spirocyclic indolines as modulators of il-17

专利摘要:
A series of substituted spirocyclic 2-oxoindoline derivatives, and analogs thereof, being potent modulators of human IL-17 activity, are consequently of benefit in the treatment and / or prevention of various human diseases, including inflammatory and autoimmune disorders.
公开号:BR112019026678A2
申请号:R112019026678-0
申请日:2018-06-12
公开日:2020-06-30
发明作者:Gareth Neil Brace；Matthew Duncan Selby；Adam Peter Smalley；Richard David Taylor；Robert James Townsend；Zhaoning Zhu；Rose Elizabeth Chappell；Hervé Jean Claude Deboves；Anne Marie Foley；Gregory Foulkes；Elizabeth Pearl Jones；Fabien Claude Lecomte；Joanna Rachel Quincey；Monika-Sarah Elisabeth Dorothea Schulze
申请人:UCB Biopharma SRL；
IPC主号:

专利说明:

[0001] [0001] The present invention relates to heterocyclic compounds, and their use in therapy. More particularly, this invention relates to pharmacologically active expirocyclic oxoindoline derivatives, and analogs thereof. These compounds act as modulators of IL-17 activity, and are therefore of benefit as pharmaceutical agents for the treatment and / or prevention of pathological conditions, including adverse inflammatory and autoimmune disorders.
[0002] [0002] IL-17A (originally called CTLA-8 and also known as IL-17) is a proinflammatory cytokine and the founding member of the IL-17 family (Rouvier et al., J. Immunol., 1993, 150 , 5445-5456). Subsequently, five additional family members (IL-17B to IL-17F) were identified, including the most closely related, IL-17F (ML-1), which shares approximately 55% amino acid sequence homology with IL-17A (Moseley et al., Cytokine Growth Factor Rev., 2003, 14, 155-174). IL-17A and IL-17F are expressed by the newly defined related autoimmune subset of helper T cells, Th17, which also expresses signature cytokines 11-21 and 11-22 (Korn et al., Ann. Rev. Immunol., 2009 , 27, 485-517). IL-17A and IL-17F are expressed as homodimers, but can also be expressed as the heterodimer IL-17A / F (Wright et al., J. Immunol., 2008, 181, 2799-2805). IL-17A and F signal through IL-17R, IL-17RC receptors or an IL-17RA / RC receptor complex (Gaffen, Cytokine, 2008, 43, 402-407). Both IL-17A and IL-17F have been associated with several autoimmune diseases.
[0003] [0003] The compounds according to the present invention, being potent modulators of human IL-17 activity, are, therefore, beneficial in the treatment and / or prevention of various human diseases, including inflammatory and autoimmune disorders.
[0004] [0004] In addition, the compounds according to the present invention can be beneficial as pharmacological standards for use in the development of new biological tests and in the search for new pharmacological agents. Thus, the compounds of this invention can be useful as radioligants in assays to detect pharmacologically active compounds.
[0005] [0005] AWO 2013/116682 and WO 2014/066726 refer to separate classes of chemical compounds that are established to modulate IL-17 activity and be useful in the treatment of medical conditions, including inflammatory diseases.
[0006] [0006] Nothing in the prior art available so far, however, discloses or suggests the exact structural class of the spirocyclic oxoindoline derivatives, and analogues thereof, as provided by the present invention.
[0007] [0007] The present invention provides a compound of formula (1) or a pharmaceutically acceptable salt thereof: Ps, SC | À 1 NT NDEÊ in Rº k [6
[0008] [0008] where
[0009] [0009] ring A represents C3-9 cycloalkyl, C3a7 heterocycloalkyl or Ca-9 heterobicycloalkyl, any of the groups may be optionally substituted by one or more substituents;
[0010] [0010] Does it represent C-R or N;
[0011] [0011] Drepresents C-Rº or N;
[0012] [0012] Erepresents C-Rº or N;
[0013] [0013] Rº represents hydrogen or C1-6a alkyl;
[0014] [0014] R'represents -CORº or -SO2Rº; or R 'represents C1-6 alkyl, C3-9 cycloalkyl, C3-9 cycloalkyl (C1- + 6) alkyl, Cs5-9 spirocycloalkyl (C1-6) alkyl, aryl, aryl (C1- + 6), hetero-cycloalkyl C3-7, heterocycloalkyl C3-7 alkyl (C1-6), heteroaryl or heteroarylalkyl (C1-6), any of the groups can be optionally substituted by one or more substituents;
[0015] [0015] R represents hydrogen, halogen, cyano, C1-6 alkyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxy, C1-6 alkoxy, difluoromethoxy, trifluoromethoxy, alkyl
[0016] [0016] Rº represents hydrogen, halogen, cyano, C1-6 alkyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxy, C1-6 alkoxy, difluoromethoxy, trifluoromethoxy, C1 + 6 sulfinyl alkyl or C1-6 sulfonyl alkyl;
[0017] [0017] Rº represents hydrogen, halogen, cyano, C1.6 alkyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxy, C1-6 alkoxy, difluoromethoxy, trifluoromethoxy, C1 + sulfinyl alkyl or C1-6 sulfonyl alkyl;
[0018] [0018] Rº represents hydrogen; or Rº represents C16 alkyl, C27 alkenyl, C3-9 cycloalkyl, C3-9 cycloalkyl (C1- + 6) alkyl, C3-9 cycloalkylidenyl (C1-6) alkyl, Ca-9 bicycloalkyl (C1-6) alkyl, Bicycloalkylidenyl Ca -9 alkyl (C1- + 6), spirocycloalkyl Cso alkyl (Ci), tricicioalkyl Co11 alkyl (Ci), aryl, arylalkyl (Ci), heterocycloalkyl C3-7, heterocycloalkyl C3-7 alkyl (C1- + 6), heterocycloalkylidenyl C3-7 alkyl (C1-6), heteroaryl or heteroarylalkyl (C1-6), any of the groups can be optionally substituted by one or more substituents; and
[0019] [0019] Rº represents C1-6 alkyl, C2-7 alkenyl, C3-9 cycloalkyl, C3-s cycloalkyl (C1 + 6), C3-9 cycloalkylidenyl (C1-6) alkyl, Ca-s bicycloalkyl (C1-) alkyl 6), bicycloalkylidenyl Ca-9 alkyl (C1-6), spirocycloalkyl Cs5-9 alkyl (C1-6), tricyclicalkyl Ca-11 alkyl (C1-6), aryl, aryl-alkyl (C1-6), C3- heterocycloalkyl 7, heterocycloalkyl C3- 7 alkyl (C1is), heterocycloalkylenyl C3a7 alkyl (C6), heteroaryl or heteroarylalkyl (C1-6), any of the groups can be optionally substituted by one or more substituents.
[0020] [0020] The present invention also provides a compound of the formula (|) as shown above or a pharmaceutically acceptable salt thereof, for use in therapy.
[0021] [0021] The present invention also provides a compound of formula (1) as shown above or a pharmaceutically acceptable salt thereof, for use in the treatment and / or prevention of disorders for which the administration of an IL-17 function modulator is indicated.
[0022] [0022] The present invention also provides the use of a compound of formula (1) as represented above or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment and / or prevention of disorders for which the administration of a modulator of the IL-17 function is indicated.
[0023] [0023] The present invention also provides a method for the treatment and / or prevention of disorders for which administration of a function modulator 11-17 is indicated which comprises administering to a patient in need of such treatment an effective amount of a compound of formula (1) as shown above or a pharmaceutically acceptable salt thereof.
[0024] [0024] Where any of the groups in the compounds of the formula (|) above is established to be optionally substituted, this group can be unsubstituted or substituted by one or more substituents. Typically, such groups will be unsubstituted or substituted by one, two or three substituents. Suitably, such groups will be unsubstituted or substituted by one or two substituents.
[0025] [0025] For use in medicine, the salts of the compounds of formula (1) will be pharmaceutically acceptable salts. Other salts may, however, be useful in the preparation of the compounds of formula (|) or their pharmaceutically acceptable salts. The standard principles underlying the selection and preparation of pharmaceutically acceptable salts are described, for example, in the Handbook of Pharmaceutical Salts: Properties, Select and Use, ed. PH Stahl & CG Wermuth, Wiley-VCH, 2002. Suitable pharmaceutically acceptable salts of the compounds of the formula (1) include acid addition salts that can, for example, be formed by mixing a solution of a compound of the formula (| ) with a solution of a pharmaceutically acceptable acid.
[0026] [0026] The present invention also includes within its scope co-crystals of the compounds of the formula (|) above. The technical term "cocrystal" is used to describe the situation where neutral molecular components are present within a crystalline compound in a defined stoichiometric ratio. The preparation of pharmaceutical crystals allows modifications to be made to the crystalline form of an active pharmaceutical ingredient, which in turn can alter its physicochemical properties without compromising its intended biological activity (see Pharmaceutical Salts and Co-cristals, ed. J. Wouters & L. Quere, RSC Publishing,
[0027] Suitable alkyl groups that may be present in the compounds for use in the invention include straight and branched C 1 alkyl groups, for example C 1-4 alkyl groups. Typical examples include methyl and ethyl groups, and straight or branched chain propyl, butyl and pentyl groups. Particular alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, 2,2-dimethylpropyl and 3-methylbutyl. Derived expressions such as "C1-6 alkoxy", "C1-6 alkyl thio", "C1-6 alkyl sulfonyl" and "C1-6 amino alkyl" should be interpreted accordingly.
[0028] [0028] Alkenyl groups which may be present in the compounds of use in the invention include straight and branched C2-7 alkenyl groups, for example C24 alkenyl groups. Typical examples include vinyl, allyl and buten-1-yl.
[0029] [0029] The term "C3a.9 cycloalkyl" as used herein refers to monovalent groups of 3 to 9 carbon atoms derived from a saturated monocyclic hydrocarbon, and may comprise analogs fused to them. Suitable C3-6 cycloalkyl groups include cyclopropyl, cyclobutyl, benzocyclobutenyl, cyclopentyl, indanyl, cyclohexyl, tetrahydronaphthalenyl, cycloheptyl, benzocycloheptenyl, cyclooctyl and cyclononanyl.
[0030] [0030] The term "C3-9 cycloalkylidenyl" as used herein refers to monovalent groups of 3 to 9 carbon atoms derived from a saturated monocyclic hydrocarbon, optionally comprising analogs fused to them, linked to the rest of the molecule via a C = C double bond. Typically, such groups include cyclobutylidenyl, cyclopentylidenyl, cyclohexylidenyl, cycloheptylidyl, cyclooctylidyl and cyclononanilidenyl.
[0031] [0031] The term "C4-9 bicycloalkyl" as used herein refers to monovalent groups of 4 to 9 carbon atoms derived from a saturated bicyclic hydrocarbon. - Typical groups - bicycloalkyl - include bicycles [1,1,1] pentanyl, bicycles [3,1,0] hexanyl, bicycles [4,1,0] heptanyl, bicycles [2,2,1] heptanyl, bicycles [2,2,2] octanyl, bicycles [3,3,0] Joctanila and bicycles [3,2,1] octanyl.
[0032] [0032] The term "C4-9 bicycloalkylidenyl" as used herein refers to monovalent groups of 4 to 9 carbon atoms derived from a saturated bicyclic hydrocarbon, linked to the rest of the molecule via a C = C double bond. such groups include bicycles [3,1,0] hexanilidenyl, bicycles [2,2,1] heptanilidenyl and bicycles [3,2,1] Joctaniliden-ila.
[0033] [0033] The term "C5-9 spirocycloalkyl" as used herein refers to saturated bicyclic ring systems containing 5 to 9 carbon atoms, where the two rings are connected by a common atom. Suitable spirocycloalkyl groups include spiro [ 2.3] hexanyl, spiro [2.4] heptanyl, spiro [3.3] heptanyl, spiro [3.4] octanyl, spiro [3.5] nonanila and spiro [4.4] nonanila.
[0034] [0034] The term "Ca-11 tricicioalkyl" as used herein refers to monovalent groups of 9 to 11 carbon atoms derived from a saturated tricyclic hydrocarbon. Typical tricycloalkyl groups include adamantanyl.
[0035] [0035] The term "aryl" as used herein refers to monovalent carbocyclic aromatic groups derived from a single aromatic ring or multiple condensed aromatic rings. Suitable aryl groups include phenyl and naphthyl, preferably phenyl.
[0036] Suitable arylalkyl (C1i.6) groups include benzyl, phenylethyl, phenylpropyl and naphthylmethyl.
[0037] [0037] The term "Ca-7 heterocycloalkyl" as used herein refers to saturated monocyclic rings containing from 3 to 7 carbon atoms and at least one heteroatom selected from oxygen, sulfur and nitrogen, and can comprise analogs fused in benzo of the same Suitable heterocycloalkyl groups include oxetanil, azetidinyl, tetrahydrofuranyl, dihydrobenzofuranyl, dihydrobenzothienyl, pyrrolidinyl, indolinyl, isoindolinyl, oxazolidinyl, thiazolidinyl, isothiazolidinyl, imidazolidinyl, pyridine, tetrahydrate, tetrahydrate, tetrahydrate, tetrahydrate 2,3,4-tetrahydro-isoquinolinyl, piperazinyl, 1,2,3 4-tetrahydroquinoxalinyl, hexahydro- [1,2,5] thiadiazolo [2,3-a] pyrazinyl, homopiperazinyl, morpholinyl, benzoxazinyl, thiomorpholinyl, azepanyl, oxazepanila, diazepanila, thiadiazepanila and azocanila.
[0038] [0038] The term "C3-7 heterocycloalkylidenyl" as used herein refers to saturated monocyclic rings containing 3 to 7 carbon atoms and at least one hetero atoms selected from oxygen, sulfur and nitrogen, linked to the rest of the molecule through a double bond C = C. Typically, such groups include tetrahydro-pyranylidenyl and piperidinylidenyl.
[0039] [0039] The term "Ca-9 heterobicycloalkyl" as used herein corresponds to Ca-9 bicycloalkyl in which one or more of the carbon atoms have been replaced by one or more heteroatoms selected from oxygen, sulfur and nitrogen. Typical heterobicycloalkyl groups include 6 -oxabicycles [3,1,0] hexanyl, 3-azabicycles [3,1,0] hexanyl, 2-0xa-5-azabicycles [2,2, N] heptanyl, 6-azabicycles [3,2,0] heptanyl , 6-oxabicycles [3,1,1] heptanyl, 3-azabicycles [3,1,1] heptanyl, 3-azabicycles [4,1,0] heptanyl, - 2-oxabicycles [2,2,2] Joctanyl, - quinuclidinyl, - 2-0x-5-azabicyclo- [2,2,2] Joctanyl, 8-oxabicyclo [3,2,1] octanyl, 3-azabicyclo [3,2,1] Joctanyl, 8-azabicyclo - [ 3.2.1] Joctanyl, 3-0xa-8-azabicyclo [3,2,1] octanila, 3,8-diazabicyclo [3,2,1] octanyl, 3,6-diazabicyclo [3,2,2] nonanila, 3-0xa-7-azabiciclo [3,3,1) nonanila, 3,7-dioxa-9-azabiciclo- [3,3,1] nonanila and 3,9-diazabiciclo [4,2,1] nonanila .
[0040] [0040] The term "heteroaryl" "as used herein refers to monovalent aromatic groups containing at least 5 atoms derived from a single ring or multiple condensed rings, where one or more carbon atoms have been replaced by one or more hetero atoms selected from oxygen, sulfur and nitrogen Suitable heteroaryl groups include furyl, benzofuryl, dibenzofuryl, thienyl, benzothienyl, thieno [2,3-c] pyrazolyl, thieno [3,4-b] [1,4] dioxinyl, dibenzothienyl, pyrrolyl groups , indolyl, pyrrolo [2,3-b] pyridinyl, pyrrolo [3,2-c] pyridinyl, pyrrolo [3,4-b] pyridinyl, pyrazolyl, pyrazolo [1,5-a] pyridinyl, pyrazole [3,4 -d] pyrimidinyl, pyrazolo [1,5-a] pyrazinyl, indazolyl, 4,5,6,7-tetrahydroindazolyl, - oxazolyl, - benzoxazolyl, - isoxazolyl, thiazolyl, benzothiazolyl, isothiazolyl, imidazolyl, benzimidazolyl, imidazo- 2 , 1-b] thiazolyl, imidazo [1,2-a] lpyridinyl, imidazo [4,5-b] pyridinyl, imidazo [1,2-b] -pyridazinyl, purinyl, imidazo [1,2-a] lpirimidinyl, imidazo [1,2-a] pir azinyl, oxadiazolyl, thiadiazolyl, triazolyl, [1,2 A] triazolo [1,5-alpyrimidinyl, benzotriazolyl, tetrazolyl, pyridinyl, quinolinyl, isoquinolinyl, naphthyridinyl, pyridazinyl, cinolinyl, phthalazinyl, quinolinyl, pyrimidinin
[0041] [0041] The term "halogen" as used herein is intended to include fluorine, chlorine, bromine and iodine atoms, typically fluorine, chlorine or bromine.
[0042] [0042] Where the compounds of formula (1) have one or more asymmetric centers, they can therefore exist as enantiomers. Where the compounds according to the invention have two or more asymmetric centers, they can additionally exist as diastereomers. The invention should be understood to extend to the use of all such enantiomers and diastereomers, and to mix them in any proportion, including racemates. Formula (1) and the formulas shown below are intended to represent all individual stereoisomers and all possible mixtures thereof, unless otherwise stated or shown. In addition, the compounds of the formula (|) can exist as tautomers, for example keto tautomers (CH2C = O) <> enol (CH = CHOH) or amide tautomers (NHC = O) & hydroxyimine (N = COH). Formula (1) and the formulas shown below are intended to represent all individual tautomers and all possible mixtures thereof, unless otherwise stated or shown.
[0043] [0043] It should be understood that each individual atom present in formula (1) or in the formulas represented below, may in fact be present “in the form of any of its naturally occurring isotopes, with the isotope (s) more abundant (s) being preferred. Thus, by way of example, each individual hydrogen atom present in formula (1) or in the formulas shown below, can be present as an * H, 2H (deuterium) or 3H (tritium) atom, preferably 1H. Similarly, by way of example, each individual carbon atom present in the formula (|) or in the formulas shown below, can be present as an atom of 12C, ºC or * C, preferably * C.
[0044] [0044] In a first embodiment, ring A represents optionally substituted C3-9 cycloalkyl. In another aspect of the embodiment, ring A represents optionally substituted C4-7 cycloalkyl.
[0045] [0045] In a second embodiment, ring A represents optionally substituted heterocycle-Ca-7 alkyl. In another aspect of the embodiment, ring A represents optionally substituted heterocycloalkyl Ca.
[0046] [0046] In a third embodiment, ring A represents optionally substituted heterobicycloalkyl Ca-s. In another aspect of the embodiment, ring A represents optionally substituted Cs-7 heterobicycloalkyl.
[0047] [0047] Typically, ring A represents cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononanyl, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, isothiazolidinyl, pyridine, pyridine, pyridine, pyridine, , morpholinyl, thiomorpholinyl, azepanyl, oxazepanyl, diazepanyl, thiadiazepanyl, azocanil, - 6-oxa-bicycles [3,1,0] hexanyl, - 6-oxabicycles [3,1,1] heptanyl or 8 oxabicycles [3,2, 1] octanyl, either group can be optionally substituted by one or more substituents.
[0048] [0048] Appropriately, ring A represents pyrrolidinyl, tetrahydropyranyl, tetrahydrothio-pyranyl or piperidinyl, either group can be optionally substituted by one or more substituents.
[0049] [0049] Suitably, ring A represents tetrahydropyranyl, tetrahydrothiopyranyl or piperidinyl, either group can be optionally substituted by one or more substituents.
[0050] [0050] In a particular embodiment, ring A represents tetrahydropyranyl, a group which can be optionally substituted by one or more substituents.
[0051] [0051] Typical examples of optional substituents on ring A include one, two or three substituents independently selected from C1-6 alkyl, halogen, cyano, trifluoro-methyl, hydroxy, oxo, C1-6 alkoxy, C1-6 alkyl uncle, C1-.6 sulfinyl alkyl, C1-6 sulfonyl alkyl, C2-6 carbonyl alkyl, amino, imino, amino C1-6 alkyl and (C1-6) amino dialkyl.
[0052] [0052] Suitable examples of optional substituents on ring A include one, two or three substituents independently selected from C16, 0x0 and imino alkyl.
[0053] [0053] Typical examples of particular substituents on ring A include one,
[0054] [0054] Suitable examples of particular substituents on ring A include one, two or three substituents independently selected from methyl, oxo and imino.
[0055] [0055] Selected values of ring A include pyrrolidinyl, tetrahydropyranyl, (methyl) -tetrahydropyranyl, tetrahydrothiopyranyl, (oxo) tetrahydrothiopyranyl, (dioxo) tetrahydrothiopyranyl, (imino) (oxo) tetrahydrohydropyranyl and petra.
[0056] [0056] Typical values for ring A include tetrahydropyranyl, tetrahydrothiopyranyl and piperidinyl.
[0057] [0057] A particular value of ring A is tetrahydropyranyl.
[0058] [0058] In one embodiment, B represents C-R2. In another modality, B represents N.
[0059] [0059] In one modality, D represents C-R $ à. In another modality, D represents N.
[0060] [0060] In one mode, E represents C-R *. In another mode, E represents N.
[0061] [0061] In a first modality, B represents C-R , D represents C-Rº and E represents C-Rº,
[0062] [0062] In a second modality, B represents C-R , D represents C-Rº and E represents N.
[0063] [0063] In a third modality, B represents C-R , D represents N and E represents C-Rº.
[0064] [0064] In a fourth modality, B represents C-R , D represents N and E represents N.
[0065] [0065] In a fifth modality, B represents N, D represents C-Rº and E represents C-Rº.
[0066] [0066] In a sixth modality, B represents N, D represents C-Rº and E represents N.
[0067] [0067] In a seventh modality, B represents N, D represents N and E represents
[0068] [0068] In an eighth modality, B represents N, D represents N and E represents N.
[0069] [0069] Suitably, the present invention provides a compound of formulas (1-1), (1-2), (1-3), (1-4) or (1-5) or a pharmaceutically acceptable salt thereof: O x À
[0070] [0070] emA, Rº%, R ', R , Rº and Rº are as defined above.
[0071] [0071] In a first modality, Rº represents hydrogen. In a second embodiment, Rº represents C1-6 alkyl, especially methyl.
[0072] [0072] Suitably, Rº represents hydrogen or methyl.
[0073] [0073] Typical examples of optional substituents on R ' include one, two or three substituents independently selected from C1 + 6 alkyl, halogen, cyano, trifluoro-methyl, hydroxy, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkyl, sulfinyl alkyl, C1- + alkyl sulfonyl, Ca2 alkyl -6 carbonyl, amino, C1-6 alkyl amino and dialkyl (C1-6) amino.
[0074] [0074] Typical examples of particular substituents on R 'include one, two or three substituents independently selected from methyl, fluorine, chlorine, bromine, cyano, trifluoro-methyl, hydroxy, oxo, methoxy, methylthio, methylsulfinyl, methylsulfonyl, acetyl, amino, methylamino and dimethylamino.
[0075] [0075] Suitably, R 'represents -CORº.
[0076] [0076] Typically, R represents hydrogen or halogen.
[0077] [0077] In a first modality, R represents hydrogen. In a second modality, R represents halogen. In a first aspect of the sport, R represents fluorine. In a second aspect of the modality, R represents chlorine. In a third modality, R represents cyan. In a fourth modality, R represents C1.6 alkyl, especially methyl. In a fifth modality, R represents fluoromethyl. In a sixth mode, R represents difluoromethyl. In a seventh modality, R represents trifluoromethyl. In an eighth modality, R represents hydroxy In a ninth modality, R represents C1s alkoxy, especially methoxy. In a tenth modality, R represents difluoromethoxy. In an eleventh mode, R represents trifluoromethoxy. In a twelfth mode, R represents C1- + 6 sulfinyl alkyl, especially methylsulfinyl. In a thirteenth modality, R represents C 1-6 alkyl sulfonyl, especially methylsulfonyl.
[0078] [0078] Appropriately, R represents hydrogen or fluorine.
[0079] [0079] Typically, R represents hydrogen or halogen.
[0080] [0080] In a first modality, Rº represents hydrogen. In a second modality, R $ represents halogen. In a first aspect of the modality, Rº represents fluorine. In a second aspect of the modality, Rº represents chlorine. In a third modality, Rº represents cyan. In a fourth modality, Rº represents C1.6 alkyl, especially methyl. In a fifth modality, Rº represents fluoromethyl. In a sixth modality, Rº represents difluoromethyl. In a seventh modality, R represents trifluoromethyl. In an eighth modality, Rº represents hydroxy In a ninth modality, Rº represents C1s alkoxy, especially methoxy. In a tenth modality, Rº represents difluoromethoxy. In an eleventh modality, R $ represents trifluoromethoxy. In a twelfth modality, Rº represents C1-6 alkyl sulfinyl, especially methylsulfinyl. In a thirteenth modality, R $ represents C1-6 alkyl sulfonyl, especially methylsulfonyl.
[0081] [0081] Appropriately, R3 represents hydrogen, fluorine or chlorine.
[0082] [0082] Suitably, Rº represents hydrogen or fluorine.
[0083] [0083] In a first modality, Rº represents hydrogen. In a second modality, Rº represents halogen. In a first aspect of the modality, Rº represents fluorine. In a second aspect of the modality, Rº represents chlorine. In a third modality, Rº represents cyan. In a fourth modality, Rº represents C1.6 alkyl, especially methyl. In a fifth modality, Rº represents fluoromethyl. In a sixth modality, Rº represents difluoromethyl. In a seventh modality, Rº represents trifluoromethyl. In an eighth modality, Rº represents hydroxy In a ninth modality, Rº represents C1s alkoxy, especially methoxy. In a tenth modality, Rº represents difluoromethoxy. In an eleventh modality, Rº represents trifluoromethoxy. In a twelfth modality, Rº represents C1- + 6 sulfinyl alkyl, especially methylsulfinyl. In a thirteenth modality, Rº represents C1i.6 sulfonyl alkyl, especially methylsulfonyl.
[0084] [0084] Generally, Rº represents hydrogen; or Rº represents C1 + 6 alkyl, C3-9 cycloalkyl, C3-9 cycloalkyl (C1- + 6) alkyl, C3-9 cycloalkylidenyl (C1-6) alkyl, Ca-s alkyl bicycloalkyl (C1-6), Cs5- spirocycloalkyl 9 (C1-6) alkyl, Ca-11 tricycloalkyl (C1) alkyl, aryl, arylalkyl (C1-6), C3-7 heterocycloalkyl, C3a-7 heterocycloalkyl (C1-6) alkyl, C3-7 heterocycloalkyl (C1 +) 6), heteroaryl or heteroarylalkyl (C1 + 6), any of the groups can be optionally substituted by one or more substituents.
[0085] [0085] Typically, Rº represents C1- + alkyl, C3-9 cycloalkyl, C3-9 cycloalkyl (C16), C3a9 cycloalkylidenyl (C1-.6), bicycloalkyl Cas alkyl (C16), C5-9 spirocycloalkyl ( C1-6), tricycloalkyl Ca-11 alkyl (C1- + 6), aryl, arylalkyl (C1- + 6), heterocycloalkyl - Ca7, heterocycloalkyl C37 —alkyl (Ci), heterocycloalkylidenyl (C1-6 alkyl) ), heteroaryl or heteroaryl-alkyl (C1-6), any of the groups can be optionally substituted by one or more substituents.
[0086] [0086] Suitably, Rº represents C1-6 alkyl, C3-9 cycloalkyl (C1-6) alkyl, Cs5-9 spirocycloalkyl (C1-6) alkyl or arylalkyl (C1-6), any of the groups can be optionally substituted by one or more substituents.
[0087] [0087] In a particular mode, Rº is other than hydrogen.
[0088] [0088] Typical values for Rº include methyl, ethyl, 2-methylpropyl, 2-methylbutyl, 3-methylbutyl, cyclopropylmethyl, cyclopentylmethyl, indanylmethyl, cyclohexylmethyl, cyclohexylethyl, cyclooctylmethyl, cyclopentylidylmethyl, cyclohexylidyl, cyclohexylidyl , 3] heptanylmethyl, adamantanylmethyl, adamantanylethyl, phenyl, benzyl, phenylethyl, phenylpropyl, naphthylmethyl, naphthylethyl, tetrahydropyranylidenylmethyl, - thienylmethyl, = thienylethyl, - indolylmethyl, - an indolylethyl, pyridinyl, pyridinyl and pyridinyl one or more substituents.
[0089] [0089] Suitable values for Rº include methyl, cyclohexylmethyl, cyclooctylmethyl, spiro [3.3] heptanylmethyl and phenylethyl, either group can be optionally substituted by one or more substituents.
[0090] [0090] Typical examples of optional substituents in Rº include one, two or three substituents independently selected from halogen, cyano, nitro, C1-6 alkyl, trifluoro-methyl, phenyl, hydroxy, oxo, C1-6 alkoxy, difluoromethoxy, trifluoromethoxy , C1-6 alkyl thio, C1-6 alkyl sulfinyl, C1-6 alkyl sulfonyl, amino, C1-6 alkyl amino, dialkyl (C1-s6) amino, C2-6 alkyl carbonylamino, (C1 + 6) heteroarylcarbonylamino, heteroarylalkyl (C1-6) carbonylamino, aminoheteroarylalkyl (C1i-6) carbonylamino, Ca6 carbonyl-amino alkoxy, C1-6 sulfonylamino alkyl, formyl, Ca-.6 alkyl carbonyl, carboxy, Cas alkyl carbonyl, aminocarbonyl, C1-6 alkyl aminocarbonyl, dialkyl (C1-6) aminocarbonyl, aminocarbonyl-amino, C1-6 alkyl aminocarbonylamino, dialkyl
[0091] [0091] Suitable examples of optional substituents in Rº include one, two or three substituents independently selected from halogen, cyano, C1-6 alkyl, trifluoromethyl, phenyl, hydroxy, C1-6 alkoxy, amino, C2-6 carbonylamino alkyl, alkyl (C1-6) heteroaryl-carbonylamino, heteroarylalkyl (C16) carbonylamino, aminoheteroarylalkyl (C1-6) carbonyl-amino and aminocarbonyl.
[0092] [0092] Suitable examples of optional substituents on Rº include one, two or three substituents independently selected from halogen, amino, C2-6 alkylcarbonylamino, (C1) heteroarylcarbonylamino, heteroaryl (C1-6) carbonylamino and aminoheteroarylalkyl (C1-6) alkyl ) carbonylamino.
[0093] [0093] Favored examples of optional substituents in Rº include one, two or three substituents independently selected from halogen, cyano, nitro, C1-6 alkyl, trifluoro-methyl, trifluoroethyl, phenyl, hydroxy, oxo, C1 + alkoxy, difluoromethoxy, trifluoro -methoxy, C1-6 alkylthio, C1-6 alkyl sulfinyl, C1-6 alkyl sulfonyl, amino, C1-6 alkyl amino, dialkyl (C1-6) amino, C2-6 carbonylamino alkyl, C2-6 carbonylamino alkoxy, C1 alkyl -6-sulfonylamino, formyl, C2-6 alkyl, carbonyl, carboxy, C2.6 alkoxy, carbonyl, aminocarbonyl, C1-6 alkyl aminocarbonyl, dialguyl (Cis) aminocarbonyl, aminosulfonyl, C1-6 alkyl amino-sulfonyl, dialkyl (C1-6) aminosulfonyl , -R5, - NHCORS, NHS (O) 2Rº, -R , -NHR and -CONHR ”, in which R% º, Rº and R are as defined below.
[0094] [0094] Selected examples of optional substituents on Rº include one, two or three substituents independently selected from halogen, C1-6 alkyl, trifluoromethyl, trifluoro-ethyl, phenyl, C1-6 alkoxy, -Rºº, -NHCORS, NHS (O ) R $, -R7, -NHR and -CONHR ”, in which R5º, Rº and R are as defined below.
[0095] [0095] Typical examples of specific substituents in the R º include one, two or three substituents independently selected from fluorine, chlorine, bromine, cyano, nitro, methyl, ethyl, isopropyl, tert-butyl, trifluoromethyl, phenyl, hydroxy, oxo , methoxy, tert-butoxy, difluoromethoxy, trifluoromethoxy, methylthio, methylsulfinyl, methylsulfonyl, amino, methylamino, tert-butylamino, dimethylamino, acetylamino, methylpyrazolylcarbonyl-amino,
[0096] [0096] Suitable examples of specific substituents in Rº include one, two or three substituents independently selected from fluorine, chlorine, bromine, cyano, methyl, trifluoromethyl, phenyl, hydroxy, methoxy, tert-butoxy, amino, acetylamino, methyl-pyrazolylcarbonyl -amino, pyridinylmethylcarbonylamino, aminopyridinylmethylcarbonylamino and aminocarbonyl.
[0097] [0097] Suitable examples of specific substituents in R ° include one, two or three substituents independently selected from chlorine, amino, acetylamino, methylpyrazolylcarbonylamino, pyridinylmethylcarbonylamino and aminopyridinylmethylcarbonylamino.
[0098] [0098] Favored examples of specific substituents in Rº include one, two or three substituents independently selected from fluorine, chlorine, bromine, cyano, nitro, methyl, ethyl, isopropyl, tert-butyl, trifluoromethyl, trifluoroethyl, phenyl, hydroxy, oxo , methoxy, isopropoxy, tert-butoxy, difluoromethoxy, trifluoromethoxy, methylthio, methylsulfinyl, methylsulfonyl, amino, methylamino, tert-butylamino, dimethylamino, acetylamino, methoxycarbonylamino, methylsulfonylaminooxycarbonyl, methoxycarbonyl, acetylcarbonate, formyl , aminocarbonyl, methylamino-carbonyl, dimethylaminocarbonyl, aminosulfonyl, methylamino-sulfonyl, dimethylamino-sulfonyl, -R% º, -NHCORS, NHS (O) 2R6, -R , -NHR and -CONHR ”, where Rºº, Ré and R are as defined below.
[0099] [0099] Selected examples of specific substituents in the R ° include one, two or three substituents independently selected from fluorine, chlorine, bromine, methyl, trifluoro-methyl, trifluoroethyl, phenyl, isopropoxy, tert-butoxy, -Rº, -NHCORS, NHS (O) 2R $, -R7, -NHR7 and -CONHR ”, in which Rº, Rº and R are as defined below.
[0100] [0100] Illustrative values for Rº include methyl, methylpyrazolylcarbonylaminomethyl, ethyl, 2-methylpropyl, 2-methylbutyl, 3-methylbutyl,
[0101] [0101] Representative values for Rº include methylpyrazolylcarbonylaminomethyl, (cyclohexyl) (pyridinylmethylcarbonylamino) methyl, (amino) (cyclooctyl)] methyl, (acetylamino) (cyclooctyl) -methyl, (cyclooctyl) (methylpyrololylcarbonylamino) methyl, (pyridinylmethylcarbonylamino) -methyl, (aminopyridinylmethylcarbonyl-amino) (cyclooctyl)] methyl, (methylpyrazolylcarbonylamino) (spiro [3.3] heptanyl)] methyl and (chlorine) (pyridinylmethylcarbonylamino) phenylethyl.
[0102] [0102] Rº generally represents C1-6 alkyl, C3-9 cycloalkyl, C3-9 cycloalkyl (C1 + 6) alkyl, C3-9 cycloalkylidenyl (C1-6) alkyl, Ca-s alkyl bicycloalkyl (C1- + 6) , spirocycloalkyl Cs-9 alkyl (C1-6), tricycloalkyl Co-11 alkyl (C1- + 6), aryl, arylalkyl (C16), - heterocycloalkyl - C37, - Heterocycloalkyl —C3a7 alkyl (Cs), heterocycloalkylidenidenyl 7 (C1-6) alkyl, heteroaryl or heteroaryl-alkyl (C1-6), any of the groups may be optionally substituted by one or more substituents.
[0103] [0103] Suitably, Rº represents C1-6 alkyl, C3-9 cycloalkyl (C16) alkyl, Cs5-s-spirocycloalkyl (C1-6) or arylalkyl (C1-6), any of the groups can be optionally substituted by one or more substituents.
[0104] [0104] Typical values for Rº include methyl, ethyl, 2-methylpropyl, 2-methylbutyl,
[0105] [0105] Suitable values for Rº include methyl, cyclohexylmethyl, cyclooctylmethyl, spiro [3.3] heptanylmethyl and phenylethyl, either group can be optionally substituted by one or more substituents.
[0106] [0106] Typical examples of optional substituents in Rº include one, two or three substituents independently selected from halogen, cyano, nitro, C1-6 alkyl, trifluoro-methyl, phenyl, hydroxy, oxo, C1-6 alkoxy, difluoromethoxy, trifluoromethoxy , C1-6 alkyl thio, C1-6 sulfinyl alkyl, C1-6 sulfonyl alkyl, amino, C1-6 alkyl amino, dialkyl (C1-6) amino, C2-6 carbonylamino alkyl, (C1-6) heteroarylcarbonylamino, heteroarylalkyl (C1-6) carbonylamino, aminoheteroarylalkyl (C1-6) carbonylamino, Ca6 carbonyl-amino alkoxy, C1-6 alkyl sulfonylamino, formyl, Ca-.6 carbonyl, carboxy, Cas alkyl, carbonyl, aminocarbonyl, C1-6 aminocarbonyl alkyl, dialkyl (C1-6) aminocarbonyl, aminocarbonyl-amino, C1-6 alkyl aminocarbonylamino, dialkyl (C1-6) aminocarbonylamino, aminosulfonyl, C1-6 alkyl aminosulfonyl and dialkyl (C1- 6) aminosulfonyl.
[0107] [0107] Suitable examples of optional substituents on Rb include one, two or three substituents independently selected from halogen, cyano, C1-6 alkyl, trifluoromethyl, phenyl, hydroxy, C1-6 alkoxy, amino, C2-6 carbonylamino alkyl, alkyl (C1-6) heteroaryl-carbonylamino, heteroarylalkyl (C1-6) carbonylamino, aminoheteroarylalkyl (C1-6) carbonyl-amino and aminocarbonyl.
[0108] [0108] Suitable examples of optional substituents on Rb include one, two or three substituents independently selected from halogen, amino, C2-6 alkylcarbonylamino, (C1-6) heteroarylcarbonylamino, heteroarylalkyl (C1-6) carbonylamino and aminoheteroarylalkyl (C1 -6) carbonylamino.
[0109] [0109] Favored examples of optional substituents on Rb include one, two or three substituents independently selected from halogen, cyano, nitro, C1-6 alkyl, trifluoro-methyl, trifluoroethyl, phenyl, hydroxy, oxo, C1-6 alkoxy, difluoromethoxy , trifluoro-methoxy, C1-6 alkyl thio, C1-6 sulfinyl alkyl, C1-6 sulfonyl alkyl, amino, C1-6 alkyl amino, dialguyl (C1-6) amino, C2-6 carbonylamino alkyl, C2-6 carbonylamino alkoxy , C1-6 alkyl sulfonylamino, formyl, C2-6 alkyl carbonyl, carboxy, C2-6 alkoxy carbonyl, aminocarbonyl, C1-6 aminocarbonyl alkyl, dialkyl (C1-6) aminocarbonyl, aminosulfonyl, C1-6 amino-sulfonyl alkyl, dialkyl (C1-6) aminosulfonyl, -R5a, -NHCOR6, NHS (0) 2R6, -R7, -NHR7 and -CONHR7, where R5a, R6 and R7 are as defined below.
[0110] [0110] Selected examples of optional substituents on Rb include one, two or three substituents independently selected from halogen, C1-6 alkyl, trifluoromethyl, trifluoro-ethyl, phenyl, C1-6 alkoxy, -R5a, -NHCOR6, NHS (0 ) 2R6, -R7, -NHR7 and -CONHR7, where R5a, R6 and R7 are as defined below.
[0111] [0111] Typical examples of specific substituents on Rb include one, two or three substituents independently selected from fluorine, chlorine, bromine, cyano, nitro, methyl, ethyl, isopropyl, tert-butyl, trifluoromethyl, phenyl, hydroxy, oxo, methoxy , tert-butoxy, difluoromethoxy, trifluoromethoxy, methylthio, methylsulfinyl, methylsulfonyl, amino, methylamino, tert-butylamino, dimethylamino, acetylamino, methylpyrazolylcarbonyl-amino, pyridinylmethylcarbonyl-amino, aminopyrylamino, aminopyridinyl, aminopyridyl , ethoxycarbonyl, tert-butoxycarbonyl, - aminocarbonyl, - methylaminocarbonyl, - dimethyl-aminocarbonyl, aminocarbonylamino, methylaminocarbonylamino, dimethylamino-carbonylamino, aminosulfonyl, methylaminosulfonyl and dimethylaminosulfonyl.
[0112] [0112] Suitable examples of specific substituents on Rb include one, two or three substituents independently selected from fluorine, chlorine, bromine, cyano, methyl, trifluoromethyl, phenyl, hydroxy, methoxy, tert-butoxy, amino, acetylamino, methyl-pyrazolylcarbonyl -amino, pyridinylmethylcarbonylamino, aminopyridinylmethylcarbonylamino and aminocarbonyl.
[0113] [0113] Suitable examples of specific substituents on Rb include one,
[0114] [0114] Favored examples of specific substituents on Rb include one, two or three substituents independently selected from fluorine, chlorine, bromine, cyano, nitro, methyl, ethyl, isopropyl, tert-butyl, trifluoromethyl, trifluoroethyl, phenyl, hydroxy, oxo , methoxy, isopropoxy, tert-butoxy, difluoromethoxy, trifluoromethoxy, methylthio, methylsulfinyl, methylsulfonyl, amino, methylamino, tert-butylamino, dimethylamino, acetylamino, methoxycarbonylamino, methylsulfonylamino, carboxymethyl, carbonyl, methylcarbonate, acetyl , aminocarbonyl, methylamino-carbonyl, dimethylaminocarbonyl, aminosulfonyl, methylaminosulfonyl, dimethylamino-sulfonyl, -R5a, -NHCOR6, NHS (O0) 2R6, -R7, -NHR7 and -CONHR7, where R5a are defined as R6 and R7.
[0115] [0115] Selected examples of specific substituents in Rb include one, two or three substituents independently selected from fluorine, chlorine, bromine, methyl, trifluoromethyl, trifluoroethyl, phenyl, isopropoxy, tert-butoxy, -R5a, -NHCORG6, NHS (O ) 2R6, -R7, -NHR7 and -CONHR7, where R5a, R6 and R7 are as defined below.
[0116] [0116] Illustrative values for Rb include methyl, methylpyrazolylcarbonylaminomethyl, ethyl, 2-methylpropyl, 2-methylbutyl, 3-methylbutyl, cyclopropylmethyl, cyclopentyl-methyl, indanylmethyl, cyclohexylmethyl, (cyclohexyl), cyclohexylmethyl, (cyclohexyl) methyl (amino) (cyclooctyl)] methyl, (acetylamino) - (cyclooctyl)] methyl, (cyclooctyl) (methylpyrazolylcarbonyl-amino) methyl, (cyclooctyl) - (pyridinylmethylcarbonylamino) methyl, (aminopyridinylmethylcarbonyl-amino) - ((cyclooctyl) methyl, methylpyrazolylcarbonylamino) (spiro [3.3] heptanyl) methyl, phenyl, chlorophenyl, benzyl, fluorobenzyl, chlorobenzyl, phenylethyl, fluorophenylethyl, chlorophenylethyl, (chlorine) phenylethyl, dichlorophenylethyl, dichlorophenylethyl, bromophenylethyl, bromophenylethyl , biphenylethyl, hydroxyphenylethyl, methoxyphenylethyl, tert-butoxyphenylethyl, (chlorine) (pyridinylmethylcarbonylamino) phenylethyl, aminocarbonylphenylethyl, phenylpropyl, chloro-
[0117] [0117] Representative Rb values include methylpyrazolylcarbonylaminomethyl, (cyclohexyl) (pyridinylmethylcarbonylamino) methyl, (amino) (cyclooctyl)] methyl, (acetylamino) (cyclooctyl) -methyl, (cyclooctyl) (methylpyrazolylcarbonylamino) methyl, (pyridinylmethylcarbonylamino) - methyl, (aminopyridinylmethylcarbonyl-amino) (cyclooctyl) methyl, (methylpyrazolylcarbonylamino) (spiro [3.3] heptanyl) methyl and (chlorine) (pyridinylmethylcarbonylamino) phenylethyl.
[0118] [0118] A particular subclass of compounds according to the invention is represented by the compounds of the formula (IA), and pharmaceutically acceptable salts thereof: Sp o n & LA, À de R dh É o (IA)
[0119] [0119] where
[0120] [0120] A, B, D, E and Rº are as defined above;
[0121] [0121] R $ represents hydrogen; or Rº represents C1-5 alkyl, C3-9 cycloalkyl, (C1-s) cycloalkyl, Cas bicycloalkyl, Cas bicycloalkyl (C1is), Cs-9 spirocycloalkyl, Cs-9 spirocycloalkyl (C1-s), tricicioalkyl Cen, tricycloalkyl Ca-11 (C1-5) alkyl, aryl, aryl-alkyl (Ci), heterocycloalkyl Ca-7, heterocycloalkyl C3-7 alkyl (C1-5), heteroaryl or heteroaryl (C1-5), any of the groups can optionally be substituted by one or more substituents;
[0122] [0122] R $ represents -NR $ ºRº * or -OR $ º; or R $ represents C1-9 alkyl, C3-9 cycloalkyl, C3-9 cycloalkyl (Ci), aryl, arylalkyl (Ci), C3a-7 heterocycloalkyl, C3-7 heterocycloalkyl (Cis), heteroaryl, heteroarylalkyl (C1- 6) or spiro [heterocycloalkyl (C3-7)] [heteroaryl], either group can be optionally substituted by one or more substituents;
[0123] [0123] R $ º represents hydrogen; or R $ º represents C1-6 alkyl, C3-7 cycloalkyl, C3-7 cycloalkylalkyl (C1-.6), aryl, arylalkyl (Ci), heterocycloalkyl Ca, heterocycloalkyl C37 alkyl (Cis), heteroaryl, heteroarylalkyl (C1i -6) or spiro [heterocycloalkyl (C37)] [heteroaryl, any of the groups can be optionally substituted by one or more substituents;
[0124] [0124] R $ represents hydrogen or C1-6 alkyl; and
[0125] [0125] R $ º represents C1-6 alkyl, C3-7 cycloalkyl, Ca-7 cycloalkyl (C1-6) alkyl, aryl, arylalkyl (C1-.6), Ca-7 heterocycloalkyl, C3a7 (C16) heterocycloalkyl, heteroaryl or heteroaryl (C1-6) alkyl, any of the groups can be optionally substituted by one or more substituents.
[0126] [0126] A second subclass of compounds according to the invention is represented by the compounds of the formula (IB), and pharmaceutically acceptable salts thereof: So un & x À A S go TEA H R (IB)
[0127] [0127] where
[0128] [0128] A B, D, E, Rº, RºeRS are as defined above.
[0129] [0129] A third subclass of compounds according to the invention is represented by the compounds of the formula (IC), and pharmaceutically acceptable salts thereof:
[0130] [0130] where
[0131] [0131] A, B, D, E, R and Rº are as defined above; and
[0132] [0132] R ”represents heteroaryl or spiro arylay [heterocycloalkyl (Ca 7) | [heteroaryl], any of the groups can be optionally substituted by one or more substituents.
[0133] [0133] A fourth subclass of compounds according to the invention is represented by the compounds of the formula (ID), and pharmaceutically acceptable salts thereof:
[0134] [0134] where
[0135] [0135] A B, D, E, Rº RºeR ”are as defined above.
[0136] [0136] A fifth subclass of compounds according to the invention is represented by the compounds of the formula (IE), and pharmaceutically acceptable salts thereof:
[0137] [0137] where
[0138] [0138] A, B, D, E, Rº, Rº and R7 are as defined above.
[0139] [0139] A sixth subclass of compounds according to the invention is represented by the compounds of the formula (SE), and pharmaceutically acceptable salts thereof: Pes o H Oo: | À | 6 AA, from Y R Ns RR O (IF)
[0140] [0140] where
[0141] [0141] AB, D, E, RºeR $ º are as defined above;
[0142] [0142] R5º represents C3-7 cycloalkyl, Cas bicycloalkyl, aryl, C3-7 heterocycloalkyl or heteroaryl, either group can be optionally substituted by one or more substituents; and
[0143] [0143] Rºº represents hydrogen or C1-6 alkyl; or
[0144] [0144] R% ºeR ”*, when taken together with the carbon atom to which they are both attached, represent C37 cycloalkyl, Cas bicycloalkyl or C3-7 heterocycloalkyl, either group can be optionally substituted by one or more substituents.
[0145] [0145] Generally, Rº represents hydrogen; or Rº represents C1-5 alkyl,
[0146] [0146] Favorably, Rº represents hydrogen; or Rº represents C1-5 alkyl, C3-9 cycloalkyl, C3- cycloalkyl + (C1-5) alkyl, Cas bicycloalkyl, Ca-s bicycloalkyl (C1-5) alkyl, Cs-9 spiro-cycloalkyl, Ca-11 tricycloalkyl, tricycloalkyl Ca-11 alkyl (C1-5), aryl, arylalkyl (C1-5), heterocycloalkyl C3-7, heterocycloalkyl C3-7 alkyl (C1-5) or heteroarylalkyl (C1-5), either group can be optionally replaced by one or more substituents.
[0147] [0147] Typically, Rº represents C1-5 alkyl, C3.9 cycloalkyl, Ca-s cycloalkyl (C1-s) alkyl, Ca-9 bicycloalkyl, Cs-9 spirocycloalkyl, Cs5-9 spirocycloalkyl (C1-5) alkyl, tricycloalkyl Ca-11, tricicioalkyl Ca-11 (C1-5) alkyl, aryl, arylalkyl (C1-5), C3-7 heterocycloalkyl, Ca7 heterocyclo-alkyl (C1i + s), heteroaryl or heteroaryl (C1-5), either group can be optionally substituted by one or more substituents. Additionally, Rº can represent bicycloalkyl Ca-s alkyl (C1-5), a group that can be optionally substituted by one or more substituents.
[0148] [0148] Appropriately, R $ represents hydrogen; or R $ represents C1-5 alkyl, C3-9 cycloalkyl, C3-9 cycloalkyl (C1-5) alkyl, Ca-s bicycloalkyl, Cs-9 spirocycloalkyl, Cs-9 spirocycloalkyl (C1-5) alkyl, Cga-11 tricycloalkyl a, trichicioalkyl Ca-11 alkyl (C1 + 5), aryl, arylalkyl (C1-5) or heteroaryl-alkyl (C1-5), any of the groups can be optionally substituted by one or more substituents.
[0149] [0149] Appropriately, Rº represents hydrogen; or R5 represents C3-9 cycloalkyl, C5-9 spiro-cycloalkyl or arylalkyl (C1-5), any of the groups may be optionally substituted by one or more substituents.
[0150] [0150] In a first modality, Rº represents hydrogen. In a second embodiment, R5 represents optionally substituted C1-5 alkyl. In a third embodiment, Rº represents optionally substituted Ca-9 cycloalkyl. In a fourth embodiment, Rº represents C3.9 cycloalkyl (C1 + 5) alkyl optionally substituted. In a fifth modality, Rº represents optionally substituted bicycloalkyl Cao. In a sixth embodiment, Rº represents bicycloalkyl Ca-9 (C1-5) alkyl optionally - substituted. In a seventh modality, Rº represents optionally substituted C5-9 spirocycloalkyl. In an eighth modality, Rº represents spirocycloalkyl Cs5-9 alkyl (C1-5) optionally substituted. In a ninth modality, Rº represents optionally substituted Ca-11 tricycloalkyl. In a tenth modality, Rº represents optionally substituted Co11 alkyl (C1is5s) tricycloalkyl. In an eleventh modality, Rº represents optionally substituted aryl. In a twelfth modality, Rº represents optionally substituted arylalkyl (C1-5). In a thirteenth modality, Rº represents optionally substituted C3-7 heterocycloalkyl. In a fourteenth modality, Rº represents optionally substituted C3.7 heterocycloalkyl (C1-5) alkyl. In a fifteenth modality, Rº represents optionally substituted heteroaryl. In a sixteenth modality, Rº represents optionally substituted heteroarylalkyl (C1-5).
[0151] [0151] In a particular modality, Rº is other than hydrogen.
[0152] [0152] Typical values for Rº include methyl, isopropyl, 1-methylpropyl, 2-methylpropyl, cyclopropyl, cyclopentyl, indanyl, cyclohexyl, cyclooctyl, cyclohexylmethyl, spiro [3.3] -heptanil, spiro [3.3] heptanylmethyl, adamantanyl, adamantanylmethyl, phenyl, benzyl, phenylethyl, naphthylmethyl, thienyl, indolyl, pyridinyl, thienylmethyl, indolylmethyl and pyridinylmethyl, any of the groups may be optionally substituted by one or more substitutes. Additional values include cyclobutyl, benzocyclobutenyl, tetrahydronaphthalenyl, cycloheptyl, benzocycloheptenyl, cyclononanyl, cyclobutylmethyl, cyclobutylethyl, bicyclo [3,1,0] hexanyl, bicyclo [2,2,1] heptanyl, bicyclo [3,3,0] octanyl, bicycles [3,2,1] octanyl, bicycles [1,1,1] pentanylmethyl, phenylpropyl, tetrahydropyranyl, azocanyl, dihydrobenzofuranylmethyl and pyrrolylethyl, any of the groups can be optionally substituted by one or more substituents.
[0153] [0153] The selected values of Rº include cyclobutyl methyl, benzocyclobutenyl, cyclopentyl, indanyl, cyclohexyl, tetrahydronaphthalenyl, cycloheptyl,
[0154] [0154] Suitable values for Rº include cyclohexyl, cyclooctyl, spiro [3.3] heptanyl and benzyl, either group can be optionally substituted by one or more substituents.
[0155] [0155] Typical examples of optional substituents in Rº include one, two or three substituents independently selected from halogen, cyano, nitro, C1 + alkyl, trifluoro-methyl, phenyl, hydroxy, oxo, C1-6 alkoxy, difluoromethoxy, trifluoromethoxy, alkyl C1-6 uncle, C1-6 sulfinyl alkyl, C1-6 sulfonyl alkyl, amino, C1-6 alkyl amino, dialkyl (C1-6) amino, C2-6 carbonylamino alkyl, C2-6 carbonylamino alkoxy, C1-6 sulfonylamino alkyl , formyl, C2.6 alkyl carbonyl, carboxy, C26 alkoxy carbonyl, aminocarbonyl, C1i6 alkyl amino-carbonyl, dialkyl (Cis) aminocarbonyl, aminosulfonyl, C1-6 alkyl aminosulfonyl and dialkyl (C1-6) aminosulfonyl. Additional examples include trifluoroethyl.
[0156] [0156] Suitable examples of optional substituents in Rº include one, two or three substituents independently selected from halogen, cyano, C1-6 alkyl, trifluoromethyl, phenyl, hydroxy, C1-6 alkoxy and aminocarbonyl, especially halogen.
[0157] [0157] Favored examples of optional substituents in Rº include one, two or three substituents independently selected from halogen, C1-6 alkyl, trifluoromethyl, phenyl and C1-6 alkoxy, especially halogen.
[0158] [0158] Typical examples of specific substituents in Rº include one, two or three substituents independently selected from fluorine, chlorine, bromine, cyano, nitro, methyl, ethyl, isopropyl, tert-butyl, trifluoromethyl, phenyl, hydroxy, oxo, methoxy , tert-butoxy, difluoromethoxy, trifluoromethoxy, methylthio, methylsulfinyl, methylsulfonyl, amino, methylamino, - tert-butylamino, - dimethylamino, - acetylamino, - methoxycarbonylamino, methylsulfonylamino, formyl, acetyl, carboxycarbonate, tertiarycarbonate, carboxycarbonate, methoxy, carboxycarbonate, methoxy
[0159] [0159] Suitable examples of specific substituents in Rº include one, two or three substituents independently selected from fluorine, chlorine, bromine, cyano, methyl, trifluoro-methyl, phenyl, hydroxy, methoxy, tert-butoxy and aminocarbonyl, especially chlorine. Additional examples include isopropoxy.
[0160] [0160] Favored examples of specific substituents in Rº include one, two or three substituents independently selected from fluorine, chlorine, bromine, methyl, trifluoromethyl, phenyl, isopropoxy and tert-butoxy, especially chlorine.
[0161] [0161] Illustrative values for Rº include hydrogen, methyl, isopropyl, 1-methylpropyl, 2-methylpropyl, cyclopropyl, cyclopentyl, indanyl, cyclohexyl, cyclooctyl, cyclohexyl-methyl, spiro [3.3] heptanyl, phenyl, chlorophenyl, benzyl , fluorobenzyl, chlorobenzyl, (chloro) (fluoro) benzyl, dichlorobenzyl, bromobenzyl, cyanobenzyl, methylbenzyl, trifluoromethylbenzyl, phenylbenzyl, hydroxybenzyl, methoxybenzyl, methyl, methyl, methyl, methyl, methyl, methyl, methyl, methyl Additional values include tert-butoximetila, cyclobutyl, metilciclobutila, dimetilciclobutila, fenilciclobutila, benzociclobutenila, metilciclopentila, difluorociclohexila, metilciclohexila, dimetilciclohexila, trifluorometilciclohexila - tetrahidronaftalenila - cicloheptila - benzocicloheptenila, ciclononanila, ciclobutilmetila, difluorociclobutilmetila, dimetilciclobutilmetila, ciclobutiletila, bicyclo [3 , 1.0] hexanyl, bicycles [2,2,1] heptanyl, bicycles [3,3,0] Joctanyl, bicycles [3,2,1] Joctanyl, bicycles [1,1,1] pentanylmethyl, adamantanyl, adamantanylmethyl , (chlorine) (fluoro) phenyl, (fluoro) (methyl) phenyl, (bromine) (chlorine) benzyl, (chlorine) - (isopropoxy) benzyl, phenylpropyl, tetrahydropyranyl, tetramethyl-tetrahydropyranyl, azocanyl, dihydro-benzofuranylmethyl and methyl.
[0162] [0162] The selected values for Rº include hydrogen, tert-butoxymethylcyclobutyl, methyl-cyclobutyl, dimethylcyclobutyl, phenylcyclobutyl, benzocyclobutyl, cyclopentyl, methylcyclopentyl, indanyl, cyclohexyl, difluorocyclohexyl, -methyl-cyclohexyl, -methyl-cyclohexyl, -methyl-cyclohexyl,
[0163] [0163] Representative values for R5 include hydrogen, cyclohexyl, cyclooctyl, spiro [3.3] -heptanil and chlorobenzyl.
[0164] [0164] The favored values of R $ include cyclohexyl, 4-methylcyclohexyl and cyclooctyl. In a first modality, Rº represents cyclohexyl. In a second embodiment, R5 represents 4-methylcyclohexyl. In a third modality, Rº represents cyclooctyl.
[0165] [0165] In a first modality, R% º represents C37 cycloalkyl optionally substituted. In a second modality, R% º represents optionally substituted C4.9 bicycloalkyl. In a third modality, R% º represents optionally substituted aryl. In a fourth embodiment, R% º represents optionally substituted C3a-7 heterocycloalkyl. In a fifth modality, Rºº represents optionally substituted heteroaryl.
[0166] [0166] Typical values of R% ºº include cyclobutyl cyclopentyl, bicyclo [1,1,1] pentanyl, phenyl, dihydrobenzofuranyl and pyrrolyl, either group can be optionally substituted by one or more substituents.
[0167] [0167] Typical examples of optional substituents on the Rº include C1-6 alkyl, halogen, cyano, trifluoromethyl, trifluoroethyl, phenyl, hydroxy, C1 + 6 alkoxy, C1-6 alkyl thio, C1 + 6 sulfinyl alkyl, C1-6 alkyl sulfonyl, C2-6 alkyl, carbonyl, amino, C1-6 alkyl, amino and dialkyl (C1-6) amino.
[0168] [0168] Selected examples of optional substituents on R% º include C1-6 alkyl and halogen.
[0169] [0169] Typical examples of particular substituents in R% º include methyl,
[0170] [0170] Selected examples of particular substituents in R% º include methyl and chlorine.
[0171] [0171] Selected values of R% º include cyclobutyl, cyclopentyl, bicyclo [1,1,1] pentanyl, phenyl, chlorophenyl, dihydrobenzofuranyl and methylpyrrolyl.
[0172] [0172] Appropriately, R * represents hydrogen, methyl or ethyl.
[0173] [0173] In a first modality, Rºº represents hydrogen. In a second modality, R * represents C1-6 alkyl, especially methyl or ethyl.
[0174] [0174] —Alternatively, R% ºº and Rºº, when taken together with the carbon atom to which they are both attached may represent C37 cycloalkyl, C4-9 bicycloalkyl or C3-7 hetero-cycloalkyl, any one of the groups may be unsubstituted or substituted by one or more substituents, typically by one or two substituents.
[0175] [0175] In a first modality, Rºº and Rºº, when taken together with the carbon atom to which they are both coupled, can adequately represent optionally substituted C3a7 cycloalkyl. Examples include cyclobutyl, benzocyclobutenyl, cyclopentyl, indanyl, cyclohexyl, tetrahydronaphthalenyl, cycloheptanyl, benzocycloheptenyl, cyclooctanyl and cyclononanyl, any of the groups may be optionally substituted by one or more substituents.
[0176] [0176] In a second modality, Rºº and Rºº, when taken together with the carbon atom to which they are both attached, can adequately represent optionally substituted C4- + bicycloalkyl. Examples include bicycles [3,1,0] hexanyl, bicycles [2,2,1] -heptanyl and bicycles [3,2,1] Joctanyl, any of the groups can be optionally substituted by one or more substituents.
[0177] [0177] In a third modality, R% ºº and Rºº, when taken together with the carbon atom to which they are both attached, can adequately represent optionally substituted C3-7 hetero-cycloalkyl. Examples include tetrahydropyranyl and piperidinyl, each of these groups can optionally be substituted by one or more substituents.
[0178] [0178] Typical examples of optional substituents in such groups include C1-6 alkyl, halogen, cyano, trifluoromethyl, trifluoroethyl, phenyl, hydroxy, C1-6 alkoxy, C1-.6 thio alkyl, C1-6 sulfinyl alkyl, C1 alkyl +6 sulfonyl, Ca.6 alkyl, carbonyl, amino, C1-6 alkyl, amino and dialkyl (C1-6) amino.
[0179] [0179] Selected examples of optional substituents in such groups include C1 + 6 alkyl, halogen, trifluoromethyl, trifluoroethyl, phenyl and Ci alkoxy.
[0180] [0180] Typical examples of particular substituents in such groups include methyl, fluorine, chlorine, bromine, cyano, trifluoromethyl, trifluoroethyl, phenyl, hydroxy, methoxy, methylthio, methylsulfinyl, methylsulfonyl, acetyl, amino, methylamino and dimethylamino.
[0181] [0181] Selected examples of particular substituents in such groups include methyl, chlorine, trifluoromethyl, trifluoroethyl, phenyl and methoxy.
[0182] [0182] The selected values of R% º and Rºº, when taken together with the carbon atom to which they are both attached, include methylcyclobutyl, dimethylcyclobutyl, phenylcyclobutyl, benzocyclobutyl, methylbenzocyclobutyl, chlorobenzocyclylbutyl, methoxy-benzocyclyl, cyclopentyl, cyclopentyl, cyclopentyl, cyclopentyl, cyclopentyl chloroindanil, cyclohexyl, methylcyclohexyl, dimethylcyclohexyl, trifluoromethylcyclohexyl, tetrahydronaphthalenyl, cycloheptanyl, benzocycloheptenyl, cyclooctanyl, cyclononanyl, bicycle [3,1,0] hexanyl, bicycle [2,2] Joctanyl, tetramethyl-tetrahydropyranyl and trifluoroethylpiperidinyl.
[0183] [0183] Generally, Rº represents -NRº% ºRº% *; or R $ represents C1-6 alkyl, C3-9 cycloalkyl, Ca-9 cycloalkyl (C1-6) alkyl, aryl, arylalkyl (C1-6), heterocycloalkyl C3-7, hetero cycloalkyl C3-7 alkyl (C1-6) ), heteroaryl or heteroaryl (C1-6) alkyl, any of the groups can be optionally substituted by one or more substituents.
