Patent Application
20190202819
The present invention relates to particular bicyclic sulfonamide derivatives, to the pharmaceutically acceptable addition salts thereof, hydrates thereof and/or solvates thereof, and also to the use thereof as inverse agonist of the retinoid-related orphan receptor gamma RORγt.
The invention also relates to a pharmaceutical composition comprising such compounds and also to the use thereof for the topical and/or oral treatment of inflammatory diseases mediated by the RORγt receptors, especially acne, atopic dermatitis and/or psoriasis.
The nuclear receptors form a large family (known as a superfamily) of transcription factors which correspond to proteins that are capable of being activated by a ligand, of binding to specific DNA sequences and of regulating the transcription of target genes. Thus, these receptors are involved in the regulation of a wide variety of biological functions, including growth, development, reproduction, differentiation and metabolism in a multitude of living organisms.
The first members of this superfamily that were identified and described in the scientific literature are the nuclear receptors of steroid hormones such as the glucocorticoid receptors and the estrogen receptors. This superfamily also comprises among its members many receptors for which no ligand has been identified. These nuclear receptors are known as “orphan receptors”.
Retinoid-related orphan receptors thus constitute a subfamily of nuclear receptors. This subfamily is composed of three members each having an intrinsic expression profile: ROR alpha (known as RORα), ROR beta (known as ROM and ROR gamma (known as RORγ). Two isoforms of the orphan receptors RORγ have already been identified, namely RORγ1, which is expressed in a variety of tissues such as the thymus, the kidneys, muscles and the liver, and RORγ2 (also known as RORγt), which is expressed exclusively in the cells of the immune system.
In particular, the receptor RORγt plays an important regulating role in cell differentiation of the Th17 lymphocytes which correspond to helper T lymphocytes whose function is to ensure the defence of the body against a large number of extracellular pathogens such as bacteria and fungal infections.
However, it has been demonstrated that the Th17 lymphocytes are also involved in a wide variety of inflammatory disorders, such as acne, and of autoimmune diseases such as psoriasis, rheumatoid arthritis or multiple sclerosis (Peck A, Mellins E D. Precarious balance; Th17 cells in host defense. Infect. Immun. 2010 January; 78(1): 32-8; Suarez-Farinas: J. Allergy Clin. Immunol. 2014; J. Invest. Dermatol. 2008, 128(11), 2625).
Specifically, the Th17 lymphocytes produce numerous cytokines which have distinct profiles, such as interleukin-17A (IL-17A), interleukin-17F (IL-17F), interleukin-26 (IL-26), interleukin-21 (IL-21), interleukin-22 (IL-22) and TNFα, the development, survival and proliferation of which depend on interleukin-23 (IL-23). These cytokines are capable of activating different types of effector cells, such as keratinocytes, thus leading to their hyperproliferation and to the additional production of pro-inflammatory cytokines, chemokines and antimicrobial peptides, which in turn recruit and activate other immune system cells in the inflamed skin, which may lead to amplification of the immune response.
Thus, activation of the Th17 lymphocytes is responsible for the recruitment of cytokines, especially of interleukin-17 (IL17), and of other types of pro-inflammatory cells, which will lead to the mediation of inflammatory disorders such as acne and/or of autoimmune diseases such as psoriasis.
Experiments conducted on mice show that a decrease in the level of expression of the RORγt receptor leads to a decrease in the activity of the Th17 lymphocytes, which consequently makes it possible to greatly reduce the expression of interleukin-17 (IL-17) (Ivanov I I, McKenzie B S, Zhou L, Tadokoro C E, Lepelley A, Lafaille J J, Cua D J, Littman D R: Cell 2006, 126, 1121-1133) and to efficiently treat inflammatory disorders and autoimmune diseases mediated by these cytokines, especially those for which high levels of interleukin-17 (IL-17) are detected.
To this end, patent application WO 2013/160 418 describes sulfonamide compounds used as inverse agonists of the RORγt receptor in order to be able to treat inflammatory disorders and autoimmune diseases. Similarly, other compounds have also been developed as inverse agonists of the RORγt receptor, such as those described in patent applications WO 2014/090 712, WO 2014/008 214, WO 2013/169 588, WO 2013/160 419, WO 2013/1 002 027, WO 2013/092 939, WO 2013/092 941, WO 2013/085 890 and WO 2012/100 732.
There is thus a real need to develop novel compounds as inverse agonists of the RORγt receptor in order to be able to efficiently treat diseases mediated by such a receptor, especially inflammatory disorders such as acne, and/or autoimmune diseases such as psoriasis or atopic dermatitis.
This aim is achieved by means of the use of particular bicyclic sulfonamide derivatives as described below, which make it possible to modulate the activity of the RORγt receptor and consequently to efficiently treat inflammatory disorders and autoimmune diseases of certain pathologies.
One subject of the present invention is thus especially one or more compounds of formula (Ia), the pharmaceutically acceptable addition salts thereof, hydrates thereof and/or solvates thereof:
in which formula (I):
The compound(s) according to the invention thus correspond to bicyclic sulfonamide derivatives, and thus to one or more sulfonamide compounds bearing in their structure at least two rings that are fused to each other.
In other words, X is a cyclic radical fused to the aromatic nucleus, comprising the elements Q1, Q2 and Q3 as defined above.
In accordance with the definition of formula (I), the endocyclic bond between the cyclic radical X1 or X2, as represented above, and the aromatic nucleus comprising the elements Q1 to Q3 is a double bond. Thus, the double bond is common between the cyclic radical X1 or X2 and the aromatic nucleus comprising the elements Q1 to Q3.
The compounds according to the invention make it possible to modulate, i.e. to inhibit, the activity of the RORγt receptor.
A subject of the present invention is also the compound(s) as defined previously, as medicament and cosmetic.
Another subject of the invention relates to the compound(s) as defined previously for their use in the treatment of diseases mediated by the RORγt receptor, especially inflammatory disorders and/or autoimmune diseases mediated by the RORγt receptor.
Moreover, the invention also relates to a pharmaceutical composition comprising, in a pharmaceutically acceptable medium, one or more compounds of formula (I) as defined previously, pharmaceutically acceptable addition salts thereof, hydrates thereof and/or solvates thereof.
The present invention also relates to the pharmaceutical composition as described previously, for its use in the treatment of diseases mediated by the RORγt receptor, especially inflammatory disorders and/or autoimmune diseases.
Finally, the invention relates to a method for treating diseases mediated by the RORγt receptor, comprising the administration, especially topically or orally, of a therapeutically effective amount of one or more compounds as defined above to a patient.
Other subjects, characteristics, aspects and advantages of the invention will emerge even more clearly on reading the description and the examples that follow.
According to one embodiment, in formula (I):
According to one embodiment, in formula (I), L represents a single bond.
According to another embodiment, in formula (I), L represents a methylene group —CH2.
Preferentially, in formula (I), L represents a single bond.
Preferably:
Preferentially, when X═X1, then R3 is other than a halogen atom and when X═X2, then R5 represents a hydrogen atom or a linear or branched C1-C3 alkyl radical optionally substituted with one or more halogen atoms.
More preferentially, R3 and R5 are different.
Even more preferentially, R3 represents a hydrogen atom or a group (CHR6)n—(Z)o—(CHR′6)p—R7.
According to one embodiment, R3 represents a hydrogen atom or a group (CHR6)n—(Z)o—(CHR′6)p—R7 and R5 represents a hydrogen atom or a linear or branched C1-C3 alkyl radical, optionally substituted with one or more halogen atoms.
Preferably, R11 and R12 are other than an —OH group.
According to one embodiment, in formula (I), R3 represents a hydrogen atom.
According to one embodiment, in formula (I), R3 represents a group (CHR6)n—(Z)o—(CHR′6)p—R7.
According to one embodiment, in formula (I), the indices n, o and p, which may be identical or different, denote zero.
According to one embodiment, in formula (I), the indices n, o and p, which may be identical or different, denote a natural integer ranging from 1 to 3.
According to one embodiment, in formula (I), the indices n and p denote zero and the index o is equal to 1.
According to one embodiment, in formula (I), Z represents a methylene group —CH2.
According to one embodiment, in formula (I), Z represents a divalent group-O—.
According to one embodiment, in formula (I), Z represents a divalent group-NH—.
According to one embodiment, in formula (I), R3 represents a group Z—R7, with Z having the meaning described previously.
According to a particular embodiment, in formula (I), R3 represents a group-CH2—R7.
According to a particular embodiment, in formula (I), R3 represents a group-O—R7.
According to a particular embodiment, in formula (I), R3 represents a group-NH—R7.
According to one embodiment, in formula (I), R7 represents a heterocyclic radical chosen from the following heterocycles:
in which:
According to one embodiment, in formula (I), R7 represents an aromatic or heteroaromatic radical chosen from:
in which:
Preferably, R11 and R12 are other than an —OH group.
Preferentially, R7 represents an aromatic or heteroaromatic radical as defined previously, optionally substituted with one or more methyl groups —CH3, one or more methoxy groups —OCH3, one or more hydroxyl groups —OH, one or more amino groups —NH2, one or more —CH2OH groups, one or more cyano groups —CN, one or more halogen atoms or one or more carbonyl functions.
According to one embodiment, the index m is equal to zero.
According to one embodiment, the index m denotes a natural integer ranging from 1 to 3.
Preferentially, the index m is equal to 1.
According to one embodiment, in formula (I), each of the elements Y1, Y2, Y3, Y4 and Y5 corresponds to a group —CR2 with R2 having the same meaning as that described previously.
According to one embodiment, in formula (I), each of the elements Y1, Y2, Y3, Y4 and Y5 corresponds to a group —CR2 with R2 representing a hydrogen atom.
According to one embodiment, in formula (I), each of the elements Y1, Y2, Y3, Y4 and Y5 corresponds to a group —CR2 with R2 representing a linear or branched C1-C5 alkyl radical.
According to one embodiment, in formula (I), each of the elements Q1, Q2 and Q3 represents a group —CR2a with R2a having the same meaning as that described previously.
According to one embodiment, in formula (I), each of the elements Q1, Q2 and Q3 represents a group —CR2a with R2a representing a hydrogen atom.
According to one embodiment, in formula (I), Q1 and Q2 represent a group —CR2a with R2a representing a hydrogen atom and Q3 represents a group —CR2a with R2a representing a linear or branched C1-C5 alkyl radical.
According to one embodiment, in formula (I), IV represents a linear or branched C3-C5 alkyl radical, preferably a branched C3-C5 and more preferentially branched C4 alkyl radical.
According to one embodiment, in formula (I), IV represents a C3-C5 cycloalkyl radical, preferably cyclopropyl.
According to one embodiment, in formula (I), R1 represents a linear or branched C2-C5 alkenyl radical.
According to one embodiment, in formula (I), R1 represents a CH2—(C3-C5)cycloalkyl radical.
According to one embodiment, in formula (I), R1 represents a C4-C5 heterocycloalkyl radical.
According to one embodiment, in formula (I), R1 represents a CH2—(C4-C6)heterocycloalkyl radical, in particular a CH2—(C4-C5)heterocycloalkyl radical.
Preferentially, R1 represents a linear or branched C3-C5 alkyl radical, or a CH2—(C4-C5)heterocycloalkyl radical.
