WO2023031308A1 - Inhibiteurs de ccr2 - Google Patents

Inhibiteurs de ccr2 Download PDF

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Publication number
WO2023031308A1
WO2023031308A1 PCT/EP2022/074259 EP2022074259W WO2023031308A1 WO 2023031308 A1 WO2023031308 A1 WO 2023031308A1 EP 2022074259 W EP2022074259 W EP 2022074259W WO 2023031308 A1 WO2023031308 A1 WO 2023031308A1
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mmol
int
alkyl
phenyl
oxy
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PCT/EP2022/074259
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English (en)
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Tjeerd Barf
Adriaan Ijzerman
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Artica Therapeutics B.V.
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Publication of WO2023031308A1 publication Critical patent/WO2023031308A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/76—Nitrogen atoms to which a second hetero atom is attached
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to novel substituted aryl sulfonamide compounds, to pharmaceutical compositions comprising these compounds and to their use in therapy.
  • the present invention relates to the use of substituted aryl sulfonamide compounds in the treatment of CC Chemokine Receptor 2 (CCR2) mediated disorders.
  • CCR2 Chemokine Receptor 2
  • Chemokines are best regarded as mini-proteins and are defined by the position and arrangement of specific cysteine residues in their amino acid sequence.
  • the cysteines are positioned such that they form disulfide bonds that maintain the structure of the chemokine.
  • Chemokines in their monomeric form thus consist of a central 3-stranded p-sheet, a C-terminal a-helix, and a short N-terminus that is not very structured and plays a critical role in receptor activation (Miller and Mayo, 2017). Variation in the precise configuration of the two cysteines closest to the N terminus allows chemokines to be split into four subclasses: CC, CXC, CX3C, and XC.
  • the CC ligands are most relevant, in which these cysteines are directly juxtaposed.
  • CXC chemokines have an amino acid between them that is variable.
  • the only CX3C chemokine has three amino acids between these two cysteines, while XC chemokines lack the first and the third cysteines of the motif.
  • Chemokines act via abundantly expressed chemokine receptors, which belong to the family of G protein-coupled receptors (GPCRs). GPCRs are cell membrane-bound proteins of which the primary sequence traverses the cell wall seven times, hence their other name of 7TM (transmembrane) receptors (Congreve et al., 2020). There are subfamilies of chemokine receptors, of which the so-called CCRs (chemokine receptors activated by a given CCL - vide supra) are most relevant for the present invention. Their role in cellular pharmacology is to transduce extracellular signals, i.e.
  • chemokines the binding of chemokines, through pertussis toxin-sensitive Gi proteins and p-arrestins to the inside of the cell, eventually leading to cell migration, adhesion and/or a variety of other biological responses.
  • the interaction between chemokine and receptor, both proteins, can be quite complicated compared to the binding of small molecule hormones and neurotransmitters. For instance, posttranslational modifications such as sulphation of tyrosines can direct and enhance the tethering of chemokines to their respective receptors, one example of which is the enhanced binding of CCL2 to CCR2 (Tan et al., 2013).
  • the less structured N terminus of the chemokine is accommodated in the so-called orthosteric binding site at the extracellular side of the receptor. This event supposedly changes the receptor’s inactive conformation to a more active one, which is responsible for signal transduction.
  • CCRs the transcripts of which can evoke alternative splicing giving rise to another layer of signaling complexity. For instance, two variants of CCR2 have been reported with different C-carboxy tails (Charo et al., 1994) that differ in their signaling properties.
  • multiple chemokines may interact with one chemokine receptor, while, conversely, one chemokine ligand may interact with multiple chemokine receptors.
  • chemokines are important regulators of leukocyte trafficking and play a central role in the immune system (Zlotnik and Yoshie, 2012). Chemokines induce migration and differentiation of immune cells, which both are essential processes during innate and adaptive immune responses (Esche et al., 2005). Many immune cells display distinct chemokine expression profiles. In general the spatio-temporal pattern of chemokine expression appears to regulate immune cell activity in health and disease (Groom and Luster, 2011 ). Moreover, chemokines interact with specific glycosaminoglycan (GAG) chains that are presented at the cell surface, adding a further layer of complexity to the release and production of chemokines among various tissues and their in vivo availability.
  • GAG glycosaminoglycan
  • chemokines The binding of chemokines to GAGs allows their immobilization and retention near their production machinery, which enables to provide steering to migrating cells (Tanino et al., 2010).
  • the exact functional consequences of chemokine-GAG interactions and the level of specificity are still largely speculative, however.
  • chemokine receptors are also expressed on many immune cells. For instance the CCR3 receptor, despite being the least ubiquitously expressed of all CCRs, is amply available on myeloid cells, including eosinophils, basophils and macrophages (Hughes and Nibbs, 2018).
  • chemokine receptors A wide variety of other biological processes can be induced by the activation of chemokine receptors on leukocytes, including proliferation, survival, differentiation, cytokine production, degranulation, and respiratory burst (Lopez-Cotarelo et al., 2017).
  • cancer cells can also evolve to express chemokine receptors and respond to chemokines with immediate consequences for local invasion, spread to lymph nodes, and metastasis formation in distant tissues (Zlotnik et al., 2011 ).
  • the role of the CCL2/CCR2 axis in tumor biology is particularly relevant.
  • CCLs cytotoxic T lymphocytes
  • DC dendritic cell maturation toward the CD103+ subtype
  • Wolf et al described CCL2 upregulation in metastatic UICC stage IV colon carcinomas and demonstrated that tumor cell-derived CCL2 activates the CCR2(+) endothelium to increase vascular permeability in vivo.
  • CCR2 deficiency in contrast, prevented colon carcinoma extravasation and metastasis (Wolf et al., 2012).
  • a meta-analysis of 11 studies in solid tumors showed that high concentrations of CCL2 are related to a worse overall survival (Wang et al., 2014).
  • CCR2 tumor-associated macrophages
  • TAMs tumor-associated macrophages
  • CCL2 interacts with CCR2 to mediate chemotaxis of monocytes and TAMs, which shapes the TME and facilitates cancer progression (Murray and Wynn, 2011 ; Qian et al., 2011 ).
  • the same CCL2-CCR2 axis recruits TAMs to induce immune evasion through PD-1 signaling in esophageal carcinogenesis (Yang et al., 2020), suggesting that therapies with blockers of CCR2 alone or in combination with e.g., anti-PD-1 antibodies can be useful in cancer.
  • phase lb clinical trials indicated that adding the CCR2 antagonist to chemotherapy leads to a higher objective tumor response compared to chemotherapy alone (Nywening et al., 2016). These results encouraged a phase Ib/ll clinical trial of the same CCR2 antagonist combined with nab-paclitaxel/gemcitabine in metastatic pancreatic ductal adenocarcinoma (NCT02732938). This clinical trial was less encouraging, with severe adverse effects in 2 out of 4 patients at high dose.
  • allosteric binding i.e. small molecules that bind chemokine receptors in areas that do not overlap with the binding site of the endogenous chemokines.
  • orthosteric antagonists targeting the chemokine receptors in this manner has at least two advantages over orthosteric binding. These are, i) because allosteric ligands do not compete with endogenous chemokines, they are able to bind their receptor even in the abundant presence of chemokines (chemokine “storm”), which may enhance efficacy.
  • the latter resides in the receptor 7TM domain facing the extracellular side accommodating an orthosteric antagonist, while the allosteric site occupied by another antagonist is rather at the intracellular interface between receptor and G protein (Zheng et al., 2016).
  • a similar, although not identical allosteric binding site was observed in the CCR9 receptor (Oswald et al., 2016), to which vercirnon, a selective CCR9 antagonist with a typical sulfonamide moiety, binds.
  • a series of biarylsulfonamides that are, in hindsight, allosteric CCR2 antagonists have been developed (Sullivan et al., 2013; Wang et al., 2011 ).
  • Such compounds are not affected by a “chemokine storm” as mentioned before, they still may have a target residence time that does not allow full target engagement. Therefore, the inventors considered it desirable to develop new compounds with improved pharmacological characteristics compared with known chemokine receptor modulators. Such improved characteristics include a long target residence time of the new compounds, to be attained through the incorporation of chemoreactive “warheads” that covalently attach the modulator to the receptor (Jorg and Scammells, 2016). In this way the residence time is “infinite”, i.e. the ligand is bound to the target and antagonizes it as long as the target is intact in terms of functionality and localization.
  • Covalent ligands have demonstrated value as tool compounds; moreover some have emerged as therapeutic agents for various (non-GPCR) targets (Ghosh et al., 2019).
  • covalent ligands have been primarily used as tool compounds due to safety concerns.
  • advantages in developing covalent drugs rather than tool compounds due to reasons mentioned above, such as prolonged target occupancy (Bauer, 2015). The latter advantage may be particularly useful in diseases in which high chemokine receptor occupancy and prolonged target inhibition are required for an adequate in vivo response (Schall and Proudfoot, 2011 ).
  • the thiocyano moiety is a hyperreactive “warhead” and therefore ill-suited for being part of a potential drug candidate.
  • the present invention avoids this issue and describes a series of compounds that are very well suited as drug candidates.
  • Another tool compound that was described by Ortiz Zacarias et al., 2021 features an acrylamide on the extended linker (compound 12); however, covalent binding for compound 12 was not demonstrated. DESCRIPTION OF THE INVENTION
  • the extended linker (used by Ortiz Zacarias et al. 2021 ) is not needed to effect covalent binding, as direct incorporation (i.e. without the extended linker) of a reactive moiety (e.g., an acrylamide) already steers the reactivity of the warhead in a controlled manner, while achieving nanomolar potency for the compounds.
  • a reactive moiety e.g., an acrylamide
  • the invention provides a compound of formula I a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer, wherein:
  • Y is selected from CR 9 , NR 22 , O and S, wherein the ring containing Y, A 2 , A 3 , A 4 and A 5 comprises three double bonds when Y is CR 9 or NR 22 and A 2 is not a bond and comprises two double bonds when A 2 is a bond, wherein the ring containing Y, A 2 , A 3 , A 4 and A 5 comprises two double bonds when Y is NR 22 , O or S;
  • a 1 is selected from N and CH;
  • a 2 is selected from N, CR 10 and a bond
  • a 3 , A 4 , and A 5 are each independently selected from NR 23 , CR 10 and C bound to the L-NR 1 R 2 group, wherein the ring containing Y, A 2 , A 3 , A 4 and A 5 comprises no more than two N atoms, wherein at least one of A 3 , A 4 or A 5 is C bound to the L-NR 1 R 2 group;
  • L is selected from a bond, CR 11 R 12 and C(O);
  • R 1 is selected from:
  • R 2 is selected from H, C1-3 alkyl and C3-7 cycloalkyl, wherein C1-6 alkyl and C3-7 cycloalkyl are optionally substituted, preferably with one or more F;
  • R 3 , R 4 and R 5 are each independently selected from H, halogen, C1-6 alkyl and C3-7 cycloalkyl, wherein C1-6 alkyl and C3-7 cycloalkyl are optionally substituted, preferably with one or more F;
  • R 6 , R 7 and R 8 are each independently selected from H, C1-6 alkyl and C3-7 cycloalkyl, wherein C1-6 alkyl and C3-7 cycloalkyl are optionally substituted, preferably with one or more F;
  • R 9 is selected from H, halogen, cyano, aryl, heteroaryl, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy, C(O)OR 24 , C(O)NR 25 R 26 and NHC(O)R 27 , wherein C1-6 alkyl, C3-7 cycloalkyl and C1-6 alkoxy are optionally substituted, preferably with one or more F; wherein R 6 , R 7 or R 8 optionally form a 4-, 5-, 6-, or 7-membered ring with Y when Y is CR 9 or NR 22 ;
  • R 10 is selected from H, halogen, cyano, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy, C(O)R 28 and C(O)OR 29 or forms a 5- or 6-membered ring comprising the C at A 2 and the C at A 3 , wherein C1-6 alkyl, C3-7 cycloalkyl and C1-6 alkoxy are optionally substituted, preferably with one or more F; wherein R 2 optionally forms a 4-, 5-, 6-, or 7-membered ring with A 3 , A 4 or A 5 when A 3 , A 4 or A 5 is CR 10 or NR 23 ;
  • R 11 and R 12 are each independently selected from H, C1-6 alkyl or C3-7 cycloalkyl, wherein C1-6 alkyl and C3-7 cycloalkyl are optionally substituted, preferably with one or more F, wherein R 11 optionally forms a 3-, 4-, 5-, or 6-membered ring with R 12 ;
  • R 13 , R 14 , R 15 and R 16 are each independently selected from H, F, and C1-6 alkyl; wherein C1-6 alkyl is optionally substituted with one or more F, OR 19 or NR 20 R 21 ; and wherein R 13 optionally forms a 3-, 4-, 5-, or 6-membered ring with R 14 or R 15 ;
  • R 22 and R 23 are each independently selected from nothing (i.e. a substituent group is absent), H or C1-6 alkyl
  • R 24 , R 25 , R 26 , R 27 , R 28 , R 29 are each independently selected from H, C1-6 alkyl and C3-7 cycloalkyl, wherein C1-6 alkyl and C3-7 cycloalkyl are optionally substituted, preferably with one or more F;
  • R 30 and R 31 are each independently selected from H, hydroxy, halogen, C1-6 alkyl and C1-6 alkoxy, wherein C1-6 alkyl and C1-6 alkoxy are optionally substituted, preferably with one or more F.
