Heterocyclic derivatives, pharmaceutical compositions and their use in the treatment or amelioration of cancer - Patents.com

Abstract

The present invention relates to a compound of formula (I) or its salt, solvate, cocrystal, tautomer, or mixture. Furthermore, the present invention relates to a pharmaceutical composition comprising said compound. Furthermore, the present invention relates to a compound of formula (I) or its salt, solvate, cocrystal, tautomer, or mixture, or pharmaceutical composition for use as a medicament, and a compound of formula (I) or its salt, solvate, cocrystal, tautomer, or mixture, or pharmaceutical composition for use in treating or alleviating cancer. Optionally, the compound of formula (I) or its salt, solvate, cocrystal, tautomer, or mixture, or pharmaceutical composition is administered in combination with a second therapeutic agent, in particular an anticancer agent.

Description

Detailed Description of the Invention

[0001] FIELD OF THEINVENTION The present invention relates to a compound of formula (I) or its salt, solvate, cocrystal, tautomer, or mixture. Furthermore, the present invention relates to a pharmaceutical composition comprising said compound. Furthermore, the present invention relates to a compound of formula (I) or its salt, solvate, cocrystal, tautomer, or mixture, or pharmaceutical composition for use as a medicament, and a compound of formula (I) or its salt, solvate, cocrystal, tautomer, or mixture, or pharmaceutical composition for use in treating or alleviating cancer. Optionally, the compound of formula (I) or its salt, solvate, cocrystal, tautomer, or mixture, or pharmaceutical composition is administered in combination with a second therapeutic agent, particularly an anti-cancer agent.

[0002] 2. Background of the Invention Cancer is one of the most serious health conditions facing individuals in both developed and developing countries. In the United States alone, it is reported that one in three people will suffer from cancer during their lifetime. Furthermore, typically, more than half of patients diagnosed with cancer ultimately die from the disease. While significant advances have been made in the early detection and treatment of certain cancers, other cancers are more difficult to detect and / or treat.

[0003] Oncogenic activity of the MAPK pathway is a signature feature of many human cancers, including melanoma and non-small cell lung cancer (NSCLC). Activated oncogenes can be pharmacologically inhibited using small molecules or antibodies. However, the clinical antitumor effects of receptor tyrosine kinase (RTK) inhibitors and inhibitors targeting other oncogenes are not sustained. Resistance to these inhibitors usually develops. More specifically, the clinical antitumor effects of EGFR inhibitors (EGFRi) are not sustained. Resistance to EGFR inhibitors usually develops within 9-19 months depending on the therapeutic agent and clinical setting (see Leonetti et al., BJC, 2019, Vol. 121, pp. 725-737). It is therefore desirable to develop modes of cancer treatment that prevent drug resistance in cancer patients.

[0004] Furthermore, genetic alterations in cancer cells often affect genes important for cell cycle regulation, proliferation, differentiation and / or signal transduction. Overall, phenotypic, signal transduction, transcriptional and metabolic plasticity and acquisition of novel genetic alterations have been found to be drivers of the development of resistance to cancer treatments, including molecular targeted inhibitors and immunotherapy (see Boumahdi et al., Nature Reviews Drug Discovery, 2019, vol. 19, pp. 39-56).

[0005] The same has been observed, for example, in the context of “castration-resistant” prostate cancer (CRPC). Prostate cancer is so highly dependent on androgen receptor (AR) function for survival and progression that long-term disease control in prostate cancer requires a course of hormonal therapy that suppresses AR signaling. However, despite AR-targeted therapies inhibiting tumor growth, the disease is rarely eliminated and resistance to therapy is acquired via restored AR function. Acquisition of the CRPC phenotype is mediated via reactivation of the AR pathway. Acetyltransferase p300 directly regulates AR levels and AR signaling activity in prostate cancer cells (Zhong et al., “p300 acetyltransferase regulates androgen-receptor degradation and PTEN-deficient prostate turn oogenesis,” Cancer Res., vol. 74, pp. 1870-1880, 2014). Thus, therapeutic modulation of p300 function targets all known adaptive mechanisms that lead to the development of CRPC. Approved therapies and those in clinical investigation primarily target only one or the other of these cellular mechanisms. Modulation of p300 function directly offers an opportunity to modulate AR activity in CRPC more broadly than current and other experimental therapeutic strategies. In addition, resistance mechanisms to recently approved drugs have been shown to be AR-dependent (Cai, C. et al. (2011) "Intratumoral de novo steroid synthesis activates androgen receptor in castration-resistant prostate cancer and is up-regulated by treatment with Cypl7Al inhibitors", Cancer Res., vol. 71, pp. 6503-6513). Targeting p300 / CBP as a therapeutic strategy for lethal PC has been validated by J. Welti et al. (Cancer discovery, March 28, 2021, DOI:10.1158 / 2159-8290).In particular, small molecule inhibitors have been shown to inhibit cell proliferation and reduce AR- and C-MYC-regulated gene expression in PC cell lines. Therefore, modulation of p300 should inhibit resistance to current therapies, potentially providing improved and sustained efficacy and greater clinical benefit.

[0006] Similarly, it was reported that the histone acetyltransferase CBP / p300 is involved in chromosomal translocations associated with relapsed leukemia and is a key regulator of cell growth. Thus, efforts to generate inhibitors of CBP / p300 are of clinical value (S. Picaud et al., "Generation of a Selective Small Molecule Inhibitor of the CBP / p300 Bromodomain for Leukemia Therapy," Cancer Res., 2015, vol. 75, pp. 5106-5119). It was further reported that a potent, selective CBP inhibitor modulated MYC expression corresponding to antitumor activity in AML tumor models, and the same compound attenuated FOXP3 expression and Treg function, further suggesting inhibition of CBP bromodomain as a novel small molecule approach to cancer immunotherapy (FARomero et al., J. Med. Chem., 2017, vol. 60, pp. 9162-9183).

[0007] In common with p300, CREB (cyclic AMP response element binding protein) binding protein (CBP) is an acetyltransferase that acts as a coactivator of transcription in human cells. Both CBP and p300 possess a single bromodomain (BRD) and a lysine acetyltransferase (KAT) domain, which are involved in the post-translational modification and recruitment of histone and non-histone proteins. There is high sequence similarity between CBP and p300 in conserved functional domains (see Duncan A. Hay et al., JACS 2014, vol. 135, pp. 9308-9319). Thus, modulation of CBP function provides a promising route for the treatment of certain cancers. Compounds that can modulate, e.g., inhibit, the function of p300 and / or CBP are therefore of interest in cancer therapy.

[0008] Tumors harboring loss-of-function mutations in CBP become p300 dependent and are uniquely sensitive to p300 inhibition (see Ogiwara et al., 2016 Cancer Discovery. 6:430-445). Conversely, tumors with mutations in p300 are uniquely sensitive to CBP inhibition. Genetic analysis has revealed that up to 15% of non-small cell and small cell lung tumors harbor these loss-of-function mutations. Similar mutations have also been found in up to 25% of bladder cancers. Compounds that can modulate, e.g., inhibit, the function of p300 and / or CBP are therefore of interest in cancer therapy for tumors with these molecular alterations.

[0009] Furthermore, CBP / p300 regulates the expression of key tumor immune checkpoint proteins, such as CTLA4 / PD-L1 (see Casey et al., Science. vol. 352; pp. 227-231, 2016), and plays an important role in the differentiation and function of T regulatory cells, which are involved in immune evasion by tumors. Thus, compounds that can modulate, e.g., inhibit, the function of p300 and / or CBP are of interest for cancer therapy in combination with agents that target the tumor immune system. In view of the above, there is a need for compounds that target p300 and / or CBP. Such compounds are expected to be able to treat cancer and / or prevent the development of drug resistance.

[0010] OBJECTS AND SUMMARY OF THE PRESENTINVENTION The object of the present invention is to provide compounds that have activity of modulating, e.g. inhibiting, p300 and CBP function, and thus provide therapeutic effect in the treatment of cancer and / or prevention of resistance. Another object of the present invention is to provide compounds suitable for use as medicines. Another object of the present invention is to provide compounds suitable for use in the treatment of cancer, preferably selected from melanoma, non-small cell lung cancer, prostate cancer, bile duct cancer, bladder cancer, pancreatic cancer, thyroid cancer, ovarian cancer, colorectal tumor, hairy cell leukemia, acute myeloid leukemia, multiple myeloma, liver cancer, breast cancer, esophageal cancer, head and neck cancer and glioma, in particular selected from multiple myeloma, acute myeloid leukemia, prostate cancer and non-small cell lung cancer. Another object of the present invention is to provide compounds suitable for use in the prevention of drug resistance in cancer patients, in particular the prevention of resistance to EGFR inhibitors or the prevention of resistance to KRAS inhibitors. Another object of the present invention is to provide compounds that can be used in combination with drugs, such as EGFR inhibitors or KRAS inhibitors, preferably to prevent the development of resistance to these drugs.Another object of the present invention is to provide compounds that are suitable for use in the treatment or amelioration of fibrotic diseases.

[0011] At least some of the above objects can be achieved by the compounds of formula (I) as defined herein or their salts, solvates, cocrystals, tautomers or mixtures, or pharmaceutical compositions comprising same, and medical uses thereof. The inventors of the present invention have surprisingly found that the compounds of formula (I) or their salts, solvates, cocrystals, tautomers or mixtures have activity modulating, in particular inhibiting, p300 and CBP function. In preferred embodiments of the present invention, the compounds exhibit selectivity over other bromodomain-containing proteins. In certain particularly preferred embodiments of the present invention, the compounds have selectivity over the BET protein family. Thus, the compounds of formula (I) as defined herein or their salts, solvates, cocrystals, tautomers or mixtures, or pharmaceutical compositions comprising same, are suitable for use as medicines, in particular for the treatment of cancer, alone or in combination with another drug, preferably another drug that prevents resistance to said drug. Thus, in a first aspect, the present invention provides a compound of formula (I)

[0012] [ka]

[0013] [In the formula, R 3a is a 5-membered heterocyclic ring containing one or more, the same or different, heteroatoms selected from O and N, and each substitutable carbon or heteroatom is independently unsubstituted or substituted with one or more, the same or different, substituents selected from C1-C3-alkyl and a 4-membered heterocyclic ring containing one or more, the same or different, heteroatoms selected from O, N, or S; R 3b is selected from H, F, Cl, and CH3;

[0014] [ka]

[0015] or a pharma- ceutically acceptable salt, solvate, co-crystal, tautomer, or mixture thereof.

[0016] Further embodiments relating to compounds of formula (I) are provided below. In a further aspect, the present invention relates to a pharmaceutical composition comprising a pharma- ceutical effective amount of a compound of formula (I) as defined above or a pharma- ceutically acceptable salt, solvate, co-crystal, tautomer, or mixture thereof, and optionally a pharma- ceutically acceptable carrier, diluent, or excipient. Still further optionally, the pharmaceutical composition of the present invention comprises a KRAS inhibitor. In a related aspect, the present invention relates to a kit comprising (i) a pharmaceutical composition according to the present invention and (ii) a pharmaceutical composition comprising a KRAS inhibitor.

[0017] In a still further aspect, the present invention relates to a compound of formula (I) as defined above or a pharma- ceutically acceptable salt, solvate, co-crystal, tautomer, or mixture thereof, or a pharmaceutical composition as defined above for use in medicine.

[0018] In a further aspect, the present invention relates to a compound of formula (I) as defined above or a pharma- ceutically acceptable salt, solvate, co-crystal, tautomer or mixture thereof, or a pharmaceutical composition as defined above, for use in the treatment or alleviation of cancer, preferably wherein the cancer is selected from melanoma, non-small cell lung cancer, prostate cancer, bile duct cancer, bladder cancer, pancreatic cancer, thyroid cancer, ovarian cancer, colorectal tumors, hairy cell leukemia, acute myeloid leukemia, multiple myeloma, liver cancer, breast cancer, esophageal cancer, head and neck cancer and glioma, in particular multiple myeloma, acute myeloid leukemia, prostate cancer and non-small cell lung cancer. In one embodiment in this context, the compound of formula (I) as defined above or a pharma- ceutically acceptable salt, solvate, co-crystal, tautomer or mixture thereof, or the pharmaceutical composition as defined above, is used in combination with a second therapeutic agent, preferably said therapeutic agent is an anti-cancer agent.

[0019] In a further aspect, the present invention relates to a compound of formula (I) as defined above or a pharma- ceutically acceptable salt, solvate, co-crystal, tautomer, or mixture thereof, or a pharmaceutical composition as defined above, in combination with an EGFR inhibitor for use in the treatment of patients suffering from non-small cell lung cancer (NSCLC), wherein NSCLC exhibits oncogenic alterations in EGFR.

[0020] In a still further aspect, the present invention relates to a compound of formula (I) or a pharma- ceutically acceptable salt, solvate, co-crystal, tautomer, or mixture thereof as defined above, or a pharmaceutical composition as defined above, in combination with a KRAS inhibitor, for use in the treatment of a patient suffering from cancer, wherein the cancer exhibits oncogenic alterations in KRAS.

[0021] In a still further aspect, the present invention relates to a compound of formula (I) as defined above or a pharma- ceutically acceptable salt, solvate, co-crystal, tautomer, or mixture thereof, or a pharmaceutical composition as defined above, for use in the treatment or amelioration of a fibrotic disease, preferably wherein the fibrotic disease is idiopathic pulmonary fibrosis (IPF) or non-alcoholic steatohepatitis (NASH).

[0022] Detailed Description of the Invention Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this invention belongs. The embodiments, preferred and highly preferred embodiments described and disclosed herein should be applied to all aspects and other embodiments, preferred and highly preferred embodiments, regardless of whether it is specifically referred to again or its repetition is avoided for the purpose of brevity.

[0023] The articles "a" and "an" are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. The word "or" is used herein to mean "and / or" unless the context clearly indicates otherwise.

[0024] The term "preferably" is used to describe features or embodiments that are not required by the invention, but that may provide improved technical effects.

[0025] As used herein, the term "about" preferably refers to ±10% of the indicated numerical value, more preferably ±5% of the indicated numerical value, and in particular the indicated numerical value itself.

[0026] The term "compound(s) of the invention" shall be understood to be equivalent to the term "compound(s) according to the invention" and encompasses compound(s) of formula (I) or a salt, solvate, co-crystal, or tautomer or mixture thereof.

[0027] The term "substituted," as used herein, means that a hydrogen atom bonded to the designated atom is replaced with the specified substituent, provided that the substitution results in a stable or chemically feasible compound. Unless otherwise specified, a substituted atom may have one or more substituents, and each substituent is independently selected.

[0028] The term "substitutable," when used in connection with a designated atom, means that attached to the atom is a hydrogen, which may be replaced with a suitable substituent.

[0029] With respect to the above term "substitutable," and particularly with respect to the phrase "each substitutable carbon or heteroatom is independently unsubstituted or substituted with one or more, which may be the same or different,," it is to be understood that this term encompasses all possible options, e.g., carbon and heteroatoms are independently unsubstituted or substituted, or, e.g., only carbon or only heteroatoms are independently unsubstituted or substituted with one or more, which may be the same or different, substituents.

[0030] When reference is made to a particular atom or moiety substituted with "one or more" substituents, the term "one or more" is intended to encompass at least one substituent, e.g., 1 to 10 substituents, preferably 1, 2, 3, 4, or 5 substituents, more preferably 1, 2, or 3 substituents, and most preferably 1 or 2 substituents. When neither the term "unsubstituted" nor the term "substituted" is expressly recited in connection with a moiety, the moiety is considered to be unsubstituted.

[0031] As used herein, the term "alkyl" refers to a monovalent, saturated, acyclic (i.e., non-cyclic) hydrocarbon group that may be straight-chained or branched. Thus, an "alkyl" group does not contain any carbon-carbon double bonds or any carbon-carbon triple bonds. "C1-C3-alkyl" refers to an alkyl group having 1 to 3 carbon atoms. Examples of such alkyl groups are methyl, ethyl, n-propyl, and iso-propyl.

[0032] As used herein, the term "heterocyclyl" or "heterocyclic ring" refers to cyclic groups including monocyclic rings as well as bridged rings, spiro rings and / or fused ring systems (e.g., which may be composed of two or three rings), said cyclic groups containing one or more (e.g., 1, 2, 3, or 4) ring heteroatoms independently selected from O, S, and N, the remaining ring atoms are carbon atoms, one or more S ring atoms (if present) and / or one or more N ring atoms (if present) may be optionally oxidized, one or more carbon ring atoms may be optionally oxidized (i.e., to form an oxo group), and further, said cyclic groups may be saturated, partially unsaturated (i.e., unsaturated but not aromatic) or aromatic.

[0033] Unless otherwise defined, "heterocyclyl" preferably refers to heteroaryl, heterocycloalkyl or heterocycloalkenyl. Preferably, the heterocycle is a monocyclic ring. The number of carbon and heteroatoms in a heterocyclic ring can be defined by indicating the number of ring members, i.e., the number of atoms (also called "ring atoms") that form the ring. For example, a 5-membered heterocyclic ring contains 5 ring atoms, and a 4-membered heterocyclic ring contains 4 ring atoms.

[0034] As used herein, the term "heteroaryl" or "aromatic heterocycle" refers to aromatic ring groups, including monocyclic aromatic rings and bridged and / or fused ring systems containing at least one aromatic ring (e.g., a ring system consisting of two or three fused rings, at least one of which is aromatic; or a bridged ring system consisting of two or three rings, at least one of which is aromatic), which contain one or more (e.g., 1, 2, 3, or 4) ring heteroatoms independently selected from O, S, and N, the remaining ring atoms being carbon atoms, with one or more S ring atoms (if present) and / or one or more N ring atoms (if present) optionally being oxidized, and further, one or more carbon ring atoms optionally being oxidized (i.e., forming an oxo group). Preferably, the aromatic heterocycle is a monocyclic ring. The number of carbons and heteroatoms in an aromatic heterocycle can be defined by indicating the number of ring members, i.e., the number of atoms (also called "ring atoms") that form the ring. For example, a 5-membered aromatic heterocycle contains 5 ring atoms. Exemplary 5-membered aromatic heterocycles include pyrrolyl, furanyl, thiophenyl, imidazolyl, pyrazolyl, oxathiolyl, isoxathiolyl, thiazolyl, isothiazolyl, triazolyl, furazanyl, oxadiazolyl, thiadiazolyl, dioxazolyl, dithiazolyl, and tetrazolyl.

[0035] Those skilled in the art will recognize that the substituents of the compounds of formula (I) may be attached to the remainder of the respective compound via corresponding specific substituents at several different positions. Unless otherwise defined, the preferred attachment positions for the various specific substituents are as illustrated in the examples.

[0036] The scope of the present invention includes salts, particularly pharma- ceutically acceptable salts of compounds of formula (I), such as salts that may be formed by protonation of an atom having a lone pair of electrons susceptible to protonation, e.g., by protonation of an amino group with an inorganic or organic acid, or as a salt of an acidic group (e.g., a carboxylic acid group) with a physiologically acceptable cation. Exemplary base addition salts include, for example: alkali metal salts, such as sodium or potassium salts; alkaline earth metal salts, such as calcium or magnesium salts; zinc salts; ammonium salts; aliphatic amine salts, such as trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, procaine salt, meglumine salt, ethylenediamine salt, or choline salt; aralkylamine salts, such as N,N-dibenzylethylenediamine salt, benzathine salt, benethamine salt; heterocyclic aromatic amine salts, such as pyridine salt, picoline salt, quinoline salt, or isoquinoline salt; quaternary ammonium salts, such as tetramethylammonium salt, tetraethylammonium salt, benzyltrimethylammonium salt, benzyltriethylammonium salt, benzyltributylammonium salt, methyltrioctylammonium salt, or tetrabutylammonium salt; and basic amino acid salts, such as arginine salt, lysine salt, or histidine salt.It is particularly preferred that the compound of formula (I) is in the form of sodium salt.Exemplary acid addition salts include, for example: mineral acid salts, such as hydrochloride, hydrobromide, hydroiodide, sulfate (e.g., sulfate or hydrogen sulfate), nitrate, phosphate (e.g., phosphate, hydrogen phosphate, or dihydrogen phosphate), carbonate, bicarbonate, perchlorate, borate, or thiocyanate; organic acid salts, such as acetate, propionate, butyrate, pentanoate, hexanoate, heptanoate, octanoate, cyclopentanepropionate, decanoate, undecanoate, oleate, stearate, lactate, maleate, oxalate, fumarate, tartrate, malate, citrate, succinate, adipate, glutamate, glycerol ... Cone salts include cone salts, glyconate salts, nicotinate salts, benzoate salts, salicylates, ascorbate salts, pamoate salts (embonate salts), camphorate salts, glucoheptanoate salts, or pivalate salts; sulfonate salts, such as methanesulfonate salts (mesylate salts), ethanesulfonate salts (esylate salts), 2-hydroxyethanesulfonate salts (isethionate salts), benzenesulfonate salts (besylate salts), p-toluenesulfonate salts (tosylate salts), 2-naphthalenesulfonate salts (napsylate salts), 3-phenylsulfonate salts, or camphorsulfonate salts; glycerophosphate salts; and acidic amino acid salts, such as aspartate salts or glutamate salts. Preferred pharmaceutically acceptable salts of the compound of formula (I) include hydrochloride salts, hydrobromide salts, mesylate salts, sulfate salts, tartrate salts, fumarate salts, acetate salts, citrate salts, and phosphate salts. Particularly preferred pharmaceutically acceptable salts of the compound of formula (I) are hydrochloride salts. Thus, it is preferred that the compound of formula (I), including any one of the specific compounds of formula (I) described herein, is in the form of a hydrochloride, hydrobromide, mesylate, sulfate, tartrate, fumarate, acetate, citrate, or phosphate salt, with it being particularly preferred that the compound of formula (I) is in the form of a hydrochloride salt.

[0037] In relation to the base addition salt of the compound of formula (I), it is pointed out that the nitrogen atom (i.e. the hydrogen atom bonded to said nitrogen atom) bridging the phenyl ring of the core structure to the rest of the core structure is acidic.Therefore, it is possible to deprotonate so as to form a base addition salt, for example a sodium salt.Therefore, in a preferred embodiment of the present invention, the preferred salt of the compound of formula (I) comprises a base addition salt, in particular a sodium salt.

[0038] With respect to acid addition salts of compounds of formula (I), it is noted that the nitrogen atom of the core structure typically does not have sufficient basicity for the formation of acid addition salts. However, for example, the substituent R 3a When R 3a When is an imidazole ring, protonation is possible, thus forming an acid addition salt, for example, the hydrochloride salt. Thus, in certain embodiments of the invention, preferred salts of compounds of formula (I) include acid addition salts, particularly the hydrochloride salt.

[0039] "Solvate" refers to an association or complex of one or more solvent molecules with the compound of formula (I). Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethylsulfoxide (DMSO), ethyl acetate, acetic acid, acetonitril, and ethanolamine. The term "hydrate" refers to a complex in which the solvent molecule is water. It should be understood that such solvates of the compound of formula (I) also include solvates of pharma- ceutically acceptable salts of the compound of formula (I).

[0040] "Co-crystal" refers to a crystal structure that contains at least two different compounds that are solid in their pure form under ambient conditions. Co-crystals are made from neutral molecular species, and all species remain neutral after crystallization. Moreover, typically and preferably, they are crystalline homogeneous phase materials in which two or more building compounds are present in a defined stoichiometric ratio. See here Wang Y and Chen A, 2013; and Springuel GR et al., 2012, and U.S. Patent No. 6,570,036.

[0041] The compounds of formula (I) have a defined stereochemistry. The present invention encompasses tautomers of the compounds of formula (I), such as imine-enamine tautomers.

[0042] The compounds of formula (I) may be amorphous or may exist in one or more different crystalline states (polymorphs), which may have different macroscopic properties, e.g., stability, or may exhibit different biological properties, e.g., activity. The present invention relates to amorphous and crystalline forms of the compounds of formula (I), mixtures of different crystalline states of the compounds of formula (I), and to amorphous or crystalline salts thereof.

[0043] The scope of the present invention also includes compounds of formula (I) in which one or more atoms have been replaced with a particular isotope of the corresponding atom. For example, the present invention includes compounds in which one or more hydrogen atoms (or, for example, all hydrogen atoms) have been replaced with a deuterium atom (i.e., 2 H; also referred to as "D"). Thus, the present invention also includes compounds of formula (I) that are deuterium-enriched. Naturally occurring hydrogen is approximately 99.98 mole % hydrogen-1 ( 1 H) and about 0.0156 mole percent deuterium ( 2Deuterium is a mixture of isotopes, including H or D. The deuterium content at one or more hydrogen positions of the compound of formula (I) can be increased using deuteration techniques known in the art. For example, the compound of formula (I) or the reactants or precursors used in the synthesis of the compound of formula (I) can be subjected to a H / D exchange reaction, for example, using deuterium (DO). Further suitable deuteration techniques are described in Atzrodt J et al., Bioorg Med Chem, vol. 20 (no. 18), pp. 5658-5667, 2012; William JS et al., Journal of Labelled Compounds and Radiopharmaceuticals, vol. 53 (no. 11-12), pp. 635-644, 2010; Modvig A et al., J Org Chem, vol. 79, pp. 5861-5868, 2014. The deuterium content can be determined, for example, using mass spectrometry or nuclear magnetic resonance spectroscopy. Unless specifically noted otherwise, the compounds of formula (I) are preferably not deuterium enriched. Thus, naturally occurring hydrogen atoms or 1H hydrogen atoms are preferably present in the compounds of formula (I).

[0044] The present invention also relates to a compound in which one or more atoms are a positron-emitting isotope of the corresponding atom, e.g. 18 F, 11 C. 13 N, 15 O. 76 Br, 77 Br, 120 I and / or 124 I. Such compounds can be used as tracers or imaging probes in positron emission tomography (PET). Thus, the present invention provides compounds of formula (I) in which (i) one or more fluorine atoms (or, for example, all fluorine atoms) are 18 (ii) one or more carbon atoms (or, for example, all carbon atoms) are replaced with an F atom; 11 (iii) one or more nitrogen atoms (or, for example, all nitrogen atoms) are replaced by a C atom; 13Compounds of formula (I) (iv) in which one or more oxygen atoms (or, for example, all oxygen atoms) are replaced by an N atom 15 (v) one or more bromine atoms (or, for example, all bromine atoms) are replaced by an O atom; 76 (vi) compounds of formula (I) in which one or more bromine atoms (or, for example, all bromine atoms) are replaced by 77 (vii) compounds of formula (I) in which one or more iodine atoms (or, for example, all iodine atoms) are replaced by Br atoms; 120 and (viii) compounds of formula (I) in which one or more iodine atoms (or, for example, all iodine atoms) are replaced by an I atom. 124 This includes compounds of formula (I) in which any I atom is replaced with a specific isotope. Generally, it is preferred that none of the atoms of the compounds of formula (I) are replaced with a specific isotope.

[0045] The term "pharmaceutical acceptable excipients" as used herein refers to compounds that are commonly included in pharmaceutical compositions, and these excipients are known to those skilled in the art. Examples of suitable excipients are the illustrative ones listed below. Typically, pharmaceutical acceptable excipients can be defined as pharmaceutical inactive.

[0046] Preferred embodiments of the present invention are defined hereinafter. As indicated above, the present invention relates to a compound of formula (I)

[0047] [ka]

[0048] [In the formula, R 3ais a 5-membered heterocyclic ring containing one or more, the same or different, heteroatoms selected from O and N, and each substitutable carbon or heteroatom is independently unsubstituted or substituted with one or more, the same or different, substituents selected from C1-C3-alkyl and a 4-membered heterocyclic ring containing one or more, the same or different, heteroatoms selected from O, N, or S; R 3b is selected from H, F, Cl, and CH3;

[0049] [ka]

[0050] or a pharma- ceutically acceptable salt, solvate, co-crystal, tautomer, or mixture thereof. In one embodiment, the present invention provides

[0051] [ka]

[0052] or a salt thereof. In one embodiment, the present invention provides

[0053] [ka]

[0054] or a salt, solvate, co-crystal, tautomer, or mixture thereof, wherein the compound of formula (I) is not any one of:

[0055] In one embodiment, the present invention provides a method for the preparation of a compound comprising the steps of:3a is a 5-membered heteroaryl ring containing one or more, the same or different, heteroatoms selected from O and N, and each substitutable carbon or heteroatom is independently unsubstituted or substituted with one or more, the same or different, substituents selected from CH and oxetanyl, or a pharma- ceutically acceptable salt, solvate, co-crystal, tautomer, or mixture thereof.

[0056] In a preferred embodiment, R 3a is selected from the group consisting of imidazolyl, triazolyl, and oxadiazolyl, and each substitutable carbon or heteroatom is independently unsubstituted or substituted with one or more, the same or different, substituents selected from CH and oxetanyl.

