compound, use of a compound and pharmaceutical composition

专利摘要:
morpholine pyrimidines and their use in therapy. The present invention relates to pyrimidinyl compounds of formula (1) wherein: their pharmaceutically acceptable salts, processes for their preparation, pharmaceutical compositions containing them and their use in therapy.
公开号:BR112012031561B1
申请号:R112012031561
申请日:2011-06-09
公开日:2019-12-03
发明作者:Wilhelmus Maria Nissink Johannes；Michael Foote Kevin；Turner Paul
申请人:Astrazeneca Ab；
IPC主号:

专利说明:

Invention Patent Descriptive Report for "COMPOUND, USE OF A COMPOUND AND PHARMACEUTICAL COMPOSITION".
[0001] The present invention relates to pyrimidinyl compounds, processes for their preparation, pharmaceutical compositions containing them and their use in therapy, for example, in the treatment of proliferative disease, such as cancer and particularly in diseases mediated by inhibitors of protein kinase related to mutated ataxia-telangiectasia and RAD-3, commonly called ATR.
[0002] ATR protein kinase (also known as FRAP-related protein 1; FRP1; MEC1; SCKL; SECKL1) is a member of the PI3-kinase-like protein kinase (PIKK) family that is involved in the repair and maintenance of the genome and its stability (reviewed in Cimprich KA and Cortez D. 2008, Nature Rev. Mol. Cell Biol. 9: 616-627). These proteins coordinate the response to DNA damage, stress and cell cycle disruption. In fact, ATM and ATR, the two members of the protein family, share several substrates downstream that are recognized components of cell cycle machinery and DNA repair, for example, Chk1, BRCA1, p53 (Lakin ND et al, 1999, Oncogene; Tibbets RS et al., 2000, Genes & Dev.). Although ATM and ATR substrates are to some degree shared, the trigger to activate the signaling cascade is not shared and ATR responds mainly to stop forks (Nyberg KA et al., 2002, Ann. Rev. Genet. 36 : 617-656; Shechter D. et al. 2004, DNA Repair 3: 901-908) and massive DNA damage lesions such as those formed by ultraviolet (UV) radiation (Wright JA et al., 1998, Proc. Natl. Acad. Sci. USA, 23: 7445-7450) or the UV mimetic agent, 4-nitroquinoline-1-oxide, 4NQO (Ikenaga M. et al. 1975, Basic Life Sci. 5b, 763-771). However, double-strand breaks (DSB) detected by ATM can be processed into single-strand breaks (SSB) by recruiting ATR; similarly SSB detected by ATR can generate DSB, activating ATM. There is, therefore, a significant mutual influence between ATM and ATR.
[0003] Mutations of the ATR gene that result in complete loss of ATR protein expression are rare and, in general, are not viable. Viability can only result under heterozygous or hypomorphic conditions. The only clear link between ATR gene mutations and disease exists in some patients with Seckel's syndrome that is characterized by growth retardation and microcephaly (O'Driscoll M et al, 2003 Nature Genet. Vol3, 497-501). Cells from patients with hypomorphic mutations of germline ATR (seckel syndrome) have a greater susceptibility to chromosome breakage in fragile sites in the presence of replication stress compared to wild cells (Casper 2004). The interruption of the ATR pathway leads to genomic instability. Patients with Seckel syndrome also have an increased incidence of cancer, which suggests the role of RTA in this disease in maintaining genome stability. In addition, duplication of the ATR gene has been described as a risk factor in rhabdomyosarcomas (Smith L et al, 1998, Nature Genetics 19, 39-46). Oncogene-directed tumorigenesis may be associated with loss of TMJ function and, therefore, increased dependence on ATR signaling (Gilad 2010). Evidence of replication stress has also been reported in several types of tumor, such as colon and ovarian cancer, and more recently, in glioblast-ma, bladder, prostate and sinus (Gorgoulis et al., 2005; Bartkova et al. 2005a; Fan et al., 2006; Tort et al., 2006; Nuciforo et al., 2007; Bartko-va et al., 2007a). Loss of the G1 checkpoint is also frequently observed during tumorigenesis. Tumor cells that are deficient in G1 checkpoint controls, in particular, p53 deficiency, are susceptible to inhibition of ATR activity and present with premature chromatin condensation (PCC) and cell death (Ngheim et al, PNAS, 98, 9092-9097).
[0004] ATR is essential for the viability of replicating cells and is activated during the S phase to regulate the triggering of replication origins and to repair damaged replication forks (Shechter D et al, 2004, Nature cell Biology Vol 6 (7) 648-655). Damage to replication forks may arise due to the exposure of cells to clinically relevant cytotoxic agents, such as hydroxyurea (HU) and platinum (O'Connell and Cimprich 2005; 118, 1-6). ATR is activated by most cancer chemotherapies (Wilsker D et al, 2007, Mol. Cancer Ther. 6 (4) 1406-1413). The biological assessment of the ability of ATR inhibitors to sensitize a wide range of chemotherapies was evaluated. The sensitization of tumor cells to chemotherapeutic agents in cell culture tests was observed and used to assess how well weak RTA inhibitors (such as caffeine) will sensitize tumor cell lines to cytotoxic agents. (Wilsker D. Et al, 2007, Mol Cancer Ther. 6 (4) 1406-1413; Sarkaria J.N. et al, 1999, Cancer Res. 59, 4375-4382). In addition, a reduction in ATR activity by siRNA or knock-in to ATR using a dominant negative form of ATR in cancer cells resulted in the sensitization of tumor cells to the effects of various therapeutic or experimental agents, such as antimetabolite (5-FU, gemcitabine, hydroxyurea, methotrexate, Tomudex), alkylating agents (cisplatin, mitomycin C, cyclophosphamide, MMS) or double-strand breakers (doxorubicin, ionizing radiation) (Cortez D. et al. 2001, Science, 294: 1713-1716 ; Collis SJ et al, 2003, Cancer Res. 63: 1550-1554; Cliby WA et al, 1998, EMBO J. 2: 159-169) suggesting that the combination of ATR inhibitors with some cytotoxic agents could be therapeutically beneficial.
[0005] An additional phenotypic test that has been described to define the activity of specific ATR inhibitor compounds is the cell cycle profile (PJ Hurley, D Wilsker and F Bunz, Oncogene, 2007, 26, 2535-2542). ATR-deficient cells have been shown to have defective cell cycle regulation and distinctive profiles, particularly after a cytotoxic cell insult. In addition, it has been proposed that there are differential responses between tumor and normal tissues in response to ATR axis modulation and this provides additional potential for therapeutic intervention by ATR inhibitory molecules (Rodriguez-Bravo V et al, Cancer Res., 2007, 67 , 11648-11656).
[0006] Another irrefutable utility of ATR-specific phenotypes is in line with the concept of synthetic lethality and the observation that tumor cells that are deficient in G1 checkpoint controls, in particular, p53 deficiency, are susceptible to inhibition of p53 activity. ATR resulting in premature chromatin condensation (PCC) and cell death (Ngheim et al, PNAS, 98, 9092-9097). In this situation, DNA phase S replication occurs, but is not completed before the start of phase M due to failure in intervening checkpoints resulting in cell death due to loss of ATR signaling. The G2 / M checkpoint is a key regulatory control involving ATR (Brown EJ and Baltimore D., 2003, Genes Dev. 17, 615-628) and is the commitment of this checkpoint and the prevention of ATR signaling to downstream partners that results in CCP. Consequently, the daughter cell genome is compromised and cell viability is lost (Ngheim et al, PNAS, 98, 9092-9097).
[0007] It was then proposed that ATR inhibition may prove to be an effective approach for future cancer therapy (Collins I. and Garret MD, 2005, Curr. Opin. Pharmacol., 5: 366-373; Kaelin WG 2005, Nature Rev. Cancer, 5: 689-698) in the appropriate genetic context, such as tumors with TMJ function defects or other S-phase checkpoints. Until recently, there is no clinical precedent for agents targeting RTA, although agents that direct the signaling axis downstream, that is, Chk1 are currently undergoing clinical evaluation (reviewed in Janetka JW et al. Curr Opin Drug Discov Devel, 2007, 10: 473-486). However, inhibitors that target ATR kinase have been described recently (Reaper 2011, Charrier 2011).
[0008] In short, ATR inhibitors have the potential to sensitize tumor cells to ionizing radiation or chemotherapeutic agents that induce DNA damage, they have the potential to induce selective death of tumor cells as well as induce synthetic lethality in subsets of tumor cells with defects in response to DNA damage. [0009] In accordance with a first aspect of the present invention, there is provided a compound of Formula (I): wherein: R1 is selected from morpholin-4-yl and 3-methylmorpholin-4-yl; R2 is n is 0 or 1; R2A, R2C, R2E and R2F are each independently, hydrogen or methyl; R2B and R2D are each independently, hydrogen or methyl R2G is selected from -NHR7 and -NHCOR8; R2H is fluorine; R3 is methyl R4 and R5 are each independently hydrogen or methyl, or R4 and R5 together with the atom to which they are attached form Ring A; Ring A is a C3-6cycloalkyl or a 4- to 6-membered saturated heterocyclic ring containing a heteroatom selected from O and N; R6 is hydrogen; R7 is hydrogen or methyl; R8 is methyl, or a pharmaceutically acceptable salt thereof.
[00010] According to a first aspect of the present invention, there is provided a compound of Formula (I): wherein: R1 is 3-methylmorpholin-4-yl; R2 is n is 0 or 1; R2A, R2C, R2E and R2F are each independently, hydrogen or methyl R2B and R2D are each independently, hydrogen or methyl R2G is selected from -NH2, -NHMe and -NHCOMe; R2H is fluorine; R3 is methyl R4 and R5 are each independently hydrogen or methyl, or R4 and R5 together with the atom to which they are attached form Ring A; Ring A is a C3-6cycloalkyl or a 4- to 6-membered saturated heterocyclic ring containing a heteroatom selected from O and N; and R6 is hydrogen, or a pharmaceutically acceptable salt thereof.
[00011] Certain compounds of formula (I) are capable of existing in stereoisomeric forms. It will be understood that the invention encompasses all geometric and optical isomers of the compounds of formula (I) and mixtures thereof, including racemate. Tautomers and mixtures thereof also form an aspect of the present invention. Solvates and mixtures thereof also form an aspect of the present invention. For example, a suitable solvate of a compound of formula (I) is, for example, a hydrate such as a hemihydrate, a monohydrate, a dihydrate or a trihydrate or an alternative amount thereof.
[00012] Figure 1: Shows the perspective view of the molecular structure of Example 2.02 obtained from crystals that were cultured and isolated by slow evaporation to dryness in air from EtOAc. The asymmetric unit contains two crystallographically unique molecules.
[00013] It should be understood that, while certain of the compounds of formula (I) defined above may exist in optically active or racemic forms due to one or more asymmetric carbon atoms or sulfur atoms, the invention includes in its definition any optically active or racemic form that has the above mentioned activity. The present invention encompasses all stereoisomers that have activity, as defined here. It should also be understood that in the names of the chiral compounds (R, S) denotes any scalemic or racemic mixture while (R) and (S) denote the enantiomers. In the absence of (R, S), (R) or (S) in the name, it should be understood that the name refers to any scalemic or racemic mixture, with a scalemic mixture containing R and S enantiomers in any relative proportions and a racemic mixture contains the R and S enantiomers in the 50:50 ratio. The synthesis of optically active forms can be performed by standard organic chemistry techniques well known in the art, for example, by synthesis from optically active starting materials or by solving a racemic form. Racemates can be separated into individual enantiomers using known procedures (see, for example Advanced Organic Chemistry: 3rd edition: author J March, p104-107). A suitable procedure involves the formation of diasteomeric derivatives by reacting the racemic material with a chiral auxiliary, followed by separation, for example, by chromatography, of the diasteomeres and then cleavage of the auxiliary species. Similarly, the aforementioned activity can be assessed using standard laboratory techniques referred to later in this document.
[00014] It will be understood that the invention encompasses compounds with one or more isotopic substitutions. For example, H can be in any isotopic form, including 1H, 2H (D), and 3H (T); C can be in any isotopic form, including 12C, 13C, and 14C; O can be in any isotopic form, including 16O and 18O; and the like.
[00015] The present invention relates to the compounds of the formula (I) as defined herein as well as the salts thereof. The salts for use in pharmaceutical compositions will be pharmaceutically acceptable salts, but other salts may be useful in the production of the compounds of Formula (I) and their pharmaceutically acceptable salts. The pharmaceutically acceptable salts of the invention can, for example, include acid addition salts of the compounds of formula (I), as defined herein, which are sufficiently basic to form such salts. Such acid addition salts include, but are not limited to, fumarate, methanesulfonate, hydrochloride, hydrobromide, citrate and maleate salts and salts formed with phosphoric and sulfuric acid. In addition, when the compounds of the formula (I) are sufficiently acidic, the salts are basic salts and examples include, but are not limited to, an alkali metal salt, for example, sodium or potassium, an alkaline earth metal salt, for example, calcium or magnesium, or an organic amine salt, for example, triethylamine, ethanolamine, diethanolamine, triethanolamine, morpholine, N-methylpiperidine, N-ethylpiperidine, dibenzylamine or amino acids such as lysine.
[00016] The compounds of formula (I) can also be supplied as hydrolyzable esters in vivo. An in vivo hydrolyzable ester of a compound of formula (I) containing a carboxy or hydroxy group is, for example, a pharmaceutically acceptable ester that is cleaved in the human or animal body to produce the original acid or alcohol. Such esters can be identified by administering, for example, intravenously to a test animal, the test compound and subsequently examining the body fluid of the test animal.
[00017] Pharmaceutically acceptable esters suitable for carboxy include C1-6alkoxymethyl esters, for example, methoxymethyl, C1-6alkanoyloxymethyl esters, for example, pivaloyloxymethyl, phthalidyl esters, C3-8cycloalkyloxyalkyloxyalkyloxyalkyloxyalkyloxyalkyl, alkoxyalkyl, alkoxyalkyl, alkoxyalkyl. -cyclohexylcarbonyloxyethyl, 1,3-dioxolen-2-onylmethyl esters, for example, 5-methyl-1,3-dioxolen-2-onylmethyl, and C1-6 alkoxycarbonyloxyethyl esters, for example, 1-methoxycarbonyloxyethyl ; and can be formed on any carboxy group in the compounds of this invention.
[00018] Pharmaceutically acceptable esters suitable for hydroxy include inorganic esters such as phosphate esters (including, cyclic phosphoramid esters) and a-acyloxyalkyl ethers and related compounds which, as a result of in vivo hydrolysis of the decomposition of the ester provide the hydroxy groups originals. Examples of α-acyloxyalkyl ethers include acetoxymethoxy and 2,2-dimethylpropionyloxymethoxy. A selection of in vivo hydrolysable esters that form hydroxy groups include C1-10 alkanoyl, for example, formyl, acetyl, benzoyl, phenylacetyl, benzoyl and substituted phenylacetyl; C1-10alkoxycarbonyl (to provide alkyl carbonate esters), for example, ethoxycarbonyl; di-C1-4alkyl carbamoyl and N- (di-C1-4alkylaminoethyl) -N-C1-4alkyl carbamoyl (to provide carbamates); di-C1-4alkylaminoacetyl and carboxyacetyl. Examples of ring substituents in phenylacetyl and benzoyl include aminomethyl, C1-4alkylaminomethyl and di- (C1-4alkyl) aminomethyl, and morpholino or pipera-zino linked by a ring nitrogen atom through a methylene bonding group at position 3 - or 4- of the benzoyl ring. Other interesting in vivo hydrolysable esters include, for example, RAC (O) OC1-6alkyl-CO-, with RA being, for example, benzyloxy-C1-4alkyl, or phenyl. Suitable substituents on a phenyl group in such esters include, for example, 4-C1-4piperazino-C1-4alkyl, pipera-zino-C1-4alkyl and morpholino-C1-4alkyl.
[00019] The compounds of formula (I) can also be administered in the form of a prodrug that is decomposed in the human or animal body to provide a compound of formula (I). Various forms of prodrugs are known in the art. For examples of such prodrug derivatives, see: a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985); b) The Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, chapter 5 "Design and Application of Prodrugs", by H. Bundgaard p. 113-191 (1991); c) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); d) H. Bundgaard, et al., Journal of Pharmaceutical Scien-ces, 77, 285 (1988); and e) N. Kakeya, et al., Chem Pharm Bull, 32, 692 (1984).
[00020] In this specification, the generic term "Cp-qalkyl" includes straight-chain and branched-chain alkyl groups. However, references to individual alkyl groups such as "propyl" are specific only to the straight chain version (ie, n-propyl and isopropyl) and references to individual branched chain alkyl groups, such as "tert-butyl" are specific only to the branched chain version.
[00021] The prefix Cp-q in Cp-qalkyl and other terms (where p and q are integers) indicate the range of carbon atoms that are present in the group, for example, C1-4alkyl includes C1alkyl (methyl), C2alkyl (ethyl ), C3alkyl (propyl as n-propyl and isopropyl) and C4alkyl (n-butyl, sec-butyl, isobutyl and tert-butyl).
[00022] The term Cp-qalkoxy comprises -O-Cp-qalkyl groups.
[00023] The term Cp-qalkanoyl comprises -C (O) alkyl groups.
[00024] The term halo includes fluorine, chlorine, bromine and iodine.
[00025] "Carbocyclyl" is a saturated, unsaturated or partially saturated monocyclic ring system containing 3 to 6 ring atoms, with a CH2 group on the ring being substituted by a C = O group. "Carbocyclyl" includes "aryl", "Cp-qcycloalkyl" and "Cp-qcycloalkenyl".
[00026] "Arila" is an aromatic monocyclic carbocyclyl ring system.
[00027] "Cp-qcycloalkenyl" is an unsaturated or partially saturated monocyclic carbocyclyl ring system containing at least 1 C = C bond and one CH2 group on the ring can be replaced by a C = O group.
[00028] "Cp-qcycloalkyl" is a saturated mo-nocicyclic carbocyclyl ring system and one CH2 group on the ring can be replaced by a C = O group.
[00029] "Heterocyclyl" is a saturated, unsaturated or partially saturated monocyclic ring system containing 3 to 6 ring atoms, of which 1, 2 or 3 ring atoms are chosen from nitrogen, sulfur or oxygen, whose ring it can be attached to carbon or nitrogen and a nitrogen or sulfur atom in the ring can be oxidized and a CH2 group in the ring can be replaced by a C = O group. "Heterocyclyl" includes "heteroaryl", "cycloetheroalkyl" and "cycloetheroalkenyl".
[00030] "Heteroaryl" is an aromatic monocyclic heterocyclyl, which has, in particular, 5 or 6 ring atoms, of which 1, 2 or 3 ring atoms are chosen from nitrogen, sulfur or oxygen, where a nitrogen or sulfur of the ring can be oxidized.
[00031] "Cycloheteroalkenyl" is an unsaturated or partially saturated monocyclic heterocyclyl ring system, which has, in particular, 5 or 6 ring atoms, of which 1, 2 or 3 ring atoms are chosen from nitrogen, sulfur or oxygen, the ring of which can be attached to carbon or nitrogen, and a nitrogen or sulfur atom in the ring can be oxidized and a CH2 group on the ring can be replaced by a C = O group.
[00032] "Cycloetheroalkyl" is a saturated monocyclic heterocyclic ring system that has, in particular, 5 or 6 ring atoms, of which 1, 2 or 3 ring atoms are chosen from nitrogen, sulfur or oxygen, whose ring may be attached to carbon or nitrogen and a nitrogen or sulfur atom in the ring may be oxidized and a CH2 group on the ring may be replaced by a C = O group.
[00033] This specification can make use of compound terms to describe groups that comprise more than one functionality. Unless otherwise described herein, such terms are to be interpreted as is known in the art. For example, Cp-qalkyl carbocyclyl comprises Cp-qalkyl substituted by C-qalkyl, Cp-qalkyl heterocyclyl comprises C-qalkyl substituted by heterocyclyl, and bis (Cp-qalkyl) amino comprises amino substituted by 2 Cp-qalkyl groups, which can be the same or different.
[00034] Halo Cp-qalkyl is a Cp-qalkyl group that is substituted by 1 or more halo substituents and particularly 1, 2 or 3 halo substituents. Similarly, other generic halo-containing terms, such as Cp-qalkoxy halo, may contain 1 or more halo substituents and particularly, 1, 2 or 3 halo substituents.
[00035] Cp-qalkyl hydroxy is a Cp-qalkyl group that is substituted by 1 or more hydroxyl substituents and, in particular, by 1, 2 or 3 hydroxy substituents. Similarly, other hydroxy-containing generic terms, such as Cp-qalkoxy hydroxy may contain 1 or more and, particularly, 1, 2 or 3 hydroxy substituents.
[00036] Cp-qalkoxy Cp-qalkyl is a Cp-qalkyl group that is substituted by 1 or more Cp-qalkoxy substituents and, in particular, 1, 2 or 3 Cp-qalkoxy substituents. Similarly, other generic terms containing Cp-qalkoxy, such as Cp-qalkoxy Cp-qalkoxy may contain 1 or more Cp-qalkoxy substituents and, particularly, 1, 2 or 3 Cp-qalkoxy substituents.
[00037] When optional substituents are chosen from "1 or 2", from "1, 2, or 3" or from "1, 2, 3 or 4" groups or substitutes, it must be understood that this The definition includes all substituents being chosen from one of the specified groups, that is, all substituents being equal or the substituents being chosen from two or more of the specified groups, i.e., the substituents not being the same.
[00038] The compounds of the present invention were named with the aid of a computer program (ACD / Name version 10.06).
[00039] The term "proliferative disease (s)" includes malignant disease (s) such as cancer, as well as non-malignant disease (s) such as inflammatory diseases, obstructive airway diseases, immune diseases or diseases cardiovascular diseases.
[00040] Suitable values for any R group or any part or substituent for such groups include: for C1-3alkyl: methyl, ethyl, propyl and iso-propyl; for C1-6alkyl: C1-3alkyl, butyl, 2-methylpropyl, tert-butyl, pentyl, 2,2-dimethyl propyl, 3-methyl butyl and hexyl; for C3-6cycloalkyl: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; for C3-6cycloalkyl C1-3alkyl: cyclopropylmethyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl and cyclohexylmethyl; for aryl: phenyl; for C1-3alkyl aryl: benzyl and phenethyl; for carbocyclyl: aryl, cyclohexenyl and C3-6cycloalkyl; for halo: fluorine, chlorine, bromine and iodine; for C1-3 alkoxy: methoxy, ethoxy, propoxy and isopropoxy; for C1-6alkoxy: C1-3alkoxy, butoxy, tert-butoxy, pentyloxy, 1-ethylpropoxy and hexyloxy; for C1-3alkanoyl: acetyl and propanoyl; for C1-6alkanoyl: acetyl, propanoyl and 2-methylpropanoyl; for heteroaryl: pyridinyl, imidazolyl, pyrimidinyl, thienyl, pyrrolyl, pyrazolyl, thiazolyl, thiazolyl, triazolyl, oxazolyl, isoxazolyl, fu-ranila, pyridazinyl and pyrazinyl; C1-3alquila for heteroaryl: pirrolilmetila, pirroliletila, imi-dazolilmetila, imidazoliletila, pirazolilmetila, pirazoliletila, furanilmetila, furaniletila, tienilmetila, teiniletila, piridinilmetila, piridiniletila, methyl-pyrazinyl, piraziniletila, pirimidinilmetila, pirimidiniletila, pirimidinilpropila, pirimidinilbutila, imidazolilpropila, imidazolilbutila, 1,3,4-triazolylpropyl and oxazolylmethyl; for heterocyclyl: heteroaryl, pyrrolidinyl, piperidinyl, pipe-razinyl, azetidinyl, morpholinyl, dihydro-2H-pyranyl, tetrahydropyridine and tetrahydrofuranyl; for saturated heterocyclyl: oxetanil, pyrrolidinyl, piperidine, piperazinyl, azetidinyl, morpholinyl, tetrahydropyranyl and tetrahydrofuran.
[00041] It should be noted that the examples given for terms used in the description are not limiting.
[00042] The specific values of Ring A, n, R1, R2, R4, R5, R6, R7 and R8 are as follows. Such values may be used individually or in combination when appropriate, with respect to any aspect of the invention, or part of it, and with any of the definitions, claims or modalities defined herein. n [00043] In one aspect n is 0.
[00044] In another aspect n is 1. R1 [00045] In one aspect, R1 is selected from morpholin-4-yl and 3-methylmorpholin-4-yl.
[00046] In another aspect, R1 is 3-methylmorpholin-4-yl.
[00047] In another aspect, R1 is [00048] In another aspect, R1 is R2 [00049] In one aspect R2 is [00050] In one aspect R2 is [00051] In one aspect R2 is [00052] In one aspect aspect R2 is [00053] [00054] [00055] [00056] [00057] R2E is hydrogen.
R2F
[00058] R2F is hydrogen.
R2G
[00059] In one aspect of the invention R2G is selected from -NHR7 and -NHCOR8.
[00060] In one aspect of the invention R2G is -NHR7.
[00061] In one aspect of the invention R2G is -NHCOR8.
[00062] In one aspect of the invention R2G is selected from - NH2, -NHMe and -NHCOMe.
[00063] In one aspect of the invention R2G is -NH2.
[00064] In one aspect of the invention R2G is -NHMe.
[00065] In one aspect of the invention R2G is -NHCOMe. R4 and R5 [00066] In one aspect of the invention R4 and R5 are hydrogen.
[00067] In one aspect of the invention R4 and R5 are methyl.
[00068] In one aspect of the invention R4 and R5 together with the atom to which they are attached form Ring A.
Ring A
[00069] In one aspect of the invention, Ring A is a C3-6cycloalkyl or a 4- to 6-membered saturated heterocyclic ring containing a heteroatom selected from O and N;
[00070] In another aspect, Ring A is a cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, tetrahydrofuryl, tetrahydropyranyl, azetidinyl, pyrrolidinyl or piperidinyl ring.
[00071] In another aspect, Ring A is a cyclopropyl, cyclobutyl, cyclopentyl, tetrahydropyranyl or piperidinyl ring.
[00072] In another aspect, Ring A is a cyclopropyl, cyclopentyl, tetrahydropyranyl or piperidinyl ring.
[00073] In another aspect, Ring A is a cyclopropyl, tetrahydropyranyl or piperidinyl ring.
[00074] In another aspect, Ring A is a cyclopropyl or tetrahydropyranyl ring.
[00075] In another aspect, Ring A is a piperidinyl ring.
[00076] In another aspect, Ring A is a tetrahydropyranyl ring. [00077] In another aspect, Ring A is a cyclopropyl ring. R6 [00078] In one respect, R6 is hydrogen. R7 [00079] In one respect, R7 is hydrogen or methyl.
[00080] In one aspect, R7 is methyl.
[00081] In one respect, R7 is hydrogen. R8 [00082] In one respect, R12 is methyl.
[00083] In one aspect of the invention, a subset of compounds of formula (I), or a pharmaceutically acceptable salt thereof, is provided; R1 is selected from morpholin-4-yl and 3-methylmorpholin-4-yl; n is 0 or 1; R2A is hydrogen; R2B is hydrogen; R2C is hydrogen; R2D is hydrogen; R2E is hydrogen; R2F is hydrogen; R2G is selected from -NHR7 and -NHCOR8; R2H is fluorine; R3 is methyl; R4 and R5 together with the atom to which they are attached form Ring A; Ring A is a C3-6cycloalkyl or a 4- to 6-membered saturated heterocyclic ring containing a heteroatom selected from O and N; R6 is hydrogen; R7 is hydrogen or methyl and R8 is methyl.
[00084] In another aspect of the invention, a subset of compounds of formula (I), or a pharmaceutically acceptable salt thereof, is provided; R1 is selected from morpholin-4-yl and 3-methylmorpholin-4-yl; n is 0 or 1; R2A is hydrogen; R2B is hydrogen; R2C is hydrogen; R2D is hydrogen; R2E is hydrogen; R2F is hydrogen; R2G is selected from -NH2, -NHMe and -NHCOMe; R2H is fluorine; R3 is methyl R4 and R5 together with the atom to which they are attached form Ring A; Ring A is a C3-6cycloalkyl or a 4- to 6-membered saturated heterocyclic ring containing a heteroatom selected from O and N; and R6 is hydrogen.
[00085] In another aspect of the invention, a subset of compounds of formula (I), or a pharmaceutically acceptable salt thereof, is provided; R1 is selected from morpholin-4-yl and 3-methylmorpholin-4-yl; n is 0 or 1; R2A is hydrogen; R2B is hydrogen; R2C is hydrogen; R2D is hydrogen; R2E is hydrogen; R2F is hydrogen; R2G is selected from -NHR7 and -NHCOR8; R2H is fluorine; R3 is methyl R4 and R5 together with the atom to which they are attached form Ring A; Ring A is a cyclopropyl, cyclobutyl, cyclopentyl, oxetanil, tetrahydrofuryl, tetrahydropyranyl, azetidinyl, pyrrolidinyl or pipe-ridinyl ring; R6 is hydrogen; R7 is hydrogen or methyl and R8 is methyl.
[00086] In another aspect of the invention, a subset of compounds of formula (I), or a pharmaceutically acceptable salt thereof, is provided; R1 is selected from morpholin-4-yl and 3-methylmorpholin-4-yl; n is 0 or 1; R2A is hydrogen; R2B is hydrogen; R2C is hydrogen; R2D is hydrogen; R2E is hydrogen; R2F is hydrogen; R2G is selected from -NH2, -NHMe and -NHCOMe; R2H is fluorine; R3 is methyl R4 and R5 together with the atom to which they are attached form Ring A; Ring A is a cyclopropyl, cyclobutyl, cyclopentyl, oxetanil, tetrahydrofuryl, tetrahydropyranyl, azetidinyl, pyrrolidinyl or pipe-ridinyl ring; and R6 is hydrogen.
[00087] In another aspect of the invention, a subset of compounds of the formula (Ia), or a pharmaceutically acceptable salt thereof, is provided; Ring A is a cyclopropyl, tetrahydropyranyl or piperidinyl ring; R2 is n is 0 or 1; R2A is hydrogen; R2B is hydrogen; R2C is hydrogen; R2D is hydrogen; R2E is hydrogen; R2F is hydrogen; R2G is selected from -NHR7 and -NHCOR8; R2H is fluorine; R3 is a methyl group; R6 is hydrogen; R7 is hydrogen or methyl and R8 is methyl.
[00088] In another aspect of the invention, a subset of compounds of the formula (Ia), (Ia) or a pharmaceutically acceptable salt thereof is provided; Ring A is a cyclopropyl, tetrahydropyranyl or piperidinyl ring; R2 is n is 0 or 1; R2A is hydrogen; R2B is hydrogen; R2C is hydrogen; R2D is hydrogen; R2E is hydrogen; R2F is hydrogen; R2G is selected from -NH2, -NHMe and -NHCOMe; R2H is fluorine; R3 is a methyl group; and R6 is hydrogen.
[00089] In another aspect of the invention, a subset of compounds of the formula (Ia), or a pharmaceutically acceptable salt thereof, is provided; Ring A is a cyclopropyl, tetrahydropyranyl or piperi-dinyl ring; R2 is n is 0 or 1; R2A is hydrogen; R2B is hydrogen; R2C is hydrogen; R2D is hydrogen; R2E is hydrogen; R2F is hydrogen; R2G is -NHR7; R2H is fluorine; R3 is a methyl group; R6 is hydrogen; and R7 is hydrogen.
