . The organic layer was separated, dried over anhydrous Na 2 SO 4 and filtered. The filtrate was evaporated to dryness to give the crude mesylate as an oil (1.36 g), which was used in the next step without further purification: 1H NMR (CDCl 3 ) δ: 4.26 (dt, J=11.3 , 6.3 Hz, 2H), 3.39 - 3.66 (m, 2H), 3.21 - 3.35 (m, J = 8.2, 8.2 Hz, 1H), 3.03 (s, 3H), 2.85 - 2.99 (m, 1H), 2.21 - 2.38 (m, 1H), 1.98 - 2.15 (m, 1H), 1.80 - 1.92 (m, 1H), 1.70 - 1.80 (m, 1H), 1.48 - 1.70 (m, 2H), 1.46 (s, 9H) , 0.97 (t, J = 7.2 Hz, 1H).

[0286] Step 3: The crude mesylate from Step 2 (0.60 g, 2.0 mmol) was dissolved in THF (10 mL) and the solution was cooled in an ice water bath. 1 M Lithium triethylborohydride in THF (4.70 mL, 4.70 mmol) was added slowly, after which the ice bath was removed and the mixture was stirred at RT for 2 h. TLC (2:1, ethyl acetate / hexanes) showed no starting material. Methanol (5 mL) was added slowly to quench the reaction and the organic solvent was removed under reduced pressure. The crude reaction mixture was partitioned between EtOAc (30 mL) and water (15 mL) and the organic layer was washed with brine (10 mL). The organic layer was separated, dried over anhydrous Na2SO4, filtered and evaporated to dryness to give crude product. This material was purified on an ISCO using a RediSep 12 g column (Hexane / EtOAc) to provide (S)-tert-butyl 3-ethylpyrrolidine-1-carboxylate as an oil (300 mg, 73% yield): 1H NMR (CDCl 3 ) δ: 3.48 (tt, J = 29.7, 9.4 Hz, 2H), 3.16 - 3.34 (m, 1H), 2.85 (dt, J = 19.8, 10.1 Hz, 1H), 1.90 - 2.11 (m, 2H), 1.45 (s, 9H), 1.36 - 1.43 (m, 3H), 0.93 (t, J = 7.4 Hz, 3H).

[0287] Step 4: The carboxylate from Step 3 (250 mg, 1.25 mmol) was dissolved in MeOH (2 mL) and 4 M HCl in dioxane (2 mL, 8 mmol) was added. The reaction was stirred at RT for 2 h. The volatile components were then removed under reduced pressure, the residue was azeotroped to dryness with ethyl acetate and the residue was dried under vacuum to afford (S)-3-ethylpyrrolidine hydrochloride as a thick oil ( 162 mg, 95% yield). Preparation of (R)-3-(methoxymethyl)pyrrolidine hydrochloride:

[0288] Step 1: 3-(Hydroxymethyl)pyrrolidine-1-carboxylic acid (R)-tert-butyl ester (1.00 g, 4.97 mmol) was dissolved in THF (20 mL) and the solution was cooled in an ice water bath. NaH 60% oily dispersion (0.60 g, 14.91 mmol) was added portionwise and the reaction mixture was stirred at 0 °C for 15 min. Iodomethane (1.55 mL, 24 mmol) was added slowly and the reaction mixture was stirred at RT overnight. Then, the reaction mixture was quenched with saturated NH 4 Cl solution and extracted with EtOAc (2×50 mL). The organic layer was separated, dried over anhydrous Na 2 SO 4 and filtered. The filtrate was evaporated to dryness and purified by silica gel column chromatography (80 g) using EtOAc-Hexane 0 to 100%. 3-(Hydroxymethyl)pyrrolidine-1-carboxylic acid (R)-tert-butyl ester (700 mg, 3.25 mmol, 65.4% yield) was obtained as a colorless oil: 1H NMR (CDCl 3 ) δ: 3.49 (dd, J = 11.0, 7.6 Hz, 1H), 3.43 (br s, 1H), 3.35 (s, 3H), 3.26 - 3.35 (m, 3H), 3.06 (dd, J = 10.7, 7.3 Hz, 1H) , 2.46 (spt, J = 7.3 Hz, 1H), 1.91 - 2.02 (m, 1H), 1.58 - 1.70 (m, 1H), 1.46 (s, 9H).

[0289] Step 2: 3-(Hydroxymethyl)pyrrolidine-1-carboxylic acid (R)-tert-butyl ester (100 mg, 0.46 mmol) from step 1 in DCM (2 mL) was mixed with 4 M HCl Dioxane (2 mL, 8.0 mmol) was mixed and the mixture was stirred at RT for 2 h. The volatile components were evaporated under reduced pressure, the residue was co-evaporated with EtOAc to dryness and the product was dried under vacuum to afford (R)-3-(methoxymethyl)pyrrolidine hydrochloride (70 mg), which was used without further purification. Preparation of Example 89:

[0290] Step 1: 2-Chloro-6-fluoroaniline (10 g) was charged into a 250 mL flask and dissolved in 40 mL of glacial acetic acid. Acetic anhydride (7.47 mL) was added at room temperature and the resulting mixture was stirred at 90 °C for 1 h, at which point LCMS analysis revealed that the reaction was complete. The volatile components were removed under reduced pressure, the residue was dissolved in DCM and slowly neutralized with saturated NaHCO 3 solution. The layers were separated and the aqueous layer was extracted 3 times with DCM. The combined organic layers were washed once with water, then dried over MgSO 4 , filtered and concentrated. After drying in vacuo, the desired product (12.79 g) was obtained as white to pale pink crystals: 1H NMR (CDCl 3 ) δ: 7.16 - 7.26 (m, 2H), 7.03 - 7.13 (m, 1H), 6.93 (br s, 1H), 2.23 (br s, 3H). MS m / z 188.1 (MH+).

[0291] Step 2: The acetamidobenzene (12.75 g) from Step 1 was dissolved in 25 mL of concentrated sulfuric acid and cooled to 0 °C in an ice bath. Nitric acid (90%, 3.31 mL) was added slowly. After 5-10 minutes, the mixture became a solid mass. Allowing to warm to room temperature produced a thick purple-red slurry. After a total of 4 h, the reaction was monitored by LCMS which revealed some remaining starting material. Add another 5 mL of sulfuric acid to improve fluidity, followed by 0.3 mL of 90% nitric acid. The mixture was stirred at room temperature for an additional 18 hours. The mixture was then cooled to 0 °C and poured onto crushed ice (ca. 150 mL). Once the ice melted, the suspension was sonicated and the yellow solid was collected by filtration, washed with water and dried (15.1 g crude product). The crude solid was poured into 50 mL of acetonitrile and refluxed to give a clear dark red solution. Heating was stopped and the mixture was allowed to cool to room temperature within 1 h, followed by stirring at room temperature for 2 h. At this point, the mixture had become a solid mass which was broken up with a spatula and sonicated. The solid was then collected by filtration and washed with a small amount of cold acetonitrile. The desired off-white nitro compound (6.63 g) was obtained as a single regioisomer as shown by NMR (the mother liquor yielded a second crop of 2.16 g containing 7% 6-chloro-2-fluoro-3-nitro Acetamidobenzene): 1H NMR (CDCl 3 ) δ:7.90 (dd, J = 9.2, 4.9 Hz, 1H), 7.24 (dd, J = 9.2, 8.4 Hz, 1H), 6.98 (br s, 1H), 2.28 (s, 3H). MS m / z 233.0 (MH+).

[0292] Step 3: To the solution of nitroacetamide (500 mg, 2.15 mmol) in 15 mL of ethanol from step 2 was added a solution of NH 4 Cl (60 mg, 1.12 mmol) in 1.35 mL of water. The mixture was warmed to 70 °C, then iron powder (600 mg, 10.75 mmol) was added in three portions with 10 min intervals. The resulting dark red to purple mixture was stirred at 70 °C for 20 h. At that point, LCMS of a filtered aliquot of the reaction mixture revealed that the reaction was complete. The mixture was filtered through a pad of celite®. The dark brown filtrate was concentrated to dryness, then poured into EtOAc with MgSO4. The suspension was stirred and subsequently filtered to give a clear pale yellow solution. The solution was concentrated to dryness to give the desired product (440 mg) as a pale yellow solid, which was used as such without further purification: 1H NMR (CDCl 3 ) δ: 6.92 (t, J = 9.0 Hz, 1H), 6.76 (br s, 1H), 6.68 (dd, J = 8.6, 4.7 Hz, 1H), 3.98 (br s, 2H), 2.24 (br s, 3H). MS m / z 203.1 (MH+).

[0293] Step 4: As described for A-9 in Scheme A, the aniline from step 3 was sulfonylated in the usual manner using 4-methoxybenzenesulfonyl chloride: 1H NMR (DMSO-d 6 ) δ: 9.89 (s, 1H), 9.67 (s, 1H), 7.57 - 7.74 (m, 2H), 7.23 (t, J = 9.2 Hz, 1H), 7.13 (dd, J = 8.8, 5.3 Hz, 1H), 7.02 - 7.10 (m, 2H), 3.82 (s, 3H), 2.00 (s, 3H). MS m / z 373.0 (MH+).

[0294] Step 5: Acetaniline (200 mg, 0.54 mmol) from Step 4 was poured into 1.5 mL of ethanol, followed by the slow addition of a 1:1 mixture of concentrated HCl and water (2 mL). The yellow slurry was then warmed to 80 °C and stirred for 1 h. At that time, add 1 mL of ethanol to improve solubility. Allow the mixture to stir for another 5 h at the same temperature (by this time, the mixture has turned into a clear yellow solution). LCMS analysis at that time showed <3% starting material remaining. The mixture was concentrated to remove most of the ethanol and subsequently cooled on ice. It was basified to pH 5-6 with 4 N NaOH. The resulting suspension was sonicated and the solid was collected by filtration and washed with water. After drying under reduced pressure, 156 mg of the desired product was obtained as a beige solid: 1H NMR (DMSO-d 6 ) δ: 9.53 (s, 1H), 7.53 - 7.72 (m, 2H), 7.00 - 7.14 (m, 2H), 6.95 (dd, J = 10.8, 8.8 Hz, 1H), 6.36 (dd, J = 8.6, 5.1 Hz, 1H), 5.39 (s, 2H), 3.81 (s, 3H). MS m / z 329.0 (M-H).

[0295] Step 6: Using the protocol described in Scheme A for the preparation of inhibitors of Formula I from the synthesis of Intermediate A-5 (Step 1, Example 1), the aniline from Step 5 was reacted with Intermediate A-10 to provide Example 89. Preparation of Example 135:

[0296] Step 1: To a 100 mL round bottom flask was added 2,6-difluoronitrobenzene (1.3 mL, 12.6 mmol) and ethyl cyanoacetate (1.6 mL, 15.1 mmol) in DMF (15 mL). Subsequently, sodium hydride (754 mg, 18.9 mmol) was added slowly at room temperature. The reaction was allowed to stir at room temperature for 15 min. The reaction was quenched with 1 M HCl until the dark red solution turned yellow and then diluted in EtOAc. The organic layer was separated and washed with NH 4 Cl solution followed by brine. The organic layer was dried over MgSO 4 , filtered and then concentrated under reduced pressure. The crude material was dissolved in DMSO (9 mL) and water (1 mL) and transferred to a 20 mL microwave vial. The reaction was heated to 120 °C and stirred for 16 h. The reaction mixture was cooled to room temperature and diluted in EtOAc, then washed with aqueous NH 4 Cl followed by brine. The organic layer was dried over MgSO 4 , filtered and then concentrated under reduced pressure. The crude material was purified by normal phase flash column chromatography using hexanes:EtOAc to afford the desired benzonitrile (2.12 g, 93%) as an orange solid. 1H NMR (400 MHz, DMSO-d 6 ) δ:7.80 (td, J=7.8, 5.5 Hz, 1 H), 7.65 (t, J=9.6 Hz, 1 H), 7.54 (d, J=7.4 Hz, 1H), 4.28 (s, 2H). MS m / z 725.4 (MH+). MS m / z 181.2 (MH+).

[0297] Step 2: Charge the phenylacetonitrile derivative from Step 1 (200 mg, 1.11 mmol) and DMSO (4 mL) into a 25 mL flask. Diphenyl(vinyl)condyl-trifluoromethanesulfonate (479 mg, 1.32 mmol) was then added at room temperature followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (0.37 ml, 2.48 mmol). The mixture was stirred at this temperature for 16 h. Once complete, aqueous NH 4 Cl was added and the aqueous layer was extracted with EtOAc. The organic layer was washed with water and once with brine. The organic layer was dried over MgSO 4 , filtered and concentrated under vacuum. The resulting residue was purified by flash chromatography on a silica gel column using EtOAc / hexanes to yield the desired cyclopropane derivative (138 mg, 60% yield). 1H NMR (400 MHz, CDCl3) δ: 7.47 - 7.59 (m, 1H), 7.29 - 7.41 (m, 2H), 1.69 - 1.85 (m, 2H), 1.29 - 1.39 (m, 2H). MS m / z 207.2 (MH+).

[0298] Step 3: To a 10 mL microwave vial was added the cyclopropane derivative of Step 2 (138 mg, 0.67 mmol). Subsequently, 3 mL of concentrated ammonium hydroxide was added to the reaction. The reaction was heated in the microwave at 130 °C for 1 h. Once complete, the reaction was diluted with water followed by extraction with EtOAc. The organic layer was washed with brine, dried over MgSO 4 , filtered and concentrated under reduced pressure to give 1-(3-amino-2-nitro-phenyl)cyclopropanenitrile (120 mg, 88 %Yield). 1H NMR (400 MHz, CDCl 3 ) δ: 7.27 (d, J = 15.26 Hz, 1H), 6.83 (d, J = 8.38 Hz, 1H), 6.86 (d, J = 7.50 Hz, 1H), 5.36 (br s, 2H), 1.71 (br s, 2H), 1.24 (br s, 2H).

[0299] Step 4: Using the procedure described in Steps 2 and 3 of General Method I of Example 138, the intermediate 1,2-phenylenediamine was reduced and closed to the benzotriazole ring.

[0300] Step 5 (Example 135): Using the procedure described in General Method A, the benzotriazole from Step 4 was coupled with Intermediate I (Ar = 2,3-dichlorophenyl). Preparation of Example 137:

[0301] Step 1: Potassium carbonate (0.35 g, 2.56 mmol) and 2-methoxyethanol (0.40 mL, 5.1 mmol) were added to 3-fluoro-2-nitro-aniline (0.10 g, 0.641 mmol) in DMF (3.2 mL) in solution. The resulting mixture was stirred at 80 °C for 10 h. Water was added and the aqueous mixture was extracted with EtOAc. The organic layers were combined, washed with brine, dried over NA 2 SO 4 , filtered and concentrated. The crude material was purified by column chromatography (silica gel, 0-100% EtOAc / hexanes) to give 3-(2-methoxyethoxy)-2-nitro-aniline (52 mg, 38% yield ). MS m / z 213.1 (MH+).

[0302] Step 2: Using the procedure described in Steps 2 and 3 of General Method I of Example 138, the intermediate 1,2-phenylenediamine was reduced and closed to the benzotriazole ring.

[0303] Step 3 (Example 137): Using the procedure described in General Method A, the benzotriazole from Step 2 was coupled with Intermediate I (Ar = 2,3-dichlorophenyl). Preparation of Examples 160 to 163 (Table 5):

[0304] Step 1: Methoxycarbonylation of 2,4,5-trifluoroaniline was carried out as described in patent WO2020 / 261156.

[0305] Step 2: To a solution of methyl 3-amino-2,5,6-trifluorobenzoate (2.72 g, 13.26 mmol) in DCE / pyridine (1:1, 16 mL) in portions at rt 2,3-Dichlorobenzenesulfonyl chloride (3.91 g, 15.9 mmol) was added. The reaction was heated to 70 °C for 16 h. The reaction was monitored by LCMS. When the reaction is complete, quench with 1 M HCl. The aqueous layer was extracted three times with EtOAc (15 mL). The combined organic layers were washed with brine, dried over MgSO 4 , filtered and evaporated to dryness. The residue was purified by chromatography on a silica gel column using 0-30% EtOAc / hexanes. The pure fractions were collected and evaporated to give methyl 3-((2,3-dichlorophenyl)sulfonamido)-2,5,6-trifluorobenzoate (5.14 g, 91% Yield): m / z = 412.0.

[0306] Step 3: To methyl 3-((2,3-dichlorophenyl)sulfonamido)-2,5,6-trifluorobenzoate (5.14 g, 12.4 mmol) from Step 2 at rt To a solution in 30 mL of THF:MeOH (5:1 ) was added 2 M KOH (37 mL, 74.5 mmol). The reaction was stirred overnight at rt. When the reaction was complete, it was evaporated to dryness and water (30 mL) and diethyl ether (30 mL) were added to the residue. The aqueous layer was washed twice with ether (20 mL). The aqueous layer was acidified to pH=2 with 1 M HCl. The aqueous layer was extracted three times with EtOAc (30 mL). The combined organic layers were washed with brine, dried over MgSO 4 , filtered and evaporated to give 3-((2,3-dichlorophenyl)sulfonylamino)-2,5,6- as a light orange oil Trifluorobenzoic acid (4.5 g, 91% yield). The compound was used as received in the next step: m / z = 398.0.

[0307] Step 4: Add 3-((2,3-dichlorophenyl)sulfonamido)-2,5,6-trifluorobenzoic acid (4.50 g, 11.2 mmol) from step 3 in acetonitrile at rt (30 mL) was added triethylamine (1.71 mL, 12.37 mmol) and diphenylphosphoryl azide (2.91 mL, 13.50 mmol). The reaction was heated to 80 °C overnight. The reaction was cooled to rt and water (30 mL) was added. The aqueous layer was extracted three times with EtOAc (30 mL). The combined organic layers were washed with brine, dried over MgSO 4 , filtered and evaporated to a dark yellow residue. The crude material was purified by chromatography on a silica gel column using 0-50% EtOAc / hexanes. Pure fractions were collected and evaporated to give 2,3-dichloro-N-(2,4,5-trifluoro-3-isocyanatophenyl)benzenesulfonamide (2.29 g, 51% Yield): m / z = 391.0..

[0308] Step 5: Add 2,3-dichloro-N-(2,4,5-trifluoro-3-isocyanatophenyl)benzenesulfonamide (1.35 g, 3.39 mmol) from step 4 in THF ( 17 mL) was added 4 M LiOH (17 mL). The pressure vessel was tightened and heated to 100 °C in an oil bath for 1 h. When the reaction was complete, it was quenched with saturated NH 4 Cl. EtOAc was added and the layers were allowed to separate. The aqueous layer was extracted two more times with EtOAc (20 mL). The combined organic layers were washed with brine, dried over MgSO, filtered and evaporated to give N-(3-amino-2,4,5-trifluorophenyl)-2,3-dichlorobenzene as a brown solid Sulfonamide (1.09 g, 86% yield). The compound was carried on to the next step without further purification: 1H NMR (400 MHz, DMSO-d 6 ) δ: 10.59 (br s, 1H), 7.94 (dd, J = 8.2, 1.6 Hz, 1H), 7.89 (dd , J = 8.2, 1.6 Hz, 1H), 7.51 (dd, J = 8.0 Hz, 1H), 6.34 - 6.43 (m, 1H), 5.72 (s, 2H). m / z = 369.0.

[0309] Step 6: The aniline of step 5 was converted to a pyrimidopyrimidine, where Ar = 2,6-dichlorophenyl, as described under General Method A (Example 36).

[0310] Step 7 (Examples 160-163, Table 5): Using appropriately substituted benzimidazoles (Examples 160, 162, 163) or benzotriazoles (Example 161 ) following the protocol in General Method A, the compound from Step 6 was synthesized. Thiomethyl intermediates are converted to inhibitors. biological activity in vitro biological activity (a) Kinase activity analysis of BRAF, CRAF and ARAF

[0311] Compound preparation: Solid samples of each material in 1 dram vials were suspended in DMSO (Fisher Scientific) at a stock concentration of 20 mM. Stock solutions were kept at -20°C and protected from light. If compound solubility at 20 mM is problematic, change the initial concentration of the DMSO stock solution to 10 mM or 5 mM.

[0312] In vitro enzyme reactions were used to evaluate the intrinsic activity of compounds on BRAF, CRAF and ARAF. For BRAF and CRAF, 0.375 nM of purified GST-tagged kinase (catalog no. B4062-10UG and cat. no. R1656-10UG) together with 75 nM kinase-dead MEK1 substrate (cat. no. 40075; BPS Bioscience) in the presence of 50 mM HEPES pH 7.5, 10 mM MgCl 2 , 1 mM EDTA, 0.01% Brij-35, and Incubate in 2mM DTT buffer. Separate reactions were performed with MEK1 substrate and ATP as blank controls. The ARAF kinase reaction was strictly identical except that the kinase concentration was increased to 3.75 nM (Cat. No. 1768-0000-1; Reaction Biology).