[0184] [0184] - Favorably, Rº represents -NR $ ºRº * or -OR6º; or R $ represents C1-9 alkyl, aryl, C37 heterocycloalkyl, heteroaryl, heteroaryl (C16) or spiro [heterocycloalkyl (C3-7)]) - [heteroaryl] 1, any of the groups may be optionally substituted by one or more substituents .
[0185] [0185] Typically, Rº represents -NR $ ºRº%; or R $ represents C1 + 6 alkyl, C3-9 cycloalkyl, C3-9 cycloalkyl (C1-6) alkyl, aryl, arylalkyl (C1), heteroaryl or heteroarylalkyl (C1-6), either group can be optionally substituted by one or more substituents. Additionally, Rº can represent -OR $ º; or Rô can represent aryl, C3-7 heterocycloalkyl or spiro [heterocycloalkyl (C3-7)] [heteroaryl], either group can be optionally substituted by one or more substituents.
[0186] [0186] - Appropriately, R $ represents C1-6 alkyl, heteroaryl or heteroarylalkyl (C1- + 6), either group can be optionally substituted by one or more substituents.
[0187] [0187] In a first embodiment, Rº represents optionally substituted C1-s alkyl. In a second embodiment, Rº represents optionally substituted C3 cycloalkyl. In a third embodiment, R $ represents optionally substituted C39 cycloalkyl (C1.6) alkyl. In a fourth modality, Rº represents optionally substituted aryl. In a fifth embodiment, R $ represents optionally substituted (C1-6) alkyl aryl. In a sixth embodiment, Rº represents optionally substituted C3-7 heterocycloalkyl. In a seventh embodiment, Rº represents optionally substituted C3-7 alkyl (C1-.6) heterocycloalkyl. In an eighth modality, Rº represents optionally substituted heteroaryl. In a ninth modality, Rº represents optionally substituted heteroaryl. In a tenth embodiment, R $ represents optionally substituted (C1-6) alkyl spiro [heterocycloalkyl (C3-7)] [heteroarill. In an eleventh modality, Rô represents -NR $ ºRº% º. In a twelfth modality, Rº represents -ORºº,
[0188] [0188] Typical values of R $ include -NR $ ºRº; and methyl, ethyl, propyl, 2-methylpropyl, butyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclohexylmethyl, phenyl, benzyl, phenylethyl, pyrazolyl, pyridinyl, triazolylmethyl, benzotriazolylmethyl or pyridinylmethyl, any of the groups may be optionally substituted by one or more . Additional values include -OR $ º; and tert-butyl, heptanyl, pyrrolidinyl, indolinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, pyrrolyl, pyrazolo [1,5-alpiridinyl, 4,5,6,7-tetrahydropyrazolyl, oxazolyl, isoxazolyl, thiazolyl, imiazolyl, isothiaolol, oxide , thiadiazolyl, triazolyl, tetrazolyl, pyridazinyl, pyrimidinyl or spiro [tetrahydrofuran] - [indole], either group can be optionally substituted by one or more substituents.
[0189] [0189] The selected amounts of R $ include -NR $ ºRº * and -OR $ º; and methyl, tert-butyl, heptanyl, phenyl, pyrrolidinyl, indolinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, pyrrolyl, pyrazolyl, pyrazolo [1,5-a] pyridinyl, 4,5,6,7-tetrahydropyrazolyl, oxazolyl, isoxazole , thiazolyl, isothiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyridinylmethyl - or spiro [tetrahydrofuran] - [indole], any one of the groups can be optionally substituted or more substituted.
[0190] [0190] Appropriate R $ values include methyl, pyrazolyl and pyridinylmethyl, either group can be optionally substituted by one or more substituents.
[0191] [0191] Typical examples of optional substituents in R $ include one, two or three substituents independently selected from halogen, cyano, nitro, C1-6 alkyl, trifluoro-methyl, phenyl, fluorophenyl, hydroxy, hydroxyalkyl (C1 + 6), 0x0, C1-6 alkoxy, difluoro-methoxy, trifluoromethoxy, C1-6 alkylthio, C1-6 alkyl sulfinyl, C1- + 6 sulfonyl alkyl, amino, aminoalkyl (C1.6), C1i6 alkyl amino, dialguyl (Ci) amino , pyrrolidinyl, morpholinyl, piperazinyl, C26 carbonylamino alkyl, C26 carbonylaminoalkyl (C1.6) alkyl, Ca.6 carbonylamino alkoxy, C1.6 sulfonylamino alkyl, formyl, C2-6 carbonyl alkyl, carboxy, Ca-6 carbonyl alkoxy, aminocarbonyl, C1-6 alkyl aminocarbonyl, dialkyl (C1.6) aminocarbonyl, aminosulfonyl, C1 + 6 aminosulfonyl alkyl and dialkyl (C1.6) aminosulfonyl. Additional examples include difluoromethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, cyclopropyl, cyclobutyl, cyclopropylmethyl, C1-6 alkoxy, C1-6 alkyl, C1-6 amino-alkyl (C1.6) and tetrahydropyranyl.
[0192] [0192] Selected examples of optional substituents in R $ include one, two or three substituents independently selected from halogen, C1-6 alkyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, cyclopropyl, cyclobutyl, cyclopropyl-methyl, hydroxy, hydroxy (C1 + 6), 0x0, C1-6 alkoxy (C1-6) alkyl, C1-6 alkyl sulfonyl, amino, aminoalkyl (C1-6), dialkyl (C1-6) aminoalkyl (C1-6)
[0193] [0193] Suitable examples of optional substituents in R $ include one, two or three substituents independently selected from halogen, cyano, C1-6 alkyl, trifluoro-methyl, phenyl, fluorophenyl, hydroxy, hydroxy (C1-6), oxo, C1-6 alkoxy, trifluoromethoxy, C1-6 alkyl sulfonyl, amino, aminoalkyl (C1-6), alkyl C1-6 amino, dialguyl (C1is) amino, pyrrolidinyl, morpholinyl, piperazinyl, Cylilyl> 26 carbonylaminoalkyl (C1-6) and carboxy.
[0194] [0194] Illustrative examples of optional substituents at R $ include one, two or three substituents independently selected from C1-6 alkyl and amino.
[0195] [0195] Typical examples of specific substituents in R $ include one, two or three substituents independently selected from fluorine, chlorine, bromine, cyano, nitro, methyl, ethyl, isopropyl, tert-butyl, trifluoromethyl, phenyl, fluorophenyl, hydroxy, hydroxymethyl, oxo, methoxy, tert-butoxy, difluoromethoxy, trifluoromethoxy, methylthio, methylsulfinyl, methylsulfonyl, amino, aminomethyl, aminoethyl, methyl-amino, tert-butylamino, - dimethylamino, —pyrrolidinyl, - “morpholinethyl,” , acetylaminoethyl, methoxycarbonylamino, methylsulfonyl-amino, formyl, acetyl, carboxy, methoxycarbonyl, - ethoxycarbonyl, - tert-butoxycarbonyl, - aminocarbonyl, - methyl-aminocarbonyl, dimethylaminocarbonyl, aminosulfonyl, methylamino-sulfonyl and dimethylamino-sulfonyl and dimethylamino-sulfonyl. Additional examples include n-propyl, 2-methylpropyl, butan-2-yl, difluoromethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, cyclopropyl, cyclobutyl, cyclopropylmethyl, hydroxyethyl, methoxymethyl, methoxyethyl, aminoisopropyl, dimethylaminohydroamine.
[0196] [0196] Selected examples of specific substituents in R $ include one, two or three substituents independently selected from fluorine, methyl, ethyl, n-propyl, isopropyl, 2-methylpropyl, butan-2-yl, tert-butyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, cyclopropyl, cyclobutyl, cyclopropylmethyl, hydroxy, hydroxyethyl, oxo, methoxymethyl, methoxyethyl, methylsulfonyl, amino, aminomethyl, aminoisopropyl, dimethyl-aminoethyl and tetrah.
[0197] [0197] Suitable examples of specific substituents in R $ include one, two or three substituents independently selected from fluorine, chlorine, cyano,
[0198] [0198] Illustrative examples of specific substituents in R $ include one, two or three substituents independently selected from methyl and amino.
[0199] [0199] Illustrative values for Rº include methyl, difluoromethyl, methylsulfonylmethyl, - aminomethyl, - methylaminomethyl, - difluoroethyl, - carboxyethyl, difluoropropyl, - 2-methyl-propyl, butyl, - cyanocyclopropyl, methyl-cyclopropyl, cyclo-cyclopropyl, ethyl-cyclopropyl, cyclo-cyclopropyl, ethyl-cyclopropyl, cyclo-cyclopropyl, ethyl-cyclopropyl, cyclo-cyclopropyl, cyclo-cyclopropyl, - trifluoromethyl-cyclopropyl, - phenylcyclopropyl, fluorophenylcyclopropyl, hydroxycyclopropyl, aminocyclopropyl, cyclobutyl, trifluoromethylcyclobutyl, cyclohexyl, cyclohexylmethyl, phenyl, fluorophenyl, chlorophenyl, methylphenyl, fluorophenyl, methylphenyl, hydroxy ) (fluoro) benzyl, dichlorobenzyl, (chlorine) (difluoro) benzyl, bromo-benzyl, cyanobenzyl, methylbenzyl, dimethylbenzyl, trifluoromethylbenzyl, phenylbenzyl, hydroxybenzyl, hydroxymethylbenzyl, dimethyl, benzyl, methyl, benzyl, methyl, aminoethylbenzyl, dimethylaminobentyl, pyrrolidinylbenzyl, (d imethyl) (pyrrolidinyl) benzyl, morpholinyl-benzyl, (dimethyl) (morpholinyl) benzyl, piperazinylbenzyl, acetylaminoethylbenzyl, phenylethyl, chlorophenylethyl, methylpyrazolyl, pyridinyl, triazolylmethyl, triazolylmethyl, benzyriazylmethyl, pyridinylmethyl, pyridinyl and methyl pyridinyl. Additional values include -NR $ ºR6>, -OR $ º, tert-butyl, hydroxyheptanyl, pyrrolidinyl, methylpyrrolidinyl, indolinyl, piperidinyl, morpholinyl, dioxothiomorpholinyl, methylpiperazinyl, methyl-pyrrolyl, dimethylpyrazolyl, fluorine (ethyl), pyridylazole, ethyl) , (ethyl) (methyl) -pyrazolyl, = n-propylpyrazolyl, isopropylpyrazolyl, 2-methylpropylpyrazolyl, butan-2-yl-pyrazolyl, difluoromethylpyrazolyl, (difluoromethyl) (methyl) pyrazolyl, difluoroethyl-pyrazole, trifluol, trifluol, trifluol, trifluol, trifluol , cyclobutylpyrazolyl, cyclopropylmethylpyrazolyl, hydroxyethylpyrazolyl, methoxyethyl-pyrazolyl, dimethylaminoethylpyrazolyl, tetrahydropyranylpyrazolyl, (methyl) (tetrahydropyranyl) -pyrazolyl, pyrazole [1,5-methyl-5-hydroxy-pyridinyl, 1,5-hydroxy-pyridine, ethyloxazolyl, isoxazolyl, methylisoxazolyl, dimethylisoxazolyl, ethyl isoxazolyl, isopropyl-
[0200] [0200] The selected values of R include -NR $ $ 29R6º, -OR6º, methyl, tert-butyl, hidroxiheptanila, phenyl, fluorofenila, metilsulfonilfenila, pyrrolidinyl, pyrrolidinyl-methyl, indolinyl, piperidinyl, morpholinyl, dioxotiomorfolinila, methyl-piperazinyl, methylpyrrolyl, methylpyrazolyl, dimethylpyrazolyl, ethylpyrazolyl, (ethyl) - (fluoro) pyrazolyl, (ethyl) (methyl) pyrazolyl, n-propylpyrazolyl, isopropylpyrazolyl, 2-methylpropylpyrazolyl, butan-2-ylpyrazylyl, difluorethyl, pyrolylmethyl methyl) pirazolila, difluoroetilpirazolila, trifluoroetilpirazolila, pirazolila-trifluoro-propyl, ciclopropilpirazolila, ciclobutilpirazolila, ciclopropilmetilpirazolila, hidroxietilpirazolila, metoxietilpirazolila, dimetilaminoetilpirazolila, tetrahidropiranilpirazolila, (methyl) (tetrahydropyranyl) pirazolila, pyrazolo [1,5-a] -piridinila, methyl-4 , 5,6,7-tetrahydropyrazolyl, oxazolyl, methyloxazolyl, ethyloxazolyl, isoxazolyl, methylisoxazolyl, dimethylisoxazolyl, ethylisoxazolyl, isop ropilisoxazolila, tert-butilisoxazolila, trifluorometilisoxazolila, isoxazolyl cyclopropyl, cyclobutyl-isoxazolyl, - metoximetilisoxazolila - aminometilisoxazolila, aminoiso-propilisoxazolila, thiazolyl, metiltiazolila = - dimetiltiazolila - isotiazolila, metilisotiazolila, methyl-imidazolyl, metiloxadiazolila, metiltiadiazolila, metiltriazolila, dimethyltriazolyl, ethyltriazolyl, methyltetrazolyl, pyridinyl, methylpyridinyl, pyridazinyl, pyrimidinyl, methylpyrimidinyl, pyridinylmethyl, aminopyridinylmethyl and spiro [tetrahydrofuran] - [oxoindol].
[0201] [0201] The representative values of R $ include methyl, methylpyrazolyl, pyridinylmethyl and aminopyridinylmethyl.
[0202] [0202] Generally, R% represents hydrogen or C1-6 alkyl.
[0203] [0203] Favorably, Rº% º represents C1-6 alkyl, C3-7 cycloalkyl, (C1-6) arylalkyl, Ca-7 heterocycloalkyl or spiro [heterocycloalkyl (C3-7)] [heteroaryl], any of the groups can be optionally substituted by one or more substituents.
[0204] [0204] Typically, R6º represents hydrogen or methyl.
[0205] [0205] In a first modality, R $ º represents hydrogen. In a second embodiment, R $ º represents optionally substituted C1.6 alkyl. In a first aspect of the modality, R $% º represents unsubstituted C1.6 alkyl, especially methyl. In a second aspect of the modality, R $% º represents C1-6 alkyl monosubstituted, disubstituted or trisubstituted. In a third modality, R $ represents optionally substituted C3-7 cycloalkyl. In a fourth modality, R $ º represents C3a7 cycloalkyl (C1-6) alkyl optionally substituted. In a fifth modality, Rº% º represents optionally substituted aryl. In a sixth modality, R $% º represents optionally substituted arylalkyl (C1-6). In a seventh embodiment, R% represents optionally substituted Ca-7 heterocycloalkyl. In an eighth embodiment, R% º represents optionally substituted heterocycloalkyl Ca-7 (C1-6) alkyl. In a ninth modality, R $ º represents optionally - substituted heteroaryl. In a tenth modality, R% º represents optionally substituted heteroarylalkyl (C1.6). In an eleventh modality, R $ º represents an optionally substituted spiro [heterocycloalkyl (C3-7)] [heteroaryl]].
[0206] [0206] Typical R $ º values include methyl, ethyl, n-propyl, isopropyl, 2,2-dimethyl-propyl, cyclohexyl, benzyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl and spiro [tetrahydrofuran] [indol], any of the groups can be optionally substituted by one or more substituents.
[0207] [0207] Typical examples of optional substituents in R $ º include one, two or three substituents independently selected from halogen, cyano, nitro, C1- + alkyl, trifluoro-methyl, phenyl, fluorophenyl, hydroxy, hydroxy (C1 + 6 ), 0x0, C1-6 alkoxy, difluoro-methoxy, trifluoromethoxy, C1-.6 alkylthio, C1-6 alkyl sulfinyl, C1- + alkyl sulfonyl, amino, amino (C1i-6) alkyl, C1i-6 amino, dialkyl (Cis) amino, pyrrolidinyl, morpholinyl, piperazinyl, C2r6 carbonylamino alkyl, C26 carbonylaminoalkyl (C16) alkyl, Car6 carbonylamino alkoxy, Ci. Sulfonylamino, formyl, C2-6 alkyl carbonyl, carboxy, C2-6 alkoxycarbonyl, carbonyl, alkylcarbonyl, carbonyl, carbonyl, carbonyl C1-6 aminocarbonyl, dialkyl (C1i.s6) aminocarbonyl, aminosulfonyl, C1 + 6 alkyl aminosulfonyl and dialkyl (C1-6) aminosulfonyl.
[0208] [0208] Selected examples of optional substituents in R $ º include one, two or three substituents independently selected from trifluoromethyl, oxo and C1-6 alkoxy.
[0209] [0209] Typical examples of specific substituents in R $ º include one, two or three substituents independently selected from fluorine, chlorine, bromine, cyano, nitro, methyl, ethyl, isopropyl, tert-butyl, trifluoromethyl, phenyl, fluorophenyl, hydroxy , hydroxymethyl, 0x0, methoxy, tert-butoxy, difluoromethoxy, trifluoromethoxy, methylthio, methylsulfinyl, methylsulfonyl, amino, aminomethyl, aminoethyl, methyl-amino, tert-butylamino, - dimethylamino, —pyrrolidinyl, = "pyrrolidinyl," amino, acetylaminoethyl, methoxycarbonylamino, methylsulfonyl-amino, formyl, acetyl, carboxy, methoxycarbonyl, —ethoxycarbonyl, tert-butoxycarbonyl, -amino-carbonyl, = methyl-aminocarbonyl, dimethylaminocarbonyl, aminosulfonyl, methylaminosulfonyl and dimethylaminosulfonyl and dimethyl.
[0210] [0210] Selected examples of specific substituents at R6º include one, two or three substituents independently selected from trifluoromethyl, oxo and methoxy.
[0211] [0211] Selected values of R $% º include methyl, ethyl, trifluoroethyl, methoxyethyl, —n-propyl, isopropyl, - 2,2-dimethylpropyl, - cyclohexyl, - benzyl, tetrahydrofuranyl, tetrahydro-pyranyl, oxotetrahydrothiopyranyl and spiro [ tetrahydrofuran] [oxoindole].
[0212] [0212] Suitably, Rºº represents hydrogen, methyl, ethyl, n-propyl or isopropyl.
[0213] [0213] Typically, Rº represents hydrogen or methyl.
[0214] [0214] In a first modality, Rº represents hydrogen. In a second embodiment, Rºº represents C1-6 alkyl. In a particular aspect of the modality, Rºº represents methyl, ethyl, n-propyl or isopropyl, especially methyl.
[0215] [0215] Favorably, Rºº represents C1-6 alkyl, Ca-7 cycloalkyl, C37 cycloalkyl (Ci), C3a7 heterocycloalkyl, Ca7 (C1-6) heterocycloalkyl or C1-6 (heteroarylalkyl), any of the groups can be optionally replaced by one or more substituents.
[0216] [0216] In a first modality, Rºº represents optionally substituted C1.6 alkyl. In a second embodiment, Rºº represents optionally substituted C37 cycloalkyl. In a third embodiment, R6º represents C3-7 cycloalkyl (C1-6) alkyl optionally substituted. In a fourth modality, Rºº represents optionally substituted aryl. In a fifth modality, Rº represents optionally substituted arylalkyl (C1-6). In a sixth embodiment, R6º represents optionally substituted C3-7 heterocycloalkyl. In a seventh embodiment, R6º represents optionally substituted heterocycloalkyl Ca-7 (C1-6) alkyl. In an eighth modality, Rºº represents optionally substituted heteroaryl. In a ninth modality, Rºº represents optionally substituted heteroarylalkyl (C1-6).
[0217] [0217] Typical values for Rºº include methyl, ethyl, isopropyl, 2-methylpropyl, tert-butyl, 2,2-dimethylpropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclohexyl-methyl, - oxetanyl, - azetidinyl, = tetrahydrofuran, = tetrahydrofuran, = - tetrahydropyranyl, tetrahydropyranyl-methyl, pyrazolylmethyl, oxazolylmethyl, isoxazolylmethyl, imidazolylmethyl and pyrazinylmethyl, any of the groups can be optionally substituted by one or more substituents.
[0218] [0218] Typical examples of optional substituents in R $ º include one, two or three substituents independently selected from halogen, cyano, nitro, C1-6 alkyl, trifluoro-methyl, phenyl, fluorophenyl, hydroxy, hydroxyalkyl (Ci), oxo , C1-6 alkoxy, difluoro-methoxy, trifluoromethoxy, C1-.6 alkylthio, C16 sulfinyl alkyl, C1 + 6 sulfonyl alkyl, amino, aminoalkyl (C16), C16 amino alkyl, dialguyl (Ci) amino, pyrrolidinyl, morpholinyl, piperazinyl, C26 carbonylamino alkyl, C26 carbonylaminoalkyl (C1-6) alkyl, Ca-.6 carbonylamino alkoxy, C1-6 sulfonylamino alkyl, formyl, C2-6 carbonyl alkyl, carboxy, C2-6 carbonyl alkoxy, aminocarbonyl, C1-6 alkyl aminocarbonyl, dialkyl (C1i.6) aminocarbonyl, aminosulfonyl, C1i6 alkyl aminosulfonyl and dialkyl (C1-6) aminosulfonyl.
[0219] [0219] Selected examples of optional substituents on R6º include one, two or three substituents independently selected from C1-6 alkyl,
[0220] [0220] Typical examples of specific substituents in R $ º include one, two or three substituents independently selected from fluorine, chlorine, bromine, cyano, nitro, methyl, ethyl, isopropyl, tert-butyl, trifluoromethyl, phenyl, fluorophenyl, hydroxy , hydroxymethyl, oxo, methoxy, tert-butoxy, difluoromethoxy, trifluoromethoxy, methylthio, metilsulfinila, methylsulfonyl, amino, aminometila, aminoetila, methylamino, tert-butylamino, - dimethylamino, -pirrolidinila, - morpholinyl, piperazinyl, acetyl-amino , acetylaminoethyl, methoxycarbonylamino, methylsulfonyl-amino, formyl, acetyl, carboxy, methoxycarbonyl, - ethoxycarbonyl, tert-butoxycarbonyl, - amino-carbonyl, - methyl-aminocarbonyl, dimethylaminocarbonyl, aminosulfonyl, methylaminosulfonyl and dimethylaminosulfonyl and dimethyl.
[0221] [0221] Selected examples of specific substituents in Rºº include one, two or three substituents independently selected from methyl, trifluoromethyl, methoxy and tert-butoxycarbonyl.
[0222] [0222] Selected values of R $ º include methyl, trifluoroethyl, methoxyethyl, isopropyl, 2-methylpropyl, tert-butyl, 2,2-dimethylpropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclohexylmethyl, oxetanyl, methyloxetanyl, tertiary -butoxycarbonylazetidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyranylmethyl, methylpyrazolylmethyl, oxazolylmethyl, isoxazolylmethyl, methylimidazolylmethyl and pyrazinylmethyl.
[0223] [0223] In a first modality, R represents aryl, which group may optionally be substituted by one or more substituents. In a second modality, R represents heteroaryl, which group may optionally be substituted by one or more substituents. In a third modality, R represents spiro [heterocycloalkyl (C3a -)] [heteroaryl], which group may optionally be substituted by one or more substituents.
[0224] [0224] Typical R 'values include phenyl, pyrazolo [1,5-a] pyrazinyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, imidazo [1,2-b] pyridazinyl, purinyl, pyridinyl, pyridazinyl, cinolinyl, pyrimidinyl, pyriminyl and spiro [tetrahydropyranyl] [indole], either group can be optionally substituted by one or more substituents.
[0225] [0225] Typical examples of optional substituents on R 'include one, two or three substituents independently selected from halogen, cyano, nitro, C1-6 alkyl, difluoromethyl, trifluoromethyl, phenyl, fluorophenyl, hydroxy, hydroxyalkyl (C1-6), oxo, C1-6 alkoxy, difluoromethoxy, trifluoromethoxy, C1-6 alkyl thio, C1-6 alkyl sulfinyl, C1 + 6 sulfonyl alkyl, amino, amino (C1-6) alkyl, C1-6 amino, dialkyl (C1.6) alkyl amino, pyrrolidinyl, morpholinyl, piperazinyl, C26 carbonylamino alkyl, C26 carbonylaminoalkyl (C16) alkyl, Car6 carbonylamino alkoxy, C1.6 sulfonylamino alkyl, formyl, C2-6 carbonyl alkyl, carbonoxy, C2-6 carbonyl alkyl, aminocarbonyl, aminocarbonyl 6 aminocarbonyl, dialkyl (C1-6) aminocarbonyl, aminosulfonyl, C1 + 6 alkyl aminosulfonyl and dialkyl (C1-6) aminosulfonyl.
[0226] [0226] Selected examples of optional substituents on R 'include one, two or three substituents independently selected from halogen, cyano, C1-6 alkyl, difluoromethyl, trifluoromethyl, oxo, C1-6 alkoxy, difluoromethoxy and (C1-6) dialkyl amino.
[0227] [0227] Typical examples of specific substituents on R include one, two or three substituents independently selected from fluorine, chlorine, bromine, cyano, nitro, methyl, ethyl, isopropyl, tert-butyl, difluoromethyl, trifluoromethyl, phenyl, fluorophenyl, hydroxy, hydroxymethyl, oxo, methoxy, isopropoxy, tert- butoxy, difluoromethoxy, trifluoromethoxy, methylthio, methylsulfinyl, methylsulfonyl, amino, aminomethyl, aminoethyl, methylamino, tert-butylamino, dimethylamino, pyrrolidinyl, morpholinyl, piperazinyl, acetylamino, acetylaminoethyl, formylamino, carbamino, formyl, carbonyl, formyl methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, aminosulfonyl, methylaminosulfonyl and dimethylaminosulfonyl.
[0228] [0228] Selected examples of specific substituents in R include one, two or three substituents independently selected from fluorine, chlorine, cyano, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, oxo, methoxy, isopropoxy, difluoromethoxy and dimethylamino.
[0229] [0229] The selected values of R include phenyl, pyrazolo [1,5-a] pyrazinyl,
[0230] [0230] A subclass of the compounds of the formula (IA) above is represented by the compounds of the formula (IIA), and pharmaceutically acceptable salts thereof: Ww
[0231] [0231] where
[0232] [0232] Wrepresents O, S, S (O), S (O) 2, S (O) (NH) or N-R '';
[0233] [0233] —R ' represents hydrogen or C1-6 alkyl; and
[0234] [0234] RºR%, RóeRS are as defined above.
[0235] [0235] Typically, W represents O, S, S (O), S (O) 2 or N-R "”.
[0236] [0236] - Appropriately, W represents O, S or N-R "7,
[0237] [0237] In a first modality, W represents O. In a second modality, W represents S. In a third modality, W represents S (O). In a fourth modality, W represents S (O). In a fifth modality, W represents S (O) (NH). In a sixth modality, W represents N-R "7.
[0238] [0238] Suitably, R'7 represents hydrogen or methyl.
[0239] [0239] In a first modality, R * represents hydrogen. In a second modality, R ' represents C1-s alkyl. In a first aspect of the modality, R'7 represents methyl.
[0240] [0240] Another subclass of the compounds of the formula (IA) above is represented by the compounds of the formula (IIB), and pharmaceutically acceptable salts thereof:
[0241] [0241] where
[0242] [0242] W, Rº, Rº and R $ are as defined above.
[0243] [0243] The specific new compounds according to the present invention include each of the compounds whose preparation is described in the accompanying Examples, and pharmaceutically acceptable salts and solvates thereof.
[0244] [0244] The compounds according to the present invention are beneficial in the treatment and / or prevention of various human diseases, including inflammatory and autoimmune disorders.
[0245] [0245] The compounds according to the present invention are useful in the treatment and / or prophylaxis of a pathological disorder that is mediated by a pro-inflammatory IL-17 cytokine or is associated with an increased level of a pro-IL-17 cytokine inflammatory. Generally, the pathological condition is selected from the group consisting of infections (viral, bacterial, fungal and parasitic), endotoxic shock associated with infection, arthritis, rheumatoid arthritis, psoriatic arthritis, systemic onset juvenile idiopathic arthritis (JIA), systemic lupus erythematosus ( SLE), asthma, chronic obstructive airway disease (COAD), chronic obstructive pulmonary disease (COPD), acute lung injury, pelvic inflammatory disease, Alzheimer's disease, Crohn's disease, inflammatory bowel disease, irritable bowel syndrome, ulcerative colitis , Castleman's disease, ankylosing spondylitis and other spondyloarthropathies, dermatomyositis, myocarditis, uveitis, exophthalmos, autoimmune thyroiditis, Peyronie's disease, celiac disease, gallbladder disease, pilonidal disease, peritonitis,
[0246] [0246] WO 2009/089036 discloses that modulators of IL-17 activity can be administered to inhibit or reduce the severity of inflammatory eye disorders, in particular inflammatory eye surface disorders including Dry Eye Syndrome (DES). Consequently, the compounds according to the present invention are useful in the treatment and / or prevention of an IL-17 mediated inflammatory eye disorder, in particular an IL-17 mediated inflammatory eye surface disorder including Dry Eye Syndrome. Inflammatory eye surface disorders include Dry Eye Syndrome, penetrating keratoplasty, corneal transplantation, lamellar or partial-thickness transplantation, selective endothelial transplantation, corneal neovascularization, keratoprosthesis surgery, inflammatory conditions of the corneal ocular surface, conjunctive healing disorders, conditions ocular autoimmune, pemphigoid syndrome, Stevens-Johnson syndrome, eye allergy, severe allergic (atopic) eye disease, conjunctivitis and microbial keratitis. The particular categories of Dry Eye Syndrome include dry keratoconjunctivitis (KCS), Sjogren's syndrome, dry keratoconjunctivitis associated with Sjohngren's syndrome, dry keratoconjunctivitis not associated with Sjogren's syndrome, dry keratitis, dry syndrome, xerophthalmia, tear film disorder , decreased lacrimal production, aqueous lacrimal deficiency (ATD), meibomian gland dysfunction and evaporative loss.
[0247] [0247] Illustratively, the compounds of the present invention may be useful in the treatment and / or prophylaxis of a pathological disorder selected from the group consisting of arthritis, rheumatoid arthritis, psoriasis, psoriatic arthritis, systemic onset juvenile idiopathic arthritis (JIA), lupus erythematosus systemic (SLE), asthma, chronic obstructive airway disease, chronic obstructive pulmonary disease, atopic dermatitis, scleroderma, systemic sclerosis, pulmonary fibrosis, inflammatory bowel diseases (including Crohn's disease and ulcerative colitis), ankylosing spondylitis and other spondyloarthropathies, cancer and pain (particularly pain associated with inflammation).
[0248] [0248] - Suitably, the compounds of the present invention are useful in the treatment and / or prophylaxis of psoriasis, psoriatic arthritis or ankylosing spondylitis.
[0249] [0249] The present invention also provides a pharmaceutical composition comprising a compound according to the invention as described above or a pharmaceutically acceptable salt thereof, in association with one or more pharmaceutically acceptable carriers.
[0250] [0250] The pharmaceutical compositions according to the invention can take a form suitable for oral, buccal, parenteral, nasal, topical, ophthalmic or rectal administration or a form suitable for administration by inhalation or insufflation.
[0251] [0251] For oral administration, pharmaceutical compositions can take the form of, for example, tablets, lozenges or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (eg, pregelatinized corn starch, polyvinylpyrrolidone or hydroxypropyl methyl cellulose); fillers (for example, lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (for example, magnesium stearate, talc or silica); disintegrants (for example, potato starch or sodium glycolate); or wetting agents (for example, sodium lauryl sulfate). The tablets can be coated by methods well known in the art. Liquid preparations for oral administration can take the form, for example, of solutions, syrups or suspensions or they can be presented as a dry product for constitution with water or another vehicle before use. Such liquid preparations can be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents, emulsifying agents, non-aqueous vehicles or preservatives. The preparations can also contain buffering salts, flavoring agents, coloring agents or sweetening agents, as appropriate.
[0252] [0252] Preparations for oral administration can be adequately formulated to give prolonged release of the active compound.
[0253] [0253] For oral administration, the compositions can take the form of tablets or lozenges formulated in the conventional way.
[0254] [0254] The compounds according to the present invention can be formulated for parenteral administration by injection, for example, by bolus injection or infusion. Injection formulations can be presented in unit dosage form, for example, in glass ampoules or multiple dose containers, for example, glass vials. Injection compositions can take forms such as suspensions, solutions or emulsions in oily or aqueous vehicles, and can contain formulating agents such as suspending, stabilizing, preserving and / or dispersing agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, for example, sterile pyrogen-free water, before use.
[0255] [0255] In addition to the formulations described above, the compounds according to the present invention can also be formulated as a depot preparation. Such long-acting formulations can be administered by implantation or intramuscular injection.
[0256] [0256] For nasal administration or administration by inhalation, the compounds according to the present invention can be conveniently delivered in the form of an aerosol spray presentation for pressurized packages or a nebulizer, with the use of a suitable propellant, for example, dichlorodifluoromethane, fluorotrichloromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas or gas mixture.
[0257] [0257] The compositions can, if desired, be presented in a packaging or dispensing device that can contain one or more unit dosage forms containing the active ingredient. The packaging or dispensing device may be accompanied by instructions for administration.
[0258] [0258] For topical administration the compounds according to the present invention can be conveniently formulated in a suitable ointment containing the active component suspended or dissolved in one or more pharmaceutically acceptable carriers. Particular carriers include, for example, mineral oil, liquid petroleum jelly, propylene glycol, polyoxyethylene, polyoxypropylene, emulsifying wax and water. Alternatively, the compounds according to the present invention can be formulated in a suitable lotion containing the active component suspended or dissolved in one or more pharmaceutically acceptable carriers. Particular carriers include, for example, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, benzyl alcohol, 2-octyldodecane and water.
[0259] [0259] For ophthalmic administration the compounds according to the present invention can be conveniently formulated as micronized suspensions in isotonic saline, adjusted to sterile pH, with or without a preservative such as a bactericidal or fungicidal agent, for example phenylmercuric nitrate, benzylalkonium chloride or chlorhexidine acetate. Alternatively, for ophthalmic administration the compounds according to the present invention can be formulated in an ointment such as petroleum jelly.
[0260] [0260] For rectal administration the compounds according to the present invention can be conveniently formulated as suppositories. These can be prepared by mixing the active component with a suitable non-irritating excipient that is solid at room temperature but liquid at the rectal temperature and will thus melt in the rectum to release the active component. Such materials include, for example, cocoa butter, beeswax and polyethylene glycols.
[0261] [0261] The amount of a compound according to the present invention required for the prophylaxis or treatment of a particular condition will vary depending on the chosen compound and the condition of the patient to be treated. In general, however, daily dosages can range from around 10 ng / kg to 1000 mg / kg, typically from 100 ng / kg to 100 mg / kg, for example, around 0.01 mg / kg to 40 mg / kg of body weight, for oral or buccal administration, around 10 ng / kg to 50 mg / kg of body weight for parenteral administration, and around 0.05 mg to around 1000 mg, for example , around 0.5 mg to around 1000 mg, for nasal administration or administration by inhalation or insufflation.
[0262] [0262] If desired, a compound according to the present invention can be co-administered with another pharmaceutically active agent, for example, an anti-inflammatory molecule.
[0263] [0263] The compounds of formula (1) above in which R 'represents -CORº can be prepared by a process comprising reacting a carboxylic acid of the formula RºCO2H or a salt thereof, for example, a lithium salt thereof, with a compound of the formula (Ill): SC | DO is nÊ NH; (II)
[0264] [0264] where A, B, D, E and Rº are as defined above, and RP corresponds to the group Rº as defined above or Rº represents a protection group of N; followed, as necessary, by the removal of the N Rr protection group.
[0265] [0265] The N R º protection group will suitably be tert-butoxycarbonyl (BOC), benzyl or 2- (trimethylsily) ethoxymethyl (SEM).
[0266] [0266] The reaction is conveniently carried out in the presence of a coupling agent. Suitable coupling agents include 2- (7-aza-1H-benzotriazole-1-i1) -1,1,3,3-tetramethyl-uronium hexafluorophosphate (HATU).
[0267] [0267] Where the compound (Ill) is reacted with a carboxylic acid of the formula RºCO> 2H, the reaction is usually carried out in the presence of a base. Suitable bases include organic amines, for example, a trialkylamine such as N, N-diisopropylethylamine. The reaction is conveniently carried out at room temperature in a suitable solvent, for example, a cyclic ether such as tetrahydrofuran or a dipolar aprotic solvent such as N, N-dimethylformamide or a chlorinated solvent such as dichloromethane.
[0268] [0268] Where compound (III) is reacted with lithium salt of a carboxylic acid of the formula RºCO> 2H, the reaction is usually carried out at room temperature in a suitable solvent, for example, a dipolar aprotic solvent such as N, N - dimethylformamide.
[0269] [0269] Where the protecting group of N Rº is BOC, the subsequent removal of it can be conveniently carried out by treatment with an acid, for example, a mineral acid such as hydrochloric acid or an organic acid such as trifluoroacetic acid.
[0270] [0270] Where the N Rº protecting group is benzyl, subsequent removal can be conveniently carried out by catalytic hydrogenation, typically by treatment with hydrogen gas in the presence of a hydrogenation catalyst, for example, palladium on vegetable carbon.
[0271] [0271] Where the protection group of N Rº is SEM, the subsequent removal of it can be conveniently carried out by treatment with a fluoride salt, for example, tetra-n-butylammonium fluoride; or by treatment with an acid, for example, a mineral acid such as hydrochloric acid or an organic acid such as trifluoroacetic acid.
[0272] [0272] Where Rº represents -CH (RS) N (H) C (O) RS, the intermediates of the formula RºCO2H can be prepared by a two-step procedure comprising: (i) reacting a carboxylic acid of the formula R $ - CO2H with a compound of the formula (IV):
[0273] [0273] where AIK 'represents C14 alkyl, for example, methyl, and Rº and Rº are as defined above; under conditions analogous to those described above for the reaction between compound (Ill) and a carboxylic acid of the formula RºCO> 2H; and (ii) saponification of the resulting material by treatment with a base.
[0274] [0274] As for the reaction between the compound (Ill) and a carboxylic acid of the formula RºCO> 2H, the coupling agent used in step (i) can suitably be HATU.
[0275] [0275] Alternatively, the coupling agent can be 2,4,6-2,4,6-tripropyl-1,3,5,2,4,6-trioxa-triphosphorinane 2,4,6-trioxide, in which case the reaction can generally be carried out in the presence of a base that can suitably include organic amines, for example, a trialkylamine such as N N-diisopropylethylamine or an aromatic base such as pyridine. The reaction is conveniently carried out at room temperature in a suitable solvent, for example, an organic ester such as ethyl acetate and / or a cyclic ether such as tetrahydrofuran.
[0276] [0276] Alternatively, the coupling agent can be a mixture of N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide chloride and 1-hydroxybenzotriazole, in which case the reaction can generally be carried out in the presence of a base, for example , an organic amine such as N N-diisopropylethylamine. The reaction is conveniently carried out at room temperature in a suitable solvent, for example, a dipolar aprotic solvent such as N N-dimethylformamide.
[0277] [0277] The saponification reaction in step (ii) will generally be carried out by treatment with a base. Suitable bases include inorganic hydroxides, for example, an alkali metal hydroxide such as lithium hydroxide. Where lithium hydroxide is used in step (ii) of the above procedure, the product can be lithium salt of the carboxylic acid of the formula RºCO2H.
[0278] [0278] Step (ii) is conveniently carried out at room temperature in water and a suitable organic solvent, for example, a cyclic ether such as tetrahydrofuran, optionally in admixture with a C14 alkanol such as methanol.
[0279] [0279] In another procedure, the compounds of formula (1) above in which R 'represents -SO2Rº can be prepared by a process which comprises reacting a compound of the formula RºSO2CI | with a compound of the formula (Ill) as defined above.
[0280] [0280] The reaction is conveniently carried out at room temperature in the presence of a base, for example, an organic base such as triethylamine, in a suitable solvent, for example, a chlorinated hydrocarbon solvent such as dichloromethane.
[0281] [0281] In another procedure, the compounds of formula (1) above in which R 'represents -COR º can be prepared by a process which comprises reacting an amide of formula R & 4CONH2 with a compound of formula (V): Bz SC | À & BOL! (V)
[0282] [0282] where A. B, D, E, Rº and Rº are as defined above, and L 'represents a suitable starting group; in the presence of a transition metal catalyst; followed, as necessary, by the removal of the N Rr protection group.
[0283] [0283] The leaving group L 'is suitably a halogen atom, for example, chlorine or bromine.
[0284] [0284] The transition metal catalyst is suitably [(2-di-tert-butylphosphino-3,6-dimethoxy-2 ', 4' 6 "-trilsopropyl-1,1" -biphenyl) -2- ( 2-amino-1,1 "- biphenyl)] palladium (ll) (tBuBrettPhos Pd G3), in which case the reaction will generally be carried out in the presence of 2- (di-tert-butylphosphino) -2 ', 4', 6 "- triisopropyl-3,6-dimethoxy-1,1" - biphenyl (tBuBrettPhos). The reaction is conveniently carried out at an elevated temperature in the presence of a base, for example, an inorganic base such as potassium carbonate, in a solvent For example, a lower alkanol such as tert-butanol is suitable.
[0285] [0285] Alternatively, the transition metal catalyst may suitably be tris (dibenzylidene-acetone) dipaladium (0), in which case the reaction will generally be carried out in the presence of 2-dicyclohexylphosphino-2 ', 4', 6'-triisopropylbiphenyl (XPhos) or 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (Xantphos). The reaction is conveniently carried out at an elevated temperature in the presence of a base, for example, a carbonate salt such as potassium carbonate or cesium carbonate, in a suitable solvent, for example, a cyclic ether such as 1,4-dioxane or a C1 + alkanol such as tert-butanol.
[0286] [0286] In another procedure, the compounds of formula (1) above in which R 'is an aryl or heteroaryl moiety can be prepared by a process comprising reacting a compound of the formula R'! - NH2 with a compound of the formula ( V) as defined above in the presence of a transition metal catalyst; followed, as necessary, by the removal of the N Rr protection group.
[0287] [0287] The transition metal catalyst is suitably tris (dibenzylidene-acetone) dipaladium (0), in which case the reaction will generally be carried out in the presence of 2- (di-tert-butyl) -phosphino-2 ', 4' , 6 "-triisopropylbiphenyl (tert-BuXPhos). The reaction is conveniently carried out at an elevated temperature in the presence of a base, for example, a tert-butoxide salt such as sodium tert-butoxide, in a suitable solvent, for example , a cyclic ether such as 1,4-dioxane.
[0288] [0288] The intermediates of the formula (V) above can be prepared by reacting the appropriate a, w-dihaloalkane with a compound of the formula (VI): <A E go (VD
[0289] [0289] in which B, D, E, L 'and R are as defined above.
[0290] [0290] The reaction is usually carried out in the presence of a base, for example, an inorganic base such as cesium carbonate. The reaction will be conveniently carried out at room or elevated temperature, as appropriate, in a suitable solvent, for example, a dipolar aprotic solvent such as N N-dimethylformamide or a carbonyl solvent such as acetone or a sulfoxide solvent such as dimethyl sulfoxide .
[0291] [0291] The intermediates of the formula (VI) above can be prepared by a two-step procedure from a compound of the formula (VII): "the BU (VID
[0292] [0292] where B, D, E, L 'and Rº are as defined above; whose procedure comprises the following steps: (i) treatment of compound (VII) with pyridinium tribromide or N-bromo-succinimide; and (ii) treatment of the 3,3-dibromo-2-oxoindoline derivative thus obtained with metallic zinc.
[0293] [0293] Step (i) is conveniently carried out at room temperature in a suitable solvent, for example, a cyclic ether such as 1,4-dioxane or a C14 alkanol such as tert-butanol, typically in admixture with water.
[0294] [0294] Step (ii) is conveniently carried out in the presence of ammonium chloride at an elevated temperature in a suitable solvent, for example, a dipolar aprotic solvent such as N N-dimethylformamide or a cyclic ether such as tetrahydrofuran. Alternatively, step (ii) can be carried out in acetic acid at room temperature in a suitable solvent, for example, a cyclic ether such as tetrahydrofuran.
[0295] [0295] Similarly, the intermediates of the formula (Ill) above can be prepared by reacting the appropriate a, w-dihaloalkane with a compound of the formula (VI-A): «AX o À
[0296] [0296] where B, D, E and Rº are as defined above, and Rº represents hydrogen or an N protecting group; under conditions analogous to those described above for the reaction of an a, w-dihaloalkane with a compound of the formula (VI); followed, as appropriate, by the removal of the N Rº and / or Rº protection group (s).
[0297] [0297] The N Rº protection group will suitably be tert-butoxycarbonyl (BOC).
[0298] [0298] Where the protection group of N Rº is BOC, the subsequent removal of it can be conveniently carried out by treatment with an acid, for example, a mineral acid such as hydrochloric acid or an organic acid such as trifluoroacetic acid.
[0299] [0299] In another procedure, the compounds of formula (IA) above can be prepared by a process which comprises reacting a compound of formula (Ill) as defined above with a compound of formula (VIII): RE PAN THE R (VI)
[0300] [0300] in which R ”and R $ are as defined above; followed, as necessary, by the removal of the N Rr protection group.
[0301] [0301] The reaction between compounds (III) and (VIII) will generally be carried out in the presence of acetic acid. The reaction is conveniently carried out at an elevated temperature in a suitable solvent, for example, a cyclic ether such as tetrahydrofuran.
[0302] [0302] Similarly, the compounds of the formula (SE) above can be prepared by a process which comprises reacting a compound of the formula (Ill) as defined above with a compound of the formula (IX): D 4 "x% RR Rº IX)
[0303] [0303] where Rº, Rºº and Rº are as defined above; under conditions analogous to those described above for the reaction between compounds (III) and (VII!); followed, as necessary, by the removal of the N Rr protection group.
[0304] [0304] Where the respective values of R5, Rºº and Rºº allow, an intermediate of the formula (VIII) can be obtained from the corresponding intermediate of the formula (IX) by conventional catalytic hydrogenation.
[0305] [0305] The intermediates of the formula (IX) above can be prepared by reacting a compound of the formula R $ ºC (O) R ”” with a compound of the formula (VIII) as defined above where Rº represents hydrogen.
[0306] [0306] The reaction is conveniently carried out by treating the reagents with titanium tetrachloride; followed by treatment of the resulting material with pyridine.
[0307] [0307] In another procedure, the compounds of the formula (IA) above can be prepared by a process which comprises reacting a carboxylic acid of the formula R $ -CO2H with a compound of the formula (X):
[0308] [0308] where A. B, D, E, Rº, Rº and Rº are as defined above; under conditions analogous to those described above for the reaction between the compound (Ill) and a carboxylic acid of the formula RºCO2H; followed, as necessary, by the removal of the N Rr protection group.
[0309] [0309] Similarly, the compounds of the formula (IA) above in which R $ represents - NR $ ºRºº can be prepared by a process which comprises reacting a carbamate derivative of the formula L2-C (O) NR $ ºRº ", in which L 'represents a suitable starting group, with a compound of the formula (X) as defined above; followed, as necessary, by the removal of the N Rr protecting group.
[0310] [0310] The starting group L it is suitably a halogen atom, for example, chlorine; or L it is suitably phenoxy.
[0311] [0311] Where L it is a halogen atom, the reaction is conveniently carried out at room temperature in the presence of a base, for example, an organic amine such as triethylamine, in a suitable solvent, for example, a chlorinated solvent such as dichloromethane.
[0312] [0312] Where L is phenoxy, the reaction is conveniently carried out at an elevated temperature in the presence of 4- (dimethylamino) pyridine, in a suitable solvent, for example, a nitrile solvent such as acetonitrile.
[0313] [0313] Similarly, the compounds of the formula (IA) above in which Rº represents - OR $ ºº can be prepared by a process which comprises reacting a compound of the formula L3-C (O0) ORºº, in which L represents a suitable leaving group, with a compound of formula (X) as defined above; followed, as necessary, by the removal of the N Rr protection group.
[0314] [0314] The starting group L it is suitably a halogen atom, for example, chlorine.
[0315] [0315] The reaction is conveniently carried out at room temperature in the presence of a base, for example, an organic amine such as triethylamine, typically in admixture with pyridine, in a suitable solvent, for example, a cyclic ether such as tetrahydrofuran.
[0316] [0316] In another procedure, the compounds of the formula (IB) above can be prepared by a process which comprises reacting a compound of the formula (X) as defined above with a compound of the formula Li-S (O) 2R6, wherein R $ is as defined above, and Lº represents a suitable starting group; followed, as necessary, by the removal of the N Rr protection group.
[0317] [0317] The starting group Lº is suitably a halogen atom, for example, chlorine.
[0318] [0318] The reaction is conveniently carried out at room temperature in the presence of a base, for example, an organic amine such as N, N-diisopropylethylamine, in a suitable solvent, for example, a chlorinated solvent such as dichloromethane.
[0319] [0319] In another procedure, the compounds of the formula (IC) above can be prepared by a process which comprises reacting a compound of the formula (X) as defined above with a compound of the formula L * -R7, wherein R is as defined above, and Lº represents a suitable starting group; followed, as necessary, by the removal of the N Rº protection group.
[0320] [0320] The starting group Lº is suitably a halogen atom, for example, chlorine or bromine.
[0321] [0321] The reaction is conveniently carried out in the presence of a base. Suitable bases include organic amines, for example, a trialkylamine such as N N-diisopropylethylamine. The reaction is typically carried out at an elevated temperature in a suitable solvent, for example, a cyclic ether such as 1,4-dioxane.
[0322] [0322] Alternatively, the reaction can be carried out in the presence of a transition metal catalyst. Suitable transition metal catalysts for use in this procedure include [(2-di-tert-butylphosphino-3,6-dimethoxy-2 ', 4', 6 "-triylsopropyl-1,1" -biphenyl) -2 methanesulfonate -2 - (2-amino-1,1 "-biphenyl)] palladium (! L!) (TBuBrettPhos Pd G3). The reaction is conveniently carried out at an elevated temperature in the presence of a base, for example, an inorganic base such as tert - potassium butoxide, in a suitable solvent or mixture of solvent The solvent or solvents can (m) be suitably selected from a cyclic ether such as 1,4-dioxane, and a sulfoxide solvent such as dimethyl sulfoxide .
[0323] [0323] The intermediates of formula (X) above can be prepared by reacting a compound of formula (Ill) as defined above with a compound of formula (XI) or a salt thereof, for example, a lithium salt thereof : IT IS
[0324] [0324] where Rº and R1 are as defined above; under conditions analogous to those described above for the reaction between compound (Ill) and a carboxylic acid of the formula RºCO> 2H; followed, as necessary, by the removal of the N Rº protection group,
[0325] [0325] In another procedure, the compounds of the formula (ID) above can be prepared by a process which comprises reacting a compound of the formula R - NH2 with a compound of the formula (XII):
[0326] [0326] emqueA.B, D, E, Rº, RºeR ”'are as defined above; under conditions analogous to those described above for the reaction between the compound (Ill) and a carboxylic acid of the formula RºCO2H; followed, as necessary, by the removal of the N Rr protection group.
[0327] [0327] The intermediates of the formula (XIl) above can be prepared by a two step procedure comprising: (i) reacting a compound of the formula (III) as defined above with a compound of the formula (XIII!) Or a salt of the even, for example, a lithium salt of the same: OH AN ont R (XI)
[0328] [0328] where R * and AIlk 'are as defined above; under conditions analogous to those described above for the reaction between compound (Ill) and a carboxylic acid of the formula RºCO> 2H; and (ii) saponification of the resulting material by treatment with a base.
[0329] [0329] The saponification reaction in step (ii) will generally be carried out by treatment with a base. Suitable bases include inorganic hydroxides, for example, an alkali metal hydroxide such as lithium hydroxide. Where lithium hydroxide is used in step (ii) of the above procedure, the product may be the lithium salt of the carboxylic acid of formula (XII).
[0330] [0330] Step (ii) is conveniently carried out at room temperature in water and a suitable organic solvent, for example, a C14 alkanol such as ethanol.
[0331] [0331] Where they are not commercially available, the starting materials of formulas (IV), (VI-A), (VII), (XI) and (XIll) can be prepared by methods analogous to those described in the accompanying Examples or by standard methods well known in the art.
[0332] [0332] It will be understood that any compound of formula (1) initially obtained from any of the above processes can, where appropriate, subsequently be made into an additional compound of formula (|) by techniques known in the art. For example, a compound of the formula (|)
[0333] [0333] A compound of the formula (1) comprising an amino portion (-NH> 2) can be acylated, for example, acetylated, by treatment with a suitable acyl halide, for example, acetyl chloride, typically in the presence of an base, for example, an organic base such as N N-diisopropylethylamine.
[0334] [0334] A compound containing an NH portion can be alkylated, for example, methylated, by treatment with the appropriate alkyl halide, for example, iodomethane, typically at room temperature in the presence of a base, for example, sodium hydride, in a suitable solvent, for example, a dipolar aprotic solvent such as N N-dimethylformamide.
[0335] [0335] A compound of formula (1) in which Rº is hydrogen can be converted into the corresponding compound in which R3 is fluorine by treatment with Selectfluorº.
[0336] [0336] A compound of the formula (1) in which R is hydrogen can be converted into the corresponding compound in which Rº is chlorine by treatment with N-chlorosuccinimide, typically in the presence of acetic acid.
[0337] [0337] Where the respective values of R5, R3ºº and Rºº allow, a compound of the formula (IA) can be obtained from the corresponding compound of the formula (SE) by conventional catalytic hydrogenation, for example, by treatment with hydrogen gas in the presence of a hydrogenation catalyst such as palladium on vegetable carbon.
[0338] [0338] A compound containing the -S- portion can be converted into the corresponding compound containing the -S (O) portion by treatment with 3-chloroperoxybenzoic acid. Likewise, a compound containing the -S- or -S (O) - moiety can be converted to the corresponding compound containing the -S (O) 2- moiety by treatment with 3-chloroperoxy-benzoic acid.
[0339] [0339] A compound containing the -S- portion can be converted into the corresponding compound containing the -S (O) (NH) - portion by treatment with ammonium carbamate and (diacetoxyiodine) benzene.
[0340] [0340] Where a mixture of products is obtained from any of the processes described above for the preparation of compounds according to the invention, the desired product can be separated from it at an appropriate stage by conventional methods such as preparative HPLC; or column chromatography using, for example, silica and / or alumina in conjunction with an appropriate solvent system.
[0341] [0341] Where the processes described above for the preparation of the compounds according to the invention give rise to mixtures of stereoisomers, these isomers can be separated by conventional techniques. In particular, where it is desired to obtain a particular enantiomer of a compound of the formula (II) it can be produced from a corresponding mixture of enantiomers using any suitable conventional procedure for resolving enantiomers. Thus, for example, diastereomeric derivatives, for example, salts, can be produced by reacting a mixture of enantiomers of formula (1), for example, a racemate, and an appropriate chiral compound, for example, a chiral base. The diastereomers can then be separated by any convenient means, for example by crystallization, and the desired enantiomer recovered, for example, by treatment with an acid in the case where the diastereomer is a salt. In another resolution process a racemate of formula (1) can be separated using chiral HPLC. In addition, if desired, a particular enantiomer can be obtained using an appropriate chiral intermediate in one of the processes described above. Alternatively, a particular enantiomer can be obtained by performing enantiomer-specific enzymatic biotransformation, for example, an ester hydrolysis using an esterase, and then purifying only the hydrolyzed enantiomerically pure acid from the unreacted ester antipode. Chromatography, recrystallization and other conventional separation procedures can also be used with intermediates or end products where it is desired to obtain a particular geometric isomer of the invention.
[0342] [0342] During any of the synthetic sequences above it may be necessary and / or desirable to protect sensitive or reactive groups in any of the molecules of interest. This can be achieved by means of conventional protecting groups, such as those described in Greene's Protective Groups in Organic Synthesis, ed. P.G.M. Wuts, John Wiley & Sons, 5th edition, 2014. Protective groups can be removed at any subsequent convenient stage using methods known in the art.
[0343] [0343] The compounds according to this invention potentially inhibit the ability of | L-17A to bind to IL-17RA. When tested in the IL-17 FRET assay described below, the compounds of the present invention exhibit an IC 50 value of UM or less, usually 5 µM or less, usually 1 UM or less, typically 500 nM or less, suitably 100 nM or less, ideally 50 nM or less, and preferably 25 nM or less (the skilled person will appreciate that a lower ICso figure indicates a more active compound).
[0344] [0344] - In addition, certain compounds according to this invention potentially inhibit the IL-6-induced release of IL-17 from human dermal fibroblasts. In fact, when tested in the HDF cell line assay described below, the compounds of the present invention exhibit an ICso value of 10 µM or less, usually 5 µM or less, usually 1 µM or less, typically 500 nM or less , suitably 100 nM or less, ideally 50 nM or less, and preferably 25 nM or less (as before, the skilled person will assess that a lower IC50 figure indicates a more active compound). IL-17 FRET assay
[0345] [0345] The purpose of this assay is to test the compounds' ability to disrupt the interaction between IL-17A and soluble IL-17 Receptor A (IL-17RA). The ability of a compound to inhibit the binding of IL-17A to IL-17RA is measured in this assay.
[0346] [0346] A human IL-17AA-TEV-Fc construct was expressed in a CHO SXE cell system and purified by protein A chromatography and size exclusion. The protein was labeled with an AlexaFluor 647 amine reactive dye (Thermo Fisher ttA20006), as per the manufacturer's instruction.
[0347] [0347] Soluble IL-17RA (33-317) -HKH-TEWV-Fc was expressed in an Expi HEK293 cell system and purified by protein A chromatography and size exclusion. The Fc label was clicked by TEV, producing IL-17RA (33-317) -HKH, and the protein was labeled with reactive amine (Thermo Fisher% PV3581).
[0348] [0348] In assay buffer [Dulbecco PBS (Sigma ft14190-094), 0.05% P20 (Thermo Scientific H28320), 1 mg / ml BSA (Sigma% A2153-500G)] the following solutions were prepared:
[0349] [0349] For the IL-17A * IL-17A-Fc-AF647 assay at 5 NM * IL-17RA-HKH-Tb at 5 nM
[0350] [0350] The compounds were serially diluted in DMSO before receiving an aqueous dilution in a 384-well dilution plate (Greiner tt781281), to give a 25% DMSO solution.
[0351] [0351] IL-17A (10 µl) was added to a black low volume assay plate (Costar 4511) and the diluted compound (5 µl) was transferred from the aqueous dilution plate. The cytokine and compound were allowed to incubate for 1 h, then IL-17RA (10 µL) was added. The plates were rolled up and incubated at room temperature for 18 to 20 h with gentle agitation (<400 rpm) before being read in a Perkin Elmer Envision plate reader (Excitation: 330 nm; Emission 615/645 nm).
[0352] [0352] Final test concentrations were 2 nM IL-17A-AF647 and 2 nM IL-17RA-Tb, 5% DMSO.
[0353] [0353] When tested in the I1L-17 FRET assay, the compounds of the attached Examples were all found to exhibit ICso values of 10 µM or better.
[0354] [0354] When tested in the IL-17 FRET assay, the compounds of the attached Examples exhibit IC 50 values generally in the range of about 0.01 nM to about 10 UM, usually in the range of about 0.01 nM to about 5 µM, typically in the range of about 0.01 nM to about 1 µM, suitably in the range of about 0.01 nM to about 500 nM, suitably in the range of about 0.01 nM to about 100 nM , ideally in the range of about 0.01 nM to about 50 nM, and preferably in the range of about 0.01 nM to about 25 nM. Inhibition of IL-17A-induced release of IL-6 from the Cell Line
[0355] [0355] The purpose of this test is to test the neutralization capacity of IL-17 proteins, in a human primary cell system. Stimulation of normal human dermal fibroblasts (HDF) with IL-17 alone produces only a very weak signal, but in combination with certain other cytokines, such as TNFa, a synergistic effect can be observed in the production of inflammatory cytokines, ie IL- 6.
[0356] [0356] HDFs were stimulated with IL-17A (50 pM) in combination with TNF-a (25 pM). The resulting IL-6 response was then measured using a FRET kit resolved with Cisbio's homogeneous time. The kit uses two monoclonal antibodies, one labeled with Eu-Cryptate (Donor) and the second with d2 or XL665 (Acceptor). The signal strength is proportional to the concentration of IL-6 present in the sample (The ratio is calculated by 665/620 x 104).
[0357] [0357] The ability of a compound to inhibit IL-6 release induced by I1L-17 from human dermal fibroblasts is measured in this assay.
[0358] [0358] HDF cells (Sigma% 4106-05n) were cultured in complete medium (DMEM + 10% FCS + 2 mM L-glutamine) and kept in a tissue culture flask using standard techniques. The cells were harvested from the tissue culture flask on the morning of the assay using TrypLE (Invitrogen 12605036). TrypLE was neutralized using complete medium (45 mL) and the cells were centrifuged at 300 x g for 3 minutes. The cells were resuspended in complete medium (5 ml) counted and adjusted to a concentration of 3.125 x 10º cells / ml before being added to the 384 well assay (Corning% 3701) at 40 ul per well. The cells were left for a minimum of three hours, at 37ºC / 5% CO ;, to adhere to the plate.
[0359] [0359] The compounds were serially diluted in DMSO before receiving an aqueous dilution in a 384-well dilution plate (Greiner 4781281), where 5 ul of the titration plate was transferred to 45 ul of complete medium and mixed to give a solution containing 10% DMSO.
[0360] [0360] Mixtures of TNFa and cytokine IL-17 were prepared in complete medium to final concentrations of 25 pM TNFa / 50 pM IL-17A, then 30 ul of the solution was added to a 384 well reagent plate (Greiner 4781281).
[0361] [0361] 10 µl of the aqueous dilution plate was transferred to the reagent plate containing 30 µl of the diluted cytokines, to give a 2.5% DMSO solution. The compounds were incubated with the cytokine mixtures for one hour at 37 ° C. After incubation, 10 µL were transferred to the assay plate to give a 0.5% DMSO solution, then incubated for 18 to 20 h at 37 ° C / 5% CO ».
[0362] [0362] From Cisbio's IL-6 FRET kit (Cisbio tt62 / L6PEB) europium cryptate and Alexa 665 were diluted in reconstitution buffer and mixed 1: 1, as per the kit insert. FRET reagents (10 µL) were added to a 384-well, white, low volume plate (Greiner t784075), then the supernatant (10 µL) was transferred from the assay plate to the Greiner reagent plate. The mixture was incubated at room temperature for 3 h with gentle agitation (<400 rpm) before being read in a Synergy Neo 2 plate reader (Excitation: 330 nm; Emission: 615/645 nm).
[0363] [0363] When tested in the above assay, the compounds of the attached Examples were found to exhibit ICso values of 10 µM or better.
[0364] [0364] When tested in the above assay, the compounds of the attached Examples exhibit ICs50 values generally in the range of about 0.01 nM to about 10 UM, usually in the range of about 0.01 nM to about 5 UM, typically in the range of about 0.01 nM to about 1 µM, suitably in the range of about 0.01 nM to about 500 nM, suitably in the range of about 0.01 nM to about 100 nM, ideally in the range from about 0.01 nM to about 50 nM, and preferably in the range of about 0.01 nM to about 25 nM.
[0365] [0365] The following Examples illustrate the preparation of compounds according to the invention. EXAMPLES
[0366] [0366] Abbreviations
[0367] [0367] DCM: dichloromethane DMF: N N-dimethylformamide
[0368] [0368] MeOH: methanolITHF: tetrahydrofuran
[0369] [0369] DMSO: dimethyl sulfoxideDIPEA: N N-diisopropylethylamine
[0370] [0370] EtOH: ethanol EtOAc: ethyl acetate
[0371] [0371] NBS: N-bromosuccinimideNCS: N-chlorosuccinimide
[0372] [0372] TFA: trifluoroacetic acidHOBt: 1-hydroxybenzotriazo!