  • the invention provides a compound of formula II a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer, wherein:
  • X is selected from a bond, CR 6 R 7 , C(O), NR 8 , O, S, SO and SO2;
  • Y is selected from CR 9 , NR 22 , O and S, wherein the ring containing Y, A 2 , A 3 , A 4 and A 5 comprises three double bonds when Y is CR 9 or NR 22 and A 2 is not a bond and comprises two double bonds when A 2 is a bond, wherein the ring containing Y, A 2 , A 3 , A 4 and A 5 comprises two double bonds when Y is NR 22 , O or S;
  • a 1 is selected from N and CH;
  • a 2 is selected from N, CR 10 and a bond
  • a 3 , A 4 , and A 5 are each independently selected from NR 23 , CR 10 and C bound to the L-NR 1 R 2 group, wherein the ring containing Y, A 2 , A 3 , A 4 and A 5 comprises no more than two N atoms, wherein at least one of A 3 , A 4 or A 5 is C bound to the L-NR 1 R 2 group;
  • L is selected from a bond, CR 11 R 12 and C(O);
  • R 1 is selected from:
  • R 2 is selected from H, C1-3 alkyl and C3-7 cycloalkyl, wherein C1-6 alkyl and C3-7 cycloalkyl are optionally substituted, preferably with one or more F;
  • R 3 , R 4 and R 5 are each independently selected from H, halogen, C1-6 alkyl and C3-7 cycloalkyl, wherein C1-6 alkyl and C3-7 cycloalkyl are optionally substituted, preferably with one or more F;
  • R 6 , R 7 and R 8 are each independently selected from H, C1-6 alkyl and C3-7 cycloalkyl, wherein C1-6 alkyl and C3-7 cycloalkyl are optionally substituted, preferably with one or more F;
  • R 9 is selected from H, halogen, C1-6 alkyl, C3-7 cycloalkyl and C1-6 alkoxy, wherein C1-6 alkyl, C3-7 cycloalkyl and C1-6 alkoxy are optionally substituted, preferably with one or more F; wherein R 6 , R 7 or R 8 optionally form a 4-, 5-, 6-, or 7-membered ring with Y when Y is CR 9 or NR 22 ;
  • R 10 is selected from H, halogen, C1-6 alkyl, C3-7 cycloalkyl or C1-6 alkoxy, wherein C1-6 alkyl, C3-7 cycloalkyl and C1-6 alkoxy are optionally substituted, preferably with one or more F; wherein R 2 optionally forms a 4-, 5-, 6-, or 7-membered ring with A 3 , A 4 or A 5 when A 3 , A 4 or A 5 is CR 10 or NR 23 ;
  • R 11 and R 12 are each independently selected from H, C1-6 alkyl or C3-7 cycloalkyl, wherein C1-6 alkyl and C3-7 cycloalkyl are optionally substituted, preferably with one or more F, wherein R 11 optionally forms a 3-, 4-, 5-, or 6-membered ring with R 12 ;
  • R 13 , R 14 , R 15 and R 16 are each independently selected from H, F, and C1-6 alkyl; wherein C1-6 alkyl is optionally substituted with one or more F, OR 19 or NR 20 R 21 ; and wherein R 13 optionally forms a 3-, 4-, 5-, or 6-membered ring with R 14 or R 15 ;
  • R 17 and R 18 are each independently selected from H, C1-6 alkyl or C3-7 cycloalkyl; wherein C1-6 alkyl or C3-7 cycloalkyl is optionally substituted, preferably with one or more F, and wherein R 17 optionally forms a 3-, 4-, 5-, or 6-membered ring with R 18 ; wherein R 13 , R 14 , R 15 , R 17 or R 18 optionally form a substituted or unsubstituted 3-, 4-, 5-, 6-, 7-, 8-, 9- or 10- membered ring with R 2 ; wherein R 16 optionally forms a substituted or unsubstituted 7-, 8-, 9- or 10- membered ring with R 2 ;
  • R 19 , R 20 and R 21 are each independently selected from H, C1-6 alkyl and C3-7 cycloalkyl, wherein C1-6 alkyl and C3-7 cycloalkyl are optionally substituted, preferably with one or more F;
  • R 22 and R 23 are each independently selected from nothing (i.e. a substituent group is absent), H or C1-6 alkyl.
  • the ring containing Y, A 2 , A 3 , A 4 and A 5 contains no N atoms. In some embodiments, the ring containing Y, A 2 , A 3 , A 4 and A 5 contains one N atom. In some embodiments, the ring containing Y, A 2 , A 3 , A 4 and A 5 contains two N atoms. In some embodiments, when A 2 is not a bond R 22 and R 23 are nothing. In some embodiments, when A 2 is a bond Y is O or S.
  • the ring containing Y, A 2 , A 3 , A 4 and A 5 comprises three double bonds when A 2 is not a bond and R 22 is nothing. In some embodiments, the ring containing Y, A 2 , A 3 , A 4 and A 5 is aromatic.
  • the ring containing Y, A 2 , A 3 , A 4 and A 5 is selected from optionally substituted phenyl, pyridine, pyrimidine, pyrazine, pyridazine, pyrrole, pyrazole, imidazole, thiazole, isothiazole, isoxazole, oxazole, furan, pyran, thiophene, thiopyran, thiazine, oxadiazole, and thiadiazole.
  • the ring containing Y, A 2 , A 3 , A 4 and A 5 is selected from optionally substituted phenyl, pyridine, pyrimidine, pyrazole, imidazole, thiazole, isothiazole, furan and thiophene. In some embodiments, the ring containing Y, A 2 , A 3 , A 4 and A 5 is optionally substituted phenyl. In some embodiments, X is selected from a bond, CR 6 R 7 , C(O), NR 8 , O, S, SO and SO2.
  • one of A 3 , A 4 or A 5 is C bound to the L-NR 1 R 2 group and the other two are selected from NR 23 and CR 10 , preferably, A 4 or A 5 is C bound to the L-NR 1 R 2 group.
  • a 3 is C bound to the L-NR 1 R 2 group and A 4 and A 5 are selected from NR 23 and CR 10 .
  • a 4 is C bound to the L-NR 1 R 2 group and A 3 and A 5 are selected from NR 23 and CR 10 .
  • a 3 is C bound to the L-NR 1 R 2 group and A 4 and A 5 are selected from NR 23 and CR 10 .
  • L is a bond or CR 11 R 12 , preferably L is a bond. In some embodiments, L is C(O) only when R 1 is:
  • C1-6 alkyl is C1-3 alkyl preferably Ci alkyl optionally wherein Ci alkyl is substituted with one or more F preferably wherein Ci alkyl is CF3.
  • C1-6 alkoxy is C1-3 alkoxy preferably Ci alkoxy optionally wherein Ci alkoxy is substituted with one or more F preferably wherein Ci alkoxy is OCF3.
  • C3-7 cycloalkyl is C3-6 cycloalkyl.
  • Y is CR 9 wherein R 9 is selected from H, F, CH3, CF3 and OCH3, preferably OCH3.
  • R 6 , R 7 or R 8 form a 6-membered ring with Y when Y is CR 9 or NR 22 optionally wherein R 9 is C1-6 alkoxy.
  • R 2 forms a 4-, 5-, 6-, or 7- membered ring with A 3 or A 5 when A 3 or A 5 is CR 10 or NR 23 optionally wherein R 10 is 0-6 alkyl or Ci-6 alkoxy.
  • R 2 forms a 5- or 6-membered ring with A 3 , A 4 or A 5 when A 3 , A 4 or A 5 is CR 10 or NR 23 optionally wherein R 10 is 0-6 alkyl or C1-6 alkoxy.
  • R 2 forms a 5- or 6-membered ring with A 3 or A 5 when A 3 or A 5 is CR 10 or NR 23 optionally wherein R 10 is 0-6 alkyl or C1-6 alkoxy.
  • R 11 and R 12 form a 3- membered ring, optionally wherein R 11 and R 12 are both alkyl.
  • Re forms a 5-or 6-membered ring with R 14 or R 15 optionally when R 13 , R 14 and R 15 are C1-6 alkyl.
  • R 19 , R 20 and R 21 are Ci alkyl.
  • R 17 forms a 5- or 6- membered ring with R 18 optionally wherein R 17 and R 18 are C1-6 alkyl.
  • R 1 is selected from:
  • R 1 is optionally wherein R 13 , R 14 and R 15 are H or F, preferably H.
  • R 13 or R 14 is each independently selected from H or F;
  • R 15 is selected from H and Ci alkyl optionally substituted with one or more F, OR 19 or NR 20 R 21 , wherein R 19 , R 20 , R 21 is C1-3 alkyl, preferably Ci alkyl; b) R 16 is Ci alkyl optionally substituted, preferably with one or more F; and/or c) R 17 and R 18 are each independently selected from H and Ci alkyl optionally substituted with one or more F, wherein R 17 and R 18 optionally form a 3-membered ring.
  • R 1 is: wherein L is selected from a bond and CR 11 R 12 ; wherein R 11 and R 12 are each independently selected from H and Ci alkyl optionally substituted with one or more F, wherein R 11 and R 12 optionally form a 3- membered ring.
  • R 1 is: and L is a bond.
  • R 16 is Ci alkyl.
  • R 1 is: and L is a bond or C(O).
  • R 2 is selected from H or Ci alkyl optionally substituted, preferably with one or more F.
  • X is selected from CR 6 R 7 , NR 8 and O; Y is CR 9 ; A 1 is N; and/or R 3 is Ci alkyl optionally substituted with one or more F.
  • X is O or CR 6 R 7 preferably R 6 and R 7 are H.
  • X is O.
  • R3 is Ci alkyl.
  • R 4 and R 5 are each independently selected from H, fluoro, chloro, bromo, Ci alkyl, CF3, CHF2, and CH2F; or b) R 4 is selected from bromo, chloro, Ci alkyl and CF3, and/or R 5 is selected from H, chloro, Ci alkyl and CF3.
  • R 3 is Ci alkyl
  • R 4 is selected from H, bromo, chloro and Ci alkyl
  • R 5 is selected from H, chloro and Ci alkyl optionally substituted with one or more F,
  • X is selected from O, C(O), CH2 and NR 8 , optionally wherein R 8 forms a 6-membered ring with
  • Y is CR 9 wherein R 9 is selected from H, F, Ci alkoxy and Ci alkyl optionally substituted with one or more F,
  • a 1 is N
  • a 2 is CR 10 wherein R 10 is selected from H, F, Ci alkoxy and Ci alkyl optionally substituted with one or more F,
  • a 3 is CR 10 wherein R 10 is selected from H, F and Ci alkyl, wherein one of A 4 or A 5 is C bound to the L-NR 1 R 2 group and the other is CR 10 wherein R 10 is H or F,
  • L is selected from a bond, CR 11 R 12 and C(O), wherein R 11 and R 12 are each independently selected from H and Ci alkyl, optionally wherein R 11 forms a 3-membered ring with R 12 ,
  • R 1 is selected from
  • R 2 is selected from H and Ci alkyl
  • R 13 is selected from H and F
  • R 14 is H
  • R 15 is selected from H, F, Ci alkyl optionally substituted with F, OCH3 or N(CH3)2,
  • R 16 is Ci alkyl, and/or
  • R 17 and R 18 are each independently selected from H, C1-6 alkyl preferably Ci alkyl, optionally wherein one of R 17 or R 18 forms a 5-membered ring with R 2 . In some embodiments,
  • R 3 is Ci alkyl
  • R 4 is chloro
  • R 5 is Ci alkyl optionally substituted with one or more F,
  • X is selected from O, C(O), CH2 and NR 8 , optionally wherein R 8 forms a 6-membered ring with
  • Y is CR 9 wherein R 9 is selected from H, F, Ci alkoxy and Ci alkyl optionally substituted with one or more F,
  • a 1 is N
  • a 2 is CR 10 wherein R 10 is selected from H, F, Ci alkoxy and Ci alkyl optionally substituted with one or more F,
  • a 3 is CR 10 wherein R 10 is selected from H, F and Ci alkyl, wherein one of A 4 or A 5 is C bound to theL-NR 1 R 2 group and the other is CR 10 wherein R 10 is H or F,
  • L is selected from a bond, CR 11 R 12 and C(O), wherein R 11 and R 12 are each independently selected from H and Ci alkyl, optionally wherein R 11 forms a 3-membered ring with R 12 ,
  • R 1 is selected from
  • R 2 is selected from H and Ci alkyl
  • R 13 is selected from H and F
  • R 14 is H
  • R 15 is selected from H, F, Ci alkyl optionally substituted with F, OCH3 or N(CH3)2,
  • R 16 is Ci alkyl, and/or
  • R 17 and R 18 are each independently selected from H, C1-6 alkyl preferably Ci alkyl, optionally wherein one of R 17 or R 18 forms a 5-membered ring with R 2 .
  • R 3 is Ci alkyl
  • R 4 is chloro
  • R 5 is Ci alkyl optionally substituted with one or more F,
  • X is selected from O and NR 8 , optionally wherein R 8 forms a 6-membered ring with Y when Y is CR 9 ,
  • Y is CR 9 wherein R 9 is selected from H, F, Ci alkoxy and Ci alkyl optionally substituted with one or more F,
  • a 1 is N
  • a 2 is CR 10 wherein R 10 is selected from H, F, Ci alkoxy and Ci alkyl optionally substituted with one or more F,
  • a 3 is CR 10 wherein R 10 is selected from H and F, wherein A 4 is C bound to the L-NR 1 R 2 group and A 5 is CR 10 wherein R 10 is H or F,
  • R 2 is H
  • R 13 and R14 are each H, and/or
  • R 15 is selected from H and Ci alkyl optionally substituted with F.
  • R 24 , R 25 , R 26 , R 27 , R 28 , R 29 may be Ci alkyl optionally substituted with one or more F.
  • R 9 may be 5- or 6- membered aryl or heteroaryl optionally phenyl.
  • At least one of R 30 or R 31 is H. In some embodiments, both R 30 and R 31 are H.
  • R 10 does not form a 5- or 6- membered ring comprising C at A 2 and C at A 3 .
  • R 10 forms a 5- or 6- membered ring comprising C at A 2 and C at A 3 the result is a fused bicyclic ring.
  • This bicyclic ring is fused at the bond between the C at A 2 and C at A 3 .
  • the fused bicyclic ring comprises the 5- or 6- membered ring comprising the C at A 2 and C at A 3 and the Y-containing ring.
  • the 5- or 6-membered ring formed by R 10 comprising the C at A 2 and C at A 3 may be aryl or heteroaryl.
  • the 5- or 6-membered ring formed by R 10 comprising the C at A 2 and C at A 3 may be a 6-membered ring. In some embodiments, the 5- or 6- membered ring formed by R 10 comprising the C at A 2 and C at A 3 comprises one or more nitrogen atoms. In some embodiments, the 5- or 6-membered ring formed by R 10 comprising the C at A 2 and C at A 3 may be a 6-membered aryl or heteroaryl which together with the Y-containing ring forms a 12-membered aryl or hetetoaryl (e.g. quinoline).
  • the quinoline ring nitrogen atom may be present in the ring formed by R 10 comprising the C at A 2 and C at A 3 or the Y-containing ring, preferably the ring formed by R 10 comprising the C at A 2 and C at A 3 .
  • Specific examples of such compounds can be found as Examples 71 and 73 herein.
  • R 3 is Ci alkyl
  • R 4 is selected from H, bromo, chloro and Ci alkyl
  • R 5 is selected from H, chloro and Ci alkyl optionally substituted with one or more F,
  • R 24 , R 25 , R 26 , R 27 , R 28 , R 29 is Ci alkyl optionally substituted with one or more F.
  • R 30 and R 31 are independently selected from H, F or hydroxy
  • Y is CR 9 wherein R 9 is selected from H, cyano, aryl, halogen (e.g. F or Cl), Ci alkoxy and Ci alkyl wherein Ci alkoxy and Ci alkyl are optionally substituted,
  • a 1 is N
  • a 2 is CR 10 wherein R 10 is selected from H, F ,Ci alkoxy and Ci alkyl optionally substituted with one or more F or wherein R 10 forms a 5- or 6 membered ring between A 2 and A 3 ,
  • a 3 is NR 23 wherein R 23 is nothing or A 3 is CR 10 wherein R 10 is selected from H, F and Ci alkyl, cyano, C(O)R 28 and C(O)OR 29 , wherein one of A 4 or A 5 is C bound to the L-NR 1 R 2 group and the other is CR 10 wherein R 10 is H or halogen (e.g. F or Cl),
  • L is selected from a bond, CR 11 R 12 and C(O), wherein R 11 and R 12 are each independently selected from H and Ci alkyl, optionally wherein R 11 forms a 3-membered ring with R 12 ,
  • R 1 is selected from
  • R 2 is selected from H and Ci alkyl
  • R 13 is selected from H and F, one of R 14 or R 15 is H and the other is selected from H, Ci alkyl optionally substituted with with F, OCH 3 or N(CH 3 ) 2 .
  • R 16 is Ci alkyl, and/or
  • R 17 and R 18 are each independently selected from H, C1-6 alkyl preferably Ci alkyl, optionally wherein one of R 17 or R 18 forms a 5-membered ring with R 2 .
  • R 1 is or ; and the ring containing Y, A 2 , A 3 , A 4 and A 5 is a 6-membered ring.
  • R 1 is wherein the ring containing Y, A 2 , A 3 , A 4 and A 5 is a 6-membered ring; and wherein A 4 or A 5 is C bound to L-NR 1 R 2 .
