PYRIDO[3,2-d]PYRIMIDINE COMPOUNDS, COMPOSITIONS COMPRISING THEM AND USES THEREOF

Abstract

Compounds, compositions, and their use in the treatment of proliferative disorders or conditions, such as those associated with RAF gene mutations and / or RAS gene mutations. The disclosed compounds have Formula I or a pharmaceutically acceptable salt or solvate thereof, wherein R1, R2, R3, X1, X2, X3, and X4 are defined as follows:

Description

[Technical Field] Related applications

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

[0002] This disclosure generally relates to pyrido[3,2-d]pyrimidine compounds, pharmaceutical compositions comprising the same, and their use in the treatment and prevention of diseases characterized as RAS-ERK pathway disorders (e.g., cancer, RAS disease). [Previous Technology]

[0003] The RAS-RAF-MEK-ERK (RAS: rat sarcoma; RAF: rapidly accelerating fibrosarcoma; MEK: mitogen-activated protein kinase; ERK: extracellular signal-regulated kinase) signaling pathway (hereinafter referred to as the RAS-ERK pathway) plays a crucial role in transmitting proliferation signals generated by growth factor receptors from the plasma membrane to the nucleus. This pathway is dysregulated in most cancers due to activation of receptor tyrosine kinases (RTKs) (e.g., ERBB1, ERBB2, FLT3, RET, KIT), activation or inactivation of RAS regulators (SOS1 and NF1), and persistent activating mutations in RAS genes (HRAS, KRAS, and NRAS; totaling 30% of cancers) and BRAF genes (8% of cancers). The prevalence of KRAS mutations is particularly high in pancreatic cancer (>90%), colorectal cancer (50%), and lung cancer (30%). In particular, BRAF mutations are found at extremely high frequencies in malignant melanoma (70%), thyroid cancer (40%), and colorectal cancer (10%) (mutation frequencies are based on the 95th edition of the Catalogue of Somatic Mutations in Cancer (COSMIC; Wellcome Trust Sanger Institute) published on November 24, 2021).

[0004] RAS proteins are small GTPases that transmit extracellular growth signals to effectors to control life processes such as cell differentiation, proliferation, and survival (Nat. Rev. Cancer 2003, 3, 459). Physiological activation of RAS occurs at the plasma membrane following PTK stimulation, leading to GTP loading of the GTPase and thus RAS activation. Activated RAS interacts with and activates a series of effector molecules, among which RAF kinase is the most critical RAS interactor in cancer development (Nature Rev. Drug Discov. 2014, 13, 828). Oncogenic mutations in glycine 12, glycine 13, or glutamic acid 61 in RAS isotypes result in aberrant and persistent signal transduction in human cancers (Nat. Rev. Cancer 2003, 3, 459) (COSMIC 95th edition, November 24, 2021).

[0005] Downstream of RAS, mammalian cells exhibit three RAF homologs (ARAF, BRAF, and CRAF), which share a conserved C-terminal kinase domain (KD) (Nat. Rev. Mol. Cell Biol. 2015, 16, 281) and an N-terminal regulatory domain (NTR) containing a RAS-binding domain (RBD). In unstimulated cells, RAF proteins are chelated in the cytoplasm as monomers. GTP-activated RAS binding to the RBD induces membrane anchoring of the RAF kinase (Nat. Rev. Mol. Cell Biol. 2015, 16, 281). Simultaneously, RAF proteins undergo kinase domain-side dimerization and catalytic activation (Nature 2009, 461, 542). Activated RAF protein transmits signals from RAF to MEK via a phosphorylation cascade and then from MEK to ERK, causing ERK to phosphorylate a series of receptors, thereby triggering a cell-specific response (Nat. Rev. Mol. Cell Biol. Oct 2020; 21(10), 607).

[0006] To date, mutations in the activating RAF allotype have been primarily limited to the BRAF gene, although rare variants have been observed in ARAF and CRAF, highlighting the functional importance of this allotype (COSMIC 95th edition, November 24, 2021). The most common cancer mutation in BRAF is the valine-substituted glutamate at position 600 (called BRAFV600E), which enhances BRAF activity by stabilizing its active form (Cell 2004, 116, 855). In addition to the V600E counterpart, a series of mutations occur at other residues (e.g., G466V, D594G, etc.), which lead to increased RAF signaling through various mechanisms (Nat. Rev. Mol. Cell Biol. 2015, 16, 281). These mutations have been categorized into three main classes (1 to 3) based on their dependence on RAS activity and RAF dimerization (Nature, August 10, 2017, 548(7666), 234-238). The crucial roles of wild-type BRAF and CRAF in mediating RAS-driven tumorigenesis through stimulation of ERK signaling have been extensively validated (Cancer Cell 2011, 19, 652; Cancer Discov. 2012, 2, 685; Nat. Commun. 2017, 8, 15262). Therefore, tumor cells depend on elevated and sustained signaling via the RAS-ERK pathway activated by RAS and RAF, providing strong support for the concept of targeting RAF family kinases in cancer.

[0007] To meet existing medical needs, a broad range of ATP-competitive RAF inhibitors have been developed over the past decade (Nat. Rev. Cancer 2017, 17, 676). Efforts have primarily focused on the most common RAS-independent BRAF mutation (BRAFV600E), leading to the development and FDA approval of sulfonamide derivatives such as vemurafenib and dabrafenib. Some of these RAF inhibitors have demonstrated impressive efficacy against metastatic melanoma carrying recurrent BRAFV600E pairs and have been approved for the treatment of this patient population (N. Engl. J. Med. 2011, 364, 2507; Lancet 2012, 380, 358). Clinical responses to BRAFV600E-dependent melanoma are induced by 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 always occurs, primarily due to reactivation of the RAS-ERK pathway, partly through mechanisms stimulating RAF dimerization. This includes upregulation of RTK signaling, RAS mutations, and BRAFV600E amplification or truncation (Sci. Signal. 2010, 3, ra84; Nature 2010, 468, 973; Nature 2011, 480, 387; Nature Commun. 2012, 3, 724).

[0008] Meanwhile, tumors exhibiting RAS activity (due to activated RAS mutations or elevated RTK signaling, but otherwise wild-type BRAF) show major resistance to BRAFV600E inhibitors (Nature 2010, 464, 431). Conversely, RAF inhibitors have been found to induce ERK signaling under conditions of elevated RAS activity, and thus enhance cell proliferation (Nature 2010, 464, 431). This counterintuitive phenomenon, termed the paradoxical effect, has also been observed in normal tissues dependent on physiological RAS activity and forms the basis for some of the adverse effects seen in melanoma patients using RAF inhibitors (such as the development of new secondary tumors, e.g., squamous cell carcinoma and keratoacanthoma) (Nat. Rev. Cancer 2014, 14, 455). Therefore, BRAFV600E is ineffective and even contraindicated in RAS-driven cancers. The underlying mechanism arises from the compound's ability to promote the dimerization of the RAF kinase domain in the presence of active RAS (Nature 2010, 464, 431). This event is not limited to BRAF, but also involves other RAF family members and is determined by the compound's binding mode and affinity (Nat. Chem. Biol. 2013, 9, 428).

[0009] Recently, two strategies have been implemented to circumvent the limitations of first-generation RAF inhibitors in RAS-mutant cancers. The first strategy relies on the observation that anomalous ERK activation is a dose-dependent phenomenon, i.e., induction occurs at subsaturated inhibitor concentrations, but this pathway is inhibited at saturated concentrations when the compound occupies two units of the RAF dimer. Therefore, this first strategy focuses on developing molecules with higher binding affinity to all RAF homologs in order to saturate RAF proteins at lower drug concentrations, thereby reducing anomalous pathway induction (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 retain a strong ability to induce RAF dimers and therefore anomalously stimulate RAS-ERK signaling, although to a lesser extent than previous generations of RAF inhibitors. Although these compounds exhibit improved properties, recent studies have shown that most of them lack ARAF isoforms, leading to anomalous pathway activation and primary resistance, as well as acquired resistance in in vitro and clinical settings (Clin Cancer Res. 2021, 27, 2061; Nature 2021, 594, 418). A second strategy involves designing compounds that are conformably biased towards the BRAF kinase domain in the inactivated state and therefore do not anomalously induce ERK signaling. This resulted in the "paradox breaker" (PB) molecule PLX8394, a derivative of PLX4032 / vemurafenib (Nature 2015, 526, 583). These molecules retain high potency against BRAF V600E and should therefore be demonstrated as suitable for the treatment of BRAF V600E-dependent melanoma. However, although PLX8394 does not induce ERK signaling in the tested RAS mutant cell lines, it remains ineffective and unsuitable for RAS mutant tumors.

[0010] There remains a need for inhibitors that can effectively and sustainably block RAS-ERK signaling and intracellular proliferation in human tumor cells carrying multiple RAS and RAF genotypes. Importantly, it would be highly desirable to develop such inhibitors that are not induced by anomalous pathways in multiple RAS-mutant tumor cell lines. [Summary of the Invention]

[0011] Based on a sample, this technique relates to a compound I:

[0011]

[0011] Among them:

[0011] R1 is selected from substituted or unsubstituted OR3, SR3, NH2, NHR3, N(R3)2, C3-8 cycloalkyl, C4-8 heterocycloalkyl, C6-10 aryl and C5-10 heteroaryl, for example selected from substituted or unsubstituted C6-10 aryl and C5-10 heteroaryl;

[0011] R2 is selected from substituted C6 aryl or C5-10 heteroaryl, substituted or unsubstituted C4-8 heterocyclic alkyl and N(R3)2;

[0011] R3 is independently selected each time it appears from substituted or unsubstituted C1-8 alkyl, C3-8 cycloalkyl, C4-8 heterocycloalkyl, C6-10 aryl and C5-10 heteroaryl;

[0011] X1 is a halogen group or an electron-withdrawing group;

[0011] X2 is selected from H, halogen groups, and electron-withdrawing groups;

[0011] X3 and X4 are each selected from H, halogen groups, electron-withdrawing groups, C1-3 alkyl groups, C3-4 cycloalkyl groups and C1-3 alkyl groups;

[0011] or its pharmaceutically acceptable salts or solvates.

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

[0013] According to another embodiment, the present technology relates to a pharmaceutical composition for use as defined in any of the foregoing embodiments, the composition comprising a compound as defined herein and a pharmaceutically acceptable carrier, diluent or excipient.

[0014] In another embodiment, the present technology relates to the use of compounds as defined herein for the treatment of diseases or conditions selected from: proliferative diseases or conditions, developmental abnormalities caused by RAS-ERK communication cascade disorder (RAS disease), or inflammatory diseases or immune system disorders.

[0015] This technology also relates to methods for treating diseases or conditions selected from: proliferative diseases or conditions, developmental abnormalities caused by RAS-ERK cascade dysregulation (RAS disease), or inflammatory diseases or immune system disorders, the method comprising administering a compound as defined herein to a subject in need. Methods for inhibiting abnormal cell proliferation are also contemplated, the method comprising contacting such cells with a compound as defined herein.

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

[0017] For example, the disease or condition is a lesion, such as those selected from melanoma, thyroid cancer (e.g., papillary thyroid carcinoma), 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 lymphoblastic leukemia, acute myeloid leukemia, non-Hodgkin's lymphoma, and hairy cell leukemia. For example, the lesion is selected from colon cancer or colorectal cancer, lung cancer, pancreatic cancer, thyroid cancer, breast cancer, and melanoma. For example, any of the uses and methods in this study involves inhibiting the RAS-ERK signaling pathway without substantially inducing the anomalous pathway.

[0018] Additional objects and features of this compound, composition, method and use will become more apparent upon reading the non-limiting description in the following illustrative examples and examples section, which should not be construed as limiting the scope of the invention. [Simplified Explanation of the Diagram]

[0019] Figure 1 shows representative IC50 inhibitor response curves for compounds that do not induce anomalous induction (YMIN>-20%) of pERK signaling in RAS mutant HCT116 cells (Examples 99, 113, 128, 139, 140) as described herein, and for compounds (PLX4720; CAS# 918505-84-7) that induce strong induction (YMIN~-600%) of this pathway in the same cell line.

[0020] Figure 2 shows an immunoblotting analysis of RAS mutant HCT-116 cells treated with a representative compound that does not induce pERK or pMEK signaling (Example 99; top), compared with a compound that induces pathways in the same cell line (PLX4720; bottom).

[0021] Figure 3 (A and B) shows the pharmacodynamic analysis results of pERK biomarkers in mice carrying xenograft tumors representing a range 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) compared to the mediator (Vehicle). Mice were orally administered Example 99 at 150 mg / kg (mpk). ERK pathway inhibition was measured using the pERK and total ERK AlphaLISA® SureFire® Ultra™ kit 4 h after oral administration of the Example 99 suspension.

[0022] Figure 4 shows the results of tumor growth inhibition (TGI) experiments conducted in A375(A) and HCT116(B). Each data point represents the mean standard error (SEM) of the average tumor size on a given day before and after treatment; the treatment period corresponds to the arrow marked "Rx". Mice were orally administered the suspension of Example 99 (dose expressed in mg / kg or mpk) or the blank preparation (mediator) once or twice daily (QD or BID). Tumors were measured three times weekly using an electronic micrometer.

Implementation Method

[0023] All technical and scientific terms and expressions used herein have the same definitions as those commonly understood by one of ordinary skill in the art to which this art pertains. Nevertheless, definitions of some terms and expressions are provided below. Where a definition of a term incorporated herein by reference in a disclosure, patent, or patent application contradicts the definition set forth in this specification, the definition herein shall prevail. Section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter disclosed.

[0023] i. Definition

[0024] The chemical structures described herein are drawn according to conventional standards. Furthermore, when the drawn atoms (such as carbon atoms) appear to include incomplete valence states, it is assumed that such valence states are satisfied by one or more hydrogen atoms, even if these hydrogen atoms are not explicitly drawn. Hydrogen atoms should be inferred to be part of the compound.

[0025] 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, unless the context clearly indicates otherwise, the singular forms "a / an" and "the" also include the plural forms. Thus, for example, a reference to a composition containing "a compound" also covers a mixture of two or more compounds. It should also be noted that, unless the context clearly indicates otherwise, the term "or" is generally used in the sense of including "and / or". Furthermore, where the terms "including / includes", "having / has / with", or variations thereof are used in the implementation and / or the claims, such terms are intended to be inclusive in a manner similar to that of the term "comprising".

[0026] The terms "about" or "approximately" mean within an acceptable range of error for a particular value as determined by someone generally skilled in the art, the range of error depending in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, according to practice in this art, "about" may mean a standard deviation within 1 or a standard deviation greater than 1. Alternatively, "about" may mean a range of up to 20%, preferably up to 10%, more preferably up to 5%, and even more preferably up to 1% of a given value. Alternatively, particularly with respect to biological systems or processes, the term may mean within an order of magnitude of a value, preferably within 5 times and more preferably within 2 times. In the case of a particular value described in this application and the claims, unless otherwise specified, the term "about" should be assumed to mean within an acceptable range of error for that particular value.

[0027] As used herein, the terms "compound," "compound described herein," "compound of this application," "pyrido[3,2-d]pyrimidine compound," "pyridopyrimidine compound," and equivalent expressions refer to the compounds described in this application, such as those covered by structural formula I, which may be referred to in any of the applicable examples, and also include exemplary compounds, such as the compounds of Examples 1 to 691, and their pharmaceutically acceptable salts, solvates, esters, and prodrugs (if applicable). Where zwitterionic form is possible, a compound may be drawn in its neutral form for practical purposes, but the compound should be understood to include its zwitterionic form. The examples herein may also exclude one or more compounds. Compounds can be identified by their chemical structure or their chemical name. In the event of a conflict between chemical structure and chemical name, the chemical structure shall prevail.

[0028] Unless otherwise stated, the structures described herein are also intended to include all isomers (e.g., mirror-image isomers, non-mirror-image isomers, and geometric (or configurational) forms of such structures, if applicable); for example, the R and S configurations in various asymmetries. Therefore, single stereochemical isomers of the compounds of the present invention, as well as mixtures of mirror-image isomers, non-mirror-image isomers, and geometric (or configurational) mixtures, are within the scope of this specification. Unless otherwise indicated, therapeutic compounds also encompass all possible tautomers of the described compounds, if present. This term also includes isotopically labeled compounds, wherein one or more atoms have atomic masses different from the most abundant atomic masses found in nature. Examples of isotopes that may be incorporated into the compounds of the present invention include, but are not limited to, any of the isotopes of 2H(D), 3H(T), 11C, 13C, 14C, 15N, 18O, 17O, and sulfur. The compounds may also exist in unsolvable and solvated forms, including hydrated forms. The compounds may exist in various crystalline or amorphous forms. In general, all physical forms are equivalent with respect to the uses covered herein and are intended to be within the scope of this invention.

[0029] When a particular enantiomer is preferred, in some embodiments it may be provided substantially free of the corresponding enantiomer and may also be enantiomer-enriched. "Enantiomer-enriched" means that the compound consists of a significantly larger proportion of one of the enantiomers. In some embodiments, the compound consists of at least about 90% by weight of the preferred enantiomer. In other embodiments, the compound consists of at least about 95%, 98%, or 99% by weight of the preferred enantiomer. The preferred enantiomer may be separated from a racemic mixture by any method known to those skilled in the art, including high-pressure liquid chromatography (HPLC) on a palmite and the formation and crystallization of a palmite salt, or prepared by asymmetric synthesis.

[0030] The term "medically acceptable salt" refers to salts of the compounds of this invention that, within the scope of reasonable medical diagnosis, are suitable for contact with human and lower animal tissues without undue toxicity, irritation, allergic reactions, or similar reactions, and whose benefits / risks are commensurate with a reasonable ratio. Medically acceptable salts are well known in the art. For example, SMBerge et al. described medically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977). Such salts can be prepared in situ during the final separation and purification of the compounds described herein, or by reacting the free basic functional group of the compound with a suitable organic or inorganic acid (acid addition salt) or by reacting the acidic functional group of the compound with a suitable organic or inorganic base (base addition salt).

[0031] The term "solvent" refers to the physical association of a compound of the present invention with one or more solvent molecules, including water molecules and non-aqueous solvent molecules. This physical association may include hydrogen bonding. In some cases, the solvate will be separable, for example when one or more solvent molecules are incorporated into the lattice of a crystalline solid. The term "solvent" encompasses both solution-phase solvates and separable solvates. Exemplary solvates include, but are not limited to, solvates of hydrates, hemihydrates, ethanolates, semi-ethanolates, n-propanolates, isopropanolates, 1-butanolates, 2-butanolates, and other physiologically acceptable solvents, such as the three classes of solvents described in the International Conference on Harmonization (ICH), Guide for Industry, Q3C Impurities: Residual Solvents (1997). Therefore, compounds described herein also include each of their solvates and mixtures thereof.

[0032] As used herein, the term "medically acceptable ester" refers to an ester of a compound formed by the method of the present invention, which is hydrolyzable in vivo and includes esters that readily decompose in the human body to leave a parent compound or its salt. Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanes, alkenes, cycloalkanes, and alkanediacids, wherein each alkyl or alkenyl moiety preferably has no more than 6 carbon atoms. Examples of specific esters include, but are not limited to, formate esters, acetate esters, propionates, butyrate esters, acrylates, and ethyl succinates having hydroxyl groups, and alkyl esters with acidic groups. Other ester groups include sulfonates or sulfate esters.

[0033] As used herein, the term "medically acceptable prodrug" refers to prodrugs of compounds formed by the methods of the present invention that, within a reasonable medical diagnostic scope, are suitable for contact with human and lower animal tissues without undue toxicity, irritation, allergic reactions, or similar reactions, are commensurate with a reasonable benefit / risk ratio, and are effective for their intended use. As used herein, "prodrug" means a compound that can be converted in vivo by metabolic pathways (e.g., by hydrolysis) to provide any compound described by the chemical formula of the present invention.

[0034] Abbreviations may also be used throughout this application, unless otherwise indicated, and are intended to have the meaning commonly understood in the art. Examples of such abbreviations include Me (methyl), Et (ethyl), Pr (propyl), i-Pr (isopropyl), Bu (butyl), t-Bu (tertiary butyl), i-Bu (isobutyl), s-Bu (secondary butyl), c-Bu (cyclobutyl), Ph (phenyl), Bn (benzyl), Bz (benzoyl), CBz or Cbz or Z (benzyl carbonate), Boc or BOC (tertiary butoxycarbonyl), and Su or Suc (butadieneimide). For further clarification, additional definitions of specific abbreviations are also included in the description of the examples section.

[0035] The number of carbon atoms in a hydrocarbon substituent can be indicated by the prefix "Cx-Cy" or "Cx-y", where x is the minimum number of carbon atoms in the substituent and y is the maximum number. However, when the prefix "Cx-Cy" or "Cx-y" is associated with a group (e.g., heterocyclic alkyl, heteroaryl, etc.) that by definition has one or more heteroatoms, then x and y are defined as the minimum and maximum number of atoms in the ring, including carbon atoms and one or more heteroatoms, respectively.

[0036] As used herein, the term "alkyl" refers to a saturated straight-chain or branched hydrocarbon group that typically contains 1 to 20 carbon atoms. For example, "C1-C8 alkyl" contains one to eight carbon atoms. Examples of alkyl groups include, but are not limited to: methyl, ethyl, propyl, isopropyl, n-butyl, tributyl, neopentyl, n-hexyl, heptyl, octyl, and similar alkyl groups.

[0037] As used herein, the term "alkenyl" refers to a straight-chain or branched hydrocarbon group containing one or more double bonds and typically containing 2 to 20 carbon atoms. For example, "C2-8 alkenyl" contains two to eight carbon atoms. Alkenyl groups include, but are not limited to, vinyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, heptenyl, octenyl, and similar alkenyl groups.

[0038] As used herein, the term "alkenyl" refers to a straight-chain or branched hydrocarbon group containing one or more triple bonds and typically containing 2 to 20 carbon atoms. For example, "C2-8 ynyl" contains two to eight carbon atoms. Representative ynyl groups include, but are not limited to, ethynyl, 1-propynyl, 1-butynyl, heptynyl, octyynyl, and similar ynyl groups.

[0039] The terms "cycloalkyl", "alicyclic", "carbocyclic", "carbocyclic group" and equivalent expressions refer to a group having three to fifteen ring members in a monocyclic or polycyclic system containing a saturated or partially unsaturated (non-aromatic) carbocyclic ring, including spirocyclic (sharing one atom), fused (sharing at least one bond), or bridged (sharing two or more bonds) carbocyclic systems. 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, bicyclic [4,3,0]nonyl, norcamphenyl, and similar cycloalkyl groups. The term cycloalkyl includes both unsubstituted and substituted cycloalkyl groups. For example, the term "C3-Cn cycloalkyl" refers to a cycloalkyl group having 3 to the indicated "n" carbon atoms in its ring structure. Unless the number of carbon atoms is otherwise specified, "low-carbon cycloalkyl" as used herein has at least 3 and equal to or less than 8 carbon atoms in its ring structure.

[0040] As used herein, the terms "heterocycle," "heterocyclic alkyl," "heterocyclic group," "heterocyclic group," and "ring of a heterocycle" 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 one or more, preferably one to four, heteroatoms as defined above, in addition to a carbon atom. When used with respect to the ring atom of a heterocycle, the term "nitrogen" includes substituted nitrogen. For example, in a saturated or partially unsaturated ring having 1 to 3 heteroatoms selected from oxygen, sulfur, or nitrogen, nitrogen may be N (as in 3,4-dihydro-2H-pyrrole), NH (as in pyrrolidyl), or NR (as in N-substituted pyrrolidyl). A heterocycle may be attached to its side group at any heteroatom or carbon atom to obtain a chemically stable structure, and any of the ring atoms may be substituted as appropriate. Examples of heterocyclic alkyl groups include, but are not limited to: 1,3-dioxacyclohexyl, pyrrolidinyl, pyrroloneyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, tetrahydrothiazolyl, isotetrahydrothiazolyl, tetrahydrofuranyl, tetrahydropiperanyl, tetrahydrothiaranyl, tetrahydrobisthiopheneyl, tetrahydrothiapheneyl, thiomorpholinyl, thiaoxyl, acrylyl, oxacyclobutyl, thioheterobutyl, homopiperidinyl, oxacyclopropyl, thioheterocyclic Heptyl, oxazonyl, diazonyl, thioazonyl, 1,2,3,6-tetrahydropyridyl, 2-pyrrolinyl, 3-pyrrolinyl, 2H-piperanyl, 4H-piperanyl, dioxane, dithienyl, dithienyl, dihydropiperanyl, dihydrothienyl, dihydrofuranyl, 3-azabicyclo[3,1,0]hexyl, 3-azabicyclo[4,1,0]heptyl, quinazinyl, quininecycloyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl and similar heterocyclic alkyl groups. Heterocyclic groups also include groups fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indololinyl, 3H-indolyl, benzodihydropiperanyl, benzopiperanyl, phenidyl, 2-azabicyclo[2.2.1]heptyl, octahydroindolyl, or tetrahydroquinolinyl, wherein the group or attachment point is on the heterocyclic ring. Heterocyclic groups can be monocyclic or bicyclic. The term "heterocyclic alkyl" refers to an alkyl group substituted with a heterocyclic group, wherein the alkyl and heterocyclic portions are substituted independently as appropriate. The term "C3-n heterocyclic alkyl" refers to a heterocyclic alkyl group having 3 to the indicated "n" atomic number in the ring structure, the atoms including carbon atoms and heteroatoms.

[0041] As used herein, the term "partially unsaturated" means a ring portion that includes at least one double or triple bond between ring atoms but is not an aromatic ring portion. The term "partially unsaturated" is intended to cover rings having multiple unsaturated sites but is not intended to include aryl or heteroaryl portions as defined herein.

[0042] The term "aryl" as used alone or as part of a larger portion of terms such as "aranyl," "aranalkoxy," "aranoxy," or "aranoxyalkyl" refers to an aromatic group having 4n+2 conjugated π (pi) electrons in a monocyclic portion, bicyclic, or tricyclic fused ring system having a total of six to 15 ring members, wherein n is an integer from 1 to 3, wherein at least one ring in the system is aromatic, and wherein each ring in the system contains three to seven ring members. The term "aryl" may be used interchangeably with the term "aryl ring." In some embodiments of the invention, "aryl" refers to an aromatic ring system that may have one or more substituents, including but not limited to phenyl, biphenyl, naphthyl, azulel, anthracene, and similar groups. The terms "aranyl" or "arylalkyl" refer to an alkyl residue attached to an aromatic ring. Examples of aryl groups include, but are not limited to, benzyl, phenethyl, and similar groups. The term "aryl" as used herein also includes groups with an aromatic ring fused to one or more non-aromatic rings, such as dihydroindenyl, indenyl, phthalimino, naphthimidyl, fumoniyl, phenidyl, or tetrahydronaphthyl and similar groups. For example, the term "C6-n aryl" refers to an aryl group having 6 to the indicated "n" atoms in its ring structure.

[0043] The term "heteroaryl" used alone or as part of a larger portion of, for example, "heteroarylalkyl" or "heteroarylalkoxy," refers to an aromatic group having 4n+2 conjugated π (pi) electrons, where n is an integer from 1 to 3 (e.g., having 5 to 18 ring atoms, preferably 5, 6, or 9 ring atoms; sharing 6, 10, or 14 π electrons in the ring array); and having one to five heteroatoms in addition to a carbon atom. The term "heteroatom" includes, but is not limited to, nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternary ammoniation of basic nitrogen. Heteroaryl can be monocyclic or two or more fused rings. As used herein, the term "heteroaryl" also includes groups in which a heteroaryl ring is fused to one or more aryl rings, cycloaliphatic rings, or heterocycles, wherein the group or attachment point is on the heteroaryl ring. Non-limiting examples of heteroaryl include thiopheneyl, furanyl, and furaylyl groups. yl / furyl), pyrroloyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridinyl, darazinyl, pyrimidinyl, pyrazinyl, triazinyl, indoleyl, 3H-indoleyl, isoindoleyl, indoleazinyl, benzothienyl / benzothiophenyl, benzofuranyl, dibenzofuranyl, inzolyl, benzoimidazolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, pyrrolopyridinyl (e.g., pyrrolo[3,2-b]pyridinyl or pyrrolo[3,2-c]pyridinyl), pyrazolo Pyridyl (e.g., pyrazolo[1,5-a]pyridyl), furanpyridyl, purinyl, imidazopyrazinyl (e.g., imidazo[4,5-b]pyrazinyl), quinolyl / quinolinyl, isoquinolyl / isoquinolinyl, quinolinone, isoquinolinone, terazinyl, quinazolinyl, quinoxolinyl, 4H-quinazinyl, naphridyl and pteridinylcarbazoyl, acridineyl, phenidyl, phenazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. Heteroaryl groups can be monocyclic or bicyclic. Heteroaryl groups include, where appropriate, substituted rings. The term "heteroarylalkyl" refers to an alkyl group substituted with a heteroaryl group, wherein the alkyl and heteroaryl portions are independently substituted, where appropriate. Examples include, but are not limited to, pyridylmethyl, pyrimidinylethyl, and similar groups. For instance, the term "C5-n heteroaryl" refers to a heteroaryl group having 5 to the indicated "n" number of atoms in a ring structure, including carbon atoms and heteroatoms.

[0044] As described herein, the compounds of the present invention may contain a "substituted" portion, as appropriate. Generally, the term "substituted," whether preceded by the term "as appropriate" or not, means that one or more hydrogens of the specified portion have been replaced by suitable substituents. Unless otherwise indicated, the "substituted" group may have suitable substituents at each substituted position of the group, and the substituents at each position may be the same or different when more than one position in any given structure is substituted by more than one substituent selected from the specified group. Combinations of substituents contemplated under the present invention are preferably combinations that result in chemically stable or chemically viable compounds. As used herein, the term "chemically stable" means that the compound is not substantially altered when subjected to conditions that allow it to be generated, detected, and, in some embodiments, recovered, purified, and used for one or more of the purposes disclosed herein.

[0045] The term "halogen group" refers to a halogen atom, namely a fluorine, chlorine, bromine or iodine atom, preferably fluorine or chlorine.

[0046] The term "substituted as appropriate" means a group that is substituted or unsubstituted by means of one, two, three or more hydrogen atoms thereof, by means of independent substitution with substituents including but not limited to the following: F, CI, Br, I, OH, CO2H, alkoxy, syloxy, thiosyloxy, NO2, CN, CF3, NH2, NHalkyl, NHalkenyl, NHynyl, NHcycloalkyl, NHaryl, NH heteroaryl, NH heterocyclic, dialkylamino, diarylamino, diheteroarylamino, O-alkyl, O-alkenyl, O-ynyl, O-cycloalkyl, O-aryl, O-heteroaryl, O-haloalkyl, O-heterocyclic, C(O)alkyl, C(O)alkenyl, C(O)ynyl, C(O)cycloalkyl, C(O)aryl, C (O) heteroaryl, C(O) heterocyclic alkyl, CO2 alkyl, CO2 alkenyl, CO2 ynyl, CO2 cycloalkyl, CO2 aryl, CO2 heteroaryl, CO2 heterocyclic alkyl, OC(O) alkyl, OC(O) alkenyl, OC(O) ynyl, OC(O) cycloalkyl, OC(O) aryl, OC(O) heteroaryl, OC(O) heterocyclic alkyl, C(O)NH2, C(O)NH alkyl, C(O)NH alkenyl, C(O)NH ynyl, C(O)NH cycloalkyl, C(O)NH aryl, C(O)NH heteroaryl, C(O)NH heterocyclic alkyl, OCO2 alkyl, OCO2 alkenyl, OCO2 ynyl, OCO2 cycloalkyl, OCO2 aryl, OCO2 heteroaryl, OCO2 heterocyclic alkyl OC(O)NH2, OC(O)NHalkyl, OC(O)NHalkenyl, OC(O)NHkynyl, OC(O)NHcycloalkyl, OC(O)NHaryl, OC(O)NHhearyl, OC(O)NHhecycloalkyl, NHC(O)alkyl, NHC(O)alkenyl, NHC(O)kynyl, NHC(O)cycloalkyl, NHC(O)aryl, NHC(O)hearyl, NHC(O)hearycycloalkyl, NHCO2alkyl, NHCO2alkenyl, NHCO2kynyl, NHCO2cycloalkyl, NHCO2aryl, NHCO2hearyl, NHCO2hearycycloalkyl, NHC(O)NH2, NHC(O)NHalkyl, NHC(O)NHalkenyl, NHC(O)NH Alkenyl, 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 alkenyl, NHC(NH)NH cycloalkyl, NHC(NH)NH aryl, NHC(NH)NH heteroaryl, NHC(NH)NH heterocycloalkyl, NHC(NH) alkyl,NHC(NH)alkenyl, NHC(NH)alkenyl, NHC(NH)cycloalkyl, NHC(NH)aryl, NHC(NH)heteroaryl, NHC(NH)heterocycloalkyl, C(NH)NHalkyl, C(NH)NHalkenyl, C(NH)NHkynyl, C(NH)NHcycloalkyl, C(NH)NHaryl, C(NH)NHheteroaryl, C(NH)NHheterocycloalkyl, P(O)(alkyl)2, P(O)(alkenyl)2, P(O)(kynyl) S(O)alkyl, P(O)alkyl, P(O)aryl, P(O)heteroaryl, P(O)heterocyclic alkyl, P(O)alkyl, P(O)OH, P(O)alkenyl, P(O)ynyl, P(O)cycloalkyl, P(O)aryl, P(O)heteroaryl, P(O)alkyl, S(O)alkyl, S(O)alkenyl, S(O)ynyl, S(O) Cycloalkyl, S(O)aryl, S(O)2alkyl, S(O)2alkenyl, S(O)2ynyl, S(O)2cycloalkyl, S(O)2aryl, S(O)heteroaryl, S(O)heterocyclicalkyl, SO2NH2, SO2NHalkyl, SO2NHalkenyl, SO2NHynyl, SO2NHcycloalkyl, SO2NHaryl, SO2NHheteroaryl, SO2NHheterocyclicalkyl, NHSO2alkyl, NHSO2alkenyl, NHSO2ynyl, NHSO 2-Cycloalkyl, NHSO2aryl, NHSO2heteroaryl, NHSO2heterocyclic alkyl, CH2NH2, CH2SO2CH3, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclic alkyl, cycloalkyl, carbocyclic, heterocyclic, polyalkoxyalkyl, polyalkoxy, methoxymethoxy, methoxyethoxy, SH, S-alkyl, S-alkenyl, S-alkynyl, S-cycloalkyl, S-aryl, S-heteroaryl, S-heterocyclic alkyl or methylthiomethyl.

[0046] ii. Compound

[0047] The description of the list of chemical groups in any definition of a variable herein includes the definition of the variable as any single group or combination of the listed groups. The description of embodiments of a variable herein includes embodiments as any single embodiment or in combination with any other embodiment or part thereof. The description of embodiments herein includes embodiments as any single embodiment or in combination with any other embodiment or part thereof. Therefore, the following embodiments are presented individually or in combination, where applicable.

[0048] The compounds of the present invention exhibit a pyrido[3,2-d]pyrimidine core structure with defined substituents attached thereto to achieve the advantageous activity of the product. Examples of pyridopyrimidine compounds as defined herein are shown by general formula I:

[0048]

[0048] Among them:

[0048] R1 is selected from substituted or unsubstituted OR3, SR3, NH2, NHR3, N(R3)2, C3-8 cycloalkyl, C4-8 heterocycloalkyl, C6-10 aryl and C5-10 heteroaryl, for example selected from substituted or unsubstituted C6-10 aryl and C5-10 heteroaryl;

[0048] R2 is selected from substituted C6 aryl or C5-10 heteroaryl, substituted or unsubstituted C4-8 heterocyclic alkyl and N(R3)2;

[0048] R3 is independently selected each time it appears from substituted or unsubstituted C1-8 alkyl, C3-8 cycloalkyl, C4-8 heterocycloalkyl, C6-10 aryl and C5-10 heteroaryl, preferably R3 is substituted or unsubstituted C1-8 alkyl (e.g. C1-3 alkyl);

[0048] X1 is a halogen group or an electron-withdrawing group;

[0048] X2 is selected from H, halogen groups, and electron-withdrawing groups;

[0048] X3 and X4 are each selected from H, halogen groups, electron-withdrawing groups, C1-3 alkyl groups, C3-4 cycloalkyl groups and C1-3 alkyl groups;

[0048] or its pharmaceutically acceptable salts or solvates.

[0049] For example, the electron-withdrawing group is selected from perhaloalkyl (e.g., CF3 or CCl3), CN, NO2, sulfonate, alkylsulfonyl (e.g., SO2Me or SO2CF3), alkyl carbonyl (e.g., C(O)Me), carboxylic acid ester, alkoxy carbonyl (e.g., C(O)OMe), and amino carbonyl (e.g., C(O)NH2). In one embodiment, X1 is Cl and X2 is F, or X1 is F and X2 is H, or both X1 and X2 are F. In another embodiment, X3 and X4 are each H. In yet another embodiment, X3 is F and X4 is H.

[0050] For example, the aminoarylsulfonamide portion in Formula I is specified as L and is preferably selected from:

[0050]

[0050] The dashed line (---) indicates a one-click operation.

