Pyrido[3,2-d]pyrimidine compounds, compositions containing same, and methods of use thereof

Abstract

Compounds, compositions, and their uses in treating proliferative diseases or conditions, e.g., where the proliferative disease or disorder is associated with RAF gene mutations and / or RAS gene mutations. The compounds disclosed have the following formula I or a pharma- ceutical acceptable salt or solvate thereof, wherein R 1 , R 2 , R 3 , X 1 , X 2 , X 3 , X 4 and Y is as defined herein. JPEG2024514227000323.jpg54170

Description

[Technical Field]

[0001] Related Applications This application claims priority under applicable law to U.S. Provisional Application No. 63 / 201,219, filed April 19, 2021, the contents of which are incorporated herein by reference in their entirety for all purposes.

[0002] The present disclosure relates generally to pyrido[3,2-d]pyrimidine compounds, pharmaceutical compositions containing same, and their use in the treatment and prevention of diseases characterized by dysregulation of the RAS-ERK pathway (e.g., cancer, RASopathies). [Background technology]

[0003] The RAS-RAF-MEK-ERK (RAS (rat sarcoma): rat sarcoma; RAF (rapidly accelerated fibrosarcoma): rapidly accelerated fibrosarcoma; MEK (mitogen-activated protein kinase): mitogen-activated protein kinase; ERK (extracellular signal-regulated kinase): extracellular signal-regulated kinase) signaling pathway (hereinafter referred to as the RAS-ERK pathway) plays a key role in transmitting growth signals generated by growth factor receptors from the cell membrane to the nucleus. This pathway is dysregulated in the majority of cancers by the activation of receptor tyrosine kinases (RTKs) (e.g., ERBB1, ERBB2, FLT3, RET, KIT) or the activation or inactivation of RAS regulators (SOS1 and NF1), as well as by constitutively activating mutations in the RAS gene (H-, K-, NRAS; 30% of cancers) and the BRAF gene (8% of cancers). The prevalence of KRAS mutations is particularly high in pancreatic cancer (over 90%), colorectal cancer (50%), and lung cancer (30%). On the other hand, BRAF mutations are found with particularly high frequency in malignant melanoma (70%), thyroid cancer (40%), and colorectal cancer (10%) (mutation frequencies are listed in COSMIC (Catalogue Of Somatic Mutations In Cancer; Wellcome Trust Sanger Institute) release v95, November 24). th (Based on 2021).

[0004] RAS proteins are small GTPases that transmit extracellular growth signals to intracellular effectors to regulate important processes such as cell differentiation, proliferation, and survival (Nat. Rev. Cancer 2003, 3, 459). Following RTK stimulation, physiological activation of RAS occurs at the plasma membrane, resulting in the loading of GTP onto the GTPase and its activation. Activated RAS interacts with and activates a series of effector molecules, with RAF kinases being the most important RAS interactor in the context of cancer development (Nature Rev. Drug Discov. 2014, 13, 828). Oncogenic mutations at glycine 12, glycine 13, or glutamine 61 in RAS isoforms cause aberrant and constitutive signaling in human cancers (Nat. Rev. Cancer 2003, 3, 459) (COSMIC release v95, November 24, 2021).

[0005] Downstream of RAS, mammalian cells express three RAF paralogs (ARAF, BRAF, and CRAF), which share a conserved C-terminal kinase domain (KD) and an N-terminal regulatory region (NTR) containing a RAS-binding domain (RBD) (Nat. Rev. Mol. Cell Biol. 2015, 16, 281). In unstimulated cells, RAF proteins are sequestered in the cytoplasm as monomers. Binding of activated GTP-bound RAS to the RBD induces membrane anchoring of RAF kinases (Nat. Rev. Mol. Cell Biol. 2015, 16, 281). Concomitantly, RAF proteins undergo side-to-side dimerization of the kinase domains, resulting in catalytic activation (Nature 2009, 461, 542). Activated RAF proteins signal through a phosphorylation cascade from RAF to MEK and then from MEK to ERK, leading to ERK phosphorylation of an array of substrates that trigger cell-specific responses (Nat. Rev. Mol. Cell Biol. 2020, Oct;21(10),607).

[0006] Activating mutations in RAF isoforms have so far been mostly restricted to the BRAF gene, but rare mutations have been observed in ARAF and CRAF, highlighting the functional importance of these isoforms (COSMIC release v95, November 24). th The most common cancer mutation in BRAF is a valine to glutamic acid substitution at position 600 (BRAF V600E(V600E allele) enhances BRAF activity by stabilizing its active form (Cell 2004, 116, 855). Apart from the V600E allele, various mutations occur at other residues (e.g., G466V, D594G, etc.) that cause increased RAF signaling through various mechanisms (Nat. Rev. Mol. Cell Biol. 2015, 16, 281). These have been classified into three major classes (1-3) depending on the level of dependence on RAS activity and RAF dimerization (Nature 2017 Aug 10;548(7666):234-238). The crucial role of wild-type BRAF and CRAF in mediating RAS-driven oncogenesis by stimulating ERK signaling has been widely validated (Cancer Cell 2011, 19, 652; Cancer Discov. 2012, 2, 685; Nat. Commun. 2017, 8, 15262). Thus, tumor cells rely on elevated and sustained signaling of the RAS-ERK pathway through activation of RAS and RAF, providing strong support for the concept of targeting RAF family kinases in cancer.

[0007] To address existing medical needs, a broad set of ATP-competitive RAF inhibitors has been developed over the past decade (Nat.Rev.Cancer 2017, 17, 76), primarily targeting the most common RAS-independent BRAF mutations (BRAF V600E ), leading to the development and FDA approval of sulfonamide derivatives, such as vemurafenib and dabrafenib. Some of these RAF inhibitors target recurrent BRAF V600E It has shown remarkable efficacy against metastatic melanoma with the BRAF allele and is approved for treating this patient population (N. Engl. J. Med. 2011, 364, 2507; Lancet 2012, 380, 358). V600EClinical responses against BRAF-dependent melanoma are due to potent, ATP-competitive inhibition of the monomeric form of this specific dimerization-independent BRAF mutant protein (Cancer Cell 2015, 28, 370). Unfortunately, acquired resistance to these agents inevitably develops, often due to reactivation of the RAS-ERK pathway, in part through mechanisms that stimulate RAF dimerization. These include upregulation of RTK signaling, RAS mutations, and BRAF V600E This includes amplification or cleavage (Sci. Signal. 2010, 3, ra84; Nature 2010, 468, 973; Nature 2011, 480, 387; Nature Commun. 2012, 3, 724).

[0008] At the same time, tumors that exhibit RAS activity due to activating RAS mutations or enhanced RTK signaling but are otherwise BRAF wild-type may be involved in the development of BRAF V600E RAF inhibitors show primary resistance to BRAF inhibitors (Nature 2010, 464, 431). Conversely, RAF inhibitors have been shown to induce ERK signaling under conditions of elevated RAS activity, thereby promoting tumor cell proliferation (Nature 2010, 464, 431). This counterintuitive phenomenon, known as the paradoxical effect, is also observed in normal tissues that depend on physiological RAS activity and is the basis for some of the side effects seen with RAF inhibitors in melanoma patients, such as the development of new secondary tumors (e.g., squamous cell carcinomas and keratoacanthomas) (Nat.Rev.Cancer 2014, 14, 455). Consequently, BRAF inhibitors are thought to be a potential therapeutic option for melanoma patients. V600EInhibitors are ineffective and even contraindicated in RAS-driven cancers. The underlying mechanism is due to the ability of compounds to promote dimerization of RAF kinase domains in the presence of activated RAS (Nature, 2010, 464, 431). This event is not limited to BRAF but also involves other RAF family members, and is determined by the binding mode and affinity of the compound (Nat. Chem. Biol. 2013, 9, 428).

[0009] To circumvent the limitations of first-generation RAF inhibitors in RAS-mutant cancers, two strategies have recently been pursued. The first strategy is based on the observation that paradoxical ERK activation is a dose-dependent phenomenon, i.e., induction occurs at subsaturating inhibitor concentrations, but the pathway is suppressed at saturating concentrations when the compound occupies both protomers of the RAF dimer. Therefore, this first strategy focused on developing molecules with high binding affinity to all RAF paralogs to saturate RAF proteins at lower drug concentrations and thereby suppress induction of the paradoxical pathway (Bioorg. Med. Chem. Lett. 2012, 22, 6237; Cancer Res. 2013, 73, 7043; J. Med. Chem. 2015, 58, 4165; Cancer Cell 2017, 31, 466; J Med Chem. 2020, 63, 2013; Clin Cancer Res. 2021, 27, 2061; Nature 2021, 594, 418). However, these compounds retained potent RAF dimer induction and thus paradoxically stimulated RAS-ERK signaling, although with a smaller amplitude than previous generation RAF inhibitors. Although this class of compounds exhibits improved properties, they have recently been shown to largely avoid ARAF isoforms, thereby leading to activation of the paradoxical pathway and the emergence of primary and acquired resistance in vitro and in the clinic (Clin Cancer Res. 2021, 27, 2061; Nature 2021, 594, 418). A second strategy consisted of designing compounds that conformationally bias the BRAF kinase domain toward an inactive state and thus paradoxically do not induce ERK signaling. This resulted in the "Paradox Breaker" (PB) molecule PLX8394, a derivative of PLX4032 / vemurafenib (Nature 2015, 526, 583). These molecules inhibit BRAF. V600E It retains high efficacy against BRAF V600EThis should prove useful for treating RAS-dependent melanoma. However, although PLX8394 does not induce ERK signaling in the RAS-mutant cell lines tested, it remains ineffective and not useful against RAS-mutant tumors. Summary of the Invention [Problem to be solved by the invention]

[0010] There remains a need for inhibitors that potently and consistently inhibit RAS-ERK signaling and cell proliferation in human tumor cells with various RAS and RAF genotypes. The development of such inhibitors is also important and highly desirable, as they do not induce paradoxical pathways in various RAS-mutant tumor cell lines. [Means for solving the problem]

[0011] According to one aspect, the present technology relates to compounds of Formula I below, or a pharmaceutically acceptable salt or solvate thereof: [ka] where: R 1 is replaced or not replaced OR 3 , S.R. 3 , NH2, NHR 3 , N(R 3 )2, C 3~8 Cycloalkyl, C 4~8 Heterocycloalkyl, C 6~10 Aryl and C 5~10 heteroaryl, e.g., substituted or unsubstituted, C 6~10 Aryl and C 5~10 heteroaryl; R 2 is a substituted C aryl or C 5~10 Heteroaryl, substituted or unsubstituted, C 4~8 Heterocycloalkyl and N(R 3 )2 is selected; R 3 is independently in each occurrence substituted or unsubstituted, C 1~8 Alkyl, C 3~8 Cycloalkyl, C 4~8 Heterocycloalkyl, C 6~10 Aryl and C 5~10 heteroaryl; X 1 is a halogen atom or an electron-withdrawing group; X 2 is selected from H, a halogen atom, and an electron-withdrawing group; X 3 and X 4 are H, halogen atoms, electron-withdrawing groups, and C 1~3 Alkyl, C 3~4 Cycloalkyl and OC 1~3 alkyl.

[0012] Compounds of formula I are also defined according to any of the embodiments and examples, alone or in combination, described throughout this specification.

[0013] According to another aspect, the present technology relates to a pharmaceutical composition for use as defined in any one of the foregoing embodiments, wherein the composition comprises a compound as defined herein together with a pharmaceutically acceptable carrier, diluent, or excipient.

[0014] In a further aspect, the present technology relates to the use of the compounds defined herein for the treatment of a disease or disorder selected from a proliferative disease or disorder, a developmental anomaly caused by dysregulation of the RAS-ERK signaling cascade (RASopathies), or an inflammatory disease or immune system disorder.

[0015] The present technology also relates to a method for treating a disease or disorder selected from a proliferative disease or disorder, a developmental anomaly (RASopathies) caused by dysregulation of the RAS-ERK signaling cascade, or an inflammatory disease or immune system disorder, comprising administering a compound as defined herein to a subject in need of such treatment.A method for inhibiting the abnormal proliferation of cells is also contemplated, comprising contacting the cells with a compound as defined herein.

[0016] In one embodiment of the above-mentioned uses and methods, the disease or disorder is selected from neoplasms and developmental anomalies, such as diseases or disorders associated with RAF gene mutations (e.g., ARAF, BRAF, or CRAF), diseases or disorders associated with RAS gene mutations (e.g., KRAS), or diseases or disorders associated with both RAF gene mutations and RAS gene mutations. In one embodiment, the disease or disorder is associated with receptor tyrosine kinase mutations or amplifications (e.g., EGFR, HER2), or mutations in downstream regulators of the receptor RAS (e.g., SOS1 gain-of-function, NF1 loss-of-function).

[0017] For example, the disease or disorder is a neoplasm, such as a neoplasm selected from melanoma, thyroid cancer (e.g., papillary thyroid cancer), colorectal cancer, ovarian cancer, breast cancer, endometrial cancer, liver cancer, sarcoma, gastric cancer, pancreatic cancer, Barrett's adenocarcinoma, glioma (e.g., ependymoma), lung cancer (e.g., non-small cell lung cancer), head and neck cancer, acute lymphocytic leukemia, acute myeloid leukemia, non-Hodgkin's lymphoma, and hairy cell leukemia. For example, the neoplasm is selected from colon cancer or colorectal cancer, lung cancer, pancreatic cancer, thyroid cancer, breast cancer, and melanoma. For example, any of the above uses and methods of the present invention comprises inhibiting the RAS-ERK signaling pathway without substantially inducing the paradoxical pathway.

[0018] Further objects and features of the compounds, compositions, methods and uses of the present invention will become apparent upon reading the non-limiting description in the following illustrative embodiments and examples section, which should not be construed as limiting the scope of the invention. [Brief explanation of the drawings]

[0019] [Figure 1] FIG. 1 shows representative IC50 inhibition dose-response curves for compounds described herein that do not induce paradoxical induction of pERK signaling (Ymin >-20%) in RAS-mutated HCT116 cells (Examples 99, 113, 128, 139, 140) and a compound (PLX4720; CAS No. 918505-84-7) that causes strong induction of the pathway (Ymin ∼-600%) in the same cell line. [Figure 2] Figure 2 shows the results of immunoblot analysis of RAS mutant HCT-116 cells treated with a representative compound (Example 99; top panel) that does not induce paradoxical induction of pERK or pMEK signaling, compared with a compound (PLX4720; bottom panel) that induces the pathways in the same cell line. [Figure 3A] Figure 3A shows the results of pharmacodynamic analysis of pERK biomarkers compared to vehicle (Vehicle) in mice bearing xenograft tumors representing a series of cancer cell lines with various mutational backgrounds (A375, A101D, A2058, RKO, HT29 SK-MEL 30, Calu-6, HepG2, Lovo, NCI-H2122, NCIH1666, and NCIH1755). Mice were orally administered the compound of Example 99 at 150 mg / kg (mpk: mg per kg). Inhibition of the ERK pathway was determined using pERK and total ERK AlphaLISA® SureFire® Ultra™ kits after 4 hours of oral administration of the suspension of Example 99. [Figure 3B]Figure 3B shows the results of pharmacodynamic analysis of pERK biomarkers compared to vehicle (Vehicle) in mice bearing xenograft tumors representing a series of cancer cell lines with various mutational backgrounds (A375, A101D, A2058, RKO, HT29 SK-MEL 30, Calu-6, HepG2, Lovo, NCI-H2122, NCIH1666, and NCIH1755). Mice were orally administered the compound of Example 99 at 150 mg / kg (mpk: mg per kg). Inhibition of the ERK pathway was determined using pERK and total ERK AlphaLISA® SureFire® Ultra™ kits after 4 hours of oral administration of a suspension of Example 99. [Figure 4] Figure 4 shows the results of tumor growth inhibition (TGI) experiments performed on A375 (A) and HCT116 (B). Each data point represents the mean (±) tumor size and standard error of the mean (SEM) on the day before and the day after treatment was initiated. The treatment period corresponds to the arrow labeled "Rx." Mice were orally administered the suspension of Example 99 (dose in mg / kg, i.e., mpk) or a blank formulation (vehicle) once or twice daily (QD or BID). Tumors were measured three times a week with an electronic microcaliper. DETAILED DESCRIPTION OF THE INVENTION

[0020] All technical and scientific terms used herein have the same definitions as commonly understood by one of ordinary skill in the art to which this technology pertains. Nevertheless, definitions of some terms and phrases used are provided below. To the extent that definitions of terms in publications, patents, and patent applications incorporated herein by reference contradict the definitions set forth herein, the definitions in this specification shall control. The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter disclosed.

[0021] i.Definition

[0022] The chemical structures described herein are drawn according to conventional standards. Also, when an atom, such as a carbon atom, is drawn with incomplete valences, it is assumed that the valences are satisfied by one or more hydrogen atoms, even if not necessarily explicitly drawn. The hydrogen atoms should be assumed to be part of the compound.

[0023] 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," "an," and "the" include the plural forms as well unless the content clearly dictates otherwise. Thus, for example, reference to a composition containing "a compound" also refers to a mixture of two or more compounds. It should also be noted that the word "or" is generally used in its sense to include "and / or" unless the context clearly dictates otherwise. Furthermore, to the extent the words "including," "includes," "having," "has," "with," or variations thereof are used in either the description and / or claims, such words are intended to be inclusive in a manner similar to the word "comprising."

[0024] The words "about" or "approximately" mean within an acceptable error range for a particular value, as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, "about" can mean within one standard deviation or more than one standard deviation, in accordance with practice in the art. Alternatively, "about" can 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, particularly with respect to biological systems or processes, the term can mean within an order of magnitude, preferably within 5-fold, and more preferably within 2-fold of a value. Where particular values ​​are described in the present specification and claims, unless otherwise specified, the word "about" meaning within an acceptable error range for the particular value should be assumed.

[0025] As used herein, the terms "compound," "compounds described herein," "compounds of the present application," "pyrido[3,2-d]pyrimidine compounds," "pyridopyrimidine compounds," and their equivalents refer to compounds described herein, e.g., compounds encompassed by Structural Formula I, optionally with reference to any applicable embodiment, and also include exemplary compounds, e.g., the compounds of Examples 1-691, and, where applicable, pharmaceutically acceptable salts, solvates, esters, and prodrugs thereof. Where a zwitterionic form is possible, the compound may be depicted as its neutral form for practical purposes, but it is understood that the compound also includes the zwitterionic form. Embodiments herein may also exclude one or more of the compounds. Compounds may be identified by either their chemical structure or their chemical name. In the event of a conflict between the chemical structure and the chemical name, the chemical structure will control.

[0026] Unless otherwise stated, structures depicted herein are also meant to include, where applicable, all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure, e.g., the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the compounds of the present application are within the scope of this specification. Unless otherwise specified, therapeutic compounds also include all possible tautomers, if any, of an exemplified compound. The term also includes isotopically labeled compounds where one or more atoms have an atomic mass different from the atomic mass most abundant in nature. Examples of isotopes that may be incorporated into the compounds of the invention are: 2 H(D), 3 H(T), 11 C. 13 C. 14 C. 15 N, 18 O. 17 The compounds may also exist in unsolvated forms as well as solvated forms, such as the solvated forms described above, including hydrates. The compounds may also exist in multiple 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 present invention.

[0027] When a particular enantiomer is preferred, it may, in some embodiments, be provided substantially free of the corresponding enantiomer, or it may be enantiomerically enriched. "Enantiomerically enriched" means that the compound is significantly enriched in one enantiomer. In some embodiments, the compound is made up of at least about 90% by weight of the preferred enantiomer. In other embodiments, the compound is made up of at least about 95%, 98%, or 99% by weight of the preferred enantiomer. The preferred enantiomer may be isolated from a racemic mixture by any method known to those skilled in the art, such as high-pressure liquid chromatography (HPLC) on a chiral support, and the methods described above, including the formation and crystallization of chiral salts, or may be prepared by asymmetric synthesis.

[0028] The expression "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention that is suitable, within the scope of sound medical judgment, for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and that is commensurate with a reasonable benefit / risk ratio. These pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al. describe these pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66:1-19 (1977). The salts can be prepared in situ during the final isolation and purification of the compounds of the present invention, or can be prepared separately by reacting a free base functional group of the compound with a suitable organic or inorganic acid (acid addition salts), or by reacting an acidic functional group of the compound with a suitable organic or inorganic base (base addition salts).

[0029] The term "solvate" refers to a physical association of one of the compounds of the present invention with one or more solvent molecules, such as those listed above, including water and non-aqueous solvent molecules. This physical association may involve hydrogen bonding. In some cases, a solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated into the crystal lattice of a 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 solvates of other physiologically acceptable solvents, such as Class 3 solvents described in the International Conference on Harmonization (ICH), Guide for Industry, Q3C Impurities: Residual Solvents (1997). Thus, the compounds described herein also encompass their respective solvates and mixtures thereof.

[0030] As used herein, the phrase "pharmaceutically acceptable ester" refers to an ester of a compound formed by a process herein that is hydrolyzable in vivo, including those that readily decompose in the human body to leave the parent compound or a salt thereof. Suitable ester groups include, for example, compounds derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic, and alkanedioic acids, where each alkyl or alkenyl moiety advantageously has six or fewer carbon atoms. Examples of specific esters include, but are not limited to, formates, acetates, propionates, butyrates, acrylates, and ethylsuccinates of hydroxyl groups, and alkyl esters of acidic groups. Other ester groups include sulfonates or sulfates.

[0031] As used herein, the phrase "pharmaceutically acceptable prodrug" refers to a prodrug of a compound formed by a process herein, which prodrug is suitable, within the scope of sound medical judgment, for use in contact with the tissues of humans and lower animals, is not associated with undue toxicity, irritation, allergic response, or the like, and is commensurate with a reasonable benefit / risk ratio and is effective for their intended use. As used herein, "prodrug" means a compound that is convertible in vivo by metabolic means (e.g., hydrolysis) to provide any compound depicted by a formula herein.

[0032] Abbreviations may also be used throughout this specification; unless otherwise specified, such abbreviations are intended to have the meaning generally understood in the art. Examples of such abbreviations are Me (methyl), Et (ethyl), Pr (propyl), i-Pr (isopropyl), Bu (butyl), t-Bu (tert-butyl), i-Bu (isobutyl), s-Bu (sec-butyl), c-Bu (cyclobutyl), Ph (phenyl), Bn (benzyl), Bz (benzoyl), CBz or Cbz or Z (carbobenzyloxy), Boc or BOC (tert-butoxycarbonyl), and Su or Suc (succinimide). For greater certainty, additional definitions of certain abbreviations are also included in the introduction to the "Examples" section.

[0033] The number of carbon atoms in a hydrocarbyl substituent is indicated by the prefix "C x ~C y " or "C x~y " where x is the minimum number of carbon atoms in the substituent and y is the maximum number of carbon atoms in the substituent. However, the prefix "C x ~C y " or "C x~y" is associated with a group that by definition incorporates one or more heteroatoms (e.g., heterocycloalkyl, heteroaryl, etc.), x and y define the minimum and maximum number of atoms in the ring, respectively, including carbon atoms and the one or more heteroatoms.

[0034] As used herein, the term "alkyl" refers to a saturated, straight- or branched-chain hydrocarbon moiety typically containing 1 to 20 carbon atoms. For example, a "C1-C8 alkyl" contains 1 to 8 carbon atoms. Examples of alkyl moieties include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl, n-hexyl, heptyl, octyl, and the like.

[0035] As used herein, the term "alkenyl" refers to a straight or branched chain hydrocarbon moiety containing one or more double bonds and typically containing from 2 to 20 carbon atoms. For example, "C 2~8 Alkenyl" contains 2 to 8 carbon atoms. Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, l-methyl-2-buten-l-yl, heptenyl, octenyl, and the like.

[0036] As used herein, the term "alkynyl" refers to a straight or branched chain hydrocarbon radical containing one or more triple bonds and typically containing from 2 to 20 carbon atoms. For example, "C 2~8 Alkynyl" contains from 2 to 8 carbon atoms. Representative alkynyl groups include, but are not limited to, for example, ethynyl, 1-propynyl, 1-butynyl, heptynyl, octynyl, and the like.

[0037] As used herein, the terms "cycloalkyl," "alicyclic," "carbocycle," "carbocyclic," and equivalents refer to groups containing monocyclic or polycyclic saturated or partially unsaturated (non-aromatic) carbocyclic rings, such as those described above, including spiro (sharing one atom), fused (sharing at least one bond), or bridged (sharing two or more bonds) carbocyclic ring systems, having 3 to 15 ring members. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopenten-1-yl, cyclopenten-2-yl, cyclopenten-3-yl, cyclohexyl, cyclohexen-1-yl, cyclohexen-2-yl, cyclohexen-3-yl, cycloheptyl, bicyclo[4,3,0]nonanyl, norbornyl, and the like. The term "cycloalkyl" encompasses both unsubstituted and substituted cycloalkyl groups. Word “C3~C n "Cycloalkyl" refers to cycloalkyl groups having three or more, and the indicated "n" number of carbon atoms in their ring structure. Unless the number of carbons is otherwise specified, as used herein, "lower cycloalkyl" groups have at least three, and no more than eight, carbon atoms in their ring structure.

[0038] As used herein, the terms "heterocycle," "heterocycloalkyl," "heterocyclyl," "heterocyclic radical," and "heterocyclic ring" are used interchangeably and refer to a chemically stable 3- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic moiety that is saturated or partially unsaturated and has, in addition to carbon atoms, one or more, preferably one to four, heteroatoms as defined above. When used in reference to a ring atom of a heterocycle, the term "nitrogen atom" includes substituted nitrogen atoms. For example, in a saturated or partially unsaturated ring having one to three heteroatoms selected from oxygen, sulfur, or nitrogen atoms, the nitrogen atom may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR (as in N-substituted pyrrolidinyl). A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a chemically stable structure, and any of the ring atoms can be optionally substituted.Examples of heterocycloalkyl groups are 1,3-dioxolanyl, pyrrolidinyl, pyrrolidonyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrodithienyl, tetrahydrothienyl, thiomorpholino, thioxanyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiazole ... These include, but are not limited to, epanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, 3-azabicyclo[3,1,0]hexanyl, 3-azabicyclo[4,1,0]heptanyl, quinolidinyl, quinuclidinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinylquinolinyl, and the like. Heterocyclyl groups also include groups in which a heterocycle is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3H-indolyl, chromanyl, chromenyl, phenanthridinyl, 2-azabicyclo[2.2.1]heptanyl, octahydroindolyl, or tetrahydroquinolinyl, where the moiety or point of attachment is on the heterocyclyl ring. Heterocyclyl groups can be monocyclic or bicyclic. The term "heterocyclylalkyl" refers to an alkyl group substituted by a heterocyclyl, where the alkyl and heterocyclyl portions independently may be optionally substituted. The term "C. 3~n "Heterocycloalkyl" refers to a heterocycloalkyl group having three or more, and the indicated "n" atoms in the ring structure, including carbon atoms and heteroatoms.

[0039] As used herein, the term "partially unsaturated" refers to a ring moiety that contains at least one double or triple bond between ring atoms, but that is not aromatic. The term "partially unsaturated" is intended to include rings with multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as defined herein.

[0040] The term "aryl," whether used alone or as part of a larger moiety, such as "aralkyl," "aralkoxy," "aryloxy," or "aryloxyalkyl," refers to an aromatic group having 4n+2 (where n is an integer from 1 to 3) conjugated π (pi) electrons in a monocyclic moiety or a bicyclic or tricyclic fused ring system having a total of 6 to 15 ring members, where at least one ring in the system is aromatic and each ring in the system contains 3 to 7 ring members. The term "aryl" may be used interchangeably with the term "aryl ring." In certain embodiments herein, "aryl" refers to an aromatic ring system, including, but not limited to, phenyl, biphenyl, naphthyl, azulenyl, anthracyl, and the like, which may bear one or more substituents. The term "aralkyl" or "arylalkyl" refers to an alkyl residue attached to an aryl ring. Examples of aralkyls include, but are not limited to, benzyl, phenethyl, and the like. Also included within the scope of the term "aryl", as used herein, are aromatic rings fused to one or more non-aromatic rings, such as indanyl, indenyl, phthalimidyl, naphthimidyl, fluorenyl, phenanthridinyl, or tetrahydronaphthyl. 6~n "Aryl" refers to aryl groups having 6 or more atoms in the ring structure, with the indicated "n" number of atoms.

[0041] The term "heteroaryl," when used alone or as part of a larger moiety, such as "heteroaralkyl" or "heteroaralkoxy," refers to an aromatic group having 4n+2 (where n is an integer from 1 to 3) conjugated π (pi) electrons (e.g., having 5 to 18 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 π electrons shared in the cyclic array) and having 1 to 5 heteroatoms in addition to carbon atoms. The term "heteroatom" includes, but is not limited to, a nitrogen, oxygen, or sulfur atom, and includes any oxidized form of a nitrogen or sulfur atom and any quaternized form of a basic nitrogen atom. A heteroaryl may be a single ring or two or more fused rings. As used herein, the term "heteroaryl" also includes groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclic rings, where the moiety or point of attachment is on the heteroaromatic ring.Non-limiting examples of heteroaryl groups include thienyl, furanyl (furyl), pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, indolyl, 3H-indolyl, isoindolyl, indolizinyl, benzothienyl (benzothiophenyl), benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, pyrrolopyridinyl (e.g., pyrrolo[3,2-b] or pyrrolo[3,2-c]pyridinyl), Heteroaryl groups include quinolyl (e.g., pyrazolo[1,5-a]pyridinyl), furopyridinyl, purinyl, imidazopyrazinyl (e.g., imidazo[4,5-b]pyrazinyl), quinolyl (quinolinyl), isoquinolyl (isoquinolinyl), quinolonyl, isoquinolonyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, naphthyridinyl, and pteridinylcarbazolyl, acridinyl, phenanthridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-l,4-oxazin-3(4H)-one. Heteroaryl groups may be monocyclic or bicyclic. Heteroaryl groups include rings that are optionally substituted. The term "heteroaralkyl" refers to an alkyl group substituted by a heteroaryl, where the alkyl and heteroaryl portions independently are optionally substituted. Examples include, but are not limited to, pyridinylmethyl, pyrimidinylethyl, and the like. For example, the term "C. 5~n "Heteroaryl" refers to heteroaryl groups having five or more, and the indicated "n" atoms in the ring structure, including carbon atoms and heteroatoms.

[0042] As described herein, the compounds herein may contain "optionally substituted" moieties. In general, the term "substituted," whether preceded by the term "optionally," means that one or more hydrogen atoms of the specified moiety are replaced with a suitable substituent. Unless otherwise indicated, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituents may be the same or different at each position. Combinations of substituents contemplated herein preferably result in the formation of chemically stable or chemically feasible compounds. As used herein, the term "chemically stable" refers to compounds that remain substantially unchanged when subjected to conditions that enable their preparation, detection, and, in some embodiments, their recovery, purification, and use for one or more purposes disclosed herein.

[0043] The term "halo" means a halogen atom, ie, a fluorine, chlorine, bromine or iodine atom, preferably a fluorine or chlorine atom.

[0044] The term "optionally substituted" refers to a group that is substituted or unsubstituted by independently replacing one, two, or more of the hydrogen atoms on the group with a substituent, such as those listed above, including, but not limited to, the following: F, CI, Br, I, OH, COH, alkoxy, oxo, thioxo, NO, CN, CF, NH, NH-alkyl, NH-alkenyl, NH-alkynyl, NH-cycloalkyl, NH-aryl, NH-heteroaryl, NH-heterocycle, dialkylamino, diarylamino, diheteroarylamino, O-aryl, O-aryl- ... 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, CO2cycloalkyl, CO2aryl, CO2heteroaryl, CO2heterocycloalkyl, OC(O)alkyl, OC(O)alkenyl, OC(O)alkynyl, OC(O)cycloalkyl alkyl, OC(O)aryl, OC(O)heteroaryl, OC(O)heterocycloalkyl, C(O)NH2, C(O)NHalkyl, C(O)NHalkenyl, C(O)NHalkynyl, C(O)NHcycloalkyl, C(O)NHaryl, C(O)NHheteroaryl, C(O)NHheterocycloalkyl, OCO2alkyl, OCO2alkenyl, OCO2alkynyl, OCO2cycloalkyl, OCO2aryl, OCO2heteroaryl, OCO2heterocycloalkyl, OC(O)NH2, OC(O)NHalkyl, OC(O)NHalkynyl nyl, OC(O)NHalkynyl, OC(O)NHcycloalkyl, OC(O)NHaryl, OC(O)NHheteroaryl, OC(O)NHheterocycloalkyl, NHC(O)alkyl, NHC(O)alkenyl, NHC(O)alkynyl, NHC(O)cycloalkyl, NHC(O)aryl, NHC(O)heteroaryl, NHC(O)heterocycloalkyl, NHCO2alkyl, NHCO2alkenyl, NHCO2alkynyl, NHCO2cycloalkyl, NHCO2aryl, NHCO2heteroaryl, NHCO2heterocycloalkyl,NHC(O)NH2, NHC(O)NH alkyl, NHC(O)NH alkenyl, NHC(O)NH alkynyl, NHC(O)NH cycloalkyl, NHC(O)NH aryl, NHC(O)NH heteroaryl, NHC(O)NH heterocycloalkyl, NHC(S)NH2, NHC(S)NH alkyl, NHC(S)NH alkenyl, NHC(S)NH alkynyl, NHC(S)NH cycloalkyl, NHC(S)NH aryl, NHC(S)NH heteroaryl, NHC(S)NH heterocycloalkyl, NHC(NH)NH2, NHC(NH NH alkyl, NHC(NH)NH alkenyl, NHC(NH)NH alkynyl, NHC(NH)NH cycloalkyl, NHC(NH)NH aryl, NHC(NH)NH heteroaryl, NHC(NH)NH heterocycloalkyl, NHC(NH) alkyl, NHC(NH) alkenyl, NHC(NH) alkynyl, NHC(NH) cycloalkyl, NHC(NH) aryl, NHC(NH) heteroaryl, NHC(NH) heterocycloalkyl, C(NH)NH alkyl, C(NH)NH alkenyl, C(NH)NH alkynyl, C(NH)NH cycloalkyl Cycloalkyl, C(NH)NHaryl, C(NH)NHheteroaryl, C(NH)NHheterocycloalkyl, 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 )(Oheterocycloalkyl)2, S(O)alkyl, S(O)alkenyl, S(O)alkynyl, S(O)cycloalkyl, S(O)aryl, S(O)2alkyl, S(O)2alkenyl, S(O)2alkynyl, S(O)2cycloalkyl, S(O)2aryl, S(O)heteroaryl, S(O)heterocycloalkyl, SO2NH2, SO2NHalkyl, SO2NHalkenyl, SO2NHalkynyl, SO2NHcycloalkyl, SO2NHaryl, SO2NHheteroaryl, SO2NHheterocycloalkyl, NHSO2alkyl,NHSO2alkenyl, NHSO2alkynyl, NHSO2cycloalkyl, NHSO2aryl, NHSO2heteroaryl, NHSO2heterocycloalkyl, CH2NH2, CH2SO2CH3, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, cycloalkyl, carbocyclic, heterocyclic, polyalkoxyalkyl, polyalkoxy, methoxymethoxy, methoxyethoxy, SH, S-alkyl, S-alkenyl, S-alkynyl, S-cycloalkyl, S-aryl, S-heteroaryl, S-heterocycloalkyl, or methylthiomethyl.

[0045] ii. compound

[0046] The recitation of a list of chemical groups in any definition of a variable herein includes definitions of that variable as any single group or combination of listed groups. The recitation of embodiments of a variable herein includes those embodiments as any single embodiment or in combination with any other embodiment or portion thereof. The recitation of an embodiment herein includes that embodiment as any single embodiment or in combination with any other embodiment or portion thereof. Thus, the following embodiments, where applicable, occur alone or in combination.

[0047] The compounds of the present invention exhibit a pyrido[3,2-d]pyrimidine core structure to which defined substituents are attached to achieve the beneficial activity of the product. Exemplary pyridopyrimidine compounds defined herein, or their pharmaceutically acceptable salts or solvates thereof, are represented by the following general formula I: [ka] where: R 1 is replaced or not replaced OR 3 , S.R. 3 , NH2, NHR 3 , N(R3 )2, C 3~8 Cycloalkyl, C 4~8 Heterocycloalkyl, C 6~10 Aryl and C 5~10 heteroaryl, for example, substituted or unsubstituted C 6~10 Aryl and C 5~10 heteroaryl; R 2 is a substituted C aryl or C 5~10 Heteroaryl, substituted or unsubstituted, C 4~8 Heterocycloalkyl and N(R 3 )2 is selected; R 3 is independently in each occurrence substituted or unsubstituted, C 1~8 Alkyl, C 3~8 Cycloalkyl, C 4~8 Heterocycloalkyl, C 6~10 Aryl and C 5~10 heteroaryl, preferably R 3 is a substituted or unsubstituted C 1~8 Alkyl (e.g., C 1~3 alkyl); X 1 is a halogen atom or an electron-withdrawing group; X 2 is selected from H, a halogen atom, and an electron-withdrawing group; X 3 and X 4 are H, halogen atoms, electron-withdrawing groups, and C 1~3 Alkyl, C 3~4 Cycloalkyl and OC 1~3 alkyl.

[0048] For example, the electron-withdrawing group is selected from perhaloalkyl (e.g., CF3 or CCl3), CN, NO2, sulfonate, alkylsulfonyl (e.g., SO2Me or SO2CF3), alkylcarbonyl (e.g., C(O)Me), carboxylate, alkoxycarbonyl (e.g., C(O)OMe), and aminocarbonyl (e.g., 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 X 1 and X 2 are both F. In another embodiment, X 3 and X 4 are each H. In yet another embodiment, X 3 is F, and X 4 is H.

[0049] For example, the aminoarylsulfonamide moiety of Formula I may be designated L and is preferably selected from the following: [ka] Here, the dashed lines (---) represent bonds.

[0050] In one example, R 2 is a substituted C aryl or C 5~10 Heteroaryl, for example, R 2 is a C6 aryl group substituted with at least one group selected from F, Cl, Br, CN, and NO2, and a substituted or unsubstituted C 1~3 Alkyl group, C 3~4 Cycloalkyl group or OC 1~3 It is an alkyl group. For example, R 2 is a group of the formula: [ka] where: R 4is 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, CHF2 and CF3; R 5 is 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 H, F, Cl, Br, NO2, NH2, and substituted or unsubstituted, C 1~3 Alkyl, C 3~4 Cycloalkyl or OC 1~3 alkyl, for example, R 6 is 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 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 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 benzoxazolinone; and (---) represents a bond; where R 4 is H or F, then R 5 , R 6 , R 7 or R 8 is other than H or F; and where R 5 If is CN, then R 4 , R 6 , R 7 or R 8 At least one of is other than H.

[0051] In one embodiment, R 8 is H. In another embodiment, R 4 is selected from F, Cl, Et and Me, R 5 , R 7 and R 8 are each H, and R 6 is selected from H, Cl, Me and OMe. In a further embodiment, R 4 is selected from F, Cl and Me, R 5 is selected from F and Cl, and R 6 , R 7 and R 8 are each H.

[0052] In another embodiment, R 4 is selected from Cl, Br and Me, R 5 is selected from H, F, Cl or methyl, R 6 is selected from H, F, Cl, Me and OMe, and R 7 and R 8 are each selected from H.