  • L is a bond or CR 11 R 12 , optionally wherein R 11 and R 12 are Ci alkyl and together form a 3-membered ring.
  • R 13 is H or F; and one of R 14 or R 15 is H and the other is selected from H, Ci alkyl optionally substituted with with F, OCH 3 or N(CH 3 ) 2 .
  • R 1 is or wherein the ring containing Y, A 2 , A 3 , A 4 and A 5 is a 6-membered ring; wherein A 4 or A 5 is C bound to L-NR 1 R 2 ,
  • R 13 is H or F; and one of R 14 or R 15 is H and the other is selected from H, Ci alkyl optionally substituted with with F, OCH 3 or N(CH 3 ) 2 .
  • R 1 is or wherein the ring containing Y, A 2 , A 3 , A 4 and A 5 is a 6-membered ring; wherein A 4 or A 5 is C bound to L-NR 1 R 2 ,
  • R 13 is H or F; one of R 14 or R 15 is H and the other is selected from H, Ci alkyl optionally substituted with with
  • L is a bond or CR 11 R 12 , optionally wherein R 11 and R 12 are Ci alkyl and toegther form a 3- membered ring.
  • R 13 when R 13 forms a ring with R 14 or R 15 the ring is not aromatic.
  • R 16 is Ci alkyl.
  • the compound is selected from a compound set forth in Table 1 :
  • the compounds forms a covalent bond with a cysteine residue of Chemokine Receptor 2 (CCR2), preferably Cys75, optionally wherein the compound forms a covalent bond with the cysteine residue under physiological conditions.
  • CCR2 Chemokine Receptor 2
  • the compounds react covalently and irreversibly with a cysteine residue of CCR2, preferably Cys75.
  • Physiological conditions refers to conditions that occur inside an organism or cell, in particular in a human.
  • a covalent bond with CCR2 would be formed following administration of a compound of the invention to a subject, in particular a human subject.
  • the compounds bind to the allosteric site of CCR2.
  • CCR2 may be human CCR2 isoform B and/or human CCR2 isoform A, preferably human CCR2 isoform B.
  • the amino acid sequence of human CCR2 isoform B is set forth as SEQ ID NO: 1 (NCBI Reference Sequence: NP_001 1 16868.1 ), in which Cys75 (C) is bold and underlined.
  • SEQ ID NO: 1 NCBI Reference Sequence: NP_001 1 16868.1
  • amino acid sequence of human CCR2 isoform A is set forth as SEQ ID NO: 2 (NCBI Reference Sequence: NP_001116513.2), in which Cys75 (C) is bold and underlined.
  • the invention also provides a complex comprising a compound of the invention covalently bound to a cysteine residue of Chemokine Receptor 2 (CCR2), preferably Cys75.
  • CCR2 Chemokine Receptor 2
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the invention together with a pharmaceutically acceptable excipient.
  • the excipient is any component of the pharmaceutical composition apart from the active ingredient (i.e. a compound of the invention).
  • the compound of the invention may be in admixture with pharmaceutically acceptable excipients and optionally other therapeutic agents.
  • the excipients must be “acceptable” in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipients thereof.
  • the excipient contributes to the overall attributes of the pharmaceutical composition, such as stability, biopharmaceutical profile, appearance, patient acceptability and ease with which the product can be manufactured.
  • the invention further includes a compound of formula I in combination with one or more other drug(s).
  • the one or more other drug(s) may comprise a chemotherapy.
  • the one or more other drug(s) may comprise a checkpoint inhibitor.
  • the compound of the invention may be administered simultaneously or sequentially with the one or more other drug(s).
  • the combination may be formulated for simultaneous or sequential administration.
  • Such combinations may be formulated as pharmaceutical compositions of the invention.
  • Non-limiting examples of pharmaceutically acceptable excipients include adjuvants, antiadherents, binders, coatings, colourings, disintegrants, flavors, glidants, lubricants, preservatives, sorbents and sweeteners.
  • compositions of the invention may be formulated for any appropriate route of administration.
  • the compositions of the invention may be formulated for oral, sublingual, subcutaneous, intravenous, intramuscular, nasal, local, or rectal administration, and the like.
  • the compositions of the invention may be formulated as unit dosage forms for administration.
  • the active ingredient may be presented as discrete units, such as tablets, capsules, powders, granulates, solutions, suspensions, and the like.
  • the pharmaceutical composition of the invention may be presented in unit-dose or multi-dose containers, e.g. injection liquids in predetermined amounts, for example in sealed vials and ampoules, and may also be stored in a freeze dried (lyophilized) condition requiring only the addition of sterile liquid carrier, e.g. water, prior to use.
  • sterile liquid carrier e.g. water
  • the active agent may be compressed into solid dosage units, such as pills, tablets, or be processed into capsules or suppositories.
  • the active agent can be applied as a fluid composition, e.g. as an injection preparation, in the form of a solution, suspension, emulsion, or as a spray, e.g. a nasal spray.
  • a fluid composition e.g. as an injection preparation
  • a spray e.g. a nasal spray
  • a spray e.g. a nasal spray.
  • Suitable carriers with which the active agent of the invention can be administered as solid compositions include lactose, starch, cellulose derivatives and the like, or mixtures thereof, used in suitable amounts.
  • aqueous suspensions, isotonic saline solutions and sterile injectable solutions may be used, containing pharmaceutically acceptable dispersing agents and/or wetting agents, such as propylene glycol or butylene glycol.
  • the invention further includes a pharmaceutical composition, as hereinbefore described, in combination with packaging material suitable for said composition, said packaging material including instructions for the use of the composition as described herein.
  • the exact dose and regimen of administration of the active ingredient, or a pharmaceutical composition thereof, may vary with the particular compound, the route of administration, and the age and condition of the individual subject to whom the medicament is to be administered.
  • parenteral administration requires lower dosages than other methods of administration which are more dependent upon absorption.
  • a dosage for humans preferably contains 0.0001 -25 mg of a compound of the invention per kg body weight.
  • the desired dose may be presented as one dose or as multiple subdoses administered at appropriate intervals throughout the day, or, in case of female recipients, as doses to be administered at appropriate daily intervals throughout the menstrual cycle.
  • the dosage as well as the regimen of administration may differ between a female and a male recipient.
  • the invention provides a compound or pharmaceutical composition of the invention for use in therapy.
  • For use in therapy encompasses all uses as a medicament, for the treatment of any suitable disease or disorder.
  • the invention also provides a compound or pharmaceutical composition of the invention for use in the treatment of a CCR2-mediated disorder or CCR2-mediated condition, optionally wherein the CCR2-mediated disorder or condition is cancer.
  • the invention also provides a compound or pharmaceutical composition of the invention for use in the treatment of cancer.
  • the invention also provides a method of treating a disease comprising administering to a patient in need thereof a therapeutically effective amount of a compound or pharmaceutical composition of the invention.
  • the invention further provides a method of treating a CCR2- mediated disorder or CCR2-mediated condition comprising administering to a patient in need thereof a therapeutically effective amount of a compound or pharmaceutical composition of the invention, optionally wherein the CCR2-mediated disorder or condition is cancer.
  • the invention also provides a method of treating cancer comprising administering to a patient in need thereof a therapeutically effective amount of a compound or pharmaceutical composition of the invention.
  • the invention also provides for the use of a compound or pharmaceutical composition of the invention for the manufacture of a medicament.
  • the invention further provides for the use of a compound or pharmaceutical composition of the invention for the manufacture of a medicament for the treatment of CCR2-mediated diseases or CCR2-mediated conditions, optionally wherein the CCR2-mediated disorder or condition is cancer.
  • the invention also provides for the use of a compound or pharmaceutical composition of the invention for the manufacture of a medicament for the treatment of cancer.
  • CCR2-mediated disorders or conditions as used herein, means any disease state or other deleterious condition in which CCR2 or its endogenous ligands play a central role. These diseases include, but are not limited to, oncological disorders in particular cancers.
  • Cancers which can be treated or prevented include, among others, locally advanced or metastatic solid tumors such as pancreatic cancer (including pancreatic ductal adenocarcinoma), liver cancer, lung cancer (including non-small cell lung cancer and small-cell lung carcinoma), breast cancer, head and neck cancer, renal cancer, skin cancer (including melanoma and basal carcinoma), nasopharynx cancer, colorectal and gastric cancer, prostate cancer, brain cancer (including glioblastoma), ovarian cancer, esophagus cancer, bladder cancer, and cancers of the cervix, endometrium, testis, mesothelial lining, muscle, connective tissue, adrenal gland, thyroid, or bone.
  • pancreatic cancer including pancreatic ductal adenocarcinoma
  • liver cancer including lung cancer (including non-small cell lung cancer and small-cell lung carcinoma), breast cancer, head and neck cancer, renal cancer, skin cancer (including melanoma and basal carcinoma), nasophary
  • cancers which can be treated or prevented include, among others, hematologic malignancies such as leukemias (including chronic lymphocytic leukemia, chronic myeloid leukemia, multiple myeloma, malignant myeloma, and acute myeloid leukemia) and lymphomas (including Hodgkin's lymphoma, non-Hodgkin's lymphoma and cutaneous T cell lymphoma).
  • leukemias including chronic lymphocytic leukemia, chronic myeloid leukemia, multiple myeloma, malignant myeloma, and acute myeloid leukemia
  • lymphomas including Hodgkin's lymphoma, non-Hodgkin's lymphoma and cutaneous T cell lymphoma.
  • the compounds or pharmaceutical compositions of the invention may also be used in the treatment or prevention of oncological disorders in which tumor-associated myeloid-derived suppressor cells (MDSCs) or tumor-associated macrophages (TAMs) play a prominent role.
  • MDSCs tumor-associated myeloid-derived suppressor cells
  • TAMs tumor-associated macrophages
  • the compounds or pharmaceutical compositions of the invention may also be used in the treatment or prevention of diseases or disorders which are not oncological.
  • the compounds or pharmaceutical compositions of the invention may also be used for the treatment or prevention of autoimmune disorders such as rheumatoid arthritis, systemic lupus erythematosus, Guillain-Barre syndrome, pancreatitis, lupus nephritis, lupus glomerulonephritis, psoriasis, Crohn’s disease, vasculitis, irritable bowel syndrome, dermatomyositis, multiple sclerosis, bronchial asthma, pemphigus, pemphigoid, scleroderma, myasthenia gravis, autoimmune hemolytic and thrombocytopenic states, Goodpasture’s syndrome (and associated glomerulonephritis and pulmonary hemorrhage), immunovasculitis, tissue graft rejection, hyperacute rejection of transplanted organs; and the like.
  • autoimmune disorders such as rheumatoid arthritis, systemic lupus erythemat
  • inflammatory disorders and related conditions such as neutropenia, sepsis, septic shock, Alzheimer’s disease, multiple sclerosis, stroke, inflammatory bowel disease (IBD), inflammation associated with severe burns, lung injury, and ischemiareperfusion injury, osteoarthritis, asthma, as well as acute (adult) respiratory distress syndrome (ARDS), chronic pulmonary obstructive disorder (
  • pathologic sequalae associated with insulin-dependent diabetes mellitus including diabetic retinopathy
  • lupus nephropathy including diabetic retinopathy
  • Heyman nephritis membranous nephritis and other forms of glomerulonephritis
  • contact sensitivity responses e.g., contact sensitivity responses
  • inflammation resulting from contact of blood with artificial surfaces that can cause complement activation, as occurs, for example, during extracorporeal circulation of blood (e.g., during hemodialysis or via a heart-lung machine, for example, in association with vascular surgery such as coronary artery bypass grafting or heart valve replacement), or in association with contact with other artificial vessel or container surfaces (e.g., ventricular blood storage bags, plasmapheresis, plateletpheresis, and the like).
  • diseases related to ischemia/reperfusion injury such as those resulting from transplants, including solid organ transplant, and syndromes such as ischemic reperfusion injury, ischemic
  • the compounds or pharmaceutical compositions of the invention may also be used for the treatment or prevention of cardiovascular and cerebrovascular disorders such as myocardial infarction, coronary thrombosis, vascular occlusion, post-surgical vascular reocclusion, atherosclerosis, traumatic central nervous system injury, and ischemic heart disease.
  • cardiovascular and cerebrovascular disorders such as myocardial infarction, coronary thrombosis, vascular occlusion, post-surgical vascular reocclusion, atherosclerosis, traumatic central nervous system injury, and ischemic heart disease.
  • the compounds or pharmaceutical compositions of the invention may also be used for the treatment or prevention of HIV infection, AIDS, viral infections, and the treatment of hepatitis C.
  • the compounds or pharmaceutical compositions of the invention may also be used for the treatment or prevention of neurodegenerative disorders and related diseases such as Alzheimer’s disease, multiple sclerosis, and cognitive function decline associated with cardiopulmonary bypass surgery and related procedures.
  • references to the treatment of a particular condition take their normal meaning in the field of medicine.
  • the terms may refer to achieving a reduction in the severity of one or more clinical symptoms associated with the condition.
  • the term may refer to achieving a reduction of the amount of cancerous cells present (e.g. in the case of a cancer forming a solid tumour, indicated by a reduction in tumour volume).
  • references to patients refer to a living subject being treated, including mammalian (in particular human) patients.
  • the treatment is in a mammal (in particular a human).
  • the term therapeutically effective amount refers to an amount of a compound that confers a therapeutic effect on the treated patient.
  • the effect may be objective (i.e. measurable by some test or marker) or subjective (i.e. the subject gives an indication of and/or feels an effect).
  • the compounds of the invention are useful because they possess pharmacological activity, and/or are metabolised in the body following (typically oral or parenteral) administration to form compounds that possess pharmacological activity.
  • compounds of the invention are useful in the treatment of cancer, which term will be readily understood by one of skill in the art.
  • compounds of the invention may possess pharmacological activity as such, certain pharmaceutically-acceptable (e.g. “protected”) derivatives of compounds of the invention may exist or be prepared which may not possess such activity, but may be administered (typically parenterally or orally) and thereafter be metabolised in the body to form compounds of the invention.
  • Such compounds (which may possess some pharmacological activity, provided that such activity is appreciably lower than that of the active compounds to which they are metabolised) may therefore be described as “prodrugs” of compounds of the invention and are within the scope of the invention.
  • references herein to compounds of particular aspects of the invention will include references to all embodiments and particular forms thereof, which embodiments and particular forms may be taken in combination to form further specific embodiments.
  • the invention also relates to those compounds wherein all specific definitions for R 1 through R 31 and all substituent groups in the various aspects of the inventions defined here above occur in any combination within the definition of the aryl sulfonamide compounds of formula I or II.
  • C1-3 alkyl means a branched or unbranched alkyl group having 1 -3 carbon atoms, being methyl, ethyl, propyl or isopropyl. Ci alkyl is preferred.
  • Ci-6 alkyl means a branched or unbranched alkyl group having 1 -6 carbon atoms, for example methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, n-pentyl and n-hexyl. C1-3 alkyl are preferred.
  • C1-6 alkoxy means an alkoxy group having 1 -6 carbon atoms, the alkyl moiety having the same meaning as previously defined. C1-2 alkoxy groups are preferred.
  • C3-7 cycloalkyl means a cycloalkyl group having 3-7 carbon atoms for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. C3-7 cycloalkyl are preferred.
  • Halogen means fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine, most preferably fluorine or chlorine.
