Pyrazolo[3,4-b]pyrazine SHP2 phosphatase inhibitor

Abstract

The present invention provides novel pyrazine derivatives of formula (I), or tautomers, solvates, or pharmaceutically acceptable salts thereof, wherein the substituents are as defined herein. The present invention also provides pharmaceutical compositions comprising the compounds, and uses of the compounds in the treatment of diseases, such as cancer. [Formula 1] TIFF2022546213000212.tif73134

Description

Technical Field

[0001] The present invention relates to novel pyrazine derivatives, pharmaceutical compositions comprising the compounds, and the use of the compounds in the treatment of diseases such as cancer.

[0002] Related applications This application claims priority to UK Patent Application No. 1911928.8, filed on August 20, 2019, the content of which is incorporated herein by reference in its entirety.

Background Art

[0003] Protein tyrosine phosphatase 2 (SHP2) containing Src homology region 2 (SH2) is a ubiquitously expressed protein tyrosine phosphatase encoded by the PTPN11 gene. SHP2 contains two N-terminal tandem SH2 domains (N-SH2, C-SH2), a catalytic phosphatase (PTP) domain, and a C-terminal tail with two tyrosine phosphorylation sites.

[0004] SHP2 switches between an "open" active form and a "closed" inactive form by an autoinhibitory interaction between the N-SH2 and the PTP domain. This naturally occurring autoinhibition is released when bis-tyrosyl phosphorylated peptides bind to the N-SH2 domain and SHP2 adopts an "open" conformation, resulting in activation of the enzyme and exposure of the PTP domain for substrate recognition and catalysis.

[0005] Mutations in PTPN11 have been associated with several human diseases including cancer. Germline PTPN11 mutations are associated with developmental disorders such as Noonan syndrome and Leopard syndrome, while somatic mutations occur in some types of malignant blood diseases such as JMML and, more rarely, in solid tumors.

[0006] SHP2 is required for signal transduction downstream of receptor tyrosine kinases (e.g., EGFR, ALK, PDGFR) and plays a constructive role in the regulation of many cellular processes such as growth factor- and cytokine-stimulated proliferation. Previous studies have shown that SHP2 acts upstream of Ras and is required for complete and sustained activation of the MAPK pathway. Since various cancers often occur when RTKs are deregulated, SHP2 is a valuable target in RTK-activated cancers. SHP2 has also been reported to play a role in the regulation of immune responses by mediating immune checkpoint pathways (e.g., PD-1), as immunoreceptor tyrosine-based inhibitory motifs (ITIMs) bind to the SH2 domain of SHP2 to mediate negative signals. Some SHP2 inhibitor compounds have been reported to show inhibitory effects on in vitro cancer cell growth and increased tumor volume in mouse xenograft models (Nature (2016) 535:148-152).

[0007] The present invention describes a novel series of compounds that selectively inhibit SHP2 and have anti-cancer activity.

Summary of the Invention

[0008] In one aspect, the present invention provides a compound of formula (I)

Chemical Formula

[0009] In a further aspect of the invention, there are provided a compound of formula (I) for use in the prevention or treatment of a disease or condition described herein, which comprises administering the compound of formula (I) to a patient, a pharmaceutical composition comprising the compound of formula (I), and a process for the synthesis of the compound of formula (I).

[0010] Definition Unless otherwise indicated by context, references to formula (I) in all sections of this document (including uses, methods, and other aspects of the invention) include references to all other sub-formulas, subgroups, embodiments, and examples defined herein.

[0011] "Potency" is a measure of drug activity expressed in units of the amount required to produce an effect of a given intensity. A very potent drug elicits a greater response at a lower concentration. Potency is proportional to affinity and efficacy. Affinity is the ability of a drug to bind to a receptor. Efficacy is the relationship between receptor occupancy and the ability to initiate a response at the molecular, cellular, tissue, or system level.

[0012] The term "inhibitor" refers to an enzyme inhibitor, which is a type of ligand or drug that blocks or attenuates a biological response mediated by SHP2. Inhibitors may mediate their effects by binding to the active site or allosteric site of the enzyme, or may interact at unique binding sites not normally involved in the biological regulation of enzyme activity. Inhibition may occur directly or indirectly and may be mediated at any physiological level by any mechanism. As a result, inhibition by a ligand or drug may manifest in functionally different ways under different circumstances. The inhibitory activity may be reversible or irreversible depending on the lifetime of the inhibitor-enzyme complex, which in turn depends on the nature of the inhibitor-enzyme binding.

[0013] As used herein, the term "mediated" is intended to be construed restrictively such that when used in combination with SHP2 as described herein (and as applied to, for example, various physiological processes, diseases, pathologies, conditions, therapies, treatments, or interventions), the processes, diseases, pathologies, conditions, treatments, and interventions to which the term applies are those in which the protein plays a biological role. When the term is applied to a disease, pathology, or condition, the biological role played by the protein may be direct or indirect and may be necessary and / or sufficient for the appearance of symptoms of the disease, pathology, or condition (or its etiology or progression). Thus, protein function (and in particular abnormal levels of function, such as overexpression or underexpression) need not necessarily be the proximate cause of a disease, pathology, or condition, but rather, diseases, pathologies, or conditions that are mediated are intended to include those having a multifactorial etiology and complex progression in which the protein in question is only partially involved. When the term is applied to a treatment, prevention, or intervention, the role played by the protein may be direct or indirect and may be necessary and / or sufficient for the result of the treatment, prevention, or intervention. Thus, pathologies or conditions mediated by a protein include the development of resistance to any particular cancer drug or treatment.

[0014] As used herein in the context of treating a medical condition, i.e., a disease state, disorder, or disease, the term "treatment" generally relates to treatment and therapy, whether in humans or animals (e.g., in veterinary applications), in which some desired therapeutic effect, such as inhibition of the progression of the medical condition, is achieved, including a decrease in the rate of progression, a halt in the rate of progression, an improvement in the medical condition, a reduction or alleviation of at least one symptom associated with or caused by the medical condition being treated, or a cure of the medical condition. For example, treatment can be a reduction of one or some symptoms of a disorder, or a complete eradication of the disorder.

[0015] As used herein in the context of treating a medical condition, i.e., a disease state, disorder, or disease, the term "prevention" (i.e., use of a compound as a preventive measure) generally relates to prevention or prophylaxis, whether in humans or animals (e.g., in veterinary applications), in which some desired preventive effect, such as prevention of the occurrence of a disease or an effect in protecting against a disease, is achieved. Prevention includes completely preventing all symptoms of a disorder indefinitely, merely delaying the onset of one or some symptoms of a disease, or reducing the likelihood of a disease occurring.

[0016] References to the prevention or treatment of medical conditions or diseases such as cancer include, within their scope, for example, alleviating or reducing the incidence of cancer.

[0017] The combinations of the present invention may produce a therapeutically effective effect as compared to the therapeutic effects of the individual compounds / drugs when administered separately.

[0018] The term "effective" includes beneficial effects such as additivity, synergy, reduction of side effects, reduction of toxicity, increase in the time to disease progression, increase in survival time, sensitization or resensitization of one agent to another agent, or improvement of response rate. Advantageously, the effective effect enables each or any of the components to be administered to a patient at a lower dose, thereby reducing the toxicity of chemotherapy while producing and / or maintaining the same therapeutic effect. The "synergistic" effect in this context refers to a therapeutic effect produced by a combination that is greater than the sum of the therapeutic effects of the drugs in the combination when presented individually. The "additive" effect in this context refers to a therapeutic effect produced by a combination that is greater than the therapeutic effect of any of the drugs in the combination when presented individually. The term "response rate" as used herein, in the case of solid tumors, refers to the degree of reduction in tumor size at a given time point, e.g., at 12 weeks. Thus, for example, a response rate of 50% means a 50% reduction in tumor size. References herein to "clinical response" refer to a response rate of 50% or more. "Partial response" is defined herein as a response rate of less than 50%.

[0019] As used herein, the term "combination" is intended to define a material when applied to two or more compounds and / or agents, in which two or more agents are related. The terms "combined" and "combining" in this context should be construed accordingly.

[0020] The relationship of two or more compounds / agents in a combination may be physical or non - physical. Examples of physically related compounds / agents include · A composition (e.g., a single formulation) containing two or more compounds / agents in a mixture (e.g., within the same unit dose), · A composition containing a material in which two or more compounds / agents are chemically / physicochemically bound (e.g., by cross - linking, molecular aggregation, or binding) to, for example, a common vehicle moiety, · A composition comprising a material in which two or more compounds / agents are chemically / physicochemically packaged together (e.g., disposed on or within lipid vesicles, particles (e.g., microparticles or nanoparticles), or emulsion droplets). · Pharmaceutical kits, pharmaceutical packs, or patient packs in which two or more compounds / agents are packaged together (e.g., as part of a series of unit doses) or presented together.

[0021] Examples of physically unrelated compounds / agents include · A material (e.g., a non-single formulation) containing at least one of two or more compounds / agents, and instructions for immediately associating at least one compound therewith to form a physical association of the two or more compounds / agents. · A material (e.g., a non-single formulation) containing at least one of two or more compounds / agents, and instructions for combination therapy with the two or more compounds / agents therewith. · A material containing at least one of two or more compounds / agents, and instructions for administration to a patient population in which the other of the two or more compounds / agents has been (or is to be) administered. · A material containing at least one of two or more compounds / agents in an amount or form adapted specifically for combination with the other of the two or more compounds / agents.

[0022] As used herein, the term "combination therapy" is intended to define a therapy that includes the use of a combination of two or more compounds / agents (as defined above). Thus, references herein to the use of compounds / agents "in combination therapy", "in combination", and "in combination with" may refer to compounds / agents administered as part of the same overall treatment regimen. Thus, the pharmacokinetics of each of the two or more compounds / agents may be different and each may be administered at the same time or at different times. Thus, it is understood that the compounds / agents of the combination may be administered together (i.e., in the same pharmaceutical formulation) or separately (i.e., in different pharmaceutical formulations), sequentially (e.g., before or after) or simultaneously. When administered simultaneously in the same formulation, it is a single formulation, while when administered simultaneously in different pharmaceutical formulations, it is non-single. The pharmacokinetics of each of the two or more compounds / agents in combination therapy may also differ for each route of administration.

[0023] As used herein, the term "pharmaceutical kit" defines a series of one or more unit doses of a pharmaceutical composition together with dosage means (e.g., measuring devices) and / or delivery means (e.g., inhalers or syringes), optionally all contained within a common outer package. In a pharmaceutical kit containing a combination of two or more compounds / agents, the individual compounds / agents may be single formulations or non-single formulations. The unit doses may be contained in blister packs. The pharmaceutical kit may optionally further include instructions for use.

[0024] As used herein, the term "pharmaceutical pack" defines a series of one or more unit doses of a pharmaceutical composition, optionally contained within a common outer package. In a pharmaceutical pack containing a combination of two or more compounds / agents, the individual compounds / agents may be single formulations or non-single formulations. The unit doses may be contained in blister packs. The pharmaceutical pack may optionally further include instructions for use.

[0025] As used herein, the term "optionally substituted" refers to a group that may be unsubstituted or substituted by a substituent as defined herein.

[0026] As used herein, the prefix "C x-y "(where x and y are integers) refers to the number of carbon atoms in a given group. Thus, C 1-6 alkyl groups contain 1 to 6 carbon atoms, C 3-6 cycloalkyl groups contain 3 to 6 carbon atoms, C 1-4 alkoxy groups contain 1 to 4 carbon atoms, and so on.

[0027] As used herein, the term "amino" refers to the group -NH2.

[0028] As used herein, the term "halo" or "halogen" refers to fluorine, chlorine, bromine, or iodine, particularly fluorine or chlorine.

[0029] All hydrogen in a compound (e.g., in an alkyl group or when referred to as hydrogen) includes all isotopes of hydrogen, particularly 1 H and 2 H (deuterium).

[0030] As used herein, the term "oxo" refers to the group =O.

[0031] As used herein, the term "C 1-4 alkyl", as a group or part of a group, refers to a straight-chain or branched-chain saturated hydrocarbon group containing 1 to 4 carbon atoms, respectively. Examples of such groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and the like.

[0032] As used herein, the term "C 2-4 alkenyl" or "C 2-6The term "alkenyl" refers to a straight-chain or branched hydrocarbon group containing 2 to 4 or 2 to 6 carbon atoms and containing a carbon-carbon double bond. Examples of such groups include C 3-4 alkenyl groups or C 3-6 alkenyl groups are included.

[0033] The term "C 2-4 alkynyl" or "C 2-6 alkynyl" refers to a straight-chain or branched hydrocarbon group having 2 to 4 or 2 to 6 carbon atoms and containing a carbon-carbon triple bond. Examples of such groups include C 3-4 alkynyl groups or C 3-6 alkynyl groups are included.

[0034] The term "C 1-4 alkoxy" as used herein refers to -O-C 1-4 alkyl group, where C 1-4 alkyl is as defined herein. Examples of such groups include methoxy, ethoxy, propoxy, butoxy, etc.

[0035] The term "C 3-6 cycloalkyl" as used herein refers to a saturated monocyclic hydrocarbon ring having 3 to 6 carbon atoms. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, etc.

[0036] The term "C 3-6 cycloalkenyl" as used herein refers to a partially saturated monocyclic hydrocarbon ring having 3 to 6 carbon atoms and having one or more (usually one) carbon-carbon double bonds. Examples of such groups include cyclopentenyl, cyclohexenyl, and cyclohexadienyl.

[0037] As used herein as a group or part of a group, the term "hydroxyC 1-4 alkyl" refers to a C 1-4 alkyl group as defined herein, in which one or more (e.g., one, two, or three) hydrogen atoms are replaced by hydroxyl groups. The term "hydroxyC 1-4 alkyl" thus includes monohydroxyC 1-4 alkyl and also polyhydroxyC 1-4 alkyl. Since the hydrogen atoms replaced by hydroxyl groups may be one, two, three, or more, hydroxyC 1-4 alkyl may have one, two, three, or more hydroxyl groups. Examples of such groups include hydroxymethyl, hydroxyethyl, hydroxypropyl, and the like.

[0038] As used herein as a group or part of a group, the term "haloC 1-4 alkyl" refers to a C 1-4 alkyl group as defined herein, in which one or more (e.g., one, two, or three) hydrogen atoms are replaced by halogen atoms. The term "haloC 1-4 alkyl" thus includes monohaloC 1-4 alkyl and also polyhalo 1-4 alkyl. Since the hydrogen atoms replaced by halogen atoms may be one, two, three, or more, haloC 1-4 alkyl may have one, two, three, or more halogen atoms. Examples of such groups include fluoroethyl, fluoromethyl, difluoromethyl, trifluoromethyl, or trifluoroethyl, and the like.

[0039] As used herein as a group or part of a group, the term "haloC 1-4 alkoxy" refers to an -O-C 1-4 alkyl group as defined herein, in which one or more (e.g., one, two, or three) hydrogen atoms are replaced by halogen atoms. The term "haloC1-4 The term "alkoxy", therefore, includes monohalo C 1-4 alkoxy and polyhalo C 1-4 alkoxy as well. Since the hydrogen atoms replaced by halogen may be one, two, three, or more, halo C 1-4 alkoxy may have one, two, three, or more halogens. Examples of such groups include fluoroethyloxy, difluoromethoxy, or trifluoromethoxy.

[0040] As used herein, the term "heterocyclyl group" shall include both aromatic and non-aromatic ring systems, unless otherwise indicated by the context. For this reason, for example, the term "heterocyclyl group" includes within its scope aromatic, non-aromatic, unsaturated, partially saturated, and saturated heterocyclic ring systems. Generally, unless otherwise indicated by the context, such groups may be monocyclic or bicyclic (including fused, spiro, and bridged bicyclic groups), and may include, for example, 3 to 12 ring members, more generally 5 to 10 ring members. References to 4 to 7 ring members include 4, 5, 6, or 7 atoms within the ring, and references to 4 to 6 ring members include 4, 5, or 6 atoms within the ring. Examples of monocyclic groups are groups containing 3, 4, 5, 6, 7, and 8 ring members, more generally 3 to 7 ring members, or 4 to 7 ring members, preferably 5, 6, or 7 ring members, more preferably 5 or 6 ring members. Examples of bicyclic groups are those containing 8, 9, 10, 11, and 12 ring members, more generally 9 to 10 ring members. The heterocyclyl group can be a heteroaryl group having 5 to 12 ring members, more generally 5 to 10 ring members. When referring to a heterocyclyl group herein, the heterocyclic ring is optionally substituted by one or more (e.g., 1, 2, 3, or 4, particularly 1 or 2) substituents as defined herein, unless otherwise indicated by the context, i.e., it may or may not be substituted.

[0041] The heterocyclyl group can be, for example, a 5- or 6-membered monocyclic ring, or a fused 5- and 6-membered ring, or two fused 6-membered rings, or a bicyclic structure formed from two fused 5-membered rings. Each ring may contain up to 5 heteroatoms specifically selected from nitrogen, sulfur, and oxygen, and oxidized nitrogen or sulfur. In particular, the heterocyclyl ring will contain up to 4 heteroatoms, more specifically up to 3 heteroatoms, more generally up to 2 heteroatoms, for example, a single heteroatom. In one embodiment, the heterocyclyl ring will contain one or two heteroatoms selected from N, O, S, and oxidized N or S. In one embodiment, the heterocyclyl ring contains at least one ring nitrogen atom. The nitrogen atom in the heterocyclyl ring can be basic as in the case of imidazole or pyridine, or essentially non-basic as in the case of indole or pyrrole nitrogen. Generally, the number of basic nitrogen atoms present in the heterocyclyl group, including any amino group substituents on the ring, will be less than 5.

[0042] The heterocyclyl group can be attached via a carbon atom or a heteroatom (e.g., nitrogen). Similarly, the heterocyclyl group can be substituted on a carbon atom or a heteroatom (e.g., nitrogen).

[0043] Examples of 5-membered aromatic heterocyclyl groups include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, pyrazolyl, triazolyl, and tetrazolyl groups.

[0044] Examples of 6-membered aromatic heterocyclyl groups include, but are not limited to, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, and triazinyl.

[0045] The term "heteroaryl" is used herein to denote a heterocyclic group having aromatic character. The term "heteroaryl" encompasses polycyclic (e.g., bicyclic) ring systems in which one or more rings are non-aromatic, provided that at least one ring is aromatic. In such polycyclic systems, the group may be attached by an aromatic ring or by a non-aromatic ring.

[0046] Examples of heteroaryl groups are monocyclic and bicyclic groups containing 5 to 12 ring members, more commonly 5 to 10 ring members.

[0047] Examples of 5-membered heteroaryl groups include, but are not limited to, pyrrole, furan, thiophene, imidazole, furazan, oxazole, oxadiazole, oxatriazole, isoxazole, thiazole, thiadiazole, isothiazole, pyrazole, triazole, and tetrazole groups.

[0048] Examples of 6-membered heteroaryl groups include, but are not limited to, pyridine, pyrazine, pyridazine, pyrimidine, and triazine.

[0049] Bicyclic heteroaryl groups include, for example, a) a benzene ring fused to a 5- or 6-membered ring containing 1, 2, or 3 ring heteroatoms, b) a pyridine ring fused to a 5- or 6-membered ring containing 0, 1, 2, or 3 ring heteroatoms, c) a pyrimidine ring fused to a 5- or 6-membered ring containing 0, 1, or 2 ring heteroatoms, d) a pyrrole ring fused to a 5- or 6-membered ring containing 0, 1, 2, or 3 ring heteroatoms, e) a pyrazole ring fused to a 5- or 6-membered ring containing 0, 1, or 2 ring heteroatoms, f) an imidazole ring fused to a 5- or 6-membered ring containing 0, 1, or 2 ring heteroatoms, g) an oxazole ring fused to a 5- or 6-membered ring containing 0, 1, or 2 ring heteroatoms, h) An isoxazole ring fused to a 5- or 6-membered ring containing 0, 1, or 2 ring heteroatoms i) A thiazole ring fused to a 5- or 6-membered ring containing 0, 1, or 2 ring heteroatoms j) An isothiazole ring fused to a 5- or 6-membered ring containing 0, 1, or 2 ring heteroatoms k) A thiophene ring fused to a 5- or 6-membered ring containing 0, 1, 2, or 3 ring heteroatoms l) A furan ring fused to a 5- or 6-membered ring containing 0, 1, 2, or 3 ring heteroatoms m) A cyclohexyl ring fused to a 5- or 6-membered ring containing 1, 2, or 3 ring heteroatoms, and n) A cyclopentyl ring fused to a 5- or 6-membered ring containing 1, 2, or 3 ring heteroatoms, which may be a group selected from these.

[0050] Specific examples of bicyclic heteroaryl groups containing a 5-membered ring fused to another 5-membered ring include, but are not limited to, imidazothiazole (e.g., imidazo[2,1-b]thiazole) and imidazoimidazole (e.g., imidazo[1,2-a]imidazole).

[0051] Specific examples of bicyclic heteroaryl groups containing a 6-membered ring fused to a 5-membered ring include, but are not limited to, benzofuran, benzothiophene, benzimidazole, benzoxazole, isobenzoxazole, benzisoxazole, benzothiazole, benzisothiazole, isobenzofuran, indole, isoindole, indolizine, indoline, isoindoline, purine (e.g., adenine, guanine), indazole, pyrazolopyrimidine (e.g., pyrazolo[1,5-a]pyrimidine), triazolopyrimidine (e.g., [1,2,4]triazolo[1,5-a]pyrimidine), benzodioxole, imidazopyridine, and pyrazolopyridine (e.g., pyrazolo[1,5-a]pyridine) groups.

[0052] Specific examples of bicyclic heteroaryl groups containing two fused 6-membered rings include, but are not limited to, quinoline, isoquinoline, chroman, thiochroman, isochroman, chromene, isochromene, benzodioxane, quinolizine, benzoxazine, pyridopyridine, quinoxaline, quinazoline, cinnoline, phthalazine, naphthyridine, and pteridine groups.

[0053] Examples of polycyclic heteroaryl groups containing aromatic and non-aromatic rings include, but are not limited to, tetrahydroisoquinoline, tetrahydroquinoline, dihydrobenzothiophene, dihydrobenzofuran, 2,3-dihydro-benzo[1,4]dioxin, benzo[1,3]dioxole, 4,5,6,7-tetrahydrobenzofuran, tetrahydrotriazolopyrazine (e.g., 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine), chroman, thiochroman, isochroman, chromene, isochromene, benzodioxane, benzoxazine, benzodiazepine, and indoline groups.

[0054] The nitrogen-containing heteroaryl ring needs to contain at least one ring nitrogen atom. The nitrogen-containing heteroaryl ring can be of the N-linked type or the C-linked type. In addition, each ring may contain up to about 4 other heteroatoms, particularly selected from nitrogen, sulfur, and oxygen. In particular, the heteroaryl ring will contain up to 3 heteroatoms, e.g., 1, 2, or 3, more generally up to 2 nitrogens, e.g., a single nitrogen. The nitrogen atoms in the heteroaryl ring can be basic as in the case of imidazole or pyridine, or essentially non-basic as in the case of indole or pyrrole nitrogen. Generally, the number of basic nitrogen atoms present in the heteroaryl group, including any amino group substituents of the ring, will be less than 5.

[0055] Examples of nitrogen-containing heteroaryl groups include monocyclic groups such as pyridyl, pyrrolyl, imidazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, furazanyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl (e.g., 1,2,3-triazolyl, 1,2,4-triazolyl), tetrazolyl, and bicyclic groups such as quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, benzisoxazole, benzothiazolyl, and benzisothiazole, indolyl, 3H-indolyl, isoindolyl, indolizinyl, isoindolinyl, purinyl (e.g., adenine [6-aminopurine], guanine [2-amino-6-hydroxypurine]), indazolyl, quinolidinyl, benzoxazinyl, benzodiazepinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl, and pteridinyl, but are not limited thereto.

[0056] Examples of nitrogen-containing polycyclic heteroaryl groups containing aromatic and non-aromatic rings include tetrahydroisoquinolinyl, tetrahydroquinolinyl, and indolinyl.

[0057] The term "non-aromatic" encompasses unsaturated ring systems, partially saturated and saturated heterocyclyl ring systems that do not have aromatic characteristics, unless otherwise indicated in the context. The terms "unsaturated" and "partially saturated" refer to a ring structure that contains atoms sharing more than one valence bond, i.e., a ring containing at least one multiple bond, e.g., a C=C, C≡C, or N=C bond. The term "saturated" refers to a ring having no multiple bonds between ring atoms. Saturated heterocyclyl groups include piperidinyl, morpholinyl, and thiomorpholinyl. Partially saturated heterocyclyl groups include pyrazolinyl, e.g., pyrazolin-2-yl and pyrazolin-3-yl.

[0058] Examples of non-aromatic heterocyclyl groups are groups having 3 to 12 ring members, more generally 5 to 10 ring members. Such groups can be monocyclic or bicyclic and have, for example, 3 to 7 ring members, in particular 4 to 6 ring members. Such groups have, in particular, 1 to 5 or 1 to 4 heteroatom ring members (more generally 1, 2, or 3 heteroatom ring members), which are usually selected from nitrogen, oxygen, and sulfur, and their oxidized forms. The heterocyclyl group can include, for example, cyclic ether moieties (such as those found in tetrahydrofuran and dioxane), cyclic thioether moieties (such as those found in tetrahydrothiophene and dithiane), cyclic amine moieties (such as those found in pyrrolidine), cyclic amide moieties (such as those found in pyrrolidone), cyclic thioamide, cyclic thioester, cyclic urea (such as those found in imidazolidin-2-one), cyclic ester moieties (such as those found in butyrolactone), cyclic sulfone (such as those found in sulfolane and sulfolene), cyclic sulfoxide, cyclic sulfonamide, and combinations thereof (such as thiomorpholine).

[0059] Specific examples include morpholinyl, piperidinyl (e.g., piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, and piperidin-4-yl), piperidinonyl, pyrrolidinyl (e.g., pyrrolidin-1-yl, pyrrolidin-2-yl, and pyrrolidin-3-yl), pyrrolidonyl, azetidinyl, pyranyl (2H-pyran or 4H-pyran), dihydrothienyl, dihydropyranyl, dihydrofuranyl, dihydrothiazolyl, tetrahydrofuranyl, tetrahydrothienyl, dioxanyl, oxanyl (also known as tetrahydropyranyl) (e.g., oxan-4-yl), imidazolinyl, imidazolidinonyl, oxazolinyl, thiazolinyl, pyrazolin-2-yl, pyrazolidinyl, piperazinonyl, piperazinyl, and N-alkylpiperazines such as N-methylpiperazinyl. Generally, typical non-aromatic heterocyclyl groups include saturated groups such as piperidinyl, pyrrolidinyl, azetidinyl, morpholinyl, piperazinyl, and N-alkylpiperazines such as N-methylpiperazinyl.

[0060] In a nitrogen-containing non-aromatic heterocyclic ring, the ring needs to contain at least one ring nitrogen atom. The nitrogen-containing heterocyclic ring can be of the N-linked type or the C-linked type. The heterocyclic group can include, for example, a cyclic amine moiety (such as that in pyrrolidinyl), a cyclic amide (such as pyrrolidinonyl, piperidinonyl, or caprolactamyl), a cyclic sulfonamide (such as isothiazolidinyl 1,1-dioxide, [1,2]thiadinanyl 1,1-dioxide, or [1,2]thiazepanyl 1,1-dioxide), and combinations thereof.

[0061] Specific examples of nitrogen-containing non-aromatic heterocyclyl groups include aziridinyl, morpholinyl, thiomorpholinyl, piperidinyl (e.g., piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, and piperidin-4-yl), pyrrolidinyl (e.g., pyrrolidin-1-yl, pyrrolidin-2-yl, and pyrrolidin-3-yl), pyrrolidonyl, dihydrothiazolyl, imidazolinyl, imidazolidinonyl, oxazolinyl, thiazolinyl, 6H-1,2,5-thiadiazinyl, pyrazolin-2-yl, pyrazolin-3-yl, pyrazolidinyl, piperazinyl, and N-alkylpiperazines such as N-methylpiperazinyl.

[0062] The heterocyclyl group can also be a polycyclic fused ring system or a bridged ring system such as the oxa and aza analogs of bicycloalkane and tricycloalkane (e.g., adamantane and oxa-adamantane). For an explanation of the distinction between fused ring systems and bridged ring systems, see Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience, pages 131 - 133, 1992.

[0063] In the definition of a cyclic group or ring, when it is stated that a cyclic group contains a certain number of heteroatom ring members, for example, as in the phrase "a 5- or 6-membered ring containing 0, 1, or 2 nitrogen ring members", this is interpreted to mean that, apart from the specified certain number of heteroatom ring members, the remaining ring members are carbon atoms.

[0064] The compound of formula (I) may contain a saturated cyclic group that can be joined to the rest of the molecule by one or more bonds. When the cyclic group is joined to the rest of the molecule by two or more bonds, these bonds (or two of these bonds) can be made to the same atom (usually a carbon atom) or different atoms of the ring. When the bond is made to the same atom of the ring, this results in a cyclic group having a single atom (usually a quaternary carbon) to which two groups are attached. In other words, when the compound of formula (I) contains a cyclic group, the group may be linked to the rest of the molecule either by a bond or by the cyclic group itself, and the rest of the molecule can have a common atom, for example, a spiro compound.

[0065] Each heterocyclyl group can be either unsubstituted or substituted with one or more (e.g., 1, 2, or 3) substituents. For example, a heterocyclyl or carbocyclyl group can be either unsubstituted or substituted with 1, 2, 3, or 4 substituents, and in particular, these are either unsubstituted or have 1, 2, or 3 substituents as defined herein. When the cyclic group is saturated, there may be two substituents attached to the same carbon (when the substituents are the same, so-called geminal or "gem" disubstituted).

[0066] Combinations of substituents are only permitted if such combinations result in a stable or chemically feasible compound (i.e., one that does not substantially change when held at 40 °C or below for at least one week).

[0067] The various functional groups and substituents that make up the compounds of the present invention are specifically selected so that the molecular weight of the compounds of the present invention does not exceed 1000. More generally, the molecular weight of the present compounds is less than 750, for example, less than 700, or less than 650, or less than 600, or less than 550. More specifically, the molecular weight is less than 525, for example, 500 or less.

Mode for Carrying Out the Invention

[0068] The present invention provides a compound of formula (I) [Chemical formula] or a tautomer or solvate or pharmaceutically acceptable salt thereof, wherein X, R 1 , R 2 , R 3 , R 6 , R 7 , R 8 , and R 9 are as defined herein.

[0069] X X is O or CR 4 R 5 .

[0070] When X is CR 4 R 5 , R 4 and R 5 are independently selected from hydrogen, halogen, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy, and halo C 1-4 alkyl.

[0071] In one embodiment, R 4 and R 5 are independently selected from hydrogen, halogen, C 1-4 alkyl, and halo C 1-4 alkyl (e.g., halo C1 alkyl).

[0072] In one embodiment, X is O and the compound of formula (I) is a compound of formula (Ia). [Chemical formula]

[0073] In one embodiment, X is CR 4 R 5 and the compound of formula (I) is a compound of formula (Ib), [Chemical formula] In the formula, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、and R 9 are as defined herein.

[0074] In particular, X is O, and the compound of formula (I) is a compound of formula (Ia).

[0075] In one embodiment, X is CR 4 R 5 and R 4 and R 5 are independently selected from hydrogen, halogen (e.g., fluorine, chlorine, bromine, or iodine, in particular, fluorine), and haloC 1-4 alkyl (e.g., monohalomethyl, dihalomethyl, and trihalomethyl where the halo is selected from fluorine, chlorine, bromine, or iodine).

[0076] In one embodiment, X is CR 4 R 5 and R 4 and R 5 are independently selected from hydrogen, fluorine, and trifluoromethyl.

[0077] In one embodiment, X is CR 4 R 5 and R 4 and R 5 are hydrogen.

[0078] In one embodiment, X is CR 4 R 5 and R 4 and R 5 are halogen (e.g., fluorine).

[0079] In one embodiment, X is CR 4 R 5and R 4 is hydrogen, and R 5 is selected from halogen (e.g., fluorine, chlorine, bromine, or iodine, especially fluorine) and halomethyl (e.g., monohalomethyl, dihalomethyl, and trihalomethyl where halo is selected from fluorine, chlorine, bromine, or iodine).

[0080] In one embodiment, X is CR 4 R 5 and R 4 is hydrogen, and R 5 is fluorine or trifluoromethyl.

[0081] In one embodiment, X is CR 4 R 5 and R 4 is hydrogen, and R 5 is fluorine.

[0082] In one embodiment, X is CR 4 R 5 and R 4 is hydrogen, and R 5 is trifluoromethyl.

[0083] In one embodiment, X is CR 4 R 5 and R 4 is hydrogen, and R 5 is selected from halogen (e.g., fluorine, chlorine, bromine, or iodine, especially fluorine) and halomethyl (e.g., monohalomethyl, dihalomethyl, and trihalomethyl where halo is selected from fluorine, chlorine, bromine, or iodine), and the compound of formula (Ib) is a compound of formula (Ib’),

Chemical formula

[0084] In one embodiment of the compound of formula (Ib’), R 5 is fluorine or trifluoromethyl, particularly fluorine.

[0085] In one embodiment, X is CR 4 R 5 wherein R 4 is hydrogen, and R 5 is selected from halogen (e.g., fluorine, chlorine, bromine, or iodine, particularly fluorine) and halomethyl (e.g., monohalomethyl, dihalomethyl, and trihalomethyl where halo is selected from fluorine, chlorine, bromine, or iodine), and the compound of formula (Ib) is a compound of formula (Ib’’),

Chemical formula

[0086] In one embodiment of the compound of formula (Ib’’), R 5 is fluorine or trifluoromethyl, particularly trifluoromethyl.

[0087] R 1 R 1 is hydrogen or hydroxyl.

[0088] In one embodiment, R 1 is hydrogen, and the compound of formula (I) is a compound of formula (II),

Chemical formula

[0089] In one embodiment, R 1 is hydroxyl, and the compound of formula (I) is the compound of formula (III),

Chemical formula

[0090] In particular, R 1 is hydroxyl, and the compound of formula (I) is the compound of formula (III).

[0091] In particular, R 1 is hydroxyl, X is O, and the compound of formula (III) is the compound of formula (III’),

Chemical formula

[0092] R 2 and R 3 R 2 and R 3 are independently selected from hydrogen, halogen, C 1-4 alkyl, halo C 1-4 alkyl, hydroxy C 1-4 alkyl, and -CN.

[0093] In one embodiment, R 2 and R 3 are independently selected from hydrogen, C 1-4 alkyl, halo C 1-4 alkyl, hydroxy C 1-4 alkyl, and -CN.

[0094] In one embodiment, R 2 and R 3 are hydrogen.

[0095] In one embodiment, R 2 is hydrogen and R 3 is selected from C 1-4 alkyl, halo C 1-4 alkyl, hydroxy C 1-4 alkyl, and -CN.

