small molecule human sting modulators

专利摘要:
The present invention relates to compounds of formula (I). The compounds can be used to modulate the Interferon Gene Stimulator (STING) protein and thereby treat diseases, such as cancer and microbial infections.
公开号:BR112019027127A2
申请号:R112019027127-9
申请日:2018-06-21
公开日:2020-07-07
发明作者:Monali Banerjee；Sandip Middya；Sourav Basu；Rajib Ghosh；David Pryde；Dharmendra Yadav；Ritesh Shrivastava；Arjun Surya
申请人:Curadev Pharma Limited；
IPC主号:

专利说明:

[001] [001] The present invention relates to small molecules for use in the modulation of the Interferon Gene Stimulating protein (STING). In this way, small molecules can be used to treat diseases, such as cancer and microbial infections, and so on. The invention extends to compounds per se pharmaceutical compositions, methods for producing the compound, and methods for modulating the STING protein.
[002] [002] The human immune system can generally be divided into two arms, referred to as the ‘innate immune system’ and ‘adaptive immune system’. The innate arm is mainly responsible for an initial inflammatory response through numerous factors such as cytokines, chemokines and complementary factors. These factors act in countless different cell types, including mast cells, macrophages, dendritic cells and natural killer cells. The adaptive arm involves a delayed and longer response to challenge through antibody production along with CD8 + and CD4 + T cell responses that are critical for immune memory.
[003] [003] Research has been conducted for many years on how the immune system can recognize and eliminate malignant tumors (Parish et. Al., Immunol and Cell Biol, 2003, 81, 106-113). One of the pioneers in this area is William Coley, who in the late 1800s noticed that a cancer patient had a complete remission of his cancer after acute infection with the bacteria Streptococcus pyogenes. Subsequent studies with Coley toxin and the Calmette-Guerin bacillus (BCG) for cancer immunotherapy have provided some clinical success, but in no way have they offered a panacea for tumor treatment (Coley, Am J Med Sci., 1893, 105, 487- 511). During the 1900s, opinions fluctuated in relation to the benefits of immunotherapy, with theories of acquired immune tolerance (Burnet, Lancet, 1967, 1, 1171-1174 and Matzinger, Ann. Rev. Immunol., 1994, 12, 991- 1045 and Smyth et. Al., Nat Imunol., 2001, 2, 293-299) and tumor-associated antigens (Rosenberg et. Al., Immunity, 1999, 10, 281-287) gaining support with the emergence of the immune system innate as an important mediator of immunity (Lanier, Nat Med. 2001, 7, 1178-1180 and Mayardomo et al., Nat Med. 1995, 1, 1297-1302 and Medzhitov et al., Trends Microbiol., 2000, 8, 452-456 and Akira et al., Nat. Immunol., 2001, 2, 675-680). The detection of pathogen-associated molecular patterns (PAMPs) such as nucleic acids is now recognized as a central strategy by which the innate immune system detects tumor-associated microbes and antigens and then initiates protective responses (Barbalat et. Al., Annu. Rev Immunol., 2011, 29, 185-214).
[004] [004] As previously described, innate immunity is initiated when PAMPs or damage-associated molecular patterns (DAMPs) are detected by pattern recognition receptors that include TLRs, NOD type receptors and RIG-I type receptors. These pattern recognition receptors respond to DAMPs and PAMPs by overloading Type-1 interferons and cytokines. Cystolic nucleic acids are known PAMPs / DAMPs and fit the STING protein to stimulate the innate immune system and promote an antitumor response. Binding of dsDNA by cyclic GMP-AMP synthase (cGAMP) (cGAS) triggers the formation of cyclic dinucleotides (CDNs). CDNs are second messenger signaling molecules produced by various bacteria and consist of two ribonucleotides that are connected via phosphodiester bonds to produce a cyclic structure. Derivatives of Cyclo-di (GMP), cyclo-di (AMP) and cyclo-hybrid (AMP / GMP) CDNs all bind to STING with subsequent activation of the interferon path (Gao et. Al., Cell, 2013, 153, 1094 -1107; Zhang et. Al., Mol. Cell, 2013, 51, 226-235). The canonical 5'-3 'phosphodiester bond is recognized along with several other bonding isomers (notably the 5'-2' bond, for example, c [G (2 ', 5') pA (3 ', 5') p]) that all link STING with various affinities (Shi et. al., PNAS, 2015, 112, 1947- 8952). These observations were corroborated by structural studies (Gao et. Al., Cell, 2013, 154, 748-762) of various CDN-binding isomers linked to human and mouse STING proteins.
[005] [005] A possible mechanism by which traditional vaccine adjuvants, such as alum, potentiate an immune response is through the release of DAMPs. Adjuvants, such as alum, trigger the release of host cell DNA, which can promote a Th2 response, induce T cell responses and the production of IgG1 and IgE. Ideally, adjuvants should be molecularly defined and capable of enhancing the magnitude and timing of a specific immune response to an antigen that offers protection against intracellular pathogens and / or reduces tumor burden.
[006] [006] Activation of the STING protein can create an activated or initiated immune system, similar to that generated by an adjuvant. This can produce a protective or prophylactic state through challenge or redemption by intracellular pathogens or tumors, which inhibits the growth or spread of pathogens or intracellular tumors.
[007] [007] It can also be realized that when a STING activator is administered therapeutically to a system in which tumors / pathogens are present, it can act beneficially in two different, but related, ways. Firstly, by direct contraction of tumors / pathogen eradication by overloading Type-I interferons and cytokines to act directly on the tumor / pathogens, as previously described. Second, a STING activator will also induce a longer-lasting immune response, such that redefining or reinoculation with a pathogen or tumors will be resisted both through a general activation of the immune system and through a specific latent antigen response to said pathogen or tumor.
[008] [008] Tumor immunovigilance occurs, for example, with thriving tumors having been immunoselected to evade immune elimination and in fact, the crucial role that the innate immune system plays in tumor clearance puts Coley's original findings in a new light. It is now clear that nucleotide fragments, cyclic oligonucleotides and double-stranded motifs can all activate the innate immune system through toll-like receptors (Horscroft, J. Antimicrob. Ther., 2012, 67 (4), 789-801 and Diebold et al., Science, 2004, 303, 1529-1531), RIG-I type receptors (Pichlmair et. al., Science, 2006, 314, 997-
[009] [009] This growing knowledge has stimulated considerable research into possible therapeutic applications of immunomodulation through some of these target classes. STING has more recently emerged as a critical signaling molecule in the innate response to cystolic nucleic acid molecules (Burdette and Vance, Nat. Immunol, 2013, 14, 19-26). STING plays a role in the transcriptional induction of Type I interferons and coregulated genes in response to nucleic acids in the cytosol. Studies in STING-deficient mice confirmed the role of STING in innate response to cystolic nucleic acid ligands, particularly double-stranded DNA and bacterial nucleic acids based on a cyclic dinucleotide structure (Ishikawa et. Al., Nature, 2009, 461 , 788-792). STING plays a critical role in the innate response to many bacterial, viral and eukaryotic pathogens (Watson et. Al., Cell, 2012, 150, 803-815; de Almeida et. Al., PLoS One, 2011, 6, e23135; Holm et. al, Nat. Immunol, 2012, 13, 737-743; Stein et. al., J. Virol., 2012, 86, 4527-4537; Sharma et. al., Immunity, 2011, 35, 194-207 ).
[0010] [0010] STING is widely expressed throughout the body in both immune and non-immune cells, for example, in the spleen, heart, thymus, placenta, lung and peripheral leukocytes, indicating a role in triggering the innate immune system in response to PAMPs / DAMPs (Sun et. al., PNAS, 2009, 106, 8653-8658). Its expression in immune cells leads to rapid amplification of the initial immune signal and maturation of APCs. It is expressed in several transformed cell lines including HEK293 human embryonic kidney cells, A549 human adenocarcinoma basal alveolar epithelial cells, THP-1 monocytic cells and U937 leukemic monocytic lymphoma cells.
[0011] [0011] STING also plays a central role in certain autoimmune disorders initiated by inappropriate recognition of auto DNA (Gall et. Al., Immunity, 2012, 36, 120-131) and has been proposed to detect membrane fusion events associated with entry viral, in a manner independent of nucleic acid detection (Holm et. al., Nat. Immunol., 2012, 13, 737-743).
[0012] [0012] STING is comprised of an N-terminal transmembrane domain, a central globular domain and a C-terminal tail. The protein forms a symmetrical dimer in the linker-linked state, with the attachment of cyclic dinucleotides to a dimer interface binding pouch. Binding of CDNs to STING activates a cascade of events through which the protein recruits and activates IκB kinase (IKK) and TANK-binding kinase (TBK1), which, after phosphorylation, activates nuclear transcription factors (NFκB) and regulatory interferon 3 (IRF3), respectively. These activated proteins translocate to the nucleus to induce transcription of genes that encode Type I interferon and cytokines to promote intercellular immune system defense. Sequence variations are known between human and mouse STING proteins, and between STING proteins in human populations. Several naturally occurring variant alleles have been identified.
[0013] [0013] Derivatives of the CDN class are currently being developed as anti-tumor agents through intratumor injection (Corrales et.al., Cell Rep., 2015, 19, 1018-1030). The small molecule acetic 5,6-dimethyl acetic xanthenone (DMXAA) based on xanthene was initially identified as a small molecule that exhibits immune modulatory activities through cytokine induction and disruption of tumor vascularization in mouse xenograft models ( Baguley and Ching, Int. J. Radiat. Oncol. Biol. Phys., 2002, 54, 1503-1511). This promising efficacy led to its investigation in a Phase II clinical trial against non-small cell lung carcinoma, but subsequently failed to reach its ultimate goals. The mechanism of activity of DMXAA against murine tumors was eventually designated in terms of its activity as an activator of murine STING. Its failure in human clinical experiments was due to the fact that DMXAA was able to activate only mouse STING and not human STING (Lara et. Al., J. Clin. Oncol., 2011, 29, 2965-2971; Conlon et al., J. Immunol., 2013, 190, 5216-5225). This lack of human activity has hampered any further attempts to develop this agent as a tumor therapy. Recently, it was observed that a related small molecule 10-carboxymethyl-9-acridanone (CMA) (Cavlar et. Al., EMBO J., 2013, 32, 1440-1450) binds to the mouse STING, but also does not the human STING. Both DMXAA and CMA have been shown to bind two molecules of each ligand to the STING dimer in a region close to the interface of the dimer.
[0014] [0014] Thus, there remains a need in the technique of improved therapies to treat diseases, such as cancer, which may be refractory to traditional therapeutic approaches. Immunological strategies show promise for the treatment of cancer, and there is a need to develop improved compositions and methods in this field. In particular, there is a need for compounds that modulate the human STING protein, as well as methods for treating diseases that can benefit from such modulation.
[0015] [0015] The present invention arose from the work of inventors in an attempt to identify modulators of the STING protein.
[0016] [0016] In a first aspect of the invention, a compound of the formula (I) is provided: (I), where X1 is CR1 or N; X2 is CR2 or N; X3 is CR3 or N; Q is C = O, S = O, SO2, C = S or CR4R5; L is optionally substituted C1-C6 alkyl, polyfluoralkyl C1-C3, optionally substituted C3-C6 cycloalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, C = O, S = O, SO2, - CH2C (O) -, -CH2CONH-, or -CONH-; Y is an optionally substituted C1-C6 alkyl, polyfluoralkyl C1-C3, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl,
[00139] [00139] The inventors have found that the compounds of formula (I) are useful in therapy or as a medicine.
[00140] Consequently, in a second aspect, a compound of formula (I) or a complex, salt, solvate, tautomeric form or pharmaceutically acceptable polymorphic form thereof, for use in therapy is provided.
[00141] [00141] The inventors also found that compounds of the formula (I) are useful in modulating the Interferon Gene Stimulating protein (STING).
[0017] [0017] Consequently, in a third aspect, a compound of the formula (I) or a complex, salt, solvate, tautomeric form or pharmaceutically acceptable polymorphic form thereof is provided for use in the modulation of the Interferon Gene Stimulating protein (STING ).
[0018] [0018] Preferably, the compound of formula (I) is for use in activating or agonizing the STING protein.
[0019] [0019] Advantageously, the compounds of the invention modulate the major human polymorphs of the human STING protein. There are several STING polymorphs reported, but the 5 polymorphs listed below are the main ones that comprise almost 99% of the total human populations. Thus, the STING protein can be a wild type polymorph (WT / R232), a HAQ polymorph, a REF polymorph (H232), an AQ polymorph or a Q polymorph. As shown in Figure 1, the wild type polymorph has arginines in the positions 71, 232 and 293 and a glycine at position 230, polymorph HAQ has a histidine at position 71, an alanine at position 230, an arginine at position 232 and a glutamine at position 293, the REF polymorph has arginines at positions 71 and 293, a glycine at position 230 and a histidine at position 232, polymorph AQ has arginines at positions 71 and 232, an alanine at position 230 and a glutamine at position 293, and polymorph Q has arginines at positions 71 and 232, a glycine at position 230 and a glutamine at position 293.
[0020] [0020] By modulating the STING protein, it is possible to treat, improve or prevent cancer, bacterial infection, viral infection, parasitic infection, fungal infection, immune mediated disorder, central nervous system disease, peripheral nervous system disease, neurodegenerative disease, mood, sleep disorder, cerebrovascular disease, peripheral artery disease or cardiovascular disease.
[0021] [0021] Thus, in a fourth aspect, a compound of the formula (I) or a complex, salt, solvate, tautomeric form or pharmaceutically acceptable polymorphic form thereof is provided for use in the treatment, improvement or prevention of a disease selected from cancer, bacterial infection, viral infection, parasitic infection, fungal infection, immune mediated disorder, central nervous system disease, peripheral nervous system disease, neurodegenerative disease, mood disorder, sleep disorder, cerebrovascular disease, peripheral artery disease or disease cardiovascular.
[0022] [0022] Preferably, the disease is cancer.
[0023] [0023] In a fifth aspect, a method is provided to modulate the Interferon Gene Stimulating protein
[0024] [0024] Preferably, the method comprises activating the STING protein.
[0025] [0025] The STING protein can be a wild type polymorph, an HAQ polymorph, a REF polymorph, an AQ polymorph or a Q polymorph.
[0026] [0026] In a sixth aspect, a method is provided to treat, ameliorate or prevent a selected cancer disease, bacterial infection, viral infection, parasitic infection, fungal infection, immune mediated disorder, central nervous system disease, nervous system disease peripheral, neurodegenerative disease, mood disorder, sleep disorder, cerebrovascular disease, peripheral artery disease or cardiovascular disease, the method comprising administering, to a subject in need of such treatment, a therapeutically effective amount of a compound of formula (I) or a complex, salt, solvate, tautomeric form or pharmaceutically acceptable polymorphic form thereof.
[0027] [0027] It can be seen that the term "prevent" can mean "reduce the likelihood of".
[0028] [0028] The neurodegenerative disease can be Alzheimer's disease or dementia. The viral disease can be Hepatitis. The parasitic infection can be malaria. The mood disorder can be depression. The sleep disorder can be insomnia.
[0029] [0029] In a preferred embodiment, the disease is cancer. The cancer can be selected from the group consisting of colorectal cancer, aerodigestive squamous cancer, lung cancer, brain cancer, liver cancer, stomach cancer, sarcoma, leukemia, lymphoma, multiple myeloma, ovarian cancer, cervical cancer, cancer breast cancer, melanoma, prostate cancer, bladder cancer, pancreatic carcinoma or renal carcinoma.
[0030] [0030] In an alternative preferred embodiment, the disease is a viral infection. Viral infection can be an infection with hepatitis C virus (HCV).
[0031] [0031] The inventors believe that countless of the compounds that fall within the scope of formula (I) are innovative and inventive per se.
[0032] [0032] The following definitions are used with respect to the compounds of the present invention unless the context otherwise indicates.
[0033] [0033] Throughout the description and in the claims of that specification the word "understand" and other forms of the word, such as "comprising" and "understand", mean including, but without being limited, and without wanting to exclude, for example, other additives, components, whole parts, or steps.
[0034] [0034] As used in the description and the appended claims, the singular forms "one", "one", "o" and "a" include plural referents, unless the context clearly dictates otherwise. Thus, for example, reference to "a composition" includes mixtures of two or more such compositions.
[0035] [0035] "Optional" or "optionally" means that the event, operation or circumstances subsequently described may or may not occur, and that the description includes cases where the event, operation or circumstance occurs and cases where it does not.
[0036] [0036] The term "alkyl", as used here, unless otherwise specified, refers to a saturated straight or branched hydrocarbon. In certain embodiments, the alkyl group is a primary, secondary, or tertiary hydrocarbon. In certain embodiments, the alkyl group includes one to six carbon atoms, that is, C1-C6 alkyl. C1-C6 alkyl includes, for example, methyl, ethyl, n-propyl (1-propyl) and isopropyl (2-propyl, 1-methylethyl), butyl, pentyl, hexyl, isobutyl, sec-butyl, tert-butyl, isopentyl , neopentyl, and isohexyl. An alkyl group can be unsubstituted or substituted with one or more of halogen, OH, OP (O) (OH) 2, OSO2R1, NHSO2R1, C1-C6 alkoxy, NR1R2, CONR1R2, CN, COOH, C5-C10 optionally substituted aryl , optionally substituted 5 to 10 membered heteroaryl, C3-C6 cycloalkyl and 3 to 8 membered heterocycle. Thus, it will be realized that an optionally substituted C1-C6 alkyl may be an optionally substituted C1-C6 haloalkyl, i.e., a C1-C6 alkyl substituted with at least one halogen, and optionally substituted additionally with one or more of OH, C1 -C6 alkoxy, NR1R2, CONR1R2, CN, COOH, an optionally substituted C5-C10 aryl, an optionally substituted 5 to 10 membered heteroaryl, C3-C6 cycloalkyl and 3 to 8 membered heterocycle. It will be appreciated that an optionally substituted C1-C6 alkyl may be an optionally substituted polyfluoralkyl. R1 and R2 can each be independently selected from the group consisting of H, halogen and optionally substituted C1-C6 alkyl.
[0037] [0037] The term "halo" includes fluorine (-F), chlorine (-Cl), bromine (-Br) and iodine (-I).
[0038] [0038] The term "polyfluoroalkyl" can denote a C1-C3 alkyl group in which two or more hydrogen atoms are replaced by fluorine atoms. The term may include perfluoralkyl groups, that is, a C1-C3 alkyl group in which all hydrogen atoms are replaced by fluorine atoms. Thus, the term C1-C3 polyfluoroalkyl includes, but is not limited to, difluoromethyl, trifluoromethyl, 2,2,2-trifluorethyl, pentafluorethyl, 3,3,3-trifluorpropyl, 2,2,3,3,3- pentafluorpropyl, and 2,2,2-trifluor-1- (trifluoromethyl) ethyl.
[0039] [0039] "Aloxy" refers to the group R15-O- where R15 is an optionally substituted C1-C6 alkyl group, an optionally substituted C3-C6 cycloalkyl group, an optionally substituted C2-C6 alkenyl or an optionally substituted C2-C6 alkynyl . Exemplary C1-C6 alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy (1-propoxy), n-butoxy and tert-butoxy. An alkoxy group can be unsubstituted or substituted with one or more of halogen, OH, OP (O) (OH) 2, OSO2R13, N (H) SO2R13, alkoxy, NR1R2, CONR1R2, CN, COOH, aryl, heteroaryl, cycloalkyl and heterocycle. R1 and R2 can each be independently selected from the group consisting of H, halogen and optionally substituted C1-C6 alkyl.
[0040] [0040] "Thioalkyl" refers to the group R15-S- where R15 is an optionally substituted C1-C6 alkyl group or an optionally substituted C3-C6 cycloalkyl group. A thioalkyl group can be unsubstituted or substituted with one or more of halogen, OH, OP (O) (OH) 2, alkoxy, NR1R2, CONR1R2, CN, COOH, aryl, heteroaryl, cycloalkyl and heterocycle. R1 and R2 can each be independently selected from the group consisting of H, halogen and optionally substituted C1-C6 alkyl.
[0041] [0041] "Arila" refers to a 5- to 10-membered aromatic hydrocarbon group. Examples of a C5-C10 aryl group include, but are not limited to, phenyl, α-naphthyl, β-naphthyl, biphenyl, tetrahydronaphthyl and indanyl. An aryl group can be unsubstituted or substituted with one or more optionally substituted C1-C6 alkyl, halogen, OH, OP (O) (OH) 2, optionally substituted C1-C6 alkoxy, NR1R2, CONR1R2, CN, COOH, NO2 , azido, C1-C3 polyfluoroalkyl, aryloxy, heteroaryloxy, 5 to 10 membered heteroaryl, 3 to 8 membered heterocycle, SO2R1, NHCOR1, OC (O) OR1, OC (O) NR1R2 and OC (O) R1. R1 and R2 can each be independently selected from the group consisting of H, halogen and optionally substituted C1-C6 alkyl.
[0042] [0042] The term "bicycle" or "bicyclic" as used here refers to a molecule that features two fused rings, whose rings are a cycloalkyl, heterocyclyl, or heteroaryl. In one embodiment, the rings are fused through a bond between two atoms. The bicyclic fraction formed from it shares a bond between the rings. In another embodiment, the bicyclic fraction is formed by the fusion of two rings through a sequence of ring atoms to form a connecting head. Similarly, a "bond" is an unbranched chain of one or more atoms connecting two bonding heads in a polycyclic compound. In another embodiment, the bicyclic molecule is a "spiro" or "spirocyclic" fraction. The spirocyclic group can be a C3-C6 cycloalkyl or a 3- to 8-membered mono- or bicyclic heterocycle that is attached via a single carbon atom of the spirocyclic fraction to a single carbon atom of a carbocyclic or heterocyclic fraction. In one embodiment, the spirocyclic group is a cycloalkyl and is linked to another cycloalkyl. In another embodiment, the spirocyclic group is a cycloalkyl and is linked to a heterocyclyl. In an additional embodiment, the spirocyclic group is a heterocyclyl and is linked to another heterocyclyl. In yet another modality, the spirocyclic group is a heterocyclyl and is linked to a cycloalkyl. A spirocyclic group can be unsubstituted or substituted with one or more optionally substituted C1-C6 alkyl, halogen, OH, C1-C6 optionally substituted alkoxy, NR1R2, CONR1R2, CN, COOH, NO2, azido, C1-C3 polyfluoroalkyl and NHCOR1 . R1 and R2 can each be independently selected from the group consisting of H, halogen and optionally substituted C1-C6 alkyl.
[0043] [0043] "Alkoxycarbonyl" refers to the alkyl-O-C (O) - group, where alkyl is an optionally substituted C1-C6 alkyl. An alkoxycarbonyl group can be unsubstituted or substituted with one or more of halogen, OH, NR1R2, CN, C1-C6 alkoxy, COOH, C5-C10 aryl, 5 to 10 membered heteroaryl or C3-C6 cycloalkyl. R1 and R2 can each be independently selected from the group consisting of H, halogen and optionally substituted C1-C6 alkyl.
[0044] [0044] "Aryloxy" refers to the Ar-O- group where Ar is an optionally substituted mono or bicyclic C5-C10 aryl group, as defined above.
[0045] [0045] "Cycloalkyl" refers to a saturated, partially saturated, partially saturated, non-aromatic, 3- to 6-membered hydrocarbon ring system. Representative examples of a C3-C6 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl. A cycloalkyl group may be unsubstituted or substituted with one or more optionally substituted C1-C6 alkyl, halogen, CN, hydroxyl, COOH, CONR1R2, NR1R2, NHCOR1, C1-C6 alkoxy, azido, C1-C3 polyfluoroalkyl, aryloxy, heteroaryloxy , 5 to 10 membered heteroaryl, SO2R1, C5-C10 optionally substituted mono or bicyclic aryl, optionally substituted 5 to 10 membered mono or bicyclic heteroaryl, optionally substituted 3 to 8 membered mono or bicyclic heterocycle, C3-C6 cycloalkyl. R1 and R2 can each be independently selected from the group consisting of H, halogen and optionally substituted C1-C6 alkyl.
[0046] [0046] "Heteroaryl" refers to a 5- to 10-membered monocyclic or aromatic bicyclic ring system in which at least one atom of the ring is a heteroatom. The or each heteroatom can be independently selected from the group consisting of oxygen, sulfur and nitrogen. Examples of 5 to 10 membered heteroaryl include furan, thiophene, indole, azaindole, oxazole, thiazole, isoxazole, isothiazole, imidazole, N-methylimidazole, pyridine, pyrimidine, pyrazine, pyrrole, N-methylpyrrole, pyrazole, N-methylpyrazole , 3,4-oxadiazole, 1,2,4-triazole, 1-methyl-1,2,4-triazole, 1H-tetrazole, 1-methyltetrazole, benzoxazole, benzothiazole,
[0047] [0047] "Heterocycle" or "heterocyclyl" refers to 3- to 8-membered monocyclic, bicyclic or linked molecules in which at least one ring atom is a heteroatom. The or each heteroatom can be independently selected from the group consisting of oxygen, sulfur and nitrogen. A heterocycle can be saturated or partially saturated. Exemplary 3- to 8-membered heterocyclyl groups include, but are not limited to, aziridine, oxirane, oxirene, ti-iran, pyrroline, pyrrolidine, dihydrofuran, tetrahydrofuran, dihydrothiophene, tetrahydrothiophene, dithiolane, piperidine, 1,2,3,6-tetrahydropyridine-1-yl, tetrahydropyran, pyran, morpholine, piperazine, tiano, thiine, piperazine, azepano, diazepan, oxazine. A heterocyclyl group can be unsubstituted or substituted with one or more of optionally substituted C1-C6 alkyl, halogen, C1-C6 alkoxy, OH, NR1R2, COOH, C1-C6 alkoxycarbonyl, CONR1R2, NO2, NHCOR1,
[0048] [0048] "Alkenyl" refers to olefinically unsaturated hydrocarbon groups that can be unbranched or branched. In certain embodiments, the alkenyl group has 2 to 6 carbons, that is, it is a C2-C6 alkenyl. C2-C6 alkenyl includes, for example, vinyl, allyl, propenyl, butenyl, pentenyl and hexenyl. An alkenyl group can be unsubstituted or substituted with one or more of C1-C6 alkyl, halogen, OH, C1-C6 alkoxy, C1-C3 polyfluoralkyl, NR1R2, CONR1R2, SO2R1, NHCOR1, CN, COOH, C5-C10 aryl, 5 to 10 membered heteroaryl, C3-C6 cycloalkyl, aryloxy, heteroaryloxy, and 3 to 8 membered heterocycle. R1 and R2 can each be independently selected from the group consisting of H, halogen and optionally substituted C1-C6 alkyl.
[0049] [0049] "Alquinyl" refers to acetylenically unsaturated hydrocarbon groups that can be unbranched or branched. In certain embodiments, the alkynyl group has 2 to 6 carbons, that is, it is a C2-C6 alkynyl. C2-C6 alkynyl includes, for example, propargyl, propynyl, butynyl, pentynyl and hexynyl. An alkynyl group can be unsubstituted or substituted with one or more of C1-C6 alkyl, halogen, OH, C1-C6 alkoxy, C1-C3 polyfluoralkyl, NR1R2, CONR1R2, SO2R1, NHCOR1, CN, COOH, C5-C10 aryl, 5 to 10 membered heteroaryl, C3-C6 cycloalkyl, aryloxy, heteroaryloxy, and 3 to 8 membered heterocycle. R1 and R2 can each be independently selected from the group consisting of H, halogen and optionally substituted C1-C6 alkyl.
[0050] [0050] "Alkylsulfonyl" refers to the alkyl-SO2- group where alkyl is an optionally substituted C1-C6 alkyl, and is as defined above.
[0051] [0051] "Heteroaryloxy" refers to the heteroaryl-O- group where the heteroaryl is an optionally substituted 5- to 10-membered mono or bicyclic heteroaryl, and is as previously defined.
[0052] [0052] "Heterocyclyloxy" refers to the heterocyclo-O- group where heterocycle is an optionally substituted 3- to 8-membered mono- or bicyclic heterocycle, and is as previously defined.
[0053] [0053] It is understood that a complex of the compound of formula (I) can be a multicomponent complex, in which the drug and at least one other component are present in stoichiometric or non-stoichiometric amounts. The complex can be other than a salt or solvate. Such complexes include clathrates (drug host inclusion complexes) and co-crystals. The latter are typically defined as crystalline complexes of neutral molecular constituents that are linked together through non-covalent interactions, but could also be a complex of a neutral molecule with a salt. Co-crystals can be prepared by crystallizing the melt, recrystallizing solvents, or physically grinding the components together - see Chem Commun, 17, 1889-1896, by O. Almarsson and M. J. Zaworotko (2004), incorporated by reference. For a general review of multicomponent complexes, see J Pharm Sci, 64 (8),
[0054] [0054] It is understood that the term "pharmaceutically acceptable salt" can be used to refer to any salt of a compound provided here that retains its biological properties and is non-toxic or otherwise undesirable for pharmaceutical use. Such salts can be derived from a variety of organic and inorganic counterions well known in the art. Such salts include, but are not limited to: (1) acid addition salts formed with organic or inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, sulfamic, adepic acetic, aspartic, trichloroacetic propionic, hexaneic acid , cyclopentylpropionic, glycolic, glutaric, pyruvic, lactic, malonic, succinic, sorbic, ascorbic, malic, maleic, fumaric, tartaric, citric, benzoic, 3- (4-hydroxybenzoyl) benzoic, picric, kinetic, mandelic, phthalic, mandelic, phthalic, mandelic, phthalic, mandelic, phthalic, mandelic, phthalic, mandelic, phthalic, mandelic, phthalic, mandelic, phyllic, mandelic, mandelic, phyllic, mandelic, mandelic, phyllic, mandelic, mandelic, phyllic, mandelic, mandelic. methanesulfonic, ethanesulfonic, 1,2-ethane-disulfonic, 2-hydroxyethanesulfonic, benzenesulfonic, 4-chlorobenzenesulfonic, 2-naphthalenesulfonic, 4-toluenesulfonic, camphoric, camphorsulfonic, 4-methylbicycle [2.2.2] -oct-2-eno-1 -carboxylic, glucoheptonic, 3-phenylpropionic, trimethylacetic, tert-butylacetic, lauryl sulfuric, gluconic, benzoic, glutamic, hydroxinaftoic, salicylic, stearic, cyclohexylsulfamic, quinic, muconic and similar acids ; or (2) base addition salts formed when an acidic proton present in the parent compound both (a) is replaced by a metal ion, for example, an alkali metal ion,
[0055] [0055] Pharmaceutically acceptable salts may include, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium and the like, and when the compound contains basic functionality, salts of non-toxic organic or inorganic acids, such as hydrohalides, for example. example, hydrochloride, hydrobromide and iodhydrate, carbonate or bicarbonate, sulfate or bisulfate, borate, phosphate, hydrogen phosphate, dihydrogen phosphate, pyroglutamate, saccharate, stearate, sulfamate, nitrate, orotate, oxalate, palmitate, pamoate, acetate, trifluoroacetate, trifluoroacetate, trifate, acetate propionate, hexanoate, cyclopentylpropionate, glycolate, glutarate, pyruvate, lactate, malonate, succinate, tannate, tartrate, tosylate, sorbate, ascorbate, malate, maleate, fumarate, tartrate, camsylate, citrate, cyclamate, benzoate, isetionate, esylate, format 3- (4-hydroxybenzoyl) benzoate, picrate, cinnamate, mandelate, phthalate, laurate, methanesulfonate
[0056] [0056] Hemisais of acids and bases can also be formed, for example, hemisulfate salts.
[0057] [0057] Those skilled in the art will realize that the aforementioned salts include those in which the counterion is optically active, for example, D-lactate, or racemic, for example, DL-tartrate.
[0058] [0058] For a review on suitable salts, see “Handbook of Pharmaceutical Salts: Properties, Selection, and Use” by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).
[0059] [0059] Pharmaceutically acceptable salts of compounds of formula (I) can be prepared by one or more of three methods: (i) by reacting the compound of formula (I) with the desired acid or base; (ii) removing an acid or base labile protecting group from a suitable precursor of the compound of formula (I) using the desired acid or base; or (iii) by converting a salt of the compound of the formula
[00142] [00142] All three reactions are typically carried out in solution. The resulting salt can precipitate and be collected by filtration, or it can be recovered by evaporation of the solvent. The degree of ionization in the resulting salt can vary from completely ionized to almost non-ionized.
[0060] [0060] It is understood that the term "solvate" can refer to a compound provided here or a salt thereof, which additionally includes a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. Where the solvent is water, the solvate is a hydrate. Pharmaceutically acceptable solvates according to the invention include those in which the crystallization solvent can be isotopically substituted, for example, D2O, d6-acetone and d6-DMSO.
[0061] [0061] A currently accepted classification system for organic hydrates is one that defines site, channel, or hydrates coordinated by isolated metal ions - see Polymorfism in Pharmaceutical Solids by KR Morris (Ed. HG Brittain, Marcel Dekker, 1995), incorporated here by reference. Isolated site hydrates are those in which water molecules are isolated from direct contact with each other by intervening organic molecules. In channel hydrates, the water molecules are in channels of the lattice where they are close to other water molecules. In metal ion coordinated hydrates, the water molecules are attached to the metal ion.
[0062] [0062] When the solvent or water is firmly bound, the complex will have a well-defined stoichiometry regardless of moisture. When, however, the solvent or water is weakly bound, as in channel solvates and hygroscopic compounds, the water / solvent content will depend on moisture and drying conditions. In such cases, no stoichiometry will be the norm.
[0063] [0063] The compounds of the invention can exist in a solid state continuum ranging from totally amorphous to totally crystalline, including polymorphs of said crystalline material. The term 'amorphous' refers to a state in which the material has no long-range order at the molecular level and, depending on the temperature, can exhibit the physical properties of a solid or liquid. Typically, such materials do not give distinct X-ray diffraction patterns and, while exhibiting the properties of a solid, are more formally described as a liquid. Upon heating, there is a change in properties from solid to liquid, which is characterized by a change in state, typically second order ('glass transition'). The term 'crystalline' refers to a solid phase in which the material has an orderly internal structure at the molecular level and gives a distinct X-ray diffraction pattern with defined peaks. Such materials, when heated sufficiently, will also exhibit the properties of a liquid, but the change from solid to liquid is characterized by a phase change, typically of the first order ('melting point').
[0064] [0064] The compounds of the invention can also exist in a mesomorphic state (mesophase or liquid crystal) when subjected to suitable conditions. The mesomorphic state is intermediate between the true crystalline state and the true liquid state (both fused and solution). Mesomorphism that arises as a result of a change in temperature is described as 'thermotropic' and, which results from the addition of a second component, such as water or another solvent, is described as 'lyotropic'. Compounds that have the potential to form lyotropic mesophases are described as 'amphiphilic' and consist of molecules that have an ionic polar head group (such as -COO-Na +, - COO-K +, or -SO3-Na +) or non-ionic (such as -N-N + (CH3) 3). For more information, see Crystals and the Polarizing Microscope by N. H. Hartshorne and A. Stuart, 4th Edition (Edward Arnold, 1970), incorporated here by reference.
[0065] [0065] L can be CH2, C = O or SO2. In this way, the compound can be represented by any of the formulas (I-I) to (I-III); H R6 O R6 O R6
[0066] [0066] It will be noticed that in the previous structures L is –CH2-. However, analogous formulas where L is C = O or SO2 are also within the scope of the present invention and are also incorporated here.
[0067] [0067] In a mode X1 is CR1, X2 is CR2 and X3 is CR3. R1, R2 and R3 can each be independently selected from the group consisting of H, halogen, and optionally substituted C1-C6 alkyl. Preferably, R1, R2 and R3 are each independently selected from the group consisting of H, halogen, and C1-C3 alkyl. More preferably, R1, R2 and R3 are each independently selected from the group consisting of H, halogen, and methyl. Above all preferably, R1, R2 and R3 are each H.
[0068] [0068] In an alternative mode, one or two of X1, X2 and X3 is N. In this way, X1 can be N, X2 can be CR2 and X3 can be CR3, X1 can be CR1, X2 can be N and X3 can be be CR3 or X1 can be CR1, X2 can be CR2 and X3 can be N.
[0069] [0069] Consequently, the compound can be represented by any of the formulas (I-I-I-I) to (I-I-I-III):
[0070] [0070] It can be seen that in the formula (I-I-I-I) a (I-I-I-III) Q is C = O. However, analogous formulas where Q is SO2, S = O, CR4R5 or C = S are also within the scope of the invention.
[0071] [0071] Preferably X2 is CR2. In this way, X1 can be CR1 or N and X3 can be CR3 or N. X1 can be N, X2 can be CR2 and X3 can be CR3, or X1 can be CR1, X2 can be
[0072] [0072] Preferably, R1 and / or R3, in embodiments where they are present, are independently H, halogen or C1-C3 alkyl. More preferably, R1 and / or R3, in embodiments where they are present, are independently H, halogen or methyl. Above all, preferably R1 and / or R3, in modalities where they are present, are H.
[0073] [0073] Compounds of formula (I) can include one or more stereogenic centers and thus can exist as optical isomers, such as enantiomers and diastereomers. All such isomers and mixtures thereof are included in the scope of the present invention.
[0074] [0074] In modalities where R9 is different from R10 then the compound of formula (I) will include a first stereogenic center. It can be seen that the first stereogenic center, or stereocenter, is the carbon atom to which R9 and R10 are covalently attached.
[0075] [0075] Compounds of formula (I) can be represented by a formula (I) -ent 1 or (I) -ent 2:
[0076] [0076] Preferably, the first stereogenic center defines an S enantiomer.
[0077] [0077] Preferably, at least one of R9 and R10 is an optionally substituted C1-C6 alkyl, halogen, H, a C3-C6 cycloalkyl or C1-C3 polyfluoralkyl. More preferably, at least one of R9 and R10 is a C1-C6 alkyl, H or a C3-C6 cycloalkyl, even more preferably a C1-C3 alkyl, H or a C3-C6 cycloalkyl, and above all preferably at least one of R9 and R10 is H, methyl, ethyl, isopropyl or cyclopropyl. In one embodiment, R9 and R10 are both H. However, in an above all preferred embodiment, one of R9 and R10 is methyl and the other is H. In one embodiment, both R9 and R10 is an optionally substituted C1-C6 alkyl. or H. In one embodiment, both R9 and R10 is a C1-C6 alkyl, more preferably a C1-C3 alkyl, even more preferably methyl, ethyl or isopropyl, and most preferably both R9 and R10 is methyl. However, in an above all preferred modality, one of R9 and R10 is methyl and the other is H.
[0078] [0078] In one embodiment, the compound is a compound of the formula (I) -ent 1, R9 is H and R10 is an optionally substituted C1-C6 alkyl, halogen, a C3-C6 cycloalkyl or C1-C3 polyfluoralkyl. Preferably R10 is a C1-C6 alkyl or a C3-C6 cycloalkyl, more preferably R10 is a C1-C3 alkyl or a C3-C6 cycloalkyl, and above all preferably R10 is methyl, ethyl, isopropyl or cyclopropyl. In an above all preferred embodiment, R10 is methyl.
[0079] [0079] As mentioned earlier, Q can be CR4R5. Thus, the compound can be a compound of the formula (I) -ent 3 or (I) -ent 4:
[0080] [0080] Alternatively, or in addition, L is a branched alkyl group. In this way, the compound can be a formula (I) -ent. 5 or (I) -ent. 6:
[0081] [0081] In yet another modality, the compound could have two chiral centers, and could be represented by a compound of the formula (II-IV) -ent 1, formula (II-IV) -ent 2, formula (II-IV ) -ent 3 or formula (II-IV) -ent 4:
[0082] [0082] It should be understood that the above compounds can exist as enantiomers and as diastereoisomeric pairs. These isomers also represent additional embodiments of the invention.
[0083] [0083] Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis of a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC) .
[0084] Alternatively, the racemate (or a racemic precursor) can be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound of formula (I) contains an acidic or basic fraction, a base or acid such as 1-phenylethylamine or tartaric acid. The resulting diastereomeric mixture can be separated by chromatography and / or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer (s) by means well known to those skilled in the art.
[0085] [0085] Chiral compounds of the invention (and chiral precursors thereof) can be obtained in enantiomerically enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% by volume of isopropanol, typically 2% to 20%, and 0 to 5% by volume of an alkylamine, typically 0.1% diethylamine. Concentration of the eluate makes the enriched mixture available.
[0086] [0086] Mixtures of stereoisomers can be separated by conventional techniques known to those skilled in the art; see, for example, “Stereochemistry of Organic Compounds” by E. L. Eliel and S. H. Wilen (Wiley, New York, 1994).
[0087] [0087] In one embodiment, R11 is selected from the group consisting of optionally substituted C1-C6 alkyl, H, hydroxyl, polyfluoralkyl C1-C3, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy and optionally C2-C6 alkenyl substituted. Preferably, R11 is selected from the group consisting of C1-C6 alkyl, C2-C4 alkenyl and H. Most preferably, R11 is a C1-C3 alkyl or H, and most preferably it is methyl or H.