  • fluoro, chloro, bromo, and iodo as used herein refer respectively to fluorine, chlorine, bromine, and iodine atoms as substituents.
  • aryl includes references to C6-14 (e.g. Ce-to) aromatic groups. Such groups may be monocyclic or bicyclic and, when bicyclic, be either wholly or partly aromatic.
  • C6-10 aryl groups that may be mentioned include phenyl, naphthyl, 1 ,2,3,4-tetrahydronaphthyl, indanyl, and the like (e.g. phenyl, naphthyl and the like, such as phenyl).
  • the point of attachment of substituents on aryl groups may be via any carbon atom of the ring system.
  • heteroaryl groups containing one or more heteroatoms selected from oxygen, nitrogen and/or sulphur.
  • Such heteroaryl groups may comprise one, two, or three rings, of which at least one is aromatic (e.g. a heteroaryl group may comprise two rings, one of which is aromatic).
  • Substituents on heteroaryl/heteroaromatic groups may, where appropriate, be located on any atom in the ring system including a heteroatom.
  • the point of attachment of heteroaryl/heteroaromatic groups may be via any atom in the ring system including (where appropriate) a heteroatom.
  • bicyclic heteroaryl/heteroaromatic groups may comprise a benzene ring fused to one or more further aromatic or non-aromatic heterocyclic rings, in which instances, the point of attachment of the polycyclic heteroaryl/heteroaromatic group may be via any ring including the benzene ring or the heteroaryl/heteroaromatic or heterocycloalkyl ring.
  • heteroaryl/heteroaromatic groups examples include pyridinyl, pyrrolyl, furanyl, thiophenyl, oxadiazolyl, thiadiazolyl, thiazolyl, oxazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, imidazolyl, imidazopyrimidinyl, imidazothiazolyl, thienothiophenyl, pyrimidinyl, furopyridinyl, indolyl, azaindolyl, pyrazinyl, pyrazolopyrimidinyl, indazolyl, pyrimidinyl, quinolinyl, isoquinolinyl, quinazolinyl, benzofuranyl, benzothiophenyl, benzoimidazolyl, benzoxazolyl, benzothiazolyl, benzoxazoly
  • heteroaryl includes polycyclic (e.g. bicyclic) groups in which one ring is aromatic (and the other(s) may or may not be aromatic).
  • heteroaryl groups that may be mentioned include e.g.
  • the attachment point is at the last group.
  • “all of the alkyl groups” of said substituent are optionally substituted, this also includes the alkyl moiety of an alkoxy group.
  • substituted means that one or more hydrogens on the designated atom/atoms is/are replaced with a selection from the indicated group, provided that the designated atom’s normal valency under the existing circumstances is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
  • “Stable compound” or “stable structure” is defined as a compound or structure that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
  • optionally substituted means optional substitution with groups, radicals or moieties such as hydroxyl, C1-6 alkyl, C1-6 alkoxy, nitrile and halogen. A preferred substituent is fluorine.
  • the compounds of Formula I or II can form salts which are also within the scope of this invention.
  • Reference to a compound of Formula I or II herein is understood to include reference to salts thereof, unless otherwise indicated.
  • the term "salt(s)", as employed herein, denotes acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic bases.
  • zwitterions inner salts
  • Salts of the compounds of the Formula I or II may be formed, for example, by reacting a compound of Formula I or II with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.
  • the compounds of Formula I or II may contain asymmetric or chiral centers, and, therefore, exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of Formula I or II as well as mixtures thereof, including racemic mixtures, form part of the present invention.
  • the present invention embraces all geometric and positional isomers. For example, if a compound of Formula I or II incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the invention unless stated otherwise.
  • Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization.
  • Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g. chiral auxiliary such as a chiral alcohol or Mosher’s acid chloride), separating the diastereomers and converting (e.g. hydrolyzing) the individual diastereomers to the corresponding pure enantiomers.
  • an appropriate optically active compound e.g. chiral auxiliary such as a chiral alcohol or Mosher’s acid chloride
  • separating the diastereomers converting (e.g. hydrolyzing) the individual diastereomers to the corresponding pure enantiomers.
  • some of the compounds of Formula I or II may be atropisomers (e.g.
  • the compounds of Formula I or II may exist in different tautomeric forms, and all such forms are embraced within the scope of the invention.
  • all keto-enol and imine-enamine forms of the compounds are included in the invention.
  • All stereoisomers (for example, geometric isomers, optical isomers and the like) of the present compounds including those of the salts, solvates, esters and prodrugs of the compounds as well as the salts, solvates and esters of the prodrugs), such as those which may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this invention, as are positional isomers.
  • Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers.
  • the chiral centers of the present invention can have the S or R configuration as defined by the ILJPAC 1974 Recommendations.
  • the use of the terms "salt”, “solvate”, “ester”, “prodrug” and the like, is intended to equally apply to the salt, solvate, ester and prodrug of enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates or prodrugs of the inventive compounds.
  • prodrug means a compound (e.g, a drug precursor) that is transformed in vivo to yield a compound of Formula I or II or a pharmaceutically acceptable salt, hydrate or solvate of the compound. The transformation may occur by various mechanisms (e.g. by metabolic or chemical processes), such as, for example, through hydrolysis in blood.
  • the compounds of the invention may form hydrates or solvates. It is known to those of skill in the art that charged compounds form hydrated species when lyophilized with water, or form solvated species when concentrated in a solution with an appropriate organic solvent.
  • the compounds of this invention include the hydrates or solvates of the compounds of Formula I or II.
  • One or more compounds of the invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embraces both solvated and unsolvated forms.
  • “Solvate” means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances, the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. "Solvate” encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like.
  • Hydrophilate is a solvate wherein the solvent molecule is H2O.
  • the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature.
  • the present invention is meant to include all suitable isotopic variations of the compounds of Formula I or II.
  • different isotopic forms of hydrogen (H) include protium ( 1 H) and deuterium ( 2 H). Protium is the predominant hydrogen isotope found in nature.
  • Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples.
  • Isotopically- enriched compounds within Formula I or II can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using appropriate isotopically-enriched reagents and/or intermediates.
  • the present invention also embraces isotopically-labelled compounds of the present invention which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 17 O, 18 0, 31 P, 32 P, 35 S, 18 F, and 36 CI, respectively.
  • Certain isotopically-labelled compounds of Formula I or II may be useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes are particularly preferred for their ease of preparation and detectability.
  • the aryl sulfonamide compounds of the invention inhibit CCR2 activity.
  • the compounds of the invention inhibit CCR2 activity with an IC50 of 10 pM or lower, less than 1 pM, less than 100 nM, or less than 10 nM.
  • IC50 means the concentration of the test compound that is required for 50% inhibition of its maximum effect in vitro.
  • the IC50 may be determined using the luminescent aequorin assay, as described herein, the details of which are provided in the biological examples.
  • a variety of assays known in the art can be used to evaluate the compounds provided herein, including (radio)ligand binding assays, signaling assays, migration assays, and other assays of cellular response.
  • a ligand binding assay can be used to determine the ability of a potential CCR2 inhibitor to block the interaction of a natural CCR2 ligand such as CCL2 with the orthosteric binding site of the CCR2 receptor, or to occupy an allosteric binding site of the CCR2 receptor.
  • Cell-based calcium assays are signaling assays that allow the study of intracellular calcium levels, which are important indicators for the activation state of G-protein coupled receptors (GPCRs) such as CCR2.
  • GPCRs G-protein coupled receptors
  • Examples of calcium assays use Fluorescent Imaging Plate Reader (FLIPR) technology involving calcium-sensitive dyes and a fluorescence plate reader or the luminescent aequorin technology.
  • FLIPR Fluorescent Imaging Plate Reader
  • Inhibition of CCR2 activity can be measured using the functional aequorin assay.
  • the principal of the luminescent aequorin assay is based on the conversion of apo-aequorin to calcium- activated photoprotein aequorin with high calcium affinity, due to the addition of coelenterazine in the cell suspension. Activation of the CCR2 will induce intracellular Ca2+ release which binds to the aequorin.
  • the protein undergoes a conformational change and through oxidation converts its prosthetic group, coelenterazine, into excited coelenteramide and CO2 (Shimomura et al, Biochemistry, 13(16) 1974, p3278).
  • Functional CCR2 activity can also be determined in a chemotaxis or migration assay in a relevant cell line.
  • a chemotaxis assay can be used to determine the ability of a CCR2 inhibitor to antagonize CCL2-mediated cell migration in vitro. This is believed to resemble chemokine- induced cell migration in vivo.
  • Anti-cancer activity of CCR2 inhibitors can be investigated preclinically in mouse xenograft models.
  • a therapeutic protocol may follow whether the compound achieves an effect on progression of tumor growth (slowing or inhibiting growth, or causing a reduction in tumour size) or establishment of a survival benefit of mice compared to a control group.
  • CCR2 inhibitor-induced decreases of MDSCs or TAMs, along with increased intratumoral levels of functional T cell populations can be determined in CCR2-expressing tumors as an indicator of therapeutic activity.
  • aryl sulfonamide derivatives of the present invention can be prepared by methods well known in the art of organic chemistry. See, for example, J. March, ‘Advanced Organic Chemistry' 4 th Edition, John Wiley and Sons. During synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This is achieved by means of conventional protecting groups, such as those described in T.W. Greene and P.G.M. Wutts ‘Protective Groups in Organic Synthesis' 3 rd Edition, John Wiley and Sons, 1999. The protective groups are optionally removed at a convenient subsequent stage using methods well known in the art.
  • the products of the reactions are optionally isolated and purified, if desired, using conventional techniques including, but not limited to, filtration, distillation, crystallization, chromatography and the like. Such materials are optionally characterized using conventional means, including physical constants and spectral data.
  • Aryl sulfonamide compounds of formula I or II, wherein R 1 -R 31 are as defined herein, can be prepared by the general synthetic route shown in scheme I.
  • Standard amide coupling procedures can be carried out with carboxylic acids in a solvent such as DMF, THF or DCM in the presence of a base such as DIPEA, N- methylmorpholine, 4-DMAP or triethylamine and in the presence of a coupling reagent such as T3P, PyBOP, TBTU, EDCI or HATU to form amide derivative V.
  • carboxylic acid chlorides can be applied in appropriate solvents and the use of a suitable base.
  • Reduction of the 3-nitro-pyridine of formula V can be accomplished in the presence of a suitable reducing agent and solvent, for example tin(ll)chloride hydrate (SnCl2.2H2O) in THF to provide 3- aminopyridine VI.
  • the compound of formula VI can be sulfonylated at room temperature using an appropriately substituted aryl sulfonyl chloride in pyridine as the solvent to give aryl sulfonamide VII.
  • double aryl sulfonylation is occurring and by treating the resulting bis-sulfonamide derivative with tetrabutylammonium fluoride (TBAF) in THF at slightly elevated temperatures the envisaged aryl sulfonamide derivatives can be generated.
  • TBAF tetrabutylammonium fluoride
  • Intermediates wherein X is S can be oxidized to SO or SO2 by means known to the skilled person.
  • protection strategies such as aryl sulfonamide protection.
  • An example of such protective strategy is the use of the (methoxy)methane (MOM) protecting group to protect the aryl sulfonamide from erroneous alkylation or acylation (Scheme II). This can be effected by treating the aryl sulfonamide X with chloro(methoxy)methane (MOM-CI) in an appropriate solvent like THF, and using a base such as triethylamine at room temperature. Later on, deprotection of the MOM group as in formula XIV can be accomplished in a mixture of trifluoro acetic acid (TFA) and water whilst heating.
  • THF trifluoro acetic acid
  • benzyl amine derivatives like the one of formula XXV can be acylated using standard amide-coupling additions to generate compound XXVI.
  • O-demethylation of XXVI can be accomplished using a suitable Lewis acid system and solvent, for example borontribromide in dichloromethane at low temperatures. Subsequent conversion steps can be essentially performed as described in Scheme I - III.
  • formula XXXI can be coupled with 3-amino-2-bromopyridine VIII using a catalytic amount of copper(l)iodide in a suitable combination of base and solvent, for example potassium phosphate and DMF under heating conditions. Subsequent conversion steps can be essentially performed as described in Scheme I - III to give formula XXXV compounds.
  • the present invention also includes within its scope all stereoisomeric forms of the compounds (aryl sulfonamide derivatives) according to the present invention resulting, for example, because of configurational or geometrical isomerism.
  • stereoisomeric forms are enantiomers, diastereoisomers, cis and trans isomers etc.
  • pyrrolidine-2- carbonitrile is used as amine
  • the present invention includes the aforementioned stereoisomers substantially free, i.e., associated with less than 5%, preferably less than 2% and in particular less than 1 % of the other stereoisomer. Mixtures of stereoisomers in any proportion, for example a racemic mixture comprising substantially equal amounts of two enantiomers are also included within the scope of the present invention.
  • chiral compounds For chiral compounds, methods for asymmetric synthesis whereby the pure stereoisomers are obtained are well known in the art, e.g. synthesis with chiral induction, synthesis starting from chiral intermediates, enantioselective enzymatic conversions, separation of stereoisomers using chromatography on chiral media. Such methods are described in Chirality In Industry (edited by A.N. Collins, G.N. Sheldrake and J. Crosby, 1992; John Wiley). Likewise methods for synthesis of geometrical isomers are also well known in the art.
  • the compounds (aryl sulfonamide derivatives) of the present invention may be isolated from the reaction mixture in the form of a pharmaceutically acceptable salt.
  • the pharmaceutically acceptable salts may also be obtained by treating the acid of formula I or II with organic or inorganic bases such as aluminum, arginine, benzathine, calcium, chloroprocaine, choline, diethanolamine, ethanolamine, ethylenediamine, lysine, magnesium, histidine, lithium, meglumine, potassium, procaine, sodium, trimethylamine, zinc and the like.
  • the pharmaceutically acceptable salts may also be obtained by treating the base of formula I or II with an organic or inorganic acids such as hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfuric acid, phosphoric acid, acetic acid, propionic acid, glycolic acid, maleic acid, malonic acid, methanesulfonic acid, fumaric acid, succinic acid, tartaric acid, citric acid, benzoic acid, ascorbic acid and the like.
  • an organic or inorganic acids such as hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfuric acid, phosphoric acid, acetic acid, propionic acid, glycolic acid, maleic acid, malonic acid, methanesulfonic acid, fumaric acid, succinic acid, tartaric acid, citric acid, benzoic acid, ascorbic acid and the like.
  • pharmaceutically acceptable salts may be selected from the above-mentioned organic or inorganic acids or basis.
  • the aryl sulfonamide derivatives of the present invention also exist as amorphous forms. Multiple crystalline forms are also possible. All the physical forms are included within the scope of the present invention.
  • the compounds may also exist as oils, solvates or in solution.
  • solvates Preparation of solvates is generally known.
  • M. Caira et al, J. Pharmaceutical Sci., 93(3), 601 -611 (2004) describe the preparation of the solvates of the antifungal fluconazole in ethyl acetate as well as from water.
  • Similar preparations of solvates, hemisolvate, hydrates and the like are described by E. C. van Tender et al, AAPS PharmSciTech., 5(1 ), article 12 (2004); and A. L. Bingham et al, Chem. Commun. 603-604 (2001 ).
  • a typical, non-limiting, process involves dissolving the inventive compound in desired amounts of the desired solvent (organic or water or mixtures thereof) at a higher than ambient temperature, and cooling the solution at a rate sufficient to form crystals which are then isolated by standard methods.
