WO2017152842A1 - Kinase inhibitors - Google Patents
Kinase inhibitors Download PDFInfo
- Publication number
- WO2017152842A1 WO2017152842A1 PCT/CN2017/075972 CN2017075972W WO2017152842A1 WO 2017152842 A1 WO2017152842 A1 WO 2017152842A1 CN 2017075972 W CN2017075972 W CN 2017075972W WO 2017152842 A1 WO2017152842 A1 WO 2017152842A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compound
- alkyl
- triazol
- room temperature
- aryl
- Prior art date
Links
- 229940043355 kinase inhibitor Drugs 0.000 title description 4
- 239000003757 phosphotransferase inhibitor Substances 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 83
- 150000003839 salts Chemical class 0.000 claims abstract description 21
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 5
- -1 3-substituted phenyl Chemical group 0.000 claims description 77
- 125000003118 aryl group Chemical group 0.000 claims description 47
- 125000001424 substituent group Chemical group 0.000 claims description 35
- 229910052736 halogen Inorganic materials 0.000 claims description 24
- 150000002367 halogens Chemical class 0.000 claims description 24
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 21
- 125000001072 heteroaryl group Chemical group 0.000 claims description 20
- 125000005842 heteroatom Chemical group 0.000 claims description 20
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- 208000023275 Autoimmune disease Diseases 0.000 claims description 16
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 16
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- 238000000034 method Methods 0.000 claims description 14
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- 125000004404 heteroalkyl group Chemical group 0.000 claims description 13
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- 230000000694 effects Effects 0.000 claims description 9
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- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 claims description 8
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- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
- C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
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- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
Definitions
- autoimmune disease also known as autoimmune disorder
- autoimmune disorder is characterized by an immune response that is overactive or wrongly directed against self-tissues 1 .
- autoimmune diseases were regarded as T cell and/or autoantibody mediated damages.
- both T and B lymphocytes and innate immune play important roles in the pathogenesis 2 .
- immunoreceptors such like T-cell antigen receptors (TCR) and B-cell antigen receptor (BCR) .
- TCR T-cell antigen receptors
- BCR B-cell antigen receptor
- PTKs protein tyrosine kinases
- ITAMs immunoreceptor tyrosine-based activation motifs
- TCR-mediated signaling pathway results in the upregulation of inflammatory cytokines such as IL-2 and interferon (IFN) - ⁇ which stimulate immune response.
- IFN interferon
- ITAM immunoreceptor tyrosine-based activation motif
- lymphocyte-specific protein tyrosine kinase (Lck) and proto-oncogene tyrosine-protein kinase (Fyn) are expressed in T cells and located in the initial stage of TCR-mediated signaling cascade 3, 10, 11 .
- Lck primarily expressed in T-cells, is constitutively associated with the cytoplasmic portions of CD4 and CD8 surface receptors. It phosphorylates the TCR and initiates TCR-linked signal transduction in mature peripheral T-cells. Lck is also expressed at all stages of thymocyte development and plays a key role in the selection and maturation of developing T-cells 10, 11 .
- Lck functions by phosphorylating ITAM in the initiation of TCR-mediated signaling pathway, which provides binding sites for the tandem SH2 domains of Syk family kinase, ZAP-70.
- ZAP-70 Once recruited, ZAP-70 is phosphorylated and activated by Lck at Tyr493 in its activation loop 12 , which leads to the autophosphorylation of ZAP-70.
- Active ZAP-70 subsequently phosphorylates adaptor proteins such like LAT, which function as scaffolds to recruit the downstream signaling molecules. This cascade culminates in the initiating transcription of genes involved in cytokine release (particularly IL-2) , and ultimately contributes to the T-cell proliferation 13 . Intervention of Lck kinase activity can have a strong immunosuppressive effect.
- Imatinib reduces TCR-induced proliferation and activation through an inhibitory effect on the LCK 14
- IC 50 147 nM
- concanavalin A-stimulated IL-2 production in whole blood with an EC 50 of approximately 80 nM 15 At the dose of 10 mg/kg/day, A-770041 was shown to prevent the rejection of hearts transplanted heterotopically across a major histocompatibility barrier for least 65 days 15, 16 .
- Rosmarinic acid (RosA) inhibits LCK by targeting SH2 domain also shows suppression of T cell activation and proliferation 17 .
- RosA-Me methyl ester derivative
- Fyn has partially overlapping functions with Lck regarding to the initiation of tyrosine phosphorylation of TCR.
- Both kinases have been shown to interact with TCR and enhance the production of interleukin-2 (IL-2) 20, 21 .
- IL-2 interleukin-2
- Genetic evidence demonstrates that Fyn activation is strictly connected with TCR-induced translocation of Lck, suggesting the involvement in T-cell activation process for Fyn.
- studies on both Lck and Fyn deficient mice indicate these kinases share limited functions during development 22-24 .
- Studies on Lck deficient T cell line (JCaM1) proved that TCR could be still phosphorylated at the specific tyrosine residue which facilitates the recruitment of ZAP-70 kinase.
- TCR phosphorylation pattern is altered and activation of ZAP-70 is defective.
- molecular marker CD69 was elevated, but NFAT activation and the production of interleukin-2 were markedly reduced.
- Dual fatty acylation with myristate and palmitate is critical in the initiation of TCR signaling pathway by Fyn and Lck.
- 2-bromopalmitate can effectively block Fyn palmitoylation.
- 2-bromopalmitate blocks the localization of endogenous palmitoylated Fyn and Lck to detergent-resistant membranes, which is followed with suppression of TCR signaling pathway and T cell activation 26 .
- polyunsaturated fatty acids (PUFAs) particularly the n-3 series are also found to inhibit the Fyn fatty acylation 26, 27 and used as immunosuppressive agents in the clinic.
- Glucocorticoid an effective immunosuppressive agent, was found to inhibit recruitment of Fyn and Lck to the T-cell receptor complex rapidly. These results identify the Lck and Fyn kinases as molecular targets of GCs, mediated via a GC receptor-dependent pathway 28 . Simultaneous inhibition of Fyn and Lck has been shown to inhibit autoimmune diseases.
- B cell depletion therapy such as clinic use of rituximab (MabThera/Rituxan; Biogen Idec/Genentech)
- Btk a Tec family kinase
- BCR B cell receptor
- BTK Upon BCR stimulation, BTK is activated by the upstream Src-family kinases Blk, Lyn, and Fyn. The activated BTK in turn phosphorylates and activates phospholipase-C ⁇ 2 (PLC ⁇ 2) which catalyzes the production of DAG and IP3 and leads to the stimulation of downstream signaling molecules, such as transcription factors NF- ⁇ B and NFAT.
- Functional mutations of Btk in mice causes X-linked immunodeficiency (Xid) , characterized by the reduced serum Ig levels 31 .
- Functional null mutations of Btk in human results in the primary immunodeficiency disease, with a lack of peripheral B cells and extremely low level of serum immunoglobulin (Ig) .
- Some covalent binders targeting the specific residue (Cys481) in Btk show high binding affinity with IC 50 below 0.5 nM and oral efficacy in established CIA mouse model, which means the dose-dependent inhibition of clinical arthritis scores and the production of anticollagen autoantibodies 6 .
- PCI-32765 also inhibits autoantibody production and the development of kidney disease in the MRL-Fas (lpr) lupus model 6 .
- RN486 was observed to significantly inhibit inflammatory response in the PCA (type I hypersensitivity) or rPCA (type III hypersensitivity) mouse models.
- PCA type I hypersensitivity
- rPCA type III hypersensitivity
- oral administration of RN486 could reduce both paw swelling and inflammatory markers in the blood by inhibiting both joint and systemic inflammation 32 .
- p38 MAPK plays a significant role in the pathogenesis of several immune-mediated diseases, including rheumatoid arthritis (RA) , syndrome, systemic lupus erythematosus (SLE) , inflammatory bowel disease (IBD) and psoriasis.
- RA rheumatoid arthritis
- SLE systemic lupus erythematosus
- IBD inflammatory bowel disease
- psoriasis psoriasis.
- the MAPK cascade is activated by Vav.
- Rac1 acts as a MAPKK kinase (MAPKKK) and is located upstream of p38 MAPK.
- p38 MAPK Upon activation, p38 MAPK regulates the expression of tumor necrosis factor (TNF) - ⁇ , interferon- (IFN) - ⁇ and other cytokines, such as IL-1, TL-6 and IL-17 via transcriptional and post-transcriptional mechanisms 33, 34 .
- TNF tumor necrosis factor
- IFN interferon-
- cytokines such as IL-1, TL-6 and IL-17
- SB203580 treatment was shown to improve clinical scores by reducing mRNA levels of proinflammatory cytokines in vivo 36 .
- some non-ATP competitive inhibitors with high selectivity such as VX-702, SCIO469, BIRB796, also show transient inhibition of pro-inflammatory disease markers and are unable to completely control disease exacerbation or progression 37 .
- the invention provides compounds of formula I:
- R 1 –R 5 are independently H, halogen, hydroxyl, methyl, trifluoromethyl, or methoxyl, particularly wherein R 1 and R 5 are independently halogen, hydroxyl, methyl, trifluoromethyl;
- -n is 3, 4, 5, 6, 8, 9 or 10; or n is 3, 5, 6 or 9;
- -R 6 is substituted or unsubstituted, homo-or hetero, 5-or 6-membered cyclic or 9 or 10 membered bi-cyclic aryl;
- -R 6 is optionally substituted: cyclopropyl; 5-membered aryl selected from pyrrole, azole (e.g. pyrazole, imidazole, triazole, tetrazole, pentazole, oxazole, isoxazole, thiazole or isothiazole) , furan, dioxole thiophene, dithiole or oxathiole, and reduced forms thereof (e.g dihydrofuran, dihydroimidazole) ; preferably 2-moieties, such as 2-azole, 2-pyrrole, 2-azole (e.g.
- 2-pyrazole 2-imidazole, 2-oxazole, 2-isoxazole, 2-thiozole, or 2-isothiozole) , 2-furan, 2-thiophene, 2-oxole, dioxole, or 2-thiole; 6 membered aryl selected from phenyl and pyridine; or 9 membered aryl is benzimidazole;
- -R 6 is phenyl, 3-substituted phenyl, 3, 4-substituted phenyl or 3, 4, 5-substituted phenyl;
- R 1 and R 5 are H, and at least one of R 1 and R 5 is halogen, hydroxyl, methyl, trifluoromethyl, or methoxyl;
- R 1 and R 5 are halogen, hydroxyl, methyl, trifluoromethyl, or methoxyl
- R 2 -R 4 are H, and R 1 and R 5 are halogen, hydroxyl, methyl, trifluoromethyl, or methoxyl;
- R 6 is substituted or unsubstituted, homo-or hetero, 5-or 6-membered cyclic or 9 or 10 membered bi-cyclic aryl;
- the compounds have a Lck or Btk-inhibiting activity corresponding to an IC 50 of 10 uM or less in a kinase assay.
- exemplary compounds comprise the following structure, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
- the invention provides pharmaceutical compositions comprising the subject compounds.
- the invention provides a pharmaceutical composition comprising a therapeutically effective amount of a subject compound in unit dosage form and one or more pharmaceutically acceptable excipients.
- the invention provides a combination comprising a therapeutically effective amount of a subject compound and a different agent therapeutically active against an autoimmune and/or inflammatory disease or cancer.
- the invention also provides methods of making and using the subject compounds, including methods of inhibiting kinase activity.
- the invention provides a method of treating a disease associated with undesirable kinase activity, which comprises administering to a person in need thereof an effective amount of a subject compound, or a prodrug thereof, wherein the disease is an allergic disease, an autoimmune disease, an inflammatory disease, or cancer, wherein the method may further comprise the antecedent step of diagnosing the disease or cancer, or the subsequent step of detecting a resultant amelioration of the disease or cancer.
- R 1 is substituted or unsubstituted phenyl
- R 2 is H, hydroxyl, C1-C4 alkyl, or C1-C4alkoyxl
- R 3 is H or methyl
- R 4 is 1-dimethylpropyl.
- the terms “a” and “an” mean one or more, the term “or” means and/or and polynucleotide sequences are understood to encompass opposite strands as well as alternative backbones described herein.
- genuses are recited as shorthand for a recitation of all members of the genus; for example, the recitation of (C1-C3) alkyl is shorthand for a recitation of all C1-C3 alkyls: methyl, ethyl and propyl, including isomers thereof.
- heteroatom as used herein generally means any atom other than carbon or hydrogen.
- Preferred heteroatoms include oxygen (O) , phosphorus (P) , sulfur (S) , nitrogen (N) , and halogens
- preferred heteroatom functional groups are haloformyl, hydroxyl, aldehyde, amine, azo, carboxyl, cyanyl, thocyanyl, carbonyl, halo, hydroperoxyl, imine, aldimine, isocyanide, iscyante, nitrate, nitrile, nitrite, nitro, nitroso, phosphate, phosphono, sulfide, sulfonyl, sulfo, and sulfhydryl.
- alkyl by itself or as part of another substituent, means, unless otherwise stated, a straight or branched chain, or cyclic hydrocarbon radical, or combination thereof, which is fully saturated, having the number of carbon atoms designated (i.e. C1-C8 means one to eight carbons) .
- alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl, (cyclohexyl) methyl, cyclopropylmethyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl and the like.
- alkenyl by itself or as part of another substituent, means a straight or branched chain, or cyclic hydrocarbon radical, or combination thereof, which may be mono-or polyunsaturated, having the number of carbon atoms designated (i.e. C2-C8 means two to eight carbons) and one or more double bonds.
- alkenyl groups include vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2- (butadienyl) , 2, 4-pentadienyl, 3- (1, 4-pentadienyl) and higher homologs and isomers thereof.
- alkynyl by itself or as part of another substituent, means a straight or branched chain hydrocarbon radical, or combination thereof, which may be mono-or polyunsaturated, having the number of carbon atoms designated (i.e. C2-C8 means two to eight carbons) and one or more triple bonds.
- alkynyl groups include ethynyl, 1-and 3-propynyl, 3-butynyl and higher homologs and isomers thereof.
- alkylene by itself or as part of another substituent means a divalent radical derived from alkyl, as exemplified by -CH 2 -CH 2 -CH 2 -CH 2 -.
- an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred in the invention.
- a “lower alkyl” or “lower alkylene” is a shorter chain alkyl or alkylene group, generally having eight or fewer carbon atoms.
- alkoxy " alkylamino” and “alkylthio” (or thioalkoxy) are used in their conventional sense, and refer to those alkyl groups attached to the remainder of the molecule via an oxygen atom, an amino group, or a sulfur atom, respectively.
- heteroalkyl by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or cyclic hydrocarbon radical, or combinations thereof, consisting of the stated number of carbon atoms and from one to three heteroatoms selected from the group consisting of O, N, P, Si and S, wherein the nitrogen, sulfur, and phosphorous atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized.
- the heteroatom (s) O, N, P and S may be placed at any interior position of the heteroalkyl group.
- the heteroatom Si may be placed at any position of the heteroalkyl group, including the position at which the alkyl group is attached to the remainder of the molecule.
- Up to two heteroatoms may be consecutive, such as, for example, -CH 2 -NH-OCH 3 and -CH 2 -O-Si (CH 3 ) 3 .
- heteroalkylene by itself or as part of another substituent means a divalent radical derived from heteroalkyl, as exemplified by -CH 2 -CH 2 -S-CH 2 -CH 2 -and -CH 2 -S-CH 2 -CH 2 -NH-CH 2 -.
- heteroalkylene groups heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like) . Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied.
- cycloalkyl and heterocycloalkyl represent, unless otherwise stated, cyclic versions of “alkyl” and “heteroalkyl” , respectively. Accordingly, a cycloalkyl group has the number of carbon atoms designated (i.e., C3-C8 means three to eight carbons) and may also have one or two double bonds.
- a heterocycloalkyl group consists of the number of carbon atoms designated and from one to three heteroatoms selected from the group consisting of O, N, Si and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized.
- heterocycloalkyl a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule.
- cycloalkyl include cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like.
- heterocycloalkyl examples include 1- (1, 2, 5, 6-tetrahydropyrid-yl) , 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, and the like.
- halo and “halogen, " by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.
- terms such as “haloalkyl, " are meant to include alkyl substituted with halogen atoms, which can be the same or different, in a number ranging from one to (2m'+1) , where m'is the total number of carbon atoms in the alkyl group.
- halo (C1-C4) alkyl is mean to include trifluoromethyl, 2, 2, 2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.
- haloalkyl includes monohaloalkyl (alkyl substituted with one halogen atom) and polyhaloalkyl (alkyl substituted with halogen atoms in a number ranging from two to (2m'+1) halogen atoms, where m'is the total number of carbon atoms in the alkyl group) .
- perhaloalkyl means, unless otherwise stated, alkyl substituted with (2m'+1) halogen atoms, where m'is the total number of carbon atoms in the alkyl group.
- perhalo (C1-C4) alkyl is meant to include trifluoromethyl, pentachloroethyl, 1, 1, 1-trifluoro-2-bromo-2-chloroethyl and the like.
- acyl refers to those groups derived from an organic acid by removal of the hydroxy portion of the acid. Accordingly, acyl is meant to include, for example, acetyl, propionyl, butyryl, decanoyl, pivaloyl, benzoyl and the like.
- aryl means, unless otherwise stated, a polyunsaturated, typically aromatic, hydrocarbon substituent which can be a single ring or multiple rings (up to three rings) which are fused together or linked covalently.
- aryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl and 1, 2, 3, 4-tetrahydronaphthalene.
- heteroaryl refers to aryl groups (or rings) that contain from zero to four heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen heteroatom are optionally quaternized.
- a heteroaryl group can be attached to the remainder of the molecule through a heteroatom.
- heteroaryl groups include 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl and 6-quinolyl.
- aryl when used in combination with other terms (e.g., aryloxy, arylthioxy, arylalkyl) includes both aryl and heteroaryl rings as defined above.
- arylalkyl is meant to include those radicals in which an aryl group is attached to an alkyl group (e.g., benzyl, phenethyl, pyridylmethyl and the like) including those alkyl groups in which a carbon atom (e.g., a methylene group) has been replaced by, for example, an oxygen atom (e.g., phenoxymethyl, 2-pyridyloxymethyl, 3- (1-naphthyloxy) propyl, and the like) .
- alkyl group e.g., benzyl, phenethyl, pyridylmethyl and the like
- an oxygen atom e.g., phenoxymethyl, 2-pyridyloxymethyl, 3- (1-naph
- R'a nd R"are attached to the same nitrogen atom they can be combined with the nitrogen atom to form a 5-, 6-or 7-membered ring.
- -NR'R is meant to include 1-pyrrolidinyl and 4-morpholinyl.