[0057] In another embodiment, the present invention provides a method for the preparation of 3b is selected from H, F, and CH3, or a pharma- ceutically acceptable salt, solvate, co-crystal, tautomer, or mixture thereof.

[0058] In a preferred embodiment, the present invention relates to a compound of formula (I)

[0059] [ka]

[0060] or a pharma- ceutically acceptable salt, solvate, co-crystal, tautomer, or mixture thereof, of formula (I) selected from the group consisting of: In one particularly preferred embodiment, the present invention provides a method for producing a medicament for the treatment of a cancer, comprising:

[0061] [ka]

[0062] or a pharma- ceutically acceptable salt, solvate, co-crystal, tautomer, or mixture thereof.

[0063] In another particularly preferred embodiment, the present invention comprises:

[0064] [ka]

[0065] or a pharma- ceutically acceptable salt, solvate, co-crystal, tautomer, or mixture thereof.

[0066] In another particularly preferred embodiment, the present invention comprises:

[0067] [ka]

[0068] or a pharma- ceutically acceptable salt, solvate, co-crystal, tautomer, or mixture thereof.

[0069] In another particularly preferred embodiment, the present invention comprises:

[0070] [ka]

[0071] or a pharma- ceutically acceptable salt, solvate, co-crystal, tautomer, or mixture thereof.

[0072] In another particularly preferred embodiment, the present invention comprises:

[0073] [ka]

[0074] or a pharma- ceutically acceptable salt, solvate, co-crystal, tautomer, or mixture thereof.

[0075] In yet another particularly preferred embodiment, the present invention provides a compound of formula (I) in the form of a sodium salt, the sodium salt of the compound of formula (I) having the following structure:

[0076] [ka]

[0077] The present invention relates to compounds of formula (I) having the formula:

[0078] The compounds of the present invention inhibit multiple myeloma cell proliferation and / or survival, preferably with an EC50 of 1000 nM or less, preferably 500 nM or less, more preferably 100 nM or less, even more preferably 50 nM or less, and especially preferably 10 nM or less, as measured indirectly by metabolic activity of OPM2 cells. This disruption of OPM2 proliferation is a well-established phenomenon induced by CBP / p300 bromodomain inhibition and correlates well with the compound's CBP / p300 bromodomain inhibition. (Raisner; Cell Reports, 2018, vol. 24, pp. 1722-1729, https: / / doi.org / 10.1016 / j.celrep.2018.07.041; own data).

[0079] The compounds of the present invention preferably bind to the bromodomains of p300 and CBP. In one embodiment, the compounds of the present invention bind to the bromodomains of p300 and CBP and have an activity with an EC50 of 1000nM or less, preferably 500nM or less, more preferably 100nM or less, even more preferably 50nM or less, and particularly preferably 10nM or less.

[0080] The present invention further relates to pharmaceutical compositions comprising the compounds of the present invention and optionally one or more pharma- ceutically acceptable excipient(s) and / or carriers.

[0081] The types of cancer that can be treated with the compounds and compositions of the present invention are typically non-melanoma skin cancer, esophagogastric adenocarcinoma, glioblastoma, bladder cancer, bladder urothelial carcinoma, esophagogastric cancer, melanoma, non-small cell lung cancer, endometrial cancer, cervical adenocarcinoma, esophageal squamous cell carcinoma, breast cancer, head and neck squamous cell carcinoma, germ cell tumors, small cell lung cancer, ovarian cancer, soft tissue sarcoma, hepatocellular carcinoma, colorectal adenocarcinoma, cervical squamous cell carcinoma, bile duct carcinoma, prostate cancer, upper tract urothelial carcinoma, diffuse glioma, colorectal cancer, duodenal ampullary carcinoma, adenocarcinoma, esophageal cancer, gastroenteritis, and pulmonary arterial cancer. The cancer is selected from renal cortical carcinoma, head and neck carcinoma, renal clear cell carcinoma, hepatobiliary carcinoma, glioma, non-Hodgkin's lymphoma, mesothelioma, salivary gland carcinoma, renal non-clear cell carcinoma, various neuroepithelial tumors, pheochromocytoma, thymic tumors, multiple myeloma, renal cell carcinoma, bone cancer, pancreatic cancer, leukemia, peripheral nervous system tumors, thyroid cancer, B-lymphoblastic leukemia, monoclonal B-cell lymphocytosis, lymphoma, hairy cell leukemia, acute myeloid leukemia, Wilms' tumor, particularly melanoma, and non-small cell lung cancer, particularly melanoma and non-small cell lung cancer. The above diseases typically show a greater than 3% mutation incidence in RTK (EGFR, ERBB2, ERBB3, ERBB4, PDGFA, PDGFB, PDGFRA, PDGFRB, KIT, FGF1, FGFR1, IGF1, IGFR, VEGFA, VEGFB, KDR) and / or MAPK pathway members (KRAS, HRAS, BRAF, RAF1, MAP3K1 / 2 / 3 / 4 / 5, MAP2K1 / 2 / 3 / 4 / 5, MAPK1 / 3 / 4 / 6 / 7 / 8 / 9 / 12 / 14, DAB, RASSF1, RAB25).

[0082] In further embodiments, the tumor is an adrenocortical carcinoma, an astrocytoma, a basal cell carcinoma, a carcinoid, a carcinoma of the heart, a carcinoma of the bile duct, a chordoma, a chronic myeloproliferative neoplasm, a craniopharyngioma, a ductal carcinoma in situ, an ependymoma, an intraocular melanoma, a gastrointestinal carcinoid tumor, a gastrointestinal stromal tumor (GIST), a gestational trophoblastic disease, a glioma, a histiocytosis, a leukemia {e.g., acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (myelogenous leukemia), a myeloma, ... leukemia (CML), hairy cell leukemia, myeloid leukemia, myelogenous leukemia), lymphoma (e.g., Burkitt's lymphoma [non-Hodgkin's lymphoma], cutaneous T-cell lymphoma, Hodgkin's lymphoma, mycosis fungoides, Sézary syndrome, AIDS-related lymphoma, follicular lymphoma, diffuse large B-cell lymphoma), melanoma, Merkel cell carcinoma, mesothelioma, myeloma (e.g., multiple myeloma), myelodysplastic syndrome, papillomatosis, paraganglioma, pheochromocytoma, pleuropulmonary blastoma, retinoblastoma, sarcoma (e.g., Ewing's sarcoma, Kaposi's sarcoma, osteosarcoma, rhabdomyosarcoma, uterine sarcoma, vascular sarcoma), Wilms tumor and / or cancer of the adrenal cortex, anus, appendix, bile duct, bladder, bone, brain, breast, bronchus, central nervous system, cervix, colon, endometrium, esophagus, eye, fallopian tube, gallbladder, gastrointestinal tract, germ cell, head and neck, heart, intestine, kidney (e.g., Wilms tumor), larynx, liver, lung (e.g., non-small cell lung cancer, small cell lung cancer), mouth, nasal cavity, oral cavity, ovary, pancreas, rectum, skin, stomach, testes, throat, thyroid gland, penis, pharynx, peritoneum, pituitary gland, prostate, rectum, salivary gland, ureter, urethra, uterus, vagina, vulva, or acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemialeukemia), acute T-cell leukemia, basal cell carcinoma, bile duct cancer, bladder cancer, brain cancer, breast cancer, bronchogenic carcinoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, proliferative changes, embryonal carcinoma, endometrial cancer, endothelial sarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen receptor positive breast cancer, essential thrombocythemia, Ewing's tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, head and neck cancer, hemangioblastoma, liver cancer, hepatocellular carcinoma, hormone insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, lung cancer, lymphangioendothelial sarcoma, Lymphangiosarcoma, lymphoblastic leukemia, lymphoma, lymphoid malignancies of T-cell or B-cell origin, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myeloid leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midline carcinoma (NMC), non-small cell lung cancer (NSCLC), oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pineal gland The cancer may be polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung cancer, solid tumors (carcinomas and sarcomas), small cell lung cancer, gastric cancer, squamous cell carcinoma, s)movioma, sweat gland carcinoma, thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumor, uterine cancer, or Wilms' tumor.

[0083] The tumor may also be one that depends on androgen receptor (AR) signaling, or that overexpresses c-Myc, or that in cancer, CBP and / or p300 function is activated.Cancers that can be treated include cancers that express AR or are otherwise associated with AR, cancers that harbor loss-of-function mutations in CBP or p300, and cancers that have activated CBP and / or p300.Cancers that can be treated include, but are not limited to, prostate cancer, breast cancer, bladder cancer, lung cancer, lymphoma and leukemia.Prostate cancer may be, for example, castration-resistant prostate cancer (CRPC).Lung cancer may be, for example, non-small cell lung cancer or small cell lung cancer.

[0084] In particular, the present invention relates to a compound of the present invention or a pharmaceutical composition of the present invention for use in the treatment or alleviation of cancer, preferably wherein the cancer is selected from melanoma, non-small cell lung cancer, prostate cancer, bile duct cancer, bladder cancer, pancreatic cancer, thyroid cancer, ovarian cancer, colorectal tumor, hairy cell leukemia, acute myeloid leukemia, multiple myeloma, liver cancer, breast cancer, esophageal cancer, head and neck cancer and glioma, in particular multiple myeloma, acute myeloid leukemia, prostate cancer and non-small cell lung cancer.

[0085] The present invention further relates to a compound of the present invention or a pharmaceutical composition of the present invention for use as indicated above, wherein said compound of the present invention or said pharmaceutical composition of the present invention is used in combination with a second therapeutic agent, preferably said therapeutic agent is an anti-cancer agent. The present invention further relates to a method of treating or ameliorating cancer, preferably wherein the cancer is selected from melanoma, non-small cell lung cancer, prostate cancer, bile duct cancer, bladder cancer, pancreatic cancer, thyroid cancer, ovarian cancer, colorectal tumors, hairy cell leukemia, acute myeloid leukemia, multiple myeloma, liver cancer, breast cancer, esophageal cancer, head and neck cancer and glioma, in particular multiple myeloma, acute myeloid leukemia, prostate cancer and non-small cell lung cancer, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the present invention or a pharmaceutical composition of the present invention.

[0086] The present invention also relates to a method for treating or ameliorating cancer by preventing or delaying drug resistance, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the present invention or a pharmaceutical composition of the present invention.

[0087] Furthermore, the present invention relates to the use of a compound of the present invention or a pharmaceutical composition of the present invention for the manufacture of a medicament for treating or ameliorating cancer.

[0088] Furthermore, the present invention relates to the use of a compound of the present invention or a pharmaceutical composition of the present invention for the manufacture of a medicament for treating or ameliorating cancer by preventing or delaying drug resistance. Non-Small Cell Lung Cancer (NSCLC) Embodiments

[0089] In one embodiment, the present invention also relates to a compound of the present invention or a pharmaceutical composition of the present invention in combination with an EGFR inhibitor for use in treating patients suffering from NSCLC, the NSCLC showing oncogenic changes in EGFR.This embodiment can also be called a compound of the present invention or a pharmaceutical composition of the present invention in combination with an EGFR inhibitor for use in treating patients suffering from NSCLC, the NSCLC being characterized by an EGFR mutation profile that is given to one or more indications of the label of the EGFR inhibitor used in combination, or the NSCLC being characterized by an EGFR mutation profile that is targeted in a clinical trial setting by the EGFR inhibitor used in combination.

[0090] In a preferred embodiment of this aspect, the oncogenic alterations in EGFR result in hyperactivation of EGFR. Oncogenic alterations in EGFR can even result in constitutively active EGFR (in the sense that the enzymatic activity, i.e., protein-kinase activity, of EGFR is constitutively active).

[0091] In a further preferred embodiment of this aspect, the oncogenic alteration in EGFR is caused by a deletion and / or insertion in exon 18 or exon 19 or exon 20 of the EGFR gene; a kinase domain duplication in the EGFR gene; an amplification of the EGFR gene; a mutation of at least one base in the EGFR gene resulting in an amino acid substitution in EGFR selected from the group consisting of L858R, G719S, G719A, G719C, V765A, T783A, S768I, S768V, L861Q, E709X, L819Q, A750P and combinations thereof; and any combination of the foregoing. It may be preferred that the oncogenic change is caused by a deletion in exon 19 of the EGFR gene; an insertion in exon 20 of the EGFR gene; at least one base mutation in the EGFR gene that results in an amino acid substitution in EGFR, selected from the group consisting of L858R, G719S, G719A, G719C, V765A, T783A, S768I, S768V, L861Q, E709X, L819Q, A750P and combinations thereof; and any combination of the above.It may be preferred that the oncogenic change is caused by a deletion in exon 19 of the EGFR gene; at least one base mutation in the EGFR gene that results in an amino acid substitution L858R in EGFR; and combinations thereof.The deletion and insertion in exon 18 of the EGFR gene is in particular a deletion that results in a deletion of E709-T710 in EGFR and an insertion of D at this position in EGFR. The deletion in exon 19 of the EGFR gene is in particular a deletion resulting in a deletion of E746-A750 or L747-E749 in EGFR. The deletion and insertion in exon 19 of EGFR is in particular a deletion resulting in a deletion of L747-A750 in EGFR and an insertion of P at this position in EGFR, or a deletion resulting in a deletion of L747-T751 in EGFR and an insertion of S at this position in EGFR.An insertion in exon 20 of the EGFR gene is in particular an insertion resulting in the insertion of an amino acid (in the sense of any amino acid or X) at a position in EGFR between two amino acids selected from the group consisting of D761-E762, A763-Y764, Y764-V765, A767-S768, S768-V769, V769-D770, D770-N771, N771-P772, P772-H773, H773-V774, V774-C775, V765-M766, and combinations thereof. Most preferably, the oncogenic change is caused by a deletion in exon 19 of the EGFR gene (particularly a deletion resulting in a deletion of E746-A750 or L747-E749 in EGFR); at least one base mutation in the EGFR gene resulting in an amino acid substitution L858R or A750P in EGFR; and combinations thereof. It is also highly preferred that the oncogenic change is caused by a deletion in exon 19 of the EGFR gene, or at least one base mutation in the EGFR gene resulting in an amino acid substitution L858R in EGFR. When "X" is referred to herein as an amino acid, "X" refers to any amino acid (but of course, where applicable, it is an amino acid different from the wild-type amino acid at each position, for example, for E709X).

[0092] In one embodiment of this aspect, NSCLC does not further show resistance alteration in EGFR.Therefore, the compound of the present invention or the pharmaceutical composition of the present invention combined with EGFR inhibitor for use in the present invention is used as first-line treatment, and the EGFR inhibitor of combination can be any EGFR inhibitor that is administered (or is applied) to treat NSCLC that shows oncogenic alteration in EGFR.

[0093] In another embodiment of this aspect, NSCLC further shows resistance change in EGFR.The resistance change in EGFR can be caused by at least one base mutation in EGFR gene, which causes amino acid substitution in EGFR, in particular selected from the group consisting of T790M, C797X (mainly C797S), L792X, G796X, L718Q, L718V, G724S, D761Y, V834L, T854A, and combinations thereof.It may be preferred that the resistance change in EGFR is caused by at least one base mutation in EGFR gene, which causes amino acid substitution in EGFR, selected from the group consisting of T790M, C797X (mainly C797S), L718Q, L718V, T854A, and combinations thereof.Most preferred that the resistance change in EGFR is caused by at least one base mutation in EGFR gene, which causes amino acid substitution T790M in EGFR. When "X" is referred to herein as an amino acid, "X" refers to any amino acid (but of course an amino acid different from the wild type amino acid at each position, where applicable, for example, C797X).

[0094] When NSCLC further shows resistance changes in EGFR, the patient has been previously treated with a (first) EGFR inhibitor that was initially effective but then became ineffective due to the development of resistance, especially due to the development of EGFR resistance changes. It is important to understand that in the combination for use in the present invention, the EGFR inhibitor in such a scenario is not the (first) EGFR inhibitor that was previously administered, but the (second or third) EGFR inhibitor that is initially therapeutically effective, although there is at least one resistance change when administered alone. It is a common observation that further resistance to this (second or third) EGFR inhibitor will develop over time, and this (second or third) EGFR inhibitor will eventually become ineffective again, so we refer to it as "initial therapeutic effectiveness". In such a scenario, the combination for use in the present invention is used as a second or third line treatment. For example, gefitinib may have been previously administered (alone as first-line treatment) to a patient suffering from NSCLC exhibiting oncogenic changes, where treatment with gefitinib became ineffective over time (typically after a period of about 10 to about 12 months), and there was a discovery (e.g., via biopsy and corresponding testing to detect EGFR mutations) that EGFR T790M resistance changes had developed in the tumor during treatment with gefitinib. In such a situation, gefitinib is not used in the combination for use in the present invention, with the exception of osimertinib, which has been shown to be effective (and is indicated) in the treatment of patients with EGFR T790M mutation-positive NSCLC, whose disease has progressed during or after receiving EGFR tyrosine kinase inhibitor (TKI) therapy.

[0095] Taking the above into consideration, in one embodiment, the present invention relates to a compound of the present invention or a pharmaceutical composition of the present invention in combination with an EGFR inhibitor for use in treating a patient suffering from NSCLC, wherein the NSCLC exhibits oncogenic alterations in EGFR, with the proviso that, if the NSCLC further exhibits resistance alterations in EGFR due to previous administration of an EGFR inhibitor, the EGFR inhibitor of the combination is not the previously administered EGFR inhibitor, and in particular is an EGFR inhibitor that is therapeutically effective despite the occurrence of resistance alterations in EGFR (i.e. resistance alterations that rendered the previously administered EGFR inhibitor therapeutically ineffective). A compound of the invention in combination with an EGFR inhibitor or a pharmaceutical composition of the invention for use according to this aspect of the invention may also be referred to as a compound of the invention in combination with an EGFR inhibitor, provided that, if the NSCLC further exhibits resistance changes in EGFR due to previous administration of an EGFR inhibitor, the EGFR inhibitor of the combination is not the previously administered EGFR inhibitor and is an EGFR inhibitor that, when administered alone, is therapeutically effective during the first treatment cycle even if resistance changes occur, or, if the NSCLC further exhibits resistance changes in EGFR due to previous administration of an EGFR inhibitor, the EGFR inhibitor of the combination is not the previously administered EGFR inhibitor and is an EGFR inhibitor that is indicated for the treatment of the NSCLC further exhibiting resistance changes in EGFR.

[0096] To take an example with respect to two specific EGFR inhibitors (i.e. "X" and "EGFR inhibitor combination"), the above paragraph may in one embodiment refer to a compound of the present invention or a pharmaceutical composition of the present invention in combination with an EGFR inhibitor for use in treating a patient suffering from NSCLC, wherein the NSCLC exhibits oncogenic alterations in EGFR, with the proviso that the EGFR inhibitor of the combination is not the EGFR inhibitor X, if the NSCLC further exhibits resistance alterations in EGFR due to previous administration of EGFR inhibitor X. It is noted that the EGFR inhibitor of the combination is therapeutically effective even in the event of the occurrence of resistance alterations in EGFR (i.e. resistance alterations that rendered the previously administered EGFR inhibitor X therapeutically ineffective).

[0097] In another embodiment of this aspect, the EGFR inhibitor is a small molecule inhibitor or an antibody.Thus, in such an embodiment, the EGFR inhibitor is not a nucleic acid-based inhibitor, for example, shRNA or RNAi directed to EGFR.In yet another embodiment of the first aspect, the EGFR inhibitor is a small molecule inhibitor.In a further embodiment of the first aspect, the EGFR inhibitor inhibits the tyrosine kinase activity of EGFR.

[0098] EGFR inhibitors include ABBV-321, abivertinib, afatinib, AFM24, alfutinib (AST2818), almonertinib (HS-10296), apatinib, ASK120067, avitinib (AC0010), AZD3759, BBT-176, BTDX-1535, BLU-451, BLU-701, and BLU- 945, brigutinib, CK-101 (RX-518), CLN-081 (TAS6417), CM93, D0316, D0317, D0318, dacomitinib, DZD9008, EMB-01, erlotinib, FCN-411, gefitinib, icotinib, keynatinib, lapatinib, lazertinib, MCL A-129, MRG003, mobocertinib, nazartinib, neratinib, olafertinib, osimertinib, poziotinib, pyrotinib, resibertinib, SH-1028 (oritinib), sutetinib, TAS2940, TAS6417, vandetanib, barlitinib, XZP-5809, amivantamab, CDP1, cetuximab, GC1118, HLX07, JMT101, M1231, necitumumab, nimotuzumab, matuzumab, panitumumab, SCT200, SI-B001, SYN004, Z650, zalutumumab, ZN-e4, ZZ06, and combinations thereof. EGFR inhibitors are instead ABBV-321, abivertinib, afatinib, alflutinib, almonertinib, apatinib, AZD3759, brigitinib, D0316, D0317, D0318, dacomitinib, DZD9008, erlotinib, FCN-411, gefitinib, icotinib, lapatinib, lazertinib, mobocertinib, nazartinib, neratinib, orafeltinib, osimertinib. It may also be selected from the group consisting of nib, poziotinib, pyrotinib, resibertinib, TAS6417, vandetanib, barlitinib, XZP-5809, amivantamab, CDP1, cetuximab, GC1118, HLX07, JMT101, M1231, necitumumab, nimotuzumab, matuzumab, panitumumab, SCT200, SI-B001, SYN004, zalutumumab, and combinations thereof.In a preferred embodiment, the EGFR inhibitor is selected from the group consisting of abivertinib, afatinib, alflutinib, almonertinib, apatinib, AZD3759, brigutinib, D0316, D0317, D0318, dacomitinib, DZD9008, erlotinib, FCN-411, gefitinib, icotinib, lapatinib, lazertinib, mobocertinib, nazartinib, neratinib, orafeltinib, osimertinib, poziotinib, pyrotinib, resibertinib, TAS6417, vandetanib, varlitinib, XZP-5809, and combinations thereof. In a more preferred embodiment, the EGFR inhibitor is gefitinib or osimertinib. Most preferably, the EGFR inhibitor is osimertinib.

[0099] In a preferred embodiment of this aspect, a compound of the invention or a pharmaceutical composition of the invention is administered to the patient in combination with an EGFR inhibitor during each treatment cycle.

[0100] In yet another embodiment of this aspect, an EGFR inhibitor is administered as the only active agent during a first treatment cycle, followed by additional administration of a compound of the present invention or a pharmaceutical composition of the present invention during subsequent treatment cycles, and no resistance changes in EGFR have yet occurred in response to administration of the EGFR inhibitor alone during the first treatment cycle (i.e., prior to administration of the combination of the present invention). As mentioned above, the occurrence of resistance changes can be assessed, for example, via biopsy and corresponding tests to detect EGFR mutations.

[0101] In another embodiment of this aspect, (i) the compound of the present invention or the pharmaceutical composition of the present invention and (ii) the EGFR inhibitor are administered as separate dosage forms or are included in a single dosage form. When (i) and (ii) are administered as separate dosage forms, the administration during each treatment cycle may be simultaneous or sequential. This includes the option that the compound of the present invention or the pharmaceutical composition of the present invention is administered first, followed by the administration of the EGFR inhibitor.

[0102] In yet another embodiment of this aspect, the treatment results in an extension of the duration of the therapeutic effect of the EGFR inhibitor compared to the duration of the therapeutic effect of the EGFR inhibitor when administered as the only active agent. In yet another embodiment, the treatment results in an increase in the therapeutic efficacy of the EGFR inhibitor compared to the therapeutic efficacy of the EGFR inhibitor when administered as the only active agent. In another embodiment, the treatment results in the prevention of resistance to the EGFR inhibitor.

[0103] In another embodiment of this aspect, the compound of the present invention is administered in a daily amount of about 1 mg to about 3000 mg, preferably about 10 mg to about 2000 mg, more preferably about 15 mg to about 1000 mg. The compound of the present invention may be preferably administered in a daily amount of about 10 mg, about 15 mg, about 20 mg, about 50 mg, about 100 mg, about 250 mg, about 500 mg, about 1000 mg, about 1500 mg, about 2000 mg, about 2500 mg, or about 3000 mg. Administration may be intermittent, i.e., not every day, but on the days when administration is performed, the daily amount described above may be administered.

[0104] In another embodiment of this aspect, the EGFR inhibitor is administered in a daily amount that is in the range of a typical daily amount (particularly, if possible, the daily amount described for the EGFR inhibitor on the label) when the EGFR inhibitor is administered as the only active agent. The typical daily amount (or the applicable daily amount, if possible) depends on the particular EGFR inhibitor to be used. Thus, gefitinib may be administered, for example, in a combination for use according to the present invention, in a daily amount of between about 50 and about 300 mg, preferably between about 100 mg and about 250 mg, and most preferably between about 150 mg and about 250 mg. Osimertinib may be administered, for example, in a combination for use according to the present invention, in a daily amount of between about 5 and about 1500 mg, preferably between about 10 mg and about 100 mg, and most preferably between about 50 mg and about 80 mg. Erlotinib may be administered, for example, in a combination for use of the present invention, in a daily dose of about 10 mg to about 300 mg, preferably about 25 mg to about 200 mg, and most preferably about 100 mg to about 150 mg. Afatinib may be administered, for example, in a combination for use of the present invention, in a daily dose of about 5 mg to about 100 mg, preferably about 10 mg to about 80 mg, and most preferably about 20 mg to about 40 mg. Dacomitinib may be administered, for example, in a combination for use of the present invention, in a daily dose of about 5 mg to about 100 mg, preferably about 10 mg to about 80 mg, and most preferably about 15 mg to about 50 mg.

[0105] In another embodiment of the first aspect, the EGFR inhibitor is administered in a daily amount lower than the typical daily amount described above when the EGFR inhibitor is administered as the only active agent.In other words, when the EGFR inhibitor is not the only active agent, but is administered in combination with the compound of the present invention or the pharmaceutical composition of the present invention, the EGFR inhibitor may be administered in an amount lower than the amount used when the EGFR inhibitor is administered as the only active agent.This means, for example, for the examples given above, that the daily amount is at the lower end of the given range, or even below these ranges. In yet a further embodiment of this aspect, the invention provides (i) a compound of the invention, in combination with (ii) an EGFR inhibitor, for use in treating a patient suffering from non-small cell lung cancer (NSCLC), wherein the NSCLC exhibits oncogenic alterations in EGFR, and the compound of the invention comprises:

[0106] [ka]

[0107] The present invention relates to a compound of the present invention, which is selected from the group consisting of:

[0108] In this embodiment, the EGFR inhibitor is osimertinib, and the oncogenic change may be preferably caused by a deletion in exon 19 of the EGFR gene (particularly a deletion resulting in a deletion of E746-A750 or L747-E749 in EGFR); at least one base mutation in the EGFR gene resulting in an amino acid substitution L858R or A750P in EGFR; and combinations thereof. At least one base mutation in the EGFR gene resulting in an amino acid substitution T790M in EGFR, which corresponds to a resistance change in EGFR, may or may not be present in the embodiment in which the EGFR inhibitor is osimertinib.

[0109] In a related aspect, the present invention is directed to a method of treating NSCLC in a patient in need thereof, comprising administering to the patient (i) an effective amount of a compound of the present invention and (ii) an effective amount of an EGFR inhibitor, wherein the NSCLC exhibits oncogenic alterations in EGFR.

[0110] In another related aspect, the present invention is directed to a method of extending the duration of therapeutic effect of an EGFR inhibitor in a patient in need thereof, comprising administering to the patient (i) an effective amount of a compound of the present invention and (ii) an effective amount of an EGFR inhibitor, wherein the NSCLC exhibits oncogenic alterations in EGFR. In other words, the duration of therapeutic effect of the EGFR inhibitor (when administered in combination) is extended compared to the duration of therapeutic effect of the EGFR inhibitor when administered as the only active agent in the treatment of NSCLC.

[0111] In another related aspect, the present invention is directed to a method for increasing the therapeutic efficacy of an EGFR inhibitor in a patient in need thereof, comprising administering to the patient (i) an effective amount of a compound of the present invention and (ii) an effective amount of an EGFR inhibitor, wherein the NSCLC exhibits oncogenic alterations in EGFR. In other words, the therapeutic efficacy of the EGFR inhibitor (when administered in combination) is increased compared to the therapeutic efficacy of the EGFR inhibitor when administered as the only active agent in the treatment of NSCLC.

[0112] In another related aspect, the present invention is directed to a method for blocking proliferation of NSCLC cells, the method comprising administering to the cells (i) an effective amount of a compound of the present invention and (ii) an effective amount of an EGFR inhibitor, wherein the NSCLC cells exhibit oncogenic alterations in EGFR.

[0113] In another related aspect, the invention is directed to a method for slowing the proliferation of NSCLC cells, the method comprising administering to the cells (i) an effective amount of a compound of the invention and (ii) an effective amount of an EGFR inhibitor, wherein the NSCLC cells exhibit oncogenic alterations in EGFR.