  • Analytical techniques such as, for example IR spectroscopy, show the presence of the solvent (or water) in the crystals as a solvate (or hydrate).
  • Figure 1A shows all interactions of Ex-8 with CCR2 in the form of a 2D-plot, including the Lys71 H-bonding interaction with the acrylamide carbonyl.
  • Figure 1 B shows all interactions of compound 12 with CCR2 in the same format.
  • Compound 12 lacks the H-bonding interaction with Lys71 and the central amide carbonyl and displays an H- bonding interaction with Lys311 instead ( Figure 1 B). This results in better proximity of the acrylamide terminal C-atom to Cys75 of 3.7 A for Ex-8 versus 6.4 A for compound 12, respectively. Docking and 2D-plot generation were performed using MOE version 2019.0102 (Chemical Computing Group).
  • Ex-8 was subjected to an automated docking procedure targeting the intracellular allosteric binding site in PDB 5T1A (rigid receptor mode) allowing 30 random placements (triangle matcher) and 30 refinements (GBVI/WSA dB) for each binding mode.
  • Top ten ranking minimal energy placements were visually inspected for maximal alignment with allosteric binding ligand CCR2-RA-[/7] (Zheng et al., 2016), and individual optimal binding modes subjected to full minimization allowing induced fit.
  • Figure 2A - 2C show that, in contrast to CCX-140B and BMS-813160, Ex-1 through Ex-54 are resistant to washout and remain covalently bound to CCR2 after extensive washing.
  • LiOH.H2O Lithium hydroxide hydrate
  • NMR Nuclear magnetic resonance
  • spectra were acquired on a Bruker 400 MHz spectrometer integrated with Avance II and III series console and in the deuterated solvent stated. All NMR spectra were acquired using the deuterated solvent as the lock. Coupling constants (J) are quoted in Hz and are recorded to the nearest 0.1 Hz. The following abbreviations are used; s, singlet; d, doublet; dd, doublet of doublets; t, triplet; m, multiplet; q, quartet; and br, broad. Assignments of signals are proposed based on the values observed.
  • Mass Spectrometry Electron Spray spectra were recorded on the Waters Single quadrupole mass spectrometers in alternating positive and negative ion mode using Flow Injection. The mass range was 120-2000 Da and scanned with a step rate of 0.2 Da. and the capillary voltage was set to 5000 V. N2-gas was used for nebulization.
  • Preparative HPLC was conducted on a column (50 x 10 mm ID, 5pm, Xterra Prep MS C18) at a flow rate of 5 ml/min, injection volume 500 pl, at room temperature and UV Detection at 210 nm.
  • Example 1 yl)oxy)Dhenyl)acrylamide
  • Ex-1 5-methyl-2-(3-nitrophenoxy)pyridin-3-amine (INT-1.1): To a stirred solution of 2-bromo-5- methylpyridin-3-amine (5.00 g, 26.7 mmol) in DMF (50.0 mL) was added 3-nitrophenol (5.58 g, 40.1 mmol), K3PO4 (17.0 g, 80.2 mmol) and copper iodide (1 .02 g, 5.35 mmol) under continued nitrogen purging. Then the reaction was heated at 120 °C for 16 h. After completion, the reaction mass was filtered through celite bed and washed with ethyl acetate.
  • reaction mixture was heated at 80 °C for 16 h. After completion, pyridine was removed from reaction mass under reduced pressure. The residue obtained was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated to afford the crude residue.
  • N-(3-((3-((4-chloro-3-(trifluoromethyl)phenyl)sulfonamido)-5-methylpyridin-2- yl)oxy)phenyl)but-2-ynamide To a stirred solution of N-(3-((4-chloro-N-((4-chloro-3- (trifluoromethyl)phenyl)sulfonyl)-3-(trifluoromethyl)phenyl)sulfonamido)-5-methylpyridin-2- yl)oxy)phenyl)but-2-ynamide INT-2.1 (240 mg, 0.313 mmol) in THF (5 mL) was added TBAF solution (1 .0 M in THF, 0.37 mL, 1 .25 mmol) at room temperature.
  • reaction was continued at 40 °C and the progress of reaction was monitored by TLC. After 2 h, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to afford the crude compound.
  • reaction mixture was allowed to stirred at same temperature for 30 min followed by addition of iodomethane (45.1 mg, 0.318 mmol). The progress of the reaction was monitored by TLC. After 1 h, the reaction mixture was quenched with ice cold water and extracted with ethyl acetate.
  • N-(3-((3-((4-chloro-3-(trifluoromethyl)phenyl)sulfonamido)-5-methylpyridin-2- yl)oxy)phenyl)-N-methylacrylamide To a stirred solution of N-(3-((4-chloro-N-((4-chloro- 3-(trifluoromethyl)phenyl)sulfonyl)-3-(trifluoromethyl)phenyl)sulfonamido)-5-methylpyridin-2- yl)oxy)phenyl)-N-methylacrylamide INT-3.1 (204 mg, 0.265 mmol) in THF (3.00 mL) was added TBAF solution (1.0 M in THF, 0.53 mL, 1.06 mmol) at room temperature and the reaction mixture was allowed to stir at 60 °C for 1 h.
  • reaction mixture was stirred at 60 °C for 2 h. After completion, the reaction mixture was diluted with ethyl acetate and washed with water and brine, dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to afford the crude compound.
  • the crude compound was purified by silica gel column chromatography using a gradient of 80-100% EtOAc/hexane and then eluted in 0-10% MeOH/DCM to afford the N-(3-((3-((4-chloro-N-(methoxymethyl)-3- (trifluoromethyl)phenyl)sulfonamido)-5-methylpyridin-2-yl)oxy)phenyl)but-2-ynamide INT-6.4 as light brown solid (650 mg, 72%); m/z 566.04 (M-H) + .
  • N-(3-((3-((4-Chloro-3-(trifluoromethyl)phenyl)sulfonamido)-5-methylpyridin-2- yl)oxy)phenyl)-N-methylbut-2-ynamide To a stirred solution of N-(3-((3-((4-chloro-N- (methoxymethyl)-3-(trifluoromethyl)phenyl)sulfonamido)-5-methylpyridin-2-yl)oxy)phenyl)-N- methylbut-2-ynamide INT-6.5 (300 mg, 0.515 mmol) in TFA (2.70 mL) and water (0.3 mL) was heated to 60 °C for 16 h.
  • N-(4-((3-Amino-5-methylpyridin-2-yl)oxy)phenyl)acrylamide INT-8.4: To a stirred solution of N-(4-((5-methyl-3-nitropyridin-2-yl)oxy)phenyl)acrylamide INT-8.3 (300 mg, 1 .00 mmol) in THF (5.00 mL) was added SnCl2.2H2O (792 mg, 3.51 mmol) and the reaction was heated to 70 °C for 2 h. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was concentrated under reduced pressure to afford the crude compound.
  • N-(4-((3-((4-Chloro-3-(trifluoromethyl)phenyl)sulfonamido)-5-methylpyridin-2- yl)oxy)phenyl)acrylamide To a stirred solution of N-(4-((3-amino-5-methylpyridin-2- yl)oxy)phenyl)acrylamide INT- 8.4 (100 mg, 0.371 mmol) in pyridine (1 .50 mL) was added 4- chloro-3-(trifluoromethyl)benzene-1 -sulfonyl chloride (104 mg, 0.371 mmol) at room temperature. Then the reaction mixture was stirred at 60 °C for 30 minutes.
  • reaction mixture was concentrated under reduced pressure and dissolved in ethyl acetate, washed with water and brine solution, dried over anhydrous sodium sulfate, filtered and concentrated to afford the crude compound.
  • reaction mixture was stirred at 60 °C for 16 h. After completion, the reaction mixture was concentrated under reduced pressure and dissolved in EtOAc and washed with water. The organic layer was dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to afford crude compound as white solid.
  • N-(4-((5-Methyl-3-nitropyridin-2-yl)oxy)phenyl)but-2-ynamide (INT-10.1): To a stirred solution of 4-[(5-methyl-3-nitropyridin-2-yl)oxy]aniline INT-8.2 (500 mg, 2.04 mmol) in THF (5.00 mL) was added DIPEA (1 .07 mL, 6.12 mmol), but-2-ynoic acid (257 mg, 3.06 mmol) and T3P (50% solution in EtOAc) (1 .82 mL, 6.12 mmol) at room temperature. Then the reaction mixture was stirred at 60 °C for 2 h. The progress of reaction was monitored by TLC.
  • N-(4-((3-Amino-5-methylpyridin-2-yl)oxy)phenyl)but-2-ynamide (INT-10.2): To a stirred solution of N-(4-((5-methyl-3-nitropyridin-2-yl)oxy)phenyl)but-2-ynamide INT-10.1 (200 mg, 0.642 mmol) in THF (2.00 mL) was added SnCl2.2H2O (507 mg, 2.25 mmol) at room temperature. Then the reaction was stirred at 60°C for 2 h. The progress of reaction was monitored by TLC. After completion, the reaction mass was concentrated under reduced pressure to afford the crude compound.
  • N-(4-((3-((4-Chloro-3-(trifluoromethyl)phenyl)sulfonamido)-5-methylpyridin-2- yl)oxy)phenyl)but-2-ynamide To a stirred solution of N- ⁇ 4-[(3-amino-5-methylpyridin-2- yl)oxy]phenyl ⁇ but-2-ynamide INT-10.2 (170 mg, 0.604 mmol) in pyridine (2.00 mL) was added 4-chloro-3-(trifluoromethyl)benzene-1 -sulfonyl chloride (169 mg, 0.604 mmol) at room temperature. Then the reaction mixture stirred at room temperature for 0.5 h.
  • N-Methyl-N-(4-((5-methyl-3-nitropyridin-2-yl)oxy)phenyl)acrylamide (INT-11.1): To a solution of N-(4-((5-methyl-3-nitropyridin-2-yl)oxy)phenyl)acrylamide INT-8.3 (410 mg, 1.37 mmol) in DMF (3.00 mL) was added CS2CO3 (2.23 g, 6.85 mmol) and methyl iodide (972 mg, 6.85 mmol). Then the reaction mixture was stirred at 60 °C for 20 h.
  • N-(4-((3-amino-5-methylpyridin-2-yl)oxy)phenyl)-N-methylacrylamide (INT-11.2): To a stirred solution of N-methyl-N- ⁇ 4-[(5-methyl-3-nitropyridin-2-yl)oxy]phenyl ⁇ prop-2-enamide INT- 11.1 (300 mg, 0.958 mmol) in THF (3.00 mL) was added SnCl2.2H2O (756 mg, 3.35 mmol) at room temperature. Then, the reaction mixture was heated at 70°C for 1 h. The progress of reaction was monitored by TLC. After completion, the reaction mass was concentrated under reduced pressure to get the crude residue.
  • N-(4-((3-((4-Chloro-3-(trifluoromethyl)phenyl)sulfonamido)-5-methylpyridin-2- yl)oxy)phenyl)-N-methylacrylamide To a stirred solution of N-(4-((3-amino-5-methylpyridin- 2-yl)oxy)phenyl)-N-methylacrylamide INT-11.2 (280 mg, 0.988 mmol) in pyridine (3.00 mL) was added 4-chloro-3-(trifluoromethyl)benzene-1 -sulfonyl chloride (303 mg, 1.09 mmol) at room temperature. Then the reaction mixture was allowed to stir at 70 °C for 12 h.
  • N-Methyl-N-(4-((5-methyl-3-nitropyridin-2-yl)oxy)phenyl)but-2-ynamide (INT-12.1): To a suspension of NaH (60% w/w) (71 .3 mg, 1 .5 eq., 1 .78 mmol) in DMF (3.00 mL) was added a DMF solution of N-(4-((5-methyl-3-nitropyridin-2-yl)oxy)phenyl)but-2-ynamide INT-10.1 (370 mg, 1.19 mmol) at 0°C. After 10 minutes, Mel (844 mg, 5.94 mmol) was added to reaction mass.
  • reaction mixture was stirred at 0°C for 20 minutes. The progress of reaction was monitored by TLC. After completion, the reaction mass was quenched with ice cold water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated to afford the crude residue.
  • the crude compound was purified by silica gel column chromatography using a gradient of 0-70% EtOAC/hexane to afford the pure N-methyl- N-(4-((5-methyl-3-nitropyridin-2-yl)oxy)phenyl)but-2-ynamide INT-12.1 as yellow solid (270 mg, 70%); m/z 326.15 (M+H) + .
  • N-(4-((3-Amino-5-methylpyridin-2-yl)oxy)phenyl)-N-methylbut-2-ynamide (INT-12.2): To a stirred solution of N-methyl-N-(4-((5-methyl-3-nitropyridin-2-yl)oxy)phenyl)but-2-ynamide INT- 12.1 (270 mg, 0.830 mmol) in THF (4.00 mL) was added SnCl2.2H2O (655 mg, 2.90 mmol) at room temperature. Then the, the reaction mixture was heated at 60°C for 2 h. The progress of reaction was monitored by TLC. After completion, the reaction mass was concentrated to afford the crude residue.
  • the crude compound was purified by silica gel column chromatography using a gradient of 80-100% EtOAC/hexane and then eluted in 0-10% MeOH/DCM to afford the pure N-(4-((3-amino-5-methylpyridin-2-yl)oxy)phenyl)-N-methylbut-2-ynamide INT-12.2 as brown solid (210 mg, 86%); m/z 296.17 (M+H) + .
  • N-(4-((3-((4-Chloro-3-(trifluoromethyl)phenyl)sulfonamido)-5-methylpyridin-2- yl)oxy)phenyl)-N-methylbut-2-ynamide To a stirred solution of N-(4-((3-amino-5- methylpyridin-2-yl)oxy)phenyl)-N-methylbut-2-ynamide INT-12.2 (210 mg, 0.711 mmol) in pyridine (3.00 mL) was added 4-chloro-3-(trifluoromethyl)benzene-1 -sulfonyl chloride (238 mg, 0.853 mmol) at room temperature.
  • N-(3-Methyl-4-((5-methyl-3-nitropyridin-2-yl)oxy)phenyl)acrylamide (INT-13.4): To a stirred solution of residue 3-methyl-4-((5-methyl-3-nitropyridin-2-yl)oxy)aniline INT-13.3 (840 mg, 3.24 mmol) in THF (10.0 mL) was added triethylamine (0.937 mL, 6.48 mmol) and acryloyl chloride (0.320 mL, 3.89 mmol) dropwise at 0 °C. Then the reaction was allowed to stir at room temperature for 2 h. The progress of the reaction was monitored by TLC. After completion, the reaction mass was diluted with water and extracted with EtOAc.
  • N-(4-((3-Amino-5-methylpyridin-2-yl)oxy)-3-methylphenyl)acrylamide (INT-13.5): To a solution of N-(3-methyl-4-((5-methyl-3-nitropyridin-2-yl)oxy)phenyl)acrylamide INT-13.4 (650 mg, 2.07 mmol) in THF (7.00 mL) was added SnCl2.2H2O (1.64 g, 7.26 mmol). Then the reaction mixture was stirred at 60 °C for 2 h. After completion, the reaction mass was diluted with water and extracted with EtOAc. The organic layer was dried over sodium sulfate, filtered and concentrated to afford the crude residue.