[0051] In one example, R2 is a substituted C6 aryl or C5-10 heteroaryl, for example, R2 is a C6 aryl substituted with at least one group selected from: F, Cl, Br, CN, NO2, and substituted or unsubstituted C1-3 alkyl, C3-4 cycloalkyl, or OC1-3 alkyl. For example, R2 is a group having the following formula:

[0051]

[0051] Among them:

[0051] R4 is selected from H, F, Cl, Br, CN and substituted or unsubstituted C1-3 alkyl, C3-4 cycloalkyl or OC1-3 alkyl, for example R4 is selected from H, F, Cl, Br, Me, Et, CN, CHF2 and CF3;

[0051] R5 is selected from H, F, Cl, CN and substituted or unsubstituted C1-3 alkyl, C3-4 cycloalkyl or OC1-3 alkyl, for example R5 is selected from H, F, Me, CF3, CN and Cl;

[0051] R6 is selected from H, F, Cl, Br, NO2, NH2 and substituted or unsubstituted C1-3 alkyl, C3-4 cycloalkyl or OC1-3 alkyl, for example R6 is selected from H, F, Cl, Br and substituted or unsubstituted C1-3 alkyl, C3-4 cycloalkyl or OC1-3 alkyl, or R6 is selected from H, F, Cl, Me, Et and OMe;

[0051] R7 is selected from H, F, Cl and substituted or unsubstituted C1-3 alkyl groups, for example, R7 is selected from H, Me, F and Cl;

[0051] R8 is selected from H, F and substituted or unsubstituted C1-3 alkyl groups, for example, R8 is selected from H, Me and F;

[0051] R4 and R5 or R5 and R6 together with their adjacent carbon atoms form a substituted or unsubstituted carbon ring or heterocycle, provided that the heterocycle (R2) is not a benzoxazolinone; and

[0051] (---) indicates one key;

[0051] Where R4 is H or F, then at least one of R5, R6, R7, or R8 is not H or F; and

[0051] Where R5 is CN, then at least one of R4, R6, R7 or R8 is not H.

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

[0053] In another embodiment, R4 is selected from Cl, Br and Me, R5 is selected from H, F, Cl or methyl, R6 is selected from H, F, Cl, Me and OMe, and R7 and R8 are each H.

[0054] In another embodiment, R4 is selected from Cl and substituted or unsubstituted C1-3 alkyl groups (e.g., Me), preferably R4 is Cl or Me; R5 is selected from H, F, Cl and substituted or unsubstituted C1-3 alkyl groups (e.g., Me), preferably R5 is F, Cl or Me; R6 is selected from H, F, Cl, substituted or unsubstituted C1-3 alkyl groups (e.g., Me) and substituted or unsubstituted OC1-3 alkyl groups (e.g., OCH3), preferably R6 is H or F, or R6 is Cl or substituted or unsubstituted C1-3 alkyl groups or substituted or unsubstituted OC1-3 alkyl groups, or CH3 or OCH3; and R7 and R8 are each H. In yet another embodiment, R6 is a substituted C1-3 alkyl group.

[0055] In another example, R2 is a substituted C5-10 heteroaryl group, such as a group having the following formula:

[0055]

[0055] Among them:

[0055] X5 is selected from NH, NC1-3 alkyl, NC3-4 cycloalkyl, O and S;

[0055] R9, R10, and R11 are each independently selected from H, F, Cl, CN, and substituted or unsubstituted C1-3 alkyl, C3-4 cycloalkyl, C(O)OC1-3 alkyl, or OC1-3 alkyl, provided that one of R9 and R11 is H and the other is not H; and

[0055] (---) indicates one key.

[0056] Alternatively, R2 is a group having the following formula:

[0056]

[0056] Among them:

[0056] X5 is selected from NH, NC1-3 alkyl, NC3-4 cycloalkyl, O and S;

[0056] R9 is selected from F, Cl, CN and substituted or unsubstituted C1-3 alkyl, C3-4 cycloalkyl, C(O)OC1-3 alkyl or OC1-3 alkyl;

[0056] R10 and R12 are each independently selected from H, F, Cl, CN, and substituted or unsubstituted C1-3 alkyl, C3-4 cycloalkyl, C(O)OC1-3 alkyl, or OC1-3 alkyl; and

[0056] (---) indicates one key.

[0057] In a preferred embodiment, R9 and R10 are each independently selected from F, C1, CN, and substituted or unsubstituted C1-3 alkyl, C3-4 cycloalkyl, C(O)OC1-3 alkyl, or OC1-3 alkyl, preferably C1 and substituted or unsubstituted C1-3 alkyl, and more preferably, both R9 and R10 are C1. In another embodiment, X5 is O or S, preferably S.

[0058] In another embodiment, R2 is a substituted C5-10 heteroaryl group, such as a group having the following formula:

[0058]

[0058] Among them:

[0058] X9, X10, X11, X12, and X13 are independently selected from N and C, wherein at least one and at most two of X9, X10, X11, X12, and X13 are N; and

[0058] R19, R20, R21, R22 and R23 are selected from H, F, Cl, Br, CN, NO2, NH2 and substituted or unsubstituted C1-3 alkyl, C3-4 cycloalkyl or OC1-3 alkyl, or are not present when the X9, X10, X11, X12 or X13 attached to them is N;

[0058] At least one of X9 and X13 is not N; and

[0058] When one of X9 and X13 is N, the other is not N or CH.

[0059] In another example, R2 is a C5-7 heterocyclic alkyl group. For example, R2 is a group having the following formula:

[0059]

[0059] Among them:

[0059] R13 is independently selected from F, Cl and substituted or unsubstituted C1-3 alkyl, C3-4 cycloalkyl or C1-3 alkoxy in each occurrence;

[0059] n is an integer selected from 0 to 8; or

[0059] n is between 2 and 8, and the two R13 atoms together with their adjacent carbon atoms form a C3-4 cycloalkyl group; and

[0059] (---) indicates one key.

[0060] In one embodiment, R13 is in the 3-position. In another embodiment, n is 1 or 2, and R13 is selected from F, Me, OMe, and CH2OMe. For example, R13 is methoxy and n is 1.

[0061] In another embodiment, R2 is N(R3)2, for example, wherein R3 is selected from substituted or unsubstituted C1-8 alkyl or C3-8 cycloalkyl.

[0062] The following are non-restrictive examples of R2:

[0062]

[0062]

[0062] Where (---) represents one key.

[0063] In one embodiment, R2 is a group selected from the following:

[0063]

[0063] Where (---) represents one key.

[0064] In another embodiment, R2 is a group selected from the following:

[0064]

[0064] Where (---) represents one key.

[0065] In another embodiment, the compound of formula I is a compound of formula II, or a pharmaceutically acceptable salt or solvate thereof:

[0065]

[0065] R1, R4, R5 and R6 are each independently as defined herein. Preferably, R4 is selected from Cl, Br and Me, R5 is selected from H, F, Cl and methyl, and R6 is selected from H, F, Cl, Me and Ome.

[0066] In yet another embodiment, the compound of formula I is a compound of formula III, or a pharmaceutically acceptable salt or solvate thereof:

[0066]

[0066] wherein R1, R9, R10, R12 and X5 are each independently defined as herein.

[0067] In one embodiment of a compound of formula I or II, R1 is a substituted or unsubstituted C5-6 heteroaryl group, or a substituted or unsubstituted C9 heteroaryl group. In another embodiment, R1 is a substituted or unsubstituted group selected from the following: thiophene, imidazolyl, pyrazolyl, triazolyl, thiazolyl, pyridinyl, pyrimidinyl, indole, indazole, benzimidazolyl, benzotriazolyl, pyrrolopyridinyl (e.g., pyrrolo[3,2-b]pyridinyl or pyrrolo[3,2-c]pyridinyl), pyrazolopyridinyl (e.g., pyrazolo[1,5-a]pyridinyl), purine, imidazopyrazinyl (e.g., imidazo[4,5-b]pyrazinyl), and quinolyl / quinolinyl.

[0068] Examples of R1 include substituted or unsubstituted groups selected from the following:

[0068]

[0068] Where (---) represents one key.

[0069] For example, R1 is selected from the following substituted or unsubstituted groups:

[0069]

[0069] Where (---) represents one key.

[0070] In one embodiment, R1 is one of the above-mentioned groups, which is further substituted by at least one substituent selected from: OH, halogen, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkyl, C5-10 heteroaryl, C3-10 cycloalkyl, C4-10 heterocycloalkyl, C(O)R15, C(O)N(R14)2, SO2R15, SO2N(R14)2, N(R16)C(O)R15, N(R16)SO2R15, N(R14) 6)C(O)N(R14)2, N(R16)SO2N(R14)2, N(R14)2, P(O)(R15)2, CH2C(O)R15, CH2C(O)N(R14)2, CH2SO2R15, CH2SO2 N(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;

[0070] Among them:

[0070] R14 is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, C4-10 heterocycloalkyl, C6 aryl and C5-10 heteroaryl, or two R14s together with their adjacent nitrogen atom to form a C4-10 heterocycloalkyl;

[0070] R15 is independently selected each time it appears from C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-7 cycloalkyl, C6 aryl, and C5-6 heteroaryl; and

[0070] R16 is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6 aryl and C5-6 heteroaryl in each occurrence;

[0070] This includes the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups in R1 (as defined in R14, R15 and R16) which may be further substituted as appropriate.

[0071] In another embodiment, R1 is a group having the following formula:

[0071]

[0071] Among them:

[0071] R17 is selected from H, OH, halogen, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkyl, C5-10 heteroaryl, C3-10 cycloalkyl, C4-10 heterocycloalkyl, C(O)R15, C(O)N(R14)2, SO2R15, SO2N(R14)2, N(R16)C(O)R15, N(R16)SO2R15, N(R16)C(O)N(R14)2, N( R16)SO2N(R14)2, N(R14)2, P(O)(R15)2, CH2C(O)R15, CH2C(O)N(R14)2, CH2SO2R15, CH2SO2N(R14)2, CH2N(R16)C(O)R15, CH2N(R16)SO2R15, CH2N(R16)C(O)N(R14)2, CH2N(R16)SO2N(R14)2 and CH2N(R14)2;

[0071] X6 is N or CH; and

[0071] X7 is N and R18 does not exist; or

[0071] X7 is C and R18 is selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkyl, C5-10 heteroaryl, C3-10 cycloalkyl, C4-10 heterocycloalkyl, C(O)R15, C(O)N(R14)2, SO2R15, SO2N(R14)2, N(R16)C(O)R15, N(R16)SO2R15, N(R16)C(O)N(R14)2, N(R16)S O2N(R14)2, N(R14)2, P(O)(R15)2, CH2C(O)R15, CH2C(O)N(R14)2, CH2SO2R15, CH2SO2N(R14)2, CH2 N(R16)C(O)R15, CH2N(R16)SO2R15, CH2N(R16)C(O)N(R14)2, CH2N(R16)SO2N(R14)2 and CH2N(R14)2;

[0071] wherein R14, R15 and R16 are as defined above;

[0071] This includes the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, or heteroaryl group in R1 (as defined in R14, R15, R16, R17, and R18) being further substituted, as appropriate; and

[0071] Where (---) represents one key.

[0072] In another embodiment, R1 is a group having the following formula:

[0072]

[0072] Among them:

[0072] X14 is selected from C and N;

[0072] X15, X16, X17 and X18 are independently selected from O, N, S and CR17, wherein R17 is as defined herein;

[0072] wherein at least one and at most three of X14, X15, X16, X17 and X18 are O, N or S and two double bonds are present in the ring to maintain aromaticity.

[0073] In another embodiment, the compound of formula I is a compound of formula IV or V, or a pharmaceutically acceptable salt or solvate thereof:

[0073]

[0073]

[0073] wherein R4, R5, R6, R17, R18, X6, X7, X14, X15, X16, X17 and X18 are each independently as defined herein. Preferably, R4 is selected from Cl, Br and Me, R5 is selected from H, F, Cl and methyl, and R6 is selected from H, F, Cl, Me and OMe.

[0074] In another embodiment, the compound of formula I is a compound of formula VI or VII, or a pharmaceutically acceptable salt or solvate thereof:

[0074] Formula VI

[0074]

[0074] wherein R9, R10, R12, R17, R18, X5, X6, X7, X14, X15, X16, X17 and X18 are each independently as defined herein.

[0075] In one embodiment of the above chemical formula, X6 is N. In another embodiment, X6 is CH.

[0076] In another embodiment, X7 is N, and R17 is selected from H, OH, CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkyl, C5-10 heteroaryl, C3-10 cycloalkyl, C4-10 heterocycloalkyl, C(O)R15, C(O)N(R14)2, SO2R15, SO2N(R14)2, N(R16)C(O) )R15, N(R16)SO2R15, N(R16)C(O)N(R14)2, N(R16)SO2N(R14)2, N(R14)2, P(O)(R1 5)2. CH2C(O)R15, CH2C(O)N(R14)2, CH2SO2R15, CH2SO2N(R14)2, CH2N(R16)C(O)R1 5. CH2N(R16)SO2R15, CH2N(R16)C(O)N(R14)2, CH2N(R16)SO2N(R14)2 and CH2N(R14)2, wherein R18 is absent, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl or heteroaryl group of R14, R15, R16 or R17 is further substituted as appropriate, preferably, R17 is selected from C1-6 alkyl, C5-10 heteroaryl, C4-10 heterocycloalkyl, N(R14)2, N(R16)C(O)R15, N(R16)SO2R15, C(O)N(R14)2 and SO2N(R14)2, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl or heteroaryl group of R14, R15, R16 or R17 is further substituted as appropriate. For example, R17 is selected from H, NH2 and, where appropriate, substituted C5-10 heteroaryl or C4-10 heterocyclic alkyl. Preferably, R17 is, where appropriate, substituted C5-10 heteroaryl or C4-10 heterocyclic alkyl.

[0077] In another embodiment, R17 is a C4-10 heterocyclic alkyl group that is substituted as appropriate, wherein the heterocyclic alkyl group may be monocyclic or bicyclic and includes 1 to 3 heteroatoms, preferably, wherein X7 is N. In a preferred embodiment, the heterocyclic alkyl group is substituted, for example, with at least one group selected from: F, OH, oxy group, CN, C1-4 alkyl and OC1-4 alkyl, wherein the C1-4 alkyl group is further substituted as appropriate (e.g., substituted with F, OH, OC1-3 alkyl, etc.). For example, the heterocyclic alkyl group may be selected from a piperidine group, piperazine group, thiomorpholine group and morpholine group that is substituted as appropriate, or a cyclic structure containing a piperidine, piperazine, thiomorpholine or morpholine ring (bridged or spirocyclic).

[0078] In another embodiment, X7 is C, for example, X7 is C and R18 is selected from C1-6 alkyl, C5-10 heteroaryl, C3-10 cycloalkyl, C4-10 heterocycloalkyl, C(O)R15, C(O)N(R14)2, SO2R15, SO2N(R14)2, N(R16)C(O)R15, N(R16)SO2R15, N(R16)C(O)N(R14)2, N(R16)SO2N(R14)2, N(R14)2, P(O)(R15)2, CH2C(O)R15, CH2C(O)N( R14)2, CH2SO2R15, CH2SO2N(R14)2, CH2N(R16)C(O)R15, CH2N(R16)SO2R15, CH2N(R16)C(O)N(R14)2, CH2N(R16)SO2N(R14)2, and CH2N(R14)2, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, or heteroaryl group of R14, R15, R16, or R18 is further substituted as appropriate. Preferably, R18 is selected from C(O)N(R14)2, SO2R15, and SO2N(R14)2. In one subclass of these embodiments, R17 is selected from H, OH, C1-6 alkyl, N(R14)2, and C5-10 heteroaryl groups substituted as appropriate. For example, R17 is selected from H, NH2 and, where appropriate, substituted C5-10 heteroaryl groups, preferably H or NH2.

[0079] In yet another embodiment, R14 is independently selected each time it appears from H, a C1-6 alkyl group which is substituted, a C3-10 cycloalkyl group which is substituted, a C4-10 heterocycloalkyl group which is substituted, and a C5-6 heteroaryl group which is substituted, or two R14s together with their adjacent nitrogen atoms to form a C4-10 heterocycloalkyl group.

[0080] In another embodiment, R17 is N(R14)2, wherein R14, together with its adjacent nitrogen atom, forms a C4-10 heterocyclic alkyl group, wherein the heterocyclic alkyl group may be monocyclic or bicyclic and includes 1 to 3 heteroatoms, preferably, wherein X7 is N. In a preferred embodiment, the heterocyclic alkyl group is substituted, for example, with at least one group selected from: F, OH, oxy group, CN, C1-4 alkyl, and OC1-4 alkyl, wherein the C1-4 alkyl group is further substituted as appropriate (e.g., substituted with F, OH, OC1-3 alkyl, etc.). For example, the heterocyclic alkyl group may be selected from piperidine, piperazine, thiomorpholine, and morpholine groups as appropriate, or a cyclic structure (bridged or spirocyclic) containing a piperidine, piperazine, thiomorpholine, or morpholine ring.

[0081] In another embodiment, R1 is selected from:

[0081]

[0081] where R14 is as defined in this document and (---) represents a one-key.

[0082] In another instance, R1 is selected from:

[0082]

[0082] where R14 is as defined in this document and (---) represents a one-key.

[0083] In another embodiment, R1 is a substituted or unsubstituted C4-6 heterocyclic alkyl group. In another example, R1 is a C4-5 heterocyclic alkyl group substituted with one or two groups selected from: halogen, OH, C1-6 alkyl, and OC1-6 alkyl. For example, R1 is an N-pyrrolidyl group substituted with one or two groups selected from F and OH, depending on the situation.

[0084] Other subclass examples are also presented in the Examples section, including each of the R1 (A group), R2 (B group), and L group. Examples of combinations are further illustrated below and in Tables 3, 4, and 5. Representative preferred compounds of Examples 1 to 691 are also described herein.

[0085] More specifically, preferred examples of R1 are selected from groups A1 to A514 as defined below:

[0085]

[0085]

[0085]

[0085]

[0085]

[0085]

[0085]

[0085]

[0085]

[0085]

[0085]

[0085]

[0085]

[0085] A453 A454 A456

[0085]

[0085]

[0085] where (---) represents the bond that acts as the attachment point between R1 and the rest of the molecule.

[0086] Preferred examples of R2 are selected from groups B1 to B56 as defined below:

[0086]

[0086]

[0086] Where (---) represents the bond that acts as the attachment point between R2 and the rest of the molecule.

[0087] The following examples depict combinations of R1 (A1 to A514), R2 (B1 to B56) and L (L1 to L3) groups that can be combined to produce compounds of formula I.

[0087] A1-L-B1; A1-L-B2; A1-L-B3; A1-L-B4 to B54; A1-L-B55; A1-L-B56;

[0087] A2-L-B1; A2-L-B2; A2-L-B3; A2-L-B4 to B54; A2-L-B55; A2-L-B56;

[0087] A3-L-B1; A3-L-B2; A3-L-B3; A3-L-B4 to B54; A3-L-B55; A3-L-B56;

[0087] A4 to A512-L-B1; A4 to A512-L-B2; A4 to A512-L-B3; A4 to A512-L-B4 to B54; A4 to A512-L-B55; A4 to A512-L-B56;

[0087] A513-L-B1; A513-L-B2; A513-L-B3; A513-L-B4 to B54; A513-L-B55; A513-L-B56;

[0087] A514-L-B1; A514-L-B2; A514-L-B3; A514-L-B4 to B54; A514-L-B55; A514-L-B56;

[0087] The exemplary compounds as defined herein include the individual compounds covered in Tables 3, 4 and 5 below Examples 1 to 691.

[0088] Examples of preferred compounds are, namely, 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, and 262 from Tables 3, 4, and 5. 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, 40 0, 401, 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, 580-583, 585, 586, 588-590, 592, 596-600, 602, 604, 605, 608-612, 614-617, 619-621, 623, 625-630, 632, 636, 638, 640, 641, 643-652, 654-660, 665 and 667-691, or their salts and / or solvates.

[0089] Examples of 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 from Tables 3, 4 and 5. 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, 592, 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, or their salts and / or solvates.

[0090] More specifically, the compounds may be selected from Examples 20, 84, 99-102, 123, 205, 251, 266, 296-299, 308, 312, 318, 321, 342, 355, 385, 387, 412, 421, 432, 462, 509, 517, 520, 524, 529, 530, 538, 539, 546, 554, from Tables 3, 4, and 5. 556, 560, 562, 568, 571, 572, 578, 580-583, 586, 588, 592, 597, 600, 605, 608, 609, 615, 617, 621, 628, 630, 632, 633, 636, 637, 641, 643, 648, 649, 665, 672-675, 679, 682 and 688, or their salts and / or solvates.

[0091] It should be understood that any of the above-described compounds may be in any amorphous, crystalline, or polymorphic form, including any salt or solvate form, or mixtures thereof. The compounds of the present invention may be further modified by adding various functionalities through any of the synthetic means described herein to enhance selective biological properties. Such modifications are known in the art and include those that increase biopermeability to a given biological system (e.g., blood, lymphatic system, central nervous system), increase oral availability, increase solubility to allow for administration by injection, alter metabolism, and change excretion rates.

[0092] These compounds can be prepared by conventional chemical synthesis, such as those illustrated in the procedures and examples of this disclosure. Other methods for synthesizing compounds of the chemical formula herein will be apparent to those skilled in the art, as will be understood by those skilled in the art. In addition, various synthetic steps can be performed alternately in sequence or order to obtain the desired compounds.

[0092] iii. Methods, uses, ingredients and administration

[0093] As used herein, the term "effective amount" means the amount of a drug or pharmaceutical agent that elicits a biological or medical response, such as that sought by a researcher or clinician, in an organization, system, animal, or human. Furthermore, the term "therapeutic effective amount" means any amount that, compared to a corresponding subject who has not received such an amount, results in the treatment, cure, prevention, or improvement of a disease, condition, or its symptoms, or reduces the rate of progression of a disease or condition. This term also includes amounts that, within its scope, effectively enhance normal physiological function.

[0094] As used herein, the term "treatment / treat / treating" means reversing, alleviating, delaying the onset of, or inhibiting the progression of a disease or condition or one or more of its symptoms as described herein. In some embodiments, treatment may be administered after one or more symptoms have appeared. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to susceptible individuals before the onset of symptoms (e.g., given a history of symptoms and / or given genetic or other susceptibility factors). Treatment may also continue after symptoms have subsided, for example, to prevent or delay their recurrence.

[0095] In one embodiment, the disease or condition to be treated is a proliferative disease or symptom or a kinase-mediated disease or symptom. More specifically, the disease or symptom to be treated includes proliferative diseases or symptom, developmental abnormalities caused by RAS-ERK cascade dysregulation (RAS disease), inflammatory diseases, or immune system disorders.

[0096] According to some examples, the proliferative diseases or conditions to be treated are cysts, inflammatory diseases, or symptom or developmental abnormalities involving persistent activating mutations in the RAS and / or RAF genes (e.g., KRAS and / or ARAF, BRAF, or CRAF mutations). The diseases or conditions may also be further associated with mutations or amplifications of receptor tyrosine kinases (e.g., EGFR, HER2) or mutations in regulators of downstream RAS receptors (e.g., gain-of-function SOS1, loss-of-function NF1). For example, compounds as defined herein are inhibitors of signaling enzymes (e.g., BRAF and CRAF) that not only participate in controlling cell proliferation in tumors carrying RAF mutations (e.g., BRAFV600E), but importantly, also participate in cell proliferation in cancers driven by mutated RAS. Therefore, the compounds of the present invention can, for example, be used to treat diseases associated with the activity of such signaling enzymes and characterized by excessive or abnormal cell proliferation.

[0097] According to one embodiment, the disease or condition is characterized by uncontrolled cell proliferation, i.e., a "proliferative condition" or "proliferative disease". More specifically, such diseases and conditions are related to cells with autonomous growth capacity, i.e., an abnormal pathological state characterized by rapid cell proliferation, which typically forms a prominent mass exhibiting partial or complete lack of structural tissue and functional coordination with normal cells.

[0098] For example, proliferative conditions or diseases are defined as "tumor," "neoplastic condition," "tumor formation," "cancer," and "tumor," and these terms collectively encompass hematopoietic sarcomas (such as lymphomas or leukemias) and solid sarcomas (such as sarcomas or carcinomas), including all types of precancerous and cancerous growth, or carcinogenic processes, metastatic tissues, or malignant transformed cells, tissues, or organs, regardless of histopathological type or stage of invasiveness. Hematopoietic sarcomas are malignant tumors affecting hematopoietic structures (structures associated with blood cell formation) and components of the immune system, including leukemias (associated with white blood cells (leukocytes) and their precursors in the blood and bone marrow) originating from the bone marrow, lymphatic, or erythrocyte lineages, and lymphomas (associated with lymphocytes). Solid sarcomas include sarcomas, which are malignant sarcomas originating from connective tissues such as muscle, cartilage, blood vessels, fibrous tissue, fat, or bone. Solid tumors also include cancers, which are malignant tumors arising from epithelial structures, including external epithelium (such as the lining of the skin, gastrointestinal tract, lungs, and cervix) and internal epithelium lining various glands (such as the chest, pancreas, and thyroid gland). Examples of tumors include leukemia and hepatocellular carcinoma, sarcoma, angioendothelial carcinoma, breast cancer, central nervous system cancers (such as astrocytoma, gliosarcoma, neuroblastoma, oligodendroglioma, and glioblastoma), prostate cancer, lung and bronchial cancer, laryngeal cancer, esophageal cancer, colon cancer, colorectal cancer, gastrointestinal cancer, melanoma, ovarian cancer and endometrial cancer, kidney cancer and bladder cancer, liver cancer, endocrine cancers (such as thyroid cancer), and pancreatic cancer. For example, diseases or conditions are selected from colon cancer, lung cancer, pancreatic cancer, thyroid cancer, breast cancer, and skin cancer. Examples of tumors 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 cancer), head and neck cancer, acute lymphoblastic leukemia, acute myeloid leukemia, non-Hodgkin's lymphoma, and hairy cell leukemia.

[0099] In one embodiment, a patient presenting with one of the hematopoietic or solid tumors mentioned above has previously received treatment with an inhibitor targeting the RAS-ERK pathway (including RTK, RAF, MEK, or ERK inhibitors) but has developed resistance to that inhibitor. Inhibitors include standard care treatments such as vemurafenib, dabrafenib, cobimetinib, trametinib, YERVOY, OPDIVO, or any combination of these medications.

[0100] In one embodiment, the disease to be treated is defined as a developmental abnormality caused by RAS-ERK communication cascade disorder (RAS disease: such as Noonan syndrome, Costello syndrome, LEOPARD syndrome, cardiofaciocutaneous syndrome, and hypertrophic cardiomyopathy).

[0101] In one embodiment, the disease to be treated is defined as an inflammatory disease or an immune system disorder. Examples of such inflammatory diseases or immune system disorders include inflammatory bowel disease, Crohn's disease, ulcerative colitis, systemic lupus erythematosus (SLE), rheumatoid arthritis, multiple sclerosis, thyroiditis, type 1 diabetes, sarcoidosis, psoriasis, allergic rhinitis, asthma, and chronic obstructive pulmonary disease (COPD).

[0102] In one embodiment, the compound as defined herein is an inhibitor of RAS-ERK signaling and cell proliferation in tumor cells carrying at least one mutated RAS or RAF genotype, and does not induce or substantially does not induce anomalous pathways.

[0103] As used herein, the term "patient or subject" refers to an animal, such as a mammal. Thus, a subject may refer to, for example, a mouse, rat, dog, cat, horse, cow, pig, guinea pig, primate including humans, and similar animals. Humans are preferred as subjects.

[0104] Therefore, the present invention further relates to a method for treating a subject, such as a human subject, suffering from a proliferative disease or condition (e.g., RAF mutation and / or RAS-driven cancer with mutation). The method includes administering a therapeutically effective amount of a compound as defined herein to the subject in need of such treatment.

[0105] In some embodiments, the present invention provides a method for treating a subject for a condition (as described herein), the method comprising administering the compound of the present invention to a subject identified as needing treatment. Identifying patients needing treatment for the conditions described above is entirely within the capabilities and knowledge of those skilled in the art. Certain methods for identifying patients at risk of developing the aforementioned conditions treatable by the subject method are recognized in the medical field, such as family history and the presence of risk factors associated with the development of the subject patient's disease state. Clinicians skilled in the art can easily identify such candidate patients by using, for example, clinical trials, physical examinations, medical / family history, and genetic testing.

[0106] The method for assessing the efficacy of treatment in a subject includes determining the pre-treatment symptoms of the disease using methods well known in the art, and subsequently administering a therapeutically effective amount of the compound of the present invention to the subject. The symptoms of the disease are determined again after appropriate time periods following administration of the compound (e.g., 1 week, 2 weeks, 1 month, 6 months). Modulation (e.g., reduction) of the symptoms and / or biomarkers (e.g., pERK or pMEK) of the disease indicates the efficacy of the treatment. Throughout the treatment process, the symptoms and / or biomarkers of the disease may be determined periodically. For example, the symptoms and / or biomarkers of the disease may be detected every few days, weeks, or months to assess further efficacy of the treatment. A reduction in the symptoms and / or biomarkers of the disease indicates that the treatment is effective.

[0107] In some embodiments, a therapeutically effective amount of a compound as defined herein may be administered to a patient alone or in combination with a pharmaceutically acceptable carrier, adjuvant or mediator.

[0108] The terms "pharmaceutically acceptable carriers, adjuvants, or mediators" and equivalent expressions refer to non-toxic carriers, adjuvants, or mediators that do not impair the pharmacological activity of the compounds they are formulated with. Pharmaceutically acceptable carriers, adjuvants, and mediators that can be used in the compositions of this disclosure include, but are not limited to: ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffers (such as phosphates), glycine, sorbic acid, potassium sorbate, mixtures of saturated vegetable fatty acid metaglycerides, 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 carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol, and lanolin.

[0109] The components described herein may be administered orally, non-enterally, by inhalation spray, topically, rectally, nasally, buccally, or via an implanted reservoir. As used herein, the term "non-enteral" includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. Other modes of administration also include intradermal or percutaneous administration.

[0110] 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, the liquid dosage form may also contain inert diluents commonly used in this technology, such as water or other solvents; solubilizers and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, methyl benzoate, propylene glycol, 1,3-butanediol, dimethylformamide, oils (specifically cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerin, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitol, and mixtures thereof. In addition to inert diluents, the oral composition may also include adjuvants, such as humectants, emulsifiers and suspending agents, surfactants, sweeteners, flavoring agents, and aromatizers.

[0111] For example, sterile injectable aqueous or oily suspensions can be formulated using suitable dispersants or wetting agents and suspending agents according to known techniques. Sterile injectable formulations can also be sterile injectable solutions, suspensions, or emulsions in non-toxic, non-enteric-acceptable diluents or solvents, such as solutions in 1,3-butanediol. Acceptable mediators and solvents include water, USP Ringer's solution, and isotonic sodium chloride solution. Furthermore, sterile, non-volatile oils are conventionally used as solvents or suspension media. For this purpose, any mild, non-volatile oil, including synthetic monoglycerides or diglycerides, can be used. Additionally, fatty acids such as oleic acid are used in the preparation of injectable formulations.

[0112] Injectable formulations may be sterilized, for example, by filtering through a bacterial retention filter, or by a sterilizing agent in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile injectable media prior to use.

[0113] To prolong the effect of the supplied compound, it is often necessary to slow down the absorption of the compound from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of a poorly water-soluble crystalline or amorphous substance. The absorption rate of the compound depends on its dissolution rate, which in turn can depend on the crystal size and crystal form. Alternatively, delayed absorption of the compound in non-enteral administration forms can be achieved by dissolving or suspending the compound in an oil-based medium. Injectable reservoir forms are prepared by forming microcapsule matrices of the compound in a biodegradable polymer such as polylactic acid-polyglycidyl lactide. The release rate of the compound can be controlled depending on the ratio of compound to polymer and the properties of the specific polymer used.

[0114] Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Reservoir injectable formulations are also prepared by encapsulating the compound in liposomes or microemulsions that are compatible with body tissues.

[0115] The composition thereof is preferably administered rectally as a suppository, which can be prepared by mixing the compound of the present invention with a suitable non-irritating excipient or carrier (such as cocoa butter, polyethylene glycol or suppository wax) that is solid at ambient temperature but liquid at body temperature and thus melts in the rectum and releases the active compound.

[0116] For oral administration, solid dosage forms 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 silica; b) binders, such as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone (PVP), sucrose, and gum arabic; c) humectants, such as glycerin; d) disintegrants, such as agar, calcium carbonate, potato or cassava starch, alginate, certain silicates, and sodium carbonate; e) solution blockers, 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; 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 buffers.

[0117] Similar solid compositions can also be used as fillers in soft and hard filled gelatin capsules using excipients such as lactose / milk sugar and high molecular weight polyethylene glycol and its analogues. Solid dosage forms such as tablets, sugar-coated tablets, capsules, pills, and granules can be prepared using coatings and shells such as enteric coatings and other coatings well known in pharmaceutical compounding techniques. They may contain depermeability agents and may also have a composition that, depending on the situation, releases the active ingredient only or preferentially in a portion of the intestine in a delayed manner. Examples of encapsulation compositions that can be used include polymeric substances and waxes. Similar solid compositions can also be used as fillers in soft and hard filled gelatin capsules using excipients such as lactose / milk sugar and high molecular weight polyethylene glycol and its analogues.

[0118] The composition may also be in the form of microencapsulation having one or more excipients as described above. Solid dosage forms such as tablets, sugar-coated tablets, capsules, pills, and granules may be prepared using coatings and shells such as enteric coatings, release-controlled coatings, and other coatings well known in pharmaceutical compounding techniques. In these solid dosage forms, the active compound may be blended with at least one inert diluent, such as sucrose, lactose, or starch. As is common practice, these dosage forms may also contain substances other than inert diluents, such as tablet lubricants and other tablet-making aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pills, the dosage form may also contain a buffer. It may contain an impermeable agent and may also have a composition that, depending on the situation, releases the active ingredient only or preferentially in a portion of the intestine in a delayed manner. Examples of encapsulation compositions that may be used include polymers and waxes.

[0119] Dosage forms for topical or transdermal administration of the compounds of the present invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalers, or patches. The active ingredient is blended under sterile conditions with a pharmaceutically acceptable carrier and, if desired, any desired preservatives or buffers. Ocular formulations, ear drops, and eye drops are also covered within the scope of the present invention. Additionally, the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of the compound to the body. These dosage forms can be prepared by dissolving or dispersing 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 providing a rate-controlled membrane or by dispersing the compound in a polymer matrix or gel.

[0120] The pharmaceutically acceptable compositions provided herein may also be administered via nasal aerosol or inhaler. These compositions are prepared according to techniques well known in pharmaceutical formulation and may be prepared into a solution in saline using benzyl alcohol or other suitable preservatives, absorption enhancers to improve bioavailability, fluorocarbons and / or other known solvents or dispersants.

[0121] The pharmaceutically acceptable compositions provided herein can be formulated for oral administration. These formulations may or may not be administered with food. In some embodiments, the pharmaceutically acceptable compositions of this disclosure are not administered with food. In other embodiments, the pharmaceutically acceptable compositions of this disclosure are administered with food.

[0122] The amount of compounds that can be combined with carriers to produce a single dosage form will vary depending on the patient being treated and the specific administration method. The provided components can be formulated to administer an inhibitor at a dose between 0.01 and 100 mg per kilogram of body weight per day to patients receiving these components.

[0123] It should also be understood that the specific dosage and treatment regimen for any particular patient depends on a variety of factors, including age, weight, general health condition, sex, diet, administration time, excretion rate, drug combination, the treating physician's diagnosis, and the severity of symptoms associated with proliferative disorders or conditions. The amount of compounds provided in the composition will also depend on the specific compounds in the composition.

[0124] The compounds or compositions described herein may be administered in any amount and via any route of administration that is effective in treating or alleviating the symptoms considered herein. The precise amount required will vary between subjects, depending on the subject's species, age and general condition; the severity of the infection; the specific drug; the administration pattern and similar factors. The compounds provided are preferably prepared in unit dosage forms to facilitate dosage administration and uniformity. As used herein, the term "unit dosage form" refers to a physically dispersed unit of the drug suitable for the patient to be treated. However, it should be understood that the total daily dose of the compounds and compositions disclosed herein will be determined by the attending physician within the scope of a reasonable medical diagnosis.

[0125] Depending on the severity of the infection being treated, the pharmaceutically acceptable composition of this disclosure may be administered to humans and other animals orally, rectally, in the non-enteral, intracerebrospinal, intraperitoneally, topically (e.g., by powder, ointment, or drops), buccally (in the form of an oral or nasal spray), or similarly. In some embodiments, the provided compound may be administered orally or in the non-enteral at a dose of about 0.01 mg to about 50 mg per kilogram of subject body weight per day, preferably about 1 mg to about 25 mg, once or more daily to achieve the desired therapeutic effect.

[0126] It should be understood that the total daily dose of the compounds and compositions of the present invention will be determined by the attending physician within the scope of a reasonable medical diagnosis. The total daily inhibitory amount of the compounds of the present invention administered to a subject in a single dose or in multiple doses may be, for example, from 0.01 mg to 50 mg per kilogram of body weight or more typically from 0.1 mg to 25 mg per kilogram of body weight. Single-dose compositions may contain such amounts or multiples thereof to constitute a daily dose. In one embodiment, a treatment regimen according to the present invention comprises administering, in a single dose or multiple doses daily, one or more of the compounds of the present invention, from about 10 mg to about 1000 mg to a patient requiring such treatment.

[0127] Depending on the disease or condition to be treated, additional therapeutic agents may also be present in the composition of this disclosure or administered separately as part of a dosage regimen, such as additional chemotherapy agents. Non-limiting examples of additional therapeutic agents that can be used in combination with the compounds of the present invention include antiproliferative compounds, such as aromatase inhibitors; antiestrogens; antiandrogens; sex-releasing hormone agonists; topoisomerase I inhibitors; topoisomerase II inhibitors; microtubule activators; alkylating agents; retinoids, carotenoids, tocopherols; cyclooxygenase inhibitors; MMP inhibitors; antimetabolites; platinum compounds; methionine aminopeptidase inhibitors; bisphosphonates; antiproliferative antibodies; heparinase inhibitors; Ras oncogenic isotype inhibitors; telomerase inhibitors; proteasome inhibitors; compounds for the treatment of hematologic malignancies; kinin spindle protein inhibitors; Hsp90 inhibitors; mTOR inhibitors; PI3K inhibitors; Flt-3 inhibitors; CDK4 / 6 inhibitors; HER2 inhibitors (Herceptin). Trastuzumab; 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); anti-tumor antibodies; nitrosourea; compounds that target / reduce the activity of protein or lipid kinases, compounds that target / reduce the activity of protein or lipid phosphatases, or any other anti-angiogenic compounds.