[0096] In one embodiment, R 2 is hydrogen and R 3 is selected from C 1-4 alkyl, halo C 1-4 alkyl, and hydroxy C 1-4 alkyl.

[0097] In one embodiment, R 2 is hydrogen and R 3 is C 1-4 alkyl, for example, -CH3.

[0098] In one embodiment, R 2 is hydrogen and R 3 is a halogen, for example, -F.

[0099] In one embodiment, R 2 is a halogen, for example, -F and R 3 is hydrogen.

[0100] In one embodiment, R 2 and R 3 are a halogen, for example, -F.

[0101] In one embodiment, R 2 is hydrogen, and R 3 is selected from C 1-4 alkyl, halo C 1-4 alkyl, hydroxy C 1-4 alkyl, and -CN, and the compound of formula (I) is a compound of formula (IV),

Chemical formula

[0102] In one embodiment, the compound of formula (IV) is a compound of formula (IV’),

Chemical formula

[0103] In one embodiment, the compound of formula (IV) is a compound of formula (IV’’),

Chemical formula

[0104] In one embodiment of the compounds of formula (IV), (IV’), and (IV’’), R 3 is C1-4 Alkyl, halo C 1-4 Alkyl, and hydroxy C 1-4 Selected from alkyl.

[0105] In one embodiment of the compounds of formula (IV), (IV’), and (IV’’), R 3 is C 1-4 Selected from alkyl, for example, -CH3.

[0106] In particular, the compound of formula (IV) is the compound of formula (IV’’), and R 3 is C 1-4 Selected from alkyl, for example, -CH3.

[0107] In one embodiment of the compounds of formula (IV), (IV’), and (IV’’), R 3 is C 1-4 Selected from alkyl, for example, -CH3, and X is O.

[0108] In particular, the compound of formula (IV) is the compound of formula (IV’’), and R 3 is C 1-4 Selected from alkyl, for example, -CH3, and X is O.

[0109] R 8 R 8 is halo C 1-4 Selected from alkyl (e.g., -CF3), -CH3, and halogen (e.g., chlorine or fluorine).

[0110] In one embodiment, R 8 is C 1-4 Selected from alkyl (e.g., -CH3), halo C 1-4 Selected from alkyl (e.g., -CF3), and chlorine.

[0111] In one embodiment, R 8 is selected from -CH3, chlorine, and fluorine.

[0112] In one embodiment, R8 is a halogen (for example, fluorine, chlorine, bromine, or iodine, for example, fluorine or chlorine), and the compound of formula (I) is a compound of formula (V), or a tautomer thereof, or a solvate, or a pharmaceutically acceptable salt,

Chemical formula

[0113] In one embodiment, R 8 is selected from methyl, chlorine, and fluorine.

[0114] In one embodiment, R 8 is selected from chlorine and fluorine.

[0115] In one embodiment, R 8 is methyl.

[0116] In particular, R 8 is fluorine.

[0117] In particular, R 8 is chlorine.

[0118] In one embodiment of the compound of formula (V), X is CR 4 R 5 .

[0119] In particular, in one embodiment of the compound of formula (V), X is O.

[0120] In one embodiment of the compound of formula (V), R 1 is hydrogen.

[0121] In particular, in one embodiment of the compound of formula (V), R 1 is hydroxyl.

[0122] In particular, in one embodiment of the compound of formula (V), X is O and R 1 is hydroxyl.

[0123] R 9 R 9 is selected from hydrogen, C 1-4 alkyl (e.g., -CH3), halo C 1-4 alkyl (e.g., -CF3), and halogen (e.g., chlorine).

[0124] In one embodiment, R 9 is selected from hydrogen, -CH3, -CF3, chlorine, and fluorine.

[0125] In one embodiment, R 9 is selected from hydrogen, -CH3, -CF3, and chlorine.

[0126] In particular, R 9 is hydrogen and the compound of formula (I) is a compound of formula (VI), or a tautomer, or a solvate, or a pharmaceutically acceptable salt thereof,

Chemical formula

[0127] In one embodiment of the compound of formula (VI), X is CR 4 R 5 is.

[0128] In particular, in one embodiment of the compound of formula (VI), X is O.

[0129] In one embodiment of the compound of formula (VI), R 1 is hydrogen.

[0130] In particular, in one embodiment of the compound of formula (VI), R 1 is hydroxyl.

[0131] In particular, in one embodiment of the compound of formula (VI), R 8 is halogen, for example, chlorine.

[0132] In particular, in one embodiment of the compound of formula (VI), X is O, R 1 is hydroxyl, and R 8 is chlorine.

[0133] R 6 and R 7 R 6 and R 7 are hydrogen, C 1-4 alkoxy, or halogen (for example, chlorine or fluorine), or R 6 and R 7 join together to form ring A optionally substituted with one or more (for example, 1, 2, or 3) R 10 groups.

[0134] In one embodiment, R 6 and R 7 are hydrogen or halogen (for example, chlorine or fluorine), or R 6 and R 7 join together to form ring A optionally substituted with one or more (for example, 1, 2, or 3) R 10 groups, and ring A is (i) a 5-membered nitrogen-containing heterocyclic ring (for example, an aromatic or non-aromatic ring) containing one or two additional heteroatoms selected from N, O, and S, optionally, a 5-membered nitrogen-containing heterocyclic ring, or (ii) a 6-membered aromatic nitrogen-containing heterocyclic ring, wherein the heterocyclic ring optionally contains one or two additional heteroatoms selected from N, O, and S, or (iii) a 6-membered non-aromatic nitrogen-containing heterocyclic ring, wherein the heterocyclic ring optionally contains one or two additional heteroatoms selected from N and S, R 10 is independently halogen, cyano, cyanoC 1-4 alkyl (e.g., -CH2-CN), hydroxyl, =O (oxo), C 1-4 alkyl (e.g., -CH3, -CH(CH3)2, or -CH2CH3), haloC 1-4 alkyl (e.g., -CHF2), C 1-4 alkoxy (e.g., -OCH3, -OCH2CH3, and -OCH(CH3)2), hydroxylC 1-4 alkyl (e.g., -CH2C(CH3)2OH, -CH(CH3)CH2OH, -CH(CH3)OH, -CH2CH2OH, or -CH2OH), C 1-4 alkoxyC 1-4 alkylene (e.g., -CH2-O-CH3, or -CH2-CH2-O-CH3), C 1-4 alkylsulfone (e.g., -SO2CH3), amino, monoC 1-4 alkylamino, diC 1-4 alkylamino (e.g., -N(CH3)2), aminoC 1-4 alkylene (e.g., -CH2NH2), -C 1-4 alkylene-C(=O)NH (2-q) (C 1-6 alkyl) q )、-C 0-4 alkylene-NHC(=O)C 1-6 alkyl, sulfonamideC 0-4 alkylene (e.g., R x is independently H and C 1-6 alkyl selected from -SO2NR x 2 or -CH2SO2NR x2), selected from optionally substituted 5- or 6-membered unsaturated heterocyclic groups containing one, two, three, or four heteroatoms selected from 3-6 membered cycloalkyl, O, N, or S, wherein the optional substituents are C 1-4 alkyl, C substituted with 3-6 membered cycloalkyl 1-4 alkyl, C substituted with an optionally substituted 5- or 6-membered unsaturated heterocyclic group containing one, two, three, or four heteroatoms selected from O, N, or S 1-4 selected from alkyl, wherein the optional substituents are C 1-4 alkyl, C substituted with an optionally substituted 4-6 membered saturated heterocyclic group containing one or two heteroatoms selected from O, N, or S 1-4 selected from alkyl, wherein the optional substituents are C 1-4 selected from alkyl and an optionally substituted 4-6 membered saturated heterocyclic group containing one or two heteroatoms selected from O, N, or S, wherein the optional substituents are C 1-4 selected from alkyl, q is selected from 0, 1, or 2.

[0135] In one embodiment, R 6 and R 7 are halogen, C 1-4 alkoxy, or fluorine, or R 6 and R 7 join together to form ring A, optionally substituted with one or more (e.g., one, two, or three) R 10 groups.

[0136] In one embodiment, R 6 and R 7 are halogen or fluorine, or R 6 and R 7 join together to form ring A, optionally substituted with one or more (e.g., one, two, or three) R 10 groups. Ring A is (i) A 5-membered nitrogen-containing heterocyclic ring (e.g., an aromatic or non-aromatic ring), wherein the heterocyclic ring optionally contains one or two additional heteroatoms selected from N, O, and S, or (ii) A 6-membered aromatic nitrogen-containing heterocyclic ring, wherein the heterocyclic ring optionally contains one or two additional heteroatoms selected from N, O, and S, or (iii) A 6-membered non-aromatic nitrogen-containing heterocyclic ring, wherein the heterocyclic ring optionally contains one or two additional heteroatoms selected from N and S, any of which is R 10 is independently halogen, cyano, cyanoC 1-4 alkyl (e.g., -CH2-CN), hydroxyl, =O (oxo), C 1-4 alkyl (e.g., -CH3, -CH(CH3)2, or -CH2CH3), haloC 1-4 alkyl (e.g., -CHF2), C 1-4 alkoxy (e.g., -OCH3, -OCH2CH3, and -OCH(CH3)2), hydroxylC 1-4 alkyl (e.g., -CH2C(CH3)2OH, -CH(CH3)CH2OH, -CH(CH3)OH, -CH2CH2OH, or -CH2OH), C 1-4 alkoxyC 1-4 alkylene (e.g., -CH2-O-CH3, or -CH2-CH2-O-CH3), C 1-4 alkylsulfone (e.g., -SO2CH3), amino, monoC 1-4 alkylamino, diC 1-4 alkylamino (e.g., -N(CH3)2), aminoC 1-4 alkylene (e.g., -CH2NH2), -C 1-4 alkylene-C(=O)NH (2-q) (C 1-6 alkyl) q )、-C 0-4 alkylene-NHC(=O)C 1-6 alkyl, sulfonamideC 0-4Alkylene (e.g., R x is independently selected from H and C 1-6 alkyl, -SO2NR x 2 or -CH2SO2NR x 2), a 3- to 6-membered cycloalkyl, one, two, three, or four heteroatoms selected from O, N, or S, and an optionally substituted 5- or 6-membered unsaturated heterocyclic group, wherein the optional substituents are selected from C 1-4 alkyl, C 1-4 alkyl substituted with a 3- to 6-membered cycloalkyl, one, two, three, or four heteroatoms selected from O, N, or S, and an optionally substituted 5- or 6-membered unsaturated heterocyclic group, C 1-4 alkyl, wherein the optional substituents are selected from C 1-4 alkyl, C 1-4 alkyl substituted with an optionally substituted 4- to 6-membered saturated heterocyclic group containing one or two heteroatoms selected from O, N, or S, wherein the optional substituents are selected from C 1-4 alkyl, and an optionally substituted 4- to 6-membered saturated heterocyclic group containing one or two heteroatoms selected from O, N, or S, wherein the optional substituents are selected from C 1-4 alkyl, q is selected from 0, 1, or 2.

[0137] In one embodiment, R 6 and R 7 are hydrogen or a halogen (e.g., chlorine or fluorine).

[0138] In one embodiment, R 6 and R 7 are hydrogen, C 1-4 alkoxy, or fluorine.

[0139] In one embodiment, R 6 and R 7 are hydrogen or C 1-4 alkoxy.

[0140] In one embodiment, R 6 and R 7 are hydrogen.

[0141] In particular, R 7 is hydrogen, R 6 is halogen (for example, chlorine or fluorine), and the compound of formula (I) is a compound of formula (VII), or a tautomer thereof, or a solvate, or a pharmaceutically acceptable salt.

Chemical formula

[0142] In particular, in one embodiment of the compound of formula (VII), R 8 is fluorine.

[0143] In particular, in one embodiment of the compound of formula (VII), R 8 is chlorine.

[0144] In one embodiment of the compound of formula (VII), X is CR 4 R 5 is.

[0145] In particular, in one embodiment of the compound of formula (VII), X is O.

[0146] In one embodiment of the compound of formula (VII), R 1 is hydrogen.

[0147] In particular, in one embodiment of the compound of formula (VII), R 1 is hydroxyl.

[0148] In particular, in one embodiment of the compound of formula (VII), R 8 is halogen, for example, chlorine or fluorine.

[0149] In particular, in one embodiment of the compound of formula (VII), R 9 is hydrogen.

[0150] In particular, in one embodiment of the compound of formula (VII), X is O, R 1 is hydroxyl, R 9 is hydrogen, and R 8 is chlorine or fluorine.

[0151] In one embodiment, R 6 and R 7 are joined to form ring A, optionally substituted with one or more (e.g., 1, 2, or 3) R 10 groups, and ring A is (i) a 5-membered nitrogen-containing heterocyclic ring (e.g., an aromatic or non-aromatic ring) that optionally contains one or two additional heteroatoms selected from N, O, and S, a 5-membered nitrogen-containing heterocyclic ring, or (ii) a 6-membered aromatic nitrogen-containing heterocyclic ring that optionally contains one or two additional heteroatoms selected from N, O, and S, a 6-membered aromatic nitrogen-containing heterocyclic ring, or (iii) a 6-membered non-aromatic nitrogen-containing heterocyclic ring that optionally contains one or two additional heteroatoms selected from N and S, a 6-membered non-aromatic nitrogen-containing heterocyclic ring,

[0152] In one embodiment, ring A is a 5-membered nitrogen-containing heterocyclic ring (e.g., an aromatic or non-aromatic ring) or a 6-membered aromatic nitrogen-containing heterocyclic ring, which optionally contains one or two additional heteroatoms selected from N, O, and S.

[0153] In one embodiment, ring A is pyrazolyl, thiazolyl, pyrazinyl, and pyridyl. Next, a benzo moiety is condensed thereto to form indazolyl, benzothiazolyl, quinoxalinyl, or quinolinyl, respectively.

[0154] In one embodiment, ring A is a 5-membered nitrogen-containing heterocyclic ring (e.g., an aromatic or non-aromatic ring), and this heterocyclic ring optionally contains one or two additional heteroatoms selected from N, O, and S.

[0155] In one embodiment, ring A is a 5-membered nitrogen-containing heterocyclic ring (e.g., an aromatic or non-aromatic ring) or a 6-membered aromatic nitrogen-containing heterocyclic ring, and this heterocyclic ring optionally contains one or two additional heteroatoms selected from N, O, and S.

[0156] In one embodiment, ring A is a 5-membered nitrogen-containing heterocyclic ring, and this heterocyclic ring optionally contains one or two additional heteroatoms selected from N, O, and S.

[0157] In one embodiment, ring A is a 5-membered nitrogen-containing heterocyclic ring, and this heterocyclic ring optionally contains one additional heteroatom selected from N, O, and S.

[0158] In one embodiment, ring A is a 5-membered nitrogen-containing heterocyclic ring, and this heterocyclic ring optionally contains one additional heteroatom which is N or S.

[0159] In one embodiment, ring A is a 5-membered aromatic nitrogen-containing heterocyclic ring, and this heterocyclic ring optionally contains one or two additional heteroatoms selected from N and S.

[0160] In one embodiment, ring A is a 5-membered nitrogen-containing heterocyclic ring, and this heterocyclic ring contains one additional heteroatom which is N.

[0161] In one embodiment, ring A is a 5-membered aromatic nitrogen-containing heterocyclic ring, and this heterocyclic ring contains one additional heteroatom which is N.

[0162] In one embodiment, ring A is a 5-membered nitrogen-containing heterocyclic ring, and this heterocyclic ring contains one additional heteroatom that is S.

[0163] In one embodiment, ring A is a 5-membered aromatic nitrogen-containing heterocyclic ring, and this heterocyclic ring contains one additional heteroatom that is S.

[0164] In one embodiment, ring A is pyrrolyl, imidazolyl, oxazolyl, oxadiazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, pyrazolyl, and triazolyl. For example, ring A is thiazolyl or pyrazolyl.

[0165] In one embodiment, ring A is a 5-membered nitrogen-containing heterocyclic ring (e.g., an aromatic or non-aromatic ring), the heterocyclic ring optionally contains one or two additional heteroatoms selected from N, O, and S, and the compound of formula (I) is a compound of formula (VIII), or a tautomer thereof, or a solvate, or a pharmaceutically acceptable salt,

Chemical formula

[0166] In one embodiment, the following moiety is

Chemical formula

[0167]

Table 1

[0168] For example, the following part is

Chemical formula

[0169] In particular, the following part is

Chemical formula

[0170] In particular, the following part is

Chemical formula

[0171] In particular, the following part is

Chemical formula

Chemical formula

Chemical formula

[0172] In particular, the following part is

Chem.

Chem.

[0173] In particular, the compound of formula (VIII) is a compound of formula (VIIIa), or a tautomer, or a solvate, or a pharmaceutically acceptable salt thereof,

Chem.

[0174] In particular, the compound of formula (VIIIa) is a compound of formula (VIIIb), or a tautomer, or a solvate, or a pharmaceutically acceptable salt thereof,

Chem.

[0175] In particular, the compound of formula (VIIIa) is a compound of formula (VIIIc), or a tautomer, or a solvate, or a pharmaceutically acceptable salt thereof,

Chem.

[0176] In particular, the compound of formula (VIII) is a compound of formula (IX), or a tautomer, or a solvate, or a pharmaceutically acceptable salt thereof, [Chemical formula] In the formula, X, R 1 , R 2 , R 3 , R 8 , R 9 , and R 10 are as defined herein.

[0177] In particular, the compound of formula (VIII) is a compound of formula (IXa), or a tautomer, or a solvate, or a pharmaceutically acceptable salt thereof, [Chemical formula] In the formula, X, R 1 , R 2 , R 3 , R 8 , and R 9 are as defined herein, and R 10 is independently selected from C 1-4 alkyl (e.g., -CH3) and halogen (e.g., chlorine). In particular, R 10 is independently selected from C 1-4 alkyl (e.g., -CH3) when on a nitrogen or carbon atom, and halogen (e.g., chlorine) when on a carbon atom.

[0178] In particular, the compound of formula (VIII) is a compound of formula (IXb), or a tautomer, or a solvate, or a pharmaceutically acceptable salt thereof, [Chemical formula] In the formula, X, R 1 , R 2 , and R 3 are as defined herein.

[0179] In particular, the compound of formula (VIII) is a compound of formula (X), or a tautomer, or a solvate, or a pharmaceutically acceptable salt thereof, [Chemical formula] In the formula, X, R 1 , R 2 , R 8 , R 9 , and R 10 are as defined herein.

[0180] In particular, in one embodiment of the compounds of formula (VIII), (VIIIa), (VIIIb), (VIIIc), (IX), (IXa), and (X), R 8 is halogen, for example, chlorine or fluorine.

[0181] In particular, in one embodiment of the compounds of formula (VIII), (VIIIa), (VIIIb), (VIIIc), (IX), (IXa), and (X), R 8 is fluorine.

[0182] In particular, in one embodiment of the compounds of formula (VIII), (VIIIa), (VIIIb), (VIIIc), (IX), (IXa), and (X), R 8 is chlorine.

[0183] In one embodiment of the compounds of formula (VIII), (VIIIa), (VIIIb), (VIIIc), (IX), (IXa), and (X), X is CR 4 R 5 is.

[0184] In particular, in one embodiment of the compounds of formula (VIII), (VIIIa), (VIIIb), (VIIIc), (IX), (IXa), and (X), X is O.

[0185] In one embodiment of the compounds of formula (VIII), (VIIIa), (VIIIb), (VIIIc), (IX), (IXa), and (X), R 1 is hydrogen.

[0186] In particular, in one embodiment of the compounds of formula (VIII), (VIIIa), (VIIIb), (VIIIc), (IX), (IXa), and (X), R 1 is hydroxyl.

[0187] In particular, in one embodiment of the compounds of formula (VIII), (VIIIa), (VIIIb), (VIIIc), (IX), (IXa), and (X), R 9 is hydrogen.

[0188] In particular, in one embodiment of the compounds of formula (VIII), (VIIIa), (VIIIb), (VIIIc), (IX), (IXa), and (X), X is O, R 1 is hydroxyl, R 9 is hydrogen, R 8 is chlorine or fluorine.

[0189] In one embodiment, ring A is (i) a 6-membered aromatic nitrogen-containing heterocyclic ring, wherein the heterocyclic ring optionally contains one or two additional heteroatoms selected from N, O, and S, or (ii) a 6-membered non-aromatic nitrogen-containing heterocyclic ring, wherein the heterocyclic ring optionally contains one or two additional heteroatoms selected from N and S.

[0190] In one embodiment, ring A is a 6-membered aromatic nitrogen-containing heterocyclic ring, and the compound of formula (I) is a compound of formula (XI), or a tautomer, solvate, or pharmaceutically acceptable salt thereof, [Chemical formula] wherein X, R 1 , R 2 , R 3 , R 8 , R 9 , and R 10 are as defined herein, and 6-Het is (i) a 6-membered aromatic nitrogen-containing heterocyclic ring, wherein the heterocyclic ring optionally contains one or two additional heteroatoms selected from N, O, and S, or (iii) a 6-membered non-aromatic nitrogen-containing heterocyclic ring, wherein the heterocyclic ring optionally contains one or two additional heteroatoms selected from N and S.

[0191] When ring A is a 6-membered nitrogen-containing ring, if the ring is aromatic, the ring may optionally contain one or two additional heteroatoms selected from N, O, and S. However, if the 6-membered nitrogen-containing ring is non-aromatic, the ring may optionally contain one or two additional heteroatoms selected from N and S, i.e., the ring cannot contain an additional heteroatom that is O.

[0192] In one embodiment, 6-Het is a 6-membered nitrogen-containing heterocyclic ring, which optionally contains one or two additional heteroatoms selected from N and S.

[0193] In particular, 6-Het is a 6-membered nitrogen-containing heterocyclic ring, which optionally contains one or two additional heteroatoms selected from N.

[0194] In particular, 6-Het is a 6-membered nitrogen-containing heterocyclic ring, which optionally contains one additional heteroatom selected from N.

[0195] In particular, 6-Het is a 6-membered nitrogen-containing heterocyclic ring, which contains one additional heteroatom that is N.

[0196] In one embodiment, the following moiety is

Chemical formula

[0197]

Table 2

[0198] In particular, the following moiety is

Chemical formula

[0199] In particular, the following moiety is

Chemical formula

Chemical formula

[0200] In particular, the following moiety is

Chemical formula

[0201] In particular, the following part is [Chemical formula] selected from Options E and G of Table II, in particular, selected from Option G.

[0202] In particular, the following part is [Chemical formula] selected from the following: [Chemical formula] (wherein c is 0, 1, 2, or 3).

[0203] In particular, the following part is [Chemical formula] are as follows: [Chemical formula] (wherein c is 0, 1, 2, or 3).

[0204] In one embodiment, the compound of formula (I) is a compound of formula (XII), or a tautomer, or a solvate, or a pharmaceutically acceptable salt thereof, [Chemical formula] wherein X, R 1, R 2 , R 3 , R 8 , R 9 , and R 10 are as defined herein.

[0205] In one embodiment, the compound of formula (XII) is a compound of formula (XIIa), or a tautomer, or a solvate, or a pharmaceutically acceptable salt thereof,

Chemical formula

[0206] In one embodiment, the compound of formula (XII) is a compound of formula (XIIb), or a tautomer, or a solvate, or a pharmaceutically acceptable salt thereof,

Chemical formula

[0207] In one embodiment, the compound of formula (XII) is a compound of formula (XIIc), or a tautomer, or a solvate, or a pharmaceutically acceptable salt thereof,

Chemical formula

[0208] In one embodiment of the compound of formula (XIIc), R 10 is halogen, cyano, C 1-4 alkyl (e.g., -CH3, -CH(CH3)2, or -CH2CH3), haloC 1-4 alkyl (e.g., -CHF2), C 1-4 alkoxy (e.g., -OCH3, -OCH2CH3, and -OCH(CH3)2), hydroxylC 1-4 alkyl (e.g., -CH2C(CH3)2OH, -CH(CH3)CH2OH, -CH(CH3)OH, -CH2CH2OH, or -CH2OH), amino, monoC 1-4 alkylamino, diC 1-4 alkylamino (e.g., -N(CH3)2), aminoC 1-4 alkylene (e.g., -CH2NH2), and an optionally substituted 4- to 6-membered saturated heterocyclic group containing one or two heteroatoms selected from O, N, or S, and the optional substituent is selected from C 1-4 alkyl.

[0209] In one embodiment of the compound of formula (XIIc), R 10 is diC 1-4 alkylamino (e.g., -N(CH3)2), C 1-4 alkoxy (e.g., -OCH3, -OCH2CH3, and -OCH(CH3)2), haloC 1-4 alkyl (e.g., -CF3), and an optionally substituted 4- to 6-membered saturated heterocyclic group containing one or two heteroatoms selected from O, N, or S, and the optional substituent is selected from C 1-4 alkyl.

[0210] In one embodiment, ring A contains a nitrogen atom adjacent to (i.e., directly bonded to) the benzene ring, and the compound of formula (I) is a compound of formula (XIIIa) or (XIIIb), or a tautomer thereof, or a solvate, or a pharmaceutically acceptable salt, i.e., the following,

Chemical formula

[0211] R 10 is independently halogen, cyano, cyanoC 1-4 alkyl (e.g., -CH2-CN), hydroxyl, =O (oxo), C 1-4 alkyl (e.g., -CH3, CH(CH3)2, or -CH2CH3), haloC 1-4 alkyl (e.g., -CHF2), C 1-4 alkoxy (e.g., -OCH3 -OCH2CH3, and -OCH(CH3)2), hydroxylC 1-4 alkyl (e.g., -CH2C(CH3)2OH, -CH(CH3)CH2OH, -CH(CH3)OH, -CH2CH2OH, or -CH2OH), C 1-4 alkoxyC 1-4 alkylene (e.g., -CH2-O-CH3, or -CH2-CH2-O-CH3), C 1-4 alkylsulfone (e.g., -SO2CH3), amino, monoC 1-4 alkylamino, diC 1-4 alkylamino (e.g., -N(CH3)2), aminoC 1-4 alkylene (e.g., -CH2NH2), -C 1-4 alkylene-C(=O)NH (2-q) (C 1-6 alkyl) q ), -C 1-4 alkylene-NHC(=O)C 1-6 alkyl, sulfonamideC 0-4 alkylene (e.g., where R x is independently selected from H and C 1-6 alkyl), -SO2NR x 2 or -CH2SO2NR x2), selected from optionally substituted 5- or 6-membered unsaturated heterocyclic groups containing one, two, three, or four heteroatoms selected from 3-6 membered cycloalkyl, O, N, or S, where the optional substituent is C 1-4 alkyl, C substituted with 3-6 membered cycloalkyl 1-4 alkyl, C substituted with an optionally substituted 5- or 6-membered unsaturated heterocyclic group containing one, two, three, or four heteroatoms selected from O, N, or S 1-4 selected from alkyl, where the optional substituent is C 1-4 alkyl, C substituted with an optionally substituted 4-6 membered saturated heterocyclic group containing one or two heteroatoms selected from O, N, or S 1-4 selected from alkyl, where the optional substituent is C 1-4 selected from alkyl and an optionally substituted 4-6 membered saturated heterocyclic group containing one or two heteroatoms selected from O, N, or S, where the optional substituent is C 1-4 selected from alkyl, q is selected from 0, 1, or 2.

[0212] In one embodiment, R 10 is independently halogen, cyano, cyanoC 1-4 alkyl (e.g., -CH2-CN), hydroxyl, =O (oxo), C 1-4 alkyl (e.g., -CH3 or -CH2CH3), haloC 1-4 alkyl, C 1-4 alkoxy (e.g., -OCH3), hydroxylC 1-4 alkyl (e.g., -CH2C(CH3)2OH, -CH(CH3)CH2OH, -CH(CH3)OH, -CH2CH2OH, or -CH2OH), C 1-4 alkoxyC 1-4 alkylene (e.g., -CH2-O-CH3 or -CH2-CH2-O-CH3), C 1-4 alkylsulfone (e.g., -SO2CH3), amino, monoC 1-4 alkylamino, diC 1-4Alkylamino (e.g., -N(CH3)2), amino C 1-4 Alkylene (e.g., -CH2NH2), -C 1-4 Alkylene-C(=O)NH (2-q) (C 1-6 Alkyl) q )、-C 1-4 Alkylene-NHC(=O)C 1-6 Alkyl, sulfonamide C 0-4 Alkylene (e.g., R x is independently selected from H and C 1-6 Alkyl, -SO2NR x 2 or -CH2SO2NR x 2), and an optionally substituted 4- to 6-membered saturated heterocyclic group containing one or two heteroatoms selected from O, N, or S, wherein the optional substituents are selected from C 1-4 Alkyl, q is selected from 0, 1, or 2.

[0213] In one embodiment, R 10 is independently halogen, cyano, cyano C 1-4 Alkyl (e.g., -CH2-CN), hydroxyl, =O (oxo), C 1-4 Alkyl (e.g., -CH3 or -CH2CH3), halo C 1-4 Alkyl, C 1-4 Alkoxy (e.g., -OCH3), hydroxyl C 1-4 Alkyl (e.g., -CH2C(CH3)2OH, -CH(CH3)CH2OH, -CH(CH3)OH, -CH2CH2OH, or -CH2OH), -C 1-4 Alkylene C 1-4 Alkoxy (e.g., -CH2-O-CH3 or -CH2-CH2-O-CH3), C 1-4 Alkylsulfone (e.g., -SO2CH3), amino, mono C 1-4 Alkylamino, di C 1-4 Alkylamino (e.g., -N(CH3)2), -C 1-4 Alkyleneamino (e.g., -CH2NH2), -C 1-4 Alkylene-C(=O)NH (2-q)(C 1-6 alkyl) q )、 -C 1-4 alkylene - NHC(=O)C 1-6 alkyl、 -C 0-4 alkylene sulfonamide (e.g., R x is independently selected from H and C 1-6 alkyl, -SO2NR x 2 or -CH2SO2NR x 2), and an optionally substituted 4 - to 6 - membered saturated heterocyclic group containing one or two heteroatoms selected from O, N, or S, and the optional substituent is selected from C 1-4 alkyl.

[0214] In one embodiment, two substituents R 10 are present, one R 10 is =O (oxo), and one R 10 is independently halogen, cyano, cyanoC 1-4 alkyl (e.g., -CH2 - CN), hydroxyl, C 1-4 alkyl (e.g., -CH3 or -CH2CH3), haloC 1-4 alkyl, C 1-4 alkoxy (e.g., -OCH3), hydroxylC 1-4 alkyl (e.g., -CH2C(CH3)2OH, -CH(CH3)CH2OH, -CH(CH3)OH, -CH2CH2OH, or -CH2OH), C 1-4 alkoxyC 1-4 alkylene (e.g., -CH2 - O - CH3 or -CH2 - CH2 - O - CH3), C 1-4 alkyl sulfone (e.g., -SO2CH3), amino, monoC 1-4 alkylamino, diC 1-4 alkylamino (e.g., -N(CH3)2), aminoC 1-4 alkylene (e.g., -CH2NH2), -C 1-4 alkylene - C(=O)NH (2-q) (C 1-6 alkyl) q 、 -C 1-4 alkylene - NHC(=O)C 1-6Alkyl, sulfonamide C 0-4 Alkylene (e.g., R x is independently H and C 1-6 alkyl selected from, -SO2NR x 2 or -CH2SO2NR x 2), and an optionally substituted 4- to 6-membered saturated heterocyclic group containing one or two heteroatoms selected from O, N, or S, and the optional substituents are C 1-4 alkyl selected from.

[0215] In one embodiment, q is 0 or 1. In particular, q is 1. In particular, q is 2.

[0216] In one embodiment, there are no substituents or one substituent R 10 is present. In particular, one substituent R 10 is present.

[0217] In particular, two substituents R 10 are present. In particular, the substituent R 10 is absent.

[0218] In one embodiment, R 10 is independently halogen, cyano, cyano C 1-4 alkyl (e.g., -CH2-CN), hydroxyl, =O (oxo), C 1-4 alkyl (e.g., -CH3 or -CH2CH3), halo C 1-4 alkyl, C 1-4 alkoxy (e.g., -OCH3), hydroxyl C 1-4 alkyl (e.g., -CH(CH3)CH2OH, -CH(CH3)OH, -CH2CH2OH, or -CH2OH), di C 1-4 alkylamino (e.g., -N(CH3)2), and C 1-4 alkoxy C 1-4 alkylene (e.g., -CH2-O-CH3) selected from, for example, in the formula, R 10 is independently halogen, cyano, hydroxyl, =O (oxo), and C 1-4It is selected from alkyl (e.g., -CH3 or -CH2CH3).

[0219] In one embodiment, R 10 is independently halogen, cyano, cyano C 1-4 alkyl (e.g., -CH2-CN), hydroxyl, =O (oxo), C 1-4 alkyl (e.g., -CH3 or -CH2CH3), halo C 1-4 alkyl, C 1-4 alkoxy (e.g., -OCH3), hydroxyl C 1-4 alkyl (e.g., -CH(CH3)CH2OH, -CH(CH3)OH, -CH2CH2OH, or -CH2OH), and C 1-4 alkoxy C 1-4 alkylene (e.g., -CH2-O-CH3), and is selected, for example, where R 10 is independently halogen, cyano, hydroxyl, =O (oxo), and C 1-4 alkyl (e.g., -CH3 or -CH2CH3).

[0220] In one embodiment, R 10 is independently halogen, cyano, cyano C 1-4 alkyl (e.g., -CH2-CN), hydroxyl, =O (oxo), C 1-4 alkyl (e.g., -CH3 or -CH2CH3), halo C 1-4 alkyl, C 1-4 alkoxy (e.g., -OCH3), hydroxyl C 1-4 alkyl (e.g., -CH(CH3)CH2OH, -CH(CH3)OH, -CH2CH2OH, or -CH2OH), and C 1-4 alkoxy C 1-4 alkylene (e.g., -CH2-O-CH3), and is selected, for example, where R 10 is independently halogen, cyano, hydroxyl, =O (oxo), and C 1-4 alkyl (e.g., -CH3 or -CH2CH3).

[0221] In one embodiment, R10 is independently selected from halogen, cyano, hydroxyl, =O (oxo), and C 1-4 alkyl (e.g., -CH3 or -CH2CH3), for example, in the formula, R 10 is independently selected from hydroxyl, =O (oxo), and C 1-4 alkyl (e.g., -CH3).

[0222] In one embodiment, R 10 is independently halogen (e.g., chlorine or fluorine), =O (oxo), C 1-4 alkyl (e.g., -CH3, -CH2CH3, -CH(CH3)2), C 1-4 alkoxy (e.g., -OCH3), and diC 1-4 alkylamino (e.g., -N(CH3)2), for example, in the formula, R 10 is independently selected from halogen, =O (oxo), and C 1-4 alkyl (e.g., -CH3 or -CH2CH3).