[0114] In the above related aspects, the embodiments outlined above for the first aspect apply equally.

[0115] The term "EGFR" as used herein refers to "epidermal growth factor receptor." EGFR is a transmembrane protein that is activated by the binding of its specific ligands, including epidermal growth factor. Upon activation by its growth factor ligands, EGFR transitions from an inactive monomeric form to an active homodimer. In addition to forming homodimers after ligand binding, EGFR can also pair with another member of the ErbB receptor family, e.g., ErbB2 / Her2 / neu, to create an activated heterodimer. EGFR dimerization stimulates its intrinsic intracellular protein-tyrosine kinase activity. This results in autophosphorylation of several tyrosine residues within the C-terminal domain of EGFR, which leads to downstream activation and signaling by several other proteins that associate with the phosphorylated tyrosines through their own phosphotyrosine-binding SH2 domains. These downstream signaling proteins initiate several signaling cascades, mainly the MAPK, Akt and JNK pathways, leading to DNA synthesis and cell proliferation. Mutations that lead to EGFR hyperactivation are associated with several cancers, including lung cancer, and can result in its constant activation, which results in uncontrolled cell division.

[0116] The term "EGFR inhibitor" as used herein refers to a molecule capable of acting on EGFR such that the intracellular downstream signaling that ultimately leads to cell proliferation is inhibited. The term "inhibited" in this context preferably means that downstream signaling is no longer occurring. However, if a given downstream signaling (set at 100%) is significantly reduced, for example to a level of about 70%, about 60%, about 50%, about 40%, about 30%, preferably about 20%, more preferably about 10% or most preferably about 5% or less, such reduction in downstream signaling is still encompassed by the term "inhibit intracellular downstream signaling". In terms of the medical use of compounds that inhibit downstream signaling, complete inhibition of signaling may not be required to achieve a sufficient therapeutic effect. Thus, it should be understood that the term "inhibit" as used herein also refers to a reduction in downstream signaling in this context, which is sufficient to achieve the desired effect. EGFR inhibitors can bind to and thus block the extracellular ligand-binding domain of EGFR. Such EGFR inhibitors are typically antibodies, in particular monoclonal antibodies selected from the group consisting of amivantamab, CDP1, cetuximab, GC1118, HLX07, JMT101, M1231, necitumumab, nimotuzumab, matuzumab, panitumumab, SCT200, SI-B001, SYN004, zalutuzumab, and combinations thereof. EGFR inhibitors can also bind to the cytoplasmic side of the receptor, thereby inhibiting EGFR tyrosine kinase activity.Such EGFR inhibitors are typically small molecules, in particular small molecules selected from the group consisting of abivertinib, afatinib, alflutinib, almonertinib, apatinib, AZD3759, brigutinib, D0316, D0317, D0318, dacomitinib, DZD9008, erlotinib, FCN-411, gefitinib, icotinib, lapatinib, lazertinib, mobocertinib, nazartinib, neratinib, orafeltinib, osimertinib, poziotinib, pyrotinib, resibertinib, TAS6417, vandetanib, varlitinib, XZP-5809, and combinations thereof.

[0117] The term "NSCLC shows oncogenic alterations in EGFR" as used herein means that NSCLC tumors have a mutated version of EGFR, and this mutated version of EGFR is involved in the development of NSCLC. In other words, the mutated version of EGFR can be considered to be associated with or responsible for the development of NSCLC, among other factors. The mutated version of EGFR is present in NSCLC tumors due to alterations in the EGFR gene, such alterations being in particular deletions in the EGFR gene, insertions in the EGFR gene, deletions and insertions in the EGFR gene, duplications in the EGFR gene, amplifications in the EGFR gene, and / or at least one base mutation in the EGFR gene, resulting in amino acid substitutions in EGFR. The corresponding specific alterations are outlined above. Combinations of such alterations in the EGFR gene are frequently found. An "oncogenic alteration in EGFR" is not a "resistant alteration in EGFR" as defined below.

[0118] The term "resistance change in EGFR" as used herein means that, by treatment with an EGFR inhibitor, NSCLC tumor acquires additional changes in EGFR (in addition to oncogenic changes), and this additional change in EGFR makes NSCLC resistant to said EGFR inhibitor treatment (i.e., the EGFR inhibitor used for treatment to which NSCLC was initially sensitive). This resistance is mediated by changes in the EGFR gene, which can be at least one base mutation in the EGFR gene, which in particular results in an amino acid substitution in EGFR. Thus, in contrast to the above-defined "oncogenic change in EGFR", "resistance change" is not considered to be associated with or responsible for the initial onset of NSCLC. Rather, this resistance change provides an additional growth advantage to NSCLC, in the sense that it confers resistance to treatment with a particular EGFR inhibitor that has been administered previously (and that was effective in treating NSCLC before the resistance change occurs as a tumor response to this treatment). A prominent "resistance alteration in EGFR" is the amino acid substitution T790M in EGFR, which is also called a gatekeeper mutation. "Resistance alteration in EGFR" is not an "oncogenic alteration in EGFR" as defined above. However, both types of alterations can of course be present in EGFR in NSCLC tumors, are frequently detected in patients, and corresponding cell lines exist as model systems (see, for example, cell line NCI-H1975).

[0119] The term "hyperactivation" of EGFR, as used herein, means that EGFR is more active compared to the wild-type situation, particularly with respect to downstream activation and signaling, thereby resulting in the growth of cancerous cells.

[0120] The term "treatment cycle", as used herein, means that after an initial assessment of a patient's condition, medication is administered for a period of time, and then the patient's condition is typically re-evaluated before initiating another treatment cycle.

[0121] Numbered embodiments relating to the above aspects are provided below. Embodiment 1: A compound according to the invention or a pharmaceutical composition according to the invention, in combination with an EGFR inhibitor, for use in the treatment of a patient suffering from non-small cell lung cancer (NSCLC), wherein the NSCLC displays oncogenic alterations in EGFR.

[0122] Embodiment 2: A compound according to the invention or a pharmaceutical composition according to the invention in combination with an EGFR inhibitor, for use according to the first embodiment, wherein oncogenic alterations in EGFR result in overactivation of EGFR.

[0123] Embodiment 3: A compound according to the invention or a pharmaceutical composition according to the invention in combination with an EGFR inhibitor, for use according to embodiment 1 or 2, wherein the oncogenic alteration is caused by: a deletion and / or insertion in exon 18 or exon 19 or exon 20 of the EGFR gene; a kinase domain duplication in the EGFR gene; an amplification of the EGFR gene; at least one base mutation in the EGFR gene, resulting in an amino acid substitution in EGFR selected from the group consisting of L858R, G719S, G719A, G719C, V765A, T783A, S768I, S768V, L861Q, E709X, L819Q, A750P and combinations thereof, where X represents any amino acid; and a combination of any of the foregoing.

[0124] Embodiment 4: A compound according to the invention or a pharmaceutical composition according to the invention in combination with an EGFR inhibitor, for use according to any of embodiments 1 to 3, wherein the oncogenic alteration is caused by a deletion in exon 19 of the EGFR gene, preferably a deletion resulting in a deletion of E746-A750 or L747-E749 in EGFR; at least one base mutation in the EGFR gene resulting in the amino acid substitution L858R or A750P in EGFR; and combinations thereof.

[0125] Embodiment 5: A compound according to the invention or a pharmaceutical composition according to the invention, in combination with an EGFR inhibitor, for use according to any of embodiments 1 to 4, provided that if the NSCLC additionally exhibits resistance changes in EGFR due to previous administration of an EGFR inhibitor, the EGFR inhibitor in combination is not a previously administered EGFR inhibitor.

[0126] Embodiment 6: A compound according to the invention or a pharmaceutical composition according to the invention in combination with an EGFR inhibitor, for use according to embodiment 5, wherein the resistance alteration in EGFR is caused by at least one base mutation in the EGFR gene, resulting in an amino acid substitution in EGFR selected from the group consisting of T790M, C797X, L792X, G796X, L718Q, L718V, G724S, D761Y, V834L, T854A, and combinations thereof, where X represents any amino acid.

[0127] Embodiment 7: A compound according to the invention or a pharmaceutical composition according to the invention in combination with an EGFR inhibitor, for use according to embodiment 5 or 6, wherein the resistance alteration in EGFR is caused by at least one base mutation in the EGFR gene, resulting in the amino acid substitution T790M in EGFR.

[0128] Embodiment 8: The EGFR inhibitor is selected from the group consisting of ABBV-321, abivertinib, afatinib, AFM24, alflutinib (AST2818), almonertinib (HS-10296), apatinib, ASK120067, avitinib (AC0010), AZD3759, BBT-176, BTDX-1535, BLU-451, BLU-701, BLU- 945, brigutinib, CK-101 (RX-518), CLN-081 (TAS6417), CM93, D0316, D0317, D0318, dacomitinib, DZD9008, EMB-01, erlotinib, FCN-411, gefitinib, icotinib, keitinib, lapatinib, lazertinib, MCLA-129, MRG003, mobocertini A compound according to the invention or a pharmaceutical composition according to the invention in combination with an EGFR inhibitor, for use according to any of embodiments 1 to 7, selected from the group consisting of: nazartinib, neratinib, orafeltinib, osimertinib, poziotinib, pyrotinib, resibertinib, SH-1028 (oritinib), stetinib, TAS2940, TAS6417, vandetanib, varlitinib, XZP-5809, amivantamab, CDP1, cetuximab, GC1118, HLX07, JMT101, M1231, necitumumab, nimotuzumab, matuzumab, panitumumab, SCT200, SI-B001, SYN004, Z650, zalutumumab, ZN-e4, ZZ06, and combinations thereof.

[0129] Embodiment 9: The EGFR inhibitor is selected from the group consisting of ABBV-321, abivertinib, afatinib, alflutinib, almonertinib, apatinib, AZD3759, brigutinib, D0316, D0317, D0318, dacomitinib, DZD9008, erlotinib, FCN-411, gefitinib, icotinib, lapatinib, lazertinib, mobocertinib, nazartinib, neratinib, orafeltinib, osimertinib, poziotinib, pyrotinib, resibertinib, TAS A compound according to the invention or a pharmaceutical composition according to the invention in combination with an EGFR inhibitor for use according to any of embodiments 1 to 8 selected from the group consisting of: 6417, vandetanib, varlitinib, XZP-5809, amivantamab, CDP1, cetuximab, GC1118, HLX07, JMT101, M1231, necitumumab, nimotuzumab, matuzumab, panitumumab, SCT200, SI-B001, SYN004, zalutumumab, and combinations thereof.

[0130] Embodiment 10: A compound according to the invention or a pharmaceutical composition according to the invention, in combination with an EGFR inhibitor, for use according to any of embodiments 1 to 9, wherein the combination is administered to the patient during each treatment cycle.

[0131] Embodiment 11: A compound according to the invention or a pharmaceutical composition according to the invention in combination with an EGFR inhibitor, for use according to any of embodiments 1 to 10, wherein (i) the compound according to the invention or the pharmaceutical composition according to the invention and (ii) the EGFR inhibitor are administered as separate dosage forms or are comprised in a single dosage form.

[0132] Embodiment 12: A compound according to the invention or a pharmaceutical composition according to the invention, in combination with an EGFR inhibitor, for use according to embodiment 11, wherein when (i) and (ii) are administered as separate dosage forms, the administration during each treatment cycle is simultaneous or sequential administration.

[0133] Embodiment 113: A compound according to the invention or a pharmaceutical composition according to the invention, in combination with an EGFR inhibitor, for use according to any of embodiments 1 to 12, wherein the treatment results in an extension of the duration of the therapeutic effect compared to the duration of the therapeutic effect of the EGFR inhibitor when administered as the only active agent, or the treatment results in an increase in the therapeutic efficacy compared to the therapeutic efficacy of the EGFR inhibitor when administered as the only active agent, or the treatment results in the prevention of resistance to the EGFR inhibitor. Embodiment 14: A compound according to the invention,

[0134] [ka]

[0135] A compound according to the invention or a pharmaceutical composition according to the invention in combination with an EGFR inhibitor for use according to any of embodiments 1 to 13, selected from the group consisting of:

[0136] Combination Embodiments with KRAS Inhibitors In one aspect, the present invention also relates to the compound of the present invention or the pharmaceutical composition of the present invention combined with a KRAS inhibitor for use in the treatment of patients suffering from cancer, said cancer showing oncogenic changes in KRAS.This aspect can also be called the compound of the present invention or the pharmaceutical composition of the present invention combined with a KRAS inhibitor for use in the treatment of patients suffering from cancer, said cancer being characterized by the KRAS mutation profile that is given to one or more indications of the label of the KRAS inhibitor (e.g., KRAS G12C) used in the combination, or said cancer being characterized by the KRAS mutation profile that is targeted in clinical trial setting by the KRAS inhibitor (e.g., KRAS G12C) used in the combination.

[0137] In a preferred embodiment of this aspect, the oncogenic alteration in KRAS results in hyperactivation of KRAS signaling.The oncogenic alteration in KRAS can even result in constitutively active KRAS signaling (in the sense that the signaling activity of GTP-bound KRAS is constitutively active).

[0138] In a further preferred embodiment of this aspect, the oncogenic change in KRAS is caused by at least one base mutation in KRAS gene, which causes the amino acid substitution in KRAS selected from the group consisting of G12C, G12V, G12D, G13D, Q61H, Q61L, Q61R, K117N, and combinations thereof.It may be preferred that the oncogenic change is caused by at least one base mutation in KRAS gene, which causes the amino acid substitution in KRAS selected from the group consisting of G12C, G12V and G12D.Most preferred that the oncogenic change in KRAS is caused by at least one base mutation in KRAS gene, which causes the amino acid substitution G12C in KRAS.

[0139] In another embodiment of this aspect, cancer is selected from the group consisting of lung cancer, colorectal cancer and pancreatic cancer.Lung cancer is preferably non-small cell lung cancer (NSCLC), can be locally advanced or metastatic NSCLC, and can be most preferably KRAS G12C mutated locally advanced or metastatic NSCLC (in the language used herein, can alternatively be formulated as treatment for patients suffering from NSCLC, optionally suffering from locally advanced or metastatic NSCLC, and this NSCLC shows oncogenic change G12C in KRAS).

[0140] In another embodiment of this aspect, the KRAS inhibitor is a small molecule inhibitor.Therefore, in such an embodiment, the KRAS inhibitor is not a nucleic acid-based inhibitor, for example, shRNA or RNAi that targets KRAS.In a further embodiment of the first aspect, the KRAS inhibitor targets KRAS G12C, i.e., targets to treat cancer that shows oncogenic change G12C in KRAS.Such inhibitor may be a covalent inhibitor, which targets the cysteine ​​at position 12 present in G12C KRAS through covalent interaction. The KRAS inhibitor can be selected from the group consisting of RSC-1255, GFH925, JAB-21822, YL-15293, JDQ443, LY3537982, D-1553, GH35, SDGR5, GH52, ERAS-9, AMG510, MRTX849, JNJ-74699157 / ARS-3248, BI 1701963, BI 1823911, BAY-293, GDC-6036, MRTX1133, RAS(ON) inhibitors, and combinations thereof. Alternatively, the KRAS inhibitor can be selected from the group consisting of AMG510, MRTX849, JNJ-74699157 / ARS-3248, BI 1701963, BI 1823911, BAY-293, GDC-6036, MRTX1133, RAS(ON) inhibitor (RAS(ON) inhibitor is preferably RMC-6291 or RMC-6236), and combinations thereof. In a more preferred embodiment, the KRAS inhibitor is AMG510 or MRTX849. It may be most preferred that the KRAS inhibitor is AMG510.

[0141] In a preferred embodiment of this aspect, the combination is administered to the patient during each treatment cycle. In another embodiment of this aspect, the compound of the present invention and the KRAS inhibitor are administered as separate dosage forms or are included in a single dosage form.When the compound of the present invention and the KRAS inhibitor are administered as separate dosage forms, their administration during each treatment cycle can be simultaneous or sequential.This includes the option that the compound of the present invention is administered first, followed by the administration of the KRAS inhibitor.

[0142] In yet another embodiment of this aspect, the treatment results in an increase in the duration of the therapeutic effect of the KRAS inhibitor compared to the duration of the therapeutic effect of the KRAS inhibitor when administered as the only active agent. In yet another embodiment, the treatment results in an increase in the therapeutic efficacy of the KRAS inhibitor compared to the therapeutic efficacy of the KRAS inhibitor when administered as the only active agent. In another embodiment, the treatment results in the prevention of resistance to the KRAS inhibitor.

[0143] In another embodiment of this aspect, the compound of the present invention is administered in a daily amount of about 1 mg to about 3000 mg, preferably about 10 mg to about 2000 mg, more preferably about 15 mg to about 1000 mg. The compound of the present invention may be preferably administered in a daily amount of about 10 mg, about 15 mg, about 20 mg, about 50 mg, about 100 mg, about 250 mg, about 500 mg, about 1000 mg, about 1500 mg, about 2000 mg, about 2500 mg, or about 3000 mg. Administration may be intermittent, i.e., the above-mentioned daily amount may be administered on the days when administration is performed, but not every day.

[0144] In another embodiment of this aspect, when the KRAS inhibitor is administered as the only active agent, the KRAS inhibitor is administered in a daily amount within the range of a typical daily amount (particularly, if possible, the daily amount described for the KRAS inhibitor on the label). The typical daily amount (or the applicable daily amount, if possible) depends on the specific KRAS inhibitor to be used. Typically, the KRAS inhibitor is administered in a daily amount between about 10 mg and about 2000 mg. Thus, AMG510 may be administered, for example, in a combination for use according to the present invention, in a daily amount between about 240 mg and about 1200 mg, between about 480 mg and about 1200 mg, or between about 600 mg and about 1200 mg, preferably between about 720 mg and about 1080 mg, more preferably between about 840 mg and about 960 mg or about 960 mg. MRTX849 may be administered, for example, in a combination for use according to the invention in a daily amount of between about 200 mg and about 1400 mg, or between about 400 mg and about 1300 mg, preferably between about 600 mg and about 1200 mg, most preferably about 1200 mg.

[0145] In another embodiment of this aspect, the KRAS inhibitor is administered in a daily amount lower than the typical daily amount described above when the KRAS inhibitor is administered as the only active agent.In other words, when the KRAS inhibitor is not the only active agent, but is administered in combination for use according to the present invention, the KRAS inhibitor can be administered in an amount lower than the amount used when the KRAS inhibitor is administered as the only active agent.This means, for example, for the examples given above, that the daily amount is at the lower end of the given range, or even below these ranges.

[0146] In yet a further embodiment of this aspect, the invention provides (i) a compound of the invention in combination with (ii) a KRAS inhibitor, for use in treating a patient suffering from cancer, wherein the cancer exhibits oncogenic alterations in KRAS, and the compound of the invention

[0147] [ka]

[0148] The present invention relates to a compound of the present invention, which is selected from the group consisting of:

[0149] In a related aspect, the present invention is directed to a method of treating cancer in a patient in need thereof, wherein the cancer exhibits oncogenic alterations in KRAS, comprising administering to the patient (i) an effective amount of a compound of the present invention and (ii) an effective amount of a KRAS inhibitor.

[0150] In another related aspect, the present invention is directed to a method for extending the duration of therapeutic effect of a KRAS inhibitor in a patient in need thereof, whose cancer exhibits oncogenic alterations in KRAS, comprising administering to the patient (i) an effective amount of a compound of the present invention and (ii) an effective amount of a KRAS inhibitor. In other words, the duration of therapeutic effect of the KRAS inhibitor (when administered in combination) is extended compared to the duration of therapeutic effect when the KRAS inhibitor is administered as the only active agent in cancer treatment.

[0151] In another related aspect, the present invention is directed to a method for increasing the therapeutic efficacy of a KRAS inhibitor in a patient in need thereof, whose cancer exhibits oncogenic alterations in KRAS, comprising administering to the patient (i) an effective amount of a compound of the present invention and (ii) an effective amount of a KRAS inhibitor. In other words, the therapeutic efficacy of the KRAS inhibitor (when administered in combination) is increased compared to the therapeutic efficacy of the KRAS inhibitor when administered as the only active agent in cancer treatment.

[0152] In another related aspect, the invention is directed to a method of blocking proliferation of cancer cells, wherein the cancer cells exhibit oncogenic alterations in KRAS, comprising administering to the cells (i) an effective amount of a compound of the invention and (ii) an effective amount of a KRAS inhibitor.

[0153] In another related aspect, the invention is directed to a method of slowing the proliferation of cancer cells, wherein the cancer cells exhibit oncogenic alterations in KRAS, comprising administering to the cells (i) an effective amount of a compound of the invention and (ii) an effective amount of a KRAS inhibitor.

[0154] In the above related aspects, the embodiments outlined above for the first aspect apply equally.

[0155] The term "KRAS" as used herein refers to the "Kirsten Rat Sarcoma" protein. KRAS is a GTPase that is a key mediator of intracellular signaling pathways involved in tumor cell growth and survival. In normal cells, KRAS functions as a molecular switch that alternates between an inactive GDP-bound state and an active GTP-bound state. The transition between these states is facilitated by guanine nucleotide exchange factors (GEFs), which load GTP and activate KRAS, and GTP hydrolysis catalyzed by GTPase-activating proteins (GAPs) to inactivate KRAS. GTP binding to KRAS promotes effector binding to initiate signaling pathways involving RAF-MEK-ERK (MAPK). Somatic activating mutations in KRAS are a hallmark of cancer and prevent GAP association, thereby stabilizing effector binding and promoting KRAS signaling. Patients with KRAS mutant tumors have significantly poorer outcomes and worse prognoses.

[0156] The term "KRAS inhibitor" as used herein refers to a molecule capable of acting on KRAS such that the intracellular downstream signaling (which ultimately results in cell proliferation) is inhibited. The term "inhibited" in this context preferably means that the downstream signaling is no longer carried out. However, if a given downstream signaling (set at 100%) is significantly reduced, for example to a level of about 70%, about 60%, about 50%, about 40%, about 30%, preferably about 20%, more preferably about 10% or most preferably about 5% or less, such reduction in downstream signaling is further encompassed by the term "inhibit intracellular downstream signaling". In terms of the medical use of compounds that inhibit downstream signaling, complete inhibition of signaling may not be required to achieve a sufficient therapeutic effect. Thus, it should be understood that the term "inhibit" as used herein also refers to a reduction in downstream signaling in this context, which is sufficient to achieve the desired effect. KRAS inhibitors can be covalently bound to KRAS, particularly to the cysteine ​​at position 12 of KRAS G12C. When a KRAS inhibitor targets and / or binds to this cysteine, the inhibitor is typically called a "KRAS G12C inhibitor" and examples of such inhibitors are AMG510 (CAS-Nr.2296729-00-3), MRTX849 (CAS-Nr.2326521-71-3), JNJ-74699157 / ARS-3248, BI 1823911, GDC-6036 and RMC-6291. Very recently, the first KRAS G12C modulator, namely LUMAKRAS (Sotorasib, equivalent to AMG510, manufactured by Amgen) tablet, has received FDA approval for the treatment of KRAS G12C mutated locally advanced or metastatic non-small cell lung cancer (NSCLC). Another KRAS G12C modulator is expected to follow soon, namely adagrasib (Mirati Therapeutics, equivalent to MRTX849). A "KRAS G12D inhibitor" is an inhibitor specific for KRAS G12D or the like.An example of KRAS G12D inhibitor is MRTX1133.Alternatively, KRAS inhibitor can also block the interaction of KRAS with other proteins, in particular KRAS-SOS1 interaction.Such KRAS-SOS1 inhibitor is, for example, BI 1701963 and BAY-293 (CAS Nr.2244904-70-7). Also so-called RAS(ON) inhibitors bind to mutated GTP-bound KRAS (e.g., G12C GTP-bound KRAS or G12V GTP-bound KRAS or G12D GTP-bound KRAS or G13D GTP-bound KRAS or Q61H GTP-bound KRAS or Q61L GTP-bound KRAS or Q61R GTP-bound KRAS) and block RAF engagement by blocking the effector face of each KRAS in that they form a ternary complex between the RAS(ON) inhibitor (synthetic ligand), KRAS and cyclophilin A (for further details, see Revolution Medicines, e.g., WO2021 / 091956). RMC-6291 inhibits KRAS by the mechanism described above. G12C Revolution Medicines' RAS targeting G12C RMC-6236 is a RAS(ON) inhibitor from Revolution Medicines that targets multiple RAS mutations, including KRAS mutations, through the mechanism described above.

[0157] The term "cancer exhibits oncogenic alterations in KRAS" as used herein means that the tumor has a mutated version of KRAS, and this mutated version of KRAS is involved in the development of cancer. In other words, the mutated version of KRAS can be considered to be associated with or responsible for the development of cancer, among other factors. The mutated version of KRAS is present in the tumor due to an alteration in the KRAS gene, and such an alteration is in particular at least one base mutation in the KRAS gene, which results in an amino acid substitution in KRAS. The corresponding specific alterations are outlined above, and a notable alteration is in particular the KRAS G12C alteration. As mentioned above, KRAS mutations are present in up to 25% of cancers, and oncogenic alterations have different prevalences in different cancers (see Box 1 of Mullard, Nature reviews DRUG DISCOVERY, Vol. 18, December 2019: pp. 887-891).

[0158] The term "hyperactivation" of KRAS, as used herein, means that KRAS is more active, particularly with respect to downstream activation and signaling, compared to the wild-type situation, thereby resulting in cancerous cell growth.

[0159] Numbered embodiments relating to the above aspects are provided below. Embodiment 1: A compound according to the invention or a pharmaceutical composition according to the invention, in combination with a KRAS inhibitor, for use in the treatment of a patient suffering from cancer, wherein the cancer exhibits oncogenic alterations in KRAS.

[0160] Embodiment 2: A compound according to the invention or a pharmaceutical composition according to the invention in combination with a KRAS inhibitor, for use according to embodiment 1, wherein oncogenic alterations in KRAS result in overactivation of KRAS signaling.

[0161] Embodiment 3: A compound according to the invention or a pharmaceutical composition according to the invention in combination with a KRAS inhibitor, for use according to embodiment 1 or 2, wherein the oncogenic alteration is caused by at least one base mutation in the KRAS gene, resulting in an amino acid substitution in KRAS, selected from the group consisting of G12C, G12V, G12D, G13D, Q61H, Q61L, Q61R, K117N, and combinations thereof.

[0162] Embodiment 4: A compound according to the invention or a pharmaceutical composition according to the invention in combination with a KRAS inhibitor for use according to any of embodiments 1 to 4, wherein the KRAS inhibitor is selected from the group consisting of RSC-1255, GFH925, JAB-21822, YL-15293, JDQ443, LY3537982, D-1553, GH35, SDGR5, GH52, ERAS-9, AMG510, MRTX849, JNJ-74699157 / ARS-3248, BI 1701963, BI 1823911, BAY-293, GDC-6036, MRTX1133, RAS(ON) inhibitors, and combinations thereof.

[0163] Embodiment 5: A compound according to the invention or a pharmaceutical composition according to the invention in combination with a KRAS inhibitor, for use according to any of embodiments 1 to 4, wherein the KRAS inhibitor is selected from the group consisting of AMG510, MRTX849, JNJ-74699157 / ARS-3248, BI 1701963, BI 1823911, BAY-293, GDC-6036, MRTX1133, RAS(ON) inhibitors, and combinations thereof.

[0164] Embodiment 6: A compound according to the invention or a pharmaceutical composition according to the invention, in combination with a KRAS inhibitor, for use according to any of embodiments 1 to 5, wherein the oncogenic alteration is caused by at least one base mutation in the KRAS gene, resulting in the amino acid substitution G12C in KRAS.

[0165] Embodiment 7: A compound according to the invention or a pharmaceutical composition according to the invention in combination with a KRAS inhibitor, for use according to any of embodiments 1 to 5, wherein the oncogenic alteration is caused by at least one base mutation in the KRAS gene, resulting in the amino acid substitution G12C in KRAS, and the KRAS inhibitor is a KRAS G12C inhibitor.

[0166] Embodiment 8: A compound according to the invention or a pharmaceutical composition according to the invention, in combination with a KRAS inhibitor, for use according to any of embodiments 1 to 7, wherein the cancer is selected from the group consisting of lung cancer, colorectal cancer and pancreatic cancer.

[0167] Embodiment 9: A compound according to the invention or a pharmaceutical composition according to the invention, in combination with a KRAS inhibitor, for use according to any of embodiments 1 to 8, wherein the combination is administered to the patient during each treatment cycle.

[0168] Embodiment 10: A compound according to the invention or a pharmaceutical composition according to the invention in combination with a KRAS inhibitor, for use according to any of embodiments 1 to 9, wherein (i) a compound according to the invention or a pharmaceutical composition according to the invention and (ii) a KRAS inhibitor are administered as separate dosage forms or are comprised in a single dosage form.