[00090] In another aspect of the invention, a subset of compounds of the formula (Ia), or a pharmaceutically acceptable salt thereof, is provided; Ring A is a cyclopropyl ring; R2 is n is 0; R2A is hydrogen; R2B is hydrogen; R2C is hydrogen; R2D is hydrogen; R2E is hydrogen; R2F is hydrogen; R2G is -NHR7; R2H is fluorine; R3 is a methyl group; R6 is hydrogen; and R7 is methyl.
[00091] In another aspect, the invention provides a compound, or a combination of compounds, selected from any of the examples or a pharmaceutically acceptable salt thereof.
[00092] In another aspect of the invention, there is provided a compound, or a combination of compounds, selected from any of 4- {4 - [(3R) -3-methylmorpholin-4-yl] -6- [ ((R) -S-methylsulfonimidoyl) methyl] pyrimidin-2-yl} -1H-pyrrolo [2,3-b] pyridine; 4- {4 - [(3R) -3-methylmorpholin-4-yl] -6- [1 - ((S) -S-methylsulfonimidoyl) cyclopropyl] pyrimidin-2-yl} -1H-pyrrole [2,3- b] pyridine; 4- {4 - [(3R) -3-methylmorpholin-4-yl] -6- [1 - ((R) -S-methylsulfonimidoyl) cyclopropyl] pyrimidin-2-yl} -1H-pyrrole [2,3- b] pyridine; N-methyl-1- {4 - [(3R) -3-methylmorpholin-4-yl] -6- [1 - ((R) -S-methylsulfonimidoyl) cyclopropyl] pyrimidin-2-yl} -1H-benzimidazole- 2-amine; N-methyl-1- {4 - [(3R) -3-methylmorpholin-4-yl] -6- [1 - ((S) -S-methylsulfonimidoyl) cyclopropyl] pyrimidin-2-yl} -1H-benzimidazole- 2-amine; 4- {4 - [(3R) -3-methylmorpholin-4-yl] -6- [1 - ((R) -S-methylsulfonimidoyl) cyclopropyl] pyrimidin-2-yl} -1H-indole; 4- {4 - [(3R) -3-methylmorpholin-4-yl] -6- [1 - ((S) -S-methylsulfonimidoyl) cyclopropyl] pyrimidin-2-yl} -1H-indole; 1- {4 - [(3R) -3-methylmorpholin-4-yl] -6- [1 - ((R) -S-methylsulfonimidoyl) cyclopropyl] pyrimidin-2-yl} -1H-benzimidazole-2-amine; 1- {4 - [(3R) -3-methylmorpholin-4-yl] -6- [1 - ((S) -S-methylsulfonimidoyl) cyclopropyl] pyrimidin-2-yl} -1H-benzimidazole-2-amine; 4-fluoro-N-methyl-1- {4 - [(3R) -3-methylmorpholin-4-yl] -6- [1 - ((R) -S-methylsulfonimidoyl) cyclopropyl] pyrimidin-2-yl} - 1H-benzimidazole-2-amine; 4-fluoro-N-methyl-1- {4 - [(3R) -3-methylmorpholin-4-yl] -6- [1 - ((S) -S-methylsulfonimidoyl) cyclopropyl] pyrimidin-2-yl} - 1H-benzimidazole-2-amine; 4- {4 - [(3R) -3-methylmorpholin-4-yl] -6- [1- (S-methylsulfonimidoyl) cyclopropyl] pyrimidin-2-yl} -1H-pyrrolo [2,3-c] pyridine; N-methyl-1- {4- [1-methyl-1 - ((S) -S-methylsulfonimidoyl) ethyl] -6 - [(3R) - 3-methylmorpholin-4-yl] pyrimidin-2-yl} - 1H-benzimidazole-2-amine; N-methyl-1- {4- [1-methyl-1 - ((R) -S-methylsulfonimidoyl) ethyl] -6 - [(3R) - 3-methylmorpholin-4-yl] pyrimidin-2-yl} - 1H-benzimidazole-2-amine; N-methyl-1- {4 - [(3R) -3-methylmorpholin-4-yl] -6- [4 - ((S) -S-methylsulfonimidoyl) tetrahydro-2H-pyran-4-yl] pyrimidin-2 -yl} -1H-benzimidazole-2-amine; N-methyl-1- {4 - [(3R) -3-methylmorpholin-4-yl] -6- [4 - ((R) -S-methylsulfonimidoyl) tetrahydro-2H-pyran-4-yl] pyrimidin-2 -yl} -1H-benzimidazole-2-amine; 4- {4 - [(3R) -3-methylmorpholin-4-yl] -6- [4 - ((S) -S-methylsulfonimidoyl) tetrahydro-2H-pyran-4-yl] pyrimidin-2-yl} - 1H-indole; 4-fluoro-N-methyl-1- {4- [1-methyl-1 - ((S) -S-methylsulfonimidoyl) ethyl] -6 - [(3R) -3-methylmorpholin-4-yl] pyrimidin-2 -yl} -1H-benzimidazole-2-amine; 4-fluoro-N-methyl-1- {4- [1-methyl-1 - ((R) -S-methylsulfonimidoyl) ethyl] -6 - [(3R) -3-methylmorpholin-4-yl] pyrimidin-2 -yl} -1H-benzimidazole-2-amine; 6-Fluoro-N-methyl-1- {4- [1-methyl-1 - ((R) -S-methylsulfonimidoyl) ethyl] -6 - [(3R) -3-methylmorpholin-4-yl] pyrimidin-2 -yl} -1H-benzimidazole-2-amine; 5-Fluoro-N-methyl-1- {4- [1-methyl-1 - ((R) -S-methylsulfonimidoyl) ethyl] -6 - [(3R) -3-methylmorpholin-4-yl] pyrimidin-2 -yl} -1H-benzimidazole-2-amine; 5-Fluoro-N-methyl-1- {4- [1-methyl-1 - ((S) -S-methylsulfonimidoyl) ethyl] -6 - [(3R) -3-methylmorpholin-4-yl] pyrimidin-2 -yl} -1H-benzimidazole-2-amine; 6-fluoro-N-methyl-1- {4- [1-methyl-1 - ((S) -S-methylsulfonimidoyl) ethyl] - 6 - [(3R) -3-methylmorpholin-4-yl] pyrimidin-2 -yl} -1H-benzimidazole-2-amine; 6-Fluoro-N-methyl-1- {4 - [(3R) -3-methylmorpholin-4-yl] -6- [1 - ((R) -S-methylsulfonimidoyl) cyclopropyl] pyrimidin-2-yl} - 1H-benzimidazole-2-amine; 5-fluoro-N-methyl-1- {4 - [(3R) -3-methylmorpholin-4-yl] -6- [1 - ((R) -S-methylsulfonimidoyl) cyclopropyl] pyrimidin-2-yl} - 1H-benzimidazole-2-amine; 5-fluoro-N-methyl-1- {4 - [(3R) -3-methylmorpholin-4-yl] -6- [1 - ((S) -S-methylsulfonimidoyl) cyclopropyl] pyrimidin-2-yl} - 1H-benzimidazole-2-amine; and 6-fluoro-N-methyl-1- {4 - [(3R) -3-methylmorpholin-4-yl] -6- [1 - ((S) -S-methylsulfonimidoyl) cyclopropyl] pyrimidin-2-yl} -1H-benzimidazole-2-amine, or a pharmaceutically acceptable salt thereof.
[00093] In another aspect of the invention, there is provided a compound, or a combination of compounds, selected from any of 4- {4 - [(3R) -3-methylmorpholin-4-yl] -6- [ (R) - (S-methylsulfonimidoyl) methyl] pyrimidin-2-yl} -1H-pyrrolo [2,3-b] pyridine; 4- {4 - [(3R) -3-methylmorpholin-4-yl] -6- [1 - ((S) -S-methylsulfonimidoyl) cyclopropyl] pyrimidin-2-yl} -1H-pyrrole [2,3- b] pyridine; 4- {4 - [(3R) -3-methylmorpholin-4-yl] -6- [1 - ((R) -S-methylsulfonimidoyl) cyclopropyl] pyrimidin-2-yl} -1H-pyrrole [2,3- b] pyridine; N-methyl-1- {4 - [(3R) -3-methylmorpholin-4-yl] -6- [1- (R) - (S-methylsulfonimidoyl) cyclopropyl] pyrimidin-2-yl} -1H-benzimidazole- 2-amine; and N-methyl-1- {4 - [(3R) -3-methylmorpholin-4-yl] -6- [1- (S) - (S-methylsulfonimidoyl) cyclopropyl] pyrimidin-2-yl} -1H-benzimidazole -2-amine, or a pharmaceutically acceptable salt thereof.
[00094] A compound of formula (I) can be prepared from a compound of formula (II), where L2 is a leaving group (such as halo or -SMe, etc.), by reaction with a compound of formula (IIIa), (IIIb) or (IIIc), where X is a suitable group (such as boronic acid or ester) in the presence of a suitable Pd catalyst and phosphine binder in a suitable solvent such as a mixture of N, N- dimethylformamide, dimethoxyethane, water and ethanol, under suitable conditions, such as heating in a microwave reactor. Alternatively, a compound of formula (I) can be prepared from a compound of formula (II), where L2 is a leaving group (such as halo or -SMe, etc.), by reaction with a compound of Formula (IIId), with a suitable base, such as NaH, Na2CO3, Cs2CO3 or K2CO3 in a suitable solvent, such as N, N-dimethylformamide or N, N-dimethylacetamide or in the presence of a suitable Pd catalyst and phosphine binder in a suitable solvent, such as dioxane.
[00095] It will be understood that a compound of formula (I) can be transformed into another compound of Formula (I) using conditions well known in the art.
[00096] The compounds of the formula (IIIa), (IIIb), (IIIc) and (IIId) are commercially available or well known in the art.
[00097] It will be understood that a compound of formula (II) can be transformed into another compound of Formula (II) by techniques such as oxidation, alkylation, reductive amination etc., which have been mentioned above or are otherwise known in the literature.
[00098] A compound of formula (II) in which R6 is hydrogen and R4 and R5 form Ring A, can be prepared by reacting a compound of formula (IV), in which PG is a suitable protecting group, such as trifluoroacetamide , with a compound of formula (V), where A is an optionally substituted 2- to 6-membered alkylene chain, in which 1 carbon can be optionally substituted by O, N or S, and where L1 is an leaving group (such as halo, tosyl, mesyl etc.), and removal of the protecting group in the presence of a suitable base, such as sodium hydride or potassium tert-butoxide in a suitable solvent, such as tetrahydrofuran or N, N-dimethylformamide, or with the use of aqueous sodium hydroxide solution and a suitable solvent, such as DCM or toluene with a suitable phase transfer agent, such as tetrabutylammonium bromide.
[00099] A compound of formula (II) in which R6 is hydrogen and R4 and R5 are both methyl, can be prepared by reacting a compound of formula (IV), in which PG is a suitable protecting group, such as trifluoroacetamide, with a compound of the formula (Va), where L1 is a leaving group (such as halo, tosyl, mesyl etc.), and removing the protecting group in the presence of a suitable base, such as sodium hydride or tert-butoxide potassium in a suitable solvent, such as tetrahydrofuran or N, N-dimethylformamide.
[000100] A compound of the formula (IV) in which PG is a suitable protecting group, such as trifluoroacetamide, can be prepared by reacting a compound of the formula (VI) with the iminoiodane (VII) which can be prepared in situ from of iodobenzene diacetate and tri-fluoroacetamide in a suitable solvent, such as DCM in the presence of a suitable base, such as magnesium oxide and a catalyst, such as rhodium acetate.
[000101] A compound of formula (I), in which R4, R5 and R6 are hydrogen, can be prepared by reacting a compound of formula (IV), in which L2 is an leaving group (such as halo or -SMe , etc.), with a compound of the formula (IIIa), (IIIb) or (IIIc), where X is a suitable group (such as boronic acid or ester) in the presence of a suitable Pd catalyst and phosphine binder in a suitable solvent, such as a mixture of N, N-dimethylformamide, dimethoxyethane, water and ethanol, under suitable conditions, such as heating in a microwave reactor and removing the trifluoroacetamide protecting group. Alternatively, a compound of formula (I), in which R4, R5 and R6 are hydrogen, can be prepared by reacting a compound of formula (IV), in which L2 is an leaving group (such as halo or -SMe, etc.), with a compound of the formula (IIId), with a suitable base, such as NaH, Na2CO3, Cs2CO3 or K2CO3 in a suitable solvent, such as N, N-dimethylformamide or N, N-dimethylacetamide or in the presence of a suitable Pd catalyst and phosphine binder in a suitable solvent, such as dioxane and the removal of trifluoroacetamide.
[000102] A compound of the formula (VI), can be prepared by reacting a compound of the formula (VIII) using conditions well known in the art.
[000103] A compound of the formula (VIII), can be prepared by reacting a compound of the formula (IX), in which L4 is an leaving group (such as halo, tosyl, mesyl etc.), with a compound of the formula ( X) optionally in the presence of a suitable base, such as triethylamine and a solvent, such as N, N-dimethylformamide.
[000104] A compound of formula (IX), can be prepared by reacting a compound of formula (XI) using conditions well known in the art.
[000105] A compound of the formula (XI), can be prepared by reacting a compound of the formula (XII) using conditions well known in the art.
[000106] A compound of the formula (XII), in which R1 is an N-linked heterocycle, such as morpholine, can be prepared by reacting a compound of the formula (XIII) with a cyclic amine, such as morpholine optionally, in the presence of a suitable base, such as triethylamine in a suitable solvent, such as DCM. A compound of formula (XII), in which R1 is a C-linked heterocycle, such as dihydropyran, can be prepared by reacting a compound of formula (XIII) with a suitable organometallic reagent (such as boronic acid R1B (OH ) 2 or the boronic ester R1B (OR) 2 etc.) in the presence of a suitable metal catalyst (such as palladium or copper) in a suitable solvent, such as 1,4-dioxane.
[000107] The compounds of the formula (XIII), cyclic amines, boronic acids {R1B (OH) 2} and boronic esters {R1B (OR) 2} are commercially available or are well known in the art.
[000108] It will be understood that when Ring A is a heterocyclic ring containing a nitrogen atom that the nitrogen atom can be adequately protected (for example, a t-butoxy-carbamate or benzyl group) and that the protecting group can be removed and, if necessary, an additional reaction carried out on nitrogen (for example, an alkylation, reducing amination or amidation) at any stage in the synthesis.
[000109] It will be understood that certain of the various ring substituents in the compounds of the present invention can be introduced by standard aromatic substitution reactions or can be generated by conventional functional group modifications before or immediately after the aforementioned processes, and as such, are included in the process aspect of the invention. For example, compounds of formula (I) can be converted to additional compounds of formula (I) by standard aromatic substitution reactions or by conventional modifications of the functional group. Such reactions and modifications include, for example, introduction of a substituent through an aromatic substitution reaction, reduction of substituents, alkylation of substituents and oxidation of substituents. Reagents and reaction conditions for such procedures are well known in the chemical arts. Specific examples of particular aromatic substitution reactions include the introduction of a nitro group using concentrated nitric acid, the introduction of an acyl group using, for example, an acyl halide and Lewis acid (such as trichloride) aluminum) under Friedel Crafts conditions; the introduction of an alkyl group using an alkyl halide and Lewis acid (such as aluminum trichloride) under Friedel Crafts conditions; and the introduction of a halogen group. Specific examples of modifications include the reduction of a nitro group to an amino group, for example, by catalytic hydrogenation with a nickel catalyst or treatment with iron in the presence of hydrochloric acid with heating; oxidation of alkylthio to alkylsulfinyl or alkylsulfonyl.
[000110] It will also be understood that, in some of the reactions mentioned here, it may be necessary / desirable to protect any sensitive groups in the compounds. Cases in which protection is necessary or desirable and suitable methods of protection are known to those skilled in the art. Conventional protecting groups can be used according to standard practice (for illustration, see T.W. Green, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991). Thus, if the reagents include groups such as amino, carboxy or hydroxy, it may be desirable to protect the group in some of the reactions mentioned here.
[000111] A suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example, an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example, a methoxycarbonyl, ethoxycarbonyl or tert-butoxy carbonyl group, a arylmethoxycarbonyl group, for example, benzyloxycarbonyl, or an aroyl group, for example, benzoyl. The deprotection conditions for the above protecting groups vary, necessarily, with the choice of the protecting group. In this way, for example, an acyl group, such as an alkanoyl or alkoxycarbonyl group or an aroyl group can be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example, lithium or sodium hydroxide. Alternatively, an acyl group, such as a tert-butoxy carbonyl group can be removed, for example, by treatment with a suitable acid, such as hydrochloric, sulfuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group, such as a benzyloxycarbonyl group, it can be removed, for example, by hydrogenation on a catalyst, such as palladium on carbon, or by treatment with a Lewis acid, for example, boron tris (trifluoroacetate). An alternative protecting group suitable for a primary amino group is, for example, a phthaloyl group that can be removed by treatment with an alkylamine, for example, dimethylaminopropylamine, or with hydrazine. [000112] A suitable protecting group for a hydroxy group is, for example, an acyl group, for example, an alkanoyl group such as acetyl, an aroyl group, for example, benzoyl, or an arylmethyl group, for example, benzyl. The deprotection conditions for the above protecting groups will necessarily vary with the choice of the protecting group. In this way, for example, an acyl group, such as an alkanoyl group or an aroyl group can be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example, lithium or sodium hydroxide. Alternatively, an arylmethyl group, such as a benzyl group, can be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
[000113] A suitable protecting group for a carboxy group is, for example, an esterification group, for example, a methyl or ethyl group, which can be removed, for example, by hydrolysis with a base, such as sodium hydroxide, or for example, a tert-butyl group that can be removed, for example, by treatment with an acid, for example, an organic acid such as trifluoroacetic acid, or for example, a benzyl group that can be removed, for example, by hydrogenation on a catalyst like palladium-on-carbon. [000114] The protecting groups can be removed at any convenient stage in the synthesis using conventional techniques well known in the art of chemistry.
[000115] Many of the intermediates defined herein are new and these are provided as an additional feature of the invention.
Biological Assays [000116] The following assays can be used to measure the effects of the compounds of the present invention as ATR kinase inhibitors.
(a) Enzyme assay - ATR
[000117] The ATR for use in the enzymatic assay in vitro was obtained from the nuclear extract of HeLa (CIL Biotech, Mons, Belgium) by immunoprecipitation with rabbit polyclonal antiserum against amino acids 400 to 480 of ATR (Tibbetts RS et al, 1999, Genes Dev. 13: 152-157) contained in the following buffer (25 mM HEPES (pH 7.4), 2 mM MgCl2, 250 mM NaCl, 0.5 mM EDTA, 0.1 mM Na3VO4, 10% v / ve glycerol 0.01% v / v Tween 20). The ATR-antibody complexes were isolated from the nuclear extract by incubation with beads of protein A-Sepharose (Sigma, # P3476) for 1 hour and then, through centrifugation to recover the beads. In the well of a 96-well plate, 10 μL of Sepharose beads containing ATR were incubated with 1 μg of S-transferase-p53N66 glutathione substrate (66 p53-terminal NH2 amino acids fused to S-transferase glutathione were expressed in E. coli ) in ATR assay buffer (50 mM HEPES (pH 7.4), 150 mM NaCl, 6 mM MgCl2, 4nM MnCl2, 0.1 mM Na3VO4, 0.1 nM DTT and 10% (v / v) glycerol) at 37 ° C in the presence or absence of inhibitor.After 10 minutes of careful stirring, ATP was added to a final concentration of 3 μΜ and the reaction continued at 37 ° C for an additional hour.The reaction was stopped by adding 100μL of PBS and the reaction was transferred to a 96-well opaque white plate (NUNC # 436033) covered with glutathione and incubated overnight at 4 ° C. This plate was then washed with 0.05% (v / v) PBS / Tween 20 ), dried with absorbent paper and analyzed by a standardized ELISA technique (Enzyme-Linked Immunosorbent Assay) with a 15 p phospho-serine antibody 53 (16G78) (Cell Signaling Technology, # 9286). The detection of the phosphorylated glutathione S-transferase-p53N66 substrate was performed in combination with a secondary goat anti-mouse antibody conjugated to conjugated horseradish peroxidase (Pierce, # 31430). A solution with enhanced chemiluminescence (NEN, Boston, MA) was used to produce a signal and the detection of chemiluminescence was performed using a TopCount plate reader (Packard, Meriden, CT).
[000118] The calculated percentage of resulting enzyme activity (Activity Base, IDBS) was then used to determine the IC 50 values for the compounds (IC 50 determined as the concentration at which 50% of the enzyme activity is inhibited).
(b) Cellular Tests - ATR
[000119] ATM and ATR have distinct and overlapping responses to DNA damage. They must share and responses must be coordinated. Both pathways can be activated by ionizing radiation, however only ATR is activated by UV. As the UV treatment is not practical for use in a high efficiency cell assay, the UV mimetic 4NQ0 (Sigma) was chosen to activate the pathway of response to ATR DNA damage.
[000120] Chk1, an ATR protein kinase downstream, plays a role in controlling the DNA damage checkpoint. The activation of Chk1 involves phosphorylation of Ser317 and Ser345 (considered as the preferred target for phosphorylation / activation by ATR). This test measures a decrease in the phosphorylation of Chk1 (Ser345) in HT29 cells of colon adenocarcinoma after treatment with a compound and with the UV mimetic 4NQ0. Dose ranges of the compound were created by dilution in 100% DMSO and then in assay medium (EMEM, 10% FCS, 1% glutamine) using a Labcyte Echo Acoustic distribution instrument. The cells were plated in 384 well Costar plates at 9 x 104 cells per ml in EMEM 40 μL, 10% FCS and 1% glutamine and cultured for 24 hours. After adding the compound, the cells were incubated for 60 minutes. A final concentration of 3 μΜ of 4NQ0 (prepared in 100% DMSO) was added using Labcyte Echo and the cells incubated for an additional 60 minutes. The cells were then fixed by adding 40 μL of a 3.7% (v / v) formaldehyde solution for 20 minutes. After removing the fixative, the cells were washed with PBS and permeabilized with 40 µL of PBS containing 0.1% Triton ™ X-100. The cells were washed and then 15 μL of a primary antibody solution (pChkl Ser345) was added and the plates incubated at 4 ° C for one night. The primary antibody is removed and 20 μL of a secondary antibody solution (Alexa Fluor 488 goat anti-rabbit, Invitrogen) and 1 μΜ of Hoescht 33258 (Invitrogen) are added for 90 min at room temperature. The plates are washed and left in 40 μL of PBS. The plates were read on an ArrayScan Vti instrument to determine staining intensities and dose responses were obtained and used to determine the IC 50 values for the compounds.
(c) Cellular Assay - SRB
[000121] The potentiation factor (PF50) for compounds is a measure of the number of times the effect of a chemotherapeutic agent is increased when used in combination with an ATR inhibitor. Specifically, this is calculated as a proportion of the IC50 of cell growth control in the presence of a chemotherapeutic agent, typically carboplatin, divided by the IC50 of cell growth in the presence of that agent and the ATR inhibitor of interest. For this purpose, HT29 cells were seeded at the appropriate density to ensure exponential growth over the assay time (typically 1000 to 1500 cells) in each well of a 96-well plate, in a volume of 80 μL and incubated overnight. at 37 ° C. Subsequently, the cells were treated with DMSO vehicle or treated with the test compounds in fixed concentrations (typically 1, 0.3 and 0.1 μΜ). After an hour of incubation at 37 ° C, cells were additionally treated with a 10-point dose response of the chemotherapeutic agent, based on their known sensitivity (typically 30-0.001 μg / ml for carboplatin). The cells were allowed to grow for 5 days at 37 ° C, after which time cell growth was assessed using the sulforodamine B (SRB) assay (Skehan, P et al, 1990 New colorimetric cytotoxic assay for anticancer-drug screening. J Natl. Cancer Inst. 82, 1107-1112.). Specifically, the medium was removed and the cells fixed with 100 μl of chilled 10% (weight / volume) trichloroacetic acid. The plates were then incubated at 4 ° C for 20 minutes before washing 4 times with water. Each well was then stained with 100 μL of 0.4% SRB (weight / volume) in 1% acetic acid for 20 minutes before an additional 4 washes with 1% acetic acid. The plates were dried for 2 hours at room temperature and the dye was solubilized by adding 100 μL of Tris Base pH 8.5 to each well. The plates were shaken before measuring the optical density at 564 nm (OD564). In order to calculate the PF50, the OD564 values obtained for the dose-response curve of the chemotherapeutic agent were expressed as a percentage of the value obtained from cells treated with vehicle alone. Similarly, to act as a control for the inclusion of the ATR inhibitor, the values of the chemotherapeutic agent tested in combination with a fixed concentration of ATR were expressed as a percentage of the value obtained from the cells treated with the corresponding concentrations of ATR inhibitor alone. From these internally controlled curves, the IC50 values were calculated and the PF50 was determined as a proportion of these values, as described above. The compounds are compared using the PF50 value at concentrations of the ATR inhibitor that show minimal inhibition of growth by itself. IC50 values were calculated with XLfit (IDBS, Surrey, UK) using a 4-parameter # 203 dose response logistic model. The upper (max) and lower (min) adjustment of the curve was free and not restricted to 100% to 0%, respectively.
[000122] The following assays can be used to measure the effects of the compounds of the present invention as inhibitors of mTOR kinase.
Enzyme Assay - mTOR Kinase (Echo) [000123] The assay used AlphaScreen technology (Gray et al., Analytical Biochemistry, 2003, 313: 234-245) to determine the ability of test compounds to inhibit phosphorylation by recombinant mTOR .
[000124] A mTOR C-terminal truncation spanning amino acid residues 1362 to 2549 of mTOR (EMBL Accession No. L34075) was stably expressed as a FLAG-labeled fusion in HEK293 cells as described by Vilella-Bach et al., Journal of Biochemistry, 1999, 274, 4266-4272. The stable cell line HEK293 labeled with FLAG mTOR (1362-2549) was routinely maintained at 37 ° C with 5% CO2 until a 70-90% confluence in Dulbecco's modified Eagle growth medium (DMEM; Invitrogen Limited, Paisley, UK catalog number 41966-029) containing 10% heat-inactivated fetal bovine serum (FCS; Sigma, Poole, Dorset, UK, catalog number No. F0392), 1% L-glutamine (Gibco, Catalog number 25030 -024) and 2 mg / ml of Geneticin (G418 sulfate; Invitrogen Limited, UK Catalog No. 10131-027). After expression in the HEK293 mammalian cell line, the expressed protein was purified using the FLAG epitope tag using standard purification techniques.
[000125] The test compounds were prepared as 10 mM stock solutions in DMSO and diluted in DMSO as needed to give a range of final test concentrations. Aliquots (120 nl) of each dilution of the compound were acoustically dispensed using a Labcyte Echo 550 in a well of a 384-well Greiner low volume (LV) white polystyrene plate (Greiner Bio-one). A mixture of 12.12μ1 of purified recombinant MTOR enzyme, 2 μM of biotinylated peptide substrate (Biotin-Ahx-Lys-Lys-Ala-Asn-Gln-Val-Phe-Leu-Gly-Phe-Thr-Tyr-Val- Ala-Pro-Ser-Val-Leu-Glu-Ser-Val-Lys-Glu-NH2; Bachem UK Ltd), ATP (20 μM) and a buffer solution [comprising Tris-HCl buffer pH 7.4 (50 mM ), EGTA (0.1 mM), bovine serum albumin (0.5 mg / mL), DTT (1.25 mM) and manganese chloride (10 mM)] were incubated at room temperature for 120 minutes.
[000126] Control wells that produced a maximum signal that corresponds to the maximum activity of the enzyme were created using 100% DMSO instead of the test compound. Control wells that produced a minimal signal corresponding to the completely inhibited enzyme were created by adding the compound LY294002 (100 µM). These test solutions were incubated for 2 hours at room temperature.
[000127] Each reaction was stopped by adding 5μl of a mixture of EDTA (150 mM), bovine serum albumin (BSA; 0.5 mg / mL) and Tris-HCl pH7.4 buffer (50 mM) containing the Monoclonal Antibody p70 S6 Kinase (T389) 1A5 (Cell Signalling Technology, Catalog No. 9206B) and Streptavidin AlphaScreen donor beads and Protein A acceptors (200 ng; Perkin Elmer, Catalog No. 6760617 were added and the assay plates were left for one night at room temperature in the dark. The resulting signals that arose from excitation by laser light at 60 nm were red using a Packard Envision instrument.
[000128] The phosphorylated biotinylated peptide is formed in situ as a result of mTOR-mediated phosphorylation. The phosphorylated biotinylated peptide that is associated with Streptavidin AlphaScreen donor spheres forms a complex with Monoclonal Antibody p70 S6 Kinase (T389) 1A5 that is associated with AlphaScreen Protein A acceptor spheres. After excitation with laser light at 680 nm, the complex donor sphere: acceptor sphere produces a signal that can be measured. Consequently, the presence of the mTOR kinase activity results in a signal in the assay. In the presence of an mTOR kinase inhibitor, the signal strength is reduced. The inhibition of the mTOR enzyme for a given test compound was expressed as an IC 50 value.
Cell Assay - phospho-Ser473 from Akt [000129] This assay determines the ability of test compounds to inhibit phosphorylation of Serine 473 in Akt as assessed by Acumen Explorer technology (Acumen Bioscience Limited), a plate reader that can be used quickly to quantify characteristics of images generated by laser tracking.
[000130] A MDA-MB-468 human breast adenocarcinoma cell line (LGC Promochem Teddington, Middlesex, UK, Catalog No. HTB-132) was routinely maintained at 37 ° C with 5% CO2 until a confluence of 70 to 90 % in DMEM containing FCS 10% inactivated by heat and L-glutamine 1%.
[000131] For the assay, cells were detached from the culture flask using "Accutase" (Innovative Cell Technologies, Inc., San Diego, CA, USA; Catalog No. AT104) using standard cell culture methods and resuspended in medium to give 3.75 x104 cells per ml. Aliquots (40 μΐ) of cells were seeded in each well of a 384-well black plate (Greiner, Catalog No. 8781091) to give a density of ~ 15,000 cells per well. The cells were incubated overnight at 37 ° C with 5% CO2 to allow the cells to adhere.
[000132] On day 2, the cells were treated with the test compounds and incubated for 2 hours at 37 ° C with 5% CO2. the test compounds were prepared as 10 mM stock solutions in DMSO. The compound is dosed using an acoustic distribution system (Labcyte Echo® Liquid Handling Systems (Labcyte Inc. 1190 Borregas Avenue, Sunnyvale, California 94089 USA). As a minimal response control, each plate contained wells that had a final concentration 100 μΜ of LY294002 (Calbiochem, Beeston, UK, Catalog No. 440202). As a maximum response control, the wells contained 1% DMSO instead of the test compound. After incubation, the contents of the plates were fixed by treatment with a 1.6% aqueous solution of formaldehyde (Sigma, Poole, Dorset, UK, Catalog No. F1635) at room temperature for 1 hour.
[000133] All subsequent suction and washing steps were performed using a Tecan plate washer (suction speed 10 mm / sec.). The fixation solution was removed and the contents of the plates were washed with phosphate buffered saline (PBS; 80 pl; Gibco, Catalog No. 10010015). The contents of the plates were treated for 10 minutes at room temperature with an aliquot (20 µl) of a cell permeabilization buffer consisting of a mixture of PBS and 0.5% Tween-2-. The "permeabilization" buffer was removed and nonspecific binding sites were blocked by treatment with 5% skimmed milk powder ["Marvel" (trademark); Premier Beverages, Stafford, GB] in a mixture of PBS and 0.05% Tween-20. The "blocking" buffer was removed and cells were incubated for 1 hour at room temperature with a rabbit anti-phospho-Akt (Ser473) antibody solution (20 μΐ per well; Cell Signalling, Hitchin, Herts, UK, No Catalog 9277) that had been diluted 1: 500 in "blocking buffer". The cells were washed three times in a mixture of PBS and 0.05% Tween-20. Subsequently, the cells were incubated for 1 hour at room temperature with Alexafluor488-labeled goat anti-rabbit IgG (20 μΐ per well; Molecular Probes, Invitrogen Limited, Paisley, UK, Catalog No. A11008) which had been diluted 1: 500 in "blocking buffer". The cells were washed three times in a mixture of PBS and 0.05% Tween-20. An aliquot of PBS (50 μΐ) was added to each well and the plates were sealed with black plate seals and the fluorescent signal was detected and analyzed.