[0223] In one embodiment, R 10 is independently halogen (e.g., chlorine), cyano, cyanoC 1-4 alkyl (e.g., -CH2-CN), C 1-4 alkoxy (e.g., -OCH3, -OCH2CH3, and -OCH(CH3)2), =O (oxo), C 1-4 alkyl (e.g., -CH3, -CH2CH3, and -CH(CH3)2), hydroxylC 1-4 alkyl (e.g., -CH2OH, -CH2CH2OH, or -CH2C(CH3)2OH), haloC 1-4 alkyl (e.g., -CHF2), diC 1-4 alkylamino (e.g., -N(CH3)2), C 1-4 alkoxyC 1-4 alkylene (e.g., -CH2-O-CH3, or -CH2-CH2-O-CH3), -C 0-4 alkylene-C(=O)NH (2-q) (C 1-6 alkyl) q)(e.g., -CO-N(CH3)2, -CH2-CH2-CO-N(CH3)2, -CH2-CO-N(CH3)2, -CH2-CO-NH(C(CH3)3), or -CH2-CO-NH(CH3), a 4- to 6-membered saturated heterocyclic group containing O or N (e.g., tetrahydrofuranyl, morpholino, azetidinyl, or oxetanyl), and an optionally substituted 5- or 6-membered unsaturated heterocyclic group containing one, two, three, or four heteroatoms selected from O, N, and S (e.g., N or O) (e.g., a 5-membered unsaturated heterocyclic group) substituted C 1-4 alkyl (e.g., C1 alkyl) selected from, and the optional substituent is C 1-4 alkyl (e.g., -CH3) selected from.

[0224] In one embodiment, R 10 is halogen (e.g., chlorine), cyano, C 1-4 alkyl (e.g., -CH3, -CH(CH3)2, or -CH2CH3), haloC 1-4 alkyl (e.g., -CHF2), C 1-4 alkoxyl (e.g., -OCH3, -OCH2CH3, or -OCH(CH3)2), C 1-4 alkoxyC 1-4 alkene (e.g., -CH2OCH3), diC 1-4 alkylamino (e.g., -N(CH3)2), or an optionally substituted (e.g., unsubstituted) 4- to 6-membered saturated heterocyclic group containing one or two heteroatoms selected from O or N, and the optional substituent is C 1-4 alkyl (e.g., morpholinyl or azetidinyl) selected from.

[0225] In one embodiment, R 10 is -C 0-4 alkylene-C(=O)NH (2-q) (C 1-6 alkyl) q which is -C 1-4 alkylene-C(=O)NH (2-q) (C 1-6 alkyl) qIt is selected from (for example, -CH2-CH2-CO-N(CH3)2, -CH2-CO-N(CH3)2, -CH2-CO-NH(C(CH3)3), or -CH2-CO-NH(CH3) and -CO-N(CH3)2).

[0226] In one embodiment, R 10 is independently selected from halogen, cyano, hydroxyl, =O (oxo), and C 1-4 alkyl (for example, -CH3 or -CH2CH3), and for example, in the formula, R 10 is independently selected from C 1-4 alkyl (for example, -CH3), halogen, or oxo.

[0227] In one embodiment, R 10 is independently selected from =O (oxo), hydroxyl, and C 1-4 alkyl (for example, -CH3 or -CH2CH3). In particular, R 10 is independently selected from =O (oxo), hydroxyl, and -CH3.

[0228] In particular, there is one substituent R 10 present, and R 10 is selected from =O (oxo), hydroxyl, and -CH3.

[0229] In particular, there is one substituent R 10 present, and R 10 is -CH3.

[0230] In one embodiment, there are two substituents R 10 present, one of the R 10 is =O (oxo), and one of the R 10 is C 1-4 alkyl (for example, -CH3 or -CH2CH3).

[0231] In one embodiment, there are two substituents R 10 present, one is halogen, for example, chlorine, and one of the R 10 is C 1-4It is alkyl (e.g., -CH3 or -CH2CH3).

[0232] In one embodiment, R 10 is C 1-4 alkyl (e.g., -CH3, -CH2CH3, or -CH(CH3)2).

[0233] In one embodiment, R 10 is halogen, e.g., chlorine.

[0234] In one embodiment, R 10 is an optionally substituted 4- to 6-membered saturated heterocyclic group containing one or two heteroatoms selected from O, N, or S, and the optional substituent is selected from C 1-4 alkyl.

[0235] In one embodiment, R 10 is an optionally substituted 4- to 6-membered saturated heterocyclic group containing one or two heteroatoms selected from O and N, and the optional substituent is selected from C 1-4 alkyl.

[0236] In one embodiment, R 10 is a 4- to 6-membered saturated heterocyclic group (e.g., morpholinyl or azetidinyl) containing one or two heteroatoms selected from O and N.

[0237] In one embodiment, R 10 is independently halogen (e.g., chlorine), C 1-4 alkoxy (e.g., -OCH3), =O (oxo), C 1-4 alkyl (e.g., -CH3 or -CH2CH3), hydroxyl C 1-4 alkyl (e.g., -CH2CH2OH or -CH2OH), di-C 1-4 alkylamino (e.g., -N(CH3)2), C 1-4 alkoxy C 1-4It is selected from an alkylene (e.g., -CH2-O-CH3 or -CH2-CH2-O-CH3) and a 4- to 6-membered saturated heterocyclic group containing O (e.g., tetrahydrofuran).

[0238] Heterocycle and substituent R 10 It is understood that the above definition applies to all possible tautomeric forms of the ring. For this reason, for example, the following compounds can exist in the following tautomeric forms, and both of them are included within the scope of formula (I).

Chemical formula

[0239] Also, for example, the following compounds can exist in the following tautomeric forms, and both of them are included within the scope of formula (I).

Chemical formula

[0240] In one embodiment, the following moiety is

Chemical formula

Chemical formula

[0241] In one embodiment, the following moiety is

Chemical formula

Chemical formula

[0242] In one embodiment, the following moiety is

Chemical formula

Chem.

[0243] In one embodiment, the following part is

Chem.

Chem.

[0244] In one embodiment, the following part is

Chem.

Chem.

[0245] In particular, in one embodiment, the following part is

Chem.

Chem.

[0246] In particular, in one embodiment, the following part is

Chem.

Chem.

[0247] In particular, in one embodiment, the following parts are

Chemical formula

Chemical formula

[0248] Combination of substituents In one embodiment, the compound of formula (I) is a compound of formula (XIV’), or a tautomer, or a solvate, or a pharmaceutically acceptable salt thereof,

Chemical formula

[0249] In one embodiment, the compound of formula (XIV’) is a compound of formula (XV), or a tautomer, or a solvate, or a pharmaceutically acceptable salt thereof,

Chemical formula

[0250] In one embodiment, the compound of formula (XV) is a compound of formula (XVI), or a tautomer, or a solvate, or a pharmaceutically acceptable salt thereof,

Chemical formula

[0251] In one embodiment, the compound of formula (XVI) is a compound of formula (XVIa), or a tautomer, or a solvate, or a pharmaceutically acceptable salt thereof, [Chemical formula] Wherein, R 3 , R 6 , R 7 , R 8 , and R 9 are as defined herein.

[0252] In one embodiment, the compound of formula (XVIa) is a compound of formula (XVIb), or a tautomer, or a solvate, or a pharmaceutically acceptable salt thereof, [Chemical formula] Wherein, R 6 , R 7 , R 8 , and R 9 are as defined herein.

[0253] In one embodiment, the compound of formula (XVIb) is a compound of formula (XVII), or a tautomer, or a solvate, or a pharmaceutically acceptable salt thereof, [Chemical formula] Wherein, R 6 , R 7 , and R 8 are as defined herein. In one embodiment, R 8 is halogen.

[0254] In one embodiment, the compound of formula (XVII) is a compound of formula (XVIII), or a tautomer, or a solvate, or a pharmaceutically acceptable salt thereof,

Chemical formula

[0255] In one embodiment of the compound of formula (XVIII), the following moiety is

Chemical formula

Chemical formula

[0256] Specifically, in one embodiment of the compound of formula (XVIII), the following moiety is

Chemical formula

Chemical formula

Chemical formula

[0257] Specific group of compounds In one aspect, the present invention provides a compound of formula (I*)

Chemical formula

[0258] In one embodiment of the compound of formula I*, the following moiety is

Chemical formula

Chemical formula

[0259] In particular, in one embodiment of the compound of formula I*, the following moiety is

Chemical formula

Chemical formula

Chemical formula

[0260] Specific compound In one embodiment, the present invention provides a compound of formula (I) which is one of Examples 1 to 27, or a tautomer, N-oxide, pharmaceutically acceptable salt, or solvate thereof.

[0261] In one embodiment, the present invention provides a compound of formula (I) selected from the following compound, or a tautomer, N-oxide, pharmaceutically acceptable salt, or solvate thereof: {6-[(3S,4S)-4-Amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-3-(3,4-dichloro-2-methyl-2H-indazol-5-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl}methanol, (3S,4S)-8-{3-[5-Chloro-3-(dimethylamino)quinoxalin-6-yl]-5-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl}-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine, {6-[(3S,4S)-4-Amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-3-(2-chlorophenyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl}methanol, {6-[(3S,4S)-4-Amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-3-(3-chloro-2-fluorophenyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl}methanol, and {6-[(3S,4S)-4-Amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-3-(5-chloro-3-methoxyquinoxalin-6-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl}methanol.

[0262] In one embodiment, the present invention provides a compound of formula (I) which is the following compound, or a tautomer, N-oxide, pharmaceutically acceptable salt, or solvate: {6-[(3S,4S)-4-Amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-3-(3,4-dichloro-2-methyl-2H-indazol-5-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl}methanol.

[0263] In one embodiment, the present invention provides a compound of formula (I) which is the following compound, or a tautomer, N-oxide, pharmaceutically acceptable salt, or solvate: (3S,4S)-8-{3-[5-chloro-3-(dimethylamino)quinoxalin-6-yl]-5-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl}-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine.

[0264] In one embodiment, the present invention provides a compound of formula (I) which is the following compound, or a tautomer, N-oxide, pharmaceutically acceptable salt, or solvate thereof: {6-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-3-(2-chlorophenyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl}methanol.

[0265] In one embodiment, the present invention provides a compound of formula (I) which is the following compound, or a tautomer, N-oxide, pharmaceutically acceptable salt, or solvate thereof: {6-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-3-(3-chloro-2-fluorophenyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl}methanol.

[0266] In one embodiment, the present invention provides a compound of formula (I) which is the following compound, or a tautomer, N-oxide, pharmaceutically acceptable salt, or solvate thereof: {6-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-3-(5-chloro-3-methoxyquinoxalin-6-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl}methanol.

[0267] To avoid misunderstanding, each of the general specific embodiments for one substituent may be combined with each of the general specific embodiments for one or more, particularly all, of the other substituents as defined herein, and it should be understood that all such embodiments are included in the present application.

[0268] In one embodiment, the present invention provides a compound of formula (I) as defined herein, or a tautomer, or a solvate, or a pharmaceutically acceptable salt thereof, wherein X, R 1 、R 2 、R 3 、R 6 、R 7 、R 8 、and R 9 are as defined herein, and the compound of formula (I) is not

Chemical formula

[0269] In one embodiment, the present invention provides a compound of formula (I) as defined herein, or a tautomer, or a solvate, or a pharmaceutically acceptable salt thereof, wherein X, R 1 、R 2 、R 3 、R 6 、R 7 、R 8 、and R 9 are as defined herein, and the compound of formula (I) is not the following:

Chemical formula

[0270] In one embodiment, the present invention provides a compound of formula (I) as defined herein, or a tautomer, or a solvate, or a pharmaceutically acceptable salt thereof, wherein X, R 1 、R 2 、R 3 、R 6 、R 7 、R 8 、and R 9 are as defined herein, and the compound of formula (I) is not Example 16 of WO2019 / 213318.

[0271] In one embodiment, the present invention provides a compound of formula (I) as defined herein, or a tautomer, or a solvate, or a pharmaceutically acceptable salt thereof, wherein X, R 1 、R 2 、R 3 、R 6 、R 7 、R 8 、and R 9 are as defined herein, and the compound of formula (I) is not the following:

Chemical formula

[0272] In one embodiment, the present invention provides a compound of formula (I) as defined herein, or a tautomer, or a solvate, or a pharmaceutically acceptable salt thereof, wherein X, R 1 、R 2 、R 3 、R 6 、R 7 、R 8 、and R 9 are as defined herein, and the compound of formula (I) is the following:

Chemical formula

[0273] In one embodiment, the present invention provides a compound of formula (I) as defined herein, or a tautomer, solvate, or pharmaceutically acceptable salt thereof, wherein X, R 1 , R 2 , R 3 , R 6 , R 7 , R 8 , and R 9 are as defined herein, and the compound of formula (I) is not Example 19C of WO2019 / 183364.

[0274] Salts, solvates, tautomers, isomers, N-oxides, esters, prodrugs, and isotopes Compounds of formula (I), its subgroups (e.g., formula (I), (Ia), (Ib), (Ib’), (Ib’’), (II), (III), (III’), (IV), (IV’), (IV’’), (V), (VI), (VII), (VIII), (VIIIa), (VIIIb), (VIIIc), (IX), (IXa), (X), (XI), (XII), (XIIa), (XIIb), (XIIb), (XIIc), (XIIIa), (XIIIb), (XIV), (XIV’), (XV), (XVI), (XVIa), (XVIb), (XVII), (XVIII), and (I*)), and any reference to an example includes, for example, as discussed below, its ionic forms, salts, solvates, isomers (including geometric and stereochemical isomers unless otherwise specified), tautomers, N-oxides, esters, prodrugs, isotopes, and protected forms, in particular, its salts, or tautomers, or isomers, or N-oxides, or solvates, still more particularly, its salts, or tautomers, or N-oxides, or solvates are also included. In one embodiment, compounds of formula (I), its subgroups (e.g., formula (I), (Ia), (Ib), (Ib’), (Ib’’), (II), (III), (III’), (IV), (IV’), (IV’’), (V), (VI), (VII), (VIII), (VIIIa), (VIIIb), (VIIIc), (IX), (IXa), (X), (XI), (XII), (XIIa), (XIIb), (XIIb), (XIIc), (XIIIa), (XIIIb), (XIV), (XIV’), (XV), (XVI), (XVIa), (XVIb), (XVII), (XVIII), and (I*)), and any reference to an example includes its salts, or tautomers, or solvates.

[0275] Salt Many compounds of formula (I) may exist in the form of salts, such as acid addition salts, or in certain cases, salts of organic and inorganic bases such as carboxylates, sulfonates, and phosphates. All such salts are within the scope of the present invention, and reference to a compound of formula (I) includes the salt forms of the compound.

[0276] The salts of the present invention can be synthesized from a parent compound containing a basic or acidic moiety by conventional chemical methods, for example, by the methods described in Pharmaceutical Salts: Properties, Selection, and Use, P. Heinrich Stahl (Editor), Camille G. Wermuth (Editor), ISBN: 3-90639-026-8, Hardcover, 388 pages, August 2002. Generally, such salts can be prepared by reacting the free acid or base form of these compounds with a suitable base or acid in water or an organic solvent, or in a mixture of the two, and generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are used.

[0277] Acid addition salts (mono- or di-salts) can be formed with a wide variety of both inorganic and organic acids. Examples of acid addition salts include acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid (e.g., L-ascorbic acid), L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, butanoic acid, (+)-camphoric acid, camphor-sulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid, glucuronic acid (e.g., D-glucuronic acid), glutamic acid (e.g., L-glutamic acid), α-oxoglutaric acid, glycolic acid, hippuric acid, hydrohalic acids (e.g., hydrobromic acid, hydrochloric acid, hydroiodic acid), isethionic acid, lactic acid (e.g., (+)-L-lactic acid, (±)-DL-lactic acid), lactobionic acid, maleic acid, malic acid, (-)-L-malic acid, malonic acid, (±)-DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, propionic acid, pyruvic acid, L-pyroglutamic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid, undecylenic acid, and valeric acid, and mono- or di-salts formed with acylated amino acids and cation exchange resins.

[0278] One particular group of salts consists of salts formed from acetic acid, hydrochloric acid, hydroiodic acid, phosphoric acid, nitric acid, sulfuric acid, citric acid, lactic acid, succinic acid, maleic acid, malic acid, isethionic acid, fumaric acid, benzenesulfonic acid, toluenesulfonic acid, methanesulfonic acid (mesylate), ethanesulfonic acid, naphthalenesulfonic acid, valeric acid, acetic acid, propanoic acid, butanoic acid, malonic acid, glucuronic acid, and lactobionic acid. One particular salt is the hydrochloride.

[0279] In one embodiment, the compound is a sodium salt or a mesylate salt.

[0280] When the compound is anionic or has an anionic functional group (e.g., -COOH may be -COO - ), the salt may be formed with an organic or inorganic base that forms a suitable cation. Examples of suitable inorganic cations include alkali metal ions such as Li + , Na + , and K + , alkaline earth metal cations such as Ca 2+ and Mg 2+ , and other cations such as Al 3+ or Zn + , but are not limited thereto. Examples of suitable organic cations include ammonium ions (i.e., NH4 + ) and substituted ammonium ions (e.g., NH3R + , NH2R2 + , NHR3 + , NR4 + ), but are not limited thereto. Examples of some suitable substituted ammonium ions are those derived from methylamine, ethylamine, diethylamine, propylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, as well as amino acids such as lysine and arginine. An example of a common quaternary ammonium ion is N(CH3)4 + .

[0281] When the compound of formula (I) contains an amine functional group, these can form quaternary ammonium salts, for example, by reaction with an alkylating agent according to methods well known to those skilled in the art. Such quaternary ammonium compounds are within the scope of formula (I).

[0282] The compounds of the present invention may exist as mono-salts or di-salts depending on the pKa of the acid with which the salt is formed.

[0283] The salt forms of the compounds of the present invention are typically pharmaceutically acceptable salts, examples of which are discussed in Berge et al., 1977, "Pharmaceutically Acceptable Salts," J. Pharm. Sci., Vol. 66, pp. 1-19. However, non-pharmaceutically acceptable salts may also be prepared as intermediate forms and subsequently converted to pharmaceutically acceptable salts. Such non-pharmaceutically acceptable salt forms, which may be useful, for example, in the purification or isolation of the compounds of the present invention, also form part of the present invention.

[0284] In one embodiment of the present invention, there is provided a pharmaceutical composition comprising a compound of formula (I) as described herein, as well as subgroups and examples thereof, in salt form, in a solution (e.g., an aqueous solution) containing a concentration of more than 10 mg / ml, typically more than 15 mg / ml, and typically more than 20 mg / ml.

[0285] N-oxide Compounds of formula (I) containing an amine functional group may also form N-oxides. References herein to compounds of formula (I) containing an amine functional group include N-oxides.

[0286] If the compound contains several amine functional groups, one or more nitrogen atoms may be oxidized to form N-oxides. Specific examples of N-oxides are N-oxides of the nitrogen atoms of tertiary amines or nitrogen-containing heterocyclyl groups.

[0287] N-oxides can be formed by treating the corresponding amine with an oxidizing agent such as hydrogen peroxide or a peracid (e.g., a peroxycarboxylic acid). For example, Advanced Organic Chemistry, by Jerry March, 4 thSee Edition, Wiley Interscience, pages. More specifically, the N-oxide can be prepared by the procedure of L.W. Deady (Syn. Comm. 1977, 7, 509-514), where the amine compound is reacted with m-chloroperoxybenzoic acid (MCPBA) in an inert solvent such as dichloromethane.

[0288] In one embodiment of the invention, the compound is, for example, R 6 or R 7 an N-oxide from the nitrogen atom on the group, for example, pyridine N-oxide.

[0289] Geometric isomers and tautomers The compounds of formula (I) may exist in a number of different geometric isomeric and tautomeric forms, and reference to a compound of formula (I) includes all such forms. To avoid misunderstanding, even if a compound may exist in one of several geometric isomeric or tautomeric forms and only one is specifically described or shown, all others are included in formula (I).

[0290] For example, a particular heteroaryl ring may exist in two tautomeric forms such as A and B shown below. For the sake of simplicity, although one form may be illustrated by the formula, the formula should be considered to include both tautomeric forms.

Chemical formula

[0291] Other examples of tautomeric forms include, for example, keto / enol (illustrated below), imine / enamine, amide / imino alcohol, amidine / en diamine, nitroso / oxime, thioketone / enethiol, and nitro / acy-nitro tautomeric pairs, and for example, keto, enol, and enolate forms.

Chemical formula

[0292] Stereoisomers Unless otherwise noted or indicated, chemical names of compounds mean mixtures in all possible stereochemically isomeric forms.

[0293] Stereocenters are illustrated in the normal way using "dashed" or "solid" wedge lines, for example, as follows.

Chem.

[0294] When a compound is described as a mixture of two diastereoisomers / epimers, the configuration of the stereocenters is not specified and is represented by a straight line.

[0295] If the compound of formula (I) contains one or more chiral centers and can exist in the form of two or more optical isomers, reference to the compound of formula (I) includes, unless the context requires otherwise, all of its optically isomeric forms, either as individual optical isomers, or as mixtures (e.g., racemic or scalemic mixtures), or as either of two or more optical isomers (e.g., enantiomers, epimers, and diastereoisomers).

[0296] Optical isomers can be characterized and distinguished by their optical activity (i.e., as + and - isomers, or d and l isomers), or they can be characterized from the perspective of their absolute stereochemistry using the "R and S" nomenclature developed by Cahn, Ingold, and Prelog. See Advanced Organic Chemistry by Jerry March, 4th Edition, John Wiley & Sons, New York, 1992, pages 109 - 114, and also Cahn, Ingold & Prelog, Angew. Chem. Int. Ed. Engl., 1966, 5, 385 - 415.

[0297] Optical isomers can be separated by a number of techniques including chiral chromatography (chromatography on a chiral support), such techniques being well known to those skilled in the art.

[0298] Alternatively to chiral chromatography, optical isomers can be separated by forming diastereoisomeric salts using chiral acids such as (+)-tartaric acid, (-)-pyroglutamic acid, (-)-di-toluoyl-L-tartaric acid, (+)-mandelic acid, (-)-malic acid, and (-)-camphorsulfonic acid, separating the diastereoisomers by preferential crystallization, and then dissociating the salt to obtain the individual enantiomers of the free base.

[0299] In addition, enantiomeric separation can be achieved by covalently attaching an enantiomerically pure chiral auxiliary to the compound and then performing diastereoisomeric separation using conventional methods such as chromatography. Subsequently, the aforementioned covalent bond is cleaved to produce the appropriate enantiomerically pure product.

[0300] When the compound of formula (I) exists in two or more optically isomeric forms, one enantiomer in a pair of enantiomers may be more advantageous than the other enantiomer, for example from the viewpoint of biological activity. For this reason, in certain situations, it may be desirable to use only one of a pair of enantiomers, or only one of a plurality of diastereoisomers, as a therapeutic agent.

[0301] Accordingly, the present invention provides a composition comprising a compound of formula (I) having one or more chiral centers, wherein at least 55% (e.g., at least 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) of the compound of formula (I) is present as a single optical isomer (e.g., an enantiomer or a diastereoisomer). In one general embodiment, 99% or more (e.g., substantially all) of the total amount of the compound of formula (I) may be present as a single optical isomer (e.g., an enantiomer or a diastereoisomer).

[0302] Compounds containing a double bond can have the E (entgegen (together)) or Z (zusammen (opposite)) stereochemistry at the double bond. Substituents on a divalent cyclic or (partially) saturated radical may have either a cis or a trans configuration. The terms cis and trans as used herein refer to the positions of substituents on the ring moiety in accordance with the nomenclature of Chemical Abstracts (J. Org. Chem. 1970, 35(9), 2849-2867).

[0303] Particularly interesting are the compounds of formula (I) that are stereochemically pure. When a compound of formula (I) is designated, for example, as R, this means that the compound substantially does not contain the S isomer. When a compound of formula (I) is designated, for example, as E, this means that the compound substantially does not contain the Z isomer. The terms cis, trans, R, S, E, and Z are well known to those skilled in the art.

[0304] Isotopic changes The present invention includes all pharmaceutically acceptable isotopically labeled compounds of the invention, i.e., compounds of formula (I) in which one or more atoms are replaced with atoms having the same atomic number but a different atomic weight or mass number than the atomic weight or mass number normally found in nature.

[0305] Examples of isotopes suitable for inclusion in the compounds of the present invention include 2 hydrogen such as H(D) and 3 H(T), 11 carbon such as 13 C, and 14 C, 36 chlorine such as 18 F, 123 iodine such as 125 I, and 131 I, 13 nitrogen such as 15 N, 15 oxygen such as 17 O, and 18 O, 32 phosphorus such as 35It contains sulfur such as S.

[0306] Certain isotope-labeled compounds of formula (I), for example those incorporating a radioisotope, are useful in drug and / or substrate tissue distribution studies. The compounds of formula (I) may also have valuable diagnostic properties in that they can be used to detect or identify the formation of complexes between the labeled compound and other molecules, peptides, proteins, enzymes, or receptors. Detection or identification methods may use compounds labeled with a labeling agent such as a radioisotope, enzyme, fluorescent substance, luminescent substance (e.g., luminol, luminol derivatives, luciferin, aequorin, and luciferase). The radioisotope tritium, i.e., 3 3H(T), and carbon-14, i.e., 14 14C are particularly useful for this purpose in view of their ease of incorporation and facile means of detection.

[0307] Substitution with heavier isotopes such as deuterium, i.e., 2 2H(D), may be used in some situations as it can provide certain therapeutic advantages resulting from improved metabolic stability, e.g., increased in vivo half-life or reduced required dosage.

[0308] In particular, any reference to hydrogen in this application should be interpreted to encompass 1 1H and 2 2H, whether or not hydrogen is explicitly defined or implicitly present to satisfy the valence of the associated atom (particularly carbon).

[0309] 11 13C, 18 18F, 15 16O, and 13 15N substitution with positron-emitting isotopes may be useful in positron emission tomography (PET) studies for investigating target occupancy.

[0310] The isotopically labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes equivalent to those described in the accompanying examples and preparations using appropriate isotopically labeled reagents in place of the unlabeled reagents previously used.

[0311] Ester Esters such as carboxylic acid esters, acyloxy esters, and phosphate esters of the compounds of formula (I) carrying a carboxylic acid group or a hydroxyl group are also included in formula (I). Examples of esters are compounds containing a -C(=O)OR group, where R is an ester substituent, e.g., C 1-7 alkyl group, C 3-12 heterocyclyl group, or C 5-12 aryl group, typically C 1-6 alkyl group. Specific examples of ester groups include, but are not limited to, -C(=O)OCH3, -C(=O)OCH2CH3, -C(=O)OC(CH3)3, and -C(=O)OPh. Examples of acyloxy (reverse ester) groups are represented by -OC(=O)R, where R is an acyloxy substituent, e.g., C 1-6 alkyl group, C 3-12 heterocyclyl group, or C 5-12 aryl group, typically C 1-6 alkyl group. Specific examples of acyloxy groups include, but are not limited to, -OC(=O)CH3 (acetoxy), -OC(=O)CH2CH3, -OC(=O)C(CH3)3, -OC(=O)Ph, and -OC(=O)CH2Ph. Examples of phosphate esters are those derived from phosphoric acid.

[0312] In one embodiment of the invention, formula (I) includes within its scope esters of the compounds of formula (I) carrying a carboxylic acid group or a hydroxyl group. In another embodiment of the invention, formula (I) does not include within its scope esters of the compounds of formula (I) carrying a carboxylic acid group or a hydroxyl group.

[0313] Solvates and crystal forms Formula (I) also includes any polymorphic forms of the compound, as well as solvates, such as hydrates, alcoholates, and the like.

[0314] The compounds of the present invention can form solvates with, for example, water (i.e., hydrates) or common organic solvents. As used herein, the term "solvate" means a physical association of a compound of the present invention with one or more solvent molecules. This physical association involves various degrees of ionic and covalent bonding, including hydrogen bonding. In certain cases, a solvate can be isolable, for example, when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid. The term "solvate" is intended to encompass both liquid-phase solvates and isolable solvates. Non-limiting examples of suitable solvates include the compounds of the present invention in combination with water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, or ethanolamine. The compounds of the present invention can exhibit their biological effects while in solution.

[0315] Solvates are well known in pharmaceutical chemistry. Solvates can be important in the preparation process of substances (e.g., in relation to their purification), the storage of substances (e.g., their stability), and the ease of handling of substances, and are often formed as part of the isolation or purification steps of chemical synthesis. A person skilled in the art can determine, by standard and long-established techniques, whether a hydrate or other solvate has been formed by the isolation or purification conditions used to prepare a given compound. Examples of such techniques include thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), X-ray crystallography (e.g., single-crystal X-ray crystallography or X-ray powder diffraction), and solid-state NMR (SS-NMR, also known as Magic Angle Spinning NMR or MAS-NMR). Such techniques are part of the standard analytical toolkit of a skilled chemist, along with NMR, IR, HPLC, and MS.

[0316] Alternatively, one of ordinary skill in the art can intentionally form the solvate using crystallization conditions that include the necessary amount of solvent for the particular solvate. Thereafter, standard methods described herein can be used to confirm whether the solvate has been formed.

[0317] Furthermore, the compounds of the present invention may have one or more polymorphic or amorphous crystalline forms and are thus intended to be included within the scope of the present invention.

[0318] Complex Formula (I) also includes, within its scope, complexes of the present compound (e.g., inclusion complexes or clathrates with compounds such as cyclodextrins, or complexes with metals). Inclusion complexes, clathrates, and metal complexes can be formed by methods well known to those skilled in the art.

[0319] Prodrug Formula (I) also includes any prodrugs of the compounds of formula (I). "Prodrug" means, for example, any compound that is converted in vivo to a biologically active compound of formula (I).

[0320] For example, some prodrugs are esters of the active compound (e.g., physiologically acceptable and metabolically labile esters). During metabolism, the ester group (-C(=O)OR) is cleaved to yield the active drug. Such esters may be formed, for example, by esterification of any of the carboxylic acid groups (-C(=O)OH) in the parent compound, which involves, where appropriate, pre-protecting any other reactive groups present in the parent compound and subsequently de-protecting as necessary.

[0321] Examples of such metabolically labile esters include esters of the formula -C(=O)OR, where R is C 1-7 alkyl (e.g., -Me, -Et, -nPr, -iPr, -nBu, -sBu, -iBu, -tBu); C 1-7Aminoalkyl (e.g., aminoethyl; 2-(N,N-diethylamino)ethyl; 2-(4-morpholino)ethyl); and acyloxy-C 1-7 Alkyl (e.g., acyloxymethyl; acyloxyethyl; pivaloyloxymethyl; acetoxymethyl; 1-acetoxyethyl; 1-(1-methoxy-1-methyl)ethyl-carboxyloyloxyethyl; 1-(benzoyloxy)ethyl; isopropoxy-carbonyl-oxymethyl; 1-isopropoxy-carbonyl-oxyethyl; cyclohexyl-carbonyl-oxymethyl; 1-cyclohexyl-carbonyl-oxyethyl; cyclohexyloxy-carbonyl-oxymethyl; 1-cyclohexyloxy-carbonyl-oxyethyl; (4-oxanyl-oxy)carbonyl-oxymethyl; 1-(4-oxanyl-oxy)carbonyl-oxyethyl; (4-oxanyl)carbonyl-oxymethyl; and 1-(4-tetrahydropyranyl)carbonyl-oxyethyl).

[0322] Also, some prodrugs are enzymatically activated to produce an active compound, or a compound that produces an active compound by further chemical reaction (e.g., in antigen-directed enzyme prodrug therapy (ADEPT), gene-directed enzyme prodrug therapy (GDEPT), and ligand-directed enzyme prodrug therapy (LIDEPT), etc.). For example, the prodrug may be a sugar derivative or other glycoside conjugate, or an amino acid ester derivative. In one embodiment, formula (I) does not include prodrugs of the compounds of formula (I) within its scope.

[0323] Method for preparing the compound of formula (I) In this section, unless otherwise indicated in the context, references to formula (I) include, unless otherwise indicated in the context, all other sub-formulas (e.g., formulas (I), (Ia), (Ib), (Ib’), (Ib’’), (II), (III), (III’), (IV), (IV’), (IV’’), (V), (VI), (VII), (VIII), (VIIIa), (VIIIb), (VIIIc), (IX), (IXa), (X), (XI), (XII), (XIIa), (XIIb), (XIIb), (XIIc), (XIIIa), (XIIIb), (XIV), (XIV’), (XV), (XVI), (XVIa), (XVIb), (XVII), (XVIII), and (I*)) and examples thereof as defined herein, in the same manner as all other sections of this application, unless otherwise indicated in the context.

[0324] The compounds of formula (I) can be prepared according to synthetic methods well known to those skilled in the art.

[0325] According to a further aspect of the invention, there is provided a process for preparing a compound of formula (I), or a tautomer, stereoisomer, N-oxide, pharmaceutically acceptable salt, or solvate thereof, which comprises (a) a compound of formula (A) or a protected derivative thereof, wherein

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0326] In one embodiment, a process for preparing a compound of formula (I), or a tautomer, stereoisomer, N-oxide, pharmaceutically acceptable salt, or solvate thereof, comprises (a) a compound of formula (A) or a protected derivative thereof, wherein

Chemical formula

Chemical formula

[0327] Preparation methods (a), (b), (c), and (d) The compound of formula (B) is either commercially available or is prepared using a method equivalent to the methods described in the Examples.

[0328] Process (a) typically involves reacting the compound of formula (A) with the compound of formula (B) in a suitable solvent, a suitable base, and a suitable catalyst at a suitable temperature. Examples of suitable bases are potassium carbonate or potassium phosphate. An example of a suitable catalyst is [1,1'-bis(diphenylphosphino)ferrocene] palladium(II) dichloride. Examples of suitable solvents are 1,2-dimethoxyethane or tetrahydrofuran.

[0329] When Z is a metal residue such as zinc halide, the process typically involves reacting a compound of formula (A) with a compound of formula (B), where V is a leaving group such as a halogen. Typically, a compound of formula (A) in which Z is a leaving group such as a halogen dissolved in a suitable solvent such as tetrahydrofuran is treated with a reagent such as an isopropylmagnesium chloride lithium chloride complex solution for a suitable time such as 35 minutes to effect complete metallation. The newly formed organomagnesium species is treated with a suitable metal salt such as zinc chloride to effect a metal exchange reaction, optionally stirred for a suitable time such as 10 minutes, and then heated to a suitable temperature such as room temperature for a time such as 40 minutes. The resulting heteroaryl zinc reagent is used directly in a cross-coupling reaction with a compound of formula (B) using a suitable catalyst such as methanesulfonato(2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl)(2′-methylamino-1,1′-biphenyl-2-yl)palladium(II) (SPhos G4 precatalyst) at a suitable temperature such as room temperature for a suitable time such as 18 hours.