- an alkyl or heteroalkyl group will have from zero to three substituents, with those groups having two or fewer substituents being preferred in the invention. More preferably, an alkyl or heteroalkyl radical will be unsubstituted or monosubstituted. Most preferably, an alkyl or heteroalkyl radical will be unsubstituted. From the above discussion of substituents, one of skill in the art will understand that the term "alkyl" is meant to include groups such as trihaloalkyl (e.g., -CF 3 and -CH 2 CF 3 ) .
- the aryl group When the aryl group is 1, 2, 3, 4-tetrahydronaphthalene, it may be substituted with a substituted or unsubstituted (C3-C7) spirocycloalkyl group.
- the (C3-C7) spirocycloalkyl group may be substituted in the same manner as defined herein for "cycloalkyl" .
- an aryl or heteroaryl group will have from zero to three substituents, with those groups having two or fewer substituents being preferred in the invention.
- an aryl or heteroaryl group will be unsubstituted or monosubstituted.
- an aryl or heteroaryl group will be unsubstituted.
- Preferred substituents for aryl and heteroaryl groups are selected from: halogen, -OR', -OC (O) R', -NR'R", -SR', -R', -CN, -NO 2 , -CO 2 R', -CONR'R", -C (O) R', -OC (O) NR'R", -NR"C (O) R', -S (O) R', -SO 2 R', -SO 2 NR'R", -NR"SO 2 R, -N 3 , -CH (Ph) 2 , perfluoro (C1-C4) alkoxy and perfluoro (C1-C4) alkyl, where R'a nd R"are as defined above.
- substituents are selected from: halogen, -OR', -OC (O) R', -NR'R", -R', -CN, -NO 2 , -CO 2 R', -CONR'R", -NR"C (O) R', -SO 2 R', -SO 2 NR'R", -NR"SO 2 R, perfluoro (C1-C4) alkoxy and perfluoro (C1-C4) alkyl.
- the substituent -CO 2 H includes bioisosteric replacements therefor; see, e.g., The Practice of Medicinal Chemistry; Wermuth, C.G., Ed.; Academic Press: New York, 1996; p. 203.
- Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -T-C (O) - (CH 2 ) q-U-, wherein T and U are independently -NH-, -O-, -CH 2 -or a single bond, and q is an integer of from 0 to 2.
- two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -A- (CH 2 ) r-B-, wherein A and B are independently -CH 2 -, -O-, -NH-, -S-, -S (O) -, -S (O) 2 -, -S (O) 2 NR'-or a single bond, and r is an integer of from 1 to 3.
- One of the single bonds of the new ring so formed may optionally be replaced with a double bond.
- two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula - (CH 2 ) s-X- (CH 2 ) t--, where s and t are independently integers of from 0 to 3, and X is -O-, -NR'-, -S-, -S (O) -, -S (O) 2 -, or -S (O) 2 NR'-.
- the substituent R'in -NR'-and -S (O) 2 NR'- is selected from hydrogen or unsubstituted (C1-C6) alkyl.
- substituents are disclosed herein and exemplified in the tables, structures, examples, and claims, and may be applied across different compounds of the invention, i.e. substituents of any given compound may be combinatorially used with other compounds.
- applicable substituents are independently substituted or unsubstituted heteroatom, substituted or unsubstituted, 0-3 heteroatom C1-C6 alkyl, substituted or unsubstituted, 0-3 heteroatom C2-C6 alkenyl, substituted or unsubstituted, 0-3 heteroatom C2-C6 alkynyl, or substituted or unsubstituted, 0-3 heteroatom C6-C14 aryl, wherein each heteroatom is independently oxygen, phosphorus, sulfur or nitrogen.
- applicable substituents are independently aldehyde, aldimine, alkanoyloxy, alkoxy, alkoxycarbonyl, alkyloxy, alkyl, amine, azo, halogens, carbamoyl, carbonyl, carboxamido, carboxyl, cyanyl, ester, halo, haloformyl, hydroperoxyl, hydroxyl, imine, isocyanide, iscyante, N-tert-butoxycarbonyl, nitrate, nitrile, nitrite, nitro, nitroso, phosphate, phosphono, sulfide, sulfonyl, sulfo, sulfhydryl, thiol, thiocyanyl, trifluoromethyl or trifluromethyl ether (OCF 3 ) .
- salts are meant to include salts of the active compounds which are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein.
- base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent.
- pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt.
- acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent.
- Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, oxalic, maleic, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like.
- inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phospho
- salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like.
- Certain specific compounds of the invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
- the neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.
- the parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the invention.
- the invention provides compounds which are in a prodrug form.
- Prodrugs of the compounds described herein are those compounds that undergo chemical changes under physiological conditions to provide the compounds of the invention.
- prodrugs can be converted to the compounds of the invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.
- Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be more bioavailable by oral administration than the parent drug.
- the prodrug may also have improved solubility in pharmacological compositions over the parent drug.
- prodrug derivatives are known in the art, such as those that rely on hydrolytic cleavage or oxidative activation of the prodrug.
- An example, without limitation, of a prodrug would be a compound of the invention which is administered as an ester (the "prodrug” ) , but then is metabolically hydrolyzed to the carboxylic acid, the active entity. Additional examples include peptidyl derivatives of a compound of the invention.
- Certain compounds of the invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the invention. Certain compounds of the invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the invention and are intended to be within the scope of the invention.
- Certain compounds of the invention possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, diastereomers, geometric isomers and individual isomers are all intended to be encompassed within the scope of the invention.
- Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as by chromatography and/or fractional crystallization.
- Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride) , separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereoisomers to the corresponding pure enantiomers.
- an appropriate optically active compound e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride
- Enantiomers can also be separated by use of a chiral HPLC column.
- a single stereoisomer e.g., a substantially pure enantiomer
- Racemic mixtures of chiral compounds of the invention can be separated and isolated by any suitable method, including: (1) formation of ionic, diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) formation of diastereomeric compounds with chiral derivatizing reagents, separation of the diastereomers, and conversion to the pure stereoisomers, and (3) separation of the substantially pure or enriched stereoisomers directly under chiral conditions. See: Wainer, Irving W., Ed. Drug Stereochemistry: Analytical Methods and Pharmacology. New York: Marcel Dekker, Inc., 1993.
- the compounds of the invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds.
- the compounds may be radiolabeled with radioactive isotopes, such as for example tritium ( 3 H) , iodine-125 ( 125 I) or carbon-14 ( 14 C) . All isotopic variations of the compounds of the invention, whether radioactive or not, are intended to be encompassed within the scope of the invention.
- therapeutically effective amount refers to the amount of the subject compound that will elicit, to some significant extent, the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician, such as when administered, is sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of the condition or disorder being treated.
- the therapeutically effective amount will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated.
- the invention also provides pharmaceutical compositions comprising the subject compounds and a pharmaceutically acceptable excipient, particularly such compositions comprising a unit dosage of the subject compounds, particularly such compositions copackaged with instructions describing use of the composition to treat an applicable disease or condition (herein) .
- compositions for administration can take the form of bulk liquid solutions or suspensions, or bulk powders. More commonly, however, the compositions are presented in unit dosage forms to facilitate accurate dosing.
- unit dosage forms refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
- Typical unit dosage forms include prefilled, premeasured ampules or syringes of the liquid compositions or pills, tablets, capsules, losenges or the like in the case of solid compositions.
- the compound is usually a minor component (from about 0.1 to about 50%by weight or preferably from about 1 to about 40%by weight) with the remainder being various vehicles or carriers and processing aids helpful for forming the desired dosing form.
- compositions may be administered separately, jointly, or combined in a single dosage unit.
- the amount administered depends on the compound formulation, route of administration, etc. and is generally empirically determined in routine trials, and variations will necessarily occur depending on the target, the host, and the route of administration, etc.
- the quantity of active compound in a unit dose of preparation may be varied or adjusted from about 1, 3, 10 or 30 to about 30, 100, 300 or 1000 mg, according to the particular application.
- unit dosage forms are packaged in a multipack adapted for sequential use, such as blisterpack, comprising sheets of at least 6, 9 or 12 unit dosage forms.
- the actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage for a particular situation is within the skill of the art.
- treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small amounts until the optimum effect under the circumstances is reached.
- the total daily dosage may be divided and administered in portions during the day if desired.
- the compounds can be administered by a variety of methods including, but not limited to, parenteral, topical, oral, or local administration, such as by aerosol or transdermally, for prophylactic and/or therapeutic treatment.
- the therapeutic protocols e.g., dosage amounts and times of administration
- the therapeutics of the invention can be administered in a therapeutically effective dosage and amount, in the process of a therapeutically effective protocol for treatment of the patient.
- microgram (ug) amounts per kilogram of patient may be sufficient, for example, in the range of about 1, 10 or 100 ug/kg to about 0.01, 0.1, 1, 10, or 100 mg/kg of patient weight though optimal dosages are compound specific, and generally empirically determined for each compound.
- a dosage regimen of the compoundss can be oral administration of from 10 mg to 2000 mg/day, preferably 10 to 1000 mg/day, more preferably 50 to 600 mg/day, in two to four (preferably two) divided doses. Intermittent therapy (e.g., one week out of three weeks or three out of four weeks) may also be used.
- the present invention provides a new solution against autoimmune diseases as well as cancers mediated by T-cells and B-cells.
- Certain autoimmune diseases such as inflammatory diseases (for example, inflammatory bowel disease, rheumatoid arthritis, glomerulonephritis and lung fibrosis, psoriasis, hypersensitivity reactions of the skin, atherosclerosis, restenosis, allergic asthma, multiple sclerosis and type 1 diabetes) are associated with inappropriate T cell activation (J.H. Hanke et al., Inflamm. Res., 1995, 357) .
- autoimmune diseases such like Hashimoto's thyroiditis, autoimmune hemolytic anemia, autoimmune atrophic gastritis of pernicious anemia, autoimmune encephalomyelitis, autoimmune orchitis, Goodpasture's disease, autoimmune thrombocytopenia including idiopathic thrombopenic purpura, sympathetic ophthalmia, myasthenia gravis, Graves'disease, primary biliary cirrhosis, chronic aggressive hepatitis, ulcerative colitis and membranous glomerulopathy, those designated as involving systemic autoimmune disorder, for example systemic lupus erythematosis, immune thrombocytopenic purpura, rhe
- the present invention can also be used to treat B-cell (humoral) based or T-cell based additional autoimmune diseases, including Cogan's syndrome, ankylosing spondylitis, Wegener's granulomatosis, autoimmune alopecia, Type I or juvenile onset diabetes, and thyroiditis.
- B-cell humoral
- T-cell T-cell based additional autoimmune diseases, including Cogan's syndrome, ankylosing spondylitis, Wegener's granulomatosis, autoimmune alopecia, Type I or juvenile onset diabetes, and thyroiditis.
- T-cell and B-cell diseases with an important role for dysfunctional T-cell and B-cell
- malignancies such as alimentary/gastrointestinal tract cancer, colon cancer, liver cancer, skin cancer including mast cell tumor and squamous cell carcinoma, breast and mammary cancer, ovarian cancer, prostate cancer, lymphoma and leukemia (including but not limited to acute myelogenous leukemia, chronic myelogenous leukemia, mantle cell lymphoma, NHL B cell lymphomas (e.g.
- B-ALL marginal zone B cell lymphoma, chronic lymphocytic leukemia, diffuse large B cell lymphoma, Burkitt lymphoma, mediastinal large B-cell lymphoma) , Hodgkin lymphoma, NK and T cell lymphomas; myelomas including multiple myeloma, myeloproliferative disorders kidney cancer, lung cancer, muscle cancer, bone cancer, bladder cancer, brain cancer, melanoma including oral and metastatic melanoma, Kaposi's sarcoma, proliferative diabetic retinopathy, and angiogenic-associated disorders including solid tumors, and pancreatic cancer [Lim et al, Haematologica, 95 (2010) pp 135-143] .
- Step 2 Synthesis of N- (2-chloro-6-fluorobenzyl) -3- (furan-2-yl) -1H-1, 2, 4-triazol-5-amine (a) :
- Step 2 Synthesis of N- (2-chloro-6-methylbenzyl) -3- (furan-2-yl) -1H-1, 2, 4-triazol-5-amine (b) :
- Step 1 Synthesis of 3- (5-amino-1H-1, 2, 4-triazol-3-yl) phenol (Intermediate 1) :
- Step 2 Synthesis of 3- (5- ( (2-chloro-6-fluorobenzyl) amino) -1H-1, 2, 4-triazol-3-yl) phenol:
- Step 1 Synthesis of 3- (3, 5-dimethoxyphenyl) -1H-1, 2, 4-triazol-5-amine (Intermediate 1) :
- Step 2 Synthesis of N- (2-chloro-6-fluorobenzyl) -3- (3, 5-dimethoxyphenyl) -1H-1, 2, 4-triazol-5-amine (12) :
- Step 3 Synthesis of 5- (5- ( (2-chloro-6-fluorobenzyl) amino) -1H-1, 2, 4-triazol-3-yl) benzene-1, 3-diol (9) :
- Step2 Synthesis of N- (2-chloro-6-fluorobenzyl) -3- (3, 4-dimethoxyphenyl) -1H-1, 2, 4-triazol-5-amine (11) :
- Step2 Synthesis of N- (2-chloro-6-fluorobenzyl) -3- (3-nitrophenyl) -1H-1, 2, 4-triazol-5-amine (13) :
- Step4 Synthesis of N- (3- (5- ( (2-chloro-6-fluorobenzyl) amino) -1H-1, 2, 4-triazol-3-yl) phenyl) acrylamide (17) :
- Step 4 Synthesis of N- (3- (5- ( (2-chloro-6-methylbenzyl) amino) -1H-1, 2, 4-triazol-3-yl) phenyl) acrylamide (20) :
- Step4 Synthesis of N- (3- (5- ( (2-chloro-6-fluorobenzyl) amino) -1H-1, 2, 4-triazol-3-yl) phenyl) -2-cyano-4, 4-dimethylpent-2-enamide (42) :
- Step4 Synthesis of N- (3- (5- ( (2-chloro-6-methylbenzyl) amino) -1H-1, 2, 4-triazol-3-yl) phenyl) -2-cyano-4, 4-dimethylpent-2-enamide (23) :
- Step4 Synthesis of N- (3- (5- ( (2-chloro-6-fluorobenzyl) amino) -1H-1, 2, 4-triazol-3-yl) phenyl) but-2-ynamide (37) :
- Step2 Synthesis of 3- ( (tert-butoxycarbonyl) (methyl) amino) benzoic acid (Intermediate 2) :
- Step3 Synthesis of tert-butyl (3- (5-amino-1H-1, 2, 4-triazol-3-yl) phenyl) (methyl) carbamate (Intermediate 3) :
- Step4 Synthesis of tert-butyl (3- (5- ( (2-chloro-6-fluorobenzyl) amino) -1H-1, 2, 4-triazol-3-yl) phenyl) (methyl) carbamate (Intermediate 4) :
- Step6 Synthesis of N- (3- (5- ( (2-chloro-6-fluorobenzyl) amino) -1H-1, 2, 4-triazol-3-yl) phenyl) -N-methylacrylamide (21)
- Step2 Synthesis of N- (2-chloro-6-fluorobenzyl) -3- (4-methoxy-3-nitrophenyl) -1H-1, 2, 4-triazol-5-amine (Intermediate 2) :
- Step3 Synthesis of 3- (3-amino-4-methoxyphenyl) -N- (2-chloro-6-fluorobenzyl) -1H-1, 2, 4-triazol-5-amine (24) :
- Step4 Synthesis of N- (5- (5- ( (2-chloro-6-fluorobenzyl) amino) -1H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) acrylamide (22) :
- Step1 Synthesis of 3- (3, 4, 5-trimethoxyphenyl) -1H-1, 2, 4-triazol-5-amine (Intermediate 1) :
- CDI N, N'-carbonyldiimidazole
- Step2 Synthesis of N- (2-chloro-6-fluorobenzyl) -3- (3, 4, 5-trimethoxyphenyl) -1H-1, 2, 4-triazol-5-amine (36) :
- Step2 Synthesis of 3- (1H-benzo [d] imidazol-2-yl) -N- (2-chloro-6-fluorobenzyl) -1H-1, 2, 4-triazol-5-amine (31) :
- Step1 Synthesis of 3, 4-bis (2-methoxyethoxy) benzoic acid (Intermediate 1) :
- Step2 Synthesis of 3- (3, 4-bis (2-methoxyethoxy) phenyl) -1H-1, 2, 4-triazol-5-amine (Intermediate 2) :
- Step3 Synthesis of 3- (3, 4-bis (2-methoxyethoxy) phenyl) -N- (2-chloro-6-fluorobenzyl) -1H-1, 2, 4-triazol-5-amine (34) :
- Step1 Synthesis of 3-methoxy-4- (3-morpholinopropoxy) benzoic acid (Intermediate 1) :
- Step2 Synthesis of 3- (3-methoxy-4- (3-morpholinopropoxy) phenyl) -1H-1, 2, 4-triazol-5-amine (Intermediate 2) :
- Step3 Synthesis of N- (2-chloro-6-fluorobenzyl) -3- (3-methoxy-4- (3-morpholinopropoxy) phenyl) -1H-1, 2, 4-triazol-5-amine (32) :
- the E. coli BL21DE3 was used for the protein expression with LB medium. Cultures were grown to an OD600nm of 1.2 at 37°C, cooled for 1 h with shaking at 18°C prior to induction for 16 h at 16°C with 0.2 mM IPTG. The proteins were purified as described previously. Briefly, cells were harvested and purified with Ni-resin and MonoQ HP column. Then the pooled protein peak fractions were purified further with Superdex-75 column using 50 mM Tris-HCl (pH 7.4) , 150 mM NaCl, 5%glycerol, 10 mM MgCl2, 5 mM DTT. All purification steps were carried out at 4 °C.
- 1000 ng inactive hMAPK14 was activated by 100 ng constitutively active hMKK6DD in the 15 ul reaction volume containing 50 uM ATP for 30 min, at 30°C.
- Kinase assay was performed using the Z’-LYTE kinase assay kit Ser/Thr 15 peptide (Invitrogen, Carlsbad, CA) .
- the standard reaction for compound screening contained 100 nM hMAPK14, 1mM peptide substrate, 100 uM ATP, 50m MHEPES (pH 7.4) , 10 mM MgCl2, 0.01%Brij-35, and 0.5%DMSO.
- Jurkat T and Ramos B cells were maintained in RPMI 1640 supplemented with 10%FBS, 100 ⁇ g of penicillin and streptomycin per ml.
- Anti-BTK (Tyr223) , anti-ZAP-70, anti-PLC ⁇ -2, anti-p-BTK (Y223) , anti-p-PLC ⁇ -2 (Y1217) , anti-p-ZAP-70 (Y319) and anti-GAPDH used for Western blotting were purchased from Cell Signaling Technology (Danvers, MA, USA) .