[000134] The fluorescence dose-response data obtained with each compound was analyzed and the degree of inhibition of Serine 473 in Akt was expressed as an IC 50 value.
[000135] Compounds that have shown reduced activity against mTOR can improve off-target effects.
[000136] Although the pharmacological properties of the compounds of formula (I) vary with structural change as expected, in general, it is believed that the activity possessed by the compounds of formula (I) can be demonstrated at the following concentrations or doses in one or more more of the tests from (a) to (d) above: [000137] Test (a): IC50 against ATR kinase less than 10 μΜ, in particular 0.001 - 1 μΜ for various compounds.
[000138] The following examples were tested in the Test enzyme assay (a): [000139] The following examples were tested in the Test cell test (b): [000140] The following examples were tested in the SRB cell assay of Test (c): [000141] Note: the averages are arithmetic means.
[000142] Compounds can be selected later on the basis of biological or physical properties that can be measured by known techniques and that can be used in the evaluation or selection of compounds for therapeutic or prophylactic application.
[000143] The compounds of the present invention are advantageous characterized by the fact that they have pharmacological activity. In particular, the compounds of the present invention modulate the ATR kinase. The inhibitory properties of the compounds of formula (I) can be demonstrated using the test procedures described here and in the experimental section. Consequently, the compounds of formula (I) can be used in the treatment (therapeutic or prophylactic) of conditions / diseases, in humans and non-human animals, which are mediated by the ATR kinase.
[000144] The invention also provides a pharmaceutical composition comprising a compound of formula (I) or its pharmaceutically acceptable salt, as defined herein in association with a pharmaceutically acceptable diluent or carrier.
[000145] The compositions of the invention can be in a form suitable for oral use (example powder, such as tablets, lozenges, hard or soft gelatin capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example, as creams, ointments, gels or aqueous or oily solutions or suspensions), for administration by inhalation (for example, as a finely divided powder or liquid aerosol), for administration by insufflation (for example, as a finely divided powder) or for parenteral administration (for example, as a sterile aqueous or oily solution for intravenous, subcutaneous, intraperitoneal or intramuscular administration or as a suppository for rectal administration).
[000146] The compositions of the invention can be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art. Therefore, compositions intended for oral use may contain, for example, one or more coloring, sweetening, flavoring and / or preserving agents.
[000147] The amount of the active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending on the treated host and the particular route of administration. For example, a formulation intended for oral administration to humans will generally contain, for example, between 1 mg to 1 g of the active agent (more suitably between 1 to 250 mg, for example, between 1 to 100 mg) composed in an appropriate amount and excipients which can vary from about 5 to about 98 weight percent of the total composition.
[000148] The dose size for therapeutic or prophylactic purposes of a compound of formula I will naturally vary according to the nature and severity of the disease state, the age and sex of the animal or the patient and the route of administration, according to well-known principles of medicine.
[000149] When using a compound of formula (I) for therapeutic or prophylactic purposes, it will generally be administered such that a daily dose in the range, for example, from 1 mg / kg to 100 mg / kg of body weight, is given, , if necessary, in divided doses. In general, smaller doses will be administered when the parenteral route is used. Thus, for example, for intravenous administration, a dose in the range, for example, from 1 mg / kg to 25 mg / kg of body weight will be used in general. Typically, unit dosage forms will contain about 10 mg to 0.5 g of a compound of that invention.
[000150] As determined here, ATR kinase is known to have a role in tumorigenesis as well as in numerous other diseases. We have found that the compounds of formula (I) have a potent anti-tumor activity that is believed to be obtained by inhibiting ATR kinase.
[000151] Consequently, the compounds of the present invention are valuable as anti-tumor agents. Particularly, the compounds of the present invention are valuable as antiproliferative, apoptotic and / or anti-invasive agents in containing and / or treating solid and / or liquid tumor disease. In particular, the compounds of the present invention are expected to be useful in preventing or treating tumors that are sensitive to ATR inhibition. In addition, the compounds of the present invention are expected to be useful in preventing or treating those tumors that are measured only or in part by ATR. The compounds can then be used to produce an inhibitory effect of the ATR enzyme in a warm-blooded animal in need of such treatment. [000152] As determined here, ATR kinase inhibitors have therapeutic value for the treatment of a proliferative disease such as cancer and, in particular, solid tumors such as carcinomas and sarcomas and lymphoid leukemias and malignancies and, in particular, for the treatment of, for example, breast, colorectal, lung (including small cell lung cancer, non-small cell lung cancer and bronchoalveolar cancer) and prostate and bile duct, bone, bladder, head and neck cancer , kidney, liver, gastrointestinal tissue, esophagus, ovary, pancreas, skin, testicles, thyroid, uterus, cervix and vulva and leukemia (including chronic lymphocytic leukemia (LLC), acute lymphocytic leukemia (LLC) and chronic myeloid leukemia (LMC) ], multiple myeloma and lymphomas.
[000153] Consequently, the anti-cancer effects that are useful in treating cancer in a patient include, but are not limited to, anti-tumor effects, the response rate, the time of disease progression and the survival rate. The anti-tumor effects of a treatment method of the present invention include, but are not limited to inhibition of tumor growth, delayed tumor growth, tumor regression, tumor shrinkage, increased time for tumor regeneration after the end of treatment , slowing the progression of the disease. Anticancer effects include prophylactic treatment as well as treatment for existing disease.
[000154] An ATR kinase inhibitor or a pharmaceutically acceptable salt thereof, may also be useful for the treatment of cancer patients including, but not limited to hematological malignancies such as leukemia, multiple myeloma, lymphomas such as Hodgkin's disease, lymphomas non-Hodgkin (including mantle cell lymphoma) and myelodysplastic syndromes as well as solid tumors and their metastases such as breast cancer, lung cancer (small cell lung cancer (SCLC), non-small cell lung cancer (NSCL) , squamous cell carcinoma), endometrial cancer, tumors of the central nervous system such as gliomas, dysembrioplastic neuroepithelial tumor, glioblastoma multiforme, mixed gliomas, medulloblastoma, retinoblastoma, neuroblastoma, germinoma and teratoma, gastrointestinal cancer, such as gastrointestinal cancer esophagus, hepatocellular (liver) carcinoma, cholangiocarcinomas, colon and rectal carcinomas , cancers of the small intestine, pancreatic cancers, skin cancers such as melanomas (in particular metastatic melanoma), thyroid cancer, head and neck cancers and cancers of the salivary glands, prostate, testis, ovary, cervix, uterus, vulva, bladder , kidney (including renal cell carcinoma, clear and renal cell oncocytoma), squamous cell carcinomas, sarcomas such as osteosarcoma, chondrosarcoma, leiomyosarcoma, soft tissue sarcoma, Ewing's sarcoma, gastrointestinal stromal tumor (GIST), sarcoma Kaposi and pediatric cancers such as rhabdomyosarcomas and neuroblastomas.
[000155] The compounds of the present invention and methods of treatment which comprise the administration or use of an ATR kinase inhibitor or a pharmaceutically acceptable salt thereof are expected to be particularly useful for the treatment of patients with lung cancer, cancer prostate cancer, melanoma, ovarian cancer, breast cancer, endometrial cancer, kidney cancer, gastric cancer, sarcomas, head and neck cancers, central nervous system tumors and their metastases and also for the treatment of patients with acute myeloid leukemia .
[000156] According to a further aspect of the invention, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined herein for use as a medicament in a warm-blooded animal such as man.
[000157] According to a further aspect of the invention, a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined herein is provided for use in producing an antiproliferative effect in a warm-blooded animal such as man.
[000158] According to a further aspect of the invention, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined herein for use in producing an apoptotic effect in a warm-blooded animal such as man.
[000159] In accordance with a further aspect of the invention, a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined herein is provided for use in a warm-blooded animal such as man as an anti-invasive agent in containment and / or treatment of proliferative disease such as cancer.
[000160] According to a further aspect of the invention, use is made of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined herein for use in producing an antiproliferative effect in a warm-blooded animal such as man.
[000161] According to an additional feature of that aspect of the invention, the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in the manufacture of a medicament for use in producing an antiproliferative effect in an animal is provided warm-blooded like man.
[000162] According to a further aspect of the invention, use is made of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined herein for use in producing an apoptotic effect in a warm-blooded animal such as man.
[000163] According to a further aspect of the invention, use is made of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined herein for use in the manufacture of a medicament for use in producing an apoptotic effect in a warm-blooded animal like man.
[000164] According to a further aspect of the invention, use is made of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined herein for use in the manufacture of a medicament for use in a warm-blooded animal such as man, as an anti-invasive agent in the containment and / or treatment of a proliferative disease such as cancer.
[000165] In accordance with an additional feature of that aspect of the invention, a method of producing an antiproliferative effect is provided in a warm-blooded animal such as man, which requires such treatment which comprises administering to said animal an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined herein.
[000166] In accordance with an additional feature of that aspect of the invention, a method of producing an anti-invasive effect by containing and / or treating a solid tumor disease in a warm-blooded animal such as man, which requires such treatment comprising administering to said animal an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined herein.
[000167] According to a further aspect of the invention, use is made of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined herein for use in the manufacture of a medicament for use in preventing or treating a disease proliferative such as cancer in a warm-blooded animal such as man.
[000168] In accordance with an additional feature of that aspect of the invention, a method is provided for the prevention or treatment of proliferative disease such as cancer in a warm-blooded animal, such as man, which requires such treatment which comprises administering said animal an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined herein.
[000169] According to a further aspect of the invention, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined herein for use in preventing or treating those tumors that are sensitive to inhibition of ATR kinase.
[000170] According to an additional feature of that aspect of the invention, use is made of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined herein in the manufacture of a medicament for use in preventing or treating those tumors that are sensitive to ATR kinase inhibition.
[000171] According to an additional feature of that aspect of the invention, a method is provided for the prevention or treatment of those tumors that are sensitive to inhibition of ATR kinase, which comprises administering to said animal an effective amount of a compound of formula (I ) or a pharmaceutically acceptable salt thereof as defined.
[000172] According to a further aspect of the invention, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined herein for use in providing an inhibitory effect of ATR kinase.
[000173] In accordance with an additional feature of that aspect of the invention, use is made of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined herein in the manufacture of a medicament for use in providing an ATR inhibitory effect. kinase.
[000174] In accordance with a further aspect of the invention, there is also provided a method for providing an inhibitory effect of ATR kinase which comprises administering an effective amount of a compound of formula I or a pharmaceutically acceptable salt as defined herein.
[000175] In accordance with a further aspect of the invention, a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined herein is provided for use in the treatment of cancer, inflammatory diseases, obstructive airway diseases, immune diseases or diseases cardiovascular diseases.
[000176] According to a further aspect of the invention, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined herein for use in the treatment of solid tumors such as carcinomas and sarcomas and lymphoid leukemias and malignancies.
[000177] In accordance with a further aspect of the invention, a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined herein for use in the treatment of breast, colorectal, lung (including small cell lung cancer) is provided. , non-small cell lung cancer and bronchoalveolar cancer) and prostate.
[000178] In accordance with a further aspect of the invention, a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined herein is provided for use in the treatment of cancer of the bile duct, bone, bladder, head and neck, kidney, liver, gastrointestinal tissue, esophagus, ovary, pancreas, skin, testicles, thyroid, uterus, cervix and vulva and leukemias (including ALL, CLL and CML), multiple myeloma and lymphomas.
[000179] In accordance with an additional aspect of the invention, a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined herein is provided for use in the treatment of cancer of the bile duct, bone, bladder, head and neck, kidney, liver, gastrointestinal tissue, esophagus, ovary, pancreas, skin, testicles, thyroid, uterus, cervix and vulva and leukemias (including ALL, CLL and CML), multiple myeloma and lymphomas.
[000180] According to a further aspect of the invention, a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined herein is provided for use in the treatment of lung cancer, prostate cancer, melanoma, ovarian cancer, cancer of breast, endometrial cancer, kidney cancer, gastric cancer, sarcomas, head and neck cancers, central nervous system tumors and their metastases and also for the treatment of patients with acute myeloid leukemia.
[000181] In accordance with a further aspect of the invention, a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided as defined herein in the manufacture of a medicament for use in the treatment of cancer, inflammatory diseases, obstructive airway diseases , immune diseases or cardiovascular diseases.
[000182] According to a further aspect of the invention, use is made of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in the manufacture of a medicament for use in the treatment of solid tumors such as carcinoma and sarcomas and leukemias and lymphoid malignancies.
[000183] In accordance with a further aspect of the invention, use is made of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in the manufacture of a medicament for use in the treatment of breast, colorectal, lung ( including small cell lung cancer, non-small cell lung cancer and bronchoalveolar cancer) and prostate.
[000184] In accordance with a further aspect of the invention, use is made of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in the manufacture of a medicament for use in the treatment of bile duct, bone, bladder cancer , head and neck, kidney, liver, gastrointestinal tissue, esophagus, ovary, pancreas, skin, testicles, thyroid, uterus, cervix and vulva and leukemias (including ALL, CLL and CML), multiple myeloma and lymphomas.
[000185] In accordance with a further aspect of the invention, use is made of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in the manufacture of a medicament for use in the treatment of lung cancer, prostate cancer, melanoma, ovarian cancer, breast cancer, endometrial cancer, kidney cancer, gastric cancer, sarcomas, head and neck cancers, central nervous system tumors and their metastases and also for the treatment of patients with acute myeloid leukemia.
[000186] According to a further aspect of the invention, a method is provided for treating cancer, inflammatory diseases, obstructive airway diseases, immune diseases or cardiovascular diseases in a warm-blooded animal, such as man, in need of such treatment comprising administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined herein.
[000187] In accordance with a further aspect of the invention, a method is provided for treating solid tumors such as carcinoma and sarcomas and lymphoid leukemias and malignancies in a warm-blooded animal, such as man, in need of such treatment comprising administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined herein.
[000188] According to a further aspect of the invention, a method is provided for treating breast, colorectal, lung (including small cell lung cancer, non-small cell lung cancer and bronchoalveolar cancer) and prostate cancer in an animal warm-blooded, like man, in need of such treatment which comprises administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined herein.
[000189] According to a further aspect of the invention, a method is provided for treating cancer of the bile duct, bone, bladder, head and neck, kidney, liver, gastrointestinal tissue, esophagus, ovary, pancreas, skin, testicles, thyroid, uterus, cervix and vulva and leukemias (including ALL, CLL and CML), multiple myeloma and lymphomas in a warm-blooded animal, such as man, in need of such treatment that comprises administering an effective amount of a compound of formula ( I) or a pharmaceutically acceptable salt thereof, as defined herein.
[000190] In accordance with an additional aspect of the invention, a method is provided for treating lung cancer, prostate cancer, melanoma, ovarian cancer, breast cancer, endometrial cancer, kidney cancer, gastric cancer, sarcomas, cancers of head and neck, tumors of the central nervous system and their metastases and acute myeloid leukemia in a warm-blooded animal, such as man, in need of such treatment that comprises administering an effective amount of a compound of formula (I) or a salt pharmaceutically acceptable form thereof, as defined herein.
[000191] As stated here, the in vivo effects of a compound of formula (I) can be exerted in part by one or more metabolites that are formed within the body of a human or animal after administration of a compound of formula (I ).
[000192] The invention further relates to combination therapies in which a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition or a formulation comprising a compound of formula (I) is administered concomitantly or sequentially or as a drug combined with other treatment for use in the control of an oncological disease.
[000193] In particular, the treatment defined herein may be applied as a single therapy or may involve, in addition to the compounds of the invention, conventional surgery or radiotherapy or chemotherapy. Consequently, the compounds of the invention can also be used in combination with existing therapeutic agents for the treatment of cancer.
[000194] Suitable agents to be used in combination include: (i) antiproliferative / antineoplastic drugs and combinations thereof, as used in clinical oncology such as alkylating agents (for example, cisplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalam, chlorambucil, busulfam and nitrosoureas); antimetabolites (for example, antifolates such as fluorpyrimidines such as 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside, hydroxyurea and gemcitabine); anti-tumor antibiotics (for example, anthracyclines such as adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mitramycin); antimitotic agents (for example, vinca alkaloids like vincristine, vinblastine, vindesine and vinorelbine and taxoids like paclitaxel and taxotere); and topoisomerase inhibitors (for example, epipodophyllotoxins such as etoposide and teniposide, ansacrine, topotecan and camptothecins); (ii) cytostatic agents, such as antiestrogens (for example, tamoxifen, toremifene, raloxifene, droloxifene and iodoxifene), estrogen receptor negative regulators (for example, fulvestrant), antiandrogens (for example, bicalutamide, flutamide, nilutamide and acetate cyproterone), LHRH antagonists or LHRH agonists (eg goserelin, leuprorelin and buserelin), progestogens (eg megestrol acetate), aromatase inhibitors (eg anastrozole, letrozole, vorazole and exemestane) and 5 inhibitors -reductase such as finasteride; (iii) anti-invasion agents (for example, inhibitors of the c-Src kinase family such as 4- (6-chloro-2,3-methylenedioxyanilino) -7- [2- (4-methylpiperazin-1-yl) ethoxy] -5-tetrahydropyran-4-yloxyquinazoline (AZD0530; International Patent Application WO 01/94341) and N- (2-chloro-6-methylphenyl) -2- {6- [4- (2-hydroxyethyl) piperazin-1- il] -2-methylpyrimidin-4-ylamino} thiazol-5-carboxamide (dasatinib, BMS-354825; J. Med. Chem., 2004, 47, 6658-6661), and metalloproteinase inhibitors such as marimastate and inhibitors of the function of plasminogen urokinase activating receptor); (iv) growth factor function inhibitors: for example, such inhibitors include antibodies against growth factor and antibodies against the growth factor receptor (for example, the anti-erbB2 antibody trastuzumab [Herceptin ™] and the anti -erbB1 cetuximab [C225]); such inhibitors also include, for example, tyrosine kinase inhibitors, for example, inhibitors of the epidermal growth factor family (e.g., tyrosine kinase inhibitors of the EGFR family such as N- (3-chloro-4-fluorphenyl) ) -7-methoxy-6- (3-morpholinopropoxy) quinazolin-4-amine (gefitinib, ZD1839), N- (3-ethynylphenyl) -6,7-bis (2-methoxyethoxy) quinazolin-4-amine (erlotinib, OSI-774) and 6-acrylamido-N- (3-chloro-4-fluorophenyl) -7- (3-morpholinopropoxy) quinazolin-4-amine (CI 1033) and erbB2 tyrosine kinase inhibitors such as lapatinib) hepatocyte growth factor family, platelet-derived growth factor family inhibitors such as imatinib, serine / threonine kinase inhibitors (for example, Ras / Raf signaling inhibitors such as farnesyl transferase inhibitors, for example, sorafenib (BAY 43-9006)) and inhibitors of cell signaling through MEK and / or Akt kinases; (v) anti-angiogenesis agents such as those that inhibit the effects of vascular endothelial growth factor [e.g., anti-vascular endothelial growth factor antibody bevacizumab (Avastin ™) and VEGF receptor tyrosine kinase inhibitors such as 4- ( 4-bromo-2-fluoranilino) -6-methoxy-7- (1-methylpiperidin-4-ylmethoxy) quinazoline (ZD6474; Example 2 of WO 01/32651), 4- (4-fluor- 2-methylindol-5- iloxy) -6-methoxy-7- (3-pyrrolidin-1-ylpropoxy) quinazoline (AZD2171; Example 240 of WO 00/47212), vatalanib (PTK787; WO 98/35985) and SU11248 (sunitinib; WO 01/60814) , and compounds that work by other mechanisms (for example, linomide, ανβ3 integrin function inhibitors and angiostatin)]; (vi) agents that cause vascular damage such as combrestatin A4 and the compounds described in International Patent Applications WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213 ; (vii) antisense therapies, for example, those that are targeted at the targets listed above, such as ISIS 2503, an antisense agent; (viii) gene therapy approaches, including approaches to replace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRC2, approaches to GDEPT (gene therapy related to prodrug activating enzyme) such as those using cytosine deaminase, thymidine kinase or the bacterial nitroreductase enzyme and approaches to increase the patient's tolerance to chemotherapy or radiotherapy such as gene therapy for resistance to multiple drugs; and (ix) immunotherapeutic approaches, including ex vivo and in vivo approaches to increase the immunogenicity of patient tumor cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T cell energy, approaches that use transfected immune cells such as cytokine-transfected dendritic cells, approaches that use cytokine-transfected tumor cell lines and approaches that use anti-idiotypic antibodies.
[000195] According to a further aspect of the invention, the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided in the preparation of a medicament for use as an adjunct in cancer therapy or to potentiate tumor cells for treatment with ionizing radiation or chemotherapeutic agents.
[000196] According to a further aspect of the invention, a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided in combination with ionizing radiation or chemotherapeutic agents for use in the treatment of cancer.
[000197] The invention will now be explained further with reference to the following illustrative examples.
[000198] Except where otherwise stated, starting materials were commercially available. All commercial solvents and reagents were laboratory grade and were used as received.
General experiment [000199] The invention will now be illustrated in the following examples in which, generally: (i) the operations were performed at room temperature (ta), that is, in the range of 17 to 25 ° C and under a gas atmosphere inert as N2 or Ar, unless otherwise specified; (ii) in general, the course of the reactions was followed by thin layer chromatography (TLC) and / or high performance liquid chromatography (HPLC), which was usually coupled to a mass spectrometer (LCMS). The reaction times that are given are not necessarily the minimum achievable; (iii) when necessary, the organic solutions were dried with anhydrous MgSO4 or Na2SO4, the processing procedures were carried out using traditional phase separation techniques or using SCX, as described in (xiii), the evaporations were carried out by evaporation rotating in vacuo or in a Genevac HT-4 / EZ-2 or Biotage V10; (iv) the yields, when present, are not necessarily the maximum achievable, and when necessary, the reactions were repeated if a larger amount of the reaction product was needed; (v) in general, the structures of the final products with formula (I) were confirmed by nuclear magnetic resonance (NMR) and / or mass spectral techniques; electron spray mass spectral data was obtained using a Waters ZMD or Waters ZQ LC mass spectrometer acquiring data from both positive and negative ions, and generally, only ions related to the original structure are reported; the proton NMR chemical displacement values were measured on the delta scale using a Bruker DPX300 spectrometer operating at 300 MHz field strength, a Bruker DRX400 operating at 400 MHz, Bruker DRX500 operating at 500 MHz or Bruker AV700 operating at 700 MHz. Unless otherwise specified, NMR spectra were obtained at 400 MHz in d6-dimethylsulfoxide. The following abbreviations were used: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad; qn, quintet. (vi) Except where otherwise indicated, compounds containing an asymmetric carbon and / or sulfur atom have not been separated; (vii) The intermediates were not necessarily completely purified, but their structures and purity were evaluated by TLC, analytical HPLC, and / or analysis by NMR and / or mass spectrometry; (viii) Except where otherwise specified, rapid column chromatography (FCC) was performed on Merck Kieselgel silica (Art. 9385) or reverse phase silica (Fluka 90 C18 silica gel) or Silicycle cartridges (40 to 40 silica) 63 μm, 4 to 330 g in weight) or in Grace resolv cartridges (4 to 120 g) or in RediSep Rf 1.5 Flash columns or in High-performance RediSep Rf Gold Flash columns (150 to 415 g in weight) or in reverse phase columns RediSep Rf Gold C18 (20 to 40 μm silica) manually or automatically using an Isco Combi Flash Companion system or similar system; (ix) Preparative reverse phase HPLC (RP HPLC) was made on C18 reverse phase silica, for example, on a Waters 'Xterra' or 'XBridge' preparative column (5μm silica, 19 mm in diameter, 100 mm in length ) or in a Phenomenex "Gemini" or 'AXIA' ^ m preparative reverse phase column, 110A, 21.1 mm in diameter, 100 mm in length) using decreasingly polar mixtures as eluent, for example [containing 0.1 to 5% formic acid or 1 to 5% aqueous ammonium hydroxide (d = 0.88)] as solvent A and acetonitrile as solvent B or MeOH: MeCN 3: 1; a typical procedure would be as follows: a solvent gradient over 9.5 minutes, at 25 mL per minute, from an 85:15 mixture (or alternative ratio, as appropriate) of solvents A and B, respectively at a 5:95 mixture of solvents A and B; (x) the following analytical HPLC methods were used; in general, reverse phase silica was used with a flow rate of about 1 mL / minute and detection was by electron spray mass spectrometry and UV absorbance at a wavelength of 254 nm. Analytical HPLC was performed on C18 reverse phase silica, on a Phenomenex "Gemini" preparative reverse phase column (5μ ^ ι of silica, 110 A, 2 mm in diameter, 50 mm in length) using decreasingly polar mixtures as eluent, for example, decreasingly polar mixtures of water (containing 0.1% formic acid or 0.1% ammonia) as solvent A and acetonitrile as solvent B or MeOH: MeCN 3: 1. A typical analytical HPLC method would be as follows: a solvent gradient over 4 minutes, at approximately 1 mL per minute, from a 95: 5 mixture of solvents A and B, respectively, to a 5:95 mixture solvents A and B; (xi) When certain compounds were obtained as an acid addition salt, for example, a monohydrochloride salt or a dihydrochloride salt, the stoichiometry of the salt was based on the number and nature of the basic groups in the compound, the exact stoichiometry of the salt it has generally not been determined, for example, through elementary analysis data; (xii) when the reactions refer to the use of a microwave, one of the following microwave reactors was used: Biotage Initiator, Personal Chemistry Emrys Optimizer, Personal Chemistry Smithcreator or CEM Explorer; (xiii) The compounds were purified by strong cation exchange chromatography (SCX) using Isolute SPE flash SCX-2 or SCX-3 columns (International Sorbent Technology Limited, Mid Glamorgan, UK); (xiv) the following preparative chiral HPLC methods were used; in general, a flow rate between 10 to 350 ml / minute and the detection was by UV absorbance at a typical wavelength of 254 nm. A sample concentration of about 1 to 100 mg / ml was used in a suitable solvent mixture, such as MeOH, EtOH or iPA, optionally mixed with isohexane or heptane with an injection volume between 0.5 and 100 ml and a run time between 10 and 150 minutes and a typical oven temperature of 25 to 35 ° C; (xv) the following analytical chiral HPLC methods were used; in general, a flow rate of 1 ml / minute and the detection was made by UV absorbance at a typical wavelength of 254 nm. A sample concentration of about 1 mg / ml was used in a suitable solvent, such as EtOH with an injection volume of about 10 μΐ and run time between 10 and 60 minutes and a typical oven temperature of 25 to 35 ° C; (xiv) the following preparatory chiral CFS (supercritical fluid chromatography) methods were used; in general, a flow rate of about 70 ml / minute and detection was by UV absorbance at a typical wavelength of 254 nm. A sample concentration of about 100 mg / ml was used in a suitable solvent, such as MeOH with an injection volume of about 0.5 μΐ and run time between 10 and 150 minutes and a typical oven temperature of 25 at 35 ° C; (xvii) In general, the names of the examples were given using ACD Name Ver 10.06 and the intermediate compounds were named using the "Structure to Name" part of the ChemDraw Ultra 11.0.2 program from CambridgeSoft; (xviii) in addition to those mentioned above, the following abbreviations were used: Example 1.01 4- {4 - [(3R) -3-Methylmorpholin-4-yl] -6 - [((R) -S- methylsulfonimidoyl) methyl] pyrimidin-2-yl} -1H-pyrrolo [2,3-b] pyridine [000200] (R) -3-Methyl-4- (6 - ((R) -S-methylsulfonimidoylmethyl) -2- (1-tosyl -1H-pyrrolo [2,3-b] pyridin-4-yl) pyrimidin-4-yl) morpholine (98 mg, 0.18 mmol) was dissolved in MeOH (10 ml) and DCM (10 ml) and heated to 50 ° C.
Sodium hydroxide, 2M aqueous solution (0.159 ml, 0.32 mmol) was then added and heating continued for 5 hours. The reaction mixture was evaporated and the residue dissolved in DME: water: MeCN 2: 1: 1 (4 ml) and then purified by preparative HPLC using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluent. Fractions containing the desired compound were evaporated and the residue was triturated with Et2O (1 ml) to provide the title compound (34.6 mg, 49%); 1H NMR (400 MHz, CDCh) 1.40 (3H, d), 3.17 (3H, s), 3.39 (1H, tt), 3.62 (1H, td), 3.77 (1H, dd), 3.85 (1H, d), 4.08 (1H, dd), 4.18 (1H, d), 4.37 - 4.48 (2H, q), 4.51 (1H, s ), 6.59 (1H, s), 7.35 (1H, t), 7.46 (1H, d), 8.06 (1H, d), 8.42 (1H, d), 10.16 (1H, s); m / z: (ES +) MH +, 387.19.
[000201] A (R) -3-methyl-4- (6 - ((R) -S-methylsulfonimidoylmethyl) -2- (1-tosyl-1H-pyrrolo [2,3-b] pyridin-4-yl) pyrimidin-4-yl) morpholine, used as a starting material, can be prepared as follows: a) (R) -3-methylmorpholine (7.18 g, 71.01 mmol) and triethylamine (12.87 ml, 92 , 31 mmol) were added to methyl 2,4-dichloropyrimidine-6-carboxylate (14.70 g, 71.01 mmol) in DCM (100 ml). The resulting mixture was stirred at room temperature for 18 hours. Water (100 ml) was added, the layers were separated and extracted with DCM (3 x 75 ml). The combined organics were dried with MgSO4, concentrated in vacuo and the residue was triturated with Et2O to produce (R) -methyl 2-chloro-6- (3-methylmorpholine) pyrimidine-4-carboxylate (14.77 g, 77% ); 1H NMR (400 MHz, CDCl3) 1.35 (3H, d), 3.34 (1H, td), 3.55 (1H, td), 3.70 (1H, dd), 3.81 (1H, d), 3.97 (3H, s), 4.03 (1H, dd), 4.12 (1H, br s), 4.37 (1H, br s), 7.15 (1H, s); m / z: (ESI +) MH +, 272.43.