[0330] The compound of formula (D) or a protected derivative thereof is obtained from commercially available starting materials and prepared using procedures from the literature or methods shown within the examples outlined in this application or methods equivalent thereto.

[0331] The compound of formula (C) or a protected derivative thereof is, particularly when R 1 is hydrogen, a compound of formula (E) in which

Chemical formula

[0332] The compound of formula (E) is obtained from commercially available starting materials and prepared using the procedures in the literature, or the methods shown within the examples outlined in this patent, or methods equivalent thereto.

[0333] The compound of formula (A) or a protected derivative thereof, where R 1 is H, of the compound of formula (E) can be obtained by reacting it with a compound of formula (D) or a protected derivative thereof, using a suitable base such as diisopropylethylamine, in a suitable solvent such as dimethyl sulfoxide or N-methyl-2-pyrrolidone, at a suitable temperature such as 80 °C to 150 °C.

[0334] The compound of formula (A) or a protected derivative thereof is a compound of formula (F) or a protected derivative thereof,

Chemical formula

[0335] The compound of formula (A) or a protected derivative thereof is, particularly when R 1 is H or -OH, a compound of formula (X') or a protected derivative thereof,

Chemical formula

[0336] The compound of formula (X') is, particularly when R 1 is OH, a compound of formula (Y) or a protected derivative thereof, where

Chemical formula

[0337] Alternatively, the compound of formula (X') or a protected derivative thereof is a compound of formula (W') or a protected derivative thereof, where

Chemical formula

[0338] The compound of formula (W’) or a protected derivative thereof is, in particular, when R 1 is hydrogen, a compound of formula (Y’) or a protected derivative thereof,

Chemical formula

[0339] The compound of formula (Y’) or a protected derivative thereof is a compound of formula (Z) or a protected derivative thereof,

Chemical formula

[0340] The compound of formula (F) or its protected derivative is a compound of formula (G) or (G’), or a mixture of (G) and (G’), and its protected derivative,

Chemical formula

[0341] The compound of formula (G) and (G’) or its protected derivative is a compound of formula (H) or its protected derivative,

Chemical formula

[0342] The compound of formula (H) or a protected derivative thereof can be obtained by reacting a compound of formula (j) with

Chemical formula

[0343] The compound of formula (K) or a protected derivative thereof is a compound of formula (L) or a protected derivative thereof,

Chemical formula

[0344] The compound of formula (L) or a protected derivative thereof is a compound of formula (M),

Chemical formula

[0345] The compound of formula (M) or a protected derivative thereof may be obtained from commercially available starting materials, from procedures in the literature, or by using the methods shown within the examples outlined in this patent, or methods equivalent thereto.

[0346] Alternatively, the compound of formula (L) or a protected derivative thereof is a compound of formula (N) or a protected derivative thereof,

Chemical formula

[0347] The compound of formula (N) or a protected derivative thereof is a compound of formula (O) or a protected derivative thereof,

Chemical formula

[0348] When X is nitrogen, the compound of formula (O) or a protected derivative thereof is a compound of formula (P),

Chemical formula

[0349] The compound of formula (P) or a protected derivative thereof can be obtained by reacting a compound of formula (Q) with

Chemical formula

[0350] The compound of formula (Q) or a protected derivative thereof can be obtained from commercially available starting materials or prepared using procedures from the literature or methods shown in the examples outlined in this patent or equivalent methods.

[0351] The compound of formula (R) or a protected derivative thereof is a compound of formula (S) or a protected derivative thereof,

Chemical formula

[0352] The compound of formula (S) or a protected derivative thereof is a compound of formula (T) or a protected derivative thereof,

Chemical formula

[0353] The compound of formula (T) or a protected derivative thereof is a compound of formula (U) or a protected derivative thereof,

Chemical formula

[0354] The compound of formula (U) or a protected derivative thereof is a compound of formula (V) or a protected derivative thereof,

Chemical formula

[0355] The compound of formula (V) or a protected derivative thereof is a compound of formula (W) or a protected derivative thereof,

Chemical formula

[0356] The compound of formula (W) or a protected derivative thereof may be obtained from commercially available starting materials, or prepared from literature procedures, or by the methods shown in the examples outlined in this patent, or methods equivalent thereto.

[0357] The compound of formula (T) or a protected derivative thereof is also a compound of formula (Z’) or a protected derivative thereof,

Chemical formula

[0358] The compound of formula (Z’) or a protected derivative thereof is prepared using the methods shown within the examples outlined in this patent or equivalent methods.

[0359] Deprotection of the protected derivative of the compound of formula (I) Process (e) typically includes any suitable deprotection reaction, the conditions of which will depend on the nature of the protecting group.

[0360] When the protecting group P represents SEM, such a deprotection reaction typically involves the use of a suitable acid in a suitable solvent, followed by removal of the hydroxymethyl adduct formed during acid deprotection of the SEM protecting group with ethylenediamine. For example, the acid may be suitably constituted with trifluoroacetic acid or hydrogen chloride, and the solvent may suitably contain dichloromethane, DMF, or methanol. Optionally, a mixture of solvents, such as water and methanol, may be used. The second step includes dissolving the crude material in a suitable solvent such as methanol after vacuum concentration and treating it with a suitable scavenging reagent such as ethylenediamine in a suitable solvent such as methanol.

[0361] When the protecting group is an N,N - dimethylsulfamoyl group (SO2NMe2), a stronger acid such as trifluoromethanesulfonic acid may be used at a suitable temperature.

[0362] R 1When =OH and the protecting group P represents SEM, such a deprotection reaction typically utilizes a suitable acid (e.g., methanesulfonic acid or TFA) in a suitable solvent (e.g., DCM with or without water), followed by using ethylenediamine or ammonia in a suitable solvent (e.g., DCM, CHCl3, IPA, MeOH, water, or a mixture thereof) to remove the hydroxymethyl adduct formed during the acid deprotection of the SEM protecting group. For example, the deprotection reaction involves the use of methanesulfonic acid in a DCM / water mixture at room temperature, and the second step involves treating the crude product with ethylenediamine and / or ammonia in a mixture of DCM and water.

[0363] R 1 When =H and the protecting group P represents THP, such a deprotection reaction typically involves using a suitable acid (e.g., HCl) in a suitable solvent (e.g., dioxane, MeOH) at room temperature to 40 °C.

[0364] In other cases, R 1 When =H and the compound is protected only by Boc, such a deprotection reaction typically involves using a suitable acid (e.g., TFA or HCl) in a suitable solvent (DCM, MeOH, dioxane).

[0365] Deprotection can be carried out according to the procedures, methods 1 to 5 described herein as general procedures for preparing the compounds of formula (I).

[0366] Formation of the pharmaceutically acceptable salt of the compound of formula (I) Salt formation can be carried out by treating the compound of formula (I) in the free base form dissolved in a suitable solvent with a stoichiometric amount or excess of a pharmaceutically acceptable organic or inorganic acid, and then isolating the resulting salt. It can be carried out by methods well known in the art, for example, by evaporation of the solvent or crystallization for isolation.

[0367] General Where appropriate, the reactions described above in processes (a), (b), and (c) are followed or preceded by one or more reactions known to those skilled in the art, carried out in an appropriate order to achieve the necessary substitutions as defined above to obtain other compounds of formula (I). Non-limiting examples of such reactions include the following, the conditions of which can be found in the literature: Protection of reactive functional groups, Deprotection of reactive functional groups, Halogenation, Dehalogenation, Dealkylation, Alkylation and arylation of amines, anilines, alcohols, and phenols, Mitsunobu reaction with a hydroxyl group, Addition cyclization reaction with an appropriate group, Reduction of nitro, ester, cyano, aldehyde, Transition metal-catalyzed coupling reaction, Acylation, Sulfonylation / introduction of a sulfonyl group, Saponification / hydrolysis of an ester group, Amidation or transesterification of an ester group, Esterification or amidation of a carboxyl group, Halogen exchange, Nucleophilic substitution by amines, thiols, or alcohols, Reductive amination, Oxime formation with carbonyl and hydroxylamine groups, S-oxidation, N-oxidation, as well as Chlorination.

[0368] A wide variety of well-known functional group interconversions for converting precursor compounds to compounds of formula I are known to those skilled in the art, Advanced Organic Chemistry by Jerry March, 4 thIt is described in "Comprehensive Organic Transformations", 2nd Edition, John Wiley & Sons, 1992. For example, possible metal-catalyzed functionalizations by reactions with organotin reagents (Stille reaction), Grignard reagents, and nitrogen nucleophiles are described in "Palladium Reagents and Catalysts" [Jiro Tsuji, Wiley, ISBN 0-470-85032-9] and Handbook of OrganoPalladium Chemistry for Organic Synthesis [Volume 1, Edited by Ei-ichi Negishi, Wiley, ISBN 0-471-31506-0].

[0369] Protecting group In many of the above reactions, it may be necessary to protect one or more groups so that the reaction does not occur at unwanted positions on the molecule. Examples of protecting groups, and methods for protecting and deprotecting functional groups, can be found in Protective Groups in Organic Synthesis (T. Green and P. Wuts; 3rd Edition; John Wiley and Sons, 1999).

[0370] The hydroxy group may be protected, for example, as an ether (-OR) or an ester (-OC(=O)R), such as a t-butyl ether; a tetrahydropyranyl (THP) ether; a benzyl, benzhydryl (diphenylmethyl), or trityl (triphenylmethyl) ether; a trimethylsilyl or t-butyldimethylsilyl ether; or an acetyl ester (-OC(=O)CH3).

[0371] An aldehyde or ketone group may be protected, for example, as an acetal (R-CH(OR)2) or a ketal (R2C(OR)2), respectively, where the carbonyl group (>C=O) is treated, for example, with a primary alcohol. An aldehyde or ketone group is readily regenerated by hydrolysis using a large excess of water in the presence of an acid.

[0372] The amino group may be protected, for example, as an amide (-NRCO-R) or a carbamate (-NRCO-OR), such as methylamide (-NHCO-CH3); benzyl carbamate (-NHCO-OCH2C6H5, -NH-Cbz, or NH-Z); tert-butyl carbamate (-NHCO-OC(CH3)3, -NH-Boc); 2-biphenyl-2-propyl carbamate (-NHCO-OC(CH3)2C6H4C6H5, -NH-Bpoc), 9-fluorenylmethyl carbamate (-NH-Fmoc), 6-nitroveratryl carbamate (-NH-Nvoc), 2-trimethylsilylethyl carbamate (-NH-Teoc), 2,2,2-trichloroethyl carbamate (-NH-Troc), allyl carbamate (-NH-Alloc), or 2-(phenylsulfonyl)ethyl carbamate (-NH-Psec).

[0373] For example, when the compound of formula I contains an amino group, the amino group can be protected using a protecting group as defined above. One preferred group is the tert-butyloxycarbonyl (Boc) group, and at the same time, additional functionalization is introduced. If subsequent modification of the amino group is not required, the protecting group is carried through a series of reactions to obtain the N-protected form of the compound of formula (I), which is then deprotected by standard methods (e.g., treatment with an acid in the case of the Boc group) to obtain the compound of formula (I).

[0374] Other protecting groups for amines such as cyclic amines and heterocyclic N-H groups include tosyl (tosyl) and mesyl (mesyl) groups, benzyl groups such as para-methoxybenzyl (PMB) group, and tetrahydropyranyl (THP) group.

[0375] The carboxylic acid group may be an ester, for example, C 1-7 alkyl ester (e.g., methyl ester, tert-butyl ester), C 1-7 haloalkyl ester (e.g., C 1-7 trihaloalkyl ester), tri C1-7 Alkylsilyl-C 1-7 alkyl ester, or C 5-20 Aryl-C 1-7 alkyl ester (for example, may be protected as a benzyl ester, nitrobenzyl ester, para-methoxybenzyl ester. The thiol group may be protected, for example, as a thioether (-SR), for example, as a benzyl thioether, acetamidomethyl ether (-S-CH2NHC(=O)CH3).

[0376] Isolation and purification of the compounds of the present invention The compounds of the present invention can be isolated and purified according to standard techniques well known to those skilled in the art. Examples of such methods include chromatographic techniques such as column chromatography (e.g., flash chromatography) and HPLC. One particularly useful technique for purifying compounds is preparative liquid chromatography using mass spectrometry as a means of detecting the purified compound emerging from the chromatography column.

[0377] Preparative LC-MS is a standard and effective method used for the purification of small organic molecules such as the compounds described in this specification. By varying the methods for liquid chromatography (LC) and mass spectrometry (MS), the separation of crude materials can be improved, and the detection of samples by MS can be enhanced. The optimization of preparative gradient LC methods involves various columns, volatile eluents and modifiers, as well as gradients. Methods for optimizing preparative LC-MS methods and then using them to purify compounds are well known in the art. Such methods are described in Rosentreter U, Huber U.; Optimal fraction collecting in preparative LC / MS; J Comb Chem.; 2004; 6(2), 159-64, and Leister W, Strauss K, Wisnoski D, Zhao Z, Lindsley C., Development of a custom high-throughput preparative liquid chromatography / mass spectrometer platform for the preparative purification and analytical analysis of compound libraries; J Comb Chem.; 2003; 5(3); 322-9. Examples of such systems for purifying compounds via preparative LC-MS are described below in the Examples section of this application (under the heading "Mass-directed purification LC-MS system").

[0378] The method of recrystallization of the compound of formula (I) and its salts can be carried out by methods well known to those skilled in the art. For example, see (P. Heinrich Stahl (Editor), Camille G. Wermuth (Editor), ISBN: 3-90639-026-8, Handbook of Pharmaceutical Salts: Properties, Selection, and Use, Chapter 8, Publisher Wiley-VCH). When the product obtained from an organic reaction is isolated directly from the reaction mixture, it is rarely pure. If the compound (or its salt) is solid, it may be purified and / or crystallized by recrystallization from a suitable solvent. A good recrystallization solvent should dissolve the substance to be purified moderately at high temperature but only a small amount of the substance at low temperature. This is because impurities should either dissolve easily at low temperature or not dissolve at all. Finally, the solvent should be easily removable from the purified product. This usually means that the boiling point is relatively low, and those skilled in the art will know or, if the information is not available, will test several solvents for the recrystallization solvent of a particular substance. To obtain a good yield of the purified material, the minimum amount of hot solvent is used to dissolve all the impure material. In practice, 3-5% more solvent than necessary is used so that the solution is not saturated. If the impure compound contains impurities that are insoluble in the solvent, these may be removed by filtration and then the solution may be crystallized. In addition, if the impure compound contains trace amounts of colored substances that are not inherent to the compound, these may be removed by adding a small amount of a decolorizing agent, such as activated carbon, to the hot solution, filtering, and then crystallizing. Usually, crystallization occurs spontaneously when the solution is cooled. If not, crystallization may be induced by cooling the solution below room temperature or by adding a single crystal (seed crystal) of the pure material. The yield can also be optimized by carrying out recrystallization and / or using an antisolvent or cosolvent. In this case, the compound is dissolved in a suitable solvent at high temperature, filtered, and then an additional solvent in which the solubility of the required compound is low is added to assist crystallization.The crystals are typically isolated using vacuum filtration, washed, and then dried, for example, in an oven or by a drying process.

[0379] Other examples of purification methods include sublimation, which includes a heating step under vacuum using, for example, a cold finger, and crystallization from a melt (Crystallization Technology Handbook 2nd Edition, edited by A. Mersmann, 2001).

[0380] Biological effects The compounds of the present invention are contemplated to be useful in medicine or therapy. The compounds of the present invention, their subgroups, and examples have been shown to inhibit SHP2. Such inhibition inhibits tumor cell growth and activates the T cell immune response against cancer cells, which may be useful for the prevention or treatment of the medical conditions or diseases described herein, for example, the diseases and conditions discussed below, and the diseases and conditions described in the above "Background of the Invention" section in which SHP2 plays a role. For this reason, for example, the compounds of the present invention may reduce or lower the incidence of cancer, diseases or conditions mediated by SHP2, for example, diseases or conditions having activating mutations within upstream components of the MAPK pathway (such as RAS, KRAS, and NRAS), or cancers activated by receptor tyrosine kinases (RTKs). The compounds of the present invention may be useful for the treatment of the adult population. The compounds of the present invention may be useful for the treatment of the pediatric population.

[0381] The compounds of the present invention have been shown to be good inhibitors of SHP2. The compounds of formula (I) can bind to SHP2 and exhibit potency against SHP2. The effectiveness of the compounds of the present invention has been determined against SHP2 using the assay protocols described herein and other methods known in the art. More specifically, the compounds of formula (I) and their subgroups have potency against SHP2.

[0382] A certain compound of the present invention has an IC 50 that is less than 0.1 μM, particularly less than 0.01 or 0.001 μM.

[0383] The function of SHP2 is involved in many diseases due to its role in cell survival and proliferation mainly through the activation of the RAS-ERK signaling pathway, as well as its role in carcinogenesis. As a result of their affinity for SHP2, the compounds are associated with disorders related to cell accumulation (e.g., cancer, autoimmune disorders, inflammation, and restenosis), disorders in which cell loss occurs due to excessive apoptosis (e.g., neurodegeneration such as stroke, heart failure, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, AIDS, ischemia (stroke, myocardial infarction), and osteoporosis), and it is expected that they can be proven useful for the treatment or prevention of a wide range of diseases or conditions, or for the treatment of autoimmune diseases such as multiple sclerosis (MS).

[0384] Therefore, the compounds of the present invention as defined herein are also expected to be useful for the treatment of other conditions, such as inflammation, hepatitis, ulcerative colitis, gastritis, autoimmune, inflammation, restenosis, stroke, heart failure, Alzheimer's disease, Parkinson's disease, Huntington's disease, myotonic dystrophy, and neurodegenerative conditions such as amyotrophic lateral sclerosis, AIDS, ischemia such as traumatic brain injury, spinal cord injury, cerebral ischemia, cerebral ischemia / reperfusion (I / R) injury, acute and chronic CNS injury ischemia, stroke or myocardial infarction, degenerative diseases of the musculoskeletal system such as osteoporosis, autoimmune diseases such as multiple sclerosis (MS) and type I diabetes, and eye diseases such as retinal degeneration resulting from loss of control of programmed cell death.

[0385] As a result of their activity against SHP2, it is expected that the compounds can be proven useful for the treatment or prevention of proliferative disorders such as cancer.

[0386] Examples of cancers (and their benign counterparts) that can be treated (or inhibited) include tumors of epithelial origin (various types of adenomas and carcinomas, including adenocarcinoma, squamous cell carcinoma, transitional cell carcinoma, and other carcinomas), for example, in the bladder and urinary tract, breast, gastrointestinal tract (including the esophagus, stomach (gastric), small intestine, colon, bowel, large intestine, rectum, and anus), liver (hepatocellular carcinoma), gallbladder and biliary tract, pancreatic exocrine gland, kidney (e.g., renal cell carcinoma), lung (e.g., adenocarcinoma, small cell lung carcinoma, non-small cell lung carcinoma, bronchioloalveolar carcinoma, and mesothelioma), head and neck (e.g., tongue, oral cavity, larynx, pharynx, nasopharynx, tonsils, salivary glands, nasal cavity, and paranasal sinuses), ovary, fallopian tube, peritoneum, vagina, vulva, penis, testis, cervix, myometrium, endometrium, thyroid (e.g., thyroid follicular carcinoma), brain, adrenal gland, prostate, skin and appendages (e.g., melanoma, basal cell carcinoma, squamous cell carcinoma, keratoacanthoma, dysplastic nevus); hematological malignancies and related lymphatic conditions (e.g., B-cell lymphomas such as acute lymphoblastic leukemia [ALL], chronic lymphocytic leukemia [CLL], diffuse large B-cell lymphoma [DLBCL], follicular lymphoma, Burkitt lymphoma, mantle cell lymphoma, T-cell lymphoma and leukemia, natural killer [NK] cell lymphoma, Hodgkin lymphoma, hairy cell lymphoma, monoclonal gammopathy of undetermined significance, plasmacytoma, multiple myeloma, and post-transplant lymphoproliferative disorder), and hematological malignancies and related myeloid cell lineage conditions (e.g., acute myeloid leukemia [AML], chronic myeloid leukemia [CML], chronic myelomonocytic leukemia [CMML], eosinophilia syndrome, polycythemia vera, essential thrombocythemia, and myeloproliferative disorders such as primary myelofibrosis, myeloproliferative syndrome, myelodysplastic syndrome, and promyelocytic leukemia), including hematological malignancies (i.e., leukemia, lymphoma) and pre-cancerous states of hematological disorders and borderline malignant tumor disorders; tumors of mesenchymal origin, for example, osteosarcoma, fibrosarcoma, chondrosarcoma, rhabdomyosarcoma, leiomyosarcoma, liposarcoma, angiosarcoma, Kaposi sarcoma, Ewing sarcoma, synovial sarcoma, epitheloid sarcoma, gastrointestinal stromal tumor. Benign and malignant histiocytomas, and sarcomas of soft tissue, bone, or cartilage such as dermatofibrosarcoma protuberans; tumors of the central or peripheral nervous system (e.g., astrocytoma (e.g., glioma), neuroma and glioblastoma, multiple myel Meningioma, epithelioma, pineal tumor, and schwannoma); endocrine tumors (e.g., pituitary tumor, adrenal tumor, islet cell tumor, parathyroid tumor, carcinoid tumor, and medullary carcinoma of the thyroid); tumors of the eye and its appendages (e.g., retinoblastoma); germ cell and trophoblastic tumors (e.g., teratoma, seminoma, undifferentiated germ cell tumor, cystic teratoma, and choriocarcinoma); and pediatric and fetal tumors (e.g., medulloblastoma, neuroblastoma, Wilms tumor, and undifferentiated neuroectodermal tumor); or congenital or non-congenital syndromes that render the patient susceptible to malignant tumors (e.g., xeroderma pigmentosum), but are not limited thereto.

[0387] Cell growth is a tightly regulated function. Cancer, which is a state of abnormal cell growth, occurs when cells replicate (increase in number) in an uncontrolled manner, grow uncontrollably (become larger), and / or experience a decrease in cell death by apoptosis (programmed cell death), necrosis, or anoikis. In one embodiment, abnormal cell growth is selected from uncontrolled cell proliferation, excessive cell growth, or a decrease in programmed cell death. In particular, the state or disease of abnormal cell growth is cancer.

[0388] Therefore, in the pharmaceutical composition, use, or method of the present invention for treating a disease or condition comprising abnormal cell growth (i.e., uncontrolled and / or rapid cell growth), the disease or condition comprising abnormal cell growth in one embodiment is cancer.

[0389] The compounds of the present invention may be useful for the treatment of metastasis and metastatic cancer. Metastasis or metastatic disease is the spread of a disease from one organ or part to another non-adjacent organ or part. Cancers that can be treated with the compounds of the present invention include primary tumors (i.e., cancer cells at the site of origin), local invasion (cancer cells that penetrate and invade the normal tissue surrounding the local area), and metastatic (or secondary) tumors, i.e., tumors formed from malignant cells that have circulated through the bloodstream (hematogenous spread), via lymphatic vessels, or across body cavities (transcoelomic) to reach other sites and tissues in the body. In particular, the compounds of the present invention may be useful for the treatment of metastasis and metastatic cancer.

[0390] In one embodiment, the hematological malignancy is leukemia. In another embodiment, the hematological malignancy is lymphoma. In one embodiment, the cancer is AML. In another embodiment, the cancer is CLL.

[0391] In one embodiment, the compounds of the present invention are for use in the prevention or treatment of leukemia such as acute or chronic leukemia, particularly acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), or chronic myeloid leukemia (CML). In one embodiment, the compounds of the present invention are for use in the prevention or treatment of acute or chronic lymphoma, particularly lymphoma such as Burkitt lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, or diffuse large B-cell lymphoma.

[0392] In one embodiment, the compounds of the present invention are for use in the prevention or treatment of acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL).

[0393] The cancer may be a cancer that is sensitive to treatment with an SHP2 inhibitor. The cancer may be a cancer that overexpresses SHP2. The cancer may be a cancer that is SHP2 wild-type. The cancer may be a cancer that is mutant SHP2. In one embodiment, the cancer has an activating mutation in SHP2.

[0394] Certain cancers include hepatocellular carcinoma, melanoma, esophageal cancer, kidney cancer, colon cancer, colorectal cancer, lung cancer, such as NSCLC, mesothelioma, or lung adenocarcinoma, breast cancer, bladder cancer, gastrointestinal cancer, ovarian cancer, and prostate cancer.

[0395] Certain cancers include cancers associated with activated SHP2 (activating mutations, amplifications, and / or wild-type SHP2 overexpression), such as hepatocellular carcinoma, breast cancer, lung cancer, colorectal cancer, and neuroblastoma.

[0396] Certain cancers include cancers having oncogenic modifications in the RAS-RAF-MEK-ERK pathway, including mutant forms of KRAS.

[0397] Certain cancers include cancers in which RTK activity drives disease or resistance to cancer therapy.

[0398] The compounds of the present invention are particularly useful for the treatment or prevention of cancers of the types associated with or characterized by elevated Ras, BRAF, and / or MEK signaling.

[0399] Elevated levels of Ras, BRAF, or MEK signaling are seen in many cancers and are associated with poor prognosis. In addition, cancers that activate Ras mutations may also be sensitive to SHP2 inhibitors. Elevated levels of Ras signaling and mutations in Ras can be identified by the techniques outlined herein.

[0400] A further subset of cancers consists of NRas melanoma and NRas AML.

[0401] Another subset of cancers consists of KRas lung cancer, KRas pancreatic cancer, and KRas colorectal cancer (CRC).

[0402] In one embodiment, the cancer is colorectal cancer, breast cancer, lung cancer, and brain tumor.

[0403] In one embodiment, the cancer is a pediatric cancer.

[0404] In one embodiment, the cancer is breast cancer, leukemia, lung cancer, liver cancer, stomach cancer, laryngeal cancer, or oral cancer.

[0405] Whether a particular cancer is a cancer sensitive to an SHP2 inhibitor can be determined by the method set forth in the section entitled "Diagnostic Methods".

[0406] A further aspect provides the use of a compound for the manufacture of a medicament for the treatment of a disease or condition described herein, particularly cancer.

[0407] Certain cancers are resistant to treatment with certain drugs. This can be due to the type of tumor (the most common epithelial malignancies are inherently chemoresistant and the prostate is relatively resistant to currently available chemotherapy or radiotherapy regimens), or resistance can arise naturally as a progression of the disease or as a result of treatment. In this regard, reference to the prostate includes prostate having resistance to anti-androgen therapy, particularly abiraterone or enzalutamide, or castration-resistant prostate. Similarly, reference to multiple myeloma includes bortezomib-insensitive multiple myeloma or refractory multiple myeloma, and reference to chronic myeloid leukemia includes imatinib-insensitive chronic myeloid leukemia and refractory chronic myeloid leukemia. In this regard, reference to mesothelioma includes mesothelioma having resistance to topoisomerase poisons, alkylating agents, anti-tubulin, anti-folate agents, platinum compounds, and radiotherapy, particularly cisplatin-resistant mesothelioma. Reference to melanoma includes melanoma resistant to treatment with BRAF and / or MEK inhibitors.

[0408] The compound may also be useful in the treatment of tumor growth, onset, resistance to chemotherapy and radiotherapy, or as an anti-metastatic agent, by sensitizing cells to chemotherapy.

[0409] All types of therapeutic anti-cancer interventions inevitably increase the stress imposed on target tumor cells. Inhibitors of SHP2 are a class of chemotherapeutic agents with the following potential: (i) sensitize malignant cells to anti-cancer agents and / or treatments, (ii) reduce or lower the incidence of resistance to anti-cancer agents and / or treatments, (iii) reverse resistance to anti-cancer agents and / or treatments, (iv) enhance the activity of anti-cancer agents and / or treatments, (v) delay or prevent the expression of resistance to anti-cancer agents and / or treatments.

[0410] In one embodiment, the present invention provides a compound for use in the treatment of a disease or condition mediated by SHP2. In a further embodiment, the disease or condition mediated by SHP2 is cancer characterized by overexpression of SHP2 and / or increased activity.

[0411] A further aspect provides the use of a compound for the manufacture of a medicament for the treatment of a disease or condition described herein, particularly cancer.

[0412] In one embodiment, a compound for use in the prevention or treatment of a disease or condition mediated by SHP2 is provided.

[0413] In one embodiment, a pharmaceutical composition comprising an effective amount of at least one defined compound is provided. In a further aspect of the present invention, a compound as defined in the present invention is provided.

[0414] In one embodiment, a method for the prevention or treatment of cancer is provided, comprising the step of administering to a mammal a medicament comprising at least one defined compound.

[0415] Diagnostic method Prior to administering a compound of formula (I), a patient may be screened to determine whether a disease or condition that the patient has or may have is susceptible to treatment with a compound that inhibits SHP2. The term "patient" includes humans such as primates and veterinary subjects, particularly human patients.

[0416] For example, a biological sample taken from a patient may be analyzed to determine whether a condition or disease such as cancer that the patient has or may have is characterized by genetic abnormalities or abnormal protein expression that result in upregulation of SHP2 levels or upregulation of biochemical pathways downstream of SHP2.

[0417] Examples of such abnormalities that result in activation or sensitization of SHP2, loss or inhibition of regulatory pathways that affect SHP2 expression, upregulation of receptors or their ligands, cytogenetic abnormalities, or the presence of mutant variants of receptors or ligands. Tumors that involve upregulation of SHP2, particularly overexpression or activating mutants of SHP2, or activating mutations in Ras isoforms such as KRAS may be particularly sensitive to inhibitors of SHP2.

[0418] Mutations in Ras have been detected in cell lines and primary tumors including, but not limited to, melanoma, colorectal cancer, non-small cell lung cancer, and cancers of the pancreas, prostate, thyroid, urinary tract, and upper airway (Cancer Res. 2012;72:2457-2467).

[0419] The term "upregulation" includes increased expression or overexpression, including gene amplification (i.e., multiple gene copies), cytogenetic abnormalities, and increased expression due to transcriptional or post-translational effects. Thus, a patient may be subjected to a diagnostic test for detecting markers characteristic of SHP2 upregulation. The term "diagnosis" includes screening. Markers include, for example, genetic markers including measurement of DNA composition to identify the presence of amplified SHP2 or mutations of SHP2, or to identify the presence of mutations of Ras (e.g., KRAS). The term "marker" also includes markers characteristic of SHP2 upregulation, including protein level, protein state, and mRNA level of the aforementioned proteins. Gene amplification includes those with more than 7 copies and gain of 2 - 7 copies.

[0420] Diagnostic assays for detecting KRAS mutations are described in de Castro et al. Br. J. Cancer. 2012 Jul 10;107(2):345 - 51. doi:10.1038 / bjc.2012.259. Epub 2012 Jun 19, "A comparison of three methods for detecting KRAS mutations in formalin-fixed colorectal cancer specimens." and the references cited herein.

[0421] Diagnostic tests and screening are typically performed on a biological sample (i.e., body tissue or body fluid) selected from a tumor biopsy sample, a blood sample (isolation and enrichment of shed tumor cells), cerebrospinal fluid, plasma, serum, saliva, fecal biopsy, sputum, chromosomal analysis, pleural fluid, ascites, oral smear, skin biopsy, or urine.

[0422] Methods for the identification and analysis of cytogenetic abnormalities, gene amplifications, mutations, and upregulation of proteins are known to those of skill in the art. Screening methods include, but are not limited to, standard methods such as DNA sequence analysis by conventional Sanger or next-generation sequencing methods, reverse transcriptase polymerase chain reaction (RT-PCR), RNA sequencing (RNAseq), NanoString hybridization proximity RNA nCounter assay, or in situ hybridization such as fluorescence in situ hybridization (FISH) or allele-specific polymerase chain reaction (PCR). Newer next-generation sequencing (NGS) technologies such as ultra-parallel sequencing enable whole exome sequencing or whole genome sequencing.

[0423] In screening by RT-PCR, the level of mRNA in a tumor is evaluated by creating a cDNA copy of the mRNA and then amplifying the cDNA by PCR. Methods of PCR amplification, primer selection, and amplification conditions are known to those of skill in the art. Nucleic acid manipulations and PCR are performed by standard methods as described, for example, in Ausubel, F.M. et al., eds. (2004) Current Protocols in Molecular Biology, John Wiley & Sons Inc., or Innis, M.A. et al., eds. (1990) PCR Protocols: a guide to methods and applications, Academic Press, San Diego. Reactions and manipulations involving nucleic acid techniques are described in Sambrook et al., (2001), 3 rdIt is also described in Ed, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press. Alternatively, a commercially available kit for RT-PCR (e.g., Roche Molecular Biochemicals), or the methodologies described in U.S. Patent Nos. 4,666,828, 4,683,202, 4,801,531, 5,192,659, 5,272,057, 5,882,864, and 6,218,529, which are incorporated herein by reference, may be used. An example of an in situ hybridization technique for evaluating mRNA expression is fluorescence in situ hybridization (FISH) (see Angerer (1987) Meth. Enzymol., 152:649).

[0424] Generally, insights hybridization includes the following main steps: (1) fixation of the tissue to be analyzed, (2) pre-hybridization treatment of the sample to increase the accessibility of the target nucleic acid and reduce non-specific binding, (3) hybridization of the nucleic acid mixture to the nucleic acid in the biological structure or tissue, (4) post-hybridization washing to remove unbound nucleic acid fragments in the hybridization, and (5) detection of the hybridized nucleic acid fragments. Probes used for such applications are typically labeled with, for example, radioisotopes or fluorescent reporters. Certain probes are long enough, for example, about 50, 100, or 200 nucleotides to about 1000 nucleotides or more, to allow specific hybridization with the target nucleic acid under stringent conditions. Standard methods for performing FISH are described in Ausubel, F.M. et al., eds. (2004) Current Protocols in Molecular Biology, John Wiley & Sons Inc and Fluorescence In Situ Hybridization: Technical Overview by John M.S. Bartlett in Molecular Diagnosis of Cancer, Methods and Protocols, 2nd ed.; ISBN: 1-59259-760-2; March 2004, pps. 077-088; Series: Methods in Molecular Medicine.

[0425] Methods for gene expression profiling are described by (DePrimo et al. (2003), BMC Cancer, 3:3). Briefly, the protocol is as follows: double-stranded cDNA is synthesized from total RNA using a (dT)24 oligomer to prime first-strand cDNA synthesis from polyadenylated mRNA, followed by synthesis of second-strand cDNA using random hexamer primers. The double-stranded cDNA is used as a template for in vitro transcription of cRNA using biotinylated ribonucleotides. After chemically fragmenting the cRNA according to the protocol described by Affymetrix (Santa Clara, CA, USA), it is hybridized overnight to gene-specific oligonucleotide probes on a Human Genome Array. Alternatively, a single nucleotide polymorphism (SNP) array, which is a type of DNA microarray, can be used to detect polymorphisms within a population.