[0169] Embodiment 11: A compound according to the invention or a pharmaceutical composition according to the invention, in combination with a KRAS inhibitor, for use according to embodiment 10, wherein when (i) and (ii) are administered as separate dosage forms, the administration is simultaneous or sequential during each treatment cycle.

[0170] Embodiment 12: A compound according to the invention or a pharmaceutical composition according to the invention in combination with a KRAS inhibitor, for use according to any of embodiments 1 to 11, wherein the treatment results in an extension of the duration of the therapeutic effect compared to the duration of the therapeutic effect of the KRAS inhibitor when administered as the only active agent; or the treatment results in an increase in the therapeutic efficacy compared to the therapeutic efficacy of the KRAS inhibitor when administered as the only active agent; or the treatment results in the prevention of resistance to the KRAS inhibitor.

[0171] Embodiment 13: A compound according to the present invention,

[0172] [ka]

[0173] A compound according to the invention or a pharmaceutical composition according to the invention, in combination with a KRAS inhibitor, for use according to any of embodiments 1 to 12, selected from the group consisting of:

[0174] Embodiment 14: A kit comprising (i) a pharmaceutical dosage form comprising a compound according to the invention and (ii) a pharmaceutical dosage form comprising a KRAS inhibitor.

[0175] Embodiment 15: A pharmaceutical dosage form comprising (i) a compound of the invention and (ii) a KRAS inhibitor.

[0176] Embodiment 16: The kit according to embodiment 14 or the pharmaceutical dosage form according to embodiment 15, wherein the KRAS inhibitor is selected from the group consisting of RSC-1255, GFH925, JAB-21822, YL-15293, JDQ443, LY3537982, D-1553, GH35, SDGR5, GH52, ERAS-9, AMG510, MRTX849, JNJ-74699157 / ARS-3248, BI 1701963, BI 1823911, BAY-293, GDC-6036, MRTX1133, RAS(ON) inhibitors, and combinations thereof.

[0177] Embodiment 17: The kit according to embodiment 16 or the pharmaceutical dosage form according to embodiment 16, wherein the KRAS inhibitor is selected from the group consisting of AMG510, MRTX849, JNJ-74699157 / ARS-3248, BI 1701963, BI 1823911, BAY-293, GDC-6036, MRTX1133, RAS(ON) inhibitors, and combinations thereof.

[0178] Embodiment 18: A compound according to the present invention is

[0179] [ka]

[0180] The kit according to embodiment 14, 16 or 17, or the pharmaceutical dosage form according to embodiment 15, 16 or 17, selected from the group consisting of:

[0181] Fibrotic Disease Embodiments The present invention also relates to a compound of the invention or a pharmaceutical composition of the invention for use in the treatment or amelioration of fibrotic diseases, in particular idiopathic pulmonary fibrosis (IPF) or non-alcoholic steatohepatitis (NASH), optionally in combination with known anti-fibrotic or anti-inflammatory agents.

[0182] The fibrotic disease can be selected from the group consisting of pulmonary fibrosis, idiopathic pulmonary fibrosis, radiation-induced pneumonitis, radiation fibrosis, acute respiratory distress syndrome, chronic obstructive pulmonary disease, interstitial lung disease, myocardial infarction, cardiac fibrosis and thickening, ischemic stroke, ischemic kidney disease, kidney fibrosis, rheumatoid arthritis, liver fibrosis, NASH (non-alcoholic steatohepatitis), chronic hepatitis, liver cirrhosis, inflammatory bowel disease, Crohn's disease, scleroderma, keloid, postoperative fibrosis, chemotherapy-induced fibrosis (e.g. chemotherapy-induced pulmonary fibrosis or ovarian cortical fibrosis), nephrogenic systemic fibrosis, retroperitoneal fibrosis, myelofibrosis, mediastinal fibrosis, cystic fibrosis, asbestosis, asthma, pulmonary hypertension, systemic fibrosis, skin fibrosis, hypertension-induced kidney and heart fibrosis. The fibrotic disease can also be interstitial lung disease (IDL), in particular idiopathic interstitial pneumonia (IIP). The IIP may also be selected from the group consisting of chronic fibrosing interstitial pneumonia, smoking-related interstitial pneumonia and acute / subacute interstitial pneumonia, and the chronic fibrosing interstitial pneumonia may be idiopathic pulmonary fibrosis (IPF) or nonspecific interstitial pneumonia (NSIP).

[0183] Specifically with regard to the treatment of NASH, known anti-fibrotic or anti-inflammatory agents may be selected from the group consisting of Vitamin E (RRR-α-tocopherol), pioglitazone (Actos), MGL-3196 (Resmetirom), elafibranor, selonsertib (SEL; GS-4997), dapagliflozin, Nesinaact25 / 15 (alogliptin benzoate 25 mg, pioglitazone hydrochloride 15 mg), losartan, aramchol, cenicriviroc, MSDC-0602K and metformin.

[0184] The compounds provided herein may be administered as compounds per se or may be formulated as pharmaceuticals.The pharmaceutical / pharmaceutical composition may optionally include one or more pharma- ceutical acceptable excipients, such as carriers, diluents, fillers, disintegrants, lubricants, binders, colorants, pigments, stabilizers, preservatives, antioxidants, and / or dissolution enhancers, or any combination thereof. In particular, the pharmaceutical compositions may contain one or more solubility enhancers, such as poly(ethylene glycol) having a molecular weight in the range of about 200 to about 5,000 Da, ethylene glycol, propylene glycol, non-ionic surfactants, tyloxapol, polysorbate 80, macrogol-15-hydroxystearate, phospholipids, lecithin, dimyristoyl phosphatidylcholine, dipalmitoyl phosphatidylcholine, distearoyl phosphatidylcholine, cyclodextrin, α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, hydroxyethyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, hydroxyethyl-γ-cyclodextrin, hydroxypropyl-γ-cyclodextrin, dihydroxypropyl-β-cyclodextrin, The cyclodextrin may include, for example, cyclohexyl ether ...

[0185] Tablets can contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate and glycine, disintegrants such as starch (preferably corn, potato or tapioca starch), sodium starch glycolate, croscarmellose sodium and certain silica complexes, and granule binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin and acacia. In addition, lubricants such as magnesium stearate, stearic acid, glyceryl behenate and talc may be included. Similar types of solid compositions can also be utilized as fillers for gelatin capsules. Preferred excipients in this regard include lactose, starch, cellulose, or high molecular weight polyethylene glycols. For aqueous suspensions and / or elixirs, the drugs may be combined with various sweetening or flavoring agents, coloring substances or dyes, emulsifying and / or suspending agents, diluents such as water, ethanol, propylene glycol and glycerin, and combinations thereof.

[0186] Pharmaceutical compositions can be formulated by techniques known to those skilled in the art, such as those published in "Remington: The Science and Practice of Pharmacy", Pharmaceutical Press, 22nd Edition. Pharmaceutical compositions can be formulated as dosage forms for oral, parenteral, e.g., intramuscular, intravenous, subcutaneous, intradermal, intraarterial, intracardiac, rectal, nasal, topical, aerosol or vaginal administration. Dosage forms for oral administration include coated and uncoated tablets, soft gelatin capsules, hard gelatin capsules, lozenges, troches, liquids, emulsions, suspensions, syrups, elixirs, powders and granules for reconstitution, dispersible powders and granules, medicated gums, chewable tablets and effervescent tablets. Dosage forms for parenteral administration include solutions, emulsions, suspensions, dispersions, and powders and granules for reconstitution. Emulsions are the preferred dosage form for parenteral administration. Dosage forms for rectal and vaginal administration include suppositories and vaginal suppositories.Dosage forms for nasal administration can be administered by inhalation and insufflation, for example, via a metered inhaler.Dosage forms for topical administration include creams, gels, ointments, ointments, patches and transdermal delivery systems.

[0187] The compounds of formula (I) or pharmaceutical compositions comprising compounds of formula (I) as described above can be administered to a subject by any convenient route of administration, whether systemically / peripherally or at the site of desired action, including, but not limited to, one or more of the following: orally (e.g., as tablets, capsules, or ingestible liquids), topically (e.g., transdermally, intranasally, ophthalmically, intraoral buccal, and sublingually), parenterally (e.g., using injection or infusion techniques, e.g., intramuscularly, intravenously, intradermally, intramuscularly ... For example, by injection, e.g., subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, or intrasternal, e.g., by implantation of a depot, including subcutaneously or intramuscularly), pulmonary (e.g., by inhalation or insufflation therapy, e.g., using an aerosol, e.g., via the mouth or nose), gastrointestinal, intrauterine, intraocular, subcutaneous, ophthalmic (including intravitreal or intracavitary), rectal, and vaginal.

[0188] When the compound or pharmaceutical composition is administered parenterally, examples of such administration include one or more of the following: administering the compound or pharmaceutical composition intravenously, intraarterially, intraperitoneally, intrathecally, intraventricularly, intraurethrally, intrasternally, intracardially, intracerebrally, intramuscularly or subcutaneously, and / or by using infusion techniques. For parenteral administration, the compound is best used in the form of a sterile aqueous solution, which may contain other substances, for example, sufficient salts or glucose to make the solution isotonic with blood. The aqueous solution should be suitably buffered (preferably pH 3-9), if necessary. The preparation of suitable parenteral formulations under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.

[0189] The compounds or pharmaceutical compositions may also be administered orally in the form of a tablet, capsule, ovule, elixir, solution or suspension, which may also contain flavoring or coloring agents for immediate, delayed, modified, sustained, pulsed or controlled release use.

[0190] Alternatively, the compound or pharmaceutical composition may be administered in the form of a suppository or pessary, or may be applied topically in the form of a gel, hydrogel, lotion, solution, cream, ointment or dusting powder.The compounds of the present invention may also be administered dermally or transdermally, for example, by the use of a skin patch.

[0191] The compound or pharmaceutical composition may be administered by sustained release system. Suitable examples of sustained release compositions include semipermeable polymer matrices in the form of shaped articles, such as films, or microcapsules. Sustained release matrices include, for example, polylactic acid (see, for example, US 3,773,919), copolymers of L-glutamic acid and gamma-ethyl-L-glutamate (Sidman, U. et al., Biopolymers 22:547-556 (1983)), poly(2-hydroxyethyl methacrylate) (R. Langer et al., J. Biomed. Mater. Res. 15:167-277 (1981) and R. Langer, Chem. Tech. 12:98-105 (1982)), ethylene vinyl acetate (R. Langer et al., Id.) or poly-D-(-)-3-hydroxybutyric acid (EP 133988). The sustained release pharmaceutical composition also includes the compound encapsulated by liposome.The liposome containing the compound of the present invention can be prepared by the method known in the art, for example, the method described in any one of the following: DE3218121; Epstein et al., Proc.Natl.Acad.Sci.(USA) 82:3688-3692 (1985); Hwang et al., Proc.Natl.Acad.Sci.(USA) 77:4030-4034 (1980); EP0052322; EP0036676; EP088046; EP0143949; EP0142641; JP83-118008; US4,485,045; US4,544,545; and EP0102324.

[0192] Said compound or pharmaceutical composition can also be administered by pulmonary, rectal or ocular route.For ophthalmic use, said compound or pharmaceutical composition can be formulated as a micronized suspension in isotonic, pH-adjusted, sterile saline or, preferably, as a solution in isotonic, pH-adjusted, sterile saline, optionally combined with a preservative, for example, benzalkonium chloride.Alternatively, they can be formulated in an ointment, for example, petrolatum.

[0193] It is also contemplated to prepare dry powder formulations of the compounds of formula (I) for pulmonary administration, particularly inhalation. Such dry powders can be prepared by spray drying under conditions that result in substantially amorphous glassy powders or substantially crystalline bioactive powders. Thus, dry powders of the compounds of the present invention can be prepared according to the emulsification / spray drying method disclosed in WO99 / 16419 or WO01 / 85136. Spray drying of solution formulations of the compounds of the present invention can be carried out, for example, as generally described in "Spray Drying Handbook", 5th Edition, K.Masters, John Wiley&Sons, Inc., NY (1991), and WO97 / 41833 or WO03 / 053411.

[0194] For topical application to the skin, the compounds or pharmaceutical compositions can be formulated into a suitable ointment, for example, containing the active compound suspended or dissolved in one or more of the following mixtures: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, emulsifying wax and water. Alternatively, they can be formulated into a suitable lotion or cream, for example, suspended or dissolved in one or more of the following mixtures: mineral oil, sorbitan monostearate, polyethylene glycol, liquid paraffin, polysorbate 60, cetyl esters wax, 2-octyldodecanol, benzyl alcohol and water.

[0195] Therefore, the present invention relates to the compound or pharmaceutical composition provided herein, wherein the corresponding compound or pharmaceutical composition is administered by any one of the following: oral route; local route, including for example transdermal, intranasal, ocular, oral buccal or sublingual route; parenteral route using injection or instillation technique, including for example subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, intrasternal, intraventricular, intraurethral or intracerebral route; pulmonary route, including for example by inhalation or insufflation therapy; gastrointestinal route; intrauterine route; intraocular route; subcutaneous route; ophthalmic route, including for example intravitreal or intracavitary route; rectal route; or vaginal route. The particularly preferred administration route of the compound or pharmaceutical composition of the present invention is oral form of administration.

[0196] Typically, a physician will determine the dosage that will be most appropriate for an individual subject. The specific dosage level and frequency of dosing for any particular individual subject may vary and will depend on a variety of factors, including age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combinations, the severity of the particular condition, and the individual subject undergoing therapy.

[0197] A proposed, but still non-limiting, dose of the compound according to the invention for administration to humans (body weight approximately 70 kg) may be 0.05-2000 mg, preferably 0.1 mg-1000 mg, of active ingredient per unit dose. The unit dose may be administered, for example, 1, 2, 3 or more times per day. The unit dose may also be administered 1-7 times per week, for example, 1, 2 or more times per day. It will be appreciated that routine variations to the dosage may be necessary depending on the age and weight of the patient / subject and the severity of the condition being treated. The exact dose and also the route of administration are ultimately left to the discretion of the attending physician.

[0198] The compound of formula (I) can be used in combination with other therapeutic agents, including in particular other anticancer agents.When the compound of the present invention is used in combination with a second therapeutic agent active against the same disease, the dosage of each compound may be different from the dosage when the compound is used alone.The combination of the compound of the present invention with a second therapeutic agent may include administering the second therapeutic agent simultaneously / concomitantly with the compound of the present invention or sequentially / separately.

[0199] Preferably, the second therapeutic agent administered in combination with the compound of the present invention is an anti-cancer drug.The anti-cancer drug administered in combination with the compound of formula (I) according to the present invention can be, for example, an androgen receptor (AR) antagonist, a receptor tyrosine kinase (RTK) inhibitor, a MAPK kinase inhibitor, a checkpoint kinase inhibitor, and / or a drug generally used in the immunotherapy of cancer.

[0200] For example, many cancers are known to involve AR, BRAF, MEK, ERK and / or EGFR expression. Thus, within the present invention, the second therapeutic agent administered in combination with the compound of the present invention may be an inhibitor of AR, BRAF, MEK, ERK and / or EGFR. In particular, in a non-limiting embodiment, (i) the androgen receptor antagonist is enzalutamide or the complementary CYP17A1 (17 alpha-hydroxylase / C17, 20 lyase) inhibitor abiraterone; (ii) the BRAFi is vermurafenib, dabrafenib, encorafenib, LGX818, PLX4720, TAK-632, MLN2480, SB590885, XL281, BMS-908662, PLX3603, RO5185426, GSK2118436 or RAF265; (iii) the MEKi is AZD6244, trametinib, selumetinib, cobimetinib, binimetinib, MEK162, RO5126766, GDC-0623, PD0325901, CI-1040, PD-035901, hypothemycin or TAK-733; (iv) the ERKi is ulixertinib, corinoxeine, SCH772984, XMD8-92, FR180204, GDC-0994, ERK5-IN-1, DEL-22379, BIX02189, ERK inhibitor (CAS No. 1049738-54-6), ERK inhibitor III (CAS No. 331656-92-9), GDC-0994, honokiol, LY3214996, CC-90003, deltonin, VRT752271, TIC10, astragaloside IV, XMD8-92, VX-11e, mogrol, or VTX11e, and / or (v) The EGFRi is selected from the group consisting of cetuximab, panitumumab, zalutumumab, nimotuzumab, matuzumab, gefitinib, erlotinib, lapatinib, neratinib, vandetanib, necitumumab, osimertinib, afatinib, dacomitinib, AP26113, EGFR inhibitor (CAS No. 879127-07-8), EGFR / ErbB-2 / ErbB-4 inhibitor (CAS No. 881001-19-0), EGFR / ErbB-2 inhibitor (CAS No. 179248-61-4), EGFR inhibitor II (BIBX 1382, CAS No. 196612-93-8), EGFR inhibitor III (CAS No. 733009-42-2), EGFR / ErbB-2 / ErbB-4 inhibitor II (CAS No. 944341-54-2) or PKCβII / EGFR inhibitor (CAS No. 145915-60-2).

[0201] In certain embodiments of the present invention, the second therapeutic agent administered in combination with the compound of the present invention may be an immunotherapy agent, in particular a cancer immunotherapy agent, such as an agent that targets CD52, PD-L1, CTLA4, CD20, or PD-1. Agents that can be used in combination with the compound of the present invention include, for example, alemtuzumab, atezolizumab, ipilimumab, nivolumab, ofatumumab, pembrolizumab, and rituximab.

[0202] The second therapeutic agent may also be selected from the following: tumor angiogenesis inhibitors (e.g., protease inhibitors, epidermal growth factor receptor kinase inhibitors, or vascular endothelial growth factor receptor kinase inhibitors); cytotoxic drugs (e.g., antimetabolites, e.g., purine and pyrimidine analog antimetabolites); antimitotic agents (e.g., microtubule stabilizing drugs or antimitotic alkaloids); platinum coordination complexes; antitumor antibiotics; alkylating agents (e.g., nitrogen mustards or nitrosoureas); endocrine agents (e.g., corticosteroids, androgens, antiandrogens, estrogens, antiestrogens, aromatase inhibitors, gonadotropin releasing hormone agonists, or somatostatin analogs); or compounds that target enzymes or receptors that are overexpressed and / or are otherwise involved in a particular metabolic pathway that is dysregulated in the tumor cells (e.g., AT P and GTP phosphodiesterase inhibitors, histone deacetylase inhibitors, protein kinase inhibitors (e.g., serine, threonine and tyrosine kinase inhibitors (e.g., Abelson protein tyrosine kinase)) and various growth factors, their receptors and corresponding kinase inhibitors (e.g., epidermal growth factor receptor (EGFR) kinase inhibitors, vascular endothelial growth factor receptor kinase inhibitors, fibroblast growth factor inhibitors, insulin-like growth factor receptor inhibitors and platelet-derived growth factor receptor kinase inhibitors); methionine, aminopeptidase inhibitors, proteasome inhibitors, cyclooxygenase inhibitors (e.g., cyclooxygenase-1 or cyclooxygenase-2 inhibitors), topoisomerase inhibitors (e.g., topoisomerase I inhibitors or topoisomerase II inhibitors), and poly ADP-ribose polymerase inhibitors (PARP inhibitors).

[0203] Alkylating agents that can be used as anti-cancer drugs in combination with the compounds of the present invention may be, for example, nitrogen mustards (e.g., cyclophosphamide, mechlorethamine (chlormethine), uramustine, melphalan, chlorambucil, ifosfamide, bendamustine, or trofosfamide), nitrosourea (e.g., carmustine, streptozocin, fotemustine, lomustine, nimustine, prednimustine, ranimustine, or semustine), alkylsulfonates (e.g., busulfan, mannosulfan, or treosulfan), aziridines (e.g., hexamethylmelamine (altretamine), triethylenemelamine, ThioTEPA (N,N'N'-triethylenethiophosphoramide), carboquone, or triaziquone), hydrazines (e.g., procarbazine), triazenes (e.g., dacarbazine), or imidazotetrazines (e.g., temozolomide).

[0204] Platinum coordination complexes that can be used as anti-cancer drugs in combination with the compounds of the invention can be, for example, cisplatin, carboplatin, nedaplatin, oxaliplatin, satraplatin, or triplatin tetranitrate.

[0205] Cytotoxic drugs that can be used as anti-cancer drugs in combination with the compounds of the invention may be, for example, antimetabolites including folate analog antimetabolites (e.g., aminopterin, methotrexate, pemetrexed, or raltitrexed), purine analog antimetabolites (e.g., cladribine, clofarabine, fludarabine, 6-mercaptopurine (including its prodrug form azathioprine), pentostatin, or 6-thioguanine), and pyrimidine analog antimetabolites (e.g., cytarabine, decitabine, 5-fluorouracil (including its prodrug forms capecitabine and tegafur), floxuridine, gemcitabine, enocitabine, or sapacitabine).

[0206] Antimitotic agents that can be used as anti-cancer drugs in combination with the compounds of the invention can be, for example, a taxane (e.g., docetaxel, larotaxel, ortataxel, paclitaxel / taxol, or tesetaxel), a vinca alkaloid (e.g., vinblastine, vincristine, vinflunine, vindesine, or vinorelbine), an epothilone (e.g., epothilone A, epothilone B, epothilone C, epothilone D, epothilone E, or epothilone F), or an epothilone B analog (e.g., ixabepilone / azaepothilone B).

[0207] Antitumor antibiotics that can be used as anticancer drugs in combination with the compounds of the present invention may be, for example, an anthracycline (e.g., aclarubicin, daunorubicin, doxorubicin, epirubicin, idarubicin, amrubicin, pirarubicin, valrubicin, or zorubicin), an anthracenedione (e.g., mitoxantrone, or pixantrone), or an antitumor antibiotic isolated from Streptomyces (e.g., actinomycin (including actinomycin D), bleomycin, mitomycin (including mitomycin C), or plicamycin).

[0208] Examples of tyrosine kinase inhibitors that can be used as anticancer drugs in combination with the compounds of the present invention include afatinib, acalabrutinib, alectinib, apatinib, axitinib, bosutinib, cabozantinib, canertinib, crenolanib, cediranib, crizotinib, damnacanthal, dasatinib, dacomitinib, entospletinib, entrectinib, erlotinib, foretinib, fostamatinib, gilteritinib, glesatinib, gefitinib, ibrutinib, and the like. It may be nib, icotinib, imatinib, linifanib, lapatinib, restortinib, motesanib, mubritinib, nintedanib, nilotinib, ONT-380, osimertinib, pazopanib, quizartinib, regorafenib, rociletinib, radotinib, savolitinib, sitravatinib, semaxanib, sorafenib, sunitinib, savolitinib, sitravatinib, tecevatinib, vatalanib, vemurafenib, or vandetanib.

[0209] Topoisomerase inhibitors that can be used as anti-cancer drugs in combination with the compounds of the present invention may be, for example, topoisomerase I inhibitors (e.g., irinotecan, topotecan, camptothecin, belotecan, rubitecan, or lamellarin D), or topoisomerase II inhibitors (e.g., amsacrine, etoposide, etoposide phosphate, teniposide, or doxorubicin).

[0210] The PARP inhibitor that can be used as an anti-cancer drug in combination with the compound of the present invention may be, for example, BMN-673, olaparib, rucaparib, veliparib, CEP9722, MK4827, BGB-290, or 3-aminobenzamide.

[0211] Additional anti-cancer drugs can also be used in combination with the compound of the present invention.Anti-cancer drugs include biological or chemical molecules such as TNF-related apoptosis-inducing ligand (TRAIL), tamoxifen, amsacrine, bexarotene, estramustine, irofulven, trabectedin, cetuximab, panitumumab, tositumomab, alemtuzumab, bevacizumab, edrecolomab, gemtuzumab, alvocidib, seliciclib, aminolevulinic acid, aminolevulinic acid methyl, efaproxiral, porfimer sodium, talaporfin, temoporfin, These may include verteporfin, alitretinoin, tretinoin, anagrelide, arsenic trioxide, atrasentan, bortezomib, carmofur, celecoxib, demecolcine, elescolomole, elsamitrusine, etoglucide, lonidamine, lucantone, masoprocol, mitobronitol, mitoguazone, mitotane, oblimersen, omacetaxine, citimagine seradenovec, tegafur, testolactone, tiazofurin, tipifarnib, vorinostat, or iniparib.

[0212] Also, biological drugs, such as antibodies, antibody fragments, antibody constructs (e.g., single chain constructs), and / or modified antibodies (e.g., CDR-grafted antibodies, humanized antibodies, "fully humanized" antibodies, etc.) directed against cancer or tumor markers / factors / cytokines involved in proliferative diseases, can be utilized in combination therapy approaches with the compounds of the present invention. The antibody can be, for example, an immuno-oncology antibody, such as ado-trastuzumab, alemtuzumab, atezolizumab, avelumab, bevacizumab, blinatumomab, brentuximab, capromab, cetuximab, ipilimumab, necitumumab, nivolumab, panitumumab, pembrolizumab, pertuzumab, ramucirumab, trastuzumab, or rituximab.

[0213] The combinations mentioned above can be conveniently presented for use in the form of pharmaceutical preparations. The individual components of such combinations can be administered in separate or combined pharmaceutical preparations, sequentially or simultaneously / concomitantly, by any convenient route. When administration is sequential, the compound of the present invention (i.e., the compound of formula (I) or its pharma- ceutically acceptable salt, solvate, cocrystal, tautomer, racemate, enantiomer, or diastereomer or mixture) or the second therapeutic agent can be administered first. When administration is simultaneous, the combination can be administered in the same pharmaceutical composition or in different pharmaceutical compositions. It should be recognized that when combined in the same preparation, the two compounds must be stable and compatible with each other and with the other components of the preparation. When formulated separately, they can be provided in any convenient preparation.

[0214] The compound of formula (I) can also be administered in combination with physical therapy, such as radiation therapy. Radiation therapy can be initiated before, after, or simultaneously with administration of the compound of the invention. For example, radiation therapy can be initiated 1-10 minutes, 1-10 hours, or 24-72 hours after administration of the compound. However, these time frames are not to be construed as limiting. The subject is exposed to radiation, preferably gamma radiation, whereby radiation may be provided in a single dose, or in multiple doses administered over the course of hours, days, and / or weeks. Gamma radiation can be delivered according to standard radiation therapy protocols, using standard doses and regimens.

[0215] Thus, the present invention relates to a compound of formula (I) or a pharma- ceutically acceptable salt, solvate, co-crystal, tautomer, racemate, enantiomer, or diastereomer or mixture thereof in combination with a pharma- ceutically acceptable excipient for use in the treatment or prevention of cancer, or a pharmaceutical composition comprising any of the abovementioned entities, wherein the compound or pharmaceutical composition is administered in combination with an anti-cancer drug and / or in combination with radiation therapy.

[0216] However, the compound of formula (I) can also be used in monotherapy, particularly in the monotherapeutic treatment or prevention of cancer (i.e., no other anti-cancer drugs are administered until treatment with the compound(s) of formula (I) has ceased). Thus, the present invention also relates to a compound of formula (I) or a pharma- ceutically acceptable salt, solvate, co-crystal, tautomer, racemate, enantiomer, or diastereomer or mixture thereof, or a pharmaceutical composition comprising any of the above-mentioned entities, in combination with a pharma- ceutically acceptable excipient, for use in the monotherapeutic treatment or prevention of cancer.

[0217] The subject or patient, e.g., a subject in need of treatment or prevention, may be an animal (e.g., a non-human animal), a vertebrate, a mammal, a rodent (e.g., a guinea pig, a hamster, a rat, a mouse), a murine (e.g., a mouse), a canine (e.g., a dog), a feline (e.g., a cat), a porcine (e.g., a pig), an equine (e.g., a horse), a primate, a simian (e.g., a monkey or an ape), a monkey (e.g., a marmoset, a baboon), an ape (e.g., a gorilla, a chimpanzee, an orangutan, a gibbon), or a human. In the context of the present invention, it is particularly envisaged that animals of economic, agricultural or scientific importance should be treated. Scientifically important organisms include, but are not limited to, mice, rats, and rabbits. Lower organisms, such as fruit flies, e.g., Drosophila melanogaster, and nematodes, e.g., Caenorhabditis elegans, can also be used in scientific methods. Non-limiting examples of agriculturally important animals are sheep, cows, and pigs, while for example, cats and dogs can be considered as economically important animals. Preferably, the subject / patient is a mammal. More preferably, the subject / patient is a human or non-human mammal (e.g., guinea pig, hamster, rat, mouse, rabbit, dog, cat, horse, monkey, ape, marmoset, baboon, gorilla, chimpanzee, orangutan, gibbon, sheep, cow, or pig). Most preferably, the subject / patient is a human.