According to one embodiment, R5 represents a hydrogen atom.
Preferably, the compound(s) of formula (I) are chosen from the compound(s) of formula (II), the pharmaceutically acceptable addition salts thereof, hydrates thereof and/or solvates thereof:
in which formula (II) R1, R3, R5 and Y1 to Y5 have the same meanings as in formula (I) described previously.
Preferentially, R3 represents a group (CHR6)n—(Z)o—(CHR′6)p—R7 with R6, Z, R′6, R7 and the indices n, o and p having the same meanings as those indicated previously.
More preferentially, R3 represents a group CH2—R7 with R7 representing a non-cationic heterocyclic radical.
Preferably, the compound(s) of formula (I) are chosen from the compound(s) of formula (III), the pharmaceutically acceptable addition salts thereof, hydrates thereof and/or solvates thereof:
in which formula (III) R1, R3, R5 and Y1 to Y5 have the same meanings as in formula (I) described previously.
Preferentially, in formula (III), R5 represents a hydrogen atom or a linear or branched C1-C3 alkyl radical optionally substituted with one or more halogen atoms.
The compounds of formula (I) may be in the form of pharmaceutically acceptable salts. Examples of pharmaceutically acceptable salts are described in Berge et al., 1977, “Sels pharmaceutiquement acceptables” [Pharmaceutically acceptable salts], J. Pharm. Sci., Vol. 66, pages 1-19.
In particular, when the compounds of formula (I) according to the invention are in the form of salts, then the electrical neutrality of said compounds is ensured by an external cationic counterion Y which may be organic or mineral.
Y may be chosen from suitable inorganic cations such as alkali metal ions, especially Na+, K+, alkaline-earth metal ions, especially Ca2+, Mg2+, or alternatively other cations such as the aluminum ion Al3+.
Y may be chosen from suitable organic cations such as the ammonium ion NH4+, substituted ammonium ions such as NH3R+, NHR2+, NR4+ with R representing a C1-C4 alkyl radical.
In particular, the substituted ammonium ions are those chosen from derivatives of ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine and tromethamine, and amino acids such as lysine and arginine.
An example of a quaternary ammonium ion may be the ion N+ (CH3)4.
The compound(s) according to the invention may be in the form of the solvates thereof.
For the purposes of the present invention, the term “solvate” means a complex of solute (i.e. the compound according to the invention or the salt of said compound) and of solvent.
If the solvent is water, then the solvate may suitably be considered as a hydrate, for example, a hemihydrate, a monohydrate, a dihydrate, a trihydrate, etc.
For example, the solvates and/or hydrates may be obtained directly at the end of the synthetic process, the target compound being isolated in the form of a hydrate, for example a monohydrate or hemihydrate, or in the form of a solvate of the reaction solvent and/or purification solvent.
Unless otherwise indicated, any reference to a compound according to the invention also includes the solvate or the hydrate of the corresponding compound.
Typical processes for the preparation and identification of hydrates and solvates are well known to those skilled in the art: see, for example, pages 202-209 of K J Guillory, “Generation of Polymorphs, Hydrates, Solvates, and Amorphous Solids” in Polymorphism in Pharmaceutical Solids, edition. Harry G. Britain, Vol. 95, Marcel Dekker, Inc., New York, 1999.
The hydrates and solvates may be isolated and characterized via methods known in the art, such as thermogravimetric analysis (TGA), TGA-mass spectroscopy, TGA-infrared spectroscopy, x-ray powder diffraction, Karl Fischer titration, high-resolution x-ray diffraction, and the like.
Preferably, the compound(s) of formula (Ia) are chosen from the compounds as described in the tables below, and also the pharmaceutically acceptable addition salts thereof, hydrates thereof and/or solvates thereof:
In the tables described above, the median inhibitory concentrations IC50 for the compounds belonging to formula (I) according to the invention have been given according to the following models:
GAL4-RORγTransactivation
The RORγtransactivation model was developed from the line HG5LN, which is a HeLa line that stably expresses a luciferase reporter gene controlled by a pentamer of the GAL4 recognition domain of yeast and of a β-globin promoter. The HG5LN line was stably transfected by the DNA-binding domain (DBD) of GAL4 fused to the ROR gamma ligand-binding domain (LBD). Molecules that inhibit the ROR gamma constitutive activity reduce the luciferase expression, thus leading to a reduction in the emitted luminescence.
The cells are seeded in 384-well plates (5000 cells in 45 μL/well of culture medium containing 10% fetal calf serum) and incubated for 4 hours at 37° C., 5% CO2. 5 μL of the test molecules (compounds described in the tables described above) are then added to each well and the plates are incubated for 18 hours at a temperature of 37° C. under 5% of CO2. 20 μL of luciferase substrate (Promega) are added to each well and the luminescence emitted is read by a microplate reader.
The luminescence units (“RLU”) are normalized by positive controls (“POS” containing a saturated concentration of N-(2,2,2-trifluoroethyl)-N-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl])benzenesulfonamide and negative controls (“NEG” containing DMSO): % inhibition=((RLU-NEG)*100)/(POS−NEG). The IC50 values are calculated from a 4-parameter logistic model using the XLFit software (IDBS).
IL-17A Secretion
This model allows measurement of the effect of inhibitors on IL-17A secretion by CD4+ cells. The cells are frozen CD4+ cells (STEMCELL, #70026), isolated from peripheral human blood and activated with anti-CD3 and anti-CD28 antibodies. The amount of IL-17a secreted is measured by the TR-FRET (kit HTRF® Human Interleukin 17A (Cisbio, #64H17PEC)) technology.
The cells are rapidly thawed, resuspended in their culture medium (RPMI inactivated 10% FCS) supplemented with soluble anti-CD28 antibodies and seeded (100 000 cells/well) in 96-well plates precoated with anti-CD3 antibodies. The cells are then treated with the ranges of inhibitors to be tested (from 1000 nM to 0.05 nM, 0.1% DMSO). After 4 days of incubation, the HTRF signal is measured using a microplate reader (λexcitation=337 nm, λemission=620/665 nm). The ratios obtained (665/620) are normalized relative to the positive control (cells activated with anti-CD3 and anti-CD28, 0.1% DMSO). The IC50 values are calculated from a 4-parameter logistic model using the XLFit software (IDBS).
Preferentially, the compounds of formula (I) according to the invention are chosen from the following compounds:
In particular, among the compounds of formula (II), compounds 1, 2, 7, 11, 21, 24, 27, 30, 32, 36, 37, 39, 40, 42, 43, 52, 54, 55, 57 and 58 are preferred.
Among the compounds of formula (III), compounds 63, 64 and 66 are preferred.
The invention also relates to the compound(s) as described previously, as medicament and cosmetic.
Preferably, the invention also relates to the compound(s) as described previously, as medicament.
Specifically, the compounds according to the invention have advantageous pharmacological properties, given that said compounds modulate, i.e. inhibit, the activity of the RORγt receptor.
Thus, these properties make the compound(s) of formula (I) as described previously usable as medicament in the treatment of diseases mediated by the RORγt receptor.
Preferably, the compound(s) according to the invention are used in the treatment of inflammatory disorders and/or autoimmune diseases mediated by the RORγt receptor.
More preferentially, the compound(s) according to the invention, preferably those chosen from the compounds corresponding to formulae (II) and (III), are used in the treatment of acne, psoriasis and/or atopic dermatitis.
According to another embodiment, the compounds according to the invention are used for cosmetic treatment of the skin.
As indicated above, the present invention also relates to a pharmaceutical composition comprising, in a pharmaceutically acceptable medium, one or more compounds of formula (I) as defined previously, pharmaceutically acceptable addition salts thereof, hydrates thereof and/or solvates thereof.
Preferably, the pharmaceutical composition comprises one or more compounds chosen from the compounds of formulae (II) and (III) as defined previously, the pharmaceutically acceptable addition salts thereof, hydrates thereof and/or solvates thereof.
More preferentially, the pharmaceutical composition comprises one or more compounds of formula (I) chosen from compounds (1) to (75) defined previously.
Even more preferentially, the pharmaceutical composition comprises one or more compounds of formula (I) chosen from compounds 1, 2, 7, 11, 21, 24, 27, 30, 32, 36, 37, 39, 40, 42, 43, 52, 54, 55, 57, 58, 63, 64 and 66.
The pharmaceutical composition according to the invention as described previously may be administered orally or topically.
Preferably, the pharmaceutical composition is conditioned in a form that is suitable for topical application.
Via the oral route, the composition may be in the form of tablets, gel capsules, coated tablets, syrups, suspensions, solutions, powders, granules, emulsions, suspensions of microspheres or nanospheres or lipid or polymeric vesicles allowing controlled release.
Via the topical route, the pharmaceutical composition according to the invention is more particularly intended for treating the skin and mucous membranes, and may be in liquid, pasty or solid form, and more particularly in the form of ointments, creams, milks, pomades, powders, impregnated pads, syndets, solutions, gels, sprays, mousses, suspensions, sticks, shampoos or washing bases. It may also be in the form of suspensions of microspheres or nanospheres or lipid or polymeric vesicles or of polymeric or gelled patches allowing controlled release.
The pharmaceutical composition is used for treating inflammatory disorders and/or autoimmune diseases mediated by the RORγt receptor.
More preferentially, the pharmaceutical composition is used in the treatment of acne and/or psoriasis.
The invention also relates to a process for treating diseases mediated by the RORγt receptor, comprising the administration, especially topically or orally, of a therapeutically effective amount of the pharmaceutical composition as defined above to a patient.
Preferably, the pharmaceutical composition is applied topically.
In accordance with another embodiment, a subject of the present invention is also one or more compounds of formula (II) as defined previously, the pharmaceutically acceptable addition salts thereof, hydrates thereof and/or solvates thereof:
in which formula (II) R1, R3, R5 and Y1 to Y5 have the same meanings as in formula (Ia) described previously.
Preferably, R3 represents a group (CHR6)n—(Z)o—(CHR′6)p—R7 with R7 representing a non-cationic heterocyclic radical, a non-cationic cycloalkyl radical or a non-cationic aromatic or heteroaromatic radical as defined previously.
Among the compounds of formula (II), compounds 1, 2, 7, 11, 21, 24, 27, 30, 32, 36, 37, 39, 40, 42, 43, 52, 54, 55, 57 and 58 are preferred.
According to this embodiment, the invention also relates to the compound(s) of formula (II), as medicament and cosmetic.
In particular, the invention relates to the compound(s) of formula (II), for their use in the treatment of inflammatory disorders and/or autoimmune diseases mediated by the RORγt receptor.
Preferentially, a subject of the invention is the compound(s) of formula (II) for their use in the treatment of acne.
As a variant, a subject of the invention is also the compound(s) of formula (II) for their use in the treatment of psoriasis.
Alternatively, the compound(s) of formula (II) according to the invention are used for cosmetic treatment of the skin.
Furthermore, the invention also relates to a pharmaceutical composition comprising, in a pharmaceutically acceptable medium, one or more compounds of formula (II) as defined previously, pharmaceutically acceptable addition salts thereof, hydrates thereof and/or solvates thereof.
The pharmaceutical composition is used for treating inflammatory disorders and/or autoimmune diseases mediated by the RORγt receptor.
