WO2025239794A1 - Ataxia telangiectasia and rad3-related inhibitors - Google Patents

Ataxia telangiectasia and rad3-related inhibitors

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Publication number
WO2025239794A1
WO2025239794A1 PCT/RU2025/050136 RU2025050136W WO2025239794A1 WO 2025239794 A1 WO2025239794 A1 WO 2025239794A1 RU 2025050136 W RU2025050136 W RU 2025050136W WO 2025239794 A1 WO2025239794 A1 WO 2025239794A1
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WIPO (PCT)
Prior art keywords
substituted
several
pyrazole
atr
methylmorpholine
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/RU2025/050136
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French (fr)
Inventor
Ilia Petrovich BULATOV
Shamil Dinarovich KADYROV
Ksenia Sergeevna SIDOROVA
Ilia Alekseevich SMETANIN
Vladimir Petrovich STUKOV
Roman Vadimovich SHUTOV
Andrey Ivanovich CHEREMUSHKIN
Aleksey Sergeevich GAVRILOV
Maksim Aleksandrovich KISELEV
Liliana Vyacheslavovna LENSHMIDT
Sergei Aleksandrovich SMOLNIKOV
Elena Alexandrovna SHPAKOVA
Dmitry Valentinovich MOROZOV
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Biocad JSC
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Biocad JSC
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Publication date
Priority claimed from RU2024113118A external-priority patent/RU2024113118A/en
Application filed by Biocad JSC filed Critical Biocad JSC
Publication of WO2025239794A1 publication Critical patent/WO2025239794A1/en
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4162—1,2-Diazoles condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings

Definitions

  • the present invention relates to ataxia telangiectasia mutated and Rad3 -related (ATR) inhibitors, also to pharmaceutically acceptable salts, solvates or stereoisomers thereof, to phar- maceutical compositions comprising the present compounds, to methods for treating diseases or disorders and to the use of the present compounds as pharmaceutical products for treating dis- eases or disorders.
  • ATR telangiectasia mutated and Rad3 -related
  • Ataxia telangiectasia mutated and Rad3 -related is a serine/threonine-protein ki- nase of the phosphatidylinositol 3 -kinase-related kinases (PIKK) family.
  • the PIKK family in addition to ATR, includes the following enzymes: ATM (ataxia telangiectasia mutated protein), DNA-PK (DNA-dependent protein kinase), mTOR (mammalian target of rapamycin), SMG1 (suppressor of morphogenesis in genitalia) and TRRAP (transformation/transcription domain- associated protein) (Cimprich and Cortez, 2008; Lempiainen and Halazonetis, 2009). All en- zymes in the PIKK family share a common domain structure.
  • ATR is a protein at 300 kDa and consisting of 2644 amino acids (Cimprich and Cortez, 2008; Gately et al., 1998).
  • ATR plays a key role in the DNA damage response (DDR) signaling pathway and is one of the two apical regulators of the DDR pathway that initiate and coordinate cellular responses to DNA damage in cooperation with other DDR proteins (Cimprich and Cortez, 2008., Jackson and Bartek, 2009).
  • DDR DNA damage response
  • ATR is activated in response to single-stranded DNA (ssDNA) structures, which can arise upon DNA damage (Cimprich and Cortez, 2008; Flynn and Zou, 2011), leading to phosphorylation and activation of CHK1, the major downstream and best-studied target of ATR (Bartek and Lukas, 2003).
  • ATR associates with a protein called ATRIP, which recognizes replication protein A-coated single-stranded DNA (Zou L, 2003).
  • CHK1 Activation of CHK1 in turn leads to stabilization of the DNA replication fork, repair of DNA damage, to phosphorylation and inhibition of activity of Cdc25 A and Cdc25C, thereby activating the intra-S and G2/M check- points of the cell cycle (Sorensen et al., 2003; Sanchez et al., 1997; Xiao et al., 2003), to mainte- nance of early cell cycle arrest and induction of apoptosis or senescence when necessary (Cim- prich and Cortez, 2008; Toledo et al., 2008).
  • ATR activity is of great importance in all highly proliferative cells, especially during the S phase in the cell cycle due to the replication stress associated with this phase (Toledo et al., 2008; Ruzankina et al., 2007).
  • ATR function is more critical in tumor cells, since high replication stress is generated due to activated oncogenes such as ras, myc and cyclin E which are known to disrupt normal cell cycle regulation (Toledo et al., 2008).
  • high replication stress which results in the generation of excessive amount of ssDNA, cells are more likely to die than to survive in the absence of immediate DNA repair (Toledo et al., 2008).
  • the ATR-activated signaling pathway is critical for tumor cell survival.
  • ATR performs post-translational regulation of synthesis of immune checkpoint protein PD-L1 in response to DNA damage, which may be promising in immunotherapy. Since ATR plays an important role in regulation of PD-L1, and tumor cells evade T cell-mediated cell death by way of upregulation of DNA damage-induced PD-L1, which is typically observed during radiotherapy and chemotherapy, it is suggested that ATR inhibition may lead to increased efficacy of radiotherapy and chemotherapy, further medi- ating immune antitumor activity (Sun et al., 2018; Dillon et al., 2019).
  • ATR signaling pathway activation of the ATR signaling pathway is observed in response to diverse anticancer chemotherapeutic drugs (Cimprich and Cortez, 2008), possibly as a response to repair chemotherapy-induced DNA dam- age that contributes to tumor cell survival and drug resistance.
  • Optionally substituted in one, two, three, four or several positions means the specified group can be substituted by a radical or any combination of radicals in one, two, three, four or from one to six positions.
  • Alkyl means an aliphatic straight chain or branched chain hydrocarbon group having from 1 to 12 carbon atoms, more preferably from 1 to 6 carbon atoms. Branched chain means alkyl chain having one or more "lower alkyl” substituents. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n- pentyl, 2-pentyl, 3-pentyl, neo-pentyl, n-hexyl. Alkyl may have substituents which may be same or different structure.
  • Alkenyl means a straight chain or branched chain hydrocarbon group having from 2 to 12 carbon atoms, or from 2 to 6 carbon atoms that contains one or more carbon-carbon double bonds. Alkenyl may have substituents which may be same or different structure.
  • Alkynyl means a straight chain or branched chain hydrocarbon group having from 2 to 12 carbon atoms, or from 2 to 6 carbon atoms that contains one or more carbon-carbon triple bound. Alkynyl may have substituents which may be same or different structure.
  • Alkyloxy means an alkyl-O- group, wherein alkyl is defined in this section.
  • alkoxy groups include, but are not limited to, methoxy, eth- oxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, iso-butoxy.
  • Alkylsulfonyl (-S(O)2-C1-C6alkyl) means "alkyl", as defined above, linked to the cor- responding fragment of a molecule via a sulfonyl group, -SO2-.
  • alkyl sulfonyls in- clude, but are not limited to, methyl sulfonyl, ethyl sulfonyl.
  • Amino group means R'R"N-group.
  • R', R", R'", R" include, but are not limited to, substituents selected from the group comprising hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, heteroalkyl or R' and R" together with the carbon atom they are attached to, can form 4-7-mem- bered heterocyclyl or heteroaryl.
  • An “annelated compound” or “condensed compound” is a cyclic compound that has two neighboring atoms in common.
  • Aryl means an aromatic monocyclic or polycyclic system having from 6 to 14 carbon atoms, more preferably from 6 to 10 carbon atoms.
  • aryl groups include, but are not limited to, phenyl, phenylene, benzenetriyl, indanyl, naphthyl, naphthylene, naphthalenetriyl and anthrylene.
  • Aryl may have one or more substituents which may be same or different structure.
  • Aryl can be annelated with a heterocycle, cycloalkyl, or heteroaryl, or can form bridge-ring compounds with alkyl, such as, but not limited to, naphthalenyl, dihydronaphthalenyl, dihydroin- denyl, indazolyl, l,3,4,5-tetrahydro-2H-benzo[b]azepinyl, indolyl, benzimidazolyl.
  • dialkylphosphine ox- ide include, but are not limited to, dimethylphosphine oxide, diethylphosphine oxide, meth- ylethylphosphine oxide, dipropylphosphine oxide, dicyclopropylphosphine oxide.
  • Halo means fluoro, chloro, bromo and iodo.
  • Heterocycle means a monocyclic or polycyclic sys- tem having from 3 to 11 carbon atoms, of which one or more carbon atoms are substituted by a heteroatom, such as nitrogen, oxygen, sulfur. Heterocycle may have one or more substituents which may be same or different structure. Nitrogen and sulfur atoms of heterocycle could be oxidized to N-oxide, S-oxide or S-dioxide. Heterocycle may be saturated, partly saturated or unsaturated.
  • Heterocycle can be annelated with cycloalkyl, aryl, or heteroaryl, and can also be a monocyclic compound, a spyro compound, or a bridge-ring compound comprising one or more heteroatoms selected from N, S, or O.
  • heterocycles include, but are not limited to, azetidine, pyrrolidine, piperidine, 2,8-diazaspiro[4.5]decane, piperazine, morpholine, diazepane, azepane, azabicycloheptane, 2-oxa-6-azaspiro[3.3]heptane, oxetane, oxolane, oxane, 2- azaspiro[ 3.3 ] heptane, 2-azabicyclo[ 2.2.1 ] heptane, 8-azabicyclo [ 3.2.1 ] octane .
  • Heteroaryl means an aromatic monocyclic or polycy-rod system having from 5 to 11 carbon atoms, preferably from 5 to 10, of which one or more carbon atoms are substituted by a heteroatom, such as nitrogen, sulfur or oxygen. Nitrogen atom of heterocycle could be oxidized to N-oxide. Heteroaryl may have one or more substituents which may be same or different structure.
  • heteroaryls include, but are not limited to, 1H- pyrrolo[2,3-b]pyridine, 7H-pyrrolo[2,3-d]pyrimidine, pyrrole, furan, pyridine, pyrazine, pyrimi- dine, pyridazine, isooxazole, isothiazole, tetrazole, oxazole, thiazole, pyrazole, furazan, 1,2,4- triazole, 1,2,3-triazole, 1,2,4-thiadiazol, quinoxaline, imidazo[l,2-a]pyridine, indole, benzimid- azole, quinoline, imidazole, pyrazole, thi enopyridine, quinazoline, naphthyridine, thienopyrimi- dine, imidazopyridine, isoquinoline.
  • Substituent means a chemical radical attached to a scaffold (fragment).
  • “Lower alkyl” means a straight chain or branched chain alkyl having from 1 to 4 carbon atoms.
  • Bridged-ring compounds are compounds in which several atoms are common between two or more rings of a single compound, which rings may comprise one or more heteroatoms selected from N, S, or O.
  • the bridged-ring compound may have one or more substituents which may be same or different structure.
  • Solvate is a molecular aggregate that consists of the compound of the present invention, including its pharmaceutically acceptable salts, with one or more solvent molecules.
  • the solvent molecules are molecules of common pharmaceutical solvents, known to be safe for recipients, e.g. water, ethanol, ethylene glycol, and the like.
  • Other solvents such as MeOH, methyl-tert- butyl ether, ethyl acetate, methyl acetate, (S)-propylene glycol, (R)-propylene glycol, 1,4-bu- tanediol can be used as intermediate solvates for obtaining more desirable solvates.
  • hydrate refers to a complex, wherein the solvent molecule is water.
  • Solvates and/or hydrates preferably exist in crystalline form.
  • Spiro compound or “spirane compound” is a bicyclic or polycyclic compound which shares a single carbon atom (spiro atom) between two rings and which may comprise one or more heteroatoms selected from N, S, or O. Spiro compound may have one or more substituents which may be same or different structure.
  • “Monocyclic compounds” or “monocyclic radicals” are compounds or radicals in which there are present three or more bound atoms forming a single ring, which may comprise one or more heteroatoms selected from N, S or O. The monocyclic compound or radical may have one or more substituents which may be same or different structure.
  • protecting group refers to groups that are used to block the reactivity of functional groups, such as an amino group, carboxyl group or hydroxy group.
  • protecting groups include, but are not limited to, tert -butyloxycarbonyl (Boc), ben- zyloxycarbonyl (Cbz), 2-(trimethylsilyl)ethoxy)methyl acetal (SEM), tri alkyl silyl, al- kyl(diaryl)silyl or alkyl.
  • carbonyl as used herein relates to the radical -C(0)-.
  • bond refers to a chemical bond of two atoms or two moieties (i.e. groups, fragments) when the atoms joined by the bond are considered to be part of larger substructure.
  • stereoisomers refers to compounds that have identical chemical composition and the same structure, but differ in the spatial arrangement of atoms or groups. Stereoisomers may include geometric isomers, enantiomers, diastereomers.
  • Partly saturated means a ring system including at least one double or triple bond.
  • the term “partly saturated” relates to cyclic systems or heterocyclic systems having many sites for saturation and does not include aryl and heteroaryl systems as they defined herein.
  • Cycloalkyl means a fully saturated carbocyclic ring that contains from 3 to 10 carbon ring atoms. Cycloalkyl may have substituents which may be same or different structure. Cyclo- alkyl may be annelated with aril, heteroaryl, heterocyclyl. Examples of cycloalkyl groups in- clude, but are not limited to, monocyclic groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, bicyclic groups, such as bicyclo- heptyl or bicyclooctyl.
  • Cycloalkyloxy or "cycloalkyloxy group” means a cycloalkyl-O- group, wherein cyclo- alkyl is defined in this section.
  • Examples of cycloalkyloxy groups include, but are not limited to, cyclohexyloxy, cyclopentyloxy, cyclobutyloxy or cyclopropyloxy.
  • excipient is used herein to describe any ingredient other than the compound(s) of the invention.
  • “Pharmaceutical composition” means a composition comprising a compound of the in- vention and at least one excipient.
  • the excipient may be selected from a group consisting of pharmaceutically acceptable and pharmacologically compatible fillers, solvents, diluents, carri- ers, auxiliary, distributing and sensing agents, delivery agents, such as preservatives, stabilizers, fillers, disintegrators, moisteners, emulsifiers, suspending agents, thickeners, sweeteners, fla- vouring agents, aromatizing agents, antibacterial agents, fungicides, lubricants, and prolonged delivery controllers, the choice and proportions of which depend on the nature and route of ad- ministration and dosage.
  • suspending agents examples include ethoxylated isostearyl alcohol, pol- yoxyethene, sorbitol and sorbitol ether, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacant and mixtures thereof as well. Protection against action of mi- croorganisms can be provided by various antibacterial and antifungal agents, such as, for exam- ple, parabens, chlorobutanole, sorbic acid, and similar compounds.
  • the composition may also contain isotonic agents, for example, sugars, sodium chloride, and similar compounds.
  • Prolonged action of the composition may be achieved by agents slowing down absorption of active ingre-TER, for example, aluminum monostearate and gelatine.
  • suitable carriers, solvents, diluents and delivery agents are water, ethanol, polyalcohols and mixtures thereof, plant oils (such as olive oil) and organic esters (such as ethyl oleate) for injections.
  • suitable carriers are water, ethanol, polyalcohols and mixtures thereof, plant oils (such as olive oil) and organic esters (such as ethyl oleate) for injections.
  • fillers are lactose, milk sugar, sodium citrate, calcium carbonate, calcium phosphate, and the like.
  • disintegrators and distributors are starch, alginic acid and its salts, silicates, and the like.
  • compositions for peroral, sublingual, trans- dermal, intramuscular, intravenous, subcutaneous, local or rectal administration of active ingre- Tr, alone or in combination with another active ingredient may be administered to animals and human in a standard administration form, in a mixture with traditional pharmaceutical carriers.
  • Suitable standard administration forms include peroral forms such as tablets, gelatin capsules, pills, powders, granules, chewing gums and peroral solutions or suspensions; sublingual and transbuccal administration forms; aerosols; implants; local, transdermal, subcutaneous, intramus- cular, intravenous, intranasal or intraocular administration forms and rectal administration forms.
  • “Pharmaceutically acceptable salt” means relatively nontoxic both organic and inorganic salts of acids and bases disclosed in the present invention. These salts may be prepared in situ in the processes of synthesis, isolation or purification of compounds or they may be prepared spe- cially. In particular, salts of bases may be prepared specially from purified base of the disclosed compound and suitable organic or inorganic acid.
  • salts prepared in this manner are hydrochlorides, hydrobromides, sulfates, bisulfates, phosphates, nitrates, acetates, oxalates, va- leriates, oleates, palmitates, stearates, laurates, borates, benzoates, lactates, tosilates, citrates, ma- leates, fumarates, succinates, tartrates, mesilates, malonates, salicylates, propionates, ethane sul- phonates, benzene sulfonates, sulfamates and the like (Detailed description of such salts proper- ties is given in: Berge S.M., et al., "Pharmaceutical Salts" J.
  • Salts of disclosed acids may be prepared by reaction of a purified acid with suitable base; furthermore, metal salts and amine salts may be synthesized as well.
  • Metal salts are salts of sodium, potassium, calcium, barium, zinc, magnesium, lithium and aluminum; sodium and potassium salts are most preferred.
  • Suitable inorganic bases from which metal salts may be prepared are: sodium hydrox- ide, carbonate, bicarbonate and hydride; potassium hydroxide and bicarbonate, lithium hydrox- ide, calcium hydroxide, magnesium hydroxide, zinc hydroxide.
  • Organic bases from which salts of disclosed acids may be prepared are amines and amino acids, the basicity of which is sufficient enough to produce a stable salt, and which are suitable for use in medical purposes (in particular, they must have low toxicity).
  • amines include ammonia, methylamine, dimethylamine, tri- methylamine, ethylamine, diethylamine, triethylamine, benzylamine, dibenzylamine, dicyclo- hexylamine, piperazine, ethylpiperidine, tri s(hydroxymethyl)aminom ethane and the like.
  • salts can be prepared using tetraalkylammonium hydroxides, such as holine, tetrame- thylammonium, tetraethylammonium, and the like.
  • Basic aminoacids i.e. lysine, ornithine and arginine, may be used as aminoacids.
  • Medical product is a compound (or a mixture of compounds as a pharmaceutical composition) in the form of tablets, granules, capsules, solutions, suspensions, emulsions, injections, ointments creams, aerosols and other ready formulations intended for restoration, improvement or modification or substitution of phys- iological functions, suppression of pathophysiological functions in humans and animals, as well as for treatment and prophylaxis of diseases, for diagnostics, anesthesia, contraception, cosmetol- ogy and others.
  • Treatment refer to a method of alleviating or abrogating a bio- logical disorder and/or at least one of attendant symptoms thereof.
  • to alleviate a dis- ease, disorder or condition means reducing the severity and/or occurrence frequency of the symp- toms of the disease, disorder, or condition.
  • references herein to "treatment” include ref- erences to palliative treatment.
  • prophylactic therapy refers to a set of measures aimed at preventing the onset, eliminating risk factors, or early detecting a disease or disorder, its exacerbation, relapse, complications or other consequences.
  • the patient, or subject of treatment, or prophylaxis is a mammal.
  • the patients include, but are not limited to, a human subject.
  • Said subject may be either male or female, of any age.
  • disorder means any condition that would benefit from treatment according to the present invention.
  • the definition of this term includes chronic and acute disorders or patho- logical conditions that predispose the mammal to the onset of diseases in question.
  • diseases to be treated include malignant solid neoplasms, or neoplasms of unspeci- fied nature, including tumors originating from blood cells and lymphoid cells.
  • Examples include: ovarian cancer, epithelial ovarian cancer, recurrent platinum-refractory ovarian cancer, recurrent platinum-sensitive ovarian cancer, clear cell ovarian cancer, with BRCA 1/2, ARID1A muta- tions, borderline ovarian tumors; primary peritoneal cancer; fallopian tube cancer; gastric and gastroesophageal junction cancer, locally advanced unresectable, metastatic, or recurrent gastric and gastroesophageal junction cancer; head and neck tumors, unresectable, locally advanced, or metastatic head and neck tumors, recurrent head and neck tumors; prostate cancer, metastatic prostate cancer, castration-resistant metastatic prostate cancer with BRCA mutations; colorectal cancer, unresectable or metastatic colorectal cancer, colon cancer, rectosigmoid junction cancer, and rectal cancer; anal cancer and perianal skin cancer; endometrial cancer, recurrent or meta- static endometrial cancer, uterine corpus cancer and uterine sar
  • “Therapeutically effective amount” refers to that amount of the therapeutic agent being administered in the course of treatment which will relieve the severity or eliminate the symptoms of the disease being treated.
  • the present invention relates to a compound of formula I: or to a pharmaceutically acceptable salt, solvate or stereoisomer thereof,
  • Ri is -NRiaRib, -S(O) 2 RI C , -P(O)RidRie, -ORir;
  • Ria, Rib, Rif are each independently -H, -(C1-C6)alkyl unsubstituted or substituted by one or several R6 a ; -C(O)(C1-C6)alkyl unsubstituted or substituted by one or several R6b; -S(O)2(Ci- Ce)alkyl unsubstituted or substituted by one or several R6 c ; -(C3-C8)cycloalkyl unsubstituted or substituted by one or several R6a; -C(O)(C3-C8)cycloalkyl unsubstituted or substituted by one or several R6 e ; -S(O)2(C3-C8)cycloalkyl unsubstituted or substituted by one or several R6f;
  • Ria and Rib together with the nitrogen atom they are attached to form a 3-7 membered het- erocycle with 1 or 2 N atoms, unsubstituted or substituted by one or several R6 g ;
  • Ric, Rid, Rie are each independently -(C1-C6)alkyl unsubstituted or substituted by one or several Rsh, -(C3-C8)cycloalkyl unsubstituted or substituted by one or several Rsi;
  • -(C3-C8)cycloalkyl unsubstituted or substituted by one or several R2b, forming a spiro compound with a 4-10 membered heterocyclyl with 1,2,3 or 4 heteroatoms selected from N, S or O, unsubstituted or substituted by one or several R2c, or -(C3-C8)cycloalkyl unsubstituted or sub- stituted by one or several R2d;
  • R3 is -H; -Hal; -CN; -NO2, -NH2; -(C1-C6)alkyl unsubstituted or substituted by one or several -OH, -Hal, -CN; -N0 2 , -NH 2 ;
  • R4 is morpholinyl unsubstituted or substituted by one or several R4 a ; morpholinyl unsubstituted or substituted by one or several R4a, forming a bridged-ring compound with -(CH2)o-4- unsubstituted or substituted by one or several R4t>;
  • R4a, R4b are each independently -H, -OH, -Hal, -CN, -NH2; -(C1-C6)alkyl unsubstituted or substituted by one or several -Hal, -OH, -CN, -NH2;
  • Rs a is -OH, -Hal, -CN, -NH2; -(C1-C6)alkyl unsubstituted or substituted by one or several -Hal, -OH, -CN, -NH 2 ;
  • R 7a , R 7 b, R 7C , R 7 d, R 7 e, R 7 f, R 7g , R 7 h, R 7 i, R 7 j, R 7 k, R 7 I, R 7m are each independently -H, - OH; -Hal; -(C1-C6)alkyl unsubstituted or substituted by one or several -OH; -Hal; -O(C1-C6)alkyl unsubstituted or substituted by one or several -OH; -Hal;
  • Hal is an F, Cl, Br, I atom.
  • R2 if Ri is -NHCH3, then R2 cannot be 1-methylpyrazolyl.
  • the present invention relates to a compound of formula II:
  • Ri is -NRiaRib, -S(O) 2 RI C , -P(O)RidRie, -ORu; Ria, Rib, Rif are each independently -H, -(C1-C6)alkyl unsubstituted or substituted by one or several R6 a ; -C(O)(C1-C6)alkyl unsubstituted or substituted by one or several R6b; -S(O)2(Ci- Ce)alkyl unsubstituted or substituted by one or several R6 c ; -(C3-C8)cycloalkyl unsubstituted or substituted by one or several R6a; -C(O)(C3-C8)cycloalkyl unsubstituted or substituted by one or several R6 e ; -S(O)2(C3-C8)cycloalkyl
  • Ria and Rib together with the nitrogen atom they are attached to form a 3-7 membered heterocycle with 1 or 2 N atoms, unsubstituted or substituted by one or several R6 g ;
  • Ric, Rid, Rie are each independently -(C1-C6)alkyl unsubstituted or substituted by one or several Rsh, -(C3-C8)cycloalkyl unsubstituted or substituted by one or several R6i;
  • -(C3-C8)cycloalkyl unsubstituted or substituted by one or several R2b, forming a spiro compound with a 4-10 membered heterocyclyl with 1,2,3 or 4 heteroatoms selected from N, S or O, unsubstituted or substituted by one or several R2c, or -(C3-C8)cycloalkyl unsubstituted or sub- stituted by one or several R2d;
  • R3 is -H; -Hal; -CN; -NO2, -NH2; -(C1-C6)alkyl unsubstituted or substituted by one or several -OH, -Hal, -CN; -NO 2 , -NH 2 ;
  • R4 is morpholinyl unsubstituted or substituted by one or several R4 a ; morpholinyl unsubstituted or substituted by one or several R4a, forming a bridged-ring compound with -(CH2)o-4- unsubstituted or substituted by one or several R4t>;
  • R4a, R4b are each independently -H, -OH, -Hal, -CN, -NH2; -(C1-C6)alkyl unsubstituted or substituted by one or several -Hal, -OH, -CN, -NH2;
  • Rsa is -OH, -Hal, -CN, -NH2; -(C1-C6)alkyl unsubstituted or substituted by one or several -Hal, -OH, -CN, -NH 2 ;
  • R7a, R7b, R7c, R7d, R7e, R/f, R7g, R7h, R71, R7j, R7k, R71, R7m are each independently -H, - OH; -Hal; -(C1-C6)alkyl unsubstituted or substituted by one or several -OH; -Hal; -O(C1-C6)alkyl unsubstituted or substituted by one or several -OH; -Hal;
  • Hal is an F, Cl, Br, I atom.
  • the present invention relates to a compound of formula III:
  • Ri is -NRiaRib, -S(O) 2 RI C , -P(O)RidRie, -ORif;
  • Ria, Rib, Rif are each independently -H, -(C1-C6)alkyl unsubstituted or substituted by one or several R6 a ; -C(O)(C1-C6)alkyl unsubstituted or substituted by one or several R6b; -S(0)2(Ci- Ce)alkyl unsubstituted or substituted by one or several R6 c ; -(C3-C8)cycloalkyl unsubstituted or substituted by one or several R6d; -C(O)(C3-C8)cycloalkyl unsubstituted or substituted by one or several Rz )C ; -S(O)2(C3-C8)cycloalkyl unsubstituted or substituted by one or several R6f;
  • Ria and Rib together with the nitrogen atom they are attached to form a 3-7 membered heterocycle with 1 or 2 N atoms, unsubstituted or substituted by one or several R6 g ;
  • Ric, Rid, Rie are each independently -(C1-C6)alkyl unsubstituted or substituted by one or several Rsh, -(C3-C8)cycloalkyl unsubstituted or substituted by one or several R6i;
  • -(C3-C8)cycloalkyl unsubstituted or substituted by one or several R.2b, forming a spiro compound with a 4-10 membered heterocyclyl with 1,2,3 or 4 heteroatoms selected from N, S or O, unsubstituted or substituted by one or several R2c, or -(C3-C8)cycloalkyl unsubstituted or sub- stituted by one or several R2d;
  • R3 is -H; -Hal; -CN; -NO2, -NH2; -(C1-C6)alkyl unsubstituted or substituted by one or several -OH, -Hal, -CN; -NO 2 , -NH 2 ;
  • R4a, R4b are each independently -H, -OH, -Hal, -CN, -NH2; -(C1-C6)alkyl unsubstituted or substituted by one or several -Hal, -OH, -CN, -NH2; d is 0,1,2 or 3;
  • R7a, R7b, R7c, R7d, R7e, R7f, R7g, R7h, R7i, R7j, R7k, R71, R7m are each independently -H, - OH; -Hal; -(C1-C6)alkyl unsubstituted or substituted by one or several -OH; -Hal; -O(C1-C6)alkyl unsubstituted or substituted by one or several -OH; -Hal;
  • Hal is an F, Cl, Br, I atom.
  • the present invention relates to a compound of formula
  • Ri is -NRiaRib, -S(O) 2 RI C , -P(O)RidRie, -ORir;
  • Ria, Rib, Rif are each independently -H, -(C1-C6)alkyl unsubstituted or substituted by one or several R6 a ; -C(O)(C1-C6)alkyl unsubstituted or substituted by one or several R6b; -S(O)2(Ci- Ce)alkyl unsubstituted or substituted by one or several R6 c ; -(C3-C8)cycloalkyl unsubstituted or substituted by one or several R6a; -C(O)(C3-C8)cycloalkyl unsubstituted or substituted by one or several R6 e ; -S(O)2(C3-C8)cycloalkyl unsubstituted or substituted by one or several R6f;
  • Ria and Rib together with the nitrogen atom they are attached to form a 3-7 membered heterocycle with 1 or 2 N atoms, unsubstituted or substituted by one or several R6 g ;
  • Ric, Rid, Rie are each independently -(C1-C6)alkyl unsubstituted or substituted by one or several Rsh, -(C3-C8)cycloalkyl unsubstituted or substituted by one or several R6i;
  • -(C3-C8)cycloalkyl unsubstituted or substituted by one or several R2b, forming a spiro compound with a 4-10 membered heterocyclyl with 1,2,3 or 4 heteroatoms selected from N, S or O, unsubstituted or substituted by one or several R2c, or -(C3-C8)cycloalkyl unsubstituted or sub- stituted by one or several R2d;
  • R3 is -H; -Hal; -CN; -NO2, -NH2; -(C1-C6)alkyl unsubstituted or substituted by one or several -OH, -Hal, -CN; -N0 2 , -NH 2 ;
  • R4a is -H, -OH, -Hal, -CN, -NH2; -(C1-C6)alkyl unsubstituted or substituted by one or several -Hal, -OH, -CN, -NH 2 ;
  • Rsa is -OH, -Hal, -CN, -NH2; -(C1-C6)alkyl unsubstituted or substituted by one or several -Hal, -OH, -CN, -NH 2 ;
  • R 7a , R 7 b, R 7 C, R 7 d, R 7 e, R 7 f, R 7g , R 7 h, R 7 i, R 7 j, R 7 k, R 7 I, R 7 m are each independently -H, - OH; -Hal; -(C1-C6)alkyl unsubstituted or substituted by one or several -OH; -Hal; -O(C1-C6)alkyl unsubstituted or substituted by one or several -OH; -Hal;
  • Hal is an F, Cl, Br, I atom.
  • the present invention relates to a compound wherein Ri is: -O(C1-C6)alkyl unsubstituted or substituted by one or several R6 a ;
  • Ri a , Rib are each independently -H, -(C1-C6)alkyl unsubstituted or sub- stituted by one or several R6 a ; -C(O)(C1-C6)alkyl unsubstituted or substituted by one or several
  • R6b -S(0)2(C1-C6)alkyl unsubstituted or substituted by one or several R6 c ; -(C3-C8)cycloalkyl unsubstituted or substituted by one or several R6d; -C(O)(C3-C8)cycloalkyl unsubstituted or sub- stituted by one or several R6 e ; or
  • Ria and Rib together with the nitrogen atom they are attached to form a 3-7 membered heterocycle unsubstituted or substituted by one or several Rs g ;
  • Ri c is independently -(C1-C6)alkyl unsubstituted or substituted by one or several R6h,
  • Rid and Ri e are independently -(C1-C6)alkyl unsubstituted or substi- tuted by one or several R6h,
  • Hal is an F, Cl, Br, I atom.
  • the present invention relates to a compound, wherein Ri is -O(Ci- Ce)alkyl unsubstituted or substituted by one or several R6 a ; -NH2; -N((C1-C6)alkyl unsubstituted or substituted by one or several R6ah; -NH((Ci-C6)alkyl unsubstituted or substituted by one or several R6a); -NH((C3-C8)cycloalkyl unsubstituted or substituted by one or several R6d);-N((C3- Cs)cycloalkyl unsubstituted or substituted by one or several R6ah; -NHC(O)((C1-C6)alkyl unsub- stituted or substituted by one or several R6a); -NHC(O)(C3-C8)cycloalkyl unsubstituted or sub- stituted by one or several R6
  • Ri a and Rib together with the nitrogen atom they are attached to form a 3-7 membered heterocycle with 1 or 2 N atoms, unsubstituted or substituted by one or several
  • R6 g selected from azetidinyl unsubstituted or substituted by one or several R6 g , pyrrolidinyl un- substituted or substituted by one or several R6 g , piperidinyl unsubstituted or substituted by one or more R6 g ;
  • Hal is an F, Cl, Br, I atom.
  • the present invention relates to a compound, wherein Ri is meth- oxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, iso-butoxy, -NH2; -N(CH3)2, - NHCH3, -N(CH 2 -CH 3 )2, -NH(CH2-CH 3 ), -NHC(0)CH 3 , -NHC(O)(CH2-CH 3 ), -NHC(O)isopro- pyl, -NHC(O)propyl, -NHC(O)butyl, -NHC(O)pentyl, -NHC(O)cyclopropyl, -NHC(O)cyclobu- tyl, -NHC(O)cyclopentyl, -NHC(O)cyclohexyl, pyrrolidinyl, oxopyrrolidinyl, azeti
  • the present invention relates to a compound wherein R2 is: -NH-(C3-C8)cycloalkyl unsubstituted or substituted by one or several R7j;
  • R7k forming a bridged-ring compound with -(CH2)I-4- unsubstituted or substituted by one or several R71; 5-6-membered heteroaryl with 1,2 or 3 N atoms, unsubstituted or substituted by one or several R7 m,
  • R7a, R7b, R7c, R7d, R7e, R/f, R7g, R7h, R71, R7j, R7k, R71, R7m are each independently -H, - OH; -Hal; -(C1-C6)alkyl unsubstituted or substituted by one or several -OH; -Hal; -O(C1-C6)alkyl unsubstituted or substituted by one or several -OH; -Hal;
  • Hal is an F, Cl, Br, I atom.
  • the present invention relates to a compound wherein R2 is:
  • R7a, R7b, R7c, R7d, R7e, R7f, R7g, R7h, R7i, R7j, R7k, R71, R7m are each independently -OH; -Hal; - (C1-C6)alkyl unsubstituted or substituted by one or several -OH; -Hal; -O(C1-C6)alkyl unsubsti- tuted or substituted by one or several -OH; -Hal;
  • Hal is an F, Cl, Br, I atom.
  • the present invention relates to a compound wherein R2 is: -S(O)2(C1-C6)alkyl unsubstituted or substituted by one or several R7h;
  • R7a, R7b, R7c, R7d, R7e, R7f, R7g, R7h, R7i, R7j, R7k, R71, R7m are each independently -OH; - Hal; -(C1-C6)alkyl unsubstituted or substituted by one or several -OH; -Hal; -O(C1-C6)alkyl un- substituted or substituted by one or several -OH; -Hal;
  • Hal is an F, Cl, Br, I atom.
  • the present invention relates to a compound, wherein R2 is methylpyrazolyl, pyrazolyl, cyclohexyl, hydroxycyclohexyl, 8-oxa-3-azabicyclo[3.2.1]octane-3- yl, methanesulfonylphenyl, pyridinylpyrazolyl, l-(pyridine-4-yl)-lH-pyrazole-4-yl, l-(pyridine- 3-yl)-lH-pyrazole-4-yl, 3-methylmorpholine-4-yl, morpholinyl, cyclopropanesulfonyl, phenyl, fluorophenyl, cyanophenyl, (trifluoromethyl)phenyl, pyridinyl, indolyl, sulfamoylphenyl, car- bamoylphenyl, piperidinylpyrazolyl, l-(piperidinyl
  • the present invention relates to a compound wherein R3 is -H, -F, -Cl, -Br, -I, -(C1-C6)alkyl unsubstituted or substituted by one or several -Hal, -OH, -CN, -NH2;
  • Hal is an F, Cl, Br, I atom.
  • R4a are each independently -H, -OH, -Hal, -CN, -NH2; -(C1-C6)alkyl unsubstituted or sub- stituted by one or several -Hal, -OH, -CN, -NH2;
  • Hal is an F, Cl, Br, I atom.
  • R4a are each independently -H, -OH, -Hal, -CN, -NH2; -(C1-C6)alkyl unsubstituted or sub- stituted by one or several -Hal, -OH, -CN, -NH2;
  • Hal is an F, Cl, Br, I atom.
  • R4a are each independently -H, -OH, -Hal, -CN, -NH2; -(C1-C6)alkyl unsubstituted or sub- stituted by one or several -Hal, -OH, -CN, -NH2;
  • Hal is an F, Cl, Br, I atom.
  • the present invention relates to a compound wherein R4 is:
  • R4a is -H, -OH, -Hal, -CN, -NH2; methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl; Hal is an F, Cl, Br, I atom.
  • the present invention relates to a compound wherein R4 is: methylmorpholinyl, 3 -methylmorpholine, morpholinyl, 8-oxa-3-azabicyclo[3.2.1]octane-3-yl,
  • the present invention relates to a compound wherein R5 is:
  • Yi, Y2 are each independently C, N or CH;
  • Rsa is -OH, -Hal, -CN, -NH2; -(C1-C6)alkyl unsubstituted or substituted by one or several -Hal, -OH, -CN, -NH 2 ;
  • Hal is an F, Cl, Br, I atom.
  • the present invention relates to a compound wherein R5 is:
  • Rsa is -OH, -Hal, -CN, -NH2; -(C1-C6)alkyl unsubstituted or substituted by one or several -Hal, -OH, -CN, -NH 2 ;
  • Hal is an F, Cl, Br, I atom.