[0053] In a further embodiment, R 4 is Cl, and substituted or unsubstituted C 1~3 alkyl (e.g., Me), preferably R 4 is Cl or Me; R 5is H, F, Cl, and substituted or unsubstituted C 1~3 alkyl (e.g., Me), preferably R 5 is F, Cl or Me; R 6 is H, F, Cl, substituted or unsubstituted C 1~3 Alkyl (e.g., Me), and substituted or unsubstituted OC 1~3 alkyl (e.g., OCH), 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 or OCH; and R 7 and R 8 are each H. In still other embodiments, R 6 is the substituted C 1~3 It is alkyl.

[0054] In another example, R 2 is the substituted C 5~10 Heteroaryl, for example, a group of the formula: [ka] where: X 5 NH, NC 1~3 Alkyl, NC 3~4 cycloalkyl, selected from O and S; R 9 , R 10 , R 11 are each independently 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, with the proviso that R 9 and R 11 one of which is H and the other is not H; and (---) represents a bond.

[0055] Alternatively, R 2 is a group of the formula: [ka] where: X 5 NH, NC 1~3 Alkyl, NC 3~4 cycloalkyl, selected from O and S; R 9 is 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 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 (---) represents a bond.

[0056] 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 R 9 and R 10 are both Cl. In another embodiment, X 5 is O or S, preferably S.

[0057] In another embodiment, R 2 is the substituted C 5~10Heteroaryl, for example, a group of the formula: [ka] where: X 9 , X 10 , X 11 , X 12 and X 13 are independently selected from N and C, where X 9 , X 10 , X 11 , X 12 and X 13 at least one and not more than two of are N; and R 19 , R 20 , R 21 , R 22 and R 23 is H, F, Cl, Br, CN, NO2, NH2, and substituted or unsubstituted C 1~3 Alkyl, C 3~4 Cycloalkyl or OC 1~3 alkyl or their bonded X 9 , X 10 , X 11 , X 12 or X 13 does not exist when N; where X 9 and X 13 is not N; and where X 9 and X 13 When at least one of the groups is N, the other group is not N or CH.

[0058] In another example, R 2 But C 5~7 Heterocycloalkyl. For example, R 2 is a group of the formula: [ka] where: R 13independently at each occurrence, F, Cl, and substituted or unsubstituted, C 1~3 Alkyl, C 3~4 Cycloalkyl or C 1~3 selected from alkoxy; n is an integer selected from 0 to 8; or n is 2 to 8, and two R 13 together with their adjacent carbon atoms, C 3~4 forming a cycloalkyl; and (---) represents a bond.

[0059] In one embodiment, R 13 is at position 3. In another embodiment, n is 1 or 2 and R 13 is selected from F, Me, OMe and CHOMe. For example, R 13 is a methoxy group, and n is 1.

[0060] In a further embodiment, R 2 is N(R 3 )2, for example, where R 3 is substituted or unsubstituted, C 1~8 Alkyl or C 3~8 cycloalkyl.

[0061] R 2 Non-limiting examples are shown below: [ka] Here, (---) represents a bond.

[0062] In one embodiment, R 2 is a group selected from the following: [ka] Here, (---) represents a bond.

[0063] In another embodiment, R 2is a group selected from the following: [ka] Here, (---) represents a bond.

[0064] In a further embodiment, the compound of formula I is a compound of formula II below, or a pharmaceutically acceptable salt or solvate thereof: [ka] where R 1 , R 4 , R 5 and R 6 are each independently as defined above, preferably R 4 is selected from Cl, Br and Me, and R 5 is selected from H, F, Cl or methyl, and R 6 is selected from H, F, Cl, Me and OMe.

[0065] In yet another embodiment, the compound of formula I is a compound of formula III: or a pharmaceutically acceptable salt or solvate thereof. [ka] where R 1 , R 9 , R 1 , R 12 , and X 5 are each independently as defined above.

[0066] In one embodiment of the compound of Formula I or Formula II, R 1 is substituted or unsubstituted, C 5~6 In another embodiment, R is a heteroaryl group, or a substituted or unsubstituted C heteroaryl group. 1is a substituted or unsubstituted group selected from thienyl, imidazolyl, pyrazolyl, triazolyl, thiazolyl, pyridyl, pyrimidinyl, indolyl, indazolyl, benzimidazolyl, benzotriazolyl, pyrrolopyridinyl (e.g., pyrrolo[3,2-b]pyridinyl or pyrrolo[3,2-c]pyridinyl), pyrazolopyridinyl (e.g., pyrazolo[1,5-a]pyridinyl), purinyl, imidazopyrazinyl (e.g., imidazo[4,5-b]pyrazinyl) and quinolyl (quinolinyl).

[0067] R 1 Examples of are substituted or unsubstituted groups selected from: [ka] Here, (---) represents a bond.

[0068] For example, R 1 is a substituted or unsubstituted group selected from: [ka] Here, (---) represents a bond.

[0069] In one embodiment, R 1 OH, halogen atoms, CN, NO2, 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, SO2R 15 , SO2N(R 14 )2, N(R 16 )C(O)R 15 , N(R 16 )SO2R 15 , N(R 16 )C(O)N(R 14)2, N(R 16 )SO2N(R 14 )2, N(R 14 )2, P(O)(R 15 )2, CH2C(O)R 15 , CH2C(O)N(R 14 )2, CH2SO2R 15 , CH2SO2N(R 14 )2, CH2N(R 16 )C(O)R 15 , CH2N(R 16 )SO2R 15 , CH2N(R 16 )C(O)N(R 14 )2, CH2N(R 16 )SO2N(R 14 )2 and CH2N(R 14 ) one of the above groups further substituted with at least one substituent selected from where: R 14 are independently in each case, H, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Cycloalkyl, C 4~10 Heterocycloalkyl, C6 aryl, and C 5~10 heteroaryl, or two R 14 together with their adjacent nitrogen atoms to form C 4~10 forming a heterocycloalkyl group; R 15 Independently, in each case, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~7 Cycloalkyl, C6 aryl, and C 5~6 heteroaryl; and R 16 are independently in each case, H, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~7 Cycloalkyl, C6 aryl, and C 5~6 heteroaryl; where R 1 (R 14 , R 15 and R 16 The alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups contained within (including the definition of) may be further optionally substituted.

[0070] In another embodiment, R 1 is a group of the formula: [ka] where: R 17 However, H, OH, halogen atoms, CN, NO2, 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, SO2R 15 , SO2N(R 14 )2, N(R 16 )C(O)R 15 , N(R 16 )SO2R 15 , N(R 16 )C(O)N(R 14 )2, N(R 16 )SO2N(R 14 )2, N(R 14 )2, P(O)(R 15 )2, CH2C(O)R 15 , CH2C(O)N(R 14 )2, CH2SO2R 15 , CH2SO2N(R 14 )2, CH2N(R 16 )C(O)R 15 , CH2N(R 16 )SO2R 15 , CH2N(R 16 )C(O)N(R 14)2, CH2N(R 16 )SO2N(R 14 )2, and CH2N(R 14 )2 is selected; X 6 is N or CH; and X 7 is N, and R 18 is not present; or X 7 is C, and R 18 But 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, SO2R 15 , SO2N(R 14 )2, N(R 16 )C(O)R 15 , N(R 16 )SO2R 15 , N(R 16 )C(O)N(R 14 )2, N(R 16 )SO2N(R 14 )2, N(R 14 )2, P(O)(R 15 )2, CH2C(O)R 15 , CH2C(O)N(R 14 )2, CH2SO2R 15 , CH2SO2N(R 14 )2, CH2N(R 16 )C(O)R 15 , CH2N(R 16 )SO2R 15 , CH2N(R 16 )C(O)N(R 14 )2, CH2N(R 16 )SO2N(R 14 )2, and CH2N(R 14 )2 is selected; where R 14 , R 15 and R 16is as defined above; where (R 14 , R 15 , R 16 , R 17 and R 18 (including the definition of)R 1 The alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, or heteroaryl contained therein may be further optionally substituted; and Here, (---) represents a bond.

[0071] In another embodiment, R 1 is the basis of the formula: [ka] where: X 14 is selected from C and N; X 15 , X 16 , X 17 and X 18 are independently O, N, S and CR 17 where R 17 is as defined herein; where X 14 , X 15 , X 16 , X 17 and X 18 At least one and not more than three of are O, N, or S, and two double bonds are present in the ring to maintain aromaticity.

[0072] In further embodiments, the compound of formula I is a compound of formula IV or V below, or a pharmaceutically acceptable salt or solvate thereof. [ka] [ka] where R 4 , R 5 , R6 , R 17 , R 18 , X 6 , X 7 , X 14 , X 15 , X 16 , X 17 and X 18 are each independently as defined herein, preferably R 4 is selected from Cl, Br and Me, R 5 is selected from H, F, Cl or methyl, and R 6 is selected from H, F, Cl, Me and OMe.

[0073] In further embodiments, the compound of formula I is a compound of formula VI or formula VII below, or a pharmaceutically acceptable salt or solvate thereof: [ka] [ka] where R 9 , R 10 , R 12 , R 17 , R 18 , X 5 , X 6 , X 7 , X 14 , X 15 , X 16 , X 17 and X 18 are each independently as defined herein.

[0074] In one embodiment of the above formula, X 6 is N. In another embodiment, X 6 is CH.

[0075] In another embodiment, X 7 is N and R 17 are H, OH, CN, and C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6Alkynyl, 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, SO2R 15 , SO2N(R 14 )2, N(R 16 )C(O)R 15 , N(R 16 )SO2R 15 , N(R 16 )C(O)N(R 14 )2, N(R 16 )SO2N(R 14 )2, N(R 14 )2, P(O)(R 15 )2, CH2C(O)R 15 , CH2C(O)N(R 14 )2, CH2SO2R 15 , CH2SO2N(R 14 )2, CH2N(R 16 )C(O)R 15 , CH2N(R 16 )SO2R 15 , CH2N(R 16 )C(O)N(R 14 )2, CH2N(R 16 )SO2N(R 14 )2 and CH2N(R 14 )2 and R 18 does not exist, where R 14 , R 15 , R 16 or R 17 The alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl or heteroaryl in the formula (I) may be optionally further substituted, and preferably R 17 is 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 )SO2R 15 , C(O)N(R14 )2 and SO2N(R 14 )2, where R 14 , R 15 , R 16 or R 17 The alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, or heteroaryl in the formula (I) may be further optionally substituted. For example, R 17 is H, NH2 and optionally substituted, C 5~10 Heteroaryl or C 4~10 heterocycloalkyl, preferably R 17 is an optionally substituted C 5~10 Heteroaryl or C 4~10 It is heterocycloalkyl.

[0076] In a further embodiment, R 17 is optionally substituted, C 4~10 heterocycloalkyl, wherein the heterocycloalkyl may be monocyclic or bicyclic and contains 1 to 3 heteroatoms, preferably wherein X 7 is N. In a preferred embodiment, the heterocycloalkyl is, for example, F, OH, oxo, CN, C 1~4 Alkyl and OC 1~4 alkyl, wherein the C 1~4 Alkyl is (e.g., F, OH, OC 1~3 For example, the heterocycloalkyl may be selected from optionally substituted piperidine, piperazine, thiomorpholine, and morpholine groups, or bicyclic structures (bridged or spiro) containing a piperidine, piperazine, thiomorpholine, or morpholine ring.

[0077] In a further embodiment, X 7 is C, for example, X 7 is C and R 18 is C 1~6 Alkyl, C 5~10Heteroaryl, C 3~10 Cycloalkyl, C 4~10 Heterocycloalkyl, C(O)R 15 , C(O)N(R 14 )2, SO2R 15 , SO2N(R 14 )2, N(R 16 )C(O)R 15 , N(R 16 )SO2R 15 , N(R 16 )C(O)N(R 14 )2, N(R 16 )SO2N(R 14 )2, N(R 14 )2, P(O)(R 15 )2, CH2C(O)R 15 , CH2C(O)N(R 14 )2, CH2SO2R 15 , CH2SO2N(R 14 )2, CH2N(R 16 )C(O)R 15 , CH2N(R 16 )SO2R 15 , CH2N(R 16 )C(O)N(R 14 )2, CH2N(R 16 )SO2N(R 14 )2 and CH2N(R 14 )2, where R 14 , R 15 , R 16 or R 18 The alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl or heteroaryl in the formula (I) may be optionally further substituted, and preferably R 18 is C(O)N(R 14 )2, SO2R 15 and SO2N(R 14 )2. In a subclass of these embodiments, R 17 are H, OH, and C 1~6 Alkyl, N(R 14 )2, and optionally substituted C 5~10 For example, R 17is H, NH2 and optionally substituted C 5~10 Heteroaryl, preferably H or NH2.

[0078] In yet another embodiment, R 14 is independently at each occurrence H, optionally substituted C 1~6 Alkyl, optionally substituted C 3~10 Cycloalkyl, optionally substituted C 4~10 Heterocycloalkyl and optionally substituted C 5~6 heteroaryl, or two R 14 together with their adjacent nitrogen atoms, optionally substituted C 4~10 It forms a heterocycloalkyl group.

[0079] In another embodiment, R 17 is N(R 14 )2, wherein the R 14 together with their adjacent nitrogen atoms, C 4~10 and form a heterocycloalkyl group, wherein the heterocycloalkyl may be monocyclic or bicyclic and contains 1 to 3 heteroatoms, preferably wherein X 7 is N. In a preferred embodiment, the heterocycloalkyl is, for example, F, OH, oxo, CN, C 1~4 Alkyl and OC 1~4 alkyl, wherein the C 1~4 Alkyl is (e.g., F, OH, OC 1~3 For example, the heterocycloalkyl is selected from optionally substituted piperidine, piperazine, thiomorpholine, and morpholine groups, or bicyclic structures (bridged or spiro) containing a piperidine, piperazine, thiomorpholine, or morpholine ring.

[0080] In another example, R 1is selected from the following: [ka] where R 14 is as defined herein, and (---) represents a bond.

[0081] In a further example, R 1 is selected from the following: [ka] where R 14 is as defined herein, and (---) represents a bond.

[0082] In a further embodiment, R 1 is a substituted or unsubstituted C 4~6 In another example, R 1 are halogen atoms, OH, C 1~6 Alkyl and OC 1~6 C optionally substituted with one or two groups selected from alkyl 4~5 Heterocycloalkyl. For example, R 1 is an N-pyrrolidinyl group substituted with one or two groups selected from F and OH.

[0083] Each R 1 (A group), R 2 Further subembodiments, including (group B) and group L, are also presented in the Examples section. Exemplary combinations are also described in Tables 3, 4, and 5 below. Representative preferred compounds of Examples 1 to 691 are also described herein.

[0084] More specifically, R 1 Preferred examples of are selected from A1 groups to A514 groups defined as follows:

[0085] [ka] JPEG2024514227000026.jpg224170JPEG2024514227000027.jpg192170JPEG20245142270000 28.jpg200170JPEG2024514227000029.jpg191170JPEG2024514227000030.jpg215170JPEG202 4514227000031.jpg221170JPEG2024514227000032.jpg200170JPEG2024514227000033.jpg23 1170JPEG2024514227000034.jpg203170JPEG2024514227000035.jpg209170JPEG20245142270 00036.jpg203170JPEG2024514227000037.jpg204170JPEG2024514227000038.jpg212170JPE G2024514227000039.jpg220170JPEG2024514227000040.jpg207170JPEG2024514227000041.j pg222170JPEG2024514227000042.jpg196170JPEG2024514227000043.jpg219170JPEG2024514 227000044.jpg218170JPEG2024514227000045.jpg216170JPEG2024514227000046.jpg147170

[0086] where (---) is R 1 represents the bond that serves as the point of attachment between the and the rest of the molecule.

[0087] R 2 Preferred examples of are selected from groups B1 to B56 defined below.

[0088] [ka] JPEG2024514227000048.jpg206170JPEG2024514227000049.jpg177170

[0089] where (---) is R 2 represents the bond that serves as the point of attachment between the and the rest of the molecule.

[0090] The following embodiments are examples of compounds of R 1 (A1~A514) group, R 2 The combinations of (B1 to B56) groups and L (L1 to L3) groups are shown below: A1-L-B1;A1-L-B2;A1-L-B3;A1-L-B4~B54;A1-L-B55;A1-L-B56; A2-L-B1;A2-L-B2;A2-L-B3;A2-L-B4~B54;A2-L-B55;A2-L-B56; A3-L-B1;A3-L-B2;A3-L-B3;A3-L-B4~B54;A3-L-B55;A3-L-B56; A4~A512-L-B1;A4~A512-L-B2;A4~A512-L-B3;A4~A512-L-B4~B54;A4~A512-L-B55;A4~A512-L-B56; A513-L-B1;A513-L-B2;A513-L-B3;A513-L-B4~B54;A513-L-B55;A513-L-B56; A514-L-B1;A514-L-B2;A514-L-B3;A514-L-B4~B54;A514-L-B55;A514-L-B56.

[0091] Exemplary compounds, as defined herein, include each single compound listed in Tables 3, 4, and 5 below, from Example 1 through Example 691.

[0092] Examples of preferred compounds are i.e. Examples 3, 6, 8, 19, 20-22, 30, 31, 43, 46, 48, 68, 76, 83, 84, 91-93, 99-102, 111, 113-115, 123, 124-128, 131, 139-141, 168, 171, 176, 177, 180, 188-190, 198, 202-206, 240, 244, 247, 248, 250-253, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 2, 264-275, 277-280, 282, 284-286, 290, 292, 294-299, 304, 305, 307-310, 312-315, 317-319, 321-323, 325, 328, 331, 333-337, 342, 346, 347, 350, 351, 354, 355, 356, 359, 361, 364-367, 370, 372, 377, 378, 381, 385-389, 395-398, 400, 4 01, 403, 408-412, 416-419, 421-423, 426-429, 431-433, 435-439, 441-445, 447-453, 454, 456, 458, 461, 462, 464, 466-469, 484, 486, 488, 490, 497, 502, 509, 511, 514, 517, 520, 524, 529, 530, 533, 538-543, 546, 548, 552-554, 556, 557 , 560, 561, 562, 568, 569, 571, 572, 574, 575, 578, 580 to 583, 585, 586, 588 to 590, 592, 596 to 600, 602, 604, 605, 608 to 612, 614 to 617, 619 to 621, 623, 625 to 630, 632, 636, 638, 640, 641, 643 to 652, 654 to 660, 665, and 667 to 691, and / or solvates thereof.

[0093] Examples of more preferred compounds include Examples 3, 6, 20-22, 43, 46, 48, 68, 76, 84, 91-93, 99-102, 123, 125, 168, 171, 177, 188, 202, 205, 206, 251, 266, 272, 296-299, 304, 305, 307-310, 312, 318, 321, 331, 342, 354, 355, 359, 364, 366, 377, 378, 381, 385-387, 389, 395, 397, 400, 401, 403, 411, 412, 416-419, 421-423, 426-429, 431-433, 435-438, 441, 443-445 , 451-454, 456, 458, 462, 466-469, 486, 497, 502, 509, 517, 520, 524, 527, 529, 530, 538-540, 546, 552, 554, 556, 558, 560, 562, 571, 572, 578, 580-583, 585, 586, 588, 589, 59 2, 597, 599, 600, 604, 605, 608-610, 615, 617, 619-621, 623, 625-628, 630, 632-638, 640, 641, 643, 645-649, 665, 671-680, 682, 683, 685, and 688-690, and / or solvates thereof.

[0094] More specifically, the compounds are Examples 20, 84, 99-102, 123, 205, 251, 266, 296-299, 308, 312, 318, 321, 342, 355, 385, 387, 412, 421, 432 from Tables 1, 3, 4 and 5. 462, 509, 517, 520, 524, 529, 530, 538, 539, 546, 554, 556, 560, 562, 568, 571, 572, 578, 580 to 583, 586, 588, 592, 597, 600, 605, 608, 609, 615, 617, 621, 628, 630, 632, 633, 636, 637, 641, 643, 648, 649, 665, 672 to 675, 679, 682, and 688, and / or solvates thereof.

[0095] It is understood that any of the above compounds may be in any amorphous, crystalline, or polymorphic form, or a combination thereof, including any salt or solvate form. The compounds herein may be further modified by appending various functional groups via any synthetic means defined herein to enhance selective biological properties. Such modifications are known in the art and include those that increase biological penetration into a given biological system (e.g., blood, lymphatic system, central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism, and alter excretion rate.

[0096] These compounds can be prepared by conventional chemical syntheses, such as those described above and illustrated in the schemes and examples of this disclosure. As can be appreciated by those of skill in the art, additional methods of synthesizing compounds of the formulae herein will be apparent to those of ordinary skill in the art. Additionally, the various synthetic steps can be performed in an alternate sequence or order to provide the desired compounds.

[0097] iii. Methods, Uses, Formulations and Administration

[0098] As used herein, the term "effective amount" refers to an amount of a drug or pharmaceutical agent that elicits the biological or medical response of a tissue, system, animal, or human that is being sought, for example, by a researcher or clinician. Moreover, the term "therapeutically effective amount" refers to an amount that results in the treatment, cure, prevention, amelioration of a disease, disorder, or symptoms thereof, or a reduction in the rate of progression of a disease or disorder, compared to a corresponding subject who does not receive such amount. This term also includes within its scope an amount effective to enhance normal physiological function.

[0099] As used herein, the terms "treatment," "treat," and "treating," as used herein, refer to reversing a disease or disorder, or one or more symptoms thereof, alleviating one or more symptoms, delaying the onset of one or more symptoms, or inhibiting the progression of one or more symptoms. In some embodiments, treatment may be administered after one or more symptoms have developed. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and / or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, e.g., to prevent or delay their recurrence.

[0100] 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 disease or disorder to be treated includes a proliferative disease or disorder, a developmental disorder caused by dysregulation of the RAS-ERK signaling cascade (RASopathies), an inflammatory disease, or an immune system disorder.

[0101] According to some examples, the proliferative disease or disorder to be treated is a neoplasm, inflammatory disease or condition, or developmental abnormality associated with constitutively activating mutations in the RAS and / or RAF genes (e.g., KRAS and / or ARAF, BRAF, or CRAF mutations). The disease or disorder may also be further associated with receptor tyrosine kinase mutations or amplifications (e.g., EGFR, HER2), or mutations in downstream regulators of the receptors RAS (e.g., SOS1 gain of function, NF1 loss of function). For example, the compounds defined herein may be used to treat RAF mutations (e.g., BRAF V600EThese compounds are inhibitors of signaling enzymes (e.g., BRAF and CRAF) that are involved in controlling cell proliferation not only in tumors carrying BRAF (Br-like receptor activator), but also, importantly, in the context of mutated RAS-driven cancers. Thus, the compounds of the present invention can be used, for example, for the treatment of diseases that are linked to the activity of these signaling enzymes and are characterized by excessive or abnormal cell proliferation.

[0102] According to one embodiment, the disease or disorder is characterized by uncontrolled cell proliferation, i.e., a "proliferative disorder" or "proliferative disease." More specifically, these diseases and disorders relate to abnormal conditions characterized by autonomously proliferating cells, i.e., rapidly proliferating cell proliferation that generally forms distinct masses that exhibit a partial or total lack of structural organization and functional coordination with normal tissue.

[0103] For example, proliferative disorders or diseases are defined as "neoplasms," "neoplastic disorders," "neoplasia," "cancer," and "tumors," which are collectively meant to include hematopoietic neoplasms (e.g., lymphomas or leukemias) and solid neoplasms (e.g., sarcomas or carcinomas), which include, for example, precancerous and cancerous growths, or cancerous processes, metastatic tissues, or malignantly transformed cells, tissues, or organs of any kind, regardless of histopathological type or stage of invasiveness. Hematopoietic neoplasms are malignant tumors affecting hematopoietic structures (structures associated with the formation of blood cells) and components of the immune system, and include, for example, leukemias (associated with leukocytes (white blood cells) and their precursors in the blood and bone marrow) and lymphomas (associated with lymphocytes) arising from the myeloid, lymphoid, or erythroid lineages. Solid neoplasms include sarcomas, which are malignant neoplasms arising from connective tissues, such as muscle, cartilage, blood vessels, fibrous tissue, fat, or bone. Solid neoplasms also include carcinomas, which are malignant neoplasms arising from epithelial structures, including external epithelia (e.g., skin and the lining of the digestive tract, lungs, and cervix), and internal epithelia covering various glands (e.g., breast, pancreas, thyroid). Examples of neoplasms include leukemia, hepatocellular carcinoma, sarcoma, hemangioendothelial carcinoma, breast cancer, central nervous system cancers (e.g., astrocytoma, gliosarcoma, neuroblastoma, oligodendroglioma, and glioblastoma), prostate cancer, lung and bronchial cancer, laryngeal cancer, esophageal cancer, colon cancer, colorectal cancer, gastrointestinal cancer, melanoma, ovarian and endometrial cancer, kidney and bladder cancer, liver cancer, endocrine cancer (e.g., thyroid), and pancreatic cancer. For example, the disease or disorder is selected from colon cancer, lung cancer, pancreatic cancer, thyroid cancer, breast cancer, and skin cancer. Examples of neoplasms include melanoma, papillary thyroid carcinoma, 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 carcinoma), head and neck cancer, acute lymphocytic leukemia, acute myeloid leukemia, non-Hodgkin's lymphoma, and hairy cell leukemia.

[0104] In one embodiment, a patient presenting with one of the above-described hematopoietic or solid neoplasms has previously been treated with, but has acquired resistance to, an inhibitor targeting the RAS-ERK pathway (including an RTK, RAF, MEK, or ERK inhibitor), including standard of care such as vemurafenib, dabrafenib, cobimetinib, trametinib, YERVOY, OPDIVO, or a combination of these agents.

[0105] In one embodiment, the disease to be treated is defined by developmental abnormalities caused by dysregulation of the RAS-ERK signaling cascade (RASopathies: e.g., Noonan syndrome, Costello syndrome, LEOPARD syndrome, cardiac anomaly syndrome, and hypertrophic cardiomyopathy).

[0106] In one embodiment, the disease to be treated is defined as an inflammatory disease or immune system disorder, examples of which 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, and chronic obstructive pulmonary disease (COPD).

[0107] In one embodiment, the compounds defined herein inhibit RAS-ERK signaling and cell proliferation in tumor cells harboring at least one mutated RAS or RAF genotype without inducing or substantially inducing the paradoxical pathway.

[0108] As used herein, the term "patient or subject" refers to an animal, e.g., a mammal. Thus, a subject can refer to, for example, a mouse, rat, dog, cat, horse, cow, pig, guinea pig, a primate, such as those described above, including a human, and the like. Preferably, the subject is a human.

[0109] Thus, the present specification further relates to a method of treating a subject, e.g., a human subject, e.g., a subject suffering from a proliferative disease or disorder, e.g., a subject suffering from a RAF-mutated cancer and / or a mutated RAS-driven cancer, comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound as defined herein.

[0110] In some embodiments, the present disclosure provides a method for treating a disorder (described herein) in a subject, comprising administering a compound of the present disclosure to a subject identified as needing such treatment. Identifying patients in need of treatment for the aforementioned disorders is within the ability and knowledge of those skilled in the art. Certain methods for identifying patients at risk of developing the aforementioned disorders that can be treated by the subject methods are understood in the medical arts, such as family history and the presence of risk factors associated with the development of the disease state in the subject patient. Those skilled in the medical arts can easily identify such candidate patients using, for example, clinical tests, physical examinations, medical / family history, and genetic assessments.

[0111] A method for assessing the effectiveness of a treatment in a subject includes determining pre-treatment symptoms of the disorder by methods known in the art, and then administering a therapeutically effective amount of a compound of the present invention to the subject. After an appropriate period (e.g., 1 week, 2 weeks, 1 month, 6 months) after administration of the compound, the symptoms of the disorder are again determined. Modulation (e.g., a decrease) of symptoms and / or biomarkers of the disorder (e.g., pERK or pMEK) indicates the effectiveness of the treatment. The symptoms and / or biomarkers of the disorder can be determined periodically throughout the treatment period. For example, the symptoms and / or biomarkers of the disorder can be checked every few days, weeks, or months to further evaluate the effectiveness of the treatment. A decrease in the symptoms and / or biomarkers of the disorder indicates that the treatment is effective.

[0112] In some embodiments, a therapeutically effective amount of a compound defined herein can be administered to a patient alone or in a composition in admixture with a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0113] The expression "pharmaceutically acceptable carrier, adjuvant, or vehicle" and equivalent expressions refer to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound it is formulated in. Pharmaceutically acceptable carriers, adjuvants, or vehicles that can be used in the compositions of the present disclosure include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and wool fat.

[0114] 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, intracavity, and intracranial injection or infusion techniques. Other modes of administration also include intradermal or transdermal administration.

[0115] 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 contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof. In addition to inert diluents, oral compositions may also include adjuvants, such as wetting agents, emulsifiers and suspending agents, surfactants, sweeteners, flavorings, and fragrances.

[0116] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions, can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations can also be sterile injectable solutions, suspensions, or emulsions in non-toxic parenterally acceptable diluents or solvents, such as solutions in 1,3-butanediol. Among the acceptable vehicles and solvents that can be used are water, Ringer's solution, USP, and isotonic sodium chloride solution. In addition, sterile fixed oils are commonly used as solvents or suspending media. For this purpose, any brand of fixed oil, including the above-mentioned fixed oils, including synthetic monoglycerides or diglycerides, can be used. In addition, fatty acids, such as oleic acid, are used in the preparation of injectables.

[0117] Injectable formulations can be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium before use.

[0118] In order to prolong the effect of a compound provided, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This can be accomplished by using a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends on its rate of dissolution, which in turn depends on crystal size and crystalline form. Alternatively, delayed absorption of parenterally administered compounds can be achieved by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are prepared by forming microencapsule matrices of the compound in biodegradable polymers, such as polylactide-polyglycolide. The release rate of the compound can be controlled by the ratio of the compound to the polymer and the nature of the polymer used.

[0119] Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes and microemulsions which are compatible with body tissue.

[0120] Compositions for rectal administration are preferably suppositories, which can be prepared by mixing the compounds herein with a suitable non-irritating excipient or carrier, such as cocoa butter, polyethylene glycol or a suppository wax, which is solid at ambient temperature but liquid at body temperature and therefore melts in the rectum and releases the active compound.

[0121] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate, and / or a) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders, such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidinone (PVP), sucrose, and acacia; c) humectants, such as glycerol; d) disintegrants, such as PEG-100; For example, agar-agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain silicates and sodium carbonate, e) solution retardants such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as cetyl alcohol and glyceryl monostearate, h) adsorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also contain buffering agents.

[0122] Solid compositions of a similar type can also be used as fillers for soft and hard-filled gelatin capsules using additives such as lactose or milk sugar and high molecular weight polyethylene glycols. Solid dosage forms such as 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 formulation art. They may optionally contain opacifying agents and can also be composed so that they release one or more active ingredients 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 for soft and hard-filled gelatin capsules using additives such as lactose or milk sugar and high molecular weight polyethylene glycols.

[0123] The compositions may also be in microencapsulated form with one or more additives, as described above. Solid dosage forms such as 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 formulation 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, as is common practice, additional substances other than inert diluents, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pills, the dosage forms may also contain buffering agents. They may optionally contain opacifying agents, and may be of a composition that releases one or more active ingredients 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.

[0124] Dosage forms for topical or transdermal administration of the compounds herein 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 any required preservatives or buffers, as needed. Ophthalmic formulations, ear drops, and eye drops are also contemplated herein. Additionally, the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of the compound into the body. Such dosage forms can be prepared by dissolving or dispensing the compound in a suitable medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate-controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0125] The pharmaceutically acceptable compositions provided herein may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared as solutions in saline using benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0126] 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 present disclosure are administered without food. In other embodiments, the pharmaceutically acceptable compositions of the present disclosure are administered with food.

[0127] 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 to be treated and the particular mode of administration. Provided compositions can be formulated so that a dosage of 0.01 to 100 mg / kg body weight / day of inhibitor can be administered to a patient receiving these compositions.

[0128] It should also be understood that the specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, the judgment of the treating physician, and the severity of symptoms associated with the proliferative disease or disorder. The amount of compound provided in the composition will also depend on the particular compound in the composition.

[0129] The compounds or compositions described herein can be administered in any amount and by any route of administration effective for treating or reducing the severity of symptoms as contemplated herein. The exact 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 specific drug, its mode of administration, and the like. The provided compounds are preferably formulated into unit dosage forms for ease of administration and uniformity of dosage. As used herein, the expression "unit dosage form" refers to a physically discrete unit of drug appropriate for the patient to be treated. However, it will be understood that the total daily usage of the compounds and compositions of the present disclosure will be determined by the attending physician within the scope of sound medical judgment.

[0130] The pharmaceutically acceptable compositions of the present disclosure can be administered to humans and other animals orally, rectally, parenterally, intraperitoneally, topically (by powder, ointment, or drops), bucally, as an oral or nasal spray, etc., depending on the severity of the infection being treated. In some embodiments, provided compounds can be administered orally or parenterally at a dosage of about 0.01 mg / kg to about 50 mg / kg, preferably about 1 mg / kg to about 25 mg / kg, of the subject's body weight per day to achieve the desired therapeutic effect, one or more times daily.

[0131] It will be understood that the total daily usage of the compounds and compositions herein can be determined by the attending physician within the scope of sound medical judgment. The total daily inhibitory dose of the compounds herein, administered to a subject in single or divided doses, can be, for example, in an amount of 0.01 to 50 mg / kg body weight, more usually 0.1 to 25 mg / kg body weight. Single dose compositions can contain such amounts or multiples thereof to make up the daily dosage. In one embodiment, a treatment regimen in accordance with the present invention comprises administering to a patient in need of such treatment, in single or multiple doses, from about 10 mg to about 1000 mg of one or more compounds herein per day.

[0132] Depending on the disease or disorder to be treated, additional therapeutic agents may also be present in the compositions of the present disclosure or may be administered separately as part of a dosing regimen, e.g., an additional chemotherapeutic agent. Non-limiting examples of additional therapeutic agents that can be used in combination with the compounds of the invention include antiproliferative compounds, such as aromatase inhibitors; antiestrogens; antiandrogens; gonadorelin agonists; topoisomerase I inhibitors; topoisomerase II inhibitors; microtubule activators; alkylating agents; retinoids, carotenoids, tocopherols; cyclooxygenase inhibitors; MMP inhibitors; antimetabolites; platin compounds; methionine aminopeptidase inhibitors; bisphosphonates; antiproliferative antibodies; heparanase inhibitors; inhibitors of Ras oncogenic isoforms; telomerase inhibitors; proteasome inhibitors; compounds used in the treatment of hematological malignancies; kinesin spindle protein inhibitors; Hsp90 inhibitors; mTOR inhibitors; PI3K inhibitors; Flt-3 inhibitors; CDK4 / 6 inhibitors; HER2 inhalants (Herceptin, EGFR inhibitors (Iressa, Tarceva, Nerlynx, Tykerb, Erbitux); RAS inhibitors; MEK inhibitors (Trametinib, Binimetinib, Cobimetinib); ERK inhibitors (Ulixertinib); anti-PD-1 antibodies (Opdivo), (Keytruda); anti-CTLA4 antibodies (Yervoy); antitumor antibiotics; nitrosoureas; compounds that target / increase protein or lipid kinase activity, or compounds that target / increase protein or lipid phosphatase activity, or further anti-angiogenic compounds.

[0133] The treatment may also be supplemented with other treatments or interventions, such as surgery, radiation therapy (e.g., gamma irradiation, neutron irradiation, electron beam irradiation, proton therapy, brachytherapy, and systemic radioisotopes), biologic response modifiers (e.g., interferons, interleukins, tumor necrosis factors (TNF)), and medications used to reduce side effects.

[0134] The description of an embodiment of a variation herein includes that embodiment as any single embodiment or in combination with any other embodiment or portion thereof. The description of an embodiment herein includes that embodiment as any single embodiment or in combination with any other embodiment or portion thereof.

[0135] Example

[0136] List of abbreviations: Ac: Acetyl AcOEt or EtOAc: ethyl acetate AcOH: acetic acid Ar: aryl ATCC: American Type Culture Collection ATP: adenosine triphosphate BINOL: [1,1'-binaphthalene]-2,2'-diol Boc: tert-butyloxycarbonyl BOP: (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate br: Broad BSA: bovine serum albumin CCL: cancer cell lines CDCl3: deuterated chloroform DCE: 1,2-dichloroethane DCM: dichloromethane DIEA (or DIPEA): N,N-diisopropylethylamine (Huenig's base) DME: 1,2-dimethoxyethane DMF: N,N-dimethylformamide DMSO: dimethyl sulfoxide DMSO-d6: Deuterated dimethyl sulfoxide DTT: dithiothreitol EA: Ethyl acetate EC 50 : Half-maximal 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 I C 50 :half-maximal inhibitory concentration IPA: Isopropanol 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: para-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 containing 0.2% Tween®-20 TBTU: O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate TEV: tobacco etch virus protease TFA: Trifluoroacetic acid THF: tetrahydrofuran TLC: Silica gel thin layer chromatography Ts: para-toluenesulfonate Y 最小 :Minimal data point of a dosage-activity curve

[0137] The following non-limiting examples are illustrative embodiments and should not be construed as further limiting the scope of the present invention. These examples will be better understood with reference to the accompanying figures.

[0138] The examples set forth herein below provide synthesis and experimental results obtained for certain exemplary compounds. As is well known to those skilled in the art, reactions are carried out in an inert atmosphere (nitrogen or argon) as necessary to protect reaction components from air and moisture. Temperatures are given in degrees Celsius (°C). Solution percentages and ratios are expressed volume-to-volume unless otherwise noted. Reactants used in the following examples may be obtained as described herein or, if not described herein, are themselves commercially available or may be prepared from commercially available materials by methods known in the art. Flash chromatography is performed on silica (SiO2) at 254 nm using commercially available normal-phase silica on a Teledyne Isco Rf Combiflash instrument. Mass spectrometry is recorded using an electrospray mass spectrometer. NMR was recorded on a 400 MHz Varian instrument.

[0139] Preparative HPLC was performed using Agilent equipment with a Phenomenex-Kinetex C18 (21 x 100 mm, 5 μm) column at a flow rate of 20 mL / min (RT) and UV detection at 220 nm and 254 nm. 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) unless otherwise noted. Where specified herein, 0.05% TFA or 0.1% AcOH or other additives were sometimes used in place of 0.1% formic acid in both solvents. As specified herein, for more difficult separations, MeCN was used in place of MeOH in both mobile phases. Specific gradient conditions are provided in the Examples below, but the following are representative: T(0) → T(3 min) was run isocratically with 10-50% solvent B depending on the polarity of the compound, followed by a 12 min gradient to 100% solvent B, with the final 5 min at 100% solvent B.

[0140] LCMS analysis was performed on an Agilent instrument. Liquid chromatography was performed on a Phenomenex Kinetex C18 column (2.6 μm; 100 Å; 3 × 30 mm) at a flow rate of 1.5 mL / min (RT) with UV detection at 220 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) with the following gradient: T(0) 100% A → T(0.5 min) 100% B → isocratic 100% B → T(2 min). MS detection was performed in parallel using APCI detection in both positive and negative modes.

[0141] Unless otherwise indicated, all numerical values ​​expressing amounts of ingredients, reaction conditions, concentrations, properties, stability, and the like used in the specification and appended claims are understood to be modified in all instances by the word "about." At the very least, each numerical parameter should be construed in light of, at least, the number of reported significant digits and by applying ordinary rounding techniques. Accordingly, unless indicated to the contrary, the numerical parameters set forth in the specification and appended 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 embodiments are approximations, the numerical values ​​set forth in the specific examples are reported as precisely as possible. However, any numerical value inherently contains certain errors resulting from variations in experiments, testing measurements, statistical analyses, and the like.