[0313] For compound treatment, 5 μL / well of test substance solutions were placed in 384-well proxy plates (Perkin Elmer) and mixed with 2× concentrated kinase reactions. A dilution series was chosen such that nine concentrations covered the range from 100 nM to 0.01 nM. If necessary (if the compound exhibits low intrinsic potency), the initial concentration of 100 nM was changed to 1 μM or 0.5 μM and further dilutions were made accordingly. The final concentration of DMSO in the assay was set at 0.05%.

[0314] BRAF and CRAF kinase reactions were performed at 30°C for a total of 2 hours and then stopped by a 1 / 2 dilution in ADP-Glo ​​reagent (Catalog # V9102; Promega; Section V912C). The reaction was then incubated for 1 h at room temperature, followed by the addition of one volume of Kinase Detection Reagent (Cat# V9102; Promega; Section V917A). Plates were then equilibrated at room temperature for 30 minutes before detection of luminescence on a Synergy Neo2 plate reader (Biotek). The effect of each compound dilution on BRAF and CRAF kinase activity is expressed as % inhibition and calculated as follows. First, an internal 100% inhibition control (average of luminescence in kinase reactions containing only kinase-dead MEK1 substrate) was subtracted from each data point. DMSO (vehicle) control mean values ​​(set at 0% inhibition) were established and used to calculate % inhibition: %Inhibition=100*(1-((luminescence signal compound) / (luminescence signal DMSO)))

[0315] ARAF kinase reactions were performed at 30°C for a total of 2 hours and then stopped by the addition of EDTA at a final concentration of 40 mM. The reaction was then detected using the AlphaLISA® SureFire® Ultra™ p-MEK 1 / 2 (Ser218 / 222) (PerkinElmer) Kit. Reactions were performed as 5 µL kinase reactions in 384-well proxy culture plates (Perkin Elmer) according to the manufacturer's instructions, followed by overnight incubation of the reactions in a humidified chamber at room temperature. After completion of the detection reaction, the signal was recorded on a Synergy Neo2 disc reader (Biotek) equipped with an AlphaLISA® filter. The effect of each compound dilution on the pMEK signal generated by the ARAF reaction is expressed as % inhibition and calculated as follows. An internal 100% inhibition control (average of luminescence in kinase reactions containing only kinase-dead MEK1 substrate) was included in each plate to measure the pMEK background and was subtracted from each data point. DMSO (vehicle) control mean values ​​(set at 0% inhibition) were also established and used to calculate % inhibition: % inhibition=100*(1-((pMEK signal compound) / (pMEK signal DMSO)))

[0316] IC50 values ​​were obtained by plotting kinase inhibition values ​​using GraphPadPrism (V7.0) or Dotmatics Screening Ultra platforms and fitting dose-activity curves using logarithmic (agonist) and response-variable slope (four parameters) functions And get. Standards included in the ARAF kinase assay were Belvarafenib (MedChem Express Cat. No. HY-109080; CAS No. 1446113-23-0), LXH254 (MedChem Express Cat. No. HY-112089; CAS No. 1800398-38 -2) and BGB283 (Cat. No. HY-18957; CAS No. 1446090-79-4).

[0317] Therefore, all substances reported here are BRAF, CRAF and ARAF ATP competitive kinase inhibitors, as demonstrated by direct inhibition of the enzyme activity in vitro. The BRAF and CRAF inhibitory potencies of the compounds are listed in Tables 2-5, while the ARAF kinase inhibitory potencies of representative analogs are listed in Table A. Preferred examples as defined in the Examples exhibit BRAF IC 50 values ​​< 10 nM and even better examples have BRAF IC 50 values ​​< 1 nM. Preferred examples as defined in the Examples exhibit CRAF IC 50 values ​​< 50 nM and even better examples have CRAF IC 50 values ​​< 10 nM. Table A. ARAF Kinase Inhibition Results example Kinase IC50(nM) ARAF 98 ** 112 * 114 *** 119 ** 128 * 129 ** Bevarafini * BGB283 * LXH254 *

[0318] For ARAF biochemical kinase assays, * indicates IC50 >20 nM, ** indicates 10-20 nM IC50 range and *** indicates IC50 < 10 nM. (b) General cell culture method

[0319] All cancer cell lines (A375, A101D, A2058, RKO, HT29 SK-MEL 30, IPC298, HepG2, HCT-116, Lovo, SW620, SW480, NCI-H358, NCI-H2122, Calu-6, NCIH2087, NCIH1755, NCIH1666 and Mewo) were obtained from ATCC and cultured in RPMI-1640 medium (Gibco) supplemented with 5% heat-inactivated fetal bovine serum (FBS, Wisent) at 5% CO 2 and 37°C. Cells were maintained in T175 flasks (Greiner). The cells were washed once in 10 mL of room temperature phosphate buffered saline (Phosphate Buffered Saline; PBS; Wisent) by removing the culture medium and at 37°C with 2 mL of 0.05% trypsin (Thermo-Fisher). Incubate for passage. Trypsin was then inactivated by adding complete growth medium and cells were then re-plated in T175 dishes at appropriate dilutions. All cell lines were routinely tested for mycoplasma contamination. Tissue types and mutation status of each cell line can be found in Table B. Table B. RAS-ERK pathway mutation status of tissue types and cancer cell lines (CCL) for pERK and antiproliferative profiling of substances described in this application. cell line organization type mutant state A375 skin BRAF V600E A101D skin BRAF V600E A2058 skin BRAF V600E RKO the colon BRAF V600E HT29 the colon BRAF V600E NCIH2087 lung BRAF L597V; KRAS Q61K NCIH1755 lung BRAF G469A NCIH1666 lung BRAF G466V SK-MEL30 skin NRAS-Q61K IPC298 skin NRAS-Q61L HepG2 liver NRAS-Q61L HCT-116 the colon KRAS G13D Lovo the colon KRAS-G13D SW620 the colon KRAS-G12V SW480 the colon KRAS G12D NCI-H358 lung KRAS-G12C NCI-H2122 lung KRAS-G12C Calu-6 lung KRAS Q61K Mewo skin NF1 LOF (c) Phospho-ERK inhibition in cultured human cancer cell lines measured by AlphaLISA® SureFire® Ultra ™ p-ERK 1 / 2 (Thr202 / Tyr204)

[0320] AlphaLISA® SureFire® Ultra™ p-ERK 1 / 2 (Thr202 / Tyr204) assays were grown in 100 μL of complete RPMI-1640 plated in 96-well flat-bottomed clear dishes (Costar) at the densities indicated in Table C performed on cells in culture medium. Cells were maintained overnight at 37°C under 5% CO 2 and subsequently treated with a dilution series of compounds for one hour. Cell density in units of cell number / cm 2 corresponds to the number of cells divided by the area of ​​one well of a 96-well plate (0.143 cm 2 ). Table C. For each cancer cell line, the number of cells plated in each well. cell line Cells / well A375 15,000 NCIH2087 30,000 NCIH1755 30,000 NCIH1666 30,000 SK-MEL30 24,000 IPC298 20,000 HepG2 20,000 HCT-116 22,000 Lovo 20,000 SW620 30,000 SW480 15,000 NCI-H358 20,000 NCI-H2122 24,000 Calu-6 15,000 Mewo 20,000

[0321] In the dilution series, 100 μL / well of the test substance dilution prepared in complete RPMI-1640 growth medium was added to the cells. Dilution series were chosen such that ten concentrations covered the range from 30 µM or 10 µM to 0.33 nM. If necessary, the initial concentration of 10 μM was increased to 100 μM or decreased to 1 μM (as in the case of A375 and NCIH1666 cells, which are generally more sensitive to the compound) and further dilutions were made accordingly. The final concentration of DMSO in the assay was set at 0.5%.

[0322] Following treatment, medium was removed and cells were lysed in 50 µL of 1× AlphaScreen Ultra Lysis Buffer (Perkin Elmer). AlphaLISA® SureFire® Ultra™ p-ERK 1 / 2 (Thr202 / Tyr204) (PerkinElmer) reactions were performed according to the manufacturer's instructions in 384-well surrogate culture plates (Perkin Elmer) using 5 µL of cell lysate, followed by incubation at room temperature. , incubate the reaction overnight in a humidified chamber. After the reaction was complete, the signal was recorded on an EnVision disc reader (Perkin Elmer) using the built-in AlphaLISA® setup.

[0323] The effect of each compound dilution on pERK signal was expressed as % inhibition and calculated as follows. An internal 100% inhibition control (1 μΜ trametinib, catalog number HY-10999; MedChem Express; CAS number 871700-17-3) was included in each plate and was used as a measure of the pERK background. First, the value obtained for trametinib was subtracted from each data point. DMSO (vehicle) control mean values ​​(set at 0% inhibition) were established and used to calculate % inhibition: % inhibition = 100*(1-((pERKsignal compound) / (pERKsignal DMSO)))

[0324] The ability of each compound to inhibit pERK signaling was expressed as an IC50 value by plotting the inhibition value for each data point of the dilution series using GraphPad Prism (V7.0) and using the log (agonist) and response-variable slope ( Four parameters) function to fit the obtained curve obtained.

[0325] Abnormal pERK induction, when present, was inferred from negative % inhibition values ​​observed in pERK IC50 curves for compounds. To classify a compound as a paradoxical inducer of pERK, the % inhibition of the minimum data point (% Y MIN ) of the dose-activity curve is set below -20%, which is considered to be within the range of expected assay variation (e.g., with % Y MIN). Compounds with Y MIN = -30% or -50% or -150% were considered to produce aberrant induction of the pathway. Compounds showing an IC50 curve with Y MIN = -10% were considered not to produce aberrant activation of the pathway). Thus, a compound inhibits this pathway in a given cell line without paradoxical induction when the following criteria are met: 1. The % inhibition at the highest tested dose (30 µM, 10 µM or 1 µM) exceeds 50%. 2. The %Y MIN of the IC 50 curve is greater than -20%; where Y MIN corresponds to the data point having the lowest value in the IC 50 curve of the compound.

[0326] Some variation in inhibition values ​​is to be expected in such experiments, as is well known to those skilled in the art. Y MIN values ​​of ±20% were considered within experimental error and not significant. Therefore, compounds with only negative values ​​beyond the assay variation (approximately >20%) are considered to induce aberrant activation of signaling cascades and are excluded from the scope of the present disclosure. Figure 1 provides the IC for a compound that induces activation of the aberrant pathway (PLX4720, commercially available from Selleck Chemicals; CAS No. 918505-84-7) and a representative compound as described herein that exhibits an unexpected and unique no-induction profile Visualization of 50 curves.

[0327] Figure 1 shows compounds as described herein that do not induce paradoxical induction of pERK signaling (Y MIN >-20%) in RAS mutant HCT116 cells (Examples 80 and 81) and result in strong induction in the same cell lines (Y MIN~-600%) Representative IC 50 inhibitory dose-response curve of the compound (PLX4720) for this pathway.

[0328] Notably, according to the criteria described above, the compounds as defined herein do not induce abnormal activation of the pathway. Further illustration of this highly desirable property can be illustrated using immunoblot analysis as described below and depicted in Figure 2 for the no-inducing compound (Example 80) and the inducing agent PLX4720.

[0329] For immunoblot analysis, 500,000 HCT-116 cells were plated in 1 mL of complete RPMI-1640 growth medium in 24-well flat-bottomed clear dishes (Costar). Cells were maintained overnight at 37°C under 5% CO 2 and subsequently treated with a dilution series of compounds for one hour. Cells were then washed once in PBS and washed in 250 µL of Igepal lysis buffer (50 mM Lyse in Tris-HCl pH 7.5, 150 mM NaCl, 1% Igepal-CA630, 1 mM EDTA, 10% glycerol) at 4 °C for 15 min with gentle shaking. Cell extracts were then clarified by centrifugation at 20,000 g for 10 minutes at 4°C. The clarified lysate was then transferred to a new tube on ice and then incubated in loading buffer (100 mM Tris-HCl pH 6.8, 4% SDS, 0.2% bromophenol blue, 20% glycerol, 200 mM β-mercaptoethanol ) for 5 minutes, then separated by SDS-PAGE and transferred to a nitrocellulose membrane (PALL). Membranes were blocked for 1 hour in Tris-buffered saline 0.2% Tween-20 (TBST; 10 mM Tris-HCl pH 8.0, 0.2% Tween-20, 150 mM NaCl) containing 2% BSA (Sigma) and then compared with Dilutions of the following primary antibodies prepared in TBST were incubated together overnight at 4°C: anti-pERK (1:2000 dilution; Sigma-Aldrich; Cat# M9692), anti-total ERK (1:1000 dilution; Cell Signaling Technology; Cat. No. 4695), anti-pMEK (1:1000 dilution; Cell Signaling Technology; Cat. No. 9121) and anti-total MEK (1:1000 dilution; Cell Signaling Technology; Cat. No. 9122). Secondary anti-mouse HRP and anti-rabbit HRP (Jackson Immunoresearch Labs; catalog numbers 115-035-146 and 111-035-144, respectively) were prepared in TBST at 1:5000 and 1:10000 dilutions, respectively. Immunoblots were revealed by exposure to X-ray film after incubation in ECL reagent for one minute.

[0330] Figure 2 shows immunoblot analysis of RAS mutant HCT-116 cells treated with a representative compound (Example 80; upper panel) that did not induce paradoxical induction of pERK or pMEK signaling, and compared to Next, treated with a compound (PLX4720; lower panel) that induces the pathway in the same cell line. Total MEK and total ERK signals were also detected by immunoblotting to ensure equal loading of protein samples under different conditions. Compound concentrations in micromolar are indicated above the immunoblot plots. The concentration range used for treatment was the same as Example 80 and PLX4720.

[0331] As shown in Tables 2-5, Example Compounds 1 to 163 exhibited pERK inhibitory activity in HCT-116 cell line with colonic G13D Ras mutation. In addition, some examples also demonstrate paradoxical induction-free inhibition of pERK signaling in the SW480 colon cell line carrying the G12D allele of KRAS (Tables 2-5). In addition, some examples from Tables 2-5 were also tested for inhibition of pERK in A375 cells containing the BRAF V600E driver mutation and found to be active as well (Table D). In Table 2-5, all compound examples 1-163 showed pERK IC 50 values ​​<30 μM in HCT116 cell line. Preferred compounds have IC50 values ​​of 1-10 µM, more preferred compounds have IC50 values ​​of 0.5-1 µM, and even more preferred compounds have IC50 values ​​of <0.5 µM.

[0332] The pERK inhibitory activity of representative compounds as defined herein was also tested on additional tumor cells carrying various NRAS, KRAS and NF1 alleles and representing a large number of tissue types (i.e. SK-MEL 30, IPC298, HepG2, HCT - 116, Lovo, SW620, SW480, NCI-H358, NCI-H2122, Calu-6 and Mewo; Table D and genotype refer to Table B) cancer cell lines exhibited good to excellent pERK inhibitory activity. The pERK inhibitory activity of the compounds was stronger in cancer cell lines carrying BRAF alleles (A375, A101D, A2058, RKO, HT29, NCIH2087, NCIH1755 and NCIH1666) (Table D).

[0333] Table D (D-1 and D-2). Non-induction pERK IC 50 values ​​and anti-proliferation EC 50 values ​​of selected compounds in a group of RAS mutant cancer cell lines (see Table B for genotype) and BRAF V600E mutation A375. D-1. example A375 A2058 HT-29 RKO A101D SK-MEL30 IPC298 HepG2 HCT116 ERK ERK ERK ERK ERK ERK ERK ERK ERK proliferate proliferate proliferate proliferate proliferate proliferate proliferate proliferate proliferate 98 +++ (10) ++ (13) +++ (27) ++ (-6.0) 98 ⁎⁎⁎ ⁎⁎⁎ ⁎⁎⁎ ⁎⁎⁎ ⁎⁎⁎ ⁎⁎⁎ ⁎⁎⁎ ⁎⁎⁎ ⁎⁎⁎ 112 +++ (6) ++ (1) ++ (-10) + (-0.8) 112 ⁎⁎⁎ ⁎⁎⁎ ⁎⁎⁎ ⁎⁎⁎ ⁎⁎⁎ ⁎⁎⁎ ⁎⁎⁎ ⁎⁎ 114 ++ (-9) ++ (1) ++ (14) + (-4.9) 114 ⁎⁎⁎ ⁎⁎⁎ ⁎⁎⁎ ⁎⁎⁎ ⁎⁎⁎ ⁎⁎ ⁎⁎⁎ ⁎⁎⁎ ⁎⁎ 119 ++ (-12) ++ (-4) ++ (30) + (-7) 119 ⁎⁎⁎ ⁎⁎⁎ ⁎⁎⁎ ⁎⁎⁎ ⁎⁎⁎ ⁎⁎⁎ ⁎⁎⁎ ⁎⁎ 128 +++ (13) ++ (8) +++ (34) ++ (7) 128 ⁎⁎⁎ ⁎⁎⁎ ⁎⁎⁎ ⁎⁎⁎ ⁎⁎⁎ ⁎⁎⁎ ⁎⁎⁎ ⁎⁎⁎ ⁎⁎⁎ 129 +++ (16) ++ (17) ++ (-2) ++ (-8) 129 ⁎⁎⁎ ⁎⁎⁎ ⁎⁎⁎ ⁎⁎⁎ ⁎⁎⁎ ⁎⁎⁎ ⁎⁎⁎ ⁎⁎⁎ ⁎⁎ Belv. +++ (-45) ++ (-63) ++ (-36) ++ (-46) Belv. ⁎⁎⁎ ⁎⁎⁎ ⁎⁎⁎ ⁎⁎⁎ ⁎⁎⁎ ⁎⁎⁎ ⁎⁎

[0334] In pERK: + indicates IC 50 >300 nM, ++ indicates 30-300 nM IC 50 range and +++ indicates IC 50 < 30 nM. For proliferation: ⁎ indicates EC 50 >3000 nM, ⁎⁎ indicates 300-3000 nM EC 50 range, ⁎⁎⁎ indicates EC 50 < 300 nM. Belv.: Belvalafini. Values ​​in parentheses are % inhibition. A blank means that the value was not determined. D-2. example Lovo NCI-H358 SW620 Calu6 NCI-H2122 SW480 Mewo NCIH2087 NCIH1755 ERK ERK ERK ERK ERK ERK ERK ERK ERK proliferate proliferate proliferate proliferate proliferate proliferate proliferate proliferate proliferate 98 ++ (27) ++ (20) ++ (36) ++ (5) ++ (26) ++ (-1) ++ (9) +++ (6) +++ (9) 98 ⁎⁎⁎ ⁎⁎⁎ ⁎⁎ ⁎⁎⁎ ⁎⁎ ⁎⁎ ⁎⁎⁎ ⁎⁎⁎ ⁎⁎⁎ 112 ++ (-1) ++ (-8) ++ (11) ++ (1) ++ (-15) ++ (-7) +++ (12) +++ (-7) +++ (12) 112 ⁎⁎⁎ ⁎⁎⁎ ⁎⁎ ⁎⁎ ⁎⁎ ⁎⁎ ⁎⁎ ⁎⁎ 114 +++ (4) + (-4) + (-13) ++ (8) ++ (0) ++ (1) ++ (-12) ++ (2) ++ (-5) 114 ⁎⁎⁎ ⁎⁎⁎ ⁎ ⁎ ⁎ ⁎ ⁎⁎ ⁎⁎ ⁎ 119 ++ (0) ++ (29) ++ (-1) ++ (-16) + (-3) ++ (-5) ++ (-12) +++ (26) ++ (0) 119 ⁎⁎ ⁎ ⁎ 128 ++ (-12) ++ (14) ++ (11) ++ (1) + (-4) ++ (-14) ++ (-7) +++ (-7) +++ (1) 128 ⁎⁎⁎ ⁎⁎⁎ ⁎⁎⁎ ⁎⁎⁎ ⁎⁎ ⁎⁎ ⁎⁎⁎ ⁎⁎⁎ ⁎⁎⁎ 129 ++ (-2) ++ (-3) + (-7) ++ (-1) + (-14) ++ (3) ++ (-5) +++ (3) +++ (-2) 129 ⁎⁎⁎ ⁎⁎⁎ ⁎⁎ ⁎⁎ ⁎⁎ ⁎⁎ ⁎⁎⁎ ⁎⁎ ⁎⁎ Belv. +++ (-12) ++ (-122) ++ (-151) ++ (-39) ++ (-9) ++ (-100) ++ (-116) +++ (-31) ++ (-79) Belv. ⁎⁎⁎ ⁎⁎ ⁎⁎ ⁎⁎⁎ ⁎⁎ ⁎⁎ ⁎⁎ ⁎⁎⁎ ⁎

[0335] In pERK: + indicates IC 50 >300 nM, ++ indicates 30-300 nM IC 50 range and +++ indicates IC 50 < 30 nM. For proliferation: ⁎ indicates EC50 >3000 nM, ⁎⁎ indicates 300-3000 nM EC50 range, ⁎⁎⁎ indicates EC50 <300 nM. Belv.: Belvalafini. Values ​​in parentheses are % inhibition. A blank means that the value was not determined.