  • N-(4-((3-((4-Chloro-3-(trifluoromethyl)phenyl)sulfonamido)-5-methylpyridin-2-yl)oxy)-3- methylphenyl)acrylamide To a solution of N-(4-((3-amino-5-methylpyridin-2-yl)oxy)-3- methylphenyl)acrylamide INT-13.5 (310 mg, 1.09 mmol) in pyridine (2.00 mL) was added 4- chloro-3-(trifluoromethyl)benzene-1 -sulfonyl chloride (336 mg, 1.20 mmol). This reaction mixture was stirred at room temperature for 2 h.
  • (2E)-N- ⁇ 4-[(3-amino-5-methylpyridin-2-yl)oxy]phenyl ⁇ but-2-enamide INT-17.2: To a stirred solution of (2E)-N- ⁇ 4-[(5-methyl-3-nitropyridin-2-yl)oxy]phenyl ⁇ but-2-enamide INT-17.1 (260 mg, 0.83 mol) in THF (4.00 mL) was added SnCl2.2H2O (757 mg, 2.90 mmol). The reaction was allowed to stir at 60°C for 2 hours. After completion, the reaction mass was added with water and extracted with EtOAc, washed with brine, dried over Na 2 SO 4 and concentrated under reduced pressure to get the crude.
  • the reaction mixture was stirred at room temperature for 1 hour. After completion, the reaction mixture was concentrated under reduced pressure to get the crude residue.
  • the crude reaction mixture was added with EtOAc and washed with water and brine solution. The organic layer was dried over Na 2 SO 4 & concentrated under reduced pressure to afford the crude.
  • N-(4-methoxy-3-(trifluoromethyl)phenyl)acrylamide (INT-31.1): To a solution of 4-methoxy- 3-(trifluoromethyl)aniline (3.00 g, 15.7 mmol) in THF (30.0 mL) was added TEA (3.40 mL, 23.5 mmol). Then acryloyl chloride (1.55 mL, 18.8 mmol) was added dropwise at 0 °C. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was diluted ethyl acetate and washed with water. The organic layer was dried over Na 2 SO 4 and concentrated under reduced pressure to afford the crude residue. The crude compound N-(4- methoxy-3-(trifluoromethyl)phenyl)acrylamide INT-31.1 (3.20 g, 83%) was used for the next step without purification.
  • N-(4-hydroxy-3-(trifluoromethyl)phenyl)acrylamide (INT-31.2): To a solution of N-(4- methoxy-3-(trifluoromethyl)phenyl)acrylamide INT-31.1 (3.20 g, 13.1 mmol) in dichloromethane (10.0 mL) was added borontribromide (2.48 mL, 26.1 mmol) dropwise at 0 °C. The progress of the reaction was monitored by TLC. After 2 hours, the reaction mixture was quenched with methanol and evaporated under reduced pressure to afford the crude compound. The crude compound was diluted with water and extracted with ethyl acetate.
  • N-(4-((5-methyl-3-nitropyridin-2-yl)oxy)-3-(trifluoromethyl)phenyl)acrylamide (INT-31.3): To a solution of N-(4-hydroxy-3-(trifluoromethyl)phenyl)acrylamide INT-31.2 (570 mg, 2.47 mmol) in N,N-dimethylformamide (6.00 mL) was added 2-bromo-5-methyl-3-nitropyridine (535 mg, 2.47 mmol), Potassium phosphate tribasic (1.57 g, 7.40 mmol) and Cui (141 mg, 0.740 mmol). Then the reaction mixture was stirred at 120 °C for 16 hours. The progress of the reaction was monitored by LCMS.
  • the suspension was washed with water and dried over sodium sulfate and concentrated under reduced pressure to afford the crude residue.
  • the crude compound was purified by silica gel column chromatography using 50% ethyl acetate in hexane to afford the desired compound.
  • Example 32 N-(1 -(4-((3-((4-chloro-3-(trifluoromethyl)Dhenyl)sulfonamido)-5-methylDyridin-2- yl)oxy)phenyl)cvclopropyl)acrylamide (Ex-32)
  • N-(1-(4-methoxyphenyl)cyclopropyl)acrylamide (INT-32.1): To a solution of 1 -(4- methoxyphenyl)cyclopropan-1 -amine (1 .00 g, 6.13 mmol) in tetrahydrofuran (10.0 mL) was added triethylamine (1 .77 mL, 12.3 mmol) followed by addition of acryloyl chloride (0.655 mL, 7.96 mmol) dropwise at 0 °C. Then the reaction mixture was stirred at 0 °C. The progress of the reaction was monitored by TLC. After 1 hour, the reaction mixture was diluted with ethyl acetate and washed with water.
  • N-(1-(4-hydroxyphenyl)cyclopropyl)acrylamide (INT-32.2): To a solution of N-(1 -(4- methoxyphenyl)cyclopropyl)acrylamide INT-32.1 (1 .25 g, 5.75 mmol) in dichloromethane (12.5 mL) was added boron tribromide (2.88 g, 1 1 .5 mmol) dropwise at 0 °C. The progress of the reaction was monitored by TLC. After 2 hours, the reaction mixture was quenched with methanol and evaporated under reduced pressure. The residue was diluted with ethyl acetate, washed with water, dried over sodium sulfate and concentrated under reduced pressure to afford the crude residue.
  • N-(1-(4-((5-methyl-3-nitropyridin-2-yl)oxy)phenyl)cyclopropyl)acrylamide (INT-32.3): To a solution of N-(1 -(4-hydroxyphenyl)cyclopropyl)acrylamide INT-32.2 (850 mg, 4.18 mmol) in dimethyl sulfoxide (9.00 mL) was added potassium carbonate (1 .73 g, 12.5 mmol) and 2- bromo-5-methyl-3-nitropyridine (908 mg, 4.18 mmol). Then the reaction mixture was stirred at 120 °C for 16 hour. The progress of the reaction was monitored by TLC.
  • N-(1-(4-((3-amino-5-methylpyridin-2-yl)oxy)phenyl)cyclopropyl)acrylamide (INT-32.4): To a solution of N-(1 -(4-((5-methyl-3-nitropyridin-2-yl)oxy)phenyl)cyclopropyl)acrylamide INT-32.3 (430 mg, 1.27 mmol) in THF (5.00 mL) was added stannous chloride dihydrate (1.00 g, 4.43 mmol). This mixture was stirred at 70 °C for 2 hours. The progress of the reaction was monitored by TLC.
  • N-(1-(4-((3-((4-chloro-3-(trifluoromethyl)phenyl)sulfonamido)-5-methylpyridin-2- yl)oxy)phenyl)cyclopropyl)acrylamide To a solution of N-(1 -(4-((3-amino-5-methylpyridin-2- yl)oxy)phenyl)cyclopropyl)acrylamide INT-32.4 (240 mg, 0.776 mmol) in pyridine (3.00 mL) was added 4-chloro-3-(trifluoromethyl)benzene-1 -sulfonyl chloride (216 mg, 0.776 mmol).
  • reaction mixture was stirred at rt for 1 h. After completion, the reaction mixture was concentrated under reduced pressure and diluted with ethyl acetate. The organic layer was washed with water dried over sodium sulfate and concentrated under reduced pressure to afford the crude residue.
  • the crude compound was purified by silica gel column chromatography using 40-50% ethyl acetate in hexane to afford the desired compound.
  • N-(3-((5-Methyl-3-nitropyridin-2-yl)methyl)phenyl)acrylamide (INT-33.5): To a solution of 3- ((5-methyl-3-nitropyridin-2-yl)methyl)aniline INT-33.4 (120 mg, 0.493 mmol) in THF (2 mL) was added triethylamine (0.143 mL, 0.987 mmol) and acryloyl chloride (53.6 mg, 0.592 mmol). The reaction mixture was stirred at room temperature for 1 h. Then, the reaction mixture was extracted with ethyl acetate, washed with water and brine solution, dried over sodium sulfate and concentrated under reduced pressure.
  • N-(3-((3-Amino-5-methylpyridin-2-yl)methyl)phenyl)acrylamide INT-33.6: To a stirred solution of N-(3-((5-methyl-3-nitropyridin-2-yl)methyl)phenyl)acrylamide INT-33.5 (100 mg, 0.336 mmol) in IPA (0.5 mL) and water (0.5 mL) was added iron powder (93.9 mg, 1 .68 mmol) and 2N HCI solution (0.2 mL) at room temperature. Then the reaction was heated at 55 °C for 30 min. The progress of reaction was monitored by TLC. Then, the reaction mass was filtered through a pad of celite.
  • N-(3-((3-((4-chloro-3-(trifluoromethyl)phenyl)sulfonamido)-5-methylpyridin-2- yl)methyl)phenyl)acrylamide To a solution of N-(3-((3-amino-5-methylpyridin-2- yl)methyl)phenyl)acrylamide INT-33.6 (60 mg, 0.224 mmol) in pyridine (1 mL) was added 4- chloro-3-(trifluoromethyl)benzene-1 -sulfonyl chloride (75.2 mg, 0.269 mmol). The reaction mixture was stirred at room temperature for 3 hours.
  • INT-43.2 (0.50 g, 90%) as light yellow solid; m/z 276.14 (M+H) + .
  • N-(4-((3-amino-5-methylpyridin-2-yl)oxy)-2-methoxyphenyl)acrylamide (INT-43.4): To a stirred solution of INT-43.3 (0.30 g, 0.91 mmol) in THF (3 mL) was added SnCl2.2H2O (719 mg, 3.19 mmol) at rt and then, the reaction was allowed to stir at 70 °C. After 2 h, the reaction mixture was concentrated under vacuum. The crude was purified by silica gel column chromatography using a gradient of 50-70% EtOAc in hexanes to get INT-43.4 (0.16 g, 56%) as light yellow solid; m/z 300.16 (M+H) + .
  • N-(4-((3-((4-chloro-3-(trifluoromethyl)phenyl)sulfonamido)-5-methylpyridin-2-yl)oxy)-2- methoxyphenyl)acrylamide To a stirred solution of INT-43.4 (0.16 g, 0.52 mmol) in pyridine (2 mL) was added 4-chloro-3-(trifluoromethyl)benzenesulfonyl chloride (0.131 g, 0.47 mmol) at rt. After 1 h, the reaction mixture was concentrated under vacuum and added EtOAc into it. The organic layer was washed with 1 N HCI, dried over Na2SO4 and concentrated under vacuum.
  • N-(4-(3-((4-chloro-3-(trifluoromethyl)phenyl)sulfonamido)-5- methylpicolinoyl)phenyl)acrylamide To a stirred solution of INT-45.7 (0.65 g, 1 .27 mmol) in DMSO (7 mL) were added acetic acid (0.077 g, 1 .27 mmol) and Cui (0.08 g, 0.26 mmol) at rt. Then, the reaction was stirred at 100 °C under continuous oxygen purging. After 24 h, the reaction mass was diluted with water and extracted with EtOAc. The organic layer was washed with water and brine solution, dried over sodium sulfate and concentrated.
  • N-(2,5-difluoro-4-methoxyphenyl)acrylamide (INT-47.3): To a stirred solution of INT-47.2 (3.10 g, 19.50 mmol) in THF (31 mL) were added EtsN (5.48 mL, 39.00 mmol) and acryloyl chloride (1 .89 mL, 23.40 mmol) at 0 °C. The reaction was allowed to stir at rt. After 1 h, the reaction mass was diluted with water and extracted with EtOAc. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to get the crude INT-47.3 (3.20 g, 77%) as light yellow solid m/z 214.09 (M+H) + .
  • N-(2,5-difluoro-4-hydroxyphenyl)acrylamide (INT-47.4): To a stirred solution of INT-47.3 (3.10 g, 14.50 mmol) in DCM (31 mL) was added BBrs (1.66 mL, 17.40 mmol) drop-wise at 0 °C. After 1 h, the reaction mixture was quenched with ice cold water and extracted with EtOAc. The organic layer was dried over sodium sulfate and concentrated to get the crude INT-47.4 (2.80 g, 96%) as light brown solid m/z 200.05 (M+H) + .
  • N-(2,5-difluoro-4-((5-methyl-3-nitropyridin-2-yl)oxy)phenyl)acrylamide (INT-47.5): To a stirred solution of INT-47.4 (2.80 g, 14.1 mmol) in DMSO (30 mL) were added 2-bromo-5- methyl-3-nitropyridine (3.05 g, 14.10 mmol) and K2CO3 (5.83 g, 42.20 mmol) at rt and the reaction mixture was allowed to stir at 110 °C. After 2 h, the reaction mass was diluted with water and extracted with EtOAc. The organic layer was washed with ice cold water and brine solution, dried over sodium sulfate and concentrated. The crude was purified by silica gel column chromatography using a gradient of 20-40% EtOAc in hexanes to get INT-47.5 (2.00 g, 42%) as white solid, m/z 334.06 (M-H)-.
  • N-(4-((3-amino-5-methylpyridin-2-yl)oxy)-2,5-difluorophenyl)acrylamide (INT-47.6): To a stirred solution of INT-47.5 (0.6 g, 1.79 mmol) in THF (6 mL) was added SnCl2.2H2O (1.41 g, 6.26 mmol) and the reaction mixture was allowed to stir at 70 °C. After 2 h, the reaction mixture was concentrated under reduced pressure.
  • N-(4-((3-((4-chloro-3-(trifluoromethyl)phenyl)sulfonamido)-5-methylpyridin-2-yl)oxy)-2,5- difluorophenyl)acrylamide To a stirred solution of INT-47.6 (0.25 g, 0.82 mmol) in pyridine (2 mL) was added 4-chloro-3-(trifluoromethyl)benzenesulfonyl chloride (0.23 g, 0.82 mmol) at rt. After 2 h, the reaction mixture was concentrated to remove pyridine. The residue was diluted with water and extracted with EtOAc. The organic layer was washed with water and 1 N HCI.
  • INT-54.2 1-(7-hydroxy-2,3-dihydro-4H-benzo[b][1 ,4]oxazin-4-yl)prop-2-en-1-one (INT-54.2): To a stirred solution of INT-54.1 (0.7 g, 3.19 mmol) in DCM (7 mL) was added BBrs (0.36 mL, 3.83 mmol) drop-wise at 0 °C. After 1 h at 0 °C, the reaction mixture was quenched with ice cold water and extracted with EtOAc. The organic layer was dried over sodium sulfate and concentrated to get INT-54.2 (0.65 g, 99%) as yellow solid; m/z 206.08 (M+H)+.
  • N-(2-((4-acryloyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)oxy)-5-methylpyridin-3-yl)-4- chloro-3-(trifluoromethyl)benzenesulfonamide To a stirred solution of INT-54.4 (0.22 g, 0.71 mmol) in pyridine (2.5 mL) was added 4-chloro-3-(trifluoromethyl)benzenesulfonyl chloride (0.20 g, 0.71 mmol) at rt. After 0.5 h, pyridine was removed from reaction mass under reduced pressure.
  • N-(3-(2-methoxyethoxy)-4-((5-methyl-3-nitropyridin-2-yl)oxy)phenyl)acrylamide INT-55.6 J1311-358449: To a stirred solution of INT-55.5 (0.70 g, 2.19 mmol) in THF (7 mL) were added EtsN (0.44 g, 4.38 mmol) and acryloyl chloride (0.24 g, 2.63 mmol) at 0 °C and allowed the reaction to stir at rt. After 1 h, the reaction mass was diluted with water and extracted with EtOAc, the organic layer was washed with brine solution and concentrated under reduced pressure.