[0373] [0373] —EM-CI: 2- (trimethylsily) ethoxymethyl chloride
[0374] [0374] EDCI.HCI: N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide chloride
[0375] [0375] HATU: 2- (7-aza-1H-benzotriazole-1-11) -1,1,3,3-tetramethyluronium hexafluorophosphate
[0376] [0376] Selectfluorº: bis (tetrafluoro-borate) of 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo [2,2,2Joctane
[0377] [0377] Pd2 (dba): z: tris (dibenzylidenoacetone) dipaladium (0)
[0378] [0378] XPhos: 2-dicyclohexylphosphino-2 ', 4', 6 '"- trilsopropylbiphenyl
[0379] [0379] Xantphos: 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene
[0380] [0380] tBuBrettPhos Pd G3: [(2-di-tert-butylphosphino-3,6-dimethoxy-2 ', 4', 6 "-trilsopropyl-1,1'-biphenyl) -2- (2'- amino-1,1'-biphenyl)] palladium (11)
[0381] [0381] h: hour.t .: room temperature
[0382] [0382] M: massRT: retention time
[0383] [0383] HPLC: High performance liquid chromatography
[0384] [0384] LCMS: Liquid Chromatography with Mass Spectrometry
[0385] [0385] ES +: Positive electrospray spraying Analytical Conditions
[0386] [0386] The compounds were named with the help of ACD / Name Lote (Network) version 11.01, and / or Accelrys Draw 4.2, and / or Elemental, Dotmatics and / or Chemaxon.
[0387] [0387] All reactions involving reagents sensitive to air or moisture were carried out under a nitrogen atmosphere using dry solvents and glassware.
[0388] [0388] NMR spectra were recorded on a Bruker Avance Ill! HD 500 MHz, 400 MHz, 300 MHz or 250 MHz.
[0389] [0389] Specific Optical Rotations were measured using a Rudolph Research Analytical Autopol 1, S2 Serial 32026 polarimeter.
[0390] [0390] AUuPLC-MS was performed in a Waters Acquity UPLC system connected to a Waters Acquity PDA detector, an ELS detector and an MSD (Positive Scan: 150- 850). Method 1
[0391] [0391] Phenomenex Kinetex-XB column, C18 2.1 x 100 mm, 1.7 um
[0392] [0392] Mobile Phase A: 0.1% formic acid in water
[0393] [0393] Mobile Phase B: 0.1% formic acid in acetonitrile
[0394] [0394] Gradient program: Flow rate 0.6 mL / minute; column temperature 40ºC
[0395] [0395] Time% of A% ofB
[0396] [0396] - 0.0095,005.00
[0397] [0397] 5.300,00100.0
[0398] [0398] - 5,800.00100.0
[0399] [0399] 5.8295,005.00 Method 2
[0400] [0400] Waters UPLCO CSHº C18 column, 2.1 mm x 100 mm, 1.7 um
[0401] [0401] Mobile Phase A: 2 mM ammonium bicarbonate adjusted to pH 10 with ammonium hydroxide
[0402] [0402] Mobile Phase B: acetonitrile
[0403] [0403] Gradient program: Flow rate 0.6 mL / minute; column temperature 40ºC
[0404] [0404] Time% of A% of B
[0405] [0405] - 0.0095,005.00
[0406] [0406] —5,300.00100.0
[0407] [0407] - 5,800.00100.0
[0408] [0408] - 5.8295,005.00 HPLC-MS
[0409] [0409] 1. Performed on a Shimadzu LCMS-2010EV system coupled to the SPD-M20A PDA and PL 2100 detectors. Method 3
[0410] [0410] Phenomenex Kinetex Core-Shell C8 column 50 x 2.1 mm, 5 um, protected by the Phenomenex column “Security Guard '
[0411] [0411] Mobile Phase A: 0.1% formic acid in water
[0412] [0412] Mobile Phase B: 0.1% formic acid in acetoniyril
[0413] [0413] Gradient program: Flow rate 1.2 mL / minute; column temperature 40ºC
[0414] [0414] Time '% of A% of B
[0415] [0415] —0.0095.005.00
[0416] [0416] 1,200.00100.0
[0417] [0417] 1,300.00100.0
[0418] [0418] 1.3195,005.00 Method 4
[0419] [0419] Waters Atlantis dC18 speaker (2.1 x 100 mm, 3 um)
[0420] [0420] Mobile Phase A: 0.1% formic acid in water
[0421] [0421] Mobile Phase B: 0.1% formic acid in acetonitrile
[0422] [0422] Gradient program: Flow rate 0.6 mL / minute; column temperature 40ºC
[0423] [0423] Time '% of A% of B
[0424] [0424] - 0.0095,005.00
[0425] [0425] - 5,000.00100.0
[0426] [0426] - 5,400.00100.0
[0427] [0427] - 5.4295,005.00
[0428] [0428] 2. Performed on an Agilent 1200-6120 LC-MS system coupled to the Detection Mass Spectrometer (230 to 400 nm and 215 nm) and Agilent 6120 (ES) Mass Spec Detection m / z 120 to 800. Method 5
[0429] [0429] Column X-Bridge C18 Waters 2.1 x 20 mm, 2.5 um
[0430] [0430] Mobile Phase A: 10 mM ammonium formate in water + 0.1% formic acid
[0431] [0431] Mobile Phase B: acetonitrile + 5% water + 0.1% formic acid
[0432] [0432] Gradient program: Flow rate 1 mL / minute
[0433] [0433] Time “% of A% of B
[0434] [0434] - 0.0094,006.00
[0435] [0435] —1.505.0095.00
[0436] [0436] 2,255.0095.00
[0437] [0437] - 2.5094,006.00 Method 6
[0438] [0438] Column X-Bridge C18 Waters 2.1 x 20 mm, 2.5 um
[0439] [0439] Mobile Phase A: 10 nM ammonium formate in water + 0.1% ammonia solution
[0440] [0440] Mobile Phase B: acetonitrile + 5% water + 0.1% ammonia solution
[0441] [0441] Gradient program: Flow rate 1 mL / minute
[0442] [0442] Time% of A% of B
[0443] [0443] - 0.0096,004.00
[0444] [0444] - 4,005,0095.00
[0445] [0445] - 5.005,0095.00
[0446] [0446] - 5,1096,004.00 Method 7
[0447] [0447] Column X-Bridge C18 Waters 2.1 x 20 mm, 2.5 um
[0448] [0448] Mobile Phase A: 10 mM ammonium formate in water + 0.1% ammonia solution
[0449] [0449] Mobile Phase B: acetonitrile + 5% water + 0.1% ammonia solution
[0450] [0450] Gradient program: Flow rate 1 mL / minute
[0451] [0451] Time% of A% of B
[0452] [0452] - 0.0096,004.00
[0453] [0453] - 1,505,0095.00
[0454] [0454] - 2,255.0095.00
[0455] [0455] - 2,5096,004.00 Purification by automated preparative reverse phase HPLC
[0456] [0456] 1. Performed using a Gilson system with a Gilson 306 pump, a Gilson 215 autoinjector, a Gilson 215 fraction collector and a Gilson UV detector
[0457] [0457] Column X-Bridge C18 Waters 30 x 100 mm, 5 um
[0458] [0458] Mobile Phase A: water + 0.2% ammonia solution
[0459] [0459] Mobile Phase B: acetonitrile + 0.2% ammonia solution
[0460] [0460] Gradient program: Flow rate 40 mL / minute
[0461] [0461] Time '% of A% of B
[0462] [0462] —0.00955
[0463] [0463] 2.00955
[0464] [0464] 2.507525
[0465] [0465] 16.503565
[0466] [0466] 17,000100
[0467] [0467] 19,000100
[0468] [0468] 19.50955
[0469] [0469] 2. Performed using a Gilson system with a Gilson 3318332 pump, a Gilson GX281 autoinjector, a Gilson GX281 fraction collector and a Gilson 159 UV detector. Method 9
[0470] [0470] Column X-Bridge C18 Waters 30 x 100 mm, 10 um
[0471] [0471] Mobile Phase A: water + 0.2% ammonia solution
[0472] [0472] Mobile Phase B: acetonitrile + 0.2% ammonia solution
[0473] [0473] Gradient program: Flow rate 40 mL / minute
[0474] [0474] Time '% of A% of B
[0475] [0475] - 0.007030
[0476] [0476] 0.557030
[0477] [0477] 11.00595
[0478] [0478] 13.10595
[0479] [0479] 13.317030 Method 10
[0480] [0480] Column X-Bridge C18 Waters 30 x 100 mm, 10 um
[0481] [0481] Mobile Phase A: water + 0.2% ammonia solution
[0482] [0482] Mobile Phase B: acetonitrile + 0.2% ammonia solution
[0483] [0483] Gradient program: Flow rate 40 mL / minute
[0484] [0484] Time% of A% ofB
[0485] [0485] —0.009010
[0486] [0486] 0.559010
[0487] [0487] 14.44595
[0488] [0488] 16.55595
[0489] [0489] 16.759010 Method 11
[0490] [0490] Sunfire C18 Waters column 30 x 100 mm, 10 um
[0491] [0491] Mobile Phase A: water + 0.1% formic acid
[0492] [0492] Mobile Phase B: acetonitrile + 0.1% formic acid
[0493] [0493] Gradient program: Flow rate 40 mL / minute
[0494] [0494] Time% of A% ofB
[0495] [0495] —0.007030
[0496] [0496] 0.557030
[0497] [0497] 11.00595
[0498] [0498] 13.10595
[0499] [0499] 13.317030
[0500] [0500] The column chromatography separations were performed using a BiotageO Isolra 4 system with pre-packaged silica gel columns BiotageO & O SNAP KP-Sil. Analysis of Chiral CFS Method 12
[0501] [0501] Waters Thar 3100 SFC system connected to a Waters 2998 PDA Method 13 detector
[0502] [0502] Waters UPC2-SQD2 Chiral SFC Separation System
[0503] [0503] Waters Thar SFC system with a Waters Thar FDM pump, a Waters Thar Alias autoinjector, a Waters Thar fraction collector and a Waters 2998 PDA detector Method 15
[0504] [0504] Waters Prep 100-SQD2
[0505] [0505] HPLC-MS was performed on a Waters ZQ system coupled to the Waters 2996 PDA and Waters 2420 detectors. Method 16
[0506] [0506] Phenomenex Gemini-NX C18 2.0 mm x 50 mm column, 3 um
[0507] [0507] Mobile Phase A: 2 mM NH4HCO; modified to pH 10 with NH.OH
[0508] [0508] Mobile Phase B: acetonitrile
[0509] [0509] Gradient program: Flow rate 1 mL / minute; column temperature 40ºC
[0510] [0510] Time% of A% of B
[0511] [0511] - 0.0099,001.00
[0512] [0512] 1,800.00100.00
[0513] [0513] 2,100.00100.00
[0514] [0514] 2.3099,001.00
[0515] [0515] - 3.5099,001.00 Method 17
[0516] [0516] Waters Atlantis dC18 column 4.6 x 50 mm, 3 um
[0517] [0517] Mobile Phase A: 0.1% formic acid in water
[0518] [0518] Mobile Phase B: 0.1% formic acid in acetonitrile
[0519] [0519] Gradient program: Flow rate 0.8 mL / minute; column temperature 40ºC
[0520] [0520] Time% of A% of B
[0521] [0521] - 0.0030,0070.00
[0522] [0522] - 3,0090,0010,0
[0523] [0523] —6.0090.0010.0
[0524] [0524] Waters Atlantis dC18 column 4.6 x 50 mm, 3 um
[0525] [0525] Mobile Phase A: 0.1% formic acid in water
[0526] [0526] Mobile Phase B: 0.1% formic acid in acetonitrile
[0527] [0527] Gradient program: Flow rate 0.6 mL / minute; column temperature 40ºC
[0528] [0528] Time '% of A% of B
[0529] [0529] —0.0050.0050.00
[0530] [0530] - 3,0095,005.00
[0531] [0531] - 6,0095,005.00
[0532] [0532] HPLC-MS was performed on an Agilent 1200-6120 LC-MS system coupled to the Detection Spectrometer (230 to 400 nm and 215 nm) and Mass Spec Detection Agilent 6120 (ES) m / z 15 120 to 800 Method 19
[0533] [0533] Column X-Bridge C18 Waters 2.1 x 20 mm, 2.5 um
[0534] [0534] Mobile Phase A: 10 mM ammonium formate in water + 0.1% formic acid
[0535] [0535] Mobile Phase B: acetonitrile + 5% water + 0.1% formic acid
[0536] [0536] Gradient program: Flow rate 1 mL / minute
[0537] [0537] Time% of A% of B
[0538] [0538] - 0.0095,005.00
[0539] [0539] - 4,005,0095.00
[0540] [0540] - 5.005,0095.00
[0541] [0541] - 5,1095,005.00
[0542] [0542] Purification by automated preparative reverse phase HPLC was performed using a Gilson system with a Gilson 331 & 332 pump, a Gilson GX281 autoinjector, a Gilson GX281 fraction collector and a Gilson 159 UV detector. Method 20
[0543] [0543] Sunfire C18 Waters column 30 x 100 mm, 10 um
[0544] [0544] Mobile Phase A: water + 0.1% formic acid
[0545] [0545] Mobile Phase B: acetonitrile + 0.1% formic acid
[0546] [0546] Gradient program: Flow rate 40 mL / minute
[0547] [0547] Time% of A% of B
[0548] [0548] - 0,0090,0010,00
[0549] [0549] - 0.5590,0010.00
[0550] [0550] 14,445.0095.00
[0551] [0551] 16,555.0095.00
[0552] [0552] 16.7590,0010.00
[0555] [0555] HPLC-MS was performed on an Agilent 1200RR-6140 LC-MS system coupled to a DAD SL detector. Method 21
[0554] [0554] Column XBridge C18 2.1 x 20 mm, 2.5 um
[0555] [0555] Mobile Phase A: 10 mM ammonium formate in water + 0.1% formic acid
[0556] [0556] Mobile Phase B: acetonitrile + 5% water + 0.1% formic acid
[0557] [0557] Gradient program: Flow rate 1 mL / minute; column temperature 40ºC
[0558] [0558] Time% of A% of B
[0559] [0559] - 0.0095,005.00
[0560] [0560] - 4,005,0095.00
[0561] [0561] - 5.005,0095.00
[0562] [0562] - 5,1095,005.00
[0563] [0563] Purification by automated preparative reverse phase HPLC was performed using a Waters Fraction Lynx Prep system coupled to an SQD2 mass spectrometer and a Waters 2998 PDA detector. Method 22
[0564] [0564] Waters XBridge Prep C18 speaker 19 x 100 mm, 5 um
[0565] [0565] Mobile Phase A: 10 mM ammonium bicarbonate in water + 0.1% ammonia solution
[0566] [0566] Mobile Phase B: acetonitrile + 5% solvent A + 0.1% ammonia solution
[0567] [0567] Gradient program: Flow rate of 20 mL / minute
[0568] [0568] Time% of A% of B
[0569] [0569] - 0.0065,0035.00
[0570] [0570] 2.5065,0035.00
[0571] [0571] 11.0050.0050.00
[0572] [0572] 11,505.0095.00
[0573] [0573] 12,505.0095.00
[0574] [0574] 13.0065.0035.00
[0575] [0575] AUuUuPLC-MS was carried out in a Waters Classic Acquity-QDa LC-MS system coupled to a Waters Acquity PDA detector. Method 23
[0576] [0576] Waters Acquity UPLC BEH column, C18 2.1 x 50 mm, 1.7 um
[0577] [0577] Mobile Phase A: 10 mM ammonium formate in water + 0.1% ammonia solution
[0578] [0578] Mobile Phase B: acetonitrile + 5% water + 0.1% ammonia solution
[0579] [0579] Gradient program: Flow rate 0.7 mL / minute; column temperature 40ºC
[0580] [0580] Time% of A% of B
[0581] [0581] - 0.0098,002.00
[0582] [0582] - 4,005,0095.00
[0583] [0583] - 5.005,0095.00
[0584] [0584] - 5,1098,002.00
[0585] [0585] Purification by automated preparative reverse phase HPLC was performed using a Waters Fraction Lynx Prep system coupled to an SQD2 mass spectrometer and a Waters 2998 PDA detector. Method 24
[0586] [0586] Waters XBridge Prep Phenil column 19 x 150 mm, 5 um
[0587] [0587] Mobile Phase A: 10 mM ammonium bicarbonate in water + 0.1% ammonia solution
[0588] [0588] Mobile Phase B: acetonitrile + 5% solvent A + 0.1% ammonia solution
[0589] [0589] Gradient program: Flow rate 20 mL / minute
[0590] [0590] Time% of A% of B
[0591] [0591] —0.0070.0030.00
[0592] [0592] 2.5070,0030.00
[0593] [0593] 11.0055.0045.00
[0594] [0594] 11,505.0095.00
[0595] [0595] 12.505.0095.00
[0596] [0596] 13.0070.0030.00 Method 25
[0597] [0597] Waters XBridge Prep Phenil column 19 x 150 mm, 5 um
[0598] [0598] Mobile Phase A: 10 mM ammonium bicarbonate in water + 0.1% ammonia solution
[0599] [0599] Mobile Phase B: acetonitrile + 5% solvent A + 0.1% ammonia solution
[0600] [0600] Gradient program: Flow rate of 20 mL / minute
[0601] [0601] Time% of A% ofB
[0602] [0602] - 0.0065,0035.00
[0603] [0603] 2.5065,0035.00
[0604] [0604] —11.0050.0050.00
[0605] [0605] —11,505,0095.00
[0606] [0606] 12,505.0095.00
[0607] [0607] 13.0065.0035.00 Method 26
[0608] [0608] Waters XBridge Prep C18 speaker 19 x 100 mm, 5 um
[0609] [0609] Mobile Phase A: 10 mM ammonium bicarbonate in water + 0.1% ammonia solution
[0610] [0610] Mobile Phase B: acetonitrile + 5% solvent A + 0.1% ammonia solution
[0611] [0611] Gradient program: Flow rate of 20 mL / minute
[0612] [0612] Time '% of A% of B
[0613] [0613] 0.0065,0035.00
[0614] [0614] 2.0065,0035.00
[0615] [0615] - 12.0050,0050.00
[0616] [0616] 16,005,0095,00
[0617] [0617] 18.0065,0035.00
[0618] [0618] uPLC-MS was performed in a Waters Classic Acquity-QDa LC-MS system coupled to a Waters Acquity PDA detector. Method 27
[0619] [0619] Waters Acquity UPLC BEH column, C18 2.1 x 50 mm, 2.5 um
[0620] [0620] Mobile Phase A: 10 mM ammonium formate in water + 0.1% ammonia solution
[0621] [0621] Mobile Phase B: acetonitrile + 5% water + 0.1% ammonia solution
[0622] [0622] Gradient program: Flow rate 1.0 mL / minute; column temperature 45ºC
[0623] [0623] “Time% of A% ofB
[0624] [0624] - 0,0095,005.00
[0625] [0625] 2,105,0095.00
[0626] [0626] 2.35,0095.00
[0627] [0627] 5.3595.005,00 Method 28
[0628] [0628] Waters Acquity UPLC BEH column, C18 2.1 x 30 mm, 1.7 um
[0629] [0629] Mobile Phase A: water / acetonitrile / formic acid (95/5/750 uL)
[0630] [0630] Mobile Phase B: water / acetonitrile / formic acid (5/95/500 uL)
[0631] [0631] Gradient program: Flow rate 0.8 mL / minute; column temperature 45ºC
[0632] [0632] Time '% of A% of B
[0633] [0633] - 0.0095,005.00
[0634] [0634] - 1,805,0095.00
[0635] [0635] 2.45,0095.00
[0636] [0636] 2,595,005.00
[0637] [0637] HPLC-MS was performed on a Shimadzu LCMS-2010EV system coupled to the SPD-M20A PDA and PL 2100 detectors.
[0638] [0638] Phenomenex Kinetex Core-Shell C8 column 50 x 2.1 mm, 2.6 um protected by the Phenomenex column “Security Guard '
[0639] [0639] Mobile Phase A: water + 0.1% formic acid
[0640] [0640] Mobile Phase B: acetonitrile + 0.1% formic acid
[0641] [0641] Gradient program: Flow rate 0.6 mL / minute; column temperature 40ºC
[0642] [0642] Time '% of A% of B
[0643] [0643] 0.00955
[0644] [0644] —4,400100
[0645] [0645] —5.400100
[0646] [0646] 5.42595
[0647] [0647] —6.00595
[0648] [0648] Purification by automated preparative reverse phase HPLC was performed using a Gilson system with a Gilson 306 pump, a Gilson 215 autoinjector, a Gilson 215 fraction collector and a Gilson 156 UV detector. Method 30
[0649] [0649] Column Sunfire C18 Waters 19 x 100 mm, 5 um
[0650] [0650] Mobile Phase A: water + 0.1% formic acid
[0651] [0651] Mobile Phase B: acetonitrile + 0.1% formic acid
[0652] [0652] Gradient program: Flow rate of 20 mL / minute
[0653] [0653] Time% of A% of B
[0654] [0654] —0.00955
[0655] [0655] —1.90955
[0656] [0656] 2.006832
[0657] [0657] 16.005842
[0658] [0658] 16.10595
[0659] [0659] 18.00595
[0660] [0660] 18,10955 Method 31
[0661] [0661] Sunfire C18 Waters speaker 19 x 100 mm, 5 um
[0662] [0662] Mobile Phase A: water + 0.1% formic acid
[0663] [0663] Mobile Phase B: acetonitrile + 0.1% formic acid
[0664] [0664] Gradient program: Flow rate 20 mL / minute
[0665] [0665] Time% of A% ofB
[0666] [0666] —0.00955
[0667] [0667] 2.00955
[0668] [0668] 2.505545
[0669] [0669] 22.505545
[0670] [0670] 23.001000
[0671] [0671] 25.001000
[0672] [0672] 25.50955
[0673] [0673] Separates by chiral HPLC Method 32
[0674] [0674] Gilson system with a Gilson 321/322 pump, a Gilson GX241 autoinjector, a Gilson PREP FC fraction collector and a Gilson 171/172 UV detector. HPLC-MS
[0675] [0675] 1) Performed on a Shimadzu LC-20AB & MS 2010. Method 33
[0676] [0676] Luna-C18 column (2) 2.0 x 30 mm, 3 um
[0677] [0677] Mobile Phase A: water + 0.037% (v / v) TEA
[0678] [0678] Mobile Phase B: acetonitrile + 0.018% (v / v) TEA
[0679] [0679] Gradient program: Flow rate 0.8 mL / minute; column temperature 40ºC
[0680] [0680] Time% of A% ofB
[0681] [0681] - 0.00100,00.0
[0682] [0682] 1,6040,060.0
[0683] [0683] 1,660.0100,0
[0684] [0684] 2,200,0100,0
[0685] [0685] 2. Performed on a Shimadzu 20D & MS2020.
[0686] [0686] Zorbax Eclipse XDB-C18 2.1 x 30 mm, 3.5 um speaker
[0687] [0687] Mobile Phase A: water + 0.037% (v / v) TFA
[0688] [0688] Mobile Phase B: acetonitrile + 0.018% (v / v) TEA
[0689] [0689] Gradient program: Flow rate 0.8 mL / minute; column temperature 40ºC
[0690] [0690] Time “% of A% of B
[0691] [0691] 0,0095.05,0
[0692] [0692] 1,005,095.0
[0693] [0693] 1,800,0100.0
[0694] [0694] 2,200,0100,0
[0695] [0695] SFC Quiral was performed on the Agilent 1100, DAD system. Method 35
[0696] [0696] Lux Cellulose-1 4.6 x 150 mm column, 3 um
[0697] [0697] Mobile Phase A: CO
[0698] [0698] Mobile Phase B: methanol (+ 0.1% NH.OH)
[0699] [0699] Gradient program: Flow rate 3 mL / minute; column temperature 35ºC
[0700] [0700] Time% of A% of B
[0701] [0701] - 0.0097,003.00
[0702] [0702] - 5.0060,0040.00
[0703] [0703] 5,1097,003.00 INTERMEDIATE 1 Methyl 4- (2,4-dinitrophenyl) tetrahydropyran-4-carboxylate
[0704] [0704] Sodium hydride (60% dispersion in mineral oil, 33 mg, 0.84 mmol) was added to a solution of methyl (2,4-dinitrophenyl) acetate (77 mg, 0.32 mmol) and 1 -bromo-2- (2-bromoethoxy) ethane (0.046 ml, 0.321 mmol) in DNF (3 ml) at 0ºC. The cooling bath was removed and the reaction mixture was stirred for 10 minutes at 20ºC, then heated to 90ºC for 4 h. The reaction mixture was cooled to room temperature and saturated aqueous ammonium chloride solution (5 ml) was added. The resulting mixture was extracted with ethyl acetate (2 x 30 ml). The organic phase was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by sparkling column chromatography, using a gradient of ethyl acetate in heptane (0 to 100%), to produce the title compound (49 mg, 49%) as a light orange gum. õ4 (250 MHz, CDCI3) 8.62 (d, J 2.5 Hz, 1H), 8.48 (dd, J 8.8, 2.5 Hz, 1H), 7.89 (d, J 8, 9 Hz, 1H), 3.97 (ddd, J 12.0, 9.5, 2.7 Hz, 2H), 3.80 (td, J 7.8, 4.1 Hz, 2H), 3, 73 (s, 3H), 2.40 (d, J 13.8 Hz, 2H), 2.10 (ddd, J 13.8, 9.5, 4.3 Hz, 2H). HPLC-MS (method 3): MH + m / z in the observed precursor ion, RT 1.08 min. INTERMEDIATE 2 6-Aminoespiro [indolino-3,4'-tetrahydropyran] -2-one
[0705] [0705] Iron powder (3.79 g, 67.8 mmol) was added to a stirred solution of Intermediate 1 (2.5 g, 4.24 mmol) in a mixture of saturated aqueous ethanol / water / chloride solution ammonium (8: 1: 1; 81 mL) and the suspension was stirred at 60ºC under a nitrogen atmosphere for 6.5 h. After cooling to room temperature, the mixture was diluted with water (100 ml) and ethanol (100 ml). The suspension was filtered through a pad of diatomaceous earth, washed sequentially with ethanol (3 x 50 ml), methanol (3 x 100 ml), water (100 ml) and ethyl acetate (3 x 100 ml). The filtrate was concentrated in vacuo. The residue was diluted with water (100 ml) and extracted with ethyl acetate (3 x 100 ml), then with isopropanol / chloroform 1: 1 (3 x 50 ml). The combined organic extracts were washed with brine (100 ml) and dried over sodium sulfate, then filtered and concentrated in vacuo. The residue was purified by sparkling column chromatography (KP-NH column), using a gradient of ethyl acetate in heptane (50 to 100%) followed by a gradient of methanol in ethyl acetate (0 to 10%), to produce the title compound (571 mg, 61%) as a brown powder. õH (500 MHz, DMSO-ds) 10.09 (s, 1H), 7.11 (d, J 8.6 Hz, 1H), 6.19 - 6.07 (m, 2H), 5.07 ( s, 2H), 3.97 (ddd, J 11.0, 6.9, 3.8 Hz, 2H), 3.76 (ddd, J 11.3, 7.5, 3.6 Hz, 2H) , 1.70 (ddd, J 11.4, 7.5, 3.7 Hz, 2H), 1.52 (ddd, J 13.3, 6.8, 3.5 Hz, 2H). HPLC-MS (method 7): MH + m / z 219, RT 1.00 minutes. INTERMEDIATE 3 Methyl (28S) -2-amino-3- (2-chlorophenyl) propanoate chloride
[0706] [0706] Thionyl chloride (2 mL, 27.42 mmol) was added to the drops to anhydrous methanol (7.5 mL) cooled to 0 ° C under nitrogen. After stirring for 5 minutes, 2-chloro-L-phenyl-alanine (5.0 g, 25.05 mmol) was added to the portions, followed by methane! anhydrous (7.5 mL). The suspension was heated to 50ºC for 5 h under nitrogen, then the volatiles were removed in vacuo. The residue was suspended in diethyl ether (20 ml) and concentrated again to yield the title compound (5.89.99%) as a brown powder. õs (500 MHz, DMSO-ds) 8.91 (br s, 3H), 7.49 - 7.39 (m, 2H), 7.35 - 7.30 (m, 2H), 4.12 (dd , J 9.0, 6.2 Hz, 1H), 3.59 (s, 3H), 3.39 - 3.32 (obs m, 1H), 3.23 (dd, J 13.8, 9, 0 Hz, 1H). HPLC-MS (method 7): MH + m / z 214, RT 1.58 minutes. INTERMEDIATE Methyl 4 (28) -3- (2-chlorophenyl) -2 - ([2- (pyridin-4-yl) acetylJamino) propanoate
[0707] [0707] DIPEA (12.4 mL, 75.03 mmol) was added slowly to a stirred suspension of Intermediate 3 (5.89 g, 23.53 mmol), 2- (pyridin-4-yl) acetic acid chloride (4.29 g, 24.71 mmol) and HATU (9.84 g, 25.88 mmol) in anhydrous DMF (47 mL). The mixture was stirred at 20ºC under nitrogen for 16 h. The volatiles were removed in vacuo and the residue was partitioned between ethyl acetate (100 ml) and saturated aqueous sodium carbonate solution (100 ml). The aqueous layer was separated and extracted with ethyl acetate (2 x 100 ml). The combined organic extracts were washed with water (50 ml) and brine (2 x 50 ml), then dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting crude dark red gum was separated by sparkling column chromatography, using a methanol gradient in DCM (0 to 6.5%), to produce the title compound (5.95 g, 76%) as a viscous orange oil . õH (500 MHz, DMSO-ds) 8.74 (d, J 8.2 Hz, 1H), 8.47 - 8.37 (m, 2H), 7.41 (dd, J 7.8, 1, 3 Hz, 1H), 7.31 - 7.19 (m, 3H), 7.16 - 7.04 (m, 2H), 4.61 (ddd, J 9.9, 8.2, 5.4 Hz, 1H), 3.62 (s, 3H), 3.45 (s, 2H), 3.25 (dd, J 13.8, 5.4 Hz, 1H), 2.97 (dd, J 13 , 8, 9.9 Hz, 1H). HPLC-MS (method 5): MH + m / z 333, RT 1.44 minutes. Chiral SFC (Method 12, Chiralpak AD-H 25 cm, 35% ethanol-65% carbon dioxide, 4 mL / minute): RT 2.42 minutes (100%). INTERMEDIATE 5
[0708] [0708] A solution of lithium hydroxide monohydrate (1.20 9, 28.53 mmol) in water (18 mL) was added to a stirred solution of Intermediate 4 (5.93 g, 17.83 mmol) in THF / MeOH (1: 1; 36 mL) at 0 ° C. The mixture was allowed to warm slowly to 20 ° C and was stirred for a total of 16 h, forming a thick suspension. The volatiles were removed in vacuo. The aqueous slurry was diluted with water (150 ml) and 1 M aqueous sodium hydroxide solution (50 ml). The aqueous layer was washed with tert-butyl methyl ether (50 ml). The organic phase was separated and extracted with aqueous 1 M sodium hydroxide solution (50 ml). The combined aqueous layers were washed with tert-butyl methyl ether (50 ml). The pH of the aqueous phase was adjusted to 5 to 6 using concentrated hydrochloric acid. The material was extracted sequentially with 1: 1 DCM / isopropanol (8 x 100 ml) and 2-methyltetrahydrofuran (12 x 100 ml). The organic extracts were washed with brine (50 ml), dried over magnesium sulfate and filtered, then combined and reduced in vacuo. The resulting crude yellow powder was crushed from DCM (100 ml), then the solids were collected by filtration, washed with DCM (2 x 50 ml) and dried under vacuum at 50ºC for 4 h, to produce the title compound ( 5.70 g, quantitative) as a yellowish white powder. õx (500 MHz, DMSO-ds) 12.87 (br s, 1H), 8.64 (d, J 8.5 Hz, 1H), 8.41 (d, J 5.4 Hz, 2H), 7 , 39 (dd, J 7.9, 1.2 Hz, 1H), 7.29 (dd, JU 7.4, 1.7 Hz, 1H), 7.24 (td, J 7.6, 1, 8 Hz, 1H), 7.19 (td, J 7.4, 1.3 Hz, 1H), 7.10 (d, J 5.9 Hz, 2H), 4.56 (ddd, J 10.4 , 8.6, 4.7 Hz, 1H), 3.43 (s, 2H), 3.28 (dd, J 13.8, 4.7 Hz, 1H), 2.91 (dd, J 13, 9, 10.5 Hz, 1H). HPLC-MS (method 7): MH + m / z 319, RT 1.26 minutes. Chiral SFC (Method 12, Chiralpak AD-H 25 cm, 25% methanol-75% carbon dioxide, 4 mL / minute): RT 2.22 minutes (100%). INTERMEDIATE 6 [(1S) -1-Cyclohexyl-2-methoxy-2-oxoethylJammonium chloride
[0709] [0709] Thionyl chloride (8 mL, 110.15 mmol) was added to the drops to anhydrous methanol (60 mL) cooled to 0 ° C under nitrogen. After stirring for 5 minutes, (2S) -amino- (cyclohexyl) etanoic acid (15.72 g, 100.00 mmol) was added to the portions, then the reaction mixture was heated at 50ºC for 5 h under nitrogen. The solvent was removed in vacuo and the residue was triturated in diethyl ether (250 ml). The solids were collected by filtration to produce the title compound (16.9 g, 81%) as a white solid. õr (500 MHz, DMSO-ds) 8.52 (s, 3H), 3.81 (d, J 5.1 Hz, 1H), 3.75 (s, 3H), 1.86 - 1.77 ( m, 1H), 1.74 - 1.67 (m, 3H), 1.65 - 1.58 (m, 2H), 1.22 - 1.12 (m, 3H), 1.12 - 1, 03 (m, 1H), 0.97 (qd, J 12.9, 12.2, 3.8 Hz, 1H). HPLC-MS (method 6): MH + m / z 172, RT 2.32 minutes. INTERMEDIATE 7 (28S) -2-cyclohexyl-2-f [2- (pyridin-4-yl) acetylJamino) methyl acetate
[0710] [0710] 2,4,6-Tripropyl-1,3,5,2,4,6-trioxatriphosphorin-2,4,6-trioxide (50% by weight solution in ethyl acetate, 39.2 ml, 66 , 44 mmol) was added in 30 minutes to a stirred solution of Intermediate 6 (6.90 g, 33.22 mmol), 2- (pyridin-4-yl) acetic acid chloride (6.92 g, 39.87 mmol) and DIPEA (19.2 mL, 116.27 mmol) in anhydrous THF (210 mL). The mixture was stirred at 20ºC under nitrogen for 3.5 h, then diluted with water (250 ml) and washed with ethyl acetate (2 x 200 ml). The pH of the aqueous phase was adjusted to pH 10 by slowly adding the 4 M aqueous solution of sodium hydroxide (21 ml), then the aqueous phase was extracted with ethyl acetate (2 x 300 ml). The organic extracts were combined, washed with water (250 ml) and brine (250 ml), then dried over anhydrous magnesium sulfate and filtered. The solvent was removed in vacuo. The residue was separated by flashing column chromatography, using a gradient of methanol in DCM (1 to 8%), to produce the title compound (4.53 g, 47%) as a yellow solid. dn (500 MHz, DMSO-ds) 8.53 - 8.44 (m, 3H), 7.30 - 7.24 (m, 2H), 4.16 (dd, J 8.7, 6.5 Hz , 1H), 3.62 (s, 3H), 3.57 (d, J 14.2 Hz, 1H), 3.54 (d, J 14.4 Hz, 1H), 1.73 - 1.50 (m, 6H), 1.25 - 1.03 (m, 4H), 0.98 (gd, J 12.5, 3.5 Hz, 1H). HPLC-MS (method 5): MH + m / z 291, RT 1.44 minutes. Chiral SFC (Method 12, Chiralpak AD-H 25 cm, 35% ethanol-65% carbon dioxide, 4 mL / minute): RT 3.07 minutes (100%). INTERMEDIATE 8 (2S) -2-cyclohexyl-2-f [2- (pyridin-4-yl) acetylLithium aminoacetate
[0711] [0711] A solution of lithium hydroxide monohydrate (0.99 9, 23.70 mmol) in water (16 mL) was added to a stirred solution of Intermediate 7 (4.53 g, 15.80 mmol) in THF / MeOH (1: 1; 32 mL) at 0 ° C. The mixture was allowed to warm slowly to 20ºC and stirred for a total of 16 h, forming a thick suspension. The volatiles were removed in vacuo, then the residue was diluted with water (20 ml). The solids were collected by filtration, then washed with water (20 ml) and methyl tert-butyl ether (20 ml), before vacuum drying at 50ºC for 16 h, to produce the title compound (3.53 g, 79 %) as a yellowish white powder. ds (500 MHz, D2O) 8.56 - 8.45 (m, 2H), 7.42 (d, J 6.1 Hz, 2H), 4.13 (d, J 5.8 Hz, 1H), 3.81 (d, J 14.9 Hz, 1H), 3.72 (d, J 14.9 Hz, 1H), 1.85 - 1.69 (m, 3H), 1.68 - 1.54 (m, 3H), 1.24 (dtt, J 16.0, 12.7, 3.3 Hz, 2H), 1.16 - 0.91 (m, 3H). HPLC-MS (method 5): MH + m / z 277, RT 1.45 minutes. Chiral SFC (Method 12, Chiralpak IC 25 cm, 40% isopropanol + 0.2% diethylamino-60% carbon dioxide, 4 mL / minute): RT 4.40 minutes (100%). INTERMEDIATE 9 Methyl 2-cyclooctylidene-2-formamidoacetate
[0712] [0712] A solution of potassium tert-butoxide in THF (1 M, 48 mL, 48 mmol) was added dropwise to a red solution of methyl isocianoacetate (4.0 mL, 41.8 mmol) in anhydrous THF ( 40 mL) at approximately -65ºC under nitrogen. After stirring for 5 minutes, a solution of cyclooctanone (5 g, 39.62 mmol) in anhydrous THF (20 mL) was added slowly at -70 ° C. The reaction mixture was stirred at -70ºC for 30 minutes, then the cooling bath was removed and the mixture was allowed to warm up to 20ºC with stirring under nitrogen for 60 h. The resulting deep red solution was quenched with water (100 mL) and stirred at 20ºC for 1 h. The residue was extracted with ethyl acetate (3 x 100 ml). The combined organic extracts were washed with brine (50 ml) and dried over magnesium sulfate, then filtered and concentrated in vacuo. The resulting crude viscous orange oil was separated by sparkling column chromatography using a gradient of ethyl acetate in heptane (90% O) to produce the title compound (5.37 g, 58%) as an orange viscous oil, which solidified at rest. Main rotamer: dn (500 MHz, DMSOdes) 9.31 (s, 1H), 8.01 (d, J 1.5 Hz, 1H), 3.60 (s, 3H), 2.52 - 2 , 47 (m, 2H), 2.31 - 2.23 (m, 2H), 1.74 - 1.60 (m, 4H), 1.50 - 1.31 (m, 6H). HPLC-MS (method 5): MNa + m / z 248, RT 1.63 minutes.
[0713] [0713] Magnesium shavings (3.15 g, 129.60 mmol) were carefully added to a stirred solution of Intermediate 9 (2.91 g, 12.95 mmol) in anhydrous methanol (65 mL) at 0 ° C under nitrogen. The suspension was stirred at 0 ° C for 1 h, then allowed to warm to 20 ° C in 2 h. Stirring of the cloudy suspension was continued at 20 ° C for 16 h. An additional portion of magnesium chips (1 g, 41.14 mmol) was added, and the suspension was stirred at 20 ° C for 3.5 h under nitrogen. The mixture was carefully concentrated in vacuo. The residue was suspended in ethyl acetate (100 ml) and water (200 ml), then cooled to 0ºC. Aqueous hydrochloric acid (1 M, 100 mL) was cautiously added, then concentrated hydrochloric acid was cautiously added (pH 5) to help dissolve the solids. The organic phase was separated, then the aqueous suspension was treated with concentrated hydrochloric acid (pH 4) and the material was extracted with ethyl acetate (100 ml). The aqueous suspension was treated with concentrated hydrochloric acid (pH 2) and the material was extracted with ethyl acetate (100 ml). The aqueous suspension was further treated with concentrated hydrochloric acid (pH 1) and the material was extracted with ethyl acetate (100 ml). The combined organic extracts were washed with brine (50 ml) and dried over magnesium sulfate, then filtered and concentrated in vacuo. The resulting crude orange viscous oil was separated by sparkling column chromatography, using a gradient of ethyl acetate in heptane (0 to 80%), to produce the title compound (1.53 g, 52%) as an orange viscous oil. . Main rotamer: dr (500 MHz, DMSO-ds) 8.46 (d, J 8.5 Hz, 1H), 8.06 (s, 1H), 4.29 (dd, J 8.6, 6.1 Hz, 1H), 3.64 (s, 3H), 2.04-1.93 (m, 1H), 1.73 - 1.19 (m, 14H). HPLC-MS (method 4): MH + m / z 228, RT 3.94 minutes. INTERMEDIATE 11 Methyl 2-amino-2-cyclooctylacetate chloride
[0714] [0714] Acetyl chloride (1.9 mL, 26.72 mmol) was cautiously added at 0 ° C to a stirred solution of Intermediate 10 (1.54 g, 6.77 mmol) in methanol (68 mL) under nitrogen. After stirring for 5 minutes, the solution was heated to 50ºC for
[0715] [0715] DIPEA (1.05 mL, 6.35 mmol) was added to a stirred solution of Intermediate 11 (500 mg, 2.12 mmol), 1-methyl-1H-pyrazole-5-carboxylic acid (269 mg, 2.12 mmol) and HATU (969 mg, 2.55 mmol) in anhydrous DMF (10 mL) under a nitrogen atmosphere. The mixture was stirred at 20ºC for 18 h, then quenched with a saturated aqueous solution of sodium hydrogen carbonate (50 ml) and water (50 ml). The material was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (2 x 50 ml) and dried over sodium sulfate, then filtered and concentrated in vacuo. The residue was purified by scintillating column chromatography, using a gradient of ethyl acetate in heptane (0 to 100%), to produce the title compound (618 mg, 99%) as a yellowish orange oil. dx (500 MHz, DMSO-ds) 8.60 (d, J 8.3 Hz, 1H), 7.46 (d, J 2.1 Hz, 1H), 7.01 (d, J 2.1 Hz , 1H), 4.37 (t, J 8.1 Hz, 1H), 4.01 (s, 3H), 3.66 (s, 3H), 2.22 - 2.08 (m, 1H), 1.80 - 1.38 (m, 13H), 1.37 - 1.29 (m, 1H). HPLC-MS (method 5): MH + m / z 308, RT 1.87 minutes. INTERMEDIATE 13 2-cyclooctyl-2 - [(2-methylpyrazol-3-carbonyl) amino] lithium acetate
[0716] [0716] To a stirred solution of Intermediate 12 (519 mg, 1.69 mmol) in THF (9 mL) and water (4.5 mL) was added lithium hydroxide monohydrate (0.106 9, 2.53 mmol). The reaction mixture was stirred at 20 ° C for 22 h, then concentrated and dried in vacuo for 4 h, to produce the title compound (505 mg, quantitative) as a yellow solid. ds (500 MHz, DMSO-ds) 7.60 (d, J 7.6 Hz, 1H), 7.42 (d, J 2.0 Hz, 1H), 6.74 (d, J 2.0 Hz , 1H), 4.01 (s, 3H), 3.88 (dd, J 7.6, 4.3 Hz, 1H), 2.11 - 2.01 (m, 1H),
[0717] [0717] Thionyl chloride (0.3 mL, 4.14 mmol) was added dropwise to acetic (2-aminopyridin-4-yl) acid (594 mg, 3.90 mmol) in methanol (12 mL) at 0ºC. The reaction mixture was allowed to warm to 20ºC and stirred for 18 h, then evaporated to dryness. The residue was partitioned between isopropanol / chloroform (1: 1; 60 ml) and saturated aqueous sodium hydrogen carbonate solution (60 ml). The layers were separated, then the aqueous phase was extracted with isopropanol / chloroform (1: 1; 2 x 60 ml). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo, to yield the title compound (605 mg, 93%) as a pinkish red solid. õx (500 MHz, DMSO-ds) 7.81 (d, J 5.2 Hz, 1H), 6.37 (dd, J 5.2, 1.4 Hz, 1H), 6.32 (s, 1H ), 5.86 (s, 2H), 3.61 (s, 3H), 3.51 (s, 2H). HPLC-MS (method 6): MH + m / z 167, RT 0.70 min. INTERMEDIATE 15 2- [2- (tert-butoxycarbonylamino) pyridin-4-yl Methylacetate
[0718] [0718] A solution of di-tert-butyl dicarbonate (433 mg, 1.98 mmol) in tert-butanol (6 mL) was added slowly to a stirred solution of Intermediate 14 (300 mg, 1.81 mmol) in tert-butanol (12 mL). The mixture was stirred at 20ºC under nitrogen for 16 h, then the volatiles were removed in vacuo. The residue was separated by sparkling column chromatography, using a gradient of ethyl acetate in heptane (0 to 100%), to produce the title compound (325 mg, 67%) as a yellowish white powder. dx (500 MHz, DMSO-ds) 9.74 (br s, 1H), 8.16 (d, J 5.1 Hz, 1H), 7.74 (s, 1H), 6.93 (dd, J 5.1, 1.4 Hz, 1H), 3.72 (s, 2H), 3.63 (s, 3H), 1.47 (s, 9H). HPLC-MS (method 5): MH + m / z 211, RT 1.67 minutes. INTERMEDIATE 16 2- [2- (tert-butoxycarbonylamino) pyridin-4-ylacetic acid
[0719] [0719] A solution of lithium hydroxide monohydrate (74 mg, 1.76 mmol) in water (1.2 mL) was added to a stirred solution of Intermediate 15 (311 mg, 1.17 mmol) in MeOH / THF (1: 1; 24 mL). The solution was stirred at 20ºC under air for 16 h,
[0720] [0720] DIPEA (380 yuL, 2.30 mmol) was added to a stirred solution of Intermediate 11 (180 mg, 0.76 mmol), Intermediate 16 (197 mg, 0.77 mmol) and HATU (350 mg, 0 , 92 mmol) in anhydrous DMF (3 mL) under a nitrogen atmosphere. The mixture was stirred at 20ºC for 18 h, then quenched with a saturated aqueous solution of sodium hydrogen carbonate (20 mL) and water (20 mL). The material was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (2 x 20 ml) and dried over sodium sulfate, then filtered and concentrated in vacuo. The residue was purified by sparkling column chromatography, using a gradient of ethyl acetate in heptane (0 to 100%), to produce the title compound (282 mg, 85%) as a yellowish orange oil. ds (500 MHz, DMSO-ds) 9.65 (s, 1H), 8.48 (d, J 8.5 Hz, 1H), 8.12 (d, J 5.1 Hz, 1H), 7, 75 (s, 1H), 6.91 (dd, J 5.1, 1.3 Hz, 1H), 4.22 (dd, J 8.4, 6.5 Hz, 1H), 3.62 (s , 3H), 3.57 (d, J 13.9 Hz, 1H), 3.46 (d, J 13.9 Hz, 1H), 2.03 - 1.93 (m, 1H), 1.69 - 1.22 (m, 14H), 1.45 (s, 9H). HPLC-MS (method 5): MH + m / z 434, RT 1.97 minutes. INTERMEDIATE 18 2 - ((2- [2- (tert-butoxycarbonylamino) pyridin-4-ylJacetyl; amino) -2-lithium cyclooctyl-acetate
[0721] [0721] Lithium hydroxide monohydrate (38 mg, 0.90 mmol) was added to a stirred solution of Intermediate 17 (260 mg, 0.680 mmol) in THF (6 mL) and water (3 mL). The reaction mixture was stirred at 20 ° C for 22 h, then concentrated and dried in vacuo for 4 h, to give the title compound (255 mg, quantitative) as a yellowish white powder. HPLC-MS (method 5): MH + m / z 420, RT 1.82 minutes. INTERMEDIATE 19 2 - ((2- [2- (tert-Butoxycarbonylamino) pyridin-4-ylJacetyl <amino) -2-cyclooctyl-N- (2-0x0- spiro [indolino-3,4'-tetrahydropyran] -6- il) acetamide
[0722] [0722] HATU (210 mg, 0.55 mmol) was added to a stirred solution of Intermediate 2 (100 mg, 0.46 mmol) and Intermediate 18 (213 mg, 0.5 mmol) in anhydrous DMF (4 mL) under a nitrogen atmosphere. The mixture was stirred at 20ºC for 15 h, then quenched with saturated aqueous sodium hydrogen carbonate solution (20 mL). Water (20 ml) and ethyl acetate (20 ml) were added, then the resulting white precipitate was filtered and washed with DCM (2 x 10 ml) and isopropanol / chloroform (1: 1; 2x 10 ml). The aqueous and organic layers were separated, then the aqueous phase was extracted with ethyl acetate (2 x 20 ml). The combined organic washes and extracts were dried over sodium sulfate, then filtered and concentrated in vacuo. The residue was triturated with dichloromethane. The resulting light yellow precipitate was filtered, then washed with dichloromethane and dried in vacuo, to yield the title compound (160 mg, 56%) as a light yellow powder. HPLC-MS (method 5): MH + m / z 620, RT 1.89 minutes. INTERMEDIATE 20 2-cyclooctyl-2 - ([2- (pyridin-4-yl) acetyl Methylaminojacetate
[0723] [0723] HATU (497 mg, 1.31 mmol) was added to a stirred solution of Intermediate 11 (257 mg, 1.09 mmol), 2- (pyridin-4-yl) acetic acid chloride (190 mg, 1 , 09 mmol) and DIPEA (0.90 mL, 5.45 mmol) in DNF (5 mL) under nitrogen. The mixture was stirred at 20ºC under nitrogen for 16 h, then quenched with a saturated aqueous solution of sodium hydrogen carbonate (10 mL). The material was extracted with ethyl acetate (3 x 10 mL). The combined organic extracts were washed with brine (2x 10 ml) and dried over sodium sulfate, then filtered and concentrated in vacuo. The residue was separated by sparkling column chromatography, using a gradient of ethyl acetate in heptane (20 to 100%) followed by a gradient of methanol in ethyl acetate (0 to 20%), to produce the title compound (201 mg, 58%) as a light orange oil. õ4 (250 MHz, CDCI3) 8.63 - 8.58 (m, 2H), 7.26 (d, J 6.0 Hz, 2H), 5.97 (d, J 8.5 Hz, 1H), 4.56 (dt, J 9.1, 4.6 Hz, 1H), 3.75 (s, 3H), 3.61 (s, 2H), 2.07 (s, 1H), 1.66 - 1.39 (m, 14H). HPLC-MS (method 7): MH + m / z 319, RT 1.77 minutes. INTERMEDIATE 21 2-cyclooctyl-2 - ([2- (pyridin-4-yl) acetylJaminoJ) lithium acetate
[0724] [0724] A solution of lithium hydroxide monohydrate (56 mg, 1.33 mmol) in water (1 mL) was added slowly to a stirred solution of Intermediate 20 (281 mg, 0.88 mmol) in MeOH / THF (1: 1; 2 mL) at 20ºC under air. The mixture was stirred at 20 ° C for 16 h, then diluted with an additional portion of MeOH / water (1: 1; 2 ml), stirred at 20 ° C for an additional 24 h. The solids were collected by filtration, and washed with water (2 mL) and diethyl ether / MeEOH / THF (10: 1: 1; 12 mL), then vacuum dried at 50 ° C for 5 h, to produce the title compound ( 172 mg, 63%) as a white powder. dx (500 MHz, DMSO-ds) 8.48 - 8.40 (m, 2H), 7.57 (d, J 8.4 Hz, 1H), 7.31 - 7.26 (m, 2H), 3.77 (dd, J 8.4, 4.5 Hz, 1H), 3.56 (d, J 13.9 Hz, 1H), 3.46 (d, J 13.9 Hz, 1H), 1 , 99 - 1.89 (m, 1H), 1.62 - 1.24 (m, 13H), 1.20 - 1.09 (m, 1H). HPLC-MS (method 5): MH + m / z 305, RT 1.49 minutes. INTERMEDIATE 22 2 - [(2-methylpyrazole-3-carbonyl) amino] Methyl Jacetate
[0725] [0725] DIPEA (370 uL, 2.24 mmol) was added to a stirred solution of glycine methyl ester chloride (70 mg, 0.56 mmol), 1-methyl-1H-pyrazole-5-carboxylic acid (71 mg, 0.57 mmol) and HATU (255 mg, 0.67 mmol) in anhydrous DMF (1 mL) under a nitrogen atmosphere. The mixture was stirred at 20ºC for 15 h, then quenched by the addition of a saturated aqueous solution of sodium hydrogen carbonate (7 ml) and water (7 ml). The material was extracted sequentially with ethyl acetate (3 x 7 ml) and isopropanol / chloroform 1: 1 (2 x 7 ml). The combined organic layers were washed with brine (2 x 7 ml) and dried over sodium sulfate, then filtered and concentrated in vacuo. The residue was purified by sparkling column chromatography, using a gradient of ethyl acetate in heptane (0 to 100%), to produce the title compound (110 mg, quantitative) as an orange brown oil. x (250 MHz, DMSO-ds) 8.92 (t, J 5.6 Hz, 1H), 7.48 (d, JU 2.1 Hz, 1H), 6.89 (d, J 2.1 Hz , 1H), 4.04 (s, 3H), 3.98 (d, J 5.9 Hz, 2H), 3.66 (s, 3H). HPLC-MS (method 6): MH + m / z 198, RT 0.52 min. INTERMEDIATE 23 2 - [(2-methylpyrazole-3-carbonyl) amino] Lithium Jacetate
[0726] [0726] Lithium hydroxide monohydrate (36 mg, 0.86 mmol) was added to a stirred solution of Intermediate 22 (140 mg, 0.71 mmol) in THF (3 mL) and water (1.5 mL) . The reaction mixture was stirred at 20 ° C for 64 h, then concentrated and dried in vacuo for 4 h, to produce the title compound (134 mg, quantitative) as a brown foam. HPLC-MS (method 5): MH + m / z 184, RT 0.12-0.16 minute. INTERMEDIATE 24 N- (2-Bromo-S-chlorophenyl) tetrahydrothiopyran-4-carboxamide
[0727] [0727] 2,4,6-Tripropyl-1,3,5,2,4,6-trioxatrifosforinane 2,4,6-trioxide (50% by weight solution in ethyl acetate, 8.1 mL, 13, 6 mmol) was added slowly to a stirred solution of 2-bromo-S5-chloroaniline (1.5 g, 7.27 mmol), thiano-4-carboxylic acid (1.0 g, 6.84 mmol) and pyridine ( 2.7 mL, 33.4 mmol) in ethyl acetate (14 mL) at 0ºC under nitrogen. The reaction mixture was allowed to warm slowly to 20 ° C and stirred for 64 h. The resulting suspension was diluted with ethyl acetate (20 ml) and quenched with water (30 ml). The solids were collected by filtration, washing sequentially with ethyl acetate (2 x 20 ml), water (20 ml) and diethyl ether (2 x ml). The solids dried at 50 ° C under vacuum for 16 h to produce the title compound (2.08 g, 86%) as a pink powder. õnH (500 MHz, DMSO-ds) 9.51 (br s, 1H), 7.71 - 7.65 (m, 2H), 7.21 (dd, J 8.6, 2.6 Hz, 1H) , 2.71 - 2.62 (m, 4H), 2.57 (tt, J 11.5, 3.1 Hz, 1H), 2.19 - 2.08 (m, 2H), 1.78 - 1.63 (m, 2H). HPLC-MS (method 5): MH + m / z 334, RT 1.90 min. INTERMEDIATE 25 N- (2-Bromo-5-chlorophenyl) -N- [2- (trimethylsily) ethoxymethyl] tetrahydrothiopyran-4-carboxamide
[0728] [0728] —Sodium hydride (60% dispersion in mineral oil, 39 mg, 0.98 mmol) was added to a stirred suspension of Intermediate 24 (250 mg, 0.75 mmol) in
[0729] [0729] Intermediate 25 (290 mg, 0.62 mmol) and sodium tert-butoxide (180 mg, 1.87 mmol) were dissolved anhydrous toluene (3.1 mL). The mixture was purged with nitrogen and sonicated for 5 minutes, then charged with [1,3-bis (2,6-diisopropylphenyl) -imidazol-2-ylidene] (3-chloropyridyl) palladium dichloride (11) (42.6 mg, 0.06 mmol). The mixture was purged with nitrogen and sonicated for 5 minutes, then sealed under nitrogen and heated to 110ºC for 16 h. After cooling to room temperature, the reaction mixture was partitioned with water (30 ml) and ethyl acetate (30 ml). The biphasic mixture was filtered through a pad of diatomaceous earth, washing with water (10 ml) and ethyl acetate (2 x 10 ml). The organic phase was separated, then the aqueous layer was extracted with ethyl acetate (2 x 30 ml). The combined organic extracts were washed with brine (20 ml) and dried over magnesium sulfate, then filtered and concentrated in vacuo. The resulting crude red oil was separated by sparkling column chromatography, using a gradient of tert-butyl methyl ether in heptane (0 to 20%), to produce the title compound (73 mg, 31%) as a light brown viscous oil . õn (500 MHz, DMSO-ds) 7.52 (d, J 8.0 Hz, 1H), 7.18 (d, J 1.9 Hz, 1H), 7.13 (dd, J 8.0, 1.9 Hz, 1H), 5.11 (s, 2H), 3.52 - 3.45 (m, 2H), 3.13 (ddd, JJ 13.1, 8.6, 4.1 Hz, 2H), 2.72 - 2.62 (m, 2H), 1.98 - 1.86 (m, 4H), 0.87 - 0.81 (m, 2H), - 0.08 (s, 9H ). HPLC-MS (method 5): MNa + m / z 406, RT 2.28 minutes. INTERMEDIATE 27 N- (2-0x0-1- [2- (trimethylsilyl) ethoxymethylJespiro [indolino-3,4 "-tetrahydro-thiopiran]) - 6- tert-Butyl ilkcarbamate
[0730] [0730] A sealed tube was loaded with Intermediate 26 (73 mg, 0.19 mmol), tert-butyl carbamate (45 mg, 0.38 mmol) and tripotassium phosphate (57 mg, 0.27 mmol). The reagents were suspended in tert-butanol (1 mL), then the mixture was purged with nitrogen and sonicated for 5 minutes. The reaction mixture was loaded with [(2-di-tert-butylphosphino-3,6-dimethoxy-2 ', 4', 6 "- trilsopropyl-1,1'-biphenyl) -2- (2'- methanesulfonate amino-1,1 "-biphenyl)] palladium (II) (4.1 mg, 0.005 mmol) and 2- (di-tert-butyl-phosphine) -2 ', 4', 6'-triisopropyl-3,6 -dimethoxy-1,1 "-biphenyl (24 mg, 0.005 mmol), then purged with nitrogen and sonicated for 5 minutes. The mixture was sealed under nitrogen and heated to 110ºC for 16 h. After cooling to room temperature, The mixture was diluted with ethyl acetate (10 ml) and filtered through a pad of diatomaceous earth, lavender with ethyl acetate (2 x 10 ml). The filtrate was concentrated in vacuo. The resulting crude red semi-solid was separated by chromatography sparkling column, using a gradient of tert-butyl methyl ether in heptane (0 to 50%), to produce the title compound (14 mg, 16%) as a yellowish white powder. ds (500 MHz, DMSO-ds) 9.41 (s, 1H), 7.43 (s, 1H), 7.34 (d, J 8.1 Hz, 1H), 7.02 (dd, J 8.1, 1.5 Hz, 1H ), 5.03 ( s, 2H), 3.52 - 3.44 (m, 2H), 3.17 - 3.01 (m, 2H), 2.74 - 2.65 (m, 2H), 1.97 - 1, 81 (m, 4H), 1.47 (s, 9H), 0.88 - 0.79 (m, 2H), -0.07 (s, 9H). HPLC-MS (method 5): MNa + m / z 487, RT 2.23 minutes. INTERMEDIATE 28 6-Aminoespiro [indolino-3,4'-tetrahydrothiopiran] -2-one
[0731] [0731] Trifluoroacetic acid (46 µl, 0.6 mmol) was added to a stirred solution of Intermediate 27 (14 mg, 0.08 mmol) in DCM (0.5 mL). The mixture was stirred under nitrogen at 20ºC for 16 h, then diluted with DCM (2 mL). An additional portion of trifluoroacetic acid (46 ul, 0.6 mmol) was added and stirring was continued at 20 ° C for 5 days under nitrogen. The mixture was diluted with DCM (2 ml) and an additional portion of trifluoroacetic acid (92 µl, 1.19 mmol) was added. Stirring was continued for 24 h at 20ºC under nitrogen, then the volatiles were removed in vacuo. The residue was subjected to azeotropy three times with dichloromethane, then dissolved in methanol (3 ml). DIPEA (50 uL, 0.3 mmol) was added, then the mixture was heated to 100 ° C under nitrogen for 1.5 h. After cooling to room temperature, the mixture was diluted with DCM (20 ml) and partitioned with aqueous 0.5 M hydrochloric acid (20 ml). The biphasic mixture was stirred and the phases were separated using a hydrophobic frit. The aqueous phase was washed with DCM / isopropanol (4: 1; 20 ml), then adjusted to pH 5-6 with solid sodium carbonate hydrogen. The material was extracted with DCM-isopropanol 4: 1 (6 x 20 mL). The combined organic filtrates were stirred with saturated aqueous sodium hydrogen carbonate solution (10 ml) and the organic phase was separated using a hydrophobic frit. The organic filtrate was concentrated in vacuo to yield the title compound (3.2 mg, 45%) as a brown powder. HPLC-MS (method 5): MH + m / z 235, RT 1.29 minutes. INTERMEDIATE 29 1'-Benzyl-6-bromoespiro [indolino-3,4'-piperidino] -2-one
[0732] [0732] A suspension of 6-bromo-1,3-dihydro-2H-indole-2-0na (424 mg, 2.00 mmol) in anhydrous THF (20 mL) was purged with nitrogen and sonicated for 10 minutes. The mixture was cooled to -78 ° C under nitrogen and 1 M sodium bis (trimethylsily) amide (10 mL, 10.0 mmol) was added slowly. After stirring for 60 minutes, N-benzylbis (2-chloro-ethyl) amine chloride (590 mg, 2.20 mmol) was added in one portion and the mixture was stirred at -78 ° C for 1 h. The cooling bath was removed and the mixture was allowed to warm to 20ºC, then heated to 70ºC for 16 h. After cooling to room temperature, the reaction mixture was quenched with saturated aqueous ammonium chloride solution (20 mL) and diluted with water (20 mL). The material was extracted with ethyl acetate (3 x 100 mL). The combined organic extracts were washed with brine (50 ml) and dried over magnesium sulfate, then filtered and concentrated in vacuo. The resulting crude dark red semi-solid was dissolved in hot DCM (-20 ml) and allowed to cool to room temperature, then ground with heptane (- 60 ml). The solids were collected by filtration, washing with heptane (2 x 20 mL). The filtrate was concentrated in vacuo, and the process was repeated, to produce the title compound (236 mg, 32%) as a light orange powder after vacuum drying at 50 ° C for 16 h. dx (500 MHz, DMSO-ds) 10.50 (br s, 1H), 7.42 (d, J 7.8 Hz, 1H), 7.39 - 7.30 (m, 4H), 7.29 - 7.22 (m, 1H), 7.12 (dd, J 8.0, 1.8 Hz, 1H), 6.98 (d, J 1.8 Hz, 1H), 3.61 (s, 2H), 2.91 - 2.70 (m, 2H), 2.62 - 2.48 (m, 2H), 1.87 - 1.74 (m, 2H), 1.72 - 1.56 ( m, 2H). HPLC-MS (method 5): MH + m / z 371, RT 1.56 minutes. INTERMEDIATE 30 6-Amino-1 "-benzylospiro [indolino-3,4'-piperidino] -2-one
[0733] [0733] A sealed tube was loaded with Intermediate 29 (326 mg, 0.88 mmol), tert-butyl carbamate (206 mg, 1.76 mmol) and tripotassium phosphate (262 mg, 1.23 mmol). The reagents were suspended in tert-butanol (4.5 mL), then the mixture was purged with nitrogen and sonicated for 5 minutes. The reaction mixture was charged with [(2-di-tert-butylphosphino-3,6-dimethoxy-2 ', 4', 6 "- triisopropyl-1,1" -biphenyl) -2- (2'- methanesulfonate amino-1,1 "-biphenyl)] palladium (11) (18.7 mg, 0.02 mmol) and 2- (di-tert-butyl-phosphino) -2 ', 4', 6" -triylsopropyl-3 , 6-dimethoxy-1,1 "-biphenyl (10.8 mg, 0.02 mmol), then purged with nitrogen and sonicated for 5 minutes. The mixture was sealed under nitrogen and heated to 110ºC for 16 h. After cooling , the mixture was partitioned between ethyl acetate (80 ml) and water (30 ml), then sonicated.The solids were removed by filtration through a pad of diatomaceous earth, washing with water (20 ml) and ethyl acetate ( The organic layer was separated, then the aqueous layer was extracted with ethyl acetate (2 x 30 ml), then the pH was adjusted to pH 11 with sodium carbonate. The combined organic extracts were washed with brine (20 ml). mL) and dried over magnesium sulfate, then filtered and reduced in vacuo. The residue was dissolved in dichloro loromethane (8.3 ml), then trifluoroacetic acid (0.65 ml, 8.44 mmol) was added. The solution was stirred at 20ºC under air for 18 h. The volatiles were removed in vacuo and the residue was adsorbed on a SCX-2 cartridge. The column was washed with DCM (50 ml) and MeOH (50 ml). The material was eluted with 1 M ammonia in MeOH (50 ml), then concentrated in vacuo. The resulting purple powder was separated by sparkling column chromatography (KP-NH column), using a gradient of ethyl acetate in heptane (0 to 100%) followed by a gradient of MeOH in ethyl acetate (0 to 10%), to produce the title compound (24 mg, 9%) as a brown viscous oil. HPLC-MS (method 5): MH + m / z 308, RT 1.07 min. INTERMEDIATE 31 N- (1-Cyclooctyl-2 - [(1'-benzyl-2-0x0spiro [indolino-3,4'-piperidino] -6-yl) amino] -2-0x0- ethyl) -2-methylpyrazole- 3-carboxamide
[0734] [0734] HATU (68 mg, 0.18 mmol) was added to a stirred suspension of Intermediate 30 (46 mg, 0.15 mmol) and Intermediate 13 (50 mg, 0.17 mmol) in anhydrous DMF (1 mL) . The mixture was stirred at 20ºC under nitrogen for 64 h, then quenched with saturated aqueous sodium carbonate solution (10 mL) and stirred for 30 minutes at 20ºC. The mixture was diluted with water (10 ml) and partitioned with DCM / isopropanol (4: 1; 20 ml). The organic phase was separated using a hydrophobic frit, then the aqueous layer was extracted with DCM / isopropanol 4: 1 (2 x 20 ml). The filtrate was concentrated in vacuo. The resulting crude orange gum was separated by sparkling column chromatography, using a gradient of ethyl acetate in heptane (0 to 100%) followed by a gradient of MeOH in ethyl acetate (0 to 20%), to produce the compound of the titer (24 mg, 28%) as a yellowish white powder. õx (500 MHz, CD30D) 7.46 (d, J 2.1 Hz, 1H), 7.44 - 7.38 (m, 3H), 7.37 - 7.31 (m, 3H), 7, 31 - 7.26 (m, 1H), 7.08 (dd, J 8.1, 1.9 Hz, 1H), 6.87 (d, J 2.1 Hz, 1H), 4.50 (d , J 8.7 Hz, 1H), 4.08 (s, 3H), 3.72 (s, 2H), 3.03 - 2.93 (m, 2H), 2.79 - 2.70 (m , 2H), 2.28 - 2.18 (m, 1H), 2.00 - 1.89 (m, 2H), 1.87 - 1.43 (m, 16H). HPLC-MS (method 5): MH + m / z 583, RT 1.75 minutes. INTERMEDIATE 32 2- (tert-butoxycarbonylamino) -2- (cyclooctyl) methyl acetate
[0735] [0735] Triethylamine (0.71 mL, 5.09 mmol) was added to a mixture of Intermediate 11 (410 mg, 1.88 mmol) and di-tert-butyl dicarbonate (444 mg, 1.89 mmol) in DCM (16 mL) and the reaction mixture was stirred at 20ºC for 64 h. The reaction mixture was washed with water (30 ml), saturated aqueous sodium hydrogen carbonate solution (30 ml) and brine (30 ml), then dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was separated by sparkling column chromatography using a gradient of ethyl acetate in heptane (0 to 100%) to produce the title compound (539 mg, 96%) as a colorless, free-flowing oil. on (250 MHz, DMSO-ds) 7.14 (d, J 8.6 Hz, 1H), 4.03 - 3.78 (m, 1H), 3.61 (s, 3H), 2.02 - 1.84 (m, 1H), 1.7-5.1419 (m, 23H). INTERMEDIATE 33 2- (tert-butoxycarbonylamino) -2- (cyclooctyl) lithium acetate
[0736] [0736] Lithium hydroxide monohydrate (75 mg, 1.78 mmol) was added to a stirred solution of Intermediate 32 (485 mg, 1.62 mmol) in 2: 1 THF-water (12 mL). The reaction mixture was stirred at 20 ° C for 15 h, then concentrated and dried in vacuo for 2 h, to produce the title compound (471 mg, quantitative) as a white solid. ôH (500 MHz, DMSO-ds) 5.78 (d, J 7.1 Hz, 1H), 3.42 - 3.38 (m, 1H), 1.96 - 1.86 (m, 1H), 1.65 - 1.46 (m, 23H). INTERMEDIATE 34 N- (1-cyclooctyl-2-0x0-2 - [(2-oxo0ospiro [indolino-3,4'-tetrahydropyran] -6-yl) - amino] tert-butyl jetylkcarbamate
[0737] [0737] HATU (596 mg, 1.57 mmol) was added to a stirred solution of Intermediate 2 (285 mg, 1.31 mmol) and Intermediate 33 (403 mg, 1.39 mmol) in anhydrous DMF (6 mL) under a nitrogen atmosphere. The mixture was stirred at 20ºC for 18 h, then quenched by the addition of a saturated aqueous solution of sodium hydrogen carbonate (50 ml) and water (50 ml). The aqueous phase was extracted with ethyl acetate (2 x 50 ml) and isopropanol-chloroform 1: 1 (2 x 50 ml). The combined organic layers were washed with brine (2 x 50 ml) and dried over magnesium sulfate, then filtered and concentrated in vacuo. The residue was separated by sparkling column chromatography using a gradient of ethyl acetate in heptane (0 to 100%), followed by a gradient of methanol in dichloromethane (0 to 100%), to produce the title compound (502 mg, 79%) as a light yellow solid. dr (500 MHz, DMSO-ds) 10.38
[0738] [0738] Trifluoroacetic acid (0.8 mL, 10.38 mmol) was added to a stirred solution of Intermediate 34 (489 mg, 1.01 mmol) in DCM (20 mL) at 20 ° C under an atmosphere of nitrogen. The reaction mixture was stirred at 20 ° C overnight. Additional trifluoroacetic acid (0.4 mL, 5.19 mmol) was added to the reaction mixture, and stirring was continued at 20 ° C for 4 h. The reaction mixture was diluted with DCM (30 ml) and quenched with saturated aqueous sodium hydrogen carbonate solution (30 ml), then extracted with isopropanol-chloroform 1: 1 (3 x 30 ml). The combined organic layers were dried over magnesium sulfate, then filtered and concentrated in vacuo, to yield the title compound (284 mg, 73%) as a brown solid. õH (500 MHz, DMSO-ds) 10.38 (s, 1H), 9.83 (br s, 1H), 7.47 - 7.37 (m, 2H), 7.06 (dd, J 8, 1, 1.9 Hz, 1H), 4.01 (ddd, J 11,0,7,1, 3,6 Hz, 2H), 3,80 (ddd, J 11,1,7,1,3, 6 Hz, 2H), 3.09 (d, J 5.8 Hz, 1H), 2.26 - 1.26 (m, 21H). uPLC-MS (method 2): MH + m / z 386, RT 3.04 minutes. INTERMEDIATE 36 Acetic 2 - [(2-methylpyrazol-3-carbonyl) amino] acetic acid
[0739] [0739] A solution of lithium hydroxide monohydrate (2.02 9, 48.10 mmol) in water (33 mL) was added to a stirred solution of Intermediate 22 (7.3 9, 37.00 mmol) in THF (67 mL). The reaction mixture was stirred at 50ºC for 2 h, then allowed to cool to room temperature. The volatiles were removed in vacuo. The aqueous residue was washed with ethyl acetate (2 x 100 ml), then acidified to pH 1-2 with 3 M hydrochloric acid. The aqueous layer was extracted with a mixture of dichloromethane: isopropanol (21; 3 x 120 ml ). The organic extracts were combined, dried over anhydrous sodium sulfate and filtered. The solvent was concentrated in vacuo to yield the title compound (6.69, 97%) as a white solid. õ1 (250 MHz, DMSO-ds) 12.66 (s, 1H), 8.81 (t, J 5.9 Hz, 1H), 7.48 (d, J 2.1 Hz, 1H), 6, 89 (d, JU 2.1 Hz, 1H), 4.05 (s, 3H), 3.90 (d, J 6.0 Hz, 2H). HPLC-MS: MH + m / z 184, RT 0.174 min. INTERMEDIATE 37 2- (2-methylpyrazol-3-yl) -4H-oxazol-5-one
[0740] [0740] To the stirred solution of Intermediate 36 (7.77 g, 36.06 mmol) in anhydrous DCM (72 mL) EDCI-HCI (8.99 g, 46.87 mmol) was added to the portions. The reaction mixture was stirred at room temperature for 1.5 h, then diluted with DCM (70 ml) and quenched with water (70 ml). The organic layer was separated, washed with water (3 x 70 ml) and brine (50 ml), then dried over anhydrous sodium sulfate and filtered. The solvent was concentrated in vacuo to yield the title compound (7.65 g, 77%) as a pink solid, which was used without further purification. dx (250 MHz, CDCIs) 7.53 (d, J 2.0 Hz, 1H), 6.82 (d, J 2.0 Hz, 1H), 4.42 (s, 2H), 4.22 ( s, 3H). HPLC-MS (method 5): [2MNa] + m / z 353 (weak), RT 0.72 min. INTERMEDIATE 38 2- (2-methylpyrazole | -3-i1) -4- (spiro [3.3] heptan-2-ylidene) oxazol-5-one
[0741] [0741] Titanium tetrachloride in DCM (1 M, 4.8 mL, 4.80 mmol) was added to anhydrous THF (9 mL) at -10 ° C. A solution of Intermediate 37 (200 mg, 1.21 mmol) in anhydrous THF (1.5 mL) and a solution of spiro [3.3] heptan-2-one (267 mg, 2.42 mmol) in anhydrous THF (1.5 mL) were added to the portions sequentially, and the reaction mixture was stirred at 0 ° C for an additional 20 minutes. Anhydrous pyridine (0.784 mL, 9.69 mmol) was added at 0 ° C in 30 minutes. The reaction mixture was stirred at 0 ° C for an additional 2 h, then at room temperature for 16 h. The reaction mixture was quenched by the addition of saturated aqueous ammonium chloride solution (20 mL) and stirring was continued for an additional 10 minutes. The solution was extracted with ethyl acetate (2 x 40 ml). The organic extracts were combined and washed with brine (20 ml), then dried over anhydrous sodium sulfate and filtered. The solvent was removed in vacuo. The residue was purified using automated chromatography, using a gradient of ethyl acetate in heptane (5 to 40%), to produce the title compound (224 mg, 72%) as a white solid. ôõx (250 MHz, CDCI3) 7.53
[0742] [0742] To a stirred solution of Intermediate 38 (224 mg, 0.87 mmol) in anhydrous acetonitrile (10 mL) was added 10% palladium on vegetable carbon (50% by weight, 44 mg, 20% by weight) in a single portion. The reaction mixture was placed under an atmosphere of hydrogen gas and stirring was continued at room temperature for 20 h. A second aliquot of 10% palladium on vegetable carbon (50% by weight, 22 mg, 10% by weight) was added and the reaction mixture was stirred under hydrogen for an additional 43 h. The catalyst was removed by filtration on diatomaceous earth, then the filter cake was rinsed with acetonitrile (2 x 5 mL). The solvent was concentrated in vacuo to yield the title compound (182 mg, 81%) as a gray oil. dn (250 MHz, CDCI3) 7.53 (d, J 2.0 Hz, 1H), 6.81 (d, JU 2.0 Hz, 1H), 4.33 (d, J 6.1 Hz, 1H ), 4.24 (s, 3H), 2.74 (pd, J 8.4, 6.4 Hz, 1H), 2.23 - 1.99 (m, 6H), 1.91 - 1.76 (m, 4H). HPLC-MS (method 6): (M - H) m / z 258, RT 3.08 minutes. INTERMEDIATE 40 methyl 2-cyclooctyl 2- (3-methylisoxazole-4-carboxamido) acetate
[0743] [0743] To a solution of 3-methylisoxazole-4-carboxylic acid (12.9 g, 66.1 mmol) in dry DNF (100 mL) at 0 ° C was added with DIPEA (54.9 g, 424.6 mmol) , EDCI.HCI (19.5 g, 101.9 mmol) and HOBt (13.8 g, 101.9 mmol). The reaction mixture was stirred for 15 minutes at 0ºC, then Intermediate 11 (20.0 g, 84.9 mmol) was added and the reaction mixture was stirred at room temperature for 48 h. The reaction mixture was poured into ice water (500 ml), and extracted with ethyl acetate (2 x 400 ml). The organic layer was separated, then washed with ice water (2x 100 ml) and 1 N HCl (2x50 ml). The organic layer was dried over Na2SO. anhydrous, then filtered and evaporated in vacuo. The crude residue was purified by silica gel scintillation column chromatography, using 15% EtOAc in hexane as the elution solvent, to yield the title compound (7.9 g, 41.3%) as a light yellow viscous oil . LC-MS (method 17): MH + m / z 309, RT 5.5 minutes. INTERMEDIATE 41 2-cyclooctyl-2- (3-methylisoxazole-4-carboxamido) lithium acetate
[0744] [0744] To a solution of Intermediate 40 (11.01 g, 35.7 mmol) in THF (90 mL) at room temperature, water (30 mL) and lithium hydroxide monohydrate (2.248 g, 53.6 mmol). The reaction mixture was stirred for 16 h, then evaporated in vacuo. To the residue was added diethyl ether (50 ml). The mixture was stirred for 10 minutes, then filtered. The resulting solid was washed with diethyl ether (50 ml) and pentane (50 ml), then dried in vacuo, to yield the title compound (9.51 g, 91%) as a yellowish white solid. õs (400 MHz, DMSO-ds) 9.69 (s, 1H), 8.21 (s, 1H), 4.11 (dd, J 8.0, 4.0 Hz, 1H), 2.35 ( s, 3H), 2.05 (br s, 1H), 1.65 - 1.35 (m, 14H). LC-MS (method 18): MH + m / z 295, RT 5.4 minutes. INTERMEDIATE 42 trans- (4-methylcyclohexyl) | methane!