  • Rsa is -OH, -Hal, -CN, -NH2; -(C1-C6)alkyl unsubstituted or substituted by one or several -Hal, -OH, -CN, -NH 2 ;
  • Hal is an F, Cl, Br, I atom.
  • the present invention relates to a compound, wherein R5 is pyra- zolyl, methylpyrazolyl, imidazolyl, pyrrolyl.
  • Compounds, described in the present invention may be obtained as, and/or used as, phar- maceutically acceptable salts.
  • the type of pharmaceutical acceptable salts include, but are not limited to: acid addition salts, formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, and the like; or with an organic acid such as formic acid, acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, trifluoroacetic acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic
  • the corresponding counterions of the pharmaceutically acceptable salts may be analyzed and identified using various methods including, but not limited to, ion exchange chromatography, ion chromatography, capillary electrophoresis, inductively coupled plasma, atomic absorption spectroscopy, mass spectrometry, or any combination thereof.
  • the salts are recovered by using at least one of the following techniques: filtration, pre- cipitation with a non-solvent followed by filtration, evaporation of the solvent, or, in the case of aqueous solutions, lyophilization.
  • a reference to a pharmaceutically acceptable salt includes the solvent addition forms or crystal forms thereof, particularly solvates or polymorphs.
  • Solvates contain either stoichiometric or non-stoichiometric amounts of a sol- vent, and may be formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol.
  • Solvates of compounds described in the pre- sent patent can be conveniently prepared or formed during the processes described in the present invention.
  • the compounds provided in the present invention can exist in unsolvated as well as solvated forms.
  • the solvated forms are considered equivalent to the unsolv- ated forms for the purposes of the compounds and methods provided in the present invention.
  • compounds described in the present invention may be provided in various forms, includ- ing but not limited to, amorphous forms, milled forms and nano-particulate forms.
  • compounds described in the present invention include crystalline forms, also known as poly- morphs.
  • Polymorphs include different crystal packing arrangements of the same elemental com- position of a compound. Polymorphs typically have different X-ray diffraction patterns, infrared spectra, melting points, different density, hardness, crystal shape, optical and electrical proper- ties, stability, and solubility. Various factors such as the recrystallization solvent, rate of crystal- lization, and storage temperature may cause one crystal form to dominate.
  • the screening and characterization of the pharmaceutically acceptable salts, polymorphs and/or solvates may be accomplished using a variety of techniques including, but not limited to, thermal analysis, x-ray diffraction, spectroscopy, vapor sorption, and microscopy.
  • Thermal anal- ysis methods address to analysis of thermo chemical degradation or thermo physical processes including, but not limited to, polymorphic transitions, and such methods are used to analyze the relationships between polymorphic forms, to determine weight loss, to find the glass transition temperature, or for excipient compatibility studies.
  • Such methods include, but are not limited to, differential scanning calorimetry (DSC), modulated differential scanning calorimetry (MDCS), thermogravimetric analysis (TGA), thermogravi-metric and infrared analysis (TG/IR).
  • Crystal- lographic methods include, but are not limited to, single crystal and powder diffractometers and synchrotron sources.
  • the various spectroscopic techniques used include, but are not limited to, Raman (combinational scattering), FTIR, UVIS, and NMR (liquid and solid state).
  • the various microscopy techniques include, but are not limited to, polarized light microscopy, scanning elec- tron microscopy (SEM) with energy dispersive x-ray analysis (EDX), environmental scanning electron microscopy with EDX (in gas or water vapor atmosphere), IR microscopy, and Raman microscopy.
  • the present invention relates to compounds selected from the group including:
  • the present invention also relates to a method for inhibiting the biological activity of ataxia telangiectasia and Rad3 -related (ATR), comprising competitively binding the catalytic domain of ATR to the compound or pharmaceutically acceptable salt, solvate or stereoisomer thereof described herein.
  • ATR ataxia telangiectasia and Rad3 -related
  • the present invention relates to a method for inhibiting the biological activity of ATR with the compound or pharmacologically acceptable salt, solvate, or stereoiso- mer thereof according to the present invention.
  • ATR-inhibiting compounds may be used to manufacture drug products intended for treat- ing any of the pathological conditions described herein, for example, compounds of formula I, pharmaceutically acceptable salts, solvates or stereoisomers will be useful in the treatment of diseases or medical conditions mediated, alone or partially, by ATR activity, for example, onco- logical diseases.
  • oncological diseases that may be amenable to treatment using the above compounds include, but are not limited to, ovarian cancer, epithelial ovarian cancer, re- current platinum-refractory ovarian cancer, recurrent platinum-sensitive ovarian cancer, clear cell ovarian cancer, with BRCA 1/2, ARID1A mutations, borderline ovarian tumors; primary peritoneal cancer; fallopian tube cancer; gastric and gastroesophageal junction cancer, locally advanced unresectable, metastatic, or recurrent gastric and gastroesophageal junction cancer; head and neck tumors, unresectable, locally advanced, or metastatic head and neck tumors, re- current head and neck tumors; prostate cancer, metastatic prostate cancer, castration-resistant metastatic prostate cancer with BRCA mutations; colorectal cancer, unresectable or metastatic colorectal cancer, colon cancer, rectosigmoid junction cancer, and rectal cancer; anal cancer and perianal skin cancer; endometrial cancer, recurrent or metastatic
  • the present invention relates to a pharmaceutical composition that comprises at least one of the compounds described herein, or pharmaceutically acceptable salt, solvate, stereoisomer thereof, and one or more pharmaceutically acceptable excipients.
  • the present invention relates to a pharmaceutical composition that comprises a ther- apeutically effective amount of at least one of the compounds described herein, or pharmaceuti- cally acceptable salt, solvate, stereoisomer thereof, and one or more pharmaceutically acceptable excipients.
  • the pharmaceutical composition comprising compounds of this invention is intended for preventing or treating a disease or disorder alone or partially mediated by ATR activity.
  • the pharmaceutical composition comprising compounds of the present invention is intended to prevent or treat a disease or disorder alone or partially medi- ated by ATR activity.
  • the pharmaceutical composition comprising compounds of the present invention is intended for producing a medicament for preventing or treating a disease or disorder alone or partially mediated by ATR activity.
  • the pharmaceutical composition comprising compounds of the present invention is intended for preventing or treating a disease or disorder alone or partially mediated by ATR activity, being an oncological disease.
  • the pharmaceutical composition comprising compounds of the present invention is intended for producing a medicament for preventing or treating a disease or disorder alone or partially mediated by ATR activity, being an oncological disease.
  • the pharmaceutical composition comprising compounds of the present invention is intended to prevent or treat oncological dis- eases including ovarian cancer, epithelial ovarian cancer, recurrent platinum-refractory ovarian cancer, recurrent platinum-sensitive ovarian cancer, clear cell ovarian cancer, with BRCA 1/2, ARID 1 A mutations, borderline ovarian tumors; primary peritoneal cancer; fallopian tube cancer; gastric and gastroesophageal junction cancer, locally advanced unresectable, metastatic, or re- current gastric and gastroesophageal junction cancer; head and neck tumors, unresectable, locally advanced, or metastatic head and neck tumors, recurrent head and neck tumors; prostate cancer, metastatic prostate cancer, castration-resistant metastatic prostate cancer with BRCA mutations; colorectal cancer, unresectable or metastatic colorectal cancer, colon cancer, rectosigmoid junc- tion cancer, and rectal cancer; anal cancer and perianal skin cancer; end
  • the pharmaceutical composition of the present invention comprises, by way of example, from about 5 wt% to about 100 wt% of active ingredients, preferably from about 10 wt% to about 60 wt% of active ingredients. It is to be understood that each dosage unit may not comprise an effective amount of an active ingredient or ingredients, because the sufficient effective amount may be achieved by administering multiple dosage unit forms.
  • a typical composition is prepared by mixing the compound of the present invention with a carrier, diluent or excipient.
  • Suitable carriers, diluents and excipients are well known to those skilled in the art and include materials such as carbohydrates, waxes, water soluble and/or swella- ble polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.
  • the particular carrier, diluent or excipient used will depend upon the means and purpose for which compound of the present invention is being applied. Solvents are generally selected based on solvents recognized by persons skilled in the art as safe to be administered to a mammal.
  • safe solvents are aqueous solvents such as water and other solvents that are soluble or miscible in water.
  • Suitable aqueous solvents include water, as the main ingredient, ethanol, pro- pylene glycol, polyethylene glycols (e.g., PEG400, PEG300), etc. and mixtures thereof.
  • compositions may also include one or more buffers, stabilizing agents, surfactants, wefting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents and other known additives to provide an elegant presentation of the drug product (i.e., compound of the present invention or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e. medicinal product).
  • the pharmaceutical compositions should pref- erably be manufactured in compliance with the GMP (Good Manufacturing Practice) require- ments.
  • compositions of the present invention are typically suitable for oral administration.
  • Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, and/or buccal, lingual, or sublingual administration by which the compound enters the blood stream directly from the mouth.
  • Formulations suitable for oral administration include solid, semi-solid and liquid systems such as tablets; soft or hard capsules containing multi- or nano-particulates, liquids, or powders; granules; lozenges (including liquid-filled); chews; gels; fast dispersing dosage forms; films; ov- ules; sprays; and buccal/mucoadhesive patches. More preferred formulations for oral administra- tion comprise tablets, granules, and capsules.
  • Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations may be employed as fillers in soft or hard capsules (made, for example, made of gelatin or hy- droxypropylmethylcellulose) and typically comprise a carrier, for example, water, ethanol, pol- yethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsify- ing agents and/or suspending agents. Liquid formulations may also be prepared by the reconsti- tution of a solid, for example, from a sachet.
  • a carrier for example, water, ethanol, pol- yethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsify- ing agents and/or suspending agents.
  • Liquid formulations may also be prepared by the reconsti- tution of a solid, for example, from a sachet.
  • parenteral administration of a pharmaceutical composition includes any route of administration characterized by physical breaching of a tissue of a subject and administration of the pharmaceutical composition through the breach in the tissue, thus generally resulting in the direct administration into the blood stream, into muscle, or into an internal organ.
  • Parenteral administration thus includes, inter alia, administration of a pharmaceutical composition by injec- tion of the composition, by application of the composition through a surgical incision, by appli- cation of the composition through a tissue-penetrating non-surgical wound, and the like.
  • parenteral administration is contemplated to include, inter alia, subcutaneous, intraperi- toneal, intramuscular, intravenous, intraarterial, intrathecal, intraventricular, intraurethral, intra- cranial, intrasynovial injection or infusions; and kidney dialytic infusion techniques.
  • Intratumoral delivery e.g. intratumoral injection, may also be advantageous.
  • R6gional perfusion is also pro- vided.
  • Formulations of pharmaceutical compositions suitable for parenteral administration typ- ically comprise the active ingredient combined with a pharmaceutically acceptable carrier, such as sterile water or sterile isotonic saline.
  • a pharmaceutically acceptable carrier such as sterile water or sterile isotonic saline.
  • Such formulations may be prepared, packaged, or sold in a form suitable for bolus administration or for continuous administration.
  • injectable formula- tions may be prepared, packaged, or sold in unit dosage form, such as in ampoules or in multi-dose containers containing a preservative.
  • Formulations for parenteral administration in- clude, inter alia, suspensions, solutions, emulsions in oily or aqueous vehicles, pastes, and the like.
  • the compounds of the invention can also be administered intranasally or by inhalation, typically in the form of a dry powder (either alone, as a mixture, or as a mixed component parti- cle, for example, mixed with a suitable pharmaceutically acceptable excipient) from a dry powder inhaler, as an aerosol pressurised container, pump, spray, atomiser (preferably an atomiser using electrohydrodynamics to produce a fine mist), or nebuliser, with or without the use of a suitable propellant, or as nasal drops.
  • a dry powder either alone, as a mixture, or as a mixed component parti- cle, for example, mixed with a suitable pharmaceutically acceptable excipient
  • atomiser preferably an atomiser using electrohydrodynamics to produce a fine mist
  • nebuliser preferably an atomiser using electrohydrodynamics to produce a fine mist
  • the pressurised container, pump, spray, atomizer, or nebuliser typically contains a solu- tion or suspension of the compound of the present invention comprising, for example, a suitable agent for dispersing, solubilising, or extending release of the active ingredient, a propellant as solvent.
  • the drug product Prior to use as dry powder or suspension, the drug product is typically micronised to a size suitable for delivery by inhalation (typically less than 5 microns). This may be achieved by any appropriate comminuting method, such as spiral jet milling, fluid bed jet milling, supercriti- cal fluid processing to form nanoparticles, high pressure homogenisation, or spray drying.
  • Capsules, blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound of the present invention, a suitable powder base and a performance modifier.
  • a suitable solution formulation for use in an atomiser using electrohydrodynamics to pro- prise a fine mist may contain a suitable dose of the compound of the present invention per actu- ation and the actuation volume may for example vary from 1 pL to 100 pL.
  • Suitable flavours, such as menthol and levomenthol, or sweeteners, such as saccharin or sodium saccharin, may be added to those formulations of the present invention intended for in- haled/intranasal administration.
  • Formulations may be formulated to be immediate and/or modified release.
  • Modified re- lease formulations include delayed, sustained, pulsed, controlled, targeted and programmed re- lease.
  • the present invention relates to a method for treating a disease or disorder alone or partially mediated by ATR activity, which comprises administering, in a ther- apeutically effective amount, any compound described above, or the pharmaceutical composition of the present invention.
  • the present invention relates to the use of the above compound for producing a medicament for treating a disease or disorder alone or partially mediated by ATR activity, which comprises administering, in a therapeutically effective amount, any compound described above, or the pharmaceutical composition of the present invention.
  • the invention relates to the method for treating described above, wherein the disease or disorder alone or partially mediated by ATR activity is an onco- logical disease.
  • the invention relates to the method for treating described above, wherein the oncological disease is selected from the group comprising ovarian cancer, epithelial ovarian cancer, recurrent platinum-refractory ovarian cancer, recurrent plati- num-sensitive ovarian cancer, clear cell ovarian cancer, with BRCA 1/2, ARID 1 A mutations, borderline ovarian tumors; primary peritoneal cancer; fallopian tube cancer; gastric and gas- troesophageal junction cancer, locally advanced unresectable, metastatic, or recurrent gastric and gastroesophageal junction cancer; head and neck tumors, unresectable, locally advanced, or met- astatic head and neck tumors, recurrent head and neck tumors; prostate cancer, metastatic prostate cancer, castration-resistant metastatic prostate cancer with BRCA mutations; colore
  • the present invention relates to the use of the compound of the present invention or the above pharmaceutical composition for treating a disease or disorder alone or partially mediated by ATR activity.
  • the present invention relates to the use described above, wherein the disease or disorder alone or partially mediated by ATR activity is an oncological disease.
  • the invention relates to the use described above, wherein the oncological disease is selected from the group comprising ovarian cancer, epithelial ovarian can- cer, recurrent platinum-refractory ovarian cancer, recurrent platinum-sensitive ovarian cancer, clear cell ovarian cancer, with BRCA 1/2, ARID1A mutations, borderline ovarian tumors; pri- mary peritoneal cancer; fallopian tube cancer; gastric and gastroesophageal junction cancer, lo- cally advanced unresectable, metastatic, or recurrent gastric and gastroesophageal junction can- cer; head and neck tumors, unresectable, locally advanced, or metastatic head and neck tumors, recurrent head and neck tumors; prostate cancer, metastatic prostate cancer, castration-resistant metastatic prostate cancer with BRCA mutations; colorectal
  • Dosage regimens may be adjusted to provide the optimum desired response. For example, a single dose may be administered, several divided doses may be administered over time or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It is especially advantageous to formulate peroral compositions in a unit dosage form for ease of administration and uniformity of dosage.
  • a unit dosage form as used herein refers to physically discrete units suited as unitary dosages for patients/subjects to be treated; each unit contains a predetermined quantity of active compound calculated to produce the desired thera- Treatmentic effect in association with the desired pharmaceutical carrier.
  • unit dosage forms of the invention are typically dictated by and directly dependent on (a) the unique characteristics of a therapeutic agent and particular therapeutic or prophylactic effect to be achieved, and (b) the limitations inherent in the art of compounding such an active compound for the treatment of sensitivity in subjects.
  • the doses and dosage regimen are adjusted in accordance with methods well-known in the ther- apeutic arts. That is, the maximum tolerable dose can be readily established, and the effective amount providing a detectable therapeutic effect to a patient may also be determined, as can the temporal requirements for administering each agent to provide a detectable therapeutic effect to a patient.
  • certain doses and administration regimens are exemplified herein, these examples in no way limit the doses and administration regimens that may be provided to a patient in practicing the embodiments of the invention.
  • dosage values may vary with the type and severity of the condition to be alleviated, and may include single or multiple doses.
  • specific dosage regimens should be adjusted over time according to the individual need and the judgment of a medical professional administering or supervising the administration of the compositions, and that dosage ranges set forth in the present description are exemplary only and are not intended to limit the scope or practice of the claimed composi- tions.
  • the dosage regimen with the compositions of the present invention may be based on a variety of factors, including the type of disease, age, weight, sex, medical condition of the patient, the severity of the condition, the route of administration, and the particular com- pound of the present invention employed.
  • the dosage regimen may vary widely, but can be determined routinely using standard methods. For example, doses may be adjusted based on pharmacokinetic and pharmacodynamic parameters, which may include clinical effects such as toxic effects or laboratory values.
  • the present invention encompasses intra-patient dose- escalation as determined by one skilled in the art. Methods for determining appropriate dosage and regimens are well-known in the art and would be understood by a skilled artisan once pro- vided the ideas disclosed herein.
  • doses used to treat an adult are usually in the range of 0.02-5000 mg per day, or from 1 to 1500 mg per day or from 2.5 to 800 mg per day.
  • a maintenance dose is ad- ministered, if necessary. Subsequently, the dosage or the frequency of administration, or both, may be reduced, as a function of the symptoms, to a level at which the improved disease, disorder or condition is retained. Patients may be however required periodic treatment on a long-term basis upon any relapse of symptoms.
  • Compound ATR_1323 was prepared in four stages in a similar manner to compound ATR_1320 using, at the first stage, compound 1.5 and 3,5-dimethyl-4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolane-2-yl)- ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ -lH-pyrazole.
  • the yields at the first, second, third and fourth stages were 64%, 41%, 75% and 43%, respectively.
  • Compound ATR_1311 was prepared in three stages in a similar manner to compound ATR_1360 using, at the first stage, compound 1.5 and sodium cyclopropanesulfinate. The yield at the first, second, and third stages was 43%, 88%, and 23%, respectively.
  • Compound ATR_1310 was prepared in four stages in a similar manner to compound ATR_1304 using, at the first stage, compound 1.4 and morpholine.
  • the yield at the first, second, third, and fourth stages was 33%, 70%, 74%, and 34%, respectively.
  • Compound ATR_1361 was prepared in a similar manner to compound ATR_1248 in the form of a mixture of isomers of ATR_1361_a and ATR_1361_b, the yield was 43%.
  • Compound ATR_1324 was prepared in a similar manner to compound ATR_1248 in the form of a mixture of isomers of ATR_1324_a and ATR_1324_b in a ratio of 81 : 19 (according to chiral HPLC), the yield was 22%.
  • Compound ATR_1350 was prepared in a similar manner to compound ATR_1248 in the form of a mixture of isomers of ATR_1350_a and ATR_1350_b in a ratio of 52:48 (according to chiral HPLC), the yield was 50%.
  • ATR_1419 using, at the first stage, compound 18.16.
  • the yields at the first, second, and third stages were 99%, 91%, and 63%, respectively.
  • Example 17 Inhibition of activity of recombinant human ATR protein in vitro.
  • the ability of the compounds of the present invention to inhibit the activity of the ATR/ ATRIP kinase complex was determined using the Amplified Luminescent Proximity Homogenous Assay (AlphaScreen) detection system from PerkinElmer.
  • the kinase reaction was carried out in a 9 pl volume using a 384-well plate (Corning Inc., order no. 4513). Test substances were titrated from 10 pM in increments of 4 at 10 concentration points in a normal strength kinase buffer A (Thermo Fisher Scientific Inc, order no. PV3189) supplemented with DTT (Sigma, order no. 646563-10X.5ML) and prepared with water (Panreac, order no. 701074). A solution of a mixture of the ATR/ ATRIP complex and GST-p53 substrate (Eurofins/DiscoverX, order no. 14-952M) was prepared in a similar buffer, mixed with test com- pounds in plate wells and preincubated for 10 minutes at 25 °C.
  • Test substances were titrated from 10 pM in increments of 4 at 10 concentration points in a normal strength kinase buffer A (Thermo Fisher Scientific Inc, order no. PV3189) supplemented with DTT (
  • the substrate phosphorylation reaction was initiated by adding an ATP solution (Signal Chem, order no. V915B) prepared in a normal strength kinase buffer.
  • the plate was centrifuged at 400 ref in a centrifuge (Eppendorf, 5804 R) for one minute and incubated for 60 minutes at 25 °C.
  • a detection solution comprising AlphaScreen Glutathione Do- nor beads (PerkinElmer, order no. 6765301), AlphaScreen Protein A Acceptor beads (Perki- nElmer, order no. 6760137M) and Anti-p53 (phospho S15) antibody (Abeam, order no. abl431) prepared in a buffer comprising Tris Base (Sigma- Aldrich, order no. 741883), EDTA Disodium Salt (Panreac, order no. 131669) and Bovine Serum Albumin (BSA) (Thermo Fisher, order no. B14) according to the PerkinElmer protocol.
  • Tris Base Sigma- Aldrich, order no. 741883
  • EDTA Disodium Salt Panreac, order no. 131669
  • Bovine Serum Albumin BSA
  • A is the upper asymptote
  • D is the lower asymptote
  • C is IC50, half-maximal in- hibitory concentration of kinase, nM
  • B is the curvature (slope).
  • IC50 is shown as a mean value from the data of multiple measurement series, "A” for IC50 ⁇ lOnM, "B” for lOnM ⁇ IC50 ⁇ 50nM, "C” for 50nM ⁇ IC50 ⁇ lOOnM.
  • R6sults of this experiment show the production of compounds with high inhibitory activ- ity against the ATR protein in vitro.
  • Example 18 Inhibition of activity of recombinant human ATM protein in vitro.
  • the ability of the compounds of the present invention to inhibit the activity of the ATM kinase was determined using the Amplified Luminescent Proximity Homogenous Assay (AlphaScreen) detection system from PerkinElmer.
  • the kinase reaction was carried out in a 9 pl volume using a 384-well plate (Corning Inc., order no. 4513). Test substances were titrated from 10 pM in increments of 5 at 10 concentration points in a normal strength kinase buffer A (Thermo Fisher Scientific Inc, order no. PV3189) supplemented with DTT (Sigma, order no. 646563-10X.5ML) and prepared with water (Panreac, order no. 701074). A solution of a mixture of the ATM protein and GST-p53 substrate (Eu- rofins/DiscoverX, order no. 14-952M) was prepared in a similar buffer, mixed with test com- pounds in plate wells and preincubated for 10 minutes at 25 °C.
  • the substrate phosphorylation reaction was initiated by adding an ATP solution (Signal Chem, order no. V915B) prepared in a normal strength kinase buffer.
  • the plate was centrifuged at 400 ref in a centrifuge (Eppendorf, 5804 R) for one minute and incubated for 60 minutes at 25 °C.
  • a detection solution comprising AlphaScreen Glutathione Do- nor beads (PerkinElmer, order no. 6765301), AlphaScreen Protein A Acceptor beads (Perki- nElmer, order no. 6760137M) and Anti-p53 (phospho S15) antibody (Abeam, order no. abl431) prepared in a buffer comprising Tris Base (Sigma- Aldrich, order no. 741883), EDTA Disodium Salt (Panreac, order no. 131669) and Bovine Serum Albumin (BSA) (Thermo Fisher, order no. B14) according to the PerkinElmer protocol.
  • Tris Base Sigma- Aldrich, order no. 741883
  • EDTA Disodium Salt Panreac, order no. 131669
  • Bovine Serum Albumin BSA
  • IC50 is shown as a mean value from the data of multiple measurement series, "C” for IC50 ⁇ 50nM, "B” for 50nM ⁇ IC50 ⁇ 500nM, "A” for IC50 > 500nM.
  • Example 19 Antiproliferative activity against sensitive cell lines in vitro.
  • Antiproliferative activity of the ATR inhibitors of the present invention was measured in a cellular assay on continuous cultures of HCT 116 cells (colorectal cancer, ATCC® CCL- 247TM) and ES-2 cells (ovarian cancer, ATCC® CRL-1978TM) using the AlamarBlue vital dye (Thermo Fisher Scientific Inc, order no. DALI 100).
  • the cells were grown in DMEM, powder, high glucose (Gibco, order no. 12100061) and RPMI-1640 (PanEco, order no. C330n), respec- tively.
  • the basal growth medium was enriched with L-glutamine at a concentration of 2 mM (PanEco, order no.
  • HCT 116 and ES-2 adherent cells were removed from the plastic with a trypsin-EDTA solution (PanEco, order no. H043n) which was thereafter inactivated with a complete DMEM or RPMI-1640 medium, respectively, centrifuged at 1000 RPM (Eppendorf, 5804 R), a cell suspension was prepared in a complete DMEM medium for HCT 116 and RPMI-1640 medium for ES-2 and added to 96-well culture plates (ServiceBio Inc, order no.
  • test compounds were dissolved in DMSO and diluted with com- plete medium to a final concentration ranging from 30 pM to 0.1 nM for the HCT 116 cell line and from 10 pM to 5 pM for the ES-2 cell line. Diluted compounds in a volume of 100 pl were introduced into the plate wells with cells in triplicates (the final concentration of DMSO was no more than 1%) and incubated at 37 °C in an incubator with 5% CO2 for 72 hours.
  • IC50 value was calculated using GraphPad Prism by approximating experimental points by four-parameter model with the optimization by Levenberg-Marquardt.
  • IC50 is shown as a mean value from the data of multiple measurement series, "A” for IC50 ⁇ lOOnM, "B” for lOOnM ⁇ IC50 ⁇ 500nM, "C” for IC50 > 500nM, "N/A” means that a given compound was not analyzed in the present test.
  • R6sults of these experiments show the preparation of compounds capable of stopping the growth of sensitive cell lines HCT 116 and ES-2 at nM concentrations.
  • Example 20 General cytotoxicity against primary HepaRG liver cells in vitro.
  • IC50 is shown as a mean value from the data of multiple measurement series, "A” for IC50 > 10 pM, "B” for 10 pM > IC50 > 1 pM, and "C” for IC50 ⁇ 1 pM.
  • R6sults of this experiment confirm production of compounds that are non-toxic in the human hepatocyte model.
  • Example 21 Determination of passive membrane permeability through PAMPA artifi- cial membrane.
  • Passive membrane permeability of the compounds described in the present invention was determined using the PAMPA (parallel artificial membrane permeability assay) model at pH 7.4.
  • PAMPA parallel artificial membrane permeability assay
  • a 96-well plate Cornning® BioCoat® Pre-coated PAMPA Plate System, order no. 353015, composed of acceptor and donor parts with cell membrane-modeling PVDF filter pre- impregnated with a lecithin-phospholipid bilayer.
  • the substance (at a concentration of 10 pM) in a 0.01 M phosphate buffer with pH 7.4 was introduced into a donor well of the plate, and pure buffer was introduced into an acceptor well; afterwards, the both parts were combined and incu- bated for 20 hours at room temperature so that the compound was redistributed between the two wells and the membrane.
  • Verapamil USP, USA, order no. 1711202
  • propranalol MCE LLC, USA, order no. HY-B0573/CS-2680
  • the samples were analyzed by reversed-phase HPLC with UV detection (Ag- ilent 1260 chromatograph with UV detector) by way of determining the peak areas thereof in the donor and acceptor cells, then calculating the permeability (Pe, cm/s) and retention factor (R, %) in the lipid bilayer.
  • Pe R6sults of investigation of passive permeability through PAMPA lipid mem- brane model.
  • Pe is shown as a mean value from the data of multiple measurement series, "A” for Pe > 5 - 10 -6 cm/s, "B” for 5 - 10 -6 cm/s > Pe > 1 • 10 -6 cm/s, and "C” for Pe ⁇ 1 • 10 -6 cm/s.
  • Example 22 Determination of cellular permeability using Caco-2 model.
  • Caco-2 cell culture (ATCC® HTB-37TM, human colorectal adenocarcinoma) at passage 50-100 was planted in clean 24-well plates (Thermo Fisher Scientific, 141002) coated with type I collagen (Sigma, C3867) at 5 pg/cm 2 .
  • the culture was differentiated for 21 days in DMEM medium (Gibco, 12800082) + 10% FBS (Gibco, 26140079). Integrity of the cell monolayer was checked by the level of passage of the Lucifer Yellow dye (Thermo Fisher Scientific, L453).
  • the fluorescence signal was measured on an Ensight microplate reader (PerkinElmer, USA) with excitation and emission wavelengths of 480 nm and 530 nm, respectively.
  • the Ag- ilent 6410 mass spectrometer (Agilent, USA) combined with the Agilent 1260 Infinity II HPLC liquid chromatograph (Agilent, USA) and a cooling autosampler controlled by MassHunter soft- ware (Agilent, USA) was used as an HPLC-MS/MS system. Chromatographic analysis was per- formed on a Cl 8 reversed-phase HPLC column (Agilent, Waters or equivalent) in a gradient elution mode in a system of mobile phases: 0.1% formic acid in acetonitrile / 0.1% formic acid in water, flow rate: 0.5 mL/min, T co iunm 350 °C. Mass spectrometric detection was performed with electrospray ionization (ESI) in multiple reaction monitoring (MRM) mode. Precursor ions, fragment ions and collision energies for each substance were selected experimentally.
  • ESI electrospray ionization
  • MRM multiple reaction monitoring
  • R6sults of these experiments show the preparation of compounds that are permeable (B) and highly permeable (A) on the Caco-2 cell model.
  • Example 23 In vitro microsomal stability study of compounds in human and mouse mi- crosomes.
  • the rate of enzymatic decomposition of the compound in liver microsomes in in vitro analysis was determined by keeping a reaction mixture comprising 0.5 mg/mL pooled human or mouse liver microsomes (XenoTech, USA, order no. H2610, order no. M1000), 1 pM test com- pound, 1.5 mM P-nicotinamide adenine dinucleotide (Carbosynth, UK, order no. NN108711101) and 1.5 mM magnesium chloride in 0.1 M sodium phosphate buffer (pH 7.4) in a solid-state thermostat at 37 °C. Incubation was carried out in three replicates.
  • R6actions were stopped at 0, 10, 20, 30 and 40 min time points by way of adding an ice mixture of acetonitrile:methanol (3: 1) comprising an internal standard.
  • R6sults of these experiments confirm production of compounds resistant (B) and highly resistant (A) to the activity of human and mouse liver microsomal enzymes.
  • Example 24 In vitro assay for determining chemical stability of compounds in simulated biological media.
  • a candidate was incubated in selected simulated media for 4 hours at 37 °C. Difference in the peak area for the time zero candidate and the candidate following 4-hour incubation in a respective medium was determined chromatographically.
  • Table 14 R6sults of chemical stability in vitro of selected compounds in simulated in- testinal fluid (SIF) and gastric fluid (SGF). S is shown as a mean value from the data of multi- ple measurement series, "A" for S > 80%, "B” for 80% > S > 50%, "C” for S ⁇ 50%.
  • Example 25 Pharmacokinetic study of compounds following oral administration in mice.
  • AUCo-t is area under the pharmacokinetic "medicinal substance concentration - time” curve from the mo- ment of administration to the last measured concentration;
  • AUCo-inf is area under the pharmaco- kinetic "medicinal substance concentration - time” curve from the moment of administration to infinity;
  • MRT is mean retention time for the medicinal substance in the body;

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Abstract

The present invention relates to novel compounds of formula (I): (Formula (I)) or pharmaceutically acceptable salt, solvate or stereoisomer thereof, which have the properties of an ataxia telangiectasia and Rad3-related inhibitor, to pharmaceutical compositions comprising said compounds, to methods of treating diseases or disorders, and the use of said compounds as pharmaceutical products for treating diseases or disorders.

Description

Ataxia telangiectasia and Rad3-related inhibitors
Field of the invention
The present invention relates to ataxia telangiectasia mutated and Rad3 -related (ATR) inhibitors, also to pharmaceutically acceptable salts, solvates or stereoisomers thereof, to phar- maceutical compositions comprising the present compounds, to methods for treating diseases or disorders and to the use of the present compounds as pharmaceutical products for treating dis- eases or disorders.
Background of the invention
Ataxia telangiectasia mutated and Rad3 -related (ATR) is a serine/threonine-protein ki- nase of the phosphatidylinositol 3 -kinase-related kinases (PIKK) family. The PIKK family, in addition to ATR, includes the following enzymes: ATM (ataxia telangiectasia mutated protein), DNA-PK (DNA-dependent protein kinase), mTOR (mammalian target of rapamycin), SMG1 (suppressor of morphogenesis in genitalia) and TRRAP (transformation/transcription domain- associated protein) (Cimprich and Cortez, 2008; Lempiainen and Halazonetis, 2009). All en- zymes in the PIKK family share a common domain structure. ATR is a protein at 300 kDa and consisting of 2644 amino acids (Cimprich and Cortez, 2008; Gately et al., 1998).
ATR plays a key role in the DNA damage response (DDR) signaling pathway and is one of the two apical regulators of the DDR pathway that initiate and coordinate cellular responses to DNA damage in cooperation with other DDR proteins (Cimprich and Cortez, 2008., Jackson and Bartek, 2009). ATR is activated in response to single-stranded DNA (ssDNA) structures, which can arise upon DNA damage (Cimprich and Cortez, 2008; Flynn and Zou, 2011), leading to phosphorylation and activation of CHK1, the major downstream and best-studied target of ATR (Bartek and Lukas, 2003). ATR associates with a protein called ATRIP, which recognizes replication protein A-coated single-stranded DNA (Zou L, 2003). Activation of CHK1 in turn leads to stabilization of the DNA replication fork, repair of DNA damage, to phosphorylation and inhibition of activity of Cdc25 A and Cdc25C, thereby activating the intra-S and G2/M check- points of the cell cycle (Sorensen et al., 2003; Sanchez et al., 1997; Xiao et al., 2003), to mainte- nance of early cell cycle arrest and induction of apoptosis or senescence when necessary (Cim- prich and Cortez, 2008; Toledo et al., 2008).
ATR activity is of great importance in all highly proliferative cells, especially during the S phase in the cell cycle due to the replication stress associated with this phase (Toledo et al., 2008; Ruzankina et al., 2007). At the same time, ATR function is more critical in tumor cells, since high replication stress is generated due to activated oncogenes such as ras, myc and cyclin E which are known to disrupt normal cell cycle regulation (Toledo et al., 2008). In response to high replication stress, which results in the generation of excessive amount of ssDNA, cells are more likely to die than to survive in the absence of immediate DNA repair (Toledo et al., 2008). Thus, the ATR-activated signaling pathway is critical for tumor cell survival.
Recently, it has also been revealed that ATR performs post-translational regulation of synthesis of immune checkpoint protein PD-L1 in response to DNA damage, which may be promising in immunotherapy. Since ATR plays an important role in regulation of PD-L1, and tumor cells evade T cell-mediated cell death by way of upregulation of DNA damage-induced PD-L1, which is typically observed during radiotherapy and chemotherapy, it is suggested that ATR inhibition may lead to increased efficacy of radiotherapy and chemotherapy, further medi- ating immune antitumor activity (Sun et al., 2018; Dillon et al., 2019). In addition, activation of the ATR signaling pathway is observed in response to diverse anticancer chemotherapeutic drugs (Cimprich and Cortez, 2008), possibly as a response to repair chemotherapy-induced DNA dam- age that contributes to tumor cell survival and drug resistance.
The development of an ATR inhibitor seems to be an urgent and promising means for the treatment of a large number of oncological diseases, as well as for improving the efficacy of current antitumor therapy.
Description
The terms used in the description of this invention appear below.
Optionally substituted in one, two, three, four or several positions means the specified group can be substituted by a radical or any combination of radicals in one, two, three, four or from one to six positions.
"Alkyl" means an aliphatic straight chain or branched chain hydrocarbon group having from 1 to 12 carbon atoms, more preferably from 1 to 6 carbon atoms. Branched chain means alkyl chain having one or more "lower alkyl" substituents. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n- pentyl, 2-pentyl, 3-pentyl, neo-pentyl, n-hexyl. Alkyl may have substituents which may be same or different structure.
"Alkenyl" means a straight chain or branched chain hydrocarbon group having from 2 to 12 carbon atoms, or from 2 to 6 carbon atoms that contains one or more carbon-carbon double bonds. Alkenyl may have substituents which may be same or different structure.
"Alkynyl" means a straight chain or branched chain hydrocarbon group having from 2 to 12 carbon atoms, or from 2 to 6 carbon atoms that contains one or more carbon-carbon triple bound. Alkynyl may have substituents which may be same or different structure.
"Alkyloxy", "Alkoxy" or "alkyloxy group" means an alkyl-O- group, wherein alkyl is defined in this section. Examples of alkoxy groups include, but are not limited to, methoxy, eth- oxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, iso-butoxy.
