Macrocyclic inhibitors of MCL-1

Abstract

The present invention relates to medicaments useful for therapy and / or prophylaxis in a subject, pharmaceutical compositions comprising such compounds and their use as MCL-1 inhibitors useful for treating diseases such as cancer. [Formula 1] TIFF2022537393000148.tif95170

Description

[Technical field]

[0001] The present invention relates to medicaments useful for therapy and / or prevention in a subject, pharmaceutical compositions comprising such compounds and their use as MCL-1 inhibitors useful for treating or preventing diseases such as cancer. [Background technology]

[0002] Cell apoptosis, or programmed cell death, is crucial for the development and homeostasis of many organs, including the hematopoietic cell lineage. Apoptosis can be initiated via the extrinsic pathway mediated by death receptors or by the intrinsic pathway using the B-cell lymphoma (BCL-2) family of proteins. Myeloid cell leukemia-1 (MCL-1) is a member of the BCL-2 family of cell survival regulators and is a crucial mediator of the intrinsic apoptosis pathway. MCL-1 is one of the five major anti-apoptotic BCL-2 proteins (MCL-1, BCL-2, BCL-XL, BCL-w, and BFL1 / A1) responsible for maintaining cell survival. MCL-1 blocks apoptosis indirectly by continuously and directly suppressing the activity of the pro-apoptotic BCL-2 family proteins Bak and Bax, and by sequestering BH3-only apoptosis sensitizer proteins such as Bim and Noxa. Activation of Bak / Bax after various types of cellular stress leads to aggregation on the outer mitochondrial membrane, which accelerates pore formation, loss of mitochondrial outer membrane potential, and subsequent release of cytochrome C into the cytosol. Cytoplasmic cytochrome C binds to Apaf-1 and initiates the recruitment of procaspase 9 to form the apoptosome structure (Cheng et al. eLife 2016;5:e17755). The assembly of the apoptosome activates executioner cysteine ​​proteases 3 / 7, and these effector caspases then cleave various cytoplasmic and nuclear proteins to induce cell death (Julian et al. Cell Death and Differentiation 2017;24,1380-1389).

[0003] Evasion of apoptosis is an established hallmark of cancer development, promoting the survival of tumor cells that would otherwise be eliminated due to oncogenic stress, growth factor deprivation, or DNA damage (Hanahan and Weinberg. (1, 2011) 1-44). Not surprisingly, therefore, MCL-1 is highly upregulated in many solid and hematological cancers compared to normal non-transformed tissue counterparts. Overexpression of MCL-1 has been implicated in the pathogenesis of several cancers where it correlates with poor outcome, recurrence, and aggressive disease. Moreover, overexpression of MCL-1 has been linked to the pathogenesis of the following cancers: prostate, lung, pancreatic, breast, ovarian, cervical, melanoma, B-cell chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), and acute lymphoblastic leukemia (ALL). The human MCL-1 locus (1q21) is frequently amplified in tumors, quantitatively increasing total MCL-1 protein levels (Beroukhim et al. Nature 2010;463(7283)899-905). MCL-1 also mediates resistance to conventional cancer therapeutics and is transcriptionally upregulated in response to inhibition of BCL-2 function (Yecies et al. Blood, 2010;115(16):3304-3313).

[0004] Small molecule BH3 inhibitors of BCL-2 have demonstrated clinical efficacy in patients with chronic lymphocytic leukemia and are FDA approved for patients with CLL or AML (Roberts et al. NEJM 2016;374:311-322). The clinical success of BCL-2 antagonism has led to the development of several MCL-1 BH3 mimetics that have shown efficacy in preclinical models of both hematological malignancies and solid tumors (Kotschy et al. Nature 2016;538 477-486, Merino et al. Sci. Transl. Med;2017(9)).

[0005] In addition to its canonical role in mediating mitochondrial integrity and cell survival after DNA damage, MCL-1 regulates several cellular processes, including non-homologous end joining (Chen et al. JCI 2018;128(1):500-516). Genetic loss of MCL-1 shows a range of phenotypes depending on the developmental timing and tissue deletion. MCL-1 knockout models reveal multiple roles for MCL-1, and loss of function has profound effects on a wide range of phenotypes. Global MCL-1 deficient mice show embryonic lethality, and studies using conditional gene deletion report mitochondrial dysfunction, impaired autophagy activity, reduced B and T lymphocytes, increased B and T cell apoptosis, and the development of heart failure / cardiomyopathy (Wang et al. Genes and Dev 2013;27 1351-1364, Steimer et al. Blood 2009;(113)2805-2815). WO2018178226 discloses MCL-1 inhibitors and methods of use thereof. WO2017182625 discloses macrocyclic MCL-1 inhibitors for treating cancer. WO2018178227 discloses the synthesis of MCL-1 inhibitors. WO2020063792 discloses indole macrocyclic derivatives. CN110845520 and WO2020103864 disclose macrocyclic indoles as MCL-1 inhibitors. CN20191114551 discloses MCL-1 inhibitors. Summary of the Invention

[0006] There remains a need for MCL-1 inhibitors that are useful for the treatment or prevention of cancers such as prostate cancer, lung cancer, pancreatic cancer, breast cancer, ovarian cancer, cervical cancer, melanoma, B-cell chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), and acute lymphoblastic leukemia (ALL).

[0007] The present invention relates to a compound of formula (I): [ka] (In the formula, X 1 teeth, [ka] (wherein "a" and "b" are the variables X 1 is attached to the rest of the molecule) represents; R 1 is hydrogen or C 1~6 represents alkyl; X 2 can be attached to the rest of the molecule in both orientations, [ka] represents; R 2 is hydrogen or C 1~6 represents alkyl; X is -S- or -N(R x )-represents; R x is hydrogen, methyl C 2~6 Alkyl, -C(=O)-C 1-6 Alkyl, -S(=O)2-C 1~6 Alkyl, C 3~6 Cycloalkyl, -C(=O)-C 3~6 Cycloalkyl or -S(=O)2-C 3~6 represents cycloalkyl, where C 2~6 Alkyl, -C(=O)-C 1~6 Alkyl, -S(=O)2-C 1~6 Alkyl, C 3~6 Cycloalkyl, -C(=O)-C 3~6 Cycloalkyl and -S(=O)2-C 3~6 Cycloalkyl is optionally selected from halo, C 1~4 C substituted with alkyl and 1, 2 or 3 halo atoms 1~4 substituted with 1, 2 or 3 substituents selected from the group consisting of alkyl and its tautomeric and stereoisomeric forms, and its pharma- ceutically acceptable salts and solvates.

[0008] The present invention also relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), a pharma- ceutically acceptable salt or solvate thereof, and a pharma- ceutically acceptable carrier or excipient.

[0009] Furthermore, the present invention relates to a compound of formula (I), a pharma- ceutically acceptable salt or solvate thereof for use as a medicament and to a compound of formula (I), a pharma- ceutically acceptable salt or solvate thereof for use in the treatment or prevention of cancer.

[0010] In a particular embodiment, the present invention relates to a compound of formula (I), a pharma- ceutically acceptable salt or solvate thereof, for use in the treatment or prevention of cancer.

[0011] The present invention also relates to the use of a compound of formula (I), a pharma- ceutically acceptable salt or solvate thereof, in combination with an additional pharmaceutical agent, for use in the treatment or prevention of cancer.

[0012] Furthermore, the present invention relates to a process for preparing a pharmaceutical composition according to the present invention, characterized in that a pharma- ceutically acceptable carrier is intimately mixed with a therapeutically effective amount of a compound of formula (I), a pharma- ceutically acceptable salt or solvate thereof.

[0013] The present invention also relates to a product comprising a compound of formula (I), a pharma- ceutically acceptable salt or solvate thereof and an additional medicinal agent as a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of cancer.

[0014] Furthermore, the present invention relates to a method for treating or preventing a cell proliferative disorder in a subject, comprising the step of administering to said subject an effective amount of a compound of formula (I) as defined herein, a pharma- ceutically acceptable salt or solvate thereof, or a pharmaceutical composition or combination as defined herein. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0015] The term "halo" or "halogen" as used herein refers to fluoro, chloro, bromo and iodo.

[0016] As used herein, the prefix "C x~y " (where x and y are integers) refers to the number of carbon atoms in a given group. Thus, C 1~6 An alkyl group contains from 1 to 6 carbon atoms, etc.

[0017] As used herein as a group or part of a group, the term “C 1~4 "Alkyl" refers to a straight or branched chain fully saturated hydrocarbon group having 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, t-butyl and the like.

[0018] As used herein as a group or part of a group, the term “C 1~6 "Alkyl" refers to a straight or branched chain completely saturated hydrocarbon group having 1 to 6 carbon atoms, such as a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an s-butyl group, an t-butyl group, an n-pentyl group, an n-hexyl group, and the like.

[0019] As used herein as a group or part of a group, the term “C 2~6 "Alkyl" refers to a straight or branched chain completely saturated hydrocarbon group having 2 to 6 carbon atoms, such as an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an s-butyl group, an t-butyl group, an n-pentyl group, an n-hexyl group, and the like.

[0020] As used herein as a group or part of a group, the term “C 3~6 "Cycloalkyl" defines a fully saturated cyclic hydrocarbon group having 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups.

[0021] It will be apparent to one skilled in the art that S(=O)2 or SO2 represents a sulfonyl moiety.

[0022] It will be apparent to one skilled in the art that CO or C(=O) represent a carbonyl moiety.

[0023] In general, whenever the term "substituted" is used in this invention, unless otherwise specified or clear from the context, it indicates that one or more hydrogens, particularly one to four hydrogens, more particularly one to three hydrogens, preferably one or two hydrogens, more preferably one hydrogen, on the atom or group designated by the term "substituted" are replaced with one selected from the indicated group, provided that the normal valences are not exceeded and that the substitution results in a chemically stable compound, i.e., a compound that is robust enough to survive isolation to a useful degree of purity from a reaction mixture.

[0024] Combinations of substituents and / or variables are permissible only if such combinations result in chemically stable compounds. "Stable compound" is intended to indicate a compound that is robust enough to survive isolation to a useful degree of purity from a reaction mixture.

[0025] Those of skill in the art will understand that the term "optionally substituted" means that the atom or group designated with "optionally substituted" may or may not be substituted (which means substituted or unsubstituted, respectively).

[0026] When two or more substituents are present on a moiety, they may replace hydrogen atoms on the same atom or they may replace hydrogen atoms on different atoms in the moiety, where possible and unless otherwise stated or apparent from the context.

[0027] Unless otherwise specified or apparent from the context, it will be apparent to those skilled in the art that a substituent on a heterocyclyl group can replace any hydrogen atom on a ring carbon atom or on a ring heteroatom (for example, a hydrogen on a nitrogen atom can be replaced by a substituent).

[0028] The compound of formula (I) is represented by the formula (Ia) and (Ib) (X2 Both directions of [ka] is) [ka] It will be clear that this includes

[0029] When any variable occurs more than one time in any constituent, each definition is independent.

[0030] The term "subject" as used herein refers to an animal, preferably a mammal (e.g., a cat, dog, primate or human), more preferably a human, who is or has been the object of treatment, observation or experiment.

[0031] As used herein, the term "therapeutically effective amount" refers to that amount of an active compound or pharmaceutical agent that elicits the biological or medical response in a tissue system or subject (e.g., a human) desired by a researcher, veterinarian, medical doctor, or other clinician, including amelioration or reversal of symptoms of the disease or disorder being treated.

[0032] The term "composition" is intended to include products comprising the specified ingredients in the specified amounts, and any product that results directly or indirectly from combining the specified ingredients in the specified amounts.

[0033] The term "treatment" as used herein is intended to refer to any process that may slow, hinder, arrest or halt the progression of a disease, but does not necessarily indicate the complete elimination of all symptoms.

[0034] As used herein, the term "compounds of the invention" or "compounds according to the invention" is intended to include compounds of formula (I) and their pharma- ceutically acceptable salts and solvates.

[0035] As used herein, any chemical formula having bonds shown only as solid lines, and not as solid or dashed wedge bonds, or otherwise depicted as having a particular configuration (e.g., R, S) about one or more atoms contemplates each possible stereoisomer or mixture of two or more stereoisomers.

[0036] In the present specification above and below, the term "compounds of formula (I)" is intended to include the tautomeric and stereoisomeric forms thereof.

[0037] The terms "stereoisomer", "stereoisomeric form" or "stereochemically isomeric form" are used interchangeably hereinbefore and hereinafter.

[0038] The present invention includes all stereoisomers of the compounds of the present invention either as a pure stereoisomer or as a mixture of two or more stereoisomers.

[0039] Enantiomers are stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a racemate or racemic mixture.

[0040] Atropisomers (or atropoisomers) are stereoisomers with a specific spatial configuration resulting from restricted rotation about a single bond due to significant steric hindrance. All atropisomeric forms of the compounds of formula (I) are intended to be included within the scope of the present invention.

[0041] In particular, the compounds disclosed herein possess axial chirality due to hindered rotation about the biaryl bond, and as such may exist as a mixture of atropisomers. When the compounds are pure atropisomers, the stereochemistry at each chiral center is determined by the R a Or S aSuch names may also be used for mixtures enriched in one atropisomer. A detailed description of atropisomerism and axial chirality, as well as the rules for assigning configurations, can be found in Eliel, EL & Wilen, SH 'Stereochemistry of Organic Compounds' John Wiley and Sons, Inc. 1994.

[0042] Diastereomers (or diastereoisomers) are stereoisomers that are not enantiomers, i.e., they are not related as mirror images. If the compound contains a double bond, the substituents may be in the E or Z configuration.

[0043] Substituents on a divalent cyclic saturated or partially saturated group can have cis or trans configurations. For example, if a compound contains a disubstituted cycloalkyl group, the substituents can be in the cis or trans configuration.

[0044] Thus, the present invention includes enantiomers, atropisomers, diastereomers, racemates, E isomers, Z isomers, cis isomers, trans isomers and mixtures thereof whenever chemically possible.

[0045] The meanings of all these terms, i.e. enantiomers, atropisomers, diastereomers, racemates, E isomers, Z isomers, cis isomers, trans isomers and mixtures thereof, are known to the person skilled in the art.

[0046] Absolute configuration is specified according to the Cahn-Ingold-Prelog system. The configuration at the asymmetric atom is designated by R or S. Separate stereoisomers of unknown absolute configuration can be designated by (+) or (-) depending on the direction they rotate plane polarized light. For example, separate enantiomers of unknown absolute configuration can be designated by (+) or (-) depending on the direction they rotate plane polarized light. Optically active (R a )-atropisomers and (S a)-atropisomers may be prepared using chiral synthons, chiral reagents, or chiral catalysts, or resolved using conventional techniques known in the art, such as chiral HPLC.

[0047] When a particular stereoisomer is identified, this means that said stereoisomer is substantially free of other isomers, i.e. associated with less than 50%, preferably less than 20%, more preferably less than 10%, even more preferably less than 5%, particularly less than 2%, most preferably less than 1% of other isomers. Thus, when a compound of formula (I) is for example specified as (R), this means that the compound is substantially free of the (S) isomer, when a compound of formula (I) is for example specified as E, this means that the compound is substantially free of the Z isomer, when a compound of formula (I) is for example specified as cis, this means that the compound is substantially free of the trans isomer and when a compound of formula (I) is for example specified as R, this means that the compound is substantially free of the a This means that the compound is substantially S a It means substantially free of atropisomers.

[0048] Pharmaceutically acceptable salts, particularly pharma-ceutically acceptable addition salts, include acid addition salts and base addition salts.Such salts can be produced by conventional means, for example by reacting free acid form or free base form with one or more equivalents of suitable base or acid, optionally in a solvent or in a medium in which the salt is not soluble, followed by removing said solvent or said medium by standard methods (for example, in vacuum, by lyophilization or by filtration).Salts can also be prepared by exchanging the counterion of the compound of the present invention in the form of a salt with another counterion, for example, by using a suitable ion exchange resin.

[0049] Pharmaceutically acceptable salts, as defined above or below, are intended to include the therapeutically active non-toxic acid and base salt forms which the compounds of formula (I) and their solvates are able to form.

[0050] Suitable acids include, for example, inorganic acids, for example hydrohalic acids such as hydrochloric acid or hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or organic acids, for example acetic acid, propanoic acid, hydroxyacetic acid, lactic acid, pyruvic acid, oxalic acid (i.e. ethanedioic acid), malonic acid, succinic acid (i.e. butanedioic acid), maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclamic acid, salicylic acid, p-aminosalicylic acid, pamoic acid, and the like. Conversely, said salt forms can be converted to the free base form by treatment with an appropriate base.

[0051] The compounds of formula (I) and solvates thereof containing acidic protons can also be converted into their non-toxic metal or amine salt forms by treatment with appropriate organic and inorganic bases.

[0052] Suitable base salt forms include, for example, ammonium salts, alkali metal salts and alkaline earth metal salts, such as lithium salts, sodium salts, potassium salts, cesium salts, magnesium salts and calcium salts, salts with organic bases, such as salts with primary, secondary and tertiary aliphatic and aromatic amines, such as methylamine, ethylamine, propylamine, isopropylamine, the four butylamine isomers, dimethylamine, diethylamine, diethanolamine, dipropylamine, diisopropylamine, di-n-butylamine, pyrrolidine, piperidine, morpholine, trimethylamine, triethylamine, tripropylamine, quinuclidine, pyridine, quinoline and isoquinoline; benzathine salts, N-methyl-D-glucamine salts, hydrabamine salts and salts with amino acids, such as arginine and lysine. Conversely, the salt forms can be converted to the free acid forms by treatment with an acid.

[0053] The term solvates comprises the solvent addition forms and salts thereof which the compounds of formula (I) are able to form. Examples of such solvent addition forms are, for example, hydrates, alcoholates etc.

[0054] The compounds of the present invention prepared by the methods described below can be synthesized in the form of a mixture of enantiomers, in particular a racemic mixture of enantiomers, which can be separated from each other according to resolution procedures known in the art. Methods for separating the enantiomeric forms of the compounds of formula (I) and its pharma-ceutically acceptable salts, N-oxides and solvates include liquid chromatography using chiral stationary phases. Said pure stereochemically isomeric forms can also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically. Preferably, when a specific stereoisomer is desired, said compounds will be synthesized by stereospecific preparation methods. These methods will advantageously use enantiomerically pure starting materials.

[0055] As used herein, the term "enantiomerically pure" means that the product contains at least 80% by weight of one enantiomer and not more than 20% by weight of the other enantiomer. It is preferred that the product contains at least 90% by weight of one enantiomer and not more than 10% by weight of the other enantiomer. In the most preferred embodiment, the term "enantiomerically pure" means that the compound contains at least 99% by weight of one enantiomer and not more than 1% of the other enantiomer.

[0056] The present invention also encompasses isotopically labeled compounds of the present invention that are identical to the compounds described herein except for the fact that one or more atoms have been replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number normally found in nature (or the most abundant one found in nature).

[0057] All isotopes and isotopic mixtures of any particular atom or element identified herein, whether naturally occurring or synthetically produced, in either naturally abundant or isotopically enriched form, are intended to be included within the scope of the compounds of the invention. Exemplary isotopes that can be incorporated into the compounds of the invention are: 2 H, 3H, 11 C. 13 C. 14 C. 13 N, 15 O. 17 O. 18 O. 32 P, 33 P, 35 S, 18 F, 36 Cl, 122 I, 123 I, 125 I, 131 I, 75 Br, 76 Br, 77 Br and 82 The radioisotopes include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine and iodine, such as Br. Preferably, the radioisotope is 2 H, 3 H, 11 C and 18 More preferably, the radioisotope is selected from the group consisting of: 2 H. Specifically, deuterated compounds are intended to be included within the scope of the present invention.