[0142] Examples of synthesis, biological activity, and properties include:

[0143] All compounds defined herein were prepared according to the methods shown in Tables 3-5. Mass spectrometry and NMR characterization data are provided for each example. Compounds were tested in the assays described in the Biological Experiments section. Conventions used for reporting biological data are provided as footnotes to each table.

[0144] Synthesis method A:

[0145] Commercially available 2,6-difluoro-3-nitrobenzoic acid A-1 (Synthesis Method A) can be converted to carbamate A-2 via the Curtius reaction according to the procedure described in J. Med. Chem. 2003, 46, 1905. Catalytic hydrogenolysis of nitroarene A-2 using hydrogen gas and a catalyst such as palladium metal on carbon or palladium hydroxide on carbon (Pearlman's catalyst) provided aniline A-3. Aniline A-3 can be converted to a sulfonylating agent, such as a 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 in the presence of an additional solvent, such as dichloromethane or tetrahydrofuran, to give sulfonamide intermediate A-4, which can be deprotected to an aniline salt, such as compound A-5, using a strong acid (e.g., a solution of anhydrous hydrochloric acid in dioxane). Alternatively, 2,6-difluoroaniline A-6 can be converted to its acetanilide A-7 using an acetylating agent, such as acetic anhydride, and then converted to the monoprotected dianiline A-8 described in International Publication WO 2012 / 101238 A1. Sulfonylation to sulfonamide A-9 is accomplished under similar conditions used to convert carbamate A-3 to sulfonamide A-4 using a sulfonylating reagent 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. Treatment of acetanilide A-9 with aqueous hydrochloric acid in the presence of a cosolvent, such as an alcohol, provides aniline salt A-5.

[0146] [ka]

[0147] Commercially available 3-amino-6-chloro-2-pyridinecarboxamide A-10 is converted to pyridopyrimidinone A-11 by applying the procedure described in J.Med.Chem. 2014, 57, 3484, and then converted to dichloro derivative A-12 using a chlorinating agent, such as thionyl chloride or phosphoryl chloride, in the presence of a catalytic amount of DMF, also in accordance with the procedure described in J.Med.Chem. 2014, 57, 3484.

[0148] Following a procedure similar to that described in International Publication No. WO 2012 / 101238 A1, intermediate A-13 can be obtained by heating dichloropyridine A-12 with aniline salt A-5 in an organic acid, such as acetic acid. The final inhibitors of the general structure WI containing N-linked heterocycles can then be obtained by heating the chloropyridine A-13 intermediate with heterocycles containing a free NH group, such as imidazole, triazole, pyrazole, benzimidazole, benzotriazole, indole, indazole, etc., in the presence of catalytic amounts of copper powder, a ligand (e.g., BINOL), and an inorganic base, such as cesium carbonate, in a solvent, such as DMSO or N-methylpyrrolidone (NMP). In some cases, the presence of copper powder and the ligand is not required, and the coupling is carried out under typical SNAr conditions by heating at temperatures between 80°C and 140°C in the presence of the same base and solvent as those described above.

[0149] Synthesis method B:

[0150] An alternative method for constructing inhibitors of general structure WI is provided by Method B. Using the same intermediate A-2 described in Method A as the starting material, 3-nitroaniline salt B-1 can be obtained by cleavage of the carbamate protecting group under acidic conditions (e.g., using a solution of anhydrous hydrogen chloride in dioxane or trifluoroacetic acid). Using similar conditions described in International Publication WO 2012 / 101238 A1, aniline salt B-1 is reacted with dichloro-pyridopyrimidine A-12 to provide intermediate B-2. Reduction of the nitro group to the corresponding aniline B-3 is carried out using a metal salt, such as tin(II) chloride, in an alcoholic solvent. Next, heating the chloropyridine B-3 intermediate with a heterocycle containing a free NH group (e.g., imidazole, triazole, pyrazole, benzimidazole, benzotriazole, indole, indazole, etc.) in a solvent such as DMSO or N-methylpyrrolidone in the presence of a catalytic amount of copper powder, a ligand (e.g., BINOL), and an inorganic base such as cesium carbonate provides the aniline B-4 containing an N-linked heterocycle on the pyridine ring. Finally, the aniline B-4 can be converted to an inhibitor of the general formula WI containing an N-linked heterocycle using a sulfonylating agent such as a sulfonyl chloride 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.

[0151] [ka]

[0152] Synthesis method C:

[0153] W-II type inhibitors containing C-linked aryl or heterocycles at the 2-position of the pyridine ring can be obtained by metal-catalyzed cross-coupling of chloropyridine A-13 with aryl or heteroaryl boronic acid and boronic acid ester derivatives, following a typical Suzuki-Miyaura protocol. An inorganic aqueous base, such as sodium or potassium carbonate or potassium phosphate, can be used as the base in a solvent such as 1,4-dioxane or 1,2-dimethoxyethane (DME), at temperatures between 70 and 110 °C under conventional thermal or microwave irradiation. Alternatively, organotin species can be used in the presence of an organic base, such as triethylamine, under similar conditions following a typical Stille coupling protocol.

[0154] [ka]

[0155] Synthesis method D:

[0156] Using the protocol described in Synthetic Method A, chloropyridine A-13 is coupled to the methyl ester of a 3-indole or 3-indazole carboxylic acid to provide intermediates D-1 or D-2, respectively, after saponification using aqueous inorganic hydroxides such as sodium hydroxide, potassium hydroxide, or lithium hydroxide. Carboxylic acids D-1 and D-2 are then reacted with primary and secondary amines using typical procedures for amide bond formation (e.g., BOP, HATU, or TBTU in the presence of an organic base such as DIEA or triethylamine at ambient temperature in a solvent such as NMP, DMF, THF, or DMSO). If a functional group on the amine reagent is reactive under the conditions for amide bond formation (e.g., an additional amine functional group), the reactive substituent is protected (e.g., as a tert-butyl carbamate), and the protecting group is removed as a final step to provide the desired inhibitor of Formula W-III.

[0157] [ka]

[0158] Synthesis method E:

[0159] Bromobenzimidazole E-2 can be prepared by reacting 3-bromo-1,2-phenylenediamine E-1 with formic acid and then formylated at low temperature using a strong base, such as an inorganic hydride in combination with an alkyllithium (e.g., tert-butyllithium), and a formylating agent, such as DMF, in an aprotic solvent, such as THF, to provide formylbenzimidazole E-3. Coupling of benzimidazole E-3 with chloropyridine A-13 is carried out under the general protocol of Method A to provide aldehyde intermediate E-4. Reaction of the aldehyde intermediate E-4 with an amine under standard reductive amination conditions (e.g., using a reducing agent such as an inorganic borohydride or cyanoborohydride in the presence of a weak organic acid such as AcOH) provides inhibitors of general formula W-IV as shown in general synthetic method E.

[0160] [ka]

[0161] Synthesis method F:

[0162] Bromobenzimidazole E-2 is commercially available or can be prepared as described under general method E (Step 1). Cross-coupling to a heteroaryl boronic acid or boronic ester can be carried out under palladium-catalyzed Suzuki-Miyaura cross-coupling conditions in the presence of a base such as sodium carbonate or potassium carbonate in a solvent such as dioxane or dimethoxyethane and water to provide intermediate F-1. Next, coupling of substituted benzimidazole derivative F-1 with chloropyridine A-13 can be carried out under the general protocol of method A to provide inhibitors of general structure WV.

[0163] [ka]

[0164] Synthesis method G:

[0165] N-tosyl-protected indole-3-sulfonyl chloride G-1 (prepared by the procedure described in Chemical and Pharmaceutical Bulletin 2009, 57, 591) is reacted with a primary or secondary amine in the presence of a tertiary base, such as DIEA or triethylamine, in a solvent such as THF to provide intermediate sulfonamide G-2 after removal of the tosyl protecting group upon treatment with an aqueous inorganic base, such as KOH. The final inhibitors of general structure W-VI are then obtained by heating sulfonamide G-2 with the chloropyridine A-13 intermediate under standard conditions as previously described.

[0166] [ka]

[0167] Synthesis method H:

[0168] 3-Indole thiocyanate H-1 (prepared according to the procedure described in Phosphorus, Sulfur, and Silicon and the Related Elements 2014, 189, 1378) is reduced to the corresponding sulfide salt using a reducing agent, e.g., sodium sulfide anhydrate, and directly alkylated with an alkyl halide without isolation to provide sulfide intermediate H-2. Sulfide intermediate H-2 is then converted to sulfone intermediate H-3 using an oxidizing agent, e.g., 3-chloroperoxybenzoic acid. The final inhibitor of general structure W-VII was then obtained by heating indole sulfone H-3 with chloropyridine A-13 intermediate under the usual conditions previously described.

[0169] [ka]

[0170] Synthesis method I:

[0171] A bright red solution of commercially available 3-fluoro-2-nitroaniline I-1 is reacted with a primary or secondary amine 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, and heated to 40°C to 120°C under thermal or microwave conditions to provide intermediate I-2. Reduction of the nitro group of intermediate I-2 can be achieved using a metal such as Fe or Zn in the presence of ammonium chloride at 40°C to 80°C in an alcoholic solvent such as isopropanol. The 1,2-phenylenediamine intermediate (see J-1) is then directly converted to the desired benzimidazole intermediate I-3 by heating with formic acid at 40°C to 80°C. The final inhibitor of general structure W-VIII is then obtained by heating benzimidazole I-3 with the chloropyridine A-13 intermediate under the usual conditions described above.

[0172] [ka]

[0173] Synthesis method J:

[0174] Nitroaniline I-2, obtained as described under Synthetic Method I, is reduced to 1,2-phenylenediamine I-1 in an alcoholic solvent, such as isopropanol, using a metal, such as Fe or Zn, in the presence of ammonium chloride at temperatures between 40°C and 80°C. The 1,2-phenylenediamine intermediate (see J-1) is then converted to the desired benzotriazole intermediate J-2 upon treatment with an inorganic nitrite, such as sodium nitrite, under acidic conditions (e.g., AcOH). The final inhibitor of general structure W-IX is then obtained by heating intermediate I-3 with chloropyridine A-13 intermediate under the usual conditions described above.

[0175] [ka]

[0176] Procedures for preparing inhibitors that do not fall within or are only partially within the general synthetic procedures described above are specifically described below.

[0177] Sulfonyl chlorides:

[0178] The following sulfonyl chlorides were obtained from commercial sources and used as received: 4-methoxybenzenesulfonyl chloride, 2,4-dichlorobenzenesulfonyl chloride, 2,4-dimethylbenzenesulfonyl chloride, 2-chlorobenzenesulfonyl chloride, 2-methylbenzenesulfonyl chloride, 4-ethylbenzenesulfonyl chloride, 2-cyanobenzenesulfonyl chloride, 2,4-dimethoxybenzenesulfonyl chloride, 2-trifluoromethylbenzenesulfonyl chloride, 3-chlorobenzenesulfonyl chloride, 3-methylbenzenesulfonyl chloride, 2,3-dichlorobenzenesulfonyl chloride, 3-chloro-2-methylbenzenesulfonyl chloride. chloride, 2-bromobenzenesulfonyl chloride, 2-chloro-4-fluorobenzenesulfonyl chloride, 2-chloro-6-fluorobenzenesulfonyl chloride, 2,5-dichlorobenzenesulfonyl chloride, 2,5-dimethylbenzenesulfonyl chloride, 2-chloro-6-methylbenzenesulfonyl chloride, 3-fluoro-2-methylbenzenesulfonyl chloride, 2-chloro-4-methylbenzenesulfonyl chloride, 1,3-benzodioxole-5-sulfonyl chloride, 2-chloro-4-(trifluoromethyl)-benzenesulfonyl chloride, 2-methyl-4-nitrobenzenesulfonyl chloride, 2-(difluoromethyl)benzenesulfonyl chloride.

[0179] Other sulfonyl chlorides were prepared by using or adapting literature procedures, as described below.

[0180] 2-Fluoro-4-methoxybenzenesulfonyl chloride:

[0181] [ka]

[0182] Following the procedure described in European Patent Application Publication No. EP 2752410 A1, 2-fluoro-4-methoxyaniline (1.00 g, 7.1 mmol) was dissolved in acetonitrile (25 mL) and concentrated hydrochloric acid (10 mL) was added. The mixture was cooled to 0 °C in an ice-salt bath. Next, a solution of NaNO (0.59 g, 8.5 mmol) in water (1 mL) was added in portions, and the mixture was stirred for 1.5 hours at 0 °C (a light brown solution with a small amount of white solid in suspension). To the resulting mixture was added AcOH (12 mL), and after stirring for 10 minutes at 0 °C, NaHSO (7.37 g, 10 equiv., 71 mmol) was added. After stirring for 5 min, Cu(II) chloride (0.96 g, 1 eq.) and CuCl (70 mg, 0.1 eq.) were added, and the green suspension was stirred in an ice bath and allowed to warm to room temperature over 1 h, after which it was stirred for an additional 18 h at room temperature (TLC R f hexanes / EtOAc). The reaction mixture was then poured into water (100 mL) and extracted with EtOAc. The extract was washed with water, dried over MgSO4, and filtered through a pad of silica gel (15 mL) using 1:1 hex / EA as the eluent. Removal of the volatiles under reduced pressure gave 1.22 g of a clear, light brown oil (TLC indicated the presence of a more polar, unidentified impurity after aqueous work-up). 1 H NMR(CDCl3) δ:7.88(t,J=8.6Hz,1H),6.76~6.93(m,2H),3.93(s,3H). uniformity 1 ~70% by H NMR.

[0183] 4-Chloro-2-methylbenzenesulfonyl chloride:

[0184] [ka]

[0185] This compound was prepared by chlorosulfonylation of meta-chlorotoluene according to the procedure described in Acta Crystallographica Section E 2009, 65(4), o800. Meta-chlorotoluene (1 mL) was dissolved in CHCl3 (4 mL), and the solution was cooled in an ice bath. Chlorosulfonic acid (2.5 mL) was added dropwise over 15 minutes, with slow evolution of HCl gas. Upon completion, the reaction mixture was allowed to warm to room temperature. TLC showed the disappearance of starting material (Rf = 0.8, in 8:2 hex / EA) and the formation of a new, slightly trailing spot (Rf = 0.7, in 8:2 hex / 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 (MgSO4), and concentrated to a colorless oil (0.87 g), which was used without further purification: 1 H NMR(CDCl3) δ:8.01(d,J=8.6Hz,1H),7.43(s,1H),7.40(dd,J=8.6,2.0Hz,1H),2.78(s,3H).

[0186] The following sulfonyl chlorides were prepared using a similar procedure with some modifications, as described below.

[0187] 4-Methoxy-2-methylbenzenesulfonyl chloride:

[0188] [ka]

[0189] 3-Methoxytoluene (6.00 g) was dissolved in CHCl3 (30 mL) and the solution was cooled to -35 °C (bath temperature). Chlorosulfonic acid (15 mL) was added dropwise over 20 min (no significant HCl / SO2 gas evolution). The clear solution was then stirred for 15 min at -30 to -25 °C (no gas evolution was observed). The reaction mixture was carefully poured onto ice (50 mL), DCM (50 mL) was added, and the slightly opalescent product organic phase was separated, washed with cold water, dried (MgSO4), and concentrated under vacuum to a colorless oil (8.28 g, 76% yield). NMR indicates the presence of a single isomer: 1 H NMR(CDCl3) δ:8.01(d,J=8.6Hz,1H),6.72~6.95(m,2H),3.90(s,3H),2.75(s,3H).

[0190] 2-Chloro-4-methoxybenzenesulfonyl chloride:

[0191] [ka]

[0192] 3-Chloroanisole (1.00 g) was dissolved in CHCl3 (4 mL) and the solution was cooled to approximately -35 °C. Chlorosulfonic acid (2.5 mL) in CHCl3 (2 mL) was added dropwise over 15 min. Upon completion, there was only baseline material by TLC (SM Rf = 0.8 in 8:2 hex / EA). Upon warming the reaction mixture to room temperature, gas evolution was observed, and isomeric products were identified by TLC (Rf = 0.30 and 0.25 in 8:2 hex / EA). After stirring at room temperature for 30 min, a white precipitate began 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 (MgSO4), and concentrated to a colorless oil that crystallized on standing as white needles (0.89 g). 1H NMR showed a mixture of two isomers in a 60:40 ratio, which were separated by flash chromatography on silica gel using 8:2 hexane / EtOAc as eluent. The desired isomer (more polar): 1 H NMR(CDCl3) δ:7.90(d,J=8.6Hz,1H),7.04~7.19(m,2H),4.08(s,3H).

[0193] 2,3-Dimethylbenzenesulfonyl chloride:

[0194] [ka]

[0195] It was isolated as the minor isomer after chlorosulfonylation of o-xylene as described in WO 2003 / 055478. 1 H NMR(CDCl3) δ:7.96(d,J=7.8Hz,1H),7.52(d,J=7.4Hz,1H),7.30(t,J=7.8Hz,1H),2.71(s,3H),2.41(s,3H).

[0196] 3-Fluoro-2-methyl-4-methoxybenzenesulfonyl chloride:

[0197] [ka]

[0198] 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). The reaction mixture was then refluxed at 60 °C overnight. The reaction mixture was then cooled to room temperature, filtered (washed with 2 x 10 mL of acetone), and concentrated under reduced pressure. The crude product was extracted with water (30 mL) and EtOAc (2 x 50 mL). The organic layer was then separated, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using 0-5% EtOAc / hexane to give 2-fluoro-3-methylanisole as a clear, colorless liquid (5.30 g, 95% yield): 1 H NMR(CDCl3) δ:6.95(td,J=8.0,1.4Hz,1H),6.85~6.71(m,2H),3.87(s,3H),2.28(d,J=2.3Hz,3H).

[0199] Step 2: To a solution of 2-fluoro-3-methylanisole (1.00 g, 7.13 mmol) from Step 1 in DCM (5.6 mL) was added a solution of chlorosulfonic acid (1.13 mL, 16.5 mmol) in DCM (5.6 mL) over 5 min. The pale brown reaction mixture containing a viscous liquid layer was stirred at room temperature for 10 min and then quenched by pouring into water (10 mL) and ice (5 g). The aqueous layer was extracted with DCM (2 x 10 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give the desired sulfonyl chloride (1.70 g, 100% yield) as a colorless liquid: 1 H NMR(CDCl3) δ:7.87(dd,J=9.0,1.8Hz,1H),6.97~6.86(m,1H),3.97(s,3H),2.66(d,J=2.8Hz,3H).

[0200] 3-chloro-2-methyl-4-methoxybenzenesulfonyl chloride:

[0201] [ka]

[0202] Following the same procedure as for 3-fluoro-2-methyl-4-methoxybenzenesulfonyl chloride (step 1), starting from 2-chloro-3-methylphenol, 2-chloro-3-methylanisole was obtained as a colorless liquid in quantitative yield: 1 H NMR(CDCl3) δ:7.12(t,J=7.9Hz,1H),6.87~6.83(m,1H),6.79(d,J=8.2Hz,1H),3.89(s,3H),2.38(s,3H).

[0203] Treatment with chlorosulfonic acid as described for 3-fluoro-2-methyl-4-methoxybenzenesulfonyl chloride (step 2) gave the desired 3-chloro-2-methyl-4-methoxybenzenesulfonyl chloride as a colorless liquid in 96% yield: 1 H NMR(CDCl3) δ:8.02(d,J=9.1Hz,1H),6.90(d,J=9.1Hz,1H),4.00(s,3H),2.83(s,3H).

[0204] 2-Ethylbenzenesulfonyl chloride:

[0205] [ka]

[0206] 2-Ethylbenzenethiol (1.46 mL, 10.3 mmol) and KCl (776 mg, 10.3 mmol) were dissolved in water (38 mL) and oxone (登録商標) (15.8 g, 25.8 mmol) was added in small portions. After stirring for 1 h at room temperature, the reaction was deemed complete by LCMS analysis, and the reaction mixture was extracted with EtOAc (4 x 5 mL). The extracts were dried (NaSO) and concentrated under reduced pressure to give a white crystalline solid (1.43 g, 68% yield), which was used as is:1 H NMR(CDCl3) δ:8.07(dd,J=8.1,1.3Hz,1H),7.66(td,J=7.6,1.3Hz,1H),7.49(d,J=7.7Hz,1H),7.45~7.38(m,1H),3.20(q,J=7.5Hz),1.36(t,J=7.5Hz).

[0207] 3-Fluoro-2-ethylbenzenesulfonyl chloride:

[0208] [ka]

[0209] Step 1: 2-Bromo-6-fluorobenzaldehyde (6.00 g, 29.5 mmol) was dissolved in dry THF (60 mL) and the solution was cooled to -78 °C under an 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 ether (2 x 50 mL). The extracts were dried (MgSO4) and concentrated, and the residue was purified by Combiflash on silica gel using 10-30% EtOAc in hexanes as eluent. (登録商標) to give the desired alcohol derivative as a colorless oil (6.20 g, 96% yield): 1 H NMR(CDCl3) δ:7.35(ddd,J=7.9,3.1,2.0Hz,1H),7.16~6.99(m,2H),5.35(q,J=6.7Hz,1H),1.61(dd,J=6.8,1.1Hz,3H).

[0210] 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. The alcohol from Step 1 (4.00 g, 18.3 mmol) in DCM (8 mL) was added and the mixture was stirred at room temperature 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). Concentration and purification by flash chromatography using hexane as eluent provided the silylated ether of the starting alcohol.

[0211] The 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 layer was back-extracted with hexane (2 x 50 mL). The combined organic phases were dried (NaSO) and concentrated to give a colorless oil, which was purified by flash chromatography on silica gel using hexane as eluent to give 2-bromo-6-fluoro-ethylbenzene (3.71 g, 100%) as a colorless oil: 1 H-NMR(CDCl3) δ:7.32(d,J=7.8Hz,1H),7.11~6.91(m,2H),2.82(dq,J=7.5,2.2Hz,2H),1.20~1.15(m,3H).

[0212] Step 3: The aryl bromide from Step 2 (3.71 g, 18.3 mmol) was dissolved in toluene (60 mL) and N,N-diisopropylethylamine (6.40 mL, 36.5 mmol) was added. The solution was then degassed by three cycles of evacuation and back-filling with nitrogen. Tris(dibenzylideneacetone)dipalladium(0) (836 mg, 0.9 mmol), 4,4-bis(diphenylphosphino)-9,9-dimethylxanthene (1.08 g, 1.83 mmol), and 2-ethylhexyl-3-mercaptopropionate (4.59 mL, 19.2 mmol) were added, and the mixture was degassed twice before refluxing under a nitrogen atmosphere overnight. The reaction mixture was then cooled to room temperature, quenched with water (50 mL), and extracted with EtOAc (2 x 50 mL). The combined organic phases were washed with 10% aqueous hydrochloric acid (75 mL) and dried (NaSO). Concentration under reduced pressure and purification of the residue by flash chromatography using 0 to 15% EtOAc in hexanes as eluent gave the desired sulfide intermediate (4.00 g) as an orange oil contaminated with some unreacted starting thiol. This material was used directly in the next step.

[0213] Step 4: The crude sulfide derivative from Step 3 (estimated 4.00 g, 11.7 mmol) was dissolved in THF (41 mL), and potassium tert-butoxide (1.0 M in THF, 14.1 mL, 14.1 mmol) was added dropwise. The resulting solution was stirred at room temperature for 1 h. The reaction was then quenched by the addition of saturated aqueous NH4Cl (40 mL) and extracted with EtOAc (2 x 30 mL). The combined organic phases were concentrated, and the dark orange residue was passed through a small pad of silica gel using hexanes for washing to give a mixture of thiol and disulfide (1.50 g), which was used directly in the next step (Caution: foul odor).

[0214] Step 5: The crude mixture of thiophenol and disulfide from step 4 (assumed to be 1.50 g, 9.6 mmol) and KCl (723 mg, 9.6 mmol) were suspended in water (40 mL) and oxone (登録商標) (14.8 g, 24 mmol) was added portionwise. After stirring for 1 h at room temperature, the reaction mixture was extracted with EtOAc (2 × 20 mL), and the extracts were dried (NaSO) and concentrated under reduced pressure to give the crude sulfonyl chloride, which was used directly to prepare the corresponding fragment A-5 and aniline A-8 (see Table 1 below).

[0215] 3-chloro-2-ethylbenzenesulfonyl chloride:

[0216] [ka]

[0217] The sulfonyl chloride was prepared following the same procedure as 3-fluoro-2-ethylbenzenesulfonyl chloride, but starting from 2-bromo-6-chlorobenzaldehyde.

[0218] Step 1 (98% yield, as a white solid): 1 H NMR(CDCl3) δ:7.49(dd,J=8.0,1.2Hz,1H),7.33(dd,J=8.0,1.2Hz,1H),7.05(t,J=8.0Hz,1H),5.58(q,J=6.9Hz,1H),1.64(d,J=6.9Hz,3H).

[0219] Step 2 (100% yield, as a colorless oil): 1 H-NMR (CDCl3) δ:7.43(dd,J=8.0,1.2Hz,1H),7.29(dd,J=8.0,1.2Hz,1H),6.96(t,J=8.0Hz,1H),2.97(q,J=7.5Hz,2H),1.17(t,J=7.5Hz,3H).

[0220] Step 3 (81% yield, as an orange oil):1 H-NMR(CDCl3) δ:7.24~7.18(m,2H),7.08(t,J=7.9Hz,1H),4.07~3.96(m,2H),3.17(t,J=7.4Hz,2H),2.96(q,J=7.5Hz,2H),2.6 4(t,J=7.4Hz,2H),1.56(dd,J=11.9,5.8Hz,2H),1.40~1.21(m,9H),1.16(t,J=7.5Hz,3H),0.89(t,J=7.4Hz,6H).

[0221] Step 4 (99% yield, as a colorless liquid): 1 H-NMR (CDCl3) δ:7.15(d,J=7.9Hz,2H),6.97~6.92(m,1H),3.41(s,1H),2.87(q,J=7.5Hz,2H),1.18(t,J=7.5Hz,3H).

[0222] Step 5 (crude material, used without purification): 1 H-NMR (CDCl3) δ:8.03(dd,J=8.2,1.3Hz,1H),7.73(dd,J=8.0.1.3Hz,1H),7.37(t,J=8.1Hz,1H),3.30(q,J=7.4Hz,2H),1.33(t,J=7.4Hz,3H).

[0223] 2-Methyl-3-(trifluoromethyl)benzenesulfonyl chloride:

[0224] [ka]

[0225] The sulfonyl chloride was prepared following the same procedure as 3-fluoro-2-ethylbenzenesulfonyl chloride, but starting from commercially available 2-methyl-3-(trifluoromethyl)bromobenzene.

[0226] Step 3 (100% yield, as an orange oil): 1H-NMR(CDCl3) δ:7.49(d,J=7.9Hz,2H),7.26~7.19(m,1H),4.06~4.00(m,2H),3.18(dd,J=9.1,5.6Hz,2H),2.6 5(dd,J=9.2,5.6Hz,2H),2.50(d,J=1.3Hz,3H),1.33~1.23(m,11H),0.88(td,J=7.4,2.3Hz,6H).

[0227] Step 4 (quantitative yield, as a colorless oil): 1 H-NMR (CDCl3) δ:7.43(dd,J=7.9,2.2Hz,2H),7.12(t,J=7.8Hz,1H),3.42(s,1H),2.43(s,3H).

[0228] Step 5 (quantitative yield, as a white solid): 1 H-NMR (CDCl3) δ:8.31(d,J=8.1Hz,1H),8.00(t,J=7.7Hz,1H),7.55(dd,J=15.6,7.6Hz,1H),2.93(s,3H).

[0229] General procedure for preparing sulfonyl chlorides from aryl bromides:

[0230] [ka]

[0231] Step 1: Aryl bromide 1 (1.00 mmol) was diluted in toluene (1.70 mL). The mixture was degassed for 5 minutes by bubbling nitrogen through the solution. Tris(dibenzylideneacetone)-dipalladium(0) (0.02 mmol), 4,4-bis(diphenylphosphino)-9,9-dimethylxanthene (0.04 mmol), and N,N-diisopropylethylamine (2.0 mmol) were added, and the mixture was again degassed for 5 minutes. Benzyl mercaptan (1 mmol) was then added, and the resulting mixture was heated at reflux (oil bath, T = 115 °C) overnight. Upon completion, the reaction was cooled to room temperature, diluted with EtOAc (20 mL), and quenched with HO (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 (NaSO), filtered, and concentrated under reduced pressure. The crude product was further purified by flash chromatography (0–10% EtOAc in hexanes, 35 mL / min, product eluted with 100% hexanes). Fractions of interest were collected and concentrated under reduced pressure to give the title compound 2.

[0232] Step 2: Compound 2 (1.00 mmol) was dissolved in acetic acid (1.90 mL) and HO (0.65 mL) was added to give a heterogeneous solution. N-chlorosuccinimide (4.00 mmol) was added portionwise. The reaction was stirred and monitored by LCMS (a sample was quenched with N-methylpiperazine). After completion of the reaction, the mixture was concentrated under reduced pressure. The resulting mixture was slowly poured into saturated aqueous NaHCO, causing gas evolution. The mixture was extracted with EtOAc (2 x 75 mL). The combined organic layers were washed with brine, dried (NaSO), filtered, and concentrated under reduced pressure. The crude compound was further purified by normal phase chromatography (0-40% EtOAc in hexane, 60 mL / min; product came out with 100% hexane). The fractions of interest were collected and concentrated under reduced pressure to give the title compound 3.

[0233] 2-Chloro-3-methylbenzenesulfonyl chloride:

[0234] [ka]

[0235] The sulfonyl chloride was prepared according to the general procedure starting from commercially available 1-bromo-2-chloro-3-methylbenzene.

[0236] Benzyl (2-chloro-3-methylphenyl) sulfide: yellow solid, 51% yield, 95% purity (at 220 nm). (ES - )MH=247.2; 1 H NMR (400MHz, CDCl3) δ7.39~7.35(m,2H),7.33~7.28(m,2H),7.28~7.23(m,1H+CDCl3),7.11~7.03(m,3H),4.15(s,2H),2.38(s,3H).

[0237] 2-Chloro-3-methylbenzenesulfonyl 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 crude.

[0238] 3-Fluoro-2-(trifluoromethyl)benzenesulfonyl chloride:

[0239] [ka]

[0240] The sulfonyl chloride was prepared following the general procedure starting from commercially available 1-bromo-3-fluoro-2-(trifluoromethyl)benzene.

[0241] Benzyl (3-fluoro-2-(trifluoromethyl)phenyl) sulfide: yellow oil, 66% yield, 98% purity (at 254 nm). (ES - )MH=285.2.

[0242] 3-Fluoro-2-(trifluoromethyl)benzenesulfonyl chloride: pale yellow oil, 93% yield, 98% purity (at 254 nm). LCMS: LCMS sample was quenched with N-methylpiperazine (resulting sulfonamide MW=326.1), (ES + )M+H=327.1.

[0243] 3-chloro-2-(trifluoromethyl)benzenesulfonyl chloride:

[0244] [ka]

[0245] The sulfonyl chloride was prepared according to the general procedure starting from commercially available 1-bromo-3-chloro-2-(trifluoromethyl)benzene.

[0246] Benzyl (3-chloro-2-(trifluoromethyl)phenyl) sulfide: White solid, 59% yield, 90% purity (at 220 nm). (ES - )MH=301.2; 1 H NMR (400MHz, CDCl3) δ7.46~7.14(m,8H+CDCl3),4.16(s,2H).

[0247] 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 crude.

[0248] 3,4-Difluoro-2-methylbenzenesulfonyl chloride:

[0249] [ka]

[0250] The sulfonyl chloride was prepared according to the general procedure starting from commercially available 1-bromo-3-chloro-2-(trifluoromethyl)benzene.

[0251] Benzyl (3,4-difluoro-2-methylphenyl) sulfide: orange oil, 96% yield, 96% purity (at 254 nm). (ES - )MH=249.2; 1 H NMR (400MHz, DMSO-d6) δ7.32~7.17 (m, 7H), 4.16 (s, 2H), 2.18 (d, J = 2.7Hz, 3H).

[0252] 3,4-Difluoro-2-methylbenzenesulfonyl chloride: pale yellow oil, 49% yield. LCMS: LCMS sample was quenched with N-methylpiperazine (resulting sulfonamide, MW=290.3), (ES + )M+H=291.2; 1 H NMR (400MHz, DMSO-d6) δ7.56(ddd,J=8.4,5.5,1.8Hz,1H),7.15(dd,J=18.4,8.4Hz,1H),2.46(d,J=2.8Hz,3H).

[0253] 2,4-Dimethyl-3-fluorobenzenesulfonyl chloride:

[0254] [ka]

[0255] The sulfonyl chloride was prepared according to the general procedure starting from commercially available 1-bromo-2,4-dimethyl-3-fluorobenzene.

[0256] Benzyl (3-fluoro-2,4-dimethylphenyl) sulfide: orange oil, 95% crude yield, 80% purity (at 254 nm). Used crude.

[0257] 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 crude.

[0258] 2-Methylpyridine-3-sulfonyl chloride:

[0259] [ka]

[0260] The sulfonyl chloride was prepared according to the general procedure starting from commercially available 3-bromo-2-methylpyridine.

[0261] 3-(Benzylthio)-2-methylpyridine: Orange liquid, 88% yield, 94% purity (at 220 nm). (ES + )M+H=215.8,(ES - )MH=214.1. 1 H NMR (400MHz, DMSO-d6) δ8.30(dd,J=4.9,1.5Hz,1H),7.57~7.45(m,1H),7.31~7.27(m,5H),7.07(dd,J=7.6,5.1Hz,1H),4.09(s,2H),2.58(s,3H).

[0262] 2-Methylpyridine-3-sulfonyl chloride: pale yellow oil, 100% yield, 95% purity (at 254 nm). LCMS sample was diluted with HO (resulting sulfonic acid, MW = 173.1) (ES - )MH=171.9; 1H NMR (400MHz, CDCl3) δ8.80(dd,J=4.8,1.6Hz,1H),8.33(dd,J=8.1,1.7Hz,1H),7.43~7.36(m,1H),3.02(s,3H).

[0263] 6-Methoxy-4-methylpyridine-3-sulfonyl chloride:

[0264] [ka]

[0265] Preparation of 2-ethylhexyl 3-((6-methoxy-4-methylpyridin-3-yl)thio)propanoate (2): 5-Bromo-2-methoxy-4-methylpyridine (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 for 5 minutes by bubbling nitrogen through the solution. Tris(dibenzylideneacetone)dipalladium(0) (1.36 g, 1.49 mmol), 4,4-bis(diphenylphosphino)-9,9-dimethylxanthene (1.75 g, 2.97 mmol), and 2-ethylhexyl-3-mercaptopropionate (7.47 mL, 31.2 mmol) were added. The mixture was again degassed for 5 minutes. The mixture was heated at reflux (oil bath, T = 117 °C) overnight. The reaction was cooled to room temperature, diluted with EtOAc (100 mL), and quenched with H2O (100 mL). The organic and aqueous layers were separated, and the aqueous layer was extracted with EtOAc (2 x 50.0 mL). The combined organic layers were washed with HCl (10% in H2O, 50.0 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (330 g silica gel column, EtOAc-hexane, 0-20%) to give the title compound as an orange oil (10.0 g, 99% yield). (ES + )M+H=340.2; 1H NMR(400MHz, CDCl3) δ8.19(s,1H),6.64(s,1H),3.99(dd,J=5.9,2.4Hz,2H),3.93(s,3H),2.96(t,J=7.3Hz,2H),2.55(t ,J=7.3Hz,2H),2.42(d,J=0.5Hz,3H),1.56(dt,J=12.1,6.0Hz,1H),1.39~1.22(m,8H),0.88(m,6H).

[0266] Preparation of 6-methoxy-4-methylpyridine-3-thiol (3): To a solution of compound 2 (10.0 g, 29.5 mmol) in THF (105 mL) at −78 °C, potassium t-butoxide (1.00 M in THF, 35.3 mL, 35.3 mmol) was added dropwise, and a precipitate formed. The resulting suspension was stirred at −78 °C for 30 min. The reaction was quenched by the addition of NH Cl (50.0 mL), and the mixture was extracted with CHCl (2 × 50.0 mL). The combined organic layers were dried (Na SO ), filtered, and concentrated under reduced pressure to give a dark orange liquid. The crude product 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. Thiol 3: (ES + ) M+H=156.9, and disulfide: R t =1.92 min,(ES + )M+H=309.0.

[0267] Preparation of 6-methoxy-4-methylpyridine-3-sulfonyl chloride (4): To a mixture of thiol 3 (4.56 g, 29.4 mmol) in HO (123 mL), potassium chloride (2.21 g, 29.3 mmol) was added, followed by portionwise addition of oxone (45.2 g, 73.5 mmol). After completion of the reaction (1 h), the mixture was extracted with EtOAc (2 × 20.0 mL), and the combined organic layers were dried (NaSO) and concentrated under reduced pressure. The crude product obtained was used without any further purification.

[0268] 3-Methylpyridine-4-sulfonyl chloride:

[0269] [ka]

[0270] 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 for 5 minutes by bubbling nitrogen through the solution. Tris(dibenzylideneacetone)-dipalladium(0) (0.02 mmol), 4,4-bis(diphenylphosphino)-9,9-dimethylxanthene (0.04 mmol), and phenylmethanethiol / benzyl mercaptan (1.00 mmol) were added. The mixture was again degassed for 5 minutes. The mixture was heated at reflux (oil bath, T=115°C) for 18 hours. The reaction was cooled to room temperature, diluted with EtOAc (10.0 mL), and quenched with HO (10.0 mL). The aqueous and organic layers were separated, and the aqueous layer was extracted with EtOAc (2 x 10.0 mL). The combined organic phases were washed with HCl (10% in HO, 10.0 mL), dried (NaSO), filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (EtOAc-hexane, 10% to 35%) to give sulfide 2 (90% yield). (ES + )M+H=216.1; 1 H NMR (400MHz, CDCl3) δ8.28(d,J=4.6,1H),8.24(s,1H),7.43~7.27(m,5H),7.20(t,J=5.4Hz,1H),4.25(s,2H),2.28(s,3H).

[0271] Step 2: Compound 2 (1.00 mmol) was dissolved in CHCl (11.5 mL) and cooled to −10° C. HCl (1.00 M in H2O, 5.70 mL) was added and stirred at −10° C. for 5 min. Sodium hypochlorite (10% solution in H2O, 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: LCMS sample was quenched with N-methylpiperazine (resulting sulfonamide, MW = 255.3); (ES + )M+H + =256.2.

[0272] 2,3-Dimethylpyridine-4-sulfonyl chloride:

[0273] [ka]

[0274] The same procedure as for 3-methylpyridine-4-sulfonyl chloride was used starting from 2,3-dimethyl-4-bromopyridine.

[0275] Step 1: 4-(benzylthio)-2,3-dimethylpyridine (2): (92% yield). (ES + )M+H=230.2; 1 H NMR (400MHz, CDCl3) δ:8.17(d,J=5.5Hz,1H),7.42~7.28(m,5H),6.99(d,J=5.5Hz,1H),4.18(s,2H),2.53(s,3H),2.24(s,3H).

[0276] Step 2: 2,3-Dimethylpyridine-4-sulfonyl chloride (3): LCMS sample was quenched with N-methylpiperazine (resulting sulfonamide, MW=269.3); (ES + )M+H+ =270.2.