[0336] For RAS mutant cancer cell lines, the %Y min values ​​of the pERK IC50 curves were all higher than -20% and were considered to show minimal or no induction and therefore the compound did not cause detectable pathway abnormalities in this group of cancer cell lines activation. In contrast, comparisons of the molecule bevarafenib (obtained from MedChem Express, Cat. No. HY-109080; CAS No. 1446113-23-0) showed mild to strong pathway induction in the same cell lines (in the In 11 out of 13 RAS mutant cell lines tested, Y MIN<-30%). (d) Proliferation inhibition of cultured human cancer cell lines (CCL) measured using CellTiter-Glo® reagent

[0337] The CellTiter-Glo® Viability Assay was plated at the density indicated in Table E (for each CCL, the number of cells plated per well of the 96-well plate used for the CellTiter-Glo® Cell Viability Assay) in 96 This was performed on cells in 40 μL of complete RPMI-1640 growth medium in well flat-bottomed white opaque culture dishes (Greiner or Corning). Cell density in units of cell number / cm 2 corresponds to the number of cells divided by the area of ​​one well of a 96-well plate (0.32 cm 2 ). Cells were maintained overnight at 37°C under 5% CO2 and subsequently treated with a dilution series of compounds for 3 days. Table E. Number of cells plated per well of 96-well plates for CellTiter-Glo® Cell Viability Assay cell line Cells / well A375 2000 A101D 2000 A2058 2000 RKO 2000 HT29 2000 NCIH2087 3600 NCIH1755 3600 NCIH1666 3600 SK-MEL30 2400 IPC298 2000 HepG2 7200 HCT-116 1500 Lovo 4800 SW620 3600 SW480 4800 NCI-H358 2400 NCI-H2122 4800 Calu-6 2400 Mewo 2400

[0338] In the dilution series, 100 μL / well of the test substance dilution prepared in complete RPMI-1640 growth medium was added to cells initially plated in 100 μL of growth medium. Dilution series were chosen such that ten concentrations covered the range from 30 µM or 10 µM to 0.33 µM. If necessary (as in the case of A375 cells, which are more sensitive to the compound), the initial concentration of 10 μM was reduced to 1 μM and further dilutions were made accordingly. The final concentration of DMSO in the assay was set at 0.5%.

[0339] After 3 days of incubation, the growth medium was removed by aspiration and 60 μL of diluted CellTiter-Glo® Reagent (10 μL CellTiter-Glo® Reagent + 50 μL PBS) was added to each well. Cells were lysed and equilibrated in CellTiter-Glo® reagent by incubation on a plate shaker for 5 min, followed by 10 min at room temperature. Luminescent signals were subsequently acquired on a Synergy Neo2 disk reader (Biotek).

[0340] The effect of each compound dilution on the proliferation of cancer cell lines was expressed as % inhibition and calculated as follows. An internal 100% inhibition control (1 μΜ Trametinib; Cat# HY-10999; MedChem Express; CAS# 871700-17-3) was included in each plate and was used as a measure of the CellTiter-Glo® signal background. Values ​​obtained by subtracting trametinib from each data point. DMSO (vehicle) control mean values ​​(set at 0% inhibition) were established and used to calculate % inhibition: % inhibition=100*(1-((CellTiter-Glo® signal compound) / (CellTiter-Glo® signal DMSO)))

[0341] The ability of each compound to inhibit proliferation was expressed as an EC50 value by plotting the effect of each data point of the dilution series using the GraphPad Prism (V7.0) or Dotmatics Screening Ultra platforms and using the logarithm (agonist) versus the response- A variable slope (four parameter) function was used to fit the obtained curves.

[0342] As shown in Table D, the active substances were active in a variety of tissue types (i.e., SK-MEL 30, IPC298, HepG2, HCT-116, Lovo, SW620, SW480, NCI-H358, NCI-H2122, Calu-6, and Mewo ; Table D and genotype reference table B) various NRAS mutations, KRAS mutations and NF1 mutation cancer cell lines exhibit antiproliferative activity. Antiproliferative activity was generally even stronger in cell lines carrying BRAF driver mutations (Table D). It is noteworthy that in KRAS mutant and BRAF mutant cell lines there is a fairly good correlation between the IC50 values ​​for the reduction in pERK and the EC50 values ​​for the antiproliferative activity of the substances (Table D). The compounds of the invention are thus effective against several tumor types and can be used in these and other indications. This demonstrates the usefulness of the compounds defined herein for the treatment of different types of tumors. (e) Results

[0343] Exemplary compound structures, synthetic methods and biological results are summarized in Tables 2 to 5 below. Each of these tables is followed by a respective table summarizing the chemical characteristics of the compounds. Table 2 example R 2 HCT116 pERK IC 50(µM) (Y min%) SW480 pERK IC 50(µM) (Y min%) Kinase IC 50 BRAF (nM) Kinase IC 50 CRAF (nM) 1 B1 + (1) ++ (6) * § 2 B2 ++ (-14) ++ (5) 3 B3 ++ (-7) ++ (9) 4 B4 ++ (-5) ++ (-2) 5 B5 + (8) ++ (8) 6 B6 + (-10) ++ (1) 7 B7 + (7) ++ (17) 8 B8 ++ (-3) ++ (15) 9 B9 + (1) + (-3) 10 B10 + (9) ++ (-9) 11 B11 ++ (10) ++ (8) 12 B12 ++ (-7) ++ (-10) 13 B13 + (-2) + (4) 14 B14 ++ (-5) ++ (-6) 15 B15 + (-3) + (0) 16 B16 + (1) ++ (3) 17 B17 + (5) ++ (3) 18 B18 + (4) ++ (11) 19 B19 + (-4) ++ (4) 20 B20 ++ (7) ++ (12) twenty one B21 ++ (2) ++ (9) twenty two B22 ++ (-1) ++ (-5) twenty three B23 ++ (0) ++ (-7) twenty four B24 + (10) ++ (13) 25 B25 + (7) + (-6) 26 B26 ++ (11) ++ (9) 27 B27 + (-6) 28 B28 ++ (3) ++ (-3) 29 B29 + (-9) + (3) 90 B36 ++ (-9.2) ** §§ 91 B53 ++ (-8) * §§ 92 B54 ++ (-12) ** §§§

[0344] For pERK analysis, + indicates the 10-30 µM IC50 range, ++ indicates the 1-10 µM IC50 range, +++ indicates the 0.5-1 µM IC50 range and ++++ indicates the IC50 <0.5 µM. The % Ymin value indicates the lowest value of each IC50 curve. Compounds exhibiting IC50 curves with Ymin values ​​above -20% were considered to show minimal or no induction and did not cause aberrant activation of detectable pathways. For BRAF biochemical kinase assays, * indicates IC50 >10 nM, ** indicates 1-10 nM IC50 range and *** indicates IC50 < 1 nM. For CRAF biochemical kinase assays, § indicates IC50 >50 nM, §§ indicates 10-50 nM IC50 range and §§§ indicates IC50 < 10 nM. Characteristics of Compounds in Table 2 example resolve resolution HRMS m / z (MH+) 1H NMR (400 MHz) 1 A 491.1 1H NMR (DMSO-d 6) δ: 10.14 (s, 1H), 10.03 (s, 1H), 9.27 (s, 1H), 8.49 (s, 1H), 7.56 – 7.76 (m, 2H), 7.16 – 7.31 (m, 2H), 7.06 – 7.12 (m, 2H), 3.81 (s, 3H), 2.68 (s, 3H) 2 B 521.1 1H NMR (DMSO-d 6) δ: 10.12 (s, 1H), 10.04 (s, 1H), 9.29 (s, 1H), 8.48 (s, 1H), 7.17 – 7.33 (m, 4H), 7.09 (d , J = 8.6 Hz, 1H), 3.83 (s, 3H), 3.72 (s, 3H), 2.71 (s, 3H) 3 B 525.3 1H NMR (DMSO-d 6) δ: 10.06 (s, 1H), 9.88 (s, 1H), 9.29 (s, 1H), 8.50 (s, 1H), 7.98 (d, J = 5.0 Hz, 1H), 7.38 (d, J = 5.0 Hz, 1H), 7.34 (td, J = 8.7, 5.8 Hz, 1H), 7.23 (td, J = 9.1, 0.9 Hz, 1H), 3.85 (s, 3H), 2.71 (s , 3H) 4 B 503.5 1H NMR (DMSO-d 6) δ: 10.08 (s, 1H), 10.04 (s, 1H), 9.30 (s, 1H), 8.50 (s, 1H), 7.56 – 7.63 (m, 1H), 7.50 (dd , J = 8.4, 2.0 Hz, 1H), 7.26 (td, J = 9.1, 6.0 Hz, 1H), 7.20 (t, J = 9.0 Hz, 1H), 6.90 (d, J = 8.5 Hz, 1H), 4.62 (t, J = 8.8 Hz, 2H), 3.21 (t, J = 8.8 Hz, 2H), 2.71 (s, 3H) 5 B 486.1 1H NMR (DMSO-d 6) δ: 10.78 (s, 1H), 10.04 (s, 1H), 9.29 (s, 1H), 8.49 (s, 1H), 8.10 (dd, J = 7.2, 1.4 Hz, 1H ), 7.95 (dd, J = 8.2, 1.0 Hz, 1H), 7.90 (td, J = 7.5, 1.4 Hz, 1H), 7.84 (td, J = 7.4, 1.0 Hz, 1H), 7.34 (td, J = 8.7, 5.7 Hz, 1H), 7.26 (t, J = 9.2 Hz, 1H), 2.69 (s, 3H) 6 B 505.1 1H NMR (DMSO-d 6) δ: 10.19 (s, 1H), 10.05 (s, 1H), 9.30 (s, 1H), 8.50 (s, 1H), 7.16 – 7.32 (m, 4H), 7.06 (d , J = 8.2 Hz, 1H), 6.15 (s, 2H), 2.71 (s, 3H) 7 B 516.1 1H NMR (DMSO-d 6) δ: 10.58 (s, 1H), 10.05 (s, 1H), 9.29 (s, 1H), 8.48 (s, 1H), 7.84 (d, J = 9.0 Hz, 1H), 7.67 (d, J = 2.7 Hz, 1H), 7.40 (dd, J = 9.0, 2.7 Hz, 1H), 7.33 (td, J = 8.6, 5.9 Hz, 1H), 7.25 (t, J = 9.0 Hz, 1H ), 3.88 (s, 3H), 2.69 (s, 3H) 8 A 509.1 1H NMR (DMSO-d 6) δ: 10.40 (s, 1H), 10.07 (s, 1H), 9.29 (s, 1H), 8.47 (s, 1H), 7.61 (t, J = 8.6 Hz, 1H), 7.29 (td, J = 8.2, 5.9 Hz, 1H), 7.22 (t, J = 9.4 Hz, 1H), 7.06 (dd, J = 12.1, 2.0 Hz, 1H), 6.89 (dd, J = 9.0, 2.0 Hz , 1H), 3.83 (s, 3H), 2.71 (s, 3H) 9 B 472.4 1H NMR (DMSO-d 6) δ: 10.12 (s, 1H), 9.81 (s, 1H), 9.31 (s, 1H), 8.54 (s, 1H), 7.48 (td, J = 8.6, 5.8 Hz, 1H ), 7.26 (td, J = 9.1, 0.9 Hz, 1H), 5.33 (dt, J = 53.3, 3.5 Hz, 1H), 3.36 – 3.52 (m, 3H), 3.31 (td, J = 9.9, 6.6 Hz, 1H), 2.73 (s, 3H), 1.96 – 2.17 (m, 2H) 10 B 504.1 1H NMR (DMSO-d 6) δ: 10.81 (s, 1H), 10.05 (br s, 1H), 9.29 (s, 1H), 8.49 (s, 1H), 8.19 (dd, J = 8.6, 2.7 Hz, 1H), 7.99 (dd, J = 9.0, 5.5 Hz, 1H), 7.79 (td, J = 8.4, 2.7 Hz, 1H), 7.36 (td, J = 8.6, 5.9 Hz, 1H), 7.27 (t, J = 9.0 Hz, 1H), 2.70 (s, 3H) 11 B 484.2 1H NMR (DMSO-d 6) δ: 10.11 (s, 1H), 9.70 (s, 1H), 9.31 (s, 1H), 8.53 (s, 1H), 7.49 (td, J = 8.8, 5.7 Hz, 1H ), 7.25 (td, J = 9.1, 1.3 Hz, 1H), 3.91 – 4.01 (m, 1H), 3.29 – 3.34 (m, 2H), 3.21 – 3.29 (m, 2H), 3.19 (s, 3H), 2.73 (s, 3H), 1.84 – 1.97 (m, 2H) 12 A,B 505.1 1H NMR (DMSO-d 6) δ: 10.17 (s, 1H), 10.03 (s, 1H), 9.29 (s, 1H), 8.48 (s, 1H), 7.67 (d, J = 8.6 Hz, 1H), 7.26 (td, J = 9.0, 5.9 Hz, 1H), 7.19 (t, J = 9.0 Hz, 1H), 6.95 (d, J = 2.3 Hz, 1H), 6.86 (dd, J = 8.8, 2.5 Hz, 1H ), 3.79 (s, 3H), 2.71 (s, 3H), 2.57 (s, 3H) 13 B 472.4 1H NMR (DMSO-d 6) δ: 10.12 (s, 1H), 9.81 (s, 1H), 9.31 (s, 1H), 8.54 (s, 1H), 7.48 (td, J = 8.6, 5.8 Hz, 1H ), 7.26 (td, J = 9.1, 0.9 Hz, 1H), 5.33 (dt, J = 53.3, 3.5 Hz, 1H), 3.36 – 3.52 (m, 3H), 3.31 (td, J = 9.9, 6.6 Hz, 1H), 2.73 (s, 3H), 1.96 – 2.17 (m, 2H) 14 B 559.1 1H NMR (DMSO-d 6) δ: 10.29 (s, 1H), 10.04 (s, 1H), 9.29 (s, 1H), 8.48 (s, 1H), 7.95 (d, J = 9.0 Hz, 1H), 7.41 (d, J = 2.7 Hz, 1H), 7.37 (dd, J = 9.0, 2.7 Hz, 1H), 7.30 (td, J = 8.6, 5.9 Hz, 1H), 7.23 (t, J = 9.4 Hz, 1H ), 3.89 (s, 3H), 2.68 (s, 3H) 15 B 529.0 1H NMR (DMSO-d 6) δ: 10.63 (s, 1H), 10.04 (s, 1H), 9.29 (s, 1H), 8.48 (s, 1H), 7.91 (d, J = 2.3 Hz, 1H), 7.87 (d, J = 8.6 Hz, 1H), 7.61 (dd, J = 8.4, 2.2 Hz, 1H), 7.30 (td, J = 8.6, 5.9 Hz, 1H), 7.22 (t, J = 9.0 Hz, 1H ), 2.69 (s, 3H) 16 B 557.0 559.0 1H NMR (DMSO-d 6) δ: 10.70 (s, 1H), 10.04 (s, 1H), 9.29 (s, 1H), 8.48 (s, 1H), 7.87 (dd, J = 9.8, 1.0 Hz, 1H ), 7.56 – 7.67 (m, 2H), 7.33 (td, J = 8.6, 5.9 Hz, 1H), 7.24 (t, J = 9.2 Hz, 1H), 2.68 (s, 3H) 17 B 553.0 555.0 1H NMR (DMSO-d 6) δ: 10.43 (s, 1H), 10.03 (s, 1H), 9.29 (s, 1H), 8.49 (s, 1H), 7.69 (d, J = 1.2 Hz, 1H), 7.62 (d, J = 8.2 Hz, 1H), 7.56 (dd, J = 8.6, 2.0 Hz, 1H), 7.29 (td, J = 9.8, 5.9 Hz, 1H), 7.22 (t, J = 9.8 Hz, 1H ), 2.71 (s, 3H), 2.59 (s, 3H) 18 B 475.1 1H NMR (DMSO-d 6) δ: 10.24 (br s, 1H), 10.03 (s, 1H), 9.29 (s, 1H), 8.50 (s, 1H), 7.53 – 7.77 (m, J = 8.2 Hz, 2H), 7.35 – 7.42 (m, J = 7.8 Hz, 2H), 7.16 – 7.30 (m, 2H), 2.71 (s, 3H), 2.36 (s, 3H) 19 B 521.1 1H NMR (DMSO-d 6) δ: 10.04 (br s, 1H), 9.29 (s, 1H), 8.48 (s, 1H), 7.58 (d, J = 9.0 Hz, 1H), 7.26 (td, J = 8.7, 5.7 Hz, 1H), 7.15 (td, J = 9.4, 1.0 Hz, 1H), 6.69 (d, J = 2.3 Hz, 1H), 6.58 (dd, J = 8.6, 2.3 Hz, 1H), 3.83 ( s, 3H), 3.82 (s, 3H), 2.68 (s, 3H) 20 B 475.1 1H NMR (DMSO-d 6) δ: 10.33 (s, 1H), 10.03 (s, 1H), 9.29 (s, 1H), 8.49 (s, 1H), 7.75 (dd, J = 8.0, 1.0 Hz, 1H ), 7.52 (td, J = 7.4, 1.2 Hz, 1H), 7.40 (d, J = 7.8 Hz, 1H), 7.34 (t, J = 7.6 Hz, 1H), 7.26 (td, J = 9.0, 5.9 Hz , 1H), 7.19 (t, J = 9.4 Hz, 1H), 2.68 (s, 3H), 2.61 (s, 3H) twenty one B 495.0 1H NMR (DMSO-d 6) δ: 10.53 (s, 1H), 10.06 (br s, 1H), 9.29 (s, 1H), 8.48 (s, 1H), 7.91 (dd, J = 7.8, 1.6 Hz, 1H), 7.62 – 7.72 (m, 2H), 7.47 – 7.54 (m, 1H), 7.17 – 7.33 (m, 2H), 2.68 (s, 3H) twenty two B 509.0 1H NMR (DMSO-d 6) δ: 10.43 (s, 1H), 10.03 (s, 1H), 9.29 (s, 1H), 8.48 (s, 1H), 7.70 (d, J = 8.2 Hz, 1H), 7.55 (s, 1H), 7.43 (dd, J = 8.6, 2.0 Hz, 1H), 7.29 (td, J = 9.0, 6.7 Hz, 1H), 7.22 (t, J = 9.0 Hz, 1H), 2.71 (s , 3H), 2.60 (s, 3H) twenty three B 489.1 1H NMR (DMSO-d 6) δ: 10.26 (br s, 1H), 10.03 (s, 1H), 9.29 (s, 1H), 8.49 (s, 1H), 7.63 (d, J = 8.2 Hz, 1H) , 7.09 – 7.32 (m, 4H), 2.70 (s, 3H), 2.57 (s, 3H), 2.30 (s, 3H) twenty four B 454.1 1H NMR (DMSO-d 6) δ: 10.11 (br s, 1H), 9.31 (s, 1H), 8.52 (s, 1H), 7.49 (td, J = 8.8, 5.9 Hz, 1H), 7.25 (t, J = 8.6 Hz, 1H), 3.18 (t, J = 6.7 Hz, 4H), 2.73 (s, 3H), 1.74 – 1.87 (m, 4H) 25 B 470.4 1H NMR (CDCl 3 ) δ: 9.33 (s, 1H), 8.74 (s, 1H), 8.15 (br s, 1H), 7.60 (td, J = 8.8, 5.4 Hz, 1H), 7.22 (br s, 1H ), 7.08 (td, J = 9.1, 1.9 Hz, 1H), 4.13 – 4.20 (m, 1H), 4.04 – 4.11 (m, 2H), 3.84 – 3.96 (m, 2H), 3.26 (s, 3H), 2.71 (s, 3H) 26 B 484.4 1H NMR (DMSO-d 6) δ: 10.11 (s, 1H), 9.70 (s, 1H), 9.31 (s, 1H), 8.53 (s, 1H), 7.49 (td, J = 8.8, 5.7 Hz, 1H ), 7.25 (td, J = 9.1, 1.3 Hz, 1H), 3.91 – 4.01 (m, 1H), 3.29 – 3.34 (m, 2H), 3.21 – 3.29 (m, 2H), 3.19 (s, 3H), 2.73 (s, 3H), 1.84 – 1.97 (m, 2H) 27 B 490.4 1H NMR (MeOH-d 4) δ: 9.18 (s, 1H), 8.49 (s, 1H), 7.56 – 7.63 (m, 1H), 7.15 (td, J = 9.1, 1.9 Hz, 1H), 3.63 (t , J = 12.8 Hz, 2H), 3.52 (t, J = 7.3 Hz, 2H), 2.74 (s, 3H), 2.39 (tt, J = 13.9, 7.1 Hz, 2H) 28 B 501.9 1H NMR (MeOH-d 4) δ: 9.20 (s, 1H), 8.53 (s, 1H), 7.63 (td, J = 8.8, 5.7 Hz, 1H), 7.14 (td, J = 9.1, 1.9 Hz, 1H ), 3.48 – 3.59 (m, 4H), 3.39 – 3.44 (m, 1H), 3.12 (dd, J = 9.9, 7.1 Hz, 1H), 2.75 (s, 3H), 2.61 (dt, J = 14.4, 7.1 Hz, 1H), 2.09 (dtd, J = 12.3, 7.3, 4.6 Hz, 1H), 1.76 (dq, J = 12.6, 8.1 Hz, 1H) 29 C 468.1 1H NMR (CDCl 3 ) δ: 9.29 (s, 1H), 8.67 (s, 1H), 8.11 (br s, 1H), 7.61 (td, J = 9.0, 5.5 Hz, 1H), 7.07 (td, J = 9.2, 2.0 Hz, 1H), 6.67 (br s, 1H), 3.44 – 3.54 (m, 2H), 3.27 – 3.38 (m, 1H), 2.88 (dd, J = 9.2, 8.0 Hz, 1H), 2.71 ( s, 3H), 2.30 (dq, J = 15.2, 7.3 Hz, 1H), 1.98 – 2.09 (m, 1H), 1.48 – 1.58 (m, 1H), 1.04 (d, J = 6.7 Hz, 3H) 90 A see example 1 493.2 1H NMR (DMSO-d 6) δ: 10.50 (s, 1H), 10.04 (s, 1H), 9.29 (s, 1H), 8.48 (s, 1H), 7.61 (d, J= 8.2 Hz, 1H), 7.48 (dd, J= 9.8, 8.2 Hz, 1H), 7.36 - 7.43 (m, 1H), 7.25 - 7.34 (m, 1H), 7.21 (dd, J= 11.3, 8.6 Hz, 1H), 2.71 (s, 3H), 2.50 (s, 3H) 91 A see example 1 523.2 1H NMR (DMSO-d 6) δ: 10.33 (br s, 1H), 10.03 (s, 1H), 9.29 (s, 1H), 8.46 (s, 1H), 7.57 (d, J= 8.2 Hz, 1H) , 7.25 - 7.34 (m, 1H), 7.16 - 7.23 (m, 1H), 7.06 - 7.15 (m, 1H), 3.87 (s, 3H), 2.71 (s, 3H), 2.48 (s, 3H) 92 A see example 1 539.2 1H NMR (DMSO-d 6) δ: 10.39 (br s, 1H), 10.03 (s, 1H), 9.29 (s, 1H), 8.46 (s, 1H), 7.76 (d, J= 9.0 Hz, 1H) , 7.25 - 7.33 (m, 1H), 7.15 - 7.23 (m, 1H), 7.12 (d, J= 9.0 Hz, 1H), 3.90 (s, 3H), 2.71 (s, 3H), 2.65 (s, 3H ) table 3 example R-1 R 2 HCT116 pERK IC 50(µM) (Y min%) SW480 pERK IC 50(µM) (Y min%) Kinase IC 50 BRAF (nM) Kinase IC 50 CRAF (nM) 30 C2 B2 ++ (-6) + (-5) 31 C3 B1 ++ (13) ++ (11) 32 C4 B1 + (1) ++ (8) 33 C3 B5 + (-4) ++ (13) 34 C5 B5 + (-3) ++ (-2.0) 35 C6 B1 + (-4) ++ (14) 36 C7 B1 ++ (10) ++ (10) 37 C8 B1 ++ (-5) ++ (-6) 38 C9 B1 + (-1) + (-3) 39 C10 B1 + (5) + (-3) 40 C5 B1 ++ (12) ++ (-7) 41 C11 B1 + (13) + (6) 42 C12 B1 + (-2) + (11) 43 C13 B1 + (11) + (0) 44 C3 B8 ++ (-2) ++ (12) 45 C7 B8 ++ (11) ++ (-8) 46 C14 B1 + (8) + (12) 47 C15 B1 ++ (6) ++ (-1) 48 C16 B1 ++ (13) ++ (6) 49 C17 B1 + (8) + (-9) 50 C16 B8 ++ (8) ++ (-9) 51 C7 B9 ++ (-8) ++ (-1) 52 C15 B8 ++ (-4) ++ (-8) 53 C5 B8 ++ (15) ++ (-4) 54 C18 B1 + (-7) + (8) 55 C7 B12 ++ (-4) ++ (-2) 56 C5 B12 ++ (-10) ++ (4) 57 C3 B12 ++ (-2) ++ (-2) * § 58 C5 B11 ++(11) ++ (16) 59 C7 B11 +++ (11) +++ (2) 60 C3 B11 ++ (9) ++ (15) 61 C3 B15 ++ (11) ++ (9) 62 C5 B15 ++ (11) +++ (2) ** §§ 63 C7 B15 ++ (-2) ++ (1) ** §§§ 64 C7 B4 ++ (2) ++ (19) 65 C5 B4 ++ (4) ++ (5) 66 C3 B4 + (10) ++ (0) 67 C19 B11 ++ (6) ++ (18) 68 C20 B11 ++ (17) ++ (0) 69 C27 B11 +++ (8) ++++ (12) 70 C7 B30 ++ (0) ++ (1) 71 C21 B11 ++ (8) ++ (-4) 72 C22 B11 ++ (20 ++ (1) 73 C7 B29 ++ (-2) ++ (7) 74 C7 B31 ++ (-3) ++ (-7) 75 C7 B28 ++ (-10) ++ (-6) 76 C7 B32 ++ (-1) ++ (-9) 77 C7 B24 ++ (-4) ++ (-4) 78 C7 B33 ++ (6) +++ (10) 79 C23 B8 +++ (-6) ++++ (-2) 80 C23 B41 ++++ (-7) ++++ (-2) *** §§§ 81 C7 B41 ++++ (-4) ++++ (3) *** §§§ 82 C23 B36 ++++ (-10) ++++ (3.2) ** §§§ 83 C7 B36 ++++ (-10) ++++ (-2) ** §§§ 93 C60 B36 ++++ (1.3) ** §§§ 94 C60 B41 ++++ (7.7) ** §§§ 95 C72 B36 ++ (-5) ** §§ 96 C81 B36 ++++ (-3.8) *** §§§ 97 C223 B36 ++++ (-6.3) *** §§ 98 C224 B36 ++++ (-6.0) ++++ (-1) *** §§ 99 C73 B36 ++++ (-3.6) *** §§ 100 C69 B36 ++++ (2.2) *** §§ 101 C225 B36 ++++ (3.5) *** §§§ 102 C196 B36 +++ (-9.5) *** §§§ 103 C114 B36 +++ (-9.9) *** §§§ 104 C83 B36 ++++ (-9.8) *** § 105 C71 B36 ++++ (-8.7) ** § 106 C184 B36 ++++ (-2.3) *** §§ 107 C220 B36 +++ (-5.2) *** §§ 108 C88 B36 ++ (-7.0) +++ §§ 109 C182 B36 ++++ (-6.5) *** §§ 110 C82 B36 ++++ (-3.7) *** §§ 111 C23 B53 ++++ (-8.1) ** §§§ 112 C23 B54 +++ (-0.8) ++++ (-7) * §§ 113 C226 B36 +++ (-7.0) ** §§ 114 C183 B36 ++++ (-4.9) ++++ (2) ** §§ 115 C7 B54 ++++ (2) ** §§ 116 C7 B53 ++++ (-1) ** § 117 C22 B54 ++ (-1) * §§ 118 C22 B53 ++ (-14) * §§ 119 C488 B54 ++++ (-7) ++++ (-5) *** §§ 120 C488 B53 ++++ (-4) ** §§ 121 C22 B36 ++ (-4) ** §§§ 122 C488 B41 ++++ (-4) *** §§§ 123 C490 B41 ++ (3) ** §§§ 124 C22 B42 ++ (-9) ** §§§ 125 C488 B42 +++ (-5) +++ §§§ 126 C488 B36 ++++ (-3) *** §§§ 127 C7 B42 ++++ (0) ** §§§ 128 C418 B41 ++++ (7) ++++ (-14) * §§ 129 C414 B41 ++++ (-8) ++++ (3) * §§ 130 C376 B41 ++++ (-13) ** §§§ 131 C419 B41 ++++ (-4) ** §§ 132 C404 B41 ++++ (-4) ** §§§ 133 C438 B41 ++++ (-6) ** §§§ 134 C312 B41 ++++ (8) ** §§§ 135 C440 B41 +++ (-14) ** §§§ 136 C435 B41 ++++ (19) ** §§§ 137 C313 B41 ++++ (11) ** §§§ 138 C441 B41 ++++ (1) * §§ 139 C434 B41 ++++ (2) *** §§§ 140 C483 B41 ++++ (-16) * §§ 141 C275 B41 ++++ (-3) ** §§ 142 C323 B41 ++++ (-15) *** §§§ 143 C346 B41 ++++ (-7) ** §§ 144 C292 B41 ++++ (-9) ** §§ 145 C472 B41 ++++ (-8) *** §§§ 146 C402 B41 ++++ (-9) *** §§§ 147 C310 B41 ++++ (-9) ** §§ 148 C7 B55 ++ (-1) * §§ 149 C438 B55 ++++ (4) * §§ 150 C7 B77 ++ (-8) ** §§ 151 C438 B77 ++++ (10) ** §§ 152 C7 B59 ++++ (-15) ** § 153 C438 B59 ++++ (-6) ** §§ 154 C7 B65 +++ (3) ** § 155 C438 B65 ++++ (-8) ** § 156 C7 B63 +++ ** §§§ 157 C7 B73 ++++ (0) *** §§§ 158 C438 B63 ++++ (-1) ** §§§ 159 C438 B73 ++++ (5) ** §§§