  • N-(4-((3-amino-5-methylpyridin-2-yl)oxy)-3-(2-methoxyethoxy)phenyl)acrylamide (INT- 55.7): To a stirred solution of INT-55.6 (0.60 g, 1 .61 mmol) in THF (6 mL) was added SnCl2.2H2O (1 .27 g, 5.62 mmol) at rt and the reaction was allowed to stir at 70 °C. After 2 h, the reaction mass was concentrated under reduced pressure.
  • N-(4-((3-((4-chloro-3-(trifluoromethyl)phenyl)sulfonamido)-5-methylpyridin-2-yl)oxy)-3-(2- methoxyethoxy)phenyl)acrylamide To a stirred solution of INT-55.7 (0.33 g, 0.96 mmol) in pyridine (4 mL) was added 4-chloro-3-(trifluoromethyl)benzenesulfonyl chloride (0.29 g, 1 .06 mmol) and the reaction was allowed to stir at rt.
  • N-(5-((3-((4-chloro-3-(trifluoromethyl)phenyl)sulfonamido)-5-methylpyridin-2- yl)oxy)pyridin-2-yl)-2-fluoroacrylamide To a stirred solution of INT-59.3 (0.40 g, 1 .39 mmol) in pyridine (4 mL) was added 4-chloro-3-(trifluoromethyl)benzene-sulfonyl chloride (0.38 g, 1 .39 mmol) and the reaction mixture was allowed to stir at rt. After 1 h, pyridine was removed from reaction mixture under reduced pressure.
  • N-(2-(4-amino-2-methoxyphenoxy)-5-methylpyridin-3-yl)-4-chloro-3- (trifluoromethyl)benzenesulfonamide (INT-60.4): To a stirred solution of INT-60.3 (0.65 g, 1 .11 mmol) in THF (7 mL) was added 4N HCI in 1 ,4-dioxane (8 mL) at 0 °C. The reaction was then allowed to stirred at rt. After 2 h, the reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure.
  • N-(3-hydroxy-4-((5-methyl-3-nitropyridin-2-yl)oxy)phenyl)acrylamide (INT-61.5): To a stirred solution of INT-61 .5 (1 .20 g, 3.25 mmol) in 1 ,4-dioxane (5 mL) was added 2N NaOH (5 mL) and the reaction mixture was allowed to stir at 50 °C. After 1 .5 h, the reaction mixture was concentrated under reduced pressure. The residue was acidified with 2N HCI and extracted with EtOAc. The organic layer was washed with water, dried over Na2SO4 and concentrated under reduced pressure.
  • N-(4-((3-((4-chloro-3-(trifluoromethyl)phenyl)sulfonamido)-5-methylpyridin-2-yl)oxy)-3- (prop-2-yn-1-yloxy)phenyl)acrylamide To a stirred solution of INT-61 .7 (0.15 g, 0.46 mmol) in pyridine (1.5 mL) was added 4-chloro-3-(trifluoromethyl)benzenesulfonyl chloride (0.13 g, 0.46 mmol) and the reaction mixture was allowed to stir at rt. After 1 h, pyridine was removed from the reaction mixture under reduced pressure.
  • N-(3-cyano-4-((5-methyl-3-nitropyridin-2-yl)oxy)phenyl)acrylamide (INT-64.2): To a stirred solution of INT-64.1 (1.40 g, 5.18 mmol) in THF (14 mL) were added EtsN (1.50 mL, 10.4 mmol) and acryloyl chloride (0.56 g, 6.22 mmol) at 0 °C and the reaction was allowed to stir at rt.
  • N-(4-((3-amino-5-methylpyridin-2-yl)oxy)-3-cyanophenyl)acrylamide (INT-64.2): To a stirred solution of INT-64.2 (0.70 g, 2.16 mmol) in THF (7 mL) was added SnCl2.2H2O (1.97 g, 7.55 mmol) at rt and the reaction was stirred at 60 °C. After 1 h, the reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure. The crude was purified by silica gel column chromatography using 30-50% EtOAc in hexanes to afford INT-64.3 (0.40 g, 63%) as yellow solid; m/z 295.13 (M+H) + .
  • N-(4-((3-((4-chloro-3-(trifluoromethyl)phenyl)sulfonamido)-5-methylpyridin-2-yl)oxy)-3- cyanophenyl)acrylamide To a stirred solution of INT-64.3 (0.40 g, 1.36 mmol) in pyridine (4 mL) was added 4-chloro-3-(trifluoromethyl)benzenesulfonyl chloride (0.38 g, 1.36 mmol) at rt. After 1 h, the reaction mixture was diluted with water, extracted with EtOAc. The organic layer was washed with 2N HCI and brine solution, dried over sodium sulfate and concentrated under reduced pressure.
  • N-(2-acetyl-4-hydroxyphenyl)acrylamide (INT-65.3): To a stirred solution of INT-65.2 (1 .20 g, 4.63 mmol) in 1 ,4-dioxane (12 mL) was added 2N NaOH (6 mL) at rt. After 0.5 h, the reaction mixture diluted with water, acidified with 2N HCI solution and extracted with EtOAc. The organic layer was dried over sodium sulfate and concentrated under reduced pressure.
  • N-(2-acetyl-4-((5-methyl-3-nitropyridin-2-yl)oxy)phenyl)acrylamide (INT-65.4): To a stirred solution of INT-65.3 (0.90 g, 4.39 mmol) in DMSO (9 mL) were added 2-bromo-5-methyl-3- nitropyridine (0.95 g, 4.39 mmol) and K2CO3 (1.21 g, 8.77 mmol) at rt and the reaction mixture was heated to 70 °C. After 1 h, the reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure.
  • N-(2-acetyl-4-((3-amino-5-methylpyridin-2-yl)oxy)phenyl)acrylamide INT-65.5 To a stirred solution of INT-65.4 (0.40 g, 1.17 mmol) in EtOAc (8 mL) was added SnCI2.2H2O (1 .32 g, 5.86 mmol) at rt then heated the reaction to 50 °C. After 2 h, the reaction mixture was basified with 2N NaOH solution and extracted with EtOAc. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to get the crude INT-65.5 (0.37 g) as light brown solid, m/z 312.11 (M+H) + .
  • N-(2-acetyl-4-((3-((4-chloro-3-(trifluoromethyl)phenyl)sulfonamido)-5-methylpyridin-2- yl)oxy)phenyl)acrylamide To a stirred solution of INT-65.5 (0.37 g, 1.19 mmol) in pyridine (4 mL) was added 4-chloro-3-(trifluoromethyl)benzenesulfonyl chloride (0.33 g, 1.19 mmol) at rt. After 0.5 h, pyridine was removed from reaction mixture under reduced pressure. The residue was diluted with water and extracted with EtOAc, the organic layer was washed with brine solution and aq. HCI.
  • N-(3-(2-(dimethylamino)ethoxy)-4-((5-methyl-3-nitropyridin-2-yl)oxy)phenyl)acrylamide (INT-66.4): To a stirred solution of INT-66.3 (0.87 g, 2.62 mmol) in THF (9 mL) were added TEA (0.74 mL, 5.24 mmol) and acryloyl chloride (0.27 mL, 3.14 mmol) at 0°C and the reaction mixture was allowed to stir at rt. After 30 min., the reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over sodium sulfate and concentrated to afford the crude INT-66.4 (0.55 g) as brown gummy solid; m/z 387.23 (M+H) + .
  • N-(4-((3-amino-5-methylpyridin-2-yl)oxy)-3-(2-(dimethylamino)ethoxy)phenyl)acrylamide (INT-66.5): To a stirred solution of INT-66.4 (0.55 g, 1.42 mmol) in EtOAc (10 mL) was added SnCl2.2H2O (1.61 g, 7.12 mmol) at rt and the reaction mixture was allowed to stir at 50 °C. After 1 h, the reaction mixture was basified with 2N NaOH solution and extracted with EtOAc. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude was purified by silica gel column chromatography using a gradient of 10-15% MeOH in DCM to get INT-66.5 (0.22 g,43%) as brown solid, m/z 357.23 (M+H) + .
  • N-(4-((3-((4-chloro-3-(trifluoromethyl)phenyl)sulfonamido)-5-methylpyridin-2-yl)oxy)-3-(2- (dimethylamino)ethoxy)phenyl)acrylamide To a stirred solution of INT-66.5 (0.22 g, 0.62 mmol) in pyridine (2.2 mL) was added 4-chloro-3-(trifluoromethyl)benzene-sulfonyl chloride (0.17 g, 0.62 mmol) and the reaction mixture was allowed to stir at rt. After 1 h, pyridine was removed from reaction mixture under reduced pressure.
  • N-(3-((diethylamino)methyl)-4-hydroxyphenyl)acetamide (INT-67.1): To a stirred solution of N-(4-hydroxyphenyl)acetamide (3.00 g, 19.8 mmol) in ethanol (30 mL) were added formaldehyde (0.72 g, 23.8 mmol) and diethylamine (1.74 g, 23.8 mmol) at rt and the reaction mixture was allowed to stir at 80 °C. After 12 h, the reaction mixture was concentrated under reduced pressure. The brown residue was diluted with EtOAc and washed with water. The organic layer was dried over sodium sulfate and concentrated under reduced pressure.
  • N-(3-((diethylamino)methyl)-4-((5-methyl-3-nitropyridin-2-yl)oxy)phenyl)acrylamide (INT- 67.4): To a stirred solution of INT-67.3 (1.70 g, 5.15 mmol) in THF (17 mL) were added TEA (1.45 mL, 10.3 mmol) and acryloyl chloride (0.53 mL, 6.17 mmol) at 0 °C and the reaction was allowed to stir at rt. After 1 h, the reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over sodium sulfate and concentrated under reduced pressure.
  • N-(4-((3-amino-5-methylpyridin-2-yl)oxy)-3-((diethylamino)methyl)phenyl)acrylamide (INT-67.5): To a stirred solution of INT-67.4 (0.40 g, 1.04 mmol) in EtOAc (8 mL) was added SnCl2.2H2O (1 .17 g, 5.2 mmol) at rt and the reaction mixture was allowed to stir at 50 °C. After 1 h, the reaction mixture was basified with 2N NaOH solution and extracted with EtOAc. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to afford the crude INT- 67.5 (0.25 g) as yellow solid; m/z 355.41 (M+H) + .
  • N-(4-((3-((4-chloro-3-(trifluoromethyl)phenyl)sulfonamido)-5-methylpyridin-2-yl)oxy)-3- ((diethylamino)methyl)phenyl)acrylamide To a stirred solution of INT-67.5 (0.25 g, 0.71 mmol) in pyridine (2.5 mL) was added 4-chloro-3-(trifluoromethyl)benzenesulfonyl chloride (0.19 mg, 0.71 mmol) at rt. After 1 h, pyridine was removed from reaction mixture under reduced pressure.
  • N-(4-((5-methyl-3-nitropyridin-2-yl)oxy)-3-(trifluoromethoxy)phenyl)acrylamide (INT-68.3): To a stirred solution of INT-68.2 (0.65 g, 1.97 mmol) in THF (7 mL) was added TEA (0.40 g, 3.95 mmol) and acryloyl chloride (0.21 g, 2.37 mmol) dropwise at 0 °C and the reaction was allowed to stir at rt. After 2 h, the reaction mixture was diluted with EtOAc and washed with water. The organic layer was dried over sodium sulfate and concentrated under reduced pressure.
  • N-(4-((3-amino-5-methylpyridin-2-yl)oxy)-3-(trifluoromethoxy)phenyl)acrylamide (INT- 68.4): To a stirred solution of INT-68.3 (0.60 g, 1 .57 mmol) in EtOAc (12 mL) was added SnCl2.2H2O (1 .24 g, 5.48 mmol) and the reaction mixture was allowed to stir at 50 °C. After 2 h, the reaction mixture was diluted with EtOAc, washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure.
  • N-(6-hydroxy-[1 ,1'-biphenyl]-3-yl)acrylamide (INT-69.2): To a stirred solution of INT-69.1 (0.60 g, 2.05 mmol) in 1 ,4-dioxane (6 mL) was added 2N NaOH (3 mL) and the reaction mixture was allowed to stir at rt. After 1 h, the reaction mixture was diluted with water, acidified with 2N HCI solution and extracted with EtOAc. The organic layer was dried over sodium sulfate and concentrated under reduced pressure.
  • N-(6-((5-methyl-3-nitropyridin-2-yl)oxy)-[1 ,T-biphenyl]-3-yl)acrylamide (INT-69.3): To a stirred solution of INT-69.2 (0.30 g, 1 .25 mmol) in DMSO (3 mL) were added 2-bromo-5- methyl-3-nitropyridine (0.27 g, 1 .25 mmol) and K2CO3 (0.52 g, 2.26 mmol) at rt. The reaction mixture was allowed to stir at 80 °C. After 1 h, the reaction mixture was diluted with water and extracted with EtOAc.
  • N-(6-((3-amino-5-methylpyridin-2-yl)oxy)-[1 ,T-biphenyl]-3-yl)acrylamide (INT-69.4): To a stirred solution of INT-69.3 (0.36 g, 0.96 mmol) in EtOAc (8 mL) was added SnCl2.2H2O (1 .08 g, 4.8 mmol) at rt and the reaction was allowed to stir at 50 °C. After 2 h, the reaction mixture was basified with 2N NaOH solution and extracted with EtOAc. The organic layer was washed with brine solution, dried over Na2SO4 and concentrated under reduced pressure.
  • N-(6-((3-((4-chloro-3-(trifluoromethyl)phenyl)sulfonamido)-5-methylpyridin-2-yl)oxy)-[1,T- biphenyl]-3-yl)acrylamide To a stirred solution of INT-69.4 (0.35 g, 1 .01 mmol) in pyridine (4 mL) was added 4-chloro-3-(trifluoromethyl)benzenesulfonyl chloride (0.28 g, 1 .01 mmol) at rt. After 1 h, pyridine was removed from the reaction mixture under reduced pressure.
  • N-(8-hydroxyquinolin-5-yl)acrylamide (INT-71.2): To a stirred solution of INT-71 .1 (0.55 g, 2.05 mmol) in 1 ,4-dioxane (6 mL) was added 2N NaOH (3 mL) solution at rt. After 1 h, the reaction mixture was diluted with water and extracted with 30% IPA in CHCI3. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude was purified by silica gel column chromatography using a gradient of 20-30% EtOAc in hexanes to afford INT-71 .2 (0.42 g, 95%) as light brown solid; m/z 214.97 (M+H) + .
  • N-(8-((5-methyl-3-nitropyridin-2-yl)oxy)quinolin-5-yl)acrylamide (INT-71 .3): To a stirred solution of INT-71 .2 (0.40 g, 1 .87 mmol) in DMSO (4 mL) were added 2-bromo-5-methyl-3- nitropyridine (0.41 g, 1 .87 mmol) and K2CO3 (0.77 g, 5.6 mmol) at rt and the reaction mixture was allowed to stir at 1 10 °C. After 2 h, the reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure.
  • N-(8-((3-amino-5-methylpyridin-2-yl)oxy)quinolin-5-yl)acrylamide (INT-71.4): To a stirred solution of INT-71 .3 (0.36 g, 1 .03 mmol) in EtOAc (8 mL) was added SnCl2.2H2O (1 .16 g, 5.14 mmol) at rt and the reaction mixture was allowed to stir at 50 °C. After 1 h, the reaction mixture was basified with 2N NaOH solution and extracted with EtOAc. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to afford the crude INT-71 .4 (0.20 g) as light brown solid; m/z 321 .21 (M+H) + .