[0128] Treatment may also be supplemented by other treatments or interventions, such as surgery, radiation therapy (e.g., gamma radiation, neutron beam radiation therapy, electron beam radiation therapy, proton therapy, brachytherapy and systemic radioisotopes), biological response modulators (e.g., interferon, interleukin, tumor necrosis factor (TNF)) and agents to reduce adverse reactions.

[0129] The description of embodiments of the variables herein includes embodiments as any single embodiment or in combination with any other embodiment or part thereof. The description of embodiments herein includes embodiments as any single embodiment or in combination with any other embodiment or part thereof.

[0129] Example

[0130] List of Abbreviations:

[0130] Ac: Acetyl

[0130] AcOEt or EtOAc: Ethyl acetate

[0130] AcOH: Acetic acid

[0130] Ar: Aryl

[0130] ATCC: American Center for Type Culture Collection

[0130] ATP: Adenosine triphosphate

[0130] BINOL: [1,1'-binaphthyl]-2,2'-diol

[0130] Boc: Tertiary butoxycarbonyl group

[0130] BOP: Hexafluorophosphate (benzotriazol-1-yloxy)trimethylamino)phosphonium (dimethylamino)phosphonium

[0130] br: Broadband

[0130] BSA: Bovine serum albumin

[0130] CCL: Cancer cell line

[0130] CDCl3: deuterated chloroform

[0130] DCE: 1,2-Dichloroethane

[0130] DCM: Dichloromethane

[0130] DIEA (or DIPEA): N,N-diisopropylethylamine (Huenig's base)

[0130] DME: 1,2-Dimethoxyethane

[0130] DMF: N,N-Dimethylformamide

[0130] DMSO: Dimethyl sulfoxide

[0130] DMSO-d6: Dimethyl deuteride

[0130] DTT: Dithiothreitol

[0130] EA: Ethyl acetate

[0130] EC50: Half-maximum effective concentration

[0130] ECL: Enhanced chemical fluorescence

[0130] EDTA: Ethylenediaminetetraacetic acid

[0130] Et2O: Diethyl ether

[0130] EtOH: Ethanol

[0130] Eu: Europium

[0130] FBS: Fetal Bovine Serum

[0130] GST: Glutathione S-transferase

[0130] HATU: O-(7-azabenzotriazol-1-yl)-N,N,N',N',-tetramethylureonium hexafluorophosphate

[0130] HEPES: 4-(2-hydroxyethyl)-1-piperazine ethanesulfonic acid

[0130] Het: Heterocyclic ring

[0130] Hex: Hexane

[0130] HRMS: High-resolution mass spectrometry

[0130] HPLC: High Performance Liquid Chromatography

[0130] HRP: Wasabi peroxidase

[0130] IC50: Half-maximal inhibitory concentration

[0130] IPA: Isopropyl alcohol

[0130] iPrOH: Isopropanol

[0130] LCMS: Liquid Chromatography-Mass Spectrometry

[0130] MeCN: Acetonitrile

[0130] MS: Mass Spectrometry

[0130] NMP: N-methylpyrrolidone

[0130] NMR: Nuclear Magnetic Resonance

[0130] ON: Overnight

[0130] PBS: Phosphate-buffered saline

[0130] pERK: Phosphorylated extracellular signal-regulated kinase

[0130] PMB: p-Methoxybenzyl

[0130] PMSF: Benzylsulfonyl fluoride

[0130] Rf: Retention Factor

[0130] RPMI-1640: Roswell Park Memorial Institute, etc.

[0130] RT: Room temperature

[0130] SDS: Sodium dodecyl sulfate

[0130] SDS-PAGE: Sodium dodecyl sulfate-polyacrylamide gel electrophoresis

[0130] SEM: Trimethylsilylethoxymethyl

[0130] SNAr: Nucleophilic aromatic substitution

[0130] TBST: Tris-buffered saline containing 0.2% Tween-20

[0130] TBTU: O-(benzotriazol-1-yl)-N,N,N',N'-tetramethylureon hexafluoroborate

[0130] TEV: Tobacco Etching Virus Protease

[0130] TFA: Trifluoroacetic acid

[0130] THF: Tetrahydrofuran

[0130] TLC: Silicone Thin-Layer Chromatography

[0130] Ts: p-Toluenesulfonate

[0130] YMIN: Minimum data point of the dose-activity curve

[0131] The following non-limiting examples are illustrative embodiments and should not be construed as further limiting the scope of the invention. These examples will be better understood with reference to the accompanying drawings.

[0132] The examples described below provide synthesis and experimental results for certain exemplary compounds. As is well known to those skilled in the art, the reactions are carried out in an inert atmosphere (nitrogen or argon) where protection of the reaction components from air and moisture is required. Temperatures are given in Celsius (°C). Unless otherwise stated, solution percentages and ratios express volume-to-volume relationships. The reactants used in the following examples are available as described herein, or if not described herein, are commercially available or can be prepared from commercially available materials by methods known in the art. Rapid chromatography was performed at 254 nm using a Teledyne Isco Rf Combiflash instrument on silicon dioxide (SiO2) with commercially available normal-phase silicon dioxide. Mass spectrometry analysis was performed using electrospray mass spectrometry. NMR was recorded on a 400 MHz Varian instrument.

[0133] Preparative HPLC was performed using an Agilent instrument with a Phenomenex-Kinetex C18 (21 × 100 mm, 5 μm) column at a flow rate of 20 mL / min (RT) and UV detection at 220 nm and 254 nm. Unless otherwise stated, the mobile phase consisted of solvent A (5% MeOH, 95% water + 0.1% formic acid) and solvent B (95% MeOH, 5% water + 0.1% formic acid). As described herein, 0.05% TFA or 0.1% AcOH or other additives were occasionally used in place of 0.1% formic acid in both solvents. As described herein, MeCN was also used in place of MeOH in both mobile phases to achieve more challenging separations. Specific gradient conditions are also provided in the examples, but the following are representative: isocratic T(0) → T(3 min), depending on the polarity of the compound, using solvent B between 10% and 50%, followed by a 12-minute gradient to 100% solvent B. Use 100% solvent B for the last 5 minutes.

[0134] LCMS analysis was performed on an Agilent instrument. Liquid chromatography was performed at 1.5 mL / min flow rate (RT) on a Phenomenex Kinetex C18 column (2.6 μm; 100 Å; 3 × 30 mm) under UV detection at 220 nm and 254 nm. The mobile phase consisted of solvent A (95% H₂O / 5% MeOH / 0.1% AcOH) and solvent B (95% MeOH / 5% H₂O / 0.1% AcOH) using the following gradient: T(0) 100% A → T(0.5 min) 100% B → isocratic 100% B to T(2 min). MS detection was performed in parallel using APCI detection in both positive and negative modes.

[0135] Unless otherwise indicated, all figures used in this specification and the claims to represent the amount of an ingredient, reaction conditions, concentration, characteristics, stability, etc., should be understood to be modified by the term "about" in all cases. At a minimum, each numerical parameter should be understood based on the number of significant digits reported and by applying general rounding techniques. Therefore, unless indicated to the contrary, the numerical parameters presented in this specification and the appended claims are approximate values ​​and may vary depending on the characteristics sought to be obtained. Although the numerical ranges and parameters described in the examples are approximate, the values ​​described in specific examples are reported as accurately as possible. However, any numerical value inherently contains some errors due to variations in experiments, test measurements, statistical analyses, etc.

[0135] Examples of synthesis, bioactivity, and characterization:

[0136] All compounds defined herein were prepared according to the methods shown in Tables 3 to 5. Mass spectrometry and NMR characterization data are provided for each of the examples. The compounds were tested in the analyses described in the section on biological experiments. Conventions for reporting biological information are provided as footnotes in the individual tables.

[0136] Synthesis Method A:

[0137] Commercially available 2,6-difluoro-3-nitrobenzoic acid A-1 (synthetic 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. The hydrogenolysis of nitroaromatic A-2 to aniline A-3 is catalyzed using hydrogen and a catalyst (such as carbon-supported palladium metal or carbon-supported palladium hydroxide (Pearlman's catalyst)). Aniline A-3 reacts with a sulfonating agent (such as sulfonyl chloride) in the presence of an organic base (such as pyridine, which can be used as a solvent), with or without a catalyst (such as 4-dimethylaminopyridine), and in or without an additional solvent such as dichloromethane or tetrahydrofuran, to produce a sulfonamide intermediate A-4, which can be protected to an aniline salt, such as A-5, using a strong acid (e.g., anhydrous hydrochloric acid solution in dioxane). Alternatively, 2,6-difluoroaniline A-6 can be converted to its acetoaniline A-7 using an acetylating agent such as acetic anhydride, and further converted to the monoprotected diphenylamine A-8 as described in WO 2012 / 101238A1. Sulfonation to sulfonamide A-9 is achieved under similar conditions to the conversion of carbamate A-3 to sulfonamide A-4 using a sulfonating agent 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 acetoaniline A-9 with aqueous hydrochloric acid in the presence of a co-solvent such as an alcohol provides aniline salt A-5.

[0137] Synthesis Method A

[0137]

[0138] Commercially available 3-amino-6-chloro-2-pyridinecarboxamide A-10 can be converted to pyridopyrimidine ketone A-11 by means of the procedure described in J.Med.Chem.2014,57,3484 and to dichloro derivative A-12 by means of a chlorinating agent such as thionyl chloride or phosphochloride in the presence of a catalytic amount of DMF, according to the procedure described in J.Med.Chem.2014,57,3484.

[0139] Following a procedure similar to that described in WO 2012 / 101238A1, intermediate A-13 can be obtained by heating dichloropyridine A-12 and aniline salt A-5 in an organic acid such as acetic acid. Subsequently, the final inhibitor of the general structure WI containing an N-linked heterocycle can be obtained by heating the dichloropyridine A-13 intermediate and a heterocycle containing a free NH group (such as imidazole, triazole, pyrazole, benzimidazole, benzotriazole, indole, indazole and similar heterocycles) in a solvent such as DMSO or N-methylpyrrolidone (NMP) in the presence of a catalytic amount of copper powder, a ligand (e.g., BINOL) and an inorganic base (e.g., cesium carbonate). In some cases, the presence of copper powder and a ligand is not necessary, and the coupling is carried out under typical SNAr conditions in the presence of the same base and solvent described above, at a temperature ranging from 80°C to 140°C.

[0139] Synthesis Method B:

[0140] Method B provides an alternative method for constructing inhibitors of the universal structure WI. Using the same intermediate A-2 as described in Method A as the starting material, 3-nitroaniline salt B-1 can be obtained by decarbamate protecting group under acidic conditions (e.g., using anhydrous hydrogen chloride in a solution of dioxane or trifluoroacetic acid). Using conditions similar to those described in WO 2012 / 101238A1, aniline salt B-1 is reacted with dichloropyridopyrimidine A-12 to provide intermediate B-2. The nitro group is reduced to the corresponding aniline B-3 using a metal salt (such as tin(II) in an alcohol solvent). Subsequently, in the presence of a catalytic amount of copper powder, a ligand (e.g., BINOL), and an inorganic base (e.g., cesium carbonate), the chloropyridine B-3 intermediate is heated in a solvent such as DMSO or N-methylpyrrolidone with a heterocycle containing a free NH group (e.g., imidazole, triazole, pyrazole, benzimidazole, benzotriazole, indole, indazole, and similar heterocycles) to produce aniline B-4, which has an N-linked heterocycle on the pyridine ring. Finally, aniline B-4 can be converted to an inhibitor of general formula WI containing an N-linked heterocycle in the presence of an organic base such as pyridine, with or without a catalyst such as 4-dimethylaminopyridine and a solvent such as dichloromethane or tetrahydrofuran, using a sulfonating agent such as sulfonyl chloride.

[0140] Synthesis Method B

[0140]

[0140] Synthesis Method C:

[0141] W-II type inhibitors containing a C-linked aryl or heterocyclic group at the 2-position of the pyridine ring can be obtained by metal-catalyzed cross-coupling of chloropyridine A-13 with aryl or heteroarylboronic acids and their derivatives, including boronic esters, according to the typical Suzuki-Miyaura scheme. Under normal thermal conditions or microwave irradiation, at temperatures ranging from 70°C to 110°C, inorganic aqueous bases such as sodium carbonate, potassium carbonate, or potassium phosphate can be used as bases in solvents such as 1,4-dioxane or 1,2-dimethoxyethane (DME). Alternatively, organotin substances can be used under similar conditions in the presence of an organic base such as triethylamine, according to the typical Stille coupling scheme.

[0141] Synthesis Method C

[0141]

[0141] Synthesis Method D:

[0142] After saponification with an aqueous solution of an inorganic hydroxide (such as sodium hydroxide, potassium hydroxide, or lithium hydroxide), chloropyridine A-13 is coupled with a methyl ester of 3-indole or 3-indazole carboxylic acid using the scheme described in Synthetic Method A to provide intermediates D-1 or D-2, respectively. Subsequently, carboxylic acids D-1 and D-2 are reacted with primary and secondary amines using a typical procedure for constructing amide bonds (e.g., BOP, HATU, or TBTU, and the like, in the presence of an organic base (such as DIEA or triethylamine) in a solvent (such as NMP, DMF, THF, or DMSO) at ambient temperature). If the functional group on the amine reagent is reactive under conditions for forming an amide bond (e.g., an additional amine functional group), the reactive substituent (e.g., tertiary butylcarbamate) can be protected and the protecting group removed as a final step to reveal the desired W-III inhibitor.

[0142] Synthesis Method D

[0142]

[0142] Synthesis Method E:

[0143] Bromobenzimidazole E-2 can be obtained by reacting 3-bromo-1,2-phenylenediamine E-1 with formic acid and, as described in WO 2004 / 076411, by methylation at low temperature using a strong base (such as a combination of an inorganic hydride and an alkyllithium (e.g., tertiary butyllithium)) and a methylating agent (such as DMF in an aprotic solvent such as THF) to provide methylbenzimidazole E-3. Coupling of benzimidazole E-3 with chloropyridine A-13 can be carried out under the general scheme of method A to provide the aldehyde intermediate E-4. The reaction of E-4 with an amine under standard reductive amination conditions (e.g., in the presence of a weak organic acid such as AcOH, using a reducing agent such as an inorganic borohydride or cyanoborohydride) provides an inhibitor of general formula W-IV as shown in general synthetic method E.

[0143] Synthesis Method E

[0143]

[0143] Synthesis Method F:

[0144] Bromobenzimidazole E-2 is commercially available or can be prepared as described in general method E (step 1). Cross-coupling with heteroarylboronic acid or borate 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. Subsequently, coupling of the substituted benzimidazole derivative F-1 with chloropyridine A-13 can be carried out under the general scheme of method A to provide an inhibitor of the universal structure WV.

[0144] Synthesis Method F

[0144]

[0144] Synthesis Method G:

[0145] After removing the toluenesulfonyl protecting group by treatment with an aqueous inorganic base such as KOH, N-toluenesulfonyl-protected indole-3-sulfochloro G-1 (prepared by the procedure described in Chemical and Pharmaceutical Bulletin 2009, 57, 591) is reacted with a primary or secondary amine in a solvent such as THF and in the presence of a tertiary base (such as DIEA or triethylamine) to provide the intermediate sulfonamide G-2. Subsequently, the final inhibitor of the universal structure W-VI is obtained by heating the sulfonamide G-2 and the chloropyridine A-13 intermediate under the usual conditions as previously described.

[0145] Synthesis Method G

[0145]

[0145] Synthesis Method H:

[0146] 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 such as sodium sulfide nonahydrate, and directly alkylated without separation from the alkyl halide to provide sulfide intermediate H-2. Subsequently, sulfide intermediate H-2 is converted to sulfide intermediate H-3 using an oxidizing agent such as 3-chloroperoxybenzyl acid. Subsequently, the final inhibitor of the universal structure W-VII is obtained by heating indole sulfide H-3 with chloropyridine A-13 intermediate under the usual conditions as previously described.

[0146] Synthesis Method H

[0146]

[0146] Synthesis Method I:

[0147] A commercially available bright red solution of 3-fluoro-2-nitroaniline I-1 is reacted with a primary or secondary amine in a solvent such as MeCN, DMSO, or NMP, and in the presence of an inorganic base (such as potassium carbonate) or an organic base (such as DIEA), to provide intermediate I-2 upon heating under hot or low-temperature conditions in the range of 40°C to 120°C. The reduction of the nitro group of intermediate I-2 can be achieved in the presence of ammonium chloride, at a temperature in the range of 40°C to 80°C, using a metal (such as Fe or Zn) in an alcoholic solvent such as isopropanol. Subsequently, upon heating with formic acid at a temperature in the range of 40°C to 80°C, the 1,2-phenylenediamine intermediate (see J-1) is directly converted to the desired benzimidazole intermediate I-3. The final inhibitor of the universal structure W-VIII is then obtained by heating benzimidazole I-3 with the chloropyridine A-13 intermediate under the usual conditions as previously described.

[0147] Synthesis Method I

[0147]

[0147] Synthesis Method J:

[0148] Nitroaniline I-2, obtained as described in synthetic method I, is reduced to 1,2-phenylenediamine J-1 in the presence of ammonium chloride at a temperature ranging from 40°C to 80°C using an alcohol solvent such as isopropanol, using a metal (such as Fe or Zn). Subsequently, under acidic conditions (e.g., AcOH), the 1,2-phenylenediamine intermediate (see J-1) is converted to the desired benzotriazole intermediate J-2 upon treatment with an inorganic nitrite such as sodium nitrite. The final inhibitor of the universal structure W-IX is then obtained by heating intermediate I-3 with chloropyridine A-13 under the usual conditions as previously described.

[0148] Synthesis Method J

[0148]

[0149] The procedure for preparing inhibitors that does not belong to or only partially belongs to the general synthetic procedure described above is described in detail below.

[0149] Sulfonyl chloride:

[0150] The following sulfonamides are obtained from commercial sources and used as is: 4-methoxybenzenesulfonamide, 2,4-dichlorobenzenesulfonamide, 2,4-dibenzenesulfonamide, 2-chlorobenzenesulfonamide, 2-toluenesulfonamide, 4-ethylbenzenesulfonamide, 2-cyanobenzenesulfonamide, 2,4-dimethoxybenzenesulfonamide, 2-trifluorotoluenesulfonamide, 3-chlorobenzenesulfonamide, 3-toluenesulfonamide, 2,3-dichlorobenzenesulfonamide, 3-chloro-2-toluenesulfonamide. 2-Bromobenzenesulfonyl chloride, 2-chloro-4-fluorobenzenesulfonyl chloride, 2-chloro-6-fluorobenzenesulfonyl chloride, 2,5-dichlorobenzenesulfonyl chloride, 2,5-dibenzenesulfonyl chloride, 2-chloro-6-toluenesulfonyl chloride, 3-fluoro-2-toluenesulfonyl chloride, 2-chloro-4-toluenesulfonyl chloride, 1,3-benzodioxane-5-sulfonyl chloride, 2-chloro-4-(trifluoromethyl)benzenesulfonyl chloride, 2-methyl-4-nitrobenzenesulfonyl chloride, 2-(difluoromethyl)benzenesulfonyl chloride.

[0151] Other sulfonyl chlorides are prepared by using or adapting the literature procedures described below.

[0151] 2-Fluoro-4-methoxybenzenesulfonyl chloride:

[0151]

[0152] Following the procedure described in EP2752410A1, 2-fluoro-4-methoxyaniline (1.00 g, 7.1 mmol) was dissolved in acetonitrile (25 mL) and concentrated HCl (10 mL) was added. The mixture was cooled to 0 °C in an ice-salt bath. Subsequently, a solution of NaNO2 (0.59 g, 8.5 mmol) in water (1 mL) was added in portions, and the mixture was stirred at 0 °C for 1.5 h (resulting in a light brown solution with a small amount of white solid suspended in it). AcOH (12 mL) was added to the resulting mixture, and after stirring at 0 °C for 10 min, NaHSO3 (7.37 g, 10 equivalents, 71 mmol) was added. After stirring for 5 min, copper(II) chloride (0.96 g, 1 equivalent) and CuCl (70 mg, 0.1 equivalent) were added, and the green suspension was stirred in an ice bath to raise the temperature to RT within 1 h. The suspension was then stirred at RT for another 18 h (in 2:1 hexane / EtOAc, TLC Rf: 0.45). 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 silicone (15 mL) pad using 1:1 hexane / EA as the solvent. The volatile components were removed under reduced pressure to give 1.22 g of a clear, light brown oil (TLC showed the presence of more polar unidentified impurities after aqueous treatment). ¹H NMR (CDCl₃) δ: 7.88 (t, J = 8.6 Hz, 1H), 6.76–6.93 (m, 2H), 3.93 (s, 3H). The homogeneity of 1H NMR is approximately 70%.

[0152] 4-Chloro-2-toluenesulfonyl chloride:

[0152]

[0153] The reaction was prepared by chlorosulfonation of m-chlorotoluene according to the procedure described in Acta Crystallographica Section E 2009, 65(4), o800. m-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 min as HCl gas slowly escaped. After this, the reaction mixture was heated to RT. TLC showed no further starting material (Rf = 0.8 in 8:2 hexane / EA) and the formation of slightly lagging new spots (Rf = 0.7 in 8:2 hexane / EA). Pour the reaction mixture onto ice (50 mL), add DCM (15 mL), separate the organic phase of the product, wash with cold water, dry (MgSO4), and concentrate to a colorless oil (0.87 g), which can be used without further purification: 1H NMR (CDCl3) δ: 8.01 (d, J=8.6 Hz, 1H), 7.43 (s, 1H), 7.40 (dd, J=8.6, 2.0 Hz, 1H), 2.78 (s, 3H).

[0154] The following sulfonyl chlorides are prepared using a similar procedure with some modifications as described below:

[0154] 4-Methoxy-2-toluenesulfonyl chloride:

[0154]

[0155] 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 escape was observed). The solution was then stirred at -30 °C to -25 °C for 15 min to clarify (no gas escape was observed). The reaction mixture was carefully poured onto ice (50 mL), DCM (50 mL) was added, and the slightly emulsified organic phase of the product was separated. The product was washed with cold water, dried (MgSO4), and concentrated to a colorless oil, which was then dried under vacuum (8.28 g, 76% yield). NMR showed the presence of a single isomer: 1H NMR (CDCl3) δ: 8.01 (d, J = 8.6 Hz, 1H), 6.72–6.95 (m, 2H), 3.90 (s, 3H), 2.75 (s, 3H).

[0155] 2-Chloro-4-methoxybenzenesulfonyl chloride:

[0155]

[0156] 1.00 g of 3-chlorophenyl methyl ether was dissolved in 4 mL of CHCl3 and the solution was cooled to approximately -35 °C. 2.5 mL of chlorosulfonic acid was added dropwise to 2 mL of CHCl3 over 15 min. After this was completed, only the baseline material was detected by TLC (SM Rf = 0.8 in 8:2 hexane / EA). Once the reaction mixture was heated to RT, gas was observed to escape and isomers were observed by TLC (Rf = 0.30 and 0.25 in 8:2 hexane / EA). After stirring at RT for 30 min, a white precipitate began to form. The reaction mixture was poured onto ice (50 mL), 15 mL of DCM was added, and the organic phase was separated, washed with cold water, dried (MgSO4), and concentrated to a colorless oil, which crystallized into a white needle-like substance (0.89 g) upon standing. ¹H NMR revealed a mixture of two isomers in a 60:40 ratio, which were separated by rapid silica gel chromatography using an 8:2 hexane / EtOAc solvent. Desired isomer (more polar): ¹H NMR (CDCl₃) δ: 7.90 (d, J = 8.6 Hz, ¹H), 7.04–7.19 (m, 2H), 4.08 (s, 3H).

[0156] 2,3-Dimethylbenzenesulfonyl chloride:

[0156]

[0157] As described in WO2003 / 055478, it was separated into a minor isomer after o-xylene chlorosulfonation. ¹H NMR (CDCl₃) δ: 7.96 (d, J = 7.8 Hz, ¹H), 7.52 (d, J = 7.4 Hz, ¹H), 7.30 (t, J = 7.8 Hz, ¹H), 2.71 (s, ³H), 2.41 (s, ³H).

[0157] 3-Fluoro-2-methyl-4-methoxybenzenesulfonyl chloride:

[0157]

[0158] Step 1: Potassium carbonate (6.58 g, 47.6 mmol) was added to a solution of 2-fluoro-3-methylphenol (4.32 mL, 39.7 mmol) in acetone (50 mL), followed by the addition of iodomethane (2.75 mL, 43.7 mmol). The reaction mixture was then refluxed at 60 °C overnight. The reaction mixture was then cooled to RT, filtered (washed with 2 × 10 mL of acetone), and concentrated under reduced pressure. The crude product was extracted from water (30 mL) and EtOAc (2 × 50 mL). The organic layer was then separated, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography using 0 to 5% EtOAc / hexane to give 2-fluoro-3-tolyl methyl ether (5.30 g, 95% yield) as a clear, colorless liquid: 1H NMR (CDCl3) δ: 6.95 (td, J=8.0, 1.4 Hz, 1H), 6.85–6.71 (m, 2H), 3.87 (s, 3H), 2.28 (d, J=2.3 Hz, 3H).

[0159] Step 2: Over a 5-minute period, a solution of chlorosulfonic acid (1.13 mL, 16.5 mmol) in DCM (5.6 mL) was added to a solution of 2-fluoro-3-tolyl methyl ether (1.00 g, 7.13 mmol) from Step 1 in DCM (5.6 mL). The light brown reaction mixture containing the viscous liquid layer was stirred at RT for 10 min and then quenched by pouring into a mixture of water (10 mL) and ice (5 g). The aqueous phase was extracted with DCM (2 × 10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the desired sulfonyl chloride (1.70 g, 100% yield) as a colorless liquid. The substance was used without further purification: 1H NMR (CDCl3) δ: 7.87 (dd, J=9.0, 1.8 Hz, 1H), 6.97-6.86 (m, 1H), 3.97 (s, 3H), 2.66 (d, J=2.8 Hz, 3H).

[0159] 3-Chloro-2-methyl-4-methoxybenzenesulfonyl chloride:

[0159]

[0160] Following a similar procedure to that for 3-fluoro-2-methyl-4-methoxybenzenesulfonyl chloride (step 1), and starting with 2-chloro-3-methylphenol, 2-chloro-3-tolyl methyl ether, a colorless liquid, was obtained in quantitative yield: 1H NMR (CDCl3) δ: 7.12 (t, J = 7.9 Hz, 1H), 6.87-6.83 (m, 1H), 6.79 (d, J = 8.2 Hz, 1H), 3.89 (s, 3H), 2.38 (s, 3H).

[0161] As described for 3-fluoro-2-methyl-4-methoxybenzenesulfonyl chloride (step 2), the desired 3-chloro-2-methyl-4-methoxybenzenesulfonyl chloride was obtained by treatment with chlorosulfonic acid in 96% yield as a colorless liquid: 1H NMR (CDCl3) δ: 8.02 (d, J=9.1 Hz, 1H), 6.90 (d, J=9.1 Hz, 1H), 4.00 (s, 3H), 2.83 (s, 3H).

[0161] 2-Ethylbenzenesulfonyl chloride:

[0161]

[0162] 2-Ethylbenzenethiol (1.46 mL, 10.3 mmol) and KCl (776 mg, 10.3 mmol) were dissolved in water (38 mL), and oxone® (15.8 g, 25.8 mmol) was added in small portions. After stirring at RT for 1 h, the reaction was considered complete by LCMS analysis, and the reaction mixture was extracted with EtOAc (4 × 5 mL). The extract was dried (Na2SO4) and concentrated under reduced pressure to give a white crystalline solid (1.43 g, 68% yield), which was used as is: 1H NMR (CDCl3) δ: 8.07 (dd, J=8.1, 1.3 Hz, 1H), 7.66 (td, J=7.6, 1.3 Hz, 1H), 7.49 (d, J=7.7 Hz, 1H), 7.45–7.38 (m, 1H), 3.20 (q, J=7.5 Hz), 1.36 (t, J=7.5 Hz).

[0162] 3-Fluoro-2-ethylbenzenesulfonyl chloride

[0162]

[0163] Step 1: Dissolve 2-bromo-6-fluorobenzaldehyde (6.00 g, 29.5 mmol) in anhydrous THF (60 mL) and cool the solution to -78 °C under an argon atmosphere. Add magnesium methyl bromide (13.4 mL, 40.3 mmol, in diethyl ether, 3.0 M solution) dropwise and stir the mixture at -78 °C for 30 min. Then quench the reaction with 10% hydrochloric acid (50 mL) and extract the product into diethyl ether (2 × 50 mL). The extract was dried (MgSO4) and concentrated, and the residue was purified by silicone Combiflash® using 10%-30% EtOAc / hexane as a solvent to obtain the desired alcohol derivative (6.20 g, 96% yield) as a colorless oil: 1H NMR (CDCl3) δ: 7.35 (ddd, J=7.9, 3.1, 2.0 Hz, 1H), 7.16-6.99 (m, 2H), 5.35 (q, J=6.7 Hz, 1H), 1.61 (dd, J=6.8, 1.1 Hz, 3H).

[0164] Step 2: Indium(III) chloride (412 mg, 1.83 mmol) was suspended in DCM (40 mL) and diisopropylsilane chloride (8.42 mL, 49.3 mmol) was added. Alcohol (4.00 g, 18.3 mmol) from the DCM (8 mL) in Step 1 was added, and the mixture was stirred at RT for 3 h to obtain a clear solution. The reaction mixture was quenched with water (50 mL), extracted with diethyl ether (3 × 20 mL), washed with brine, and dried (MgSO4). The solution was concentrated and purified by rapid chromatography using hexane as a solvent to provide a silyl ether of the starting alcohol.

[0165] The substance was dissolved in DCE (41 mL) and dichloroisopropylsilane (0.78 mL, 4.6 mmol) and indium(III) chloride (103 mg, 4.6 mmol) were added. The mixture was stirred at 80 °C for 3 h. After cooling to ambient temperature, the reaction mixture was diluted with hexane (100 mL), washed with water (100 mL), and the aqueous phase was back-extracted with hexane (2 × 50 mL). The combined organic phases were dried (Na2SO4) and concentrated to obtain a colorless oil, which was purified by rapid silica gel chromatography using hexane as a solvent to obtain a colorless oil of 2-bromo-6-fluoro-ethylbenzene (3.71 g, 100%): 1H-NMR (CDCl3) δ: 7.32 (d, J = 7.8 Hz, 1H), 7.11–6.91 (m, 2H), 2.82 (dq, J = 7.5, 2.2 Hz, 2H), 1.20–1.15 (m, 3H).

[0166] Step 3: The aryl bromide (3.71 g, 18.3 mmol) from Step 2 was dissolved in toluene (60 mL) and N,N-diisopropylethylamine (6.40 mL, 36.5 mmol) was added. The solution was then degassed by three cycles of vacuum and nitrogen backfilling. Tris(dibenzylacetone)-dipalladium(O) (836 mg, 0.9 mmol), 4,4-bis(diphenylphosphino)-9,9-dimethyldibenzopiperanone (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 more, followed by reflux under nitrogen atmosphere overnight. The reaction mixture was then cooled to RT, quenched with water (50 mL), and extracted with EtOAc (2 × 50 mL). The combined organic phases were washed with 10% HCl aqueous solution (75 mL) and dried (Na2SO4). The residue was concentrated under reduced pressure and purified by rapid chromatography using 0-15% EtOAc / hexane as a solvent to obtain the desired sulfide intermediate (4.00 g) as an orange oily substance contaminated with some unreacted initial thiols. This substance was used as is in the next step.

[0167] Step 4: Dissolve the crude sulfide derivative from Step 3 (4.00 g, assumed to be 11.7 mmol) in THF (41 mL) and add potassium tert-butoxide (1.0 M in THF, 14.1 mL, 14.1 mmol) dropwise. Stir the resulting solution at RT for 1 h. Subsequently, the reaction is quenched by adding saturated NH4Cl aqueous solution (40 mL) and extracted with EtOAc (2 × 30 mL). The combined organic phases are concentrated and the deep orange residue is washed through a small silicone pad with hexane to give a mixture of thiols and disulfides (1.50 g), which is used as is in the next step (Note: foul odor).

[0168] Step 5: The crude mixture of thiophenol and disulfide from Step 4 (1.50 g, assumed to be 9.6 mmol) and KCl (723 mg, 9.6 mmol) were suspended in water (40 mL), and oxone® (14.8 g, 24 mmol) was added in portions. After stirring at RT for 1 h, the reaction mixture was extracted with EtOAc (2 × 20 mL), and the extract was dried (Na2SO4) and concentrated under reduced pressure to obtain crude sulfonyl chloride, which was used as is to prepare the corresponding fragments A-5 and aniline A-8 (see Table 1).

[0168] 3-Chloro-2-ethylbenzenesulfonyl chloride:

[0168]

[0169] The sulfonyl chloride was prepared according to the same procedure as for 3-fluoro-2-ethylbenzenesulfonyl chloride, but starting with 2-bromo-6-chlorobenzaldehyde:

[0169] Step 1 (white solid, 98% yield): 1H NMR (CDCl3) δ: 7.49 (dd, J=8.0, 1.2 Hz, 1H), 7.33 (dd, J=8.0, 1.2 Hz, 1H), 7.05 (t, J=8.0 Hz, 1H), 5.58 (q, J=6.9 Hz, 1H), 1.64 (d, J=6.9 Hz, 3H).

[0170] Step 2 (colorless oily substance, 100% yield): 1H-NMR (CDCl3) δ: 7.43 (dd, J=8.0, 1.2 Hz, 1H), 7.29 (dd, J=8.0, 1.2 Hz, 1H), 6.96 (t, J=8.0 Hz, 1H), 2.97 (q, J=7.5 Hz, 2H), 1.17 (t, J=7.5 Hz, 3H).

[0171] Step 3 (orange oily substance, 81% yield): 1H-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), 2.64 (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).

[0172] Step 4 (colorless liquid, 99% yield): 1H-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).

[0173] Step 5 (crude material used without further purification): 1H-NMR (CDCl3) δ: 8.03 (dd, J=8.2, 1.3 Hz, 1H), 7.73 (dd, J=8.0, 1.3 Hz, 1H), 7.37 (t, J=8.1 Hz, 1H), 3.30 (q, J=7.4 Hz, 2H), 1.33 (t, J=7.4 Hz, 3H).

[0173] 2-Methyl-3-(trifluoromethyl)benzenesulfonyl chloride:

[0173]

[0174] The sulfonyl chloride is prepared according to the same procedure as for 3-fluoro-2-ethylbenzenesulfonyl chloride, but starting with commercially available 2-methyl-3-(trifluoromethyl)bromobenzene:

[0174] Step 3 (orange oily substance, 100% yield): 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), 2.65 (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).

[0175] Step 4 (colorless oily substance, quantitative yield): 1H-NMR (CDCl3) δ: 7.43 (dd, J=7.9, 2.2 Hz, 2H), 7.12 (t, J=7.8 Hz, 1H), 3.42 (s, 1H), 2.43 (s, 3H).

[0176] Step 5 (white solid, quantitative yield): 1H-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).

[0176] General procedure for preparing sulfonyl chloride from aryl bromides:

[0176]

[0177] Step 1: Dissolve aryl bromide 1 (1.00 mmol) in toluene (1.70 mL). Degas the mixture by bubbling through the solution with nitrogen for 5 min. Add tris(dibenzylacetone)-dipalladium (0) (0.02 mmol), 4,4-bis(diphenylphosphino)-9,9-dimethyldibenzopiperanone (0.04 mmol), and N,N-diisopropylethylamine (2.0 mmol), and then degas the mixture again for 5 min. Then add benzyl mercaptan (1 mmol) and heat the resulting mixture under reflux overnight (oil bath T=115 °C). After completion, cool the reaction to room temperature, dilute with EtOAc (20 mL), and quench with H2O (20 mL). Extract the aqueous layer with EtOAc (2 × 20 mL). Wash the combined organic layers with brine (50.0 mL), dry (Na2SO4), filter, and concentrate under reduced pressure. The crude material was further purified by rapid chromatography (0-10% EtOAc / hexane, 35 mL / min, product dissolved in 100% hexane). The fraction of interest was collected and concentrated under reduced pressure to give title compound 2.

[0178] Step 2: Compound 2 (1.00 mmol) was dissolved in acetic acid (1.90 mL) and H2O (0.65 mL) was added to obtain a heterogeneous solution. N-chlorosuccinimide (4.00 mmol) was added fractionally. The reaction was stirred and monitored by LCMS (sample quenched with N-methylpiperazine). After the reaction was complete, the mixture was concentrated under reduced pressure. The resulting mixture was slowly poured into a saturated aqueous solution of NaHCO3 that produced a gas release. The mixture was extracted with EtOAc (2 × 75 mL). The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude compound was further purified by normal phase chromatography (0-40% EtOAc / hexane, 60 mL / min, product separated with 100% hexane). The fraction of interest was collected and concentrated under reduced pressure to give title compound 3.

[0178] 2-Chloro-3-toluenesulfonyl chloride:

[0178]

[0179] The sulfonyl chloride is prepared according to a general procedure starting with commercially available 1-bromo-2-chloro-3-toluene:

[0179] (2-chloro-3-tolyl)benzyl sulfide: yellow solid, 51% yield, 95% purity (at 220 nm). (ES-)MH = 247.2; 1H NMR (400 MHz, CDCl3) δ 7.39–7.35 (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).

[0180] 2-Chloro-3-toluenesulfonyl chloride: Pale yellow oil, 70% yield, 60% purity (at 254 nm). LCMS: LCMS sample was quenched with N-methylpiperazine (resulting sulfonamide MW = 288.8) (ES+)M+H = 289.2. Used as crude material.

[0180] 3-Fluoro-2-(trifluoromethyl)benzenesulfonyl chloride:

[0180]

[0181] The sulfonyl chloride is prepared according to a general procedure starting with commercially available 1-bromo-3-fluoro-2-(trifluoromethyl)benzene:

[0181] (3-fluoro-2-(trifluoromethyl)phenyl)benzyl sulfide: yellow oil, 66% yield, 98% purity (at 254 nm). (ES-)MH = 285.2.