[0426] Alternatively, the protein products expressed from the mRNA can be assayed by immunohistochemistry of tumor samples, solid-phase immunoassays using microtiter plates, Western blot, two-dimensional SDS-polyacrylamide gel electrophoresis, ELISA, flow cytometry, and other methods known in the art for the detection of specific proteins, e.g., by capillary electrophoresis. The detection methods can include the use of site-specific antibodies. One of ordinary skill in the art will recognize that all such well-known techniques can be used in the present case for the detection of upregulation of SHP2, the detection of SHP2 or SHP2 variants or mutants, or the loss of negative regulators of SHP2.

[0427] Abnormal levels of proteins such as SHP2 can be measured using standard protein assays, such as the assays described herein. Elevated levels or overexpression can also be detected in tissue samples, such as tumor tissue, by measuring protein levels using an assay such as the assay from Chemicon International. The protein of interest is immunoprecipitated from the sample lysate and its level is measured. The assay methods also include the use of markers.

[0428] In other words, overexpression of SHP2 or mutant SHP2 can be measured by tumor biopsy.

[0429] Methods for evaluating gene copy changes include techniques commonly used in cytogenetic laboratories such as MLPA (Multiplex Ligation-dependent Probe Amplification), multiplex PCR methods for detecting abnormal copy numbers, or other PCR techniques capable of detecting gene amplification, acquisition, and deletion.

[0430] Where appropriate, ex-functional assays, such as measuring circulating leukemia cells in cancer patients, can also be utilized to evaluate the response to challenge with an SHP2 inhibitor.

[0431] Thus, all of these techniques can be used to identify tumors particularly suitable for treatment with the compounds of the present invention.

[0432] Accordingly, a further aspect of the present invention includes the use of a compound according to the present invention for the manufacture of a medicament for the treatment or prevention of a medical condition or disease state in a patient who has been screened and determined to be suffering from or at risk of suffering from a disease or condition that is susceptible to the effects of treatment with an SHP2 inhibitor.

[0433] Another aspect of the present invention includes a compound according to the present invention for use in the prevention or treatment of cancer in a patient selected from a subpopulation having amplification of SHP2.

[0434] Another aspect of the invention includes the compounds of the invention for use in the prevention or treatment of cancer in patients having a loss of a negative regulator of SHP2.

[0435] Another aspect of the invention includes the compounds of the invention for use in the prevention or treatment of cancer in patients selected from a subpopulation having RTK-driven activation of the MAPK signaling pathway.

[0436] Also, determination by MRI of vascular normalization in combination with circulating biomarkers (e.g., measurement of blood volume, relative vessel diameter, and vascular permeability using MRI gradient echo, spin echo, and contrast agent enhancement methods) may be used to identify patients suitable for treatment with the compounds of the invention.

[0437] Accordingly, a further aspect of the invention is a method for the diagnosis and treatment of SHP2-mediated conditions or disorders, the method comprising: (i) screening a patient to determine whether a disease or condition that the patient has or may have is susceptible to treatment with an SHP2 inhibitor; and (ii) administering to the patient a compound of formula (I) as defined herein and sub-groups or examples thereof, if the patient's disease or condition is thus shown to be susceptible.

[0438] Advantages of the compounds of the present invention The compounds of formula (I) have a number of advantages over compounds of the prior art. The compounds of the invention may have certain advantages in one or more of the following aspects: (i) excellent potency, (ii) excellent in vivo efficacy, (iii) excellent PK, (iv) excellent metabolic stability, (v) excellent oral bioavailability, (vi) excellent physicochemical properties, and / or (vii) excellent safety profile or therapeutic index (TI).

[0439] Excellent potency and in vivo efficacy The compounds of formula (I) have an increased affinity for SHP2 and, in particular, an increased cell potency against cell lines known to be sensitive to SHP2 antagonists.

[0440] Enhanced engagement with the target is a highly desirable property in pharmaceutical compounds as it allows for a reduction in the dosage of the drug and a favorable separation between SHP2 activity and toxic effects (the "therapeutic window").

[0441] The compounds of formula (I) have improved cell potency and / or improved selectivity against SHP2 cell lines. As a result of the increased potency against SHP2, the compounds of the present invention may have increased in vivo efficacy in cancer cell lines and in vivo models.

[0442] Excellent PK and metabolic stability The compounds of formula (I) may have advantageous ADMET properties, such as better metabolic stability (e.g., determined in mouse liver microsomes), a better P450 profile, a short half-life, and / or beneficial clearance (e.g., low or high clearance). Many compounds of formula (I) have also been found to have an improved PK profile.

[0443] These features can provide the advantage that more drug is available in the systemic circulation to reach the appropriate site of action to exert its therapeutic effect. An increase in the drug concentration in the tumor to exert a pharmacological effect can lead to an improvement in efficacy, thereby allowing for a reduction in the dosage. For this reason, the compounds of formula (I) should require a lower dosage and be easier to formulate and administer.

[0444] This results in a favorable separation between SHP2 activity and toxic effects (the "therapeutic window"). Many compounds of formula (I) have a reduction in Cmax required for efficacy (due to better SHP2 potency and / or PK).

[0445] Excellent oral bioavailability The compounds of the present invention have physicochemical properties suitable for oral exposure (oral exposure or AUC). In particular, the compounds of formula (I) may exhibit improved oral bioavailability or improved reproducibility of oral absorption. Oral bioavailability can be defined as the percentage ratio (F) of the plasma exposure of the compound when administered by the oral route to the plasma exposure of the compound when administered by the intravenous (i.v.) route.

[0446] Compounds with an oral bioavailability (F value) exceeding 10%, 20%, or 30%, and more particularly exceeding 40%, are particularly advantageous in that they can be administered orally or parenterally rather than parenterally.

[0447] Excellent physicochemical properties The compounds of formula (I) may have advantageous physiochemical properties, in particular chemical stability under acidic conditions and a decrease in lipophilicity.

[0448] Lipophilicity can be measured using the partition coefficient (logP) or the distribution coefficient (logD). The partition coefficient is the ratio of the concentration of the unionized compound between two immiscible phases (n-octanol and water) at equilibrium, while the distribution coefficient is the ratio of the sum of the concentrations of all forms (ionized and unionized) of the compound in each of the two phases. High lipophilicity is associated with poor drug-like properties such as low water solubility, poor pharmacokinetic properties (low oral bioavailability), undesirable drug metabolism, and high promiscuity. Compounds with optimal lipophilicity can increase the probability of success in drug discovery. However, due to the lipophilicity of the target involved, it can be difficult to achieve a decrease in logP (or calculated logP, clogP) while maintaining an acceptable level of potency to inhibit protein-protein interaction (PPI).

[0449] Excellent safety profile or therapeutic index (TI) In the late 1990s, when it was found that several pharmaceuticals approved by the US FDA were involved in deaths due to heart failure, they had to be withdrawn from the US market. Subsequently, the side effects of these drugs were found to be the onset of arrhythmia caused by the blockade of the hERG channel in heart cells. The hERG channel is one member of the potassium ion channel family, and its first member was identified in mutant Drosophila in the late 1980s (see Jan, L.Y. and Jan, Y.N. (1990). A Superfamily of Ion Channels. Nature, 345(6277):672). The biophysical properties of the hERG potassium ion channel are described in Sanguinetti, M.C., Jiang, C., Curran, M.E., and Keating, M.T. (1995). A Mechanistic Link Between an Inherited and an Acquired Cardiac Arrhythmia: HERG encodes the Ikr potassium channel. Cell, 81:299-307, and Trudeau, M.C., Warmke, J.W., Ganetzky, B., and Robertson, G.A. (1995). HERG, a Human Inward Rectifier in the Voltage-Gated Potassium Channel Family. Science, 269:92-95. Therefore, elimination of hERG blockade activity remains an important consideration in the development of any new drug.

[0450] Compounds with reduced hERG activity and / or good separation between activity and hERG activity have a larger "therapeutic window" or "therapeutic index". One method for measuring hERG activity is the patch-clamp electrophysiological method. Alternative methods for measuring functional hERG activity include hERG binding assays that can use commercially available membranes isolated from cells stably expressing the hERG channel or commercially available cell lines expressing the hERG channel.

[0451] The compound may also have an improved cardiac safety index (CSI) [CSI = hERG IC50 / Cmax (unbound)] (Shultz et al, J. Med. Chem., 2011; Redfern et al, Cardiovasc. Res., 2003). This can be due to an increase in hERG IC50 required for efficacy or a decrease in Cmax (resulting from better potency and / or PK). Certain compounds may exhibit CV advantages in vivo.

[0452] Certain compounds have reduced hERG ion channel blocking activity. The compound has an average IC for hERG 50 that can be more than 30-fold, 40-fold, or 50-fold the IC of the compound in the cell proliferation assay 50 value.

[0453] Pharmaceutical formulation Although it is possible to administer the active compound alone, the active compound is generally presented as a pharmaceutical composition (e.g., a formulation).

[0454] Accordingly, the present invention further provides a method for preparing a pharmaceutical composition comprising the pharmaceutical composition defined above and at least one compound of formula (I) (and its subgroups as defined herein) together with one or more pharmaceutically acceptable excipients and optionally other therapeutic or prophylactic agents described herein (e.g., mixed).

[0455] The pharmaceutically acceptable excipient can be selected from, for example, carriers (e.g., solid, liquid, or semi-solid carriers), adjuvants, diluents, fillers or extenders, granulating agents, coating agents, release control agents, binders, disintegrants, lubricants, preservatives, antioxidants, buffers, suspending agents, thickening agents, flavoring agents, sweetening agents, taste-correcting agents, stabilizers, or any other excipient conventionally used in pharmaceutical compositions. Examples of excipients for various types of pharmaceutical compositions are shown in more detail below.

[0456] As used herein, the term “pharmaceutically acceptable” refers to compounds, materials, compositions, and / or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with the tissues of a subject (e.g., a human subject) without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio. Each excipient must also be “acceptable” in the sense of being compatible with the other ingredients of the formulation.

[0457] The pharmaceutical compositions containing the compounds of formula (I) can be formulated according to known techniques. See, for example, Remington’s Pharmaceutical Sciences, Mack Publishing Company, Easton, PA, USA.

[0458] The pharmaceutical compositions can be in any form suitable for oral, parenteral, topical, intranasal, intratracheal, sublingual, ocular, otic, rectal, intravaginal, or transdermal administration. When parenteral administration of the composition is intended, the composition can be formulated for intravenous, intramuscular, intraperitoneal, subcutaneous administration, or for direct delivery to a target organ or tissue by injection, infusion, or other delivery means. Delivery can be by bolus injection, short-term infusion, or long-term infusion, and can be effected via passive delivery or through the use of a suitable infusion pump or syringe pump.

[0459] Pharmaceutical formulations adapted for parenteral administration may include antioxidants, buffers, bacteriostats, co-solvents, surfactants, organic solvent mixtures, cyclodextrin complexing agents, emulsifiers (to form and stabilize emulsion formulations), liposome components for forming liposomes, gellable polymers for forming polymer gels, lyoprotectants, and in particular, combinations of agents to stabilize the active ingredient in a soluble form and to render the formulation isotonic with the blood of the intended recipient. Aqueous and non-aqueous sterile injection solutions are included, which may also include aqueous and non-aqueous sterile suspensions which may contain suspending and thickening agents (R.G. Strickly, Solubilizing Excipients in oral and injectable formulations, Pharmaceutical Research, Vol 21(2)2004, p201 - 230).

[0460] The formulation may be presented in unit-dose or multi-dose containers, for example, sealed ampoules, vials, and pre-filled syringes, and may be stored in a freeze-dried (lyophilized) state that requires only the addition of a sterile liquid carrier, for example, water for injection, immediately prior to use. In one embodiment, the formulation is provided as the active pharmaceutical ingredient in a bottle for later reconstitution using a suitable diluent.

[0461] The pharmaceutical formulation can be prepared by lyophilizing the compound of formula (I) or a subgroup thereof. Lyophilization refers to the procedure of freeze-drying the composition. Thus, freeze-drying and lyophilization are used synonymously herein.

[0462] Immediate injection solutions and suspensions may be prepared from sterile powders, granules, and tablets.

[0463] The pharmaceutical composition of the present invention for parenteral injection may also include a pharmaceutically acceptable sterile aqueous or non-aqueous solution, dispersion, suspension, or emulsion, and a sterile powder for reconstitution into a sterile injectable solution or dispersion immediately before use. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents, or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, etc.), carboxymethyl cellulose and their suitable mixtures, vegetable oils (such as sunflower oil, safflower oil, corn oil, or olive oil), and injectable organic esters such as ethyl oleate. Appropriate fluidity can be maintained, for example, by the use of thickening substances such as lecithin, maintaining the required particle size in the case of dispersions, and the use of surfactants.

[0464] The composition of the present invention may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. The action of microorganisms may be reliably prevented by including various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, etc. It may also be desirable to include agents for adjusting isotonicity, such as sugars, sodium chloride, etc. Delayed absorption of injectable pharmaceutical forms may be achieved by including agents that delay absorption, such as aluminum monostearate and gelatin.

[0465] In one typical embodiment of the present invention, the pharmaceutical composition is in a form suitable for intravenous administration, for example, by injection or infusion. In the case of intravenous administration, the solution may be administered as it is, or injected into an infusion bag (containing a pharmaceutically acceptable diluent such as 0.9% saline or 5% dextrose) before administration.

[0466] In another typical embodiment, the pharmaceutical composition is in a form suitable for subcutaneous (s.c.) administration.

[0467] Pharmaceutical dosage forms suitable for oral administration include tablets (coated or uncoated), capsules (hard or soft shell), caplets, pills, troches, syrups, solutions, powders, granules, elixirs, and suspensions, sublingual tablets, wafers, or patches such as buccal patches.

[0468] For this reason, tablet compositions may contain the active compound in unit dose together with an inert diluent or carrier such as sugar or sugar alcohol, for example, lactose, sucrose, sorbitol, or mannitol, and / or a non-sugar-derived diluent such as sodium carbonate, calcium phosphate, calcium carbonate, or a cellulose or its derivative such as microcrystalline cellulose (MCC), methylcellulose, ethylcellulose, hydroxypropylmethylcellulose, and starch such as corn starch. Tablets may also contain a binder and granulating agent such as polyvinylpyrrolidone, a disintegrant (e.g., a swelling cross-linked polymer such as cross-linked carboxymethylcellulose), a lubricant (e.g., stearate), a preservative (e.g., parabens), an antioxidant (e.g., BHT), a buffer (e.g., phosphate or citrate buffer), and a foaming agent such as a citric acid / bicarbonate mixture. Such excipients are well known and need not be considered in detail here.

[0469] Tablets may be designed to release the drug upon contact with gastric juice (immediate release tablets) or to release it in a controlled manner over a long period upon contact with a specific region of the gastrointestinal tract (controlled release tablets).

[0470] Capsule formulations may be of hard gelatin type or soft gelatin type and can contain the active ingredient in solid, semi-solid, or liquid form. Gelatin capsules can be formed from animal gelatin or their synthetic or plant-derived equivalents.

[0471] Solid dosage forms (e.g., tablets, capsules, etc.) may or may not be coated. The coating can function as a protective film (e.g., polymer, wax, or varnish, etc.), or as a mechanism for controlling drug release, or for aesthetic or identification purposes. A coating (e.g., an Eudragit™ type polymer) can be designed to release the active ingredient at a desired location within the gastrointestinal tract. Thus, by selecting a coating that degrades under certain pH conditions within the gastrointestinal tract, the compound can be selectively released in the stomach, or in the ileum, duodenum, jejunum, or colon.

[0472] Instead of, or in addition to, a coating, the drug can be presented in a solid matrix containing a release control agent, e.g., a release retardant adapted to release the compound in a controlled manner in the gastrointestinal tract. Alternatively, the drug can be presented in a polymer coating, e.g., a polymethacrylate polymer coating, adapted to selectively release the compound under various acidic or alkaline conditions within the gastrointestinal tract. Alternatively, the matrix material or release retardant coating can take the form of an erodible polymer (e.g., maleic anhydride polymer) that erodes substantially continuously as the dosage form passes through the gastrointestinal tract. Another alternative is that the coating can be designed to disintegrate under the action of intestinal microorganisms. As a further alternative, the active compound can be formulated in a delivery system that provides osmotic control of the release of the compound. Osmotic release and other delayed release or sustained release formulations (e.g., formulations based on ion exchange resins) can be prepared according to methods well known to those skilled in the art.

[0473] The compound of formula (I) may be formulated with a carrier and administered in the form of nanoparticles. Increasing the surface area of the nanoparticles aids their absorption. In addition, the nanoparticles provide the possibility of direct penetration into cells. Nanoparticle drug delivery systems are described in "Nanoparticle Technology for Drug Delivery", edited by Ram B Gupta and Uday B. Kompella, Informa Healthcare, ISBN 9781574448573, published on March 13, 2006. Nanoparticles for drug delivery are also described in J. Control. Release, 2003, 91(1-2), 167-172, and Sinha et al., Mol. Cancer Ther. August 1, (2006) 5, 1909.

[0474] Pharmaceutical compositions typically contain from about 1% (w / w) to about 95% active ingredient and from 99% (w / w) to 5% (w / w) of a pharmaceutically acceptable excipient or combination of excipients. Typically, the composition contains from about 20% (w / w) to about 90%, (w / w) of active ingredient and from 80% (w / w) to 10% of a pharmaceutically acceptable excipient or combination of excipients. Pharmaceutical compositions contain from about 1% to about 95%, typically from about 20% to about 90% of active ingredient. The pharmaceutical compositions according to the invention may be in unit dosage forms such as, for example, in the form of ampoules, vials, suppositories, pre-filled syringes, dragees, tablets or capsules.

[0475] The pharmaceutically acceptable excipients can be selected according to the desired physical form of the formulation and can be, for example, diluents (such as solid diluents like fillers or extenders, as well as liquid diluents like solvents and co-solvents), disintegrants, buffers, lubricants, flow aids, release control (such as release inhibiting or delaying polymers or waxes) agents, binders, granulating agents, pigments, plasticizers, antioxidants, preservatives, flavoring agents, taste-correcting agents, tonicity modifiers, and coating agents.

[0476] One skilled in the art would have the expertise to select the appropriate amounts of ingredients for use in a formulation. For example, tablets and capsules typically contain from 0 to 20% disintegrant, 0 to 5% lubricant, 0 to 5% glidant, and / or 0 to 99% (w / w) filler / diluent (depending on the drug dose). They may also contain from 0 to 10% (w / w) polymer binder, 0 to 5% (w / w) antioxidant, and 0 to 5% (w / w) pigment. In addition, sustained release tablets may contain from 0 to 99% (w / w) polymer (depending on the dose). The film coating of a tablet or capsule typically contains from 0 to 10% (w / w) release control (e.g., retardant) polymer, 0 to 3% (w / w) pigment, and / or 0 to 2% (w / w) plasticizer.

[0477] Parenteral formulations typically contain from 0 to 20% (w / w) buffer, 0 to 50% (w / w) co-solvent, and / or 0 to 99% (w / w) water for injection (WFI) (depending on the dose and whether it is freeze-dried). Formulations for intramuscular depot preparations may also contain from 0 to 99% (w / w) oils.

[0478] Pharmaceutical compositions for oral administration can be obtained by combining the active ingredient with a solid carrier, granulating the resulting mixture if desired, adding appropriate excipients if desired or necessary, and then treating the mixture to form tablets, dragee cores, or capsules. They can also be incorporated into a polymeric or waxy matrix that allows for the diffusion or release of a measured amount of the active ingredient.

[0479] The compounds of the present invention can also be formulated as solid dispersions. A solid dispersion is a homogeneous and very fine dispersion phase of two or more solids. A solid solution (a molecularly dispersed system), which is a type of solid dispersion, is well known for use in pharmaceutical technology (Chiou and Riegelman, J. Pharm. Sci., 60, 1281-1300 (1971)) and is useful for increasing the dissolution rate and the bioavailability of poorly water-soluble drugs.

[0480] The present invention also provides a solid pharmaceutical form comprising the solid solution described herein. Solid pharmaceutical forms include tablets, capsules, chewable tablets, and dispersible or effervescent tablets. Known excipients can be blended with the solid solution to provide the desired pharmaceutical form. For example, capsules can comprise a solid solution blended with (a) a disintegrant and a lubricant, or (b) a disintegrant, a lubricant, and a surfactant. In addition, capsules can comprise a bulking agent such as lactose or microcrystalline cellulose. Tablets can comprise a solid solution blended with at least one disintegrant, a lubricant, a surfactant, a bulking agent, and a glidant. Chewable tablets can comprise a solid solution blended with a bulking agent, a lubricant, and optionally an additional sweetening agent (such as an artificial sweetener) and a suitable flavoring agent. The solid solution can also be formed by spraying a solution of the drug and a suitable polymer onto the surface of an inert carrier such as sugar beads (“nonpareils”). These beads can then be filled into capsules or compressed into tablets.

[0481] The pharmaceutical preparation may be presented to the patient in a “patient pack” that contains the entire course of treatment in a single package, usually a blister pack. The patient pack has advantages over the traditional prescription in which the pharmacist dispenses the patient supply of the pharmaceutical form from a bulk supply, since the patient always has access to the package insert included in the patient pack, which is usually lacking in the patient's prescription. It has been shown that including the package insert improves patient compliance with the physician's instructions.

[0482] Compositions for topical use and nasal delivery include ointments, creams, sprays, patches, gels, drops, and inserts (e.g., intraocular inserts). Such compositions can be formulated according to known methods.

[0483] Examples of formulations for rectal or vaginal administration include pessaries and suppositories that can be formed, for example, from a molded or waxy material containing the active compound. Solutions of the active compound can also be used for rectal administration.

[0484] Compositions for administration by inhalation may take the form of an inhalable powder composition or a liquid or powder spray and can be administered in a standard manner using a powder inhaler device or an aerosol dispensing device. Such devices are well known. In the case of administration by inhalation, powder formulations typically contain the active compound together with an inert solid powder diluent such as lactose.

[0485] The compounds of formula (I) will generally be presented in unit dosage form and will thus typically contain an amount of the compound sufficient to provide the desired level of biological activity. For example, the formulation may contain from 1 nanogram to 2 grams of the active ingredient, for example from 1 nanogram to 2 milligrams of the active ingredient. Within these ranges, particular sub-ranges of the compounds are from 0.1 milligram to 2 grams of the active ingredient (more generally from 10 milligrams to 1 gram, for example from 50 milligrams to 500 milligrams), or from 1 microgram to 20 milligrams (for example from 1 microgram to 10 milligrams, for example from 0.1 milligram to 2 milligrams of the active ingredient).

[0486] In the case of oral compositions, the unit dosage form may contain from 1 milligram to 2 grams, more typically from 10 milligrams to 1 gram, for example from 50 milligrams to 1 gram, for example from 100 milligrams to 1 gram of the active compound.

[0487] The active compound will be administered to a patient in need thereof (e.g., a human or animal patient) in an amount sufficient to achieve the desired therapeutic effect.

[0488] Therapeutic method The compounds of formula (I) and sub-groups as defined herein may be useful for the prevention or treatment of a wide variety of conditions or disorders mediated by SHP2. Examples of such conditions and disorders are shown above.

[0489] The compound is generally administered to a subject in need thereof, e.g., a human or animal patient, typically a human.

[0490] The compound will typically be administered in a therapeutically or prophylactically useful, generally non-toxic amount. However, in certain circumstances (e.g., in the case of life-threatening diseases), the advantages of administering a compound of formula (I) may outweigh any disadvantages of toxic effects or side effects, and in such cases, it may be desirable to administer the compound in an amount associated with some degree of toxicity.

[0491] The compound may be administered over a long period of time or only for a short period of time to maintain a beneficial therapeutic effect. Alternatively, the compound may be administered in a continuous manner or in a manner that provides intermittent dosing (e.g., a pulsatile manner).

[0492] A typical daily dose of a compound of formula (I) can range from 100 picograms to 100 milligrams per kilogram of body weight. The compounds of the invention can also be administered by bolus or continuous infusion.

[0493] The amount of compound administered and the type of composition used will be commensurate with the nature of the disease or physiological condition being treated and will be at the discretion of the physician.

[0494] It may also be beneficial to use the compounds of the invention as a single agent or to combine the compounds of the invention with another agent that treats two of the characteristics of cancer development by acting via different mechanisms to modulate cell proliferation. Combination experiments can be conducted as described, for example, in Chou TC, Talalay P. Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regulat 1984;22:27-55.

[0495] The compounds defined herein can be administered as the sole therapeutic agent or in combination therapy with one or more other compounds (or therapies) for the treatment of certain medical conditions, such as neoplastic diseases like cancer as defined above. In one embodiment, the combination therapy comprises a compound of formula I and one or more other anti-cancer compounds (or therapies) for treating cancer. For the treatment of the above-mentioned medical conditions, the compounds of the present invention can advantageously be used in combination with one or more other agents, more specifically, other anti-cancer agents or adjuvants (auxiliary agents in treatment) in cancer treatment.

[0496] Examples of other therapeutic agents or treatments that can be administered with (simultaneously or at different time intervals) the compound of formula (I) include, but are not limited to, the following. 1. Topoisomerase I inhibitors, 2. Antimetabolites and nucleoside derivatives, 3. Vinca alkaloids, epothilones, tubulin-binding agents, and tubulin-targeting agents including taxanes, 4. DNA-binding agents such as platinum agents and anthracyclines, and topoisomerase II inhibitors, 5. Alkylating agents, 6. Monoclonal antibodies, 7. Anti-hormonal agents such as GnRA, estrogen receptor antagonists, selective estrogen receptor modulators (SERMs), aromatase inhibitors, anti-androgens, 8. Signal transduction inhibitors, 9. Proteasome inhibitors, 10. DNA methyltransferase inhibitors, 11. Recombinant interferons, and retinoids, 12. Chromatin-targeted therapies, 13. Radiation therapy, and / or 14. Other therapeutic or prophylactic agents.

[0497] Examples of other therapeutic agents or therapies that can be administered (either simultaneously or at different time intervals) together with the compound of formula (I) include, but are not limited to, the following. I. Platinum compounds, II. Taxane compounds, III. Topoisomerase I inhibitors, IV. Topoisomerase II inhibitors, V. Vinca alkaloids, VI. Nucleoside derivatives, VII. Antimetabolites, VIII. Alkylating agents, IX. Other cytotoxic agents, X. Anthracyclines, anthraquinones, and related drugs, XI. Epothilones, XII. DNA methyltransferase inhibitors, XIII. Histone methyltransferase inhibitors, XIV. Antifolates, XV. Cytotoxic antibiotics, XVI. Tubulin binders, XVII. Signal transduction inhibitors, XVIII. Mitotic kinase inhibitors, XIX. CDK inhibitors, XX. PI3K / AKT pathway inhibitors, XXI. ERK inhibitors, XXII. Hsp90 inhibitors, XXIII. Monoclonal antibodies, antibody derivatives, bispecific antibodies, and "antibody-like" therapeutic proteins or other therapeutic proteins, and related agents, XXIV. Estrogen receptor antagonists or selective estrogen receptor modulators (SERMs) or inhibitors of estrogen synthesis, XXV. Aromatase inhibitors and related drugs, XXVI. Antiandrogens (i.e., androgen receptor antagonists) and related agents, XXVII. Hormones and their analogs, XXVIII. Steroids, XXIX. Steroid cytochrome P450 17 alpha-hydroxylase-17,20-lyase inhibitor (CYP17), XXX. Gonadotropin-releasing hormone agonist or antagonist (GnRA), XXXI. Glucocorticoid, XXXII. Differentiation inducer, XXXIII. Hedgehog pathway inhibitor, XXXIV. Dehydrogenase inhibitor, XXXV. Exportin 1 inhibitor, XXXVI. Polymerase inhibitor, XXXVII. Farnesyl transferase inhibitor, XXXVIII. Chromatin targeting therapy, XXXIX. Agent targeting the ubiquitin-proteasome pathway including proteasome inhibitor, XL. Photodynamic agent, XLI. Anticancer agent derived from marine organisms, XLII. Radiolabeled agent for radioimmunotherapy, XLIII. Telomerase inhibitor, XLIV. Matrix metalloproteinase inhibitor, XLV. Recombinant interferon and interleukin, XLVI. Selective immune response regulator, XLVII. Therapeutic vaccine, XLVIII. Cytokine activator, XLIX. Cytokine conjugate, L. Arsenic trioxide, LI. Inhibitor of G protein-coupled receptor (GPCR), LII. Enzyme, LIII. DNA repair inhibitor, LIV. Agonist of death receptor, LV. Other immunotherapies, LVI. Regulator of cell death (apoptosis), LVII. Gene modifier or editing factor, LVIII. Inhibitor of bromodomain, LIX. Radiation therapy for curative, palliative, or prophylactic purposes (or for adjuvant or neoadjuvant purposes), and / or LX. Prophylactic agents (adjuvants), i.e., agents that reduce or mitigate some of the side effects associated with chemotherapeutic agents.

[0498] In one embodiment, the combination therapy comprises a compound of formula I and one or more other anti-cancer compounds (or therapies) for treating cancer, optionally in combination with radiation therapy and / or prophylactic agents. In one embodiment, the combination therapy comprises a compound of formula I in combination with radiation therapy and / or prophylactic agents.