[0058] Certain isotopically labeled compounds of the invention (e.g., 3 H and 14 C) can be useful, for example, in assays of substrate tissue distribution. 3 H) and carbon-l4( 14 C) isotopes are useful for their ease of preparation and detectability. 2 Substitution with heavier isotopes, such as H), may afford certain therapeutic advantages resulting from greater metabolic stability (such as increased in vivo half-life or reduced dosage requirements), and therefore may be preferred. 15 O. 13 N, 11 C and 18Positron-emitting isotopes such as F are useful in positron emission tomography (PET) studies. PET imaging in cancer is useful for locating and identifying tumors, staging the disease, and facilitating the determination of appropriate treatment. Human cancer cells overexpress many receptors or proteins that are potential disease-specific molecular targets. Radiolabeled tracers that bind with high affinity and specificity to such receptors or proteins on tumor cells have great potential for imaging and targeted radionuclide therapy (Charron, Carlie L. et al. Tetrahedron Lett. 2016, 57(37), 4119-4127). Furthermore, target-specific PET radiotracers can be used as biomarkers to examine and evaluate pathology, for example, by measuring target expression and treatment response (Austin R. et al. Cancer Letters (2016), doi:10.1016 / j.canlet.2016.05.008).

[0059] The present invention particularly relates to compounds of formula (I) as defined herein, X 1 teeth, [ka] (wherein "a" and "b" are the variables X 1 is attached to the rest of the molecule) represents; R 1 is hydrogen or C 1~6 represents alkyl; X 2 can be attached to the rest of the molecule in both orientations, [ka] represents; R 2 is hydrogen or C 1~6 represents alkyl; X is -S- or -N(R x )-represents; R xis hydrogen, methyl, C 2~6 Alkyl, -C(=O)-C 1~6 Alkyl, -S(=O)2-C 1~6 Alkyl, C 3~6 Cycloalkyl, -C(=O)-C 3~6 Cycloalkyl or -S(=O)2-C 3~6 represents cycloalkyl, where C 2~6 Alkyl, -C(=O)-C 1~6 Alkyl, -S(=O)2-C 1~6 Alkyl, C 3~6 Cycloalkyl, -C(=O)-C 3~6 Cycloalkyl and -S(=O)2-C 3~6 Cycloalkyl is optionally selected from halo, C 1~4 C substituted with alkyl and 1, 2 or 3 halo atoms 1~4 substituted with 1, 2 or 3 substituents selected from the group consisting of alkyl and tautomeric and stereoisomeric forms thereof, and pharma- ceutically acceptable salts and solvates thereof, except that the following and their tautomeric and stereoisomeric forms are excluded:

[0060] [Table 1]

[0061] The present invention particularly relates to compounds of formula (I) as defined herein, X 1 teeth, [ka] (wherein "a" and "b" are the variables X 1 is attached to the rest of the molecule) represents; R 1 is hydrogen or C 1~6 represents alkyl; X 2 can be attached to the rest of the molecule in both orientations, [ka] represents; R 2 is hydrogen or C 1~6 represents alkyl; X is -S- or -N(R x )-represents; R x is hydrogen, methyl or C 2~6 represents an alkyl group) and its tautomeric and stereoisomeric forms, and its pharma- ceutically acceptable salts and solvates.

[0062] The present invention particularly relates to compounds of formula (I) as defined herein, X 1 teeth, [ka] (wherein "a" and "b" are the variables X 1 is attached to the rest of the molecule) represents; R 1 is C 1~4 represents alkyl; X 2 can be attached to the rest of the molecule in both orientations, [ka] represents; R 2 is C 1~4 represents alkyl; X is -S- or -N(R x )-represents; R x represents hydrogen or methyl) and its tautomeric and stereoisomeric forms, and its pharma- ceutically acceptable salts and solvates.

[0063] The present invention particularly relates to compounds of formula (I) as defined herein, X 1 teeth, [ka] (wherein "a" and "b" are the variables X 1 is attached to the rest of the molecule) represents; R 1 represents methyl; X 2 can be attached to the rest of the molecule in both orientations, [ka] represents; R 2 represents methyl; X is -S- or -N(R x )-represents; R x represents hydrogen or methyl) and its tautomeric and stereoisomeric forms, and its pharma- ceutically acceptable salts and solvates.

[0064] In one embodiment, the present invention provides a compound of formula (I), x )-) as well as the pharma- ceutically acceptable salts and solvates thereof or any subgroup thereof as described in any of the other embodiments.

[0065] In one embodiment, the present invention provides a compound of formula (I), x )-; and R x represents hydrogen) and the pharma- ceutically acceptable salts and solvates thereof or any subgroup thereof as described in any of the other embodiments.

[0066] In one embodiment, the present invention provides a compound of formula (I), x )-; and R x represents methyl) and pharma- ceutically acceptable salts and solvates thereof or any subgroup thereof as described in any of the other embodiments.

[0067] In one embodiment, the present invention relates to a compound of formula (I), 1 teeth, [ka] and pharma- ceutically acceptable salts and solvates thereof or any subgroup thereof as described in any of the other embodiments.

[0068] In one embodiment, the present invention relates to a compound of formula (I), 1 teeth, [ka] and pharma- ceutically acceptable salts and solvates thereof or any subgroup thereof as described in any of the other embodiments.

[0069] In one embodiment, the present invention provides a compound of formula (I), 1 represents hydrogen) and the pharma- ceutically acceptable salts and solvates thereof or any subgroup thereof mentioned in any of the other embodiments.

[0070] In one embodiment, the present invention provides a compound of formula (I), 1 is C 1~6 and phenyl, phenyl or phenyl alkyl) as well as the pharma- ceutically acceptable salts and solvates thereof or any subgroup thereof as described in any of the other embodiments.

[0071] In one embodiment, the present invention provides a compound of formula (I), 1 is C 2~4 and phenyl, phenyl or phenyl alkyl) as well as the pharma- ceutically acceptable salts and solvates thereof or any subgroup thereof as described in any of the other embodiments.

[0072] In one embodiment, the present invention provides a compound of formula (I), 1represents methyl) and pharma- ceutically acceptable salts and solvates thereof or any subgroup thereof as described in any of the other embodiments.

[0073] In one embodiment, the present invention provides a compound of formula (I), 2 represents hydrogen) and the pharma- ceutically acceptable salts and solvates thereof or any subgroup thereof mentioned in any of the other embodiments.

[0074] In one embodiment, the present invention provides a compound of formula (I), 1 and R 2 At least one of the groups is hydrogen or C 2~6 and phenyl, phenyl or phenyl alkyl) as well as the pharma- ceutically acceptable salts and solvates thereof or any subgroup thereof as described in any of the other embodiments.

[0075] In one embodiment, the present invention provides a compound of formula (I), 1 and R 2 is other than methyl) and pharma- ceutically acceptable salts and solvates thereof or any subgroup thereof as described in any of the other embodiments.

[0076] In one embodiment, the present invention provides a compound of formula (I), 2 is C 1~6 and phenyl, phenyl or phenyl alkyl) as well as the pharma- ceutically acceptable salts and solvates thereof or any subgroup thereof as described in any of the other embodiments.

[0077] In one embodiment, the present invention provides a compound of formula (I), 2 is C 2~6 and phenyl, phenyl or phenyl alkyl) as well as the pharma- ceutically acceptable salts and solvates thereof or any subgroup thereof as described in any of the other embodiments.

[0078] In one embodiment, the present invention provides a compound of formula (I), 2 is hydrogen C 2~6and phenyl, phenyl or phenyl alkyl) as well as the pharma- ceutically acceptable salts and solvates thereof or any subgroup thereof as described in any of the other embodiments.

[0079] In one embodiment, the present invention provides a compound of formula (I), 2 represents methyl) and the pharma- ceutically acceptable salts and solvates thereof or any subgroup thereof as described in any of the other embodiments.

[0080] In one embodiment, the present invention provides a compound of formula (I), i)R 1 and R 2 is other than methyl; or ii) R x is methyl or -S(=O)2-C 1~6 (other than alkyl) and pharma- ceutically acceptable salts and solvates thereof or any subgroup thereof as described in any of the other embodiments.

[0081] In one embodiment, the present invention provides a compound of formula (I), x is hydrogen, C 2~6 Alkyl, -C(=O)-C 1~6 Alkyl, C 3~6 Cycloalkyl, -C(=O)-C 3~6 Cycloalkyl or -S(=O)2-C 3~6 represents cycloalkyl; 2~6 Alkyl, -C(=O)-C 1~6 Alkyl, C 3~6 Cycloalkyl, -C(=O)-C 3~6 Cycloalkyl and -S(=O)2-C 3~6 Cycloalkyl is optionally selected from halo, C 1~4 C substituted with alkyl and 1, 2 or 3 halo atoms 1~4 and n is 0, 1 or 2. The present invention relates to those compounds of formula (I) wherein R is substituted with 1, 2 or 3 substituents selected from the group consisting of alkyl, and phenyl, ...

[0082] In one embodiment, the present invention provides a compound of formula (I), x is hydrogen or C 2~6 and phenyl, phenyl or phenyl alkyl) as well as the pharma- ceutically acceptable salts and solvates thereof or any subgroup thereof as described in any of the other embodiments.

[0083] In one embodiment, the present invention relates to those compounds of formula (I) and pharma- ceutically acceptable salts and solvates thereof or any subgroup thereof as described in any of the other embodiments, wherein the compound of formula (I) has the formula (Ix): [ka] The compounds are limited to:

[0084] It will be apparent that all variables in the structure of formula (Ix) are defined as defined for the compounds of formula (I) or any subgroups thereof described in any of the other embodiments.

[0085] In one embodiment, the present invention relates to those compounds of formula (I) and pharma- ceutically acceptable salts and solvates thereof or any subgroup thereof as described in any of the other embodiments, wherein the compounds of formula (I) have the formula (Iy): [ka] The compounds are limited to:

[0086] It will be apparent that all variables in the structure of formula (Iy) are defined as defined for the compounds of formula (I) or any subgroups thereof described in any of the other embodiments.

[0087] In one embodiment, the invention relates to those compounds of formula (I) and pharma- ceutically acceptable salts and solvates thereof or any subgroup thereof as set forth in any of the other embodiments, wherein the following compounds and their tautomeric and stereoisomeric forms are excluded:

[0088] [Table 2]

[0089] In one embodiment, the scope of this invention does not include the excluded compounds and their pharma- ceutically acceptable salts.In one embodiment, the scope of this invention does not include the excluded compounds and their pharma- ceutically acceptable salts and solvates.

[0090] In one embodiment, the present invention relates to subgroups of formula (I) as defined in the General Reaction Scheme.

[0091] In one embodiment, the compound of formula (I) is selected from the group consisting of any of the exemplified compounds, their tautomeric and stereoisomeric forms, and pharma- ceutically acceptable salts and solvates thereof.

[0092] All possible combinations of the embodiments presented above are considered to fall within the scope of the present invention.

[0093] Methods for Preparing Compounds In this section, as with all other sections, unless the context indicates otherwise, reference to formula (I) also includes all other subgroups and examples thereof defined herein.

[0094] The general preparation of some representative examples of compounds of formula (I) are illustrated below and in the specific examples, and are generally prepared from starting materials that are either commercially available or prepared by standard synthetic methods commonly used by those skilled in the art of organic chemistry. The following schemes are merely intended to illustrate examples of the invention and are not intended to limit the invention in any way.

[0095] Alternatively, the compounds of the present invention can be prepared by reaction protocols analogous to those depicted in the general schemes below, in combination with standard synthetic methods commonly used by one skilled in the art.

[0096] Those skilled in the art will understand that, although not always explicitly shown in the reactions described in the schemes, reactive functional groups (e.g., hydroxy, amino or carboxy groups) may need to be protected if desired in the final product to avoid them unnecessarily participating in the reaction. In general, conventional protecting groups can be used in accordance with standard practice. Protecting groups can be removed at a convenient subsequent stage using methods known in the art.

[0097] Those skilled in the art will appreciate that in the reactions described in the schemes it may be desirable or necessary to carry out the reactants under an inert atmosphere, such as, for example, under an atmosphere of N2 gas.

[0098] It will be apparent to one skilled in the art that it may be necessary to cool the reaction mixture before reaction work-up (which refers to the series of operations required to isolate and purify the products of a chemical reaction, such as quenching, column chromatography, extraction, etc.).

[0099] Those skilled in the art will appreciate that heating the reaction mixture under stirring may improve the reaction outcome. In some reactions, microwave heating may be used instead of conventional heating to reduce the overall reaction time.

[0100] Those skilled in the art will appreciate that alternative sequences of chemical reactions shown in the schemes below may also provide the desired compounds of formula (I).

[0101] Those skilled in the art will appreciate that the intermediates and final compounds depicted in the schemes below may be further functionalized according to methods known to those skilled in the art. The intermediates and compounds described herein may be isolated in their free form or as a salt or solvate. The intermediates and compounds described herein may be synthesized in the form of mixtures of tautomeric and stereoisomeric forms that can be separated from one another according to resolution procedures known in the art.

[0102] [ka] In the compounds of formula (Ia) and (Ib), all variables are as defined for formula (I) within the scope of the present invention.

[0103] Those skilled in the art can carry out similar reaction protocols using 1 but, [ka] It will be appreciated that the compound of the present invention may also be used to prepare compounds of the present invention, which represent

[0104] To obtain such compounds, an alternative pyrazole-boronic acid salt must be used during the conversion process of the intermediate of formula (XVIII) to the intermediate of formula (XVII). The following synthetic reaction steps are similar to those described for compounds (Ia) and (Ib).

[0105] In the scheme below, Me means methyl, Et means ethyl, and Ac means acetyl.

[0106] The compound of formula (Ia) may be represented by the formula (III) [ka] (In the formula, X, R 1 and R 2 is as defined in formula (Ia) in a suitable solvent such as water or a mixture of water and a suitable organic solvent such as dioxane or THF or a mixture of MeOH and THF in the presence of a suitable base such as LiOH or NaOH at a suitable temperature such as room temperature or 60° C.

[0107] Similarly, the compound of formula (Ib) may be a compound of formula (IV) [ka] (In the formula, X, R 1 and R 2 is as defined in formula (Ib). in a suitable solvent such as water or a mixture of water and a suitable organic solvent such as dioxane or THF or a mixture of MeOH and THF in the presence of a suitable base such as LiOH or NaOH at a suitable temperature such as room temperature or 60° C.

[0108] The intermediate of formula (III) and the intermediate of formula (IV) are represented by the formula (V) [ka] (Wherein, X and R 1 is as defined in formula (Ia) or formula (Ib). with a suitable alkylating agent, such as, for example, an alkyl halide, in a suitable solvent, such as, for example, DMF or acetonitrile, in the presence of a suitable base, such as, for example, triethylamine (EtN), N,N-diisopropylethylamine (iPrEtN) or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), at a suitable temperature, such as, for example, room temperature or 60° C., followed by suitable separation, such as chromatographic separation, of the isomers (III) and (IV).

[0109] When X is defined as S (sulfur), the intermediate of formula (V) is represented by the formula (VI) [ka] (In the formula, P 2 is defined as a suitable protecting group such as, for example, paramethoxybenzyl (PMB), dimethoxybenzyl (DMB) or tetrahydropyranyl (THP), and X is defined in this chemical protocol as S (sulfur). with a suitable deprotecting agent, such as, for example, HCl or trifluoroacetic acid (TFA) or 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), in a suitable solvent, such as, for example, 1,4-dioxane, CH2Cl2 or toluene, at a suitable temperature, such as, for example, room temperature or 80°C.

[0110] X is NR x (In the formula, R x is as defined in formula (I), the intermediate of formula (V) is represented by formula (VII) [ka] (In the formula, P 2 is a suitable protecting group such as, for example, paramethoxybenzyl (PMB), dimethoxybenzyl (DMB) or tetrahydropyranyl (THP). with a suitable deprotecting agent, such as, for example, HCl or TFA or DDQ, in a suitable solvent, such as, for example, 1,4-dioxane, CH2Cl2 or toluene, at a suitable temperature, such as, for example, room temperature or 80°C.

[0111] The intermediate of formula (VII) is represented by the formula (VIII) [ka] (In the formula, P 2 is as defined in formula (VII). with a suitable alkylating agent, such as an alkyl halide, in a suitable solvent, such as DMF or acetonitrile, in the presence of a suitable base, such as EtN, iPrEtN or DBU, at a suitable temperature, such as room temperature or 60° C.

[0112] Alternatively, the intermediate of formula (VII) can be prepared by reacting the intermediate of formula (VIII) with a suitable aldehyde, such as, for example, formaldehyde, and a suitable reducing agent, such as, for example, NaBH3CN, in a suitable solvent, such as, for example, CH2Cl2, at a suitable temperature, such as, for example, room temperature.

[0113] The intermediate of formula (VIII) can be represented by the formula (VI), 2 is as defined in formula (VII) and X is defined as a nitrogen protected by a protecting group such as, for example, 2-nitrophenylsulfonyl, with a suitable deprotecting agent such as, for example, thiophenol in the presence of a suitable base such as, for example, KCO, in a suitable solvent such as, for example, acetonitrile or DMF, at a suitable temperature such as, for example, room temperature or 80° C.

[0114] The intermediate of formula (VI) is represented by the formula (IX) [ka] wherein X is as defined in formula (Ia), and P 2 can be a suitable protecting group such as, for example, paramethoxybenzyl (PMB), dimethoxybenzyl (DMB) or tetrahydropyranyl (THP), or can be a suitable alkyl substituent such as, for example, methyl. can be prepared by reacting the intermediate of formula (I) with a suitable reagent, such as, for example, diethyl azodicarboxylate (DEAD) or di-tert-butyl azodicarboxylate (DBAD), in the presence of a suitable phosphine, such as, for example, PPh3, in a suitable solvent, such as, for example, THF, toluene or mixtures thereof, at a suitable temperature, such as, for example, room temperature or 60° C.

[0115] The intermediate of formula (IX) is a compound of formula (X) [ka] (Wherein, X and P 2 is as defined in formula (IX), and SiP 3 is a suitable protecting group, such as, for example, tert-butyldimethylsilyl (TBDMS) or tert-butyldiphenylsilyl (TBDPS). can be prepared by reacting the intermediate of formula (I) with a deprotecting reagent, such as, for example, tetrabutylammonium fluoride (TBAF), in a suitable solvent, such as, for example, THF, at a suitable temperature, such as, for example, room temperature or 60° C.

[0116] When X is defined as S (sulfur), the intermediate of formula (V) is represented by the formula (XI) [ka] (In the formula, SiP 3 is as defined in formula (X) and L is a suitable leaving group such as, for example, a halogen or an alkylsulfonate. by reacting an intermediate of formula (XII) [ka] (In the formula, SiP 3 and P 2 is as defined in formula (X). in the presence of a suitable base, such as, for example, K2CO3, in a suitable solvent, such as, for example, MeOH, at a suitable temperature, such as, for example, room temperature or 60°C.

[0117] When X is defined as a nitrogen protected by a protecting group such as, for example, 2-nitrophenylsulfonyl, the intermediate of formula (X) is represented by formula (XIII): [ka] (In the formula, SiP 3 is as defined in formula (X). by reacting an intermediate of formula (XIV) [ka] (In the formula, SiP 3 and P 2 is as defined in formula (X). with a suitable reagent, such as, for example, DEAD or DBAD, in the presence of a suitable phosphine, such as, for example, triphenylphosphine (PPh3), in a suitable solvent, such as, for example, THF, toluene or mixtures thereof, at a suitable temperature, such as, for example, room temperature or 60° C.

[0118] The intermediate of formula (XIII) is represented by the formula (XV) [ka] (In the formula, SiP 3 is as defined in formula (X). with a suitable protected nitrogen, such as, for example, 2-nitrophenylsulfonamide, in the presence of a suitable reagent, such as, for example, DEAD or DBAD, in the presence of a suitable phosphine, such as, for example, PPh3, in a suitable solvent, such as, for example, THF, toluene or mixtures thereof, at a suitable temperature, such as, for example, room temperature or 60° C.

[0119] The intermediate of formula (XI) may be prepared by reacting the intermediate of formula (XV) with a suitable alkylsulfonyl chloride, such as, for example, mesyl chloride, in the presence of a suitable base, such as, for example, triethylamine, in a suitable solvent, such as, for example, CH2Cl2, at a suitable temperature, such as, for example, room temperature.

[0120] Alternatively, the intermediate of formula (XI) can be prepared in two steps by reacting the intermediate of formula (XV) with a suitable alkylsulfonyl chloride, such as, for example, mesyl chloride, in the presence of a suitable base, such as, for example, triethylamine, in a suitable solvent, such as, for example, CH2Cl2, at a suitable temperature, such as, for example, room temperature, followed by reaction with a suitable metal halide, such as, for example, potassium iodide, in a suitable solvent, such as, for example, acetonitrile, at a suitable temperature, such as, for example, room temperature or 60°C.