[000202] The liquids were concentrated on silica and purified by chromatography on silica eluting with a gradient of 20 to 40% EtOAc in isohexane. The product-containing fractions were combined and evaporated to provide (R) -methyl 2-chloro-6- (3-methylmorpholine) pyrimidine-4-carboxylate (1.659 g, 9%); 1H NMR (400 MHz, CDCl3) 1.35 (3H, d), 3.33 (1H, td), 3.55 (1H, td), 3.69 (1H, dd), 3.80 (1H, d), 3.97 (3H, s), 4.03 (1H, dd), 4.12 (1H, br s), 4.36 (1H, br s), 7.15 (1H, s); m / z: (ESI +) MH +, 272.43. b) Lithium borohydride, 2M in THF (18 ml, 36.00 mmol) was added dropwise to (R) -methyl 2-chloro-6- (3-methylmorpholine) pyrimidine-4-carboxylate (16.28 g, 59 , 92 mmol) in THF (200 ml) at 0 ° C, over a period of 20 minutes under nitrogen. The resulting solution was stirred at 0 ° C for 30 minutes and then left to warm to room temperature and stirred for an additional 18 hours. Water (200 ml) was added and the THF evaporated. The aqueous layer was extracted with EtOAc (2 x 100 ml) and the organic phases were combined, dried with MgSO4 and then evaporated to provide (R) - (2-chloro-6- (3-methylmorpholine) pyrimidin-4- il) methanol (14.54 g, 100%) which was used in the next step without purification; 1H NMR (400 MHz, CDCl3) 1.32 (3H, d), 2.65 (1H, br s), 3.25 - 3.32 (1H, m), 3.51 - 3.57 (1H, m), 3.67 - 3.70 (1H, m), 3.78 (1H, d), 3.98 - 4.09 (2H, m), 4.32 (1H, br s), 4, 59 (2H, s), 6.44 (1H, s); m / z: (ESI +) MH +, 244.40. c) Methanesulfonyl chloride (4.62 ml, 59.67 mmol) was added dropwise to (R) - (2-chloro-6- (3-methylmorpholine) pyrimidin-4-yl) methanol (14.54 g, 59.67 mmol) and triethylamine (8.32 ml, 59.67 mmol) in DCM (250 ml) at 25 ° C over a period of 5 minutes. The resulting solution was stirred at 25 ° C for 90 minutes. The reaction mixture was suppressed with water (100 ml) and extracted with DCM (2 x 100 ml). The organic phases were combined, dried with MgSO4, filtered and evaporated to provide (R) - (2-chloro-6- (3-methylmorpholine) pyrimidin-4-yl) methyl methanesulfonate (20.14 g, 105%) which was used in the next step without further purification; 1H NMR (400 MHz, CDCl3) 1.33 (3H, d), 3.13 (3H, s), 3.27 - 3.34 (1H, m), 3.51 - 3.57 (1H, m ), 3.66 - 3.70 (1H, m), 3.79 (1H, d), 3.99 - 4.03 (2H, m), 4.34 (1H, br s), 5.09 (2H, d), 6.52 (1H, s); m / z: (ESI +) MH +, 322.83.
[000203] Alternatively, this step can be performed as follows: In a fixed 3 L reaction vessel with a Huber 360 heater / cooler attached, under an atmosphere of nitrogen, triethylamine (0.120 L, 858.88 mmol) was added in one portion to a stirred solution of (R) - (2-chloro-6- (3-methylmorpholine) pyrimidin-4-yl) methanol (161 g, 660.68 mmol) in DCM (7.5 vol) (1.2 L) at 20 ° C (exotherm seen at 3 ° C). The mixture was cooled to 5 ° C and then methanesulfonyl chloride (0.062 L, 792.81 mmol) was added by dripping over 15 minutes, not allowing the internal temperature to exceed 15 ° C. The reaction mixture was stirred at 15 ° C for 2 hours and then kept (without stirring) overnight at room temperature under a nitrogen atmosphere. Water (1.6 L, 10 vol) was added and the aqueous layer was separated and then extracted with DCM (2 x 1.6 L, 2 x 10 vol). The organics were combined, washed with 50% brine / water (1.6 L, 10 vol), dried over magnesium sulfate, filtered and then evaporated to provide a mixture of approximately two thirds of (R) - methanesulfonate (2-chloro-6- (3-methylmorpholine) pyrimidin-4-yl) methyl and one third of (R) -4- (2-chloro-6- (chloromethyl) pyrimidin-4-yl) -3-methylmorpholine ( 216 g) which was used in the next step without further purification. d) Lithium iodide (17.57 g, 131.27 mmol) was added to (R) - (2-chloro-6- (3-methylmorpholine) pyrimidin-4-yl) methanesulfonate (19.2 g, 59.67 mmol) in dioxane (300 ml) and heated to 100 ° C for 2 hours under nitrogen. The reaction mixture was suppressed with water (200 ml) and extracted with EtOAc (3 x 200 ml). The organic layers were combined and washed with 2M sodium bisulfite solution (400 ml), water (400 ml), brine (400 ml) dried with MgSO4 and then evaporated. The residue was triturated with Et2O to provide (R) -4- (2-chloro-6- (iodomethyl) pyrimidin-4-yl) -3-methylmorpholine (13.89 g, 66%); 1H NMR (400 MHz, CDCls) 1.32 (3H, d), 3.28 (1H, td), 3.54 (1H, td), 3.69 (1H, dd), 3.78 (1H, d), 3.98 - 4.02 (2H, m), 4.21 (2H, s), 4.29 (1H, br s), 6.41 (1H, s); m / z: (ESI +) MH + 354.31.
[000204] The mother liquids were concentrated and ground with Et2O to provide an additional batch of (R) -4- (2-chloro-6- (iodomethyl) pyrimidin-4-yl) -3-methylmorpholine (2.46 g, 12%); 1H NMR (400 MHz, CDCh) 1.32 (3H, d), 3.28 (1H, td), 3.54 (1H, td), 3.69 (1H, dd), 3.78 (1H, d), 3.98 -4.02 (2H, m), 4.21 (2H, s), 4.30 (1H, s), 6.41 (1H, s); m / z: (ESI +) MH +, 354.31.
[000205] Alternatively, this step can be performed as follows: (R) - (2-chloro-6- (3-methylmorpholine) pyrimidin-4-yl) methanesulfonate (80 g, 248.62 mmol) and iodide lithium (83 g, 621.54 mmol) were dissolved in dioxane (300 ml) and then heated to 107 ° C for 1 hour. The reaction mixture was suppressed with water (250 ml), extracted with EtOAc (3 x 250 ml). The organic layer was dried over MgSO4, filtered and evaporated. The residue was dissolved in DCM and Et2O was added, the mixture was passed through silica (4 inches) and eluted with Et2O. The product-containing fractions were evaporated and the residue was then triturated with Et2O to provide a solid that was collected by filtration and dried under vacuum to provide (R) -4- (2-chloro-6- (iodomethyl) pyrimidin- 4-yl) -3-methylmorpholine (75 g, 86%); m / z: (ESI +) MH +, 354.27. e) (R) -4- (2-Chloro-6- (iodomethyl) pyrimidin-4-yl) -3-methylmorpholine (17.0 g, 48.08 mmol) was dissolved in DMF (150 ml), this , sodium methanothio-late (3.37 g, 48.08 mmol) was added and the reaction was stirred for 1 hour at 25 ° C. The reaction mixture was suppressed with water (50 ml) and then extracted with Et2O (3 x 50 ml). The organic layer was dried over MgSO4, filtered and then evaporated. The residue was purified by medium pressure chromatography on silica, eluting with a gradient of 50 to 100% EtOAc in isohexane. The pure fractions were evaporated to provide (R) -4- (2-chloro-6- (methylthiomethyl) pyrimidin-4-yl) - 3-methylmorpholine (12.63 g, 96%); m / z: (ES +) MH +, 274.35.
[000206] Alternatively, (R) -4- (2-chloro-6- (methylthiomethyl) pyrimidin-4-yl) -3-methylmorpholine, can be prepared as shown below: In a fixed 3 L vessel, sodium thiomethoxide sodium (21% in water) (216 g, 646.69 mmol) was added dropwise over 5 minutes to a stirred solution of a mixture of approximately two thirds of (R) - (2-chloro-6- methanesulfonate (3-methylmorpholine) pyrimidin-4-yl) methyl and one third of (R) -4- (2-chloro-6- (chloromethyl) pyrimidin-4-yl) -3-methylmorpholine (130.2 g, 431 mmol ) and sodium iodide (1.762 ml, 43.11 mmol) in MeCN (1 L) at room temperature (temperature dropped from 20 ° C to 18 ° C throughout the addition and then, in the next 5 minutes increased to 30 ° Ç). The reaction mixture was stirred for 16 hours and then diluted with EtOAc (2 L), and washed sequentially with water (750 ml) and saturated brine (1 L). The organic layer was dried over MgSO4, filtered and then evaporated to provide (R) -4- (2-chloro-6- (methylthiomethyl) pyrimidin-4-yl) -3-methylmorpholine (108 g, 91%); 1H NMR (400 MHz, DMSO-de) 1.20 (3H, d), 2.07 (3H, s), 3.11 - 3.26 (1H, m), 3.44 (1H, td), 3.53 (2H, s), 3.59 (1H, dd), 3.71 (1H, d), 3.92 (1H, dd), 3.92 - 4.04 (1H, br s), 4.33 (1H, s), 6.77 (1H, s); m / z: (ES +) MH +, 274.36. f) (R) -4- (2-Chloro-6- (methylthiomethyl) pyrimidin-4-yl) -3-methylmorpholine (12.63 g, 46.13 mmol) was dissolved in DCM (100 ml), this , mCPBA (7.96 g, 46.13 mmol) was added in one portion and the reaction mixture was stirred for 10 minutes at 25 ° C. An additional portion of mCPBA (0.180 g) was added. The reaction mixture was suppressed with saturated Na2CO3 solution (50 ml) and extracted with DCM (3 x 50 ml). The organic layer was dried over MgSO4, filtered and then evaporated. The residue was dissolved in DCM (80 ml) in a 150 ml conical flask which was placed in a beaker containing Et2O (200 ml) and the system was covered with laboratory film and then left for 3 days. The obtained crystals were filtered, crushed and sonicated with Et2O. The crystallization procedure was repeated to provide (R) -4- (2-chloro-6 - ((R) -methylsulfinylmethyl) pyrimidin-4-yl) -3-methylmorpholine as white needles (3.87 g, 29%) ; 1H NMR (400 MHz, CDCh) 1.33 (3H, d), 2.62 (3H, s), 3.30 (1H, td), 3.53 (1H, td), 3.68 (1H, dd), 3.76 (2H, dd), 3.95 (1H, d), 4.00 (1H, dd), 4.02 (1H, s), 4.32 (1H, s), 6, 42 (1H, s).
[000207] The liquid remaining from the first vapor diffusion was purified by flash chromatography on silica, eluting with a gradient of 0 to 5% MeOH in DCM. The pure fractions were evaporated to provide (R) -4- (2-chloro-6 - ((S) - methylsulfinylmethyl) pyrimidin-4-yl) -3-methylmorpholine as an orange gum (5.70 g, 43%) ; 1H NMR (400 MHz, CDCh) 1.33 (3H, d), 2.62 (3H, d), 3.29 (1H, td), 3.54 (1H, td), 3.68 (1H, dd), 3.73 - 3.82 (2H, m), 3.94 (1H, dd), 4.00 (2H, dd), 4.33 (1H, s), 6.42 (1H, s ).
[000208] Alternatively, this step can be performed as follows: Sodium meta-periodate (64.7 g, 302.69 mmol) was added in a portion to (R) -4- (2-chloro-6- (methylthiomethyl) pyrimidin-4-yl) -3-methylmorpholine (82.87 g, 302.69 mmol) in water (500 ml), EtOAc (1000 ml) and MeOH (500 ml). The resulting solution was stirred at 20 ° C for 16 hours. Sodium metabisulfite (50 g) was added and the mixture was stirred for 30 minutes. The reaction mixture was filtered and then partially evaporated to remove MeOH. The organic layer was separated, dried over MgSO4, filtered and then evaporated. The aqueous layer was washed with DCM (3 x 500 ml). The organic layers were combined, dried over MgSO4, filtered and then evaporated. The residues were combined and dissolved in DCM (400 ml) and purified by medium pressure chromatography (flash) on silica, eluting with a gradient of 0 to 5% MeOH in DCM. Fractions containing the product were evaporated and the residue was dissolved in DCM (400 ml) and then divided into four 450 ml bottles. A cap of aluminum foil was placed over the top of each bottle and some holes were drilled in each cap. The flasks were placed in pairs in a large dish containing Et2O (1000 ml), and then covered and sealed with a second glass dish and left for 11 days. The resulting white needles were collected by filtration and dried under vacuum. The crystals were dissolved in DCM (200 ml) and placed in a 450 ml bottle. A cap of aluminum foil was placed over the top of the bottle and some holes were made in the cap. The flask was placed in a large dish containing Et2O (1500 ml) and then covered and sealed with a second glass dish and left for 6 days. The resulting crystals were collected by filtration and dried under vacuum to provide (R) -4- (2-chloro-6 - ((R) -methylsulfinylmethyl) pyrimidin-4-yl) -3-methylmorpholine (16.53 g, 19 %); 1H NMR (400 MHz, CDCl3) 1.33 (3H, d), 2.61 (3H, s), 3.29 (1H, td), 3.53 (1H, td), 3.68 (1H, dd), 3.76 (2H, dd), 3.95 (1H, d), 3.99 (1H, dd), 4.02 (1H, s), 4.31 (1H, s), 6, 41 (1H, s). Chiral HPLC: (HP1100 5 system, 20μm Chiralpak AD-H column (250 mm x 4.6 mm) eluting with hexane / EtOH / TEA 50/50 / 0.1) Rf, 12.192 98.2%.
[000209] The filtrate from the first vapor diffusion was concentrated in vacuo to provide an approximate 5: 2 mixture of (R) -4- (2-chloro-6 - ((S) -methylsulfinylmethyl) pyrimidin-4-yl) -3-methylmorpholine and (R) -4- (2-chloro-6 - ((R) -methylsulfinylmethyl) pyrimidin-4-yl) -3-methylmorpholine (54.7 g, 62%). [000210] Alternatively, this step can be performed as follows: Sodium meta-periodate (2.87 g, 13.44 mmol) was added in one portion to (R) -4- (2-chloro-6- ( methylthiomethyl) pyrimidin-4-yl) -3-methylmorpholine (3.68 g, 13.44 mmol) in water (10.00 ml), EtOAc (20 ml) and MeOH (10.00 ml). The resulting solution was stirred at 20 ° C for 16 hours. The reaction mixture was diluted with DCM (60 ml) and then filtered. The DCM layer was separated and the aqueous layer was washed with DCM (3 x 40 ml). The organics were combined, dried over MgSO4, filtered and then evaporated. The residue was purified by medium pressure chromatography (flash) on silica, eluting with a gradient of 0 to 7% MeOH in DCM. The pure fractions were evaporated to provide (R) -4- (2-chloro-6- (methylsulfinylmethyl) pyrimidin-4-yl) -3-methylmorpholine (2.72 g, 70%); 1H NMR (400 MHz, DMSO-de) 1.22 (3H, d), 2.64 (3H, d), 3.14 - 3.26 (1H, m), 3.45 (1H, td), 3.59 (1H, dd), 3.73 (1H, d), 3.88 - 3.96 (2H, m), 4.00 (1H, d), 4.07 (1H, dt), 4 , 33 (1H, s), 6.81 (1H, s); m / z: (ESI +) MH +, 290.43.
[000211] The (3R) -4- (2-chloro-6- (methylsulfinylmethyl) pyrimidin-4-yl) -3-methylmorpholine (2.7 g, 9.32 mmol) was purified by preparative chiral column chromatography Merck 100 mm 20 μm Chiralpak AD, eluting isocratically with a 50: 50: 0.1 mixture of iso-Hexane: EtOH: TEA as eluent. The product-containing fractions were evaporated to provide (R) -4- (2-chloro-6 - ((S) -methylsulfinylmethyl) pyrimidin-4-yl) -3-methylmorpholine (1.38 g, 51%) as the first compound to elute; 1H NMR (400 MHz, CDCl3) 1.29 (3H, dd), 2.56 (3H, s), 3.15 - 3.33 (1H, m), 3.46 (1H, tt), 3, 55 - 3.83 (3H, m), 3.85 - 4.06 (3H, m), 4.31 (1H, s), 6.37 (1H, s). Chiral HPLC: (HP1100 6 system, 20μm Chiralpak AD column (250 mm x 4.6 mm) eluting with isohexane / EtOH / TEA 50/50 / 0.1) Rf, 7.197> 99%.
[000212] E (R) -4- (2-chloro-6 - ((R) -methylsulfinylmethyl) pyrimidin-4-yl) -3-methylmorpholine (1.27 g, 47%) as the second compound to elute; 1H NMR (400 MHz, CDCh) 1.28 (3H, d), 2.58 (3H, s), 3.26 (1H, td), 3.48 (1H, td), 3.62 (1H, dt), 3.77 (2H, dd), 3.88 - 4.13 (3H, m), 4.28 (1H, s), 6.37 (1H, s). Chiral HPLC: (HP1100 6 system, 20μm Chiralpak AD column (250 mm x 4.6 mm) eluting with isohexane / EtOH / TEA 50/50 / 0.1) Rf, 16,897> 99%. g) Iodobenzene diacetate (18.98 g, 58.94 mmol) was added to (R) -4- (2-chloro-6 - ((R) -methylsulfinylmethyl) pyrimidin-4-yl) -3-methylmorpholine ( 17.08 g, 58.94 mmol), 2,2,2-trifluoroacetamide (13.33 g, 117.88 mmol), magnesium oxide (9.50 g, 235.76 mmol) and rhodium acetate dimer (II) (0.651 g, 1.47 mmol) in DCM (589 ml) under air. The resulting suspension was stirred at 20 ° C for 24 hours. Additional 2,2,2-trifluoroacetamide (13.33 g, 117.88 mmol), magnesium oxide (9.50 g, 235.76 mmol), iodobenzene diacetate (18.98 g, 58.94 mmol) and rhodium (II) acetate dimer (0.651 g, 1.47 mmol) was added and the suspension was stirred at 20 ° C for 3 days. The reaction mixture was filtered and then silica gel (100 g) was added to the filtrate and the solvent was removed in vacuo. The resulting powder was purified by flash chromatography on silica, eluting with a gradient of 20 to 50% EtOAc in isohexane. The pure fractions were evaporated to provide N - [({2-chloro-6 - [(3R) -3-methylmorpholin-4-yl] pyrimidin-4-yl} methyl) (methyl) oxide-À6- (R) - sulfanilidene] -2,2,2-trifluoroacetamide (19.39 g, 82%); 1H NMR (400 MHz, DMSO-cfe) 1.22 (3H, d), 3.17 - 3.27 (1H, m), 3.44 (1H, td), 3.59 (1H, dd), 3.62 (3H, s), 3.74 (1H, d), 3.95 (1H, dd), 4.04 (1H, br s), 4.28 (1H, s), 5.08 ( 2H, q), 6.96 (1H, s); m / z: (ESI +) MH +, 401.12 and 403.12. h) Dichlorobis (triphenylphosphine) palladium (II) (8.10 mg, 0.01 mmol) was added in one portion to N - [({2-chloro-6 - [(3R) -3-methylmorpholin-4-H ] pinmidin-4-Ha} metH) (metH) oxide ^ 6- (R) -sulfanilidene] -2,2,2-trifluoroacetamide (185 mg, 0.46 mmol), 2M aqueous Na2CO3 solution (0.277 ml, 0 , 55 mmol) and 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1-tosyl-1H-pyrrolo [2,3-b] pyridine (193 mg, 0.48 mmol) in DME: water 4: 1 (5 ml) at room temperature. The reaction mixture was stirred at 90 ° C for 1 hour, filtered and then purified by preparative HPLC using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to provide (R) -3-methyl-4- (6 - ((R) -S-methylsulfonimidoylmethyl) -2- (1-tosyl-1H-pyrrolo [2,3-b] pyridin-4-yl) pyrimidin-4-yl) morpholine (102 mg, 41%); 1H NMR (400 MHz, CDCls) 1.33 (3H, d), 3.21 - 3.38 (1H, m), 3.42 (3H, d), 3.45 - 3.57 (1H, m ), 3.61 - 3.70 (1H, m), 3.78 (1H, d), 4.01 (1H, dd), 3.90 -4.15 (1H, br s), 4.30 (1H, s), 4.64 (1H, dd), 4.84 (1H, dd), 6.49 (1H, d); m / z: (ESI +) MH +, 541.35 [000213] A 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl) -1-tosyl-1H-pyrrole [ 2,3-b] pyridine, used as a starting material, can be prepared as follows: a) To a 3L fixed vessel, 3-chlorobenzoperoxoic acid (324 g, 1444.67 mmol) was added in 1H portions -pyrrole [2,3-b] pyridine (150 g, 1244.33 mmol) in DME (750 ml) and heptane (1500 ml) at 20 ° C over a period of 1 hour under nitrogen. The resulting slurry was stirred at 20 ° C for 18 hours. The precipitate was collected by filtration, washed with DME / heptane (1/2 5 vol) (750 ml) and dried under vacuum at 40 ° C to provide 1H-pyrrole [2,3-b] pyridine 7-oxide 3-chlorobenzoate (353 g, 97%) as a cream solid, which was used without further purification; 1H NMR (400 MHz, DMSO-d6) 6.59 (1H, d), 7.07 (1H, dd), 7.45 (1H, d), 7.55 (1H, t), 7.65 ( 1H, dd), 7.70 (1H, ddd), 7.87 - 7.93 (2H, m), 8.13 (1H, d), 12.42 (1H, s), 13.32 (1H , s). b) A 2M solution of potassium carbonate (910 ml, 1819.39 mmol) was added dropwise to a stirred slurry of 1H-pyrrolo [2,3-b] pyridine 7-oxide 3-chlorobenzoate (352.6 g, 1212.93 mmol) in water (4.2 vol) (1481 ml) at 20 ° C over a period of 1 hour, adjusting the pH to 10. To the resulting slurry was added water (2 vol ) (705 ml) stirred at 20 ° C for 1 hour. The slurry was cooled to 0 ° C for 1 hour and the slurry was filtered, the solid was washed with water (3 vol of 1050ml) and dried in a vacuum oven at 40 ° C over P2O5 overnight to provide 1H-pyrrolo [2,3-b] pyridine 7-oxide (118 g, 73%); 1H NMR (400 MHz, DMSO-d6) 6.58 (1H, d), 7.06 (1H, dd), 7.45 (1H, d), 7.64 (1H, d), 8.13 ( 1H, d), 12.44 (1H, s); m / z: (ES +) (MH + MeCN) +, 176.03. c) To a fixed 3L vessel under a nitrogen atmosphere, methanesulfonic anhydride (363 g, 2042.71 mmol) was added in 1H-pyrrole [2,3-b] pyridine 7-oxide portions (137 g, 1021.36 mmol), and tetramethylammonium bromide (236 g, 1532.03 mmol) in DMF (10 vol) (1370 ml) cooled to 0 ° C, over a period of 30 minutes under nitrogen. The resulting suspension was stirred at 20 ° C for 24 hours. The reaction mixture was suppressed with water (20 vol, 2740 ml) and the reaction mixture was adjusted to pH 7 with 50% sodium hydroxide (approximately 200 ml). Water (40 vol, 5480 ml) was charged and the mixture was cooled to 10 ° C over 30 minutes. The solid was filtered, washed with water (20 vol, 2740 ml) and the solid was dissolved in DCM / methanol (4: 1, 2000 ml), dried with MgSO4 and evaporated to provide a light brown solid. The solid was poured into hot methanol (2000 ml) and water was added by dripping until the solution became cloudy and was left overnight. The solid was removed by filtration and discarded, the solution was evaporated and the solid was recrystallized from MeCN (4000 ml). The solid was filtered and washed with MeCN to provide 4-bromo-1H-pyrrolo [2,3-b] pyridine (68.4 g, 34%) as a pink solid; 1H NMR (400 MHz, DMSO-ch) 6.40 - 6.45 (1H, m), 7.33 (1H, d), 7.57 - 7.63 (1H, m), 8.09 (1H , t), 12.02 (1H, s); m / z: (ES +) MH +, 198.92. The raw mother liquids were purified by Companion RF (reverse phase C18 column, 415g), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents (starting at 26% to 46% MeCN). Fractions containing the desired compound were evaporated to provide 4-bromo-1H-pyrrolo [2,3-b] pyridine (5.4 g, 3%) as a pink solid; 1H NMR (400 MHz, DMSO-cfe) 6.43 (1H, dd), 7.33 (1H, d), 7.55 -7.66 (1H, m), 8.09 (1H, d), 12.03 (1H, s); m / z: (ES +) MH +, 199.22. d) Sodium hydroxide (31.4 ml, 188.35 mmol) was added to 4-bromo-1H-pyrrolo [2,3-b] pyridine (10.03 g, 50.91 mmol), tosyl chloride ( 19.41 g, 101.81 mmol) and tetrabutylammonium hydrogen sulfate (0.519 g, 1.53 mmol) in DCM (250 ml) at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The reaction was suppressed by the addition of saturated aqueous NH4Cl, the organic layer was removed and the aqueous layer was further extracted with DCM (3 x 25 ml). The combined organics were washed with brine (100 ml), dried with Na2SO4 and then concentrated under reduced pressure. The residue was purified by medium pressure chromatography (flash) on silica, eluting with a gradient of 0 to 20% EtOAc in isohexane. The pure fractions were evaporated to provide 4-bromo-1-tosyl-1H-pyrrolo [2,3-b] pyridine (14.50 g, 81%); 1H NMR (400 MHz, CDCl3) 2.38 (3H, s), 6.64 (1H, d), 7.28 (2H, d), 7.36 (1H, d), 7.78 (1H, d), 8.06 (2H, d), 8.22 (1H, d); m / z: (ES +) MH +, 353.23. e) 1,1'-Bis (diphenylphosphino) ferrocenodichloropalladium (II) (3.37 g, 4.13 mmol) was added in one portion to 4-bromo-1-tosyl-1H-pyrrole [2,3-b] pyridine (14.5 g, 41.28 mmol), bis (pinacolate) diboro (20.97 g, 82.57 mmol) and potassium acetate (12.16 g, 123.85 mmol) in anhydrous DMF (300 ml ) at room temperature. The resulting mixture was stirred under nitrogen at 90 ° C for 24 hours. After cooling to room temperature, 1N aqueous NaOH was added until the aqueous layer was at pH 10. The aqueous layer was washed with DCM (1L), carefully acidified to pH 4 with 1N aqueous HCl, and then extracted with DCM (3 x 300 ml). The organic layer was concentrated under reduced pressure to provide a dark brown solid. The solid was triturated with diethyl ether, filtered and dried to provide 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1-tosyl-1H-pyrrole [2,3 -b] pyridine (7.058 g, 43%); 1H NMR (400 MHz, CDCh) 1.36 (12H, s), 2.35 (3H, s), 7.01 (1H, d), 7.22 (2H, d), 7.52 (1H, d), 7.74 (1H, d), 8.03 (2H, m), 8.42 (1H, d); m / z: (ES +) MH +, 399.40. The mother liquids were concentrated in vacuo and the residue was triturated in isohexane, filtered and dried to provide an additional sample of 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) - 1-tosyl-1H-pyrrolo [2,3-b] pyridine (3.173 g, 19%); 1H NMR (400 MHz, CDCh) 1.36 (12H, s), 2.35 (3H, s), 7.01 (1H, d), 7.23 (2H, d), 7.52 (1H, d), 7.74 (1H, d), 8.03 (2H, d), 8.42 (1H, d); m / z: (ES +) MH +, 399.40.
Example 2.01 and Example 2.02 4- {4 - [(3R) -3-methylmorpholin-4-yl] -6- [1 - ((S) -S-methylsulfonimidoyl) cyclopropyl] pyrimidin-2-yl} -1H-pyrrole [2,3-b] pyridine, and 4- {4 - [(3R) -3-methylmorpholin-4-yl] -6- [1 - ((R) -S-methylsulfonimidoyl) cyclopropyl] pyrimidin-2-yl } -1H-pyrrolo [2,3-b] pyridine [000214] (3R) -3-Methyl-4- (6- (1- (S-methylsulfonimidoyl) cyclopropyl) -2- (1-tosyl-1H-pyrrole [2,3-b] pyridin-4-yl) pyrimidin-4-yl) morpholine (1.67 g, 2.95 mmol) was dissolved in DME: water 4: 1 (60 ml) and heated to 50 ° C . Sodium hydroxide, 2M aqueous solution (2.58 ml, 5.16 mmol) was then added and heating continued for 18 hours. The reaction mixture was acidified with 2M HCl (~ 2 ml) to pH 5. The reaction mixture was evaporated to dryness and the residue was dissolved in EtOAc (250 ml), and washed with water (200 ml). The organic layer was dried over MgSO4, filtered and evaporated on silica gel (10 g). The resulting powder was purified by medium pressure chromatography on silica, eluting with a gradient of 0 to 7% MeOH in DCM. The pure fractions were evaporated and the residue was purified by preparative chiral chromatography on a Merck 50mm column, 20μm ChiralCel OJ, eluting isocratically with 50% isohexane in EtOH / MeOH (1: 1) (modified with TEA) as eluant. Fractions containing the desired compound were evaporated to dryness to provide the title compound: 4- {4 - [(3R) -3-methylmorpholin-4-yl] -6- [1 - ((R) -S-methylsulfonimidoil ) cyclopropyl] pyrimidin-2-yl} -1H-pyrrolo [2,3-b] pyridine (0.538g, 44%) as the first compound to elute; 1H NMR (400 MHz, DMSO-d6) 1.29 (3H, d), 1.51 (3H, m), 1.70 - 1.82 (1H, m), 3.11 (3H, s), 3.28 (1H, m, hidden by water peak), 3.48 - 3.60 (1H, m), 3.68 (1H, dd), 3.75 - 3.87 (2H, m), 4.02 (1H, dd), 4.19 (1H, d), 4.60 (1H, s), 7.01 (1H, s), 7.23 (1H, dd), 7.51 - 7 , 67 (1H, m), 7.95 (1H, d), 8.34 (1H, d), 11.76 (1H, s); m / z: (ES +) MH +, 413.12. Chiral HPLC: (HP1100 4 system, 5μm Chiralcel OJ-H column (250 mm x 4.6 mm) eluting with isohexane / EtOH / MeOH / TEA 50/25/25 / 0.1) Rf, 9.013> 99 %. The crystals were cultured and isolated by slow evaporation to dryness in air from EtOAc. These crystals were used to obtain the structure shown in figure 1 by X-ray diffraction (see below). Example 2.02: 4- {4 - [(3R) -3-methylmorpholin-4-yl] -6- [1 - (((R) -S-methylsulfonimidoyl) cyclopropyl] pyrimidin-2-yl} -1H-pyrrole [2 , 3-b] pyridine (326 mg, 0.79 mmol) was dissolved in DCM (3 ml). Silica gel (0.5 g) was added and the mixture was concentrated in vacuo. The resulting powder was purified by flash chromatography on silica, eluting with a gradient of 0 to 5% MeOH in DCM. The pure fractions were evaporated to dryness and the residue was crystallized from EtOAc / n-heptane to provide 4- {4 - [(3R) -3-methylmorpholin-4-yl] -6- [1 - ((R ) -S-methylsulfonimidoyl) cyclopropyl] pyrimidin -2-yl} -1H-pyrrolo [2,3-b] pyridine (256 mg, 79%) as a white crystalline solid; 1H NMR (400 MHz, DMSO-d6) 1.29 (3H, d), 1.39 - 1.60 (3H, m), 1.71 - 1.81 (1H, m), 3.10 (3H , d), 3.21 - 3.29 (1H, m), 3.52 (1H, td), 3.67 (1H, dd), 3.80 (2H, t), 4.01 (1H, dd), 4.19 (1H, d), 4.59 (1H, s), 7.01 (1H, s), 7.23 (1H, dd), 7.54 - 7.62 (1H, m ), 7.95 (1H, d), 8.34 (1H, d), 11.75 (1H, s). DSC peak (Mettler-Toledo DSC 820, sample run at a heating rate of 10 ° C per minute from 30 ° C to 350 ° C in a perforated aluminum pan), 224.11 ° C.