[0499] Specific examples of anti-cancer agents or adjuvants (or salts thereof) include, but are not limited to, any of the agents selected from the following groups (I) to (LIX) and optionally group (LX). I. Platinum compounds, such as cisplatin (optionally in combination with amifostine), carboplatin, oxaliplatin, dicycloplatin, heptaplatin, lobaplatin, nedaplatin, satraplatin, or triplatin tetranitrate, particularly cisplatin, carboplatin, or oxaliplatin, II. Taxane compounds, such as paclitaxel, paclitaxel protein-bound particles (Abraxane™), docetaxel, cabazitaxel, larotaxel; ortataxel, tesetaxel, or simotaxel, particularly paclitaxel, paclitaxel protein-bound particles (Abraxane™), or docetaxel, III. Topoisomerase I inhibitors, such as camptothecin compounds, such as camptothecin, irinotecan (CPT11), SN-38, topotecan, bryostatin, calistatin, nogitecan, velotecan, exatecan, rubitecan, or lurtotecan, particularly camptothecin, irinotecan, or topotecan, IV. Topoisomerase II inhibitors, such as antitumor epipodophyllotoxins or podophyllotoxin derivatives, such as etoposide, teniposide, sobuzoxane, edotecarin, amonafide, amrubicin, or pixantrone, particularly etoposide or teniposide, V. Vinca alkaloids, such as vinblastine, vincristine, liposomal vincristine (Onco-TCS), vinorelbine, vindesine, vinflunine, vinbesil, eribulin, or talisbulin, particularly vinblastine, vincristine, or vinorelbine, VI. Nucleoside derivatives, such as 5-fluorouracil (5-FU, optionally combined with leucovorin, such as LV5FU2), gemcitabine, capecitabine, tegafur (optionally combined with uracil known as UFT, or combined with gimeracil and oteracil potassium known as TS-1 or S1), cladribine, cytarabine (Ara-C, cytosine arabinoside), fludarabine, clofarabine, nelarabine; foldecitabine, doxifluridine, galocitabine, sapacitabine, emitefur, or troxacitabine; VII. Antimetabolites, such as clofarabine, aminopterin, or methotrexate, azacitidine, cytarabine, floxuridine, pentostatin, thioguanine, thiopurine, 6-mercaptopurine, hydroxyurea (hydroxycarbamide), or trifluridine (optionally combined with tipiracil); VIII. Alkylating agents such as nitrogen mustard or nitrosourea, for example, cyclophosphamide, chlorambucil, carmustine (BCNU), ambamustine, bendamustine, thiotepa, melphalan, treosulfan, lomustine (CCNU), busulfan, dacarbazine, estramustine, fotemustine, ifosfamide (optionally in combination with mesna), pipobroman, procarbazine, streptozocin, temozolomide, uracil, mechlorethamine, mechlorethamine oxide hydrochloride, methylcyclohexyl chloroethyl nitrosourea, nimustine (ACNU), prednimustine, mechlorethamine, etoglucid; streptozotocin, irofulven, mitolactol, glufosfamide, evofosfamide, or altretamine, triethylenemelamine, trimethylolmelamine, triethylenephosphoramide, triethylenethiophosphoramide, and ethyleneimine and methylamelamine containing trimethylolmelamine, IX. Other cytotoxic agents such as drastatin, eleutherobin, pancratistatin, sarcodictyin A, or spongistatin, X. Anthracyclines, anthraquinones, and related drugs, for example, daunorubicin, doxorubicin (optionally in combination with dexrazoxane), liposomal formulations of doxorubicin (e.g., Caelyx (trademark), Myocet (trademark), Doxil (trademark)), idarubicin, mitoxantrone, epirubicin, amsacrine, or valrubicin, XI. Epothilones, for example, ixabepilone, patupilone, BMS-310705, epothilone A, epothilone B, desoxyepothilone B (also known as epothilone D or KOS-862), aza-epothilone B (also known as BMS-247550), laulimalide, isolaulelimide, or luetherobin, XII. DNA methyltransferase inhibitors, for example, temozolomide, azacitidine, decitabine (alone or in combination with a cytidine deaminase inhibitor such as sedazurin), or guadecitabine (SGI-110), XIII. Histone methyltransferase inhibitors, such as EZH2 inhibitors like tazemetostat, PF-06821497, CPI-1205, or CPI-0209, XIV. Antifolates, such as methotrexate, pemetrexed disodium, raltitrexed, pralatrexate, edatrexate, or trimethoprim, XV. Cytotoxic antibiotics, such as actinomycin D, bleomycin, mitomycin C, dactinomycin, calminomycin, daunomycin, levamisole, plicamycin, mitramycin, aclarubicin, pirarubicin, anthramycin, azaserine, cactinomycin, calicheamicin, carubicin, cardinophilin, chromomycin, detorubicin, esorubicin, esperamicin, geldanamycin, marcellomycin, olivomycin, peplomycin, puromycin, keramycin, rebeccamycin, rhodomycin, streptozocin, streptonigrin, tubercidin, dynemicin A including dynemicin, CC-1065 (including its adozelesin, carzelesin, and bizelesin synthetic analogs), duocarmycin (including the synthetic analog pibrozelesin (KW-2189)), or dinostatin, XVI. Tubulin binders, such as combretastatin, cortisone, dexamethasone, noscapine, or nocodazole, XVII. Kinase inhibitors, such as receptor tyrosine kinase inhibitors (e.g., EGFR (epidermal growth factor receptor (Erbb1) inhibitor), VEGFR (vascular endothelial growth factor receptor) inhibitor, PDGFR (platelet-derived growth factor receptor) inhibitor, FGFR (fibroblast growth factor), Axl inhibitor, MTKI (multi-target kinase inhibitor), c-Kit inhibitor, other Erbb inhibitors, such as, Errb2 (HER2), Errb3 (HER3), or Errb4 (HER4), Trk inhibitor, Flt3 inhibitor, JAK inhibitor, RET inhibitor, MET inhibitor, Btk inhibitor, ALK inhibitor, ROS1 inhibitor, FYN inhibitor, Src inhibitor, Bcr-Abl inhibitor, hexokinase inhibitor, Raf inhibitor, ROCK inhibitor, MEK inhibitor, or PI3K inhibitor, such as imatinib, erlotinib, gefitinib, afatinib (dual EGFR / HER2), brigatinib (ALK / EGFR), osimertinib (EGFR), almonertinib (EGFR), ormutinib (EGFR), icotinib (EGFR), alflutinib (EGFR), lazertinib (EGFR), zolifertinib (EGFR), mefatinib (EGFR), stetinib (EGFR), dasatinib, lapatinib, dovitinib (CHIR 258), axitinib (AG-13736), nilotinib, vandetanib, batatinib, saracatinib (AZD-0530), bosutinib, bafetinib (NS-187), avibertinib (EGFR, Btk), mobocertinib (EGFR, Erbb2), anlotinib (multi-kinase), avapritinib (KIT, PDGF), lenvatinib (E-7080) (multi-kinase), pyrotinib (multi-kinase), lonidamine (hexokinase), BMS-690514, nintedanib (tyrosine kinase), ponatinib (multi-kinase), tivozanib (KRN-951) (multi-kinase), R-1530 (multi-kinase), bataranib (PDGF, VEGF), PF-337210 (VEGF), AEE-788 (multi-kinase), tesevatinib (XL-647) (multi-kinase), K-0706, ripretinib (KIT, PDGF), dacomitinib (EGFR, Erbb2 / Erbb4), neratinib (EGFR, Erbb2 / Erbb4), balverine (EGFR, Erbb2 / Erbb4) Erbb2 (Herceptin), Larotrectinib (Trk), Erdafitinib (FGFR), Infigratinib (FGFR), Pemigatinib (FGFR), Rogaratinib (FGFR), Derazantinib (FGFR), E-7090 (FGFR), HMPL-453 (FGFR), Zorifertinib (FGFR), Futibatinib (FGFR), Brivanib (FGFR, VEGFR), Ki 23057 (FGFR), Sulfatinib (FGFR, VEGFR), Pazopanib (GW 786034), Cediranib (KIT, VEGFR, PDGFR), Orantinib (FGF, PDGF, VEGF), H3B-6527, MAX-40279, ICP-105, Telatinib (BAY-57-9352) (KIT, PDGFR, VEGFR), Pegaptanib (VEGFR), Semaxanib (MAPK, VEGFR), Quizartinib (AC-220) (Flt3, KIT, PDGFR), Crenolanib (CP 868596) (Flt3, PDGFR), Restaurtinib (Multi-kinase), Cabozantinib (XL-184) (VEGFR2, Axl, MET, RET), Selpercatinib (RET), Capmatinib (MET), MK-2461 (MET), SU-11274 (MET), PHA-665752 (MET), Ibrutinib (Btk), Acalabrutinib (Btk), Asciminib (Bcr-Abl), Flumatinib (Abl), Zanubrutinib (Btk), Ruxolitinib (JAK), Itacitinib (JAK), Pacritinib (JAK), Momelotinib (JAK), INCB-52793 (JAK), Gusacitinib (JAK / SYK), Irgatinib (JAK), Serdulatinib (Syk, JAK), Fedratinib (TG-101348) (Flt3, Jak2, RET), Tandutinib (Flt3, KIT, PDGF), Pexidartinib (KIT, Flt3), Midostaurin (Flt3, KIT, PKC), Zotarolimus (FLT3), Alectinib (ALK), Crizotinib (ALK), Ceritinib (ALK), Lorlatinib (ALK, Ros1), Entrectinib (ALK, Ros1, TRK), Masitinib (Multi-kinase), Sorafenib, Sunitinib, Vemurafenib (PLX4032 or RG7204), Dabrafenib, Encorafenib, Regorafenib (BAY-7. 3 - 4506)(FGFR3, KIT), selumetinib (AZD6244), trametinib (GSK121120212), binimetinib (BRAF, MEK), cobimetinib (MEK), mildabemetinib (PD325901)(MEK), refametinib (MEK), uprosertib (AKT, MEK), pimasertib (MEK), dactolisib (BEZ235), buparlisib (BKM - 120; NVP - BKM - 120), alpelisib (BYL719)(PI3), copanlisib (BAY - 80 - 6946), paxalisib (PI3K / mTOR / AKT pathway), S - 49076 (multi - kinase), rigosertib (multi - kinase), levastinib (multi - kinase), ZSTK - 474, fimepinoside (CUDC - 907)(PI3K and HDAC), apitolisib (GDC - 0980; RG - 7422), pictilisib (GDC - 0941, RG - 7321, GNE - 477), idelalisib (formerly CAL - 101, GS 1101, GS - 1101, IC87114), serabelisib (MLN1117, INK1117)(PI3K), sapitinib (MLN0128(INK128)), duvelisib (IPI - 145, INK1197)(PI3K), ipatasertib (GDC - 0068), afuresertib, MK - 2206, MK - 8156, SKLB - 1028, LY294002, SF1126 or PI - 103, sonolisib (PX - 866), GSK1059615(PI3K), piraralisib (XL147)(PI3K); signal transduction inhibitors such as SF - 1126 (multi - kinase) or AT13148, or pan - Raf inhibitors, for example, PLX8394, RAF - 265, or other signal transduction inhibitors, for example, temsirolimus, everolimus (RAD 001), including mTOR inhibitors, and RAS inhibitors, for example, AMG - 510, LY - 3499446, MRTX - 849, or ARS - 3248, or isoprenyl transferase inhibitors, for example, anthroquinonol, XVIII. Aurora kinase inhibitors, such as mitotic kinases such as AT9283, barasertib (AZD1152), danusertib (PHA-739358), alisertib (MLN-8237), or CYC-116, or polo-like kinases (PLK inhibitors) such as PLK-1 or PLK-4, including rigosertib, onvansertib, CYC-140, GSK-461364, CFI-400945, or volasertib, XIX. CDK inhibitors, including CDK4 inhibitors such as palbociclib (PD332991), abemaciclib, dinaciclib, lerociclib, trilaciclib, and ribociclib (LEE-011), AT7519, roscovitine, seliciclib, alvocidib (flavopiridol), abemaciclib, dinaciclib (SCH-727965), 7-hydroxy-staurosporine (UCN-01), JNJ-7706621, PHA533533, ZK-304709, zotarolimus, or AZD-5438, PI3K / AKT pathway inhibitors containing XX.PKA / B and / or PKB(akt) inhibitors, PI3K inhibitors, mTOR inhibitors, and / or calmodulin inhibitors (forkhead translocation inhibitors), such as, for example, apitolisib, buparlisib, copanlisib, pictilisib, dactolisib, idelalisib, serabelisib, duvelisib, ipatasertib, alpelisib, afuresertib, paxalisib, sonolisib, piraralisib, fimepinoside (CUDC-907), SKLB-1028, GSK1059615 (PI3K), ZSTK-474, GSK-2636771, sumotolib (LY-3023414), LY294002, SF1126, and PI-103 and other PI3K inhibitors, sirolimus (originally known as rapamycin), and rapamycin analogs such as RAD 001 (everolimus), CCI 779 (temsirolimus), AP23573, and ridafolimus and other mTOR inhibitors, sapitinib (MLN0128 (INK128), a dual inhibitor of mTOR complex I (mTORCI) and mTORC2, PKA / B (or C) inhibitors, such as, for example, perifosine, ipatasertib, aproselitinib, afuresertib, MK-2206, MK-8156, AT13148, capivasertib (AZD5363), triciribine, enzastaurin, XL-418, GSK-690693, or RX-0201, XXI. ERK inhibitors containing ulixertinib, ASTX029, LY3214996, LTT462, MK-8353, SCH772984, AZD-0364, ASN-007, or KO-947, XXII. Hsp90 inhibitors, for example, onalespib (AT13387), herbimycin, geldanamycin (GA), 17 - allylamino - 17 - demethoxygeldanamycin (17 - AAG), for example, NSC - 330507, Kos - 953, and CNF - 1010, 17 - dimethylaminoethylamino - 17 - demethoxygeldanamycin hydrochloride (17 - DMAG), for example, NSC - 707545 and Kos - 1022, NVP - AUY922 (VER - 52296), NVP - BEP800, CNF - 2024 (oral purine BIIB - 021), alvespimycin, ganetespib (STA - 9090), SNX - 5422 (SC - 102112), or IPI - 504, or pimitespib, XXIII. Monoclonal antibodies (conjugated or unconjugated to radioisotopes, toxins, or other agents, such as cytotoxic anticancer agents like antibody-drug conjugates), antibody derivatives, bispecific antibodies, and "antibody-like" therapeutic proteins (DART®, Duobodies®, Bites®, XmAbs®, TandAbs®, or Fab derivatives, etc.), or other therapeutic proteins and related agents such as anti-CD, anti-VEGFR, anti-HER2, or anti-EGFR antibodies, e.g., rituximab (CD20), ofatumumab (CD20), ibritumomab tiuxetan (CD20), GA101 (CD20), tositumomab (CD20), belimumab (CD20), epratuzumab (CD22), lintuzumab (CD33), gemtuzumab ozogamicin (CD33), alemtuzumab (CD52), galiximab (CD80), trastuzumab (HER2 antibody), pertuzumab (HER2), trastuzumab-DM1 (HER2), ado-trastuzumab emtansine, fam-trastuzumab deruxtecan, ertumaxomab (HER2 and CD3), cetuximab (EGFR), matuzumab (EGFR), panitumumab (EGFR), necitumumab (EGFR), nimotuzumab (EGFR), zalutumumab (EGFR), bevacizumab (VEGF), ramucirumab (VEGFR), catumaxumab (EpCAM and CD3), abagovomab (CA125), farletuzumab (folate receptor), elotuzumab (CS1), denosumab (RANK ligand), figitumumab (IGF1R), CP751,871 (IGF1R), mapatumumab (TRAIL receptor), metMAB (met), mitsumomab (GD3 ganglioside), napumomab estafenatox (5T4), siltuximab (IL6), zanilimumab (CD4), SGN40 (CD40), ficlatuzumab (anti-HGF), blinatumomab (CD3 regulator; B lymphocyte antigen CD19 regulator), tafasitamab-cxix (CD19), brentuximab vedotin (CD30), daratumumab (IgG1 kappa antibody), moxetumomab, ranibizumab (anti-VEGF), enfortumab vedotin, sacituzumab Zumabogovitecan, Obinutuzumab (CD20), Inotuzumab Ozogamicin (CD22), Belantamab Mafodotin, Brentuximab Vedotin (CD30), Obinutuzumab (CD20), Mogamulizumab (CCR4), Polatuzumab Vedotin (CD79b), Isatuximab (CD38), Dinutuximab (GD2), Olaratumab (IMC 3G3, PDGF mAb), Margetuximab, anti-FGFR MAb (IMC-D11), anti-PDGF receptor-beta mAb (1B3), Aflibercept (AVE-0005) (VEGF trap), or an immunomodulatory antibody (agents such as checkpoint inhibitors or CTLA-4 blocking antibodies and / or antibodies against PD-1 and PD-L1 and / or PD-L2, for example, Ipilimumab (CTLA4), MK-3475 (Pembrolizumab, formerly Lambrolizumab, anti-PD-1), Nivolumab (anti-PD-1), BMS-936559 (anti-PD-L1), MPDL320A, AMP-514, or MEDI4736 (anti-PD-L1)), or Tremelimumab (formerly Tisilimumab, CP-675,206, anti-CTLA-4); Atezolizumab (anti-PDL1), Durvalumab (anti-PDL1), Avelumab (anti-PDL1), Semiprimab (anti-PD-1), Pidilizumab (anti-PD-1); PDR-001 (anti-PD-1), Spartalizumab (anti-PD-1), Ipilimumab (anti-CTLA-4), Abatacept (antibody fragment and conjugate with CTLA-4), Relatlimab, LAG-525, TSR-033, IBI-110, or FS-118 and other anti-LAG3, and anti-OX40 (CD134) agents, such as MOXR0916, MEDI6469, PF-04518600, MEDI0562, BMS 986178, ISB-830, KY-1005, or INCAGN-1949, XXIV. An estrogen receptor antagonist or selective estrogen receptor modulator (SERM) or an inhibitor of estrogen synthesis, for example, tamoxifen, fulvestrant, toremifene, droloxifene, faslodex, raloxifene, or keoxifene, XXV. Aromatase inhibitors and related drugs, such as exemestane, anastrozole, letrozole, testolactone aminoglutethimide, mitotane, or vorozole; fadrozole, liarozole, atamestane, formestane, dexaminoglutethimide, or trilostane, XXVI. Anti-androgens (i.e., androgen receptor antagonists) and related agents, such as bicalutamide, nilutamide, flutamide, cyproterone, ketoconazole, apalutamide, darolutamide, or enzalutamide, XXVII. Hormones and their analogs, such as medroxyprogesterone, diethylstilbestrol (also known as diethylstilboestrol), or octreotide; finasteride, fludrocortisone, fluoxymesterone, arzoxifene, pasireotide, or pasireotide, XXVIII. Steroids, such as drostanolone propionate, megestrol acetate, nandrolone (decanoate, fenpropionate), fluoxymesterone, gossypol, calusterone, epitioestanol, or mepitiostane, XXIX. Steroid cytochrome P450 17alpha-hydroxylase-17,20-lyase inhibitors (CYP17), such as abiraterone, or fadrozole, XXX. Gonadotropin-releasing hormone agonists or antagonists (GnRA), such as abarelix, goserelin acetate, histrelin acetate, leuprolide acetate, triptorelin, buserelin, deslorelin; leuprolide, or nafarelin, XXXI. Glucocorticoids, such as prednisone, prednisolone, or dexamethasone, XXXII. Differentiating agents such as retinoids, rexinoids, vitamin D, or retinoic acid, and retinoic acid metabolism blockers (RAMBA), such as acitretin, alitretinoin, bexarotene, or tretinoin; fenretinide, isotretinoin, or RII retinamide, XXXIII. Hedgehog pathway inhibitors such as glasdegib, vismodegib, or sonidegib, XXXIV. A dehydrogenase inhibitor, such as a dihydroorotate dehydrogenase inhibitor containing enasidenib, ibosidenib, borasidenib, IDH-305, ortasidenib, DS-1001b, enfuldenib, ralfinamide, brequinar, ASLAN-003, AG-636, BAY-2402234, or PTC-299, or a pyruvate dehydrogenase inhibitor such as devimistat or KULA-18, XXXV. An exportin 1 inhibitor such as selinexor, eltanexor, verzenexor, or ferrezor; a polymerase inhibitor such as a DNA or RNA polymerase inhibitor containing lurbinectedin, XXXVI. A farnesyltransferase inhibitor, for example, tipifarnib, XXXVII. Chromatin-targeted therapy such as a histone deacetylase (HDAC) inhibitor, for example, sodium butyrate, suberoylanilide hydroxamic acid (SAHA), depsipeptide (FR 901228), dacinostat (NVP-LAQ824), R306465 / JNJ-16241199, JNJ-26481585, trichostatin A, vorinostat, chlamydocin, A-173, JNJ-MGCD-0103, PXD-101, apicidin; belinostat, panobinostat, romidepsin, resminostat, abexinostat, entinostat, xevinostat, pracinostat, tefinostat, mocetinostat, givinostat, or fimetinostat, XXXVIII. Drugs targeting the ubiquitin-proteasome pathway, including proteasome inhibitors, such as bortezomib, carfilzomib, ixazomib, marizomib (salinosporamide a), oprozomib, ubenimex CEP-18770, MLN-9708, or ONX-0912; NEDD8 inhibitors; HDM2 antagonists, idasanutlin (RG7388), HDM-201, KRT-232 (AMG-232), nutlin 3a, RG7112, CGM-097, ALRN-6924, Debio-0123, LY-3143921, MI-773 (SAR405838), mirademetan (DS-3032b), APG-115, or BI-907828, or ASTX295 or UBX0101; inhibitors of deubiquitinase (DUB); or inhibitors of ubiquitin-specific proteases, such as HBX-41108, XXXIX. Photodynamic drugs, such as porfimer sodium or temoporfin, XL. Anticancer agents derived from marine organisms, such as trabectedin, XLI. Radiolabeled drugs for radioimmunotherapy with beta particle-emitting isotopes (e.g., iodine-131, yttrium-90) or alpha particle-emitting isotopes (e.g., bismuth-213 or actinium-225), such as ibritumomab, iodine tositumomab, alpharadin 223; yttrium ibenguane, or lutetium Lu177-dotatate, XLII. Telomerase inhibitors, such as telomestatin, XLIII. Matrix metalloproteinase inhibitors, such as batimastat, marimastat, prinomastat, or metastat, XLIV. Recombinant interferons (such as interferon-γ and interferon α) and interleukins (such as interleukin 2), such as aldesleukin, denileukin diftitox, interferon alpha 2a, interferon alpha 2b, or pegylated interferon alpha 2b, XLV. Selective immune response regulators, such as thalidomide, thalidomide derivatives such as lenalidomide, or pomalidomide (ENMD 0995, CC-4047), XLVI. Therapeutic vaccines such as Sipuleucel-T (Proveng), OncoVex, intravesical BCG live, mDC3 vaccine, PEPIDH1M vaccine, T-VEC or IDH1-targeted vaccine, XLVII. Cytokine activators include picibanil, romurtide, schizophyllan, viridin, or thymosin, XLVIII. Cytokine conjugates such as cytokine-toxin conjugates containing tagraxofusp, XLIX. Arsenic trioxide; L. Inhibitors of G protein-coupled receptors (GPCRs), such as atrasentan LI. Enzymes such as L-asparaginase, pegaspargase, rasburicase, or pegademase, LII. DNA repair inhibitors such as PARP inhibitors, such as olaparib, rucaparib, veliparib, iniparib, INO-1001, AG-014699, ONO-2231, or talazoparib, LIII. Agonists of death receptors (e.g., TNF-related apoptosis-inducing ligand (TRAIL) receptors), such as mapatumumab (formerly HGS-ETR1), conatumumab (formerly AMG 655), PRO95780, lexatumumab, dularemmin, CS-1008, apomab, or recombinant TRAIL ligands such as recombinant human TRAIL / Apo2 ligand, LIV. Other immunotherapies, such as oncolytic viruses such as talimogene laherparepvec (T-VEC); CAR-T cell therapies such as anti-CD-19 CAR T cell therapy, such as tisagenlecleucel, axicabtagene ciloleucel, lisocabtagene, idecabtagene, brexucabtagene autoleucel (KTE-X19); engineered T cell receptor (TCR-T) therapy; TLR agonists such as motolimod, imiquimod, lintetimod, or resiquimod, or immune checkpoint inhibitors such as PD-1 / PD-L1 inhibitors, such as razertinib, CA-170, CCX-4503, PCC0208025 (BMS202), GS-4224, INCB-086550, or RRx-001, LV. Regulators of cell death (apoptosis) including Bcl-2 (B-cell lymphoma 2) antagonists such as venetoclax (ABT-199 or GDC-0199), ABT-737, ABT-263, TW-37, subtoclax, obatoclax, and including MIM1 and IAP agonists (including LCL-161 (Novartis), Debio-1143 (Debiopharma / Ascenta), AZD5582, Birinapant / TL-32711 (TetraLogic), CUDC-427 / GDC-0917 / RG-7459 (Genentech), JP1201 (Joyant), T-3256336 (Takeda), GDC-0152 (Genentech), ASTX660, or HGS-1029 / AEG-40826 (HGS / Aegera)); and inhibitors of myeloid cell leukemia-1 (MCL-1, a member of the BCL2 family) (including AMG-176, MIK665, and S63845), LVI. Gene modification factors or editing factors such as CRISPR / Cas9, zinc finger nucleases or synthetic nucleases, or TALEN, Inhibitors of bromodomains, including BET inhibitors such as GSK525762, GSK2820151, OTX-015 / MK-8628, BMS-986158, CPI-0610, RO6870810 / TEN-010, RVX000222, FT-1101, ABBV-075, BAY1238097, INCB054329, INCB057643, PLX51107, or ZEN003694, LVIII. Radiation therapy for curative, palliative, or prophylactic purposes (or for adjuvant or neo-adjuvant purposes), and / or LIX. Prophylactic (adjuvant) agents, i.e., agents that reduce or mitigate some of the side effects associated with chemotherapeutic agents, e.g., a) Antiemetics, b) Agents that prevent or shorten the duration of chemotherapy-related neutropenia and prevent complications resulting from a decrease in the levels of platelets, erythrocytes, or leukocytes, e.g., colony-stimulating factor analogs such as interleukin-11 (e.g., oprelvekin), erythropoietin (EPO) (e.g., epoetin alpha, epoetin beta) or its analogs (e.g., darbepoetin alpha), granulocyte macrophage colony-stimulating factor (GM-CSF) (e.g., sargramostim), or granulocyte colony-stimulating factor (G-CSF) or its analogs (e.g., filgrastim, pegfilgrastim, lenograstim, leridistim, molgramostim, nartograstim), c) Agents that inhibit bone resorption, such as denosumab or bisphosphonates, e.g., zoledronate, zoledronic acid, pamidronate, or ibandronate, d) Agents that suppress the inflammatory response, such as dexamethasone, prednisone, or prednisolone, e) Agents used to lower the blood concentrations of growth hormone and IGF-I (and other hormones) in patients with acromegaly or other rare hormone-producing tumors, e.g., synthetic forms of the hormone somatostatin, e.g., octreotide acetate, lanreotide, f) An antidote to drugs that reduce the levels of folic acid such as leucovorin or folic acid, g) Agents for pain such as morphine, diamorphine, or fentanyl, for example, opiates, h) COX-2 inhibitors, for example, non-steroidal anti-inflammatory drugs (NSAIDs) such as celecoxib, etoricoxib, or lumiracoxib, i) Agents for mucositis, for example, palifermin, j) Agents that regulate the metabolism of anti-cancer drugs, that is, PK enhancers, for example, P450 (for example, 3A4 inhibitors) such as cobimetinib, or cytidine deaminase inhibitors (for example, zebularine, tetrahydro uridine, or sedazuridine) or thymidine phosphorylase inhibitors (for example, tipiracil), and / or k) Agents for the treatment of side effects including anorexia, cachexia, edema, or thromboembolic attacks, such as megestrol acetate.

[0500] In one embodiment, the compound of formula I is combined with an inhibitor of the RAS-MAPK pathway such as a BRAF inhibitor, a RAF inhibitor, a MEK inhibitor, or an ERK inhibitor as described herein.

[0501] Each of the compounds present in the combination of the present invention may be administered via different routes at individually varying dosage schedules. Thus, the pharmacology of each of the two or more agents may be different and each may be administered at the same time or at different times. One of ordinary skill in the art will know the dosing regimens and combination therapies to use based on their ordinary general knowledge. For example, the compounds of the present invention may be used in combination with one or more other agents administered according to their existing combination regimens. Examples of standard combination regimens are provided below.

[0502] When the compound of formula (I) is administered in combination therapy with one, two, three, four, or more other therapeutic agents (typically one or two, more typically one), the compounds can be administered simultaneously or sequentially. In the latter case, two or more compounds will be administered for a period of time, in amounts, and in a manner sufficient to ensure that beneficial or synergistic effects are achieved. In one embodiment, the compound of formula (I) is administered to a patient who is undergoing treatment with one or more therapeutic compounds. The typical methods and order of administration, as well as the respective dosages and regimens for each component of the combination, will depend on the particular other pharmaceutical agents and compounds of the invention being administered, their route of administration, the particular tumor being treated, and the particular host being treated.

[0503] The weight ratio of the compound according to the invention to one or more other anticancer agents when administered as a combination can be determined by one of ordinary skill in the art. The ratio and the exact dosage and frequency of administration will depend, as is well known to one of ordinary skill in the art, on the particular compound according to the invention and the other anticancer agents used, the particular condition being treated, the severity of the condition being treated, the age, weight, gender, diet, time of administration, and general physical condition of the particular patient, the mode of administration, and other medications the individual may be taking. Further, it is obvious that the effective daily dose may be increased or decreased depending on the response of the subject being treated and / or the evaluation of the physician prescribing the compounds of the invention.

[0504] The compounds of the present invention may also be administered in combination with a suitable standard regimen of chemotherapy, which may be determined by those skilled in the art (for example, as described in JCO Clin Cancer Inform 4:60-70), and this includes, for example, PC (paclitaxel and carboplatin), FR (fludarabine and rituximab), CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), CVP (cyclophosphamide, vincristine, and prednisone), FCM (fludarabine, cyclophosphamide, and mitoxantrone), FCR (fludarabine, cyclophosphamide, and rituximab), hyperCVAD (multi-fraction cyclophosphamide, vincristine, doxorubicin, dexamethasone, methotrexate, and cytarabine), ICE (ifosfamide, carboplatin, and etoposide), MCP (mitoxantrone, chlorambucil, and prednisolone), R-CHOP (rituximab and CHOP), RCVP (rituximab and CVP), R-FCM (rituximab and FCM), R-ICE (rituximab-ICE), ICE-V (ICE and vincristine), R-MCP (rituximab-MCP), or FOLFOX or FLOX (folinic acid, fluorouracil, and oxaliplatin).

[0505] The compounds of the present invention may also be administered in combination with non-chemotherapy treatments such as radiotherapy, photodynamic therapy, gene therapy, surgery, and dietary management. Radiotherapy may be for curative, palliative, adjuvant, neo-adjuvant, or prophylactic purposes.

[0506] The compounds of the present invention also have therapeutic use in sensitizing tumor cells for radiotherapy and chemotherapy. Thus, the compounds of the present invention can be used as a "radiotherapy sensitizer" and / or "chemotherapy sensitizer", or can be administered in combination with another "radiotherapy sensitizer" and / or "chemotherapy sensitizer". In one embodiment, the compounds of the present invention are for use as a chemotherapy sensitizer.

[0507] The term "radiation therapy sensitizer" is defined as a molecule that is administered to a patient in a therapeutically effective amount to increase the sensitivity of cells to ionizing radiation and / or to facilitate the treatment of diseases treatable with ionizing radiation.

[0508] The term "chemotherapy sensitizer" is defined as a molecule that is administered to a patient in a therapeutically effective amount to increase the sensitivity of cells to chemotherapy and / or to facilitate the treatment of diseases treatable with chemotherapeutic agents.

[0509] Many cancer treatment protocols currently employ radiation therapy sensitizers in combination with X-ray irradiation. Examples of X-ray activated radiation therapy sensitizers include metronidazole, misonidazole, desmethylmisonidazole, pimonidazole, etanidazole, nimorazole, mitomycin C, RSU 1069, SR 4233, EO9, RB 6145, nicotinamide, 5-bromodeoxyuridine (BUdR), 5-iododeoxyuridine (IUdR), bromodeoxycytidine, fluorodeoxyuridine (FudR), hydroxyurea, cisplatin, and their therapeutically effective analogs and derivatives.

[0510] In photodynamic therapy (PDT) of cancer, visible light is used as the radiation activator of the sensitizer. Examples of photodynamic radiation therapy sensitizers include, but are not limited to, hematoporphyrin derivatives, Photofrin, benzoporphyrin derivatives, tin etiopurpurin, pheophorbide-a, bacteriochlorophyll-a, naphthalocyanine, phthalocyanine, zinc phthalocyanine, and their therapeutically effective analogs and derivatives.

[0511] Radiation therapy sensitizers may be administered in combination with one or more other compounds in a therapeutically effective amount, including, but not limited to, compounds that facilitate the incorporation of the radiation therapy sensitizer into target cells, therapeutic agents, nutrients, and / or compounds that control the flow of oxygen to target cells, chemotherapeutic agents that act on tumors with or without additional irradiation, or other therapeutically effective compounds for treating cancer or other diseases.

[0512] The chemosensitizer may be administered in combination with one or more other compounds in a therapeutically effective amount, including, but not limited to, compounds that promote the incorporation of the chemosensitizer into target cells, therapeutic agents, nutrients, and / or compounds that control the flow of therapeutic agents, chemotherapeutic agents acting on tumors, or other therapeutically effective compounds for treating cancer or other diseases. Calcium antagonists, such as verapamil, have been found to be useful in establishing chemosensitivity in tumor cells resistant to accepted chemotherapeutic agents in combination with antitumor agents and enhancing the effectiveness of such compounds in drug-sensitive malignancies.

[0513] For use in combination therapy with another chemotherapeutic agent, the compound of formula (I) and one, two, three, four, or more other therapeutic agents can be formulated together, for example, in a dosage form containing two, three, four, or more therapeutic agents, i.e., in a single pharmaceutical composition containing all the components. Alternatively, the individual therapeutic agents can be formulated separately and presented together in the form of a kit, optionally together with instructions for their use.

[0514] In one embodiment, the present invention further provides a combination drug in which the compound of formula (I) and at least one or more therapeutic agents are physically associated. In one embodiment, the compound of formula (I) and at least one or more therapeutic agents are (a) in a mixture, (b) chemically / physicochemically linked, (c) chemically / physicochemically packaged together, or (d) not mixed but packaged together or presented together.

[0515] In another embodiment, the compound of formula (I) and at least one or more therapeutic agents are non-physically associated. In a further embodiment, this optionally further comprises (a) instructions for immediately associating the compound of formula (I) with at least one or more compounds to form a physical association of these two or more compounds, or (b) instructions for a combination therapy using the compound of formula (I) and at least one or more therapeutic agents, or (c) instructions for administration to a patient population.

[0516] When the individual agents are presented in kit form, the kit may comprise two or more separate pharmaceutical compositions, namely a compound of formula (I) and one or more further pharmaceutical compounds. The kit may include a container for containing separate compositions such as divided bottles or divided foil packets. Additional examples of containers include syringes, boxes, and bags. In some embodiments, the kit includes instructions for using the separate components. The kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral and parenteral), when administered at different dosing intervals, or when titration of the individual components of the combination is desired by the prescribing medical professional.

[0517] In a further embodiment, the present invention provides a combination of a compound as defined herein and another therapeutic agent, such as another therapeutic agent as defined above.

[0518] In another embodiment, the present invention provides a pharmaceutical composition comprising a compound as defined herein together with a pharmaceutically acceptable carrier and one or more therapeutic agents as defined above.

[0519] In one embodiment, the pharmaceutical composition comprises a compound of formula I together with a pharmaceutically acceptable carrier and optionally one or more therapeutic agents.

[0520] In another embodiment, the present invention relates to the use of a combination according to the present invention in the manufacture of a pharmaceutical composition for inhibiting the growth of tumor cells.

[0521] In a further embodiment, the present invention relates to a product comprising a compound of formula I and one or more anti-cancer agents as a combined preparation for simultaneous, separate or sequential use in the treatment of a patient suffering from cancer.

[0522] In a further embodiment, the present invention relates to a compound of formula (I) for use in the treatment of a disease or condition as defined herein, wherein the patient is undergoing treatment with one or more other therapeutic compounds.

Examples

[0523] The present invention will now be illustrated, without limitation, by reference to specific embodiments described in the following examples. Compounds are named using an automated naming package such as AutoNom (MDL), using IUPAC rules, or as named by the chemical supplier. The following abbreviations are used in the examples.

[0524]

Table 3

[0525] Synthesis method All starting materials and solvents were obtained from commercial sources or prepared according to literature citations. Unless otherwise stated, all reactants were stirred. Organic solutions were dried over anhydrous magnesium sulfate as specified. Hydrogenation was carried out in a Parr hydrogenation apparatus, Thales H-cube flow reactor, under the described conditions or under a hydrogen balloon. Microwave reactions were performed in a CEM Discover and Smithcreator microwave reactor and heated to a constant temperature using variable output microwave irradiation. Normal-phase column chromatography was carried out as specified using an automated flash chromatography system such as a CombiFlash Companion or CombiFlash RF system with a pre-packed silica (230 - 400 mesh, 40 - 63 μm) cartridge. SCX was purchased from Supelco and treated with 1 M hydrochloric acid before use. Unless otherwise stated, the reaction mixture to be purified was first diluted with MeOH and acidified with a few drops of AcOH. This solution was loaded directly onto the SCX and washed with MeOH. Next, the desired substance was eluted by washing with a solvent such as 1% NH3 in MeOH. NH2 ion exchange silica gel purification was carried out using Strata NH2 (55 μm, 70 Å), loaded directly onto the NH2 column, and eluted with a solvent such as methanol. The Biotage® KP-NH SNAP silica gel column was purchased from Biotage®. Reverse-phase purification was carried out using a Biotage® SNAP Ultra C18 silica gel column, purchased from Biotage®.

[0526] NMR data 11H NMR spectra were obtained on a 400 MHz Bruker Avance III spectrometer, AL400 (400 MHz, JEOL), Mercury 400 (400 MHz, Agilent Technologies, Inc.), a 500 MHz Bruker Avance III HD NMR spectrometer, or a Bruker Avance NEO NMR spectrometer (400 MHz). Either the central peak of chloroform-d, dimethyl sulfoxide-d6, or the internal standard of tetramethylsilane was used as a reference. For NMR data, when the number of assigned protons is less than the theoretical number of protons in the molecule, signals that appear to be missing are assumed to be hidden by solvent and / or water peaks. In addition, when the spectrum was obtained in a protic NMR solvent, exchange of NH and / or OH protons with the solvent occurs, and such signals are usually not observed.

[0527] Analytical and preparative LC-MS system Description of the analytical LC-MS system and method In the following examples, the compounds were characterized by mass spectrometry using the systems and operating conditions shown below. When atoms with different isotopes are present and a single mass is cited, the mass cited for the compound is the monoisotopic mass (i.e., 35 Cl, 79 Br, etc.). [Table 4] [Table 5] [Table 6]

[0528] Alternatively, LCMS spectra were measured using an SQD manufactured by Waters Corporation under the following two conditions, and the [M+H] + value was shown. MS detection: ESI positive UV detection: 254 nm Column flow rate: 0.5 mL / min Mobile phase: water / acetonitrile (0.1% formic acid) Injection volume: 1 μL Method Column: Acguity BEH, 2.1×50 mm, 1.7 μm

Table 7

[0529] Description of the preparative LC-MS system and method Preparative LC-MS is a standard and effective method used for the purification of organic small molecules such as the compounds described in this specification. By varying the methods for liquid chromatography (LC) and mass spectrometry (MS), the separation of crude substances can be improved, and the detection of samples by MS can be enhanced. The optimization of preparative gradient LC methods involves various columns, volatile eluents and modifiers, as well as gradients. Methods for optimizing preparative LC-MS methods and then using them to purify compounds are well known in the art. Such methods are described in Rosentreter U, Huber U.; Optimal fraction collecting in preparative LC-MS; J Comb Chem.; 2004; 6(2), 159-64, and Leister W, Strauss K, Wisnoski D, Zhao Z, Lindsley C., Development of a custom high-throughput preparative liquid chromatography / mass spectrometer platform for the preparative purification and analytical analysis of compound libraries; J Comb Chem.; 2003; 5(3); 322-9.