[0121] The intermediate of formula (XV) is represented by the formula (XVI) [ka] can be prepared by reacting the intermediate of formula (I) with a suitable O-protected propyl halide or alkyl sulfonate, such as, for example, (3-bromopropoxy)(tert-butyl)dimethylsilane, in the presence of a suitable base, such as, for example, CsCO, in a suitable solvent, such as, for example, DMF, at a suitable temperature, such as, for example, room temperature.

[0122] The intermediate of formula (XVI) is represented by the formula (XVII) [ka] can be prepared by reaction of the intermediate of formula (I) with a suitable deprotecting agent, such as, for example, trifluoromethanesulfonic acid or TFA, in a suitable solvent, such as, for example, CH 2 Cl 2 , at a suitable temperature, such as, for example, room temperature.

[0123] The intermediate of formula (XVII) is represented by the formula (XVIII) [ka] with a suitable substituted pyrazole derivative, such as for example 3-(((4-methoxybenzyl)oxy)methyl)-1,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, in the presence of a suitable catalyst, such as for example Pd2(dba)3, in the presence of a suitable phosphine ligand, such as for example S-Phos, in the presence of a suitable base, such as for example sodium bicarbonate, in a suitable solvent, such as for example dioxane, water or a mixture thereof, at a suitable temperature, such as for example 100° C.

[0124] The intermediate of formula (XVIII) is represented by the formula (XIX) [ka] can be prepared by reacting the intermediate of formula (I) with a suitable acid, such as, for example, sulfuric acid, in a suitable solvent, such as, for example, acetic acid, at a suitable temperature, such as, for example, 70°C.

[0125] The intermediate of formula (XIX) may be prepared by reacting (3-bromo-4-chlorophenyl)hydrazine with methyl 2-oxobutanoate in the presence of a suitable acid, such as hydrochloric acid, in a suitable solvent, such as methanol, at a suitable temperature, such as 65° C.

[0126] The intermediate of formula (XII) is a compound of formula (XX) [ka] (In the formula, SiP 3 and P 2 is as defined in formula (X) and L is a suitable leaving group. can be prepared by reacting the intermediate with potassium thioacetate in a suitable solvent, such as DMF, at a suitable temperature, such as room temperature.

[0127] The intermediate of formula (XX) may be prepared by reacting the intermediate of formula (XIV) with a suitable reagent, such as, for example, mesyl chloride or thionyl chloride, optionally in the presence of a suitable base, such as, for example, triethylamine, in a suitable solvent, such as, for example, CH2Cl2, at a suitable temperature, such as, for example, 0° C. or room temperature.

[0128] The intermediate of formula (XIV) is represented by the formula (XXII) [ka] (In the formula, SiP 3 and P 2 is as defined in formula (X). can be prepared by reacting an intermediate of the formula: with a suitable reducing agent, such as, for example, DIBALH, in a suitable solvent, such as, for example, THF, at a suitable temperature, such as, for example, 0° C. or room temperature.

[0129] The intermediate of formula (XXII) is represented by the formula (XXIII) [ka] (In the formula, P 2 is as defined in formula (X). with a suitable trisubstituted silyl chloride, such as, for example, TBDMSCl (tert-butyldimethylsilyl chloride) or TBDPSCl (tert-butyldiphenylsilyl chloride), in the presence of a suitable base, such as, for example, imidazole, in a suitable solvent, such as, for example, DMF, at a suitable temperature, such as, for example, room temperature.

[0130] The intermediate of formula (XXIII) is represented by the formula (XXIV) [ka] (In the formula, P 2 is as defined in formula (X) and L is a suitable leaving group such as, for example, chloride or mesylate. with 3-(acetylthio)naphthalen-1-yl acetate in the presence of a suitable base, such as KCO, in a suitable solvent, such as methanol, at a suitable temperature, such as room temperature.

[0131] The intermediate of formula (XXIV) is represented by the formula (XXV) [ka] (In the formula, P 2 is as defined in formula (X). with a suitable reagent, such as, for example, mesyl chloride or thionyl chloride, optionally in the presence of a suitable base, such as, for example, triethylamine, in a suitable solvent, such as, for example, CH2Cl2, at a suitable temperature, such as, for example, 0° C. or room temperature.

[0132] The intermediate of formula (XXV) is represented by the formula (XXVI) [ka] (In the formula, P 2 is as defined in formula (X). can be prepared by reacting an intermediate of the formula: with a suitable deprotecting agent, such as, for example, TBAF, in a suitable solvent, such as, for example, THF, at a suitable temperature, such as, for example, room temperature.

[0133] The intermediate of formula (XXVI) may be prepared by reacting ethyl 5-(((tert-butyldiphenylsilyl)oxy)methyl)-1H-pyrazole-3-carboxylate with a suitable protecting group precursor, such as, for example, paramethoxybenzyl chloride, dimethoxybenzyl chloride or similarly a suitable alkyl halide, such as, for example, methyl iodide, in the presence of a suitable base, such as, for example, sodium bis(trimethylsilyl)amide, in a suitable solvent, such as, for example, THF, at a suitable temperature, such as, for example, 0° C. or room temperature.

[0134] Alternatively, the intermediate of formula (XXVI) can be prepared by reacting ethyl 5-(((tert-butyldiphenylsilyl)oxy)methyl)-1H-pyrazole-3-carboxylate with a suitable protecting group precursor, such as, for example, 3,4-dihydro-2H-pyran, in the presence of a suitable catalyst, such as, for example, p-toluenesulfonic acid (PTSA), in a suitable solvent, such as, for example, tetrahydrofuran (THF) or CHCl, at a suitable temperature, such as, for example, 0° C. or room temperature.

[0135] Alternatively, the intermediate of formula (VI) may be a compound of formula (XXVII) [ka] wherein X is as defined in formula (Ia), and P 2 may be a suitable protecting group, such as, for example, tetrahydropyranyl (THP), or a suitable alkyl substituent, such as, for example, methyl, and L 1 is a suitable leaving group, e.g., mesylate, etc. in the presence of a suitable base, such as K2CO3, in a suitable solvent, such as acetonitrile, at a suitable temperature, such as 80°C.

[0136] The intermediate of formula (XXVII) is represented by the formula (XXVIII) [ka] (In the formula, L 2 is a suitable leaving group, e.g., iodide, etc. with 3-(acetylthio)naphthalen-1-yl acetate in the presence of a suitable base, such as, for example, KCO, in the presence of a suitable catalyst, such as, for example, PPh, in a suitable solvent, such as, for example, methanol or THF or a mixture thereof, at a suitable temperature, such as, for example, 0° C. or room temperature.

[0137] The intermediate of formula (XXVIII) is represented by the formula (XXIX) [ka] by first reacting the intermediate bis-mesylate salt with a suitable activating agent, such as, for example, mesyl anhydride, in the presence of a suitable base, such as, for example, DIPEA, in a suitable solvent, such as, for example, THF, at a suitable temperature, such as, for example, 0° C. or room temperature; and then reacting the resulting intermediate bis-mesylate salt with a suitable halide, such as, for example, sodium iodide, in a suitable solvent, such as, for example, THF, at a suitable temperature, such as, for example, room temperature.

[0138] The intermediate of formula (XXIX) is a compound of formula (XXX) [ka] (In the formula, P 1 and P 2 is a suitable protecting group, such as, for example, TBDMS or TBDPS. can be prepared by reacting an intermediate of the formula: with a suitable deprotecting agent, such as, for example, TBAF, in a suitable solvent, such as, for example, THF, at a suitable temperature, such as, for example, room temperature.

[0139] The intermediate of formula (XXX) is represented by the formula (XXXI) [ka] where X' is a suitable activated / protected form of X, such as, for example, a thioacetate salt. can be prepared by reacting an intermediate of formula (XI) with an intermediate of formula (XI) in the presence of a suitable base, such as, for example, K2CO3, in a suitable solvent, such as, for example, MeOH, at a suitable temperature, such as, for example, room temperature.

[0140] Alternatively, the intermediate of formula (XXX) can be prepared by reacting an intermediate of formula (XXXI), where X' is a suitable activated / protected form of X, such as, for example, 2-nitrophenylsulfonamide, with an intermediate of formula (XV) in the presence of a suitable reagent, such as, for example, DEAD or DBAD, and in the presence of a suitable phosphine, such as, for example, triphenylphosphine (PPh3), in a suitable solvent, such as, for example, THF, toluene or mixtures thereof, at a suitable temperature, such as room temperature or 60°C.

[0141] Formula (XXXI) (wherein X' is a precursor of S (sulfur)) can be converted to formula (XXXII) [ka] by first reacting an intermediate of the formula (I) with a suitable activating agent, such as, for example, MsCl, in the presence of a suitable base, such as, for example, EtN, in a suitable solvent, such as, for example, THF, at a suitable temperature, such as, for example, room temperature; and then reacting the resulting activated intermediate with a suitable source of X', such as, for example, potassium thioacetate, in a suitable solvent, such as, for example, DMF or THF or a mixture thereof, at a suitable temperature, such as, for example, room temperature.

[0142] Alternatively, the compound of formula (XXXI) (wherein X′ is NR x The intermediate of formula (XXXII), which is a precursor of, can be prepared by reacting an intermediate of formula (XXXII) with a suitable X' precursor, such as, for example, 2-nitrophenylsulfonamide, in the presence of a suitable reagent, such as, for example, DEAD or DBAD, and in the presence of a suitable phosphine, such as, for example, triphenylphosphine (PPh3), in a suitable solvent, such as, for example, THF, toluene or mixtures thereof, at a suitable temperature, such as, for example, room temperature or 60°C.

[0143] The intermediate of formula (XXXII) may be prepared by reacting the intermediate of formula (XXVI) with a suitable reducing agent, such as, for example, DIBAL-H, in a suitable solvent, such as, for example, THF, at a suitable temperature, such as, for example, 0° C.

[0144] It will be apparent to one skilled in the art that intermediates of formula (XXVII) may carry a protecting group P2 on the other pyrazole nitrogen, in which case an analogous synthetic route can be used starting from the corresponding isomer of intermediate (XXVI).

[0145] It will be appreciated that, where appropriate functional groups are present, the compounds of the various formulae, or any intermediates used in their preparation, may be further derivatized by one or more standard synthetic methods using condensation, substitution, oxidation, reduction or cleavage reactions. Particular substitution approaches include conventional alkylation, arylation, heteroarylation, acylation, sulfonylation, halogenation, nitration, formylation and coupling procedures.

[0146] The compounds of formula (I) may be synthesized in the form of a racemic mixture of enantiomers that can be separated from each other according to resolution procedures known in the art. Racemic compounds of formula (I) that contain a basic nitrogen atom may be converted into the corresponding diastereomeric salt forms by reaction with a suitable chiral acid. The diastereomeric salt forms are then separated, for example, by selective or fractional crystallization, and the enantiomers are then liberated by alkali. Alternative methods for separating the enantiomeric forms of the compounds of formula (I) include liquid chromatography using chiral stationary phases. The pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically.

[0147] In the preparation of the compounds of the present invention, it may be necessary to protect remote functional groups (e.g., primary or secondary amines) of intermediates. The requirement for such protection will vary depending on the nature of the remote functional group and the conditions of the preparation method. Suitable amino-protecting groups (NH-Pg) include acetyl, trifluoroacetyl, t-butoxycarbonyl (Boc), benzyloxycarbonyl (CBz) and 9-fluorenylmethyleneoxycarbonyl (Fmoc). The need for such protection is readily determined by one skilled in the art. For a general overview of protecting groups and their use, see TW Greene and PG M Huts, Protective Groups in Organic Synthesis, 4th ed., Wiley, Hoboken, New Jersey, 2007.

[0148] Compound pharmacology The compounds of the present invention have been found to inhibit one of a number of MCL-1 activities, such as MCL-1 anti-apoptotic activity.

[0149] MCL-1 inhibitors are compounds that block one or more MCL-1 functions, such as its ability to bind to and inhibit the pro-apoptotic effectors Bak and Bax or BH3-only sensitizers such as Bim, Noxa, or Puma.

[0150] The compounds of the invention may inhibit the pro-survival functions of MCL-1 and may therefore be useful in treating and / or preventing, particularly in treating, diseases susceptible to the effects of the immune system, such as cancer.

[0151] In another embodiment of the invention, the compounds of the invention exhibit anti-tumor properties, for example, through immune modulation.

[0152] In one embodiment, the present invention is directed to a method for treating and / or preventing cancer, wherein the cancer is selected from the cancers described herein, comprising the step of administering to a subject (preferably a human) in need thereof a therapeutically effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt or solvate thereof.

[0153] In one embodiment, the present invention relates to a method for treating and / or preventing cancer, comprising the step of administering to a subject, preferably a human, in need thereof a therapeutically effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt or solvate thereof, wherein the cancer is selected from the group consisting of acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), B-cell acute lymphoblastic leukemia, B-cell chronic lymphocytic leukemia (CLL), bladder cancer, breast cancer, chronic lymphocytic leukemia, chronic myelogenous leukemia, colon adenocarcinoma, diffuse large B-cell lymphoma, esophageal cancer, follicular lymphoma, gastric cancer, head and neck cancer (including but not limited to head and neck squamous cell carcinoma). , but are not limited to, hematopoietic cancer, hepatocellular carcinoma, Hodgkin's lymphoma, liver cancer, lung cancer (including but not limited to lung adenocarcinoma), lymphoma, medulloblastoma, melanoma, monoclonal gammopathy of unknown significance, multiple myeloma, myelodysplastic syndrome, myelofibrosis, myeloproliferative neoplasms, ovarian cancer, ovarian clear cell carcinoma, ovarian seminal epithelial cystadenoma, pancreatic cancer, polycythemia vera, prostate cancer, rectal adenocarcinoma, renal cell carcinoma, smoldering multiple myeloma, T-cell acute lymphoblastic leukemia, T-cell lymphoma, and Waldenstrom's macroglobulinemia.

[0154] In another embodiment, the present invention relates to a method for treating and / or preventing cancer, comprising the step of administering to a subject, preferably a human, in need thereof a therapeutically effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt or solvate thereof, wherein the cancer is preferably selected from the group consisting of acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), B-cell acute lymphoblastic leukemia, B-cell chronic lymphocytic leukemia (CLL), breast cancer, chronic lymphocytic leukemia, chronic myelogenous leukemia, and the like. In one embodiment, the present invention is directed to a method for treating myeloma, wherein the myeloma is selected from the group consisting of myelodysplastic syndromes, myelofibrosis, myeloproliferative neoplasms, smoldering multiple myeloma, T-cell acute lymphoblastic leukemia, T-cell lymphoma, and Waldenstrom's macroglobulinemia.

[0155] In another embodiment, the present invention relates to a method for treating and / or preventing cancer, comprising the step of administering to a subject, preferably a human, in need thereof a therapeutically effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt or solvate thereof, wherein the cancer is adenocarcinoma, benign monoclonal gammopathy, biliary cancer (including but not limited to cholangiocarcinoma), bladder cancer, breast cancer (including but not limited to adenocarcinoma of the breast, papillary carcinoma of the breast, breast carcinoma, medullary carcinoma of the breast), brain tumors (including but not limited to meningiomas), gliomas (including but not limited to astrocytoma, certain dendrocyte tumors; medulloblastomas), bronchial carcinoma, cervical cancer (including but not limited to cervical adenocarcinoma), chordoma, trophoblastic tumor, colorectal cancer (including but not limited to colon cancer, rectal cancer, cancer, including but not limited to colorectal adenocarcinoma), epithelial carcinoma, endothelial carcinoma (including but not limited to Kaposi's sarcoma, multiple idiopathic hemorrhagic sarcoma), endometrial cancer (including but not limited to uterine carcinoma, uterine sarcoma), esophageal cancer (including but not limited to esophageal adenocarcinoma, Barrett's adenocarcinoma), Ewing's sarcoma, gastric cancer (including but not limited to gastric adenocarcinoma), gastrointestinal stromal tumor (GIST), head and neck cancer (including but not limited to head and neck squamous cell carcinoma), hematopoietic cancer (e.g. For example, acute lymphocytic leukemia (ALL) (including, but not limited to, B-cell ALL, T-cell ALL), acute myeloid leukemia (AML) (e.g., B-cell AML, T-cell AML), chronic myeloid leukemia (CML) (e.g., B-cell CML, T-cell CML) and chronic lymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell CLL), lymphomas such as Hodgkin's lymphoma (HL) (including, but not limited to, B-cell HL, T-cell HL) and non-Hodgkin's lymphomas. Lymphoma (NHL) (e.g., B-cell NHL such as diffuse large cell lymphoma (DLCL) (e.g., diffuse large B-cell lymphoma (DLBCL)), follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphoma (including, but not limited to, mucosa-associated lymphoid tissue (MALT) lymphoma, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma,Burkitt's lymphoma, lymphoplasmacytic lymphoma (including but not limited to Waldenstrom's macroglobulinemia), immunoblastic large cell lymphoma, hairy cell leukemia (HCL), precursor B-cell lymphoblastic lymphoma and primary central nervous system (CNS) lymphoma, precursor T-cell lymphoblastic lymphoma / leukemia, T-cell NHL such as marginal T-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (including but not limited to mycosis fungoides, Sézary syndrome)), angioimmunoblastic T-cell lymphoma, extranodal Natural killer T-cell lymphoma, enteropathic T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, anaplastic large cell lymphoma, mixed leukemia / lymphoma of one or more of the above, multiple myeloma (MM), heavy chain disease (including but not limited to alpha chain disease, gamma chain disease, mu chain disease), immunocytic amyloidosis, kidney cancer (including but not limited to nephroblastoma, also known as Wilms' tumor, renal cell carcinoma), liver cancer (including but not limited to hepatocellular carcinoma (HCC), malignant hepatoma), lung cancer (bronchogenic carcinoma, non-small cell lung cancer (NSCLC) , squamous cell carcinoma (SLC), adenocarcinoma of the lung, Lewis lung carcinoma, pulmonary neuroendocrine tumors, typical carcinoid, atypical carcinoid, small cell lung carcinoma (SCLC), and large cell neuroendocrine carcinoma), myelodysplastic syndromes (MDS), myeloproliferative disorders (MPD), polycythemia vera (PV), essential thrombocythemia (ET), primary myelofibrosis (AMM), also known as myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic myelogenous leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES), ovarian cancer (cystadenocarcinoma, ovarian embryonal carcinoma, ovarian cyst ... stage cancer, ovarian adenocarcinoma), pancreatic cancer (including but not limited to pancreatic adenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), islet cell carcinoma), prostate cancer (including but not limited to prostate adenocarcinoma), skin cancer (including but not limited to squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC)), and soft tissue sarcoma (e.g., malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma),

[0156] In another embodiment, the present invention relates to a method for treating and / or preventing cancer, comprising the step of administering to a subject, preferably a human, in need thereof a therapeutically effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt or solvate thereof, wherein the cancer is benign monoclonal gammopathy, breast cancer (including, but not limited to, adenocarcinoma of the breast, papillary carcinoma of the breast, carcinoma of the breast, medullary carcinoma of the breast), hematopoietic cancer (e.g., acute lymphocytic leukemia (ALL) (including, but not limited to, B-cell ALL, T-cell ALL), acute myeloid leukemia (AML) (e.g., B-cell AML, , T-cell AML), chronic myeloid leukemia (CML) (e.g., B-cell CML, T-cell CML) and chronic lymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell CLL), lymphomas (B-cell HL, T-cell HL) such as Hodgkin's lymphoma (HL) and non-Hodgkin's lymphoma (NHL) (e.g., B-cell NHL such as diffuse large cell lymphoma (DLCL) (e.g., diffuse large B-cell lymphoma (DLBCL)), follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), mantle cell lymphoma (MCL), peripheral leukemia, Marginal zone B-cell lymphoma (including, but not limited to, mucosa-associated lymphoid tissue (MALT) lymphoma, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt's lymphoma, lymphoplasmacytic lymphoma (including, but not limited to, Waldenstrom's macroglobulinemia), immunoblastic large cell lymphoma, hairy cell leukemia (HCL), precursor B-cell lymphoblastic lymphoma and primary central nervous system (CNS) lymphoma, precursor T-cell lymphoblastic lymphoma / leukemia, marginal T-cell lymphoma (PTCL), etc. T-cell NHL (e.g., cutaneous T-cell lymphoma (CTCL) (including, but not limited to, mycosis fungoides, Sézary syndrome), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy-type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, anaplastic large cell lymphoma, mixed leukemia / lymphoma of one or more of the above listed, multiple myeloma (MM), heavy chain disease (including, but not limited to, alpha chain disease, gamma chain disease, mu chain disease), immunocytic amyloidosis, liver cancer (including, but not limited to, hepatocellular carcinoma (HCC), malignant liver cancer),The present invention is directed to a method in which the cancer is selected from the group consisting of lung cancer (bronchogenic carcinoma, non-small cell lung cancer (NSCLC), squamous cell lung carcinoma (SLC), adenocarcinoma of the lung, Lewis lung carcinoma, pulmonary neuroendocrine tumors, typical carcinoid, atypical carcinoid, small cell lung carcinoma (SCLC) and large cell neuroendocrine carcinoma), myelodysplastic syndromes (MDS), myeloproliferative disorders (MPD), prostate cancer (including but not limited to prostate adenocarcinoma),

[0157] In another embodiment, the present invention is directed to a method for treating and / or preventing cancer, comprising the step of administering to a subject, preferably a human, in need thereof a therapeutically effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt or solvate thereof, wherein the cancer is selected from the group consisting of prostate cancer, lung cancer, pancreatic cancer, breast cancer, ovarian cancer, cervical cancer, melanoma, B-cell chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL).