[0277] Sulfonyl chloride of group B49:

[0278] [ka]

[0279] 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 NaHCO. The solution was stirred for 16 h at room temperature. Upon completion, EtOAc was added to the reaction mixture, and the organic layer was separated, washed with brine, dried over MgSO, then filtered and concentrated. The residue was adsorbed onto SiO and then purified on SiO with EtOAc in hexane to give the desired protected aminopyridine (1000 mg, 2.72 mmol, 64%). 1 H NMR (400MHz, DMSO-d6) δ:10.35(s,1H),8.09(d,J=8.61Hz,1H),7.47(d,J=9.00Hz,1H),7.23~7.44(m,4H),5.16(s,2H),2.53(s,3H). MS m / z 369.2(MH + ).

[0280] Step 2: A degassed solution of iodopyridine from Step 1 (0.61 g, 1.66 mmol), tris(dibenzylideneacetone)-dipalladium(0) chloroform adduct (86 mg, 0.0828 mmol), 9,9-dimethyl-9h-xanthene-4,5-diyl)bis(diphenylphosphine) (96 mg, 0.166 mmol), DIPEA (0.576 mL, 3.31 mmol), and benzyl mercaptan (0.233 mL, 1.99 mmol) in toluene (15 mL) was stirred at 115 °C under N for 3 h. After completion, SiO was added to the reaction mixture and it was concentrated in vacuo. The residue was purified on a SiO column with EtOAc in hexane to give the expected sulfide (560 mg, 93%). 1 H NMR(400MHz, CDCl3) δ:7.71(d,J=8.61Hz,1H),7.54(d,J=8.61Hz,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 + ).

[0281] 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 h. The reaction mixture was evaporated to dryness, then diluted with EtOAc and washed with water followed by brine. The organic layer was dried over MgSO, filtered, and concentrated in vacuo to give the desired sulfonyl chloride B49 (282 mg, 99%), which was used as is: 1 H NMR (400MHz, CDCl3) δ:8.28(d,J=9.00Hz,1H),8.02(d,J=9.00Hz,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 + ).

[0282] 2,2-Difluorobenzo[d][1,3]dioxole-4-sulfonyl chloride:

[0283] [ka]

[0284] Thionyl chloride (5.96 mL) was added dropwise to water (30 mL) over 20 minutes, and the mixture was stirred at room temperature for 48 hours to produce a sulfur dioxide-containing solution. In a separate vessel, 2,2-difluorobenzo[d][1,3]dioxol-4-amine (1.00 g, 5.78 mmol) was added dropwise to ice-cold concentrated hydrochloric acid (7 mL), producing a white precipitate. A solution of sodium nitrite (523 mg, 7.5 mmol) in water (2 mL) was added dropwise to the aniline hydrochloride over 5 minutes to produce an orange reaction mixture. The orange suspension was then slowly added at 5°C to the sulfur dioxide solution from above to which 10 mg of cuprous chloride had been added. The mixture was stirred in an ice bath for an additional 2 hours (gas evolution was observed, and an orange liquid was deposited at the bottom of the flask). After completion was determined by LCMS analysis, the reaction mixture was extracted with DCM (2 x 20 mL), dried (NaSO), filtered, and used without further purification to give the desired sulfonyl chloride as an orange oil (100% crude yield): 1 H-NMR (400MHz, CDCl3) δ7.65(dd,J=8.4,1.1Hz,1H),7.44(dd,J=8.1,1.1Hz,1H),7.32(t,J=8.2Hz,1H).

[0285] 4-chloro-3-fluoro-2-methylbenzenesulfonyl chloride:

[0286] [ka]

[0287] Preparation of N-(3-fluoro-2-methylphenyl)pivalamide (2): To a solution of 3-fluoro-2-methylaniline (10.9 mL, 93.0 mmol) in THF (240 mL) at 0 °C, triethylamine (14.9 mL, 106 mmol) was added, followed by pivaloyl chloride (13.1 mL, 105 mmol) over 10 min. The mixture was warmed to room temperature and stirred for 2 h. The volatiles were evaporated under reduced pressure, and the residue was partitioned between HO (250 mL) and EtOAc (150 mL). The organic and aqueous layers were separated. The aqueous layer was extracted with EtOAc (4 × 60 mL). The combined organic layers were washed with brine (60 mL), dried (NaSO), and concentrated under reduced pressure to give the title compound (18.5 g, 95% yield) as a solid. (ES + )M+H=210.2.

[0288] Preparation of N-(4-chloro-3-fluoro-2-methylphenyl)pivalamide (3): To compound 2 (4.20 g, 20.1 mmol) in DMF (50.0 mL) at room temperature, N-chlorosuccinimide (2.76 g, 20.1 mmol) was added (in three portions) over 10 minutes. The mixture was heated at 80° C. for 90 minutes. Additional N-chlorosuccinimide (541 mg, 4.01 mmol) was added, and this was stirred at 80° C. for 45 minutes. 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 (3×20 mL). The combined organic layers were washed with H2O (3 x 30 mL), brine (20.0 mL), dried (Na2SO4), and concentrated under reduced pressure to give the crude compound (5.20 g). The crude product was dissolved in cyclohexane (30 mL) and heated at 45-50 °C until all solids were dissolved. The solution was cooled to room temperature, and the precipitated white solid was filtered and washed with cyclohexane (3 x 5 mL) to give the title compound (1.95 g, 40% yield) as a solid. (ES + )M+H=244.1.

[0289] Preparation of 4-chloro-3-fluoro-2-methylaniline (4): To a solution of compound 3 (1.60 g, 6.57 mmol) in dioxane (18 mL) at room temperature, HCl (6.00 M in water, 23 mL, 138 mmol) was added over 5 min. The mixture was heated at 100 °C for 20 h. The mixture was cooled to room temperature. Solid KCO (exothermic) was added portionwise until a pH of 8–9 was obtained. The mixture was extracted with EtOAc (4 × 20 mL). The combined organic layers were washed with brine (20 mL), dried (NaSO), and concentrated under reduced pressure to give 1.6 g of crude product, which was dried under vacuum for 24 h to give the title compound (850 mg, 81% yield) as an oil, which was used in the next reaction without further purification. 1 H NMR (400MHz, CDCl3) δ6.99(t,J=8.3Hz,1H),6.40(d,J=8.6Hz,1H),2.22~2.06(m,3H).

[0290] Preparation of 4-chloro-3-fluoro-2-methylbenzene-1-sulfonyl chloride (5): Under ice cooling, thionyl chloride (29.1 mL, 395 mmol) was added dropwise to HO (92.1 mL) over 20 min. This solution containing sulfur dioxide was stirred at 0 °C for 2 h and then 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. This was stirred at 0 °C for 5 min. A solution of sodium nitrite (1.70 g, 24.4 mmol) in HO (2 mL) was added dropwise over approximately 10 min. The above-described sulfur dioxide solution containing copper(I) chloride (38.4 mg, 376 μmol) was slowly added to the reaction mixture over 40 min at 5 °C. The mixture was further stirred under ice cooling for 2 hours and then at room temperature for 4 days. The mixture was diluted with CHCl (20 mL). The aqueous and organic layers were separated. The aqueous layer was extracted with CHCl (3×20 mL). The combined organic layers were dried (NaSO), filtered, and concentrated to give crude compound 5 (1.95 g, 30% yield, 70% purity) as an oil. The crude product was used in the next step without further purification. LCMS: LCMS sample was quenched with N-methylpiperazine (resulting sulfonamide, MW=306.784); (ES + )M+H=307.1; 1 H NMR (400MHz, CDCl3) δ7.81(d,J=8.4Hz,1H),7.46(t,J=7.5Hz,1H),2.69(s,3H).

[0291] 3-Methyl-2-thiophenylsulfonyl chloride:

[0292] [ka]

[0293] Prepared by chlorosulfonylation of 3-methylthiophene as described in US Pat. No. 3,991,081.1 H NMR(CDCl3) δ:7.67(d,J=5.1Hz,1H),7.03(d,J=5.1Hz,1H),2.63(s,3H).

[0294] 3-Chloro-2-thiophenylsulfonyl chloride:

[0295] [ka]

[0296] 3-Chlorothiophene (1.00 g) was dissolved in CHCl3 (10 mL) and the solution was cooled to -30 °C. Chlorosulfonic acid (2.4 mL) was added dropwise over 5 min (no significant gas evolution). The orange-brown solution was then stirred for 30 min, the temperature was allowed to rise to -10 °C, and then to room temperature over an additional 30 min. The reaction mixture was then stirred at room temperature for 2 h (no gas evolution was observed, and TLC indicated product formation (Rf = 0.4 in 8:2 hex / EA)). The reaction mixture was poured onto ice (50 mL), DCM (25 mL) was added, and the milky-white product organic phase was separated, washed with cold water, dried (MgSO4), and concentrated to a yellow oil, which was dried under vacuum and used without further purification (0.55 g). 1 H NMR(CDCl3) δ:7.76(d,J=5.7Hz,1H),7.16(d,J=5.7Hz,1H).

[0297] 4-chloro-3-methylthiophene-2-sulfonyl chloride:

[0298] [ka]

[0299] 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) at room temperature. This was heated at 160 °C in an oil bath for 24 h. The crude product was poured onto HO (50 mL). The resulting mixture was stirred for 10 min at room temperature. The brown-green solid that formed was filtered and washed with water (3 × 10.0 mL) and EtO (4 × 10.0 mL). The filtrate was extracted with EtO (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% yield of crude product). 1 H NMR (400MHz, CDCl3) δ7.09(d,J=3.5Hz,1H),6.99~6.95(m,1H),2.22~2.21(m,3H).

[0300] Preparation of 4-chloro-3-methylthiophene-2-sulfonyl chloride: 3-Chloro-4-methylthiophene (1.00 g, 7.54 mmol) was dissolved in CHCl3 (4.43 mL), and a solution of chlorosulfonic acid (1.19 mL, 17.3 mmol) in CHCl3 (1.48 mL) was added over 5 minutes at room temperature. The mixture was stirred for 10 minutes. Phosphorus pentachloride (4.13 g, 18.9 mmol) was added to the reaction mixture, followed by CHCl3 (7.50 mL). This was heated at 50 °C for 1 hour. The reaction mixture was slowly added to aqueous NaHCO3 + ice (30 mL). This was stirred for 10 minutes. Extraction was performed with CHCl2 (4 x 10 mL). The combined organic layers were dried (NaSO) and concentrated under reduced pressure to give the title compound (1.30 g, 30% yield, 40% purity) as an oil, which was used in the next reaction without further purification. LCMS: The LCMS sample was quenched with N-methylpiperazine; (ES + )M+H=295.1; 1H NMR (400MHz, CDCl3) δ7.57(s,1H),2.57(s,3H).

[0301] 3,4-Dichlorothiophene-2-sulfonyl chloride:

[0302] [ka]

[0303] Preparation of 3,4-dichlorothiophene: In a 100 mL flask, copper(I) chloride (13.9 g, 137 mmol) was added to 3,4-dibromothiophene (5.03 mL, 45.5 mmol) in DMF (32 mL) at room temperature. This was heated at 160 °C in an oil bath for 24 h. The crude product was poured onto HO (100 mL) and diluted with EtO (60 mL). The mixture was stirred for 10 min at room temperature. The brown-green solid that formed was filtered and washed with HO (3 x 20 mL) and then EtO (4 x 20 mL). The filtrate was extracted with EtO (4 x 30 mL). The combined organic layers were washed with H2O (2 x 30 mL), brine (30 mL), dried (MgSO4), and concentrated under reduced pressure to give the title compound 2 (5.50 g, 79% yield) as a red oil. 1 H NMR (400MHz, CDCl3) δ7.21(s,2H).

[0304] 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 a solution of chlorosulfonic acid (757 μL, 11.0 mmol) in CHCl (1.99 mL) over 5 min. The mixture was stirred for 20 min at room temperature. Phosphorus pentachloride (5.77 g, 26.3 mmol) was added to the mixture in four portions. The mixture was heated at 50 °C for 18 h. The volatiles were removed under reduced pressure, and the residue was dissolved in CHCl (25 mL) and washed with saturated aqueous NaHCO (3 × 15 mL), HO (3 × 10 mL), and brine (10 mL). The organic layer was dried (NaSO) 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.

[0305] (3R)-3-Methoxy-1-pyrrolidinesulfonyl chloride:

[0306] [ka]

[0307] (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 minutes to give a fine white suspension. In a separate flask, 4 mL of toluene was cooled to -40 °C in an acetonitrile / dry ice bath. Sulfuryl chloride (0.71 mL, 8.7 mmol) was added, and the solution was stirred for 5 minutes. The pyrrolidine suspension was then added dropwise to the cold (-40 °C) sulfuryl chloride solution over 10 minutes. 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 the desired product (0.40 g) as a light brown oil, which was used without further purification. 1 H NMR(CDCl3) δ:4.07(tt,J=4.6,2.1Hz,1H),3.48~3.69(m,4H),3.36(s,3H),2.12~2.23(m,1H),1.98~2.12(m,1H).

[0308] General Synthetic Method A: Preparation of Difluoroaniline Hydrochloride Intermediate A-5 (Ar=4-Methoxyphenyl) from tert-Butyl Carbamate A-2

[0309] [ka]

[0310] Step 1—Preparation of 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) on carbon (130 mg) were suspended in MeOH (50 mL), and the mixture was stirred under a hydrogen-containing balloon for 18 h, when TLC analysis (Rf=0.45 in 2:1 hexane / EtOAc) showed the reduction to be complete. The suspension was then removed by filtration and cooled to 50° C. for 18 h. (登録商標)The mixture was filtered through a pad of HCl, the catalyst was removed using MeOH to wash, and the solvent was evaporated under reduced pressure. Upon exposure to air, the originally colorless solution turned a very dark greenish-blue color. The crude intermediate aniline A-3 was obtained as a dark greenish-purple foam, which was used immediately in the next step without further purification: 1 H NMR (DMSO-d6) δ:8.58(s,1H),6.77(td,J=9.4,2.0Hz,1H),6.60(td,J=9.4,5.5Hz,1H),4.97(s,2H),1.43(s,9H).

[0311] Step 2—Preparation of Sulfonamide A-4 (Ar=4-Methoxyphenyl): Crude aniline A-3 from Step 1 (assumed 18 mmol) was dissolved in THF (30 mL) and excess 4-methoxyphenylsulfonyl chloride (7.53 g, 36 mmol) was added, 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 and brine, and then dried over MgSO. The desiccant slurry was passed through a 75 mL pad of silica gel using EtOAc to wash and remove the desiccant and baseline material. Removal of the solvent gave a brown oil, which was purified by flash chromatography on silica (∼250 mL) using 20–50% EtOAc in hexanes as the eluent. After drying under vacuum, product A-4 was obtained. 1 The product was obtained as a brownish foam (8.16 g) contaminated with unreacted sulfonyl chloride in a 2:1 ratio by H NMR. The material was used directly as is in the next step: 1 H NMR(CDCl3) δ:7.68(d,J=9.0Hz,2H),7.41(td,J=8.8,5.5Hz,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(MH), m / z 313.0(MH-Boc).

[0312] Step 3—Preparation of Aniline Hydrochloride A-5 (Ar=4-Methoxyphenyl): The crude carbamate A-4 (8.16 g) from Step 3 was stirred in 4 N hydrochloric acid in dioxane (25 mL) at room temperature for 1.5 h, during which time a beige solid gradually precipitated. After 1.5 h, an additional 10 mL of 4 N hydrochloric acid in dioxane was added, and stirring was continued for another 1 h. The reaction mixture was then diluted with 50 mL of diethyl ether, and the beige precipitate was collected by filtration, washed with ether, and dried under vacuum. The aniline salt A-5 (4.38 g) was obtained in pure form in an overall yield of 68% from the nitroarene A-2: 1 H NMR (DMSO-d6) δ:9.73(s,1H),7.62(d,J=8.6Hz,2H),7.06(d,J=9.0Hz,2H),6.69~6.88(m,1H),6.30(td,J=8.6,5.5Hz,1H),3.81(s,3H). MS m / z 313.0(MH).

[0313] General Synthetic Method A: Preparation of Difluoroaniline Hydrochloride Intermediate A-5 (Ar = 2,3-Dichlorophenyl) from Acetanilide A-8

[0314] [ka]

[0315] Preparation of acetanilide A-8: Acetanilide A-7 can be prepared by acetylating 2,6-difluoroaniline A-6 with acetic anhydride according to the literature procedure described in Bioorg. Med. Chem. 2016, 24, 2215. Intermediate A-7 is converted to acetanilide A-8 by sequential nitration followed by reduction of the nitro group to the aniline as described in International Publication No. WO 2012 / 101238 A1.

[0316] 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 equiv., 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 h, after which the conversion was judged complete as monitored by LCMS. The reaction mixture was cooled to room temperature and then partitioned between EtOAc and 2-Me-THF (1:1) and water. 1N hydrochloric acid solution was added until the pH was slightly acidic. A significant amount of off-white solid was present in the biphasic mixture and filtered off (first crop). The layers of the filtrate were separated, and the aqueous layer was extracted twice more with EtOAc. The combined organic extracts were washed once with water, then once with brine, dried over MgSO, filtered, and concentrated to a volume of ~20 mL. The resulting suspension was sonicated, and the solid was collected by filtration and washed with EtOH (second crop). Both crops 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: 1 H NMR(DMSO-d6) δ:10.61(s,1H),9.67(s,1H),7.95(dd,J=8.0,1.4Hz,1H),7.85(dd,J=8.0,1.4Hz,1H),7.51(t,J=8.0Hz,1H),7.05~7.18(m,2H),2.00(s,3H). MS m / z 395.0(MH + ).

[0317] Step 2—Preparation of Aniline Hydrochloride A-5 (Ar = 2,3-Dichlorophenyl): In a 500 mL round-bottom flask, acetanilide A-9 (7.00 g, 17.7 mmol) was suspended in ethanol (65 mL), and a 1:1 mixture of concentrated HCl and water (65 mL) was added. The flask was fitted with a stoppered reflux condenser and heated to 80°C with stirring. After 24 h, conversion was ∼70%, as judged by LCMS monitoring. Additional EtOH (65 mL) and 6 N hydrochloric acid (65 mL) were added to the suspension, and stirring was resumed at 80°C for an additional 7 h, after which LCMS indicated complete conversion to the desired aniline. The reaction mixture was diluted with 50 mL of water while 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 three times and then dried under vacuum to give 7.2 g of the desired product A-5 as its HCl salt in the form of a yellow solid: 1 H NMR(DMSO-d6) δ:10.30(s,1H),7.93(dd,J=8.2,1.2Hz,1H),7.83(dd,J=8.0,1.4Hz,1H),7.49(t,J=8.0Hz,1H),6.68~6.96(m,1H),6.31(td,J=8.6,5.5Hz,1H). MS m / z 350.9(MH).

[0318] The following A-5 intermediates were prepared in a similar sequence using the relevant sulfonyl chloride via either carbamate A-2 or acetanilide A-8 as listed in Table 1 below.

[0319] [Table 1] JPEG2024514227000092.jpg218170JPEG2024514227000093.jpg228170JPEG2024514227000094.jpg87170

[0320] General Synthetic Method A - Preparation of Inhibitor WI from Intermediate A-5

[0321] [ka]

[0322] Step 1—Preparation of Pyridopyrimidone A-11: Adapting the procedure described in J. Med. Chem. 2014, 57, 3484, commercially available 3-amino-6-chloropicolinamide A-10 (9.00 g, 52.5 mmol) was suspended in 116 mL of triethyl orthoformate in a 250 mL round-bottom flask, and 4-methylbenzenesulfonic acid hydrate (0.027 g, 0.14 mmol) was added to the brown suspension. The unstoppered flask was opened to the atmosphere, and the mixture was stirred in an oil bath set at 140 °C. After 52 h, LCMS indicated complete consumption of the starting material. The beige suspension was cooled to room temperature and then concentrated under reduced pressure to a slurry of ∼15–20 mL. It was then diluted with 20 mL of a 1:1 EtOAc / EtO mixture and sonicated. The solid was collected by filtration, washed with 10-15 mL of EtOAc / Et2O mixture, and dried under vacuum to give compound A-11 (6.73 g, 70% yield): 1 H NMR (DMSO-d6) δ:12.74(br.s.,1H),8.20(s,1H),8.15(d,J=8.6Hz,1H),7.88(d,J=8.6Hz,1H). MS m / z 182.0(MH + ).

[0323] Step 2—Preparation of dichloropyridopyrimidine A-12: Following the procedure described in J. Med. Chem. 2014, 57, 3484, pyrimidone A-11 (8.61 g, 47 mmol) was suspended in thionyl chloride (60 mL), and two drops of DMF were added to the mixture. The flask was fitted with a reflux condenser and heated in an oil bath at 80° C. for 6 hours, whereby the thick, pasty slurry became a dark brown solution over approximately 30 minutes. LCMS analysis indicated that the starting material was essentially completely consumed. After cooling to room temperature, the mixture was concentrated, and then concentrated under reduced pressure. Compound A-12 (9.51 g), obtained as a beige solid, was used directly without further purification: 1 H NMR (CDCl3) δ:9.14(s,1H),8.35(d,J=9.0Hz,1H),7.87(d,J=9.0Hz,1H).

[0324] Step 3—Preparation of Chloropyridine Intermediate A-13 (Ar=4-Methoxyphenyl): Following a similar protocol as described in WO 2012 / 101238 A1, crude dichloropyridopyrimidine A-12 (0.44 g, 2.2 mmol, 1.2 equiv.) and aniline hydrochloride A-5 (Ar=4-methoxyphenyl: 0.65 g, 1.8 mmol) were dissolved in acetic acid (5 mL), and the mixture was stirred at 50° C. for 1 h (LCMS showed complete conversion). The reaction mixture was diluted with three volumes of water, and the resulting beige suspension was stirred vigorously for 30 min. The product was then collected by filtration, washed with water, and dried under vacuum to give chloropyridine A-13 (Ar=4-methoxyphenyl) as a beige solid (0.88 g). 1 H NMR(DMSO-d6) δ:10.10(br.s,2H),8.50(s,1H),8.28(d,J=9.0Hz,1H),7.99(d,J=9.0Hz,1H) ,7.67(d,J=8.9Hz,2H),7.13~7.30(m,2H),7.09(d,J=9.0Hz,2H),3.81(s,3H). MS m / z 478.0(MH + ).

[0325] The following A-13 chloropyridine intermediates were prepared in a similar manner and are listed in Table 2.

[0326] [Table 2] JPEG2024514227000097.jpg217170JPEG2024514227000098.jpg234170JPEG2024514227000099.jpg214170JPEG2024514227000100.jpg95170

[0327] Step 4—Preparation of Example 1 (WI: Ar = 4-methoxyphenyl, Het = 1-benzimidazolyl): Chloropyridine A-13 (Ar = 4-methoxyphenyl; 25 mg, 0.05 mmol), benzimidazole (11 mg, 0.09 mmol, 1.8 equiv.), copper powder (0.3 mg), racemic BINOL (0.5 mg), and cesium carbonate (2.3 equiv., 39 mg, 0.12 mmol) were weighed into a 4 mL vial, and DMSO (0.7 mL) was added. The vial was capped, and the mixture was stirred at 125 °C for 2 h (a dark orange-brown solution was formed). LCMS showed complete conversion to the desired product. The reaction mixture was acidified with AcOH (200 μL) and injected onto a preparative reverse-phase HPLC column using a 30–100% MeOH / 0.05% TFA gradient. After lyophilization, the inhibitor 1-TFA salt was obtained as a beige powder (17 mg).

[0328] Other examples of inhibitors prepared in a similar manner are listed below in Tables 3 and 4 (Method A).

[0329] Synthesis of inhibitor WI using synthetic method B (Example 8):

[0330] [ka]

[0331] Step 1: Carbamate A-2 (1.50 g) was dissolved in 8.2 mL of 4 M hydrochloric acid solution in dioxane. After 5 min at room temperature, the pale brown solution became a pale yellow suspension. It was stirred for 16 h (LCMS showed complete conversion to the desired product). The reaction mixture was concentrated to dryness under reduced pressure, and the solid residue was co-evaporated with toluene (2x) and dried under vacuum. The resulting pale green solid (1.11 g, 97% yield) was used directly without further purification: 1 H NMR (DMSO-d6) δ:7.31(ddd,J=9.2,8.0,5.5Hz,1H),7.10~7.18(m,1H).

[0332] Step 2: The aniline hydrochloride salt B-1 from Step 1 (600 mg, 2.85 mmol) and dichloropyridopyrimidine A-12 (1.1 equiv., 627 mg, 3.13 mmol) were suspended in AcOH (8 mL) and stirred at 50 °C for 1.5 h, at which point the reaction was found to be complete by LCMS. The dark brown solution was cooled to room temperature and then slowly poured into 30 mL of ice / water. Once the ice had melted, the suspension was sonicated and the solid was collected by filtration and washed with water. After drying under vacuum, the chloropyridine B-2 (878 mg, 91% yield) was obtained as a beige solid, which was used directly without further purification: 1 H NMR(DMSO-d6) δ:10.39(s,1H),8.61(s,1H),8.33(d,J=9.0Hz,1H),8.29(td,J=9.2,5.9Hz,1H),8.04(d,J=9.0Hz,1H),7.56(td,J=9.0,1.0Hz,1H). MS m / z 338.0(MH + ).

[0333] Step 3: Nitroarene B-2 (875 mg, 2.6 mmol) and tin(II) dichloride dihydrate (5 equiv., 2.92 g, 13 mmol) were suspended in 20 mL of ethanol. The mixture was heated to 60 °C to give a deep orange solution and stirred at that temperature for 2 h, at which point the reaction was analyzed by LCMS and found to be complete. The mixture was cooled to room temperature and then concentrated under reduced pressure to remove most of the ethanol. The concentrate was taken up in EtOAc (150 mL), and 1 N NaOH solution was added until two nearly clear layers were obtained. The layers were separated, and the aqueous layer was extracted three more times with 50 mL of EtOAc. The combined organic layers were washed with water, then brine, dried over MgSO, concentrated, and dried under vacuum. Aniline B-3 (792 mg, 99% yield) was obtained as a light brownish yellow solid, which was used directly without further purification: 1 H NMR(DMSO-d6) δ:9.99(s,1H),8.53(s,1H),8.27(d,J=8.6Hz,1H),7.98(d,J=8.6Hz,1H),6.89(td,J=9.2,1.6Hz,1H),6.74(td,J=9.4,5.5Hz,1H),5.07(s,2H). MS m / z 308.0(MH + ).

[0334] Step 4—Preparation of Aniline B-4 (Het = 1-Benzimidazolyl): Chloropyridopyrimidine B-3 (495 mg, 1.6 mmol) was placed in a 50 mL flask and dissolved in 6 mL of DMSO. Next, benzimidazole (1.15 equiv., 220 mg, 1.85 mmol), cesium carbonate (2.3 equiv., 1.21 g, 3.7 mmol), copper powder (0.01 equiv., 1 mg), and BINOL (0.01 equiv., 4.5 mg) were added. The resulting dark mixture was stirred at 100° C. for 2 h, at which point LCMS analysis confirmed ∼40% conversion. The temperature was increased to 120° C., and the mixture was stirred for an additional 2 h, at which point only traces of starting aniline were present. The mixture was cooled to room temperature and then neutralized (pH 7) with 1N hydrochloric acid. It was then partitioned between water (75 mL) and DCM (100 mL). After stirring, ∼5 g of celite (登録商標) is added to the brown emulsion, which is (登録商標) The filtrate (two clear layers) was transferred to a separatory funnel, and the layers were separated. The aqueous layer was extracted twice with DCM, and the combined organic layers were washed twice with water and once with brine. The organic portion was then dried over MgSO, filtered, and concentrated. The residue was purified by flash chromatography (combiflash) on a 24 g column using a gradient of 100% DCM to 40% i-PrOH in DCM. The appropriate fractions (Rf = 0.25 in 1:9 i-PrOH / DCM) were combined and concentrated to give 124 mg of compound B-4 (Het = 1-benzimidazolyl) as a dark yellow solid, which is a 1:1 molar mixture of the desired product and unreacted benzimidazole. The crude material was used for the sulfonylation step (step 5 below) without further purification: 1H NMR(DMSO-d6) δ:9.79(s,1H),9.39(s,1H),8.56(s,1H),8.52(d,J=9.4Hz,1H),8.47(d,J=9.0Hz,1H),8.39(d,J=7.8Hz,1H),7 .83(d,J=7.4Hz,1H),7.37~7.49(m,2H),6.95(td,J=9.2,1.6Hz,1H),6.78(td,J=9.4,5.5Hz,1H),5.13(s,2H). MS m / z 390.1(MH + ).

[0335] Step 5 (Example 8): 2-Chlorobenzenesulfonyl chloride (2 equiv., 26 mg, 0.12 mmol) was weighed into a 4 mL vial and dissolved in 0.5 mL of THF. Crude aniline B-4 (24 mg, 0.06 mmol) was then added, followed by pyridine (6 equiv., 30 μL, 0.37 mmol). The resulting mixture was stirred at 50° C. for 18 h, at which point the reaction was found to be complete by LCMS (also present in the mixture was a by-product corresponding to the addition of sulfonyl chloride to benzimidazole, a residue that contaminated the starting material (MS m / z 293.0: MHCl). + ). The reaction mixture was cooled to room temperature, then quenched by the addition of 0.2 mL of acetic acid and diluted to 2 mL with methanol. The product was isolated by preparative HPLC (MeOH / HO / 0.1% formic acid, 50% to 100% methanol gradient). Fractions containing the major peak were pooled and partially concentrated to remove the methanol. The resulting suspension was dissolved by adding a few milliliters of acetonitrile, and the solution was then frozen and lyophilized. 9.8 mg of the desired product (Example 8) was obtained as a beige solid.

[0336] Other examples of inhibitors prepared in a similar manner are listed below in Tables 3 and 4 (Method B).

[0337] Synthesis of inhibitor W-II via Suzuki-Miyaura cross-coupling using synthetic method C and organoboron reagents (Examples 71 and 510):

[0338] [ka]

[0339] A 2 mL microwave vial was charged with 30 mg (1 equiv.) of chloropyridopyrimidine A-13, 2 equiv. of 6-methoxypyridyl-3-boronic acid (19 mg), and 4 equiv. of anhydrous potassium carbonate (34 mg). Next, DME (1.5 mL) and water (0.5 mL) were added, and nitrogen gas was bubbled through the mixture for 2 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.05 equiv., 3.5 mg) was added, nitrogen gas was bubbled through the mixture for an additional 2 minutes, and the vial was sealed. The reaction mixture was then irradiated in a microwave oven for 1 hour at 90 °C, at which point LCMS analysis confirmed the reaction was complete. The reaction mixture was treated with 0.6 mL of acetic acid and concentrated to ∼0.5 mL under reduced pressure. It was then diluted to 2 mL with methanol and DMSO, filtered, and purified by preparative HPLC (MeOH / HO / 0.1% formic acid, 50% to 100% methanol gradient). Appropriate fractions were combined and partially concentrated to remove the methanol. The resulting suspension was dissolved by adding a few milliliters of acetonitrile, and the solution was then frozen and lyophilized. The inhibitor of Example 71 was obtained as a beige solid (15 mg).

[0340] Other examples of inhibitors prepared in a similar manner using the appropriate chloropyridine fragment A-13 (Table 2) and commercially available boronic acids or boronic esters are listed below under Method C in Table 4. Analogs of the compound of Example 510 were prepared in a similar manner using commercially available boronic esters, cesium carbonate as the base, trans-dichlorobis(triphenylphosphine)-palladium(II) as the catalyst, and dioxane as the solvent.

[0341] Synthesis of inhibitor W-II via Stille cross-coupling using synthetic method C and organotin reagents (Example 561):

[0342] [ka]

[0343] Step 1: To a −78° C. solution of the commercially available bromide (100 mg, 0.497 mmol) in THF (5 mL) under N was added a 2.5 M solution of nBuLi in hexanes (0.24 mL, 0.597 mmol) and stirred at this temperature for 30 min. After this, tri-n-butyltin chloride (0.13 mL, 0.497 mmol) was added and the resulting solution was stirred for 30 min. Upon completion, EtOAc was added and the organic layer was washed with brine, then dried over MgSO, filtered, and concentrated under vacuum to provide the organotin intermediate (154 mg, 75%). MS m / z 413.2 (MH + ).

[0344] Step 2: A vial containing the organotin reagent from Step 1 (40 mg, 0.0968 mmol), 2,3-dichloro-N-[3-[(6-chloropyrido[3,2-d]pyrimidin-4-yl)amino]-2,4-difluoro-phenyl]benzenesulfonamide (50 mg, 0.0968 mmol), copper(I) iodide (1.2 mg, 0.0290 mmol), (R)-(+)-2,2″-bis(diphenylphosphino)-1,1″-binaphthyl (12 mg, 0.0194 mmol), and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (7.1 mg, 0.00968 mmol) in 1:1 PhMe-DMF (0.5 mL) was degassed and purged with N three times. The mixture was stirred at 90 °C for 16 h under a N atmosphere. Upon completion, the reaction mixture was diluted with EtOAc and then washed three times with 10% aqueous KF solution, followed by brine. The organic layer was dried over MgSO, filtered, and concentrated in vacuo. The residue was purified by reverse-phase HPLC using 0.1% aqueous HCOOH in ACN to give Example 561 (2.7 mg, 5%) upon lyophilization. 1 H NMR (400 MHz, DMSO-d6) δ:10.73(br.s.,1H),9.44(s,1H),8.76(d,J=9.00Hz,1H),8.39~8.62(m,2H) ,8.23(d,J=8.22Hz,1H),7.91(dd,J=1.17,7.83Hz,2H),7.51(t,J=8.02Hz,2 H),7.27(br.s.,1H),7.17(br.s.,1H),6.83(d,J=8.22Hz,1H),4.41(s,1H), 3.98~4.15(m,2H),3.51~3.60(m,2H),1.54~1.79(m,4H),1.17~1.38(m,3H). MS m / z 712.3(MH + ).

[0345] Other examples of inhibitors prepared in a similar manner using the appropriate chloropyridine fragment A-13 (Table 2) and either commercially available organotin compounds or bromides converted to the corresponding organotin species described above in Step 1 are listed under Method C in Table 4 (Examples 562-565, 590, and 591).

[0346] General Method for the Synthesis of Inhibitors of Formula W-III (Method D, X=CH) - Synthesis of Compound Example 109:

[0347] [ka]

[0348] Step 1—Preparation of Carboxylic Acid D-1: Chloropyridopyrimidine A-13 (Ar = 2-chlorophenyl) (150 mg, 0.3 mmol, 1 equiv.) was placed in a 4 mL vial, followed by methyl indole-3-carboxylate (71 mg, 0.4 mmol, 1.3 equiv.), copper(0) (0.6 mg, 0.03 equiv.), BINOL (2.7 mg, 0.03 equiv.), cesium carbonate (150 mg, 0.47 mmol, 1.5 equiv.), and DMSO (1.5 mL). The resulting mixture was stirred at 100 °C for 1.75 h to give a dark brown solution (LCMS analysis indicated complete conversion). The reaction was cooled to room temperature, and then 6 equiv. (0.5 mL) of 4 N sodium hydroxide was added to the mixture. It was stirred at 50° C. for 1 h (LCMS shows complete conversion to the carboxylic acid). The mixture was diluted with water (2 mL) and poured onto celite. (登録商標) The mixture was filtered through a plug to remove insoluble particles. It was then acidified with 1N hydrochloric acid to pH 1 and diluted with 10 mL of water to give a gel-like suspension (not filterable). The mixture was extracted three times with EtOAc, and the combined organic layers were washed twice with water and once with brine, then dried over MgSO, filtered, and concentrated to give 220 mg of the crude carboxylic acid as a yellow solid: 1H NMR(DMSO-d6) δ:12.56(br.s.,1H),10.53(s,1H),9.99(s,1H),8.97(s,1H),8.50(s,1H), 8.47(d,J=9.0Hz,1H),8.43(d,J=9.4Hz,1H),8.23~8.29(m,1H),8.16~8.22 (m,1H),7.91(dd,J=8.0,1.4Hz,1H),7.62~7.71(m,2H),7.48~7.55(m,1H), 7.35~7.44(m,2H),7.24~7.33(m,1H),7.21~7.24(m,1H),7.16~7.21(m,1H). MS m / z 607.0(MH + ).

[0349] Step 2—Preparation of Inhibitor W-III (Example 109): To the crude carboxylic acid from Step 1 (30 mg, 1 equiv.) in NMP (1 mL) was added DIEA (40 μL, 6 equiv.) and HATU (30 mg, 2 equiv.). The solution was stirred for 2–3 minutes to give a dark yellow solution. Morpholine (7 mg, 2 equiv.) was added, and the reaction mixture was stirred at room temperature for 3 hours, at which point the reaction was determined to be complete by LCMS. The reaction was quenched by adding 0.2 mL of acetic acid, then diluted to 2 mL with methanol, filtered, and purified by preparative HPLC (MeOH / HO / 0.1% formic acid, 50% to 100% methanol gradient). The appropriate fractions were combined and partially concentrated to remove the methanol. The resulting suspension was dissolved by adding a few milliliters of acetonitrile, and the solution was then frozen and lyophilized to give amide Example 109 (14.5 mg) as an off-white solid.

[0350] Other examples of inhibitors prepared in a similar manner are listed under Method D in Table 4 below.

[0351] General Method for the Synthesis of Inhibitors of Formula W-III (Method D, X=N) - Synthesis of Compound Example 127:

[0352] [ka]

[0353] Step 1—Preparation of Carboxylic Acid D-2: Chloropyridopyrimidine A-13 (Ar = 3-chloro-2-methylphenyl) (300 mg, 0.6 mmol, 1 equiv.) was placed in a 4 mL vial, followed by 3-indazolecarboxylic acid methyl ester (140 mg, 0.79 mmol, 1.3 equiv.), copper(0) (1 mg, 0.03 equiv.), BINOL (5 mg, 0.03 equiv.), cesium carbonate (295 mg, 0.91 mmol, 1.5 equiv.), and DMSO (2 mL). The vial was capped, and the mixture was stirred at 100° C. for 1.5 hours to give a dark brown solution. LCMS analysis confirmed that the reaction was essentially complete. The reaction was cooled to room temperature, and then 6 equiv. (0.9 mL) of 4N sodium hydroxide solution was added. The mixture was stirred at 50° C. for 1.5 h (LCMS showed complete saponification of the methyl ester). The mixture was diluted with water (3 mL) and poured onto celite. (登録商標) The mixture was filtered through a plug to remove insoluble particles. It was then acidified with 1N hydrochloric acid to pH 1 and diluted with 10 mL of water. After sonication, a fine suspension was obtained. The solid was collected by filtration and dried under vacuum. The crude carboxylic acid D-2 (Ar = 3-methyl-2-chlorophenyl) was obtained as a beige solid (398 mg): 1H NMR(DMSO-d6) δ:13.70(br.s,1H),10.58(s,1H),9.48(s,1H),9.03(d,J=8.6Hz,1H),8.65(d,J=9.0Hz,1H),8.54(br.s.,1H),8.48(d,J=9.0Hz,1H),8.26(d,J=7.8Hz,1H),7.79(d,J=7.8Hz,1H),7.75(d,J=7.8Hz,1H),7.68(t,J=7.6Hz,1H),7.54(t,J=7.6Hz,1H),7.40(t,J=8.0Hz,1H),7.28~7.36(m,1H),7.25(t,J=9.0Hz,1H),2.66(s,3H)。MS m / z 622.0(MH + )。

[0354] Step 2—Preparation of Inhibitor W-III (Example 127): The crude carboxylic acid from Step 1 (30 mg, 1 equiv.) was dissolved in NMP (1 mL), and DIEA (50 μL, 6 equiv.) and HATU (37 mg, 2 equiv.) were added. The solution was stirred at room temperature for 2–3 minutes to give a dark yellow solution. N-Boc-piperazine (18 mg, 2 equiv.) was then added, and the reaction mixture was stirred at room temperature for 2 hours, at which point the reaction was determined to be complete by LCMS. The reaction was quenched by adding 1 mL of a saturated solution of ammonium chloride and then diluted to 4 mL with water. The resulting suspension was then sonicated, and the solids were collected by filtration. They were then washed with water and dried under vacuum. The solids were then taken up in DCM (1 mL) and MeOH (0.5 mL) and treated with 1 mL of 4 N hydrochloric acid solution. After stirring at room temperature for 2 hours, LCMS analysis indicated complete cleavage of the Boc protecting group. The mixture was concentrated to dryness, and the residue was dissolved in MeOH and purified by preparative HPLC (MeOH / HO / 0.1% formic acid, 30% to 100% methanol gradient). Appropriate fractions were combined and partially concentrated to remove the methanol. The resulting suspension was dissolved by adding a few milliliters of acetonitrile, and the solution was then frozen and lyophilized. The amide of Example 127 (14 mg) was obtained as a pale yellow solid.