"Alkylsulfonyl" (-S(O)2-C1-C6alkyl) means "alkyl", as defined above, linked to the cor- responding fragment of a molecule via a sulfonyl group, -SO2-. Examples of alkyl sulfonyls in- clude, but are not limited to, methyl sulfonyl, ethyl sulfonyl.
"Amino group" means R'R"N-group.
"Aminocarbonyl" means -C(=O)NR"'R"" group.
Examples of R', R", R'", R"" include, but are not limited to, substituents selected from the group comprising hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, heteroalkyl or R' and R" together with the carbon atom they are attached to, can form 4-7-mem- bered heterocyclyl or heteroaryl.
An "annelated compound" or "condensed compound" is a cyclic compound that has two neighboring atoms in common.
"Aryl" means an aromatic monocyclic or polycyclic system having from 6 to 14 carbon atoms, more preferably from 6 to 10 carbon atoms. Examples of aryl groups include, but are not limited to, phenyl, phenylene, benzenetriyl, indanyl, naphthyl, naphthylene, naphthalenetriyl and anthrylene. Aryl may have one or more substituents which may be same or different structure. Aryl can be annelated with a heterocycle, cycloalkyl, or heteroaryl, or can form bridge-ring compounds with alkyl, such as, but not limited to, naphthalenyl, dihydronaphthalenyl, dihydroin- denyl, indazolyl, l,3,4,5-tetrahydro-2H-benzo[b]azepinyl, indolyl, benzimidazolyl.
"Dialkylphosphine oxide" or "dialkylphosphoryl" (-P(O)((C i-Ce)alkyl)2) or (-P(O)((C 3- Cio)cycloalkyl)2) means "alkyl" or "cycloalkyl" as defined above, linked to the corresponding ^> = 0 fragment of the molecule via a phosphoryl group ' . Examples of dialkylphosphine ox- ide include, but are not limited to, dimethylphosphine oxide, diethylphosphine oxide, meth- ylethylphosphine oxide, dipropylphosphine oxide, dicyclopropylphosphine oxide.
"Halo", "Halogen", "Hal" means fluoro, chloro, bromo and iodo.
"Heterocycle", "heterocyclyl", "heterocyclic ring" means a monocyclic or polycyclic sys- tem having from 3 to 11 carbon atoms, of which one or more carbon atoms are substituted by a heteroatom, such as nitrogen, oxygen, sulfur. Heterocycle may have one or more substituents which may be same or different structure. Nitrogen and sulfur atoms of heterocycle could be oxidized to N-oxide, S-oxide or S-dioxide. Heterocycle may be saturated, partly saturated or unsaturated. Heterocycle can be annelated with cycloalkyl, aryl, or heteroaryl, and can also be a monocyclic compound, a spyro compound, or a bridge-ring compound comprising one or more heteroatoms selected from N, S, or O. Examples of heterocycles include, but are not limited to, azetidine, pyrrolidine, piperidine, 2,8-diazaspiro[4.5]decane, piperazine, morpholine, diazepane, azepane, azabicycloheptane, 2-oxa-6-azaspiro[3.3]heptane, oxetane, oxolane, oxane, 2- azaspiro[ 3.3 ] heptane, 2-azabicyclo[ 2.2.1 ] heptane, 8-azabicyclo [ 3.2.1 ] octane .
"Heteroaryl", "heteroarylyl", "heteroaryl ring" means an aromatic monocyclic or polycy- clic system having from 5 to 11 carbon atoms, preferably from 5 to 10, of which one or more carbon atoms are substituted by a heteroatom, such as nitrogen, sulfur or oxygen. Nitrogen atom of heterocycle could be oxidized to N-oxide. Heteroaryl may have one or more substituents which may be same or different structure. Examples of heteroaryls include, but are not limited to, 1H- pyrrolo[2,3-b]pyridine, 7H-pyrrolo[2,3-d]pyrimidine, pyrrole, furan, pyridine, pyrazine, pyrimi- dine, pyridazine, isooxazole, isothiazole, tetrazole, oxazole, thiazole, pyrazole, furazan, 1,2,4- triazole, 1,2,3-triazole, 1,2,4-thiadiazol, quinoxaline, imidazo[l,2-a]pyridine, indole, benzimid- azole, quinoline, imidazole, pyrazole, thi enopyridine, quinazoline, naphthyridine, thienopyrimi- dine, imidazopyridine, isoquinoline.
"Substituent" means a chemical radical attached to a scaffold (fragment).
"Lower alkyl" means a straight chain or branched chain alkyl having from 1 to 4 carbon atoms.
"Bridged-ring compounds" are compounds in which several atoms are common between two or more rings of a single compound, which rings may comprise one or more heteroatoms selected from N, S, or O. The bridged-ring compound may have one or more substituents which may be same or different structure.
"Solvate" is a molecular aggregate that consists of the compound of the present invention, including its pharmaceutically acceptable salts, with one or more solvent molecules. The solvent molecules are molecules of common pharmaceutical solvents, known to be safe for recipients, e.g. water, ethanol, ethylene glycol, and the like. Other solvents, such as MeOH, methyl-tert- butyl ether, ethyl acetate, methyl acetate, (S)-propylene glycol, (R)-propylene glycol, 1,4-bu- tanediol can be used as intermediate solvates for obtaining more desirable solvates.
The term "hydrate" refers to a complex, wherein the solvent molecule is water.
Solvates and/or hydrates preferably exist in crystalline form.
"Spiro compound" or "spirane compound" is a bicyclic or polycyclic compound which shares a single carbon atom (spiro atom) between two rings and which may comprise one or more heteroatoms selected from N, S, or O. Spiro compound may have one or more substituents which may be same or different structure. "Monocyclic compounds" or "monocyclic radicals" are compounds or radicals in which there are present three or more bound atoms forming a single ring, which may comprise one or more heteroatoms selected from N, S or O. The monocyclic compound or radical may have one or more substituents which may be same or different structure.
The term "protecting group" refers to groups that are used to block the reactivity of functional groups, such as an amino group, carboxyl group or hydroxy group. Examples of protecting groups include, but are not limited to, tert -butyloxycarbonyl (Boc), ben- zyloxycarbonyl (Cbz), 2-(trimethylsilyl)ethoxy)methyl acetal (SEM), tri alkyl silyl, al- kyl(diaryl)silyl or alkyl.
The term "oxo" as used herein relates to the radical =0.
The term "carbonyl" as used herein relates to the radical -C(0)-.
The term "carboxy" as used herein relates to the radical -C(0)0-.
The term "carboxyl" as used herein relates to the radical -C(0)0H.
The terms "bond", "chemical bond", or "single bond" refer to a chemical bond of two atoms or two moieties (i.e. groups, fragments) when the atoms joined by the bond are considered to be part of larger substructure.
The term "stereoisomers" refers to compounds that have identical chemical composition and the same structure, but differ in the spatial arrangement of atoms or groups. Stereoisomers may include geometric isomers, enantiomers, diastereomers.
"Partly saturated" means a ring system including at least one double or triple bond. The term "partly saturated" relates to cyclic systems or heterocyclic systems having many sites for saturation and does not include aryl and heteroaryl systems as they defined herein.
"Cycloalkyl" means a fully saturated carbocyclic ring that contains from 3 to 10 carbon ring atoms. Cycloalkyl may have substituents which may be same or different structure. Cyclo- alkyl may be annelated with aril, heteroaryl, heterocyclyl. Examples of cycloalkyl groups in- clude, but are not limited to, monocyclic groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, bicyclic groups, such as bicyclo- heptyl or bicyclooctyl.
"Cycloalkyloxy" or "cycloalkyloxy group" means a cycloalkyl-O- group, wherein cyclo- alkyl is defined in this section. Examples of cycloalkyloxy groups include, but are not limited to, cyclohexyloxy, cyclopentyloxy, cyclobutyloxy or cyclopropyloxy.
The term "excipient" is used herein to describe any ingredient other than the compound(s) of the invention.
"Pharmaceutical composition" means a composition comprising a compound of the in- vention and at least one excipient. The excipient may be selected from a group consisting of pharmaceutically acceptable and pharmacologically compatible fillers, solvents, diluents, carri- ers, auxiliary, distributing and sensing agents, delivery agents, such as preservatives, stabilizers, fillers, disintegrators, moisteners, emulsifiers, suspending agents, thickeners, sweeteners, fla- vouring agents, aromatizing agents, antibacterial agents, fungicides, lubricants, and prolonged delivery controllers, the choice and proportions of which depend on the nature and route of ad- ministration and dosage. Examples of suspending agents are ethoxylated isostearyl alcohol, pol- yoxyethene, sorbitol and sorbitol ether, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacant and mixtures thereof as well. Protection against action of mi- croorganisms can be provided by various antibacterial and antifungal agents, such as, for exam- ple, parabens, chlorobutanole, sorbic acid, and similar compounds. The composition may also contain isotonic agents, for example, sugars, sodium chloride, and similar compounds. Prolonged action of the composition may be achieved by agents slowing down absorption of active ingre- dient, for example, aluminum monostearate and gelatine. Examples of suitable carriers, solvents, diluents and delivery agents are water, ethanol, polyalcohols and mixtures thereof, plant oils (such as olive oil) and organic esters (such as ethyl oleate) for injections. Examples of fillers are lactose, milk sugar, sodium citrate, calcium carbonate, calcium phosphate, and the like. Examples of disintegrators and distributors are starch, alginic acid and its salts, silicates, and the like. Ex- amples of lubricants are magnesium stearate, sodium lauryl sulfate, talc, and polyethylene glycol of high molecular weight as well. The pharmaceutical composition for peroral, sublingual, trans- dermal, intramuscular, intravenous, subcutaneous, local or rectal administration of active ingre- dient, alone or in combination with another active ingredient may be administered to animals and human in a standard administration form, in a mixture with traditional pharmaceutical carriers. Suitable standard administration forms include peroral forms such as tablets, gelatin capsules, pills, powders, granules, chewing gums and peroral solutions or suspensions; sublingual and transbuccal administration forms; aerosols; implants; local, transdermal, subcutaneous, intramus- cular, intravenous, intranasal or intraocular administration forms and rectal administration forms.
"Pharmaceutically acceptable salt" means relatively nontoxic both organic and inorganic salts of acids and bases disclosed in the present invention. These salts may be prepared in situ in the processes of synthesis, isolation or purification of compounds or they may be prepared spe- cially. In particular, salts of bases may be prepared specially from purified base of the disclosed compound and suitable organic or inorganic acid. Examples of salts prepared in this manner are hydrochlorides, hydrobromides, sulfates, bisulfates, phosphates, nitrates, acetates, oxalates, va- leriates, oleates, palmitates, stearates, laurates, borates, benzoates, lactates, tosilates, citrates, ma- leates, fumarates, succinates, tartrates, mesilates, malonates, salicylates, propionates, ethane sul- phonates, benzene sulfonates, sulfamates and the like (Detailed description of such salts proper- ties is given in: Berge S.M., et al., "Pharmaceutical Salts" J. Pharm. Sci. 1977, 66: 1-19). Salts of disclosed acids may be prepared by reaction of a purified acid with suitable base; furthermore, metal salts and amine salts may be synthesized as well. Metal salts are salts of sodium, potassium, calcium, barium, zinc, magnesium, lithium and aluminum; sodium and potassium salts are most preferred. Suitable inorganic bases from which metal salts may be prepared are: sodium hydrox- ide, carbonate, bicarbonate and hydride; potassium hydroxide and bicarbonate, lithium hydrox- ide, calcium hydroxide, magnesium hydroxide, zinc hydroxide. Organic bases from which salts of disclosed acids may be prepared are amines and amino acids, the basicity of which is sufficient enough to produce a stable salt, and which are suitable for use in medical purposes (in particular, they must have low toxicity). Such amines include ammonia, methylamine, dimethylamine, tri- methylamine, ethylamine, diethylamine, triethylamine, benzylamine, dibenzylamine, dicyclo- hexylamine, piperazine, ethylpiperidine, tri s(hydroxymethyl)aminom ethane and the like. Be- sides, salts can be prepared using tetraalkylammonium hydroxides, such as holine, tetrame- thylammonium, tetraethylammonium, and the like. Basic aminoacids, i.e. lysine, ornithine and arginine, may be used as aminoacids.
"Medicinal product (drug, therapeutic product, medicine, medicament)" is a compound (or a mixture of compounds as a pharmaceutical composition) in the form of tablets, granules, capsules, solutions, suspensions, emulsions, injections, ointments creams, aerosols and other ready formulations intended for restoration, improvement or modification or substitution of phys- iological functions, suppression of pathophysiological functions in humans and animals, as well as for treatment and prophylaxis of diseases, for diagnostics, anesthesia, contraception, cosmetol- ogy and others. "Treat", "treatment" and "therapy" refer to a method of alleviating or abrogating a bio- logical disorder and/or at least one of attendant symptoms thereof. The term "to alleviate" a dis- ease, disorder or condition means reducing the severity and/or occurrence frequency of the symp- toms of the disease, disorder, or condition. Further, references herein to "treatment" include ref- erences to palliative treatment.
"Prophylaxis", "prophylactic therapy" refers to a set of measures aimed at preventing the onset, eliminating risk factors, or early detecting a disease or disorder, its exacerbation, relapse, complications or other consequences.
In one aspect, the patient, or subject of treatment, or prophylaxis, is a mammal. Examples of the patients include, but are not limited to, a human subject. Said subject may be either male or female, of any age.
The term "disorder" means any condition that would benefit from treatment according to the present invention. The definition of this term includes chronic and acute disorders or patho- logical conditions that predispose the mammal to the onset of diseases in question. Non-limiting examples of diseases to be treated include malignant solid neoplasms, or neoplasms of unspeci- fied nature, including tumors originating from blood cells and lymphoid cells. Examples include: ovarian cancer, epithelial ovarian cancer, recurrent platinum-refractory ovarian cancer, recurrent platinum-sensitive ovarian cancer, clear cell ovarian cancer, with BRCA 1/2, ARID1A muta- tions, borderline ovarian tumors; primary peritoneal cancer; fallopian tube cancer; gastric and gastroesophageal junction cancer, locally advanced unresectable, metastatic, or recurrent gastric and gastroesophageal junction cancer; head and neck tumors, unresectable, locally advanced, or metastatic head and neck tumors, recurrent head and neck tumors; prostate cancer, metastatic prostate cancer, castration-resistant metastatic prostate cancer with BRCA mutations; colorectal cancer, unresectable or metastatic colorectal cancer, colon cancer, rectosigmoid junction cancer, and rectal cancer; anal cancer and perianal skin cancer; endometrial cancer, recurrent or meta- static endometrial cancer, uterine corpus cancer and uterine sarcomas; cervical cancer, mesothe- lioma of the pleura, peritoneum and other sites; pancreatic cancer, inoperable or metastatic pan- creatic cancer; malignant tumors of the biliary system, advanced or metastatic cancer of the bil- iary tract; primary malignant tumors of bone; lung cancer, non-small cell lung cancer, small cell lung cancer; breast cancer, metastatic triple-negative breast cancer with or without BRCA muta- tions; cutaneous melanoma; metastatic tumors with an ATM mutation; chronic lymphocytic leu- kemia, myelodysplastic syndrome, chronic myelomonocytic leukemia; esophageal cancer; ma- lignant tumors of the liver; tumors of unknown primary; renal cell carcinoma; bladder cancer and urothelial cancer; gastrointestinal stromal tumors; soft tissue sarcomas; non-melanocytic skin tumors; adrenal cortical cancer, neuroendocrine tumors, primary CNS tumors and metastatic brain tumors, mediastinal tumors, and trophoblastic tumors.
"Therapeutically effective amount" refers to that amount of the therapeutic agent being administered in the course of treatment which will relieve the severity or eliminate the symptoms of the disease being treated.
As used in the present description and claims that follow, unless otherwise dictated by the context, the words "have", "include," and "comprise" or variations thereof such as "has", "having," "includes", "including", "comprises," or "comprising," will be understood to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers.
Detailed description of the invention
The present invention relates to a compound of formula I: or to a pharmaceutically acceptable salt, solvate or stereoisomer thereof,
Ri is -NRiaRib, -S(O)2RIC, -P(O)RidRie, -ORir;
Ria, Rib, Rif are each independently -H, -(C1-C6)alkyl unsubstituted or substituted by one or several R6a; -C(O)(C1-C6)alkyl unsubstituted or substituted by one or several R6b; -S(O)2(Ci- Ce)alkyl unsubstituted or substituted by one or several R6c; -(C3-C8)cycloalkyl unsubstituted or substituted by one or several R6a; -C(O)(C3-C8)cycloalkyl unsubstituted or substituted by one or several R6e; -S(O)2(C3-C8)cycloalkyl unsubstituted or substituted by one or several R6f;
Ria and Rib together with the nitrogen atom they are attached to form a 3-7 membered het- erocycle with 1 or 2 N atoms, unsubstituted or substituted by one or several R6g;
Ric, Rid, Rie are each independently -(C1-C6)alkyl unsubstituted or substituted by one or several Rsh, -(C3-C8)cycloalkyl unsubstituted or substituted by one or several Rsi;
R2 is
5-10 membered heteroaryl with 1,2,3 or 4 heteroatoms selected from N, S or O unsubsti- tuted or substituted by one or several R2a;
-(C3-C8)cycloalkyl unsubstituted or substituted by one or several R2b;
-(C3-C8)cycloalkyl unsubstituted or substituted by one or several R2b, forming a spiro compound with a 4-10 membered heterocyclyl with 1,2,3 or 4 heteroatoms selected from N, S or O, unsubstituted or substituted by one or several R2c, or -(C3-C8)cycloalkyl unsubstituted or sub- stituted by one or several R2d;
-(C3-C8)cycloalkyl unsubstituted or substituted by one or several R2b, forming a bridged- ring compound with -(CH2)I-4- unsubstituted or substituted by one or several RfC;
4-10-membered heterocyclyl, with 1,2,3 or 4 heteroatoms selected from N, S or O, un- substituted or substituted by one or several R2f;
4-10-membered heterocyclyl, with 1,2,3 or 4 heteroatoms selected from N, S or O, un- substituted or substituted by one or several R2f, forming a bridged-ring compound with -(CH2)I- 4- unsubstituted or substituted by one or several Rjc;
4-10-membered heterocyclyl with 1,2,3 or 4 heteroatoms selected from N, S or O, unsub- stituted or substituted by one or several R2f, forming a spiro compound with a 4-10 membered heterocyclyl with 1,2,3 or 4 heteroatoms selected from N, S or O, unsubstituted or substituted by one or several R2f, or -(C3-C8)cycloalkyl unsubstituted or substituted by one or several R2d;
6-10-membered aryl unsubstituted or substituted by one or several R2g;
6-10-membered aryl unsubstituted or substituted by one or several R2g, fused with 5-6 membered heteroaryl with 1,2 or 3 atoms selected from N, S or O, unsubstituted or substituted by one or several R2h;
-S(O)2R2i;
-NR2jR2k;
-OR21;
-(C1-C6)alkyl unsubstituted or substituted by one or several R2m; R-2a, R-2b, R2C, R2d, R2e, R2f, R2g, R2h, R21, R2j, R2k, R21, R2m are each independently -H, - OH, =0; -Hal, -CN, -NR7aR7b, -C(O)NR7cR7d; -S(O)2R7e; -S(O)2NR7fR7g; -S(O)(NH)R7g; -(Ci- Ce)alkyl unsubstituted or substituted by one or several R7h; -O(C1-C6)alkyl unsubstituted or sub- stituted by one or several R7i; -C(O)(C1-C6)alkyl unsubstituted or substituted by one or several R7i; -C(O)O(C1-C6)alkyl unsubstituted or substituted by one or several R7i; -(C3-C8)cycloalkyl unsubstituted or substituted by one or several R7j; -O(C3-C8)cycloalkyl unsubstituted or substi- tuted by one or several R7j; 4-10-membered heterocyclyl with 1,2,3 or 4 heteroatoms selected from N, S or O, unsubstituted or substituted by one or several R7k; 4-10-membered heterocyclyl with 1,2,3 or 4 heteroatoms selected from N, S or O, unsubstituted or substituted by one or several R7k, forming a bridged-ring compound with -(CH2)I-4- unsubstituted or substituted by one or several R7I; 5-6-membered heteroaryl with 1,2 or 3 N atoms, unsubstituted or substituted by one or several R7 mi
R3 is -H; -Hal; -CN; -NO2, -NH2; -(C1-C6)alkyl unsubstituted or substituted by one or several -OH, -Hal, -CN; -N02, -NH2;
R4 is morpholinyl unsubstituted or substituted by one or several R4a; morpholinyl unsubstituted or substituted by one or several R4a, forming a bridged-ring compound with -(CH2)o-4- unsubstituted or substituted by one or several R4t>;
R4a, R4b are each independently -H, -OH, -Hal, -CN, -NH2; -(C1-C6)alkyl unsubstituted or substituted by one or several -Hal, -OH, -CN, -NH2;
R5 is
5-6-membered heteroaryl with 1,2 or 3 N atoms, unsubstituted or substituted by one or several Rsa;
Rsa is -OH, -Hal, -CN, -NH2; -(C1-C6)alkyl unsubstituted or substituted by one or several -Hal, -OH, -CN, -NH2;
Rsa, Rsb, Rsc, R6a, Rse, R6f, R6g, R6h, R6i are each independently -OH, =0, -Hal, -CN, - NH2, -(C1-C6)alkyl unsubstituted or substituted by one or several -Hal, -OH, -CN, -NH2; -O(Ci- Ce)alkyl unsubstituted or substituted by one or several -Hal, -OH, -CN, -NH2;
R7a, R7b, R7C, R7d, R7e, R7f, R7g, R7h, R7i, R7j, R7k, R7I, R7m are each independently -H, - OH; -Hal; -(C1-C6)alkyl unsubstituted or substituted by one or several -OH; -Hal; -O(C1-C6)alkyl unsubstituted or substituted by one or several -OH; -Hal;
Hal is an F, Cl, Br, I atom.
In some embodiments, if Ri is -NHCH3, then R2 cannot be 1-methylpyrazolyl.
In some embodiments, the present invention relates to a compound of formula II:
II or to a pharmaceutically acceptable salt, solvate or stereoisomer thereof, Ri is -NRiaRib, -S(O)2RIC, -P(O)RidRie, -ORu; Ria, Rib, Rif are each independently -H, -(C1-C6)alkyl unsubstituted or substituted by one or several R6a; -C(O)(C1-C6)alkyl unsubstituted or substituted by one or several R6b; -S(O)2(Ci- Ce)alkyl unsubstituted or substituted by one or several R6c; -(C3-C8)cycloalkyl unsubstituted or substituted by one or several R6a; -C(O)(C3-C8)cycloalkyl unsubstituted or substituted by one or several R6e; -S(O)2(C3-C8)cycloalkyl unsubstituted or substituted by one or several R6f;
Ria and Rib together with the nitrogen atom they are attached to form a 3-7 membered heterocycle with 1 or 2 N atoms, unsubstituted or substituted by one or several R6g;
Ric, Rid, Rie are each independently -(C1-C6)alkyl unsubstituted or substituted by one or several Rsh, -(C3-C8)cycloalkyl unsubstituted or substituted by one or several R6i;
R2 is
5-10 membered heteroaryl with 1,2,3 or 4 heteroatoms selected from N, S or O unsubsti- tuted or substituted by one or several R2a;
-(C3-C8)cycloalkyl unsubstituted or substituted by one or several R2b;
-(C3-C8)cycloalkyl unsubstituted or substituted by one or several R2b, forming a spiro compound with a 4-10 membered heterocyclyl with 1,2,3 or 4 heteroatoms selected from N, S or O, unsubstituted or substituted by one or several R2c, or -(C3-C8)cycloalkyl unsubstituted or sub- stituted by one or several R2d;
-(C3-C8)cycloalkyl unsubstituted or substituted by one or several R2b, forming a bridged- ring compound with -(CH2)I-4- unsubstituted or substituted by one or several R7c;
4-10-membered heterocyclyl, with 1,2,3 or 4 heteroatoms selected from N, S or O, un- substituted or substituted by one or several R2f;
4-10-membered heterocyclyl, with 1,2,3 or 4 heteroatoms selected from N, S or O, un- substituted or substituted by one or several R2f, forming a bridged-ring compound with -(CH2)I- 4- unsubstituted or substituted by one or several R7c;
4-10-membered heterocyclyl with 1,2,3 or 4 heteroatoms selected from N, S or O, unsub- stituted or substituted by one or several R2f, forming a spiro compound with a 4-10 membered heterocyclyl with 1,2,3 or 4 heteroatoms selected from N, S or O, unsubstituted or substituted by one or several R2f, or -(C3-C8)cycloalkyl unsubstituted or substituted by one or several R2d;
6-10-membered aryl unsubstituted or substituted by one or several R2g;
6-10-membered aryl unsubstituted or substituted by one or several R2g, fused with 5-6 membered heteroaryl with 1,2 or 3 atoms selected from N, S or O, unsubstituted or substituted by one or several R2h;
-S(O)2R2i;
-NR2jR2k;
-OR21;
-(C1-C6)alkyl unsubstituted or substituted by one or several R2m;
R2a, R2b, R2C, R2d, R2e, R2f, R2g, R2h, R21, R2j, R2k, R21, R2m are each independently -H, - OH, =0; -Hal, -CN, -NR7aR7b, -C(O)NR7cR7d; -S(O)2R7e; -S(O)2NR7fR7g; -S(O)(NH)R7g; -(Ci- Ce)alkyl unsubstituted or substituted by one or several R7h; -O(C1-C6)alkyl unsubstituted or sub- stituted by one or several R7i; -C(O)(C1-C6)alkyl unsubstituted or substituted by one or several R7i; -C(O)O(C1-C6)alkyl unsubstituted or substituted by one or several R7i; -(C3-C8)cycloalkyl unsubstituted or substituted by one or several R7j; -O(C3-C8)cycloalkyl unsubstituted or substi- tuted by one or several R7j; 4-10-membered heterocyclyl with 1,2,3 or 4 heteroatoms selected from N, S or O, unsubstituted or substituted by one or several R7k; 4-10-membered heterocyclyl with 1,2,3 or 4 heteroatoms selected from N, S or O, unsubstituted or substituted by one or several R7k, forming a bridged-ring compound with -(CH2)I-4- unsubstituted or substituted by one or several R71; 5-6-membered heteroaryl with 1,2 or 3 N atoms, unsubstituted or substituted by one or several R7 mi
R3 is -H; -Hal; -CN; -NO2, -NH2; -(C1-C6)alkyl unsubstituted or substituted by one or several -OH, -Hal, -CN; -NO2, -NH2;
R4 is morpholinyl unsubstituted or substituted by one or several R4a; morpholinyl unsubstituted or substituted by one or several R4a, forming a bridged-ring compound with -(CH2)o-4- unsubstituted or substituted by one or several R4t>;
R4a, R4b are each independently -H, -OH, -Hal, -CN, -NH2; -(C1-C6)alkyl unsubstituted or substituted by one or several -Hal, -OH, -CN, -NH2;
Rsa is -OH, -Hal, -CN, -NH2; -(C1-C6)alkyl unsubstituted or substituted by one or several -Hal, -OH, -CN, -NH2;
Rsa, R6b, R6c, R6a, Rse, R6f, R6g, R6h, R6i are each independently -OH, =0, -Hal, -CN, - NH2, -(C1-C6)alkyl unsubstituted or substituted by one or several -Hal, -OH, -CN, -NH2; -O(Ci- Ce)alkyl unsubstituted or substituted by one or several -Hal, -OH, -CN, -NH2;
R7a, R7b, R7c, R7d, R7e, R/f, R7g, R7h, R71, R7j, R7k, R71, R7m are each independently -H, - OH; -Hal; -(C1-C6)alkyl unsubstituted or substituted by one or several -OH; -Hal; -O(C1-C6)alkyl unsubstituted or substituted by one or several -OH; -Hal;
Hal is an F, Cl, Br, I atom.
In some embodiments, the present invention relates to a compound of formula III:
III or to a pharmaceutically acceptable salt, solvate or stereoisomer thereof,
Ri is -NRiaRib, -S(O)2RIC, -P(O)RidRie, -ORif;
Ria, Rib, Rif are each independently -H, -(C1-C6)alkyl unsubstituted or substituted by one or several R6a; -C(O)(C1-C6)alkyl unsubstituted or substituted by one or several R6b; -S(0)2(Ci- Ce)alkyl unsubstituted or substituted by one or several R6c; -(C3-C8)cycloalkyl unsubstituted or substituted by one or several R6d; -C(O)(C3-C8)cycloalkyl unsubstituted or substituted by one or several Rz)C; -S(O)2(C3-C8)cycloalkyl unsubstituted or substituted by one or several R6f;
Ria and Rib together with the nitrogen atom they are attached to form a 3-7 membered heterocycle with 1 or 2 N atoms, unsubstituted or substituted by one or several R6g;
Ric, Rid, Rie are each independently -(C1-C6)alkyl unsubstituted or substituted by one or several Rsh, -(C3-C8)cycloalkyl unsubstituted or substituted by one or several R6i;
R2 is
5-10-membered heteroaryl with 1,2,3 or 4 heteroatoms selected from N, S or O, unsub- stituted or substituted by one or several R2a; -(C3-C8)cycloalkyl unsubstituted or substituted by one or several R2t>;
-(C3-C8)cycloalkyl unsubstituted or substituted by one or several R.2b, forming a spiro compound with a 4-10 membered heterocyclyl with 1,2,3 or 4 heteroatoms selected from N, S or O, unsubstituted or substituted by one or several R2c, or -(C3-C8)cycloalkyl unsubstituted or sub- stituted by one or several R2d;
-(C3-C8)cycloalkyl unsubstituted or substituted by one or several R2b, forming a bridged- ring compound with -(CH2)I-4- unsubstituted or substituted by one or several R7c;
4-10-membered heterocyclyl, with 1,2,3 or 4 heteroatoms selected from N, S or O, un- substituted or substituted by one or several R2f;
4-10-membered heterocyclyl, with 1,2,3 or 4 heteroatoms selected from N, S or O, un- substituted or substituted by one or several R2f, forming a bridged-ring compound with -(CH2)I- 4- unsubstituted or substituted by one or several R7c;
4-10-membered heterocyclyl with 1,2,3 or 4 heteroatoms selected from N, S or O, unsub- stituted or substituted by one or several R2f, forming a spiro compound with a 4-10 membered heterocyclyl with 1,2,3 or 4 heteroatoms selected from N, S or O, unsubstituted or substituted by one or several R2f, or -(C3-C8)cycloalkyl unsubstituted or substituted by one or several R2d;
6-10-membered aryl unsubstituted or substituted by one or several R2g;
6-10-membered aryl unsubstituted or substituted by one or several R2g, fused with 5-6 membered heteroaryl with 1,2 or 3 atoms selected from N, S or O, unsubstituted or substituted by one or several R2h;
-S(O)2R2i;
-NR2jR2k;
-OR21;
-(C1-C6)alkyl unsubstituted or substituted by one or several R2m;
R2a, R2b, R2C, R2d, R2e, R2f, R2g, R2h, R21, R2j, R2k, R21, R2m are each independently -H, - OH, =0; -Hal, -CN, -NR7aR7b, -C(O)NR7cR7d; -S(O)2R7e; -S(O)2NR7fR7g; -S(O)(NH)R7g; -(Ci- Ce)alkyl unsubstituted or substituted by one or several R7h; -O(C1-C6)alkyl unsubstituted or sub- stituted by one or several R7i; -C(O)(C1-C6)alkyl unsubstituted or substituted by one or several R7i; -C(O)O(C1-C6)alkyl unsubstituted or substituted by one or several R7i; -(C3-C8)cycloalkyl unsubstituted or substituted by one or several R7j; -O(C3-C8)cycloalkyl unsubstituted or substi- tuted by one or several R7j; 4-10-membered heterocyclyl with 1,2,3 or 4 heteroatoms selected from N, S or O, unsubstituted or substituted by one or several R7k; 4-10-membered heterocyclyl with 1,2,3 or 4 heteroatoms selected from N, S or O, unsubstituted or substituted by one or several R7k, forming a bridged-ring compound with -(CH2)I-4- unsubstituted or substituted by one or several R7I; 5-6-membered heteroaryl with 1,2 or 3 N atoms, unsubstituted or substituted by one or several R7 mi
R3 is -H; -Hal; -CN; -NO2, -NH2; -(C1-C6)alkyl unsubstituted or substituted by one or several -OH, -Hal, -CN; -NO2, -NH2;
R4a, R4b are each independently -H, -OH, -Hal, -CN, -NH2; -(C1-C6)alkyl unsubstituted or substituted by one or several -Hal, -OH, -CN, -NH2; d is 0,1,2 or 3;
Rsa is -OH, -Hal, -CN, -NH2; -(C1-C6)alkyl unsubstituted or substituted by one or several -Hal, -OH, -CN, -NH2; R6a, R6b, R6c, Rsa, Rse, R6f, R6g, Rsh, R6i are each independently -OH, =0, -Hal, -CN, - NH2, -(C1-C6)alkyl unsubstituted or substituted by one or several -Hal, -OH, -CN, -NH2; -O(Ci- Ce)alkyl unsubstituted or substituted by one or several -Hal, -OH, -CN, -NH2;
R7a, R7b, R7c, R7d, R7e, R7f, R7g, R7h, R7i, R7j, R7k, R71, R7m are each independently -H, - OH; -Hal; -(C1-C6)alkyl unsubstituted or substituted by one or several -OH; -Hal; -O(C1-C6)alkyl unsubstituted or substituted by one or several -OH; -Hal;
Hal is an F, Cl, Br, I atom.
In some embodiments, the present invention relates to a compound of formula
III, wherein
(i) if d=0, then the compound of formula III is the compound:
Illa; or
(ii) if d=l, then the compound of formula III is the compound:
Illb; or
(iii) if d=2, then the compound of formula III is the compound:
IIIc, or to a pharmaceutically acceptable salt, solvate or stereoisomer thereof,
Ri is -NRiaRib, -S(O)2RIC, -P(O)RidRie, -ORir;
Ria, Rib, Rif are each independently -H, -(C1-C6)alkyl unsubstituted or substituted by one or several R6a; -C(O)(C1-C6)alkyl unsubstituted or substituted by one or several R6b; -S(O)2(Ci- Ce)alkyl unsubstituted or substituted by one or several R6c; -(C3-C8)cycloalkyl unsubstituted or substituted by one or several R6a; -C(O)(C3-C8)cycloalkyl unsubstituted or substituted by one or several R6e; -S(O)2(C3-C8)cycloalkyl unsubstituted or substituted by one or several R6f;
Ria and Rib together with the nitrogen atom they are attached to form a 3-7 membered heterocycle with 1 or 2 N atoms, unsubstituted or substituted by one or several R6g;
Ric, Rid, Rie are each independently -(C1-C6)alkyl unsubstituted or substituted by one or several Rsh, -(C3-C8)cycloalkyl unsubstituted or substituted by one or several R6i;
R2 is
5-10 membered heteroaryl with 1,2,3 or 4 heteroatoms selected from N, S or O unsubsti- tuted or substituted by one or several R2a;
-(C3-C8)cycloalkyl unsubstituted or substituted by one or several R2b;
-(C3-C8)cycloalkyl unsubstituted or substituted by one or several R2b, forming a spiro compound with a 4-10 membered heterocyclyl with 1,2,3 or 4 heteroatoms selected from N, S or O, unsubstituted or substituted by one or several R2c, or -(C3-C8)cycloalkyl unsubstituted or sub- stituted by one or several R2d;
-(C3-C8)cycloalkyl unsubstituted or substituted by one or several R2b, forming a bridged- ring compound with -(CH2)I-4- unsubstituted or substituted by one or several RfC;
4-10-membered heterocyclyl, with 1,2,3 or 4 heteroatoms selected from N, S or O, un- substituted or substituted by one or several R2f;
4-10-membered heterocyclyl, with 1,2,3 or 4 heteroatoms selected from N, S or O, un- substituted or substituted by one or several R2f, forming a bridged-ring compound with -(CH2)I- 4- unsubstituted or substituted by one or several Rjc;
4-10-membered heterocyclyl with 1,2,3 or 4 heteroatoms selected from N, S or O, unsub- stituted or substituted by one or several R2f, forming a spiro compound with a 4-10 membered heterocyclyl with 1,2,3 or 4 heteroatoms selected from N, S or O, unsubstituted or substituted by one or several R2f, or -(C3-C8)cycloalkyl unsubstituted or substituted by one or several R2d;
6-10-membered aryl unsubstituted or substituted by one or several R2g;
6-10-membered aryl unsubstituted or substituted by one or several R2g, fused with 5-6 membered heteroaryl with 1,2 or 3 atoms selected from N, S or O, unsubstituted or substituted by one or several R2h;
-S(O)2R2i;
-NR2jR2k;
-OR21; -(C1-C6)alkyl unsubstituted or substituted by one or several R2m;
R-2a, R-2b, R2C, R2d, R2e, R2f, R2g, R2h, R21, R2j, R2k, R21, R2m are each independently -H, - OH, =0; -Hal, -CN, -NR7aR7b, -C(O)NR7cR7d; -S(O)2R7e; -S(O)2NR7fR7g; -S(O)(NH)R7g; -(Ci- Ce)alkyl unsubstituted or substituted by one or several R7h; -O(C1-C6)alkyl unsubstituted or sub- stituted by one or several R7i; -C(O)(C1-C6)alkyl unsubstituted or substituted by one or several R7i; -C(O)O(C1-C6)alkyl unsubstituted or substituted by one or several R7i; -(C3-C8)cycloalkyl unsubstituted or substituted by one or several R7j; -O(C3-C8)cycloalkyl unsubstituted or substi- tuted by one or several R7j; 4-10-membered heterocyclyl with 1,2,3 or 4 heteroatoms selected from N, S or O, unsubstituted or substituted by one or several R7k; 4-10-membered heterocyclyl with 1,2,3 or 4 heteroatoms selected from N, S or O, unsubstituted or substituted by one or several R7k, forming a bridged-ring compound with -(CH2)I-4- unsubstituted or substituted by one or several R7I; 5-6-membered heteroaryl with 1,2 or 3 N atoms, unsubstituted or substituted by one or several R7 mi
R3 is -H; -Hal; -CN; -NO2, -NH2; -(C1-C6)alkyl unsubstituted or substituted by one or several -OH, -Hal, -CN; -N02, -NH2;
R4a is -H, -OH, -Hal, -CN, -NH2; -(C1-C6)alkyl unsubstituted or substituted by one or several -Hal, -OH, -CN, -NH2;
Rsa is -OH, -Hal, -CN, -NH2; -(C1-C6)alkyl unsubstituted or substituted by one or several -Hal, -OH, -CN, -NH2;
Rsa, R6b, R6c, R6a, Rse, R6f, R6g, Rsh, R6i are each independently -OH, =0, -Hal, -CN, - NH2, -(C1-C6)alkyl unsubstituted or substituted by one or several -Hal, -OH, -CN, -NH2; -O(Ci- Ce)alkyl unsubstituted or substituted by one or several -Hal, -OH, -CN, -NH2;
R7a, R7b, R7C, R7d, R7e, R7f, R7g, R7h, R7i, R7j, R7k, R7I, R7m are each independently -H, - OH; -Hal; -(C1-C6)alkyl unsubstituted or substituted by one or several -OH; -Hal; -O(C1-C6)alkyl unsubstituted or substituted by one or several -OH; -Hal;
Hal is an F, Cl, Br, I atom.