In accordance with another embodiment, a subject of the present invention is also one or more compounds of formula (III) as defined previously, the pharmaceutically acceptable addition salts thereof, hydrates thereof and/or solvates thereof:
in which formula (III) R1, R3, R5 and Y1 to Y5 have the same meanings as in formula (I) described previously.
Preferably, R3 represents a group (CHR6)n—(Z)o—(CHR′6)p—R7 with R7 representing a non-cationic heterocyclic radical, a non-cationic cycloalkyl radical or a non-cationic aromatic or heteroaromatic radical as defined previously.
Among the compounds of formula (III), compounds 63, 64 and 66 are preferred.
According to this embodiment, the invention also relates to the compound(s) of formula (III), as medicament and cosmetic.
In particular, the invention relates to the compound(s) of formula (III), for their use in the treatment of inflammatory disorders and/or autoimmune diseases mediated by the RORγt receptor.
Preferentially, a subject of the invention is the compound(s) of formula (III) for their use in the treatment of acne.
As a variant, a subject of the invention is also the compound(s) of formula (III) for their use in the treatment of psoriasis.
Alternatively, the compound(s) of formula (III) according to the invention are used for cosmetic treatment of the skin.
Furthermore, the invention also relates to a pharmaceutical composition comprising, in a pharmaceutically acceptable medium, one or more compounds of formula (III) as defined previously, pharmaceutically acceptable addition salts thereof, hydrates thereof and/or solvates thereof.
The pharmaceutical composition is used for treating inflammatory disorders and/or autoimmune diseases mediated by the RORγt receptor.
The examples that follow serve to illustrate the invention without, however, being limiting in nature.
The standard LCMS method for analyzing the products is as follows: BEH C18 standard column (150×2.1 mm, 1.8 μm) solvent: water/acetonitrile 0.1% formic acid. The preparative HPLC purifications were performed on a C18 column using, as eluent: 85% acetonitrile in water/0.1% formic acid.
Isobutyraldehyde (6.33 ml; 0.07 mol) in tetrahydrofuran (100 ml) is added to 4-ethylaniline (9.48 ml; 0.08 mol). The mixture is stirred for 2 hours at room temperature. Sodium triacetoxyborohydride (22.04 g; 0.10 mol) is then added. The mixture is stirred overnight at room temperature, water (100 ml) are added and the resulting mixture is extracted with ethyl acetate (2×100 ml). The organic phases are combined, washed with brine (100 ml), dried (Na2SO4) and concentrated.
The crude product is chromatographed on silica gel (eluent: heptane/dichloromethane from 0 to 50% of dichloromethane). The (4-ethylphenyl)isobutylamine is obtained in the form of an orange oil with a compliant 1H NMR.
MS: [M+H]=179
1H-Indazole-5-sulfonyl chloride (502 mg; 2.20 mmol) is added to (4-ethylphenyl)isobutylamine (300 mg; 1.69 mmol) and pyridine (820 μl; 10.15 mmol) in tetrahydrofuran (6 ml). The reaction medium is stirred for 7 hours at room temperature, hydrolyzed and extracted with ethyl acetate. The organic phases are combined, washed with brine, dried (Na2SO4) and concentrated.
The crude product is chromatographed on silica gel (eluent: heptane/ethyl acetate, from 20 to 50% of ethyl acetate). The N-(4-ethylphenyl)-N-isobutyl-1H-indazole-5-sulfonamide (357 mg; 59%) is obtained in the form of a cream-colored solid with a compliant 1H NMR.
MS: [M+H]=358
4-(Bromomethyl)tetrahydropyran (90 mg; 0.50 mmol) is added to N-(4-ethylphenyl)-N-isobutyl-1H-indazole-5-sulfonamide (150 mg; 0.42 mmol) and cesium carbonate (137 mg; 0.42 mmol) in N,N-dimethylformamide (12 ml). The reaction medium is stirred for 30 minutes at a temperature of 100° C. under microwave irradiation, hydrolyzed and extracted with ethyl acetate. The organic phases are combined, washed with brine, dried (Na2SO4) and concentrated.
The crude product is chromatographed on silica gel (eluent: heptane/ethyl acetate, 40% of ethyl acetate). The N-(4-ethylphenyl)-N-isobutyl-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indazole-5-sulfonamide (97 mg; 50%) is obtained in the form of a white powder.
1H NMR (400 MHz, DMSO-d6) δ 0.85 (d, J=6.6 Hz, 7H), 1.17 (t, J=7.6 Hz, 4H), 1.22-1.53 (m, 6H), 2.16-2.31 (m, 1H), 2.59 (q, J=7.6 Hz, 2H), 3.15-3.44 (m, 6H), 3.83 (ddd, J=11.5, 4.4, 2.0 Hz, 3H), 4.39 (d, J=7.2 Hz, 3H), 6.92-7.05 (m, 3H), 7.10-7.21 (m, 3H), 7.26 (dd, J=9.1, 1.8 Hz, 1H), 7.74 (d, J=9.3 Hz, 1H), 8.10 (d, J=1.7 Hz, 1H), 8.62 (s, 1H).
MS: [M+H]=456
With a procedure similar to that described for the synthesis of example 1, the compounds of the table below are obtained:
1-(3-Hydroxymethylazetidin-1-yl)ethanone (0.27 g; 2.09 mmol) in toluene (1 ml) is added to a mixture of N-(4-ethylphenyl)-N-isobutyl-1H-indazole-5-sulfonamide (0.20 g; 0.56 mmol) and (triphenyl-λ5-phosphanylidene)acetonitrile (0.51 g; 1.68 mmol) in anhydrous toluene (3 ml) under argon. The reaction medium is stirred for 3 days at a temperature of 95° C., hydrolyzed and extracted with ethyl acetate. The organic phase is washed, dried (Na2SO4), filtered and concentrated.
The crude product is purified by preparative HPLC (C18 column, eluent: acetonitrile in water/0.1% of formic acid). The 1-(1-acetylazetidin-3-ylmethyl)-1H-indazole-5-sulfonic acid (4-ethylphenyl)isobutylamide (136 mg; 51%) is obtained in the form of a pale yellow solid.
1H NMR (DMSO-d6) δ: 0.85 (d, J=6.6 Hz, 6H), 1.17 (t, J=7.6 Hz, 3H), 1.42 (hept, J=6.8 Hz, 1H), 1.73 (s, 3H), 2.59 (q, J=7.6 Hz, 2H), 3.07-3.20 (m, 1H), 3.30-3.36 (m, 2H), 3.69 (dd, J=9.6, 5.6 Hz, 1H), 3.89 (t, J=9.0 Hz, 1H), 3.98 (dd, J=8.5, 5.5 Hz, 1H), 4.18 (t, J=8.4 Hz, 1H), 4.71 (d, J=7.3 Hz, 2H), 6.96 (d, J=8.4 Hz, 2H), 7.17 (d, J=8.4 Hz, 2H), 7.48 (dd, J=9.0, 1.7 Hz, 1H), 7.89-7.97 (m, 1H), 8.09 (d, J=1.7 Hz, 1H), 8.31 (d, J=0.9 Hz, 1H)
MS: [M+H]=469
By following the same procedure as that for example 9, 1-(tetrahydropyran-4-yl)-1H-indazole-5-sulfonic acid (4-ethylphenyl)isobutylamide (22 mg; 36%) is obtained in the form of a white solid.
1H NMR (DMSO-d6) δ: 0.85 (d, J=6.7 Hz, 6H), 1.18 (t, J=7.6 Hz, 3H), 1.41 (non, J=6.5 Hz, 1H), 1.85-1.97 (m, 2H), 2.15 (qd, J=12.3, 4.6 Hz, 2H), 2.60 (q, J=7.6 Hz, 2H), 3.30-3.32 (m, 2H), 3.58 (td, J=11.9, 2.0 Hz, 2H), 3.98-4.07 (m, 2H), 4.99 (td, J=11.3, 5.7 Hz, 1H), 6.98 (d, J=8.4 Hz, 2H), 7.18 (d, J=8.4 Hz, 2H), 7.44 (dd, J=8.9, 1.7 Hz, 1H), 7.94 (d, J=8.9 Hz, 1H), 8.11 (d, J=1.6 Hz, 1H), 8.32 (s, 1H)
MS: [M+H]=442
A mixture of N-(4-ethylphenyl)-N-isobutyl-1H-indazole-5-sulfonamide (0.20 g; 0.56 mmol), cesium carbonate (0.27 g; 0.84 mmol) and 1-(3-bromopyrrolidin-1-yl)ethanone (0.13 g; 0.67 mmol) in 1-methyl-2-pyrrolidone (3 ml) is stirred for 5 hours at a temperature of 80° C., hydrolyzed and extracted with ethyl acetate. The organic phase is washed with water, dried (Na2SO4), filtered and concentrated.
The crude product is purified by preparative HPLC (C18 column, eluent: acetonitrile in water/0.1% of formic acid). The 1-(1-acetylpyrrolidin-3-yl)-1H-indazole-5-sulfonic acid (4-ethylphenyl)isobutylamide (29 mg; 11%) is obtained in the form of a white solid.
Mixture of two conformers: 1H NMR (DMSO-d6) δ: 0.85 (dd, J=6.7, 1.1 Hz, 6H), 1.18 (t, J=7.6 Hz, 3H), 1.33-1.50 (m, 1H), 2.01 (s, 3H), 2.60 (q, J=7.6 Hz, 2H), 3.34 (d, J=2.4 Hz, 2H), 3.46-3.54 (m, 1H), 3.59-3.65 (m, 1H), 3.65-3.72 (m, 1H), 3.76-3.82 (m, 1H), 3.85 (dd, J=12.3, 6.8 Hz, 1H), 4.05 (dd, J=10.8, 7.0 Hz, 1H), 5.57 (ddt, J=27.8, 11.5, 6.2 Hz, 1H), 6.90-7.03 (m, 2H), 7.16-7.21 (m, 2H), 7.49 (ddd, J=8.8, 5.4, 1.7 Hz, 1H), 7.92 (t, J=9.0 Hz, 1H), 8.11 (dd, J=3.4, 1.6 Hz, 1H), 8.32-8.41 (m, 1H)
MS: [M+H]=469
With a procedure similar to that for intermediate 1.1, corresponding to a reductive amination between 1 equivalent of aldehyde and 1.15 equivalents of aniline in tetrahydrofuran in the presence of 1.45 equivalents of sodium triacetoxyborohydride, the anilines of the table below are obtained:
With a procedure similar to that for intermediate 1.2, by reacting 1 equivalent of N-substituted anilines (derived from the above table or corresponding commercial products) with 1.3 equivalents of 1H-indazole-5-sulfonyl chloride in tetrahydrofuran (20 vol) in the presence of 6 equivalents of pyridine, the intermediates of the table below are obtained:
A mixture of 1H-indazole-5-sulfonyl chloride (200 mg; 0.88 mmol), pyridine (3 ml), potassium iodide (7.3 mg; 0.04 mmol), 4-dimethylaminopyridine (5.4 mg; 0.04 mmol) and N-(4-ethylphenyl)-N-(2,2,2-trifluoroethyl)amine hydrochloride (231 mg; 0.96 mmol) is stirred for 16 hours at a temperature of 100° C.