[000215] And the title compound: 4- {4 - [(3R) -3-methylmorpholin-4-yl] -6- [1 - ((S) -S-methylsulfonimidoyl) cyclopropyl] pyrimidin-2-yl} -1H-pyrrolo [2,3-b] pyridine (0.441 g, 36%) as the second compound to elute; 1H NMR (400 MHz, DMSO-d6) 1.28 (3H, d), 1.40 - 1.58 (3H, m), 1.70 - 1.80 (1H, m), 3.10 (3H , d), 3.23 - 3.27 (1H, m), 3.51 (1H, dt), 3.66 (1H, dd), 3.80 (2H, d), 4.01 (1H, dd), 4.21 (1H, d), 4.56 (1H, s), 6.99 (1H, s), 7.22 (1H, dd), 7.54 - 7.61 (1H, m ), 7.94 (1H, d), 8.33 (1H, d), 11.75 (1H, s); m / z: (ES +) MH +, 413.12. Chiral HPLC: (HP1100 4 system, 5μm Chiralcel OJ-H column (250 mm x 4.6 mm) eluting with isohexane / EtOH / MeOH / TEA 50/25/25 / 0.1) Rf, 15.685> 99 %. Example 2.01: 4- {4 - [(3R) -3-methylmorpholin-4-yl] -6- [1 - ((S) -S-methylsulfonimidoyl) cyclopropyl] pyrimidin-2-yl} -1H-pyrrole [2,3-b] pyridine (66.5 mg) was purified by crystallization from EtOH / water to provide 4- {4 - [(3R) -3-methylmorpholin-4-yl] -6- [1- ((S) -S-methylsulfonimidoyl) cyclopropyl] pyrimidin-2-yl} -1H-pyrrolo [2,3-b] pyridine (0.050 g); 1H NMR (400 MHz, CDCl3) 1.40 (3H, d), 1.59 (2H, s), 1.81 (2H, s), 2.41 (1H, s), 3.16 (3H, s), 3.39 (1H, td), 3.59 - 3.67 (1H, m), 3.77 (1H, dd), 3.86 (1H, d), 4.07 (1H, dd ), 4.17 (1H, d), 4.54 (1H, s), 6.91 (1H, s), 7.34 (1H, t), 7.43 (1H, t), 8.05 (1H, d), 8.41 (1H, d), 9.14 (1H, s).
Crystal X-ray diffraction from the first eluted compound (structure shown in figure 1) C20H24N6O2S crystal data
Mr = 412.52 V = 1026.4 (2) Â3 Triclinic, P1 Z = 2 a = 10.1755 (13) Â Mo Ka, radiation λ = 0.71073 Â b = 10.4411 (13) Â μ = 0.19 mm-1 c = 11.2879 (14) Â T = 200 K α = 95.528 (2) ° 0.20 χ 0.10 χ 0.05 mm β = 108.796 (2) ° γ = 111.292 (2 ) ° Bruker APEX-II CCD 14550 diffractometer data collection independent reflections Absorption correction: Multi-scan 9935 reflections with I> 2σ (Ι) Tmin = 0.964, Tmax = 0.991 Rint = 0.024 18381 measured reflections RF2> 2σ (^) ] = 0.056 constricted H atom parameters wR (F2) = 0.147 Δρmax = 0.31 and Â-3 S = 1.02 Δρmin = -0.38 and Â-3 14550 reflections Absolute structure: Flack HD (1983), Acta Cryst.A39, 876- 881 parameter Flack: 0.03 (5) 527 parameters 3 restrictions [000216] A (3R) -3-methyl-4- (6- (1- (S-methylsulfonimidoyl) cyclopropyl) -2 - (1-tosyl-1H-pyrrolo [2,3-b] pyridin-4-yl) pyrimidin-4-yl) morpholine, used as a starting material, can be prepared as follows: a) Iodobenzene diacetate (6 , 54 g, 20.29 mmol) fo i added to (3R) -4- (2-chloro-6- (methylsulfinylmethyl) pyrimidin-4-yl) -3-methylmorpholine (5.88 g, 20.29 mmol), 2,2,2-trifluoroacetamide (4 , 59 g, 40.58 mmol), magnesium oxide (3.27 g, 81.16 mmol) and rhodium (II) acetate dimer (0.224 g, 0.51 mmol) in DCM (169 ml) under air . The resulting suspension was stirred at room temperature for 3 days. Additional 2,2,2-trifluoroacetamide (1.15 g, 10.15 mmol), magnesium oxide 0.818 g, 20.29 mmol), rhodium (II) dimer (0.056 g, 0.13 mmol) and iodobenzene diacetate (1.64 g, 5.07 mmol) was added and the suspension was stirred at room temperature for an additional 24 hours. The reaction mixture was filtered and silica gel (3 g) was added to the filtrate, and then the mixture was evaporated. The resulting powder was purified by medium pressure chromatography (flash) on silica, eluting with a gradient of 20 to 50% EtOAc in isohexane. Fractions containing the product were evaporated and the residue was triturated with isohexane / methyl tert-butyl ether to provide a solid that was collected by filtration and dried under vacuum to provide N - [({2-chloro-6 - [(3R) -3-methylmorpholin-4-yl] pyrimidin-4-yl} methyl) (methyl) oxide ^ 6-sulfanilidene] -2,2,2-trifluoroacetamide (6.64 g, 82%); 1H NMR (400 MHz, CDCl3) 1.33 (3H, d), 3.28 (1H, dd), 3.43 (3H, d), 3.46 - 3.59 (1H, m), 3, 62 - 3.71 (1H, m), 3.79 (1H, d), 3.90 - 4.50 (2H, br s), 4.21 (1H, s), 4.66 (1H, dd ), 4.86 (1H, dd), 6.50 (1H, d); m / z: (ES +) MH +, 401.01, 402.93. b) Sodium hydroxide (Sigma-Aldrich 415413, d = 1.515 g / ml, 50 ml of a 50% solution, 937.57 mmol) was added to N - [({2-chloro-6 - [(3R) -3-metHmorfolin-4-H] pinmidin-4-yl} methyl) (metH) oxide ^ 6-sulfanilidene] -2,2,2-trifluoroacetamide (5.2 g, 12.97 mmol), 1.2- dibromoethane (4.47 ml, 51.90 mmol) and tetrabutylammonium hydrogen sulfate (0.441 g, 1.30 mmol) in toluene (500 ml). The resulting mixture was stirred at room temperature for 24 hours. Additional 1,2-dibromoethane (1.00 ml, 11.60 mmol) was added and the mixture was stirred at room temperature for an additional 2 hours. The reaction mixture was diluted with EtOAc (500 ml), and washed sequentially with water (750 ml) and saturated brine (100 ml). The organic layer was dried over MgSO4, filtered and evaporated. The residue was dissolved in DCM (100 ml) and then purified by medium pressure chromatography (flash) on silica, eluting with a gradient of 0 to 5% MeOH in DCM. The pure fractions were evaporated to dryness to provide (3R) -4- (2-chloro-6- (1- (S-methylsulfonimidoyl) cyclopropyl) pyrimidin-4-yl) -3-methylmorpholine (1.383 g, 32%) ; 1H NMR (400 MHz, CDCh) 1.32 (3H, d), 1.39 - 1.48 (2H, m), 1.69 - 1.77 (2H, m), 3.12 (3H, s ), 3.22 - 3.36 (1H, m), 3.54 (1H, td), 3.68 (1H, dd), 3.78 (1H, d), 3.90 - 4.10 ( 1H, br s), 4.00 (1H, dd), 4.33 (1H, br s), 6.79 (1H, d); m / z: (ES +) MH +, 331.08, 333.00.
[000217] Alternatively, this step can be done as follows: Sodium hydroxide (Sigma-Aldrich 415413, d = 1.515 g / ml, 217 ml of a 50% solution, 4059.84 mmol) was added to N- [ ({2-chloro-6 - [(3R) -3-methylmorpholin-4-yl] pyrimidin-4-yl} methyl) (methyl) oxide ^ 6-sulfanilidene] -2,2,2-trifluoroacetamide (27,12 g, 67.66 mmol), 1,2-dibromoethane (23.32 ml, 270.66 mmol) and tetraoctylammonium bromide (3.70 g, 6.77 mmol) in methyl THF (1000 ml) at 20 ° C under nitrogen. The resulting mixture was stirred at 20 ° C for 24 hours. Additional 1,2-dibromoethane (23.32 ml, 270.66 mmol) was added and the mixture was stirred at 20 ° C for an additional 24 hours. The reaction mixture was diluted with methyl THF (1000 ml) and the aqueous layer was separated. The organic layer was further diluted with EtOAc (1000 ml) and washed with water (1500 ml). The organic layer was dried over MgSO4, filtered and then evaporated. The residue was purified by flash chromatography on silica, eluting with a gradient of 0 to 5% MeOH in DCM. The pure fractions were evaporated to provide (3R) -4- (2-chloro-6- (1- (S-methylsulfonimidoyl) cyclopropyl) pyrimidin-4-yl) -3-methylmorpholine (14.80 g, 66%); 1H NMR (400 MHz, DMSO-d6) 1.21 (3H, d), 1.39 (3H, m), 1.62 - 1.71 (1H, m), 3.01 (3H, s), 3.43 (1H, tt), 3.58 (1H, dd), 3.72 (1H, d), 3.82 (1H, d), 3.93 (1H, dd), 4.01 (1H , s), 4.38 (1H, s), 6.96 (1H, d); m / z: (ES +) MH +, 331.46 and 333.43. d) Dichlorobis (triphenylphosphine) palladium (II) (0.073 g, 0.10 mmol) was added in one portion to (3R) -4- (2-chloro-6- (1- (S-methylsulfonimidoyl) cyclopropyl) pyrimidin- 4-yl) -3-methylmorpholine (1.383 g, 4.18 mmol), 2M aqueous sodium carbonate solution (2.50 ml, 5.02 mmol) and 4- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolane-2-yl) -1-tosyl-1H-pyrrolo [2,3-b] pyridine (1,665 g, 4.18 mmol) in DME: water 4: 1 (100 ml) under nitrogen. The reaction mixture was stirred at 90 ° C for 6 hours. The reaction mixture was concentrated and diluted with EtOAc (400 ml), and washed sequentially with water (300 ml) and saturated brine (75 ml). The organic layer was dried over MgSO4, filtered and evaporated on silica gel (30 g). The resulting powder was purified by flash chromatography on silica, eluting with a gradient of 0 to 5% MeOH in DCM. The pure fractions were evaporated to dryness to provide (3R) -3-methyl-4- (6- (1- (S-methylsulfonimidoyl) cyclopropyl) -2- (1-tosyl-1H-pyrrole [2,3-b ] pyridin-4-yl) pyrimidin-4-yl) morpholine (2.174 g, 92%); 1H NMR (400 MHz, CDCl3) 1.37 (3H, d), 1.56 (2H, m), 1.83 (2H, q), 2.37 (4H, s), 3.16 (3H, s), 3.36 (1H, td), 3.60 (1H, td), 3.74 (1H, dd), 3.85 (1H, d), 4.01 - 4.19 (2H, m ), 4.49 (1H, s), 6.95 (1H, d), 7.28 (2H, d, hidden by CDCL3 peak), 7.44 (1H, t), 7.82 (1H, d), 8.02 - 8.11 (3H, m), 8.52 (1H, d); m / z: (ES +) MH +, 567.11.
[000218] Alternatively, Example 2.01 and Example 2.02, can be prepared as shown below: sodium hydroxide, 2M aqueous solution (9.95 ml, 19.90 mmol) was added to (3R) -3-methyl -4- (6- (1- (S-methylsulfonimidoyl) cyclopropyl) -2- (1-tosyl-1H-pyrrolo [2,3-b] pyridin-4-yl) pyrimidin-4-yl) morpholine (6, 44 g, 11.37 mmol) in DME (100 ml) / water (25.00 ml). The resulting solution was stirred at 50 ° C for 18 hours. Additional NaOH, 2M aqueous solution (18 ml, 36.00 mmol), was added and the mixture was stirred at 50 ° C for an additional 3 days. The reaction mixture was acidified with 2M HCl (~ 22 ml) to pH5. The reaction mixture was evaporated and the residue was dissolved in DCM (250 ml), and washed with water (200 ml). The organic layer was dried over MgSO4, filtered and then evaporated to approximately 50 ml by volume. The solution was purified by medium pressure chromatography (flash) on silica, eluting with a gradient of 0 to 7% MeOH in DCM. The pure fractions were evaporated to provide 4- {4 - [(3R) -3-methylmorpholin-4-yl] - 6- [1- (S-methylsulfonimidoyl) cyclopropyl] pyrimidin-2-yl} -1H-pyrrole [2 , 3-b] pyridine (2.440 g, 52%); 1H NMR (400 MHz, DMSO-d6) 1.27 (3H, d), 1.42 (1H, dd), 1.47 - 1.58 (2H, m), 1.68 - 1.80 (1H , m), 3.10 (3H, s), 3.24 - 3.31 (1H, m), 3.51 (1H, t), 3.66 (1H, dd), 3.80 (1H, d), 3.83 - 3.88 (1H, m), 4.00 (1H, dd), 4.20 (1H, s), 4.57 (1H, s), 6.99 (1H, d ), 7.22 (1H, dd), 7.53 - 7.63 (1H, m), 7.94 (1H, d), 8.34 (1H, t), 11.80 (1H, s) ; m / z: (ES +) MH +, 413.47.
[000219] In a separate experiment, NaOH, 2M aqueous solution (7.60 ml, 15.19 mmol), was added to (3R) -3-methyl-4- (6- (1- (S-methylsulfonimidoyl) cyclopropyl) -2- (1-tosyl-1H-pyrrolo [2,3-b] pyridin-4-yl) pyrimidin-4-yl) morpholine (4.92 g, 8.68 mmol) in DME (100 ml) / water (25.00 ml). The resulting solution was stirred at 50 ° C for 18 hours. The reaction mixture was acidified with 2M HCl (~ 5 ml) to pH5. The reaction mixture was evaporated and the residue was dissolved in DCM (250 ml), and washed with water (200 ml). The organic layer was dried over MgSO4, filtered and then evaporated to approximately 50 ml by volume. The resulting solution was purified by medium pressure chromatography on silica, eluting with a gradient of 0 to 7% MeOH in DCM. The pure fractions were evaporated to dryness to provide 4- {4 - [(3R) -3-methylmorpholin-4-yl] -6- [1- (S-methylsulfonimidoyl) cyclopropyl] pyrimidin-2-yl} -1H- pyrrolo [2,3-b] pyridine (2,160 g, 60%); 1H NMR (400 MHz, DMSO-d6) 1.28 (3H, d), 1.41 - 1.59 (3H, m), 1.76 (1H, dt), 3.10 (3H, d), 3.31 (1H, d), 3.52 (1H, t), 3.67 (1H, dd), 3.80 (2H, d), 4.01 (1H, dd), 4.21 (1H , d), 4.58 (1H, s), 7.00 (1H, d), 7.22 (1H, dd), 7.54 - 7.63 (1H, m), 7.95 (1H, d), 8.33 (1H, d), 11.75 (1H, s); m / z: (ES +) MH +, 413.19.
[000220] The two samples of 4- {4 - [(3R) -3-methylmorpholin-4-yl] -6- [1- (S-methylsulfonimidoyl) cyclopropyl] pyrimidin-2-yl} -1H-pyrrole [2 , 3-b] pyridine were combined (4.56 g, 11.05 mmol) and purified by preparative chiral chromatography on a Merck 100mm ChiralCel OJ column (1550g), eluting isocratically with 50% isohexane in EtOH / MeOH (1: 1) (modified with TEA) as eluent. The fractions containing the first compound to be eluted were combined and evaporated. The residue was dissolved in DCM (50 ml) and concentrated in vacuo on silica (20 g). The resulting powder was purified by medium pressure chromatography on silica, eluting with a gradient of 0 to 7% MeOH in DCM. The pure fractions were evaporated to provide the title compound 4- {4 - [(3R) -3-methylmorpholin-4-yl] -6- [1 - ((R) -S-methylsulfonimi-doyl) cyclopropyl] pyrimidin- 2-yl} -1H-pyrrolo [2,3-b] pyridine (1,789 g, 39%); 1H NMR (400 MHz, DMSO-d6) 1.27 (3H, d), 1.43 (1H, dd), 1.46 - 1.58 (2H, m), 1.69 - 1.77 (1H , m), 3.10 (3H, s), 3.27 (1H, td), 3.51 (1H, td), 3.66 (1H, dd), 3.80 (1H, d), 3 , 85 (1H, s), 4.01 (1H, dd), 4.19 (1H, d), 4.59 (1H, s), 6.99 (1H, s), 7.22 (1H, dd), 7.54 - 7.63 (1H, m), 7.94 (1H, d), 8.33 (1H, d), 11.80 (1H, s); m / z: (ES +) MH +, 413.50. Chiral HPLC: (Kronlab prep system, 20μm Chiralpak OJ column (250 mm x 4.6 mm) eluting with hexane / EtOH / MeOH / TEA 50/25/25 / 0.1) Rf, 9.684 99.4%.
[000221] The fractions containing the second compound to be eluted were combined and evaporated. The residue was dissolved in DCM (50 ml) and concentrated in vacuo on silica gel (20 g). The resulting powder was purified by medium pressure chromatography on silica, eluting with a gradient of 0 to 7% MeO in DCM. The pure fractions were evaporated to provide the title compound 4- {4 - [(3R) -3-methylmorpholin-4-yl] -6- [1 - ((S) -S-methylsulfonimidoyl) cyclopropyl] pyrimidin-2- yl} -1H-pyrrolo [2,3-b] pyridine (2.85 g, 62%); 1H NMR (400 MHz, DMSO-d6) 1.27 (3H, d), 1.38 - 1.46 (1H, dd), 1.51 (2H, m), 1.72 - 1.81 (1H , m), 3.10 (3H, s), 3.26 (1H, td), 3.51 (1H, td), 3.66 (1H, dd), 3.80 (1H, d), 3 , 84 (1H, s), 3.94 - 4.04 (1H, dd), 4.21 (1H, d), 4.56 (1H, s), 6.99 (1H, s), 7, 22 (1H, dd), 7.53 - 7.63 (1H, m), 7.94 (1H, d), 8.33 (1H, d), 11.80 (1H, s); m / z: (ES +) MH +, 413.53. Chiral HPLC: (Kronlab prep system, 20μm Chiralpak OJ column (250 mm x 4.6 mm) eluting with hexane / EtOH / MeOH / TEA 50/25/25 / 0.1) Rf, 18.287 99.3%.
[000222] Example 2.02 can also be prepared as follows: dichlorobis (triphenylphosphine) palladium (II) (2.59 mg, 3.69 μmol) was added in one portion to (3R) -4- (2-chloro-6- (1 - (((R) -S-methylsulfonimidoyl) cyclopropyl) pyrimidin-4-yl) -3-methylmorpholine (63 mg, 0.15 mmol), 2M aqueous Na2CO3 solution (0.089 ml, 0.18 mmol) and 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolano-2-yl) -1-tosyl-1H-pyrrolo [2,3-b] pyridine (58.8 mg, 0.15 mmol) in DME: 4: 1 water (5 ml) at room temperature. The reaction mixture was stirred at 90 ° C for 4 hours. Sodium hydroxide, 2M aqueous solution (0.131 ml, 0.26 mmol), was added and the mixture was heated at 50 ° C for 18 hours. The reaction mixture was acidified with 2M HCl to pH7. The reaction mixture was filtered and then purified by preparative HPLC using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. The pure fractions were evaporated and the residue was triturated with isohexane and Et2O to provide a solid that was collected by filtration and dried under vacuum to provide the title compound (44.0 mg, 71%); 1H NMR (400 MHz, DMSO-d6) 1.29 (3H, d), 1.40 - 1.61 (3H, m), 1.70 - 1.81 (1H, m), 3.10 (3H , d), 3.53 (1H, dd), 3.68 (1H, dd), 3.77 - 3.87 (2H, m), 4.02 (1H, dd), 4.19 (1H, d), 4.58 (1H, s), 7.01 (1H, d), 7.23 (1H, dd), 7.55 - 7.61 (1H, m), 7.95 (1H, d ), 8.34 (1H, d), 11.75 (1H, s); m / z: (ES +) MH +, 413.19. Chiral HPLC: (HP1100 4 system, 5μm Chiralcel OJ-H column (250 mm x 4.6 mm) eluting with isohexane / EtOH / MeOH / TEA 50/25/25 / 0.1) Rf, 9.023 88, 0%, 15.796 12.0%.
[000223] A (3R) -4- (2-chloro-6- (1 - ((R) -S-methylsulfonimidoyl) cyclopropyl) pyrimidin-4-yl) -3-methylmorpholine, used as a starting material, can be prepared as follows: sodium hydroxide (Sigma-Aldrich 415413, d = 1.515 g / ml, 155 ml of a 50% solution, 2902.66 mmol) was added to N - [({2-chloro-6- [ (3R) -3-methylmorpholin-4-yl] pinmidin-4-yl} methyl) (methyl) oxide ^ 6- (R) -sulfanilidene] -2,2,2-trifluoroacetamide (19.39 g, 48.38 mmol), 1,2-dibromoethane (16.68 mL, 193.51 mmol) and tetraoctylammonium bromide (2.65 g, 4.84 mmol) in methyl THF (1000 ml) at 20 ° C under nitrogen. The resulting mixture was stirred at 20 ° C for 24 hours. The reaction mixture was diluted with methyl THF (1000 ml) and the aqueous layer was separated. The organic layer was further diluted with EtOAc (1000 ml) and then washed with water (1500 ml). The organic layer was dried over MgSO4, filtered and evaporated. The residue was purified by flash chromatography on silica, eluting with a 0 to 5% MeOH gradient in DCM. The pure fractions were evaporated to dryness to provide (3R) -4- (2-chloro-6- (1 - ((R) -S-methylsulfonimidoyl) cyclopropyl) pyrimidin-4-yl) -3-methylmorpholine (6, 88 g, 43%); 1H NMR (400 MHz, CDCh) 1.32 (3H, d), 1.43 (2H, q), 1.72 (2H, q), 2.35 (1H, s), 3.09 (3H, s), 3.29 (1H, td), 3.53 (1H, td), 3.67 (1H, dd), 3.78 (1H, d), 4.00 (2H, dd), 4, 32 (1H, s), 6.79 (1H, s); m / z: (ES +) MH +, 331.18 and 333.15.
[000224] Example 2.02 can also be prepared as follows: A 2M NaOH solution (14.86 ml, 29.72 mmol) was added to (3R) -3-methyl-4- (6- (1- ((R) -S-methylsulfonimidoyl) cyclopropyl) -2- (1-tosyl-1H-pyrrolo [2,3-b] pyridin-4-yl) pyrimidin-4-yl) morpholine (8.42 g, 14, 86 mmol) in DME: 4: 1 water (134 ml). The resulting solution was stirred at room temperature for 4 days. In a separate experiment, a 2M NaOH solution (7.06 ml, 14.12 mmol) was added to (3R) -3-methyl-4- (6- (1 - ((R) -S-methylsulfonimidoyl) cyclopropyl) -2- (1-tosyl-1H-pyrrolo [2,3-b] pyridin-4-yl) pyrimidin-4-yl) morpholine (4 g, 7.06 mmol) in DME: water 4: 1 ( 63.5 ml). The resulting solution was stirred at room temperature for 18 hours. The reaction mixtures from the two procedures were combined and then neutralized with 2M HCl. The mixture was evaporated on reverse phase silica gel (40 g) and the resulting powder was purified by medium pressure chromatography on reverse phase silica, eluting with a gradient of 20 to 60% ACN in water with 1% ammonia . The pure fractions were evaporated to dryness to provide the title compound (7.05 g, 78%); 1H NMR (400 MHz, DMSO-d6) 1.27 (3H, t), 1.39 - 1.6 (3H, m), 1.7 - 1.8 (1H, m), 3.10 (3H , s), 3.26 (1H, d), 3.52 (1H, td), 3.67 (1H, dd), 3.80 (2H, t), 3.97 - 4.02 (1H, m), 4.19 (1H, d), 4.59 (1H, s), 7.00 (1H, s), 7.22 (1H, dd), 7.53 - 7.61 (1H, m ), 7.95 (1H, d), 8.33 (1H, d), 11.75 (1H, s); m / z: (ES +) MH +, 413.08.
[000225] A (3R) -3-methyl-4- (6- (1 - ((R) -S-methylsulfonimidoyl) cyclopropyl) -2- (1-tosyl-1H-pyrrolo [2,3-b] pyridin -4-yl) pyrimidin-4-yl) morpholine, used as a starting material, can be prepared as follows: a) A solution of 4- (4,4,5,5-tetramethyl-1,3,2- dioxaborolane-2-yl) -1-tosyl-1H-pyrrolo [2,3-b] pyridine (21.15 g, 53.11 mmol) in DME (212 ml) was added to a solution of (3R) -4 - (2-chloro-6- (1 - ((R) -S-methylsulfonimidoyl) cyclopropyl) pyrimidin-4-yl) -3-methylmorpholine (12.55 g, 37.93 mmol) in DME: water 4: 1 (55 ml). 2M aqueous sodium carbonate solution (22.76 ml, 45.52 mmol) and di-chlorobis (triphenylphosphine) palladium (II) (0.666 g, 0.95 mmol) were added. The resulting solution was stirred at 90 ° C for 2 hours under nitrogen. The reaction mixture was diluted with EtOAc (400 ml), and washed with water (400 ml). The organic layer was dried over MgSO4, filtered and evaporated. The residue was dissolved in DCM (100 ml) and a portion was purified by flash chromatography on silica, eluting with a gradient of 0 to 5% MeOH in DCM. The pure fractions were evaporated to provide (3R) -3-methyl-4- (6- (1 - ((R) -S-methylsulfonimidoyl) cyclopropyl) -2- (1-tosyl-1H-pyrrole [2,3- b] pyridin-4-yl) pyrimidin-4-yl) morpholine (8.42 g, 39%); 1H NMR (400 MHz, CDCls) 1.36 (3H, d), 1.52 (2H, dd), 1.80 (2H, dd), 2.24 - 2.46 (3H, s), 3, 10 (3H, s), 3.36 (1H, td), 3.60 (1H, td), 3.74 (1H, dd), 3.84 (1H, d), 3.99 - 4.18 (2H, m), 4.47 (1H, s), 6.91 (1H, s), 7.23 - 7.3 (3H, m, hidden by CDCh), 7.45 (1H, d), 7.81 (1H, d), 8.08 (3H, dd), 8.51 (1H, d); m / z: (ES +) MH +, 567.4.
[000226] The rest of the material was evaporated and the residue was dissolved in DCM (500 ml) and concentrated in vacuo on silica (100 g). The resulting powder was purified by flash chromatography on silica, eluting with a gradient of 0 to 5% MeOH in DCM. The pure fractions were evaporated to dryness to provide (3R) -3-methyl-4- (6- (1 - ((R) - S-methylsulfonimidoyl) cyclopropyl) -2- (1-tosyl-1H-pyrrole [2 , 3-b] pyridin-4-yl) pyrimidin-4-yl) morpholine (4.00 g, 19%); 1H NMR (400 MHz, DMSO-d6) 1.19 - 1.31 (3H, m), 1.37 - 1.58 (3H, m), 1.75 (1H, ddd), 2.34 (3H , s), 3.04 (3H, d), 3.2 - 3.27 (1H, m), 3.46 - 3.54 (1H, m), 3.65 (1H, dd), 3, 78 (1H, d), 3.82 (1H, s), 3.99 (1H, dd), 4.16 (1H, d), 4.54 (1H, s), 7.04 (1H, s ), 7.42 (2H, d), 7.54 (1H, d), 8.01 (3H, dd), 8.10 (1H, d), 8.49 (1H, d); m / z: (ES +) MH +, 567.00.
[000227] Example 2.02 can also be prepared as follows: a 2M NaOH solution (0.2 ml, 0.40 mmol) was added to (3R) -3-methyl-4- (6- (1- ((R) -S-methylsulfonimidoyl) cyclopropyl) -2- (1-tosyl-1H-pyrrolo [2,3-b] pyridin-4-yl) pyrimidin-4-yl) morpholine (0.107 g, 0.19 mmol ) in DME: 4: 1 water (4 ml). The resulting solution was stirred at 50 ° C for 18 hours and then more 2M NaOH solution (0.2 ml, 0.40 mmol) was added and the solution was stirred at 50 ° C for 3 hours. The reaction mixture was evaporated to dryness and the residue was dissolved in DCM (10 ml), and washed with water (10 ml). The organic layer was dried over MgSO4, filtered and then evaporated. The residue was purified by preparative HPLC (Waters SunFire column, 5μ silica, 19 mm in diameter, 100 mm in length), using decreasingly polar mixtures of water (containing 0.1% formic acid) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to provide the title compound (0.026 g, 30%) as the formate salt; 1H NMR (400 MHz, DMSO-d6) 1.28 (3H, d), 1.38 - 1.47 (1H, m), 1.47 - 1.57 (2H, m), 1.75 (1H , dd), 3.11 (1H, s), 3.28 (1H, dd), 3.52 (1H, dd), 3.67 (1H, dd), 3.81 (1H, d), 3 , 98 - 4.04 (1H, m), 4.18 (1H, s), 4.58 (1H, s), 7.00 (1H, s), 7.22 (1H, d), 7, 59 (1H, d), 7.95 (1H, d), 8.34 (1H, d), 8.41 (3H, s), 11.83 (1H, s); m / z: (ES +) MH +, 413.11.
[000228] Example 2.02 can also be prepared as follows: dichlorobis (triphenylphosphine) palladium (II) (0.061 g, 0.09 mmol) was added to (3R) -4- (2-chloro-6- (1- ((R) -S-methylsulfonimidoyl) cyclopropyl) pyrimidin-4-yl) -3-methylmorpholine (1.15 g, 3.48 mmol), 2M sodium carbonate solution (6.95 ml, 13.90 mmol ) and 1H-pyrrole [2,3-b] pyridin-4-ylboronic acid (1.877 g, 3.48 mmol) under nitrogen. The resulting solution was stirred at 85 ° C for 6 hours. The reaction mixture was diluted with EtOAc (200 ml), and washed sequentially with water (200 ml) and saturated brine (100 ml). The organic layer was dried over MgSO4, filtered and then evaporated on silica gel (10 g). The resulting powder was purified by flash chromatography on silica, eluting with a gradient of 0 to 5% MeOH in DCM. The pure fractions were evaporated to provide the title compound (0.660 g, 46%); 1H NMR (400 MHz, CDCh) 1.39 (3H, d), 1.53 - 1.61 (2H, m), 1.78 - 1.84 (2H, m), 2.43 (1H, s ), 3.16 (3H, s), 3.39 (1H, td), 3.63 (1H, td), 3.77 (1H, dd), 3.86 (1H, d), 4.07 (1H, dd), 4.17 (1H, d), 4.53 (1H, s), 6.92 (1H, s), 7.34 (1H, dd), 7.41 - 7.47 ( 1H, m), 8.06 (1H, d), 8.43 (1H, d), 9.60 (1H, s); m / z: (ES +) MH +, 413.12. Chiral HPLC: (HP1100 4 system, 5μm Chiralcel OJ-H column (250 mm x 4.6 mm) eluting with heptane / EtOH / MeOH / TEA 50/25/25 / 0.1) Rf, 8.113 98.9% .