[0158] In another embodiment, the present invention is directed to a method for treating and / or preventing cancer, comprising the step of administering to a subject, preferably a human, in need thereof a therapeutically effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt or solvate thereof, wherein the cancer is multiple myeloma.

[0159] The compounds according to the invention or pharmaceutical compositions comprising said compounds may also have therapeutic application in combination with inhibitors of the PD1 / PDL1 immune checkpoint axis, e.g. immunomodulatory agents such as antibodies (or peptides) which bind to and / or inhibit the activity of PD-1 or the activity of PD-L1 and / or CTLA-4 or engineered chimeric antigen receptor T cells (CART) targeting tumor-associated antigens.

[0160] The compounds according to the invention or pharmaceutical compositions comprising said compounds may also be combined with radiotherapy or chemotherapy drugs (including but not limited to anti-cancer drugs) or any other medicinal agent administered to a subject having cancer to treat the cancer in said subject or to treat or prevent side effects associated with treating the cancer in said subject.

[0161] The compounds according to the invention or pharmaceutical compositions containing said compounds may also be combined with other agents that stimulate or enhance the immune response, such as, for example, vaccines.

[0162] In one embodiment, the present invention is directed to a method for treating and / or preventing cancer, wherein the cancer is selected from the cancers described herein, comprising administering to a subject (preferably a human) in need thereof a therapeutically effective amount of a combination or combined therapy; the combination or combined therapy comprising a compound of formula (I) of the present invention and one or more anti-cancer agents selected from the group consisting of: (a) immunomodulators (inhibitors of the PD1 / PDL1 immune checkpoint axis, e.g. antibodies (or peptides) which bind to and / or inhibit the activity of PD-1 or the activity of PD-L1 and / or CTLA-4; (b) genetically engineered chimeric antigen receptor T cells (CART) targeting tumor-associated antigens; (c) radiation therapy; (d) chemotherapy; and (e) agents that stimulate or enhance an immune response, such as a vaccine.

[0163] The present invention relates to compounds of formula (I) and their pharma- ceutically acceptable salts and solvates, for use as medicaments.

[0164] The present invention is directed to compounds of formula (I) and pharma- ceutically acceptable salts and solvates thereof for use in inhibiting MCL-1 activity.

[0165] Unless otherwise specified, the term "anti-cancer agent" as used herein is intended to include "anti-tumor cell proliferation agents" and "anti-neoplastic agents."

[0166] The present invention is directed to compounds of formula (I) and their pharma- ceutically acceptable salts and solvates thereof for use in treating and / or preventing the above mentioned diseases, preferably cancer.

[0167] The present invention is directed to compounds of formula (I) and their pharma- ceutically acceptable salts and solvates for treating and / or preventing the above mentioned diseases, preferably cancer.

[0168] The present invention is directed to compounds of formula (I) and their pharma- ceutically acceptable salts and solvates for the treatment and / or prevention, in particular for the treatment, of diseases as described herein, preferably cancer (e.g. multiple myeloma).

[0169] The present invention is directed to compounds of formula (I) and their pharma- ceutically acceptable salts and solvates for use in the treatment and / or prophylaxis of diseases as described herein, preferably cancer (e.g. multiple myeloma).

[0170] The present invention is directed to compounds of formula (I) and pharma- ceutically acceptable salts and solvates thereof for treating and / or preventing MCL-1 mediated diseases or conditions, preferably cancer, more preferably the cancers mentioned above (e.g. multiple myeloma).

[0171] The present invention is directed to compounds of formula (I) and their pharma- ceutically acceptable salts and solvates for use in the treatment and / or prophylaxis, in particular for use in the treatment, of MCL-1 mediated diseases or conditions, preferably cancer, more preferably cancer as mentioned above (e.g. multiple myeloma).

[0172] The present invention relates to compounds of formula (I) and their pharma- ceutically acceptable salts and solvates for the manufacture of a medicament.

[0173] The present invention relates to compounds of formula (I) and pharma- ceutically acceptable salts and solvates thereof for the manufacture of a medicament for inhibiting MCL-1.

[0174] The present invention relates to compounds of formula (I) and their pharma- ceutically acceptable salts and solvates for the manufacture of a medicament for the treatment and / or prevention, in particular for the treatment, of cancer, preferably the cancers described herein. More particularly, the cancer is a cancer that responds to the inhibition of MCL-1 (e.g. multiple myeloma).

[0175] The present invention is directed to compounds of formula (I) and their pharma- ceutically acceptable salts and solvates for the manufacture of a medicament for the treatment and / or prevention, in particular for the treatment, of any one of the above mentioned disease conditions.

[0176] The present invention is directed to compounds of formula (I) and their pharma- ceutically acceptable salts and solvates for the manufacture of a medicament for the treatment and / or prevention of any one of the above mentioned disease conditions.

[0177] The compounds of formula (I) and their pharma- ceutically acceptable salts and solvates may be administered to a subject, preferably a human, for the treatment and / or prevention of any one of the above mentioned diseases.

[0178] In view of the utility of the compounds of formula (I) and their pharma- ceutically acceptable salts and solvates, there is provided a method of treating a subject, preferably a mammal such as a human, suffering from any of the above-mentioned diseases or slowing the progression of any of the above-mentioned diseases in a subject, a human; or a method of preventing a subject, preferably a mammal such as a human, from suffering from any of the above-mentioned diseases.

[0179] The method comprises the administration, i.e. systemic or local, preferably oral or intravenous, more preferably oral, of an effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt or solvate thereof to a subject, such as a human.

[0180] Those skilled in the art will recognize that a therapeutically effective amount of a compound of the present invention is an amount that has sufficient therapeutic activity, and that this amount will vary depending, inter alia, on the type of disease, the concentration of the compound in the therapeutic formulation, and the condition of the patient. In one embodiment, the therapeutically effective daily amount may be about 0.005 mg / kg to 100 mg / kg of body weight.

[0181] The amount of a compound according to the invention, also referred to herein as active ingredient, required to achieve a therapeutic effect may vary individually, for example, depending on the particular compound, the route of administration, the age and condition of the recipient, and the particular disorder or disease being treated. The methods of the invention may also include administering the active ingredient in a dosing regimen of one to four doses taken per day. In these methods of the invention, the compounds according to the invention are preferably formulated prior to administration.

[0182] The present invention also provides a composition for treating and / or preventing the disorders mentioned herein, preferably the cancers described herein, said composition comprising a therapeutically effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt or solvate thereof and a pharma- ceutically acceptable carrier or diluent.

[0183] While it is possible for the active ingredient (e.g., a compound of the present invention) to be administered alone, it is preferable to administer it as a pharmaceutical composition. Thus, the present invention further provides a pharmaceutical composition comprising a compound according to the present invention together with a pharma- ceutically acceptable carrier or diluent. The carrier or diluent must be "acceptable" in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipient thereof.

[0184] The pharmaceutical compositions of the present invention can be prepared by any method known in the art of pharmacy, for example, as described in Gennaro et al., Remington's Pharmaceutical Sciences (1896). th ed., Mack Publishing Company, 1990; see for details, Part 8: Pharmaceutical preparations and their Manufacture).

[0185] The compounds of the invention may be administered alone or in combination with one or more additional therapeutic agents. Combination therapy includes administration of a single pharmaceutical formulation containing a compound of the invention and one or more additional therapeutic agents, and administration of a compound of the invention and each additional therapeutic agent in separate pharmaceutical formulations.

[0186] Thus, in one embodiment, the present invention is directed to a product further comprising a compound according to the invention as a first active ingredient and one or more anti-cancer agents as further additional active ingredients as a combined preparation for simultaneous, separate or sequential use in the treatment of patients suffering from cancer.

[0187] The one or more other anti-cancer agents and the compound according to the invention may be administered simultaneously (e.g., in separate compositions or unitary compositions) or sequentially in any order. In one embodiment, two or more compounds are administered within a period and / or in an amount and / or manner sufficient to ensure a beneficial or synergistic effect. It will be understood that the preferred method and order of administration, as well as the respective dosages and dosing schedules of each component of the combination, will vary depending on the particular other agent and compound of the invention being administered, their routes of administration, the particular condition, particularly the tumor, being treated, and the particular host being treated.

[0188] The following examples further illustrate the invention. EXAMPLES

[0189] Several methods for preparing the compounds of the present invention are described in the following examples. Unless otherwise specified, all starting materials were obtained from commercial suppliers and used without further purification, or could be synthesized by one of ordinary skill in the art by using well-known methods.

[0190] [Table 3]

[0191] [Table 4]

[0192] As will be appreciated by one of skill in the art, compounds synthesized using the protocols provided may contain residual solvents or small amounts of impurities.

[0193] Those skilled in the art will understand that, even if not explicitly mentioned in the following experimental protocols, typically after column chromatographic purification, the desired fractions are collected and the solvent is evaporated.

[0194] If stereochemistry is not indicated, this means that it is a mixture of stereoisomers, unless otherwise indicated or clear from the context.

[0195] Preparation of intermediates For intermediates used as crude materials or partially purified intermediates in the next reaction step, in some cases no molar amount for such intermediate in the next reaction step is mentioned, or instead an estimated molar amount or theoretical molar amount for such intermediate in the next reaction step is given in the reaction protocols described below.

[0196] Methyl (E)-2-(2-(3-bromo-4-chlorophenyl)hydrazono)butanoate (Intermediate 1) [ka] A solution of (3-bromo-4-chlorophenyl)hydrazine (4.655 g, 18.047 mmol) and methyl 2-oxobutanoate (1.02 equiv) in HCl (93 mL, 1.25 M in MeOH) was refluxed for 90 min. The reaction was cooled to room temperature and the volatiles were removed under reduced pressure to give 5.768 g of intermediate 1 as a brown oily residue that solidified within a few minutes. The crude material was used as is in the next step.

[0197] Methyl 4-bromo-5-chloro-3-methyl-1H-indole-2-carboxylate (Intermediate 2) [ka] A suspension of intermediate 1 (5.768 g, crude) in acetic acid (37 mL) was heated to 70° C. Sulfuric acid (4.81 mL, 5 equiv.) was added dropwise over 10 min (an exotherm occurred and a precipitate formed). After a further 15 min, the reaction was cooled to room temperature and then to 0° C. by adding ice. The solid precipitate was filtered and washed with water until the filtrate was of neutral pH. The solid was triturated with cold heptane / diisopropyl ether (8 / 2, 50 mL) to give an off-white solid. This solid was purified by preparative SFC (stationary phase: Chiralpak Daicel IG 20×250 mm, mobile phase: CO2, EtOH+0.4% i-PrNH2) to give intermediate 2 (1.745 g, 32%).

[0198] Methyl 5-chloro-4-(3-(((4-methoxybenzyl)oxy)methyl)-1,5-dimethyl-1H-pyrazol-4-yl)-3-methyl-1H-indole-2-carboxylate (Intermediate 3) [ka] Intermediate 2 (500 mg), 3-(((4-methoxybenzyl)oxy)methyl)-1,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (800 mg, 1.3 eq.), Pd2(dba)3 (76 mg, 0.05 eq.) and S-Phos (68 mg, 0.1 eq.) were weighed in a pressure tube under N2. Dioxane (10.5 mL) and saturated aqueous NaHCO3 (4.5 mL) were added and the mixture was heated at 100° C. for 2 h. The reaction was cooled to room temperature and diluted with EtOAc (40 mL) and water (40 mL). The organic layer was separated and the aqueous phase was extracted with EtOAc (40 mL). The combined organic layers were dried over MgSO4, filtered and evaporated. The crude mixture was purified by flash chromatography on silica gel (40 g, gradient: heptane 100% to heptane / EtOAc 4 / 6). Intermediate 3 (790 mg, 89%) was obtained as a yellowish oil that solidified on standing. Intermediate 3 was used as such in the next reaction step.

[0199] Methyl 5-chloro-4-(3-(hydroxymethyl)-1,5-dimethyl-1H-pyrazol-4-yl)-3-methyl-1H-indole-2-carboxylate (Intermediate 4) [ka] Trifluoromethanesulfonic acid (0.888 mL, 5 equiv.) was added to a solution of intermediate 3 (1080 mg) in DCM (25 mL). The reaction was stirred at room temperature for 1 h. The reaction was diluted with DCM (100 mL) and treated with saturated NaHCO3 (30 mL). The organic phase was separated and the aqueous phase was extracted with DCM (50 mL x 3). The combined organic layers were dried over MgSO4, filtered and evaporated. Intermediate 4 (625 mg, 89%) was obtained as a yellowish solid, which was used as such in the next step.

[0200] Methyl 1-(3-((tert-butyldimethylsilyl)oxy)propyl)-5-chloro-4-(3-(hydroxymethyl)-1,5-dimethyl-1H-pyrazol-4-yl)-3-methyl-1H-indole-2-carboxylate (Intermediate 5) [ka] Cesium carbonate (732 mg, 1.25 equiv.) was added to a solution of intermediate 4 (625 mg) in DMF (10 mL) under nitrogen atmosphere. (3-Bromopropoxy)(tert-butyl)dimethylsilane (0.458 mL, 1.1 equiv.) was added dropwise and the reaction was stirred at room temperature overnight. The reaction was diluted with EtOAc (100 mL) and water (50 mL). The organic layer was separated and washed with brine (2×30 mL). The combined aqueous layers were extracted with EtOAc (50 mL). The combined organic layers were dried over MgSO4, filtered and evaporated. The crude mixture was purified by flash chromatography on silica gel (40 g, gradient: heptane 100% to EtOAc 100%) to give intermediate 5 (360 mg, 38%) as a white solid.

[0201] Methyl 1-(3-((tert-butyldimethylsilyl)oxy)propyl)-5-chloro-4-(1,5-dimethyl-3-(((methylsulfonyl)oxy)methyl-1H-pyrazol-4-yl)-3-methyl-1H-indole-2-carboxylate (Intermediate 6) [ka] Mesyl chloride (0.12 mL, 2.5 equiv.) was added dropwise to a solution of intermediate 5 (320 mg) and triethylamine (0.256 mL, 3 equiv.) in DCM (10 mL) with stirring at 0° C. under nitrogen. The reaction was then warmed to room temperature and stirred at room temperature. Additional triethylamine (3 equiv.) and mesyl chloride (2.5 equiv.) were added and stirring was continued at room temperature for 1 h. The reaction mixture was diluted with DCM (10 mL) and treated with saturated aqueous NaHCO3 (5 mL). The organic phase was separated and the aqueous layer was extracted with DCM (10 mL). The combined organic layers were dried over MgSO4, filtered and evaporated to give intermediate 6 (368 mg, quantitative), which was used directly in the next step.

[0202] Methyl 1-(3-((tert-butyldimethylsilyl)oxy)propyl)-5-chloro-4-(3-(iodomethyl)-1,5-dimethyl-1H-pyrazol-4-yl)-3-methyl-1H-indole-2-carboxylate (Intermediate 7) [ka] Potassium iodide (1.021 g, 10 equiv.) was added to a solution of intermediate 6 (368 mg) in acetonitrile (5 mL). The reaction was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc (50 mL) and filtered through Dicalite®. Water (25 mL) was added to the filtrate and after some stirring the organic layer was separated. The aqueous layer was back extracted with EtOAc (25 mL). The combined organic layers were dried over MgSO4, filtered and evaporated to give intermediate 7 which was used directly in the next step.

[0203] Methyl 5-(((4-((tert-butyldimethylsilyl)oxy)naphthalen-2-yl)thio)methyl)-1-methyl-1H-pyrazole-3-carboxylate (Intermediate 8) [ka] Imidazole (258 mg, 1.4 equiv.) was added to a solution of methyl 5-(((4-hydroxynaphthalen-2-yl)thio)methyl)-1-methyl-1H-pyrazole-3-carboxylate (890 mg) and TBDMSCl (511 mg, 1.25 equiv.) in DMF (17.8 mL). The reaction was stirred at room temperature for 48 h. The reaction mixture was diluted with EtOAc (100 mL) and water (50 mL). The organic layer was separated and washed with brine (2×50 mL). The combined aqueous layers were extracted with EtOAc (50 mL). The combined organic layers were dried over MgSO4, filtered and evaporated. The crude mixture was purified by flash chromatography on silica gel (40 g, gradient: heptane 100% to heptane / EtOAc 6 / 4) to give intermediate 8 (1.24 g, quantitative).

[0204] 5-(((4-((tert-butyldimethylsilyl)oxy)naphthalen-2-yl)thio)methyl)-1-methyl-1H-pyrazol-3-yl)methanol (Intermediate 9) [ka] DIBALH (1M in heptane, 5.82 mL, 2.5 equiv.) was added dropwise to a solution of intermediate 8 in THF (40 mL) at 0° C. under nitrogen atmosphere and the reaction was stirred at 0° C. for 30 min. Additional DIBALH (1 equiv.) was added and the reaction mixture was stirred for an additional 10 min. The reaction was treated with wet THF (40 mL) and, after a few minutes, stirred with water (10 mL, initial dropwise addition). The mixture was allowed to warm to room temperature and then Celite® was added. After stirring for 5 min, the mixture was filtered and washed with EtOAc. The filtrate was treated with MgSO4, filtered and evaporated to give crude intermediate 9 (892 mg, 92%) as a colorless paste that solidified on standing. Intermediate 9 was used as is in the next step.

[0205] 5-(((4-((tert-butyldimethylsilyl)oxy)naphthalen-2-yl)thio)methyl)-3-(chloromethyl)-1-methyl-1H-pyrazole (Intermediate 10) [ka] Thionyl chloride (0.187 mL, 1.2 equiv.) was added dropwise to a solution of intermediate 9 (892 mg) in DCM (20 mL) with stirring at 0° C. under nitrogen atmosphere. The reaction was then allowed to warm to room temperature and stirred for 1 h. The reaction mixture was cooled to 0° C., diluted with DCM (20 mL) and quenched with a saturated aqueous solution of NaHCO3 (20 mL). The organic layer was separated and the aqueous layer was extracted with DCM (20 mL). The combined organic layers were dried over MgSO4, filtered and evaporated. Intermediate 10 (931 mg, quant.) was obtained as a colorless oil which was used without further purification.

[0206] S-((5-(((4-((tert-butyldimethylsilyl)oxy)naphthalen-2-yl)thio)methyl)-1-methyl-1H-pyrazol-3-yl)methyl)ethanethioate (Intermediate 11) [ka] Potassium thioacetate (295 mg, 1.2 equiv.) was added to a solution of intermediate 10 (931 mg) in DMF (10 mL) under nitrogen atmosphere. The reaction was stirred at room temperature for 1 h. The reaction mixture was diluted with EtOAc (50 mL) and water (30 mL). The aqueous layer was separated and the organic layer was washed with brine (2×30 mL). The combined aqueous layers were back-extracted with EtOAc (50 mL). The combined organic layers were dried over MgSO4, filtered and evaporated. The crude mixture was purified by flash chromatography on silica gel (40 g, gradient: heptane 100% to heptane / EtOAc 6 / 4) to give intermediate 11 (900 mg, 88% over two steps) as a colorless paste.