[0182] 3-Fluoro-2-(trifluoromethyl)benzenesulfonyl chloride: Pale yellow oil, 93% yield, 98% purity (at 254 nm). LCMS: LCMS sample quenched with N-methylpiperazine (resulting sulfonamide MW = 326.1) (ES+)M+H = 327.1

[0182] 3-Chloro-2-(trifluoromethyl)benzenesulfonyl chloride:

[0182]

[0183] The sulfonyl chloride is prepared according to a general procedure starting with commercially available 1-bromo-3-chloro-2-(trifluoromethyl)benzene:

[0183] (3-chloro-2-(trifluoromethyl)phenyl)benzyl sulfide: white solid, 59% yield, 90% purity (at 220 nm). (ES-)MH = 301.2; 1H NMR (400 MHz, CDCl3) δ 7.46–7.14 (m, 8H+CDCl3), 4.16 (s, 2H).

[0183] 3-Chloro-2-(trifluoromethyl)benzenesulfonyl chloride

[0183] Colorless oily substance, 66% yield. LCMS: The LCMS sample was quenched with N-methylpiperazine (the resulting sulfonamide MW = 343.5) (ES+)M+H = 343.2. Used as crude material.

[0183] 3,4-Difluoro-2-toluenesulfonyl chloride:

[0183]

[0184] The sulfonyl chloride is prepared according to a general procedure starting with commercially available 1-bromo-3-chloro-2-(trifluoromethyl)benzene:

[0184] (3,4-Dichloro-2-tolyl)benzyl sulfide: Orange oil, 96% yield, 96% purity (at 254 nm). (ES-)MH = 249.2; 1H NMR (400 MHz, DMSO-d6) δ 7.32–7.17 (m, 7H), 4.16 (s, 2H), 2.18 (d, J = 2.7 Hz, 3H).

[0185] 3,4-Difluoro-2-toluenesulfonyl chloride: Pale yellow oil, 49% yield. LCMS: LCMS sample quenched with N-methylpiperazine (sulfonamide MW=290.3) (ES+)M+H=291.2; 1H NMR (400MHz, DMSO-d6)δ 7.56 (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).

[0185] 2,4-Dimethyl-3-fluorobenzenesulfonyl chloride:

[0185]

[0186] The sulfonyl chloride is prepared according to a general procedure starting with commercially available 1-bromo-2,4-dimethyl-3-fluorobenzene:

[0186] (3-Fluoro-2,4-Dimethyl)benzyl sulfide: Orange oil, 95% crude yield, 80% purity (at 254 nm). Used as a crude product.

[0187] 3-Fluoro-2,4-Dimethylbenzene-1-sulfonyl chloride: Orange oil, 89% crude yield, 74% purity (at 254 nm). LCMS: LCMS sample quenched with N-methylpiperazine (resulting sulfonamide MW = 286.4) (ES+)M+H = 287.1. Used as crude material.

[0187] 2-Methylpyridine-3-sulfonyl chloride:

[0187]

[0188] The sulfonyl chloride is prepared according to a general procedure starting with commercially available 3-bromo-2-methylpyridine:

[0188] 3-(benzylthio)-2-methylpyridine: orange liquid, 88% yield, 94% purity (at 220 nm), (ES+)M+H=215.8, (ES-)MH=214.1. ¹H NMR (400 MHz, DMSO-d6) δ 8.30 (dd, J=4.9, 1.5 Hz, 1H), 7.57–7.45 (m, 1H), 7.31–7.27 (m, 5H), 7.07 (dd, J=7.6, 5.1 Hz, 1H), 4.09 (s, 2H), 2.58 (s, 3H).

[0189] 2-Methylpyridine-3-sulfochloro: pale yellow oil, 100% yield, 95% purity (at 254 nm), LCMS sample diluted with H2O (the resulting sulfonic acid MW=173.1) (ES-)MH=171.9; 1H NMR (400MHz, CDCl3) δ 8.80 (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).

[0189] 6-Methoxy-4-methylpyridine-3-sulfochloro:

[0189]

[0190] Preparation of 2-ethylhexyl 3-((6-methoxy-4-methylpyridin-3-yl)thio)propionate (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 by bubbling through the solution with nitrogen for 5 min. Tris(dibenzylacetone)dipalladium (0) (1.36 g, 1.49 mmol), 4,4-bis(diphenylphosphino)-9,9-dimethyldibenzopiperanone (1.75 g, 2.97 mmol) and 2-ethylhexyl-3-mercaptopropionate (7.47 mL, 31.2 mmol) were added. The mixture was degassed again for 5 min. The mixture was heated under reflux overnight (oil bath T = 117 °C). 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 × 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 material was purified by rapid chromatography (330 g silica column, EtOAc-hexane, 0-20%) to give the title compound (10.0 g, 99% yield) as an orange oil. (ES+)M+H=340.2; 1H NMR (400MHz, CDCl3)δ 8.19(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).

[0191] Preparation of 6-methoxy-4-methylpyridine-3-thiol (3): Potassium tert-butoxide (1.00 M in THF, 35.3 mL, 35.3 mmol) was added dropwise to a solution of 2 (10.0 g, 29.5 mmol) in THF (105 mL) at -78 °C, and a precipitate was formed. The resulting suspension was stirred at -78 °C for 30 min. The reaction was quenched by adding NH4Cl (50.0 mL) and the mixture was extracted with CH2Cl2 (2 × 50.0 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated under reduced pressure to give a deep orange liquid. The crude material was purified by rapid chromatography (100% hexane) 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: Rt=1.92min, (ES+)M+H=309.0.

[0192] Preparation of 6-methoxy-4-methylpyridine-3-sulfonyl chloride (4): Potassium chloride (2.21 g, 29.3 mmol) was added to a mixture of thiol 3 (4.56 g, 29.4 mmol) in H2O (123 mL), followed by the addition of OXONE (45.2 g, 73.5 mmol) fractionally. After the reaction was complete (1 h), the mixture was extracted with EtOAc (2 × 20.0 mL), and the combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. The crude product obtained was used without further purification.

[0192] 3-Methylpyridine-4-sulfonyl chloride:

[0192]

[0193] Step 1: Dissolve 4-bromopyridine (1.00 mmol) in toluene (1.70 mL) and add N,N-diisopropylethylamine (2.00 mmol). Degas the mixture by bubbling it through the solution with nitrogen for 5 min. Add tris(dibenzylacetone)-dipalladium (0) (0.02 mmol), 4,4-bis(diphenylphosphino)-9,9-dimethyldibenzopiperanone (0.04 mmol), and phenylmethanethiol / benzylthiol (1.00 mmol). Degas the mixture again for 5 min. Heat the mixture under reflux for 18 h (oil bath T=115 °C). Cool the reaction to room temperature, dilute with EtOAc (10.0 mL), and quench with H2O (10.0 mL). The aqueous and organic layers were separated, and the aqueous layer was extracted with EtOAc (2 × 10.0 mL). The combined organic phases were washed with brine HCl (10% in H2O, 10.0 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude material was purified by rapid chromatography (EtOAc-hexane, 10% to 35%) to give sulfide 2 (90% yield). (ES+)M+H = 216.1; 1H NMR (400 MHz, CDCl3) δ 8.28 (d, J = 4.6, 1H), 8.24 (s, 1H), 7.43–7.27 (m, 5H), 7.20 (t, J = 5.4 Hz, 1H), 4.25 (s, 2H), 2.28 (s, 3H).

[0194] Step 2: Dissolve compound 2 (1.00 mmol) in CH2Cl2 (11.5 mL) and cool to -10 °C. Add HCl (1.00 M in H2O, 5.70 mL) and stir at -10 °C for 5 min. Add sodium hypochlorite (10% solution in H2O, 3.00 mmol) over 10 min, keeping the temperature below 0 °C. Stir the mixture at 0 °C for 10 min. Separate the organic layer from the aqueous layer. Dry the organic layer (Na2SO4). The crude sulfonyl chloride is used in the next step without further purification or evaporation: Quench the LCMS sample with N-methylpiperazine (resulting in sulfonamide MW = 255.3); (ES+)M+H+ = 256.2.

[0194] 2,3-Dimethylpyridine-4-sulfonyl chloride:

[0194]

[0195] Starting with 2,3-dimethyl-4-bromopyridine, the same procedure as for 3-methylpyridine-4-sulfonylurea is used:

[0195] Step 1: 4-(benzylthio)-2,3-dimethylpyridine (2): (92% yield). (ES+)M+H=230.2; 1H 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).

[0196] Step 2: 2,3-Dimethylpyridine-4-sulfonyl chloride (3): Quench the LCMS sample with N-methylpiperazine (the resulting sulfonamide MW=269.3); (ES+)M+H+=270.2.

[0196] Sulfonated chloride with group B49:

[0196]

[0197] Step 1: Add 20 mL of saturated NaHCO3 aqueous solution to a solution of commercially available aminopyridine (1.00 g, 4.27 mmol) and N-benzylaminomethyl chloride (0.9421 g, 5.5546 mmol) in EtOAc (20 mL). Stir the solution at RT for 16 h. Once complete, add EtOAc to the reaction mixture and separate the organic layer, wash with brine, dry with MgSO4, then filter and concentrate. Adsorb the residue onto SiO2, and then purify it on SiO2 by EtOAc / hexane to obtain the desired protected aminopyridine (1000 mg, 2.72 mmol, 64%). 1H 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+).

[0198] Step 2: The degassed solution of iodopyridine (0.61 g, 1.66 mmol), tris(dibenzylacetone)-dipalladium(O)chloroform adduct (86 mg, 0.0828 mmol), 9,9-dimethyl-9h-dibenzopiperan-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) from Step 1 in toluene (15 mL) was stirred at 115 °C for 3 h under N2. Once complete, SiO2 was added to the reaction mixture and concentrated under vacuum. The residue was purified on a SiO2 column with EtOAc / hexane to provide the desired sulfide (560 mg, 93%). 1H NMR(400MHz, CDCl3)δ: 7.71(d,J=8.61Hz,1H),7.54(d,J=8.61Hz,1H),7.46(br.s.,1H),7.3 1-7.43(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+).

[0199] Step 3: Add N-chlorosuccinimide (330 mg, 2.47 mmol) to a solution of the sulfide (300 mg, 0.823 mmol) from Step 2 in 16 mL of water containing 90% AcOH. Stir the reaction mixture at room temperature for 3 hours. Evaporate the reaction mixture to dryness, then dilute in EtOAc and wash with water, followed by washing with brine. Dry the organic layer with MgSO4, filter, and concentrate under vacuum to obtain the desired sulfonyl chloride B49 (282 mg, 99%), which is used as is: 1H NMR (400 MHz, CDCl3) δ: 8.28 (d, J = 9.00 Hz, 1H), 8.02 (d, J = 9.00 Hz, 1H), 7.72 (br. s., H), 7.34–7.60 (m, 5H), 5.27 (s, 2H), 2.86 (s, 3H). MS m / z 341.2 (MH+).

[0199] 2,2-Difluorobenzo[d][1,3]dioxo-4-sulfonyl chloride:

[0199]

[0200] Thionyl chloride (5.96 mL) was added dropwise to water (30 mL) over a period of 20 min, and the mixture was stirred at RT for 48 h to generate a solution containing sulfur dioxide. In a separate container, 2,2-difluorobenzo[d][1,3]dioxo-4-amine (1.00 g, 5.78 mmol) was added dropwise to ice-cooled HCl (7 mL) over a period of 5 min to generate a white precipitate. A solution of sodium nitrite (523 mg, 7.5 mmol) in water (2 mL) was added dropwise to aniline hydrochloride over a period of 5 min to generate an orange reaction mixture. Subsequently, the orange suspension was gradually added to the sulfur dioxide solution mentioned above, to which 10 mg of cuprous chloride had previously been added. The mixture was stirred in an ice bath for another 2 h (gas was observed to escape and orange liquid was observed to settle at the bottom of the flask). After LCMS analysis confirmed the presence of the desired sulfonyl chloride, the reaction mixture was extracted with DCM (2 × 20 mL), dried (Na₂SO₄), filtered, and concentrated to obtain the desired sulfonyl chloride (100% crude yield) as an orange oil, which was used without further purification: 1H-NMR (400 MHz, CDCl₃) δ 7.65 (dd, J = 8.4, 1.1 Hz, 1H), 7.44 (dd, J = 8.1, 1.1 Hz, 1H), 7.32 (t, J = 8.2 Hz, 1H).

[0200] 4-Chloro-3-fluoro-2-toluenesulfonyl chloride:

[0200]

[0201] Preparation of N-(3-fluoro-2-tolyl)trimethylacetylamine (2): Triethylamine (14.9 mL, 106 mmol) was added to a THF (240 mL) solution of 3-fluoro-2-tolylamine (10.9 mL, 93.0 mmol) at 0 °C for 10 min, followed by the addition of trimethylacetyl chloride (13.1 mL, 105 mmol). The mixture was heated to room temperature and stirred for 2 h. The evaporating components were evaporated under reduced pressure, and the residue was partitioned between H2O (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 (Na2SO4), and concentrated under reduced pressure to give the title compound as a solid (18.5 g, 95% yield). (ES+)M+H = 210.2.

[0202] Preparation of N-(4-chloro-3-fluoro-2-tolyl)trimethylacetamide (3): N-chlorosuccinimide (2.76 g, 20.1 mmol) was added to a DMF (50.0 mL) solution of compound 2 (4.20 g, 20.1 mmol) in 3 portions at room temperature for 10 min. The mixture was heated at 80 °C for 90 min. Additional N-chlorosuccinimide (541 mg, 4.01 mmol) was added and stirred at 80 °C for 45 min. The mixture was cooled to room temperature and diluted with EtOAc (30 mL) and water (60 mL). The organic and aqueous layers were separated. The aqueous layer was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with H₂O (3 × 30 mL) and brine (20.0 mL), dried (Na₂SO₄), and concentrated under reduced pressure to give a crude compound (5.20 g). The crude compound was dissolved in cyclohexane (30 mL) and heated at 45–50 °C until all solids dissolved. The solution was cooled to room temperature. The precipitated white solid was filtered off and washed with cyclohexane (3 × 5 mL) to give the title compound as a solid (1.95 g, 40% yield). (ES⁺)M⁺H = 244.1.

[0203] Preparation of 4-chloro-3-fluoro-2-toluidine (4): HCl (6.00 M in water, 23 mL, 138 mmol) was added to a solution of dioxane (18 mL) of compound 3 (1.60 g, 6.57 mmol) at room temperature for 5 min. The mixture was heated at 100 °C for 20 h. The mixture was cooled to room temperature. Solid K2CO3 was added fractionally (exothermic) until pH = 8-9 was obtained. The mixture was extracted with EtOAc (4 × 20 mL). The combined organic layers were washed with brine (20 mL), dried (Na2SO4), and concentrated under reduced pressure to give 1.6 g of crude material, which was dried under vacuum for 24 h to give the title compound (850 mg, 81% yield) as an oil. It was used in the next reaction without further purification. 1H NMR (400MHz, CDCl3) δ 6.99 (t, J = 8.3 Hz, 1H), 6.40 (d, J = 8.6 Hz, 1H), 2.22-2.06 (m, 3H).

[0204] Preparation of 4-chloro-3-fluoro-2-toluene-1-sulfonyl chloride (5): Thionyl chloride (29.1 mL, 395 mmol) was added dropwise to H2O (92.1 mL) under ice cooling for 20 min. This solution containing sulfur dioxide was stirred at 0 °C for 2 h and then at room temperature for 18 h. Separately, concentrated HCl (23 mL) was added partically to compound 4 (3.00 g, 18.8 mmol) at 0 °C to obtain a beige precipitate. This was stirred at 0 °C for 5 min. Sodium nitrite (1.70 g, 24.4 mmol) was added dropwise to a solution of H2O (2 mL) over approximately 10 min. The sulfur dioxide solution containing copper chloride (I) mentioned above (38.4 mg, 376 μmol) was gradually added to the reaction mixture at 5 °C for 40 min. The mixture was further stirred for 2 h under ice cooling, followed by stirring at room temperature for 4 days. The mixture was diluted with CH2Cl2 (20 mL). The aqueous and organic layers were separated. The aqueous layer was extracted with CH2Cl2 (3 × 20 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated to give crude compound 5 as an oil (1.95 g, 30% yield, 70% purity). The crude material was used in the next step without further purification. LCMS: The LCMS sample was quenched with N-methylpiperazine (resulting in sulfonamide MW = 306.784); (ES+)M+H = 307.1; 1H NMR (400 MHz, CDCl3) δ 7.81 (d, J = 8.4 Hz, 1H), 7.46 (t, J = 7.5 Hz, 1H), 2.69 (s, 3H).

[0204] 3-Methyl-2-phenylthiosulfonyl chloride:

[0204]

[0205] As described in U.S. Patent 3,991,081, it is prepared by chlorosulfonation of 3-methylthiophene. 1H NMR (CDCl3) δ: 7.67 (d, J = 5.1 Hz, 1H), 7.03 (d, J = 5.1 Hz, 1H), 2.63 (s, 3H).

[0205] 3-Chloro-2-phenylthiosulfonyl chloride:

[0205]

[0206] 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 obvious gas escape). The orange-brown solution was then stirred for 30 min, and the temperature was raised to -10 °C over another 30 min, followed by a rise to RT. The reaction mixture was then stirred at RT for 2 h (no gas escape was observed, and TLC showed product formation (Rf = 0.4 in 8:2 hexane / EA)). The reaction mixture was poured onto ice (50 mL), DCM (25 mL) was added, and the organic phase of the emulsion was separated. The product was washed with cold water, dried (MgSO4), and concentrated to a yellow oil (0.55 g). This oil was dried under vacuum and used without further purification. 1H NMR(CDCl3)δ: 7.76(d,J=5.7Hz,1H), 7.16(d,J=5.7Hz,1H).

[0206] 4-Chloro-3-methylthiophene-2-sulfonyl chloride:

[0206]

[0207] Preparation of 3-chloro-4-methylthiophene: In a 100 mL flask, copper chloride (I) (5.76 g, 56.5 mmol) was added to DMF (20.1 mL) containing 3-bromo-4-methylthiophene (3.16 mL, 28.2 mmol) at room temperature. The mixture was heated in an oil bath at 160 °C for 24 h. The crude material was poured onto H2O (50 mL). The resulting mixture was stirred at room temperature for 10 min. The resulting brownish-green solid was filtered and washed with water (3 × 10.0 mL) and Et2O (4 × 10.0 mL). The filtrate was extracted with Et2O (3 × 25.0 mL). The combined organic layers were washed with H2O (2 × 20.0 mL) and brine (20.0 mL), dried (Na2SO4), and concentrated under reduced pressure to give an orange oil (0.890 g, 59% crude material yield). 1H NMR (400MHz, CDCl3) δ 7.09 (d, J=3.5Hz, 1H), 6.99-6.95 (m, 1H), 2.22-2.21 (m, 3H).

[0208] Preparation of 4-chloro-3-methylthiophene-2-sulfochlorochloro: 3-chloro-4-methylthiophene (1.00 g, 7.54 mmol) was dissolved in CHCl3 (4.43 mL), and at room temperature for 5 min, a solution of chlorosulfonic acid (1.19 mL, 17.3 mmol) in CHCl3 (1.48 mL) was added. The mixture was stirred for 10 min. Phosphorus pentachloride (4.13 g, 18.9 mmol) was added to the reaction mixture, followed by CHCl3 (7.50 mL). The mixture was heated at 50 °C for 1 h. The reaction mixture was slowly added to an aqueous solution of NaHCO3 + ice (30 mL). The mixture was stirred for 10 min. Extraction was performed with CH2Cl2 (4 × 10 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to give the title compound as an oil (1.30 g, 30% yield, 40% purity). It 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)δ 7.57(s,1H),2.57(s,3H).

[0208] 3,4-Dichlorothiophene-2-sulfonyl chloride:

[0208]

[0209] Preparation of 3,4-dichlorothiophene: In a 100 mL flask, copper chloride (I) (13.9 g, 137 mmol) was added to DMF (32 mL) containing 3,4-dibromothiophene (5.03 mL, 45.5 mmol) at room temperature. The mixture was heated in an oil bath at 160 °C for 24 h. The crude mixture was poured onto H2O (100 mL) and diluted with Et2O (60 mL). The mixture was stirred at room temperature for 10 min. The resulting brownish-green solid was filtered, washed with H2O (3 × 20 mL), and then washed with Et2O (4 × 20 mL). The filtrate was extracted with Et2O (4 × 30 mL). The combined organic layers were washed with H2O (2 × 30 mL) and 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. 1H NMR (400MHz, CDCl3) δ 7.21 (s, 2H).

[0210] Preparation of 3,4-dichlorothiophene-2-sulfonyl chloride: A solution of chlorosulfonic acid (757 μL, 11.0 mmol) in CHCl3 (1.99 mL) was added to a solution of compound 2 (1.61 g, 10.5 mmol) in CHCl3 (5.98 mL) over a period of 5 min. The mixture was stirred at room temperature for 20 min. 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 volatile components were removed under reduced pressure, and the residue was dissolved in CH2Cl2 (25 mL) and washed with saturated NaHCO3 aqueous solution (3 × 15 mL), H2O (3 × 10 mL), and brine (10 mL). The organic layer was dried (Na2SO4) and concentrated under reduced pressure to give title compound 3 (2.32 g, 88% yield). LCMS: The LCMS sample was quenched with N-methylpiperazine (the resulting sulfadiazine MW = 315.240); (ES+)M+H = 315.1.

[0210] (3R)-3-methoxy-1-pyrrolidinesulfonyl chloride:

[0210]

[0211] (R)-3-methoxypyrrolidine hydrochloride (0.30 g, 2.1 mmol) was suspended in a mixture of 4 mL toluene and 2 mL DCM. Triethylamine (0.64 mL, 4.6 mmol) was added, and the mixture was sonicated for 4–5 min to obtain a fine white suspension. In a separate flask, 4 mL of toluene was cooled to -40 °C in an acetonitrile / dry ice bath. Thionyl chloride (0.71 mL, 8.7 mmol) was added, and the solution was stirred for 5 min. Subsequently, the pyrrolidine suspension was added dropwise to the cold (-40 °C) thiocyanate solution over 10 min. The resulting suspension was stirred at the same temperature for 1 hour, and then allowed to warm to room temperature. The solid was filtered off and washed with toluene. The filtrate was concentrated to obtain the desired product (0.40 g) as a light brown oil, which was used without further purification. 1H 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).

[0211] General synthesis method A: Difluoroaniline hydrochloride intermediate A-5 (Ar=4-methoxyphenyl) is prepared from tributyl carbamate A-2.

[0211]

[0212] Step 1 - Preparation of aniline intermediate A-3: Nitroaromatic A-2 (5.00 g, 18 mmol, prepared according to the procedure described in J. Med. Chem. 2003, 46, 1905) and 20% Pd(OH)2 / C (130 mg) were suspended in MeOH (50 mL). When the reduction was complete as indicated by TLC analysis (Rf = 0.45 in 2:1 hexane / EtOAc), the mixture was stirred under a hydrogen-filled balloon for 18 h. The suspension was filtered through a Celite® pad to remove the catalyst, washed with MeOH, and the solvent was evaporated under reduced pressure. Upon exposure to air, the originally colorless solution rapidly turned into a very deep blue-green. A crude intermediate, aniline A-3, which was a dark purple-green foamy substance, was obtained and used immediately in the next step without further purification: 1H NMR (DMSO-d6) δ: 8.58 (s, 1H), 6.77 (td, J=9.4, 2.0 Hz, 1H), 6.60 (td, J=9.4, 5.5 Hz, 1H), 4.97 (s, 2H), 1.43 (s, 9H).

[0213] Step 2 - Preparation of sulfonamide A-4 (Ar = 4-methoxyphenyl): Crude aniline A-3 from Step 1 (assumed to be 18 mmol) was dissolved in THF (30 mL) and excess 4-methoxyphenylsulfonyl chloride (7.53 g, 36 mmol) was added, followed by the addition of 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 NaHCO3 aqueous solution and brine, and dried over MgSO4. The desiccant slurry was passed through a 75 mL silicone pad and washed with EtOAc to remove the desiccant and baseline material. The solvent was removed to obtain a brown oily substance, which was purified by rapid chromatography in silica (approximately 250 mL) using 20%–50% EtOAc / hexane as the solvent. After drying under vacuum, product A-4 (8.16 g) was obtained as a brown, foamy substance, which was contaminated by unreacted sulfonyl chloride via a 2:1 ratio ¹H NMR. This substance was used directly in the next step as is: ¹H NMR (CDCl₃) δ: 7.68 (d, J = 9.0 Hz, 2H), 7.41 (td, J = 8.8, 5.5 Hz, 1H), 6.85–6.98 (m, 3H), 6.57 (br.s, 1H), 5.85 (br.s, 1H), 3.85 (s, 3H), 1.46 (s, 9H). MS m / z 413.0 (MH), m / z 313.0 (MH-Boc).

[0214] 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 dioxane (25 mL) containing 4N HCl for 1.5 h at RT, during which a beige solid gradually precipitated. After 1.5 h, another 10 mL of dioxane containing 4N HCl was added and stirring was continued for another 1 h. Subsequently, the reaction mixture was diluted with 50 mL of diethyl ether and the beige precipitate was collected by filtration, washed with diethyl ether, and dried under vacuum. Aniline salt A-5 (4.38 g) in pure form was obtained from nitroaromatic A-2 in 68% overall yield: ¹H NMR (DMSO-d6) δ: 9.73 (s, ¹H), 7.62 (d, J = 8.6 Hz, 2H), 7.06 (d, J = 9.0 Hz, 2H), 6.69–6.88 (m, ¹H), 6.30 (td, J = 8.6, 5.5 Hz, 1H), 3.81 (s, 3H). MS m / z 313.0 (MH).

[0214] General synthesis method A: Prepare difluoroaniline hydrochloride intermediate A-5 (Ar=2,3-dichlorophenyl) from acetaniline A-8.

[0214]

[0215] Preparation of Acetaniline A-8: Acetaniline A-7 can be prepared by acetylation of 2,6-difluoroaniline A-6 with acetic anhydride according to the procedure described in Bioorg.Med.Chem.2016,24,2215. As described in WO 2012 / 101238A1, intermediate A-7 is converted to acetyline A-8 by sequential nitration followed by reduction of the nitro group to aniline.

[0216] 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 equivalents, 14.7 mL) was added to the brown solution, followed by the addition of 2,3-dichlorobenzenesulfonyl chloride (1.2 equivalents, 13.45 g). The resulting reaction mixture was stirred at 45 °C for 3.5 hours, and the conversion was then determined by LCMS monitoring. The reaction mixture was cooled to room temperature and then partitioned between EtOAc and 2-Me-THF (1:1) and water. 1 N HCl solution was added until a slightly acidic pH was obtained. A significant amount of grayish-white solid was present in the two-phase mixture and filtered out (first batch). The filtrate layer was separated, and the aqueous layer was extracted twice more with EtOAc. The combined organic extracts were washed once with water, then with brine, dried over MgSO4, filtered, and concentrated to approximately 20 mL. The resulting suspension was sonicated, and the solid was collected by filtration and washed with EtOH (second batch). The two batches were combined and dried under reduced pressure. A-9 (15.3 g, 85% yield) was given as a beige solid and used without further purification: ¹H NMR (DMSO-d6) δ: 10.61 (s, ¹H), 9.67 (s, ¹H), 7.95 (dd, J=8.0, 1.4 Hz, ¹H), 7.85 (dd, J=8.0, 1.4 Hz, ¹H), 7.51 (t, J=8.0 Hz, ¹H), 7.05–7.18 (m, 2H), 2.00 (s, 3H). MS m / z 395.0 (MH+).

[0217] Step 2 - Preparation of aniline hydrochloride A-5 (Ar = 2,3-dichlorophenyl): In a 500 mL round-bottom flask, acetylaniline 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 equipped with a stoppered reflux condenser and heated at 80 °C with stirring. After 24 hours, the conversion was judged to be ~70% by LCMS monitoring. Additional EtOH (65 mL) and 6N HCl (65 mL) were added to the suspension and stirred at 80 °C for at least 7 hours, after which LCMS indicated complete conversion to the desired aniline. The reaction mixture was diluted with 50 mL of water while still warm and filtered through a cotton plug to remove any small amount of insoluble matter. It was then concentrated to dryness under reduced pressure. The residue was azeotropically dried by evaporating toluene three times under reduced pressure, followed by drying under vacuum to give 7.2 g of the desired product A-5 as a yellow solid, which was then used as its HCl salt. ¹H NMR (DMSO-d6) δ: 10.30 (s, ¹H), 7.93 (dd, J = 8.2, 1.2 Hz, ¹H), 7.83 (dd, J = 8.0, 1.4 Hz, ¹H), 7.49 (t, J = 8.0 Hz, ¹H), 6.68–6.96 (m, ¹H), 6.31 (td, J = 8.6, 5.5 Hz, ¹H). MS m / z 350.9 (MH).

[0218] The following A-5 intermediates are prepared using the relevant sulfonyl chloride and in a similar sequence to that described in Table 1 using carbamate A-2 or acetanilide A-8:

[0218]

[0218]

[0218]

[0218] General synthetic method A - Preparation of inhibitor WI from intermediate A-5:

[0218]

[0219] Step 1 - Preparation of pyridopyrimidine ketone A-11: Using the procedure described in J.Med.Chem.2014,57,3484, commercially available 3-amino-6-chloromethylpyridinium amide 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-toluenesulfonic acid hydrate (0.027 g, 0.14 mmol) was added to the brown suspension. The mixture was stirred in an oil bath set to 140 °C with the flask open to air. After 52 hours, LCMS showed complete consumption of the starting material. The beige suspension was cooled to room temperature and then concentrated under reduced pressure to about 15-20 mL of slurry. This slurry was then diluted with 20 mL of a 1:1 EtOAc / Et2O mixture and sonicated. The solid was then collected by filtration, washed with 10–15 mL of an EtOAc / Et₂O mixture, and dried under vacuum to give A-11 (6.73 g, 70% yield): ¹H NMR (DMSO-d₆) δ: 12.74 (br.s., ¹H), 8.20 (s, ¹H), 8.15 (d, J = 8.6 Hz, ¹H), 7.88 (d, J = 8.6 Hz, ¹H). MS m / z 182.0 (MH⁺).

[0220] Step 2 - Preparation of dichloropyridinidine A-12: Following the procedure described in J. Med. Chem. 2014, 57, 3484, pyrimidinone A-11 (8.61 g, 47 mmol) was suspended in thionyl chloride (60 mL) and 2 drops of DMF were added to the mixture. The flask was equipped with a reflux condenser and heated in an oil bath at 80 °C for 6 hours, at which point the viscous paste turned into a dark brown solution over approximately 30 minutes. LCMS analysis revealed that the starting material was essentially completely consumed. After cooling to room temperature, the mixture was concentrated and then dried under reduced pressure. A-12 (9.51 g) obtained as a beige solid was used as is without further purification: 1H NMR (CDCl3) δ: 9.14 (s, 1H), 8.35 (d, J = 9.0 Hz, 1H), 7.87 (d, J = 9.0 Hz, 1H).

[0221] Step 3: Preparation of chloropyridine intermediate A-13 (Ar=4-methoxyphenyl): Following a similar procedure as described in WO 2012 / 101238A1, crude dichloropyridinidine A-12 (0.44 g, 2.2 mmol, 1.2 equivalents) 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 3 times its volume 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. Chloroprene A-13 (Ar=4-methoxyphenyl) (0.88 g) was obtained as a beige solid. ¹H NMR (DMSO-d6) δ: 10.10 (br. s, 2H), 8.50 (s, 1H), 8.28 (d, J=9.0 Hz, 1H), 7.99 (d, J=9.0 Hz, 1H), 7.67 (d, J=8.9 Hz, 2H), 7.13–7.30 (m, 2H), 7.09 (d, J=9.0 Hz, 2H), 3.81 (s, 3H). MS m / z 478.0 (MH+).

[0222] The following A-13 chloropyridine intermediates were prepared in a similar manner and are described in Table 2:

[0222]

[0222]

[0222]

[0222]

[0223] Step 4 - Preparation of Example 1 (WI: Ar=4-methoxyphenyl, Het=1-benzimidazolyl): Pyridine A-13 (Ar=4-methoxyphenyl; 25 mg, 0.05 mmol), benzimidazole (11 mg, 0.09 mmol, 1.8 equivalents), Cu powder (0.3 mg), racemic BINOL (0.5 mg), and cesium carbonate (2.3 equivalents, 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 (producing a deep orange-brown solution). LCMS showed complete conversion to the desired product. The reaction mixture was acidified with AcOH (200 μL) and injected into a preparative reverse-phase HPLC using a gradient of 30%-100% MeOH and 0.05% TFA. After lyophilization, a beige powder of the inhibitor 1-TFA salt (17 mg) was obtained.

[0224] Other examples of inhibitors prepared in a similar manner are described in Tables 3 and 4 (Method A).

[0224] Using synthesis method B to synthesize inhibitor WI (Example 8):

[0224]

[0225] Step 1: Carbamate A-2 (1.50 g) was dissolved in 8.2 mL of dioxane containing 4 M HCl solution. After 5 minutes at room temperature, the light brown solution turned into a light 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 twice with toluene and dried under vacuum. The resulting light green solid (1.11 g, 97% yield) was used as is without further purification: 1H NMR (DMSO-d6) δ: 7.31 (ddd, J = 9.2, 8.0, 5.5 Hz, 1H), 7.10–7.18 (m, 1H).

[0226] Step 2: The aniline hydrochloride B-1 (600 mg, 2.85 mmol) and dichloropyridinidine A-12 (1.1 equivalent, 627 mg, 3.13 mmol) from Step 1 were suspended in AcOH (8 mL) and stirred at 50 °C for 1.5 h. The reaction was confirmed 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 melted, the suspension was sonicated, and the solids were collected by filtration and washed with water. After drying under vacuum, chloropyridine B-2 (878 mg, 91% yield) was obtained as a beige solid and used as is without further purification: ¹H NMR (DMSO-d6) δ: 10.39 (s, ¹H), 8.61 (s, ¹H), 8.33 (d, J = 9.0 Hz, ¹H), 8.29 (td, J = 9.2, 5.9 Hz, ¹H), 8.04 (d, J = 9.0 Hz, ¹H), 7.56 (td, J = 9.0, 1.0 Hz, ¹H). MS m / z 338.0 (MH+).

[0227] Step 3: Nitroaromatic B-2 (875 mg, 2.6 mmol) and tin(II) dichloride dihydrate (5 equivalents, 2.92 g, 13 mmol) were suspended in 20 mL of ethanol. The mixture was heated to 60 °C to obtain a deep orange solution, and stirred at this temperature for 2 h. The reaction was then 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 poured into EtOAc (150 mL) and 1 N NaOH solution was added until two almost clear phases were obtained. The layers were separated and the aqueous layer was extracted three times with 50 mL of EtOAc. The combined organic layer was washed with water, then with brine, dried over MgSO4, filtered, concentrated, and dried under vacuum. Aniline B-3 (792 mg, 99% yield) was obtained as a pale yellowish-brown solid and used as is without further purification: ¹H NMR (DMSO-d6) δ: 9.99 (s, ¹H), 8.53 (s, ¹H), 8.27 (d, J = 8.6 Hz, ¹H), 7.98 (d, J = 8.6 Hz, ¹H), 6.89 (td, J = 9.2, 1.6 Hz, ¹H), 6.74 (td, J = 9.4, 5.5 Hz, ¹H), 5.07 (s, 2H). MS m / z 308.0 (MH+).

[0228] Step 4 - Preparation of aniline B-4 (Het=1-benzimidazolyl): Chloropyridinium pyrimidine B-3 (495 mg, 1.6 mmol) was placed in a 50 mL flask and dissolved in 6 mL of DMSO. Then, benzimidazole (1.15 equivalents, 220 mg, 1.85 mmol), cesium carbonate (2.3 equivalents, 1.21 g, 3.7 mmol), copper powder (0.01 equivalents, 1 mg), and BINOL (0.01 equivalents, 4.5 mg) were added. The resulting dark mixture was stirred at 100 °C for 2 h. LCMS analysis at this point revealed a conversion of ~40%. The temperature was increased to 120 °C and the mixture was stirred for another 2 h, at which point only trace amounts of starting aniline remained. The mixture was cooled to room temperature and then neutralized with 1 N HCl (pH 7). It was then partitioned between water (75 mL) and DCM (100 mL). After stirring, approximately 5 g of celite® was added to the brown emulsion, which was then filtered through a celite® pad and washed with DCM. The filtrate (two clear layers) was transferred to a separatory funnel and the layers were separated. The aqueous phase was extracted twice more with DCM, and the combined organic layers were washed twice with water and once with brine. The organic fraction was then dried over MgSO4, filtered, and concentrated. The residue was purified by combiflash chromatography using a 24 g column with a gradient of 100% DCM to 40% i-PrOH / DCM. The appropriate fractions (Rf=0.25 in 1:9 i-PrOH / DCM) were combined and concentrated to give 124 mg of B-4 (Het=1-benzimidazole) as a deep yellow solid, which was a 1:1 molar mixture of the desired product and unreacted benzimidazole. The crude material was used in the sulfonation step (step 5) without further purification: ¹H NMR (DMSO-d6) δ: 9.79 (s, ¹H), 9.39 (s, ¹H), 8.56 (s, ¹H), 8.52 (d, J = 9.4 Hz, ¹H), 8.47 (d, J = 9.0 Hz, ¹H), 8.39 (d, J = 7.8 Hz, ¹H), 7.83 (d, J = 7.4 Hz, ¹H), 7.37–7.49 (m, 2H), 6.95 (td, J = 9.2, 1.6 Hz, 1H), 6.78 (td, J = 9.4, 5.5 Hz, 1H), 5.13 (s, 2H). MS m / z 390.1 (MH+).