[0355] Other examples of inhibitors prepared in a similar manner are listed under Method D in Table 4 below.

[0356] General Method for the Synthesis of Inhibitors of Formula W-IV (Method E) - Synthesis of Compound Example 227:

[0357] [ka]

[0358] Step 1—Preparation of Intermediate E-2: 3-Bromo-1,2-phenylenediamine (2.00 g, 10.7 mmol) was placed in a 50 mL flask with 15 mL of formic acid. The mixture was refluxed in a 120° C. oil bath and stirred for 4 hours. The mixture was concentrated under reduced pressure to a dark oily residue, diluted with water, and cooled in an ice bath. Neutralization of the mixture was initiated with 1 N NaOH and completed with saturated NaHCO3 solution. The dark brown solid was collected by filtration on a Buchner funnel and washed with water. The solid was then dried under vacuum to give 1.91 g of the desired bromobenzimidazole E-2 as a dark brown solid, which was used as is: 1 H NMR (DMSO-d6) δ:12.81(br.s.,1H),8.30(s,1H),7.58(d,J=8.2Hz,1H),7.41(d,J=7.8Hz,1H),7.14(t,J=8.0Hz,1H). MS m / z 197.0(MH + ).

[0359] Step 2—Preparation of Intermediate E-3: Adapting the procedure described in International Publication WO 2004 / 076411 A2, bromobenzimidazole E-2 (350 mg, 1.776 mmol) was dissolved in 8 mL of anhydrous THF. A 60% dispersion of sodium hydride in mineral oil (78 mg, 1.95 mmol) was added at room temperature. After 10 minutes, the reaction was cooled to −78° C., and 1.4 M of tert-butyllithium in pentane (2.66 mL, 3.73 mmol) was added dropwise. The reaction mixture became very thick and was difficult to stir. After 30 minutes, the mixture was quenched by the addition of DMF (0.55 mL, 7.1 mmol). It was allowed to warm to room temperature and then partitioned between EtOAc and a 1:1 mixture of water and saturated NaHCO solution. The layers were separated, and the aqueous layer was further extracted three times with EtOAc. The combined organic layers were washed once with brine and then dried over Na2SO4. The organic layer was then filtered and concentrated to a residue. The resulting dark brown gummy solid was triturated twice with 2 mL of hexane to remove the mineral oil from the NaH. The solid was then taken up in 6 mL of EtOAc and sonicated. The solid was collected by filtration and evaporated under vacuum to give compound E-3 (117 mg) as a dark brown solid: 1 H NMR (DMSO-d6) δ: 13.01 (br.s., 1H), 10.17 (s, 1H), 8.31 (s, 1H), 8.04 (d, J = 7.8 Hz, 1H), 7.88 (d, J = 7.4 Hz, 1H), 7.43 (t, J = 7.8 Hz, 1H). A second crop of product (148 mg, ∼80% homogeneity) was recovered from the mother liquor.

[0360] Step 3—Preparation of Intermediate E-4: Chloropyridopyrimidine A-13 (Ar = 2-chlorophenyl: 75 mg, 1 equiv.) was placed in a 4 mL vial along with crude benzimidazole E-3 from Step 2 (26 mg, 1.15 equiv.), copper(0) (0.3 mg, 0.03 equiv.), BINOL (1.3 mg, 0.03 equiv.), cesium carbonate (76 mg, 1.5 equiv.), and DMSO (1 mL). The resulting mixture was stirred at 100 °C for 1 h, at which point LCMS indicated complete reaction. The mixture was cooled to room temperature and then quenched by the addition of 0.1 mL of acetic acid. The mixture was diluted to 10 mL with water and then sonicated. The precipitate was collected by filtration and washed with water. The brown solid was then dried under vacuum. Crude intermediate E-4 (98 mg) was obtained as a brown solid and used as is in step 4: 1 H NMR(DMSO-d6) δ:10.85(br.s.,1H),10.53(br.s.,1H),9.84(s,1H),9.54(br.s.,1H),8.76(d,J=7.4Hz,1H),8.45~8.63(m,2 H),7.92(d,J=7.4Hz,1H),7.88(d,J=7.4Hz,1H),7.55~7.73(m,3H),7.51(t,J=7.2Hz,1H),7.12~7.34(m,2H). MS m / z 592.1(MH + ).

[0361] Step 4—Preparation of Inhibitor W-IV (Example 227): 3-Fluoroazetidine hydrochloride (17 mg, 0.15 mmol) was placed in a 4 mL vial with 1 mL of methanol and 4 N sodium hydroxide solution (0.038 mL, 0.15 mmol). Crude aldehyde E-4 (30 mg, 0.051 mmol) from Step 3 was then added, and the mixture was heated at 50° C. for 10 minutes. Sodium cyanoborohydride (9.55 mg, 0.15 mmol) was finally added. The reaction mixture was stirred at 50° C. for an additional 2 hours, at which point conversion was found to be complete by LCMS. It was quenched by the addition of 0.2 mL of acetic acid in 0.5 mL of DMSO, the solution was filtered, and the product was isolated by preparative HPLC (30% to 100% MeOH gradient, 0.1% formic acid in HO). The appropriate fractions were pooled and concentrated to remove methanol, then frozen and lyophilized. Example 227 (12.7 mg) was isolated as an off-white solid.

[0362] General Method for the Synthesis of Inhibitors of Formula WV (Method F) - Synthesis of Compound Example 243:

[0363] [ka]

[0364] Step 1: Bromobenzimidazole E-2 (70 mg, 0.355 mmol), potassium carbonate (196 mg, 1.42 mmol), and 3-pyridylboronic acid (57 mg, 0.46 mmol) were placed in a 4 mL vial, and dioxane (2 mL) and water (0.7 mL) were added. Argon gas was bubbled through the mixture for 1 min, and then tetrakis(triphenylphosphine)palladium(0) (16.4 mg, 0.014 mmol) was added. Argon gas was again bubbled through the solution for 3 min, and the vial was sealed and heated at 100 °C for 2 h. Conversion to the desired product was judged complete by LCMS analysis. The reaction mixture was cooled to room temperature, diluted with EtOAc, and washed with brine. After drying over MgSO, the extract was concentrated under reduced pressure and the residue was purified by flash chromatography using EtN pre-treated silica and a gradient of DCM-20% iPrOH / DCM to provide the desired benzimidazole intermediate (58 mg, 84% yield): 1 H NMR (DMSO-d6) δ: 12.71 (broad 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 + ).

[0365] Step 2 (Example 243): The crude benzimidazole from Step 1 was coupled to chloropyridine A-13 (Ar = 2-chlorophenyl) using copper / BINOL catalysis as described for Example 1 (Step 4) in General Method A.

[0366] Other compounds (e.g., Examples 251, 272, 273, and 342) were prepared in a similar manner using the appropriate commercially available boronic acid and chloropyridine intermediate A-13 (Ar = 3-fluoro-2-methylphenyl or 2,3-dichlorophenyl) in step 1.

[0367] General Method for the Synthesis of Inhibitors of Formula W-VI (Method G) - Synthesis of Compound Example 437:

[0368] [ka]

[0369] Step 1: To a vial equipped with a stir bar was added 1-(p-tolylsulfonyl)indole-3-sulfonyl chloride (117 mg, 0.316 mmol) (Chemical and Pharmaceutical Bulletin 2009, 57, 591) in anhydrous THF (1.5 mL). The solution was cooled to 0 °C, and DIEA (0.11 mL, 0.633 mmol) was added dropwise. Next, N-(2-methoxyethyl)ethylamine (0.039 mL, 0.316 mmol) was added dropwise, and the reaction mixture was allowed to warm gently to room temperature. The reaction was stirred at room temperature for 1 hour. Upon completion, 10% aqueous KOH was added dropwise (same solvent). The reaction was heated at 60 °C overnight. Upon completion, the reaction mixture was diluted with EtOAc, and NH4Cl was added. The layers were separated. The organic layer was washed with brine, then dried over MgSO, filtered, and concentrated to dryness to give the expected sulfonamide derivative (86 mg, 96%) as a pale orange oil. MS m / z 283.2 (MH + ).

[0370] Step 2 (Example 437): The indole sulfonamide from Step 1 was coupled to chloropyridine A-13 (Ar = 2,3-dichlorophenyl) using copper / BINOL catalysis as described for Example 1 (Step 4) in General Method A.

[0371] Other examples of inhibitors prepared in a similar manner using the appropriate amine in step 1 are listed under Method G in Table 4 below.

[0372] General Method for the Synthesis of Inhibitors of Formula W-VII (Method H) - Synthesis of Compound Example 466:

[0373] [ka]

[0374] Step 1: To a solution of 1H-indol-3-yl thiocyanate (Phosphorus, Sulfur and Silicon and the Related Elements 2014, 189, 1378) (100 mg, 0.574 mmol) in iPrOH (5 mL) was added sodium sulfide anhydrate (414 mg, 1.72 mmol) dissolved in 0.5 mL of water, and the resulting mixture was stirred at 50 °C for 2 h. After this, 4-chlorotetrahydropyran (0.19 mL, 1.72 mmol) was added and stirred at 50 °C overnight. 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, and then concentrated in vacuo to give the crude sulfide, which was used directly in the next step without further purification.

[0375] 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 hours. Upon completion, the reaction was quenched by adding 10 mL of a 1:1 solution of saturated NaHCO3 and 10% Na2SO3 solution. The resulting suspension was stirred at room temperature for 15 minutes. EtOAc was added and the organic layer was separated. The organic layer was washed with water (15 mL), then saturated brine solution (15 mL), dried (MgSO4), and filtered before concentrating and drying to provide the expected sulfone (154 mg, 98%), which was dissolved in DMSO and used directly in the next step without further purification. MS m / z 266.2 (MH + ).

[0376] Step 3 (Example 466): The indole from Step 2 was coupled to chloropyridine A-13 (Ar = 2,3-dichlorophenyl) using copper / BINOL catalysis as described for Example 1 (Step 4) in General Method A.

[0377] Other examples of inhibitors prepared in a similar manner using the appropriate alkylating agent in step 1 are listed under Method H in Table 4 below.

[0378] General Method for the Synthesis of Inhibitors of Formula W-VIII (Method I) - Synthesis of Compounds of Examples 524 and 665:

[0379] Example 524 (for step 2, iron metal as reducing agent):

[0380] [ka]

[0381] Step 1: 4-Methylpiperidin-4-ol (0.24 g, 1.84 mmol) and potassium carbonate (0.49 g, 3.52 mmol) were added to a solution of 3-fluoro-2-nitro-aniline (0.25 g, 1.60 mmol) 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 crude 1-(3-amino-2-nitro-phenyl)-4-methyl-piperidin-4-ol (0.40 g, 94% yield) was used for the next step without further purification. MS m / z 252.2 (MH + ).

[0382] Step 2 (using iron as a reducing agent): Iron (0.37 g, 6.70 mmol) and ammonium chloride (0.36 g, 6.70 mmol) were added to a mixture of 1-(3-amino-2-nitro-phenyl)-4-methyl-piperidin-4-ol (0.34 g, 1.34 mmol) and formic acid (1.9 mL, 49.6 mmol) in iPrOH (6.5 mL). The resulting mixture was heated to 90° C. and stirred for 10 hours. The reaction mixture was cooled to room temperature and then filtered through Celite. (登録商標) The solution was concentrated and the crude product was purified by column chromatography (silica gel, 0-15% MeOH in DCM) to give 1-(1H-benzimidazol-4-yl)-4-methyl-piperidin-4-ol (0.17 g, 55% yield) as a reddish foamy solid. MS m / z 232.2 (MH + ). 1 H NMR(400MHz,DMSO-d6) 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=1.66,3.72Hz,2H),1.41~1.74(m,4H),1.16(s,3H).

[0383] Step 3 (Example 524): The benzimidazole from Step 2 was coupled to chloropyridine A-13 (Ar = 2,3-dichlorophenyl) using copper / BINOL catalysis as described for Example 1 (Step 4) in General Method A.

[0384] Example 665 (Zinc metal as reducing agent for step 2):

[0385] [ka]

[0386] Step 1: Potassium carbonate (1.01 g, 7.33 mmol) and 4-isopropylpiperidin-4-ol (262 mg, 1.83 mmol) (International Publication No. WO 2014 / 139144, 2014, A1) were added to a bright red solution of 3-fluoro-2-nitro-aniline (0.25 g, 1.60 mmol) in ACN (3 mL). The resulting mixture was stirred at 80 °C for 16 h. EtOAc was added and the suspension was centrifuged. The supernatant was separated and concentrated under vacuum to give the desired nitroaniline (400 mg, 78% yield).

[0387] Step 2 (using zinc as the reducing agent): To a solution of the nitroaniline from Step 1 (280 mg, 1.25 mmol) in isopropyl alcohol (8 mL) was added zinc (820 mg, 12.5 mmol) and ammonium chloride (671 mg, 12.5 mmol). The suspension was stirred at 60°C for 10 minutes, and then formic acid (1.9 mL, 50.2 mmol) was added. The resulting mixture was heated at 60°C and stirred for 2 hours. Upon completion, EtOAc was added and the suspension was centrifuged. The supernatant was separated and concentrated under vacuum. The residue was purified on silica gel with MeOH in DCM to give the expected benzimidazole derivative (284 mg, 76% yield). 1H NMR(400MHz,DMSO-d6) δ:9.16(br.s.,1H),7.22~7.45(m,2H),7.05(br.s.,1H),3.76~4.35(m,2H),3.01~3. 30(m,2H),1.83(dt,J=3.94,12.66Hz,2H),1.46~1.71(m,3H),0.92(d,J=6.88Hz,6H). MS m / z 360.2(MH + ). MS m / z 360.2(MH + ).

[0388] Step 3 (Example 665, Table 4): The benzimidazole from Step 2 was coupled to chloropyridine A-13 (Ar = 2,3-dichlorophenyl) using copper / BINOL catalysis as described for Example 1 (Step 4) in General Method A.

[0389] Other examples of inhibitors prepared in a similar manner using the appropriate amine in step 1 and either Fe or Zn as the reducing agent in step 2 are listed under Method I in Table 4 below.

[0390] General Method for the Synthesis of Inhibitors of Formula W-IX (Method J) - Synthesis of Compound Example 600:

[0391] [ka]

[0392] Step 1: Piperidine-4-carbonitrile hydrochloride (0.103 g, 0.705 mmol) and potassium carbonate (177 mg, 1.28 mmol) were added to a bright red solution of 3-fluoro-2-nitro-aniline (100 mg, 0.641 mmol) in ACN (5 mL). The resulting mixture was stirred at 90° C. for 16 h. The reaction mixture was diluted with EtOAc (5 mL) and centrifuged. The supernatant containing the desired nitroaniline was separated and used directly in the next step. MS m / z 247.2 (MH + ).

[0393] Step 2: To the solution of nitroaniline from step 1, ammonium chloride (685 mg, 12.8 mmol) and zinc (419 mg, 6.41 mmol) were added. The resulting suspension was stirred at 40° C. for 1 h. The reaction mixture was diluted with EtOAc (30 mL) and then centrifuged. The supernatant was separated and concentrated under vacuum. The resulting 1,2-phenylenediamine (101 mg, 73%) was used directly in the next step. MS m / z 217.2 (MH + ).

[0394] Step 3: The product from Step 2 was dissolved in AcOH (3 mL), then sodium nitrite (32 mg, 0.647 mmol) was added and stirred at room temperature for 1 h. The reaction mixture was diluted with EtOAc (60 mL) and washed with water (2 x 20 mL), followed by saturated NaHCO solution (2 x 20 mL), then brine (20 mL). The separated organic layer was dried over MgSO, filtered, and concentrated in vacuo to give the desired benzotriazole (75 mg, 0.330 mmol, 51%). 1 H NMR(400MHz,DMSO-d6) δ:7.30(t,J=7.88Hz,1H),7.20(d,J=8.00Hz,1H),6.63(d,J=7.50Hz,1H),3.85(br.s.,2H), 3.45(t,J=9.38Hz,2H),3.15(td,J=4.24,8.41Hz,1H),2.00~2.22(m,2H),1.85~2.00(m,2H). MS m / z 228.2(MH + ).

[0395] Step 4: A solution of benzotriazole (17 mg, 0.076 mmol) from Step 3, 2,3-dichloro-N-[3-[(6-chloropyrido[3,2-d]pyrimidin-4-yl)amino]-2,4-difluoro-phenyl]benzenesulfonamide (30 mg, 0.058 mmol), copper(II) sulfate pentahydrate (1.9 mg, 0.0077 mmol), trans-2-phenyl-1-cyclopropanecarboxylic acid (1.3 mg, 0.0077 mmol), and potassium carbonate (21 mg, 0.155 mmol) in DMSO (1.5 mL) was stirred at 100° C. for 3 h. After completion, the mixture was cooled to room temperature, diluted with DMSO, and purified by HPLC (MeOH+0.1% formic acid in water+0.1% formic acid) to give Example 600 (11 mg, 25%). 1 H NMR(400MHz,DMSO-d6) δ:9.45(br.s.,1H),8.76(d,J=9.01Hz,1H),8.45~8.63(m,2H),8.31(d,J= 8.00Hz,1H),7.73~8.02(m,2H),7.41~7.70(m,2H),7.25(br.s.,1H),7.13 (br.s.,1H),6.87(d,J=8.00Hz,1H),4.01(d,J=12.38Hz,2H),3.60(t,J=1 0.38Hz,2H),3.20(br.s.,2H),2.11(br.s.,2H),1.96(d,J=10.01Hz,2H). MS m / z 707.2(MH + ).

[0396] Other examples of inhibitors prepared in a similar manner using the appropriate amine in step 1 are listed under Method J in Table 4 below.

[0397] General Method for the Synthesis of Inhibitors of Formula WX (Method K) - Synthesis of Compound Example 112:

[0398] [ka]

[0399] Step 1: 3-Indole sulfonyl chloride was prepared as described in Org. Lett. 2011, 13, 3588. A solution of indole (3 g, 25.6 mmol) and sulfur trioxide-pyridine (4.08 g, 25.6 mmol) in pyridine (15 mL) was heated to reflux (115 °C) with stirring for 2 h. After 2 h, the reaction was cooled to room temperature and diluted with water (20 mL). The aqueous layer was washed twice with diethyl ether (20 mL). The aqueous layer was evaporated to dryness to give crude 1H-indole-3-sulfonate pyridinium salt (5.30 g, 75% yield) as a white solid. The crude material was used directly in the next step.

[0400] Step 2: Crude 1H-indole-3-sulfonate pyridinium (4.60 g, 16.7 mmol) from Step 1 of the previous step was dissolved in a 1:1 mixture of sulfolane:acetonitrile (50 mL). The white suspension was cooled to 0 °C, and POCl (3.42 mL, 36.7 mmol) was added dropwise with stirring, resulting in a light brown solution. The reaction was heated at 70 °C for 1 h. After 1 h, the orange solution was cooled to 0 °C. The cooled orange solution was added dropwise to 250 mL of ice water. A white precipitate formed during the addition. The solid was filtered, washed with water, and dried under vacuum to give 1H-indole-3-sulfonyl chloride (740 mg, 21% yield) as a gray solid.

[0401] Step 3 (General Procedure): A solution of 1H-indole-3-sulfonyl chloride (100 mg, 0.463 mmol) from Step 2 in anhydrous THF (3 mL) was cooled to 0 °C, and the amine (2 equiv.) was added dropwise. Next, DIPEA (0.24 mL, 1.39 mmol) was added, and the reaction mixture was warmed to room temperature. The reaction progress was monitored by LCMS. When the reaction was complete, it was quenched with saturated NH4Cl to pH = 7. The aqueous layer was extracted with EtOAc (3 times). The combined organic layers were washed with water, brine, dried over MgSO4, filtered, and afforded the desired sulfonamide.

[0402] Step 3 (R1 = R2 = Me, Example 112): The sulfonyl chloride (200 mg, 0.9 mmol) was placed in a 25 mL flask, to which THF (4 mL) was added, followed by dimethylamine hydrochloride (2 equiv., 150 mg, 1.9 mmol) and DIEA (4 equiv., 0.65 mL, 3.7 mmol). The solution immediately turned pale yellow, and a yellow gummy oil settled at the bottom. Stirred at room temperature for 20 minutes (LCMS showed complete consumption of the sulfonyl chloride). The mixture was partitioned between EtOAc and a saturated solution of NH4Cl. The aqueous layer was extracted with EtOAc, and the combined organic layers were washed once more with saturated NH4Cl solution and then with brine. It was then dried over MgSO4, filtered, and concentrated to dryness to give 65 mg of a beige crystalline solid, which was used directly without further purification: 1 H NMR(DMSO-d6) δ:12.17(br.s.,1H),7.96(d,J=3.1Hz,1H),7.81(d,J=7.8Hz,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 + ).

[0403] Step 4 (Example 112, Table 4): Prepared from the indole sulfonamide from Step 3 and chloropyridine A-13 (Ar = 2-chlorophenyl) using general method A

[0404] Other examples of inhibitors prepared in a similar manner using the appropriate amine in step 1 are listed under Method K in Table 4 below.

[0405] Preparation of the compound of Example 69:

[0406] [ka]

[0407] Step 1: Following general synthetic method A, chloropyridine A-13 (Ar = 4-methoxy-2-methylphenyl) was coupled to 3-cyanoindole in the presence of copper powder, BINOL, and cesium carbonate in DMSO at 100 °C to give the expected crude 3-cyanoindole derivative after acidic aqueous workup and extraction into EtOAc. The material was used directly in step 2, but an aliquot of the cyano derivative was purified by reverse-phase HPLC for characterization: 1 H NMR(DMSO-d6) δ:10.17(br.s.,1H),9.93(s,1H),9.29(s,1H),8.52(s,1H),8.45~8.51(m,2H),8.36(d,J=8.2Hz,1H),7.76~7.87(m,1H),7.68(d, J=9.0Hz,1H),7.39~7.59(m,2H),7.15~7.32(m,2H),6.95(d,J=2.7Hz,1H),6.87(dd,J=8.8,2.5Hz,1H),3.79(s,3H),2.58(s,3H). MS m / z 598.1(MH + ).

[0408] Step 2: The crude nitrile from Step 1 (35 mg, 1.0 equiv.) and ethanol (0.5 mL) were placed in a 4 mL vial, followed by 102 μL of 4 N NaOH (7 equiv.) to give a dark yellow solution. To this solution at room temperature was added ~30 μL (4 equiv.) of a 30% hydrogen peroxide solution in water (some effervescence was observed). After stirring at room temperature for 10 minutes, LCMS showed complete consumption of the starting material and the formation of a new peak with the desired mass for the amide product. The reaction was quenched by the addition of a few crystals of sodium thiosulfate and 0.5 mL of acetic acid. It was then diluted to 2 mL with methanol, filtered, and purified by preparative HPLC (MeOH / HO / 0.1% formic acid, 50% → 100% methanol gradient). The appropriate fractions were combined and partially concentrated to remove the methanol. The resulting suspension was dissolved by adding a few milliliters of acetonitrile, and the solution was then frozen and lyophilized to give 7.4 mg of the inhibitor of Example 69 as a yellow solid.

[0409] Example 104 was prepared in a similar manner using A-13 (Ar=2-chlorophenyl).

[0410] Preparation of the compounds of Examples 70, 83 and 85:

[0411] [ka]

[0412] Example 70: 7-Nitrobenzimidazole was prepared from 3-nitrophenylene-1,2-diamine as described in J. Chem. Phys. 2011, 115, 11403 and coupled to A-13 (Ar=4-methoxy-2-methylphenyl) using general method A.

[0413] Step 1 (Example 83): 7-Nitrobenzimidazole (see Example 70, 250 mg) and 20% Pd(OH) / C (Pearlman's catalyst, 10 mg, 0.01 equiv.) were suspended in MeOH (3 mL) and stirred under a balloon atmosphere of H gas for 4 h (SM slowly goes into solution as the reduction proceeds). After complete conversion as indicated by LCMS, the suspension was filtered through a membrane using MeOH for washing, and the volatiles were removed under reduced pressure. The material was used without further purification: 1 H NMR (DMSO-d6) δ:7.99(s,1H),6.87(t,J=7.8Hz,1H),6.73(d,J=7.8Hz,1H),6.35(d,J=7.8Hz,1H).

[0414] Step 2 (Example 83): Using the aminobenzimidazole from Step 1, chloropyridine A-13 (Ar=2-chlorophenyl) and general method A, the inhibitor Example 83 was isolated after two consecutive reverse HPLC purifications using a gradient of 30→100% MeOH-0.1% formic acid followed by 10→100% MeCN-0.1% AcOH: 1 H NMR(DMSO-d6) δ:10.53(br.s.,1H),9.87(s,1H),9.17(s,1H),8.49(s,1H),8.44(s,2H),7.92(dd,J=8.0,1.4Hz,1H),7.61~7.72(m,2H),7.47~7.56(m,1H) ),7.41(d,J=7.8Hz,1H),7.28(td,J=9.0,5.5Hz,1H),7.22(t,J=9.0Hz,1H),7.11(t,J=8.0Hz,1H),6.57(d,J=7.4Hz,1H),5.51(br.s.,2H). MS m / z 579.1.

[0415] Other examples of inhibitors prepared in a similar manner using the aminobenzimidazole (fragment A31) from step 1 and the corresponding A-13 chloropyridine are listed under Method A in Table 4 below.

[0416] Step 3 (Example 85): The aminobenzimidazole from Step 2 (23 mg) was dissolved in acetic acid (1 mL) and acetic anhydride (13 mg, 3 equiv.) was added. Stirred at room temperature for 3 hours (LCMS showed complete conversion to the desired mass). The material was diluted to 1.8 mL with DMSO and purified by preparative HPLC using a 30 to 100% MeOH-0.1% formic acid gradient.

[0417] Preparation of the compound of Example 75:

[0418] [ka]

[0419] Step 1: 7-Benzimidazole carboxylic acid (500 mg, 3.1 mmol) was suspended in DCM (5 mL) and DMF was added dropwise, followed by oxalyl chloride (0.5 mL, 5.9 mmol). The beige slurry was stirred at room temperature for 1 h. The volatiles were then removed under reduced pressure, and the residue was resuspended in THF, and the volatiles were removed once more. The residue was then suspended in THF (5 mL), concentrated aqueous ammonia (1 mL) was added, and the mixture was stirred for 30 min at room temperature (the beige suspension gradually changed to a brick-red suspension). LCMS showed a 1:1 mixture of the starting acid and the desired amide. The solids were removed by filtration, and the filtrate was evaporated to dryness under reduced pressure. The residue was used directly in the next step.

[0420] Step 2 (Example 75): The crude benzimidazole from Step 1 was coupled to chloropyridine A-13 (Ar = 4-methoxy-2-methylphenyl) using copper / BINOL catalysis as described for Example 1 (Step 4) in General Method A.

[0421] Preparation of the compounds of Examples 80 and 81:

[0422] The nitrile group of the compound of Example 77 was hydrolyzed to the corresponding amide using the procedure described for Example 69. Example 81 was prepared in a similar manner from Example 78.

[0423] Preparation of the compounds of Examples 94 and 95:

[0424] [ka]

[0425] Step 1: To a suspension of the starting chloropyridopyrimidine A-13 (Ar = 2-chlorophenyl, 50 mg, 0.1 mmol) in acetonitrile (2 mL) in a 5 mL vial, 1.1 equivalents of 1-ethoxyvinyl-tributyltin (42 mg, 0.11 mmol) was added. Nitrogen was bubbled through the mixture for 5-7 minutes, and then bis(triphenylphosphine)palladium dichloride (0.1 equivalent, 7 mg) was added. Nitrogen was bubbled through the suspension for an additional 4-5 minutes, and then the vial was sealed and the mixture was heated at 80 °C to give a pale yellow solution, which was stirred at that temperature for 18 hours (LCMS showed complete conversion). The mixture was cooled to room temperature and filtered through celite. (登録商標) The solution was filtered through a plug of HCl, using EtOAc to rinse to remove insoluble black particles. The filtrate was concentrated to dryness under reduced pressure, and the resulting pale yellow foam was used directly without further purification (108 mg): MS m / z 518.0 (M H + ).

[0426] Step 2: The crude enol ether from Step 1 (53 mg, 0.10 mmol) was dissolved in THF (1 mL), and water (0.1 mL) was added, followed by 1.1 equivalents of N-bromosuccinimide (20 mg, 0.11 mmol) at room temperature. The resulting mixture was stirred for 1 h (LCMS showed complete conversion). The mixture was diluted with 3-4 mL of toluene and concentrated to an oily residue. It was then taken up in 4-5 mL of DCM and dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography through a 3 g silica gel cartridge using a gradient of 10% EtOAc in hexanes to 60% EtOAc in hexanes. The appropriate fractions were combined and concentrated to give the desired product as a pale yellow solid, which was used directly in the next step. 1 H NMR and LCMS show some contamination with succinimide): 1 H NMR(DMSO-d6) δ:10.38(s,1H),8.58(s,1H),8.35~8.42(m,2H),7.91(dd,J=7.8,1.2Hz,1 H),7.59~7.73(m,4H),7.47~7.59(m,2H),7.20~7.35(m,2H),5.43(s,1H). MS m / z 568(MH + ).

[0427] Step 3: To a suspension of the crude bromomethyl ketone from Step 2 (25 mg, 0.04 mmol) in ethanol (1 mL) was added thiourea (5 mg, 0.07 mmol, 1.5 equiv.). The resulting mixture was brought to 80 °C and stirred at that temperature for 2 h (LCMS showed complete conversion). The mixture was diluted to 2 mL with DMSO, filtered, and purified by preparative HPLC (MeOH / HO / 0.1% formic acid, 50% to 100% methanol gradient). Appropriate fractions were combined and partially concentrated to remove the methanol. The resulting suspension was dissolved by adding a few milliliters of acetonitrile, and the solution was then frozen and lyophilized. 5.5 mg of the desired product (Example 94) was obtained as a yellow solid.

[0428] Example 95 was prepared in a similar manner by replacing thiourea in step 3 with 1,2,4-oxadiazole.

[0429] Preparation of compounds of Examples 96 and 115:

[0430] [ka]

[0431] Step 1: The methyl ester of 4-nitro-3-indolecarboxylic acid was prepared by nitration of methyl 3-indolecarboxylate as described in WO 2008 / 113760 and Bioorg. Med. Chem. Lett. 2011, 21, 1782. The indole derivative was reacted with chloropyridine A-13 (Ar = 2-chlorophenyl) under standard conditions of general method A.

[0432] Step 2: The crude methyl ester from step 1 (33 mg, 0.05 mmol) was suspended in MeOH (1 mL), and 4 N NaOH (75 μL, 6 equiv.) and LiOH (2 mg, 0.05 mmol) were added. The mixture was stirred at room temperature for 18 h and then at 50° C. for 2 h until conversion (LCMS) was complete. The reaction mixture was then acidified with 1 N hydrochloric acid, and the precipitated product was collected by filtration, washed with water, and dried under vacuum to give the desired carboxylic acid (30 mg): MS m / z 650.0 (M−H).

[0433] Step 3: The crude nitroindole carboxylic acid from step 2 (30 mg, 0.046 mmol) was dissolved in NMP (0.8 mL). To the yellow solution, 8 equivalents of DIEA (64 μL) was added, followed by 2 equivalents of HATU (35 mg). The mixture was stirred for 2 to 3 minutes, and then dimethylamine hydrochloride (7.4 mg, 2 equivalents) was added. The resulting dark yellow solution was stirred at room temperature for 3 hours, at which point the reaction was determined to be complete by LCMS. The reaction was quenched by adding 1 N hydrochloric acid solution until an acidic pH was reached. The mixture was diluted with 8 mL of water, sonicated, and the resulting solids were collected by filtration through a small fritted glass funnel. They were then dried under reduced pressure overnight, and the product was used directly for subsequent nitro reduction (27 mg): MS m / z 679 (MH + ).

[0434] Step 4: To a suspension of the crude acid from Step 3 (27 mg, 0.040 mmol) in ethanol (1 mL) and EtOAc (0.5 mL) was added 4 equivalents of SnCl-2H0 (36 mg). The resulting mixture was brought to 60 °C and stirred for 2 h (confirmed complete by LCMS). The mixture was concentrated to remove the EtOH and then diluted with EtOAc (4 mL) and water (0.5 mL). ∼1 mL of 1 N NaOH solution was added to the thick emulsion / suspension, but the mixture did not clear. The mixture was concentrated to near dryness, and then ∼0.5 g of sodium sulfate decahydrate was added to the flask along with some fresh EtOAc. The suspension was sonicated, decanted, and the EtOAc extract was filtered. This was repeated once more with EtOAc, then once with DCM, and once with a 1:1 mixture of the two. The combined extracts were then dried over Na2SO4, filtered again, and concentrated. The residue was taken up in DMSO (1.5 mL) and purified by preparative HPLC (MeOH / HO / 0.1% formic acid, 50% to 100% methanol gradient). Appropriate fractions were combined and partially concentrated to remove the methanol. The resulting suspension was dissolved by adding a few milliliters of acetonitrile, and the solution was then frozen and lyophilized (6.6 mg of Example 96 as a yellow solid).

[0435] Example 115 was prepared in a similar manner by replacing dimethylamine hydrochloride in step 4 with morpholine.

[0436] Preparation of the compound of Example 100:

[0437] [ka]

[0438] Step 1: 7-Nitrobenzotriazole was prepared as an orange-pink solid from 3-nitro-1,2-phenylenediamine using the procedure described in WO2010 / 069833: 1 H NMR (DMSO-d6) δ:8.58(d,J=8.2Hz,1H),8.46(d,J=7.8Hz,1H),7.63(t,J=8.0Hz,1H).

[0439] Step 2: The nitrobenzotriazole from step 1 was hydrogenolyzed over 20% Pd(OH) on carbon using a balloon atmosphere of hydrogen gas to provide the desired aminobenzotriazole as an orange solid, which was used without purification: 1 H NMR (DMSO-d6) δ:7.11(t,J=7.8Hz,1H),6.81(d,J=8.2Hz,1H),6.38(d,J=7.8Hz,1H),5.86(br.s.,2H).

[0440] Step 3: Using the aminobenzotriazole from Step 2, chloropyridine A-13 (Ar = 2,3-dichlorophenyl) and general method A, the inhibitor Example 100 was formed as a mixture of isomers, which were separated by reverse-phase HPLC under standard conditions. Example 100 was present as the most abundant isomer.

[0441] Other examples prepared in a similar manner using the corresponding A-13 chloropyridines include Examples 91-93 and 206.

[0442] Preparation of the compound of Example 103:

[0443] This compound was prepared following the procedure described for Example 69, using the corresponding 3-cyanoindazole in place of 3-cyanoindole and A-13 (Ar=2-chlorophenyl).

[0444] Preparation of the compound of Example 116:

[0445] [ka]

[0446] Step 1: 3-Benzyloxy-1,2-phenylenediamine was prepared according to the procedure described in International Publication No. WO 1992 / 021663 A1. The diamine (1.00 g, 4.67 mol) was suspended in formic acid (10 mL), and the mixture was stirred at 100° C. for 4 h (LCMS showed complete conversion). The reaction mixture was cooled to room temperature, and most of the formic acid was removed under reduced pressure. The residue was slowly added to excess saturated aqueous NaHCO3 (CAUTION: foaming). The free base initially appeared as a dark beige gum, which turned into a light beige precipitate after stirring. The product was collected by filtration, washed with water, and dried under vacuum (0.96 g, 1:1 mixture of tautomers, 1 by H NMR): 1 H NMR(DMSO-d6) δ:12.72(br.s.,0.5H),12.44(br.s.,0.5H),8.10(s,1H),7.56(d,J=7.0Hz,1H),7.50(d,J=7.4Hz,1H),7.29~7.45(m,3H), 7.25(d,J=7.8Hz,0.5H),7.02~7.18(m,1.5H),6.87(d,J=7.8Hz,0.5H),6.75(d,J=7.0Hz,0.5H),5.36(s,1H),5.28(s,1H). MS m / z 225.1(MH + ).

[0447] Step 2: The benzimidazole from Step 1 was coupled to chloropyridine A-13 (Ar = 3-chloro-2-methyl) using the general procedure of Method A. After 1 h at 95 °C, the reaction mixture was poured into water, acidified with AcOH and a small amount of 1 N HCl, and extracted with EtOAc. The extract was washed with water and brine, dried (MgSO), and concentrated under reduced pressure. The residue and 20% Pd(OH) on carbon catalyst were suspended in THF (3 mL) and AcOH (1 mL) and stirred under a balloon of H gas for 18 h (LCMS showed product, some remaining starting material, and impurities). The reaction mixture was filtered to remove the catalyst, concentrated, and the residue was dissolved in 1.8 mL of DMSO and purified by preparative HPLC using a 50-100% MeOH-0.1% HCOOH gradient. The compound of Example 116 (90% homogeneity) was obtained.

[0448] Preparation of the compound of Example 117:

[0449] [ka]

[0450] Step 1: 3-Benzyloxy-1,2-phenylenediamine was prepared according to the procedure described in International Publication No. WO 1992 / 021663 A1. The diamine (1.00 g, 4.67 mmol) was dissolved in AcOH (8 mL), and sodium nitrite (0.335 g, 4.9 mmol) was added portionwise. A mildly exothermic reaction ensued, accompanied by slight gas evolution. The mixture was stirred at room temperature for 15 minutes and then at 60° C. for 3.5 hours (LCMS showed complete conversion). The reaction mixture was cooled to room temperature, diluted with an equal volume of water, and stirred at room temperature for 1 hour. The beige precipitate was collected. The product was washed with water and dried under vacuum (1.01 g): 1H NMR (CDCl3) δ:7.43~7.57(m,3H),7.28~7.43(m,4H),6.84(d,J=7.8Hz,1H),5.36(s,2H). MS m / z 226.1(MH + ).

[0451] Step 2: Following the same procedure described for Example 116, benzotriazole from Step 1 (30 mg) was coupled to chloropyridine A-13 (Ar = 3-chloro-2-methyl) using the general procedure of Method A, and the product was hydrogenolyzed to remove the benzyl ether protecting group to give Example 117 (15 mg).

[0452] Preparation of compounds of Examples 120-122:

[0453] General procedure D described for Example 127 was used, substituting methyl indazole-3-carboxylate for methyl 5-methyl-pyrazole-3-carboxylate in step 1.

[0454] Preparation of compounds of Examples 136-138:

[0455] General procedure D described for Example 127 was used substituting methyl indazole-3-carboxylate for ethyl 2-methyl-imidazole-4-carboxylate in step 1.