[0207] Methyl 1-(3-((tert-butyldimethylsilyl)oxy)propyl)-5-chloro-4-(3-((((5-(((4-hydroxynaphthalen-2-yl)thio)methyl)-1-methyl-1H-pyrazol-3-yl)methyl)thio)methyl)-1,5-dimethyl-1H-pyrazol-4-yl)-3-methyl-1H-indole-2-carboxylate (Intermediate 12) [ka] Potassium carbonate (170 mg, 2 equiv.) was added to a solution of intermediate 7 (387 mg, crude) and intermediate 11 (407 mg, 1.4 equiv.) in nitrogen-degassed MeOH (7 mL). The reaction mixture was stirred at room temperature for 2 h. The volatiles were removed under reduced pressure and the residue was partitioned between EtOAc (20 mL) and water (10 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (10 mL). The combined organic layers were dried over MgSO4, filtered and evaporated. The crude mixture was purified by flash column chromatography on silica gel (12 g, gradient: heptane 100% to EtOAc 100%) to give two batches of intermediate 12 (290 mg, impure; and 135 mg pure).

[0208] Methyl 5-chloro-4-(3-((((5-(((4-hydroxynaphthalen-2-yl)thio)methyl)-1-methyl-1H-pyrazol-3-yl)methyl)thio)methyl)-1,5-dimethyl-1H-pyrazol-4-yl)-1-(3-hydroxypropyl)-3-methyl-1H-indole-2-carboxylate (Intermediate 13) [ka] TBAF (1M in THF, 0.247 mL, 1.5 equiv.) was added dropwise to a solution of intermediate 12 (135 mg) in THF (5 mL) under nitrogen atmosphere. The reaction was stirred at room temperature for 16 h. Volatiles were removed under reduced pressure. The residue was dissolved in EtOAc (20 mL), washed with water (10 mL) and brine (10 mL), dried over MgSO4, filtered and evaporated. The crude mixture was purified by flash chromatography on silica gel (12 g, gradient: DCM 100% to DCM / MeOH 95 / 5) to give intermediate 13 (96 mg, 83% yield) as a white foamy solid.

[0209] Methyl 1 5 -Chloro-1 3 ,2 1 ,2 5 ,6 1 -Tetramethyl-1 1 H,2 1 H,6 1 H-10-Oxa-4,8-dithia-1(4,1)-indra-2(4,3),6(3,5)-dipyrazo-9(3,1)-naphthalene acyclotridecaphane-1 2 -Carboxylate (Intermediate 14: S a or R a ; one atropisomer, but absolute stereochemistry undetermined) (Intermediate 15:R a Or S a ; one atropisomer, but absolute stereochemistry undetermined) [ka] A solution of intermediate 13 (100 mg) and di-tert-butyl azodicarboxylate (65 mg, 2 eq.) in toluene (6 mL) and THF (0.4 mL) was added to a solution of triphenylphosphine (75 mg, 2 eq.) in toluene (4 mL) using a syringe pump (0.075 mL / min). The reaction mixture was stirred at room temperature overnight. The volatiles were removed under reduced pressure. The residue was dissolved in EtOAc (40 mL) and washed with water (20 mL) and brine (20 mL). The organic layer was dried over MgSO4, filtered and evaporated. The crude product was purified by chromatography on silica gel (40 g, gradient: DCM 100% to DCM / MeOH 95 / 5). The product was still contaminated with triphenylphosphine oxide, so to separate the atropisomers, the product was purified by preparative SFC (stationary phase: Chiralcel Diacel OJ 20×250 mm, mobile phase: CO2, EtOH+0.4% i-PrNH2) to give intermediate 14 (S a or R a atropisomer, 27 mg, 28%) and intermediate 15 (R a Or S a The atropisomer was obtained in an amount of 29 mg, 30%).

[0210] Methyl 1-(3-((tert-butyldimethylsilyl)oxy)propyl)-5-chloro-4-(1,5-dimethyl-3-(((2-nitrophenyl)sulfonamido)methyl-1H-pyrazol-4-yl)-3-methyl-1H-indole-2-carboxylate (Intermediate 16) [ka] A solution of di-tert-butyl azodicarboxylate (78 mg, 2 eq.) in DCM (1 mL) was added dropwise to a suspension of intermediate 5 (88 mg), 2-nitrobenzenesulfonamide (38 mg, 1.1 eq.) and triphenylphosphine (89 mg, 2 eq.) in DCM (2.5 mL) at room temperature under nitrogen atmosphere with stirring. After 15 min, the reaction mixture was directly loaded onto a silica gel column (12 g) and the product was purified by eluting with a gradient from heptane 100% to heptane / EtOAc 1 / 1. Intermediate 16 (120 mg, quant.) was obtained as a yellow solid.

[0211] 3-(((tert-Butyldiphenylsilyl)oxy)methyl)-5-(chloromethyl)-1-methyl-1H-pyrazole (Intermediate 17) [ka] Thionyl chloride (270 μL, 1.2 equiv.) was added dropwise to a solution of (3-(((tert-butyldiphenylsilyl)oxy)methyl)-1-methyl-1H-pyrazol-5-yl)methanol (1.18 g, 3.1 mmol) in DCM with stirring at 0° C. under a nitrogen atmosphere. The reaction was then allowed to warm to room temperature and stirred for 45 min. The reaction was cooled to 0° C., diluted with DCM (30 mL) and quenched with saturated aqueous NaHCO3 (20 mL). The organic layer was separated and the aqueous layer was extracted with DCM (30 mL). The combined organic layers were dried over MgSO4, filtered and evaporated to give intermediate 17 (1.17 g) as a colorless oil which was used without further purification.

[0212] 3-(((3-((tert-butyldiphenylsilyl)oxy)methyl)-1-methyl-1H-pyrazol-5-yl)methyl)thio)naphthalen-1-ol (Intermediate 18) [ka] K2CO3 was added to a solution of intermediate 17 (820 mg, 2.05 mmol) and 3-(acetylthio)naphthalen-1-yl acetate (588 mg, 2.26 mmol) in MeOH. The reaction mixture was stirred at room temperature for 1 h. The mixture was concentrated in vacuo. The residue was dissolved in EtOAc (40 mL) and water (25 mL). The organic layer was separated and washed with water (15 mL) and brine (15 mL). The combined aqueous layers were back-extracted with EtOAc (30 mL). The combined organic layers were dried over MgSO4, filtered and evaporated. The residue was purified by flash chromatography on silica gel (24 g, gradient: heptane 100% to heptane / EtOAc 6 / 4). Yield: intermediate 18 (825 mg; 74% yield) as a pink solid.

[0213] 3-(((tert-butyldiphenylsilyl)oxy)methyl)-5-(((4-((4-methoxybenzyl)oxy)naphthalen-2-yl)thio)methyl)-1-methyl-1H-pyrazole (Intermediate 19) [ka] K2CO3 (423 mg, 2 equiv.) was added portionwise to a solution of intermediate 18 (825 mg, 1.53 mmol) and 4-methoxybenzyl chloride (260 μL, 1.25 equiv.) in DMF (8 mL) under nitrogen atmosphere. The reaction was stirred at room temperature for 3 h. Then, more 4-methoxybenzyl chloride (207 μL, 1 equiv.) was added and stirring was continued at room temperature for 2 h. The reaction was diluted with EtOAc (50 mL) and water (20 mL). The organic layer was separated and washed with brine (2×20 mL). The combined aqueous layers were back-extracted with EtOAc (30 mL). The combined organic layers were dried over MgSO4, filtered and evaporated. The residue was purified by flash chromatography on silica gel (40 g, gradient: heptane 100% to heptane / EtOAc 6 / 4). Intermediate 19 (950 mg) was obtained as a brownish paste, which was used without further purification.

[0214] 5-(((4-((4-Methoxybenzyl)oxy)naphthalen-2-yl)thio)methyl)-1-methyl-1H-pyrazol-3-yl)methanol (Intermediate 20) [ka] TBAF (2.16 mL, 1.5 equiv., 1M in THF) was added dropwise to a solution of intermediate 19 (950 mg) in anhydrous THF under nitrogen atmosphere. The reaction was stirred at room temperature for 3 h. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between EtOAc (60 mL) and saturated aqueous NH4Cl (30 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (30 mL). The combined organic layers were dried over MgSO4, filtered and evaporated. The residue was purified by flash chromatography on silica gel (40 g, gradient from 100% heptane to 100% EtOAc). A second purification was performed by flash chromatography on silica gel (120 g, gradient: DCM 100% to DCM / MeOH 96 / 4) to give intermediate 20 (362 mg, 60%) as a white solid.

[0215] Methyl 1-(3-((tert-butyldimethylsilyl)oxy)propyl)-5-chloro-4-(3-(((N-((5-(((4-((4-methoxybenzyl)oxy)naphthalen-2-yl)thio)methyl)-1-methyl-1H-pyrazol-3-yl)methyl)-2-nitrophenyl)sulfonamido)methyl)-1,5-dimethyl-1H-pyrazol-4-yl)-3-methyl-1H-indole-2-carboxylate (Intermediate 21) [ka] A solution of di-tert-butyl azodicarboxylate (81 mg, 1.5 eq.) in DCM (2 mL) was added dropwise over 15 min to a suspension of intermediate 16 (165 mg), intermediate 20 (108 mg, 1.1 eq.) and triphenylphosphine (92 mg, 1.5 eq.) in DCM (2 mL) with stirring under nitrogen atmosphere at room temperature. After 15 min, additional triphenylphosphine (18 mg, 0.3 eq.) and di-tert-butyl azodicarboxylate (16 mg, 0.3 eq.) in DCM (0.5 mL) were added dropwise. The solvent was evaporated and the residue was purified by flash chromatography on silica gel (40 g, gradient: heptane 100% to heptane / EtOAc 2 / 8) to give intermediate 21. After combination with other batches, a total of 480 mg of intermediate 21 was obtained, which was used directly in the next reaction step.

[0216] Methyl 5-chloro-1-(3-hydroxypropyl)-4-(3-(((N-((5-(((4-((4-methoxybenzyl)oxy)naphthalen-2-yl)thio)methyl)-1-methyl-1H-pyrazol-3-yl)methyl)-2-nitrophenyl)sulfonamido)methyl)-1,5-dimethyl-1H-pyrazol-4-yl)-3-methyl-1H-indole-2-carboxylate (Intermediate 22) [ka] TBAF (452 ​​μL, 1.1 eq., 1M in THF) was added dropwise to a solution of intermediate 21 (455 mg) in anhydrous THF under nitrogen atmosphere at room temperature. After stirring for 15 min, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc (50 mL) and washed with water (25 mL) and brine (25 mL). The organic layer was dried over MgSO4, filtered and evaporated. The residue was purified by flash column chromatography on silica gel (24 g, gradient: DCM 100% to DCM / MeOH 95 / 5) to give intermediate 22 (418 mg, quantitative) as a foamy solid.

[0217] Methyl 5-chloro-4-(3-(((N-((5-(((4-hydroxynaphthalen-2-yl)thio)methyl)-1-methyl-1H-pyrazol-3-yl)methyl)-2-nitrophenyl)sulfonamido)methyl)-1,5-dimethyl-1H-pyrazol-4-yl)-1-(3-hydroxypropyl)-3-methyl-1H-indole-2-carboxylate (Intermediate 23) [ka] Trifluoromethanesulfonic acid (156 μL, 5 equiv.) was added dropwise to a solution of intermediate 22 (350 mg) in anisole (10 mL) and stirred at 0° C. The reaction was stirred at 0° C. for 15 min. The reaction mixture was diluted with DCM (30 mL) and treated with saturated aqueous NaHCO3 (20 mL). The organic phase was separated and the aqueous layer was extracted with DCM (10 mL). The combined organic layers were dried over MgSO4, filtered and evaporated. The residue was purified by flash column chromatography on silica gel (40 g, gradient: DCM 100% to DCM / MeOH 95:5) to give intermediate 23 (175 mg) as a foamy white solid.

[0218] Methyl 15-chloro-13,21,25,61-tetramethyl-4-((2-nitrophenyl)sulfonyl)-11H,21H,61H-10-oxa-8-thia-4-aza-1(4,1)-indra-2(4,3),6(3,5)-dipyrazo-9(3,1)-naphthalene acyclotridecaphane-12-carboxylate (Intermediate 24) [ka] A solution of intermediate 23 and di-tert-butyl azodicarboxylate (185 mg, 4 equiv.) in toluene (6 mL) and THF (0.6 mL) was added using a syringe pump (0.1 mL / min) to a stirred solution of triphenylphosphine (210 mg, 4 equiv.) in toluene (6 mL) at 70° C. Once the addition was complete, the reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel (40 g, gradient: DCM 100% to DCM / MeOH 98 / 2) to give intermediate 24 (95 mg, 55%).

[0219] Methyl 15-chloro-13,21,25,61-tetramethyl-11H,21H,61H-10-oxa-8-thia-4-aza-1(4,1)-indra-2(4,3),6(3,5)-dipyrazo-9(3,1)-naphthalene acyclotridecaphane-12-carboxylate (Intermediate 25) [ka] Thiophenol (57 μL, 5 eq.) was added dropwise to a suspension of intermediate 24 and K2CO3 (77 mg, 5 eq.) in acetonitrile under nitrogen atmosphere. The reaction was stirred at room temperature overnight. Further thiophenol (57 μL, 5 eq.) and K2CO3 (77 mg, 5 eq.) were added to the reaction mixture, which was stirred at room temperature for 30 min. Additional thiophenol (28 μL, 2.5 eq.) and K2CO3 (39 mg, 2.5 eq.) were added and the reaction mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with DCM (20 mL) and Celite® was added. The mixture was filtered over Celite® and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (24 g, gradient: DCM 100% to DCM / MeOH 90 / 10) to give intermediate 25 (48 g, 64%).

[0220] Methyl 15-chloro-13,21,25,61,4-pentamethyl-11H,21H,61H-10-oxa-8-thia-4-aza-1(4,1)-indola-2(4,3),6(3,5)-dipyrazo-9(3,1)-naphthalene acyclotridecaphane-12-carboxylate [ka] Formaldehyde (16 μL, 3 equiv., 37% in water) was added to a solution of intermediate 25 (48 mg) and acetic acid (12 μL, 3 equiv.) in DCM (0.7 mL) at room temperature. Sodium triacetoxyborohydride (45 mg, 3 equiv.) was then added and the reaction mixture was stirred at room temperature for 1 h. The reaction was quenched with saturated aqueous NaHCO3 (2.5 mL) and diluted with water (2.5 mL) and DCM (10 mL). The organic phase was separated and the aqueous layer was extracted with DCM (2×10 mL). The combined organic layers were dried over MgSO4, filtered and evaporated. The residue was purified by flash column chromatography on silica gel (24 g, gradient: DCM 100% to DCM / MeOH 93 / 7) to give intermediate 26 (mixture of atropisomers) as a white solid (30 mg, 61% yield).

[0221] Another batch of intermediate 26 was prepared in the same manner and subsequently separated into its atropisomers by preparative SFC (stationary phase: Chiralpak Daicel IG 20×250 mm, mobile phase: CO2, iPrOH+0.4% i-PrNH2) to give intermediate 27 (R a Or S a atropisomers) and intermediate 28 (S a or R a atropisomers) were obtained.

[0222] Intermediate 29 [ka] 3-(Hydroxymethyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-carboxylic acid ethyl ester [847139-28-0] (5.2 g, 20.45 mmol) was dissolved in anhydrous DMF (60 mL) under nitrogen atmosphere. Imidazole (2.088 g, 1.5 eq.) and DMAP (0.25 g, 0.1 eq.) were added. TBDPSCl (6.91 mL, 1.3 eq.) was added slowly and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc (250 mL) and water (200 mL). The organic layer was separated and washed with brine (3×100 mL). The combined aqueous layers were extracted with EtOAc (150 mL). The combined organic layers were dried over MgSO4, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (120 g, gradient: heptane 100% to heptane / EtOAc 8 / 2) to give intermediate 29 (11.56 g, yield: 97%) as a colorless paste.

[0223] Intermediate 30 [ka] LiAlH4 (2M in THF, 10.97 mL, 1.1 equiv.) was added dropwise to a solution of intermediate 29 (9.826 g, 19.94 mmol) in THF (80 mL) with stirring at 0° C. under nitrogen atmosphere. After 15 min, the reaction mixture was treated with wet THF (25 mL), then water (5 mL, added dropwise), then warmed to room temperature. Celite, then MgSO4 and EtOAc were added. After stirring for 5 min, the suspension was filtered and washed with EtOAc. The filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (120 g, gradient: heptane 100% to heptane / EtOAc 1 / 1) to give intermediate 30 (8.54 g, yield: 95%) as a colorless paste.

[0224] Intermediate 31 [ka] MsCl (1.84 mL, 1.25 equiv.) was added dropwise to a solution of intermediate 30 (8.54 g, 18.95 mmol) and Et3N (3.95 mL, 1.5 equiv.) in THF (85 mL) with stirring under nitrogen atmosphere at 0° C. The reaction mixture was then warmed to room temperature and stirred at room temperature for 1 h. A solution of KSAc (3.246 g, 1.5 equiv.) in DMF (85 mL) was added and stirring was continued at room temperature for 3 h. The reaction mixture was diluted with EtOAc (250 mL) and water (200 mL). The aqueous layer was separated and the organic layer was washed with brine (3×150 mL). The combined aqueous layers were back-extracted with EtOAc (200 mL). The combined organic layers were dried over MgSO4, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (120 g, gradient: heptane 100% to heptane / EtOAc 8 / 2) to give intermediate 31 (8.78 g, 91%) as a yellow paste.

[0225] Intermediate 32 [ka] A solution of intermediate 7 (5.34 g, 1.2 equiv.) and intermediate 31 (3.593 g, 7.06 mmol) in anhydrous MeOH (86 mL) was placed in a round bottom flask. The solution was degassed and backfilled with nitrogen three times. The reaction mixture was then cooled to 0° C. and K2CO3 (1.952 g, 2 equiv.) was added. The resulting mixture was degassed and backfilled with nitrogen twice, then warmed to room temperature and stirred under a stream of nitrogen for 3 h. The reaction mixture was concentrated in vacuo. EtOAc and water were added to the resulting residue. The layers were separated and the aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered and evaporated to give intermediate 32 (7.47 g, 98%) as an orange sticky foam, which was used without further purification.

[0226] Intermediate 33 [ka] TBAF (1M in THF, 11.1 mL, 1.6 equiv.) was added to a stirred solution of intermediate 32 (7.47 g, 6.94 mmol) in anhydrous THF (130 mL) under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 2.5 h, after which additional TBAF (1M in THF, 8 mL, 1.15 equiv.) was added. After stirring for 1 h, the solvent was evaporated. The residue was dissolved in EtOAc, washed with water, then with brine, dried over MgSO4, filtered and evaporated. The residue was purified by flash column chromatography (silica, MeOH in DCM 0 / 100 to 5 / 95) to give intermediate 33 (3.51 g, yield: 82%) as a pale yellow solid.

[0227] Intermediate 34 [ka] DIPEA (282 μL, 4 equiv.) followed by MsO (283 mg, 4 equiv.) was added to a solution of intermediate 33 (250 mg, 0.406 mmol) in THF (14 mL) and cooled to 0° C. Once the addition was complete, the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was then cooled to 0° C. before NaI (304 mg, 5 equiv.) was added. After 30 min, the reaction was allowed to warm to room temperature and stirred at this temperature for 4 h. The reaction mixture was diluted with EtOAc (30 mL), washed with saturated aqueous sodium thiosulfate (25 mL), saturated NH4Cl (25 mL) and brine (25 mL), dried over MgSO4, filtered and concentrated under reduced pressure (bath temperature: 30° C. to prevent decomposition) to give intermediate 34 (380 mg, 66% yield) as a colorless oil, which was used without further purification.