[0530] Several systems for purifying compounds via preparative LC-MS are described below. Those skilled in the art will understand that alternative systems and methods may be used in place of those described. From the information provided herein, or using alternative chromatography systems, those skilled in the art can purify the compounds described herein by preparative LC-MS.

[0531] Mass-directed purification LC-MS system Preparative LC-MS is a standard and effective method used for the purification of small organic molecules such as the compounds described herein. By varying the methods for liquid chromatography (LC) and mass spectrometry (MS), the separation of crude materials can be improved, and the detection of samples by MS can be enhanced. Optimization of the preparative gradient LC method involves various columns, volatile eluents and modifiers, as well as gradients. Methods for optimizing preparative LC-MS methods and then using them to purify compounds are well known in the art. Such methods are described in Rosentreter U, Huber U.; Optimal fraction collecting in preparative LC / MS; J Comb Chem.; 2004; 6(2), 159-64, and Leister W, Strauss K, Wisnoski D, Zhao Z, Lindsley C., Development of a custom high-throughput preparative liquid chromatography / mass spectrometer platform for the preparative purification and analytical analysis of compound libraries; J Comb Chem.; 2003; 5(3); 322-9.

[0532] One such system for purifying compounds via preparative LC-MS is described below, and those skilled in the art will understand that alternative systems and methods may be used. In particular, instead of the reverse-phase method described herein, a normal-phase preparative LC-based method may be used. Most preparative LC-MS systems utilize reverse-phase LC and volatile acidic modifiers, as this approach is very effective for purifying small molecules and the eluent is compatible with positive-ion electrospray mass spectrometry. To purify compounds, alternative chromatographic solutions, such as normal-phase LC, or buffer mobile phases, basic modifiers, etc., may be used instead, as outlined in the analytical methods described above.

[0533] Agilent 1260 LC-MS preparative system Equipment: Autosampler: G2260A Prep ALS Pumps: Two G1361A Prep Pumps for preparative flow gradient, G1311C Quat Pump VL for pumping modifiers in preparative flow, G1310B Iso Pump for makeup pump flow UV Detector: G1365C 1260 MWD MS Detector: G6120B Quadrupole LC-MS Fraction Collector: Two G1364B 1260 FC-PS G1968D Active Splitter

[0534] Software: Agilent OpenLab C01.06

Table 8

[0535]

Table 9

[0536] Eluent: Solvent A: Water Solvent B: Acetonitrile Solvent C: Desired available modifying factor: 2.5% Trifluoroacetic acid in water 2.5% Formic acid in water 250 mM Ammonium bicarbonate in water, pH 9.4 250 mM Ammonium acetate

[0537] Supplementary solvent: 90:10 Methanol:Water + 0.2% Formic acid (for all chromatography types)

[0538] Method: According to the analytical traces, the most appropriate preparative chromatography type was selected. A typical practice was the performance of analytical LC-MS using the type of chromatography (low pH or high pH) most suitable for the structure of the compound. If the analytical traces showed good chromatography, a suitable preparative method of the same type was selected. The typical operating conditions for both low pH and high pH chromatography methods were as follows. Flow rate: 25 mL / min Gradient: Usually, all gradients had a step of 95% A + 5% B (with additional modifying factor C) for the first 0.4 minutes. Next, according to the analytical traces, a 6.6-minute gradient was selected to achieve good separation (e.g., 5% - 50% B for early-retained compounds, 35% - 80% B for mid-retained compounds, etc.). Washing: A 1.6-minute washing step was performed at the end of the gradient Make-up flow rate: 0.8 mL / min

[0539] Solvent: All compounds were usually dissolved in 100% MeOH or 100% DMSO. From the information provided, one of ordinary skill in the art can purify the compounds described herein by preparative LC-MS.

[0540] Waters Fractionlynx system Equipment: 2767 Dual Loop Autosampler / Fraction Collector 2525 Fraction Collector Pump CFO (Column Fluid Organizer) for Column Selection RMA (Waters Reagent Manager) as Make-up Pump Waters ZQ Mass Spectrometer Waters 2996 Photo Diode Array Detector Waters ZQ Mass Spectrometer

[0541] Software: Masslynx 4.1

Table 10

[0542] Alternatively, reversed-phase preparative HPLC column chromatography was performed under the following conditions.

Table 11

[0543] Agilent InfinityLab LC / MSD LCMS analysis was performed using either a Waters X-Select CSH C18 (2.5 μm, 4.6×30 mm) or a Waters X-Bridge BEH C18 (2.5 μm, 4.6×30 mm), maintained at a temperature of 40 °C, and eluted at a constant flow rate of 2.5 ml / min over 4 or 15 minutes using a linear acetonitrile gradient suitable for the lipophilicity of the compounds. The aqueous portion of the mobile phase was either 0.1% formic acid (CSH C18 column) or 10 mM ammonium bicarbonate (BEH C18 column). The LC-UV chromatogram was recorded at 254 nm using an Agilent VWD or DAD detector. The mass spectrum was recorded using an Agilent MSD detector with electrospray ionization switching between positive and negative ion modes. The sample concentration was adjusted to obtain a sufficient UV response.

[0544] Waters Acquity QDa UPLC / MS analysis was performed using either a Waters Acquity CSH C18 column or a BEH C18 column (2.1×30 mm), maintained at a temperature of 40 °C, and eluted at a constant flow rate of 0.77 ml / min over 3 or 10 minutes using a linear acetonitrile gradient suitable for the lipophilicity of the compounds. The aqueous portion of the mobile phase was either 0.1% formic acid (CSH C18 column) or 10 mM ammonium bicarbonate (BEH C18 column). The LC-UV chromatogram was recorded from 210 to 400 nm using a Waters Acquity PDA detector. The mass spectrum was recorded using a Waters Acquity QDa detector with electrospray ionization switching between positive and negative ion modes. The sample concentration was adjusted to obtain a sufficient UV response.

[0545] Achiral preparative chromatography For the exemplified compounds described, when indicated, HPLC purification was carried out using methods developed in accordance with the recommendations described in Snyder L.R., Dolan J.W., High-Performance Gradient Elution The Practical Application of the Linear-Solvent-Strength Model, Wiley, Hoboken, 2007.

[0546] Chiral preparative chromatography Preparative separation using a chiral stationary phase (CSP) is a natural technique for the resolution of enantiomeric mixtures. Similarly, it can also be applied to the separation of diastereomers and achiral molecules. Methods for optimizing preparative chiral separation on CSPs and then using them to purify compounds are well known in the art. Such methods are described in Beesley T.E., Scott R.P.W.; Chiral Chromatography; Wiley, Chichester, 1998.

[0547] Preparation 1: 6-Chloro-3-iodo-5-methyl-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazine [Chemical formula]

[0548] Step 1: 6-Chloro-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazine A solution of 6-chloro-1H-pyrazolo[3,4-b]pyrazine (17.85 g, 113.7 mmol) and TsOH·H2O (0.1 eq) in THF (150 mL) was cooled on ice (internal temperature about 10 °C). Dihydropyran (20.6 mL, 227.4 mmol) was added slowly over 5 minutes. The cooling bath was removed and the reaction mixture was stirred for 90 minutes. EtOAc (250 mL) was added and the organic phase was washed with saturated NaHCO3 (150 mL), brine and then dried (MgSO4). This was repeated for a further 17.8 g. The organic layers from both runs were evaporated to give about 55 g of an orange solid. TBME (40 mL) and heptane (400 mL) were added and the mixture was heated to 90 °C and then cooled. A very small amount of a brown precipitate appeared and this was removed by filtration. The filtrate was stirred until the product crystallized. The product was collected by filtration to give Batch 1 (20 g) as a white crystalline solid. The filtrate was concentrated to about 30 mL and then diluted with heptane (100 mL) to induce crystallization. Batch 2 (15.8 g, white crystalline solid) was collected by filtration. MS: [M+H] + =239. 1 H NMR (500 MHz, DMSO-d6) δ 8.79 (s, 1H), 8.61 (s, 1H), 5.95 (dd, J = 10.2, 2.6 Hz, 1H), 3.94 (qd, J = 13.2, 4.1, 1.9 Hz, 1H), 3.77 - 3.69 (m, 1H), 2.49 - 2.41 (m, 1H), 2.08 - 2.01 (m, 1H), 1.95 (dq, J = 13.0, 3.5 Hz, 1H), 1.86 - 1.72 (m, 1H), 1.62 - 1.55 (m, 2H).

[0549] Step 2: 6-Chloro-1-(oxan-2-yl)-1H-4λ 5 -pyrazolo[3,4-b]pyrazin-4-one 6-Chloro-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazine (18 g, 75.41 mmol) was dissolved in MeCN (150 mL) and cooled on ice. Urea hydrogen peroxide complex (14.9 g, 158.4 mmol) was added in portions. While maintaining the internal temperature below 10 °C, trifluoroacetic anhydride (20.9 mL, 150.8 mmol) was added dropwise as a 30 mL (MeCN) solution over 15 minutes. The reaction mixture was stirred at 0 - 5 °C for 30 minutes and then warmed to room temperature over 1 hour. A thick precipitate formed and an additional 50 mL of MeCN was added to fluidize it. The mixture was poured into a stirred mixture of 4 M sodium thiosulfate (100 mL), NaHCO3 (50 g solid), and ice-cold water (300 mL). The mixture was stirred for 10 minutes and then DCM (300 mL) was added. The DCM layer was isolated and the aqueous layer was extracted with additional DCM (2 × 100 mL). The DCM layers were combined, washed with water (200 mL), dried (MgSO4), and evaporated to dryness. This process was repeated for an additional 18 g of 6-chloro-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazine. The crude products from both runs were combined and recrystallized from EtOAc (300 mL). The crystalline material was collected by filtration, dissolved in PhMe, and evaporated to give 6-chloro-1-(oxan-2-yl)-1H-4λ 5 -pyrazolo[3,4-b]pyrazin-4-one (11 g, 28%, product 1). The filtrate was concentrated and dissolved in hot EtOAc (40 mL). Heptane (400 mL) was added and the mixture was heated until all materials dissolved. The solution was cooled and the product crystallized out. The product was collected by filtration, dissolved in PhMe, and evaporated to give 6-chloro-1-(oxan-2-yl)-1H-4λ 5 -pyrazolo[3,4-b]pyrazin-4-one (18.46 g, 48%, product 2). MS: [M+H] + = 255. 11H NMR (500 MHz, DMSO-d6) δ 8.70 (s, 1H), 8.55 (s, 1H), 5.91 (dd, J = 10.1, 2.6 Hz, 1H), 4.01 - 3.91 (m, 1H), 3.79 - 3.68 (m, 1H), 2.45 - 2.34 (m, 1H), 2.08 - 1.97 (m, 1H), 1.93 (dq, J = 13.1, 3.6 Hz, 1H), 1.86 - 1.73 (m, 1H), 1.61 - 1.55 (m, 2H).

[0550] Step 3: 6-Chloro-5-methyl-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazine Methylmagnesium chloride (3.0 M in diethyl ether) (163 ml, 489 mmol) was added dropwise to a solution of 6-chloro-1-(oxan-2-yl)-1H-4λ 5 -pyrazolo[3,4-b]pyrazin-4-one (41.5 g, 163 mmol) in toluene (833 ml) over 1 hour 15 minutes while cooling to -60 °C (internal temperature) in a dry ice / acetone bath. The mixture was stirred at this temperature for 6 hours, then quenched with saturated NH4Cl (400 mL) and diluted with water (300 mL) and EtOAc (300 mL). The phases were separated and the aqueous phase was extracted with EtOAc (2 × 300 mL). The organics were combined, washed with brine (300 mL), dried (MgSO4), and concentrated to give a crude product as a red solid (38.6 g). The crude residue was dissolved in acetonitrile (50 mL) while refluxing. The solution was cooled to room temperature. The precipitate was isolated by filtration, washed with i-hexane (50 mL) to give a beige solid (ca. 17 g). The solid (Product 1) was heated once again in acetonitrile (25 mL) while refluxing. The solution was cooled to room temperature and the peach-colored brown solid was filtered, washed with hexane (10 mL), and dried in a vacuum oven at 40 °C overnight to give the title compound as a peach-colored brown solid (11.92 g). MS: [M+H] + = 253, 255. 11H NMR (500 MHz, DMSO-d6) δ 8.47 (s, 1H), 5.91 (dd, J = 10.2, 2.6 Hz, 1H), 3.97 - 3.88 (m, 1H), 3.77 - 3.66 (m, 1H), 2.70 (s, 3H), 2.49 - 2.42 (m, 1H), 2.06 - 2.00 (m, 1H), 1.94 (dq, J = 13.1, 3.5 Hz, 1H), 1.83 - 1.72 (m, 1H), 1.61 - 1.55 (m, 2H).

[0551] Step 4: 6-Chloro-5-methyl-1H-pyrazolo[3,4-b]pyrazine A solution of hydrogen chloride (4.0 M in 1,4-dioxane, 128 ml, 513 mmol) was added dropwise to a suspension of 6-chloro-5-methyl-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazine (33.21 g, 131 mmol) in methanol (633 ml). The brown mixture was stirred at room temperature overnight. After concentration, the residue was dissolved in MeOH-CHCl3 (1 / 1 mixture, 400 mL), and then basified with an aqueous NaHCO3 solution (55 g in 400 mL). The separated aqueous layer was extracted with MeOH-CHCl3 (1 / 1 mixture, 4 × 400 mL). The organics were combined, washed with brine (300 mL), dried over Na2SO4, filtered, and then concentrated in vacuo to give a crude beige solid (28.5 g). This material was suspended in i-hexane (3 x 200 mL), collected by filtration, and dried under vacuum at 40 °C overnight to give a beige solid of 6-chloro-5-methyl-1H-pyrazolo[3,4-b]pyrazine (20.73 g, 121 mmol, 92% yield). MS: [M+H] + = 169. 1 1H NMR (500 MHz, DMSO-d6) δ 14.13 (s, 1H), 8.41 (s, 1H), 2.68 (s, 3H).

[0552] Step 5: 6-Chloro-3-iodo-5-methyl-1H-pyrazolo[3,4-b]pyrazine 1-Iodopyrrolidine-2,5-dione (55.3 g, 246 mmol) was added to a solution of 6-chloro-5-methyl-1H-pyrazolo[3,4-b]pyrazine (20.73 g, 123 mmol) in N,N-dimethylformamide (409 mL). The mixture was stirred at 50 °C for 6 hours. The reaction mixture was slowly added to a rapidly stirred mixture of saturated aqueous sodium thiosulfate (400 mL) and water (400 mL). The precipitate was collected by filtration and washed with water (3 × 200 mL) and i-hexane (100 mL). The solid was dissolved in THF (300 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give 6-chloro-3-iodo-5-methyl-1H-pyrazolo[3,4-b]pyrazine as a yellowish-white solid (19.42 g, 64.6 mmol, 52.6% yield) (dried in a vacuum oven at 40 °C). The aqueous layer was extracted with EtOAc (3 × 400 mL). The organics were combined, dried over Na2SO4, and concentrated in vacuo to give a reddish-brown oil. Water (200 mL) was added. A beige solid formed, which was filtered and washed with water (2 × 200 mL). The solid was dried in a vacuum oven at 40 °C. 6-Chloro-3-iodo-5-methyl-1H-pyrazolo[3,4-b]pyrazine as a beige solid (12.86 g, 41.5 mmol, 33.7% yield) was isolated. MS: [M+H] + =295. 1 H NMR (500 MHz, DMSO-d6) δ 14.49 (s, 1H), 2.70 (s, 3H).

[0553] Step 6: 6-Chloro-3-iodo-5-methyl-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazine 3,4-Dihydro-2H-pyran (50 mL, 547 mmol) and p-toluenesulfonic acid monohydrate (2.085 g, 10.96 mmol) were added to a solution of 6-chloro-3-iodo-5-methyl-1H-pyrazolo[3,4-b]pyrazine (32.28 g, 110 mmol) in THF (647 mL). The mixture was stirred at room temperature overnight. The mixture was concentrated to half its volume under vacuum at 30 °C, and then the mixture was poured into an aqueous solution (300 mL) of NaHCO3 (36.8 g, 438 mmol). The aqueous layer was extracted with EtOAc (200 mL). The organics were combined, washed with brine (200 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give a peach-colored orange solid, which was dry-packed onto silica gel and purified by chromatography on silica gel (330 g column; gradient elution, 0 to 100%, DCM / hexane) to give a white solid (33.98 g). The solid was suspended in i-hexane (100 mL), stirred for 1 hour, filtered, washed with i-hexane (50 mL), and dried in a vacuum oven at 40 °C. 6-Chloro-3-iodo-5-methyl-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazine as a white solid (31.29 g, 81 mmol, 73.9% yield) was isolated. MS: [M+H] + = 379. 1 H NMR (500 MHz, DMSO-d6) δ 5.88 (dd, J = 10.3, 2.5 Hz, 1H), 3.97 - 3.88 (m, 1H), 3.77 - 3.66 (m, 1H), 2.72 (s, 3H), 2.47 - 2.37 (m, 1H), 2.06 - 1.98 (m, 1H), 1.94 (dq, J = 13.0, 3.4 Hz, 1H), 1.83 - 1.71 (m, 1H), 1.64 - 1.52 (m, 2H).

[0554] Preparation 2: 6-Chloro-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyrazine

Chem.

[0555] Preparation 3: (6-Chloro-3-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[3,4-b]pyrazin-5-yl)methanol

Chem.

[0556] Preparation 4: 5-Bromo-4-chloro-2-methyl-2H-indazole [Chemical formula] An aqueous solution (98 ml) of sodium nitrite (58.6 g, 0.85 mol) was added to an acetic acid solution (3 L) of 4-bromo-3-chloro-2-methylaniline (150 g, 0.68 mol) cooled in an ice bath with mechanical stirring, and the mixture was aged at ambient temperature for 1 hour. Most of the solvent was evaporated, the residue was suspended in water (500 mL), filtered, washed with water (250 ml × 4) and gasoline (250 ml × 4), and dried in vacuo at 40 °C to give 5-bromo-4-chloro-1H-indazole (130 g). 11H NMR (400 MHz, DMSO-d6): 13.61 (1H, s), 8.16 (1H, s), 7.62 (1H, d), 7.53 (1H, dd).

[0557] Solid trimethyloxonium tetrafluoroborate (258 g, 1.74 mol) was charged to a solution of 5-bromo-4-chloro-1H-indazole (367 g, 1.59 mol) in EtOAc (1.9 L) cooled in an ice bath, and the resulting mixture was stirred at ambient temperature for 4 h. The reaction mixture was diluted with gasoline (1.9 L), aged for 10 min, then filtered and washed with gasoline (400 mL × 2). The filter cake was combined with saturated sodium bicarbonate (1.5 L) and EtOAc (2 L), and the phases were separated. The organic phase was washed with saturated sodium bicarbonate, dried (MgSO4), and concentrated in vacuo to afford the title compound (236 g). 1 1H NMR (400 MHz, DMSO-d6): 8.53 (1H, s), 7.56 (1H, dd), 7.48 (1H, d), 4.20 (3H, s).

[0558] Preparation 5: 5-Bromo-4-chloro-2-ethyl-2H-indazole

Chemical Structure

[0559] Preparation 6: 5-Bromo-3,4-dichloro-2-methyl-2H-indazole

Chem.

[0560] Preparation 7: 5-Bromo-4-chloro-2,3-dimethyl-2H-indazole

Chem.

[0561] Preparation 8: 7-Bromo-2,8-dichloroquinoxaline

Chem.

[0562] Step 1: 4-Bromo-3-chloro-2-nitroaniline In a 2 L three-necked flask, an AcOH solution (600 mL) of 3-chloro-2-nitroaniline (60 g, 348 mmol) was treated portionwise with NBS (61.9 g, 348 mmol). The resulting orange solution was heated at 80 °C for 1.5 h. The reaction mixture was cooled to room temperature and poured into stirred ice water (800 mL). The resulting orange precipitate was collected by filtration and washed with water (200 mL). The orange residue was collected and dissolved in EtOAc (500 mL). The solution was dried over MgSO4, filtered, and the solvent was concentrated in vacuo to give an orange solid (86.5 g). The residue was recrystallized from 10% EtOAc / iso-hexane (500 mL). The resulting solid was filtered, rinsed with iso-hexane (100 mL), and dried in vacuo to give a pale orange solid (39.88 g, 158.6 mmol, 46%). The filtrate was concentrated in vacuo to give an orange solid. The residue was recrystallized from 10% Ac / iso-hexane (250 mL). The resulting solid was filtered, rinsed with iso-hexane (50 mL), and dried in vacuo to give a pale orange solid (20 g, 79.53 mmol, 23%). 1H NMR, in DMSO-d6: (7.55 (1H, d), 6.84 (1H, d), 6.40 (2H, s).

[0563] Step 2: tert-Butyl N-(4-bromo-3-chloro-2-nitrophenyl)-N-[(tert-butoxy)carbonyl]carbamate In a 2 L three-necked flask, a solution of 4-bromo-3-chloro-2-nitroaniline (59.88 g, 226 mmol) in THF (400 mL) at a temperature below 10 °C (internal temperature, ice bath) was treated portionwise with a solution of di-tert-butyl dicarbonate (99 g, 452 mmol) in THF (200 mL). N,N-Dimethylpyridin-4-amine (2.76 g, 22.62 mmol) was added portionwise, and the resulting orange solution was stirred at room temperature for 18 h. The reaction mixture was concentrated in vacuo to give a light brown solid. The residue was triturated with iso-hexane (300 mL). The resulting solid was filtered, washed with iso-hexane (50 mL), and dried in vacuo to give the desired product (97.5 g, 214 mmol, 94% yield) as a sticky colorless solid. 1 1H NMR, in CDCl3: 7.81 (1H, d), 7.16 (1H, d), 1.45 (18H, s).

[0564] Step 3: tert-Butyl N-(4-bromo-3-chloro-2-nitrophenyl)carbamate In a 2 L three-necked flask, a solution of tert-butyl N-(4-bromo-3-chloro-2-nitrophenyl)-N-[(tert-butoxy)carbonyl]carbamate (97.5 g, 214 mmol) in DCM (600 mL) was treated with a solution of trifluoroacetic acid (32.9 mL, 427 mmol) in DCM (250 mL). The resulting orange solution was stirred at room temperature for 0.5 h. The reaction mixture was quenched to neutral pH with saturated aqueous NaHCO3 (300 mL). The phases were separated and the aqueous layer was extracted with DCM (2 × 100 mL). The orange extracts were combined, dried over MgSO4, filtered, and concentrated in vacuo to give tert-butyl N-(4-bromo-3-chloro-2-nitrophenyl)carbamate (75 g, 212 mmol, 99% yield) as a pale orange solid. 1 1H NMR, in CDCl3: 8.06 (1H, d), 7.72 (1H, d), 7.12 (1H, s), 1.53 (9H, s).

[0565] Step 4: Ethyl 2-[(4-bromo-3-chloro-2-nitrophenyl)[(tert-butoxy)carbonyl]amino]acetate In a 1 L three-necked flask, a DMF suspension (300 mL) of tert-butyl N-(4-bromo-3-chloro-2-nitrophenyl)carbamate (75 g, 211 mmol) and cesium carbonate (138 g, 422 mmol) at less than 10 °C (internal temperature, ice bath) was treated portionwise with a DMF solution (125 mL) of ethyl 2-bromoacetate (24.59 ml, 222 mmol). The resulting orange suspension was stirred at less than 10 °C for 0.5 h. The reaction mixture was partitioned between EtOAc (300 mL) and water (300 mL). The aqueous layer was extracted with EtOAc (2 × 200 mL). The combined organic extracts were washed with saturated brine (2 × 100 mL), dried over MgSO4, filtered, and concentrated in vacuo to give a dark orange oil (100 mL). The dark orange oil was added to stirred water (200 mL). The resulting orange precipitate was collected by filtration, washed with water (50 mL), and dried in vacuo to give an orange solid (107 g, 196 mmol, 93% yield). 1 1H NMR, in DMSO-d6: 8.14 (1H, d), 7.57 (1H, t), 4.40 - 3.98 (4H, m), 1.41 - 1.15 (12H, m).

[0566] Step 5: Ethyl 2-[(4-bromo-3-chloro-2-nitrophenyl)amino]acetate In a 2 L three-necked flask, a DCM solution (600 mL) of ethyl 2-[(4-bromo-3-chloro-2-nitrophenyl)[(tert-butoxy)carbonyl]amino]acetate (107 g, 196 mmol) was treated portionwise with a DCM solution (200 mL) of trifluoroacetic acid (75 ml, 978 mmol). The resulting orange solution was stirred at room temperature for 18 h. The reaction mixture was quenched with saturated aqueous NaHCO3 (700 mL), followed by slow addition of solid NaHCO3 (40 g, 476 mmol) to bring to neutral pH. The phases were separated and the aqueous layer was extracted with DCM (2 × 250 mL). The combined organic extracts were washed with saturated brine (1 × 150 mL), dried over MgSO4, filtered, and concentrated in vacuo to give ethyl 2-[(4-bromo-3-chloro-2-nitrophenyl)amino]acetate as a pale orange solid (77.47 g, 184 mmol, 94% yield). 11H NMR, in DMSO-d6: 7.68 (1H, d), 6.78 (1H, d), 6.70 (1H, t), 4.12 (2H, q), 4.04 (2H, d), 1.20 (3H, t).

[0567] Step 6: 7-Bromo-8-chloro-1,2,3,4-tetrahydroquinoxalin-2-one In a 2 L three-necked flask, a solution of ethyl 2-[(4-bromo-3-chloro-2-nitrophenyl)amino]acetate (35.93 g, 96 mmol) in THF (200 mL) and MeOH (200 mL) at 0 °C (internal temperature, ice bath) was treated portionwise with an aqueous solution (200 mL) of sodium dithionite (71.2 g, 409 mmol). The resulting orange suspension was stirred at room temperature for 2 h. The reaction mixture was diluted with water (50 mL), and solid sodium carbonate (65 g, 613 mmol) was added portionwise slowly until pH 9. MeOH and THF were removed in vacuo, and the aqueous solution was extracted with Me-THF (2 × 250 mL). The organic extracts were combined, washed with saturated brine (1 × 150 mL), dried over MgSO4, filtered, and concentrated in vacuo to give 7-bromo-8-chloro-3,4-dihydroquinoxalin-2(1H)-one (26.4 g, 96 mmol, 94% yield) as a thick green solid. 1 1H NMR, in DMSO-d6: 9.93 (1H, s), 7.14 (1H, d), 6.63 (1H, d), 6.40 (1H, br s), 3.75 (2H, s).

[0568] Step 7: 7-Bromo-8-chloroquinoxalin-2-ol In a 2 L three-necked flask, a solution of 7-bromo-8-chloro-1,2,3,4-tetrahydroquinoxalin-2-one (60 g, 174 mmol) in THF (425 mL) and MeOH (425 mL) at a temperature below 10 °C (internal temperature, ice bath) was treated portionwise with potassium tert-butoxide (39.1 g, 349 mmol). The resulting orange suspension was stirred under a stream of air at room temperature for 18 h. Water (200 mL) was added, followed by slow addition of AcOH (50 mL). The resulting orange precipitate was collected by filtration, washed with water (100 mL) and then with TBME (50 mL), and dried in vacuo to give 7-bromo-8-chloroquinoxalin-2-ol as a pale orange solid (41.81 g, 155 mmol, 89% yield). 1 H NMR, in DMSO-d6: 8.17 (1H, s), 7.69 - 7.55 (2H, br s).

[0569] Step 8: 7-Bromo-2,8-dichloroquinoxaline In a 1 L three-necked flask, a suspension of 7-bromo-8-chloroquinoxalin-2-ol (35 g, 129 mmol) in MeCN (300 mL) at 50 °C under N2 was treated dropwise with a solution of phosphoryl trichloride (36.2 mL, 388 mmol) in MeCN (50 mL). The resulting brown suspension was heated at 80 °C for 3 h and then cooled to room temperature. The dark brown reaction mixture was concentrated in vacuo and POCl3 was removed by azeotroping with PhMe (250 mL). The brown residue was dissolved in MeCN (500 mL) and the mixture was quenched by slow addition to water (ca. 30 °C). EtOAc (500 mL) was added and the mixture was filtered to give a dark brown solid. The crude solid was dissolved in EtOAc (200 mL) and combined with the filtrate. The phases were separated. The aqueous layer was extracted with EtOAc (3 × 200 mL). The organic extracts were combined, washed with saturated brine (1 × 200 mL), dried over MgSO4, filtered, and concentrated in vacuo to give a dark orange solid (34.52 g, 96%, crude). The crude product was purified by chromatography on silica gel (330 g cartridge, 0 to 30% DCM / iso-hexane) to give 7-bromo-2,8-dichloroquinoxaline as a pale greyish-white solid (27.69 g, 99 mmol, 76% yield). 11H NMR, in DMSO-d6: 9.13 (1H, s), 8.23 (1H, d), 8.08 (1H, d).

[0570] Preparation 9: 7-Bromo-8-chloro-2-methoxyquinoxaline

Chem.

[0571] Preparation 10: 7-Bromo-8-chloro-N,N-dimethylquinoxalin-2-amine

Chem.

[0572] Preparation 11: 2-(Azetidin-1-yl)-7-bromo-8-chloroquinoxaline

Chem.

[0573] Preparation 12: 7-Bromo-8-chloro-2-(morpholin-4-yl)quinoxaline

Chem.

[0574] Preparation 13: 4-Chloro-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole

Chem.

[0575] Method A 5-Bromo-4-chloro-2-methyl-2H-indazole (12.14 g, 49.45 mmol), bis(pinacolato)diboron (18.83 g, 74.18 mmol), dichloromethane (4.038 g, 4.945 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex, and potassium acetate (9.706 g, 98.90 mmol) in 1,4-dioxane (120 mL) were degassed, purged with nitrogen, and stirred at 120 °C for 5 h. The reaction mixture was cooled to room temperature, filtered through a pad of celite, and washed with EtOAc. The filtrate was concentrated in vacuo. The residue was purified by column chromatography on NH silica gel (gradient elution, 0 to 70% EtOAc / hexane) to afford the title compound (14.36 g). MS: [M+H] += 293,295.

[0576] Method B i PrMgCl·LiCl (1.3 M in THF, 63 mL, 82.0 mmol) was added to a solution of 5-bromo-4-chloro-2-methyl-2H-indazole (10.00 g, 40.73 mmol) in THF (100 mL), and the mixture was cooled in an ice bath to an internal temperature of less than 5 °C under nitrogen. The mixture was maintained at an internal temperature of less than 10 °C throughout the addition and then stirred at less than 5 °C for 5 h. The mixture was cooled to an internal temperature of -10 °C, and isopropoxypinacolborane (25.00 mL, 122.6 mmol) was added. The mixture was stirred at this temperature for 1 h and then quenched with water. After addition of saturated aqueous NH4Cl, the aqueous mixture was extracted with EtOAc. The combined organic phases were washed with water, brine, dried (MgSO4), and concentrated. The residue was dissolved in IPA, water was added to cause precipitation, and the solid was collected by filtration. The solid was further triturated with gasoline and collected by filtration to afford a pale yellow solid (10.18 g, 34.79 mmol, 85%).

[0577] Preparation 14: 4-Chloro-2-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole

Chemical Structure

[0578] Preparation 15: (3,4-Dichloro-2-methyl-2H-indazol-5-yl)boronic acid

Chemical formula

[0579] Preparation 16: 8-Chloro-N,N-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoxalin-2-amine

Chemical formula

[0580] The following boronate was prepared in a similar manner.

Table 12

[0581] Preparation 17: 3,4-Dichloro-2-methyl-2H-indazole-5-carbaldehyde

Chem.

[0582] Preparation 18: 4-Chloro-2-methyl-2H-indazole-5-carbaldehyde

Chemical Structure

[0583] Preparation 19: (3,4-Dichloro-2-methyl-2H-indazol-5-yl)(3,5-dichloro-6-methylpyrazin-2-yl)methanol

Chemical Structure

[0584] Preparation 20: (4-Chloro-2-methyl-2H-indazol-5-yl)(3,5-dichloro-6-methylpyrazin-2-yl)methanol

Chemical Structure

[0585] Preparation 21: 3,4-Dichloro-5-(3,5-dichloro-6-methylpyrazine-2-carbonyl)-2-methyl-2H-indazole

Chemical Structure

[0586] Preparation 22: 4-Chloro-5-(3,5-dichloro-6-methylpyrazine-2-carbonyl)-2-methyl-2H-indazole

Chem.

[0587] Preparation 23: (S)-2-Oxa-8-azaspiro[4.5]decan-4-amine

Chem.

[0588] Preparation 24: (1R)-8-Azaspiro[4.5]decan-1-amine

Chem.

[0589] Preparation 25: (3S,4S)-3-Methyl-2-oxa-8-azaspiro[4.5]decan-4-amine hydrochloride

Chem.

[0590] Step 1: Ethyl (2S)-2-[(tert-butyldimethylsilyl)oxy]propionate The reaction mixture of ethyl (2S)-2-hydroxypropionate (95.0 g, 0.8 mol) in DCM (1 L) was cooled to 0 °C, then imidazole (81.6 g, 1.2 mol) and TBSCl (133.3 g, 0.88 mol) were added, and the mixture was stirred at ambient temperature for about 1.5 h. The reaction mixture was poured into water (1.0 L), extracted with DCM (2 × 500 mL), washed with brine, dried over Na2SO4, concentrated in vacuo, and purified by silica column (petroleum ether / EtOAc = 50 / 1 to 20 / 1) to give the product as a colorless oil (180.0 g, 97%). 1 H NMR (500 MHz, CDCl3) δ: 4.33 (s, 1H), 4.22 (s, 2H), 1.44 (d, J = 6.7 Hz, 3H), 1.32 (t, J = 7.1 Hz, 3H), 0.97 (s, 9H), 0.15 (s, 6H).

[0591] Step 2: (2S)-2-[(tert-butyldimethylsilyl)oxy]propanal A toluene solution (800 mL) of ethyl (2S)-2-[(tert-butyldimethylsilyl)oxy]propionate (131.0 g, 0.56 mol) was cooled to -60 °C, DIBAL-H (1.5 M, 560 mL, 0.85 mol) was added dropwise, and the mixture was stirred at -60 °C for 2 h. The reaction mixture was poured into water (800 mL), extracted with EtOAc (2 × 500 mL), washed with brine, dried over Na2SO4, concentrated in vacuo to give a crude product. This was used in the next step without purification.