Silver(I) fluoride (5.6 mg; 0.04 mmol) is added to the reaction medium, which is stirred for 3 days at a temperature of 80° C.
The crude product is purified by preparative HPLC (C18 column, eluent: acetonitrile in water/0.1% of formic acid). The 1H-indazole-5-sulfonic acid (4-ethylphenyl)(2,2,2-trifluoroethyl)amide (20 mg; 6%) is obtained in the form of a clear yellow oil.
MS: [M+H]=384
A mixture of 1H-indazole-5-sulfonyl chloride (200 mg; 0.88 mmol), pyridine (3.0 ml), potassium iodide (14 mg; 0.08 mmol), 4-dimethylaminopyridine (5.4 mg; 0.04 mmol) and (2-chlorophenyl)isobutylamine (600 mg; 3.27 mmol) is stirred for 3 days at a temperature of 100° C.
The crude product is purified by preparative HPLC (C18 column, eluent: acetonitrile in water/0.1% of formic acid). The 1H-indazole-5-sulfonic acid (2-chlorophenyl)isobutylamide (10 mg; 3%) is obtained in the form of a yellow oil with a compliant 1H NMR.
MS: [M+H]=364
With the same procedure as that used for intermediate 30.2, 1H-indazole-5-sulfonic acid cyclopropylmethyl(4-ethylphenyl)amide (40 mg; 12%) is obtained in the form of a yellow oil with a compliant 1H NMR.
MS: [M+H]=373
(2-Fluoro-6-methylphenyl)isobutylamine (520 mg; 2.87 mmol) is added to a solution of 1H-indazole-5-sulfonyl chloride (297.4 mg; 1.30 mmol) in acetonitrile (1.25 ml) and the reaction medium is stirred for 40 minutes with microwave irradiation at a temperature of 100° C. The reaction medium is treated with 1N hydrochloric acid solution and extracted with ethyl acetate. The organic phases are combined, washed with water, dried (MgSO4), filtered and concentrated.
The crude product is chromatographed on silica gel (eluent: heptane/ethyl acetate, from 0 to 60% of ethyl acetate). The 1H-indazole-5-sulfonic acid (2-fluoro-6-methylphenyl)isobutylamide (305 mg; 65%) is obtained in the form of a white solid with a compliant 1H NMR.
MS: [M+H]=362
With a procedure similar to that described for the synthesis of example 1, the addition of 1.2 equivalents of 4-(bromomethyl)tetrahydropyran to 1 equivalent of N-substituted 1H-indazole-5-sulfonamide (prepared previously) in N,N-dimethylformamide in the presence of 1 equivalent of cesium carbonate under microwave irradiation at 100° C. leads to the compounds in the table below:
A mixture of 1H-indazole-5-sulfonyl chloride (1.00 g; 4.39 mmol), pyridine (5.0 ml) and 4-ethylaniline (603 μl; 4.82 mmol) is stirred for 4 hours at 50° C. The reaction medium is diluted with ethyl acetate and extracted. The organic phase is washed with saturated ammonium chloride solution, with saturated sodium hydrogen carbonate solution and with water. It is dried (MgSO4), filtered and concentrated to dryness.
The crude product is chromatographed on silica gel (eluent: heptane/ethyl acetate, from 0 to 40% of ethyl acetate). The 1H-indazole-5-sulfonic acid (4-ethylphenyl)amide (1.32 g; 100%) is obtained in the form of an orange oil with a compliant 1H NMR.
MS: [M+H]=302
A mixture of 1H-indazole-5-sulfonic acid (4-ethylphenyl)amide (1.30 g; 4.31 mmol), cesium carbonate (2.11 g; 6.47 mmol) and 4-(bromomethyl)tetrahydropyran (680 μl; 5.18 mmol; 1.20 eq.) in N-methyl-2-pyrrolidone (10 ml) is stirred for 16 hours at a temperature of 50° C. The reaction medium is diluted with ethyl acetate (30 ml). The organic phase is washed with saturated NH4Cl solution (20 ml), with saturated NaHCO3 solution (20 ml) and with water (20 ml). The organic phase is dried (MgSO4), filtered and concentrated.
The crude product is purified by preparative HPLC (C18 column, eluent: acetonitrile in water/0.1% of formic acid). The 1-(tetrahydropyran-4-ylmethyl)-1H-indazole-5-sulfonic acid (4-ethylphenyl)(tetrahydropyran-4-ylmethyl)amide (360 mg; 17%) is obtained in the form of a white solid.
1H NMR (DMSO-d6) δ: 1.08-1.23 (m, 5H), 1.25-1.47 (m, 5H), 1.52-1.62 (m, 2H), 2.60 (q, J=7.5 Hz, 2H), 3.13 (td, J=11.6, 2.2 Hz, 2H), 3.23 (td, J=11.3, 3.0 Hz, 2H), 3.43 (d, J=7.2 Hz, 2H), 3.72-3.87 (m, 4H), 4.38 (d, J=7.1 Hz, 2H), 6.97 (d, J=8.4 Hz, 2H), 7.17 (d, J=8.4 Hz, 2H), 7.46 (dd, J=9.0, 1.7 Hz, 1H), 7.84-7.98 (m, 1H), 8.10 (d, J=1.7 Hz, 1H), 8.29 (d, J=0.9 Hz, 1H)
MS: [M+H]=498
Intermediate 51.1: Mixture of N-(4-ethylphenyl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indazole-5-sulfonamide and N-(4-ethylphenyl)-2-((tetrahydro-2H-pyran-4-yl)methyl)-2H-indazole-5-sulfonamide.
The mixture of N-(4-ethylphenyl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indazole-5-sulfonamide and N-(4-ethylphenyl)-2-((tetrahydro-2H-pyran-4-yl)methyl)-2H-indazole-5-sulfonamide (170.00 mg; 10%) is obtained in the form of a solid with a compliant 1H NMR.
MS: [M+H]=400
A spatulaful of molecular sieves is added to a mixture of N-(4-ethylphenyl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indazole-5-sulfonamide and N-(4-ethylphenyl)-2-((tetrahydro-2H-pyran-4-yl)methyl)-2H-indazole-5-sulfonamide (170 mg; 0.43 mmol), triethylamine (180 μl; 1.28 mmol), copper(II) acetate (232 mg; 1.28 mmol) and cyclopropylboronic acid (220 mg; 2.55 mmol) in dichloromethane (3 ml).
The reaction medium is stirred for 16 hours at room temperature under 1 atmosphere of oxygen and filtered through Celite, which is rinsed with dichloromethane (50 ml) and with water (20 ml). The organic phase is extracted, washed with a mixture (1/1) of aqueous ammonia and saturated NH4Cl solution (2×50 ml) and then with water (50 ml), dried (MgSO4), filtered and concentrated.
The crude product is purified by preparative HPLC (C18 column, eluent: acetonitrile in water/0.1% of formic acid). The 1-(tetrahydropyran-4-ylmethyl)-1H-indazole-5-sulfonic acid cyclopropyl(4-ethylphenyl)amide 002 (40 mg; 21%) is obtained in the form of a white solid.
1H NMR (DMSO-d6) δ: 0.62 (t, J=3.2 Hz, 2H), 0.76 (dt, J=7.1, 3.6 Hz, 2H), 1.14-1.22 (m, 4H), 1.23-1.42 (m, 4H), 2.16 (dd, J=10.8, 5.1 Hz, 1H), 2.58-2.71 (m, 3H), 3.17-3.29 (m, 3H), 3.76-3.89 (m, 2H), 4.38 (d, J=7.1 Hz, 2H), 6.87-7.02 (m, 2H), 7.15 (d, J=8.4 Hz, 2H), 7.46 (dd, J=8.8, 1.7 Hz, 1H), 7.91 (d, J=8.9 Hz, 1H), 8.15 (d, J=1.6 Hz, 1H), 8.33 (d, J=0.9 Hz, 1H)
MS: [M+H]=440
A mixture of 1H-indazole-5-sulfonyl chloride (500.0 mg; 2.19 mmol), pyridine (3.0 ml) and 2-(trifluoromethyl)aniline (306.18 μl; 2.41 mmol) is stirred for 16 hours at a temperature of 40° C. The reaction medium is diluted with ethyl acetate and extracted. The organic phase is washed with saturated ammonium chloride solution, with saturated sodium hydrogen carbonate solution and with water. It is dried (MgSO4), filtered and concentrated to dryness.
The crude product is chromatographed on silica gel (eluent: heptane/ethyl acetate, from 0 to 40% of ethyl acetate).
The 1H-indazole-5-sulfonic acid (2-trifluoromethylphenyl)amide (300 mg; 40%) is obtained in the form of a white solid with a compliant 1H NMR.
MS: [M+H]=342
Cesium carbonate (30 mg; 1.32 mmol) and 4-(bromomethyl)tetrahydropyran (127 μl; 0.97 mmol) are added to a solution of 1H-indazole-5-sulfonic acid (2-trifluoromethylphenyl)amide (300 mg; 0.88 mmol) in 1-methyl-2-pyrrolidone (3 ml). The reaction medium is stirred for 16 hours at room temperature. 1-Bromo-2-methylpropane (287 μl; 2.64 mmol) is added and the reaction medium is stirred for 6 hours at 80° C. The reaction medium is diluted with ethyl acetate, washed with saturated ammonium chloride solution and then with saturated sodium hydrogen carbonate solution and with water. The organic phase is dried (MgSO4), filtered and concentrated to dryness.
The crude product is purified by preparative HPLC (C18 column, eluent: acetonitrile in water/0.1% of formic acid). The 1-(tetrahydropyran-4-ylmethyl)-1H-indazole-5-sulfonic acid isobutyl(2-trifluoromethylphenyl)amide (80 mg; 16%) is obtained in the form of a beige-colored solid.
1H NMR (DMSO-d6) δ: 0.71 (d, J=6.7 Hz, 3H), 0.85-0.93 (m, 3H), 1.25-1.43 (m, 4H), 1.48 (dtd, J=8.8, 6.6, 4.6 Hz, 1H), 2.12-2.25 (m, 1H), 3.15 (dd, J=13.4, 4.6 Hz, 1H), 3.24 (td, J=10.8, 10.4, 2.2 Hz, 2H), 3.46 (dd, J=13.4, 8.8 Hz, 1H), 3.78-3.86 (m, 2H), 4.41 (d, J=7.1 Hz, 2H), 6.99 (dd, J=5.7, 3.7 Hz, 1H), 7.56 (dd, J=9.0, 1.7 Hz, 1H), 7.58-7.64 (m, 2H), 7.85 (dt, J=5.6, 3.7 Hz, 1H), 7.96 (d, J=8.9 Hz, 1H), 8.18-8.24 (m, 1H), 8.35 (s, 1H).
MS: [M+H]=496
A mixture of 1H-indazole-5-sulfonyl chloride (250.0 mg; 1.10 mmol) and 4-(trifluoromethyl)aniline (388.6 μl; 2.41 mmol) in acetonitrile (1.7 ml) is stirred for 40 minutes at a temperature of 100° C. under microwave irradiation. The reaction medium is diluted with ethyl acetate and extracted.