In some embodiments, the present invention relates to a compound wherein Ri is: -O(C1-C6)alkyl unsubstituted or substituted by one or several R6a;
-NRiaRib, wherein Ria, Rib are each independently -H, -(C1-C6)alkyl unsubstituted or sub- stituted by one or several R6a; -C(O)(C1-C6)alkyl unsubstituted or substituted by one or several
R6b; -S(0)2(C1-C6)alkyl unsubstituted or substituted by one or several R6c; -(C3-C8)cycloalkyl unsubstituted or substituted by one or several R6d; -C(O)(C3-C8)cycloalkyl unsubstituted or sub- stituted by one or several R6e; or
Ria and Rib together with the nitrogen atom they are attached to form a 3-7 membered heterocycle unsubstituted or substituted by one or several Rsg;
-S(O)2Ric, wherein Ric is independently -(C1-C6)alkyl unsubstituted or substituted by one or several R6h,
-P(O)RidRie, wherein Rid and Rie are independently -(C1-C6)alkyl unsubstituted or substi- tuted by one or several R6h,
R6a, R6b, R6c, Rse, Rsg, Rih are each independently -OH, =0, -Hal, -CN, -NH2, -(C1-C6)al- kyl unsubstituted or substituted by one or several -Hal, -OH, -CN, -NH2; -O(C1-C6)alkyl unsub- stituted or substituted by one or several -Hal, -OH, -CN, -NH2;
Hal is an F, Cl, Br, I atom.
In some embodiments, the present invention relates to a compound, wherein Ri is -O(Ci- Ce)alkyl unsubstituted or substituted by one or several R6a; -NH2; -N((C1-C6)alkyl unsubstituted or substituted by one or several R6ah; -NH((Ci-C6)alkyl unsubstituted or substituted by one or several R6a); -NH((C3-C8)cycloalkyl unsubstituted or substituted by one or several R6d);-N((C3- Cs)cycloalkyl unsubstituted or substituted by one or several R6ah; -NHC(O)((C1-C6)alkyl unsub- stituted or substituted by one or several R6a); -NHC(O)(C3-C8)cycloalkyl unsubstituted or sub- stituted by one or several R6a; -NHS(O)2((C1-C6)alkyl unsubstituted or substituted by one or sev- eral R6a); -S(O)2((C1-C6)alkyl unsubstituted or substituted by one or several R6a); -P(O)((Ci- Ce)alkyl unsubstituted or substituted by one or several R6a)2; or
-NRiaRib, wherein Ria and Rib together with the nitrogen atom they are attached to form a 3-7 membered heterocycle with 1 or 2 N atoms, unsubstituted or substituted by one or several
R6g, selected from azetidinyl unsubstituted or substituted by one or several R6g, pyrrolidinyl un- substituted or substituted by one or several R6g, piperidinyl unsubstituted or substituted by one or more R6g;
R6a, R6a, R6g are each independently -OH, =0, -Hal, -CN, -NH2, -(C1-C6)alkyl unsubsti- tuted or substituted by one or several -Hal, -OH, -CN, -NH2; -O(C1-C6)alkyl unsubstituted or substituted by one or several -Hal, -OH, -CN, -NH2;
Hal is an F, Cl, Br, I atom.
In some embodiments, the present invention relates to a compound, wherein Ri is meth- oxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, iso-butoxy, -NH2; -N(CH3)2, - NHCH3, -N(CH2-CH3)2, -NH(CH2-CH3), -NHC(0)CH3, -NHC(O)(CH2-CH3), -NHC(O)isopro- pyl, -NHC(O)propyl, -NHC(O)butyl, -NHC(O)pentyl, -NHC(O)cyclopropyl, -NHC(O)cyclobu- tyl, -NHC(O)cyclopentyl, -NHC(O)cyclohexyl, pyrrolidinyl, oxopyrrolidinyl, azetidinyl, - NH(cyclopropyl), -NHS(O)2CH3, -S(O)2CH3, -P(O)(CH3)2.
In some embodiments, the present invention relates to a compound wherein R2 is: -NH-(C3-C8)cycloalkyl unsubstituted or substituted by one or several R7j;
-N((C1-C6)alkyl unsubstituted or substituted by one or several R7h)-(C3-C8)cycloalkyl un- substituted or substituted by one or several R7j;
-NH-(C3-C8)heterocyclyl, with 1,2,3 or 4 heteroatoms selected from N, S or O, unsubsti- tuted or substituted by one or several R2f, forming a bridged-ring compound with -(CH2)i-4- un- substituted or substituted by one or several R26;
-N(-(C1-C6)alkyl unsubstituted or substituted by one or several R7h)-(C3-C8)heterocyclyl, with 1,2,3 or 4 heteroatoms selected from N, S or O, unsubstituted or substituted by one or several R2f, forming a bridged-ring compound with -(CH2)i-4- unsubstituted or substituted by one or sev- eral R2e;
-S(0)2(C1-C6)alkyl unsubstituted or substituted by one or several R7h;
-S(O)2(C3-C8)cycloalkyl unsubstituted or substituted by one or several R7j;
-O-(C3-C8)heterocyclyl, with 1,2,3 or 4 heteroatoms selected from N, S or O, unsubsti- tuted or substituted by one or several R2f;
-O-(C3-C8)heterocyclyl, with 1,2,3 or 4 heteroatoms selected from N, S or O, unsubsti- tuted or substituted by one or several R2f, forming a bridged-ring compound with -(CH2)i-4- un- substituted or substituted by one or several R26; or
wherein m= 0,1,2 or 3, wherein p = 0,1, 2, 3 or 4, wherein n = 0,1, 2, 3 or 4, Ce)alkyl unsubstituted or substituted by one or several R7h; -O(C1-C6)alkyl unsubstituted or sub- stituted by one or several R7i; -C(O)(C1-C6)alkyl unsubstituted or substituted by one or several R7i; -C(O)O(C1-C6)alkyl unsubstituted or substituted by one or several R7i; -(C3-C8)cycloalkyl unsubstituted or substituted by one or several R7j; -O(C3-C8)cycloalkyl unsubstituted or substi- tuted by one or several R7j; 4-10-membered heterocyclyl with 1,2,3 or 4 heteroatoms selected from N, S or O, unsubstituted or substituted by one or several R7k; 4-10-membered heterocyclyl with 1,2,3 or 4 heteroatoms selected from N, S or O, unsubstituted or substituted by one or several
R7k, forming a bridged-ring compound with -(CH2)I-4- unsubstituted or substituted by one or several R71; 5-6-membered heteroaryl with 1,2 or 3 N atoms, unsubstituted or substituted by one or several R7 m,
R7a, R7b, R7c, R7d, R7e, R/f, R7g, R7h, R71, R7j, R7k, R71, R7m are each independently -H, - OH; -Hal; -(C1-C6)alkyl unsubstituted or substituted by one or several -OH; -Hal; -O(C1-C6)alkyl unsubstituted or substituted by one or several -OH; -Hal;
Hal is an F, Cl, Br, I atom.
In some embodiments, the present invention relates to a compound wherein R2 is:
-S(O)2(C1-C6)alkyl unsubstituted or substituted by one or several R7h;
-S(O)2(C3-C8)cycloalkyl unsubstituted or substituted by one or several R7j;
wherein m = 0,1,2 or 3, wherein p = 0,1, 2, 3 or 4, wherein n = 0,1, 2, 3 or 4,
R-2a, R-2b, R2C, R2d, R2e, R2f, R2g, R2h, R21, R2j, R2k, R21 are each independently -OH, =0, -Hal, -CN, -NR6aRsb, -C(O)NR6cR6d; -(C1-C6)alkyl unsubstituted or substituted by one or several R6e; -O(Ci- Ce)alkyl unsubstituted or substituted by one or several R6e; -C(O)(C1-C6)alkyl unsubstituted or substituted by one or several R6e; -(C3-C8)cycloalkyl unsubstituted or substituted by one or sev- eral R6r; -O(C3-C8)cycloalkyl unsubstituted or substituted by one or several R7j; 4-10-membered heterocyclyl with 1,2,3 or 4 heteroatoms selected from N, S or O, unsubstituted or substituted by one or several R6g; 5-6-membered heteroaryl with 1,2 or 3 N atoms, unsubstituted or substituted by one or several R6h; -S(O)2R6i; -S(O)(NH)R6j; -N=S(O)R6kR6i;
R7a, R7b, R7c, R7d, R7e, R7f, R7g, R7h, R7i, R7j, R7k, R71, R7m are each independently -OH; -Hal; - (C1-C6)alkyl unsubstituted or substituted by one or several -OH; -Hal; -O(C1-C6)alkyl unsubsti- tuted or substituted by one or several -OH; -Hal;
Hal is an F, Cl, Br, I atom.
In some embodiments, the present invention relates to a compound wherein R2 is: -S(O)2(C1-C6)alkyl unsubstituted or substituted by one or several R7h;
-S(O)2(C3-C8)cycloalkyl unsubstituted or substituted by one or several R7j;
wherein q = 0, 1 or 2, wherein y = 0 or 1,
R-2a, R-2b, R2C, R2d, R2e, R2f, R2g, R2h, R21, R2j, R2k, R21 are each independently -OH, =0, - Hal, -CN, -NR.6aR.6b, -C(O)NR6cR6d; -(C1-C6)alkyl unsubstituted or substituted by one or several
R6e; -O(C1-C6)alkyl unsubstituted or substituted by one or several R6e; -C(O)(C1-C6)alkyl unsub- stituted or substituted by one or several R6e; -(C3-C8)cycloalkyl unsubstituted or substituted by one or several Rsr; -O(C3-C8)cycloalkyl unsubstituted or substituted by one or several R7j; 4-10- membered heterocyclyl with 1,2,3 or 4 heteroatoms selected from N, S or O, unsubstituted or substituted by one or several R6g; 5-6-membered heteroaryl with 1,2 or 3 N atoms, unsubstituted or substituted by one or several R6h; -S(0)2R6i; -S(O)(NH)R6j; -N=S(O)R6kR6i;
R7a, R7b, R7c, R7d, R7e, R7f, R7g, R7h, R7i, R7j, R7k, R71, R7m are each independently -OH; - Hal; -(C1-C6)alkyl unsubstituted or substituted by one or several -OH; -Hal; -O(C1-C6)alkyl un- substituted or substituted by one or several -OH; -Hal;
Hal is an F, Cl, Br, I atom.
In some embodiments, the present invention relates to a compound, wherein R2 is methylpyrazolyl, pyrazolyl, cyclohexyl, hydroxycyclohexyl, 8-oxa-3-azabicyclo[3.2.1]octane-3- yl, methanesulfonylphenyl, pyridinylpyrazolyl, l-(pyridine-4-yl)-lH-pyrazole-4-yl, l-(pyridine- 3-yl)-lH-pyrazole-4-yl, 3-methylmorpholine-4-yl, morpholinyl, cyclopropanesulfonyl, phenyl, fluorophenyl, cyanophenyl, (trifluoromethyl)phenyl, pyridinyl, indolyl, sulfamoylphenyl, car- bamoylphenyl, piperidinylpyrazolyl, l-(piperidin-4-yl)-lH-pyrazole-4-yl, dimethylpyrazolyl, 3- hydroxy-8-oxabicyclo[3.2.1]octane-3-yl, cyclopropyl, cyclobutyl, cyclopentyl, tetrahydropyridi- nyl, l,2,3,6-tetrahydropyridine-4-yl, (fluoropyridinyl)dimethylpyrazolyl, l-(5-fluoropyridine-3- yl)-3,5-dimethyl-lH-pyrazole-4-yl, l-(pyridine-3-yl)-3,5-dimethyl-lH-pyrazole-4-yl, cyanocy- clohexyl, methanesulfonylcyclopropyl, 8-oxabicyclo[3.2.1]oct-2-ene-3-yl, l-[imino(me- thyl)oxo-X6-sulfanyl]cyclopropyl, aminomethylmorpholinylpyrazolyl, carbamoylcyclohexyl, pi- peridinyl, pyrazolylindolyl, l-(lH-pyrazole-3-yl)-lH-indole-5-yl, methanesulfonyl, methylmor- phoniline, 8-oxabicyclo[3.2.1]octane-3-yl, pyridinylpiperazinyl, piperazinyl, 4-(pyridine-2- yl)piperazine-l-yl, oxaspiro[5.5]undecane-9-yl, 3-oxaspiro[5.5]undecane-9-yl, 2-ox- aspiro[3.5]nonane-7-yl, 2-thiaspiro[3.5]nonane-7-yl, oxaspiro[3.5]nonane-7-yl, thia- spiro[3.5]nonane-7-yl, 8-azabicyclo[3.2.1]octane-3-yl, 8-azabicyclo[3.2.1]octane-3-yloxy, oxa- nyl, (hydroxycyclohexyl)aminyl, tetramethyloxanyl, difluorocyclohexyl, fluorocyclohexyl, 2,2- dioxo-2k6-thiaspiro[3.5]nonane-7-yl, 4-ethyl-4-hydroxy cyclohexyl, 8-methyl-3,8-diazabicy- clo[3.2.1]octane-3-yl, 8-oxa-3-azabicyclo[3.2.1]octane-3-yl, 3,8-diazabicyclo[3.2.1]octane-3-yl, acetyl-3,8-diazabicyclo[3.2.1]octane-8-yl 3,8-diazabicyclo[3.2.1]octane-8-yl, 3-methyl-3,8-di- azabicyclo[3.2.1]octane-8-yl, 3-acetyl-3,8-diazabicyclo[3.2.1]octane-8-yl, {9-methyl-9-azabi- cyclo[3.3.1]nonane-3-yl}aminyl, {9-azabicyclo[3.3.1]nonane-3-yl}aminyl, 3-hydroxy-8-azabi- cyclo[3.2.1]octane-8-yl, 5-hydroxy-2-azabicyclo[2.2.1]heptane-2-yl, 3-methoxy-8-azabicy- clo[3.2.1]octane-8-yl, 8-azabicyclo[3.2.1]octane-8-yl, 5-methoxy-2-azabicyclo[2.2.1]heptane-2- yl, 2-azabicyclo[2.2.1]heptane-2-yl, 3-methanesulfonyl-3,8-diazabicyclo[3.2.1]octane-8-yl, 9- methyl-9-azabicyclo[3.3.1]nonane-3-yl, 9-methyl-9-azabicyclo[3.3.1]nonane-3-yl.
In some embodiments, the present invention relates to a compound wherein R3 is -H, -F, -Cl, -Br, -I, -(C1-C6)alkyl unsubstituted or substituted by one or several -Hal, -OH, -CN, -NH2;
Hal is an F, Cl, Br, I atom.
In some embodiments, the present invention relates to a compound wherein R4 is: wherein p = 0,1, 2, 3 or 4,
R4a are each independently -H, -OH, -Hal, -CN, -NH2; -(C1-C6)alkyl unsubstituted or sub- stituted by one or several -Hal, -OH, -CN, -NH2;
Hal is an F, Cl, Br, I atom.
In some embodiments, the present invention relates to a compound wherein R4 is: wherein q=0, 1 or 2,
R4a are each independently -H, -OH, -Hal, -CN, -NH2; -(C1-C6)alkyl unsubstituted or sub- stituted by one or several -Hal, -OH, -CN, -NH2;
Hal is an F, Cl, Br, I atom.
In some embodiments, the present invention relates to a compound wherein R4 is: wherein p=0, 1 or 2,
R4a are each independently -H, -OH, -Hal, -CN, -NH2; -(C1-C6)alkyl unsubstituted or sub- stituted by one or several -Hal, -OH, -CN, -NH2;
Hal is an F, Cl, Br, I atom.
In some embodiments, the present invention relates to a compound wherein R4 is:
R4a is -H, -OH, -Hal, -CN, -NH2; methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl; Hal is an F, Cl, Br, I atom.
In some embodiments, the present invention relates to a compound wherein R4 is: methylmorpholinyl, 3 -methylmorpholine, morpholinyl, 8-oxa-3-azabicyclo[3.2.1]octane-3-yl,
3-azabicyclo[3.2.1]octane-3-yl.
In some embodiments, the present invention relates to a compound wherein R5 is:
Yi, Y2 are each independently C, N or CH;
Rsa is -OH, -Hal, -CN, -NH2; -(C1-C6)alkyl unsubstituted or substituted by one or several -Hal, -OH, -CN, -NH2;
Hal is an F, Cl, Br, I atom.
In some embodiments, the present invention relates to a compound wherein R5 is:
wherein m = 0, 1, 2, 3 or 4,
Rsa is -OH, -Hal, -CN, -NH2; -(C1-C6)alkyl unsubstituted or substituted by one or several -Hal, -OH, -CN, -NH2;
Hal is an F, Cl, Br, I atom.
In some embodiments, the present invention relates to a compound wherein R5 is: wherein y = 0, or 1,
Rsa is -OH, -Hal, -CN, -NH2; -(C1-C6)alkyl unsubstituted or substituted by one or several -Hal, -OH, -CN, -NH2;
Hal is an F, Cl, Br, I atom.
In some embodiments, the present invention relates to a compound, wherein R5 is pyra- zolyl, methylpyrazolyl, imidazolyl, pyrrolyl.
Compounds, described in the present invention, may be obtained as, and/or used as, phar- maceutically acceptable salts. The type of pharmaceutical acceptable salts, include, but are not limited to: acid addition salts, formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, and the like; or with an organic acid such as formic acid, acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, trifluoroacetic acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2 -ethanedi sulfonic acid, 2-hydroxyethanedisulfonic acid, benzenesulfonic acid, toluenesulfonic acid, 2-naphtha- lenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-ene-l -carboxylic acid, glucoheptonic acid, 4,4’- methylenebis-3-hydroxy-2-ene-l -carboxylic acid, 3 -phenylpropionic acid, trimethylacetic acid, tert-butyl acetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like.
The corresponding counterions of the pharmaceutically acceptable salts may be analyzed and identified using various methods including, but not limited to, ion exchange chromatography, ion chromatography, capillary electrophoresis, inductively coupled plasma, atomic absorption spectroscopy, mass spectrometry, or any combination thereof.
The salts are recovered by using at least one of the following techniques: filtration, pre- cipitation with a non-solvent followed by filtration, evaporation of the solvent, or, in the case of aqueous solutions, lyophilization. It should be understood that a reference to a pharmaceutically acceptable salt includes the solvent addition forms or crystal forms thereof, particularly solvates or polymorphs. Solvates contain either stoichiometric or non-stoichiometric amounts of a sol- vent, and may be formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of compounds described in the pre- sent patent can be conveniently prepared or formed during the processes described in the present invention. In addition, the compounds provided in the present invention can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolv- ated forms for the purposes of the compounds and methods provided in the present invention.
Compounds described in the present invention may be provided in various forms, includ- ing but not limited to, amorphous forms, milled forms and nano-particulate forms. In addition, compounds described in the present invention include crystalline forms, also known as poly- morphs. Polymorphs include different crystal packing arrangements of the same elemental com- position of a compound. Polymorphs typically have different X-ray diffraction patterns, infrared spectra, melting points, different density, hardness, crystal shape, optical and electrical proper- ties, stability, and solubility. Various factors such as the recrystallization solvent, rate of crystal- lization, and storage temperature may cause one crystal form to dominate.
The screening and characterization of the pharmaceutically acceptable salts, polymorphs and/or solvates may be accomplished using a variety of techniques including, but not limited to, thermal analysis, x-ray diffraction, spectroscopy, vapor sorption, and microscopy. Thermal anal- ysis methods address to analysis of thermo chemical degradation or thermo physical processes including, but not limited to, polymorphic transitions, and such methods are used to analyze the relationships between polymorphic forms, to determine weight loss, to find the glass transition temperature, or for excipient compatibility studies. Such methods include, but are not limited to, differential scanning calorimetry (DSC), modulated differential scanning calorimetry (MDCS), thermogravimetric analysis (TGA), thermogravi-metric and infrared analysis (TG/IR). Crystal- lographic methods include, but are not limited to, single crystal and powder diffractometers and synchrotron sources. The various spectroscopic techniques used include, but are not limited to, Raman (combinational scattering), FTIR, UVIS, and NMR (liquid and solid state). The various microscopy techniques include, but are not limited to, polarized light microscopy, scanning elec- tron microscopy (SEM) with energy dispersive x-ray analysis (EDX), environmental scanning electron microscopy with EDX (in gas or water vapor atmosphere), IR microscopy, and Raman microscopy. In another embodiment, the present invention relates to compounds selected from the group including:
The present invention also relates to a method for inhibiting the biological activity of ataxia telangiectasia and Rad3 -related (ATR), comprising competitively binding the catalytic domain of ATR to the compound or pharmaceutically acceptable salt, solvate or stereoisomer thereof described herein.
In one embodiment, the present invention relates to a method for inhibiting the biological activity of ATR with the compound or pharmacologically acceptable salt, solvate, or stereoiso- mer thereof according to the present invention.
ATR-inhibiting compounds may be used to manufacture drug products intended for treat- ing any of the pathological conditions described herein, for example, compounds of formula I, pharmaceutically acceptable salts, solvates or stereoisomers will be useful in the treatment of diseases or medical conditions mediated, alone or partially, by ATR activity, for example, onco- logical diseases. Examples of oncological diseases that may be amenable to treatment using the above compounds include, but are not limited to, ovarian cancer, epithelial ovarian cancer, re- current platinum-refractory ovarian cancer, recurrent platinum-sensitive ovarian cancer, clear cell ovarian cancer, with BRCA 1/2, ARID1A mutations, borderline ovarian tumors; primary peritoneal cancer; fallopian tube cancer; gastric and gastroesophageal junction cancer, locally advanced unresectable, metastatic, or recurrent gastric and gastroesophageal junction cancer; head and neck tumors, unresectable, locally advanced, or metastatic head and neck tumors, re- current head and neck tumors; prostate cancer, metastatic prostate cancer, castration-resistant metastatic prostate cancer with BRCA mutations; colorectal cancer, unresectable or metastatic colorectal cancer, colon cancer, rectosigmoid junction cancer, and rectal cancer; anal cancer and perianal skin cancer; endometrial cancer, recurrent or metastatic endometrial cancer, uterine cor- pus cancer and uterine sarcomas; cervical cancer, mesothelioma of the pleura, peritoneum and other sites; pancreatic cancer, inoperable or metastatic pancreatic cancer; malignant tumors of the biliary system, advanced or metastatic cancer of the biliary tract; primary malignant tumors of bone; lung cancer, non-small cell lung cancer, small cell lung cancer; breast cancer, metastatic triple-negative breast cancer with or without BRCA mutations; cutaneous melanoma; metastatic tumors with an ATM mutation; chronic lymphocytic leukemia, myelodysplastic syndrome, chronic myelomonocytic leukemia; esophageal cancer; malignant tumors of the liver; tumors of unknown primary; renal cell carcinoma; bladder cancer and urothelial cancer; gastrointestinal stromal tumors; soft tissue sarcomas; non-melanocytic skin tumors; adrenal cortical cancer, neu- roendocrine tumors, primary CNS tumors and metastatic brain tumors, mediastinal tumors, and trophoblastic tumors.
In one embodiment, the present invention relates to a pharmaceutical composition that comprises at least one of the compounds described herein, or pharmaceutically acceptable salt, solvate, stereoisomer thereof, and one or more pharmaceutically acceptable excipients. In one embodiment, the present invention relates to a pharmaceutical composition that comprises a ther- apeutically effective amount of at least one of the compounds described herein, or pharmaceuti- cally acceptable salt, solvate, stereoisomer thereof, and one or more pharmaceutically acceptable excipients. In another one embodiment, the pharmaceutical composition comprising compounds of this invention is intended for preventing or treating a disease or disorder alone or partially mediated by ATR activity.
In another one embodiment, the pharmaceutical composition comprising compounds of the present invention is intended to prevent or treat a disease or disorder alone or partially medi- ated by ATR activity.
In another one embodiment, the pharmaceutical composition comprising compounds of the present invention is intended for producing a medicament for preventing or treating a disease or disorder alone or partially mediated by ATR activity.
In another one embodiment, the pharmaceutical composition comprising compounds of the present invention is intended for preventing or treating a disease or disorder alone or partially mediated by ATR activity, being an oncological disease.
In another one embodiment, the pharmaceutical composition comprising compounds of the present invention is intended for producing a medicament for preventing or treating a disease or disorder alone or partially mediated by ATR activity, being an oncological disease.
In another one embodiment of the present invention, the pharmaceutical composition comprising compounds of the present invention is intended to prevent or treat oncological dis- eases including ovarian cancer, epithelial ovarian cancer, recurrent platinum-refractory ovarian cancer, recurrent platinum-sensitive ovarian cancer, clear cell ovarian cancer, with BRCA 1/2, ARID 1 A mutations, borderline ovarian tumors; primary peritoneal cancer; fallopian tube cancer; gastric and gastroesophageal junction cancer, locally advanced unresectable, metastatic, or re- current gastric and gastroesophageal junction cancer; head and neck tumors, unresectable, locally advanced, or metastatic head and neck tumors, recurrent head and neck tumors; prostate cancer, metastatic prostate cancer, castration-resistant metastatic prostate cancer with BRCA mutations; colorectal cancer, unresectable or metastatic colorectal cancer, colon cancer, rectosigmoid junc- tion cancer, and rectal cancer; anal cancer and perianal skin cancer; endometrial cancer, recurrent or metastatic endometrial cancer, uterine corpus cancer and uterine sarcomas; cervical cancer, mesothelioma of the pleura, peritoneum and other sites; pancreatic cancer, inoperable or meta- static pancreatic cancer; malignant tumors of the biliary system, advanced or metastatic cancer of the biliary tract; primary malignant tumors of bone; lung cancer, non-small cell lung cancer, small cell lung cancer; breast cancer, metastatic triple-negative breast cancer with or without BRCA mutations; cutaneous melanoma; metastatic tumors with an ATM mutation; chronic lym- phocytic leukemia, myelodysplastic syndrome, chronic myelomonocytic leukemia; esophageal cancer; malignant tumors of the liver; tumors of unknown primary; renal cell carcinoma; bladder cancer and urothelial cancer; gastrointestinal stromal tumors; soft tissue sarcomas; non-melano- cytic skin tumors; adrenal cortical cancer, neuroendocrine tumors, primary CNS tumors and met- astatic brain tumors, mediastinal tumors, and trophoblastic tumors.
The pharmaceutical composition of the present invention comprises, by way of example, from about 5 wt% to about 100 wt% of active ingredients, preferably from about 10 wt% to about 60 wt% of active ingredients. It is to be understood that each dosage unit may not comprise an effective amount of an active ingredient or ingredients, because the sufficient effective amount may be achieved by administering multiple dosage unit forms.
A typical composition is prepared by mixing the compound of the present invention with a carrier, diluent or excipient. Suitable carriers, diluents and excipients are well known to those skilled in the art and include materials such as carbohydrates, waxes, water soluble and/or swella- ble polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like. The particular carrier, diluent or excipient used will depend upon the means and purpose for which compound of the present invention is being applied. Solvents are generally selected based on solvents recognized by persons skilled in the art as safe to be administered to a mammal. In general, safe solvents are aqueous solvents such as water and other solvents that are soluble or miscible in water. Suitable aqueous solvents include water, as the main ingredient, ethanol, pro- pylene glycol, polyethylene glycols (e.g., PEG400, PEG300), etc. and mixtures thereof. The compositions may also include one or more buffers, stabilizing agents, surfactants, wefting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents and other known additives to provide an elegant presentation of the drug product (i.e., compound of the present invention or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e. medicinal product). The pharmaceutical compositions should pref- erably be manufactured in compliance with the GMP (Good Manufacturing Practice) require- ments.
The pharmaceutical compositions of the present invention are typically suitable for oral administration. Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, and/or buccal, lingual, or sublingual administration by which the compound enters the blood stream directly from the mouth.
Formulations suitable for oral administration include solid, semi-solid and liquid systems such as tablets; soft or hard capsules containing multi- or nano-particulates, liquids, or powders; granules; lozenges (including liquid-filled); chews; gels; fast dispersing dosage forms; films; ov- ules; sprays; and buccal/mucoadhesive patches. More preferred formulations for oral administra- tion comprise tablets, granules, and capsules.
Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations may be employed as fillers in soft or hard capsules (made, for example, made of gelatin or hy- droxypropylmethylcellulose) and typically comprise a carrier, for example, water, ethanol, pol- yethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsify- ing agents and/or suspending agents. Liquid formulations may also be prepared by the reconsti- tution of a solid, for example, from a sachet.
The pharmaceutical compositions of the invention may also be administered parenterally. As used herein, "parenteral administration" of a pharmaceutical composition includes any route of administration characterized by physical breaching of a tissue of a subject and administration of the pharmaceutical composition through the breach in the tissue, thus generally resulting in the direct administration into the blood stream, into muscle, or into an internal organ. Parenteral administration thus includes, inter alia, administration of a pharmaceutical composition by injec- tion of the composition, by application of the composition through a surgical incision, by appli- cation of the composition through a tissue-penetrating non-surgical wound, and the like. In par- ticular, parenteral administration is contemplated to include, inter alia, subcutaneous, intraperi- toneal, intramuscular, intravenous, intraarterial, intrathecal, intraventricular, intraurethral, intra- cranial, intrasynovial injection or infusions; and kidney dialytic infusion techniques. Intratumoral delivery, e.g. intratumoral injection, may also be advantageous. R6gional perfusion is also pro- vided.
Formulations of pharmaceutical compositions suitable for parenteral administration typ- ically comprise the active ingredient combined with a pharmaceutically acceptable carrier, such as sterile water or sterile isotonic saline. Such formulations may be prepared, packaged, or sold in a form suitable for bolus administration or for continuous administration. Injectable formula- tions may be prepared, packaged, or sold in unit dosage form, such as in ampoules or in multi-dose containers containing a preservative. Formulations for parenteral administration in- clude, inter alia, suspensions, solutions, emulsions in oily or aqueous vehicles, pastes, and the like.
The compounds of the invention can also be administered intranasally or by inhalation, typically in the form of a dry powder (either alone, as a mixture, or as a mixed component parti- cle, for example, mixed with a suitable pharmaceutically acceptable excipient) from a dry powder inhaler, as an aerosol pressurised container, pump, spray, atomiser (preferably an atomiser using electrohydrodynamics to produce a fine mist), or nebuliser, with or without the use of a suitable propellant, or as nasal drops.
The pressurised container, pump, spray, atomizer, or nebuliser typically contains a solu- tion or suspension of the compound of the present invention comprising, for example, a suitable agent for dispersing, solubilising, or extending release of the active ingredient, a propellant as solvent.
Prior to use as dry powder or suspension, the drug product is typically micronised to a size suitable for delivery by inhalation (typically less than 5 microns). This may be achieved by any appropriate comminuting method, such as spiral jet milling, fluid bed jet milling, supercriti- cal fluid processing to form nanoparticles, high pressure homogenisation, or spray drying.
Capsules, blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound of the present invention, a suitable powder base and a performance modifier.
A suitable solution formulation for use in an atomiser using electrohydrodynamics to pro- duce a fine mist may contain a suitable dose of the compound of the present invention per actu- ation and the actuation volume may for example vary from 1 pL to 100 pL. Suitable flavours, such as menthol and levomenthol, or sweeteners, such as saccharin or sodium saccharin, may be added to those formulations of the present invention intended for in- haled/intranasal administration.
Formulations may be formulated to be immediate and/or modified release. Modified re- lease formulations include delayed, sustained, pulsed, controlled, targeted and programmed re- lease.
In one embodiment, the present invention relates to a method for treating a disease or disorder alone or partially mediated by ATR activity, which comprises administering, in a ther- apeutically effective amount, any compound described above, or the pharmaceutical composition of the present invention.
In one embodiment, the present invention relates to the use of the above compound for producing a medicament for treating a disease or disorder alone or partially mediated by ATR activity, which comprises administering, in a therapeutically effective amount, any compound described above, or the pharmaceutical composition of the present invention.
In yet another one embodiment, the invention relates to the method for treating described above, wherein the disease or disorder alone or partially mediated by ATR activity is an onco- logical disease. In yet another one embodiment, the invention relates to the method for treating described above, wherein the oncological disease is selected from the group comprising ovarian cancer, epithelial ovarian cancer, recurrent platinum-refractory ovarian cancer, recurrent plati- num-sensitive ovarian cancer, clear cell ovarian cancer, with BRCA 1/2, ARID 1 A mutations, borderline ovarian tumors; primary peritoneal cancer; fallopian tube cancer; gastric and gas- troesophageal junction cancer, locally advanced unresectable, metastatic, or recurrent gastric and gastroesophageal junction cancer; head and neck tumors, unresectable, locally advanced, or met- astatic head and neck tumors, recurrent head and neck tumors; prostate cancer, metastatic prostate cancer, castration-resistant metastatic prostate cancer with BRCA mutations; colorectal cancer, unresectable or metastatic colorectal cancer, colon cancer, rectosigmoid junction cancer, and rec- tal cancer; anal cancer and perianal skin cancer; endometrial cancer, recurrent or metastatic en- dometrial cancer, uterine corpus cancer and uterine sarcomas; cervical cancer, mesothelioma of the pleura, peritoneum and other sites; pancreatic cancer, inoperable or metastatic pancreatic cancer; malignant tumors of the biliary system, advanced or metastatic cancer of the biliary tract; primary malignant tumors of bone; lung cancer, non-small cell lung cancer, small cell lung can- cer; breast cancer, metastatic triple-negative breast cancer with or without BRCA mutations; cu- taneous melanoma; metastatic tumors with an ATM mutation; chronic lymphocytic leukemia, myelodysplastic syndrome, chronic myelomonocytic leukemia; esophageal cancer; malignant tu- mors of the liver; tumors of unknown primary; renal cell carcinoma; bladder cancer and urothelial cancer; gastrointestinal stromal tumors; soft tissue sarcomas; non-melanocytic skin tumors; ad- renal cortical cancer, neuroendocrine tumors, primary CNS tumors and metastatic brain tumors, mediastinal tumors, and trophoblastic tumors.
In one embodiment, the present invention relates to the use of the compound of the present invention or the above pharmaceutical composition for treating a disease or disorder alone or partially mediated by ATR activity.
In yet another one embodiment, the present invention relates to the use described above, wherein the disease or disorder alone or partially mediated by ATR activity is an oncological disease. In another one embodiment, the invention relates to the use described above, wherein the oncological disease is selected from the group comprising ovarian cancer, epithelial ovarian can- cer, recurrent platinum-refractory ovarian cancer, recurrent platinum-sensitive ovarian cancer, clear cell ovarian cancer, with BRCA 1/2, ARID1A mutations, borderline ovarian tumors; pri- mary peritoneal cancer; fallopian tube cancer; gastric and gastroesophageal junction cancer, lo- cally advanced unresectable, metastatic, or recurrent gastric and gastroesophageal junction can- cer; head and neck tumors, unresectable, locally advanced, or metastatic head and neck tumors, recurrent head and neck tumors; prostate cancer, metastatic prostate cancer, castration-resistant metastatic prostate cancer with BRCA mutations; colorectal cancer, unresectable or metastatic colorectal cancer, colon cancer, rectosigmoid junction cancer, and rectal cancer; anal cancer and perianal skin cancer; endometrial cancer, recurrent or metastatic endometrial cancer, uterine cor- pus cancer and uterine sarcomas; cervical cancer, mesothelioma of the pleura, peritoneum and other sites; pancreatic cancer, inoperable or metastatic pancreatic cancer; malignant tumors of the biliary system, advanced or metastatic cancer of the biliary tract; primary malignant tumors of bone; lung cancer, non-small cell lung cancer, small cell lung cancer; breast cancer, metastatic triple-negative breast cancer with or without BRCA mutations; cutaneous melanoma; metastatic tumors with an ATM mutation; chronic lymphocytic leukemia, myelodysplastic syndrome, chronic myelomonocytic leukemia; esophageal cancer; malignant tumors of the liver; tumors of unknown primary; renal cell carcinoma; bladder cancer and urothelial cancer; gastrointestinal stromal tumors; soft tissue sarcomas; non-melanocytic skin tumors; adrenal cortical cancer, neu- roendocrine tumors, primary CNS tumors and metastatic brain tumors, mediastinal tumors, and trophoblastic tumors.