[0345] For pERK analysis, + indicates 10-30 µM IC 50 range, ++ indicates 1-10 µM IC 50 range, +++ indicates 0.5-1 µM IC 50 range and ++++ indicates IC 50<0.5 µM. The % Y min value indicates the minimum value of each IC50 curve. Compounds exhibiting IC50 curves with Y min values ​​above -20% were considered to show minimal or no induction and did not cause aberrant activation of detectable pathways. For BRAF biochemical kinase assays, * indicates IC 50 >10 nM, ** indicates 1-10 nM IC 50 range and *** indicates IC 50 < 1 nM. For CRAF biochemical kinase assays, § indicates IC 50 >50 nM, §§ indicates 10-50 nM IC 50 range and §§§ indicates IC 50 < 10 nM. Characteristics of Compounds in Table 3 example resolve resolution HRMS m / z (MH+) 1H NMR (400 MHz) 30 B 555.6 1H NMR (DMSO-d 6) δ: 10.31 (s, 1H), 9.53 (s, 1H), 8.77 (s, 1H), 8.55 (s, 1H), 7.99 (s, 1H), 7.30 (dd, J = 8.5, 2.2 Hz, 1H), 7.24 – 7.28 (m, 1H), 7.23 (d, J = 2.2 Hz, 1H), 7.07 (d, J = 8.5 Hz, 1H), 3.80 (s, 3H), 3.74 (s, 3H), 2.22 (d, J = 0.9 Hz, 3H) 31 B 532.1 1H NMR (DMSO-d 6) δ: 10.11 (br s, 1H), 9.56 (s, 1H), 9.13 (s, 1H), 8.23 ​​(s, 1H), 7.67 (d, J = 9.0 Hz, 2H) , 7.13 – 7.31 (m, 2H), 7.08 (d, J = 9.0 Hz, 2H), 5.50 (d, J = 54 Hz, 1H), 3.99 (br s, 1H), 3.81 (s, 3H), 3.54 – 3.72 (m, 1H), 2.24 – 2.40 (m, 3H) 32 B 525.1 1H NMR (DMSO-d 6) δ: 10.41 (s, 1H), 10.17 (s, 1H), 9.73 (s, 1H), 8.70 (s, 1H), 8.68 (br s, 1H), 7.77 (d, J = 2.0 Hz, 1H), 7.62 – 7.73 (m, 2H), 7.23 – 7.31 (m, 2H), 7.05 – 7.14 (m, 2H), 3.81 (s, 3H), 3.05 (s, 3H) 33 B 527.1 1H NMR (DMSO-d 6) δ: 10.76 (s, 1H), 9.69 (br s, 1H), 9.13 (s, 1H), 8.26 (s, 1H), 8.10 (d, J = 7.4 Hz, 1H) , 7.93 – 7.98 (m, 1H), 7.89 (t, J = 7.6 Hz, 1H), 7.84 (td, J = 7.8, 1.0 Hz, 1H), 7.31 (td, J = 8.6, 6.3 Hz, 1H), 7.24 (t, J = 9.0 Hz, 1H), 3.97 (br s, 1H), 3.84 (br s, 1H), 3.73 (br s, 1H), 3.63 (s, 1H), 2.24 – 2.36 (m, 3H ) 34 A 534.1 1H NMR (DMSO-d 6) δ: 10.80 (br s, 1H), 10.34 (s, 1H), 9.72 (br s, 1H), 9.70 (s, 1H), 8.68 (s, 1H), 8.11 (dd , J = 7.4, 1.6 Hz, 1H), 7.98 (dd, J = 8.2, 1.2 Hz, 1H), 7.91 (td, J = 7.6, 1.2 Hz, 1H), 7.86 (td, J = 7.8, 1.6 Hz, 1H), 7.25 – 7.43 (m, 2H), 2.64 (s, 3H), 2.31 (s, 3H) 35 A 511.1 1H NMR (DMSO-d 6) δ: 10.37 (s, 1H), 10.18 (br s, 1H), 9.57 (s, 1H), 8.89 (s, 1H), 8.59 (s, 1H), 8.28 (s, 1H), 7.68 (d, J = 9.0 Hz, 2H), 7.18 – 7.34 (m, 3H), 7.09 (d, J = 9.0 Hz, 2H), 3.81 (s, 3H) 36 A 561.1 1H NMR (DMSO-d 6) δ: 10.29 (s, 1H), 9.68 (s, 1H), 9.61 (s, 1H), 8.70 (d, J = 8.2 Hz, 1H), 8.60 (s, 1H), 7.82 (d, J = 7.8 Hz, 1H), 7.65 – 7.75 (m, 2H), 7.48 (td, J = 7.8, 0.8 Hz, 1H), 7.41 (td, J = 7.4, 1.0 Hz, 1H), 7.19 – 7.35 (m, 2H), 7.05 – 7.16 (m, J = 9.0 Hz, 2H), 3.81 (s, 3H) 37 A 539.1 1H NMR (DMSO-d 6) δ: 10.17 (br s, 1H), 10.14 (s, 1H), 9.54 (s, 1H), 8.56 (s, 1H), 8.00 (s, 1H), 7.68 (d, J = 8.6 Hz, 2H), 7.18 – 7.34 (m, 2H), 7.09 (d, J = 9.0 Hz, 2H), 3.81 (s, 3H), 2.75 (s, 3H), 2.14 (s, 3H) 38 A 532.1 1H NMR (DMSO-d 6) δ: 10.12 (br s, 1H), 9.56 (s, 1H), 9.13 (s, 1H), 8.23 ​​(s, 1H), 7.57 – 7.75 (m, 2H), 7.13 – 7.27 (m, 2H), 7.08 (d, J = 9.0 Hz, 2H), 5.51 (d, J = 53.2 Hz, 1H), 3.89 – 4.05 (m, 2H), 3.81 (s, 3H), 3.56 – 3.77 (m, 2H), 2.12 – 2.38 (m, 2H) 39 A 550.1 1H NMR (DMSO-d 6) δ: 10.11 (br s, 1H), 9.66 (s, 1H), 9.18 (s, 1H), 8.28 (s, 1H), 7.54 - 7.78 (m, 2H), 7.14 - 7.28 (m, 2H), 7.04 - 7.12 (m, 2H), 4.09 (t, J = 13.3 Hz, 2H), 3.90 (t, J = 7.2 Hz, 2H), 3.81 (s, 3H), 2.53 - 2.68 (m, 2H) 40 A 539.1 1H NMR (DMSO-d 6) δ: 10.16 (s, 2H), 9.55 (s, 1H), 8.75 (s, 1H), 8.57 (s, 1H), 7.53 - 7.75 (m, 2H), 7.18 - 7.38 (m, 2H), 6.94 - 7.18 (m, 2H), 3.81 (s, 3H), 2.55 (s, 3H), 2.14 (s, 3H) 41 A 530.1 1H NMR (DMSO-d 6) δ: 10.11 (s, 1H), 9.49 (br s, 1H), 9.09 (s, 1H), 8.20 (s, 1H), 7.51 - 7.76 (m, 2H), 7.12 - 7.26 (m, 2H), 7.05 - 7.12 (m, 2H), 5.03 (d, J = 3.5 Hz, 1H), 4.43 (sxt, J = 3.5 Hz, 1H), 3.81 (s, 3H), 3.76 (br s, 1H), 3.61 - 3.71 (m, 3H), 2.06 (s, 1H), 1.87 - 2.00 (m, 1H) 42 A 530.1 1H NMR (DMSO-d 6) δ: 10.11 (s, 1H), 9.49 (br s, 1H), 9.09 (s, 1H), 8.20 (s, 1H), 7.51 - 7.76 (m, 2H), 7.12 - 7.26 (m, 2H), 7.05 - 7.12 (m, 2H), 5.03 (d, J = 3.5 Hz, 1H), 4.43 (sxt, J = 3.5 Hz, 1H), 3.81 (s, 3H), 3.76 (br s, 1H), 3.61 - 3.71 (m, 3H), 2.06 (s, 1H), 1.87 - 2.00 (m, 1H) 43 A 500.1 1H NMR (DMSO-d 6) δ: 10.10 (br s, 1H), 9.47 (s, 1H), 9.07 (s, 1H), 8.23 ​​(s, 1H), 7.52 - 7.77 (m, 2H), 7.21 ( td, J = 9.0, 5.9 Hz, 1H), 7.15 (t, J = 9.0 Hz, 1H), 7.03 - 7.11 (m, J = 9.0 Hz, 2H), 4.20 (t, J = 7.6 Hz, 4H), 3.80 (s, 3H), 2.37 (quin, J = 7.5 Hz, 2H) 44 A 550.1 1H NMR (DMSO-d 6) δ: 10.37 (br s, 1H), 9.58 (s, 1H), 9.13 (s, 1H), 8.21 (s, 1H), 7.61 (t, J = 8.8 Hz, 1H) , 7.26 (td, J = 9.0, 6.3 Hz, 1H), 7.18 (t, J = 9.4 Hz, 1H), 7.05 (dd, J = 12.3, 2.2 Hz, 1H), 6.88 (dd, J = 8.8, 2.2 Hz, 1H), 3.87 - 4.17 (m, 2H), 3.82 (s, 3H), 3.52 - 3.77 (m, 2H), 2.12 - 2.38 (m, 2H) 45 A 579.1 1H NMR (DMSO-d 6) δ: 10.45 (s, 1H), 10.31 (s, 1H), 9.68 (s, 1H), 9.62 (s, 1H), 8.71 (d, J = 8.2 Hz, 1H), 8.58 (s, 1H), 7.82 (d, J = 7.8 Hz, 1H), 7.63 (t, J = 8.8 Hz, 1H), 7.48 (t, J = 7.6 Hz, 1H), 7.41 (t, J = 7.6 Hz, 1H), 7.33 (td, J = 8.6, 6.3 Hz, 1H), 7.27 (t, J = 8.6 Hz, 1H), 7.07 (dd, J = 12.3, 2.2 Hz, 1H), 6.90 (dd, J = 9.0, 2.3 Hz, 1H), 3.83 (s, 3H) 46 A 475.1 1H NMR (DMSO-d 6) δ: 10.14 (br s, 1H), 10.00 (s, 1H), 9.36 (s, 1H), 8.46 (s, 1H), 7.61 - 7.71 (m, 2H), 7.24 ( td, J = 8.6, 5.5 Hz, 1H), 7.19 (t, J = 9.8 Hz, 1H), 7.04 - 7.12 (m, 2H), 4.12 (s, 3H), 3.81 (s, 3H) 47 A 518.1 1H NMR (DMSO-d 6) δ: 10.11 (br s, 1H), 9.59 (s, 1H), 9.13 (s, 1H), 8.27 (s, 1H), 7.48 - 7.75 (m, 2H), 7.22 ( td, J = 9.0, 5.9 Hz, 1H), 7.17 (t, J = 9.0 Hz, 1H), 7.04 - 7.13 (m, J = 9.0 Hz, 2H), 5.55 (dspt, J = 57.5, 2.9 Hz, 0H ), 4.54 (ddd, J = 21.5, 11.7, 6.3 Hz, 2H), 4.25 (dd, J = 24.3, 10.2 Hz, 2H), 3.81 (s, 3H) 48 A 536.1 1H NMR (DMSO-d 6) δ: 10.12 (br s, 1H), 9.71 (s, 1H), 9.20 (s, 1H), 8.33 (s, 1H), 7.64 - 7.71 (m, J = 9.0 Hz, 2H), 7.23 (td, J = 9.0, 6.3 Hz, 1H), 7.18 (t, J = 9.0 Hz, 1H), 7.04 - 7.13 (m, J = 9.0 Hz, 2H), 4.62 (t, J = 12.3 Hz, 4H), 3.81 (s, 3H) 49 A 562.1 1H NMR (DMSO-d 6) δ: 10.13 (br s, 1H), 10.11 (s, 1H), 9.41 (s, 1H), 8.52 (s, 1H), 7.90 - 7.95 (m, 1H), 7.77 ( dt, J = 7.0, 1.6 Hz, 1H), 7.62 - 7.75 (m, 4H), 7.24 (td, J = 9.0, 6.3 Hz, 1H), 7.18 (t, J = 9.4 Hz, 1H), 7.09 (d , J = 9.0 Hz, 2H), 3.81 (s, 3H) 50 A 554.1 1H NMR (DMSO-d 6) δ: 10.38 (s, 1H), 9.73 (s, 1H), 9.21 (s, 1H), 8.30 (s, 1H), 7.60 (t, J = 8.6 Hz, 1H), 7.27 (td, J = 9.0, 6.3 Hz, 1H), 7.19 (t, J = 9.4 Hz, 1H), 7.05 (dd, J = 12.3, 2.2 Hz, 1H), 6.88 (dd, J = 8.8, 2.2 Hz , 1H), 4.62 (t, J = 12.3 Hz, 4H), 3.82 (s, 3H) 51 B 542.6 1H NMR (DMSO-d 6) δ: 10.38 (br s, 1H), 9.85 (s, 1H), 9.70 (s, 1H), 9.65 (s, 1H), 8.73 (d, J = 8.5 Hz, 1H) , 8.65 (s, 1H), 7.83 (d, J = 7.6 Hz, 1H), 7.47 - 7.56 (m, 2H), 7.42 (td, J = 7.6, 1.1 Hz, 1H), 7.32 (td, J = 9.1 , 1.3 Hz, 1H), 5.34 (dt, J = 53.6, 3.2 Hz, 1H), 3.49 - 3.52 (m, 1H), 3.39 - 3.48 (m, 2H), 3.33 (td, J = 9.9, 6.8 Hz, 1H), 1.98 - 2.18 (m, 2H) 52 A 536.1 1H NMR (DMSO-d 6) δ: 10.37 (br s, 1H), 9.60 (s, 1H), 9.13 (s, 1H), 8.25 (s, 1H), 7.61 (t, J = 8.6 Hz, 1H) , 7.25 (td, J = 8.6, 6.3 Hz, 1H), 7.17 (t, J = 9.4 Hz, 1H), 7.04 (dd, J = 12.3, 2.2 Hz, 1H), 6.88 (dd, J = 9.0, 2.3 Hz, 1H), 5.55 (dspt, J = 57.5, 3.1 Hz, 0H), 4.54 (ddd, J = 21.5, 11.0, 5.9 Hz, 2H), 4.25 (dd, J = 23.9, 10.6 Hz, 2H), 3.80 (s, 3H) 53 A 557.1 1H NMR (DMSO-d 6) δ: 10.42 (br s, 1H), 10.17 (s, 1H), 9.55 (s, 1H), 8.75 (s, 1H), 8.54 (s, 1H), 7.62 (t, J = 8.6 Hz, 1H), 7.31 (td, J = 8.6, 5.9 Hz, 1H), 7.24 (t, J = 9.0 Hz, 1H), 7.06 (dd, J = 12.3, 2.2 Hz, 1H), 6.89 ( dd, J = 8.6, 2.3 Hz, 1H), 3.83 (s, 3H), 2.55 (s, 3H), 2.14 (s, 3H) 54 A 552.1 1H NMR (DMSO-d 6) δ: 10.17 (br s, 1H), 9.35 (s, 1H), 8.48 (s, 1H), 7.67 (d, J = 9.0 Hz, 2H), 7.20 - 7.29 (m, 1H), 7.16 (t, J = 9.0 Hz, 1H), 7.00 - 7.13 (m, 4H), 6.45 (d, J = 7.8 Hz, 1H), 6.41 (t, J = 2.0 Hz, 1H), 6.36 ( dd, J = 7.8, 2.0 Hz, 1H), 5.28 (br s, 2H), 3.81 (s, 3H) 55 A 575.1 1H NMR (DMSO-d 6) δ: 10.29 (s, 1H), 10.22 (br s, 1H), 9.68 (s, 1H), 9.61 (s, 1H), 8.70 (d, J = 8.2 Hz, 1H) , 8.59 (s, 1H), 7.82 (d, J = 7.8 Hz, 1H), 7.68 (d, J = 8.6 Hz, 1H), 7.45 - 7.53 (m, 1H), 7.37 - 7.45 (m, 1H), 7.18 - 7.35 (m, 2H), 6.96 (d, J = 2.3 Hz, 1H), 6.87 (dd, J = 8.8, 2.5 Hz, 1H), 3.79 (s, 3H), 2.59 (s, 3H) 56 A 553.2 1H NMR (DMSO-d 6) δ: 10.18 (s, 1H), 10.16 (s, 1H), 9.54 (s, 1H), 8.75 (s, 1H), 8.56 (s, 1H), 7.67 (d, J = 8.6 Hz, 1H), 7.28 (td, J = 8.6, 5.9 Hz, 1H), 7.21 (t, J = 9.4 Hz, 1H), 6.95 (d, J = 2.3 Hz, 1H), 6.86 (dd, J = 8.8, 2.5 Hz, 1H), 3.79 (s, 3H), 2.58 (s, 3H), 2.55 (s, 3H), 2.14 (s, 3H) 57 A 546.2 1H NMR (DMSO-d 6) δ: 10.14 (br s, 1H), 9.57 (s, 1H), 9.13 (s, 1H), 8.23 ​​(s, 1H), 7.67 (d, J = 9.0 Hz, 1H) , 7.22 (td, J = 9.0, 5.9 Hz, 1H), 7.16 (t, J = 9.4 Hz, 1H), 6.94 (d, J = 2.3 Hz, 1H), 6.85 (dd, J = 8.8, 2.5 Hz, 1H), 5.44 (d, J = 53.6 Hz, 1H), 3.90 - 4.07 (m, 2H), 3.78 (s, 3H), 3.54 - 3.71 (m, 2H), 2.57 (s, 3H), 2.23 - 2.39 (m, 2H) 58 B 532.2 1H NMR (DMSO-d 6) δ: 10.49 (br s, 1H), 9.74 (s, 2H), 8.74 (s, 1H), 8.47 (s, 1H), 7.54 (td, J = 8.7, 5.8 Hz, 1H), 7.32 (td, J = 9.1, 1.6 Hz, 1H), 3.94 - 3.99 (m, 1H), 3.22 - 3.38 (m, 4H), 3.19 (s, 3H), 3.06 (s, 3H), 2.37 (d, J = 1.3 Hz, 3H), 1.93 (dq, J = 6.5, 4.1 Hz, 2H) 59 B 554.1 1H NMR (DMSO-d 6) δ: 10.37 (s, 1H), 9.78 (br s, 1H), 9.70 (s, 1H), 9.64 (s, 1H), 8.73 (d, J = 8.2 Hz, 1H) , 8.65 (s, 1H), 7.83 (d, J = 7.4 Hz, 1H), 7.45 - 7.58 (m, 2H), 7.38 - 7.45 (m, 1H), 7.31 (td, J = 9.0, 1.6 Hz, 1H ), 3.90 - 4.03 (m, 1H), 3.22 - 3.37 (m, 4H), 3.20 (s, 3H), 1.93 (td, J = 7.6, 4.3 Hz, 2H) 60 B 525.2 1H NMR (DMSO-d 6) δ: 9.78 (br s, 1H), 9.69 (s, 1H), 9.16 (s, 1H), 8.32 (s, 1H), 7.47 (td, J = 8.8, 5.7 Hz, 1H), 7.24 (td, J = 9.1, 1.3 Hz, 1H), 5.47 (d, J = 53.6 Hz, 1H), 3.92 - 3.99 (m, 1H), 3.80 (dd, J = 39.7, 13.6 Hz, 1H ), 3.61 - 3.71 (m, 1H), 3.29 - 3.34 (m, 1H), 3.20 - 3.29 (m, 3H), 3.19 (s, 3H), 2.13 - 2.39 (m, 2H), 1.88 - 1.95 (m , 2H) 61 B 570.1 1H NMR (DMSO-d 6) δ: 10.61 (br s, 1H), 9.57 (s, 1H), 9.13 (s, 1H), 8.22 (s, 1H), 7.90 (d, J = 2.0 Hz, 1H) , 7.87 (d, J = 8.6 Hz, 1H), 7.60 (dd, J = 8.4, 2.2 Hz, 1H), 7.22 - 7.31 (m, 1H), 7.18 (t, J = 9.0 Hz, 1H), 5.50 ( d, J = 53.6 Hz, 1H), 3.88 - 4.20 (m, 2H), 3.78 (dd, J = 38.0, 11.7 Hz, 1H), 3.63 (q, J = 7.8 Hz, 1H), 2.12 - 2.41 (m , 2H) 62 B 577.1 1H NMR (DMSO-d 6) δ: 10.65 (br s, 1H), 10.14 (s, 1H), 9.53 (s, 1H), 8.73 (s, 1H), 8.53 (s, 1H), 7.89 (d, J = 2.0 Hz, 1H), 7.86 (d, J = 8.6 Hz, 1H), 7.59 (dd, J = 8.6, 2.0 Hz, 1H), 7.29 (td, J = 8.6, 5.9 Hz, 1H), 7.21 ( t, J = 9.0 Hz, 1H), 2.53 (s, 3H), 2.12 (s, 3H) 63 B 599.0 1H NMR (DMSO-d 6) δ: 10.69 (s, 1H), 10.30 (s, 1H), 9.68 (s, 1H), 9.61 (s, 1H), 8.70 (d, J = 7.8 Hz, 1H), 8.59 (s, 1H), 7.93 (d, J = 2.0 Hz, 1H), 7.89 (d, J = 8.6 Hz, 1H), 7.82 (d, J = 7.8 Hz, 1H), 