[0229] Step 5 (Example 8): 2-Chlorobenzenesulfonyl chloride (2 equivalents, 26 mg, 0.12 mmol) was weighed into a 4 mL vial and dissolved in 0.5 mL THF. Crude aniline B-4 (24 mg, 0.06 mmol) was then added, followed by pyridine (6 equivalents, 30 μL, 0.37 mmol). The resulting mixture was stirred at 50 °C for 18 h, at which point the reaction was confirmed to be complete by LCMS (byproducts were also present in the mixture, corresponding to the addition of sulfonyl chloride to the residual benzimidazole contaminating the starting material) (MS m / z 293.0: MH+). The reaction mixture was cooled to room temperature, then quenched by adding 0.2 mL of acetic acid and diluted to 2 mL with methanol. The product was separated by preparative HPLC (MeOH / H2O / 0.1% formic acid conditions, 50%→100% methanol gradient). Fractions containing the main peak were combined and partially concentrated to remove methanol. The suspension was dissolved by adding a few milliliters of acetonitrile, and then the solution was frozen and lyophilized. 9.8 mg of the desired product as a beige solid was obtained (Example 8).

[0230] Other examples of inhibitors prepared in a similar manner are described in Tables 3 and 4 (Method B).

[0230] The inhibitor W-II was synthesized using synthetic method C and organoboron reagent via Suzuki-Miyaura cross-linking coupling (Examples 71 and 510):

[0230]

[0231] 30 mg (1 equivalent) of chloropyridinium pyrimidine A-13, 2 equivalents of 6-methoxypyridyl-3-boric acid (19 mg), and 4 equivalents of anhydrous potassium carbonate (34 mg) were added to a 2 mL microwave-safe vial. DME (1.5 mL) and water (0.5 mL) were then added, and nitrogen was bubbled through the mixture for 2 minutes. Tetra(triphenylphosphine)palladium (0) (0.05 equivalent, 3.5 mg) was added, and nitrogen was bubbled through the mixture again for 2 minutes, and the vial was sealed. The reaction mixture was then irradiated in a microwave at 90 °C for 1 h. LCMS analysis at this point indicated that the reaction was complete. The reaction mixture was treated with 0.6 mL of acetic acid and concentrated to approximately 0.5 mL under reduced pressure. It was then diluted to 2 mL with methanol and DMSO, filtered, and purified by preparative HPLC (MeOH / H2O / 0.1% formic acid conditions, 50%→100% methanol gradient). Appropriate fractions were separated and partially concentrated to remove methanol. The suspension was dissolved by adding a few milliliters of acetonitrile, and then the solution was frozen and lyophilized. Example 71 inhibitor (15 mg) was obtained as a beige solid.

[0232] Other examples of inhibitors prepared in a similar manner using a suitable chloropyridine fragment A-13 (Table 2) and commercially available boric acid or borate esters are listed in Table 4 under Method C. An analogue of Example 510 was prepared in a similar manner using a commercially available borate ester, cesium carbonate as a base, trans-dichlorobis(triphenylphosphine)-palladium(II) as a catalyst, and dioxane as a solvent.

[0232] Synthesis of inhibitor W-II via Stieler cross-linking using synthetic method C and organotin reagent (Example 561):

[0232]

[0233] Step 1: Under N2, at -78°C, a solution of 2.5 M nBuLi in hexane (0.24 mL, 0.597 mmol) was added to a commercially available bromide solution (100 mg, 0.497 mmol) in THF (5 mL), and the mixture was stirred at this temperature for 30 min. Subsequently, tri-n-butyltin chloride (0.13 mL, 0.497 mmol) was added, and the resulting solution was stirred for 30 min. After completion, EtOAc was added, and the organic layer was washed with brine, dried over MgSO4, filtered, and concentrated under vacuum to provide an organotin intermediate (154 mg, 75%). MS m / z 413.2 (MH+).

[0234] Step 2: Degas the vial containing the organotin reagent (40 mg, 0.0968 mmol), 2,3-dichloro-N-[3-[(6-chloropyridino[3,2-d]pyrimidin-4-yl)amino]-2,4-difluoro-phenyl]benzenesulfonamide (50 mg, 0.0968 mmol), copper iodide (I) (1.2 mg, 0.0290 mmol), (R)-(+)-2,2"-bis(diphenylphosphine)-1,1"-binaphthyl (12 mg, 0.0194 mmol) and 1,1'-bis(diphenylphosphine)ferrocene-palladium(ii)dichloromethane complex (7.1 mg, 0.00968 mmol) from Step 1 in PhMe-DMF 1:1 (0.5 mL) and purge with N2 3 times. The mixture was stirred at 90°C for 16 hours under a nitrogen atmosphere. Once complete, the reaction mixture was diluted with EtOAc, followed by washing three times with 10% KF aqueous solution, and then with brine. The organic layer was dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by reverse-phase HPLC with an aqueous solution of ACN / 0.1% HCOOH to give Example 561 (2.7 mg, 5%) after lyophilization. NMR(400MHz,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,2H),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+).

[0235] Other examples of inhibitors prepared in a similar manner using appropriate chloropyridine fragment A-13 (Table 2) and commercially available organotin compounds or bromides converted to the corresponding organotin substances in step 1 above are listed in Table 4 under method C (examples 562-565, 590 and 591).

[0235] General method for synthesizing inhibitors of W-III (method D, X=CH) - Synthesis of Example 109:

[0235]

[0236] Step 1 - Preparation of carboxylic acid D-1: 150 mg of pyrimidine A-13 (Ar = 2-chlorophenyl) (150 mg, 0.3 mmol, 1 equivalent) was placed in a 4 mL vial, followed by methyl indole-3-carboxylate (71 mg, 0.4 mmol, 1.3 equivalent), copper (0) (0.6 mg, 0.03 equivalent), BINOL (2.7 mg, 0.03 equivalent), cesium carbonate (150 mg, 0.47 mmol, 1.5 equivalent), and DMSO (1.5 mL). The resulting mixture was stirred at 100 °C for 1.75 h to obtain a dark brown solution (LCMS showed complete conversion). The reaction was cooled to room temperature, and then 6 equivalents (0.5 mL) of 4N sodium hydroxide was added to the mixture. The mixture was stirred at 50 °C for 1 h (LCMS showed complete conversion to carboxylic acid). The mixture was diluted with water (2 mL) and filtered through a celite® stopper to remove insoluble particles. The mixture was then acidified to approximately pH 1 with 1N HCl and diluted with 10 mL of water to obtain a gel-like suspension (non-filterable). The mixture was extracted three times with EtOAc, and the combined organic layers were washed twice with water and once with brine. The mixture was then dried over MgSO4, filtered, and concentrated to give 220 mg of 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),8.1 6-8.22(m,1H),7.91(dd,J=8.0,1.4Hz,1H),7.62-7.71(m,2H),7.48-7.55(m,1 H),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+).

[0237] Step 2 - Preparation of Inhibitor W-III (Example 109): DIEA (40 μL, 6 equivalents) and HATU (30 mg, 2 equivalents) were added to the crude carboxylic acid (30 mg, 1 equivalent) from NMP (1 mL) in Step 1. The solution was stirred for 2–3 min to obtain a deep yellow solution. Morpholine (7 mg, 2 equivalents) was added and the reaction mixture was stirred at room temperature for 3 h, at which point the reaction was confirmed to be complete by LCMS. The reaction was quenched by adding 0.2 mL of acetic acid, then diluted to 2 mL with methanol and purified by preparative HPLC (MeOH / H2O / 0.1% formic acid conditions, 50%→100% methanol gradient). Appropriate fractions were separated and partially concentrated to remove methanol. The resulting suspension was dissolved by adding a few mL of acetonitrile, and then the solution was frozen and lyophilized. A acetamide, Example 109 (14.5 mg), was obtained as a grayish-white solid.

[0238] Other examples of inhibitors prepared in a similar manner are listed in Table 4 under Method D.

[0238] General method for synthesizing inhibitors of W-III (method D, X=N) - Synthesis of Example 127:

[0238]

[0239] Step 1 - Preparation of Carboxylic Acid D-2: Chloroprene-pyrimidine A-13 (Ar = 3-chloro-2-tolyl) (300 mg, 0.6 mmol, 1 equivalent) was placed in a 4 mL vial, followed by methyl 3-indazolecarboxylate (140 mg, 0.79 mmol, 1.3 equivalent), copper (0) (1 mg, 0.03 equivalent), BINOL (5 mg, 0.03 equivalent), cesium carbonate (295 mg, 0.91 mmol, 1.5 equivalent), and DMSO (2 mL). The vial was stoppered and the mixture was stirred at 100 °C for 1.5 h to obtain a dark brown solution. LCMS analysis showed that the reaction was essentially complete. The reaction was cooled to room temperature, and then 6 equivalents (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 filtered through a celite® stopper while still warm to remove insoluble particles. It was then acidified with 1 N HCl to approximately 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. Crude carboxylic acid D-2 (Ar=3-methyl-2-chlorophenyl) (398 mg) was obtained as a beige solid. ¹H NMR (DMSO-d6) δ: 13.70 (br.s, 1H), 10.58 (s, 1H), 9.48 (s, 1H), 9.03 (d, J=8.6 Hz, 1H), 8.65 (d, J=9.0 Hz, 1H), 8.54 (br.s., 1H), 8.48 (d, J=9.0 Hz, 1H), 8.26 (d, J=7.8 Hz, 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=7.6H z,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+).

[0240] Step 2 - Preparation of Inhibitor W-III (Example 127): Crude carboxylic acid (30 mg, 1 equivalent) from Step 1 was dissolved in NMP (1 mL), and DIEA (50 μL, 6 equivalent) and HATU (37 mg, 2 equivalent) were added. The solution was stirred at room temperature for 2–3 min to obtain a deep yellow solution. N-Boc-piperazine (18 mg, 2 equivalent) was then added, and the reaction mixture was stirred at room temperature for 2 h, at which point the reaction was found to be complete by LCMS. The reaction was quenched by adding 1 mL of saturated ammonium chloride solution, followed by dilution with water to 4 mL. The resulting suspension was then sonicated, and the solid was collected by filtration. The solid was then washed with water and dried under vacuum. The solid was then poured into DCM (1 mL) and MeOH (0.5 mL) and treated with 1 mL of 4N HCl solution in dioxane. After stirring at room temperature for 2 hours, LCMS analysis showed that the Boc protecting group was completely cleaved. The mixture was concentrated to dryness, and the residue was dissolved in MeOH and purified by preparative HPLC (MeOH / H2O / 0.1% formic acid, 30%→100% methanol gradient). Appropriate fractions were separated and partially concentrated to remove methanol. The resulting suspension was dissolved by adding a few mL of acetonitrile, and the solution was then frozen and lyophilized. Example 127 acetamide (14 mg) was obtained as a pale yellow solid.

[0241] Other examples of inhibitors prepared in a similar manner are listed in Table 4 under Method D.

[0241] General method for synthesizing inhibitors of W-IV (Method E) - Synthesis of Example 227:

[0241]

[0242] Step 1 - Preparation of intermediate E-2: 2.00 g (10.7 mmol) of 3-bromo-1,2-phenylenediamine was placed in a 50 mL flask along with 15 mL of formic acid. The mixture was refluxed in an oil bath at 120 °C and stirred for 4 h. 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 began with 1 N NaOH and ended with a saturated NaHCO3 solution. The dark brown solid was collected by filtration through a Buchner funnel and washed with water. The solid was then dried under vacuum to obtain 1.91 g of the desired bromobenzimidazole E-2 as a dark brown solid, which was used as is: ¹H NMR (DMSO-d6) δ: 12.81 (br.s., ¹H), 8.30 (s, ¹H), 7.58 (d, J=8.2 Hz, ¹H), 7.41 (d, J=7.8 Hz, ¹H), 7.14 (t, J=8.0 Hz, ¹H). MS m / z 197.0 (MH+).

[0243] Step 2 - Preparation of intermediate E-3: Following the procedure described in WO 2004 / 076411A2, bromobenzimidazole E-2 (350 mg, 1.776 mmol) was dissolved in 8 mL of anhydrous THF. A 60% sodium hydride dispersion (78 mg, 1.95 mmol) in mineral oil was added at room temperature. After 10 minutes, the reaction was cooled to -78°C and 1,4 moles of tert-butyllithium (2.66 mL, 3.73 mmol) was added dropwise to pentane. The reaction mixture became extremely viscous and difficult to stir. After 30 minutes, the mixture was quenched by adding DMF (0.55 mL, 7.1 mmol). The mixture was then heated to room temperature and partitioned between a 1:1 mixture of EtOAc, water, and a saturated solution of NaHCO3. 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 obtain the residue. The resulting dark brown colloidal solid was ground twice with 2 mL of hexane to remove mineral oil from NaH. The solid was then poured into 6 mL of EtOAc and sonicated. The solid was collected by filtration and dried under suction to obtain a dark brown solid, E-3 (117 mg): 1H 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 batch of product (148 mg, ~80% homogeneity) was recovered from the mother liquor.

[0244] Step 3 - Preparation of intermediate E-4: Chloroprene-pyrimidine A-13 (Ar = 2-chlorophenyl: 75 mg, 1 equivalent) was packaged together with crude benzimidazole E-3 (26 mg, 1.15 equivalent), copper (0) (0.3 mg, 0.03 equivalent), BINOL (1.3 mg, 0.03 equivalent), cesium carbonate (76 mg, 1.5 equivalent), and DMSO (1 mL) from Step 2 into a 4 mL vial. The resulting mixture was stirred at 100 °C for 1 h, at which point LCMS showed complete reaction. The mixture was cooled to room temperature and then quenched by adding 0.1 mL of acetic acid. The mixture was diluted with water to 10 mL and then sonicated. The precipitate was collected by filtration and washed with water. The brown solid was then dried under vacuum. A crude intermediate, E-4 (98 mg), was obtained as a brown solid and used in step 4 as is: ¹H 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 = 7.4 Hz, ¹H), 8.45–8.63 (m, 2H), 7.92 (d, J = 7.4 Hz, 1H), 7.88 (d, J = 7.4 Hz, 1H), 7.55–7.73 (m, 3H), 7.51 (t, J = 7.2 Hz, 1H), 7.12–7.34 (m, 2H). MS m / z 592.1 (MH+).

[0245] Step 4 - Preparation of the inhibitor W-IV (Example 227): 3-Fluoroacetate hydrochloride (17 mg, 0.15 mmol) was placed in a 4 mL vial along with 1 mL of methanol and 0.038 mL of 4N sodium hydroxide solution (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. Finally, sodium cyanoborohydride (9.55 mg, 0.15 mmol) was added. The reaction mixture was stirred at 50 °C for another 2 h, at which point the conversion was complete as indicated by LCMS. The reaction was quenched by adding 0.2 mL of acetic acid solution to 0.5 mL of DMSO. The solution was filtered, and the product was separated by preparative HPLC (30% → 100% MeOH / H2O gradient, 0.1% formic acid). Appropriate fractions were separated and concentrated to remove methanol, followed by freezing and lyophilization. The compound of example 227 (12.7 mg) was isolated as a grayish-white solid.

[0245] General method for the synthesis of inhibitors of synthetic WV (method F) - Synthesis of Example 243:

[0245]

[0246] Step 1: A 4 mL vial containing bromobenzimidazole E-2 (70 mg, 0.355 mmol), potassium carbonate (196 mg, 1.42 mmol), and 3-pyridylboronic acid (57 mg, 0.46 mmol) was added, along with dioxane (2 mL) and water (0.7 mL). Argon gas was bubbled through the mixture for 1 minute, followed by the addition of tetra(triphenylphosphine)palladium (0) (16.4 mg, 0.014 mmol). Argon gas was bubbled through the solution again for 3 minutes. The vial was sealed and heated at 100 °C for 2 hours (until LCMS analysis indicated conversion to the desired product). The reaction mixture was cooled to RT, diluted with EtOAc, and washed with brine. After drying on MgSO4, the extract was concentrated under reduced pressure and the residue was purified by rapid chromatography using Et3N-pretreated silica and a DCM-20% iPrOH / DCM gradient to provide the desired benzimidazole intermediate (58 mg, 84% yield): 1H NMR (DMSO-d6) δ: 12.71 (broadband s, 1H), 9.24 (s, 1H), 8.57 (dd, J=5.1, 1.6 Hz, 1H), 8.43 (broad d, J=5.5 Hz, 1H), 8.31 (s, 1H), 7.61 (d, J=7.8 Hz, 1H), 7.52 (ddd, J=7.8, 4.7, 0.8 Hz, 1H), 7.47 (d, J=7.4 Hz, 1H), 7.34 (t, J=7.8 Hz, 1H). MS m / z 196.1 (MH+).

[0247] Step 2 (Example 243): As described in Example 1 (Step 4) of General Method A, the crude benzimidazole from Step 1 is coupled with chloropyridine A-13 (Ar=2-chlorophenyl) using copper / BINOL catalysis.

[0248] Other compounds (e.g., Examples 251, 272, 273 and 342) were prepared in a similar manner using the appropriate commercially available boric acid and chloropyridine intermediate A-13 (Ar = 3-fluoro-2-tolyl or 2,3-dichlorophenyl) from step 1.

[0248] General method for synthesizing inhibitors of W-VI (Method G) - Synthesis of Example 437:

[0248]

[0249] Step 1: Add 1-(p-toluenesulfonyl)indole-3-sulfonyl chloride (117 mg, 0.316 mmol) in anhydrous THF (1.5 mL) to a vial equipped with a stir bar (Chemical and Pharmaceutical Bulletin 2009, 57, 591). Cool the solution to 0°C and add DIEA (0.11 mL, 0.633 mmol) dropwise. Then add N-(2-methoxyethyl)ethylamine (0.039 mL, 0.316 mmol) dropwise and slowly heat the reaction mixture to room temperature. Stir the reaction at room temperature for 1 h. After completion, add 10% KOH aqueous solution dropwise (equal to the solvent volume). Heat the reaction at 60°C overnight. After completion, dilute the reaction mixture with EtOAc and add NH4Cl aqueous solution. Separate the layers. The organic layer was washed with brine, then dried over MgSO4, filtered, and concentrated to dryness to give the expected sulfadiazine derivative (86 mg, 96%) as a light orange oil. MS m / z 283.2 (MH+).

[0250] Step 2 (Example 437): As described in Example 1 (Step 4) of General Method A, the indolesulfonamide from Step 1 is coupled with chloropyridine A-13 (Ar=2,3-dichlorophenyl) using a copper / BINOL catalysis.

[0251] Other examples of inhibitors prepared in a similar manner using an appropriate amine in step 1 are listed in Table 4 under method G.

[0251] General method for synthesizing inhibitors of W-VII (Method H) - Synthesis of Example 466:

[0251]

[0252] Step 1: Sodium sulfide nonahydrate (414 mg, 1.72 mmol) was added to a solution of 1H-indole-3-yl-thiocyanate (Phosphorus, Sulfur and Silicon and the Related Elements 2014, 189, 1378) (100 mg, 0.574 mmol) in iPrOH (5 mL), dissolved in 0.5 mL of water, and the resulting mixture was stirred at 50 °C for 2 h. Subsequently, 4-chlorotetrahydropyran (0.19 mL, 1.72 mmol) was added and the mixture was 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 under vacuum to obtain a crude sulfide, which was used directly in the next step without further purification.

[0253] Step 2: The sulfide from Step 1 was dissolved in DCM and 3-chloroperoxybenzyl acid (297 mg, 1.72 mmol) was added and stirred at room temperature for 2 h. After completion, the reaction was quenched by adding 10 mL of a 1:1 solution of saturated NaHCO3 aqueous solution and 10% Na2SO3 aqueous solution. The resulting suspension was stirred at room temperature for 15 min. EtOAc was added and the organic layer was separated. The organic layer was washed with water (15 mL) and then with saturated brine (15 mL). The organic layer was separated, dried (MgSO4), filtered, and then concentrated to dryness to provide the desired sulfide (154 mg, 98%), which was dissolved in DMSO and used directly in the next step without further purification. MS m / z 266.2 (MH+).

[0254] Step 3 (Example 466): As described in Example 1 (Step 4) of General Method A, the indole from Step 2 is coupled with chloropyridine A-13 (Ar=2,3-dichlorophenyl) using copper / BINOL catalysis.

[0255] Other examples of inhibitors prepared in a similar manner using a suitable alkylating agent in step 1 are listed in Table 4 below method H.

[0255] General method for synthesizing inhibitors of W-VIII (Method I) - Synthesis of Examples 524 and 665:

[0255] Example 524 (Iron metal as a reducing agent in step 2):

[0255]

[0256] 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. The 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-methylpiperidin-4-ol (0.40 g, 94% yield) was used in the next step without further purification. MS m / z 252.2 (MH+).

[0257] 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) in iPrOH (6.5 mL) and formic acid (1.9 mL, 49.6 mmol). The resulting mixture was heated to 90 °C and stirred for 10 h. The reaction mixture was cooled to room temperature and filtered by Celite®. The solution was concentrated and the crude material was purified by column chromatography (silicone, 0%-15% MeOH / DCM) to give 1-(1H-benzimidazol-4-yl)-4-methyl-piperidin-4-ol (0.17 g, 55% yield) as a slightly reddish foamy solid. MS m / z 232.2 (MH+). 1H 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).

[0258] Step 3 (Example 524): As described in Example 1 (Step 4) of General Method A, the benzimidazole from Step 2 is coupled with chloropyridine A-13 (Ar=2,3-dichlorophenyl) using copper / BINOL catalysis.

[0259] Example 665 (Zinc metal as a reducing agent in step 2):

[0259]

[0260] Step 1: Potassium carbonate (1.01 g, 7.33 mmol) and 4-isopropylpiperidin-4-ol (262 mg, 1.83 mmol) (WO2014 / 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 obtain the desired nitroaniline (400 mg, 78% yield). MS m / z 280.2 (MH+).

[0261] Step 2 (using zinc as a reducing agent): Add zinc (820 mg, 12.5 mmol) and ammonium chloride (671 mg, 12.5 mmol) to the solution of nitroaniline (280 mg, 1.25 mmol) from Step 1 in isopropanol (8 mL). Stir the suspension at 60 °C for 10 min, then add formic acid (1.9 mL, 50.2 mmol). Heat the resulting mixture at 60 °C and stir for 2 h. After completion, add EtOAc and centrifuge the suspension. Separate the supernatant and concentrate under vacuum. Purify the residue on silica gel with MeOH / DCM to give the desired 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+).

[0262] Step 3 (Example 665, Table 4): As described in Example 1 (Step 4) of General Method A, the benzimidazole from Step 2 is coupled with chloropyridine A-13 (Ar=2,3-dichlorophenyl) using copper / BINOL catalysis.

[0263] Other examples of inhibitors prepared in a similar manner using a suitable amine in step 1 and Fe or Zn as a reducing agent in step 2 are listed in Table 4 below Method I.

[0263] General method for synthesizing inhibitors of W-IX (Method J) - Synthesis of Example 600:

[0263]

[0264] Step 1: Piperidine-4-carboxynitrile 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-nitroaniline (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 as is for the next step. MS m / z 247.2 (MH+).

[0265] Step 2: Add ammonium chloride (685 mg, 12.8 mmol) and zinc (419 mg, 6.41 mmol) to the nitroaniline solution from Step 1. Stir the resulting suspension at 40 °C for 1 h. Dilute the reaction mixture with EtOAc (30 mL) and then centrifuge. Separate the supernatant and concentrate under vacuum. Use the resulting 1,2-phenylenediamine (101 mg, 73%) as is in the next step. MS m / z 217.2 (MH+).

[0266] Step 3: The product from Step 2 was dissolved in AcOH (3 mL), followed by the addition of sodium nitrite (32 mg, 0.647 mmol) and stirring at room temperature for 1 h. The reaction mixture was diluted with EtOAc (60 mL), washed with water (2 × 20 mL), then with a saturated aqueous solution of NaHCO3 (2 × 20 mL), and then with brine (20 mL). The separated organic layer was dried over MgSO4, filtered, and concentrated under vacuum to give the desired benzotriazole (75 mg, 0.330 mmol, 51%). 1H 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(b r.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+).

[0267] Step 4: The solution of benzotriazole (17 mg, 0.076 mmol), 2,3-dichloro-N-[3-[(6-chloropyridino[3,2-d]pyrimidin-4-yl)amino]-2,4-difluoro-phenyl]benzenesulfonamide (30 mg, 0.058 mmol), copper sulfate (II) 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) from Step 3 in DMSO (1.5 mL) was stirred at 100 °C for 3 h. Once completed, the mixture was cooled to room temperature, diluted with DMSO, and purified by HPLC (MeOH + 0.1% formic acid / water + 0.1% formic acid) to obtain Example 600 (11 mg, 25%). 1H 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=10.38Hz,2H),3.20(br.s.,2H),2.11(br.s.,2H),1.96(d,J=10.01Hz,2H). MS m / z 707.2 (MH+).

[0268] Other examples of inhibitors prepared in a similar manner using an appropriate amine in step 1 are listed in Table 4 below method J.

[0268] General method for the synthesis of inhibitors of synthetic WX (method K) - Synthesis of Example 112:

[0268]

[0269] Step 1: 3-Indolesulfonyl 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-sulfonic acid pyridinium (5.30 g, 75% yield) as a white solid. The crude material was used as is in the next step.

[0270] Step 2: The crude 1H-indole-3-sulfonic acid pyridinium (4.60 g, 16.7 mmol) from Step 1 of the previous step was dissolved in a 1:1 mixture of cyclobutane and acetonitrile (50 mL). The white suspension was cooled to 0 °C, and POCl3 (3.42 mL, 36.7 mmol) was added dropwise with stirring to give a light brown solution. The reaction was heated to 70 °C for 1 h. After 1 h, the orange solution was cooled to 0 °C. The cold orange solution was added dropwise to 250 mL of ice water. During the addition, a white precipitate formed. The solid was filtered, washed with water, and dried under vacuum to give a gray solid of 1H-indole-3-sulfonic acid chloride (740 mg, 21% yield).

[0271] Step 3 (General Procedure): The 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 equivalents) was added dropwise. DIPEA (0.24 mL, 1.39 mmol) was then added and the reaction mixture was heated to room temperature. The progress of the reaction 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 and brine, dried over MgSO4, filtered, and concentrated to obtain the desired sulfonamide.

[0272] Step 3 (R1=R2=Me, Example 112): Sulfochloride (200 mg, 0.9 mmol) was placed in a 25 mL flask, and THF (4 mL) was added, followed by dimethylamine hydrochloride (2 equivalents, 150 mg, 1.9 mmol) and DIEA (4 equivalents, 0.65 mL, 3.7 mmol). The solution quickly turned pale yellow, and a yellow, gelatinous oily substance settled at the bottom. After stirring at RT for 20 minutes (LCMS showed complete consumption of sulffochloride), the mixture was partitioned between EtOAc and a saturated NH4Cl solution. The aqueous layer was extracted with EtOAc, and the combined organic layers were washed once more with a saturated NH4Cl solution, followed by washing with brine. Subsequently, it was dried over MgSO4, filtered, and concentrated to dryness to obtain 65 mg of beige crystalline solid, which was used as is without further purification: ¹H NMR (DMSO-d6) δ: 12.17 (br.s., ¹H), 7.96 (d, J=3.1 Hz, ¹H), 7.81 (d, J=7.8 Hz, ¹H), 7.49–7.57 (m, ¹H), 7.22–7.28 (m, ¹H), 7.16–7.22 (m, ¹H), 2.58 (s, 6H). MS m / z 225.1 (MH+).

[0273] Step 4 (Example 112, Table 4): Prepared using general method A from indolesulfonamide and chloropyridine A-13 (Ar=2-chlorophenyl) from step 3.

[0274] Other examples of inhibitors prepared in a similar manner using an appropriate amine in step 1 are listed in Table 4 under method K.

[0274] Preparation of Example 69:

[0274]

[0275] Step 1: Following general synthesis method A, chloropyridine A-13 (Ar=4-methoxy-2-tolyl) was coupled with 3-cyanoindole in DMSO at 100°C in the presence of copper powder, BINOL and cesium carbonate to provide a crude desired 3-cyanoindole derivative after treatment with acidic aqueous solution and extraction into EtOAc. The substance was used directly in step 2, but aliquots of the cyano derivative were purified by reverse-phase HPLC for characterization: 1H 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 = 8.2 Hz, 1H), 7.76–7.87 (m, 1H), 7.68 (d, J = 9.0 Hz, 1H), 7.39–7.59 (m, 2H), 7.15–7.32 (m, 2H), 6.95 (d, J = 2.7 Hz, 1H), 6.87 (dd, J = 8.8, 2.5 Hz, 1H), 3.79 (s, 3H), 2.58 (s, 3H). MS m / z 598.1 (MH+).

[0276] Step 2: The crude nitrile (35 mg, 1.0 equivalent) from Step 1 and ethanol (0.5 mL) were placed in a 4 mL vial, followed by 102 μL of 4N NaOH (7 equivalent), yielding a deep yellow solution. Approximately 30 μL (4 equivalent) of 30% hydrogen peroxide aqueous solution was added to this solution at room temperature (some bubbles were observed). After stirring for 10 minutes at room temperature, LCMS showed a new peak indicating complete consumption of the starting material and formation of the acetylamine product. The reaction was quenched by adding some sodium thiosulfate crystals and 0.5 mL of acetic acid. The solution was then diluted to 2 mL with methanol, filtered, and purified by preparative HPLC (MeOH / H2O / 0.1% formic acid conditions, 50%→100% methanol gradient). Appropriate fractions were separated and partially concentrated to remove methanol. The resulting suspension was dissolved by adding a few mL of acetonitrile, and the solution was then frozen and lyophilized. 7.4 mg of the inhibitor of Example 69 as a yellow solid was obtained.

[0277] Example 104 was prepared in a similar manner using A-13 (Ar=2-chlorophenyl).

[0277] Preparation of Examples 70, 83 and 85:

[0277]

[0278] Example 70: 7-Nitrobenzimidazole is prepared from 3-nitrophenyl-1,2-diamine as described in J. Chem. Phys. 2011, 115, 11403 and coupled with A-13 (Ar = 4-methoxy-2-tolyl) using general method A.

[0279] Step 1 (Example 83): 7-Nitrobenzimidazole (see Example 70, 250 mg) and 20% Pd(OH)2 / C (Pellmann catalyst, 10 mg, 0.01 equivalent) were suspended in MeOH (3 mL) and stirred for 4 h under a H2 balloon atmosphere (SM was slowly added to the solution as reduction proceeded). After complete conversion as shown by LCMS, the suspension was filtered through a membrane, washed with MeOH, and volatile components were removed under reduced pressure. The substance was used without further purification: 1H NMR (DMSO-d6) δ: 7.99 (s, 1H), 6.87 (t, J = 7.8 Hz, 1H), 6.73 (d, J = 7.8 Hz, 1H), 6.35 (d, J = 7.8 Hz, 1H).

[0280] Step 2 (Example 83): Using the aminobenzimidazole and chloropyridine A-13 (Ar = 2-chlorophenyl) from Step 1 and General Method A, after two consecutive reverse-phase HPLC purifications using a gradient of 30→100% MeOH-0.1% formic acid followed by 10→100% MeCN-0.1% AcOH, the inhibitor of Example 83, 1H, was separated. 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),7.47-7.5 6(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.

[0281] Other examples of preparations using aminobenzimidazole (fragment A31) from step 1 and the corresponding A-13 chloropyridine in a similar manner are listed in Table 4 under method A.

[0282] Step 3 (Example 85): Dissolve the aminobenzimidazole (23 mg) from Step 2 in acetic acid (1 mL) and add acetic anhydride (13 mg, 3 equivalents). Stir at RT for 3 h (LCMS showed complete conversion to the desired mass). Dilute the substance to 1.8 mL with DMSO and purify by preparative HPLC using a gradient of 30→100% MeOH-0.1% formic acid.

[0282] Preparation of Example 75:

[0282]

[0283] Step 1: 7-Benzimidazolium carboxylic acid (500 mg, 3.1 mmol) was suspended in DCM (5 mL) and one drop of DMF was added, followed by the addition of oxaliplatin (0.5 mL, 5.9 mmol). The beige slurry was stirred at RT for 1 h. The volatile components were then removed under reduced pressure, and the residue was resuspended in THF and the volatile components were removed again. The residue was then resuspended in THF (5 mL) and concentrated ammonia (1 mL) was added, and the mixture was stirred at RT for 30 min (the beige suspension gradually turned into a brick-colored suspension). LCMS indicated a 1:1 mixture of the starting acid and the desired oxaliplatin. 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.

[0284] Step 2 (Example 75): As described in Example 1 (Step 4) of General Method A, the crude benzimidazole from Step 1 is coupled with chloropyridine A-13 (Ar=4-methoxy-2-tolyl) using copper / BINOL catalysis.

[0284] Preparation of Examples 80 and 81:

[0285] Using the procedure described for Example 69, the nitrile group of the compound of Example 77 was hydrolyzed to the corresponding amide. Example 81 was prepared in a similar manner from Example 78.

[0285] Preparation of Examples 94 and 95:

[0285]

[0286] Step 1: Add 1.1 equivalents of 1-ethoxyvinyl-tributyltin (42 mg, 0.11 mmol) to the suspension of starting chloropyridinium-pyrimidine A-13 (Ar = 2-chlorophenyl, 50 mg, 0.1 mmol) in acetonitrile (2 mL). Bubble the mixture through nitrogen for 5–7 minutes, then add palladium tetra(triphenylphosphine)dichloride (0.1 equivalents, 7 mg). Bubble the suspension through nitrogen again for 4–5 minutes, then seal the vial and heat the mixture at 80 °C to obtain a pale yellow solution. Stir at this temperature for 18 h (LCMS indicates conversion complete). Cool the mixture to room temperature, filter through a celite® stopper to remove insoluble black particles, and wash with EtOAc. Concentrate the filtrate under reduced pressure to dryness, and the resulting pale yellow foam (108 mg) is used as is without further purification: MS m / z 518.0 (MH+).

[0287] 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 at room temperature, followed by 1.1 equivalents of N-bromosuccinimide (20 mg, 0.11 mmol). 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 poured into 4–5 mL of DCM, dried over Na2SO4, filtered, and concentrated. The residue was purified by rapid chromatography through a 3 g silicone cartridge using a gradient from 10% EtOAc / hexane to 60% EtOAc / hexane. The appropriate fractions were combined and concentrated to obtain the desired product as a pale yellow solid, which was then used as is in the next step (1H NMR and LCMS showed some contamination by succinimide): 1H NMR (DMSO-d6) δ: 10.38 (s, 1H), 8.58 (s, 1H), 8.35–8.42 (m, 2H), 7.91 (dd, J=7.8, 1.2 Hz, 1H), 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+).

[0288] Step 3: Thiourea (5 mg, 0.07 mmol, 1.5 equivalents) was added to the suspension of crude bromomethyl ketone (25 mg, 0.04 mmol) from Step 2 in ethanol (1 mL). The resulting mixture was heated 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 / H2O / 0.1% formic acid conditions, 50%→100% methanol gradient). Appropriate fractions were separated and partially concentrated to remove methanol. The resulting suspension was dissolved by adding a few mL of acetonitrile, and then the solution was frozen and lyophilized. 5.5 mg of the desired product as a yellow solid was obtained (Example 94).

[0289] Example 95 was prepared by replacing thiourea in step 3 with 3-carboxythioamine of 1,2,4-oxadiazole.

[0289] Preparation of Examples 96 and 115:

[0289]

[0290] Step 1: Methyl 4-nitro-3-indolecarboxylate is prepared by nitration of methyl 3-indolecarboxylate, as described in WO 2008 / 113760 and Bioorg.Med.Chem.Lett.2011,21,1782. The indole derivative is reacted with chloropyridine A-13 (Ar=2-chlorophenyl) under standard conditions of general method A.

[0291] Step 2: The crude methyl ester (33 mg, 0.05 mmol) from Step 1 was suspended in MeOH (1 mL), and 4N NaOH (75 μL, 6 equivalents) and LiOH (2 mg, 0.05 mmol) were added. The mixture was stirred at RT for 18 h and then at 50 °C for 2 h to complete the conversion (LCMS). The reaction mixture was then acidified with 1N HCl and the precipitate was collected by filtration, washed with water and dried under vacuum to give the desired carboxylic acid (30 mg): MS m / z 650.0 (MH).

[0292] Step 3: Dissolve the crude nitroindolecarboxylic acid (30 mg, 0.046 mmol) from Step 2 in NMP (0.8 mL). Add 8 equivalents of DIEA (64 μL) to the yellow solution, followed by 2 equivalents of HATU (35 mg). Stir the mixture for 2–3 min, then add dimethylamine hydrochloride (7.4 mg, 2 equivalents). Stir the resulting deep yellow solution at room temperature for 3 h, at which point the reaction is confirmed to be complete by LCMS. Quench the reaction by adding 1 N HCl solution until an acidic pH is obtained. Dilute the mixture with 8 mL of water, sonicate, and collect the solid by filtration through a small sintered glass funnel. The solid is then dried under reduced pressure overnight, and the product (27 mg) is used as is for subsequent nitro reduction: MS m / z 679 (MH+).

[0293] Step 4: Add 4 equivalents of SnCl₂-2H₂O (36 mg) to the suspension of crude acid (27 mg, 0.040 mmol) from Step 3 in ethanol (1 mL) and EtOAc (0.5 mL). Heat the resulting mixture to 60 °C and stir for 2 h (as indicated by LCMS). Concentrate the mixture to remove EtOH, then dilute with EtOAc (4 mL) and water (0.5 mL). Add about 1 mL of 1N NaOH solution to the thick emulsion / suspension, but do not clarify the mixture. Concentrate the mixture to almost dryness, then add about 0.5 g of sodium sulfate decahydrate along with some freshly prepared EtOAc to the flask. Sonicate the suspension, decantate, and filter the EtOAc extract. Repeat once with EtOAc, then once with DCM, and then once with a 1:1 mixture of both. The combined extracts were then dried over Na2SO4, filtered once, and concentrated. The residue was poured into DMSO (1.5 mL) and purified by preparative HPLC (MeOH / H2O / 0.1% formic acid, 50%→100% methanol gradient). Appropriate fractions were separated and partially concentrated to remove methanol. The resulting suspension was dissolved by adding a few mL of acetonitrile, and the solution was then frozen and lyophilized (Example 96: 6.6 mg as a yellow solid).