[0218] The term "treatment" of a disorder or disease as used herein (e.g., "treatment" of cancer) is well known in the art. "Treatment" of a disorder or disease means that the disorder or disease is suspected or diagnosed in a patient / subject. A patient / subject suspected of having a disorder or disease typically exhibits certain clinical and / or pathological symptoms that can be readily determined by a skilled artisan to be caused by a particular pathological condition (i.e., the disorder or disease can be diagnosed).

[0219] "Treatment" of a disorder or disease may result in, for example, halting the progression of the disorder or disease (e.g., no worsening of symptoms) or slowing the progression of the disorder or disease (where the halting of progression is only of a temporary nature). "Treatment" of a disorder or disease may also result in a partial response (e.g., relief of symptoms) or complete response (e.g., disappearance of symptoms) of a subject / patient suffering from a disorder or disease. Thus, "treatment" of a disorder or disease may also refer to the remission of the disorder or disease, which may, for example, result in halting the progression of the disorder or disease or slowing the progression of the disorder or disease. Such a partial or complete response may be followed by relapse. It is understood that a subject / patient may experience a wide range of responses to the treatment (e.g., exemplary responses as described herein above). Treatment of a disorder or disease may include, among others, curative treatment (preferably resulting in a complete response and ultimately curing the disorder or disease) and palliative treatment (including symptom relief).

[0220] "Amelioration" of a disorder or disease can result in, for example, a halt to the progression of the disorder or disease or a slowing of the progression of the disorder or disease.

[0221] The term "prevention" of a disorder or disease as used herein (e.g., "prevention" of cancer) is also well known in the art. For example, a patient / subject suspected of being susceptible to a disorder or disease may particularly benefit from the prevention of the disorder or disease. The subject / patient may have a susceptibility or predisposition to the disorder or disease, including, but not limited to, a genetic predisposition. Such a predisposition may be determined by standard methods or assays, for example, using genetic markers or phenotypic indicators. It is understood that the disorder or disease to be prevented according to the present invention has not been diagnosed or cannot be diagnosed in the patient / subject (e.g., the patient / subject does not exhibit any clinical or pathological symptoms). Thus, the term "prevention" includes the use of a compound of the present invention before the attending physician has diagnosed or determined, or can diagnose or determine, any clinical and / or pathological symptoms.

[0222] It is to be understood that the present invention specifically relates to any and all combinations of the features and embodiments described herein, including any combination of the general and / or preferred features / embodiments. In particular, the present invention specifically relates to each combination of the meanings (including the general and / or preferred meanings) for the various groups and variables contained in formula (I).

[0223] In this specification, several documents, including patent applications and scientific documents, are cited. The disclosures of these documents are not considered relevant to the patentability of the present invention, but are incorporated herein by reference in their entirety. More specifically, all referenced documents are incorporated by reference to the same extent as if each individual document was specifically and individually indicated to be incorporated by reference.

[0224] The present invention may be better understood with reference to the following examples, which are intended to be representative of certain embodiments of the invention and are not intended to limit the scope of the invention. EXAMPLES

[0225] Working Example General Experimental Method LCMS method: Method A: Equipment: Agilent 1260 Bin. Pump: G1312B, Degasser; Autosampler, ColCom; DAD: Agilent G1315D, 220-320 nm; MSD: Agilent LC / MSD G6130B ESI, pos / neg 100-800, ELSD Alltech 3300 Gas flow 1.5 mL / min, Gas temperature: 40° C.; Column: Waters XSelect™ C18, 30×2.1 mm, 3.5 μ, Temperature: 35° C., Flow rate: 1 mL / min, Gradient: t0=5% A, t 1.6分 = 98%A, t 3分 = 98% A, post time: 1.3 min, eluent A: 0.1% formic acid in acetonitrile, eluent B: 0.1% formic acid in water). Method B: Equipment: Agilent 1260 Bin. Pump: G1312B, Degasser; Autosampler, ColCom; DAD: Agilent G1315D, 220-320 nm; MSD: Agilent LC / MSDG6130B ESI, pos / neg 100-800, ELSD Alltech3300 Gas flow 1.5 mL / min, Gas temperature: 40° C.; Column: Waters XSelect™ C18, 50×2.1 mm, 3.5μ, Temperature: 35° C., Flow rate: 0.8 mL / min, Gradient: t0=5% A, t 3.5分 = 98%A, t 6分 = 98% A, post time: 2 min; eluent A: 0.1% formic acid in acetonitrile, eluent B: 0.1% formic acid in water). Method C: Equipment: Agilent 1260 Bin. Pump: G1312B, degasser; autosampler, ColCom; DAD: Agilent G1315C, 220-320 nm; MSD: Agilent LC / MSD G6130B ESI, pos / neg 100-800; Column: Waters XSelect™ CSH C18, 30×2.1 mm, 3.5μ; Temperature: 25° C.; Flow rate: 1 mL / min; Gradient: t0=5% A, t 1.6分 = 98%A, t 3分= 98% A, post time: 1.3 min, eluent A: 95% acetonitrile + 10 mM ammonium bicarbonate in 5% acetonitrile in water, eluent B: 10 mM ammonium bicarbonate in water (pH = 9.5). Method D: Instrument: Agilent 1260 Bin. Pump: G1312B, Degasser; Autosampler, ColCom; DAD: Agilent G1315C, 220-320 nm; MSD: Agilent LC / MSD G6130B ESI, pos / neg 100-800; Column: Waters XSelect™ CSH C18, 50×2.1 mm, 3.5μ; Temperature: 25° C.; Flow rate: 0.8 mL / min; Gradient: t0=5% A, t 3.5分 = 98%A, t 6分 = 98% A, post time: 2 min, eluent A: 95% acetonitrile + 10 mM ammonium bicarbonate in 5% acetonitrile in water, eluent B: 10 mM ammonium bicarbonate in water (pH = 9.5).

[0226] UPLC method: Method A: Instrument: Agilent Infinity II; Bin. Pump: G7120A, Multisampler, VTC, DAD: Agilent G7117B, 220-320 nm, PDA: 210-320 nm, MSD: Agilent G6135B ESI, pos / neg 100-1000, ELSD G7102A: Evap 40 °C, Neb 50 °C, Gas flow 1.6 mL / min, Column: Waters XSelect CSH C18, 50 × 2.1 mm, 2.5 μm Temperature: 25 °C, Flow rate: 0.6 mL / min, Gradient: t0 = 5% B, t 2分 =98%B,t 2.7分 = 98% B, post time: 0.3 min, eluent A: 10 mM ammonium bicarbonate in water (pH = 9.5), eluent B: acetonitrile. Method B: Instrument: Agilent Infinity II; Bin. Pump: G7120A, Multisampler, VTC, DAD: Agilent G7117B, 220-320 nm, PDA: 210-320 nm, MSD: Agilent G6135B ESI, pos / neg 100-1000, ELSD G7102A: Evap 40°C, Neb 40°C, Gas flow 1.6 mL / min, Column: Waters XSelect™ CSH C18, 50 x 2.1 mm, 2.5 μm Temperature: 40°C, Flow rate: 0.6 mL / min, Gradient: t0 = 5% B, t 2分 =98%B,t 2.分 = 98% B, post time: 0.3 min, eluent A: 0.1% formic acid in water, eluent B: 0.1% formic acid in acetonitrile.

[0227] GCMS method: Method A: Instrument: GC: Agilent 6890N G1530N and MS: MSD 5973 G2577A, EI-positive, Det.temp.: 280 °C; Mass range: 50-550; Column: RXi-5MS 20m, ID 180 μm, df 0.18 μm; Average velocity: 50 cm / sec; Injection volume: 1 μl; Injector temperature: 250 °C; Split ratio: 100 / 1; Carrier gas: He; Initial temperature: 100 °C; Initial time: 1.5 min; Solvent delay: 1.0 min; Rate 75 °C / min; Final temperature 250 °C; Hold time 4.3 min. Method B: Instrument: GC: Agilent 6890N G1530N, FID: Det.temp: 300 °C and MS: MSD 5973 G2577A, EI-positive, Det.temp.: 280 °C. Mass range: 50-550; Column: Restek RXi-5MS 20m, ID 180 μm, df 0.18 μm; Average velocity: 50 cm / sec; Injection volume: 1 μl; Injector temperature: 250 °C; Split ratio: 20 / 1; Carrier gas: He; Initial temperature: 60 °C; Initial time: 1.5 min; Solvent delay: 1.3 min; Rate 50 °C / min; Final temperature 250 °C; Hold time 3.5 min. Method C: Instrument: GC: Agilent 6890N G1530N, FID: Det.temp: 300 °C and MS: MSD 5973 G2577A, EI-positive, Det.temp.: 280 °C. Mass range: 50-550; Column: Restek RXi-5MS 20m, ID 180 μm, df 0.18 μm; Average velocity: 50 cm / sec; Injection volume: 1 μl; Injector temperature: 250 °C; Split ratio: 20 / 1; Carrier gas: He; Initial temperature: 100 °C; Initial time: 1.5 min; Solvent delay: 1.3 min; Rate 75 °C / min; Final temperature 250 °C; Hold time 4.5 min.

[0228] Chiral LC: Method A: (Apparatus: Agilent 1260 Quart. Pump: G1311C, Autosampler, ColCom, DAD: Agilent G4212B, 220-320 nm, Column: Chiralcel® OD-H 250×4.6 mm, Temperature: 25° C., Flow rate: 1 mL / min, Isocratic: 90 / 10, Time: 30 min, Eluent A: Heptane, Eluent B: Ethanol). Preparative reversed phase chromatography: Method A: Instrument type: Revelis™ preparative MPLC; Column: Phenomenex LUNA C18 (150×25 mm, 10μ); Flow rate: 40 mL / min; Column temperature: room temperature; Eluent A: 0.1% (v / v) formic acid in water, Eluent B: 0.1% (v / v) formic acid in acetonitrile; Gradient: t=0 min 5% B, t=1 min 5% B, t=2 min 30% B, t=17 min 70% B, t=18 min 100% B, t=23 min 100% B; Detection UV: 220 / 254 nm. Appropriate fractions are combined and lyophilized. Method B: Instrument type: Revelis™ preparative MPLC; Column: Waters XSelect™ CSH C18 (145×25 mm, 10μ); Flow rate: 40 mL / min; Column temperature: room temperature; Eluent A: 10 mM ammonium bicarbonate in water pH=9.0); Eluent B: 99% acetonitrile + 1% 10 mM ammonium bicarbonate in water; Gradient: t=0 min 5% B, t=1 min 5% B, t=2 min 30% B, t=17 min 70% B, t=18 min 100% B, t=23 min 100% B; Detection UV: 220 / 254 nm. Appropriate fractions are combined and lyophilized.

[0229] Chiral (preparative) SFC Method A: (Column: SFC instrument module: Waters Prep100q SFC System, PDA: Waters 2998, Fraction collector: Waters 2767; Column: Phenomenex Lux Amylose-1 (250 x 20 mm, 5 μm), Column temperature: 35 °C; Flow rate: 100 mL / min; ABPR: 170 bar; Eluent A: CO2, Eluent B: 20 ​​mM ammonia in methanol; isocratic 10% B, Time: 30 min, Detection: PDA (210-320 nm); PDA-based fraction collection). Method B: (Column: SFC instrument module: Waters Prep100q SFC System, PDA: Waters 2998, Fraction collector: Waters 2767; Column: Phenomenex Lux Celulose-1 (250 x 20 mm, 5 μm); Column temperature: 35 °C; Flow rate: 100 mL / min; ABPR: 170 bar; Eluent A: CO2, Eluent B: 20 ​​mM ammonia in methanol; isocratic 10% B, Time: 30 min, Detection: PDA (210-320 nm); PDA-based fraction collection). Method C: (Column: SFC instrument module: Waters Prep100q SFC System, PDA: Waters 2998; Column: Chiralpak IC (100 × 4.6 mm, 5 μm); Column temperature: 35 °C; Flow rate: 2.5 mL / min; ABPR: 170 bar; Eluent A: CO2, Eluent B: Methanol and 20 mM ammonia; t = 0 min 5% B, t = 5 min 50% B, t = 6 min 50% B, Detection: PDA (210-320 nm); PDA-based fraction collection). Method D: (Column: SFC Instrument Module: Waters Prep 100 SFC UV / MS based system; Waters 2998 Photodiode Array (PDA) Detector; Waters Acquity QDa MS Detector; Waters 2767 Sample Manager; Column: Waters Torus 2-PIC 130A OBD (250 × 19 mm, 5 μm); Column Temperature: 35 °C; Flow Rate: 70 mL / min; ABPR: 120 bar; Eluent A: CO2, Eluent B: 20 ​​mM ammonia in methanol; Linear gradient: t = 0 min 10% B, t = 4 min 50% B, t = 6 min 50% B; Detection: PDA (210-400 nm); Fraction collection based on PDA TIC).

[0230] Starting materials Standard reagents and solvents were obtained at the highest commercially available purity and were used as received. Specific reagents purchased are listed below.

[0231] [Table 1]

[0232] Intermediate 1: Synthesis of 1-((2S,5R)-5-(4-chloro-6-(pyrazin-2-yl)pyrimidin-2-yl)-2-methylpiperidin-1-yl)ethan-1-one

[0233] [ka]

[0234] To a solution of methyl 6-methylnicotinate (100 g, 662 mmol) in acetic acid (250 mL) in a 1 L steel autoclave, platinum(IV) oxide (0.5 g, 2.202 mmol) was added, and the reaction mixture was then stirred at 60° C. under 10 bar hydrogen atmosphere. Rapid hydrogen consumption was observed and the autoclave was recharged several times until hydrogen consumption ceased. The mixture was cooled to room temperature and filtered through Celite. The filtrate was carefully concentrated to yield methyl 6-methylpiperidine-3-carboxylate acetate as a mixture of diastereoisomers (143.8 g, 100%), which was used directly in the next step. GCMS (Method A): t R 2.40 (80%) and 2.48 min (20%), 100%, MS(EI) 157.1(M) + Methyl 6-methylpiperidine-3-carboxylate acetate (2.1 kg, 9924 mmol) as a mixture of diastereoisomers was diluted with dichloromethane (4 L) and 4 M sodium hydroxide solution was added slowly until pH 9. The layers were separated and the aqueous layer was extracted twice with dichloromethane (after each extraction the aqueous layer was rebasified to pH 9 with 4 M sodium hydroxide solution). The combined organic layers were dried over sodium sulfate and concentrated (35° C., 450 mbar) to a smaller volume (approximately 2 L) to yield methyl 6-methylpiperidine-3-carboxylate (2.8 kg, 8905 mmol) as a approx. 50% yellow solution in dichloromethane. 1H NMR (400 MHz, CDCl3, mixture of rotamers) δ 5.10 (s,.3H), 3.63 (s, 1H), 3.49 - 3.42 (m, 2.2H), 3.41 - 3.34 (m, 0.8H), 3.18 - 3.10 (m, 0.8H), 3.09 - 3.03 (m, 0.2H), 2.64 - 2.54 (m, 0.8H), 2.53 - 2.34 (m, 1.2H), 2.30 - 2.20 (m, 1H), 1.95 - 1.76 (m, 1H), 1.53 - 1.36 (m, 1H), 1.35 - 1.21 (m, 1H), 1.04 - 0.90 (m, 1H), 0.89 - 0.84 (m, 0.8H), 0.83 - 0.76 (m, 2.2H).To a solution of N-acetyl-D-leucine (1 kg, 5.77 mol) in ethanol (1.5 L) was added a solution of methyl 6-methylpiperidine-3-carboxylate (934 g, 2.38 mol) in ethyl acetate (3 L) and the mixture was heated to 40°C. The resulting solution was allowed to warm to room temperature over 16 h during which time a precipitate formed. The precipitate was filtered off, washed with diethyl ether (500 mL) and air-dried to yield crude methyl (3R,6S)-6-methylpiperidine-3-carboxylate acetyl-D-leucinate (287 g, 34%) as a white solid. The crude methyl (3R,6S)-6-methylpiperidine-3-carboxylate acetyl-D-leucinate (287 g, 869 mmol) was crystallized from a hot 1:2 mixture of ethanol and ethyl acetate (1 L). The precipitate was filtered off and the filter cake was triturated in a 1:1 mixture of diethyl ether and n-pentane (500 mL). The precipitate was filtered off and air-dried to yield methyl (3R,6S)-6-methylpiperidine-3-carboxylate acetyl-D-leucinate (128 g, 44%) as a white solid. 1H-NMR (400 MHz, DMSO-d6) δ 7.80 (d, J = 8.2 Hz, 1H), 5.80 - 5.00 (s, 2H), 4.20 - 4.04 (m, 1H), 3.63 (s, 3H), 3.32 - 3.21 (m, 1H), 2.93 - 2.80 (m, 2H), 2.73 - 2.65 (m, 1H), 2.04 - 1.94 (m, 1H), 1.82 (s, 3H), 1.68 - 1.49 (m, 3H), 1.49 - 1.37 (m, 2H), 1.30 - 1.15 (m, 1H), 1.02 (d, J = 6.4 Hz, 3H), 0.85 (m, 6H). To a solution of methyl (3R,6S)-6-methylpiperidine-3-carboxylate acetyl-D-leucinate (128 g, 387 mmol) in dichloromethane (1 L) was added saturated sodium carbonate solution (1 L). The biphasic system was stirred vigorously for 10 min and the layers were separated. The organic layer was dried over sodium sulfate and filtered to produce a clear solution. Triethylamine (65 mL, 465 mmol) and acetic anhydride (44 mL, 465 mmol) were then added and the mixture was stirred at room temperature for 1 h. The mixture was washed with saturated aqueous sodium bicarbonate, dried over sodium sulfate and concentrated to produce methyl (3R,6S)-1-acetyl-6-methylpiperidine-3-carboxylate (93 g) as a pale yellow solid. 1H-NMR (400 MHz, CDCl3, mixture of rotamers) δ 5.02 - 4.87 (m, 0.5H), 4.84 - 4.68 (m, 0.5H), 4.18 - 4.05 (m, 0.5H), 3.89 - 3.77 (m, 0.5H), 3.71 (d, J = 11.6 Hz, 3H), 3.31 - 3.18 (m, 0.5H), 2.79 - 2.67 (m, 0.5H), 2.51 - 2.31 (m, 1H), 2.11 (d, J = 6.7 Hz, 3H), 2.01 - 1.90 (m, 1H), 1.88 - 1.55 (m, 3H), 1.33 - 1.21 (m, 1.5H), 1.20 - 1.06 (m, 1.5H). An autoclave was charged with methyl (3R,6S)-1-acetyl-6-methylpiperidine-3-carboxylate (93 g, 387 mmol) in 7N ammonia in methanol (600 mL, 4200 mmol) and heated to 60° C. for 3 days. The mixture was concentrated to give (3R,6S)-1-acetyl-6-methylpiperidine-3-carboxamide (102 g) as a pale yellow oil. Quantitative yield was assumed and the product was used directly in the next step. 1 H-NMR (400 MHz, DMSO-d6, mixture of rotamers) δ 7.38 (s, 1H), 6.89 (d, J = 24.7 Hz, 1H), 4.76 - 4.59 (m, 0.5H), 4.39 - 4.24 (m, 0.5H), 4.16 - 4.01 (m, 0.5H), 3.72 - 3.51 (m, 0.5H), 3.14 - 2.99 (m, 0.5H), 2.68 - 2.51 (m, 0.5H), 2.30 - 2.12 (m, 0.5H), 2.11 - 1.92 (m, 3.5H), 1.78 - 1.38 (m, 4H), 1.23 - 1.11 (m, 1.5H), 1.09 - 0.94 (m, 1.5H); Chiral LC (Method A) t R= 12.35 min, >98% ee.To a solution of (3R,6S)-1-acetyl-6-methylpiperidine-3-carboxamide (50 g, 271 mmol) in dichloromethane (500 mL) was added triethyloxonium tetrafluoroborate (77 g, 407 mmol) in portions and the mixture was stirred at room temperature for 4 h. Slowly, 7N ammonia in methanol (200 mL, 9.15 mol) was added and the mixture was stirred at room temperature for 16 h. The mixture was concentrated to yield (3R,6S)-1-acetyl-6-methylpiperidine-3-carboximidamide (50 g) as a pink solid, which was used directly in the next step. To a solution of 5.4 M sodium methoxide in methanol (99 mL, 535 mmol) in methanol (200 mL) was added (3R,6S)-1-acetyl-6-methylpiperidine-3-carboximidamide (49 g, 267 mmol) in methanol (400 mL) and dimethyl malonate (61.4 mL, 535 mmol). The mixture was heated to 50° C. and stirred for 24 hours. The mixture was acidified with concentrated hydrochloric acid (pH approx. 3) and concentrated to a smaller volume. The residue was filtered through silica (20% methanol in dichloromethane) and concentrated to produce an orange oil. The crude product was purified by silica column chromatography (0% to 20% methanol in dichloromethane) to give 1-((2S,5R)-5-(4,6-dihydroxypyrimidin-2-yl)-2-methylpiperidin-1-yl)ethan-1-one (12 g, 17%) as a colorless gum. LCMS (Method C): R 0.17 min, 100%, MS(ESI)252.1(M+H) +A solution of 1-((2S,5R)-5-(4,6-dihydroxypyrimidin-2-yl)-2-methylpiperidin-1-yl)ethan-1-one (12 g, 47.8 mmol) in phosphorus oxychloride (80 mL, 858 mmol) was stirred at 60° C. for 24 h. The reaction mixture was concentrated and coevaporated twice with toluene to produce a yellow oil. The oil was dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated to produce a yellow oil. The oil was purified by silica column chromatography (0% to 20% tetrahydrofuran in toluene) to give 1-((2S,5R)-5-(4,6-dichloropyrimidin-2-yl)-2-methylpiperidin-1-yl)ethan-1-one (1.5 g, 11%) as a colorless gum. 1 H-NMR (400 MHz, DMSO-d6, mixture of rotamers) δ 7.95 (d, J = 7.3 Hz, 1H), 4.85 - 4.72 (m, 1H), 4.69 - 4.62 (m, 1H), 4.23 - 4.13 (m, 1H), 4.07 - 3.98 (m, 1H), 3.97 - 3.88 (m, 1H), 3.00 - 2.89 (m, 1H), 2.81 - 2.67 (m, 1H), 2.09 - 1.72 (m, 7H), 1.71 - 1.58 (m, 2H), 1.25 - 1.14 (m, 3H), 1.12 - 1.05 (m, 2H); LCMS (Method B): t R 3.34 minutes, MS (ESI) 288.0 (M+H) + Chiral UPLC (Method: A) R2.54 min, >95% ee and de. 2-Tributylstannylpyrazine (607 mg, 1.65 mmol), 1-((2S,5R)-5-(4,6-dichloropyrimidin-2-yl)-2-methylpiperidin-1-yl)ethan-1-one (500 mg, 1.74 mmol) and bis(triphenylphosphine)palladium(II) chloride (244 mg, 0.34 mmol) in 1,4-dioxane (20 mL) were heated to 100° C. under argon and stirred for 32 h. The mixture was diluted with dichloromethane containing 1% triethylamine and coated onto silica. This was purified by silica column chromatography (0% to 40% acetonitrile in dichloromethane containing 1% triethylamine) to give 1-((2S,5R)-5-(4-chloro-6-(pyrazin-2-yl)pyrimidin-2-yl)-2-methylpiperidin-1-yl)ethan-1-one (Intermediate 1, 134 mg, 18%) as an orange gum. 1 H-NMR (400 MHz, DMSO-d6, mixture of rotamers) δ 9.46 - 9.41 (m, 1H), 8.80 - 8.76 (m, 1H), 8.65 - 8.59 (m, 1H), 8.33 - 8.29 (m, 1H), 7.66 - 7.59 (m, 1H), 4.86 - 4.70 (m, 0.5H), 4.27 - 4.17 (m, 0.5H), 4.09 - 3.97 (m, 0.5H), 3.55 - 3.41 (m, 0.5H), 3.06 - 2.98 (m, 0.5H), 2.88 - 2.82 (m, 0.5H), 2.10 - 1.90 (m, 6H), 1.89 - 1.76 (m, 0.5H), 1.75 - 1.61 (m, 1.5H), 1.29 - 1.20 (m, 1.5H), 1.17 - 1.10 (m, 1.5H); LCMS (Method C): t R 1.81 min, MS (ESI) 331.1 (M+H) + .

[0235] Synthetic Procedure for Final Product Example 1 Synthesis of 1-((2S,5R)-5-(4-((3-fluoro-5-(1-methyl-1H-imidazol-4-yl)phenyl)amino)-6-(pyrazin-2-yl)pyrimidin-2-yl)-2-methylpiperidin-1-yl)ethan-1-one (001)

[0236] [ka]

[0237] To a mixture of 1-((2S,5R)-5-(4-chloro-6-(pyrazin-2-yl)pyrimidin-2-yl)-2-methylpiperidin-1-yl)ethan-1-one (Intermediate 1, 4.64 g, 8.95 mmol) in 2-propanol (60 mL) was added 3-bromo-5-fluoroaniline (2.21 g, 11.63 mmol) and concentrated hydrochloric acid (1.49 mL, 17.90 mmol). The mixture was stirred at 60° C. for 4 days and at room temperature for 1 day. The mixture was neutralized to pH 7 using saturated aqueous sodium bicarbonate and concentrated in vacuo. The residue was extracted three times with ethyl acetate and twice with a mixture of 10% methanol in dichloromethane. The combined organic layers were dried over sodium sulfate, filtered, and coated onto silica. The residue was purified by silica column chromatography (0% to 10% methanol in dichloromethane) to give 1-((2S,5R)-5-(4-((3-bromo-5-fluorophenyl)amino)-6-(pyrazin-2-yl)pyrimidin-2-yl)-2-methylpiperidin-1-yl)ethan-1-one (2.58 g, 56%) as an off-white solid. LCMS (Method C):t R 2.02 min, 94%, MS(ESI) 485.0 and 487.0(M+H) +Under nitrogen atmosphere, 1-((2S,5R)-5-(4-((3-bromo-5-fluorophenyl)amino)-6-(pyrazin-2-yl)pyrimidin-2-yl)-2-methylpiperidin-1-yl)ethan-1-one (2.88 g, 5.70 mmol) and 1-methyl-4-(tributylstannyl)-1H-imidazole (2.54 g, 6.84 mmol) were dissolved in dry 1,4-dioxane (55 mL) and tetrakis(triphenylphosphine)palladium(0) (1.32 g, 1.14 mmol) was added. The mixture was stirred at 110° C. for 3 days, allowed to cool to room temperature, and coated onto silica. The coated mixture was purified twice by silica column chromatography (0% to 10% methanol in dichloromethane). The product was further purified by preparative reverse phase chromatography (Method A) and concentrated in vacuo. The residue was extracted three times with ethyl acetate, and the combined organic layers were dried over sodium sulfate, filtered, and dried under vacuum. The residue was purified by chiral (preparative) SFC (Method D) and lyophilized to yield 1-((2S,5R)-5-(4-((3-fluoro-5-(1-methyl-1H-imidazol-4-yl)phenyl)amino)-6-(pyrazin-2-yl)pyrimidin-2-yl)-2-methylpiperidin-1-yl)ethan-1-one (001, 1.21 g, 44%) as a white solid. 1H-NMR (400 MHz, DMSO-d6, mixture of rotamers) δ 10.14 (d, J = 8.5 Hz, 1H), 9.56 (d, J = 12.7 Hz, 1H), 8.84 - 8.78 (m, 2H), 7.98 (d, J = 6.0 Hz, 1H), 7.76 - 7.62 (m, 4H), 7.22 - 7.14 (m, 1H), 4.88 - 4.73 (m, 1H), 4.28 - 4.19 (m, 0.5H), 4.09 (dd, J = 13.6, 4.1 Hz, 0.5H), 3.75 - 3.66 (m, 3H), 3.57 - 3.47 (m, 0.5H), 3.02 - 2.89 (m, 1H), 2.85 - 2.74 (m, 0.5H), 2.14 - 2.00 (m, 5H), 1.93 - 1.82 (m, 0.5H), 1.77 - 1.65 (m, 1.5H), 1.33 - 1.27 (m, 1.5), 1.19 - 1.13 (m, 1.5H); UPLC (Method A): t R 1.45 min, 97%, MS (ESI) 487.2 (M+H) + .