Dosage regimens may be adjusted to provide the optimum desired response. For example, a single dose may be administered, several divided doses may be administered over time or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It is especially advantageous to formulate peroral compositions in a unit dosage form for ease of administration and uniformity of dosage. A unit dosage form as used herein refers to physically discrete units suited as unitary dosages for patients/subjects to be treated; each unit contains a predetermined quantity of active compound calculated to produce the desired thera- peutic effect in association with the desired pharmaceutical carrier. Specification for the unit dosage forms of the invention is typically dictated by and directly dependent on (a) the unique characteristics of a therapeutic agent and particular therapeutic or prophylactic effect to be achieved, and (b) the limitations inherent in the art of compounding such an active compound for the treatment of sensitivity in subjects.
Thus, a skilled artisan would appreciate, based upon the disclosure provided herein, that the doses and dosage regimen are adjusted in accordance with methods well-known in the ther- apeutic arts. That is, the maximum tolerable dose can be readily established, and the effective amount providing a detectable therapeutic effect to a patient may also be determined, as can the temporal requirements for administering each agent to provide a detectable therapeutic effect to a patient. Thus, while certain doses and administration regimens are exemplified herein, these examples in no way limit the doses and administration regimens that may be provided to a patient in practicing the embodiments of the invention.
It is to be noted that dosage values may vary with the type and severity of the condition to be alleviated, and may include single or multiple doses. Furthermore, it is to be understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the judgment of a medical professional administering or supervising the administration of the compositions, and that dosage ranges set forth in the present description are exemplary only and are not intended to limit the scope or practice of the claimed composi- tions. Furthermore, the dosage regimen with the compositions of the present invention may be based on a variety of factors, including the type of disease, age, weight, sex, medical condition of the patient, the severity of the condition, the route of administration, and the particular com- pound of the present invention employed. Thus, the dosage regimen may vary widely, but can be determined routinely using standard methods. For example, doses may be adjusted based on pharmacokinetic and pharmacodynamic parameters, which may include clinical effects such as toxic effects or laboratory values. Thus, the present invention encompasses intra-patient dose- escalation as determined by one skilled in the art. Methods for determining appropriate dosage and regimens are well-known in the art and would be understood by a skilled artisan once pro- vided the ideas disclosed herein.
Typically, doses used to treat an adult are usually in the range of 0.02-5000 mg per day, or from 1 to 1500 mg per day or from 2.5 to 800 mg per day.
Once improvement of the patient’s conditions has occurred, a maintenance dose is ad- ministered, if necessary. Subsequently, the dosage or the frequency of administration, or both, may be reduced, as a function of the symptoms, to a level at which the improved disease, disorder or condition is retained. Patients may be however required periodic treatment on a long-term basis upon any relapse of symptoms.
The foregoing ranges are merely suggestive, as the number of variables in regard to an individual treatment regime is large, and considerable excursions from these recommended val- ues are not uncommon. These dosages may be altered depending on a number of variables, not limited to the activity of the compound used, the disorder or condition to be treated, the method of administration, the requirements of the individual subject, the severity of the disorder or con- dition being treated, and the judgment of the physician.
The following examples are provided for better understanding of the invention. These examples are for purposes of illustration only and are not to be construed as limiting the scope of the invention in any manner.
All publications, patents, and patent applications cited in this specification are incorpo- rated herein by reference. Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be readily appar- ent to those of ordinary skill in the art in light of the teachings of this invention that certain changes and modifications may be made thereto without departing from the spirit or scope of the appended embodiments.
Examples
List of abbreviations:
9-BBN - 9-borabicyclo[3.3.1]nonane
AcOH - acetic acid
DCM - dichloromethane
DIPEA - diisopropylamine
DMEDA - 1,2-dimethylethylenediamine
DMF - dimethylformamide DMSO - dimethyl sulfoxide DPEPhos - [oxidi(2,l-phenylene)]bis(diphenylphosphine) LAH - lithium aluminium hydride MeCN - acetonitrile Mel - methyl iodide
MeOH - methanol
MTBE - methyl tert-butyl ether
MW - micro wave radiation
NCS - N-chlorosuccinimide
NIS - N-iodosuccinimide
Pd(dppf)C12 - l,r-bis(diphenylphosphino)ferrocene)palladium(II) di chloride
Pd(OAc)2 - palladium(II) acetate
Pd(PPh3)4 - tetrakis(triphenylphosphine)palladium
PTSA*H2O - para-toluenesulfonic acid hydrate
RuPhos - 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl
TBAF*H2O - tetrabutylammonium fluoride hydrate
TEA - triethylamine
TFA - trifluoroacetic acid
TFAA - trifluoroacetic anhydride
THF - tetrahydrofuran
THP - 2-tetrahydropyranyl
XantPhos - (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine)
Example 1. Synthesis of compounds 1.7 and 1.11
Synthesis of compound 1.2 ) Synthesis of aldoxime
A suspension of compound 1.1 (16.7 g, 60.8 mmol) and hydroxylamine hydro- chloride (4.70 g, 66.9 mmol) in 130 mL of FEO was stirred at 90 °C for 4 h. After cooling the reaction mixture, a precipitate formed, which was filtered off, washed with H2O, and the residual solvent was removed under reduced pressure. ) Synthesis of nitrile
The resulting residue was suspended in 300 mL of DCM; TFAA (17.1 mL, 122 mmol) and then TEA (17.0 mL, 122 mmol) were added dropwise at 0°C. The reaction mixture was stirred at room temperature for 2 h. After standard treatment, the product was isolated using column chromatography on silica gel. The yield was 14.2 g (88%) of compound 1.2.
Synthesis of compound 1.4
A mixture of compound 1.2 (4.70 g, 16.8 mmol), amine 1.3 (2.57 g, 18.5 mmol), K2CO3 (4.69 g, 33.6 mmol) in 25 mL of DMSO was stirred at 100 °C in a closed vessel for 1 h. After standard treatment, the product was isolated using column chromatography on silica gel. The yield was 5.34 g (92%) of compound 1.4.
Synthesis of compound 1.5
A mixture of compound 1.4 (16.4 g, 45.3 mmol), hydrazine hydrate (11.1 mL, 227 mmol) in 165 mL of terLbutanol was stirred at 110 °C in a closed vessel for 5 h. After standard treatment, the product was isolated using column chromatography on silica gel. The yield was 12.6 g (78%) of compound 1.5.
Synthesis of compound 1. 7
A suspension of compound 1.5 (0.300 g, 0.790 mmol), boronic ester 1.6 (0.232 g, 1.11 mmol), Pd(dppf)C12 (0.059 g, 0.080 mmol), K2CO3 (0.441 g, 3.16 mmol) in a mixture of 3.6 mL of 1,4-dioxane and 0.9 mL of water was stirred at 100 °C for 2 h. After standard treatment, the product was isolated using column chromatography on silica gel. The yield was 0.235 g (95%) of compound 1.7.
Synthesis of compound 1.9
Compound 1.9 was prepared in a similar manner to compound 1.4 from compounds 1.2 and 1.8, the yield was 96%.
Synthesis of compound 1.10
Compound 1.10 was prepared in a similar manner to compound 1.5, the yield was 67%.
Synthesis of compound 1.11
Compound 1.11 was prepared in a similar manner to compound 1.7, the yield was 48%.
Example 2. Synthesis of compound ATR 1248
Synthesis of compound 2.1
To a solution of compound 1.7 (0.335 g, 1.05 mmol), PTSA*H2O (0.605 g, 3.15 mmol) in 7 mL of MeCN dropwise while stirring added was a solution ofNaNCh (0.159 g, 2.31 mmol), KI (0.458 g, 2.73 mmol) in 2 mL of water at 0 °C. The mixture was then stirred at room temper- ature for 8 h. After standard treatment, the product was isolated using column chromatography on silica gel. The yield was 0.150 g (34%) of compound 2.1.
Synthesis of compound 2.2
A mixture of compound 2.1 (0.155 g, 0.350 mmol), Cui (0.067 g, 0.350 mmol), K3PO4 (0.306 g, 1.40 mmol), 1,10-phenanthroline (0.096 g, 0.520 mmol) in 7 mL ofMeOH was stirred in a microwave synthesizer at 95 °C for 1 h 20 min. After standard treatment, the product was isolated using column chromatography on silica gel. The yield was 0.110 g (96%) of compound 2.2.
Synthesis of compound 2.4
A mixture of compound 2.2 (0.110 g, 0.330 mmol), pyrazole 2.3 (0.114 g, 0.400 mmol), Cui (0.032 g, 0.160 mmol), 1,10-phenanthroline (0.060 g, 0.330 mmol), K2CO3 (0.138 g, 0.990 mmol) in 2 mL of DMSO was stirred at 100 °C for 3 h in a microwave synthesizer. After standard treatment, the product was isolated using column chromatography on silica gel. The yield was 0.146 g (95%) of compound 2.4.
Synthesis of compound ATR 1248
Compound 2.4 (0.146 g, 0.290 mmol) was dissolved in 3 mL of DCM, TFA (2.30 mL, 29.0 mmol) was added, the mixture was stirred for 12 h. After standard treatment, the product was isolated using preparative HPLC. The yield was 0.092 g (81%) of compound ATR_1248.
Example 3. Synthesis of compounds ATR 1305, ATR 1306, ATR 1308, ATR 1309, ATR 1312, ATR 1314, ATR 1315, ATR 1316, ATR 1318, ATR 1319, ATR 1321, ATR 1322, ATR 1325, ATR 1326, ATR 1327, ATR 1354, ATR 1356 and ATR 1406
3.3 ATR_1327 ATR_1354
Synthesis of compound 3.2
Compound 3.2 was prepared in a similar manner to compound 1.7 from compounds 1.5 and 3.1, the yield was 96%.
Synthesis of compound 3.3
Compound 3.3 was prepared in a similar manner to compound 2.4, the yield was 81%.
Synthesis of compound ATR l 327 Compound ATR_1327 was prepared in a similar manner to compound ATR_1248, the yield was 50%.
Synthesis of compound ATR l 354
Hydrogen was passed through a mixture of compound ATR_1327 (0.050 g, 0.120 mmol) and Pd/C 10% (0.013 g, 0.012 mmol) in 50 mL of ethanol at 50 °C. After completion of the reaction (conversion monitoring by HPLC-MS) and standard work-up, the product was isolated using preparative HPLC. The yield was 0.017 g (37%).
The following compounds were prepared in three stages in a similar manner to compound ATR_1327 using compound 1.5 and corresponding starting reagents at the first stage:
*the first stage of the synthesis of compound ATR_1325 employed the following condi- tions: MW at 150 °C for 2 h.
Example 4. Synthesis of compounds ATR 1249, ATR 1330 and ATR 1339
Synthesis of compound 4.1 Compound 4.1 was prepared in a similar manner to compound 2.4, the yield was 76%.
Synthesis of compound ATR 1249
Compound ATR_1249 was prepared in a similar manner to compound ATR_1248, the yield was 29%.
The following compounds were prepared in two stages in a similar manner to compound ATR_1249 using corresponding starting reagents at the first stage:
Synthesis of compounds 5.1 and 5.2
To a suspension of compound 4.1 (0.350 g, 0.730 mmol) in 10 mL of DMF added was NaH (0.053 g, 1.31 mmol) at 0 °C and stirred at room temperature for 1 h. Subsequently, io- doethane (0.099 mL, 1.17 mmol) was added at 0 °C and stirred at room temperature for 12 h. After standard treatment, the products were isolated using column chromatography on silica gel. The yield was 0.190 g (53%) of compound 5.1 and 0.098 g (27%) of compound 5.2.
Synthesis of compound ATR l 328
Compound ATR_1328 was prepared in a similar manner to compound ATR_1248, the yield was 64%.
Synthesis of compound ATR l 329
Compound ATR_1329 was prepared in a similar manner to compound ATR_1248, the yield was 65%.
The following compounds were prepared in two stages in a similar manner to compounds ATR_1328 and ATR_1329 using compound 4.1 and iodomethane at the first stage:
Example 6. Synthesis of compounds ATR 1294, ATR 1295, ATR 1364, ATR 1365 and ATR 1366
Synthesis of compound 6.1
To a solution of compound 4.1 (0.157 g, 0.330 mmol), DIPEA (0.352 mL, 1.98 mmol) in 4 mL of DCM dropwise added was a solution of acetyl chloride (0.071 mL, 0.990 mmol) in 2 mL of DCM at 0 °C and stirred for 1 h. Then K2CO3 (0.230 g, 1.65 mmol) and 3 mL of MeOH were added. After standard treatment, the product was isolated using column chromatography on silica gel. The yield was 0.161 g (96%) of compound 6.1.
Synthesis of compound ATR l 294
Compound ATR_1294 was prepared in a similar manner to compound ATR_1248, the yield was 71%.
The following compounds were prepared in two stages in a similar manner to compound ATR_1294 using compound 4.1 and corresponding starting reagents at the first stage:
Example 7. Synthesis of compound ATR 1297 Synthesis of compound 7.1
To a solution of compound 4.1 (0.652 g, 1.35 mmol) in 8.5 mL of H2SO4 and 10 mL of H2O dropwise added was a solution of NaNO2 (0.336 g, 4.73 mmol) in 3 mL of H2O at 0 °C and stirred for 1 h. Then a solution of KI (3.06 g, 18.2 mmol) in 7 mL of H2O was added. The reaction mixture was then heated to room temperature and stirred for 30 min. After standard treatment, the product was isolated using column chromatography on silica gel. The yield was 0.422 g (54%) of compound 7.1.
Synthesis of compound 7.2
A mixture of compound 7.1 (0.120 g, 0.200 mmol), sodium methanesulfmate (0.083 g, 0.800 mmol), Cui (0.019 g, 0.100 mmol) in 4 mL of DMF was stirred in a microwave synthesizer at 180 °C for 1 h. After standard treatment, the product was isolated using column chromatog- raphy on silica gel. The yield was 0.085 g (81%) of compound 7.2.
Synthesis of compound ATR l 297
Compound ATR_1297 was prepared in a similar manner to compound ATR_1248, the yield was 35%.
Example 8. Synthesis of compound ATR 1298
Synthesis of compound 8.1
A mixture of compound 7.1 (0.146 g, 0.240 mmol), dimethylphosphine oxide (0.039 g, 0.480 mmol), Pd(OAc)2 (0.008 g, 0.040 mmol), XantPhos (0.044 g, 0.070 mmol), K2CO3 (0.134 g, 0.960 mmol) in 4 mL of 1,4-dioxane was stirred at 100 °C for 3 h. After standard treatment, the product was isolated using column chromatography on silica gel. The yield was 0.085 g (68%) of compound 8.1.
Synthesis of compound ATR l 298
Compound ATR_1298 was prepared in a similar manner to compound ATR_1248, the yield was 56%.
Example 9. Synthesis of compounds ATR 1320 and ATR 1323
Synthesis of compound 9.2
Compound 9.2 was prepared in a similar manner to compound 1.7 from compounds 1.5 and 9.1, the yield was 97%.
Synthesis of compound 9.3
Compound 9.3 was prepared in a similar manner to compound 2.4, the yield was 51%.
Synthesis of compound 9.4
A mixture of compound 9.3 (0.225 g, 0.350 mmol), TBAF*H2O (0.460 g, 1.40 mmol), ethylenediamine (0.284 mL, 4.20 mmol) in 5 mL of DMF was stirred at 115 °C for 8 h. After standard treatment, the product was isolated using column chromatography. The yield was 0.127 g (81%) of compound 9.4.
Synthesis of compound ATR l 320
Compound ATR_1320 was prepared in a similar manner to compound ATR_1248, the yield was 42%.
Compound ATR_1323 was prepared in four stages in a similar manner to compound ATR_1320 using, at the first stage, compound 1.5 and 3,5-dimethyl-4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolane-2-yl)-{[2-(trimethylsilyl)ethoxy]methyl}-lH-pyrazole. The yields at the first, second, third and fourth stages were 64%, 41%, 75% and 43%, respectively.
Example 10. Synthesis of compound ATR 1313
Synthesis of compound 10.1 A suspension of compound 1.5 (2.10 g, 5.55 mmol), hexamethyldistannane (3.31 g, 9.99 mmol), Pd(PPh3)4 (0.842 g, 0.720 mmol) in 30 mL of 1,4-dioxane was stirred at 100 °C for 16 h. After standard treatment, the product was isolated using column chromatography on silica gel. The yield was 2.16 g (98%) of compound 10.1.
Synthesis of compound 10.2
A suspension of compound 10.1 (0.320 g, 0.770 mmol), 2-iodobenzonitrile (0.450 g, 1.92 mmol), Pd(PPhs)4 (0.090 g, 0.080 mmol), Cui (0.044 g, 0.230 mmol) in 8 mL of DMF was stirred at 100 °C for 1 h. After standard treatment, the product was isolated using column chromatog- raphy on silica gel. The yield was 0.143 g (56%) of compound 10.2.
Synthesis of compound 10.3
Compound 10.3 was prepared in a similar manner to compound 2.4, the yield was 38%.
Synthesis of compound ATR 1313
Compound ATR_1313 was prepared in a similar manner to compound ATR_1248, the yield was 34%.
Example 11. Synthesis of compounds ATR 1302, ATR 1303, ATR 1381, ATR 1383, ATR 1385, ATR 1407, ATR 1411, ATR 1412, ATR 1415 and ATR 1416
11.10 Synthesis of compound 11.2
Compound 11.2 was prepared in a similar manner to compound 1.7 from compounds 1.5 and 1.11, the yield was 89%.
Synthesis of compound 11.3
Compound 11.3 was prepared in a similar manner to compound 2.4, the yield was 64%.
Synthesis of compound 11.4
Hydrogen was passed at 50 °C through a mixture of compound 11.3 (0.090 g, 0.180 mmol) and Pd(OH)2/C 20% (0.013 g, 0.018 mmol) in 50 mL of ethanol. After completion of the reaction (conversion control by HPLC-MS) and standard work-up, the product was isolated by silica gel column chromatography. The yield was 0.084 g (97%) of compound 11.4.
Synthesis of compound ATR l 302
Compound ATR_1302 was prepared in a similar manner to compound ATR_1248, the yield was 58%.
Synthesis of compound 11.5
Compound 11.5 was prepared in a similar manner to compound ATR_1248, the yield was 72% using column chromatography.
Synthesis of compound ATR l 303
To a solution of compound 11.5 (0.121 g, 0.300 mmol), iron(II) phthalocyanine (0.189 g, 0.300 mmol) in 30 mL of ethanol while passing oxygen portionwise added was NaBHj (0.058 g, 1.50 mmol) and the mixture was stirred at room temperature for 18 h. After standard treatment, the product was isolated using preparative HPLC. The yield was 0.016 g (13%) of compound ATR 1303
Synthesis of compound 11.7
To a solution of diisopropylamine (0.564 mL, 3.95 mmol) in 20 mL of THF added was dropwise 1.40 mL (3.50 mmol) of a 2.5 M solution of //-butyl lithium in hexane at -78 °C, the mixture was stirred at the same temperature for 30 min. Next, a solution of compound 11.6 (0.500 g, 3.04 mmol) in 5 mL of THF was added dropwise, the mixture was stirred at the same temper- ature for 30 min. Then a solution of N-phenyl-bis(trifluoromethanesulfonimide) (1.45 g, 4.04 mmol) in 5 mL of THF was added, the mixture was stirred at the same temperature for 30 min, then at room temperature for 2 h. After standard treatment, the product was isolated using column chromatography. The yield was 0.780 g (89%) of compound 11.7.
Synthesis of compound 11.8
To a solution of compound 11.7 (0.420 g, 1.38 mmol) in 11 mL of DCM added was 3- chloroperoxybenzoic acid (0.750 g, 3.04 mmol), the mixture was stirred at room temperature for 1 h. After standard treatment, the product was isolated using column chromatography. The yield was 0.429 g (97%) of compound 11.8.
Synthesis of compound 11.9
A suspension of compound 11.8 (0.379 g, 1.12 mmol), bis(pinacolato)diboron (0.350 g,
I.35 mmol, KOAc (0.341 g, 3.37 mmol) and Pd(dppf)C12 (0.017 g, 0.022 mmol) in 5 mL of DMSO was stirred at 90 °C for 2 h. After standard treatment, the product was isolated using column chromatography. The yield was 0.294 g (88%) of compound 11.9.
Synthesis of compound 11.10
Compound 11.10 was prepared from compound 11.7 in a similar manner to compound
II.9 in 88% yield.
The following compounds were prepared in four stages in a similar manner to compound ATR_1302 using compound 1.5 and corresponding starting reagents at the first stage:
*the third stage of the synthesis of compounds ATR_1383, ATR_1411, ATR_1412 em- ployed the following conditions: a mixture of a starting preproduct (1 equiv), Pd/C 10% (0.2 equiv), Pd(OH)2/C 20% (0.1 equiv) and NaBEU (5 equiv), heating in a closed vessel at 50 °C, conversion monitoring by HPLC-MS;
**at the fourth stage of the synthesis of compound ATR 1416, spiro[2.5]octan-6-yl was converted into 4-ethyl-4-hydroxy cyclohexyl as a result of the opening of the cyclopropane ring.
Example 12. Synthesis of compounds ATR 1311 and ATR 1360
Synthesis of compound 12.1
A mixture of compound 1.5 (0.300 g, 0.790 mmol), sodium methanesulfmate (0.086 g, 0.830 mmol), Cui (0.03 g, 0.160 mmol), DMEDA (0.047 mL, 0.400 mmol) in 6 mL DMSO was stirred at 100 °C in a closed vessel for 4.5 h. After standard treatment, the product was isolated using column chromatography on silica gel. The yield was 0.174 g (71%) of compound 12.1.
Synthesis of compound 12.2
Compound 12.2 was prepared in a similar manner to compound 2.4, the yield was 74%.
Synthesis of compound ATR l 360
Compound ATR_1360 was prepared in a similar manner to compound ATR_1248, the yield was 32%.
Compound ATR_1311 was prepared in three stages in a similar manner to compound ATR_1360 using, at the first stage, compound 1.5 and sodium cyclopropanesulfinate. The yield at the first, second, and third stages was 43%, 88%, and 23%, respectively.
Example 13. Synthesis of compounds ATR 1363 and ATR 1370
Synthesis of compound 13.1
A mixture of compound 7.1 (0.248 g, 0.370 mmol), pyrrolidin-2-one (3.18 g, 3.70 mmol), Cui (0.071 g, 0.370 mmol), K2CO3 (0.517 g, 3.70 mmol), TMEDA (0.087 g, 0.740 mmol) was stirred in a microwave synthesizer at 120 °C for 2 h. After standard treatment, the product was isolated using column chromatography on silica gel. The yield was 0.180 g (91%) of compound 14.1
Synthesis of compound A TR 1370
Compound ATR_1370 was prepared in a similar manner to compound ATR_1248, the yield was 80%.
Synthesis of compound ATR l 363
A mixture of compound ATR_1370 (0.036 g, 0.078 mmol) and 9-BBN (0.780 mL, 0.390 mmol) in 1 mL of THF was stirred at 100°C for 24 h in a closed vessel. After standard treatment, the product was isolated using preparative chromatography. The yield was 0.007 g (19%) of compound ATR_1363.
Example 14. Synthesis of compound ATR 1317
Synthesis of compound 14.2
Compound 14.2 was prepared in a similar manner to compound 1.7 from compounds 1.5 and 14.1, the yield was 98%.
Synthesis of compound 14.3
Compound 14.3 was prepared in a similar manner to compound 2.4, the yield was 58%.
Synthesis of compound 14.4
Compound 14.4 was prepared in a similar manner to compound ATR_1248, the yield was 93%, using column chromatography.
Synthesis of compound ATR l 317
A mixture of compound 14.4 (0.180 g, 0.301 mmol) and NaOH (0.060 g, 1.50 mmol) in 6 mL of MeOH and 3 mL of H2O was stirred at room temperature for 16 h. After standard treat- ment, the product was isolated using preparative chromatography. The yield was 0.055 g (50%) of compound ATR_1317.
Example 15. Synthesis of compounds ATR 1304 and ATR 1310
Synthesis of compound 15.1
A mixture of compound 1.4 (1.13 g, 3.22 mmol), compound 1.8 (0.944 g, 6.12 mmol), Pd(OAc)2 (0.111 g, 0.483 mmol), DPEPhos (0.531 g, 0.967 mmol) and Cs2CO3 (4.45 g, 13.5 mmol) in 113 mL of toluene was stirred at 105 °C for 3 h. After standard treatment, the product was isolated using column chromatography. The yield was 0.284 g (27%) of compound 15.2.
Synthesis of compound 15.2
Compound 15.2 was prepared in a similar manner to compound 1.5 , the yield was 61%.
Synthesis of compound 15.3
Compound 15.3 was prepared in a similar manner to compound 2.4, the yield was 83%.
Synthesis of compound ATR l 304
Compound ATR_1304 was prepared in a similar manner to compound ATR_1248, the yield was 7%.
Compound ATR_1310 was prepared in four stages in a similar manner to compound ATR_1304 using, at the first stage, compound 1.4 and morpholine. The yield at the first, second, third, and fourth stages was 33%, 70%, 74%, and 34%, respectively.
Example 16. Synthesis of compound ATR 1465 .
Synthesis of compound 16.1
To a solution of compound 15.2 (0.605 g, 1.72 mmol) portionwise added was at -10 °C NCS (0.249 g, 1.81 mmol), the mixture was stirred for 30 min. After standard treatment, the product was isolated using column chromatography. The yield was 0.108 g (17%) of compound 16.1
Synthesis of compound 16.2 Compound 16.2 was prepared in a similar manner to compound 2.4 , the yield was 67%.
Synthesis of compound ATR 1465
Compound ATR_1465 was prepared in a similar manner to compound ATR_1248, the yield was 12%.
Example 17. Synthesis of compounds ATR 1324, ATR 1350 and ATR 1361
Synthesis of compound 17.2
Compound 17.2 was prepared in a similar manner to compound 1.7, the yield was 83%.
Synthesis of compound 17.3
Compound 17.3 was prepared in a similar manner to compound 2.4, the yield was 87%.
Synthesis of compound 17.4
Compound 17.4 was prepared in a similar manner to compound ATR_1354, the yield was 82% without the use of preparative HPLC.
Synthesis of compound ATR l 361
Compound ATR_1361 was prepared in a similar manner to compound ATR_1248 in the form of a mixture of isomers of ATR_1361_a and ATR_1361_b, the yield was 43%.
Synthesis of compound 17.5
Compound 17.5 was prepared in a similar manner to compound ATR_1303, the yield was 96% without the use of preparative HPLC.
Synthesis of compound ATR l 324
Compound ATR_1324 was prepared in a similar manner to compound ATR_1248 in the form of a mixture of isomers of ATR_1324_a and ATR_1324_b in a ratio of 81 : 19 (according to chiral HPLC), the yield was 22%.
Synthesis of compound ATR 1350
Compound ATR_1350 was prepared in a similar manner to compound ATR_1248 in the form of a mixture of isomers of ATR_1350_a and ATR_1350_b in a ratio of 52:48 (according to chiral HPLC), the yield was 50%.
Example 18. Synthesis of compounds ATR 1459, ATR_1459_b, ATR 1460 and ATR 1461
Synthesis of compound 18.3
A mixture of compound 18.1 (12.0 g, 49.7 mmol), amine 18.2 (7.01 mL, 61.7 mmol), and triethylamine (10.2 g, 99.5 mmol) in 100 mL of DMSO was stirred at 90 °C for 3 h. After standard treatment, the product was isolated using column chromatography. The yield was 13.6 g (85%) of compound 18.3.
Synthesis of compound 18.5
A mixture of compound 18.3 (2.00 g, 5.90 mmol), compound 18.4 (1.55 g, 7.08 mmol), Pd(OAc)2 (0.135 g, 0.590 mmol), RuPhos (0.567 g, 1.18 mmol) and CS2CO3 (3.30 g, 10.0 mmol) in 30 mL of 1,4-di oxane was stirred at 105 °C for 2 h. After standard treatment, the product was isolated using column chromatography. The yield was 2.39 g (99%) of compound 18.5.
Synthesis of compound 18.6
To a solution of compound 18.5 (2.43 g, 5.67 mmol) in 61 mL of DMF added was por- tionwise at -5 °C NIS (1.44 g, 6.36 mmol), the mixture was stirred at the same temperature for 1.5 h. After standard treatment, the yield was 3.00 g (99%) of compound 18.6.
Synthesis of compound 18.7
A mixture of compound 18.6 (3.07 g, 5.49 mmol), Zn(CN)2 (0.789 g, 6.58 mmol) and Pd(PPhs)4 in 46 mL of DMF was stirred in a closed vessel at 100 °C for 4 h. After standard treatment, the product was isolated using column chromatography. The yield was 1.90 g (80%) of compound 18.7.
Synthesis of compound 18.8 Compound 18.8 was prepared in a similar manner to compound 1.5, the yield was 99%.
Synthesis of compound 18.9
Compound 18.9 was prepared in a similar manner to compound 2.4, the yield was 51%.
Synthesis of compound ATR 1459
Compound ATR_1459 was prepared in a similar manner to compound ATR_1248, the yield was 32%.
Synthesis of compound ATR_1459_b
Compound ATR_1459 (0.041 g, 0.100 mmol) was dissolved in 2 mL of DCM, a solution of salicylic acid (0.014 g, 0.100 mmol) in 2 mL of DCM was added, the solvent was evaporated, the precipitate was washed with MTBE. The yield was 0.053 g (98%) of compound ATR 1459 a
Synthesis of compound 18.10
Compound 18.7 (0.050 g, 0.114 mmol) was dissolved in 2 mL of DCM, TFA (0.439 mL, 5.68 mmol) was added, the mixture was stirred at room temperature for 5 h. After standard treat- ment, the yield was 0.037 g (99%) of compound 18.10.
Synthesis of compound 18.11
To a solution of compound 18.10 (0.489 g, 1.43 mmol) in 13 mL of DCM added was DIPEA (1.53 mL, 8.59 mmol), then acetyl chloride (0.155 mL, 2.15 mmol) was added dropwise at 0 °C, and stirred at the same temperature for 30 min. After standard treatment, the yield was 0.530 g (99%) of compound 18.11.
Synthesis of compound 18.12
Compound 18.12 was prepared in a similar manner to compound 1.5, the yield was 85%.
Synthesis of compound 18.13
Compound 18.13 was prepared in a similar manner to compound 2.4, the yield was 17%.
Synthesis of compound ATR 1461
Compound ATR_1461 was prepared in a similar manner to compound ATR_1248, the yield was 4%.
Synthesis of compound 18.14
To a solution of compound 18.10 (0.589 g, 1.69 mmol) and AcOH (0.196 mL, 3.39 mmol) in a mixture of 10 mL of DCM and 5 mL of MeOH added was 37% aqueous formaldehyde solution (0.381 mL, 5.08 mmol), and stirred at room temperature for 1 h. Then the reaction mix- ture was cooled to 0 °C, NaBEL (0.131 g, 3.39 mmol) was added portionwise, and stirred at the same temperature for 1 h. After standard treatment, the yield was 0.580 g (99%) of compound 18.14.
Synthesis of compound 18.15
Compound 18.15 was prepared in a similar manner to compound 1.5, the yield was 99%.
Synthesis of compound 18.16
Compound 18.16 was prepared in a similar manner to compound 2.4, the yield was 99%.
Synthesis of compound ATR 1460
Compound ATR_1460 was prepared in a similar manner to compound ATR_1248, the yield was 16%.
Example 19. Synthesis of compounds ATR 1410, ATR 1463, ATR 1464, ATR 1467, ATR 1470, ATR 1471 and ATR 1482
Synthesis of compound 19.1
A mixture of compound 1.4 (9.00 g, 24.6 mmol) and CsF (26.5 g, 172 mmol) in 200 mL of DMSO was stirred at 90 °C for 3 h. After standard treatment, the product was isolated using column chromatography. The yield was 4.81 g (82%) of compound 19.1.
Synthesis of compound 19.3
A mixture of compound 19.1 (2.00 g, 7.94 mmol), compound 19.2 (1.06 g, 7.94 mmol) and DIPEA (4.14 mL, 23.8 mmol) in 40 mL of DMSO was stirred at 90 °C for 1.5 h. After standard treatment, the product was isolated using column chromatography. The yield was 1.23 g (45%) of compound 19.3.
Synthesis of compound 19.4
Compound 19.4 was prepared in a similar manner to compound 1.5, the yield was 99%.
Synthesis of compound 19.5
Compound 19.5 was prepared in a similar manner to compound 2.4, the yield was 80%.
Synthesis of compound ATR l 464
Compound ATR_1464 was prepared in a similar manner to compound ATR_1248, the yield was 17%.
Synthesis of compound 19.6
To a solution of compound 19.3 (0.350 g, 0.980 mmol) in 4 mL of DMF added was at 0 °C Mel (0.616 mL, 9.80 mmol), then NaH (0.078 g, 1.96 mmol), the reaction mixture was stirred at 0 °C for 30 min and brought to room temperature. After standard treatment, the product was isolated using column chromatography. The yield was 0.271 g (77%) of compound 19.6.
Synthesis of compound 19.7
Compound 19.7 was prepared in a similar manner to compound 1.5, the yield was 99%.
Synthesis of compound 19.8
Compound 19.8 was prepared in a similar manner to compound 2.4, the yield was 46%.
Synthesis of compound ATR 1470
Compound ATR_1470 was prepared in a similar manner to compound ATR_1248, the yield was 23%.
The following compounds were prepared in four stages in a similar manner to compound ATR_1464 using compound 19.1 and corresponding starting reagents at the first stage:
Example 20. Synthesis of compounds ATR 1417, ATR 1418, ATR 1419,
ATR 1420, ATR 1492, ATR 1493 and ATR 1494
Synthesis of compound 20.1
A mixture of compound 15.3 (0.237 g, 0.460 mmol) and ethyl formate (7.88 mL, 96.6 mmol) was stirred in a closed vessel at 105 °C for 120 h. After completion of the reaction, the reaction mixture was cooled, the product was filtered off and washed with MTBE. The yield was 0.179 g (75%) of compound 20.1.
Synthesis of compound 20.2 Compound 20.2 was prepared in a similar manner to compound ATR_1248, the yield was 42% without the use of preparative HPLC.
Synthesis of compound ATR l 417
To a solution of compound 20.2 (0.060 g, 0.109 mmol) in 1 mL of THF added was LAH (0.264 g, 0.657 mmol), the mixture was stirred at 60 °C for 3 h. After standard treatment, the product was isolated using preparative HPLC. The yield was 0.017 g (37%) of compound ATR 1417
Synthesis of compound 20.3
To a solution of compound 15.3 (0.300 g, 0.588 mmol) in 9 mL of DMF added was NaH (0.042 g, 1.06 mmol), and stirred at room temperature for 1 h. The reaction mixture was then cooled to 0 °C and added was Mel (0.059 mL, 0.941 mmol), and stirred at room temperature for 2 h. After standard treatment, the product was isolated using column chromatography. The yield was 0.153 g (50%) of compound 20.3.
Synthesis of compound A TR I 418
Compound ATR_1418 was prepared in a similar manner to compound ATR_1248, the yield was 50%.
Synthesis of compound 20.4
Compound 20.4 was prepared in a similar manner to compound 6.1, the yield was 85%.
Synthesis of compound ATR 1420
Compound ATR_1420 was prepared in a similar manner to compound ATR_1248, the yield was 57
Synth
Compound ATR_1419 was prepared in a similar manner to compound ATR_1417, the yield was 38%.
The following compounds were prepared in three stages in a similar manner to compound ATR_1417 using corresponding starting reagents at the first stage:
Synthesis of compound ATR l 494
Compound ATR_1494 was prepared in three stages in a similar manner to compound
ATR_1419 using, at the first stage, compound 18.16. The yields at the first, second, and third stages were 99%, 91%, and 63%, respectively.
Example 21. Synthesis of compound ATR 1337
Synthesis of compound 21.2
Compound 21.2 was prepared in a similar manner to compound 19.3, the yield was 83%.
Synthesis of compound 21.3
Compound 21.3 was prepared in a similar manner to compound 1.7, the yield was 87%.
Synthesis of compound 21.4
Compound 21.4 was prepared in a similar manner to compound 1.5, the yield was 60%.
Synthesis of compound 21.5
Compound 21.5 was prepared in a similar manner to compound 2.4, the yield was 70%.
Synthesis of compound A TR 1337
Compound ATR_1337 was prepared in a similar manner to compound ATR_1248, the yield was 45%.
Example 22. Analysis of resulting compounds.
The purity and structure of the resulting compounds was confirmed by chromatog- raphy/mass spectrometry LS/MS-ESI and 1H NMR spectroscopy (Table 1).