[0592] Step 3: 4-Ethyl 4-[(2S)-2-[(tert-butyldimethylsilyl)oxy]-1-hydroxypropyl]piperidine-1,4-dicarboxylic acid 1-tert-Butyl A solution of diisopropylamine (65.0 g, 0.64 mol) in THF (400 mL) was cooled to -20 °C. n-BuLi (2.5 M, 224 mL, 0.56 mol) was added dropwise, and then the mixture was stirred at -10 °C for 1 h. Piperidine-1,4-dicarboxylic acid 1-tert-butyl 4-ethyl (110.0 g, 0.43 mol) in THF (200 mL) was added dropwise at -10 °C, and then the mixture was stirred under N₂ at -10 °C to ambient temperature for 1 h. (2S)-2-[(tert-Butyldimethylsilyl)oxy]propanal (120.0 g, 0.64 mol) in THF (200 mL) was added dropwise at -10 °C, and then the mixture was stirred at -10 °C to 0 °C for 2 h. The reaction mixture was poured into saturated NH₄Cl (1 L), extracted with EtOAc (2 × 500 mL), the combined EtOAc phases were washed with brine, dried over Na₂SO₄, concentrated in vacuo, and purified by silica column (petroleum ether / EtOAc = 50 / 1 to 30 / 1 to 20 / 1) to give the product as a yellow oil (70.0 g, 37%). 1 H NMR (400 MHz, CDCl₃) δ: 4.29 - 4.09 (m, 2H), 4.06 - 3.88 (m, 2H), 3.79 (d, 1H), 3.60 - 3.48 (m, 1H), 2.78 (s, 2H), 2.66 - 2.25 (m, 1H), 2.24 - 1.94 (m, 2H), 1.74 (m, 2H), 1.50 - 1.37 (m, 9H), 1.34 - 1.18 (m, 5H), 1.12 (d, 3H), 0.91 (s, 10H), 0.04 (s, 6H).

[0593] Step 4: tert-Butyl 4-[(2S)-2-[(tert-butyldimethylsilyl)oxy]-1-hydroxypropyl]-4-(hydroxymethyl)piperidine-1-carboxylate To a solution of 4-[(2S)-2-[(tert-butyldimethylsilyl)oxy]-1-hydroxypropyl]piperidine-1,4-dicarboxylic acid 1-tert-butyl 4-ethyl (70.0 g, 0.157 mol) in THF (700 mL), LiBH₄ (2 M, 118 mL, 0.236 mol) was added at 0 °C, and then the mixture was stirred at ambient temperature overnight. The mixture was poured into water (500 mL), stirred at ambient temperature for 20 min, extracted with EtOAc (2 × 300 mL), washed with brine, dried over Na₂SO₄, and concentrated in vacuo to give the crude product (60.0 g). This was used in the next step without purification.

[0594] Step 5: tert-Butyl 4-[(2S)-1,2-dihydroxypropyl]-4-(hydroxymethyl)piperidine-1-carboxylate To a solution of cooled (0 °C) tert-butyl 4-[(2S)-2-[(tert-butyldimethylsilyl)oxy]-1-hydroxypropyl]-4-(hydroxymethyl)piperidine-1-carboxylate (60.0 g, 0.149 mol) in THF (600 mL) was added TBAF (1 M, 223 mL, 0.223 mol), and the mixture was stirred at ambient temperature for 2 h. NaHCO3 (aqueous, 600 mL) was added, the mixture was stirred at ambient temperature for 10 min, extracted with EtOAc (2 × 300 mL), washed with brine, dried over Na2SO4, concentrated in vacuo, and purified by silica column (DCM / MeOH = 100 / 1 to 50 / 1 to 30 / 1) to give the product as a yellow oil (37.0 g, 86%). 1 H NMR (400 MHz, CDCl3) δ: 4.02 - 3.87 (m, 1H), 3.74 (m, 4H), 3.36 (d, 4H), 3.10 (s, 2H), 1.66 (s, 3H), 1.40 (s, 10H), 1.31 (s, 3H).

[0595] Step 6: tert-Butyl (3S)-4-hydroxy-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-carboxylate To a solution of ice-cooled tert-butyl 4-[(2S)-1,2-dihydroxypropyl]-4-(hydroxymethyl)piperidine-1-carboxylate (37.0 g, 0.127 mol) in THF (400 mL) was added NaH (17.8 g, 0.44 mol) portionwise, and then a solution of TsCl (25.5 g, 0.134 mol) in THF (200 mL) was added. The reaction mixture was stirred at 0 °C for 2 h. The reaction mixture was poured into ice and NH4Cl (aqueous, 600 mL), extracted with EtOAc (3 × 400 mL), washed with brine, dried over Na2SO4, concentrated in vacuo, and purified by silica column (DCM / MeOH = 100 / 1 to 50 / 1 to 30 / 1) to give the product as a yellow oil (20.0 g, 58%). 1 H NMR (400 MHz, CDCl3) δ: 3.94 - 3.57 (m, 4H), 3.45 (d, 1H), 2.96 (s, 2H), 1.70 (s, 3H), 1.42 (s, 10H), 1.29 (m, 4H).

[0596] Step 7: tert-Butyl (3S)-3-methyl-4-oxo-2-oxa-8-azaspiro[4.5]decan-8-carboxylate To a solution of ice-cooled (3S)-4-hydroxy-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl (20.0 g, 0.074 mol) in DCM (200 mL) was added DMP (37.5 g, 0.088 mol) portionwise. The reaction mixture was stirred at ambient temperature for 1 h, poured into NaHCO3 (aqueous), extracted with DCM, washed with brine, dried over Na2SO4, and concentrated in vacuo to afford the product as a yellow oil (19.0 g, 95%). This was used directly in the next step.

[0597] Step 8: tert-Butyl (3S,4S)-3-methyl-4-[(2-methylpropan-2-sulfinyl)amino]-2-oxa-8-azaspiro[4.5]decan-8-carboxylate To a solution of (3S)-tert-butyl 3-methyl-4-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate (11.0 g, 0.04 mol) in THF (250 mL) were added (R)-2-methylpropan-2-sulfinamide (9.9 g, 0.08 mol) and Ti(OEt)4 (36.5 g, 0.16 mol), and the reaction mixture was stirred at 75 °C overnight. The reaction mixture was cooled to -10 °C, LiBH4 (2 M, 30 mL, 0.06 mol) was added dropwise, and the mixture was stirred at -10 °C for 1 h. The reaction mixture was poured into ice and NH4Cl (aqueous, 300 mL) and EtOAc (300 mL), stirred at ambient temperature for 20 min, and then filtered through celite. The reaction mixture was extracted with EtOAc (2 × 300 mL), washed with brine, dried over Na2SO4, concentrated in vacuo, and purified by silica column (petroleum ether / EtOAc = 10 / 1 to 5 / 1 to 3 / 1 to 2 / 1) to afford the product (7.0 g, 47%). 1 H NMR (400 MHz, DMSO-d6) δ: 5.07 (d, J = 11.0 Hz, 1H), 4.06 (s, 1H), 3.74 (m, 3H), 3.37 (d, 3H), 2.84 (s, 2H), 1.69 - 1.50 (m, 2H), 1.39 (s, 11H), 1.15 (s, 9H), 1.06 (m, 3H).

[0598] Step 9: (3S,4S)-3-Methyl-2-oxa-8-azaspiro[4.5]decan-4-amine hydrochloride To a solution of tert-butyl (3S,4S)-3-methyl-4-[(2-methylpropan-2-sulfinyl)amino]-2-oxa-8-azaspiro[4.5]decane-8-carboxylate (5.8 g, 15.5 mmol) in MeOH (20 mL) was added HCl / dioxane (4 M, 39 mL, 155 mmol), and the mixture was stirred at 50 °C for 2 h. The reaction mixture was cooled to ambient temperature and concentrated in vacuo. The crude product was dissolved in water (50 mL) and extracted with EtOAc (3 × 40 mL). The aqueous phase was lyophilized to afford the HCl salt of the product as a yellow solid (4.0 g). MS: [M+H] += 171. 1 H NMR (400 MHz, DMSO-d6) δ: 4.44 (m, 1H), 4.05 - 3.88 (m, 2H), 3.67 (s, 1H), 3.58 - 3.39 (m, 2H), 3.22 - 3.01 (m, 2H), 1.98 (m, 4H), 1.34 (s, 3H).

[0599] Preparation 26: tert-Butyl 1-oxo-8-azaspiro[4.5]des-2-ene-8-carboxylate

Chemical Structure

[0600] Step 1: tert-Butyl 4-formyl-4-(prop-2-en-1-yl)piperidine-1-carboxylate The reaction mixture of tert-butyl 4-formylpiperidine-1-carboxylate (1200.0 g, 5.63 mol) in THF (10 L) was cooled to -25 °C, and then allyl bromide (816.5 g, 6.75 mol) and subsequently t-BuOK (757.8 g, 6.75 mol) were added portionwise. The reaction mixture was stirred at -25 °C to -15 °C for about 45 min, then poured into ice NH4Cl (aqueous, 8 L), extracted with EtOAc, washed with brine, dried over Na2SO4, and concentrated in vacuo. The crude product was purified by silica column (petroleum ether / EtOAc = 50 / 1 to 20 / 1 to 10 / 1) to afford the title compound as a colorless oil (920.0 g, 64.5%). 1 H NMR (CDCl3): 9.49 (1H, s), 5.63 (1H, m), 5.09 (2H, m), 3.79 (2H, m), 2.96 (2H, m), 2.23 (2H, d), 1.93 (2H, m), 1.44 (10H, m).

[0601] Step 2: tert-Butyl 4-(1-hydroxyprop-2-en-1-yl)-4-(prop-2-en-1-yl)piperidine-1-carboxylate A solution of tert-butyl 4-formyl-4-(prop-2-en-1-yl)piperidine-1-carboxylate (400.0 g, 1.58 mol) in THF (4 L) was cooled to -60 °C, vinyl-magnesium bromide (1.90 L, 1.90 mol) was added, and the mixture was stirred at room temperature for 1 hour. The mixture was poured into NH4Cl (aqueous, 5 L), extracted with EtOAc, washed with brine, dried over Na2SO4, and concentrated in vacuo to give the product as a brown oil (426.0 g, 95.8%). 1 H NMR (CDCl3): 5.93 (2H, m), 5.24 (2H, m), 5.07 (2H, t), 4.00 91H, d), 3.69 (2H, m), 3.12 (2H, m), 2.30 (1H, m), 2.19 (1H, m), 1.74 (1H, m), 1.60 - 1.53 (2H, m)1.49 (11H, m).

[0602] Step 3: tert-Butyl 1-hydroxy-8-azaspiro[4.5]des-2-ene-8-carboxylate To a solution of tert-butyl 4-(1-hydroxyprop-2-en-1-yl)-4-(prop-2-en-1-yl)piperidine-1-carboxylate (10.0 g, 35.3 mmol) in toluene (150 mL) was added the second-generation Grubbs catalyst (0.91 g, 1.07 mmol), and the reaction was stirred at 90 °C for 7 hours. The mixture was purified by silica column (petroleum ether / EtOAc = 20 / 1 to 10 / 1 to 5 / 1) to give the desired product as a brown oil (7.1 g, 78.9%). 1 H NMR (CDCl3): 5.92 (1H, m), 5.83 (1H, m), 4.30 (1h, s), 3.58 (2H, m), 3.16 (2H, m), 2.22 (2H, dd), 1.74 (2H, m), 1.46 - 1.76 (12H, m).

[0603] Step 4: tert-Butyl 1-oxo-8-azaspiro[4.5]des-2-ene-8-carboxylate A solution of tert-butyl 1-hydroxy-8-azaspiro[4.5]dec-2-ene-8-carboxylate (100.0 g, 0.39 mol) in DCM (600 mL) was cooled to 0 °C, then Dess-Martin (184 g, 0.43 mol) was added and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into NaHCO3 (1.8 L) and NaHSO3 (1.5 L), extracted with DCM, the combined DCM phases were washed with brine, dried over Na2SO4 and concentrated in vacuo to give the crude product. The crude product was poured into petroleum ether / EtOAc = 4:1, stirred overnight, filtered and concentrated in vacuo to give the title compound as a pale red solid (57.6 g, 58%). 1 1H NMR (CDCl3): 7.6 (1H, m), 6.18 (1H, m), 4.09 (2H, br s), 2.90 (2H, m), 2.61 (2H, s), 1.77 (2H, m), 1.46 (9H, s), 1.27 (2H, d).

[0604] Preparation 27: (1R)-1-{[(tert-Butoxy)carbonyl]amino}-3,3-difluoro-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl

Chemical Structure

[0605] Step 1: (3R)-3-Hydroxy-1-oxo-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl The reaction was carried out in three batches.

[0606] A mixture of CuCl (0.59 g, 6.0 mmol), (S)-Tol-BINAP (4.05 g, 6.0 mmol), and t-BuONa (0.57 g, 6.0 mmol) in THF (450 mL) was stirred at room temperature for 30 minutes. B2pin2 (55.6 g, 0.22 mol) in THF (250 mL) was added, and the mixture was stirred at room temperature for 15 minutes. tert-Butyl 1-oxo-8-azaspiro[4.5]dec-2-ene-8-carboxylate (50.0 g, 0.2 mol) in THF (250 mL) and MeOH (12.7 g, 0.4 mol) was added, and the reaction mixture was stirred at room temperature overnight. Water (1 L) and NaBO3 (153.1 g, 0.99 mol) were added, and the reaction mixture was stirred at room temperature for 1 hour. Three batches were combined, filtered, extracted with EtOAc, washed with brine, dried over Na2SO4, and concentrated in vacu...

Claims

1. A compound of formula (I) or a tautomer, solvate or pharmaceutically acceptable salt thereof: 【Chemical 1】 [R １ is hydrogen or hydroxyl, and R ２ and R ３ are each, independently, hydrogen, halogen, C １－４ alkyl, halo C １－４ alkyl, hydroxy C １－４ alkyl, and -CN, X is O or CR ４ R ５ and R ４ and R ５ are, independently, hydrogen, halogen, hydroxyl, C １－４ alkyl, C １－４ alkoxy, and halo C １－４ alkyl selected from, R ６ and R ７ are joined to form a ring A optionally substituted by one or more R １０ groups. Ring A is (i) a 5-membered nitrogen-containing heterocyclic ring, said heterocyclic ring optionally containing one or two additional heteroatoms selected from N, O, and S, a 5-membered nitrogen-containing heterocyclic ring, or (ii) a 6-membered aromatic nitrogen-containing heterocyclic ring, said heterocyclic ring optionally containing one or two additional heteroatoms selected from N, O, and S, a 6-membered aromatic nitrogen-containing heterocyclic ring, or (iii) a 6-membered non-aromatic nitrogen-containing heterocyclic ring, said heterocyclic ring optionally containing one or two additional heteroatoms selected from N and S, a 6-membered non-aromatic nitrogen-containing heterocyclic ring, any of R ８ is selected from halo C １－４ alkyl, -CH ３ , and halogen, R ９ is selected from hydrogen, C １－４ alkyl, halo C １－４ alkyl, and halogen, R １０ is, independently, halogen, cyano, Cyano C １－４ alkyl, hydroxyl, =O (oxo), C １－４ alkyl, Halo C １－４ alkyl, C １－４ alkoxy, Hydroxyl C １－４ alkyl, C １－４ alkoxy C １－４ alkylene, C １－４ alkyl sulfone, amino, Mono C １－４ alkylamino, DiC １－４ alkylamino, Amino C １－４ alkylene, -C １－４ alkylene-C(=O)NH （２－ｑ） (C １－６ alkyl) ｑ ) -C ０－４ alkylene-NHC(=O)C １－６ alkyl, Sulfonamide C ０－４ alkylene, 3- to 6-membered cycloalkyl, An optionally substituted 5- or 6-membered unsaturated heterocyclic group containing one, two, three, or four heteroatoms selected from O, N, and S, wherein the optional substituent is C １－４ An optionally substituted 5- or 6-membered unsaturated heterocyclic group selected from alkyl C substituted with 3- to 6-membered cycloalkyl １－４ alkyl C substituted with an optionally substituted 5- or 6-membered unsaturated heterocyclic group containing one, two, three, or four heteroatoms selected from O, N, and S １－４ alkyl, wherein said optional substituent is C １－４ alkyl selected from C1-4 alkyl C substituted with an optionally substituted 4- to 6-membered saturated heterocyclic group containing one or two heteroatoms selected from O, N, and S １－４ alkyl, wherein the optional substituent is C １－４ alkyl selected from C1-4 alkyl, and An optionally substituted 4- to 6-membered saturated heterocyclic group containing one or two heteroatoms selected from O, N, and S, wherein the optional substituent is C １－４ An optionally substituted 4- to 6-membered saturated heterocyclic group selected from alkyl, and q is selected from 0, 1, and 2].

2. Ring A is optionally substituted by one, two, or three R １０ groups and / or Ring A is a 5-membered nitrogen-containing heterocyclic aromatic or non-aromatic ring, said heterocyclic ring optionally containing one or two additional heteroatoms selected from N, O, and S, a 5-membered nitrogen-containing heterocyclic aromatic or non-aromatic ring, and / or R ８ is -CF ３ , chlorine, or fluorine, and / or R ９ is -CH ３ , -CF ３ , or chlorine, and / or R １０ is selected from -CH ２ -CN, -CH ３ -, -CH(CH ３ ), ２ -, -CH ２ CH ３ -, -CHF ２ -, -OCH ３ -, -OCH ２ CH ３ -, -OCH(CH ３ ), ２ -, -CH ２ C(CH ３ ), ２ OH, -CH(CH ３ ), CH ２ OH, -CH(CH ３ ), OH, -CH ２ CH ２ OH, -CH ２ OH, -CH ２ -O-CH ３ -, -CH ２ -CH ２ -O-CH ３ -, -SO ２ CH ３ -, -N(CH ３ ), ２ -, -CH ２ NH ２ -, -SO ２ NR ｘ ２ and -CH ２ SO ２ NR ｘ ２ independently selected from, where R ｘ is independently selected from H and C １－６ alkyl, the compound of formula (I) according to claim 1 or a tautomer, solvate or pharmaceutically acceptable salt thereof.

3. The compound of formula (I) according to claim 1 or a tautomer, solvate or pharmaceutically acceptable salt thereof, wherein X is O.

4. X is CR ４ R ５ and R ４ and R ５ are each, independently, hydrogen, halogen, and C optionally substituted by one or more halogens １－４ alkyl, a compound of formula (I) according to claim 1, or a tautomer, solvate or pharmaceutically acceptable salt thereof.

5. X is CR ４ R ５ and R ４ and R ５ are each independently C alkyl optionally substituted by one or more halogens １ The compound of formula (I) according to claim 4, or a tautomer, solvate or pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:

6. X is CR ４ R ５ wherein R ４ is hydrogen and R ５ is selected from halogen and halomethyl, a compound of formula (I) according to claim 1 or 4, or a tautomer, solvate or pharmaceutically acceptable salt thereof.

7. X is CR ４ R ５ wherein R ４ is hydrogen, and R ５ is selected from fluorine, chlorine, bromine, iodine, monohalomethyl, dihalomethyl, and trihalomethyl, where halo is selected from fluorine, chlorine, bromine, and iodine, the compound of formula (I) according to claim 6 or a tautomer, solvate or pharmaceutically acceptable salt thereof.

8. X is CR ４ R ５ wherein R ４ is hydrogen and R ５ is fluorine, a compound of formula (I) according to claim 7, or a tautomer, solvate or pharmaceutically acceptable salt thereof.

9. R １ The compound of formula (I) according to any one of claims 1 to 8, or a tautomer, solvate or pharmaceutically acceptable salt thereof, wherein R is hydroxyl.

10. R １ The compound of formula (I) according to any one of claims 1 to 9, or a tautomer, solvate or pharmaceutically acceptable salt thereof, wherein R is hydrogen.

11. R ２ is hydrogen, and R ３ is C １－４ alkyl, halo C １－４ alkyl, hydroxy C １－４ alkyl, and -CN, a compound of formula (I) according to any one of claims 1 to 10 or a tautomer, solvate or pharmaceutically acceptable salt thereof.

12. R ２ is hydrogen, and R ３ is C １－４ alkyl, a compound of formula (I) according to any one of claims 1 to 11, or a tautomer, solvate or pharmaceutically acceptable salt thereof.

13. R ２ is hydrogen, and R ３ is -CH ３ The compound of formula (I) according to claim 12, or a tautomer, solvate or pharmaceutically acceptable salt thereof, wherein R is hydrogen and R is -CH

14. R ８ is selected from -CH ３ , chlorine, and fluorine, a compound of formula (I) according to any one of claims 1 to 13 or a tautomer, solvate or pharmaceutically acceptable salt thereof.

15. R ８ The compound of formula (I) according to any one of claims 1 to 14, or a tautomer, solvate or pharmaceutically acceptable salt thereof, wherein R is chlorine.

16. R ９ The compound of formula (I) according to any one of claims 1 to 15, or a tautomer, solvate or pharmaceutically acceptable salt thereof, wherein R is hydrogen.

17. The compound of formula (I) according to any one of claims 1 to 16 or a tautomer, solvate or pharmaceutically acceptable salt thereof, wherein Ring A is a 5-membered nitrogen-containing heterocyclic ring or a 6-membered aromatic nitrogen-containing heterocyclic ring, said heterocyclic ring optionally containing one or two additional heteroatoms selected from N, O, and S.

18. The compound according to claim 17 or a tautomer, solvate or pharmaceutically acceptable salt thereof, wherein Ring A is a 5-membered nitrogen-containing heterocyclic ring, said heterocyclic ring optionally containing one or two additional heteroatoms selected from N, O, and S.

19. Ring A is a 5-membered nitrogen-containing heteroaromatic or non-aromatic ring, said heteroaromatic ring optionally containing one or two additional heteroatoms selected from N, O, and S, a compound of formula (I) according to claim 17 or 18, or a tautomer, solvate or pharmaceutically acceptable salt thereof.

20. Ring A is a 5-membered aromatic nitrogen-containing heteroaromatic ring, said heteroaromatic ring optionally containing one or two additional heteroatoms selected from N and S, a compound according to claim 18 or 19, or a tautomer, pharmaceutically acceptable salt or solvate thereof.

21. Ring A is (i) a 6-membered aromatic nitrogen-containing heteroaromatic ring, said heteroaromatic ring optionally containing one or two additional heteroatoms selected from N, O, and S, a 6-membered aromatic nitrogen-containing heteroaromatic ring, or (ii) a 6-membered non-aromatic nitrogen-containing heteroaromatic ring, said heteroaromatic ring optionally containing one or two additional heteroatoms selected from N and S, a 6-membered non-aromatic nitrogen-containing heteroaromatic ring, a compound according to any one of claims 1 to 16, or a tautomer, pharmaceutically acceptable salt or solvate thereof.

22. In formula (I), the following: [Chemical Formula 2] substructure is selected from the groups described in Table I 【Table 1】 [Chemical] 【Chem.】 【Chem.】 or Table II 【Table 2】 [Chemical] a compound according to any one of claims 1 to 16, or a tautomer, solvate or pharmaceutically acceptable salt thereof.

23. In formula (I), the following: 【Chemical Formula 3】 substructure is selected from the following groups: 【Chemical Formula 4】 or is selected from the following groups: 【Chemical Formula 5】 a compound according to claim 22, or a tautomer, pharmaceutically acceptable salt or solvate thereof.

24. In formula (I), the following: 【Chemical Formula 6】 substructure is selected from the following groups: 【Chemical Formula 7】 or is selected from the following groups: 【Chemical 8】 a compound according to claim 23 or a tautomer, solvate or pharmaceutically acceptable salt thereof.

25. R １０ is, independently, halogen, cyano, cyanoC １－４ alkyl, hydroxyl, =O (oxo), C １－４ alkyl, haloC １－４ alkyl, C １－４ alkoxy, hydroxylC １－４ alkyl, diC １－４ alkylamino, and C １－４ alkoxyC １－４ alkylene, a compound according to any one of claims 1 to 24 or a tautomer, solvate or pharmaceutically acceptable salt thereof.

26. R １０ is independently, -CH ２ -CN, -CH ３ , -CH ２ CH ３ , -OCH ３ , -CH(CH ３ )CH ２ OH, -CH(CH ３ )OH, -CH ２ CH ２ OH, -CH ２ OH, -N(CH ３ ) ２ , and -CH ２ -O-CH ３ selected from, the compound according to claim 25 or a tautomer, solvate or pharmaceutically acceptable salt thereof.

27. R １０ is, independently, halogen, cyano, hydroxyl, =O (oxo), -CH ３ and -CH ２ CH ３ The compound according to claim 25, or a tautomer, solvate or pharmaceutically acceptable salt thereof, selected from

28. R １０ is, independently, halogen, cyano, hydroxyl, =O (oxo), C １－４ alkoxy, diC １－４ alkylamino, and C １－４ alkyl, and the compound according to any one of claims 1 to 25, or a tautomer, solvate or pharmaceutically acceptable salt thereof.

29. R １０ is independently selected from -OCH ３ , -N(CH ３ ), -CH ２ , and -CH ３ , and the compound according to claim 28 or a tautomer, solvate or pharmaceutically acceptable salt thereof, which is selected from -CH ２ CH ３ .

30. R １０ is, independently, hydroxyl, =O (oxo), and -CH ３ The compound according to claim 28, or a tautomer, solvate or pharmaceutically acceptable salt thereof, selected from.

31. R ６ and R ７ are joined to form ring A, having the same definition as in claim 1, and the compound of formula (I) is the following formula (XVIII): 【Chemical Formula 9】 a compound according to claim 1, or a tautomer, pharmaceutically acceptable salt or solvate thereof.

32. Said compound is (1R,3R)-8-[3-(4-chloro-2-methyl-2H-indazol-5-yl)-5-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl]-3-(trifluoromethyl)-8-azaspiro[4.5]decan-1-amine, (1R)-8-[3-(4-chloro-2-methyl-2H-indazol-5-yl)-5-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl]-3,3-difluoro-8-azaspiro[4.5]decan-1-amine, (4S)-8-[3-(4-chloro-2-methyl-2H-indazol-5-yl)-5-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl]-2-oxa-8-azaspiro[4.5]decan-4-amine, (4S)-8-[3-(3,4-dichloro-2-methyl-2H-indazol-5-yl)-5-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl]-2-oxa-8-azaspiro[4.5]decan-4-amine, (4S)-8-[3-(4-chloro-2-ethyl-2H-indazol-5-yl)-5-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl]-2-oxa-8-azaspiro[4.5]decan-4-amine, (3S,4S)-8-[3-(4-chloro-2-methyl-2H-indazol-5-yl)-5-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl]-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine, {6-[(1R)-1-amino-3,3-difluoro-8-azaspiro[4.5]decan-8-yl]-3-(4-chloro-2-methyl-2H-indazol-5-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl}methanol, {6-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-3-(3,4-dichloro-2-methyl-2H-indazol-5-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl}methanol, (3S,4S)-8-[3-(5-chloro-3-methoxyquinoxalin-6-yl)-5-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl]-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine, (3S,4S)-8-{3-[5-chloro-3-(dimethylamino)quinoxalin-6-yl]-5-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl}-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine, (4S)-8-{3-[5-chloro-3-(dimethylamino)quinoxalin-6-yl]-5-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl}-2-oxa-8-azaspiro[4.5]decan-4-amine, 7-{6-[(1R)-1-amino-8-azaspiro[4.5]decan-8-yl]-5-methyl-1H-pyrazolo[3,4-b]pyrazin-3-yl}-8-chloro-N,N-dimethylquinoxalin-2-amine, (4S)-8-[3-(5-chloro-3-methoxyquinoxalin-6-yl)-5-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl]-2-oxa-8-azaspiro[4.5]decan-4-amine, (1R)-8-[3-(5-chloro-3-methoxyquinoxalin-6-yl)-5-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl]-8-azaspiro[4.5]decan-1-amine, (1R)-8-[3-(3,4-dichloro-2-methyl-2H-indazol-5-yl)-5-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl]-8-azaspiro[4.5]decan-1-amine, {6-[(1R)-1-amino-3,3-difluoro-8-azaspiro[4.5]decan-8-yl]-3-(3,4-dichloro-2-methyl-2H-indazol-5-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl}methanol, {6-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-3-[5-chloro-3-(dimethylamino)quinoxalin-6-yl]-1H-pyrazolo[3,4-b]pyrazin-5-yl}methanol, {6-[(1R,3S)-1-amino-3-fluoro-8-azaspiro[4.5]decan-8-yl]-3-(3,4-dichloro-2-methyl-2H-indazol-5-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl}methanol, {6-[(3S,4S)-4-Amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-3-(4-chloro-2,3-dimethyl-2H-indazol-5-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl}methanol, {6-[(3S,4S)-4-Amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-3-(5-chloro-3-methoxyquinoxalin-6-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl}methanol, (3S,4S)-8-{3-[3-(Azetidin-1-yl)-5-chloroquinoxalin-6-yl]-5-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl}-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine, and (3S,4S)-8-{3-[5-Chloro-3-(morpholin-4-yl)quinoxalin-6-yl]-5-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl}-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine, selected from the group consisting of the compound according to claim 1, or a tautomer, pharmaceutically acceptable salt, or solvate thereof.

33. The compound according to claim 1, or a tautomer, solvate, or pharmaceutically acceptable salt thereof, wherein the compound is {6-[(1R)-1-amino-3,3-difluoro-8-azaspiro[4.5]decan-8-yl]-3-(4-chloro-2-methyl-2H-indazol-5-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl}methanol.

34. The compound according to claim 1, or a tautomer, solvate, or pharmaceutically acceptable salt thereof, wherein the compound is {6-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-3-(3,4-dichloro-2-methyl-2H-indazol-5-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl}methanol.

35. The compound or a tautomer, solvate or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is (3S,4S)-8-[3-(5-chloro-3-methoxyquinoxalin-6-yl)-5-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl]-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine.

36. The compound or a tautomer, solvate or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is (3S,4S)-8-{3-[5-chloro-3-(dimethylamino)quinoxalin-6-yl]-5-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl}-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine.

37. The compound or a tautomer, solvate or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is (1R)-8-[3-(3,4-dichloro-2-methyl-2H-indazol-5-yl)-5-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl]-8-azaspiro[4.5]decan-1-amine.

38. The compound or a tautomer, solvate or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is {6-[(1R)-1-amino-3,3-difluoro-8-azaspiro[4.5]decan-8-yl]-3-(3,4-dichloro-2-methyl-2H-indazol-5-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl}methanol.

39. The compound or a tautomer, solvate or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is {6-[(1R,3S)-1-amino-3-fluoro-8-azaspiro[4.5]decan-8-yl]-3-(3,4-dichloro-2-methyl-2H-indazol-5-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl}methanol.

40. A combination medicament comprising the compound of formula (I) as defined in any one of claims 1 to 39 or a tautomer, solvate or pharmaceutically acceptable salt thereof together with one or more other therapeutic agents.

41. A combination medicament comprising the compound of formula (I) as defined in claim 40 or a tautomer, solvate or pharmaceutically acceptable salt thereof together with one or two anti-cancer agents.

42. A pharmaceutical composition comprising a compound of formula (I) as defined in any one of claims 1 to 39 or a tautomer, solvate or pharmaceutically acceptable salt thereof, or a combination medicament as defined in claim 40.

43. A compound as defined in any one of claims 1 to 39 or a tautomer, solvate or pharmaceutically acceptable salt thereof for use in cancer therapy.

44. The combination medicament according to claim 40 for use in cancer therapy.

45. The pharmaceutical composition according to claim 42 for use in cancer therapy.

46. A compound as defined in any one of claims 1 to 39 or a tautomer, solvate or pharmaceutically acceptable salt thereof for use in the prevention or treatment of SHP2-mediated cancer.

47. The combination medicament according to claim 40 for use in the prevention or treatment of SHP2-mediated cancer.

48. The pharmaceutical composition according to claim 42 for use in the prevention or treatment of SHP2-mediated cancer.

49. A compound as defined in any one of claims 1 to 39 or a tautomer, solvate or pharmaceutically acceptable salt thereof for use in the prevention or treatment of cancer.

50. The combination medicament according to claim 40 for use in the prevention or treatment of cancer.

51. The pharmaceutical composition according to claim 42 for use in the prevention or treatment of cancer.

52. Use of a compound as defined in any one of claims 1 to 39 or a tautomer, solvate or pharmaceutically acceptable salt thereof for the manufacture of a medicament for use in the prevention or treatment of cancer.

53. Use of the combination medicament according to claim 40 for the manufacture of a medicament for use in the prevention or treatment of cancer.

54. Use of the pharmaceutical composition according to claim 42 for the manufacture of a medicament for use in the prevention or treatment of cancer.

55. A compound as defined in any one of claims 1 to 39 or a tautomer, solvate or pharmaceutically acceptable salt thereof for use in the prevention or treatment of cancer, wherein the compound is used in combination with one or more other therapeutic agents or therapies.

56. The combination medicament according to claim 40 for the manufacture of a medicament for use in the prevention or treatment of cancer, wherein the compound is used in combination with one or more other therapeutic agents or therapies.

57. The pharmaceutical composition according to claim 42 for manufacturing a pharmaceutical for use in the prevention or treatment of cancer, wherein the compound is used in combination with one or more other therapeutic agents or therapies.

58. A compound or a tautomer thereof as defined in any one of claims 1 to 39, or a pharmaceutically acceptable salt, for use in the prevention or treatment of cancer, wherein the compound is used in combination with one or more other anti-cancer agents.

59. The combination pharmaceutical according to claim 40 for manufacturing a pharmaceutical for use in the prevention or treatment of cancer, wherein the compound is used in combination with one or more other anti-cancer agents.

60. The pharmaceutical composition according to claim 42 for manufacturing a pharmaceutical for use in the prevention or treatment of cancer, wherein the compound is used in combination with one or more other anti-cancer agents.

61. A compound or a tautomer, solvate or pharmaceutically acceptable salt thereof as defined in any one of claims 1 to 39 for use in combination therapy with one or more other therapeutic agents or cancer therapies.

62. The compound or a tautomer, solvate or pharmaceutically acceptable salt thereof according to claim 61 for use in combination therapy with one or more other anti-cancer agents.

63. A compound or a tautomer, solvate or pharmaceutically acceptable salt thereof as defined in any one of claims 1 to 39 for use in the prevention or treatment of hepatocellular carcinoma, melanoma, esophageal cancer, kidney cancer, colon cancer, colorectal cancer, lung cancer, mesothelioma, or lung adenocarcinoma, breast cancer, bladder cancer, gastrointestinal cancer, ovarian cancer, or prostate cancer.

64. The combination pharmaceutical according to claim 40 for use in the prevention or treatment of hepatocellular carcinoma, melanoma, esophageal cancer, kidney cancer, colon cancer, colorectal cancer, lung cancer, mesothelioma, or lung adenocarcinoma, breast cancer, bladder cancer, gastrointestinal cancer, ovarian cancer, or prostate cancer.

65. The pharmaceutical composition according to claim 42 for use in the prevention or treatment of hepatocellular carcinoma, melanoma, esophageal cancer, kidney cancer, colon cancer, colorectal cancer, lung cancer, mesothelioma, or lung adenocarcinoma, breast cancer, bladder cancer, gastrointestinal cancer, ovarian cancer, or prostate cancer.

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