[0294] Example 115 was prepared in a similar manner by replacing the dimethylamine hydrochloride in step 4 with morpholine.

[0294] Preparation of Example 100:

[0294]

[0295] Step 1: Using the procedure described in WO 2010 / 069833, prepare 7-nitrobenzotriazole as an orange-pink solid from 3-nitro-1,2-phenylenediamine: 1H NMR (DMSO-d6) δ: 8.58 (d, J=8.2 Hz, 1H), 8.46 (d, J=7.8 Hz, 1H), 7.63 (t, J=8.0 Hz, 1H).

[0296] Step 2: Using a hydrogen balloon atmosphere, the nitrobenzotriazole from Step 1 is hydrogenated on carbon-supported 20% Pd(OH)2 to provide the desired aminobenzotriazole as an orange solid, which is used without purification: 1H 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).

[0297] Step 3: Using the aminobenzotriazole from Step 2, chloropyridine A-13 (Ar = 2,3-dichlorophenyl), and general method A, the inhibitor of Example 100 is formed as a mixture of isomers, which are separated by reverse-phase HPLC under normal conditions. Example 100 is present in the most abundant isomer form.

[0298] Other examples prepared in a similar manner and using the corresponding A-13 chloropyridine include Examples 91-93 and 206.

[0298] Preparation of Example 103:

[0299] The compound was prepared by using the corresponding 3-cyanoindazole instead of 3-cyanoindole and A-13 (Ar=2-chlorophenyl) according to the procedure described for Example 69.

[0299] Preparation of Example 116:

[0299]

[0300] Step 1: Prepare 3-benzyloxy-1,2-phenylenediamine according to the procedure described in WO1992 / 021663A1. The diamine (1.00 g, 4.67 mmol) was suspended in formic acid (10 mL), and the mixture was stirred at 100 °C for 4 h (LCMS indicated complete conversion). The reaction mixture was cooled to RT, and most of the formic acid was removed under reduced pressure. The residue was slowly added to an excess of saturated NaHCO3 aqueous solution (note: foaming). The free base initially appeared as a dark beige gel, but after stirring, it became a light beige precipitate. The product was collected by filtration, washed with water, and dried under vacuum (0.96 g, a 1:1 mixture of tautomers as shown by 1H NMR): 1H NMR (DMSO-d6) δ: 12.72 (br.s., 0.5H), 12.44 (br.s., 0.5H), 8.10 (s, 1H), 7.56 (d, J = 7.0 Hz, 1H), 7.50 (d, J = 7.4 Hz, 1H), 7.29–7.45 (m, 3H), 7.25 (d, J = 7.8 Hz, 0.5H), 7.02–7.18 (m, 1.5H), 6.87 (d, J = 7.8 Hz, 0.5H), 6.75 (d, J = 7.0 Hz, 0.5H), 5.36 (s, 1H), 5.28 (s, 1H). MS m / z 225.1 (MH+).

[0301] Step 2: Using the general procedure of Method A, the benzimidazole from Step 1 was coupled with chloropyridine A-13 (Ar = 3-chloro-2-methyl). After 1 h at 95°C, the reaction mixture was poured into water, acidified with AcOH and a small amount of 1N HCl, and extracted with EtOAc. The extract was washed with water and brine, dried (MgSO4), and concentrated under reduced pressure. The residue and char (5 mg) supported catalyst were suspended in 20% Pd(OH)2 in THF (3 mL) + AcOH (1 mL) and stirred under H2 balloon 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 DMSO and purified by preparative HPLC using a gradient of 50-100% MeOH-0.1% HCOOH. Example 116 (90% homogeneity) was obtained.

[0301] Preparation of Example 117:

[0301]

[0302] Step 1: Prepare 3-benzyloxy-1,2-phenylenediamine according to the procedure described in WO1992 / 021663A1. 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 in portions. A slightly exothermic reaction occurred, with a small amount of gas escaping. The mixture was stirred at RT for 15 min and then at 60 °C for 3.5 h (LCMS showed complete conversion). The reaction mixture was cooled to RT, diluted with an equal volume of water, and stirred at RT for 1 h, then 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 = 7.8 Hz, 1H), 5.36 (s, 2H). MS m / z 226.1 (MH+).

[0303] Step 2: Following the same procedure as described for Example 116, the benzotriazole (30 mg) from Step 1 was coupled with 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 obtain Example 117 (15 mg).

[0303] Preparation of Examples 120-122:

[0304] Using the general method D described for Example 127, methyl 5-methylpyrazole-3-carboxylate is used instead of methyl indazole-3-carboxylate in step 1.

[0304] Preparation of Examples 136-138:

[0305] Using the general method D described for Example 127, ethyl 2-methyl-indazole-4-carboxylate was used instead of methyl indazole-3-carboxylate in step 1.

[0305] Preparation of Examples 145 and 146:

[0306] Using the general method D described for Example 127, methyl pyrazole-3-carboxylate is used instead of methyl indazole-3-carboxylate in step 1.

[0306] Preparation of Examples 147 and 148:

[0307] Using the general method D described for Example 127, ethyl 3-methylpyrazole-4-carboxylate was used instead of methyl indazole-3-carboxylate in step 1. An 85:15 mixture of isomers was used in step 2. Examples 147 and 148 were isolated as major components.

[0307] Preparation of Examples 149 and 150:

[0307]

[0308] Aminobenzimidazole (Example 83, 30 mg) was dissolved in pyridine (0.5 mL) and morpholinamine methyl chloride (31 mg, 4 equivalents) was added. The mixture was stirred at 60 °C for 2 h (as shown by LCMS to be completely converted to the desired mass). The purple-red solution was concentrated under reduced pressure, and the residue was dissolved in 3:1 DMSO-AcOH (1.8 mL). The substance was purified by preparative HPLC using a gradient of 50%→100% MeOH-0.1% HCOOH.

[0309] Example 150 was prepared in a similar manner but using N,N-dimethylamine methyl chloride instead of morpholinamine methyl chloride. The reaction was heated to 75°C for 18 hours to complete the reaction.

[0309] Preparation of Examples 151 and 152:

[0310] Using the general method D described for Example 127, methyl 1,2,4-triazole-3-carboxylate is used instead of methyl indazole-3-carboxylate in step 1.

[0310] Preparation of Examples 153-155:

[0311] Using the general method D described for Example 127, ethyl 4-methylpyrazole-3-carboxylate was used instead of methyl indazole-3-carboxylate in step 1.

[0311] Preparation of Example 207:

[0311]

[0312] Step 1: At -78°C, n-butyllithium (6.24 mL, 9.98 mmol, 1.6 M in hexane) was slowly added to a solution of 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (1.80 g, 9.1 mmol) in anhydrous THF (16 mL) prepared according to the procedure described in WO 2013 / 041457. Once the addition was complete, the pale yellow solution was stirred at -78°C for 5 minutes, followed by the slow addition of carbon tetrabromide (3.31 g, 9.98 mmol) in 8 mL of THF. The solution turned deep yellow, then very deep yellow at the end of the addition. It was stirred at the same temperature for 15 minutes, followed by quenching with saturated ammonium chloride solution. After warming to room temperature, EtOAc was added and the dark brown to black biphase mixture was treated with celite® and filtered to promote phase separation. The layers were separated, and the aqueous layer was extracted twice more with EtOAc. The combined organic layers were washed once with brine, dried over MgSO4, and filtered. After concentration, the residue was purified by rapid column chromatography (combiflash, 40 g column, 0%→40% EtOAc / hexane; by TLC, the product was slightly visible under UV light, and the fractions were examined using KMnO4 staining). 1.944 g of the desired product as a pale yellowish-brown oil was obtained: ¹H NMR (CDCl3) δ: 7.11 (d, J=1.2 Hz, 1H), 7.06 (d, J=1.2 Hz, 1H), 5.28 (s, 2H), 3.54 (t, J=7.8 Hz, 2H), 0.92 (t, J=8.2 Hz, 2H), 0.00 (s, 9H).

[0313] Step 2: N-toluenesulfonyl-3-indoleboronic acid ester (132 mg, 0.33 mmol), bromoimidazole (111 mg, 0.4 mmol) from the SEM-protected solution of Step 1, potassium carbonate (184 mg, 1.33 mmol), DMF (3 mL), and water (1 mL) were placed in a microwave-safe vial. Nitrogen gas was bubbled through the suspension for 3–4 min. Tetra(triphenylphosphine)palladium(0) (19 mg, 0.017 mmol) was added, and nitrogen gas was bubbled through the mixture again for 3–4 min under sonication. The vial was then capped and irradiated in the microwave at 80 °C for 1 h. At this point, LCMS analysis showed that the borate ester had been consumed. The reaction mixture was cooled to room temperature, then diluted with water and extracted three times with a 2:1 EtOAc / hexane mixture. The combined organic layers were washed twice with water and once with brine. The mixture was then dried over MgSO4, filtered, and concentrated. The residue was purified by rapid chromatography (isco combiflash, 12g silicone column, 0%→35% EtOAc / hexane gradient). After combining and concentrating appropriate fractions, 33 mg of the desired product was obtained (along with 8 mg of homocoupled bisindole byproduct): ¹H NMR (CDCl₃) δ: 8.20 (d, J = 7.8 Hz, 1H), 8.09 (s, 1H), 8.03 (d, J = 8.2 Hz, 1H), 7.79 (d, J = 8.6 Hz, 2H), 7.38 (t, J = 7.4 Hz, 1H), 7.32 (t, J = 7.8 Hz, 1H), 7.20–7.26 (m, 3H), 7.14 (s, 1H), 5.32 (s, 2H), 3.64 (t, J = 8.2 Hz, 2H), 2.35 (s, 3H), 1.01 (t, J = 8.6 Hz, 2H), 0.04 (s, 9H). MS m / z 468.0 (MH⁺).

[0314] Step 3: The product from Step 2 (32 mg) was dissolved in methanol (3 mL) and pulverized potassium hydroxide (115 mg, 30 equivalents) was added. The resulting solution was refluxed for 4 h (LCMS showed complete consumption of the starting material). The reaction was quenched by adding saturated ammonium chloride, followed by the addition of water and EtOAc. The layers were separated and the aqueous layer was extracted again with EtOAc. The combined organic extracts were washed once with water, then once with brine, dried over MgSO4, filtered, and concentrated. After drying under reduced pressure, the desired indole derivative (23 mg) was obtained as a beige solid, which was used as is in the next step: MS m / z 324.0 (MH+).

[0315] Step 4: Following general method A, under copper catalysis, chloropyridine A-13 (Ar = 2,3-dichlorophenyl, 38 mg, 0.07 mmol) was coupled with indole (23 mg, 0.07 mmol) from step 3 by heating at 100 °C for 1.5 h to provide the expected crude product (65 mg) directly for 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 = 7.8 Hz, 1H), 7.90 (d, J = 7.8 Hz, 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),7.2 3(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+).

[0316] Step 5: The substance protected by crude SEM from Step 4 was suspended in 2 mL of ethanol, followed by the addition of 1 mL of 6N HCl. The resulting suspension was heated to 80°C and stirred at this temperature for 4.5 h. The reaction was then concentrated to a residue, which was redissolved in 1.5 mL of DMSO, filtered, and the filtrate was purified by preparative HPLC (MeOH / H2O / 0.1% formic acid, 30%→100% methanol gradient). Fractions containing the desired product were contaminated with co-dissolved impurities. The fractions were combined, concentrated, and lyophilized. The powder was redissolved in DMSO / MeOH and purified a second time by preparative HPLC (MeOH / H2O / 0.05% TFA, 30%→100% methanol gradient). The appropriate fractions were concentrated, frozen, and lyophilized to obtain 16.3 mg of the desired product 207 as a TFA salt (yellow powder).

[0316] Preparation of Example 208:

[0316]

[0317] Step 1: Methyl 1H-indazole-3-carboxylate (350 mg, 1.98 mmol) was placed together with 5 mL of anhydrous EtOH and hydrazine hydrate (0.244 mL, 4.97 mmol) into a pressure tube. The tube was sealed and heated in an oil bath at 100 °C. After 4 h, the reaction was indicated by LCMS to be complete. The colorless solution was cooled in an ice-water bath with stirring to obtain a significant amount of crystalline substance. The white solid was collected by filtration and washed with a small amount of Et2O. After drying, 255 mg of acehydrazine was obtained: 1H 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).

[0318] Step 2: Add triethylamine (0.59 mL, 4.26 mmol) to the solution of 1H-indazole-3-carbazine (250 mg, 1.42 mmol) from Step 1 in 3 mL of DMF. Cool the colorless solution to 0 °C in an ice-water bath, then add one part di(1H-imidazol-1-yl)methyl ketone (345 mg, 2.13 mmol). The solution immediately turns yellow. Remove it from the ice bath and stir overnight at room temperature. At this point, LCMS analysis of the aliquots showed that the reaction was complete. Dilute it with water, then acidify it with 1N HCl and stir for 10 minutes to destroy any remaining CDI. The white solid was then collected by filtration, dried under reduced pressure, and used as is in the next step (300 mg): MS m / z 203.0 (MH+). Step 3: Following standard method A, under copper catalysis, chloropyridine A-13 (Ar = 2,3-dichlorophenyl, 35 mg, 0.068 mmol) was coupled with indole (25 mg, 0.075 mmol) from step 3 by heating at 100 °C for 1.5 h to provide inhibitor 208 (25 mg) as a beige powder after reverse-phase HPLC purification (MeCN / H2O, 0.1% acetic acid, 60%→100% MeCN gradient).

[0318] Preparation of Example 209:

[0318]

[0319] Step 1: The crude product (80 mg, 0.4 mmol) from Step 2 synthesized in Example 208 was placed into 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 part. The reaction was stirred at room temperature for 60 h. It was then diluted with water and saturated ammonium chloride solution. The resulting suspension was sonicated and the solid was collected by filtration. The solid was washed with water and dried under reduced pressure to obtain 45 mg of the desired product as a grayish-white solid. ¹H NMR (DMSO-d6) δ: 13.75 (br.s., ¹H), 8.12 (d, J = 8.2 Hz, ¹H), 7.66 (d, J = 8.2 Hz, ¹H), 7.48 (t, J = 7.6 Hz, ¹H), 7.31 (t, J = 7.6 Hz, ¹H), 3.12 (s, 6H). MS m / z 230.1 (MH+).

[0320] Step 2: Following general method A, under copper catalysis, chloropyridine A-13 (Ar = 2,3-dichlorophenyl, 35 mg, 0.068 mmol) was coupled with indole (17 mg, 0.075 mmol) from step 3 by heating at 100 °C for 1.5 hours. The mixture was then cooled to room temperature and quenched by adding 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 (32 mg) was obtained as a beige powder.

[0321] Example 210 was prepared in a similar manner by replacing the methylamine hydrochloride in step 1 with dimethylamine hydrochloride. Example 211 was prepared by replacing the dimethylamine hydrochloride in step 1 with 4-methoxybenzylamine. After coupling with chloropyridine A-13 (Ar = 2,3-dichlorophenyl), the PMB protecting group was removed by heating in DCM at 60°C-70°C for 6 h.

[0321] Preparation of Example 212:

[0321]

[0322] Step 1: Prepare 3-iodoinazole by iodination of indazole according to the procedure described in WO 2011 / 138265.

[0323] Step 2 / 3: Protect 3-iodoinazole as an N-Boc derivative and tin-alkylate it to a 3-trimethyltinane derivative according to the procedure described in WO 2016 / 058544.

[0324] Step 4: The stanane derivative from Step 3 (270 mg, 0.71 mmol) was placed into a 4 mL vial, followed by 2-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazolium (197 mg, 0.71 mmol), tetrakis(triphenylphosphine)palladium (0) (41 mg, 0.035 mmol), and 2 mL of toluene prepared in Step 1 of Example 207. The vial was degassed with argon for 2 minutes, then sealed and heated at 110 °C for 20 h. The black reaction mixture was poured into water, extracted with EtOAc, washed with brine, and dried (MgSO4). The product was concentrated to give a mixture of N-Boc (42 mg) and NH-indazole (54 mg) products, which could be separated by rapid chromatography. N-Boc product: 1H 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 product was suspended in DCM and TFA (150 μL) was added. After stirring for 2 hours, the conversion to deprotected indazole was determined by LCMS. Toluene (2 mL) was added and the volatile components were removed under reduced pressure to obtain the desired indazole, which was used in the next step without further purification: MS m / z 315.2 (MH+).

[0325] Step 5: Using general method A, the starting chloro-pyridopyrimidine A-13 (Ar = 2,3-dichlorophenyl, 58 mg, 1 equivalent) was coupled with the indazole from Step 4 (41 mg, 1.15 equivalent). After stirring at 100°C for 3 h, the reaction was shown to be complete by LCMS. The mixture was cooled to room temperature and then quenched by adding 0.15 mL of acetic acid. Water (5 mL) was then added and the suspension was sonicated. The solid was collected on a sintered glass filter and washed with water and hexane (54 mg). The crude material was dissolved in TFA (0.5 mL) and stirred at room temperature for 3 h, at which point LCMS showed complete deprotection of SEM groups. The mixture was concentrated to a residue and then poured into 1 mL of DMSO and 0.5 mL of MeOH. The mixture was filtered and the filtrate was purified by preparative HPLC (MeOH / H2O, 0.05% TFA, 60%→100% MeOH gradient). The appropriate fractions were separated and concentrated to remove methanol. Acetonitrile was added, and the solution was frozen and lyophilized. Example 212 (21.5 mg) was obtained as a yellow solid.

[0326] Example 213 was prepared in a similar manner using the corresponding A-13 (Ar=2-chlorophenyl).

[0326] Preparation of Example 223:

[0326]

[0327] Step 1: Protect tryptamine as a Boc-carbamate and oxidize it to a protected aminomethyl ketone as described in J.Am.Chem.Soc.2004,126,12888.

[0328] Step 2: Using general method A, the indole derivative from Step 1 was coupled with A-13 (Ar = 2-chlorophenyl). The crude product was deprotected by stirring in a 2:1 DCM-TFA solution for 30 minutes. Example 223 (yellow solid) was separated into TFA salts after reverse-phase HPLC purification (30% → 100% MeOH - 0.05% TFA).

[0328] Preparation of Example 224:

[0328]

[0329] At room temperature, 1N sodium hydroxide solution (0.082 mL, 0.082 mmol) was added to a suspension of crude aminomethyl ketone 223-TFA salt (50 mg, 0.068 mmol) in methanol (0.6 mL). The suspension turned into a dark solution. Then, 37 wt% formic acid solution (55 mg, 0.681 mmol) was added and the mixture was stirred at 40 °C for 5 min. Sodium cyanoborohydride (13 mg, 0.20 mmol) was added and the solution was stirred at 50 °C for 2 h (LCMS showed complete consumption of the starting material and formation of the desired product). The reaction was quenched by adding 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% → 100% MeOH - 0.1% formic acid). The appropriate fraction was separated and concentrated to remove methanol, then frozen and lyophilized. Example 224 (3.3 mg) was obtained as a pale yellow solid.

[0329] Preparation of Example 237:

[0329]

[0330] Step 1: Following a similar procedure to that described in Method E for the preparation of E-3 (Step 2), but replacing DMF with N,N-dimethylacetamide for the carbonylation step, convert bromobenzimidazole E-2, as described in general Method E (Step 1), into an acetyl derivative. A product as a brown solid (131 mg) is obtained, which is used directly in the next step.

[0331] Step 2: Using general method A, the benzimidazole derivative (50 mg) from step 1 is coupled with A-13 (Ar = 2-chlorophenyl, 130 mg) at 100 °C for 3 hours. A crude intermediate (168 mg) in the form of a brown solid was obtained and used directly in the next step: 1H NMR (DMSO-d6) δ: 10.53 (br.s., 1H), 9.84 (s, 1H), 9.45 (br.s., 1H), 8.66 (d, J = 8.2 Hz, 1H), 8.47–8.59 (m, 3H), 7.92 (dd, J = 7.8, 1.2 Hz, 1H), 7.86 (d, J = 7.0 Hz, 1H), 7.61–7.71 (m, 2H), 7.55 (t, J = 7.8 Hz, 1H), 7.47–7.53 (m, 1H), 7.28 (td, J = 8.7, 5.7 Hz, 1H), 7.22 (t, J = 9.2 Hz, 1H), 3.01 (s, 3H). MS m / z 605.8 (MH+).

[0332] Step 3: Morpholine (17 mg, 0.20 mmol) was added together with 1 mL of methanol to a 1-drylan vial. Then, 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 another 7 hours. After ~70% conversion (LCMS), the reaction was quenched by adding 0.5 mL of DMSO containing acetic acid solution (0.2 mL). The solution was filtered and purified by preparative HPLC (30% → 100% MeOH - 0.1% formic acid). The appropriate fractions were separated and concentrated to remove methanol, followed by freezing and lyophilization. Example 237 (10 mg) was obtained as a pale yellow solid.

[0333] In a similar manner, dimethylamine hydrochloride was used instead of morpholine and an equal amount of 4N NaOH was added to neutralize the hydrochloride to obtain Example 238.

[0333] Preparation of Examples 239 and 652 (Table 5):

[0333]

[0334] Step 1: 10 g of 2-chloro-6-fluoroaniline 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 h. LCMS analysis showed that the reaction was complete. The volatile components were removed under reduced pressure, and the residue was dissolved in DCM and slowly neutralized with saturated NaHCO3 solution. The layers were separated, and the aqueous layer was extracted three times with DCM. The combined organic layers were washed once with water, dried over MgSO4, filtered, and concentrated. After vacuum drying, the desired product (12.79 g) in white to pale pink crystals was obtained: 1H 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+).

[0335] Step 2: Pour the acetanilide (12.75 g) from Step 1 into 25 mL of concentrated sulfuric acid and cool to 0°C in an ice bath. Slowly add nitric acid (90%, 3.31 mL). After 5-10 minutes, the mixture solidifies. Heat to room temperature, producing a thick, purplish-red slurry. After a total of 4 hours, monitor the reaction by LCMS, showing some remaining starting material. Add another 5 mL of sulfuric acid to improve flowability, followed by 0.3 mL of 90% nitric acid. Stir the mixture at room temperature for another 18 hours. Then cool the mixture to 0°C and pour it onto crushed ice (approximately 150 mL). Once the ice melts, sonicate the suspension and collect the yellow solid by filtration, wash with water, and dry (15.1 g crude product). Pour the crude solid into 50 mL of acetonitrile and reflux to obtain a clear, deep red solution. Stop heating and allow the mixture to cool to room temperature for 1 hour, then stir at room temperature for 2 hours. At that time, the mixture solidified into a block, which was broken up with a spatula and sonicated. The solid was then collected by filtration and washed with a small amount of cold acetonitrile. As shown by NMR, the desired grayish-white nitro compound (6.63 g) was obtained as a single regioisomeric compound (the mother liquor produced a second batch of 2.16 g containing 7% 6-chloro-2-fluoro-3-nitroacetanilide): 1H NMR (CDCl3) δ: 7.90 (dd, J=9.2, 4.9 Hz, 1H), 7.24 (dd, J=9.2, 8.4 Hz, 1H), 6.98 (br.s., 1H), 2.28 (s, 3H). MS m / z 233.0 (MH+).

[0336] Step 3: Add NH4Cl solution (60 mg, 1.12 mmol) in 1.35 mL of water to the solution of nitroacetanilide (500 mg, 2.15 mmol) from Step 2 in 15 mL of ethanol. Heat the mixture to 70 °C, then add iron powder (600 mg, 10.75 mmol) in three portions, 10 minutes apart. Stir the resulting dark red to purplish-red mixture at 70 °C for 20 h. At this point, LCMS of filtered aliquots of the reaction mixture showed that the reaction was complete. Filter the mixture using a celite® pad. Concentrate the dark brown filtrate to dryness, then pour it into EtOAc containing MgSO4. Stir the suspension, then filter to obtain a clear, pale yellow solution. The solution was concentrated to dryness to obtain the desired product (440 mg) as a pale yellow solid, which was used as is without further purification: ¹H NMR (CDCl₃) δ: 6.92 (t, J = 9.0 Hz, ¹H), 6.76 (br.s., ¹H), 6.68 (dd, J = 8.6, 4.7 Hz, ¹H), 3.98 (br.s., 2H), 2.24 (br.s., 3H). MS m / z 203.1 (MH⁺).

[0337] Step 4: Sulfonate the aniline from Step 3 using 4-methoxybenzenesulfonyl chloride in the usual manner described for A-9 in General Method A: ¹H NMR (DMSO-d6) δ: 9.89 (s, ¹H), 9.67 (s, ¹H), 7.57–7.74 (m, 2H), 7.23 (t, J = 9.2 Hz, 1H), 7.13 (dd, J = 8.8, 5.3 Hz, 1H), 7.02–7.10 (m, 2H), 3.82 (s, 3H), 2.00 (s, 3H). MS m / z 373.0 (MH+).

[0338] Step 5: The acetanilide (200 mg, 0.54 mmol) from Step 4 was added to 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 heated to 80°C and stirred for 1 hour. At this point, 1 mL of ethanol was added to improve solubility. The mixture was stirred at the same temperature for another 5 hours (at which point, the mixture became a clear yellow solution). LCMS analysis showed <3% of the starting material remaining. The mixture was concentrated to remove most of the ethanol and then cooled on ice. It was alkalized to pH 5-6 with 4N NaOH. The resulting suspension was sonicated, and the solids were collected by filtration and washed with water. After drying under reduced pressure, the desired product was obtained in the form of 156 mg beige solid: ¹H 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, 8.8 Hz, ¹H), 6.36 (dd, J = 8.6, 5.1 Hz, 1H), 5.39 (s, 2H), 3.81 (s, 3H). MS m / z 329.0 (MH).

[0339] Step 6: As described for the preparation of A-13 in general method A, aniline (75 mg, 0.23 mmol) from step 5 is coupled with dichloropyridinidine A-12 (125 mg, 0.63 mmol) from AcOH at 50 °C. The expected product (125 mg) as a beige solid was obtained: ¹H NMR (DMSO-d6) δ: 10.18 (s, ¹H), 9.95 (s, ¹H), 8.50 (s, ¹H), 8.27 (d, J = 8.6 Hz, ¹H), 7.99 (d, J = 9.0 Hz, ¹H), 7.65–7.69 (m, 2H), 7.33 (t, J = 9.0 Hz, 1H), 7.26 (dd, J = 9.0, 5.5 Hz, 1H), 7.04–7.12 (m, 2H), 3.81 (s, 3H). MS m / z 496.0 (MH+).

[0340] Step 7 (Example 239, Table 5): As described in Example 1 (Step 4) of General Method A, benzimidazole is coupled with chloropyridine from Step 6 using a copper / BINOL catalysis.

[0341] Example 652 (Table 5) was prepared in a similar manner using 2,3-dichlorophenylsulfonyl chloride from step 4 and fragment A31 from step 7.

[0341] Preparation of Examples 240, 646 and 647 (Table 5):

[0341]

[0342] Step 1: Dissolve 2-fluoro-3-nitrobenzoic acid (1.50 g, 8.1 mmol) in DCM (7 mL) and add 2 drops of DMF, followed by fractional addition of oxalic acid chloride (1.23 mL). Stir the mixture at RT for 0 min, then remove the volatile components under reduced pressure and dry the acid chloride residue under vacuum for 1 / 2 h. Dissolve the white solid in DCM (5 mL) and add DMF (3 mL), followed by addition of NaN3 (0.58 g, 1.1 equivalents). Stir at RT for 35 min. Then add tertiary BuOH (0.86 mL) and preheat the mixture in an oil bath to 65 °C. Reflux the mixture for 4 h (N2 escapes). Cool back to RT, remove DCM under reduced pressure, pour into water (100 mL), and extract the product into EtOAc. Wash the extract with NaHCO3, water, and brine and dry (MgSO4). Concentration under reduced pressure yielded a pale yellow crystalline solid, which was then dried under vacuum: ¹H NMR (CDCl₃) δ: 8.46 (t, J = 7.2 Hz, ¹H), 7.59–7.73 (m, ¹H), 7.24 (td, J = 8.6, 1.0 Hz, ¹H), 6.87 (br.s., ¹H), 1.55 (s, 9H). MS m / z 155.1 (MH-Boc).

[0343] Step 2: The nitroaromatic hydrocarbon (0.74 g) from Step 1 and 4 N HCl in dioxane (5 mL) were stirred at RT for 18 h (a precipitate gradually formed in the first 30 min). LCMS showed complete conversion. The precipitate was diluted with diethyl ether (30 mL), collected, washed with ether, and dried in air. White solid (0.45 g): 1H NMR (DMSO-d6) δ: 7.14–7.20 (m, 1H), 7.04–7.14 (m, 2H).

[0344] Step 3: The aniline hydrochloride (143 mg, 0.74 mmol) from Step 2 and dichloropyridinidine A-12 (178 mg, 0.89 mmol) were suspended in AcOH (3 mL), and the mixture was stirred at 55 °C until aniline was completely consumed as shown by LCMS (add additional A-13 as needed to complete the conversion). The reaction mixture was filtered to remove insoluble hydroxypyrimidine contaminants (washed with AcOH), and the orange filtrate was diluted with water to precipitate the product as a light orange solid. The substance was collected by filtration, washed with water and dried (198 mg): ¹H NMR (DMSO-d6) δ: 10.35 (s, ¹H), 8.65 (s, ¹H), 8.32 (d, J = 8.6 Hz, ¹H), 8.14 (t, J = 6.8 Hz, ¹H), 8.06 (t, J = 7.8 Hz, ¹H), 8.02 (d, J = 8.6 Hz, ¹H), 7.51 (t, J = 8.2 Hz, ¹H). MS m / z 320.0 (MH+).

[0345] Step 4: The nitroaromatic hydrocarbon (198 mg, 0.62 mmol) and the dehydrated tin(II) chloride (630 mg, 2.8 mmol) from Step 3 were suspended in EtOH (7 mL) and the mixture was stirred at 65 °C for 2 h (LCMS showed completion). The reaction mixture was poured into 1 N NaOH and extracted with EtOAc. The extract was washed with water, dried (MgSO4), and concentrated to give aniline (176 mg) as an orange solid: ¹H NMR (DMSO-d6) δ: 9.74 (s, 1H), 8.60 (s, 1H), 8.27 (d, J = 8.6 Hz, 1H), 7.98 (d, J = 9.0 Hz, 1H), 6.99–7.12 (m, 1H), 6.90 (t, J = 8.0 Hz, 1H), 6.66 (td, J = 8.2, 1.6 Hz, 1H), 5.22 (s, 2H). MS m / z 290.1 ​​(MH+).

[0346] Step 5: Dissolve aniline (176 mg, 0.6 mmol) from Step 4 in THF (4 mL) and add pyridine (0.2 mL, 2.4 mmol), followed by 3-chloro-2-toluenesulfonyl chloride (150 mg, 0.67 mmol). Stir the mixture at RT for 18 h (LCMS shows aniline remaining). Add another 25 mg of sulfonyl chloride and continue stirring at 55 °C for another 7 h (LCMS shows completion). Cool the beige slurry to RT, acidify with AcOH (0.25 mL), dilute with 1:1 EtOAc-ethyl ether, collect the solid by filtration, wash with ether and dry (210 mg): 1H NMR(DMSO-d6)δ: 10.61(br.s.,1H),8.86(d,J=4.7Hz,1H),8.58(s,1H),8.29 (d,J=9.0Hz,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),7.3 8(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+).

[0347] Step 6 (Example 240, Table 5): As described in Example 1 (Step 4) of General Method A, benzimidazole is coupled with chloropyridine from Step 5 using copper / BINOL catalysis.

[0348] Example 646 (Table 5) was prepared in a similar manner using 2,3-dichlorophenylsulfonyl chloride from step 5.

[0349] Example 647 (Table 5) was prepared in a similar manner using 2,3-dichlorophenylsulfonyl chloride from step 4 and fragment A31 from step 6.

[0349] Preparation of Example 241 (Table 5):

[0349]

[0350] Step 1: 3-Indazole carboxylic acid (250 mg, 1.5 mmol) was suspended in DCM (3 mL) and oxalic acid (0.26 mL, 3 mmol) was added, followed by 2 drops of DMF. The mixture was stirred at RT for 18 h (to obtain an emulsion suspension). Volatile components 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, forming a white precipitate. After 1 h, the reaction mixture was diluted with 1 N HCl 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: ¹H NMR (CDCl3) δ: 8.40 (d, J = 8.2 Hz, 1H), 8.10 (d, J = 8.2 Hz, 1H), 7.65–7.71 (m, 1H), 7.52 (t, J = 7.4 Hz, 1H), 3.67–3.97 (m, 8H). MS m / z 230.1 (MH).

[0351] Step 2 (Example 241): As described in Example 1 (Step 4) of General Method A, the indazole from Step 1 is coupled with the chloropyridine from Step 5 of Example 240 using copper / BINOL catalysis.

[0351] Preparation of Example 242 (Table 4):

[0351]

[0352] Aminobenzimidazole (50 mg, 0.082 mmol) from Example 99 was dissolved in THF (1 mL) and propionaldehyde (14.2 mg, 0.245 mmol, 3 equivalents) was added. After stirring at RT for 2 minutes, sodium cyanoborohydride (10.2 mg, 0.163 mmol) was added and the mixture was stirred at RT overnight to provide a mixture of starting material and product. The addition of a second portion of propionaldehyde and sodium borohydride did not provide further conversion, so the reaction mixture was quenched with 10% formic acid in MeOH (1 mL), filtered, and the product was separated by preparative HPLC using a 60% → 100% MeOH-0.1% formic acid gradient. The crude product was purified a second time by preparative HPLC using a 30% → 100% MeOH-0.1% TFA gradient to provide the product of Example 242.

[0352] Preparation of Example 316 (Table 3):

[0352]

[0353] Preparation of 4-chloro-3-methylthiophene-2-sulfonyl chloride (2 and 3): 1-chloro-4-methylthiophene 1 (1.00 g, 7.54 mmol) was dissolved in 4.43 mL of CHCl3 at room temperature for 5 min. A solution of chlorosulfonic acid (1.19 mL, 17.3 mmol) in 1.48 mL of CHCl3 was added. The mixture was stirred for 10 min. Phosphorus pentachloride (4.13 g, 18.9 mmol) was added to the reaction mixture, followed by 7.50 mL of CHCl3. The mixture was heated at 50 °C for 1 h. The reaction mixture was slowly added to an aqueous solution of NaHCO3 + ice (30.0 mL). The mixture was stirred for 10 min. Extraction was performed with CH2Cl2 (4 × 10 mL). The combined organic layers were dried (Na₂SO₄), filtered, and concentrated under reduced pressure to obtain a mixture (1.30 g) of the main isomers, compounds 2 and 3, in an oily form. This mixture was used in the next reaction without further purification. LCMS: The LCMS sample was quenched with N-methylpiperazine; (ES⁺)M⁺H = 295.1

[0354] Preparation of N-(3-(4-chloro-3-methylthiophene-2-sulfonamido)-2,6-difluorophenyl)acetamide (5 and 6): Aniline 4 (400 mg, 2.15 mmol) was added to a CH2Cl2 solution of a mixture of compounds 2 and 3 (1.30 g, 2.37 mmol), followed by the addition of triethylamine (904 μL, 6.45 mmol). The mixture was stirred at room temperature for 18 h. The reaction mixture was slowly added to ice water (20 mL) and stirred at room temperature for 10 min. The precipitated solid was filtered off, washed with MTBE (3 × 5 mL), and dried under vacuum to give a mixture of compounds 5 and 6 as solids (900 mg). LCMS: (ES+)M+H = 381.1.

[0355] Preparation of N-(3-amino-2,4-difluorophenyl)-4-chloro-3-methylthiophene-2-sulfonamide (7): A mixture of compounds 5 and 6 (900 mg, 2.36 mmol) was dissolved in EtOH (5.49 mL) and HCl (6.00 N in H2O, 0.6 mL) was added at room temperature. The mixture was heated in an oil bath at 80 °C for 18 h. The volatile components were then removed under reduced pressure. The residue was dissolved in EtOAc (30 mL) and H2O (10 mL). A saturated aqueous solution of NaHCO3 was added until pH=8 was obtained. The aqueous layer and the organic layer were separated. The aqueous layer was washed with EtOAc (3 × 10 mL). The combined organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. The title compound (35 mg) was purified by rapid chromatography (50 g silicone column, EtOAc / hexane, 0-70% within 10 CV), and further purified (12 g silicone column, EtOAc / hexane, 20%-60%) to give the title compound 7 (17 mg, 1.76%, 84% purity) as an oil. (ES-)M+H=337.1; 1H NMR (400 MHz, CDCl3) δ 7.20 (m, 1H), 7.03 (br s, 1H), 6.87 (td, J=8.8, 5.4 Hz, 1H), 6.73 (td, J=9.8, 2.0 Hz, 1H), 2.21 (s, 3H).

[0356] Preparation of 3-chloro-N-(3-(((6-chloropyridino[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 h. The mixture was cooled to room temperature. The volatile components were removed under reduced pressure to give the title compound 9 (22 mg, crude substance), which was a pale yellow oil. It was used in the next reaction without further purification. (ES+)M+H=502.1 and (ES-)MH=500.2.

[0357] Preparation of N-(3-((6-(1H-benzo[d]imidazol-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 atmosphere. 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% within 15 CV) to give title compound 10 (Example 316, Table 3) (5.30 mg, 30% yield, 93% purity). (ES+)M+H=584.3 and (ES-)MH=582.3; 1H NMR (400MHz, DMSO-d6)δ 10.64(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(br m,1H),7.38-7.27(m,2H),7.16(dd,J=14.3,8.3Hz,1H),7.02(br m,1H),2.07-1.99(m,3H).