[0456] Preparation of compounds of Examples 145 and 146:

[0457] General procedure D described for Example 127 was used substituting methyl indazole-3-carboxylate for methyl pyrazole-3-carboxylate in step 1.

[0458] Preparation of compounds of Examples 147 and 148:

[0459] General method D described for Example 127 was used, substituting methyl indazole-3-carboxylate for ethyl 3-methyl-pyrazole-4-carboxylate in step 1. An 85:15 mixture of isomers was carried forward. The compounds of Examples 147 and 148 were isolated as the major components.

[0460] Preparation of compounds of Examples 149 and 150:

[0461] [ka]

[0462] Aminobenzimidazole (Example 83, 30 mg) was dissolved in pyridine (0.5 mL) and morpholine carbamoyl chloride (31 mg, 4 equiv.) was added. The mixture was stirred at 60° C. for 2 h (complete conversion to the desired mass by LCMS). The burgundy solution was concentrated under reduced pressure, the residue was dissolved in 3:1 DMSO-AcOH (1.8 mL), and the material was purified by preparative HPLC using a gradient of 50 to 100% MeOH-0.1% HCOOH.

[0463] Example 150 was prepared in a similar manner, except that NN-dimethylcarbamoyl chloride was used instead of morpholinecarbamoyl chloride. The reaction was completed after heating at 75° C. for 18 hours.

[0464] Preparation of compounds of Examples 151 and 152:

[0465] General procedure D described for Example 127 was used substituting methyl indazole-3-carboxylate for methyl 1,2,4-triazole-3-carboxylate in step 1.

[0466] Preparation of compounds of Examples 153-155:

[0467] General procedure D described for Example 127 was used substituting ethyl 4-methyl-pyrazole-3-carboxylate in step 1 for methyl indazole-3-carboxylate.

[0468] Preparation of the compound of Example 207:

[0469] [ka]

[0470] Step 1: To a solution of 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (1.80 g, 9.1 mmol) prepared according to the procedure described in International Publication No. WO 2013 / 041457 in anhydrous THF (16 mL) at −78° C., n-butyllithium (6.24 ml, 9.98 mmol of 1.6 M in hexane) was slowly added. Upon completion of the addition, the pale yellow solution was slowly added to a solution of carbon tetrabromide (3.31 g, 9.98 mmol) in 8 mL of THF at −78° C. The solution turned deep yellow and then very dark brown at the end of the addition. It was stirred at the same temperature for 15 min and then quenched with a saturated solution of ammonium chloride. After warming to room temperature, EtOAc was added, and the dark brown to black biphasic mixture was filtered through celite. (登録商標) The mixture was treated with HCl and filtered to facilitate phase separation. The layers were separated, and the aqueous layer was extracted twice with EtOAc. The combined organic layers were washed once with brine, then dried over MgSO4, and filtered. After concentration, the residue was purified by flash column chromatography (combiflash, 40 g column, 0% → 40% EtOAc in hexanes; product slightly UV-visible by TLC, KMnO4 staining was used to identify fractions) to give 1.944 g of the desired product as a pale yellow-brown oil: 1H NMR(CDCl3) δ:7.11(d,J=1.2Hz,1H),7.06(d,J=1.2Hz,1H),5.28(s,2H),3.54(t,J=7.8Hz,2H),0.92(t,J=8.2Hz,2H),0.00(s,9H).

[0471] Step 2: N-tosyl-3-indole boronic ester (132 mg, 0.33 mmol), the SEM-protected bromoimidazole from Step 1 (111 mg, 0.4 mmol), potassium carbonate (184 mg, 1.33 mmol), DMF (3 mL), and water (1 mL) were placed in a microwave vial. Nitrogen was bubbled through the suspension for 3-4 minutes. Tetrakis(triphenylphosphine)palladium(0) (19 mg, 0.017 mmol) was added, and nitrogen was bubbled through the mixture while sonicating for an additional 3-4 minutes. The vial was then capped and irradiated in a microwave at 80 °C for 1 hour, at which point LCMS analysis confirmed that the boronic ester had been consumed. The reaction mixture was cooled to room temperature, then diluted with water and extracted three times with a 2:1 mixture of EtOAc / hexanes. The combined organic layers were washed twice with water and once with brine. They were then dried over MgSO, filtered, and concentrated. The residue was purified by flash chromatography (Isco Combiflash, 12 g silica gel column, 0% to 35% EtOAc, hexanes gradient). After pooling and concentration of the appropriate fractions, 33 mg of the desired product was obtained (8 mg of the homocoupled bis-indole by-product was also obtained): 1H NMR(CDCl3) δ:8.20(d,J=7.8Hz,1H),8.09(s,1H),8.03(d,J=8.2Hz,1H),7.79(d,J=8.6Hz,2H),7.38(t,J=7.4Hz,1H),7.32(t,J=7.8Hz ,1H),7.20~7.26(m,3H),7.14(s,1H),5.32(s,2H),3.64(t,J=8.2Hz,2H),2.35(s,3H),1.01(t,J=8.6Hz,2H),0.04(s,9H). MS m / z 468.0(MH + ).

[0472] Step 3: The product from Step 2 was dissolved in methanol (3 mL) and crushed potassium hydroxide (115 mg, 30 equiv.) was added. The resulting solution was refluxed for 4 h (LCMS showed complete consumption of the starting material). The reaction was quenched by the addition of saturated ammonium chloride solution, followed by the addition of water and EtOAc. The layers were separated and the aqueous layer was extracted once more with EtOAc. The combined organic extracts were washed once with water and then once with brine, dried over MgSO4, filtered, and concentrated. After drying under reduced pressure, the desired indole derivative was obtained as a beige solid (23 mg) and used directly in the next step: MS m / z 324.0 (MH + ).

[0473] Step 4: Following general method A, chloropyridine A-13 (Ar = 2,3-dichlorophenyl, 38 mg, 0.07 mmol) and the indole from step 3 (23 mg, 0.07 mmol) were coupled by heating at 100 °C for 1.5 h under copper catalysis to provide the expected crude product (65 mg), which was used directly in the next step: 1H NMR(DMSO-d6) δ:10.72(s,1H),9.81(s,1H),8.89(br.s.,1H),8.49~8.62(m,2H),8.37~8.49(m,2H),7 .98~8.07(m,1H),7.95(d,J=7.8Hz,1H),7.90(d,J=7.8Hz,1H),7.79~7.88(m,1H),7.54( t,J=8.2Hz,1H),7.50(t,J=8.2Hz,1H),7.44(t,J=7.0Hz,1H),7.27~7.34(m,1H),7.23(t ,J=8.8Hz,1H),5.68(s,2H),3.55(t,J=8.0Hz,2H),0.83(t,J=8.6Hz,2H),-0.15(s,9H). MS m / z 793.1(MH + ).

[0474] Step 5: The SEM-protected crude material from Step 4 was suspended in 2 mL of ethanol, and 1 mL of 6 N hydrochloric acid was added. The resulting suspension was brought to 80 °C, where it was stirred for 4.5 hours. The reaction was then concentrated to a residue, which was redissolved in 1.5 mL of DMSO, filtered, and the filtrate purified by preparative HPLC (MeOH / HO / 0.1% formic acid, 30% to 100% methanol gradient). All fractions containing the desired product were contaminated with a coeluting impurity. The fractions were combined, concentrated, and lyophilized. The powder was redissolved in DMSO / MeOH and purified a second time by preparative HPLC (MeOH / HO / 0.05% TFA, 30% to 100% methanol gradient). The appropriate fractions were concentrated, frozen, and lyophilized to give 16.3 mg of the desired product 207 as the TFA salt (yellow powder).

[0475] Preparation of the compound of Example 208:

[0476] [ka]

[0477] Step 1: Methyl 1H-indazole-3-carboxylate (350 mg, 1.98 mmol) was placed in a pressure tube with 5 mL of EtOH (anhydrous) and hydrazine hydrate (0.244 mL, 4.97 mmol). The tube was sealed and heated to 100 °C in an oil bath. After 4 h, LCMS confirmed the reaction was complete. The colorless solution was cooled with stirring in an ice-water bath, giving a significant amount of crystalline material. The white solid was collected by filtration and washed with a small amount of EtO. After drying, 255 mg of the hydrazide was obtained: 1 H NMR(DMSO-d6) δ:12.98(br.s.,1H),9.55(br.s.,1H),8.14(d,J=8.2Hz,1H),7.60(d,J=8.6Hz,1H),7.40(t,J=7.6Hz,1H),7.23(t,J=7.4Hz,1H),4.46(br.s.,2H). MS m / z 175.1(MH).

[0478] Step 2: To a solution of 1H-indazole-3-carbohydrazide from Step 1 (250 mg, 1.42 mmol) in 3 mL of DMF was added triethylamine (0.59 mL, 4.26 mmol). The colorless solution was cooled to 0°C in an ice-water bath, and then di(1H-imidazo1-1-yl)methanone (345 mg, 2.13 mmol) was added in one portion. The solution immediately turned yellow. It was removed from the ice bath and stirred at room temperature overnight, by which time LCMS analysis of an aliquot confirmed the reaction was complete. It was diluted with water, then acidified with 1N hydrochloric acid, and stirred for 10 minutes to destroy any remaining CDI. The white solid was then collected by filtration, dried under reduced pressure, and used directly in the next step (300 mg): MS m / z 203.0 (MH + ).

[0479] Step 3: Following general method A, chloropyridine A-13 (Ar = 2,3-dichlorophenyl, 35 mg, 0.068 mmol) and the indole from step 3 (25 mg, 0.075 mmol) were coupled by heating at 100 °C for 1.5 h under copper catalysis to provide inhibitor 208 (25 mg) as a beige powder after reverse-phase HPLC purification (MeCN / HO, 0.1% acetic acid, 60% → 100% MeCN gradient).

[0480] Preparation of the compound of Example 209:

[0481] [ka]

[0482] Step 1: From the synthesis of Example 208, the crude product from Step 2 was placed in a 4 mL vial, followed by dimethylamine hydrochloride (64.5 mg, 0.79 mmol), DMF (2 mL), and DIEA (0.21 mL, 1.18 mmol). The yellow solution was stirred for 2 minutes, and then BOP reagent (193 mg, 0.44 mmol) was added in one portion. The reaction was stirred at room temperature for 60 hours. It was then diluted with water and a saturated solution of ammonium chloride. The resulting suspension was sonicated, and the solid was collected by filtration, washed with water, and dried under reduced pressure to give 45 mg of the desired product as an off-white solid: 1 H NMR (DMSO-d6) δ:13.75(br.s.,1H),8.12(d,J=8.2Hz,1H),7.66(d,J=8.2Hz,1H),7.48(t,J=7.6Hz,1H),7.31(t,J=7.6Hz,1H),3.12(s,6H). MS m / z 230.1(MH + ).

[0483] Step 2: Following general method A, chloropyridine A-13 (Ar = 2,3-dichlorophenyl, 35 mg, 0.068 mmol) and the indole from step 3 (17 mg, 0.075 mmol) were coupled by heating at 100 °C for 1.5 h under copper catalysis. The mixture was then cooled to room temperature and quenched by the addition of 0.2 mL of acetic acid. Methanol (2 mL) was then added, and the suspension was sonicated. The solid was collected and washed with a small amount of methanol, then dried under reduced pressure. Example 209 was obtained as a beige powder (32 mg).

[0484] Example 210 was prepared in a similar manner, replacing dimethylamine hydrochloride with methylamine hydrochloride in step 1. Example 211 was prepared by replacing dimethylamine hydrochloride with 4-methoxybenzylamine in step 1. Following coupling to chloropyridine A-13 (Ar = 2,3-dichlorophenyl), the PMB protecting group was removed by heating in DCM at 60-70 °C for 6 h.

[0485] Preparation of the compound of Example 212:

[0486] [ka]

[0487] Step 1: 3-Iodoindazole was prepared by iodination of indazole according to the procedure described in WO2011 / 138265.

[0488] Step 2 / 3: 3-Iodoindazole was protected as the N-Boc derivative and stannylated to the 3-trimethylstannane derivative according to the procedure described in WO2016 / 058544.

[0489] Step 4: The stannane derivative from Step 3 (270 mg, 0.71 mmol) was placed in a 4 mL vial, followed by 2-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (197 mg, 0.71 mmol) prepared in Step 1 of Example 207, tetrakistriphenylphosphinepalladium(0) (41 mg, 0.035 mmol), and 2 mL of toluene. The vial was degassed with argon for 2 minutes, then sealed and heated at 110° C. for 20 hours. The black reaction mixture was poured into water, extracted with EtOAc, washed with brine, and dried (MgSO). Concentration gave a mixture of the N-Boc product (42 mg) and the NH-indazole product (54 mg), which were separated by flash chromatography. N-Boc product: 1 H NMR(CDCl3) δ:8.64(d,J=7.8Hz,1H),8.17(d,J=8.6Hz,1H),7.58(t,J=7.8Hz,1H),7.42(t,J=7.4Hz,1H),7.31(d ,J=9.0Hz,2H),6.07(s,2H),3.63(t,J=8.6Hz,2H),1.75(s,9H),0.93(t,J=7.8Hz,2H),-0.09(s,9H). MS m / z 415.2(MH + ). The N-Boc material was suspended in DCM and TFA (150 μL) was added. After stirring for 2 h, conversion to the deprotected indazole was judged complete by LCMS. Toluene (2 mL) was added and the volatiles were removed under reduced pressure to give the desired indazole, which was used in the next step without further purification: MS m / z 315.2 (MH + ).

[0490] Step 5: The starting chloro-pyridopyrimidine A-13 (Ar = 2,3-dichlorophenyl, 58 mg, 1 equiv.) was coupled to the indazole from Step 4 (41 mg, 1.15 equiv.) using general procedure A. After stirring at 100 °C for 3 h, LCMS confirmed the reaction was complete. The mixture was cooled to room temperature and then quenched by the addition of 0.15 mL of acetic acid. Water (5 mL) was then added, and the suspension was sonicated. The solid was collected on a fritted glass filter (54 mg) and washed with water and hexanes. The crude material was dissolved in TFA (0.5 mL) and stirred at room temperature for 3 h, at which point LCMS indicated complete deprotection of the SEM group. The mixture was concentrated to a residue and then taken up in 1 mL of DMSO and 0.5 mL of MeOH. It was filtered, and the filtrate was purified by preparative HPLC (MeOH / HO, 0.05% TFA, 60% to 100% MeOH gradient). The appropriate fractions were combined and concentrated to remove the methanol. Some acetonitrile was added, and the solution was frozen and lyophilized. Example 212 (21.5 mg) was obtained as a yellow solid.

[0491] Example 213 was prepared in a similar manner using the corresponding A-13 (Ar=2-chlorophenyl).

[0492] Preparation of the compound of Example 223:

[0493] [ka]

[0494] Step 1: Tryptamine was protected as the Boc-carbamate and oxidized to the protected aminomethyl ketone as described in J. Am. Chem. Soc. 2004, 126, 12888.

[0495] Step 2: Using the general method, the indole derivative from Step 1 was coupled to Compound A-13 (Ar = 2-chlorophenyl). The crude product was deprotected by stirring in 2:1 DCM-TFA for 30 minutes. Example 223 (yellow solid) was isolated as the TFA salt after reverse-phase HPLC purification (30% → 100% MeOH-0.05% TFA).

[0496] Preparation of the compound of Example 224:

[0497] [ka]

[0498] To a suspension of crude aminomethyl ketone 223-TFA salt (50 mg, 0.068 mmol) in methanol (0.6 mL) at room temperature, 1 N sodium hydroxide solution (0.082 mL, 0.082 mmol) was added. The suspension became a dark solution. Next, a 37 wt% solution of formaldehyde (55 mg, 0.681 mmol) was added, and the mixture was stirred at 40°C for 5 minutes. Sodium cyanoborohydride (13 mg, 0.20 mmol) was added, and the solution was stirred at 50°C for 2 hours (LCMS indicated complete consumption of the starting material and formation of the desired product). The reaction was quenched by the addition of 0.2 mL of acetic acid and diluted to 2 mL with DMSO. The mixture was filtered through a syringe filter and purified by preparative HPLC (30% to 100% MeOH-0.1% formic acid). The appropriate fractions were pooled and concentrated to remove methanol, then frozen and lyophilized to give Example 224 (3.3 mg) as a pale yellow solid.

[0499] Preparation of the compound of Example 237:

[0500] [ka]

[0501] Step 1: Bromobenzimidazole E-2, prepared as described under general method E (Step 1), was converted to the acetyl derivative following a procedure similar to that described in Method E for the preparation of E-3 (Step 2), except that DMF was replaced with N,N-dimethylacetamide for the carbonylation step. The product was obtained as a brown solid (131 mg), which was used directly in the next step.

[0502] Step 2: The benzimidazole derivative from step 1 (50 mg) was coupled to compound A-13 (Ar = 2-chlorophenyl, 130 mg) using general method A at 100 °C for 3 hours. The expected crude intermediate was obtained as a brown solid (168 mg), which was used directly in the next step: 1 H NMR(DMSO-d6) δ:10.53(br.s.,1H),9.84(s,1H),9.45(br.s.,1H),8.66(d,J=8.2Hz,1H),8.47~8.59(m,3H),7.92(dd,J=7.8,1.2Hz,1H),7.86(d,J=7 .0Hz,1H),7.61~7.71(m,2H),7.55(t,J=7.8Hz,1H),7.47~7.53(m,1H),7.28(td,J=8.7,5.7Hz,1H),7.22(t,J=9.2Hz,1H),3.01(s,3H). MS m / z 605.8(MH + ).

[0503] Step 3: Morpholine (17 mg, 0.20 mmol) was placed in a 1-dram vial with 1 mL of methanol. Next, crude acetylbenzimidazole (40 mg, 0.066 mmol) from Step 2 was added, and the mixture was heated at 50°C for 10 minutes. Sodium cyanoborohydride (12.5 mg, 0.2 mmol) was added, and the reaction mixture was stirred at 50°C for 20 hours (LCMS showed ∼50% conversion). Another portion of morpholine (17 mg, 0.2 mmol) and sodium cyanoborohydride (12.5 mg, 0.2 mmol) was added, and the mixture was stirred at 70°C for an additional 7 hours. After ∼70% conversion (LCMS), the reaction was quenched by the addition of a solution of acetic acid (0.2 mL) in 0.5 mL of DMSO. The solution was filtered and purified by preparative HPLC (30%→100% MeOH-0.1% formic acid). The appropriate fractions were pooled and concentrated to remove methanol, then frozen and lyophilized to give Example 237 (10 mg) as a pale yellow solid.

[0504] Example 238 was obtained in a similar manner by replacing morpholine with dimethylamine hydrochloride and adding an equivalent amount of 4N NaOH to neutralize the hydrochloride salt.

[0505] Preparation of Examples 239 and 652 (Table 5):

[0506] [ka]

[0507] Step 1: 2-Chloro-6-fluoroaniline (10 g) was placed in 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 hour, at which point LCMS analysis confirmed the reaction was complete. The volatiles were removed under reduced pressure, and the residue was dissolved in DCM and neutralized with a saturated solution of NaHCO3. The layers were separated, and the aqueous layer was extracted three times with DCM. The combined organic layers were washed once with water, then dried over MgSO4, filtered, and concentrated. After drying in vacuo, the desired product was obtained as white to pale pink crystals (12.79 g): 1 H NMR (CDCl3) 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 + ).

[0508] Step 2: The acetanilide from Step 1 (12.75 g) was taken up in 25 mL of concentrated sulfuric acid and cooled to 0 °C in an ice bath. Nitric acid (90%, 3.31 mL) was slowly added. After 5–10 min, the mixture became a solid mass. It was allowed to warm to room temperature, resulting in the formation of a thick, burgundy sludge. After a total of 4 h, the reaction was monitored by LCMS, which confirmed some remaining starting material. An additional 5 mL of sulfuric acid was added to improve fluidity, followed by 0.3 mL of 90% nitric acid. The mixture was stirred at room temperature for an additional 18 h. The mixture was then cooled to 0 °C and poured onto crushed ice (~150 mL). Once the ice had 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 taken up in 50 mL of acetonitrile and refluxed to give a clear, dark red solution. The heat was turned off, and the mixture was allowed to cool to room temperature over 1 hour, then stirred at room temperature for 2 hours. By that time, the mixture had turned into a solid mass, which was broken up with a spatula and sonicated. The solid was 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-nitroacetanilide): 1 H NMR(CDCl3) δ:7.90(dd,J=9.2,4.9Hz,1H),7.24(dd,J=9.2,8.4Hz,1H),6.98(br.s.,1H),2.28(s,3H). MS m / z 233.0(MH + ).

[0509] Step 3: To a solution of nitroacetanilide (500 mg, 2.15 mmol) from step 2 in 15 mL of ethanol was added a solution of NH4Cl (60 mg, 1.12 mmol) in 1.35 mL of water. The mixture was warmed to 70°C, and then iron powder (600 mg, 10.75 mmol) was added in three portions at 10 minute intervals. The resulting dark red to burgundy mixture was stirred at 70°C for 20 hours, at which point LCMS of a filtered aliquot of the reaction mixture confirmed the reaction was complete. The mixture was filtered through celite. (登録商標) The mixture was filtered through a pad of hexane. The dark brown filtrate was concentrated to dryness and then taken up in EtOAc, to which MgSO4 was added. The suspension was stirred and then 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 directly without further purification: 1 H NMR (CDCl3) δ:6.92(t,J=9.0Hz,1H),6.76(br.s.,1H),6.68(dd,J=8.6,4.7Hz,1H),3.98(br.s.,2H),2.24(br.s.,3H). MS m / z 203.1(MH + ).

[0510] Step 4: The aniline from step 3 was sulfonylated using 4-methoxybenzenesulfonyl chloride in the usual manner described for compound A-9 in general method A: 1 H NMR(DMSO-d6) δ:9.89(s,1H),9.67(s,1H),7.57~7.74(m,2H),7.23(t,J=9.2Hz,1H),7 .13(dd,J=8.8,5.3Hz,1H),7.02~7.10(m,2H),3.82(s,3H),2.00(s,3H). MS m / z 373.0(MH + ).

[0511] Step 5: Acetanilide (200 mg, 0.54 mmol) from Step 4 was taken up in 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 brought to 80°C and stirred for 1 hour. At that time, 1 mL of ethanol was added to improve solubility. The mixture was stirred at the same temperature for an additional 5 hours (by which time the mixture had become a clear yellow solution). LCMS analysis at this time indicated less than 3% starting material remained. The mixture was concentrated to remove most of the ethanol and then chilled on ice. It was basified to pH 5-6 with 4N 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: 1 H NMR(DMSO-d6) δ:9.53(s,1H),7.53~7.72(m,2H),7.00~7.14(m,2H),6.95(dd,J=10.8,8.8Hz,1H),6.36(dd,J=8.6,5.1Hz,1H),5.39(s,2H),3.81(s,3H). MS m / z 329.0(MH).

[0512] Step 6: The aniline from step 5 (75 mg, 0.23 mmol) was coupled to dichloropyridopyrimidine A-12 (125 mg, 0.63 mmol) in AcOH at 50° C. as described for the preparation of compound A-13 in general method A. The expected product (125 mg) was obtained as a beige solid: 1 H NMR(DMSO-d6) δ:10.18(s,1H),9.95(s,1H),8.50(s,1H),8.27(d,J=8.6Hz,1H),7.99(d,J=9.0Hz,1H),7.65~7 .69(m,2H),7.33(t,J=9.0Hz,1H),7.26(dd,J=9.0,5.5Hz,1H),7.04~7.12(m,2H),3.81(s,3H). MS m / z 496.0(MH + ).

[0513] Step 7 (Example 239, Table 5): The benzimidazole was coupled to the chloropyridine from step 6 using copper / BINOL catalysis as described for Example 1 (Step 4) in general method A.

[0514] Example 652 (Table 5) was prepared in an analogous manner using 2,3-dichlorophenylsulfonyl chloride in step 4 and fragment A31 for step 7.

[0515] Preparation of compounds of Examples 240, 646 and 647 (Table 5):

[0516] [ka]

[0517] Step 1: 2-Fluoro-3-nitrobenzoic acid (1.50 g, 8.1 mmol) was dissolved in DCM (7 mL) and 2 drops of DMF were added, followed by the portionwise addition of oxalyl chloride (1.23 mL). The mixture was stirred overnight at room temperature, after which the volatiles were removed under reduced pressure, and the acid chloride residue was dried under vacuum for ½ hour. The white solid was dissolved in DCM (5 mL) and DMF (3 mL) was added, followed by NaN (0.58 g, 1.1 equiv.). Stirring was continued at room temperature for 35 minutes. Next, tert-BuOH (0.86 mL) was added, and the mixture was immersed in a preheated oil bath at 65 °C. The mixture was refluxed for 4 hours (N development). After cooling to room temperature, the DCM was removed under reduced pressure, poured into water (100 mL), and the product was extracted into EtOAc. The extract was washed with NaHCO, water, and brine, and dried (MgSO). Concentration under reduced pressure gave a pale yellow crystalline solid: 1 H NMR(CDCl3) δ:8.46(t,J=7.2Hz,1H),7.59~7.73(m,1H),7.24(td,J=8.6,1.0Hz,1H),6.87(br.s.,1H),1.55(s,9H). MS m / z 155.1 (MH-Boc).

[0518] Step 2: The nitroarene from step 1 (0.74 g) and 4N hydrochloric acid in dioxane (5 mL) were stirred at room temperature for 18 hours (a precipitate gradually formed over the first 30 minutes). LCMS showed complete conversion. After dilution with diethyl ether (30 mL), the precipitate was collected, washed with ether, and the white solid was dried in air: 1 H NMR (DMSO-d6) δ:7.14~7.20(m,1H),7.04~7.14(m,2H).

[0519] Step 3: Aniline hydrochloride (143 mg, 0.74 mmol) from Step 2 and dichloropyridopyrimidine A-12 (178 mg, 0.89 mmol) were suspended in AcOH (3 mL), and the mixture was stirred at 55 °C until the aniline was completely consumed by LCMS. (Additional compound A-13 was added as needed to complete the addition.) The reaction mixture was filtered to remove insoluble hydroxypyrimidine contaminants (using AcOH for washing), and the orange filtrate was diluted with water to precipitate the product as a pale orange solid. The material was collected by filtration, washed with water, and dried (198 mg): 1 H NMR(DMSO-d6) δ:10.35(s,1H),8.65(s,1H),8.32(d,J=8.6Hz,1H),8.14(t,J=6.8Hz,1H),8.06(t,J=7.8Hz,1H),8.02(d,J=8.6Hz,1H),7.51(t,J=8.2Hz,1H). MS m / z 320.0(MH + ).

[0520] Step 4: The nitroarene from Step 3 (198 mg, 0.62 mmol) and tin(II) chloride dehydrate (630 mg, 2.8 mmol) were suspended in EtOH (7 mL), and the mixture was stirred at 65° C. for 2 h (LCMS indicated completion). The reaction mixture was poured into 1 N NaOH and extracted with EtOAc. The extract was washed with water, dried (MgSO), and concentrated to give the aniline as an orange solid: 1H NMR(DMSO-d6) δ:9.74(s,1H),8.60(s,1H),8.27(d,J=8.6Hz,1H),7.98(d,J=9.0Hz,1H),6.99 ~7.12(m,1H),6.90(t,J=8.0Hz,1H),6.66(td,J=8.2,1.6Hz,1H),5.22(s,2H). MS m / z 290.1(MH + ).

[0521] Step 5: The aniline from step 4 (176 mg, 0.6 mmol) was dissolved in THF (4 mL) and pyridine (0.2 mL, 2.4 mmol) was added, followed by 3-chloro-2-methylbenzenesulfonyl chloride (150 mg, 0.67 mmol). The mixture was stirred at room temperature for 18 hours (LCMS showed aniline remaining). An additional 25 mg of sulfonyl chloride was added and stirring was continued at 55° C. for an additional 7 hours (LCMS showed completion). The beige slurry was cooled to room temperature, acidified with AcOH (0.25 mL), diluted with 1:1 EtOAc-ether, and the solid was collected by filtration, washed with ether, and dried (210 mg): 1 H NMR(DMSO-d6) δ:10.61(br.s.,1H),8.86(d,J=4.7Hz,1H),8.58(s,1H),8.29(d,J=9.0H z,1H),8.21(d,J=6.3Hz,1H),8.00(d,J=8.6Hz,1H),7.93(t,J=6.5Hz,1H ),7.81(d,J=7.8Hz,1H),7.74(d,J=7.8Hz,1H),7.52(br.s.,1H),7.38(t ,J=8.2Hz,1H),7.17(d,J=5.1Hz,2H),6.98(d,J=6.7Hz,1H),2.66(s,3H). MS m / z 480.0(MH + ).

[0522] Step 6 (Example 240, Table 5): Benzimidazole was coupled to chloropyridine using copper / BINOL catalysis as described for Example 1 (Step 4) in general method A.

[0523] Example 646 (Table 5) was prepared in an analogous manner using 2,3-dichlorophenylsulfonyl chloride in step 5.

[0524] Example 647 (Table 5) was prepared in an analogous manner using 2,3-dichlorophenylsulfonyl chloride in step 4 and fragment A31 for step 6.

[0525] Preparation of the compound of Example 241 (Table 5):

[0526] [ka]

[0527] Step 1: 3-Indazolecarboxylic acid (250 mg, 1.5 mmol) was suspended in DCM (3 mL) and oxalyl chloride (0.26 mL, 3 mmol) was added, followed by 2 drops of DMF. The mixture was stirred at room temperature for 18 hours (a milky white suspension was obtained). The volatiles were removed under reduced pressure. The residue was suspended in THF (3 mL) and morpholine (0.3 mL, 3.4 mmol) was added. An exothermic reaction occurred as a white precipitate formed. After 1 hour, the reaction mixture was diluted with 1N hydrochloric acid and extracted with EtOAc. The extract was washed with brine, dried (MgSO4), and concentrated to give a white foam, which was used in Step 2 without further purification: 1 H NMR(CDCl3) δ:8.40(d,J=8.2Hz,1H),8.10(d,J=8.2Hz,1H),7.65~7.71(m,1H),7.52(t,J=7.4Hz,1H),3.67~3.97(m,8H). MS m / z 230.1(MH).

[0528] Step 2 (Example 241): The indazole from Step 1 was coupled to the chloropyridine from Step 5 of Example 240 using copper / BINOL catalysis as described for Example 1 (Step 4) in General Method A.

[0529] Preparation of Example 242 compound (Table 4):

[0530] [ka]

[0531] The aminobenzimidazole from Example 99 (50 mg, 0.082 mmol) was dissolved in THF (1 mL) and propionaldehyde (14.2 mg, 0.245 mmol, 3 equiv.) was added. After stirring for 2 minutes at room temperature, sodium cyanoborohydride (10.2 mg, 0.163 mmol) was added and the mixture was stirred overnight at room temperature to give a mixture of starting material and product. Since addition of a second portion of propionaldehyde and sodium borohydride did not result in further addition, the reaction mixture was quenched with 10% formic acid in MeOH (1 mL) and the product was isolated by preparative HPLC using a gradient of 60% to 100% MeOH-0.1% formic acid. The crude product was purified a second time by preparative HPLC using a gradient of 30→100% MeOH-0.1% TFA to give the product of Example 242.

[0532] Preparation of Example 316 compound (Table 3):

[0533] [ka]

[0534] Preparation of 4-chloro-3-methylthiophene-2-sulfonyl chloride (2 and 3): 3-Chloro-4-methylthiophene 1 (1.00 g, 7.54 mmol) was dissolved in CHCl (4.43 mL), and a solution of chlorosulfonic acid (1.19 mL, 17.3 mmol) in CHCl (1.48 mL) was added over 5 min at room temperature. The mixture was stirred for 10 min. Phosphorus pentachloride (4.13 g, 18.9 mmol) was added to the reaction mixture, followed by CHCl (7.50 mL). This was heated at 50 °C for 1 h. The reaction mixture was slowly added to aqueous NaHCO + ice (30.0 mL). This was stirred for 10 min and extracted with CHCl (4 × 10 mL). The combined organic layers were dried (NaSO), filtered, and concentrated under reduced pressure to give a mixture of the major isomers, compound 2 and compound 3 (1.30 g), as an oil, which was used in the next reaction without further purification. LCMS: The LCMS sample was quenched with N-methylpiperazine; (ES + )M+H=295.1.

[0535] Preparation of N-(3-(4-chloro-3-methylthiophene-2-sulfonamido)-2,6-difluorophenyl)acetamide (5 and 6): To a solution of a mixture of compound 2 and compound 3 (1.30 g, 2.37 mmol) in CHCl was added aniline 4 (400 mg, 2.15 mmol), followed by triethylamine (904 μL, 6.45 mmol). This was stirred at room temperature for 18 hours. The reaction mixture was slowly added to ice water (20 mL) and stirred at room temperature for 10 minutes. The precipitated solid was filtered, washed with MTBE (3×5 mL), and dried under vacuum to give a mixture of compounds 5 and 6 (900 mg). LCMS: (ES + )M+H=381.1.

[0536] Preparation of N-(3-amino-2,4-difluorophenyl)-4-chloro-3-methylthiophene-2-sulfonamide (7): A mixture of compound 5 and compound 6 (900 mg, 2.36 mmol) was dissolved in EtOH (5.49 mL), and HCl (6.00 N in HO, 0.6 mL) was added at room temperature. This was heated in an oil bath at 80 °C for 18 h. The volatiles were then removed under reduced pressure. The residue was dissolved in EtOAc (30 mL) and HO (10 mL). Saturated aqueous NaHCO was added until a pH of 8 was obtained. The aqueous and organic layers were separated. The aqueous layer was washed with EtOAc (3 × 10 mL). The combined organic layers were dried (NaSO), filtered, and concentrated under reduced pressure. Flash chromatography (50 g silica gel column, EtOAc / hexanes, 0–70% over 10 CV) gave the title compound (35 mg), which was repurified (12 g silica gel column, EtOAc / hexanes, 20–60%) to give the title compound 7 (17 mg, 1.76%, 84% purity) as an oil. (ES - )M+H=337.1; 1 H NMR (400MHz, CDCl3) δ7.20(m,1H),7.03(brs,1H),6.87(td,J=8.8,5.4Hz,1H),6.73(td,J=9.8,2.0Hz,1H),2.21(s,3H).

[0537] Preparation of 3-chloro-N-(3-((6-chloropyrido[3,2-d]pyrimidin-4-yl)amino)-2,4-difluorophenyl)-4-methylthiophene-2-sulfonamide (9): Compound 7 (15.3 mg, 45.2 μmol) was added to compound 8 (9.04 mg, 45.2 μmol) in acetic acid (200 μL). The mixture was heated at 50° C. for 2 hours. The mixture was cooled to room temperature. The volatiles were removed under reduced pressure to give the title compound 9 (22 mg, crude) as a pale yellow oil, which was used in the next reaction without further purification. (ES + )M+H=502.1 and (ES - )MH=500.2.

[0538] Preparation of N-(3-((6-(1H-benzo[d]imidazo1-1-yl)pyrido[3,2-d]pyrimidin-4-yl)amino)-2,4-difluorophenyl)-3-chloro-4-methylthiophene-2-sulfonamide 10 (Example 316, Table 3): Benzimidazole (4.32 mg, 35.8 μmol), compound 9 (15.0 mg, 29.9 μmol), and cesium carbonate (11.8 mg, 35.8 μmol) were mixed in DMSO (200 μL) under nitrogen. The reaction was stirred at 80° C. for 21 h. The mixture was cooled to room temperature, and the residue was purified by reverse-phase chromatography (12 g, acetonitrile / water containing 0.1% AmF, 20-70% over 15 CV) to give the title compound 10 (Example 316, Table 3) (5.30 mg, 30% yield, 93% purity). (ES + ) M + H = 584.3 and (ES - )MH=582.3; 1 H NMR(400MHz,DMSO-d6) δ10.64(s,1H),9.76(s,1H),9.29(s,1H),8.44~8.43(m,1H),8.43~8.36(m,2H),8.28(d,J=8.1Hz,1H),7.73(d,J =7.7Hz,1H),7.60(brm,1H),7.38~7.27(m,2H),7.16(dd,J=14.3,8.3Hz,1H),7.02(brm,1H),2.07~1.99(m,3H).

[0539] Preparation of Example 320 compound (Table 3):

[0540] [ka]

[0541] Preparation of methyl 3-chloro-4-(chlorosulfonyl)thiophene-2-carboxylate (2): To a solution of 2,3-dimethylthiophene 1 (499 μL, 4.46 mmol) in EtO (8.00 mL) was added butyllithium (2.50 M in hexane, 1.96 mL, 4.90 mmol) at 0 °C. The mixture was stirred at 0 °C for 1 h. The mixture was cooled to −78 °C. Ethyl chloroformate (476 μL, 4.90 mmol) was added dropwise. The mixture was stirred at −78 °C for 1 h. The reaction mixture was diluted with 1.00 M NH4Cl (10 mL) and Et2O (20.0 mL). The mixture was warmed to room temperature and stirred for 30 min. The aqueous and organic layers were separated, and the aqueous layer was extracted with Et2O (3 × 15.0 mL). The combined organic layers were dried (MgSO), filtered, and concentrated under reduced pressure. Purification by flash chromatography (25 g silica gel column, EtOAc / hexanes, 0–30% over 15 CV) gave the title compound 2 (554 mg, 49% yield, 73% purity) as a dark green oil. 1 H NMR (400MHz, CDCl3) δ7.49(s,1H),4.30(q,J=7.1Hz,2H),2.36(s,3H),2.13(s,3H),1.35(t,J=7.1Hz,3H).

[0542] Preparation of ethyl 3-(chlorosulfonyl)-4,5-dimethylthiophene-2-carboxylate (3): To a solution of ethyl 4,5-dimethylthiophene-2-carboxylate (2) (1.00 g, 5.43 mmol) in THF (2.99 mL) was added sulfur powder (1.67 g, 6.52 mmol). This was cooled to -78 °C. Freshly prepared lithium diisopropylamide solution (1.00 M in THF, 6.79 mL, 6.79 mmol) was added dropwise to the mixture. The mixture was stirred at -78 °C for 30 minutes and then allowed to warm slowly to room temperature over 4 hours. The mixture was cooled to 0 °C. CHCl (5.00 mL) was added to the mixture, followed by HCl (1.00 M in H0, 5.50 mL). This was stirred at 0°C for 10 minutes, and sodium hypochlorite (10% solution in H2O, 11.8 mL, 16.3 mmol) was added dropwise. This was stirred at 0°C for 20 minutes, and then at room temperature for 2 hours. Additional HCl (1.00 M in H2O, 5.50 mL) was added, followed by sodium hypochlorite (10% solution in H2O, 5.91 mL, 8.15 mmol). This was stirred at room temperature for 20 hours. The reaction mixture was diluted with NH4Cl (1.00 M in H2O, 20.0 mL) and Et2O (30.0 mL). This was stirred at room temperature for 30 minutes. The aqueous and organic layers were separated. The aqueous layer was extracted with Et2O (3 x 25.0 mL). The combined organic layers were dried (MgSO), filtered, and concentrated to give the crude title compound (1.58 g, 40% yield, 40% purity). An LCMS sample was quenched with N-methylpiperazine (resulting sulfonamide, MW = 346.4); (ES + )M+H=347.3.