[0088] [0088] Preferably, R11 is an optionally substituted C1-C6 alkyl, an optionally substituted C2-C6 alkenyl, a C3-C6 cycloalkyl or C1-C3 polyfluoralkyl. More preferably, R11 is a C1-C6 alkyl, a C2-C6 alkenyl, or a C3-C6 cycloalkyl, even more preferably a C1-C3 alkyl, a C2-C3 alkenyl or a C3-C6 cycloalkyl, and above all preferably R11 is methyl, ethyl, isopropyl or cyclopropyl.
[0089] [0089] In an above all preferred mode, R11 is methyl.
[0090] [0090] In a preferred embodiment, Q is C = O, SO2 or CR4R5. More preferably, Q is C = O or CR4R5. Preferably, R4 and R5 are each independently selected from the group consisting of H, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl or R4 and R5 together with the atom to which they are attached form a spirocyclic ring. More preferably, R4 and R5 are each independently selected from the group consisting of optionally substituted H and C1-C6 alkyl. In this way, R4 and R5 can both be H. Alternatively, R4 and R5 can both be Me or R4 can be Me and R5 can be H.
[0091] [0091] Above all, preferably Q is C = O.
[0092] [0092] L can be C = O or SO2. However, in a preferred embodiment, L is optionally substituted C1-C6 alkyl, -CH2C (O) - or -CH2CONH-. Preferably, L is optionally substituted C1-C3 alkyl, more preferably -CH2-, -CH2CH2-, -CH2CH2CH2-, C (Me) H, CF2 or C (H) F and above all preferably -CH2-.
[0093] [0093] Preferably, R6 is a ring optionally substituted with one or more groups R12, wherein the ring is selected from the group consisting of a mono or bicyclic C5-C10 aryl; 5 to 10 membered mono or bicyclic heteroaryl; and a C3-C6 cycloalkyl. More preferably, R6 is a ring optionally substituted with one or more groups R12, wherein the ring is selected from the group consisting of a mono or bicyclic C5-C10 aryl; and mono or bicyclic heteroaryl of 5 to 10 members. Preferably above all, R6 is a mono or bicyclic C5-C10 aryl optionally substituted with one or more R12 groups.
[0094] [0094] In some modalities R6 is not replaced.
[0095] [0095] Alternatively, R6 may comprise a ring substituted with between 1 and 5 groups R12. In this way, the ring could be replaced with 1, 2, 3, 4 or 5 R12 groups.
[0096] [0096] An R12 group can be a halogen. The halogen can be fluorine, chlorine, bromine or iodine, more preferably fluorine, chlorine or bromine, still more preferably fluorine or chlorine, and above all preferably fluorine.
[0097] [0097] An R12 group may be an optionally substituted C1-C6 alkyl, and more preferably an optionally substituted C1-C3 alkyl. In some modalities,
[0098] [0098] An R12 group can be an optionally substituted C1-C6 alkoxy. In this way, an R12 group can be -OR15, where R15 is an optionally substituted C1-C6 alkyl group, an optionally substituted C3-C6 cycloalkyl group, an optionally substituted C2-C6 alkenyl or an optionally substituted C2-C6 alkynyl. Preferably, R15 is an optionally substituted C1-C3 alkyl group, an optionally substituted C2-C3 alkenyl or an optionally substituted C2-C3 alkynyl. In some embodiments, the C1-C6 alkoxy may be unsubstituted. Thus, an R12 group can be methoxy, ethoxy, n-propoxy (1-propoxy), n-butoxy and tert-butoxy. In a preferred embodiment, an R12 group is methoxy or -OCH2CHCH2. Alternatively, the C1-C6 alkoxy can be substituted with one or more groups selected from –OH, -NH2, CN, OP (O) (OH) 2, COOH, a halogen, OSO2R13, N (H) SO2R13, a C3- C6 cycloalkyl and a 3- to 8-membered heterocycle. R13 can be independently selected from the group consisting of optionally substituted H and C1-C6 alkyl. Preferably, R13 is selected from the group consisting of H and C1-C6 alkyl, more preferably H and C1-C3 alkyl. In a preferred embodiment R13 is Me. The C3-C6 cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. The 3- to 8-membered heterocycle can be aziridine, oxirane, oxirene, ti-iran, pyrroline, pyrrolidine, dihydrofuran, tetrahydrofuran, dihydrothiophene, tetrahydrothiophene, dithiolane, piperidine, 1,2,3,6 -tetrahydropyridine-1-yl, tetrahydropyran, pyran, morpholine, piperazine, tiano, thineine, piperazine, azepano, diazepan or oxazine. Preferably, the 3- to 8-membered heterocycle is morpholine.
[0099] [0099] In one embodiment, an R12 group is an optionally substituted alkoxy, that is, –OR15. R15 can be an optionally substituted C1-C6 alkyl.
[00100] [00100] In one embodiment, R15 is a C1-C6 alkyl substituted with a halogen, preferably a chlorine or fluorine and above all preferably a fluorine. In a preferred embodiment, the group R15 is a halogenated methyl, more preferably a fluorinated methyl and above all preferably -CHF2 or -CF3. In this way, an R12 group can be -OCHF2 or -OCF3.
[00101] [00101] Alternatively, R15 may be a C1-C6 alkyl substituted with one or more substituents selected from the group consisting of OH, OP (O) (OH) 2, OSO2R1, NHSO2R1, C1-C6 alkoxy, NR1R2, CONR1R2, CN , COOH, C5-C10 optionally substituted aryl, optionally substituted 5-10 membered heteroaryl, C3-C6 cycloalkyl and 3-8 membered heterocycle, more preferably R15 is a substituted C1-C6 alkyl with one or more substituents selected from the group that consists of OH, OP (O) (OH) 2, NHSO2R1, COOH and 3- to 8-membered heterocycle. Thus, a group R12 can be,,,,,, or where a is an integer between 1 and 6, and ebec are both integers between 0 and 5 where the sum of b and c is an integer between 0 and 5. In this way, a can be 1, 2, 3, 4, 5 or 6, and is preferably 1, 2 or 3. In this way, b and c can be 0, 1, 2, 3, 4 or 5. Preferably, b and c are both integers between 0 and 2 where the sum of b and c is an integer between 0 and 2. In a preferred embodiment, b is 1 and c is 1. A group R12 can be, or.
[00102] [00102] An R12 group can be NR13R14. R13 and R14 can each be independently selected from the group consisting of optionally substituted H and C1-C6 alkyl. Preferably, R13 and R14 are each independently selected from the group consisting of optionally substituted H and C1-C3 alkyl. In one embodiment, R13 and R14 are both H. In this way, a group R12 can be NH2. Alternatively, at least one of R13 and R14 can be an optionally substituted C1-C6 alkyl, preferably an optionally substituted C1-C3 alkyl. The or each alkyl may be unsubstituted. In this way, the or each alkyl can be methyl, ethyl, n-propyl (1-propyl) and isopropyl (2-propyl, 1-methylethyl), butyl, pentyl, hexyl, isobutyl, sec-butyl, tert-butyl, isopentyl , neopentyl, isohexyl or neohexyl. In this way, an R12 group can be N (H) Me or N (Me) 2. Alternatively, the or each alkyl can be replaced with a halogen, -OH, CN or NH2 group. In one embodiment, an R12 group can be –NH (CH2) mOH, where m is an integer between 1 and 6, more preferably between 1 and 3. In a preferred embodiment, m is 2 or 3.
[00103] [00103] A group R12 can be CONR13R14. R13 and R14 can each be independently selected from the group consisting of optionally substituted H and C1-C6 alkyl. Preferably, R13 and R14 are each independently selected from the group consisting of optionally substituted H and C1-C3 alkyl. In one embodiment, R13 and R14 are both H. Thus, a group R12 can be CONH2. Alternatively, at least one of R13 and R14 can be an optionally substituted C1-C6 alkyl, preferably optionally substituted C1-C3 alkyl. Preferably, the alkyl is substituted with an OH group. Thus, in one embodiment, a group R12 can be, where n is an integer between 1 and 6. Preferably, n is an integer between 1 and 3, and most of all preferably n is 2.
[00104] [00104] An R12 group can be COOR13. R13 can be independently selected from the group consisting of optionally substituted H and C1-C6 alkyl. Preferably, R13 is selected from the group consisting of H and C1-C6 alkyl, more preferably H and C1-C3 alkyl. In a preferred embodiment R13 is H or Me.
[00105] [00105] An R12 group can be OSO2R13. R13 can be selected from the group consisting of optionally substituted H and C1-C6 alkyl. Preferably, R13 is selected from the group consisting of H and C1-C6 alkyl, more preferably H and C1-C3 alkyl. In a preferred embodiment R13 is Me.
[00106] [00106] An R12 group can be NR13SO2R14. R13 and R14 can be independently selected from the group consisting of optionally substituted H and C1-C6 alkyl. Preferably, R13 and R14 are selected from the group consisting of H and C1-C6 alkyl, more preferably H and C1- C3 alkyl. In a preferred embodiment, R13 is H and R14 is Me.
[00107] [00107] An R12 group can be NR13C (O) R14. R13 and R14 can be independently selected from the group consisting of optionally substituted H and C1-C6 alkyl. Preferably, R13 and R14 are selected from the group consisting of H and an optionally substituted C1-C3 alkyl. The or each alkyl can be replaced with a halogen, - OH, CN or NH2 group. In a preferred embodiment, R13 is H and R14 is an optionally substituted methyl. Preferably, R14 is Me or –CH2NH2. In this way, an R12 group can be - NHC (O) CH3 or –NHC (O) CH2NH2.
[00108] [00108] An R12 group can be O (CH2) nOC (O) R13. N is preferably an integer between 1 and 6, more preferably between 1 and 3. In a preferred embodiment n is 2. R13 can be optionally substituted H or C1-C6 alkyl. In one embodiment, R13 is an optionally substituted C1-C6 alkyl, more preferably an optionally substituted C1-C3 alkyl, and above all preferably an optionally substituted methyl. Alkyl may be substituted with an optionally substituted halogen, OH, CN, NR1R2 or an optionally substituted C5-C10 aryl or mono. Preferably, the alkyl is substituted with NR1R2. Preferably, R1 and R2 are each independently selected from the group consisting of H and C1-C6 alkyl, more preferably H and C1-C3 alkyl. Above all preferably, R1 and R2 are both H. In this way, a group R12 can be, where m is an integer between 1 and 6, more preferably between 1 and 3, and most of all preferably it is 1. More preferably, more preferably an R12 group can be ________________, and above all preferably it is
[00109] [00109] ___________________.
[00110] [00110] An R12 group can be OC (O) OR13. R13 can be optionally substituted H or C1-C6 alkyl. In one embodiment, R13 is an optionally substituted C1-C6 alkyl, more preferably an optionally substituted C1-C3 alkyl, and above all preferably an optionally substituted methyl. Alkyl may be substituted with an optionally substituted halogen, OH, CN, NR1R2 or an optionally substituted C5-C10 aryl or mono. Preferably, the alkyl is substituted with an optionally substituted C5-C10 mono or bicyclic aryl. The optionally substituted mono or bicyclic C5-C10 aryl is preferably optionally substituted phenyl. In this way, a group R12 can be, where m is an integer between 1 and 6, p is an integer between 0 and 5 and o or each R16 is independently selected from the group consisting of an optionally substituted C1-C6 alkyl , halogen, OH, OP (O) (OH) 2, optionally substituted C1-C6 alkoxy, NR1R2, CONR1R2, CN, COOH, NO2, azido, C1-C3 polyfluoroalkyl, aryloxy, heteroaryloxy, 5 to 10 membered heteroaryl, heterocycle 3 to 8 members, SO2R1, NHCOR1 and –OC (O) O- (optionally substituted C1-C6 alkyl). In a preferred embodiment, m is 1. In a preferred embodiment, p is 1. In a preferred embodiment R16 is NHCOR1. Preferably, R1 is a C1-C6 alkyl, more preferably a C1-C3 alkyl and above all preferably a methyl. Thus, in a preferred embodiment, an R12 group can be.
[00111] [00111] An R12 group can be OC (O) NR13 (CH2) nCOOR14. R13 can be optionally substituted H or C1-C6 alkyl, preferably H or a C1-C6 alkyl, more preferably H or a C1-C3 alkyl and above all preferably methyl. Preferably, n is an integer between 1 and 6. In this way, n can be 1, 2, 3, 4, 5 or 6, and above all is preferably 1, 2 or 3. In a preferred embodiment, n is 2 R14 can be optionally substituted H or C1-C6 alkyl. In one embodiment, R14 is an optionally substituted C1-C6 alkyl, more preferably an optionally substituted C1-C3 alkyl, and most preferably preferably an optionally substituted methyl. The C1-C6 alkyl can be substituted with an optionally substituted C5-C10 mono or bicyclic aryl. The optionally substituted mono or bicyclic C5-C10 aryl is preferably optionally substituted phenyl. In one embodiment, the C5-C10 mono or bicyclic aryl is unsubstituted. Thus, in a preferred embodiment, a group R12 may be _________________, where each n is independently an integer between 0 and 6, preferably between 1 and 6, more preferably between 1 and 3. In an above all preferred embodiment, an R12 group can be.
[00112] [00112] An R12 group can be OC (O) NR13R14. R13 can be optionally substituted H or C1-C6 alkyl, preferably H or a C1-C6 alkyl, more preferably H or a C1-C3 alkyl and above all preferably methyl. R14 can be H or an optionally substituted C1-C6 alkyl, preferably H or an optionally substituted C1-C3 alkyl, more preferably an optionally substituted C1-C2 alkyl. The alkyl can be substituted with one or more of halogen, OH, OP (O) (OH) 2, C1-C6 alkoxy, NR1R2, CONR1R2, CN or COOH. In a preferred embodiment, the alkyl is substituted with NR1R2. R1 and R2 can each be independently selected from the group consisting of optionally substituted H, halogen and C1-C6 alkyl, plus H or a C1-C6 alkyl, even more preferably H or a C1- C3 alkyl, and most preferably preferably H or methyl. In a preferred embodiment, R1 is H and R2 is methyl. Thus, in a preferred embodiment, an R12 group can be _______________, where a is an integer between 1 and 6, preferably between 1 and 3. In a more preferred embodiment, an R12 group can be.
[00113] [00113] An R12 group can be an optionally substituted mono or bicyclic C5-C10 aryl. The optionally substituted mono or bicyclic C5-C10 aryl can be an optionally substituted phenyl. The C5-C10 aryl mono- or bicyclic group can be substituted with one or more of an optionally substituted C1-C6 alkyl, halogen, OH, optionally substituted C1-C6 alkoxy or CN. In one mode,
[00114] [00114] An R12 group can be an optionally substituted C3-C6 cycloalkyl. In some embodiments, C3-C6 cycloalkyl may be unsubstituted. In this way, the C3-C6 cycloalkyl can be a cyclopropyl, a cyclobutyl, a cyclopentyl or a cyclohexyl. In a preferred embodiment, an R12 group is a cyclopropyl.
[00115] [00115] Alternatively, or in addition, an R12 group can be CN, OH, OP (O) (OH) 2 or azido.
[00116] [00116] Preferably, R6 is a C5-C10 mono or bicyclic aryl or a 5 to 10 membered mono or bicyclic heteroaryl, optionally substituted with one or more R12 groups. More preferably, R6 is a phenyl or a pyridinyl, optionally substituted with one or more R12 groups. Preferably, the C5-C10 mono or bicyclic aryl or the 5- to 10-membered mono or bicyclic heteroaryl are substituted with one or more R12 groups. The one or more R12 groups can be as previously defined. More preferably, the or each R12 group is independently selected from halogen, methyl, CF3, OH, CH2OH, OPO (OH) 2, OMe, OCHF2, OCF3, OCH2CHCH2, O (CH2) mOH, O (CH2) mOPO (OH) 2, ______________, OCH2C (OH) HCH2OH, NH2, NHMe, C (O) NH2, CO (CH2) mOH,, OCH2CH2NS (O) 2Me e, where m is an integer between 1 and 6. More preferably, m is an integer between 1 and 3. More preferably, the one or more R12 groups preferably comprise one or more halogens. The one or more R12 groups can comprise one or 2 halogens. Preferably, the one or more halogens comprise one or more chlorines and / or fluorine, above all preferably one or more fluorine. The one or more R12 groups may additionally comprise one or more groups selected from methyl, OH, OMe, C (O) NH2, OCH2CH2OH, OCH2CH2CH2OH, OCH2C (OH) HCH2OH,, NH2 and OCH2CH2NS (O) 2Me.
[00117] [00117] In one mode, R6 can comprise:,,,,, or.
[00118] [00118] Preferably, Y is an optionally substituted C1-C6 alkyl, more preferably a C1-C3 alkyl, even more preferably -CH2-, -CH2CH2-, - CH2CH2CH2-, -CH (CH3) -, -CH (F) - and -CF2- and above all preferably -CH2-.
[00119] [00119] Preferably, R8 is an optionally substituted mono or bicyclic C5-C10 aryl, an optionally substituted 5 to 10 membered mono or bicyclic heteroaryl, an optionally substituted C3-C6 cycloalkyl or an optionally substituted heterocyclyl C3-C6.
[00120] [00120] In some embodiments, R8 may be an optionally substituted C3-C6 cycloalkyl or heterocyclyl C3-C6. R8 can comprise a C6 cycloalkyl or a 6-membered heterocycle. The C6 cycloalkyl or 6-membered heterocycle can be substituted with an optionally substituted C1-C6 alkyl or an optionally substituted mono or bicyclic C5-C10 aryl. Preferably, the C6 cycloalkyl or 6-membered heterocycle is substituted with a phenyl or a C1-C3 alkyl substituted with a phenyl, more preferably the C6 cycloalkyl or 6-membered heterocycle is replaced with a phenyl or -CH2-phenyl.
[00121] [00121] However, in a preferred embodiment, R8 is an optionally substituted C5-C10 mono or bicyclic aryl or an optionally substituted 5 to 10 membered mono or bicyclic heteroaryl. R8 can be optionally substituted phenyl, optionally substituted pyridine, optionally substituted naphthyl, optionally substituted furanyl, optionally substituted benzofuranyl, optionally substituted thiophene, optionally substituted pyridofuran, optionally substituted benzoxazole or optionally substituted benzothiazole. The C5-C10 mono or bicyclic aryl or the 5 to 10 membered mono or bicyclic heteroaryl can be substituted with between 1 and 5 substituents. In this way, the C5-C10 mono or bicyclic aryl or the 5 to 10 membered mono or bicyclic heteroaryl can be substituted with 1, 2, 3, 4 or 5 substituents. In one embodiment, the C5-C10 mono or bicyclic aryl or the 5- to 10-membered mono or bicyclic heteroaryl is substituted with 3 substituents. The or each substituent can be independently selected from the list consisting of C1-C6 alkyl, halogen, OH, C1-C6 alkoxy, CONR1R2, CN, azido, NO2, NH2, OCH2CH2OH, OCH2C (O) OH, OP (O) ( OH) 2 and an optionally substituted 3- to 8-membered mono- or bicyclic heterocycle. The optionally substituted 3- to 8-membered mono- or bicyclic heterocycle is preferably a 6-membered heterocycle, more preferably it is optionally substituted piperazinyl, and most preferably it is N-methylpiperazinyl. Preferably, the C5-C10 mono or bicyclic aryl or the 5- to 10-membered mono or bicyclic heteroaryl can be substituted with at least one C1-C6 alkyl, C1-C6 alkoxy or halogen, even more preferably at least one C1-C3 alkyl , C1-C3 alkoxy or halogen, and above all preferably at least one methyl, OMe and / or fluorine.
[00122] [00122] In a preferred embodiment, R8 is an optionally substituted benzofuranyl. Preferably, R8 is an unsubstituted benzofuranyl.
[00123] [00123] In an alternative preferred embodiment, R8 is an optionally substituted furanyl. Furanyl may be an unsubstituted furanyl. Alternatively, furanyl can be replaced. Preferably, the furanyl is substituted with at least one of C1-C3 alkyl or halogen, more preferably at least one of methyl or fluorine and above all preferably with a methyl group.
[00124] [00124] In an alternative preferred embodiment, R8 is an optionally substituted phenyl. Phenyl may be unsubstituted. Alternatively, phenyl can be substituted. Preferably, the phenyl is substituted with at least one of C1-C3 alkyl, C1-C3 alkoxy or halogen, more preferably at least one of methyl, methoxy or fluorine and above all preferably with 1, 2 or 3 fluorine.
[00125] [00125] In a preferred embodiment, X1 is CR1; X2 is CR2; X3 is CR3; Q is CO; L is -CH2-; Y is -CH2-; and R7 is H.
[00126] [00126] In an additional preferred embodiment X1 is N; X2 is CR2; X3 is CR3; Q is CO; L is -CH2-; Y is -CH2-; and R7 is H.
[00127] [00127] In an additional preferred embodiment, X1 is CR1; X2 is CR2; X3 is CR3; Q is CR4R5; L is C = O; Y is -CH2-; and R7 is H.
[00128] [00128] In an additional preferred embodiment, X1 is CR1; X2 is CR2; X3 is CR3; Q is CR4R5; L is SO2; Y is -CH2-; and R7 is H.
[00129] [00129] In an additional preferred embodiment, X1 is CR1. Preferably, X2 is CR2. Preferably, X3 is CR3. Preferably, Q is C = O or CR4R5. Preferably, L is optionally substituted C 1 -C 3 alkyl. L is above all preferably C1-C2 alkyl. Preferably, Y is an optionally substituted C1-C6 alkyl, more preferably a C1-C3 alkyl, and most preferably preferably a C1-C2 alkyl. Preferably, R1, R2 and R3 are each independently selected from the group consisting of optionally substituted H, halogen, CN, C1-C6 alkyl, C1-C3 polyfluoralkyl, and optionally substituted mono or bicyclic C1-C6 cycloalkyl. Preferably, R4 and R5 are each independently selected from the group consisting of H and C1-C6 alkyl. Preferably, R6 is a ring optionally substituted with one or more groups R12, wherein the ring is selected from the group consisting of a mono or bicyclic C5-C10 aryl; a 5 to 10 membered mono or bicyclic heteroaryl; and a C3-C6 cycloalkyl. Preferably, R7 is H. Preferably, R8 is an optionally substituted mono or bicyclic C5-C10 aryl, an optionally substituted mono or bicyclic heteroaryl
[00130] [00130] In a more preferred embodiment X1 is CH. Preferably, X2 is CH. Preferably, X3 is CH. Preferably, Q is C = O. Preferably, L is a C1-C2 alkyl. More preferably, L is -CH2-. Preferably, Y is a C1-C2 alkyl. More preferably, Y is -CH2-. Preferably, R6 is a ring optionally substituted with one or more groups R12, wherein the ring is selected from the group consisting of a mono or bicyclic C5-C10 aryl; and a 5- to 10-membered mono or bicyclic heteroaryl. Preferably, R6 is a phenyl or a pyridinyl optionally substituted with one or more R12 groups. Preferably, R6 is substituted with at least one group R12 selected from the group consisting of a halogen, -OH, optionally substituted C1-C4 alkoxy, amino, optionally substituted C1-C3 alkyl or C (O) NH2. Above all, preferably, R6 is replaced with one or two halogens. The or each halogen is preferably independently chlorine or fluorine. Optionally, the C5-C10 aryl can also be replaced with a hydroxyl.
[00131] [00131] Preferably, R7 is H. Preferably, R8 is an optionally substituted mono or bicyclic C5-C10 aryl or an optionally substituted 5 to 10 membered mono or bicyclic heteroaryl. Above all preferably, R8 is an optionally substituted phenyl ring. Preferably, R8 is replaced with at least one halogen. Preferably, R8 is substituted with 1, 2 or 3 halogens, more preferably 2 or 3 halogens. Preferably, the or each halogen is fluorine. Preferably, R9 and R10 are each independently selected from the group consisting of optionally substituted C1-C6 alkyl, optionally substituted C2-C4 alkenyl, H, halogen, CN and azido. More preferably, R9 and R10 are each independently selected from the group consisting of C1-C3 alkyl and H. Most preferably, R9 and R10 are each independently selected from the group consisting of CH3 and H. Preferably, R11 is selected from the group. consisting of optionally substituted C1-C6 alkyl, optionally substituted C2-C4 alkenyl and H. More preferably, R11 is selected from the group consisting of C1-C3 alkyl and H. Most preferably, R11 is selected from the group consisting of CH3 and H. Preferably, the first stereogenic center defines an S enantiomer.
[00132] [00132] It will be noticed that an 'agonist', an 'effector' or an activator, when they refer to a ligand and STING, comprise a molecule, combination of molecules, or a complex, which stimulate STING. On the contrary, a
[00133] [00133] Preferably, the compound of formula (I) is an activator of the STING protein.
[00134] [00134] It will be realized that the compounds described here or a salt, solvate, tautomeric form or pharmaceutically acceptable polymorphic form thereof can be used in a drug that can be used in monotherapy (ie use of the compound alone), to modulate the STING protein and / or treatment, improves or prevents a disease.
[00135] [00135] Alternatively, the compounds or a pharmaceutically acceptable salt, solvate, tautomeric or polymorphic form thereof can be used as an adjunct to, or in combination with, known therapies to modulate the STING protein and / or treatment, improvement or prevention of a disease.
[00136] [00136] Thus, in one aspect, a second therapeutic agent can be administered with a compound of the formula (I). The compound of formula (I) can be administered before, after, and / or together with the second therapeutic agent. The second therapeutic agent may comprise an antiviral agent, an anti-inflammation agent, conventional chemotherapy, an anti-cancer vaccine and / or hormone therapy. Alternatively, or in addition, the second therapeutic agent may comprise a B7 co-stimulatory molecule, interleukin-2, interferon-g, GM-CSF, a CTLA-4 antagonist (such as Ipilimumab and tremilimumab), an IDO inhibitor or IDO / inhibitor TDO (such as Epacadostat and GDC-0919), a PD-1 inhibitor (such as Nivolumab, Pembrolizumab, Pidilizumab, AMP-224, and MDX-1106), a PD-L1 inhibitor (such as Durvalumab, Avelumab and Atezolizumab ), an OX-40 ligand, a LAG3 inhibitor, a CD40 ligand, a 41BB / CD137 ligand, a CD27 ligand, Bacillus Calmette-Guerin (BCG), liposomes, alum, complete or incomplete Freund's adjuvant, a TLR agonist (such as Poli I: C, MPL, LPS, bacterial flagellin, imiquimod, resiquimod, loxoribin and a CpG dinucleotide) and / or detoxified endotoxins.
[00137] [00137] Methods for coadministration with an additional therapeutic agent are well known in the art (Hardman et. Al. (Eds.), Goodman and Gilman's The Pharmacological Basis of Therapeutics, 10th ed., 2001, McGraw-Hill New York, NY; Grouping and Peterson (eds.), Pharmacotherapeutics for Advanced Practice: A Practical Approach, 2001, Lippincott, Williams and Wilkins, Philadelphia, PA; Chabner and Longo (eds.), Cancer Chemotherapy and Biotherapy, 2001, Lippincott, Williams and Wilkins, Philadelphia, PA).
[00138] [00138] In one aspect, the disease is cancer and a chemotherapeutic agent can be administered with a compound of the formula (I). The chemotherapeutic agent can be selected from an additional group consisting of a cancer vaccine, a targeted drug, a targeted antibody, an antibody fragment, an antimetabolite, an antineoplastic, an antifolate, a toxin, an alkylating agent, an DNA strand break, a secondary DNA groove binding agent, a pyrimidine analog, a ribonucleotide reductase inhibitor, a tubulin interactive agent, an anti-hormonal agent, an immunomodulator, an anti-adrenal agent, a cytokine, therapy radiation therapy, cell therapy, cell depletion therapy such as B cell depletion therapy and hormonal therapy. Alternatively or in addition, the chemotherapeutic agent may comprise abiraterone, altretamine, anhydrovinblastine, auristatin, bexarotene, bicalutamide, bleomycin, caquetin, cemadotine, chlorambucil, cyclophosphamide, docetaxol, doxetaxel, carboplatin, ethoxycin, cisplatin, detoxine, cisplatin, detoxine, cisplatin, detoxine , 5-fluorouracil, finasteride, flutamide, hydroxyurea, streptozocin, mitomycin, methotrexate, taxanes, tamoxifen, vinblastine, vincristine and / or vindesine.
[00139] [00139] The compound of formula (I) can be combined into compositions having numerous different forms depending, in particular, on the way in which the composition has to be used. Thus, for example, the composition can be in the form of a powder, tablet, capsule, liquid, ointment, cream, gel, hydrogel, aerosol, spray, micellar solution, transdermal patch, liposome suspension or any other suitable form that can be administered to a person or animal in need of treatment. It will be realized that the medication vehicle according to the invention should be one that is well tolerated by the subject to whom it is given.
[00140] [00140] Medicines comprising the compounds described here can be used in a number of ways. Suitable modes of administration include oral, intratumor, parenteral, topical, inhaled / intranasal, rectal / intravaginal, and ocular / aural administration.
[00141] [00141] Formulations suitable for the aforementioned modes of administration can be formulated to have immediate and / or modified release. Modified release formulations include delayed, sustained, pulsed, controlled, targeted and programmed release.
[00142] [00142] The compounds of the invention can be administered orally. Oral administration may involve swallowing, as soon as the compound enters the gastrointestinal tract, or oral or sublingual administration, by which the compound enters the bloodstream directly through the mouth. Formulations suitable for oral administration include solid formulations such as tablets, capsules containing particles, liquids, or powders, lozenges (including liquid filled ones), gums, multi and nanoparticles, gels, solid solution, liposome, films, eggs, sprays, liquid formulations and buccal / mucoadhesive dressings.
[00143] [00143] Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations can be employed as fillers in soft or hard capsules and typically comprise a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methyl cellulose, or a suitable oil, and one or more emulsifying agents and / or suspending agents . Liquid formulations can also be prepared by reconstituting a solid, for example, a sachet.
[00144] [00144] The compounds of the invention can also be used in fast dissolving, rapid disintegrating dosage forms such as those described in Expert Opinion in Therapeutic Patents, 11 (6), 981-986, by Liang and Chen (2001).
[00145] [00145] For tablet dosage forms, depending on the dose, the drug can comprise from 1% by weight to 80% by weight of the dosage form, more typically from 5% by weight to 60% by weight of the dosage form. In addition to the drug, pills usually contain a disintegrant. Examples of disintegrants include sodium glycolate starch, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, hydroxypropyl cellulose substituted with lower alkyl, starch, pre-gelatinized starch and alginate. Generally, the disintegrant will comprise from 1% by weight to 25% by weight, preferably from 5% by weight to 20% by weight of the dosage form.
[00146] [00146] Binders are generally used to impart cohesive qualities to a tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose. Tablets can also contain diluents, such as lactose (monohydrate, spray dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose,
[00147] [00147] Tablets may also optionally comprise surface active agents, such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc. When present, surface active agents can comprise from 0.2% by weight to 5% by weight of the tablet, and glidants can comprise from 0.2% by weight to 1% by weight of the tablet.
[00148] [00148] Pills also generally contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulfate. Lubricants generally comprise from 0.25% by weight to 10% by weight, preferably from 0.5% by weight to 3% by weight of the tablet. Other possible ingredients include antioxidants, colorants, flavoring agents, preservatives and flavor masking agents.
[00149] Exemplary tablets contain up to about 80% of drug, from about 10% by weight to about 90% by weight of binder, from about 0% by weight to about 85% by weight of diluent, from about from 2% by weight to about 10% by weight of disintegrant, and from about 0.25% by weight to about 10% by weight of lubricant. Tablet combinations can be pressed directly or by roll to form tablets. Combinations of tablets or portions of combinations may alternatively be wetted, dried, or fused granules, frozen fused, or extruded prior to tabletting. The final formulation can comprise one or more layers and can be coated or uncoated; it can still be encapsulated. Tablet formulation is discussed in "Pharmaceutical Dosage Forms: Tablets", Vol. 1, by H. Lieberman and L. Lachman (Marcel Dekker, New York, 1980).
[00150] [00150] Modified release formulations suitable for the purposes of the invention are described in US Patent No. 6,106,864. Details of other suitable release technologies such as high-energy dispersions and osmotic and coated particles should be noted in “Pharmaceutical Technology On-line”, 25 (2), 1-14, by Verma et al (2001). The use of chewing gum to obtain controlled release is described in WO 00/35298.
[00151] [00151] The compounds of the invention can also be administered directly into the bloodstream, muscle, or an internal organ. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracrania, intramuscular and subcutaneous. Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques.
[00152] [00152] Parenteral formulations are typically aqueous solutions that may contain excipients such as salts, carbohydrates and buffering agents (preferably at a pH of 3 to 9), but, for some applications, they may be more suitably formulated as a non-aqueous solution sterile or as a dry form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water.
[00153] [00153] The preparation of parenteral formulations under sterile conditions, for example, by lyophilization, can easily be carried out using standard pharmaceutical techniques well known to those skilled in the art.
[00154] [00154] The solubility of compounds of formula (I) used in the preparation of parenteral solutions can be increased by the use of appropriate formulation techniques, such as the incorporation of solubility enhancing agents. Formulations for parenteral administration can be formulated to have immediate and / or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted, and programmed release. Thus compounds of the invention can be formulated as a solid, semi-solid, or thixotropic liquid for administration as an implanted deposit providing modified release of the active compound. Examples of such formulations include drug-coated stents and poly (dl-lactic-glycolic) (PGLA) microspheres.
[00155] [00155] The compounds of the invention can also be administered topically to the skin or mucosa, that is, dermally or transdermally. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, powder dressings, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages and microemulsions. Liposomes can also be used. Typical carriers include alcohol, water, mineral oil, liquid oil, white oil, glycerin, polyethylene glycol and propylene glycol. Penetration enhancers can be incorporated - see, for example, J Pharm Sci, 88 (10), 955-958, by Finnin and Morgan (October 1999).
[00156] [00156] Other means of topical administration include administration by electroporation, iontophoresis, phonophoresis, sonophoresis and microneedle or needle-free injection (eg Powderject ™, Bioject ™, etc.).
[00157] [00157] The compounds of the invention may also be administered intranasally or by inhalation, typically in the form of a dry powder (either alone, as a mixture, for example, in a dry combination with lactose, or as a mixed component particle, for example). example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurized container, pump, spray, atomizer (preferably an atomizer using electrohydrodynamics to produce a fine mist), or nebulizer, with or without the use of a suitable propellant, such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-hepta-fluorpropane. For intranasal use, the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin.
[00158] [00158] The pressurized container, pump, spray, atomizer, or nebulizer contains a solution or suspension of the compound (s) of the invention comprising, for example, ethanol, aqueous ethanol, or an alternative agent for dispersing, solubilizing, or extend active release, a propellant (s) as a solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.
[00159] [00159] Before use in a dry powder or suspension formulation, the drug product is micronized to a size suitable for administration by inhalation (typically less than 5 microns). This can be achieved by any appropriate reduction method, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenization, or spray drying.
[00160] [00160] Capsules (produced, for example, from gelatin or hydroxypropylmethylcellulose), blisters and cartridges for use in an inhaler or insufflator can be formulated to contain a powder mixture of the compound of the invention, a suitable powder base such as lactose or starch and a performance modifier such as L-leucine, mannitol, or magnesium stearate. The lactose can be anhydrous or in the form of the monohydrate, preferably the latter. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.
[00161] [00161] A solution formulation suitable for use in an atomizer using electrohydrodynamics to produce a fine mist can contain from 1μg to 20mg of the compound of the invention per actuation and the actuation volume can vary from 1μL to 100μL. A typical formulation can comprise a compound of the formula (I), propylene glycol, sterile water, ethanol and sodium chloride. Alternative solvents that can be used instead of propylene glycol include glycerol and polyethylene glycol.
[00162] [00162] Suitable flavors, such as menthol and levomenthol, or sweeteners, such as saccharin or sodium saccharin, can be added to those formulations of the invention intended for inhaled / intranasal administration.
[00163] [00163] In the case of dry powder inhalers and aerosols, the dosage unit is determined by means of a valve that delivers a measured quantity. Units according to the invention are typically arranged to deliver a metered dose or "breath" containing from 1μg to 100mg of the compound of formula (I). The general daily dose will typically be in the range of 1μg to 200mg which can be administered in a single dose or, more commonly, as divided doses throughout the day.
[00164] [00164] The compounds of the invention may be administered rectally or vaginally, for example, in the form of a suppository, pessary, microbicide, vaginal ring or enema. Cocoa butter is a traditional suppository base, but several alternatives can be used as appropriate.
[00165] [00165] The compounds of the invention can also be administered directly to the eye or ear, typically in the form of drops of a suspension or micronized solution in sterile isotonic saline, adjusted to pH. Other formulations suitable for ocular and auricular administration include ointments, biodegradable (for example, absorbable gel sponges, collagen) and non-biodegradable (for example, silicone) implants, cachets, lenses and particulate or vesicular systems, such as niosomes or liposomes. A polymer such as cross-linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, a cellulosic polymer, for example, hydroxypropylmethylcellulose, hydroxyethylcellulose, or methyl cellulose, or a heteropolysaccharide polymer, for example, gellan gum, can be incorporated together with such a preservative. like benzalkonium chloride. Such formulations can also be administered by iontophoresis.
[00166] [00166] The compounds of the invention can also be administered directly to a site of interest by injecting a solution or suspension containing the active drug substance. The site of interest can be a tumor and the compound can be administered by intratumor injection. Typical injection solutions are comprised of propylene glycol, sterile water, ethanol and sodium chloride. Alternative solvents that can be used instead of propylene glycol include glycerol and polyethylene glycol.
[00167] [00167] The compounds of the invention can be combined with soluble macromolecular entities, such as cyclodextrin and suitable derivatives thereof or polymers containing polyethylene glycol, in order to improve their solubility, dissolution rate, taste masking, bioavailability and / or stability for use in any of the aforementioned modes of administration.
[00168] [00168] It has been observed that drug-cyclodextrin complexes, for example, are generally useful for most dosage forms and routes of administration. Both inclusion and non-inclusion complexes can be used. As an alternative to direct complexation with the drug, cyclodextrin can be used as an auxiliary additive, that is, as a carrier, diluent, or solubilizer. Most commonly used for these purposes are alpha-, beta- and gamma-cyclodextrins, examples of which can be found in International Patent Applications No. WO 91/11172, WO 94/02518 and WO 98/55148.
[00169] [00169] It will be realized that the amount of the compound that is required is determined by its biological activity and bioavailability, which in turn depends on the mode of administration, the physicochemical properties of the compound,
[00170] [00170] Generally, for administration to a human, the total daily dose of the compounds of the invention is typically in the range 100μg to 10g, such as 1mg to 1g, for example, 10mg to 500mg. For example, oral administration may require a total daily dose of 25mg to 250mg. The total daily dose can be administered in single or divided doses and may, at the doctor's discretion, fall outside the typical range given here. These dosages are based on an average human subject having a weight of about 60kg to 70kg. The doctor can easily determine doses for subjects whose weight falls outside that range, such as children and the elderly.
[00171] [00171] However, skilled in the art realized that for agents that modulate the immune system, both the dose and the frequency of administration may be different from those of more traditional therapies. In particular, for agents that stimulate the immune system, for example, through modulation of STING, they can be administered in small doses, and very rarely, for example, twice weekly, weekly or monthly. Smaller doses can also be effective when administered topically to a small area of the skin.
[00172] [00172] The compound can be administered before, during or after the onset of action of the disease to be treated.
[00173] [00173] Known procedures, such as those conventionally employed by the pharmaceutical industry (for example, in vivo experimentation, clinical experiments, etc.), can be used to form specific formulations comprising the compounds according to the invention and precise therapeutic regimens (such as as daily doses of the compounds and the frequency of administration). The inventors believe that they are the first to describe a pharmaceutical composition to treat a disease, based on the use of the compounds of the invention.
[00174] Accordingly, in a seventh aspect of the invention, there is provided a pharmaceutical composition comprising a compound according to the first aspect, or a pharmaceutically acceptable salt, solvate, tautomeric or polymorphic form thereof, and a pharmaceutically acceptable carrier.
[00175] [00175] The invention also provides, in an eighth aspect, a process for producing the composition according to the seventh aspect, the process comprising bringing into contact a therapeutically effective amount of a compound of the first aspect, or a salt, solvate, form tautomeric or pharmaceutically acceptable polymorphic form thereof, and a pharmaceutically acceptable carrier.
[00176] [00176] A "subject" can be a vertebrate, mammal, or domestic animal. Consequently, compounds, compositions and medicaments according to the invention can be used to treat any mammal, for example, farm animals (for example, a horse), pets, or can be used in other veterinary applications. Above all, preferably, however, the subject is a human being.
[00177] [00177] A "therapeutically effective amount" of compound is any amount that, when administered to a subject, is the amount of drug that is needed to treat the target disease, or produce the desired effect, that is, modulate the STING protein.
[00178] [00178] For example, the therapeutically effective amount of compound used can be from about 0.01 mg to about 800 mg, and preferably from about 0.01 mg to about 500 mg. It is preferred that the amount of compound is from about 0.1 mg to about 250 mg, and above all preferably from about 0.1 mg to about 20 mg.
[00179] [00179] A "pharmaceutically acceptable carrier" as referred to herein, is any known compound or combination of known compound that are known to those skilled in the art as useful in formulating pharmaceutical compositions.