[0238] Example 2 Synthesis of 1-((2S,5R)-5-(4-((3-fluoro-5-(1H-pyrazol-4-yl)phenyl)amino)-6-(pyrazin-2-yl)pyrimidin-2-yl)-2-methylpiperidin-1-yl)ethan-1-one (002)

[0239] [ka]

[0240] To a mixture of 1-((2S,5R)-5-(4-chloro-6-(pyrazin-2-yl)pyrimidin-2-yl)-2-methylpiperidin-1-yl)ethan-1-one (Intermediate 1, 457 mg, 1.38 mmol) and 3-fluoro-5-iodoaniline (326 mg, 1.38 mmol) in 2-propanol (10 mL) was added concentrated hydrochloric acid (0.23 mL, 2.75 mmol). The mixture was stirred at 60° C. for 16 hours. The mixture was concentrated in vacuo, redissolved in water, neutralized with saturated aqueous sodium bicarbonate, and extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and coated onto silica. The residue was purified by silica column chromatography (0% to 100% ethyl acetate in n-heptane) followed by silica column chromatography (0% to 10% methanol in dichloromethane) to yield 1-((2S,5R)-5-(4-((3-fluoro-5-iodophenyl)amino)-6-(pyrazin-2-yl)pyrimidin-2-yl)-2-methylpiperidin-1-yl)ethan-1-one (403 mg, 47%) as an off-white solid. LCMS (Method C):t R 2.20 minutes, 86%, MS(ESI)533.0(M+H) +Under nitrogen atmosphere, 1-((2S,5R)-5-(4-((3-fluoro-5-iodophenyl)amino)-6-(pyrazin-2-yl)pyrimidin-2-yl)-2-methylpiperidin-1-yl)ethan-1-one (50 mg, 0.09 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (54.7 mg, 0.28 mmol) and sodium carbonate (29.9 mg, 0.28 mmol) were dissolved in 1,2-dimethoxyethane (1 mL) and water (0.33 mL), and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride dichloromethane complex (7.67 mg, 9.39 μmol) was added. The mixture was stirred at 90 °C for 3 days. The reaction mixture was allowed to cool to room temperature, filtered onto C18-material, coated onto silica, and purified by silica column chromatography (0% to 10% methanol in dichloromethane). The product was further purified by preparative reverse phase chromatography (Method B) and lyophilized to yield 1-((2S,5R)-5-(4-((3-fluoro-5-(1H-pyrazol-4-yl)phenyl)amino)-6-(pyrazin-2-yl)pyrimidin-2-yl)-2-methylpiperidin-1-yl)ethan-1-one (002, 20.0 mg, mmol, 45%) as a white solid. 1H-NMR (400 MHz, DMSO-d6, mixture of rotamers) δ13.06 (s, 1H), 10.13 (d, J = 7.8 Hz, 1H), 9.56 (d, J = 14.3 Hz, 1H), 8.91 - 8.70 (m, 2H), 8.33 - 7.82 (m, 2H), 7.73 - 7.61 (m, 3H), 7.21 - 7.09 (m, 1H), 4.88 - 4.72 (m, 1H), 4.28 - 4.18 (m, 0.5H), 4.18 - 4.01 (m, 0.5H), 3.53 - 3.43 (m, 0.5H), 3.01 - 2.89 (m, 1H), 2.85 - 2.74 (m, 0.5H), 2.13 - 2.00 (m, 5H), 1.93 - 1.82 (m, 0.5H), 1.78 - 1.63 (m, 1.5H), 1.31 - 1.23 (m Hz, 1.5H), 1.19 - 1.09 (m 1.5H); UPLC (Method A): t R 1.44 min, 99%, MS (ESI) 473.2 (M+H) + .

[0241] Example 3 Synthesis of 1-((2S,5R)-5-(4-((3-fluoro-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)amino)-6-(pyrazin-2-yl)pyrimidin-2-yl)-2-methylpiperidin-1-yl)ethan-1-one (003)

[0242] [ka]

[0243] A mixture of 3-bromoaniline (0.13 mL, 1.16 mmol), 1,3,5-trimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (302 mg, 1.28 mmol) and sodium carbonate (370 mg, 3.49 mmol) in 1,2-dimethoxyethane (8 mL) and water (2 mL) was degassed with argon for 5 minutes. Bis(triphenylphosphine)palladium(II) dichloride (40.8 mg, 0.06 mmol) was added and the mixture was heated at 100° C. for 16 hours. The mixture was allowed to cool to room temperature, diluted with water and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica column chromatography (0% to 75% ethyl acetate in n-heptane) to afford 3-(1,3,5-trimethyl-1H-pyrazol-4-yl)aniline (100 mg, 43%) as a yellow oil. 1 H-NMR (400 MHz, DMSO-d6) δ 7.05 - 6.99 (m, 1H), 6.48 - 6.42 (m, 2H), 6.38 - 6.33 (m, 1H), 5.03 (s, 2H), 3.67 (s, 3H), 2.18 (s, 3H), 2.09 (s, To a mixture of 3H).1-((2S,5R)-5-(4-chloro-6-(pyrazin-2-yl)pyrimidin-2-yl)-2-methylpiperidin-1-yl)ethan-1-one (Intermediate 1, 100 mg, 0.25 mmol) and 3-(1,3,5-trimethyl-1H-pyrazol-4-yl)aniline (60.4 mg, 0.30 mmol) in 2-propanol (4 mL) was added concentrated hydrochloric acid (0.02 mL, 0.25 mmol). The mixture was stirred at 70° C. for 16 hours, allowed to cool to room temperature, and concentrated in vacuo. The residue was dissolved in methanol, purified by chiral (preparative) SFC (Method D) and lyophilized to yield 1-((2S,5R)-2-methyl-5-(4-(pyrazin-2-yl)-6-((3-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)amino)pyrimidin-2-yl)piperidin-1-yl)ethan-1-one (003, 68.2 mg, 55%) as a white solid. 1H-NMR (400 MHz, DMSO-d6, mixture of rotamers) δ 9.94 (d, J = 7.5 Hz, 1H), 9.55 (dd, J = 13.0, 1.3 Hz, 1H), 8.98 - 8.65 (m, 2H), 7.87 - 7.71 (m, 1H), 7.66 (d, J = 2.1 Hz, 1H), 7.62 - 7.50 (m, 1H), 7.43 - 7.35 (m, 1H), 6.94 (d, J = 7.5 Hz, 1H), 4.86 - 4.76 (m, 0.5H), 4.71 - 4.61 (m, 0.5H), 4.25 - 4.14 (m, 0.5H), 4.06 - 3.96 (m, 0.5H), 3.70 (s, 3H), 3.52 - 3.41 (m, 0.5H), 2.96 - 2.81 (m, 1H), 2.77 - 2.68 (m, 0.5H), 2.25 (s, 3H), 2.16 (s, 3H), 2.11 - 1.90 (m, 5H), 1.90 - 1.76 (m, 0.5H), 1.74 - 1.58 (m, 1.5H), 1.22 - 1.16 (m, 1.5H), 1.11 - 1.04 (m, 1.5H); UPLC (Method A): t R 1.50 min, 99%, MS (ESI) 497.4 (M+H) + . Using the appropriate starting materials, the following compounds were prepared following procedures similar to Example 3 and purified using reverse phase chromatography methods A / B and / or prep-SFC.

[0244] [Table 2]

[0245] Example 4 Synthesis of 1-((2S,5R)-5-(4-((3-fluoro-5-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)amino)-6-(pyrazin-2-yl)pyrimidin-2-yl)-2-methylpiperidin-1-yl)ethan-1-one (006)

[0246] [ka]

[0247] To a mixture of 3-fluoro-5-nitrobenzoic acid (200 mg, 1.08 mmol) and acetohydrazide (96 mg, 1.30 mmol) in dry N,N-dimethylformamide (10 mL) was added N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (249 mg, 1.30 mmol) and 1-hydroxy-7-azabenzotriazole (14.71 mg, 0.11 mmol). The mixture was stirred at room temperature for 3 days. The reaction mixture was diluted with ethyl acetate and saturated aqueous sodium bicarbonate. The layers were separated and the organic layer was washed with saturated aqueous sodium bicarbonate. The organic layer was dried over sodium sulfate, filtered, and dried under vacuum. The residue was dissolved in dry tetrahydrofuran (10 mL) and (methoxycarbonylsulfamoyl)triethylammonium hydroxide (643 mg, 2.70 mmol) was added. The mixture was stirred at room temperature for 90 minutes and then diluted with ethyl acetate and saturated aqueous sodium bicarbonate. The layers were separated and the aqueous phase was extracted twice with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and coated onto silica. The residue was purified by silica column chromatography (0% to 100% ethyl acetate in n-heptane) to yield 2-(3-fluoro-5-nitrophenyl)-5-methyl-1,3,4-oxadiazole (131 mg, 54%) as a yellow oil. 1 LCMS (Method A): t R 1.73 min, 99%, MS (ESI) 224.0 (M+H) +Under nitrogen atmosphere, 2-(3-fluoro-5-nitrophenyl)-5-methyl-1,3,4-oxadiazole (130 mg, 0.58 mmol) was dissolved in ethanol (5 mL) and 10% palladium on carbon (50% wet, 12.40 mg, 0.06 mmol) was added. Hydrogen atmosphere was then introduced and the mixture was stirred at room temperature for 16 h. The mixture was filtered through Celite, the filter cake was washed with ethanol and the filtrate was coated on silica. The residue was purified by column chromatography (0% to 10% methanol in dichloromethane) to yield 3-fluoro-5-(5-methyl-1,3,4-oxadiazol-2-yl)aniline (76 mg, 68%) as a dark viscous material. 1 H-NMR (400 MHz, DMSO-d6) δ 7.05 - 7.00 (m, 1H), 6.82 - 6.75 (m, 1H), 6.55 - 6.47 (m, 1H), 5.87 (s, 2H), 2.56 (s, 3H). Under nitrogen atmosphere, 1-((2S,5R)-5-(4-chloro-6-(pyrazin-2-yl)pyrimidin-2-yl)-2-methylpiperidin-1-yl)ethan-1-one (Intermediate 1, 50 mg, 0.15 mmol), 3-fluoro-5-(5-methyl-1,3,4-oxadiazol-2-yl)aniline (37.8 mg, 0.20 mmol) and cesium carbonate (147 mg, 0.45 mmol) were dissolved in 1,4-dioxane (2 mL) and tris(dibenzylideneacetone)dipalladium(0) (13.80 mg, 0.02 mmol) and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (14.37 mg, 0.03 mmol) were added. The mixture was heated in a microwave at 100 °C for 2 h. The mixture was filtered over C18-material, purified by preparative reverse-phase chromatography (Method A) and lyophilized to yield 1-((2S,5R)-5-(4-((3-fluoro-5-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)amino)-6-(pyrazin-2-yl)pyrimidin-2-yl)-2-methylpiperidin-1-yl)ethan-1-one (006, 40 mg, 54%) as a white solid. 1H-NMR (400 MHz, DMSO-d6, mixture of rotamers) δ 10.42 (d, J = 6.4 Hz, 1H), 9.56 (d, J = 14.4 Hz, 1H), 8.85 - 8.78 (m, 2H), 8.38 - 8.30 (m, 1H), 8.06 - 7.95 (m, 1H), 7.68 (d, J = 3.1 Hz, 1H), 7.43 - 7.34 (m, 1H), 4.88 - 4.74 (m, 1H), 4.28 - 4.21 (m, 0.5H), 4.18 - 4.07 (m, 0.5H), 3.56 - 3.45 (m, 0.5H), 3.03 - 2.91 (m, 1H), 2.86 - 2.72 (m, 0.5H), 2.59 (s, 3H), 2.19 - 1.98 (m, 5H), 1.93 - 1.82 (m, 0.5H), 1.77 - 1.65 (m, 1.5H), 1.34 - 1.23 (m, 1.5H), 1.22 - 1.12 (m, 1.5H); UPLC (Method B): t R 1.49 minutes, 100%, MS (ESI) 489.2 (M+H) + .

[0248] Example 5 Synthesis of 1-((2S,5R)-5-(4-((3-(1-isopropyl-1H-1,2,3-triazol-4-yl)phenyl)amino)-6-(pyrazin-2-yl)pyrimidin-2-yl)-2-methylpiperidin-1-yl)ethan-1-one (007)

[0249] [ka]

[0250] To a mixture of 3-nitrophenylacetylene (173 mg, 1.18 mmol), L-ascorbic acid sodium salt (46.6 mg, 0.24 mmol) and anhydrous copper(II) sulfate (37.5 mg, 0.24 mmol) in a mixture of t-butanol (5 mL) and water (5 mL) was added a 2.5 M solution of 2-azidopropane in N,N-dimethylformamide (0.47 mL, 1.18 mmol). The reaction mixture was stirred at 35 °C for 16 h and subsequently diluted with water and ethyl acetate. The mixture was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and dried under vacuum. The residue was purified by silica column chromatography (0% to 50% ethyl acetate in n-heptane) to yield 1-isopropyl-4-(3-nitrophenyl)-1H-1,2,3-triazole (147.8 mg, 54%) as a white solid. LCMS (Method C):t R 1.93 minutes, 100%, MS(ESI)233.1(M+H) + Iron (106 mg, 1.90 mmol) was added to a stirred solution of ammonium chloride (102 mg, 1.90 mmol) in water (3 mL). A suspension of 1-isopropyl-4-(3-nitrophenyl)-1H-1,2,3-triazole (147 mg, 0.63 mmol) in a mixture of methanol (1.5 mL) and tetrahydrofuran (1.5 mL) was added slowly. The mixture was stirred at 70° C. for 3 hours, allowed to cool to room temperature, and diluted with water and ethyl acetate. The organic layer was decanted and this process was repeated three times. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under vacuum to yield 3-(1-isopropyl-1H-1,2,3-triazol-4-yl)aniline (133 mg, 104%) as a yellow gum, which was carried on crude without further purification. 1H-NMR (400 MHz, DMSO-d6) δ 8.47 (s, 1H), 7.11 (t, J = 2.0 Hz, 1H), 7.06 (t, J = 7.7 Hz, 1H), 6.93 (dt, J = 7.6, 1.4 Hz, 1H), 6.54 - 6.48 (m, 1H), 5.15 (s, 2H), 4.87 - 4.73 (m, 1H), 1.52 (d, J = 6.7 Hz, 6H); LCMS (Method C): t R 1.61 min, 98%, MS (ESI) 203.1 (M+H) + To a mixture of 1-((2S,5R)-5-(4-chloro-6-(pyrazin-2-yl)pyrimidin-2-yl)-2-methylpiperidin-1-yl)ethan-1-one (Intermediate 1, 100 mg, 0.25 mmol) and 3-(1-isopropyl-1H-1,2,3-triazol-4-yl)aniline (60.7 mg, 0.30 mmol) in 2-propanol (4 mL) was added concentrated hydrochloric acid (0.02 mL, 0.25 mmol). The mixture was stirred at 70° C. for 16 hours, allowed to cool to room temperature, and dried under vacuum. The residue was purified by chiral (preparative) SFC (Method D) and lyophilized to yield 1-((2S,5R)-5-(4-((3-(1-isopropyl-1H-1,2,3-triazol-4-yl)phenyl)amino)-6-(pyrazin-2-yl)pyrimidin-2-yl)-2-methylpiperidin-1-yl)ethan-1-one (007, 77.8 mg, 63%) as a white solid. 1H-NMR (400 MHz, DMSO-d6, mixture of rotamers) δ 10.01 (d, J = 6.2 Hz, 1H), 9.56 (d, J = 12.3 Hz, 1H), 8.83 - 8.77 (m, 2H), 8.62 (d, J = 6.1 Hz, 1H), 8.44 (d, J = 10.1 Hz, 1H), 7.71 - 7.61 (m, 2H), 7.54 - 7.38 (m, 2H), 4.93 - 4.74 (m, 2H), 4.26 - 4.17 (m, 0.5H), 4.14 - 4.02 (m, 0.5H), 3.55 - 3.46 (m, 0.5H), 3.00 - 2.85 (m, 1H), 2.81 - 2.70 (m, 0.5H), 2.18 - 1.95 (m, 5H), 1.91 - 1.78 (m, 0.5H), 1.76 - 1.61 (m, 1.5H), 1.54 (dd, J = 6.7, 3.5 Hz, 6H), 1.29 - 1.23 (m, 1.5H), 1.16 - 1.05 (m, 1.5H); UPLC (Method A): t R 1.52 min, 97%, MS (ESI) 498.4 (M+H) + .

[0251] The following compounds were prepared following procedures similar to Example 5 using the appropriate starting materials and purified using reverse phase chromatography methods A / B and / or prep-SFC.

[0252] [Table 3]

[0253] Example 6 Synthesis of 1-((2S,5R)-5-(4-((3-fluoro-5-(1H-1,2,3-triazol-4-yl)phenyl)amino)-6-(pyrazin-2-yl)pyrimidin-2-yl)-2-methylpiperidin-1-yl)ethan-1-one (009)

[0254] [ka]

[0255] Under argon, 1-fluoro-3-iodo-5-nitrobenzene (2 g, 7.49 mmol) was dissolved in N,N-dimethylformamide (30 mL) and bis(triphenylphosphine)palladium(II) dichloride (0.26 g, 0.38 mmol) and copper(I) iodide (0.14 g, 0.75 mmol), tetrabutylammonium iodide (0.55 g, 1.50 mmol), triethylamine (1.56 mL, 11.24 mmol) and trimethylsilylacetylene (1.81 mL, 12.73 mmol) were added. The mixture was stirred at 70° C. for 16 hours. The mixture was allowed to cool to room temperature, poured into saturated aqueous ammonium chloride solution and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was coated onto a hydromatrix and purified twice by silica column chromatography (0% to 15% ethyl acetate in n-heptane) to yield ((3-fluoro-5-nitrophenyl)ethynyl)trimethylsilane (680 mg, 38%) as a brown viscous material. 1 H-NMR (400 MHz, CDCl3) δ 8.14 - 8.09 (m, 1H), 7.91 - 7.84 (m, 1H), 7.51 - 7.44 (m, 1H), 0.28 - 0.26 (m, 9H).To a solution of ((3-fluoro-5-nitrophenyl)ethynyl)trimethylsilane (880 mg, 3.71 mmol) in methanol (35 mL) was added potassium carbonate (256 mg, 1.85 mmol) and the mixture was stirred at room temperature for 3 h. The mixture was concentrated in vacuo to give an oil. The oil was diluted with diethyl ether and water. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo to give 1-ethynyl-3-fluoro-5-nitrobenzene (514 mg, 84%) as an orange solid. 1H-NMR (400 MHz, CDCl3) δ 8.18 - 8.12 (m, 1H), 7.96 - 7.89 (m, 1H), 7.55 - 7.48 (m, 1H), 3.28 (s, 1H). Under an argon atmosphere, azidotrimethylsilane (0.49 mL, 3.75 mmol) and copper(I) iodide (23.82 mg, 0.13 mmol) were added to a stirred solution of 1-ethynyl-3-fluoro-5-nitrobenzene (413 mg, 2.50 mmol) in dry N,N-dimethylformamide (20 mL) and methanol (2 mL). The mixture was stirred at 100 °C for 16 h, allowed to cool to room temperature, and poured into saturated aqueous sodium bicarbonate. The mixture was extracted three times with ethyl acetate, and the combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica column chromatography (0% to 50% ethyl acetate in n-heptane) to yield 4-(3-fluoro-5-nitrophenyl)-1H-1,2,3-triazole (460 mg, 88%) as a white solid. 1 H-NMR (400 MHz, DMSO-d6) δ 15.50 (s, 1H), 8.70 (s, 1H), 8.59 - 8.53 (m, 1H), 8.26 - 8.19 (m, 1H), 8.14 - 8.07 (m, 1H).To a stirred solution of 4-(3-fluoro-5-nitrophenyl)-1H-1,2,3-triazole (460 mg, 2.21 mmol) in ethanol (30 mL) under a nitrogen atmosphere, 10% palladium on carbon (50% wet, 47.0 mg, 0.22 mmol) was added. A hydrogen atmosphere was then introduced and the mixture was stirred at room temperature for 6 days. The mixture was filtered through Celite and the filter cake was rinsed with ethanol. The combined filtrate was concentrated in vacuo and purified by silica column chromatography (0% to 60% ethyl acetate in n-heptane) to yield 3-fluoro-5-(1H-1,2,3-triazol-4-yl)aniline (309 mg, 78%) as a yellow solid. 1H-NMR (400 MHz, DMSO-d6) δ 15.11 (s, 1H), 8.22 (s, 1H), 6.95 - 6.89 (m, 1H), 6.78 - 6.70 (m, 1H), 6.34 - 6.26 (m, 1H), 5.55 (s, 2H). LCMS (Method A): t R 1.11 min, 87%, MS (ESI) 179.0 (M+H) + To a solution of 1-((2S,5R)-5-(4-chloro-6-(pyrazin-2-yl)pyrimidin-2-yl)-2-methylpiperidin-1-yl)ethan-1-one (Intermediate 1, 100 mg, 0.30 mmol) and 3-fluoro-5-(1H-1,2,3-triazol-4-yl)aniline (64.4 mg, 0.36 mmol) in 2-propanol (4 mL) was added concentrated hydrochloric acid (0.05 mL, 0.51 mmol) and the mixture was heated at 70° C. for 16 h. The mixture was concentrated in vacuo, purified by preparative reverse-phase chromatography (Method A) and lyophilized to yield 1-((2S,5R)-5-(4-((3-fluoro-5-(1H-1,2,3-triazol-4-yl)phenyl)amino)-6-(pyrazin-2-yl)pyrimidin-2-yl)-2-methylpiperidin-1-yl)ethan-1-one (009, 88 mg, 62%) as a white solid. 1H-NMR (400 MHz, DMSO-d6, mixture of rotamers) δ 15.18 (s, 1H), 10.25 (d, J = 4.8 Hz, 1H), 9.56 (d, J = 14.5 Hz, 1H), 8.87 - 8.78 (m, 2H), 8.38 (s, 1H), 8.10 (d, J = 15.1 Hz, 1H), 7.91 - 7.82 (m, 1H), 7.68 (d, J = 2.1 Hz, 1H), 7.39 - 7.32 (m, 1H), 4.89 - 4.79 (m, 0.5H), 4.79 - 4.65 (m, 0.5H), 4.28 - 4.18 (m, 0.5H), 4.14 - 4.06 (m, 0.5H), 3.54 - 3.45 (m, 0.5H), 3.01 - 2.90 (m, 1H), 2.85 - 2.74 (m, 0.5H), 2.17 - 1.95 (m, 5H), 1.94 - 1.79 (m, 0.5H), 1.77 - 1.64 (m, 1.5H), 1.32 - 1.24 (m, 1.5H), 1.19 - 1.04 (m, 1.5H); UPLC (Method A): t R 1.29 min, 96%, MS (ESI) 474.2 (M+H) + ; Chiral SFC (Method D): t R 3.45 minutes, 97%, MS (ESI) 474.1 (M+H) + .

[0256] Example 7 Synthesis of 1-((2S,5R)-5-(4-((3-chloro-5-(1H-1,2,3-triazol-4-yl)phenyl)amino)-6-(pyrazin-2-yl)pyrimidin-2-yl)-2-methylpiperidin-1-yl)ethan-1-one (010)

[0257] [ka]

[0258] Under argon, 1-bromo-3-chloro-5-nitrobenzene (1.24 g, 5.24 mmol) was dissolved in N,N-dimethylformamide (40 mL) and bis(triphenylphosphine)palladium(II) dichloride (0.18 g, 0.26 mmol) and copper(I) iodide (0.10 g, 0.52 mmol), tetrabutylammonium iodide (0.39 g, 1.05 mmol), triethylamine (1.09 mL, 7.87 mmol) and trimethylsilylacetylene (1.27 mL, 8.92 mmol) were added. The mixture was stirred at 70° C. for 16 h. The mixture was allowed to cool to room temperature and concentrated in vacuo. The residue was coated onto a hydromatrix and purified by silica column chromatography (0% to 10% ethyl acetate in n-heptane) to yield ((3-chloro-5-nitrophenyl)ethynyl)trimethylsilane (1.0 g, 75%) as a brown viscous material. 1 GCMS (Method C): t R 4.18 min, 94%, MS (EI) 238.1 (M).To a solution of ((3-chloro-5-nitrophenyl)ethynyl)trimethylsilane (1.0 g, 3.94 mmol) in methanol (40 mL) was added potassium carbonate (0.27 g, 1.97 mmol). The mixture was stirred at room temperature for 16 h and concentrated in vacuo to give an oil. The oil was diluted with diethyl ether and water. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to give 1-chloro-3-ethynyl-5-nitrobenzene (700 mg, 98%) as a beige solid. 1H-NMR (400 MHz, CDCl3) δ 8.25 - 8.17 (m, 2H), 7.80 - 7.74 (m, 1H), 3.28 (s, 1H). Under an argon atmosphere, azidotrimethylsilane (0.76 mL, 5.78 mmol) and copper(I) iodide (47 mg, 0.25 mmol) were added to a stirred solution of 1-chloro-3-ethynyl-5-nitrobenzene (700 mg, 3.86 mmol) in dry N,N-dimethylformamide (30 mL) and methanol (3 mL). The mixture was stirred at 100 °C for 16 h, allowed to cool to room temperature, and poured into saturated aqueous sodium bicarbonate. The mixture was extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was coated onto a hydromatrix and purified by silica column chromatography (0% to 50% ethyl acetate in n-heptane) to give 4-(3-chloro-5-nitrophenyl)-1H-1,2,3-triazole (650 mg, 75%) as a white solid. LCMS (Method C): R 1.64 min, 95%, MS(ESI)225.0(M+H) + Iron powder (224 mg, 4.01 mmol) was added to a stirred solution of ammonium chloride (214 mg, 4.01 mmol) in water (6 mL). A suspension of 4-(3-chloro-5-nitrophenyl)-1H-1,2,3-triazole (300 mg, 1.34 mmol) in methanol (3 mL) and tetrahydrofuran (3 mL) was added slowly and the mixture was stirred at 70° C. for 3 h. The mixture was allowed to cool to room temperature, diluted with water and ethyl acetate, and stirred for 15 min. The organic layer was decanted and this process was repeated three times. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to yield 3-chloro-5-(1H-1,2,3-triazol-4-yl)aniline (143 mg, 55%) as a yellow gum. 1H-NMR (400 MHz, DMSO-d6) δ 15.12 (s, 1H), 8.26 (s, 1H), 7.07 - 7.01 (m, 1H), 7.01 - 6.96 (m, 1H), 6.59 - 6.54 (m, 1H), 5.55 (s, 2H); LCMS (Method C): t R 1.41min, 87%, MS (ESI) 195.0 (M+H) + To a solution of 1-((2S,5R)-5-(4-chloro-6-(pyrazin-2-yl)pyrimidin-2-yl)-2-methylpiperidin-1-yl)ethan-1-one (Intermediate 1, 100 mg, 0.25 mmol) and 3-chloro-5-(1H-1,2,3-triazol-4-yl)aniline (58.4 mg, 0.30 mmol) in 2-propanol (4 mL) was added concentrated hydrochloric acid (0.02 mL, 0.25 mmol). The mixture was stirred at 70° C. for 16 hours, allowed to cool to room temperature, and concentrated in vacuo. The residue was purified by chiral (preparative) SFC (Method D) followed by preparative reverse phase chromatography (Method A) and freeze-dried to yield 1-((2S,5R)-5-(4-((3-chloro-5-(1H-1,2,3-triazol-4-yl)phenyl)amino)-6-(pyrazin-2-yl)pyrimidin-2-yl)-2-methylpiperidin-1-yl)ethan-1-one (010, 50 mg, 41%) as a white solid. 1H-NMR (400 MHz, DMSO-d6, mixture of rotamers) δ 15.17 (br s, 1H), 10.23 (d, J = 4.8 Hz, 1H), 9.56 (d, J = 15.0 Hz, 1H), 8.88 - 8.79 (m, 2H), 8.40 (s, 1H), 8.22 (d, J = 8.5 Hz, 1H), 8.15 - 8.05 (m, 1H), 7.68 (d, J = 2.4 Hz, 1H), 7.60 - 7.53 (m, 1H), 4.90 - 4.79 (m, 0.5H), 4.76 - 4.64 (m, 0.5H), 4.27 - 4.19 (m, 0.5H), 4.12 - 3.99 (m, 0.5H), 3.54 - 3.45 (m, 0.5H), 3.04 - 2.89 (m, 1H), 2.85 - 2.74 (m, 0.5H), 2.14 - 2.00 (m, 5H), 1.93 - 1.79 (m, 0.5H), 1.77 - 1.62 (m, 1.5H), 1.34 - 1.27 (m, 1.5H), 1.21 - 1.12 (m, 1.5H); UPLC (Method A): t R 1.36 min, 99%, MS (ESI) 490.2 (M+H) + .