Equipment data:
Table 1. Chromatography/mass spectrometry
Table 2. NMR spectrometer
Table 3. Analytical data for exemplary compounds
Table 4. Analytical data for exemplary compounds
Example 17. Inhibition of activity of recombinant human ATR protein in vitro.
The ability of the compounds of the present invention to inhibit the activity of the ATR/ ATRIP kinase complex (Eurofins/DiscoverX, order no. 14-953M) was determined using the Amplified Luminescent Proximity Homogenous Assay (AlphaScreen) detection system from PerkinElmer.
The kinase reaction was carried out in a 9 pl volume using a 384-well plate (Corning Inc., order no. 4513). Test substances were titrated from 10 pM in increments of 4 at 10 concentration points in a normal strength kinase buffer A (Thermo Fisher Scientific Inc, order no. PV3189) supplemented with DTT (Sigma, order no. 646563-10X.5ML) and prepared with water (Panreac, order no. 701074). A solution of a mixture of the ATR/ ATRIP complex and GST-p53 substrate (Eurofins/DiscoverX, order no. 14-952M) was prepared in a similar buffer, mixed with test com- pounds in plate wells and preincubated for 10 minutes at 25 °C.
After the incubation time, the substrate phosphorylation reaction was initiated by adding an ATP solution (Signal Chem, order no. V915B) prepared in a normal strength kinase buffer. The plate was centrifuged at 400 ref in a centrifuge (Eppendorf, 5804 R) for one minute and incubated for 60 minutes at 25 °C.
After the incubation time, a detection solution comprising AlphaScreen Glutathione Do- nor beads (PerkinElmer, order no. 6765301), AlphaScreen Protein A Acceptor beads (Perki- nElmer, order no. 6760137M) and Anti-p53 (phospho S15) antibody (Abeam, order no. abl431) prepared in a buffer comprising Tris Base (Sigma- Aldrich, order no. 741883), EDTA Disodium Salt (Panreac, order no. 131669) and Bovine Serum Albumin (BSA) (Thermo Fisher, order no. B14) according to the PerkinElmer protocol. The mixture was incubated for 120 minutes, detec- tion was performed using EnSight Multimode Plate R6ader, PerkinElmer. IC50 value was calcu- lated using Graphpad Prism 9.0 by approximating experimental points by four-parameter model with the optimization by Levenberg-Marquardt:
A — D y = o + - y— ,
1 + $)B where A is the upper asymptote; D is the lower asymptote; C is IC50, half-maximal in- hibitory concentration of kinase, nM; B is the curvature (slope).
Table 5. R6sults of biochemical assay for inhibition of activity of recombinant human ATR protein in vitro. IC50 is shown as a mean value from the data of multiple measurement series, "A" for IC50 < lOnM, "B" for lOnM < IC50 < 50nM, "C" for 50nM < IC50 < lOOnM.
Table 6. R6sults of biochemical assay for inhibition of activity of recombinant human ATR protein in vitro. IC50 is shown as a mean value from the data of multiple measurement series, the values are given in nM.
R6sults of this experiment show the production of compounds with high inhibitory activ- ity against the ATR protein in vitro.
Example 18. Inhibition of activity of recombinant human ATM protein in vitro.
The ability of the compounds of the present invention to inhibit the activity of the ATM kinase (Eurofins/DiscoverX, order no. 14-933) was determined using the Amplified Luminescent Proximity Homogenous Assay (AlphaScreen) detection system from PerkinElmer.
The kinase reaction was carried out in a 9 pl volume using a 384-well plate (Corning Inc., order no. 4513). Test substances were titrated from 10 pM in increments of 5 at 10 concentration points in a normal strength kinase buffer A (Thermo Fisher Scientific Inc, order no. PV3189) supplemented with DTT (Sigma, order no. 646563-10X.5ML) and prepared with water (Panreac, order no. 701074). A solution of a mixture of the ATM protein and GST-p53 substrate (Eu- rofins/DiscoverX, order no. 14-952M) was prepared in a similar buffer, mixed with test com- pounds in plate wells and preincubated for 10 minutes at 25 °C.
After the incubation time, the substrate phosphorylation reaction was initiated by adding an ATP solution (Signal Chem, order no. V915B) prepared in a normal strength kinase buffer. The plate was centrifuged at 400 ref in a centrifuge (Eppendorf, 5804 R) for one minute and incubated for 60 minutes at 25 °C.
After the incubation time, a detection solution comprising AlphaScreen Glutathione Do- nor beads (PerkinElmer, order no. 6765301), AlphaScreen Protein A Acceptor beads (Perki- nElmer, order no. 6760137M) and Anti-p53 (phospho S15) antibody (Abeam, order no. abl431) prepared in a buffer comprising Tris Base (Sigma- Aldrich, order no. 741883), EDTA Disodium Salt (Panreac, order no. 131669) and Bovine Serum Albumin (BSA) (Thermo Fisher, order no. B14) according to the PerkinElmer protocol. The mixture was incubated for 240 minutes, detec- tion was performed using EnSight Multimode Plate R6ader, PerkinElmer. IC50 value was calcu- lated using Graphpad Prism 9.0 by approximating experimental points by four-parameter model with the optimization by Levenberg-Marquardt.
Table 7. R6sults of biochemical assay for inhibition of activity of recombinant human ATM protein in vitro. IC50 is shown as a mean value from the data of multiple measurement series, "C" for IC50 < 50nM, "B" for 50nM < IC50 < 500nM, "A" for IC50 > 500nM.
The results of this experiment confirm production of compounds selective for ATM ki- nase.
Example 19. Antiproliferative activity against sensitive cell lines in vitro.
Antiproliferative activity of the ATR inhibitors of the present invention was measured in a cellular assay on continuous cultures of HCT 116 cells (colorectal cancer, ATCC® CCL- 247™) and ES-2 cells (ovarian cancer, ATCC® CRL-1978™) using the AlamarBlue vital dye (Thermo Fisher Scientific Inc, order no. DALI 100). The cells were grown in DMEM, powder, high glucose (Gibco, order no. 12100061) and RPMI-1640 (PanEco, order no. C330n), respec- tively. The basal growth medium was enriched with L-glutamine at a concentration of 2 mM (PanEco, order no. Q032), 10% and 5% fetal bovine serum (Gibco, order no. 16140-071), re- spectively. The night before the measurement, HCT 116 and ES-2 adherent cells were removed from the plastic with a trypsin-EDTA solution (PanEco, order no. H043n) which was thereafter inactivated with a complete DMEM or RPMI-1640 medium, respectively, centrifuged at 1000 RPM (Eppendorf, 5804 R), a cell suspension was prepared in a complete DMEM medium for HCT 116 and RPMI-1640 medium for ES-2 and added to 96-well culture plates (ServiceBio Inc, order no. CCP-96H) at 2 * 103 cells (HCT 116) and 1 * 103 cells (ES-2) in 100 pL of me- dium per well. The next day, test compounds were dissolved in DMSO and diluted with com- plete medium to a final concentration ranging from 30 pM to 0.1 nM for the HCT 116 cell line and from 10 pM to 5 pM for the ES-2 cell line. Diluted compounds in a volume of 100 pl were introduced into the plate wells with cells in triplicates (the final concentration of DMSO was no more than 1%) and incubated at 37 °C in an incubator with 5% CO2 for 72 hours. After the in- cubation, 20 mL of the AlamarBlue reagent was added to the wells, the contents of the plates were stirred in an orbital shaker (Biosan, Latvia), then further incubated for 5.5-6 hours at 37 °C in an incubator with 5% CO2. The number of viable cells was detected using the EnSight™ Multimode Microplate R6ader microplate spectrophotometer (PerkinElmer) by way of measur- ing a fluorescent signal at an excitation wavelength (ZEx) of 540 nm and an emission wave- length (ZEm) of 590 nm.
IC50 value was calculated using GraphPad Prism by approximating experimental points by four-parameter model with the optimization by Levenberg-Marquardt.
Table 8. R6sults of antiproliferative assay on HCT 116 and ES-2 cell lines. IC50 is shown as a mean value from the data of multiple measurement series, "A" for IC50 < lOOnM, "B" for lOOnM < IC50 < 500nM, "C" for IC50 > 500nM, "N/A" means that a given compound was not analyzed in the present test.
Table 9. R6sults of antiproliferative assay on HCT 116 and ES-2 cell lines. IC50 is shown as a mean value from the data of multiple measurement series, the values are given in nM, "N/A"
R6sults of these experiments show the preparation of compounds capable of stopping the growth of sensitive cell lines HCT 116 and ES-2 at nM concentrations.
Example 20. General cytotoxicity against primary HepaRG liver cells in vitro.
General cytotoxicity of ATR inhibitors according to the present invention was investi- gated using primary differentiated HepaRG cells (Biopredic Int, order no. HPR101). 2 weeks before the measurement, the cells were thawed and maintained in Basal hepatic cell medium (Biopredic Int, order no. MIL700079) supplemented with HepaRG maintenance/metabolism me- dium supplement with antibiotics (Biopredic Int, order no. ADD620C). The medium in vials with cells was changed every 2-3 days. The night before the test, the cells were plated in wells of 96- well plates (ServiceBio Inc., order no. CCP-96H) at 25* 103 cells in 100 pL of medium per well. The next day, test compounds were introduced into plate wells with cells, untitrated at a concen- tration ranging from 100 pM to 5 nM, and incubated for 72 hours. Cell viability was assessed as described above.
Table 10. R6sults of general toxicity investigation on primary HepaRG cells. IC50 is shown as a mean value from the data of multiple measurement series, "A" for IC50 > 10 pM, "B" for 10 pM > IC50 > 1 pM, and "C" for IC50 < 1 pM.
R6sults of this experiment confirm production of compounds that are non-toxic in the human hepatocyte model.
Example 21. Determination of passive membrane permeability through PAMPA artifi- cial membrane.
Passive membrane permeability of the compounds described in the present invention was determined using the PAMPA (parallel artificial membrane permeability assay) model at pH 7.4. We used a 96-well plate (Corning® BioCoat® Pre-coated PAMPA Plate System, order no. 353015), composed of acceptor and donor parts with cell membrane-modeling PVDF filter pre- impregnated with a lecithin-phospholipid bilayer. The substance (at a concentration of 10 pM) in a 0.01 M phosphate buffer with pH 7.4 was introduced into a donor well of the plate, and pure buffer was introduced into an acceptor well; afterwards, the both parts were combined and incu- bated for 20 hours at room temperature so that the compound was redistributed between the two wells and the membrane. Verapamil (USP, USA, order no. 1711202) and propranalol (MCE LLC, USA, order no. HY-B0573/CS-2680) were used as control compounds with high and me- dium permeability. The samples were analyzed by reversed-phase HPLC with UV detection (Ag- ilent 1260 chromatograph with UV detector) by way of determining the peak areas thereof in the donor and acceptor cells, then calculating the permeability (Pe, cm/s) and retention factor (R, %) in the lipid bilayer.
Table 11. R6sults of investigation of passive permeability through PAMPA lipid mem- brane model. Pe is shown as a mean value from the data of multiple measurement series, "A" for Pe > 5 - 10-6 cm/s, "B" for 5 - 10-6 cm/s > Pe > 1 • 10-6 cm/s, and "C" for Pe < 1 • 10-6 cm/s.
R6sults of these experiments confirm production of compounds capable of passively pen- etrating a lipid membrane.
Example 22. Determination of cellular permeability using Caco-2 model.
Caco-2 cell culture (ATCC® HTB-37™, human colorectal adenocarcinoma) at passage 50-100 was planted in clean 24-well plates (Thermo Fisher Scientific, 141002) coated with type I collagen (Sigma, C3867) at 5 pg/cm2. The culture was differentiated for 21 days in DMEM medium (Gibco, 12800082) + 10% FBS (Gibco, 26140079). Integrity of the cell monolayer was checked by the level of passage of the Lucifer Yellow dye (Thermo Fisher Scientific, L453). The fluorescence signal was measured on an Ensight microplate reader (PerkinElmer, USA) with excitation and emission wavelengths of 480 nm and 530 nm, respectively. For determination of forward and reversed transport, used were 10 pM solutions of candidates and standards (chlor- promazine, etoposide, propranolol, vinblastine) prepared in buffer (Hanks' solution + 1% BSA (Amresco, 0332-100) + 10 mM HEPES (PanEco, QI 34) + 15 mM D-glucose (Panreac, 143140.1210), pH 7.4) with a final DMSO concentration of 1%. Plates with samples were incu- bated in a CO2 incubator on a shaker at 225 rpm for 2 hours. Subsequently, 100 pL of aliquots were taken from the apical (A) and basal (B) chambers and added to 300 pL of acet on it rile: meth- anol (3: 1 v/v) solution comprising the analytical internal standard (200 ng/mL tolbutamide). Samples were then centrifuged to remove the precipitated protein, supernatants were analyzed using HPLC-MS/MS to determine the concentration of the compound in the samples. The Ag- ilent 6410 mass spectrometer (Agilent, USA) combined with the Agilent 1260 Infinity II HPLC liquid chromatograph (Agilent, USA) and a cooling autosampler controlled by MassHunter soft- ware (Agilent, USA) was used as an HPLC-MS/MS system. Chromatographic analysis was per- formed on a Cl 8 reversed-phase HPLC column (Agilent, Waters or equivalent) in a gradient elution mode in a system of mobile phases: 0.1% formic acid in acetonitrile / 0.1% formic acid in water, flow rate: 0.5 mL/min, Tcoiunm =350 °C. Mass spectrometric detection was performed with electrospray ionization (ESI) in multiple reaction monitoring (MRM) mode. Precursor ions, fragment ions and collision energies for each substance were selected experimentally.
Permeability values for forward and reversed transport were calculated using the formula: where Papp is the effective permeability constant, m/s, Va is the volume of the acceptor solution, Area is the membrane surface area (Thermo - 0.47 cm2), t is the retention time (2 hours = 7200 s), cd(0) is the concentration of the analyte solution in the donor cell at the initial moment of time, pM, ca^ is the concentration of the analyte solution in the acceptor cell after 2 hours, pM.
Efflux values were calculated using the formula: where Papp B-A is the value of reverse permeability, Papp A-B is the value of forward permeability.
Table 12. R6sults of determination of cellular permeability using Caco-2 model. Papp A-B is shown as a mean value from the data of multiple measurement series, "A" for PappA-B > 10-10 6 cm/s, "B" for 10-10 6 cm/s > Papp A-B > 5-10 6 cm/s, and "C" for Papp A-B < 5-10 6 cm/s.
The parameter efflux is shown as "+" for efflux < 5, for efflux > 5.
R6sults of these experiments show the preparation of compounds that are permeable (B) and highly permeable (A) on the Caco-2 cell model.
Example 23. In vitro microsomal stability study of compounds in human and mouse mi- crosomes.
The procedure for investigating the metabolism of selected compounds was carried out in microsomal fractions of the liver (of human and mice) in the presence of a phase I metabolism cofactor (NADPH).
The rate of enzymatic decomposition of the compound in liver microsomes in in vitro analysis was determined by keeping a reaction mixture comprising 0.5 mg/mL pooled human or mouse liver microsomes (XenoTech, USA, order no. H2610, order no. M1000), 1 pM test com- pound, 1.5 mM P-nicotinamide adenine dinucleotide (Carbosynth, UK, order no. NN108711101) and 1.5 mM magnesium chloride in 0.1 M sodium phosphate buffer (pH 7.4) in a solid-state thermostat at 37 °C. Incubation was carried out in three replicates.
To determine the stability of compounds under sample preparation conditions, prepared was an aliquot in two replicates with the test compound and a microsomal fraction devoid of the NADPH cofactor, which was incubated for 40 minutes at 37 °C.
R6actions were stopped at 0, 10, 20, 30 and 40 min time points by way of adding an ice mixture of acetonitrile:methanol (3: 1) comprising an internal standard.
Samples were then centrifuged to remove the precipitated protein, supernatants were an- alyzed using HPLC-MS/MS to determine in vitro clearance (CLint) of the compounds. The Ag- ilent 6410 mass spectrometer (Agilent, USA) combined with the Agilent 1260 Infinity II HPLC liquid chromatograph (Agilent, USA) and a cooling autosampler controlled by MassHunter soft- ware (Agilent, USA) was used as an HPLC-MS/MS system. Chromatographic analysis was per- formed on a Cl 8 reversed-phase HPLC column (Agilent, Waters or equivalent) in a gradient elution mode in a system of mobile phases: 0.1% formic acid in water / 0.1% formic acid in acetonitrile, flow rate: 0.5 mL/min, Tcoiunm =350 °C. Mass spectrometric detection was performed with electrospray ionization in multiple reaction monitoring mode. Precursor ions, fragment ions and collision energies for each substance were selected experimentally. A graph of dependence of the logarithmic ratio between substance's peak area and internal standard's peak area vs time was built. The dependent coefficient of this line corresponded to the elimination rate constant k, on the basis of which the in vitro clearance value CLint was calculated: Based on resulting in vitro clearance CLint values, the microsomal stability of the selected compounds for humans and mice was concluded.
Table 13. Stability results of selected compounds in vitro in human (RLM) and mouse (MLM) microsomes. CLint is shown as a mean value from multiple measurements, "A" for CLint < 20 pl/(min-mg of protein), "B" for 50 pl/(min-mg of protein)> CLint > 20 pl/(min-mg of protein), "C" for CLint > 50 pl/(min-mg of protein), and "N/A" means that a given compound
R6sults of these experiments confirm production of compounds resistant (B) and highly resistant (A) to the activity of human and mouse liver microsomal enzymes.
Example 24. In vitro assay for determining chemical stability of compounds in simulated biological media.
Chemical stability of the candidates was determined in simulated gastric fluid (SGF, pH 1.0-1.4) and simulated intestinal fluid (SIF, pH 7.4-7.6).
A candidate was incubated in selected simulated media for 4 hours at 37 °C. Difference in the peak area for the time zero candidate and the candidate following 4-hour incubation in a respective medium was determined chromatographically.
Substance stability in each medium was calculated using the formula: 100 where S is substance stability in the respective medium, At=4 is the value of the peak area of test candidate solution in the chromatogram after the incubation time, At=0 is the value of the peak area of test candidate solution in the chromatogram at the initial moment in time. Table 14. R6sults of chemical stability in vitro of selected compounds in simulated in- testinal fluid (SIF) and gastric fluid (SGF). S is shown as a mean value from the data of multi- ple measurement series, "A" for S > 80%, "B" for 80% > S > 50%, "C" for S < 50%.
The results of these experiments confirm the production of compounds that are highly stable (A) in simulated biological media.
Example 25. Pharmacokinetic study of compounds following oral administration in mice.
From the compounds of the present invention prepared was a homogeneous suspension supplemented with 1% DMSO and 0.2% HPMC and it was administered to outbred nonlinear laboratory mice ICR (CD-I) at 10 mg/kg by oral gavage. Blood samples were collected at 0.5, 1, 2, 4, 6, 8, 12 and 24 h. Concentrations of the compounds were determined by HPLC-MS/MS.
Pharmacokinetic parameters of the compounds are shown in Table 15:
Table 15
Note: kel is the terminal rate constant for elimination of substance from plasma; Tl/2 is the terminal half-life which is the time after which half of the mass of a medicinal substance is eliminated from plasma. Tmax is time to maximum concentration of a medicinal substance in plasma; Cmax is maximum concentration of a medicinal substance in blood plasma; AUCo-t is area under the pharmacokinetic "medicinal substance concentration - time" curve from the mo- ment of administration to the last measured concentration; AUCo-inf is area under the pharmaco- kinetic "medicinal substance concentration - time" curve from the moment of administration to infinity; MRT is mean retention time for the medicinal substance in the body; Fabs - absolute bioavailability of a substance following oral administration.
It follows from the results that the compounds being the subject of the present invention have good absorption following oral administration and high exposure in mice.

Claims

Claims or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein Ri is -NRiaRib, -S(O)2Ric, -P(O)RidRie, -ORu;
Ria, Rib, Rif are each independently -H, -(C1-C6)alkyl unsubstituted or substituted by one or several
R6a; -C(O)(C1-C6)alkyl unsubstituted or substituted by one or several R6b; -S(O)2(C1-C6)alkyl unsubstituted or substituted by one or several R6c; -(C3-C8)cycloalkyl unsubstituted or substituted by one or several R6a; -C(O)(C3-C8)cycloalkyl unsubstituted or substituted by one or several R6e; - S(O)2(C3-C8)cycloalkyl unsubstituted or substituted by one or several R6f;
Ria and Rib together with the nitrogen atom they are attached to form a 3-7 membered heterocycle with 1 or 2 N atoms, unsubstituted or substituted by one or several R6g;
Ric, Rid, Rie are each independently -(C1-C6)alkyl unsubstituted or substituted by one or several
R6h, -(C3-C8)cycloalkyl unsubstituted or substituted by one or several R6i;
R2 is
5-10 membered heteroaryl with 1,2,3 or 4 heteroatoms selected from N, S or O unsubstituted or substituted by one or several R2a;
-(C3-C8)cycloalkyl unsubstituted or substituted by one or several R2b;
-(C3-C8)cycloalkyl unsubstituted or substituted by one or several R2b, forming a spiro compound with a 4-10 membered heterocyclyl with 1,2,3 or 4 heteroatoms selected from N, S or O, unsubstituted or substituted by one or several R2c, or -(C3-C8)cycloalkyl unsubstituted or substituted by one or several R2d;
-(C3-C8)cycloalkyl unsubstituted or substituted by one or several R2b, forming a bridged-ring compound with -(CH2)I-4- unsubstituted or substituted by one or several R2e;
4-10-membered heterocyclyl, with 1,2,3 or 4 heteroatoms selected from N, S or O, unsubstituted or substituted by one or several R2f;
4-10-membered heterocyclyl, with 1,2,3 or 4 heteroatoms selected from N, S or O, unsubstituted or substituted by one or several R2f, forming a bridged-ring compound with -(CH2)I-4- unsubstituted or substituted by one or several R26;
4-10-membered heterocyclyl with 1,2,3 or 4 heteroatoms selected from N, S or O, unsubstituted or substituted by one or several R2f, forming a spiro compound with a 4-10 membered heterocyclyl with 1,2,3 or 4 heteroatoms selected from N, S or O, unsubstituted or substituted by one or several R2f, or -(C3-C8)cycloalkyl unsubstituted or substituted by one or several R2d;
6-10-membered aryl unsubstituted or substituted by one or several R2g;
6-10-membered aryl unsubstituted or substituted by one or several R2g, fused with 5-6 membered heteroaryl with 1,2 or 3 atoms selected from N, S or O, unsubstituted or substituted by one or several R2h;
-S(O)2R2i;
-NR2jR2k; -(C1-C6)alkyl unsubstituted or substituted by one or several R2m;
R2a, R2b, R2C, R2d, R2e, R2f, R2g, R2h, R21, R2j, R2k, R21, R2m are each independently -H, -OH, =0; - Hal, -CN, -NR7aR7b, -C(O)NR7cR7d; -S(O)2R7e; -S(O)2NR7fR7g; -S(O)(NH)R7g; -(Ci-C6)alkyl unsubstituted or substituted by one or several R7h; -O(C1-C6)alkyl unsubstituted or substituted by one or several R7i; -C(O)(C1-C6)alkyl unsubstituted or substituted by one or several R7i; -C(O)O(Ci- Ce)alkyl unsubstituted or substituted by one or several R7i; -(C3-C8)cycloalkyl unsubstituted or substituted by one or several R7j; -O(C3-C8)cycloalkyl unsubstituted or substituted by one or several R7j; 4-10-membered heterocyclyl with 1,2,3 or 4 heteroatoms selected from N, S or O, unsubstituted or substituted by one or several R7k; 4-10-membered heterocyclyl with 1,2,3 or 4 heteroatoms selected from N, S or O, unsubstituted or substituted by one or several R7k, forming a bridged-ring compound with -(CH2)I-4- unsubstituted or substituted by one or several R7I; 5-6-membered heteroaryl with 1,2 or 3 N atoms, unsubstituted or substituted by one or several R7m;
R3 is -H; -Hal; -CN; -NO2, -NH2; -(C1-C6)alkyl unsubstituted or substituted by one or several -OH, - Hal, -CN; -N02, -NH2;
R4 is morpholinyl unsubstituted or substituted by one or several R4a; morpholinyl unsubstituted or substituted by one or several R4a, forming a bridged-ring compound with -(CH2)O-4- unsubstituted or substituted by one or several R4t>;
R4a, R4b are each independently -H, -OH, -Hal, -CN, -NH2; -(C1-C6)alkyl unsubstituted or substituted by one or several -Hal, -OH, -CN, -NH2;
R5 is
5-6-membered heteroaryl with 1,2 or 3 N atoms, unsubstituted or substituted by one or several Rsa;
Roa is -OH, -Hal, -CN, -NH2; -(C1-C6)alkyl unsubstituted or substituted by one or several -Hal, -OH, -CN, -NH2;
R6a, R6b, R6c, R6a, Rse, R6f, Rsg, R6h, Rsi are each independently -OH, =0, -Hal, -CN, -NH2, -(Ci- Ce)alkyl unsubstituted or substituted by one or several -Hal, -OH, -CN, -NH2; -O(C1-C6)alkyl unsubstituted or substituted by one or several -Hal, -OH, -CN, -NH2;
R7a, R7b, R7C, R7d, R7e, R7f, R7g, R7h, R7i, R7j, R7k, R7I, R7m are each independently -H, -OH; -Hal; - (C1-C6)alkyl unsubstituted or substituted by one or several -OH; -Hal; -O(C1-C6)alkyl unsubstituted or substituted by one or several -OH; -Hal;
Hal is an F, Cl, Br, I atom.
2. The compound of claim 1, which is a compound of formula II
II or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein Ri is -NRiaRib, -S(0)2Ric, -P(O)RidRie, -ORu;
Ria, Rib, Ru are each independently -H, -(C1-C6)alkyl unsubstituted or substituted by one or several
R6a; -C(O)(C1-C6)alkyl unsubstituted or substituted by one or several R6b; -S(0)2(C1-C6)alkyl unsubstituted or substituted by one or several R6c; -(C3-C8)cycloalkyl unsubstituted or substituted by one or several R6a; -C(O)(C3-C8)cycloalkyl unsubstituted or substituted by one or several R6e; - S(O)2(C3-C8)cycloalkyl unsubstituted or substituted by one or several R6r;
Ria and Rib together with the nitrogen atom they are attached to form a 3-7 membered heterocycle with 1 or 2 N atoms, unsubstituted or substituted by one or several R6g;
Ric, Rid, Rie are each independently -(C1-C6)alkyl unsubstituted or substituted by one or several
R6h, -(C3-C8)cycloalkyl unsubstituted or substituted by one or several R6i;
R2 is
5-10 membered heteroaryl with 1,2,3 or 4 heteroatoms selected from N, S or O unsubstituted or substituted by one or several R2a;
-(C3-C8)cycloalkyl unsubstituted or substituted by one or several R2b;
-(C3-C8)cycloalkyl unsubstituted or substituted by one or several R2b, forming a spiro compound with a 4-10 membered heterocyclyl with 1,2,3 or 4 heteroatoms selected from N, S or O, unsubstituted or substituted by one or several R2c, or -(C3-C8)cycloalkyl unsubstituted or substituted by one or several R2d;
-(C3-C8)cycloalkyl unsubstituted or substituted by one or several R2b, forming a bridged-ring compound with -(CH2)I-4- unsubstituted or substituted by one or several R7e;
4-10-membered heterocyclyl, with 1,2,3 or 4 heteroatoms selected from N, S or O, unsubstituted or substituted by one or several R2L
4-10-membered heterocyclyl, with 1,2,3 or 4 heteroatoms selected from N, S or O, unsubstituted or substituted by one or several R2f, forming a bridged-ring compound with -(CH2)I-4- unsubstituted or substituted by one or several R7e;
4-10-membered heterocyclyl with 1,2,3 or 4 heteroatoms selected from N, S or O, unsubstituted or substituted by one or several R2f, forming a spiro compound with a 4-10 membered heterocyclyl with 1,2,3 or 4 heteroatoms selected from N, S or O, unsubstituted or substituted by one or several R2f, or -(C3-C8)cycloalkyl unsubstituted or substituted by one or several R2d;
6-10-membered aryl unsubstituted or substituted by one or several R2g;
6-10-membered aryl unsubstituted or substituted by one or several R2g, fused with 5-6 membered heteroaryl with 1,2 or 3 atoms selected from N, S or O, unsubstituted or substituted by one or several R2h;
-S(O)2R2i;
-NR2jR2k;
-OR21;
-(C1-C6)alkyl unsubstituted or substituted by one or several R2m;
R2a, R2b, R2C, R2d, R2e, R2f, R2g, R2h, R21, R2j, R2k, R21, R2m are each independently -H, -OH, =0; - Hal, -CN, -NR7aR7b, -C(O)NR7cR7d; -S(O)2R7e; -S(O)2NR7fR7g; -S(O)(NH)R7g; -(C1-C6)alkyl unsubstituted or substituted by one or several R7h; -O(C1-C6)alkyl unsubstituted or substituted by one or several R7i; -C(O)(C1-C6)alkyl unsubstituted or substituted by one or several R7i; -C(O)O(Ci- Ce)alkyl unsubstituted or substituted by one or several R7i; -(C3-C8)cycloalkyl unsubstituted or substituted by one or several R7j; -O(C3-C8)cycloalkyl unsubstituted or substituted by one or several R7j; 4-10-membered heterocyclyl with 1,2,3 or 4 heteroatoms selected from N, S or O, unsubstituted or substituted by one or several R7k; 4-10-membered heterocyclyl with 1,2,3 or 4 heteroatoms selected from N, S or O, unsubstituted or substituted by one or several R7k, forming a bridged-ring compound with -(CH2)I-4- unsubstituted or substituted by one or several R7I; 5-6-membered heteroaryl with 1,2 or 3 N atoms, unsubstituted or substituted by one or several R7m; R3 is -H; -Hal; -CN; -NO2, -NH2; -(C1-C6)alkyl unsubstituted or substituted by one or several -OH, - Hal, -CN; -NO2, -NH2;
R4 is morpholinyl unsubstituted or substituted by one or several R4a; morpholinyl unsubstituted or substituted by one or several R4a, forming a bridged-ring compound with -(CH2)O-4- unsubstituted or substituted by one or several R4t>;
R4a, R4b are each independently -H, -OH, -Hal, -CN, -NH2; -(C1-C6)alkyl unsubstituted or substituted by one or several -Hal, -OH, -CN, -NH2;
Rsa is -OH, -Hal, -CN, -NH2; -(C1-C6)alkyl unsubstituted or substituted by one or several -Hal, -OH, -CN, -NH2;
R6a, R6b, R6c, R6a, 6e, R6f, R6g, R6h, Rsi are each independently -OH, =0, -Hal, -CN, -NH2, -(Ci- Ce)alkyl unsubstituted or substituted by one or several -Hal, -OH, -CN, -NH2; -O(C1-C6)alkyl unsubstituted or substituted by one or several -Hal, -OH, -CN, -NH2;
R7a, R7b, R7c, R7d, R7e, R7f, R7g, R7h, R7i, R7j, R7k, R71, R7m are each independently -H, -OH; -Hal; - (C1-C6)alkyl unsubstituted or substituted by one or several -OH; -Hal; -O(C1-C6)alkyl unsubstituted or substituted by one or several -OH; -Hal;
Hal is an F, Cl, Br, I atom.
3. The compound of claim 1, which is a compound of formula III
III or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein Ri is -NRiaRib, -S(O)2Ric, -P(O)RidRie, -ORu;
Ria, Rib, Rif are each independently -H, -(C1-C6)alkyl unsubstituted or substituted by one or several
R6a; -C(O)(C1-C6)alkyl unsubstituted or substituted by one or several R6b; -S(O)2(C1-C6)alkyl unsubstituted or substituted by one or several R6c; -(C3-C8)cycloalkyl unsubstituted or substituted by one or several R6a; -C(O)(C3-C8)cycloalkyl unsubstituted or substituted by one or several R6e; - S(O)2(C3-C8)cycloalkyl unsubstituted or substituted by one or several R6f;
Ria and Rib together with the nitrogen atom they are attached to form a 3-7 membered heterocycle with 1 or 2 N atoms, unsubstituted or substituted by one or several R6g;
Ric, Rid, Rie are each independently -(C1-C6)alkyl unsubstituted or substituted by one or several
R6h, -(C3-C8)cycloalkyl unsubstituted or substituted by one or several R6i;
R2 is
5-10-membered heteroaryl with 1,2,3 or 4 heteroatoms selected from N, S or O, unsubstituted or substituted by one or several R2a;
-(C3-C8)cycloalkyl unsubstituted or substituted by one or several R2b;
-(C3-C8)cycloalkyl unsubstituted or substituted by one or several R2b, forming a spiro compound with a 4-10 membered heterocyclyl with 1,2,3 or 4 heteroatoms selected from N, S or O, unsubstituted or substituted by one or several R2c, or -(C3-C8)cycloalkyl unsubstituted or substituted by one or several R2d;
-(C3-C8)cycloalkyl unsubstituted or substituted by one or several R2b, forming a bridged-ring compound with -(CH2)I-4- unsubstituted or substituted by one or several R7c;
4-10-membered heterocyclyl, with 1,2,3 or 4 heteroatoms selected from N, S or O, unsubstituted or substituted by one or several Fbr;
4-10-membered heterocyclyl, with 1,2,3 or 4 heteroatoms selected from N, S or O, unsubstituted or substituted by one or several R2f, forming a bridged-ring compound with -(CH2)I-4- unsubstituted or substituted by one or several R7c;
4-10-membered heterocyclyl with 1,2,3 or 4 heteroatoms selected from N, S or O, unsubstituted or substituted by one or several R2f, forming a spiro compound with a 4-10 membered heterocyclyl with 1,2,3 or 4 heteroatoms selected from N, S or O, unsubstituted or substituted by one or several R2f, or -(C3-C8)cycloalkyl unsubstituted or substituted by one or several R2d;
6-10-membered aryl unsubstituted or substituted by one or several R2g;
6-10-membered aryl unsubstituted or substituted by one or several R2g, fused with 5-6 membered heteroaryl with 1,2 or 3 atoms selected from N, S or O, unsubstituted or substituted by one or several R2h;
-S(O)2R2i;
-NR2jR2k;
-OR21;
-(C1-C6)alkyl unsubstituted or substituted by one or several R2m;
R2a, R2b, R2C, R2d, R2e, R2f, R2g, R2h, R21, R2j, R2k, R21, R2m are each independently -H, -OH, =0; - Hal, -CN, -NR7aR7b, -C(O)NR7cR7d; -S(O)2R7e; -S(O)2NR7fR7g; -S(O)(NH)R7g; -(Ci-C6)alkyl unsubstituted or substituted by one or several R7h; -O(C1-C6)alkyl unsubstituted or substituted by one or several R7i; -C(O)(C1-C6)alkyl unsubstituted or substituted by one or several R7i; -C(O)O(Ci- Ce)alkyl unsubstituted or substituted by one or several R7i; -(C3-C8)cycloalkyl unsubstituted or substituted by one or several R7j; -O(C3-C8)cycloalkyl unsubstituted or substituted by one or several R7j; 4-10-membered heterocyclyl with 1,2,3 or 4 heteroatoms selected from N, S or O, unsubstituted or substituted by one or several R7k; 4-10-membered heterocyclyl with 1,2,3 or 4 heteroatoms selected from N, S or O, unsubstituted or substituted by one or several R7k, forming a bridged-ring compound with -(CH2)I-4- unsubstituted or substituted by one or several R7I; 5-6-membered heteroaryl with 1,2 or 3 N atoms, unsubstituted or substituted by one or several R7m;
R3 is -H; -Hal; -CN; -NO2, -NH2; -(C1-C6)alkyl unsubstituted or substituted by one or several -OH, - Hal, -CN; -NO2, -NH2;
R4a, R4b are each independently -H, -OH, -Hal, -CN, -NH2; -(C1-C6)alkyl unsubstituted or substituted by one or several -Hal, -OH, -CN, -NH2; , - Ce)alkyl unsubstituted or substituted by one or several -Hal, -OH, -CN, -NH2; -O(C1-C6)alkyl unsubstituted or substituted by one or several -Hal, -OH, -CN, -NH2;
R7a, R7b, R7C, R7d, R7e, R7f, R7g, R7h, R7i, R7j, R7k, R7I, R7m are each independently -H, -OH; -Hal; - (C1-C6)alkyl unsubstituted or substituted by one or several -OH; -Hal; -O(C1-C6)alkyl unsubstituted or substituted by one or several -OH; -Hal; Hal is an F, Cl, Br, I atom.