[00180] [00180] In one embodiment, the pharmaceutically acceptable carrier can be a solid, and the composition can be in the form of a powder or tablet. A solid pharmaceutically acceptable carrier can include one or more substances that can also act as flavoring agents, lubricants, solubilizers, suspending agents, dyes, fillers, glidants, compression aids, inert binders, sweeteners, preservatives, dyes,
[00181] [00181] However, the pharmaceutical carrier can be a liquid, and the pharmaceutical composition is in the form of a solution. Liquid vehicles are used in the preparation of solutions, suspensions, emulsions, syrups, elixirs and pressurized compositions. The compound according to the invention can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fats. The liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, coloring, viscosity regulators,
[00182] [00182] Liquid pharmaceutical compositions, which are sterile solutions or suspensions, can be used, for example, by intramuscular, intrathecal, epidural, intraperitoneal, intravenous and particularly subcutaneous injection. The compound can be prepared as a sterile solid composition that can be dissolved or suspended at the time of administration using sterile water, saline, or other appropriate sterile injectable medium.
[00183] [00183] The compound and compositions of the invention can be administered in the form of a sterile solution or suspension containing other solutes or suspending agents (for example, enough saline or glucose to produce the isotonic solution), bile salts, acacia, gelatin, monoleate sorbitan, polysorbate 80 (sorbitol oleate esters and their anhydrides copolymerized with ethylene oxide) and the like. The compounds used according to the invention can also be administered orally in both a liquid and a solid composition. Compositions suitable for oral administration include solid forms, such as pills, capsules, granules, tablets, and powders, and liquid forms, such as solutions, syrups, elixirs, and suspensions. Useful forms for parenteral administration include sterile solutions, emulsions, and suspensions.
[00184] [00184] Also included in the scope of the invention are soft drugs or anti-drugs that are compounds of formula (I) that contain metabolically or hydrolytically labile fractions that in vivo are converted into inactive derivatives. The processes by which the active drug substance is converted to an inactive derivative include, but are not limited to, ester hydrolysis, S-oxidation, N-oxidation, dealkylation and metabolic oxidation as described, for example, in Pearce et al ., Drug Metab. Dispos., 2006, 34, 1035-1040 and B. Testa, Prodrug and Soft Drug Design, in Comprehensive Medicinal Chemistry II, Volume 5, Elsevier, Oxford, 2007, pp. 1009-1041 and Bodor, N. Chem. Tech. 1984, 14, 28–38.
[00185] [00185] Those skilled in the art will know which active drug ingredients can be converted into a prodrug, which is a metabolically labile derivative that is converted in the body to the active drug substance. Also included in the scope of the invention are prodrugs that are compounds of formula (I) that contain metabolically or hydrolytically labile fractions that in vivo are converted into the active drug of formula (I). The processes by which the prodrug is converted to the active drug substance include, but are not limited to, ester hydrolysis, phosphate ester hydrolysis, S-oxidation, N-oxidation, dealkylation and metabolic oxidation as described in Beaumont et. al., Curr. Drug Metab., 2003, 4, 461-485 and Huttenen et. al., Pharmacol. Revs., 2011, 63, 750-771. The aforementioned prodrug fractions may therefore include functional groups that include carbonates, carbamates, esters, amides, ureas and lactams. Such prodrug derivatives may offer improved solubility, stability or permeability compared to the parent drug substance, or may allow the drug substance to be better administered via an alternative route of administration, for example, as an intravenous solution.
[00186] [00186] The invention also extends to a conjugate of a compound of formula (I).
[00187] [00187] Thus, in a further aspect of the invention, a conjugate of the formula (VI) is provided: (VI) wherein, C is a compound of the formula (I) L1 is a linker; T is a target fraction; and a is an integer between 1 and 10.
[00188] [00188] Such conjugates can be designed to specifically target certain cell types or tumor types by means of the target fraction, which directs the compound of formula (I) exactly to those cells or tumors and administers the STING activator in a specific way of the cell. The principle of such targeted administration will be known to those skilled in the art as being strictly related to ADC (antibody-drug conjugate) technology, for example, as described in Polakis, P., Pharmacol. Revs., 2016, 68, 3-19. The ligand will then be designed to cleave and the active compound would then diffuse into the cell and make contact with STING protein.
[00189] [00189] T can comprise an antibody, an antibody fragment, a nucleic acid based molecule, a carbohydrate, a peptide or a modified peptide.
[00190] [00190] In one embodiment, T comprises an antibody or antibody fragment. The antibody or antibody fragment can be designed to target the Human Growth Epidermal Factor Receptor (EGFR), a plasminogen activator, an antigen associated with cytotoxic T lymphocyte (CTLA) such as CTLA-4, vascular endothelial growth factor ( VEGF), neurotrophic factors such as BDNF, a nerve growth factor, platelet-derived growth factor (PDGF), transforming growth factor (TGF), EpCAM, FLT3, PSMA, PSCA, STEAP, CEA, folate receptor, the CD33 / CD30 / CD79 / CD22 receptors, the product of the SLC34A2 gene, the mesothelin protein, the tyrosine kinase EphA2, the cell surface antigens Muc1 / Muc16, ALK, AFP, brc-abl, caspase-8, CD20, CD40 , CD123, CDK4, c-kit, cMET, ErbB2 / Her2, ErbB3 / Her3, ErbB4 / Her4, Her2, OX40, p53, PAP, PAX3, PAX5, Ras, Rho or any other tumor antigen known to those skilled in the art.
[00191] [00191] The invention extends to both total antibodies as well as antigen-binding fragments or regions of the corresponding full-length antibody.
[00192] [00192] The antibody or antigen-binding fragment thereof may be monovalent, divalent or polyvalent. Monovalent antibodies are dimers (HL) comprising a heavy chain (H) associated by a disulfide bond with a light chain (L). Divalent antibodies are tetramers (H2L2) comprising two dimers associated with at least one disulfide bond. Polyvalent antibodies can also be produced, for example, by linking multiple dimers. The basic structure of an antibody molecule consists of two identical light chains and two identical heavy chains that associate non-covalently and can be linked by disulfide bonds. Each heavy and light chain contains a variable region at the amino terminal of about 110 amino acids, and constant sequences in the rest of the chain. The variable region includes several hyperemiable regions, or Complementarity Determining Regions (CDRs), which form the antigen-binding site of the antibody molecule and determines its specificity for the antigen or variant or fragment thereof (for example, an epitope). On either side of the heavy and light chain CDRs is a framework region, a relatively conserved sequence of amino acids that anchors and guides the CDRs. Antibody fragments can include a bispecific antibody (BsAb) or a chimeric antigen receptor (CAR).
[00193] [00193] The constant region consists of one of the five heavy chain sequences (μ, γ, ζ, α, or ε) and one of the two light chain sequences (κ or λ). The heavy chain constant region sequences determine the antibody isotype and the effector functions of the molecule.
[00194] [00194] Preferably, the antibody or antigen-binding fragment thereof is isolated or purified.
[00195] [00195] In a preferred embodiment, the antibody or antigen-binding fragment thereof comprises a polyclonal antibody, or an antigen-binding fragment thereof. The antibody or antigen-binding fragment thereof can be generated in a rabbit, mouse or rat.
[00196] [00196] In another preferred embodiment, the antibody or antigen-binding fragment thereof comprises a monoclonal antibody or an antigen-binding fragment thereof. Preferably, the antibody is a human antibody. As used herein, the term "human antibody" can mean an antibody, such as a monoclonal antibody, that comprises substantially the same amino acid sequences as the heavy and light chain CDR as seen in a particular human antibody that exhibits immunospecificity. An amino acid sequence, which is substantially the same as a heavy or light chain CDR, exhibits a considerable amount of sequence identity when compared to a reference sequence. Such an identity is definitely known or recognizable as representing the amino acid sequence of the particular human antibody. Substantially the same heavy and light chain CDR amino acid sequence can have, for example, secondary modifications or conservative amino acid substitutions.
[00197] [00197] The term "human monoclonal antibody" can include a monoclonal antibody with substantially or entirely human CDR amino acid sequences produced, for example, by recombinant methods such as production by a phage library, lymphocytes or hybridoma cells.
[00198] [00198] The term "humanized antibody" can mean an antibody of a non-human species (for example, mouse or rabbit) whose protein sequences have been modified to increase its similarity to antibodies produced naturally in humans.
[00199] [00199] The antibody can be a recombinant antibody. The term "human recombinant antibody" can include a human antibody produced using recombinant DNA technology.
[00200] [00200] The term "antigen-binding region" can mean a region of the antibody having specific binding affinity for its target antigen or a variant or fragment thereof. Preferably, the fragment is an epitope. The binding region can be a hypervariable CDR or a functional portion thereof. The expression "functional portion" of a CDR can mean a sequence within the CDR that shows specific affinity for the target antigen. The functional portion of a CDR may comprise a linker that specifically binds to the target antigen or a fragment thereof.
[00201] [00201] The term "CDR" can mean a hypervariable region in the heavy and light variable chains. There may be one, two, three or more CDRs on each of the antibody's heavy and light chains. Usually, there are at least three CDRs in each strand that, when configured together, form the antigen-binding site, that is, the three-dimensional combination site with which the antigen binds or specifically reacts. However, it has been postulated that there may be four CDRs in the heavy chains of some antibodies.
[00202] [00202] The definition of CDR also includes overlap or subsets of amino acid residues when compared against each other. The exact residue numbers that comprise a particular CDR or functional portion thereof will vary depending on the sequence and size of the CDR. Those skilled in the art can routinely determine which residues comprise a particular CDR given the sequence of amino acids in the variable region of the antibody.
[00203] [00203] The term "functional fragment" of an antibody can mean a portion of the antibody that retains functional activity. A functional activity can be, for example, antigen binding activity or specificity. A functional activity can also be, for example, an effector function provided by an antibody constant region. The term "functional fragment" is also intended to include, for example, fragments produced by digestion or protease reduction of a human monoclonal antibody and by recombinant DNA methods known to those skilled in the art. Functional fragments of human monoclonal antibody include, for example, individual heavy or light chains and fragments thereof, such as VL, VH and Fd; monovalent fragments, such as Fv, Fab, and Fab '; divalent fragments such as F (ab ') 2 fragments; Single chain Fv (scFv); and Fc.
[00204] [00204] The term "VL fragment" can mean a fragment of the light chain of a human monoclonal antibody that includes all or part of the variable region of the light chain,
[00205] [00205] The term "VH fragment" can mean a fragment of the heavy chain of a human monoclonal antibody that includes all or part of the variable region of the heavy chain, including CDRs.
[00206] [00206] The expression "Fd fragment" can mean the heavy chain variable region coupled to the first heavy chain constant region, that is, VH and CH-1. The "Fd fragment" does not include the light chain, or the second and third regions in the heavy chain.
[00207] [00207] The expression "Fv fragment" can mean a fragment of binding to the monovalent antigen of a human monoclonal antibody, including all or part of the variable regions of heavy and light chains, and absent of the constant regions of heavy and light chains. The variable regions of heavy and light chains include, for example, CDRs. For example, an Fv fragment includes all or part of the amino terminal variable region of about 110 amino acids from both heavy and light chains.
[00208] [00208] The term "Fab fragment" can mean a fragment of binding to the monovalent antigen of a human monoclonal antibody that is larger than an Fv fragment. For example, a Fab fragment includes the variable regions, and all or part of the first heavy and light chain constant domain. Thus, a Fab fragment additionally includes, for example, amino acid residues of about 110 to about 220 of the heavy and light chains.
[00209] [00209] The term "Fab fragment" can mean a fragment of binding to the monovalent antigen of a human monoclonal antibody that is larger than a Fab fragment. For example, a Fab 'fragment includes the entire light chain, the entire variable region of heavy chain, and all or part of the first and second constant domain of the heavy chain. For example, a Fab 'fragment may additionally include part or all of the 220 to 330 heavy chain amino acid residues.
[00210] [00210] The term "fragment F (ab ') 2" can mean a fragment of binding to the divalent antigen of a human monoclonal antibody. An F (ab ') 2 fragment includes, for example, all or part of the variable regions of two heavy chains and two light chains, and may additionally include all or part of the first constant domain of two heavy chains and two light chains.
[00211] [00211] The term "single chain Fv (scFv)" can mean a fusion of the variable regions of the heavy (VH) and light (VL) chains connected with a short linker peptide.
[00212] [00212] The term "bispecific antibody (BsAb)" can mean a bispecific antibody comprising two scFv linked to each other by a shorter linked peptide.
[00213] [00213] Those skilled in the art know that the exact limits of an antibody fragment are not important, as long as the fragment maintains a functional activity. Using well-known recombinant methods, skilled in the art, they can design a sequence of polynucleotides to express a functional fragment with any desired views for a particular application. A functional fragment of the antibody may comprise or consist of a fragment with substantially the same variable regions of the heavy and light chain as the human antibody.
[00214] [00214] The antigen-binding fragment thereof may comprise or consist of any of the selected fragments from a group consisting of VH, VL, Fd, Fv, Fab, Fab ', scFv, F (ab') 2 and Fc .
[00215] [00215] The antigen-binding fragment thereof may comprise or consist of any of the VL antigen-binding region sequences, any of the VH antigen-binding region sequences, or a combination of the VH-binding region sequences VL and VH antigen of a human antibody. The appropriate number and combination of VH and VL antigen binding region sequences can be determined by those skilled in the art depending on the desired affinity and specificity and the intended use of the antigen binding fragment. Functional fragments or antigen-binding fragments of antibodies can be easily produced and isolated using methods well known to those skilled in the art. Such methods include, for example, proteolytic methods, recombinant methods and chemical synthesis. Proteolytic methods for the isolation of functional fragments comprise using human antibodies as a starting material. Enzymes suitable for proteolysis of human immunoglobulins may include, for example, papain, and pepsin. The appropriate enzyme can be easily chosen by those skilled in the art, depending on, for example, whether monovalent or divalent fragments are required. For example, papain cleavage results in two monovalent Fab 'fragments that bind antigen and an Fc fragment. Cleavage of pepsin, for example, results in a divalent F (ab ') fragment. An F (ab ') 2 fragment of the invention can be further reduced using, for example, DTT or 2-mercaptoethanol to produce two monovalent Fab' fragments.
[00216] [00216] Functional or antigen-binding fragments of antibodies produced by proteolysis can be purified by affinity and column chromatographic procedures. For example, antibodies and undigested Fc fragments can be removed by binding to protein A. In addition, functional fragments can be purified by virtue of their charge and size, using, for example, ion exchange and gel filtration chromatography. Such methods are well known to those skilled in the art.
[00217] [00217] The antibody or antigen-binding fragment thereof can be produced by recombinant methodology. Preferably, a polynucleotide that encodes desired regions of the antibody heavy and light chains is initially isolated. Such regions can include, for example, all or part of the variable region of the heavy and light chains. Preferably, such regions can particularly include the antigen binding regions of the heavy and light chains, preferably the antigen binding sites, above all preferably the CDRs.
[00218] [00218] The polynucleotide encoding the antibody or antigen-binding fragment thereof according to the invention can be produced using methods known to those skilled in the art. The polynucleotide that encodes the antibody or antigen-binding fragment thereof can be directly synthesized by methods of oligonucleotide synthesis known in the art. Alternatively,
[00219] [00219] As used here, the term "immunospecificity" may mean that the binding region is capable of immunoreacting with the target antigen, or a variant or fragment thereof, specifically binding the same. The antibody or antigen-binding fragment thereof can selectively interact with an antigen with an affinity constant of approximately 10-5 to 10-13 M-1, preferably 10-6 to 10-9 M-1, even more preferably, 10-10 to 10-12 M-1.
[00220] [00220] The term "immunorreage" can mean that the binding region is capable of eliciting an immune response by binding with SEQ ID No: 3, or an epitope thereof.
[00221] [00221] The term "epitope" can mean any region of an antigen with the ability to elicit, and combine with, an antibody-binding region or antigen-binding fragment thereof.
[00222] [00222] In one embodiment, T comprises a molecule based on nucleic acid. The nucleic acid-based molecule can be an aptamer. The nucleic acid-based molecule can target the tumor CD33 / CD34 or PSMA antigen, or any other tumor antigen known to those skilled in the art, for example, as described in Orava, E., Biochem. Biophys. Acta, 2010, 1798, 2190-2200.
[00223] [00223] Aptamers are nucleic acid or peptide molecules that assume a specific sequence-dependent format, and bind to specific target ligands based on a lock and key fit between the aptamer and ligand. Typically, aptamers can comprise both single- and double-stranded DNA molecules (ssDNA or dsDNA) or single-stranded RNA (ssRNA) molecules. Peptide aptamers consist of a short peptide variable domain, affixed at both ends to a protein scaffold. Aptamers can be used to bind to both nucleic and non-nucleic acid targets.
[00224] [00224] Suitable aptamers can be selected from clusters of random sequence, of which specific aptamers can be identified that bind to the selected antigen with high affinity. Methods for the production and selection of aptamers having the desired specificity are well known to those skilled in the art, and include the SELEX process (systemic evolution of ligands by exponential enrichment). In summary, large oligonucleotide libraries are produced, allowing the isolation of large amounts of functional nucleic acids by an iterative process of in vitro selection and subsequent amplification through polymerase chain reaction. Preferred methodologies for producing aptamers include those described in WO 2004/042083.
[00225] [00225] In an alternative embodiment, T comprises a peptide or a modified peptide. The modified peptide or peptide may comprise the RGD sequence motif, as described in Mousavizadeh, A., Colloids Surfaces B., 2017, 158, 507-517.
[00226] [00226] L1 can comprise a carbonate, a carbamate, an ester, an amide, a urea and / or a lactam functional group (Beck, A. et. Al., Nat. Revs. Drug Disc., 2017, 16, 315 -337). Said ligands will be known to those skilled in the art as any 'stable' ligands that are resistant to degradation in cells and systemic circulation or 'conditionally labile' ligands that are designed to degrade in cells and / or systemic circulation after a triggering event defined, which can be a change in pH or a metabolic process such as ester or amide hydrolysis. Specific hydrolysis processes have been described, such as peptidase cleavage of a dipeptide, for example, the valine-citrulline dipeptide fraction contained in the clinically preceding ADC brentuximab vedotine or in the hydrolysis of a labile hydrazone fraction to gemtuzumab ozogamycin. Non-cleavable ligands include those contained in the clinically preceding ADC trastuzumab etansine.
[00227] [00227] a can be 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.
[00228] [00228] L1 may comprise an extended chain of carbon atoms or hetero atoms, for example, a linear or branched polyethylene glycol (PEG) chain, an optionally substituted natural or unnatural amino acid sequence or an optionally substituted linear or branched alkyl chain . The lysate can be seen as comprising an optionally substituted backbone, and the backbone of carbon atoms and / or heteroatoms. The backbone can consist of between 2 and 100 atoms, more preferably between 10 and 80 atoms or between 20 and 60 atoms. The backbone atoms can define one or more optionally substituted C5-C10 aryl, optionally substituted 5 to 10 membered heteroaryl, optionally substituted C3-C6 cycloalkyl and / or optionally substituted 3 to 8 membered heterocycle rings on the backbone. Atoms in the backbone can consist of carbon, nitrogen and / or oxygen atoms. The backbone atoms can be replaced with H, OH, = O, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl and / or optionally substituted C1-C6 alkoxy. L1 can also contain a functional handle group that allows the STING modulator to be chemically combined with the target fraction by means of a covalent bond. For example, thiol groups, or cysteine residues can be attached to the linker or spacer group via a maleimide group. Alternative conjugation chemicals include reactive lysine groups, such as succinyl esters, pentafluorfenyl esters, β-lactam amides, isocyanates, and isothiocyanates; reactive azide groups, such as alkynes and forced alkynes; reactive cysteine groups, such as maleimides, α-haloacetamides, pyridyl disulfides and vinyl sulfoxides; and reactive ketone groups, such as hydroxylamines, hydrazines and acyl hydrazides.
[00229] [00229] Linkers can be joined to a compound of formula (I) through a C atom, an O atom, an N atom or an S atom and can be functionalized with groups that include, but are not limited to the following;
[00230] [00230] Binders can be cleavable, non-cleavable, hydrophilic or hydrophobic.
[00231] [00231] A non-cleavable linker may be insensitive to protease.
[00232] [00232] L1 can include alkyl chains (for example, n-hexyl, n-pentyl, n-butyl, n-propyl), chains containing heteroatom (for example, ethyloxy, propyloxy, butyloxy, pentyloxy, hexyloxy, ethylene dioxide, polyethylene glycol (PEG)), amino acids (gicinyl, alaninyl, aminopropanoic acid, aminobutanoic acid, aminopentanoic acid, aminohexanoic acid) and peptide unit.
[00233] [00233] The inventors have observed that compounds of the current invention can be functionalized at various locations with a variety of ligands and spacers to provide conjugated molecules. Said binders can include auto-immolating groups (for example, a p-aminobenzyl ether or amine and / or a valine-citrulline unit) that are designed to release the parent STING modulator through a hydrolytic event, for example, after amide hydrolysis , peptide or carbamate.
[00234] [00234] The scope of the invention includes all pharmaceutically acceptable isotopically labeled compounds of the invention in which one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number that predominates in nature.
[00235] [00235] Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as 2H and 3H, carbon, such as 11C, 13C and 14C, chlorine, such as 36Cl, fluorine, such as 18F, iodine, such as 123I and 125I, nitrogen, such as 13N and 15N, oxygen, such as 15O, 17O and 18O, phosphorus, such as 32P, and sulfur, such as 35S.
[00236] [00236] Certain isotopically labeled compounds of the invention, for example, those that incorporate a radioactive isotope, are useful in studies of drug and / or substrate tissue distribution. Radioactive isotope tritium, that is, 3H, and carbon-14, that is, 14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Substitution with isotopes such as deuterium, i.e., 2H, may provide certain therapeutic advantages resulting from increased metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and therefore may be preferred in some circumstances. Replacement with positron emission isotopes, such as 11C, 18F, 15O and 13N, can be useful in Positron Emission Topography (PET) studies to examine substrate receptor occupation.
[00237] [00237] Isotopically labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the attached Examples and Preparations using an appropriate isotopically labeled reagent in place of the previously used unlabeled reagent.
[00238] [00238] According to a further aspect of the invention, a compound of formula (II) or (III) is provided: wherein, X1, X2, X3, Q, L, Y, R6, R7, R8, R9, R10 and R11 are as defined in the first aspect; and R is H or a C1-C6 alkyl, or a complex, salt, solvate, tautomeric form or pharmaceutically acceptable polymorphic form thereof.
[00239] [00239] It will be realized that compounds of formula (II) and (III) can be used to synthesize compounds of formula (I).
[00240] [00240] Preferably, X2 is CH.
[00241] [00241] Preferably, Q is C = O, SO2 or CR4R5. More preferably, Q is C = O.
[00242] [00242] Preferably, L is C1-C6 alkyl, more preferably C1-C3 alkyl, and above all preferably -CH2-.
[00243] [00243] Preferably, R6 is optionally substituted C5-C10 aryl. More preferably, R6 is substituted phenyl. Even more preferably, R6 is phenyl substituted with at least one halogen and / or an OH group. Above all, preferably, R6 is phenyl substituted with one or two halogens. Preferably, the or each halogen is chlorine or fluorine.
[00244] [00244] Preferably, R is H or methyl, ethyl, benzyl or tert-butyl. More preferably, R is H or methyl.
[00245] [00245] Preferably, Y is C1-C6 alkyl, more preferably C1-C3 alkyl, and most preferably preferably -CH2-.
[00246] [00246] Preferably, R7 is H.
[00247] [00247] Preferably, R8 is an optionally substituted mono or bicyclic C5-C10 aryl, an optionally substituted 5 to 10 membered mono or bicyclic heteroaryl, an optionally substituted C3-C6 cycloalkyl or an optionally substituted heterocyclyl C3-C6. Preferably, R8 is a C5-C10 mono or bicyclic aryl or a 5 to 10 membered mono or bicyclic heteroaryl substituted with between 1 and 5 substituents, and the or each substituent is independently selected from the list consisting of C1- C6 alkyl, halogen , OH, C1-C6 alkoxy, C1-C3 polyfluoroalkyl, CONR1R2, CN and azido. More preferably, R8 may be an optionally substituted phenyl, an optionally substituted pyridine, an optionally substituted naphthyl, an optionally substituted furanyl, an optionally substituted benzofuranyl, an optionally substituted thiophene, an optionally substituted pyridofuran, an optionally substituted benzoxazole or an optionally substituted benzothiazole . Preferably, R9 and R10 are each independently selected from the group consisting of C1-C6 alkyl, H, halogen, CN and azido. More preferably, R9 and R10 are each independently selected from the group consisting of C1-C3 alkyl and H. Most preferably, R9 and R10 are each independently selected from the group consisting of CH3 and H. Preferably, R11 is selected from the group. which consists of C1-C6 alkyl, H, C1-C6 alkoxy and C2-C6 alkenyl. More preferably, R11 is selected from the group consisting of C1-C3 alkyl and H. More preferably, R11 is selected from the group consisting of CH3 and H.
[00248] [00248] The compounds of formula (II) can be selected from:
[00249] [00249] The compound of the formula (III) can be selected from:
[00250] [00250] The application describes a compound of the formula (IV): (IV)
[00251] [00251] The additional application describes a compound of the formula (IV): (IV) or a pharmaceutically acceptable salt or prodrug thereof, wherein: X is CR9R10, O, S, S = O or SO2; X1 is CR1 or N; X2 is CR2 or N; X3 is CR3 or N; the or each Z is independently CR11R12 or NR11; n is 1 or 2; Q is C = O, S = O, SO2, C = S or CR4R5; L is optionally substituted C1-C6 alkyl, polyfluoralkyl C1-C3, optionally substituted C3-C6 cycloalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, C = O, S = O, SO2, - CH2C (O) -, -CH2CONH-, or -CONH-;
[00143] [00143] Preferably, when X is S; X1, X2 and X3 will be CH; n will be 1; Z will be CH2; Q will be C = O; L will be –CH2–; Y will be –CH2–; R7 will be H; and R6 will be an optionally substituted phenyl so R8 will not be a heteroaryl or tetrahydrofuranyl of
[00144] [00144] Preferably, when X is S; X1, X2 and X3 will be CH; n will be 1; Z will be CH2; Q will be C = O; L is –CH2–; R7 is H; and R6 is _______ so R8 will not be an unsubstituted phenyl or unsubstituted cyclohexane.
[00252] [00252] Preferably, when X is S; X1, X2 and X3 will be CH; n will be 1; Z will be CH2; Q will be C = O; L will be –CH2–; Y will be an optionally substituted C1-C2 alkyl; R7 will be H; and R6 will be an optionally substituted phenyl so R8 will not be an optionally substituted 5- or 6-membered heteroaryl, an optionally substituted phenyl or tetrahydrofuranyl.
[00253] [00253] The additional application describes a compound of the formula (V): (V) or a pharmaceutically acceptable salt or prodrug thereof, wherein: X1 is CR1 or N; X2 is CR2 or N; X3 is CR3 or N; Q is C = O, S = O, SO2, C = S or CR4R5; L is optionally substituted C1-C6 alkyl, polyfluoralkyl C1-C3, optionally substituted C3-C6 cycloalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, C = O, S = O, SO2, - CH2C (O) -, -CH2CONH-, or -CONH-; Y is an optionally substituted C1-C6 alkyl, polyfluoralkyl C1-C3, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3-C6 cycloalkyl; R1, R2 and R3 are each independently selected from the group consisting of H, halogen, CN, hydroxyl, COOH, CONR1R2, NR1R2, NHCOR1, optionally substituted C1-C6 alkyl, optionally substituted C1-C3 polyfluoralkyl, optionally substituted C1-C6 alkylsulfonyl, Optionally substituted C3-C6 mono or bicyclic cycloalkyl, Optionally substituted C2-C6 alkenyl, Optionally substituted C2-C6 alkynyl, Optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkoxycarbonyl group, Optionally substituted C5-C10 alkoxycarbonyl group, heteroaryl from 5 to 10 members optionally substituted mono or bicyclic, optionally substituted 3 to 8 members mono or bicyclic heterocycle, optionally substituted aryloxy, optionally substituted heteroaryloxy, and optionally substituted heterocyclyloxy; R4 and R5 are each independently selected from the group consisting of H, halogen, optionally substituted C1-C6 alkyl, (C3-C6) optionally substituted cycloalkyl or R4 and R5 together with the atom to which they are attached form a spirocyclic ring; R6 is optionally substituted C5-C10 mono or bicyclic aryl, optionally substituted 5 to 10 membered mono or bicyclic heteroaryl, optionally substituted C3-C6 cycloalkyl or an optionally substituted 3 to 8 membered mono or bicyclic heterocycle; R7 is H, optionally substituted C1-C6 alkyl, optionally substituted sulfonyl, optionally substituted C1-C6 alkylsulfonyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C2-C6 alkenyl and optionally substituted C2-C6 alkynyl; R8 is an optionally substituted C5-C10 mono or bicyclic aryl, optionally substituted 5 to 10 membered mono or bicyclic heteroaryl, optionally substituted mono or bicyclic C3-C6 cycloalkyl or an optionally substituted mono- or bicyclic 3- to 8-membered heterocycle; R9 and R10 are each independently selected from the group consisting of optionally substituted C1-C6 alkyl, H, halogen, CN, hydroxyl, CO2H, CONR1R2, azido, sulfonyl, NR1R2, NHCOR1, C1-C3 polyfluoroalkyl, C1-C6 thioalkyl optionally substituted, C1-C6 alkylsulfonyl optionally substituted, C3-C6 cycloalkyl optionally substituted, C2-C6 alkenyl optionally substituted, C2-C6 alkynyl optionally substituted, C1-C6 alkoxy optionally substituted, C1-C6 alkoxycarbonyl optionally substituted, C5-C10 aryl mono or optionally substituted bicyclic, optionally substituted 5 to 10 membered mono or bicyclic heteroaryl, optionally substituted heterocycle, optionally substituted aryloxy, and an optionally substituted heteroaryloxy; or R9 and R10 together with the C atom to which they are attached can combine to form an optionally substituted spirocyclic ring; and R11 is selected from the group consisting of optionally substituted C1-C6 alkyl, H, hydroxyl, CONR1R2, sulfonyl, NR1R2, NHCOR1, C1-C3 polyfluoroalkyl, C1-C6 optionally substituted thioalkyl, optionally substituted C1-C6 alkylsulfonyl, C3-C6 optionally substituted cycloalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkoxycarbonyl, optionally substituted mono or bicyclic C5-C10, 5 to 10 membered mono or bicyclic heteroaryl optionally substituted bicyclic, optionally substituted heterocycle, optionally substituted aryloxy, and optionally substituted heteroaryloxy; or a complex, salt, solvate, tautomeric form or pharmaceutically acceptable polymorphic form thereof.
[00145] [00145] All the resources described here (including any attached claims, drawings and summary) and / or all stages of any method or process so described can be combined with any of the foregoing aspects in any combination, except combinations where at least some of such features and / or steps are mutually exclusive.
[00254] [00254] For a better understanding of the invention, and to show what modalities of it can be carried out, reference will now be made, by way of example, to the attached Figures, in which: Figure 1 shows the allele frequency of the main polymorphisms human STING derived from the Genome 1000 Project database; Figure 2 are Western blots of human STING proteins combined with compounds of the invention or a vehicle control (VC) and incubated with antibodies specific for phosphorylated STING (pSTING), phosphorylated IRF3 (pIRF3), ACTIN, total STING (STING), and IRF3;
[00255] [00255] Compounds of formula (I) can be prepared from compounds of formula (II) and (III) using an amide bonding reaction, as shown below.
[00256] [00256] Typical conditions employ activation of the carboxylic acid of the compound of formula (II) using a suitable organic base and a suitable coupling agent. Preferred coupling agents are both EDCI with HOBt, T3P, HATU, HBTU and BOP. Preferred organic bases comprise both DIPEA and TEA in a suitable organic solvent such as DCM, DMF, DMA or MeCN. The reaction can be shaken or stirred at room temperature.
[00257] [00257] Compounds of formula (II) and (III) are commercially available or can be synthesized by those skilled in the art. In particular, methods for synthesizing compounds of formula (II) are described in the General Schemes
[00258] [00258] Compounds of formula (II) can be synthesized from the esters of formula (IV), where R is methyl, ethyl, benzyl or tert-butyl, by a hydrolysis reaction.
[00259] [00259] The compound of formula (IV) can be reacted with an alkali or suitable base to cause it to undergo hydrolysis and provide a compound of formula (II). The suitable alkali or base can be LiOH, KOH, NaOH or K2CO3, and the reaction can be conducted in an aqueous solution. General Layout 3
[00260] [00260] Alternatively, compounds of formula (II) can be obtained from a halide of formula (V) as shown in the General Scheme below.
[00261] [00261] Firstly, the compound of formula (V) undergoes a cyanation reaction to give a compound of formula (VI). This could be done when using CuCN or ZnCN2 in a polar solvent at elevated temperatures with a suitable catalyst. The polar solvent could be NMP, DMF, DMA or MeCN or the catalyst could be tetrakistriphenylphosphine palladium (o). The formula compound
[00262] [00262] In an additional alternative process, the compound of formula (V) can undergo a direct carbonylation reaction to produce a compound of formula (II), as shown below.
[00263] [00263] The reaction could be conducted using CO gas in the presence of a suitable catalyst in an appropriate polar solvent. The catalyst can be aPd, Rh, Ir or Fe catalyst, and the solvent can be NMP, DMF, DMA or MeCN with the reaction carried out in the presence of a suitable nucleophile such as water or alcohols (to prepare the corresponding esters). General Layout 5
[00264] [00264] Compounds of formulas (IV), (V) and (VI) can be synthesized by those skilled in the art by means of an alkylation / acylation / sulfonylation reaction with a compound of formula (VII), where G is a leaving group such as an optionally substituted alkylaryl (het) halide, triflate or tosylate, alkyl, aryl (het), cycloalkyl, alkylcycloalkyl.
[00265] [00265] A compound of formula (IX) can be prepared in a seven-step process, as shown below, from a compound of formula (XVI), where R is methyl, ethyl, benzyl or tert-butyl.
[00266] [00266] First, the compound of the formula (XVI) can be brominated, using both Br2 and a source of bromine, such as NBS, to give a compound of the formula (XV). That compound can then be aminated, using NH2R9, to provide a compound of the formula (XIV). The nitro group in the compound of the formula (XV) can then be reduced by suitable reducing agents to provide a compound of the formula (XIII). The compound of the formula (XIII) can then be reacted with a suitable carbonyl source to provide a compound of the formula (XII). The carbonyl source can be 1,1-carbonyl diimidazole, phosgene or triphosgene.
[00267] [00267] The compound of the formula (XII) can then undergo an alkylation / acylation / sulfonylation reaction, as described in General Scheme 5, to give a compound of the formula (XI). This compound can undergo a hydrolysis reaction, as described in General Scheme 2, to give a compound of the formula (X). Finally, that compound can be reacted with a compound of formula (III), as described in General Scheme 1, to give a compound of formula (IX).
[00146] [00146] It will be noticed that the compound of the formula (IX) is a compound of the formula (I) where Q is C = O. General Layout 7
[00268] [00268] A compound of the formula (XVII) can be prepared in an eight-step process, as shown below, from a compound of the formula (XXV), where R is methyl, ethyl, benzyl or tert-butyl.
[00269] [00269] Firstly, the compound of the formula (XXV) can be protected by acetylation groups using reagents such as TFAA, BOC-anhydride and acetic anhydride to give a compound of the formula (XXIV). That compound can be alkylated using a suitable alkyl halide (R11-G) in the presence of a suitable base such as NaH, K2CO3, KHCO3, Cs2CO3 or tBuCOOK / Na to give a compound of the formula (XXIII). A subsequent nitration reaction can be performed on the compounds of the formula (XXIII) with a mixture of nitration to give a compound of the formula (XXII). The nitro group in the compounds of formula (XXII) can then be reduced either by Pd-catalyzed hydrogenation methods or by using the sodium dithionite and TBASH method as described in General Procedure 11 to give the corresponding amino derivative which in further reaction with chloroformate ethyl in the presence of a suitable organic or inorganic base such as pyridine or K2CO3 provides a compound of the formula (XXI). This compound can undergo a cyclization process to give a compound of formula (XX) using a suitable base and solvent combination such as K2CO3 and methanol.
[00270] [00270] The compound of the formula (XX) can then undergo an alkylation / acylation / sulfonylation reaction, as described in General Scheme 5, to give a compound of the formula (XIX). This compound can undergo a hydrolysis reaction, as described in General Scheme 2, to give a compound of the formula (XVIII). Finally, that compound can then be reacted with a compound of formula (III), as described in General Scheme 1, to give a compound of formula (XVII).
[00271] [00271] It will be noticed that the compound of the formula (XVII) is a compound of the formula (I) where Q is C = O. General Layout 8
[00272] [00272] A compound of the formula (XXX) can be converted into a compound of the formula (XXIX) which can be further derivatized into (XXVIII), (XXVII) and (XXVI) as described below.
[00273] [00273] First, the compound of the formula (XXX) can undergo a demethylation reaction with suitable reagents such as BBr3, BCl3, AlCl3, or HBr in appropriate solvents such as DCM, DCE, toluene or water to produce the corresponding phenolic compounds of the formula (XXIX). Second, these compounds can then be used under different conditions to obtain different products. An alcohol or extended chain amine can be formed by reacting (XXIX) with an alcohol substituted with halo / amine or ester suitable to give a compound of the formula (XXVIII). Finally, the compounds of the formula (XXIX) can also be transformed into their corresponding phosphate prodrugs such as a compound of the formulas (XXVII) and (XXVI) using appropriate phosphorylation reagents. General outline 9
[00274] [00274] A compound of the formula (XXXV) can be translated into many forms of its parent's prodrug as described below. F
[00275] [00275] First, the compound of the formula (XXXVI) can undergo a demethylation reaction to form a compound of the formula (XXXV) as described in the General Scheme
[00276] [00276] A compound of the formula (XXIX) can be further converted to dihydroxy derivatives of the compound of the formula (XXXVII), (XXXVIII) and (XXXIX) as described below.
[00277] [00277] Firstly, the compound of the formula (XXIX) can be converted to an allyl derivative of the formula (XL) by treatment with allyl bromide in the presence of a mild base such as NaH, K2CO3, NaHCO3, tBuCOOK or organic base such such as TEA or DIPEA. Second, this compound can undergo a dihydroxylation reaction with osmium tetroxide or KMnO4 to provide a compound of the formula (XXXIX) as a racemic mixture. The compound of the formula (XL) can also undergo an asymmetric dihydroxylation reaction with a chiral auxiliary AD-mix-α and AD-mix-β to produce the corresponding R-enantiomer (XXXVIII) and S-enantiomer (XXXVII) respectively. General Layout 11
[00278] [00278] A compound of the formula (XLII) can be prepared in a six step process, as shown below, from a compound of the formula (XLVI) and 2,4-difluoro-3-methylbenzoic acid, where R is H, methyl, ethyl, ethanol,
[00279] [00279] First, commercially available 2,4-difluoro-3-methylbenzoic acid is converted into the corresponding methyl ester which can be treated with NBS in a brominated step resulting in the formation of methyl 3- (bromomethyl) -2,4-difluorbenzoate . Second, a compound of the formula (XLVI) that can be prepared according to methods described in General Scheme 7 can undergo an amidation reaction with an appropriate amine to produce a compound of the formula (XLV). That compound can then be subjected to an alkylation reaction with methyl 3- (bromomethyl) -2,4-difluorbenzoate in the presence of a soft base as described in General Scheme 7 to provide a compound of the formula (XLIV) which by basic hydrolysis can give a compound of the formula (XLIII). Finally, the compound of the formula (XLIII) can undergo an amide coupling reaction with an appropriate amine in the presence of a suitable amide coupling reagent (such as HATU, HBTU, CDI, HOBT, EDCI or TPP) to provide compounds of the formula (XLII).
[00280] [00280] To a stirred solution of a carboxylic acid (II) (1.28 mmol) in a suitable solvent, such as DCM, DMF, DMA or MeCN, (10 mL) was added amine (III) (1.2 eq .) and a coupling reagent, such as T3P, HATU, EDCI, HOBT, BOP or HBTU, (1.5 eq.), followed by the addition of an organic base, such as DIPEA or TEA, (2.0 eq. ) in drops in the solution and the mixture allowed to stir at RT for 2-3 h. When UPLC or TLC showed completion of the reaction, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with aqueous NaHCO3 solution followed by dilute aqueous HCl and finally with brine, and then dried over anhydrous Na2SO4. The solvent was evaporated under low pressure to obtain the crude material which was purified by Combi-flash using mixtures of EtOAc in hexanes as the eluant to provide a compound of formula (I) (70-80% yield) as a light yellow solid. A similar procedure can be followed to synthesize all the amides of formula (I). General Purification and Analytical Methods
[00281] [00281] All final compounds were purified by both Combi-flash and prep-HPLC purification, and analyzed for product purity and identity by UPLC or LCMS according to one of the following conditions.
[00282] [00282] Preparative HPLC was performed on a Waters self-purification instrument using either a C18 YMC Triart column (250 x 20 mm, 5 µm) or a Phenyl Hexyl column (250 x 21.2 mm, 5 µm) operating between room temperature and 50 ° C with a flow rate of 16.0 - 50.0 mL / min.