- Ramos B cells or Jurkat T cells (2*106) were incubated with or without different concentrations of compound for 1.5 h at 37°C in a 5%CO2 incubator. Then goat antihuman IgM F (ab’) 2 (10 ug/mL; Invitrogen) or Dynabeads Human T-activactor CD3/CD28 was added to stimulate Ramos B cells or Jurkat T cells respectively for 5 min at 37°C. The cells were centrifuged, washed once with cold DPBS and lysed with RIPA buffer (Sigma-Aldrich) containing phosphatase inhibitor cocktail 2 and Protease Inhibitor Cocktail (both from Sigma-Aldrich) on ice for 20 min. The samples then centrifuged at 20, 000g for 20 min at 4°C. The supernatants were collected and diluted 5-fold with loading buffer, then subjected to SDS-PAGE, followed by immunoblotting.
- ab goat antihuman IgM F (ab’) 2 (10 ug
- MAPKAP kinase 2 is essential for LPS-induced TNF-alpha biosynthesis. Nat Cell Biol 1, 94-97, doi: 10.1038/10061 (1999) .
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Abstract
Compounds that inhibit kinase Lck or Btk, pharmaceutically acceptable salts, hydrides, stereoisomers and pharmaceutical compositions thereof are disclosed.
Description
Inventors: Niu Huang, Xiangbing Qi, Yanli Wang, Yuze Sun., all of Beijing, CN Applicant/Assignee: National Institute of Biological Sciences, Beijing
Introduction
Autoimmune disease, also known as autoimmune disorder, is characterized by an immune response that is overactive or wrongly directed against self-tissues1. Traditionally, autoimmune diseases were regarded as T cell and/or autoantibody mediated damages. According to recent studies, both T and B lymphocytes and innate immune play important roles in the pathogenesis2. At the molecular level, the activation of T and B lymphocytes is dependent on the signaling cascades through immunoreceptors, such like T-cell antigen receptors (TCR) and B-cell antigen receptor (BCR) . These immunoreceptors can be activated by the ligand binding and then results in the activation of downstream kinase targets. A complex network of protein tyrosine kinases (PTKs) is involved in the essential pathways. The activated PTKs in turn phosphorylate the immunoreceptor tyrosine-based activation motifs (ITAMs) in the cytoplasmic face of receptor-associated transmembrane adaptors. Through series of posttranslational modifications such like phosphorylation, downstream effectors such as transcription factors that modulate gene expression of various inflammatory cytokines are initiated3, 4.
Protein kinases play important roles in the activation of B and T cells. In response to the extracellular mediators and changes in the environment, protein kinases participate in the signaling events controlling the activation, growth and differentiation of T and B cells. Some small kinase inhibitors have shown therapeutic potential in treating rheumatoid arthritis, psoriasis and so on5-9.
In the over-activated T lymphocytes, TCR-mediated signaling pathway results in the upregulation of inflammatory cytokines such as IL-2 and interferon (IFN) -γ which stimulate immune response. It has been established that the key initiating event in T cell activation is the increased phosphorylation of immunoreceptor tyrosine-based activation motif (ITAM) in TCR-CD3 complex which is completed by the Src family PTKs. This family is made up of eight different members: Src, Lck, Fyn, Lyn, Hck, Fgr, Blk, and Yes. Among them, lymphocyte-specific protein tyrosine kinase (Lck) and proto-oncogene tyrosine-protein kinase (Fyn) are expressed in T cells and located in the initial stage of TCR-mediated signaling cascade3, 10, 11.
Lck, primarily expressed in T-cells, is constitutively associated with the cytoplasmic portions of CD4 and CD8 surface receptors. It phosphorylates the TCR and initiates TCR-linked signal transduction in mature peripheral T-cells. Lck is also expressed at all stages of thymocyte development and plays a key role in the selection and maturation of developing T-cells10, 11.
Specifically, Lck functions by phosphorylating ITAM in the initiation of TCR-mediated signaling pathway, which provides binding sites for the tandem SH2 domains of Syk family kinase, ZAP-70. Once recruited, ZAP-70 is phosphorylated and activated by Lck at Tyr493 in its activation loop12, which leads to the autophosphorylation of ZAP-70. Active ZAP-70 subsequently phosphorylates adaptor proteins such like LAT, which function as scaffolds to recruit the downstream signaling molecules. This cascade culminates in the initiating transcription of genes involved in cytokine release (particularly IL-2) , and ultimately contributes to the T-cell proliferation13. Intervention of Lck kinase activity can have a strong immunosuppressive effect. For instances, Imatinib reduces TCR-induced proliferation and activation through an inhibitory effect on the LCK14, and oral administration of A-770041, a selective Lck inhibitor (IC50=147 nM) , can inhibit concanavalin A-stimulated IL-2 production in whole blood with an EC50 of approximately 80 nM15. At the dose of 10 mg/kg/day, A-770041 was shown to prevent the rejection of hearts transplanted heterotopically across a major histocompatibility barrier for least 65 days15, 16. Rosmarinic acid (RosA) inhibits LCK by targeting SH2 domain also shows suppression of T cell activation and proliferation17. At dose of 50 mg/kg/day, daily administration of RosA for 15 days was found to suppress synovitis in a murine collagen induced arthritis model18. The methyl ester derivative (RosA-Me) inhibits the expression of IL-2 gene and T cell proliferation much stronger than the counterpart (RosA) . Oral administration of RosA-Me at dose of 50 mg/kg/day greatly reduced the indexes of inflammation and arthritic in mice compared with RosA and MTX19.
As another member of Src family, Fyn has partially overlapping functions with Lck regarding to the initiation of tyrosine phosphorylation of TCR. Both kinases have been shown to interact with TCR and enhance the production of interleukin-2 (IL-2) 20, 21. Genetic evidence demonstrates that Fyn activation is strictly connected with TCR-induced translocation of Lck, suggesting the involvement in T-cell activation process for Fyn. However, studies on both Lck and Fyn deficient mice indicate these kinases share limited functions during development22-24. Studies on Lck deficient T cell line (JCaM1) proved that TCR could be still phosphorylated at the specific tyrosine residue which facilitates the recruitment of ZAP-70 kinase. In contrast, the TCR phosphorylation pattern is altered and activation of ZAP-70 is defective. During this process the expression of molecular marker CD69 was elevated, but NFAT activation and the production of interleukin-2 were markedly reduced. These results indicate Fyn can catalyze the phosphorylation of ITAM in the absence of Lck, while cannot compensate for the loss of Lck to a large extent. Furthermore, the outcome of TCR signal transduction may be determined by the choice that which kinase member of Src family is used to initiate signaling cascade25.
Dual fatty acylation with myristate and palmitate is critical in the initiation of TCR signaling pathway by Fyn and Lck. 2-bromopalmitate can effectively block Fyn palmitoylation. In Jurkat T cells, 2-bromopalmitate blocks the localization of endogenous palmitoylated Fyn and Lck to detergent-resistant membranes, which is followed with suppression of TCR signaling pathway and T cell activation26. In addition, polyunsaturated fatty acids (PUFAs) particularly the n-3 series are also found to inhibit the Fyn fatty acylation 26, 27 and used as immunosuppressive agents in the clinic. Glucocorticoid (GC) , an effective immunosuppressive agent, was found to inhibit recruitment of Fyn and Lck to the T-cell receptor complex rapidly. These results identify the Lck and Fyn kinases as molecular targets of GCs, mediated via a GC receptor-dependent pathway28. Simultaneous inhibition of Fyn and Lck has been shown to inhibit autoimmune diseases.
The success of B cell depletion therapy (BCDT) , such as clinic use of rituximab (MabThera/Rituxan; Biogen Idec/Genentech) , in the treatment of rheumatoid arthritis suggests the essential role of B cells in some autoimmune disease29. The expression of BTK, a Tec family kinase, is restricted to B cells, monocytes, macrophages, neutrophils and mast cells, while not found in T or natural killer (NK) cells. Btk is a key regulator of B-cell development, activation, signaling, and survival. It is specifically required for B cell activation following engagement of the B cell receptor (BCR) 30. Upon BCR stimulation, BTK is activated by the upstream Src-family kinases Blk, Lyn, and Fyn. The activated BTK in turn phosphorylates and activates phospholipase-Cγ2 (PLCγ2) which catalyzes the production of DAG and IP3 and leads to the stimulation of downstream signaling molecules, such as transcription factors NF-κB and NFAT. Functional mutations of Btk in mice causes X-linked immunodeficiency (Xid) , characterized by the reduced serum Ig levels31. Functional null mutations of Btk in human results in the primary immunodeficiency disease, with a lack of peripheral B cells and extremely low level of serum immunoglobulin (Ig) .
Some covalent binders targeting the specific residue (Cys481) in Btk, such as Ibrutinib (PCI-32765) and AVL-292, show high binding affinity with IC50 below 0.5 nM and oral efficacy in established CIA mouse model, which means the dose-dependent inhibition of clinical arthritis scores and the production of anticollagen autoantibodies6. In addition, PCI-32765 also inhibits autoantibody production and the development of kidney disease in the MRL-Fas (lpr) lupus model6. Another inhibitor RN486 of Btk (IC50=4.0 nM) can completely stop the disease progression in NZB × NZW mouse model with systemic lupus erythematosus (SLE) . Administration of RN486 was observed to significantly inhibit inflammatory response in the PCA (type I hypersensitivity) or rPCA (type III hypersensitivity) mouse models. As to RA
model, oral administration of RN486 could reduce both paw swelling and inflammatory markers in the blood by inhibiting both joint and systemic inflammation32.
Besides of the above-mentioned kinases involved in TCR and BCR proximal signaling pathway, accumulating studies suggest that p38 MAPK plays a significant role in the pathogenesis of several immune-mediated diseases, including rheumatoid arthritis (RA) , syndrome, systemic lupus erythematosus (SLE) , inflammatory bowel disease (IBD) and psoriasis. In TCR and BCR signaling pathway, the MAPK cascade is activated by Vav. As the downstream effector, Rac1 acts as a MAPKK kinase (MAPKKK) and is located upstream of p38 MAPK. Upon activation, p38 MAPK regulates the expression of tumor necrosis factor (TNF) -α, interferon- (IFN) -γ and other cytokines, such as IL-1, TL-6 and IL-17 via transcriptional and post-transcriptional mechanisms33, 34. The success of antibodies treatment suggested the key roles of cytokines and p38 MAPK in autoimmune diseases development. Some small p38 inhibitors have shown promising feedbacks in both preclinical and early clinical studies. However, most follow-up clinical trials failed due to either poor efficacy or severe toxicity. VX-745, a p38 MAPK inhibitor occupying ATP pocket, was discontinued due to liver toxicity despite the promising results in phase II trials for RA35. In colitis model induced by dextran sodium sulphate (DSS) , SB203580 treatment was shown to improve clinical scores by reducing mRNA levels of proinflammatory cytokines in vivo36. Additionally, some non-ATP competitive inhibitors with high selectivity, such as VX-702, SCIO469, BIRB796, also show transient inhibition of pro-inflammatory disease markers and are unable to completely control disease exacerbation or progression37.
The unacceptable toxicities and low efficiency in the clinical trials suggest administrating of p38 MAPK inhibitor might not be the best solution for anti-inflammatory therapy. Extended studies suggested the multi-faceted role of p38 MAPK in regulating numerous cellular processes other than inflammation. The multiplicity of function underlies the high toxicity with the strong inhibition. Furthermore, it appears that the existed compensatory mechanisms further weaken the efficiency of treatment. These studies highlight the necessity to develop new agents targeting more upstream kinases with pathogenesis relevance simultaneously. Inhibitors with multi-target-directed properties and moderate but balanced affinities represent a better choice of treatment, with respect to both limited toxicity and sustained clinical response.
Summary of the Invention
The invention provides compounds of formula I:
R1–R5 are independently H, halogen, hydroxyl, methyl, trifluoromethyl, or methoxyl, particularly wherein R1 and R5 are independently halogen, hydroxyl, methyl, trifluoromethyl; and
R6 is optionally-substituted Cn cyclic hydrocarbyl, where n = 3-18, and comprising up to n-1 heteroatoms independently selected from N, O, S and P, particularly wherein said hydrocarbyl is selected from cycloalkyl, aryl, heteroaryl, or heterocyclyl; or a stereoisomer or pharmaceutically acceptable salt thereof.
In particular embodiments:
-n is 3, 4, 5, 6, 8, 9 or 10; or n is 3, 5, 6 or 9;
-R6 is substituted or unsubstituted, homo-or hetero, 5-or 6-membered cyclic or 9 or 10 membered bi-cyclic aryl;
-R6 is optionally substituted: cyclopropyl; 5-membered aryl selected from pyrrole, azole (e.g. pyrazole, imidazole, triazole, tetrazole, pentazole, oxazole, isoxazole, thiazole or isothiazole) , furan, dioxole thiophene, dithiole or oxathiole, and reduced forms thereof (e.g dihydrofuran, dihydroimidazole) ; preferably 2-moieties, such as 2-azole, 2-pyrrole, 2-azole (e.g. 2-pyrazole, 2-imidazole, 2-oxazole, 2-isoxazole, 2-thiozole, or 2-isothiozole) , 2-furan, 2-thiophene, 2-oxole, dioxole, or 2-thiole; 6 membered aryl selected from phenyl and pyridine; or 9 membered aryl is benzimidazole;
-R6 is phenyl, 3-substituted phenyl, 3, 4-substituted phenyl or 3, 4, 5-substituted phenyl;
-R6 substituents are selected from: halogen, -OR', -OC (O) R', -NR'R", -SR', -R', -CN, -NO2, -CO2R', -CONR'R", -C (O) R', -OC (O) NR'R", -NR"C (O) R', -NR"CO2R', -NR'-C (O) NR"R″′, -NR'-SO2NR"R″′, -NH-C (NH2) =NH, -NR'C (NH2) =NH, -NH-C (NH2) =NR', -S (O) R', -SO2R', -SO2NR'R", -NR"SO2R, -N3, -CH (Ph) 2, perfluoro (C1-C4) alko-xy and perfluoro (C1-C4) alkyl, in a number ranging from zero to the total number of open valences on the aromatic ring system; and where R', R"and R″′are independently selected from hydrogen, (C1-C8) alkyl and heteroalkyl, unsubstituted aryl and heteroaryl, (unsubstituted aryl) - (C1-C4) alkyl and (unsubstituted aryl) oxy- (C1-C4) alkyl;
-R2-R4 are H, and at least one of R1 and R5 is halogen, hydroxyl, methyl, trifluoromethyl, or methoxyl;
-R2-R4 are H, and R1 and R5 are halogen, hydroxyl, methyl, trifluoromethyl, or methoxyl;
-all combinations thereof, such as wherein:
R2-R4 are H, and R1 and R5 are halogen, hydroxyl, methyl, trifluoromethyl, or methoxyl;
R6 is substituted or unsubstituted, homo-or hetero, 5-or 6-membered cyclic or 9 or 10 membered bi-cyclic aryl; and
R6 substituents are selected from: halogen, -OR', -OC (O) R', -NR'R", -SR', -R', -CN, -NO2, -CO2R', -CONR'R", -C (O) R', -OC (O) NR'R", -NR"C (O) R', -NR"CO2R', -NR'-C (O) NR"R″′, -NR'-SO2NR"R″′, -NH-C (NH2) =NH, -NR'C (NH2) =NH, -NH-C (NH2) =NR', -S (O) R', -SO2R', -SO2NR'R", -NR"SO2R, -N3, -CH (Ph) 2, perfluoro (C1-C4) alko-xy and perfluoro (C1-C4) alkyl, in a number ranging from zero to the total number of open valences on the aromatic ring system; and where R', R"and R″′are independently selected from hydrogen, (C1-C8) alkyl and heteroalkyl, unsubstituted aryl and heteroaryl, (unsubstituted aryl) - (C1-C4) alkyl and (unsubstituted aryl) oxy- (C1-C4) alkyl; and/or
-the compounds have a Lck or Btk-inhibiting activity corresponding to an IC50 of 10 uM or less in a kinase assay.
Representative, exemplary compounds comprise the following structure, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
The invention provides pharmaceutical compositions comprising the subject compounds. In aspects, the invention provides a pharmaceutical composition comprising a therapeutically
effective amount of a subject compound in unit dosage form and one or more pharmaceutically acceptable excipients. In aspects, the invention provides a combination comprising a therapeutically effective amount of a subject compound and a different agent therapeutically active against an autoimmune and/or inflammatory disease or cancer.
The invention also provides methods of making and using the subject compounds, including methods of inhibiting kinase activity. In aspects, the invention provides a method of treating a disease associated with undesirable kinase activity, which comprises administering to a person in need thereof an effective amount of a subject compound, or a prodrug thereof, wherein the disease is an allergic disease, an autoimmune disease, an inflammatory disease, or cancer, wherein the method may further comprise the antecedent step of diagnosing the disease or cancer, or the subsequent step of detecting a resultant amelioration of the disease or cancer.
The invention encompasses all combination of the particular embodiments recited herein.
Description of Particular Embodiments of the Invention
The following descriptions of particular embodiments and examples are provided by way of illustration and not by way of limitation. Those skilled in the art will readily recognize a variety of noncritical parameters that could be changed or modified to yield essentially similar results. The invention provides myriad embodiments.
All possible combinations are encompassed as though each was expressly recited; hence, the aspects and embodiments include, for example, the combination wherein R1 is substituted or unsubstituted phenyl; R2 is H, hydroxyl, C1-C4 alkyl, or C1-C4alkoyxl, R3 is H or methyl, and R4 is 1-dimethylpropyl.
Unless contraindicated or noted otherwise, in these descriptions and throughout this specification, the terms “a” and “an” mean one or more, the term “or” means and/or and polynucleotide sequences are understood to encompass opposite strands as well as alternative backbones described herein. Furthermore, genuses are recited as shorthand for a recitation of all members of the genus; for example, the recitation of (C1-C3) alkyl is shorthand for a recitation of all C1-C3 alkyls: methyl, ethyl and propyl, including isomers thereof.
The following words, phrases and symbols are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise.
The term "heteroatom" as used herein generally means any atom other than carbon or hydrogen. Preferred heteroatoms include oxygen (O) , phosphorus (P) , sulfur (S) , nitrogen (N) , and halogens, and preferred heteroatom functional groups are haloformyl, hydroxyl, aldehyde,
amine, azo, carboxyl, cyanyl, thocyanyl, carbonyl, halo, hydroperoxyl, imine, aldimine, isocyanide, iscyante, nitrate, nitrile, nitrite, nitro, nitroso, phosphate, phosphono, sulfide, sulfonyl, sulfo, and sulfhydryl.
The term "alkyl, " by itself or as part of another substituent, means, unless otherwise stated, a straight or branched chain, or cyclic hydrocarbon radical, or combination thereof, which is fully saturated, having the number of carbon atoms designated (i.e. C1-C8 means one to eight carbons) . Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl, (cyclohexyl) methyl, cyclopropylmethyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl and the like.