[000229] 1H-pyrrole [2,3-b] pyridin-4-ylboronic acid, used as a starting material, can be prepared as follows: 4-Bromo-1H-pyrrole [2,3-b] pyridine (0.944 g, 4.79 mmol) in THF (10 ml) was added dropwise to sodium hydride (0.240 g, 5.99 mmol) in THF (10 ml) at 20 ° C under nitrogen. The resulting mixture was stirred at 20 ° C for 10 minutes. The reaction mixture was cooled to -78 ° C and n-butyl lithium in hexanes (2.396 ml, 5.99 mmol) was added dropwise over 10 minutes and stirred at -78 ° C for 10 minutes. Triisopropyl borate (3.32 mL, 14.37 mmol) was added dropwise over 2 minutes and the reaction mixture was allowed to warm up naturally to room temperature over 1.5 hours. The reaction mixture was suppressed with water (10 ml) and C18 silica gel was added (10 g) and the mixture was concentrated in vacuo. The resulting solid was purified by medium pressure chromatography on reverse phase silica, eluting with a gradient of 5 to 40% acetonitrile in water. The pure fractions were evaporated to provide 1H-pyrrole [2,3-b] pyridin-4-ylboronic acid (0.590 g, 76%); m / z: (ES +) MH +, 162.88.
[000230] Example 2.02 can also be prepared as follows: 4- {4 - [(3R) -3-Methylmorpholin-4-yl] -6- [1 - ((R) -S-methylsulfonimidoyl) cyclopropyl] pyrimidin -2-yl} -1H-pyrrolo [2,3-b] pyridine (approximately 10 g, 25 mmol) was suspended in MTBE (500 ml) and stirred at reflux for 2 hours. The suspension was allowed to cool slowly and stirred at room temperature overnight. The solid was collected by filtration and dried in vacuo to provide the title compound (7.12 g) as a white crystalline solid; 1H NMR (400 MHz, DMSO-d6) 1.28 (3H, d), 1.44 (1H, dd), 1.47 - 1.58 (2H, m), 1.76 (1H, dt), 3.11 (3H, s), 3.26 (1H, dd), 3.52 (1H, td), 3.67 (1H, dd), 3.81 (1H, d), 3.85 (1H , d), 4.02 (1H, dd), 4.20 (1H, d), 4.59 (1H, s), 7.00 (1H, s), 7.23 (1H, dd), 7 , 57 - 7.62 (1H, m), 7.95 (1H, d), 8.34 (1H, d), 11.81 (1H, s); m / z: (ES +) MH +, 413.12. Mpt. (Bu-chi B-545 melting point) 222 ° C. Chiral HPLC: (HP1100 7 system, 5μm column Chiralcel OJ (250 mm x 4.6 mm) eluting with heptane / (EtOH / MeOH 50/50) / TEA 50/50 / 0.1) Rf, 9.836 99.8 %.
Example 2.03 and Example 2.04 N-Methyl-1- {4 - [(3R) -3-methylmorpholin-4-yl] -6- [1 - ((R) -S-methylsulfonimidoyl) cyclopropyl] pyrimidin-2-yl} -1H-benzimidazole-2-amine and N-methyl-1- {4 - [(3R) -3-methylmorpholin-4-yl] -6- [1 - ((S) -S-methylsulfonimidoyl) cyclopropyl] pyrimidin- 2-yl} -1H-benzimidazole-2-amine [000231] Cesium carbonate (942 mg, 2.89 mmol) was added to (3R) -4- (2-chloro-6- (1- (S-methylsulfonimidoil ) cyclopropyl) pyrimidin-4-yl) -3-methylmorpholine (319 mg, 0.96 mmol) and N-methyl-1H-benzo [d] imidazole-2-amine (284 mg, 1.93 mmol) in DMA ( 10 ml). The resulting suspension was stirred at 80 ° C for 45 hours. An additional portion of N-methyl-1H-benzo [d] imidazole-2-amine (284 mg, 1.93 mmol), cesium carbonate (942 mg, 2.89 mmol) and sodium methanesulfinate (98 mg, 0 , 96 mmol) were added and the suspension was stirred at 80 ° C for 70 hours. The reaction mixture was filtered and then evaporated. The residue was dissolved in EtOAc (250 ml), and washed sequentially with water (250 ml) and saturated brine (75 ml). The organic layer was dried over MgSO4, filtered and evaporated on silica gel (5 g). The resulting powder was purified by flash chromatography on silica, eluting with a gradient of 0 to 5% MeOH in DCM. The pure fractions were evaporated and the residue was purified by preparative chiral chromatography on a Merck 50mm column, 20μm Chiralpak AS, eluting isocratically with 70% isohexane in IPA (modified with Et3N) as eluent. Fractions containing the desired compound were evaporated to provide the title compound: N-methyl-1- {4 - [(3R) -3-methylmorpholin-4-yl] -6- [1 - ((R) -S- methylsulfonimidoyl) cyclopropyl] pyrimidin-2-yl} -1H-benzimidazole-2-amine (166 mg, 39%) as the first compound to elute; 1H NMR (400 MHz, DMSO-d6) 1.29 (3H, d), 1.47 (2H, dq), 1.55 - 1.66 (1H, m), 1.69 - 1.89 (1H , m), 3.01 (3H, s), 3.04 (3H, d), 3.30 - 3.39 (1H, m), 3.52 (1H, td), 3.66 (1H, dd), 3.80 (1H, d), 3.95 (1H, s), 4.01 (1H, dd), 4.09 (1H, d), 4.51 (1H, s), 6, 77 (1H, s), 6.97 (1H, t), 7.08 (1H, t), 7.25 (1H, d), 8.08 (1H, d), 8.67 (1H, d ); m / z: (ES +) MH +, 442.09. Chiral HPLC: (HP1100 4 system, 20μm Chiralpak AS column (250 mm x 4.6 mm) eluting with isohexane IPA / TEA 70/30 / 0.1) Rf, 12.219> 99%; and the title compound: N-methyl-1- {4 - [(3R) -3-methylmorpholin-4-yl] -6- [1 - ((S) -S-methylsulfonimidoyl) cyclopropyl] pyrimidin-2-yl } -1H-benzimidazole-2-amine (123 mg, 29%) as the second compound to elute; 1H NMR (400 MHz, DMSO-d6) 1.33 (3H, t), 1.45 - 1.61 (2H, m), 1.61 - 1.68 (1H, m), 1.80 - 1 , 89 (1H, m), 3.07 (3H, s), 3.09 (3H, d), 3.39 (1H, dd), 3.58 (1H, td), 3.72 (1H, dd), 3.86 (1H, d), 4.01 (1H, s), 4.06 (1H, dd), 4.15 (1H, d), 4.55 (1H, s), 6, 82 (1H, s), 7.03 (1H, t), 7.14 (1H, t), 7.31 (1H, d), 8.14 (1H, d), 8.73 (1H, d ); m / z: (ES +) MH +, 442.09. Chiral HPLC: (HP1100 4 system, 20μm Chiralpak AS column (250 mm x 4.6 mm) eluting with isohexane IPA / TEA 70/30 / 0.1) Rf, 25.093> 99%.
[000232] Example 2.03 can also be prepared as follows: (3R) -4- (2-Chloro-6- (1 - ((R) -S-methylsulfonimidoyl) cyclopropyl) pyrimidin -4-yl) -3- methylmorpholine (179 mg, 0.54 mmol), N-methyl-1H-benzo [d] imidazole-2-amine (159 mg, 1.08 mmol) and cesium carbonate (529 mg, 1.62 mmol) were suspended in DMA (2 ml) and sealed in a microwave tube. The reaction mixture was heated to 80 ° C for 90 minutes in a microwave reactor and then cooled to room temperature. The reaction mixture was filtered and then purified by preparative HPLC using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to provide a solid (55.0 mg). In an additional procedure: (R) -4- (2-Chloro-6- (1 - ((R) -S-methylsulfonimidoyl) cyclopropyl) pyrimidin-4-yl) -3-methylmorpholine (89 mg, 0.27 mmol ), N-methyl-1H-benzo [d] imidazole-2-amine (79 mg, 0.54 mmol) and cesium carbonate (263 mg, 0.81 mmol) were suspended in DMA (2 ml) and sealed in a microwave tube. The reaction mixture was heated to 80 ° C for 5 hours in a microwave reactor and then cooled to room temperature. The reaction mixture was filtered, and combined with the solid from the previous procedure and then purified by preparative HPLC using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. The fractions containing the desired compound were evaporated and the residue was purified by preparative HPLC using decreasingly polar mixtures of water (containing 0.1% formic acid) and MeCN as eluents. Fractions containing the desired compound were evaporated and the residue was purified again by preparative HPLC using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to provide the title compound (38.4 mg, 32%); 1H NMR (400 MHz, DMSO-d6) 1.29 (3H, d), 1.52 (3H, m), 1.72 - 1.86 (1H, m), 3.02 (3H, s), 3.03 (3H, d), 3.26 - 3.33 (1H, m), 3.52 (1H, t), 3.66 (1H, d), 3.80 (1H, d), 4 , 01 (2H, m), 4.12 (1H, s, hidden by methanol peak), 4.51 (1H, s), 6.77 (1H, s), 6.98 (1H, t), 7.09 (1H, t), 7.25 (1H, d), 8.08 (1H, d), 8.71 (1H, d); m / z: (ES +) MH +, 442.16. Chiral HPLC: (HP1100 4 system, 20μm Chiralpak AS column (250 mm x 4.6 mm) eluting with isohexaneIPA / TEA 70/30 / 0.1) Rf, 11.984 97.9%.
[000233] N-methyl-1H-benzo [d] imidazol-2-amine, used as a starting material, can be prepared as follows: 2-Chloro-1H-benzo [d] imidazole (20 g, 131, 08 mmol) was loaded into a high pressure autoclave PV10832 (Hastelloy 450ml) with methylamine (260 mL, 131.08 mmol) and sealed in its trolley and the resulting solution was heated to 160 ° C in a 60 high pressure jet cell for 16 hours. The pressure in the autoclave reached 1.1 MPa (11 bar). The solvent was removed under reduced pressure to provide a brown oil. EtOH was added and the solvent was removed again to provide a brown foam. The foam was dissolved in a minimum of hot acetone. This was then left to cool naturally. The resulting solid was filtered, generating N-methyl-1H-benzo [d] imidazole-2-amine (9.91 g, 51%); 1H NMR (400 MHz, DMSO-d6) 2.83 (3H, s), 6.87 - 7.00 (2H, m), 7.05 - 7.25 (2H, m), 7.49 (1H , s).
Example 2.05 and Example 2.06 4- {44 (3R) -3-Methylmorfolin-4-ill-6-n - (((R) -S-methylsulfonimidoyl) cyclopropillpirimidin-2-yl} -1H-indole and 4- {4- [(3R) -3- methylmorpholin-4-ill-6- [1 - (((S) -S-methylsulfonimidoyl) cyclopropillpirimidin-2-yl} -1H-indole [000234] Dichlorobis (triphenylphosphine) palladium (II) (8 , 49 mg, 0.01 mmol) (3R) -4- (2-chloro-6- (1- (S-methylsulfonimidoyl) cyclopropyl) pyrimidin-4-yl) -3-methylmorpholine (400 mg, 1.21 mmol), 2M aqueous sodium carbonate solution (0.725 ml, 1.45 mmol) and 1H-indole-4-ylboronic acid (234 mg, 1.45 mmol) in DME: water 4: 1 (8.575 ml) and the mixture was sealed in a microwave tube. The reaction mixture was heated to 110 ° C for 1 hour in a microwave reactor and then cooled to room temperature. The mixture was diluted with EtOAc (50 ml) and washed sequentially with water (50 ml) and saturated brine (50 ml). The organic layer was evaporated and the residue was purified by medium pressure chromatography (flash) on silica, eluting with a gradient of 0 to 100% EtOAc in DCM. The pure fractions were evaporated and the residue was purified by preparative chiral chromatography on a 20μm Chiralpak IA column (50mm x 250mm), eluting isocratically with a 50: 50: 0.1 mixture of Hexane: EtOH: TEA as eluant. The product-containing fractions were evaporated to provide the title compound: 4- {4 - [(3R) -3-methylmorpholin-4-yl] -6- [1 - ((S) -S-methylsulfonimidoyl) cyclopropyl] pyrimidin -2-yl} -1H-indole (43.8 mg, 24%) as the first compound to elute; 1H NMR (400 MHz, DMSO-d6) 1.33 (3H, d), 1.49 (1H, dd), 1.52 - 1.63 (2H, m), 1.75 - 1.84 (1H , m), 3.16 (3H, s), 3.53 - 3.62 (1H, m), 3.72 (1H, dd), 3.79 - 3.89 (2H, m), 4, 06 (1H, dd), 4.23 (1H, d), 4.65 (1H, s), 6.96 (1H, s), 7.25 (1H, t), 7.37 (1H, s ), 7.50 (1H, t), 7.59 (1H, d), 8.09 - 8.13 (1H, m), 11.27 (1H, s); m / z: (ES +) MH +, 412.24. Chiral HPLC: (HP1100 4 system, 20μm Chiralpak AS column (250 mm x 4.6 mm) eluting with hexane / EtOH / TEA 50/50 / 0.1) Rf, 8,690> 99%.
[000235] And the title compound: 4- {4 - [(3R) -3-methylmorpholin-4-yl] -6- [1 - ((R) -S-methylsulfonimidoyl) cyclopropyl] pyrimidin-2-yl} -1H-indole (93.5 mg, 52%) as the second compound to elute; 1H NMR (400 MHz, DMSO-d6) 1.28 (3H, d), 1.41 - 1.46 (1H, m), 1.50 (2H, td), 1.75 (1H, dd), 3.11 (3H, s), 3.52 (1H, dd), 3.64 - 3.70 (1H, m), 3.73 - 3.83 (2H, m), 4.01 (1H, d), 4.20 (1H, d), 4.56 (1H, s), 6.89 (1H, s), 7.19 (1H, t), 7.32 (1H, s), 7, 44 (1H, s), 7.53 (1H, d), 8.04 - 8.08 (1H, m), 11.22 (1H, s); m / z: (ES +) MH +, 412.24. Chiral HPLC: (HP1100 4 system, 20μm Chiralpak AS column (250 mm x 4.6 mm) eluting with hexane / EtOH / TEA 50/50 / 0.1) Rf, 36.980> 99%.
[000236] Example 2.06 can also be prepared as follows: Dichlorobis (triphenylphosphine) palladium (II) (1.994 mg, 2.84 μmol) was added in one portion to (3R) -4- (2-chloro-6- (1 - (((S) -S-methylsulfonimidoyl) cyclopropyl) pyrimidin-4-yl) -3-methylmorpholine (0.094 g, 0.28 mmol), 2M aqueous sodium carbonate solution (0.170 ml, 0.34 mmol ) and 1H-indole-4-ylboronic acid (0.055 g, 0.34 mmol) in DME: 4: 1 water (2.015 ml) and sealed in a microwave tube. The reaction mixture was heated to 110 ° C for 1 hour in a microwave reactor and then cooled to room temperature. The cooled reaction mixture was passed through a PS-thiol cartridge and then purified by preparative HPLC eluting with decreasingly polar mixtures of water (containing 0.1% formic acid) and MeCN. The fractions containing the product were evaporated and the residue was then purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 2M NH3 / MeOH and the pure fractions were evaporated to provide the title compound (0.075 g, 64%); 1H NMR (400 MHz, DMSO-d6) 1.27 (3H, d), 1.39 - 1.56 (3H, m), 1.69 - 1.78 (1H, m), 3.10 (3H , d), 3.52 (1H, td), 3.66 (1H, dd), 3.72 - 3.83 (2H, m), 4.00 (1H, dd), 4.20 (1H, d), 4.57 (1H, s), 6.89 (1H, d), 7.18 (1H, t), 7.31 (1H, t), 7.43 (1H, t), 7, 53 (1H, d), 8.05 (1H, dd), 11.21 (1H, s); m / z. (ES +) MH +, 412.55. Chiral HPLC: (HP1100 4 system, 5μm Chiralpak AS-H column (250 mm x 4.6 mm) eluting with heptane / EtOH / TEA 50/50 / 0.1) Rf, 4.511> 99%.
[000237] A (3R) -4- (2-chloro-6- (1 - ((S) -S-methylsulfonimidoyl) cyclopropyl) pyrimidin-4-yl) -3-methylmorpholine, used as a starting material, can be prepared as follows: a) Iodobenzene diacetate (78 g, 243.29 mmol) was added to (3R) -4- (2-chloro-6 - ((S) -methylsulfinylmethyl) pyrimidin-4-yl) -3 - methylmorpholine (70.5 g, 243.29 mmol), 2,2,2-trifluoroacetamide (55.0 g, 486.57 mmol), magnesium oxide (39.2 g, 973.15 mmol) and dimer rhodium (II) acetate (2.69 g, 6.08 mmol) in DCM (2433 ml) under air. The resulting suspension was stirred at 20 ° C for 24 hours. Additional 2,2,2-trifluoroacetamide (13.75 g, 121.64 mmol), magnesium oxide (9.81 g, 243.29 mmol), iodobenzene diacetate (19.59 g, 60.82 mmol) and rhodium (II) acetate dimer (0.672 g, 1.52 mmol) was added and the suspension was stirred at 20 ° C for 1 day. The reaction mixture was filtered and then silica gel (200 g) was added to the filtrate and the solvent was removed in vacuo. The resulting powder was purified by medium pressure chromatography (flash) on silica, eluting with a gradient of 20 to 50% EtOAc in heptane. The pure fractions were concentrated and the resulting precipitate was collected by filtration to provide N - [({2-chloro-6 - [(3R) -3-methylmorpholin-4-yl] pyrimidin-4-yl} methyl) (methyl) 6-sulfanilidene oxide] -2,2,2-trifluoroacetamide as a 7: 1 mixture of S: R isomers (26.14 g, 27%); 1H NMR (400 MHz, CDCl3) 1.33 (3H, d), 3.28 (1H, dd), 3.42 (3H, d), 3.46 - 3.57 (1H, m), 3, 61 - 3.70 (1H, m), 3.79 (1H, d), 4.02 (1H, dd), 4.65 (1H, d), 4.85 (1H, dd), 6.49 (1H, d); m / z: (ES +) MH +, 400.94 and 402.85. Chiral HPLC: (HP1100 4 system, 5μm Chiralpak AD-H column (250 mm x 4.6 mm) eluting with 50/50 heptane / EtOH) Rf, 4.367 12.5%, 6.053 87.5%.
[000238] The mother liquids were concentrated in vacuo to produce a colorless gum. The gum was triturated with isohexane to provide a solid which was collected by filtration and dried under vacuum to provide N - [({2-chloro-6 - [(3R) -3-methylmorpholin-4-yl] pyrimidin-4-yl } methyl) (methyl) oxide-λ6-sulfanilidene] -2,2,2-trifluoroacetamide as a 2.8: 1 mixture of R: S isomers (47.1 g, 48%); 1H NMR (400 MHz, CDCh) 1.33 (3H, d), 3.31 (1H, t), 3.42 (3H, d), 3.47 - 3.57 (1H, m), 3, 62 - 3.70 (1H, m), 3.79 (1H, d), 4.02 (1H, dd), 4.65 (1H, dd), 4.86 (1H, dd), 6.49 (1H, d); m / z: (ES +) MH +, 400.94 and 402.86. Chiral HPLC: (HP1100 4 system, 5μm Chiralpak AD-H column (250 mm x 4.6 mm) eluting with 50/50 heptane / EtOH) Rf, 4.365 73.5%, 6.067 26.4%. b) Hydrated cesium hydroxide (0.390 g, 3.43 mmol) was added to a 7: 1 mixture of the S: R isomers of N - [({2-chloro-6 - [(3R) -3-methylmorpholin-4 -yl] pyrimidin-4-yl} methyl) (methyl) oxide ^ 6-sulfanilidene] -2,2,2-trifluoroacetamide (0.209 g, 0.69 mmol), 1,2-dibromoethane (0.236 ml, 2.74 mmol) and tetraoctylamonium bromide (0.037 g, 0.07 mmol) in methyl THF (2 ml) at 20 ° C under nitrogen. The resulting mixture was stirred at 20 ° C for 16 hours. Additional 1,2-dibromoethane (0.236 ml, 2.74 mmol) was added and the mixture was stirred at 20 ° C for 24 hours. A second portion of hydrated cesium hydroxide (0.390 g, 3.43 mmol) was added and the mixture was stirred over the weekend. The reaction mixture was filtered and silica gel (5 g) was added to the filtrate. The mixture was concentrated in vacuo and the resulting powder was then purified by medium pressure chromatography on silica, eluting with a 0 to 5% MeOH gradient in DCM. The pure fractions were evaporated to provide (3R) -4- (2-chloro-6- (1 - ((S) -S-methylsulfonimidoyl) cyclopropyl) pyrimidin-4-yl) -3-methylmorpholine (0.099 g, 44% ); 1H NMR (400 MHz, CDCls) 1.31 (3H, t), 1.43 (2H, h), 1.67 - 1.75 (2H, m), 2.33 (1H, s), 3, 09 (3H, s), 3.29 (1H, td), 3.53 (1H, td), 3.67 (1H, dd), 3.78 (1H, d), 4.00 (2H, dd + s broad), 4.33 (1H, s), 6.78 (1H, s); m / z: (ES +) MH +, 331.04 and 332.99. Chiral HPLC: (HP1100 4 system, 5μm Chiralpak AD-H column (250 mm x 4.6 mm) eluting with heptane / IPA / TEA 70/30 / 0.1) Rf, 5.948 89.5%.
Example 2.07 and Example 2.08 1 - {4 - [(3R) -3-Methylmorpholin-4-yl] -6- [1 - ((R) -S-methylsulfonimidoyl) cyclopropyl] pyrimidin-2-yl} -1H-benzimidazole -2-amine and 1 - {4 - [(3R) -3-methylmorpholin-4-yl] -6- [1 - ((S) -S-methylsulfonimidoyl) cyclopropyl] pyrimidin-2-yl} -1H-benzimidazole -2-amine [000239] Cesium carbonate ((1,773 g, 5.44 mmol) was added to (3R) -4- (2-chloro-6- (1- (S-methylsulfonimidoyl) cyclopropyl) pyrimidin-4- il) -3-methylmorpholine 0.3g, 0.91mmol) and 1H-benzo [d] imidazole-2-amine ((0.121g, 0.91mmol) in DMA (9.07ml). The resulting suspension was stirred at 80 ° C for 3 days The reaction mixture was evaporated and the residue was dissolved in EtOAc (500 ml), and the mixture was then washed sequentially with water (400 ml) and saturated brine (100 ml). aqueous was washed with EtOAc (4 x 500 ml). The organic layers were combined and then dried with MgSO4, filtered and evaporated. The residue was dissolved in DCM (100 ml) and the resulting solution was purified by medium chromatography. on silica, eluting with a gradient of 0 to 15% MeOH in DCM. The pure fractions were evaporated and the residue was purified by preparative chiral chromatography on a 20μm Chiralpak IA column (50mm x 250mm), eluting isocratically with a 50: 50: 0.2: 0.1 mixture of Hexane: IPA: AcOH: TEA as eluents . The product-containing fractions were evaporated to provide the first eluted title compound (0.045 g, 23%); 1H NMR (400 MHz, DMSO-d6) 1.29 (3H, d), 1.40 - 1.49 (2H, m), 1.50 - 1.58 (1H, m), 1.71 - 1 , 84 (1H, m), 3.02 (3H, s), 3.52 (1H, t), 3.67 (1H, d), 3.80 (1H, d), 3.93 (1H, s), 4.01 (1H, d), 4.09 (1H, s), 4.48 (1H, s), 6.87 (1H, s), 6.97 (1H, dd), 7, 07 (1H, dd), 7.18 (1H, d), 7.65 (2H, s), 8.08 (1H, d); m / z: (ES +) MH +, 428.10. Chiral HPLC: (HP1100 3 system, 20μm Chiralpak IA column (250 mm x 4.6 mm) eluting with hexane / IPA / AcOH / TEA 50/50 / 0.2 / 0.1) Rf, 5.653 93.8% .
[000240] And the second title compound eluted (0.030 g, 15%); 1H NMR (400 MHz, DMSO-d6) 1.30 (3H, d), 1.44 (2H, s), 1.50 - 1.58 (1H, m), 1.72 - 1.82 (1H , m), 3.01 (3H, s), 3.47 - 3.57 (1H, m), 3.63 - 3.70 (1H, m), 3.78 (1H, s), 3, 94 (1H, s), 3.97 - 4.05 (1H, m), 4.04 - 4.13 (1H, m), 4.43 - 4.55 (1H, m), 6.88 ( 1H, s), 6.98 (1H, d), 7.07 (1H, s), 7.18 (1H, d), 7.66 (2H, s), 8.07 (1H, d), ; m / z: (ES +) MH +, 428.10. Chiral HPLC: (HP1100 4 system, 20μm Chiralpak IA column (250 mm x 4.6 mm) eluting with hexane / IPA / AcOH / TEA 50/50 / 0.2 / 0.1) Rf, 7.031 96.9% .
Example 2.09 and Example 2.10 4-Fluoro-N-methyl-1- {4 - [(3R) -3-methylmorpholin-4-yl] -6- [1 - ((R) -S-methylsulfonimidoyl) cyclopropyl] pyrimidin- 2-yl} -1H-benzimidazole-2-amine and 4-fluoro-N-methyl-1- {4 - [(3R) -3-methylmorpholin-4-yl] -6- [1 - ((S) - S-methylsulfonimidoyl) cyclopropyl] pyrimidin-2-yl} -1H-benzimidazol-2-amine [000241] Cesium carbonate (1.891 g, 5.80 mmol) was added to (3R) -4- (2-chlorine-6 - (1- (S-methylsulfonimidoyl) cyclopropyl) pyrimidin-4-yl) -3-methylmorpholine (0.64g, 1.93mmol) and 7-fluoro-N-methyl-1H-benzo [d] imidazole-2- amine (0.639 g, 3.87 mmol) in DMA (20.15 ml). The resulting suspension was stirred at 80 ° C for 45 hours. Additional portions of 7-fluoro-N-methyl-1H-benzo [d] imidazol-2-amine (0.639 g, 3.87 mmol), cesium carbonate (1.891 g, 5.80 mmol) and sodium methanesulfinate (0.197 g, 1.93 mmol) were added and the suspension was stirred at 80 ° C for an additional 70 hours. The reaction mixture was filtered and the filtrate was diluted with EtOAc (250 ml) and then washed sequentially with water (250 ml) and saturated brine (75 ml). The organic layer was dried over MgSO4, filtered and then evaporated directly on silica (5 g). The resulting powder was purified by flash chromatography on silica, eluting with a gradient of 0 to 5% MeOH in DCM. The pure fractions were evaporated and the residue was purified by preparative chiral HPLC on a 20μm Chiralpak IA column (50mm x 250mm), eluting with a 50: 50: 0.2: 0.1 mixture of Hexane: IPA: AcOH: TEA as eluents . The product-containing fractions were evaporated to provide the first title compound to elute (0.138 g, 16%); 1H NMR (400 MHz, DMSO-d6) 1.30 (3H, d), 1.50 (2H, dd), 1.60 (1H, d), 1.80 (1H, s), 3.01 ( 3H, s), 3.06 (3H, d), 3.33 (1H, d), 3.51 (1H, d), 3.66 (1H, d), 3.80 (1H, d), 3.99 (1H, s), 4.02 (1H, s), 4.08 (1H, s), 4.50 (1H, s), 6.79 (1H, s), 6.96 (2H , dd), 7.92 (1H, d), 8.79 (1H, d); m / z: (ES +) MH +, 460.08. Chiral HPLC: (HP1100 4 system, 20μm Chiralpak AS column (250 mm x 4.6 mm) eluting with heptane / IPA / TEA 70/30 / 0.1) Rf, 10.697> 99%.
[000242] And the second title compound to elute (0.183 g, 21%); 1H NMR (400 MHz, DMSO-d6) 1.29 (3H, d), 1.50 (2H, d), 1.59 (1H, d), 1.79 (1H, s), 3.02 ( 3H, s), 3.06 (3H, d), 3.33 (1H, d), 3.52 (1H, t), 3.67 (1H, d), 3.80 (1H, d), 3.98 (1H, s), 4.01 (1H, d), 4.08 (1H, s), 4.50 (1H, s), 6.79 (1H, s), 6.96 (2H , dd), 7.92 (1H, d), 8.79 (1H, d); m / z: (ES +) MH +, 460.08. Chiral HPLC: (HP1100 4 system, 20μm Chiralpak AS column (250 mm x 4.6 mm) eluting with heptane / IPA / TEA 70/30 / 0.1) Rf, 18.427 99.8%.
[000243] 7-fluoro-N-methyl-1H-benzo [d] imidazole-2-amine, used as a starting material, was prepared as follows: a) 3-Fluorobenzene-1,2-diamine (0.600 g , 4.76 mmol) was dissolved in THF (14.82 ml) and 1,1'-carbonyldiimidazole (0.848 g, 5.23 mmol) was added at room temperature. The reaction mixture was stirred overnight at room temperature and then heated for 24 hours at 50 ° C. The mixture was cooled to room temperature and ammonia in MeOH (1.5 ml) was added and the mixture was stirred for 30 minutes. The mixture was diluted with water (40 ml) and the resulting brown solid was collected by filtration, washed with water and then vacuum dried to provide 4-fluoro-1H-benzo [d] imidazole-2 (3H) -one (0.700 g, 97%) which was used in the next step without further purification; 1H NMR (400 MHz, DMSO-d6) 6.81 (2H, ddd), 6.88 - 6.95 (1H, m), 10.82 (1H, s), 11.08 (1H, s); m / z: (ES-) M-H-, 151.19. b) A solution of 4-fluoro-1H-benzo [d] imidazole-2 (3H) -one (0.7 g, 4.60 mmol) in phosphorus oxychloride (14.11 ml, 151.39 mmol) heated to 100 ° C for 18 hours. The reaction mixture was cooled to room temperature and the excess phosphorus oxychloride was evaporated in vacuo. The residue was neutralized slowly (attention: exotherm) with saturated sodium bicarbonate solution (10 ml), and the mixture was then extracted with EtOAc (3 x 20 ml). The combined organic layers were washed with saturated brine and then dried with Na2SO4, filtered and evaporated to provide 2-chloro-7-fluoro-1H-benzo [d] imidazole (0.740 g, 94%) which was used in the next step without further purification; 1H NMR (400 MHz, DMSO-d6) 7.01 - 7.11 (1H, m), 7.23 (1H, td), 7.32 (1H, s), 13.59 (1H, s); m / z: (ES +) MH +, 171.20. c) 2-Chloro-7-fluoro-1H-benzo [d] imidazole (1.7 g, 9.97 mmol) was loaded into a high pressure autoclave PV10832 (Parr 160 ml) with methylamine (40% EtOH solution , 50 ml, 9.97 mmol) and sealed in your cart and the resulting solution was heated to 160 ° C in a 60 high pressure jet cell for 16 hours. The pressure in the autoclave reached 1.3 MPa (13 bar). The mixture was evaporated and the residue dissolved in MeOH and then added to an SCX column. The column was eluted with 7N ammonia in MeOH and the fractions containing the product were evaporated to leave a brown oil. The oil was purified by medium pressure chromatography on silica, eluting with a gradient of 5 to 20% MeOH in DCM. The pure fractions were evaporated to provide 7-fluoro-N-methyl-1H-benzo [d] imidazole-2-amine (1.230 g, 75%); 1H NMR (400 MHz, DMSO-d6) 2.88 (3H, d), 6.54 (1H, bs), 6.67 - 6.73 (1H, m), 6.81 (1H, dd), 6.95 (1H, d); m / z: (ES +) MH +, 166.00.