[00283] [00283] Mobile phase 1: A = 20mM Ammonium Bicarbonate in water, B = Acetonitrile; Gradient Profile: Initial composition of the mobile phase of 80% A and 20% B, then 60% A and 40% B after 3 min., Then 30% A and 70% B after 20 min. ., then at 5% A and 95% B after 21 min., maintained in that composition for 1 min. for washing the column, then returned to the initial composition for 3 min.
[00284] [00284] Mobile phase 2: A = 10mM Ammonium Acetate in water, B = Acetonitrile; Gradient Profile: Initial composition of the mobile phase of 90% A and 10% B, then 70% A and 30% B after 2 min., Then 20% A and 80% B after 20 min. ., then at 5% A and 95% B after 21 min., maintained in that composition for 1 min. for column washing, then returned to initial composition for 3 min. LCMS Method
[00285] [00285] Method 5 min general: column C18 Zorbax Extend (50 x 4.6 mm, 5µm) operating at room temperature and a flow rate of 1.2 mL / min. Mobile phase: A = 10 mM Ammonium Acetate in water, B = Acetonitrile; Gradient Profile: from 90% A and 10% B to 70% A and 30 B in 1.5 min, and then to 10% A and 90% B in 3.0 min, maintained in this composition for 1.0 min, and finally returned to the initial composition for 2.0 min. UPLC method
[00286] [00286] UPLC was performed on a Waters self-purification instrument using a C18 Zorbax Extend column (50 x 4.6 mm, 5µm) at room temperature and a flow rate of 1.5mL / min. Mobile phase 1: A = 5 mM Ammonium Acetate in water, B = 5 mM Ammonium Acetate in Acetonitrile / water 90:10; Gradient profile of 95% A and 5% B to 65% A and 35% B in 2 min., Then 10% A and 90% B in 3.0 min., Maintained in this composition for 4.0 min. and finally returned to the initial composition for 5.0 min.
[00287] [00287] Mobile phase 2: A = 0.05% formic acid in water, B = Acetonitrile; Gradient profile of 98% A and 2% B for 1 min., Then 90% A and 10% B for 1 min., Then 2% A and 98% B for 2 min. and then returned to the initial composition for 3 min. General Procedure 2
[00288] [00288] To a stirred solution of ester (IV) (1.49 mmol) in a mixture of MeOH or THF (10 mL) and water (5 mL) was added LiOH, NaOH or KOH (2.0 eq.) To RT and the resulting reaction mixture was stirred at RT for 2-16 h. TLC showed complete consumption of the ester (IV), whereby the solvent was evaporated under low pressure and the resulting residue was washed with ether. The residue was then acidified with 1N HCl at pH 2-4, which resulted in the formation of a precipitate, which was filtered and washed with water and then dried under low pressure at 50-60 ° C to provide the desired carboxylic acid of the formula ( II) (70-85% yield) as an ice-white solid. General Procedure 3 O R6 H L 6 O L R X3 N G R O Q (VII) R X3 N
[00289] [00289] To a stirred solution of a compound of the formula (VIII) (2.77 mmol, 1.0 eq.) In DMF or THF (4 mL / mmol) was added K2CO3, Cs2CO3, Na2CO3, NaOH or NaH (2 , 0 eq.) - in the case where NaOH was used, TBAB (0.1 eq.) Was also added as a phase transfer catalyst - followed by the addition of a compound of formula (VII) (1.5 eq.) and the mixture allowed to stir at RT for 0.5-1 h. The reaction was monitored by TLC. After the end of the reaction, the reaction mixture was diluted with water, extracted with EtOAc, and the organic layers were washed with brine and dried over anhydrous Na2SO4. The organics were evaporated under low pressure to obtain the crude product which was purified by Combi-flash using mixtures of EtOAc in hexanes as the eluant to provide compounds of the formula (IV) (80-90% yield) as colorless oil. Option B
[00290] [00290] Alternatively, to a stirred solution of a compound of the formula (VIII) (2.77 mmol) in DCM or MeCN or THF (4 mL / mmol) was added TEA or DIPEA (2.0 eq.) Followed by addition of a compound of formula (VII) (1.5 eq.) and allowed to stir completely at RT for 0.5 to 1 h. The progress of the reaction was monitored by TLC. After the end of the reaction, the mixture was diluted with water, extracted with
[00291] [00291] To a stirred solution of a compound of the formula (XLIII) (1.0 eq.) In a suitable solvent such as carbon tetrachloride or trifluormethylbenzene (100 ml) were added NBS (1.2 eq.) And AIBN or benzoyl peroxide (0.1 eq.). The reaction mixture was heated to 70-100 ° C for 12-16 h. After complete consumption of starting material, the reaction mixture was finished with a saturated solution of Na2S2O3 and extracted with EtOAc. The combined organic layers were washed with brine and then dried over anhydrous Na2SO4. The crude product obtained after concentration of the organic layer under low pressure was purified by column chromatography to provide a compound of the formula (XLII) in 30-40% yield. General Procedure 5
[00292] [00292] To a stirred solution of a compound of the formula (XLII) (9,124 mmol, 1.0 eq.) In a suitable solvent such as THF was added an appropriate amine, such as MeNH2, (25 mL, 2M solution in THF ) at RT for 10-16 h. After the completion of the reaction, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with a saturated brine solution, dried over anhydrous Na2SO4 and concentrated under low pressure to provide a compound of the formula (XLI) (60-70% yield) as a red pasty solid. General Procedure 6 Option A: (Reduction by Sodium Dithionate)
[00293] [00293] To a stirred solution of a compound of the formula (XIV) (1.0 mmol, 1.0 eq.) In a mixture of both MeCN: H2O and THF: H2O (12 mL / mmol, 2: 1) sodium hydrosulfite (8.0 eq.), ammonium tetra butyl hydrosulfate (0.5 eq.) and potassium carbonate (6.0 eq.) were added to RT and then the mixture was stirred for 1 h. The progress of the reaction was monitored by TLC and or LCMS. After the completion of the reaction, solvents were evaporated under low pressure to give an oily liquid which was dissolved in 1N HCl and extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. The organics were filtered and evaporated under low pressure to give a compound of the formula (XIII) (90-95% yield) as a yellowish solid.
[00294] [00294] To a stirred solution of a compound of the formula (XIV) (12.85 mmol, 1.0 eq.) In EtOAc, MeOH or EtOH (9.4 mL / mmol, 120 mL) was added Pd-C 10 % (50% w / w in water) (77.8 mg / mmol) under an inert atmosphere at room temperature. The reaction mixture was purged with H2 gas using balloon pressure and then allowed to stir further for 3-5 h at room temperature. The course of the reaction was monitored by TLC and / or LCMS. After the end of the reaction, the reaction mass was diluted with EtOAc, carefully filtered through a bed of celite and washed with EtOAc 4-5 times until the mother liquor did not show any remaining compounds by TLC. Then the collected organic layers were dried over anhydrous Na2SO4, filtered and concentrated under low pressure to give a compound of the formula (XIII) (80-85% yield) as a yellow semi-solid. The product was pure enough to use in the next step without any further purification. General Procedure 7
[00295] [00295] To a stirred solution of a compound of the formula (XL) (3.61 mmol, 1.0 eq.) In a suitable solvent, such as DCM or THF (5 mL / mmol) was added a suitable carbonyl source equipped with suitable leaving groups, such as 1,1-carbonyl-diimidazole, phosgene or triphosgene (1.1 eq.) followed by a suitable base, such as TEA or DIPEA (3.0 eq.) at 0-5 ° C and the reaction mixture was stirred at room temperature under an inert atmosphere for 2-4 h. The reaction mixture was completed by adding saturated aqueous NaHCO3 solution and extracted with DCM. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under low pressure to provide a crude residue that was purified by silica gel column chromatography and eluted with 1% MeOH in DCM to provide a compound of the formula (XXXIX) (20 -30% yield) as an ice-white solid. General Procedure 8
[00296] [00296] To a stirred solution of a compound of the formula (XXV) (0.279 mol, 1.0 eq.) In toluene (1.8 ml / mmol) was added TFAA (2.0 eq.) At 10-15 ° C in drops for 20-30 min., And the resulting reaction mixture was stirred at 25-30 oC for 1-5 h. The progress of the reaction was monitored by UPLC-MS. The reaction mixture was poured into crushed ice and extracted with EtOAc. The combined organic layers were washed successively with a saturated solution of NaHCO3, brine and then dried over anhydrous Na2SO4. The filtered organics were evaporated under low pressure to provide the compound of the formula (XXIV) (90-96% yield) as a white solid. The product was pure enough to use in the next step without any further purification. General Procedure 9
[00297] [00297] To a stirred solution of NaH (1.2 eq, 60% oil suspension) in DMF (1.65 ml / mmol) was added a mixture of a compound of the formula (XXIV) (0.272 mol, 1.0 eq.) and an alkyl or aryl halide (R11-G) (2.0 eq.) in DMF (1.1 mL / mmol) in drops using a drip funnel for 20-30 min. at 10-15 oC and the resulting reaction mixture then stirred for 2 h at 20-25 oC. The completion of the reaction was confirmed by UPLC-MS. The reaction mixture was poured into a mixture of ice water and extracted with EtOAc. The combined organics were washed with 1N hydrochloric acid, a saturated solution of NaHCO3 and then brine. The organic layer was dried over anhydrous Na2SO4 and evaporated under low pressure to provide a compound of the formula (XXIII) (90-96% yield) as an ice-white solid. The product was pure enough to use in the next step without any further purification. General Procedure 10
[00298] [00298] A compound of the formula (XXIII) (0.262 mol, 1.0 eq.) Was added in a mixture of pre-prepared nitration of concentrated sulfuric acid (2.17 mL / mmol) and steaming nitric acid (0.73 mL / mmol) in portions while maintaining the internal temperature between 0-5 oC for a period of 30 min. The resulting mixture was stirred at 20-25 oC for 1-2 h. The completion of the reaction was confirmed by UPLC-MS and after consumption of the starting material the reaction mixture was poured into a mixture of ice water and extracted with EtOAc. The combined organics were washed with a saturated NaHCO3 solution followed by a saturated brine solution, dried over anhydrous Na2SO4 and evaporated under low pressure to provide a compound of the formula (XXII) (92-98% yield) as a thick brown oil. The product was pure enough to use in the next step without any further purification. General Procedure 11 Option A
[00299] [00299] To a stirred solution of a compound of the formula (XXII) (59.8 mmol, 1.0 eq.) In 1,4-dioxane (3.34 mL / mmol, degassed with nitrogen) was added Pd-C 10% (0.167 g / mmol, 50% w / w in water) under an inert atmosphere and the resulting reaction mixture was stirred under H2 gas balloon pressure at RT overnight. The progress of the reaction was monitored by TLC and UPLC-MS which showed complete conversion of the nitro group to its corresponding amino group. Then the H2 gas flask was removed and solid K2CO3 (1.66 eq.) Was added to the reaction vessel followed by addition in drops of ethyl chloroformate (1.34 eq.) At RT. The resulting reaction mixture was further stirred overnight. UPLC-MS showed completion of the reaction; then the reaction mixture was filtered through a bed of celite and the bed was washed with DCM. The filtrate was evaporated under low pressure to give a crude product which was dissolved in EtOAc, washed with water followed by brine, dried over anhydrous Na2SO4 and evaporated under low pressure to provide crude product as a thick oil which was purified by trituration with n- hexane and dried to provide a compound of the formula (XXI) (80-85% yield) as a white solid. Option B:
[00300] [00300] To a stirred solution of a compound of the formula (XXII) (251.47 mmol, 1.0 eq.) In THF (6.68 ml / mmol) was added a solution of K2CO3 (6.0 eq.) in water (3 ml / mmol) at 10-15 oC followed by addition in portions of sodium dithionite (8.0 eq.), TBASH (0.5 eq.) and water (0.4 ml / mmol). The resulting reaction mixture was stirred at RT (20-25 oC) for an additional 2-3 h. The reaction was monitored by UPLC-MS and after completion the reaction mixture was allowed to settle to allow separation of the organic and aqueous layers. The aqueous layer was then extracted with THF. The combined organic layers were dried over anhydrous Na2SO4 and then pyridine (0.8 ml / mmol) was added. The organic mixture was then evaporated at ~ 40 ° C under low pressure to make the crude product available which was dissolved in DCM (6.7 ml / mmol) and another portion of pyridine (0.8 ml / mmol) was added followed by addition in drops of ethyl chloroformate (5.0 eq.) at 10-15 oC. The resulting reaction mixture was further stirred at RT for 2-3 h. UPLC-MS showed completion of the reaction. The reaction mixture was diluted with water and allowed to settle to separate the layers. The aqueous layer was washed with DCM and the combined organics were washed with 0.5N HCl, a saturated solution of NaHCO3 and finally with brine. The obtained organic layer was dried over anhydrous Na2SO4 and evaporated under low pressure to make the crude product available as a thick yellowish oil. The oil was purified by trituration with hexane to give a compound of the formula (XXI) (90-94% yield) as a weak yellow sticky solid. General Procedure 12
[00301] [00301] To a stirred solution of a compound of the formula (XXI) (146.0 mmol, 1.0 eq.) In methanol (3.8 ml / mmol) was added K2CO3 (2.0 eq.) At RT and the resulting reaction mixture was heated to 60-65 oC for 2-3 h. The progress of the reaction was monitored by UPLC-MS and after completion, the reaction mass was cooled to 5-10 ° C and neutralized with 2N HCl to obtain a pH ~ 3-4. The solvents were evaporated under low pressure at 40-45 ° C to give the crude product which was dissolved in EtOAc, washed successively with a saturated brine solution, 2N HCl, NaHCO3 solution and finally again with brine, dried over anhydrous Na2SO4 evaporated. under low pressure to provide crude compound as a brownish solid. This was purified by trituration with hexane to provide a compound of the formula (XX) (80-85% yield) as an ice-white to light yellow solid.
[00302] [00302] To a stirred solution of a compound of the formula (XXX) (0.96 mmol, 1.0 eq.) In DCM (26 mL / mmol) was added BBr3 (5 mL / mmol, 1.0M solution in DCM ) and the mixture was stirred at RT for 1-2 h. The reaction progress was monitored by UPLC-MS and after the end of the reaction the mixture was diluted with DCM and water. The organic layer was separated and washed with NaHCO3 solution followed by brine. The organic layer was dried over anhydrous Na2SO4 and evaporated under low pressure to provide the crude product which was purified by Combi-flash to give a compound of the formula (XXIX) (80-85% yield) as a white solid. General Procedure 14
[00303] [00303] To a stirred solution of a compound of the formula (XXIX) (0.099 mmol, 1.0 eq.) In DMF (20 ml / mmol) was added K2CO3 (3.0 eq.) Followed by the addition of a halide of substituted alkyl [X– (CH2) m-GH]; where X is halogen, G is O, NH, COO and GH is COOR) (2.0 eq.) and the entire reaction mixture was heated to 60 ° C overnight. After the end of the reaction, the mixture was diluted with water and extracted with EtOAc. The organics were washed with brine, dried over anhydrous Na2SO4 and evaporated under low pressure to provide crude product which was purified by Combi-flash using a mixture of EtOAc in hexane as the eluent to give a compound of the formula (XXVIII) (30-35% yield) as a white solid. General Procedure 15
[00304] [00304] A compound of the formula (XXVIII) (where m is> 1) (0.56 mmol, 1.0 eq.) Was dissolved in pure POCl3 (9.0 eq.) At 0-5 ° C and the mixture The reaction was allowed to warm slowly to RT for 1 h. After complete conversion of the starting material, the reaction mixture was dissolved in MeCN (2.5 mL / mmol) and a mixture of silver nitrate (0.35 eq.) In water (5 mL / mmol) was added in drops at 0-5 ° C. The resulting reaction mixture was further stirred for 1-2 h at the same temperature and then kept in the refrigerator for 18-20 h to provide a solid that was filtered, and the filtrate evaporated under low pressure to provide the crude product that was purified by prep-HPLC to give a compound of the formula (XXVII) (40-45% yield) as a light yellow solid. General Procedure 16
[00305] [00305] To a stirred solution of a compound of the formula (XXIX) (0.30 mmol, 1.0 eq.) In dry DMF (6 ml / mmol) was added K2CO3 (1.5 eq.) And after 15 min . dibenzyl phosphate (chloromethyl) (1.1 eq.) was added under an atmosphere of N2. The reaction mixture was stirred at 55-60 oC for 2-3 h.
[00306] [00306] To a stirred solution of a compound of the formula (XXIX) (0.30 mmol, 1.0 eq.) In dry acetonitrile (15 mL / mmol) was added tetrazole (1.0 eq.) Followed by dibenzyl- diisopropylphosphoramidite (1.4 eq.) under an inert atmosphere and the mixture was allowed to stir at RT for 2-3 h. The course of the reaction was monitored by TLC and LCMS and after completion the reaction mixture was evaporated under low pressure to give the crude product which was dissolved in DCM (20 mL / mmol) and added m-CPBA (1.5 eq. ) at 0-5 oC under an inert atmosphere. The reaction mixture was then stirred at 0-5 oC for 1-2 h. The course of the reaction was monitored by TLC and LCMS and after completion the reaction mixture was diluted with water and extracted with EtOAc. The combined organics were washed with brine, dried over anhydrous Na2SO4 and concentrated under low pressure to give the oxidized compound (90-95% yield) as crude. The deprotection of the benzyl groups was performed by the method described in General Procedure 16 to give the final product of the formula (XXVI). General Procedure 18
[00307] [00307] To a stirred solution of a compound of the formula (XXXV) (0.096 mmol, 1.0 eq.) In DMF (20 mL / mmol) was added NaH (0.03 g / mmol, 60% w / w in mineral oil) at 0-5 oC and the reaction mixture was stirred for 15-20 min. at the same temperature. Then 4-nitrophenyl carbonate substituted with separately synthesized R12O (for example, as described in US 1996/5585397) (3.0 eq.) Was dissolved in DMF (20 mL / mmol) and added to the reaction mixture and the total busy at RT all night. The progress of the reaction was monitored by TLC and LCMS and after the completion of the reaction the mixture was diluted with water and extracted with EtOAc. The combined organics were washed with a saturated brine solution, dried over anhydrous Na2SO4 and concentrated under low pressure to give the crude compound which was purified by both column chromatography and prep-HPLC to provide a compound of the formula (XXXI) (20- 30% yield) as a white solid. General Procedure 19
[00308] [00308] To a stirred solution of a compound of the formula (XXXV) (0.08 mmol, 1.0 eq.) In DMF (25 mL / mmol) was added NaH (0.125 g / mmol, 60% w / w in mineral oil) at 0 - 5 oC and the reaction mixture was stirred for 15 min. at the same temperature. Then, 4-nitrophenyl carbamate substituted with separately synthesized R12R13N (for example, as described in Syn. Comm., 2007, 37, 1927) (1.2 eq.) In DMF (10 mL / mmol) was added to the mixture. reaction and the total heated to 75-80 oC for 2-3 days. The progress of the reaction was monitored by TLC and LCMS and after 2-3 days the mixture was diluted with water and extracted with EtOAc. The combined organics were washed with NaHCO3 and brine solution, dried over anhydrous Na2SO4 and concentrated under low pressure to give the crude compound which was purified by column chromatography to provide a compound of the formula (XXXIV) (20-30% yield) like a white solid. General Procedure 20
[00309] [00309] To a stirred solution of a compound of the formula (XXIX) (0.30 mmol, 1.0 eq.) In DMF (15 mL / mmol) was added K2CO3 (2.5 eq.) And then allyl bromide (1.2 eq.) At RT. The entire reaction mixture was further stirred at RT for 1-2 h. The course of the reaction was monitored by TLC and LCMS and after completion the reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under low pressure to give the crude product which was purified by column chromatography to provide a compound of the formula (XL) (80-90% yield) as a white solid . General Procedure 21
[00310] [00310] To a stirred solution of a compound of the formula (XL) (0.11 mmol, 1.0 eq.) In acetone (9 mL / mmol) was added osmium tetroxide (1.0 eq), NMO (1 , 2 eq.) And water (0.1 ml / mmol) at RT and the resulting reaction mixture was stirred at RT for 20-30 min. After the end of the reaction (monitored by TLC); the reaction mixture was poured into a saturated Na2SO3 solution and extracted with EtOAc. The organic layer was washed with brine solution, dried over anhydrous Na2SO4 and concentrated under low pressure to give the crude product which was purified by column chromatography or prep-HPLC to provide a compound of the formula (XXXIX) (30-35% of yield) as a white solid. General Procedure 22
[00311] [00311] To a stirred solution of a compound of the formula (XL) (0.14 mmol, 1.0 eq.) In tert-butanol (7 mL / mmol) and water (7 mL / mmol) at 0-5 ⁰C AD-mix-α (1.8 g / mmol) was added and the reaction mixture was stirred at 0-5 ⁰C overnight. The course of the reaction was monitored by TLC and LCMS and after completion the reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine solution, dried over anhydrous Na2SO4 and concentrated under low pressure to give crude product which was purified by column chromatography or prep-HPLC to provide a compound of the formula (XXXVIII) (44-50% yield ) as a white solid. General Procedure 23
[00312] [00312] To a stirred solution of a compound of the formula (0.14 mmol, 1.0 eq.) In tert-butanol (7 mL / mmol) and water (7 mL / mmol) at 0-5 ⁰C was added AD -mix-β (1.8 g / mmol) and the reaction mixture was stirred at 0-5 ⁰C all night. The reaction was processed as for General Procedure 22 and the crude product purified by column chromatography or prep-HPLC to provide a compound of the formula (XXXVII) (40-50% yield) as a white solid. General Procedure 24
[00313] [00313] To a stirred solution of a compound of the formula (XLIII) (0.26 mmol, 1.0 eq.) In THF (20 mL / mmol) was added HATU (1.2 eq.) Followed by TEA (2 , 0 eq.) And the reaction mixture was stirred at RT for 15 min., Then an optionally substituted alkyl / aryl amine (R-NH2) (10.0 eq.) Was added. The resulting reaction mixture was further stirred at RT for 2 h. Additional rates of HATU, TEA and amine may be required for complete consumption of the starting material. After the end of the reaction, the mixture was diluted with water and extracted with EtOAc. The combined organics were washed with brine, dried over anhydrous Na2SO4 and concentrated under low pressure to give the crude product which was purified by column chromatography to provide a compound of the formula (XLII) (20-30% yield) as a yellow solid. . Examples
[00314] [00314] Nuclear magnetic resonance (NMR) spectra were in all cases consistent with the proposed structures. Characteristic chemical translocations (δ) are given in parts per million field below tetramethylsilane (for 1H-NMR) and field above trichloro-fluorine-methane (for 19F NMR) using conventional abbreviations for designating main peaks: for example, s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, ample. The following abbreviations have been used for common solvents: CDCl3, deuterochloroform; d6-DMSO, deuterodimethylsulfoxide; and CD3OD, deuteromethanol.
[00315] [00315] Mass spectra, MS (m / z), were recorded using electrospray ionization (ESI). Where relevant and unless otherwise stated, the provided m / z data is for isotopes 19F, 35Cl, 79Br and 127I.
[00316] [00316] All chemicals, reagents and solvents were purchased from commercial sources and used without further purification. All reactions were carried out under a nitrogen atmosphere unless otherwise noted.
[00317] [00317] Flash column chromatography was performed using pre-packaged silica gel cartridges on a Combi-Flash platform. Prep-HPLC purification was performed according to the General purification and analytical methods described previously. Thin layer chromatography (TLC)
[00318] [00318] Example 1 was prepared according to the methods described in General Procedures 1-3, and the methods described below. Preparation 1: Methyl-3-methyl-2-oxo-1,2,3,4-tetrahydroquinazolin-7-carboxylate Step 1: Methyl-4- (bromomethyl) -3-nitrobenzoate
[00319] [00319] To a stirred solution of methyl-4-methyl-3-nitrobenzoate (4.0 g, 20.51 mmol) in trifluoro toluene (85 mL) was added NBS (5.477 g, 30.77 mmol) and peroxide. benzoyl (0.746 g, 3.08 mmol) at RT. The resulting reaction mixture was heated at 100 ° C for 16 h. After completion, the reaction mixture was finished with a saturated Na2S2O3 solution (100 mL) and extracted with EtOAc. The combined organics were washed with brine, dried over sodium sulfate and concentrated under low pressure to give the crude product which was purified by column chromatography using 2% EtOAc in hexanes as the eluent to provide the title compound (2.5 g, 44% yield) as a brown pasty solid. 1H NMR (400 MHz; CDCl3): δ 3.97 (s, 3H), 4.83 (s, 2H), 7.66 (d, J = 7.32 Hz, 1H), 8.24 (d, J = 6.64 Hz, 1H), 8.65 (s, 1H). Step 2: Methyl-4 - ((methylamino) methyl) -3-nitrobenzoate
[00320] [00320] MeNH2 (25 mL, 1M THF solution) was added to methyl-4- (bromomethyl) -3-nitrobenzoate (Step 1) (2.5 g, 9.12 mmol) at RT and the resulting reaction mixture RT was stirred for 16 h. The progress of the reaction was monitored by TLC and after completion, the reaction mixture was diluted with water (80 mL) and extracted with EtOAc. The combined organics were washed with brine, dried over anhydrous Na2SO4 and concentrated under low pressure to provide the title compound (1.4 g, 68% yield) as a red pasty solid. LCMS m / z: 225 [M + H]. Step 3: Methyl-3-amino-4 - ((methylamino) methyl) benzoate
[00321] [00321] To a stirred solution of methyl-4- ((methylamino) methyl) -3-nitrobenzoate (Step 2) (1.4 g, 6.25 mmol) in EtOAc (25 mL) was added Pd / C 10% (0.5 g, 10% w / w on carbon) under an atmosphere of N2 gas. The resulting reaction mixture was stirred at RT for 3 h under an H2 gas balloon pressure. The reaction was monitored by TLC and after completion the reaction mixture was filtered through a bed of celite and washed with EtOAc. The filtrate was concentrated under low pressure to give the crude product which was purified by column chromatography to provide the title compound (1.2 g, 99% yield) as a brownish gum. LCMS m / z: 195 [M + H]. Step 4: Methyl-3-methyl-2-oxo-1,2,3,4-tetrahydroquinazolin-7-carboxylate
[00322] [00322] To a stirred solution of methyl-3-amino-4- ((methylamino) methyl) benzoate (Step 3) (0.7 g, 3.61 mmol) in DCM (15 mL) was added triphosgene (1, 07 g, 3.61 mmol) followed by TEA (1.26 mL, 9.02 mmol) at 0-5 ° C and the reaction mixture was stirred at RT under an inert atmosphere for 3 h. After the end of the reaction (monitored by TLC / LCMS), the reaction mixture was finished with saturated NaHCO3 solution (30 mL) and extracted with DCM. The combined organics were washed with water followed by brine, dried over anhydrous Na2SO4 and concentrated under low pressure to give the crude product which was purified by column chromatography on silica gel using 1% MeOH in DCM as eluent to provide the title compound (0, 19 g, 24% yield) as an ice-white solid. LCMS m / z: 221 [M + H]. Preparation 2: Methyl 1- (3,5-difluorbenzyl) -3-methyl-2-oxo-1,2,3,4-tetrahydroquinazolin-7-carboxylate
[00323] [00323] To a stirred solution of 3-methyl-2-oxo-1,2,3,4-tetrahydro-quinazolin-7-carboxylic acid methyl ester (Preparation 1) (0.19 g, 0.86 mmol) in DMF (5 mL) NaH (0.038 g, 0.95 mmol, suspension in 60% mineral oil) was added at 0-5 ° C and the total stirred for 15 min. then, 3,5-difluorbenzylbromide (0.134 ml, 1.04 mmol) was added and the reaction mixture was allowed to stir at RT for 1 h. The progress of the reaction was monitored by TLC and after completion the reaction mixture was finished with saturated ammonium chloride solution (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with water followed by brine, dried over anhydrous Na2SO4, filtered and concentrated under low pressure to give the crude product which was purified by Combi-flash eluting with 28% EtOAc in hexane as eluent to provide title compound (0 , 13 g, 43.5% yield) as an ice-white solid. LCMS m / z: 347 [M + H]. Preparation 3: 1- (3,5-difluorbenzyl) -3-methyl-2-oxo- 1,2,3,4-tetrahydroquinazolin-7-carboxylic acid
[00324] [00324] To a stirred solution of 1- (3,5-difluoro-benzyl) -3-methyl-2-oxo-1,2,3,4-tetrahydro-quinazolin-7-carboxylic acid methyl ester ( Preparation 2) (0.13 g, 0.38 mmol) in THF-H2O (1: 1, 2 mL) LiOH.H2O (0.0174 g, 0.41 mmol) was added at 0-5 ° C. The reaction mixture was stirred at RT for 6 h. After the end of the reaction (monitored by TLC and
[00325] [00325] To a stirred solution of 1- (3,5-difluoro-benzyl) -3-methyl-2-oxo-1,2,3,4-tetrahydro-quinazolin-7-carboxylic acid (Preparation 3) (0.04 g, 0.12 mmol) in DCM (3 mL) TEA (0.034 mL, 0.24 mmol) and HATU (0.0687 g, 0.18 mmol) were added at 0-5 ° C and the total was stirred for 15 min. Then 2,4,6-trifluoro benzyl amine (0.016 mL, 0.13 mmol) was added and the reaction mixture was stirred at RT for 16 h. The course of the reaction was monitored by TLC and or LCMS and after completion of the reaction; the mixture was diluted with DCM and washed with water, 1N HCl, saturated sodium bicarbonate solution and brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under low pressure to obtain a crude material that was purified by prep-TLC using 70% EtOAc-hexane as the eluent to provide the title compound (Example 1) (0.0178 g, 31 , 1% yield and 96.6% purity) as a white solid. LCMS m / z: 476.3 [M + H]; 1H NMR (400 MHz; DMSO-d6): δ 2.95 (s, 3H), 4.38 (s, 2H), 4.52 (s, 2H), 5.11 (s, 2H), 6, 93 (d, J = 6.64 Hz, 2H), 7.11-7.16 (m, 4H), 7.23 (d, J = 7.52 Hz, 1H), 7.42 (d, J = 7.08 Hz, 1H), 8.81 (bs, 1H).
[00326] [00326] Examples 2-13 were made in a manner analogous to Example 1 starting from the appropriate quinazoline and using the appropriate benzyl and amine halides as described for General Procedures 1-3. Example Name 1H-NMR LCMS Structure -ple IUPAC [M + H] (400 MHz; DMSO- 1- (3,5- d6): δ 2.20 (s, difluorb 3H), 2.96 (s, nzil) -3- 3H), 4.34 (d, J = methyl-N- 4.96 Hz, 2H), ((5- 4.53 (s, 2H), methylfura 5.12 (s, 2H), n -2- 5.96 (s, 1H), 2 yl) methyl) 6.05 (s, 1H), 426.1 -2-oxo-6.95 (d, J = 6.88 1.2.3 , 4- Hz, 2H), 7.09 (t, tetra- J = 8.96 Hz, 1H), hydroquin 7.16 (s, 1H), azolin-7- 7.24 (d, J = 7, 84 carboxami Hz, 1H), 7.47 (d, da J = 8.32 Hz, 1H), 8.84 (bs, 1H). 3- cycloprop (400 MHz; DMSO-yl-1- d6): δ 0.60 (bs, (3.5-2H), 0.75 (bs, difluorb 2H), 2.66 (bs, nzil) - 2- 1H), 4.38 (s, oxo-N-2H), 4.48 (s, (2.4.6-2H), 5.11 (bs, 3 502.3 trifluorb 2H), 6, 92 (bs, enzil) - 2H), 7.11-7.13 1,2,3,4- (m, 4H), 7.27 (d, tetra- J = 6.48 Hz, 1H), hydroquin 7.40-7.41 (m, azolin-7-1H), 8.79 (bs, 1H carboxami). gives
[00327] [00327] Examples 14-72 were made in a manner analogous to Example 1 starting from the appropriate quinazoline and using the appropriate benzyl halides and amines as described in General Procedures 1-3. Exe
[00328] [00328] Example 70 was prepared according to the methods described in General Procedures 1-3, and the methods described below. Preparation 5: methyl-3-methyl-3,4-dihydro-1H-benzo [c] [1,2,6] thiadiazine-7-carboxylate 2,2-dioxide
[00329] [00329] To a stirred solution of methyl-3-amino-4- ((methylamino) methyl) benzoate (Preparation 1) (0.6 g, 3.09 mmol) in pyridine (20 mL) was added sulfamide (0, 89 g, 9.28 mmol) at 0-5 ° C. The resulting reaction mixture was heated to RT and then heated to reflux for 4 h. After the end of the reaction, the mixture was finalized with 2N HCl and extracted with EtOAc. The collected organic layer was washed with brine solution, dried over anhydrous Na2SO4 and concentrated under low pressure to give the crude compound which was purified by Combi-flash using EtOAc / 30% hexane as the eluent to provide the title compound (0.22 g , 28% yield and> 95% purity) as a yellow solid. LCMS m / z: 257.6 [M + H]. Preparation 6: methyl-1- (3,5-difluorbenzyl) -3-methyl-3,4-dihydro-1H-benzo [c] [1,2,6] thiadiazine-7- 2,2-dioxide carboxylate
[00330] [00330] To a stirred solution of 2,2-methyl-3-methyl-3,4-dihydro-1H-benzo [c] [1,2,6] thiadiazine-7-carboxylate (Preparation 5) (0.17 g, 0.66 mmol) in DMF (5 mL) at 0-5 ° C, potassium tert-butoxide (0.081 g, 0.73 mmol) was added and the total stirred for another 10-15 min . at the same temperature. Then, 3,5-difluorbenzyl bromide (0.137 g, 0.66 mmol) was added and the reaction mixture was stirred at RT for 1 h. The progress of the reaction was monitored by TLC and after completion, the reaction mixture was diluted with water and extracted with EtOAc. The collected organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under low pressure to give the crude product which was purified by Combi-flash using 15% EtOAc / hexane as the eluent to provide the title compound (0.22 g, 86 , 7% yield and> 85% purity) as a yellow solid. LCMS m / z: 383 [M + H]. Preparation 7: 1- (3,5-difluorbenzyl) -3-methyl-3,4-dihydro-1H-benzo [c] [1,2,6] thiadiazine-7-carboxylic acid 2,2-dioxide
[00331] [00331] To a stirred solution of 2,2-methyl-1- (3,5-difluorbenzyl) -3-methyl-3,4-dihydro-1H-benzo [c] [1,2,6 ] thiadiazine-7-carboxylate (Preparation 6) (0.22 g, 0.68 mmol) in a mixture of THF: MeOH: H2O (4.5 mL, 1: 1: 1) LiOH.H2O (0.114 g) was added , 2.71 mmol) at RT and the reaction mixture was further stirred at the same temperature for 2 h. The progress of the reaction was monitored by TLC and LCMS and after completion, the solvents were evaporated under low pressure and the residue was dissolved in water and acidified with 1N HCl at pH 3-5. The resulting aqueous solution was extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under low pressure to provide the title compound (0.18 g, 85% yield and purity> 97%) as a light yellow solid. LCMS m / z: 367 [M + H]. Preparation 8: 1- (3,5-difluorbenzyl) -3-methyl- N- (2,4,6-trifluorbenzyl) -3,4-dihydro-1H-benzo 2,2-dioxide [c] [ 1,2,6] thiadiazine-7-carboxamide (Example 70) F F O F THE N N S O H N F F
[00332] [00332] To a stirred solution of 1- (3,5-difluorbenzyl) -3-methyl-3,4-dihydro-1H-benzo 2,2-dioxide [c] [1,2,6] thiadiazine-7-carboxylic (Preparation 7) (0.06 g, 0.16 mmol) in DCM (2 mL) TEA (0.045 mL, 0.33 mmol) was added at 0-5 ° C followed by HBTU (0.074 g , 0.20 mmol) and the mixture allowed to stir for 5 min at the same temperature. Then, 2,4,6-trifluorbenzylamine (0.028 g, 0.18 mmol) was added and the reaction mixture was brought to RT and stirred for 3 h. The completion of the reaction was monitored by TLC and LC. After the end of the reaction; the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under low pressure to make the crude product available which was purified by Combi-flash using 30% EtOAc / hexane as the eluent to give the title compound (0.015 g, 18% yield and purity 96.8%) as an ice-white solid. LCMS m / z: 512 [M + H]; 1H NMR (500 MHz; DMSO-d6): δ 2.75 (s, 3H), 4.41 (s, 2H), 4.78 (s, 2H), 5.12 (s, 2H), 7, 10-7.20 (m, 6H), 7.31 (d, J = 5.52 Hz, 1H), 7.50 (d, J = 5.84 Hz, 1H), 8.88 (s, 1H ). Example 71: 1- (2-chloro-6-fluorbenzyl) -3-methyl-2-oxo-N- (2,4,6-trifluorbenzyl) -1,2,3,4-tetrahydropyride [3,2 - d] pyrimidine-7-carboxamide
[00333] [00333] Example 71 was prepared according to the methods described in General Procedures 1-3 and 6-7, and in the methods described below. Preparation 9: Methyl-3-methyl-2-oxo-1,2,3,4-tetrahydropyride [3,2-d] pyrimidine-7-carboxylate
[00334] [00334] To a stirred solution of methyl-6-formyl-5-nitronicotinate (0.9 g, 4.28 mmol) in MeOH (30 mL) was added methylamine hydrochloride (0.32 g, 4.71 mmol) followed by sodium triacetoxyborohydrate (1.82 g, 8.57 mmol) at RT and the resulting reaction mixture was stirred at the same temperature for 2 min. Then a saturated NH4Cl solution was added to the reaction mixture to finish the excess sodium triacetoxyborohydrate. Then BOC anhydride (1.4 g, 6.42 mmol) was added to the mixture and the total was stirred at RT for 30 min. The completion of the reaction was confirmed by TLC and LCMS after which the mixture was diluted with water and extracted with EtOAc. The combined organics were washed with brine, dried over anhydrous Na2SO4 and concentrated under low pressure to give the crude product which was purified by column chromatography to provide the title compound (0.52 g, 37% yield and purity> 60%) like a white solid. LCMS m / z: 326 [M + H]. Step 2: Methyl-5-amino-6 - ((((tert-butoxycarbonyl) (methyl) amino) methyl) nicotinate
[00335] [00335] To a stirred solution of methyl-6 - (((tert-
[00336] [00336] To a stirred solution of methyl-5-amino-6- ((((tert-butoxycarbonyl) (methyl) amino) -methyl) nicotinate (Step 2) (0.6 g, 2.03 mmol) in THF ( 20 mL) phenyl chloroformate (0.48 g, 3.05 mmol) was added to RT and the resulting reaction mixture was stirred at RT for 2 h. The progress of the reaction was monitored by TLC and LCMS and after completion the mixture was diluted with water and extracted with EtOAc. The combined organics were washed with brine, dried over anhydrous Na2SO4 and concentrated under low pressure to give the title compound (0.95 g, purity> 67%) as crude which was used in the next step without further purification. LCMS m / z: 416 [M + H].
[00337] [00337] To a stirred solution of methyl-6 - ((((tert-butoxycarbonyl) (methyl) amino) methyl) -5- ((phenoxycarbonyl) amino) nicotinate (Step 3) (0.95 g, 2.29 mmol ) in DCM (20 ml) TFA (2.8 ml) was added at 0-5 oC and the reaction mixture was then stirred at RT for 2 h. After complete consumption of the starting materials, the solvents were evaporated under low pressure to give a residue which was dissolved in DMF and neutralized with TEA. The resulting neutralized reaction mass was diluted with water and extracted with EtOAc. The combined organics were washed with brine, dried over anhydrous Na2SO4 and concentrated under low pressure to give the crude product which was purified by column chromatography to give the title compound (0.165 g, 33% yield and> 99% purity) as a white solid. LCMS m / z: 222.63 [M + H]. Example 71: 1- (2-chloro-6-fluorbenzyl) -3-methyl-2-oxo-N- (2,4,6-trifluorbenzyl) -1,2,3,4-tetrahydropyride [3,2 - d] pyrimidine-7-carboxamide
[00338] [00338] 1- (2-chloro-6-fluorbenzyl) -3-methyl-2-oxo-N- (2,4,6-trifluorbenzyl) -1,2,3,4-tetrahydropyride [3,2 - d] pyrimidine-7-carboxamide (Example 71) was prepared from methyl-3-methyl-2-oxo-1,2,3,4-tetra-
[00339] [00339] Examples 72 and 73 were made in a manner analogous to Example 71 starting from the appropriate substituted pyridine and using the appropriate benzyl and amine halides as described for General Procedures 1-3 and 6-7. Exe 1H-NMR LCMS mpl Structure Name IUPAC [M + H] o 1- (3,5- (500 MHz; difluorbenzi DMSO-d6): δ l) -3-methyl- 2.99 (s, 3H), 2 -oxo-N- 4.43 (s, 2H), (2.4.6- 4.65 (s, 2H), trifluorbenz 5.10 (s, 2H), 477.3 72 il) -1.2 , 3.4 - 6.99 (d, J = 9 tetra - 5.6 Hz, 2H), hydropyride [7.12 - 7.17 (m, 3.2 - 3H), 7.37 (s, d ] pyrimidine 1H), 8.53 (s, -7- 1H), 9.04 (s, 1H carboxamide), N- (500 MHz; DMSO (benzofuran-d6): δ 2.96 (s, 2-ylmethyl ) - 3H), 4.55 (s, 1- (2-chloro-2H), 4.65 (s, 6- 2H), 5.22 (s, fluorbenzyl) 2H), 6.77 (s, - 3-methyl-2- 1H), 7.06 (m, 479.4 73 oxo-1,2,3,4-1H), 7.15-7.31 4 tetra- (m, 4H), 7, 53- hydropyride [7.59 (m, 3.2-2H), 7.75 (s, d] 1H pyrimidine), 8.62 (s, -7-1H), 9.26 (s, 1H carboxamide) .