4. The compound of claim 3, wherein
(i) if d=0, then the compound of formula III will relate to the compound:
Illa; or
(ii) if d=l, then the compound of formula III will relate to the compound:
Illb; or
(iii) if d=2, then the compound of formula III will relate to the compound:
IIIc, or to a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein Ri is -NRiaRib, -S(O)2Ric, -P(O)RidRie, -ORu;
Ria, Rib, Rif are each independently -H, -(C1-C6)alkyl unsubstituted or substituted by one or several
R6a; -C(O)(C1-C6)alkyl unsubstituted or substituted by one or several R6b; -S(O)2(C1-C6)alkyl unsubstituted or substituted by one or several R6c; -(C3-C8)cycloalkyl unsubstituted or substituted by one or several R6a; -C(O)(C3-C8)cycloalkyl unsubstituted or substituted by one or several R6e; - S(O)2(C3-C8)cycloalkyl unsubstituted or substituted by one or several R6f;
Ria and Rib together with the nitrogen atom they are attached to form a 3-7 membered heterocycle with 1 or 2 N atoms, unsubstituted or substituted by one or several R6g;
Ric, Rid, Rie are each independently -(C1-C6)alkyl unsubstituted or substituted by one or several
R6h, -(C3-C8)cycloalkyl unsubstituted or substituted by one or several R6i;
R2 is 5-10 membered heteroaryl with 1,2,3 or 4 heteroatoms selected from N, S or O unsubstituted or substituted by one or several R2a;
-(C3-C8)cycloalkyl unsubstituted or substituted by one or several R2t>;
-(C3-C8)cycloalkyl unsubstituted or substituted by one or several R2b, forming a spiro compound with a 4-10 membered heterocyclyl with 1,2,3 or 4 heteroatoms selected from N, S or O, unsubstituted or substituted by one or several R2c, or -(C3-C8)cycloalkyl unsubstituted or substituted by one or several R2d;
-(C3-C8)cycloalkyl unsubstituted or substituted by one or several R2b, forming a bridged-ring compound with -(CH2)I-4- unsubstituted or substituted by one or several R7c;
4-10-membered heterocyclyl, with 1,2,3 or 4 heteroatoms selected from N, S or O, unsubstituted or substituted by one or several R2f;
4-10-membered heterocyclyl, with 1,2,3 or 4 heteroatoms selected from N, S or O, unsubstituted or substituted by one or several R2f, forming a bridged-ring compound with -(CH2)I-4- unsubstituted or substituted by one or several R7c;
4-10-membered heterocyclyl with 1,2,3 or 4 heteroatoms selected from N, S or O, unsubstituted or substituted by one or several R2f, forming a spiro compound with a 4-10 membered heterocyclyl with 1,2,3 or 4 heteroatoms selected from N, S or O, unsubstituted or substituted by one or several R2f, or -(C3-C8)cycloalkyl unsubstituted or substituted by one or several R2d;
6-10-membered aryl unsubstituted or substituted by one or several R2g;
6-10-membered aryl unsubstituted or substituted by one or several R2g, fused with 5-6 membered heteroaryl with 1,2 or 3 atoms selected from N, S or O, unsubstituted or substituted by one or several R2h;
-S(O)2R2i;
-NR2jR2k;
-OR21;
-(C1-C6)alkyl unsubstituted or substituted by one or several R2m;
R2a, R2b, R2C, R2d, R2e, R2f, R2g, R2h, R21, R2j, R2k, R21, R2m are each independently -H, -OH, =0; - Hal, -CN, -NR7aR7b, -C(O)NR7cR7d; -S(O)2R7e; -S(O)2NR7fR7g; -S(O)(NH)R7g; -(Ci-C6)alkyl unsubstituted or substituted by one or several R7h; -O(C1-C6)alkyl unsubstituted or substituted by one or several R7i; -C(O)(C1-C6)alkyl unsubstituted or substituted by one or several R7i; -C(O)O(Ci- Ce)alkyl unsubstituted or substituted by one or several R7i; -(C3-C8)cycloalkyl unsubstituted or substituted by one or several R7j; -O(C3-C8)cycloalkyl unsubstituted or substituted by one or several R7j; 4-10-membered heterocyclyl with 1,2,3 or 4 heteroatoms selected from N, S or O, unsubstituted or substituted by one or several R7k; 4-10-membered heterocyclyl with 1,2,3 or 4 heteroatoms selected from N, S or O, unsubstituted or substituted by one or several R7k, forming a bridged-ring compound with -(CH2)I-4- unsubstituted or substituted by one or several R7I; 5-6-membered heteroaryl with 1,2 or 3 N atoms, unsubstituted or substituted by one or several R7m;
R3 is -H; -Hal; -CN; -NO2, -NH2; -(C1-C6)alkyl unsubstituted or substituted by one or several -OH, - Hal, -CN; -NO2, -NH2;
R4a is -H, -OH, -Hal, -CN, -NH2; -(C1-C6)alkyl unsubstituted or substituted by one or several -Hal, - OH, -CN, -NH2;
Rsa is -OH, -Hal, -CN, -NH2; -(C1-C6)alkyl unsubstituted or substituted by one or several -Hal, -OH, -CN, -NH2; R6a, R6b, R6c, R6d, Rse, R6f, R6g, Rsh, Rsi are each independently -OH, =0, -Hal, -CN, -NH2, -(Ci- Ce)alkyl unsubstituted or substituted by one or several -Hal, -OH, -CN, -NH2; -O(C1-C6)alkyl unsubstituted or substituted by one or several -Hal, -OH, -CN, -NH2;
R7a, R7b, R7c, R7d, R7e, R7f, R7g, R7h, R7i, R7j, R7k, R71, R7m are each independently -H, -OH; -Hal; - (C1-C6)alkyl unsubstituted or substituted by one or several -OH; -Hal; -O(C1-C6)alkyl unsubstituted or substituted by one or several -OH; -Hal;
Hal is an F, Cl, Br, I atom.
5. The compound of claim 1, wherein Ri is:
-O(C1-C6)alkyl unsubstituted or substituted by one or several R6a;
-NRiaRib, wherein Ria, Rib are each independently -H, -(C1-C6)alkyl unsubstituted or substituted by one or several R6a; -C(O)(C1-C6)alkyl unsubstituted or substituted by one or several R6b; -S(0)2(Ci- Ce)alkyl unsubstituted or substituted by one or several R6c; -(C3-C8)cycloalkyl unsubstituted or substituted by one or several R6d; -C(O)(C3-C8)cycloalkyl unsubstituted or substituted by one or several R6e; or
Ria and Rib together with the nitrogen atom they are attached to form a 3-7 membered heterocycle unsubstituted or substituted by one or several R6g;
-S(O)2Ric, wherein Ric is independently -(C1-C6)alkyl unsubstituted or substituted by one or several
R6h,
-P(O)RidRie, wherein Rid and Rie are independently -(C1-C6)alkyl unsubstituted or substituted by one or several Rsh,
R6a, R6b, R6c, Rse, R6g, R6h are each independently -OH, =0, -Hal, -CN, -NH2, -(C1-C6)alkyl unsubstituted or substituted by one or several -Hal, -OH, -CN, -NH2; -O(C1-C6)alkyl unsubstituted or substituted by one or several -Hal, -OH, -CN, -NH2;
Hal is an F, Cl, Br, I atom.
6. The compound of claim 5, wherein Ri is methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, iso-butoxy, -NH2; -N(CH3)2, -NHCH3, -N(CH2-CH3)2, -NH(CH2-CH3), -NHC(0)CH3, - NHC(O)(CH2-CH3), -NHC(O)isopropyl, -NHC(O)propyl, -NHC(O)butyl, -NHC(O)pentyl, - NHC(O)cyclopropyl, -NHC(O)cyclobutyl, -NHC(O)cyclopentyl, -NHC(O)cyclohexyl, pyrrolidinyl, oxopyrrolidinyl, azetidinyl, -NH(cyclopropyl), -NHS(O)2CH3, -S(O)2CH3, -P(O)(CH3)2.
7. The compound of claim 1, wherein R2 is:
-NH-(C3-C8)cycloalkyl unsubstituted or substituted by one or several R7j;
-N((C1-C6)alkyl unsubstituted or substituted by one or several R7h)-(C3-C8)cycloalkyl unsubstituted or substituted by one or several R7j;
-NH-(C3-C8)heterocyclyl, with 1,2,3 or 4 heteroatoms selected from N, S or O, unsubstituted or substituted by one or several R2f, forming a bridged-ring compound with -(CH2)i-4- unsubstituted or substituted by one or several R.2C;
-N(-(C1-C6)alkyl unsubstituted or substituted by one or several R7h)-(C3-C8)heterocyclyl, with 1,2,3 or 4 heteroatoms selected from N, S or O, unsubstituted or substituted by one or several R2f, forming a bridged-ring compound with -(CH2)i-4- unsubstituted or substituted by one or several R2e;
-S(0)2(C1-C6)alkyl unsubstituted or substituted by one or several R7h;
-S(O)2(C3-C8)cycloalkyl unsubstituted or substituted by one or several R7j;
-O-(C3-C8)heterocyclyl, with 1,2,3 or 4 heteroatoms selected from N, S or O, unsubstituted or substituted by one or several Fbr; -O-(C3-C8)heterocyclyl, with 1,2,3 or 4 heteroatoms selected from N, S or O, unsubstituted or substituted by one or several R2f, forming a bridged-ring compound with -(CH2)I-4- unsubstituted or substituted by one or several R26; or
wherein m= 0,1,2 or 3, wherein p = 0,1, 2, 3 or 4, wherein n = 0,1, 2, 3 or 4,
Xi, X2 are each independently S, SO2, O, N or NH;
Yi, Y2 are each independently C, N, or CH; R-2a, R-2b, R2C, R2d, R2e, R2f, R2g, R2h, R21, R2j, R2k, R21, R2m are each independently -H, -OH, =0; -Hal, -CN, -NR7aR7b, -C(O)NR7cR7d; -S(O)2R7e; -S(O)2NR7f R7g; -S(O)(NH)R7g; -(Ci-C6)alkyl unsubstituted or substituted by one or several R7h; -O(C1-C6)alkyl unsubstituted or substituted by one or several R7i; -C(O)(C1-C6)alkyl unsubstituted or substituted by one or several R7i; -C(O)O(Ci- Ce)alkyl unsubstituted or substituted by one or several R7i; -(C3-C8)cycloalkyl unsubstituted or substituted by one or several R7j; -O(C3-C8)cycloalkyl unsubstituted or substituted by one or several R7j; 4-10-membered heterocyclyl with 1,2,3 or 4 heteroatoms selected from N, S or O, unsubstituted or substituted by one or several R7k; 4-10-membered heterocyclyl with 1,2,3 or 4 heteroatoms selected from N, S or O, unsubstituted or substituted by one or several R7k, forming a bridged-ring compound with -(CH2)I-4- unsubstituted or substituted by one or several R7I; 5-6-membered heteroaryl with 1,2 or 3 N atoms, unsubstituted or substituted by one or several R7m;
R7a, R7b, R7C, R7d, R7e, R7f, R7g, R7h, R7i, R7j, R7k, R7I, R7m are each independently -H, -OH; - Hal; -(C1-C6)alkyl unsubstituted or substituted by one or several -OH; -Hal; -O(C1-C6)alkyl unsubstituted or substituted by one or several -OH; -Hal;
Hal is an F, Cl, Br, I atom.
8. The compound of claim 7, wherein R2 is:
wherein m = 0, 1, 2 or 3, wherein p = 0,1, 2, 3 or 4, wherein n = 0,1, 2, 3 or 4,
R-2a, R-2b, R2C, R2d, R2e, R2f, R2g, R2h, R21, R2j, R2k, R21 are each independently -OH, =0, -Hal, -CN, - NR6aRsb, -C(O)NR6cR6d; -(C1-C6)alkyl unsubstituted or substituted by one or several R6e; -O(Ci- Ce)alkyl unsubstituted or substituted by one or several R6e; -C(O)(C1-C6)alkyl unsubstituted or substituted by one or several R6e; -(C3-C8)cycloalkyl unsubstituted or substituted by one or several
R6r; -O(C3-C8)cycloalkyl unsubstituted or substituted by one or several R7j; 4-10-membered heterocyclyl with 1,2,3 or 4 heteroatoms selected from N, S or O, unsubstituted or substituted by one or several R6g; 5-6-membered heteroaryl with 1,2 or 3 N atoms, unsubstituted or substituted by one or several Rsh; -S(O)2R6i; -S(O)(NH)R6j; -N=S(O)R6kR6i;
R7a, R7b, R7c, R7d, R7e, R7f, R7g, R7h, R7i, R7j, R7k, R71, R7m are each independently -OH; -Hal; -(Ci- Ce)alkyl unsubstituted or substituted by one or several -OH; -Hal; -O(C1-C6)alkyl unsubstituted or substituted by one or several -OH; -Hal;
Hal is an F, Cl, Br, I atom.
9. The compound of claim 8, wherein R2 is: methylpyrazolyl, pyrazolyl, cyclohexyl, hydroxycyclohexyl, 8-oxa-3-azabicyclo[3.2.1]octane-3-yl, methanesulfonylphenyl, pyridinylpyrazolyl, l-(pyridine-4-yl)-lH-pyrazole-4-yl, l-(pyridine-3-yl)- lH-pyrazole-4-yl, 3-methylmorpholine-4-yl, morpholinyl, cyclopropanesulfonyl, phenyl, fluorophenyl, cyanophenyl, (trifluoromethyl)phenyl, pyridinyl, indolyl, sulfamoylphenyl, carbamoylphenyl, piperidinylpyrazolyl, l-(piperidin-4-yl)-lH-pyrazole-4-yl, dimethylpyrazolyl, 3-hydroxy-8-oxabicyclo[3.2.1]octane-3-yl, cyclopropyl, cyclobutyl, cyclopentyl, tetrahydropyridinyl, l,2,3,6-tetrahydropyridine-4-yl, (fluoropyridinyl)dimethylpyrazolyl, l-(5- fluoropyridine-3 -y 1 ) -3 , 5 -dimethyl - 1 H-pyrazole-4-yl, 1 -(pyridine-3 -y 1 ) -3 , 5 -dimethyl - 1 H-pyrazol e-4- yl, cyanocyclohexyl, methanesulfonylcyclopropyl, 8-oxabicyclo[3.2.1]oct-2-ene-3-yl, l-[imino(methyl)oxo-X6-sulfanyl]cyclopropyl, aminomethylmorpholinylpyrazolyl, carbamoylcyclohexyl, piperidinyl, pyrazolylindolyl, l-(lH-pyrazole-3-yl)-lH-indole-5-yl, methanesulfonyl, methylmorphoniline, 8-oxabicyclo[3.2.1]octane-3-yl, pyridinylpiperazinyl, piperazinyl, 4-(pyridine-2-yl)piperazine-l-yl, oxaspiro[5.5]undecane-9-yl, 3- oxaspiro[5.5]undecane-9-yl, 2-oxaspiro[3.5]nonane-7-yl, 2-thiaspiro[3.5]nonane-7-yl, oxaspiro[3.5]nonane-7-yl, thiaspiro[3.5]nonane-7-yl, 8-azabicyclo[3.2.1]octane-3-yl, 8- azabicyclo[3.2.1]octane-3-yloxy, oxanyl, (hydroxycyclohexyl)aminyl, tetramethyloxanyl, difluorocyclohexyl, fluorocyclohexyl, 2,2-dioxo-2X6-thiaspiro[3.5]nonane-7-yl, 4-ethyl-4- hydroxy cyclohexyl, 8-methyl-3,8-diazabicyclo[3.2.1]octane-3-yl,
8-oxa-3-azabicyclo[3.2.1]octane-3-yl, 3,8-diazabicyclo[3.2.1]octane-3-yl, acetyl -
3,8-diazabicyclo[3.2.1]octane-8-yl 3,8-diazabicyclo[3.2.1]octane-8-yl,
3-methyl-3,8-diazabicyclo[3.2.1]octane-8-yl, 3-acetyl-3,8-diazabicyclo[3.2.1]octane-8-yl,
{9-methyl-9-azabicyclo[3.3.1]nonane-3-yl}aminyl, {9-azabicyclo[3.3.1]nonane-3-yl}aminyl, 3- hydroxy-8-azabicyclo[3.2.1]octane-8-yl, 5-hydroxy-2-azabicyclo[2.2.1]heptane-2-yl,
3-methoxy-8-azabicyclo[3.2.1]octane-8-yl, 8-azabicyclo[3.2.1]octane-8-yl,
5-methoxy-2-azabicyclo[2.2.1]heptane-2-yl, 2-azabicyclo[2.2.1]heptane-2-yl,
3-methanesulfonyl-3,8-diazabicyclo[3.2.1]octane-8-yl, 9-methyl-9-azabicyclo[3.3.1]nonane-3-yl,
9-methyl-9-azabicyclo[3.3.1 ]nonane-3 -yl .
10. The compound of claim 1, wherein R3 is -H, -F, -Cl, -Br, -I, -(C1-C6)alkyl unsubstituted or substituted by one or several -Hal, -OH, -CN, -NH2;
Hal is an F, Cl, Br, I atom.
11. The compound of claim 1, wherein R4 is: wherein p = 0, 1, 2, 3 or 4,
R4a are each independently -H, -OH, -Hal, -CN, -NH2; -(C1-C6)alkyl unsubstituted or substituted by one or several -Hal, -OH, -CN, -NH2;
Hal is an atom of F, Cl, Br, I.
12. The compound of claim 11, wherein R4 is: wherein p=0, 1 or 2,
R4a are each independently -H, -OH, -Hal, -CN, -NH2; -(C1-C6)alkyl unsubstituted or substituted by one or several -Hal, -OH, -CN, -NH2;
Hal is an F, Cl, Br, I atom.
13. The compound of claim 12, wherein R4 is: methylmorpholinyl, 3 -methylmorpholine, morpholinyl, 8-oxa-3-azabicyclo[3.2.1]octane-3-yl, 3- azabi cy cl o [3.2.1 ] octane-3 -y 1.
14. The compound of claim 1, wherein R5 is:
Yi, Y2 are each independently C, N or CH;
Rsa is -OH, -Hal, -CN, -NH2; -(C1-C6)alkyl unsubstituted or substituted by one or several -Hal, -OH, -CN, -NH2;
Hal is an F, Cl, Br, I atom.
15. The compound of claim 14, wherein R5 is:
wherein m = 0, 1, 2, 3 or 4,
Rsa is -OH, -Hal, -CN, -NH2; -(C1-C6)alkyl unsubstituted or substituted by one or several -Hal, -OH, -CN, -NH2;
Hal is an F, Cl, Br, I atom.
16. The compound of claim 1, wherein R5 is: pyrazolyl, methylpyrazolyl, imidazolyl, pyrrolyl.
17. The compound of claim 1, which is:
(3R)-4-[3-methoxy-4-(l-methyl-lH-pyrazole-5-yl)-l-(lH-pyrazole-3-yl)-lH-pyrazolo[3,4-b]pyridi ne-6-yl]-3 -methylmorpholine (ATR 1248);
4-[3-methoxy -4-(l -methyl- lH-pyrazole-5-yl)-l-(lH-pyrazole-3-yl)-lH-pyrazolo[3,4-b]pyridine-6-y l]-3-methylmorpholine (ATR_1248_a);
4-(l-methyl-lH-pyrazole-5-yl)-6-[(3R)-3-methylmorpholine-4-yl]-l-(lH-pyrazole-3-yl)-lH- pyrazolo[3,4-b]pyridine-3 -amine (ATR 1249);
4-( 1 -methyl- 1 H-pyrazole-5 -y 1 )- 6 - (3 -methylmorpholine-4-yl)- 1 -( 1 H-pyrazole-3 -yl)- 1 H- pyrazolo[3,4-b]pyridine-3 -amine (ATR_1249_a);
4-(l-methyl-lH-pyrazole-5-yl)-6-[(3R)-3-methylmorpholine-4-yl]-l-(lH-pyrazole-3-yl)-lH- pyrazolo[3,4-b]pyridine-3 -amine hydrochloride (ATR_1249_b);
4-(l-methyl-lH-pyrazole-5-yl)-6-(3- methylmorpholine-4-yl)-l-(lH-pyrazole-3-yl)-lH-pyrazolo[3,4-b]pyridine-3-amine hydrochloride
(ATR_1249_c);
N-methyl-4-(l -methyl- lH-pyrazole-5-yl)-6-[(3R)-3-methylmorpholine-4-yl]-l -(lH-pyrazole-3-yl)- lH-pyrazolo[3,4-b]pyridine-3-amine (ATR 1292);
N-methyl-4-(l -methyl- lH-pyrazole-5-yl)-6-(3-methylmorpholine-4-yl)- l-(lH-pyrazole-3 -yl)-lH- pyrazolo[3,4-b]pyridine-3 -amine (ATR_1292_a);
N,N-dimethyl-4-(l-methyl-lH-pyrazole-5-yl)-6-[(3R)-3-methylmorpholine-4-yl]-l-(lH-pyrazole-3- yl)-lH-pyrazolo[3,4-b]pyridine-3-amine (ATR 1293);
N,N-dimethyl-4-(l-methyl-lH-pyrazole-5-yl)-6-(3-methylmorpholine-4-yl)-l-(lH-pyrazole-3-yl)- lH-pyrazolo[3,4-b]pyridine-3-amine (ATR_1293_a);
N-[4-(l -methyl- lH-pyrazole-5-yl)-6-[(3R)-3-methylmorpholine-4-yl]- 1 -(lH-pyrazole-3-yl)-lH- pyrazolo[3,4-b]pyridine-3-yl]acetamide (ATR 1294); N-[4-(l -methyl- lH-pyrazole-5-yl)-6-(3-methylmorpholine-4-yl)-l -(lH-pyrazole-3-yl)- 1H- pyrazolo[3,4-b]pyridine-3-yl]acetamide (ATR_1294_a);
N-[4-(l -methyl- lH-pyrazole-5-yl)-6-[(3R)-3-methylmorpholine-4-yl]-l-(lH-pyrazole-3-yl)-lH- pyrazolo[3,4-b]pyridine-3-yl]methanesulfonamide (ATR_1295);
N-[4-(l -methyl- lH-pyrazole-5-yl)-6-(3-methylmorpholine-4-yl)-l-(lH-pyrazole-3-yl)-lH- pyrazolo[3,4-b]pyridine-3-yl]methanesulfonamide (ATR_1295_a);
(3R)-4-[3-methanesulfonyl-4-(l-methyl-lH-pyrazole-5-yl)-l-(lH-pyrazole-3-yl)-lH-pyrazolo[3,4- b]pyridine-6-yl]-3-methylmorpholine (ATR 1297);
4-[3-methanesulfonyl-4-(l-methyl-lH-pyrazole-5-yl)-l-(lH-pyrazole-3-yl)-lH-pyrazolo[3,4- b]pyridine-6-yl]-3-methylmorpholine (ATR_1297_a);
(3R)-4- [3 -(dimethylphosphoryl)-4-( 1 -methyl- 1 H-pyrazole-5 -yl)- 1 -( 1 H-pyrazole-3 -yl)- 1 H- pyrazolo[3,4-b]pyridine-6-yl]-3-methylmorpholine (ATR 1298);
4-[3-(dimethylphosphoryl)-4-(l-methyl-lH-pyrazole-5-yl)-l-(lH-pyrazole-3-yl)-lH-pyrazolo[3,4- b]pyridine-6-yl]-3-methylmorpholine (ATR_1298_a);
N-cy cl opropyl-4-(l -methyl- lH-pyrazole-5-yl)-6-[(3R)-3-methylmorpholine-4-yl]-l-(lH-pyrazole-
3-yl)-lH-pyrazolo[3,4-b]pyridine-3-amine (ATR 1301);
N-cy cl opropyl-4-(l -methyl- lH-pyrazole-5-yl)-6-(3-methylmorpholine-4-yl)-l-(lH-pyrazole-3-yl)- 1 H-py razol o [3 , 4-b ] py ri dine-3 -amine ( ATR_ 1301 a) ;
4-cyclohexyl-6-[(3R)-3-methylmorpholine-4-yl]-l-(lH-pyrazole-3-yl)-lH-pyrazolo[3,4-b]pyridine-
3-amine (ATR_1302);
4-cy cl ohexyl-6-(3-methylmorpholine-4-yl)-l-(lH-pyrazole-3-yl)-lH-pyrazolo[3,4-b]pyri dine-3- amine (ATR_1302_a); l-{3-amino-6-[(3R)-3-methylmorpholine-4-yl]-l-(lH-pyrazole-3-yl)-lH-pyrazolo[3,4-b]pyridine-
4-yl } cyclohexane- 1 -ol (ATR_1303); l-[3-amino-6-(3-methylmorpholine-4-yl)-l-(lH-pyrazole-3-yl)-lH-pyrazolo[3,4-b]pyridine-4- yl]cyclohexane- 1 -ol (ATR l 303_a);
6-[(3R)-3-methylmorpholine-4-yl]-4-{8-oxa-3-azabicyclo[3.2.1]octane-3-yl}-l-(lH-pyrazole-3-yl)- lH-pyrazolo[3,4-b]pyridine-3-amine (ATR 1304);
6-(3-methylmorpholine-4-yl)-4-{8-oxa-3-azabicyclo[3.2.1]octane-3-yl}-l-(lH-pyrazole-3-yl)-lH- pyrazolo[3,4-b]pyri dine-3 -amine (ATR_1304_a);
4-(3-methanesulfonylphenyl)-6-[(3R)-3-methylmorpholine-4-yl]-l-(lH-pyrazole-3-yl)-lH- pyrazolo[3,4-b]pyri dine-3 -amine (ATR 1305);
4-(3-methanesulfonylphenyl)-6-(3-methylmorpholine-4-yl)-l-(lH-pyrazole-3-yl)-lH-pyrazolo[3,4- b]pyri dine-3 -amine (ATR_1305_a);
4-(4-methanesulfonylphenyl)-6-[(3R)-3-methylmorpholine-4-yl]-l-(lH-pyrazole-3-yl)-lH- pyrazolo[3,4-b]pyri dine-3 -amine (ATR_1306);
4-(4-methanesulfonylphenyl)-6-(3-methylmorpholine-4-yl)-l-(lH-pyrazole-3-yl)-lH-pyrazolo[3,4- b]pyri dine-3 -amine (ATR_1306_a);
6-[(3R)-3-methylmorpholine-4-yl]-l-(lH-pyrazole-3-yl)-4-[l-(pyridine-3-yl)-lH-pyrazole-4-yl]- lH-pyrazolo[3,4-b]pyridine-3-amine (ATR 1308);
6-(3 -methylmorpholine-4-yl)- 1 -( lH-pyrazole-3 -yl)-4-[ 1 -(pyri dine-3 -yl)- lH-pyrazole-4-yl]- 1H- pyrazolo[3,4-b]pyri dine-3 -amine (ATR_1308_a);
6-[(3R)-3-methylmorpholine-4-yl]-l-(lH-pyrazole-3-yl)-4-[l-(pyridine-4-yl)-lH-pyrazole-4-yl]- lH-pyrazolo[3,4-b]pyridine-3-amine (ATR 1309); 6-(3-methylmorpholine-4-yl)-l-(lH-pyrazole-3-yl)-4-[l-(pyridine-4-yl)-lH-pyrazole-4-yl]-lH- pyrazolo[3,4-b]pyridine-3 -amine (ATR_1309_a);
6-[(3R)-3-methylmorpholine-4-yl]-4-(morpholine-4-yl)-l-(lH-pyrazole-3-yl)-lH-pyrazolo[3,4- b]pyridine-3 -amine (ATR 1310);
6-(3 -methylmorpholine-4-yl)-4-(morpholine-4-yl)- 1 -( lH-pyrazole-3 -yl)- lH-pyrazolo[3 ,4- b]pyridine-3 -amine (ATR_1310_a);
4-(cyclopropanesulfonyl)-6-[(3R)-3-methylmorpholine-4-yl]-l-(lH-pyrazole-3-yl)-lH- pyrazolo[3,4-b]pyridine-3 -amine (ATR 1311);
4-(cyclopropanesulfonyl)-6-(3-methylmorpholine-4-yl)-l-(lH-pyrazole-3-yl)-lH-pyrazolo[3,4- b]pyridine-3 -amine (ATR 131 l a);
4-(2-fluorophenyl)-6- [(3 R)-3 -methylmorpholine-4-yl] - 1 -( 1 H-pyrazole-3 -yl)- 1 H-pyrazolo[3 ,4- b]pyridine-3 -amine (ATR 1312);
4-(2-fluorophenyl)-6-(3-methylmorpholine-4-yl)-l-(lH-pyrazole-3-yl)-lH-pyrazolo[3,4-b]pyridine-
3-amine (ATR_1312_a);
2-{3-amino-6-[(3R)-3-methylmorpholine-4-yl]-l-(lH-pyrazole-3-yl)-lH-pyrazolo[3,4-b]pyridine-
4-yl (benzonitrile (ATR 1313);
2- [3 -amino-6-(3 -methylmorpholine-4-yl)- 1 -( 1 H-pyrazole-3 -yl)- 1 H- pyrazolo[3,4-b]pyridine-4-yl]benzonitrile (ATR 1313_a);
6-[(3R)-3-methylmorpholine-4-yl]-l-(lH-pyrazole-3-yl)-4-[2-(trifluoromethyl)phenyl]-lH- pyrazolo[3,4-b]pyridine-3 -amine (ATR 1314);
6-(3-methylmorpholine-4-yl)-l-(lH-pyrazole-3-yl)-4-[2-(trifluoromethyl)phenyl]-lH-pyrazolo[3,4- b]pyridine-3 -amine (ATR_1314_a);
6-[(3R)-3-methylmorpholine-4-yl]-l-(lH-pyrazole-3-yl)-4-(pyridine-3-yl)-lH-pyrazolo[3,4- b]pyridine-3 -amine (ATR 1315);
6-(3 -methylmorpholine-4-yl)- 1 -( lH-pyrazole-3 -yl)-4-(pyridine-3 -yl)- lH-pyrazolo[3 ,4-b]pyridine-3
-amine (ATR l 315_a);
6-[(3R)-3-methylmorpholine-4-yl]-l-(lH-pyrazole-3-yl)-4-(pyridine-4-yl)-lH-pyrazolo[3,4- b]pyridine-3 -amine (ATR 1316);
6-(3 -methylmorpholine-4-yl)- 1 -( lH-pyrazole-3 -yl)-4-(pyridine-4-yl)- lH-pyrazolo[3 ,4-b]pyridine-3
-amine (ATR_1316_a);
4-(lH-indole-5-yl)-6-[(3R)-3-methylmorpholine-4-yl]-l-(lH-pyrazole-3-yl)-lH-pyrazolo[3,4- b]pyridine-3 -amine (ATR 1317);
4-(lH-indole-5-yl)-6-[3-methylmorpholine-4-yl]-l-(lH-pyrazole-3-yl)-lH-pyrazolo[3,4-b]pyridine-
3-amine (ATR_1317_a);
3-{3-amino-6-[(3R)-3-methylmorpholine-4-yl]-l-(lH-pyrazole-3-yl)-lH-pyrazolo[3,4-b]pyridine-
4-yl (benzene- 1 -sulfonamide (ATR l 318);
3-[3-amino-6-(3-methylmorpholine-4-yl)-l-(lH-pyrazole-3-yl)-lH-pyrazolo[3,4-b]pyridine-4- yl]benzene-l -sulfonamide (ATR 1318_a);
3-{3-amino-6-[(3R)-3-methylmorpholine-4-yl]-l-(lH-pyrazole-3-yl)-lH-pyrazolo[3,4-b]pyridine-
4-yl (benzamide (ATR l 319);
3-[3-amino-6-(3-methylmorpholine-4-yl)-l-(lH-pyrazole-3-yl)-lH-pyrazolo[3,4-b]pyridine-4- yl]benzamide (ATR_1319_a);
6-[(3R)-3-methylmorpholine-4-yl]-l-(lH-pyrazole-3-yl)-4-(lH-pyrazole-4-yl)-lH-pyrazolo[3,4- b]pyridine-3 -amine (ATR 1320); 6-(3 -methylmorpholine-4-yl)- 1 -( lH-pyrazole-3 -yl)-4-( lH-pyrazole-4-yl)- lH-pyrazolo[3 ,4- b]pyridine-3 -amine (ATR_1320_a);
4-(l-methyl-lH-pyrazole-4-yl)-6-[(3R)-3-methylmorpholine-4-yl]-l-(lH-pyrazole-3-yl)-lH- pyrazolo[3,4-b]pyridine-3 -amine (ATR 1321);
4-( 1 -methyl- 1 H-pyrazole-4-yl)-6-(3 -methylmorpholine-4-yl)- 1 -( 1 H-pyrazole-3 -yl)- 1 H- pyrazolo[3,4-b]pyridine-3 -amine (ATR_1321_a)
6-[(3R)-3-methylmorpholine-4-yl]-4-[l-(piperidine-4-yl)-lH-pyrazole-4-yl]-l-(lH-pyrazole-3-yl)- lH-pyrazolo[3,4-b]pyridine-3-amine (ATR 1322);
6-(3-methylmorpholine-4-yl)-4-[l-(piperidine-4-yl)-lH-pyrazole-4-yl]-l-(lH-pyrazole-3-yl)-lH- pyrazolo[3,4-b]pyridine-3 -amine (ATR_1322_a);
6-[(3R)-3-methylmorpholine-4-yl]-4-[l-(piperidine-4-yl)-lH-pyrazole-4-yl]-l-(lH-pyrazole-3-yl)- lH-pyrazolo[3,4-b]pyridine-3-amine acetate (ATR_1322_b);
6-(3-methylmorpholine-4-yl)-4-[l-(piperidine-4-yl)-lH-pyrazole-4-yl]-l-(lH-pyrazole-3-yl)-lH-py razolo[3,4-b]pyridine-3-amine acetate (ATR_1322_c);
4-(3,5-dimethyl-lH-pyrazole-4-yl)-6-[(3R)-3-methylmorpholine-4-yl]-l-(lH-pyrazole-3-yl)-lH- pyrazolo[3,4-b]pyridine-3 -amine (ATR 1323);
4-(3,5-dimethyl-lH-pyrazole-4-yl)-6-(3-methylmorpholine-4-yl)-l-(lH-pyrazole-3-yl)-lH- pyrazolo[3,4-b]pyridine-3 -amine (ATR_1323_a);
3-{3-amino-6-[(3R)-3-methylmorpholine-4-yl]-l-(lH-pyrazole-3-yl)-lH-pyrazolo[3,4-b]pyridine-
4-yl}-8-oxabicyclo[3.2.1]octane-3-ol (ATR_1324);
(lR,3S,5S)-3-{3-amino-6-[(3R)-3-methylmorpholine-4-yl]-l-(lH-pyrazole-3-yl)-lH-pyrazolo[3,4- b]pyridine-4-yl}-8-oxabicyclo[3.2.1]octane-3-ol (ATR_1324_a);
(lR,3R,5S)-3-{3-amino-6-[(3R)-3-methylmorpholine-4-yl]-l-(lH-pyrazole-3-yl)-lH-pyrazolo[3,4- b]pyridine-4-yl}-8-oxabicyclo[3.2.1]octane-3-ol (ATR_1324_b);
3-[3-amino-6-(3-methylmorpholine-4-yl)-l-(lH-pyrazole-3-yl)-lH-pyrazolo[3,4-b]pyridine-4-yl]-
8-oxabicyclo[3.2.1 ]octane-3-ol (ATR l 324_c);
4-cyclopropyl-6-[(3R)-3-methylmorpholine-4-yl]-l-(lH-pyrazole-3-yl)-lH-pyrazolo[3,4- b]pyridine-3 -amine (ATR 1325);
4-cyclopropyl-6-(3-methylmorpholine-4-yl)-l-(lH-pyrazole-3-yl)-lH-pyrazolo[3,4-b]pyridine-3- amine (ATR_1325_a);
2-{3-amino-6-[(3R)-3-methylmorpholine-4-yl]-l-(lH-pyrazole-3-yl)-lH-pyrazolo[3,4-b]pyridine-
4-yl}benzamide (ATR_1326);
2-[3-amino-6-(3-methylmorpholine-4-yl)-l-(lH-pyrazole-3-yl)-lH-pyrazolo[3,4-b]pyridine-4- yl]benzamide (ATR_1326_a);
6-[(3R)-3-methylmorpholine-4-yl]-l-(lH-pyrazole-3-yl)-4-(l,2,3,6-tetrahydropyridine-4-yl)-lH- pyrazolo[3,4-b]pyridine-3 -amine (ATR 1327);
6-(3-methylmorpholine-4-yl)-l-(lH-pyrazole-3-yl)-4-(l,2,3,6-tetrahydropyridine-4-yl)-lH- pyrazolo[3,4-b]pyridine-3 -amine (ATR_1327_a);
6-[(3R)-3-methylmorpholine-4-yl]-l-(lH-pyrazole-3-yl)-4-(l,2,3,6-tetrahydropyridine-4-yl)-lH- pyrazolo[3,4-b]pyridine-3 -amine acetate (ATR_1327_b);
6-(3-methylmorpholine-4-yl)-l-(lH-pyrazole-3-yl)-4-(l,2,3,6-tetrahydropyridine-4-yl)-lH-pyrazolo [3,4-b]pyridine-3-amine acetate (ATR_1327_c);