[0745] [0745] To a cold solution (5C at -20ºC) of trans4-methylcyclohexanecarboxylic acid (68.5 g, 0.481 mol) in THF (550 mL) was added a solution of aluminum lithium hydride (2, A4M in THF, 200 mL, 0.48 mol) slowly over about 1 h. The mixture was stirred at -20ºC for 1.5 h, then allowed to warm up to room temperature. The mixture was cooled in an ice-salt bath before water (16 ml), aqueous sodium hydroxide solution (15% by weight, 16 ml), and water (40 ml) were slowly and cautiously added. The resulting viscous mixture was stirred for 10 minutes, then diethyl ether (500 ml) was added. The resulting suspension was filtered through a pad of diatomaceous earth. The solvents were evaporated under reduced pressure to produce the title compound (63.5 g, 100%) as a clear, colorless mobile oil. dH (500 MHz, CDCI3) 3.44 (d, J 6.3 Hz, 2H), 1.79 - 1.69 (m, 4H), 1.47 - 1.23 (m, 3H), 1, 04 - 0.89 (m, 4H), 0.88 (d, J 6.6 Hz, 3H). INTERMEDIATE 43 trans-4-methylcyclohexanecarbaldehyde
[0746] [0746] A cold solution (-10ºC to -5ºC) of Intermediate 42 (30.31 g, 0.229 mol)
[0747] [0747] To a solution of Intermediate 43 (34.9 g, 229 mmol) and (S) <4-methylbenzenesulfinamide (35.6 g, 229 mmol) in DCM (1.2 L) was added titanium ethoxide (IV) (85 to 90% purity, 174.5 g, 160 ml). The resulting solution was heated to reflux for 2 h. The reaction mixture was cooled to room temperature, then water (300 ml) was added slowly. The resulting thick paste was filtered through a pad of diatomaceous earth, then rinsed with DCM (300 ml) and water (300 ml). The two phases were separated. The DCM phase was dried over anhydrous sodium sulfate and filtered, then the solvent was evaporated, to give the title compound (55.7 g, 78%) as a yellow oil, which partially solidified on standing. ox (250 MHz, CDCl3) 8.11 (d, J 4.9 Hz, 1H), 7.70 - 7.49 (m, 2H), 7.29 (m, 2H), 2.40 (s, 2H), 2.38 - 2.24 (m, 1H), 2.06 - 1.66 (m, 4H), 1.53 - 1.16 (m, 4H), 1.07 - 0.91 ( m, 2H), 0.89 (d, J 6.5 Hz, 3H). INTERMEDIATE 45 N- [I (S) -Ciano (trans-4-methylcyclohexyl) methyl] - (S) -4-methylbenzenesulfinamide
[0748] [0748] To a solution of diethyl aluminum cyanide (1 M in toluene, 103 mL, 103 mmol) in THF (400 mL) at -78 ° C was added anhydrous isopropyl alcohol (5.3 mL, 69 mmol). The mixture was stirred at -78ºC for 30 to 60 minutes, then cannulated in a solution of Intermediate 44 (90% pure, 20.2 g, 69 mmol) in THF (800 mL) at -
[0749] [0749] To a stirred solution of Intermediate 45 (6.6 g, 22.73 mmol) in dry methanol (130 mL) was added about half the volume of 4 M hydrogen chloride in 1,4-dioxane (120 mL) ) drops in 2 minutes, after which an exotherm up to 26ºC has occurred. The reaction mixture was cooled externally and half the remaining volume of 4 M hydrogen chloride in 1,4-dioxane was added in 3 minutes. After 5 minutes, the flask was capped and the reaction mixture was stirred at room temperature for 2 h. The volatiles were concentrated in vacuo. Diethyl ether (100 mL) was added, then the mixture was sonicated and stirred for 15 minutes. The solids were separated by filtration and washed with diethyl ether (3 x 100 mL), then dried under a stream of nitrogen gas, to produce the title compound (4.10 g, 96%) as a white solid. õH (500 MHz, DMSO-ds) 9.20 (s, 3H), 4.50 (d, J 5.5 Hz, 1H), 1.92 - 1.77 (m, 3H), 1.77 - 1.67 (m, 2H), 1.29 (ddp, J 11.4, 6.8, 3.4 Hz, 1H), 1.148 - 1.01 (m, 2H), 0.95 - 0.83 (m, 5H). HPLC-MS (method 1): MH * m / z 153, RT 0.46 minutes (100%). Chiral LC (method 12, Amylose-2 25 cm, 80% heptane-20% 2-propanol, 1 ml / min): RT 8.84 minutes (S, 93%). INTERMEDIATE 47 [(S) -Carboxy (trans-4-methylcyclohexyl) methylJammonium chloride
[0750] [0750] A stirred solution of Intermediate 46 (4.05 g, 21.46 mmol) in a mixture of acetic acid (17 mL) and concentrated hydrochloric acid (85 mL) was heated to an external temperature of 130ºC (105ºC internal temperature ). After 3 h, another portion of the concentrated hydrochloric acid (25 mL) was added, followed by another portion (25 mL) after an additional 2 h. The reaction mixture was heated for 1 h, then cooled. The precipitated solid was filtered and rinsed with tert-butyl methyl ether, then dried in vacuo, to yield the title compound (3.04 g, 68%) as a white solid. õs (500 MHz, DMSO-ds) 8.35 (s, 3H), 3.69 (d, J 4.2 Hz, 1H), 1.82 - 1.65 (m, 4H), 1.64 - 1.54 (m, 1H), 1.32 - 1.18 (m, 2H), 1.15 - 1.02 (m, 1H), 0.93 - 0.80 (m, 5H). HPLC-MS (method 3): MH * m / z 172, RT 0.63 minutes. INTERMEDIATE 48 (28) -2- (tert-butoxycarbonylamino) -2- (trans-4-methylcyclohexyl) acetic acid
[0751] [0751] To a stirred suspension of Intermediate 47 (25.1 g, 120.8 mmol) in water (350 mL) was added sodium carbonate (55 g, 0.52 mol), followed by di-tertiary dicarbonate butyl (39.6 g, 181 mmol) in 1,4-dioxane (500 ml). The reaction mixture was mechanically stirred for 4 h. The volatiles were removed in vacuo, then the suspension was cooled and 1 N hydrochloric acid was carefully added to obtain a pH of 1. The mixture was extracted with ethyl acetate (3 x 250 ml). The organic layers were combined, washed in turn with water (200 ml) and brine (200 ml), then filtered through phase separation paper. The volatiles were evaporated. The resulting solid was triturated in heptane (500 ml) and filtered, then washed with heptane (2 x 100 ml) and dried in an oven, to give the title compound (28.8 g, 87%) as a white solid. õ1 (500 MHz, DMSO-ds)
[0752] [0752] To a stirred solution of Intermediate 48 (503 mg, 1.85 mmol) in dry DNF (10 mL) Intermediate 2 (405 mg, 1.86 mmol), HATU (850 mg, 2.24 mmol) were added and DIPEA (0.92 mL, 5.57 mmol) at room temperature. The reaction mixture was stirred for 2.5 days. With external cooling (15ºC), water (40 mL) was added. The precipitated solid was filtered off and washed with water (2 x ml). The filter cake was dissolved in ethyl acetate (10 ml) and passed through a sintered funnel, then rinsed thoroughly with ethyl acetate (2x5 ml). The excess water was separated from the filtrate. The organic layer was washed with a 1: 1 mixture of water and brine (20 ml), and brine (10 ml), then dried over magnesium sulfate, filtered and concentrated in vacuo. The crude residue was absorbed on silica gel (44 g) using dichloromethane and purified by automated chromatography, using a gradient of ethyl acetate in heptane (100% O), to produce the title compound (648 mg, 70%) like a white solid. õn (500 MHz, DMSO-ds) 10.39 (s, 1H), 9.99 - 9.81 (m, 1H), 7.42 (d, J 8.1 Hz, 1H), 7.38 ( d, J 1.8 Hz, 1H), 7.09 - 7.02 (m, 1H), 6.89 - 6.48 (m, 1H), 4.06 - 3.95 (m, 2H), 3.89 (t, J 8.2 Hz, 1H), 3.84 - 3.66 (m, 2H), 1.79 - 1.69 (m, 3H), 1.69 - 1.44 (m , 6H), 1.40 - 1.28 (m, 9H), 1.28 - 1.20 (m, 1H), 1.21 - 1.06 (m, 1H), 1.06 - 0.93 (m, 1H), 0.90 - 0.75 (m, 5H). uPLC-MS (method 1): MH + m / z 472, RT 3.52 minutes. INTERMEDIATE 50 (28) -2-Amino-2- (4-methylcyclohexyl) -N- (2-oxospiro [indolino-3,4'-tetrahydropyran] -6-yl) acetamide (trans isomer)
[0753] [0753] A stirred solution of Intermediate 49 (606 mg, 1.29 mmol) in DCM
[0754] [0754] DIPEA (0.13 mL, 0.8 mmol) was added to a stirred suspension of Intermediate 74 (100 mg, 0.38 mmol), Intermediate 48 (125 mg, 0.46 mmol) and HATU (188 mg , 0.5 mmol) in anhydrous DCM (3.8 mL). The mixture was stirred at 20ºC under nitrogen for 60 h, then quenched with saturated aqueous sodium carbonate solution (10 mL) and diluted with water (10 mL). The material was extracted with DCM (3 x 25 mL) using a hydrophobic frit. The organic filtrate was concentrated in vacuo. The resulting viscous orange oil was separated by sparkling column chromatography, using a gradient of ethyl acetate in heptane (0 to 100%), to produce the title compound (102 mg, 52%) as a yellowish white powder. dn (500 MHz, DMSO-ds) 10.58 (s, 1H), 10.14 (s, 1H), 7.09 (d, J 1.5 Hz, 1H), 7.05 (d, 2JHF 12 , 4 Hz, 1H), 6.91 (d, J 8.2
[0755] [0755] Trifluoroacetic acid (161 µL, 2.09 mmol) was added to a stirred solution of Intermediate 51 (102 mg, 0.21 mmol) in DCM (1 mL). The mixture was stirred at 20ºC under nitrogen for 16 h, then diluted with DCM-isopropanol 4: 1 (20 mL) and quenched with saturated aqueous sodium carbonate solution (10 mL) and water (10 mL). The biphasic mixture was stirred at 20ºC for 30 minutes, then the organic phase was separated using a hydrophobic frit. The aqueous layer was extracted with DCM-isopropanol 4: 1 (3 x 10 ml). The organic filtrate was concentrated in vacuo to yield the title compound (105 mg, quantitative) as a brown powder. õs (500 MHz, DMSO-ds) 10.58 (s, 1H), 7.14 (d, J 1.7 Hz, 1H), 7.08 (dd, 2JHF 12.5, J 1.6 Hz, 1H), 4.06 (t, J 10.1 Hz, 2H), 3.75 (dt, J 11.2, 3.9 Hz, 2H), 3.06 (d, J 5.8 Hz, 1H ), 2.00 (ddd, J 14.3, 10.4, 4.5 Hz, 2H), 1.75 - 1.61 (m, 5H), 1.54 - 1.40 (m, 2H) , 1.31 - 1.12 (m, 2H), 1.07 - 0.94 (m, 1H), 0.93 - 0.76 (m, 5H). HPLC-MS (method 5): MH + m / z 390, RT 1.60 minutes. INTERMEDIATE 53 2 - [(3-methylisoxazole | -4-carbonyl) amino] Methyl jacetate
[0756] [0756] To a stirred solution of 3-methylisoxazole-4-carboxylic acid (20 g, 157 mmol) in anhydrous DMF (140 mL) under an atmosphere of nitrogen was successively added DIPEA (63.1 g, 488 mmol), EDCI .HCI (36.2 9, 189 mmol), HOBt (25.5 g, 189 mmol) and glycine methyl ester chloride (25.5 g, 157 mmol). The mixture was stirred at 20ºC for 12 h, then quenched by the addition of a saturated aqueous solution of sodium hydrogen carbonate (500 mL). The material was extracted sequentially with ethyl acetate (4 x 1.5 L). The combined organic layers were washed with brine (2 L) and dried over sodium sulfate, then filtered and concentrated in vacuo,
[0757] [0757] A solution of lithium hydroxide monohydrate (43.4 g, 1.03 mol) in methanol (930 mL) was added to a stirred solution of Intermediate 53 (186 9, 0.94 mol) in THF ( 1.7 L). The reaction mixture was stirred at room temperature for 3 h, then concentrated in vacuo. The aqueous residue was acidified to pH 1 with 6M aqueous hydrochloric acid solution (279 ml), then left at room temperature. After 1 h, the resulting crystalline solid was filtered off, then dried in vacuo, to yield the title compound (19 g, 78%) as a yellowish white solid. dn (400 MHz, DMSO-ds) 9.32 (s, 1H), 8.77 (t, J 6.0 Hz, 1H), 3.88 (s, J 8.0 Hz, 2H), 2, 37 (s, 3H). LC-MS (method 34): MH + m / z 185, RT 0.29 minute. INTERMEDIATE 55 2- (3-methylisoxazole | -4-i1) -4H-oxazole | -5-o0na
[0758] [0758] To a stirred solution of Intermediate 54 (44.2 g, 240 mmol) in anhydrous DCM (440 mL) was added EDCI-HCI (59.8 g, 312 mmol) to the portions. The reaction mixture was stirred at room temperature for 1.5 h, then diluted with DCM (200 ml) and quenched with water (500 ml). The organic layer was separated and washed with brine (2 x 500 ml), then dried over anhydrous sodium sulfate and filtered. The solvent was concentrated in vacuo to yield the title compound (34 g, 86%) as a yellow solid, which was used without further purification. dn (400 MHz, CDCl3) 8.83 (s, 1H), 4.37 (s, 2H), 2.56 (s, 3H). LC-MS (method 34): [M - HJ m / z 167, RT 0.76 minutes. INTERMEDIATE 56 4- (5-Methoxybicyclo [4,2,0] Jocta-1 (6), 2,4-trien-7-ylidene) -2- (3-methyl-1,2-0xazol-4-i1) -4,5- dihydro-1,3-oxazol-5-o0na
[0759] [0759] Titanium tetrachloride in DCM (1 M, 2.7 mL, 2.7 mmol) was added to anhydrous THF (4 mL) at -10 ° C. A solution of Intermediate 55 (0.146 g, 0.88 mmol) in anhydrous THF (1 mL) and a solution of 5-methoxybicyclo [4,2,0] octa-1,3,5-trien-7-one (0 ,1
[0760] [0760] Lithium hexamethyldisilazane in THF (1M, 8.13 mL, 8.13 mmol) was added to a mixture of Intermediate 84 (25 g, 6.78 mmol), tris (dibenzylidenoacetone) dipaladium - (0) (031 9 034 mmol) (and (2 biphenyl) dicyclohexylphosphine (0.285 g, 0.81 mmol) in anhydrous THF (50 mL) under nitrogen. The reaction mixture was stirred at 65 ° C under nitrogen for 4 h. The reaction mixture was cooled at 0ºC and 1 N HCI (21 mL) was added, the reaction mixture was stirred at 0ºC for 10 minutes, then quenched with sodium carbonate (pH 11) and extracted with ethyl acetate (3 x 100 mL). The combined organic materials were washed with brine (100 ml) and dried over magnesium sulfate, then filtered and concentrated in vacuo.The residue was purified by sparkling column chromatography (KP-NH cartridge) using a gradient of heptane in ethyl acetate ( 0 to 100%), to produce the title compound (1.65 g, 69%) as a brown solid. Δ (500 MHz, DMSOdes) 8.11 (s, 1H), 6.23 (s, 1H), 6.03 (s, 2H) , 5.06 (s, 2H), 4.03 (ddd, J 10.2, 5.9, 4.0 Hz, 2H), 3.84 (ddd, J 11.7, 8.4, 3, 3 Hz, 2H), 3.59 - 3.47 (m, 2H), 1.86 (ddd, J 12.7, 8.3, 3.9
[0761] [0761] DIPEA (35.4 mL, 214 mmol) was added to a stirred solution of methyl 2-amino-acetate chloride (8.96 mL, 71.4 mmol), 2-ethylpyrazole-3-carboxylic acid ( 10 g, 71.4 mmol) and HATU (32.56 g, 85.6 mmol) in anhydrous DMF (90 mL) under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 16 h, then diluted with water (50 ml) and saturated aqueous sodium hydrogen carbonate solution (50 ml). The aqueous layer was extracted with tert-butyl methyl ether (3 x 200 ml), followed by 9: 1 DOCM / MeOH (2 x 150 ml), then 4: 1 DCM / MeOH (2 x 150 ml). The organic extracts were combined and concentrated in vacuo. The resulting material was purified by sparkling column chromatography, using a gradient of ethyl acetate in heptane (0 to 80%), to produce the title compound (20.9 g, 78%) as a yellow oil. dr (250 MHz, CDCI3) 7.47 (d, J 2.0 Hz, 1H), 6.58 (d, J 2.1 Hz, 1H), 6.53 (br s, 1H), 4.59 (q, J 7.2 Hz, 2H), 4.18 (d, J 5.2 Hz, 2H), 3.80 (s, 3H), 1.43 (t, J 7.2 Hz, 3H) . HPLC-MS (method 5): MH + m / z 212, RT 0.86 minutes. INTERMEDIATE 59 Jacetic acid 2 - [(2-ethylpyrazol-3-carbonyl) amino]
[0762] [0762] A solution of lithium hydroxide monohydrate (3.02 9, 72.0 mmol) in water (60 mL) was added to a stirred solution of Intermediate 58 (56% pure, 20.88 g, 55 , 36 mmol) in THF (120 mL). The reaction mixture was stirred at 50 ° C for 3 h. The volatiles were removed in vacuo and the aqueous residue was extracted with ethyl acetate (2 x 100 ml). The aqueous phase was treated with aqueous 3 M hydrochloric acid (pH 1-2) and extracted with DCM / MeOH 9: 1 (2 x 100 ml), followed by DCM / MeOH 4: 1 (2 x 200 ml). The organic extracts were combined and concentrated in vacuo to give the title compound (7.85 g, 37%) as a yellow oil. The aqueous phase was further extracted with isopropanol / DCM 1: 1 (4 x 150 ml) to give a second batch of the title compound (6.27 g, 40%) as a white solid. õ1 (500 MHz, CDCI3) 7.53 (d, J 2.0 Hz, 1H), 6.61 (d, J 2.0 Hz, 1H), 6.59 - 6.51 (m, 1H), 4.63 (q, J 7.2 Hz, 2H), 4.26 (d, J 5.2 Hz, 2H), 1.47 (t, J 7.2 Hz, 3H). HPLC-MS (method 5): MH + m / z 198, RT 0.33 min. INTERMEDIATE 60 2- (2-Ethylpyrazol-3-yl) -4H-oxazol-5-one
[0763] [0763] To the stirred solution of Intermediate 59 (51% purity, 7.85 g, 20.3 mmol) in dry DCM (50 mL) was added EDCI.HCI (1: 1) (5.06 g, 26, 39 mmol) to the portions. The reaction mixture was stirred at room temperature for 2 h, then concentrated in vacuo. The resulting orange oil was diluted with water (50 ml) and extracted with tert-butyl methyl ether (3 x 70 ml). The organic extracts were combined, washed with water (3 x 50 ml) and brine (50 ml), and dried over sodium sulfate, then filtered and concentrated in vacuo, to produce the title compound (2.8 g, 66% ) as an orange oil. ô (500 MHz, CDCI3) 7.56 (d, J 2.0 Hz, 1H), 6.82 (d, J 2.0 Hz, 1H), 4.66 (q, J 7.2 Hz, 2H ), 4.43 (s, 2H), 1.46 (t, J 7.2 Hz, 3H). HPLC-MS (method 3): MH + m / z 180, RT 0.59 min. INTERMEDIATE 61 (PROCEDURE F) 4- (5-Chlorobicyclo [4,2,0] octa-1,3,5-trien-7-ylidene) -2- (1-ethyl-1H-pyrazol-5-1) - 4,5-dihydro- 1,3-0xazole-5-0na
[0764] [0764] Titanium tetrachloride in DCM (1 M, 2.62 mL, 2.62 mmol) was added to anhydrous THF (3.5 mL) at -10 ° C. A solution of Intermediate 60 (178 mg, 0.854 mmol) in anhydrous THF (1.5 mL) and a solution of 5-chlorobicyclo [4,2,0] octa-1,3,5-tri-7-one (100 mg, 0.66 mmol) in anhydrous THF (1.5 mL) were added to the portions sequentially. The reaction mixture was stirred at 0 ° C for 20 minutes, then anhydrous pyridine (0.46 ml, 5.69 mmol) was added to the drops at 0 ° C in 30 minutes. The reaction mixture was stirred at 0ºC for 2 h, and at room temperature for an additional 16 h, then quenched by the addition of saturated aqueous ammonium chloride solution (7 mL). Stirring was continued for an additional 10 minutes, then the solution was extracted with ethyl acetate (2 x 15 ml). The organic extracts were combined, washed with brine (15 ml) and dried over magnesium sulfate, then filtered and concentrated in vacuo. The residue was purified by sparkling column chromatography,
[0765] [0765] Titanium tetrachloride in DCM (1M, 3.6 mL, 3.63 mmol) was added to anhydrous THF (6 mL) at -10 ° C. A solution of Intermediate 37 (150 mg, 0.908 mmol) in anhydrous THF (1.5 mL) and a solution of adamantane-1-carbaldehyde (298 mg, 1.82 mmol) in anhydrous DCM (2 mL) were added to the portions sequentially. The reaction mixture was stirred at 0ºC for 20 minutes, then anhydrous pyridine (0.60 mL, 7.42 mmol) was added at 0ºC in 30 minutes. The reaction mixture was stirred at 0ºC for 2 h, and at room temperature for an additional 16 h, then quenched by the addition of saturated aqueous ammonium chloride solution (15 mL). Stirring was continued for an additional 10 minutes, then the solution was extracted with ethyl acetate (2 x 30 ml). The organic extracts were combined and washed with brine (10 ml), then dried over anhydrous sodium sulfate and filtered. The solvent was removed in vacuo. The residue was purified using automated chromatography, using a gradient of ethyl acetate in heptane (5 to 40%), to produce the title compound (24 mg, 8.5%) as a beige solid. dn (250 MHz, CDCI3) 7.55 (d, J 2.1 Hz, 1H), 6.90 (d, J 21 Hz, 1H), 6.49 (s, 1H), 4.30 (s, 3H), 2.10 - 2.03 (m, 3H), 2.03 - 1.97 (m, 6H), 1.80 - 1.73 (m, 6H). HPLC-MS (method 4): MH + m / z 312, RT 3.20 minutes. INTERMEDIATE 63 (PROCEDURE G) N- (2- (1-Adamantyl) -1 - [(2-0x0spiro [indolino-3,4'-tetrahydropyran] -6-yl) carbamoyl] -vinyl) - 2-methylpyrazole-3 -carboxamide
[0766] [0766] To a stirred solution of Intermediate 2 (17 mg, 0.078 mmol) and Intermediate 62 (24 mg, 0.078 mmol) in anhydrous acetonitrile (3 mL) was added acetic acid (0.045 mL, 0.78 mmol). The reaction mixture was stirred at 60 ° C for 19 h. The solvent was removed in vacuo and the residue was triturated in DCM (2 ml). The solid was collected by filtration and further vacuum dried to produce the title compound (20 mg, 42%) as an orange solid. HPLC-MS (method 5): MH + m / z 530, RT 1.82 minutes (87%) and RT 2.20 minutes (13%). INTERMEDIATE 64 4- [1- (Bicyclo [1,1,1] pentan-1-yl) ethylidene] -2- (2-methylpyrazol-3-yl) oxazol-5-one
[0767] [0767] Titanium tetrachloride in DCM (1 M, 4.8 mL, 4.80 mmol) was added to anhydrous THF (9 mL) at -10 ° C. A solution of Intermediate 37 (200 mg, 1.21 mmol) in anhydrous THF (1.5 mL) and 1- (bicycle [1,1,1] pentan-1-yl) ethan-1-one (90%, 297 mg, 2.42 mmol) in anhydrous THF (1.5 mL) were added to the portions sequentially. The reaction mixture was stirred at 0ºC for 20 minutes, then anhydrous pyridine (0.784 mL, 9.69 mmol) was added at 0ºC in 30 minutes. The reaction mixture was stirred at 0ºC for 2 h, and at room temperature for an additional 16 h, then quenched by the addition of saturated aqueous ammonium chloride solution (20 mL). Stirring was continued for an additional 10 minutes, then the solution was extracted with ethyl acetate (2 x 40 ml). The organic extracts were combined and washed with brine (20 ml), then dried over anhydrous sodium sulfate and filtered. The solvent was removed in vacuo. The residue was purified by automated chromatography, using a gradient of ethyl acetate in heptane (5 to 40%), to produce the title compound (235 mg, 73%) as a yellow solid. dx (250 MHz, CDCI3) 7.53 (d, JU 2.1 Hz, 1H), 6.85 (d, J 2.1 Hz, 1H), 4.29 (s, 3H), 2.60 ( s, 1H), 2.30 (s, 3H), 2.22 (s, 6H). HPLC-MS (method 5): MH + m / z 258, RT 2.13 minutes. INTERMEDIATE 65 4-Cycloheptylidene-2- (2-methylpyrazol-3-yl) oxazol-5-one
[0768] [0768] Titanium tetrachloride in DCM (1 M, 4.8 mL, 4.80 mmol) was added to anhydrous THF (9 mL) at -10 ° C. A solution of Intermediate 37 (200 mg, 1.21 mmol) in anhydrous THF (1.5 mL) and a solution of cycloheptanone (272 mg, 2.42 mmol) in anhydrous THF (1.5 mL) were added to the portions sequentially. The reaction mixture was stirred at 0 ° C for 20 minutes, then anhydrous pyridine (0.784 ml, 9.69 mmol) was added at 0 ° C in 30 minutes. The reaction mixture was stirred at 0ºC for 2h, and at room temperature for an additional 16h, then quenched by the addition of saturated aqueous ammonium chloride solution (20 mL). Stirring was continued for an additional 10 minutes, then the solution was extracted with ethyl acetate (2 x 40 ml). The organic extracts were combined and washed with brine (20 ml), then dried over anhydrous sodium sulfate and filtered. The solvent was removed in vacuo. The residue was purified by chromatography, using a gradient of ethyl acetate in heptane (5 to 40%), to produce the title compound (201 mg, 64%) as a beige solid. õH (250 MHz, CDCI3) 7.53 (d, J 1.9 Hz, 1H), 6.86 (d, J 1.9 Hz, 1H), 4.28 (s, 3H), 3.12 - 3.05 (m, 2H), 3.02 - 2.94 (m, 2H), 1.83 - 1.73 (m, 4H), 1.65 - 1.57 (m, 4H). HPLC-MS (method 4): MH + m / z 260, RT 3.09 minutes. INTERMEDIATE 66 (PROCEDURE H) 4-Cycloheptyl 2- (2-methylpyrazol | -3-yl) -4H-oxazol-5-one
[0769] [0769] To a stirred solution of Intermediate 65 (120 mg, 0.52 mmol) in anhydrous THF (6 mL) was added 10% palladium on vegetable carbon (50% by weight, 12 mg, 20% by weight) as a single portion. The reaction mixture was placed under a hydrogen gas atmosphere (3 vacuum / nitrogen gas cycles followed by 3 vacuum / hydrogen gas cycles). Stirring was continued at room temperature for 5 h. Anhydrous acetonitrile (6 mL) was added and stirred under an atmosphere of hydrogen gas was continued for an additional 16 h. The catalyst was removed by filtration on diatomaceous earth, rinse the filter cake with dry THF (2x5 mL). The solvent was concentrated in vacuo to produce the title compound (66 mg, 65%) as a light gray oil. HPLC-MS (method 4): (M - H) - m / z 260, RT 3.13 minutes. INTERMEDIATE 67 4- (Bicycles [3,2,1] octan-3-ylidene) -2- (2-methylpyrazol-3-yl) oxazol-5-one
[0770] [0770] Titanium tetrachloride in DCM (1M, 4.8 mL, 4.80 mmol) was added to anhydrous THF (9 mL) at -10 ° C. A solution of Intermediate 37 (200 mg, 1.21 mmol) in anhydrous THF (1.5 mL) and a solution of bicycles [3.2.1] Joctan-3-one (301 mg, 2.42 mmol) in Anhydrous THF (1.5 mL) was added to the portions sequentially. The reaction mixture was stirred at 0 ° C for 20 minutes, then anhydrous pyridine (0.784 ml, 9.69 mmol) was added at 0 ° C in 30 minutes. The reaction mixture was stirred at 0ºC for 2 h, and at room temperature for an additional 16 h, then quenched by the addition of saturated aqueous ammonium chloride solution (20 mL). Stirring was continued for an additional 10 minutes, then the solution was extracted with ethyl acetate (2 x 40 ml). The organic extracts were combined and washed with brine (20 ml), then dried over anhydrous sodium sulfate and filtered. The solvent was removed in vacuo. The residue was purified by chromatography, using a gradient of ethyl acetate in heptane (5 to 40%), to produce the title compound (261 mg, 79%) as a yellow solid. dx (250 MHz, CDCI3) 7.53 (d, J 2.1 Hz, 1H), 6.86 (d, JU 2.1 Hz, 1H), 4.27 (s, 3H), 3.75 - 3.64 (m, 1H), 3.35 - 3.24 (m, 1H), 2.56 - 2.46 (m, 2H), 2.38 (t, J 16.2 Hz, 2H), 1.77 (t, J 11.4 Hz, 2H), 1.71 - 1.62 (m, 2H), 1.49 - 1.36 (m, 2H). HPLC-MS (method 4): MH + m / z 272, RT 3.15 minutes. INTERMEDIATE 68 4- (Bicycles [3,2,1] octan-3-yl) -2- (2-methylpyrazol-3-i1) -4H-oxazol-5-one
[0771] [0771] To a stirred solution of Intermediate 67 (200 mg, 0.74 mmol) in anhydrous acetonitrile (10 mL) was added 10% palladium on vegetable carbon (50% by weight, 40 mg, 20% by weight) as a single portion. The reaction mixture was placed under an atmosphere of hydrogen gas. Stirring was continued at room temperature for 6 h. The catalyst was removed by filtration on diatomaceous earth, rinse the filter cake with dry acetonitrile (2 x 5 mL). The solvent was concentrated in vacuo to produce the title compound (200 mg, 84%) as a light gray oil. dn (250 MHz, CDCI3) 7.53 (d, J 2.1 Hz, 1H), 6.79 (d, J 2.0 Hz, 1H), 4.33 (d, J 6.6 Hz, 1H ), 4.24 (s, 3H), 2.34 - 2.24 (m, 2H), 2.23 - 2.02 (m, 3H), 1.95 - 1.83 (m, 1H), 1.77 - 1.64 (m, 3H), 1.47 - 1.35 (m, 3H), 1.21 - 1.43 (m, 1H). HPLC-MS (method 4): (M - H) m / z 272, RT 3.13 minutes. INTERMEDIATE 69 4- (5-Chloro-7-bicycles [4,2,0] octa-1 (6), 2,4-trienylidene) -2- (2-methylpyrazol-3-yl) oxazol-5-0na
[0772] [0772] Titanium tetrachloride in DCM (1 M, 4.8 mL, 4.80 mmol) was added to anhydrous THF (9 mL) at -10 ° C. A solution of Intermediate 37 (200 mg, 1.21 mmol) in anhydrous THF (1.5 mL) and a solution of 5-chlorobicyclo [4,2,0] octa-1,3,5-trien-7-one (369 mg, 242 mmol) in anhydrous THF (1.5 mL) were added to the portions sequentially. The reaction mixture was stirred at 0 ° C for 20 minutes, then anhydrous pyridine (0.784 ml, 9.69 mmol) was added at 0 ° C in 30 minutes. The reaction mixture was stirred at 0ºC for 2 h, and at room temperature for an additional 16 h, then quenched by the addition of saturated aqueous ammonium chloride solution (20 mL). Stirring was continued for an additional 10 minutes, then the solution was extracted with ethyl acetate (2 x 40 ml). The organic extracts were combined and washed with brine (20 ml), then dried over anhydrous sodium sulfate and filtered. The solvent was removed in vacuo. The residue was purified by automated chromatography, using a gradient of ethyl acetate in heptane (5 to 50%), to produce the title compound (159 mg, 44%) as a yellow solid. dn (250 MHz, CDCI3) 7.57 (d, J 2.1 Hz, 1H), 7.39 (dd, J 8.2, 6.8 Hz, 1H), 7.33 (d, J7.5 Hz, 1H), 7.20 (d, J 6.8 Hz, 1H), 6.92 (d, J 2.1 Hz, 1H), 4.38 (s, 3H), 4.09 (s, 2H). HPLC-MS (method 4): MH + m / z 300, RT 3.18 minutes. INTERMEDIATE 70 4- (2,3-Dimethylcyclobutylidene) -2- (2-methylpyrazol-3-yl) oxazol-5-o0na
[0773] [0773] —Titanium tetrachloride in DCM (1 M, 4.8 mL, 4.80 mmol) was added to anhydrous THF (9 mL) at -10 ° C. A solution of Intermediate 37 (200 mg, 1.21 mmol) in anhydrous THF (1.5 mL) and a solution of 2,3-dimethylcyclobutan-1-one (238 mg, 2.42 mmol) in anhydrous THF (1 , 5 ml) were added to the portions sequentially. The reaction mixture was stirred at 0ºC for 20 minutes, then anhydrous pyridine (0.784 mL, 9.69 mmol) was added at 0ºC in 30 minutes. The reaction mixture was stirred at 0ºC for 2 h, and at room temperature for an additional 16 h, then quenched by the addition of saturated aqueous ammonium chloride solution (20 mL). Stirring was continued for an additional 10 minutes, then the solution was extracted with ethyl acetate (2 x 40 ml). The organic extracts were combined and washed with brine (20 ml), then dried over anhydrous sodium sulfate and filtered. The solvent was removed in vacuo. The residue was purified by automated chromatography, using a gradient of ethyl acetate in heptane (5 to 40%) to produce the title compound (mixture of stereoisomers; 173 mg, 58%) as a yellow solid. HPLC-MS (method 4): MH + m / z 246, RT 2.90 minutes (49%) and RT 2.95 minutes (51%). INTERMEDIATE 71
[0774] [0774] Di-tert-butyl dicarbonate (853.88 mg, 3.91 mmol) in THF (8 mL) was added to the drops in a stirred suspension of 6-bromo-4-fluoroindolin-2-one (900 mg , 3.91 mmol) and sodium hydrogen carbonate (1.15 g, 13.689 mmol) in THF (10 mL). The reaction mixture was heated, with stirring, to 50ºC for 4.5 h, then the solid was removed by filtration and the solvent was removed in vacuo. The residue was purified by scintillating column chromatography, using a gradient of methyl tert-butyl ether in heptane (0 to 20%), to yield the title compound (1.04 g, 80%) as a yellow solid. ds (500 MHz, CDCI3) 7.86 (s, 1H), 7.07 (dd, J 7.9, 1.5 Hz, 1H), 3.60 (s, 2H), 1.64 (s, 9H). HPLC-MS (method 5): MH + m / z 328.2, 330.0, RT 2.05 minutes. INTERMEDIATE 72 6-bromo-4-fluoro-2-o0x0espiro [tert-butyl indolino-3,4'-tetrahydropyran] -1-carboxylate
[0775] [0775] A stirred solution of Intermediate 71 (0.8 g, 2.42 mmol) and 1-iodine-2- (2-iodo-ethoxy) ethane (0.38 mL, 2.67 mmol) in anhydrous DMF ( 16 mL) was cooled to -15ºC and purged with nitrogen for 5 minutes, then cesium carbonate (3.16 g, 9.69 mmol) was added. The reaction mixture was stirred for 2 h, with heating to 20ºC. Water (30 ml) was added and the aqueous layer was extracted with tert-butyl methyl ether (3 x 30 ml). The combined organic layers were washed with water (2 x 30 ml) and brine (30 ml), then dried over sodium sulfate, filtered and concentrated. The resulting crude material was purified by flashing column chromatography, using a gradient of methyl tert-butyl ether in heptane (0 to 15%), to produce the title compound (927.9 mg, 86%) as a yellow solid. õn (500 MHz, CDCI3) 7.90 (d, J 1.3 Hz, 1H), 7.06 (dd, J 9.1, 1.6 Hz, 1H), 4.26 (t, J 11, 8 Hz, 2H), 3.89 (dd, J 11.9, 3.6 Hz, 2H), 2.45 - 2.33 (m, 2H), 1.75 - 1.69 (m, 2H) , 1.65 (s, 9H). HPLC-MS (method 5): [M + H-BOC] + m / z 300.0, 302.0, RT 2.11 minutes. INTERMEDIATE 73 6- (tert-butoxycarbonylamino) -4-fluoro-2-oxo-spiro [indolino-3,4'-tetrahydro-pyran] -1- tert-butyl carboxylate
[0776] [0776] Palladium (II) acetate (17 mg, 0.08 mmol) was added to a mixture degassed by nitrogen from Intermediate 72 (476 mg, 1.19 mmol), tert-butyl carbamate (170 mg, 1, 45 mmol), XPhos (30 mg, 0.06 mmol) and cesium carbonate (776 mg, 2.38 mmol) anhydrous toluene (5 mL). The reaction mixture was heated to 90ºC for 3 h. The cooled reaction mixture was filtered through diatomaceous earth and rinsed with toluene (2 x 5 ml). The filtrate was concentrated in vacuo. The crude residue was purified by scintillating column chromatography, using a gradient of tert-butyl methyl ether in heptane (0 to 20%), to produce the title compound (533 mg, 87%) as a light brown oil which, in the resting, crystallized to a yellowish white solid. õ1 (250 MHz, CDCI3) 7.63 (d, J 1.6 Hz, 1H), 7.11 (dd, J 11.8, 1.5 Hz, 1H), 6.56 (s, 1H), 4.25 (t, J 11.5 Hz, 2H), 3.95 - 3.80 (m, 2H), 2.46 - 2.26 (m, 2H), 1.72 (d, J 14, 6 Hz, 2H), 1.64 (s, 9H), 1.51 (s, 9H). HPLC-MS (method 5): [M - HJ m / z 435.0, RT 2.09 minutes. INTERMEDIATE 74 6-Amino-4-fluoroospiro [indolino-3,4'-tetrahydropyran] -2-one
[0777] [0777] Trifluoroacetic acid (2.72 mL, 33.4 mmol) was added to a solution of Intermediate 73 (86%, 339 mg, 0.67 mmol) in DCM (4.75 mL) at 20 ° C. The reaction mixture was stirred at 20ºC for 3 h, then quenched with saturated aqueous sodium hydrogen carbonate solution (20 mL) and extracted with DCM (3 x 15 mL). The organic extracts were combined, filtered through a hydrophobic frit and concentrated in vacuo. The resulting crude material was purified by scintillating column chromatography, using a gradient of tert-butyl methyl ether in heptane (0 to 100%) followed by a MeOH gradient in tert-butyl methyl ether (0 to 10%). The relevant fractions were combined and concentrated in vacuo to yield the title compound (53.9 mg, 41%) as a yellowish white solid. õx (500 MHz, DMSO-ds) 10.27 (s, 1H), 5.95 (d, J 1.6 Hz, 1H), 5.88 (dd, J 12.8, 1.6 Hz, 1H ), 5.42 (s, 2H), 4.04 (t, J 10.1 Hz, 2H), 3.79 - 3.69 (m, 2H), 1.93 (ddd, J 14.2, 10.3, 4.4 Hz, 2H), 1.69 - 1.59 (m, 2H). uPLC-MS (method 1): MH + m / z 237.1, RT 1.49 min. INTERMEDIATE 75 4- (4-methylcyclohexylidene) -2- (2-methylpyrazol-3-yl) oxazol-5-one
[0778] [0778] Titanium tetrachloride in DCM (1 M, 48 mL, 48.0 mmol) was added to anhydrous THF (90 mL) at -10 ° C. A solution of Intermediate 37 (2.00 g, 12.10 mmol)
[0779] [0779] Acetic acid (0.09 mL, 1.63 mmol) was added to a stirred solution of Intermediate 74 (73.3 mg, 0.11 mmol) and Intermediate 75 (39 ul, 0.45 mmol) in Anhydrous THF (1 ml). The reaction mixture was stirred at 60ºC for 18 h under nitrogen in a sealed tube, then the solvent was removed in vacuo. The residue was purified by sparkling column chromatography, using a gradient of tert-butyl methyl ether in heptane (0 to 100%) followed by a MeOH gradient in tert-butyl methyl ether (0 to 20%), to produce the compound of the title (73 mg, 91%) as a yellowish white solid. dn (500 MHz, CDCI3) 9.33 (s, 1H), 8.56 (s, 1H), 8.18 (s, 1H), 7.72 (s, 1H), 7.44 (d, J 2.1 Hz, 1H), 6.82 (d, J 2.1 Hz, 1H), 6.54 (d, J 9.3 Hz, 1H), 4.26 (t, J 10.2 Hz, 2H), 4.16 (s, 3H), 3.94 - 3.87 (m, 2H), 2.83 (d, J 12.6 Hz, 1H), 2.73 - 2.67 (m, 1H), 2.30 - 2.19 (m, 2H), 2.16 - 2.05 (m, 1H), 2.04 - 1.94 (m, 1H), 1.90 - 1.82 ( m, 2H), 1.79 - 1.71 (m, 2H), 1.67 - 1.61 (m, 1H), 1.46 - 1.40 (m, 2H), 0.92 (d, J 6.5 Hz, 3H). uPLC-MS
[0780] [0780] DIPEA (0.15 mL, 0.92 mmol) was added to a stirred solution of Intermediate 2 (100 mg, 0.46 mmol), (2S) -1 (tert-butoxycarbonyl) amino acid (cyclohexyl) etanoic (118 mg, 0.46 mmol) and HATU (209 mg, 0.55 mmol) in anhydrous THF (2.5 mL) under an atmosphere of nitrogen. The reaction mixture was stirred at 20ºC for 72 h, then water (5 ml) and saturated aqueous sodium hydrogen carbonate solution (2.5 ml) were added. Stirring was continued for an additional 10 minutes. The milky reaction mixture was extracted with ethyl acetate (2x 10 mL). The organic extracts were combined and washed with brine (10 ml), then dried over anhydrous sodium sulfate and filtered. The solvent was removed in vacuo. The residue was purified by sparkling column chromatography, using a gradient of ethyl acetate in heptane (5 to 100%), to produce the title compound (166 mg, 77%) as a colorless glass. dn (250 MHz, DMSO-ds) 10.38 (s, 1H), 9.95 (s, 1H), 7.42 (d, J 8.1 Hz, 1H), 7.38 (d, J 1 , 8 Hz, 1H), 7.07 (dd, J 8.2, 1.7 Hz, 1H), 6.84 (d, J 8.7 Hz, 1H), 4.08 - 3.96 (m , 2H), 3.95 - 3.86 (m, 1H), 3.85 - 3.72 (m, 2H), 1.81 - 1.50 (m, 10H), 1.38 (s, 9H ), 1.18 - 0.96 (m, 5H). HPLC-MS (method 5): MH + m / z 458.2, RT 1.84 minutes. INTERMEDIATE 78 (28) -2-Amino-2-cyclohexyl-N- (2-oxo-spiro [indolino-3,4 "-tetrahydropyran]) - 6-yl) acetamide
[0781] [0781] Trifluoroacetic acid (0.40 ml, 5.25 mmol) was added to the drops to a stirred suspension of Intermediate 77 (165 mg, 0.35 mmol) in DCM (1.4 ml). The reaction mixture was stirred at 20ºC for 2.5 h. DCM (10 ml) and water (5 ml) were added, followed by a 4 M aqueous solution of sodium hydroxide (1.4 ml), and stirring was continued for 5 minutes. The organic phase was collected, and the aqueous phase was further extracted with a mixture of DCM-isopropanol (2: 1, 2x 10 mL). The organic phases were combined and stirred with brine (5 ml). The organic phase was separated using a hydrophobic frit, then the solvent was concentrated in vacuo,
[0782] [0782] Prepared from Intermediate 107 (150 mg, 0.26 mmol) and 2-isopropylpyrazole-3-carboxylic acid (61.1 mg, 0.4 mmol) according to Procedure A, and purified by chromatography on sparkling column, using a gradient of tert-butyl methyl ether in heptane (0 to 100%), to give the title compound (115.4 mg, 57%) as a white powder. õH (500 MHz, DMSO-ds) 10.74 (s, 1H), 8.60 (s, 1H), 8.53 (d, J 8.0 Hz, 1H), 8.05 (s, 1H) , 7.61 (d, J 1.9 Hz, 1H), 7.04 (d, J 2.0 Hz, 1H), 5.54 - 5.44 (m, 1H), 5.19 (s, 2H), 4.60 (t, J 8.2 Hz, 1H), 4.15 -4.08 (m, 2H), 3.96 (t, J 8.0 Hz, 2H), 3.64 - 3.57 (m, 2H), 1.99 - 1.86 (m, 4H), 1.86 - 1.74 (m, 4H), 1.71 - 1.61 (m, 1H), 1, 50 - 1.29 (m, 9H), 1.21 - 1.40 (m, 1H), 1.02 - 0.90 (m, 6H), 0.00 (s, 9H). HPLC-MS (method 3): MH + m / z 639.2, RT 1.45 minutes. INTERMEDIATE 80 (28) -2K [6- (Difluoromethyl) pyridazin-3-ylJamino) -2- (4-methylcyclohexyl) -N- (2-0x0-1- [2- (trimethylsilyl) ethoxymethylJespiro [yrrole [3,2 -c] pyridine-3,4 "-tetrahydropyran]) - 6-yl) -acetamide (trans isomer)
[0783] [0783] Intermediate 107 (100 mg, 0.18 mmol) was dissolved in anhydrous 1,4-dioxane (0.5 mL) and DIPEA (0.09 mL, 0.53 mmol) and treated with 3-chloro- 6- (difluoromethyl) - pyridazine (50 mg, 0.3 mmol). The reaction mixture was stirred at 140ºC for 18 h, then cooled to 20ºC and quenched with saturated aqueous sodium hydrogen carbonate solution (10 mL). The aqueous layer was extracted with DCM (3 x 20 ml). The organic extracts were combined and washed with brine (10 ml), then dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by sparkling column chromatography, using a gradient of tert-butyl methyl ether in heptane (0 to 100%) followed by a MeOH gradient in tert-butyl methyl ether (0 to 20%), to produce the compound of the title (113.3 mg, 33%) as an orange oil. HPLC-MS (method 5): MH + m / z 631.0, RT 2.16 minutes. INTERMEDIATE 81 6-Chlorine-1 - ([2- (trimethylsily) ethoxymethyl) -1 H-pyrrole [3,2-c] pyridine
[0784] [0784] To a solution of 6-chloro-1H-pyrrolo [3,2-c] pyridine (5.00 g, 32.8 mmol) in DNF (20 mL) was added NaH (1.57 g, 39, 3 mmol) at 0ºC. The reaction mixture was stirred for 1 h, then SEM-CI (6.56 g, 39.3 mmol) was added at 0 ° C. The reaction mixture was stirred at room temperature for 1 h, then quenched with H2O (100 ml) and extracted with DCM (3 x 100 ml). The organic layer was separated and washed with brine (3 x 100 ml), then dried over anhydrous Na2SO and concentrated in vacuo. The crude material was purified by column chromatography (10 to 15% EtOAc in hexanes) to produce the title compound (7.00 g, 75%) as a yellow oil. dn (400 MHz, CD30D) -0.07 (s, 9H), 0.87 (t, J 7.83 Hz, 2H), 3.52 (t, J 7.83 Hz, 2H), 5.57 (s, 2H), 6.71 (d, J 2.93 Hz, 1H), 7.50 (d, J 3.42 Hz, 1H), 7.64 (s, 1H), 8.61 (s , 1H). HPLC-MS (method 6): MH + m / z 283.3, RT 2.12 minutes. INTERMEDIATE 82 3,3-Dibromo-6-chloro-1- [2- (trimethylsili) ethoxymethyl] pyrrole [3,2-c] pyridin-2-one
[0785] [0785] —A solution of Intermediate 81 (3.50 g, 12.4 mmol) in 1,4-dioxane (50 mL) was added pyridinium tribromide (19.8 g, 61.9 mmol) to the portions at 0ºC . The reaction mixture was stirred at room temperature for 1 h, then quenched with H2O (100 ml), stirred for 10 minutes and extracted with EtOAc (2 x 100 ml). The organic layer was separated and washed with brine (2 x 100 ml), then dried over Na2SO, anhydrous and concentrated in vacuo, to produce the title compound (5.00 g, 78%) as a red oil, which was used without further purification. dx (400 MHz, CDCI3) 0.00 (s, 9H), 0.92 - 1.00 (m, 2H), 3.59 - 3.65 (m, 2H), 5.31 (s, 2H) , 7.33 - 7.37 (m, 1H), 8.75 (s, 1H). HPLC-MS (method 6): MH + m / z 457.0, RT 2.40 minutes. INTERMEDIATE 83 6-Chlorine-1 - ([2- (trimethylsilyl) ethoxymethyl) -1,3-dihydro-2H-pyrrolo [3,2-c] pyridin-2-one
[0786] [0786] —A solution of Intermediate 82 (5.00 g, 10.9 mmol) in THF (70 mL) was added Zn (7.16 g, 109 mmol) at 0 ° C, followed by the addition of drops of saturated solution of NHaCI (20 ml). The reaction mixture was stirred at room temperature for 3 h, then diluted with EtOAc (300 ml) and filtered through a pad of Celite. The filtrate was washed with water (2 x 100 ml), then dried over Na2SO. anhydrous and vacuum concentrated. The crude material was purified by column chromatography (25 to 30% EtOAc in hexanes) to produce the title compound (2.00 9, 45%) as a light yellow oil. ô1 (400 MHz, CD3OD) 0.01 (s, 9H), 0.90 - 0.98 (m, 2H), 3.57 - 3.67 (m, 2H), 3.72 (s, 2H) , 5.17 (s, 2H), 7.18 (s, 1H), 8.14 (s, 1H). HPLC-MS (method 6): MH + m / z 299.2, RT 2.08 minutes. INTERMEDIATE 84 Chlorine-1 '([2- (trimethylsily) ethoxymethyl) -2,3,5,6-tetrahydrospiro [yran-4,3 "-pyrrole [3,2- clpiridin) -2' (1'H) - ona
[0787] [0787] To a solution of Intermediate 83 (2.00 g, 6.69 mmol) in acetone (30 mL) was added Cs2CO; (6.54 g, 20.1 mmol) at 0 ° C. The reaction mixture was stirred at 0 ° C for 10 minutes, then 1-iodo-2- (2-iodoethoxy) ethane (4.36 9, 13.4 mmol) was added at 0 ° C. The reaction mixture was stirred at room temperature for 6 h, then concentrated in vacuo. The residue was diluted with EtOAc (500 ml) and washed with water (2 x 200 ml). The organic layer was separated and washed with brine (200 ml), then dried over Na2SO. anhydrous and concentrated in vacuo. The crude material was purified by column chromatography (15 to 20% EtOAc in hexanes) to produce the title compound (1.20 9, 48%) as a yellowish white solid. dn (400 MHz, DMSO-ds) -0.08 (s, 9H), 0.84 (t, J 7.83 Hz, 2H), 1.74 - 1.85 (m, 4H), 3.50 (t, J 8.07 Hz, 2H), 3.80 - 3.86 (m, 2H), 3.96 - 4.06 (m, 2H), 5.13 (s, 2H), 7.31 (s, 1H), 8.58 (s, 1H). HPLC-MS (method 6): MH + m / z 369.0, RT 3.18 minutes. INTERMEDIATE 85 N- (2-Amino-1-cyclooctyl-2-0x0ethyl) -2-methylpyrazole-3-carboxamide
[0788] [0788] To a solution of Intermediate 13 (0.30 g, 1.02 mmol) in DCM (15 mL) were added HATU (0.58 g, 1.53 mmol) and NHaCI (0.22 g, 4, 09 mmol). The reaction mixture was stirred at 0ºC for 10 minutes, followed by the addition of DIPEA (0.55 mL, 3.07 mmol). The reaction mixture was stirred at room temperature for 16 h, then diluted with DCM (100 ml), and washed with H2O (2 x 50 ml) and brine (2 x 25 ml). The organic layer was separated, then dried over Na2SO. anhydrous and concentrated in vacuo. The crude material was purified by column chromatography (60 to 70% EtOAc in hexanes) to produce the title compound (0.23 g, 71%) as a yellowish white solid. dn (400 MHz, DMSO-ds) 1.28 - 1.37 (m, 3H), 1.40 - 1.49 (m, 4H), 1.51 - 1.67 (m, 7H), 2, 02 - 2.10 (m, 1H), 4.02 (s, 3H), 4.27 (t, J 8.80 Hz, 1H), 6.99 (d, J 1.96 Hz, 1H), 7.06 (br s, 1H), 7.43 (d, J 1.96 Hz, 1H), 7.50 (br s, 1H), 8.19 (d, J 9.29 Hz, 1H). HPLC-MS (method 6): MH + m / z 293.1, RT 1.66 minutes. INTERMEDIATE 86 N- [1-Cyclooctyl-2-0x0-2 - (((2-0x0-1- [2- (trimethylsilyl) ethoxymethylJespiro [yrrole [3,2-c] pyridine-3,4-tetrahydropyran] -6- ilkamino) ethyl] -2-methylpyrazole-3-carboxamide
[0789] [0789] To a solution of Intermediate 85 (0.16 g, 0.54 mmol) in 1,4-dioxane (5 mL) was added Intermediate 84 (0.20 g, 0.54 mmol) and Cs2COs; 3 (0.53 g, 1.63 mmol). The reaction mixture was purged with argon for 10 minutes, then Pd2 (dba) s (0.05 g, 0.05 mmol) and Xantphos (0.03 g, 0.05 mmol) were added. The reaction mixture was heated at 100ºC for 16 h, then diluted with EtOAc (30 ml), filtered through a pad of Celite and washed with water (2 x 20 ml). The organic layer was separated, dried over Na2SO2. anhydrous and concentrated in vacuo. The crude material was purified by column chromatography (60 to 70% EtOAc in hexanes) to yield the title compound (0.08 g, 23%) as a light yellow solid. ox (400 MHz, DMSO-ds) -0.11 (s, 9H), 0.80 - 0.90 (m, 2H), 1.38 - 1.59 (m, 10H), 1.62 - 1 , 77 (m, 5H), 1.78 - 1.87 (m, 2H), 2.16 - 2.19 (m, 1H), 3.49 (t, J 7.58 Hz, 2H), 3 , 80 - 3.91 (m, 3H), 3.97 - 4.00 (m, 1H), 4.02 (s, 4H), 4.59 (t, J 8.31 Hz, 1H), 5 , 07 (s, 2H), 7.02 (s, 1H), 7.46 (s, 1H), 7.93 (s, 1H), 8.42 (d, J 8.31 Hz, 1H), 8.50 (s, 1H), 10.71 (s, 1H). HPLC-MS (method 6): MH + m / z 625.3, RT 2.37 minutes. INTERMEDIATE 87 2- (5-bromo-3-nitropyridin-2-yl) diethyl mnalonate