[00340] [00340] Example 74 was prepared according to the methods described in General Procedures 1-3 and 4-7, and the methods described below. Preparation 10: Methyl-3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazolin-7-carboxylate THE H AT THE THE
[00341] [00341] To a stirred solution of commercially available 4-ethyl-3-nitro-benzoyl (2.0 g, 10.25 mmol) in MeOH (30 mL) was added thionyl chloride (1.12 mL, 15.37 mmol) at 0-5 ° C and the reaction mixture was stirred at 50 ° C for 16 h under an N2 gas atmosphere. The reaction mixture was concentrated and NaHCO3 solution (50 ml) was added and the mixture extracted with EtOAc (3 x 50 ml). The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated under low pressure to provide the title compound (1.8 g, 84.0% yield) as a light yellow liquid. 1H NMR
[00342] [00342] To a stirred solution of 4-ethyl-3-nitro-benzoic acid methyl ester (Step 1) (2.5 g, 11.96 mmol) in trifluoro toluene (50 mL) was added NBS (3.194 g, 17.94 mmol) and benzoyl peroxide (0.435 g, 1.79 mmol) and the reaction mixture was heated at 100 ° C for 16 h. The progress of the reaction was monitored by TLC and after completion the reaction mixture was finalized with a saturated solution of Na2S2O3 (50 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with water followed by brine, dried over anhydrous Na2SO4, filtered and concentrated under low pressure to give crude material which was purified by column chromatography using 5-6% EtOAc in hexane as the eluent to provide the title compound ( 2.0 g, 58.0% yield) as a brown sticky liquid. 1H NMR (400 MHz; DMSO-d6): δ 2.05 (d, J = 6.6 Hz, 3H), 3.91 (s, 3H), 5.82 (q, J = 6.6 Hz, 1H), 8.12 (d, J = 8.2 Hz, 1H), 8.26 (d, J = 7.96 Hz, 1H), 8.37 (s, 1H). Step 3: Methyl-4- (1- (methylamino) ethyl) -3-nitrobenzoate
[00343] [00343] To a stirred solution of methyl ester of acid
[00344] [00344] A stirred solution of 4- (1-methylamino-ethyl) -3-nitro-benzoic acid methyl ester (Step 3) (2.0 g, 8.40 mmol) in EtOAc (30 mL) was purged with nitrogen gas for 10 min. and then 10% Pd-C (1.0 g, 50% w / w in water) was added. The mixture was hydrogenated under an H2 gas balloon pressure for 16 h at RT. After the end of the reaction the mixture was filtered through a bed of celite and washed with MeOH / DCM 5%. The filtrate was concentrated under low pressure to provide the title compound (1.5 g, 85.7% yield) as a light yellow gum. LCMS m / z: 209.3 [M + H]. Step 5: Methyl-3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazolin-7-carboxylate
[00345] [00345] To a stirred solution of 3-amino-4- (1-methylamino-ethyl) -benzoic acid methyl ester (Step 4) (2.0 g, 9.62 mmol) in THF (30.0 mL) triphosgene (1.712 mg, 5.77 mmol) was added at 0-5 ° C and the total stirred for 10 min, TEA (2.67 mL, 19.23 mmol) was added and the reaction mixture was allowed to stir further at RT for 16 h. The reaction mixture was completed by adding NaHCO3 solution and diluted with EtOAc (30 ml) and water (30 ml). The organic layer was separated and concentrated under low pressure. The crude material was purified by Combi-flash eluting with 70% EtOAc in hexane as the eluant to provide the title compound (0.5 g, 22.2% yield) as a brown solid. LCMS m / z: 235.3 [M + H]. Preparation 11: Methyl-1- (2-chloro-6-fluorbenzyl) -3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazolin-7-carboxylate
[00346] [00346] To a stirred solution of 3,4-dimethyl-2-oxo-1,2,3,4-tetrahydro-quinazolin-7-carboxylic acid methyl ester (Preparation 10) (0.38 g, 1 , 62 mmol) in DMF (5 mL) NaH (72 mg, 1.79 mmol, 60% dispersion in mineral oil) was added at 0-5 ° C and the mixture stirred for 15 min. 2- Bromomethyl-1-chloro-3-fluorobenzene (0.28 mL, 1.95 mmol) was added and the reaction mixture was further stirred at RT for 1 h. The progress of the reaction was monitored by TLC and LCMS and after completion the mixture was finalized by adding water and extracted with EtOAc. The organic layer was washed with water followed by brine, dried over anhydrous Na2SO4, filtered and concentrated under low pressure to provide crude material which was purified by Combi-flash eluting with 15% EtOAc in hexane to provide the title compound (0.45 g , 73.5% yield) as an ice-white solid. LCMS m / z: 376.9 [M + H]. Preparation 12: 1- (2-chloro-6-fluorbenzyl) -3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazolin-7-carboxylic acid F
[00347] [00347] To a stirred solution of 1- (2-chloro-6-fluoro-benzyl) -3,4-dimethyl-2-oxo-1,2,3,4-tetrahydro-quinazolin- 7-carboxylic (Preparation 11) (0.4 g, 1.06 mmol) in THF: H2O (6 mL, 1: 1) LiOH.H2O (49.15 mg, 1.17 mmol) was added and the mixture was reaction was stirred at RT for 4 h. The course of the reaction was monitored by TLC and LCMS and after completion the reaction mixture was acidified with 1N HCl solution and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with water followed by brine, dried over anhydrous Na2SO4, filtered and concentrated under low pressure to provide the title compound (0.25 g, 64.8% yield) as an ice-white solid. LCMS m / z: 362.9 [M + H]. Preparation 13: 1- (2-chloro-6-fluorbenzyl) -3,4-dimethyl-2-oxo- N- (2,4,6-trifluorbenzyl) -1,2,3,4-tetrahydroquinazolin-7 - carboxamide (Example 74)
[00348] [00348] To a stirred solution of 1- (2-chloro-6-fluoro-benzyl) -3,4-dimethyl-2-oxo-1,2,3,4-tetrahydro-quinazolin-7-carboxylic acid (Preparation 12) (0.25 g, 0.69 mmol) in DCM (5 mL) TEA (0.192 mL, 1.38 mmol) and HATU (0.394 g, 1.04 mmol) were added at 0-5 ° C and the total was stirred for 10 min. Then 2,4,6-trifluorbenzylamine (0.101 mL, 0.83 mmol) was added and the reaction mixture was allowed to stir at RT for 16 h. The progress of the reaction was monitored by TLC and LCMS and after completion the mixture was diluted with water (15 ml) and extracted with DCM (3 x 20 ml). The combined organic layers were washed with 1N HCl (10 ml), saturated sodium bicarbonate solution (10 ml) and finally with water. The organic layer was separated, dried over anhydrous Na2SO4, filtered and concentrated under low pressure to give crude material which was purified by prep-HPLC to provide the title compound (0.15 g, 42.9% yield and 99.57 purity %) as a white solid. LCMS m / z: 506.1 [M + H]; 1H NMR (400 MHz; DMSO-d6): δ 1.22 (d, J = 6.08 Hz, 3H), 2.93 (s, 3H), 4.41 - 4.53 (m, 3H), 4.90 (d, J = 15.6 Hz, 1H), 5.54 (d, J = 16.08 Hz, 1H), 7.14-7.19 (m, 4H), 7.24-7 , 32 (m 2H), 7.39 (d, J = 7.64 Hz, 1H), 7.44 (s, 1H), 8.75 (bs, 1H). Chiral separation of Example 74:
[00349] [00349] 1- (2-chloro-6-fluorbenzyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorbenzyl) -1,2,3,4-tetrahydroquinazolin-7 - racemic carboxamide (Example 74) (0.15 g) was subjected to chiral separation to provide two enantiomers; Enantiomer 1, Example 75 (26.2 mg, purity 99.72%, chiral purity 100% ee) Enantiomer 2, Example 76 (24.7 mg, purity 99.36%, chiral purity 97.86% ee) Chiral Separation:
[00350] [00350] Chiral separation was performed using an Agilent HPLC (1200 series) under the following conditions; Chiralpak ID column (21 x 250 mm), 5µm Mobile phase Hexane / Ethanol: 70/30 Flow rate 21.0 mL / min. Running time 30 min. Wavelength 220 nm Solubility Methanol
[00351] [00351] Both enantiomers were subsequently individually synthesized from chiral starting materials to confirm the absolute configuration of each enantiomer, as described below. Example 76: (S) -1- (2-chloro-6-fluorbenzyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorbenzyl) -1,2,3,4-tetra -hydroquinazolin- 7-carboxamide F
[00352] [00352] Example 76 was prepared according to the methods described in General Procedures 1-3 and 8-12, and the methods described below. Preparation 14: (S) -methyl-3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazolin-7-carboxylate Step 1: (S) -methyl-4- (1- (2 , 2.2-
[00353] [00353] To a stirred solution of commercially available (S) -methyl-4- (1-aminoethyl) benzoate (50.0 g, 0.28 mol) in toluene (500 ml) was added TFAA (79 ml, 0, 56 mol) at 10-15 ° C in drops for 20-30 min., And the resulting reaction mixture was stirred at 25 oC for 1 h. The progress of the reaction was monitored by UPLC-MS. The reaction mixture was poured into crushed ice (1,000 g) and extracted with EtOAc (2 x 1,000 ml). The combined organic layers were washed successively with saturated NaHCO3 solution (1,000 ml) and saturated brine solution (1,000 ml) and then dried over anhydrous Na2SO4. The filtered organics were evaporated under low pressure to provide the title compound (75.0 g, yield 96.5%, purity 99.6%) as a white solid. LCMS m / z: 274.01 [M-H]. Step 2: (S) -methyl-4- (1- (2,2,2-trifluor-N-methylacetamido) ethyl) benzoate
[00354] [00354] To a stirred solution of sodium hydride (13.0 g, 0.327 mol, 60% oil suspension) in DMF (450 mL) was added a mixture of (S) -methyl-4- (1- (2 , 2,2-trifluoroacetamido) ethyl) benzoate (Step 1) (75.0 g, 0.27 mol) and methyl iodide (34.1 ml, 0.54 mol) in DMF (300 ml) in drops using a drip funnel for 20-30 min. at 10-15 oC and the resulting mixture then stirred for 2 h at 25 oC. The completion of the reaction was confirmed by UPLC-MS. The reaction mixture was poured into a mixture of ice water (3500 ml) and extracted with EtOAc (3 x 1,000 ml). The organic layer was washed with 1N HCl (500 ml), saturated NaHCO3 solution (500 ml) and a saturated brine solution (1,000 ml). The organic layer was dried over anhydrous Na2SO4 and evaporated under low pressure to provide the title compound in freezing overnight (76.0 g, yield 96.4%, purity 99.3%) as an ice-white solid. 1H NMR (500 MHz; DMSO-d6): δ 1.58 (d, J = 7.05 Hz, 3H), 1.67 (d, J = 6.75 Hz, 1H), 2.84 (s, 2H), 3.86 (s, 3H), 5.71 - 5.75 (q, J = 6.95 Hz, 1H), 7.45-7.49 (m, 2H), 7.97-8 , 01 (m, 2H). Step 3: (S) -Methyl 3-nitro-4- (1- (2,2,2-trifluor-N-methylacetamido) ethyl) benzoate
[00355] [00355] Concentrated sulfuric acid (570 mL) was loaded into a 2 L round base flask equipped with a guard tube and thermal bag and cooled to 0-5 oC with an external brine bath. Steaming nitric acid (190 mL) was added in drops via a drip funnel to maintain the internal temperature between 0-10 oC for a period of 20 min. Then (S) -methyl-4- (1- (2,2,2-trifluor-N-methylacetamido) ethyl) benzoate (Step 2) (76.0 g, 0.26 mol) was added in portions maintaining the temperature internal temperature between 0-5 oC for a period of 30 min. The resulting mixture was stirred at 25 oC for 1 h. The completion of the reaction was confirmed by UPLC-MS. The reaction mixture was poured into a mixture of ice water (3500 mL) and extracted with EtOAc
[00356] [00356] To a stirred solution of (S) -methyl-3-nitro-4- (1- (2,2,2-trifluor-N-methylacetamido) -ethyl) benzoate (Step 3) (20.0 g, 59.8 mmol) in 1,4-dioxane (200 mL, degassed with nitrogen) 10% Pd-C (4.0 g, 50% w / w in water) was added under an inert atmosphere and the resulting reaction mixture it was stirred under a H2 gas balloon pressure at RT all night. The progress of the reaction was monitored by TLC and UPLC-MS which showed incomplete conversion of starting material. Then the reaction mixture was filtered and washed with 1,4-dioxane carefully and equally divided into three parts and again 10% Pd-C (3 x 2.0 g, 50% w / w in water) was added to each part, individually stirred in an H2 gas balloon at RT for 8 h. UPLC-MS showed completion of reactions in all three reaction vessels. Then the hydrogen gas flask was removed from each vessel and added solid K2CO3 (3 x 13.77 g, 99.78 mmol) to each vessel followed by addition in drops of ethyl chloroformate (3 x 7.6 mL, 79.85 mmol) at RT. The resulting reaction mixture was further stirred at RT overnight. UPLC-MS showed completion of the reaction, all three reactions were filtered through a bed of celite in a filtration flask, and the bed was washed with DCM. The filtrate was evaporated under low pressure to give a crude product which was dissolved in EtOAc (500 ml), washed with water (2 x 250 ml) followed by brine (200 ml), dried over anhydrous Na2SO4 and evaporated under low pressure to make available the crude product (25.0 g) as a thick oil which was purified by trituration with n-hexane (2 x 75 ml) and dried to provide the title compound (18.11 g, 80% yield, purity> 96% ) as a white solid. LCMS m / z: 375.20 [M-H]. Option B:
[00357] [00357] To a stirred solution of (S) -methyl-3-nitro-4- (1- (2,2,2-trifluor-N-methylacetamido) -ethyl) benzoate (Step 3) (84.0 g 251 , 47 mmol) in THF (1680 mL) a solution of K2CO3 (208.0 g, 1.508 mmol) in water (740 mL) at 10-15 oC was added followed by the addition of portions of sodium dithionite (350.0 g , 2011.9 mmol), TBASH (42.62 g, 125.7 mmol) and water (100 mL); after 10 min. an exotherm was observed and the internal temperature reached ~ 30 ° C. The resulting reaction mixture was stirred at RT (20-25 oC) for 3 h. The reaction was monitored by UPLC-MS and after completion the reaction mixture was left to allow separation of the organic and aqueous layers. The aqueous layer was then extracted with THF (1,000 ml). The combined organic layers were dried over anhydrous Na2SO4 and then pyridine (202 mL) was added to the filtered organics. The mixture was then evaporated at ~ 40 ° C under low pressure to provide the crude product which was dissolved in DCM (1680 ml) and another portion of added pyridine (202 ml) followed by addition in drops of ethyl chloroformate (119, 7 mL, 1257 mmol) at 10-15 oC. The resulting reaction mixture was further stirred at RT for 3 h. UPLC-MS showed completion of the reaction. The reaction mixture was diluted with water (1500 ml), and the layers were separated. The aqueous layer was washed with DCM (1,000 ml), and the combined organic layers were washed with 0.5N HCl (2 x 2000 ml), a saturated solution of NaHCO3 (1,000 ml) and finally with brine (1,000 ml), dried over anhydrous Na2SO4 and evaporated under low pressure to make the crude product (150.0 g) available as a thick yellowish oil. The oil was purified by hexane (3 x 200 ml) to give the title compound (90.0 g, 94% yield, purity> 63%) as a weak yellow sticky solid. LCMS m / z: 377.18 [M + H]. Step 5: (S) -methyl-3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazolin-7-carboxylate
[00358] [00358] To a stirred solution of (S) -methyl-3- ((ethoxycarbonyl) amino) -4- (1- (2,2,2-trifluor-N-methylacetamido) ethyl) benzoate (Step 4) (55 , 0 g 146.0 mmol) in methanol (550 mL) K2CO3 (40.0 g, 292.0 mmol) was added at RT and the resulting reaction mixture was heated at 60 oC for 2 h. The progress of the reaction was monitored by
[00359] [00359] To a stirred solution of (S) -methyl-3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazolin-7 carboxylate (Preparation 14) (28.7 g, 122, 64 mmol) in DMF (200 mL) NaH (5.4 g, 134.9 mmol, 60% oil suspension) was added followed by benzyl 2-chloro-6-fluorine bromide (18.5 mL, 134.9 mmol) in portions at 15-20 ° C and the total stirred further at RT for 30 min. UPLC-MS showed completion of the reaction, so the reaction mixture was finished with crushed ice water and stirred for 1 h. A solid precipitated, which was filtered and washed with water (500 ml) and hexane (3 x 400 ml) to obtain the wet product (90.0 g) which was dried in a vacuum oven at 60 ° C overnight to provide the title compound (40.0 g, 86.7% yield, purity> 97.8%) as an ice-white to light yellow solid. LCMS m / z: 377.11 [M + H]. Preparation 16: (S) -1- (2-chloro-6-fluorbenzyl) -3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazolin-7 carboxylic acid
[00360] [00360] To a stirred solution of (S) -methyl-1- (2-chloro-6-fluorbenzyl) -3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazolin-7- carboxylate (Preparation 15) (40.0 g,
[00361] [00361] To a stirred solution of (S) -1- (2-chloro-6-fluorbenzyl) -3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazolin-7-carboxylic acid (Preparation 16) (35.2 g, 97.23 mmol) in DCM (1400 mL) HBTU (44.2 g, 116.6 mmol) was added followed by TEA (35 mL, 243.0 mmol) at 10- 15 oC and stirring continued for about 5-10 min. 2,4,6-trifluorbenzylamine (15.6 ml, 106.9 mmol) was added and the reaction maintained at RT for 1 h. The reaction was monitored by UPLC-MS and after the completion of the reaction the mixture was diluted with water (1,000 ml) and the organic layer was separated, washed with 2N HCl (2 x 500 ml), NaHCO3 solution (4 x 2000 ml ) and finally with brine (500 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under low pressure to provide the crude product (48.0 g) as an ice-white solid that was purified by crystallization dissolving in acetone (960 ml) at 40-45 ° C to obtain a yellowish clean solution and then activated charcoal (2.4 g) was added and the total was stirred at 45 ° C for 30 min. The resulting mixture was filtered through a sintered G-2 funnel with a bed of celite. The bed was washed with acetone (240 ml) to give a clean yellowish filtrate, to which n-hexane (3600 ml) was added to give white slurry which was stirred at RT for 1.5 h. The slurry was filtered through a Buchner funnel and washed with hexane (500 mL) to make the product wet as a white solid (41.0 g) which was dried in a vacuum oven at 70 oC overnight. to give the title compound (42.5 g, 88.5% yield, 99.9% purity and 100% chiral purity) as a white solid. LCMS m / z: 506.20 [M + H]; 1H NMR (500 MHz; DMSO-d6): δ 1.23 (d, J = 6.55 Hz, 3H), 2.94 (s, 3H), 4.38-4.42 (dd, J1 = 4 , 85 Hz, J2 = 14.4 Hz, 1H), 4.46-4.50 (dd, J1 = 5.35 Hz, J2 = 14.55 Hz, 1H), 4.51- 4.55 (q , J = 6.4 Hz, 1H), 4.91 (d, J = 15.75 Hz, 1H), 5.55 (d, J = 15.8 Hz, 1H), 7.13-7.19 (m, 1H), 7.21 (t, J = 7.9 Hz, 3H), 7.28-7.35 (m, 2H), 7.41 (d, J = 7.85 Hz, 1H) , 7.46 (s, 1H), 8.78 (t, J = 5.0 Hz, 1H); Specific rotation [α] D: [-24.27 °] at 25 ° C. Example 75: (R) -1- (2-chloro-6-fluorbenzyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorbenzyl) -1,2,3,4-tetra -hydroquinazolin- 7-carboxamide Cl F O F AT THE N H N F F
[00362] [00362] Example 75 was prepared according to the methods described, for example 76, and the methods described below.
[00363] [00363] Preparation 18: (R) -methyl-3,4-dimethyl-2-oxo- 1,2,3,4-tetrahydroquinazolin-7-carboxylate Step 1: (R) -methyl-4- (1 - (2,2,2- trifluoracetamido) ethyl) benzoate
[00364] [00364] To a stirred solution of commercially available (R) -methyl-4- (1-aminoethyl) benzoate (1.0 g, 5.58 mmol) in CHCl3 (10 mL) was added TFAA (2.35 g, 11.17 mmol) at 10-15 ° C in drops and the resulting reaction mixture was stirred at 25 oC for 40 min. The progress of the reaction was monitored by UPLC-MS. The reaction mixture was poured into crushed ice water and extracted with EtOAc. The combined organic layers were washed successively with saturated NaHCO3 solution and brine solution and then dried over anhydrous Na2SO4. The filtered organics were evaporated under low pressure to provide the title compound (1.4 g, 91% yield and> 98% purity) as a white solid. LCMS m / z: 274.05 [M + H]. Step 2: (R) -methyl 3-nitro-4- (1- (2,2,2-trifluoracetamido) ethyl) benzoate
[00365] [00365] Concentrated sulfuric acid (10 ml) was cooled to 0-5 oC and then steaming nitric acid (5 ml) in drops through a drip funnel to maintain the internal temperature between 0-10 oC for a period of 20 min. Then (R) -methyl-4- (1- (2,2,2-trifluoracetamido) ethyl) benzoate (Step 1) (1.4 g, 5.09 mmol) was added in portions over a period of 30 min. , maintaining the internal temperature between 0-5 oC. The resulting mixture was stirred at 25 oC for 1 h. The completion of the reaction was confirmed by TLC and LCMS. The reaction mixture was poured into a mixture of ice water and extracted with DCM. The combined organic layers were washed with a saturated NaHCO3 solution followed by a saturated brine solution, dried over anhydrous Na2SO4 and evaporated under low pressure to provide the title compound (1.5 g, 92% yield and> 98% purity) as a white solid. LCMS m / z: 319.05 [M + H]. Step 3: (R) -methyl-3-nitro-4- (1- (2,2,2-trifluor-N-methylacetamido) ethyl) benzoate
[00366] [00366] To a stirred solution of (R) -methyl-3-nitro-4- (1- (2,2,2-trifluoracetamido) -ethyl) benzoate (Step 2) (1.4 g, 4.38 mmol ) in DMF (15 mL) NaH (0.217 g, 60% oil suspension) was added in portions at 0-5 oC. The resulting mixture was stirred at RT for 3 h. The completion of the reaction was confirmed by TLC and UPLC-MS and after the completion the mixture was poured into a mixture of ice water and extracted with EtOAc. The organic layer was washed with 1N hydrochloric acid, saturated NaHCO3 solution and brine solution. The organic layer was dried over anhydrous Na2SO4 and evaporated under low pressure to provide the title compound (0.9 g, yield 55% and purity> 96%) as crude which was used in the next step without any further purification. LCMS m / z: 335.12 [M + H]. Step 4: (R) -methyl-3-amino-4- (1- (2,2,2-trifluor-N-methylacetamido) ethyl) benzoate
[00367] [00367] To a stirred solution of (R) -methyl 3-nitro-4- (1- (2,2,2-trifluor-N-methylacetamido) -ethyl) benzoate (Step 3) (0.9 g, 2.70 mmol) in EtOAc (10 mL) 10% Pd-C (0.1 g, 50% w / w in water) was added under an inert atmosphere. The reaction mixture was stirred overnight under an H2 gas balloon pressure. The reaction progress was monitored by TLC and LCMS and after completion the reaction mixture was filtered through a bed of celite under an atmosphere of N2. The filtrate was dried over sodium sulfate and concentrated under low pressure to give the crude compound which was purified by Combi-flash using 30% EtOAc in hexane as the eluent to provide the title compound (0.8 g, 97.5% yield and purity> 71%) as a white solid. LCMS m / z: 305.09 [M + H]. Step 5: (R) -methyl-3 - ((ethoxycarbonyl) amino) -4- (1- (2,2,2-trifluor-N-methylacetamido) ethyl) benzoate
[00368] [00368] To a stirred solution of (R) -methyl (R) -methyl 3-amino-4- (1- (2,2,2-trifluor-N-methylacetamido) -ethyl) benzoate (Step 4) 1.97 mmol) in DCE (10 mL) dry pyridine (0.807 g, 10.22 mmol) was added to RT under an inert atmosphere. The resulting reaction mixture was stirred at RT for 10 min. then ethyl chloroformate (0.255 g, 2.37 mmol) was added and the total was further stirred at RT for 1 h. The completion of the reaction was monitored by TLC and LCMS and after completion the mixture was diluted with water and the layer was separated. The aqueous layer was washed with DCM and the combined organic layers were washed with 0.5N HCl, a saturated solution of NaHCO3 and finally with brine, dried over anhydrous Na2SO4 and evaporated under low pressure to provide the crude product which was purified by chromatography. column to give the title compound (0.4 g, 54% yield and purity> 94%) as a white solid. LCMS m / z: 377.24 [M + H]. Step 6: (R) -methyl-3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazolin-7-carboxylate
[00369] [00369] To a stirred solution of 3- ((ethoxycarbonyl) amino) -4- (1- (2,2,2-trifluor-N-methylacetamido) ethyl) (R) -methyl benzoate (Step 5) (0 , 17 g, 0.45 mmol) in a mixture of MeOH and water solvents (6 mL, 2: 1) was added K2CO3 (0.125 g, 0.90 mmol) at RT and the resulting reaction mixture was heated to 60 ° C for 20 min. The reaction mixture was cooled to RT and diluted with a saturated solution of NaHCO3 and extracted with EtOAc. The organic layer was washed with 1N HCl followed by brine. The organic layer was then dried over anhydrous Na2SO4 and concentrated under low pressure to give the title compound (0.07 g, 66.6% yield and> 97% purity) as a white solid. Example 75: (R) -1- (2-chloro-6-fluorbenzyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorbenzyl) -1,2,3,4-tetra -hydroquinazolin- 7-carboxamide
[00370] [00370] Example 75 was prepared from (R) -methyl-3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazolin-7-carboxylate (Preparation 18) according to methods described in Preparations 15-17 and General Procedure 1-3. Yield 46%; Purity 98.4%; Chiral purity 99.4%; LCMS m / z: 506.22 [M + H]; 1H NMR (400 MHz; DMSO-d6): δ 1.23 (d, J = 6.2 Hz, 3H), 2.93 (s, 3H), 4.42-4.46 (m, 2H), 4.50-4.53 (m, 1H), 4.91 (d, J = 15.96 Hz, 1H), 5.54 (d, J = 15.48, 1H), 7.12-7, 20 (m, 4H), 7.29-7.32 (m, 2H), 7.39 (d, J = 7.6 Hz, 1H), 7.44 (s, 1H), 8.74 (bs , 1H); Specific rotation [α] D: [+ 21.17 °] at 25 ° C. Example 77: (S) -1 - ((5-chloro-3-fluor-2-methylpyridin-4-yl) methyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorbenzyl ) - 1,2,3,4-tetrahydroquinazolin-7-carboxamide
[00371] [00371] Example 77 was prepared according to the methods described in General Procedures 1-3, and the methods described below. Preparation 19: 5-chloro-3-fluorine-2-methylisonicotinic acid
[00372] [00372] To a stirred solution of commercially available 5-chloro-3-fluor-2-methylpyridine (1.0 g, 6.87 mmol) in dry THF (10 mL) was added n-BuLi (4.12 mL, 8.24 mmol, 2M solution in hexane) in drops at -78 oC and stirring continued for another 2 h. The reaction mixture was completed by adding excess dry ice pellets and stirring well for an additional 1 h. The reaction mixture was concentrated under low pressure to a semi-solid mass, which was dissolved in water (10 ml) and washed with EtOAc (25 ml). The aqueous layer was acidified with 1N HCl to maintain pH ~ 1 and then extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and evaporated under low pressure to give the title compound (1.06 g, 81% yield and purity> 96%) as a yellowish solid that was used in the next step without any additional purification. LCMS m / z: 189.95 [M + H]. Preparation 20: Methyl-5-chloro-3-fluorine-2-methylisonicotinate
[00373] [00373] To a stirred solution of 5-chloro-3-fluoro-2-methylisonicotinic acid (Preparation 19) (1.05 g, 5.54 mmol) in DMF (11 mL) was added K2CO3 (1.531 g, 11, 08 mmol) followed by Me2SO4 (0.838 g, 6.65 mmol) at 0-5 oC and then the reaction mixture was stirred at RT for 2 h. The progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was diluted with cold water, extracted with EtOAc and washed with brine. The combined organic layers were dried over anhydrous Na2SO4 and evaporated under low pressure to give the title compound (0.95 g, 84% yield and> 96% purity) as a reddish brown liquid which was used in the next step without any further purification. LCMS m / z: 203.98 [M + H]. Preparation 21: (5-chloro-3-fluor-2-methylpyridin-4-yl) methanol
[00374] [00374] To a stirred solution of methyl-5-chloro-3-fluorine-2-methylisonicotinate (Preparation 20) (0.85 g, 4.18 mmol) in dry THF (12 mL) was added DIBAL-H (16 , 67 mL, 1M solution in hexane) in drops at 0-5 oC and the whole reaction mixture was stirred at room temperature for 6 h. After the completion of the reaction, it was terminated with a solution of sodium and potassium tartrate. The finished reaction mixture was extracted with EtOAc, washed with brine and dried over anhydrous Na2SO4. The solvent was evaporated under low pressure to give the crude product which was purified by prep-HPLC to provide the title compound (0.25 g, 34% yield and> 99% purity) as a white solid. LCMS m / z: 175.98 [M + H]. Preparation 22: 4- (bromomethyl) -5-chloro-3-fluorine-2-methylpyridine
[00375] [00375] To a stirred solution of (5-chloro-3-fluor-2-methylpyridin-4-yl) methanol (Preparation 21) (0.06 g, 0.34 mmol) in dry THF (2 mL) was added PBr3 (0.081 mL, 0.85 mmol) at -10 oC. The total was stirred at RT for 2 h. After the end of the reaction, the mixture was poured into ice water and extracted with EtOAC. The combined organic layer was washed with brine, dried over anhydrous Na2SO4 and evaporated under low pressure to give the title compound (0.075 g, 81.5% yield and purity> 92%) as a yellowish liquid which was used in the next step without any additional purification. LCMS m / z: 237.89 [M + H]. Preparation 23: 4- (chloromethyl) -3-fluorine-5-methoxy-2-methylpyridine
[00376] [00376] To a stirred solution of (3-fluor-5-methoxy-2-methylpyridin-4-yl) methanol (Preparation 21) (0.080 g, 0.47 mmol) in dry DCM (1 mL) was added TEA ( 0.195 ml, 0.14 mmol) followed by MeSO2Cl (0.0831 g, 0.70 mmol) at 0-5 oC and the mixture then stirred overnight at RT. The reaction was monitored by TLC and LCMS and after consumption of the starting material; the reaction mixture was diluted with DCM and washed with cold water and then brine. The combined organic layers were dried over anhydrous Na2SO4 and concentrated under low pressure to give the title compound (0.08 g, 90% yield, purity> 77%) as a pale yellow liquid which was used in the next step without any further purification. LCMS m / z: 189.99 [M + H].
[00377] [00377] The following intermediates were synthesized according to methods similar to those described previously in Preparations 19-23) starting from the appropriate substituted pyridine. Structure Name IUPAC Structure Name IUPAC 4- (bromomethyl) -3- 4- (bromomethyl) - fluorine-2- 3,5- methylpyridine difluorpyridine
[00378] [00378] (S) -1 - ((5-chloro-3-fluor-2-methylpyridin-4-yl) methyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorbenzyl ) - 1,2,3,4-tetrahydroquinazolin-7-carboxamide (Example 77) was prepared from (S) -methyl-3,4-dimethyl-2-oxo- 1,2,3,4- tetrahydroquinazolin-7-carboxylate (Preparation 14, Step 5) and 4- (bromomethyl) -5-chloro-3-fluoro-2-methylpyridine (Preparation 22) according to the methods described in Preparations 2, 3 and 4 and General Procedures 1-3. LCMS m / z: 521.13 [M + H]; 1H NMR (500 MHz; DMSO-d6): δ 1.24 (d, J = 6.5 Hz, 3H), 2.35 (d, J = 2.9 Hz, 3H), 2.93 (s, 3H), 4.44-4.45 (m, 2H), 4.56-4.57 (m, 1H), 5.0 (d, J = 16.15 Hz, 1H), 5.45 (d , J = 16.25 Hz, 1H), 7.18-7.24 (m, 3H), 7.40-7.45 (m, 2H), 8.37 (s, 1H), 8.81 ( t, J = 4.8 Hz, 1H). Example 78: (S) -1- (2,6-difluoro-4-hydroxybenzyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorbenzyl) -1,2,3,4 -tetra- hydroquinazolin-7-carboxamide
[00379] [00379] Example 78 was prepared according to the methods described in General Procedures 1-3 and 13, and the methods described below. Preparation 24: (S) -1- (2,6-difluoro-4-methoxybenzyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorbenzyl) -1,2,3,4 -tetrahydroquinazolin-7-carboxamide (Example 79) F O F O F AT THE HN N F F
[00380] [00380] To a stirred solution of (S) -1- (2,6-difluoro-4-methoxybenzyl) -3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazolin-7 -carboxylic (Preparation 52) (0.7 g, 1.86 mmol) in DCM (70 mL) was added HBTU (0.846 g, 2.23 mmol) followed by addition of TEA (0.67 mL, 4.65 mmol) ) at 10-15 oC and stirring continued for another 15 min. 2,4,6-trifluorbenzylamine (0.299 mL, 2.04 mmol) was added to RT and the total was stirred at RT for 1 h. The reaction was monitored by UPLC-MS and after the end of the reaction, the mixture was diluted with water (50 ml), the organic layer was separated, washed with 2N HCl (2 x 25 ml), followed by NaHCO3 solution (4 x 5 ml) and finally with brine (25 ml). The combined organic layer was dried over anhydrous Na2SO4 and evaporated under low pressure to provide the crude product which was purified by Combi-flash to provide the title compound (0.07 g, 82% yield and 99.6% purity) as a solid White ice. LCMS m / z: 520.17 [M + H]; 1H NMR (500 MHz; DMSO-d6): δ 1.16 (d, J = 6.15 Hz, 3H), 2.94 (bs, 3H), 3.73 (bs, 3H), 4.39- 4.43 (m, 1H), 4.47- 4.51 (m, 2H), 4.73 (d, J = 15.7 Hz, 1H), 5.55 (d, J = 15.7 Hz , 1H), 6.67 (d, J = 9.9 Hz, 2H), 7.18-7.23 (m, 3H), 7.40 (d, J = 7.55 Hz, 1H), 7 , 44 (s, 1H), 8.81 (bs, 1H). Preparation 25: (S) -1- (2,6-difluoro-4-hydroxybenzyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorbenzyl) -1,2,3,4 -tetrahydroquinazolin-7-carboxamide (Example 78)
[00381] [00381] To a stirred solution of (S) -1- (2,6-difluoro-4-methoxybenzyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorbenzyl) - 1, 2,3,4-tetrahydroquinazolin-7-carboxamide (Example 79) (0.5 g, 0.96 mmol) in DCM (25 ml) BBr3 (5 ml, 1.0M solution in DCM) was added and mixture stirred at RT for 2 h. The reaction was monitored by UPLC-MS and after the end of the reaction the mixture was diluted with DCM (100 ml) and water (100 ml). The organic layer was separated and washed with NaHCO3 solution (50 ml) followed by brine (50 ml). The organic layer was dried over anhydrous Na2SO4 and evaporated under low pressure to provide the crude product which was purified by Combi-flash to give the title compound (0.4 g, 82% yield and 99.6% purity) as a white solid . LCMS m / z: 506.18 [M + H]; 1H NMR (500 MHz; DMSO-d6): δ 1.15 (d, J = 5.9 Hz, 3H), 2.93 (bs, 3H), 4.39-4.42 (m, 1H), 4.48-4.51 (m, 2H), 4.67 (d, J = 15.7 Hz, 1H), 5.51 (d, J =
[00382] [00382] Examples 80 and 81 were prepared according to the methods described in General Procedures 14, and the methods described below. Example 80: (S) -1- (2,6-difluoro-4- (2-hydroxyethoxy) benzyl) - 3,4-dimethyl-2-oxo-N- (2,4,6-trifluorbenzyl) -1, 2,3,4-tetrahydroquinazolin-7-carboxamide Preparation 26: (S) -ethyl-2- (4 - ((3,4-dimethyl-2-oxo-7 - ((2,4,6-trifluorbenzyl ) carbamoyl) -3,4-dihydroquinazolin-1 (2H) -yl) methyl) -3,5-difluorphenoxy) acetate
[00383] [00383] To a stirred solution of (S) -1- (2,6-difluoro-4-hydroxybenzyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorbenzyl) - 1, 2,3,4-tetrahydroquinazolin-7-carboxamide (Example 78) (0.05 g, 0.099 mmol) in DMF (2 mL) NaH (0.0047 g, 0.12 mmol, 50% suspension in oil) at 0-5 ⁰C and the resulting mixture was stirred at the same temperature for 10 min., then ethyl bromoacetate (0.0198 g, 0.12 mmol) was added at 0-5 ⁰C and the reaction mixture was stirred additionally for 40 min. The course of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was finished with a saturated NH4Cl solution, extracted with EtOAc and washed with brine. The collected organic layer was dried over anhydrous Na2SO4, filtered and concentrated under low pressure to give the title compound (0.05 g, 85% yield and 98.8% purity) as an ice-white solid that was used in the next step without any additional purification. LCMS m / z: 592.17 [M + H]. Preparation 27: (S) -1- (2,6-difluoro-4- (2-hydroxyethoxy) benzyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorbenzyl) -1, 2,3,4-tetrahydroquinazolin-7-carboxamide (Example 80)
[00384] [00384] To a stirred solution of (S) -ethyl-2- (4 - ((3,4-dimethyl-2-oxo-7 - ((2,4,6-trifluorbenzyl) carbamoyl) -3,4- dihydroquinazolin-1 (2H) -yl) methyl) -3,5-difluorphenoxy) acetate (Preparation 26) (0.06 g, 0.10 mmol) in ethanol (2 mL) NaBH4 (0.0306 g , 0.81 mmol) at 0-5 ⁰C. The reaction mixture was then stirred at RT for 3 h. The course of the reaction was monitored by TLC and LCMS and after the completion of the reaction the mixture was finalized with a saturated solution of NH4Cl, extracted with EtOAc and washed with brine. The organic layer was concentrated under low pressure to give the crude product which was purified by column chromatography to provide the title compound (0.024 g, 43% yield and 96.8% purity) as a white solid. LCMS m / z: 550.16 [M + H]; 1H NMR (500 MHz; DMSO-d6): δ 1.16 (d, J = 6.45 Hz,
[00385] [00385] To a stirred solution of (S) -1- (2,6-difluoro-4-hydroxybenzyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorbenzyl) - 1, 2,3,4-tetrahydroquinazolin-7-carboxamide (Example 78) (0.050 g, 0.099 mmol) in DMF (2 mL) K2CO3 (0.041 g, 0.29 mmol) was added followed by the addition of 3-bromopropanol ( 0.018 mL, 0.198 mmol) and the total heated to 60 ° C overnight. After the end of the reaction, the mixture was diluted with water and extracted with EtOAc. The organics were washed with brine, dried over anhydrous Na2SO4 and evaporated under low pressure to provide the crude product which was purified by Combi-flash (column 4.0 g) using EtOAc 90% in hexane as the eluent to give the title compound (0.017 g , 30.9% yield and 99.5% purity) as a white solid. LCMS m / z: 564.19 [M + H]; 1H NMR (500 MHz; DMSO-d6): δ 1.15 (d, J = 4.7 Hz, 3H), 1.80 (bs, 2H), 2.94 (s, 3H), 3.50- 3.51 (m, 2H), 3.99 (bs, 2H), 4.39-4.42 (m, 1H), 4.48-4.56 (m, 3H), 4.73 (d, J = 15.6 Hz, 1H), 5.53 (d, J = 15.45 Hz, 1H), 6.65 (d, J = 9.45 Hz, 2H), 7.19-7.21 ( m, 3H), 7.39-7.45 (m, 2H),
[00386] [00386] Example 82 was prepared according to the methods described in General Procedure 15, and the methods described below. Example 82: (S) -3- (4 - ((3,4-dimethyl-2-oxo-7 - ((2,4,6-trifluorbenzyl) carbamoyl) -3,4-dihydroquinazolin dihydrogen phosphate -1 (2H) -yl) methyl) -3,5-difluorfenoxy) propyl
[00387] [00387] (S) -1- (2,6-difluoro-4- (3-hydroxypropoxy) benzyl) - 3,4-dimethyl-2-oxo-N- (2,4,6-trifluorbenzyl) -1, 2,3,4-tetrahydroquinazolin-7-carboxamide (Example 81) (0.32 g, 0.56 mmol) was absorbed in pure POCl3 (0.48 mL, 5.11 mmol) at 0 ° C and then the reaction mixture cooled naturally to RT for 1 h. The completion of the reaction was monitored by TLC and after complete conversion of the starting material, the reaction mixture was dissolved in MeCN (1.5 mL) and a mixture of silver nitrate (0.192 g, 1.13 mmol) in water ( 3 ml) was added in drops at 0-5 ° C. The resulting reaction mixture was further stirred for 1 h at the same temperature and then kept in the refrigerator for 18 h to provide a solid that was filtered, and the filtrate evaporated under low pressure to provide the crude product that was purified by prep-HPLC for give the title compound (0.15 g, 41% yield and 99.3% purity) as a light yellow solid. LCMS m / z: 644.11 [M + H]; 1H NMR (500 MHz; DMSO-d6): δ 1.16 (d, J = 6.3 Hz, 3H), 1.97 (t, J = 5.9
[00388] [00388] Example 83 was prepared according to the methods described in General Procedure 16, and the methods described below. Example 83: (S) - (4 - ((3,4-dimethyl-2-oxo-7 - ((2,4,6-trifluorbenzyl) carbamoyl) -3,4-dihydroquinazolin-1 dihydrogen phosphate (2H) -yl) methyl) -3,5-difluorfenoxy) methyl Preparation 28: (S) -dibenzyl phosphate - ((4 - ((3,4-dimethyl-2-oxo-7 - ((2,4 , 6-trifluorbenzyl) carbamoyl) -3,4-dihydroquinazolin-1 (2H) -yl) methyl) -3,5-difluorfenoxy) methyl)
[00389] [00389] To a stirred solution of (S) -1- (2,6-difluoro-4-hydroxybenzyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorbenzyl) - 1, 2,3,4-tetrahydroquinazolin-7-carboxamide (Example 78) (0.15 g, 0.30 mmol) in dry DMF (2 mL) K2CO3 (0.0615 g, 0.44 mmol) was added and after 15 min. dibenzyl phosphate (chloromethyl) (0.106 g, 0.327 mmol) was added under an atmosphere of N2. The reaction mixture was stirred at 60 oC for 3 h. After the end of the reaction, the mixture was diluted with EtOAc and washed with water followed by brine solution. The organic layer was then dried over anhydrous Na2SO4 and evaporated to dryness under low pressure to give the crude product which was purified by Prep-HPLC to provide the title compound (0.09 g, 38% yield and> 99% purity) as a white solid. LCMS m / z: 796.24 [M + H]. Preparation 29: (S) - (4 - ((3,4-dimethyl-2-oxo-7 - ((2,4,6-trifluorbenzyl) carbamoyl) -3,4-dihydroquinazolin-1 dihydrogen phosphate (2H) -yl) methyl) -3,5-difluorfenoxy) methyl (Example 83)
[00390] [00390] To a stirred solution of (S) - dibenzyl phosphate ((4 - ((3,4-dimethyl-2-oxo-7 - ((2,4,6-trifluorbenzyl) carbamoyl) -3,4- dihydroquinazolin-1 (2H) -yl) methyl) -3,5-difluorphenoxy) methyl) (Preparation 28) (0.07 g, 0.14 mmol) in THF (2 mL) 10% Pd-C was added (0.03 g, 50% w / w in water) at RT under an inert atmosphere. The resulting mixture was stirred at RT for 15 min. under H2 gas balloon pressure and after the end of the reaction the mixture was diluted with EtOAc and passed through a short celite bed. The filtrate was evaporated to dryness under low pressure to give the crude product which was purified by Prep-HPLC to provide the title compound (0.028 g, 51.8% yield and> 99% purity) as a white solid. LCMS m / z: 616.14 [M + H]; 1H NMR (500 MHz; DMSO-d6): δ 1.16
[00391] [00391] Example 84 was prepared according to the methods described in General Procedure 17, and the methods described below. Preparation 30: (S) -dibenzyl phosphite (4 - ((3,4-dimethyl-2-oxo-7 - ((2,4,6-trifluorbenzyl) carbamoyl) -3,4-dihydroquinazolin-1 ( 2H) -yl) methyl) -3,5-difluorophenyl)
[00392] [00392] To a stirred solution of (S) -1- (2,6-difluoro-4-hydroxybenzyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorbenzyl) - 1, 2,3,4-tetrahydroquinazolin-7-carboxamide (Example 78) (0.15 g, 0.30 mmol) in dry acetonitrile (5 mL) was added tetrazole (0.026 mL, 0.30 mmol) followed by dibenzyl -di-isopropylphosphoramidite (0.20 mL, 0.71 mmol) under an inert atmosphere and the mixture allowed to stir at RT for 3 h. The course of the reaction was monitored by TLC and LCMS and after completion, the reaction mixture was evaporated under low pressure to dryness to give the title compound (0.21 g, 95% yield and purity> 66%) as crude which was used in the next step without any further purification. LCMS m / z: 750.21 [M + H]. Preparation 31: (S) -dibenzyl- (4 - ((3,4-dimethyl-2-oxo-7 - ((2,4,6-trifluorbenzyl) carbamoyl) -3,4-dihydroquinazolin-1 phosphate (2H) -yl) methyl) -3,5-difluorophenyl)
[00393] [00393] To a stirred phosphite solution of (S) - dibenzyl- (4 - ((3,4-dimethyl-2-oxo-7 - ((2,4,6-trifluorbenzyl) carbamoyl) -3,4- dihydroquinazolin-1 (2H) -yl) methyl) -3,5-difluorophenyl) (Preparation 30) (0.21 g, 0.28 mmol) in DCM (8 ml) m-CPBA (0.077 g, 0.45 mmol) at 0-5 oC under an inert atmosphere and the reaction mixture was then stirred at 0-5 oC for 1 h. The course of the reaction was monitored by TLC and LCMS and after completion the reaction mixture was diluted with water and extracted with EtOAc. The combined organics were washed with brine, dried over anhydrous Na2SO4 and concentrated under low pressure to give the title compound (0.1 g, 93% yield and> 98% purity) as crude which was used in the next step without any further purification. LCMS m / z: 766.20 [M + H].