The organic phase is washed with saturated ammonium chloride solution, with saturated sodium hydrogen carbonate solution and with water. It is dried (MgSO4), filtered and concentrated to dryness.
The 1H-indazole-5-sulfonic acid (4-trifluoromethylphenyl)amide (297 mg; 79%) is obtained in the form of a yellowish solid with a compliant 1H NMR.
MS: [M+H]=342
With a procedure similar to that described for example 52, 1-(tetrahydropyran-4-ylmethyl)-1H-indazole-5-sulfonic acid isobutyl(4-trifluoromethylphenyl)amide (178 mg; 40%) is obtained in the form of a white solid.
1H NMR (DMSO-d6) δ: 0.84 (d, J=6.6 Hz, 6H), 1.22-1.51 (m, 5H), 2.07-2.24 (m, 1H), 3.23 (td, J=11.4, 2.9 Hz, 2H), 3.42 (d, J=7.3 Hz, 2H), 3.81 (ddd, J=11.6, 4.2, 2.1 Hz, 2H), 4.37 (d, J=7.1 Hz, 2H), 7.37 (d, J=8.2 Hz, 2H), 7.43 (dd, J=8.9, 1.8 Hz, 1H), 7.73 (d, J=8.6 Hz, 2H), 7.91 (d, 1H), 8.13 (d, J=1.6 Hz, 1H), 8.31 (d, J=1.0 Hz, 1H).
MS: [M+H]=496
With a procedure similar to that described for intermediate 53.1, 1H-indazole-5-sulfonic acid (2-cyano-4-methylphenyl)amide (342.4 mg; 100%) is obtained in the form of a yellowish solid with a compliant 1H NMR.
MS: [M+H]=313
With a procedure similar to that described for example 52, 1-(tetrahydropyran-4-ylmethyl)-2H-indazole-5-sulfonic acid (2-cyano-4-methylphenyl)isobutylamide (129.7 mg; 20%) is obtained in the form of a white solid.
1H NMR (Chloroform-d) δ: 0.93 (d, J=6.7 Hz, 6H), 1.42-1.53 (m, 4H), 1.54-1.67 (m, 1H), 2.21-2.39 (m, 1H), 2.42 (s, 3H), 3.37 (td, J=11.3, 3.5 Hz, 2H), 3.45 (d, J=7.2 Hz, 2H), 3.98 (dt, J=11.7, 2.6 Hz, 2H), 4.32 (d, J=7.2 Hz, 2H), 7.25 (d, J=8.2 Hz, 1H), 7.41 (dd, J=8.2, 2.1 Hz, 1H), 7.45 (d, J=2.1 Hz, 1H), 7.52 (d, J=8.9 Hz, 1H), 7.78 (dd, J=8.9, 1.6 Hz, 1H), 8.15 (d, J=1.0 Hz, 1H), 8.18 (d, J=1.6 Hz, 1H).
MS: [M+H]=467
With a procedure similar to that described for intermediate 53.1, 1H-indazole-5-sulfonic acid (4,6-dimethylpyridin-3-yl)amide (151 mg; 46%) is obtained in the form of a yellowish solid with a compliant 1H NMR.
MS: [M+H]=303
With a procedure similar to that described for example 52, 1-(tetrahydropyran-4-ylmethyl)-1H-indazole-5-sulfonic acid (4,6-dimethylpyridin-3-yl)isobutylamide (17 mg; 7%) is obtained in the form of a white solid.
1H NMR (DMSO-d6) δ: 0.78 (d, J=6.7 Hz, 3H), 0.95 (d, J=6.6 Hz, 3H), 1.18-1.56 (m, 5H), 2.13-2.27 (m, 4H), 2.41 (s, 3H), 3.19-3.29 (m, 3H), 3.44 (dd, J=13.3, 8.6 Hz, 1H), 3.78-3.89 (m, 2H), 4.40 (d, J=7.0 Hz, 2H), 7.21 (s, 1H), 7.56 (dd, J=8.9, 1.8 Hz, 1H), 7.68 (s, 1H), 7.96 (d, J=8.8 Hz, 1H), 8.16 (d, J=1.7 Hz, 1H), 8.33 (s, 1H).
MS: [M+H]=457
With a procedure similar to that described for intermediate 53.1, 1H-indazole-5-sulfonic acid (4-dimethylaminophenyl)amide (281 mg; 81%) is obtained in the form of a fluffy white solid with a compliant 1H NMR.
MS: [M+H]=317
With a procedure similar to that described for example 52, 1-(tetrahydropyran-4-ylmethyl)-1H-indazole-5-sulfonic acid (4-dimethylaminophenyl)isobutylamide (19 mg; 4%) is obtained in the form of a white solid.
11-1H NMR (Chloroform-d) δ: 0.94 (d, J=6.7 Hz, 6H), 1.38-1.55 (m, 3H), 1.62 (dd, J=13.2, 6.3 Hz, 2H), 2.31 (dt, J=11.0, 5.6 Hz, 1H), 2.97 (s, 6H), 3.30 (d, J=7.3 Hz, 2H), 3.38 (td, J=11.3, 3.1 Hz, 2H), 3.99 (ddd, J=11.7, 4.4, 2.1 Hz, 2H), 4.31 (d, J=7.1 Hz, 2H), 6.60 (d, J=8.4 Hz, 2H), 6.84-6.91 (m, 2H), 7.41-7.46 (m, 1H), 7.60 (dd, J=8.9, 1.6 Hz, 1H), 8.08 (d, J=1.7 Hz, 1H), 8.11 (d, J=0.9 Hz, 1H).
MS: [M+H]=471
With a procedure similar to that described for intermediate 53.1, 1H-indazole-5-sulfonic acid (2-fluoro-4-methylphenyl)amide (189 mg; 94%) is obtained in the form of a yellowish solid with a compliant 1H NMR.
MS: [M+H]=306
With a procedure similar to that described for example 52, 1-(tetrahydropyran-4-ylmethyl)-1H-indazole-5-sulfonic acid (2-fluoro-4-methylphenyl)isobutylamide (19 mg; 4%) is obtained in the form of a white solid.
1H 1H NMR (Chloroform-d) δ: 0.93 (d, J=6.6 Hz, 6H), 1.47 (td, J=11.2, 10.7, 4.2 Hz, 3H), 1.54-1.69 (m, 2H), 2.30 (dd, J=10.7, 4.6 Hz, 1H), 2.36 (s, 3H), 3.24-3.47 (m, 5H), 3.95-4.03 (m, 2H), 4.31 (d, J=7.1 Hz, 2H), 6.82 (dd, J=11.5, 1.8 Hz, 1H), 6.94 (dd, J=8.2, 1.8 Hz, 1H), 7.16 (t, J=8.1 Hz, 1H), 7.45 (dt, J=9.0, 0.9 Hz, 1H), 7.67 (dd, J=8.9, 1.6 Hz, 1H), 8.13 (dd, J=9.3, 1.2 Hz, 2H).
MS: [M+H]=460
A mixture of 4-ethylaniline (513 μl; 4.13 mmol), oxetane-3-carbaldehyde (807.3 mg; 3.75 mmol) and tetrahydrofuran (2.5 ml) is stirred for 2 hours at room temperature. Sodium triacetoxyborohydride (1.19 g; 5.63 mmol) is added and the reaction medium is stirred for 16 hours at room temperature, hydrolyzed and extracted with ethyl acetate.
The organic phases are combined, washed with brine, dried (Na2SO4) and concentrated.
The crude product is chromatographed on silica gel (eluent: heptane/ethyl acetate, from 0 to 40% of ethyl acetate). The 2-chloromethyl-3-(4-ethylphenylamino)propan-1-ol (340 mg; 40%) is obtained in the form of an orange oil with a 1H NMR showing the opening of the oxetane.
MS: [M+H]=228
A mixture of 1H-indazole-5-sulfonyl chloride (368.5 mg; 1.62 mmol), pyridine (3.0 ml; 37.17 mmol) and (4-ethylphenyl)oxetan-3-ylmethylamine (340 mg; 1.78 mmol) is stirred for 30 minutes at a temperature of 100° C. under microwave irradiation.
The reaction medium is diluted with ethyl acetate. The organic phase is washed with saturated ammonium chloride solution, with saturated sodium hydrogen carbonate solution and with water. It is dried (MgSO4), filtered and concentrated to dryness.
The crude product is chromatographed on silica gel (eluent: heptane/ethyl acetate, from 0 to 40% of ethyl acetate). The 1H-indazole-5-sulfonic acid (2-chloromethyl-3-hydroxypropyl)(4-ethylphenyl)amide (260 mg; 39%) is obtained in the form of a colorless oil with a compliant 1H NMR.
MS: [M+H]=408
A mixture of 1H-indazole-5-sulfonic acid (2-chloromethyl-3-hydroxypropyl)(4-ethylphenyl)amide (1.26 g; 0.64 mmol), cesium carbonate (0.31 mg; 0.96 mmol) and 4-(bromomethyl)tetrahydropyran (100 μl; 0.76 mmol) in N-methyl-2-pyrrolidone (4 ml) is stirred for 1 hour at a temperature of 80° C. The reaction medium is diluted with ethyl acetate (20 ml).
The organic phase is washed with saturated NH4Cl solution, with saturated NaHCO3 solution and with water. The organic phase is dried (MgSO4), filtered and concentrated.
The crude product is purified by preparative HPLC (C18 column, eluent: acetonitrile in water/0.1% of formic acid). The 1-(tetrahydropyran-4-ylmethyl)-1H-indazole-5-sulfonic acid (3-chloro-2-hydroxymethylpropyl)(4-ethylphenyl)amide (100 mg; 31%) is obtained in the form of a colorless oil. 1H NMR (DMSO-d6) δ: 1.18 (t, J=7.6 Hz, 3H), 1.25-1.43 (m, 4H), 1.73 (p, J=6.4 Hz, 1H), 2.61 (q, J=7.6 Hz, 2H), 3.23 (td, J=11.3, 3.0 Hz, 2H), 3.35-3.41 (m, 1H), 3.46-3.52 (m, 1H), 3.52-3.63 (m, 2H), 3.69 (qd, J=10.8, 4.9 Hz, 2H), 3.82 (ddd, J=11.4, 4.3, 2.2 Hz, 2H), 4.39 (d, J=7.0 Hz, 2H), 4.69 (t, J=5.1 Hz, 1H), 6.95-7.02 (m, 2H), 7.16-7.22 (m, 2H), 7.44 (dd, J=9.0, 1.8 Hz, 1H), 7.92 (d, J=8.9 Hz, 1H), 8.10 (d, J=1.6 Hz, 1H), 8.31 (s, 1H)
MS: [M+H]=506
60% sodium hydride (17.4 mg; 0.43 mmol) is added to a solution of 1-(tetrahydropyran-4-ylmethyl)-1H-indazole-5-sulfonic acid (3-chloro-2-hydroxymethylpropyl)(4-ethylphenyl)amide (100 mg; 0.20 mmol) in tetrahydrofuran (3 ml). The reaction medium is stirred for 1 hour at a temperature of 80° C. and then for 16 hours at a temperature of 30° C.