[0543] Preparation of ethyl 3-(N-(3-acetamido-2,4-difluorophenyl)sulfamoyl)-4,5-dimethylthiophene-2-carboxylate (5): Crude sulfonyl chloride 3 (1.58 g, 40% purity, 2.15 mmol) was dissolved in THF (11.3 mL). To this solution, aniline 4 (400 mg, 2.15 mmol) was added at room temperature, followed by pyridine (209 μL, 2.58 mmol). The resulting mixture was stirred at room temperature for 18 h. The mixture was diluted with EtOAc (30.0 mL) and water (15.0 mL). The aqueous and organic layers were separated. The aqueous layer was extracted with EtOAc (3 × 15.0 mL). The combined organic layers were washed with brine (15.0 mL), dried (NaSO), filtered, and concentrated under reduced pressure to give the crude compound as an oil. Purification by flash chromatography (40 g silica gel column, EtOAc / hexanes, 0-60% over 15 CV) gave the title compound (370 mg, 40%) as an oil. (ES + ) M + H = 433.3 and (ES - )MH=431.3.

[0544] Preparation of N-(3-(4-chlorothiophene-3-sulfonamido)-2,6-difluorophenyl)acetamide (6): Compound 5 (350 mg, 809 μmol) was taken up in THF (4.17 mL) and MeOH (1.04 mL). NaOH (5.00 M in HO, 600 μL) was added to the mixture. The mixture was stirred for 10 min and then acidified using HCl (10% in HO, 10.0 mL). Volatiles were removed. The residue was azeotroped with toluene (3×10.0 mL) and dried under vacuum over the weekend to give 330 mg of crude carboxylic acid. A microwave vial (5 mL) was charged with the crude carboxylic acid (330 mg), copper(II) acetate (75.6 mg, 408 μmol), and 1,10-phenanthroline (149 mg, 816 μmol), and the mixture was suspended in NMP (2.79 mL) / quinoline (697 μL). The vial was flushed with nitrogen and then subjected to microwave irradiation at 180 °C for 10 min using high absorbance. The crude product was diluted with EtOAc (10 mL) and washed with HO (15 mL), HCl (10% in HO, 2 × 10 mL), and brine (15 mL). The organic layer was dried (NaSO), filtered, and concentrated under reduced pressure to give crude title compound 6 (310 mg), which was used in the next step without any further purification. (ES + ) M + H = 361.2 and (ES - )MH=359.2.

[0545] Preparation of N-(3-amino-2,4-difluorophenyl)-4,5-dimethylthiophene-3-sulfonamide (7): Compound 6 (290 mg, 805 μmol) was suspended in EtOH (3.34 mL), and HCl (6.00 N in HO, 1.00 mL) was added. The reaction mixture was stirred at 80 °C overnight. The solution was cooled to room temperature, and the volatiles were evaporated under reduced pressure. The residue was azeotroped with MeOH (3 × 10.0 mL). The residue was purified by reverse-phase chromatography (25 g column, CHCN / water containing 0.1% AmF, 5-50%) to give the title compound (139 mg, 54% yield), which was used in the next reaction without further purification. (ES + ) M + H = 319.1 and (ES - )MH=317.2.

[0546] Preparation of N-(3-((6-chloropyrido[3,2-d]pyrimidin-4-yl)amino)-2,4-difluorophenyl)-4,5-dimethylthiophene-3-sulfonamide (9): Aniline 7 (130 mg, 408 μmol) was added to compound 8 (98.0 mg, 490 μmol) in acetic acid (1.05 mL). The mixture was heated at 50° C. for 4 h. The mixture was cooled to room temperature and poured onto an ice-water mixture (50.0 mL). The mixture was stirred for 20 min. A solid formed, which was filtered, washed with HO (8×10.0 mL), and dried under vacuum overnight to give a beige solid (182 mg, 85% purity). This was triturated with CHCN / MTBE (1:25, 5 x 5.00 mL) and dried overnight to give the title compound 9 as a solid (165 mg, 80% yield, 94% purity). (ES + ) M + H = 482.3 and (ES - )MH=480.4; 1H NMR(400MHz,DMSO-d6) δ:10.19(s,1H),10.13(s,1H),8.55~8.51(m,1H),8.32~8.24(m,1H),8.05~7.96(m,1H ),7.90~7.86(m,1H),7.31~7.23(m,1H),7.20~7.12(m,1H),2.30(s,3H),2.21(s,3H).

[0547] Preparation of Example 320 (Table 3): Benzimidazole was coupled to chloropyridine 9 described above using copper / BINOL catalysis as described for Example 1 (Step 4) in General Method A.

[0548] Preparation of Example 329 compound (Table 4):

[0549] [ka]

[0550] Step 1: To a nitrogen-purged (x3) 10 mL microwave vial equipped with a magnetic stir bar was added 4-bromo-1H-benzo[d]imidazole (99 mg, 0.502 mmol), dicyanozinc (70.8 mg, 0.603 mmol), and palladium tetrakistriphenylphosphine (116 mg, 0.100 mmol) in DMF (4 mL). The reaction was heated to 90 °C and stirred for 16 h. The reaction was cooled to room temperature and then extracted with EtOAc. The organic layer was washed with NaHCO, brine, dried over NaSO, and then loaded onto Celite. The crude material was purified by SiO using MeOH in DCM to give 1H-benzo[d]imidazole-4-carbonitrile (31 mg, 43.1% yield) as a pale pink solid. 1 H NMR (400MHz, DMSO-d6) δ:13.04(br.s.,1H),8.45(s,1H),7.90(d,J=7.83Hz,1H),7.68(d,J=7.83Hz,1H),7.20~7.44(m,1H). MS m / z 142.2(MH+ ).

[0551] Step 2 (Example 329, Table 4): The benzimidazole fragment from Step 1 was coupled to chloropyridine A-13 (Ar = 3-fluoro-2-methylphenyl) using copper / BINOL catalysis as described for Example 1 (Step 4) in General Method A.

[0552] Preparation of compounds of Examples 334, 335, 336 and 346 (Table 4):

[0553] [ka]

[0554] Step 1: Chloropyridine fragment A-13 (Ar = 3-fluoro-2-methylphenyl) (40 mg, 0.083 mmol), methyl 1H-pyrazole-3-carboxylate (13.67 mg, 0.108 mmol), [1,1'-binaphthalene]-2,2'-diol (5.97 mg, 0.021 mmol), copper (1.32 mg, 0.021 mmol), and cesium carbonate (40.7 mg, 0.125 mmol) were placed in a 4 mL vial, followed by DMSO (700 μL). The orange / brown solution was stirred at 100 °C for 16 h. Upon completion, the reaction was cooled to room temperature, and a 4 N aqueous solution of sodium hydroxide (125 μL, 0.50 mmol) was added to the reaction mixture, which was then stirred at 50 °C for an additional 1 h. The reaction mixture was cooled to room temperature and transferred to 1.5 mL of 1 N aqueous hydrochloric acid, and the formation of a precipitate was observed. The precipitate was filtered, washed with water, and dried under high vacuum to give the desired product, 1-(4-((2,6-difluoro-3-(3-fluoro-2-methylphenylsulfonamido)phenyl)amino)-pyrido[3,2-d]pyrimidin-6-yl)-1H-pyrazole-3-carboxylic acid (43.3 mg, 0.078 mmol, 94% yield), as a yellow solid. MS m / z 556.2 (MH + ).

[0555] Step 2: The activated ester was prepared by dissolving the acid from Step 1 (30 mg, 0.054 mmol) and HATU (41.1 mg, 0.108 mmol) in NMP (1 mL), followed by DIEA (56.4 μL, 0.324 mmol). The solution was stirred at room temperature for 2-3 minutes, and then N-methyl-1-(pyridin-4-yl)methanamine (13.4 μL, 0.108 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. Upon completion, the reaction was quenched by the addition of 0.5 mL of formic acid, diluted with DMSO, and purified by HPLC (ACN / HO / 0.1% formic acid) to give the product of Example 334 in Table 4 (5.7 mg, 8.64 μmol, 16% yield) as a beige solid. 1 H NMR(400MHz,DMSO-d6) δ:10.52(br.s.,1H),10.13(s,0.5H),10.09(s,0.5H),9.39(br.s.,0.5H),9.33(br.s.,0.5H) ,8.58(br.s.,2H),8.38~8.53(m,2H),8.32(d,J=9.00Hz,0.5H),8.02(d,J=9.00Hz,0.5H),7.61 (dd,J=4.30,7.43Hz,1H),7.47(d,J=8.22Hz,1H),7.14~7.43(m,5H),7.08(d,J=2.74Hz,0.5H), 7.01(d,J=2.74Hz,0.5H),5.11(s,1),4.77(s,1H),3.39(s,1.5H),3.03(s,1.5H),2.51(s,3H). MS m / z 660.2(MH + ).

[0556] The compounds of Examples 335, 336 and 346 (Table 4) were prepared in an analogous manner using the appropriate commercially available pyrazole ester.

[0557] Preparation of compounds of Examples 339 and 340 (Table 4):

[0558] [ka]

[0559] Step 1: A stirred solution of 1-boc-3-piperidone (5.00 g, 25.1 mmol) in DMF-DMA (20.8 mL) was heated at 100° C. for 1 h. After completion, the reaction mixture was cooled to room temperature and the volatiles were evaporated under reduced pressure to give a yellow gummy material. This was co-evaporated with EtOH (5.00 mL×3) to give a mixture of regioisomeric products. The material was used crude in the next step: (ES + )M+H=225.1.

[0560] Step 2: A mixture of the compound from Step 1 and hydrazine hydrate solution (3.19 mL, 50.2 mmol) was mixed in EtOH (33.5 mL). The mixture was heated at 80° C. for 1 h. When LCMS showed complete consumption of the starting material, it was cooled to room temperature. The volatiles were evaporated under reduced pressure, and the residue was purified by silica gel chromatography using 20-60% ethyl acetate in hexanes. The desired product was obtained in 60% yield. A mixture of isomeric pyrazole derivatives was obtained as a gummy solid (4.04 g, 72% yield): (ES + )M+H=224.1.

[0561] Step 3: The product mixture from Step 2 (335 mg, 1.50 mmol), A-13 (Ar = 3-fluoro-2-methylphenyl, 480 mg, 1.00 mmol), copper metal (6.36 mg, 100 μmol), 1,1'-bi-2-naphthol (58.5 mg, 200 μmol), and cesium carbonate (757 mg, 2.30 mmol) were mixed in DMSO (4.00 mL). The reaction was stirred at 125 °C for 3 h. After cooling to room temperature, the reaction was diluted with water (30.0 mL) and ethyl acetate (30.0 mL) and filtered through Celite. The filtrate was extracted with ethyl acetate (30.0 mL x 2). The combined organic layers were washed with brine, dried, and concentrated. The residue was purified by silica gel chromatography on 80 g using 50-70% ethyl acetate in hexanes. The desired product emerged as a yellow solid mixture of regioisomers (567 mg, 85% yield) at 70% ethyl acetate in hexanes (ES). + )M+H=667.2.

[0562] Step 4: The mixture of regioisomeric carbamates from step 4 (567 mg, 850 μmol) was dissolved in dioxane (4.25 mL). To the solution was added HCl (4.0 M in dioxane, 2.13 mL, 8.50 mmol) at room temperature. The reaction was stirred at room temperature for 2 days. The reaction was filtered and washed with dioxane. The mixture of regioisomeric hydrochlorides was obtained as a yellow solid (542 mg, quantitative yield): (ES + )M-HCl+H=567.2.

[0563] Isolation of regioisomeric pyrazoles from step 4: The mixture of regioisomeric carbamates from step 3 (1.0 g, 1.5 mmol) was dissolved in dioxane (7.5 mL). To the solution was added HCl (4 M in dioxane, 3.75 mL, 15 mmol) at room temperature. The reaction was stirred at room temperature for 2 days. The reaction was filtered and washed with dioxane. A mixture of regioisomeric hydrochloride salts (850 mg, quantitative yield) was obtained as a yellow solid. The solid was purified by reverse-phase column chromatography using 0-20-40% ACN in 10 mM ammonium formate; the first isomer (isomer a) came out at 15% ACN in 10 mM ammonium formate, and the second isomer (isomer b) came out at 40% ACN in 10 mM ammonium formate. Both compounds were concentrated and the residue was treated with 4 M hydrochloric acid in 0.5 mL of dioxane, the resulting suspension was sonicated and then filtered to give the hydrochlorides of isomer a (130 mg, 15% yield) and isomer b (230 mg, 27% yield) as white solids: (ES + )M-HCl+H=567.2.

[0564] Step 5 (Examples 339 and 340, Table 4): The mixture of isomers from Step 4 (85.0 mg, 150 μmol) was dissolved in MeOH (1.50 mL). To the solution was added glycolaldehyde dimer (56.9 mg, 450 μmol). After 5 minutes, sodium triacetoxyborohydride (163 mg, 750 μmol) was added. The reaction was stirred overnight at room temperature. The reaction was quenched with water (10.0 mL) and extracted with ethyl acetate (10 mL x 2). The organic layers were combined and washed with brine, dried, and concentrated. The residue was purified on a reverse-phase column using 0-40-60% ACN in 10 mM ammonium formate. The compound of Example 339 was prepared in 20% ACN in 10 mM ammonium formate, and the compound of Example 340 was prepared in 40% ACN in 10 mM ammonium formate. After lyophilization, the compound of Example 339 (10 mg, 11% yield) was obtained as a white solid. The compound of Example 340 (10 mg, 11% yield) was obtained as a white solid.

[0565] Preparation of Example 343 compound (Table 4):

[0566] [ka]

[0567] Step 1: The commercially available imidazole starting material, which can also be prepared according to the procedure described in Tet. Lett. 2002, 43(1), 61, was coupled to chloropyridine A-13 (Ar = 3-fluoro-2-methylphenyl) using copper / BINOL catalysis as described for Example 1 (Step 4) in General Method A.

[0568] Step 2 (Example 343, Table 4): To a 20 mL scintillation vial equipped with a magnetic stir bar was added the product from Step 1 (91 mg, 0.157 mmol) and 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide (997 mg, 1.57 mmol). The reaction was heated at 65° C. for 48 hours. Upon completion, the reaction was cooled to room temperature. Water was added to the reaction, which precipitated the product. The product was filtered, washed with water, collected, and then dried under vacuum overnight to give (E)-N-(3-((6-(4-(2-cyanovinyl)-1H-imidazo1-yl)pyrido[3,2-d]pyrimidin-4-yl)amino)-2,4-difluorophenyl)-3-fluoro-2-methylbenzenesulfonamide (63 mg, 69% yield) as a beige solid. 1 H NMR(400MHz,DMSO-d6) δ:10.53(s,1H),10.16(s,1H),9.13(s,1H),8.74(s,1H),8.50(s,1H),8.38~8.48(m,2H),7.61(d,J=7.83Hz,1H),7.57(d,J=16.04Hz,1 H),7.49(t,J=8.41Hz,1H),7.40(dt,J=5.48,8.02Hz,1H),7.28~7.36(m,1H),7.22~7.28(m,1H),6.24(d,J=16.04Hz,1H),2.51(s,3H). MS m / z 563.2(MH + ).

[0569] Preparation of compounds of Examples 345 and 361 (Table 4):

[0570] [ka]

[0571] Step 1: To a 5 mL vial equipped with a magnetic stir bar under a N atmosphere was added methyl 4-benzimidazolecarboxylate (100 mg, 0.568 mmol) in anhydrous THF (2 mL). The reaction was cooled to 0 °C. A solution of 1 M lithium aluminum hydride in THF (0.44 mL, 0.437 mmol) was added slowly over 5 min. The reaction was allowed to warm to room temperature and stirred for 4 h. The reaction was pushed to completion with another portion of 1 M lithium aluminum hydride in THF (0.250 mL). The reaction was stirred for an additional 1 h. The reaction was quenched with MeOH. The reaction was loaded onto Celite and then purified on SiO using MeOH in DCM to give the desired benzyl alcohol derivative (58 mg, 0.391 mmol, 90% yield) as a yellow solid. MS m / z 149.2(MH + ).

[0572] Step 2 (Example 345): The benzyl alcohol from Step 1 was coupled to chloropyridine A-13 (Ar = 3-fluoro-2-methylphenyl) using copper / BINOL catalysis as described for Example 1 (Step 4) in General Method A.

[0573] Step 3: To a 20 mL scintillation vial was added N-[2,4-difluoro-3-[[6-[4-(hydroxymethyl)benzimidazol-1-yl]pyrido[3,2-d]pyrimidin-4-yl]amino]phenyl]-3-fluoro-2-methyl-benzenesulfonamide (1.00 equiv., 138 mg, 0.233 mmol) and DIEA (2.00 equiv., 81 μL, 0.467 mmol) in DMF (3.1259 mL). 2-(Trimethylsilyl)ethoxymethyl chloride (stabilized, tech.) (1.10 equiv., 46 μL, 0.257 mmol) was then added to the suspension. The reaction was heated to 40° C. and stirred for 24 hours. The reaction was quenched with saturated NH4Cl and then extracted with brine and EtOAc (x3). The organics were collected, dried over MgSO4, filtered, and then concentrated under reduced pressure. The crude liquid was purified by normal-phase flash column chromatography using MeOH in DCM. The desired fractions were collected and concentrated under reduced pressure to give the desired protected sulfonamide (153 mg, 91%) as a yellow solid. 1 H NMR(400MHz,DMSO-d6) δ:9.88(br.s.,1H),9.30(s,1H),8.49(br.s.,3H),8.25(d,J=8.2Hz,1H),7.66(d,J=7.8Hz,1H),7.54(t,J=8.2Hz,1H),7.39~7.48(m,2H), 7.29~7.39(m,2H),5.26(br.s.,1H),5.07(s,2H),5.00(s,2H),3.60~3.68(m,2H),2.39(d,J=2.3Hz,3H),0.82~0.90(m,2H),-0.03(s,9H). MS m / z 722.2(MH + ).

[0574] Step 4 (Example 361): A 20 mL vial was charged with the product from Step 3 (1.00 equiv., 150 mg, 0.208 mmol) and N,N-diisopropylethylamine (2.00 equiv., 72 μL, 0.416 mmol) in DMF (2 mL). Methanesulfonyl chloride (1.50 equiv., 24 μL, 0.312 mmol) was then added. The reaction was stirred at room temperature overnight. The reaction was quenched with saturated NaHCO and then extracted with EtOAc (×3). The organics were collected, dried over MgSO, filtered, and then concentrated under reduced pressure. The crude product was dissolved in MeCN (2 mL), and then potassium cyanide (2.00 equiv., 27 mg, 0.416 mmol) was added. The reaction was stirred at room temperature for 36 hours. The reaction was quenched with 10% LiCl and then extracted with EtOAc (x3). The organics were collected, dried over MgSO, filtered, and then concentrated under reduced pressure. The crude material was dissolved in 1 mL of DCM and 1 mL of TFA and stirred at room temperature for 48 hours. The DCM was removed under reduced pressure. The crude material was dissolved in DMSO and then purified by preparative HPLC using water:MeCN + 0.1% formic acid to give, after lyophilization, an analog of the compound of Example 361 (36 mg, 0.0593 mmol, 29%) as a pale yellow solid. 1 H NMR(400MHz,DMSO-d6) δ:10.51(br.s.,1H),9.82(s,1H),9.38(s,1H),8.46~8.55(m,3H),8.36(d,J=7.8Hz,1H),7.63(d,J=7.8Hz,1H),7.4 1~7.50(m,3H),7.35~7.41(m,1H),7.29(td,J=9.0,6.3Hz,1H),7.19(t,J=9.4Hz,1H),4.38(s,2H),2.50(br.s.,3H). MS m / z 601.2(MH + ).

[0575] Preparation of compound of Example 347 (Table 4):

[0576] [ka]

[0577] To a 20 mL scintillation vial was added the compound of Example 343 (50 mg, 0.089 mmol) and 5% Pd / C (10 mg, 5.2 μmol) in MeOH (2 mL). The reaction was stirred at room temperature under 1 atmosphere of H for 16 hours. The reaction was filtered through a pad of Celite and then concentrated under reduced pressure. The crude material was purified by HPLC using water:MeOH + 1% formic acid to give the compound of Example 347 in Table 4 (17 mg, 34% yield). 1 H NMR(400MHz,DMSO-d6) δ:10.51(br.s.,1H),10.00(s,1H),8.96(s,1H),8.43~8.49(m,1H),8.32~8.43(m,2H),8.30(s,1H),7.62(d,J=7 .83Hz,1H),7.41~7.49(m,1H),7.33~7.41(m,1H),7.23~7.33(m,1H),7.18(br.s.,1H),2.87(s,4H),2.50(s,3H). MS m / z 565.4(MH + ).

[0578] Preparation of compounds of Examples 348 and 349 (Table 4):

[0579] [ka]

[0580] Commercially available 3H-imidazo[4,5-c]pyridin-4-amine (CAS no. 6811-77-4) was coupled to chloropyridine A-13 using copper / BINOL catalysis as described for Example 1 (Step 4) in General Method A, except that 1.2 equivalents of copper metal were used.

[0581] Preparation of Example 353 compound (Table 4):

[0582] [ka]

[0583] The starting Cbz-protected aminopyridine derivative was obtained in the usual manner by coupling the chloropyridine fragment (Table 2) containing fragment B49 with 4-aminobenzimidazole using the copper / BINOL catalyst described for Example 1 (Step 4) in General Method A. To a solution of this intermediate (12 mg, 0.0168 mmol) in MeOH (1 mL) was added 5% palladium hydroxide on carbon (23 mg, 0.0084 mmol) and stirred under 1 atmosphere of H2 for 1 h. After completion, the suspension was filtered and concentrated in vacuo. The residue was diluted with DMSO and purified by HPLC using MeCN in 0.1% formic acid to give compound 353 (Table 4) (2.0 mg, 20%). 1 H NMR (400MHz, acetic acid d4) δ:9.15(s,1H),8.56~8.84(m,2H),8.42(d,J=9.00Hz,1H),8.08(s,1H),7.98(d,J=9.39Hz,1H),7. 54(s,1H),7.29(s,1H),7.18(s,1H),6.85(d,J=7.83Hz,1H),6.75(d,J=9.39Hz,1H),2.65(s,3H). MS m / z 575.2(MH + ).

[0584] Preparation of compounds of examples 356 and 664:

[0585] [ka]

[0586] The mixture of regioisomeric pyrazoles from Step 4 of Example 339 / 340 (100.0 mg, 177 μmol) was dissolved in MeOH (1.77 mL). To the solution, formaldehyde (65.7 μL, 883 μmol) was added, followed by AcOH (1 drop). After 5 minutes, sodium triacetoxyborohydride (192 mg, 883 μmol) was added. The reaction was stirred at room temperature overnight. The reaction was concentrated to remove MeOH, and then it was diluted with water and ethyl acetate. The aqueous and organic layers were separated, and the aqueous layer was extracted with ethyl acetate (10 mL x 3). The combined organic layers were dried and concentrated under reduced pressure. The residue was purified on a 30 g reverse-phase column using 0-30-60% ACN in 10 mM ammonium formate. The compound of Example 664 was prepared in 30% ACN in 10 mM ammonium formate, and the compound of Example 356 was prepared in 50% ACN in 10 mM ammonium formate. After lyophilization, both the compound of Example 664 (20 mg, 20% yield) and the compound of Example 356 (13 mg, 13% yield) were obtained as white solids.

[0587] Preparation of compounds of Examples 357 and 393 (Table 4):

[0588] [ka]

[0589] The mixture of regioisomeric pyrazoles from Step 4 of Example 339 / 340 (50.0 mg, 88.2 μmol) was dissolved in CHCl (1.00 mL). To the solution was added acetic anhydride (4.63 μL, 48.5 μmol), followed by N,N-diisopropylethylamine (11.6 μL, 66.2 μmol). The reaction was stirred at room temperature overnight. AcO (10.0 μL) was added to the reaction and stirred for another day. The volatiles were removed under reduced pressure, and the residue was directly purified on a reverse-phase column (30 g) using 0-30-60% ACN in 10 mM ammonium bicarbonate. The compound of Example 393 was prepared in 30% ACN in 10 mM ammonium bicarbonate, and the compound of Example 357 was prepared in 40% ACN in 10 mM ammonium bicarbonate. After lyophilization, the compound of Example 393 (10 mg, 19% yield) and the compound of Example 357 (20 mg, 37% yield) were obtained as white solids.

[0590] Preparation of compounds of Examples 362 and 383 (Table 4):

[0591] [ka]

[0592] Step 1: Isomer b (30.0 mg, 53.0 μmol) from Step 4 of Example 339 / 340 and N-boc-2-aminoacetaldehyde (26.6 mg, 159 μmol) were dissolved in MeOH (530 μL). After 5 min, sodium triacetoxyborohydride (57.6 mg, 265 μmol) was added to the solution. The reaction was stirred overnight at room temperature. The reaction was directly purified on a reverse-phase column using 0-40-70% ACN in 10 mM ammonium formate. The desired carbamate analog emerged at 55% ACN in 10 mM ammonium formate, and the appropriate fractions were lyophilized to give a yellow solid (7.5 mg, 20% yield): (ES + )M+H=710.0.

[0593] Step 2 (Example 362, Table 4): To the carbamate from Step 1 (30.0 mg, 53 μmol) in dioxane (500 μL) was added hydrochloric acid (4.00 M in dioxane, 26.4 μL, 106 μmol). The reaction was stirred overnight at room temperature. Volatiles were removed under reduced pressure, and the residue was directly purified on a reverse-phase column using 0-20-40% ACN in 10 mM ammonium formate. The compound of Example 362 was obtained as a yellow solid (5.10 mg, 79% yield) after lyophilization in 30% ACN in 10 mM ammonium formate.

[0594] Step 3 (Example 383, Table 4): To a solution of compound 362 (21.5 mg, 35.3 μmol) in CHCl (0.5 mL) and AcOH (0.05 mL) was added acetic anhydride (3.7 μL, 38.8 μmol), followed by N,N-diisopropylethylamine (9.3 μL, 52.9 μmol). The reaction was stirred at room temperature overnight. Volatiles were removed under reduced pressure, and the residue was directly purified on a reverse-phase column using 0-40-60% ACN in 10 mM ammonium formate. Example 383 was run at 60% ACN in 10 mM ammonium formate and, after lyophilization, was obtained as a yellow solid (10.8 mg, 47% yield).

[0595] Preparation of Example 369 compound (Table 4):

[0596] [ka]

[0597] To a solution of Example 368 nitroarene (26 mg, 0.043 mmol) in 1:1 MeOH / DCM (1 mL) was added 5% palladium hydroxide on carbon (23 mg, 0.0084 mmol) and stirred under 1 atmosphere of H for 16 hours. After completion, the suspension was filtered and concentrated in vacuo. The residue was diluted with DMSO and purified by HPLC using MeCN in 0.1% aqueous formic acid to give Example 369 (2.0 mg, 20%). 1 H NMR (400MHz, acetic acid-d4) δ:9.18(br.s.,1H),8.57~8.84(m,2H),8.42(d,J=9.00Hz,1H),8.08(s,1H),7.51~7.69(m,2H),7.29(td,J=3. MS m / z 574.2(MH + ).

[0598] Preparation of the compounds of Examples 375, 350 and 351 (Table 4):

[0599] [ka]

[0600] Step 1: 3-[tert-Butyl(dimethyl)silyl]oxypropanal (0.38 mL, 1.80 mmol) was added to a solution of 1H-benzimidazol-4-amine (80 mg, 0.601 mmol) in MeOH (7.5 mL). The reaction was heated at 50° C. for 20 minutes and then cooled to room temperature. Sodium cyanoborohydride (0.151 g, 2.40 mmol) was added and the reaction was stirred at 50° C. for 16 hours. The solvent was removed under reduced pressure and then DCM (3 mL) was added, followed by TFA (3 mL). The reaction was stirred at room temperature for 30 minutes. The solvent was removed under reduced pressure and the crude product was dissolved in MeOH. IRA-67 resin was added and the solution was filtered through a cotton plug and then concentrated under reduced pressure to give 3-(1H-benzimidazol-4-ylamino)propan-1-ol (60 mg, 53% yield). MS m / z 192.2 (MH + ).

[0601] Step 2: 3-[tert-Butyl(dimethyl)silyl]oxypropanal (98 μL, 0.471 mmol) was added to a solution of 3-(1H-benzimidazol-4-ylamino)propan-1-ol (60 mg, 0.314 mmol) in MeOH (3.1 mL). The reaction was heated at 50° C. for 15 minutes and then cooled to room temperature. Sodium cyanoborohydride (59 mg, 0.941 mmol) was added, and the reaction was then heated to 50° C. and stirred for 10 hours. LCMS analysis indicated that a significant amount of starting material was still present. The solvent was removed under reduced pressure, and then DCM (3 mL) was added, followed by TFA (3 mL). The reaction was stirred at room temperature for 30 minutes and then concentrated. The crude product was diluted with MeOH and IRA-67 resin was added. The mixture was filtered through a cotton plug. Sodium cyanoborohydride (3.00 equiv, 59 mg, 0.941 mmol) was added. The reaction was heated to 50°C and stirred over the weekend. Upon completion, TFA (1 mL) and IRA-67 were added. The resulting mixture was filtered and the solution was concentrated. The crude material was left under vacuum for 2 days to give 3-[1H-benzimidazol-4-yl(3-hydroxypropyl)amino]propan-1-ol (32 mg, 41% yield). MS m / z 250.2 (MH + ).

[0602] Step 3 (Example 375, Table 4): The benzimidazole fragment from Step 2 was coupled to chloropyridine A-13 (Ar = 3-fluoro-2-methylphenyl) using copper / BINOL catalysis as described for Example 1 (Step 4) in General Method A.

[0603] The compound of Example 350 (Table 4) was prepared in a similar manner using 2-[tert-butyl(dimethyl)silyl]oxyacetaldehyde for Step 1. The monoalkylated 4-aminobenzimidazole obtained in Step 1 was then converted to the compound of Example 350 using the procedure described above for Step 3.

[0604] Example 351 (Table 4) was prepared in a similar manner to Example 375 using 3-[tert-butyl(dimethyl)silyl]oxyacetaldehyde for both Step 1 and Step 2.

[0605] Preparation of compounds of Examples 376 and 384 (Table 4):

[0606] [ka]

[0607] Step 1: A solution of LiHMDS (1 M in THF, 0.76 mL, 0.759 mmol) was added to a solution of 1-(2-trimethylsilylethoxymethyl)benzimidazol-4-amine (described in International Publication No. WO202105591) (50 mg, 0.190 mmol) in DMF (1.9 mL). The resulting mixture was stirred at room temperature for 20 minutes, and then 1-bromo-2-methoxyethane (6.00 equiv., 107 μL, 1.14 mmol) was added. The reaction was stirred at room temperature for 45 minutes. Next, an additional 6 equiv. of 1-bromo-2-methoxyethane (107 μL) was added, and the resulting mixture was stirred for 2 days. Upon completion, a solution of NH4Cl (saturated in water) was added, and the aqueous mixture was extracted with EtOAc. The organics were combined, dried over MgSO4, and concentrated. The crude product was purified by column chromatography (silica gel, 0-80% EtOAc in hexanes) to give N,N-bis(2-methoxyethyl)-1-(2-trimethylsilylethoxymethyl)benzimidazol-4-amine (40 mg, 56% yield) as a pale yellow oil. MS m / z 380.4 (MH + ).

[0608] Step 2: N,N-bis(2-methoxyethyl)-1-(2-trimethylsilylethoxymethyl)benzimidazol-4-amine (40 mg, 0.105 mmol) in a mixture of TFA (1 mL) and DCM (1 mL). The reaction was stirred at room temperature for 1 hour and then heated at 40° C. for 1.5 hours. The reaction was cooled to room temperature. The reaction was concentrated under reduced pressure and then redissolved in MeOH. IRA-67 resin was added and the mixture was filtered through a cotton plug. The solution was concentrated under reduced pressure to give N,N-bis(2-methoxyethyl)-1H-benzimidazol-4-amine (26 mg, 100% yield) as a tan oil. MS m / z 250.2 (MH + ).

[0609] Step 3 (Example 376, Table 4): The benzimidazole fragment from Step 2 was coupled to chloropyridine A-13 (Ar = 3-fluoro-2-methylphenyl) using copper / BINOL catalysis as described for Example 1 (Step 4) in General Method A.

[0610] Example 384 (Table 4) was prepared in a similar manner using 1-bromo-3-methoxypropane in step 1.

[0611] Preparation of Example 382 compound (Table 4):

[0612] [ka]

[0613] Step 1: A solution of 1-(p-toluenesulfonyl)pyrrole (5 g, 22.6 mmol), prepared as described in International Publication No. WO 2021 / 97057, page 2021, in dry CH3CN (100 mL) was cooled in an ice bath and treated dropwise with chlorosulfonic acid (9.0 mL, 136 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 72 hours. Upon completion, the mixture was then poured onto ice / water, and a precipitate formed. The solid was filtered to provide 1-(p-tolylsulfonyl)pyrrole-3-sulfonyl chloride (2.53 g, 35% yield). MS m / z (MH + ).

[0614] Step 2: To a vial equipped with a stir bar was added 1-(p-tolylsulfonyl)pyrrole-3-sulfonyl chloride (86 mg, 0.27 mmol) from Step 1 in anhydrous THF (2 mL). To this solution was added DIEA (0.094 mL, 0.541 mmol) and N,N,N″-trimethylethylenediamine (0.042 mL, 0.325 mmol). The resulting solution was stirred at room temperature for 1 hour. Upon completion, 10% aqueous KOH (2 mL) was added dropwise. The reaction was heated at 60° C. overnight. Upon completion, the reaction mixture was diluted with EtOAc, and aqueous NH4Cl was added. The layers were separated. The organic layer was washed with brine, then dried over MgSO, filtered, and concentrated to dryness to give N-[2-(dimethylamino)ethyl]-N-methyl-1H-pyrrole-3-sulfonamide (48 mg, 77% yield) as a pale orange oil. 1 H NMR (400MHz, CDCl3) δ:ppm 2.35~2.48(m,6H), 2.61~2.85(m,6H), 3.01~3.24(m,2H), 6.46(br.s.,1H), 6.85(br.s.,1H). MS m / z 232.2(MH + ).

[0615] Step 3 (Example 382, ​​Table 4): The pyrrole fragment from Step 2 was coupled to chloropyridine A-13 (Ar = 3-fluoro-2-methylphenyl) using copper / BINOL catalysis as described for Example 1 (Step 4) in General Method A.

[0616] Preparation of Example 391 compound (Table 4):

[0617] [ka]

[0618] Isomer b (28.3 mg, 49.9 μmol) from Step 4 of Example 339 / 340 was added to 3-hydroxypropanal (22.2 mg, 300 μmol), followed by DCE (1.0 mL), followed by one drop of AcOH and sodium triacetoxyborohydride (65.1 mg, 300 μmol). The reaction was stirred at room temperature overnight. The reaction was purified by preparative HPLC, and Example 391 (6.3 mg, 20% yield) was obtained as a white solid.

[0619] Preparation of Example 392 compound (Table 4):

[0620] [ka]

[0621] Step 1: Isomer b from Step 4 of Example 339 / 340 (30.0 mg, 53.0 μmol), N,N-diisopropylethylamine (23.2 μL, 132 μmol), and Boc-Gly-OH (11.4 mg, 63.5 μmol) were dissolved in DMF (600 μL). To the solution was added HATU (30.8 mg, 79.4 μmol). The reaction was stirred at room temperature overnight. Water (5.00 mL) was added to the reaction, and the precipitated product was filtered to give the desired carbamate (38.0 mg, 99% yield) as a beige solid: (ES +)M+H=724.3.

[0622] Step 2 (Example 392, Table 4): To a solution of the product from Step 1 (38.0 mg, 52.5 μmol) in dioxane (1.00 mL) was added HCl (4 M, dioxane) (131 μL, 525 μmol). The reaction was stirred at room temperature over the weekend. Volatiles were removed under reduced pressure, and the residue was purified by reverse-phase column chromatography using 0-20-40% ACN in 10 mM ammonium formate. Example 392 was run at 25% ACN in 10 mM ammonium formate and obtained as a white solid (27.6 mg, 84% yield) after lyophilization.

[0623] Preparation of Example 414 compound (Table 4):

[0624] Example 414 was prepared in a similar manner to Example 392, except that isomer b from step 4 of Examples 339 / 340 was used.

[0625] Preparation of Example 415 compound (Table 4):

[0626] [ka]

[0627] Step 1: Isomer b (15.0 mg, 26.5 μmol) from Step 4 of Example 339 / 340 and N-boc-2-aminoacetaldehyde (13.3 mg, 79.4 μmol) were dissolved in DCE (375 μL). After 5 min, sodium triacetoxyborohydride (17.3 mg, 79.4 μmol) was added to the solution. The reaction was stirred at room temperature overnight. The reaction was quenched with water (5.00 mL) and extracted with DCM (5 mL x 3). The combined organic layers were concentrated under reduced pressure. The resulting crude residue 7a (18.8 mg, 100% yield) was used directly in the next step: (ES + )M+H=710.3.

[0628] Step 2: The crude product from Step 1 (18.8 mg, 26.5 μmol) was dissolved in dioxane (250 μL), and then HCl (4 M in dioxane, 66.3 μL, 265 μmol) was added. The reaction was stirred overnight at room temperature. Volatiles were removed under reduced pressure, and the residue was purified by reverse-phase column chromatography using 0-20-40% ACN in 10 mM ammonium formate. The compound of Example 415 was run at 25% ACN in 10 mM ammonium formate and, after lyophilization, was obtained as a white solid (formate form) (8.20 mg, 51% yield).

[0629] Preparation of Example 420 compound (Table 4):

[0630] [ka]

[0631] Step 1: To a 100 mL round-bottom flask was added 4-bromo-1H-benzimidazole (1.00 g, 5.08 mmol), 2-(trimethylsilyl)ethoxymethyl chloride (1.1 mL, 6.09 mmol), and 60% NaH (244 mg, 6.09 mmol) in anhydrous DMF (10 mL). The reaction was stirred at room temperature for 1 hour. Upon completion, the reaction was quenched with saturated NH4Cl and then extracted with EtOAc (x3). The organics were washed with brine, separated, dried over MgSO4, filtered, and then concentrated under reduced pressure. The crude material was loaded onto Celite and then purified on SiO using EtOAc in hexanes to give 2-[(4-bromobenzimidazol-1-yl)methoxy]ethyl-trimethyl-silane (1.18 g, 71% yield) as a brown oil. MS m / z 327.2 (MH + ).

[0632] Step 2: To a flame-dried 5 mL microwave vial, 2-[(4-bromobenzimidazol-1-yl)methoxy]ethyl-trimethyl-silane (500 mg, 1.53 mmol) and bis(pinacolato)diboron (776 mg, 3.06 mmol) were added in DMF (0.30 mL) under a N atmosphere. Next, 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (279 mg, 0.382 mmol) and potassium acetate (450 mg, 4.58 mmol) were added to the solution. The reaction was sparged with a balloon of argon for several minutes, sealed, and then heated to 100° C. and stirred for 16 hours. The reaction was cooled to room temperature. The crude reaction was used as the crude mixture in the next step.

[0633] Step 3: To the crude reaction mixture was added 4-amino-3-bromopyridine (34 mg, 0.20 mmol), tetrakis(triphenylphosphine)palladium(0) (35 mg, 0.0305 mmol), and sodium carbonate (97 mg, 0.914 mmol). The reaction mixture was sparged with a balloon of argon for 5-10 minutes, sealed, and then heated at 100 °C for 24 hours. Upon completion, the reaction mixture was cooled to room temperature. The reaction mixture was diluted with brine and extracted with EtOAc (x3). The organics were collected, dried over MgSO, filtered, and then concentrated under reduced pressure. The crude material was loaded onto Celite and then purified on SiO2 using MeOH in DCM to give 3-[1-(2-trimethylsilylethoxymethyl)benzimidazol-4-yl]pyridin-4-amine (72 mg, 69% yield) as a brown film. MS m / z 341.2 (MH + ).