[0228] Intermediate 35 [ka] Intermediate 34 (380 mg, 0.378 mmol) was dissolved in a mixture of MeOH (17 mL) and THF (5 mL). The reaction mixture was degassed and backfilled with nitrogen twice. Ethanethiolic acid, S-[4-(acetyloxy)-2-naphthalenyl] ester [2143010-96-0] (98 mg, 1 eq.) and PPh3 (10 mg, 0.1 eq.) were added to the mixture, which was degassed and backfilled with nitrogen twice. Once all the reagents were in solution, the mixture was cooled to 0° C., after which K2CO3 (130 mg, 2.5 eq.) was added. The reaction mixture was then degassed and backfilled with nitrogen twice. The reaction mixture was stirred at 0° C. for 1 h. The reaction mixture was diluted with DCM (30 mL) and water (20 mL). The layers were separated and the aqueous layer was extracted with DCM (30 mL). The combined organic layers were washed with saturated aqueous NH4Cl (20 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (heptane:EtOAc - 3:1 to 1:3) to give intermediate 35 (160 mg, yield: 44%) as a yellow foam.

[0229] Intermediate 36 [ka] Intermediate 35 (156 mg, 0.164 mmol) was dissolved in ACN (3 mL). The resulting solution was added via syringe pump (0.02 mL / min) to a solution of K2CO3 (45 mg, 2 equiv.) in ACN (3 mL) at 82 °C. After the addition was complete, the reaction mixture was concentrated under reduced pressure to give a yellow oil. The oil was purified by flash column chromatography on silica gel (heptane:EtOAc - 1:0 to 1:1) to give intermediate 36 (107 mg, yield: 82%) as a clear oil that solidified on standing.

[0230] Intermediate 37 and Intermediate 38 [ka] HCl in MeOH (1.25 M, 5 mL, 50 equiv.) was added to a solution of intermediate 36 (100 mg, 0.126 mmol) in THF (5 mL). The reaction mixture was stirred at room temperature for 4 h. The reaction mixture was concentrated under reduced pressure to give a white solid. The white solid was purified by preparative SFC (stationary phase: Chiralpak Diacel AD 20×250 mm, mobile phase: CO2, EtOH+0.4% i-PrNH2) to give intermediate 37 (35 mg, yield: 39%) and intermediate 38 (34 mg, yield: 38%) as a clear oil that solidified on standing.

[0231] Intermediate 39 [ka] A mixture of intermediate 2 (37.4 g, 123.6 mmol), (3-bromopropoxy)-tert-butyldimethylsilane [89031-84-5] (37.56 g, 1.2 equiv.) and K2CO3 (51.25 g, 3 equiv.) in ACN (300 mL) was stirred at 80 °C overnight. The reaction mixture was cooled to room temperature and filtered. The filter cake was washed with EtOAc (100 mL). The filtrate was concentrated and the residue was purified by column chromatography on silica gel (eluent: petroleum ether / EtOAc 100 / 0 to 10 / 90) to give intermediate 39 (42 g, 71%) as a red gum.

[0232] Intermediate 40 [ka] Acetone (37 μL, 4 equiv.) and AcOH (14 μL, 2 equiv.) were added to a solution of intermediate 25 (83 mg, 0.124 mmol) in DCE (2 mL) in a sealed tube. The reaction mixture was stirred at room temperature for 20 min. NaBH(OAc)3 (53 mg, 2 equiv.) was added and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with DCM and washed with a saturated aqueous solution of Na2CO3. The organic layer was dried over MgSO4, filtered and evaporated to give intermediate 40 (61 mg, yield: 69%) as an oil.

[0233] Intermediate 41 and Intermediate 42 [ka] Under nitrogen atmosphere, iodoethane (40 μL, 2.51 equiv.) was added to a suspension of intermediate 38 (140 mg, 0.197 mmol) and Cs2CO3 (193.3 mg, 3 equiv.) in DMF (3 mL) in a sealed tube. The reaction mixture was stirred at room temperature for 4.5 h. Water (10 mL) was added and the mixture was extracted with EtOAc (20 mL). The layers were separated and the aqueous layer was further extracted with EtOAc (10 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and evaporated. The residue was purified by flash column chromatography on silica gel (DCM:MeOH - 100 / 0 to 95 / 5). The resulting mixture was purified by preparative SFC (stationary phase: Chiralcel Diacel OJ 20×250 mm, mobile phase: CO, EtOH+0.4% i-PrNH) to give intermediate 41 (49.1 mg, 35% yield) and intermediate 42 (62 mg, 45% yield).

[0234] Intermediate 43 and Intermediate 44 [ka] Under nitrogen atmosphere, 2-bromopropane (67 μL, 2.63 equiv.) was added to a suspension of intermediate 38 (200 mg, 0.28 mmol) and Cs2CO3 (278.7 mg, 3 equiv.) in DMF (4.4 mL) in a sealed tube. The reaction mixture was stirred for 16 h at room temperature. Water (15 mL) was added and the mixture was extracted with EtOAc (30 mL). The layers were separated and the aqueous layer was further extracted with EtOAc (15 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and evaporated. The residue was purified by flash column chromatography on silica gel (DCM:MeOH - 100 / 0 to 95 / 5) to give intermediate 43 (93 mg, yield: 46%) and intermediate 44 (116 mg, yield: 58%), both as colorless oils.

[0235] Intermediate 45 [ka] Lithium borohydride (32.2 g, 4 equiv.) was slowly added to a solution of 1H-pyrazole-3-carboxylic acid, 4-bromo-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-, ethyl ester [2246368-58-9] (130 g, 369.7 mmol) in 2-Me-THF (1 L) at 0° C. The reaction mixture was allowed to warm to room temperature and continued to stir at room temperature overnight. The reaction was quenched by addition of water (800 mL). The mixture was extracted with EtOAc (800 mL×2). The combined organic layers were washed with brine (500 mL), dried over Na2SO4, filtered and evaporated to give intermediate 45 (105 mg, yield: 94%) as a white solid.

[0236] Intermediate 46 [ka] DMAP (16.28 g, 0.4 equiv.) and Et3N (92.38 mL, 2 equiv.) were added to a solution of intermediate 45 (100 g, 333.2 mmol) in THF (1 L). TBDMSCl (75.3 g, 1.5 equiv.) was added at room temperature and the reaction mixture was stirred for 16 h. The reaction was quenched by addition of saturated aqueous NaHCO3 (800 mL) and the mixture was extracted with EtOAc (1 L x 2). The combined organic layers were washed with brine (800 mL), dried over Na2SO4, filtered and evaporated. The residue was purified by column chromatography on silica gel (petroleum ether / EtOAc, 100 / 0 to 30 / 70) to give intermediate 46 (130 g, yield: 94%) as a colorless oil.

[0237] Intermediate 47 [ka] BuLi (104.55 mL, 1 equiv.) was slowly added to a solution of intermediate 46 (108 g, 261.4 mmol) in THF (1 L) under nitrogen atmosphere at -78 °C, and the reaction mixture was stirred at -78 °C for 1 h. Then, 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (97.2 g, 2 equiv.) was slowly added, and the reaction mixture was stirred at room temperature for 2 h. Saturated aqueous NH4Cl (800 mL) was slowly added to quench the reaction. The mixture was extracted with EtOAc (1 L x 2). The combined organic layers were washed with brine (800 mL), dried over Na2SO4, filtered and evaporated to give intermediate 47 (140 g, presumed quantitative) as a yellow oil.

[0238] Intermediate 48 [ka] TBAF (1M in THF, 192.4 mL, 1.2 equiv.) was added dropwise to a solution of intermediate 47 (70 g, 160 mmol) in DCM (700 mL) at room temperature under nitrogen atmosphere. The reaction mixture was stirred at room temperature overnight. The reaction mixture was added to a stirred aqueous solution of saturated NaHCO3 (500 mL) and the mixture was extracted with EtOAc (700 mL x 2). The combined organic layers were washed with brine (500 mL), dried over Na2SO4, filtered and evaporated. The residue was purified by column chromatography on silica gel (petroleum ether / EtOAc, 100 / 0 to 50 / 50) to give intermediate 48 (35 g, yield: 62%) as a white solid.

[0239] Intermediate 49 [ka] K2CO3 (6.9 g, 2 equiv.) was added to a solution of intermediate 39 (12 g, 24.9 mmol) and intermediate 48 (9.6 g, 1.2 equiv.) in water (40 mL) and dioxane (200 mL). Pd(amphos)Cl2[887919-35-9] (0.8 g, 0.05 equiv.) was added under nitrogen atmosphere and the reaction mixture was stirred at 60 °C for 2 h. Water (40 mL) was added to the mixture and extracted with EtOAc (60 mL x 2). The combined organic layers were washed with brine, dried over Na2SO4, filtered and evaporated. The residue was purified by column chromatography on silica gel (petroleum ether / EtOAc, 100 / 0 to 60 / 40) to give intermediate 49 (15 g, yield: 99%) as a yellow solid.

[0240] Intermediate 50 [ka] A solution of intermediate 49 (23 g, 37.8 mmol) and 2-nitrobenzenesulfonamide (11.48 g, 1.5 equiv.) was prepared in DCM (150 mL) under nitrogen atmosphere and cooled to 0° C. To this solution was added DTBAD (13.1 g, 1.5 equiv.) and PPh3 (14.9 g, 1.5 equiv.). The reaction mixture was stirred at room temperature for 3 h. The solvent was evaporated and the residue was purified by flash column chromatography on silica gel (petroleum ether / EtOAc 100 / 0 to 50 / 50) to give intermediate 50 (24.6 g, 83% yield) as a yellow liquid.

[0241] Intermediate 51 [ka] Imidazole (6.64 g, 3 equiv.) was added to a solution of 5-[[(4-hydroxy-2-naphthalenyl)thio]methyl]-1-methyl-1H-pyrazole-3-carboxylic acid methyl ester [2245716-34-9] (11 g, 32.5 mmol) and TBDMSCl (9.8 g, 2 equiv.) in DCM (75 mL). The reaction mixture was stirred at room temperature for 16 h. The reaction was quenched by addition of saturated aqueous NH4Cl (20 mL) and the mixture was extracted with DCM (30 mL x 2). The combined organic layers were dried over Na2SO4, filtered and evaporated. The crude product was purified by column chromatography on silica gel (petroleum ether / EtOAc, 100 / 0 to 30 / 70) to give intermediate 51 (14 g, yield: 97%) as a white solid.

[0242] Intermediate 52 [ka] DIBAL-H (1M solution in toluene, 28.5 mL, 1.8 equiv.) was slowly added to a solution of intermediate 51 (7 g, 15.8 mmol) in THF (100 mL). The reaction mixture was stirred at room temperature for 2 h. The reaction was quenched by addition of water (10 mL) at 0° C., followed by addition of 10% aqueous NaOH (10 mL). MgSO4 (30 g) was added and the mixture was stirred at room temperature for 15 min. The solid was filtered and washed with EtOAc (100 mL). The filtrate was evaporated. The residue was purified by column chromatography on silica gel (petroleum ether / EtOAc, 100 / 0 to 20 / 80) to give intermediate 52 (5.8 g, yield: 88%) as a white solid.

[0243] Intermediate 53 [ka] Intermediate 50 (24.6 g, 31.5 mmol) and intermediate 52 (15.6 g, 1.2 equiv.) in DCM (250 mL) were prepared under nitrogen atmosphere and cooled to 0° C. Then, DTBAD (10.8 g, 1.5 equiv.) and PPh3 (12.4 g, 1.5 equiv.) were added and the reaction mixture was stirred at room temperature for 16 h. The solvent was evaporated and the residue was purified by flash column chromatography on silica gel (petroleum ether / EtOAc 100 / 0 to 60 / 40) to give intermediate 53 (32 g, yield: 76%) as a yellow liquid.

[0244] Intermediate 54 [ka] TBAF (1M in THF, 27.1 mL, 3 equiv.) was added to a solution of intermediate 53 (12 g, 9 mmol) in THF (80 mL). The reaction mixture was stirred at room temperature for 16 h. EtOAc (100 mL) was added and the mixture was washed with water (50 mL×2). The organic layer was washed with brine (50 mL), dried over Na2SO4, filtered and evaporated. The residue was purified by column chromatography on silica gel (petroleum ether / EtOAc, 100 / 0 to 0 / 100) to give intermediate 54 (11.7 g, yield: 87%) as a yellow liquid.

[0245] Intermediate 55 [ka] DTBAD (0.9 g, 3 equiv.) was added to a solution of intermediate 54 (2 g, 1.35 mmol) and PPh3 (1 g, 3 equiv.) in DCM (80 mL) under nitrogen atmosphere at 0 °C. The reaction mixture was stirred at room temperature for 16 h. The solvent was evaporated and the residue was purified by flash column chromatography on silica gel (petroleum ether / EtOAc 100 / 0 to 20 / 80) to give intermediate 55 (2 g, yield: 66%) as a yellow liquid.

[0246] Intermediate 56 [ka] Thiophenol (10 g, 6.7 equiv.) was added to a solution of intermediate 55 (20.7 g, 13.6 mmol) and K2CO3 (5.6 g, 3 equiv.) in ACN (150 mL). The reaction mixture was stirred at room temperature for 24 h. More thiophenol (6.5 g, 4.4 equiv.) was added and the reaction mixture was stirred at room temperature for another 48 h. Water (40 mL) was added and the mixture was extracted with EtOAc (80×2 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated. The residue was purified by column chromatography on silica gel (DCM / MeOH, 100 / 0 to 90 / 10) to give intermediate 56 (5.4 g, yield: 44%) as a white solid.

[0247] Intermediate 57 [ka] NaBH3CN (100 mg, 3 equiv.) was added to a solution of intermediate 56 (470 mg, 0.528 mmol) and paraformaldehyde (238 mg, 5 equiv.) in MeOH (8 mL). The reaction mixture was stirred at room temperature for 3 h. The reaction was quenched by addition of water (20 mL) and the mixture was extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine, dried over Na2SO4, filtered and evaporated. The residue was purified by column chromatography on silica gel (DCM / MeOH, 100 / 0 to DCM / MeOH 90 / 10) to give intermediate 57 (400 mg, yield: 80%) as a yellow solid.

[0248] Intermediate 58 and Intermediate 59 [ka] HCl (4M in dioxane, 935 μL, 10 equiv.) was added to a solution of intermediate 57 (350 mg, 0.374 mmol) in dioxane (3 mL). The reaction mixture was stirred at room temperature for 3 h. The solvent was evaporated and the residue was purified by SFC (column: Daicel Chiralpak AD (250 mm×30 mm, 10 μm); mobile phase: A:CO2, B:(0.1% NH3.H2O)iPrOH, A:B=60:40) to give intermediate 58 (85 mg, yield: 34%) and intermediate 59 (80 mg, yield: 32%).

[0249] Intermediate 60 [ka] Ms2O (2.775 g, 2 equiv.) was slowly added to a solution of intermediate 49 (4.8 g, 7.966 mmol) and DIPEA (3 g, 3 equiv.) in THF (80 mL) at 0° C. The reaction mixture was stirred at room temperature for 24 h. LiI (3.2 g, 3 equiv.) was then added to the reaction mixture at 0° C. and stirring was continued at room temperature for 24 h. The reaction was quenched by addition of water (40 mL) and the mixture was extracted with DCM (80 mL×2). The combined organic layers were evaporated to give intermediate 60 (5.7 g, yield: 73%), which was used without further purification.

[0250] Intermediate 61 [ka] K2CO3 (2.435 g, 3 equiv.) and PPh3 (154 mg, 0.1 equiv.) were added to a solution of intermediate 60 (5.7 g, 5.873 mmol) and ethanethiolic acid, S-[[5-[[[4-(acetyloxy)-2-naphthalenyl]thio]methyl]-1-methyl-1H-pyrazol-3-yl]methyl] ester [2245716-36-1] (3.835 g, 1.5 equiv.) in MeOH (100 mL). The reaction mixture was stirred at room temperature for 16 h. The solvent was evaporated and the residue was partitioned between water (40 mL) and EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc (50 mL x 2). The combined organic layers were dried over Na2SO4, filtered and evaporated to give intermediate 61 (8 g, yield: 63%), which was used without further purification.

[0251] Intermediate 62 [ka] TBAF (1M in THF, 11.2 mL, 3 equiv.) was added to a solution of intermediate 61 (8 g, 41% purity, 3.731 mmol) in THF (50 mL) and the reaction mixture was stirred at room temperature for 16 h. EtOAc (60 mL) was added to the mixture and the solution was washed with water (40 mL×2) and brine (20 mL), dried over Na2SO4, filtered and evaporated. The residue was purified by flash column chromatography on silica gel (petroleum ether / EtOAc 100 / 0 to 0 / 100). The isolated product was purified again by preparative HPLC (column: YMC-Triart Prep C18 150×40 mm×7 μm, gradient: water (0.04% NH3.H2O+10 mM NH4.HCO3) / ACN 40 / 60 to 30 / 70) to give intermediate 62 (2.5 g, yield: 84%) as a white solid.

[0252] Intermediate 63 [ka] DIBAD (2.42 g, 3 equiv.) was added to a solution of intermediate 62 (2.5 g, 3.196 mmol) and PBu3 (2.37 mL, 3 equiv.) in DCM (150 mL) under nitrogen atmosphere at 0° C. The reaction mixture was stirred at room temperature for 16 h. The solvent was evaporated and the residue was purified by flash column chromatography on silica gel (petroleum ether / EtOAc 100 / 0 to 30 / 70) to give intermediate 63 (2.4 g, yield: 79%) as a white solid.

[0253] Intermediate 64 and Intermediate 65 [ka] HCl (4M in dioxane, 6.33 mL, 10 equiv.) was added to a solution of intermediate 63 (2.4 g, 2.534 mmol) in dioxane (30 mL) and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was adjusted to pH 8 by slow addition of saturated aqueous NaHCO3, then extracted with DCM (30 mL x 2). The combined organic layers were washed with brine, dried over Na2SO4, filtered and evaporated. The residue was purified by flash column chromatography on silica gel (petroleum ether / EtOAc, 100 / 0 to 0 / 100) to give a racemic mixture of intermediate 64 and intermediate 65. This mixture was separated into its atropisomers by SFC (column: Daicel Chiralpak AD (250 mm × 30 mm, 10 μm); mobile phase: A: CO2, B: 0.1% NH3.H2O in EtOH, A:B = 55:45) to 1.8 g to give intermediate 64 (630 mg, yield: 48%) and intermediate 65 (620 mg, yield: 47%).

[0254] Preparation of compounds 1 5 -Chloro-1 3 ,2 1 ,2 5 ,6 1 -Tetramethyl-1 1 H,2 1 H,6 1 H-10-Oxa-4,8-dithia-1(4,1)-indra-2(4,3),6(3,5)-dipyrazo-9(3,1)-naphthalene acyclotridecaphane-1 2 -Carboxylic acid, S a or R a Atropisomer (one atropisomer, but absolute stereochemistry undetermined) (Compound 1) [ka] S a or R a Atropisomer (one atropisomer, but absolute stereochemistry undetermined) A solution of lithium hydroxide (15 mg, 10 equiv.) in water (0.6 mL) was added to a solution of intermediate 14 (42 mg) in THF (1.8 mL) / MeOH (1.8 mL). The reaction mixture was stirred at 60° C. for 2 h. The reaction mixture was cooled to room temperature, HCl (1 mL, 1M in water) was added, and the volatiles were removed in vacuo. The residue was purified by preparative HPLC (stationary phase: RP XBridge Prep C18 OBD-10 μm, 30×150 mm, mobile phase: 0.25% NH4HCO3 in water, CH3CN). The product was then triturated in DIPE, filtered, and dried in vacuum at 60° C. to give compound 1 (30 mg, 73%). LC-MS m / z 672[M+H]+(LCMS method code 2) 1 H NMR(400MHz,DMSO-d6,27°C)δ ppm 1.90(s,3H)1.98(s,3H)2.30-2.43(m,2H)2.91(d,J=14.0Hz,1H)3.10(d,J=14.0Hz,1H)3.15(d, J=13.2Hz,1H)3.25-3.28(m,1H)3.68(s,3H)3.74(s,3H)3.79-3.99(m,2H)4.18(d,J=15.5Hz,1H) 4.30(d,J=15.5Hz,1H)4.51-4.63(m,1H)4.89(s,1H)5.00-5.10(m,1H)6.64(s,1H)7.19(d,J=8. 9Hz,1H)7.38(s,1H)7.43-7.53(m,2H)7.66(d,J=9.0Hz,1H)7.69-7.75(m,1H)8.10-8.17(m,1H).