[0790] [0790] To a solution of diethyl malonate (25.3 g, 158 mmol) in DNF (45 mL) was added K2CO; (43.6 g, 316 mmol) at 0 ° C. The mixture was stirred for 10 minutes, then 5-bromo-2-chloro-3-nitropyridine (25.0 g, 105 mmol) was added. The reaction mixture was stirred at room temperature for 16 h, then diluted with EtOAc (250 ml) and washed with water (3 x 250 ml). The organic layer was separated, dried over anhydrous Na2SO.s and concentrated in vacuo. The crude material was purified by column chromatography (20% EtOAc in hexanes) to give the title compound (26.0 g, 68%) as a yellowish white solid. õ1 (400 MHz, DMSO-ds) 1.19 (t, J 6.85 Hz, 6H), 4.16 - 4.27 (m, 4H), 5.58 (s, 1H), 8.89 ( s, 1H), 9.09 (s, 1H). HPLC-MS (method 6): MH + m / z 360.9, RT 2.04 minutes. INTERMEDIATE 88 2- (5-bromo-3-nitropyridin-2-yl) ethyl acetate
[0791] [0791] To a solution of Intermediate 87 (26.0 g, 72.0 mmol) in DMSO: water (1: 1, 90 mL) was added lithium chloride (4.58 g, 108 mmol). The reaction mixture was heated at 100ºC for 16 h, then diluted with H2O (110 ml) and extracted with EtOAc (3 x 110 ml). The organic layer was separated, dried over NazSO. anhydrous and concentrated in vacuo. The crude residue was purified by column chromatography (10% EtOAc in hexanes) to give the title compound (14.0 g, 67%) as a white solid. õs (400 MHz, DMSO-ds) 1.16 - 1.21 (m, 3H), 4.07 - 4.11 (m, 2H), 4.21 (s, 2H), 8.82 (d, J 245 Hz, 1H), 9.04 (d, J 1.96 Hz, 1H). HPLC-MS (method 6): MH + m / z 290.8, RT 1.90 min. INTERMEDIATE 89 6-Bromo-1,3-dihydro-2H-pyrrolo [3,2-b] pyridin-2-one
[0792] [0792] To a solution of Intermediate 88 (10.0 g, 34.6 mmol) in acetic acid (200 mL) was added iron (9.51 g, 173 mmol). The reaction mixture was stirred at 60ºC for 4 h, then diluted with EtOAc (200 ml), stirred for 15 minutes, filtered through a pad of Celite, and washed with EtOAc (3 x 200 ml). The organic layer was separated, dried over Na2SO. anhydrous and concentrated in vacuo. The crude residue was dissolved in 5% MeOH in EtOAc (30 ml) and absorbed in Fluorosyl. The resulting slurry was filtered through a pad of Celite and washed with 5% MeOH in EtOAc (3 x 200 ml). The organic layer was dried over Na2SO. anhydrous and concentrated in vacuo, to yield the title compound (5.00 g, 68%) as a brown solid. õs (400 MHz, DMSO-ds) 3.57 (s, 2H), 7.30 (s, 1H), 8.17 (s, 1H), 10.67
[0793] [0793] To a solution of Intermediate 89 (2.00 g, 9.39 mmol) in DMSO (20 mL) was added Cs2COs (3.05 g, 9.39 mmol) at 0 ° C. The reaction mixture was stirred for minutes, then 1-iodo-2- (2-iodoethoxy) ethane (3.05 g, 9.39 mmol) was added. The reaction mixture was stirred at room temperature for 5 h, then quenched with water (50 ml) and extracted with EtOAc (3 x 50 ml). The organic layer was separated, dried over anhydrous Na2SO and concentrated in vacuo. The crude residue was purified by column chromatography (20% EtOAc in hexanes) to yield the title compound (0.45 g, 17%) as a light brown liquid. ox (400 MHz, DMSO-ds) 1.58 - 1.67 (m, 2H), 1.77 - 1.83 (m, 2H), 3.85 - 3.96 (m, 2H), 3, 98 - 4.08 (m, 2H), 7.39 (d, J 1.96 Hz, 1H), 8.25 (d, J 1.96 Hz, 1H), 10.78 (s, 1H). HPLC-MS (method 6): MH + m / z 283.1, RT 1.54 min. INTERMEDIATE 91 6'-Bromo-1 '([2- (trimethylsilyl) ethoxylmethyl) -2,3,5,6-tetrahydrospiro [yran-4,3'-pyrrolo [3,2- b] pyridin) -2' ( 1'H) -one
[0794] [0794] To a solution of Intermediate 90 (0.40 g, 1.41 mmol) in THF (10 mL) was added NaH (0.05 g, 2.12 mmol) at 0 ° C. The reaction mixture was stirred for 30 minutes, then SEM-CI (0.35 g, 2.12 mmol) was added. The reaction mixture was stirred at room temperature for 3 h, then diluted with water (50 ml) and extracted with DCM (3 x 50 ml). The organic layer was separated, washed with H2O (100 ml) and brine (100 ml), then dried over Na2SO. anhydrous and concentrated in vacuo. The crude residue was purified by column chromatography (20% EtOAc in hexanes) to give the title compound (0.40 g, 43%) as a white solid. HPLC-MS (method 6): MH + m / z 415.1, RT 2.34 minutes. INTERMEDIATE 92 N- [1-Cyclooctyl-2-0x0-2 - (((2-0x0-1- [2- (trimethylsilyl) ethoxymethylJespiro [yrrole [3,2-b] pyridine-3,4 "-tetrahydropyran] -6 -yl) amino) ethyl] -2-methylpyrazole-3-carboxamide
[0795] [0795] To a solution of Intermediate 91 (0.30 g, 0.73 mmol) in tert-butanol (10 mL), Intermediate 85 (0.21 g, 0.73 mmol) and K2COs (0.20 g , 1.45 mmol). The reaction mixture was purged with argon for 10 minutes, then Pd2 (dba) 3 (0.07 g, 0.07 mmol) and XPhos (0.03 g, 0.07 mmol) were added. The reaction mixture was heated at 100ºC for 16 h, then diluted with EtOAc (100 ml) and filtered through a pad of Celite. The filtrate was washed with water (2 x 50 ML). The organic layer was separated, dried over Na2SO. anhydrous and concentrated in vacuo. The crude residue was purified by column chromatography (50 to 60% EtOAc in hexanes) to give the title compound (0.16 g, 29%) as a light yellow solid. ds (400 MHz, DMSO-ds) -0.10 (s, 6H), 0.81 - 0.88 (m, 2H), 1.38 - 1.48 (m, 4H), 1.50 - 1 , 61 (m, 4H), 1.63 - 1.73 (m, 3H), 1.78 - 1.86 (m, 2H), 2.69 (s, 3H), 3.15 - 3.17 (m, 6H), 3.49 (t, J 7.78 Hz, 2H), 3.90 - 3.98 (m, 2H), 4.03 (s, 2H), 4.07 - 4.12 (m, 3H), 4.47 (t, J 8.66 Hz, 1H), 5.11 (s, 2H), 7.06 (d, J 2.01 Hz, 1H), 7.46 (d , J 2.01 Hz, 1H), 7.93 (d, J 1.76 Hz, 1H), 8.42 (d, J 1.76 Hz, 1H), 8.57 (d, J 8.28 Hz, 1H), 10.56 (s, 1H). HPLC-MS (method 6): MH + m / z 625.3, RT 2.34 minutes. INTERMEDIATE 93 2,4-Dichloro-7 ([2- (trimethylsilyl) ethoxymethyl) -7 H-pyrrolo [2,3-d] pyrimidine
[0796] [0796] To a solution of 2,4-dichloropyrrolo [2,3-d] pyrimidine (10.0 g, 53.2 mmol) in DNF (50 mL) was added NaH (1.91 g, 79.8 mmol ) at 0ºC. The reaction mixture was stirred at 0 ° C for 30 minutes, then SEM-CI (9.30 ml, 79.8 mmol) was added at 0 ° C. The reaction mixture was stirred at room temperature for 2 h, then quenched with ice water (200 g) and extracted with diethyl ether (3 x 150 ml). The organic layer was separated, washed with water (100 ml) and brine (100 ml), then dried over anhydrous Na2SO.s and concentrated in vacuo. The crude residue was purified by column chromatography (0 to 20% EtOAc in hexanes) to produce the title compound (12.0 g, 71%) as a yellow oil. HPLC-MS (method 6): MH + m / z 317.9, RT 2.47 minutes. INTERMEDIATE 94 2 - [(2-Chloropyrrolo [2,3-d] pyrimidin-7-yl) methoxy] ethyl (trimethyl) silane
[0797] [0797] To a solution of Intermediate 93 (1.50 g, 4.71 mmol) in EtOH (15 mL) was added 10% palladium on vegetable carbon (0.15 g, 1.41 mmol), followed by triethylamine ( 3.28 mL, 23.6 mmol). The reaction mixture was stirred at room temperature for 1 h under hydrogen pressure, then filtered through a pad of Celite. The filtrate was concentrated in vacuo. The crude residue was purified by column chromatography (0 to 20% EtOAc in hexanes) to give the title compound (0.36 g, 27%) as a yellow oil. dn (400 MHz, DMSO-ds) -0.10 (s, 9H), 0.80 - 0.88 (m, 2H), 3.52 (t, J 8.07 Hz, 2H), 5.58 (s, 2H), 6.74 (d, J 3.42 Hz, 1H), 7.78 (d, J 3.91 Hz, 1H), 8.97 (s, 1H). HPLC-MS (method 6): MH + m / z 283.9, RT 2.14 minutes. INTERMEDIATE 95 5,5-Dibromo-2-chloro-7 - ([2- (trimethylsilyl) ethoxymethyl) -5,7-dihydro-6H-pyrrolo [2,3-d] pyrimidin-6-one
[0798] [0798] To a solution of Intermediate 94 (1.00 g, 3.52 mmol) in tert-butanol (10 mL) and water (10 mL) was added NBS (1.88 g, 10.6 mmol) at temperature environment. The reaction mixture was stirred at room temperature for 3 h, then diluted with water (50 ml), neutralized with saturated aqueous NaHCOs; and extracted with EtOAc (3 x 50 ml). The organic layer was separated, washed with water (50 ml) and brine (50 ml), then dried over Na2SO. anhydrous and concentrated in vacuo, to produce the title compound (2.00 g crude) as a yellowish white solid, which was used without further purification. dx (400 MHz, DMSO-ds) -0.06 (s, 9H), 0.88 (t, J 7.83 Hz, 2H), 3.59 - 3.67 (m, 2H), 5.13 (s, 2H) 8.97 (s, 1H). INTERMEDIATE 96 2-Chlorine-7 - ([2- (trimethylsilyl) ethoxymethyl) -5,7-dihydro-6H-pyrrolo [2,3-d] pyrimidin-6-one
[0799] [0799] To a solution of Intermediate 95 (2.00 g, 4.37 mmol) in THF (20 mL) and acetic acid (5 mL) was added Zn (1.43 g, 21.9 mmol) at 0 ° C. The reaction mixture was stirred at room temperature for 2 h, then filtered through a pad of Celite. The filtrate was diluted with water (30 ml) and extracted with EtOAc (3 x 50 ml). The organic layer was separated, washed with water (30 ml), and brine (30 ml), then dried over Na2SO. anhydrous and concentrated in vacuo. The crude residue was purified by column chromatography (0 to 20% EtOAc in hexanes) to produce the title compound (0.93 g, 71%) as a red oil. dn (400 MHz, DMSO-ds)
[0800] [0800] To a solution of Intermediate 96 (0.90 g, 3.00 mmol) in DNF (10 mL) was added Cs2CO; (2.93 g, 9.01 mmol), followed by 1-bromo-2- (2-bromoethoxy) ethane (1.04 g, 4.50 mmol). The reaction mixture was stirred at room temperature for 4 h, then poured into ice and extracted with EtOAc (3 x 100 ml). The organic layer was separated, washed with water (100 ml) and brine (100 ml), then dried over anhydrous Na2SO.s and concentrated in vacuo. The crude residue was purified by column chromatography (0 to 20% EtOAc in hexanes) to give the title compound (0.43 9, 38%) as an orange solid. dx (400 MHz, DMSO-ds) -0.06 (s, 9H), 0.87 (t, J 8.07 Hz, 2H), 1.70 - 1.78 (m, 2H), 1.82 - 1.95 (m, 2H), 3.55 - 3.63 (m, 2H), 3.77 - 3.86 (m, 2H), 3.93 - 4.00 (m, 2H), 5 , 05 (s, 2H), 8.85 (s, 1H). HPLC-MS (method 6): MH + m / z 370.0, RT 2.21 minutes. INTERMEDIATE 98 N- [1-Cyclooctyl-2-0x0-2- (16-0x0-7- [2- (trimethylsilyl) ethoxymethylJespiro [yrrole [2,3-d] - pyrimidine-5.4 "-tetrahydropyran] -2 -yl <amino) ethyl] -2-methylpyrazole-3-carboxamide
[0801] [0801] To a solution of Intermediate 97 (0.25 g, 0.688 mmol) and Intermediate 85 (0.20 g, 0.688 mmol) in 1,4-dioxane (5 mL) were added Cs2CO; s (0.44 g , 1.35 mmol), Pd2 (dba) 3 (0.06 g, 0.10 mmol) and Xantphos (0.04 g, 0.07 mmol). The reaction mixture was heated to 80ºC for 16 h, then filtered through a pad of Celite. The filtrate was extracted with EtOAc (3 x 20 ml). The organic layer was separated, washed with water (10 ml) and brine (10 ml), then dried over Na2SO: anhydrous and concentrated in vacuo. The crude residue was purified by column chromatography (0 to 30% EtOAc in hexanes) to give the title compound (0.26 g, 31%) as an orange solid. ds (400 MHz, DMSO-ds) -0.10 (s, 9H), 0.85 - 0.88 (m, 2H). 1.43 - 1.47 (m, 8H), 1.56 (d, J 12.31 Hz, 2H), 1.60 -1.74 (m, 6H), 1.85 - 1.94 (m , 2H), 2.15 - 2.23 (m, 1H), 3.61 (t, J 7.88 Hz, 2H), 3.83 (t, J 9.35 Hz, 2H), 3.95 - 3.97 (m, 2H), 4.03
[0802] [0802] A suspension of 6-bromo-1,2-dihydrospiro [indole-3,4'-oxo] -2-one (555 mg, 1.95 mmol) in DNF (8 mL) was treated with methyl iodide (135 uL, 2.2 mmol), then cooled to 0ºC under a nitrogen atmosphere and treated with sodium hydride (60% dispersion in mineral oil, 80 mg, 2.0 mmol). The resulting mixture was allowed to warm to 20 ° C in 2 h, then diluted with water (50 ml) and extracted with EtOAc (2 x 25 ml). The combined organic extracts were washed with water (2 x ml) and brine (30 ml), then dried over MgSO:, filtered and concentrated in vacuo, to yield the title compound (550 mg, 94%) as a white solid. õn (400 MHz, DMSO-ds) 7.50 (d, J 7.9 Hz, 1H), 7.28 (d, J 1.8 Hz, 1H), 7.22 (dd, J 7.9, 1.8 Hz, 1H), 4.04 (ddd, J 11.6, 6.9, 4.8 Hz, 2H), 3.85 - 3.75 (m, 2H), 3.13 (s, 3H), 1.72 (ddd, J 5.8, 4.5, 1.9 Hz, 4H). INTERMEDIATE 100 N-tert-butyl carbamate (N-1-methyl-2-oxospiro [indolino-3,4'-tetrahydropyran] -6-yl)
[0803] [0803] A suspension of Intermediate 99 (550 mg, 1.9 mmol), cesium carbonate (1.3 g, 4 mmol), tert-butyl carbamate (250 mg, 2.1 mmol), XPhos (45 mg , 0.09 mmol) and palladium acetate (25 mg, 0.11 mmol) in toluene (10 mL) was heated to 90ºC under a nitrogen atmosphere for 18 h. The reaction mixture was cooled, then diluted with EtOAc (50 ml) and water (50 ml). The layers were separated and the aqueous layer was extracted with EtOAc (50 ml, then 20 ml). The combined organic phases were washed with brine (40 ml) and dried over MgSO2, then filtered and concentrated in vacuo. The residue was purified by flashing column chromatography, using a gradient of ethyl acetate in heptane (60% O), to produce the title compound (570 mg, 92%) as a white powder. õx (400 MHz, DMSO-ds) 9.42 (s, 1H), 7.43 (d, J 8.1 Hz, 1H), 7.29 (d, J 1.9 Hz, 1H), 6, 99 (dd, J 8.1, 1.9 Hz, 1H), 4.04 (m, 2H), 3.81 (ddd, J 11.2, 6.7, 3.9 Hz, 2H), 3 .09 (s, 3H), 1.77 - 1.58
[0804] [0804] A solution of Intermediate 100 (740 mg, 2.22 mmol) in DCM (10 mL) was cooled to 0 ° C, then treated with TFA (5 mL). The reaction mixture was stirred under a nitrogen atmosphere for 18 h, then concentrated in vacuo. The residue was applied to an SCX2 ion exchange cartridge and eluted with methanol, followed by NH3 in methanol (3 M), to give the title compound (350 mg, 68%) as a beige waxy solid. õH (400 MHz, DMSO-ds) 7.21 - 7.12 (m, 1H), 6.26 - 6.18 (m, 2H), 5.16 (s, 2H), 4.00 (ddd, J 11.2, 7.2, 3.7 Hz, 2H), 3.78 (ddd, J 11.2, 7.2, 3.7 Hz, 2H), 3.04 (s, 3H), 1 , 70 (ddd, J 13.4, 7.2, 3.7 Hz, 2H), 1.56 (ddd, J 13.5, 7.3, 3.7 Hz, 2H). HPLC-MS (Method 21): MH + m / z 233, RT 0.57 min. INTERMEDIATE 102 N- (1-cyclooctyl-2 - [(1-methyl-2-0xo0ospiro [indolino-3,4 "-tetrahydropyran] -6-yl) amino] -2-oxoethyl)-tert-butyl carbamate
[0805] [0805] Prepared from Intermediate 101 and Intermediate 33 by a method analogous to that used to prepare Intermediate 34 to give the title compound (quantitative) as a white solid. õH (400 MHz, DMSO-ds) 10.09 (s, 1H), 7.49 (d, J 8.1 Hz, 1H), 7.41 (d, J 1.9 Hz, 1H), 7, 22 (dd, J 8.1, 1.9 Hz, 1H), 6.90 (d, J 8.8 Hz, 1H), 4.04 (ddd, J 11.2, 7.3, 3.7 Hz, 2H), 3.96 (t, J 8.4 Hz, 1H), 3.82 (ddd, J 11.1, 6.7, 4.0 Hz, 2H), 3.10 (s, 3H ), 1.95 (br s, 1H), 1.77-1.25 (m, 27H). HPLC-MS (Method 6): MH + m / z 500, RT 2.58 minutes. INTERMEDIATE 103 2-Amino-2-cyclooctyl-N- (1-methyl-2-oxoxospiro [indolino-3,4'-tetrahydropyran] -6-yl) -acetamide chloride;
[0806] [0806] Intermediate 102 (50 mg, 0.10 mmol) was dissolved in methanol (1 mL) and HCI (4 M in 1,4-dioxane, 0.25 mL, 1.00 mmol) was added. The reaction mixture was stirred at 20 ° C for 48 h, then concentrated in vacuo, to produce the title compound (43 mg, quantitative) as a pink oil, which was used without further purification. HPLC-MS (method 7): MH + m / z 400, RT 1.21 minutes.
[0807] [0807] Prepared from Intermediate 2 (2.4 g, 11.1 mmol) and 2- (tert-butoxycarbonyl-amino) -2- (4-methylcyclohexyl) acetic acid (3.6 g, 13.26 mmol ) by a method analogous to that used to prepare Intermediate 49 to give the title compound (4.3 g, 69%) as a white solid. õs (400 MHz, DMSO-ds) 10.39 (s, 1H), 10.06 - 9.84 (m, 1H), 7.48 - 7.21 (m, 2H), 7.08 (td, J 8.8, 8.2, 1.9 Hz, 1H), 6.88 (m, 1H), 4.15 - 3.95 (m, 2H), 3.95 - 3.66 (m, 3H ), 1.98 - 1.43 (m, 9H), 1.38 (s, 14H), 1.01 - 0.65 (m, 3H). HPLC-MS (method 7): [M + 2H-'Bu] + m / z 416, RT 2.40 minutes. INTERMEDIATE 105 2-Amino-2- (4-methylcyclohexyl) -N- (2-oxospiro [indolino-3,4'-tetrahydropyran] -6-yl) - acetamide
[0808] [0808] Prepared from Intermediate 104 (2.11 g, 4.5 mmol) by a method analogous to that used to prepare Intermediate 50 to give the title compound (1.53 g, 92%) as a white solid . HPLC-MS (Method 7): MH + m / z 372, RT 1.11 minutes. INTERMEDIATE 106 NI (18) -1- (4-methylcyclohexyl) -2-0x0-2 - ((2-0x0-1- [2- (trimethylsilyl) ethoxy-methylJespiro [yrrole [3,2-c] pyridine-3 , 4 "-tetrahydropyran] -6-ylkamino) ethyl | carbamate - tert-butyl (trans isomer)
[0809] [0809] Prepared from Intermediate 57 (2.7 g, 7.74 mmol) and Intermediate 48 (2 g, 7.87 mmol) by a method analogous to that used to prepare Intermediate 49 to give the title compound ( 4.2 g, 95%) as a white solid. ôõH (300 MHz, DMSO-ds) 10.41 (s, 1H), 8.51 (s, 1H), 7.93 (s, 1H), 6.96 (d, J 9.2 Hz, 1H) , 5.08 (s, 2H), 3.85 (t, J 8.5 Hz, 2H), 3.50 (t, J 7.8 Hz, 2H), 2.00 (s, 1H), 1 , 90 - 1.43 (m, 9H), 1.38 (m, 9H), 1.18 (m, 4H), 0.85 (m, 8H), -0.09 (s, 9H). HPLC-MS (method 6): MH + m / z 603, RT 1.55 minutes. INTERMEDIATE 107 (28) -2-Amino-2- (4-methylcyclohexyl) -N- (2-0x0-1- [2- (trimethylsilyl) ethoxymethyl] -
[0810] [0810] To a solution of Intermediate 106 (4.2 g, 7.0 mmol) dissolved in methanol (50 mL) was added HCI (4 M in 1,4-dioxane, 17 mL, 68 mmol) at 20 ° C. The reaction mixture was stirred for 18 h, then concentrated in vacuo, to yield the title compound (3.74 g, 100%) as a light pink solid, which was used without further purification. 1 (3800 MHz, DMSO-ds) 11.19 (s, 1H), 8.55 (s, 1H), 8.40 (s, 2H), 7.87 (s, 1H), 5.19 - 5 , 02 (m, 2H), 4.08 - 3.97 (m, 2H), 3.96 - 3.79 (m, 3H), 3.61 - 3.41 (m, 2H), 1.90 - 1.55 (m, 8H), 1.32 - 0.97 (m, 3H), 0.96 - 0.75 (m, 8H), -0.08 (s, 9H). HPLC-MS (method 6): MH + m / z 503, RT 1.32 minutes.
[0811] [0811] Prepared from Intermediate 107 (2.57 g, 4.77 mmol) and 3-ethylisoxazol-4-carboxylic acid (850 mg, 5.72 mmol) according to Procedure A, and purified by chromatography on sparkling column using a gradient of 0 to 100% ethyl acetate in hexanes, to give the title compound (2.70 g, 91%) as a yellowish white solid. ôH (300 MHz, DMSO-ds) 10.68 (s, 1H), 9.39 (s, 1H), 8.50 (d, J 0.7 Hz, 1H), 8.40 (d, J 7 , 9 Hz, 1H), 7.95 (s, 1H), 5.11 - 5.04 (m, 2H), 4.54 (m, 1H), 4.15 - 3.99 (m, 2H) , 3.90 - 3.77 (m, 2H), 3.55 - 3.43 (m, 2H), 3.20 - 3.12 (m, 2H), 2.80 - 2.74 (m, 2H), 1.90 - 1.49 (m, 9H), 1.27 - 1.06 (m, 6H), 0.95 - 0.73 (m, 5H), -0.11 (s, 9H ). HPLC-MS (method 7): MH + m / z 626, RT 1.65 minutes.
[0812] [0812] Prepared from Intermediate 107 (2.56 g, 4.75 mmol) and 1-ethyl-1H-pyrazole-S5-carboxylic acid (840 mg, 5.69 mmol) according to Procedure A, and purified by sparkling column chromatography using a gradient of 0 to 100% ethyl acetate in hexanes, to give the title compound (2.73 g, 92%) as a yellowish white solid. ds (300 MHz, DMSO-ds) 10.66 (s, 1H), 8.54 - 8.40 (m, 2H), 7.94 (s, 1H), 7.49 (d, J 2.0 Hz, 1H), 7.00 (d, J 2.0 Hz, 1H), 5.08 (s, 2H), 4.50 - 4.38 (m, 2H), 4.06 - 3.94 ( m, 1H), 3.90 - 3.79 (m, 2H), 3.49 (t, J 7.8 Hz, 2H), 1.90 - 1.51 (m, 10H), 1.35 - 1.24 (m, 5H), 0.92 - 0.78 (m, 9H), -0.11 (s, 9H). HPLC-MS (method 6): MH + m / z 625, RT 1.37 minutes. INTERMEDIATE 110 3-Cyclopropyl-N - [(1S) -1- (4-methylcyclohexyl) -2-0x0-2 - ((2-0x0-1- [2- (trimethylsilyl) - ethoxymethylJespiro [yrrole [3,2- c] pyridine-3,4 "-tetrahydropyran] -6-ylamino) Jetyl] -isoxazo | -4- carboxamide (trans isomer)
[0813] [0813] Prepared from Intermediate 107 (100 mg, 0.19 mmol) and 3-cyclopropyl-isoxazole-4-carboxylic acid (36 mg, 0.22 mmol) according to Procedure A, and purified by chromatography on sparkling column using a gradient of 0 to 100% ethyl acetate in hexanes, to give the title compound (100 mg, 85%) as a clear oil, which was used without further purification. HPLC-MS (method 7): MH + m / z 638, RT 1.57 minutes. INTERMEDIATE 111 (PROCEDURE E) NI (18) -1- (4-methylcyclohexyl) -2-0x0-2 - ((2-0x0-1- [2- (trimethylsilyl) ethoxy-methylJespiro [yrrole [3,2-c ] pyridine-3,4'-tetrahydropyran] -6-ilk> amino) ethyl | cyclobutyl carbamate (trans isomer)
[0814] [0814] A solution of Intermediate 107 (100 mg, 0.19 mmol) in THF (5 mL) was treated with triethylamine (38 mg, 0.37 mmol) and pyridine (22 mg, 0.28 mmol), followed by slow addition of cyclobutyl chloroformate (25 mg, 0.19 mmol). The reaction mixture was stirred at 20ºC for 18 h, then diluted with water and extracted with DCM, the combined organic layers were passed through a hydrophobic frit phase separator cartridge and concentrated in vacuo. The resulting crude yellow oil was purified by sparkling column chromatography, using a gradient of 0 to 100% ethyl acetate in hexanes, to produce the title compound (120 mg, in quant.) As a clear oil, which was used without further purification. HPLC-MS (method 7): MH + m / z 601, RT 1.61 minutes. INTERMEDIATE 112
[0815] [0815] Prepared from Intermediate 107 (40 mg, 0.074 mmol) and 1- (3,3,3-trifluoro-propyl) -1H-pyrazole-S-carboxylic acid (19.5 mg, 0.089 mmol) according to with Procedure A, and purified by sparkling column chromatography using a gradient of 0 to 100% ethyl acetate in hexanes, to give the title compound (50 mg, 97%) as a clear oil. HPLC-MS (method 6): MH + m / z 693, RT 1.44 minutes.
[0816] [0816] Prepared from Intermediate 107 (40 mg, 0.074 mmol) and 3-cyclobutylisoxazole-4-carboxylic acid (15 mg, 0.089 mmol) according to Procedure A, and purified by sparkling column chromatography using a gradient of 100% ethyl acetate in hexanes, to give the title compound (45 mg, 93%) as a clear oil. HPLC-MS (method 7): MH + m / z 652, RT 1.59 minutes. INTERMEDIATE 114 2 - [(6-Chloropyrrolo [2,3-b] pyridin-1-yl)] methoxyethyl (trimethyl) silane
[0817] [0817] To a solution of 6-chloro-1H-pyrrolo [2,3-b] pyridine (10.0 g, 65.5 mmol) in DNF (100 mL) was added NaH (1.89 g, 78, 6 mmol) at 0ºC. SEM-CI (13.9 mL, 78.6 mmol) was added to the drops at 0 ° C. The reaction mixture was stirred at room temperature for 3 h, then poured on ice and extracted with EtOAc (3 x 100 ml). The combined organic layers were separated, washed with water (100 ml) and brine (50 ml), then dried over Na2SO. anhydrous and vacuum concentrated. The crude residue was purified by column chromatography (0 to 5% EtOAc in hexanes) to give the title compound (16.0 g, 86%) as a light yellow oil. ds (400 MHz, DMSO-ds) -0.12 (s, 9H), 0.79 - 0.85 (m, 2H), 3.47 - 3.52 (m, 2H), 5.57 (s , 2H), 6.58 (d, J 3.42 Hz, 1H), 7.18 (d, J 7.83 Hz, 1H), 7.66 (d, J 3.42 Hz, 1H),
[0818] [0818] To a solution of pyridinium tribromide (3.39 g, 10.6 mmol) in 1,4-dioxane (10 mL) was added a solution of Intermediate 114 (1.00 g, 3.54 mmol) in 1 , 4-dioxane (5 mL) at room temperature. The reaction mixture was stirred for 15 minutes, then diluted with water (500 ml) and extracted with EtOAc (3 x 250 ml). The combined organic layers were separated, washed with water (250 ml) and brine (250 ml), then dried over Na2SO. anhydrous and vacuum concentrated. The crude residue was purified by column chromatography (0 to 5% EtOAc in hexanes) to produce the title compound (1.29, 74%) as a red oil. dn (400 MHz, DMSO-ds) -0.08 (s, 9H), 0.83 - 0.91 (m, 2H), 3.62 (t, J 8.07 Hz, 2H), 5.14 (s, 2H), 7.40 (d, J 7.83 Hz, 1H), 8.20 (d, J 8.31 Hz, 1H). INTERMEDIATE 116 6-Chloro-1- [2- (trimethylsilyl) ethoxymethyl] -3H-pyrrole [2,3-b] pyridin-2-one
[0819] [0819] To a solution of Intermediate 115 (15.0 g, 32.8 mmol) in THF (150 mL) and water (50 mL) was added Zn (10.7 g, 164 mmol), followed by the addition of NHCI (8.79 g, 164 mmol) at 0 ° C. The reaction mixture was stirred at room temperature for 2 h, then filtered through a pad of Celite. The filtrate was diluted with water (100 ml) and extracted with EtOAc (3 x 100 ml). The combined organic layers were separated, washed with water (100 ml), brine (100 ml), then dried over Na2SO. anhydrous and concentrated in vacuo. The crude residue was purified by column chromatography (0 to 20% EtOAc in hexanes) to produce the title compound (6.00 g, 61%) as a colorless oil. ô1 (400 MHz, DMSO-ds) - 0.05 (s, 9H), 0.83 - 0.91 (m, 2H), 3.57 - 3.81 (m, 2H), 3.70 (s , 2H), 5.04 (s, 2H), 7.15 (d, J 7.34 Hz, 1H), 7.69 (d, J 7.82 Hz, 1H). HPLC-MS (method 6): MH + m / z 296.9, RT 2.23 minutes. INTERMEDIATE 117 6-Chloro-1- [2- (trimethylsilyl) ethoxymethylJespiro [yrrole [2,3-b] pyridine-3,4'-tetrahydro-pyran] -2-one
[0820] [0820] To a solution of Intermediate 116 (6.00 g, 20.1 mmol) in DNF (120 mL) was added Cs2CO; 3 (26.2 g, 80.3 mmol), followed by the addition of 1-bromo- 2- (2-bromoethoxy) -ethane (6.17 mL, 40.2 mmol). The reaction mixture was stirred at room temperature for 16 h, then diluted with water (50 ml) and extracted with EtOAc (3 x 100 ml). The combined organic layers were separated, washed with water (100 ml) and brine (100 ml), then dried over Na2SO. anhydrous and vacuum concentrated. The crude residue was purified by column chromatography (0 to 20% EtOAc in hexanes) to give the title compound (4.00 g, 45%) as a red solid. δx (400 MHz, DMSO-ds) -0.02 (s, 9H), 0.83 - 0.92 (m, 2H), 1.75 - 1.85 (m, 4H) 3.58 (t, Jy 7.91 Hz, 2H) 3.75 - 3.87 (m, 2H), 3.96 - 4.06 (m, 2H), 5.06 (s, 2H), 7.19 (d, J 7.53 Hz, 1H), 8.09 (d, J 7.78 Hz, 1H). HPLC-MS (method 6): [(M - 100) + H] + m / z 269.0, RT 3.28 minutes. INTERMEDIATE 118 N- [1-Cyclooctyl-2-0x0-2 - (((2-0x0-1- [2- (trimethylsilyl) etoxymethylJespiro [yrrole [2,3-b] - pyridine-3,4'-tetrahydropyran] - 6-yl) amino) ethyl] -2-methylpyrazole-3-carboxamide
[0821] [0821] To a solution of Intermediate 117 (0.10 g, 0.27 mmol) in tert-butanol (5 mL), Intermediate 85 (0.08 g, 0.27 mmol) and K2CO; 3 (0.075 g) were added. , 0.54 mmol). The reaction mixture was purged with argon for 10 minutes, then Pd2 (dba) 3 (0.02 g, 0.03 mmol) and XPhos (0.01 g, 0.03 mmol) were added. The reaction mixture was heated at 100ºC for 16 h, then diluted with EtOAc (100 ml) and filtered through a pad of Celite. The organic layer was washed with water (2 x 50 ml). The organic layer was separated, dried over Na2SO. anhydrous and concentrated in vacuo. The crude residue was purified by column chromatography (40 to 50% ethyl acetate in hexane) to give the title compound (0.11 g, 50%) as a light yellow solid. δ (400 MHz, DMSO-ds) -0.10 (s, 9H), 0.83 - 0.89 (m, 2H), 1.21 - 1.26 (m, 2H), 1.37 - 1 , 56 (m, 9H), 1.62 - 1.72 (m, 5H), 1.77 - 1.86 (m, 2H), 2.15 - 2.18 (m, 1H), 3.57 (t, J 8.07 Hz, 2H), 3.79 - 3.88 (m, 2H), 3.96 - 4.00 (m, 2H), 4.02 (s, 3H), 4.61 - 4.70 (m, 1H), 5.10 (s, 2H), 7.02 (d, J 1.96 Hz, 1H), 7.46 (d, J 2.45 Hz, 1H), 7 , 82 (d, J 8.31 Hz, 1H), 8.03 (d, J 7.82 Hz, 1H), 8.46 (d, J 8.80 Hz, 1H), 10.68 (s, 1H). HPLC-MS (method 6): MH + m / z 625.8, RT 2.44 minutes.
[0822] [0822] To a stirred solution of 6-bromo-1,2-dihydrospiro [indole-3,4 '"- 0xane] -2-one (10 g, 35.4 mmol) in a mixture of THF (150 mL) and DMF (150 mL), previously cooled to -5ºC, sodium hydride (60%, 1.7 g, 42.5 mmol) was added to the portions, stirring was continued at 0ºC for an additional 30 minutes, then SEM -CI (3.9 mL, 22.4 mmol) was added to the drops.The reaction mixture was allowed to warm to room temperature and stirred overnight, then poured into ice-water (600 mL) and extracted with acetate. ethyl (3 x 300 mL). The organic extracts were combined, washed with saturated aqueous sodium hydrogen carbonate solution (300 mL) and brine (2 x 200 mL), then dried (Na2SO; 3), filtered and concentrated in vacuo. The residue was purified by scintillating column chromatography, using 100% EtOAc in heptane as the eluant, to produce the title compound (11.84 9, 81%) as a white solid. Õ1 (500 MHz, DMSO- ds) 7.62 (d, J 8.0 Hz, 1H), 7.39 (d, J 1.8 Hz , 1H), 7.35 (dd, J 8.0, 1.8 Hz, 1H), 5.20 (s, 2H), 4.12 (ddd, J 11.7, 8.3, 3.5 Hz, 2H), 3.99 - 3.81 (m, 2H), 3.61 - 3.54 (m, 2H), 1.87 (ddd, J 12.5, 8.3, 4.0 Hz , 2H), 1.83 - 1.75 (m, 2H), 0.92 (t, J 7.9 Hz, 2H), 0.00 (s, 9H). HPLC-MS (method 5): MH + m / z 294, RT 2.17 minutes. INTERMEDIATE 120 2-O0x0-1- [2- (trimethylsilyl) ethoxymethylJespiro [indolino-3,4'-tetrahydropyran] -6-carboxylic acid
[0823] [0823] To a stirred solution of Intermediate 119 (1.00 g, 2.425 mmol) in anhydrous THF (20 mL), previously cooled to -78ºC under nitrogen, was added 2.5 M n-butyllithium (0.98 mL, 2.45 mmol) to the drops. The temperature was maintained at -78ºC for minutes, then carbon dioxide (-4.0 g, as dry ice pellets) was added to the portions. Stirring was continued at -78 ° C for an additional 20 minutes. The reaction mixture was quenched with saturated aqueous ammonium chloride solution (2 ml) and water (1 ml), then allowed to warm to room temperature and diluted with water (20 ml) and brine (20 ml). The reaction mixture (pH 8) was extracted with ethyl acetate (30 ml), and the aqueous phase was discarded. The organic phase was extracted with aqueous 1 M sodium hydroxide solution (2 x 20 ml). The basic aqueous extracts were combined (pH 12) and the pH was adjusted to pH 4 with 12 M hydrochloric acid, then to pH 1-2 with 1 M hydrochloric acid. The acidic aqueous phase was extracted with DCM (3 x 20 mL ). The organic extracts were combined, dried over anhydrous sodium sulfate and filtered. The solvent was removed in vacuo to produce the title compound (230 mg, 24%) as a light orange solid. õ1 (250 MHz, DMSO-ds) 7.71 (s, 2H), 7.59 (s, 1H), 5.46 (s, 2H), 4.06 (ddd, J 11.6, 8.1 , 3.7 Hz, 2H), 3.89 - 3.79 (m, 2H), 3.50 (t, J 7.7 Hz, 2H), 1.87 - 1.67 (m, 4H), 0.84 (t, J 8.1 Hz, 2H), - 0.09 (s, 9H). HPLC-MS (method 5): [M - HJ) m / z 376, RT 1.90 min. INTERMEDIATE 121 N- (1-Cyclooctyl-2-0x0-2 - [(2-0x0piro [indolino-3,4'-tetrahydropyran] -6-yl) amino] Jetyl) -2- o0x0-1- [2- ( trimethylsilyl) ethoxymethylJespiro [indolino-3,4'-tetrahydropyran] -6-carboxamide
[0824] [0824] Prepared from Intermediate 35 (50 mg, 0.13 mmol) and Intermediate 120 (54 mg, 0.14 mmol) according to Procedure A, and purified by sparkling column chromatography using a methanol gradient over dichloromethane (1 to 10%), to give the title compound (73 mg, 75%) as a clear glass. õnH (250 MHz, DMSO-ds) 10.38 (s, 1H), 10.22 (s, 1H), 8.52 (d, J 8.6 Hz, 1H), 7.68 (s, 2H) , 7.64 (s, 1H), 7.43 (d, J 8.2 Hz, 1H), 7.38 (d, J 1.8 Hz, 1H), 7.13 (dd, J 8.2 , 1.8 Hz, 1H), 5.16 (s, 2H), 4.51 (t, J 9.0 Hz, 1H), 4.11 - 3.96 (m, 4H), 3.85 ( d, J 12.0 Hz, 4H), 3.51 (t, J 7.9 Hz, 2H), 2.27 - 2.12 (m, 1H), 1.82 - 1.36 (m, 22H ), 0.84 (dd, J 8.5, 7.3 Hz, 2H), - 0.11 (s, 9H). HPLC-MS (method 5): [M - HJ m / z 743, RT 2.16 minutes. INTERMEDIATE 122 2-methyl-N- (1- (4-methylcyclohexylidene) -2-0x0-2 - [(2-0xo0ospiro [indoline-3,4 "- tetrahydropyran] -6-yl) amino] ethyl) pyrazol-3 -carboxamide
[0825] [0825] Prepared from Intermediate 2 (70 mg, 0.3 mmol) and Intermediate 75 (78 mg, 0.3 mmol) according to Procedure G, and purified by preparative chromatography (method 8), to give the title compound (21.5 mg, 15%) as a white solid. uPLC-MS (method 28): [M - HJ) m / z 478, RT 1.28 minutes. INTERMEDIATE 123 6-Amino-5-fluoroospiro [indolino-3,4'-tetrahydropyran]) - 2-one
[0826] [0826] A suspension of Intermediate 2 (400 mg, 1.83 mmol) in THF (10 mL) was treated with 1-chloromethyl-4-fluoro-1,4-diazoniabicycle bis (tetrafluoroborate) [2,2,2 ] octane (700 mg, 1.98 mmol). The reaction mixture was stirred at 20ºC under a nitrogen atmosphere for 24 h, then diluted with saturated aqueous sodium hydrogen carbonate solution (40 mL). More NaHCO; solid was added until pH 8.5 was reached. The mixture was extracted with EtOAc (2 x 70 ml). The combined organic extracts were washed with brine (50 ml) and dried over MgSO:, then filtered and concentrated in vacuo. The crude residue was purified by reverse phase HPLC (method 8) to produce, after lyophilization, the title compound (22 mg, 5%) as a white solid. dn (250 MHz, DMSO-ds) 10.13 (s, 1H), 7.19 (d, J 11.2 Hz, 1H), 6.32 (d, J 7.8 Hz, 1H), 5, 12 (s, 2H), 3.98 (ddd, J 11.3, 7.3, 3.7 Hz, 2H), 3.76 (ddd, J 11.2, 7.1, 3.8 Hz, 2H), 1.69 (ddd, J 13.5, 7.1, 3.7 Hz, 2H), 1.58 (ddd, J 13.5, 7.3, 3.8 Hz, 2H). HPLC-MS (Method 6): MH + m / z 237, RT 0.81 minutes. INTERMEDIATE 124 T7-nitro-1,3,4,9-tetrahydropyride [3,4-b] tert-butyl indole-2-carboxylate
[0827] [0827] Di-tert-butyl dicarbonate (1.11 g, 5.09 mmol) was added to a stirred suspension of 7-nitro-2,3,4,9-tetrahydro-1H-beta-carboline (1 g , 4.6 mmol) in tert-butanol (46 mL) at 20 ° C. The mixture was stirred at 20ºC for 16 h. The volatiles were removed in vacuo, then the residue was suspended in methyl tert-butyl ether (20 mL) and sonicated. The solids were collected by filtration and washed with tert-butyl methyl ether (3 x 10 mL). The filtrate was concentrated, then the previous procedure was repeated to produce a second crop of solid. The combined solids were vacuum dried to produce the title compound (1.37 g, 93%) as a canary yellow powder. ds (500 MHz, DMSO-ds) 11.69 (br s, 1H), 8.27 (d, J2.0 Hz, 1H), 7.88 (dd, J 8.8, 2.1 Hz, 1H ), 7.57 (d, J 8.7 Hz, 1H), 4.65 (s, 2H), 3.68 (t, J 5.7 Hz, 2H), 2.74 (t, J 5, 5 Hz, 2H), 1.44 (s, 9H). HPLC-MS (method 7): MH + m / z 318, RT 2.01 minutes. INTERMEDIATE 125 6-nitro-2-oxospospiro [indolino-3,3'-pyrrolidino] -1 "-tert-butylcarboxylate
[0828] [0828] 1-Bromopyrrolidine-2,5-dione (400 mg, 2.25 mmol) was added to the portions in 10 minutes to a stirred suspension of Intermediate 124 (680 mg, 2.12 mmol) in THF-acetic acid: 1: 1: 1 water (36 mL) at 0ºC under nitrogen. The mixture was allowed to warm to approximately 20ºC in 2.5 h, then quenched with saturated aqueous sodium carbonate solution (pH 10). The resulting material was extracted with ethyl acetate (3 x 50 ml). The combined organic extracts were washed with saturated aqueous sodium carbonate solution (30 ml) and brine (30 ml), then dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting orange gum was separated by sparkling column chromatography, using a gradient of ethyl acetate in heptane (0 to 80%), to produce the title compound (679 mg, 93%) as a light yellow powder. ô1 (250 MHz, DMSO-ds, 353K) 10.65 (br s, 1H), 7.88 (dd, J 8.2, 2.2 Hz, 1H), 7.60 (d, J 2.1 Hz, 1H), 7.48 (d, J 8.2 Hz, 1H), 3.78 - 3.59 (m, 2H), 3.59 (d, J 11.3 Hz, 1H), 3, 53 (d, J 11.1 Hz, 1H), 2.36 - 2.08 (m, 2H), 1.45 (s, 9H). HPLC-MS (method 7): MNa + m / z 356, RT 1.83 minutes. INTERMEDIATE 126 6-amino-2-oxospiro [indoline-3,3'-pyrrolidine] -1 "-tert-butylcarboxylate
[0829] [0829] A suspension of Intermediate 125 (679 mg, 2.04 mmol) and 10% palladium on carbon (50% aqueous moisture, 200 mg, 0.09 mmol) in ethanol (16 mL) was stirred under an atmosphere of hydrogen for 4 h. The solids were removed by filtration through a pad of diatomaceous earth, washing with ethanol (4 x 20 mL), and the filtrate was concentrated in vacuo. The resulting pink-red powder was separated by sparkling column chromatography, using a gradient of ethyl acetate in heptane (20 to 100%), to produce the title compound (633 mg, 97%) as a light brown powder. ds (250 MHz, DMSO-ds, 353K) 9.93 (br s, 1H), 6.87 - 6.76 (m, 1H), 6.23 - 6.14 (m, 2H), 4.88 (br s, 2H), 3.71 - 3.49 (m, 2H), 3.45 (d, J 10.8 Hz, 1H), 3.33 (d, J 10.8 Hz, 1H), 2.12 (ddd, J 12.5, 7.9, 6.5 Hz, 1H), 2.03 - 1.88 (m, 1H), 1.43 (s, 9H). HPLC-MS (method 7): MNa + m / z 326, RT 1.64 minutes. INTERMEDIATE 127 6- (f2-cyclooctyl-2 - [(3-methylisoxazole | -4-carbonyl) amino] acetyl) amino) -2-oxospiro [indolino-3,3'-pyrrolidine] -1'-carboxylate butyl
[0830] [0830] HATU (143 mg, 0.38 mmol) was added to a mixture of Intermediate
[0831] [0831] Aqueous solution of lithium hydroxide (2 M, 2.6 mL, 5.2 mmol) was added to a stirred solution of Intermediate 12 (1.45 g, 4.29 mmol) in THF / MeOH 1: 1 (17.2 mL). The mixture was stirred at 20ºC under air for 16 h. The volatiles were removed in vacuo and the residue was diluted with water (20 ml), then washed with tert-butyl methyl ether (2 x 20 ml). The combined organic washes were extracted with aqueous sodium hydroxide solution (20 ml). The combined alkaline aqueous phases were treated with aqueous 3 M hydrochloric acid (pH 1) and extracted with ethyl acetate (3 x mL). The combined organic extracts were washed with brine (20 ml) and dried over magnesium sulfate, then filtered and concentrated in vacuo, to produce the title compound (1.48 g, 91%) as a white powder. ôõ1 (500 MHz, DMSOdes) 12.69 (br s, 1H), 8.42 (d, J 8.6 Hz, 1H), 7.45 (d, J 2.0 Hz, 1H), 7 .01 (d, J 2.1 Hz, 1H), 4.33 (dd, J 8.5, 7.3 Hz, 1H), 4.02 (s, 3H), 2.19 - 2.06 ( m, 1H), 1.75 - 1.27 (m, 14H). HPLC-MS (method 5): MH + m / z 294, RT 1.71 minutes. INTERMEDIATE 129 tert-butyl 6- (tert-butoxycarbonylamino) -2-oxoindoline-1-carboxylate
[0832] [0832] Di-tert-butyl dicarbonate (33.5 g, 153 mmol) was added to the portions in a stirred suspension of 6-amino-1,3-dihydro-2H-indole-2-one (9.1 g , 61.4 mmol) and sodium hydrogen carbonate (18.1 g, 215 mmol) in THF (120 mL) at 20ºC under nitrogen. The mixture was heated to 70ºC for 3.5 h. An additional portion of di-tert-butyl dicarbonate (6.8 g, 31.2 mmol) was added, and heating was continued at 70 ° C for 1.5 h. An additional portion of di-tert-butyl dicarbonate (6.8 g, 31.2 mmol) was added, and heating was continued at 70 ° C for 5 h. After cooling to room temperature, the mixture was diluted with ethyl acetate (100 ml), and the solids were removed by filtration through a pad of diatomaceous earth, washing with ethyl acetate (2 x 100 ml). The filtrate was concentrated in vacuo. The resulting dark red gum was separated by sparkling column chromatography, using a gradient of ethyl acetate in heptane (0 to 35%), then ground with 4: 1 ethyl acetate / heptane to produce the title compound (16, 23 g, 76%) as a brown powder. õx (500 MHz, DMSO-ds) 9.42 (s, 1H), 8.03 (s, 1H), 7.17 - 7.08 (m, 2H), 3.64 (s, 2H), 1 , 57 (s, 9H), 1.47 (s, 9H). HPLC-MS (method 5): MNa + m / z 371, RT 1.94 min. INTERMEDIATE 130 (28) -2- (2-ethoxy-2-0xo0ethoxy) ethyl propanoate
[0833] [0833] Ethyl (28) -2-hydroxypropanoate (4.8 mL, 42.0 mmol) was added to a stirred suspension of potassium carbonate (5.81 g, 42.0 mmol) in anhydrous DMF (42 mL ). The suspension was stirred at 20ºC under nitrogen for 20 minutes, then ethyl bromoacetate (4.7 mL, 42.4 mmol) was added. The reaction mixture was stirred at 20ºC under nitrogen for 64 h, then diluted with tert-butyl methyl ether (50 mL). The solids were removed by filtration, and washed with methyl tert-butyl ether (2 x 50 ml). The filtrate was concentrated in vacuo. The resulting orange oil was separated by Kkugelrohr distillation (160 to 210 ° C, 18 mbar) to produce the title compound (4.57 g, 27%) as a colorless oil. dx (500 MHz, CDCI3) 4.27 (d, J 16.5 Hz, 1H), 4.25 - 4.17 (m, 4H), 4.14 (q, J 6.9 Hz, 1H), 4.07 (d, J 16.5 Hz, 1H), 1.48 (d, J 6.9 Hz, 3H), 1.31 - 1.25 (m, 6H). INTERMEDIATE 131
[0834] [0834] Solution of aluminum lithium hydride in diethyl ether (AM, 7.3 mL, 29.2 mmol) was added to the stirred solution of Intermediate 130 (4.57 9, 224 mmol) in anhydrous THF (45 mL) at 0ºC under nitrogen. The mixture was stirred at 0ºC for 1 h, then at 20ºC for 16 h. The reaction mixture was cautiously quenched by the addition of drops of water (0.55 ml), followed by a 2 M aqueous solution of sodium hydroxide (1.32 ml), then water (1.64 ml). The suspension was stirred at room temperature for 30 minutes, then diluted with acetone (50 ml) and filtered through a pad of diatomaceous earth. The residues were washed with acetone (2 x 50 ml) and the filtrate was concentrated in vacuo. The brown oil was separated by kugelrohr distillation (90 to 120 ° C, <1 mbar) to produce the title compound (818 mg, 22%) as a colorless, free-flowing oil. dx (500 MHz, CDCI3) 3.77 - 3.69 (m, 3H), 3.64 - 3.57 (m, 2H), 3.55 - 3.45 (m, 2H), 3.25 ( br s, 2H), 1.12 (d, J 6.2 Hz, 3H). INTERMEDIATE 132 (28S) -1-sludge-2- (2-iodoethoxy) propane
[0835] [0835] sludge (8.64 g, 34.0 mmol) was added to the portions to a stirred solution of triphenylphosphine (7.14 g, 27.2 mmol) and 1H-imidazole (1.85 g, 27.2 mmol ) in 3: 1 diethyl ether / acetonitrile (54 mL) at 20ºC under nitrogen. After stirring at 20ºC for 30 minutes, a solution of Intermediate 131 (0.82 g, 6.81 mmol) in diethyl ether (3 mL) was added slowly, followed by a rinse with diethyl ether (2 mL). The reaction mixture was stirred at 20ºC in the dark for 22 h. The suspension was diluted with tert-butyl methyl ether (50 ml) and filtered through a pad of diatomaceous earth, lavender well with tert-butyl methyl ether (4 x 30 ml). The filtrate was filtered through a second pad of diatomaceous earth, washing well with tert-butyl methyl ether (2 x 30 ml), then concentrated in vacuo. The resulting dark red viscous oil was separated by the sparkling column chromatography, using a gradient of ethyl acetate in heptane (0 to 5%), to produce the title compound (1.44 g, 59%) as a free flowing oil. brown. õn (500 MHz, CDCI3) 3.81 - 3.69 (m, 2H), 3.54 - 3.44 (m, 1H), 3.30 - 3.22 (m, 3H), 3.20 ( dd, J 10.3, 5.7 Hz, 1H), 1.29 (d, J 6.1 Hz, 3H).
[0836] [0836] A stirred solution of Intermediate 129 (600 mg, 1.72 mmol) and Intermediate 132 (640 mg, 1.26 mmol) in anhydrous DMF (11.5 mL) was purged with a stream of nitrogen under sonication for 5 minutes. minutes. The solution was cooled to - 10ºC under nitrogen, then cesium carbonate (2.24 g, 6.89 mmol) was added to the portions in 10 minutes. The suspension was allowed to warm slowly to 20 ° C, and stirred for a total of 16 h. The mixture was extinguished by the slow addition of acetic acid (0.31 mL), and stirred at 20ºC for 5 minutes. The suspension was diluted with water (50 mL) and stirred at 20ºC for 5 minutes, then the solids were collected by filtration. The solids were washed with water (2 x 25 ml), then dissolved in ethyl acetate (30 ml). The organic filtrate was collected, and the residues were washed with ethyl acetate (2 x 20 mL). The combined organic filtrate was filtered through hydrophobic filter paper and concentrated in vacuo. The resulting orange gum was separated by sequential sparkling column chromatography, using a gradient of ethyl acetate in heptane (0 to 30%), then preparative HPLC (method 31), to produce the title compound (86.5 mg, 16 %) as a white powder. õ1 (500 MHz, DMSO-ds) 9.49 (s, 1H), 8.14 (d, J 1.6 Hz, 1H), 7.74 (d, J 8.4 Hz, 1H), 7, 16 (dd, J 8.3, 1.8 Hz, 1H), 4.04 - 3.83 (m, 3H), 1.90 (td, J 13.1, 5.8 Hz, 1H), 1 , 62 - 1.54 (obs. M, 1H), 1.58 (s, 9H), 1.50 - 1.44 (obs. M, 1H), 1.47 (s, 9H), 1.40 (d, J 12.7 Hz, 1H), 1.10 (d, J 6.0 Hz, 3H). uPLC-MS (method 1): [M + 2H-BOC] + m / z 333, RT 4.01 minutes. Chiral SFC (method 13, Lux C4 25 cm, 20% MeOH-80% carbon dioxide, 4 mL / minute): RT 1.61 minutes (98%). INTERMEDIATE 134 (2'S, 3R) -6- (tert-butoxycarbonylamino) -2'-methyl-2-oxospiro [indolino-3,4'- tetrahydropyran] -1-tert-butyl carboxylate
[0837] [0837] A stirred solution of Intermediate 129 (600 mg, 1.72 mmol) and Intermediate 132 (640 mg, 1.26 mmol) in anhydrous DMF (11.5 mL) was purged with a stream of nitrogen under sonication for 5 minutes. minutes. The solution was cooled to -
[0838] [0838] Trifluoroacetic acid (0.57 mL, 7.40 mmol) was added to a stirred solution of Intermediate 134 (160 mg, 0.37 mmol) in DCM (1.9 mL). The mixture was stirred in air for 4 h, then diluted with DCM (4 ml) and quenched with saturated aqueous sodium carbonate solution (3 ml) and water (3 ml). The organic phase was separated using a hydrophobic frit and the aqueous layer was extracted with DCM (2 x 6 ml). The organic filtrate was concentrated in vacuo to yield the title compound (99 mg, 98%) as a yellowish white powder. ôõn (500 MHz, DMSO-ds) 9.99 (s, 1H), 6.80 (d, J 7.9 Hz, 1H), 6.13 (dd, J 8.0, 2.0 Hz, 1H ), 6.09 (d, J 1.9 Hz, 1H), 5.04 (br s, 2H), 4.24 - 4.09 (m, 2H), 3.70 (dd, J 11.3 , 4.3 Hz, 1H), 1.78 (td, J 13.3, 5.1 Hz, 1H), 1.56 - 1.39 (m, 3H), 1.05 (d, J 6, 2 Hz, 3H). uPLC-MS (method 1): MH + m / z 233, RT 1.00 minutes.