N-ethyl-4-(l -methyl- lH-pyrazole-5-yl)-6-[(3R)-3-methylmorpholine-4-yl]- 1 -(lH-pyrazole-3-yl)- lH-pyrazolo[3,4-b]pyridine-3-amine (ATR 1328); N-ethyl-4-(l -methyl- lH-pyrazole-5-yl)-6-(3-methylmorpholine-4-yl)-l -(lH-pyrazole-3-yl)- 1H- pyrazolo[3,4-b]pyri dine-3 -amine (ATR_1328_a);
N,N-diethyl-4-(l-methyl-lH-pyrazole-5-yl)-6-[(3R)-3-methylmorpholine-4-yl]-l-(lH-pyrazole-3- yl)-lH-pyrazolo[3,4-b]pyridine-3-amine (ATR 1329);
N,N-diethyl-4-(l-methyl-lH-pyrazole-5-yl)-6-(3-methylmorpholine-4-yl)-l-(lH-pyrazole-3-yl)- lH-pyrazolo[3,4-b]pyridine-3-amine (ATR_1329_a);
4-(l-methyl-lH-pyrazole-5-yl)-6-{8-oxa-3-azabicyclo[3.2.1]octane-3-yl}-l-(lH-pyrazole-3-yl)-lH- pyrazolo[3,4-b]pyri dine-3 -amine (ATR 1330);
4-(l-methyl-lH-pyrazole-5-yl)-6-{8-oxa-3-azabicyclo[3.2.1]octane-3-yl}-l-(lH-pyrazole-3-yl)-lH- pyrazolo[3,4-b]pyri dine-3 -amine hydrochloride (ATR_1330_a);
5-fluoro-4-(l -methyl- lH-pyrazole-5-yl)-6-[(3R)-3-methylmorpholine-4-yl]-l-(lH-pyrazole-3-yl)- lH-pyrazolo[3,4-b]pyridine-3-amine (ATR 1337);
5 -fluoro-4-( 1 -methyl- 1 H-pyrazol e-5 -y 1) -6 - (3 -methylmorpholine-4-yl)- 1 -( 1 H-pyrazole-3 -yl)- 1 H- pyrazolo[3,4-b]pyri dine-3 -amine (ATR_1337_a); l-(5-methyl-lH-pyrazole-3-yl)-4-(l-methyl-lH-pyrazole-5-yl)-6-[(3R)-3-methylmorpholine-4-yl]-
1 H-pyrazol o [3 , 4-b ] pyri dine-3 -amine ( ATR_ 1339); l-(5-methyl-lH-pyrazole-3-yl)-4-(l-methyl-lH-pyrazole-5-yl)-6-(3-methylmorpholine-4-yl)-lH- pyrazolo[3,4-b]pyri dine-3 -amine (ATR_1339_a);
4-[l-(5-fluoropyridine-3-yl)-3,5-dimethyl-lH-pyrazole-4-yl]-6-[(3R)-3-methylmorpholine-4-yl]-l-
(lH-pyrazole-3-yl)-lH-pyrazolo[3,4-b]pyri dine-3 -amine (ATR 1344);
4- [ 1 -(5 -fluoropyri dine-3 -y 1 )- 3 , 5 -dimethyl - 1 H-pyrazole-4-yl]-6-(3 -methylmorpholine-4-yl)- 1 -( 1 H- pyrazole-3-yl)-lH-pyrazolo[3,4-b]pyridine-3-amine (ATR_1344_a); l-{3-amino-6-[(3R)-3-methylmorpholine-4-yl]-l-(lH-pyrazole-3-yl)-lH-pyrazolo[3,4-b]pyridine-
4-yl } cyclohexane- 1 -carbonitrile (ATR_1345); l-[3-amino-6-(3-methylmorpholine-4-yl)-l-(lH-pyrazole-3-yl)-lH-pyrazolo[3,4-b]pyridine-4- y 1 ] cy cl ohexane- 1 -carb onitril e ( ATR_ 1345 a);
4-(l-methanesulfonylcyclopropyl)-6-[(3R)-3-methylmorpholine-4-yl]-l-(lH-pyrazole-3-yl)-lH- pyrazolo[3,4-b]pyri dine-3 -amine (ATR 1348);
4-(l-methanesulfonylcyclopropyl)-6-(3-methylmorpholine-4-yl)-l-(lH-pyrazole-3-yl)-lH- pyrazolo[3,4-b]pyri dine-3 -amine (ATR_1348_a);
6-[(3R)-3-methylmorpholine-4-yl]-4-{8-oxabicyclo[3.2.1]oct-2-ene-3-yl}-l-(lH-pyrazole-3-yl)-
1 H-pyrazol o [3 , 4-b ] pyri dine-3 -amine ( ATR_ 1350);
6-[(3R)-3-methylmorpholine-4-yl]-4-[(lS,5R)-8-oxabicyclo[3.2.1]oct-2- ene-3-yl]-l-(lH-pyrazole-3-yl)-lH-pyrazolo[3,4-b]pyridine-3-amine (ATR_1350_a);
6-[(3R)-3-methylmorpholine-4-yl]-4-[(lR,5S)-8-oxabicyclo[3.2.1]oct-2- ene-3-yl]-l-(lH-pyrazole-3-yl)-lH-pyrazolo[3,4-b]pyridine-3-amine (ATR_1350_b);
6-(3-methylmorpholine-4-yl)-4-{8-oxabicyclo[3.2.1]oct-2-ene-3-yl}-l-(lH-pyrazole-3-yl)-lH- pyrazolo[3,4-b]pyri dine-3 -amine (ATR_1350_c);
(R)-(l-{3-amino-6-[(3R)-3-methylmorpholine-4-yl]-l-(lH-pyrazole-3-yl)-lH-pyrazolo[3,4- b]pyridine-4-yl}cyclopropyl)(imino)methyl-X6-sulfanone (ATR_1351);
{ l-[3-amino-6-(3-methylmorpholine-4-yl)-l-(lH-pyrazole-3-yl)-lH-pyrazolo[3,4-b]pyridine-4- yl]cyclopropyl}(imino)methyl- Z/’-siilfanone (ATR_1351_a); l-{3-amino-6-[(3R)-3-methylmorpholine-4-yl]-l-(lH-pyrazole-3-yl)-lH-pyrazolo[3,4-b]pyridine- 4-yl } cyclohexane- 1 -carboxamide (ATR_1352); 1-[3-amino-6-(3-methylmorpholine-4-yl)-l-(lH-pyrazole-3-yl)-lH-pyrazolo[3,4-b]pyridine-4- yl]cyclohexane- 1 -carboxamide (ATR l 352_a);
6-[(3R)-3-methylmorpholine-4-yl]-4-(piperidine-4-yl)-l-(lH-pyrazole-3-yl)-lH-pyrazolo[3,4- b]pyridine-3 -amine (ATR 1354);
6-(3-methylmorpholine-4-yl)-4-(piperidine-4-yl)-l-(lH-pyrazole-3-yl)-lH-pyrazolo[3,4-b]pyridine-
3 -amine (ATR_1354_a);
6-[(3R)-3-methylmorpholine-4-yl]-l-(lH-pyrazole-3-yl)-4-[l-(lH-pyrazole-3-yl)-lH-indole-5-yl]-
1 H-py razol o [3 , 4-b ] pyri dine-3 -amine ( ATR_ 1356);
6-(3-methylmorpholine-4-yl)-l-(lH-pyrazole-3-yl)-4-[l-(lH-pyrazole-3-yl)-lH-indole-5-yl]-lH-py razolo[3 ,4-b]pyri dine-3 -amine (ATR l 356_a);
4-methanesulfonyl-6-[(3R)-3-methylmorpholine-4-yl]-l-(lH-pyrazole-3-yl)-lH-pyrazolo[3,4- b]pyri dine-3 -amine (ATR 1360);
4-methanesulfonyl-6-(3-methylmorpholine-4-yl)-l-(lH-pyrazole-3-yl)-lH-pyrazolo[3,4-b]pyridine- 3 -amine (ATR_1360_a);
6-[(3R)-3-methylmorpholine-4-yl]-4-{8-oxabicyclo[3.2.1]octane-3-yl}-l-(lH-pyrazole-3-yl)-lH- pyrazolo[3,4-b]pyri dine-3 -amine (ATR 1361);
6-[(3R)-3-methylmorpholine-4-yl]-4-[(lR,3S,5S)-8-oxabicyclo[3.2.1]octane-3-yl]-l-(lH-pyrazole- 3-yl)-lH-pyrazolo[3,4-b]pyridine-3-amine (ATR_1361_a);
6-[(3R)-3-methylmorpholine-4-yl]-4-[(lR,3R,5S)-8-oxabicyclo[3.2.1]octane-3-yl]-l-(lH-pyrazole- 3-yl)-lH-pyrazolo[3,4-b]pyridine-3-amine (ATR_1361_b);
6-(3-methylmorpholine-4-yl)-4-{8-oxabicyclo[3.2.1]octane-3-yl}-l-(lH-pyrazole-3-yl)-lH- pyrazolo[3,4-b]pyri dine-3 -amine (ATR_1361_c);
(3R)-3-methyl-4-[4-(l-methyl-lH-pyrazole-5-yl)-l-(lH-pyrazole-3-yl)-3-(pyrrolidine-l-yl)-lH- pyrazolo[3,4-b]pyridine-6-yl]morpholine (ATR 1363);
3-methyl-4-[4-(l -methyl- lH-pyrazole-5-yl)-l -(lH-pyrazole-3-yl)-3-(pyrrolidine-l -yl)-lH- pyrazolo[3,4-b]pyridine-6-yl]morpholine (ATR_1363_a);
N-[4-(l -methyl- lH-pyrazole-5-yl)-6-[(3R)-3-methylmorpholine-4-yl]-l-(lH-pyrazole-3-yl)-lH- pyrazolo[3,4-b]pyri dine-3 -yl]propanamide (ATR 1364);
N-[4-(l -methyl- lH-pyrazole-5-yl)-6-(3-methylmorpholine-4-yl)-l -(lH-pyrazole-3-yl)- 1H- pyrazolo[3,4-b]pyri dine-3 -yl]propanamide (ATR_1364_a);
2-methyl-N-[4-(l-methyl-lH-pyrazole-5-yl)-6-[(3R)-3-methylmorpholine-4-yl]-l-(lH-pyrazole-3- yl)-lH-pyrazolo[3,4-b]pyridine-3-yl]propanamide (ATR 1365);
2-methyl-N-[4-(l-methyl-lH-pyrazole-5-yl)-6-(3-methylmorpholine-4-yl)-l-(lH-pyrazole-3-yl)- lH-pyrazolo[3,4-b]pyridine-3-yl]propanamide (ATR_1365_a);
N-[4-(l -methyl- lH-pyrazole-5-yl)-6-[(3R)-3-methylmorpholine-4-yl]-l-(lH-pyrazole-3-yl)-lH- pyrazolo[3,4-b]pyridine-3-yl]cyclopropanecarboxamide (ATR 1366);
N-[4-(l -methyl- lH-pyrazole-5-yl)-6-(3-methylmorpholine-4-yl)-l -(lH-pyrazole-3-yl)- 1H- pyrazolo[3,4-b]pyridine-3-yl]cyclopropanecarboxamide (ATR_1366_a);
(3R)-4-[3-(azetidine-l-yl)-4-(l-methyl-lH-pyrazole-5-yl)-l-(lH-pyrazole-3-yl)-lH-pyrazolo[3,4- b]pyridine-6-yl]-3-methylmorpholine (ATR 1368);
4-[3-(azetidine-l-yl)-4-(l-methyl-lH-pyrazole-5-yl)-l-(lH-pyrazole-3-yl)-lH-pyrazolo[3,4- b]pyridine-6-yl]-3-methylmorpholine (ATR_1368_a); l-[4-(l -methyl- lH-pyrazole-5-yl)-6-[(3R)-3-methylmorpholine-4-yl]-l-(lH-pyrazole-3-yl)-lH- pyrazolo[3,4-b]pyri dine-3 -yl]pyrrolidine-2-one (ATR 1370); 1 - [4 - ( 1 -methyl- 1 H-pyrazole-5 -y 1 )- 6 - (3 -methylmorpholine-4-yl)- 1 -( 1 H-pyrazole-3 -yl)- 1 H- pyrazolo[3,4-b]pyri dine-3 -yl]pyrrolidine-2-one (ATR_1370_a);
6-[(3R)-3-methylmorpholine-4-yl]-l-(lH-pyrazole-3-yl)-4-[4-(pyridine-2-yl)piperazine-l-yl]-lH- pyrazolo[3,4-b]pyridine-3 -amine (ATR 1374);
6-(3-methylmorpholine-4-yl)-l-(lH-pyrazole-3-yl)-4-[4-(pyridine-2-yl)piperazine-l-yl]-lH- pyrazolo[3,4-b]pyri dine-3 -amine (ATR_1374_a);
6-[(3R)-3-methylmorpholine-4-yl]-4-{3-oxaspiro[5.5]undecan-9-yl}-l-(lH-pyrazole-3-yl)-lH- pyrazolo[3,4-b]pyri dine-3 -amine (ATR 1381);
6-(3 -methylmorpholine-4-yl)-4- { 3 -oxaspiro[5.5 ]undecan-9-yl } - 1 -( 1 H-pyrazole-3 -yl)- 1 H- pyrazolo[3,4-b]pyri dine-3 -amine (ATR_1381_a);
6-[(3R)-3-methylmorpholine-4-yl]-4-{2-oxaspiro[3.5]nonane-7-yl}-l-(lH-pyrazole-3-yl)-lH- pyrazolo[3,4-b]pyri dine-3 -amine (ATR 1383);
6-(3 -methylmorpholine-4-yl)-4- { 2-oxaspiro[3.5 ]nonane-7 -yl } - 1 -( 1 H-pyrazole-3 -yl)- 1 H- pyrazolo[3,4-b]pyri dine-3 -amine (ATR_1383_a);
6-[(3R)-3-methylmorpholine-4-yl]-l-(lH-pyrazole-3-yl)-4-{2-thiaspiro[3.5]nonane-7-yl}-lH- pyrazolo[3,4-b]pyri dine-3 -amine (ATR 1385);
6-(3 -methylmorpholine-4-yl)- 1 -( 1 H-pyrazole-3 -yl)-4- { 2-thiaspiro[3.5 ]nonane-7 -yl } - 1 H- pyrazolo[3,4-b]pyri dine-3 -amine (ATR_1385_a);
4-{8-azabicyclo[3.2.1]octane-3-yloxy}-6-[(3R)-3-methylmorpholine-4-yl]-l-(lH-pyrazole-3-yl)-
1 H-py razol o [3 , 4-b ] pyri dine-3 -amine ( ATR_ 1395);
4-{8-azabicyclo[3.2.1]octane-3-yloxy}-6-(3-methylmorpholine-4-yl)-l-(lH-pyrazole-3-yl)-lH- pyrazolo[3,4-b]pyri dine-3 -amine (ATR_1395_a);
4-(l,4-dimethyl-lH-pyrazole-5-yl)-6-[(3R)-3-methylmorpholine-4-yl]-l-(lH-pyrazole-3-yl)-lH- pyrazolo[3,4-b]pyri dine-3 -amine (ATR 1406);
4-(l,4-dimethyl-lH-pyrazole-5-yl)-6-(3-methylmorpholine-4-yl)-l-(lH-pyrazole-3-yl)-lH- pyrazolo[3,4-b]pyri dine-3 -amine (ATR_1406_a);
6-[(3R)-3-methylmorpholine-4-yl]-4-(oxane-4-yl)-l-(lH-pyrazole-3-yl)-lH-pyrazolo[3,4- b]pyri dine-3 -amine (ATR 1407);
6-(3 -methylmorpholine-4-yl)-4-(oxane-4-yl)- 1 -( lH-pyrazole-3 -yl)- lH-pyrazolo[3 ,4-b]pyri dine-3 - amine (ATR_1407_a);
(lr,4r)-4-({3-amino-6-[(3R)-3-methylmorpholine-4-yl]-l-(lH-pyrazole-3-yl)-lH-pyrazolo[3,4-b]py ridine-4-yl } amino)cy clohexane- 1 -ol (ATR 1410);
4-{[3-amino-6-(3-methylmorpholine-4-yl)-l-(lH-pyrazole-3-yl)-lH-pyrazolo[3,4-b]pyridine-4-yl]a mino}cyclohexane-l-ol (ATR_1410_a);
6-[(3R)-3-methylmorpholine-4-yl]-l-(lH-pyrazole-3-yl)-4-(2,2,6,6-tetramethyloxane-4-yl)-lH-pyra zolo[3,4-b]pyri dine-3 -amine (ATR 1411);
6-(3-methylmorpholine-4-yl)-l-(lH-pyrazole-3-yl)-4-(2,2,6,6-tetramethyloxane-4-yl)-lH-pyrazolo[
3, 4-b]pyri dine-3 -amine (ATR 141 l a);
4-(4,4-difluorocyclohexyl)-6-[(3R)-3-methylmorpholine-4-yl]-l-(lH-pyrazole-3-yl)-lH-pyrazolo[3, 4-b]pyri dine-3 -amine (ATR 1412);
4-(4,4-difluorocyclohexyl)-6-(3-methylmorpholine-4-yl)-l-(lH-pyrazole-3-yl)-lH-pyrazolo[3,4-b]p yri dine-3 -amine (ATR_1412_a);
7-{3-amino-6-[(3R)-3-methylmorpholine-4-yl]-l-(lH-pyrazole-3-yl)-lH-pyrazolo[3,4-b]pyridine-4 -yl}-2 X6-thiaspiro[3.5]nonane-2, 2-dione (ATR_1415); 7-[3-amino-6-(3-methylmorpholine-4-yl)-l-(lH-pyrazole-3-yl)-lH-pyrazolo[3,4-b]pyridine-4-yl]-2 X6-thiaspiro[3.5]nonane-2, 2-dione (ATR_1415_a);
4-{3-amino-6-[(3R)-3-methylmorpholine-4-yl]-l-(lH-pyrazole-3-yl)-lH-pyrazolo[3,4-b]pyridine-4
-yl } - 1 -ethyl cyclohexane- 1 -ol (ATR l 416);
(lr,4s)-4-{3-amino-6-[(3R)-3-methylmorpholine-4-yl]-l-(lH-pyrazole-3-yl)-lH-pyrazolo[3,4-b]pyr idine-4-yl } - 1 -ethyl cyclohexane- 1 -ol (ATR l 416_a);
(ls,4r)-4-{3-amino-6-[(3R)-3-methylmorpholine-4-yl]-l-(lH-pyrazole-3-yl)-lH-pyrazolo[3,4-b]pyr idine-4-yl } - 1 -ethylcyclohexane- 1 -ol (ATR l 416_b);
4-[3-amino-6-(3-methylmorpholine-4-yl)-l-(lH-pyrazole-3-yl)-lH-pyrazolo[3,4-b]pyridine-4-yl]-l -ethylcyclohexane- 1 -ol (ATR l 416_c);
N-methyl-6-[(3R)-3-methylmorpholine-4-yl]-4-{8-oxa-3-azabicyclo[3.2.1]octane-3-yl}-l-(lH- pyrazole-3-yl)-lH-pyrazolo[3,4-b]pyridine-3-amine (ATR 1417);
N-methyl-6-(3 -methylmorpholine-4-yl)-4- { 8-oxa-3 -azabicyclo[3.2.1 ]octane-3 -yl } - 1 -(IH-pyrazole-
3-yl)-lH-pyrazolo[3,4-b]pyridine-3-amine (ATR_1417_a);
N,N-dimethyl-6-[(3R)-3-methylmorpholine-4-yl]-4-{8-oxa-3-azabicyclo[3.2.1]octane-3-yl}-l-(lH- pyrazole-3-yl)-lH-pyrazolo[3,4-b]pyridine-3-amine (ATR 1418);
N,N-dimethyl-6-(3 -methylmorpholine-4-yl)-4-{ 8-oxa-3 -azabicyclo[3.2.1 ]octane-3 -yl } - 1 -( 1H- pyrazole-3-yl)-lH-pyrazolo[3,4-b]pyridine-3-amine (ATR_1418_a);
N-ethyl-6-[(3R)-3-methylmorpholine-4-yl]-4-{8-oxa-3-azabicyclo[3.2.1]octane-3-yl}-l-(lH- pyrazole-3-yl)-lH-pyrazolo[3,4-b]pyridine-3-amine (ATR 1419);
N-ethyl-6-(3-methylmorpholine-4-yl)-4-{8-oxa-3-azabicyclo[3.2.1]octane-3-yl}-l-(lH-pyrazole-3- yl)-lH-pyrazolo[3,4-b]pyridine-3-amine (ATR_1419_a);
N-{6-[(3R)-3-methylmorpholine-4-yl]-4-{8-oxa-3-azabicyclo[3.2.1]octane-3-yl}-l-(lH-pyrazole-3- yl)-lH-pyrazolo[3,4-b]pyridine-3-yl}acetamide (ATR 1420);
N-[6-(3-methylmorpholine-4-yl)-4-{8-oxa-3-azabicyclo[3.2.1]octane-3-yl}-l-(lH-pyrazole-3-yl)-
1 H-pyrazol o [3 , 4-b ] pyri dine-3 -yl ] acetamide ( ATR_ 1420_a) ;
5-methyl-6-[(3R)-3-methylmorpholine-4-yl]-4-{8-oxa-3-azabicyclo[3.2.1]octane-3-yl}-l-(lH-pyraz ole-3-yl)-lH-pyrazolo[3,4-b]pyri dine-3 -amine (ATR 1450);
5-methyl-6-(3-methylmorpholine-4-yl)-4-{8-oxa-3-azabicyclo[3.2.1]octane-3-yl}-l-(lH-pyrazole-3 -yl)-lH-pyrazolo[3,4-b]pyridine-3-amine (ATR_1450_a);
4-{8-methyl-3,8-diazabicyclo[3.2.1]octane-3-yl}-6-[(3R)-3-methylmorpholine-4-yl]-l-(lH-pyrazol e-3-yl)-lH-pyrazolo[3,4-b]pyri dine-3 -amine (ATR 1458);
4-{8-methyl-3,8-diazabicyclo[3.2.1]octane-3-yl}-6-(3-methylmorpholine-4-yl)-l-(lH-pyrazole-3-yl )-lH-pyrazolo[3,4-b]pyri dine-3 -amine (ATR_1458_a);
4-{3,8-diazabicyclo[3.2.1]octane-8-yl}-6-[(3R)-3-methylmorpholine-4-yl]-l-(lH-pyrazole-3-yl)-lH -pyrazolo[3,4-b]pyri dine-3 -amine (ATR 1459);
4-{3,8-diazabicyclo[3.2.1]octane-8-yl}-6-(3-methylmorpholine-4-yl)-l-(lH-pyrazole-3-yl)-lH-pyra zolo[3,4-b]pyri dine-3 -amine (ATR_1459_a);
4-{3,8-diazabicyclo[3.2.1]octane-8-yl}-6-[(3R)-3-methylmorpholine-4-yl]-l-(lH-pyrazole-3-yl)-lH -pyrazolo[3,4-b]pyri dine-3 -amine salicylate (ATR_1459_b);
4-{3,8-diazabicyclo[3.2.1]octane-8-yl}-6-(3-methylmorpholine-4-yl)-l-(lH-pyrazole-3-yl)-lH-pyra zolo[3,4-b]pyri dine-3 -amine salicylate (ATR_1459_c);
4-{3-methyl-3,8-diazabicyclo[3.2.1]octane-8-yl}-6-[(3R)-3-methylmorpholine-4-yl]-l-(lH-pyrazol e-3 -yl)- 1 H-pyrazolo[3 ,4-b]pyri dine-3 -amine (ATR l 460); 4-{3-methyl-3,8-diazabicyclo[3.2.1]octane-8-yl}-6-(3-methylmorpholine-4-yl)-l-(lH-pyrazole-3-yl )-lH-pyrazolo[3,4-b]pyridine-3 -amine (ATR_1460_a); l-(8-{3-amino-6-[(3R)-3-methylmorpholine-4-yl]-l-(lH-pyrazole-3-yl)-lH-pyrazolo[3,4-b]pyridin e-4-yl}-3,8-diazabicyclo[3.2.1]octane-3-yl)ethane-l-one (ATR 1461);
1-{8-[3-amino-6-(3-methylmorpholine-4-yl)-l-(lH-pyrazole-3-yl)-lH-pyrazolo[3,4-b]pyridine-4-yl
]-3,8-diazabicyclo[3.2.1]octane-3-yl}ethane-l-one (ATR_1461_a);
6-[(3R)-3-methylmorpholine-4-yl]-l-(lH-pyrazole-3-yl)-N4-[(lR,3r,5S)-9-methyl-9-azabicyclo[3.3 , l]nonane-3-yl]-lH-pyrazolo[3,4-b]pyridine-3,4-diamine (ATR 1463);
N4-{9-methyl-9-azabicyclo[3.3.1]nonane-3-yl}-6-(3-methylmorpholine-4-yl)-l-(lH-pyrazole-3-yl) -lH-pyrazolo[3,4-b]pyridine-3,4-diamine (ATR_1463_a);
(lR,3R,5S)-8-{3-amino-6-[(3R)-3-methylmorpholine-4-yl]-l-(lH-pyrazole-3-yl)-lH-pyrazolo[3,4- b]pyridine-4-yl}-8-azabicyclo[3.2.1]octane-3-ol (ATR 1464);
8-[3-amino-6-(3-methylmorpholine-4-yl)-l-(lH-pyrazole-3-yl)-lH-pyrazolo[3,4-b]pyridine-4-yl]-8 -azabicyclo[3.2. l]octane-3-ol (ATR_1464_a);
5-chloro-6-[(3R)-3-methylmorpholine-4-yl]-4-{8-oxa-3-azabicyclo[3.2.1]octane-3-yl}-l-(lH-pyraz ole-3-yl)-lH-pyrazolo[3,4-b]pyridine-3 -amine (ATR 1465);
5-chloro-6-(3-methylmorpholine-4-yl)-4-{8-oxa-3-azabicyclo[3.2.1]octane-3-yl}-l-(lH-pyrazole-3- yl)-lH-pyrazolo[3,4-b]pyridine-3-amine (ATR_1465_a);
5-fluoro-6-[(3R)-3-methylmorpholine-4-yl]-4-{8-oxa-3-azabicyclo[3.2.1]octane-3-yl}-l-(lH-pyraz ole-3-yl)-lH-pyrazolo[3,4-b]pyridine-3-amine (ATR 1466);
5 -fluoro-6-(3 -methylmorpholine-4-yl)-4- { 8 -oxa-3 -azabi cyclo[3.2.1] octane-3 -yl } - 1 -( 1 H-pyrazole-3 - yl)-lH-pyrazolo[3,4-b]pyridine-3-amine (ATR_1466_a);
(lS,4S,5S)-2-{3-amino-6-[(3R)-3-methylmorpholine-4-yl]-l-(lH-pyrazole-3-yl)-lH-pyrazolo[3,4-b ]pyridine-4-yl}-2-azabicyclo[2.2. l]heptane-5-ol (ATR_1467);
2-[3-amino-6-(3-methylmorpholine-4-yl)-l-(lH-pyrazole-3-yl)-lH-pyrazolo[3,4-b]pyridine-4-yl]-2
-azabicyclo[2.2. l]heptane-5-ol (ATR_1467_a);
4-[(lR,3R,5S)-3-methoxy-8-azabicyclo[3.2.1]octane-8-yl]-6-[(3R)-3-methylmorpholine-4-yl]-l-(l
H-pyrazole-3-yl)-lH-pyrazolo[3,4-b]pyridine-3 -amine (ATR 1470);
4-{3-methoxy-8-azabicyclo[3.2.1]octane-8-yl}-6-(3-methylmorpholine-4-yl)-l-(lH-pyrazole-3-yl)- lH-pyrazolo[3,4-b]pyridine-3-amine (ATR_1470_a);
4-[(lS,4S,5S)-5-methoxy-2-azabicyclo[2.2.1]heptane-2-yl]-6-[(3R)-3-methylmorpholine-4-yl]-l-(l H-pyrazole-3-yl)-lH-pyrazolo[3,4-b]pyridine-3 -amine (ATR 1471);
4-{5-methoxy-2-azabicyclo[2.2.1]heptane-2-yl}-6-(3-methylmorpholine-4-yl)-l-(lH-pyrazole-3-yl) -lH-pyrazolo[3,4-b]pyridine-3-amine (ATR_1471_a);
4-{3-methanesulfonyl-3,8-diazabicyclo[3.2.1]octane-8-yl}-6-[(3R)-3-methylmorpholine-4-yl]-l-(l
H-pyrazole-3-yl)-lH-pyrazolo[3,4-b]pyridine-3 -amine (ATR 1476);
4-{3-methanesulfonyl-3,8-diazabicyclo[3.2.1]octane-8-yl}-6-(3-methylmorpholine-4-yl)-l-(lH-pyr azole-3-yl)-lH-pyrazolo[3,4-b]pyridine-3 -amine (ATR_1476_a);
N4-methyl-6-[(3R)-3- methylmorpholine-4-yl]-l-(lH-pyrazole-3-yl)-N4-[(lR,3r,5S)-9-methyl-9-azabicyclo[3.3.1]nonane-
3-yl]-lH-pyrazolo[3,4-b]pyridine-3,4-diamine (ATR 1482);
N4-methyl-6-(3- methylmorpholine-4-yl)-l-(lH-pyrazole-3-yl)-N4-[(lR,3r,5S)-9-methyl-9-azabicyclo[3.3.1]nonane-
3-yl]-lH-pyrazolo[3,4-b]pyridine-3,4-diamine (ATR_1482_a); N-methyl-4-{3-methyl-3,8-diazabicyclo[3.2.1]octane-8-yl}-6-[(3R)-3-methylmorpholine-4-yl]-l-(l H-pyrazole-3-yl)-lH-pyrazolo[3,4-b]pyridine-3-amine (ATR 1492);
N-methyl-4-{3-methyl-3,8-diazabicyclo[3.2.1]octane-8-yl}-6-(3-methylmorpholine-4-yl)-l-(lH-pyr azole-3-yl)-lH-pyrazolo[3,4-b]pyridine-3 -amine (ATR_1492_a);
4-[(lR,3R,5S)-3-methoxy-8-azabicyclo[3.2.1]octane-8-yl]-N-methyl-6-[(3R)-3-methylmorpholine- 4-yl]-l-(lH-pyrazole-3-yl)-lH-pyrazolo[3,4-b]pyridine-3-amine (ATR 1493);
4-{3-methoxy-8-azabicyclo[3.2.1]octane-8-yl}-N-methyl-6-(3-methylmorpholine-4-yl)-l-(lH-pyra zole-3-yl)-lH-pyrazolo[3,4-b]pyridine-3 -amine (ATR_1493_a);
N-ethyl-4-{3-methyl-3,8-diazabicyclo[3.2.1]octane-8-yl}-6-[(3R)-3-methylmorpholine-4-yl]-l-(lH -pyrazole-3-yl)-lH-pyrazolo[3,4-b]pyridine-3 -amine (ATR 1494);
N-ethyl-4-{3-methyl-3,8-diazabicyclo[3.2.1]octane-8-yl}-6-(3-methylmorpholine-4-yl)-l-(lH-pyra zole-3-yl)-lH-pyrazolo[3,4-b]pyridine-3 -amine (ATR_1494_a).
18. A method for inhibiting the biological activity of ATR in a subject, comprising contacting ATR with the compound of any one of claims 1-17.
19. A pharmaceutical composition comprising a therapeutically effective amount of the compound of any one of claims 1-17, or a pharmaceutically acceptable salt, solvate, stereoisomer thereof, and one or more pharmaceutically acceptable excipients.
20. The pharmaceutical composition of claim 19, intended for preventing or treating a disease or disorder mediated by ATR activity.
21. The pharmaceutical composition of claim 20, intended for preventing or treating a disease or disorder mediated by ATR activity, wherein the disease or disorder is an oncological disease.
22. The pharmaceutical composition of claim 21, wherein the oncological disease is selected from the group comprising ovarian cancer, epithelial ovarian cancer, recurrent platinum -refractory ovarian cancer, recurrent platinum-sensitive ovarian cancer, clear cell ovarian cancer, with BRCA 1/2, ARID1A mutations, borderline ovarian tumors; primary peritoneal cancer; fallopian tube cancer; gastric and gastroesophageal junction cancer, locally advanced unresectable, metastatic, or recurrent gastric and gastroesophageal junction cancer; head and neck tumors, unresectable, locally advanced, or metastatic head and neck tumors, recurrent head and neck tumors; prostate cancer, metastatic prostate cancer, castration-resistant metastatic prostate cancer with BRCA mutations; colorectal cancer, unresectable or metastatic colorectal cancer, colon cancer, rectosigmoid junction cancer, and rectal cancer; anal cancer and perianal skin cancer; endometrial cancer, recurrent or metastatic endometrial cancer, uterine corpus cancer and uterine sarcomas; cervical cancer, mesothelioma of the pleura, peritoneum and other sites; pancreatic cancer, inoperable or metastatic pancreatic cancer; malignant tumors of the biliary system, advanced or metastatic cancer of the biliary tract; primary malignant tumors of bone; lung cancer, non-small cell lung cancer, small cell lung cancer; breast cancer, metastatic triple-negative breast cancer with or without BRCA mutations; cutaneous melanoma; metastatic tumors with an ATM mutation; chronic lymphocytic leukemia, myelodysplastic syndrome, chronic myelomonocytic leukemia; esophageal cancer; malignant tumors of the liver; tumors of unknown primary; renal cell carcinoma; bladder cancer and urothelial cancer; gastrointestinal stromal tumors; soft tissue sarcomas; non-melanocytic skin tumors; adrenal cortical cancer, neuroendocrine tumors, primary CNS tumors and metastatic brain tumors, mediastinal tumors, trophoblastic tumors.
23. A method for treating a disease or disorder mediated by ATR activity, comprising administering, in a therapeutically effective amount, the compound of any one of claims 1-17 or a pharmaceutically acceptable salt, solvate, stereoisomer thereof, or the pharmaceutical composition of claim 19 to a subject.
24. The method for treating a disease or disorder of claim 23, wherein the disease or disorder mediated by ATR activity is an oncological disease.
25. The method for treating a disease or disorder of claim 24, wherein the oncological disease is selected from the group comprising ovarian cancer, epithelial ovarian cancer, recurrent platinum- refractory ovarian cancer, recurrent platinum-sensitive ovarian cancer, clear cell ovarian cancer, with BRCA 1/2, ARID1A mutations, borderline ovarian tumors; primary peritoneal cancer; fallopian tube cancer; gastric and gastroesophageal junction cancer, locally advanced unresectable, metastatic, or recurrent gastric and gastroesophageal junction cancer; head and neck tumors, unresectable, locally advanced, or metastatic head and neck tumors, recurrent head and neck tumors; prostate cancer, metastatic prostate cancer, castration-resistant metastatic prostate cancer with BRCA mutations; colorectal cancer, unresectable or metastatic colorectal cancer, colon cancer, rectosigmoid junction cancer, and rectal cancer; anal cancer and perianal skin cancer; endometrial cancer, recurrent or metastatic endometrial cancer, uterine corpus cancer and uterine sarcomas; cervical cancer, mesothelioma of the pleura, peritoneum and other sites; pancreatic cancer, inoperable or metastatic pancreatic cancer; malignant tumors of the biliary system, advanced or metastatic cancer of the biliary tract; primary malignant tumors of bone; lung cancer, non-small cell lung cancer, small cell lung cancer; breast cancer, metastatic triple-negative breast cancer with or without BRCA mutations; cutaneous melanoma; metastatic tumors with an ATM mutation; chronic lymphocytic leukemia, myelodysplastic syndrome, chronic myelomonocytic leukemia; esophageal cancer; malignant tumors of the liver; tumors of unknown primary; renal cell carcinoma; bladder cancer and urothelial cancer; gastrointestinal stromal tumors; soft tissue sarcomas; non-melanocytic skin tumors; adrenal cortical cancer, neuroendocrine tumors, primary CNS tumors and metastatic brain tumors, mediastinal tumors, trophoblastic tumors.
26. Use of the compound of any one of claims 1-17 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, or of the pharmaceutical composition of claim 19 for treating a disease or disorder mediated by ATR activity.
27. The use of claim 26, wherein the disease or disorder mediated by ATR activity is an oncological disease.
28. The use of claim 27, wherein the oncological disease is selected from the group comprising ovarian cancer, epithelial ovarian cancer, recurrent platinum-refractory ovarian cancer, recurrent platinum-sensitive ovarian cancer, clear cell ovarian cancer, with BRCA 1/2, ARID1A mutations, borderline ovarian tumors; primary peritoneal cancer; fallopian tube cancer; gastric and gastroesophageal junction cancer, locally advanced unresectable, metastatic, or recurrent gastric and gastroesophageal junction cancer; head and neck tumors, unresectable, locally advanced, or metastatic head and neck tumors, recurrent head and neck tumors; prostate cancer, metastatic prostate cancer, castration-resistant metastatic prostate cancer with BRCA mutations; colorectal cancer, unresectable or metastatic colorectal cancer, colon cancer, rectosigmoid junction cancer, and rectal cancer; anal cancer and perianal skin cancer; endometrial cancer, recurrent or metastatic endometrial cancer, uterine corpus cancer and uterine sarcomas; cervical cancer, mesothelioma of the pleura, peritoneum and other sites; pancreatic cancer, inoperable or metastatic pancreatic cancer; malignant tumors of the biliary system, advanced or metastatic cancer of the biliary tract; primary malignant tumors of bone; lung cancer, non-small cell lung cancer, small cell lung cancer; breast cancer, metastatic triple-negative breast cancer with or without BRCA mutations; cutaneous melanoma; metastatic tumors with an ATM mutation; chronic lymphocytic leukemia, myelodysplastic syndrome, chronic myelomonocytic leukemia; esophageal cancer; malignant tumors of the liver; tumors of unknown primary; renal cell carcinoma; bladder cancer and urothelial cancer; gastrointestinal stromal tumors; soft tissue sarcomas; non-melanocytic skin tumors; adrenal cortical cancer, neuroendocrine tumors, primary CNS tumors and metastatic brain tumors, mediastinal tumors, trophoblastic tumors.
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