[0255] 1 5 -Chloro-1 3 ,2 1 ,2 5 ,6 1 -Tetramethyl-1 1 H,2 1 H,6 1 H-10-Oxa-4,8-dithia-1(4,1)-indra-2(4,3),6(3,5)-dipyrazo-9(3,1)-naphthalene acyclotridecaphane-1 2 -Carboxylic acid, R a Or S aAtropisomer (one atropisomer, but absolute stereochemistry undetermined) (compound 2) [ka] R a Or S a Atropisomer (one atropisomer, but absolute stereochemistry undetermined) A solution of lithium hydroxide (15 mg, 10 equiv.) in water (0.6 mL) was added to a solution of intermediate 15 (43 mg) in THF (1.8 mL) / MeOH (1.8 mL). The reaction mixture was heated at 60° C. for 2 h. The reaction mixture was cooled to room temperature, HCl (1 mL, 1M in water) was added, and the volatiles were removed in vacuo. The residue was purified by preparative HPLC (stationary phase: RP XBridge Prep C18 OBD-10 μm, 30×150 mm, mobile phase: 0.25% NH4HCO3 in water, CH3CN). The product was then triturated in DIPE, filtered, and dried in vacuum at 60° C. to give compound 2 (30 mg, 71%). LC-MS m / z 672[M+H]+(LCMS method code 2) 1 H NMR(400MHz,DMSO-d6,27°C)δ ppm 1.90(s,3H)1.98(s,3H)2.30-2.42(m,2H)2.91(d,J=14.0Hz,1H)3.10(d,J=14.0Hz,1H)3.15(d, J=13.2Hz,1H)3.25-3.28(m,1H)3.68(s,3H)3.74(s,3H)3.81-3.97(m,2H)4.17(d,J=15.5Hz,1H) 4.30(d,J=15.5Hz,1H)4.51-4.63(m,1H)4.89(s,1H)5.00-5.10(m,1H)6.64(s,1H)7.19(d,J=8. 9Hz,1H)7.38(s,1H)7.43-7.53(m,2H)7.66(d,J=9.0Hz,1H)7.69-7.75(m,1H)8.09-8.17(m,1H).

[0256] 15-Chloro-13,21,25,61,4-pentamethyl-11H,21H,61H-10-oxa-8-thia-4-aza-1(4,1)-indola-2(4,3),6(3,5)-dipyrazo-9(3,1)-naphthalene acyclotridecaphane-12-carboxylic acid (S a and R a Mixture of atropisomers) (Compound 3) [ka] A solution of lithium hydroxide (21 mg, 20 equiv.) in water (1 mL) was added to a solution of intermediate 26 (30 mg) in THF (2.5 mL) and MeOH (2.5 mL). The mixture was stirred at 60° C. for 4 h. The reaction mixture was cooled to room temperature and the solution was purified by preparative HPLC (stationary phase: RP XBridge Prep C18 OBD-5 μm, 50×250 mm, mobile phase: 0.25% aqueous NH4HCO3, CH3CN) to give compound 3 (22 mg, 75%) as a white solid (S a and R a (mixture of atropisomers). LC-MS m / z 669[M+H]+(LCMS method code 1) 1 H NMR(400MHz,DMSO-d6,27°C)δ ppm 1.76(s,3H),1.90(s,3H),1.98(s,3H),2.35-2.48(m,2H),2.74(d,J=12.2Hz,1H),2.77(d,J=13.3Hz, 1H),3.04(d,J=13.3Hz,1H),3.30(d,J=12.2Hz,1H),3.75(s,3H),3.76(s,3H),3.77-3.83(m,1H),4.23 -4.39(m,3H),4.43-4.54(m,1H),4.70(s,1H),5.05-5.14(m,1H),6.86(d,J=1.1Hz,1H),7.29(s,1H), 7.34(d,J=9.0Hz,1H),7.38-7.48(m,2H),7.64-7.69(m,1H),7.78(d,J=9.0Hz,1H),7.99-8.05(m,1H).

[0257] 15-Chloro-13,21,25,61-tetramethyl-11H,21H,61H-10-oxa-8-thia-4-aza-1(4,1)-indola-2(4,3),6(3,5)-dipyrazo-9(3,1)-naphthalene acyclotridecaphane-12-carboxylic acid(S a and R a Mixture of atropisomers) (Compound 4) [ka] A solution of lithium hydroxide (12 mg, 15 equiv.) in water (0.5 mL) was added to a solution of intermediate 25 (22 mg) in THF (0.8 mL) and MeOH (0.8 mL). The mixture was stirred at 60° C. for 4 h. The reaction mixture was cooled to room temperature and the solution was purified by preparative HPLC (stationary phase: RP XBridge Prep C18 OBD-5 μm, 50×250 mm, mobile phase: 0.25% aqueous NH4HCO3, CH3CN) to give compound 4 (17 mg, 79%) as a white solid (S a and R a (mixture of atropisomers). LC-MS m / z 655[M+H]+(LCMS method code 2) 1 H NMR (400MHz, DMSO-d 6, 27°C)δ ppm 1.92(s,3H),1.93(s,3H),2.35-2.44(m,2H),3.22-3.30(m,2H),3.33(d,J=13.0Hz ,1H),3.39(d,J=13.0Hz,1H),3.74(s,3H),3.77(s,3H),3.82-3.92(m,1H),3.93-4 .04(m,1H),4.26(d,J=15.7Hz,1H),4.43(d,J=15.7Hz,1H),4.47-4.56(m,1H),5.0 3(s,1H),5.07-5.17(m,1H),6.79(d,J=0.8Hz,1H),7.23(d,J=8.9Hz,1H),7.32(br s,1H),7.38-7.49(m,2H),7.65-7.71(m,2H),8.03-8.08(m,1H).

[0258] compound 5 [ka] R a Or S a Atropisomer (one atropisomer, but absolute stereochemistry undetermined) Compound 5 was prepared following a similar procedure to compound 3, starting from intermediate 27 instead of intermediate 26. 1 H NMR(400MHz,DMSO-d6)δ ppm 1.76(s,3H),1.88(s,3H),1.97(s,3H),2.36-2.46(m,2H),2.70(d,J=12.2Hz,1H),2.75(d,J=13.3Hz,1H) ,3.04(d,J=13.3Hz,1H),3.32(d,J=12.2Hz,1H),3.72-3.80(m,7H),4.25-4.34(m,2H),4.37(d,J=15.5Hz, 1H),4.41-4.52(m,1H),4.64(s,1H),5.04-5.13(m,1H),6.86(d,J=1.6Hz,1H),7.28(s,1H),7.34(d,J=9.0 Hz,1H),7.37-7.42(m,1H),7.42-7.47(m,1H),7.63-7.68(m,1H),7.79(d,J=9.0Hz,1H),7.98-8.03(m,1H)

[0259] compound 6 [ka] S a or R a Atropisomer (one atropisomer, but absolute stereochemistry undetermined) Compound 6 was prepared following a similar procedure to compound 5, starting from intermediate 28 instead of intermediate 27. 1H NMR(400MHz,DMSO-d6)δ ppm 1.76(s,3H),1.88(s,3H),1.96(s,3H),2.35-2.46(m,2H),2.70(d,J=12.3Hz,1H),2.75(d,J=13.3Hz,1H),3. 04(d,J=13.3Hz,1H),3.32(d,J=12.2Hz,1H),3.71-3.80(m,7H),4.25-4.34(m,2H),4.37(d,J=15.5Hz,1H),4 .41-4.51(m,1H),4.64(s,1H),5.09(dt,J=14.6,4.5Hz,1H),6.86(d,J=1.6Hz,1H),7.28(s,1H),7.34(d,J=8 .9Hz,1H),7.37-7.42(m,1H),7.42-7.47(m,1H),7.64-7.68(m,1H),7.79(d,J=9.0Hz,1H),7.98-8.03(m,1H)

[0260] compound 7 [ka] S a or R a Atropisomer (one atropisomer, but absolute stereochemistry undetermined) LiOH (14 mg, 15 equiv.) was added to a solution of intermediate 37 (27 mg, 0.04 mmol) in a mixture of MeOH (1 mL), THF (1 mL) and water (0.5 mL). The resulting reaction mixture was stirred at 60° C. for 4 h. The reaction mixture was concentrated under reduced pressure to give a white solid. The solid was dissolved in water (5 mL) and acidified to pH 4-5 with 1 M aqueous HCl to give a white precipitate that formed after acidification. The aqueous layer was extracted with DCM (3×20 mL). The combined organic phase was dried over MgSO4 and concentrated under reduced pressure to give a white solid. The crude product was purified by flash column chromatography on silica gel (DCM:MeOH - 1:0-9:1) to give a white solid that was triturated with DIPE and filtered to give compound 7 (24 mg, yield: 86%) as a white solid. 1H NMR(400MHz,DMSO-d6)δ ppm 1.90(s,3H),1.99(s,3H),2.31-2.42(m,2H),3.02(d,J=14.3Hz,1H),3.20(br dd,J=13.9,3.7Hz,2H),3.75(s,3H),3.79-3.93(m,3H),4.05-4.16(m,2H),4.57(ddd,J=14.1,9.1,4.6Hz,1H),4.90(s,1H),4.97-5.08(m,1 H),6.66(d,J=1.6Hz,1H),7.11(d,J=8.9Hz,1H),7.38(s,1H),7.43-7.54(m,3H),7.56-7.65(m,2H),7.71-7.77(m,1H),8.17(d,J=8.0Hz,1H)

[0261] compound 8 [ka] R a Or S a Atropisomer (one atropisomer, but absolute stereochemistry undetermined) Compound 8 was prepared following a similar procedure to compound 7, starting from intermediate 38 instead of intermediate 37. 1 H NMR(400MHz,DMSO-d6)δ ppm 1.90(s,3H),1.99(s,3H),2.30-2.42(m,2H),3.02(d,J=14.3Hz,1H),3.20(dd,J=13.9,3.9Hz,3H ),3.35(s,1H),3.75(s,3H),3.86(dq,J=17.0,8.6Hz,2H),4.06-4.16(m,2H),4.57(ddd,J=14.2,9 .1,4.5Hz,1H),4.90(s,1H),5.03(dt,J=14.6,4.8Hz,1H),6.66(d,J=1.6Hz,1H),7.11(d,J=8.9Hz ,1H),7.38(s,1H),7.44-7.54(m,2H),7.56-7.62(m,1H),7.71-7.78(m,1H),8.17(d,J=8.0Hz,1H)

[0262] compound 9 [ka] LiOH (1M in water, 607 μL, 4 equiv.) was added to a solution of intermediate 40 (108 mg, 0.152 mmol) in THF (1.5 mL) and the reaction mixture was stirred at room temperature for 16 h. To drive the reaction to completion, additional LiOH (1M in water, 607 μL, 4 equiv.) was added and the reaction mixture was stirred at room temperature for 48 h. The reaction mixture was diluted with DCM (2 mL) and acidified to pH 3 with Amberlite® IR-120 (H+) resin. The mixture was filtered to remove the resin and the resin was washed with ACN and MeOH. The solvent was evaporated. The residue was purified by flash column chromatography (RPC18, ACN:MeOH 1:1 / 25 mM NH4HCO3, 41 / 59 to 83 / 17). The organic solvent was evaporated from the collected fractions and the resulting aqueous suspension was acidified to pH 3 with 1M HCl solution and extracted with EtOAc (×3). The combined organic layers were dried over MgSO4, filtered and evaporated to give intermediate 9 (69 mg, yield: 64%) as a white solid. 1 H NMR(400MHz,373K,DMSO-d6)δ ppm:8.05(d,J=7.4Hz,1H),7.68(d,J=7.8Hz,1H),7.63(d,J=9.0Hz,1H),7.50-7.38(m ,2H),7.35(s,1H),7.27(d,J=8.7Hz,1H),6.64(s,1H),5.28(s,1H),5.15-5.02(m,1H) ,4.68-4.55(m,1H),4.30(d,J=15.5Hz,1H),4.16(d,J=15.5Hz,1H),4.01-3.92(m,1H) ,3.81(s,3H),3.73(s,3H),2.40-2.29(m,2H),2.01(s,3H),1.97(s,3H),1.04-0.12(br m,6H).

[0263] compound 10 [ka] R a Or S a Atropisomer (one atropisomer, but absolute stereochemistry undetermined) LiOH (25 mg, 15 equiv.) was added to a solution of intermediate 41 (49 mg, 0.07 mmol) in a mixture of MeOH (1.6 mL), THF (1.6 mL) and water (0.8 mL). The resulting reaction mixture was stirred at 60° C. for 4 h. The reaction mixture was concentrated under reduced pressure to give a white solid. The solid was dissolved in water (15 mL) and acidified to pH 4-5 with 1 M aqueous HCl, a white precipitate formed after acidification. The aqueous layer was extracted with DCM (2×20 mL) and the combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (DCM:MeOH - 100:0 to 95:5) to give a solid which was triturated with Et2O and filtered to give compound 10 (34.5 mg, yield: 72%) as an off-white solid. 1 H NMR(400MHz,chloroform-d)δ ppm 1.35(t,J=7.2Hz,3H),2.03(s,3H),2.22(s,3H),2.33-2.47(m,2H),2.82(d,J=14.4Hz,1H),3.18(d ,J=13.3Hz,1H),3.27(d,J=14.6Hz,1H),3.46-3.53(m,3H),3.64-3.75(m,1H),3.81-3.97(m,7H),4. 59(ddd,J=14.5,8.2,3.9Hz,1H)5.14-5.24(m,2H),6.10(d,J=1.3Hz,1H),7.08(d,J=8.9Hz,1H),7.3 3(d,J=9.1Hz,1H),7.49-7.59(m,2H),7.60(s,1H),7.69-7.77(m,1H),8.34(dd,J=8.1,0.89Hz,1H).

[0264] compound 11 [ka] R aOr S a Atropisomer (one atropisomer, but absolute stereochemistry undetermined) Compound 11 was prepared following a similar procedure to compound 10, starting from intermediate 42 instead of intermediate 41. 1 H NMR(400MHz,chloroform-d)δ ppm 1.27(t,J=7.21Hz,3H),1.99(s,3H),2.20(s,3H),2.33-2.54(m,2H),3.04(d,J=14.74Hz,1H),3.24(d,J=14.74Hz,1 H),3.28(d,J=14.32Hz,1H),3.45(d,J=14.32Hz,1H),3.58(td,J=9.48,3.50Hz,1H),3.82-3.98(m,7H),4.09(d,J=1 5.15Hz,1H),4.57-4.68(m,1H),5.11(s,1H),5.16(dt,J=14.55,4.27Hz,1H),6.58(d,J=1.36Hz,1H),6.89(d,J=8.9 9Hz,1H),7.24(d,J=9.09Hz,1H),7.46-7.52(m,2H),7.53(s,1H),7.68-7.73(m,1H),8.34(dd,J=8.31,1.31Hz,1H).

[0265] compound 12 [ka] R a Or S a Atropisomer (one atropisomer, but absolute stereochemistry undetermined) LiOH (45 mg, 15 equiv.) was added to a solution of intermediate 43 (90 mg, 0.13 mmol) in a mixture of MeOH (2.8 mL), THF (2.8 mL) and water (1.5 mL). The resulting reaction mixture was stirred at 50° C. for 3 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (DCM:MeOH - 100:0 to 95:5) to give compound 12 (66 mg, yield: 75%) as an off-white solid. 1H NMR (400MHz, chloroform-d) δ ppm 1.34-1.54(m,1H),1.42(d,J=6.60Hz,3H),1.49(d,J=6.38Hz,2H),2.00(s,3H),2.21(s,3H),2.37-2.49(m,2H),2. 79(d,J=13.86Hz,1H),3.20(d,J=13.64Hz,1H),3.29-3.36(m,1H),3.38-3.45(m,1H),3.46-3.56(m,1H),3.76-3.9 5(m,6H),4.48(spt,J=6.60Hz,1H),4.54-4.64(m,1H),5.02(s,1H),5.16(dt,J=14.58,4.15Hz,1H),6.22(d,J=1.3 2Hz,1H),7.00(d,J=8.80Hz,1H),7.30(d,J=9.02Hz,1H),7.45-7.57(m,3H),7.66-7.72(m,1H),8.28-8.36(m,1H).

[0266] compound 13 [ka] R a Or S a Atropisomer (one atropisomer, but absolute stereochemistry undetermined) LiOH (57 mg, 15 equiv.) was added to a solution of intermediate 44 (114 mg, 0.16 mmol) in a mixture of MeOH (3.6 mL), THF (3.6 mL) and water (1.8 mL). The reaction mixture was stirred at 60 °C for 3 h. The reaction mixture was concentrated under reduced pressure, diluted with water (15 mL) and acidified to pH 4-5 with 1 M aqueous HCl. The aqueous layer was extracted with DCM (2 x 10 mL) and then with a 1:1 mixture of EtOAc:THF (10 mL). The combined organic layers were dried over MgSO4, filtered and evaporated. The residue was purified by flash chromatography on silica gel (DCM:MeOH - 100:0 to 95:5) to give compound 13 (91 mg, yield: 81%) as an off-white solid. 1H NMR(400MHz,chloroform-d)δ ppm 1.24(d,J=6.58Hz,3H),1.31(d,J=6.58Hz,3H),1.98(s,3H)2.17(s,3H),2.31-2.52(m,2H),3.09(d,J=14.74Hz,1 H),3.28(dd,J=14.27,9.56Hz,2H),3.43(d,J=13.90Hz,1H),3.47-3.56(m,1H),3.83-3.92(m,5H),4.10(d,J=15.1 5Hz,1H),4.29(spt,J=6.55Hz,1H),4.55-4.69(m,1H),5.15(dt,J=14.58,4.36Hz,1H),5.21(s,1H),6.55(d,J=1.3 6Hz,1H),6.82(d,J=8.99Hz,1H),7.21(d,J=9.09Hz,1H),7.44-7.52(m,3H),7.65-7.73(m,1H),8.29-8.36(m,1H).

[0267] compound 14 [ka] R a Or S a Atropisomer (one atropisomer, but absolute stereochemistry undetermined) A solution of LiOH.HO (27 mg, 5 equiv.) in water (0.5 mL) was added to a solution of intermediate 58 (85 mg, 0.127 mmol) in THF (3 mL). The reaction mixture was stirred at 45° C. for 16 h. HCl (0.5 M in water) was added until pH 6 was reached. The solvent was evaporated and the residue was purified by preparative HPLC (column: Phenomenex Gemini-NX 150×30 mm×5 μm; gradient: water (0.05% HCl) / ACN, 77 / 23 to 47 / 53) to give compound 14 (35 mg, yield: 41%) as a white solid. 1H NMR(400MHz,DMSO-d6)δ ppm 1.89(br d,J=7.28Hz,8H)2.39(br s,2H)3.20-3.27(m,2H)3.40-3.48(m,3H)3.73(s,5H)4.24(br s,2H)4.54(br s,2H)5.00-5.13(m,1H)6.69(br s,1H)7.28(br d,J=8.82Hz,2H)7.35-7.48(m,2H)7.64(br d,J=8.16Hz,1H)7.80(d,J=9.04Hz,1H)7.98(br d,J=6.61Hz,1H)13.22(br s,1H)

[0268] compound 15 [ka] S a or R a Atropisomer (one atropisomer, but absolute stereochemistry undetermined) Compound 15 was prepared following a similar procedure to compound 14, starting from intermediate 59 instead of intermediate 58. 1 H NMR(400MHz,DMSO-d6)δ ppm 1.83(s,5H)1.93(s,3H)2.27-2.41(m,2H)3.08(br s,2H)3.17-3.28(m,3H)3.73(s,4H)4.17-4.34(m,3H)4.40-4.62(m,2H)4.99-5.10(m,1H)6. 77(s,1H)7.23(s,1H)7.30-7.46(m,3H)7.62(d,J=7.94Hz,1H)7.79(d,J=9.04Hz,1H)7.97(br d,J=7.94Hz,1H)12.86(br s,1H)

[0269] compound 16 [ka] R a Or S a Atropisomer (one atropisomer, but absolute stereochemistry undetermined) Compound 16 was prepared following a similar procedure to compound 14, starting from intermediate 64 instead of intermediate 58. 1 H NMR(400MHz, methanol-d4)δ ppm 1.92(s,3H)2.01(s,3H)2.45(br s,2H)2.58-2.70(m,2H)2.84-2.92(m,1H)3.08(d,J=14.33Hz,1H)3.76(s,3H)3.78-3.89(m,2H)3.96-4.06(m,2H)4.61-4. 69(m,2H)5.14-5.23(m,1H)6.43(s,1H)7.06(d,J=8.82Hz,1H)7.19(s,1H)7.41-7.49(m,2H)7.53(d,J=9.04Hz,1H)7.63(br dd,J=6.50,2.76Hz,1H)8.09-8.16(m,1H)

[0270] compound 17 [ka] S a or R a Atropisomer (one atropisomer, but absolute stereochemistry undetermined) Compound 17 was prepared following a similar procedure to compound 14, starting from intermediate 65 instead of intermediate 58. 1H NMR (400MHz, methanol-d4) δ ppm 1.92(s,3H) 2.01(s,3H) 2.44(br dd,J=9.59,4.30Hz,2H)2.57-2.69(m,2H)2.84-2.92(m,1H)3.08(d,J=14.33Hz,1H)3.75(s,3H)3.76-3.90(m,2H)3.94-4.03(m,2H) 4.58-4.70(m,2H)5.12-5.22(m,1H)6.42(s,1H)7.06(d,J=9.04Hz,1H)7.18(s,1H)7.40-7.47(m,2H)7.52(d,J=9.04Hz,1H)7.62(br dd,J=6.62,2.65Hz,1H)8.07-8.16(m,1H)

[0271] analytical analysis High performance liquid chromatography (HPLC) measurements were performed using an LC pump, diode array (DAD) or UV detector, and column as specified in each method. Additional detectors were included when necessary (see methods table below).