[0839] [0839] Trifluoroacetic acid (0.29 mL, 3.76 mmol) was added to a stirred solution of Intermediate 133 (81 mg, 0.19 mmol) in DCM (1 mL). The mixture was stirred at 20ºC under air for 4 h, then diluted with DCM (5 ml) and quenched with saturated aqueous sodium carbonate solution (3 ml) and water (3 ml). The organic phase was separated using a hydrophobic frit and the aqueous layer was extracted with DCM (2 x 6 ml). The organic filtrate was concentrated in vacuo to yield the title compound (44.9 mg, 97%) as a yellowish white powder. dx (500 MHz, DMSO-ds) 10.17 (s, 1H), 7.32 (d, J 8.1 Hz, 1H), 6.16 (d, J 2.1 Hz, 1H), 6, 12 (dd, J 8.0, 2.1 Hz, 1H), 5.08 (br s, 2H), 3.96 - 3.81 (m, 3H), 1.84 (ddd, J 13.0 , 11.2, 7.4 Hz, 1H), 1.57 - 1.48 (m, 1H), 1.30 - 1.24 (m, 1H), 1.21 - 1.16 (m, 1H ), 1.09 (d, J 6.1 Hz, 3H). uPLC-MS (method 1): MH + m / z 233, RT 1.00 minutes. INTERMEDIATE 137 (2R) -2- (2-ethoxy-2-0xo0ethoxy) ethyl propanoate
[0840] [0840] Ethyl (2R) -2-hydroxypropanoate (4.8 mL, 42.01 mmol) was added to a stirred suspension of potassium carbonate (5.81 g, 42.0 mmol) in anhydrous DMF (42 mL ). The suspension was stirred at 20ºC under nitrogen for 20 minutes, then ethyl bromoacetate (4.7 mL, 42.38 mmol) was added. The reaction mixture was stirred at 20ºC under nitrogen for 64 h, then diluted with tert-butyl methyl ether (50 mL). The solids were removed by filtration, washing with tert-butyl methyl ether (2 x 50 mL). The filtrate was concentrated in vacuo. The resulting orange oil was separated by distillation of kugelrohr (130 to 185 ° C, 11 mbar) to produce the title compound (4.26 g, 30%) as a colorless oil. dx (500 MHz, CDCI3) 4.27 (d, J 16.5 Hz, 1H), 4.25 - 4.17 (m, 4H), 4.14 (q, J 6.9 Hz, 1H), 4.07 (d, J 16.5 Hz, 1H), 1.47 (d, J 6.9 Hz, 3H), 1.31 - 1.26 (m, 6H). INTERMEDIATE 138 (2R) -2- (2-Hydroxyethoxy) propan-1-ol
[0841] [0841] Solution of aluminum lithium hydride in diethyl ether (4 M, 6.8 mL, 27.2 mmol) was added to the stirred solution of Intermediate 137 (4.26 9,
[0842] [0842] sludge (9.55 g, 37.63 mmol) was added to the portions to a stirred solution of triphenylphosphine (7.90 g, 30.12 mmol) and 1H-imidazole (2.06 g, 30.26 mmol ) in 3: 1 diethyl ether / acetonitrile (60 mL) at 20ºC under nitrogen. After stirring at 20 ° C for 30 minutes, a solution of Intermediate 138 (0.90 g, 7.52 mmol) in diethyl ether (3 mL) was added slowly, followed by a rinse with diethyl ether (2 mL). The reaction mixture was stirred at 20ºC in the dark for 22 h. The suspension was diluted with tert-butyl methyl ether (50 ml) and filtered through a pad of diatomaceous earth, washing well with tert-butyl methyl ether (4 x 30 ml). The filtrate was filtered through a second pad of diatomaceous earth, washing well with tert-butyl methyl ether (2 x 30 ml), then concentrated in vacuo. The resulting dark red viscous oil was separated by the sparkling column chromatography, using a gradient of ethyl acetate in heptane (0 to 5%), to produce the title compound (1.32 g, 47%) as a free flowing oil. brown. õn (500 MHz, CDCI3) 3.80 - 3.69 (m, 2H), 3.55 - 3.44 (m, 1H), 3.29 - 3.22 (m, 3H), 3.20 ( dd, J 10.3, 5.7 Hz, 1H), 1.380 (d, J 6.1 Hz, 3H). INTERMEDIATE 140 (2'R, 3S) -6- (tert-butoxycarbonylamino) -2 '"- methyl-2-oxospiro [indolino-3,4'- tetrahydropyran] -1-tert-butyl carboxylate
[0843] [0843] A stirred solution of Intermediate 129 (600 mg, 1.72 mmol) and Intermediate 139 (640 mg, 1.38 mmol) in anhydrous DMF (11.5 mL) was purged with a stream of nitrogen under sonication for 5 minutes. minutes. The solution was cooled to - 10ºC under nitrogen and cesium carbonate (2.24 g, 6.89 mmol) was added to the portions in 10 minutes. The suspension was allowed to warm slowly to 20 ° C and stirred for a total of 16 h. The mixture was extinguished by the slow addition of acetic acid (0.31 mL) and stirred at 20ºC for 5 minutes. The suspension was diluted with water (50 mL) and stirred at 20ºC for 5 minutes, then the solids were collected by filtration. The solids were washed with water (2 x 25 ml), then dissolved in ethyl acetate (30 ml). The organic filtrate was collected, and the residues were washed with ethyl acetate (2 x 20 mL). The combined organic filtrate was filtered through hydrophobic filter paper and concentrated in vacuo. The resulting orange gum was separated by sequential sparkling column chromatography, using a gradient of ethyl acetate in heptane (0 to 30%), then preparative HPLC (method 31), to produce the title compound (180 mg, 30%) like a white powder. dr (500 MHz, DMSO-ds) 9.45 (s, 1H), 8.05 (d, J 1.2 Hz, 1H), 7.23 (d, J 8.2 Hz, 1H), 7, 15 (dd, J 8.2, 1.8 Hz, 1H), 4.19 - 4.00 (m, 2H), 3.77 (dd, J 11.5, 4.4 Hz, 1H), 1 , 86 (td, J 13.4, 5.0 Hz, 1H), 1.71 (d, J 13.6 Hz, 1H), 1.64 (d, J 13.2 Hz, 1H), 1, 58 (s, 9H), 1.52 (dd, J 13.7, 11.3 Hz, 1H), 1.47 (s, 9H), 1.08 (d, J 6.2 Hz, 3H). uPLC-MS (method 1): [M + 2H-BOC] + m / z 333, RT 4.06 minutes. Chiral SFC (method 13, Lux C4 25 cm, 15% MeOH-85% carbon dioxide, 4 mL / minute): RT 1.96 minutes (99%). INTERMEDIATE 141 (2'R, 3S) -6-Amino-2'-methylphospiro [indolino-3,4 "-tetrahydropyran] -2-one
[0844] [0844] Trifluoroacetic acid (0.62 mL, 8.05 mmol) was added to a stirred solution of Intermediate 140 (175 mg, 0.41 mmol) in DCM (2 mL). The mixture was stirred at 20ºC under air for 4 h, then diluted with DCM (4 ml) and quenched with saturated aqueous sodium carbonate solution (3 ml) and water (3 ml). The organic phase was separated using a hydrophobic frit, and the aqueous layer was extracted with DCM (2 x 6 ml). The organic filtrate was concentrated in vacuo to yield the title compound (104 mg, quantitative) as a yellowish white powder. ds (500 MHz, DMSO-ds) 9.99
[0845] [0845] To a solution of Intermediate 2 (390 mg, 1.79 mmol) and lithium salt of 2-cyclohexyl-3-ethoxy-3-oxo-propionic acid (398 mg, 1.86) in DNF (7 mL, 90 , 50 mmol) HATU (840 mg, 2.14 mmol) was added. The reaction mixture was stirred at 20ºC for 18 h, then partitioned between EtOAc and water. The organic layers were combined, dried and concentrated in vacuo. The residue was separated by scintillating column chromatography, using a gradient of ethyl acetate in hexane (0 to 100%), to produce the title compound (623 mg, 84%). HPLC-MS (method 7): MH + m / z2 415, RT 1.24 minutes. INTERMEDIATE 143 2-Cyclohexyl-3-0x0-3 - [(2-oxo0ospiro [indolino-3,4 "-tetrahydropyran] -6- i)> amino] propionic acid
[0846] [0846] A solution of LiOH (36 mg, 1.50 mmol) in water (5 mL, 277.55 mmol) was added dropwise to a solution of Intermediate 142 (623 mg, 1.50 mmol) in ethanol (10 mL, 172.00 mmol). The reaction mixture was stirred at 20 ° C for 72 h, then concentrated in vacuo, to produce the title compound (580 mg, 100%) as a lithium salt. HPLC-MS (method 7): MH + m / z 387, RT 0.85 min. INTERMEDIATE 144 N- (2-Amino-3-fluorophenyl) -2-cyclohexyl-N '- (2-oxospiro [indolino-3,4'-tetrahydro-pyran]) - 6-yl) propanediamide
[0847] [0847] To a solution of 3-fluorobenzene-1,2-diamine (35 mg, 0.26 mmol) and Intermediate 143 (116 mg, 0.30 mmol) in DNF (2 mL, 25.90 mmol) HATU (124 mg, 0.32 mmol). The reaction mixture was stirred at 20 ° C for 40 h, then water was added at 0 ° C. The resulting precipitate was collected by filtration to produce the title compound (97 mg, 75%) as a brown solid. HPLC-MS (method 7): MH + m / z 495, RT 1.25 minutes. INTERMEDIATE 145 N- (2-Aminophenyl) -2-cyclohexyl-N '- (2-oxospiro [indolino-3,4'-tetrahydropyran] -6-yl) - propanediamide
[0848] [0848] To a solution of o-phenylenediamine (10 mg, 0.09 mmol) and Intermediate 165 (39 mg, 0.10 mmol) in DNF (1 mL, 12.90 mmol) was added HATU (45 mg, 0 , 12 mmol). The reaction mixture was stirred at 20ºC for 18 h, then partitioned between EtOAc and water. The organic layers were separated and washed with brine, then dried and concentrated in vacuo, to yield the title compound (40 mg, 91%). HPLC-MS (method 7): MH + m / z 477, RT 1.18 minutes. INTERMEDIATE 146 2- (azocan-1-yl) diethyl propanedioate
[0849] [0849] To a solution of heptamethyleneimine (2.25 mL, 17.70 mmol) in acetonitrile (40 mL, 763.00 mmol) was added K2COs; (4.90 g, 35.00 mmol), followed by a solution of diethyl 2-bromopropanedioate (4.25 g, 17.80 mmol) in acetonitrile (40 mL, 763.00 mmol). The reaction mixture was stirred at 20 ° C for 3 h, then concentrated in vacuo. The residue was separated by sparkling column chromatography, using a gradient of ethyl acetate in hexane (0 to 50%), to produce the title compound (3.78 g, 78%) as a colorless oil. ox (400 MHz, CDCI3) 4.23 (q, J 7.1 Hz, 4H), 4.12 (s, 1H), 2.83 (t, J 5.4 Hz, 4H), 1.68 - 1.53 (m, 10H), 1.29 (t, J 7.1 Hz, 6H). LC-MS (method 7): MH + m / z 272, RT 1.59 minutes. INTERMEDIATE 147 2- (Azocan-1-yl) -3-ethoxy-3-0xo-propionic acid
[0850] [0850] A solution of LiOH (22 mg, 0.92 mmol) in water (1 mL, 55.51 mmol) was added dropwise to a cold (0 ° C) solution of Intermediate 146 (250 mg, 0.92 mmol) in EtOH (4 mL, 68.70 mmol). The reaction mixture was slowly heated to 20 ° C and stirred for 4.5 h, then concentrated in vacuo, to produce the title compound (225 mg, 100%) as a lithium salt. LC-MS (method 7): MH + m / z 244, RT 0.85 minutes.
[0851] [0851] To a solution of Intermediate 2 (190 mg, 0.87 mmol) and Intermediate 147 (224 mg, 0.92 mmol) in DNF (4 mL, 51.70 mmol) was added HATU (410 mg, 1, 05 mmol). The reaction mixture was stirred at 20ºC for 18 h, then partitioned between EtOAc and water. The organic layers were washed with brine, dried and concentrated in vacuo. The residue was separated by sparkling column chromatography, using a gradient of ethyl acetate in hexane (100% O), to produce the title compound (125 mg, 32%) as a white solid. õH (400 MHz, CDCl3) 8.97 (s, 1H), 7.63 (d, J 1.9 Hz, 1H), 7.44 (s, 1H), 7.30 (d, J 8.1 Hz, 1H), 6.87 (dd, J 8.1, 2.0 Hz, 1H), 4.38 - 4.17 (m, 4H), 4.10 (s, 1H), 3.92 ( ddd, J 11.8, 5.5, 4.3 Hz, 2H), 2.93 - 2.72 (m, 4H), 2.08 - 1.59 (m, 14H), 1.33 (t , 7.1 Hz, 3H). LC-MS (method 6): MH + m / z 444, RT 2.31 minutes. INTERMEDIATE 149 2- (Azocan-1-i1) -3-0x0-3 - [(2-oxospiro [indolino-3,4'-tetrahydropyran] -6-yl) amino] - propionic acid
[0852] [0852] A solution of LiOH (12 mg, 0.50 mmol) in water (2 mL, 111.02 mmol) was added dropwise to a solution of Intermediate 148 (106 mg, 0.24 mmol) in EtOH (5 mL, 85.90 mmol). The reaction mixture was stirred at 20 ° C for 18 h, then concentrated in vacuo, to produce the title compound (99 mg, 100%) as a lithium salt. LC-MS (method 7): MH + m / z 416, RT 0.91 minutes. INTERMEDIATE 150 N - [(1S) -1-cyclohexyl-2-0x0-2 - ((2-0x0-1- [2- (trimethylsilyl) ethoxymethyl] -spiro [yrrole [3,2- clpyridine-3,4 ' -tetrahydropyran] -6-yl> <> amino) ethyl | tert-butyl carbamate
[0856553] [0856553] To a solution of (2S) -2- (tert-butoxycarbonylamino) -2-cyclohexylacetic acid (1.47 g, 5.72 mmol) and Intermediate 57 in anhydrous DCM (40 mL) were added HATU (2, 69 g, 6.87 mmol) and DIPEA (1.99 mL, 11.44 mmol). The reaction mixture was stirred at 20ºC for 18 h. More (28S) -2- (tert-butoxycarbonylamino) -2-cyclohexylacetic acid (1.47 g, 5.72 mmol), HATU (2.69 g, 6.87 mmol) and DIPEA (1.99 mL,
[0854] [0854] Trifluoroacetic acid (12 mL, 150 mmol) was added to a stirred solution of Intermediate 150 (3 g, 5.10 mmol) in DCM (10 mL) at 0 ° C. The mixture was stirred at 20ºC for 18 h, then concentrated in vacuo. The crude residue was dissolved in acetonitrile (5 ml), followed by the addition of an aqueous solution of ammonium hydroxide (5 ml) at 0ºC. The reaction mixture was stirred at 20ºC for 20 minutes, then concentrated in vacuo. The crude residue was partitioned between EtOAc and a 2 M aqueous NaOH solution, and the aqueous phase was extracted with DCM: isopropanol (10%) (3 x mL). The combined organic layers were concentrated in vacuo to yield the title compound (1.8 g, 74%) as a solid. õs (300 MHz, CDCI3) 9.38 (s, 1H), 8.28 (s, 1H), 8.10 (s, 1H), 4.22 (ddd, J 11.2, 6.9, 3 , 8 Hz, 2H), 3.93 (ddd, J 11.6,7.6, 3.6 Hz, 2H), 3.51 (d, J 3.9 Hz, 1H), 2.05 (ddd , J 13.9, 7.7, 3.8 Hz, 4H), 1.86 - 1.57 (m, 8H), 1.49 - 1.04 (m, 6H). HPLC-MS (method 7): MH + m / z 359, RT 0.60 min. [a] 2ºp = -77.80º (c 7.5, methanol). INTERMEDIATE 152 N- (2-oxospiro [indolino-3,4'-tetrahydropyran] -6-yl) phenyl carbamate
[0855] [0855] To a stirred solution of Intermediate 2 (500 mg, 2.3 mmol) and pyridine
[0856] [0856] Di-tert-butyl dicarbonate (1.29 g, 5.89 mmol) was added to a stirred suspension of 2-amino-2- (4-chloro-3-fluorophenyl) acetic acid (1.0 g , 4.91 mmol) in THF (3.2 mL) and 1 M aqueous sodium carbonate solution (9.8 mL, 9.8 mmol). The suspension was stirred at 20ºC under nitrogen for 16 h. The mixture was diluted with water (30 ml) and 1 M aqueous sodium hydroxide solution (10 ml), then washed with tert-butyl methyl ether (2 x 50 ml). The combined organic layers were extracted with aqueous 1 M sodium hydroxide solution (40 ml). The combined aqueous layers were acidified with concentrated hydrochloric acid (pH 2) and the aqueous phase was extracted with ethyl acetate (3 x 60 ml). The combined organic layers were washed with brine (50 ml) and dried over anhydrous magnesium sulfate, then filtered and concentrated in vacuo, to yield the title compound (1.52 g, 96%) as a white solid. dn (250 MHz, DMSO-ds) 13.06 (br s, 1H), 7.70 (d, J 8.3 Hz, 1H), 7.58 (t, J 8.1 Hz, 1H), 7 , 47 (dd, J 10.5, 1.9 Hz, 1H), 7.29 (dd, J 8.2, 1.9 Hz, 1H), 5.18 (d, J 8.6 Hz, 1H ), 1.39 (s, 9H). HPLC-MS (method 3): MNa + m / z 326, RT 1.77 minutes. INTERMEDIATE 154 N- [1- (4-Chloro-3-fluorophenyl) -2-0x0-2 - ((2-0x0-1- [2- (trimethylsilyl) ethoxy-
[0857] [0857] HATU (999 mg, 2.63 mmol) was added to a stirred suspension of Intermediate 57 (765 mg, 2.19 mmol), Intermediate 153 (700 mg, 2.19 mmol) and DIPEA (0.9 mL , 5.47 mmol) in DCM (25 mL). The mixture was stirred at 20ºC under nitrogen for 16 h, then partitioned between DCM (50 ml) and water (50 ml). The aqueous layer was separated and washed with DCM (2 x 50 ml). The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by sparkling column chromatography, using a gradient of ethyl acetate in heptane (0 to 100%), to give the title compound (937 mg, 67%) as an orange solid. ds (500 MHz, DMSO-ds) 11.01 (s, 1H), 8.61 (s, 1H), 7.95 (s, 1H), 7.84 (d, J 7.8 Hz, 1H) , 7.77 - 7.65 (m, 2H), 7.55 (d, J 8.3 Hz, 1H), 5.67 (d, JU 7.5 Hz, 1H), 5.21 (d, J 11.2 Hz, 1H), 5.19 (d, J 11.3 Hz, 1H), 4.16 - 4.08 (m, 2H), 4.02 - 3.91 (m, 2H), 3.69 - 3.53 (m, 2H), 2.03 - 1.89 (m, 2H), 1.88 - 1.76 (m, 2H), 1.53 (s, 9H), 1, 07 - 0.86 (m, 2H), 0.00 (s, 9H). HPLC-MS (method 3): MH + m / z 635, RT 2.19 minutes. INTERMEDIATE 155 2-Amino-2- (4-chloro-3-fluorophenyl) -N- (2-0x0-1- [2- (trimethylsily) ethoxymethylJespiro- [yrrole [3,2-c] pyridine-3-chloride, 4 "-tetrahydropyran] -6-yl) acetamide
[0858] [0858] Solution of hydrogen chloride in 1,4-dioxane (4 M, 3.66 mL, 14.64 mmol) was added to a stirred solution of Intermediate 154 (929 mg, 1.46 mmol) in MeOH (16 mL) under nitrogen at room temperature. The reaction mixture was stirred at room temperature overnight, then concentrated in vacuo, to yield the title compound (759 mg, 78%) as a yellowish orange solid. dn (500 MHz, DMSO-ds) 11.53 (br s, 1H), 9.17 (br s, 2H), 8.64 (s, 1H), 8.01 - 7.84 (m, 2H) , 7.81 (dd, J 10.2, 1.8 Hz, 1H), 7.64 (d, J 8.3 Hz, 1H), 5.54 - 5.39 (m, 1H), 5, 29 - 5.12 (m, 2H), 4.21 - 4.08 (m, 2H), 4.02 - 3.93 (m, 2H, obs), 3.66 - 3.55 (m, 2H ), 2.03 - 1.74 (m, 4H), 1.05 - 0.88 (m, 2H), 0.00 (s, 9H). HPLC-MS (method 3): MH + m / z 535, RT 1.85 minutes. INTERMEDIATE 156 N- [1- (4-Chloro-3-fluorophenyl) -2-0x0-2 - ((2-0x0-1- [2- (trimethylsilyl) ethoxymethyl] -
[0859] [0859] HATU (206 mg, 0.54 mmol) was added to a stirred suspension of Intermediate 155 (300 mg, 0.45 mmol), 1-ethyl-1H-pyrazole-5-carboxylic acid (63 mg, 0, 45 mmol) and DIPEA (0.28 mL, 1.58 mmol) in DCM (6 mL). The mixture was stirred at 20ºC under nitrogen for 16 h, then partitioned between DCM (25 ml) and water (25 ml). The aqueous layer was separated and washed with DCM (2 x 25 ml). The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by sparkling column chromatography, using a gradient of ethyl acetate in heptane (0 to 100%), to produce the title compound (811 mg, 89%) as an orange gum. dn (500 MHz, DMSO-ds) 11.16 (s, 1H), 9.12 (d, J 7.0 Hz, 1H), 8.62 (s, 1H), 8.00 (s, 1H) , 7.84 - 7.71 (m, 2H), 7.63 (d, 1.2 Hz, 1H), 7.60 (dd, J 8.4, 1.8 Hz, 1H), 7, 20 (d, Jy 2.1 Hz, 1H), 6.05 (d, J 7.0 Hz, 1H), 5.21 (d, J 11.2 Hz, 1H), 5.18 (d, J 11.2 Hz, 1H), 4.59 (q, J 7.2 Hz, 2H), 4.16 - 4.09 (m, 2H), 4.04 - 3.90 (m, 2H), 3 , 66 - 3.55 (m, 2H), 2.02-1.89 (m, 2H), 1.89 - 1.78 (m, 2H), 1.41 (t, J 7.1 Hz, 3H), 1.04 - 0.90 (m, 2H), 0.00 (s, 9H). HPLC-MS (method 3): MH + m / z 657, RT 2.11 minutes. INTERMEDIATE 157 2- (tert-Butoxycarbonylamino) -2- (4-fluoro-3-methylphenyl) acetic acid
[0860] [0860] Di-tert-butyl dicarbonate (1.43 g, 6.55 mmol) was added to a stirred suspension of 2-amino-2- (4-fluoro-3-methylphenyl) acetic acid (1.0 g , 5.46 mmol) in THF (3.6 mL) and 1 M aqueous sodium carbonate solution (10.9 mL, 10.9 mmol). The suspension was stirred at 20ºC under nitrogen for 16 h. The mixture was diluted with water (30 ml) and 1 M aqueous sodium hydroxide solution (10 ml), then washed with tert-butyl methyl ether (2 x 50 ml). The combined organic layers were extracted with aqueous 1 M sodium hydroxide solution (40 ml). The combined aqueous layers were acidified with concentrated hydrochloric acid (pH 2) and extracted with ethyl acetate (3 x 60 ml). The combined organic layers were washed with brine (50 ml) and dried over magnesium sulfate, then filtered and concentrated in vacuo, to produce the title compound (1.26 9, 77%) as a light orange oil. õ1 (250 MHz, DMSO-ds) 12.77 (br s, 1H), 7.53 (d, J 8.0 Hz, 1H), 7.32 (dd, J 7.4, 2.1 Hz, 1H), 7.29 - 7.19 (m, 1H), 7.17 - 7.03 (m, 1H), 5.06 (d, J 8.2 Hz, 1H), 2.22 (d, J 1.7 Hz, 3H), 1.39 (s, 9H). HPLC-MS (method 3): MNa + m / z 306, RT 1.77 minutes. INTERMEDIATE 158 N- [1- (4-fluoro-3-methylphenyl) -2-0x0-2 - ((2-0x0-1- [2- (trimethylsili) ethoxy-methylJespiro [yrrole [3,2-c] pyridine -3.4 "-tetrahydropyran] -6-yl> <amino) ethyl | tert-butyl carbamate
[0861] [0861] HATU (1.06 g, 2.79 mmol) was added to a stirred suspension of Intermediate 57 (812 mg, 2.32 mmol), Intermediate 157 (700 mg, 2.32 mmol) and DIPEA (0, 96 ml, 5.81 mmol) in DCM (27 ml). The mixture was stirred at 20ºC under nitrogen for 16 h, then partitioned between DCM (50 ml) and water (50 ml). The aqueous layer was separated and washed with DCM (2 x 50 ml). The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by scintillating column chromatography, using a gradient of ethyl acetate in heptane (0 to 100%), to give the title compound (1.09 g, 76%) as a yellow solid. dx (500 MHz, DMSO-ds) 10.86 (s, 1H), 8.58 (s, 1H), 7.96 (s, 1H), 7.60 (d, J 7.7 Hz, 1H) , 7.55 (dd, J 7.4, 1.8 Hz, 1H), 7.52 - 7.45 (m, 1H), 7.29 -7.17 (m, 1H), 5.55 ( d, J 7.4 Hz, 1H), 5.148 (s, 2H), 4.14 - 4.07 (m, 2H), 4.00 - 3.86 (m, 2H), 3.65 - 3, 54 (m, 2H), 2.40 - 2.28 (m, 3H), 1.99 - 1.87 (m, 2H), 1.87 - 1.74 (m, 2H), 1.51 ( s, 9H), 1.08 - 0.83 (m, 2H), 0.00 (s, 9H). HPLC-MS (method 3): MH + m / z 615, RT 2.17 minutes. INTERMEDIATE 159 2-Amino-2- (4-fluoro-3-methylphenyl) -N- (2-0x0-1- [2- (trimethylsilyl) ethoxymethylJespiro- [yrrole [3,2-c] pyridine-3-chloride], 4'-tetrahydropyran] -6-yl) acetamide
[0862] [0862] Solution of hydrogen chloride in 1,4-dioxane (4 M, 4.44 mL, 17.73 mmol) was added to a stirred solution of Intermediate 158 (1.09 g, 1.73 mmol) in MeOH (19 mL) under nitrogen at room temperature. The reaction was stirred at room temperature overnight, then concentrated in vacuo, to yield the title compound (1.1 g, quantitative) as a yellowish orange solid. dn (500
[0863] [0863] HATU (226 mg, 0.59 mmol) was added to a stirred suspension of Intermediate 159 (300 mg, 0.50 mmol), 1-ethyl-1H-pyrazole-5-carboxylic acid (69 mg, 0, 50 mmol), and DIPEA (0.30 mL, 1.73 mmol) in DCM (6 mL). The mixture was stirred at 20ºC under nitrogen for 16 h, then partitioned between DCM (25 ml) and water (25 ml). The aqueous layer was separated and washed with DCM (2 x 25 ml). The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by sparkling column chromatography, using a gradient of ethyl acetate in heptane (0 to 100%), to give the title compound (425 mg, 78%) as an orange gum. dn (500 MHz, DMSO-ds) 10.90 (s, 1H), 8.87 (d, J 6.9 Hz, 1H), 8.47 (s, 1H), 7.89 (s, 1H) , 7.51 - 7.46 (m, 2H), 7.45 - 7.39 (m, 1H), 7.19 - 7.12 (m, 1H), 7.06 (d, J 2.1 Hz, 1H), 5.83 (d, J 6.8 Hz, 1H), 5.11 - 5.03 (m, 2H), 4.46 (q, J 7.1 Hz, 2H), 4, 07 - 3.95 (m, 2H), 3.89 - 3.78 (m, 2H), 3.51 - 3.43 (m, 2H), 2.24 (d, J 1.4 Hz, 3H ), 1.88 - 1.76 (m, 2H), 1.75 - 1.63 (m, 2H), 1.28 (t, J7.1 Hz, 3H), 0.85 - 0.78 ( m, 2H), -0.12 (s, 9H). HPLC-MS (method 3): MH + m / z 637, RT 2.08 minutes. EXAMPLE 1 Soy NOT
[0864] [0864] (28) -3- (2-Chlorophenyl) -N- (2-oxospiro [indolino-3,4'-tetrahydropyran] -6-yl) -2- f ([2- (pyridin-4-i ) -acetylJamino) propenamide and (2R) -3- (2-Chlorophenyl) -N- (2-oxospiro- [indolino-3,4'-tetrahydro-pyran] -6-yl) -24 [2- (pyridin- 4-yl) acetyl (amino) propanamide
[0865] [0865] DIPEA (40 µL, 0.24 mmol) was added to a stirred suspension of Intermediate 2 (40 mg, 0.18 mmol), Intermediate 5 (61 mg, 0.19 mmol) and HATU (77 mg, 0 , 20 mmol) in anhydrous THF (1 mL). The mixture was stirred at 20ºC under nitrogen for 16 h, then quenched with saturated aqueous sodium carbonate solution (6 mL) and stirred for 30 minutes at 20ºC. The mixture was diluted with water (6 ml) and partitioned with DCM / isopropanol (4: 1; 30 ml). The organic phase was separated using a hydrophobic frit, then the aqueous layer was extracted with DCM / isopropanol 4: 1 (2 x 20 ml). The filtrate was concentrated in vacuo. The resulting crude orange gum was separated by preparative HPLC (method 10) to produce the title compound (54 mg, 54% yield, 46% ee) as a yellowish white powder after lyophilization. dx (500 MHz, DMSO-ds) 10.39 (s, 1H), 10.09 (s, 1H), 8.63 (d, J 8.3 Hz, 1H), 8.45-8.38 ( m, 2H), 7.42 (d, J 8.1 Hz, 1H), 7.39 (dd, J 7.8, 1.3 Hz, 1H), 7.33 - 7.27 (m, 2H ), 7.23 (td, J7.6, 1.9 Hz, 1H), 7.19 (td, J 7.4, 1.4 Hz, 1H), 7.16 - 7.12 (m, 2H ), 7.06 (dd, J 8.1, 1.9 Hz, 1H), 4.79 (td, J 8.5, 6.1 Hz, 1H), 4.01 (ddd, J 11.1 , 7.2, 3.6 Hz, 2H), 3.79 (ddd, J 11.1, 7.0, 3.7 Hz, 2H), 3.52 (d, J 14.3 Hz, 1H) , 3.48 (d, J 14.3 Hz, 1H), 3.17 (dd, J 14.1, 5.9 Hz, 1H), 3.04 (dd, J 14.1, 8.7 Hz , 1H), 1.77 - 1.68 (m, 2H), 1.67 - 1.56 (m, 2H). uPLC-MS (method 2): MH + m / z 519, RT 2.60 minutes. SFC Method Chiral 12, Chiralcel OD-H 25 cm, 25% methanol-75% carbon dioxide, 4 mL / minute: RT 5.29 minutes (27%, R); RT 6.12 minutes (73%, S).
[0866] [0866] The racemate (29 mg) was separated by the chiral preparative SFC method 15, Lux Cellulose-1 Column 21.2 x 250 mm, 5 µm, isocratic 25% MeOH (+ 0.1% NH4OH), to produce enantiomer (S) (eutomer) (3 mg) and enantiomer (R) (5 mg) as yellowish white powders. Method SFC Chiral 13, Lux Cellulose-1 4.6 x 150 mm, 3 µm, flow rate 3.5 mL / minute, isocratic 25% MeOH column + 0.1% NHaOH: RT 5.62 minutes (100 %, R); RT 6.35 minutes (100%, S). EXAMPLE 2
[0867] [0867] (28S) -2-Cyclohexyl-N- (2-oxospiro [indolino-3,4'-tetrahydropyran] -6-i1) -2 - ([2- (pyridin-4-yl) acetyl] aminojacetamide and (2R) -2-Cyclohexyl-N- (2-oxospiro [indoline-3,4 '"- tetrahydropyran) -6-i1) -2 - ([2- (pyridin-4-yl) acetylJamino) acetamide
[0868] [0868] HATU (90 mg, 0.24 mmol) was added to a stirred suspension of Intermediate 8 (62 mg, 0.22 mmol) and Intermediate 2 (50 mg, 0.23 mmol) in anhydrous DMF (1.1 mL). The suspension was stirred at 20ºC for 16 h, then quenched with saturated aqueous sodium carbonate solution (3 mL) and water (3 mL) and stirred at 20ºC for 1 h. The mixture was diluted with water (6 ml), then the material was extracted with DCM (3 x ml) and DCM / isopropanol 4: 1 (3 x 15 ml), using a hydrophobic frit to separate the phases. The organic filtrates were combined and concentrated in vacuo. The resulting crude orange gum was separated by preparative HPLC (method 10) to produce the title compound (77 mg, 70% yield, 64% ee) as a yellowish white powder after lyophilization. dx (500 MHz, DMSO-ds) 10.39 (br s, 1H), 10.12 (s, 1H), 8.50 - 8.45 (m, 2H), 8.42 (d, J 8, 5 Hz, 1H), 7.43 (d, J 8.1 Hz, 1H), 7.36 (d, J 1.9 Hz, 1H), 7.32 - 7.25 (m, 2H), 7 .09 (dd, J 8.1, 1.9 Hz, 1H), 4.29 (t J 8.1 Hz, 1H), 4.01 (ddd, J 11.1, 7.2, 3.6 Hz, 2H), 3.80 (ddd, J 11.0, 7.0, 3.7 Hz, 2H), 3.61 (d, J 14.1 Hz, 1H), 3.56 (d, J 14.1 Hz, 1H), 1.79 - 1.49 (m, 10H), 1.23 -0.92 (m, 5H). uPLC-MS (method 2): MH + m / z 477, RT 2.61 minutes. Chiral SFC, Method 12, Chiralcel OD-H cm, 30% methanol-70% carbon dioxide, 4 mL / minute: RT 2.30 minutes (18%, R); RT 2.62 minutes (82%, S). EXAMPLE 3 the 2nd WN
[0869] [0869] N- (1-Cyclooctyl-2-0x0-2 - [(2-0xo0ospiro [indolino-3,4'-tetrahydropyran]) - 6- i)> amino] Jetyl) -2-methyl-pyrazole-3 -carboxamide
[0870] [0870] HATU (210 mg, 0.55 mmol) was added to a stirred solution of Intermediate 2 (100 mg, 0.46 mmol) and Intermediate 13 (150 mg, 0.5 mmol) in anhydrous DMF (4 mL) under a nitrogen atmosphere. The mixture was stirred at 20ºC for 15h, then quenched with saturated aqueous sodium hydrogen carbonate solution (20 mL) and water (20 mL). The material was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (2 x 20 ml) and dried over sodium sulfate, then filtered and concentrated in vacuo. The residue was purified by preparative HPLC (method 10) to produce to produce the title compound (116 mg, 51%) as a white solid. dx (500 MHz, DMSO-ds) 10.39 (s, 1H), 10.22 (s, 1H), 8.52 (d, J 8.6 Hz, 1H), 7.45 (d, J 2 , 1 Hz, 1H), 7.43 (d, J 8.2 Hz, 1H), 7.38 (d, J 1.9 Hz, 1H), 7.12 (dd, J 8.1, 1, 9 Hz, 1H), 7.05 (d, JL 2.1 Hz, 1H), 4.44 (t, J 8.9 Hz, 1H), 4.05 - 3.96 (m, 2H), 4 , 03 (s, 3H), 3.80 (ddd, J 11.0, 6.9, 3.7 Hz, 2H), 2.22 - 2.09 (m, 1H), 1.77 - 1, 34 (m, 18H). uPLC-MS (method 2): MH + m / z 494, RT 3.29 minutes. EXAMPLE 4 fo) ZA "NEN o o
[0871] [0871] NÃ (1S or 1R) -1-Cyclooctyl-2-0x0-2 - [(2-oxospiro [indoline-3,4 "- tetrahydropyran] -6-yl) -amino] Jetyl) -2-methylpyrazole- 3-carboxamide
[0872] [0872] Example 3 (100 mg) was separated by the chiral preparative SFC method 15, ChiralPak IC column 20 x 250 mm, 5 µm, flow rate 100 mL / minute, gradient at 40% MeOH (+0.1 % NH.OH), to produce the title compound (eutomer) (25 mg) as a yellowish white powder. Chiral SFC Method 13, ChiralPak IC 4.6 x 150 mm, 3 µm, flow rate 3.5 mL / min, gradient 25 to 40% MeOH (+ 0.1% NH.OH): RT 3 , 76 minutes (100% ee, eutomer).
[0873] [0873] 24 [2- (2-Aminopyridin-4-yl) acetylJamino) -2-cyclooctyl-N- (2-oxo-spiro [indolino-3,4 "-tetrahydro-pyran] -6-yl) acetamide
[0874] [0874] Trifluoroacetic acid (0.18 mL, 2.34 mmol) was added to a stirred solution of Intermediate 19 (142 mg, 0.23 mmol) in DCM (5 mL) at 20 ° C under a nitrogen atmosphere. The reaction mixture was stirred at 20 ° C overnight and diluted with dichloromethane (25 mL), then cautiously quenched with saturated aqueous sodium hydrogen carbonate solution (30 mL) and extracted with isopropanol / chloroform 1: 1 (3 x 30 mL ). The combined organic layers were dried over sodium sulfate, then filtered and concentrated in vacuo. The residue was separated by preparative HPLC (method 10) to produce the title compound (42.9 mg, 36%) as a white solid. õx (500 MHz, DMSO-ds) 10.38 (s, 1H), 10.13 (s, 1H), 8.32 (d, J 8.9 Hz, 1H), 7.78 (d, J 5 , 4 Hz, 1H), 7.42 (d, J 8.1 Hz, 1H), 7.35 (d, J 1.8 Hz, 1H), 7.09 (dd, J 8.1, 1, 8 Hz, 1H), 6.45 - 6.42 (m, 1H), 6.37 (s, 1H), 6.03 (br s, 2H), 4.30 (t, J 8.4 Hz, 1H), 4.00 (ddd, J 11.0, 7.1, 3.6 Hz, 2H), 3.79 (ddd, J 11.0, 6.9, 3.7 Hz, 2H), 3 , 43 (d, J 13.8 Hz, 1H), 3.37 - 3.24 (m, 1H, obscured by the water peak), 2.01 - 1.92 (m, 1H), 1.77 - 1.70 (m, 2H), 1.68 - 1.26 (m, 16H). uPLC-MS (method 1): MH + m / z 520, RT 2.04 minutes. EXAMPLE 6 oO.
[0875] [0875] —2-Cyclooctyl-N- (2-oxospiro [indolino-3,4'-tetrahydropyran] -6-yl) -2 - ([2- (pyridin-4-i1) -acetylJamino) acetamide
[0876] [0876] HATU (228 mg, 0.6 mmol) was added to a stirred suspension of Intermediate 21 (171 mg, 0.55 mmol) and Intermediate 2 (126 mg, 0.58 mmol) in anhydrous DMF (2.9 mL). The mixture was stirred at 20ºC under nitrogen for 16 h, then quenched with saturated aqueous sodium carbonate solution (6 mL) and water (6 mL) and stirred at 20ºC for 30 minutes. The mixture was diluted with water (12 ml), then the material was extracted with DCM / isopropanol 4: 1 (3 x 15 ml), using a hydrophobic frit to separate the phases. The organic filtrate was concentrated in vacuo. The resulting crude orange gum was separated by preparative HPLC (method 9) to produce the title compound (268 mg, 96%) as a yellowish white powder after lyophilization. dn (500 MHz, DMSO-ds) 10.38 (br s, 1H), 10.14 (br s, 1H), 8.52 - 8.39 (m, 3H), 7.42 (d, J 8 , 1 Hz, 1H), 7.35 (d, J 1.8 Hz, 1H), 7.30 - 7.25 (m, 2H), 7.08 (dd, J 8.1, 1.8 Hz , 1H), 4.31 (t, J 8.3 Hz, 1H), 4.00 (ddd, J 11.0, 7.1, 3.6 Hz, 2H), 3.79 (ddd, J 11 , 0, 7.0, 3.7 Hz, 2H), 3.60 (d, J 14.0 Hz, 1H), 3.53 (d, J 14.0 Hz, 1H), 2.02 - 1 , 91 (m, 1H), 1.78 - 1.68 (m, 2H), 1.68 - 1.26 (m, 16H). uPLC-MS (method 2): MH + m / z 505, RT 2.97 minutes. EXAMPLE 7 THE The RN
[0877] [0877] (28 or 2R) -2-Cyclooctyl-N- (2-oxospiro [indolino-3,4'-tetrahydropyran] -6-i1) -2- f ([2- (pyridin-4-yl) acetylJamino ) acetamide
[0878] [0878] Example 6 (268 mg) was separated by the chiral preparative SFC method 14 (18:82 methanol-carbon dioxide, Chiralcel OD-H 25 cm column, 15 mL / minute) to produce the title compound (eutomer) (65 mg) as a yellowish white powder after lyophilization. SFC Method Chiral 12, Chiralcel OD-H 25 cm, 20% methanol- 80% carbon dioxide, 4 mL / minute: RT 7.97 minutes (100%).
[0879] [0879] 2-methyl-N- (2-0x0-2 - [(2-0x0espiro [indolino-3,4'-tetrahydropyran]) - 6-yl)> amino] Jetyl) -pyrazole-3-carboxamide
[0880] [0880] HATU (67 mg, 0.18 mmol) was added to a stirred solution of Intermediate 2 (32 mg, 0.15 mmol) and Intermediate 23 (30 mg, 0.16 mmol) in anhydrous DMF (1 mL) under a nitrogen atmosphere. The mixture was stirred at 20ºC for 18 h, then quenched by the addition of saturated aqueous sodium hydrogen carbonate solution (7 ml) and water (7 ml). The material was extracted with ethyl acetate (3 x 7 ml). The combined organic layers were washed with brine (2 x 7 ml) and dried over sodium sulfate, then filtered and concentrated in vacuo. The residue was separated by preparative HPLC (method 10) to produce the title compound (16 mg, 27%) as a white solid. dn (500 MHz, DMSO-ds) 10.41 (s, 1H), 10.07 (s, 1H), 8.81 (t, J 5.9 Hz, 1H), 7.48 (d, J 2 , 0 Hz, 1H), 7.44 (d, J 8.1 Hz, 1H), 7.36 (d, J 1.7 Hz, 1H), 7.08 (dd, J 8.1, 1, 8 Hz, 1H), 6.92 (d, J 2.0 Hz, 1H), 4.05 (s, 3H), 4.03 - 3.97 (m, 4H), 3.80 (ddd, J 11.1, 7.0, 3.7 Hz, 2H), 1.77 - 1.69 (m, 2H), 1.67 - 1.58 (m, 2H). uPLC-MS (method 1): MH + m / z 384, RT 1.60 min. EXAMPLE 9 Ss. [)
[0881] [0881] N- (1-Cyclooctyl-2-0x0-2 - [(2-0xo0ospiro [indoline-3,4'-tetrahydrothiopyran] -6- i)> amino] -ethyl) -2-methylpyrazole-3-carboxamide
[0882] [0882] HATU (10 mg, 0.038 mmol) was added to a stirred solution of Intermediate 28 (4.8 mg, 0.014 mmol) and Intermediate 13 (6 mg, 0.02 mmol) in anhydrous DMF (0.2 mL) . The mixture was stirred at 20ºC under nitrogen for 16 h, then quenched with saturated aqueous sodium carbonate solution (10 mL) and stirred for 30 minutes at 20ºC. The mixture was partitioned with 4: 1 DCM / isopropanol (10 ml). The organic phase was separated using a hydrophobic frit, then the aqueous layer was extracted with 4: 1 DCM / isopropanol (2 x 10 ml). The filtrate was concentrated in vacuo. The resulting crude brown film was separated by preparative HPLC (method 8) to produce the title compound (0.5 mg, 6%) as a white powder. õn (500 MHz, CDCI3) 10.32 (br s, 1H), 8.36 (s, 1H), 8.17 (s, 1H), 7.91 (d, J 6.9 Hz, 1H), 7.40 (d, JU 2.1 Hz, 1H), 7.22 (d, J 8.0 Hz, 1H), 6.87 (d, J 2.1 Hz, 1H), 6.67 (dd , J 8.0, 1.9 Hz, 1H), 441 - 4.30 (m, 1H), 4.13 (s, 3H), 3.32 - 3.16 (m, 2H), 2.78 - 2.65 (m, 2H), 2.35 - 2.24 (m, 1H), 2.13 - 1.99 (m, 2H), 1.98 - 1.82 (m, 3H), 1 , 77 - 1.11 (m, 13H). uPLC-MS (method 1): MH + m / z 510, RT 3.54 minutes. EXAMPLE 10 N.
[0883] [0883] N- (1-Cyclooctyl-2-0x0-2 - [(2-0xo0ospiro [indolino-3,4'-piperidino] -6- i)> amino] Jetyl) -2-methylpyrazole-3-carboxamide
[0884] [0884] A suspension of Intermediate 31 (34.5 mg, 0.06 mmol) and 10% palladium on carbon (50% aqueous moisture, 25 mg, 0.012 mmol) in ethanol (4 mL) was stirred under an atmosphere of hydrogen at 20ºC for 18 h. The solids were removed by filtration through a pad of diatomaceous earth, washing with ethanol! (8 x 25 mL). The filtrate was concentrated in vacuo. The resulting crude brown powder was separated by preparative HPLC (method 11), then the fractions containing the product were treated with saturated aqueous sodium carbonate solution (pH 11) and extracted with DCM / isopropanol 4: 1 (3 x 20 mL) using a hydrophobic frit. The organic filtrate was concentrated in vacuo to produce the title compound (12 mg, 39%) as a white powder after lyophilization. ds (500 MHz, DMSO-ds) 10.31 (s, 1H), 10.21 (s, 1H), 8.53 (d, J 8.5 Hz, 1H), 7.45 (d, J] 2.0 Hz, 1H), 7.39 (d, J 8.1 Hz, 1H), 7.37 (d, J 1.7 Hz, 1H), 7.11 (dd, J 8.2, 1 , 9 Hz, 1H), 7.05 (d, J 2.1 Hz, 1H), 4.44 (t, J 8.9 Hz, 1H), 4.03 (s, 3H), 3.10 - 2.99 (m, 2H), 2.94 - 2.83 (m, 2H), 2.21 - 2.11 (m, 1H), 1.73 - 1.34 (m, 18H). uPLC-MS (method 1): MH + m / z 493, RT 2.09 minutes. EXAMPLE 11 O. o
[0885] [0885] 2-Acetamido-2-cyclooctyl-N- (2-oxospiro [indolino-3,4'-tetrahydropyran] -6- i) acetamide
[0886] [0886] Acetyl chloride (15 µl, 0.21 mmol) was added to a solution of Intermediate 35 (70 mg, 0.18 mmol) and DIPEA (63 µL, 0.36 mmol) in DCM (2 mL) and the solution was stirred at 20ºC for 18 h. More acetyl chloride (7.5 µL, 0.11 mmol) was added, and the reaction mixture was stirred at 20 ° C for an additional 2 h. To the reaction mixture, saturated aqueous sodium hydrogen carbonate solution (20 mL) and 1: 1 isopropanol-chloroform (20 mL) were added. The layers were separated and the aqueous layer was extracted with isopropanol-chloroform 1: 1 (2 x 20 ml). The combined organic layers were dried over magnesium sulfate, then filtered and concentrated in vacuo. The residue was separated by preparative HPLC (method 9) to produce the title compound (34.1 mg, 44%) as a white solid. on (500 MHz, DMSO-ds) 10.38 (s, 1H), 10.09 (s, 1H), 8.06 (d, J 8.8 Hz, 1H), 7.42 (d, J 8 , 1 Hz, 1H), 7.36 (d, J 1.8 Hz, 1H), 7.09 (dd, J 8.1, 1.9 Hz, 1H), 4.29 (t, J 8, 5 Hz, 1H), 4.00 (ddd, J 11.1, 7.2, 3.6 Hz, 2H), 3.80 (ddd, J 11.1, 6.9, 3.7 Hz, 2H ), 1.94 (s, 1H), 1.87 (s, 3H), 1.77 - 1.68 (m, 2H), 1.69 - 1.27 (m, 16H). uPLC-MS (method 2): MH + m / z 428, RT 2.94 minutes. EXAMPLE 12
[0887] [0887] N- (1-Cyclooctyl-2 - [(5-fluoro-2-oxo-spiro [indolino-3,4'-tetrahydropyran] -6- i)> amino] -2-0x0ethyl) -2-methylpyrazole-3 -carboxamide
[0888] [0888] Selectfluorº (35 mg, 0.101 mmol) was added to a solution of Example 3 (50 mg, 0.101 mmol) in anhydrous DMF (1 mL). The reaction mixture was stirred at room temperature for 16 h, then saturated aqueous sodium hydrogen carbonate solution (5 ml) and 1: 1 isopropanol-chloroform (20 ml) were added. The layers were separated and the aqueous layer was extracted with isopropanol-chloroform 1: 1 (2 x 20 ml). The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was separated by preparative HPLC (method 9) to produce the title compound (13.1 mg, 25%) as a white solid. õx (500 MHz, DMSO-ds) 10.34 (s, 1H), 9.94 (s, 1H), 8.48 (s, 1H), 7.50 (d, J 10.4 Hz, 1H) , 7.45 (d, J 2.0 Hz, 1H), 7.39 (d, J 6.5 Hz, 1H), 7.02 (d, 12.0 Hz, 1H), 4.59 (d , J 8.6 Hz, 1H), 4.03 (s, 3H), 4.02 - 3.96 (m, 2H), 3.84 - 3.72 (m, 2H), 2.22 - 2 , 14 (m, 1H), 1.75 - 1.61 (m, 7H), 1.5 9 - 1.38 (m, 11H). * ºF NMR (250 MHz, DMSO- de) 5 -132.6. uPLC-MS (method 1) MH + m / z 512, RT 3.21 minutes. EXAMPLE 13 O. o
[0889] [0889] 2-methyl-N- (2-0x0-2 - [(2-oxoxospiro [indolino-3,4'-tetrahydropyran] -6-yl) amino] - 1- (spiro- [3,3] heptan -2-yl) ethyl) pyrazol-3-carboxamide
[0890] [0890] To a stirred solution of Intermediate 2 (25 mg, 0.115 mmol) and
[0891] [0891] 2-Ethyl-NX (18) -2 - [(4-fluoro-2-0xospiro [indolino-3,4 "-tetrahydropyran] -6- i)> amino] -1- (4-methyl-cyclohexyl ) -2-oxoethyl) pyraz | -3-carboxamide (trans isomer)
[0892] [0892] DIPEA (70 µL, 0.42 mmol) was added to a suspension of 1-ethyl-1H-pyrazole-S-carboxylic acid (40 mg, 0.29 mmol) and HATU (105 mg, 0.28 mmol) ) in DCM (1 mL) at 20ºC under nitrogen. The suspension was stirred at 20ºC under nitrogen for 1 h. A solution of Intermediate 52 (81.14 mg, 0.21 mmol) in DCM (1 mL) was added. The mixture was stirred at 20ºC under nitrogen for 16 h, then diluted with DCM (20 mL) and quenched with saturated aqueous sodium carbonate solution (10 mL) and water (10 mL). The biphasic mixture was stirred at 20ºC for 30 minutes, then the organic phase was separated using a hydrophobic frit. The aqueous layer was extracted with DCM (3 x 20 ml), and the organic filtrate was concentrated in vacuo. The resulting brown powder was separated by preparative sequential HPLC (method 10), then by a sparkling column chromatography, using a gradient of ethyl acetate in heptane (25 to 100%), to produce, after lyophilization, the title compound ( 26.8 mg, 25%) as a white powder. õs (500 MHz, DMSO-ds) 10.59 (s, 1H), 10.35 (s, 1H), 8.52 (d, J 7.9 Hz, 1H), 7.47 (d, JU 2 , 0 Hz, 1H), 7.12 - 7.06 (m, 2H), 7.01 (d, JU 2.0 Hz, 1H), 4.45 (q, J 7.2 Hz, 2H), 4.30 (t, J 8.5 Hz, 1H), 4.06 (t, J 10.2 Hz, 2H), 3.80 - 3.69 (m, 2H), 2.01 (ddd, J 14.3, 10.5, 4.4 Hz, 2H), 1.90 - 1.73 (m, 2H), 1.73 - 1.64 (m, 4H), 1.60 - 1.48 ( m, 1H), 1.35 - 1.22 (m, 4H), 1.22 - 1.11 (m, 1H), 1.08 - 0.97 (m, 1H), 0.93 - 0, 80 (m, 5H). uPLC-MS (method 1): MH + m / z 512, RT 3.36 minutes. EXAMPLE 15
[0893] [0893] 2- (5-Methoxybicyclo [4,2,0] octa-1,3,5-trien-7-ylidene) -2 - [(3-methylisoxazo | -4-yl) - formamide] -N- (2-0x0-1,2-dihydrospiro [indole-3,4'-oxane] -6-yl) acetamide (isomer 1)
[0894] [0894] Acetic acid (0.1 mL, 1.75 mmol) was added to a solution of Intermediate 56 (50 mg, 0.17 mmol) and Intermediate 57 (89%, 42 mg, 0.17 mmol) in THF anhydrous (1.1 mL). The reaction mixture was stirred at 60ºC for 18 h, then cooled to room temperature and concentrated in vacuo. The residue was purified by preparative HPLC (method 11) to produce, after lyophilization, the title compound (20.3 mg, 22%) as a white solid. dx (500 MHz, DMSO-ds) 10.41 (br s, 1H), 9.80 (br s, 1H), 9.59 (br s, 1H), 9.46 (s, 1H), 7, 50 (d, J 1.9 Hz, 1H), 7.45 (d, J 8.2 Hz, 1H), 7.36 (dd, J 8.4, 7.2 Hz, 1H), 7.24 (dd, J 8.2, 1.9 Hz, 1H), 6.91 (d, J7.1 Hz, 1H), 6.87 (d, J 8.6 Hz, 1H), 4.03 (ddd , J 11.0, 7.1, 3.6 Hz, 2H), 3.91 (s, 2H), 3.82 (ddd, J 11.0, 6.9, 3.6 Hz, 2H), 3.57 (s, 3H), 2.42 (s, 3H), 1.87-1.72 (m, 2H), 1.70 - 1.56 (m, 2H). HPLC-MS (method 1): MH + m / z 515, RT 2.66 minutes. EXAMPLE 16
[0895] [0895] (28) -2 - [(1-methyl-1H-pyrazol-5-yl 'formamide] -N- (2-0x0-1,2-dihydrospiro [indole-3,4'-oxane] -6 -i1) -2 - [(11.48) -4-methylcyclohexylJacetamide - (trans isomer)
[0896] [0896] To a stirred solution of Intermediate 50 (370 mg, 1 mmol) in dry DNF (8 mL) was added 1-methyl-1H-pyrazol-5-carboxylic acid (127 mg, 1.01 mmol), then HATU (455 mg, 1.2 mmol) and DIPEA (0.5 mL, 3.03 mmol), at room temperature. The reaction mixture was stirred for at least 18 hours. With external cooling, water (40 mL) was added to the reaction mixture. The precipitated solid was filtered off and washed with water (2 x 10 ml). The filter cake was dissolved in ethyl acetate (20 ml) and the excess water was separated. The organic layer was washed with a 1: 1 mixture of water and brine (10 ml), and brine (10 ml), then dried over magnesium sulfate, filtered and concentrated in vacuo. The crude residue was adsorbed on silica gel (3.1 g), using DCM, and purified by automated chromatography, using a gradient of ethyl acetate in heptane (100% O), then a gradient of methanol in ethyl acetate (0 to 7%). The isolated material was triturated in a mixture of ethyl acetate (2 ml) and heptane (20 ml), then filtered off, washed with heptane (4 x 10 ml) and dried, to produce the title compound (279 mg, 58%) as a white solid. õH (500 MHz, DMSO-ds) 10.38 (s, 1H), 10.17 (s, 1H), 8.47 (d, J 8.1 Hz, 1H), 7.45 (d, J 2 , 0 Hz, 1H), 7.43 (d, J 8.1 Hz, 1H), 7.39 (d, J 1.8 Hz, 1H), 7.11 (dd, J 8.2, 1, 9 Hz, 1H), 7.05 (d, J 2.1 Hz, 1H), 4.34 (t, J 8.5 Hz, 1H), 4.04 - 3.96 (m, 5H), 3 , 84 - 3.75 (m, 2H), 1.85 (d, J 12.6 Hz, 1H), 1.81 - 1.65 (m, 5H), 1.65 - 1.52 (m, 3H), 1.34 - 1.12 (m, 2H), 1.09 - 0.97 (m, 1H), 0.93 - 0.79 (m, 5H). uPLC-MS (method 1): MH + m / z 480, RT 3.01 minutes. Chiral SFC
[0897] [0897] N- (1- (1-Adamantylmethyl) -2-0x0-2 - [(2-oxo-spiro [indolino-3,4 "- tetrahydropyran] -6-yl) -amino] Jetyl) -2-methylpyrazole- 3-carboxamide
[0898] [0898] To a stirred suspension of Intermediate 63 (20 mg, 0.038 mmol) in a mixture of THF (1 ml) and ethanol (1 ml) was added 10% palladium on vegetable carbon (50% by weight, 4 mg, 20% by weight) as a single portion. The reaction mixture was transferred to a pressure vessel and placed under an atmosphere of hydrogen gas. Stirring was continued at room temperature for 24 h at 7 bar of hydrogen pressure. A second 10% aliquot of palladium on vegetable carbon (50% by weight, 4 mg, 20% by weight) was added as a single portion and stirring was continued at room temperature for 30 h under 7 bar of hydrogen pressure. A third 10% aliquot of palladium on vegetable carbon (50% by weight, 4 mg, 20% by weight) was added as a single portion and stirring was continued at room temperature for 70 h under 7 bar of hydrogen pressure (time total reaction time 124 h). The catalyst was removed by filtration on diatomaceous earth, rinse the filter cake with THF (2x5 mL). The solvent was concentrated in vacuo to yield the title compound (9.5 mg, 42%) as a beige solid. õH (500 MHz, DMSO-ds) 10.40 (s, 1H), 10.07 (s, 1H), 8.58 (d, J 7.9 Hz, 1H), 7.46 (d, J 2 , 0 Hz, 1H), 7.43 (d, J 8.2 Hz, 1H), 7.36 (d, J 1.8 Hz, 1H), 7.13 (dd, J 8.2, 1, 9 Hz, 1H), 7.00 (d, J 2.1 Hz, 1H), 4.65 (td, J 8.4, 3.8 Hz, 1H), 4.03 (s, 3H), 4 , 04 - 3.97 (m, 2H), 3.80 (ddd, J 11.3, 7.2, 3.8 Hz, 2H), 1.91 (s, 3H), 1.76 - 1, 69 (m, 3H), 1.68 - 1.62 (m, 6H), 1.57 - 1.50 (m, 7H), 1.23 (s, 2H). uPLC-MS (method 2): MH + m / z 532, RT 3.54 minutes. EXAMPLE 18 O. WN
[0899] [0899] Nf (2- (Bicyclo [1,1,1] pentan-1-yl) -1 - [(2-oxospiro [indolino-3,4 "- tetrahydropyran] -6-yl) -carbamoyl] prop- 1-enyl) -2-methylpyrazole-3-carboxamide
[0900] [0900] To a stirred solution of Intermediate 2 (50 mg, 0.229 mmol) and Intermediate 64 (59 mg, 0.229 mmol) in anhydrous THF (2.3 mL) was added acetic acid (0.131 mL, 2.29 mmol). The reaction mixture was stirred at 60ºC for 16h. The solvent was removed in vacuo, and the residue was triturated in a 1: 1 mixture of DOM and diethyl ether (1 ml). The solid was collected by filtration, rinsing the cake with diethyl ether (2 x 0.5 ml), then vacuum dried, to produce the title compound (79.3 mg, 71%) as a beige solid. dn (500 MHz, DMSO-ds) 10.37 (s, 1H), 10.08 (s, 1H), 9.55 (s, 1H), 7.51 (d, J 2.1 Hz, 1H) , 7.49 (d, J 1.6 Hz, 1H), 7.43 (d, J 8.2 Hz, 1H), 7.16 (dd, J 8.2, 1.8 Hz, 1H), 7.07 (d, JU 2.1 Hz, 1H), 4.02 (s, 3H), 4.02 - 3.97 (m, 2H), 3.80 (ddd, J 11.0.7, 0, 3.7 Hz, 2H), 2.45 (s, 1H), 2.02 (s, 6H), 1.81 (s, 3H), 1.74 (ddd, J 12.9, 6, 8, 3.5 Hz, 2H), 1.62 (ddd, J 13.1, 7.0, 3.7 Hz, 2H). uPLC-MS (method 1): MH + m / z 476, RT 2.69 minutes. EXAMPLE 19 "Ps
[0901] [0901] N- (1-Cycloheptylidene-2-0x0-2 - [(2-0xo0ospiro [indolino-3,4'-tetrahydropyran] - 6-yl) amino] -ethyl) -2-methylpyrazole-3-carboxamide
[0902] [0902] To a stirred solution of Intermediate 2 (50 mg, 0.229 mmol) and Intermediate 65 (60 mg, 0.229 mmol) in anhydrous THF (2.3 mL) was added acetic acid (0.131 mL, 2.29 mmol). The reaction mixture was stirred at 60 ° C for 6 h. Acetic acid (0.131 ml, 2.29 mmol) was added and heating at 60 ° C was continued for an additional 21 h. The solvent was removed in vacuo, and the residue was purified by preparative HPLC at low pH (method 11), to produce, after lyophilization, the title compound (35.4 mg, 32%) as a white solid. õH (500 MHz, DMSO-ds) 10.36 (s, 1H), 9.88 (s, 1H), 9.43 (s, 1H), 7.49 (d, J 2.0 Hz, 1H) , 7.46 (s, 1H), 7.41 (dy J 8.2 Hz, 1H), 7.14 (dd, J 8.2, 1.7 Hz, 1H), 7.07 (d, J 1.9 Hz, 1H), 4.01 (s, 3H), 4.04 - 3.98 (m, 2H), 3.80 (ddd, J 11.1, 7.0, 3.7 Hz, 2H), 2.56 - 2.53 (m, 2H), 2.43 - 2.39 (m, 2H), 1.73 (ddd, J 12.9, 6.9, 3.6 Hz, 2H ), 1.66 - 1.58 (m, 6H), 1.52 (s, 4H). uPLC-MS (method 1): MH + m / z 478, RT 2.74 minutes. EXAMPLE 20 (PROCEDURE |) o. NeN "%
[0903] [0903] N- (1-Cicloheptil-2-0x0-2 - [(2-0xo0ospiro [indolino-3,4'-tetrahydropyran] -6- i)> amino] -ethyl) -2-methylpyrazole-3-carboxamide
[0904] [0904] To a stirred solution of Intermediate 2 (30 mg, 0.137 mmol) and Intermediate 66 (60%, 60 mg, 0.137 mmol) in anhydrous THF (1.4 mL) was added acetic acid (0.131 mL, 2.29 mmol). The reaction mixture was stirred at 60ºC for 16 h. The solvent was removed in vacuo, and the residue was purified by preparative HPLC at low pH (method 11), to produce, after lyophilization, the title compound (23.8 mg, 36%) as a white solid. õ1 (500 MHz, DMSO-ds) 10.39 (s, 1H), 10.19 (s, 1H), 8.48 (d, J 8.5 Hz, 1H), 7.45 (d, Jy 2 , 1 Hz, 1H), 7.43 (d, J 8.1 Hz, 1H), 7.38 (d, J 1.9 Hz, 1H), 7.12 (dd, J 8.1, 2, 0 Hz, 1H), 7.05 (d, J 2.1 Hz, 1H), 4.45 (t, J 8.6 Hz, 1H), 4.02 (s, 3H), 4.00 (ddd , J 11.0, 7.1, 3.8 Hz, 2H), 3.80 (ddd, J 11.0, 7.0, 3.7 Hz, 2H), 2.11 - 2.03 (m , 1H), 1.73 (ddd, J 13.0, 6.8, 3.5 Hz, 3H), 1.67-1.59 (m, 5H), 1.57 - 1.29 (m, 8H). uPLC-MS (method 1): MH + m / z 480, RT 2.95 minutes. EXAMPLE 21 New "Ps
[0905] [0905] N- (1- (Bicycles [3,2,1] octan-3-i1) -2-0x0-2 - [(2-0x0piro [indolino-3,4 "- tetrahydropyran] -6-yl) amino] ethyl) -2-methylpyrazole-3-carboxamide (single isomer)
[0906] [0906] To a stirred solution of Intermediate 2 (80 mg, 0.367 mmol) and Intermediate 68 (90%, 111 mg, 0.367 mmol) in anhydrous THF (3.7 mL) was added acetic acid (0.210 mL, 3.67 mmol). The reaction mixture was stirred at 60ºC for 16 h. The solvent was removed in vacuo, and the residue was purified by preparative HPLC at low pH (method 11). After lyophilization, the resulting white solid (91.3 mg) was further separated using SFC Chiral (method 14, Chiralcel OD-H 25 cm, 20% methanol-80% carbon dioxide, 15 mL / min) to produce the title compound (30 mg, 36%) as a white solid. õH (500 MHz, DMSO-ds) 10.39 (s, 1H), 10.21 (s, 1H), 8.48 (d, J 8.6 Hz, 1H), 7.45 (d, J 2 , 0 Hz, 1H), 7.43 (d, J 8.2 Hz, 1H), 7.39 (d, J 1.7 Hz, 1H), 7.15 (dd, J 8.2, 1, 8 Hz, 1H), 7.03 (d, J 2.0 Hz, 1H), 4.52 (dd, J 10.8, 8.8 Hz, 1H), 4.04 (s, 3H), 4 .00 (ddd, J 11.0, 7.2, 3.5 Hz, 2H), 3.80 (ddd, J 11.0, 6.9, 3.7 Hz, 2H), 2.21 - 2 , 11 (m, 3H), 1.90 (dt, J 14.1, 7.2 Hz, 1H), 1.81 - 1.75 (m, 1H), 1.73 (ddd, J 12.6 , 6.8, 3.5 Hz, 2H), 1.67 -1.63 (m, 3H), 1.63 - 1.58 (m, 2H), 1.57 - 1.51 (m, 1H ), 1.46 (d, J 10.9 Hz, 1H), 1.23 (dd, J 13.7, 5.8 Hz, 2H), 1.20 - 1.14 (m, 1H). uPLC-MS (method 1): MH + m / z 492, RT 3.03 minutes. Chiral SFC (method 12, Chiralcel OD-H 25 cm, 20% methanol-80% carbon dioxide, 4 ml / min): RT 9.05 minutes (99%). EXAMPLE 22
[0907] [0907] Nf (1- (5-Chloro-7-bicyclo [4,2,0] octa-1 (6), 2,4-trienylidene) -2-0x0-2 - [(2- oxoospiro-findolino- 3,4'-tetrahydropyran] -6-yl) amino] Jetyl) -2-methylpyrazole-3-carboxamide (isomer 1)
[0908] [0908] To a stirred solution of Intermediate 2 (60 mg, 0.275 mmol) and Intermediate 69 (80 mg, 0.275 mmol) in anhydrous THF (1.8 mL) was added acetic acid (0.158 mL, 2.75 mmol). The reaction mixture was stirred at 60ºC for 16h. The solvent was removed in vacuo, and the residue was triturated in DCM (1 ml), to produce the title compound (100 mg, 70%) as a yellowish white solid. õn (500 MHz, DMSO-ds) 10.42 (s, 1H), 10.16 (s, 2H), 7.53 (d, J 2.1 Hz, 1H), 7.50 (d, J 1 , 9 Hz, 1H), 7.46 (d, J 8.2 Hz, 1H), 7.38 (dd, J 8.2, 7.1 Hz, 1H), 7.33 - 7.27 (m , 2H), 7.22 (dd, J 8.2, 1.9 Hz, 1H), 7.14 (d, J 2.1 Hz, 1H), 4.06 (s, 3H), 4.02 (ddd, J 11.0, 7.2, 3.7 Hz, 2H), 3.94 (s, 2H), 3.82 (ddd, J 11.1, 7.0, 3.8 Hz, 2H ), 1.78 - 1.72 (m, 2H), 1.64 (ddd, J 13.1, 7.0, 3.6 Hz, 2H). uPLC-MS (method 1): MH + m / z 518, RT 2.71 minutes. EXAMPLE 23 O. we N e
[0909] [0909] N- (1- (2,3-Dimethylcyclobutylidene) -2-0x0-2 - [(2-0xospiro [indolino-3,4'- tetrahydro-pyran] -6-yl) amino] Jetyl) -2 -methylpyrazole-3-carboxamide (isomer 5)
[0910] [0910] To a stirred solution of Intermediate 2 (50 mg, 0.229 mmol) and Intermediate 70 (56 mg, 0.229 mmol) in anhydrous THF (2.3 mL) was added acetic acid (0.131 mL, 2.29 mmol). The reaction mixture was stirred at 60ºC for 16h. The solvent was removed in vacuo, and the residue was purified by preparative HPLC at low pH (method 11). After lyophilization, the resulting white solid (72.5 mg) was further separated using SFC Chiral (method 14, Chiralpak IC 25 cm, 25% methanol-75% carbon dioxide, 15 ml / min) to produce the compound of the title (4.8 mg, 4.5%) as a white solid. õH (500 MHz, CD3O0D) 7.51 (d, J 2.1 Hz, 1H), 7.41 (d, J 8.2 Hz, 1H), 7.39 (d, J 1.9 Hz, 1H ), 7.10 (dd, J 8.1, 2.0 Hz, 1H), 6.92 (d, J 2.1 Hz, 1H), 4.16 (ddd, J 11.5, 7.6 , 3.7 Hz, 2H), 4.13 (s, 3H), 3.92 (ddd, J 11.2, 6.8, 3.8 Hz, 2H), 3.33 (dd, J 3, 7, 2.0 Hz, 1H), 3.22 (ddd, J 17.5, 8.7, 1.5 Hz, 1H), 2.84 (d, J 17.2 Hz, 1H), 2, 66 - 2.57 (m, 1H), 1.87 (ddd, J 13.4, 6.7, 3.8 Hz, 2H), 1.76 (ddd, J 13.7, 7.6, 3 , 8 Hz, 2H), 1.11 (d, Jy 2.9 Hz, 3H), 1.10 (d, J 2.5 Hz, 3H). uPLC-MS (method 1): MH + m / z 464, RT 2.52 minutes. Chiral SFC (method 12, Chiralpak IC 25 hundred, 25% methanol-75% carbon dioxide, 4 ml / min): RT 17.86 minutes (90%, 100% ee). EXAMPLE 24 (PROCEDURE A) O.