[00394] [00394] To a stirred solution of (S) - dibenzyl- (4 - ((3,4-dimethyl-2-oxo-7 - ((2,4,6-trifluorbenzyl) carbamoyl) -3,4- dihydroquinazolin-1 (2H) -yl) methyl) -3,5-difluorophenyl) (Preparation 31) (0.1 g, 0.13 mmol) in dry THF (4 mL) 10% Pd-C ( 0.001 g, 50% w / w in water) under an inert atmosphere and the resulting reaction mixture was stirred at RT overnight under a H2 gas balloon pressure. The course of the reaction was monitored by TLC and LCMS and after completion, the reaction mixture was diluted with EtOAc and carefully filtered through a bed of celite and washed twice with EtOAc under an inert atmosphere. The organic collected was dried over anhydrous Na2SO4 and concentrated under low pressure to give the crude product which was purified by prep-HPLC to provide the title compound (0.04 g, 40% yield and 99.36% purity) as a white solid. . LCMS m / z: 586.12 [M + H]; 1H NMR (500 MHz; DMSO-d6): δ 1.16 (d, J = 5.2 Hz, 3H), 2.93 (s, 3H), 4.50-4.40 (m, 3H), 4.72 (d, J = 15.6 Hz, 1H), 5.52 (d, J = 15.4 Hz, 1H), 6.80 (d, J = 10.4 Hz, 2H), 7, 23-7.16 (m, 3H), 7.38 (d, J = 7.3 Hz, 1H), 7.47 (s, 1H), 8.78 (s, 1H).
[00395] [00395] Example 85 was prepared according to the methods described in General Procedure 18, and the methods described below. Example 85: (S) -4-Acetamidobenzyl- (4 - ((3,4-dimethyl-2-oxo-7 - ((2,4,6-trifluorbenzyl) carbamoyl) -3,4-dihydroquinazolin carbonate -1 (2H) -yl) methyl) -3,5-difluorophenyl) H N F O O O THE F O F AT THE N H N F F
[00396] [00396] To a stirred solution of (S) -1- (2,6-difluoro-4-hydroxybenzyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorbenzyl) - 1, 2,3,4-tetrahydroquinazolin-7-carboxamide (Example 78) (0.05 g, 0.099 mmol) in DMF (2 mL) NaH (0.003 g, 60% w / w in mineral oil) was added at 0 -5 oC and the reaction mixture was stirred for 15 min. at the same temperature. Then, separately synthesized 4-acetamidobenzyl- (4-nitrophenyl) -carbonate (preparation described in US 1996/5585397) (0.1 g, 0.30 mmol) was dissolved in DMF (2 mL) and added to the reaction mixture and the total stirred at RT for 30 min. The progress of the reaction was monitored by TLC and LCMS and after the completion of the reaction the mixture was diluted with water and extracted with EtOAc. The combined organics were washed with brine solution, dried over anhydrous Na2SO4 and concentrated under low pressure to give the crude compound which was purified by prep-HPLC to provide the title compound (0.015 g, 21.7% yield and 99.75 purity %) as a white solid. LCMS m / z: 697.19 [M + H]; 1H
[00397] [00397] Example 86 was prepared according to the methods described in General Procedure 19, and the methods described below. Example 86: (S) -benzyl-3 - ((((4 - ((3,4-dimethyl-2-oxo-7- ((2,4,6-trifluorbenzyl) carbamoyl) -3,4-dihydroquinazolin - 1 (2H) -yl) methyl) -3,5-difluorfenoxy) carbonyl) (methyl) amino) propanoate
[00398] [00398] To a stirred solution of (S) -1- (2,6-difluoro-4-hydroxybenzyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorbenzyl) - 1, 2,3,4-tetrahydroquinazolin-7-carboxamide (Example 78) (0.040 g, 0.079 mmol) in DMF (0.4 ml) NaH (0.0095 g, 60% w / w in mineral oil) was added at 0-5 oC and the reaction mixture was stirred for 15 min. at the same temperature. Then, separately synthesized benzyl-3- (methyl ((4-nitrophenoxy) carbonyl) amino) -propanoate (Syn. Comm. 2007, 37, 1927) (0.034 g, 0.095 mmol) in DMF (0.2 mL) was added in the reaction mixture and the total heated to 80 oC for 20 h. The progress of the reaction was monitored by TLC and LCMS and after completion the reaction mixture was diluted with water and extracted with EtOAc. The combined organics were washed with NaHCO3 and brine solution, dried over anhydrous Na2SO4 and concentrated under low pressure to give the crude compound which was purified by prep-HPLC to provide the title compound (0.022 g, 38% yield and 99.78 purity %) as a white solid. LCMS m / z: 725.19 [M + H]; 1H NMR (500 MHz; DMSO-d6): δ 1.17 (d, J = 6.2 Hz, 3H), 2.67 (t, J = 6.8 Hz, 1H), 2.75 (t, J = 6.7 Hz, 1H), 2.88 (s, 1H), 2.93 (s, 3H), 2.97 (s, 2H), 3.52 (t, J = 6.9 Hz, 1H), 3.62 (t, J = 6.7 Hz, 1H), 4.42-4.38 (m, 1H), 4.53-4.46 (m, 2H), 4.83 (d , J = 15.7 Hz, 1H), 5.09 (d, J = 5.7 Hz, 2H), 5.54 (d, J = 15.9 Hz, 1H), 6.93 (d, J = 8.8 Hz, 2H), 7.22-7.18 (m, 3H), 7.37-7.33 (m, 5H), 7.42 (d, J = 7.6 Hz, 1H) , 7.47 (bs, 1H), 8.82 (s, 1H). Example 87: (S) -1- (2-chloro-6-fluoro-3-hydroxybenzyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorbenzyl) -1,2,3 , 4-tetrahydroquinazolin-7-carboxamide
[00399] [00399] Example 87 was prepared according to the methods described in General Procedures 1-2 and 13, and the methods described below. Preparation 33: (S) -methyl-1- (2-chloro-6-fluor-3-methoxybenzyl) -3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazolin-7-carboxylate
[00400] [00400] A stirred solution of (S) -methyl-3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazolin-7-carboxylate (Preparation 14, Step 5) (0.28 g , 1.19 mmol) in DMF (5 mL) was cooled to 15-20 ° C with a cold water bath and NaH (0.053 g, 1.31 mmol) was then added in portions. After the addition was complete, 2-chloro-6-fluoro-3-methoxy-benzyl bromide (0.331 g, 1.31 mmol) was then added. The resulting mixture was kept at 20-25 oC for 30 min. The progress of the reaction was monitored by UPLC-MS and after completion the mixture was finished by pouring into a mixture of crushed ice / water (100 mL) and the total stirred for 30 min. The resulting solution was extracted with EtOAc, washed with brine, dried over anhydrous Na2SO4 and evaporated under low pressure to give the crude product which was purified by Combi-flash (column 24.0 g) and eluted with EtOAc 74% in hexane as eluant to provide title compound (0.448 g, 92% yield and> 95% purity) as a white solid. LCMS m / z: 407 [M + H]. Preparation 34: (S) -1- (2-chloro-6-fluor-3-methoxybenzyl) -3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazolin-7-carboxylic acid
[00401] [00401] To a stirred solution of (S) -methyl 1- (2-chloro-6-fluor-3-methoxybenzyl) -3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazolin -7-carboxylate (Preparation 33) (0.448 g, 1.10 mmol) in THF / MeOH / water (10 mL, 2: 1: 1) LiOH (0.37 g, 8.82 mmol) was added at RT and the total kept at the same temperature for another 3 h. The reaction was monitored by UPLC-MS and after completion, the solvents were evaporated under low pressure to give the crude which was diluted with water and washed with diethyl ether (2 x 20 mL). The aqueous layer was cooled in ice water to ~ 10-15 ° C and acidified with 6N HCl at pH ~ 2-3. The resulting solution was extracted with EtOAc, washed with brine, dried over anhydrous Na2SO4 and evaporated under low pressure to provide the title compound (0.4 g, 92.5% yield and purity> 95%) as an ice-white solid that was used in the next step without any further purification. LCMS m / z: 393 [M + H]. Preparation 35: (S) -1- (2-chloro-6-fluor-3-methoxybenzyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorbenzyl) -1,2,3 , 4-tetrahydroquinazolin-7-carboxamide (Example 88) F THE
[00402] [00402] To a stirred solution of (S) -1- (2-chloro-6-fluoro-3-methoxybenzyl) -3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazolin -7-carboxylic (Preparation 34) (0.4 g, 1.02 mmol) in DCM (20 mL) was added HBTU (0.464 g, 1.22 mmol) followed by TEA (0.368 mL, 2.55 mmol) to 10-15 oC and the total was stirred for 5 min. 2,4,6-trifluorbenzylamine (0.164 ml, 1.12 mmol) was then added and the temperature maintained at RT for 1 h. The progress of the reaction was monitored by UPLC-MS and after completion the reaction mixture was diluted with water (100 mL) and the separated organic layer was washed with 2N HCl, followed by saturated NaHCO3 solution and finally with brine solution. The combined organics were dried over anhydrous Na2SO4 and evaporated under low pressure to provide the title compound (0.52 g, 98% yield and 99.8% purity) as an ice-white solid that was used in the next step without any further purification. LCMS m / z: 536.13 [M + H]; 1H NMR (500 MHz; DMSO-d6): δ 1.22 (d, J = 6.4 Hz, 3H), 2.94 (s, 3H), 3.81 (s, 3H), 4.38- 4.49 (m, 2H), 4.50-4.53 (m, 1H), 4.90 (d, J = 15.75 Hz, 1H), 5.54 (d, J = 15.7 Hz , 1H), 7.05-7.07 (m, 1H), 7.10-7.14 (m, 1H), 7.19-7.22 (m, 3H), 7.40 (d, J = 7.8 Hz, 1H), 7.44 (s, 1H), 8.77 (bs, 1H). Preparation 36: (S) -1- (2-chloro-6-fluor-3-hydroxybenzyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorbenzyl) -1,2,3 , 4-tetrahydroquinazolin-7-carboxamide (Example 87)
[00403] [00403] To a stirred solution of (S) -1- (2-chloro-6-fluor-3-methoxybenzyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorbenzyl) - 1,2,3,4-tetrahydroquinazolin-7-carboxamide (Example 88) (2.0 g, 3.74 mmol) in DCM (20 mL) BBr3 (9.345 mL, 9.35 mmol, 1M solution was added in DCM) at 0-25 oC and the reaction mixture was stirred for 1 h. The progress of the reaction was monitored by TLC and LCMS and after the completion of the reaction the mixture was finalized with a saturated solution of NaHCO3 and extracted with EtOAc. The organic layer was washed with a saturated solution of NaHCO3, brine and dried over anhydrous Na2SO4. The solvent was concentrated under low pressure to provide the crude product which was purified by prep-HPLC to give the title compound (1.1 g, 56.45% yield and 99.5% purity) as a white solid, LCMS m / z: 522.15 [M + H]; 1H NMR (500 MHz; DMSO-d6): δ 1.23 (d, J = 6.55 Hz, 3H), 2.94 (s, 3H), 4.38-4.41 (m, 1H), 4.46-4.54 (m, 2H), 4.86 (d, J = 15.75 Hz, 1H), 5.52 (d, J = 15.75 Hz, 1H), 6.84-6 , 87 (m, 1H), 6.95 (t, J = 9.45 Hz, 1H), 7.18 - 7.22 (m, 3H), 7.39 (d, J = 7.75 Hz, 1H), 7.43 (s, 1H), 8.77 (t, J = 4.8 Hz, 1H), 10.15 (bs, 1H). Example 89: (S) -2-Chloro-3 - ((3,4-dimethyl-2-oxo-7 - ((2,4,6-trifluorbenzyl) carbamoyl) -3,4-di- hydroquinazolin-1 (2H) -yl) methyl) -4-fluorophenyl F HO OH P THE
[00404] [00404] Example 89 was prepared according to the methods described in General Procedure 17 and the methods described below Preparation 37: (S) -Dibenzyl phosphate (2-chloro-3 - ((3,4-dimethyl-2 -oxo-7 - ((2,4,6-trifluorbenzyl) carbamoyl) -3,4-dihydroquinazolin-1 (2H) -yl) methyl) -4-fluorophenyl)
[00405] [00405] To a stirred solution of (S) -1- (2-chloro-6-fluor-3-hydroxybenzyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorbenzyl) - 1,2,3,4-tetrahydroquinazolin-7-carboxamide (Example 87) (0.15 g, 0.28 mmol) in acetonitrile (10 mL) DMAP (0.004 g, 0.031 mmol) was added followed by CCl4
[00406] [00406] To a stirred solution of (S) - dibenzyl- (2-chloro-3 - (((3,4-dimethyl-2-oxo-7 - ((2,4,6-trifluorbenzyl) carbamoyl) carbamoyl) - 3,4-dihydroquinazolin-1 (2H) -yl) methyl) -4-fluorophenyl) (Preparation 37) (0.18 g, 0.23 mmol) in THF (10 mL) 10% Pd-C was added (0.05 g, 50% w / w in water) under an inert atmosphere at RT and the total was stirred under H2 gas balloon pressure for 1 h. After the end of the reaction (monitored by LCMS or TLC) the mixture was filtered through a bed of celite and washed carefully with THF under an atmosphere of N2 gas. The solvent was evaporated under low pressure to give the crude product which was purified by prep-HPLC using ammonium acetate buffer to provide the title compound (0.055 g, 40% yield and 99.8% purity) as a white solid, LCMS m / z: 602.2 [M + H]; 1H NMR (500 MHz; DMSO-d6 + D2O): δ 1.22 (s, 3H), 2.94 (s, 3H), 4.50-4.42 (m, 3H), 4.87 (d , J = 14.9 Hz, 1H), 5.52 (d, J = 15.3 Hz, 1H), 6.98 (s, 1H), 7.52-7.19 (m, 7H), 8 , 78 (s, 1H). Example 90: (S) - (2-Chloro-3 - ((3,4-dimethyl-2-oxo-7 - ((2,4,6-trifluorbenzyl) carbamoyl) -3,4-di dihydrogen phosphate) - hydroquinazolin-1 (2H) -yl) methyl) -4-fluorophenoxy) methyl
[00407] [00407] Example 90 was prepared according to the methods described in General Procedure 16, and the methods described below. Preparation 39: (S) -dibenzyl phosphate ((2-chloro-3 - ((3,4-dimethyl-2-oxo-7 - ((2,4,6-trifluorbenzyl) carbamoyl) -3,4-di - hydroquinazolin-1 (2H) -yl) methyl) -4-fluorophenoxy) methyl) F THE THE P O O
[00408] [00408] To a stirred solution of (S) -1- (2-chloro-6-fluor-3-hydroxybenzyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorbenzyl) - 1,2,3,4-tetrahydroquinazolin-7-carboxamide (Example 87) (0.15 g, 0.29 mmol) in dry DMF (3 mL) K2CO3 (0.079 g, 0.58 mmol) was added to 0-5 oC under an N2 gas atmosphere in a sealed tube. Then after 15 min. dibenzyl phosphate (chloromethyl) (0.113 g, 0.35 mmol) was added and the resulting reaction mixture was stirred at 60 oC for 5 h. After the end of the reaction (monitored by TLC and LCMS) it was cooled to RT and poured into cold water and extracted with EtOAc. The combined organics were washed with brine, dried over anhydrous Na2SO4 and evaporated under low pressure to dryness to give the title compound (0.165 g, 70% yield and 95% purity) as a yellowish solid which was used in the next step without any purification additional. LCMS m / z: 812.21 [M + H]. Preparation 40: (S) - (2-Chloro-3 - ((3,4-dimethyl-2-oxo-7 - ((2,4,6-trifluorbenzyl) carbamoyl) -3,4-di dihydrogen phosphate) - hydroquinazolin-1 (2H) -yl) methyl) -4-fluorophenoxy) methyl (Example 90)
[00409] [00409] To a stirred solution of (S) - dibenzyl phosphate ((2-chloro-3 - ((3,4-dimethyl-2-oxo-7 - ((2,4,6-trifluorbenzyl) carbamoyl) - 3,4-dihydroquinazolin-1 (2H) -yl) methyl) -4-fluorophenoxy) -methyl) (Preparation 39) (0.165 g, 0.20 mmol) in THF (3 mL) Pd / C 10 was added % (80 mg, 50% w / w in water) under an atmosphere of N2 gas. The resulting reaction mixture was stirred under H2 gas balloon pressure at RT for an additional 15 min. After the end of the reaction (monitored by UPLC-MS) the mixture was diluted with EtOAc and passed through a bed of celite. The collected filtrate was evaporated under low pressure to give the crude product which was purified by prep-HPLC to give the title compound (0.028 g, 22% yield and> 98% purity) as a white solid. LCMS m / z: 632.04 [M + H]; 1H NMR (500 MHz; DMSO-d6): δ 1.22 (s, 3H), 2.93 (s, 3H), 4.51-4.39 (m, 3H), 4.90 (d, J = 15.3 Hz, 1H), 5.38 (d, J = 6.6 Hz, 2H), 5.51 (d, J = 15.6 Hz, 1H), 7.08 (t, J = 9 , 0 Hz, 2H), 7.20 (bs, 3H), 7.38 (bs, 2H), 7.47 (s, 1H), 8.79 (s, 1H).
[00410] [00410] After the same procedures described in Preparations 37-40, several Examples containing phosphate were synthesized as shown in the following tables. Examples of which phosphates were derived are shown in the tables. Ex. (Deri- LCMS Structure IUPAC NMR Name [M + H] de) (500 MHz; DMSO-d6): δ 1.16 (d, di- J = 5.85 Hz, hydrogenof 3H), 2.95 (s, 3H phosphate), 3.95 (s, (S) -2- (2- 1H), 4.02-4.07 ((3.4- (m, 2H), 4.12 dimethyl- 2- (s, 1H), 4.42 oxo-7- (s, 2H), 4.50 ((2.4.6- (s, J = 6.2 Hz, Ex trifluorb 1H), 4.92 (d, J 628.1 91 (Ex. nzil) carba = 15.65 Hz, 2 242) moil) -34- 1H), 5.53 (d, J [MH] di- = 16.2 Hz, 1H ), hydrokine 6.80 (d, J = zolin- 8.55 Hz, 1H), 1 (2H) - 7.12-7.15 (m, yl) methyl) - 3H), 7.19-7, 24 3.4- (m, 1H), 7.34 difluorfen (d, J = 7.75 oxy) ethyl Hz, 1H), 7.49 (s, 1H), 9.13 (bs, 1H).
[00411] [00411] Examples 137, 138, 139 and 140 were prepared according to the methods described in General Procedures 14, 14, 18 and 19 respectively, and the methods described below. Example 137: (S) -1- (2-chloro-6-fluoro-3- (2-hydroxyethoxy) benzyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorbenzyl) - 1,2,3,4-tetrahydroquinazolin-7-carboxamide
[00412] [00412] To a stirred solution of (S) -1- (2-chloro-6-fluor-3-hydroxybenzyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorbenzyl) - 1,2,3,4-tetrahydroquinazolin-7-carboxamide (Example 87) (0.06 g, 0.12 mmol) in dry DMF (2 mL) under an inert atmosphere NaH (0.005 g, 0, 13 mmol, suspension in 60% mineral oil) at 0-5 ° C and the total stirred for 10 min. ethyl bromoacetate (0.029 g, 0.17 mmol) was then added to the reaction mixture and stirring continued for 5 min. at the same temperature. The reaction mixture was allowed to warm to RT and further stirred for 2 h. The completion of the reaction was monitored by TLC and LCMS and after completion the mixture was finalized with saturated ammonium chloride solution and extracted with EtOAc. The combined organics were washed with brine, dried over anhydrous Na2SO4 and concentrated under low pressure to provide the title compound (0.08 g, purity> 80%) as a yellow viscous oil which was used in the next step without any further purification. LCMS m / z: 608.15 [M + H]. Preparation 42: (S) -1- (2-chloro-6-fluoro-3- (2-hydroxyethoxy) benzyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorbenzyl) - 1,2,3,4-tetrahydroquinazolin-7-carboxamide (Example 137)
[00413] [00413] To a stirred solution of (S) -ethyl-2- (2-chloro-3- (((3,4-dimethyl-2-oxo-7 - ((2,4,6-trifluorbenzyl) carbamoyl) - 3,4-dihydroquinazolin-1 (2H) -yl) methyl) -4-fluorophenoxy) - acetate (Preparation 41) (0.075 g, 0.13 mmol) in methanol (3 mL) NaBH4 (0.078 g, 1.27 mmol) and LiCl (0.054 g, 1.27 mmol) at 0-5 ° C and the reaction mixture was stirred at RT for 30 min. After consumption of the starting material the solvents were evaporated under low pressure to give a residue which was diluted with water and extracted with EtOAc. The combined organics were washed with brine, dried over anhydrous Na2SO4 and concentrated under low pressure to provide the crude product which was purified by prep-HPLC to give the title compound (0.02 g, 28.7% yield and 98.46 purity %) as an ice-white solid. LCMS m / z: 566.12 [M + H]; 1H NMR (500 MHz; DMSO-d6): δ 1.23 (bs, 3H), 2.94 (s, 3H), 3.72 (bs, 2H), 4.02 (bs, 2H), 4, 41-4.52 (m, 3H), 4.90 (bs, 2H), 5.54 (d, J = 14.55 Hz, 1H), 7.08-7.20 (m, 5H), 7 , 40-7.45 (m, 2H), 8.78 (bs, 1H). Example 138: (S) -1- (2-chloro-6-fluoro-3- (3-hydroxypropoxy) benzyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorbenzyl) - 1,2,3,4-tetrahydroquinazolin-7-carboxamide F The OH
[00414] [00414] To a stirred solution of (S) -1- (2-chloro-6-fluor-3-hydroxybenzyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorbenzyl) - 1,2,3,4-tetrahydroquinazolin-7-carboxamide (Example 87) (0.04 g, 0.077 mmol) in dry DMF (2 mL) at room temperature under an inert atmosphere K2CO3 (0.053 g, 0 , 23 mmol) and KI (1.0 mg) at RT and stirring continued for 10 min. 3-Bromopropanol (0.0159 g, 0.12 mmol) was added to the reaction mixture and the total stirred at RT overnight. The progress of the reaction was monitored by TLC and LCMS and after completion the reaction mixture was finalized with H2O and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under low pressure to provide the crude product which was purified by prep-HPLC to give the title compound (0.02 g, 45% yield and 98.94% purity) like a white solid. LCMS m / z: 580.14 [M + H]; 1H NMR (500 MHz; DMSO-d6): δ 1.22 (d, J = 6.6 Hz, 3H), 1.85 (t, J = 6.1 Hz, 2H), 2.94 (s, 3H), 3.55-3.58 (m, 2H), 4.06 (d, J = 3.1 Hz, 2H), 4.41 - 4.37 (m, 1H), 4.66-4 , 46 (m, 3H), 4.91 (d, J = 15.7 Hz, 1H), 5.54 (d, J = 15.7 Hz, 1H), 7.11-7.05 (m, 2H), 7.22-7.18 (m, 3H), 7.44-7.39 (m, 2H), 8.78 (bs, 1H). Example 139: (S) -4-Acetamidobenzyl- (2-chloro-3- ((3,4-dimethyl-2-oxo-7 - ((2,4,6-trifluorbenzyl) carbamoyl) - 3,4 carbonate) -di-hydroquinazolin-1 (2H) -yl) methyl) -4-fluorophenyl) F THE O O O
[00415] [00415] To a stirred solution of (S) -1- (2-chloro-6-fluor-3-hydroxybenzyl) -3,4-dimethyl-2-oxo-N- (2,4,6-
[00416] [00416] To a stirred solution of (S) -1- (2-chloro-6-fluor-3-hydroxybenzyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorbenzyl) - 1,2,3,4-tetrahydroquinazolin-7-carboxamide (Example 87) (0.042 g, 0.08 mmol) in DMF (2 mL) NaH (0.01 g, 60% w / w in oil) was added mineral) at 0-5 oC and the reaction mixture was stirred for 15 min. at the same temperature.
[00417] [00417] Example 141 was prepared according to the methods described in General Procedures 1-3 and 24, and the methods described below. Preparation 43: Methyl-3- (bromomethyl) -2,4-difluorbenzoate
[00418] [00418] To a stirred solution of commercially available methyl-2,4-difluor-3-methylbenzoate (0.136 g, 0.73 mmol) in CCl4 (5 mL) was added NBS (0.143 g, 0.80 mmol) followed by AIBN (0.01 g, 0.06 mmol) at RT. The resulting reaction mixture was refluxed for 3 h. The completion of the reaction was monitored by TLC and LCMS after which the reaction mixture was diluted with water and extracted with EtOAc. The combined organics were washed with a saturated brine solution, dried over anhydrous Na2SO4 and concentrated under low pressure to give the crude product which was purified by column chromatography to provide title compound (0.18 g, 92% yield and purity 99 %) as a sticky solid ice white. Preparation 44: (S) -3,4-Dimethyl-2-oxo-1,2,3,4-tetrahydroquinazolin-7-carboxylic acid
[00419] [00419] To a stirred solution of (S) -methyl-3,4-dimethyl-
[00420] [00420] To a stirred solution of (S) -3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazolin-7-carboxylic acid (Preparation 44) (0.25 g, 1, 14 mmol) in THF (5 mL) HATU (0.52 g, 1.36 mmol) was added followed by TEA (0.17 g, 1.70 mmol). The resulting reaction mixture was stirred at RT for 1 h and then 2,4,6-trifluorbenzyl amine (0.219 g, 1.36 mmol) added and the total further stirred at RT for 2 h. The completion of the reaction was monitored by TLC and LCMS. The reaction mixture was diluted with water and extracted with EtOAc. The combined organics were washed with a saturated brine solution, dried over anhydrous Na2SO4 and concentrated under low pressure to provide the crude product which was purified by column chromatography to give the title compound (0.28 g, 68% yield and purity 99 %) as a white solid. LCMS m / z: 364 [M + H]. Preparation 46: (S) -methyl-3 - ((3,4-dimethyl-2-oxo-7 - ((2,4,6-trifluorbenzyl) carbamoyl) -3,4-dihydroquinazolin-1 (2H) - yl) methyl) -2,4-difluorbenzoate
[00421] [00421] To a stirred solution of (S) -3,4-dimethyl-2-oxo- N- (2,4,6-trifluorbenzyl) -1,2,3,4-tetrahydroquinazolin-7-carboxamide ( Preparation 45) (0.12 g, 0.34 mmol) in DMF (5 mL) NaH (0.01 g, 60% w / w in mineral oil) was added at 0-5 oC and stirring continued for 15 min. To this mixture was added methyl-3- (bromomethyl) -2,4-difluorbenzoate (Preparation 43) (0.1 g, 0.38 mmol) and then the reaction mixture was further stirred for 30 min. at 0-5 oC.
[00422] [00422] To a stirred solution of (S) -methyl-3 - ((3,4-dimethyl-2-oxo-7 - ((2,4,6-trifluorbenzyl) carbamoyl) -3,4-dihydroquinazolin -1 (2H) -yl) methyl) -2,4-difluorbenzoate (Preparation 46) (0.2 g, 0.37 mmol) in a THF: H2O: MeOH solvent mixture (8 mL, 2: 1: 1 ) LiOH.H2O (0.036 g, 0.73 mmol) was added to RT and the resulting reaction mixture was further stirred at RT for 2 h.
[00423] [00423] To a stirred solution of (S) -3 - ((3,4-dimethyl-2-oxo-7 - ((2,4,6-trifluorbenzyl) -carbamoyl) -3,4-dihydroquinazolin -1 (2H) -yl) methyl) -2,4 difluorbenzoic (Example 142) (0.14 g, 0.26 mmol) in THF (6 mL) was added HATU (0.119 g, 0.31 mmol) followed by TEA (0.053 g, 0.52 mmol) and the reaction mixture was stirred at RT for 15 min., Then ammonium formate (0.165 g, 2.63 mmol) was added and the resulting reaction mixture was further stirred at RT for 2 h.
[00424] [00424] To a stirred solution of (S) -3 - ((3,4-dimethyl-2-oxo-7 - ((2,4,6-trifluorbenzyl) -carbamoyl) -3,4-dihydroquinazolin -1 (2H) -yl) methyl) -2,4 difluorbenzoic (Example 142) (0.16 g, 0.30 mmol) in THF (5 mL) was added HATU (0.137 g, 0.36 mmol) followed by TEA (0.046 g, 0.45 mmol) and the reaction mixture was stirred at RT for 1 h, then 2-aminoethanol (0.022 g, 0.36 mmol) was added and the resulting mixture was further stirred at RT for 2 h . The progress of the reaction was monitored by TLC and LCMS and after completion the reaction mass was diluted with water and extracted with EtOAc. The combined organics were washed with NaHCO3 solution followed by brine, dried over anhydrous Na2SO4 and concentrated under low pressure to give the crude product which was purified by column chromatography to give the title compound (0.065 g, 37.5% yield and purity 99.8%) as a yellow solid. LCMS m / z: 577.17 [M + H]; 1H NMR (500 MHz; DMSO-d6): δ 1.17 (d, J = 6.4 Hz, 3H), 2.93 (s, 3H), 3.31-3.27 (m, 2H), 3.49-3.45 (m, 2H), 4.55-4.40 (m, 3H), 4.74 (t, J = 5.5 Hz, 1H), 4.91 (d, J = 15.8 Hz, 1H), 5.55 (d, J = 15.9 Hz, 1H), 7.12 (t, J = 8.9 Hz, 1H), 7.22-7.19 (m, 3H), 7.42 (d, J = 7.8 Hz, 1H), 7.47 (s, 1H), 7.56-7.51 (m, 1H), 8.23 (bs, 1H), 8.85 (t, J = 5.0 Hz, 1H).
[00425] [00425] Examples 144-147 were prepared according to the methods described in General Procedures 20-23, and the methods described below. Example 144: (S) -1- (4- (allyoxy) -2,6-difluorbenzyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorbenzyl) -1,2,3 , 4-tetrahydroquinazolin-7-carboxamide F O F O F AT THE N H N F F
[00426] [00426] To a stirred solution of (S) -1- (2,6-difluoro-4-hydroxybenzyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorbenzyl) - 1, 2,3,4-tetrahydroquinazolin-7-carboxamide (Example 78) (0.15 g, 0.30 mmol) in DMF (5 mL) was added K2CO3 (0.171 g, 0.74 mmol) and then sodium bromide allyl (0.043 g, 0.36 mmol) at RT. The entire reaction mixture was further stirred at RT for 1 h. The course of the reaction was monitored by TLC and LCMS and after completion the reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under low pressure to give the crude product which was purified by column chromatography to provide the title compound (0.14 g, 86.5% yield and 96.27 purity) %) as a white solid. LCMS m / z: 546.24 [M + H]; 1H NMR (500 MHz; DMSO-d6): δ 1.16 (d, J = 6.1 Hz, 3H), 2.94 (s, 3H), 4.42-4.39 (m, 1H), 4.55-4.46 (m, 4H), 4.74 (d, J = 15.7 Hz, 1H), 5.25 (d, J = 10.4 Hz, 1H), 5.38 (d , J = 16.9 Hz, 1H), 5.52 (d, J = 15.4 Hz, 1H), 6.00-5.95 (m, 1H), 6.69 (d, J = 10, 1 Hz, 2H), 7.23-7.18 (m, 3H), 7.40 (d, J = 7.5 Hz, 1H), 7.45 (s, 1H), 8.80 (s, 1H).
[00427] [00427] To a stirred solution of (S) -1- (4- (allyoxy) -2,6-difluorbenzyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorbenzyl) - 1,2,3,4-tetrahydroquinazolin-7-carboxamide (Example 144) (0.06 g, 0.11 mmol) in acetone (1 mL) osmium tetroxide (0.0028 g, 0.011 mmol) was added , NMO (0.0154 g, 0.13 mmol) and water (0.1 mL) at RT and the resulting reaction mixture was stirred at RT for 30 min. After the end of the reaction; the reaction mixture was poured into a saturated Na2SO3 solution and extracted with EtOAc. The organic layer was washed with brine solution, dried over anhydrous Na2SO4 and concentrated under low pressure to give crude product which was purified by prep-HPLC to provide title compound (0.020 g, 31.5% yield and 99.3% purity ) as a white solid. LCMS m / z: 580.2 [M + H]; 1H NMR (500 MHz; DMSO-d6): δ 1.16 (d, J = 6.1 Hz, 3H), 2.93 (s, 3H), 3.40-3.38 (m, 2H), 3.73 (d, J = 4.6 Hz, 1H), 3.84 (bs, 1H), 3.96 (d, J = 9.8 Hz, 1H), 4.52-4.39 (m , 3H), 4.75-4.70 (m, 2H), 4.99 (d, J = 4.4 Hz, 1H), 5.52 (d, J = 15.7 Hz, 1H), 6 , 65 (d, J = 24.9 Hz, 2H), 7.23-7.18 (m, 3H), 7.39 (d, J = 7.7 Hz, 1H), 7.45 (s, 1H), 8.80 (bs, 1H). Example 146: (S) -1- (4 - ((R) -2,3-dihydroxypropoxy) -2,6-difluorbenzyl) -3,4-dimethyl-2-oxo-N- (2,4, 6-trifluorbenzyl) -
[00428] [00428] To a stirred solution of (S) -1- (4- (allyoxy) -2,6-difluorbenzyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorbenzyl) - 1,2,3,4-tetrahydroquinazolin-7-carboxamide (Example 144) (0.075 g, 0.14 mmol) in tert-butanol (1 ml) and water (1 ml) at 0-5 ⁰C AD was added -mix-α (0.258 g) and the reaction mixture was stirred at 0 ⁰C overnight. The course of the reaction was monitored by TLC and LCMS and after completion the reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine solution, dried over anhydrous Na2SO4 and concentrated under low pressure to give crude product which was purified by prep-HPLC to provide title compound (0.037 g, 46.4% yield and 99.7% purity ) as a white solid. LCMS m / z: 580.2 [M + H]; 1H NMR (500 MHz; DMSO-d6): δ 1.16 (d, J = 6.0 Hz, 3H), 2.93 (s, 3H), 3.40-3.38 (t, J = 5 , 3 Hz, 2H), 3.74 - 3.71 (m, 1H), 3.85-3.82 (m, 1H), 3.97 (d, J = 7.2 Hz, 1H), 4 , 43-4.39 (m, 1H), 4.52-4.47 (m, 2H), 4.68 (t, J = 5.2 Hz, 1H), 4.74 (d, J = 15 , 9 Hz, 1H), 4.98 (d, J = 4.7 Hz, 1H), 5.52 (d, J = 15.6 Hz, 1H), 6.65 (d, J = 9.9 Hz, 2H), 7.23 - 7.18 (m, 3H), 7.40 (d, J = 7.7 Hz, 1H), 7.45 (s, 1H), 8.79 (s, 1H ). Example 147: (S) -1- (4 - ((S) -2,3-dihydroxypropoxy) -2,6-difluorbenzyl) -3,4-dimethyl-2-oxo-N- (2,4, 6-trifluorbenzyl) - 1,2,3,4-tetrahydroquinazolin-7-carboxamide
[00429] [00429] To a stirred solution of (S) -1- (4- (allyoxy) -2,6-difluorbenzyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorbenzyl) - 1,2,3,4-tetrahydroquinazolin-7-carboxamide (Example 144) (0.075 g, 0.14 mmol) in tert-butanol (1 ml) and water (1 ml) at 0-5 ⁰C AD was added -mix-β (0.258 g) and the reaction mixture was stirred at 0-5 ⁰C overnight.