[0357] Preparation of Example 320 (Table 3):

[0357]

[0358] Preparation of methyl 3-chloro-4-(chlorosulfonylurea)thiophene-2-carboxylate (2): Butyllithium (2.50 M in hexane, 1.96 mL, 4.90 mmol) was added to an Et2O solution (8.00 mL) of 2,3-dimethylthiophene 1 (499 μL, 4.46 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 heated to room temperature and stirred for 30 min. The aqueous layer and organic layer were separated. The aqueous layer was extracted with Et2O (3 × 15.0 mL). The combined organic layer was dried (MgSO4), filtered, and concentrated under reduced pressure. The title compound 2, a dark green oil, was purified by rapid chromatography (25 g silicone column, EtOAc / hexane, 0-30% within 15 CV) (554 mg, 49% yield, 73% purity). ¹H NMR (400 MHz, CDCl₃) δ 7.49 (s, 1H), 4.30 (q, J = 7.1 Hz, 2H), 2.36 (s, 3H), 2.13 (s, 3H), 1.35 (t, J = 7.1 Hz, 3H).

[0359] Preparation of ethyl 3-(chlorosulfonylurea)-4,5-dimethylthiophene-2-carboxylate (3): Sulfur powder (1.67 g, 6.52 mmol) was added to THF (2.99 mL) of ethyl 4,5-dimethylthiophene-2-hexanoate 2 (1.00 g, 5.43 mmol). The mixture was cooled to -78 °C. Freshly prepared lithium diisopropylamine 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 min, and then slowly heated to room temperature over 4 h. The mixture was cooled to 0 °C. CH2Cl2 (5.00 mL) was added to the mixture, followed by HCl (1.00 M in H2O, 5.50 mL). The mixture was stirred at 0°C for 10 min, and sodium hypochlorite (10% solution in H₂O, 11.8 mL, 16.3 mmol) was added dropwise. The mixture was stirred at 0°C for 20 min, followed by stirring at room temperature for 2 h. 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). The mixture was stirred at room temperature for 20 h. The reaction mixture was diluted with NH₄Cl (1.00 M in H₂O, 20.0 mL) and Et₂O (30.0 mL). The mixture was stirred at room temperature for 30 min. The aqueous and organic layers were separated. The aqueous layer was extracted with Et₂O (3 × 25.0 mL). The combined organic layers were dried (MgSO₄), filtered, and concentrated to give the crude title compound (1.58 g, 40% yield, 40% purity). The LCMS sample was quenched with N-methylpiperazine (the resulting sulfadiazine MW = 346.4); (ES+)M+H = 347.3.

[0360] Preparation of ethyl 3-(N-(3-acetamino-2,4-difluorophenyl)aminesulfonyl)-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). Aniline 4 (400 mg, 2.15 mmol) was added to the solution 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 layer and organic layer were separated. The aqueous layer was extracted with EtOAc (3 × 15.0 mL). The combined organic layer was washed with brine (15.0 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure to give a crude compound in an oily form. The title compound (370 mg, 40%) was purified as an oil by rapid chromatography (40 g silicone column, EtOAc / hexane, 0-60% within 15 CV). (ES+)M+H = 433.3 and (ES-)MH = 431.3.

[0361] Preparation of N-(3-(4-chlorothiophene-3-sulfonamido)-2,6-difluorophenyl)acetamide (6): Compound 5 (350 mg, 809 μmol) was poured into THF (4.17 mL) and MeOH (1.04 mL). NaOH (5.00 M in H2O, 600 μL) was added to the mixture. The mixture was stirred for 10 min, and then acidified with HCl (10% in H2O, 10.0 mL). Volatile components were removed. The residue was azeotropically treated with toluene (3 × 10.0 mL) and dried under vacuum for a total time to give 330 mg of crude carboxylic acid. Crude carboxylic acid (330 mg), copper(II) acetate (75.6 mg, 408 μmol), and 1,10-phenanthroline (149 mg, 816 μmol) were packed into a microwave-safe vial (5 mL) and the mixture was suspended in NMP (2.79 mL) / quinoline (697 μL). The vial was rinsed with nitrogen and then irradiated with microwaves at 180 °C for 10 min using high absorbance. The crude compound was diluted with EtOAc (10.0 mL) and washed with H2O (15.0 mL), HCl (10% in H2O, 2 × 10.0 mL), and brine (15.0 mL). The organic layer was dried (Na2SO4), 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.

[0362] 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 H2O, 1.00 mL) was added. The reaction mixture was stirred overnight at 80 °C. The solution was cooled to room temperature and the evaporating components were evaporated under reduced pressure. The residue was azeotropically reacted with MeOH (3 × 10.0 mL). The residue was purified by reverse-phase chromatography (25 g column, CH3CN / 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.

[0363] Preparation of N-(3-((6-chloropyridino[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 into an ice-water mixture (50.0 mL). The mixture was stirred for 20 min. The resulting solid was filtered, washed with H2O (8 × 10.0 mL), and dried under vacuum overnight to give a beige solid (182 mg, 85% purity). The compound was ground with CH3CN / MTBE (1:25, 5 × 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 (400 MHz, 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).

[0364] Preparation of Example 320 (Table 3): Benzimidazole was coupled with chloropyridine 9 as described above using copper / BINOL catalysis, as described in Example 1 (step 4) of General Method A.

[0364] Preparation of Example 329 (Table 4):

[0364]

[0365] Step 1: Add 4-bromo-1H-benzo[d]imidazole (99 mg, 0.502 mmol), zinc dicyandiamide (70.8 mg, 0.603 mmol), and tetra(triphenylphosphine)palladium (116 mg, 0.100 mmol) in DMF (4 mL) to a 10 mL microwave-safe vial purged with nitrogen (×3). Heat the reaction to 90 °C and stir for 16 h. Cool the reaction to room temperature and then extract with EtOAc. Wash the organic layer with NaHCO3 and brine, dry with Na2SO4, and then load it onto diatomaceous earth. Purify the crude material with SiO2 using MeOH / DCM to obtain 1H-benzo[d]imidazole-4-carboxynitrile (31 mg, 43.1% yield) as a light pink solid. 1H 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+).

[0366] Step 2 (Example 329, Table 4): As described in Example 1 (Step 4) of General Method A, the benzimidazole fragment from Step 1 is coupled with chloropyridine A-13 (Ar=3-fluoro-2-tolyl) using copper / BINOL catalysis.

[0366] Preparation of Examples 334, 335, 336 and 346 (Table 4):

[0366]

[0367] Step 1: The chloropyridine fragment A-13 (Ar=3-fluoro-2-tolyl) (40 mg, 0.083 mmol), methyl 1H-pyrazole-3-carboxylate (13.67 mg, 0.108 mmol), [1,1'-binaphthyl]-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 700 μL of DMSO. The orange / brown solution was stirred at 100 °C for 16 h. Once complete, the reaction was cooled to room temperature and an aqueous solution of 4N sodium hydroxide (125 μL, 0.50 mmol) was added to the reaction mixture, which was then stirred at 50 °C for another hour. The reaction mixture was cooled to room temperature and transferred to 1.5 mL of 1N HCl aqueous solution, and precipitate formation was observed. The precipitate was filtered, washed with water, and dried under high vacuum to obtain the desired product, 1-(4-((2,6-difluoro-3-(3-fluoro-2-tolylsulfonamido)phenyl)amino)-pyrido[3,2-d]pyrimidin-6-yl)-1H-pyrazol-3-carboxylic acid (43.3 mg, 0.078 mmol, 94% yield), as a yellow solid. MS m / z 556.2 (MH+).

[0368] Step 2: The activated ester was prepared by dissolving the acid (30 mg, 0.054 mmol) and HATU (41.1 mg, 0.108 mmol) from Step 1 in NMP (1 mL), followed by dissolving 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)methylamine (13.4 μL, 0.108 mmol) was added. The reaction mixture was stirred at room temperature for 16 h. Once complete, the reaction was quenched by adding 0.5 mL of formic acid, diluted with DMSO, and purified by HPLC (ACN / H2O / 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. 1H 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+).

[0369] Examples 335, 336 and 346 (Table 4) were prepared in a similar manner using a suitable commercially available pyrazole ester.

[0369] Preparation of Examples 339 and 340 (Table 4):

[0369]

[0370] Step 1: The stirred solution of 1-boc-3-piperidinone (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 evaporating components were evaporated under reduced pressure to obtain a yellow gel-like substance. This was co-evaporated with EtOH (5.00 mL × 3) to form a mixture of regioisomeric products. The substance was used as crude material in the next step: (ES+)M+H = 225.1.

[0371] Step 2: The 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 evaporating components were evaporated under reduced pressure and the residue was purified by silica gel chromatography with 20%-60% ethyl acetate / hexane. The desired product yield was 60%. A mixture of isomeric pyrazole derivatives as a gelatinous solid was obtained (4.04 g, 72% yield): (ES+)M+H = 224.1.

[0372] Step 3: A mixture of the product from Step 2 (335 mg, 1.50 mmol), A-13 (Ar = 3-fluoro-2-tolyl, 480 mg, 1.00 mmol), copper metal (6.36 mg, 100 μmol), 1,1'-di-2-naphthol (58.5 mg, 200 μmol), and cesium carbonate (757 mg, 2.30 mmol) was mixed in DMSO (4.00 mL). The reaction was heated to 125 °C for 3 h. After cooling to room temperature, the reaction mixture was diluted with water (30.0 mL) and ethyl acetate (30.0 mL) and diluted with diatomaceous earth. The filtrate was extracted with ethyl acetate (30.0 mL × 2). The combined organic layers were washed with brine, dried, and concentrated. The residue was purified by silica gel chromatography (80 g) with 50%-70% ethyl acetate / hexane. The desired product was produced as a yellow solid mixture of regioisomers in 70% ethyl acetate / hexane (567 mg, 85% yield): (ES+)M+H=667.2.

[0373] Step 4: Dissolve the regioisocarbamate mixture from Step 4 (567 mg, 850 μmol) in dioxane (4.25 mL). Add HCl (4.0 M in dioxane, 2.13 mL, 8.50 mmol) to the solution at room temperature. Stir the reaction mixture at room temperature for 2 days. Filter the reaction mixture and wash with dioxane. Obtain a mixture of regioisocarbamates as a yellow solid (542 mg, quantitative yield): (ES+)M-HCl+H=567.2.

[0374] Separation of regioisomeric pyrazoles from step 4: A mixture of regioisomeric carbamates from step 3 (1.0 g, 1.5 mmol) was dissolved in dioxane (7.5 mL). HCl (4 M in dioxane, 3.75 mL, 15 mmol) was added to the solution at room temperature. The reaction mixture was stirred at room temperature for 2 days. The reaction was filtered and washed with dioxane. A mixture of regioisomeric hydrochlorides (850 mg, quantitative yield) was obtained as a yellow solid. The solid was purified by reverse-phase column containing 0–20%–40% ACN in 10 mM ammonium formate. The first isomer (isomer a) was produced with 15% ACN in 10 mM ammonium formate, and the second isomer (isomer b) was produced with 40% ACN in 10 mM ammonium formate. The two compounds were concentrated and the residue was treated with 4M HCl in 0.5 mL of dioxane. The resulting suspension was subjected to sonication and then filtered to obtain hydrochloride salts of isomer a (130 mg, 15% yield) and isomer b (230 mg, 27% yield) as white solids: (ES+)M-HCl+H=567.2.

[0375] Step 5 (Examples 339 and 340, Table 4): Dissolve the mixture of isomers from Step 4 (85.0 mg, 150 μmol) in MeOH (1.50 mL). Add hydroxyacetaldehyde dimer (56.9 mg, 450 μmol) to the solution. After 5 min, add sodium triacetoxyborohydride (163 mg, 750 μmol). Stir the reaction overnight at room temperature. Quench the reaction with water (10.0 mL) and extract with ethyl acetate (10 mL × 2). Laminate the organic compound and wash with brine, dry and concentrate. Purify the residue on a reverse-phase column with 0-40%-60% ACN in 10 mM ammonium formate. The compound of Example 339 was produced with 20% ACN in 10 mM ammonium formate, and the compound of Example 340 was produced with 40% ACN in 10 mM ammonium formate. After lyophilization, Example 339 (10 mg, 11% yield) was obtained as a white solid. Example 340 (10 mg, 11% yield) was obtained as a white solid.

[0375] Preparation of Example 343 (Table 4):

[0375]

[0376] Step 1: A commercially available imidazole starting material (which can also be prepared according to the procedure described in Tet. Lett. 2002, 43(1), 61) is coupled with chloropyridine A-13 (Ar=3-fluoro-2-tolyl) using a copper / BINOL catalyst as described in Example 1 (Step 4) of General Method A.

[0377] Step 2 (Example 343, Table 4): Add the product from Step 1 (91 mg, 0.157 mmol) and 2,4,6-trioxide-2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphine (997 mg, 1.57 mmol) to a 20 mL scintillation vial equipped with a magnetic stir bar. Heat the reaction to 65 °C for 48 h. Once complete, cool the reaction to room temperature. Add water to the reaction, causing the product to precipitate. Filter the product, wash with water, collect and then dry under vacuum overnight to give (E)-N-(3-((6-(4-(2-cyanovinyl)-1H-imidazol-1-yl)pyrido[3,2-d]pyrimidin-4-yl)amino)-2,4-difluorophenyl)-3-fluoro-2-toluenesulfonamide (63 mg, 69% yield) as a beige solid. 1H 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,1H),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+).

[0377] Preparation of Examples 345 and 361 (Table 4):

[0377]

[0378] Step 1: Under a N2 atmosphere, methyl 4-benzimidazole carboxylate (100 mg, 0.568 mmol) in anhydrous THF (2 mL) was added to a 5 mL vial equipped with a magnetic stir bar. The reaction was cooled to 0 °C. Over 5 min, a solution of 1 M lithium aluminum hydride in THF (0.44 mL, 0.437 mmol) was slowly added. The reaction was heated to room temperature and stirred for 4 h. Another portion of 1 M lithium aluminum hydride in THF (0.250 mL) was added to drive the reaction to completion. The reaction was stirred for another 1 h. The reaction was quenched with MeOH. The reaction was loaded onto diatomaceous earth and subsequently purified on SiO2 using MeOH / 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+).

[0379] Step 2 (Example 345): As described in Example 1 (Step 4) of General Method A, the benzyl alcohol from Step 1 is coupled with chloropyridine A-13 (Ar=3-fluoro-2-tolyl) using copper / BINOL catalysis.

[0380] Step 3: To a 20 mL scintillation vial, add N-[2,4-difluoro-3-[[6-[4-(hydroxymethyl)benzimidazol-1-yl]pyrido[3,2-d]pyrimidin-4-yl]amino]phenyl]-3-fluoro-2-methylbenzenesulfonamide (1.00 equivalent, 138 mg, 0.233 mmol) and DIEA (2.00 equivalent, 81 μL, 0.467 mmol) to the suspension. Next, add technically stable 2-(trimethylsilyl)ethoxymethyl chloride (1.10 equivalent, 46 μL, 0.257 mmol) to the suspension. Heat the reaction to 40 °C and stir for 24 h. Quench the reaction with saturated NH4Cl and then extract with brine and EtOAc (×3). The organic matter was collected, dried over MgSO4, filtered, and subsequently concentrated under reduced pressure. The crude liquid was purified by normal-phase rapid column chromatography using MeOH / DCM. The desired fraction was collected and concentrated under reduced pressure to obtain the desired protected sulfonamide (153 mg, 91%) as a yellow solid. 1H NMR (400MHz, DMSO-d6) δ: 9.88(br.s.,1 H),9.30(s,1 H),8.49(br.s.,3 H),8.25(d,J=8.2Hz,1 H),7.66(d,J=7.8Hz,1 H),7.54(t,J=8.2Hz,1 H),7.39-7.48(m,2 H),7.29-7.39(m,2 H),5.26(br.s.,1 H),5.07(s,2 H),5.00(s,2 H),3.60-3.68(m,2 H),2.39(d,J=2.3Hz,3 H),0.82-0.90(m,2 H),-0.03(s,9 H). MS m / z 722.2(MH+).

[0381] Step 4 (Example 361): Add the product from Step 3 (1.00 equivalent, 150 mg, 0.208 mmol) and N,N-diisopropylethylamine (2.00 equivalent, 72 μL, 0.416 mmol) to a 20 mL vial of DMF (2 mL). Next, add methanesulfonyl chloride (1.50 equivalent, 24 μL, 0.312 mmol). Stir the reaction overnight at room temperature. Quench the reaction with saturated NaHCO3 and then extract with EtOAc (×3). Collect the organic matter, dry it with MgSO4, filter it, and then concentrate it under reduced pressure. Dissolve the crude matter in MeCN (2 mL) and then add potassium cyanide (2.00 equivalent, 27 mg, 0.416 mmol). Stir the reaction at room temperature for 36 h. Quench the reaction with 10% LiCl and then extract with EtOAc (×3). Organic matter was collected, dried over MgSO4, filtered, and subsequently concentrated under reduced pressure. The crude material was dissolved in 1 mL DCM and 1 mL TFA and stirred at room temperature for 48 h. DCM was removed under reduced pressure. The crude material was dissolved in DMSO and subsequently purified by preparative HPLC using water:MeCN + 0.1% formic acid to give an analogue of Example 361 (36 mg, 0.0593 mmol, 29%) as a pale yellow solid after lyophilization. 1H NMR (400MHz, DMSO-d6) δ: 10.51(br.s.,1 H),9.82(s,1 H),9.38(s,1 H),8.46-8.55(m,3 H),8.36(d,J=7.8Hz,1 H),7.63(d,J=7.8Hz,1 H),7.41-7.50(m,3 H),7.35-7.41(m,1 H),7.29(td,J=9.0,6.3Hz,1 H),7.19(t,J=9.4Hz,1 H),4.38(s,2 H),2.50(br.s.,3 H). MS m / z 601.2(MH+).

[0381] Preparation of Example 347 (Table 4):

[0381]

[0382] Compound of Example 343 (50 mg, 0.089 mmol) and 5% Pd / C (10 mg, 5.2 μmol) in MeOH (2 ml) were added to a 20 ml scintillation vial. The reaction was stirred at room temperature for 16 h at 1 atm H2. The reaction was filtered through a diatomaceous earth pad and then concentrated under reduced pressure. The crude material was purified by HPLC using water:MeOH + 1% formic acid to give compound of Example 347 (17 mg, 34% yield) as shown in Table 4. 1H 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+).

[0382] Preparation of Examples 348 and 349 (Table 4):

[0382]

[0383] As described in Example 1 (step 4) of General Method A, commercially available 3H-imidazo[4,5-c]pyridine-4-amine (CAS No. 6811-77-4) is coupled with chloropyridine A-13 using a copper / BINOL catalyst, except that 1.2 equivalents of Cu metal are used.

[0383] Preparation of Example 353 (Table 4):

[0383]

[0384] The starting Cbz-protected aminopyridine derivative was obtained by coupling fragment B49 (Table 2) containing the chloropyridine fragment with 4-aminobenzimidazole using a copper / BINOL catalyst, as described in Example 1 (step 4) of General Method A. A solution of this intermediate (12 mg, 0.0168 mmol) in MeOH (1 mL) was added with 5% palladium hydroxide / carbon (23 mg, 0.0084 mmol) and stirred at 1 atm H2 for 1 h. Once complete, the suspension was filtered and concentrated under vacuum. The residue was diluted with DMSO and purified by HPLC with MeCN in 0.1% formic acid aqueous solution to give 353 (Table 4) (2.0 mg, 20%). 1H 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=9.39H z,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+).

[0384] Preparation of Examples 356 and 664:

[0384]

[0385] A mixture of regioisomeric pyrazoles (100.0 mg, 177 μmol) from step 4 of Examples 339 / 340 was dissolved in MeOH (1.77 mL). Formaldehyde (65.7 μL, 883 μmol) was added to the solution, followed by AcOH (1 drop). After 5 min, sodium triacetoxyborohydride (192 mg, 883 μmol) was added. The reaction was stirred overnight at room temperature. The reaction was concentrated to remove MeOH and then diluted with water and ethyl acetate. The aqueous and organic layers were separated, and the aqueous layer was extracted with ethyl acetate (10 mL × 3). The combined organic layers were dried and concentrated under reduced pressure. The residue was purified using a reverse-phase column (30 g) with 0-30%-60% ACN in 10 mM ammonium formate. The compound of Example 664 was produced with 30% ACN in 10 mM ammonium formate, and the compound of Example 356 was produced with 50% ACN in 10 mM ammonium formate. After lyophilization, both were given as white solids: 664 (20 mg, 20% yield) and 356 (13 mg, 13% yield).

[0385] Preparation of Examples 357 and 393 (Table 4):

[0385]

[0386] A mixture of regioisomeric pyrazoles (50.0 mg, 88.2 μmol) from step 4 of Examples 339 / 340 was dissolved in CH2Cl2 (1.00 mL). Acetic anhydride (4.63 μL, 48.5 μmol) was added to the solution, followed by N,N-diisopropylethylamine (11.6 μL, 66.2 μmol). The reaction was stirred overnight at room temperature. Ac2O (10.0 μL) was added to the reaction and stirred for another day. The volatile components were removed under reduced pressure and the residue was purified directly on a reverse-phase column (30 g) using 0-30%-60% ACN in 10 mM ammonium bicarbonate. The compound of Example 393 was produced with 30% ACN in 10 mM ammonium bicarbonate, and the compound of Example 357 was produced with 40% ACN in 10 mM ammonium bicarbonate. After freeze-drying, 393 (10 mg, 19% yield) and 357 (20 mg, 37% yield) were obtained as white solids.

[0386] Preparation of Examples 362 and 383 (Table 4):

[0386]

[0387] Step 1: Isomer b (30.0 mg, 53.0 μmol) from Step 4 of Examples 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 purified directly on a reverse-phase column using 0-40%-70% ACN in 10 mM ammonium formate. The desired carbamate analog was produced in 10 mM ammonium formate with 55% ACN and the appropriate fraction was lyophilized to a yellow solid (7.5 mg, 20% yield): (ES+)M+H = 710.0.

[0388] Step 2 (Example 362, Table 4): Add hydrochloric acid (4.00 M in dioxane, 26.4 μL, 106 μmol) to dioxane (500 μL) containing 30.0 mg, 53 μmol of carbamate from Step 1. Stir the reaction overnight at room temperature. Remove the volatile components under reduced pressure and purify the residue directly on a reverse-phase column using 0-20%-40% ACN in 10 mM ammonium formate. After lyophilization, the compound of Example 362 is produced as a yellow solid (5.10 mg, 79% yield) in 10 mM ammonium formate with 30% ACN.

[0389] Step 3 (Example 383, Table 4): Acetic anhydride (3.7 μL, 38.8 μmol) was added to a solution of compound 362 (21.5 mg, 35.3 μmol) in CH2Cl2 (0.5 mL) and AcOH (0.05 mL), followed by the addition of N,N-diisopropylethylamine (9.3 μL, 52.9 μmol). The reaction was stirred overnight at room temperature. The volatile components were removed under reduced pressure, and the residue was purified directly on a reverse-phase column using 0–40%–60% ACN in 10 mM ammonium formate. After lyophilization, the compound of Example 383 was obtained as a yellow solid (10.8 mg, 47% yield) in 10 mM ammonium formate with 60% ACN.

[0389] Preparation of Example 369 (Table 4):

[0389]

[0390] 5% palladium hydroxide / carbon (23 mg, 0.0084 mmol) was added to a solution of nitroaromatic hydrocarbon (26 mg, 0.043 mmol) in MeOH / DCM 1:1 (1 mL) and the mixture was stirred at 1 atm H2 for 16 h. Once complete, the suspension was filtered and concentrated under vacuum. The residue was diluted with DMSO and purified by HPLC with MeCN in 0.1% formic acid aqueous solution to give the compound of Example 369 (2.0 mg, 20%). 1H 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=3.96,8.12Hz,1H),6.98-7.18(m,1H),6.84(d,J=7.83Hz,1H),6.57(s,1H),6.52(d,J=8.61Hz,1H),2.53(s,3H)MS m / z 574.2(MH+).

[0390] Preparation of Examples 375, 350 and 351 (Table 4):

[0390]

[0391] Step 1: 3-[tributyl(dimethyl)silyl]oxypropionaldehyde (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 to 50 °C for 20 min 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 h. The solvent was removed under reduced pressure and DCM (3 mL) was added, followed by TFA (3 mL). The reaction was stirred at room temperature for 30 min. 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)prop-1-ol (60 mg, 53% yield). MS m / z 192.2 (MH+).

[0392] Step 2: 3-[tributyl(dimethyl)silyl]oxypropionaldehyde (98 μL, 0.471 mmol) was added to a solution of 3-(1H-benzimidazol-4-ylamino)prop-1-ol (60 mg, 0.314 mmol) in MeOH (3.1 mL). The reaction was heated to 50 °C for 15 min 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 h. LCMS analysis showed that a significant amount of the starting material was still present. The solvent was removed under reduced pressure and DCM (3 mL) was added, followed by TFA (3 mL). The reaction was stirred at room temperature for 30 min and concentrated. The crude material was diluted with MeOH and IRA-67 resin was added. The mixture was filtered through a cotton plug. Sodium cyanoborohydride (3.00 equivalent, 59 mg, 0.941 mmol) was added. The reaction was heated to 50°C and stirred over the entire weekend. Once complete, TFA (1 mL) and IRA-67 were added. The resulting mixture was filtered and the solution concentrated. The crude material was left to stand under vacuum for 2 days to give 3-[1H-benzimidazol-4-yl(3-hydroxypropyl)amino]prop-1-ol (32 mg, 41% yield). MS m / z 250.2 (MH+).

[0393] Step 3 (Example 375, Table 4): As described in Example 1 (Step 4) of General Method A, the benzimidazole fragment from Step 2 is coupled with chloropyridine A-13 (Ar=3-fluoro-2-tolyl) using copper / BINOL catalysis.

[0394] Example 350 (Table 4) was prepared in a similar manner using 2-[tri-butyl(dimethyl)silyl]oxyacetaldehyde from step 1. Subsequently, the monoalkylated 4-aminobenzimidazole obtained in step 1 was converted into the compound of Example 350 using the procedure described in step 3 above.

[0395] Example 351 (Table 4) was prepared in the same manner as Example 375 using 3-[tri-butyl(dimethyl)silyl]oxyacetaldehyde from steps 1 and 2.

[0395] Preparation of Examples 376 and 384 (Table 4):

[0395]

[0396] Step 1: A solution of LiHMDS (1M in THF, 0.76 mL, 0.759 mmol) was added to a solution of 1-(2-trimethylsilylethoxymethyl)benzimidazole-4-amine (described in WO 202105591) (50 mg, 0.190 mmol) in DMF (1.9 mL). The resulting mixture was stirred at rt for 20 min and 1-bromo-2-methoxyethylene (6.00 equivalents, 107 μL, 1.14 mmol) was added. The reaction was stirred at rt for 45 min. Next, an additional 6 equivalents of 1-bromo-2-methoxyethylene (107 μL) was added and the resulting mixture was stirred for 2 days. Once complete, an NH4Cl (saturated in water) solution was added and the aqueous mixture was extracted with EtOAc. The organic matter was combined, dried over MgSO4, filtered, and concentrated. The crude material was purified by column chromatography (silicone, 0-80% EtOAc / hexane) to give N,N-bis(2-methoxyethyl)-1-(2-trimethylsilylethoxymethyl)benzimidazole-4-amine (40 mg, 56% yield) as a pale yellow oil. MS m / z 380.4 (MH+).

[0397] Step 2: N,N-bis(2-methoxyethyl)-1-(2-trimethylsilylethoxymethyl)benzimidazole-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 h and heated to 40 °C for 1.5 h. The reaction was cooled to room temperature. The reaction was concentrated under reduced pressure and then dissolved 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-benzimidazole-4-amine (26 mg, 100% yield) as a yellowish-brown oil. MS m / z 250.2 (MH+).

[0398] Step 3 (Example 376, Table 4): As described in Example 1 (Step 4) of General Method A, the benzimidazole fragment from Step 2 is coupled with chloropyridine A-13 (Ar=3-fluoro-2-tolyl) using copper / BINOL catalysis.

[0399] The compound of Example 384 was prepared in a similar manner using the 1-bromo-3-methoxypropane from step 1 (Table 4): MS m / z 278.4 (MH+).

[0399] Preparation of Example 382 (Table 4):

[0399]

[0400] Step 1: The solution of 1-(p-toluenesulfonyl)pyrrole (5 g, 22.6 mmol) prepared as described on page 2021 of WO2021 / 97057 in anhydrous CH3CN (100 mL) was cooled in an ice bath and treated dropwise with chlorosulfonic acid (9.0 mL, 136 mmol). The reaction mixture was heated to room temperature and stirred for 72 h. Once complete, the mixture was poured onto ice / water and a precipitate appeared. The solid was filtered to provide 1-(p-toluenesulfonyl)pyrrole-3-sulfochloro (2.53 g, 35% yield). MS m / z (MH+).

[0401] Step 2: Add 1-(p-toluenesulfonyl)pyrrole-3-sulfochloro (86 mg, 0.27 mmol) from the anhydrous THF (2 mL) in Step 1 to a vial equipped with a stir bar. DIEA (0.094 mL, 0.541 mmol) and N,N,N"-trimethylethylenediamine (0.042 mL, 0.325 mmol) were added to the solution. The resulting solution was stirred at room temperature for 1 h. After this was complete, 10% KOH aqueous solution (2 mL) was added dropwise. The reaction was heated at 60 °C overnight. After this was complete, the reaction mixture was diluted with EtOAc and NH4Cl aqueous solution was added. The layers were separated. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated to dryness to give N-[2-(dimethylamino)ethyl]-N-methyl-1H-pyrrole-3-sulfonamide (48 mg, 77% yield) as a light orange oil. 1H NMR (400 MHz, CDCl3) δ: ppm 2.35-2.48 (m, 6 H) 2.61-2.85 (m, 6 H) 3.01-3.24 (m, 2 H) H)6.46(br.s.,1 H)6.85(br.s.,1 H). MS m / z 232.2(MH+).

[0402] Step 3 (Example 382, ​​Table 4): As described in Example 1 (Step 4) of General Method A, the pyrrole fragment from Step 2 is coupled with chloropyridine A-13 (Ar=3-fluoro-2-tolyl) using copper / BINOL catalysis.

[0402] Preparation of Example 391 (Table 4):

[0402]

[0403] Isomer b (28.3 mg, 49.9 μmol) from step 4 of Examples 339 / 340 was added to 3-hydroxypropanal (22.2 mg, 300 μmol), followed by DCE (1.0 mL), then a drop of AcOH and sodium triacetoxyborohydride (65.1 mg, 300 μmol). The reaction was stirred overnight at room temperature. The reaction was purified by preparative HPLC to give the compound of Example 391 (6.3 mg, 20% yield) as a white solid.

[0403] Preparation of Example 392 (Table 4):

[0403]

[0404] Step 1: Dissolve isomer b (30.0 mg, 53.0 μmol), N,N-diisopropylethylamine (23.2 μL, 132 μmol), and Boc-Gly-OH (11.4 mg, 63.5 μmol) from Step 4 of Examples 339 / 340 in DMF (600 μL). Add HATU (30.8 mg, 79.4 μmol) to the solution. Stir the reaction overnight at room temperature. Add water (5.00 mL) to the reaction and filter the precipitated product to produce the desired carbamate (38.0 mg, 99% yield) as a beige solid: (ES+)M+H = 724.3.

[0405] Step 2 (Example 392, Table 4): Add HCl (4M in dioxane, 131 μL, 525 μmol) to a solution of the product (38.0 mg, 52.5 μmol) from Step 1 in 1.00 mL of dioxane. Stir the reaction at room temperature over the entire weekend. Remove the volatile components under reduced pressure and purify the residue using a reverse-phase column containing 0-20%-40% ACN in 10 mM ammonium formate. After lyophilization, the compound of Example 392 was produced with 25% ACN in 10 mM ammonium formate and given as a white solid (27.6 mg, 84% yield).

[0405] Preparation of Example 414 (Table 4):

[0406] The compound of Example 414 was prepared in a manner similar to that of the compound of Example 392, except that isomer b from step 4 of Examples 339 / 340 was used.

[0406] Preparation of Example 415 (Table 4):

[0406]

[0407] Step 1: Isomer b (15.0 mg, 26.5 μmol) from Step 4 of Examples 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 overnight at room temperature. The reaction was quenched with water (5.00 mL) and extracted by DCM (5 mL × 3). The combined organic layers were concentrated under reduced pressure and the resulting crude residue 7a (18.8 mg, 100% yield) was used directly in the next step: (ES+)M+H = 710.3.

[0408] Step 2: The crude product from Step 1 (18.8 mg, 26.5 μmol) was dissolved in dioxane (250 μL), followed by the addition of HCl (4 M in dioxane, 66.3 μL, 265 μmol). The reaction was stirred overnight at room temperature. Volatile components were removed under reduced pressure, and the residue was purified by reverse-phase column preparation with 0-20%-40% ACN in 10 mM ammonium formate. After lyophilization, the compound of Example 415 was produced with 25% ACN in 10 mM ammonium formate and given as a white solid (formate) (8.20 mg, 51% yield).

[0408] Preparation of Example 420 (Table 4):

[0408]

[0409] Step 1: Add 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) to a 100 mL round-bottom flask and stir the reaction at room temperature for 1 h. Once complete, quench the reaction with saturated NH4Cl and then extract with EtOAc (×3). Collect the organic matter, wash with brine, separate, dry with MgSO4, filter, and then concentrate under reduced pressure. Load the crude material onto diatomaceous earth and then purify it on SiO2 containing EtOAc / hexane to give 2-[(4-bromobenzimidazole-1-yl)methoxy]ethyl-trimethylsilane (1.18 g, 71% yield) as a brown oil. MS m / z 327.2 (MH+).

[0410] Step 2: Under a N2 atmosphere, add 2-[(4-bromobenzimidazol-1-yl)methoxy]ethyl-trimethyl-silane (500 mg, 1.53 mmol) and bis(pinacol)diborane (776 mg, 3.06 mmol) in DMF (0.30 mL) to a flame-dried 5 mL microwave-safe vial. Next, add 1,1'-bis(diphenylphosphine)ferrocene-palladium(ii)dichloromethane complex (279 mg, 0.382 mmol) and potassium acetate (450 mg, 4.58 mmol) to the solution. Spray the reaction mixture with an argon balloon for a few minutes, seal it, and then heat it to 100 °C and stir for 16 h. Cool the reaction mixture to room temperature. Use the crude reactants as a crude mixture for the next step.

[0411] Step 3: Add 4-amino-3-bromopyridine (34 mg, 0.20 mmol), tetrakis(triphenylphosphine)palladium(0) (35 mg, 0.0305 mmol), and potassium carbonate (97 mg, 0.914 mmol) to the crude reactants. Inject the reaction mixture with an argon balloon for about 5–10 min, seal, and then heat to 100 °C for 24 h. Once complete, cool the reaction mixture to room temperature. Dilute the reaction mixture with brine and extract with EtOAc (×3). Collect the organic matter, dry it with MgSO4, filter, and then concentrate it under reduced pressure. Load the crude mixture onto diatomaceous earth and then purify it on SiO2 with MeOH / DCM to give 3-[1-(2-trimethylsilylethoxymethyl)benzimidazol-4-yl]pyridine-4-amine (72 mg, 69% yield) as a brown film. MS m / z 341.2 (MH+).

[0412] Step 4: Add 72 mg (0.210 mmol) of 3-[1-(2-trimethylsilylethoxymethyl)benzimidazol-4-yl]pyridine-4-amine to a 20 mL scintillation vial containing 2 mL of DCM and 2 mL of TFA. Stir the reaction at room temperature for 16 h. Once complete, remove the solvent under reduced pressure and then dry under vacuum to give 68 mg (100% yield) of 3-(1H-benzimidazol-4-yl)pyridine-4-amine TFA salt as a brown oil. MS m / z 211.2 (MH+).

[0413] Step 5 (Example 420, Table 4): As described in Example 1 (Step 4) of General Method A, the benzimidazole fragment from Step 4 is coupled with chloropyridine A-13 (Ar=3-fluoro-2-tolyl) using copper / BINOL catalysis.

[0413] Preparation of Example 424 (Table 4):

[0413]

[0414] Step 1: Add 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) to a 20 mL scintillation vial. Stir the reaction at room temperature for 2 h. Quench the reaction with saturated NH4Cl and then extract with EtOAc (×3). Collect the organic matter, dry it with MgSO4, filter it, and then concentrate it under reduced pressure. Load the crude material onto diatomaceous earth and then purify it on SiO2 containing EtOAc / hexane 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+).

[0415] Step 2: Under a N2 atmosphere, add the protected benzimidazole (200 mg, 0.631 mmol) and bis(pinacol)diboron (320 mg, 1.26 mmol) from Step 1 to a flame-dried 5 mL microwave-safe vial containing DMF (0.3000 mL). Next, add the 1,1'-bis(diphenylphosphine)ferrocene-palladium(ii)dichloromethane complex (231 mg, 0.315 mmol) to the solution, followed by potassium acetate (186 mg, 1.89 mmol). Spray the reaction with an argon balloon for a few minutes, seal, and then heat to 100 °C and stir for 24 h. Cool the reaction to room temperature. Extract the reaction mixture, dilute with brine, and extract with EtOAc (×3). Collect the organic matter, dry with MgSO4, filter through a diatomaceous earth stopper, and then concentrate under reduced pressure. The crude material was loaded onto diatomaceous earth and subsequently purified on SiO2 containing EtOac / hexane. The desired fraction was collected and concentrated under reduced pressure to give 1-[(4-methoxyphenyl)methyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboropent-2-yl)benzimidazole (82 mg, 36% yield) as a brown oil. MS m / z 365.4 (MH+).

[0416] Step 3: Under a N2 atmosphere, add 1-[(4-methoxyphenyl)methyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboropent-2-yl)benzimidazole (56 mg, 0.154 mmol) and 2-amino-3-bromopyridine (35 mg, 0.200 mmol) to a flame-dried 5 mL microwave-safe vial. Next, add sodium carbonate (49 mg, 0.461 mmol) to the solution, followed by tetra(triphenylphosphine)palladium(0) (18 mg, 0.0154 mmol). Inject the reaction with an argon balloon for about 5–10 min, seal, and then heat to 80 °C and stir for 16 h. Cool the reaction to room temperature. Dilute the reaction with brine and extract with EtOAc (×3). Collect the organic matter, dry with MgSO4, filter, and then concentrate under reduced pressure. The crude material was loaded onto diatomaceous earth and subsequently purified on SiO2 containing MeOH / DCM. The desired fraction was collected and concentrated under reduced pressure to give 3-[1-[(4-methoxyphenyl)methyl]benzimidazol-4-yl]pyridine-2-amine (15 mg, 0.0445 mmol, 29% yield) as a white solid. MS m / z 331.2 (MH+).