[0911] [0911] N- (1-Cyclooctyl-2-0x0-2 - [(2-oxoospospiro [indolino-3,4'-tetrahydropyran] -6- i)> amino] Jetyl) -2-ethyl-pyrazol-3- carboxamide
[0912] [0912] HATU (148 mg, 0.39 mmol) was added to a stirred suspension of Intermediate 35 (100 mg, 0.26 mmol) and 1-ethyl-1H-pyrazol-5-carboxylic acid (43.6 mg, 0.31 mmol) in anhydrous DMF (1 mL) and DIPEA (107 µL, 0.65 mmol). The suspension was stirred at 20ºC for 17 h. The reaction mixture was quenched with saturated aqueous sodium carbonate solution (5 ml) and water (5 ml), and stirred at 20ºC for 5 minutes, then extracted with tert-butyl methyl ether (2 x 20 ml). The combined organic extracts were washed with water (2 x 10 ml) and brine (10 ml), then dried over sodium sulfate, filtered and concentrated in vacuo. The resulting crude material was purified by sparkling column chromatography, using a gradient of tert-butyl methyl ether in heptane (0 to 100%) followed by a MeOH gradient in tert-butyl methyl ether (0 to 10%), to produce , after lyophilization, the title compound (85.7 mg, 59%) as a colorless solid. 5H (500 MHz, CDCI3) 10.22 (br s, 1H), 8.36 (s, 1H), 8.15 (s, 1H), 7.90 (d, J 6.6 Hz, 1H), 7.40 (d, J 2.1 Hz, 1H), 7.29 - 7.26 (m, 1H), 6.83 (d, J 2.0 Hz, 1H), 6.67 (dd, J 8.1, 1.9 Hz, 1H), 4.62 - 4.47 (m, 2H), 4.40 - 4.32 (m, 1H), 4.27 - 4.19 (m, 2H) , 3.96 - 3.87 (m, 2H), 2.36 - 2.26 (m, 1H), 1.92 - 1.67 (m, 8H), 1.57 - 1.41 (m, 8H), 1.38 (t, J 7.2 Hz, 3H), 1.380 - 1.09 (m, 2H). uPLC-MS (method 1): MH + m / z 508.4, RT 3.36 minutes. EXAMPLE 25 N-N o
[0913] [0913] N - (((18S) -1-Cyclooctyl-2-0x0-2 - [(2-0xo0ospiro [indoline-3,4'-tetrahydropyran] -6- iN) amino] Jetyl) -2-ethylpyrazole-3 -carboxamide
[0914] [0914] Example 24 (75 mg) was separated by the preparative chiral SFC (method 14, 25 cm Chiralpak IC column, carbon dioxide: MeOH 70:30, 15 mL / min) to produce the title compound (eutomer) ( 5 mg) as a white solid, together with the racemate (43 mg). The racemate was separated by the preparative chiral SFC (method 14, 25 cm Chiralpak IC column, isocratic carbon dioxide: MeOH 70:30, 15 mL / min) to produce more of the title compound (eutomer) (13.4 mg) as a white solid. on (500 MHz, CDCI3) 10.28 (s, 1H), 8.41 (s, 1H), 8.19 (s, 1H), 7.97 (d, J7.7 Hz, 1H), 7, 40 (d, J 2.0 Hz, 1H), 7.32 - 7.18 (m, 1H), 6.83 (d, J 2.0 Hz, 1H), 6.66 (dd, J 8, 0, 1.8 Hz, 1H), 4.59 - 4.44 (m, 2H), 4.42 - 4.33 (m, 1H), 4.28 - 4.16 (m, 2H), 3 , 97 - 3.81 (m, 2H), 2.36 (d, J 8.7 Hz, 1H), 1.98 - 1.86 (m, 2H), 1.85 - 1.68 (m, 6H), 1.65 - 1.60 (m, 2H), 1.57 - 1.41 (m, 8H), 1.36 (t, Jy 7.2 Hz, 3H). uPLC-MS (method 1): MH + m / z 508.3, RT 3.28 minutes. Chiral SFC (method 12, 25 cm Chiralpak IC column,
[0915] [0915] Nf (1-Ciclooctil-2-0x0-2 - [(2-0x0espiro [indolino-3,4'-tetrahydropyran] -6-yl)> amino] Jetyl) -2- (2,2-difluoroethyl) pyrazole-3-carboxamide
[0916] [0916] Prepared from Intermediate 35 (46 mg, 0.12 mmol) and 2- (2,2-difluoroethyl) -pyrazole-3-carboxylic acid (25 mg, 0.14 mmol) according to Procedure A , and purified by sparkling column chromatography using a gradient of tert-butyl methyl ether in heptane (0 to 100%) followed by a MeOH gradient in tert-butyl methyl ether (0 to 20%), to give the title compound (20.6 mg, 29%) as a colorless solid. dx (500 MHz, CDCI3) 10.30 (br s, 1H), 8.14 - 8.07 (m, 2H), 8.01 (d, J7.2 Hz, 1H), 7.41 (d, J 2.0 Hz, 1H), 7.22 (d, J 8.0 Hz, 1H), 6.88 (d, J 2.0 Hz, 1H), 6.60 (dd, J 8.0, 1.8 Hz, 1H), 6.02 (tt, J 56.2, 4.5 Hz, 1H), 4.97 - 4.72 (m, 2H), 4.27 (t, J 9.0 Hz, 1H), 4.18 - 4.11 (m, 2H), 3.90 - 3.80 (m, 2H), 2.23 (d, J 9.0 Hz, 1H), 1.88 - 1.52 (m, 10H), 1.46 - 1.27 (m, 8H). uPLC-MS (method 1): MH + m / z 544.3, RT 3.38 minutes. EXAMPLE 27 The
[0917] [0917] N- (1-Cyclooctyl-2-0x0-2 - [(2-0xo0ospiro [indolino-3,4'-tetrahydropyran]) - 6-yl)> amino] ethyl) -3-ethyl-lsoxazole-4 -carboxamide
[0918] [0918] Prepared from Intermediate 35 (46 mg, 0.12 mmol) and 3- acid
[0919] [0919] N- (2 - [(4-Fluoro-2-0x0espiro [indolino-3,4'-tetrahydropyran] -6-yl) amino] -1- (4-methyl-cyclohexyl) -2-0x0ethyl) - 2-methylpyrazole | 1-3-carboxamide
[0920] [0920] 10% palladium on vegetable carbon (50% by weight, 5.3 mg, 2.47 umol) was added as a single portion to a stirred suspension of Intermediate 76 (73 mg, 0.1 mmol) in a mixture of THF (2.5 ml) and ethanol (2.5 ml). The reaction mixture was placed under an atmosphere of hydrogen gas and stirred at 20ºC for 18 h. The catalyst was removed by filtration on diatomaceous earth, rinse the filter cake with MeOH (2 x 15 mL). The solvent was concentrated in vacuo and the residue was dissolved in a mixture of THF (2.5 ml) and ethanol (2.5 ml). The solution was treated with 10% palladium on vegetable carbon (50% by weight, 52.52 mg, 0.02 mmol) as a single portion. The reaction mixture was placed under an atmosphere of hydrogen gas and stirred at 20ºC for 4 h. The catalyst was removed by filtration on diatomaceous earth, rinse the filter cake with MeOH (2 x 15 mL). The solvent was concentrated in vacuo. The resulting crude material was purified by preparative HPLC
[0921] [0921] N - (((18) -1-Cyclohexyl-2-0x0-2 - [(2-oxospiro [indolino-3,4'-tetrahydropyran] -6- yl)> amino] -ethyl) -2-propylpyrazole -3-carboxamide
[0922] [0922] Prepared from Intermediate 78 (50 mg, 0.14 mmol) and 2-propylpyrazole-3-carboxylic acid (25.9 mg, 0.17 mmol) according to Procedure A, and purified by preparative HPLC (method 20), to give the title compound (33.5 mg, 44%) as a colorless solid. dx (500 MHz, DMSO-ds) 10.39 (s, 1H), 10.17 (s, 1H), 8.48 (d, J 8.1 Hz, 1H), 7.48 (d, J 2 , 0 Hz, 1H), 7.44 (d, J 8.1 Hz, 1H), 7.39 (d, J 1.9 Hz, 1H), 7.12 (dd, J 8.2, 1, 9 Hz, 1H), 7.01 (d, J 2.0 Hz, 1H), 4.41 (t J 7.1 Hz, 2H), 4.38 (t, J 8.6 Hz, 1H), 4.06 - 3.97 (m, 2H), 3.89 - 3.75 (m, 2H), 1.92 - 1.78 (m, 2H), 1.78 - 1.66 (m, 6H ), 1.66 - 1.53 (m, 4H), 1.26 - 1.09 (m, 4H), 1.08 - 0.97 (m, 1H), 0.77 (t, J 7, 4 Hz, 3H). uPLC-MS (method 1): MH + m / z 494.3, RT 3.04 minutes. EXAMPLE 30
[0923] [0923] N - ((18) -1-Cyclohexyl-2-0x0-2 - [(2-oxospiro [indolino-3,4'-tetrahydropyran] -6- yl)> amino] -ethyl) -2-isopropylpyrazole -3-carboxamide
[0924] [0924] Prepared from Intermediate 78 (50 mg, 0.14 mmol) and 2-isopropyl-pyrazole-3-carboxylic acid (25.9 mg, 0.17 mmol) according to Procedure A, and purified by Preparative HPLC (method 20), to give the title compound (35.3 mg, 49%) as a colorless solid. ds (500 MHz, DMSO-ds) 10.39 (s, 1H), 10.17 (s, 1H), 8.45 (d, J 8.1 Hz, 1H), 7.50 (d, J 1 , 9 Hz, 1H), 7.44 (d, J 8.1 Hz, 1H), 7.40 (d, J 1.8 Hz, 1H), 7.12 (dd, J 8.2, 1, 9 Hz, 1H), 6.95 (d, J 2.0 Hz, 1H), 5.39 (hept, J 6.5 Hz, 1H), 4.36 (t, J 8.5 Hz, 1H) , 4.05 - 3.98 (m, 2H), 3.83 - 3.74 (m, 2H), 1.89 - 1.79 (m, 2H), 1.77 - 1.67 (m, 4H), 1.68 - 1.54 (m, 4H), 1.37 (d, J 6.6 Hz, 3H), 1.35 (d, J 6.6 Hz, 3H), 1.25 - 1.09 (m, 4H), 1.09 - 0.94 (m, 1H). uPLC-MS (method 1): MH + m / z 494.2, RT 3.05 minutes. EXAMPLE 31 O. Ho
[0925] [0925] —2-lsopropyl-NX (1S) -1- (4-methylcyclohexyl) -2-0x0-2 - [(2-0xo0spiro [1H-pyrrole [3,2-c] -pyridine-3,4 " -tetrahydropyran] -6-yl) amino] ethyl) pyrazol-3-carboxamide (trans isomer)
[0926] [0926] Trifluoroacetic acid (0.42 mL, 5.42 mmol) was added dropwise to a solution of Intermediate 79 (115 mg, 0.18 mmol) in DCM (1 mL) under an atmosphere of nitrogen and cooled to 0ºC. The reaction mixture was stirred at 20ºC for 18h. The volatiles were removed in vacuo and the residue was dissolved in acetonitrile (1 ml) and aqueous ammonium hydroxide solution (1 ml). The reaction mixture was stirred at 20ºC for 15 minutes, then the volatiles were removed in vacuo. The residue was diluted with water (3 ml) and the aqueous phase was extracted with DCM (3 x 10 ml). The combined organic extracts were passed through a hydrophobic frit and dried under vacuum. The resulting crude material was purified by preparative HPLC (method 20) to produce the title compound (50.8 mg, 54%) as a white solid. õn (500 MHz, DMSO-ds) 10.78 (s, 1H), 10.47 (s, 1H), 8.39 - 8.33 (m, 2H), 7.65 (s, 1H), 7 , 43 (d, J 1.9 Hz, 1H), 6.85 (d, J 1.9 Hz, 1H), 5.28 (h, J 6.5 Hz, 1H), 4.40 (t, J 8.3 Hz, 1H), 3.97 - 3.89 (m, 2H), 3.82 - 3.64 (m, 2H), 1.80 - 1.67 (m, 4H), 1, 64 - 1.45 (m, 5H), 1.28 (dd, J 14.3, 6.6 Hz, 6H), 1.24 - 1.10 (m, 2H), 1.00 (q, J 12.1, 11.6 Hz, 1H), 0.88 - 0.70 (m, 5H). uPLC-MS (method 1): MH + m / z 509.3, RT 2.72 minutes. EXAMPLE 32 o. 2 IT IS
[0927] [0927] (28) -2K [6- (Difluoromethyl) pyridazin-3-ylJamino) -2- (4-methylcyclohexyl) -N- (2-0x0- spiro [1H-pyrrole [3,2-c] pyridine- 3,4'-tetrahydropyran] -6-yl) acetamide (trans isomer)
[0928] [0928] Trifluoroacetic acid (0.27 mL, 3.45 mmol) was added dropwise to a solution of Intermediate 80 (113 mg, 0.06 mmol) in DCM (0.5 mL) under an atmosphere of nitrogen and cooled to 0ºC. The reaction mixture was stirred at 20ºC for 18 h. The volatiles were removed in vacuo and the residue was dissolved in acetonitrile (1 ml) and aqueous ammonium hydroxide solution (1 ml). The mixture was stirred at 20ºC for 15 minutes, then the volatiles were removed in vacuo. The residue was diluted with water (3 ml) and the aqueous phase extracted with DCM (3 x 10 ml). The combined organic extracts were passed through a hydrophobic frit and concentrated in vacuo. The resulting crude material was purified by preparative HPLC (method 10) to produce the title compound (0.6 mg, 2%) as a yellowish white gum. õn (500 MHz, CDCI3) 10.84 (s, 1H), 9.09 - 8.77 (m, 1H), 8.32 - 8.22 (m, 1H), 8.07 (s, 1H) , 7.36 - 7.29 (m, 1H), 6.92 - 6.83 (m, 1H), 6.80 - 6.48 (m, 2H), 4.81 - 4.70 (m, 1H), 4.16 - 4.09 (m, 2H), 3.91 - 3.75 (m, 2H), 2.02 - 1.93 (m, 2H), 1.91 - 1.84 ( m, 1H), 1.81 - 1.59 (m, 6H), 1.28 - 1.20 (m, 2H), 1.16 - 1.09 (m, 1H), 0.83 - 0, 76 (m, 5H). uPLC-MS (method 1): MH + m / z 501.2, RT 2.54 minutes. EXAMPLE 33
[0929] [0929] N- (1-Cyclooctyl-2-0x0-2 - [(2-0xo0spiro [1 H-pyrrolo [3,2-c] pyridine-3,4 "- tetrahydropyran] -6-yl) amino] Jetyl ) -2-methylpyrazole-3-carboxamide
[0930] [0930] To a solution of Intermediate 86 (0.20 g, 0.29 mmol) in DCM (5 mL) was added TFA (0.44 mL, 5.76 mmol) at 0 ° C. The reaction mixture was stirred at room temperature for 16 h, then concentrated in vacuo. The crude residue was dissolved in acetonitrile (3 ml) and aqueous ammonium hydroxide solution (25% in water, 3 ml) was added at 0ºC. The reaction mixture was stirred at room temperature for 3 h, then concentrated in vacuo. The crude residue was purified by column chromatography (5% methanolic ammonia in DCM), followed by preparative HPLC (method 8), to produce the title compound (0.023 g, 16%) as a white solid. õH (400 MHz, DMSO-ds) 1.34 - 1.73 (m, 16H), 1.77 - 1.89 (m, 2H), 2.15 - 2.18 (m, 1H), 3, 78 - 3.84 (m, 3H), 3.95 - 3.98 (m, 1H), 4.01 (s, 3H), 4.57 (t, J 8.31 Hz, 1H), 7, 01 (s, 1H), 7.47 (s, 1H), 7.71 (s, 1H), 8.41 (s, 1H), 8.45 (d, J 8.31 Hz, 1H), 10 , 63 (br s, 1H), 10.86 (br s, 1H). HPLC-MS (method 6): MH + m / z 495.0, RT 2.44 minutes. EXAMPLE 34 N. N, the
[0931] [0931] N- (1-Cyclooctyl-2-0x0-2 - [(2-o0xo0spiro [1H-pyrrolo [3,2-b] pyridine-3,4 "- tetrahydropyran] -6-yl) amino] ethyl) -2-methylpyrazole-3-carboxamide
[0932] [0932] To a solution of Intermediate 92 (0.16 g, 0.26 mmol) in DCM (5 mL) was added TFA (0.78 mL, 10.2 mmol) at 0 ° C. The reaction mixture was stirred at room temperature for 16 h, then concentrated in vacuo. Acetonitrile (4 mL) and aqueous ammonium hydroxide solution (25% in water, 4 mL) were added at 0ºC. The reaction mixture was stirred at room temperature for 3 h, then concentrated in vacuo. The crude residue was purified by column chromatography (6 to 8% MeOH in DCM) and preparative HPLC (method 8) to produce the title compound (0.021 g, 16%) as a yellowish white solid. õn (400 MHz, DMSO-ds) 1.36 - 1.53 (m, 8H), 1.54 - 1.69 (m, 7H), 1.75 - 1.79 (m, 3H), 2, 15 - 2.17 (m, 1H), 3.84 - 3.94 (m, 2H), 4.02 (s, 3H), 4.05 - 4.10 (m, 2H), 4.45 ( t, J 8.56 Hz, 1H), 7.05 (s, 1H), 7.45 (s, 1H), 7.74 (s, 1H), 8.25 (s, 1H), 8.60 (d, J 8.31 Hz, 1H), 10.49 (br s, 1H), 10.58 (br s, 1H). HPLC-MS (method 6): MH + m / z 495.0, RT 2.40 minutes. EXAMPLE 35
[0933] [0933] N- (1-Cyclooctyl-2-0x0-2 - [(6-0x0spiro [7 H-pyrrolo [2,3-d] pyrimidine-5.4 "- tetrahydro-pyran] -2-1) amino ] Jetyl) -2-methylpyrazole-3-carboxamide
[0934] [0934] To a solution of Intermediate 98 (0.25 g, 0.40 mmol) in DCM (5 mL) was added TFA (1.19 mL, 16.0 mmol) at 0 ° C. The reaction mixture was stirred at room temperature for 16 h, then concentrated in vacuo. The residue was diluted with acetonitrile (10 ml) and aqueous ammonium hydroxide solution (10 ml) at 0ºC. The reaction mixture was stirred at room temperature for 3 h, then concentrated in vacuo. The crude residue was purified by column chromatography (0 to 100% EtOAc in hexanes) and preparative HPLC (method 8) to produce the title compound (0.03 g, 8%) as a white solid. õx (400 MHz, DMSO-ds) 1.36 - 1.51 (m, 8H), 1.55 (d, J 10.27 Hz, 2H), 1.61 - 1.64 (m, 6H), 1.80 - 1.93 (m, 2H), 2.15 - 2.17 (m, 1H), 3.79 (t, J 9.78 Hz, 2H), 3.92 - 3.99 (m , 2H), 4.02 (s, 3H), 4.61 - 4.64 (m, 1H), 7.01 (d, J 1.47 Hz, 1H), 7.46 (d, J 1, 47 Hz, 1H), 8.42 (d, J 8.80 Hz, 1H), 8.66 (s, 1H), 10.66 (s, 1H), 11.52 (br s, 1H). HPLC-MS (method 6): MH + m / z 496.0, RT 3.49 minutes. EXAMPLE 36 The
[0935] [0935] N- (1-Cyclooctyl-2-0x0-2 - [(2-oxoospospiro [indolino-3,4'-tetrahydropyran] -6-yl)> amino] Jetyl) -3-methyl-isoxazol-4- carboxamide
[0936] [0936] Prepared from Intermediate 35 and 3-methyl-4-isoxazolcarboxylic acid according to Procedure A to give the title compound (18%) as a white solid. õH (400 MHz, DMSO-ds) 10.40 (s, 1H), 10.25 (s, 1H), 9.44 (s, 1H), 8.51 (d, J 8.5 Hz, 1H) , 7.44 (d, J 8.1 Hz, 1H), 7.39 (d, J 1.9 Hz, 1H), 7.13 (dd, J 8.1, 2.0 Hz, 1H), 4.46 (t, J 8.7 Hz, 1H), 4.01 (ddd, J 11.1, 7.1, 3.7 Hz, 2H), 3.80 (ddd, J 11.1, 7 , 1.3.8 Hz, 2H), 2.38 (s, 3H), 2.09 (br s, 1H), 1.79 - 1.36 (m, 18H). HPLC-MS (method 21): MH + m / z 495, RT 2.17 minutes. EXAMPLE 37
[0937] [0937] NX (18) -1-Cyclooctyl-2-0x0-2 - [(2-oxospiro [indolino-3,4'-tetrahydropyran] -6- i) amino] -ethyl) -3-methylisoxazole-4- carboxamide
[0938] [0938] Example 36 was separated by the chiral preparative HPLC using an Agilent 1100, DAD system on a Lux Cellulose-1 21.2 x 250 mm, 5 µm column, eluting with 100% MeOH (+ 0.1% NH. OH) and a flow rate of 10 mL / min, to give the title compound (2 mg, 2%) as a white solid. HPLC-MS (Method 21): MH + m / z 495, RT 2.11 minutes. Chiral HPLC in a Lux Cellulose-1 4.6 x 150 mm, 3 µm column, eluting with 100% MeOH + 0.1% NH.4OH, 1 mL / min, 40ºC, RT 2.20 minutes (100% ). EXAMPLE 38
[0939] [0939] NX (18S) -1-Ciclohexil-2-0x0-2 - [(2-o0xo0espiro [indolino-3,4 "-tetrahydropyran]) - 6- i)> amino] Jetyl) -3-methylisoxazol-4 -carboxamide
[0940] [0940] Prepared from Intermediate 78 and 3-methyl-4-isoxazolcarboxylic acid according to Procedure A to give the title compound (216 mg, 79%) as a white solid. õH (300 MHz, DMSO-ds) 10.40 (s, 1H), 10.20 (s, 1H), 9.44 (s, 1H), 8.45 (d, J 8.2 Hz, 1H) , 7.44 (d, J 8.1 Hz, 1H), 7.39 (d, J 1.9 Hz, 1H), 7.12 (dd, J 8.1, 2.0 Hz, 1H), 4.40 (t, J 8.4 Hz, 1H), 4.01 (ddd, J 10.9, 7.0, 3.6 Hz, 2H), 3.80 (ddd, J 11.1, 6 , 9, 3.8 Hz, 2H), 2.37 (s, 3H), 1.87 - 1.51 (m, 10H), 1.47 (m, 5H). HPLC-MS
[0941] [0941] 2-methyl-N- (1- (4-methylcyclohexylidene) -2-0x0-2 - [(2-oxospiro [indolino-3,4 "- tetrahydropyran] -6-yl) amino] Jetyl) pyrazole- 3-carboxamide (isomer 1)
[0942] [0942] Intermediate 122 was separated by chiral preparative HPLC using an Agilent 1100, DAD system on a Lux Cellulose-1 250 mm x 21.2 mm, 3 µm column, eluting with 12% MeOH (+ 0.1% NHa4OH) and a flow rate of 100 mL / min, to give the title compound as a white solid. õn (400 MHz, DMSO-ds) 10.37 (s, 1H), 10.07 (s, 1H), 9.71 (s, 1H), 7.48 (m, 2H), 7.42 (d , J 8.2 Hz, 1H), 7.16 (d, J 8.0 Hz, 1H), 7.08 (s, 1H), 4.13 - 3.93 (m, 5H), 3.81 (ddd, J 11.1, 7.2, 3.8 Hz, 2H), 2.80 (d, J 13.9 Hz, 1H), 2.62 (d, J 13.6 Hz, 1H), 2.06 (m, 1H), 1.89 (m, 1H), 1.86 - 1.54 (m, 2H), 1.28 - 1.05 (m, 5H), 0.93 - 0, 81 (m 5H). HPLC-MS (Method 21): MH + m / z 478, RT 1.79 minutes. Chiral SFC (Method 35): RT 4.5 minutes. EXAMPLE 40 o. = N P O
[0943] [0943] N- (1-Cyclooctyl-2 - [(1-methyl-2-o0xo0spiro [indolino-3,4'-tetrahydropyran] -6- iN)> amino] -2-0x0ethyl) -3-ethylisoxazole-4 -carboxamide
[0944] [0944] Prepared from Intermediate 103 (50 mg, 0.14 mmol) and 3-ethylisoxazole-4-carboxylic acid (14.2 mg, 0.10 mmol) according to Procedure A, and purified by preparative HPLC (method 22), to give the title compound (7 mg, 13%) as a yellowish white solid. dx (400 MHz, DMSO-ds) 10.32 (s, 1H), 9.42 (s, 1H), 8.50 (d, J 8.6 Hz, 1H), 7.53 - 7.39 ( m, 2H), 7.26 (dd, J 8.1, 1.9 Hz, 1H), 4.49 (t, J 8.6 Hz, 1H), 4.04 (ddd, J 11.3, 7.3, 3.8 Hz, 2H), 3.82 (ddd, J 11.1, 6.5, 4.0 Hz, 2H), 3.10 (s, 3H), 2.92 - 2, 77 (m, 2H), 2.15 - 2.03 (m, 1H), 1.84 - 1.26 (m, 18H), 1.18 (t, J 7.5 Hz, 3H). HPLC-MS (method 6): MH + m / z 523, RT 2.33 minutes. EXAMPLE 41 Oo. Are HUH
[0945] [0945] NX ((18S) -1-cyclooctyl-2-0x0-2 - [(2-0x0piro [indolino-3,4'-tetrahydropyran] -6- i)> amino] Jetyl) tert-butyl carbamate
[0946] [0946] Intermediate 34 (500 mg) was purified by the chiral preparative SFC (method 15). and second elution peak gave the title compound (133 mg, 27%) as a yellowish white solid. ôõH (400 MHz, DMSO-ds) 10.38 (s, 1H), 9.99 (s, 1H), 7.43 (d, J 8.1 Hz, 1H), 7.37 (d, J 1 , 8 Hz, 1H), 7.08 (dd, J 8.1, 2.0 Hz, 1H), 6.89 (d, J 8.8 Hz, 1H), 4.01 (ddd, J 11, 1, 7.1, 3.7 Hz, 2H), 3.94 (t, J 8.3 Hz, 1H), 3.81 (ddd, J 11.1.7.1, 3.8 Hz, 2H ), 1.94 (s, 1H), 1.79 - 1.69 (m, 2H), 1.68 - 1.25 (m, 25H). HPLC-MS (method 6): [IM + 2H-Bu] + m / 2 430, RT 2.40 minutes. uPLC-MS (method 23): [M + 2H-'Bu] + m / z 430, RT 2.49 minutes. EXAMPLE 42 (PROCEDURE B) o. SOS N EO
[0947] [0947] - 2-Cyclooctyl-N- (2-oxospiro [indolino-3,4'-tetrahydropyran] -6-yl) -2- (pyridazin-3-yl-amino) - acetamide
[0948] [0948] Intermediate 35 (20 mg, 0.052 mmol), 3-bromopyridazine (8.25 mg, 0.052 mmol), tBuBrettPhos Pd-G3 (4.52 mg, 0.0052 mmol) and sodium tert-butoxide (10 mg, 0.10 mmol) were added to a sealed flask and dissolved in 1,4-dioxane (0.7 ml) / DMSO (0.07 ml). The reaction mixture was stirred at 105ºC for 18 h, then filtered through celite and concentrated in vacuo. The resulting brown oil was purified by preparative HPLC (method 24) to produce, after lyophilization, the title compound (2 mg, 8%) as a yellowish white solid. x (400 MHz, DMSO-ds) 10.37 (s, 1H), 10.23 (s, 1H), 8.42 (dd, J 4.4, 1.4 Hz, 1H), 7.46 - 7.36 (m, 2H), 7.23 (dd, J 9.0, 4.4 Hz, 1H), 7.11 (dd, J 8.2, 2.0 Hz, 1H), 6.99 (dt, J 8.7, 1.6 Hz, 2H), 4.66 (t, J 8.1 Hz, 1H), 4.01 (ddd, J 11.1, 7.0, 3.8 Hz , 2H), 3.80 (ddd, J 11.2, 7.1, 3.8 Hz, 2H), 1.81 - 1.34 (m, 19H). HPLC-MS (method 21): [M - H] + m / z 463, RT 1.77 minutes.
[0949] [0949] EXAMPLE 43 O. AND
[0950] [0950] (28) -2-Cyclohexyl-2 - [(6-ethylpyridazin-3-yl) amino] -N- (2-oxospiro [indolino-3,4 '"- tetrahydropyran] -6-yl) acetamide
[0951] [0951] Prepared from Intermediate 78 (50 mg, 0.14 mmol) and 3-bromo-6-ethyl-pyridazine hydrobromide (31.2 mg, 0.11 mmol) according to Procedure B, and purified by preparative HPLC (method 22), to give the title compound (6 mg, 12%) as a yellowish white solid. dn (300 MHz, DMSO-ds) 10.38 (s, 1H), 10.16 (s, 1H), 7.46 - 7.36 (m, 2H), 7.21 - 7.07 (m, 2H), 6.95 (d, J 9.1 Hz, 1H), 6.79 (d, J 8.3 Hz, 1H), 4.55 (t, J 7.8 Hz, 1H), 4, 01 (ddd, J 11.1, 7.0, 3.7 Hz, 2H), 3.80 (td, JU 7.1, 3.5 Hz, 2H), 2.67 (q, J 7.6 Hz, 2H), 1.87 - 1.51 (m, 9H), 1.30 - 1.01 (m, 9H). HPLC-MS (method 6): MH + m / z 464, RT 1.80 minutes. EXAMPLE 44
[0952] [0952] (28S) -2-Cyclohexyl-2 - [(6-isopropylpyridazin-3-yl) amino] -N- (2-oxospiro [indolino-3,4'-tetrahydro-pyran] -6-yl) acetamide
[0953] [0953] Prepared from Intermediate 78 (30 mg, 0.084 mmol) and 3-bromo-6-isopropyl-pyridazine (16.9 mg, 0.084 mmol) according to Procedure B, and purified by preparative HPLC (method 25 ), to give the title compound (2 mg, 5%) as a yellowish white solid. õx (600 MHz, DMSO-ds) 10.38 (s, 1H), 10.14 (s, 1H), 7.45 - 7.38 (m, 2H), 7.20 (d, J 9.2 Hz, 1H), 7.12 (dd, J 8.2, 2.0 Hz, 1H), 6.96 (d, J 9.2 Hz, 1H), 6.78 (d, J 8.3 Hz , 1H), 4.54 (t, J 7.9 Hz, 1H), 4.01 (ddd, J 11.2, 7.2, 3.7 Hz, 2H), 3.80 (ddd, J 11 , 3, 7.2, 3.7 Hz, 2H), 2.98 (m, 1H), 1.87 (m, 2H), 1.77 - 1.69 (m, 3H), 1.68 - 1.55 (s, 3H), 1.37 (m, 1H), 1.23 - 1.10 (m, 12H). HPLC-MS (method 6): MH + m / z 478, RT 1.94 min. EXAMPLE 45 o. N = | IT'S THE
[0954] [0954] (2S) -2- (Cinnolin-3-ylamino) -2-cyclohexyl-N- (2-oxospiro [indolino-3,4 "- tetrahydropyran] -6-yl) - acetamide
[0955] [0955] Prepared from Intermediate 78 (30 mg, 0.084 mmol) and 3-bromokinoline (14.62 mg, 0.070 mmol) according to Procedure B, and purified by preparative HPLC (method 25), to give the compound of the title (1.5 mg, 4%) as a yellowish white solid. ôõs (300 MHz, DMSO-ds) 10.38 (s, 1H), 10.25 (s, 1H),
[0956] [0956] 2 - [(6-Ethylpyridazin-3-yl) amino] -2- (4-methylcyclohexyl) -N- (2-oxospiro [indolino-3,4-tetrahydro-pyran] -6-yl) acetamide
[0957] [0957] Prepared from Intermediate 105 (30 mg, 0.084 mmol) and 3-bromo-6-ethyl-pyridazine hydrobromide (38 mg, 0.135 mmol) according to Procedure B, and purified by preparative HPLC (method 25 ), to give the title compound (3 mg, 5%) as a yellowish white solid. ox (400 MHz, DMSO-ds) 10.38 (s, 1H), 10.21 (m, 1H), 7.46 - 7.30 (m, 2H), 7.24 - 7.02 (m, 2H), 6.94 (m, 1H), 6.81 (m, 1H), 4.84 - 4.42 (m, 1H), 4.01 (ddd, J 11.1, 7.1, 3 , 7 Hz, 2H), 3.79 (td, J 7.4, 3.7 Hz, 2H), 2.67 (m, 3H), 1.89 (m, 1H), 1.83 - 1, 34 (m, 7H), 1.17 (m, 6H), 1.03 - 0.73 (m, 5H). HPLC-MS (method 6): MH + m / z 478, RT 1.97 minutes.
[0958] [0958] - EXAMPLE 47 o. healthy = N
[0959] [0959] —2-Eti-NX (18S) -1- (4-methylcyclohexyl) -2-0x0-2 - [(2-0x0ospiro [indoline-3,4 "- tetrahydro-pyran] -6-yl) amino ] Jetyl) pyrazol-3-carboxamide (trans isomer)
[0960] [0960] Prepared from Intermediate 50 (30 mg, 0.084 mmol) and 1-ethyl-1H-pyrazole-S-carboxylic acid (49 mg, 0.35 mmol) according to Procedure A, and purified by chromatography on sparkling column using a gradient of 0 to 100% ethyl acetate in hexanes, to give the title compound (81 mg, 47%) as a yellowish white solid. õ1 (400 MHz, DMSO-ds) 10.40 (s, 1H), 10.18 (s, 1H), 8.50 (d, J 8.1 Hz, 1H), 7.59 - 7.20 ( m, 3H), 7.12 (dd, J 8.2, 2.0 Hz, 1H), 7.02 (d, 2.1 Hz, 1H), 4.46 (q, J 7.2 Hz, 2H), 4.34 (t, J 8.5 Hz, 1H), 4.13 - 3.89 (m, 2H), 3.89 - 3.66 (m, 2H), 1.98 - 1, 42 (m, 9H), 1.42 - 1.12 (m, 5H), 0.86 (d, J 6.4 Hz, 6H). HPLC-MS (method 6): MH + m / z 494, RT 2.05 minutes. uPLC-MS (method 23): MH + m / z 494, RT 1.62 minutes. [a] 2% = -4.30º (c 10.0, methanol). EXAMPLE 48 O. H SE
[0961] [0961] 3-Ethyl-N - ((1S) -1- (4-methylcyclohexyl) -2-0x0-2 - [(2-0xo0ospiro [indolino-3,4 "- tetrahydropyran] -6-yl) amino] ethyl <isoxazol-4-carboxamide (trans isomer)
[0962] [0962] Prepared from Intermediate 50 (52 mg, 0.14 mmol) and 3-ethylisoxazole-4-carboxylic acid (19.8 mg, 0.14 mmol) according to Procedure A, and purified by chromatography on sparkling column using a gradient of O to 100% ethyl acetate in hexanes, to give the title compound (51 mg, 74%) as a yellowish white solid. õx (400 MHz, DMSO-ds) 10.40 (s, 1H), 10.18 (s, 1H), 9.41 (s, 1H), 8.47 (d, J 8.1 Hz, 1H) , 7.56 - 7.25 (m, 2H), 7.11 (dd, J 8.2, 2.0 Hz, 1H), 4.37 (t, J 8.3 Hz, 1H), 4, 01 (ddd, J 10.9, 6.9, 3.6 Hz, 2H), 3.89 - 3.70 (m, 2H), 2.84 (q, J7.5 Hz, 2H), 1, 96 - 1.38 (m, 9H), 1.17 (m, 5H), 0.86 (m, 6H). HPLC-MS (method 6): MH + m / z 495, RT 2.10 minutes. uPLC-MS (method 23): MH + m / z 495, RT 1.67 minutes. [a] 2% = -0.60º (c 10.0, methanol). EXAMPLE 49 THE.
[0963] [0963] 3-methyl-N - ((18S) -1- (4-methylcyclohexyl) -2-0x0-2 - [(2-oxo0ospiro [indolino-3,4 "- tetrahydro-pyran] -6-yl) amino] Jetyl) Nisoxazo | -4-carboxamide (trans isomer)
[0964] [0964] Prepared from Intermediate 50 (52 mg, 0.14 mmol) acid and 3-methylisoxazol-4-carboxylic acid (15.4 mg, 0.121 mmol) according to Procedure A, and purified by sparkling column chromatography using a gradient of 0 to 100% ethyl acetate in hexanes, to give the title compound (51 mg, 88%) as a yellowish white solid. ds (400 MHz, DMSO-ds) 10.40 (s, 1H), 10.19 (s, 1H), 9.44 (d, J 0.7 Hz, 1H), 8.46 (d, J 8 , 2 Hz, 1H), 7.54 - 7.25 (m, 2H), 7.12 (dd, J 8.2, 2.0 Hz, 1H), 4.38 (t, J 8.4 Hz , 1H), 4.01 (ddd, J 11.1, 7.1, 3.7 Hz, 2H), 3.80 (td, J 7.3, 3.6 Hz, 2H), 2.37 ( s, 3H), 1.94 - 1.42 (m, 9H), 1.42 - 0.93 (m, 3H), 0.86 (d, J 6.5 Hz, 5H). HPLC-MS (method 6): MH + m / z 481, RT 1.98 minutes. uPLC-MS (method 23): MH + m / z 481, RT 1.58 minutes. [The] = + 5.65º (c 10.0, methanol).
[0965] [0965] EXAMPLE 50 (PROCEDURE C) O. dr Ss E
[0966] [0966] 3-Ethyl-NX (18) -1- (4-methylcyclohexyl) -2-0x0-2 - [(2-o0xo0ospiro [1 H-pyrrolo [3,2-c] - pyridine-3,4 ' -tetrahydropyran] -6-yl) amino] Jetyl) isoxazol-4-carboxamide (trans isomer)
[0967] [0967] —A solution of Intermediate 108 (2.70 g, 4.32 mmol) in DCM (20 mL) at 0 ° C was added to the drops trifluoroacetic acid (5 mL, 66.13 mmol). The mixture was stirred at 20ºC for 1.5 h. Another portion of trifluoroacetic acid (5 mL, 66.13 mmol) was added at 0 ° C. The reaction mixture was stirred at 20 ° C for an additional 18 h, then concentrated in vacuo. The residue was dissolved in a mixture of acetonitrile (2 mL) and aqueous ammonium hydroxide solution (28% v / v, 2mL). The mixture was stirred at 20ºC for 1 h. The residue was concentrated in vacuo, then partitioned between DCM and water. The aqueous phase was basified with 2 M aqueous NaOH solution, then extracted with DCM: MeOH (10: 1). The organic layer was concentrated in vacuo. The crude residue was purified by sparkling column chromatography, using a gradient of O to 100% DCM in ethyl acetate, to produce, after lyophilization, the title compound (1.36 g, 64%) as a white solid. . õ1 (300 MHz, DMSO-ds) 10.86 (s, 1H), 10.57 (s, 1H), 9.40 (s, 1H), 8.45 - 8.36 (m, 2H), 7 , 71 (s, 1H), 4.52 (t, J 8.0 Hz, 1H), 4.05 - 3.94 (m, 2H), 3.84 - 3.75 (m, 2H), 2 , 83 (q, J 7.5 Hz, 2H), 1.80 - 1.57 (m, 10H), 1.32 - 1.06 (m, 4H), 0.94 - 0.77 (m, 6H). HPLC-MS (method 6): MH + m / z 496, RT 2.17 minutes. uPLC-MS (method 23): MH + m / z 496, RT 1.56 minutes. EXAMPLE 51 Í (Sao ç NN NO FO
[0968] [0968] 2-Ethyl-NX (18) -1- (4-methylcyclohexyl) -2-0x0-2 - [(2-o0xo0espiro [1 H-pyrrolo [3,2-c] - pyridine-3,4 ' -tetrahydropyran] -6-yl) amino] Jetyl) pyrazol-3-carboxamide (trans isomer)
[0969] [0969] Prepared from Intermediate 109 (2.73 g, 4.36 mmol) according to Procedure C, and purified by sparkling column chromatography using a gradient of O to 100% ethyl acetate in hexanes, to give the title compound (1.6 g, 74%) as a white solid. õx (400 MHz, DMSO-ds) 10.87 (s, 1H), 10.57 (s, 1H), 8.49 - 8.39 (m, 2H), 7.72 (s, 1H), 7 , 49 (d, J 2.0 Hz, 1H), 6.99 (d, J 2.1 Hz, 1H), 4.53 - 4.40 (m, 3H), 4.06 - 3.94 ( m, 2H), 3.88 - 3.76 (m, 2H), 1.88 - 1.50 (m, 7H), 1.33 - 1.17 (m, 6H), 1.14 - 0, 99 (m, 1H), 0.95 - 0.78 (m, 6H). HPLC-MS (method 6): MH + m / z 495, RT 1.92 minutes. uPLC-MS (method A): MH + m / z 495, RT 1.51 minutes. [The] = -13.50º (c 10.0, methanol). EXAMPLE 52 (PROCEDURE D) O. DO, Ant Ss
[0970] [0970] (28) -2-Cyclohexyl-2 - ([methyl (tetrahydropyran-4-yl) carbamoylJamino) -N- (2-oxospiro-findolino-3,4 "-tetrahydropyran]) - 6-yl) acetamide
[0971] [0971] Intermediate 78 (30 mg, 0.084 mmol) and N-methyl-N- (oxan-4-yl) carbamoyl chloride (18 mg, 0.097 mmol) were dissolved in DCM (1 mL) and triethylamine (14 uL , 10.24 mg, 0.1007 mmol) was added. The reaction mixture was stirred at 20ºC for 18 h. More N-methyl-N- (oxan-4-yl) carbamoyl chloride (18 mg, 0.097 mmol) and triethylamine (14 µl, 10.24 mg, 0.1007 mmol) were added. The reaction mixture was stirred at 20 ° C for an additional 5 h, then concentrated in vacuo. The resulting crude clear oil was purified by sparkling column chromatography, using a gradient of O to 100% ethyl acetate in hexanes, to produce, after lyophilization, the title compound (15 mg, 36%) as a white solid. . õn (400 MHz, DMSO-ds) 10.38 (s, 1H), 10.01 (s, 1H), 7.46 - 7.36 (m, 2H), 7.09 (dd, J 8.1 , 1.9 Hz, 1H), 6.05 (d, J 8.3 Hz, 1H), 4.22 - 3.96 (m, 4H), 3.88 (dd, J 10.6, 5, 3 Hz, 2H), 3.80 (ddd, J 11.1, 7.0, 3.7 Hz, 2H), 3.41-3.31 (m, 2H, obscured by the water spike at 3.31 ppm), 2.72 (s, 3H), 1.86 - 1.49 (m, 12H), 1.46 - 1.34 (m, 2H), 1.24 - 1.06 (m, 4H) , 1.02 - 0.86 (m, 1H). HPLC-MS (method 6): MH + m / z 499, RT 1.83 minutes. EXAMPLE 53 ns are
[0972] [0972] 3-Cyclopropyl-N - ((1S) -1- (4-methylcyclohexyl) -2-0x0-2 - [(2-0xo0ospiro [1H-
[0973] [0973] Prepared from Intermediate 110 (100 mg, 0.16 mmol) according to Procedure C, and purified by sparkling column chromatography using a gradient of O to 100% ethyl acetate in hexanes, to give the title compound (56 mg, 76% yield) as a white solid. õs (400 MHz, DMSO-ds) 10.87 (s, 1H), 10.59 (s, 1H), 9.37 (s, 1H), 8.44 - 8.35 (m, 2H), 7 , 72 (s, 1H), 4.54 (t, J 8.0 Hz, 1H), 3.99 (dt, J 11.7, 4.8 Hz, 2H), 3.88 - 3.76 ( m, 2H), 2.43 (tt, J 8.4, 5.1 Hz, 1H), 1.88 - 1.52 (m, 9H), 1.36 - 1.14 (m, 2H), 1.14 - 0.9 (m, 10H). HPLC-MS (method 6): MH + m / z 508, RT 2.29 minutes.
[0974] [0974] N - ((18) -1- (4-methylcyclohexyl) -2-0x0-2 - [(2-0x0piro [1H-pyrrolo [3,2-c] - pyridine-3,4'-tetrahydro- pyran] -6-yl) amino] cyclobutyl ethylkcarbamate (trans isomer)
[0975] [0975] Prepared from Intermediate 111 (60 mg, 0.10 mmol) according to Procedure C, and purified by sparkling column chromatography using a gradient of O to 100% ethyl acetate in hexanes followed by preparative HPLC (method 22), to give the title compound (11 mg, 23%) as a white solid. dn (400 MHz, DMSO-ds) 10.87 (s, 1H), 10.35 (s, 1H), 8.39 (s, 1H), 7.69 (s, 1H), 7.27 (d , J 8.4 Hz, 1H), 4.80 (p, J 7.5 Hz, 1H), 4.12 - 3.94 (m, 3H), 3.81 (dd, J 11.5, 8 , 6 Hz, 2H), 2.26 - 2.16 (m, 2H), 2.07 - 1.86 (m, 2H), 1.85 - 1.72 (m, 2H), 1.66 - 1.38 (m, 7H), 1.30 - 0.93 (m, 4H), 0.93 - 0.58 (m, 6H). HPLC-MS (method 6): MH + m / z 471, RT 2.33 minutes.
[0976] [0976] NX (18) -1- (4-methylcyclohexyl) -2-0x0-2 - [(2-o0xo0ospiro [1H-pyrrole [3,2-clpyridine-3,4 "-tetrahydro-pyran) -6- il) amino] Jetyl) -2- (3,3,3-trifluoropropyl) pyrazole | -3-carboxamide (trans isomer)
[0977] [0977] Prepared from Intermediate 112 (50 mg, 0.072 mmol) according to Procedure C, and purified by sparkling column chromatography using a gradient of O to 100% ethyl acetate in hexanes, to give the compound of title (21 mg, 52%) as a white solid. õH (400 MHz, DMSO-ds) 10.87 (s, 1H), 10.59 (s, 1H), 8.54 (d, J 8.1 Hz, 1H), 8.44 - 8.39 ( m, 1H), 7.72 (d, J 0.7 Hz, 1H), 7.56 (d, J 2.0 Hz, 1H), 7.10 (d, J 2.1 Hz, 1H), 4.80 - 4.63 (m, 2H), 4.52 (t, J 8.3 Hz, 1H), 3.99 (dt, J 10.2, 4.6 Hz, 2H), 3.87 - 3.77 (m, 2H), 2.87 - 2.70 (m, 2H), 1.88 - 1.74 (m, 3H), 1.74 - 1.40 (m, 4H), 1 , 36 - 1.06 (m, 3H), 1.04 - 0.91 (m, 1H), 0.90 - 0.75 (m, 6H). HPLC-MS (method 6): MH + m / z 563, RT 2.17 minutes. EXAMPLE 56 O. ns S So Ó 1 O-N
[0978] [0978] 3-Cyclobutyl-N - ((1S) -1- (4-methylcyclohexyl) -2-0x0-2 - [(2-oxospiro [1H-pyrrole [3,2-c] -pyridine-3,4 "-tetrahydropyran] -6-yl) amino] ethylNisoxazol-4-carboxamide (trans isomer)
[0979] [0979] Prepared from Intermediate 113 (45 mg, 0.069 mmol) according to Procedure C, and purified by sparkling column chromatography using a gradient of O to 100% ethyl acetate in hexanes followed by O to 20% of methanol in ethyl acetate, to give the title compound (16 mg, 44%) as a white solid. õH (400 MHz, DMSO-ds) 10.86 (s, 1H), 10.57 (s, 1H), 9.39 (s, 1H), 8.41 (s, 1H), 8.35 (d , J 8.0 Hz, 1H), 7.71 (s, 1H), 4.51 (t, J 8.1 Hz, 1H), 4.03 - 3.94 (m, 2H), 3.91 - 3.77 (m, 3H), 2.34 - 2.14 (m, 4H), 1.98 - 1.91 (m, 1H), 1.89 - 1.76 (m, 4H), 1 .74 - 1.48 (m, 5H), 1.33 - 1.23 (m, 2H), 1.11 - 0.98 (m, 1H), 0.93 - 0.76 (m, 6H) . HPLC-MS (method 6): MH + m / z 522, RT 2.19 minutes. EXAMPLE 57 o. * NNN o
[0980] [0980] Nf (1-Cyclooctyl-2-0x0-2 - [(2-o0xo0spiro [1H-pyrrolo [2,3-b] pyridine-3,4 "- tetrahydropyran] -6-yl) amino] ethyl) - 2-methylpyrazole-3-carboxamide
[0981] [0981] To a solution of Intermediate 118 (0.23 g, 0.36 mmol) in DCM (5 mL) was added TFA (0.55 mL, 7.20 mmol) at 0 ° C. The reaction mixture was stirred at room temperature for 16 h, then concentrated in vacuo. Acetonitrile (3 ml) and NHa4OH (25% solution in H2O, 3 ml) were added at 0ºC. The reaction mixture was stirred at room temperature for 3 h, then concentrated in vacuo. The crude residue was purified by column chromatography (3 to 4% MeOH in DCM) to produce the title compound (0.042 g, 22%) as a yellowish white solid. õn (400 MHz, DMSO-ds) 1.34 - 1.70 (m, 16H), 1.77 - 1.87 (m, 2H), 2.14 - 2.17 (m, 1H), 3, 80 (t, J 8.41 Hz, 2H), 3.93 - 4.00 (m, 2H), 4.02 (s, 3H), 4.59 (t, J 8.41 Hz, 1H), 7.02 (s, 1H), 7.46 (s, 1H), 7.69 (d, J 8.03 Hz, 1H), 7.94 (d, J 8.03 Hz, 1H), 8, 45 (d, J 8.53 Hz, 1H), 10.49 (s, 1H), 11.01 (br s, 1H). HPLC-MS (method 6): MH + m / z 495.0, RT 2.65 minutes. EXAMPLE 58 Cc o À
[0982] [0982] N- (2 - [(5-Chloro-2-oxo-spiro [indolino-3,4 "-tetrahydropyran] -6-yl) amino] -1- cyclooctyl-2-0x0ethyl) -2-methylpyrazole-3- carboxamide
[0983] [0983] NCS (36 mg, 0.27 mmol) was added to the portions to a solution of Example 3 (45 mg, 0.09 mmol) in acetic acid (2 mL) at 20 ° C. The reaction mixture was stirred at 20 ° C for 10 minutes, then heated to 70 ° C for 10 minutes, then concentrated in vacuo. The residue was diluted with ethyl acetate (50 ml), washed with saturated aqueous sodium bicarbonate solution and brine, then dried over sodium sulfate. The organic layers were concentrated in vacuo. The residue was purified by preparative HPLC (method 9) to produce the title compound (4.5 mg, 9%) as a yellowish white powder. õx (500 MHz, CDCl3) 10.44 (s, 1H), 8.41 (s, 1H), 8.40 (s, 1H), 7.93 (d, J 7.4 Hz, 1H), 7 , 38 (d, J] 2.1 Hz, 1H), 7.37 (s, 1H), 6.86 (d, J 2.1 Hz, 1H), 4.45 - 4.37 (m, 1H ), 4.27 - 4.18 (m, 2H), 4.13 (s, 3H), 3.95 - 3.85 (m, 2H), 2.35 - 2.23 (m, 1H), 1.92 - 1.82 (m, 3H), 1.82 - 1.49 (m, 15H). uPLC-MS (method 2) MH + m / z 528 and 530, RT 3.56 minutes. EXAMPLE 59 O o
[0984] [0984] N- (1-Cyclooctyl-2-0x0-2 - [(2-0xo0ospiro [indolino-3,4'-tetrahydropyran]) - 6-yl)> amino] Jetyl) -2-oxoospiro [indolino-3 , 4'-tetrahydropyran] -6-carboxamide
[0985] [0985] Prepared from Intermediate 121 (70 mg, 0.094 mmol) according to Procedure C, and purified by preparative HPLC (method 11), to give the title compound (10.5 mg, 18%) as a white solid. onx (500 MHz, DMSO-ds) 10.57 (s, 1H), 10.39 (s, 1H), 10.19 (s, 1H), 8.50 (d, J 8.6 Hz, 1H) , 7.60 (d, JU 7.8 Hz, 1H), 7.54 (dd, JU 7.8, 1.5 Hz, 1H), 7.43 (d, J 8.2 Hz, 1H), 7.39 (d, J 1.9 Hz, 1H), 7.33 (d, J 1.4 Hz, 1H), 7.12 (dd, J 8.2, 1.9 Hz, 1H), 4 , 46 (t, J 8.8 Hz, 1H), 4.06 - 3.98 (m, 4H), 3.85 - 3.77 (m, 4H), 2.22 - 2.13 (m, 1H), 1.77 - 1.58 (m, 12H), 1.57 - 1.38 (m, 10H). HPLC-MS (method 1): MH + m / z 615, RT 3.13 minutes. EXAMPLE 60 o. the Pos
[0986] [0986] 2-Cyclooctyl-2- (methanesulfonamido) -N- (2-oxospiro [indolino-3,4 "- tetrahydropyran] -6-yl) -acetamide
[0987] [0987] Methanesulfonyl chloride (12 µl, 0.415 mmol) was added to a stirred solution of Intermediate 35 (50 mg, 0.12 mmol) and DIPEA (43 µL, 0.25 mmol) in anhydrous DCM (2 mL). The reaction mixture was stirred at 20ºC for 16 h. More methanesulfonyl chloride (6 µL, 0.08 mmol) was added. The reaction mixture was stirred at 20 ° C for an additional 6 h, then diluted with DCM (7 ml). The resulting material was washed with water (7 ml) and brine (7 ml), then dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (method 10) to produce the title compound (26.7 mg, 47%) as a brown powder. õn (500 MHz, DMSO-ds) 10.40 (s, 1H), 10.18 (s, 1H), 7.53 - 7.46 (m, 1H), 7.44 (d, J 8.1 Hz, 1H), 7.37 (d, J 1.8 Hz, 1H), 7.09 (dd, J 8.1, 1.9 Hz, 1H), 4.01 (ddd, J 11.1, 7.1, 3.6 Hz, 2H), 3.80 (ddd, J 11.1, 7.0, 3.7 Hz, 2H), 3.77 - 3.69 (m, 1H), 2, 81 (s, 3H), 1.98 - 1.87 (m, 1H), 1.80 - 1.30 (m, 18H). HPLC-MS (method 1): MH + m / z 464, RT 2.90 minutes. EXAMPLE 61
[0988] [0988] 2-Cyclooctyl-2 - [(2-methylpyrazo | -3-yl) sulfonylamino] -N- (2-oxospiro [indolino-3,4'-tetrahydropyran] -6-yl) acetamide
[0989] [0989] 1-Methyl-1H-pyrazol-5-sulfonyl chloride (41 mg, 0.23 mmol) was added to a stirred solution of Intermediate 35 (100 mg, 0.15 mmol) and DIPEA (54 µL, 0 , 31 mmol) in anhydrous DCM (3 mL). The reaction mixture was stirred at 20ºC for 16 h, then diluted with DCM (10 ml). The resulting material was washed with water (10 ml) and brine (10 ml), then dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (method 10) to produce the title compound (20 mg, 24%) as an orange powder. δ (500 MHz, DMSO-ds) 10.36 (s, 1H), 9.93 (s, 1H), 8.65 (br s, 1H), 7.39 (d, J 8.1 Hz, 1H ), 7.34 (d, J 1.7 Hz, 1H), 7.12 (s, 1H), 6.87 (dd, J 8.2, 1.9 Hz, 1H), 6.64 (s , 1H), 4.05 - 3.95 (m, 2H), 3.98 (s, 3H), 3.79 (ddd, J 10.7, 6.8, 3.6 Hz, 2H), 3 , 71 - 3.62 (m, 1H), 1.94 - 1.84 (m, 1H), 1.77 - 1.68 (m, 2H), 1.68 - 1.26 (m, 16H) . HPLC-MS (method 1): MH + m / z 530, RT 3.13 minutes. EXAMPLE 62
[0990] [0990] N- (1-Cyclooctyl-2-0x0-2 - [(2-0xo0ospiro [indolino-3,3'-pyrrolidino] -6-yl)> amino] ethyl) -3-methylisoxazol-4-carboxamide ( isomer 1)
[0991] [0991] Trifluoroacetic acid (0.23 mL, 2.99 mmol) was added to a stirred suspension of Intermediate 127 (89.8 mg, 0.15 mmol) in DCM (1.2 mL). The mixture was stirred at 20ºC for 2 h, then quenched with saturated aqueous sodium carbonate solution (10 mL). The resulting material was extracted with DCM / isopropanol 4: 1 (4 x 20 mL) using a hydrophobic frit. The organic filtrate was concentrated in vacuo. The resulting orange gum was separated by preparative sequential HPLC (method 10), chiral preparative HPLC (method 32, MeOH + 0.2% diethylamine, Chiralcel OD-H column 25 cm at 9 mL / minute), and chiral preparative SFC ( method 14, MeOH 25:75 + 0.2% diethylamino-carbon dioxide, Chiralpak IC 25 cm 15 mL / minute column, to produce the title compound (1.4 mg, 2%) as a yellowish white powder . õu (500 MHz, CD3OD) 9.12 (s, 1H), 7.43 (s, 1H), 7.27 (d, J 8.1 Hz, 1H), 7.14 (d, J 8.1 Hz, 1H), 4.49 (d, J 8.4 Hz, 1H), 3.47 - 3.24 (obs. M, 3H), 3.11 (d, J 10.8 Hz, 1H), 2.43 (s, 3H), 2.34 - 2.07 (m, 3H), 1.84 - 1.44 (m, 14H). uPLC-MS (method 1): MH + m / z 480, RT 2.21 minutes. Chiral SFC (method 12, Chiralpak IC 25 cm, 35% MeOH + 0.2% diethylamino-65% carbon dioxide, 4 mL / min): RT 3.89 minutes (100%). EXAMPLE 63
[0992] [0992] N- (1-Cyclooctyl-2-0x0-2 - [(2-0xo0ospiro [indolino-3,3'-pyrrolidino] -6- i) amino] ethyl) -3-methylisoxazol-4-carboxamide (isomer 2)
[0993] [0993] Trifluoroacetic acid (0.23 mL, 2.99 mmol) was added to a stirred suspension of Intermediate 127 (89.8 mg, 0.15 mmol) in DCM (1.2 mL). The mixture was stirred at 20ºC for 2 h, then quenched with saturated aqueous sodium carbonate solution (10 mL). The resulting material was extracted with DCM / isopropanol 4: 1 (4 x 20 mL) using a hydrophobic frit. The organic filtrate was concentrated in vacuo. The resulting orange gum was separated by preparative sequential HPLC (method 10), chiral preparative HPLC (method 32, MeOH + 0.2% diethylamine,
[0994] [0994] N- (1-Cyclooctyl-2 - [(1 ', 2-dioxospiro [indolino-3,4 "-thian] -6-yl) amino] -2-oxoethyl) -2-methylpyrazole-3-carboxamide
[0995] [0995] 3-Chloroperbenzoic acid (70%, 98 mg, 0.4 mmol) was added to a stirred suspension of Example 9 (176 mg, 0.34 mmol) in DCM (3.4 mL) at 0 ° C under nitrogen. The reaction mixture was stirred at 0ºC for 3.5 h, then quenched with 10% aqueous sodium sulfate / saturated aqueous sodium carbonate solution 1: 1 (40 mL). The resulting material was extracted with 1: 1 ethyl acetate / 2-methyltetrahydrofuran (3 x 30 ml). The combined organic extracts were washed with saturated aqueous sodium carbonate solution (20 ml) and brine (20 ml), then dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting crude yellowish white powder was separated by preparative HPLC (method 10) to produce, after lyophilization, the title compound (23.3 mg, 13%) as a white powder. õ1 (500 MHz, DMSO-ds) 10.47 (br s, 1H), 10.25 (s, 1H), 8.53 (d, J 8.5 Hz, 1H), 7.53 (d, J 8.1 Hz, 1H,
[0996] [0996] N-f1-Cyclooctyl-2-0x0-2 - [(1 ', 1', 2-trioxospiro [indolino-3,4'-tiano] -6- i) amino] ethyl) -2-methylpyrazole- 3-carboxamide
[0997] [0997] 3-Chloroperbenzoic acid (70%, 98 mg, 0.4 mmol) was added to a stirred suspension of Example 9 (176 mg, 0.34 mmol) in DCM (3.4 mL) at 0 ° C under nitrogen. The reaction mixture was stirred at 0ºC for 3.5 h, then quenched with 10% aqueous sodium sulfate / saturated aqueous sodium carbonate solution 1: 1 (40 mL). The resulting material was extracted with 1: 1 ethyl acetate / 2-methyltetrahydrofuran (3 x 30 ml). The combined organic extracts were washed with saturated aqueous sodium carbonate solution (20 ml) and brine (20 ml), then dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting crude yellowish white powder was separated by preparative HPLC (method 10) to produce, after lyophilization, the title compound (71.7 mg, 38%) as a white powder. õn (500 MHz, DMSO-ds) 10.62 (br s, 1H), 10.27 (s, 1H), 8.53 (d, J 8.5 Hz, 1H), 7.45 (d, Jy 2.0 Hz, 1H), 7.42 (d, J 1.8 Hz, 1H), 7.31 (d, J 8.1 Hz, 1H), 7.15 (dd, J 8.2, 1 , 8 Hz, 1H), 7.05 (d, J 2.1 Hz, 1H), 4.43 (t, J 8.8 Hz, 1H), 4.02 (s, 3H), 3.74 - 3.60 (m, 2H), 3.17 - 3.05 (m, 2H), 2.35 - 2.25 (m, 2H), 2.22 - 2.03 (m, 3H), 1, 73 - 1.33 (m, 14H). uPLC-MS (method 1): MH + m / z 542, RT 3.00 minutes.