[0259] Example 8 Synthesis of 1-((2S,5R)-5-(4-((3-(1-ethyl-1H-1,2,3-triazol-4-yl)phenyl)amino)-6-(pyrazin-2-yl)pyrimidin-2-yl)-2-methylpiperidin-1-yl)ethan-1-one (011)

[0260] [ka]

[0261] To a stirred solution of 3-nitrophenylacetylene (500 mg, 3.40 mmol), sodium azide (265 mg, 4.08 mmol), L-ascorbic acid sodium salt (673 mg, 3.40 mmol) and ethyl iodide (0.33 mL, 4.08 mmol) in methanol (15 mL) and water was added copper(I) iodide (32.4 mg, 0.17 mmol). The mixture was heated to reflux for 3 days, followed by stirring at room temperature for 2 days. The mixture was concentrated in vacuo and the residue was dissolved in water, ethyl acetate and saturated aqueous ammonium chloride. The layers were separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed twice with brine, dried over sodium sulfate, filtered and concentrated in vacuo to yield 1-ethyl-4-(3-nitrophenyl)-1H-1,2,3-triazole (427 mg, 58%) as a yellow solid. 1 H-NMR (400 MHz, DMSO-d6) δ 8.89 (s, 1H), 8.68 - 8.61 (m, 1H), 8.34 - 8.25 (m, 1H), 8.24 - 8.14 (m, 1H), 7.81 - 7.67 (m, 1H), 4.47 (q, J = 7.3 Hz, 2H), 1.51 (t, J = 7.3 Hz, 3H); LCMS (Method C): t R 1.69 min, 90%, MS (ESI) 219.1 (M+H) + A suspension of 1-ethyl-4-(3-nitrophenyl)-1H-1,2,3-triazole (427 mg, 1.96 mmol) in a mixture of methanol (5 mL) and tetrahydrofuran (5 mL) was added to a stirred mixture of ammonium chloride (314 mg, 5.87 mmol) and iron powder (328 mg, 5.87 mmol) in water (10 mL). The mixture was heated at 70° C. for 3 h, allowed to cool to room temperature, and the organic solvents were removed in vacuo. The residue was stirred with ethyl acetate for 15 min, the organic layer was decanted, and this process was repeated twice. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to yield 3-(1-ethyl-1H-1,2,3-triazol-4-yl)aniline (357 mg, 88%) as a brown gum. 1H-NMR (400 MHz, DMSO-d6) δ 8.41 (s, 1H), 7.16 - 7.00 (m, 2H), 6.92 (d, J = 7.6 Hz, 1H), 6.51 (d, J = 8.0 Hz, 1H), 5.17 (s, 2H), 4.40 (q, J = 7.3 Hz, 2H), 1.47 (t, J = 7.3 Hz, 3H); LCMS (Method C): t R 1.39min, 88%, MS (ESI) 189.1 (M+H) + To a solution of 1-((2S,5R)-5-(4-chloro-6-(pyrazin-2-yl)pyrimidin-2-yl)-2-methylpiperidin-1-yl)ethan-1-one (Intermediate 1, 100 mg, 0.25 mmol) and 3-(1-ethyl-1H-1,2,3-triazol-4-yl)aniline (64.2 mg, 0.30 mmol) in 2-propanol (4 mL) was added concentrated hydrochloric acid (0.02 mL, 0.25 mmol). The mixture was stirred at 70° C. for 16 hours, allowed to warm to room temperature and concentrated in vacuo. The residue was purified by chiral (preparative) SFC (Method D) and lyophilized to yield 1-((2S,5R)-5-(4-((3-(1-ethyl-1H-1,2,3-triazol-4-yl)phenyl)amino)-6-(pyrazin-2-yl)pyrimidin-2-yl)-2-methylpiperidin-1-yl)ethan-1-one (011, 72.2 mg, 60%) as a white solid. 1H-NMR (400 MHz, DMSO-d6, mixture of rotamers) δ 10.01 (d, J = 5.8 Hz, 1H), 9.56 (dd, J = 11.5, 1.0 Hz, 1H), 8.84 - 8.77 (m, 2H), 8.57 (d, J = 6.5 Hz, 1H), 8.46 (s, 1H), 7.71 - 7.60 (m, 2H), 7.54 - 7.39 (m, 2H), 4.87 - 4.76 (m, 1H), 4.44 (p, J = 7.3 Hz, 2H), 4.28 - 4.15 (m, 0.5H), 4.13 - 4.03 (m, 0.5H), 3.57 - 3.45 (m, 0.5H), 3.00 - 2.85 (m, 1H), 2.82 - 2.72 (m, 0.5H), 2.16 - 1.98 (m, 5H), 1.91 - 1.80 (m, 0.5H), 1.77 - 1.59 (m, 1.5H), 1.49 (td, J = 7.3, 1.5 Hz, 3H), 1.31 - 1.22 (m, 1.5H), 1.17 - 1.09 (m, 1.5H); UPLC (Method A): t R 1.45 min, 99%, MS (ESI) 484.4 (M+H) + ; Chiral SFC (Method D): t R 3.00 min, 99%, MS (ESI) 484.2 (M+H) + .

[0262] Example 9 Synthesis of 1-((2S,5R)-2-methyl-5-(4-((4-methyl-3-(1-methyl-1H-1,2,3-triazol-4-yl)phenyl)amino)-6-(pyrazin-2-yl)pyrimidin-2-yl)piperidin-1-yl)ethan-1-one (012)

[0263] [ka]

[0264] Under argon, 2-iodo-1-methyl-4-nitrobenzene (1.17 g, 4.43 mmol) was dissolved in dry N,N-dimethylformamide (15 mL) and bis(triphenylphosphine)palladium(II) dichloride (0.16 g, 0.22 mmol) and copper(I) iodide (0.08 g, 0.44 mmol), tetrabutylammonium iodide (0.33 g, 0.89 mmol), triethylamine (0.92 mL, 6.64 mmol), and trimethylsilylacetylene (1.07 mL, 7.53 mmol) were added. The mixture was stirred at 70° C. for 16 hours. The mixture was allowed to cool to room temperature, poured into saturated ammonium chloride, and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated in vacuo. The dark oil was coated onto a hydromatrix and purified by silica column chromatography (0% to 10% ethyl acetate in n-heptane) to yield trimethyl((2-methyl-5-nitrophenyl)ethynyl)silane (596 mg, 95%) as a dark yellow oil. 1 H-NMR (400 MHz, CDCl3) δ 8.28 (d, J = 2.4 Hz, 1H), 8.05 (dd, J = 8.5, 2.4 Hz, 1H), 7.35 (d, J = 8.4 Hz, 1H), 2.53 (s, 3H), 0.34 - 0.27 (m, 9H).To a solution of trimethyl((2-methyl-5-nitrophenyl)ethynyl)silane (596 mg, 2.55 mmol) in methanol (25 mL) was added potassium carbonate (177 mg, 1.28 mmol) and the mixture was stirred at room temperate for 3 h. The mixture was concentrated in vacuo to give an oil. The oil was diluted with ethyl acetate and water. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was coated onto a hydromatrix and purified by silica column chromatography (0% to 10% ethyl acetate in n-heptane) to yield 2-ethynyl-1-methyl-4-nitrobenzene (156 mg, 38%) as a yellow oil. 1H-NMR (400 MHz, CDCl3) δ 8.31 (d, J = 2.5 Hz, 1H), 8.09 (dd, J = 8.5, 2.5 Hz, 1H), 7.38 (d, J = 8.5 Hz, 1H), 3.41 (s, 1H), 2.55 (s, 3H).To a solution of 2-ethynyl-1-methyl-4-nitrobenzene (156 mg, 0.97 mmol) in water (2 mL) and t-butanol (2 mL) was added iodomethane (0.05 mL, 0.78 mmol), sodium azide (50.7 mg, 0.78 mmol), N,N-diisopropylethylamine (0.14 mL, 0.78 mmol) and copper(I) iodide (13.53 mg, 0.07 mmol). The mixture was stirred at 50° C. for 16 hours. The mixture was diluted with water and ethyl acetate, and aqueous saturated sodium bicarbonate was added. The layers were separated and the aqueous phase was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica column chromatography (0% to 75% ethyl acetate in n-heptane) to yield 1-methyl-4-(2-methyl-5-nitrophenyl)-1H-1,2,3-triazole (75.6 mg, 36%) as a white solid. 1H-NMR (400 MHz, CDCl3) δ 8.59 (d, J = 2.5 Hz, 1H), 8.11 (dd, J = 8.4, 2.5 Hz, 1H), 7.76 (s, 1H), 7.44 (d, J = 8.5 Hz, 1H), 4.22 (s, 3H), 2.61 (s, 3H).To a solution of 1-methyl-4-(2-methyl-5-nitrophenyl)-1H-1,2,3-triazole (75 mg, 0.34 mmol) in methanol (1.5 mL) and tetrahydrofuran (1.5 mL) was added water (3 mL), ammonium chloride (55.2 mg, 1.03 mmol) and iron (57.6 mg, 1.03 mmol). The mixture was heated at 70 °C for 4 h and then concentrated in vacuo. The aqueous residue was stirred with ethyl acetate for 15 min, the organic layer was decanted, and this process was repeated twice. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to yield 4-methyl-3-(1-methyl-1H-1,2,3-triazol-4-yl)aniline (56.9 mg, 88%) as a brown gum. 1H-NMR (400 MHz, DMSO-d6) δ 8.20 (s, 1H), 7.02 (d, J = 2.4 Hz, 1H), 6.92 (d, J = 8.1 Hz, 1H), 6.48 (dd, J = 8.1, 2.5 Hz, 1H), 4.94 (s, 2H), 4.08 (s, 3H), 2.23 (s, 3H).To a solution of 1-((2S,5R)-5-(4-chloro-6-(pyrazin-2-yl)pyrimidin-2-yl)-2-methylpiperidin-1-yl)ethan-1-one (Intermediate 1, 80 mg, 0.24 mmol) and 4-methyl-3-(1-methyl-1H-1,2,3-triazol-4-yl)aniline (54.5 mg, 0.29 mmol) in 2-propanol (5 mL), concentrated hydrochloric acid was added and the mixture was stirred at 70° C. for 16 h. The mixture was concentrated in vacuo, purified by preparative reverse-phase chromatography (Method A) and lyophilized to yield 1-((2S,5R)-2-methyl-5-(4-((4-methyl-3-(1-methyl-1H-1,2,3-triazol-4-yl)phenyl)amino)-6-(pyrazin-2-yl)pyrimidin-2-yl)piperidin-1-yl)ethan-1-one (012, 49.1 mg, 42%) as a white solid. 1H-NMR (400 MHz, DMSO-d6, mixture of rotamers) δ 9.93 (d, J = 6.9 Hz, 1H), 9.54 (dd, J = 12.3, 1.1 Hz, 1H), 8.82 - 8.76 (m, 2H), 8.37 - 8.22 (m, 2H), 7.68- 7.58 (m, 2H), 7.29 (d, J = 8.2 Hz, 1H), 4.87 - 4.76 (m, 0.5H), 4.77 - 4.66 (m, 0.5H), 4.26 - 4.15 (m, 0.5H), 4.14 - 4.08 (m, 3H), 4.06 - 3.98 (m, 0.5H), 3.52 - 3.40 (m, 0.5H), 2.95 - 2.81 (m, 1H), 2.80 - 2.68 (m, 0.5H), 2.43 - 2.36 (m, 3H), 2.13 - 1.91 (m, 5H), 1.89 - 1.77 UPLC (Method A): t R 1.42 min, 99%, MS (ESI) 484.4 (M+H) + .

[0265] The following compounds were prepared following procedures similar to Example 9 using the appropriate starting materials and purified using reverse phase chromatography methods A / B and / or prep-SFC.

[0266] [Table 4]

[0267] Example 10 Synthesis of 1-((2S,5R)-2-methyl-5-(4-((3-methyl-5-(1-methyl-1H-1,2,3-triazol-4-yl)phenyl)amino)-6-(pyrazin-2-yl)pyrimidin-2-yl)piperidin-1-yl)ethan-1-one (014)

[0268] [ka]

[0269] Under an argon atmosphere, to a solution of 3-bromo-5-nitrotoluene (1 g, 4.63 mmol) in dry 1,4-dioxane (20 mL) was added hexa-n-butylditin (11.57 mL, 23.14 mmol) and tetrakis(triphenylphosphine)palladium(0) (1.07 g, 0.93 mmol). The mixture was stirred at 110 °C for 16 h. The mixture was allowed to cool to room temperature, filtered through silica, and concentrated in vacuo to give a dark oil. The dark oil was coated onto a hydromatrix and purified by silica column chromatography (0% to 50% ethyl acetate in n-heptane) to yield tributyl(3-methyl-5-nitrophenyl)stannane (1.3 g, 66%) as a yellow oil. 1H-NMR (400 MHz, CDCl3) δ 8.15 - 8.02 (m, 1H), 7.95 - 7.90 (m, 1H), 7.61 - 7.48 (m, 1H), 2.48 - 2.40 (m, 3H), 1.78 - 1.43 (m, 6H), 1.43 - 1.21 (m, 6H), 1.21 - 0.99 (m, 6H), 0.99 - 0.80 (m, 9H). Under an argon atmosphere, tributyl(3-methyl-5-nitrophenyl)stannane (1.3 g, 3.05 mmol) and 4-bromo-1-methyl-1,2,3-triazole (0.49 g, 3.05 mmol) were dissolved in dry 1,4-dioxane (15 mL). Tetrakis(triphenylphosphine)palladium(0) (0.71 g, 0.61 mmol) was then added and the mixture was heated at 100° C. for 16 h. The mixture was allowed to cool to room temperature, diluted with ethyl acetate and washed with saturated aqueous potassium fluoride. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed twice with brine, dried over sodium sulfate, filtered and coated onto silica. The coated product was purified by silica column chromatography (0% to 50% ethyl acetate in n-heptane) to yield 1-methyl-4-(3-methyl-5-nitrophenyl)-1H-1,2,3-triazole (590 mg, 40%) as an off-white solid. LCMS (Method C):t R 1.84 min, 62%, MS(ESI)219.1(M+H) +Under an argon atmosphere, 1-methyl-4-(3-methyl-5-nitrophenyl)-1H-1,2,3-triazole (590 mg, 1.07 mmol) was dissolved in ethanol (20 mL) and 10% palladium on carbon (50% wet, 227 mg, 0.11 mmol) was added. A hydrogen atmosphere was introduced and the mixture was stirred at room temperature for 16 h. The mixture was filtered through Celite, the filter cake was rinsed with ethanol and the combined filtrates were concentrated in vacuo. The crude product was purified twice by silica column chromatography (0% to 5% methanol in dichloromethane) to yield 3-methyl-5-(1-methyl-1H-1,2,3-triazol-4-yl)aniline (122 mg, 61%) as a sticky yellowish oil. LCMS (Method C):t R 1.40 minutes, 94%, MS(ESI)198.1(M+H) + To a solution of 1-((2S,5R)-5-(4-chloro-6-(pyrazin-2-yl)pyrimidin-2-yl)-2-methylpiperidin-1-yl)ethan-1-one (Intermediate 1, 100 mg, 0.30 mmol) and 3-methyl-5-(1-methyl-1H-1,2,3-triazol-4-yl)aniline (68.1 mg, 0.36 mmol) in 2-propanol (4 mL) was added concentrated hydrochloric acid (0.05 mL, 0.51 mmol). The mixture was stirred at 70° C. for 16 hours, allowed to cool to room temperature, and concentrated in vacuo. The crude product was purified by preparative reverse phase chromatography (Method A) followed by chiral (preparative) SFC (Method D) and freeze-dried to yield 1-((2S,5R)-2-methyl-5-(4-((3-methyl-5-(1-methyl-1H-1,2,3-triazol-4-yl)phenyl)amino)-6-(pyrazin-2-yl)pyrimidin-2-yl)piperidin-1-yl)ethan-1-one (014, 46.8 mg, 32%) as a white solid. 1H-NMR (400 MHz, DMSO-d6, mixture of rotamers) δ 9.95 (d, J = 5.3 Hz, 1H), 9.59 - 9.50 (m, 1H), 8.87 - 8.77 (m, 2H), 8.47 (d, J = 15.0 Hz, 1H), 8.18 (s, 1H), 7.65 (s, 1H), 7.60 (d, J = 15.0 Hz, 1H), 7.33 (d, J = 20.8 Hz, 1H), 4.87 - 4.77 (m, 1H), 4.28 - 4.15 (m, 0.5H), 4.13 - 4.02 (m, 3.5H), 3.55 - 3.46 (m, 0.5H), 2.99 - 2.86 (m, 1H), 2.84 - 2.71 (m, 0.5H), 2.41 - 2.34 (m, 3H), 2.15 - 1.96 (m, 5H), 1.93 - 1.78 (m, 0.5H), 1.77 - 1.56 (m, 1.5H), 1.34 - 1.26 (m, 1.5H), 1.19 - 1.07 (m, 1.5H); UPLC (Method A): t R 1.44 min, 100%, MS (ESI) 484.4 (M+H) + .

[0270] Example 11 Synthesis of 1-((2S,5R)-5-(4-((3-(1,5-dimethyl-1H-1,2,3-triazol-4-yl)phenyl)amino)-6-(pyrazin-2-yl)pyrimidin-2-yl)-2-methylpiperidin-1-yl)ethan-1-one (015) and 1-((2S,5R)-5-(4-((3-(2,5-dimethyl-2H-1,2,3-triazol-4-yl)phenyl)amino)-6-(pyrazin-2-yl)pyrimidin-2-yl)-2-methylpiperidin-1-yl)ethan-1-one (016)

[0271] [ka]

[0272] A microwave vial was charged with 3-nitrobenzaldehyde (2.5 g, 16.54 mmol), cyclohexylamine (2.08 mL, 18.20 mmol) and nitroethane (2.39 mL, 33.1 mmol) in acetic acid (25 mL) and the mixture was heated in a microwave at 120 °C for 1 h. The mixture was diluted with water and extracted three times with dichloromethane. The combined organic layers were washed three times with saturated aqueous sodium bicarbonate, dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by silica column chromatography (0% to 50% dichloromethane in n-heptane) to yield 1-nitro-3-(2-nitroprop-1-en-1-yl)benzene (2.88 g, 80%) as a bright yellow solid. 1 LCMS (Method A): t R 1.96 min, 95%, MS (ESI) 209.2 (M+H) + A solution of 1-nitro-3-(2-nitroprop-1-en-1-yl)benzene (2.88 g, 13.17 mmol) and sodium azide (1.3 g, 20.00 mmol) in dimethylsulfoxide (30 mL) was heated to 90° C. for 16 h. The mixture was allowed to cool to room temperature and poured into water (150 mL). The fine white solid was crushed and ground at room temperature for 2 h. The solid was collected by filtration, washed with water, and dried in a vacuum oven at 40° C. for 16 h to yield 5-methyl-4-(3-nitrophenyl)-1H-1,2,3-triazole (2.12 g, 79%) as a white solid. 1 H-NMR (400 MHz, DMSO-d6) δ 15.07 (s, 1H), 8.54 - 8.48 (m, 1H), 8.22 (dd, J = 7.8, 2.2 Hz, 1H), 7.78 (t, J = 8.0 Hz, 1H), 2.52 (s, 3H); LCMS (Method A): t R1.71 min, 96%, MS (ESI) 205.1 (M+H) + To a solution of 1,5-methyl-4-(3-nitrophenyl)-1H-1,2,3-triazole (500 mg, 2.45 mmol) in dry N,N-dimethylformamide (20 mL) was added potassium carbonate (440 mg, 3.18 mmol) and iodomethane (0.20 mL, 3.18 mmol). The mixture was stirred at room temperature for 16 h, concentrated in vacuo, diluted with dichloromethane, stirred at room temperature for 10 min, and filtered through sand. The filtrate was purified by column chromatography (0% to 50% ethyl acetate in n-heptane) to yield 1,5-dimethyl-4-(3-nitrophenyl)-1H-1,2,3-triazole (173 mg, 32%) and 2,4-dimethyl-5-(3-nitrophenyl)-2H-1,2,3-triazole (299 mg, 56%) as white solids. 1,5-Dimethyl-4-(3-nitrophenyl)-1H-1,2,3-triazole: LCMS (Method C):t R 1.77 min, 98%, MS(ESI)219.0(M+H) + 2,4-Dimethyl-5-(3-nitrophenyl)-2H-1,2,3-triazole: LCMS (Method C): t R 1.97 minutes, 100%, MS(ESI):219.0(M+H) + To a mixture of ammonium chloride (167 mg, 3.12 mmol) and iron powder in water (8 mL) was added a solution of 1,5-dimethyl-4-(3-nitrophenyl)-1H-1,2,3-triazole (170 mg, 0.78 mmol) in methanol (4 mL) and tetrahydrofuran (4 mL). The suspension was stirred at 70° C. for 2 h and the organic solvent was removed in vacuo. The aqueous solution was stirred with ethyl acetate for 10 min and the organic layer was decanted, this process was repeated twice. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to yield 3-(1,5-dimethyl-1H-1,2,3-triazol-4-yl)aniline (153 mg, 104%) as a brown gum, which was carried on crude without further purification. 1H-NMR (400 MHz, DMSO-d6) δ 7.08 (t, J = 7.8 Hz, 1H), 6.95 - 6.90 (m, 1H), 6.78 (d, J = 7.5 Hz, 1H), 6.55 - 6.50 (m, 1H), 5.17 (s, 2H), 3.95 (s, 3H), 2.41 (s, 3H); LCMS (Method C): t R 1.36 min, 97%, MS (ESI) 189.1 (M+H) + To a solution of 1-((2S,5R)-5-(4-chloro-6-(pyrazin-2-yl)pyrimidin-2-yl)-2-methylpiperidin-1-yl)ethan-1-one (Intermediate 1, 100 mg, 0.30 mmol) and 3-(1,5-dimethyl-1H-1,2,3-triazol-4-yl)aniline (68.1 mg, 0.36 mmol) in 2-propanol (4 mL) was added concentrated hydrochloric acid (0.05 mL, 0.51 mmol) and stirred at 70° C. for 16 hours. The mixture was allowed to cool to room temperature, concentrated in vacuo, purified by preparative reverse phase chromatography (Method A) followed by chiral (preparative) SFC (Method D) and lyophilized to yield 1-((2S,5R)-5-(4-((3-(1,5-dimethyl-1H-1,2,3-triazol-4-yl)phenyl)amino)-6-(pyrazin-2-yl)pyrimidin-2-yl)-2-methylpiperidin-1-yl)ethan-1-one (015, 58.5 mg, 40%) as a white solid. 1H-NMR (400 MHz, DMSO-d6, mixture of rotamers) δ 10.03 (d, J = 5.1 Hz, 1H), 9.56 (dd, J = 13.4, 1.2 Hz, 1H), 8.83 - 8.77 (m, 2H), 8.26 (s, 0.5H), 8.20 (s, 0.5H), 7.78 - 7.68 (m, 1H), 7.67 (d, J = 2.1 Hz, 1H), 7.49 - 7.41 (m, 1H), 7.38 - 7.32 (m, 1H), 4.88 - 4.77 (m, 0.5H), 4.73 - 4.66 (m, 0.5H), 4.27 - 4.15 (m, 0.5H), 4.08 - 4.01 (m, 0.5H), 3.99 (s, 3H), 3.53 - 3.48 (m, 0.5H), 2.99 - 2.84 (m, 1H), 2.78 - 2.69 (m, 0.5H), 2.50 UPLC (Method A): t R 1.39 min, 100%, MS (ESI) 484.4 (M+H) + .

[0273] [ka]

[0274] Following a procedure similar to 015, 2,4-dimethyl-5-(3-nitrophenyl)-2H-1,2,3-triazole was converted to 1-((2S,5R)-5-(4-((3-(2,5-dimethyl-2H-1,2,3-triazol-4-yl)phenyl)amino)-6-(pyrazin-2-yl)pyrimidin-2-yl)-2-methylpiperidin-1-yl)ethan-1-one (016). 1H-NMR (400 MHz, DMSO-d6, mixture of rotamers) δ 10.03 (d, J = 7.2 Hz, 1H), 9.56 (dd, J = 13.7, 1.1 Hz, 1H), 8.83 - 8.77 (m, 2H), 8.33 (s, 0.5H), 8.27 (s, 0.5H), 7.75 - 7.64 (m, 2H), 7.45 (td, J = 7.9, 2.1 Hz, 1H), 7.35 (d, J = 7.8 Hz, 1H), 4.88 - 4.77 (m, 0.5H), 4.76 - 4.68 (m, 0.5H), 4.26 - 4.16 (m, 0.5H), 4.09 - 3.99 (m, 3.5H), 3.55 - 3.47 (m, 0.5H), 3.01 - 2.86 (m, 1H), 2.81 - 2.69 (m, 0.5H), 2.45 (s, 3H), 2.17 - 1.93 (m, 5H), 1.91 - 1.76 (m, 0.5H), 1.75 - 1.63 (m, 1.5H), 1.27 - 1.19 (m, 1.5H), 1.15 - 1.08 (m, 1.5H); UPLC (Method A): t R 1.57 min, 100%, MS (ESI) 484.4 (M+H) + .

[0275] Example 12 Synthesis of 1-((2S,5R)-2-methyl-5-(4-((3-(1-methyl-1H-1,2,3-triazol-5-yl)phenyl)amino)-6-(pyrazin-2-yl)pyrimidin-2-yl)piperidin-1-yl)ethan-1-one (017)

[0276] [ka]

[0277] A mixture of 3-nitrophenylacetylene (500 mg, 3.40 mmol), trimethylsilylmethyl azide (0.56 mL, 3.74 mmol) and chloro(pentamethylcyclopentadienyl)bis(triphenylphosphine)ruthenium(II) (276 mg, 0.34 mmol) in tetrahydrofuran (20 mL) was stirred at 70° C. for 16 h. The mixture was concentrated in vacuo and purified by silica column chromatography (20% to 50% ethyl acetate in n-heptane) to give 5-(3-nitrophenyl)-1-((trimethylsilyl)methyl)-1H-1,2,3-triazole (614 mg, 65%) as a brown oil. LCMS (Method C):t R 2.07 minutes, 100%, MS(ESI)277.1(M+H) + Using an ice bath, a solution of 5-(3-nitrophenyl)-1-((trimethylsilyl)methyl)-1H-1,2,3-triazole (710 mg, 2.57 mmol) in tetrahydrofuran (25 mL) was cooled to 0° C. and 1 M tetra-n-butylammonium fluoride in tetrahydrofuran (2.57 mL, 2.57 mmol) was added slowly. The mixture was stirred at 0° C. for 1 h, quenched with water, and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica column chromatography (0% to 50% ethyl acetate in n-heptane) to yield 1-methyl-5-(3-nitrophenyl)-1H-1,2,3-triazole (289 mg, 55%) as a white solid. LCMS (Method C):t R 1.68 min, 99%, MS(ESI)205.1(M+H) +To a mixture of iron powder (237 mg, 4.25 mmol) and ammonium chloride (227 mg, 4.25 mmol) in water (30 mL) was slowly added a suspension of 1-methyl-5-(3-nitrophenyl)-1H-1,2,3-triazole (289 mg, 1.42 mmol) in methanol (10 mL). The mixture was stirred at 70° C. for 3 h, the mixture was allowed to cool to room temperature, and the organic solvents were removed in vacuo. The red slurry was diluted with water and ethyl acetate and stirred for 15 min. The organic layer was decanted and this process was repeated twice. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was co-evaporated with dichloromethane to yield 3-(1-methyl-1H-1,2,3-triazol-5-yl)aniline (232 mg, 94%) as a brown solid. LCMS (Method C):t R 1.29 min, 95%, MS(ESI)175.1(M+H) + To a solution of 1-((2S,5R)-5-(4-chloro-6-(pyrazin-2-yl)pyrimidin-2-yl)-2-methylpiperidin-1-yl)ethan-1-one (Intermediate 1, 100 mg, 0.30 mmol) and 3-(1-methyl-1H-1,2,3-triazol-5-yl)aniline (70.9 mg, 0.41 mmol) in 2-propanol (4 mL) was added concentrated hydrochloric acid (0.05 mL, 0.51 mmol) and the mixture was stirred at 70° C. for 3 days. The mixture was concentrated in vacuo and purified by preparative reverse phase chromatography (Method A) followed by chiral (preparative) SFC (Method D) and lyophilized to yield 1-((2S,5R)-2-methyl-5-(4-((3-(1-methyl-1H-1,2,3-triazol-5-yl)phenyl)amino)-6-(pyrazin-2-yl)pyrimidin-2-yl)piperidin-1-yl)ethan-1-one (017, 48.6 mg, 34%) as a white solid. 1H-NMR (400 MHz, DMSO-d6, mixture of rotamers) δ 10.13 (d, J = 7.7 Hz, 1H), 9.56 (dd, J = 13.2, 1.2 Hz, 1H), 8.84 - 8.77 (m, 2H), 8.16 (s, 1H), 7.92 (d, J = 2.2 Hz, 1H), 7.78 - 7.72 (m, 1H), 7.68 (d, J = 2.3 Hz, 1H), 7.54 (td, J = 7.9, 2.5 Hz, 1H), 7.29 (d, J = 7.6 Hz, 1H), 4.87 - 4.75 (m, 0.5H), 4.75 - 4.67 (m, 0.5H), 4.24 - 4.16 (m, 0.5H), 4.11 (s, 3H), 4.07 - 3.95 (m, 0.5H), 3.48 - 3.39 (m, 0.5H), 2.95 - 2.84 (m, 1H), 2.79 - 2.70 UPLC (Method A): t R 1.36 min, 100%, MS (ESI) 470.2 (M+H) + .