[0634] Step 4: To a 20 mL scintillation vial was added 3-[1-(2-trimethylsilylethoxymethyl)-benzimidazol-4-yl]pyridin-4-amine (72 mg, 0.210 mmol) in DCM (2 mL) and TFA (2 mL). The reaction was stirred at room temperature for 16 hours. Upon completion, the solvent was removed under reduced pressure and then dried under vacuum to give 3-(1H-benzimidazol-4-yl)pyridin-4-amine TFA salt (68 mg, 100% yield) as a brown oil. MS m / z 211.2 (MH + ).

[0635] Step 5 (Example 420, Table 4): The benzimidazole fragment from Step 4 was coupled to chloropyridine A-13 (Ar = 3-fluoro-2-methylphenyl) using copper / BINOL catalysis as described for Example 1 (Step 4) in General Method A.

[0636] Preparation of Example 424 compound (Table 4):

[0637] [ka]

[0638] Step 1: To a 20 mL scintillation vial was added 4-bromo-1H-benzimidazole (500 mg, 2.54 mmol), 60% NaH (122 mg, 3.05 mmol), and 4-methoxybenzyl chloride (413 μL, 3.05 mmol) in DMF (5 mL). The reaction was stirred at room temperature for 2 h. The reaction was quenched with saturated NH4Cl and then extracted with EtOAc (x3). The organics were collected, dried over MgSO4, filtered, and then concentrated under reduced pressure. The crude material was loaded onto Celite and then purified on SiO2 using EtOAc in hexanes to give 4-bromo-1-[(4-methoxyphenyl)methyl]benzimidazole (735 mg, 91% yield) as a brown oil. 1H NMR(400MHz,DMSO-d6) δ:8.50(s,1H),7.57(dd,J=8.2,0.8Hz,1H),7.29(ddd,J=8.6,3.1,2.0Hz ,2H),7.14(t,J=7.8Hz,2H),6.86~6.89(m,2H),5.43(s,2H),3.70(s,3H). Minor isomers: 8.46(s,1H),7.70(dd,J=8.0,1.0Hz,1H),7.42(d,J=7.8Hz,2H),7.04(d,J=9.0Hz,2H),6.90(m,J=3.5Hz,2H),5.72(s,2H),3.70(s,3H). MS m / z 317.2(MH + ).

[0639] Step 2: To a flame-dried 5 mL microwave vial was added the protected benzimidazole from Step 1 (200 mg, 0.631 mmol) and bis(pinacolato)diboron (320 mg, 1.26 mmol) in DMF (0.3000 mL) under a N atmosphere. Next, 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (231 mg, 0.315 mmol) and then potassium acetate (186 mg, 1.89 mmol) were added to the solution. The reaction was sparged with a balloon of argon for several minutes, sealed, and then heated to 100 °C and stirred for 24 h. The reaction was cooled to room temperature. The reaction was diluted with brine and extracted with EtOAc (x3). The organics were collected, dried over MgSO, filtered through a plug of celite, and then concentrated under reduced pressure. The crude material was loaded onto celite and then purified on SiO using EtOAc in hexanes. The desired fractions were collected and concentrated under reduced pressure to give 1-[(4-methoxyphenyl)methyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzimidazole (82 mg, 36% yield) as a brown oil. MS m / z 365.4 (MH + ).

[0640] Step 3: To a flame-dried 5 mL microwave vial under a N atmosphere, 1-[(4-methoxyphenyl)methyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzimidazole (56 mg, 0.154 mmol) and 2-amino-3-bromopyridine (35 mg, 0.200 mmol) were added. Sodium carbonate (49 mg, 0.461 mmol) and then tetrakis(triphenylphosphine)palladium(0) (18 mg, 0.0154 mmol) were added to the solution. The reaction was sparged with a balloon of argon for 5-10 minutes, sealed, and then heated to 80 °C and stirred for 16 hours. The reaction was cooled to room temperature. The reaction was diluted with brine and extracted with EtOAc (x3). The organics were collected, dried over MgSO, filtered, and then concentrated under reduced pressure. The crude material was loaded onto Celite and then purified on SiO using MeOH in DCM. The desired fractions were collected and concentrated under reduced pressure to give 3-[1-[(4-methoxyphenyl)methyl]benzimidazol-4-yl]pyridin-2-amine (15 mg, 0.0445 mmol, 29% yield) as a white solid. MS m / z 331.2 (MH + ).

[0641] Step 4: To a 20 mL scintillation vial was added 3-[1-[(4-methoxyphenyl)methyl]-benzimidazol-4-yl]pyridin-2-amine (15 mg, 0.0445 mmol) in TFA (2 mL). The reaction was heated to 80° C. and stirred for 96 h. The solvent was removed under reduced pressure, and the product was then co-evaporated with toluene (×3) to give 3-(1H-benzimidazol-4-yl)pyridin-2-amine TFA salt (14 mg, 100%). MS m / z 211.2 (MH + ).

[0642] Step 5 (Example 424, Table 4): The benzimidazole fragment from Step 4 was coupled to chloropyridine A-13 (Ar = 3-fluoro-2-methylphenyl) using copper / BINOL catalysis as described for Example 1 (Step 4) in General Method A.

[0643] Preparation of compounds of Examples 425 and 460 (Table 4):

[0644] [ka]

[0645] Step 1: Compound A-13 (800 mg, 1.67 mmol) and hydrazine (1.00 M solution in THF, 3.33 mL, 3.33 mmol) were mixed in THF (6.67 mL). The reaction was stirred at 80 °C overnight. The reaction was cooled to room temperature, and hexane (50 mL) was added. The solid formed was filtered and washed with hexane (5 mL x 2). It was dried under air circulation to give 819 mg of a beige solid. The crude solid product was further purified with 0-10% MeOH in CHCl. ​​The desired product was eluted with 10% MeOH in DCM to give the expected hydrazine derivative (550 mg, 69% yield) as a beige solid: (ES + )M+H=476.1.

[0646] Step 2: The product from Step 1 (350 mg, 736 μmol) and the crude vinylamide (206 mg, 810 μmol) obtained in Step 1 of Example 339 / 340 were combined in EtOH (3.68 mL), and the reaction was stirred overnight at room temperature. The reaction was concentrated to remove EtOH, and AcOH (5.25 mL) was added. The reaction was stirred at 80°C for 1 hour. The volatiles were removed under reduced pressure, and the residue was purified by reverse-phase column chromatography using 0-50-100% ACN in 10 mM ammonium formate. The desired pyrazole derivative (85 mg, 17% yield) was run at 90% ACN in 10 mM ammonium formate and obtained as a white solid after lyophilization: (ES + )M+H=667.2.

[0647] Step 3: To a solution of the product from Step 2 (85.0 mg, 127 μmol) in dioxane (637 μL) was added HCl (4 M in dioxane, 319 μL, 1.27 mmol). The reaction was stirred at room temperature overnight. HCl (4 M in dioxane, 0.5 mL, 1.98 mmol) was added, and then it was heated at 50° C. for an additional day. The reaction was filtered and washed with dioxane (2.0 mL). The desired hydrochloride salt (70.0 mg, 97% yield) was obtained as a beige solid: (ES + )M+H=567.3.

[0648] Step 4 (Example 425, Table 4): The hydrochloride salt from Step 3 (20.0 mg, 35.3 μmol) and glycolaldehyde dimer (17.9 mg, 141 μmol) were dissolved in DCE (500 μL). After 5 min, sodium triacetoxyborohydride (38.4 mg, 177 μmol) was added to the solution. The reaction was stirred at room temperature for 2 h. Volatiles were removed under reduced pressure, and the solid residue was purified by reverse phase elution using 0-20-50% ACN in 10 mM ammonium bicarbonate. The title compound 425 was obtained as a yellow solid (8.00 mg, 37% yield) after lyophilization.

[0649] Step 4 (Example 460, Table 4): The hydrochloride salt from Step 3 (15.0 mg, 26.5 μmol) and aqueous formaldehyde (9.86 μL, 132 μmol) were dissolved in DCE (265 μL). To the solution, sodium triacetoxyborohydride (28.8 mg, 132 μmol) was added, followed by AcOH (1 drop). The reaction was stirred at room temperature overnight. The volatiles were removed under reduced pressure. To the solid residue, MeOH (1.00 mL) and water (10 mL) were added. The mixture was filtered to give solid A, which was set aside. The resulting filtrate was extracted with ethyl acetate (5 mL x 5). The organic layers were combined and concentrated to give solid B. Solid A and solid B were combined, and MeOH (2 mL) was added. The slurry was heated to 80° C. until the solids were dissolved, then it was cooled to room temperature and filtered to give Example 460 (11.3 mg, 74% yield) as a yellow solid.

[0650] Preparation of compounds of Examples 443 and 444 (Table 4):

[0651] These two analogs were prepared following general method G using 5-fluoroindole and the appropriate amine as starting materials. The indole sulfonamide was coupled to chloropyridine A-13 (Ar = 2,3-dichlorophenyl) using copper / BINOL catalysis as described for Example 1 (Step 4) in general method A.

[0652] Preparation of the compounds of Examples 447, 456, 457 and 461 (Table 4):

[0653] [ka]

[0654] Step 1: 3-Indole sulfone ester was prepared from 1H-indol-3-yl thiocyanate (Phosphorus, Sulfur and Silicon and the Related Elements 2014, 189, 1378) as described under general method H. To a solution of this material (100 mg, 0.309 mmol) in DCM (3 mL) at −78° C., 1 M diisobutylaluminum hydride solution (2.5 mL, 3.72 mmol) was added in two portions. The reaction mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was diluted with diethyl ether (30 mL) and cooled to 0° C. The reaction was quenched by the slow addition of 0.15 mL of water, followed by 0.15 mL of 15% aqueous sodium hydroxide and 0.37 mL of water. The solution was warmed to room temperature and stirred for 15 minutes. Anhydrous magnesium sulfate was added to the stirred solution. After 15 minutes, the suspension was filtered to remove the salts. Evaporation to dryness gave the corresponding alcohol (68 mg, 87%) as a solid. 1 H NMR(400MHz, CDCl3) δ:8.91(br.s.,1H),7.87~8.08(m,1H),7.81(d,J=3.13Hz,1H),7.43~7.61(m,1H),7.32~7.43(m,2H),3.81(d,J=6.65Hz,2H),1.39(s,6H). MS m / z 254.2(MH + ).

[0655] Step 2 (Example 447, Table 4): The indole sulfone from Step 1 was coupled to chloropyridine A-13 (Ar = 2,3-dichlorophenyl) using copper / BINOL catalysis as described for Example 1 (Step 4) in General Method A.

[0656] Step 3: A stirred solution of the alcohol from Step 1 (350 mg, 1.38 mmol) in DCM (4 mL) was treated with 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benzodioxol-3-(1h)-one (1289 mg, 3.04 mmol). After 2 h at room temperature, saturated aqueous NaSO (1.0 mL) and saturated aqueous NaHCO (1.0 mL) were added, and the biphasic mixture was stirred for 30 min. The mixture was diluted with DCM (3 mL), the layers were separated, and the aqueous layer was extracted with CHCl (2 × 4 mL). The combined organic extracts were dried over MgSO, filtered, and concentrated to give the desired aldehyde intermediate (350 mg, 96%). 1 H NMR(400MHz, CDCl3) δ:9.86(s,1H),8.88(br.s.,1H),7.87~7.98(m,1H),7.73(d,J=3.13Hz,1H),7.44~7.52(m,1H),7.29~7.40(m,2H),1.55(s,6H). MS m / z 250.2(MH - ).

[0657] Step 4: The aldehyde from step 3 (30 mg, 0.119 mmol) and morpholine (0.021 mL, 0.239 mmol) were combined in ACN (1 mL) containing 1 drop of acetic acid and stirred for 16 h at 70 °C. DCE was then added, followed by sodium triacetoxyborohydride (127 mg, 0.597 mmol), and the resulting suspension was stirred at room temperature for 16 h. The reaction was quenched by adding saturated aqueous NaHCO (5 mL) and stirred for 15 min. The solution was extracted with EtOAc (3 x 10 mL). The organic phase was washed with brine (10 mL), separated, dried over MgSO, filtered, and concentrated in vacuo to give the desired aminosulfone (29 mg, 75%). MS m / z 286.2 (MH - ).

[0658] Step 5 (Example 457, Table 4): The indole sulfone from Step 4 was coupled to chloropyridine A-13 (Ar = 2,3-dichlorophenyl) using copper / BINOL catalysis as described for Example 1 (Step 4) in General Method A to provide Example 457.

[0659] Other analogs in Table 4 (456 and 461) were prepared in this manner using the appropriate amine in step 4.

[0660] Preparation of the compound of Example 465 (Table 4):

[0661] [ka]

[0662] Step 1: To a solution of 1H-indol-3-yl-thiocyanate (Phosphorus, Sulfur and Silicon and the Related Elements 2014, 189, 1378) (500 mg, 2.87 mmol) in iPrOH (15 mL) was added sodium sulfide anhydrate (2068 mg, 8.61 mmol) dissolved in 1 mL of water, and the resulting mixture was stirred at 50° C. for 2 hours. After this, 1-piperidinecarboxylic acid, 4-bromo-,1,1-dimethylethyl ester (1.1 mL, 5.74 mmol) was added and stirred at 50° C. overnight. 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 MgSO4, and then concentrated in vacuo to give the crude sulfide, which was used directly in the next step without further purification.

[0663] Step 2: The sulfide from Step 1 was dissolved in DCM and 3-chloroperoxybenzoic acid (1486 mg, 8.61 mmol) was added and stirred at room temperature for 2 hours. Upon completion, the reaction was quenched by adding 10 mL of a 1:1 solution of saturated aqueous NaHCO3 and 10% aqueous Na2SO3. The resulting suspension was stirred at room temperature for 15 minutes. EtOAc was added and the organic layer was separated. The organic layer was washed with water (15 mL) and then saturated brine (15 mL). The organic layer was separated, dried (MgSO4), and concentrated to dryness after filtration. The residue was purified on silica gel using EtOAc in hexane to provide the desired sulfone (985 mg, 94% yield). 1 H NMR(400MHz,DMSO-d6) δ:12.29(br.s.,1H),8.00(d,J=3.13Hz,1H),7.77(d,J=7.43Hz,1H),7.54(d,J=7.83Hz,1H),7.14~7.3 0(m,2H),3.80~4.08(m,3H),2.72(br.s.,2H),1.99(s,1H),1.91(d,J=10.96Hz,2H),1.24~1.35(m,9H). MS m / z 365.2(MH + ).

[0664] Step 3: The indole sulfone from step 2 was coupled to chloropyridine A-13 (Ar=2,3-dichlorophenyl) using copper / BINOL catalysis as described for Example 1 (step 4) in general method A.

[0665] Step 4 (Example 465, Table 4): The N-Boc-protected piperidone from Step 3 (170 mg, 0.201 mmol) was stirred in TFA (1.0 mL, 13.1 mmol) for 30 min and concentrated in vacuo. The residue was co-evaporated with ACN to provide Example 465 (170 mg, 93%). 1H NMR(400MHz,DMSO-d6) δ:9.84(s,1H),9.05(s,1H),8.54(s,1H),8.43~8.52(m,2H),8.34(d,J=8.61Hz,1H), 8.16(s,1H),7.88~7.99(m,2H),7.65(dd,J=1.17,7.83Hz,1H),7.43~7.59(m,2H),7. 36(t,J=8.02Hz,1H),6.96~7.13(m,1H),6.72~6.89(m,1H),3.47~3.60(m,1H),3.24( br.s.,2H),2.78(t,J=11.93Hz,2H),2.14(d,J=12.13Hz,2H),1.72(d,J=9.39Hz,2H). MS m / z 744.3(MH + ).

[0666] Preparation of the compound of Example 467 (Table 4):

[0667] [ka]

[0668] Step 1: Lithium aluminum hydride (26 mg, 0.686 mmol) was added to a cold (0 °C) stirred solution of tert-butyl 4-(1H-indol-3-ylsulfonyl)piperidine-1-carboxylate (Example 465, Step 2: 50 mg, 0.137 mmol) in 25 mL of EtO. After stirring for 16 h at room temperature, the reaction mixture was diluted with EtO and cooled to 0 °C. The reaction was quenched by the slow addition of 0.150 mL of water, followed by 0.150 mL of 15% aqueous sodium hydroxide and 0.370 mL of water. The solution was warmed to room temperature and stirred for 15 minutes. Anhydrous magnesium sulfate was added to the stirred solution. After 15 minutes, the suspension was filtered to remove salts. Evaporation to dryness gave the desired N-methylpiperidine sulfone (68 mg, 87%) as a solid. MS m / z 279.2 (MH + ).

[0669] Step 2: The indole sulfone from Step 1 was coupled to chloropyridine A-13 (Ar=2,3-dichlorophenyl) using copper / BINOL catalysis as described for Example 1 (Step 4) in General Method A to provide the product of Example 467 after reverse-phase HPLC using ACN in 0.1% aqueous HCOOH.

[0670] Preparation of Examples 468-470 and 474-479 (Table 4):

[0671] [ka]

[0672] Example 465 (25 mg, 0.0291 mmol), 3-oxetanone (0.0055 mL, 0.0873 mmol), and DIEA (1 eq., 0.0051 mL, 0.0291 mmol) were suspended in DCE (1 mL) and stirred at 60° C. for 30 min. Sodium triacetoxyborohydride (19 mg, 0.0873 mmol) was then added, and the suspension was stirred for 16 h at 60° C. After completion, the solvent was removed under vacuum, and the residue was purified on reverse-phase HPLC using 0.1% aqueous HCOOH in ACN to give Example 474 (12 mg, 49%). 1 H NMR(400MHz,DMSO-d6) δ:9.97(s,1H),8.92(s,1H),8.36~8.64(m,4H),8.28(d,J=8.61Hz,1H),7.83~8.03(m,3H),7.44~7.50(m,3H),7.42(s,1H) ),4.38~4.51(m,2H),4.31(t,J=6.06Hz,3H),2.72(br.s.,2H),2.31(s,1H),1.99(br.s.,2H),1.75(m,2H),1.63(m,2H). MS m / z 800.3(MH + ).

[0673] Other examples were prepared in a similar manner using the appropriate aldehyde or ketone, which can be found in Table 4 (eg, Examples 468-470 and 475-479).

[0674] Preparation of the compound of Example 472 (Table 4):

[0675] [ka]

[0676] Step 1: To a stirred suspension of 3-iodoindole (600 mg, 2.47 mmol) in dry dioxane (10 mL) at room temperature, methylphosphonoylmethane (212 mg, 2.72 mmol), (9,9-dimethyl-9h-xanthene-4,5-diyl)bis(diphenylphosphine) (143 mg, 0.247 mmol), and cesium carbonate (1207 mg, 3.70 mmol) were added. The reaction mixture was degassed and refilled with argon three times. Tris(dibenzylideneacetone)dipalladium (113 mg, 0.123 mmol) was added to the reaction mixture, and the reaction vial was sealed. The reaction mixture was heated to 90° C. and stirred for 16 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude material was purified ...

Claims

1. A compound of formula I: 【Chemistry 1】 Where: R 1 is replaced or not replaced, OR 3 , S.R. 3 , N.H. 2 , N.H.R. 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 replaced by C 6 Aryl or C 5～10 Heteroaryl, substituted or unsubstituted, C 4～8 Heterocycloalkyl and N(R 3 ) 2 Selected from: R 3 is independently at each occurrence substituted or unsubstituted; C 1～8 Alkyl, C 3～8 Cycloalkyl, C 4～8 Heterocycloalkyl, C 6～10 Aryl and C 5～10 heteroaryl; X 1 is a halogen atom or an electron-withdrawing group; X 2 is selected from H, a halogen atom, and an electron withdrawing group; X 3 and X 4 are H, halogen atoms, electron-withdrawing groups, and C 1～3 Alkyl, C 3～4 Cycloalkyl and OC 1～3 is selected from alkyl.

2. R 2 is a group of the formula 【Chemistry 2】 Where: R 4 is H, F, Cl, Br, CN, and substituted or unsubstituted, C 1～3 Alkyl, C 3～4 Cycloalkyl or OC 1～3 alkyl; R 5 is H, F, Cl, CN, and substituted or unsubstituted, C 1～3 Alkyl, C 3～4 Cycloalkyl or OC 1～3 alkyl; R 6 are H, F, Cl, Br, NO 2 , N.H. 2 , and substituted or unsubstituted, C 1～3 Alkyl, C 3～4 Cycloalkyl or OC 1～3 alkyl; R 7 is H, F, Cl, and substituted or unsubstituted C 1～3 alkyl; R 8 is H, F, and substituted or unsubstituted C 1～3 alkyl; 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 is not a benzoxazolinone; and (---) represents a bond; Here, R 4 is H or F, then R 5 , R 6 , R 7 or R 8 is other than H or F; and Here, R 5 If is CN, then R 4 , R 6 , R 7 or R 8 At least one of is other than H.

3. R 4 is Cl, and substituted or unsubstituted C 1～3 alkyl; R 5 is H, F, Cl, and substituted or unsubstituted C 1～3 alkyl; R 6 is H, F, Cl, substituted or unsubstituted C 1～3 Alkyl and substituted or unsubstituted OC 1～3 alkyl; and R 7 and R 8 are H, The compound according to claim 2.

4. R 2 The compound according to claim 1, wherein is a group of the formula 【Chemistry 3】 Where: X 5 NH, NC 1～3 Alkyl, NC 3～4 cycloalkyl, O and S; R 9 , R 10 , R 11 are each independently 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, where R 9 and R 11 is H and the other is not H; and (---) represents a bond.

5. R 2 The compound according to claim 1, wherein is a group of the formula 【Chemistry 4】 Where: X 5 NH, NC 1～3 Alkyl, NC 3～4 cycloalkyl, O and S; R 9 is 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 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 (---) represents a bond.

6. R 2 The compound according to claim 1, wherein is a group of the formula 【Chemistry 5】 Where: X 9 , X 10 , X 11 , X 12 and X 13 is independently selected from N and C, where X 9 , X 10 , X 11 , X 12 and X 13 at least one and not more than two of are N; and R 19 , R 20 , R 21 , R 22 and R 23 H, F, Cl, Br, CN, NO 2 , N.H. 2 , and substituted or unsubstituted, C 1～3 Alkyl, C 3～4 Cycloalkyl or OC 1～3 alkyl or their combined X 9 , X 10 , X 11 , X 12 Or X 13 does not exist when is N; where X 9 and X 13 is not N; and where X 9 is N, X 13 is not N and X 13 -R 23 is not CH; Where X 13 is N, then X 9 is not N and X 9 -R 19 is not CH.

7. R 2 The compound according to claim 1, wherein is a group of the formula 【Chemistry 6】 Where: R 13 independently at each occurrence, F, Cl, and substituted or unsubstituted, C 1～3 Alkyl, C 3～4 Cycloalkyl or C 1～3 alkoxy; n is an integer selected from 0 to 8; or n is 2 to 8, and two R 13 together with their adjacent carbon atoms, C 3～4 forms a cycloalkyl; and (---) represents a bond.

8. R 2 The compound of claim 1 , wherein is a group selected from the following: 【Chemistry 7】 Here, (---) represents a bond.

9. R 1 2. The compound according to claim 1, wherein is a substituted or unsubstituted group selected from thienyl, imidazolyl, pyrazolyl, triazolyl, thiazolyl, pyridyl, pyrimidinyl, indolyl, indazolyl, benzimidazolyl, benzotriazolyl, pyrrolopyridinyl, pyrazolopyridinyl, purinyl, imidazopyrazinyl and quinolyl(quinolinyl).

10. R 1 The compound according to claim 1, wherein is a group of the formula 【Chemistry 12】 Where: R 17 H, OH, halogen atoms, 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 , S.O. 2 R 15 , S.O. 2 N(R 14 ) 2 , N(R 16 )C(O)R 15 , N(R 16 )SO 2 R 15 , N(R 16 )C(O)N(R 14 ) 2 , N(R 16 )SO 2 N(R 14 ) 2 , N(R 14 ) 2 , P(O)(R 15 ) 2 , C.H. 2 C(O)R 15 , C.H. 2 C(O)N(R 14 ) 2 , C.H. 2 SO 2 R 15 , C.H. 2 SO 2 N(R 14 ) 2 , C.H. 2 N(R 16 )C(O)R 15 , C.H. 2 N(R 16 )SO 2 R 15 , C.H. 2 N(R 16 )C(O)N(R 14 ) 2 , C.H. 2 N(R 16 )SO 2 N(R 14 ) 2 , and C.H. 2 N(R 14 ) 2 Selected from: X 6 is N or CH; and X 7 is N, and R 18 is not present; or X 7 is C, and R 18 But, 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 , S.O. 2 R 15 , S.O. 2 N(R 14 ) 2 , N(R 16 )C(O)R 15 , N(R 16 )SO 2 R 15 , N(R 16 )C(O)N(R 14 ) 2 , N(R 16 )SO 2 N(R 14 ) 2 , N(R 14 ) 2 , P(O)(R 15 ) 2 , C.H. 2 C(O)R 15 , C.H. 2 C(O)N(R 14 ) 2 , C.H. 2 SO 2 R 15 , C.H. 2 SO 2 N(R 14 ) 2 , C.H. 2 N(R 16 )C(O)R 15 , C.H. 2 N(R 16 )SO 2 R 15 , C.H. 2 N(R 16 )C(O)N(R 14 ) 2 , C.H. 2 N(R 16 )SO 2 N(R 14 ) 2 , and C.H. 2 N(R 14 ) 2 Selected from: Where: R 14 independently in each case, 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 together with their adjacent nitrogen atoms, C 4～10 forming a heterocycloalkyl group, wherein said alkyl, said alkenyl, said alkynyl, said cycloalkyl, said heterocycloalkyl, or said heteroaryl may be further substituted; R 15 In each case, 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 said alkyl, said alkenyl, said alkynyl, said cycloalkyl, said heterocycloalkyl, or said heteroaryl may be further substituted; and R 16 independently in each case, 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 said alkyl, said alkenyl, said alkynyl, said cycloalkyl, said heterocycloalkyl, or said heteroaryl may be further substituted; and Here, (---) represents a bond.

11. X 7 is N and R 17 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 , S.O. 2 R 15 , S.O. 2 N(R 14 ) 2 , N(R 16 )C(O)R 15 , N(R 16 )SO 2 R 15 , N(R 16 )C(O)N(R 14 ) 2 , N(R 16 )SO 2 N(R 14 ) 2 , N(R 14 ) 2 , P(O)(R 15 ) 2 , C.H. 2 C(O)R 15 , C.H. 2 C(O)N(R 14 ) 2 , C.H. 2 SO 2 R 15 , C.H. 2 SO 2 N(R 14 ) 2 , C.H. 2 N(R 16 )C(O)R 15 , C.H. 2 N(R 16 )SO 2 R 15 , C.H. 2 N(R 16 )C(O)N(R 14 ) 2 , C.H. 2 N(R 16 )SO 2 N(R 14 ) 2 , and C.H. 2 N(R 14 ) 2 and R 18 11. The compound of claim 10, wherein is absent, wherein said alkyl, said alkenyl, said alkynyl, said cycloalkyl, said heterocycloalkyl, or said heteroaryl is optionally further substituted.

12. R 1 The compound according to claim 1, wherein is a group of the formula 【Chemistry 13】 Where: X 14 is selected from C and N; X 15 , X 16 , X 17 and X 18 are independently O, N, S and CR 17 Selected from: where R 17 is H, OH, a halogen atom, 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 2 R 15 , SO 2 N(R 14 ) 2 , N(R 16 )C(O)R 15 , N(R 16 )SO 2 R 15 , N(R 16 )C(O)N(R 14 ) 2 , N(R 16 )SO 2 N(R 14 ) 2 , N(R 14 ) 2 , P(O)(R 15 ) 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, wherein said alkyl, said alkenyl, said alkynyl, said cycloalkyl, said heterocycloalkyl, or said heteroaryl may be further substituted; where X 14 , X 15 , X 16 , X 17 and X 18 At least one and not more than three of is O, N or S, and two double bonds are present in the ring to ensure aromaticity is maintained.

13. R 1 The compound of claim 1, wherein is selected from the following: 【Chemistry 14】 Where: R 14 is independently at each occurrence selected from 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 together with their adjacent nitrogen atom form a C 4-10 heterocycloalkyl group, wherein said alkyl, said alkenyl, said alkynyl, said cycloalkyl, said heterocycloalkyl, or said heteroaryl may be further substituted; R 15 is independently at each occurrence selected from 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 said alkyl, said alkenyl, said alkynyl, said cycloalkyl, said heterocycloalkyl, or said heteroaryl may be further substituted; and and (---) represents a bond.

14. The compound according to claim 1, wherein the compound is a compound of formula II: 【Chemistry 16】 Here, R 1 is as defined in claim 1; 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; 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; 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; 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 is not a benzoxazolinone; wherein when R 4 is H or F, then at least one of R 5 or R 6 is other than H or F; and wherein when R 5 is CN, then at least one of R 4 or R 6 is other than H.

15. The compound according to claim 14, wherein the compound is of formula IV: 【Chemistry 17】 Where X 6 is N or CH; and X 7 is N and R 18 is absent; or X 7 is C and R 18 is 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 2 R 15 , SO 2 N(R 14 ) 2 , N(R 16 )C(O)R 15 , N(R 16 )SO 2 R 15 , N(R 16 )C(O)N(R 14 ) 2 , N(R 16 )SO 2 N(R 14 ) 2 , N(R 14 ) 2 , P(O)(R 15 ) 2 , CH 2 C(O)R 15 , CH 2 C(O)N(R 14 ) 2 , CH 2 SO 2 R 15 , CH 2 SO 2 N(R 14 ) 2 , CH 2 N(R 16 )C(O)R 15 , CH 2 N(R 16 )SO 2 R 15 , CH 2 N(R 16 )C(O)N(R 14 ) 2, CH2N(R16)SO2N(R14)2, and CH2N(R14)2; R 4 is selected from Cl, and substituted or unsubstituted C 1-3 alkyl; R 5 is selected from H, F, Cl, and substituted or unsubstituted C 1-3 alkyl; R 6 is selected from H, F, Cl, substituted or unsubstituted C 1-3 alkyl, and substituted or unsubstituted OC 1-3 alkyl; 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 is not a benzoxazolinone; wherein when R 4 is H or F, then R 5 or R 6 is other than H or F; and wherein when R 5 is CN, then R 4 or R 6 is other than H. R 17 is H, OH, a halogen atom, 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 2 R 15 , SO 2 N(R 14 ) 2 , N(R 16 )C(O)R 15 , N(R 16 )SO 2 R 15 , N(R 16 )C(O)N(R 14 ) 2 , N(R 16 )SO 2 N(R 14 ) 2 , N(R 14 ) 2 , P(O)(R 15 ) 2 , CH 2 C(O)R 15 , CH 2 C(O)N(R 14 ) 2 , CH 2 SO 2 R 15 , CH 2 SO 2 N(R 14 ) 2 , CH 2 N(R 16 )C(O)R 15 , CH 2 N(R 16 )SO 2 R 15 , CH 2 N(R 16 )C(O)N(R 14)2, CH2N(R16)SO2N(R14)2, and CH2N(R14)2; Where: R 14 is independently at each occurrence selected from 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 together with their adjacent nitrogen atom form a C 4-10 heterocycloalkyl group, wherein said alkyl, said alkenyl, said alkynyl, said cycloalkyl, said heterocycloalkyl, or said heteroaryl may be further substituted; R 15 is independently at each occurrence selected from 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 said alkyl, said alkenyl, said alkynyl, said cycloalkyl, said heterocycloalkyl, or said heteroaryl may be further substituted; and R 16 is independently at each occurrence 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 said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, or heteroaryl may be further substituted.

16. The compound according to claim 14, wherein the compound is a compound of formula V: 【Chemistry 18】 Here, R 4 , R 5 and R 6 is as defined in claim 14, X 14 is selected from C and N; X 15 , X 16 , X 17 and X 18 are independently selected from O, N, S and CR 17 ; wherein at least one and not more than three of X 14 , X 15 , X 16 , X 17 and X 18 are O, N or S, and two double bonds are present in the ring to maintain aromaticity; where R 17 is H, OH, a halogen atom, 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 2 R 15 , SO 2 N(R 14 ) 2 , N(R 16 )C(O)R 15 , N(R 16 )SO 2 R 15 , N(R 16 )C(O)N(R 14 ) 2 , N(R 16 )SO 2 N(R 14 ) 2 , N(R 14 ) 2 , P(O)(R 15 ) 2 , CH 2 C(O)R 15 , CH 2 C(O)N(R 14 ) 2 , CH 2 SO 2 R 15 , CH 2 SO 2 N(R 14 ) 2 , CH 2 N(R 16 )C(O)R 15 , CH 2 N(R 16 )SO 2 R 15 , CH 2 N(R 16 )C(O)N(R14)2, CH2N(R16)SO2N(R14)2, and CH2N(R14)2; Where: R 14 is independently at each occurrence selected from 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 together with their adjacent nitrogen atom form a C 4-10 heterocycloalkyl group, wherein said alkyl, said alkenyl, said alkynyl, said cycloalkyl, said heterocycloalkyl, or said heteroaryl may be further substituted; R 15 is independently at each occurrence selected from 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 said alkyl, said alkenyl, said alkynyl, said cycloalkyl, said heterocycloalkyl, or said heteroaryl may be further substituted; and R 16 is independently at each occurrence 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 said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, or heteroaryl may be further substituted.

17. The compound according to claim 1, wherein the compound is a compound of formula III: 【Chemistry 19】 Here, R 1 is as defined in claim 1; 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; X 5 is selected from NH, NC 1-3 alkyl, NC 3-4 cycloalkyl, O and S.

18. The compound according to claim 17, wherein the compound is a compound of formula VI: 【Chemistry 20】 Here, R 9 , R 10 , R 12 , and X 5 are each as defined in claim 17; R 17 is H, OH, a halogen atom, 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 2 R 15 , SO 2 N(R 14 ) 2 , N(R 16 )C(O)R 15 , N(R 16 )SO 2 R 15 , N(R 16 )C(O)N(R 14 ) 2 , N(R 16 )SO 2 N(R 14 ) 2 , N(R 14 ) 2 , P(O)(R 15 ) 2 , CH 2 C(O)R 15 , CH 2 C(O)N(R 14 ) 2 , CH 2 SO 2 R 15 , CH 2 SO 2 N(R 14 ) 2 , CH 2 N(R 16 )C(O)R 15 , CH 2 N(R 16 )SO 2 R 15 , CH 2 N(R 16 )C(O)N(R 14)2, CH2N(R16)SO2N(R14)2, and CH2N(R14)2; X 6 is N or CH; and X 7 is N and R 18 is absent; or X 7 is C and R 18 is 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 2 R 15 , SO 2 N(R 14 ) 2 , N(R 16 )C(O)R 15 , N(R 16 )SO 2 R 15 , N(R 16 )C(O)N(R 14 ) 2 , N(R 16 )SO 2 N(R 14 ) 2 , N(R 14 ) 2 , P(O)(R 15 ) 2 , CH 2 C(O)R 15 , CH 2 C(O)N(R 14 ) 2 , CH 2 SO 2 R 15 , CH 2 SO 2 N(R 14 ) 2 , CH 2 N(R 16 )C(O)R 15 , CH 2 N(R 16 )SO 2 R 15 , CH 2 N(R 16 )C(O)N(R 14 ) 2, CH2N(R16)SO2N(R14)2, and CH2N(R14)2; Where: R 14 is independently at each occurrence selected from 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 together with their adjacent nitrogen atom form a C 4-10 heterocycloalkyl group, wherein said alkyl, said alkenyl, said alkynyl, said cycloalkyl, said heterocycloalkyl, or said heteroaryl may be further substituted; R 15 is independently at each occurrence selected from 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 said alkyl, said alkenyl, said alkynyl, said cycloalkyl, said heterocycloalkyl, or said heteroaryl may be further substituted; and R 16 is independently at each occurrence 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 said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, or heteroaryl may be further substituted.

19. The compound according to claim 17, wherein the compound is of formula VII: 【Chemistry 21】 Here, R 9 , R 10 , R 12 and X 5 are each as defined in claim 17; X 14 is selected from C and N; X 15 , X 16 , X 17 and X 18 are independently selected from O, N, S and CR 17 ; wherein at least one and not more than three of X 14 , X 15 , X 16 , X 17 and X 18 are O, N or S, and two double bonds are present in the ring to maintain aromaticity; where R 17 is H, OH, a halogen atom, 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 2 R 15 , SO 2 N(R 14 ) 2 , N(R 16 )C(O)R 15 , N(R 16 )SO 2 R 15 , N(R 16 )C(O)N(R 14 ) 2 , N(R 16 )SO 2 N(R 14 ) 2 , N(R 14 ) 2 , P(O)(R 15 ) 2 , CH 2 C(O)R 15 , CH 2 C(O)N(R 14 ) 2 , CH 2 SO 2 R 15 , CH 2 SO 2 N(R 14 ) 2 , CH 2 N(R 16 )C(O)R 15 , CH 2 N(R 16 )SO 2 R 15 , CH 2 N(R 16 )C(O)N(R14)2, CH2N(R16)SO2N(R14)2, and CH2N(R14)2; Where: R 14 is independently at each occurrence selected from 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 together with their adjacent nitrogen atom form a C 4-10 heterocycloalkyl group, wherein said alkyl, said alkenyl, said alkynyl, said cycloalkyl, said heterocycloalkyl, or said heteroaryl may be further substituted; R 15 is independently at each occurrence selected from 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 said alkyl, said alkenyl, said alkynyl, said cycloalkyl, said heterocycloalkyl, or said heteroaryl may be further substituted; and R 16 is independently at each occurrence 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 said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, or heteroaryl may be further substituted.

20. 2. The compound according to claim 1, wherein the compound is selected from the compounds in the table below, or a salt thereof and / or a solvate thereof. 【Chemical 22】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】

21. 2. The compound according to claim 1, wherein the compound is selected from the following: or a salt thereof and / or a solvate thereof. 【Chemistry 23】 【change】 【change】

22. 2. The compound according to claim 1, wherein the compound is selected from the following: or a salt thereof and / or a solvate thereof. 【Chemistry 24】 【change】 【change】

23. A pharmaceutical composition comprising a compound according to any one of claims 1 to 22, together with a pharma- ceutically acceptable carrier, diluent or excipient.

24. A compound according to any one of claims 1 to 22 for the treatment of a disease or disorder selected from a proliferative disease or disorder, developmental disorders caused by dysregulation of the RAS-ERK signalling cascade (RASopathies), or an inflammatory disease or immune system disorder.

25. The compound of claim 24, wherein the disease or disorder is associated with a RAF gene mutation or a RAS gene mutation.

26. 26. The compound of claim 25, wherein the disease 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 lymphocytic leukemia, acute myeloid leukemia, non-Hodgkin's lymphoma, and hairy cell leukemia.

27. ​​A drug for use in treating a disease or disorder comprising a compound according to any one of claims 1 to 22, wherein the disease or disorder is selected from a proliferative disease or disorder, a developmental disorder caused by dysregulation of the RAS-ERK signaling cascade (RASopathies), or an inflammatory disease or immune system disorder.

28. The agent described in claim 27, wherein the disease or disorder is associated with a RAF gene mutation or a RAS gene mutation.

29. The agent described in claim 28, wherein the disease 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 lymphocytic leukemia, acute myeloid leukemia, non-Hodgkin's lymphoma, and hairy cell leukemia.

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