[0272] The flow from the column was introduced into a mass spectrometer (MS) configured with an atmospheric pressure ion source. It is within the knowledge of one of ordinary skill in the art to set tuning parameters (e.g., scan range, dwell time, etc.) to obtain ions that allow identification of the nominal monoisotopic molecular weight (MW) of the compound. Data collection was performed using appropriate software.

[0273] For compounds, the retention times (R t ) and ions. Unless otherwise stated in the data tables, the molecular ions reported are [M+H] + (protonated molecule) and / or [MH] - (deprotonated molecule). If the compound could not be directly ionized, the type of adduct was specified (i.e. [M+NH4] + , [M+HCOO] - For molecules with multiple isotopic patterns (Br, Cl), the reported values ​​are those obtained for the lowest isotopic mass. All results contained experimental uncertainties normally associated with the methods used.

[0274] In the following, "SQD" means single quadrupole detector, "MSD" means mass selective detector, "RT" means room temperature, "BEH" means crosslinked ethylsiloxane / silica hybrid, "DAD" means diode array detector, and "HSS" means high strength silica.

[0275] [Table 5]

[0276] [Table 6]

[0277] [Table 7]

[0278] [Table 8]

[0279] SFC-MS method SFC measurements were performed using an analytical supercritical fluid chromatography (SFC) system consisting of a binary pump for delivering carbon dioxide (CO2) and modifiers, an autosampler, a column oven, a diode array detector with a high-pressure flow cell capable of withstanding high pressures up to 400 bar. If configured with a mass spectrometer (MS), the flow from the column was introduced into the (MS). It is within the knowledge of a person skilled in the art to set tuning parameters (e.g., scan range, data acquisition time, etc.) to obtain ions that allow identification of the nominal monoisotopic mass (MW) of the compound. Data collection was performed using appropriate software. Analytical SFC / MS method (flow rate in mL / min; column temperature (T) (°C); analysis time (min), back pressure (BPR) (bar). "i-PrNH2" means isopropylamine, "EtOH" means ethanol, "min" means minutes, "DEA" means diethylamine.

[0280] [Table 9]

[0281] [Table 10]

[0282] NMR 1H NMR spectra were recorded on Bruker Avance III and Avance NEO spectrometers. CDCl3 was used as the solvent unless otherwise stated. Chemical shifts are expressed in ppm relative to tetramethylsilane.

[0283] Pharmacological analysis Biological Example 1 Cell viability assay of Molp8 multiple myeloma cell line using Annexin V and 7AAD The principle of Annexin V / 7AAD is based on the location of phosphatidylserine in the plasma membrane and the integrity of the membrane barrier. During early apoptosis, phosphatidylserine loses its normal distribution pattern within the inner leaflet of the plasma membrane and appears on the outer surface of the plasma membrane. Annexin proteins are calcium-dependent phospholipid-binding proteins that can bind to phosphatidylserine on the outer membrane during cell death. The viability dye 7AAD is excluded from entering cells with intact plasma membranes but accumulates in cells that have lost membrane integrity. Annexin Fitc is excited by a 488 nm laser (excitation maxima: 490 nm, emission maxima: 525 nm) as is 7AAD (excitation: 488 nm, emission: 650 nm), allowing this assay to be completed on any multicolor flow cytometer.

[0284] The assay conditions were optimized using the following 1× reaction buffer: 5 mM HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid), 70 mM NaCl, 1.25 mM CaCl2, pH 7.4. The reagents / substances used in the assay are listed in the table below.

[0285] [Table 11]

[0286] Molp 8 cells were human multiple myeloma cells in suspension ( * Cells were counted twice a week and culture densities ranged from 0.5–1.5 × 10 cells per mL. 6 (Maintained at individual.)

[0287] Assay procedure On day 1, 5 x 10 cells per well 4 Viable cells were plated in 96-well U-bottom plates and cells were placed in 100 μL of RPMI + 10% FBS. An 11-point compound dilution plate was prepared with 3-fold steps (final concentration range: 10 μM to 0.1 nM) and added at a concentration of 1 μL per well. Plates were then incubated at 37°C and 5% CO2 for 3 days.

[0288] On day 4, the cells were pelleted and the medium was discarded. The cells were then resuspended in 50 μL of AnnexinV-Fitc (1:40 dilution) and 7AAD (1:100 dilution) in Annexin binding buffer, then incubated in the dark at room temperature for 30 minutes. Then, 50 μL of binding buffer (total volume 100 μL) was added to the cells. No washing step was required.

[0289] Within 2 hours, the PeCy5 (7AAD) and Fitc (annexin) channels were recorded using a BD Canto with a minimum collection per singlet of 10,000 events.

[0290] analysis The activity of the test compounds was calculated based on the percentage of viable cells. LC = median low control value = Low control: untreated cells (viability less than 100%) HC = median high control value = High control: cells treated with 10 μM drug (survival > 0%)

[0291] A best-fit curve was fitted to the plot of percent viable cells versus compound concentration by the least-sum-squares method. From this, the IC 50 The values ​​(inhibitory concentration causing 50% inhibition) were obtained. An estimate of the slope of the plot for the Hill coefficient was also obtained.

[0292] Representative compounds of formula (I) of the present invention were tested according to the procedures described in Biological Example 1, with the results listed in the table below. Compounds were tested more than once and the results of each determination are listed separately.

[0293] The IC50 values ​​reported in the table below are subject to tolerances associated with the assay and equipment used.

[0294] [Table 12]

[0295] Biological Example 2 MCL-1 is a regulator of apoptosis and is highly overexpressed in tumor cells that escape cell death. This assay evaluates the cellular potency of small molecule compounds that target regulators of the apoptosis pathway, primarily MCL-1, Bfl-1, Bcl-2 and other proteins of the Bcl-2 family. Protein-protein inhibitors that disrupt the interaction of anti-apoptotic regulators with BH3-domain proteins initiate apoptosis.

[0296] Activation of the apoptotic pathway was measured using CellEvent™ Caspase-3 / 7 Green ReadyProbes™ Reagent (Thermo Fisher C10423, C10723). This assay produces green fluorescent staining in cells that enter the apoptotic pathway. The CellEvent® Caspase-3 / 7 Green Reagent is a four amino acid peptide (DEVD) conjugated to a nucleic acid binding dye that is non-fluorescent when not bound to DNA. The CellEvent® Caspase-3 / 7 Green Reagent is essentially non-fluorescent because the DEVD peptide inhibits the binding of the dye to DNA. Upon activation of caspase-3 / 7 in apoptotic cells, the DEVD peptide is cleaved and the free dye is able to bind to DNA and produce bright green fluorescence. Activation of caspase-3 and caspase-7 is downstream of inhibition of MCL-1 or other apoptotic inhibiting proteins in cell lines that depend on them.

[0297] The live cell readout on the IncuCyte allows caspase activation to be followed over time. The kinetic readout was useful because (a) it resolves differences in onset times that can be associated with differences in the mechanism of apoptosis induction, i.e., it is more direct or indirect; and (b) it allows recognition of artifacts resulting from autoinduced fluorescence or precipitating compounds. The IncuCyte readout also allows normalization for cell number, since suspended cells are difficult to distribute uniformly.

[0298] Signals were measured every 2 hours for 22 hours. The ratio of caspase masked to confluence masked as raw data per image was calculated and kinetic traces for each well were exported to Genedata Screener for analysis.

[0299] Values ​​were extracted from kinetic traces at 6, 12 and 22 hours in Genedata Screener. Values ​​were normalized to the negative control (untreated cells). Standard dose-response analysis was performed on the normalized data.

[0300] The following data were reported at each of the three above mentioned time points: (a) dose-response curves, (b) qAC50 and qAC50 mode, and (c) maximum activity.

[0301] The substances used in this assay are listed in the table below.

[0302] [Table 13]

[0303] Cells were maintained in culture medium containing 10% heat-inactivated (HI) FBS, 2 mM L-glutamine, and 50 μg / mL gentamicin in phenol red-free RPMI-1640. Cells were split at 400,000 / mL twice weekly.

[0304] On day 1, plates containing individual wells with test compounds at a concentration of 10 mM, at 150 nL per well. Final concentrations ranged from 100 μM to 10 pM of compound (no compound control), and compounds were allowed to thaw at room temperature for 1 hour. 25 μL of pre-warmed medium was added by multidrop to each well (columns 1, 3-22, 24), plus a DMSO control (0.6% DMSO) in column 2. Plates were sealed using Breathe-Easy® sealing membranes and shaken at room temperature for 30 minutes to allow dissolution of test compounds in the medium. Plates were then kept in an incubator at 37° C., 5% CO2 for 1 hour.

[0305] MOLP8 cells in media at 40000 / 25 μL (20000 / 50 μL final in assay) were prepared with CellEvent™ Caspase-3 / 7 Green Detection Reagent at 4 μM (2 μM final in assay). Once prepared, cells were added to the test compound plate at 20000, the plate was immediately placed in the IncuCyte and imaging was started using the following settings: 10x objective, 2 second exposure time in the green channel, 2 hour interval, capture stopped after 22 hours.

[0306] For analysis in IncuCyte, a basic analysis protocol was defined to calculate "confluence" and "caspase" areas from "phase" and "green" images, respectively, as follows: (a) Confluence: Segmentation Adjust 1, Hole Fill 0, Adjust Size -2, No Filter (b) Caspase: Top-Hat Segmentation, Radius 10, Threshold 0.3 GCU, Sensitivity 0, Hole Fill 0, Adjust Size 1 and 20 μm 2Edge Split On with a filter on a minimum area of ​​100 nm. Analysts are trained on a sufficient number of positive and negative control wells and compound treated wells to verify that the "confluence" layer detects both live and dead (condensed) cells. "Caspase Area / Confluence Area" approximates the cell fraction positive for caspase 3 / 7 dye, calculated "by image".

[0307] Assay analysis was completed in Genedata Screener using a predefined template. More specifically, the assay-specific settings for the experimental analysis were as follows: (a) plate layout: negative control wells contained no compound but DMSO and were defined as "neutral control", (b) trace channel: there should be one trace channel with the name "measurement channel" of type "measurement". This was the raw data from the IncuCyte; and (c) layers: three layers with the names "average 6 hours", "average 12 hours" and "average 22 hours" of type "aggregation: time series". They contained the average values ​​of measurements from the 5.5-6.5 hour, 11.5-12.5 hour and 21.5-22.5 hour values, respectively.

[0308] Normalization and correction: Each of the three strata was normalized to the control rate, using the neutral control as the median reference and the stimulator control as the scaled reference. CR is the mean of the median reference values, and μ SC If was the average of the scale reference values, then the normalized value would be

number

[0309] Test results for layered compounds: Using the standard fit model as follows, where S inf ,I C 50 and h are free parameters, and S0 was fixed to be 0.

number

[0310] The robust Z'-factor or "RZ'-factor" was calculated in Screener. After excluding outlier kinetic traces in control wells (see below), for any MOLP8 cells tested at any FBS concentration and any time point (6 h, 12 h, 22 h), the RZ'-value must be RZ ≥ 0.5.

[0311] "Global SD" was calculated in Screener as the robust standard deviation of the positive or negative controls (whichever was larger) after normalization. After excluding outlier dynamic traces in control wells (see below), for MOLP8 cells tested at any FBS concentration and for any time point (6 h, 12 h, 22 h), the global SD must be Global SD ≦ 10.

[0312] Representative compounds of formula (I) of the present invention were tested according to the procedures described in Biological Example 2, with the results listed in the table below. The AC50 values ​​reported in the table below are subject to the tolerances associated with the assay and equipment used.

[0313] [Table 14]

[0314] Biological Example 3 MCL-1 is a regulator of apoptosis and is highly overexpressed in tumor cells that escape cell death. This assay evaluates the cellular potency of small molecule compounds that target regulators of the apoptosis pathway, primarily MCL-1, Bfl-1, Bcl-2 and other proteins of the Bcl-2 family. Protein-protein inhibitors that disrupt the interaction of anti-apoptotic regulators with BH3-domain proteins initiate apoptosis.

[0315] The Caspase-Glo® 3 / 7 assay is a luminescent assay that measures caspase-3 and caspase-7 activity in purified enzyme preparations or in adherent or suspension cell cultures. The assay provides a luminogenic caspase-3 / 7 substrate that contains the tetrapeptide sequence DEVD. Cleavage of this substrate releases aminoluciferin, a substrate for luciferase that is used to generate light. Addition of a single Caspase-Glo® 3 / 7 reagent in an "add-mix-measure" format results in cell lysis followed by caspase cleavage of the substrate and generation of a "glow-type" luminescent signal.

[0316] This assay uses the MOLP-8 human multiple myeloma cell line, which is sensitive to MCL-1 inhibition.

[0317] material: Perkin Elmer Envision ·Multidrop 384 and small volume dispensing cassettes ·centrifuge ·Countess Automated Cell Counter ·Countess Counting Chamber Slides Assay Plates: ProxiPlate-384 Plus, White 384-shallow well microplates Sealing tape: Topseal A plus ·T175 culture flask

[0318] [Table 15]

[0319] [Table 16]

[0320] Cell culture: Cell culture was performed at 0.2–2.0 × 10 cells. 6Cells were maintained at 100 / mL. Cells were harvested by collection into a 50 mL conical tube. Cells were then pelleted at 500 g for 5 minutes, after which the supernatant was removed and resuspended in fresh pre-warmed culture medium. Cells were counted and diluted as necessary.

[0321] Caspase-Glo Reagent: The assay reagent was prepared by transferring the buffer solution to the substrate vial and mixing. The solution could be stored at 4°C for up to a week with very little loss of signal.

[0322] Assay procedure: Compounds were delivered in assay-ready plates (Proxiplates) and stored at -20°C. One reference compound plate containing reference compounds was always included in the assay. Plates were spotted with 40 nL of compound (0.5% DMSO final in cells; serial dilutions; top concentration 30 μM, 1 / 3 dilution, 10 doses, in duplicate). Compounds were used at room temperature and 4 μL of pre-warmed medium was added to all wells except columns 2 and 23. Negative controls were prepared by adding 1% DMSO in medium. Positive controls were prepared by adding the appropriate positive control compound at a final concentration of 60 μM in medium. Plates were prepared by adding 4 μL of negative control to column 23, 4 μL of positive control to column 2, and 4 μL of cell suspension to all wells in the plate. Plates with cells were then incubated for 2 hours at 37°C. The assay signal reagent was Caspase-Glo solution as described above and 8 μL was added to all wells. The plates were then sealed and measured after 30 minutes.

[0323] The activity of the test compounds was calculated as the percentage change in apoptosis induction as follows: LC = median low control value = Median reference value in Screener =DMSO =0% HC = median high control value =Scale reference value in Screener = 30 μM positive control = 100% apoptosis induction %Effect(AC 50 )=100-(Sample-LC) / (HC-LC) * 100 % Control = (Sample / HC) * 100 %ControlMin=(Sample-LC) / (HC-LC) * 100

[0324] [Table 17] The present invention includes the following embodiments. [Claim 1] Formula (I) [ka] (In the formula, X 1 teeth, [ka] (wherein "a" and "b" are the variables X 1 is attached to the rest of the molecule) represents; R 1 is hydrogen or C 1~6 represents alkyl; X 2 can be attached to the rest of the molecule in both orientations, [ka] represents; R 2 is hydrogen or C 1~6 represents alkyl; X is -S- or -N(R x )-represents; R x is hydrogen, methyl, C 2~6 Alkyl, -C(=O)-C 1~6 Alkyl, -S(=O) 2 -C 1~6 Alkyl, C 3~6 Cycloalkyl, -C(=O)-C 3~6 Cycloalkyl or -S(=O) 2 -C 3~6 represents cycloalkyl, where C 2~6 Alkyl, -C(=O)-C 1~6 Alkyl, -S(=O) 2 -C 1~6 Alkyl, C 3~6 Cycloalkyl, -C(=O)-C 3~6 Cycloalkyl and -S(=O) 2 -C 3~6 Cycloalkyl is optionally selected from halo, C 1~4 C substituted with alkyl and 1, 2 or 3 halo atoms 1~4 substituted with 1, 2 or 3 substituents selected from the group consisting of alkyl or a tautomeric or stereoisomeric form thereof or a pharma- ceutically acceptable salt or solvate thereof. [Claim 2] X 1 teeth,

change

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Claims

1. Formula (I) 【Chemistry 1】 (In the formula, X １ teeth, 【Chemistry 2】 (wherein "a" and "b" are the variables X １ is attached to the rest of the molecule) represents; R １ is hydrogen or C １～６ represents alkyl; X ２ can be attached to the rest of the molecule in both orientations, 【Chemistry 3】 represents; R ２ is hydrogen or C １～６ represents alkyl; X is -S- or -N(R ｘ )-represents; R ｘ is hydrogen, methyl, C ２～６ Alkyl, -C(=O)-C １～６ Alkyl, -S(=O) ２ -C １～６ Alkyl, C ３～６ Cycloalkyl, -C(=O)-C ３～６ Cycloalkyl or -S(=O) ２ -C ３～６ represents cycloalkyl, where C ２～６ Alkyl, -C(=O)-C １～６ Alkyl, -S(=O) ２ -C １～６ Alkyl, C ３～６ Cycloalkyl, -C(=O)-C ３～６ Cycloalkyl and -S(=O) ２ -C ３～６ Cycloalkyl is optionally selected from halo, C １～４ C substituted with alkyl and 1, 2 or 3 halo atoms １～４ and substituted with 1, 2 or 3 substituents selected from the group consisting of alkyl, or a tautomeric or stereoisomeric form thereof or a pharma- ceutically acceptable salt or solvate thereof (however, 【Chemistry 6】 and its tautomeric or stereoisomeric forms.)

2. X １ teeth, 【Chemistry 4】 (wherein "a" and "b" are the variables X １ is attached to the rest of the molecule) represents; R １ is C １～６ represents alkyl; R ２ is C １～６ represents alkyl; R ｘ The compound according to claim 1 , wherein represents hydrogen or methyl.

3. X is -N(R ｘ 3. The compound according to claim 1 or 2, wherein

4. X １ teeth, 【Chemistry 5】 2. The compound according to claim 1 , wherein

5. A pharmaceutical composition comprising a compound according to any one of claims 1 to 4 and a pharma- ceutically acceptable carrier or diluent.

6. A process for preparing a pharmaceutical composition according to claim 5, comprising the step of mixing a pharma- ceutically acceptable carrier with a therapeutically effective amount of a compound according to any one of claims 1 to 4.

7. A pharmaceutical composition according to claim 5 for use as a medicament.

8. The pharmaceutical composition according to claim 5 for use in the prevention or treatment of cancer.

9. 9. The pharmaceutical composition of claim 8, wherein the cancer is selected from prostate cancer, lung cancer, pancreatic cancer, breast cancer, ovarian cancer, cervical cancer, melanoma, B-cell chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL).

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