The term "alkenyl" , by itself or as part of another substituent, means a straight or branched chain, or cyclic hydrocarbon radical, or combination thereof, which may be mono-or polyunsaturated, having the number of carbon atoms designated (i.e. C2-C8 means two to eight carbons) and one or more double bonds. Examples of alkenyl groups include vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2- (butadienyl) , 2, 4-pentadienyl, 3- (1, 4-pentadienyl) and higher homologs and isomers thereof.
The term "alkynyl" , by itself or as part of another substituent, means a straight or branched chain hydrocarbon radical, or combination thereof, which may be mono-or polyunsaturated, having the number of carbon atoms designated (i.e. C2-C8 means two to eight carbons) and one or more triple bonds. Examples of alkynyl groups include ethynyl, 1-and 3-propynyl, 3-butynyl and higher homologs and isomers thereof.
The term "alkylene" by itself or as part of another substituent means a divalent radical derived from alkyl, as exemplified by -CH2-CH2-CH2-CH2-. Typically, an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred in the invention. A "lower alkyl" or "lower alkylene" is a shorter chain alkyl or alkylene group, generally having eight or fewer carbon atoms.
The terms "alkoxy, " "alkylamino" and "alkylthio" (or thioalkoxy) are used in their conventional sense, and refer to those alkyl groups attached to the remainder of the molecule via an oxygen atom, an amino group, or a sulfur atom, respectively.
The term "heteroalkyl, " by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or cyclic hydrocarbon radical, or combinations thereof, consisting of the stated number of carbon atoms and from one to three heteroatoms selected from the group consisting of O, N, P, Si and S, wherein the nitrogen, sulfur, and phosphorous atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. The heteroatom (s) O, N, P and S may be placed at any interior position of the heteroalkyl group. The heteroatom Si may be placed at any position of the
heteroalkyl group, including the position at which the alkyl group is attached to the remainder of the molecule. Examples include -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N (CH3) -CH3, -CH2-S-CH2-CH3, -CH2-CH2, -S (O) -CH3, -CH2-CH2-S (O) 2-CH3, -CH=CH-O-CH3, -Si (CH3) 3, -CH2-CH=N-OCH3, and -CH=CH-N (CH3) 2. Up to two heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3 and -CH2-O-Si (CH3) 3.
Similarly, the term "heteroalkylene, " by itself or as part of another substituent means a divalent radical derived from heteroalkyl, as exemplified by -CH2-CH2-S-CH2-CH2-and -CH2-S-CH2-CH2-NH-CH2-. For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like) . Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied.
The terms "cycloalkyl" and "heterocycloalkyl" , by themselves or in combination with other terms, represent, unless otherwise stated, cyclic versions of "alkyl" and "heteroalkyl" , respectively. Accordingly, a cycloalkyl group has the number of carbon atoms designated (i.e., C3-C8 means three to eight carbons) and may also have one or two double bonds. A heterocycloalkyl group consists of the number of carbon atoms designated and from one to three heteroatoms selected from the group consisting of O, N, Si and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. Additionally, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Examples of cycloalkyl include cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Examples of heterocycloalkyl include 1- (1, 2, 5, 6-tetrahydropyrid-yl) , 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, and the like.
The terms "halo" and "halogen, " by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as "haloalkyl, " are meant to include alkyl substituted with halogen atoms, which can be the same or different, in a number ranging from one to (2m'+1) , where m'is the total number of carbon atoms in the alkyl group. For example, the term "halo (C1-C4) alkyl" is mean to include trifluoromethyl, 2, 2, 2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like. Thus, the term "haloalkyl" includes monohaloalkyl (alkyl substituted with one halogen atom) and polyhaloalkyl (alkyl substituted with halogen atoms in a number ranging from two to (2m'+1) halogen atoms, where m'is the total number of carbon atoms in the alkyl group) . The term "perhaloalkyl" means, unless otherwise stated, alkyl substituted with (2m'+1) halogen atoms, where m'is the total number of carbon atoms in the alkyl group. For example the term "perhalo (C1-C4) alkyl" is
meant to include trifluoromethyl, pentachloroethyl, 1, 1, 1-trifluoro-2-bromo-2-chloroethyl and the like.
The term "acyl" refers to those groups derived from an organic acid by removal of the hydroxy portion of the acid. Accordingly, acyl is meant to include, for example, acetyl, propionyl, butyryl, decanoyl, pivaloyl, benzoyl and the like.
The term "aryl" means, unless otherwise stated, a polyunsaturated, typically aromatic, hydrocarbon substituent which can be a single ring or multiple rings (up to three rings) which are fused together or linked covalently. Non-limiting examples of aryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl and 1, 2, 3, 4-tetrahydronaphthalene.
The term heteroaryl, "refers to aryl groups (or rings) that contain from zero to four heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen heteroatom are optionally quaternized. A heteroaryl group can be attached to the remainder of the molecule through a heteroatom. Non-limiting examples of heteroaryl groups include 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl and 6-quinolyl.
For brevity, the term "aryl" when used in combination with other terms (e.g., aryloxy, arylthioxy, arylalkyl) includes both aryl and heteroaryl rings as defined above. Thus, the term "arylalkyl" is meant to include those radicals in which an aryl group is attached to an alkyl group (e.g., benzyl, phenethyl, pyridylmethyl and the like) including those alkyl groups in which a carbon atom (e.g., a methylene group) has been replaced by, for example, an oxygen atom (e.g., phenoxymethyl, 2-pyridyloxymethyl, 3- (1-naphthyloxy) propyl, and the like) .
Each of the above terms (e.g., "alkyl, " "heteroalkyl, " "aryl" and "heteroaryl" ) is meant to include both substituted and unsubstituted forms of the indicated radical. Preferred substituents for each type of radical are provided below.
Substituents for the alkyl and heteroalkyl radicals (as well as those groups referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl and heterocycloalkenyl) can be a variety of groups selected from: -OR', =O, =NR', =N-OR', -NR'R", -SR', halogen, -SiR'R"R″′, -OC (O) R', -C (O) R', -CO2R', -CONR'R", -OC (O) NR'R", -NR"C (O) R', -NR'-C (O) NR"R″′, -NR'-SO2NR″′, -NR"CO2R', -NH-C (NH2) =NH, -NR'C (NH2) =NH, -NH-C (NH2) =NR', -S (O) R', -SO2R', -SO2NR'R", -NR"SO2R, -CN and -NO2, in a number ranging from zero to three, with those groups having zero, one or two substituents
being particularly preferred. R', R"and R″′each independently refer to hydrogen, unsubstituted (C1-C8) alkyl and heteroalkyl, unsubstituted aryl, aryl substituted with one to three halogens, unsubstituted alkyl, alkoxy or thioalkoxy groups, or aryl- (C1-C4) alkyl groups. When R'a nd R"are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 5-, 6-or 7-membered ring. For example, -NR'R"is meant to include 1-pyrrolidinyl and 4-morpholinyl. Typically, an alkyl or heteroalkyl group will have from zero to three substituents, with those groups having two or fewer substituents being preferred in the invention. More preferably, an alkyl or heteroalkyl radical will be unsubstituted or monosubstituted. Most preferably, an alkyl or heteroalkyl radical will be unsubstituted. From the above discussion of substituents, one of skill in the art will understand that the term "alkyl" is meant to include groups such as trihaloalkyl (e.g., -CF3 and -CH2CF3) .
Preferred substituents for the alkyl and heteroalkyl radicals are selected from: -OR', =O, -NR'R", -SR', halogen, -SiR'R"R″′, -OC (O) R', -C (O) R', -CO2R', -CONR'R", -OC (O) NR'R", -NR"C (O) R', -NR"CO2R', -NR'-SO2NR"R″′, -S (O) R', -SO2R', -SO2NR'R", -NR"SO2R, -CN and -NO2, where R'a nd R"are as defined above. Further preferred substituents are selected from: -OR', =O, -NR'R", halogen, -OC (O) R', -CO2R', -CONR'R", -OC (O) NR'R", -NR"C (O) R', -NR"CO2R', -NR'-SO2NR"R″′, -SO2R', -SO2NR'R", -NR"SO2R, -CN and -NO2.
Similarly, substituents for the aryl and heteroaryl groups are varied and selected from: halogen, -OR', -OC (O) R', -NR'R", -SR', -R', -CN, -NO2, -CO2R', -CONR'R", -C (O) R', -OC (O) NR'R", -NR"C (O) R', -NR"CO2R', -NR'-C (O) NR"R″′, -NR'-SO2NR"R″′, -NH-C (NH2) =NH, -NR'C (NH2) =NH, -NH-C (NH2) =NR', -S (O) R', -SO2R', -SO2NR'R", -NR"SO2R, -N3, -CH (Ph) 2, perfluoro (C1-C4) alko-xy and perfluoro (C1-C4) alkyl, in a number ranging from zero to the total number of open valences on the aromatic ring system; and where R', R"and R″′are independently selected from hydrogen, (C1-C8) alkyl and heteroalkyl, unsubstituted aryl and heteroaryl, (unsubstituted aryl) - (C1-C4) alkyl and (unsubstituted aryl) oxy- (C1-C4) alkyl. When the aryl group is 1, 2, 3, 4-tetrahydronaphthalene, it may be substituted with a substituted or unsubstituted (C3-C7) spirocycloalkyl group. The (C3-C7) spirocycloalkyl group may be substituted in the same manner as defined herein for "cycloalkyl" . Typically, an aryl or heteroaryl group will have from zero to three substituents, with those groups having two or fewer substituents being preferred in the invention. In one embodiment of the invention, an aryl or heteroaryl group will be unsubstituted or monosubstituted. In another embodiment, an aryl or heteroaryl group will be unsubstituted.
Preferred substituents for aryl and heteroaryl groups are selected from: halogen, -OR', -OC (O) R', -NR'R", -SR', -R', -CN, -NO2, -CO2R', -CONR'R", -C (O) R', -OC (O) NR'R", -NR"C (O) R', -S (O) R', -SO2R', -SO2NR'R", -NR"SO2R, -N3, -CH (Ph) 2, perfluoro (C1-C4) alkoxy
and perfluoro (C1-C4) alkyl, where R'a nd R"are as defined above. Further preferred substituents are selected from: halogen, -OR', -OC (O) R', -NR'R", -R', -CN, -NO2, -CO2R', -CONR'R", -NR"C (O) R', -SO2R', -SO2NR'R", -NR"SO2R, perfluoro (C1-C4) alkoxy and perfluoro (C1-C4) alkyl.
The substituent -CO2H, as used herein, includes bioisosteric replacements therefor; see, e.g., The Practice of Medicinal Chemistry; Wermuth, C.G., Ed.; Academic Press: New York, 1996; p. 203.
Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -T-C (O) - (CH2) q-U-, wherein T and U are independently -NH-, -O-, -CH2-or a single bond, and q is an integer of from 0 to 2. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -A- (CH2) r-B-, wherein A and B are independently -CH2-, -O-, -NH-, -S-, -S (O) -, -S (O) 2-, -S (O) 2NR'-or a single bond, and r is an integer of from 1 to 3. One of the single bonds of the new ring so formed may optionally be replaced with a double bond. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula - (CH2) s-X- (CH2) t--, where s and t are independently integers of from 0 to 3, and X is -O-, -NR'-, -S-, -S (O) -, -S (O) 2-, or -S (O) 2NR'-. The substituent R'in -NR'-and -S (O) 2NR'-is selected from hydrogen or unsubstituted (C1-C6) alkyl.
Preferred substituents are disclosed herein and exemplified in the tables, structures, examples, and claims, and may be applied across different compounds of the invention, i.e. substituents of any given compound may be combinatorially used with other compounds.
In particular embodiments applicable substituents are independently substituted or unsubstituted heteroatom, substituted or unsubstituted, 0-3 heteroatom C1-C6 alkyl, substituted or unsubstituted, 0-3 heteroatom C2-C6 alkenyl, substituted or unsubstituted, 0-3 heteroatom C2-C6 alkynyl, or substituted or unsubstituted, 0-3 heteroatom C6-C14 aryl, wherein each heteroatom is independently oxygen, phosphorus, sulfur or nitrogen.
In more particular embodiments, applicable substituents are independently aldehyde, aldimine, alkanoyloxy, alkoxy, alkoxycarbonyl, alkyloxy, alkyl, amine, azo, halogens, carbamoyl, carbonyl, carboxamido, carboxyl, cyanyl, ester, halo, haloformyl, hydroperoxyl, hydroxyl, imine, isocyanide, iscyante, N-tert-butoxycarbonyl, nitrate, nitrile, nitrite, nitro, nitroso, phosphate, phosphono, sulfide, sulfonyl, sulfo, sulfhydryl, thiol, thiocyanyl, trifluoromethyl or trifluromethyl ether (OCF3) .
The term "pharmaceutically acceptable salts" is meant to include salts of the active compounds which are prepared with relatively nontoxic acids or bases, depending on the
particular substituents found on the compounds described herein. When compounds of the invention contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. When compounds of the invention contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, oxalic, maleic, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like. Certain specific compounds of the invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
The neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the invention.
In addition to salt forms, the invention provides compounds which are in a prodrug form. Prodrugs of the compounds described herein are those compounds that undergo chemical changes under physiological conditions to provide the compounds of the invention. Additionally, prodrugs can be converted to the compounds of the invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be more bioavailable by oral administration than the parent drug. The prodrug may also have improved solubility in pharmacological compositions over the parent drug. A wide variety of prodrug derivatives are known in the art, such as those that rely on hydrolytic cleavage or oxidative activation of the prodrug. An example, without limitation, of a prodrug would be a compound of the invention
which is administered as an ester (the "prodrug" ) , but then is metabolically hydrolyzed to the carboxylic acid, the active entity. Additional examples include peptidyl derivatives of a compound of the invention.
Certain compounds of the invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the invention. Certain compounds of the invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the invention and are intended to be within the scope of the invention.
Certain compounds of the invention possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, diastereomers, geometric isomers and individual isomers are all intended to be encompassed within the scope of the invention.
Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as by chromatography and/or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride) , separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereoisomers to the corresponding pure enantiomers. Enantiomers can also be separated by use of a chiral HPLC column.
A single stereoisomer, e.g., a substantially pure enantiomer, may be obtained by resolution of the racemic mixture using a method such as formation of diastereomers using optically active resolving agents (Eliel, E. and Wilen, S. Stereochemistry of Organic Compounds. New York: John Wiley & Sons, Inc., 1994; Lochmuller, C.H., et al. "Chromatographic resolution of enantiomers: Selective review. " J. Chromatogr., 113 (3) (1975) : pp. 283-302) . Racemic mixtures of chiral compounds of the invention can be separated and isolated by any suitable method, including: (1) formation of ionic, diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) formation of diastereomeric compounds with chiral derivatizing reagents, separation of the diastereomers, and conversion to the pure stereoisomers, and (3) separation of the substantially pure or enriched stereoisomers directly under chiral conditions. See: Wainer, Irving W., Ed. Drug Stereochemistry: Analytical Methods and Pharmacology. New York: Marcel Dekker, Inc., 1993.
The compounds of the invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example tritium (3H) ,
iodine-125 (125I) or carbon-14 (14C) . All isotopic variations of the compounds of the invention, whether radioactive or not, are intended to be encompassed within the scope of the invention.
The term "therapeutically effective amount" refers to the amount of the subject compound that will elicit, to some significant extent, the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician, such as when administered, is sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of the condition or disorder being treated. The therapeutically effective amount will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated.
The invention also provides pharmaceutical compositions comprising the subject compounds and a pharmaceutically acceptable excipient, particularly such compositions comprising a unit dosage of the subject compounds, particularly such compositions copackaged with instructions describing use of the composition to treat an applicable disease or condition (herein) .
The compositions for administration can take the form of bulk liquid solutions or suspensions, or bulk powders. More commonly, however, the compositions are presented in unit dosage forms to facilitate accurate dosing. The term "unit dosage forms" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. Typical unit dosage forms include prefilled, premeasured ampules or syringes of the liquid compositions or pills, tablets, capsules, losenges or the like in the case of solid compositions. In such compositions, the compound is usually a minor component (from about 0.1 to about 50%by weight or preferably from about 1 to about 40%by weight) with the remainder being various vehicles or carriers and processing aids helpful for forming the desired dosing form.
Suitable excipients or carriers and methods for preparing administrable compositions are known or apparent to those skilled in the art and are described in more detail in such publications as Remington's Pharmaceutical Science, Mack Publishing Co, NJ (1991) . In addition, the compounds may be advantageously used in conjunction with other therapeutic agents as described herein or otherwise known in the art, particularly other anti-autoimmune agents. Hence the compositions may be administered separately, jointly, or combined in a single dosage unit.
The amount administered depends on the compound formulation, route of administration, etc. and is generally empirically determined in routine trials, and variations will necessarily occur depending on the target, the host, and the route of administration, etc.
Generally, the quantity of active compound in a unit dose of preparation may be varied or adjusted from about 1, 3, 10 or 30 to about 30, 100, 300 or 1000 mg, according to the particular application. In a particular embodiment, unit dosage forms are packaged in a multipack adapted for sequential use, such as blisterpack, comprising sheets of at least 6, 9 or 12 unit dosage forms. The actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage for a particular situation is within the skill of the art. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small amounts until the optimum effect under the circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day if desired.
The compounds can be administered by a variety of methods including, but not limited to, parenteral, topical, oral, or local administration, such as by aerosol or transdermally, for prophylactic and/or therapeutic treatment. Also, in accordance with the knowledge of the skilled clinician, the therapeutic protocols (e.g., dosage amounts and times of administration) can be varied in view of the observed effects of the administered therapeutic agents on the patient, and in view of the observed responses of the disease to the administered therapeutic agents.
The therapeutics of the invention can be administered in a therapeutically effective dosage and amount, in the process of a therapeutically effective protocol for treatment of the patient. For more potent compounds, microgram (ug) amounts per kilogram of patient may be sufficient, for example, in the range of about 1, 10 or 100 ug/kg to about 0.01, 0.1, 1, 10, or 100 mg/kg of patient weight though optimal dosages are compound specific, and generally empirically determined for each compound.
In general, routine experimentation in clinical trials will determine specific ranges for optimal therapeutic effect, for each therapeutic, each administrative protocol, and administration to specific patients will also be adjusted to within effective and safe ranges depending on the patient condition and responsiveness to initial administrations. However, the ultimate administration protocol will be regulated according to the judgment of the attending clinician considering such factors as age, condition and size of the patient as well as compounds potency, severity of the disease being treated. For example, a dosage regimen of the compoundss can be oral administration of from 10 mg to 2000 mg/day, preferably 10 to 1000 mg/day, more preferably 50 to 600 mg/day, in two to four (preferably two) divided doses. Intermittent therapy (e.g., one week out of three weeks or three out of four weeks) may also be used.