Example 2.11 4- {4 - [(3R) -3-methylmorpholin-4-yl] -6- [1- (S-methylsulfonimidoyl) cyclopropyl] pyrimidin-2-yl} -1H-pyrrole [2,3-c] pyridine [000244] 4- (4 - ((R) -3-methylmorpholine) -6- (1- (S-methylsulfonimidoyl) cyclopropyl) pyrimidin-2-yl) -1H-pyrrolo [2,3-c] pyridine- Tert-butyl 1-carboxylate (0.223 g, 0.44 mmol) was added to TFA (5 ml) and DCM (5.00 ml). The resulting solution was stirred at room temperature for 1 hour. The reaction mixture was evaporated and the residue was purified by preparative HPLC using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated and the residue was triturated with Et2O to provide a solid that was collected by filtration and dried under vacuum to provide the title compound (0.086 g, 48%); 1H NMR (400 MHz, DMSO-d6) 1.29 (3H, d), 1.40 - 1.60 (3H, m), 1.76 (1H, d), 3.11 (3H, s), 3.12 - 3.21 (1H, m), 3.53 (1H, t), 3.68 (1H, d), 3.80 (2H, d), 4.01 (1H, d), 4 , 20 (1H, s), 4.58 (1H, s), 6.95 (1H, d), 7.28 (1H, s), 7.71 (1H, s), 8.83 (1H, s), 9.08 (1H, s), 11.75 (1H, s); m / z: (ES +) MH +, 413.16.
[000245] 4- (4 - ((R) -3-methylmorpholine) -6- (1- (S-methylsulfonimidoyl) cyclopropyl) pyrimidin-2-yl) -1H-pyrrolo [2,3-c] pyridine- Tert-butyl 1-carboxylate, used as a starting material, was prepared as follows: 1,1'-Bis (diphenylphosphino) ferrocenodichloropalladium (II) (0.906 g, 1.25 mmol) was added to 4-bromo-1H -tert-butyl [2,3-c] pyridine-1-carboxylate (1.24 g, 4.17 mmol), potassium acetate (2.87 g, 29.21 mmol) and diboronic bis (pinacolate) (4.73 g, 18.63 mmol) in dioxane (100 ml) under nitrogen. The resulting solution was stirred at reflux for 3 days to provide a mixture at an approximate 2: 1 ratio between the boc product and the de-boc product. To this mixture, dichlorobis (triphenylphosphine) palladium (II) (0.017 g, 0.02 mmol), (3R) -4- (2-chloro-6- (1- (S-methylsulfonimidoyl) cyclopropyl) pyrimidin- 4-yl) -3-methylmorpholine (0.318 g, 0.96 mmol), 2M aqueous sodium carbonate solution (0.577 mL, 1.15 mmol) under nitrogen. The reaction mixture was stirred at 90 ° C for 6 hours. The reaction mixture was concentrated, diluted with EtOAc (400 ml), and then washed sequentially with water (300 ml) and saturated brine (75 ml). The organic layer was dried over MgSO4, filtered and then evaporated directly on silica (30 g). The resulting powder was purified by flash chromatography on silica, eluting with a gradient of 0 to 5% MeOH in DCM. The pure fractions were evaporated to dryness to provide 4- (4 - ((R) -3-methylmorpholine) -6- (1- (S-methylsulfonimidoyl) cyclopropyl) pyrimidin-2-yl) -1H-pyrrole [2, Fer-butyl 3-c] pyridine-1-carboxylate (0.227 g, 46%); 1H NMR (400 MHz, DMSO-d6) 1.28 (3H, d), 1.40 - 1.61 (3H, m), 1.68 (9H, s), 1.76 (1H, dd), 3.09 (3H, d), 3.24 (1H, m), 3.52 (1H, t), 3.67 (1H, dd), 3.79 (2H, d), 4.00 (1H , dd), 4.19 (1H, s), 4.56 (1H, s), 7.00 (1H, d), 7.57 (1H, d), 8.00 (1H, d), 9 , 25 (1H, s), 9.37 (1H, s); m / z: (ES +) MH +, 513.19.
Example 3.01 and Example 3.02 N-methyl-1- {4- [1-methyl-1 - ((S) -S-methylsulfonimidoyl) ethyl] -6 - [(3R) -3-methylmorpholin-4-yl] pyrimidin- 2-yl} -1H-benzimidazole-2-amine and N-methyl-1- {4- [1-methyl-1 - ((R) -S-methylsulfonimidoyl) ethyl] -6 - [(3R) -3- methylmorpholin-4-yl] pyrimidin-2-yl} -1H-benzimidazole-2-amine [000246] Cesium carbonate (3.19 g, 9.79 mmol) was added to N - [(2- {2-chlorine -6 - [(3R) -3-methylmorpholin-4-yl] pyrimidin-4-yl} propan-2-ylXmethyl) oxide ^ 6-sulfanilidene] -2,2,2-trifluoracetamide (0.7 g, 1, 63 mmol) and N-methyl-1H-benzo [d] imidazole-2-amine (0.360 g, 2.45 mmol) in DMA (10 ml). The resulting suspension was stirred at 80 ° C for 5 hours. The resulting mixture was filtered and then concentrated in vacuo. The residue was purified by preparative HPLC, using decreasing polar mixtures of water (containing 1% NH3) and MeCN as eluents. The fractions containing the desired compound were evaporated to dryness and the residue was purified by preparative chiral HPLC on a Merck 50mm column, 20μm ChiralCel OJ, eluting isocratically with 20% EtOH in isohexane (modified with Et3N) as eluent. The fractions containing the first compound to be eluted were evaporated and the residue dissolved in DCM (20 ml) and then evaporated over silica (1 g). The resulting powder was purified by medium pressure chromatography on silica, eluting with a gradient of 0 to 7% MeOH in DCM. The pure fractions were evaporated to provide the title compound: N-methyl-1- {4- [1-methyl-1 - ((R) -S-methylsulfo-nimidoyl) ethyl] -6 - [(3R) -3 -methylmorpholin-4-yl] pyrimidin-2-yl} -1H-benzimidazole-2-amine (66.3 mg, 36%); 1H NMR (400 MHz, DMSO-d6) 1.30 (3H, d), 1.76 (6H, d), 2.78 (3H, d), 3.03 (3H, d), 3.33 - 3.41 (1H, m), 3.47 - 3.58 (1H, m), 3.68 (1H, dd), 3.81 (1H, d), 3.89 (1H, s), 4 , 02 (1H, dd), 4.12 (1H, d), 4.53 (1H, s), 6.80 (1H, s), 6.98 (1H, dd), 7.08 (1H, t), 7.24 (1H, d), 8.10 (1H, d), 8.69 (1H, d); m / z: (ES +) MH +, 444.18. Chiral HPLC: (HP1100 5 system, 20μm Chiralcel OJ column (250 mm x 4.6 mm) eluting with iso-Hexane / EtOH / TEA 80/20 / 0.1) Rf, 21.886> 99%.
[000247] The fractions containing the second compound to be eluted were evaporated and the residue dissolved in DCM (20 ml) and then evaporated over silica gel (1 g). The resulting powder was purified by medium pressure chromatography on silica, eluting with a gradient of 0 to 7% MeOH in DCM. The pure fractions were evaporated to provide the title compound: N-methyl-1- {4- [1-methyl-1- ((S) -S-methylsulfonimidoyl) ethyl] -6 - [(3R) -3-methylmorpholin -4-yl] pyrimidin-2-yl} -1H-benzimidazole-2-amine (62.4 mg, 34%); 1H NMR (400 MHz, DMSO-d6) 1.31 (3H, d), 1.76 (6H, d), 2.78 (3H, d), 3.03 (3H, d), 3.33 - 3.39 (1H, m), 3.54 (1H, td), 3.68 (1H, dd), 3.81 (1H, d), 3.88 (1H, s), 4.02 (1H , dd), 4.12 (1H, d), 4.53 (1H, s), 6.80 (1H, s), 6.92 - 7.01 (1H, m), 7.08 (1H, td), 7.24 (1H, d), 8.10 (1H, d), 8.69 (1H, d); m / z: (ES +) MH +, 444.15, Chiral HPLC: (HP1100 5 system, 20μm Chiralcel OJ column (250 mm x 4.6 mm) eluting with iso-Hexane / EtOH / TEA 80/20 / 0.1 ) Rf, 34.353 99.4%.
[000248] A N - [(2- {2-chloro-6 - [(3R) -3-methylmorpholin-4-yl] pyrimidin-4-yl} propan-2-yl) (methyl) oxide ^ 6-sulfanilidene ] -2,2,2-trifluoracetamide, used as starting material, was prepared as follows: a) (3R) -4- (2-Chloro-6- (methylsulfinylmethyl) pyrimidin-4-yl) -3-methylmorpholine (1.75 g, 6.04 mmol) was dissolved in DMF (34.6 ml), to which NaH (0.604 g, 15.10 mmol) was added slowly and the reaction mixture was stirred for 5 minutes in RT. To the mixture, methyl iodide (0.944 ml, 15.10 mmol) was quickly added and the mixture was stirred for 1 hour. The reaction mixture was suppressed with a saturated NH4Cl solution (50 ml), extracted with DCM (3 x 50 ml) and the combined organic layers were passed through a phase separation column and then evaporated to provide a yellow gum. Water (50 ml) was added to the gum and the mixture extracted with EtOAc (3 x 50 ml). The combined organic layers were dried over MgSO4, filtered and then evaporated. The residue was purified by medium pressure chromatography on silica, eluting with a gradient of 0 to 3% MeOH in DCM. The pure fractions were evaporated to provide (3R) -4- (2-chloro-6- (2- (methylsulfinyl) propan-2-yl) pyrimidin-4-yl) -3-methylmorpholine (1.693 g, 88%); 1H NMR (400 MHz, DMSO-d6) 1.19 (3H, d), 1.49 (6H, dd), 2.17 (3H, t), 3.19 (1H, dd), 3.37 - 3.48 (1H, m), 3.57 (1H, dd), 3.71 (1H, d), 3.92 (1H, d), 4.03 (1H, s), 4.41 (1H , s), 6.70 (1H, s); m / z: (ES +) MH +, 318.04 and 320.04. b) Iodobenzene diacetate (1.716 g, 5.33 mmol) was added in (3R) -4- (2-chloro-6- (2- (methylsulfinyl) propan-2-yl) pyrimidin-4-yl) -3 -methylmorpholine (1.693 g, 5.33 mmol), magnesium oxide (0.859 g, 21.31 mmol), 2,2,2-trifluoracetamide (1.204 g, 10.65 mmol) and rhodium (II) acetate dimer (0.059 g, 0.13 mmol) in DCM (100 mL). The resulting suspension was stirred at room temperature for 18 hours. The reaction mixture was filtered through Celite and then concentrated under vacuum on silica (15 g). The resulting powder was purified by medium pressure chromatography on silica, eluting with a gradient of 0 to 10% MeOH in DCM. The pure fractions were evaporated to provide N - [(2- {2-chloro-6 - [(3R) -3-methylmorpholin-4-yl] pyrimidin-4-yl} propan-2-HXmetH) ^ 6-sufaniHdeno oxide ] -2,2,2-tnfluoracetamide (0.700 g, 31%); 1H NMR (400 MHz, DMSO-d6) 1.20 (3H, dd), 1.83 (6H, d), 3.20 (1H, dd), 3.41 (1H, dddd), 3.56 ( 1H, d), 3.59 (3H, d), 3.72 (1H, d), 3.94 (1H, dd), 4.07 (1H, s), 4.45 (1H, s), 6.93 (1H, d); m / z: (ES +) MH +, 429.4 and 431.5.
Example 4.01 and example 4.02 N-Methyl-1- {44 (3R) -3-methylmorpholin-4-ill-644 - ((S) -S-methylsulfonimidoyl) tetrahydro-2H-pyran-4-yl] pyrimidin- 2-yl} -1H-benzimidazole-2-amine and N-methyl-1- {4 - [(3R) -3-methylmorpholin-4-yl] -6- [4 - ((R) -S-methylsulfonimidoyl) tetrahydro-2H-pyran-4-yl] pyrimidin-2-yl} -1H-benzimidazol-2-amine [000249] Cesium carbonate (2.076 g, 6.37 mmol) was added to N - [(4- {2-chloro-6 - [(3R) -3-methylmorpholin-4-yl] pyrimidin-4-yl} tetrahydro-2H-pyran-4-HXmetH) oxide ^ 6-sufaniHdeno] -2,2,2 -tnfluoracetamide (1.00 g, 2.12 mmol), sodium methanesulfonate (0.217 g, 2.12 mmol) and N-methyl-1H-benzo [d] imidazole-2-amine (0.313 g, 2.12 mmol ) in DMA (20 ml). The resulting suspension was stirred at 80 ° C for 18 hours. The reaction mixture was filtered and then evaporated. The residue was dissolved in EtOAc (100 ml) and washed sequentially with water (100 ml) and then with saturated brine (10 ml). The aqueous layer was washed with EtOAc (2 x 100 ml). The organic layers were combined, dried over MgSO4, filtered and then evaporated. The residue was purified by medium pressure chromatography on silica, eluting with a gradient of 0 to 7% MeOH in DCM. The product-containing fractions were evaporated and the residue was purified by preparative chiral HPLC on a ChiralCel OD column, isocratically eluting with 50% hexane in EtOH (modified with Et3N) as eluent. Fractions containing isomer 1, eluted first, were evaporated and the residue dissolved in DCM (10 ml) and then evaporated over silica (0.5 g). The resulting powder was purified by medium pressure chromatography on silica, eluting with a gradient of 0 to 7% MeOH in DCM. The pure fractions were evaporated to dryness to provide isomer 1 (58.0 mg, 36%); 1H NMR (400 MHz, DMSO-d6) 1.31 (3H, d), 2.19 -2.35 (2H, m), 2.65 - 2.75 (5H, m), 3.02 (2H , d), 3.24 (2H, dd), 3.33 - 3.39 (1H, m), 3.56 (1H, td), 3.71 (1H, dd), 3.81 (1H, d), 3.87 - 3.97 (2H, m), 4.03 (1H, dd), 4.06 (1H, s), 4.16 (1H, d), 4.53 (1H, s ), 6.90 (1H, s), 6.99 (1H, td), 7.09 (1H, td), 7.26 (1H, dd), 8.06 (1H, d), 8.39 (1H, q); m / z: (ES +) MH +, 486.53. Chiral HPLC: (HP1100 4 system, 20μm Chiralpak OJ column (250 mm x 4.6 mm) eluting with Hexane / EtOH / TEA 50/50 / 0.1) Rf, 8.874> 99%.
[000250] Fractions containing isomer 2, eluted second, were evaporated and the residue dissolved in DCM (10 ml) and then evaporated over silica (0.5 g). The resulting powder was purified by medium pressure chromatography on silica, eluting with a gradient of 0 to 7% MeOH in DCM. The pure fractions were evaporated to dryness to provide isomer 2 (71.8 mg, 44%); 1H NMR (400 MHz, DMSO-d6) 1.30 (3H, d), 2.19 - 2.36 (2H, m), 2.61 - 2.76 (5H, m), 3.02 (3H , d), 3.18 - 3.27 (2H, m), 3.36 (1H, dd), 3.56 (1H, td), 3.71 (1H, dd), 3.81 (1H, d), 3.93 (2H, dd), 4.00 - 4.08 (2H, m), 4.17 (1H, d), 4.52 (1H, s), 6.91 (1H, s ), 6.99 (1H, td), 7.09 (1H, td), 7.26 (1H, d), 8.06 (1H, d), 8.39 (1H, q); m / z: (ES +) MH +, 486.57. Chiral HPLC: (HP1100 4 system, 20μm Chiralpak OJ column (250 mm x 4.6 mm) eluting with Hexane / EtOH / TEA 50/50 / 0.1) Rf, 12.742> 99%.
[000251] N - [(4- {2-chloro-6 - [(3R) -3-methylmorpholin-4-yl] pyrimidin-4-yl} tetrahydro-2H-pyran-4-yl) (methyl ) ^ 6-sulfanilidene] -2,2,2-trifluoracetamide oxide, used as starting material, can be prepared as follows: a) Sodium hydroxide (50% w / w) (20.04 ml, 379.60 mmol) was added to (3R) -4- (2-chloro-6- (methylsulfinylmethyl) pyrimidin-4-yl) -3-methylmorpholine (2.2 g, 7.59 mmol), 1-bromo-2- ( 2-bromoethoxy) ethane (3.79 ml, 30.37 mmol) and tetraoctylammonium bromide (0.415 g, 0.76 mmol) in methyl THF (20.05 ml). The resulting mixture was stirred at room temperature for 90 minutes. The reaction mixture was dissolved in methyl THF (50 ml), and washed sequentially with water (50 ml) and saturated brine (5 ml). The organic layer was dried over Mag-SO4, filtered and then evaporated over silica (30 g). The resulting powder was purified by medium pressure chromatography on silica, eluting with a gradient of 0 to 5% MeOH in DCM. The pure fractions were evaporated to provide (3R) -4- (2-chloro-6- (4- (methylsulfinyl) tetrahydro-2H-pyran-4-yl) pyrimidin-4-yl) -3-methylmorpholine (1,360 g, 50%); 1H NMR (400 MHz, DMSO-d6) 1.84 - 1.96 (1H, m), 2.02 (1H, td), 2.09 (3H, d), 2.27 - 2.45 (2H , m), 3.14 (1H, d), 3.10 - 3.26 (3H, m), 3.24 (1H, d), 3.33 - 3.41 (1H, m), 3, 45 (1H, td), 3.60 (1H, dd), 3.71 (1H, d), 3.78 -3.87 (1H, m), 3.87 - 3.97 (2H, m) , 4.07 (1H, d), 4.32 - 4.48 (1H, m), 6.76 (1H, s); m / z: (ES +) MH +, 360.11 and 362.06.
[000252] Iodobenzene diacetate (0.788 g, 2.45 mmol) was added to (3R) -4- (2-chloro-6- (4- (methylsulfinyl) tetrahydro-2H-pyran-4-yl) pyrimidin-4 -yl) -3-methylmorpholine (0.88 g, 2.45 mmol), magnesium oxide (0.394 g, 9.78 mmol), 2,2,2-trifluoracetamide (0.553 g, 4.89 mmol) and dimer rhodium (II) acetate (0.027 g, 0.06 mmol) in DCM (20 ml). The resulting suspension was stirred at room temperature for 18 hours. The reaction mixture was filtered through Celite and then concentrated under vacuum on silica (50 g). The resulting powder was purified by medium pressure chromatography on silica, eluting with a gradient of 20 to 60% EtOAc in isohexane. The pure fractions were evaporated to provide N - [(4- {2-chloro-6 - [(3R) -3-metHmorfoHn-4-H] pyrimidin-4-H} tetrahydro-2H-pyran-4-HXmetH ) 6-sulfanilidene oxide] -2,2,2-trifluoracetamide (1.018 g, 88%); 1H NMR (400 MHz, DMSO-d6) 1.34 (3H, dd), 2.49 (1H, td), 2.63 (2H, ddd), 2.75 - 2.82 (1H, m), 3.26 (3H, d), 3.29 - 3.41 (3H, m), 3.49 (1H, s), 3.51 - 3.60 (1H, m), 3.63 - 3, 73 (1H, m), 3.80 (1H, d), 3.98 - 4.11 (4H, m), 6.68 (1H, d); m / z: (ES-) M-H-, 469.04 and 471.04.
Example 4.03 4- {4 - [(3R) -3-Methylmorpholin-4-yl] -6- [4 - ((S) -S-methylsulfonimidoyl) tetrahydro-2H-pyran-4-yl] pyrimidin-2 -il} -1H-indole α hn ^ * V h [000253] A solution of N - [(4- {2-chloro-6 - [(3R) -3-methylmorpholin-4-H] pyrimidin-4- H} tetrahydro-2H-pyran-4-HXmetH) oxide ^ 6- (S) -sulfanylidene] -2,2,2-trifluoracetamide (50 mg, 0.11 mmol), 1H-indole-4-ylboronic acid (17.09 mg, 0.11 mmol), 4,4'-di-tert-butylbiphenyl (5.66 mg, 0.02 mmol) and potassium carbonate (29.3 mg, 0.21 mmol) in DME : degassed water (4: 1) (2.5 mL) was added to bis (di-tert-butyl (4-dimethylaminophenyl) phosphine) dichloropalladium (II) (A-Fos) (7.52 mg, 10.62 μmol ) under nitrogen. The resulting mixture was stirred at room temperature for 2 hours and then at 55 ° C for 20 hours. The reaction mixture was filtered and then purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the product were evaporated to provide the title compound (20.80 mg, 43%); 1H NMR (500 MHz, DMSO-d6) 1.28 (3H, d), 2.19 - 2.36 (2H, m), 2.72 (3H, d), 2.84 (2H, t), 3.18 (1H, t), 3.20 - 3.29 (2H, m), 3.56 (1H, td), 3.71 (1H, dd), 3.81 (2H, d), 3 , 95 (2H, t), 4.03 (1H, dd), 4.29 (1H, d), 4.59 (1H, s), 6.87 (1H, d), 7.20 (1H, t), 7.27 (1H, t), 7.41 - 7.49 (1H, m), 7.54 (1H, dd), 8.11 (1H, dd), 11.24 (1H, s ); m / z: (ES +) MH +, 456.54.
[000254] N - [(4- {2-chloro-6 - [(3R) -3-methylmorpholin-4-yl] pyrimidin-4-yl} tetrahydro-2H-pyran-4-yl) (methyl ) ^ 6- (S) -sulfanylidene] -2,2,2-itrifluoracetamide oxide, used as a starting material, can be prepared as follows: a) 1-bromo-2- (2-bromoethoxy) ethane (2,323 ml , 18.63 mmol) was added to (R) -4- (2-chloro-6 - ((S) -methylsulfinylmethyl) pyrimidin-4-yl) -3-methylmorpholine (1.8 g, 6.21 mmol) , sodium hydroxide (16.40 ml, 310.58 mmol) and tetraoctylammonium bromide (0.340 g, 0.62 mmol) in methyl THF (12.34 ml). The resulting mixture was stirred at room temperature for 24 hours. The reaction mixture was diluted with methyl THF (50 ml), and then washed with water (100 ml). The organic layer was dried over MgSO4, filtered and evaporated over silica (5 g). The resulting powder was purified by medium pressure chromatography on silica, eluting with a gradient of 0 to 5% MeOH in DCM. The pure fractions were evaporated to provide (R) -4- (2-chloro-6- (4 - ((S) -methylsulfinyl) tetrahydro-2H-pyran-4-yl) pyrimidin-4-yl) -3 -methylmorpholine (1.461 g, 65%); 1H NMR (400 MHz, CDCl3) 1.34 (3H, d), 1.84 - 1.94 (1H, m), 2.10 (3H, s), 2.24 - 2.37 (2H, m ), 2.44 (1H, ddd), 3.30 (1H, td), 3.41 (1H, ddd), 3.51 - 3.64 (2H, m), 3.65 - 3.73 ( 1H, m), 3.75 - 3.82 (1H, m), 3.90 - 4.08 (4H, m), 4.36 (1H, s), 6.46 (1H, s); m / z: (ES +) MH +, 360.15 and 362.11. b) Iodobenzene diacetate (1.437 g, 4.46 mmol) was added to (R) -4- (2-chloro-6- (4 - ((S) -methylsulfinyl) tetrahydro-2H-pyran-4- il) pyrimidin-4-yl) -3-methylmorpholine (1.46 g, 4.06 mmol), 2,2,2-itrifluoracetamide (0.459 g, 4.06 mmol), rhodium (II) acetate dimer ( 0.045 g, 0.10 mmol) and magnesium oxide (0.654 g, 16.23 mmol) in DCM (20.29 ml). The resulting suspension was stirred at room temperature for 48 hours. 2,2,2-itrifluoracetamide (0.459 g, 4.06 mmol), magnesium oxide (0.654 g, 16.23 mmol), iodobenzene diacetate (1.437 g, 4.46 mmol) and rhodium acetate dimer (II ) (0.045 g, 10 mmol) were added and the suspension was stirred at room temperature for an additional 24 hours. The reaction mixture was filtered and then evaporated over silica (5 g). The resulting powder was purified by medium pressure chromatography on silica, eluting with a gradient of 20 to 100% EtOAc in isohexane. The pure fractions were evaporated to provide N - [(4- {2-chloro-6 - [(3R) -3-metHmorfoHn-4-H] pinmidin-4-H} tetrahydro-2H-pyran-4-H ) (methyl) oxide ^ 6- (S) -sulfanilidene] -2,2,2-trifluoracetamide (1.421 g, 74%); 1H NMR (400 MHz, DMSO-d6) 1.20 (3H, d), 2.19 - 2.31 (2H, m), 2.72 - 2.84 (2H, m), 3.11 - 3 , 28 (3H, m), 3.40 - 3.45 (1H, m), 3.46 (3H, s), 3.53 - 3.61 (1H, m), 3.74 (1H, d ), 3.94 (3H, d), 4.12 (1H, s), 4.47 (1H, s), 7.05 (1H, s); m / z: (ES +) MH +, 471.04 and 473.00.
Example 5.01 and Example 5.02 4-Fluoro-N-methyl-1- {4- [1-methyl-1 - ((S) -S-methylsulfonimidoyl) ethyl] -6 - [(3R) -3-methylmorfolin-4- yl] pyrimidin-2-yl} -1H-benzimidazol-2-amine and 4-fluoro-N-methyl-1- {4- [1-methyl-1 - ((R) -S-methylsulfonimidoyl) ethyl] -6 - [(3R) -3-methylmorpholin-4-yl] pyrimidin-2-yl} -1H-benzimidazole-2-amine α α HVO fS hn ^ HV ° fS HN "& F t ^ F
[000255] Cesium carbonate (2.74 g, 8.41 mmol) was added to an approximate 4.3: 1 mixture of R: S isomers of N - [(2- {2-chloro-6 - [(3R) - 3-methylmorpholin-4-yl] pyrimidin-4-yl} propan-2-yl) (methyl) oxide ^ 6-sulfanilidene] -2,2,2-itrifluoracetamide (0.00 g, 1.40 mmol), methanesulfinate sodium (0.143 g, 1.40 mmol) and 7-fluor-N-methyl-1H-benzo [d] imidazole-2-amine (0.347 g, 2.10 mmol) in DMA (8 ml). The resulting suspension was stirred at 80 ° C for 5 hours. The reaction mixture was filtered, eluted with EtOAc (100 ml), and washed sequentially with water (100 ml), water (100 ml), and saturated brine (100 ml). The organic layer was dried over MgSO4, filtered and then evaporated. The residue was purified by medium pressure chromatography on silica, eluting with a gradient of 0 to 5% MeOH in DCM. The pure fractions were evaporated and the residue purified by preparative chiral chromatography on a Merck 50mm, 20μm Chiracel OJ column eluting isocratically with heptane / (EtOH / MeOH 50/50) / TEA 75/25 / 0.1 as eluent. The product-containing fractions were evaporated to provide the title compound: 4-fluor-N-methyl-1- {4- [1-methyl-1 - ((R) -S-methylsulfonimidoyl) ethyl] -6 - [( 3R) -3-methylmorpholin-4-yl] pyrimidin-2-yl} -1H-benzimidazole-2-amine (278 mg, 43%) as the first compound to elute; 1H NMR (400 MHz, DMSO-d6) 1.30 (3H, d), 1.77 (6H, d), 2.79 (3H, s), 3.05 (3H, d), 3.35 ( 1H, dd), 3.47 - 3.59 (1H, td), 3.69 (1H, dd), 3.81 (1H, d), 3.93 (1H, s), 4.03 (1H , dd), 4.12 (1H, d), 4.53 (1H, s), 6.83 (1H, s), 6.90 - 7.01 (2H, m), 7.92 - 7, 96 (1H, m), 8.81 (1H, q); m / z: (ES +) MH +, 462.53, Chiral HPLC: (Gilson prep, 50mm 20μm Chiralcel OJ column eluting with Heptane / (EtOH / MeOH 50/50) / TEA 75/25 / 0.1) Rf, 10,163> 99% and 4-fluor-N-methyl-1- {4- [1-methyl-1 - ((S) -S-methylsulfonimidoyl) ethyl] -6 - [(3R) -3-methylmorpholin-4- yl] pyrimidin-2-yl} -1H-benzimidazole-2-amine_ (96 mg, 15%) as the second compound to elute; 1H NMR (400 MHz, DMSO-d6) 1.33 (3H, d), 1.79 (6H, d), 2.83 (3H, s), 3.09 (3H, d), 3.38 ( 1H, dd), 3.59 (1H, td), 3.73 (1H, dd), 3.86 (1H, d), 3.97 (1H, s), 4.06 (1H, dd), 4.16 (1H, d), 4.59 (1H, s), 6.88 (1H, s), 6.94 - 7.05 (2H, m), 7.94 - 8.02 (1H, m), 8.86 (1H, q); m / z: (ES +) MH +, 462.53. Chiral HPLC: (Gilson prep, 50mm 20μm Chiralcel OJ column eluting with Heptane / (EtOH / MeOH 50/50) / TEA 75/25 / 0.1) Rf, 14.239> 99%.
[000256] N - [(2- {2-chloro-6 - [(3R) -3-methylmorpholin-4-yl] pyrimidin-4-yl} propan-2-yl) (methyl) oxide ^ 6-sulfanilidene ] -2,2,2-itrifluoracetamide, used as starting material, was prepared as follows: a) Methyl iodide (4.70 ml, 75.09 mmol) was added to (R) -4- (2- chloro-6 - ((R) -methylsulfinylmethyl) pyrimidin-4-yl) -3-methylmorpholine (5.44 g, 18.77 mmol), tetraoctylammonium bromide (1.026 g, 1.88 mmol) and sodium hydroxide ( 49.6 ml, 938.64 mmol) in methyl THF (110 ml). The resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with water (250 ml). The organic layer was dried over MgSO4, filtered and evaporated over silica gel (10 g). The resulting powder was purified by medium pressure chromatography on silica, eluting with a gradient of 0 to 5% MeOH in DCM. The pure fractions were evaporated to provide (R) -4- (2-chloro-6- (2 - ((R) -methylsulfinyl) propan-2-yl) pyrimidin-4-yl) -3-methylmorpholine (3.10 g, 52%); 1H NMR (400 MHz, CDCfe) 1.32 (3H, t), 1.59 (3H, s), 1.64 (3H, s), 2.23 (3H, d), 3.22 - 3, 36 (1H, m), 3.48 - 3.59 (1H, m), 3.69 (1H, dd), 3.73 - 3.81 (1H, m), 4.00 (1H, dd) , 4.05 (1H, d), 4.31 (1H, s), 6.45 (1H, d); m / z: (ES +) MH +, 318.02 and 319.98. b) Iodobenzene diacetate (2.77 g, 8.59 mmol) was added to a mixture of (3R) -4- (2-chloro-6- (2- (methylsulfinyl) propan-2-yl) pyrimidin-4 -yl) -3-methylmorpholine (1.03 g, 3.24 mmol), (3R) -4- (2-chloro-6- (2 - ((R) -methylsulfinyl) propan-2-yl) pyrimidin- 4-yl) -3-methylmorpholine (1.7 g, 5.35 mmol), magnesium oxide (1.385 g, 34.36 mmol), 2.2.2-itrifluoracetamide (1.942 g, 17.18 mmol) and rhodium (II) acetate dimer (0.095 g, 0.21 mmol) in DCM (72 ml). The resulting suspension was stirred at room temperature for 70 hours. Magnesium oxide (0.69g, 17.18mmol), iodobenzene diacetate (1.38g, 4.30mmol), 2,2,2-itrifluoracetamide (0.97g, 8.59mmol) and dimer Additional rhodium (II) acetate (0.048 g, 0.105 mmol) was added and the mixture was stirred at room temperature for 18 hours. The reaction mixture was filtered through Celite and then concentrated in vacuo. The residue was purified by medium pressure chromatography on silica, eluting with a gradient of 20 to 50% EtOAc in heptane. The pure fractions were evaporated to provide an approximate 4.3: 1 mixture of R: S N - [(2- {2-chloro-6 - [(3R) -3-methylmorpholin-4-yl] pyrimidin-4-yl} propan-2-ylXmethyl) ^ 6-sulfanilidene] -2,2,2-trifluoracetamide (1.705 g, 46%); 1H NMR (400 MHz, DMSO-d6) 1.18 (3H, d), 1.83 (6H, s), 3.20 - 3.24 (1H, m), 3.36 - 3.48 (1H , m), 3.53 - 3.65 (4H, m), 3.68 - 3.79 (1H, m), 3.94 (1H, dd), 4.03 - 4.07 (1H, m ), 4.43 - 4.47 (1H, m), 6.94 (1H, s); m / z: (ES-) M-H-, 427.26.