7.63 (dd, J = 8.6 , 2.0 Hz, 1H), 7.48 (t, J = 7.2 Hz, 1H), 7.41 (t, J = 8.2 Hz, 1H), 7.35 (td, J = 9.0, 5.5 Hz, 1H), 7.28 (t, J = 9.0 Hz, 1H) 64 B 573.2 1H NMR (DMSO-d 6) δ: 10.31 (br.s., 1H), 10.14 (s, 1H), 9.68 (s, 1H), 9.64 (s, 1H), 8.71 (d, J = 8.2 Hz, 1H), 8.62 (s, 1H), 7.82 (d, J = 7.9 Hz, 1H), 7.62 (d, J = 1.6 Hz, 1H), 7.37 – 7.57 (m, 3H), 7.17 – 7.37 (m, 2H ), 6.91 (d, J = 8.5 Hz, 1H), 4.62 (t, J = 8.8 Hz, 2H), 3.22 (t, J = 8.8 Hz, 1H) 65 B 551.5 1H NMR (DMSO-d 6) δ: 10.42 (br s, 1H), 10.12 (s, 1H), 9.73 (s, 1H), 8.70 (s, 1H), 8.45 (br s, 1H), 7.60 - 7.63 (m, 1H), 7.50 (dd, J = 8.5, 2.2 Hz, 1H), 7.25 - 7.28 (m, J = 8.2 Hz, 2H), 6.90 (d, J = 8.5 Hz, 1H), 4.62 (t, J = 8.8 Hz, 2H), 3.22 (t, J = 8.8 Hz, 2H), 3.05 (s, 3H), 2.36 (d, J = 1.3 Hz, 3H) 66 B 544.5 1H NMR (DMSO-d 6) δ: 10.07 (s, 1H), 9.73 (br.s., 1H), 9.14 (s, 1H), 8.29 (s, 1H), 7.60 (d, J = 1.6 Hz, 1H), 7.50 (d, J = 8.5 Hz, 1H), 7.16 – 7.26 (m, 2H), 6.89 (d, J = 8.5 Hz, 1H), 5.51 (d, J = 52 Hz, 1H), 4.62 ( t, J = 8.8 Hz, 2H), 3.60 – 4.10 (m, 4H), 3.21 (t, J = 9.0 Hz, 2H), 2.11 – 2.34 (m, 2H) 67 B 555.6 1H NMR (CDCl 3 ) δ: 9.77 (br s, 1H), 9.69 (s, 1H), 9.22 (s, 1H), 8.32 (s, 1H), 7.44 - 7.51 (m, 2H), 7.32 - 7.39 ( m, 2H), 7.24 (t, J = 9.1 Hz, 1H), 5.02 (br s, 4H), 3.91 - 4.00 (m, 1H), 3.33 (dd, J = 10.7, 4.7 Hz, 1H), 3.21 - 3.30 (m, 3H), 3.19 (s, 3H), 1.84 - 1.97 (m, 2H) 68 B 553.2 1H NMR (DMSO-d 6) δ: 10.26 (s, 1H), 9.74 (s, 1H), 9.62 (s, 1H), 8.87 (d, J = 8.5 Hz, 1H), 8.82 (d, J = 3.5 Hz, 1H), 8.58 (s, 1H), 7.69 (dt, J = 7.6, 0.9 Hz, 1H), 7.52 (td, J = 8.9, 5.8 Hz, 1H), 7.38 (ddd, J = 8.4, 7.3, 1.3 Hz, 1H), 7.30 (td, J = 9.1, 1.6 Hz, 1H), 7.27 (td, J = 7.3, 0.9 Hz, 1H), 6.91 (dd, J = 3.8, 0.6 Hz, 1H), 3.95 - 3.99 (m, 1H), 3.34 (dd, J = 10.7, 4.7 Hz, 1H), 3.22 - 3.31 (m, 3H), 3.20 (s, 3H), 1.83 - 2.03 (m, 2H) 69 B 554.5 1H NMR (DMSO-d 6) δ: 10.36 (br s, 1H), 9.86 (s, 1H), 9.74 (s, 1H), 9.70 (s, 1H), 8.72 (s, 1H), 7.53 (td, J = 8.8, 5.7 Hz, 1H), 7.31 (td, J = 9.1, 1.6 Hz, 1H), 3.92 - 4.00 (m, 1H), 3.33 (dd, J = 10.7, 4.7 Hz, 1H), 3.20 - 3.31 (m, 5H), 3.19 (s, 3H), 2.67 - 2.76 (m, 2H), 1.90 - 1.97 (m, 2H), 1.80 - 1.90 (m, 4H) 70 C 568.5 1H NMR (DMSO-d 6) δ: 10.38 (s, 1H), 9.77 (s, 1H), 9.70 (s, 1H), 9.65 (s, 1H), 8.73 (d, J = 8.2 Hz, 1H), 8.64 (s, 1H), 7.83 (d, J = 7.9 Hz, 1H), 7.54 (td, J = 8.8, 5.7 Hz, 1H), 7.47 - 7.51 (m, 1H), 7.40 - 7.45 (m, 1H) , 7.32 (td, J = 9.5, 1.6 Hz, 1H), 3.34 (dd, J = 9.8, 7.6 Hz, 1H), 3.18 - 3.32 (m, 4H), 3.20 (s, 3H), 2.96 (dd, J = 9.6, 7.1 Hz, 1H), 2.45 (dt, J = 14.3, 7.3 Hz, 1H), 1.94 (dtd, J = 12.2, 7.3, 4.4 Hz, 1H), 1.58 (dq, J = 12.6, 7.9 Hz, 1H) 71 B 554.5 1H NMR (DMSO-d 6) δ: 10.39 (s, 1H), 9.74 (br s, 1H), 9.67 (s, 1H), 8.85 (br s, 1H), 8.61 (s, 1H), 8.47 (dd , J = 4.7, 1.6 Hz, 1H), 8.12 (dd, J = 7.7, 1.7 Hz, 1H), 7.52 (td, J = 8.8, 5.7 Hz, 1H), 7.32 (dd, J = 7.9, 4.7 Hz, 1H), 7.29 (t, J = 9.1 Hz, 1H), 6.91 (d, J = 4.1 Hz, 1H), 3.93 - 4.01 (m, 1H), 3.23 - 3.30 (m, 3H), 3.19 (s, 3H ), 1.89 - 1.96 (m, 2H) 72 B 555.5 1H NMR (DMSO-d 6) δ: 10.38 (s, 1H), 9.76 (s, 1H), 9.70 (s, 1H), 9.65 (s, 1H), 8.73 (d, 8.2 Hz, 1H), 8.65 ( s, 1H), 7.83 (d, J = 7.9 Hz, 1H), 7.46 – 7.60 (m, 1H), 7.39 – 7.46 (m, 1H), 7.23 – 7.39 (m, 1H), 3.97 (m, 1H) , 3.26 – 3.37 (m, 3H), 3.22 – 3.26 (m, 1H), 3.20 (s, 3H), 1.88 – 2.00 (m, 2H) 73 C 538.2 1H NMR (DMSO-d 6) δ: 10.36 (br s, 1H), 9.69 (s, 1H), 9.64 (s, 1H), 8.72 (d, J = 7.8 Hz, 1H), 8.63 (s, 1H) , 7.83 (d, J = 7.8 Hz, 1H), 7.53 (td, J = 9.0, 5.9 Hz, 1H), 7.45 - 7.51 (m, 1H), 7.41 (td, J = 7.8, 1.2 Hz, 1H), 7.30 (td, J = 9.4, 1.2 Hz, 1H), 3.37 (dd, J = 9.4, 7.0 Hz, 1H), 3.19 (td, J = 9.0, 7.0 Hz, 1H), 2.73 (dd, J = 9.0, 8.2 Hz, 1H), 2.22 (dq, J = 14.7, 7.2 Hz, 1H), 1.91 - 2.03 (m, 1H), 1.44 (dq, J = 12.3, 8.4 Hz, 1H), 0.96 (d, J = 6.7 Hz, 3H) 74 C 536.1 1H NMR (DMSO-d 6) δ: 10.37 (br s, 1H), 9.70 (s, 1H), 9.65 (s, 1H), 8.73 (d, J = 8.2 Hz, 1H), 8.65 (s, 1H) , 7.83 (d, J = 7.8 Hz, 1H), 7.46 - 7.53 (m, 1H), 7.39 - 7.45 (m, 1H), 7.30 (t, J = 8.8 Hz, 1H), 3.29 (br.s, 4H ), 1.55 (dd, J = 7.2, 3.3 Hz, 2H), 0.58 (td, J = 7.7, 4.9 Hz, 1H), 0.23 (q, J = 4.3 Hz, 1H) 75 B 572.1 1H NMR (DMSO-d 6) δ: 10.36 (br s, 1H), 9.70 (s, 1H), 9.64 (s, 1H), 8.73 (d, J = 8.2 Hz, 1H), 8.64 (s, 1H) , 7.83 (d, J = 7.8 Hz, 1H), 7.46 - 7.60 (m, 2H), 7.38 - 7.45 (m, 1H), 7.29 (t, J = 8.8 Hz, 1H), 3.56 - 3.75 (m, 2H ), 3.41 (dd, J = 9.6, 7.6 Hz, 1H), 3.16 - 3.26 (m, 1H), 3.01 (dd, J = 9.8, 7.0 Hz, 1H), 2.57 (dt, J = 14.6, 7.4 Hz, 1H), 1.92 - 2.09 (m, 1H), 1.68 (dq, J = 12.6, 7.9 Hz, 1H) 76 C 552.2 1H NMR (DMSO-d 6) δ: 10.36 (br s, 1H), 9.70 (s, 1H), 9.64 (s, 1H), 8.73 (d, J = 8.2 Hz, 1H), 8.62 (s, 1H) , 7.83 (d, J = 7.8 Hz, 1H), 7.45 - 7.59 (m, 2H), 7.37 - 7.45 (m, 1H), 7.29 (t, J = 9.0 Hz, 1H), 3.38 (dd, J = 9.4 , 7.4 Hz, 1H), 3.17 (td, J = 9.4, 6.7 Hz, 1H), 2.77 (t, J = 9.0 Hz, 1H), 1.89 - 2.11 (m, 2H), 1.38 - 1.53 (m, 1H) , 1.25 - 1.38 (m, 2H), 0.83 (t, J = 7.4 Hz, 3H) 77 C 524.1 1H NMR (DMSO-d 6) δ: 10.37 (s, 1H), 9.73 (s, 1H), 9.70 (s, 1H), 9.64 (s, 1H), 8.72 (d, J = 7.8 Hz, 1H), 8.64 (s, 1H), 7.83 (d, J = 7.8 Hz, 1H), 7.54 (td, J = 9.0, 5.9 Hz, 1H), 7.46 - 7.52 (m, 1H), 7.38 - 7.45 (m, 1H) , 7.32 (td, J = 9.2, 1.6 Hz, 1H), 3.11 - 3.25 (m, 4H), 1.81 (dt, J = 6.5, 3.4 Hz, 4H) 78 C 590.1 1H NMR (DMSO-d 6) δ: 10.36 (s, 1H), 9.70 (s, 1H), 9.64 (s, 1H), 8.73 (d, J = 7.8 Hz, 1H), 8.65 (s, 1H), 7.83 (d, J = 7.8 Hz, 1H), 7.46 - 7.57 (m, 2H), 7.39 - 7.45 (m, 1H), 7.30 (t, J = 9.0 Hz, 1H), 4.79 - 4.91 (m, 1H) , 3.49 (dd, J = 11.2, 4.9 Hz, 1H), 3.34 - 3.39 (m, 1H), 3.26 - 3.30 (m, 2H), 2.08 - 2.21 (m, 1H), 1.94 - 2.06 (m, 1H) 79 A 594.1 1H NMR (DMSO-d 6) δ: 10.45 (br s, 1H), 10.27 (s, 1H), 9.64 (s, 1H), 9.39 (s, 1H), 8.55 (s, 1H), 7.84 (dd, J = 8.2, 0.9 Hz, 1H), 7.63 (t, J = 8.8 Hz, 1H), 7.22 - 7.39 (m, 2H), 7.13 (t, J = 7.9 Hz, 1H), 7.07 (dd, J = 12.5 , 2.4 Hz, 1H), 6.90 (dd, J = 8.9, 2.6 Hz, 1H), 6.58 (dd, J = 7.8, 1.0 Hz, 1H), 5.50 (br s, 2H), 3.83 (s, 3H) 80 A 614.1 1H NMR (DMSO-d 6) δ: 10.76 (br s, 1H), 10.26 (s, 1H), 9.64 (s, 1H), 9.38 (s, 1H), 8.56 (s, 1H), 7.95 (dd, J = 7.9, 1.1 Hz, 1H), 7.91 (dd, J = 7.9, 1.6 Hz, 1H), 7.84 (d, J = 8.3 Hz, 1H), 7.54 (t, J = 8.1 Hz, 1H), 7.20 - 7.39 (m, 2H), 7.12 (t, J = 7.9 Hz, 1H), 6.57 (dd, J = 7.8, 1.0 Hz, 1H), 5.50 (br s, 2H) 81 A 599.0 1H NMR (DMSO-d 6) δ: 10.77 (br s, 1H), 10.30 (s, 1H), 9.68 (s, 1H), 9.60 (s, 1H), 8.70 (d, J = 7.8 Hz, 1H) , 8.59 (s, 1H), 7.97 (dd, J = 8.1, 1.5 Hz, 1H), 7.91 (dd, J = 7.9, 1.6 Hz, 1H), 7.82 (dd, J = 7.2, 0.9 Hz, 1H), 7.55 (t, J = 8.1 Hz, 1H), 7.48 (td, J = 7.3, 1.2 Hz, 1H), 7.42 (dd, J = 7.8, 1.5 Hz, 1H), 7.21 - 7.38 (m, 2H) 82 A 578.1 1H NMR (DMSO-d 6) δ: 10.55 (br s, 1H), 10.26 (s, 1H), 9.64 (s, 1H), 9.38 (s, 1H), 8.56 (s, 1H), 7.84 (dd, J = 8.1, 0.7 Hz, 1H), 7.62 (d, J = 7.3 Hz, 1H), 7.50 (td, J = 9.5, 1.2 Hz, 1H), 7.42 (dd, J = 8.1, 5.6 Hz, 1H), 7.21 - 7.39 (m, 2H), 7.12 (t, J = 7.9 Hz, 1H), 6.57 (dd, J = 7.8, 1.0 Hz, 1H), 5.50 (br s, 2H), 2.51 (s, 3H) 83 A 563.1 1H NMR (DMSO-d 6) δ: 10.55 (br s, 1H), 10.29 (s, 1H), 9.68 (s, 1H), 9.61 (s, 1H), 8.70 (d, J = 7.6 Hz, 1H) , 8.59 (s, 1H), 7.76 - 7.88 (m, 1H), 7.62 (d, J = 7.8 Hz, 1H), 7.17 - 7.56 (m, 6H), 2.51 (s, 3H) 93 A 579.1 1H NMR (DMSO-d 6) δ: 10.51 (s, 1H), 10.10 (s, 1H), 9.71 (s, 1H), 8.61 (s, 1H), 7.79 (d, J = 8.2 Hz, 1H), 7.62 (d, J = 7.8 Hz, 1H), 7.49 (t, J = 9.0 Hz, 1H), 7.41 (td, J = 8.2, 5.9 Hz, 1H), 7.39 (t, J = 8.2 Hz, 1H), 7.32 (td, J = 8.7, 6.1 Hz, 1H), 7.24 (t, J = 9.4 Hz, 1H), 6.62 (d, J = 7.4 Hz, 1H), 6.36 (s, 2H), 2.50 (br s, 3H) 94 A 615.0 1H NMR (DMSO-d 6) δ: 10.73 (br s, 1H), 10.11 (s, 1H), 9.71 (s, 1H), 8.61 (s, 1H), 7.95 (d, J = 8.2 Hz, 1H) , 7.90 (dd, J = 7.8, 1.2 Hz, 1H), 7.80 (d, J = 8.2 Hz, 1H), 7.54 (t, J = 8.0 Hz, 1H), 7.39 (t, J = 7.8 Hz, 1H) , 7.27 - 7.36 (m, 1H), 7.24 (t, J = 9.2 Hz, 1H), 6.62 (d, J = 7.8 Hz, 1H), 6.36 (s, 2H) 95 f 699.1 1H NMR (DMSO-d 6) δ: 10.56 (br s, 1H), 10.46 (br s, 1H), 9.68 (s, 1H), 9.35 (s, 1H), 8.96 (d, J = 8.2 Hz, 1H ), 8.58 (s, 1H), 7.96 (d, J = 7.8 Hz, 1H), 7.62 (d, J = 7.8 Hz, 1H), 7.53 (dd, J = 9.0, 7.8 Hz, 1H), 7.28 - 7.48 (m, 4H), 7.17 - 7.26 (m, 1H), 2.74 (s, 6H) 96 f 724.2 1H NMR (DMSO-d 6) δ: 10.47 (s, 1H), 9.68 (s, 1H), 9.33 (s, 1H), 8.96 (d, J = 8.2 Hz, 1H), 8.58 (s, 1H), 7.93 (d, J = 7.8 Hz, 1H), 7.62 (d, J = 7.4 Hz, 1H), 7.51 - 7.56 (m, 1H), 7.30 - 7.49 (m, 5H), 7.19 - 7.27 (m, 1H) , 3.07 (br s, 4H), 2.37 - 2.43 (m, 4H), 2.13 (s, 3H) 97 E. 633.3 1H NMR (DMSO-d 6) δ: 10.56 (br s, 1H), 10.28 (s, 1H), 9.63 (s, 1H), 9.07 (s, 1H), 8.87 (d, J= 8.5 Hz, 1H) , 8.54 (s, 1H), 7.72 (d, J= 7.8 Hz, 1H), 7.62 (d, J= 7.8 Hz, 1H), 7.38 – 7.50 (m, 3H), 7.30 – 7.35 (m, 2H), 7.24 (t, J= 8.7 Hz, 1H), 3.12 (br s, 6H), 2.50 (s, 3H). 98 E. 710.2 1H NMR (DMSO-d 6) δ: 10.57 (br s, 1H), 10.27 (s, 1H), 9.63 (s, 1H), 9.12 (s, 1H), 8.90 (d, J= 8.0 Hz, 1H) , 8.57 (br s, 2H), 8.55 (s, 1H), 7.77 (d, J= 7.5 Hz, 1H), 7.62 (d, J= 7.8 Hz, 1H), 7.25 – 7.50 (m, 8H), 4.81 (s, 2H), 3.13 (br s, 3H), 2.50 (s, 3H). 99 E. 688.2 1H NMR (DMSO-d 6) δ: 10.33 (s, 1H), 9.63 (s, 1H), 9.09 (s, 1H), 8.88 (d, J= 8.2 Hz, 1H), 8.54 (s, 1H), 7.67 (d, J= 7.8 Hz, 1H), 7.62 (d, J= 7.8 Hz, 1H), 7.42 – 7.48 (m, 2H), 7.28 – 7.41 (m, 3H), 7.21 (t, J= 9.0 Hz , 1H), 3.68 (br s, 4H), 2.50 (s, 3H), 2.39 (br s, 4H), 2.22 (s, 3H). 100 E. 675.2 1H NMR (DMSO-d 6) δ: 10.57 (s, 1H), 10.32 (s, 1H), 9.64 (s, 1H), 9.11 (s, 1H), 8.89 (d, J= 8.5 Hz, 1H), 8.54 (s, 1H), 7.71 (d, J= 7.8 Hz, 1H), 7.62 (d, J= 7.8 Hz, 1H), 7.41 – 7.49 (m, 2H), 7.29 – 7.40 (m, 3H), 7.23 (t, J= 8.7 Hz, 1H), 3.65 (br s, 8H), 2.50 (s, 3H). 101 E. 663.4 1H NMR (DMSO-d 6) δ: 10.56 (s, 1H), 10.30 (s, 1H), 9.63 (s, 1H), 9.05 (s, 1H), 8.88 (d, J= 8.5 Hz, 1H), 8.54 (s, 1H), 7.69 (br s, 1H), 7.62 (d, J= 7.8 Hz, 1H), 7.49 (t, J= 8.7 Hz, 1H), 7.39 – 7.45 (m, 2H), 7.31 – 7.37 (m, 2H), 7.26 (t, J= 9.1 Hz, 1H), 4.80 (br s, 1H), 3.58 – 3.66 (m, 4H), 3.13 (s, 3H), 2.51 (s, 3H). 102 E. 689.5 1H NMR (DMSO-d 6) δ: 10.56 (s, 1H), 10.35 (s, 1H), 9.63 (s, 1H), 9.08 (s, 1H), 8.88 (d, J= 8.5 Hz, 1H), 8.54 (s, 1H), 7.63 (dd, J= 12.0, 7.9 Hz, 2H), 7.50 (t, J= 8.7 Hz, 1H), 7.39 – 7.46 (m, 2H), 7.31 – 7.37 (m, 2H) , 7.26 (t, J= 9.4 Hz, 1H), 4.82 (d, J= 4.1 Hz, 1H), 3.77 (td, J= 8.1, 4.3 Hz, 1H), 3.27 – 3.33 (m, 4H), 2.50 ( s, 3H), 1.78 (s, 2H), 1.39 (s, 2H). 103 E. 689.5 1H NMR (DMSO-d 6) δ: 10.56 (s, 1H), 10.36 (s, 1H), 9.63 (s, 1H), 9.08 (s, 1H), 8.88 (d, J= 8.5 Hz, 1H), 8.54 (s, 1H), 7.63 (dd, J= 11.4, 7.8 Hz, 2H), 7.39 – 7.51 (m, 3H), 7.30 – 7.36 (m, 2H), 7.25 (t, J= 8.5 Hz, 1H) , 4.86 – 4.99 (m, 1H), 3.75 – 3.91 (m, 1H), 3.50 (br s, 1H), 3.31 (s, 1H), 3.23 (br s, 1H), 2.82 – 3.11 (m, 1H) , 2.50 (s, 3H), 1.88 – 1.90 (m, 1H), 1.75 (br s, 1H), 1.42 – 1.45 (m, 2H). 