[0278] Example 13 Synthesis of 1-((2S,5R)-5-(4-((4-fluoro-3-(1-methyl-1H-1,2,3-triazol-4-yl)phenyl)amino)-6-(pyrazin-2-yl)pyrimidin-2-yl)-2-methylpiperidin-1-yl)ethan-1-one (018)

[0279] [ka]

[0280] To a suspension of 3-ethynyl-4-fluoroaniline (50 mg, 0.37 mmol), L-ascorbic acid sodium salt (36.6 mg, 0.19 mmol) and copper(II) sulfate (14.76 mg, 0.09 mmol) in t-butanol (1 mL) and water (1 mL) was added trimethylsilylmethyl azide (0.06 mL, 0.37 mmol) and the mixture was stirred at room temperature for 16 h. The mixture was filtered through Celite and the residue was rinsed with methanol. The filtrate was concentrated in vacuo to yield 4-fluoro-3-(1-((trimethylsilyl)methyl)-1H-1,2,3-triazol-4-yl)aniline (98 mg, 100%) as a yellow gum, which was used as such without further purification. LCMS (Method A):t R 1.72 min, 92%, MS(ESI)265.1(M+H) +Under an argon atmosphere, 1-((2S,5R)-5-(4-chloro-6-(pyrazin-2-yl)pyrimidin-2-yl)-2-methylpiperidin-1-yl)ethan-1-one (Intermediate 1, 80 mg, 0.24 mmol), 4-fluoro-3-(1-((trimethylsilyl)methyl)-1H-1,2,3-triazol-4-yl)aniline (98 mg, 0.37 mmol) and cesium carbonate (157 mg, 0.48 mmol) were suspended in dry 1,4-dioxane (4 mL). 2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (22.99 mg, 0.05 mmol) and tris(benzylideneacetone)dipalladium(0) (22.08 mg, 0.02 mmol) were then added and the mixture was heated to 90°C for 16 hours. The mixture was allowed to cool to room temperature, diluted with methanol, filtered through Celite, rinsed with methanol, and the filtrate concentrated in vacuo. The residue was redissolved in tetrahydrofuran (4 mL) and 1M tetrabutylammonium fluoride in tetrahydrofuran (0.29 mL, 0.29 mmol) was added and the mixture was stirred at room temperature for 16 hours. The mixture was filtered through Celite, rinsed with methanol, and the filtrate concentrated in vacuo. The residue was purified by preparative reverse phase chromatography (Method B), purified by chiral (preparative) SFC (Method D) and lyophilized to yield 1-((2S,5R)-5-(4-((4-fluoro-3-(1-methyl-1H-1,2,3-triazol-4-yl)phenyl)amino)-6-(pyrazin-2-yl)pyrimidin-2-yl)-2-methylpiperidin-1-yl)ethan-1-one (018, 9.8 mg, 8%) as a white solid. 1H-NMR (400 MHz, DMSO-d6, mixture of rotamers) δ 10.05 (d, J = 5.5 Hz, 1H), 9.55 (d, J = 14.1 Hz, 1H), 8.83 - 8.64 (m, 3H), 8.42 (d, J = 3.7 Hz, 1H), 7.78 - 7.67 (m, 1H), 7.63 (d, J = 3.4 Hz, 1H), 7.34 (td, J = 9.7, 8.9, 2.3 Hz, 1H), 4.86 - 4.78 (m, 0.5H), 4.74 - 4.66 (m, 0.5H), 4.26 - 4.16 (m, 0.5H), 4.16 - 4.04 (m, 3.5H), 3.57 - 3.48 (m, 0.5H), 3.02 - 2.86 (m, 1H), 2.81 - 2.69 (m, 0.5H), 2.16 - 1.96 (m, 5H), 1.92 - 1.77 (m, 0.5H), 1.77 - 1.59 (m, 1.5H), 1.30 - 1.23 (m, 1.5H), 1.19 - 1.10 (m, 1.5H); UPLC (Method B): t R 1.34 min, 100%, MS (ESI) 488.2 (M+H) + .

[0281] The following compounds were prepared following procedures similar to Example 13 using the appropriate starting materials and purified using reverse phase chromatography methods A / B and / or prep-SFC.

[0282] [Table 5]

[0283] Example 14 Synthesis of 1-((2S,5R)-5-(4-((3-chloro-5-(1-methyl-1H-1,2,3-triazol-4-yl)phenyl)amino)-6-(pyrazin-2-yl)pyrimidin-2-yl)-2-methylpiperidin-1-yl)ethan-1-one (021)

[0284] [ka]

[0285] Under argon, azidotrimethylsilane (0.76 mL, 5.78 mmol) and copper(I) iodide (47 mg, 0.25 mmol) were added to a stirred solution of 1-chloro-3-ethynyl-5-nitrobenzene (700 mg, 3.86 mmol) in N,N-dimethylformamide (30 mL) and methanol (3 mL). The mixture was stirred at 100 °C for 16 h. The mixture was allowed to cool to room temperature, poured into saturated aqueous ammonium chloride solution, and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was coated onto a hydromatrix and purified by silica column chromatography (0% to 50% ethyl acetate in n-heptane) to yield 4-(3-chloro-5-nitrophenyl)-1H-1,2,3-triazole (650 mg, 75%) as a white solid. LCMS (Method C):t R 1.64 min, 95%, MS(ESI)225.0(M+H) + To a solution of 4-(3-chloro-5-nitrophenyl)-1H-1,2,3-triazole (290 mg, 1.29 mmol) in N,N-dimethylformamide (10 mL) was added potassium carbonate (232 mg, 1.68 mmol) and iodomethane (0.11 mL, 1.68 mmol). The mixture was stirred at room temperature for 16 h and concentrated in vacuo. The residue was coated onto a hydromatrix and purified by silica column chromatography (0% to 50% ethyl acetate in n-heptane) to yield 4-(3-chloro-5-nitrophenyl)-1-methyl-1H-1,2,3-triazole (100 mg, 33%) as a yellow viscous material. 1H-NMR (400 MHz, DMSO-d6) δ 8.55 - 8.45 (m, 1H), 8.30 - 8.19 (m, 1H), 8.19 - 8.09 (m, 1H), 7.95 (s, 1H), 4.21 (s, 3H).To a solution of 4-(3-chloro-5-nitrophenyl)-1-methyl-1H-1,2,3-triazole (100 mg, 0.42 mmol) in water (3 mL), tetrahydrofuran (1.5 mL) and methanol (1.5 mL) was added ammonium chloride (67.2 mg, 1.26 mmol) and iron powder (70.2 mg, 1.26 mmol). The mixture was heated to 70° C. for 3 h, the mixture was allowed to cool to room temperature and stirred with ethyl acetate. After 15 min, the organic layer was decanted and the process was repeated twice. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give 3-chloro-5-(1-methyl-1H-1,2,3-triazol-4-yl)aniline (80 mg, 91%) as a brown oil. LCMS (Method C):t R 1.68 min, 97%, MS(ESI)209.0(M+H) + To a mixture of 1-((2S,5R)-5-(4-chloro-6-(pyrazin-2-yl)pyrimidin-2-yl)-2-methylpiperidin-1-yl)ethan-1-one (Intermediate 1, 100 mg, 0.25 mmol) and 3-chloro-5-(1-methyl-1H-1,2,3-triazol-4-yl)aniline (80 mg, 0.38 mmol) in 2-propanol (5 mL) was added concentrated hydrochloric acid (few drops) and the mixture was stirred at 70° C. for 3 days. The suspension was filtered through Celite, the filter cake was rinsed three times with diethyl ether and dried in a vacuum oven at 40° C. for 16 h to yield 1-((2S,5R)-5-(4-((3-chloro-5-(1-methyl-1H-1,2,3-triazol-4-yl)phenyl)amino)-6-(pyrazin-2-yl)pyrimidin-2-yl)-2-methylpiperidin-1-yl)ethan-1-one (021, 104 mg, 82%) as a white solid. 1H-NMR (400 MHz, DMSO-d6, mixture of rotamers) δ 10.34 (d, J = 9.9 Hz, 1H), 9.56 (d, J = 13.0 Hz, 1H), 8.85 - 8.79 (m, 2H), 8.61 (d, J = 7.0 Hz, 1H), 8.30 - 8.22 (m, 1H), 8.15 - 8.01 (m, 1H), 7.69 (d, J = 2.7 Hz, 1H), 7.55 - 7.50 (m, 1H), 4.87 - 4.80 (m, 0.5H), 4.80 - 4.70 (m, 0.5H), 4.30 - 4.18 (m, 0.5H), 4.14 - 4.04 (m, 3.5H), 3.55 - 3.46 (m, 0.5H), 3.02 - 2.92 (m, 1H), 2.88 - 2.76 (m, 0.5H), 2.16 - 1.97 (m, 5H), 1.93 - 1.79 (m, 0.5H), 1.77 - 1.61 (m, 1.5H), 1.36 - 1.27 (d, J = 6.9 Hz, 1.5H), 1.19 - 1.13 (m, 1.5H). UPLC (Method A): t R 1.55 min, 97%, MS (ESI) 504.2 (M+H) + ; Chiral SFC (Method D): t R 3.18 minutes, 97%, MS (ESI) 504.1 (M+H) + .

[0286] Example 15 Synthesis of 1-((2S,5R)-5-(4-((3-fluoro-5-(1-(oxetan-3-yl)-1H-1,2,3-triazol-4-yl)phenyl)amino)-6-(pyrazin-2-yl)pyrimidin-2-yl)-2-methylpiperidin-1-yl)ethan-1-one (022)

[0287] [ka]

[0288] To a solution of 1-ethynyl-3-fluoro-5-nitrobenzene (prepared in Example 6, 125 mg, 0.76 mmol) in t-butanol (4 mL) and water (4 mL) was added 3-azidooxetane (0.5 M in MTBE, 1.51 mL, 0.76 mmol), followed by L-ascorbic acid sodium salt (30.0 mg, 0.15 mmol) and copper(II) sulfate (24.2 mg, 0.15 mmol). The mixture was stirred at room temperature for 16 h and at 35° C. for 16 h. The mixture was diluted with ethyl acetate and water, the biphasic mixture was filtered through Celite, and the layers of the filtrate were separated. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was triturated in diethyl ether for 1 h. The solid was filtered off, washed with diethyl ether and dried in a vacuum oven at 40° C. for 16 h to yield 4-(3-fluoro-5-nitrophenyl)-1-(oxetan-3-yl)-1H-1,2,3-triazole (113 mg, 57%) as a beige solid. 1 H-NMR (400 MHz, DMSO-d6) δ 9.27 (s, 1H), 8.60 - 8.57 (m, 1H), 8.24 - 8.18 (m, 1H), 8.14 - 8.07 (m, 1H), 5.97 - 5.88 (m, 1H), 5.12 - 5.05 (m, 2H), 4.96 - 4.90 (m, 2H); LCMS (Method A): t R 1.92 minutes, 100%, MS (ESI) 265.1 (M+H) +To a suspension of 4-(3-fluoro-5-nitrophenyl)-1-(oxetan-3-yl)-1H-1,2,3-triazole (139 mg, 0.53 mmol) in methanol (1.5 mL), tetrahydrofuran (1.5 mL) and water (3 mL) was added ammonium chloride (84 mg, 1.58 mmol) and iron powder (88 mg, 1.58 mmol). The mixture was stirred at 70° C. for 4 h and at room temperature for 16 h. The mixture was diluted with ethyl acetate and water and stirred vigorously for 15 min. The organic layer was decanted and this procedure was repeated twice. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to yield 3-fluoro-5-(1-(oxetan-3-yl)-1H-1,2,3-triazol-4-yl)aniline (108 mg, 75%) as a brown oil. 1 H-NMR (400 MHz, DMSO-d6) δ 8.78 (s, 1H), 6.98 - 6.96 (m, 1H), 6.76 - 6.70 (m, 1H), 6.32 - 6.26 (m, 1H), 5.90 - 5.81 (m, 1H), 5.57 (s, 2H), 5.06 - 5.01 (m, 2H), 4.96 - 4.90 (m, 2H); LCMS (Method C): t R 1.43 min, 85%, MS (ESI) 235.1 (M+H) +. Under argon, 1-((2S,5R)-5-(4-chloro-6-(pyrazin-2-yl)pyrimidin-2-yl)-2-methylpiperidin-1-yl)ethan-1-one (Intermediate 1, 80 mg, 0.24 mmol), 3-fluoro-5-(1-(oxetan-3-yl)-1H-1,2,3-triazol-4-yl)aniline (106 mg, 0.39 mmol), 2 -Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (22.99 mg, 0.05 mmol), tris(dibenzylideneacetone)dipalladium(0) (22.1 mg, 0.02 mmol) and cesium carbonate (157 mg, 0.48 mmol) were suspended in dry 1,4-dioxane (4 mL) and the mixture was stirred at 90° C. for 16 h. The mixture was allowed to cool to room temperature, diluted with methanol and filtered through Celite. The residue was rinsed with methanol and the filtrate was concentrated in vacuo. The crude product was purified by chiral (preparative) SFC (Method D) and lyophilized to yield 1-((2S,5R)-5-(4-((3-fluoro-5-(1-(oxetan-3-yl)-1H-1,2,3-triazol-4-yl)phenyl)amino)-6-(pyrazin-2-yl)pyrimidin-2-yl)-2-methylpiperidin-1-yl)ethan-1-one (022, 60.5 mg, 47%) as a pale yellow solid. 1H-NMR (400 MHz, DMSO-d6, mixture of rotamers) δ 10.27 (d, J = 9.7 Hz, 1H), 9.57 (d, J = 12.9 Hz, 1H), 8.94 (d, J = 8.4 Hz, 1H), 8.85 - 8.79 (m, 2H), 8.16 (d, J = 7.2 Hz, 1H), 7.88 (dd, J = 33.8, 11.6 Hz, 1H), 7.71 - 7.66 (m, 1H), 7.37 - 7.30 (m, 1H), 5.96 - 5.86 (m, 1H), 5.10 - 5.03 (m, 2H), 5.00 - 4.91 (m, 2H), 4.89 - 4.72 (m, 1H), 4.28 - 4.19 (m, 0.5H), 4.14 - 4.07 (m, 0.5H), 3.55 - 3.46 (m, 0.5H), 3.02 - 2.90 (m, 1H), 2.85 - 2.75 UPLC (Method B): t R 1.42 min, 96%, MS (ESI) 530.4 (M+H) + .

[0289] The following compounds were prepared following procedures similar to Example 15 using the appropriate starting materials and purified using reverse phase chromatography methods A / B and / or prep-SFC.

[0290] [Table 6]

[0291] Example 16 Synthesis of sodium (2-((3R,6S)-1-acetyl-6-methylpiperidin-3-yl)-6-(pyrazin-2-yl)pyrimidin-4-yl)(2-fluoro-3-(1-methyl-1H-1,2,3-triazol-4-yl)phenyl)amide (019.Na)

[0292] [ka]

[0293] To a suspension of 1-((2S,5R)-5-(4-((2-fluoro-3-(1-methyl-1H-1,2,3-triazol-4-yl)phenyl)amino)-6-(pyrazin-2-yl)pyrimidin-2-yl)-2-methylpiperidin-1-yl)ethan-1-one (019, 50 mg, 0.10 mmol) in tetrahydrofuran (1 mL) was added 1 M aqueous sodium hydroxide (0.10 mL, 0.10 mmol) and the mixture was stirred at room temperature for 1 min to produce a pale yellow solution. The solution was concentrated and coevaporated twice with toluene (1 mL). The residue was suspended in diethyl ether (2 mL) and stirred for 1 min. The solid was filtered off and air-dried under a stream of nitrogen to yield sodium (2-((3R,6S)-1-acetyl-6-methylpiperidin-3-yl)-6-(pyrazin-2-yl)pyrimidin-4-yl)(2-fluoro-3-(1-methyl-1H-1,2,3-triazol-4-yl)phenyl)amide (019.Na, 45 mg, 86%) as a yellow solid. 1H-NMR (400 MHz, DMSO-d6, mixture of rotamers) δ 9.50 (d, J = 6.0 Hz, 1H), 8.74 (s, 2H), 8.38 (dd, J = 8.4, 3.8 Hz, 1H), 7.91 - 7.67 (m, 2H), 7.57 - 7.34 (m, 1H), 7.30 - 7.11 (m, 1H), 4.85 - 4.73 (m, 0.5H), 4.71 - 4.60 (m, 0.5H), 4.21 - 4.15 (m, 0.5H), 4.15 - 4.08 (m, 3H), 4.00 - 3.92 (m, 0.5H), 2.93 - 2.80 (m, 0.5H), 2.80 - 2.70 (m, 0.5H), 2.70 - 2.56 (m, 1H), 2.16 - 1.86 (m, 5H), 1.86 - 1.72 (m, 0.5H), 1.72 - 1.56 (m, 1.5H), 1.27 - 1.18 (m, 1.5H), 1.12 - 1.09 (m, 1.5H).

[0294] The following compounds were prepared following procedures similar to Example 16 using the appropriate starting materials.

[0295] [Table 7]

[0296] Example 17 Synthesis of 1-((2S,5R)-5-(4-((3-fluoro-5-(1-methyl-1H-imidazol-4-yl)phenyl)amino)-6-(pyrazin-2-yl)pyrimidin-2-yl)-2-methylpiperidin-1-yl)ethan-1-one hydrochloride (001.HCl)

[0297] [ka]

[0298] To a suspension of 1-((2S,5R)-5-(4-((3-fluoro-5-(1-methyl-1H-imidazol-4-yl)phenyl)amino)-6-(pyrazin-2-yl)pyrimidin-2-yl)-2-methylpiperidin-1-yl)ethan-1-one (001, 51.7 mg, 0.11 mmol) in dry diethyl ether (1 mL) was added 1M hydrochloric acid in diethyl ether (0.27 ml, 5.31 mmol) and the mixture was stirred at room temperature for 20 minutes. The resulting solid was filtered off and washed with diethyl ether to yield a yellow solid. The solid was dried under vacuum for 8 hours (40° C.) to yield 1-((2S,5R)-5-(4-((3-fluoro-5-(1-methyl-1H-imidazol-4-yl)phenyl)amino)-6-(pyrazin-2-yl)pyrimidin-2-yl)-2-methylpiperidin-1-yl)ethan-1-one hydrochloride (001.HCl, 40.7 mg, 71%) as a yellow solid. 1 H-NMR (400 MHz, DMSO-d6, mixture of rotamers) δ 10.44 (d, J = 15.2 Hz, 1H), 9.58 (d, J = 10.2 Hz, 1H), 9.20 - 9.00 (m, 1H), 8.82 (s, 2H), 8.24 - 7.92 (m, 2H), 7.86 - 7.64 (m, 2H), 7.40 - 7.27 (m, 1H), 4.93 - 4.77 (m, 1H), 4.36 - 4.18 (m, 0.5H), 4.15 - 4.03 (m, 0.5H), 3.99 - 3.85 (m, 3H), 3.03 - 2.73 (m, 1.5H), 2.20 - 1.94 (m, 5.5H), 1.94 - 1.80 (m, 0.5H), 1.78 - 1.61 (m, 1.5H), 1.30 - 1.20 (m, 1.5H), 1.17 - 1.05 (m, 1.5H).

[0299] Example 18 Synthesis of sodium (2-((3R,6S)-1-acetyl-6-methylpiperidin-3-yl)-6-(pyrazin-2-yl)pyrimidin-4-yl)(3-(1-methyl-1H-1,2,3-triazol-4-yl)phenyl)amide (024.Na)

[0300] [ka]

[0301] To a solution of 1-((2S,5R)-5-(4-chloro-6-(pyrazin-2-yl)pyrimidin-2-yl)-2-methylpiperidin-1-yl)ethan-1-one (Intermediate 1, 120 mg, 0.36 mmol) in 2-propanol (2 mL) was added 3-(1-methyl-1H-1,2,3-triazol-4-yl)aniline (188 mg, 1.08 mmol) and hydrochloric acid (0.08 mL, 1.08 mmol). The mixture was stirred at 70° C. for 16 hours, poured into saturated aqueous sodium bicarbonate, and extracted twice with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated to produce a yellow oil. The oil was purified by reverse phase chromatography (Method B) and lyophilized to yield 1-((2S,5R)-2-methyl-5-(4-((3-(1-methyl-1H-1,2,3-triazol-4-yl)phenyl)amino)-6-(pyrazin-2-yl)pyrimidin-2-yl)piperidin-1-yl)ethan-1-one (102 mg, 60%) as a white solid. 1H-NMR (400 MHz, DMSO-d6, mixture of rotamers)δ 10.01 (d, J = 5.6 Hz, 1H), 9.56 (dd, J = 11.0, 1.1 Hz, 1H), 8.80 (d, J = 1.5 Hz, 2H), 8.54 - 8.42 (m, 2H), 7.72 - 7.54 (m, 2H), 7.53 - 7.39 (m, 2H), 4.86 - 4.76 (m, 1H), 4.27 - 4.16 (m, 0.5H), 4.15 - 4.03 (m, 3.5H), 3.58 - 3.42 (m, 0.5H), 3.00 - 2.86 (m, 1H), 2.86 - 2.68 (m, 0.5H), 2.17 - 1.96 (m, 5H), 1.93 - 1.77 (m, 0.5H), 1.76 - 1.64 (m, 1.5H), 1.27 (d, J = 6.8 Hz, 1.5H), 1.13 (d, J = 7.0 Hz, 1.5H); LCMS (Method D): t R 3.31 minutes, MS (ESI) 470.2 (M+H) + To a suspension of 1-((2S,5R)-2-methyl-5-(4-((3-(1-methyl-1H-1,2,3-triazol-4-yl)phenyl)amino)-6-(pyrazin-2-yl)pyrimidin-2-yl)piperidin-1-yl)ethan-1-one (50 mg, 0.11 mmol) in tetrahydrofuran (1 mL) was added 1 M aqueous sodium hydroxide (0.11 mL, 0.11 mmol) and the mixture was stirred at room temperature for 1 min to produce a pale yellow solution. The solution was concentrated and coevaporated twice with toluene (1 mL). The residue was suspended in diethyl ether (2 mL) and stirred for 1 min. The solid was filtered off and air-dried under a stream of nitrogen to give sodium (2-((3R,6S)-1-acetyl-6-methylpiperidin-3-yl)-6-(pyrazin-2-yl)pyrimidin-4-yl)(3-(1-methyl-1H-1,2,3-triazol-4-yl)phenyl)amide (024.Na, 46 mg, 88%) as a yellow solid. 1H-NMR (400 MHz, DMSO-d6, mixture of rotamers) δ 9.44 (s, 1H), 8.68 (s, 2H), 8.38 (d, J = 15.5 Hz, 1H), 8.00 (s, 1H), 7.49 - 7.02 (m, 4H), 4.84 - 4.63 (m, 1H), 4.33 - 4.14 (m, 0.5H), 4.07 (d, J = 7.4 Hz, 3H), 4.04 - 3.89 (m, 0.5H), 2.98 - 2.82 (m, 0.5H), 2.73 - 2.53 (m, 1H), 2.12 - 1.89 (m, 5.5H), 1.88 - 1.73 (m, 0.5H), 1.72 - 1.57 (m, 1.5H), 1.28 - 1.19 (m, 1.5H), 1.14 - 1.05 (m, 1.5H). Assay Data

[0302] Assay 1 Multiple myeloma cell efficacy: 10000 OPM-2 (ACC50; DSMZ) were plated in wells of a 384-well plate (Greiner 781090). Cells were treated with a range of doses of compound or vehicle for 4 days. At the end of the experiment, cells were directly stained with PrestoBlue (ThermoFisher Scientific; A13262) for 2 hours at 37°C in a humidified incubator according to the manufacturer's instructions. To assess relative cell numbers, PrestoBlue signals were measured using either a Tecan M1000Pro reader or a Tecan Sparks reader according to the manufacturer's instructions. Background (no cells) values ​​were subtracted and set relative to the vehicle control. EC for each compound was 0.01 mg / mL. 50 To assess the EC, relative fluorescence values ​​were plotted against compound concentration after logarithmic transformation. Data were fitted to a non-linear equation with variable slope (four parameters) using graphpad prism software. Cellular efficacy of compounds was assessed in the multiple myeloma cell line OPM-2 using the cell proliferation / viability assay PrestoBlue. EC50 The values ​​are classified as shown below.

[0303] Assay 2 CBP bromodomain binding assay (TR-FRET) Compound solutions of 10 mM in DMSO were pre-diluted in DSMO to obtain 25x stock solutions in DMSO. These were then diluted to 4x in assay buffer. A dilution series was performed in assay buffer, keeping DMSO concentration stable. 5μl of compound in assay buffer was transferred to an assay plate (provided by the assay kit) and the TR-FRET assay (Cayman chemicals; 600850) was performed using the provider's instructions. After 1 hour incubation in the dark at room temperature, the assay plate was read on a Tecan M1000 plate reader or on a Tecan Sparks reader using TR-FRET mode (upper reading; excitation 340nM bandwidth 20nM; emission 620nM bandwidth 7nM; optimal gain determined for the first well, number of flashes: 5; flash frequency 100Hz; integration time: 500μs, time lag: 100μs, room temperature). The TR-FRET ratio was calculated by dividing the 670 nm emission by the 620 nm emission. Values ​​were log transformed and fitted to a dose-response curve using nonlinear regression with variable slope (4 parameters) to estimate EC50 values.

[0304] [Table 8-1]

[0305] [Table 8-2]

[0306] [Table 8-3]

Claims

1. Compounds of formula (I) 【Chemistry 1】 [In the formula, R ３ａ is a 5-membered heterocyclic ring, said heterocyclic ring containing one or more, the same or different, heteroatoms selected from O and N, and each substitutable carbon or heteroatom is independently unsubstituted or C １ ~C ３ - substituted with one or more, the same or different, substituents selected from alkyl and a 4-membered heterocyclic ring, said heterocyclic ring containing one or more, the same or different, heteroatoms selected from O, N or S; R ３ｂ is H, F, Cl, and CH ３ is selected from 【Chemistry 2】 or a pharma- ceutically acceptable salt, solvate, co-crystal, tautomer, or mixture thereof.

2. R ３ａ is a 5-membered heteroaryl ring, said heteroaryl ring containing one or more, the same or different, heteroatoms selected from O and N, and each substitutable carbon or heteroatom is independently unsubstituted or selected from CH ３ 2. The compound of claim 1 , substituted with one or more, the same or different, substituents selected from:

3. R ３ｂ H, F, and CH ３ 3. The compound according to claim 1 or 2, selected from:

4. The compound of formula (I) 【Chemistry 3】 2. The compound of claim 1 selected from the group consisting of:

5. The compound of formula (I) 【Chemistry 4】 5. The compound of claim 4,

6. The compound of formula (I) 【Chemistry 5】 5. The compound of claim 4,

7. The compound of formula (I) 【Chemistry 6】 5. The compound of claim 4,

8. The compound of formula (I) 【Chemistry 7】 5. The compound of claim 4,

9. The compound of formula (I) 【Chemistry 8】 5. The compound of claim 4,

10. 13. A pharmaceutical composition comprising a pharma- ceutical effective amount of a compound according to claim 1 or 4, and optionally a pharma- ceutical acceptable carrier, diluent or excipient.

11. A pharmaceutical composition according to claim 10 for use in medicine.

12. 11. The pharmaceutical composition according to claim 10, for use in the treatment or alleviation of cancer.

13. 13. The pharmaceutical composition for use according to claim 12, wherein the cancer is selected from melanoma, non-small cell lung cancer, prostate cancer, bile duct cancer, bladder cancer, pancreatic cancer, thyroid cancer, ovarian cancer, colorectal tumors, hairy cell leukemia, acute myeloid leukemia, multiple myeloma, liver cancer, breast cancer, esophageal cancer, head and neck cancer and glioma.

14. The pharmaceutical composition for use according to claim 12, wherein the pharmaceutical composition is used in combination with a second therapeutic agent, the second therapeutic agent being an anticancer agent.

15. 11. The pharmaceutical composition of claim 10, in combination with an EGFR inhibitor, for use in treating a patient suffering from non-small cell lung cancer (NSCLC), wherein the NSCLC exhibits oncogenic alterations in EGFR.

16. 11. The pharmaceutical composition according to claim 10, for use in the treatment or alleviation of said fibrotic disease.

17. 17. The pharmaceutical composition for use according to claim 16, wherein the fibrotic disease is idiopathic pulmonary fibrosis (IPF) or non-alcoholic steatohepatitis (NASH).

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