  • N-(8-((3-((4-chloro-3-(trifluoromethyl)phenyl)sulfonamido)-5-methylpyridin-2- yl)oxy)quinolin-5-yl)acrylamide To a stirred solution of INT-71 .4 (0.20 g, 0.63 mmol) in pyridine (2 mL) was added 4-chloro-3-(trifluoromethyl)benzenesulfonyl chloride (0.17 g, 0.63 mmol) at rt. After 1 h, pyridine was removed from the reaction mixture under reduced pressure. The residue was diluted with water and extracted with EtOAc, the organic layer was washed with brine solution and aq. HCI.
  • 8-Aminoquinolin-5-ol (INT-73.1): To a stirred solution of 8-nitroquinolin-5-ol (1 .60 g, 8.41 mmol) in HCI (16 mL) was added SnCl2.2H2O (7.59 g, 33.7 mmol) at rt and the reaction mixture was allowed to stir at 1 10 °C. After 3 h, the reaction mixture was basified with ammonia solution and extracted with EtOAc. The organic layer was dried over Na 2 SO 4 and concentrated to get the crude INT-73.1 (0.86 g) as black solid; m/z 161 .08 (M+H) + .
  • N-(5-((3-((4-chloro-3-(trifluoromethyl)phenyl)sulfonamido)-5-methylpyridin-2- yl)oxy)pyrimidin-2-yl)-2-fluoroacrylamide To a stirred solution of INT-74.5 (0.30 g, 0.652 mmol) in THF (3 mL) was added DIPEA (0.4 mL, 2.28 mmol), 2-fluoroacrylic acid (0.12 g, 1 .3 mmol) and T3P 50% in EtOAc (0.58 mL, 0.98 mmol) at rt and the reaction mixture was allowed to stir at 50 °C.
  • 6-((5-Methyl-3-nitropyridin-2-yl)oxy)pyridin-3-amine (INT-75.1): To a stirred solution of 2- bromo-5-methyl-3-nitropyridine (2.50 g, 1 1 .5 mmol) and 5-aminopyridin-2-ol (1 .27 g, 1 1 .5 mmol) in DMF (25 mL) was added CS2CO3 (7.51 g, 23 mmol) at rt and the reaction was stirred at 90 °C. After 6h, the reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine solution, dried over Na2SO4 and concentrated under reduced pressure.
  • N-(6-((3-amino-5-methylpyridin-2-yl)oxy)pyridin-3-yl)-2-fluoroacrylamide (INT-75.3): To a stirred solution of INT-75.2 (0.28 g, 0.88 mmol) in EtOAc (3 mL) was added SnCl2.2H2O (0.99 g, 4.4 mmol) at rt and the reaction was stirred at 50 °C.
  • N-(6-((3-((4-chloro-3-(trifluoromethyl)phenyl)sulfonamido)-5-methylpyridin-2- yl)oxy)pyridin-3-yl)-2-fluoroacrylamide To a stirred solution of INT-75.3 (0.20 g, 0.69 mmol) in pyridine (2 mL) was added 4-chloro-3-(trifluoromethyl)benzenesulfonyl chloride (0.19 g, 0.69 mmol) at rt and the reaction mixture was allowed to stir at rt. After 1 h, the reaction mixture was concentrated under reduced pressure. The residue was dissolved with EtOAc, washed with brine solution and aq.
  • N-(4-((3-amino-5-methylpyridin-2-yl)oxy)phenyl)-2-fluoroacrylamide (INT-76.5): To a stirred solution of INT-76.3 (2.10 g, 6.62 mmol) in EtOAc (40 mL) was added SnCl2.2H2O (7.47 g, 33.1 mmol) at rt and the reaction mixture was allowed to stir at 50 °C. After 2 h, the reaction mixture was basified with 2N NaOH solution and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to afford the crude INT-76.5 (1 .80 g) as yellow solid; m/z 288.36 (M+H) + .
  • N-(4-((3-((4-chlorophenyl)sulfonamido)-5-methylpyridin-2-yl)oxy)phenyl)-2- fluoroacrylamide To a stirred solution of INT-76.5 (0.15 g, 0.52 mmol) in pyridine (3 mL) was added 4-chlorobenzenesulfonyl chloride (0.1 1 g, 0.52 mmol) and the reaction mixture was allowed to stir at rt. After 30 min., the reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with 2N HCI solution and brine solution, dried over Na2SO4 and concentrated under reduced pressure.
  • N-(2-hydroxy-5-nitrophenyl)acetamide (INT-78.1): To a stirred solution of 2-amino-4- nitrophenol (6.00 g, 38.9 mmol) in water (60 mL) was added AC2O (1 1 mL, 1 17 mmol) and the reaction mixture was allowed to stir at rt. After 1 h, the solid formed was collected by filtration and washed with ether and dried over vacuum to afford the crude INT-78.1 (6.60 g) as a light yellow solid; m/z 195.01 (M-H)-.
  • N-(5-amino-2-hydroxyphenyl)acetamide (INT-78.2): To a stirred solution of INT-78.1 (6.60 g, 33.6 mmol) in MeOH (70 mL) and THF (30 mL) was added 10% Pd/C w/w (1 .79 g, 1 .68 mmol) at rt and the reaction mixture was allowed to stir under hydrogen at 50 °C in a par vessel. After 4 h, the reaction mixture was filtered through celite bed. The filtrate was concentrated under reduced pressure.
  • N-(5-amino-2-((5-methyl-3-nitropyridin-2-yl)oxy)phenyl)acetamide (INT-78.3): To a stirred solution of INT-78.2 (3.00 g, 18.1 mmol) in DMSO (30 mL) was added 2-bromo-5-methyl-3- nitropyridine (3.92 g, 18.1 mmol) and K2CO3 (4.99 g, 36.1 mmol) at rt and the reaction mixture was allowed to stir at 70 °C. After 1 h, the reaction mixture was diluted with water and extracted with EtOAc, the organic layer was washed with brine solution, dried over Na 2 SO 4 and concentrated under reduced pressure.
  • N-(3-acetamido-4-((5-methyl-3-nitropyridin-2-yl)oxy)phenyl)acrylamide (INT-78.4): To a stirred solution of INT-78.3 (1 .50 g, 4.96 mmol) in THF (15 mL) were added EtsN (1 .39 mL, 9.92 mmol) and acryloyl chloride (0.51 mL, 5.95 mmol) at 0 °C and the reaction mixture was allowed to stir at rt. After 0.5 h, the reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated under reduced pressure.
  • N-(3-acetamido-4-((3-amino-5-methylpyridin-2-yl)oxy)phenyl)acrylamide (INT-78.5): To a stirred solution of INT-78.4 (0.7 g, 1 .96 mmol) in EtOAc (14 mL) was added SnCl2.2H2O (2.22 g, 9.82 mmol) at rt and the reaction mixture was allowed to stir at 50 °C. After 1 h, the reaction mixture was concentrated under reduced pressure.
  • N-(3-acetamido-4-((3-((4-chloro-3-(trifluoromethyl)phenyl)sulfonamido)-5-methylpyridin- 2-yl)oxy)phenyl)acrylamide _To a stirred solution of INT-78.5 (0.3 g, 0.92 mmol) in pyridine (3 mL) was added 4-chloro-3-(trifluoromethyl)benzenesulfonyl chloride (0.26 g, 0.92 mmol) and the reaction mixture was allowed to stir at rt. After 2 h, pyridine was removed from the reaction mixture under reduced pressure.
  • N-(1-(5-(methoxymethoxy)pyridin-2-yl)cyclopropyl)acrylamide (INT-82.3): To a stirred solution of INT-82.2 (0.71 g, 3.66 mmol) in THF (10 mL) were added EtsN (1 .53 mL, 11 mmol) and acryloyl chloride (0.354 mL, 4.39 mmol) at 0 °C. The resulting reaction mixture was allowed to stir at rt. The progress of the reaction was monitored by TLC. After 0.5 h, the reaction mixture was quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure.
  • the crude compound was purified by silica gel column chromatography using a gradient of 10-12% of MeOH in DCM to afford INT-82.3 (0.7 g, 77%) as a pale yellow gum; m/z 249.14 (M+H) + .
  • N-(1-(5-hydroxypyridin-2-yl)cyclopropyl)acrylamide (INT-82.4): To a stirred solution of INT- 82.3 (0.96 g, 3.86 mmol) in MeOH (15 mL) was added 6N HCI in water (3 mL) at rt. The resulting reaction mixture was stirred at 80 °C. After 1 h, the reaction mixture was quenched with saturated sodium bicarbonate solution and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure.
  • N-(1-(5-((5-methyl-3-nitropyridin-2-yl)oxy)pyridin-2-yl)cyclopropyl)acrylamide (INT-82.5): To a stirred solution of INT-82.4 (0.41 g, 2.01 mmol) and 2-bromo-5-methyl-3-nitropyridine (0.57 g, 2.61 mmol) in NMP (8 mL) was added CS2CO3 (1 .96 g, 6.02 mmol) at rt. The resulting reaction mixture was stirred at 90 °C. After 2 h, the reaction mixture was quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure.
  • N-(1-(5-((3-amino-5-methylpyridin-2-yl)oxy)pyridin-2-yl)cyclopropyl)acrylamide (INT- 82.6): To a stirred solution of INT-82.5 (0.19 g, 0.56 mmol) in EtOAc (2.05 mL) was added SnCl2.2H2O (0.64 g, 2.79 mmol) at rt. The resulting reaction mixture was stirred at 60 °C. After 1 h, the reaction mixture was quenched with 2N NaOH solution and extracted with EtOAc.
  • N-(1-(5-((3-((4-chloro-3-(trifluoromethyl)phenyl)sulfonamido)-5-methylpyridin-2- yl)oxy)pyridin-2-yl)cyclopropyl)acrylamide To a stirred solution INT-82.6 (0.13 g, 0.42 mmol) in pyridine (1 .3 mL) was added 4-chloro-3-(trifluoromethyl)benzenesulfonyl chloride (0.12 g, 0.42 mmol) at rt. After 0.5 h, the reaction mixture was concentrated under reduced pressure. The crude compound was diluted with EtOAc, and washed with water and brine.
  • N-(5-((5-methyl-3-nitropyridin-2-yl)oxy)pyridin-2-yl)acrylamide (INT-83.2): To a stirred solution of INT-83.1 (0.60 g, 2.44 mmol) in THF (6 mL) were added TEA (0.49 g, 4.87 mmol) and acryloyl chloride (0.24 g, 2.68 mmol) at 0 °C and then the reaction mixture was allowed to stir at rt. After 30 min., the reaction mixture was diluted with EtOAc and washed with water. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure.
  • N-(5-((3-amino-5-methylpyridin-2-yl)oxy)pyridin-2-yl)acrylamide (INT-83.3): To a stirred solution of INT-83.2 (0.40 g, 1 .33 mmol) in EtOAc (8 mL) was added SnCl2.2H2O (1 .05 g, 4.66 mmol) at rt and the reaction mixture was allowed to stir at 50 °C. After 2 h, the reaction mixture was neutralized by 2N NaOH solution, diluted with water and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated to get the crude INT-83.3 (0.09 g) as brown solid. The crude was forwarded for next reaction, low yield due to multiple spots in reaction, degradation observed. LCMS was not consistent.
  • N-(5-((3-((4-chloro-3-(trifluoromethyl)phenyl)sulfonamido)-5-methylpyridin-2- yl)oxy)pyridin-2-yl)acrylamide To a stirred solution of INT-83.3 (0.08 g, 0.29 mmol) in pyridine (0.8 mL) was added 4-chloro-3-(trifluoromethyl)benzenesulfonyl chloride (0.08 g, 0.29 mmol) and the reaction mixture was allowed to stir at rt. After 1 h, the reaction mixture was concentrated under reduced pressure to remove pyridine. The residue was diluted with water and extracted with EtOAc.
  • INT-84.2 (2.30 g) as light yellow solid; m/z 305.20 (M+H) + .
  • INT-84.4 To a stirred solution of INT-84.3 (1.80 g, 6.54 mmol) in THF (18 mL) was added DIPEA (3.43 mL, 19.6 mmol), (E)-4-bromobut-2-enoic acid (1.08 g, 6.54 mmol) and HATU (3.73 g, 9.81 mmol) at rt and the reaction was stirred at 40 °C. After 2 h, the reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine solution, dried over Na2SO4, filtered and concentrated under reduced pressure.
  • Tert-butyl (5-((5-methyl-3-nitropyridin-2-yl)oxy)pyrazin-2-yl)carbamate (INT-87.2): To a stirred solution of INT-87.1 (0.69 g, 2.24 mmol) in toluene (6.98 mL) were added tert-butyl carbamate (0.79 g, 6.73 mmol), K2CO3 (0.93 g, 6.73 mmol), Pd(OAc)2 (0.05 g, 0.23 mmol) and X-Phos (0.22 g, 0.45 mmol) sequentially under nitrogen purging. The reaction mixture was purged with nitrogen for 10 min. and stirred at 90 °C.
  • N-(5-((3-amino-5-methylpyridin-2-yl)oxy]pyrazin-2-yl)-2-fluoroprop-2-enamide (INT-87.5): To a stirred solution of INT-87.4 (0.18 g, 0.58 mmol) in EtOAc (3 mL) was added SnCl2.2H2O (0.66 g, 2.90 mmol) at rt and the reaction mixture was allowed to stir at 60 °C. After 1 h, the reaction mixture was basified with 2N NaOH solution and extracted with EtOAc.
  • N-(5-((3-((4-chloro-3-(trifluoromethyl)phenyl)sulfonamido)-5-methylpyridin-2-yl)oxy)-1- methyl-1H-pyrazol-3-yl)-2-fluoroacrylamide To a stirred solution of INT-88.5 (0.20 g, 0.43 mmol) in DMF (2 mL) were added DIPEA (0.27 mL, 1 .30 mmol), 2-fluoroacrylamide (0.058 g, 0.65 mmol) and HATU (0.25 g, 0.65 mmol) at rt and the reaction mixture was allowed to stir at 40 °C.
  • INT-89.2 4-((5-Methyl-3-nitropyridin-2-yl)oxy)benzoic acid (INT-89.2): To a stirred solution of INT- 89.1 (5.00 g, 17.3 mmol) in MeOH (25 mL) and THF (25 mL) was added 2N NaOH (20 mL) and the reaction mixture was allowed to stir at rt. After 1 h, the reaction mixture was concentrated under reduced pressure. The residue was acidified with 2N HCI, the solid was filtered and dried over vacuum to afford INT-89.2 (4.20 g, 88%) as yellow solid; m/z 275.21 (M+H) + .

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Abstract

La présente invention concerne de nouveaux composés d'arylsulfonamide substitués, des compositions pharmaceutiques comprenant ces composés et leur utilisation en thérapie. En particulier, la présente invention concerne l'utilisation de composés arylsulfonamide substitués selon la formule (I) dans le traitement de troubles médiés par le récepteur 2 de chimiokine (CCR2), par exemple le cancer.
PCT/EP2022/074259 2021-08-31 2022-08-31 Inhibiteurs de ccr2 WO2023031308A1 (fr)

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WO1992020687A1 (fr) * 1991-05-10 1992-11-26 Merck & Co., Inc. Pyrimidinones substituees portant des groupes fonctionnels acides, utilisees comme antagonistes d'angiotensine ii
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