104 E. 689.3 1H NMR (DMSO-d 6) δ: 9.92 (br s, 1H), 9.68 (s, 1H), 8.90 (d, J= 8.5 Hz, 1H), 8.59 (s, 1H), 8.00 (d, J= 8.2 Hz, 1H), 7.69 (t, J= 7.8 Hz, 1H), 7.63 (d, J= 7.8 Hz, 1H), 7.49 (t, J= 7.4 Hz, 1H), 7.45 (d, J= 8.9 Hz , 1H), 7.39 (td, J= 8.0, 5.9 Hz, 1H), 7.29 (td, J= 8.7, 5.7 Hz, 1H), 7.19 (t, J= 8.5 Hz, 1H), 3.85 (br s, 2H ), 3.79 (br s, 2H), 2.50 (br s, 3H), 2.48 (br s, 2H), 2.08 (br s, 2H), 2.25 (s, 3H). 105 E. 634.3 1H NMR (DMSO-d 6) δ: 10.52 (br s, 1H), 9.93 (s, 1H), 9.67 (s, 1H), 8.89 (d, J= 8.5 Hz, 1H), 8.58 (s, 1H) , 8.02 (d, J= 8.0 Hz, 1H), 7.68 (td, J= 7.1, 1.0 Hz, 1H), 7.63 (d, J= 7.8 Hz, 1H), 7.45 – 7.50 (m, 2H), 7.40 ( td, J= 7.8, 5.7 Hz, 1H), 7.31 (td, J= 8.9, 5.9 Hz, 1H), 7.22 (t, J= 8.9 Hz, 1H), 3.33 (s, 3H), 3.14 (s, 3H ), 2.50 (s, 3H). 106 E. 711.2 1H NMR (DMSO-d 6) δ: 10.52 (br s, 1H), 9.93 (s, 0.6H), 9.78 (s, 0.4H), 9.69 (s, 0.6H), 9.65 (s, 0.4H), 8.92 (d, J= 8.7 Hz, 1H), 8.88 (d, J= 8.2 Hz, 1H), 8.59 (t, J= 5.0 Hz, 2H), 8.47 (d, J= 5.7 Hz, 1H), 8.10 ( t, J= 8.0 Hz, 1H), 7.69 (dd, J= 15.8, 8.7 Hz, 1H), 7.63 (d, J= 7.8 Hz, 1H), 7.46 – 7.53 (m, 2H), 7.38 – 7.43 (m , 3H), 7.29 – 7.35 (m, 1H), 7.22 – 7.27 (m, 1H), 5.14 (s, 0.8H), 4.87 (s, 1.2H), 3.38 (s, 1.8H), 3.11 (s, 1.2H), 2.50 (s, 3H). 107 E. 664.3 1H NMR (DMSO-d 6) δ: 10.54 (br s, 1H), 9.95 (d, J= 6.2 Hz, 1H), 9.68 (d, J= 2.7 Hz, 1H), 8.89 (t, J= 9.8 Hz , 1H), 8.59 (d, J= 2.1 Hz, 1H), 8.01 (d, J= 8.2 Hz, 1H), 7.69 (t, J= 7.8 Hz, 1H), 7.62 (d, J= 7.8 Hz, 1H ), 7.46 – 7.53 (m, 2H), 7.39 – 7.44 (m, 1H), 7.30 – 7.36 (m, 1H), 7.26 (t, J= 9.1 Hz, 1H), 4.90 – 5.06 (m, 1H), 3.83 (t, J= 5.5 Hz, 1H), 3.70 – 3.73 (m, 1H), 3.65 – 3.68 (m, 1H), 3.64 (t, J= 5.3 Hz, 1H), 3.34 (s, 1H), 3.14 (s, 2H), 2.50 (s, 3H). 108 E. 690.3 1H NMR (DMSO-d 6) δ: 10.54 (br s, 1H), 9.95 (s, 1H), 9.68 (s, 1H), 8.89 (d, J= 8.5 Hz, 1H), 8.58 (s, 1H) , 7.96 (d, J= 8.0 Hz, 1H), 7.69 (ddd, J= 8.5, 7.1, 0.9 Hz, 1H), 7.62 (d, J= 7.5 Hz, 1H), 7.49 (q, J= 7.2 Hz, 2H), 7.41 (td, J= 8.0, 5.5 Hz, 1H), 7.32 (td, J= 8.7, 5.9 Hz, 1H), 7.25 (dd, J= 9.1, 0.7 Hz, 1H), 4.82 (br s, 1H), 4.17 (dt, J= 12.3, 4.3 Hz, 1H), 4.02 (dt, J= 12.6, 3.7 Hz, 1H), 3.80 (tt, J= 8.1, 3.8 Hz, 1H), 3.47 (ddd, J = 13.2, 9.7, 3.2 Hz, 2H), 2.50 (s, 3H), 1.88 – 1.91 (m, 1H), 1.76 – 1.79 (m, 1H), 1.35 – 1.52 (m, 2H). 109 E. 690.3 1H NMR (DMSO-d 6) δ: 10.54 (br s, 1H), 9.94 (s, 1H), 9.67 (d, J= 3.2 Hz, 1H), 8.89 (dd, J =8.5, 4.1 Hz, 1H) , 8.58 (d, J= 1.4 Hz, 1H), 7.96 (d, J= 8.0 Hz, 1H), 7.69 (t, J= 7.7 Hz, 1H), 7.63 (d, J= 7.8 Hz, 1H), 7.48 (t, J= 7.9 Hz, 2H), 7.40 (td, J= 7.8, 6.2 Hz, 1H), 7.31 (td, J= 8.7, 5.7 Hz, 1H), 7.22 (t, J= 8.7 Hz, 1H) , 5.10 (d, J= 4.1 Hz, 0.5H), 4.88 (d, J= 4.1 Hz, 0.5H), 4.30 (dd, J= 12.5, 3.5 Hz, 0.5H), 3.97 (d, J= 13.3 Hz , 0.5H), 3.89 (dd, J= 12.8, 2.7 Hz, 1H), 3.63 (dt, J= 8.2, 4.1 Hz, 0.5), 3.55 (br s, 0.5H), 3.45 – 3.50 (m, 1H) , 3.46 (dd, J= 12.8, 7.5 Hz, 0.5H), 3.04 (dd, J= 12.3, 8.7 Hz, 0.5H), 2.50 (s, 3H), 1.70 – 1.91 (m, 2H), 1.41 – 1.53 (m, 2H). 110 E. 676.3 1H NMR (DMSO-d 6) δ: 10.54 (br s, 1H), 9.93 (s, 1H), 9.68 (s, 1H), 8.90 (d, J= 8.7 Hz, 1H), 8.59 (s, 1H) , 8.05 (d, J= 8.2 Hz, 1H), 7.70 (ddd, J= 8.2, 7.0, 0.9 Hz, 1H), 7.63 (d, J= 7.8 Hz, 1H), 7.50 (t, J= 7.5 Hz, 2H), 7.40 (dd, J= 13.5, 7.8 Hz, 1H), 7.31 (dd, J= 14.6, 8.9 Hz, 1H), 7.22 (t, J= 8.0 Hz, 1H), 3.92 – 3.94 (m, 2H ), 3.78 – 3.80 (m, 2H), 3.74 – 3.76 (m, 2H), 3.63 – 3.66 (m, 2H), 2.50 (s, 3H). 111 A 608.3 1H NMR (DMSO-d 6) δ: 10.37 (br s, 1H), 10.25 (s, 1H), 9.64 (s, 1H), 9.38 (s, 1H), 8.55 (s, 1H), 7.84 (d, J = 7.8 Hz, 1H), 7.58 (d, J = 9.0 Hz, 1H), 7.28 - 7.36 (m, 1H), 7.20 - 7.27 (m, 1H), 7.13 (dd, J = 9.0 Hz, 2H), 6.57 (d, J = 7.8 Hz, 1H), 5.50 (s, 2H), 3.88 (s, 3H). 112 A 624.3 1H NMR (DMSO-d 6) δ: 10.44 (br s, 1H), 10.25 (s, 1H), 9.64 (s, 1H), 9.38 (s, 1H), 8.55 (s, 1H), 7.84 (d, J = 7.8 Hz, 1H), 7.77 (d, J = 9.0 Hz, 1H), 7.29 - 7.37 (m, 1H), 7.24 (dd, J = 11.0, 9.0 Hz, 1H), 7.12 (dd, J = 9.0 , 7.0 Hz, 2H), 6.57 (d, J = 7.8 Hz, 1H), 5.50 (br s, 2H), 3.91 (s, 3H), 2.67 (s, 3H). 113 f 746.1 1H NMR (DMSO-d 6) δ: 10.56 (br s, 1H), 10.45 (s, 1H), 9.69 (s, 1H), 9.44 (s, 1H), 8.98 (d, J = 8.2 Hz, 1H) , 8.50 - 8.61 (m, 3H), 8.00 (d, J = 7.8 Hz, 1H), 7.61 (d, J = 7.4 Hz, 1H), 7.55 (dd, J = 9.4, 7.4 Hz, 1H), 7.27 - 7.50 (m, 6H), 7.15 - 7.25 (m, 1H), 4.35 (s, 2H), 2.74 (s, 3H) 114 A 640.4 1H NMR (DMSO-d 6) δ: 10.56 (br s, 1H), 10.31 (s, 1H), 9.71 (s, 1H), 9.66 (s, 1H), 9.24 (br s, 1H), 8.80 (d , J = 8.2 Hz, 1H), 8.57 - 8.66 (m, 2H), 8.43 (dt, J = 8.1, 1.8 Hz, 1H), 7.66 - 7.73 (m, 1H), 7.54 - 7.65 (m, 3H), 7.45 - 7.53 (m, 1H), 7.23 - 7.45 (m, 3H) 115 A 609.4 1H NMR (400 MHz, DMSO-d 6) δ: 10.44 (br s, 1H), 10.28 (s, 1H), 9.68 (s, 1H), 9.61 (s, 1H), 8.70 (d, J = 7.8 Hz , 1H), 8.57 (s, 1H), 7.82 (d, J = 7.4 Hz, 1H), 7.78 (d, J = 9.0 Hz, 1H), 7.48 (ddd, J = 8.2, 7.0, 1.2 Hz, 1H) , 7.41 (td, J = 7.8, 1.2 Hz, 1H), 7.27 - 7.36 (m, 1H), 7.16 - 7.26 (m, 1H), 7.12 (d, J = 9.4 Hz, 1H), 3.90 (s, 3H ), 2.67 (s, 3H) 116 A 593.4 1H NMR (400 MHz, DMSO-d 6) δ: 10.38 (br s, 1H), 10.27 (s, 1H), 9.67 (s, 1H), 9.62 (s, 1H), 8.70 (d, J = 8.2 Hz , 1H), 8.58 (s, 1H), 7.82 (d, J = 7.4 Hz, 1H), 7.59 (dd, J = 9.0, 0.8 Hz, 1H), 7.48 (ddd, J = 7.8, 7.1, 0.8 Hz, 1H), 7.41 (td, J = 7.8, 1.2 Hz, 1H), 7.24 - 7.36 (m, 1H), 7.14 - 7.24 (m, 1H), 7.10 (t, J = 8.6 Hz, 1H), 3.87 (s , 3H), 2.49 (br s, 3H) 117 A 610.2 1H NMR (400 MHz, DMSO-d 6) δ: 10.41 (br s, 1H), 10.20 (s, 1H), 9.76 (s, 1H), 8.79 (d, J = 8.6 Hz, 1H), 8.63 (s , 1H), 8.27 (d, J = 8.6 Hz, 1H), 7.79 (ddd, J = 7.8, 7.0, 0.8 Hz, 1H), 7.78 (d, J = 9.0 Hz, 1H), 7.62 (ddd, J = 8.2, 7.4, 0.8 Hz, 1H), 7.32 (td, J = 8.6, 6.3 Hz, 1H), 7.21 (br. t, J = 9.0 Hz, 1H), 7.13 (d, J = 8.6 Hz, 1H), 3.91 (s, 3H), 2.66 (s, 3H) 118 A 594.4 1H NMR (400 MHz, DMSO-d 6 ) δ: 10.35 (br s, 1H), 10.21 (s, 1H), 9.76 (s, 1H), 8.79 (d, J = 8.2 Hz, 1H), 8.63 (s , 1H), 8.27 (d, J = 8.2 Hz, 1H), 7.79 (ddd, J = 8.2, 7.4, 0.8 Hz, 1H), 7.63 (ddd, J = 7.8, 7.0, 0.8 Hz, 1H), 7.59 ( dd, J = 9.0, 1.2 Hz, 1H), 7.31 (td, J = 8.4, 6.3 Hz, 1H), 7.21 (t, J = 8.6 Hz, 1H), 7.13 (t, J = 8.6 Hz, 1H), 3.88 (s, 3H), 2.48 (d, J = 2.7 Hz, 3H) 119 f 772.4 1H NMR (400 MHz, DMSO-d 6) δ: 10.44 (br s, 1H), 9.67 (s, 1H), 9.36 (s, 1H), 8.95 (d, J = 8.2 Hz, 1H), 8.56 (s , 1H), 8.14 (s, 1H), 7.96 (d, J = 7.8 Hz, 1H), 7.78 (d, J = 9.0 Hz, 1H), 7.53 (ddd, J = 8.2, 7.4, 0.8 Hz, 1H) , 7.44 (ddd, J = 7.8, 7.0, 0.8 Hz, 1H), 7.31 (td, J = 8.8, 5.9 Hz, 1H), 7.17 (t, J = 9.0 Hz, 1H), 7.10 (d, J = 9.0 Hz, 1H), 3.90 (s, 3H), 3.16 - 3.22 (m, 4H), 2.82 (s, 3H), 2.67 (s, 3H), 2.21 (s, 6H) 120 f 756.4 1H NMR (400 MHz, DMSO-d 6) δ: 10.45 (br s, 1H), 9.67 (s, 1H), 9.36 (s, 1H), 8.96 (d, J = 8.6 Hz, 1H), 8.56 (s , 1H), 8.14 (s, 1H), 7.96 (d, J = 7.8 Hz, 1H), 7.59 (d, J = 8.6 Hz, 1H), 7.53 (t, J = 7.8 Hz, 1H), 7.44 (t , J = 7.4 Hz, 1H), 7.30 (td, J = 8.7, 5.7 Hz, 1H), 7.17 (t, J = 9.0 Hz, 1H), 7.09 (t, J = 8.6 Hz, 1H), 3.87 (s , 3H), 3.19 (t, J = 6.7 Hz, 4H), 2.82 (s, 3H), 2.47 (d, J = 6.7 Hz, 3H), 2.18 (s, 6H) 121 A 564.3 1H NMR (400 MHz, DMSO-d 6 ) δ: 10.52 (br s, 1H), 10.20 (s, 1H), 9.77 (s, 1H), 8.79 (d, J = 8.2 Hz, 1H), 8.65 (s , 1H), 8.27 (d, J = 8.2 Hz, 1H), 7.80 (t, J = 7.6 Hz, 1H), 7.64 (t, J = 3.5 Hz, 1H), 7.62 (t, J = 3.5 Hz, 1H ), 7.49 (t, J = 8.8 Hz, 1H), 7.41 (td, J = 7.6, 6.3 Hz, 1H), 7.28 - 7.36 (m, 1H), 7.24 (t, J = 9.0 Hz, 1H), 2.49 - 2.50 (m, 3H) 122 f 762.4 1H NMR (400 MHz, DMSO-d 6) δ: 10.41 (br s, 1H), 9.67 (s, 1H), 9.39 (s, 1H), 8.96 (d, J = 8.6 Hz, 1H), 8.58 (s , 1H), 8.14 (s, 1H), 7.97 (d, J = 7.8 Hz, 1H), 7.92 (d, J = 7.8 Hz, 1H), 7.80 (d, J = 7.8 Hz, 1H), 7.53 (t , J = 7.8 Hz, 1H), 7.45 (td, J = 7.7, 2.9 Hz, 2H), 7.23 (td, J = 8.8, 6.3 Hz, 1H), 7.06 (t, J = 9.0 Hz, 1H), 3.24 (t, J = 6.7 Hz, 2H), 2.82 (s, 3H), 2.69 (t, J = 6.1 Hz, 2H), 2.35 (s, 6H) 123 A 617.2 1H NMR (400 MHz, DMSO-d 6) δ: 10.78 (br s, 1H), 10.30 (s, 1H), 9.68 (s, 1H), 9.66 (s, 1H), 8.61 (s, 1H), 8.54 (d, J = 8.2 Hz, 1H), 7.92 (d, J = 7.8 Hz, 1H), 7.85 (br. d, J = 6.3 Hz, 1H), 7.42 - 7.53 (m, J = 8.2, 8.2, 4.7 Hz, 2H), 7.25 (d, J = 8.2 Hz, 1H), 7.27 (d, J = 8.2 Hz, 1H), 7.12 (br s, 1H) 124 A 580.2 1H NMR (400 MHz, DMSO-d 6 ) δ: 10.58 (s, 1H), 10.21 (s, 1H), 9.77 (s, 1H), 8.79 (d, J = 8.2 Hz, 1H), 8.65 (s, 1H), 8.27 (d, J = 8.2 Hz, 1H), 7.77 - 7.83 (m, 2H), 7.75 (d, J = 8.2 Hz, 1H), 7.63 (t, J = 7.4 Hz, 1H), 7.39 ( t, J = 8.0 Hz, 1H), 7.33 (td, J = 8.6, 5.9 Hz, 1H), 7.25 (t, J = 9.0 Hz, 1H), 2.66 (s, 3H) 125 f 742.4 1H NMR (400 MHz, DMSO-d 6) δ: 10.62 (s, 1H), 10.44 (s, 1H), 9.70 (s, 1H), 9.46 (br s, 1H), 9.39 (s, 1H), 8.98 (d, J = 8.2 Hz, 1H), 8.60 (s, 1H), 8.01 (d, J = 7.8 Hz, 1H), 7.77 (t, J = 7.4 Hz, 2H), 7.56 (t, J = 7.8 Hz , 1H), 7.47 (t, J = 7.6 Hz, 1H), 7.39 (t, J = 8.0 Hz, 1H), 7.31 - 7.37 (m, 1H), 7.29 (t, J = 9.0 Hz, 1H), 3.41 (t, J = 5.5 Hz, 2H), 3.36 (t, J = 4.7 Hz, 2H), 2.88 (d, J = 3.5 Hz, 6H), 2.83 (s, 3H), 2.68 (s, 3H) 126 f 726.4 1H NMR (400 MHz, DMSO-d 6) δ: 10.45 (br s, 1H), 9.67 (s, 1H), 9.37 (s, 1H), 8.96 (d, J = 8.6 Hz, 1H), 8.58 (s , 1H), 7.97 (d, J = 7.8 Hz, 1H), 7.63 (d, J = 7.4 Hz, 1H), 7.53 (t, J = 7.4 Hz, 1H), 7.45 (d, J = 7.8 Hz, 1H ), 7.43 (dd, J = 6.7, 3.5 Hz, 1H), 7.38 (dd, J = 7.8, 5.5 Hz, 1H), 7.31 (td, J = 8.8, 5.9 Hz, 1H), 7.19 (t, J = 9.0 Hz, 1H), 3.23 (t, J = 6.5 Hz, 2H), 2.82 (s, 3H), 2.66 (t, J = 6.1 Hz, 2H), 2.51 (d, J = 2.3 Hz, 3H), 2.33 (s, 6H) 127 A 579.2 1H NMR (400 MHz, DMSO-d 6) δ: 10.61 (br s, 1H), 10.27 (s, 1H), 9.67 (s, 1H), 9.62 (s, 1H), 8.71 (d, J = 8.6 Hz , 1H), 8.59 (s, 1H), 7.81 (dd, J = 10.2, 8.2 Hz, 2H), 7.70 (br s, 1H), 7.48 (ddd, J = 8.2, 7.4, 0.8 Hz, 1H), 7.41 (ddd, J = 8.2, 7.0, 1.2 Hz, 1H), 7.36 (t, J = 8.2 Hz, 1H), 7.30 (br s, 1H), 7.19 (br s, 1H), 2.67 (s, 3H) 128 h 766.2 1H NMR (400 MHz, DMSO-d 6 ) δ:10.77 (br s, 1H), 10.23 (s, 1H), 9.66 (s, 1H), 9.43 (s, 1H), 8.58 (s, 1H), 8.26 (d, J = 8.3 Hz, 1H), 7.94 (d, J = 7.9 Hz, 1H), 7.91 (dd, J = 7.9, 1.4 Hz, 1H), 7.53 (t, J = 8.0 Hz, 1H), 7.28 - 7.39 (m, 2H), 7.25 (t, J = 9.0 Hz, 1H), 6.84 (d, J = 7.9 Hz, 1H), 6.00 (s, 1H), 4.22 (d, J = 11.9 Hz, 2H) , 3.09 (dd, J = 12.1, 10.8 Hz, 2H), 1.94 (td, J = 12.7, 4.4 Hz, 2H), 1.80 (d, J = 12.4 Hz, 2H) 129 h 738.4 1H NMR (400 MHz, DMSO-d 6 ) δ:10.77 (br s, 1H), 10.22 (s, 1H), 9.65 (s, 1H), 9.40 (s, 1H), 8.58 (s, 1H), 8.23 (d, J = 8.1 Hz, 1H), 7.95 (d, J = 7.9 Hz, 1H), 7.91 (dd, J = 8.0, 1.5 Hz, 1H), 7.53 (t, J = 8.0 Hz, 1H), 7.34 (td, J = 8.8, 5.8 Hz, 1H), 7.29 (t, J = 8.1 Hz, 1H), 7.26 (t, J = 9.0 Hz, 1H), 6.79 (d, J = 7.9 Hz, 1H), 3.77 (t, J = 6.8 Hz, 2H), 3.57 - 3.68 (m, 2H), 3.51 (ddd, J = 11.9, 7.7, 4.3 Hz, 2H), 1.91 (quin, J = 6.9 Hz, 2H), 1.66 - 1.82 (m, 6H) 130 h 712.2 1H NMR (400 MHz, DMSO-d 6 ) δ:10.77 (br s, 1H), 10.22 (s, 1H), 9.65 (s, 1H), 9.39 (s, 1H), 8.57 (s, 1H), 8.21 (d, J = 8.1 Hz, 1H), 7.95 (d, J = 8.0 Hz, 1H), 7.91 (dd, J = 8.0, 1.4 Hz, 1H), 7.54 (t, J = 8.1 Hz, 1H), 7.34 (td, J = 8.9, 6.1 Hz, 1H), 7.19 - 7.31 (m, 2H), 6.79 (d, J = 8.0 Hz, 1H), 4.30 (s, 1H), 3.76 (dt, J = 12.0, 4.5 Hz, 2H), 3.36 - 3.45 (m, 2H), 1.58 - 1.78 (m, 4H), 1.20 (s, 3H) 131 h 712.2 1H NMR (400 MHz, DMSO-d 6 ) δ:10.77 (br s, 1H), 10.23 (s, 1H), 9.65 (s, 1H), 9.40 (s, 1H), 8.58 (s, 1H), 8.23 (d, J = 8.1 Hz, 1H), 7.95 (d, J = 8.0 Hz, 1H), 7.91 (dd, J = 8.0, 1.5 Hz, 1H), 7.54 (t, J = 8.0 Hz, 1H), 7.34 (td, J = 8.8, 6.0 Hz, 1H), 7.20 - 7.31 (m, 2H), 6.78 (d, J = 7.9 Hz, 1H), 3.97 (dt, J = 12.4, 3.8 Hz, 2H), 3.40 ( spt, J = 4.1 Hz, 1H), 3.30 (s, 3H), 3.13 (ddd, J = 12.3, 9.8, 2.5 Hz, 2H), 1.94 - 2.11 (m, 2H), 1.64 (dtd, J = 12.5, 9.2, 3.5 Hz, 2H) 132 h 707.2 1H NMR (400 MHz, DMSO-d 6 ) δ:10.77 (br s, 1H), 10.23 (s, 1H), 9.66 (s, 1H), 9.42 (s, 1H), 8.58 (s, 1H), 8.27 (d, J = 8.1 Hz, 1H), 7.95 (d, J = 8.0 Hz, 1H), 7.91 (dd, J = 7.9, 1.4 Hz, 1H), 7.54 (t, J = 8.0 Hz, 1H), 7.29 - 7.40 (m, 2H), 7.26 (t, J = 9.0 Hz, 1H), 6.82 (d, J = 7.9 Hz, 1H), 3.66 - 3.86 (m, 2H), 3.38 (ddd, J = 11.8, 8.3 , 2.9 Hz, 2H), 3.12 (tt, J = 8.2, 4.1 Hz, 1H), 2.09 (ddd, J = 9.3, 6.2, 2.8 Hz, 2H), 1.87 - 2.02 (m, 2H) 133 h 726.2 1H NMR (400 MHz, DMSO-d 6 ) δ:10.77 (br s, 1H), 10.23 (s, 1H), 9.65 (s, 1H), 9.39 (s, 1H), 8.57 (s, 1H), 8.21 (d, J = 8.1 Hz, 1H), 7.95 (d, J = 8.0 Hz, 1H), 7.91 (dd, J = 7.9, 1.4 Hz, 1H), 7.54 (t, J = 8.0 Hz, 1H), 7.34 (td, J = 8.4, 6.0 Hz, 1H), 7.21 - 7.31 (m, 2H), 6.79 (d, J = 7.9 Hz, 1H), 4.08 (s, 1H), 3.81 - 3.95 (m, 2H), 3.25 (td, J = 11.9, 2.8 Hz, 2H), 1.68 (td, J = 12.5, 4.0 Hz, 2H), 1.56 - 1.64 (m, 2H), 1.46 (q, J = 7.4 Hz, 2H), 0.89 (t, J = 7.4 Hz, 3H) 134 h 672.2 1H NMR (400 MHz, DMSO-d 6) δ: 10.16 (br s, 1H), 9.63 (s, 1H), 9.44 (s, 1H), 8.58 (s, 1H), 8.14 (s, 1H), 8.09 (d, J = 8.00 Hz, 1H), 7.80 - 7.98 (m, 1H), 7.42 (br s, 1H), 7.25 (t, J = 8.13 Hz, 1H), 6.61 (d, J = 8.25 Hz, 1H ), 6.52 (s, 1H), 4.76 (t, J = 5.07 Hz, 1H), 3.93 (t, J = 6.19 Hz, 2H), 3.69 (q, J = 5.92 Hz, 2H), 3.13 (s, 3H ) 135 see text 665.2 1H NMR (400 MHz, DMSO-d 6) δ: 10.74 (br s, 1H), 10.19 (s, 1H), 9.77 (s, 1H), 8.76 (d, J = 8.26 Hz, 1H), 8.66 (s , 1H), 7.84 - 7.99 (m, 2H), 7.73 - 7.84 (m, 1H), 7.69 (d, J = 7.25 Hz, 1H), 7.53 (t, J = 8.07 Hz, 1H), 7.32 (d, J = 6.13 Hz, 1H), 7.22 (br s, 1H), 2.04 - 2.11 (m, 2H), 1.91 - 2.02 (m, 2H) 136 I 727.4 1H NMR (400 MHz, DMSO-d 6 ) δ: 10.74 (s, 1H), 10.13 (s, 1H), 9.74 (s, 1H), 8.63 (s, 1H), 8.08 (d, J = 8.13 Hz, 1H), 7.95 (d, J = 8.00 Hz, 1H), 7.91 (dd, J = 1.19, 7.94 Hz, 1H), 7.53 (dt, J = 6.00, 7.94 Hz, 2H), 7.29 - 7.44 (m, 1H ), 7.07 - 7.29 (m, 1H), 6.84 (d, J = 8.00 Hz, 1H), 4.06 - 4.29 (m, 3H), 3.37 - 3.58 (m, 2H), 1.56 - 1.81 (m, 4H), 1.47 (q, J = 7.34 Hz, 2H), 0.89 (t, J = 7.44 Hz, 3H) 137 see text 674.2 1H NMR (400 MHz, DMSO-d 6) δ: 10.74 (br s, 1H), 10.20 (s, 1H), 9.68 - 9.85 (m, 1H), 8.50 - 8.71 (m, 1H), 8.30 (d, J = 8.38 Hz, 1H), 7.80 - 8.03 (m, 2H), 7.66 (t, J = 8.13 Hz, 1H), 7.53 (t, J = 8.00 Hz, 1H), 7.31 (d, J = 6.00 Hz, 1H), 7.22 (br s, 1H), 7.09 (d, J = 7.88 Hz, 1H), 4.48 (dd, J = 3.63, 5.25 Hz, 2H), 3.84 (dd, J = 3.63, 5.25 Hz, 2H) , 3.35 - 3.46 (m, 3H) 138 I 739.3 1H NMR (400 MHz, DMSO-d 6) δ: 10.74 (s, 1H), 10.14 (s, 1H), 9.68 - 9.75 (m, 1H), 8.63 (s, 1H), 8.10 (d, J = 8.25 Hz, 1H), 7.95 (d, J = 8.00 Hz, 1H), 7.90 (dd, J = 1.38, 8.00 Hz, 1H), 7.53 (dt, J = 4.06, 8.04 Hz, 2H), 7.28 - 7.38 (m , 1H), 7.05 - 7.28 (m, 1H), 6.84 (d, J = 8.00 Hz, 1H), 3.86 - 4.13 (m, 2H), 3.79 (t, J = 6.75 Hz, 2H), 3.70 (ddd, J = 3.94, 8.54, 12.54 Hz, 2H), 1.85 - 2.02 (m, 2H), 1.68 - 1.84 (m, 6H) 139 I 728.2 1H NMR (400 MHz, DMSO-d 6) δ: 10.10 (br s, 1H), 9.68 - 9.76 (m, 1H), 8.62 - 8.68 (m, 1H), 8.19 (d, J = 7.88 Hz, 1H) , 8.13 (s, 1H), 7.91 (dd, J = 1.25, 7.88 Hz, 1H), 7.87 (d, J = 8.13 Hz, 1H), 7.56 (t, J = 8.07 Hz, 1H), 7.49 (t, J = 8.00 Hz, 1H), 7.20 - 7.33 (m, 1H), 7.12 (br s, 1H), 6.84 (d, J = 8.00 Hz, 1H), 4.59 (br s, 1H), 3.79 (br s, 4H), 3.61 (br s, 2H), 2.82 (br s, 4H), 2.61 (br s, 2H) 140 h 686.2 1H NMR (400 MHz, DMSO-d 6) δ: 10.76 (br s, 1H), 10.19 (s, 1H), 9.64 (s, 1H), 9.37 (s, 1H), 8.51 - 8.59 (m, 1H) , 8.02 (d, J = 8.13 Hz, 1H), 7.91 (d, J = 7.88 Hz, 2H), 7.51 (br s, 1H), 7.09 - 7.38 (m, 3H), 6.32 (d, J = 7.88 Hz , 1H), 4.75 (d, J = 6.00 Hz, 1H), 4.63 (d, J = 6.00 Hz, 1H), 4.28 (t, J = 7.94 Hz, 2H), 3.99 (dd, J = 5.63, 7.88 Hz , 2H), 3.12 (td, J = 6.11, 19.17 Hz, 1H) 141 G 690.2 1H NMR (400 MHz, DMSO-d 6) δ: 10.78 (br s, 1H), 10.55 (s, 1H), 9.68 (s, 1H), 9.43 (s, 1H), 8.96 (d, J= 8.38 Hz , 1H), 8.58 (s, 1H), 7.81 - 8.02 (m, 3H), 7.54 (dt, J= 4.75, 7.69 Hz, 2H), 7.46 (t, J= 7.50 Hz, 1H), 7.31 - 7.40 ( m, 1H), 7.26 (t, J= 9.13 Hz, 1H), 3.40 (q, J= 7.30 Hz, 2H), 1.22 (t, J= 7.38 Hz, 3H) 142 G 746.2 1H NMR (400 MHz, DMSO-d 6 ) δ: 10.78 (s, 1H), 10.54 (s, 1H), 9.69 (s, 1H), 9.42 (s, 1H), 8.97 (d, J= 8.38 Hz, 1H), 8.58 (s, 1H), 7.83 - 8.03 (m, 3H), 7.50 - 7.62 (m, 2H), 7.41 - 7.50 (m, 1H), 7.30 - 7.41 (m, 1H), 7.27 (d, J= 8.88 Hz, 1H), 3.91 (dd, J= 4.00, 11.13 Hz, 2H), 3.58 (tt, J= 3.60, 11.91 Hz, 1H), 3.29 (br s, 1H), 1.90 (d, J= 10.76 Hz, 2H), 1.68 (dq, J= 4.57, 12.32 Hz, 2H) 143 G 753.2 1H NMR (400 MHz, DMSO-d 6) δ: 10.78 (br s, 1H), 10.53 (s, 1H), 9.68 (s, 1H), 9.34 (s, 1H), 8.94 (d, J= 8.50 Hz , 1H), 8.58 (s, 1H), 8.47 (d, J= 5.88 Hz, 2H), 7.96 (d, J= 8.00 Hz, 1H), 7.91 (dd, J= 1.38, 8.00 Hz, 1H), 7.62 (d, J= 8.00 Hz, 1H), 7.51 (t, J= 7.50 Hz, 1H), 7.54 (t, J= 8.07 Hz, 1H), 7.30 - 7.42 (m, 2H), 7.15 - 7.30 (m, 3H), 4.86 (s, 2H) 144 G 760.2 1H NMR (400 MHz, DMSO-d 6 ) δ: 10.78 (s, 1H), 10.54 (s, 1H), 9.69 (s, 1H), 9.43 (s, 1H), 8.96 (d, J= 8.51 Hz, 1H), 8.58 (s, 1H), 7.95 (d, J= 7.75 Hz, 2H), 7.91 (dd, J= 1.31, 7.94 Hz, 1H), 7.51 - 7.60 (m, 2H), 7.42 - 7.51 (m , 1H), 7.35 (d, J= 6.63 Hz, 1H), 7.26 (br s, 1H), 3.65 - 3.83 (m, 2H), 3.40 (d, J= 6.25 Hz, 2H), 3.22 - 3.28 (m , 2H), 2.11 - 2.29 (m, 1H), 1.67 - 1.88 (m, 2H), 1.30 - 1.45 (m, 2H) 145 h 725.2 1H NMR (400 MHz, DMSO-d 6) δ: 10.16 (br s, 1H), 9.63 (s, 1H), 9.47 (s, 1H), 8.59 (s, 1H), 8.27 (d, J= 8.25 Hz , 1H), 7.93 (dd, J= 1.38, 7.88 Hz, 1H), 7.73 (d, J= 7.75 Hz, 1H), 7.41 (t, J= 7.94 Hz, 1H), 7.31 (t, J= 8.07 Hz , 1H), 7.16 (dt, J= 6.07, 9.04 Hz, 1H), 6.94 (t, J= 9.01 Hz, 1H), 6.80 (d, J= 8.00 Hz, 1H), 4.41 (d, J= 12.13 Hz , 2H), 2.90 - 3.21 (m, 2H), 2.82 (t, J= 11.63 Hz, 2H), 2.65 (s, 6H), 2.01 - 2.13 (m, 2H), 1.70 - 1.87 (m, 2H) 146 h 727..2 1H NMR (400 MHz, DMSO-d 6) δ: 10.20 (s, 1H), 9.64 (s, 1H), 9.45 (s, 1H), 8.59 (s, 1H), 8.28 (d, J= 8.13 Hz, 1H), 7.92 (dd, J= 1.38, 7.88 Hz, 1H), 7.84 (d, J= 7.88 Hz, 1H), 7.47 (t, J= 7.94 Hz, 1H), 7.32 (t, J= 8.13 Hz, 1H), 7.16 - 7.28 (m, 1H), 7.10 (t, J= 8.82 Hz, 1H), 6.78 (d, J= 8.00 Hz, 1H), 3.54 - 3.69 (m, 6H), 2.85 (br s, 4H), 2.60 - 2.73 (m, 2H) 147 h 698.3 1H NMR (400 MHz, DMSO-d 6 ) δ: 10.77 (s, 1H), 10.27 (s, 1H), 9.65 (s, 1H), 9.39 (s, 1H), 8.57 (s, 1H), 7.94 ( d, J = 8.13 Hz, 1H), 7.81 - 7.93 (m, 2H), 7.53 (t, J = 8.07 Hz, 1H), 7.29 - 7.41 (m, 1H), 7.25 (br s, 1H), 7.21 ( t, J = 8.07 Hz, 1H), 6.52 (d, J = 8.88 Hz, 1H), 5.99 (t, J = 5.94 Hz, 1H), 3.71 - 3.86 (m, 2H), 3.64 (q, J = 7.75 Hz, 1H), 3.54 (dd, J = 5.32, 8.44 Hz, 1H), 3.25 (t, J = 6.63 Hz, 2H), 2.60 - 2.75 (m, 1H), 1.91 - 2.13 (m, 1H), 1.67 (dd, J = 5.57, 12.82 Hz, 1H) 148 A 559.2 1H NMR (400 MHz, DMSO-d 6) δ: 10.28 (s, 1H), 9.67 (s, 1H), 9.62 (s, 1H), 8.70 (d, J= 8.13 Hz, 1H), 8.60 (s, 1H), 7.79 (d, J= 7.88 Hz, 1H), 7.82 (d, J= 7.88 Hz, 1H), 7.54 (d, J= 6.88 Hz, 1H), 7.37 - 7.52 (m, 3H), 7.33 ( t, J= 7.44 Hz, 1H), 7.04 - 7.30 (m, 2H), 3.05 (q, J= 7.38 Hz, 2H), 1.21 (t, J= 7.44 Hz, 3H) 149 h 686.4 1H NMR (400 MHz, DMSO-d 6) δ: 10.41 (br s, 1H), 10.22 (s, 1H), 9.65 (s, 1H), 9.40 (s, 1H), 8.59 (s, 1H), 8.21 (d, J= 8.13 Hz, 1H), 7.78 (d, J= 7.88 Hz, 1H), 7.58 (t, J= 7.50 Hz, 1H), 7.47 (d, J= 7.63 Hz, 1H), 7.35 (t , J= 7.57 Hz, 1H), 7.17 - 7.32 (m, 3H), 6.79 (d, J= 8.00 Hz, 1H), 4.08 (s, 1H), 3.89 (d, J= 11.88 Hz, 2H), 3.16 - 3.29 (m, 2H), 3.04 (q, J= 7.38 Hz, 2H), 1.53 - 1.77 (m, 4H), 1.46 (q, J= 7.30 Hz, 2H), 1.21 (t, J= 7.44 Hz, 3H), 0.89 (t, J= 7.38 Hz, 3H) 150 A 611.2 1H NMR (400 MHz, DMSO-d 6) δ: 10.85 (br s, 1H), 10.30 (s, 1H), 9.68 (s, 1H), 9.63 (s, 1H), 8.70 (d, J= 8.00 Hz , 1H), 8.57 (s, 1H), 7.82 (d, J= 7.88 Hz, 1H), 7.72 (br s, 1H), 7.22 - 7.51 (m, 6H) 151 h 738.4 1H NMR (400 MHz, DMSO-d 6) δ: 10.85 (br s, 1H), 10.23 (s, 1H), 9.65 (s, 1H), 9.41 (s, 1H), 8.56 (s, 1H), 8.21 (d, J= 8.26 Hz, 1H), 7.73 (d, J= 6.00 Hz, 1H), 7.42 - 7.51 (m, 1H), 7.32 - 7.42 (m, 2H), 7.29 (t, J= 8.07 Hz, 2H), 6.79 (d, J= 8.00 Hz, 1H), 4.08 (s, 1H), 3.89 (d, J= 11.88 Hz, 2H), 3.18 - 3.29 (m, 2H), 1.52 - 1.76 (m, 4H ), 1.46 (q, J= 7.34 Hz, 2H), 0.89 (t, J= 7.44 Hz, 3H) 152 A 579.3 1H NMR (400 MHz, DMSO-d 6) δ: 10.53 (br s, 1H), 10.28 (s, 1H), 9.68 (s, 1H), 9.62 (s, 1H), 8.71 (d, J= 8.13 Hz , 1H), 8.60 (s, 1H), 7.81 (t, J= 8.69 Hz, 2H), 7.62 (br s, 1H), 7.45 - 7.54 (m, 1H), 7.41 (t, J= 7.57 Hz, 2H ), 7.26 (br s, 2H), 2.40 (s, 3H) 153 h 706.3 1H NMR (400 MHz, DMSO-d 6) δ: 10.55 (br s, 1H), 10.22 (s, 1H), 9.65 (s, 1H), 9.23 - 9.49 (m, 1H), 8.58 (s, 1H) , 8.21 (d, J= 8.13 Hz, 1H), 7.79 (d, J= 7.75 Hz, 1H), 7.64 (d, J= 7.50 Hz, 1H), 7.39 (t, J= 7.75 Hz, 1H), 7.28 (t, J= 8.00 Hz, 2H), 7.11 - 7.25 (m, 1H), 6.79 (d, J= 8.00 Hz, 1H), 4.08 (s, 1H), 3.89 (d, J= 11.76 Hz, 2H) , 3.17 - 3.29 (m, 2H), 2.40 (s, 3H), 1.54 - 1.82 (m, 4H), 1.46 (q, J= 7.38 Hz, 2H), 0.89 (t, J= 7.44 Hz, 3H) 154 A 581.2 1H NMR (400 MHz, DMSO-d 6) δ: 10.59 (br s, 1H), 10.28 (s, 1H), 9.68 (s, 1H), 9.61 (s, 1H), 8.70 (d, J= 8.13 Hz , 1H), 8.58 (s, 1H), 7.82 (d, J= 7.88 Hz, 1H), 7.64 (dd, J= 5.07, 8.57 Hz, 1H), 7.37 - 7.54 (m, 3H), 7.27 - 7.37 ( m, 1H), 7.23 (br s, 1H), 2.54 - 2.59 (m, 3H) 155 h 708.4 1H NMR (400 MHz, DMSO-d 6) δ: 10.58 (br s, 1H), 10.21 (s, 1H), 9.65 (s, 1H), 9.39 (s, 1H), 8.57 (s, 1H), 8.21 (d, J= 8.13 Hz, 1H), 7.63 (dd, J= 4.88, 8.63 Hz, 1H), 7.45 (q, J= 8.80 Hz, 1H), 7.18 - 7.39 (m, 3H), 6.79 (d, J= 8.00 Hz, 1H), 4.08 (s, 1H), 3.89 (d, J= 11.76 Hz, 2H), 3.17 - 3.29 (m, 2H), 2.56 (d, J= 2.25 Hz, 3H), 1.64 - 1.75 (m, 2H), 1.55 - 1.64 (m, 2H), 1.46 (q, J= 7.25 Hz, 2H), 0.89 (t, J= 7.44 Hz, 3H) 156 A 633.2 1H NMR (400 MHz, DMSO-d 6) δ: 10.75 (br s, 1H), 10.32 (s, 1H), 9.68 (s, 1H), 9.61 (s, 1H), 8.70 (d, J = 8.0 Hz , 1H), 8.60 (s, 1H), 8.10 (d, J = 8.0 Hz, 1H), 8.03 (d, J = 8.0 Hz, 1H), 7.86 (t, J = 8.1 Hz, 1H), 7.82 (d , J = 7.9 Hz, 1H), 7.48 (t, J = 7.6 Hz, 1H), 7.41 (t, J = 7.7 Hz, 1H), 7.36 (dd, J = 8.3, 6.0 Hz, 1H), 7.30 (t , J = 9.3 Hz, 1H) 157 A 605.2 1H NMR (400 MHz, DMSO-d 6) δ: 11.05 (br s, 1H), 10.35 (s, 1H), 9.69 (s, 1H), 9.64 (s, 1H), 8.71 (d, J = 8.1 Hz , 1H), 8.62 (s, 1H), 8.21 (s, 1H), 7.83 (d, J = 7.8 Hz, 1H), 7.49 (t, J = 7.9 Hz, 1H), 7.42 (t,...