[0998] [0998] N- (1-Cyclooctyl-2 [(2'S, 3R) -2 "-methyl-2-oxospiro [indolino-3,4" - tetrahydropyran] -6-yl] -amino) -2-0x0ethyl) - 2-methylpyrazole-3-carboxamide (isomer 1)
[0999] [0999] DIPEA (76 uL, 0.46 mmol) was added to a stirred suspension of Intermediate 135 (96.7 mg, 0.35 mmol), Intermediate 128 (127 mg, 0.39 mmol) and HATU (161 mg , 0.42 mmol) in anhydrous THF (1.75 mL). The mixture was stirred at 20ºC under nitrogen for 16 h, then quenched with saturated aqueous sodium carbonate solution (3 mL) and water (3 mL) and stirred at 20ºC for 1 h. The mixture was extracted with 4: 1 DCM / isopropanol (4 x 5 mL) using a hydrophobic frit, then the organic filtrate was concentrated in vacuo. The resulting brown powder was separated by the preparative chiral SFC (method 14, ethanol-carbon dioxide 15:85, Chiralpak IC cm column, 15 mL / minute) to produce, after lyophilization, the title compound (52.2 mg, 28%) as a yellowish white powder. ôH (500 MHz, DMSO-ds) 10.30 (s, 1H), 10.20 (s, 1H), 8.52 (d, J 8.6 Hz, 1H), 7.45 (d, J 2 , 0 Hz, 1H), 7.34 (d, J 1.6 Hz, 1H), 7.15 (d, J 8.1 Hz, 1H), 7.11 (dd, J 8.1, 1, 7 Hz, 1H), 7.05 (d, J 2.0 Hz, 1H), 4.43 (t, J 8.9 Hz, 1H), 4.27 - 4.10 (m, 2H), 4 , 03 (s, 3H), 3.73 (dd, J 11.1, 4.6 Hz, 1H), 2.22 - 2.09 (m, 1H), 1.87 (td, J 13.4 , 5.0 Hz, 1H), 1.74 - 1.33 (m, 17H), 1.07 (d, J 6.2 Hz, 3H). uPLC-MS (method 1): MH + m / z 508, RT 3.30 minutes. Chiral SFC (method 12, Chiralpak IC 25 cm, 20% ethanol-80% carbon dioxide, 4 mL / minute): RT 5.65 minutes (98%, isomer 1). EXAMPLE 67 THE.
[01000] [01000] N- (1-Cyclooctyl-2 - ([(2'S, 3R) -2'-methyl-2-0xo0ospiro [indolino-3,4 "- tetrahydropyran] -6-yl] -amino) -2-0x0ethyl ) -2-methylpyrazole-3-carboxamide (isomer 2)
[01001] [01001] DIPEA (76 uL, 0.46 mmol) was added to a stirred suspension of Intermediate 135 (96.7 mg, 0.35 mmol), Intermediate 128 (127 mg, 0.39 mmol) and HATU (161 mg , 0.42 mmol) in anhydrous THF (1.75 mL). The mixture was stirred at 20ºC under nitrogen for 16 h, then quenched with saturated aqueous sodium carbonate solution (3 mL) and water (3 mL) and stirred at 20ºC for 1 h. The mixture was extracted with 4: 1 DCM / isopropanol (4 x 5 mL) using a hydrophobic frit, then the organic filtrate was concentrated in vacuo. The resulting brown powder was separated by the preparative chiral SFC (method 14, ethanol-carbon dioxide 15:85, Chiralpak IC cm column, 15 mL / minute) to produce, after lyophilization, the title compound (31.1 mg, 16%) as a white powder. du (500 MHz, DMSO-ds) 10.30 (s, 1H), 10.20 (s, 1H), 8.52 (d, J 8.6 Hz, 1H), 7.45 (d, J 2 , 0 Hz, 1H), 7.35 (d, J 1.6 Hz, 1H), 7.15 (d, J 8.1 Hz, 1H), 7.10 (dd, J 8.1, 1, 7 Hz, 1H), 7.05 (d, J 2.0 Hz, 1H), 4.43 (t, J 8.9 Hz, 1H), 4.27 - 4.10 (m, 2H), 4 , 03 (s, 3H), 3.73 (dd, J 11.0, 4.7 Hz, 1H), 2.22 - 2.09 (m, 1H), 1.86 (td, J 13.3 , 5.0 Hz, 1H), 1.74 - 1.32 (m, 17H), 1.07 (d, J 6.2 Hz, 3H). uPLC-MS (method 1): MH + m / z 508, RT 3.29 minutes. Chiral SFC (method 12, Chiralpak IC 25 cm, 20% ethanol-80% carbon dioxide, 4 mL / minute): RT 7.23 minutes (98%, isomer 2). EXAMPLE 68
[01002] [01002] N- (1-Cyclooctyl-2-f ([(2'S, 38S) -2 "-methyl-2-oxospiro [indolino-3,4" - tetrahydropyran] -6-yl] -amino) -2- 0x0ethyl) -2-methylpyrazole-3-carboxamide (isomer 3)
[01003] [01003] DIPEA (39 uL, 0.24 mmol) was added to a stirred suspension of Intermediate 136 (44.9 mg, 0.22 mmol), Intermediate 128 (65 mg, 0.2 mmol) and HATU (83 mg , 0.22 mmol) in anhydrous THF (1 mL). The mixture was stirred at 20ºC under nitrogen for 16 h, then quenched with saturated aqueous sodium carbonate solution (3 mL) and water (3 mL) and stirred at 20ºC for 1 h. The mixture was extracted with DCM / isopropanol 4: 1 (4x5 ml) using a hydrophobic frit, then the organic filtrate was concentrated in vacuo. The resulting brown powder was separated by preparative chiral HPLC (method 34, heptane-isopropanol70: 30, Chiralpak AD-H column 25 cm, 18 mL / minute) to produce, after lyophilization, the title compound (30.6 mg, 33%) as a white powder. dn (500 MHz, DMSO-ds) 10.48 (s, 1H), 10.24 (s, 1H), 8.52 (d, J 8.6 Hz, 1H), 7.67 (d, J 8 , 3 Hz, 1H), 7.46 (d, JU 2.0 Hz, 1H), 7.42 (d, J 1.8 Hz, 1H), 7.12 (dd, J 8.2, 1, 9 Hz, 1H), 7.05 (d, J 2.0 Hz, 1H), 4.44 (t, J 8.9 Hz, 1H), 4.03 (s, 3H), 4.01 -3 , 81 (m, 3H), 2.23 - 2.04 (m, 1H), 1.87 (td, J 13.0, 6.1 Hz, 1H), 1.74 - 1.29 (m, 16H), 1.25 (d, J 13.4 Hz, 1H), 1.10 (d, J 6.0 Hz, 3H). uPLC-MS (method 1): MH + m / z 508, RT 3.22 minutes. Chiral SFC (method 12, Chiralcel OD-H 25 cm, 15% MeOH-85% carbon dioxide, 4 mL / minute): RT 10.70 minutes (100%). EXAMPLE 69
[01004] [01004] N- (1-Cyclooctyl-2 ([(2'R, 3S) -2'-methyl-2-0xospiro [indolino-3,4 "- tetrahydropyran] -6-yl] -amino) -2- 0x0ethyl) -2-methylpyrazole-3-carboxamide (isomer 4)
[01005] [01005] DIPEA (85 uL, 0.51 mmol) was added to a stirred suspension of Intermediate 141 (102 mg, 0.4 mmol), Intermediate 128 (142 mg, 0.44 mmol) and HATU (180 mg, 0 , 47 mmol) in anhydrous THF (2 mL). The mixture was stirred at 20ºC under nitrogen for 16 h, then quenched with saturated aqueous sodium carbonate solution (3 mL) and water (3 mL) and stirred at 20ºC for 1 h. The mixture was extracted with 4: 1 DCM / isopropanol (4 x 5 mL) using a hydrophobic frit, then the organic filtrate was concentrated in vacuo. The resulting brown powder was separated by the chiral preparative HPLC (method 32, heptane-isopropanol / 50: 50, Chiralpak AD-H column 25 cm, 18 mL / minute) to produce, after lyophilization, the title compound (73.4 mg, 36%) as a white powder. ôõx (500 MHz, DMSO-ds) 10.30 (s, 1H), 10.20 (s, 1H), 8.52 (d, J 8.6 Hz, 1H), 7.45 (d, J 2 , 0 Hz, 1H), 7.35 (d, J 1.6 Hz, 1H), 7.15 (d, J 8.1 Hz, 1H), 7.10 (dd, J 8.1, 1, 7 Hz, 1H), 7.05 (d, J 2.0 Hz, 1H), 4.43 (t, J 8.9 Hz, 1H), 4.27 - 4.11 (m, 2H), 4 , 03 (s, 3H), 3.73 (dd, J 11.0, 4.6 Hz, 1H), 2.23 - 2.10 (m, 1H), 1.86 (td, J 13.4 , 5.0 Hz, 1H), 1.75 - 1.32 (m, 17H), 1.07 (d, J 6.2 Hz, 3H). uPLC-MS (method 1): MH + m / z 508, RT 3.29 minutes. Chiral SFC (method 12, Chiralcel OD-H 25 cm, 20% MeOH-80% carbon dioxide, 4 mL / minute): RT 5.29 minutes (99%). EXAMPLE 70 o a o
[01006] [01006] N- (1-Cyclooctyl-2 - [(1 "-imino-1 ', 2-dioxospiro [indolino-3,4'-thian] -6-yl) amino] - 2-0x0-ethyl) - 2-methylpyrazole-3-carboxamide (mixture of isomers 1)
[01007] [01007] Example 9 (39 mg, 0.08 mmol), ammonium carbamate (12 mg, 0.15 mmol) and (diacetoxyiodine) benzene (62 mg, 0.19 mmol) were dissolved in MeOH (1 mL) . The reaction mixture was stirred at 20ºC under nitrogen for 16 h, then the volatiles were removed in vacuo. The resulting brown powder was separated by preparative HPLC (method 10) to produce, after lyophilization, the title compound (6.2 mg, 14%) as a white powder. õ1 (500 MHz, DMSO-ds) 10.56 (br s, 1H), 10.26 (s, 1H), 8.54 (d, J 8.6 Hz, 1H), 7.45 (d, J 2.1 Hz, 1H), 7.40 (d, J 1.8 Hz, 1H), 7.21 (d, J 8.1 Hz, 1H), 7.15 (dd, J 8.2, 1 , 8 Hz, 1H), 7.05 (d, J 2.1 Hz, 1H), 4.43 (t, J 8.8 Hz, 1H), 4.02 (s, 3H), 3.68 ( s, 1H), 3.67 - 3.59 (m, 2H), 3.09 - 2.94 (m, 2H), 2.33 - 2.24 (m, 2H), 2.21 - 2, 11 (m, 1H), 2.02 - 1.94 (m, 2H), 1.74 - 1.32 (m, 14H). uPLC-MS (method 1): MH + m / z 541, RT 2.54 minutes.
[01008] [01008] EXAMPLE 71 o a o
[01009] [01009] N- (1-Cyclooctyl-2 - [(1 "-imino-1 ', 2-dioxospiro [indolino-3,4'-thian] -6-yl) amino] - 2-0x0-ethyl) - 2-methyl-pyrazol-3-carboxamide (mixture of isomers 1)
[01010] [01010] Example 9 (39 mg, 0.08 mmol), ammonium carbamate (12 mg, 0.145 mmol)
[01011] [01011] EXAMPLE 72 o F
[01012] [01012] 2-Cyclohexyl-2- (4-fluoro-1H-benzimidazol | -2-yl) -N- (2-oxospiro [indolino-3,4'- tetrahydro-pyran] -6-yl) acetamide
[01013] [01013] Intermediate 144 (97 mg, 0.20 mmol) was dissolved in acetic acid (2 mL, 34.90 mmol). The reaction mixture was stirred at 65 ° C for 18 h, then concentrated in vacuo. The crude residue was purified by preparative HPLC (method 26) to produce the title compound (2 mg, 2%) as a white solid. ôõs (300 MHz, DMSO-ds) 12.59 (s, 1H), 10.44 (d, J 9.6 Hz, 2H), 7.47 - 7.27 (m, 3H), 7.19 - 7.08 (m, 2H), 6.93 (dd, J 11.0, 7.9 Hz, 1H), 4.07 - 3.94 (m, 2H), 3.89 (d, J 10, 6 Hz, 1H), 3.85 - 3.72 (m, 2H), 2.35 - 2.20 (m, 1H), 1.79 - 1.57 (m, 8H), 1.31 - 1 , 42 (m, 5H), 0.99 - 0.87 (m, 1H). LC-MS (method 6): MH + m / z 477, RT 2.04 minutes. EXAMPLE 73
[01014] [01014] 2- (1H-Benzimidazol-2-yl) -2-cyclohexyl-N- (2-oxospiro [indolino-3,4 "- tetrahydropyran] -6-yl) - acetamide
[01015] [01015] Intermediate 145 (40 mg, 0.08 mmol) was dissolved in acetic acid (1 mL, 17.45 mmol). The reaction mixture was stirred at 20 ° C for 2 h, then heated to 65 ° C for 18 h. The reaction mixture was concentrated in vacuo, and the residue was separated by sparkling column chromatography, using a gradient of ethyl acetate in hexane (0 to 100%). The resulting crude solid was purified by preparative HPLC (method 22) to produce the title compound (3 mg, 8%) as a white solid. õH (300 MHz, DMSO-ds) 12.28 (s, 1H), 10.48 (s, 1H), 10.42 (s, 1H), 7.63 - 7.45 (m, 2H), 7 , 43 (d, J 8.2 Hz, 1H), 7.37 (d, J 1.9 Hz, 1H), 7.21 - 7.05 (m, 3H), 4.00 (ddd, J 10 , 7, 6.7, 3.3 Hz, 2H), 3.87 - 3.74 (m, 3H), 2.31 - 2.23 (m, 1H), 1.81 - 1.55 (m , 8H), 1.33 - 1.12 (m, 5H), 0.98 - 0.85 (m, 1H). HPLC-MS (method 6): MH + m / z 459, RT 2.26 minutes.
[01016] [01016] EXAMPLE 74 O. Oo v S n
[01017] [01017] 2-Cyclohexyl-N, N'-bis (2-oxospiro [indolino-3,4'-tetrahydropyran] -6-yl) propanediamide
[01018] [01018] To a solution of Intermediate 2 (63 mg, 0.29 mmol) and Intermediate 143 (116 mg, 0.30 mmol) in DNF (2 mL, 25.90 mmol) was added HATU (136 mg, 0, 35 mmol). The reaction mixture was stirred at 20 ° C for 2 h. Water was added to the reaction mixture at 0ºC and the resulting solid was collected by filtration. The crude solid was purified by preparative HPLC (method 24) to produce the title compound (60 mg, 35%) as a white solid. õn (300 MHz, DMSO-ds) 10.41 (s, 2H), 9.99 (s, 2H), 7.44 (d, J 8.2 Hz, 2H), 7.38 (d, J 1 , 9 Hz, 2H), 7.09 (dd, J 8.2, 2.0 Hz, 2H), 4.01 (ddd, J 11.0.7.1, 3.7 Hz, 4H), 3 , 87 - 3.72 (m, 4H), 3.21 (d, J 10.5 Hz, 1H), 2.29 - 2.14 (m, 1H), 1.81 - 1.55 (m, 13H), 1.28 - 0.99 (m, 5H). HPLC-MS (method 23): MH + m / z 587, RT 2.30 minutes. EXAMPLE 75 TOMO
[01019] [01019] 2-Cyclohexyl-N '- (2-0x0spiro [indolino-3,4'-tetrahydropyran] -6-yl) -N- phenylpropane-diamide
[01020] [01020] To a solution of aniline (0.02 mL, 0.2 mmol) and Intermediate 143 (50 mg, 0.13 mmol) in DNF (0.5 mL) were added HATU (65 mg, 0.17 mmol) ) and DIPEA (0.09 mL, 0.5 mmol). The reaction mixture was stirred at 20ºC for 1 h, then diluted in EtOAc (10 ml), washed with a 1: 1 mixture of water and brine (10 ml) and dried over Na2SO2. The crude residue was purified by column chromatography (hexane to EtOAc), followed by preparative HPLC (method 24), to yield the title compound (13 mg, 22%) as a white solid. ox (400 MHz, CD3OD) 7.61 - 7.55 (m, 2H), 7.48 - 7.43 (m, 2H), 7.38 - 7.31 (m, 2H), 7.17 - 7.10 (m, 2H), 4.18 (m, 2H), 3.94 (m, 2H), 3.12 (d, J 10.1 Hz, 1H), 2.19 (q, J 10 , 9 Hz, 1H), 1.94 - 1.68 (m, 9H), 1.27 (m, 6H). HPLC-MS (method 6): MH + m / z 462, RT 2.27 minutes. EXAMPLE 76 O. O THE
[01021] [01021] 2- (Azocan-1-yl) -N, N'-bis (2-oxospiro [indolino-3,4'-tetrahydropyran] -6- i) propanediamide
[01022] [01022] To a solution of Intermediate 2 (25 mg, 0.12 mmol) and Intermediate 149 (50 mg, 0.12 mmol) in DNF (1 mL, 12.90 mmol) was added HATU (55 mg, 0, 15 mmol). The reaction mixture was stirred at 20ºC for 18 h. Water was added to the reaction mixture, and the resulting white precipitate was collected by filtration and washed with more water. The crude residue was purified by preparative HPLC (Method 22) to produce the title compound (4 mg, 6%) as a white solid. dr (400 MHz, DMSO- de) 10.43 (s, 2H), 9.91 (s, 2H), 7.46 (d, J 8.2 Hz, 2H), 7.40 (d, J 2 , 0 Hz, 2H), 7.06 (dd, J 8.2, 2.0 Hz, 2H), 4.14 (s, 1H), 4.06 - 3.98 (m, 4H), 3, 81 (ddd, J 11.0, 6.7, 3.5 Hz, 4H), 2.82 (t, J 5.4 Hz, 4H), 1.78 - 1.52 (m, 18H). LC-MS (method 21): MH m / z 614, RT 1.94 minutes. EXAMPLE 77 O.
[01023] [01023] N- (1-Cyclooctyl-2-0x0-2 - [(2-0xo0ospiro [indolino-3,4'-tetrahydropyran] -6- iN)> amino] Jetyl) -8-hydroxyoctanamide
[01024] [01024] Prepared from Intermediate 35 (50 mg, 0.13 mmol) and 8-hydroxy-octanoic acid (23 mg, 0.14 mmol) according to Procedure A, and purified by preparative HPLC (method 20) , to give the title compound (45.2 mg, 66%) as a white powder. õH (500 MHz, DMSO-ds) 10.38 (s, 1H), 10.08 (s, 1H), 7.99 (d, J 8.8 Hz, 1H), 7.42 (d, J 8 , 1 Hz, 1H), 7.36 (d, J 1.8 Hz, 1H), 7.09 (dd, J 8.2, 1.8 Hz, 1H), 4.35 - 4.26 (m , 2H), 4.00 (ddd, J 11.0, 7.1, 3.6 Hz, 2H), 3.79 (ddd, J 11.0, 6.9, 3.6 Hz, 2H), 3.39 - 3.28 (obs. M, 2H), 2.23 - 2.06 (m, 2H), 2.00 - 1.89 (m, 1H), 1.79 - 1.69 (m , 2H), 1.69 - 1.28 (m, 20H), 1.27 - 1.48 (m, 6H). uPLC-MS (method 1): MH + m / z 528, RT 3.06 minutes. EXAMPLE 78 O. Pao À NO Nº N “x Do N. o
[01025] [01025] 2-Cyclooctyl-N- (2-o0xospiro [indolino-3,4 "-tetrahydropyran] -6-i1) -2 - [(2-oxoospiro [indolino-3,4'-tetrahydropyran] -6-yl ) carbamoylamino] acetamide
[01026] [01026] A suspension of Intermediate 152 (65 mg, 0.19 mmol), Intermediate 35 (99 mg, 0.26 mmol) and 4- (dimethylamino) pyridine (60 mg, 0.49 mmol) in acetonitrile (3 mL ) was heated to 60ºC under a nitrogen atmosphere for 18 h. The reaction mixture was concentrated in vacuo and triturated with water (5 ml). The resulting material was filtered and washed with a small amount of water. The resulting white solid was purified by reverse phase HPLC (method 25, with methanol as solvent A) to give, after lyophilization, the title compound (85 mg, 74%) as a white solid. ox (400 MHz, DMSO-ds) 10.40 (s, 1H), 10.30 (s, 1H), 10.18 (s, 1H), 8.73 (s, 1H), 7.44 (d , J 8.1 Hz, 1H), 7.37 (d, J 1.9 Hz, 1H), 7.35 (d, J 8.1 Hz, 1H), 7.22 (d, J 1.9 Hz, 1H), 7.11 (dd, J 8.2, 1.9 Hz, 1H), 6.75 (dd, J 8.1, 2.0 Hz, 1H), 6.45 (d, J 8.8 Hz, 1H), 4.27 (dd, J 8.9, 6.4 Hz, 1H), 4.01 (ddt, J 11.1, 7.4, 3.7 Hz, 4H), 3.86 - 3.74 (m, 4H), 1.96 (d, J 8.4 Hz, 1H), 1.80 - 1.21 (m, 22H). HPLC-MS (Method 21): MH + m / z 628, RT 2.16 minutes. EXAMPLES 79 to 143
[01027] [01027] The title compounds were prepared in a three-step sequence: * Chiral SFC analysis (Step 1: reaction of Intermediate 37 with the appropriate commercially available aldehyde or ketone according to Procedure F. * Step 2: reaction of the material thus obtained according to Procedure H. * Step3: reaction of the material thus obtained with Intermediate 2 according to Procedure |.
[01028] [01028] method 12) with the following conditions:
[01029] [01029] A: Chiralpak IC 25 cm, 15% methanol-85% carbon dioxide, 4 mL / minute
[01030] [01030] B: Lux C-4 25 cm, 35% methanol-65% carbon dioxide (0.2% v / v NH; 3), 4 mL / minute
[01031] [01031] C: Chiralcel OD-H 25 cm, 25% methanol-75% carbon dioxide, 4 mL / minute
[01032] [01032] D: Chiralpak AS-H 25 cm, 30% methanol-70% carbon dioxide, 4 mL / minute
[01033] [01033] E: Chiralpak IC 25 cm, 20% methanol-80% carbon dioxide, 15 mL / minute
[01034] [01034] F: Chiralpak IC 25 cm, 25% isopropanol-75% carbon dioxide, 4 mL / minute
[01035] [01035] G: Lux C-3 25 cm, 25% methanol-75% carbon dioxide, 4 mL / minute
[01036] [01036] H: Chiralcel OD-H 25 cm, 20% methanol-80% carbon dioxide, 4 mL / minute
[01037] [01037] | l: Chiralpak AS-H 25 cm, 15% ethanol-85% carbon dioxide, 4 mL / minute Mass | Lcms | Ex Method. | Structure Product by RT for them and ENS x N- (1-Cyclobutyl-2-0x0-2 - [(2- 2 2 oxospiro [1H-indol-3,4 "- 79 AN oxane] -6-yl) amino ] Jetyl) -2- 438.2 1.06 27 = methyl-pyrazole-3-carboxamide N- (3- [2-Chlorine-5- (propan-2- º itoxy) phenyl] -1-0x0-1 - [(2- A [| oxospiro [1H-indole-3,4 "- E oxane] - 6-yl) amino] lpropan- 566.4 | 1.39 27 o 2-yl) -2-methyl -pyrazol-3-carboxamide N- (3- (5-Bromo-2-chloro-Q phenyl) - 1-0x0-1 - [(2- 81 R n E oxospiro- [1H- "indole-3,4" - 588.1 | 1.35 27 Br 8 * | oxane] -6-yl) -amino] propan- 2-i1) -2-methyl-pyrazol-3-carboxamide N- [3- (2-Chlorophenyl) -1-0x0-1- [(2-oxospiro [1H-indol- & AA LD) 3,4-oxane] -6- 82 vowel i)> amino] propan-2- in-2- 508,4 | 1 , 24 27 and methylpyrazo | x N- (3-Cyclobutyl-1-0x0-1 - [(2- C 2 O oxospiro [1H-indol-3.4 "- 83 o oxane AN] -6-yl) amino] lpropan- / 452.3 [1.17 27 2-yl - 2-methylpyraz! -3- carboxamide Sex 2-methyl-N- [1- (oxan-4-yl) -2- 2 o o0x0-2 - [(2-0xo0espiro [ 1 H- 84 * & no indole- 3.4 "-0xane] -6- | 468.3 | 0.83 27 iN) amino] Jetyl) - pyrazole-3-carboxamide N- (3- (2-Chloro- 6-fluoro- 8 | phenyl) - 1-0x0-1 - [(2-os;;; 85 Oxo-spiro- [1H- indole-3.4 "- 526 1.16 27 oxane] -6-yl) - amino] propan-2-i1) -2-methyl-pyrazol-3-carboxamide o 2-methyl-N- (1- (3-methyl-cyclo-butyl) -2-0x0-2- [ (2-0x0- 86 o <, À x spiro [1H-indole-3.4 "- 4522 | 111 27 ps oxane] -6-yl) - '' amino] Jetyl) pyraz | -3-carboxamide o. . N- (1- (1,2,3,3a, 4,5,6,6a) Octa-IE o N o0x0-2 - [(2-0xo0ospiro [1H-
[01038] [01038] Selected * H NMR data: Major isomer 1: dx (500 MHz, DMSO-ds) 10.39 (s, 1H), 10.21 (s, 1H), 8.46 (d, J7.5 Hz, 1H), 7.45 (t, J 2.2 Hz, 1H), 7.43 (d, J 6.1 Hz, 1H), 7.38 - 7.36 (m, 1H), 7, 10 (d, J 8.2 Hz, 1H), 7.02 (d, J 2.1 Hz, 1H), 4.47 (dd, J 9.9, 7.5 Hz, 1H), 4.02 (s, 3H), 4.03 - 3.98 (m, 2H), 3.80 (ddd, J 11.0, 6.8, 3.5 Hz, 2H), 2.32 - 2.24 ( m, 1H), 2.15 - 1.99 (m, 1H), 1.99 - 1.92 (m, 2H), 1.77 - 1.69 (m, 2H), 1.66 - 1, 55 (m, 3H), 1.47 - 1.35 (m, 1H), 0.87 (d, J 6.5 Hz, 3H). 2 Minor isomer 2: δx (500 MHz, DMSO-ds) 10.39 (s, 1H), 10.17 (s, 1H), 8.52 (d, J 7.2 Hz, 1H), 7.46 (d, J 2.1 Hz, 1H), 7.45 (d, J 6.0 Hz, 1H), 7.38 - 7.36 (m, 1H), 7.12 - 7.08 (m, 1H), 6.99 (d, J 2.1 Hz, 1H), 4.55 (dd, J 11.8, 7.1 Hz, 1H), 4.02 (s, 3H), 3.99 ( dd, J 7.3, 3.7 Hz, 2H), 3.80 (ddd, J 11.0, 6.8, 3.5 Hz, 2H), 2.84 - 2.73 (m, 1H) , 2.42 - 2.37 (m, 1H), 2.15 - 1.99 (m, 1H), 1.96 (q, J 9.1 Hz, 1H), 1.77 - 1.69 ( m, 3H), 1.66 - 1.60 (m, 2H), 1.47 - 1.35 (m, 1H), 1.05 (d, J 7.1 Hz, 3H). Major isomer 3: dn (500 MHz, DMSO-ds) 10.39 (d, J 24 Hz, 1H), 10.12 (s, 1H), 8.52 (d, J 8.5 Hz, 1H), 7.47 (d, J 2.1 Hz, 1H), 7.44 - 7.41 (m, 1H), 95 | 7.35 (d, J1.9 Hz, 1H), 7.10 (dd, J 8.2, 1.9 Hz, 1H), 7.04 (d, J 2.1 Hz, 1H), 4.65 (t, J 8.8 Hz, 1H), 4.03 (s, 3H ), 4.00 (ddd, J 10.9, 7.1, 3.7 Hz, 2H), 3.79 (ddd, J 10.5, 6.3, 3.4 Hz, 2H), 2, 37 - 2.31 (m, 1H), 2.25 - 2.15 (m, 1H), 1.99
[01039] [01039] The title compounds were prepared in a sequence of three steps: * Step 1: reaction of Intermediate 37 with the commercially available aldehyde or ketone - appropriate according to Procedure F. * Step 2: reaction of the material thus obtained according to Procedure H. * Step3: reaction of the material thus obtained with Intermediate 123 according to Procedure |. Mass | LCMS Dela Ex. | Structure Product by RT LCMS LCMS | (min) No
[01040] [01040] The title compounds were prepared in a two-step sequence: * Step 1: Reaction of Intermediate 37 with the commercially available aldehyde or ketone - appropriate according to Procedure F.
[01041] [01041] Selected * H NMR data: õH (500 MHz, DMSO-ds) 10.40 (s, 1H), 10.06 (s, 1H), 10.00 (s, 1H), 7.70 ( d, J 7.9 Hz, 1H), 7.56 (d, J 2.0 Hz, 1H), 7.50 (d, J 1.7 Hz, 1H), 7.44 (d, J 8, 1 Hz, 1H), 7.40 (d, J 7.4 Hz, 1H), 7.32 (t, J 7.7 Hz, 1H), 163 7.24 (t, JU 7.6 Hz, 1H ), 7.22 (d, J 1.9 Hz, 1H), 7.20 (d, J 1.9 Hz, 1H), 4.06 (s, 3H), 4.04 - 3.99 (m , 2H), 3.81 (ddd, J 10.9, 6.9, 3.6 Hz, 2H), 3.10 (dd, J 7.9, 5.0 Hz, 2H), 2.98 ( dd, J 7.7, 4.8 Hz, 2H), 1.75 (ddd, J 12.8, 6.9, 3.5 Hz, 2H), 1.63 (ddd, J 13.2, 7 , 0, 3.7 Hz, 2H). ôõH (500 MHz, DMSO-ds) 10.38 (s, 1H), 9.75 (s, 1H), 9.44 (s, 1H), 7.50 (d, J 2.0 Hz, 1H) , 7.46 (d, J 1.8 Hz, 1H), 7.42 (d, J 8.2 Hz, 1H), 168 7.17 (dd, J 8.2, 1.9 Hz, 1H) , 7.05 (d, J 2.1 Hz, 1H), 4.03 (s, 3H), 4.03 - 3.99 (m, 2H), 3.81 (ddd, J 11.1, 7 , 1, 3.7 Hz, 2H), 2.68 (t, J 6.7 Hz, 2H), 2.43 (t, J 6.9 Hz, 2H), 1.75 - 1.59 (m , 8H). õH (500 MHz, DMSO-ds) 10.37 (s, 1H), 10.03 (s, 1H), 9.65 (s, 1H), 7.49 (d, J 2.1 Hz, 1H) , 7.47 (d, J 1.4 Hz, 1H), 7.41 (d, J 8.2 Hz, 1H), 182 7.16 (dd, J 8.2, 1.7 Hz, 1H) , 7.07 (d, J 2.0 Hz, 1H), 4.03 - 3.97 (m, 2H), 4.01 (s, 3H), 3.80 (ddd, J 11.1, 7 , 1, 3.7 Hz, 2H), 1.73 (ddd, J 13.0, 6.9, 3.6 Hz, 2H), 1.61 (ddd, J 13.1, 7.0, 3 , 6 Hz, 2H). EXAMPLES 184 & 185
[01042] [01042] The title compounds were prepared in a two-step sequence: * Step 1: Reaction of Intermediate 55 with the commercially available aldehyde or ketone - appropriate according to Procedure F.
[01043] [01043] Selected * H NMR data: Ex. * H NMR data õH (500 MHz, DMSO-ds) 10.38 (s, 1H), 9.70 (d, J 6.6 Hz, 1H), 9.38 (d, J 2.1 Hz, 1H), 9.37 (s, 1H), 7.46 - 7.43 (m, 1H), 7.41 (d, J 8.6 Hz, 1H ), 7.20 - 7.13 (m, 1H), 4.01 (ddd, J 10.8, 7.0, 3.6 Hz, 2H), 3.80 (ddd, J 10.8, 6 , 9, 3.5 Hz, 2H), 2.84 (dd, J 17.3, 6.9 Hz, 0.5H), 2.76 185 (dd, J 18.3, 5.0 Hz, 0 , 5H), 2.68-2.61 (m, 0.5H), 2.60 - 2.54 (m, 0.5H), 2.51 - 244 (m, 1H), 2.42 (t , J 8.7 Hz, 0.5H), 2.37 (s, 3H), 2.23 (dd, J 17.4, 9.0 Hz, 0.5H), 2.06 - 1.97 ( m, 1H), 1.89 - 1.80 (m, 1H), 1.79 - 1.71 (m, 2H), 1.65 - 1.58 (m, 2H), 1.31 - 1, 19 (m, 1H), 1.07 - 0.95 m, 3H). EXAMPLES 186 to 189
[01044] [01044] The title compounds were prepared in a three-step sequence: * Step 1: Reaction of Intermediate 55 or Intermediate 60, as appropriate, with the appropriate commercially available aldehyde or ketone according to Procedure F. * Step2: reaction of the material thus obtained with Intermediate 57 according to Procedure G. * Step 3: reaction of the material thus obtained according to Procedure C. Mass | LCMS Ex Method. | Structure Product by RT PMS LCMS | (min) No. N- (1- (5-Methoxy-7-bicyclo. [4,2,0] octa-1,3,5-1, ot | trieniidene) - 2-0x0-2 - [(2- AAA oxospiro [1H- pyrrolo [3,2- 186 & clpyridine-3,4 "-oxane] -6- 5164 | 1.15 27 1 iNaminoJetyl) -3- - methyl / - isoxazol-4-carboxamide (isomer 1) N - (1- (5-Chlorine-7-bicyclo. [4,2 0] octa-1,3,5-2 to the trienylidene) - * 2-0x0-2 - [(2- ANAÇÃ Ns oxospiro [1H - pyrrole [3.2-187 dx clpyridine-3.4 "- - oxane] -6- 520.3 [119 27 1 iN)> amino] Jetyl) -3-methyl - isoxazole-4-carboxamide isomer 1 N- (1- (5-Chloro-7-bicyclo- E [e [4,2,0] octa-1,3,5-: 7 AY "oxospiro [1H-pyrrolo [3,2- | 583.4 | 1.23 27 Clpyridine-3,4'-oxane] -6- FZ i)> amino] ethyl) -2-ethylpyraz | -3- carboxamide (isomer 1 N- (1- (7-Bicyclo [4,2,0] octa- and its 1,3,5-trienylidene) -2-0x0-2- Zi 9% ”| I (2-oxospiro [ 1H- 189 AK pyrrolo [3,2- c] J-pyridine-3,4 "- | 485,4 / [1,11 27 CY oxane] -6-yl) - aminoJetyl) -2- methylpyrazo | -3 - carboxamide (isomer 1 EXAMPLES 190 to 204
[01045] [01045] The title compounds were prepared according to Procedure A from Intermediate 78 and the appropriate carboxylic acid.
[01046] [01046] The title compounds were prepared according to Procedure D from Intermediate 78 and appropriate carbamoyl chloride. Mass | LcmMs | Ex Method. Product Structure by RT p LCMS | (min) | CMS No. (28) -2-Cyclohexyl-2- [di- Dá (propan-2- 205 QoS yl) carbamoylamino] - N- (2- 485.6 [1.54 | 27 PN oxospiro [1H-indol- 3.4 "- oxane] -6-yl) acetamide N $ (1S) -1-Cyclohexyl-2-0x0-" =. 2- [(2-oxospiro [1H-indole-neo | 34-oxane] -6- 206 ZOO iaminoJetyl-1,1- - dioxo- | 9194 [11 27 1,4-thiazinane-4-carboxamide NK (18S ) -1-Cyclohexyl-2-0x0- (3 | [2- [(2-oxospira [1H-indol- 207 US 3,4-oxane] -6- | 471,4 [1,14 | 27 EN iN)) amino] Jetyl) - “morpholino-4-carboxamide
[01047] [01047] The title compounds were prepared according to Procedure E from Intermediate 78 and the appropriate chloroform. Mass | LcmMs | Ex Method. | Structure Product by RT p; LCMS LCMS | (min) No. o NX (1S) -1-cyclohexyl-2-0x0- o 2- [(2-0xo-spiro [1H-indol- 209 DOI Ç 3,4- oxane] -6- | 458,5 | 1,48 27 Dyl)> amino] Jetyl) - 2-methylpropyl carbamate AN; ; no 3 o S) 1 Sit TindO Ã - [(2-0xo0spiro [1H-indol- 210 QD 3,4 -oxane] -6-ylJamino] -etin | 2945 [1.39 27 = | propan-2- carbamate ila P NÁX (18S) -1-cyclohexyl-2-0x0- non 2- [(2-oxo-spiro [1H-indol- 211 TI 3.4 ”- oxane] -6- | 460.5 | 1.23 27 º Do i)> amino] Jetyl) - e carbamate | 2-methoxyethyl Y NX (18) -1-cyclohexyl-2-0x0- non 2- [((2-oxo-spiro [1H-indol- 212 TI 3.4 "- oxane] -6-yl) amino] Jetyl) | 472.5 | 1.56 27 º Of 2,2-dimethyl-propyl carbamate
[01048] [01048] The title compounds were synthesized according to Procedure B from Intermediate 78 and the appropriate halogen heterocycle. [Former TJestrora —JProduto = - | Massa [LCMS by RT by LCMS | (min) | LCMS No. ua (28) -2-Cyclohexyl-2 - [(6- Ç FD methyl-pyridazin-3-yl) amino] -
[01049] [01049] Selected * H NMR data: 'H NMR Sh data (400 MHz, DMSO-ds) 10.38 (s, 1H), 10.10 (s, 1H), 7.45 - 7.38 ( m, 2H), 7.16 - 7.01 (m, 2H), 6.82 (d, J 9.4 Hz, 1H), 6.61 (d, J 8.4 Hz, 242 1H), 5 , 21 - 5.07 (m, 1H), 4.43 (t, J 7.8 Hz, 1H), 4.01 (ddd, J 11.1, 7.1, 3.7 Hz, 2H), 3.80 (ddd, J 11.2, 7.0, 3.8 Hz, 2H), 1.93 - 1.81 (m, 1H), 1.79 - 1.55 (m, 9H), 1 , 39 - 1.08 (m, 11H). EXAMPLES 247 & 248
[01050] [01050] “The title compounds were prepared according to Procedure B from Intermediate 105 and the appropriate halogen heterocycle. Mass | LCMS Dela Ex. Product Structure by RT LCMS LCMS | (min) No. o UE 2- (4-methylcyclohexyl) -2 - [(6- 2% PA methylpyridazin-3-yl) amino] - 27 EN o N- (2-oxospiro [1H-indol- 464.5 | 1.32 27 3,4'- oxane] -6-yl) acetamide 2- (4-methylcyclohexyl) -N- (2AD | oxospiro [1H-indol-3,4 "- 248 That oxane] -6-yl) -2 - ([6- (trifluoro- | 518.5 | 1.55 27 methyl) -pyridazin-3-ylJamino) - acetamide EXAMPLES 249 to 263
[01051] [01051] The title compounds were prepared according to Procedure A from Intermediate 35 and the appropriate carboxylic acid. [Ex Product Structure or Mass [LCMS by RT by LCMS | (min) | LCMS No.
[01052] [01052] The title compounds were prepared according to Procedure D from Intermediate 35 and appropriate carbamoyl chloride. Mass | Lcms | Ex Method. | Structure Product by RT p LCMS | (min) | SMS No. Í d 2-Cyclooctyl-2- (methyl- À NIN carbamoylamino) -N- (2-0x0- 264 Spiro [1H-indol-3.4 "- 41433 [119 | 27 oxane] - 6-yl ) acetamide o 2-Cyclooctyl-2- (dimethyl- Fx A Axk | carbamoylamino) -N- (2-0xo0- 265 Spiro [1H-indole-3.4 "- 457.3 [1.29 | 27 oxane] - 6-yl) acetamide EXAMPLES 266 & 267
[01053] [01053] The title compounds were prepared according to Procedure E from Intermediate 35 and the appropriate chloroform. Mass | LcmMs | Ex Method. | Structure Product by RT p: LCMS LCMS | (min) No o. GIVES N-f1-cyclooctyl-2-0x0-2 - [(2- 266 | º Fo oxospiro [1H-indol-3.4 "- 4725 | 1.54 27 oxane] -6-yl) amino] Jetyl) - '' propan-2-yl carbamate e. N- (1-cyclooctyl-2-0x0-2 - [(2- Only the oxospiro [1H-indol-3,4 "- 267 FO oxane] -6- il) amino] -ethyl) - 526.6 1.82 27 cyclohexylmethyl carbamate EXAMPLES 268 to 282
[01054] [01054] The title compounds were prepared according to Procedure B from Intermediate 35 and the appropriate halogen heterocycle.
[01055] [01055] Selected '* H NMR data: * H NMR data 3H (400 MHz, DMSO-ds) 10.37 (s, 1H), 10.18 (s, 1H), 7.45 - 7.35 (m, 2H), 7.16 - 7.07 (m, 2H), 6.93 (d, J 9.1 Hz, 1H), 6.77 (d, J 8.7 Hz, 273 1H), 4.64 - 4.55 (m, 1H), 4.01 (ddd, J 11.2, 7.2, 3.7 Hz, 2H), 3.80 (ddd, J 11.2, 7.1 , 3.8 Hz, 2H), 2.35 (s, 3H), 2.07 (m, 1H), 1.80 - 1.29 (m, 18H). SH (400 MHz, DMSO-ds) 10.39 (s, 1H), 10.31 (s, 1H), 7.81 (d, J 8.4
[01056] [01056] The title compound was prepared from Example 203 according to a procedure analogous to that described for the preparation of Example 12. Mass method | LCMS by Ex. | Product Structure by RT
[01057] [01057] The title compounds were prepared according to Procedure A from Intermediate 151 and the appropriate carboxylic acid. Mass | LCMS | Ex Method. | Structure Product by RT by LCMS LCMS min No. NX (18S) -1-Cyclohexyl-2-0x0- and 2- [(2-0xo0ospiro [1H- XII Year | pyrrole [3,2- cJ-pyridine-3,4 "- 284 nes oxane] - 6-yl) - aminoJetin-2- | 67.4 [1.16 27 methylpyrazole-3-carboxamide
[01058] [01058] The title compound was prepared according to Procedure D from Intermediate 151 and appropriate carbamoyl chloride. Mass | Lcms | Ex Method. | Product Structure by RT p LcmMS | (min) | -CMS No. (28S) -2-Cyclohexyl-2 - ([methyl- O |; (oxan-4- 287 | KO TO iNcarbamoillamino) - N- (2- 500.5 | 1.15 27 and oxospiro [1H-pyrrolo [3,2-clpyridine-3,4 "-oxane] -6-yl) - acetamide EXAMPLES 288 to 336
[01059] [01059] The title compounds were prepared in a two-step sequence: * Step 1: reaction of Intermediate 107 with the appropriate carboxylic acid according to Procedure A. * Step 2: reaction of the material thus obtained according to Procedure C. Mass | LcmMs | Ex Method. Product Structure by RT MS LCMS | (min) No
[01060] [01060] Selected * H NMR data: * H NMR data õH (400 MHz, DMSO-ds) 10.86 (s, 1H), 10.57 (s, 1H), 9.35 (s, 1H) , 8.51 - 8.24 (m, 2H), 7.71 (d, J 0.7 Hz, 1H), 4.51 (t J 8.1 Hz, 1H), 289 3.99 (dt, J 10.9, 4.8 Hz, 2H), 3.88 - 3.70 (m, 2H), 3.55 - 3.36 (m, 1H), 1.97 - 1.77 (m, 3H ), 1.77 - 1.45 (m, 6H), 1.22 (dd, J 11.2, 6.9 Hz, 7H), 1.16 - 1.00 (m, 1H), 1.00 - 0.66 (m, 6H). õH (400 MHz, DMSO-ds) 10.89 (s, 1H), 10.58 (s, 1H), 8.50 (d, J7.9 Hz, 1H), 8.41 (s, 1H), 7.70 (s, 1H), 7.50 (d, J 2.0 Hz, 1H), 6.98 (d, J 323 2.0 Hz, 1H), 4.48 (t, J 8.3 Hz, 1H), 4.39 - 4.16 (m, 2H), 3.99 (dt, J 10.3, 4.7 Hz, 2H), 3.89 - 3.72 (m, 2H), 1.91 - 1.42 (m, 8H), 1.38 - 1.14 (m, 3H), 1.07 (m, 1H), 0.86 (d, J 6.4 Hz, 6H), 0.44 - 0.20 (m, 4H). õH (500 MHz, DMSO-ds) 10.89 - 10.79 (m, 1H), 10.57 - 10.48 (m, 1H), 8.48 - 8.38 (m, 2H), 7, 72 (s, 1H), 7.55 - 7.50 (m, 1H), 6.93 - 334 6.86 (m, 1H), 5.26 - 5.04 (m, 1H), 4.54 - 4.41 (m, 1H), 4.06 - 3.93 (m, 2H), 3.87 - 3.75 (m, 2H), 1.88 - 1.73 (m, 5H), 1 , 73 - 1.51 (m, 6H), 1.40 - 1.32 (m, 3H), 1.32 - 1.47 (m, 2H), 1.12 - 1.00 (m, 1H) , 0.93 - 0.79 (m, 5H), 0.69 - 0.57 (m, 3H). HH (400 MHz, DMSO-ds) 10.86 (s, 1H), 10.58 (s, 1H), 9.43 (d, J 0.8 336 Hz, 1H), 8.44 - 8.35 (m, 2H), 7.72 (s, 1H), 4.53 (t, J 8.1 Hz, 1H), 4.03 - 3.95 (m, 2H), 3.80 - 3.70 (m, 2H), 2.36 (s, 3H), 1.90 - 1.45 (m, 8H), 1.40 - 1.16 (m, 2H), 1.10 - 0.96 (m , 1H), 0.90 - 0.70 (m, 6H). EXAMPLES 337 to 351
[01061] [01061] The title compounds were prepared in a two-step sequence: * Step 1: Reaction of Intermediate 107 with appropriate carbamoyl chloride according to Procedure D. * Step 2: reaction of the material thus obtained according to Procedure C. Ex. | Mass Product Structure | LCMS | Method by RT by
[01062] [01062] The title compound was prepared in a sequence of two steps: * Step 1: reaction of Intermediate 107 with tert-butyl chloroform according to Procedure E. * Step 2: reaction of the material thus obtained according to the Procedure C. Mass | Lcms | Ex Method. | Product Structure by RT p Lcms | (min) | -CMS No. NX (18) -1- (4-methyl- SM cyclohexyl)) - 2-0x0-2 - [(2- 352 [| A No oxo-spiro [1H-pyrrole [3, 2- | 1735 [145 27 FI clpiridino-3,4- - oxane] -6- '' al i) amino] ethyl) - tert-Butyl carbamate (trans isomer EXAMPLES 353 to 355
[01063] [01063] The title compounds were prepared in a two-step sequence:
[01064] [01064] EXAMPLE 356 i (-N
[01065] [01065] N- (1- (4-Chloro-3-fluorophenyl) -2-0x0-2 - [(2-0x0piro [1H-pyrrolo [3,2-c] pyridine-3,4 "-tetrahydro-pyran ] -6-yl) amino] Jetyl) -2-ethylpyrazole-3-carboxamide
[01066] [01066] Trifluoroacetic acid (0.93 mL, 12.07 mmol) was added dropwise to a cold solution of Intermediate 156 (115 mg, 0.18 mmol) in DCM (15 mL) under nitrogen at 0ºC. The reaction mixture was allowed to warm to room temperature, then stirred for 18 h. The volatiles were concentrated in vacuo, and the residue was dissolved in acetonitrile (7.5 ml) and aqueous ammonium hydroxide solution (7.5 ml). The reaction mixture was stirred at 20ºC for 15 minutes, then the volatiles were concentrated in vacuo. The residue was diluted with water (20 ml), and the aqueous phase was extracted with DCM (3 x 20 ml). The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by sparkling column chromatography, using a gradient of ethyl acetate in heptane (100% O) followed by a MeOH-DCM gradient (0 to 100%), to produce, after lyophilization, the compound of title (170 mg, 80%) as a white solid. õH (500 MHz, DMSO-ds) 10.92 (br s, 1H), 10.88 (br s, 1H), 8.99 (d, J 7.0 Hz, 1H), 8.40 (s, 1H), 7.72 - 7.62 (m, 2H), 7.60 (dd, J 10.4, 1.9 Hz, 1H), 7.49 (d, JU 2.0 Hz, 1H), 7.45 (dd, J 8.4, 1.8 Hz, 1H), 7.05 (d, J 2.0 Hz, 1H), 5.91 (d, J 6.8 Hz, 1H), 4 , 52 - 4.39 (m, 2H), 4.04 - 3.91 (m, 2H), 3.87 - 3.72 (m, 2H), 1.89 - 1.73 (m, 2H) , 1.69 - 1.54 (m, 2H), 1.28 (t, J 7.1 Hz, 3H). uPLC-MS (method 1): MH + m / z 527, RT 2.52 minutes. EXAMPLE 357 i ( THE F
[01067] [01067] 2-Ethyl-N1- (4-fluoro-3-methylphenyl) -2-0x0-2 - [(2-0xo0ospiro [1H-pyrrolo [3,2-c] - pyridine-3,4'-tetrahydropyran ] -6-yl) amino] Jetyl) pyrazol-3-carboxamide
[01068] [01068] Trifluoroacetic acid (0.93 mL, 12.07 mmol) was added to the drops to a solution of Intermediate 160 (469 mg, 0.37 mmol) in DCM (20 mL) under a nitrogen atmosphere, and cooled at 0ºC. The reaction mixture was stirred at 20ºC for 18 h. The volatiles were concentrated in vacuo, then the residue was dissolved in acetonitrile (9.5 ml) and aqueous ammonium hydroxide solution (9.5 ml). The reaction mixture was stirred at 20ºC for 15 minutes, and the volatiles were concentrated in vacuo.
The residue was diluted with water (20 ml), and the aqueous phase was extracted with DCM (3 x ml). The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo.
The residue was purified by sparkling column chromatography, using a gradient of ethyl acetate in heptane (0 to 100%) followed by a MeOH-DCM gradient (0 to 100%), to give, after lyophilization, the title compound (160 mg, 84%) as a white solid. dn (500 MHz, DMSO-ds) 10.86 (br s, 1H), 10.79 (br s, 1H), 8.87 (d, J 6.7 Hz, 1H), 8.38 (s, 1H), 7.67 (s, 1H), 7.55 - 7.45 (m, 2H), 7.43 - 7.36 (m, 1H), 7.19 - 7.11 (m, 1H) , 7.04 (d, J 2.0 Hz, 1H), 5.82 (d, J 5.6 Hz, 1H), 4.52 -4.39 (m, 2H), 4.03 - 3, 93 (m, 2H), 3.86 - 3.72 (m, 2H), 2.24 (s, 3H), 1.88 - 1.75 (m, 2H), 1.68 - 1.54 ( m, 2H), 1.28 (t, J 7.1 Hz, 3H). uPLC-MS (method 1): MH + m / z 507, RT 2.34 minutes.

权利要求:
Claims (18)
[1]
1. Compound of the formula (|) or a pharmaceutically acceptable salt thereof, characterized by the fact that: Px, SC | A i N nÊ nº Rº k
OD in which ring A represents C39 cycloalkyl, C3a7 heterocycloalkyl or Ca-9 heterobicycloalkyl, any of the groups may be optionally substituted by one or more substituents; B represents C-R or N; D represents C-R or N; E represents C-Rº or N; Rº represents hydrogen or C1-6 alkyl; R 'represents -CORº or -SO2Rº; or R 'represents C1-6 alkyl, C39 cycloalkyl, C3-9 cycloalkyl (C1- + 6) alkyl, C5-9 spirocycloalkyl (C1-6) alkyl, aryl, arylalkyl (C1- + 6), C3- hetero-cycloalkyl 7, heterocycloalkyl Ca-7 (C1-6) alkyl, heteroaryl or heteroarylalkyl (C1-s6), any of the groups can be optionally substituted by one or more substituents; R represents hydrogen, halogen, cyano, C1-6 alkyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxy, C1-6 alkoxy, difluoromethoxy, trifluoromethoxy, C1-6 sulfinyl alkyl or C1-6 sulfonyl alkyl; R represents hydrogen, halogen, cyano, C16 alkyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxy, C1-6 alkoxy, difluoromethoxy, trifluoromethoxy, C1 + sulfinyl alkyl or C1-6 sulfonyl alkyl; Rº represents hydrogen, halogen, cyano, Ci alkyl, fluoromethyl,
difluoromethyl, trifluoromethyl, hydroxy, C1-6 alkoxy, difluoromethoxy, trifluoromethoxy, C1 + sulfinyl alkyl or C1-6 sulfonyl alkyl; R represents hydrogen; or Rº represents C1 + 6 alkyl, C2-7 alkenyl, C3-9 cycloalkyl, C3-9 cycloalkyl (C1- + 6) alkyl, C3-9 cycloalkylidenyl (C1-6) alkyl, Ca-9 bicycloalkyl (C1-6 alkyl) ), bicycloalkylidenyl Ca-9 alkyl (C1- + 6), spirocycloalkyl Cso alkyl (Ci), tricycloalkyl With alkyl (Cis), aryl, arylalkyl (Ci), heterocycloalkyl C3-7, heterocycloalkyl C3-7 alkyl (C1 +), heterocycloalkyl C3-7 alkyl (C1-6), heteroaryl or heteroarylalkyl (C1-6), any of the groups can be optionally substituted by one or more substituents; and Rº represents C1-6 alkyl, C2-7 alkenyl, C3.9 cycloalkyl, C3.9 cycloalkyl (C1 + 6) alkyl, C3.9 cycloalkylidenyl (C1.6) alkyl, bicycloalkyl Cas alkyl (C1 + 6), bicycloalkylidenyl Cao (C1-6) alkyl, C5-9 spirocycloalkyl (C1-6) alkyl, Ca-11 alkyl (C1-6) tricyclicalkyl, aryl, aryl-alkyl (C1-s8), C3-7 heterocycloalkyl, C3-7 heterocycloalkyl (C1-6) alkyl, C3-7 heterocycloalkylenyl (C1-6) alkyl, heteroaryl or (C1-6) heteroarylalkyl, any of the groups may be optionally substituted by one or more substituents.
[2]
2. Compound according to claim 1, characterized in that it is represented by formulas (1-1), (1-2), (1-3), (I4) or (1-5) or a pharmaceutically acceptable salt the same:
QL O
R R x e, LX to EQ
R RH R H (1) (1-2)
R R o: | O. | À 1 SO N NÓ nº
R E A R (1-3) (1-4) No LR
XY o. | 2 Rn is Y
R RH (5) where A, Rº, R ', R , Rº and Rº are according to claim 1.
[3]
3. Compound according to claim 1 or claim 2, characterized by the fact that R 'represents -CORº, where Rº is according to claim 1.
[4]
4. Compound according to claim 3, characterized by the fact that Rº represents -CH (R5) N (H) C (O) RS, -CH (R5) N (H) S (O) 2R $, - C (= CR IR N (H) C (O) RS, -CH (RS) R ', -CH (RS) N (H) R' or -CH (R9) C (O) N (H) R ', where Rº represents hydrogen, or Rº represents C1 + 5 alkyl, Ca cycloalkyl, C1-5 cycloalkylalkyl, Cas bicycloalkyl, Cas bicycloalkyl (Ci), Cs5-9 spirocycloalkyl, Cs-9 spirocycloalkyl (C1-s), tricicioalkyl Cen, tricycloalkyl Cg11 alkyl (C1-s), aryl, aryl-alkyl (C1), heterocycloalkyl C37, heterocycloalkyl C3-7 alkyl (C1-5), heteroaryl or heteroarylalkyl (C1-5), any of the groups can be optionally substituted by one or more substituents; R5º represents C3-7 cycloalkyl, Ca-9 bicycloalkyl, aryl, C3-7 heterocycloalkyl or heteroaryl, any of the groups can be optionally substituted by one or more substituents; and
R * º represents hydrogen or C1-6 alkyl; or Rºº and Rº ”, when taken together with the carbon atom to which they are both attached, represent C37 cycloalkyl, Cas bicycloalkyl or C3-7 heterocycloalkyl, either group can be optionally substituted by one or more substituents; R $ represents -NR6ºRº * or -OR6º; or R $ represents C1-9 alkyl, C3 + cycloalkyl, C3.9 cycloalkyl (C1) alkyl, aryl, arylalkyl (C1), C3-7 heterocycloalkyl, C37 alkyl (C1i6), heteroaryl, heteroarylalkyl (C1is) or heteroaryl (C3a-7)] [heteroaryl, any of the groups can be optionally substituted by one or more substituents; R $ º represents hydrogen; or R $ º represents C1-6 alkyl, C3a7 cycloalkyl, C37 cycloalkyl (C1i-6) alkyl, aryl, arylalkyl (Ci), C37 heterocycloalkyl, C3-7 heterocycloalkyl (Ci), heteroaryl, heteroarylalkyl (C1i6) or spiro [heterocycloalkyl (C3a-7)] [heteroaryl, any of the groups can be optionally substituted by one or more substituents; Rº represents hydrogen or C1-6 alkyl; R $ º represents C1-6 alkyl, Ca-7 cycloalkyl, Ca7 cycloalkyl (C1-6) alkyl, aryl, arylalkyl (C1-6), heterocycloalkyl C3-7, heterocycloalkyl C3a-7 alkyl (C1 + 6), heteroaryl or heteroaryl (C1-6) alkyl, any of the groups can be optionally substituted by one or more substituents; and R ”represents heteroaryl or spiro [heterocycloalkyl (C37)) [heteroaryl], any of the groups may be optionally substituted by one or more substituents.
[5]
Compound according to claim 4, characterized in that it is represented by the formula (IIA) or a pharmaceutically acceptable salt thereof:
W.
R | o: 6
N AY o | ç R n R O (IA) where W represents O, S, S (O), S (O) 2, S (O) (NH) or N-R'7; R'7 represents hydrogen or C1-6 alkyl; Rº and Rô are as defined in claim 1; and Rº and Rô are as defined in claim 4.
[6]
A compound according to claim 4, characterized in that it is represented by the formula (IIB) or a pharmaceutically acceptable salt thereof:
W NSN o H o: | Í 6
N A N WO o |
R H R O (IB) where R is as defined in claim 1; Rº and Rº are as defined in claim 4; and W is as defined in claim 5.
[7]
A compound according to any one of claims 4 to 6, characterized in that R ° represents C1-5 alkyl, C3-9 cycloalkyl, C3 cycloalkyl + (C1-5) alkyl, Ca4-9 bicycloalkyl, Ca-9 bicycloalkyl ( C1-5) alkyl, Cs5-9 spirocycloalkyl, Ca-11 tricyclicalkyl, Cea-11 tricyclicalkyl (C1) alkyl, aryl, aryl-alkyl (Cs), C3-7 heterocycloalkyl, C3-7 hetero-alkylalkyl (C1-5) ) or heteroarylalkyl (C1-5),
either group can be optionally substituted by one, two or three substituents - independently - selected from halogen, C1-6 alkyl, trifluoromethyl, phenyl and C1-6 alkoxy.
[8]
A compound according to any one of claims 4 to 7, characterized by the fact that Rº represents -NR6 $ ºRº * or -OR6º; or R $ represents C10 alkyl, aryl, C3-7 heterocycloalkyl, heteroaryl, heteroaryl (C1-6) alkyl or spiro [heterocycloalkyl (C37)] [heteroaryl, any of the groups may be optionally substituted by one, two or three independently selected substituents halogen, C1-6 alkyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, cyclopropyl, cyclobutyl, cyclopropylmethyl, hydroxy, hydroxyalkyl (C1-6), 0x0, C16 alkyl, C16 alkyl, alkyl, alkyl, alkyl aminoalkyl (C1-6), dialkyl (C1-6) aminoalkyl (C1-6) and tetrahydropyranyl.
[9]
Compound according to claim 1, characterized in that it is as specifically disclosed herein in any of the Examples.
[10]
A compound of the formula (1) according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that it is for use in therapy.
[11]
A compound of the formula (1) according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that it is for use in the treatment and / or prevention of disorders for which the administration of an IL-function modulator 17 is indicated.
[12]
A compound of the formula (|) according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that it is for use in the treatment and / or prevention of an inflammatory or autoimmune disorder.
[13]
Pharmaceutical composition, characterized in that it comprises a compound of formula (1) according to claim 1 or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier.
[14]
Pharmaceutical composition according to claim 13, characterized in that it additionally comprises an ingredient
7I7 additional pharmaceutically active.
[15]
15. Use of a compound of the formula (1) according to claim 1 or a pharmaceutically acceptable salt thereof, characterized by the fact that it is for the manufacture of a medicament for the treatment and / or prevention of disorders for which administration of a modulator of the IL-17 function is indicated.
[16]
16. Use of a compound of formula (1) according to claim 1 or a pharmaceutically acceptable salt thereof, characterized by the fact that it is for the manufacture of a medicament for the treatment and / or prevention of an inflammatory or autoimmune disorder.
[17]
17. Method for the treatment and / or prevention of disorders for which the administration of an IL-17 function modulator is indicated, characterized by the fact that it comprises administering to a patient in need of such treatment an effective amount of a compound of formula (1) as defined in claim 1 or a pharmaceutically acceptable salt thereof.
[18]
18. Method for the treatment and / or prevention of an inflammatory or autoimmune disorder, characterized in that it comprises administering to a patient in need of such treatment an effective amount of a compound of formula (1) as defined in claim 1 or a pharmaceutically acceptable salt thereof.

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WO2021255086A1|2020-06-18|2021-12-23|Leo Pharma A/S|Small molecule modulators of il-17|

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WO2021255085A1|2020-06-18|2021-12-23|Leo Pharma A/S|Small molecule modulators of il-17|

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EP3943495A1|2020-07-24|2022-01-26|Leo Pharma A/S|Small molecule modulators of il-17|

法律状态:
2021-11-03| B350| Update of information on the portal [chapter 15.35 patent gazette]|

优先权:

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申请号 | 申请日 | 专利标题

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GBGB1709456.6A|GB201709456D0|2017-06-14|2017-06-14|Therapeutic agents|

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GB1709456.6|2017-06-14|

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PCT/EP2018/065558|WO2018229079A1|2017-06-14|2018-06-12|Spirocyclic indolines as il-17 modulators|

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