[0417] Step 4: Add 3-[1-[(4-methoxyphenyl)methyl]benzimidazol-4-yl]pyridine-2-amine (15 mg, 0.0445 mmol) to a 20 mL scintillation vial containing 2 mL of TFA. Heat the reaction to 80 °C and stir for 96 h. Remove the solvent under reduced pressure and then co-evaporate the product with toluene (×3) to give 3-(1H-benzimidazol-4-yl)pyridine-2-amine TFA salt (14 mg, 100%). MS m / z 211.2 (MH+).

[0418] Step 5 (Example 424, Table 4): As described in Example 1 (Step 4) of General Method A, the benzimidazole fragment from Step 4 is coupled with chloropyridine A-13 (Ar=3-fluoro-2-tolyl) using copper / BINOL catalysis.

[0418] Preparation of Examples 425 and 460 (Table 4):

[0418]

[0419] 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 overnight at 80 °C. The reaction was cooled to room temperature and hexane (50 mL) was added. The resulting solid was filtered and washed with hexane (5 mL × 2). It was dried under circulating air to produce 819 mg of beige solid. The crude solid product was further purified by 0-10% MeOH / CH2Cl2. The desired product was produced by 10% MeOH / DCM, yielding the expected hydrazine derivative as a beige solid (550 mg, 69% yield): (ES+)M+H = 476.1.

[0420] Step 2: The product from Step 1 (350 mg, 736 μmol) and the crude ethylene analog amide (206 mg, 810 μmol) obtained in Step 1 of Examples 339 / 340 were mixed 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 h. The volatile components were removed under reduced pressure, and the residue was purified by reverse-phase column containing 0-50%-100% ACN in 10 mM ammonium formate. After lyophilization, the desired pyrazole derivative (85 mg, 17% yield) was produced as a white solid in 10 mM ammonium formate with 90% ACN: (ES+)M+H = 667.2.

[0421] Step 3: Add HCl (4M in dioxane, 319 μL, 1.27 mmol) to a solution of the product (85.0 mg, 127 μmol) from Step 2 in 637 μL of dioxane. Stir the reaction overnight at room temperature. Add HCl (4M in dioxane, 0.5 mL, 1.98 mmol) and then heat to 50 °C for one more day. Filter the reaction mixture and wash with dioxane (2.0 mL). Obtain the desired hydrochloride (70.0 mg, 97% yield) as a beige solid: (ES+)M+H = 567.3.

[0422] Step 4 (Example 425, Table 4): The hydrochloride (20.0 mg, 35.3 μmol) and hydroxyacetaldehyde dimer (17.9 mg, 141 μmol) from Step 3 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. The volatile components were removed under reduced pressure and the solid residue was purified by reverse-phase column containing 0-20%-50% ACN in 10 mM ammonium bicarbonate. After lyophilization, the title compound 425 (8.00 mg, 37% yield) was obtained as a yellow solid.

[0423] Step 4 (Example 460, Table 4): Dissolve the hydrochloride (15.0 mg, 26.5 μmol) from Step 3 and the aqueous formaldehyde solution (9.86 μL, 132 μmol) in DCE (265 μL). Add sodium triacetoxyborohydride (28.8 mg, 132 μmol) to the solution, followed by AcOH (1 drop). Stir the reaction overnight at room temperature. Remove the volatile components under reduced pressure. Add MeOH (1.00 mL) and water (10 mL) to the solid residue. Filter the mixture to obtain solid A and set it aside. Extract the resulting filtrate with ethyl acetate (5 mL × 5). Combine the organic layers and concentrate to produce solid B. Combine solids A and B and add MeOH (2 mL). Heat the slurry to 80°C until the solid dissolves. Then cool it to room temperature and filter to obtain the compound of Example 460 (11.3 mg, 74% yield) as a yellow solid.

[0423] Examples 443 and 444 (Table 4):

[0424] Using 5-fluoroindole as a starting material and a suitable amine, these two analogues were prepared according to general method G. As described in Example 1 (step 4) of general method A, indolesulfonamide was coupled with chloropyridine A-13 (Ar = 2,3-dichlorophenyl) using a copper / BINOL catalyst.

[0424] Preparation of Examples 447, 456, 457 and 461 (Table 4):

[0424]

[0425] Step 1: 3-Indole ester was prepared from 1H-indole-3-yl-thiocyanate (Phosphorus, Sulfur and Silicon and the Related Elements 2014, 189, 1378) as described in general method H. At -78°C, a 1M solution of diisobutylaluminum hydride (2.5 mL, 3.72 mmol) was added in two portions to a solution of the substance (100 mg, 0.309 mmol) in DCM (3 mL). The reaction mixture was heated to room temperature and stirred for 2 h. The reaction mixture was diluted with diethyl ether (30 mL) and cooled to 0°C. The reaction was quenched by slowly adding 0.15 mL of water, followed by 0.15 mL of a 15% sodium hydroxide aqueous solution and 0.37 mL of water. The solution was heated to room temperature and stirred for 15 min. Anhydrous magnesium sulfate was added to the stirred solution. After 15 min, the suspension was filtered to remove the salt. Evaporation to dryness gave the corresponding alcohol as a solid (68 mg, 87%). ¹H NMR (400 MHz, CDCl₃) δ: 8.91 (br. s., ¹H), 7.87–8.08 (m, ¹H), 7.81 (d, J = 3.13 Hz, ¹H), 7.43–7.61 (m, ¹H), 7.32–7.43 (m, 2H), 3.81 (d, J = 6.65 Hz, 2H), 1.39 (s, 6H). MS m / z 254.2 (MH⁺).

[0426] Step 2 (Example 447, Table 4): As described in Example 1 (Step 4) of General Method A, the indole from Step 1 is coupled with chloropyridine A-13 (Ar=2,3-dichlorophenyl) using a copper / BINOL catalysis.

[0427] Step 3: The stirred solution of the alcohol (350 mg, 1.38 mmol) from Step 1 in DCM (4 mL) was treated with 1,1,1-tris(ethoxy)-1,1-dihydro-1,2-benzodioxane-3-(1h)-one (1289 mg, 3.04 mmol). After 2 h at RT, saturated aqueous solutions of Na2SO3 (1.0 mL) and NaHCO3 (1.0 mL) were added, and the two-phase mixture was stirred for 30 min. The mixture was diluted with DCM (3 mL), the layers were separated, and the aqueous layer was then extracted with CH2Cl2 (2 × 4 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated to give the desired aldehyde intermediate (350 mg, 96%). 1H 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-).

[0428] Step 4: The aldehyde (30 mg, 0.119 mmol) and morpholine (0.021 mL, 0.239 mmol) from Step 3 were mixed with one drop of acetic acid in ACN (1 mL) and stirred at 70 °C for 16 h. DCE was then added, followed by sodium triethoxyborohydride (127 mg, 0.597 mmol), and the resulting suspension was stirred at room temperature for 16 h. The reaction was quenched with a saturated NaHCO3 aqueous solution (5 mL) and stirred for 15 min. The solution was extracted with EtOAc (3 × 10 mL). The organic phase was washed with brine (10 mL), separated, dried over MgSO4, filtered, and concentrated under vacuum to obtain the desired amino monoxide (29 mg, 75%). MS m / z 286.2 (MH-).

[0429] Step 5 (Example 457, Table 4): As described for Example 1 (Step 4) in General Method A, the indole from Step 4 is coupled with chloropyridine A-13 (Ar=2,3-dichlorophenyl) using copper / BINOL catalysis to provide the compound of Example 457.

[0430] Using the appropriate amine from step 4, other analogues (456 and 461) in Table 4 are prepared in this manner.

[0430] Preparation of Example 465 (Table 4):

[0430]

[0431] Step 1: Sodium sulfide nonahydrate (2068 mg, 8.61 mmol) was added to a solution of 1H-indo-3-yl-thiocyanate (Phosphorus, Sulfur and Silicon and the Related Elements 2014, 189, 1378) (500 mg, 2.87 mmol) in iPrOH (15 mL), dissolved in 1 mL of water, and the resulting mixture was stirred at 50 °C for 2 h. Subsequently, 1-piperidinic acid, 4-bromo-1,1-dimethylethyl ester (1.1 mL, 5.74 mmol) was added and the mixture was stirred overnight at 50 °C. The reaction mixture was diluted with EtOAc (30 mL) and separated. The organic layer was washed with water (15 mL), followed by brine (15 mL), dried over MgSO4, and then concentrated under vacuum to obtain a crude sulfide, which was used directly in the next step without further purification.

[0432] Step 2: The sulfide from Step 1 was dissolved in DCM and 3-chloroperoxybenzyl acid (1486 mg, 8.61 mmol) was added and stirred at room temperature for 2 h. After completion, the reaction was quenched by adding 10 mL of a 1:1 solution of saturated NaHCO3 aqueous solution and 10% Na2SO3 aqueous solution. The resulting suspension was stirred at room temperature for 15 min. EtOAc was added and the organic layer was separated. The organic layer was washed with water (15 mL) and then with saturated brine (15 mL). The organic layer was separated, dried (MgSO4), filtered, and then concentrated to dryness. The residue was purified on silica gel containing EtOAc / hexane to provide the desired sulfide (985 mg, 94% yield). 1H 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) ,7.14-7.30(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+).

[0433] Step 3: As described in Example 1 (Step 4) of General Method A, the indole from Step 2 is coupled with chloropyridine A-13 (Ar=2,3-dichlorophenyl) using copper / BINOL catalysis.

[0434] Step 4 (Example 465, Table 4): The N-Boc-protected piperidone (170 mg, 0.201 mmol) from Step 3 was stirred in TFA (1.0 mL, 13.1 mmol) for 30 minutes, followed by concentration under vacuum. The residue was co-evaporated with ACN to provide Example 465 (170 mg, 93%). ¹H NMR (400 MHz, 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 = 8.61 Hz, 1H), 8.16 (s, 1H), 7.88–7.99 (m, 2H), 7.65 (dd, J = 1.17, 7.83 Hz, 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+).

[0434] Preparation of Example 467 (Table 4):

[0434]

[0435] Step 1: Lithium aluminum hydride (26 mg, 0.686 mmol) was added to tributyl 4-(1H-indol-3-ylsulfonylurea)piperidine-1-carboxylic acid (Example 465, Step 2: 50 mg, 0.137 mmol) in 25 mL of Et₂O in a cold (0 °C) stirred solution. After stirring at room temperature for 16 h, the reaction mixture was diluted with Et₂O and cooled at 0 °C. The reaction was quenched by slowly adding 0.150 mL of water, followed by 0.150 mL of 15% sodium hydroxide aqueous solution and 0.370 mL of water. The solution was warmed to room temperature and stirred for 15 min. Anhydrous magnesium sulfate was added to the stirred solution. After 15 min, the suspension was filtered to remove the salt. Evaporation to dryness gave N-methylpiperidine sulfonate as a solid (68 mg, 87%). MS m / z 279.2 (MH+).

[0436] Step 2: As described in Example 1 (Step 4) of General Method A, the indole from Step 1 is coupled with chloropyridine A-13 (Ar = 2,3-dichlorophenyl) using copper / BINOL catalysis to provide the product of Example 467 after reverse-phase HPLC with ACN in 0.1% HCOOH.

[0436] Preparation of Examples 468-470 and 474-479 (Table 4):

[0436]

[0437] Example 465 (25 mg, 0.0291 mmol), 3-oxocyclobutanone (0.0055 mL, 0.0873 mmol), and DIEA (1 equivalent, 0.0051 mL, 0.0291 mmol) were suspended in DCE (1 mL) and stirred at 60 °C for 30 min. Then, sodium triethoxyborohydride (19 mg, 0.0873 mmol) was added, and the suspension was stirred at 60 °C for 16 h. Once complete, the solvent was removed under vacuum, and the residue was purified by reverse-phase HPLC with ACN in 0.1% HCOOH aqueous solution to obtain Example 474 (12 mg, 49%). 1H 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+).

[0438] Other examples were prepared in a similar manner using appropriate aldehydes or ketones and can be found in Table 4 (e.g., Examples 468-470 and 475-479).

[0438] Preparation of Example 472 (Table 4):

[0438]

[0439] Step 1: At room temperature, methylphosphonic methane (212 mg, 2.72 mmol), (9,9-dimethyl-9h-dibenzopiperan-4,5-diyl)bis(diphenylphosphine) (143 mg, 0.247 mmol), and cesium carbonate (1207 mg, 3.70 mmol) were added to a stirred solution of 3-iodoindole (600 mg, 2.47 mmol) in anhydrous dioxane (10 mL). The reaction mixture was degassed and backfilled three times with argon. Tris(diphenylmethyleneacetone)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 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude material was purified by rapid column chromatography with EtOac / hexane to obtain the desired 3-indolephosphine oxide (220 mg, 46%, 50% homogeneity). MS m / z 194.2 (MH+).

[0440] Step 2 (Example 472, Table 4): As described in Example 1 (Step 4) of General Method A, the indole from Step 2 is coupled with the chloropyridine intermediate A-13 using a copper / BINOL catalysis.

[0440] Preparation of Example 483 (Table 4):

[0440]

[0441] Step 1: O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (0.173 g, 0.454 mmol) was added to a mixture of 3-methoxypropionic acid (0.047 g, 0.454 mmol), commercially available 1H-indole-3-amine (0.030 g, 0.227 mmol), and N,N-diisopropylethylamine (2.4 mL, 1.36 mmol) in DMF (1.1 mL). The resulting mixture was stirred at rt for 1.5 h. Water was added and the aqueous mixture was extracted with EtOAc. The organic layers were combined, dried over MgSO4, filtered, and subsequently concentrated under reduced pressure. The crude material was loaded onto Celite® and subsequently purified by column chromatography (silicone, 30%–100% EtOAc / hexane) to give N-(1H-indol-3-yl)-3-methoxy-propionic acid (0.049 g, 99% yield) as a brown oil. MS m / z 219.2 (MH+). 1H NMR (400MHz, DMSO-d6) δ: 10.74(br.s.,1 H),9.81(s,1 H),7.76(d,J=8.2Hz,1 H),7.71(d,J=2.3Hz,1 H),7.32(d,J=7.8Hz,1 H),7.08(td,J=7.4,1.2Hz,1 H),6.99(td,J=7.5,1.0Hz,1 H),3.64(t,J=6.3Hz,2 H),3.25(s,3 H),2.62(t,J=6.3Hz,2 H).

[0442] Step 2 (Example 483, Table 4): As described in Example 1 (Step 4) of General Method A, the indole from Step 2 is coupled with the chloropyridine intermediate A-13 using a copper / BINOL catalysis.

[0442] Preparation of Example 484 (Table 4):

[0442]

[0443] Step 1: According to general method H, arsenic acetal is prepared using commercially available 3-bromopropanal dioxane acetal as an alkylating agent, and then coupled to fragment A-13 (Ar=2,3-dichlorophenyl) using copper / BINOL catalysis as described in Example 1 (Step 4) of general method A.

[0444] The acetal (305 mg, 0.393 mmol) in THF (4 mL) was then hydrolyzed to the corresponding aldehyde by heating at 120 °C under microwave irradiation for 10 min in the presence of 1 M H2SO4 aqueous solution (5 equivalents). The reaction was then quenched with 1 M Na2CO3 and extracted with EtOAc (10 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and evaporated to give 2,3-dichloro-N-(2,4-difluoro-3-((6-(3-((3-sideoxypropyl)sulfonyl)-1H-indol-1-yl)pyrido[3,2-d]pyrimidin-4-yl)amino)phenyl)benzenesulfonamide (188 mg, 67% yield) as a yellow foam: m / z = 719.2 (M+H).

[0445] Step 2 (Example 484, Table 4): Dimethylamine HCl (17 mg, 0.209 mmol) and DIPEA (0.055 mL, 0.313 mmol) were added to a solution of the aldehyde (50 mg, 0.0697 mmol) from Step 1 in DCE (1 mL). The reaction was stirred at rt for 15 min. Triacetyl borohydride sodium (44 mg, 0.209 mmol) was then added fractionally at rt. The reaction was stirred at rt and then LCMS was performed. When the reaction was complete, the reaction was evaporated to dryness and the residue was dissolved in 1 mL DMSO. The product was purified by PREP-HPLC using 20–80% MeCN / water + 0.01% formic acid. The pure fraction was collected, evaporated, and lyophilized to give the compound of Example 484 (8 mg, 15%) as a white solid: 1H NMR (400MHz, DMSO-d6) δ: 9.94(s,1H),9.01(s,1H),8.52(s,1H),8.44-8.50(m,2H),8.32(d,J=8.6Hz,1H),7.89-7.98(m,2H),7.81(d,J=8.6Hz, 1H),7.41-7.54(m,3H),7.14-7.25(m,1H),6.97-7.08(m,1H),3.40-3.4 6(m,3H),2.54-2.60(m,1H),2.27(s,6H),1.83-1.92(m,2H); m / z=748.4.

[0445] Preparation of Example 486 (Table 4):

[0446] Following the procedure described for Example 357 and using A-13 (Ar = 2,3-dichlorophenyl), an analogue of Example 486 was obtained. Characterization of the relevant intermediates for each step is provided below:

[0446] Step 1:

[0446]

[0446] (ES+)M+H=703.4, (ES-)MH=701.4

[0446] Step 2:

[0446]

[0447] At room temperature, a solution of HCl (4 M in dioxane, 6.0 mL, 24.2 mmol) was added to a solution of compound 2a (1.70 g, 2.42 mmol) in dioxane (5 mL). The reaction mixture was stirred at room temperature for 3 days. A solution of HCl (4 M in dioxane, 3.0 mL, 12.0 mmol) was added, and the mixture was stirred at room temperature for another 24 h. The reaction mixture was filtered, and the filtered solid was washed with MTBE to give a yellow solid (1.58 g, 102% yield, 62% purity at 254...

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof, formula I, wherein: R1 is selected from substituted or unsubstituted OR3, SR3, NH2, NHR3, N(R3)2, C3-8 cycloalkyl, C4-8 heterocycloalkyl, C6-10 aryl, and C5-10 heteroaryl; R2 is selected from substituted C6 aryl or C5-10 heteroaryl, substituted or unsubstituted C4-8 heterocycloalkyl, and N(R3)2; R3 is independently selected from substituted or unsubstituted C1-8 alkyl, C3-8 cycloalkyl, C4-8 heterocycloalkyl, C6-10 aryl, and C5-10 heteroaryl each time it appears; X1 is a halogroup, perhaloalkyl, CN, NO2, sulfonate, alkylsulfonyl, alkylcarbonyl, carboxylic acid ester, alkoxycarbonyl, or aminocarbonyl; X2 is selected from H, halogroup, perhaloalkyl, CN, NO2, sulfonate, alkylsulfonyl, alkylcarbonyl, carboxylic acid ester, alkoxycarbonyl, and aminocarbonyl; X3 and X4 are each selected from H, halogen, perhaloalkyl, CN, NO2, sulfonate, alkylsulfonyl, alkylcarbonyl, carboxylic acid ester, alkoxycarbonyl, aminocarbonyl, C1-3 alkyl, C3-4 cycloalkyl and OC1-3 alkyl.

2. The compound as claimed in claim 1 or a pharmaceutically acceptable salt thereof, wherein R2 is a group of one of the following formula: ; wherein: R4 is selected from H, F, Cl, Br, CN, and a substituted or unsubstituted C1-3 alkyl, C3-4 cycloalkyl, or OC1-3 alkyl; R5 is selected from H, F, Cl, CN, and a substituted or unsubstituted C1-3 alkyl, C3-4 cycloalkyl, or OC1-3 alkyl; R6 is selected from H, F, Cl, Br, NO2, NH2, and a substituted or unsubstituted C1-3 alkyl, C3-4 cycloalkyl, or OC1-3 alkyl; R7 is selected from H, F, Cl, and a substituted or unsubstituted C1-3 alkyl; R8 is selected from H, F, and a substituted or unsubstituted C1-3 alkyl; or R4 and R5 or R5 and R6 together with their adjacent carbon atoms form a substituted or unsubstituted carbon ring or heterocycle, provided that the heterocycle is not benzoxazolinone; and (---) indicates a single bond; Where R4 is H or F, then at least one of R5, R6, R7 or R8 is not H or F; and where R5 is CN, then at least one of R4, R6, R7 or R8 is not H.

3. The compound as described in claim 2 or a pharmaceutically acceptable salt thereof, wherein: R4 is selected from Cl and a substituted or unsubstituted C1-3 alkyl group; R5 is selected from H, F, Cl and a substituted or unsubstituted C1-3 alkyl group; R6 is selected from H, F, Cl, a substituted or unsubstituted C1-3 alkyl group and a substituted or unsubstituted C1-3 alkyl group; and R7 and R8 are each H.

4. The compound as claimed in claim 1 or a pharmaceutically acceptable salt thereof, wherein R2 is a group of one of the following formula: Wherein: X5 is selected from NH, NC1-3 alkyl, NC3-4 cycloalkyl, O and S; R9, R10 and R11 are each independently selected from H, F, Cl, CN and a substituted or unsubstituted C1-3 alkyl, C3-4 cycloalkyl, C(O)OC1-3 alkyl or OC1-3 alkyl, provided that one of R9 and R11 is H and the other is not H; and (---) indicates a single bond.

5. The compound as claimed in claim 1 or a pharmaceutically acceptable salt thereof, wherein R2 is a group of one of the following formula: Wherein: X5 is selected from NH, NC1-3 alkyl, NC3-4 cycloalkyl, O and S; R9 is selected from F, Cl, CN and a substituted or unsubstituted C1-3 alkyl, C3-4 cycloalkyl, C(O)OC1-3 alkyl or OC1-3 alkyl; R10 and R12 are each independently selected from H, F, Cl, CN and a substituted or unsubstituted C1-3 alkyl, C3-4 cycloalkyl, C(O)OC1-3 alkyl or OC1-3 alkyl; and (---) indicates a single bond.

6. A compound as claimed in claim 1 or a pharmaceutically acceptable salt thereof, wherein R2 is a group of one of the following formula: Wherein: X9, X10, X11, X12, and X13 are independently selected from N and C, wherein at least one and at most two of X9, X10, X11, X12, and X13 are N; and R19, R20, R21, R22, and R23 are selected from H, F, Cl, Br, CN, NO2, NH2, and a substituted or unsubstituted C1-3 alkyl, C3-4 cycloalkyl, or OC1-3 alkyl, or are absent when the attached X9, X10, X11, X12, or X13 is N; wherein at least one of X9 and X13 is not N; and wherein when X9 is N, then X13 is not N, and X13-R23 is not CH; and wherein when X13 is N, then X9 is not N, and X9-R19 is not CH.

7. A compound as claimed in claim 1 or a pharmaceutically acceptable salt thereof, wherein R2 is a group of one of the following formula: Wherein: R13 is independently selected from F, Cl and a substituted or unsubstituted C1-3 alkyl, C3-4 cycloalkyl or C1-3 alkoxy group each time it appears; n is an integer selected from 0 to 8; or n is between 2 and 8, and two R13s together with their adjacent carbon atoms form a C3-4 cycloalkyl group; and (---) indicates a bond.

8. The compound as claimed in claim 1 or a pharmaceutically acceptable salt thereof, wherein R2 is a group selected from one of the following: where (---) represents a single bond.

9. A compound or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 8, wherein R1 is a substituted or unsubstituted group selected from one of the following: thiophene, imidazolyl, pyrazolyl, triazolyl, thiazolyl, pyridinyl, pyrimidinyl, indolyl, inzolyl, benzimidazolyl, benzotriazolyl, pyrrolopyridinyl, pyrazolopyridinyl, purine, imidazopyrazinyl, and quinolyl.

10. A compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 8, wherein R1 is a group of the following formula: Wherein: R17 is selected from H, OH, halogen, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkyl, C5-10 heteroaryl, C3-10 cycloalkyl, C4-10 heterocycloalkyl, C(O)R15, C(O)N(R14)2, SO2R15, SO2N(R14)2, N(R16)C(O)R15, N(R16)SO2R15, N(R16)C(O)N(R14)2, N(R16) )SO2N(R14)2, N(R14)2, P(O)(R15)2, CH2C(O)R15, CH2C(O)N(R14)2, CH2SO2R15, CH2SO2N(R14)2, CH 2N(R16)C(O)R15, CH2N(R16)SO2R15, CH2N(R16)C(O)N(R14)2, CH2N(R16)SO2N(R14)2 and CH2N(R14)2; X6 is N or CH; and X7 is N and R18 is absent; or X7 is C and R18 is selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkyl, C5-10 heteroaryl, C3-10 cycloalkyl, C4-10 heterocycloalkyl, C(O)R15, C(O)N(R14)2, SO2R15, SO2N(R14)2, N(R16)C(O)R15, N(R16)SO2R15, N(R16)C(O)N(R14)2 , N(R16)SO2N(R14)2, N(R14)2, P(O)(R15)2, CH2C(O)R15, CH2C(O)N(R14)2, CH2SO2R15, CH2SO2N(R14)2 , CH2N(R16)C(O)R15, CH2N(R16)SO2R15, CH2N(R16)C(O)N(R14)2, CH2N(R16)SO2N(R14)2 and CH2N(R14)2; R14, each time it appears, is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, C4-10 heterocycloalkyl, C6 aryl, and C5-10 heteroaryl, or two R14s together with their adjacent nitrogen atom form a C4-10 heterocycloalkyl; R15, each time it appears, is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, C6 aryl, and C5-10 heteroaryl; and R16, each time it appears, is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, C6 aryl, and C5-10 heteroaryl; wherein the alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, or heteroaryl group is further substituted as appropriate; and wherein (---) indicates a single bond.

11. The compound as claimed in claim 10 or a pharmaceutically acceptable salt thereof, wherein X7 is N, and R17 is selected from H, OH, CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkyl, C5-10 heteroaryl, C3-10 cycloalkyl, C4-10 heterocycloalkyl, C(O)R15, C(O)N(R14)2, SO2R15, SO2N(R14)2, N(R16)C(O)R15, N(R16)SO2R15, N(R16)C(O)N(R14)2, N(R16)SO2N(R14)2. 4) 2, N(R14)2, P(O)(R15)2, CH2C(O)R15, CH2C(O)N(R14)2, CH2SO2R15, CH2SO2N(R14)2, CH2N(R16)C(O)R15, CH2N(R16)SO2R15, CH2N(R16)C(O)N(R14)2, CH2N(R16)SO2N(R14)2 and CH2N(R14)2, and R18 is absent, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl or heteroaryl group is further substituted as appropriate.

12. A compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 8, wherein R1 is a group of the following formula: Wherein: X14 is selected from C and N; X15, X16, X17 and X18 are independently selected from O, N, S and CR17, wherein R17 is selected from H, OH, halogen, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkyl, C5-10 heteroaryl, C3-10 cycloalkyl, C4-10 heterocycloalkyl, C(O)R15, C(O)N(R14)2, SO2R15, SO2N(R14)2, N(R16)C(O)R15, N(R16)SO2R15, N(R16)C (O)N(R14)2, N(R16)SO2N(R14)2, N(R14)2, P(O)(R15)2, CH2C(O)R15, CH2C(O)N(R14)2, CH2SO2R15, CH2SO2N( R14)2, CH2N(R16)C(O)R15, CH2N(R16)SO2R15, CH2N(R16)C(O)N(R14)2, CH2N(R16)SO2N(R14)2 and CH2N(R14)2; R14, each time it appears, is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, C4-10 heterocycloalkyl, C6 aryl, and C5-10 heteroaryl, or two R14s together with their adjacent nitrogen atoms form a C4-10 heterocycloalkyl; R15, each time it appears, is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, C6 aryl, and C5-10 heteroaryl; and R16, each time it appears, is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, C6 aryl, and C5-10 heteroaryl; wherein the alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, or heteroaryl group is further substituted as appropriate; At least one and at most three of X14, X15, X16, X17 and X18 are O, N or S, and two double bonds are present in the ring to maintain aromaticity.

13. A compound or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 8, wherein R1 is selected from: wherein R14, each time it appears, is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, C4-10 heterocycloalkyl, C6 aryl, and C5-10 heteroaryl, or two R14s together with their adjacent nitrogen atom form a C4-10 heterocycloalkyl; and R15, each time it appears, is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, C6 aryl, and C5-10 heteroaryl; wherein the alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, or heteroaryl group is further substituted as appropriate; and (---) indicates a single bond.

14. A compound as claimed in claim 2 or a pharmaceutically acceptable salt thereof, wherein the compound is of formula II: Formula II wherein R4 is selected from H, F, Cl, Br, CN and a substituted or unsubstituted C1-3 alkyl, C3-4 cycloalkyl or OC1-3 alkyl; R5 is selected from H, F, Cl, CN and a substituted or unsubstituted C1-3 alkyl, C3-4 cycloalkyl or OC1-3 alkyl; R6 is selected from H, F, Cl, Br, NO2, NH2 and a substituted or unsubstituted C1-3 alkyl, C3-4 cycloalkyl or OC1-3 alkyl; or R4 and R5 or R5 and R6 together with their adjacent carbon atoms form a substituted or unsubstituted carbon ring or heterocycle, provided that the heterocycle is not benzoxazolinone; Where R4 is H or F, then at least one of R5 or R6 is not H or F; and where R5 is CN, then at least one of R4 or R6 is not H.

15. The compound as claimed in claim 14 or a pharmaceutically acceptable salt thereof, wherein R4 is selected from Cl, Br and Me, R5 is selected from H, F, Cl or methyl, and R6 is selected from H, F, Cl, Me and OMe.

16. A compound as claimed in claim 14 or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula IV: Formula IV wherein R17 is selected from H, OH, halogen, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkyl, C5-10 heteroaryl, C3-10 cycloalkyl, C4-10 heterocycloalkyl, C(O)R15, C(O)N(R14)2, SO2R15, SO2N(R14)2, N(R16)C(O)R15, N(R16)SO2R15, N(R16)C(O)N(R14)2 ... 6)SO2N(R14)2, N(R14)2, P(O)(R15)2, CH2C(O)R15, CH2C(O)N(R14)2, CH2SO2R15, CH2SO2N(R14)2, C H2N(R16)C(O)R15, CH2N(R16)SO2R15, CH2N(R16)C(O)N(R14)2, CH2N(R16)SO2N(R14)2 and CH2N(R14)2; X6 is N or CH; and X7 is N and R18 is absent; or X7 is C and R18 is selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkyl, C5-10 heteroaryl, C3-10 cycloalkyl, C4-10 heterocycloalkyl, C(O)R15, C(O)N(R14)2, SO2R15, SO2N(R14)2, N(R16)C(O)R15, N(R16)SO2R15, N(R16)C(O)N(R14)2 , N(R16)SO2N(R14)2, N(R14)2, P(O)(R15)2, CH2C(O)R15, CH2C(O)N(R14)2, CH2SO2R15, CH2SO2N(R14)2 , CH2N(R16)C(O)R15, CH2N(R16)SO2R15, CH2N(R16)C(O)N(R14)2, CH2N(R16)SO2N(R14)2 and CH2N(R14)2; R14, each time it appears, is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, C4-10 heterocycloalkyl, C6 aryl, and C5-10 heteroaryl, or two R14s together with their adjacent nitrogen atoms form a C4-10 heterocycloalkyl; R15, each time it appears, is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, C6 aryl, and C5-10 heteroaryl; and R16, each time it appears, is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, C6 aryl, and C5-10 heteroaryl; wherein the alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, or heteroaryl group is further substituted as appropriate.

17. A compound as claimed in claim 14 or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula V: Formula V wherein X14 is selected from C and N; X15, X16, X17 and X18 are independently selected from O, N, S and CR17, wherein R17 is selected from H, OH, halogen, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkyl, C5-10 heteroaryl, C3-10 cycloalkyl, C4-10 heterocycloalkyl, C(O)R15, C(O)N(R14)2, SO2R15, SO2N(R14)2, N(R16)C(O)R15, N(R16)SO2R15, N(R16)C (O)N(R14)2, N(R16)SO2N(R14)2, N(R14)2, P(O)(R15)2, CH2C(O)R15, CH2C(O)N(R14)2, CH2SO2R15, CH2SO2N( R14)2, CH2N(R16)C(O)R15, CH2N(R16)SO2R15, CH2N(R16)C(O)N(R14)2, CH2N(R16)SO2N(R14)2 and CH2N(R14)2; R14, each time it appears, is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, C4-10 heterocycloalkyl, C6 aryl, and C5-10 heteroaryl, or two R14s together with their adjacent nitrogen atoms form a C4-10 heterocycloalkyl; R15, each time it appears, is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, C6 aryl, and C5-10 heteroaryl; and R16, each time it appears, is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, C6 aryl, and C5-10 heteroaryl; wherein the alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, or heteroaryl group is further substituted as appropriate; At least one and at most three of X14, X15, X16, X17 and X18 are O, N or S, and two double bonds are present in the ring to maintain aromaticity.

18. The compound as claimed in claim 5 or a pharmaceutically acceptable salt thereof, wherein the compound is of formula III: Formula III.

19. A compound as claimed in claim 18 or a pharmaceutically acceptable salt thereof, wherein the compound is of formula VI: Formula VI wherein R17 is selected from H, OH, halogen, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkyl, C5-10 heteroaryl, C3-10 cycloalkyl, C4-10 heterocycloalkyl, C(O)R15, C(O)N(R14)2, SO2R15, SO2N(R14)2, N(R16)C(O)R15, N(R16)SO2R15, N(R16)C(O)N(R14)2 ... 6)SO2N(R14)2, N(R14)2, P(O)(R15)2, CH2C(O)R15, CH2C(O)N(R14)2, CH2SO2R15, CH2SO2N(R14)2, C H2N(R16)C(O)R15, CH2N(R16)SO2R15, CH2N(R16)C(O)N(R14)2, CH2N(R16)SO2N(R14)2 and CH2N(R14)2; X6 is N or CH; and X7 is N and R18 is absent; or X7 is C and R18 is selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkyl, C5-10 heteroaryl, C3-10 cycloalkyl, C4-10 heterocycloalkyl, C(O)R15, C(O)N(R14)2, SO2R15, SO2N(R14)2, N(R16)C(O)R15, N(R16)SO2R15, N(R16)C(O)N(R14)2 , N(R16)SO2N(R14)2, N(R14)2, P(O)(R15)2, CH2C(O)R15, CH2C(O)N(R14)2, CH2SO2R15, CH2SO2N(R14)2 , CH2N(R16)C(O)R15, CH2N(R16)SO2R15, CH2N(R16)C(O)N(R14)2, CH2N(R16)SO2N(R14)2 and CH2N(R14)2; R14, each time it appears, is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, C4-10 heterocycloalkyl, C6 aryl, and C5-10 heteroaryl, or two R14s together with their adjacent nitrogen atoms form a C4-10 heterocycloalkyl; R15, each time it appears, is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, C6 aryl, and C5-10 heteroaryl; and R16, each time it appears, is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, C6 aryl, and C5-10 heteroaryl; wherein the alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, or heteroaryl group is further substituted as appropriate.

20. A compound as claimed in claim 18 or a pharmaceutically acceptable salt thereof, wherein the compound is of formula VII: Formula VII wherein X14 is selected from C and N; X15, X16, X17 and X18 are independently selected from O, N, S and CR17, and R17 is selected from H, OH, halogen, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkyl, C5-10 heteroaryl, C3-10 cycloalkyl, C4-10 heterocycloalkyl, C(O)R15, C(O)N(R14)2, SO2R15, SO2N(R14)2, N(R16)C(O)R15, N(R16)SO2R15, N(R16)C(O)N(R14)2, N(R16) )SO2N(R14)2, N(R14)2, P(O)(R15)2, CH2C(O)R15, CH2C(O)N(R14)2, CH2SO2R15, CH2SO2N(R14)2, CH 2N(R16)C(O)R15, CH2N(R16)SO2R15, CH2N(R16)C(O)N(R14)2, CH2N(R16)SO2N(R14)2 and CH2N(R14)2; R14, each time it appears, is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, C4-10 heterocycloalkyl, C6 aryl, and C5-10 heteroaryl, or two R14s together with their adjacent nitrogen atoms form a C4-10 heterocycloalkyl; R15, each time it appears, is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, C6 aryl, and C5-10 heteroaryl; and R16, each time it appears, is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 cycloalkyl, C6 aryl, and C5-10 heteroaryl; wherein the alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, or heteroaryl group is further substituted as appropriate; At least one and at most three of X14, X15, X16, X17 and X18 are O, N or S, and two double bonds are present in the ring to maintain aromaticity.

21. A compound as described in claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the following table: .

22. The compound as claimed in claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the following compounds: , , , , , , , , , , , , , , , , and.

23. The compound as claimed in claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the following compounds: , , , , , , , , and.

24. The compound as described in claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the following compounds:

25. A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 24, and a pharmaceutically acceptable carrier, diluent, or excipient.

26. Use of a compound as defined in any one of claims 1 to 24 in the manufacture of a medicament for treating a disease or condition selected from: a proliferative disease or condition, a developmental disorder (RAS disease) caused by RAS-ERK cascade dysregulation, an inflammatory disease, or an immune system disorder.

27. The use as described in claim 26, wherein the disease or condition is associated with a mutation in a RAF gene.

28. The use as described in claim 27, wherein the disease or condition is associated with a mutation in the ARAF, BRAF, or CRAF gene.

29. The use as described in claim 27, wherein the disease is a tumor selected from melanoma, thyroid cancer, colorectal cancer, ovarian cancer, breast cancer, endometrial cancer, liver cancer, sarcoma, gastric cancer, pancreatic cancer, Barrett's adenocarcinoma, glioma, ependymoma, lung cancer, head and neck cancer, acute lymphoblastic leukemia, acute myeloid leukemia, non-Hodgkin's lymphoma, and hairy cell leukemia.

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