The reaction medium is diluted with ethyl acetate (20 ml). The organic phase is washed with saturated NH4Cl solution (20 ml), with saturated NaHCO3 solution (20 ml) and with water (20 ml). The organic phase is dried (MgSO4), filtered and concentrated.
The crude product is purified by preparative HPLC (C18 column, eluent: acetonitrile in water/0.1% of formic acid). The 1-(tetrahydropyran-4-ylmethyl)-1H-indazole-5-sulfonic acid (4-ethylphenyl)oxetan-3-ylmethylamide (35.0 mg; 33%) is obtained in the form of a white solid.
1H NMR (Methanol-d4) δ: 1.20 (t, J=7.6 Hz, 3H), 1.31-1.51 (m, 5H), 2.27 (tq, J=10.6, 6.2, 5.6 Hz, 1H), 2.62 (q, J=7.6 Hz, 2H), 3.01 (hept, J=7.3 Hz, 1H), 3.31-3.43 (m, 2H), 3.92 (d, J=7.7 Hz, 3H), 4.33-4.42 (m, 3H), 4.56-4.66 (m, 2H), 6.88 (d, J=8.2 Hz, 2H), 6.93-7.03 (m, 1H), 7.13 (d, J=8.1 Hz, 2H), 7.58 (dd, J=8.9, 1.7 Hz, 1H), 7.74 (d, J=8.8 Hz, 1H), 8.13 (s, 1H)
MS: [M+H]=470
(4-Ethylphenyl)isobutylamine (417.5 mg; 2.35 mmol) is added to methyl 5-chlorosulfonyl-1H-indazole-7-carboxylate (300 mg; 1.07 mmol) in acetonitrile (4 ml). The reaction medium is stirred for 1 hour 20 minutes at a temperature of 100° C. under microwave irradiation.
The reaction medium is diluted with ethyl acetate, washed with 1N hydrochloric acid solution, and then with saturated sodium hydrogen carbonate solution and with water, dried (MgSO4), filtered and concentrated.
The methyl 5-[(4-ethylphenyl)isobutylsulfamoyl]-1H-indazole-7-carboxylate (429.8 mg; 97%) is obtained in the form of a white solid with a compliant 1H NMR.
MS: [M+H]=416
4-(Bromomethyl)tetrahydropyran (97.6 μl; 0.74 mmol) is added to a mixture of methyl 5-[(4-ethylphenyl)isobutylsulfamoyl]-1H-indazole-7-carboxylate (280.0 mg; 0.67 mmol) and cesium carbonate (329 mg; 1 mmol) in 1-methyl-2-pyrrolidone (2.8 ml). The reaction medium is stirred at a temperature of 80° C. overnight.
The crude product is filtered and then purified by preparative HPLC (C18 column, eluent: acetonitrile in water/0.1% of formic acid). The methyl 5-[(4-ethylphenyl)isobutylsulfamoyl]-1-(tetrahydropyran-4-ylmethyl)-1H-indazole-7-carboxylate (223.4 mg; 63%) is obtained in the form of a white solid.
NMR (DMSO-d6) δ: 0.85 (d, J=6.6 Hz, 6H), 1.18 (t, J=7.6 Hz, 3H), 1.25 (dt, J=11.1, 5.3 Hz, 4H), 1.33-1.55 (m, 1H), 1.86-2.12 (m, 1H), 2.60 (q, J=7.6 Hz, 2H), 3.18 (td, J=11.1, 3.6 Hz, 2H), 3.35 (s, 2H), 3.79 (dt, J=11.4, 3.3 Hz, 2H), 3.93 (s, 3H), 4.57 (d, J=7.2 Hz, 2H), 6.93-7.06 (m, 2H), 7.12-7.23 (m, 2H), 7.80 (d, J=1.7 Hz, 1H), 8.37 (d, J=1.9 Hz, 1H), 8.48 (s, 1H)
MS: [M+H]=514
Aqueous ammonia (1.05 ml) is added to a solution of methyl 5-[(4-ethylphenyl)isobutylsulfamoyl]-1-(tetrahydropyran-4-ylmethyl)-1H-indazole-7-carboxylate (210.0 mg; 0.41 mmol) in N,N-dimethylformamide (1.05 ml).
The reaction medium is stirred for 3 days at room temperature and for 2 days at a temperature of 60° C. The reaction medium is diluted and extracted with dichloromethane. The organic phases are combined, dried (MgSO4), filtered and concentrated to dryness.
The crude product is filtered and then purified by preparative HPLC (C18 column, eluent: acetonitrile in water/0.2% of ammonium carbonate). The 5-[(4-ethylphenyl)isobutylsulfamoyl]-1-(tetrahydropyran-4-ylmethyl)-1H-indazole-7-carboxylic amide is obtained in the form of a white solid.
1H NMR (Chloroform-d) δ: 0.94 (d, J=6.7 Hz, 6H), 1.25 (t, J=7.6 Hz, 3H), 1.38-1.51 (m, 4H), 1.59-1.69 (m, 1H), 2.08-2.21 (m, 1H), 2.67 (q, J=7.6 Hz, 2H), 3.25-3.39 (m, 4H), 3.90-4.01 (m, 2H), 4.59 (d, J=7.2 Hz, 2H), 5.75 (s, 1H), 6.00 (s, 1H), 6.94-7.00 (m, 2H), 7.11-7.18 (m, 2H), 7.62 (d, J=1.7 Hz, 1H), 8.15 (d, J=1.6 Hz, 1H), 8.19 (s, 1H) MS: [M+H]=499
N-Bromosuccinimide (120 mg; 0.67 mmol) is added to a solution of 1H-indazole-5-sulfonic acid (4-ethylphenyl)isobutylamide (200 mg; 0.56 mmol) in dichloromethane (5 ml). The reaction medium is stirred for 16 hours at room temperature, diluted with dichloromethane and extracted.
The organic phase is washed with saturated NH4Cl solution, with saturated NaHCO3 solution and with water, dried (MgSO4), filtered and concentrated to dryness.
The 3-bromo-1H-indazole-5-sulfonic acid (4-ethylphenyl)isobutylamide (260 mg; 100%) is obtained in the form of a pale yellow solid with a compliant 1H NMR.
MS: [M+H]=436
A mixture of 3-bromo-1H-indazole-5-sulfonic acid (4-ethylphenyl)isobutylamide (260 mg; 0.60 mmol), cesium carbonate (388 mg; 1.19 mmol) and 4-(bromomethyl)tetrahydropyran (160 mg; 0.89 mmol) in N-methyl-2-pyrrolidone (3 ml) is stirred for 1 hour at a temperature of 80° C.
The reaction medium is diluted with ethyl acetate (30 ml). The organic phase is washed with saturated NH4Cl solution (20 ml), with saturated NaHCO3 solution (20 ml) and with water (20 ml), dried (MgSO4), filtered and concentrated to dryness.
The 3-bromo-1-(tetrahydropyran-4-ylmethyl)-1H-indazole-5-sulfonic acid (4-ethylphenyl)isobutylamide (350 mg; 100%) is obtained in the form of a clear yellow oil with a compliant 1H NMR.
MS: [M+H]=534
2.5 M n-Butyllithium (900 μl; 2.24 mmol) is added, under argon, to a solution of 3-bromo-1-(tetrahydropyran-4-ylmethyl)-1H-indazole-5-sulfonic acid (4-ethylphenyl)isobutylamide (200 mg; 0.37 mmol) in tetrahydrofuran (3 ml) at a temperature of −78° C. The reaction medium is stirred for 30 minutes, paraformaldehyde (980 mg; 2.24 mmol) is then added, the temperature is allowed to return to room temperature and the medium is then stirred for 3 hours at a temperature of 60° C.
The reaction medium is hydrolyzed with 1M hydrochloric acid solution (5 ml) at room temperature for 10 days, and diluted with ethyl acetate (50 ml).
The organic phase is washed with saturated NH4Cl solution (20 ml), with saturated NaHCO3 solution (20 ml) and with water (20 ml), dried (MgSO4), filtered and concentrated to dryness.
The crude product is purified by preparative HPLC (C18 column, eluent: acetonitrile in water/0.1% of formic acid). The 3-hydroxymethyl-1-(tetrahydropyran-4-ylmethyl)-1H-indazole-5-sulfonic acid (4-ethylphenyl)isobutylamide (20 mg; 11%) is obtained in the form of a colorless oil.
1H NMR (CD3OD-d4) δ: 0.90 (d, J=6.7 Hz, 7H), 1.22 (t, J=7.6 Hz, 3H), 1.27-1.58 (m, 4H), 1.71 (d, J=12.7 Hz, 2H), 2.16 (s, 1H), 2.64 (q, J=7.7 Hz, 2H), 3.35 (s, 2H), 3.41 (t, J=11.6 Hz, 2H), 3.96 (dd, J=11.9, 4.1 Hz, 2H), 4.66 (s, 2H), 6.92 (d, J=9.0 Hz, 1H), 7.00 (d, J=7.9 Hz, 2H), 7.16 (d, J=8.0 Hz, 2H), 7.44 (d, J=8.6 Hz, 1H), 8.03 (d, J=2.4 Hz, 1H)
MS: [M+H]=486
A solution of (4-ethylphenyl)isobutylamine (0.80 g; 4.51 mmol) and pyridine (0.36 ml; 4.51 mmol) in tetrahydrofuran (8 ml) is added to a solution of 5-chlorosulfonyl-2-fluorobenzoic acid (1.44 g; 5.87 mmol) in tetrahydrofuran (8 ml).
The reaction medium is stirred for 19 hours at room temperature, hydrolyzed with aqueous 1N HCl solution and diluted with ethyl acetate.
The organic phase is washed with aqueous 1N HCl solution. The organic phase is dried (Na2SO4), filtered and concentrated.
The crude product is chromatographed on silica gel (eluent: dichloromethane/methanol, from 0 to 10% of methanol) and then by preparative HPLC (C18 column, eluent: from 60% to 70% of acetonitrile in water/0.1% of formic acid). The 5-[(4-ethylphenyl)isobutylsulfamoyl]-2-fluorobenzoic acid (0.56 g; 33%) is obtained in the form of an off-white solid with a compliant 1H NMR.
MS: [M−H]=378
A solution of 5-[(4-ethylphenyl)isobutylsulfamoyl]-2-fluorobenzoic acid (0.59 g; 1.55 mmol) in thionyl chloride (5.0 ml) is stirred for 3 hours at reflux and then concentrated to dryness. The 5-[(4-ethylphenyl)isobutylsulfamoyl]-2-fluorobenzoyl chloride (0.62 g; 100%) is obtained in the form of a brown oil.
MS: [M−H]=397
A 0.5M solution of ammonia in dioxane (8.4 ml; 4.2 mmol) is added portionwise over a period of 43 hours to a solution of 5-[(4-ethylphenyl)isobutylsulfamoyl]-2-fluorobenzoyl chloride (0.31 g; 0.78 mmol) in tetrahydrofuran (3 ml). The reaction medium is hydrolyzed with aqueous NaHCO3 solution and extracted with ethyl acetate.
The extracted organic phase is washed with 1N sodium hydroxide, dried (Na2SO4), filtered and concentrated. The crude product is chromatographed on silica gel (eluent: heptane/ethyl acetate, from 20 to 50% of ethyl acetate). The 5-[(4-ethylphenyl)isobutylsulfamoyl]-2-fluorobenzamide (0.17 g; 58%) is obtained in the form of a white solid with a compliant 1H NMR.