Claims

1. A compound of formula I, wherein: R1 is a group of the following formula: R17 is selected from H, OH, halogen, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C1-6 alkyl, C5-10 heteroaryl, C3-10 cycloalkyl, C4-10 heterocycloalkyl, C(O)R15, C(O)N(R14)2, SO2R15, SO2N(R14)2, N(R16)C(O)R15, N(R16)SO2R15, N(R16)C(O)N(R14)2, N(R16) )SO2N(R14)2, N(R14)2, P(O)(R15)2, CH2C(O)R15, CH2C(O)N(R14)2, CH2SO2R15, CH2SO2N(R14)2, CH 2N(R16)C(O)R15, CH2N(R16)SO2R15, CH2N(R16)C(O)N(R14)2, CH2N(R16)SO2N(R14)2 and CH2N(R14)2; X6 is N or CH; and X7 is N and R18 is absent; or X7 is C and R18 is selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkyl, C5-10 heteroaryl, C3-10 cycloalkyl, C4-10 heterocycloalkyl, C(O)R15, C(O)N(R14)2, SO2R15, SO2N(R14)2, N(R16)C(O)R15, N(R16)SO2R15, N(R16)C(O)N(R14)2 , N(R16)SO2N(R14)2, N(R14)2, P(O)(R15)2, CH2C(O)R15, CH2C(O)N(R14)2, CH2SO2R15, CH2SO2N(R14)2 , CH2N(R16)C(O)R15, CH2N(R16)SO2R15, CH2N(R16)C(O)N(R14)2, CH2N(R16)SO2N(R14)2 and CH2N(R14)2; R14, each time it appears, is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, C4-10 heterocycloalkyl, C6 aryl, and C5-10 heteroaryl, or two R14s together with their adjacent nitrogen atoms to form a C4-10 heterocycloalkyl; R15, each time it appears, is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, C6 aryl, and C5-10 heteroaryl; and R16, each time it appears, is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, C6 aryl, and C5-10 heteroaryl; wherein the alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, or heteroaryl group may be further substituted; and wherein (---) indicates a single bond;R2 is selected from groups B21, B36, B41, B42, B52, B53, B54, B59, B65, or B73 as defined below: X1 is a halogroup or an electron-withdrawing group; X2 is selected from H, a halogroup, and an electron-withdrawing group; X3 and X4 are each selected from H, a halogroup, an electron-withdrawing group, a C1-3 alkyl group, a C3-4 cycloalkyl group, and an OC1-3 alkyl group; Y is selected from H, a halogroup, CN, OH, an OC1-8 alkyl group, NH2, NHC1-8 alkyl group, N(C1-8 alkyl)2, and a substituted or unsubstituted C1-8 alkyl group; or a pharmaceutically acceptable salt thereof.

2. The compound as claimed in claim 1, wherein R1 is selected from: wherein R14 and R15 are as defined in claim 1 and (---) denotes a bond.

3. The compound as claimed in claim 1, wherein Y is H, X1 is F, X2 is F, X3 is H, X4 is H, and R1 and R2 are defined as follows:

4. A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 3, and a pharmaceutically acceptable carrier, diluent, or excipient.

5. Use of a compound as defined in any one of claims 1 to 3 for the preparation of a medicament for the treatment of a disease or condition selected from: a proliferative disease or condition, a developmental disorder (RAS disease) caused by RAS-ERK cascade dysregulation, an inflammatory disease, or an immune system disorder.

6. The use as described in claim 5, wherein the disease or condition is selected from a cyst and a developmental abnormality.

7. The use as described in claim 5 or 6, wherein the disease or condition is associated with a RAF gene mutation or a RAS gene mutation.

8. The use as described in claim 7, wherein the disease or condition is associated with a mutation in an ARAF, BRAF, or CRAF gene.

9. The use as described in claim 7, wherein the disease or condition is associated with a KRAS gene mutation.

10. The use as described in claim 5 or 6, wherein the disease or condition is associated with a mutation or amplification of a receptor tyrosine kinase or a mutation or amplification of a regulator of one of the downstream RAS of the receptor.

11. The use as described in claim 10, wherein the disease or condition is associated with a mutation or amplification of an EGFR or HER2 receptor tyrosine kinase.

12. The use as described in claim 10, wherein the disease or condition is associated with an amplification in gaining SOS1 function or losing NF1 function.

13. The use as described in claim 6, wherein the tumor is selected from melanoma, thyroid cancer, colorectal cancer, ovarian cancer, breast cancer, endometrial cancer, liver cancer, sarcoma, gastric cancer, pancreatic cancer, Barrett's adenocarcinoma, glioma, lung cancer, head and neck cancer, acute lymphoblastic leukemia, acute myeloid leukemia, non-Hodgkin's lymphoma, and hairy cell leukemia.

14. The use as described in claim 13, wherein the thyroid cancer is papillary thyroid cancer.

15. The use as described in claim 13, wherein the glioma is an ependymoma.

16. The use as described in claim 13, wherein the lung cancer is non-small cell lung cancer.

Images