The present invention provides a new solution against autoimmune diseases as well as cancers mediated by T-cells and B-cells. Certain autoimmune diseases such as inflammatory diseases (for example, inflammatory bowel disease, rheumatoid arthritis, glomerulonephritis and
lung fibrosis, psoriasis, hypersensitivity reactions of the skin, atherosclerosis, restenosis, allergic asthma, multiple sclerosis and type 1 diabetes) are associated with inappropriate T cell activation (J.H. Hanke et al., Inflamm. Res., 1995, 357) . In addition, the acute rejection of transplanted organs as well as Graft versus Host Disease (GvHD) after allogeneic bone marrow and stem cell transplantation can also be interpreted as a consequence of inappropriate T cell activation. Derailed B lymphocyte activation is a hallmark of many autoimmune diseases, such like Hashimoto's thyroiditis, autoimmune hemolytic anemia, autoimmune atrophic gastritis of pernicious anemia, autoimmune encephalomyelitis, autoimmune orchitis, Goodpasture's disease, autoimmune thrombocytopenia including idiopathic thrombopenic purpura, sympathetic ophthalmia, myasthenia gravis, Graves'disease, primary biliary cirrhosis, chronic aggressive hepatitis, ulcerative colitis and membranous glomerulopathy, those designated as involving systemic autoimmune disorder, for example systemic lupus erythematosis, immune thrombocytopenic purpura, rheumatoid arthritis, Sjogren's syndrome, Reiter's syndrome, polymyositis-dermatomyositis, systemic sclerosis, polyarteritis nodosa, multiple sclerosis and bullous pemphigoid. The present invention can also be used to treat B-cell (humoral) based or T-cell based additional autoimmune diseases, including Cogan's syndrome, ankylosing spondylitis, Wegener's granulomatosis, autoimmune alopecia, Type I or juvenile onset diabetes, and thyroiditis. Other disease with an important role for dysfunctional T-cell and B-cell is malignancies, such as alimentary/gastrointestinal tract cancer, colon cancer, liver cancer, skin cancer including mast cell tumor and squamous cell carcinoma, breast and mammary cancer, ovarian cancer, prostate cancer, lymphoma and leukemia (including but not limited to acute myelogenous leukemia, chronic myelogenous leukemia, mantle cell lymphoma, NHL B cell lymphomas (e.g. precursor B-ALL, marginal zone B cell lymphoma, chronic lymphocytic leukemia, diffuse large B cell lymphoma, Burkitt lymphoma, mediastinal large B-cell lymphoma) , Hodgkin lymphoma, NK and T cell lymphomas; myelomas including multiple myeloma, myeloproliferative disorders kidney cancer, lung cancer, muscle cancer, bone cancer, bladder cancer, brain cancer, melanoma including oral and metastatic melanoma, Kaposi's sarcoma, proliferative diabetic retinopathy, and angiogenic-associated disorders including solid tumors, and pancreatic cancer [Lim et al, Haematologica, 95 (2010) pp 135-143] . We provide series of multi-target-directed small-molecule kinase inhibitors by focusing on a collection of well-defined and highly-related kinase targets which are involved in the above indications, including but not limited to Lck, Fyn, Btk, p38 MAPK.
It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application
and scope of the appended claims. All publications, patents, and patent applications cited herein, including citations therein, are hereby incorporated by reference in their entirety for all purposes.
Examples
Reagents and chemicals
Chromatography columns used for protein purification, NI-NTA-agarose, MonoQ HP column and Superdex 75 were purchased from GE Healthcare. Reagents used for crystallization were obtained from Hampton Research. The DNA sequences encoding the human mitogen-activated protein kinase 14 (hMAPK14) and the human mitogen-activated protein kinase kinase 6 (MKK6) were purchased from OpenBiosystems. All reactions were carried out under an inert atmosphere of nitrogen or argon unless otherwise noted. DMF, DMSO (99.9%, extra dry) was used as received. All other reagents were purchased commercially and used as received, unless otherwise noted. NMR spectra were recorded with Bruker spectrometers. 1H (400 MHz) and NMR chemical shifts are reported relative to internal TMS (δ = 0.00 ppm) or to residual protiated solvent. Data are presented as follows: chemical shift (ppm) , multiplicity (s= singlet, d = doublet, t = triplet, q = quartet, sept = septet, m = multiplet, br = broad) , coupling constant J (Hz) and integration.
Synthesis:
i) Aminoguanidinium nitrate, NaOH, H2O, reflux;
ii) a) 2-chloro-6-fluorobenzaldehyde, toluene, reflux; b) NaBH3CN, acetic acid, room temperature.
Step1: Synthesis of 3- (furan-2-yl) -1H-1, 2, 4-triazol-5-amine (1) :
A suspension ofAminoguanidinium nitrate (22.0 g, 160.5 mmol) in acetonitrile (200 mL) was cooled to 0 ℃, NaOH (20.0 g, 500.0 mmol) was added in portions, the mixture was stirred at room temperature for 3 h. Then, furan-2-carbonyl chloride (20.0 g, 153.2 mmol) was added dropwise at 0℃. After the addition, the mixture was stirred at room temperature for 6 h. The solvent was then removed by rotatory evaporation, the residue was dissolved in water (200 mL) , and heated to reflux for 5 h. The solvent was removed under reduced pressure to give a crude product, which was purified by column chromatography (silica gel, dichloromethane/methanol = 50: 1 to 10: 1) to give 3- (furan-2-yl) -1H-1, 2, 4-triazol-5-amine (1) as a white solid (8.5 g, yield 37%) . Mass spectrum (ESI) m/z calc. for C6H6N4O [M +H] + 151.05, found 151.10. 1H NMR
(400 MHz, d6-DMSO) δ (ppm) 12.07 (s, 1H) , 7.68 (s, 1H) , 6.71–6.61 (m, 1H) , 6.54 (s, 1H) , 6.08 (s, 2H) .
Step 2: Synthesis of N- (2-chloro-6-fluorobenzyl) -3- (furan-2-yl) -1H-1, 2, 4-triazol-5-amine (a) :
The mixture of 3- (furan-2-yl) -1H-1, 2, 4-triazol-5-amine (1) (8.5 g, 56.6 mmol) and 2-chloro-6-fluorobenzaldehyde (17 g, 107.2 mmol) in anhydrous toluene (100 mL) was heated to reflux for 8 h. After cooling to room temperature, NaBH3CN (5.0 g, 79.6 mmol) and acetic acid (20mL) were added. Then, the mixture was stirred at room temperature for 3 h. The reaction mixture was quenched with water (10 mL) and the solvent was removed under reduced pressure. The residue was purified by reversed phase flash column chromatography (C18) to give N- (2-chloro-6-fluorobenzyl) -3- (furan-2-yl) -1H-1, 2, 4-triazol-5-amine (a) as a white solid (3.2 g, yield 19.3%) . Mass spectrum (ESI) m/z calc. for C13H10ClFN4O [M+H] + 293.05 , 295.05, found 293.2, 295.3. 1H NMR (400 MHz, d6-DMSO) δ 12.22 (s, 1H) , 7.70 (s, 1H) , 7.37 (dd, J = 20.6, 7.3 Hz, 2H) , 7.24 (t, J = 8.7 Hz, 1H) , 6.94 (s, 1H) , 6.73 (s, 1H) , 6.55 (s, 1H) , 4.50 (s, 2H) .
Step 2: Synthesis of N- (2-chloro-6-methylbenzyl) -3- (furan-2-yl) -1H-1, 2, 4-triazol-5-amine (b) :
The mixture of 3- (furan-2-yl) -1H-1, 2, 4-triazol-5-amine (1) (50 mg, 0.33 mmol) and 2-chloro-6-methylbenzaldehyde (97.3 mg, 0.63 mmol) in anhydrous toluene (5 mL) was heated to reflux for 8 h. After cooling to room temperature, NaBH3CN (29.5mg, 0.47 mmol) and acetic acid (0.5 mL) were added. Then, the mixture was stirred at room temperature for 3 h. The reaction mixture was quenched with water (1 mL) and the solvent was removed under reduced pressure. The residue was purified by reversed phase flash column chromatography (C18) to give N- (2-chloro-6-methylbenzyl) -3- (furan-2-yl) -1H-1, 2, 4-triazol-5-amine (b) as a white solid (12 mg, yield 12.3%) . Mass spectrum (ESI) m/z calc. for C14H13ClFN4O [M+H] + 289.08 , 291.07, found 289.40, 291.40. 1H NMR (400 MHz, d6-DMSO/methanol) δ 12.17 (s, 1H) , 7.70 (s, 1H) , 7.31 (d, J = 7.5 Hz, 1H) , 7.22 (dd, J = 17.4, 7.1 Hz, 2H) , 6.82 (s, 1H) , 6.73 (s, 1H) , 6.56 (s, 1H) , 4.48 (d, J = 4.9 Hz, 2H) , 2.44 (s, 3H) .
Step 1: Synthesis of 3- (5-amino-1H-1, 2, 4-triazol-3-yl) phenol (Intermediate 1) :
A suspension of Aminoguanidinium nitrate (5.46 g, 39.82 mmol) and K2CO3 (5.5 g,
39.82 mmol) in N, N-dimethylformamide (DMF) (50 mL) was stirred at room temperature for 1 h. A solution of 3-hydroxybenzoic acid (5.0 g, 36.2 mmol) in N, N-dimethylformamide (DMF) (30 mL) was treated with N, N'-carbonyldiimidazole (CDI) (6.46 g, 39.82 mmol) at 0 ℃. After then, the solution was stirred at room temperature for 1 h. Then, the solution was added dropwise to the suspension. After the addition, the reaction mixture was stirred at room temperature for 3 h. The mixture was then heated to 100 ℃ for 5 h. After cooling to room temperature, it was filtered, and the solvent was removed under reduced pressure. The residue was purified by column chromatography (silica gel, dichloromethane/methanol = 100: 1 to 10: 1) to give 3- (5-amino-1H-1, 2, 4-triazol-3-yl) phenol (1) as white solid (2.67g, yield 41.9%) . Mass spectrum (ESI) m/z calc. for C8H8N4O [M-H] -175.07, found 175.10. 1H NMR (400 MHz, d6-DMSO) δ 12.06 (s, 1H) , 9.47 (s, 1H) , 7.36–7.29 (m, 2H) , 7.17 (t, J = 8.0 Hz, 1H) , 6.77–6.67 (m, 1H) , 6.00 (s, 2H) .
Step 2: Synthesis of 3- (5- ( (2-chloro-6-fluorobenzyl) amino) -1H-1, 2, 4-triazol-3-yl) phenol:
The mixture of 3- (5-amino-1H-1, 2, 4-triazol-3-yl) phenol (1) (5.0 g, 28.38 mmol) , 2-chloro-6-fluorobenzaldehyde (5.0 g, 31.53 mmol) and p-toluenesulfonicacid (500 mg, 2.90 mmol) in isopropanol (50 mL) was heated to reflux overnight. The solution was allowed to cool to room temperature before NaBH3CN (4.0 g, 63.65mmol) and acetic acid (2 mL) were added. Then, the resulting mixture was stirred at room temperature for 10h before quenched with water. The solvent was removed under reduced pressure. The residue was purified by column chromatography (silica gel, dichloromethane/methanol = 100: 1 to 10: 1) to give 3- (5- ( (2-chloro-6-fluorobenzyl) amino) -1H-1, 2, 4-triazol-3-yl) phenol as white solid (1.2 g, yield 13.3%) , and restore compound 31 (1.8 g) . Mass spectrum (ESI) m/z calc. for C15H12ClFN4O [M+H] + 319.07, 321.07, found 319.40, 321.20. 1H NMR (400 MHz, d6-DMSO) δ 12.15 (s, 1H) , 9.43 (s, 1H) , 7.35 (s, 4H) , 7.13-7.27 (m, 2H) , 6.90 (s, 1H) , 6.75 (s, 1H) , 4.51 (s, 2H) .
(i) a) Aminoguanidinium nitrate, NaOH, DMF, 0 ℃; b) CDI, DMF, 0℃ to room temperature; c) H2O, reflux;
(ii) a) 2-chloro-6-fluorobenzaldehyde , toluene , reflux; b) NaBH3CN, acetic acid, room temperature;
(iii) BBr3, cyclohexene, DCM, 0 ℃.
Step 1: Synthesis of 3- (3, 5-dimethoxyphenyl) -1H-1, 2, 4-triazol-5-amine (Intermediate 1) :
A suspension of Aminoguanidinium nitrate (824.7 mg, 6.02 mmol) and NaOH (240.6 mg, 6.02 mmol) in N, N-dimethylformamide (DMF) (10 mL) was cooled to 0 ℃. A solution of 3, 5-dimethoxybenzoic acid (1.0 g, 5.49 mmol) and N, N-Diisopropylethylamine (DIPEA) (780 mg, 6.03 mmol) in N, N-dimethylformamide (DMF) (10 mL) was treated with N, N'-carbonyldiimidazole (CDI) (890 mg, 5.49 mmol) at 0 ℃. After then, the solution was stirred at room temperature for 3 h. Then, the solution was added dropwise to the suspension. After the addition, the reaction mixture was stirred at room temperature for 3 h. The solvent was then removed by rotatory evaporation, the residue was dissolved in water (70 mL) , and heated to reflux for 18 h. After cooling to room temperature, it was filtered, and the solid was re-crystallized from methanol to give 3- (3, 5-dimethoxyphenyl) -1H-1, 2, 4-triazol-5-amine (Intermediate 1) as off-white solid (260 mg, yield 21.5%) . Mass spectrum (ESI) m/z calc. for C10H12N4O2 [M+H] + 221.10, found 221.40. 1H NMR (400 MHz, d6-DMSO) δ 12.08 (s, 1H) , 7.05 (dd, J = 10.8, 2.3 Hz, 2H) , 6.46 (s, 1H) , 6.08 (s, 2H) , 3.71 (s, 6H) .
Step 2: Synthesis of N- (2-chloro-6-fluorobenzyl) -3- (3, 5-dimethoxyphenyl) -1H-1, 2, 4-triazol-5-amine (12) :
The mixture of 3- (3, 5-dimethoxyphenyl) -1H-1, 2, 4-triazol-5-amine (Intermediate 1) (50 mg, 0.23 mmol) and 2-chloro-6-fluorobenzaldehyde (36 mg, 0.23 mmol) in anhydrous toluene (10 mL) /DMSO (0.1 mL) was heated to reflux for 3 h. The solution was allowed to cool to room temperature before NaBH3CN (42.8 mg, 0.68 mmol) and acetic acid (1mL) were added. Then, the resulting mixture was stirred at room temperature for 10h before quenched with water. The solvent was removed under reduced pressure. The residue was washed with water (25mL) to provide a solid that was re-crystallized from ethyl acetate/petroleum ether solution to give N- (2-chloro-6-fluorobenzyl) -3- (3, 5-dimethoxyphenyl) -1H-1, 2, 4-triazol-5-amine (12) as a white solid (30 mg, yield 36.4%) . Mass spectrum (ESI) m/z calc. for C17H16ClFN4O2 [M+H] + 363.09, 365.09, found 363.20, 365.20. 1H NMR (400 MHz, d6-DMSO) δ 7.97 (s, 1H) , 7.51 (d, J = 8.0 Hz, 1H) , 7.41 (t, J = 8.0 Hz, 1H) , 7.31 (d, J = 8.2 Hz, 1H) , 7.12 (s, 2H) , 6.57 (s, 1H) , 4.67 (s, 2H) , 3.80 (s, 6H) .
Step 3: Synthesis of 5- (5- ( (2-chloro-6-fluorobenzyl) amino) -1H-1, 2, 4-triazol-3-yl) benzene-1, 3-diol (9) :
A mixture of compound 12 (18 mg, 0.05 mmol) and cyclohexene (2mL) in dichloromethane (DCM) (10 mL) was cooled to 0 ℃. A solution of BBr3 (220mg, 0.88mmol) in dichloromethane (DCM) (1 mL) was added dropwise to the mixture. After the addition, the reaction mixture was stirred at 0 ℃ for 18 h. The solvent was then removed by rotatory
evaporation, the residue was purified by reversed phase HPLC (C18) to give5- (5- ( (2-chloro-6-fluorobenzyl) amino) -1H-1, 2, 4-triazol-3-yl) benzene-1, 3-diol (9) as a white solid (3 mg, yield 18.1%) . Mass spectrum (ESI) m/z calc. for C15H12ClFN4O2 [M+H] + 335.06, 337.06, found 335.05, 337.10. 1H NMR (400 MHz, CD3OD) δ 7.32 (dt, J = 11.3, 8.1 Hz, 2H) , 7.12 (t, J = 8.6 Hz, 1H) , 6.85 (s, 2H) , 6.32 (s, 1H) , 4.64 (s, 2H) .
(i) a) Aminoguanidinium nitrate, NaOH, methanol, 0 ℃; b) CDI, DMF, 0 ℃ to room temperature; c) H2O, reflux;
(ii) a) 2-chloro-6-fluorobenzaldehyde , toluene , reflux; b) NaBH3CN, acetic acid, room temperature.
Step1: Synthesis of 3- (3, 4-dimethoxyphenyl) -1H-1, 2, 4-triazol-5-amine (Intermediate 1) :
A suspension of Aminoguanidinium nitrate (13.55 g, 98.83 mmol) and NaOH (240.6 mg, 6.02 mmol) in methanol (100 mL) was stirred at room temperature for 3 h, the solvent was evaporated off, and the residue was resolved by N, N-dimethylformamide (DMF) (100 mL) . A solution of 3, 4-dimethoxybenzoic acid (15.0 g, 82.34mmol) in N, N-dimethylformamide (DMF) (150 mL) was treated with N, N'-carbonyldiimidazole (CDI) (14.69 g, 90.59mmol) at 0 ℃. After then, the solution was stirred at room temperature for 3 h. Then, the solution was added dropwise to the suspension. After the addition, the reaction mixture was stirred at room temperature for 3 h. The solvent was then removed by rotatory evaporation; the residue was dissolved in water (150 mL) , and heated to reflux for 18 h. After cooling to room temperature, it was filtered, and the solid was re-crystallized from methanol to give 3- (3, 4-dimethoxyphenyl) -1H-1, 2, 4-triazol-5-amine (Intermediate 1) as off-white solid (9.38 g, yield 51.7%) . Mass spectrum (ESI) m/z calc. for C10H12N4O2 [M+H] + 221.10, found 221.40. 1H NMR (400 MHz, d6-DMSO) δ 11.95 (s, 1H) , 7.46–7.39 (m, 2H) , 6.98 (d, J = 8.8 Hz, 1H) , 5.93 (s, 2H) , 3.77 (d, J = 3.4 Hz, 6H) .