MS: [M−H]=379
Triethylamine (0.19 ml; 1.35 mmol) and then trifluoroacetic anhydride (93 μl; 0.67 mmol) are added to a solution of 5-[(4-ethylphenyl)isobutylsulfamoyl]-2-fluorobenzamide (0.17 g; 0.45 mmol) at 0° C. The reaction medium is stirred for 1 hour, hydrolyzed for 15 minutes and extracted with ethyl acetate. The organic phases are combined, dried (Na2SO4), filtered and concentrated.
The 3-cyano-N-(4-ethylphenyl)-4-fluoro-N-isobutylbenzenesulfonamide (0.17 g; 89%) is obtained in the form of a white solid (HPLC purity=85%) with a compliant 1H NMR.
MS: [M−H]=361
Hydrazine hydrate (1.25 ml; 25.7 mmol) is added to a suspension of 3-cyano-N-(4-ethylphenyl)-4-fluoro-N-isobutylbenzenesulfonamide (0.19 g; 0.45 mmol) in ethanol (2.5 ml). The reaction medium is stirred for 50 minutes at a temperature of 100° C. in a tube. The reaction medium is concentrated.
The crude product is purified by preparative HPLC (C18 column, eluent: acetonitrile in water/0.2% of ammonium carbonate). The 3-amino-1H-indazole-5-sulfonic acid (4-ethylphenyl)isobutylamide (78 mg; 53%) is obtained in the form of a solid.
1H NMR (DMSO-d6) δ: 0.85 (d, J=6.6 Hz, 6H), 1.17 (t, J=7.5 Hz, 3H), 1.34-1.48 (m, 1H), 2.59 (q, J=7.7 Hz, 2H), 3.28-3.32 (m, 2H), 5.73 (s, 2H), 6.96 (d, J=7.8 Hz, 2H), 7.16 (d, J=7.8 Hz, 2H), 7.26 (d, J=8.8 Hz, 1H), 7.32 (d, J=8.8 Hz, 1H), 8.19 (s, 1H), 11.91 (s, 1H).
MS: [M−H]=373
3-Amino-1H-indazole-5-sulfonic acid (4-ethylphenyl)isobutylamide (54 mg; 0.14 mmol) in dimethyl sulfoxide (0.80 ml) is added to potassium hydroxide (29 mg; 0.44 mmol) at 85% in dimethyl sulfoxide (0.20 ml). The reaction medium is stirred for 5 minutes and 4-(bromomethyl)tetrahydropyran (27 mg; 0.15 mmol) in dimethyl sulfoxide (0.50 ml) is then added. Stirring is continued for 3 hours 20 minutes, followed by hydrolysis with a few drops of water and filtration through a filter syringe. The filtrate is purified by preparative HPLC (C18 column, eluent: acetonitrile in water/0.1% of formic acid).
The 3-amino-1-(tetrahydropyran-4-ylmethyl)-1H-indazole-5-sulfonic acid (4-ethylphenyl)isobutylamide (30 mg; 44%) is obtained in the form of a colorless oil.
1H NMR (DMSO-d6) δ: 0.85 (d, J=6.6 Hz, 6H), 1.17 (t, J=7.6 Hz, 3H), 1.21-1.47 (m, 5H), 2.59 (q, J=7.6 Hz, 2H), 3.23 (td, J=11.5, 2.4 Hz, 2H), 3.77-3.88 (m, 2H), 4.03 (d, J=7.0 Hz, 2H), 6.92-7.01 (m, 2H), 7.16 (d, J=8.3 Hz, 2H), 7.26 (dd, J=8.9, 1.8 Hz, 1H), 7.51 (d, J=8.9 Hz, 1H), 8.17 (d, J=1.7 Hz, 1H).
MS: [M−H]=471
A mixture of 1H-indazole-6-sulfonyl chloride (500 mg; 2.31 mmol), pyridine (3 ml) and (4-ethylphenyl)oxetan-3-ylmethylamine (491 mg; 2.77 mmol) is stirred for 30 minutes at a temperature of 50° C. The reaction medium is diluted with ethyl acetate.
The organic phase is washed with saturated NH4Cl solution, with saturated NaHCO3 solution and with water. It is dried over magnesium sulfate, filtered and concentrated to dryness.
The crude product is chromatographed on silica gel (eluent: heptane/ethyl acetate, from 0 to 40% of ethyl acetate). The 1H-Indazole-6-sulfonic acid (4-ethylphenyl)isobutylamide (640 mg; 78%) is obtained in the form of a colorless oil and is obtained with a compliant 1H NMR.
MS: [M+H]=358
N-Bromosuccinimide (956 mg; 5.37 mmol) is added to a solution of 1H-indazole-6-sulfonic acid (4-ethylphenyl)isobutylamide (1.60 g; 4.48 mmol) in dichloromethane (10 ml). The reaction medium is stirred for 16 hours at room temperature and diluted with dichloromethane.
The organic phase is extracted and washed with saturated ammonium chloride solution, with saturated sodium hydrogen carbonate solution and with water. It is dried (MgSO4), filtered and concentrated to dryness. The 3-bromo-1H-indazole-6-sulfonic acid (4-ethylphenyl)isobutylamide (1.9 g; 97%) is obtained in the form of a pale yellow solid with a compliant 1H NMR.
MS: [M+H]=436
A mixture of 3-bromo-1H-indazole-6-sulfonic acid (4-ethylphenyl)isobutylamide (700 mg; 1.60 mmol), pyridinium p-toluenesulfonate (202 mg; 0.80 mmol) and 3,4-dihydro-2H-pyran (0.58 ml; 6.42 mmol) in tetrahydrofuran (10 ml) is stirred for 16 hours at 80° C. The reaction medium is diluted with ethyl acetate (20 ml) and extracted.
The organic phase is washed with saturated NH4Cl solution, with saturated NaHCO3 solution and with water, dried (MgSO4), filtered and concentrated to dryness.
The crude product is purified by preparative HPLC (C18 column, eluent: acetonitrile in water/0.1% of formic acid). The 3-bromo-1-(tetrahydropyran-2-yl)-1H-indazole-6-sulfonic acid (4-ethylphenyl)isobutylamide (500 mg; 57%) is obtained in the form of a white solid.
1H NMR (DMSO-d6) δ: 0.86 (dd, J=13.3, 6.7 Hz, 6H), 1.18 (t, J=7.6 Hz, 3H), 1.38-1.63 (m, 3H), 1.68-1.81 (m, 1H), 1.98 (d, J=10.7 Hz, 2H), 2.60 (q, J=7.6 Hz, 2H), 3.36-3.41 (m, 2H), 3.67-3.76 (m, 1H), 6.00 (dd, J=9.3, 2.4 Hz, 1H), 6.95-7.02 (m, 2H), 7.16-7.21 (m, 2H), 7.41 (dd, J=8.5, 1.4 Hz, 1H), 7.83 (d, J=8.8 Hz, 1H), 7.99 (s, 1H)
MS: [M+H]=520
A mixture of p-toluenesulfonyl hydrazide (286 mg; 1.54 mmol), 4-formyltetrahydropyran (175 mg; 1.54 mmol) and 1,4-dioxane (2 ml) is stirred for 1 hour under argon. Lithium tert-butoxide (125 mg; 1.54 mmol), X-PHOS (18 mg; 0.04 mmol), tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct (40 mg; 0.04 mmol) and 3-bromo-1-(tetrahydropyran-2-yl)-1H-indazole-6-sulfonic acid (4-ethylphenyl)isobutylamide (200 mg; 0.38 mmol) are added under argon, and the reaction medium is stirred for 5 hours at 100° C.
The reaction medium is diluted with 20 ml of ethyl acetate and extracted. The organic phase is washed with saturated NH4Cl solution (20 ml), with saturated NaHCO3 solution (20 ml) and with water (20 ml), dried (MgSO4), filtered and concentrated.
The crude product is chromatographed on silica gel (eluent: heptane/ethyl acetate, from 0 to 100% of ethyl acetate).
The 1-(tetrahydropyran-2-yl)-3-(tetrahydropyran-4-ylidenemethyl)-1H-indazole-6-sulfonic acid (4-ethylphenyl)isobutylamide (100 mg; 48%) is obtained in the form of a yellow oil with a compliant 1H NMR.
MS: [M+H]=538
A mixture of 1-(tetrahydropyran-2-yl)-3-(tetrahydropyran-4-ylidenemethyl)-1H-indazole-6-sulfonic acid (4-ethylphenyl)isobutylamide (100 mg; 0.19 mmol), acetic acid (6 ml) and water (2 ml) is stirred for 5 hours at a temperature of 80° C. The reaction medium is diluted with 20 ml of ethyl acetate and extracted. The organic phase is washed with saturated NH4Cl solution (20 ml), with saturated NaHCO3 solution (20 ml) and with water (20 ml), dried (MgSO4), filtered and concentrated.
The crude product is chromatographed on silica gel (eluent: heptane/ethyl acetate, from 0 to 100% of ethyl acetate). The 3-(tetrahydropyran-4-ylidenemethyl)-1H-indazole-6-sulfonic acid (4-ethylphenyl)isobutylamide (80 mg; 93%) is obtained in the form of a white solid.
1H NMR (DMSO-d6) δ: 0.85 (d, J=6.7 Hz, 7H), 1.17 (t, J=7.6 Hz, 3H), 1.41 (dt, J=13.6, 6.8 Hz, 1H), 2.60 (q, J=7.3 Hz, 2H), 2.93 (t, J=5.4 Hz, 2H), 3.65 (t, J=5.5 Hz, 2H), 3.73 (t, J=5.4 Hz, 2H), 6.61 (s, 1H), 6.95 (d, J=8.3 Hz, 2H), 7.13-7.21 (m, 2H), 7.22 (dd, J=8.5, 1.5 Hz, 1H), 7.63-7.67 (m, 1H), 7.98 (d, J=8.5 Hz, 1H).
MS: [M+H]=454
3-(Tetrahydropyran-4-ylidenemethyl)-1H-indazole-6-sulfonic acid (4-ethylphenyl)isobutylamide (60 mg; 0.13 mmol) in methanol (3 ml) in the presence of palladium (5% Pd on activated charcoal: Degussa type) (14 mg) is placed for 16 hours under hydrogen (1 atm). The reaction medium is filtered through Celite. The filtrate is concentrated to dryness. The crude product is chromatographed on silica gel (eluent: heptane/ethyl acetate, from 0 to 100% of ethyl acetate). The 3-(tetrahydropyran-4-ylmethyl)-1H-indazole-6-sulfonic acid (4-ethylphenyl)isobutylamide (30 mg; 50%) is obtained in the form of a white solid.
1H NMR (DMSO-d6) δ: 0.85 (d, J=6.4 Hz, 6H), 1.17 (t, J=7.6 Hz, 3H), 1.23-1.48 (m, 3H), 1.56 (d, J=13.4 Hz, 2H), 1.97 (d, J=11.7 Hz, 1H), 2.56-2.65 (m, 2H), 2.90 (d, J=7.0 Hz, 2H), 3.26 (t, J=11.3 Hz, 2H), 3.82 (dd, J=11.6, 3.8 Hz, 2H), 6.97 (d, J=8.1 Hz, 2H), 7.19 (dd, J=14.2, 8.2 Hz, 3H), 7.62 (s, 1H), 7.95 (d, J=8.3 Hz, 1H), 13.15 (s, 1H).