[00430] [00430] Example 148 was prepared according to the methods described in General Procedures 1-3, and the methods described below. Preparation 49: Methyl-3,4-dimethyl-2-oxo-1,2,3,4-tetrahydropyride [3,2-d] pyrimidine-7-carboxylate Step 1: Methyl-5-nitro-6- ( (trimethylsilyl) ethynyl) nicotinate
[00431] [00431] A stirred solution of commercially available methyl 6-chloro-5-nitronicotinate (1.0 g, 4.62 mmol) in THF (20 mL) was degassed with N2, and then ethinyltrimethylsilane (0.544 g, 5.54 mmol), Pd (PPh3) 2Cl2 (0.324 g, 0.46 mmol), CuI (0.017 g, 0.089 mmol) and triethylamine (10 mL) were added sequentially. The resulting reaction mixture was heated to 80 oC for 3 h. The completion of the reaction was monitored by TLC and LCMS after which the reaction mixture was diluted with water and extracted with EtOAc. The combined organics were washed with brine solution, dried over anhydrous Na2SO4 and concentrated under low pressure to give the crude product which was purified by column chromatography to provide the title compound
[00432] [00432] To a stirred solution of methyl 5-nitro-6- ((trimethylsilyl) ethinyl) nicotinate (Step 1) (0.65 g, 2.34 mmol) in anhydrous DCM (25 mL) and MeOH (25 mL ) 3 drops of acetic acid were added followed by KF (0.069 g, 1.18 mmol) at 0-5 ° C and the total stirred at the same temperature for 10 min. The reaction was monitored by TLC and after completion the reaction mixture was finished with NaHCO3 solution and extracted with EtOAc. The combined organic layer was dried over Na2SO4 and evaporated under low pressure to give the title compound (0.54 g, 100% yield and purity> 85%) as a light yellow gum which was used in the next step without any further purification. LCMS m / z: 205.78 [M +]. Step 3: Methyl-5-amino-6-ethylnicotinate
[00433] [00433] To a stirred solution of methyl-6-ethynyl-5-nitronicotinate (Step 2) (0.48 g, 2.32 mmol) in anhydrous EtOAc (15 mL) was added 10% Pd-C (0.0272 g, 0.26 mmol, 10% w / w on carbon) under an atmosphere of N2 gas and the resulting mixture then purged twice with N2 gas followed by H2 gas. The reaction mixture was stirred at RT under a H2 gas balloon pressure for 3 h. After the end of the reaction, the mixture was filtered through a bed of short celite and the bed was washed with EtOAc x 3 under an inert atmosphere. The combined filtrate was evaporated to dryness under low pressure to give the title compound (0.39 g, 95% yield and> 92% purity) as a brown gum. LCMS m / z: 181.02 [M + H]. Step 4: Methyl-5 - ((ethoxycarbonyl) amino) -6-ethylnicotinate
[00434] [00434] To a solution of methyl-5-amino-6-ethylnicotinate (Step 3) (0.39 g, 2.16 mmol) in anhydrous DCE (15 mL) and pyridine (0.37 g, 4.67 mmol ) ethyl chloroformate (0.28 g, 2.58 mmol) was added in drops under an atmosphere of nitrogen at 0-5 ° C. The resulting reaction mixture was stirred at RT for 3 h and after the end of the reaction the reaction mass was finished with water and extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous Na2SO4 and evaporated under low pressure to give the crude compound which was purified by column chromatography to provide the title compound (0.34 g, 63% yield and purity> 91%) like a solid white ice. LCMS m / z: 253.01 [M + H]. Step 5: Methyl-6- (1-bromoethyl) -5- ((ethoxycarbonyl) amino) nicotinate
[00435] [00435] To a solution of methyl-5 - ((ethoxycarbonyl) amino) - 6-ethylnicotinate (Step 4) (0.2 g, 0.79 mmol) in CCl4 (20 mL) was added NBS (0.155 g, 0 , 87 mmol) and AIBN
[00436] [00436] To a stirred solution of methyl-6- (1-bromoethyl) - 5 - ((ethoxycarbonyl) amino) nicotinate (Step 5) (0.2 g, 0.60 mmol) in acetonitrile (5 ml) was added K2CO3 (0.417 g, 3.01 mmol) and MeNH2.HCl (0.061 g, 0.90 mmol) under an atmosphere of nitrogen and the combined reaction mixture was stirred at RT for 14 h. After that time, the solvent was evaporated under low pressure to give a residue that was dissolved in water and extracted twice with DCM. The combined organics were dried over Na2SO4 and evaporated under low pressure to give the title compound (0.18 g, 106% yield and purity> 70%) as a brown solid that was used in the next step without any further purification. LCMS m / z: 282.2 [M + H]. Step 7: Methyl-3,4-dimethyl-2-oxo-1,2,3,4-tetra-
[00437] [00437] To a stirred solution of methyl-5- ((ethoxycarbonyl) amino) -6- (1- (methylamino) ethyl) –nicotinate (Step 6) (0.18 g, 0.64 mmol) in MeOH (5 ml) K2CO3 (0.09 g, 1.33 mmol) was added and the reaction was stirred at 60 ° C for 2 h. The reaction was monitored by TLC and after completion the solvent was evaporated under low pressure to give a residue that was dissolved in water and extracted twice with DCM. The organics were dried over Na2SO4 and evaporated under low pressure to provide the crude product which was purified by column chromatography on silica gel using 52% EtOAc in hexane mixture as eluent to provide the title compound (0.07 g, yield 46.6 % yield and purity> 87%) as a white solid. LCMS m / z: 236.02 [M + H]. Preparation 50: 1- (2-chloro-6-fluorbenzyl) -3,4-dimethyl-2-oxo- N- (2,4,6-trifluorbenzyl) -1,2,3,4-tetrahydropyride [3 , 2- d] pyrimidine-7-carboxamide (Example 148)
[00438] [00438] To a stirred solution of 1- (2-chloro-6-fluorbenzyl) -3,4-dimethyl-2-oxo-1,2,3,4-tetrahydropyride [3,2-d] pyrimidine -7-carboxylic (prepared from Preparation 49 product according to the methods described in General Procedures 2 and 3) (0.04 g, 0.11 mmol) in anhydrous DMF (2 mL) TEA (0.034 g) was added , 0.34 mmol) and HATU (0.05 g, 0.13 mmol) under an atmosphere of N2 gas at RT. After stirring for 10-15 min., 2,4,6-trifluorbenzyl amine (0.018 g, 0.11 mmol) was added to the reaction mixture and stirring continued for an additional 1 h. The progress of the reaction was monitored by TLC or LCMS and after completion the mixture was finalized with water and extracted with EtOAc. The combined organics were washed with brine, dried over Na2SO4 and evaporated under low pressure to give the crude compound which was purified by prep-HPLC to provide the title compound (0.005 g, 10% yield and 99.0% purity) as a solid. White. LCMS m / z: 507.10 [M + H]; 1H NMR (500 MHz; DMSO-d6): δ 1.28 (d, J = 6.6 Hz, 3H), 2.97 (s, 3H), 4.42-4.52 (m, 2H), 4.57-4.61 (q, J = 6.6 Hz, 1H), 4.92 (d, J = 15.75 Hz, 1H), 5.49 (d, J = 15.7 Hz, 1H ), 7.16-7.24 (m, 3H), 7.30-7.37 (m, 2H), 7.76 (s, 1H), 8.52 (s, 1H), 9.01 ( bs, 1H). Example 149: (S) -N, 1-bis (2,6-difluoro-4-methoxybenzyl) -3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazolin-7-carboxamide F OMe F O F AT THE N H
[00439] [00439] Example 149 was prepared according to the methods described in General Procedures 1-3, and the methods described below. Preparation 51 (S) - Methyl 1- (2,6-difluor-4-methoxybenzyl) -3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazolin-7-carboxylate
[00440] [00440] To a stirred solution of (S) -methyl 3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazolin-7-carboxylate (Preparation 14) (0.1 g, 0 , 43 mmol) in DMF (3 mL) NaH (0.014 g, suspension in 60% mineral oil) was added at 0-5 oC under an inert atmosphere and the total allowed to stir for 15 min. Then, 2- (bromomethyl) -1,3-difluor-5-methoxybenzene (0.119 g, 0.47 mmol) was added to the reaction mixture which was allowed to further stir at RT for 2 h. The progress of the reaction was monitored by TLC and LCMS and after completion the mixture was finalized with a saturated solution of NH4Cl and extracted with EtOAc. The organics were washed with cold water followed by brine, dried over anhydrous Na2SO4 and evaporated under low pressure to give the title compound (0.166 g, 100% yield and purity> 95%) as a white solid. LCMS m / z: 391.14 [M + H]. Preparation 52: (S) -1- (2,6-Difluoro-4-methoxybenzyl) - 3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazolin-7-carboxylic acid
[00441] [00441] To a stirred solution of 1- (2,6-difluoro-4-methoxybenzyl) -3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazolin-7-carboxylate ) -methyl (Preparation 51)
[00442] [00442] To a stirred solution of (S) -1- (2,6-difluoro-4-methoxybenzyl) -3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazolin-7 -carboxylic (Preparation 52) (0.05 g, 0.13 mmol) in DMF (3 mL) HATU (0.076 g, 0.20 mmol) and TEA (0.037 mL, 0.27 mmol) were added at RT and the total allowed to stir for 15-20 min. Then, (2,6-difluor-4-methoxyphenyl) methanamine (0.020 ml, 0.13 mmol) was added and the mixture further stirred at RT for 2 h. The course of the reaction was monitored by TLC and LCMS and after completion the mixture was diluted with water and extracted with EtOAc. The combined organics were washed with a saturated solution of K2CO3, 1N HCl and brine. The organic layer was dried over anhydrous Na2SO4 and evaporated under low pressure to obtain the crude product which was purified by prep-HPLC to provide the title compound (0.04 g, 57% yield and 99.9% purity) as a white solid. ice. LCMS m / z: 532.22 [M + H]; 1H NMR (500 MHz; DMSO-d6): δ 1.16 (d, J = 6.3 Hz, 3H), 2.94 (s, 3H), 3.73 (s, 3H), 3.78 ( s, 3H), 4.36-4.39 (m, 1H), 4.42-4.46 (m, 1H), 4.50-4.52 (m, 1H), 4.74 (d, J = 15.65 Hz, 1H), 5.53 (d, J = 15.5 Hz, 1H), 6.67 (d, J = 9.95 Hz, 2H), 6.75 (d, J = 9.35 Hz, 2H), 7.18 (d, J = 7.85 Hz, 1H), 7.41 (d, J = 7.75 Hz, 1H), 7.46 (bs, 1H), 8 , 70 (bs, 1H). Example 150: (S) -N, 1-bis (2,6-difluoro-4-hydroxybenzyl) -3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazolin-7-carboxamide
[00443] [00443] To a stirred solution of (S) -N, 1-bis (2,6-difluor-4-methoxybenzyl) -3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazolin -7-carboxamide (Example 149) (0.11 g, 0.21 mmol) in DCM (4 mL) BBr3 (0.41 mL, 0.41 mmol, 1M DCM solution) was added at 0-5 ⁰C and the reaction mixture stirred at room temperature for 30 min. The course of the reaction was monitored by TLC and LCMS which showed incomplete conversion of starting material. Another portion of BBr3 (1.2 ml, 1.22 mmol) was added and after consumption of the starting material was confirmed by TLC, the reaction mixture was finished with a saturated solution of NaHCO3 and extracted with EtOAc. The combined organics were washed with brine, dried over anhydrous Na2SO4 and concentrated under low pressure to obtain the crude compound which was purified by prep-HPLC to give the title compound (0.06 g, 57% yield and 99.6% purity) like a white solid. LCMS m / z: 504.19 [M + H]; 1H NMR (500 MHz; DMSO-d6): δ 1.15 (d, J = 6.6 Hz, 3H), 2.93 (s, 3H), 4.31 - 4.52 (m, 3H), 4.68 (d, J = 15.70 Hz, 1H), 5.50 (d, J = 15.65 Hz, 1H), 6.37 (d, J = 9.85 Hz, 2H), 6, 46 (d, J = 9.25 Hz, 2H), 7.17 (d, J = 7.75 Hz, 1H), 7.40 (d, J = 7.80 Hz, 1H), 7.44 ( bs, 1H), 8.62 (bs, 1H), 10.38 (bs, 2H). Example 151: (S) -1- (2-chloro-6-fluorbenzyl) -N- (2-hydroxyethyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorbenzyl) - 1 , 2,3,4-tetrahydroquinazolin-7-carboxamide Preparation 54: (4S) -1- (2-chloro-6-fluorbenzyl) -3,4-dimethyl-2-oxo-N- (2 - (( tetrahydro-2H-pyran-2-yl) oxy) ethyl) -N- (2,4,6-trifluorbenzyl) -1,2,3,4-tetrahydroquinazolin-7-carboxamide
[00444] [00444] To a stirred solution of (S) -1- (2-chloro-6-fluorbenzyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorbenzyl) - 1,2, 3,4-tetrahydroquinazolin-7-carboxamide (Example 76) (0.1 g, 0.20 mmol) in DMF (3 mL) NaH (5.7 g, 60% suspension in mineral oil) was added at 0 -5 ° C and the reaction mixture was stirred at the same temperature for 15 min. In this reaction mixture 2- (2-bromoethoxy) tetrahydro-2H-pyran (0.05 g, 0.24 mmol) was added and the total stirred further overnight. The next day, the reaction mixture was heated to 60-65 oC for 2 h and a 2nd identical portion of both NaH and 2- (2-bromoethoxy) tetrahydro-2H-pyran was added and stirring continued at 60-65 oC for 2 h. The progress of the reaction was monitored by TLC and LCMS which showed incomplete conversion of the starting material. An identical 3rd portion of both NaH and 2- (2-bromoethoxy) tetrahydro-2H-pyran was added and the mixture heated for 2 h. After the starting material had been consumed, the reaction mixture was finished with a saturated solution of ammonium chloride and extracted with EtOAc. The combined organics were washed with brine, dried over anhydrous Na2SO4 and concentrated under low pressure to give the title compound (0.095 g, 75% yield and purity> 65%) as crude which was used in the next step without any further purification. LCMS m / z: 634 [M + H]. Preparation 55: (S) -1- (2-chloro-6-fluorbenzyl) -N- (2-hydroxyethyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorbenzyl) - 1 , 2,3,4-tetrahydroquinazolin-7-carboxamide (Example 151)
[00445] [00445] To a stirred solution of (4S) -1- (2-chloro-6-fluorbenzyl) -3,4-dimethyl-2-oxo-N- (2 - ((tetrahydro-2H-pyran-2 -yl) oxy) ethyl) -N- (2,4,6-trifluorbenzyl) -1,2,3,4-tetra-
[00446] [00446] Examples 152-300 were made in a manner analogous to Examples 74-76 starting from the appropriate quinazoline and using the appropriate benzyl halides and amines as described for General Procedures 1-14. Example Name 1H-NMR LCMS Structure for IUPAC [M + H] 1- (3,5- (400 MHz; DMSO- difluorb d6): δ 1.28 (d, J nzil) - = 6.48 Hz, 3H) , 3.4-2.98 (s, 3H), dimethyl- 4.40 (s, 2H), 2-oxo-N- 4.63 (q, J = 6.50 (2.4.6- Hz , 1H), 5.12 (s, 152 trifluorb 2H), 6.88 (d, J = 490.3 enzil) - 6.8 Hz, 2H), 1,2,3,4- 7,08-7 , 15 (m, tetra-4H), 7.24 (d, J = hydroquin 7.84 Hz, 1H), azolin-7- 7.44 (d, J = 7.76 carboxami Hz, 1H), 8, 81 (t, da J = 5.02 Hz, 1H), 1- (2- (400 MHz; DMSO-fluorine-6- d6): δ 1.14 (d, J 153 methoxyben = 6.12 Hz, 3H ), 501.8 zyl) -3.4- 2.94 (s, 3H), dimethyl-3.79 (s, 3H),
[00140] [00140] = 6.5 Hz, 3H), - ((3- 2.46 (d, J = 2.85 fluorine-2 Hz, 3H), 2.97 (s, methylpyri 3H), 4.39 (d, J = din-4- 5.05 Hz, 2H), il) methyl) 4.63-4.67 (q, J = -3.4- 6.4 Hz, 1H), 5.13 dimethyl - (d, J = 17.7 Hz, 2-oxo-N- 487.1 180 1H), 5.20 (d, J = (2.4.6 - 9 17.65 Hz, 1H), trifluorb 6 , 80 (t, J = 5.1 enzil) - Hz, 1H), 7.14 - 1.2.3.4 - 7.18 (m, 3H), tetra- 7.28 (d, J = 7 , 9 hydroquin Hz, 1H), 7.46-azolin-7- 7.48 (m, 1H), carboxami 8.16 (d, J = 4.9 Hz, 1H), 8.86 (t, J = 5.1 Hz, 1H). 1- (2- (500 MHz; DMSO-fluorine-4- d6): δ 1.24 (d, J 488.1 181 hydroxib = 6.3 Hz, 3H), 3 nzil) - 2.96 (s, 3H), 3.4- 4.45-4.40 (m,
[00447] [00447] 5 x 105 clonally selected Luciferase HEK293T-hSTING cells were seeded in 384-well plates in growth medium and stimulated with innovative compounds. After 20hrs of supernatant stimulus was removed and secretory reporter gene activity was measured using the Quanti-Luc detection system (Invitrogen) in a Spectrosmax i3X luminometer.
[00448] [00448] In the following tables, EC50 value ranges for exemplary compounds are given. The EC50 ranges are indicated as “A” for values less than or equal to 1 μM, “B” for values greater than 1 μM and less than or equal to 10 μM, and “C” for values greater than 10 μM.
[00449] [00449] All compounds were first tested in a primary classification to obtain a 'number of times of induction' on baseline levels of protein activity. Only those compounds that had an induction number> 1 were included in the table and all are considered 'active'. R232 human activity Ex Activated Activated- Ex Activated- Activated- Ex. Ex. dade. dity 16 1 A 68 C A 234 C 8 16 2 C 69 C A 235 B 9 17 3 C 70 B A 236 A 0 17 4 A 71 B A 237 A 1 17 5 A 72 B B 238 A 2
[00450] [00450] Selected compounds were further tested against STING protein of cynomolgus monkeys overexpressed in HEK293 T cells. STING activity of cynomolgus monkeys Activated Active Activated Activated Ex. Ex. Ex. Ex. Of 76 to 141 A 254 B 241 A 77 A 144 A 255 A 188 A 78 A 145 A 256 B 202 A 79 A 146 A 257 B 206 A 80 A 147 A 258 A 137 A 81 A 149 A 259 A 182 A 82 A 154 A 260 A 183 A 83 A 162 A 261 A 184 A 84 A 164 A 262 A 103 A 85 A 165 A 263 B 294
[00451] [00451] Human single STING nucleotide polymorphisms have been described that can affect the functional potency of compounds that modulate the activity of the STING protein (see Yi et. Al., PLoS One, October 2013, 8 (10), e77846). The 5 main polymorphisms of human STING are shown in Figure 1, with their prevalence in human populations indicated.
[00452] [00452] The following tables show the potency of selected compounds of the invention against the most common polymorphisms. H232 / REF H232 H232 Active ex. Active ex. Of 20 B 38 B 76 A 39 C 153 A 193 A
[00453] [00453] THP1-Dual ™ cells (Invitrogen) were derived from the human THP-1 monocyte cell line by stable integration of two inducible reporter constructs. As a result, THP1-Dual ™ cells allowed the simultaneous study of the NF-κB path, monitoring the SEAP path activity, and the secreted IRF, evaluating the activity of a secreted luciferase (Lucia). 5 x 105 THP1-Dual ™ cells were seeded in 384-well plates in growth medium and stimulated with innovative compounds. After 20h of stimulus supernatants were removed and reporter proteins were easily measured in the cell culture supernatant using QUANTI-Blue ™ (Invitrogen), a SEAP detection reagent, and QUANTI-Luc ™ (Invitrogen), a luciferase detection reagent on a Spectrosmax i3X luminometer.
[00141] [00141] EC50 value ranges are given for exemplary compounds tested in the previous test. The EC50 ranges are indicated as “A” for values less than or equal to 1 μM, “B” for values greater than 1 μM and less than or equal to 10 μM, and “C” for values greater than 10 μM. IRF / NFκB THP-IRF THP- THP- THP- activi- NFκB IRF NFκB Ex. Activity ex- activity activity 20 BB 38 CB 76 AA 39 CC 153 AA 193 AA 154 AA 196 AA 167 CC 204 CC 169 AA 162 AA 171 AA 54 BB 174 BB 203 AA 175 CC 206 AA 177 AA 208 BB 179 AA 212 CC 180 AA 213 BB 227 BB 77 AA 148 BB 237 BB 232 AA 78 AA 235 CC 238 BB 252 BB 239 BB 88 AA 182 AA 80 BB 241 AA 257 AA 242 AA 87 AA 243 CC 137 AA 246 AA 261 AA 264 BB 262 AA 141 AA 81 AA 281 AA 268 BB 283 AA 138 AA 285 AA 188 AA 85 AA 290 AA 296 AA 147 AA 185 BB 298 AA 293 AA Western blot Assay
[00454] [00454] 5 x 105 HEK293T-hSTIN clonally selected Luciferase cells were seeded in 24-well plates in 500 µL of growth medium and stimulated with innovative compounds or a vehicle control (VC), that is, the solvent without any compounds . After 2hr of stimulus, cells were harvested by centrifugation and cell precipitates were lysed in RIPA buffer (tris-Cl 20mM, NaCl 150mM, EDTA 0.5mM, NP40 1%, SDS 0.05%) containing 1x phosphatase inhibitor cocktail 3 (Sigma) and 1x protease inhibitor (Roche) to extract the soluble fraction of protein. 10 µg of extracted protein were electrophoresed on 10% SDS-PAGE gels and transferred to Immobilon-P membranes (Millipore). Blots were incubated with specific antibodies for phosphorylated STING (Ser366), phosphorylated IRF3 (Ser396), total STING, ACTIN (Cell Signaling) and IRF3 (Abcam). Secondary antibody HRP Anti-rabbit marker (Abcam) and Clarity MaxTM western ECL substrate (Biorad) were used to visualize strips with the help of the BioRad XRS plus imager. The assays are shown in Figure 2. Analysis of Cytokines by ELISA
[00455] [00455] 2 x 105 freshly isolated human PBMCs using Histopaque (Sigma) from different healthy donors were stimulated with innovative compounds (10µM) in 200µL of growth medium for 6 h. After treatment, supernatant media were collected and stored at -80 ° C in different aliquots for analysis of secreted cytokine. Cytokines IFNβ, IFNα, IL6, CXCL10 and TNFα were measured using the respective manufacturers' recommendations. IFNβ, IFNα were acquired by PBL Assay science, IL6, CXCL10 were sought by Abcam and TNFα was acquired from R&D Sistemas. The results are shown in Figure 3. Tumor Experiments In Vivo
[00456] [00456] 1 x 106 CT26 tumor cells stably expressing R232.hSTING were injected subcutaneously into
[00457] [00457] The inventors have synthesized a large number of compounds that fall under the general formula (I). They showed that these compounds activate the STING protein, and thus could be used to treat a number of diseases, including cancer.

权利要求:
Claims (42)
[1]
1. A compound characterized by the fact that it is of formula (I): (I) where: X1 is CR1 or N; X2 is CR2 or N; X3 is CR3 or N; Q is C = O, S = O, SO2, C = S or CR4R5; L is optionally substituted C1-C6 alkyl, polyfluoroalkyl C1-C3, optionally substituted C3-C6 cycloalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, C = O, S = O, SO2, - CH2C (O) -, -CH2CONH-, or -CONH-; R1, R2 and R3 are each selected independently from the group consisting of H, halogen, CN, hydroxyl, COOH, CONR1R2, NR1R2, NHCOR1, optionally substituted C1-C6 alkyl, optionally substituted C1-C3 polyfluoroalkyl, optionally substituted C1-C6 alkylsulfonyl, Optionally substituted mono or bicyclic C3-C6 cycloalkyl, Optionally substituted C2-C6 alkenyl, Optionally substituted C2-C6 alkynyl, Optionally substituted C1-C6 alkoxy, Optionally substituted C1-C6 alkoxycarbonyl, Optionally substituted C5-C10 mono or bicyclic heteroaryl 10 optionally substituted bicyclic members, optionally substituted 3 to 8 membered mono- or bicyclic heterocycle, optionally substituted aryloxy, optionally substituted heteroaryloxy and optionally substituted heterocyclyloxy; R4 and R5 are each independently selected from the group consisting of H, halogen, optionally substituted C1-C6 alkyl, optionally substituted (C3-C6) cycloalkyl; or R4 and R5 together with the atom to which they are attached, form a spirocyclic ring; R6 is a ring optionally substituted by one or more groups R12, wherein the ring is selected from the group consisting of an optionally substituted C5-C10 mono or bicyclic aryl, 5 to 10 membered mono or bicyclic heteroaryl, a C3-C6 cycloalkyl; and an optionally substituted 3- to 8-membered mono- or bicyclic heterocycle; Y is a C1-C6 alkyl, C1-C3 polyfluoroalkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3-C6 cycloalkyl or an optionally substituted 3- to 8-membered mono or bicyclic heterocycle; R7 is H, optionally substituted C1-C6 alkyl, optionally substituted sulfonyl, optionally substituted C1-C6 alkylsulfonyl, optionally substituted C3-C6 cycloalkyl, optionally C2-C6 alkenyl and optionally substituted C2-C6 alkynyl; R8 is an optionally substituted mono or bicyclic C5-C10 aryl, optionally substituted 5- to 10-membered mono or bicyclic heteroaryl, optionally substituted mono or bicyclic C3-C6 cycloalkyl or optionally substituted 3- to 8-membered mono or bicyclic heterocycle; R9 and R10 are each independently selected from the group consisting of optionally substituted C1-C6 alkyl, H, halogen, CN, hydroxyl, CO2H, CONR1R2, azido, sulfonyl, C1-C3 polyfluoroalkyl, C1-C6 optionally substituted thioalkyl, C1- C6 alkylsulfonyl optionally substituted, C3-C6 cycloalkyl optionally substituted, C2-C6 alkenyl optionally substituted, C2-C6 alkynyl optionally substituted, C1-C6 alkoxy optionally substituted, C1-C6 alkoxycarbonyl optionally substituted, C5-C10 mono or bicyclic aryl optionally substituted, optionally substituted 5 to 10 membered heteroaryl, optionally substituted heterocycle, optionally substituted heterocycle, optionally substituted aryloxy and optionally substituted heteroaryloxy; or R9 and R10 together with the atom C to which they are attached can combine to form an optionally substituted spirocyclic ring; and R11 is selected from the group consisting of optionally substituted C1-C6 alkyl, H, hydroxyl, C1-C3 polyfluoroalkyl, C1-C6 thioalkyl, optionally substituted C1-C6 alkylsulfonyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C2-C6 alkenyl , Optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkoxycarbonyl, optionally substituted C5-C10 mono or bicyclic aryl, optionally substituted 5-membered heteroaryl, optionally substituted heterocycle, optionally substituted aryloxy and a heteroaryloxy optionally replaced; the or each R12 group is selected independently from the group consisting of halogen, OH, OP (O) (OH) 2, NR13R14,
CONR13R14, CN, COOR13, NO2, azido, SO2R13, OSO2R13, NR13SO2R14, NR13C (O) R14, O (CH2) nOC (O) R13, NR13 (CH2) nOC (O) R14, OC (O) R13, OC ( O) OR13, OC (C) NR13R14, OC (O) O (CH2) nCOOR14, OC (O) NR13 (CH2) nCOOR14, C1-C6 optionally substituted alkyl, optionally substituted C1-C6 alkoxy, optionally substituted aryloxy, optionally heteroaryloxy substituted, an optionally substituted mono or bicyclic C5-C10 aryl, an optionally substituted 5 to 10 membered mono or bicyclic heteroaryl, an optionally substituted C3-C6 cycloalkyl and an optionally substituted 3 to 8 membered mono or bicyclic heterocycle; R13 and R14 are each independently selected from the group consisting of optionally substituted H, C1-C6 alkyl, optionally substituted mono- or bicyclic C3-C6 alkyl, optionally substituted mono- or bicyclic C5-C10, 5- to 10-membered mono or bicyclic heteroaryl optionally substituted 3 to 8 membered mono or bicyclic bicyclic and optionally heterocycle; and n is an integer between 0 and 6; or a complex, salt, solvate, tautomeric form or pharmaceutically acceptable polymorphic form thereof.
[2]
2. Compound according to claim 1, characterized by the fact that X1 is CR1, X2 is CR2 and X3 is CR3.
[3]
3. Compound according to claim 1, characterized by the fact that one or two of X1, X2 and X3 is N.
[4]
4. A compound according to any one of the preceding claims, characterized by the fact that R1, R2 and R3 each H.
[5]
5. A compound according to any one of the preceding claims, characterized by the fact that R9 is different from R10, so that the compound of formula (I) defines the carbon atom to which R9 and R10 are covalently attached is a first stereogenic center and defines an S enantiomer.
[6]
6. Compound according to claim 5, characterized in that the compound is a compound of the formula (I) -ent 1: (I) -ent 1 R9 is H and R10 is an optionally substituted C1-C6 alkyl, halogen, C3-C6 cycloalkyl or C1-C3 polyfluoroalkyl.
[7]
7. Compound according to claim 6, characterized by the fact that R10 is methyl.
[8]
8. A compound according to any one of the preceding claims, characterized in that R11 is selected from the group consisting of optionally substituted C1-C6 alkyl, H, hydroxyl, optionally substituted C1-C3 polyfluoroalkyl, C3-C6 cycloalkyl, C1 -C6 optionally substituted and C2-C6 alkenyl optionally substituted.
[9]
Compound according to claim 8, characterized by the fact that R11 is methyl.
[10]
10. Compound according to any one of the preceding claims, characterized by the fact that Q is C = O, SO2 or CR4R5.
[11]
A compound according to claim 10,
characterized by the fact that Q is C = O.
[12]
12. A compound according to any one of the preceding claims, characterized in that L is an optionally substituted C1-C6 alkyl, -CH2C (O) - or - CH2CONH-.
[13]
Compound according to claim 12, characterized by the fact that L is -CH2-, -CH2CH2-, - CH2CH2CH2-, C (Me) H, CF2 or C (H) F.
[14]
14. A compound according to any one of the preceding claims, characterized by the fact that R6 is a ring optionally substituted by one or more groups R12, wherein the ring is selected from the group consisting of an optionally mono or bicyclic C5-C10 aryl substituted or optionally substituted 5- to 10-membered mono or bicyclic heteroaryl.
[15]
15. A compound according to claim 14, characterized by the fact that R6 comprises a ring substituted by between 1 and 5 groups R12, and the or each group R12 is selected independently from the list consisting of halogen, C1-C6 alkyl, CN, C1-C6 alkoxy, C1-C3 polyfluoroalkyl, azide, NR1R2, CONR1R2, OR1, OH and OP (O) (OH) 2.
[16]
16. A compound according to claim 14 or 15, characterized by the fact that R6 is a phenyl or a naphthyl optionally substituted by one or more R12 groups.
[17]
17. A compound according to claim 16, characterized by the fact that R6 is a phenyl or a naphthyl substituted by 1 or 2 halogens.
[18]
18. A compound according to claim 16, characterized by the fact that phenyl or naphthyl is also replaced by a hydroxyl.
[19]
19. A compound according to any one of the preceding claims, characterized by the fact that R7 is H or an optionally substituted C1-C6 alkyl.
[20]
20. A compound according to any one of the preceding claims, characterized in that Y is an optionally substituted C1-C6 alkyl.
[21]
21. A compound according to any one of the preceding claims, characterized by the fact that R8 is an optionally substituted mono or bicyclic C5-C10 aryl or an optionally substituted 5 to 10 membered heteroaryl.
[22]
22. A compound according to claim 21, characterized in that R8 is an optionally substituted phenyl, an optionally substituted pyridine, an optionally substituted naphthyl, an optionally substituted furanyl, an optionally substituted benzofuranyl, an optionally substituted benzofuranyl, a thiophene optionally substituted, an optionally substituted pyridofuran, an optionally substituted benzoxazole or an optionally substituted benzothiazole.
[23]
23. A compound according to claim 21 or 22, characterized in that R8 comprises between 1 and 5 substituents, and the or each substituent is selected independently from the list consisting of C1-C6 alkyl, halogen, OH, C1- C6 alkoxy, CONR1R2, CN, azide, NO2, NH2, OCH2CH2OH, OCH2C (O) OH, OP (O) (OH) 2 and an optionally substituted 3- to 8-membered mono- or bicyclic heterocycle.
[24]
24. Compound according to claim 1, characterized by the fact that:
X1 is CR1; X2 is CR2; X3 is CR3; Q is C = O or CR4R5; L is optionally substituted C1-C3 alkyl; Y is optionally substituted C1-C6 alkyl; R1, R2 and R3 are each independently selected from the group consisting of H, halogen, CN, C1-C6 alkyl, optionally substituted C1-C3 polyfluoroalkyl and optionally substituted mono or bicyclic C3-C6 cycloalkyl; R4 and R5 are each independently selected from the group consisting of H and C1-C6 alkyl; R6 is a ring optionally substituted by one or more groups R12, in which the ring is selected from the group consisting of a C5-C10 mono or bicyclic aryl, 5 to 10 membered mono or bicyclic heteroaryl, a C3-C6 cycloalkyl; R7 is H; R8 is an optionally substituted C5-C10 mono or bicyclic aryl, an optionally substituted 5 to 10 membered mono or bicyclic heteroaryl; R9 and R10 are each independently selected from the group consisting of optionally substituted C1-C6 alkyl, H, halogen, CN, hydroxyl, azido, NR1R2, C1- C3 polyfluoroalkyl, C3-C6 cycloalkyl optionally substituted, C1-C6 alkoxy optionally substituted or optionally substituted C2-C6 alkenyl; and R11 is selected from the group consisting of optionally substituted C1-C6 alkyl, H, hydroxyl, NR1R2,
polyfluoroalkyl C1-C3, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy or optionally substituted C2-C6 alkenyl.
[25]
25. A compound according to claim 24, characterized by the fact that: X1 is CH; X2 is CH; X3 is CH; Q is C = O; L is a C1-C2 alkyl; Y is a C1-C2 alkyl; R6 is a ring optionally substituted by one or more groups R12, wherein the ring is selected from the group consisting of a mono or bicyclic C5-C10, 5 to 10 membered mono or heteroaryl aryl; R8 is an optionally substituted C5-C10 mono or bicyclic aryl or an optionally substituted 5 to 10 membered mono or bicyclic heteroaryl; R9 and R10 are each independently selected from the group consisting of optionally substituted C1-C6 alkyl, optionally substituted C2-C4 alkenyl, H, halogen, CN and azido; and R11 is selected from the group consisting of optionally substituted C1- C6 alkyl, optionally substituted C2-C4 alkenyl and H.
[26]
26. A compound according to claim 24, characterized by the fact that: L is -CH2-; Y is -CH2-; R6 is a phenyl or pyridinyl optionally substituted by one or more groups R12; R8 is an optionally substituted phenyl ring; R9 and R10 are each independently selected from the group consisting of C1-C3 alkyl and H; and R11 is selected from the group consisting of C1-C3 alkyl and H.
[27]
27. A compound according to claim 25 or 26, characterized in that: R6 is a ring optionally substituted by at least one group R12, wherein the or each group R12 is independently selected from the group consisting of a halogen , -OH, optionally substituted C1-C4 alkoxy, amino, optionally substituted C1-C3 alkyl or C (O) NH2; R8 is replaced by at least one halogen; R9 and R10 are each independently selected from the group consisting of CH3 and H; and R11 is selected from the group consisting of CH3 and H.
[28]
28. A compound according to claim 27, characterized in that: R6 is replaced by one or two halogens and the or each halogen is independently chlorine or fluorine; and R8 is replaced by 2 or 3 halogens and the or each halogen is fluorine.