Step2: Synthesis of N- (2-chloro-6-fluorobenzyl) -3- (3, 4-dimethoxyphenyl) -1H-1, 2, 4-triazol-5-amine (11) :
The mixture of 3- (3, 4-dimethoxyphenyl) -1H-1, 2, 4-triazol-5-amine (Intermediate 1) (8
g, 36.33mmol) , 2-chloro-6-fluorobenzaldehyde (8 g, 50.46mmol) and p-toluenesulfonicacid (625.5 mg, 3.63 mmol) in isopropanol (40 mL) was heated to reflux overnight. The solution was allowed to cool to room temperature before NaBH3CN (5.0 g, 79.56mmol) and acetic acid (1mL) were added. Then, the resulting mixture was stirred at room temperature for 5 h before quenched with water. The solvent was removed under reduced pressure. The residue was purified by column chromatography (silica gel, dichloromethane/methanol = 50: 1 to 10: 1) to give N- (2-chloro-6-fluorobenzyl) -3- (3, 4-dimethoxyphenyl) -1H-1, 2, 4-triazol-5-amine (11) as white solid (4.5 g, yield 34.1%) . Mass spectrum (ESI) m/z calc. for C17H16ClFN4O2 [M+H] + 363.09, 365.09, found 363.40, 365.40. 1H NMR (400 MHz, d6-DMSO, mixture of rotamers 2: 1) δ 13.13 (s, 0.5H) , 12.06 (s, 1H) , 7.50–7.41 (m, 3H) , 7.40–7.29 (m, 3H) , 7.28–7.15 (m, 2H) , 7.05 (d, J = 8.2 Hz, 0.5H) , 6.98 (d, J = 8.8 Hz, 1H) , 6.87 (t, J = 5.4 Hz, 1H) , 6.12 (t, J = 6 Hz, 0.5H) , 4.53 (d, J = 4.9 Hz, 2H) , 4.45 (d, J = 5.2 Hz, 1H) , 3.78 (d, J = 6.9 Hz, 9H) .
Step1: Synthesis of 3- (3-nitrophenyl) -1H-1, 2, 4-triazol-5-amine (Intermediate 1) :
A suspension of Aminoguanidinium nitrate (2.58g, 18.82mmol) and NaOH (789.79mg, 19.75mmol) in methanol (30 mL) was stirred at room temperature for 3 h, the solvent was evaporated off, and the residue was resolved by N, N-dimethylformamide (DMF) (30 mL) . A solution of 3-nitrobenzoic acid (3.0g, 17.95mmol) and N, N-Diisopropylethylamine (DIPEA) (2.55g, 19.73mmol) in N, N-dimethylformamide (DMF) (30 mL) was treated with N, N'-carbonyldiimidazole (CDI) (3.2g, 19.73mmol) at 0 ℃. The solution was stirred at room temperature for 3 h. Then, it was added dropwise to the suspension. After the addition, the reaction mixture was stirred at room temperature for 3 h. The solvent was removed by rotatory evaporation, the residue was dissolved in water (100 mL) , and heated to reflux for 18 h. After cooling to room temperature, it was filtered, and the solid was re-crystallized from methanol to give 3- (3-nitrophenyl) -1H-1, 2, 4-triazol-5-amine (1) as yellow solid (3.0g, yield 81.5%) . Mass
spectrum (ESI) m/z calc. for C8H7N5O2 [M+H] + 206.06, found 206.20. 1H NMR (400 MHz, d6-DMSO) δ 12.38 (s, 1H) , 8.65–8.60 (m, 1H) , 8.28 (d, J = 7.8 Hz, 1H) , 8.22–8.16 (m, 1H) , 7.71 (t, J = 8.0 Hz, 1H) , 6.22 (s, 2H) .
Step2: Synthesis of N- (2-chloro-6-fluorobenzyl) -3- (3-nitrophenyl) -1H-1, 2, 4-triazol-5-amine (13) :
The mixture of 3- (3-nitrophenyl) -1H-1, 2, 4-triazol-5-amine (1) (300 mg, 1.46mmol) and 2-chloro-6-fluorobenzaldehyde (300mg, 1.89mmol) in anhydrous toluene (10 mL) /DMSO (0.1 mL) was heated to reflux for 15 h. The solution was allowed to cool to room temperature before NaBH3CN (200 mg, 3.18mmol) and acetic acid (1mL) were added. Then, the resulting mixture was stirred at room temperature for 3 h before quenched with water. The solvent was removed under reduced pressure. The residue was purified by column chromatography (silica gel, dichloromethane/methanol = 50: 1 to 10: 1) to give N- (2-chloro-6-fluorobenzyl) -3- (3-nitrophenyl) -1H-1, 2, 4-triazol-5-amine (2a) as a light-yellow solid (150 mg, yield 29.5%) . Mass spectrum (ESI) m/z calc. for C15H11ClFN5O2 [M+H] + 348.06, 350.06, found 348.10, 350.10. 1H NMR (400 MHz, CD3OD) δ 8.82 (s, 1H) , 8.34 (d, J = 7.8 Hz, 1H) , 8.29–8.22 (m, 1H) , 7.69 (t, J = 8.0 Hz, 1H) , 7.40–7.27 (m, 2H) , 7.14 (t, J = 8.8 Hz, 1H) , 4.70 (s, 2H) .
Step3: Synthesis of 3- (3-aminophenyl) -N- (2-chloro-6-fluorobenzyl) -1H-1, 2, 4-triazol-5-amine (16) :
The mixture of N- (2-chloro-6-fluorobenzyl) -3- (3-nitrophenyl) -1H-1, 2, 4-triazol-5-amine (2a) (50 mg, 0.14mmol) and hydrazine hydrate (0.5 mL, 80%in water) in ethanol (10 mL) was heated to 60 ℃. Then, Raney-Ni (10 mg) was added. The resulting mixture was stirred at this temperature for 3 h. After cooling to room temperature, it was filtered, the solvent was removed under reduced pressure. The residue was purified by column chromatography (silica gel, dichloromethane/methanol = 50: 1 to 10: 1) to give 3- (3-aminophenyl) -N- (2-chloro-6-fluorobenzyl) -1H-1, 2, 4-triazol-5-amine (3a) as a white solid (36 mg, yield 78.8%) . Mass spectrum (ESI) m/z calc. for C15H13ClFN5 [M+H] + 318.08, 320.08, found 318.10, 320.10. 1H NMR (400 MHz, CD3OD) δ 7.33 (ddd, J = 19.0, 9.5, 6.9 Hz, 2H) , 7.27–7.19 (m, 2H) , 7.19–7.08 (m, 2H) , 6.78 (d, J = 7.8 Hz, 1H) , 4.64 (s, 2H) .
Synthesis of N- (2-chloro-6-methylbenzyl) -3- (3-nitrophenyl) -1H-1, 2, 4-triazol-5-amine (15)
To a stirred mixture of 3- (3-nitrophenyl) -1H-1, 2, 4-triazol-5-amine (1) (100 mg, 0.49mmol) and 2-chloro-6-methylbenzaldehyde (150.69mg, 0.97mmol) in anhydrous toluene (6 mL) /ethanol (0.5 mL) was heated to reflux for 15 h. After cooling to room temperature, NaBH3CN (100 mg, 1.59mmol) and acetic acid (1mL) were added at 0 ℃. Then, the mixture
was stirred at room temperature for 3 h. The solvent was removed under reduced pressure. The residue was purified by column chromatography (silica gel, dichloromethane/methanol = 50: 1 to 10: 1) to give N- (2-chloro-6-methylbenzyl) -3- (3-nitrophenyl) -1H-1, 2, 4-triazol-5-amine (2b) as a light-yellow solid (34 mg, yield 20.3%) , and restore 3- (3-nitrophenyl) -1H-1, 2, 4-triazol-5-amine (1) (40mg) . Mass spectrum (ESI) m/z calc. for C16H14ClN5O2 [M+H] + 344.08, 346.08, found 344.40, 346.40. 1H NMR (400 MHz, CD3OD) δ 8.84–8.81 (m, 1H) , 8.37–8.33 (m, 1H) , 8.29–8.24 (m, 1H) , 7.70 (t, J = 8.0 Hz, 1H) , 7.30 (m, 1H) , 7.22–7.19 (m, 2H) , 4.68 (s, 2H) , 2.52 (s, 3H) .
Step3: Synthesis of 3- (3-aminophenyl) -N- (2-chloro-6-methylbenzyl) -1H-1, 2, 4-triazol-5-amine (19)
The mixture of compound N- (2-chloro-6-methylbenzyl) -3- (3-nitrophenyl) -1H-1, 2, 4-triazol-5-amine (2b) (30 mg, 0.087mmol) and hydrazine hydrate (0.3 mL, 80%in water) in ethanol (5 mL) was heated to 60 ℃. Then, Raney-Ni (10 mg) was added. The resulting mixture was stirred at this temperature for 3 h. After cooling to room temperature, it was filtered, the solvent was removed under reduced pressure. The residue was purified by reversed phase flash column chromatography (C18) to give 3- (3-aminophenyl) -N- (2-chloro-6–methylbenzyl) -1H-1, 2, 4-triazol-5-amine (3b) as a white solid (20 mg, yield 73%) . Mass spectrum (ESI) m/z calc. for C16H16ClN5 [M+H] + 314.11, 316.11, found 314.40, 316.40. 1H NMR (400 MHz, CD3OD) δ 7.28 (m, 3H) , 7.19 (m, 3H) , 6.79 (s, 1H) , 4.62 (s, 2H) , 2.50 (s, 3H) .
Step4: Synthesis of N- (3- (5- ( (2-chloro-6-fluorobenzyl) amino) -1H-1, 2, 4-triazol-3-yl) phenyl) acrylamide (17) :
The mixture of compound 3a (12.0 mg, 0.038 mmol) and triethylamine (5.0mg, 0.049 mmol) in tetrahydrofuran (THF) (0.5 mL) was allowed to cool to 0℃ before acryloyl chloride (3.45mg, 0.038 mmol) was added. Then, the resulting mixture was stirred at room temperature for 3 h before quenched with water. The solvent was removed under reduced pressure. The residue was purified by reversed phase HPLC (C18) to give N- (3- (5- ( (2-chloro-6-fluorobenzyl) amino) -1H-1, 2, 4-triazol-3-yl) phenyl) acrylamide (a) as a white solid (2.6 mg, yield 18.5%) . Mass spectrum (ESI) m/z calc. for C18H15ClFN5O [M+H] + 372.09, 374.09, found 372.30, 374.20. 1H NMR (400 MHz, CD3OD) δ 8.12 (s, 1H) , 7.77 (s, 1H) , 7.73–7.63 (m, 1H) , 7.40 (s, 1H) , 7.37–7.27 (m, 2H) , 7.14 (t, J = 8.1 Hz, 1H) , 6.46 (dd, J = 17.0, 9.6 Hz, 1H) , 6.38 (dd, J = 17.0, 2.3 Hz, 1H) , 5.79 (dd, J = 9.6, 2.3 Hz, 1H) , 4.67 (s, 2H) .
Step 4: Synthesis of N- (3- (5- ( (2-chloro-6-methylbenzyl) amino) -1H-1, 2, 4-triazol-3-yl) phenyl) acrylamide (20) :
The mixture of compound 3b (4.0 mg, 0.013 mmol) and triethylamine (30.0 mg, 0.3
mmol) in tetrahydrofuran (THF) (0.5 mL) was allowed to cool to 0℃ before acryloyl chloride (2.0mg, 0.022mmol) was added. Then, the resulting mixture was stirred at room temperature for 3 h before quenched with water. The solvent was removed under reduced pressure. The residue was purified by reversed phase HPLC (C18) to give N- (3- (5- ( (2-chloro-6-methylbenzyl) amino) -1H-1, 2, 4-triazol-3-yl) phenyl) acrylamide (b) as a white solid (3.1 mg, yield 66.1%) . Mass spectrum (ESI) m/z calc. for C19H18ClN5O [M+H] + 368.12, 370.12, found 368.40, 370.40. 1H NMR (400 MHz, d6-DMSO) δ 10.25 (s, 1H) , 8.19 (s, 1H) , 7.75 (d, J = 9.0 Hz, 1H) , 7.62 (d, J = 7.9 Hz, 1H) , 7.36 (d, J = 7.9 Hz, 1H) , 7.32 (dd, J = 6.8, 4.8 Hz, 1H) , 7.22 (dd, J = 12.1, 4.7 Hz, 2H) , 6.46 (dd, J = 17.0, 10.1 Hz, 1H) , 6.27 (dd, J = 17.0, 2.0 Hz, 1H) , 5.76 (dd, J = 10.1, 2.0 Hz, 1H) , 4.52 (d, J = 5.4 Hz, 2H) , 2.48 (s, 3H) .
Step4: Synthesis of N- (3- (5- ( (2-chloro-6-fluorobenzyl) amino) -1H-1, 2, 4-triazol-3-yl) phenyl) -2-cyano-4, 4-dimethylpent-2-enamide (42) :
A suspension of pivalaldehyde (202.5 mg, 1.79mmol, 75%in t-BuOH) , 2-cyanoacetic acid (150.0mg, 1.74mmol) and KOH (200.0mg, 3.56mmol) in methanol (2 mL) was heated to 40 ℃ for 5 h. After the starting material was consumed by TLC analysis, the mixture was adjust pH to 3 ~ 4 by 3 M HCl, extracted with ethyl acetate (50 ml) . The ethyl acetate solution was dried and concentrated to give 2-cyano-4, 4-dimethylpent-2-enoic acid as white solid (100 mg, yield 37.3%) . Mass spectrum (ESI) m/z calc. for C8H11NO2 [M-H] -152.08, found 152.20. 1H NMR (400 MHz, CDCl3) (Z) -2-cyano-4, 4-dimethylpent-2-enoic acid δ 4.35 (s, 1H) , 0.90 (s, 9H) ; (E) -2-cyano-4, 4-dimethylpent-2-enoic acid δ 7.73 (s, 1H) , 1.33 (s, 9H) .
The mixture of compound 3a (30.0 mg, 0.094mmol) , 2-cyano-4, 4-dimethylpent-2-enoic acid (15.0 mg, 0.098mmol) and N, N-dimethylpyridin-4-amine (DMAP) (2 mg, 0.016mmol) in N, N-dimethylformamide (DMF) (2 mL) was allowed to cool to 0 ℃ before EDCI (40.0 mg, 0.209mmol) was added. Then, the resulting mixture was stirred at room temperature for 20 h before quenched with water. The solvent was removed under reduced pressure. The residue was purified by column chromatography (silica gel, dichloromethane/methanol = 50: 1 to 10: 1) to give N- (3- (5- ( (2-chloro-6-fluorobenzyl) amino) -1H-1, 2, 4-triazol-3-yl) phenyl) -2-cyano-4, 4-dimethylpent-2-enamide (c) as a white solid (14 mg, yield32.7%) . Mass spectrum (ESI) m/z calc. for C23H22ClFN6O [M+H] +453.15, 455.15, found 453.20, 455.30.
Step4: Synthesis of N- (3- (5- ( (2-chloro-6-methylbenzyl) amino) -1H-1, 2, 4-triazol-3-yl) phenyl) -2-cyano-4, 4-dimethylpent-2-enamide (23) :
The mixture of compound 3b (10.0 mg, 0.032 mmol) , 2-cyano-4, 4-dimethylpent-2-enoic acid (5.0 mg, 0.033 mmol) and N, N-dimethylpyridin-4-amine (DMAP) (0.4mg, 0.0032mmol) in N, N-dimethylformamide (DMF) (2 mL) was allowed to cool to 0 ℃ before EDCI (15.0 mg,
0.078mmol) was added. Then, the resulting mixture was stirred at room temperature for 20 h before quenched with water. The solvent was removed under reduced pressure. The residue was purified by column chromatography (silica gel, dichloromethane/methanol = 50: 1 to 10: 1) to give N- (3- (5- ( (2-chloro-6-methylbenzyl) amino) -1H-1, 2, 4-triazol-3-yl) phenyl) -2-cyano-4, 4-dimethylpent-2-enamide (d) as a white solid (5.0 mg, yield35%) . Mass spectrum (ESI) m/z calc. for C24H25ClN6O [M+H] +449.18, 451.18, found 449.50, 451.30. 1H NMR (400 MHz, CDCl3, mixture of rotamers) δ 7.94 (s, 1H) , 7.84 (d, J = 7.7 Hz, 1H) , 7.79 (s, 0.2H) , 7.42 (t, J = 7.8 Hz, 1H) , 7.32 (d, J = 8.7 Hz, 1H) , 7.23 (d, J = 7.3 Hz, 1H) , 7.15–7.09 (m, 2H) , 5.05 (s, 1H) , 4.67 (s, 2H) , 4.35 (d, J = 2.8 Hz, 1H) , 3.81 (d, J = 2.9 Hz, 1H) , 2.51 (s, 3H) , 1.33 (s, 1.3H) , 1.03 (s, 9H) .
Step4: Synthesis of N- (3- (5- ( (2-chloro-6-fluorobenzyl) amino) -1H-1, 2, 4-triazol-3-yl) phenyl) but-2-ynamide (37) :
The mixture of compound 3a (15.0 mg, 0.047mmol) , but-2-ynoic acid (10.0 mg, 0.118mmol) and N, N-dimethylpyridin-4-amine (DMAP) (2 mg, 0.016mmol) in N, N-dimethylformamide (DMF) (2 mL) was allowed to cool to 0 ℃ before EDCI (40.0 mg, 0.209mmol) was added. Then, the resulting mixture was stirred at room temperature for 20 h before quenched with water. The solvent was removed under reduced pressure. The residue was purified by column chromatography (silica gel, dichloromethane/methanol = 50: 1 to 10: 1) to give N- (3- (5- ( (2-chloro-6-fluorobenzyl) amino) -1H-1, 2, 4-triazol-3-yl) phenyl) but-2-ynamide as a white solid (5 mg, yield 27.6%) . Mass spectrum (ESI) m/z calc. for C19H15ClFN5O [M+H] +384.09, 386.09, found 384.30, 86.43. 1H NMR (400 MHz, CD3OD) δ 8.05 (s, 1H) , 7.68-7.66 (m, 2H) , 7.38-7.29 (m, 3H) , 7.20-7.13 (m, 1H) , 4.67 (s, 2H) , 2.04 (s, 3H) .
Step1: Synthesis of 3- ( (tert-butoxycarbonyl) amino) benzoic acid (Intermediate 1) :
The mixture of 3-aminobenzoic acid (500 mg, 3.65 mmol) and triethylamine (1.11 g, 10.97 mmol) in methanol (6 mL) was allowed to cool to 0 ℃ before di-tert-butyl dicarbonate (880 mg, 4.03mmol) was added. Then, the resulting mixture was stirred at room temperature for 10 h before quenched with water. The solvent was removed under reduced pressure. The residue was purified by column chromatography (silica gel, dichloromethane/methanol = 100: 1 to 10: 1) to give 3- ( (tert-butoxycarbonyl) amino) benzoic acid (1) as a white solid (800 mg, yield
92.5%) . Mass spectrum (ESI) m/z calc. for C12H15NO4 [M-H] -236.10, found 236.10. 1H NMR (400 MHz, d6-DMSO) δ 12.90 (s, 1H) , 9.55 (s, 1H) , 8.14 (s, 1H) , 7.62 (d, J = 8.5 Hz, 1H) , 7.53 (d, J = 7.8 Hz, 1H) , 7.36 (t, J = 7.9 Hz, 1H) , 1.48 (s, 9H) .