MS: [M+H]=456
Bis(tri-t-butylphosphine)palladium(0) (49 mg; 0.10 mmol) is added to a mixture, degassed under argon, of 3-bromo-1-(tetrahydropyran-2-yl)-1H-indazole-6-sulfonic acid (4-ethylphenyl)isobutylamide (500 mg; 0.96 mmol), cesium carbonate (940 mg; 2.88 mmol) and vinylboronic anhydride-pyridine complex (462 mg; 1.92 mmol) in 1,4-dioxane (3 ml) and water (1 ml).
The reaction medium is stirred for 3 hours at a temperature of 90° C. and filtered through Celite. The filtrate is diluted with ethyl acetate and extracted.
The organic phase is washed with 20 ml of saturated sodium hydrogen carbonate solution and with 20 ml of water. The organic phase is washed with saturated NH4Cl solution (20 ml), with saturated NaHCO3 solution (20 ml) and with water (20 ml), dried (MgSO4), filtered and concentrated.
The crude product is chromatographed on silica gel (eluent: heptane/ethyl acetate, from 0 to 100% of ethyl acetate). The 1-(tetrahydropyran-2-yl)-3-vinyl-1H-indazole-6-sulfonic acid (4-ethylphenyl)isobutylamide (400 mg; 89%) is obtained in the form of a beige-colored solid with a compliant 1H NMR.
MS: [M+H]=468
1-(Tetrahydropyran-2-yl)-3-vinyl-1H-indazole-6-sulfonic acid (4-ethylphenyl)isobutylamide (400 mg; 0.86 mmol) is added to a mixture of (DHQ)2PHAL (1.20 g; 1.46 mmol), tert-butyl alcohol (10 ml) and water (10 ml) cooled to a temperature of 0° C. The reaction medium is stirred for 16 hours at a temperature of 40° C. Sodium sulfite (5 g) is added.
The reaction medium is stirred for 45 minutes, diluted with ethyl acetate (30 ml) and extracted. The organic phases are combined, washed with saturated Na2SO3 solution (20 ml) and with water (20 ml), dried (MgSO4), filtered and concentrated. The crude product is chromatographed on silica gel (eluent: heptane/ethyl acetate, from 0 to 100% of ethyl acetate).
The 3-(1,2-dihydroxyethyl)-1-(tetrahydropyran-2-yl)-1H-indazole-6-sulfonic acid (4-ethylphenyl)isobutylamide (380 mg; 89%) is obtained in the form of a clear oil with a compliant 1H NMR.
MS: [M+H]=502
Sodium metaperiodate (1.62 g; 7.58 mmol) is added to a mixture of 3-(1,2-dihydroxyethyl)-1-(tetrahydropyran-2-yl)-1H-indazole-6-sulfonic acid (4-ethylphenyl)isobutylamide (380 mg; 0.76 mmol), acetone (2 ml), tetrahydrofuran (2 ml) and water (2 ml).
The reaction medium is stirred for 2 hours 30 minutes at a temperature of 35° C., diluted with ethyl acetate (30 ml) and water (20 ml) and extracted.
The organic phases are combined, washed with saturated Na2SO3 solution (20 ml) and with water (20 ml), dried (MgSO4), filtered and concentrated. The 3-formyl-1-(tetrahydropyran-2-yl)-1H-indazole-6-sulfonic acid (4-ethylphenyl)isobutylamide (120 mg; 34%) is obtained in the form of a white solid with a compliant 1H NMR.
MS: [M+H]=470
Morpholine (45 μl; 0.51 mmol) and sodium triacetoxyborohydride (119 mg; 0.56 mmol) are added to a solution of 3-formyl-1-(tetrahydropyran-2-yl)-1H-indazole-6-sulfonic acid (4-ethylphenyl)isobutylamide (120 mg; 0.26 mmol) in tetrahydrofuran (3 ml). The reaction medium is stirred for 2 hours at room temperature. The reaction medium is diluted with ethyl acetate (20 ml) and water (10 ml) and extracted.
The organic phase is washed with saturated NH4Cl solution (20 ml), with saturated NaHCO3 solution (20 ml) and with water (20 ml), dried (MgSO4) and concentrated.
The 3-morpholin-4-ylmethyl-1-(tetrahydropyran-2-yl)-1H-indazole-6-sulfonic acid (4-ethylphenyl)isobutylamide (130 mg; 94%) is obtained in the form of an oil with a compliant 1H NMR.
MS: [M+H]=541
A mixture of 3-morpholin-4-ylmethyl-1-(tetrahydropyran-2-yl)-1H-indazole-6-sulfonic acid (4-ethylphenyl)isobutylamide (130 mg; 0.24 mmol), acetic acid (30 ml) and water (10 ml) and a few drops of trifluoroacetic acid is stirred for 4 days at a temperature of 80° C. The reaction medium is diluted with 50 ml of ethyl acetate and extracted.
The organic phase is washed with saturated NH4Cl solution (20 ml), with saturated NaHCO3 solution (20 ml) and with water (20 ml), dried (MgSO4), filtered and concentrated.
The crude product is purified by preparative HPLC (C18 column, eluent: acetonitrile in water/0.1% of formic acid). The 3-morpholin-4-ylmethyl-1H-indazole-6-sulfonic acid (4-ethylphenyl)isobutylamide (70 mg; 64%) is obtained in the form of a white solid after recrystallization from an acetone/water mixture.
1H NMR (DMSO-d6) δ: 0.85 (d, J=6.7 Hz, 6H), 1.18 (t, J=7.6 Hz, 3H), 2.44 (t, J=4.5 Hz, 4H), 2.61 (t, J=7.6 Hz, 2H), 3.33-3.37 (m, 2H), 3.87 (s, 2H), 6.95-7.00 (m, 2H), 7.15-7.21 (m, 2H), 7.25 (dd, J=8.5, 1.5 Hz, 1H), 8.06 (d, J=8.5 Hz, 1H), 13.27 (s, 1H).
MS: [M+H]=457
cis-2,6-Dimethylmorpholine (50 μl; 0.38 mmol) and sodium triacetoxyborohydride (122 mg; 0.57 mmol) are added to a solution of 3-formyl-1-(tetrahydropyran-2-yl)-1H-indazole-6-sulfonic acid (4-ethylphenyl)isobutylamide (90 mg; 0.19 mmol) in tetrahydrofuran (2 ml).
The reaction medium is stirred for 16 hours at room temperature. The reaction medium is diluted with ethyl acetate (20 ml) and water (10 ml) and extracted. The organic phase is washed with saturated NH4Cl solution (20 ml), with saturated NaHCO3 solution (20 ml) and with water (20 ml), dried (MgSO4) and concentrated. The 3-((2S,6R)-2,6-dimethylmorpholin-4-ylmethyl)-1-(tetrahydropyran-2-yl)-1H-indazole-6-sulfonic acid (4-ethylphenyl)isobutylamide (90 mg; 83%) is obtained in the form of an oil with a compliant 1H NMR.
MS: [M+H]=570
A mixture of 3-((2S,6R)-2,6-dimethylmorpholin-4-ylmethyl)-1-(tetrahydropyran-2-yl)-1H-indazole-6-sulfonic acid (4-ethylphenyl)isobutylamide (90 mg; 0.16 mmol), acetic acid (10 ml) and water (10 ml) and one drop of trifluoroacetic acid is stirred for 16 hours at a temperature of 80° C. The reaction medium is diluted with 50 ml of ethyl acetate and extracted.
The organic phase is washed with saturated NH4Cl solution (20 ml), with saturated NaHCO3 solution (20 ml) and with water (20 ml), dried (MgSO4), filtered and concentrated.
The crude product is purified by preparative HPLC (C18 column, eluent: acetonitrile in water/0.1% of formic acid). The 3-((cis)-2,6-dimethylmorpholin-4-ylmethyl)-1H-indazole-6-sulfonic acid (4-ethylphenyl)isobutylamide (52 mg; 67%) is obtained in the form of a colorless oil.
1H NMR (DMSO-d6) δ: 0.85 (d, J=6.5 Hz, 6H), 1.02 (d, J=6.1 Hz, 6H), 1.18 (t, J=7.5 Hz, 3H), 1.42 (dt, J=13.3, 7.1 Hz, 1H), 1.74 (t, J=10.7 Hz, 2H), 2.55-2.65 (m, 2H), 2.70-2.80 (m, 2H), 3.33-3.44 (m, 2H), 3.55 (t, J=7.8 Hz, 2H), 3.85 (s, 2H), 6.98 (d, J=8.0 Hz, 2H), 7.17 (d, J=8.3 Hz, 2H), 7.23 (d, J=8.6 Hz, 1H), 7.66 (s, 1H), 8.03 (d, J=8.6 Hz, 1H), 8.20 (s, 1H), 13.25 (s, 1H).
MS: [M+H]=485
With a procedure similar to that described for intermediate 67.1, 3-((S)-3-methylmorpholin-4-ylmethyl)-1-(tetrahydropyran-2-yl)-1H-indazole-6-sulfonic acid (4-ethylphenyl)isobutylamide (90 mg; 85%) is obtained in the form of an oil with a compliant 1H NMR.
MS: [M+H]=555
With a procedure similar to that described for example 66, 3-((S)-3-methylmorpholin-4-ylmethyl)-1H-indazole-6-sulfonic acid (4-ethylphenyl)isobutylamide (42 mg; 54%) is obtained in the form of a colorless oil.
1H NMR (DMSO-d6) δ: 0.86 (d, J=6.8 Hz, 6H), 1.09-1.22 (m, 7H), 1.42 (dt, J=13.9, 6.9 Hz, 1H), 2.16-2.27 (m, 1H), 2.61 (t, J=7.6 Hz, 2H), 3.38 (d, J=19.0 Hz, 5H), 3.58-3.72 (m, 3H), 6.98 (d, J=7.9 Hz, 2H), 7.18 (d, J=7.9 Hz, 2H), 7.26 (d, J=8.5 Hz, 1H), 7.65 (s, 1H), 8.04 (d, J=8.6 Hz, 1H), 8.24 (s, 1H), 13.24 (s, 1H).
MS: [M+H]=471
| Number | Date | Country | Kind |
|---|---|---|---|
| 1463035 | Dec 2014 | FR | national |
| 1556341 | Jul 2015 | FR | national |
This application is a continuation of U.S. application Ser. No. 15/537,678, filed Jun. 19, 2017, which is the National Stage of PCT/EP2015/080689, filed Dec. 18, 2015, published on Jun. 23, 2016 as WO 2016/097391 A1, which claims priority to French Application No. 1463035, filed Dec. 19, 2014 and to French Application No. 1556341, filed Jul. 3, 2015. The contents of these applications are herein incorporated by reference in their entirety.
| Number | Date | Country | |
|---|---|---|---|
| Parent | 15537678 | Jun 2017 | US |
| Child | 16297115 | US |