Example 5.03, example 5.04, example 5.05 and example 5.06 6-Fluoro-N-methyl-1- {4- [1-methyl-1 - ((R) -S-methylsulfonimidoyl) ethyl] -6 - [(3R) - 3-methylmorpholin-4-yl] pyrimidin-2-yl} -1H-benzimidazol-2-amine, 5-Fluoro-N-methyl-1- {4- [1-methyl-1 - ((R) -S- methylsulfonimidoyl) ethyl] -6 - [(3R) -3-methylmorpholin-4-yl] pyrimidin-2-yl} -1H-benzimidazol-2-amine, 5-Fluoro-N-methyl-1- {4- [1 -methyl-1 - ((S) -S-methylsulfonimidoyl) ethyl] -6 - [(3R) -3-methylmorpholin-4-yl] pyrimidin-2-yl} -1H-benzimidazole-2-amine and 6-fluoro -N-methyl-1- {4- [1-methyl-1 - ((S) -S-methylsulfonimidoyl) ethyl] -6 - [(3R) -3-methylmorpholin-4-yl] pyrimidin-2-yl} -1H-benzimidazole-2-amine [000257] Cesium carbonate (5.01 g, 15.39 mmol) was added to an approximately 4.3: 1 mixture of N - [(2- { 2-chloro-6 - [(3R) -3-methylmorpholin-4-yl] pyrimidin-4-yl} propan-2-yl) (methyl) oxide-λ6-sulfanilidene] -2,2,2-trifluoroacetamide (1 , 10 g, 2.56 mmol), sodium methanesulfinate (0.262 g, 2.56 mmol) and 6-fluoro-N-methyl-1H-benzo [d] imidazole-2-amine (0.720 g, 4.36 mmol ) in DMA (16 ml). The resulting suspension was stirred at 80 ° C for 5 hours. The reaction mixture was filtered. The reaction mixture was diluted with EtOAc (100 ml), and washed sequentially with water (100 ml), water (100 ml), and saturated brine (100 ml). The organic layer was dried over MgSO4, filtered and then evaporated. The residue was purified by flash chromatography on silica, eluting with a gradient of 0 to 5% MeOH in DCM. The pure fractions were evaporated and the residue was purified by preparative chiral CFS on a 5μm Chiracel OJ-H SFC column (250mm x 10mm), eluting with CO2 / MeOH + 0.5 N, NDMEA 90/10 as eluent. The product-containing fractions were evaporated to provide the title compound: 6-fluoro-N-methyl-1- {4- [1-methyl-1 - ((R) -S-methylsulfonimidoyl) ethyl] -6 - [( 3R) -3-methylmorpholin-4-yl] pyrimidin-2-yl} -1H-benzimidazole-2-amine (198 mg, 17%) as the first compound to elute; 1H NMR (400 MHz, DMSO-d6) 1.32 (3H, d), 1.77 (6H, d), 2.78 (3H, s), 3.02 (3H, d), 3.33 - 3.40 (1H, m), 3.55 (1H, td), 3.69 (1H, dd), 3.83 (1H, d), 3.92 (1H, s), 3.97 - 4 , 15 (2H, m), 4.53 (1H, d), 6.84 (1H, s), 6.91 - 6.95 (1H, m), 7.21 (1H, dd), 7, 89 (1H, dd), 8.66 (1H, q); m / z: (ES +) MH +, 462.51. Chiral CFS: (Berger Minigram, 5μm Chiralcel OJ-H column (250mm x 4.6mm) eluting with CO2 / MeOH / N, NDMEA 90/10 / 0.5) Rf, 5.56 98.9%.
[000258] And the title compound: 5-fluoro-N-methyl-1- {4- [1-methyl-1 - ((S) - S-methylsulfonimidoyl) ethyl] -6 - [(3R) -3- methylmorpholin-4-yl] pyrimidin-2-yl} -1H-benzimidazole-2-amine (61 mg, 5%) as the fourth compound to elute; 1H NMR (400 MHz, DMSO-d6) 1.30 (3H, d), 1.77 (6H, d), 2.78 (3H, s), 3.03 (3H, d), 3.32 - 3.36 (1H, m), 3.54 (1H, td), 3.68 (1H, dd), 3.81 (1H, d), 3.91 (1H, s), 3.97 - 4 , 15 (2H, m), 4.53 (1H, d), 6.72 - 6.84 (2H, m), 7.04 (1H, dd), 8.06 (1H, dd), 8, 86 (1H, q); m / z: (ES +) MH +, 462.53. Chiral CFS: (Berger Minigram, 5μm Chiralcel OJ-H column (250mm x 4.6mm) eluting with CO2 / MeOH / N, NDMEA 90/10 / 0.5) Rf, 10.29 96.3%.
[000259] The fractions containing the second and third eluted compounds were purified CFS by preparative chiral on a 5μm Chiralcel OD-H column (250mm x 4.6mm) eluting with CO2 / MeOH / N, NDMEA 85/15 / 0.5 as eluent. The product-containing fractions were evaporated to provide the title compound: 5-fluoro-N-methyl-1- {4- [1-methyl-1 - ((R) -S-methylsulfonimidoyl) ethyl] -6 - [( 3R) -3-methylmorpholin-4-yl] pyrimidin-2-yl} -1H-benzimidazole-2-amine (106 mg, 9%) as the second compound to elute; 1H NMR (400 MHz, DMSO-d6) 1.30 (3H, d), 1.76 (6H, d), 2.78 (3H, s), 3.03 (3H, d), 3.31 - 3.39 (1H, m), 3.54 (1H, td), 3.69 (1H, dd), 3.81 (1H, d), 3.92 (1H, s), 3.97 - 4 , 18 (2H, m), 4.52 (1H, d), 6.73 - 6.84 (2H, m), 7.04 (1H, dd), 8.07 (1H, dd), 8, 86 (1H, q); m / z: (ES +) MH +, 462.53. Chiral CFS: (Berger Minigram, 5μm Chiralcel OD-H column (250mm x 4.6mm) eluting with CO2 / MeOH / N, NDMEA 85/15 / 0.5) Rf, 10.94 98.9%.
[000260] Fractions containing the first compound to be eluted were repurified by preparative chiral CFS on a 5μm Chiralcel OD-H column (250mm x 4.6mm) eluting with CO2 / MeOH / N, NDMEA 85/15 / 0.5 as eluent. The product-containing fractions were evaporated to provide the title compound: 6-fluoro-N-methyl-1- {4- [1-methyl-1 - ((S) -S-methylsulfonimidoyl) ethyl] -6 - [( 3R) -3-methylmorpholin-4-yl] pyrimidin-2-yl} -1H-benzimidazole-2-amine (12 mg, 1%); 1H NMR (400 MHz, DMSO-d6) 1.14 (3H, d), 1.58 (6H, d), 2.60 (3H, s), 2.83 (3H, d), 3.16 - 3.25 (1H, m), 3.35 (1H, td), 3.50 (1H, dd), 3.64 (1H, d), 3.72 (1H, s), 3.79 - 3 , 98 (2H, m), 4.34 (1H, d), 6.65 (1H, s), 6.69 - 6.77 (1H, m), 7.03 (1H, dd), 7, 71 (1H, dd), 8.48 (1H, q); m / z: (ES +) MH +, 462.53. Chiral CFS: (Berger Minigram, 5μm Chiralcel OD-H column (250mm x 4.6mm) eluting with CO2 / MeOH / N, NDMEA 85/15 / 0.5) Rf, 7.47 88.4%.
[000261] 6-fluoro-N-methyl-1H-benzo [d] imidazole-2-amine, used as a starting material, can be prepared as follows: a) 4-Fluorobenzene-1,2-diamine (2 g, 15.86 mmol) was dissolved in THF (49.4 ml) and 1,1'-carbonyldiimidazole (2.83 g, 17.44 mmol) was added at room temperature. The reaction mixture was stirred overnight at room temperature. To this, concentrated ammonia solution (1.5 ml) was added and the mixture was stirred for 30 minutes and then diluted with water (100 ml). The resulting solid was collected by filtration, washed with water, followed by Et2O and then vacuum dried to provide 5-fluoro-1H-benzo [d] imidazole-2 (3H) -one (1,250 g, 52%); 1H NMR (400 MHz, DMSO-d6) 6.66 - 6.79 (2H, m), 6.81 - 6.94 (1H, m), 10.64 (1H, s), 10.76 (1H , s); m / z: (ES +) MH +, 151.19. b) A solution of 5-fluoro-1H-benzo [d] imidazole-2 (3H) -one (1.25 g, 8.22 mmol) in phosphorus oxychloride (25.2 ml, 270.34 mmol) heated for 18 hours at 100 ° C. The reaction mixture was cooled to room temperature and the excess POCl3 was evaporated in vacuo. The residue was neutralized with saturated NaHCO3 solution (10 ml) and extracted with EtOAc (3x 20 ml). The organic phase was washed with brine and then dried with MgSO4, filtered and concentrated under reduced pressure to provide 2-chloro- 6-fluoro-1H-benzo [d] imidazole (1.146 g, 82%); 1H NMR (400 MHz, DMSO-d6) 7.09 (1H, ddd), 7.36 (1H, dd), 7.53 (1H, dd); m / z: (ES +) MH +, 171.34. c) 2-Chloro-6-fluoro-1H-benzo [d] imidazole (1.146 g, 6.72 mmol) was loaded into a high pressure autoclave PV10832 (Parr 160 ml) with 40% methylamine solution in EtOH (50 ml, 6.72 mmol) and sealed in your cart and the resulting solution was heated to 160 ° C in a 60 high pressure jet cell for 16 hours. The pressure in the autoclave reached 1.3 MPa (13 bar). The reaction mixture was evaporated and the residue dissolved in MeOH and added to an SCX column. The desired product was eluted from the column using 7M NH3 / MeOH. The product-containing fractions were evaporated and the residue was purified by medium pressure chromatography on silica, eluting with a gradient of 0 to 10% MeOH in DCM. The pure fractions were evaporated to provide 6-fluoro-N-methyl-1H-benzo [d] imidazole-2-amine (0.707 g, 64%); 1H NMR (400 MHz, DMSO-d6) 2.27 (3H, d), 6.38 - 6.44 (2H, m), 6.67 (1H, dd), 6.79 - 6.84 (1H , m); m / z: (ES +) MH +, 166.31.
Example 5.07, example 5.08, example 5.09 and example 5.10 6-Fluoro-N-methyl-1- {4 - [(3R) -3-methylmorpholin-4-yl] -6- [1 - ((R) -S- methylsulfonimidoyl) cyclopropyl] pyrimidin-2-yl} -1H-benzimidazol-2-amine and 5-fluoro-N-methyl-1- {4 - [(3R) -3-methylmorpholin-4-yl] -6- [1 - (((R) -S-methylsulfonimidoyl) cyclopropyl] pyrimidin-2-yl} -1H-benzimidazol-2-amine and 5-fluoro-N-methyl-1- {44 (3R) -3-methylmorfolin-4-ill -641 - ((S) -S-methylsulfonimidoyl) cyclopropyl] pyrimidin-2-yl} -1H-benzimidazol-2-amine and 6-fluoro-N-methyl-1- {4 - [(3R) -3-methylmorfolin -4-yl] -6- [1 - ((S) -S-methylsulfonimidoyl) cyclopropyl] pyrimidin-2-yl} -1H-benzimidazole-2-amine [000262] Cesium carbonate (9.28 g, 28.47 mmol) was added to a mixture of approximately 4: 1 of the (3R) -4- (2-chloro-6- (1- (S-methylsulfonimidoyl) cyclopropyl) pyrimidin-4-yl R: S isomers) -3-methylmorpholine (1.57 g, 4.75 mmol), sodium methanesulfinate (0.484 g, 4.75 mmol) and 6-fluoro-N-methyl-1H-benzo [d] imidazole-2-amine (1,332 g, 8.07 mmol) in DMA (23 ml). The resulting suspension was stirred at 80 ° C for 5 hours. The reaction mixture was filtered. The reaction mixture was diluted with EtOAc (100 ml), and washed sequentially with water (100 ml), water (100 ml), and saturated brine (100 ml). The organic layer was dried over MgSO4, filtered and evaporated. The residue was purified by flash chromatography on silica, eluting with a gradient of 0 to 5% MeOH in DCM. The pure fractions were evaporated and the residue was then purified by preparative chiral CFS on a 5μm Chiralcel OJ-H column (20mm x 250mm), using CO2 / MeOH / N, N DMEA 90/10 / 0.5 as eluent . Fractions containing the desired compound were evaporated to provide the title compound: 6-fluoro-N-methyl-1- {4 - [(3R) -3-methylmorpholin-4-yl] -6- [1 - ((R ) -S-methylsulfonimidoyl) cyclopropyl] pyrimidin-2-yl} -1H-benzimidazole-2-amine (225 mg, 10%) as the first compound to elute; 1H NMR (400 MHz, DMSO-d6) 1.31 (3H, d), 1.4 - 1.54 (2H, m), 1.57 - 1.64 (1H, m), 1.77 - 1 , 82 (1H, m), 3.00 - 3.04 (6H, m), 3.33-3.37 (1H, m), 3.53 (1H, td), 3.67 (1H, dd ), 3.81 (1H, d), 3.93 - 4.13 (3H, m), 4.49 - 4.51 (1H, m), 6.80 (1H, s), 6.93 ( 1H, ddd), 7.22 (1H, dd), 7.87 (1H, dd), 8.64 (1H, q); m / z: (ES +) MH +, 460.50. Chiral CFS: (Berger Minigram, 5μm Chiralcel OJ-H column (250mm x 4.6mm) eluting with CO2 / MeOH / N, NDMEA 90/10 / 0.5) Rf, 7.70 99.9%.
[000263] And the title compound: 5-fluoro-N-methyl-1- {4 - [(3R) -3-methylmorpholin-4-yl] -6- [1 - ((R) -S-methylsulfonimidoyl) cyclopropyl] pyrimidin-2-yl} -1H-benzimidazole-2-amine (142 mg, 7%) as the second compound to elute; 1H NMR (400 MHz, DMSO-d6) 1.50 (3H, d), 1.61 - 1.77 (2H, m), 1.76 - 1.89 (1H, m), 1.94 - 2 , 06 (1H, m), 3.24 (3H, s), 3.27 (3H, d), 3.52 - 3.56 (1H, m), 3.75 (1H, td), 3, 89 (1H, dd), 4.03 (1H, d), 4.15 - 4.37 (3H, m), 4.70 - 4.74 (1H, m), 6.94 - 7.06 ( 2H, m), 7.27 (1H, dd), 8.28 (1H, dd), 9.07 (1H, q); m / z: (ES +) MH +, 460.50. Chiral CFS: (Berger Minigram, 5μm Chiralcel OJ-H column (250mm x 4.6mm) eluting with CO2 / MeOH / N, NDMEA 90/10 / 0.5) Rf, 10.59 99.8%.
[000264] And the title compound: 6-fluoro-N-methyl-1- {4 - [(3R) -3-methylmorpholin-4-yl] -6- [1 - ((S) -S-methylsulfonimidoyl) cyclopropyl] pyrimidin-2-yl} -1H-benzimidazole-2-amine (36.5 mg, 2%) as the third compound to elute; 1H NMR (400 MHz, DMSO-d6) 1.31 (3H, d), 1.44 - 1.54 (2H, m), 1.57 - 1.64 (1H, m), 1.77 - 1 , 82 (1H, m), 3.00 - 3.04 (6H, m), 3.33 -3.37 (1H, m), 3.53 (1H, td), 3.67 (1H, dd ), 3.81 (1H, d), 3.93 - 4.13 (3H, m), 4.49 - 4.51 (1H, m), 6.80 (1H, s), 6.93 ( 1H, ddd), 7.22 (1H, dd), 7.87 (1H, dd), 8.64 (1H, q); m / z: (ES +) MH +, 460.50. Chiral CFS: (Berger Minigram, 5μm Chiralcel OJ-H column (250mm x 4.6mm) eluting with CO2 / MeOH / N, NDMEA 90/10 / 0.5) Rf, 12.72 97.4%.
[000265] And the title compound: 5-fluoro-N-methyl-1- {4 - [(3R) -3-methylmorpholin-4-yl] -6- [1 - ((S) -S-methylsulfonimidoyl) cyclopropyl] pyrimidin-2-yl} -1H-benzimidazole-2-amine (80 mg, 4%) as the fourth compound to elute; 1H NMR (400 MHz, DMSO-d6) 1.27 (3H, d), 1.43 - 1.51 (2H, m), 1.55 - 1.63 (1H, m), 1.72 - 1 , 83 (1H, m), 3.03 (3H, s), 3.06 (3H, d), 3.28 - 3.37 (1H, m), 3.52 (1H, td), 3, 67 (1H, dd), 3.79 (1H, d), 3.93 - 4.14 (3H, m), 4.46 - 4.49 (1H, m), 6.72 - 6.82 ( 2H, m), 7.05 (1H, dd), 8.05 (1H, dd), 8.84 (1H, q); m / z: (ES +) MH +, 460.50. Chiral CFS: (Berger Minigram, 5μm Chiralcel OJ-H column (250mm x 4.6mm) eluting with CO2 / MeOH / N, NDMEA 90/10 / 0.5) Rf, 25.03 99.5%.
[000266] The 4: 1 mixture of the R: S isomers of (3R) -4- (2-chloro-6- (1- (S-methylsulfonimidoyl) cyclopropyl) pyrimidin-4-yl) -3-methylmorpholine, used as starting material, was prepared as follows: Sodium hydroxide (50%, 80 ml, 1496.99 mmol) was added to a mixture of approximately 4: 1 of the R: S isomers of (3R) -4- (2 -chloro-6- (S-methylsulfonimidoylmethyl) pyrimidin-4-yl) -3-methylmorpholine (10 g, 24.95 mmol), 1,2-dibromoethane (8.60 ml, 99.80 mmol) and tetraoctylammonium bromide (1.364 g, 2.49 mmol) in methyl THF (500 ml) at 20 ° C under nitrogen. The resulting mixture was stirred at 20 ° C for 24 hours. The reaction mixture was diluted with methyl THF (500 ml) and the aqueous layer was separated. The mixture was further diluted with EtOAc (1000 ml) and washed with water (1500 ml). The organic layer was dried over MgSO4, filtered and evaporated. The residue was purified by flash chromatography on silica, eluting with a gradient of 0 to 5% MeOH in DCM. The pure fractions were evaporated to dryness to provide an approximately 4: 1 mixture of the (3R) -4- (2-chloro-6- (1- (S-methylsulfonimidoyl) cyclopropyl) pyrimidinyl R: S isomers 4-yl) -3-methylmorpholine (1.570 g, 19%); 1H NMR (400 MHz, DMSO-d6) 1.18 (3H, d), 1.25 - 1.50 (3H, m), 1.59 - 1.71 (1H, m), 3.01 (3H , s), 3.19 (1H, t), 3.39 - 3.46 (1H, m), 3.52 - 3.61 (1H, m), 3.72 (1H, d), 3, 86 (1H, s), 3.93 (1H, dd), 4.01 - 4.05 (1H, m), 4.38 (1H, s), 6.95 (1H, s); m / z: (ES +) MH +, 331.39.

权利要求:
Claims (16)
[1]
1. Compound characterized by the fact that it presents Formula (I): (I) in which: R1 is selected from morpholin-4-yl and 3-methylmorpholin-4-yl; R2 is n is 0 or 1; R2A, R2C, R2E and R2F are each independently, hydrogen or methyl R2B and R2D are each independently, hydrogen or methyl R2G is selected from -NHR7 and -NHCOR8; R2H is fluorine; R3 is methyl R4 and R5 are each independently hydrogen or methyl, or R4 and R5 together with the atom to which they are attached form Ring A; Ring A is a C3-6cycloalkyl or a 4- to 6-membered saturated heterocyclic ring containing a heteroatom selected from O and N; R6 is hydrogen; R7 is hydrogen or methyl R8 is methyl, or a pharmaceutically acceptable salt thereof.
[2]
2. Compound according to claim 1, characterized by the fact that R4 and R5 together with the atom to which they are attached form Ring A, and Ring A is a C3-6cycloalkyl or a 4 to 6 saturated heterocyclic ring members containing a heteroatom selected from O and N.
[3]
Compound according to claim 1 or 2, characterized by the fact that Ring A is a cyclopropyl, tetrahydropyranyl or piperidinyl ring.
[4]
Compound according to any one of claims 1 to 3, characterized by the fact that R2A is hydrogen; R2B is hydrogen; R2C is hydrogen; R2D is hydrogen; R2E is hydrogen; and R2F is hydrogen.
[5]
Compound according to any one of claims 1 to 4, characterized in that R1 is 3-methylmorpholin-4-yl.
[6]
Compound according to any one of claims 1 to 5, characterized in that the compound of formula (I) is a compound of formula (Ia), (Ia) or a pharmaceutically acceptable salt thereof.
[7]
A compound according to claim 6, or a pharmaceutically acceptable salt thereof, characterized by the fact that: Ring A is a cyclopropyl ring; R2 is n is 0 or 1; R2A is hydrogen; R2B is hydrogen; R2C is hydrogen; R2D is hydrogen; R2E is hydrogen; R2F is hydrogen; R2G is -NHR7; R2H is fluorine; R3 is a methyl group; R6 is hydrogen; and R7 is hydrogen or methyl, or a pharmaceutically acceptable salt thereof.
[8]
8. Compound according to claim 1, characterized by the fact that the compound of formula (I) is selected from any of 4- {4 - [(3R) -3-methylmorpholin-4-yl] - 6 - [((R) -S-methylsulfonimidoyl) methyl] pyrimidin-2-yl} -1H-pyrrolo [2,3-b] pyridine; 4- {4 - [(3R) -3-methylmorpholin-4-yl] -6- [1 - ((S) -S-methylsulfonimidoyl) cyclopropyl] pyrimidin-2-yl} -1H-pyrrole [2,3- b] pyridine; 4- {4 - [(3R) -3-methylmorpholin-4-yl] -6- [1 - ((R) -S-methylsulfonimidoyl) cyclopropyl] pyrimidin-2-yl} -1H-pyrrole [2,3- b] pyridine; N-methyl-1- {4 - [(3R) -3-methylmorpholin-4-yl] -6- [1 - ((R) -S- methylsulfonimidoyl) cyclopropyl] pyrimidin-2-yl} -1H-benzimidazole- 2-amine; N-methyl-1- {4 - [(3R) -3-methylmorpholin-4-yl] -6- [1 - ((S) -S-methylsulfonimidoyl) cyclopropyl] pyrimidin-2-yl} -1H-benzimidazole- 2-amine; 4- {4 - [(3R) -3-methylmorpholin-4-yl] -6- [1 - ((R) -S-methylsulfonimidoyl) cyclopropyl] pyrimidin-2-yl} -1H-indole; 4- {4 - [(3R) -3-methylmorpholin-4-yl] -6- [1 - ((S) -S-methylsulfonimidoyl) cyclopropyl] pyrimidin-2-yl} -1H-indole; 1- {4 - [(3R) -3-methylmorpholin-4-yl] -6- [1 - ((R) -S-methylsulfonimidoyl) cyclopropyl] pyrimidin-2-yl} -1H-benzimidazole-2-amine; 1- {4 - [(3R) -3-methylmorpholin-4-yl] -6- [1 - ((S) -S-methylsulfonimidoyl) cyclopropyl] pyrimidin-2-yl} -1H-benzimidazole-2-amine; 4-fluoro-N-methyl-1- {4 - [(3R) -3-methylmorpholin-4-yl] -6- [1 - ((R) -S-methylsulfonimidoyl) cyclopropyl] pyrimidin-2-yl} - 1H-benzimidazole-2-amine; 4-fluoro-N-methyl-1- {4 - [(3R) -3-methylmorpholin-4-yl] -6- [1 - ((S) -S-methylsulfonimidoyl) cyclopropyl] pyrimidin-2-yl} - 1H-benzimidazole-2-amine; 4- {4 - [(3R) -3-methylmorpholin-4-yl] -6- [1- (S-methylsulfonimidoyl) cyclopropyl] pyrimidin-2-yl} -1H-pyrrolo [2,3-c] pyridine; N-methyl-1- {4- [1-methyl-1 - ((S) -S-methylsulfonimidoyl) ethyl] -6 - [(3R) - 3-methylmorpholin-4-yl] pyrimidin-2-yl} - 1H-benzimidazole-2-amine; N-methyl-1- {4- [1-methyl-1 - ((R) -S-methylsulfonimidoyl) ethyl] -6 - [(3R) - 3-methylmorpholin-4-yl] pyrimidin-2-yl} - 1H-benzimidazole-2-amine; N-methyl-1- {4 - [(3R) -3-methylmorpholin-4-yl] -6- [4 - ((S) -S-methylsulfonimidoyl) tetrahydro-2H-pyran-4-yl] pyrimidin-2 -yl} -1H-benzimidazole-2-amine; N-methyl-1- {4 - [(3R) -3-methylmorpholin-4-yl] -6- [4 - ((R) -S-methylsulfonimidoyl) tetrahydro-2H-pyran-4-yl] pyrimidin-2 -yl} -1H-benzimidazole-2-amine; 4- {4 - [(3R) -3-methylmorpholin-4-yl] -6- [4 - ((S) -S-methylsulfonimidoyl) tetrahydro-2H-pyran-4-yl] pyrimidin-2-yl} - 1H-indole; 4-fluoro-N-methyl-1- {4- [1-methyl-1 - ((S) -S-methylsulfonimidoyl) ethyl] - 6 - [(3R) -3-methylmorpholin-4-yl] pyrimidin-2 -yl} -1H-benzimidazole-2-amine; 4-fluoro-N-methyl-1- {4- [1-methyl-1 - ((R) -S-methylsulfonimidoyl) ethyl] -6 - [(3R) -3-methylmorpholin-4-yl] pyrimidin-2 -yl} -1H-benzimidazole-2-amine; 6-Fluoro-N-methyl-1- {4- [1-methyl-1 - ((R) -S-methylsulfonimidoyl) ethyl] -6 - [(3R) -3-methylmorpholin-4-yl] pyrimidin-2 -yl} -1H-benzimidazole-2-amine; 5-Fluoro-N-methyl-1- {4- [1-methyl-1 - ((R) -S-methylsulfonimidoyl) ethyl] -6 - [(3R) -3-methylmorpholin-4-yl] pyrimidin-2 -yl} -1H-benzimidazole-2-amine; 5-Fluoro-N-methyl-1- {4- [1-methyl-1 - ((S) -S-methylsulfonimidoyl) ethyl] -6 - [(3R) -3-methylmorpholin-4-yl] pyrimidin-2 -yl} -1H-benzimidazole-2-amine; 6-fluoro-N-methyl-1- {4- [1-methyl-1 - ((S) -S-methylsulfonimidoyl) ethyl] - 6 - [(3R) -3-methylmorpholin-4-yl] pyrimidin-2 -yl} -1H-benzimidazole-2-amine; 6-Fluoro-N-methyl-1- {4 - [(3R) -3-methylmorpholin-4-yl] -6- [1 - ((R) -S-methylsulfonimidoyl) cyclopropyl] pyrimidin-2-yl} - 1H-benzimidazole-2-amine; 5-fluoro-N-methyl-1- {4 - [(3R) -3-methylmorpholin-4-yl] -6- [1 - ((R) -S-methylsulfonimidoyl) cyclopropyl] pyrimidin-2-yl} - 1H-benzimidazole-2-amine; 5-fluoro-N-methyl-1- {4 - [(3R) -3-methylmorpholin-4-yl] -6- [1 - ((S) -S-methylsulfonimidoyl) cyclopropyl] pyrimidin-2-yl} - 1H-benzimidazole-2-amine; and 6-fluoro-N-methyl-1- {4 - [(3R) -3-methylmorpholin-4-yl] -6- [1 - ((S) -S-methylsulfonimidoyl) cyclopropyl] pyrimidin-2-yl} -1H-benzimidazole-2-amine, or a pharmaceutically acceptable salt thereof.
[9]
Compound according to claim 1, characterized in that the compound of formula (I) is 4- {4 - [(3R) -3-methylmorpholin-4-yl] -6- [1 - ((S ) -S-methylsulfonimidoyl) cyclopropyl] pyrimidin-2-yl} -1H-pyrrolo [2,3-b] pyridine, or a pharmaceutically acceptable salt thereof.
[10]
Compound according to claim 1, characterized in that the compound of formula (I) is 4- {4 - [(3R) -3-methylmorpholin-4-yl] -6- [1 - ((S ) -S-methylsulfonimidoyl) cyclopropyl] pyrimidin-2-yl} -1H-pyrrolo [2,3-b] pyridine.
[11]
Compound according to claim 1, characterized in that the compound of formula (I) is 4- {4 - [(3R) -3-methylmorpholin-4-yl] -6- [1 - ((R ) -S-methylsulfonimidoyl) cyclopropyl] pyrimidin-2-yl} -1H-pyrrolo [2,3-b] pyridine or a pharmaceutically acceptable salt thereof.
[12]
Compound according to claim 1, characterized in that the compound of formula (I) is 4- {4 - [(3R) -3-methylmorpholin-4-yl] -6- [1 - ((R ) -S-methylsulfonimidoyl) cyclopropyl] pyrimidin-2-yl} -1H-pyrrolo [2,3-b] pyridine.
[13]
13. A compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 12, characterized in that it is for preparing a pharmaceutical composition for use in the treatment of cancer.
[14]
Pharmaceutical composition characterized by the fact that it comprises a compound of the formula (I), or a pharmaceutically acceptable salt thereof, as defined in any one of claims 1 to 12, in association with a pharmaceutically acceptable adjuvant, diluent or carrier .
[15]
15. Use of a compound of the formula (I), or a pharmaceutically acceptable salt thereof, as defined in any of claims 1 to 12, characterized by the fact that it is for the manufacture of a medicament for use in preventing or treatment of tumors that are sensitive to ATR kinase inhibition.
[16]
16. Invention, characterized by any of its embodiments or categories of claim encompassed by the material initially disclosed in the patent application or in its examples presented here.

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法律状态:
2018-01-16| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|

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2019-05-21| B07E| Notice of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|Free format text: NOTIFICACAO DE ANUENCIA RELACIONADA COM O ART 229 DA LPI |

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2019-07-16| B06T| Formal requirements before examination [chapter 6.20 patent gazette]|

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2019-10-15| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|

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2019-12-03| B16A| Patent or certificate of addition of invention granted|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 09/06/2011, OBSERVADAS AS CONDICOES LEGAIS. (CO) 20 (VINTE) ANOS CONTADOS A PARTIR DE 09/06/2011, OBSERVADAS AS CONDICOES LEGAIS |

优先权:

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申请号 | 申请日 | 专利标题

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US35371310P| true| 2010-06-11|2010-06-11|

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PCT/GB2011/051074|WO2011154737A1|2010-06-11|2011-06-09|Morpholino pyrimidines and their use in therapy|

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