Step2: Synthesis of 3- ( (tert-butoxycarbonyl) (methyl) amino) benzoic acid (Intermediate 2) :
The mixture of 3- ( (tert-butoxycarbonyl) amino) benzoic acid (1) (1.0 g, 4.21 mmol) in N, N-dimethylformamide (DMF) (10 mL) was allowed to cool to 0 ℃ before sodium hydride (505.7 mg, 12.64 mmol, 60%dispersion in mineral oil) was added. The mixture was stirred at this temperature for 1 h before iodomethane (1.26 g, 8.80 mmol) was added. The resulting mixture was stirred at room temperature for 5 h before quenched with water. The solvent was removed under reduced pressure, the residue was dissolved in methanol (10 mL) /water (1 mL) , before sodium hydroxide (337.2 mg, 8.43 mmol) was added. After the starting material was consumed by TLC analysis, the mixture was adjust pH to 3 ~ 4 by 3 M HCl, extracted with Ethyl Acetate (50 ml) . The ethyl acetate solution was dried and concentrated to give 3- ( (tert-butoxycarbonyl) (methyl) amino) benzoic acid (2) as white solid (950 mg, yield 89.7%) . Mass spectrum (ESI) m/z calc. for C13H17NO4 [M-H] -250.12, found 250.10. 1H NMR (400 MHz, d6-DMSO) δ 13.06 (s, 1H) , 7.83 (t, J = 1.8 Hz, 1H) , 7.75–7.72 (m, 1H) , 7.53 (ddd, J = 8.0, 2.3, 1.2 Hz, 1H) , 7.49–7.43 (m, 1H) , 3.20 (s, 3H) , 1.40 (s, 9H) .
Step3: Synthesis of tert-butyl (3- (5-amino-1H-1, 2, 4-triazol-3-yl) phenyl) (methyl) carbamate (Intermediate 3) :
A suspension of aminoguanidinium nitrate (360 mg, 2.63mmol) and K2CO3 (660mg, 4.78mmol) in N, N-dimethylformamide (DMF) (3 mL) was stirred at room temperature for 1 h. A solution of 3- ( (tert-butoxycarbonyl) (methyl) amino) benzoic acid (2) (600 mg, 2.39mmol) in N, N-dimethylformamide (DMF) (30 mL) was treated with N, N'-carbonyldiimidazole (CDI) (426 mg, 2.63mmol) at 0℃. The solution was stirred at room temperature for 1 h. Then it was added to the suspension. The resulting mixture was stirred at room temperature for 3 h , then it was heated to 100 ℃ for 3 h. The mixture was cooled to room temperature, and filtered, concentrated. The residue was purified by column chromatography (silica gel, dichloromethane/methanol = 100: 1 to 10: 1) to give tert-butyl (3- (5-amino-1H-1, 2, 4-triazol-3-yl) phenyl) (methyl) carbamate (3) as yellow oil (220g, yield 31.8%) . Mass spectrum (ESI) m/z calc. for C14H19N5O2 [M+H] + 290.15, found 290.20. 1H NMR (400 MHz, CDCl3) δ 7.85–7.80 (m, 1H) , 7.73–7.67 (m, 1H) , 7.61 (s, 1H) , 7.29 (t, J = 7.9 Hz, 1H) , 7.23–7.18 (m, 1H) , 7.04 (s, 2H) , 3.23 (s, 3H) , 1.46 (s, 9H) .
Step4: Synthesis of tert-butyl (3- (5- ( (2-chloro-6-fluorobenzyl) amino) -1H-1, 2, 4-triazol-3-yl) phenyl) (methyl) carbamate (Intermediate 4) :
The mixture of tert-butyl (3- (5-amino-1H-1, 2, 4-triazol-3-yl) phenyl) (methyl) carbamate (3) (200 mg, 0.69 mmol) , 2-chloro-6-fluorobenzaldehyde (200mg, 1.26 mmol) and p-toluenesulfonicacid (11.9 mg, 0.069 mmol) in isopropanol (5 mL) was heated to reflux overnight. The solution was allowed to cool to room temperature before NaBH3CN (120 mg, 1.91mmol) and acetic acid (0.5 mL) were added. Then, the resulting mixture was stirred at room temperature for 5 h before quenched with water. The solvent was removed under reduced pressure. The crude tert-butyl (3- (5- ( (2-chloro-6-fluorobenzyl) amino) -1H-1, 2, 4-triazol-3-yl) phenyl) (methyl) carbamate (4) was used directly without further purification.
Step5: Synthesis of N- (2-chloro-6-fluorobenzyl) -3- (3- (methylamino) phenyl) -1H-1, 2, 4-triazol-5-amine (18) :
The mixture of crude tert-butyl (3- (5- ( (2-chloro-6-fluorobenzyl) amino) -1H-1, 2, 4-triazol-3-yl) phenyl) (methyl) carbamate (4) (100 mg) tetrahydrofuran (THF) (5 mL) was cooled to 0℃ before trifluoroacetic acid (10 mL) was added. Then, the resulting mixture was stirred at room temperature for 5 h. The solvent was removed under reduced pressure. The residue was purified by column chromatography (silica gel, dichloromethane/methanol = 100: 1 to 10: 1) to give N- (2-chloro-6-fluorobenzyl) -3- (3- (methylamino) phenyl) -1H-1, 2, 4-triazol-5-amine (5) as a white solid (45mg, yield 19.6%, two steps) . Mass spectrum (ESI) m/z calc. for C16H15ClFN5 [M+H] + 332.10, 334.10, found 332.40, 334.30. 1H NMR (400 MHz, d6-DMSO, mixture of rotamers, 2: 1) δ13.17 (s, 0.5H) , 12.07 (s, 1H) , 7.35 (s, 3H) , 7.23 (s, 1.5H) , 7.12 (s, 4.5H) , 6.85 (s, 1H) , 6.48-6.52 (m, 1.5H) , 6.13 (s, 0.6H) , 5.71-5.75 (m, 1.5H) , 4.51 (s, 3H) , 2.69 (s, 4.5H) .
Step6: Synthesis of N- (3- (5- ( (2-chloro-6-fluorobenzyl) amino) -1H-1, 2, 4-triazol-3-yl) phenyl) -N-methylacrylamide (21)
The mixture of compound 29 (32 mg, 0.096mmol) and N-ethyl-N-isopropylpropan-2-amine (DIPEA) (50mg, 0.39mmol) in tetrahydrofuran (THF) (0.5 mL) was cooled to 0 ℃ before acryloyl chloride (20mg, 0.22mmol) was added. Then, the resulting mixture was stirred at room temperature for 3 h. The solvent was removed under reduced pressure. The residue was solved by methanol (2 mL) /water (0.5 mL) , and then NaOH (10 mg, 0.25 mmol) was added, the reaction mixture was stirred at room temperature for 5h, concentrated. The residue was purified by column chromatography (silica gel, dichloromethane/methanol = 100: 1 to 10: 1) to give N- (3- (5- ( (2-chloro-6-fluorobenzyl) amino) -1H-1, 2, 4-triazol-3-yl) phenyl) -N-methylacrylamide as a white solid (6.3 mg, yield17%) . Mass spectrum (ESI) m/z calc. for C19H17ClFN5O [M+H] + 386.11, 388.11, found 386.50, 388.40. 1H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 7.9 Hz, 1H) , 7.83 (t, J = 1.7 Hz, 1H) , 7.43 (t, J = 7.8 Hz, 1H) , 7.25–7.19 (m, 2H) , 7.18–7.14 (m, 1H) , 7.00-7.05 (m, 1H) , 6.34 (dd, J = 16.8, 1.9 Hz, 1H) , 6.09 (dd, J = 16.5, 10.3 Hz, 1H) , 5.50 (dd, J = 10.3,
1.6 Hz, 1H) , 5.37 (s, 1H) , 4.68 (d, J = 5.3 Hz, 2H) , 3.36 (s, 3H) .
Step1: Synthesis of 3- (4-methoxy-3-nitrophenyl) -1H-1, 2, 4-triazol-5-amine (Intermediate 1) :
A suspension of Aminoguanidinium nitrate (139 mg, 1.01 mmol) and KOH (57 mg, 1.02 mmol) in methanol (2 mL) was stirred at room temperature for 1.5 h, concentrated. The residue was diluted with N, N-dimethylformamide (DMF) (2 mL) . A solution of 4-methoxy-3-nitrobenzoic acid (197 mg, 1.0mmol) in N, N-dimethylformamide (DMF) (5 mL) was treated with N, N'-carbonyldiimidazole (CDI) (190 mg, 1.17mmol) at 0℃. The solution was stirred at room temperature for 1.5 h. Then it was added dropwise to the suspension. After the addition, the reaction mixture was stirred at room temperature for 2 h. The solvent was removed by rotatory evaporation, the residue was dissolved in water (50 mL) , and heated to reflux for 5 h. After cooling to room temperature, it was filtered, and the solid was re-crystallized from methanol to give 3- (4-methoxy-3-nitrophenyl) -1H-1, 2, 4-triazol-5-amine (1) as light-yellow solid (110 mg, yield 46.8%) . Mass spectrum (ESI) m/z calc. for C9H9N5O3 [M+H] + 236.07, found 236.20. 1H NMR (400 MHz, d6-DMSO) δ 12.15 (s, 1H) , 8.26 (d, J = 1.4 Hz, 1H) , 8.11 (dd, J = 8.8, 2.1 Hz, 1H) , 7.42 (d, J = 8.9 Hz, 1H) , 6.14 (s, 2H) , 3.95 (s, 3H) .
Step2: Synthesis of N- (2-chloro-6-fluorobenzyl) -3- (4-methoxy-3-nitrophenyl) -1H-1, 2, 4-triazol-5-amine (Intermediate 2) :
The mixture of 3- (4-methoxy-3-nitrophenyl) -1H-1, 2, 4-triazol-5-amine (1) (100 mg, 0.43mmol) and 2-chloro-6-fluorobenzaldehyde (150 mg, 0.95mmol) in anhydrous toluene (10 mL) was heated to reflux for 15 h. The solution was allowed to cool to room temperature before NaBH3CN (45 mg, 0.72mmol) and acetic acid (1mL) were added. Then, the resulting mixture was stirred at room temperature for 3 h before quenched with water. The solvent was removed under reduced pressure. The residue was purified by column chromatography (silica gel, dichloromethane/methanol = 50: 1 to 10: 1) to give N- (2-chloro-6-fluorobenzyl) -3- (4-methoxy-3-nitrophenyl) -1H-1, 2, 4-triazol-5-amine (2) as a light-yellow solid (70 mg, yield 43.6%) used in next step directly. Mass spectrum (ESI) m/z calc. for C16H13ClFN5O3 [M+H] + 378.07, 380.07, found 378.30, 380.30.
Step3: Synthesis of 3- (3-amino-4-methoxyphenyl) -N- (2-chloro-6-fluorobenzyl) -1H-1, 2, 4-triazol-5-amine (24) :
The mixture of N- (2-chloro-6-fluorobenzyl) -3- (4-methoxy-3-nitrophenyl) -1H-1, 2, 4-triazol-5-amine (2) (70 mg, 0.19mmol) and hydrazine hydrate (1.0 mL, 80%in water) in ethanol (10 mL) was heated to 60℃. Then, Raney-Ni (10 mg) was added. the resulting mixture was stirred at room temperature for 3 h. After cooling to room temperature, it was filtered, the solvent was removed under reduced pressure. The residue was purified by column chromatography (silica gel, dichloromethane/methanol = 50: 1 to 10: 1) to give 3- (3-amino-4-methoxyphenyl) -N- (2-chloro-6-fluorobenzyl) -1H-1, 2, 4-triazol-5-amine (3) as a white solid (50 mg, yield 77.6%) . Mass spectrum (ESI) m/z calc. for C16H15ClFN5O [M+H] + 348.09, 350.09, found 348.50, 350.60. 1H NMR (400 MHz, CD3OD) δ 7.36–7.23 (m, 4H) , 7.11 (t, J = 8.3 Hz, 1H) , 6.89 (d, J = 8.2 Hz, 1H) , 4.63 (s, 2H) , 3.88 (s, 3H) .
Step4: Synthesis of N- (5- (5- ( (2-chloro-6-fluorobenzyl) amino) -1H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) acrylamide (22) :
The mixture of compound 3 (8.0 mg, 0.023mmol) and N-ethyl-N-isopropylpropan-2-amine (DIPEA) (12.0mg, 0.093mmol) in tetrahydrofuran (THF) (0.5 mL) was cooled to 0℃ before acryloyl chloride (5.0mg, 0.055mmol) was added. The resulting mixture was stirred at room temperature for 30 min before quenched with water. The solvent was removed under reduced pressure. The residue was solved by methanol (2 mL) /water (0.5 mL) , and then NaOH (5.0 mg, 0.13mmol) was added, the reaction mixture was stirred at room temperature for 1 h. Concentrated and the residue was purified by column chromatography (silica gel, dichloromethane/methanol = 100: 1 to 10: 1) to give N- (5- (5- ( (2-chloro-6-fluorobenzyl) amino) -1H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) -acrylamide as a white solid (5.1mg, yield55.2%) . Mass spectrum (ESI) m/z calc. for C19H17ClFN5O2 [M-H] -400.11, 401.11, found 400.40, 402.40. 1H NMR (400 MHz, CDCl3) δ 8.94 (s, 1H) , 7.91 (s, 1H) , 7.73 (dd, J = 8.5, 2.1 Hz, 1H) , 7.21-7.16 (m, 2H) , 7.03-6.97 (m, 1H) , 6.94 (d, J = 8.6 Hz, 1H) , 6.42 (dd, J = 16.9, 1.4 Hz, 1H) , 6.30 (dd, J = 16.9, 10.1 Hz, 1H) , 5.77 (dd, J = 10.0, 1.4 Hz, 1H) , 5.09 (s, 1H) , 4.68 (d, J = 5.0 Hz, 2H) , 3.94 (s, 3H) .
Step1: Synthesis of 3- (3, 4, 5-trimethoxyphenyl) -1H-1, 2, 4-triazol-5-amine (Intermediate
1) :
A suspension of aminoguanidinium nitrate (137 mg, 1.0mmol) and K2CO3 (276mg, 2.0mmol) in N, N-dimethylformamide (DMF) (3 mL) was stirred at room temperature for 1 h. A solution of 3, 4, 5-trimethoxybenzoic acid (212 mg, 1.0mmol) in N, N-dimethylformamide (DMF) (5 mL) was treated with N, N'-carbonyldiimidazole (CDI) (162 mg, 1.0 mmol) at 0℃. The solution was stirred at room temperature for 1 h. Then it was added to the suspension. The resulting mixture was stirred at room temperature for 3 h , then it was heated to 100 ℃ for 3 h. The mixture was cooled to room temperature, filtered and concentrated to give crude 3- (3, 4, 5-trimethoxyphenyl) -1H-1, 2, 4-triazol-5-amine (Intermediate 1) as white solid (180mg) which was used in next step directly. Mass spectrum (ESI) m/z calc. for C11H14N4O3 [M+H] + 251.11, found 241.20.
Step2: Synthesis of N- (2-chloro-6-fluorobenzyl) -3- (3, 4, 5-trimethoxyphenyl) -1H-1, 2, 4-triazol-5-amine (36) :
The mixture of 3- (3, 4, 5-trimethoxyphenyl) -1H-1, 2, 4-triazol-5-amine (Intermediate 1) (180 mg, 0.72 mmol) , 2-chloro-6-fluorobenzaldehyde (180mg, 1.14 mmol) and p-toluenesulfonicacid (20.00 mg, 0.12 mmol) in isopropanol (5 mL) was heated to reflux overnight. The solution was allowed to cool to room temperature before NaBH3CN (180 mg, 2.86 mmol) and acetic acid (1.5 mL) were added. Then, the resulting mixture was stirred at room temperature for 5 h before quenched with water. The solvent was removed under reduced pressure, and the residue was purified by column chromatography (silica gel, dichloromethane/methanol = 100: 1 to 10: 1) to give N- (2-chloro-6-fluorobenzyl) -3- (3, 4, 5-trimethoxyphenyl) -1H-1, 2, 4-triazol-5-amine as a white solid (65 mg, yield 16.6%, 2steps) . Mass spectrum (ESI) m/z calc. for C18H18ClFN4O3 [M+H] + 393.11, 395.11 found 393.33, 395.27. 1H NMR (400 MHz, CDCl3) δ 7.96 (s, 1H) , 7.25-7.22 (m, 1H) , 7.18 (s, 2H) , 7.15-7.11 (m, 1H) , 7.06-7.02 (m, 1H) , 5.22 (t, J = 5.6Hz, 1H) , 4.65 (d, J = 5.6Hz, 2H) , 3.89 (s, 6H) , 3.87 (s, 3H) .
Step1: Synthesis of 3- (1H-benzo [d] imidazol-2-yl) -1H-1, 2, 4-triazol-5-amine (Intermediate 1) :
A suspension of aminoguanidinium nitrate (150 mg, 1.09 mmol) and K2CO3 (150 mg, 1.09 mmol) in N, N-dimethylformamide (DMF) (3 mL) was stirred at room temperature for 1 h. A solution of 1H-benzo [d] imidazole-2-carboxylic acid (162 mg, 1.0mmol) in N, N-dimethylformamide (DMF) (5 mL) was treated with N, N'-carbonyldiimidazole (CDI) (180 mg,
1.1 mmol) at 0℃. The solution was stirred at room temperature for 1 h. Then it was added to the suspension. The resulting mixture was stirred at room temperature for 3 h , then it was heated to 100 ℃ for 3 h. The mixture was cooled to room temperature, filtered and concentrated to give crude 3- (1H-benzo [d] imidazol-2-yl) -1H-1, 2, 4-triazol-5-amine (Intermediate 1) as white solid (290mg, ~40%purity) which was used in next step directly. Mass spectrum (ESI) m/z calc. for C9H8N6 [M+H] + 201.08, found 201.20.
Step2: Synthesis of 3- (1H-benzo [d] imidazol-2-yl) -N- (2-chloro-6-fluorobenzyl) -1H-1, 2, 4-triazol-5-amine (31) :
The mixture of 3- (1H-benzo [d] imidazol-2-yl) -1H-1, 2, 4-triazol-5-amine (Intermediate 1) (50 mg, 0.25 mmol, 40%purity) , 2-chloro-6-fluorobenzaldehyde (50mg, 0.32 mmol) and p-toluenesulfonicacid (5.00 mg, 0.03 mmol) in ethanol (5 mL) was heated to reflux overnight. The solution was allowed to cool to room temperature before NaBH3CN (50 mg, 0.80mmol) and acetic acid (1.5 mL) were added. Then, the resulting mixture was stirred at room temperature for 5 h before quenched with water. The solvent was removed under reduced pressure , and the residue was purified by column chromatography (silica gel, dichloromethane/methanol = 100: 1 to 10: 1) to give 3- (1H-benzo [d] imidazol-2-yl) -N- (2-chloro-6-fluorobenzyl) -1H-1, 2, 4-triazol-5-amine as a white solid (1.4 mg) . Mass spectrum (ESI) m/z calc. for C16H12ClFN6 [M+H] + 343.08, 345.08 found 343.33, 345.27. 1H NMR (400 MHz, CD3OD) δ 7.62 (s, 2H) , 7.32-7.27 (m, 4H) , 7.20-7.14 (m, 1H) , 4.72 (s, 2H) .