[29]
29. A compound according to claim 28, characterized by the fact that R6 is further replaced by a hydroxyl.
[30]
30. Compound according to claim 1, characterized by the fact that the compound is: 1- (3,5-difluorobenzyl) -3-methyl-2-oxo-N- (2,4,6-trifluorobenzyl) - 1,2,3,4-tetrahydroquinazoline-7-
carboxamide; 1- (3,5-difluorobenzyl) -3-methyl-N - (((5-methylfuran-2-yl) methyl) -2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 3-cyclopropyl-1- (3,5-difluorobenzyl) -2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3,4-tetrahydroquinazoline-7-carboxamide; N- (2,4-difluorobenzyl) -1- (3,5-difluorobenzyl) -3-methyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1- (2-chloro-6-fluorobenzyl) -3-methyl-2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1- (4-fluorobenzyl) -3-methyl-2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1- (3,5-difluorobenzyl) -3-ethyl-2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1- (2,4-difluorobenzyl) -3-methyl-2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1- (2-fluor-6-methylbenzyl) -3-methyl-2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1- (2-fluoro-6-methoxybenzyl) -3-methyl-2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1- (2-bromo-6-fluorobenzyl) -3-methyl-2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3,4-tetrahydroquinazoline-7-carboxamide;
1- (2-fluorobenzyl) -3-methyl-2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1- (2-fluor-3-methylbenzyl) -3-methyl-2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1- (3-carbamoylbenzyl) -3-methyl-2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1- (3,5-difluorobenzyl) -3-isopropyl-2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3,4-tetrahydroquinazoline-7-carboxamide; N- (benzofuran-2-ylmethyl) -1- (3,5-difluorobenzyl) -3-methyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1- (2-chloro-4-fluorobenzyl) -3-methyl-2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1- (3,5-difluorobenzyl) -2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1- (2-chlorobenzyl) -3-methyl-2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3,4-tetrahydroquinazoline-7-carboxamide; 3-methyl-1 - ((2-methylthiazol-5-yl) methyl) -2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3,4-tetrahydroquinazoline-7-carboxamide ; 1- (2-chloro-6-fluorobenzyl) -2-oxo-3- (pyrimirin-2-yl) -N- (2,4,6-trifluorobenzyl) -1,2,3,4-tetrahydroquinazoline- 7-carboxamide; 1- (2-chloro-6-fluorobenzyl) -N - ((6-methoxybenzofuran-2-
yl) methyl) -3-methyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1- (2-chloro-6-fluorobenzyl) -N - ((6-fluorobenzofuran-2-yl) methyl) -3-methyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxamide ; 1- (2-chloro-6-fluorobenzyl) -N - (((5-fluorobenzofuran-2-yl) methyl) -3-methyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxamide ; 1- (2-chloro-6-fluorobenzyl) -3-methyl-N- (3- (oxazol-2-yl) benzyl) -2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxamide ; N- (2- (1H-1,2,4-triazol-1-yl) ethyl) -1- (2-chloro-6-fluorobenzyl) -3-methyl-2-oxo-1,2,3,4 -tetrahydroquinazoline-7-carboxamide; 1- (2-chloro-6-fluorobenzyl) -N - (((5-hydroxybenzofuran-2-yl) methyl) -3-methyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxamide ; 1- (2-chloro-6-fluorobenzyl) -3-methyl-N- (3- (1-methyl-1H-pyrazol-3-yl) benzyl) -2-oxo-1,2,3,4-tetra -hydroquinazoline - 7-carboxamide; 1- (2-chloro-6-fluorobenzyl) -3-methyl-N- (3- (1-methyl-1H-pyrazol-5-yl) benzyl) -2-oxo-1,2,3,4-tetra -hydroquinazoline - 7-carboxamide; 1- (2-chloro-6-fluorobenzyl) -N- (2-fluorobenzyl) -3-methyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1- (2-chloro-6-fluorobenzyl) -3-methyl-N- (3- (4-methylpiperazin-1-yl) benzyl) -2-oxo-1,2,3,4-tetrahydroquinazoline-7 -carboxamide; N- (benzofuran-5-ylmethyl) -1- (2-chloro-6-fluorobenzyl) -3-methyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxamide;
3-methyl-1 - (((5-methylisoxazol-3-yl) methyl) -2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3,4-tetrahydroquinazoline-7-carboxamide ; 1- (2-chloro-6-fluorobenzyl) -3- (1-methyl-1H-imidazol-4-ol) -2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3, 4-tetrahydroquinazoline-7-carboxamide; 1 - ((1,2,5-thiadiazol-3-yl) methyl) -3-methyl-2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3,4-tetrahydroquinazoline Carboxamide; 3-methyl-1 - ((2-methyloxazol-4-yl) methyl) -2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3,4-tetrahydroquinazoline-7-carboxamide ; 3-methyl-1 - (((1-methyl-1H-imidazol-4-yl) methyl) -2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3,4-tetrahydroquinazoline Carboxamide; 3-methyl-1 - ((5-methyl-2- (m-tolyl) oxazol-4-yl) methyl) -2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3, 4-tetrahydroquinazoline-7-carboxamide; 1- (2-cyano-6-fluorobenzyl) -3-methyl-2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3,4-tetrahydroquinazoline-7-carboxamide; 3-methyl-1 - ((5-methyl-2- (p-tolyl) oxazol-4-yl) methyl) -2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3, 4-tetrahydroquinazoline-7-carboxamide; 1- (2-chloro-6-fluorobenzyl) -N- (2-fluoro-6-methoxybenzyl) -3-methyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1 - ((2- (4-fluorophenyl) -5-methyloxazol-4-yl) methyl) -3-methyl-2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3,4 -tetrahydroquinazoline-7-carboxamide;
N- (benzo [d] [1,3] dioxol-4-ylmethyl) -1- (2-chloro-6-fluorobenzyl) -3-methyl-2-oxo-1,2,3,4-tetrahydroquinazoline - 7-carboxamide; 1- (2-chloro-6-fluorobenzyl) -N - ((2,3-dihydrobenzo [b] [1,4] dioxin-5-yl) methyl) -3-methyl-2-oxo-1, 2, 3,4-tetrahydroquinazoline-7-carboxamide; 1 - (((6-fluoroimidazo [1,2-a] pyridin-2-yl) methyl) -3-methyl-2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3,4 -tetrahydroquinazoline-7-carboxamide; 1- (4-fluoro-2-methoxybenzyl) -3-methyl-2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1- (2-chloro-6-fluorobenzyl) -N - ((7-methoxybenzofuran-2-yl) methyl) -3-methyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxamide ; 1- (2-chloro-6-fluorobenzyl) -3-methyl-N - (((5-nitrobenzofuran-2-yl) methyl) -2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxamide ; 1- (2-chloro-6-fluorobenzyl) -3-methoxy-2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3,4-tetrahydroquinazoline-7-carboxamide; N- (benzofuran-4-ylmethyl) -1- (2-chloro-6-fluorobenzyl) -3-methyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1- (2-chloro-6-fluorobenzyl) -3-methyl-N - (((1-methyl-1H-indazol-6-yl) methyl) -2-oxo-1,2,3,4-tetrahydroquinazoline Carboxamide; N- (benzofuran-6-ylmethyl) -1- (2-chloro-6-fluorobenzyl) -3-methyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 3-methyl-1 - (((1-methyl-1H-pyrazol-5-yl) methyl) -2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3,4-tetrahydroquinazoline -7-
carboxamide; 3-methyl-1 - (((3-methylisoxazol-5-yl) methyl) -2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3,4-tetrahydroquinazoline-7-carboxamide ; 3-methyl-1 - (((1-methyl-1H-1,2,3-triazol-4-yl) methyl) -2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3 , 4-tetrahydroquinazoline-7-carboxamide; 1- (2-fluor-6- (trifluoromethyl) benzyl) -3-methyl-2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3,4-tetrahydroquinazoline-7-carboxamide ; 1 - ((1,5-dimethyl-1H-pyrazol-3-yl) methyl) -3-methyl-2-oxo- N- (2,4,6-trifluorobenzyl) -1,2,3,4-tetra -hydroquinazoline-7-carboxamide; N - (((5-aminobenzofuran-2-yl) methyl) -1- (2-chloro-6-fluorobenzyl) -3-methyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxamide ; 1- (2-chloro-6-fluorobenzyl) -3-methyl-2-oxo-N - (((2-oxoindolin-5-yl) methyl) -1,2,3,4-tetrahydroquinazoline-7-carboxamide ; 1- (2-chloro-6-fluorobenzyl) -N- (2,6-difluor-4-methoxybenzyl) -3-methyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1- (2-chloro-6-fluorobenzyl) -N- (4-fluoro-2-methoxybenzyl) -3-methyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1- (2,6-dichlorobenzyl) -3-methyl-2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1- (2-fluoro-3-methoxybenzyl) -3-methyl-2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3,4-tetrahydroquinazoline-7-
carboxamide; 1 - (((3-cyclopropylisoxazol-5-yl) methyl) -3-methyl-2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3,4-tetrahydroquinazoline-7-carboxamide ; 1- (imidazo [1,2-a] pyridin-2-ylmethyl) -3-methyl-2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3,4-tetrahydroquinazoline- 7-carboxamide; 1- (6-chloro-2-fluor-3-methylbenzyl) -3-methyl-2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3,4-tetrahydroquinazoline-7- carboxamide; 1 - (((4-bromo-1,3-dimethyl-1H-pyrazol-5-yl) methyl) -3-methyl-2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3 , 4-tetrahydroquinazoline-7-carboxamide; 3- (benzyloxy) -1- (2-chloro-6-fluorobenzyl) -2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1- (2-chloro-6-fluorobenzyl) -3-hydroxy-2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1- (3,5-difluorobenzyl) -3-methyl-N- (2,4,6-trifluorobenzyl) -3,4-dihydro-1H-benzo [c] [1,2,6] thiadiazine- 7 2,2-dioxide carboxamide; 1- (2-chloro-6-fluorobenzyl) -3-methyl-2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3,4-tetrahydropyride [3,2- d] pyrimidine-7-carboxamide; 1- (3,5-difluorobenzyl) -3-methyl-2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3,4-tetrahydropyride [3,2- d] pyrimidine- 7-carboxamide; N- (benzofuran-2-ylmethyl) -1- (2-chloro-6-fluorobenzyl) -3-methyl-2-oxo-1,2,3,4-tetrahydropyride [3,2-d] pyrimidine- 7-
carboxamide; 1- (2-chloro-6-fluorobenzyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3,4-tetrahydroquinazoline-7-carboxamide; (S) -1- (2-chloro-6-fluorobenzyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3,4-tetrahydroquinazoline- 7-carboxamide; (R) -1- (2-chloro-6-fluorobenzyl) -3,4-hydroxy-2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3,4-tetrahydroquinazoline- 7-carboxamide; (S) -1 - ((5-chloro-3-fluoro-2-methylpyridin-4-yl) methyl) - 3,4-dimethyl-2-oxo-N- (2,4,6-trifluorobenzyl) -1 , 2,3,4-tetrahydroquinazoline-7-carboxamide; (S) -1- (2,6-difluor-4-hydroxybenzyl) -3,4-dimethyl-2-oxo- N- (2,4,6-trifluorobenzyl) -1,2,3,4-tetra- hydroquinazoline-7-carboxamide; (S) -1- (2,6-difluor-4-hydroxybenzyl) -3,4-dimethyl-2-oxo- N- (2,4,6-trifluorobenzyl) -1,2,3,4-tetra- hydroquinazoline-7-carboxamide; (S) -1- (2,6-difluoro-4- (2-hydroxyethoxy) benzyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3 , 4-tetrahydroquinazoline-7-carboxamide; (S) -1- (2,6-difluoro-4- (3-hydroxypropoxy) benzyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3 4-tetrahydroquinazoline-7-carboxamide; (S) -3- (4 - ((3,4-dimethyl-2-oxo-7 - ((2,4,6-trifluorobenzyl) carbamoyl) -3,4-dihydroquinazolin-1 (2H) - yl ) methyl) -3,5-difluorophenoxy) propyl dihydrogen phosphate; (S) - (4 - ((3,4-dimethyl-2-oxo-7 - ((2,4,6-trifluorobenzyl) carbamoyl) -3,4-dihydroquinazolin-1 (2H) -
il) methyl) 3,5-difluorophenoxy) methyl dihydrogen phosphate; (S) -4 - ((3,4-dimethyl-2-oxo-7 - ((2,4,6-trifluorobenzyl) carbamoyl) -3,4-dihydroquinazolin-1 (2H) -yl) methyl) -3,5-difluorophenyl dihydrogen phosphate; (S) - (4 - ((3,4-dimethyl-2-oxo-7 - ((2,4,6, - trifluorobenzyl) carbamoyl) -3,4-dihydroquinalozin-1 (2H) - yl) methyl) -3,5-difluorophenoxy) methyl dihydrogen phosphate; (S) - (4 - ((3,4-dimethyl-2-oxo-7 - ((2,4,6, - trifluorobenzyl) carbamoyl) -3,4-dihydroquinalozin-1 (2H) - yl) methyl) -3,5-difluorophenyl) methyl dihydrogen phosphate; (S) -4-Acetamidobenzyl- (4 - ((3,4-dimethyl-2-oxo-7- ((2,4,6, -trifluorobenzyl) carbamoyl) -3,4-dihydroquinazolin-1 (2H ) -yl) methyl) -3,5-difluorophenyl) carbonate; (S) -Benzyl-3 - ((((4 - ((3,4-dimethyl-2-oxo-7- (2,4,6, - trifluorobenzyl) carbamoyl) -3,4-dihydroquinazolin-1 ( 2H) -yl) methyl) -3,5-difluorophenoxy) carbonyl) (methyl) amino) propanoate; (S) -1- (2-chloro-6-fluoro-3-hydroxybenzyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3,4- tetrahydroquinazoline-7-carboxamide; (S) -1- (2-chloro-6-fluoro-3-hydroxybenzyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3,4- tetrahydroquinazoline-7-carboxamide; (S) -2-chloro-3 - ((3,4-dimethyl-2-oxo-7 - ((2,4,6-trifluorobenzyl) carbamoyl) -3,4-dihydroquinazolin-1 (2H) - il) methyl) -4-fluorophenyl-dihydrogen phosphate; (S) - (2-Chloro-3 - ((3,4-dimethyl-2-oxo-7 - ((2,4,6-trifluorobenzyl) carbamoyl)) - 3,4-dihydroquinazolin-1 (2H ) - yl) methyl) -4-fluorophenoxy) methyl dihydrogen phosphate; (S) -2- (2 - ((3,4-dimethyl-2-oxo-7 - ((2,4,6-
trifluorobenzyl) carbamoyl) -3,4-dihydroquinazolin-1 (2H) -yl) methyl) -3,4-difluorophenoxy) ethyl dihydrogen phosphate; (S) -4 - ((3,4-dimethyl-2-oxo-7 - ((2,4,6-trifluorobenzyl) carbamoyl) -3,4-dihydroquinazolin-1 (2H) -yl) methyl) -3 fluorophenyl dihydrogen phosphate; (S) -2 - ((1- (2-chloro-6-fluorobenzyl) -3,4-dimethyl-2-oxo- 1,2,3,4-tetrahydroquinazoline-7-carboxamido) methyl) -5 - fluorophenyl dihydrogen phosphate; (S) -3- (2 - ((3,4-dimethyl-2-oxo-7 - ((2,4,6-trifluorobenzyl) carbamoyl) -3,4-dihydroquinazolin-1 (2H) - yl ) methyl) -3,5-difluorophenoxy) propyl dihydrogen phosphate; (S) -2- (2-chloro-3 - ((3,4-dimethyl-2-oxo-7 - ((2,4,6-trifluorobenzyl) carbamoyl) -3,4-dihydroquinazolin-1 ( 2H) -yl) methyl) -4-fluorophenoxy) ethyl dihydrogen phosphate; (S) -3- (2-chloro-3 - (((3,4-dimethyl-2-oxo-7 - ((2,4,6-trifluorobenzyl) carbamoyl) -3,4-dihydroquinazolin-1 ( 2H) -yl) methyl) -4-fluorophenoxy) propyl dihydrogen phosphate; (S) -2- (4 - ((3,4-dimethyl-2-oxo-7 - ((2,4,6-trifluorobenzyl) carbamoyl) -3,4-dihydroquinazolin-1 (2H) - yl ) methyl) -3,5-difluorophenoxy) ethyl dihydrogen phosphate; (S) -3-chloro-4 - ((3,4-dimethyl-2-oxo-7 - ((2,4,6-trifluorobenzyl) carbamoyl) -3,4-dihydroquinazolin-1 (2H) - il) methyl) -5-fluorophenyl dihydrogen phosphate; (S) -2 - ((3,4-dimethyl-2-oxo-7 - ((2,4,6-trifluorobenzyl) carbamoyl) -3,4-dihydroquinazolin-1 (2H) -yl) methyl) Difluorophenyl dihydrogen phosphate; (S) -2 - ((1- (2-chloro-6-fluorobenzyl) -3,4-dimethyl-2-oxo- 1,2,3,4-tetrahydroquinazoline-7-carboxamido) methyl) -3 - fluorophenyl dihydrogen phosphate; (S) -4 - ((1- (2-chloro-6-fluorobenzyl) -3,4-dimethyl-2-oxo-
1,2,3,4-tetrahydroquinazoline-7-carboxamido) methyl) -3,5-difluorophenyl dihydrogen phosphate; (S) -3 - ((3,4-dimethyl-2-oxo-7 - ((2,4,6-trifluorobenzyl) carbamoyl) -3,4-dihydroquinazolin-1 (2H) -yl) methyl) -2,4-difluorophenyl dihydrogen phosphate; (S) -2- (3 - ((3,4-dimethyl-2-oxo-7 - ((2,4,6-trifluorobenzyl) carbamoyl) -3,4-dihydroquinazolin-1 (2H) - yl ) methyl) -2,4-difluorophenoxy) ethyl dihydrogen phosphate; (S) -3- (3 - ((3,4-dimethyl-2-oxo-7 - ((2,4,6-trifluorobenzyl) carbamoyl) -3,4-dihydroquinazolin-1 (2H) - yl ) methyl) -2,4-difluorophenoxy) propyl dihydrogen phosphate; (S) -2 - ((3,4-dimethyl-2-oxo-7 - ((2,4,6-trifluorobenzyl) carbamoyl) -3,4-dihydroquinazolin-1 (2H) -yl) methyl) Difluorophenyl dihydrogen phosphate; (S) -1- (2-Chloro-6-fluoro-3- (2-hydroxyethoxy) benzyl) - 3,4-dimethyl-2-oxo-N- (2,4,6-trifluorobenzyl) -1,2 , 3,4-tetrahydroquinazoline-7-carboxamide; (S) -1- (2-Chloro-6-fluoro-3- (3-hydroxypropoxy) benzyl) - 3,4-dimethyl-2-oxo-N- (2,4,6-trifluorobenzyl) -1,2 , 3,4-tetrahydroquinazoline-7-carboxamide; (S) -4-Acetamidobenzyl- (2-chloro-3 - ((3,4-dimethyl-2-oxo- 7 - ((2,4,6-trifluorobenzyl) carbamoyl) -3,4-dihydroquinazolin- 1 (2H) -yl) methyl) -4-fluorophenyl) carbonate; (S) -Benzyl 3 - (((2-chloro-3 - ((3,4-dimethyl-2-oxo-7- ((2,4,6-trifluorobenzyl) carbamoyl) -3,4-dihydroquinazolin - 1 (2H) -yl) methyl) -4-fluorophenoxy) carbonyl) (methyl) amino) propanoate; (S) -1- (3-carbamoyl-2,6-difluorobenzyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3,4-tetra- hydroquinazoline-7-carboxamide;
(S) -3 - ((3,4-Dimethyl-2-oxo-7 - ((2,4,6-trifluorobenzyl) carbamoyl) -3,4-dihydroquinazolin-1 (2H) -yl) methyl acid ) -2,4-difluorobenzoic; (S) -1- (2,6-difluoro-3 - ((2-hydroxyethyl) carbamoyl) benzyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorobenzyl) -1, 2,3,4-tetrahydroquinazoline-7-carboxamide; (S) -1- (4- (allyloxy) -2,6-difluorobenzyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3,4- hydroquinazoline-7-carboxamide; (4S) -1- (4- (2,3-Dihydroxypropoxy) -2,6-difluoro-benzyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorobenzyl) - 1,2,3,4-dihydroquinazoline-7-carboxamide; (S) -1- (4 - ((R) -2,3-Dihydroxypropoxy) -2,6-difluoro-benzyl) -3,4-dimethyl-2-oxo-N- (2,4,6 -trifluorobenzyl) - 1,2,3,4-tetrahydroquinazoline-7-carboxamide; (S) -1- (4 - ((S) -2,3-Dihydroxypropoxy) -2,6-difluoro-benzyl) -3,4-dimethyl-2-oxo-N- (2,4,6 -trifluorobenzyl) - 1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1- (2-Chloro-6-fluorobenzyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3,4-tetrahydropyride [3,2- d] pyrimidine-7-carboxamide; (S) -N, 1-bis (2,6-difluoro-4-methoxybenzyl) -3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxamide; (S) -N, 1-bis (2,6-difluoro-4-hydroxybenzyl) -3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxamide; (S) -1- (2-Chloro-6-fluorobenzyl) -N- (2-hydroxyethyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorobenzyl) -1,2, 3,4-dihydroquinazoline-7-carboxamide; 1- (3,5-difluorobenzyl) -3,4-dimethyl-2-oxo-N- (2,4,6-
trifluorobenzyl) -1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1- (2-fluoro-6-methoxybenzyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3,4-tetrahydroquinazoline-7-carboxamide ; 1- (2-bromo-6-fluorobenzyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1- (2-fluoro-6-hydroxybenzyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1- (2-fluoro-6-methylbenzyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1- (6-chloro-2-fluoro-3-methylbenzyl) -3,4-dimethyl-2-oxo- N- (2,4,6-trifluorobenzyl) -1,2,3,4-tetrahydroquinazoline- 7-carboxamide; 1- (2-fluoro-3-methylbenzyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1- (2,6-difluoro-4-methoxybenzyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3,4-tetrahydroquinazoline-7- carboxamide; 1- (2-fluoro-5-methoxybenzyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1- (5-carbamoyl-2-fluorobenzyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3,4-tetrahydroquinazoline-7-carboxamide; (S) -1- (2-fluoro-3-methylbenzyl) -3,4-dimethyl-2-oxo-N-
(2,4,6-trifluorobenzyl) -1,2,3,4-tetrahydroquinazoline-7-carboxamide; (S) -1- (6-chloro-2-fluoro-3-methylbenzyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3,4- hydroquinazoline-7-carboxamide; (S) -1- (2-fluoro-4-methylbenzyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3,4-tetrahydroquinazoline- 7-carboxamide; 1- (2-amino-6-fluorobenzyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1- (2-fluoro-6- (methylamino) benzyl) -3,4-dimethyl-2-oxo- N- (2,4,6-trifluorobenzyl) -1,2,3,4-tetrahydroquinazoline-7 - carboxamide; 1- (2- (dimethylamino) -6-fluorobenzyl) -3,4-dimethyl-2-oxo- N- (2,4,6-trifluorobenzyl) -1,2,3,4-tetrahydroquinazoline-7- carboxamide; 1 - (((5-chloro-3-fluoro-2-methylpyridin-4-yl) methyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3 , 4-tetrahydroquinazoline-7-carboxamide; (S) -1- (6-chloro-2,3-difluorobenzyl) -3,4-dimethyl-2-oxo- N- (2,4,6-trifluorobenzyl) -1,2,3,4-tetra- hydroquinazoline-7-carboxamide; 1- (2,3-difluoro-6-methoxybenzyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3,4-tetrahydroquinazoline-7- carboxamide; (S) -1- (2-chloro-3,6-difluorobenzyl) -3,4-dimethyl-2-oxo- N- (2,4,6-trifluorobenzyl) -1,2,3,4-tetra- hydroquinazoline-7-carboxamide; 1 - (((3-fluoro-2-methylpyridin-4-yl) methyl) -3,4-dimethyl-
2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1- (2-fluoro-4-hydroxybenzyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3,4-tetrahydroquinazoline-7-carboxamide; (S) -1- (2-amino-6-fluorobenzyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3,4-tetrahydroquinazoline- 7-carboxamide; (S) -1- (2-fluoro-5-methoxybenzyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3,4-tetrahydroquinazoline- 7-carboxamide; (S) -1 - ((5-chloro-3-fluoro-2-methoxypyridin-4-yl) methyl) - 3,4-dimethyl-2-oxo-N- (2,4,6-trifluorobenzyl) -1 , 2,3,4-tetrahydroquinazoline-7-carboxamide; (S) -methyl 2-chloro-3 - (((3,4-dimethyl-2-oxo-7 - ((2,4,6-trifluorobenzyl) carbamoyl) -3,4-dihydroquinazolin-1 (2H) -yl) methyl) -4-fluorobenzoate; (S) -1- (3-carbamoyl-2-chloro-6-fluorobenzyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3,4- hydroquinazoline-7-carboxamide; (S) -2- (4 - ((3,4-dimethyl-2-oxo-7 - ((2,4,6-trifluorobenzyl) carbamoyl) -3,4-dihydroquinazolin-1 (2H) - yl ) methyl) -3,5-difluorophenoxy) ethyl-2-aminoacetate; (S) -1- (3-amino-2-chloro-6-fluorobenzyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3,4- hydroquinazoline-7-carboxamide; 1- (2-chloro-6-fluorobenzyl) -4-methyl-2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1-benzyl-3,4-dimethyl-2-oxo-N- (2,4,6-trifluorobenzyl) -
1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1- (2-fluorobenzyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1- (2,6-difluorobenzyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1- (2-fluoro-6- (trifluoromethyl) benzyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3,4-tetrahydroquinazoline-7 -carboxamide; N- (2,4-difluorobenzyl) -1- (2-fluorobenzyl) -3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 3,4-dimethyl-1 - ((2-methylpyridin-4-yl) methyl) -2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3,4-tetrahydroquinazoline-7 - carboxamide; 3,4-dimethyl-1 - (((3-methylisoxazol-5-yl) methyl) -2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3,4-tetrahydroquinazoline-7 - carboxamide; 3,4-dimethyl-1 - (((5-methylisoxazol-3-yl) methyl) -2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3,4-tetrahydroquinazoline-7 - carboxamide; 2 - ((3,4-dimethyl-2-oxo-7 - ((2,4,6-trifluorobenzyl) carbamoyl) -3,4-dihydroquinazolin-1 (2H) -yl) methyl) -3-fluorophenyl methanesulfonate; 1- (2,4-difluoro-6- (trifluoromethoxy) benzyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3,4-tetrahydroquinazoline -7-carboxamide; 1 - (((3-fluoropyridin-4-yl) methyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3,4-tetrahydroquinazoline-7 - carboxamide;
1- (2-chloro-6-fluorobenzyl) -3,4-dimethyl-N - (((5-methyl-furan-2-yl) methyl) -2-oxo-1,2,3,4-tetrahydroquinazoline Carboxamide; N- (benzofuran-2-ylmethyl) -1- (2-chloro-6-fluorobenzyl) - 3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxamide; N, 1-dibenzyl-3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1- (2,6-dimethylbenzyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1- (2- (difluoromethoxy) -6-fluorobenzyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3,4-tetrahydroquinazoline-7- carboxamide; 1- (2-fluoro-4-methoxybenzyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1- (4-fluorobenzyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1- (4-chloro-2-fluorobenzyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1- (2-bromo-6-fluoro-3-methylbenzyl) -3,4-dimethyl-2-oxo- N- (2,4,6-trifluorobenzyl) -1,2,3,4-tetrahydroquinazoline- 7-carboxamide; 1- (2-chloro-4-fluorobenzyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1- (4-chloro-2,6-difluorobenzyl) -3,4-dimethyl-2-oxo-N-
(2,4,6-trifluorobenzyl) -1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1 - ((1,3-dimethyl-1H-pyrazol-5-yl) methyl) -N - (((5-fluorobenzofuran-2-yl) methyl) -3,4-dimethyl-2-oxo-1,1 2, - 3,4-dihydroquinazoline 7-carboxamide; 1 - (((4-fluoro-1,3-dimethyl-1H-pyrazol-5-yl) methyl) -N- ((5-fluorobenzofuran-2-yl) methyl) -3,4-dimethyl-2-oxo- - 1,2,3,4-tetrahydroquinazoline 7-carboxamide; 1- (2-fluoro-6- (methylsulfonamido) benzyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3,4-tetrahydroquinazoline- 7-carboxamide; 1- (2-acetamido-6-fluorobenzyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3,4-tetrahydroquinazoline-7-carboxamide; (S) -1 - ((3-fluoropyridin-2-yl) methyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3,4-tetra - hydroquinazoline-7-carboxamide; 2- (4 - ((3,4-dimethyl-2-oxo-7 - ((2,4,6-trifluorobenzyl) carbamoyl) -3,4-dihydroquinazolin-1 (2H) -yl) methyl) - 3-fluorophenoxy) acidic; 2- (3 - ((3,4-dimethyl-2-oxo-7 - ((2,4,6-trifluorobenzyl) carbamoyl) -3,4-dihydroquinazolin-1 (2H) -yl) methyl) - 4-fluorophenoxy) acidic; 1- (2-fluoro-4- (2-hydroxyethoxy) benzyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3,4-tetrahydroquinazoline -7-carboxamide; 1- (2-fluoro-5-hydroxybenzyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3,4-tetrahydroquinazoline-7-carboxamide; (S) -1 - (((3-bromo-5-fluoropyridin-4-yl) methyl) -3,4-
dimethyl-2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1- (2-fluoro-5- (2-hydroxyethoxy) benzyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3,4-tetrahydroquinazoline -7-carboxamide; 2- (2 - ((3,4-dimethyl-2-oxo-7 - ((2,4,6-trifluorobenzyl) carbamoyl) -3,4-dihydroquinazolin-1 (2H) -yl) methyl) - 3-fluorophenoxy) acidic; 1- (2-chloro-6-fluorobenzyl) -N- (4-hydroxybenzyl) -3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1- (2-fluoro-6- (2-hydroxyethoxy) benzyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3,4-tetrahydroquinazoline -7-carboxamide; 1 - (((5-fluoro-2-methylpyridin-4-yl) methyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3,4-tetra - hydroquinazoline-7-carboxamide; 1 - (((3-fluoro-6-methylpyridin-2-yl) methyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3,4-tetra - hydroquinazoline-7-carboxamide; (S) -1- (4-azidobenzyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3,4-tetrahydroquinazoline-7-carboxamide; 2- (4 - ((1- (2-chloro-6-fluorobenzyl) -3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxamido) methyl) phenoxy acid) acetic; (S) -1- (2,3-difluoro-6-methoxybenzyl) -3,4-dimethyl-2-oxo- N- (2,4,6-trifluorobenzyl) -1,2,3,4-tetra- hydroquinazoline-7-carboxamide; (S) -1- (2,3-difluoro-6-hydroxybenzyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3,4-tetra-
hydroquinazoline-7-carboxamide; (S) -1- (4-aminobenzyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3,4-tetrahydroquinazoline-7-carboxamide; (S) -2- (2 - ((3,4-dimethyl-2-oxo-7 - ((2,4,6-trifluorobenzyl) carbamoyl) -3,4-dihydroquinazolin-1 (2H) - yl ) methyl) -3,4-difluorophenoxy) acetic; (S) -1- (2-chloro-6-fluorobenzyl) -N- (2-fluoro-6-methoxybenzyl) -3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazoline Carboxamide; (S) -1- (2-chloro-6-fluorobenzyl) -N- (2,6-difluoro-4-methoxybenzyl) -3,4-dimethyl-2-oxo-1,2,3,4-tetra- hydroquinazoline-7-carboxamide; (S) -1- (2-chloro-6-fluorobenzyl) -N- (4-fluoro-2-methoxybenzyl) -3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazoline- 7-carboxamide; (S) -1- (2-chloro-6-fluorobenzyl) -N- (3-fluoro-5-methoxybenzyl) -3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazoline- 7-carboxamide; (S) -1- (2-chloro-6-fluorobenzyl) -N- (2-fluoro-3-methoxybenzyl) -3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazoline- 7-carboxamide; (S) -1- (2-chloro-6-fluorobenzyl) -N- (3-fluoro-5-hydroxybenzyl) -3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazoline- 7-carboxamide; (S) -1- (2-chloro-6-fluorobenzyl) -N- (2-fluoro-6-hydroxybenzyl) -3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazoline- 7-carboxamide; (S) -1- (2-chloro-6-fluorobenzyl) -N- (2,6-difluoro-4-hydroxybenzyl) -3,4-dimethyl-2-oxo-1,2,3,4-tetra-
hydroquinazoline-7-carboxamide; (S) -1- (2-chloro-6-fluorobenzyl) -N- (4-fluoro-2-hydroxybenzyl) -3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazoline- 7-carboxamide; (S) -1- (2,3-difluoro-6- (2-hydroxyethoxy) benzyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3 , 4-tetrahydroquinazoline-7-carboxamide; (S) -1- (2,6-difluoro-3-hydroxybenzyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3,4-tetra- hydroquinazoline-7-carboxamide; (S) -1- (2,6-difluoro-3- (2-hydroxyethoxy) benzyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3 , 4-tetrahydroquinazoline-7-carboxamide; (S) -1- (2,6-difluoro-3- (3-hydroxypropoxy) benzyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3 , 4-tetrahydroquinazoline-7-carboxamide; (S) -1- (2,6-difluoro-3-methoxybenzyl) -3,4-dimethyl-2-oxo- N- (2,4,6-trifluorobenzyl) -1,2,3,4-tetra- hydroquinazoline-7-carboxamide; (S) -1- (2,4-difluoro-6-methoxybenzyl) -3,4-dimethyl-2-oxo- N- (2,4,6-trifluorobenzyl) -1,2,3,4-tetra- hydroquinazoline-7-carboxamide; (S) -1- (2,4-difluoro-6-hydroxybenzyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3,4-tetra- hydroquinazoline-7-carboxamide; (S) -1 - ((3-fluoro-2-methylpyridin-4-yl) methyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3 , 4-tetrahydroquinazoline-7-carboxamide; (S) -1- (2-fluoro-5-hydroxybenzyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3,4-tetrahydroquinazoline- 7-
carboxamide; (S) -1- (2-fluoro-5- (2-hydroxyethoxy) benzyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3,4 -tetrahydroquinazoline-7-carboxamide; (S) -1- (2-fluoro-6 - ((2-hydroxyethyl) amino) benzyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorobenzyl) -1,2, 3,4-tetrahydroquinazoline-7-carboxamide; (S) -1- (2-fluoro-4,5-dimethoxybenzyl) -3,4-dimethyl-2-oxo- N- (2,4,6-trifluorobenzyl) - 1,2,3,4-tetra- hydroquinazoline-7-carboxamide; (S) -1- (2-chloro-6-fluorobenzyl) -N- (3-fluoro-5- (2-hydroxyethoxy) benzyl) -3,4-dimethyl-2-oxo-1,2,3,4 -tetrahydroquinazoline-7-carboxamide; (S) -1- (2-chloro-6-fluorobenzyl) -N- (2-fluoro-3-hydroxybenzyl) -3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazoline- 7-carboxamide; - (2-fluoro-5- (hydroxymethyl) benzyl) -3,4-dimethyl-2-oxo- N- (2,4,6-trifluorobenzyl) -1,2,3,4-tetrahydroquinazoline-7- carboxamide; (S) -1- (2,6-difluoro-3- (hydroxymethyl) benzyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3,4 -tetrahydroquinazoline-7-carboxamide; (S) -1- (2,3-difluoro-5-methoxybenzyl) -3,4-dimethyl-2-oxo- N- (2,4,6-trifluorobenzyl) -1,2,3,4-tetra- hydroquinazoline-7-carboxamide; (S) -1- (2-fluoro-5- (3-hydroxypropoxy) benzyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3,4 -tetrahydroquinazoline-7-carboxamide; (S) -1- (2- (2-aminoacetamido) -6-fluorobenzyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3,4-
hydroquinazoline-7-carboxamide; (S) -1- (5-amino-2-fluorobenzyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3,4-tetrahydroquinazoline- 7-carboxamide; (S) -1- (2-fluoro-4,5-dihydroxybenzyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3,4-tetra- hydroquinazoline-7-carboxamide; (S) -1- (2,4-difluoro-6- (3-hydroxypropoxy) benzyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3 , 4-tetrahydroquinazoline-7-carboxamide; (S) -1- (2-chloro-6-fluorobenzyl) -N- (2-fluoro-3- (2-hydroxyethoxy) benzyl) -3,4-dimethyl-2-oxo-1,2,3,4 -tetrahydroquinazoline-7-carboxamide; (S) -2- (4 - ((3,4-dimethyl-2-oxo-7 - ((2,4,6-trifluorobenzyl) carbamoyl) -3,4-dihydroquinazolin-1 (2H) - yl ) methyl) -3,5-difluorophenoxy) acetic; (S) -1- (2-fluoro-6 - ((3-hydroxypropyl) amino) benzyl) - 3,4-dimethyl-2-oxo-N- (2,4,6-trifluorobenzyl) -1,2, -3,4-dihydroquinazoline 7-carboxamide; (S) -1- (2-fluoro-3-methoxybenzyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorobenzyl) - 1,2,3,4-tetrahydroquinazoline- 7-carboxamide; (S) -1- (4- (3-aminopropoxy) -2,6-difluorobenzyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3, -4-tetrahydroquinazoline 7-carboxamide; (S) -1- (2,3-difluoro-5-hydroxybenzyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3,4-tetra- hydroquinazoline-7-carboxamide; (S) -1- (2,3-difluoro-5- (2-hydroxyethoxy) benzyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3 , 4-tetra-
hydroquinazoline-7-carboxamide; (S) -1- (2,3-difluoro-5- (3-hydroxypropoxy) benzyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3 , 4-tetrahydroquinazoline-7-carboxamide; (S) -1- (2-chloro-6-fluorobenzyl) -N- (4-fluoro-2- (2-hydroxyethoxy) benzyl) -3,4-dimethyl-2-oxo-1,2,3,4 -tetrahydroquinazoline-7-carboxamide; (S) -1- (6-amino-2,3-difluorobenzyl) -3,4-dimethyl-2-oxo- N- (2,4,6-trifluorobenzyl) -1,2,3,4-tetra- hydroquinazoline-7-carboxamide; (S) -1- (4-amino-2,6-difluorobenzyl) -3,4-dimethyl-2-oxo- N- (2,4,6-trifluorobenzyl) -1,2,3,4-tetra- hydroquinazoline-7-carboxamide; (S) -1 - ((5-chloro-3-fluoro-2-oxo-1,2-dihydropyridin-4-yl) methyl) -3,4-dimethyl-2-oxo-N- (2, 4,6-trifluorobenzyl) - 1,2,3,4-tetrahydroquinazoline-7-carboxamide; (S) -1 - ((5-chloro-3-fluoro-1-methyl-2-oxo-1,2-dihydropyridin-4-yl) methyl) -3,4-dimethyl-2-oxo-N - (2,4,6-trifluorobenzyl) -1,2,3,4-tetrahydroquinazoline-7-carboxamide; (4S) -1- (2,6-difluoro-3- (1-hydroxyethyl) benzyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3 , 4-tetrahydroquinazoline-7-carboxamide; (S) -1- (2,6-difluoro-4- (2- (methylsulfonamido) ethoxy) benzyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorobenzyl) -1, 2,3,4-tetrahydroquinazoline-7-carboxamide; (S) -1- (2,6-difluoro-4- (2-morpholinoethoxy) benzyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3 , 4-tetrahydroquinazoline-7-carboxamide; (S) -1- (4- (2-aminoethoxy) -2,6-difluorobenzyl) -3,4-
dimethyl-2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3,4-tetrahydroquinazoline-7-carboxamide; (S) -1- (2-chloro-6-fluoro-4-methoxybenzyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3,4- hydroquinazoline-7-carboxamide; (S) -4- (4 - ((3,4-dimethyl-2-oxo-7 - ((2,4,6-trifluorobenzyl) carbamoyl) -3,4-dihydroquinazolin-1 (2H) - yl ) methyl) -3,5-difluorophenoxy) butanoic; (S) -1 - ((3,5-difluoropyridin-4-yl) methyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorobenzyl) - 1,2,3,4 -tetrahydroquinazoline-7-carboxamide; (S) -1 - ((3-fluoro-5-methoxy-2-methylpyridin-4-yl) methyl) - 3,4-dimethyl-2-oxo-N- (2,4,6-trifluorobenzyl) -1 , 2,3,4-tetrahydroquinazoline-7-carboxamide; (S) -1 - ((5-chloro-3-fluoro-1- (2-hydroxyethyl) -2-oxo-1,2-dihydropyridin-4-yl) methyl) -3,4-dimethyl-2 -oxo-N- (2,4,6-trifluorobenzyl) -1,2,3,4-tetrahydroquinazoline-7-carboxamide; (S) -1- (2-chloro-6-fluoro-4-hydroxybenzyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorobenzyl) -1,2,3,4- hydroquinazoline-7-carboxamide; (S) -1- (4- (2-aminoethoxy) -2-chloro-6-fluorobenzyl) -3,4-dimethyl-2-oxo-N- (2,4,6-trifluorobenzyl) -1,2, 3,4-tetrahydroquinazoline-7-carboxamide; or (S) -2-chloro-3 - ((3,4-dimethyl-2-oxo-7-carbamoyl ((2,4,6-trifluorobenzyl)) - 3,4-dihydroquinazolin-1 (2H) -yl) methyl) - 4-fluorophenyl methyl (2- (methylamino) ethyl) carbamate hydrochloride.
[31]
31. Pharmaceutical composition, characterized in that it comprises a compound, as defined in any one of claims 1 to 30, or a complex, salt, solvate, tautomeric form or pharmaceutically acceptable polymorphic form thereof and a pharmaceutically acceptable carrier.
[32]
32. A compound according to any one of claims 1 to 30, or a complex, salt, solvate, tautomeric form or pharmaceutically acceptable polymorphic form thereof or a composition, as defined in claim 29, characterized by the fact that it is for use in therapy.
[33]
33. A compound according to any one of claims 1 to 30, or a complex, salt, solvate, tautomeric form or pharmaceutically acceptable polymorphic form thereof, or a composition, as defined in claim 29, characterized in that it is for use in protein modulation of the protein stimulator of the interferon genes (STING).
[34]
34. Compound or composition for use according to claim 33, characterized by the fact that the compound is for use in activating the STING protein.
[35]
35. A compound according to any one of claims 1 to 30, or a complex, salt, solvate, tautomeric form or pharmaceutically acceptable polymorphic form thereof, or a composition, as defined in claim 29, characterized by the fact that it is for use in the treatment, improvement or prevention of a selected cancer disease, bacterial infection, viral infection, parasitic infection, immunomediated disorder, central nervous system disease, peripheral nervous system disease, neurodegenerative disease, mood disorder,
sleep disorder, cerebrovascular disease, peripheral arterial disease or cardiovascular disease.
[36]
36. Compound or composition for use according to claim 35, characterized by the fact that the disease is cancer.
[37]
37. Compound or composition for use according to claim 36, characterized by the fact that the cancer is selected from the group consisting of colorectal cancer, aero-digestive squamous cancer, lung cancer, brain cancer, liver cancer, stomach cancer, sarcoma, leukemia, lymphoma, multiple myeloma, ovarian cancer, uterine cancer, breast cancer, melanoma, prostate cancer, pancreatic carcinoma or renal carcinoma.
[38]
38. A compound or composition for use according to any one of claims 33 to 37, characterized in that the compound or composition is for use with a second therapeutic agent, optionally wherein the second therapeutic agent comprises an antiviral agent, a anti-inflammation agent, conventional chemotherapy, anticancer vaccine and / or hormone therapy.
[39]
39. A compound or composition for use according to claim 38, characterized in that the second therapeutic agent comprises a co-stimulatory molecule B7, interleukin-2, interferon-g, GM-CSF, a CTLA-4 antagonist (such as Ipilimumab and tremilimumab), an IDO inhibitor or IDO / TDO inhibitor (such as Epacadostat and GDC-0919), a PD-1 inhibitor (such as Nivolumab, Pembrolizumab, Pidilizumab, AMP-224 and MDX-1106), an inhibitor of PD-L1 (such as Durvalumabe, Avelumab and Atezolizumab), an OX-40 ligand, a LAG3 inhibitor, a CD40 ligand, a ligand
41BB / CD137, a CD27 ligand, Bacille Calmette-Guerin (BCG), liposomes, alum, Freund's complete or incomplete adjuvant, an agonist TLR (such as Poli I: C, MPL, LPS, bacterial flagellin, imiquimod, resiquimod, loxoribin and a CpG dinucleotide) and / or detoxified endotoxins.
[40]
40. Compound characterized by the fact that it is of formula (II) or (III): Formula (III) Formula (II) in which X1, X2, X3, Q, L, Y, R6, R7, R8, R9, R10 and R11 are as defined in any one of claims 1 to 29; and R is H or a C1-C6 alkyl, or a complex, salt, solvate, tautomeric form or pharmaceutically acceptable polymorphic form thereof.
[41]
41. Compound according to claim 40, characterized by the fact that the compound is selected from:
Cl Cl
O O O OH
N OF N OF
O O
N N Cl OMe Cl OH
O O
N OF N OF
O O
N N
[42]
42. Conjugate characterized by the fact that it is of formula (VI):
wherein C is a compound of formula (I) as defined in any one of claims 1 to 29; L1 is a linker; T is a target fraction; and a is an integer between 1 and 10.

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JP2020524719A|2020-08-20|

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KR20200031616A|2020-03-24|

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法律状态:
2021-11-03| B350| Update of information on the portal [chapter 15.35 patent gazette]|

优先权:

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申请号 | 申请日 | 专利标题

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GB1709959.9|2017-06-22|

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