Step1: Synthesis of 3, 4-bis (2-methoxyethoxy) benzoic acid (Intermediate 1) :
A suspension of 3, 4-dihydroxybenzoic acid (1.0 g, 6.49 mmol) , TBAI (239.67 mg, 0.65 mmol) and K2CO3 (3.59 g, 25.98 mmol) in N, N-dimethylformamide (DMF) (10 mL) was heated to 100℃ for 1 h. The mixture was allowed to cool to 50℃ before 1-chloro-2-methoxyethane (2.45g, 25.92 mmol) was added. The resulting mixture was stirred at 85℃ for 15 h before cooled to room temperature. It was filtered and concentrated, the residue was solved by THF (40mL) /H2O (10 mL) , and KOH (1.09 g, 19.5mmol ) was added. The resulting solution was stirred at room temperature for 5 h before it was quenched by 1N HCl. Extracted by ethyl acetate (30mL, 3times) , the organic phase was washed by brine (15mL) , dried over Na2SO4, filtered and concentrated to give 3, 4-bis (2-methoxyethoxy) benzoic acid (Intermediate 1) as a clear oil (1.32g, yield 75.33%) . 1H NMR (400 MHz, CDCl3) δ 7.48 (d, J =8.4Hz, 1H) , 7.65 (s, 1H) , 6.94 (d, J=8.4Hz, 1H) , 4.24-4.16 (m, 4H) , 3.82-3.76 (m, 4H) , 3.47 (s, 6H) .
Step2: Synthesis of 3- (3, 4-bis (2-methoxyethoxy) phenyl) -1H-1, 2, 4-triazol-5-amine (Intermediate 2) :
A suspension of aminoguanidinium nitrate (737.08 mg, 5.38 mmol) and K2CO3 (743.02 mg, 5.38 mmol) in N, N-dimethylformamide (DMF) (5 mL) was stirred at room temperature for 1 h. A solution of 3, 4-bis (2-methoxyethoxy) benzoic acid (Intermediate 1) (1.32 g, 4.89 mmol) in N, N-dimethylformamide (DMF) (10 mL) was treated with N, N'-carbonyldiimidazole (CDI) (871.77 mg, 5.38 mmol) at 0℃. The solution was stirred at room temperature for 1 h. Then it was added to the suspension. The resulting mixture was stirred at room temperature for 3 h , then it was heated to 100 ℃ for 10 h. The mixture was cooled to room temperature, filtered and concentrated. The residue was purified by reversed phase HPLC (C18) to give 3- (3, 4-bis (2-methoxyethoxy) phenyl) -1H-1, 2, 4-triazol-5-amine (Intermediate 2) as white solid (800mg, yield 53.09%) . 1H NMR (400 MHz, d6-DMSO) δ 11.93 (s, 1H) , 7.43-7.40 (m, 2H) , 6.99-6.97 (m, 1H) , 6.01 (s, 2H) , 4.12-4.09 (m, 4H) , 3.69-3.64 (m, 4H) , 3.33 (s, 6H) .
Step3: Synthesis of 3- (3, 4-bis (2-methoxyethoxy) phenyl) -N- (2-chloro-6-fluorobenzyl) -1H-1, 2, 4-triazol-5-amine (34) :
The mixture of 3- (3, 4-bis (2-methoxyethoxy) phenyl) -1H-1, 2, 4-triazol-5-amine (Intermediate 2) (800 mg, 2.59 mmol) , 2-chloro-6-fluorobenzaldehyde (1.03 g, 6.49 mmol) and p-toluenesulfonicacid (44.7 mg, 0.26 mmol) in isopropanol (10 mL) was heated to reflux overnight. The solution was allowed to cool to room temperature before NaBH3CN (652.2 mg, 10.38 mmol) and acetic acid (1.5 mL) were added. Then, the resulting mixture was stirred at room temperature for 5 h before quenched with water. The solvent was removed under reduced pressure , and the residue was purified by column chromatography (silica gel, dichloromethane/methanol = 100: 1 to 10: 1) to give 3- (3, 4-bis (2-methoxyethoxy) phenyl) -N- (2-chloro-6-fluorobenzyl) -1H-1, 2, 4-triazol-5-amine as a white solid (120 mg, yield 10.26%) . Mass spectrum (ESI) m/z calc. for C21H24ClFN4O4 [M+H] + 451.15, 453.15, found 451.44, 453.37. 1H NMR (400 MHz, CDCl3) δ 7.46 (s, 1H) , 7.45-7.43 (d, J = 8Hz, 1H) , 7.25-7.22 (m, 2H) , 7.03-7.0 (m, 1H) , 6.92-6.90 (d, J = 8Hz, 1H) , 5.18 (t, J=6.8Hz, 1H ) , 4.65 (d, J=6.8Hz, 2H ) , 4.19-4.16 (m, 4H) , 3.79-3.75 (m, 4H) , 3.44 (s, 6H) .
Step1: Synthesis of 3-methoxy-4- (3-morpholinopropoxy) benzoic acid (Intermediate 1) :
A suspension of methyl 4-hydroxy-3-methoxybenzoate (914.2 mg, 5.02 mmol) , TBAI (185.4 mg, 0.50 mmol) and K2CO3 (763 mg, 5.52 mmol) in N, N-dimethylformamide (DMF) (10
mL) was heated to 100℃ for 1 h. The mixture was allowed to cool to 50℃ before 4- (3-chloropropyl) morpholine (903.3 mg, 5.52 mmol) was added. The resulting mixture was stirred at 85℃ for 15 h before cooled to room temperature. It was filtered and concentrated, the residue was solved by THF (40 mL) /H2O (10 mL) , and KOH (1.09 g, 19.5 mmol ) was added. The resulting solution was stirred at room temperature for 5 h before it was quenched by 1N HCl. Extracted by ethyl acetate (30 mL, 3 times) , the organic phase was washed by brine (15 mL) , dried over Na2SO4, filtered and concentrated to give 3-methoxy-4- (3-morpholinopropoxy) benzoic acid (Intermediate 1) as a clear oil (1.30 g, yield 87.72%) which was used in next step without further purification.
Step2: Synthesis of 3- (3-methoxy-4- (3-morpholinopropoxy) phenyl) -1H-1, 2, 4-triazol-5-amine (Intermediate 2) :
A suspension of aminoguanidinium nitrate (1.40 g, 10.21 mmol) and K2CO3 (1.41 g, 10.21 mmol) in N, N-dimethylformamide (DMF) (10 mL) was stirred at room temperature for 1 h. A solution of 3-methoxy-4- (3-morpholinopropoxy) benzoic acid (Intermediate 1) (0.90 g, 3.05 mmol) in N, N-dimethylformamide (DMF) (10 mL) was treated with N, N'-carbonyldiimidazole (CDI) (1.10 g, 6.78 mmol) at 0℃. The solution was stirred at room temperature for 1 h. Then it was added to the suspension. The resulting mixture was stirred at room temperature for 3 h, then it was heated to 100 ℃ for 10 h. The mixture was cooled to room temperature, filtered and concentrated. The residue was purified by reversed phase HPLC (C18) to give 3- (3-methoxy-4- (3-morpholinopropoxy) phenyl) -1H-1, 2, 4-triazol-5-amine (Intermediate 2) as white solid (520 mg, purity 80%) which was used in next step directly. Mass spectrum (ESI) m/z calc. for C16H23N5O3 [M+H] + 334.18, found 334.31.
Step3: Synthesis of N- (2-chloro-6-fluorobenzyl) -3- (3-methoxy-4- (3-morpholinopropoxy) phenyl) -1H-1, 2, 4-triazol-5-amine (32) :
The mixture of 3- (3-methoxy-4- (3-morpholinopropoxy) phenyl) -1H-1, 2, 4-triazol-5-amine (Intermediate 2) (480 mg, 1.15 mmol, 80%purity) , 2-chloro-6-fluorobenzaldehyde (913.12 mg, 5.76 mmol) and p-toluenesulfonicacid (19.83 mg, 0.12 mmol) in isopropanol (10 mL) was heated to reflux overnight. The solution was allowed to cool to room temperature before NaBH3CN (723.81 mg, 11.52 mmol) and acetic acid (1.5 mL) were added. Then, the resulting mixture was stirred at room temperature for 5 h before quenched with water. The solvent was removed under reduced pressure, and the residue was purified by column chromatography (silica gel, dichloromethane/methanol = 100: 1 to 10: 1) to give N- (2-chloro-6-fluorobenzyl) -3- (3-methoxy-4- (3-morpholinopropoxy) phenyl) -1H-1, 2, 4-triazol-5-amine as a white solid (85 mg, yield 15.51%) . Mass spectrum (ESI) m/z calc. for C23H27ClFN5O3 [M+H] + 476.18, 478.18, found 476.39 , 478.27. 1H NMR (400 MHz, CDCl3) δ 7.46 (s, 1H) , 7.45-7.43 (d,
J = 8.4Hz, 1H) , 7.25-7.22 (m, 2H) , 7.03-7.0 (m, 1H) , 6.92-6.90 (d, J = 8.4Hz, 1H) , 5.08 (brs, 1H ) , 4.65 (dd, J=6.8, 1.2 Hz , 2H ) , 4.15-4.10 (m, 2H) , 3.90 (s, 3H) , 3.75-3.72 (m, 4H) , 2.61-2.58 (m, 2H) , 2.54 (brs, 4H) , 2.08-2.04 (m, 2H) .
Plasmid construction
Human p38MAPK and MKK6 were cloned to pet28a vector using Nco I/Not I, Nde I and Sal I restriction site, respectively. Then S207D/T211D mutagenesis on pet28a-hMKK6 was carried out with Site-Directed Mutagenesis Kit from Transgen. The inserted genes were sequenced to ensure that the sequence was correct.
Purification of the fusion proteins
The E. coli BL21DE3 was used for the protein expression with LB medium. Cultures were grown to an OD600nm of 1.2 at 37℃, cooled for 1 h with shaking at 18℃ prior to induction for 16 h at 16℃ with 0.2 mM IPTG. The proteins were purified as described previously. Briefly, cells were harvested and purified with Ni-resin and MonoQ HP column. Then the pooled protein peak fractions were purified further with Superdex-75 column using 50 mM Tris-HCl (pH 7.4) , 150 mM NaCl, 5%glycerol, 10 mM MgCl2, 5 mM DTT. All purification steps were carried out at 4 ℃.
P38 MAPK Kinase assay
1000 ng inactive hMAPK14 was activated by 100 ng constitutively active hMKK6DD in the 15 ul reaction volume containing 50 uM ATP for 30 min, at 30℃. Kinase assay was performed using the Z’-LYTE kinase assay kit Ser/Thr 15 peptide (Invitrogen, Carlsbad, CA) . The standard reaction for compound screening contained 100 nM hMAPK14, 1mM peptide substrate, 100 uM ATP, 50m MHEPES (pH 7.4) , 10 mM MgCl2, 0.01%Brij-35, and 0.5%DMSO.
Cell culture
Jurkat T and Ramos B cells were maintained in RPMI 1640 supplemented with 10%FBS, 100 μg of penicillin and streptomycin per ml.
Antibodies
Anti-BTK (Tyr223) , anti-ZAP-70, anti-PLCγ-2, anti-p-BTK (Y223) , anti-p-PLCγ-2 (Y1217) , anti-p-ZAP-70 (Y319) and anti-GAPDH used for Western blotting were purchased from Cell Signaling Technology (Danvers, MA, USA) .
B and T cell Activation and Phospho-Blots
Ramos B cells or Jurkat T cells (2*106) were incubated with or without different concentrations of compound for 1.5 h at 37℃ in a 5%CO2 incubator. Then goat antihuman IgM F (ab’) 2 (10 ug/mL; Invitrogen) or Dynabeads Human T-activactor CD3/CD28 was added to
stimulate Ramos B cells or Jurkat T cells respectively for 5 min at 37℃. The cells were centrifuged, washed once with cold DPBS and lysed with RIPA buffer (Sigma-Aldrich) containing phosphatase inhibitor cocktail 2 and Protease Inhibitor Cocktail (both from Sigma-Aldrich) on ice for 20 min. The samples then centrifuged at 20, 000g for 20 min at 4℃. The supernatants were collected and diluted 5-fold with loading buffer, then subjected to SDS-PAGE, followed by immunoblotting.
Inhibition activity of compounds against some autoimmune disease-related kinase targets.
*N.A.: not available
We also determined the phosphorylation levels of protein targets in signaling pathway
of Ramos B cells treated with compounds or not. Ramos B cells treated with or without compounds for 1.5 h were activated (+) or inactivated (-) with IgM F (ab′) 2 for 5 min. The lysates of harvested cells were subjected to SDS-PAGE and immunoblotting experiments. Exemplary compounds 1, 6, 11, 17 and 20 were shown to inhibit the autophosphorylation of BTK, as well as the phosphorylation of BTK’s physiological substrate PLCγin a dose-dependent manner after activating the BCR pathway in Ramos cells with goat antihuman IgM F (ab’) 2. The cellular activities of the above compounds were consistent with the performance in the enzymatic experiments.
We also determined phosphorylation levels of protein targets in signaling pathway of Jurkat T cells treated with compounds or not. Jurkat T cells treated with or without with compounds for 1.5 h were activated (+) or unactivated (-) with Dynabeads Human T-activactor CD3/CD28 for 5 min. The lysates of harvested cells were subjected to SDS-PAGE and immunoblotting experiments. Exemplary compounds 1, 6, 11, 17 and 20 were shown to inhibit the phosphorylation of LCK’s physiological substrate ZAP-70 and LAT in a dose-dependent manner after activating the TCR pathway in Jurkat cells with Dynabeads Human T-activator CD3/CD28. The cellular activities of the above compounds were consistent with the performance in the enzymatic experiments.
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Claims (15)
- A compound of formula I:wherein:R1–R5 are independently H, halogen, hydroxyl, methyl, trifluoromethyl, or methoxyl, particularly wherein R1 and R5 are independently halogen, hydroxyl, methyl, trifluoromethyl; andR6 is optionally-substituted Cn cyclic hydrocarbyl, where n = 3-18, and comprising up to n-1 heteroatoms independently selected from N, O, S and P, particularly wherein said hydrocarbyl is selected from cycloalkyl, aryl, heteroaryl, or heterocyclyl;or a stereoisomer or pharmaceutically acceptable salt thereof.
- The compound of claim 1, wherein n is 3, 5, 6 or 9.
- The compound of claim 1, wherein R6 is substituted or unsubstituted, homo-or hetero, 5-or 6-membered cyclic or 9 or 10 membered bi-cyclic aryl.
- The compound of claim 1 wherein R6 is optionally substituted:-cyclopropyl;-5 membered aryl selected from pyrrole, pyrazole, imidazole, triazole, tetrazole, pentazole, oxazole, isoxazole, thiazole or isothiazole, furan, dioxole thiophene, dithiole or oxathiole, and reduced forms thereof, including dihydrofuran, and dihydroimidazole;-6 membered aryl selected from phenyl and pyridine; or-9 membered aryl is benzimidazole.
- The compound of claim 1 wherein R6 is phenyl, 3-substituted phenyl, 3, 4-substituted phenyl or 3, 4, 5-substituted phenyl.
- The compound of claim 1 wherein R6 substituents are selected from: halogen, -OR', -OC (O) R', -NR'R", -SR', -R', -CN, -NO2, -CO2R', -CONR'R", -C (O) R', -OC (O) NR'R", -NR"C (O) R', -NR"CO2R', -NR'-C (O) NR"R'", -NR'-SO2NR"R'", -NH-C (NH2) =NH, - NR'C (NH2) =NH, -NH-C (NH2) =NR', -S (O) R', -SO2R', -SO2NR'R", -NR"SO2R, -N3, -CH (Ph) 2, perfluoro (C1-C4) alko-xy and perfluoro (C1-C4) alkyl, in a number ranging from zero to the total number of open valences on the aromatic ring system; and where R', R"and R'"are independently selected from hydrogen, (C1-C8) alkyl and heteroalkyl, unsubstituted aryl and heteroaryl, (unsubstituted aryl) - (C1-C4) alkyl and (unsubstituted aryl) oxy- (C1-C4) alkyl.
- The compound of claim 1 wherein R2-R4 are H, and at least one of R1 and R5 is halogen, hydroxyl, methyl, trifluoromethyl, or methoxyl.
- The compound of claim 1 wherein R2-R4 are H, and R1 and R5 are halogen, hydroxyl, methyl, trifluoromethyl, or methoxyl;
- The compound of claim 1 wherein:R2-R4 are H, and R1 and R5 are halogen, hydroxyl, methyl, trifluoromethyl, or methoxyl;R6 is substituted or unsubstituted, homo-or hetero, 5-or 6-membered cyclic or 9 or 10 membered bi-cyclic aryl; andR6 substituents are selected from: halogen, -OR', -OC (O) R', -NR'R", -SR', -R', -CN, -NO2, -CO2R', -CONR'R", -C (O) R', -OC (O) NR'R", -NR"C (O) R', -NR"CO2R', -NR'-C (O) NR"R'", -NR'-SO2NR"R'", -NH-C (NH2) =NH, -NR'C (NH2) =NH, -NH-C (NH2) =NR', -S (O) R', -SO2R', -SO2NR'R", -NR"SO2R, -N3, -CH (Ph) 2, perfluoro (C1-C4) alko-xy and perfluoro (C1-C4) alkyl, in a number ranging from zero to the total number of open valences on the aromatic ring system; and where R', R"and R'"are independently selected from hydrogen, (C1-C8) alkyl and heteroalkyl, unsubstituted aryl and heteroaryl, (unsubstituted aryl) - (C1-C4) alkyl and (unsubstituted aryl) oxy- (C1-C4) alkyl.
- The compound of claim 1, having a Lck or Btk-inhibiting activity corresponding to an IC50 of 10 uM or less in a kinase assay.
- A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 in unit dosage form and one or more pharmaceutically acceptable excipients.
- A combination comprising a therapeutically effective amount of a compound of claim 1 and a different agent therapeutically active against an autoimmune and/or inflammatory disease or cancer.
- A method of treating a disease associated with undesirable kinase activity, which comprises administering to a person in need thereof an effective amount of a compound of claim 1, or a prodrug thereof, wherein the disease is an allergic disease, an autoimmune disease, an inflammatory disease, or cancer.
- The method of claim 14 further comprising the antecedent step of diagnosing the disease or cancer, or the subsequent step of detecting a resultant amelioration of the disease or cancer.
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